Artículos originales (todos) *** Original articles (all)

Cancer Pharmacogenomics.

December 2012 - January 2013


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TÍTULO / TITLE:  - Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Lancet. 2013 Jan 4. pii: S0140-6736(12)61424-X. doi: 10.1016/S0140-6736(12)61424-X.

            ●● Enlace al texto completo (gratuito o de pago) 1016/S0140-6736(12)61424-X

AUTORES / AUTHORS:  - Burmester GR; Blanco R; Charles-Schoeman C; Wollenhaupt J; Zerbini C; Benda B; Gruben D; Wallenstein G; Krishnaswami S; Zwillich SH; Koncz T; Soma K; Bradley J; Mebus C

INSTITUCIÓN / INSTITUTION:  - Charite-University Medicine Berlin, Berlin, Germany. Electronic address: gerd.burmester@charite.de.

RESUMEN / SUMMARY:  - BACKGROUND: Rheumatoid arthritis is a heterogeneous chronic disease, and no therapeutic agent has been identified which is universally and persistently effective in all patients. We investigated the effectiveness of tofacitinib (CP-690,550), a novel oral Janus kinase inhibitor, as a targeted immunomodulator  and disease-modifying therapy for rheumatoid arthritis. METHODS: We did a 6-month, double-blind, parallel-group phase 3 study at 82 centres in 13 countries, including North America, Europe, and Latin America. 399 patients aged  18 years or older with moderate-to-severe rheumatoid arthritis and inadequate response to tumour necrosis factor inhibitors (TNFi) were randomly assigned in a  2:2:1:1 ratio with an automated internet or telephone system to receive twice a day treatment with: tofacitinib 5 mg (n=133); tofacitinib 10 mg (n=134); or placebo (n=132), all with methotrexate. At month 3, patients given placebo advanced to either tofacitinib 5 mg twice a day (n=66) or 10 mg twice a day (n=66). Primary endpoints included American College of Rheumatology (ACR)20 response rate, mean change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI), and rates of disease activity score (DAS)28-4(ESR) less than 2.6 (referred to as DAS28<2.6), all at month 3. The full analysis set for the primary analysis included all randomised patients who received at least one dose of study medication and had at least one post-baseline assessment. This trial is registered with www.ClinicalTrials.gov, number NCT00960440. FINDINGS: At month 3, ACR20 response rates were 41.7% (55 of 132 [95% CI vs placebo 6.06-28.41]; p=0.0024) for tofacitinib 5 mg twice a day and 48.1% (64 of 133; [12.45-34.92]; p<0.0001) for tofacitinib 10 mg twice a day versus 24.4% (32 of 131) for placebo. Improvements from baseline in HAQ-DI were -0.43 ([-0.36 to -0.15]; p<0.0001) for 5 mg twice a day and -0.46 ([-0.38 to -0.17]; p<0.0001) for 10 mg twice a day tofacitinib versus -0.18 for placebo; DAS28<2.6 rates were 6.7% (eight of 119; [0-10.10]; p=0.0496) for 5 mg twice a day tofacitinib and 8.8% (11 of 125 [1.66-12.60]; p=0.0105) for 10 mg twice a day tofacitinib versus 1.7% (two of 120) for placebo. Safety was consistent with phase 2 and 3 studies. The most common adverse events in months 0-3 were diarrhoea (13 of 267; 4.9%), nasopharyngitis (11 of 267; 4.1%), headache (11 of 267; 4.1%), and urinary tract infection (eight of 267; 3.0%) across tofacitinib groups, and nausea (nine of 132; 6.8%) in the placebo group. INTERPRETATION: In this treatment-refractory population, tofacitinib with methotrexate had rapid and clinically meaningful improvements in signs and symptoms of rheumatoid arthritis  and physical function over 6 months with manageable safety. Tofacitinib could provide an effective treatment option in patients with an inadequate response to  TNFi. FUNDING: Pfizer.




TÍTULO / TITLE:  - Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Lancet. 2012 Dec 4. pii: S0140-6736(12)61963-1. doi: 10.1016/S0140-6736(12)61963-1.

            ●● Enlace al texto completo (gratuito o de pago) 1016/S0140-6736(12)61963-1

AUTORES / AUTHORS:  - Davies C; Pan H; Godwin J; Gray R; Arriagada R; Raina V; Abraham M; Alencar VH; Badran A; Bonfill X; Bradbury J; Clarke M; Collins R; Davis SR; Delmestri A; Forbes JF; Haddad P; Hou MF; Inbar M; Khaled H; Kielanowska J; Kwan WH; Mathew BS; Muller B; Nicolucci A; Peralta O; Pernas F; Petruzelka L; Pienkowski T; Rajan B; Rubach MT; Tort S; Urrutia G; Valentini M; Wang Y; Peto R

INSTITUCIÓN / INSTITUTION:  - Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, UK. Electronic address: atlas@ctsu.ox.ac.uk.

RESUMEN / SUMMARY:  - BACKGROUND: For women with oestrogen receptor (ER)-positive early breast cancer,  treatment with tamoxifen for 5 years substantially reduces the breast cancer mortality rate throughout the first 15 years after diagnosis. We aimed to assess  the further effects of continuing tamoxifen to 10 years instead of stopping at 5  years. METHODS: In the worldwide Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial, 12 894 women with early breast cancer who had completed 5 years of treatment with tamoxifen were randomly allocated to continue tamoxifen to 10 years or stop at 5 years (open control). Allocation (1:1) was by central computer, using minimisation. After entry (between 1996 and 2005), yearly follow-up forms recorded any recurrence, second cancer, hospital admission, or death. We report effects on breast cancer outcomes among the 6846 women with ER-positive disease, and side-effects among all women (with positive, negative, or unknown ER status). Long-term follow-up still continues. This study is registered, number ISRCTN19652633. FINDINGS: Among women with ER-positive disease, allocation to continue tamoxifen reduced the risk of breast cancer recurrence (617 recurrences in 3428 women allocated to continue vs 711 in 3418 controls, p=0.002), reduced breast cancer mortality (331 deaths vs 397 deaths, p=0.01), and reduced overall mortality (639 deaths vs 722 deaths, p=0.01). The reductions in adverse breast cancer outcomes appeared to be less extreme before than after year 10 (recurrence rate ratio [RR] 0.90 [95% CI 0.79-1.02] during years 5-9 and 0.75 [0.62-0.90] in later years; breast cancer mortality RR 0.97 [0.79-1.18] during years 5-9 and 0.71 [0.58-0.88] in later years). The cumulative risk of recurrence during years 5-14 was 21.4% for women allocated to continue versus 25.1% for controls; breast cancer mortality during years 5-14 was 12.2% for women allocated to continue versus 15.0% for controls (absolute mortality reduction 2.8%). Treatment allocation seemed to have no effect on breast cancer outcome among 1248 women with ER-negative disease, and an intermediate effect among 4800 women with unknown ER status. Among all 12 894 women, mortality without recurrence from causes other than breast cancer was little affected (691  deaths without recurrence in 6454 women allocated to continue versus 679 deaths in 6440 controls; RR 0.99 [0.89-1.10]; p=0.84). For the incidence (hospitalisation or death) rates of specific diseases, RRs were as follows: pulmonary embolus 1.87 (95% CI 1.13-3.07, p=0.01 [including 0.2% mortality in both treatment groups]), stroke 1.06 (0.83-1.36), ischaemic heart disease 0.76 (0.60-0.95, p=0.02), and endometrial cancer 1.74 (1.30-2.34, p=0.0002). The cumulative risk of endometrial cancer during years 5-14 was 3.1% (mortality 0.4%) for women allocated to continue versus 1.6% (mortality 0.2%) for controls (absolute mortality increase 0.2%). INTERPRETATION: For women with ER-positive disease, continuing tamoxifen to 10 years rather than stopping at 5 years produces a further reduction in recurrence and mortality, particularly after year 10. These results, taken together with results from previous trials of 5 years of tamoxifen treatment versus none, suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis. FUNDING: Cancer Research UK, UK Medical Research Council, AstraZeneca  UK, US Army, EU-Biomed.




TÍTULO / TITLE:  - Prognostic and Predictive Value of Tumor-Infiltrating Lymphocytes in a Phase III  Randomized Adjuvant Breast Cancer Trial in Node-Positive Breast Cancer Comparing  the Addition of Docetaxel to Doxorubicin With Doxorubicin-Based Chemotherapy: BIG 02-98.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Clin Oncol. 2013 Jan 22.

            ●● Enlace al texto completo (gratuito o de pago) 1200/JCO.2011.41.0902

AUTORES / AUTHORS:  - Loi S; Sirtaine N; Piette F; Salgado R; Viale G; Van Eenoo F; Rouas G; Francis P; Crown JP; Hitre E; de Azambuja E; Quinaux E; Di Leo A; Michiels S; Piccart MJ; Sotiriou C

INSTITUCIÓN / INSTITUTION:  - Sherene Loi, Nicolas Sirtaine, Roberto Salgado, Francoise Van Eenoo, Ghizlane Rouas, Stefan Michiels, Martine J. Piccart, and Christos Sotiriou, Institut Jules Bordet, Brussels; Fanny Piette and Emmanuel Quinaux, International Drug Development Institute, Louvain-la-Neuve, Belgium; Giuseppe Viale, University of Milan, Milan; Angelo Di Leo, Hospital of Prato, Prato, Italy; Prudence Francis, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australian and New Zealand Breast Cancer Trials Group, Newcastle, New South Wales, Australia, and International Breast Cancer Study Group, Bern, Switzerland; John P.A. Crown, Irish Clinical Oncology Research Group, Dublin, Ireland; and Erika Hitre, National Institute of Oncology, Budapest, Hungary.

RESUMEN / SUMMARY:  - PURPOSEPrevious preclinical and clinical data suggest that the immune system influences prognosis and response to chemotherapy (CT); however, clinical relevance has yet to be established in breast cancer (BC). We hypothesized that increased lymphocytic infiltration would be associated with good prognosis and benefit from immunogenic CT-in this case, anthracycline-only CT-in selected BC subtypes. PATIENTS AND METHODSWe investigated the relationship between quantity and location of lymphocytic infiltrate at diagnosis with clinical outcome in 2009 node-positive BC samples from the BIG 02-98 adjuvant phase III trial comparing anthracycline-only CT (doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil [CMF] or doxorubicin plus cyclophosphamide followed by CMF) versus CT combining doxorubicin and docetaxel (doxorubicin plus docetaxel followed by CMF or doxorubicin followed by docetaxel followed by CMF). Readings were independently performed by two pathologists. Disease-free survival (DFS), overall survival (OS), and interaction with type of CT associations were studied. Median follow-up was 8 years.ResultsThere was no significant prognostic association in the global nor estrogen receptor (ER) -positive/human epidermal growth factor receptor 2 (HER2) -negative population. However, each 10% increase  in intratumoral and stromal lymphocytic infiltrations was associated with 17% and 15% reduced risk of relapse (adjusted P = .1 and P = .025), respectively, and 27% and 17% reduced risk of death in ER-negative/HER2-negative BC regardless of CT type (adjusted P = .035 and P = .023), respectively. In HER2-positive BC, there was a significant interaction between increasing stromal lymphocytic infiltration (10% increments) and benefit with anthracycline-only CT (DFS, interaction P = .042; OS, P = .018). CONCLUSIONIn node-positive, ER-negative/HER2-negative BC, increasing lymphocytic infiltration was associated with excellent prognosis. Further validation of the clinical utility of tumor-infiltrating lymphocytes in this context is warranted. Our data also support the evaluation of immunotherapeutic approaches in selected BC subtypes.




TÍTULO / TITLE:  - Re: Intracutaneous and Intravesical Immunotherapy with Keyhole Limpet Hemocyanin  Compared with Intravesical Mitomycin in Patients with Non-Muscle-Invasive Bladder Cancer: Results from a Prospective Randomized Phase III Trial.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Urol. 2013 Feb;189(2):483-4. doi: 10.1016/j.juro.2012.10.103. Epub 2012 Oct 29.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.juro.2012.10.103





TÍTULO / TITLE:  - Health-related quality of life outcomes of lenalidomide in transfusion-dependent  patients with Low- or Intermediate-1-risk myelodysplastic syndromes with a chromosome 5q deletion: Results from a randomized clinical trial.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Leuk Res. 2013 Mar;37(3):259-65. doi: 10.1016/j.leukres.2012.11.017. Epub 2012 Dec 27.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.leukres.2012.11.017

AUTORES / AUTHORS:  - Revicki DA; Brandenburg NA; Muus P; Yu R; Knight R; Fenaux P

INSTITUCIÓN / INSTITUTION:  - United BioSource Corporation, Bethesda, MD, USA. Electronic address: Dennis.Revicki@unitedbiosource.com.

RESUMEN / SUMMARY:  - We report health-related quality of life (HRQL) outcomes assessed using the Functional Assessment of Cancer Therapy-Anemia (FACT-An) among 167 RBC transfusion-dependent patients with IPSS Low-/Intermediate-1-risk del5q31 MDS treated with lenalidomide versus placebo in a randomized phase 3 clinical trial,  MDS-004. Mean baseline to 12 week changes in FACT-An Total scores improved following treatment with lenalidomide 5 and 10mg (+5.7 and +5.7, respectively) versus placebo (-2.8) (both p<0.05). Clinically important changes in HRQL from baseline were observed at weeks 12, 24, 36, and 48 among RBC-TI>/=26 week responders in both treatment groups. Lenalidomide treatment may be effective in improving HRQL outcomes.




TÍTULO / TITLE:  - The BCR-ABL1 T315I mutation and additional genomic abberations are dominant genetic lesions associated with disease progression in chronic myelogenous leukemia patients resistant to tyrosine kinase inhibitor therapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Leuk Lymphoma. 2013 Jan 4.

            ●● Enlace al texto completo (gratuito o de pago) 3109/10428194.2012.762649

AUTORES / AUTHORS:  - Malcikova J; Razga F; Jurcek T; Dvorakova D; Zackova D; Toskova M; Sebejova L; Smardova J; Oltova A; Vankova G; Jurackova L; Trbusek M; Pospisilova S; Mayer J; Racil Z




TÍTULO / TITLE:  - Prognostic and predictive value of tumor VEGF gene amplification in metastatic breast cancer treated with paclitaxel with and without bevacizumab; results from  ECOG 2100 trial.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Jan 22.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-3029

AUTORES / AUTHORS:  - Schneider BP; Gray R; Radovich M; Shen F; Vance GH; Li L; Jiang G; Miller KD; Gralow J; Dickler MN; Cobleigh M; Perez EA; Shenkier TN; Nielsen KV; Muller S; Thor AD; Sledge GW; Sparano JA; Davidson NE; Badve S

INSTITUCIÓN / INSTITUTION:  - Medicine, Indiana University Melvin and Bren Simon Cancer Center.

RESUMEN / SUMMARY:  - Purpose Clinically validated biomarkers for anti-angiogenesis agents are not available. We have previously reported associations between candidate VEGFA SNPs  and overall survival (OS) in E2100. The associations between tumor VEGFA amplification and outcome are evaluated here. Patients and Methods E2100 was a phase III trial comparing paclitaxel with or without bevacizumab for patients with metastatic breast cancer. Fluorescence in situ hybridization to assess gene  amplification status for VEGFA was performed on paraffin embedded tumors from 363 patients in E2100. Evaluation for association between amplification status and outcomes was performed. Results ER+ or PR+ tumors were less likely to have VEGFA  amplification compared with ER/PR- tumors (p=0.020). VEGFA amplification was associated with worse OS (20.2 vs. 25.3 months; p=0.013) in univariate analysis with a trend for worse OS in multivariate analysis (p=0.08). There was a significant interaction between VEGFA amplification, hormone-receptor status, and study arm. Patients with VEGFA amplification and triple negative breast cancers (TNBCs) or HER2 amplification had inferior OS (p=0.047); amplification did not affect OS for those who were ER+ or PR+ and HER2-. Those who received bevacizumab with VEGFA amplification had inferior PFS (p=0.010) and OS (p=0.042); no association was seen in the control arm. Test for interaction between study arm and VEGFA amplification with OS was not significant. Conclusion VEGFA amplification in univariate analysis was associated with poor outcomes; this was  particularly prominent in HER2+ or TNBCs. Additional studies are necessary to confirm the trend for poor OS seen on multivariate analysis for patients treated  with bevacizumab.




TÍTULO / TITLE:  - Minimal residual disease detectable by quantitative assessment of WT1 gene before allogeneic stem cell transplantation in patients in first remission of acute myeloid leukemia has an impact on their future prognosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Transplant. 2013 Jan;27(1):E21-9. doi: 10.1111/ctr.12046. Epub 2012 Dec 12.

            ●● Enlace al texto completo (gratuito o de pago) 1111/ctr.12046

AUTORES / AUTHORS:  - Valkova V; Polak J; Markova M; Vitek A; Hajkova H; Salek C; Prochazka B; Cetkovsky P; Trneny M

INSTITUCIÓN / INSTITUTION:  - Department of Bone Marrow Transplantation, Institute of Haematology and Blood Transfusion, Prague, Czech Rep; Institute of Experimental Haematology, First Faculty of Medicine, Charles University, Prague, Czech Rep.

RESUMEN / SUMMARY:  - Overall 42 patients (pts) transplanted in hematological CR1 were retrospectively  analyzed. Median follow-up was 15 months (range 2-77). The expression of WT1 gene was measured according to the European Leukaemia Net recommendations. At the time of allogeneic stem cell transplantation (allo-SCT) 29 pts were WT1-negative and 13 pts were WT1-positive. In the univariate analysis, significantly better results were observed in the group of WT1 neg in terms of progression-free survival (in three yr 77% vs. 27%, p = 0.001). In multivariate analysis, the only significant feature in terms of better OS was WT1 negativity (p = 0.029). Our results show that minimal residual disease status measured by quantitative assessment of WT1 gene in acute myeloid leukemia pts in CR1 significantly affects their future prognosis after allo-SCT.




TÍTULO / TITLE:  - Somatic Mutations and Deletions of the E-Cadherin Gene Predict Poor Survival of Patients With Gastric Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Clin Oncol. 2013 Jan 22.

            ●● Enlace al texto completo (gratuito o de pago) 1200/JCO.2012.44.4612

AUTORES / AUTHORS:  - Corso G; Carvalho J; Marrelli D; Vindigni C; Carvalho B; Seruca R; Roviello F; Oliveira C

INSTITUCIÓN / INSTITUTION:  - Giovanni Corso, Daniele Marrelli, and Franco Roviello, University of Siena and Instituto Toscano Tumori; Carla Vindigni, Azienda Ospedaliera Universitaria Senese, Siena, Italy; Giovanni Corso, Joana Carvalho, Raquel Seruca, and Carla Oliveira, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP); Giovanni Corso, Joana Carvalho, Raquel Seruca, and Carla Oliveira, University of Porto, Portugal; Beatriz Carvalho, VU University Medical  Center, Amsterdam, the Netherlands.

RESUMEN / SUMMARY:  - PURPOSEThe prognosis of gastric cancer (GC) is poor, and the molecular pathogenesis players are vastly unknown. Surgery remains the primary option in GC treatment. The aim of this study was to investigate the impact of somatic CDH1 alterations in prognosis and survival of patients with GC. PATIENTS AND METHODSA  series of patients with sporadic and familial GC (diffuse and intestinal; n = 246) were analyzed for somatic CDH1 mutations, promoter hypermethylation, and loss of heterozygosity (LOH) by polymerase chain reaction sequencing. E-cadherin  protein expression was determined by immunohistochemistry. Associations between molecular, clinicopathologic, and survival data were analyzed.ResultsCDH1 somatic alterations were found in approximately 30% of all patients with GC. Both histologic types of sporadic GC displayed LOH in 7.5%, mutations in 1.7%, and hypermethylation in 18.4% of patients. Primary tumors from hereditary diffuse GC, lacking germline CDH1 alterations, showed exclusively CDH1 promoter hypermethylation in 50% of patients. Familial intestinal GC (FIGC) tumors showed  LOH in 9.4% and hypermethylation in 17.0%. CDH1 alterations did not associate with a particular pattern of E-cadherin expression. Importantly, the worst patient survival rate among all GCs analyzed was seen in patients with tumors carrying CDH1 structural alterations, preferentially those belonging to FIGC families. CONCLUSIONCDH1 somatic alterations exist in all clinical settings and histotypes of GC and associate with different survival rates. Their screening at  GC diagnosis may predict patient prognosis and is likely to improve management of patients with this disease.




TÍTULO / TITLE:  - Angioedema in a Patient With Renal Cell Cancer Treated With Everolimus in Combination With an Angiotensin-Converting Enzyme Inhibitor.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Clin Oncol. 2013 Jan 7.

            ●● Enlace al texto completo (gratuito o de pago) 1200/JCO.2012.44.5106

AUTORES / AUTHORS:  - Rothermundt C; Gillessen S

INSTITUCIÓN / INSTITUTION:  - Kantonsspital St Gallen, St Gallen, Switzerland.




TÍTULO / TITLE:  - Factors predicting the response to oral fluoropyrimidine drugs: a phase II trial  on the individualization of postoperative adjuvant chemotherapy using oral fluorinated pyrimidines in stage III colorectal cancer treated by curative resection (ACT-01 Study).

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Rep. 2013 Feb;29(2):437-44. doi: 10.3892/or.2012.2177. Epub 2012 Dec 10.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2012.2177

AUTORES / AUTHORS:  - Mori T; Ohue M; Takii Y; Hashizume T; Kato T; Kotake K; Sato T; Tango T

INSTITUCIÓN / INSTITUTION:  - Tokyo Metropolitan Cancer and Infectious Disease Center, Komagome Hospital, Tokyo, Japan. m.takeo@cick.jp

RESUMEN / SUMMARY:  - We evaluated the predictive relevance of several biomarkers on the survival of patients with stage III colorectal cancer treated with adjuvant chemotherapy of oral fluoropyrimidines. This was a multicenter phase II trial on adult patients with histologically confirmed resected stage III (Dukes’ C) colorectal cancer. Patients received oral doxifluridine (800 mg/m2/day) in 3 divided doses, or oral  uracil/tegafur (UFT) (400 mg/m2/day) in 2 divided doses for 5 days, every 7 days  for 12 months with a 5-year follow-up. Outcome measures were disease-free survival and tissue markers [thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD) protein levels and TP, DPD, thymidylate synthase (TS) and orotate phosphoribosyltransferase (OPRT) mRNA levels in tumor samples and TS tandem-repeat type in blood samples]. There was a significant association between the intratumoral TP/DPD enzyme ratio and disease-free survival when the model included the drug, the parameter and the interactions between them [hazard ratio  (HR)=2.76; P=0.00469]. The 5-year disease-free survival rate was statistically significantly higher in patients with high TP/DPD ratios [median >/=2.63: 71.9%;  95% confidence interval (CI) 61.4-80.0] compared to patients with low TP/DPD ratios (<2.63: 57.0%; 95% CI 46.3-66.3) (log-rank P=0.0277) following adjuvant therapy with oral fluoropyrimidines. No significant association was observed between the intratumoral TP/DPD enzyme ratio (cut-off value 2.0) and the disease-free survival rate in the doxifluridine group; primary endpoint (log-rank P=0.6850). The magnitude of the intratumoral TP/DPD enzyme ratio may be a potential indicator for the individualization of postoperative adjuvant chemotherapy with oral fluoropyrimidines for stage III colorectal cancer.




TÍTULO / TITLE:  - Outcome of azacitidine treatment in patients with therapy-related myeloid neoplasms with assessment of prognostic risk stratification models.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Leuk Res. 2013 Jan 16. pii: S0145-2126(12)00483-3. doi: 10.1016/j.leukres.2012.12.012.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.leukres.2012.12.012

AUTORES / AUTHORS:  - Duong VH; Lancet JE; Alrawi E; Al-Ali NH; Perkins J; Field T; Epling-Burnette PK; Zhang L; List AF; Komrokji RS

INSTITUCIÓN / INSTITUTION:  - H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

RESUMEN / SUMMARY:  - Azacitidine’s efficacy in therapy-related myeloid neoplasms (t-MN) has not been well-studied. In our retrospective review of 84 t-MN patients treated with azacitidine, median overall survival (OS) was 14.5 months and overall response rate was 43%, including 11% complete remission, 4% marrow complete remission, and 11% partial remission. In patients who underwent allogeneic transplant (25%), median OS was 19.2 versus 12.8 months (P=0.023) for those who did not. Response rates were comparable to those reported for de novo myelodysplastic syndrome. When we analyzed outcomes according to five scoring systems, only the Global MD Anderson Risk Model predicted survival with statistical significance.




TÍTULO / TITLE:  - STAT3 suppresses transcription of proapoptotic genes in cancer cells with the involvement of its N-terminal domain.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Proc Natl Acad Sci U S A. 2013 Jan 22;110(4):1267-72. doi: 10.1073/pnas.1211805110. Epub 2013 Jan 3.

            ●● Enlace al texto completo (gratuito o de pago) 1073/pnas.1211805110

AUTORES / AUTHORS:  - Timofeeva OA; Tarasova NI; Zhang X; Chasovskikh S; Cheema AK; Wang H; Brown ML; Dritschilo A

INSTITUCIÓN / INSTITUTION:  - Departments of Oncology and Radiation Medicine, and Drug Discovery Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057.

RESUMEN / SUMMARY:  - Activation of STAT3 in cancers leads to gene expression promoting cell proliferation and resistance to apoptosis, as well as tumor angiogenesis, invasion, and migration. In the characterization of effects of ST3-H2A2, a selective inhibitor of the STAT3 N-terminal domain (ND), we observed that the compound induced apoptotic death in cancer cells associated with robust activation of proapoptotic genes. Using ChIP and tiling human promoter arrays, we found that activation of gene expression in response to ST3-H2A2 is accompanied by altered STAT3 chromatin binding. Using inhibitors of STAT3 phosphorylation and a dominant-negative STAT3 mutant, we found that the unphosphorylated form of STAT3 binds to regulatory regions of proapoptotic genes and prevents their expression in tumor cells but not normal cells. siRNA knockdown confirmed the effects of ST3-HA2A on gene expression and chromatin binding to be STAT3 dependent. The STAT3-binding region of the C/EBP-homologous protein (CHOP) promoter was found to be localized in DNaseI hypersensitive site of chromatin in  cancer cells but not in nontransformed cells, suggesting that STAT3 binding and suppressive action can be chromatin structure dependent. These data demonstrate a suppressive role for the STAT3 ND in the regulation of proapoptotic gene expression in cancer cells, providing further support for targeting STAT3 ND for  cancer therapy.




TÍTULO / TITLE:  - BCR-ABL1 transcript at 3 months predicts long-term outcomes following second generation tyrosine kinase inhibitor therapy in the patients with chronic myeloid leukaemia in chronic phase who failed Imatinib.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Br J Haematol. 2012 Dec 24. doi: 10.1111/bjh.12187.

            ●● Enlace al texto completo (gratuito o de pago) 1111/bjh.12187

AUTORES / AUTHORS:  - Kim DD; Lee H; Kamel-Reid S; Lipton JH

INSTITUCIÓN / INSTITUTION:  - Department of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.

RESUMEN / SUMMARY:  - The BCR-ABL1 transcript level at 3 months can predict long-term outcomes following frontline therapy with Imatinib or Dasatinib in chronic myeloid leukaemia (CML) patients. However, data is lacking for second-generation tyrosine kinase inhibitor (2GTKI) therapy after Imatinib failure. A total of 112 patients  with CML in chronic phase receiving 2GTKI after Imatinib failure were reviewed. Treatment outcomes including complete cytogenetic (CCyR), major molecular (MMR) and molecular response 4.5 (4.5 log reduction of BCR-ABL1 transcript level, MR(4.5) ), treatment failure, progression-free and overall survival (OS) were compared according to BCR-ABL1 transcript levels at 3 or 6 months, divided into <1%(IS) , 1-10%(IS) and >/=10%(IS) . BCR-ABL1 transcript level at 3 months showed better correlation with OS (P < 0.001) than that at 6 months (P = 0.147). Better  OS was also observed in the patients achieving <1%(IS) (100%) and 1-10%(IS) (100%) than those with >/=10%(IS) at 3 months (70.6%, P < 0.001). Those with <1%(IS) showed the best CCyR, MMR and MR(4.5) rates; 1-10%(IS) , intermediate; and >/=10%(IS) , the lowest CCyR, MMR and MR(4.5) rates. The group with <1%(IS) at 3 months maintained significantly lower BCR-ABL1 transcript level compared to  other two groups. In conclusion, the BCR-ABL1 transcript level at 3 months is the most relevant surrogate for outcomes following 2GTKI therapy after Imatinib failure.




TÍTULO / TITLE:  - Predicting infections in high-risk patients with myelodysplastic syndrome/acute myeloid leukemia treated with azacitidine: Aretrospective multicenter study.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Am J Hematol. 2013 Feb;88(2):130-4. doi: 10.1002/ajh.23368.

            ●● Enlace al texto completo (gratuito o de pago) 1002/ajh.23368

AUTORES / AUTHORS:  - Merkel D; Filanovsky K; Gafter-Gvili A; Vidal L; Aviv A; Gatt ME; Silbershatz I; Herishanu Y; Arad A; Tadmor T; Dally N; Nemets A; Rouvio O; Ronson A; Herzog-Tzarfati K; Akria L; Braester A; Hellmann I; Yeganeh S; Nagler A; Leiba R; Mittelman M; Ofran Y

INSTITUCIÓN / INSTITUTION:  - Division of Hematology, Sheba Medical Center, Tel-Hashomer, Tel Aviv University,  Israel.

RESUMEN / SUMMARY:  - Hypomethylating agents have become the standard therapy for patients with high-risk myelodysplastic syndrome (MDS). In Israel, azacitidine (AZA) is routinely used. Yet, infectious complications are common during AZA therapy. The  current study was aimed to evaluate the incidence and predisposing risk factors for infections in AZA-treated patients. This retrospective study included patients treated with AZA in 18 Israeli medical institutions between 2008 and 2011. Data on 184 patients [157 high-risk MDS and 27 acute myeloid leukemia (AML)], with a median age of 71.6 (range 29-92) were recorded. Overall, 153 infectious events were reported during 928 treatment cycles (16.5%) administered  to 100 patients. One hundred fourteen, 114/153 (75%) events required hospitalization and 30 (19.6%) were fatal. In a univariate analysis, unfavorable  cytogenetics, low neutrophil, hemoglobin (Hb) and platelet (PLT) counts were found to be associated with infections (24.4% vs. 12.9%, P < 0.0001; 27% vs. 13.5%, P < 0.0001; 20.4% vs. 11%, P < 0.0001 and 29.2% vs. 14.2%, P < 0.0001, respectively). In multivariate analysis, only low Hb level, low PLT count, and unfavorable cytogenetics remained significant. Prior to therapy, poor cytogenetics, PLT count below 20 x 10(9) /L and neutrophil count below 0.5 x 10(9) /L were predictive of the risk of infection during the first two cycles of  therapy. In conclusion, patients with unfavorable cytogenetics, presenting with low neutrophil and PLT counts, are susceptible to infections. Evaluation of infection risk should be repeated prior to each cycle. Patients with poor cytogenetics in whom AZA is prescribed despite low PLT count are particularly at  high risk for infections and infection prophylaxis may be considered. Am. J. Hematol. 88:130-134, 2013. © 2012 Wiley Periodicals, Inc.




TÍTULO / TITLE:  - High expression of crystallin alphaB represents an independent molecular marker for unfavourable ovarian cancer patient outcome and impairs TRAIL- and cisplatin-induced apoptosis in human ovarian cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Cancer. 2012 Dec 6. doi: 10.1002/ijc.27975.

            ●● Enlace al texto completo (gratuito o de pago) 1002/ijc.27975

AUTORES / AUTHORS:  - Volkmann J; Reuning U; Rudelius M; Hafner N; Schuster T; V Rose AB; Weimer J; Hilpert F; Kiechle M; Durst M; Arnold N; Schmalfeldt B; Meindl A; Ramser J

INSTITUCIÓN / INSTITUTION:  - Clinic of Gynecology and Obstetrics, Klinikum rechts der Isar, Technische Universitaet Muenchen, Munich, Germany.

RESUMEN / SUMMARY:  - Dysregulated apoptotic pathways are regarded as major reasons for chemoresistance development as a particular challenge in ovarian cancer therapy. In search of molecular factors affecting human ovarian cancer cell apoptosis and, consequently, patient survival, we examined tumors of 103 platinum-/taxane-treated ovarian cancer patients by mRNA-array hybridization, qPCR, and immunohistochemistry. We identified high expression of crystallin alphaB (CRYAB), a proposed negative regulator of tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis. By Kaplan Meier analysis, this factor turned out to be significantly associated with poor patient outcome [overall survival (OS) p = 0.001, recurrence-free survival (RFS) p = 0.003]. Elevated hazard ratios (HR) were estimated with regard to OS (HR = 2.11, 95% CI 1.10-4.06) and RFS (HR = 1.92, 95% CI 1.07-3.47) in multivariable analyses. These associations were confirmed in independent, publicly available mRNA data comprising 431 patients for OS (p < 0.001) and 413 for RFS (p < 0.001)(.) Our findings were validated by studying apoptotic events in cultured human ovarian cancer cells which were stably transfected to express elevated CRYAB levels. These data emphasized the crucial role of CRYAB in human ovarian cancer biology since TRAIL- as well as cisplatin-induced apoptosis was significantly impaired as a function of enhanced CRYAB expression. Taken together, we identified CRYAB as an independent biomarker for unfavourable outcome of human ovarian cancer patients. Since TRAIL is currently tested as anti-cancer drug and large proportions of the present patient cohort displayed low CRYAB levels in their tumors, CRYAB may enable the selection of patient subgroups benefiting most from  TRAIL-containing therapy.




TÍTULO / TITLE:  - Phase I clinical trial of a peptide vaccine combined with tegafur-uracil plus leucovorin for treatment of advanced or recurrent colorectal cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Rep. 2013 Mar;29(3):951-9. doi: 10.3892/or.2013.2231. Epub 2013 Jan 10.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2013.2231

AUTORES / AUTHORS:  - Matsushita N; Aruga A; Inoue Y; Kotera Y; Takeda K; Yamamoto M

INSTITUCIÓN / INSTITUTION:  - Department of Surgery, Institute of Gastroenterology, Tokyo Women’s Medical University, Tokyo, Japan.

RESUMEN / SUMMARY:  - Recently, analysis of tumor antigens using micro-arrays has revealed upregulation of cancer-testis antigens RNF43 and TOMM34 and vascular endothelial growth factor receptors VEGFR1 and VEGFR2 in colorectal cancer. A phase I clinical trial of peptide vaccine therapy together with oral anticancer drugs was conducted to treat advanced colorectal cancer using synthesized peptides of these tumor antigens in order to confirm the safety, immunogenicity and activity of this treatment. The subjects were patients with a human leukocyte antigen (HLA) type of A2402 who had inoperable colorectal cancer but had failed to respond to or were unable to undergo standard chemotherapy. Four peptides (RNF43, TOMM34, VEGFR1 and VEGFR2) were emulsified with incomplete Freund’s adjuvant (Montanide), and the resulting solution was administered subcutaneously once a week. Patients  received the oral anticancer drug tegafur-uracil plus leucovorin for four weeks continuously as part of one course followed by one week of rest. The primary endpoint of the trial was observation of adverse events as determined by the NCI-CTCAE criteria, and the secondary endpoints were the size of the tumor and the number of cytotoxic T lymphocytes (CTLs) in the peripheral blood after treatment. Vaccine therapy was administered 148 times to 10 patients from July 2008 to December 2009. The adverse events were grade 1 redness and induration, a  grade 2 skin ulcer at the vaccination site and grade 1 pyrexia. All patients tolerated treatment. Tumor imaging revealed that after 1 course of treatment 1 patient had partial response (PR), 7 had stable disease (SD) and 2 had progressive disease. A CTL assay of 10 patients revealed an increase in peptide-specific CTLs in patients with PR and SD, and the clinical responses of those patients were observed. KaplanMeier analysis indicated that patients who had a strong CTL reaction had a tendency to have longer progressionfree survival  and overall survival.




TÍTULO / TITLE:  - Phase II and Biomarker Study of the Dual MET/VEGFR2 Inhibitor Foretinib in Patients With Papillary Renal Cell Carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Clin Oncol. 2013 Jan 10;31(2):181-6. doi: 10.1200/JCO.2012.43.3383. Epub 2012 Dec 3.

            ●● Enlace al texto completo (gratuito o de pago) 1200/JCO.2012.43.3383

AUTORES / AUTHORS:  - Choueiri TK; Vaishampayan U; Rosenberg JE; Logan TF; Harzstark AL; Bukowski RM; Rini BI; Srinivas S; Stein MN; Adams LM; Ottesen LH; Laubscher KH; Sherman L; McDermott DF; Haas NB; Flaherty KT; Ross R; Eisenberg P; Meltzer PS; Merino MJ; Bottaro DP; Linehan WM; Srinivasan R

INSTITUCIÓN / INSTITUTION:  - Urologic Oncology Branch, National Cancer Institute, 9000 Rockville Pike, Bldg 10, Room 1-5940, Bethesda, MD 20892; ramasrin@mail.nih.gov.

RESUMEN / SUMMARY:  - PURPOSE Foretinib is an oral multikinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors. Activating mutations or amplifications in MET have been described in patients with papillary renal cell carcinoma (PRCC). We aimed to evaluate the efficacy and safety of foretinib in patients with PRCC. PATIENTS AND METHODS Patients were enrolled onto the study in two cohorts with different dosing schedules of foretinib: cohort A, 240 mg once per day on days 1 through 5  every 14 days (intermittent arm); cohort B, 80 mg daily (daily dosing arm). Patients were stratified on the basis of MET pathway activation (germline or somatic MET mutation, MET [7q31] amplification, or gain of chromosome 7). The primary end point was overall response rate (ORR). Results Overall, 74 patients were enrolled, with 37 in each dosing cohort. ORR by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 was 13.5%, median progression-free survival was 9.3  months, and median overall survival was not reached. The presence of a germline MET mutation was highly predictive of a response (five of 10 v five of 57 patients with and without germline MET mutations, respectively). The most frequent adverse events of any grade associated with foretinib were fatigue, hypertension, gastrointestinal toxicities, and nonfatal pulmonary emboli. CONCLUSION Foretinib demonstrated activity in patients with advanced PRCC with a  manageable toxicity profile and a high response rate in patients with germline MET mutations.




TÍTULO / TITLE:  - Clinical outcomes in elderly patients administered gefitinib as first-line treatment in epidermal growth factor receptor-mutated non-small-cell lung cancer: retrospective analysis in a Nagano Lung Cancer Research Group Study.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Med Oncol. 2013 Mar;30(1):450. doi: 10.1007/s12032-012-0450-2. Epub 2013 Jan 13.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12032-012-0450-2

AUTORES / AUTHORS:  - Tateishi K; Ichiyama T; Hirai K; Agatsuma T; Koyama S; Hachiya T; Morozumi N; Shiina T; Koizumi T

INSTITUCIÓN / INSTITUTION:  - First Department of Internal Medicine, Shinshu University, Matsumoto City, Japan.

RESUMEN / SUMMARY:  - The clinical efficacy and outcomes of gefitinib therapy as a first-line treatment for elderly patients with non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations were analyzed retrospectively. We analyzed chemotherapy-naive NSCLC patients aged 75 years or older who had EGFR mutations (exon 19 deletion mutation or L858R), who were initially treated with gefitinib (250 mg) once daily in Nagano Prefecture. A total of 55 patients (16 men, 39 women) with a median age of 81.1 years (range; 75-94 years) treated between April 2007 and July 2012 were analyzed. The overall response rate and disease control rate were 72.7 % (95 % confidence interval (CI); 59.5-82.9 %) and 92.7 % (95 % CI; 82.0-97.6 %), respectively. Median progression-free survival and overall survival from the start of gefitinib treatment were 13.8 months (95 % CI; 9.9-18.8 months) and 29.1 months (95 % CI; 22.4 months-not reached), respectively. Two-year survival rate was 59.5 % (95 % CI; 41.0-78.0 %). Major grade 3 toxicities were skin rash (1.8 %) and increased levels of aspartate aminotransferase or alanine aminotransferase (7.3 %). First-line treatment with gefitinib for elderly EGFR-mutated NSCLC patients was effective and well tolerated. The results suggest that first-line gefitinib should be considered as  a preferable standard treatment in elderly patients with advanced NSCLC harboring EGFR mutations.




TÍTULO / TITLE:  - Prognostic significance of progesterone receptor-positive tumor cells within immunohistochemically defined luminal a breast cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Clin Oncol. 2013 Jan 10;31(2):203-9. doi: 10.1200/JCO.2012.43.4134. Epub 2012 Dec 10.

            ●● Enlace al texto completo (gratuito o de pago) 1200/JCO.2012.43.4134

AUTORES / AUTHORS:  - Prat A; Cheang MC; Martin M; Parker JS; Carrasco E; Caballero R; Tyldesley S; Gelmon K; Bernard PS; Nielsen TO; Perou CM

INSTITUCIÓN / INSTITUTION:  - Vall d’Hebron Institute of Oncology (VHIO), Pg Vall d’Hebron, 119-129, 08035, Barcelona, España; aprat@vhio.net.

RESUMEN / SUMMARY:  - PURPOSE Current immunohistochemical (IHC)-based definitions of luminal A and B breast cancers are imperfect when compared with multigene expression-based assays. In this study, we sought to improve the IHC subtyping by examining the pathologic and gene expression characteristics of genomically defined luminal A and B subtypes. PATIENTS AND METHODS Gene expression and pathologic features were collected from primary tumors across five independent cohorts: British Columbia Cancer Agency (BCCA) tamoxifen-treated only, Grupo Español de Investigacion en Cancer de Mama 9906 trial, BCCA no systemic treatment cohort, PAM50 microarray training data set, and a combined publicly available microarray data set. Optimal cutoffs of percentage of progesterone receptor (PR) -positive tumor cells to predict survival were derived and independently tested. Multivariable Cox models  were used to test the prognostic significance. Results Clinicopathologic comparisons among luminal A and B subtypes consistently identified higher rates of PR positivity, human epidermal growth factor receptor 2 (HER2) negativity, and histologic grade 1 in luminal A tumors. Quantitative PR gene and protein expression were also found to be significantly higher in luminal A tumors. An empiric cutoff of more than 20% of PR-positive tumor cells was statistically chosen and proved significant for predicting survival differences within IHC-defined luminal A tumors independently of endocrine therapy administration. Finally, no additional prognostic value within hormonal receptor (HR) -positive/HER2-negative disease was observed with the use of the IHC4 score when  intrinsic IHC-based subtypes were used that included the more than 20% PR-positive tumor cells and vice versa. CONCLUSION Semiquantitative IHC expression of PR adds prognostic value within the current IHC-based luminal A definition by improving the identification of good outcome breast cancers. The new proposed IHC-based definition of luminal A tumors is HR positive/HER2 negative/Ki-67 less than 14%, and PR more than 20%.




TÍTULO / TITLE:  - High expression of the Ets-related gene (ERG) is an independent prognostic marker for relapse-free survival in patients with acute promyelocytic leukemia.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Ann Hematol. 2012 Dec 19.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00277-012-1648-2

AUTORES / AUTHORS:  - Hecht A; Nowak D; Nowak V; Hanfstein B; Faldum A; Buchner T; Spiekermann K; Sauerland C; Lengfelder E; Hofmann WK; Nolte F

INSTITUCIÓN / INSTITUTION:  - Department of Hematology and Oncology, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.

RESUMEN / SUMMARY:  - In acute promyelocytic leukemia (APL), relapse occurs in about 15 % of cases and  is a major cause for death. Molecular markers identifying patients at high risk for relapse are not well established. High expression of the transcription factor Ets-related gene (ERG) is associated with inferior overall survival (OS) and disease-free survival in different types of hematologic malignancies. There are no data available about the impact of ERG expression in APL. ERG expression levels were analyzed in bone marrow samples of 86 APL patients at initial diagnosis. High ERG expression was significantly associated with an inferior OS in patients who had reached first complete remission. It was also significantly correlated with inferior relapse-free survival (RFS) and time to relapse (i.e., relapse-free interval, RFI). In multivariate analysis, high ERG expression had an independent negative impact on RFS and RFI. High ERG expression was significantly associated with inferior OS, RFS, and RFI. Moreover, in multivariate analysis, it maintained its value as an independent negative prognostic factor with regard to  RFS and RFI. Therefore, ERG expression might serve as a molecular marker for risk stratification in APL and might identify patients who could benefit from intensified treatment regimens.




TÍTULO / TITLE:  - Higher Expression of Receptor Tyrosine Kinase Axl, and Differential Expression of its Ligand, Gas6, Predict Poor Survival in Lung Adenocarcinoma Patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Ann Surg Oncol. 2012 Dec 16.

            ●● Enlace al texto completo (gratuito o de pago) 1245/s10434-012-2795-3

AUTORES / AUTHORS:  - Ishikawa M; Sonobe M; Nakayama E; Kobayashi M; Kikuchi R; Kitamura J; Imamura N; Date H

INSTITUCIÓN / INSTITUTION:  - Department of Thoracic Surgery, Faculty of Medicine, Kyoto University, Kyoto, Japan, mishi@kuhp.kyoto-u.ac.jp.

RESUMEN / SUMMARY:  - BACKGROUND: Downstream activation through receptor tyrosine kinases (RTKs) plays  important roles in carcinogenesis. In this study, we assessed the clinical involvement of Axl, an RTK, and its ligand, Gas6, in surgically treated lung adenocarcinoma. METHODS: Axl and Gas6 mRNA and protein expression levels were quantified using quantitative real-time polymerase chain reaction and immunohistochemistry, respectively, in completely resected lung adenocarcinoma tissues (n = 88) and were evaluated for correlation with clinicopathologic features and patient survival. RESULTS: Higher expressions of Axl mRNA/protein and Gas6 protein were significantly related to worse clinicopathological features and prognosis (5-year overall survival rates: Axl mRNA low: 72.3 %, high: 49.7 %, P = 0.047; Axl protein low: 77.5 %, high: 38.6 %, P < 0.001; and Gas6 protein low: 70.5 %, high: 48 %, P = 0.042). On the contrary, higher Gas6 mRNA expression was related to better clinicopathological features and prognosis (5-year overall  survival rates: Gas6 mRNA low: 59.2 %, high: 81.8 %, P = 0.054). Multivariate analysis suggests that high Axl mRNA expression may be an independent factor for  poor patient prognosis (P = 0.04). CONCLUSIONS: In lung adenocarcinoma, Axl and Gas6 expression levels were associated with tumor advancement and patient survival, thus rendering them as reliable biomarkers and potential targets for treatment of lung adenocarcinoma.




TÍTULO / TITLE:  - Cancer therapy combination: green tea and a phosphodiesterase 5 inhibitor?

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Clin Invest. 2013 Jan 25:1-3. doi: 10.1172/JCI67589.

            ●● Enlace al texto completo (gratuito o de pago) 1172/JCI67589


RESUMEN / SUMMARY:  - The major constituent of green tea, (-)-epigallocatechin-3-O-gallate (EGCG), has  been shown to have cancer-preventive and therapeutic activities. Numerous molecular targets for EGCG have been proposed, but the mechanisms of its anticancer activities are not clearly understood. In this issue of the JCI, Kumazoe et al. report that EGCG activates 67-kDa laminin receptor (67LR), elevates cGMP levels, and induces cancer cell apoptosis. Furthermore, a phosphodiesterase 5 inhibitor, vardenafil, synergizes with EGCG to induce cancer  cell death. This is a provocative observation with important implications for cancer therapy. It also raises several issues for further investigation, such as  the mechanism by which EGCG specifically activates 67LR.




TÍTULO / TITLE:  - IL-21R gene polymorphisms and serum IL-21 levels predict virological response to  interferon-based therapy in Asian chronic hepatitis C patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Antivir Ther. 2013 Jan 7. doi: 10.3851/IMP2502.

            ●● Enlace al texto completo (gratuito o de pago) 3851/IMP2502

AUTORES / AUTHORS:  - Hsu CS; Hsu SJ; Liu WL; Liu CH; Chen CL; Liu CJ; Chen PJ; Chen DS; Kao JH

INSTITUCIÓN / INSTITUTION:  - Division of Gastroenterology, Department of Internal Medicine, Buddhist Tzu Chi General Hospital, Taipei Branch.

RESUMEN / SUMMARY:  - BACKGROUND: IL-21R polymorphisms have been identified as potential predictors of  virologic outcomes in Western chronic hepatitis C (CHC) patients receiving interferon-based treatment. We aimed to examine the associations of IL-21R genotypes and serum IL-21 levels with virologic responses to interferon-based treatment in Asian CHC patients. METHODS: Genomic and clinical data were collected from 178 consecutive Taiwanese HCV genotype 1 patients who received interferon-based therapy and 72 non-HCV healthy subjects. Among them, serum IL-21 levels, IL-21R and IL28B genotypes were determined in 124 CHC patients and healthy controls. RESULTS: Among patients with IL28B rs8099917 non-TT genotypes,  patients with IL-21R rs3093390 CC genotype had a higher SVR rate than those with  non-CC genotypes (CC vs. non-CC: 14/24 vs. 0/4, P=0.031). Compared to non-HCV controls, CHC patients had higher serum IL-21 levels [HCV vs. non-HCV: 377.8+/-780.9 vs. 70.5+/-33.2(pg/mL), P=0.001]. Patients with SVR had higher pretreatment serum IL-21 levels than those without (Adjusted Odds Ratio, 95%CI: 0.23, 0.07-0.80, P=0.021). CONCLUSIONS: CHC patients have higher serum IL-21 levels than healthy adults. Higher pretreatment serum IL-21 levels and IL-21R polymorphisms may serve as potential factors predictive of treatment outcomes in  CHC patients with interferon-based therapy.




TÍTULO / TITLE:  - Combined analysis of intratumoral human equilibrative nucleoside transporter 1 (hENT1) and ribonucleotide reductase regulatory subunit M1 (RRM1) expression is a powerful predictor of survival in patients with pancreatic carcinoma treated with adjuvant gemcitabine-based chemotherapy after operative resection.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Surgery. 2012 Dec 17. pii: S0039-6060(12)00628-9. doi: 10.1016/j.surg.2012.10.010.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.surg.2012.10.010

AUTORES / AUTHORS:  - Nakagawa N; Murakami Y; Uemura K; Sudo T; Hashimoto Y; Kondo N; Sueda T

INSTITUCIÓN / INSTITUTION:  - Department of Surgery, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan. Electronic address: naoyaman423@hiroshima-u.ac.jp.

RESUMEN / SUMMARY:  - BACKGROUND: Although postoperative adjuvant chemotherapy for pancreatic carcinoma improves survival in some patients, its efficacy varies among individuals. The aim of this study was to determine the usefulness of intratumoral expression of human equilibrative nucleoside transporter 1 (hENT1) and ribonucleotide reductase regulatory subunit M1 (RRM1) as predictive markers of the efficacy of adjuvant gemcitabine-based chemotherapy for pancreatic carcinoma after operative resection. METHODS: The expression of intratumoral hENT1 and RRM1 was examined immunohistochemically in 109 patients with pancreatic carcinoma who received adjuvant gemcitabine-based chemotherapy after operative resection. Relationships  between clinicopathologic factors, including hENT1 and RRM1 expression, and disease-free and overall survival (DFS and OS) were evaluated by univariate and multivariate analyses. RESULTS: The 5-year DFS and OS rates for the 109 patients  were 26% and 31%, respectively. In univariate analysis, both hENT1 and RRM1 expression were significantly associated with DFS (hENT1, P = .004; RRM1, P = .011) and OS (hENT1, P = .001; RRM1, P = .040). In multivariate analysis, both were independent factors for DFS (hENT1, P = .001; RRM1, P = .009) and OS (hENT1, P = .001, RRM1, P = .019). Evaluation of the combination analysis of both was also identified as a powerful independent predictor of DFS (P < .001) and OS (P < .001). CONCLUSION: Expression of hENT1 and RRM1 is predictive of the efficacy of  adjuvant gemcitabine-based chemotherapy for pancreatic carcinoma after operative  resection. In addition, their combined analysis has greater predictive value than either factor alone.




TÍTULO / TITLE:  - Prognostically relevant gene signatures of high-grade serous ovarian carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Clin Invest. 2013 Jan 2;123(1):517-25. doi: 10.1172/JCI65833. Epub 2012 Dec 21.

            ●● Enlace al texto completo (gratuito o de pago) 1172/JCI65833

AUTORES / AUTHORS:  - Verhaak RG; Tamayo P; Yang JY; Hubbard D; Zhang H; Creighton CJ; Fereday S; Lawrence M; Carter SL; Mermel CH; Kostic AD; Etemadmoghadam D; Saksena G; Cibulskis K; Duraisamy S; Levanon K; Sougnez C; Tsherniak A; Gomez S; Onofrio R; Gabriel S; Chin L; Zhang N; Spellman PT; Zhang Y; Akbani R; Hoadley KA; Kahn A; Kobel M; Huntsman D; Soslow RA; Defazio A; Birrer MJ; Gray JW; Weinstein JN; Bowtell DD; Drapkin R; Mesirov JP; Getz G; Levine DA; Meyerson M

RESUMEN / SUMMARY:  - Because of the high risk of recurrence in high-grade serous ovarian carcinoma (HGS-OvCa), the development of outcome predictors could be valuable for patient stratification. Using the catalog of The Cancer Genome Atlas (TCGA), we developed subtype and survival gene expression signatures, which, when combined, provide a  prognostic model of HGS-OvCa classification, named “Classification of Ovarian Cancer” (CLOVAR). We validated CLOVAR on an independent dataset consisting of 879 HGS-OvCa expression profiles. The worst outcome group, accounting for 23% of all  cases, was associated with a median survival of 23 months and a platinum resistance rate of 63%, versus a median survival of 46 months and platinum resistance rate of 23% in other cases. Associating the outcome prediction model with BRCA1/BRCA2 mutation status, residual disease after surgery, and disease stage further optimized outcome classification. Ovarian cancer is a disease in urgent need of more effective therapies. The spectrum of outcomes observed here and their association with CLOVAR signatures suggests variations in underlying tumor biology. Prospective validation of the CLOVAR model in the context of additional prognostic variables may provide a rationale for optimal combination of patient and treatment regimens.




TÍTULO / TITLE:  - Differential effect of adjuvant taxane-based and taxane-free chemotherapy regimens on the CK-19 mRNA-positive circulating tumour cells in patients with early breast cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Br J Cancer. 2013 Jan 17. doi: 10.1038/bjc.2012.597.

            ●● Enlace al texto completo (gratuito o de pago) 1038/bjc.2012.597

AUTORES / AUTHORS:  - Xenidis N; Perraki M; Apostolaki S; Agelaki S; Kalbakis K; Vardakis N; Kalykaki A; Xyrafas A; Kakolyris S; Mavroudis D; Georgoulias V

INSTITUCIÓN / INSTITUTION:  - 1] Department of Medical Oncology, University Hospital of Heraklion, PO Box 1352, 711 10 Heraklion, Crete, Greece [2] Department of Medical Oncology, University Hospital of Alexandroupolis, Alexandroupolis, Greece.

RESUMEN / SUMMARY:  - Background:To determine the effect of adjuvant taxane-free and taxane-based chemotherapy regimens on the elimination of circulating tumour cells (CTCs) in patients with early breast cancer.Methods:The presence of CK-19 mRNA-positive CTCs in the peripheral blood was evaluated before and after chemotherapy, using a real-time RT-PCR assay, in a historical comparison of two cohorts of women with stage I-III breast cancer treated with adjuvant taxane-free (N=211; FE(75)C or E(75)C) and taxane-based (N=334; T/E(75)C or T/E(75)) chemotherapy.Results:Taxane-based chemotherapy resulted in a higher incidence of  CTCs’ elimination than taxane-free regimens since 49.7% (74 of 149) and 33.0% (29 of 88) of patients with detectable CTCs before chemotherapy, respectively, turned negative post-chemotherapy (P=0.015). Patients treated with taxane-free regimens  had a significantly lower disease-free survival (DFS) (P=0.035) than patients treated with taxane-based regimens; this difference was observed in patients with but not without detectable CTCs before chemotherapy (P=0.018 and P=0.481, respectively). The incidence of deaths was significantly higher in the taxane-free cohort of patients with but not without detectable CTCs before chemotherapy compared with that of the taxane-based cohort (P=0.002). Multivariate analysis revealed that the chemotherapy regimen was significantly associated with prolonged DFS (HR: 2.00; 95% CI=1.20-3.34).Conclusion:Elimination of CK-19 mRNA-positive CTCs during adjuvant chemotherapy seems to be an efficacy  indicator of treatment and is associated with a favourable clinical outcome of patients with detectable CTCs before chemotherapy.British Journal of Cancer advance online publication, 17 January 2013; doi:10.1038/bjc.2012.597 www.bjcancer.com.




TÍTULO / TITLE:  - mRECIST and EASL responses at early time point by contrast-enhanced dynamic MRI predict survival in patients with unresectable hepatocellular carcinoma (HCC) treated by doxorubicin drug-eluting beads transarterial chemoembolization (DEB TACE).

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Ann Oncol. 2012 Dec 5.

            ●● Enlace al texto completo (gratuito o de pago) 1093/annonc/mds605

AUTORES / AUTHORS:  - Prajapati HJ; Spivey JR; Hanish SI; El-Rayes BF; Kauh JS; Chen Z; Kim HS

INSTITUCIÓN / INSTITUTION:  - Departments of Interventional Radiology and Image Guided Medicine.

RESUMEN / SUMMARY:  - BackgroundWe analyzed the magnetic resonance imaging (MRI) responses by world health organization (WHO), response evaluation criteria in solid tumor (RECIST),  European Association for the Study of Liver (EASL), and modified RECIST (mRECIST) guidelines and correlated with survival after doxorubicin (Adriamycin; Pharmacia  & Upjohn, Peapac, NJ). drug-eluting beads transarterial chemoembolization (DEB TACE) in patients with unresectable hepatocellular carcinoma (HCC).Patients and methodsThe early target and overall imaging responses were studied in 120 consecutive patients treated with DEB TACE for unresectable HCC, using RECIST, WHO, EASL, and mRECIST guidelines on contrast-enhanced dynamic liver MRI. The median period between the DEB TACE and assessment scan was 33.50 days. Survival analyses were carried out with the Kaplan-Meier method and the Cox proportional model.ResultsWHO and RECIST1.1 had poor correlation with survival. mRECIST and EASL had significant correlation with survival with target lesion response rates  of 63.3% and 48.3% and with overall response rates of 52.5% and 39.2%, respectively. The responders of EASL and mRECIST had significant median survival  (P </= 0.0001). Moreover, mRECIST was better than EASL in predicting survival, because the survival difference between responders and non-responders of overall  response was statistically significant (P = 0.013) for mRECIST, but not for EASL  (P = 0.064).ConclusionsEASL and mRECIST responses measured on MRI at an early time point after DEB TACE predicted survival. mRECIST response demonstrated higher survival correlation than EASL.




TÍTULO / TITLE:  - Time from Prior Chemotherapy Enhances Prognostic Risk Grouping in the Second-line Setting of Advanced Urothelial Carcinoma: A Retrospective Analysis of Pooled, Prospective Phase 2 Trials.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur Urol. 2012 Nov 26. pii: S0302-2838(12)01417-0. doi: 10.1016/j.eururo.2012.11.042.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.eururo.2012.11.042

AUTORES / AUTHORS:  - Sonpavde G; Pond GR; Fougeray R; Choueiri TK; Qu AQ; Vaughn DJ; Niegisch G; Albers P; James ND; Wong YN; Ko YJ; Sridhar SS; Galsky MD; Petrylak DP; Vaishampayan UN; Khan A; Vogelzang NJ; Beer TM; Stadler WM; O’Donnell PH; Sternberg CN; Rosenberg JE; Bellmunt J

INSTITUCIÓN / INSTITUTION:  - University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL,  USA.

RESUMEN / SUMMARY:  - BACKGROUND: Outcomes for patients in the second-line setting of advanced urothelial carcinoma (UC) are dismal. The recognized prognostic factors in this context are Eastern Cooperative Oncology Group (ECOG) performance status (PS) >0, hemoglobin level (Hb) <10g/dl, and liver metastasis (LM). OBJECTIVES: The purpose of this retrospective study of prospective trials was to investigate the prognostic value of time from prior chemotherapy (TFPC) independent of known prognostic factors. DESIGN, SETTING, AND PARTICIPANTS: Data from patients from seven prospective trials with available baseline TFPC, Hb, PS, and LM values were used for retrospective analysis (n=570). External validation was conducted in a second-line phase 3 trial comparing best supportive care (BSC) versus vinflunine  plus BSC (n=352). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cox proportional hazards regression was used to evaluate the association of factors, with overall  survival (OS) and progression-free survival (PFS) being the respective primary and secondary outcome measures. RESULTS AND LIMITATIONS: ECOG-PS >0, LM, Hb <10g/dl, and shorter TFPC were significant prognostic factors for OS and PFS on multivariable analysis. Patients with zero, one, two, and three to four factors demonstrated median OS of 12.2, 6.7, 5.1, and 3.0 mo, respectively (concordance statistic=0.638). Setting of prior chemotherapy (metastatic disease vs perioperative) and prior platinum agent (cisplatin or carboplatin) were not prognostic factors. External validation demonstrated a significant association of TFPC with PFS on univariable and most multivariable analyses, and with OS on univariable analyses. Limitations of retrospective analyses are applicable. CONCLUSIONS: Shorter TFPC enhances prognostic classification independent of ECOG-PS >0, Hb <10g/dl, and LM in the setting of second-line therapy for advanced UC. These data may facilitate drug development and interpretation of trials.




TÍTULO / TITLE:  - Low p14ARF expression in neuroblastoma cells is associated with repressed histone mark status, and enforced expression induces growth arrest and apoptosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Hum Mol Genet. 2013 Jan 23.

            ●● Enlace al texto completo (gratuito o de pago) 1093/hmg/ddt020

AUTORES / AUTHORS:  - Dreidax D; Gogolin S; Schroeder C; Muth D; Brueckner LM; Hess EM; Zapatka M; Theissen J; Fischer M; Ehemann V; Schwab M; Savelyeva L; Westermann F

INSTITUCIÓN / INSTITUTION:  - Division of Tumor Genetics B030, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.

RESUMEN / SUMMARY:  - The TP53 tumor suppressor pathway is abrogated by TP53 mutations in the majority  of human cancers. Increased levels of wildtype TP53 in aggressive neuroblastomas  appear paradox but are tolerated by tumor cells due to co-activation of the TP53  ubiquitin ligase, MDM2. The role of the MDM2 antagonist, p14(ARF), in controlling the TP53-MDM2 balance in neuroblastoma is unresolved. In the present study, we show that conditional p14(ARF) expression substantially suppresses viability, clonogenicity and anchorage-independent growth in p14(ARF)-deficient or MYCN-amplified neuroblastoma cell lines. Furthermore, ectopic 14(ARF) expression  induced accumulation of cells in the G1 phase and apoptosis, which was paralleled by accumulation of TP53 and its targets. Comparative genomic hybridization analysis of 193 primary neuroblastomas detected one homozygous deletion of CDKN2A (encoding both p14(ARF) and p16(INK4A)) and heterozygous loss of CDKN2A in 22% of tumors. Co-expression analysis of p14(ARF) and its transactivator, E2F1, in a set of 68 primary tumors revealed only a weak correlation, suggesting that further regulatory mechanisms govern p14(ARF) expression in neuroblastomas. Intriguingly, analyses utilizing chromatin immunoprecipitation revealed different histone mark-defined epigenetic activity states of p14(ARF)in neuroblastoma cell lines that correlated with endogenous p14(ARF) expression but not with episomal p14(ARF) promoter reporter activity, indicating that the native chromatin context serves to epigenetically repress p14(ARF) in neuroblastoma cells. Collectively, the data pinpoint p14(ARF) as a critical factor for efficient TP53 response in neuroblastoma cells and assign p14(ARF) as a neuroblastoma suppressor candidate that is impaired by genomic loss and epigenetic repression.




TÍTULO / TITLE:  - Human NK Cells Selective Targeting of Colon Cancer-Initiating Cells: A Role for Natural Cytotoxicity Receptors and MHC Class I Molecules.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Immunol. 2013 Jan 23.

            ●● Enlace al texto completo (gratuito o de pago) 4049/jimmunol.1201542

AUTORES / AUTHORS:  - Tallerico R; Todaro M; Di Franco S; Maccalli C; Garofalo C; Sottile R; Palmieri C; Tirinato L; Pangigadde PN; La Rocca R; Mandelboim O; Stassi G; Di Fabrizio E; Parmiani G; Moretta A; Dieli F; Karre K; Carbone E

INSTITUCIÓN / INSTITUTION:  - Department of Experimental and Clinical Medicine, University of “Magna Graecia,”  88100 Catanzaro, Italy;

RESUMEN / SUMMARY:  - Tumor cell populations have been recently proposed to be composed of two compartments: tumor-initiating cells characterized by a slow and asymmetrical growth, and the “differentiated” cancer cells with a fast and symmetrical growth. Cancer stem cells or cancer-initiating cells (CICs) play a crucial role in tumor  recurrence. The resistance of CICs to drugs and irradiation often allows them to  survive traditional therapy. NK cells are potent cytotoxic lymphocytes that can recognize tumor cells. In this study, we have analyzed the NK cell recognition of tumor target cells derived from the two cancer cell compartments of colon adenocarcinoma lesions. Our data demonstrate that freshly purified allogeneic NK  cells can recognize and kill colorectal carcinoma-derived CICs whereas the non-CIC counterpart of the tumors (differentiated tumor cells), either autologous or allogeneic, is less susceptible to NK cells. This difference in the NK cell susceptibility correlates with higher expression on CICs of ligands for NKp30 and NKp44 in the natural cytotoxicity receptor (NCR) group of activating NK receptors. In contrast, CICs express lower levels of MHC class I, known to inhibit NK recognition, on their surface than do the “differentiated” tumor cells. These data have been validated by confocal microscopy where NCR ligands and MHC class I molecule membrane distribution have been analyzed. Moreover, NK cell receptor blockade in cytotoxicity assays demonstrates that NCRs play a major role in the recognition of CIC targets. This study strengthens the idea that biology-based therapy harnessing NK cells could be an attractive opportunity in solid tumors.




TÍTULO / TITLE:  - 67-kDa laminin receptor increases cGMP to induce cancer-selective apoptosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Clin Invest. 2013 Jan 25. pii: 64768. doi: 10.1172/JCI64768.

            ●● Enlace al texto completo (gratuito o de pago) 1172/JCI64768

AUTORES / AUTHORS:  - Kumazoe M; Sugihara K; Tsukamoto S; Huang Y; Tsurudome Y; Suzuki T; Suemasu Y; Ueda N; Yamashita S; Kim Y; Yamada K; Tachibana H

RESUMEN / SUMMARY:  - The 67-kDa laminin receptor (67LR) is a laminin-binding protein overexpressed in  various types of cancer, including bile duct carcinoma, colorectal carcinoma, cervical cancer, and breast carcinoma. 67LR plays a vital role in growth and metastasis of tumor cells and resistance to chemotherapy. Here, we show that 67LR functions as a cancer-specific death receptor. In this cell death receptor pathway, cGMP initiated cancer-specific cell death by activating the PKCdelta/acid sphingomyelinase (PKCdelta/ASM) pathway. Furthermore, upregulation  of cGMP was a rate-determining process of 67LR-dependent cell death induced by the green tea polyphenol (-)-epigallocatechin-3-O-gallate (EGCG), a natural ligand of 67LR. We found that phosphodiesterase 5 (PDE5), a negative regulator of cGMP, was abnormally expressed in multiple cancers and attenuated 67LR-mediated cell death. Vardenafil, a PDE5 inhibitor that is used to treat erectile dysfunction, significantly potentiated the EGCG-activated 67LR-dependent apoptosis without affecting normal cells and prolonged the survival time in a mouse xenograft model. These results suggest that PDE5 inhibitors could be used to elevate cGMP levels to induce 67LR-mediated, cancer-specific cell death.




TÍTULO / TITLE:  - Circulating tumor cells as therapy-related biomarkers in cancer patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Immunol Immunother. 2013 Jan 12.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00262-012-1387-1

AUTORES / AUTHORS:  - Gorges TM; Pantel K

INSTITUCIÓN / INSTITUTION:  - Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany, t.gorges@uke.de.

RESUMEN / SUMMARY:  - Carcinomas (tumors of epithelial origin) are responsible for most of all new cancers in the industrialized countries. Due to the high mortality rate caused by the metastatic spread of aggressive cancer cells, there is an urgent demand in finding new biomarkers, which should detect early formation of metastases and monitor efficacy of systemic adjuvant therapy in a timely manner. It has been considered that the molecular analysis of cells which are shed from tumors into the blood system (circulating tumor cells (CTCs)) might provide new insights for  the clinical management of cancer, probably far earlier than using traditional high-resolution imaging technologies. Clinical trials indicated that CTCs can be  deployed for diagnostic, monitoring, and prognostic purposes. Furthermore, these  cells are discussed to be suitable as predictive markers. In any case, identification of CTCs requires innovative and challenging technologies as detection methods should be specific, sensitive, standardized, and highly reproducible. Although many different approaches have been developed until now, only the CellSearch method has been cleared by the American Food and Drug Administration. Although the detection of CTCs has already shown to have a prognostic impact in many tumor entities including breast, prostate, lung and colon cancer, ongoing and future studies are aimed to explore whether CTCs can be used for an individual therapy decision making including novel immunotherapeutic  approaches. This review discusses (1) different detection strategies for CTCs, (2) their clinical impact, and (3) the potential use of CTCs guiding the treatment of individual cancer patients.




TÍTULO / TITLE:  - Risk Model and Nomogram for Dysphagia and Xerostomia Prediction in Head and Neck  Cancer Patients Treated by Radiotherapy and/or Chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Dysphagia. 2013 Jan 26.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00455-012-9445-6

AUTORES / AUTHORS:  - Teguh DN; Levendag PC; Ghidey W; van Montfort K; Kwa SL

INSTITUCIÓN / INSTITUTION:  - Radiation Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, Netherlands, d.teguh@erasmusmc.nl.

RESUMEN / SUMMARY:  - In our randomized trial on hyperbaric oxygen (HBO), it was shown that HBO could reduce dysphagia and xerostomia, which are frequently encountered after (chemo-)  radiotherapy (RT) and/or surgery for head and neck cancer (HNC). A risk model and nomogram are developed to select those patients who most likely will respond to HBO treatment. A total of 434 HNC patients treated from 2000 to 2008 were analyzed and filled out the EORTC QLQC-30 and H&N35 questionnaires. Age, gender,  chemotherapy, T and N stages, site, radiotherapy technique, RT boost, surgery of  the primary tumor and neck, bilateral RT, and dose were analyzed in a statistical model. The discriminative value of the model was evaluated based on receiver operating characteristics (ROC), the area under the curve (AUC), sensitivity, specificity, and proportion of correctly classified measures. Significant factors in predicting swallowing problems are age, follow-up duration, tumor site, chemotherapy, surgery of the primary tumor and neck, and dose. For dry mouth, the significant factors are age, gender, tumor site, N stage, chemotherapy, and bilateral irradiation. For dysphagia and xerostomia, the area under the ROC curve is 0.7034 and 0.7224, respectively, with a specificity of 89/77 %, sensitivity of 27/58 %, and a positive predictive value of 83/67 % for dysphagia and xerostomia, respectively. The developed predictive risk model could be used to select patients for costly hyperbaric oxygen treatment to prevent or reduce severe late  side effects of HNC treatment. Our model serves as a guideline for the Department of Radiation Oncology to reduce costs by excluding patients not amenable to hyperbaric oxygen protocols. The nomogram presented is a useful tool for clinicians in assessing patient risks when deciding on follow-up strategies (e.g., hyperbaric oxygen treatment) after RT or surgery for HNC.




TÍTULO / TITLE:  - High FAK combined with low JWA expression: clinical prognostic and predictive role for adjuvant fluorouracil-leucovorin-oxaliplatin treatment in resectable gastric cancer patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Gastroenterol. 2013 Jan 11.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00535-012-0724-7

AUTORES / AUTHORS:  - Chen Y; Xia X; Wang S; Wu X; Zhang J; Zhou Y; Tan Y; He S; Qiang F; Li A; Roe OD; Zhou J

INSTITUCIÓN / INSTITUTION:  - Department of Molecular Cell Biology and Toxicology, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public Health, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, People’s Republic of China.

RESUMEN / SUMMARY:  - BACKGROUND: The multifunctional protein JWA was previously identified as a novel  regulator of focal adhesion kinase (FAK/PTK2) in suppressing cancer cell adhesion, invasion and metastasis. JWA is downregulated in gastric cancer (GC) and a prognostic and predictive biomarker for resectable GC. However, the value of FAK combined with JWA for GC patients as a biomarker has not been studied. Here we evaluated the roles of FAK alone and combined with JWA in GC patients treated with surgery alone or combined with adjuvant platinum-based chemotherapy. METHODS: Two tissue microarrays were constructed of specimens from resected GC (n = 709 in total) for detection of FAK and JWA expression by immunohistochemistry.  Correlations between both proteins and clinicopathological features as well as prognostic and predictive values were evaluated. RESULTS: Compared with adjacent  non-cancerous tissues, FAK protein levels were remarkably up-regulated in GC lesions (P < 0.001). High FAK alone or combined with low JWA expression significantly correlated with worse overall survival (OS) (both P < 0.001 in two  cohorts). Simultaneously, JWA plus FAK expression was a more valuable prognostic  biomarker than JWA or FAK alone. Moreover, the patients with high FAK only or combined with low JWA had significant benefit from adjuvant fluorouracil-leucovorin-oxaliplatin (FLO) therapy compared with those with surgery alone (P = 0.003); however, the cases with adjuvant fluorouracil-leucovorin-cisplatin (FLP) therapy did not show these effects. CONCLUSION: FAK plus JWA may serve as a more prognostic and predictive biomarker  for GC than each separately with a potential clinical application.




TÍTULO / TITLE:  - Human Leukocyte Antigen-G Is Frequently Expressed in Glioblastoma and May Be Induced in Vitro by Combined 5-Aza-2’-Deoxycytidine and Interferon-gamma Treatments: Results from a Multicentric Study.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Am J Pathol. 2013 Feb;182(2):540-52. doi: 10.1016/j.ajpath.2012.10.021. Epub 2012 Dec 4.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ajpath.2012.10.021

AUTORES / AUTHORS:  - Wastowski IJ; Simoes RT; Yaghi L; Donadi EA; Pancoto JT; Poras I; Lechapt-Zalcman E; Bernaudin M; Valable S; Carlotti CG Jr; Flajollet S; Jensen SS; Ferrone S; Carosella ED; Kristensen BW; Moreau P

INSTITUCIÓN / INSTITUTION:  - Commissariat a l’Energie Atomique et aux Energies Alternatives, Institut des Maladies Emergentes et des Therapies Innovantes, Service de Recherches en Hemato-Immunologie, Hopital Saint-Louis, Paris, France; Universite Paris-Diderot, Sorbonne Paris-Cite, UMR E5, Institut Universitaire d’Hematologie, Hopital Saint-Louis, Paris, France.

RESUMEN / SUMMARY:  - Human leukocyte antigen-G (HLA-G) is a nonclassical major histocompatibility complex (MHC) class I molecule involved in immune tolerance processes, playing an important role in the maintenance of the semi-allogeneic fetus. Although HLA-G expression is restricted in normal tissues, it is broadly expressed in malignant  tumors and may favor tumor immune escape. We analyzed HLA-G protein and mRNA expression in tumor samples from patients with glioblastoma collected in France,  Denmark, and Brazil. We found HLA-G protein expression in 65 of 108 samples and mRNA in 20 of 21 samples. The absence of HLA-G protein expression was associated  with a better long-term survival rate. The mechanisms underlying HLA-G gene expression were investigated in glioma cell lines U251MG, D247MG, and U138MG. Induction of HLA-G transcriptional activity was dependent of 5-aza-2’-deoxycytidine treatment and enhanced by interferon-gamma. HLA-G protein  expression was observed in U251MG cells only. These cells exhibited a permissive  chromatin state at the HLA-G gene promoter and the highest levels of induced HLA-G transcriptional activity following 5-aza-2’-deoxycytidine treatment. Several antigen-presenting machinery components were up-regulated in U251MG cells after demethylating and IFN-gamma treatments, suggesting an effect on the up-regulation of HLA-G cell surface expression. Therefore, because of its role in tumor tolerance, HLA-G found to be expressed in glioblastoma samples should be taken into consideration in clinical studies on the pathology and in the design of therapeutic strategies to prevent its expression in HLA-G-negative tumors.




TÍTULO / TITLE:  - Methylation of breast cancer susceptibility gene 1 (BRCA1) predicts recurrence in patients with curatively resected stage I non-small cell lung cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer. 2013 Jan 18. doi: 10.1002/cncr.27754.

            ●● Enlace al texto completo (gratuito o de pago) 1002/cncr.27754

AUTORES / AUTHORS:  - Harada H; Miyamoto K; Yamashita Y; Nakano K; Taniyama K; Miyata Y; Ohdan H; Okada M

INSTITUCIÓN / INSTITUTION:  - Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan; Institute for Clinical Research, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Japan; Department of Respiratory Surgery, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Japan.

RESUMEN / SUMMARY:  - BACKGROUND: Even after early detection and curative resection of early stage non-small cell lung cancer (NSCLC), a significant fraction of patients develop recurrent disease. Molecular biomarkers that can predict the risk of recurrence thus need to be identified to improve clinical outcomes. METHODS: Using the methylation-specific polymerase chain reaction assay, promoter methylation of the breast cancer susceptibility gene 1 (BRCA1) was assessed in cancer tissues from 70 patients with curatively resected stage I NSCLC. The clinical relevance of BRCA1 methylation status was evaluated in terms of outcome of the disease. RESULTS: Methylation of the BRCA1 promoter was detected in 13 of 70 patients (18.6%). Multiple logistic regression analysis revealed that BRCA1 methylation was an independent risk factor for recurrence (P = .0197) and that patients with  BRCA1 methylation demonstrated significantly poorer recurrence-free survival compared to those without (P = .0139). Cox’s proportional hazard regression analysis revealed that BRCA1 methylation was an independent risk factor for recurrence-free survival (P = .0155). CONCLUSIONS: Methylated BRCA1 can be a potential biomarker that predicts the prognosis after curative resection of stage I NSCLC. Considering that BRCA1 plays a role in chemotherapy-induced apoptosis, it is plausible that identification of methylated BRCA1 could provide information that is clinically relevant to tailored adjuvant therapy. Cancer 2013. © 2013 American Cancer Society.




TÍTULO / TITLE:  - Clinical and safety profile of high-dose interleukin-2 treatment in elderly patients with metastatic melanoma and renal cell carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncology. 2013;84(2):123-6. doi: 10.1159/000342764. Epub 2012 Dec 7.

            ●● Enlace al texto completo (gratuito o de pago) 1159/000342764

AUTORES / AUTHORS:  - Clark JM; Kelley B; Titze J; Fung H; Maciejewski J; Nathan S; Rich E; Basu S; Kaufman HL

INSTITUCIÓN / INSTITUTION:  - Department of General Surgery, Rush University Medical Center, Chicago, Ill., USA.

RESUMEN / SUMMARY:  - Objective: High-dose interleukin-2 (IL-2) is effective immunotherapy for the treatment of metastatic melanoma and renal cell carcinoma (RCC) but has been contraindicated in elderly patients. This study assessed the safety and therapeutic efficacy of high-dose IL-2 in patients >/=65 years of age with metastatic melanoma and RCC. Methods: A prospectively collected clinical database of 104 consecutive melanoma or RCC patients treated with high-dose IL-2 between 2009 and 2012 was used to compare clinical outcomes and adverse events in patients >/=65 years of age with those of younger patients. Results: There were 22 (21%) patients >/=65 years and 82 (79%) patients <65 years of age. The mean number of IL-2 doses was lower in older patients during cycle 1 of treatment (7.2 vs. 8.6, p = 0.012). There were no other differences in dosing pattern by age group. There was a higher rate of selected cardiac, constitutional, hematologic,  metabolic and renal toxicities in younger patients (p < 0.05). Overall, objective responses and survival were not affected by age, though older patients had a higher partial response rate (p = 0.04). Conclusions: IL-2 is safe and has comparable therapeutic effectiveness in patients >/=65 years. Age should not be considered a contraindication to treatment with IL-2 in otherwise eligible patients.




TÍTULO / TITLE:  - Tetrahydropyrroloquinolinone type dual inhibitors of aromatase/aldosterone synthase as a novel strategy for breast cancer patients with elevated cardiovascular risks.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Med Chem. 2013 Jan 24;56(2):460-70. doi: 10.1021/jm301408t. Epub 2013 Jan 3.

            ●● Enlace al texto completo (gratuito o de pago) 1021/jm301408t

AUTORES / AUTHORS:  - Yin L; Hu Q; Hartmann RW

INSTITUCIÓN / INSTITUTION:  - Pharmaceutical and Medicinal Chemistry, Saarland University & Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) , Campus C2-3, D-66123 Saarbrucken, Germany.

RESUMEN / SUMMARY:  - The application of aromatase inhibitors to postmenopausal breast cancer patients  increases the risk of cardiovascular diseases (CVD), which is believed to be caused by the abnormally high concentrations of aldosterone as a consequence of the estrogen deficiency. Dual inhibitors of aromatase (CYP19) and aldosterone synthase (CYP11B2) are therefore proposed as a novel strategy for the adjuvant therapy to reduce the CVD risk for these patients. By combining decisive structural features of CYP11B2 and CYP19 inhibitors into a common template, a series of pyridinylmethyl substituted 1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-ones were designed and synthesized. Interestingly, the substituents on the methylene bridge showed strong influences on the inhibitory activities leading to opposite effects, that  is, a given substituent showed an increase in inhibition of one enzyme, while it  led to a decrease for the other enzyme. The compromise of this conflict led to compounds 3j, 3k, 3n, and 3p as potent and selective dual inhibitors of CYP19 and CYP11B2, especially compound 3p, which exhibited IC(50) values of 32 and 41 nM for CYP19 and CYP11B2, respectively, and a high selectivity toward CYP17 and CYP11B1. This compound is considered as a candidate for further evaluation in vivo.




TÍTULO / TITLE:  - ABT-737 Resistance in B-Cells Isolated from Chronic Lymphocytic Leukemia Patients and Leukemia Cell Lines is Overcome by the Pleiotropic Kinase Inhibitor Quercetin Through Mcl-1 Down-regulation.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochem Pharmacol. 2013 Jan 24. pii: S0006-2952(13)00048-8. doi: 10.1016/j.bcp.2013.01.011.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bcp.2013.01.011

AUTORES / AUTHORS:  - Russo M; Spagnuolo C; Volpe S; Tedesco I; Bilotto S; Russo GL

INSTITUCIÓN / INSTITUTION:  - Institute of Food Sciences, National Research Council, 83100 Avellino, Italy.

RESUMEN / SUMMARY:  - Chronic Lymphocytic Leukemia (CLL) is the most frequent form of leukemia in adult population and despite numerous studies, it is considered an incurable disease. Since CLL is characterized by overexpression of pro-survival Bcl-2 family members, treatment with their antagonists, such as ABT-737, represent a promising new therapeutic strategy. ABT-737 is a BH3 mimetic agent which binds Bcl-2, Bcl-X(L) and Bcl-w with high affinity, while weakly interacts with Mcl-1 and Bfl-1. Previous studies demonstrated that quercetin, a flavonoid naturally present in food and beverages, was able to sensitize B-cells isolated from CLL patients to apoptosis when associated with death ligands or fludarabine, through  a mechanism involving Mcl-1 down-regulation. Here, we report that the association between ABT-737 and quercetin synergistically induces apoptosis in B-cells and in five leukemic cell lines (Combination Index <1). Peripheral blood mononuclear cell from healthy donors were not affected by quercetin treatment. The molecular  pathways triggered by quercetin have been investigated in HPB-ALL cells, characterized by the highest resistance to both ABT-737 and quercetin when applied as single molecules, but highly sensitivity to the co-treatment. In this  cell line, quercetin down-regulated Mcl-1 through the inhibition of PI(3)K/Akt signaling pathway, leading to Mcl-1 instability. The same mechanism was confirmed in B-cells. These results may open new clinical perspectives based on a translational approach in CLL therapy.




TÍTULO / TITLE:  - Outcome of allogeneic SCT in patients with chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Ann Hematol. 2012 Dec 19.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00277-012-1650-8

AUTORES / AUTHORS:  - Oyekunle A; Zander AR; Binder M; Ayuk F; Zabelina T; Christopeit M; Stubig T; Alchalby H; Schafhausen P; Lellek H; Wolschke C; Muller I; Bacher U; Kroger N

INSTITUCIÓN / INSTITUTION:  - Department for Stem Cell Transplantation, University Cancer Center Hamburg (UCCH), Martinistr. 52, 20246, Hamburg, Germany.

RESUMEN / SUMMARY:  - The introduction of tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML) led to a dramatic change in the role of allogeneic stem cell transplantation (SCT) with a rapid decline in the number of patients receiving SCT in first chronic phase (CP1). We evaluated 68 consecutive patients in all phases of CML (male/female = 39:29, 27 in CP1), who received SCT from related/unrelated donors (related/unrelated = 23:45) under myeloablative or reduced intensity conditioning (MAC/RIC = 45:23). Forty-eight patients (71 %) received TKIs pre-SCT, 20 patients post-SCT (29 %). Overall survival (OS) of CP1  patients achieved a plateau of 85 % at 10 months. Relapse-free survival (RFS) of  CP1 patients was 85 % at 1 and 2 years, and 81 % at 5 years. Multivariate analysis showed adverse OS and RFS for patients transplanted >CP1 (hazard ratio (HR) = 6.61 and 4.62) and those who had grade III-IV aGvHD (HR = 2.45 and 1.82).  Patients with advanced CML had estimated OS of 65 and 47 %; and RFS of 41 and 32  % at 1 and 2 years respectively. Therefore, for patients with advanced CML phases, allogeneic SCT provides an acceptable chance of cure. Transplant research should focus on improving conditioning regimens and post-SCT management for this  subgroup of CML patients.




TÍTULO / TITLE:  - Dual inhibition of Bcl-2 and Bcl-xL strikingly enhances PI3K inhibition-induced apoptosis in human myeloid leukemia cells through a GSK3- and Bim-dependent mechanism.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Res. 2012 Dec 12.

            ●● Enlace al texto completo (gratuito o de pago) 1158/0008-5472.CAN-12-1365

AUTORES / AUTHORS:  - Rahmani M; Aust MM; Attkisson E; Williams DC Jr; Ferreira-Gonzalez A; Grant S

INSTITUCIÓN / INSTITUTION:  - Internal Medicine, Virginia Commonwealth University.

RESUMEN / SUMMARY:  - Effects of concomitant inhibition of the PI3K/AKT/mTOR pathway and Bcl-2/Bcl-xL (BCL2L1) were examined in human myeloid leukemia cells. Tetracycline-inducible Bcl-2 and Bcl-xL dual knockdown sharply increased PI3K/AKT/mTOR inhibitor lethality. Conversely, inducible knockdown or dominant-negative AKT increased whereas constitutively active AKT reduced lethality of the Bcl-2/Bcl-xL inhibitor ABT-737. Furthermore, PI3K/mTOR inhibitors (e.g., BEZ235, PI-103) synergistically increased ABT-737-mediated cell death in multiple leukemia cell lines and reduced colony-formation in leukemic but not normal CD34+ cells. Notably, increased lethality was observed in 4/6 primary AML specimens. Responding, but not non-responding, samples exhibited basal AKT phosphorylation. PI3K/mTOR inhibitors markedly down-regulated Mcl-1 but increased Bim binding to Bcl-2/Bcl-xL; the latter effect was abrogated by ABT-737. Combined treatment also markedly diminished Bax/Bak binding to Mcl-1, Bcl-2 or Bcl-xL. Bax, Bak, or Bim (BCL2L11)  knockdown, or Mcl-1 over-expression significantly diminished regimen-induced apoptosis. Interestingly, pharmacologic inhibition or shRNA knockdown of GSK3alpha/beta significantly attenuated Mcl-1 down-regulation and decreased apoptosis. In a systemic AML xenograft model, dual tet-inducible knockdown of Bcl-2/Bcl-xL sharply increased BEZ235 anti-leukemic effects. In a subcutaneous xenograft model, BEZ235 and ABT-737 co-administration significantly diminished tumor growth, down-regulated Mcl-1, activated caspases, and prolonged survival. Together, these findings suggest that anti-leukemic synergism between PI3K/AKT/mTOR inhibitors and BH3 mimetics involves multiple mechanisms, including Mcl-1 down-regulation, release of Bim from Bcl-2/Bcl-xL as well as Bak and Bax from Mcl-1/Bcl-2/Bcl-xL, and GSK3alpha/beta, culminating in Bax/Bak activation and apoptosis. They also argue that combining PI3K/AKT/mTOR inhibitors with BH3-mimetics warrants attention in AML, particularly in the setting of basal AKT  activation and/or addiction.




TÍTULO / TITLE:  - Chronic lymphocytic leukemia cells induce defective LFA-1-directed T cell motility by altering Rho GTPase signaling that is reversible with lenalidomide.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Blood. 2013 Jan 16.

            ●● Enlace al texto completo (gratuito o de pago) 1182/blood-2012-08-448332

AUTORES / AUTHORS:  - Ramsay AG; Evans R; Kiaii S; Svensson L; Hogg N; Gribben JG

INSTITUCIÓN / INSTITUTION:  - Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, United Kingdom;

RESUMEN / SUMMARY:  - T lymphocytes have an essential role in adaptive immunity and rely on the activation of integrin lymphocyte function-associated antigen-1 (LFA-1) to mediate cell arrest and migration. In cancer, malignant cells modify the immune microenvironment to block effective host anti-tumor responses. Here we show for the first time that CD4 and CD8 T cells from patients with chronic lymphocytic leukemia (CLL) exhibit globally impaired LFA-1-mediated migration and that this defect is mediated by direct tumor cell contact. We show that following coculture of previously healthy T cells with CLL cells, subsequent LFA-1 engagement leads to altered Rho GTPase activation signaling by down-regulating RhoA and Rac1, while up-regulating Cdc42. Of clinical relevance, repair of this T cell defect was demonstrated using the immunomodulatory drug lenalidomide that completely rescued adhesion and motility function by restoring normal Rho GTPase activation  signaling. Our report identifies a novel cancer immune evasion mechanism whereby  tumor cells induce Rho GTPase signaling defects in T cells that prevent appropriate LFA-1 activation and motility. We believe these findings identify important biomarkers and highlight the clinical utility of immunotherapy to rescue normal T cell function in CLL that are likely to have relevance in other cancers.




TÍTULO / TITLE:  - Endoplasmic reticulum ribosome-binding protein 1 (RRBP1) overexpression is frequently found in lung cancer patients and alleviates intracellular stress-induced apoptosis through the enhancement of GRP78.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncogene. 2013 Jan 14. doi: 10.1038/onc.2012.514.

            ●● Enlace al texto completo (gratuito o de pago) 1038/onc.2012.514

AUTORES / AUTHORS:  - Tsai HY; Yang YF; Wu AT; Yang CJ; Liu YP; Jan YH; Lee CH; Hsiao YW; Yeh CT; Shen CN; Lu PJ; Huang MS; Hsiao M

INSTITUCIÓN / INSTITUTION:  - 1] Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan [2] Genomics Research Center, Academia Sinica, Taipei, Taiwan.

RESUMEN / SUMMARY:  - Lung cancer is the leading cause of cancer deaths and is the most occurring malignancy worldwide. Unraveling the molecular mechanisms involved in lung tumorigenesis will greatly improve therapy. During early tumorigenesis, rapid proliferating tumor cells require increased activity of endoplasmic reticulum (ER) for protein synthesis, folding and secretion, thereby are subjected to ER stress. Ribosome-binding protein 1 (RRBP1) was originally identified as a ribosome-binding protein located on the rough ER and associated with unfolding protein response (UPR). In this report, we investigated the role of RRBP1 in lung cancer. RRBP1 was highly expressed in lung cancer tissue, as compared with adjacent normal tissues as assessed by immunohistochemistry (IHC) using lung cancer tissue array (n=87). Knockdown of RRBP1 by short-hairpin RNAs caused ER stress and significantly reduced cell viability and tumorigenicity. This effect was associated with a significant reduction in the expression of glucose-regulated protein 78 (GRP78). UPR regulator GRP78, an anti-apoptotic protein that is widely upregulated in cancer, has a critical role in chemotherapy resistance in some cancers. According to our results, cells with a higher level of RRBP1 were more resistant to ER stress. Ectopic expression of RRBP1 alleviated apoptosis that was induced by the ER-stress agent tunicamycin, 2-deoxy-D-glucose  (2DG) or doxorubicin via enhancing GRP78 protein expression. A strong correlation was observed between the expression of RRBP1 and GRP78 in tumor biopsies using the database GSE10072. Our results also indicated that RRBP1 may involve in the regulation of mRNA stability of UPR components including ATF6 and GRP78. Taken together, RRBP1 could alleviate ER stress and help cancer cell survive. RRBP1 is  critical for tumor cell survival, which may make it a useful target in lung cancer treatment and a candidate for the development of new targeted therapeutics.Oncogene advance online publication, 14 January 2013; doi:10.1038/onc.2012.514.




TÍTULO / TITLE:  - Increased expression of discoidin domain receptor 2 (DDR2): a novel independent prognostic marker of worse outcome in breast cancer patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Med Oncol. 2013 Mar;30(1):397. doi: 10.1007/s12032-012-0397-3. Epub 2013 Jan 10.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12032-012-0397-3

AUTORES / AUTHORS:  - Ren T; Zhang J; Zhang J; Liu X; Yao L

INSTITUCIÓN / INSTITUTION:  - State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular  Biology, the Fourth Military Medical University, Changle Western Road, Xi’an, Shaanxi, 710032, People’s Republic of China.

RESUMEN / SUMMARY:  - The discoidin domain receptors, DDR1 and DDR2, have been linked with numerous human cancers. We sought to determine expression level and distribution of DDRs in human breast cancer, and investigate prognostic determinates to determine whether levels of DDRs could predict survival. Tumor samples from 122 breast cancer patients were analyzed for relative expression of DDRs. An additional 24 matched tumor and normal tissues were tested for differential expression of DDR1  and DDR2. DDR2 was found to be significantly increased by 6-fold (P = 0.0005) and DDR1 decreased (P = 0.0001) in tumor vs. normal breast tissue. DDR1 expression was not predictive for patient survival; however, DDR2 expression was significantly associated with disease-free (HR = 0.55, 95 % CI = 0.24-0.78, P = 0.026) and overall survival (HR = 0.46, 95 % CI = 0.35-0.84, P = 0.019). Multivariate analysis revealed DDR2 is an independent favorable predictor for prognosis independent of tumor stage, histology, and patient age. The present research provided the first evidence that increased DDR2 mRNA expression in primary human breast cancer might be a powerful, independent predictor of recurrence and outcome.




TÍTULO / TITLE:  - Clinical Impact of Immune Microenvironment in Stage I Lung Adenocarcinoma: Tumor  Interleukin-12 Receptor beta2 (IL-12Rbeta2), IL-7R, and Stromal FoxP3/CD3 Ratio Are Independent Predictors of Recurrence.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Clin Oncol. 2013 Feb 1;31(4):490-8. doi: 10.1200/JCO.2012.45.2052. Epub 2012 Dec 26.

            ●● Enlace al texto completo (gratuito o de pago) 1200/JCO.2012.45.2052

AUTORES / AUTHORS:  - Suzuki K; Kadota K; Sima CS; Nitadori J; Rusch VW; Travis WD; Sadelain M; Adusumilli PS

INSTITUCIÓN / INSTITUTION:  - Division of Thoracic Surgery, Center for Cell Engineering, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; adusumip@mskcc.org.

RESUMEN / SUMMARY:  - PURPOSE Mounting evidence suggests that tumor-infiltrating immune cells have prognostic value for patients with solid organ malignancies. Our aim was to investigate the prognostic significance of the immune microenvironment in patients with stage I lung adenocarcinoma (ADC). PATIENTS AND METHODS Using tissue microarray and immunohistochemistry, we investigated eight types of tumor-infiltrating immune cells in the tumor nest and tumor-associated stroma as  well as tumor expression of five cytokines in a uniform cohort of 956 patients with stage I lung ADC (478 each in training and validation cohorts). Results Although a high density of stromal forkhead box P3 (FoxP3) -positive cells was associated with shorter recurrence-free probability (RFP; P = .043), the relative proportion of stromal FoxP3 to CD3 was a stronger predictor of recurrence (5-year RFP, 85% for high v 77% for low ratio; P = .004). High expression of tumor interleukin-12 receptor beta2 (IL-12Rbeta2) was associated with better outcome (5-year RFP, 90% for high v 80% for low expression; P = .026), whereas high expression of tumor IL-7R was associated with worse outcome (5-year RFP, 76% for  high v 86% for low expression; P = .001). In multivariate analysis, these immune  markers were independently associated with recurrence. Although IL-7R remained significant for poor overall survival, all the markers remained prognostic for recurrence in patients with stages IA and IB disease as well as for patients with tumors </= 2 cm. CONCLUSION Our investigation confirms the biologic and prognostic significance of the tumor immune microenvironment for patients with stage I lung ADC and provides support for its use to stratify clinical outcome and immunotherapeutic interventions.




TÍTULO / TITLE:  - The Predictive Value of C-reactive Protein for Prognosis in Patients with Upper Tract Urothelial Carcinoma Treated with Radical Nephroureterectomy: A Multi-institutional Study.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur Urol. 2012 Dec 1. pii: S0302-2838(12)01425-X. doi: 10.1016/j.eururo.2012.11.050.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.eururo.2012.11.050

AUTORES / AUTHORS:  - Tanaka N; Kikuchi E; Shirotake S; Kanao K; Matsumoto K; Kobayashi H; Miyazaki Y; Ide H; Obata J; Hoshino K; Hayakawa N; Ito Y; Kosaka T; Kodaira K; Oyama M; Miyajima A; Momma T; Nakagawa K; Ueno M; Oya M

INSTITUCIÓN / INSTITUTION:  - Department of Urology, Keio University School of Medicine, Tokyo, Japan; Department of Urology, Saitama City Hospital, Saitama, Japan.

RESUMEN / SUMMARY:  - BACKGROUND: Few studies have discussed the prognostic impact of serum C-reactive  protein (CRP) level in upper tract urothelial carcinoma (UTUC). OBJECTIVE: To investigate whether the perioperative level of CRP provides additional prognostic information following radical nephroureterectomy (RNU). DESIGN, SETTING, AND PARTICIPANTS: A total of 564 patients with UTUC from a retrospective multi-institutional cohort were included. The median follow-up was 32 mo. INTERVENTION: All patients underwent RNU without neoadjuvant chemotherapy, while  106 patients (18.8%) received adjuvant chemotherapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Associations between perioperative CRP level and outcome were assessed using multivariate analysis. A serum CRP level >0.50mg/dl was defined as elevated. RESULTS AND LIMITATIONS: Preoperative CRP (pre-CRP) level was elevated in 136 patients (24.1%). Multivariate analysis showed that pre-CRP elevation was an independent predictor of subsequent disease recurrence (hazard ratio [HR]: 1.47 for CRP 0.51-2.00; HR: 1.89 for CRP >2.00). Five-year recurrence-free survival rates were 69.2% in patients with pre-CRP levels </=0.50mg/dl, 54.3% in patients with pre-CRP levels between 0.51 and 2.00mg/dl, and 35.4% in patients with pre-CRP levels >2.00mg/dl (p<0.001). Similar results were found in cancer-specific mortality, showing that pre-CRP elevation was an independent predictor of worse outcome (HR: 1.74 for CRP 0.51-2.00; HR: 2.31 for  CRP >2.00). In a subgroup analysis of the elevated pre-CRP group, postoperative normalisation of CRP level was an independent predictor of better outcome. This study is limited by its retrospective nature as well as its heterogeneous group of patients and variable follow-up protocols resulting from the multi-institution design. CONCLUSIONS: Serum CRP may become a possible biomarker in UTUC, suggesting that patients with an elevated pre-CRP level could be predicted to have subsequent disease recurrence and cancer-specific mortality, while postoperative normalisation of CRP level was an independent predictor for prognosis.




TÍTULO / TITLE:  - Significance of folate receptor alpha and thymidylate synthase protein expression in patients with non-small-cell lung cancer treated with pemetrexed.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Thorac Oncol. 2013 Jan;8(1):19-30. doi: 10.1097/JTO.0b013e31827628ff.

            ●● Enlace al texto completo (gratuito o de pago) 1097/JTO.0b013e31827628ff

AUTORES / AUTHORS:  - Christoph DC; Asuncion BR; Hassan B; Tran C; Maltzman JD; O’Shannessy DJ; Wynes MW; Gauler TC; Wohlschlaeger J; Hoiczyk M; Schuler M; Eberhardt WE; Hirsch FR

INSTITUCIÓN / INSTITUTION:  - Department of Medicine, Division of Medical Oncology, University of Colorado Denver, Aurora, Colorado 80045, USA.

RESUMEN / SUMMARY:  - INTRODUCTION: Folate receptor alpha (FRA) regulates cellular uptake of folates and antifolates. Information about FRA protein expression in metastatic non-small-cell lung cancer (NSCLC) is limited. We investigated FRA as a biomarker for pemetrexed-based chemotherapy and compared it with thymidylate synthase (TS), the main target of pemetrexed. METHODS: Pretreatment tumor specimens from 207 patients with advanced NSCLC were assessed for FRA and TS protein expression by immunohistochemistry using the H-score (range, 0-300) and correlated to patients’ clinicopathological data, radiographic response, progression-free survival (PFS), and overall survival (OS). RESULTS: Low total (cytoplasmic and nuclear) TS protein expression (H-score < 210) was associated with improved PFS (median: 5.6  versus 3.5 months; hazard ratio [HR] = 0.6379, p = 0.0131) and prolonged OS (median: 22.5 versus 11.5 months; HR = 0.5680,p = 0.0107). An association between lower TS levels and response to pemetrexed-based therapy was found-mean H-score 187 +/- 5, median 180 for responders versus mean H-score 201 +/- 4, median 210, for non-responders, p = 0.0244. High intracellular FRA expression (H-score >/=110) was associated with prolonged OS (28.9 versus 11.7 months, HR = 0.5316, p = 0.0040) and a trend for association with PFS (5.6 versus 4.1 months, HR = 0.7395, p = 0.0801) was noted. Membranous FRA expression was seen in 83% of patients, moreover, high membranous expression (H-score >/=20) was associated with improved PFS (5.6 versus 3.7 months, HR = 0.6445, p = 0.0306) and OS (22.1 versus 11.5 months, HR = 0.5378, p = 0.0131). CONCLUSIONS: A large number of NSCLC patients have high expression of FRA and/or a low level of TS expression. Expression levels of FRA and TS were associated with clinical benefit from pemetrexed therapy.




TÍTULO / TITLE:  - Adjuvant therapy with tamoxifen compared to aromatase inhibitors for 257 male breast cancer patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Breast Cancer Res Treat. 2013 Jan;137(2):465-70. doi: 10.1007/s10549-012-2355-3.  Epub 2012 Dec 9.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10549-012-2355-3

AUTORES / AUTHORS:  - Eggemann H; Ignatov A; Smith BJ; Altmann U; von Minckwitz G; Rohl FW; Jahn M; Costa SD

INSTITUCIÓN / INSTITUTION:  - University Women’s Clinic, Otto-von-Guericke University, Gerhart-Hauptmann Str. 35, 39108, Magdeburg, Germany, holm.eggemann@med.ovgu.de.

RESUMEN / SUMMARY:  - To determine the impact of adjuvant treatment with tamoxifen and aromatase inhibitors (AI) on the survival of men with breast cancer. We analyzed 257 male patients with hormone-receptor-positive breast cancer from numerous German population-based cancer registries treated with tamoxifen (N = 207) or aromatase  inhibitors (N = 50). The median follow-up was 42.2 (range 2-115) months. Median age at diagnosis was 68 (range 36-91) years. Thirty-seven (17.9 %) patients treated with tamoxifen and 16 (32.0 %) patients treated with AI died (log rank p  = 0.007). After the adjustment for the patient’s age, tumor size, node status, and tumor grading, the AI treatment was linked to a 1.5-fold increase in risk of  mortality compared to tamoxifen (HR 1.55; 95 % CI: 1.13-2.13; p = 0.007). The overall survival in male breast cancer was significantly better after adjuvant treatment with tamoxifen compared to an aromatase inhibitor. Tamoxifen should be  considered as the treatment of choice for hormone-receptor-positive male breast cancer.




TÍTULO / TITLE:  - High throughput kinase inhibitor screens reveal TRB3 and MAPK-ERK/TGFbeta pathways as fundamental Notch regulators in breast cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Proc Natl Acad Sci U S A. 2013 Jan 29;110(5):1714-9. doi: 10.1073/pnas.1214014110. Epub 2013 Jan 14.

            ●● Enlace al texto completo (gratuito o de pago) 1073/pnas.1214014110

AUTORES / AUTHORS:  - Izrailit J; Berman HK; Datti A; Wrana JL; Reedijk M

INSTITUCIÓN / INSTITUTION:  - Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Toronto, ON, Canada M5G 2M9.

RESUMEN / SUMMARY:  - Expression of the Notch ligand Jagged 1 (JAG1) and Notch activation promote poor-prognosis in breast cancer. We used high throughput screens to identify elements responsible for Notch activation in this context. Chemical kinase inhibitor and kinase-specific small interfering RNA libraries were screened in a  breast cancer cell line engineered to report Notch. Pathway analyses revealed MAPK-ERK signaling to be the predominant JAG1/Notch regulator and this was supported by gene set enrichment analyses in 51 breast cancer cell lines. In accordance with the chemical screen, kinome small interfering RNA high throughput screens identified Tribbles homolog 3 (TRB3), a known regulator of MAPK-ERK, among the most significant hits. We demonstrate that TRB3 is a master regulator of Notch through the MAPK-ERK and TGFbeta pathways. Complementary in vitro and in vivo studies underscore the importance of TRB3 for tumor growth. These data demonstrate a dominant role for TRB3 and MAPK-ERK/TGFbeta pathways as Notch regulators in breast cancer, establishing TRB3 as a potential therapeutic target.




TÍTULO / TITLE:  - Rapid loss of response after withdrawal of treatment with azacitidine: a case series in patients with higher-risk myelodysplastic syndromes or chronic myelomonocytic leukemia.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur J Haematol. 2013 Jan 21. doi: 10.1111/ejh.12079.

            ●● Enlace al texto completo (gratuito o de pago) 1111/ejh.12079

AUTORES / AUTHORS:  - Voso MT; Breccia M; Lunghi M; Poloni A; Niscola P; Finelli C; Bari A; Musto P; Zambello R; Fianchi L; Alimena G; Leone G

INSTITUCIÓN / INSTITUTION:  - Department of Hematology, Universita’ Cattolica S. Cuore, Rome.

RESUMEN / SUMMARY:  - In patients with myelodysplastic syndromes (MDS), the likelihood of having a sustained response to azacitidine is increased by maximizing treatment duration.  This is important as prognosis post-relapse is poor. There is also the concern that early termination of treatment may result in rapid disease progression. We reviewed outcomes in 13 patients who discontinued azacitidine (decitabine in one  patient), while still responding to the treatment. Most patients rapidly relapsed; median time to progression was 5.4 months. Reasons for treatment discontinuation included comorbidities, infections and patient choice. These findings illustrate the risk of prematurely terminating azacitidine therapy in MDS. © 2013 John Wiley & Sons A/S.




TÍTULO / TITLE:  - A 12-Gene Set Predicts Survival Benefits from Adjuvant Chemotherapy in Non-Small-Cell Lung Cancer Patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Jan 28.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-2321

AUTORES / AUTHORS:  - Tang H; Xiao G; Behrens C; Schiller J; Allen J; Chow CW; Suraokar M; Corvalan A; Mao JH; White M; Wistuba II; Minna JD; Xie Y

INSTITUCIÓN / INSTITUTION:  - Department of Clinical Sciences, University of Texas Southwesten Medical Center.

RESUMEN / SUMMARY:  - PURPOSE: Prospectively identifying who will benefit from adjuvant chemotherapy (ACT) would improve clinical decisions for non-small-cell lung cancer (NSCLC) patients. In this study, we aim to develop and validate a functional gene set that predicts the clinical benefits of ACT in NSCLC. EXPERIMENTAL DESIGN: An 18-hub-gene prognosis signature was developed through a systems biology approach, and its prognostic value was evaluated in six independent cohorts. The 18-hub-gene set was then integrated with genome-wide functional (RNAi) data and genetic aberration data to derive a 12-gene predictive signature for ACT benefits in NSCLC. RESULTS: Using a cohort of 442 Stage I-III NSCLC patients who underwent surgical resection, we identified an 18-hub-gene set which robustly predicted the prognosis of patients with adenocarcinoma in all validation datasets across four  microarray platforms. The hub genes, identified through a purely data-driven approach, have significant biological implications in tumor pathogenesis, including NKX2-1, Aurora Kinase A, PRC1, CDKN3, MBIP, RRM2. The 12-gene predictive signature was successfully validated in two independent datasets (N=90 and N=176). The predicted benefit group showed significant improvement in survival after ACT (UT Lung SPORE data: hazard ratio=0.34, p=0.017; JBR.10 clinical trial data: hazard ratio=0.36, p=0.038), while the predicted non-benefit group showed no survival benefit for two datasets (hazard ratio=0.80, p=0.70; hazard ratio= 0.91, p=0.82). CONCLUSIONS: This is the first study to integrate genetic aberration, genome-wide RNAi data, and mRNA expression data to identify a functional gene set that predicts which resectable patients with non-small-cell lung cancer will have a survival benefit with ACT.




TÍTULO / TITLE:  - Multicenter Validation of Cyclin D1, MCM7, TRIM29, and UBE2C as Prognostic Protein Markers in Non-Muscle-Invasive Bladder Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Am J Pathol. 2013 Feb;182(2):339-49. doi: 10.1016/j.ajpath.2012.10.017. Epub 2012 Nov 28.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ajpath.2012.10.017

AUTORES / AUTHORS:  - Fristrup N; Birkenkamp-Demtroder K; Reinert T; Sanchez-Carbayo M; Segersten U; Malmstrom PU; Palou J; Alvarez-Mugica M; Pan CC; Ulhoi BP; Borre M; Orntoft TF; Dyrskjot L

INSTITUCIÓN / INSTITUTION:  - Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.

RESUMEN / SUMMARY:  - Transcripts from the four genes encoding cyclin D1, MCM7, TRIM29, and UBE2C have  previously been included in gene expression signatures for outcome prediction in  stage Ta/T1 urothelial carcinomas. We investigated the prognostic value of the protein expressions in Ta/T1 urothelial carcinomas patients. We used four different tissue microarrays (TMAs) with a total of 859 Ta/T1 urothelial carcinomas from Danish, Swedish, Spanish, and Taiwanese patient cohorts with long-term follow-up. Protein expression was measured by IHC, and antibody specificity was validated by Western blotting. We found the expression of cyclin  D1, MCM7, TRIM29, and UBE2C to be significantly associated with progression to muscle-invasive bladder cancer (log-rank test; P < 0.001) in the Danish training  cohort (n = 283). Multivariate Cox regression analysis identified cyclin D1 (P =  0.003), TRIM29 (P = 0.001), and UBE2C (P < 0.001) as independent prognostic markers. The prognostic value of the four proteins was validated in a joint validation cohort from Sweden, España, and Taiwan (n = 576). Computer-assisted image analysis of the prognostic markers produced results comparable to those obtained by manual scoring. Finally, a four-protein maximum-likelihood classifier was trained on the Danish training cohort and applied to the validation cohort. The four protein markers may help optimize treatment of patients with Ta/T1 bladder cancer. Additional prospective studies are needed for further validation  of their clinical relevance.




TÍTULO / TITLE:  - CD30 expression defines a novel subset of diffuse large B-cell lymphoma with favorable prognosis and distinct gene expression signature: a report from The International DLBCL Rituximab-CHOP Consortium Program Study.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Blood. 2013 Jan 23.

            ●● Enlace al texto completo (gratuito o de pago) 1182/blood-2012-10-461848

AUTORES / AUTHORS:  - Hu S; Xu-Monette ZY; Balasubramanyam A; Manyam GC; Visco C; Tzankov A; Liu WM; Miranda RN; Zhang L; Montes-Moreno S; Dybkaer K; Chiu A; Orazi A; Zu Y; Bhagat G; Richards KL; Hsi ED; Choi WW; van Krieken JH; Huang Q; Huh J; Ai W; Ponzoni M; Ferreri AJ; Zhao X; Winter JN; Zhang M; Li L; Moller MB; Piris MA; Li Y; Go RS; Wu L; Medeiros LJ; Young KH

INSTITUCIÓN / INSTITUTION:  - Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States;

RESUMEN / SUMMARY:  - CD30, originally identified as a cell-surface marker of Reed-Sternberg and Hodgkin cells of classical Hodgkin lymphoma, is also expressed by several types of non-Hodgkin lymphoma, including a subset of diffuse large B-cell lymphoma (DLBCL). However, the prognostic and biological importance of CD30 expression in  DLBCL is unknown. Here we report that CD30 expression is a favorable prognostic factor in a cohort of 903 de novo DLBCL patients. CD30 was expressed in approximately 14% of DLBCL patients. Patients with CD30(+) DLBCL had superior 5-year overall survival (CD30(+) 79% vs CD30- 59%, P=.001) and progression-free survival (P=.003). The favorable outcome of CD30 expression was maintained in both the germinal center B-cell and activated B-cell subtypes. Gene-expression profiling revealed the up-regulation of genes encoding negative regulators of NF-kB activation and lymphocyte survival, and down-regulation of those involving  B-cell receptor signaling and B-cell proliferation, as well as prominent cytokine and stromal signatures in CD30(+) DLBCL patients, suggesting a distinct molecular basis for its favorable outcome. Given the superior prognostic value, unique gene-expression signature and significant value of CD30 as a therapeutic target for Brentuximab vedotin in ongoing successful clinical trials, it would be appropriate to consider CD30(+) DLBCL as a distinct subgroup of DLBCL.




TÍTULO / TITLE:  - CA 15-3 is a predictive and prognostic biomarker in patients with metastasized breast cancer undergoing Selective Internal Radiation Therapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Clin Pharmacol Ther. 2013 Jan;51(1):63-66.

AUTORES / AUTHORS:  - Fahmueller YN; Nagel D; Hoffmann RT; Tatsch K; Jakobs T; Stieber P; Holdenrieder S

INSTITUCIÓN / INSTITUTION:  - Institute of Clinical Chemistry, Institute of Clinical Radiology, Clinics of Nuclear Medicine, University-Hospital Munich-Grosshadern, Munich, Institute of Radiological Diagnostics, Hospital of the Technical University Dresden, Dresden,  Department of Nuclear Medicine, Municipal Hospital Karlsruhe Inc. Karlsruhe, Department of Diagnostics and Interventional Radiology, Hospital Barmherzige Bruder Munich, Munich, and Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.




TÍTULO / TITLE:  - Persistence in patients with breast cancer treated with tamoxifen or aromatase inhibitors: a retrospective database analysis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Breast Cancer Res Treat. 2013 Jan 20.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10549-013-2417-1

AUTORES / AUTHORS:  - Hadji P; Ziller V; Kyvernitakis J; Bauer M; Haas G; Schmidt N; Kostev K

INSTITUCIÓN / INSTITUTION:  - Department of Gynecology, Endocrinology and Oncology, Phillips-University of Marburg, Marburg, Germany.

RESUMEN / SUMMARY:  - Compliance and persistence are often underestimated in breast cancer (BC) treatment. The aim of our study was to analyze the persistence with tamoxifen (TAM) and aromatase inhibitors (AI) in postmenopausal women with hormone-receptor-positive BC and to identify determinants of non-persistence. We  used data of the Disease Analyzer database (IMS HEALTH, Germany) including 2,067  general practices and 397 gynecological practices. Out of a dataset of 15 million patients, we identified BC patients with a first-time TAM or AI prescriptions from October 2001 to December 2010. For persistence analyses, 12,412 women on tamoxifen, 2,796 on anastrozole, 647 on exemestane, and 1,657 on letrozole met the inclusion/exclusion criteria. Within 3 years of follow-up, the discontinuation rates increased to 52.2 % for tamoxifen, 47 % for anastrozole, 55.1 % for exemestane, and 44.3 % for letrozole treated women. A minor proportion of patients switched to a different endocrine treatment; 33 % tamoxifen, 20 % anastrozole, 22.9 % exemestane, and 23 % letrozole. The multivariate hazard ratios of the cox regression models showed that patients younger than 50 were most likely to discontinue initial therapy when compared with the reference group of women over 70 (p < 0.001). In contrast, patients treated in gynecologist practice had significantly longer persistence than patients who obtained their prescriptions in general practitioner practice (p < 0.001). In addition, the presence of the co morbidities like diabetes (p < 0.001) or depression (p < 0.002) was also associated with decreased risk of treatment discontinuation. Persistence with all endocrine treatments in women with hormone-receptor-positive BC is low and needs to be significantly increased to improved outcome in clinical practice. Further research is required to understand this complex issue.




TÍTULO / TITLE:  - Independent Validation of a Prognostic Genomic Signature (ColoPrint) for Patients With Stage II Colon Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Ann Surg. 2013 Jan 4.

            ●● Enlace al texto completo (gratuito o de pago) 1097/SLA.0b013e31827c1180

AUTORES / AUTHORS:  - Maak M; Simon I; Nitsche U; Roepman P; Snel M; Glas AM; Schuster T; Keller G; Zeestraten E; Goossens I; Janssen KP; Friess H; Rosenberg R

INSTITUCIÓN / INSTITUTION:  - *Department of Surgery, Klinikum rechts der Isar, Technische Universitat Munchen, Munich, Germany daggerAgendia NV, Amsterdam, The Netherlands Departments of double daggerEpidemiology and Statistics section signPathology, Technische Universitat Munchen, Munich, Germany paragraph signDepartment of Surgery, Leiden  University Medical Center, Leiden, The Netherlands ||Department of Surgery, Kantonsspital, Baden, Switzerland.

RESUMEN / SUMMARY:  - OBJECTIVES:: The aim of this study was to independently validate a genomic signature developed both to assess recurrence risk in stage II patients and to assist in treatment decisions. BACKGROUND:: Adjuvant therapy is recommended for high-risk patients with stage II colon cancer, but better tools to assess the patients’ prognosis accurately are still required. METHODS:: Previously, an 18-gene signature had been developed and validated on an independent cohort, using full genome microarrays. In this study, the gene signature was translated and validated as a robust diagnostic test (ColoPrint), using customized 8-pack arrays. In addition, clinical validation of the diagnostic ColoPrint assay was performed on 135 patients who underwent curative resection (R0) for colon cancer  stage II in Munich. Fresh-frozen tissue, microsatellite instability status, clinical parameters, and follow-up data for all patients were available. The diagnostic ColoPrint readout was determined blindly from the clinical data. RESULTS:: ColoPrint identified most stage II patients (73.3%) as at low risk. The 5-year distant-metastasis free survival was 94.9% for low-risk patients and 80.6% for high-risk patients. In multivariable analysis, ColoPrint was the only significant parameter to predict the development of distant metastasis with a hazard ratio of 4.28 (95% confidence interval, 1.36-13.50; P = 0.013). Clinical risk parameters from the American Society of Clinical Oncology (ASCO) recommendation did not add power to the ColoPrint classification. Technical validation of ColoPrint confirmed stability and reproducibility of the diagnostic platform. CONCLUSIONS:: ColoPrint is able to predict the development of distant metastasis of patients with stage II colon cancer and facilitates the identification of patients who may be safely managed without chemotherapy.




TÍTULO / TITLE:  - Telomerase is an independent prognostic marker of overall survival in patients with colorectal cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Br J Cancer. 2013 Jan 15. doi: 10.1038/bjc.2012.602.

            ●● Enlace al texto completo (gratuito o de pago) 1038/bjc.2012.602

AUTORES / AUTHORS:  - Bertorelle R; Briarava M; Rampazzo E; Biasini L; Agostini M; Maretto I; Lonardi S; Friso ML; Mescoli C; Zagonel V; Nitti D; De Rossi A; Pucciarelli S

INSTITUCIÓN / INSTITUTION:  - Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto, IRCCS, Via Gattamelata 64, 35128 Padova, Italy.

RESUMEN / SUMMARY:  - Background:Colorectal cancer (CRC) is an important cause of cancer-related death. Prediction of recurrence is an important issue in the treatment of disease, particularly for stage II patients. The level of telomere-specific reverse transcriptase (hTERT), the catalytic component of the telomerase complex, increases along with CRC progression, but its prognostic value is still unclear.Methods:One hundred and thirty-seven CRC patients were studied for hTERT  expression in tumour cells by real-time PCR. hTERT level was evaluated as a prognostic factor of overall survival (OS) in all patients and of disease recurrence in a subgroup of 50 stage II patients.Results:The median hTERT level was 93.8 copies (interquartile range 48-254). Patients with high hTERT levels (above the median) showed a significantly worse survival than those with low hTERT levels (below the median; log-rank test P<0.0001; hazard ratio (HR)=3.30 (95% confidence interval (CI) 1.98-5.52); P<0.0001). The negative prognostic value of high hTERT level is independent of the pathological stage and microsatellite instability (HR=2.09 (95% CI 1.20-3.64), P=0.009). Moreover, in stage II CRC, high hTERT levels identified patients with a higher risk of disease recurrence (HR=3.06 (95% CI 1.03-9.04), P=0.043) and death (HR=3.24 (95% CI 1.37-7.71), P=0.008).Conclusion:hTERT level is an independent prognostic marker of OS in CRC patients. In addition, assessment of hTERT level could improve stratification of stage II CRC patients for the risk of disease recurrence.British Journal of Cancer advance online publication, 15 January 2013; doi:10.1038/bjc.2012.602 www.bjcancer.com.




TÍTULO / TITLE:  - Role of EGFR SNPs in survival of advanced lung adenocarcinoma patients treated with Gefitinib.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Gene. 2013 Jan 9. pii: S0378-1119(12)01646-0. doi: 10.1016/j.gene.2012.12.087.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.gene.2012.12.087

AUTORES / AUTHORS:  - Zhang L; Yuan X; Chen Y; Du XJ; Yu S; Yang M

INSTITUCIÓN / INSTITUTION:  - Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.

RESUMEN / SUMMARY:  - AIM: As a novel molecularly targeting agent for non-small-cell lung cancer (NSCLC), Gefitinib can block its tyrosine kinase activity of the epidermal growth factor receptor (EGFR). Genetic variations in EGFR may affect its protein function or expression and lead to diverse outcomes in NSCLC patients after Gefitinib therapy. Therefore, this prospective study examined whether EGFR single nucleotide polymorphisms (SNPs) are associated with different survival time in advanced lung adenocarcinoma patients treated with Gefitinib. METHODS: One hundred and twenty-eight patients with stage IIIB or IV lung adenocarcinoma receiving Gefitinib target therapy between 2008 and 2010 were recruited in this study. Six EGFR haplotype-tagging SNPs were genotyped by the Sequenom MassArray system. Survival by different genotypes was compared using Kaplan-Meier methods.  Cox proportional hazards models were applied to estimate the effect of prognostic factors on overall survival (OS) and progression-free survival (PFS). RESULTS: After the median 16.6months of follow-up, the unfavorable EGFR rs2293347AA or GA  genotype was significantly correlated with shorter OS (AA vs. GG: 2.0 vs. 21.0months; hazard ratio (HR)=2.44, 95% confidence interval (CI)=1.06-5.56; P=0.036; GA vs. GG: 15.0 vs. 21.0months; HR=1.75, 95%CI=1.08-2.86, P=0.025) compared with the favorable rs2293347GG genotype. The prognostic significance of  EGFR rs4947492 polymorphism on OS also existed (GG carriers vs. AA carriers: median OS=24.6 vs. 14.9months, HR=0.29, 95%CI=0.10-0.83, P=0.021). No significant associations were found among other EGFR SNPs and survival. CONCLUSION: EGFR rs2293347 and rs4947492 SNPs might be potential predictive markers of OS in advanced lung adenocarcinoma patients treated with Gefitinib.




TÍTULO / TITLE:  - Erratum to: Identification of clinical predictive factors of oxaliplatin-induced  chronic peripheral neuropathy in colorectal cancer patients treated with adjuvant Folfox IV.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Support Care Cancer. 2013 Jan 25.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00520-013-1724-8

AUTORES / AUTHORS:  - Vincenzi B; Frezza AM; Schiavon G; Spoto C; Silvestris N; Addeo R; Catalano V; Graziano F; Santini D; Tonini G

INSTITUCIÓN / INSTITUTION:  - Medical Oncology, Universita Campus Bio-Medico, Via Alvaro del Portillo 200, 00128, Rome, Italy.




TÍTULO / TITLE:  - Identification of clinical predictive factors of oxaliplatin-induced chronic peripheral neuropathy in colorectal cancer patients treated with adjuvant Folfox  IV.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Support Care Cancer. 2012 Nov 30.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00520-012-1667-5

AUTORES / AUTHORS:  - Vincenzi B; Frezza AM; Schiavon G; Spoto C; Addeo R; Catalano V; Graziano F; Santini D; Tonini G

INSTITUCIÓN / INSTITUTION:  - Medical Oncology, Universita Campus Bio-Medico, Via Alvaro del Portillo 200, 00128, Rome, Italy.

RESUMEN / SUMMARY:  - PURPOSE: Oxaliplatin-induced neuropathy is a dose-related side effect which occurs in almost 40 % of patients treated with oxaliplatin. Aim of the present study was to identify reliable clinical factors predicting its development and duration. METHODS: One hundred sixty-nine completely resected colorectal cancer patients treated with adjuvant Folfox IV regimen were retrospectively included. The following pre-treatment clinical parameters were collected: hypocalcaemia, hypomagnesaemia, hypoalbuminaemia, anaemia, diabetes, chronic renal failure (CRF), folate deficiency, vitamin B(12) deficiency, number of cycles received and habit to alcohol consumption. Incidence, grade (NCI-CTCAE v.3) and duration of neuropathy were recorded. RESULTS: Incidence of neuropathy was found to be higher in patients with pre-treatment anaemia (p = 0.001), hypoalbuminaemia (p = 0.01) and hypomagnesaemia (p = 0.001) as well in those with habit to alcohol consumption (p = 0.003). Neuropathy durations were conversely associated with age, being longer in younger patients (p = 0.03), and again with hypoalbuminaemia (p = 0.04) and hypomagnesaemia (p = 0.002). No correlation was found with gender, hypocalcaemia, diabetes and CRF. The correlation between vitamin B(12) and folate levels and the development of neurotoxicity were not analysed because of the high number of missing data in the population. CONCLUSIONS: Age, anaemia, hypoalbuminaemia, hypomagnesaemia and alcohol consumption are reliable and easily assessable clinical factors predicting incidence and length of oxaliplatin-induced neuropathy.




TÍTULO / TITLE:  - Isolated central nervous system relapse in patient with blast-crisis chronic myeloid leukemia in durable complete cytogenetic remission on dasatinib treatment: pharmacokinetics and ABL mutation analysis in cerebrospinal fluid.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Leuk Lymphoma. 2012 Dec 22.

            ●● Enlace al texto completo (gratuito o de pago) 3109/10428194.2012.745933

AUTORES / AUTHORS:  - Zhou HS; Dai M; Wei Y; Wang Q; Xu N; Yin C; Meng F

INSTITUCIÓN / INSTITUTION:  - Department of Hematology, Nanfang Hospital, Southern Medical University , Guangzhou , China.




TÍTULO / TITLE:  - A Phase II Study of Sorafenib in Patients with Platinum-Pretreated, Advanced (Stage IIIb or IV) Non-Small Cell Lung Cancer with a KRAS Mutation.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Jan 23.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-1779

AUTORES / AUTHORS:  - Dingemans AM; Mellema WW; Groen HJ; van Wijk A; Burgers SA; Kunst PW; Thunnissen E; Heideman DA; Smit EF

INSTITUCIÓN / INSTITUTION:  - Authors’ Affiliations: Department of Pulmonary Diseases and GROW- School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht; Departments of Pulmonology and Pathology, VU University Medical Center; Department of Thoracic Oncology, Netherlands Cancer Institute; Department of Pulmonology, Academic Medical Center, Amsterdam; and Department of Pulmonology, University Medical Center Groningen, Groningen, the Netherlands.

RESUMEN / SUMMARY:  - PURPOSE: Sorafenib inhibits the Ras/Raf pathway, which is overactive in cancer patients with a KRAS mutation. We hypothesized that patients with non-small cell  lung cancer (NSCLC) with KRAS mutation will benefit from treatment with sorafenib.EXPERIMENTAL DESIGN: In this phase II study, patients with KRAS-mutated, stage IIIb or IV NSCLC that progressed after at least one platinum-containing regimen were treated with sorafenib. Treatment consisted of sorafenib 400 mg twice daily until disease progression or unacceptable toxicity.  Pretreatment serum from each patient was obtained to predict outcome using a proteomic assay (VeriStrat). Primary endpoint was disease control rate (DCR) at 6 weeks.RESULTS: Fifty-nine patients were entered between May 2010 and February 2011. Fifty-seven patients started sorafenib. Mean age was 58.5 (SD = +/-8.1) years, 16 male/41 female, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0/1/2 24/30/3. At 6 weeks, 5 partial response, 25 stable disease, and 27 progressive disease were observed; DCR was 52.6%. Median duration of treatment was 9 weeks. The median progression-free survival (PFS) was 2.3 months and median overall survival (OS) was 5.3 months. Patients with a prediction of good prognosis according to VeriStrat serum proteomics assay showed a significantly superior PFS [HR, 1.4; 95% confidence interval (CI), 1.0-1.9] but not OS (HR, 1.3; 95% CI, 0.9-1.7). Sorafenib-related grade III/IV toxicity was reported in 10 patients (17.5%); all but one patient experienced grade III skin toxicity (14.0%) or grade III gastrointestinal toxicity (8.8%).CONCLUSION: Treatment with sorafenib has relevant clinical activity in patients with NSCLC harboring KRAS mutations. Further randomized study with this agent is warranted as single-agent  or combination therapy. Clin Cancer Res; 19(3); 1-9. ©2012 AACR.




TÍTULO / TITLE:  - Predictive value of epidermal growth factor receptor expression for first-line chemotherapy plus cetuximab in patients with head and neck and colorectal cancer: Analysis of data from the EXTREME and CRYSTAL studies.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur J Cancer. 2012 Dec 19. pii: S0959-8049(12)00914-8. doi: 10.1016/j.ejca.2012.11.018.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ejca.2012.11.018

AUTORES / AUTHORS:  - Licitra L; Storkel S; Kerr KM; Van Cutsem E; Pirker R; Hirsch FR; Vermorken JB; von Heydebreck A; Esser R; Celik I; Ciardiello F

INSTITUCIÓN / INSTITUTION:  - Head and Neck Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori,  Milan, Italy.

RESUMEN / SUMMARY:  - BACKGROUND: The phase III EXTREME and CRYSTAL studies demonstrated that the addition of cetuximab to chemotherapy significantly improved survival in the first-line treatment of recurrent/metastatic squamous cell carcinoma of the head  and neck (SCCHN) and KRAS wild-type metastatic colorectal cancer (mCRC). In advanced non-small-cell lung cancer (NSCLC), high EGFR expression was identified  as a tumour biomarker that can predict survival benefit associated with the addition of cetuximab to first-line chemotherapy. We investigated whether tumour  EGFR expression level was predictive of cetuximab benefit in EXTREME and CRYSTAL  study patients. METHODS: Prospectively collected tumour immunohistochemistry data were used to generate an EGFR immunohistochemistry score (scale 1-300) for patients in the EXTREME and CRYSTAL studies. For each study, the association between tumour immunohistochemistry score and cetuximab benefit was investigated. The EXTREME and CRYSTAL studies are registered with Clinical Trials.gov, numbers  NCT00122460 and NCT00154102, respectively. FINDINGS: Tumour EGFR immunohistochemistry data were available for 411 of 442 (93%) patients from the EXTREME study intention-to-treat (ITT) population and 664 of 666 (100%) patients  from the ITT population of the CRYSTAL study with EGFR-expressing, KRAS wild-type disease. The distribution of immunohistochemistry scores was similar between the  treatment arms of each study, but differed between studies. A clinically relevant benefit for progression-free and overall survival associated with the addition of cetuximab to chemotherapy was seen across the full score range in EXTREME study patients. Similarly, CRYSTAL study patients derived a clinical benefit across the full score range, with no meaningful association between EGFR expression level and benefit. INTERPRETATION: The addition of cetuximab to chemotherapy improved survival in the first-line treatment of recurrent/metastatic SCCHN and KRAS wild-type mCRC regardless of tumour EGFR expression level, indicating that in contrast to findings in NSCLC, EGFR expression level is not a clinically useful predictive biomarker in these settings.




TÍTULO / TITLE:  - Gene mutation profiles and prognostic implications in Korean patients with T-lymphoblastic leukemia.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Ann Hematol. 2013 Jan 25.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00277-012-1664-2

AUTORES / AUTHORS:  - Huh HJ; Lee SH; Yoo KH; Sung KW; Koo HH; Jang JH; Kim K; Kim SJ; Kim WS; Jung CW; Lee KO; Kim SH; Kim HJ

INSTITUCIÓN / INSTITUTION:  - Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul, 135-710, South Korea.

RESUMEN / SUMMARY:  - Genetic alterations implicated in the leukemogenesis of T cell acute lymphoblastic leukemia (T-ALL) have been identified in recent years. In this study, we investigated gene mutation profiles and prognostic implications in a series of Korean T-ALL patients. The study patients were 29 Korean patients with  T-ALL; 13 adults (45 %) and 16 children (55 %; male-to-female ratio, 25:4). Clinical, hematologic, and cytogenetic findings were reviewed. We performed mutation analyses for NOTCH1, FBXW7, PHF6, and IL7R genes and survival analyses according to the mutational status. Gene mutations were identified in 66 % of the patients in our series (19/29). Eighteen patients (62 %) had NOTCH1/FBXW7 mutations. Sixteen patients (55 %) had NOTCH1 mutations including nine novel mutations, and eight patients (28 %) had known FBXW7 mutations. Eight patients (28 %; six males and two females) had PHF6 mutations including four novel mutations. Three patients (10 %) had IL7R mutations, which were all novel in-frame insertion or deletion-insertions. The gene mutation profile combined with cytogenetics and FISH study for the p16 gene detected genetic aberrations in 90 % of patients (26/29). There was no significant difference in the frequency of gene mutations between the pediatric and adult patients with T-ALL. Survival analyses suggested a favorable prognostic implication of NOTCH1 mutations in adult T-ALL. Gene mutation studies for NOTCH1, FBXW7, PHF6, and IL7R could detect genetic alterations in a majority of Korean T-ALL patients with novel mutations.  We observed similar mutation profiles between adult and pediatric T-ALL, and a favorable prognostic implication of NOTCH1 mutations in adult T-ALL.




TÍTULO / TITLE:  - Effect of HER2 on prognosis and benefit from peri-operative chemotherapy in early oesophago-gastric adenocarcinoma in the MAGIC trial.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Ann Oncol. 2012 Dec 11.

            ●● Enlace al texto completo (gratuito o de pago) 1093/annonc/mds622

AUTORES / AUTHORS:  - Okines AF; Thompson LC; Cunningham D; Wotherspoon A; Reis-Filho JS; Langley RE; Waddell TS; Noor D; Eltahir Z; Wong R; Stenning S

INSTITUCIÓN / INSTITUTION:  - Department of Medicine, The Royal Marsden NHS Foundation Trust, London and Surrey.

RESUMEN / SUMMARY:  - BackgroundPerioperative epirubicin, cisplatin and fluorouracil (ECF) chemotherapy improves survival in operable oesophago-gastric cancer [Adjuvant Gastric Cancer Infusional Chemotherapy (MAGIC) trial HR 0.75 (0.6-0.93)]. HER2 amplification is  reported to predict enhanced benefit from anthracyclines in breast cancer. We sought to define whether HER2 predicts benefit from ECF in oesophago-gastric cancer.Patients and methodsDiagnostic biopsies and/or resection specimens were collected from 415 of 503 MAGIC trial patients (82.5%). HER2 was evaluated by immunohistochemistry (IHC) and brightfield dual in situ hybridisation (BDISH) in  tissue microarrays. The prognostic and predictive impact of HER2 status was investigated.ResultsConcordance between HER2 over-expression (IHC3+) and amplification was 96%. Results of HER2 assessment in biopsy and resection specimens were concordant in 92.9% (145/156). HER2 positive rate (IHC3+, or IHC2+/BDISH positive) was 10.9% in the whole cohort and 10.4% in resection specimens. A further 4.0% of resections were IHC negative/BDISH positive. HER2 status was neither prognostic, nor (in pre-treatment biopsies) predicted enhanced benefit from chemotherapy [HER2 positive HR 0.74 (0.14-3.77); HER2 negative HR 0.58 (0.41-0.82), interaction P = 0.7]. However, the power of the predictive analysis was limited by the small number of HER2 positive pre-treatment biopsies.ConclusionsHER2 status is not an independent prognostic biomarker in early oesophago-gastric adenocarcinoma.




TÍTULO / TITLE:  - DNA Ploidy is an Independent Predictor of Survival in Breast Invasive Ductal Carcinoma: A Long-term Multivariate Analysis of 393 Patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Ann Surg Oncol. 2012 Dec 20.

            ●● Enlace al texto completo (gratuito o de pago) 1245/s10434-012-2804-6

AUTORES / AUTHORS:  - Pinto AE; Pereira T; Santos M; Branco M; Dias A; Silva GL; Ferreira MC; Andre S

INSTITUCIÓN / INSTITUTION:  - Servico de Anatomia Patologica, Instituto Portugues de Oncologia de Lisboa, EPE,  Lisbon, Portugal, aepinto@ipolisboa.min-saude.pt.

RESUMEN / SUMMARY:  - PURPOSE: To evaluate “classic” prognostic parameters, as well as DNA ploidy and S-phase fraction (SPF), in relation to disease-free (DFS) and disease-specific (DSS) survival in breast invasive ductal carcinoma (IDC) with long-term follow-up study. METHODS: The study involved 393 patients with IDC and median follow-up of  134 months (50-240). Histological grading, tumor size, axillary nodal involvement, pathological staging and hormone receptor status were considered as  established prognostic markers. Ploidy and SPF were determined prospectively by DNA flow cytometry using fresh/frozen tissue. A Cox regression model was used for statistical analysis of the prognostic variables. RESULTS: There were 105 (26.7 %) deaths and 140 (35.6 %) disease recurrences during follow-up. Two hundred thirty-one (58.8 %) tumors were aneuploid. High SPF and aneuploidy were associated with tumors with higher grade of differentiation, greater size and negative hormone receptors. Higher SPF and advanced disease stage are correlated. In univariate analysis, all the clinicopathological and cytometric features, including patients <40 years and a subgroup presenting hypertetraploid/multiploid tumors, are significantly correlated with clinical outcome, apart from SPF and estrogen receptors for DFS. In multivariate analysis, nodal involvement, DNA aneuploidy and lack of progesterone receptors (for DSS) retained statistically significant association with shorter survival. In node-negative patients, ploidy  (for DFS) and estrogen receptors (for DSS) significantly predicted survival. In both subgroups of node-positive patients and those (n = 195) with intermediate differentiation tumors (G2), aneuploidy was an indicator of worse prognosis. CONCLUSIONS: Along with nodal status and hormone receptor expression, DNA ploidy  is an independent predictor of long-term survival in IDC.




TÍTULO / TITLE:  - Prognostic Significance of Carbohydrate Antigen 19-9 in Unresectable Locally Advanced Pancreatic Cancer Treated With Dose-Escalated Intensity Modulated Radiation Therapy and Concurrent Full-Dose Gemcitabine: Analysis of a Prospective Phase ½ Dose Escalation Study.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Radiat Oncol Biol Phys. 2012 Dec 19. pii: S0360-3016(12)03817-5. doi: 10.1016/j.ijrobp.2012.11.020.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ijrobp.2012.11.020

AUTORES / AUTHORS:  - Vainshtein JM; Schipper M; Zalupski MM; Lawrence TS; Abrams R; Francis IR; Khan G; Leslie W; Ben-Josef E

INSTITUCIÓN / INSTITUTION:  - Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan. Electronic address: jvainsh@med.umich.edu.

RESUMEN / SUMMARY:  - PURPOSE: Although established in the postresection setting, the prognostic value  of carbohydrate antigen 19-9 (CA19-9) in unresectable locally advanced pancreatic cancer (LAPC) is less clear. We examined the prognostic utility of CA19-9 in patients with unresectable LAPC treated on a prospective trial of intensity modulated radiation therapy (IMRT) dose escalation with concurrent gemcitabine. METHODS AND MATERIALS: Forty-six patients with unresectable LAPC were treated at  the University of Michigan on a phase ½ trial of IMRT dose escalation with concurrent gemcitabine. CA19-9 was obtained at baseline and during routine follow-up. Cox models were used to assess the effect of baseline factors on freedom from local progression (FFLP), distant progression (FFDP), progression-free survival (PFS), and overall survival (OS). Stepwise forward regression was used to build multivariate predictive models for each endpoint. RESULTS: Thirty-eight patients were eligible for the present analysis. On univariate analysis, baseline CA19-9 and age predicted OS, CA19-9 at baseline and 3 months predicted PFS, gross tumor volume (GTV) and black race predicted FFLP, and CA19-9 at 3 months predicted FFDP. On stepwise multivariate regression modeling, baseline CA19-9, age, and female sex predicted OS; baseline CA19-9 and  female sex predicted both PFS and FFDP; and GTV predicted FFLP. Patients with baseline CA19-9 </=90 U/mL had improved OS (median 23.0 vs 11.1 months, HR 2.88,  P<.01) and PFS (14.4 vs 7.0 months, HR 3.61, P=.001). CA19-9 progression over 90  U/mL was prognostic for both OS (HR 3.65, P=.001) and PFS (HR 3.04, P=.001), and  it was a stronger predictor of death than either local progression (HR 1.46, P=.42) or distant progression (HR 3.31, P=.004). CONCLUSIONS: In patients with unresectable LAPC undergoing definitive chemoradiation therapy, baseline CA19-9 was independently prognostic even after established prognostic factors were controlled for, whereas CA19-9 progression strongly predicted disease progression and death. Future trials should stratify by baseline CA19-9 and incorporate CA19-9 progression as a criterion for progressive disease.




TÍTULO / TITLE:  - The endoplasmic reticulum stress marker, glucose-regulated protein-78 (GRP78) in  visceral adipocytes predicts endometrial cancer progression and patient survival.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Gynecol Oncol. 2012 Nov 28. pii: S0090-8258(12)00890-6. doi: 10.1016/j.ygyno.2012.11.024.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ygyno.2012.11.024

AUTORES / AUTHORS:  - Matsuo K; Gray MJ; Yang DY; Srivastava SA; Tripathi PB; Sonoda LA; Yoo EJ; Dubeau L; Lee AS; Lin YG

INSTITUCIÓN / INSTITUTION:  - Division of Gynecologic Oncology, Department of Obstetrics/Gynecology, University of Southern California, Los Angeles, CA, USA.

RESUMEN / SUMMARY:  - OBJECTIVE: Currently, accurately identifying endometrial cancer patients at high  risk for recurrence remains poor. To ascertain if changes in the endoplasmic reticulum (ER) stress marker, glucose-regulated-protein-78 (GRP78) can serve as a prognosticator in endometrial cancer, we examined GRP78 expression in patient samples to determine its association with clinical outcome. METHODS: A retrospective cohort study was conducted in endometrial cancer patients. Archived specimens of visceral adipocytes and paired endometrial tumors were analyzed by immunohistochemistry for GRP78 and another ER stress marker, C/EBP homologous protein (CHOP). Expression of these markers was correlated with clinico-pathological information and outcomes. RESULTS: GRP78 expression in visceral adipocytes was detected in 95% of the 179 endometrial cancer patients with analyzable visceral adipocytes. Within individual samples, 24% of adipocytes (range, 0-90%, interquartile range 18%-38%) exhibited GRP78 expression. High visceral adipocyte GRP78 expression positively correlated with advanced-stage disease (p=0.007) and deep myometrial invasion (p=0.004). High visceral adipocyte GRP78 expression was significantly associated with decreased disease-free survival (DFS) in multivariate analyses (hazard ratio 2.88, 95% CI 1.37-6.04, p=0.005). CHOP expression paralleled the GRP78 expression in adipocytes (r=0.55,  p<0.001) and in the tumor (p=0.018). CONCLUSIONS: Our study demonstrates that the ER stress markers, GRP78 and CHOP, are elevated in endometrial cancer patients. Furthermore, GRP78 expression levels in visceral adipocytes from these patients were significantly correlated to disease stage and patient survival. Our results  demonstrate, for the first time, that the GRP78 levels in endometrial cancer patients may be a prognosticator and aid with clinical risk stratification and focused surveillance.




TÍTULO / TITLE:  - Glutathione S-transferase M1-null genotype as risk factor for SOS in oxaliplatin-treated patients with metastatic colorectal cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Br J Cancer. 2013 Jan 3. doi: 10.1038/bjc.2012.590.

            ●● Enlace al texto completo (gratuito o de pago) 1038/bjc.2012.590

AUTORES / AUTHORS:  - Vreuls CP; Olde Damink SW; Koek GH; Winstanley A; Wisse E; Cloots RH; van den Broek MA; Dejong CH; Bosman FT; Driessen A

INSTITUCIÓN / INSTITUTION:  - Department of Pathology, Maastricht University Medical Centre, Maastricht, The Netherlands.

RESUMEN / SUMMARY:  - Background:Oxaliplatin is used as a neo-adjuvant therapy in hepatic colorectal carcinoma metastasis. This treatment has significant side effects, as oxaliplatin is toxic to the sinusoidal endothelial cells and can induce sinusoidal obstruction syndrome (SOS), which is related to decreased overall survival. Glutathione has an important role in the defence system, catalysed by glutathione S-transferase (GST), including two non-enzyme producing polymorphisms (GSTM1-null and GSTT1-null). We hypothesise that patients with a non-enzyme producing polymorphism have a higher risk of developing toxic injury owing to oxaliplatin.Methods:In the nontumour-bearing liver, the presence of SOS was studied histopathologically. The genotype was determined by a semi-nested PCR.Results:Thirty-two of the 55 (58%) patients showed SOS lesions, consisting of 27% mild, 22% moderate and 9% severe lesions. The GSTM1-null genotype was present in 25 of the 55 (46%). Multivariate analysis showed that the GSTM1-null genotype  significantly correlated with the presence of (moderate-severe) SOS (P=0.026).Conclusion:The GSTM1-null genotype is an independent risk factor for SOS. This finding allows us, in association with other risk factors, to conceive  a potential risk profile predicting whether the patient is at risk of developing  SOS, before starting oxaliplatin, and subsequently might result in adjustment of  treatment.British Journal of Cancer advance online publication, 3 January 2013; doi:10.1038/bjc.2012.590 www.bjcancer.com.




TÍTULO / TITLE:  - Azacitidine fails to eradicate leukemic stem/progenitor cell populations in patients with acute myeloid leukemia and myelodysplasia.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Leukemia. 2012 Nov 6. doi: 10.1038/leu.2012.312.

            ●● Enlace al texto completo (gratuito o de pago) 1038/leu.2012.312

AUTORES / AUTHORS:  - Craddock C; Quek L; Goardon N; Freeman S; Siddique S; Raghavan M; Aztberger A; Schuh A; Grimwade D; Ivey A; Virgo P; Hills R; McSkeane T; Arrazi J; Knapper S; Brookes C; Davies B; Price A; Wall K; Griffiths M; Cavenagh J; Majeti R; Weissman I; Burnett A; Vyas P

INSTITUCIÓN / INSTITUTION:  - 1] Centre for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, UK [2]  Cancer Research UK Clinical Trials Unit, School of Cancer Sciences, University of Birmingham, Birmingham, UK.

RESUMEN / SUMMARY:  - Epigenetic therapies demonstrate significant clinical activity in acute myeloid leukemia (AML) and myelodysplasia (MDS) and constitute an important new class of  therapeutic agents. However hematological responses are not durable and disease relapse appears inevitable. Experimentally, leukemic stem/progenitor cells (LSC)  propagate disease in animal models of AML and it has been postulated that their relative chemo-resistance contributes to disease relapse. We serially measured LSC numbers in patients with high-risk AML and MDS treated with 5’-azacitidine and sodium valproate (VAL-AZA). Fifteen out of seventy-nine patients achieved a complete remission (CR) or complete remission with incomplete blood count recovery (CRi) with VAL-AZA therapy. There was no significant reduction in the size of the LSC-containing population in non-responders. While the LSC-containing population was substantially reduced in all patients achieving a CR/CRi it was never eradicated and expansion of this population antedated morphological relapse. Similar studies were performed in seven patients with newly diagnosed AML treated with induction chemotherapy. Eradication of the LSC-containing population was observed in three patients all of whom achieved a durable CR in contrast to patients with resistant disease where LSC persistence was observed. LSC quantitation provides a novel biomarker of disease response and relapse in patients with AML treated with epigenetic therapies. New drugs that target this cellular population in vivo are required.Leukemia advance online publication, 7 December 2012; doi:10.1038/leu.2012.312.




TÍTULO / TITLE:  - Coming full circle: 70 years of chronic lymphocytic leukemia cell redistribution, from glucocorticoids to inhibitors of B cell receptor signaling.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Blood. 2012 Dec 20.

            ●● Enlace al texto completo (gratuito o de pago) 1182/blood-2012-08-452607

AUTORES / AUTHORS:  - Burger JA; Montserrat E

INSTITUCIÓN / INSTITUTION:  - Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States;

RESUMEN / SUMMARY:  - Chronic lymphocytic leukemia (CLL) cells proliferate in pseudofollicles within the lymphatic tissues, where signals from the microenvironment and B cell receptor (BCR) signaling drive the expansion of the CLL clone. Mobilization of tissue-resident cells into the blood removes CLL cells from this nurturing milieu and sensitizes them to cytotoxic drugs. This concept recently gained momentum after establishing the clinical activity of kinase inhibitors that target BCR signaling (SYK, BTK, PI3Kdelta inhibitors). Besides anti-proliferative activity,  these drugs cause CLL cell redistribution with rapid lymph node shrinkage, along  with a transient surge in lymphocytosis, prior to inducing objective remissions.  Inactivation of critical CLL homing mechanism (chemokine receptors, adhesion molecules), thwarting tissue retention and recirculation into the tissues, appears to be the basis for this striking clinical activity. This effect of BCR-signaling inhibitors resembles re-distribution of CLL cells after glucocorticoids, described as early as in the 1940s. As such, we are witnessing a renaissance of the concept of leukemia cell redistribution in modern CLL therapy. Here, we review the molecular basis of CLL cell trafficking, homing, and redistribution, and similarities between old and new drugs affecting these processes. Also, we outline how these discoveries are changing our understanding  of CLL biology and therapy.




TÍTULO / TITLE:  - Prognostic value of CA 19-9, CEA, CRP, LDH and bilirubin levels in locally advanced and metastatic pancreatic cancer: results from a multicenter, pooled analysis of patients receiving palliative chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Cancer Res Clin Oncol. 2013 Jan 13.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00432-012-1371-3

AUTORES / AUTHORS:  - Haas M; Heinemann V; Kullmann F; Laubender RP; Klose C; Bruns CJ; Holdenrieder S; Modest DP; Schulz C; Boeck S

INSTITUCIÓN / INSTITUTION:  - Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Marchioninistr. 15, 81377,  Munich, Germany.

RESUMEN / SUMMARY:  - PURPOSE: CA 19-9 is the only established tumor marker in pancreatic cancer (PC);  the prognostic role of other serum markers like CEA, CRP, LDH or bilirubin has not yet been defined. METHODS: We pooled pre-treatment data on CA 19-9, CEA, CRP, LDH and bilirubin levels from two German multicenter randomized phase II trials together with prospective patient data from one high-volume German Cancer Center. Marker levels were assessed locally before the start of palliative first-line therapy for advanced PC and serially during treatment (for CA 19-9 only). Clinical and biomarker data (overall 12 variables) were correlated with the efficacy endpoints time-to-progression (TTP) and overall survival (OS) by using uni- and multivariate Cox models. RESULTS: Data from 291 patients were included in this pooled analysis; 253 patients (87 %) received treatment within prospective clinical trials. Median TTP in the study cohort was 5.1 months and median OS 9.0 months. In univariate analysis, pre-treatment CA 19-9 (HR 1.55), LDH (HR 2.04) and CEA (HR 1.89) levels were significantly associated with TTP. Regarding OS, baseline CA 19-9 (HR 1.46), LDH (HR 2.07), CRP (HR 1.69) and bilirubin (HR 1.62) were significant prognostic factors. Within multivariate analyses, pre-treatment log [CA 19-9] (as continuous variable for TTP) and log [bilirubin] as well as log [CRP] (for OS) had an independent prognostic value. A  CA 19-9 decline of >/=25 % during the first two chemotherapy cycles was predictive for TTP and OS, independent of the applied CA 19-9 assay. CONCLUSION:  Baseline CA 19-9 and CA 19-9 kinetics during first-line chemotherapy are prognostic in advanced PC. Besides that finding other serum markers like CRP, LDH and bilirubin can also provide prognostic information on TTP and OS.




TÍTULO / TITLE:  - Combined Treatment With Peroxisome Proliferator-Activated Receptor (PPAR) Gamma Ligands and Gamma Radiation Induces Apoptosis by PPARgamma-Independent Up-Regulation of Reactive Oxygen Species-Induced Deoxyribonucleic Acid Damage Signals in Non-Small Cell Lung Cancer Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Radiat Oncol Biol Phys. 2013 Jan 16. pii: S0360-3016(12)03838-2. doi: 10.1016/j.ijrobp.2012.11.040.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ijrobp.2012.11.040

AUTORES / AUTHORS:  - Han EJ; Im CN; Park SH; Moon EY; Hong SH

INSTITUCIÓN / INSTITUTION:  - Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.

RESUMEN / SUMMARY:  - PURPOSE: To investigate possible radiosensitizing activities of the well-known peroxisome proliferator-activated receptor (PPAR)gamma ligand ciglitazone and novel PPARgamma ligands CAY10415 and CAY10506 in non-small cell lung cancer (NSCLC) cells. METHODS AND MATERIALS: Radiosensitivity was assessed using a clonogenic cell survival assay. To investigate the mechanism underlying PPARgamma ligand-induced radiosensitization, the subdiploid cellular DNA fraction was analyzed by flow cytometry. Activation of the caspase pathway by combined PPARgamma ligands and gamma-radiation treatment was detected by immunoblot analysis. Reactive oxygen species (ROS) were measured using 2,7-dichlorodihydrofluorescein diacetate and flow cytometry. RESULTS: The 3 PPARgamma ligands induced cell death and ROS generation in a PPARgamma-independent manner, enhanced gamma-radiation-induced apoptosis and caspase-3-mediated poly (ADP-ribose) polymerase (PARP) cleavage in vitro. The combined PPARgamma ligand/gamma-radiation treatment triggered caspase-8 activation, and this initiator caspase played an important role in the combination-induced apoptosis. Peroxisome proliferator-activated receptor-gamma ligands may enhance the gamma-radiation-induced DNA damage response, possibly by  increasing gamma-H2AX expression. Moreover, the combination treatment significantly increased ROS generation, and the ROS scavenger N-acetylcysteine inhibited the combined treatment-induced ROS generation and apoptotic cell death. CONCLUSIONS: Taken together, these results indicated that the combined treatment  of PPARgamma ligands and gamma-radiation synergistically induced DNA damage and apoptosis, which was regulated by ROS.




TÍTULO / TITLE:  - A patient with retroperitoneal fibrosis treated with tamoxifen who develops pancreatic carcinoma: remarks regarding the presence of estrogen receptors-a relationship between fibrosis and neoplastic processes?

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Pancreas. 2013 Jan;42(1):174-5. doi: 10.1097/MPA.0b013e318255adec.

            ●● Enlace al texto completo (gratuito o de pago) 1097/MPA.0b013e318255adec

AUTORES / AUTHORS:  - Velciov S; Gluhovschi C; Petrica L; Gluhovschi A

INSTITUCIÓN / INSTITUTION:  - Department of Nephrology County Emergency Hospital Timisoara “V. Babes” University of Medicine and Pharmacy Timisoara, Romania s_velciov@yahoo.com Department of Obstetrics and Gynecology County Emergency Hospital Timisoara “V. Babes” University of Medicine and Pharmacy Timisoara, Romania.




TÍTULO / TITLE:  - Expression of PTEN and survivin in cervical cancer: promising biological markers  for early diagnosis and prognostic evaluation.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Br J Biomed Sci. 2012;69(4):143-6.

AUTORES / AUTHORS:  - Lu D; Qian J; Yin X; Xiao Q; Wang C; Zeng Y

INSTITUCIÓN / INSTITUTION:  - Department of Obstetrics and Gynecology, Yangzhou University Medical College, Yangzhou, P R. China. ludan1968@yahoo.com.cn

RESUMEN / SUMMARY:  - This study aims to evaluate the expression of the antioncogene phosphatase and tensin (PTEN) homologue and survivin, a protein encoded by the anti-apoptotic gene baculoviral inhibitor of apoptosis repeat containing 5 (BIRC5), in the progression of cervical neoplasia and to elucidate the relationship between PTEN  and survivin expression based on clinicopathological features in squamous cell carcinoma of the uterine cervix. A total of 20 patients with cervical ectropion and squamous metaplasia, 30 with cervical intraepithelial neoplasia, and 49 with  cervical squamous cell carcinoma were enrolled in the study. Immunohistochemical  staining was performed to detect PTEN and survivin expression in each group. Normal cervical epithelium from 10 people served as the control. Results showed that PTEN expression progressively decreased with the continuum from normal epithelium to squamous cell carcinoma (P < 0.05), whereas survivin expression progressively increased (P < 0.05). Furthermore, positive PTEN immunostaining was associated with clinical stage and tumour size (P < 0.05). The level of PTEN expression in the metastatic pelvic lymph node group was significantly lower compared with the non-metastatic pelvic lymph node group (P < 0.01). Positive PTEN immunostaining was not associated with age or degree of differentiation (P > 0.05). Positive survivin immunostaining was associated with clinical stage and tumour size (P < 0.05). Survivin-positive expression in the metastatic pelvic lymph node group was significantly higher compared with the nonmetastatic pelvic  lymph node group (P < 0.01). No obvious relationship was found between survivin expression and patient age (P > 0.05). PTEN expression negatively correlated with survivin expression in cervical intraepithelial neoplasia and cervical squamous cell carcinoma (P < 0.01). PTEN and survivin expression correlated with incidence and progression of uterine cervical cancer. Positive expression levels of PTEN and survivin provide potential evaluation indices for early diagnosis and prognosis of uterine cervical cancer, and these biomarkers are also potentially promising therapeutic targets.




TÍTULO / TITLE:  - beta-Catenin-Dependent Lysosomal Targeting of Internalized Tumor Necrosis Factor-alpha Suppresses Caspase-8 Activation in Apoptosis-Resistant Colon Cancer  Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Biol Cell. 2012 Dec 21.

            ●● Enlace al texto completo (gratuito o de pago) 1091/mbc.E12-09-0662

AUTORES / AUTHORS:  - Han J; Sridevi P; Ramirez M; Ludwig KJ; Wang JY

INSTITUCIÓN / INSTITUTION:  - Moores Cancer Center, University of California San Diego, La Jolla, CA, 92093-0820.

RESUMEN / SUMMARY:  - The Wnt/beta-catenin pathway is constitutively activated in over 90% of human colorectal cancer. Activated beta-catenin stimulates cell proliferation and survival, however, its anti-apoptotic mechanisms are not fully understood. We show here that activated beta-catenin is required to suppress caspase-8 activation but only in colon cancer cells that are resistant to tumor necrosis factor-a (TNF) induced apoptosis. We found that lysosomal delivery of internalized TNF occurred at a faster pace in apoptosis-resistant than in apoptosis-sensitive colon cancer cells. Retardation of endosomal trafficking through V-ATPase inhibition enhanced caspase-8 activation in the apoptosis-resistant but not sensitive cells. Interestingly, knockdown of beta-catenin also prolonged TNF association with the early endosome and enhanced  caspase-8 activation in the apoptosis-resistant but not sensitive colon cancer cells. In a mouse model of inflammation-associated colon tumors, we found nuclear expression of beta-catenin, resistance to TNF-induced apoptosis, and reactivation of apoptosis in vivo by cotreatment of TNF with a V-ATPase inhibitor. Together, these results suggest that activated beta-catenin can facilitate endosomal trafficking of internalized TNF to suppress caspase-8 activation in colon cancer  cells.




TÍTULO / TITLE:  - Predictors of Psychopathological Outcome During Peg-Interferon and Ribavirin Therapy in Patients with Chronic HCV-Correlated Hepatitis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Interferon Cytokine Res. 2013 Jan;33(1):9-14. doi: 10.1089/jir.2012.0060. Epub  2012 Dec 31.

            ●● Enlace al texto completo (gratuito o de pago) 1089/jir.2012.0060

AUTORES / AUTHORS:  - Dell’osso B; Prati G; Palazzo MC; Rumi MG; Cavallaro F; Aghemo A; Colombo M; Altamura AC

INSTITUCIÓN / INSTITUTION:  - 1 Department of Psychiatry, Fondazione IRCSS Ca Granda Ospedale Maggiore Policlinico, Universita degli Studi di Milano , Milan, Italy .

RESUMEN / SUMMARY:  - Peg-interferon (Peg-IFN) and ribavirin (RBV) therapy is reported to induce psychiatric symptoms and syndromes in 20% of patients treated for Hepatitis C Virus (HCV) infection. Present study was aimed to quantify the phenomenon and assess the influence of psychiatric counseling over antiviral completion rate and the use of psychometric tools, in terms of prediction of psychopathological outcome. Ninety-six HCV patients were assessed, before antiviral treatment, by means of the Sheehan Disability Scale (SDS), Mood Disorder Questionnaire (MDQ), Symptom Checklist-90, and Internal State Scale (ISS). Sociodemographic and clinical variables and completion rate were collected. Binary logistic regression was performed to evaluate whether scores were predictive of psychiatric visit, development of psychiatric disorders, and need for treatment. Ninety-five patients (99%) completed antiviral treatment; 27 subjects (29%) needed psychiatric visit: among them, mood disorder was diagnosed in 15 (16%) and were pharmacologically treated. Baseline SDS and MDQ higher scores were found to be predictive of psychiatric visit [odds ratio (OR)=1.258, P<0.001 and OR=1.425, P=0.05, respectively]. Furthermore, higher MDQ score (P=0.017) and ISS hostility  scores (OR=1.048, P=0.014) at baseline predicted the subsequent development of mood episodes, while ISS activation correlated negatively (OR=0.948, P=0.009). Finally, the need for treatment was predicted by higher scores at the MDQ and ISS activation items (OR=2.467, P=0.030; OR=0.970, P=0.038). Present findings suggest that psychiatric counseling may be needed in almost 30% of HCV patients on antiviral treatment, with positive influence over the completion rate. Baseline higher scores at psychometric questionnaires-MDQ-in particular, predictors of psychopathological outcome during Peg-IFN and RBV therapy in patients with chronic HCV-correlated hepatitis reflecting individual functioning before starting antiviral therapy and positive history for mood disorders, seem to predict psychiatric visit, onset of mood episodes, and need for psychopharmacological treatment. Further investigation is warranted to confirm results.




TÍTULO / TITLE:  - Prognosis of patients with primary central nervous system lymphoma after high-dose chemotherapy followed by autologous stem cell transplantation.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Haematologica. 2013 Jan 8.

            ●● Enlace al texto completo (gratuito o de pago) 3324/haematol.2012.076075

AUTORES / AUTHORS:  - Schorb E; Kasenda B; Atta J; Kaun S; Morgner A; Hess G; Elter T; von Bubnoff N; Dreyling M; Ringhoffer M; Krause S; Derigs G; Klimm B; Niemann D; Fritsch K; Finke J; Illerhaus G


RESUMEN / SUMMARY:  - Background. High-dose chemotherapy followed by autologous stem cell transplantation has been shown to be feasible and highly effective in newly diagnosed primary central nervous system lymphoma. In this retrospective multicenter study we investigated prognosis and baseline risk factors in patients with primary central nervous system lymphoma who underwent this treatment approach. Design and Methods. We retrospectively analyzed 105 immunocompetent patients with primary central nervous system lymphoma who underwent high-dose chemotherapy followed by autologous stem cell transplantation with or without whole brain radiotherapy as first line consolidation treated at 12 German centers between 1997 and 2011. We estimated survival rates and investigated the impact of age, performance status, serum lactate dehydrogenase level, and deep brain involvement on overall and progression-free survival. Patients were additionally  categorized into three prognostic groups according to the Memorial Sloan Kettering Cancer Center prognostic model. Results. After a median follow-up of 47 months, median progression free survival and overall survival was reached after 85 and 121 months; 2 and 5-years overall survival rates were 82% and 79%, respectively. The Memorial Sloan Kettering Cancer Center prognostic model did not predict survival. Only age revealed some evidence of prognostic relevance. Overall response rate was 95%; of those patients with progressive disease before  high-dose chemotherapy, 7/20 achieved ongoing complete remission after therapy without whole brain radiation therapy. Transplantation-associated mortality was 2.8%. Conclusions. High-dose chemotherapy followed by autologous stem cell transplantation is a highly effective and safe treatment modality for selected primary central nervous system lymphoma patients. Superiority compared to standard chemotherapy still warrants further investigation.




TÍTULO / TITLE:  - Integrin alpha4 blockade sensitizes drug resistant pre-B acute lymphoblastic leukemia to chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Blood. 2013 Jan 14.

            ●● Enlace al texto completo (gratuito o de pago) 1182/blood-2012-01-406272

AUTORES / AUTHORS:  - Hsieh YT; Gang EJ; Geng H; Park E; Huantes S; Chudziak D; Dauber K; Schaefer P; Scharman C; Shimada H; Shojaee S; Klemm L; Parameswaran R; Loh M; Kang ES; Koo HH; Hoffman WK; Andrade J; Crooks GM; Willman CL; Muschen M; Papayannopoulou T; Heisterkamp N; Bonig H; Kim YM

INSTITUCIÓN / INSTITUTION:  - Department of Pediatrics, Division of Hematology and Oncology, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine,  Los Angeles, CA, United States;

RESUMEN / SUMMARY:  - The bone marrow (BM) provides chemoprotection for acute lymphoblastic leukemia (ALL) cells thus contributing to the lack of efficacy of current therapies. Integrin alpha4 (alpha4) mediates adhesion of normal and malignant B-cell precursors in BM, and, according to gene expression analyses from 207 children with high-risk pre-B ALL with minimal residual disease, is particularly highly expressed in patients with the poorest outcome. Therefore, we tested whether interference with alpha4-mediated stromal adhesion might be a new ALL treatment.  For this purpose, two models of leukemia were used, one genetic (conditional alpha4 ablation of BCR-ABL1 (p210+)-induced murine leukemia) and one pharmacological (anti-functional alpha4 antibody treatment of primary pre-B ALL). Conditional deletion of alpha4 sensitized leukemia cell to Nilotinib. Adhesion of primary pre-B ALL cells was alpha4-dependent and alpha4 blockade sensitized primary ALL cells towards chemotherapy. Combination of chemotherapy with an anti-integrin alpha4 antibody, Natalizumab, prolonged survival of NOD/SCID recipients of primary ALL suggesting adjuvant integrin alpha4 inhibition as a novel strategy for pre-B ALL.




TÍTULO / TITLE:  - High intratumoral expression of fibroblast activation protein (FAP) in colon cancer is associated with poorer patient prognosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Tumour Biol. 2013 Jan 18.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s13277-012-0638-2

AUTORES / AUTHORS:  - Wikberg ML; Edin S; Lundberg IV; Van Guelpen B; Dahlin AM; Rutegard J; Stenling R; Oberg A; Palmqvist R

INSTITUCIÓN / INSTITUTION:  - Department of Medical Biosciences, Pathology, Umea University, Building 6M, 2nd floor, Umea, SE-901 85, Sweden, maria.wikberg@medbio.umu.se.

RESUMEN / SUMMARY:  - -An active stroma is important for cancer cell invasion and metastasis. We investigated the expression of fibroblast activation protein (FAP) in relation to patient prognosis in colorectal cancer. Colorectal cancer specimens from 449 patients were immunohistochemically stained with a FAP antibody and evaluated in  the tumor center and tumor front using a semiquantitative four-level scale. FAP was expressed by fibroblasts in 85-90 % of the tumors examined. High versus no/low expression in the tumor center was associated with poor prognosis (multivariate hazard ratio, HR = 1.72; 95 % CI 1.07-2.77, p = 0.025). FAP expression in the tumor front, though more frequent than in the tumor center, was not associated with prognosis. FAP expression in the tumor center was more common in specimens with positive microsatellite instability (MSI) screening status and  in patients with high CpG island methylator phenotype (CIMP) status. However, inclusion of MSI screening status and CIMP status in the multivariate analysis strengthened the risk estimates for high FAP expression in the tumor center (HR = 1.89; 95 % CI 1.13-3.14; p = 0.014), emphasizing the role of FAP as an independent prognostic factor. Stromal FAP expression is common in colorectal cancer, and we conclude that high FAP expression in the tumor center, but not the tumor front, is an independent negative prognostic factor.




TÍTULO / TITLE:  - Tumor cell-derived placental growth factor sensitizes antiangiogenic and antitumor effects of anti-VEGF drugs.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Proc Natl Acad Sci U S A. 2013 Jan 8;110(2):654-9. doi: 10.1073/pnas.1209310110.  Epub 2012 Dec 24.

            ●● Enlace al texto completo (gratuito o de pago) 1073/pnas.1209310110

AUTORES / AUTHORS:  - Hedlund EM; Yang X; Zhang Y; Yang Y; Shibuya M; Zhong W; Sun B; Liu Y; Hosaka K; Cao Y

INSTITUCIÓN / INSTITUTION:  - Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77  Stockholm, Sweden.

RESUMEN / SUMMARY:  - The role of placental growth factor (PlGF) in modulation of tumor angiogenesis and tumor growth remains an enigma. Furthermore, anti-PlGF therapy in tumor angiogenesis and tumor growth remains controversial in preclinical tumor models.  Here we show that in both human and mouse tumors, PlGF induced the formation of dilated and normalized vascular networks that were hypersensitive to anti-VEGF and anti-VEGFR-2 therapy, leading to dormancy of a substantial number of avascular tumors. Loss-of-function using plgf shRNA in a human choriocarcinoma significantly accelerated tumor growth rates and acquired resistance to anti-VEGF drugs, whereas gain-of-function of PlGF in a mouse tumor increased anti-VEGF sensitivity. Further, we show that VEGFR-2 and VEGFR-1 blocking antibodies displayed opposing effects on tumor angiogenesis. VEGFR-1 blockade and genetic deletion of the tyrosine kinase domain of VEGFR-1 resulted in enhanced tumor angiogenesis. These findings demonstrate that tumor-derived PlGF negatively modulates tumor angiogenesis and tumor growth and may potentially serve as a predictive marker of anti-VEGF cancer therapy.




TÍTULO / TITLE:  - Prognostic Significance of Serum Levels of Vascular Endothelial Growth Factor and Insulin-Like Growth Factor-1 in Advanced Gastric Cancer Patients Treated with FOLFOX Chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Chemotherapy. 2013 Jan 4;58(6):426-434.

            ●● Enlace al texto completo (gratuito o de pago) 1159/000345918

AUTORES / AUTHORS:  - Oh SY; Kwon HC; Kim SH; Lee S; Lee JH; Graves CA; Camphausen K; Kim HJ

INSTITUCIÓN / INSTITUTION:  - Department of Internal Medicine, Dong-A University College of Medicine, Busan, Korea.

RESUMEN / SUMMARY:  - Background: Tumor vascular endothelial growth factor (VEGF) is a key angiogenic factor and may have an impact on tumor progression and response to chemotherapy.  The insulin-like growth factor (IGF) system is related to cell proliferation and  tumor growth. However, there is limited available data regarding the clinical and prognostic significance of VEGF or IGF-1 in advanced gastric cancer. The aim of this study was to evaluate the prognostic significance of serum VEGF and IGF-1 levels in advanced gastric cancer patients who were treated with oxaliplatin/5-fluorouracil (FOLFOX). Methods: The study population consisted of 100 advanced gastric cancer patients (median age 56 years). Patients were treated with oxaliplatin 85 mg/m(2) as a 2-hour infusion on day 1 plus leucovorin 20 mg/m(2) over 10 min, followed by a 5-fluorouracil (5-FU) bolus 400 mg/m(2) and 22 h of continuous infusion of 600 mg/m(2) on days 1-2. Treatment was repeated in 2-week intervals. The levels of serum VEGF and IGF-1 were measured using enzyme-linked immunoassays. Results: There was a significant correlation between  the serum level of VEGF and Lauren’s classification (p = 0.030) and previous operations (p = 0.010). IGF-1 was associated with the number of metastases (p = 0.012). The median level of serum VEGF was decreased after FOLFOX chemotherapy (p = 0.034). However, none of the measured serum markers were significantly correlated with response. In univariate analysis, overall survival (p < 0.001) was significantly shorter in patients with high serum levels of VEGF. Multivariate analysis revealed that VEGF was an independent factor for overall survival (HR 2.221; 95% CI 1.377-3.583, p = 0.001). Furthermore, IGF-1 had no significant influence on the clinical outcome. Conclusion: A high level of serum  VEGF is an independent prognostic factor in patients with advanced gastric cancer treated with chemotherapy. This may help to identify the patients who are more sensitive to the FOLFOX regimen.




TÍTULO / TITLE:  - Antiproliferative effects of pomegranate extract in MCF-7 breast cancer cells are associated with reduced DNA repair gene expression and induction of double strand breaks.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Carcinog. 2013 Jan 28. doi: 10.1002/mc.21995.

            ●● Enlace al texto completo (gratuito o de pago) 1002/mc.21995

AUTORES / AUTHORS:  - Shirode AB; Kovvuru P; Chittur SV; Henning SM; Heber D; Reliene R

INSTITUCIÓN / INSTITUTION:  - Department of Environmental Health Sciences, University at Albany, State University of New York, Albany, New York; Cancer Research Center, University at Albany, Rensselaer, New York.

RESUMEN / SUMMARY:  - Pomegranate extract (PE) inhibits the proliferation of breast cancer cells and stimulates apoptosis in MCF-7 breast cancer cells. While PE is a potent antioxidant, the present studies were conducted to examine the mechanisms of action of PE beyond antioxidation by studying cellular and molecular mechanisms underlying breast tumorigenesis. PE inhibited cell growth by inducing cell cycle  arrest in G(2) /M followed by the induction of apoptosis. In contrast, antioxidants N-acetylcysteine and Trolox did not affect cell growth at doses containing equivalent antioxidant capacity as PE, suggesting that growth inhibition by PE cannot solely be attributed to its high antioxidant potential. DNA microarray analysis revealed that PE downregulated genes associated with mitosis, chromosome organization, RNA processing, DNA replication and DNA repair, and upregulated genes involved in regulation of apoptosis and cell proliferation. Both microarray and quantitative RT-PCR indicated that PE downregulated important genes involved in DNA double strand break (DSB) repair by homologous recombination (HR), such as MRE11, RAD50, NBS1, RAD51, BRCA1, BRCA2, and BRCC3. Downregulation of HR genes correlated with increased levels of their predicted microRNAs (miRNAs), miR-183 (predicted target RAD50) and miR-24 (predicted target BRCA1), suggesting that PE may regulate miRNAs involved in DNA repair processes.  Further, PE treatment increased the frequency of DSBs. These data suggest that PE downregulates HR which sensitizes cells to DSBs, growth inhibition and apoptosis. Because HR represents a novel target for cancer therapy, downregulation of HR by  PE may be exploited for sensitization of tumors to anticancer drugs. © 2013 Wiley Periodicals, Inc.




TÍTULO / TITLE:  - Intrinsic molecular subtypes of glioma are prognostic and predict benefit from adjuvant procarbazine, lomustine, and vincristine chemotherapy in combination with other prognostic factors in anaplastic oligodendroglial brain tumors: a report from EORTC study 26951.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Clin Oncol. 2013 Jan 20;31(3):328-36. doi: 10.1200/JCO.2012.44.1444. Epub 2012  Dec 26.

            ●● Enlace al texto completo (gratuito o de pago) 1200/JCO.2012.44.1444

AUTORES / AUTHORS:  - Erdem-Eraslan L; Gravendeel LA; de Rooi J; Eilers PH; Idbaih A; Spliet WG; den Dunnen WF; Teepen JL; Wesseling P; Sillevis Smitt PA; Kros JM; Gorlia T; van den Bent MJ; French PJ

INSTITUCIÓN / INSTITUTION:  - Department of Neurology, Be 438, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, the  Netherlands; p.french@erasmusmc.nl.

RESUMEN / SUMMARY:  - PURPOSE Intrinsic glioma subtypes (IGSs) are molecularly similar tumors that can  be identified based on unsupervised gene expression analysis. Here, we have evaluated the clinical relevance of these subtypes within European Organisation for Research and Treatment of Cancer (EORTC) 26951, a randomized phase III clinical trial investigating adjuvant procarbazine, lomustine, and vincristine (PCV) chemotherapy in anaplastic oligodendroglial tumors. Our study includes gene expression profiles of formalin-fixed, paraffin-embedded (FFPE) clinical trial samples. PATIENTS AND METHODS Gene expression profiling was performed in 140 samples, 47 fresh frozen samples and 93 FFPE samples, on HU133_Plus_2.0 and HuEx_1.0_st arrays, respectively. Results All previously identified six IGSs are  present in EORTC 26951. This confirms that different molecular subtypes are present within a well-defined histologic subtype. Intrinsic subtypes are highly prognostic for overall survival (OS) and progression-free survival (PFS). They are prognostic for PFS independent of clinical (age, performance status, and tumor location), molecular (1p/19q loss of heterozygosity [LOH], IDH1 mutation, and MGMT methylation), and histologic parameters. Combining known molecular (1p/19q LOH, IDH1) prognostic parameters with intrinsic subtypes improves outcome prediction (proportion of explained variation, 30% v 23% for each individual group of factors). Specific genetic changes (IDH1, 1p/19q LOH, and EGFR amplification) segregate into different subtypes. We identified one subtype, IGS-9 (characterized by a high percentage of 1p/19q LOH and IDH1 mutations), that especially benefits from PCV chemotherapy. Median OS in this subtype was 5.5 years after radiotherapy (RT) alone versus 12.8 years after RT/PCV (P = .0349; hazard ratio, 2.18; 95% CI, 1.06 to 4.50). CONCLUSION Intrinsic subtypes are highly prognostic in EORTC 26951 and improve outcome prediction when combined with other prognostic factors. Tumors assigned to IGS-9 benefit from adjuvant PCV.




TÍTULO / TITLE:  - DNase is a prognostic marker in liver cancer patients receiving transarterial chemoembolization therapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Clin Pharmacol Ther. 2013 Jan;51(1):80-3.

AUTORES / AUTHORS:  - Kohles N; Nagel D; Jungst D; Stieber P; Holdenrieder S

INSTITUCIÓN / INSTITUTION:  - Institute of Clinical Chemistry, University-Hospital Munich-Grosshadern, Munich,  Department of Otorhinolaryngology, Helios-Klinikum Erfurt, Erfurt, Medical Clinic II, University-Hospital Munich-Grosshadern, Munich, and Institute of Clinical Chemistry and Clinical Pharmacology, University-Hospital Bonn, Bonn, Germany.




TÍTULO / TITLE:  - KRAS Mutation in Patients with Lung Cancer: A Predictor for Poor Prognosis but Not for EGFR-TKIs or Chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Ann Surg Oncol. 2012 Dec 4.

            ●● Enlace al texto completo (gratuito o de pago) 1245/s10434-012-2754-z

AUTORES / AUTHORS:  - Guan JL; Zhong WZ; An SJ; Yang JJ; Su J; Chen ZH; Yan HH; Chen ZY; Huang ZM; Zhang XC; Nie Q; Wu YL

INSTITUCIÓN / INSTITUTION:  - Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.

RESUMEN / SUMMARY:  - BACKGROUND: The prognostic and predictive value of KRAS mutations in patients with lung cancer is controversial. Biases in disease stage, treatment regimen, small-scale patient studies, and biomarker status have led to inconsistent results in previous reports. METHODS: The KRAS and EGFR genes were examined in 1935 consecutive patients with non-small cell lung cancer. All patients were divided into KRAS mutation (KRAS group), EGFR mutation (EGFR group), and KRAS/EGFR wild type (WT group) groups. Randomly selected cases were paired with patients with the KRAS mutation, the EGFR mutation, and KRAS/EGFR wild type patients according to tumor, node, metastasis stage, time of first visit within 1 year, and pathology. Progression-free survival (PFS) and overall survival were evaluated by Kaplan-Meier and Cox models. RESULTS: The KRAS mutation rate for lung adenocarcinoma was 5.90 %. The overall survival was 14.47, 20.57, and 42.73  months for the KRAS group, WT group, and EGFR group, respectively (P < 0.001). Multivariate analysis indicated that KRAS mutation status was an independent prognostic factor (hazard ratio 2.69, 95 % confidence interval 1.91-3.80, P < 0.001). No difference was found in PFS and tumor responsiveness between patients  with a KRAS mutation and those with wild type KRAS/EGFR for chemotherapy and EGFR tyrosine kinase inhibitors (TKI). PFS did not significantly differ for chemotherapy among the three groups (P = 0.270). CONCLUSIONS: KRAS mutation is a  poor prognosis factor, but it is not an independent predictor of response to EGFR-TKI or chemotherapy in patients with lung cancer.




TÍTULO / TITLE:  - Newcastle disease virus Malaysian strain AF2240 induces apoptosis in MCF-7 human  breast carcinoma cells at an early stage of the virus life cycle.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Mol Med. 2013 Mar;31(3):525-32. doi: 10.3892/ijmm.2013.1244. Epub 2013 Jan  15.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ijmm.2013.1244

AUTORES / AUTHORS:  - Ghrici M; El Zowalaty M; Omar AR; Ideris A

INSTITUCIÓN / INSTITUTION:  - Department of Veterinary Pathology and Microbiology, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor Darul Ehsan, Malaysia.

RESUMEN / SUMMARY:  - Newcastle disease virus (NDV) AF2240 Malaysian strain is a very virulent avian virus. NDV strain AF2240 was previously demonstrated to induce apoptosis in human breast carcinoma MCF-7 cells. However, at which stage of the NDV life cycle apoptosis is induced and whether NDV replication and protein synthesis are involved in apoptosis induction have yet to be determined. In the present study,  we investigated the time course of NDV strain AF2240 nucleoprotein (NP) gene expression and the early apoptotic signs in the form of activation of caspase-8 and mitochondrial transition pore opening. In addition, the induction of apoptosis by both ultraviolet-inactivated and cycloheximide-treated NDV-infected  MCF-7 cells were examined. Our findings showed that NDV strain AF2240 induced apoptosis at 1 h post-infection (pi) through activation of mitochondrial transition pore opening and at 2 h through activation of caspase-8, while the NP  gene was expressed at 6 h pi. The induced apoptosis was independent of both virus replication and protein synthesis. In conclusion, NDV strain AF2240 induces apoptosis at an early stage of its life cycle, possibly during virus binding or fusion with the cell membrane. The mitochondrial-related pathway may be the central activator in NDV strain AF2240-induced apoptosis.




TÍTULO / TITLE:  - Prognostic significance of programmed cell death-1-positive cells in follicular lymphoma patients may alter in the rituximab era.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur J Haematol. 2013 Jan 19. doi: 10.1111/ejh.12075.

            ●● Enlace al texto completo (gratuito o de pago) 1111/ejh.12075

AUTORES / AUTHORS:  - Takahashi H; Tomita N; Sakata S; Tsuyama N; Hashimoto C; Ohshima R; Matsuura S; Ogawa K; Yamamoto W; Kameda Y; Enaka M; Inayama Y; Kasahara M; Takekawa Y; Onoda N; Motomura S; Ishigatsubo Y; Takeuchi K

INSTITUCIÓN / INSTITUTION:  - Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

RESUMEN / SUMMARY:  - Programmed cell death-1 (PD-1) is involved in one of the inhibitory pathways of the B7-cluster of differentiation (CD)28 family; this pathway is known to be involved in the attenuation of T cell responses and promotion of T cell tolerance. PD-1 is known to negatively regulate T cell receptor-mediated proliferation and cytokine production, lead to alternation in the tumor microenvironment. Although several studies have shown that high levels of PD-1-positive cells in follicular lymphoma (FL) patients influence their prognosis, those studies included patients treated without rituximab, and the prognostic impact of PD-1 positivity in the rituximab-era (R-era) has not yet been elucidated. We retrospectively studied 82 patients with FL uniformly treated with standard R-CHOP therapy at 6 institutions between 2001 and 2009 (median follow-up for survivors: 55 months). We also collected and examined biopsy specimens for diagnosis with respect to PD-1 positivity. The PD-1 positivity was  significantly higher in male patients and patients with high beta-2 microglobulin (B2M >/= 3.0) (p = 0.03 and 0.003, respectively). Three-year progression free survival (PFS) and overall survival (OS) were 60% and 86%, respectively. By univariate analysis, elevated LDH (p = 0.07) worsened PFS. Male gender (p = 0.03), high FLIPI score (p = 0.05), and high B2M levels (p = 0.08) worsened OS. Multivariate analysis detected no significant prognostic factors, including PD-1  positivity. However, in male subgroup, high levels of PD-1-positive cells were found to be a prognostic factor for PFS. Addition of rituximab might have altered the prognostic impact of PD-1 positive cells. © 2013 John Wiley & Sons A/S.




TÍTULO / TITLE:  - The prognostic significance of p21 and Her-2 gene expression and mutation/polymorphism in patients with gastric adenocarcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Med Oncol. 2013 Mar;30(1):357. doi: 10.1007/s12032-012-0357-y. Epub 2012 Dec 29.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12032-012-0357-y

AUTORES / AUTHORS:  - Ozen A; Kocak Z; Sipahi T; Oz-Puyan F; Cakina S; Saynak M; Ibis C; Karagol H

INSTITUCIÓN / INSTITUTION:  - Department of Radiation Oncology, Medical Faculty Hospital, Trakya University, 22030, Edirne, Turkey, dralovettin@gmail.com.

RESUMEN / SUMMARY:  - Analyses of gene expression status and genetic polymorphisms are methods to identify novel histopathological prognostic factors. In patients with gastric cancer, some cell cycle regulators p53, p21, p27 and Her-2 oncogene have been proposed as prognostic factors. We aimed to investigate the expression and mutation/polymorphism of p21 and Her-2 and also relationship between that genes status and histopathological factors and prognosis in patients with gastric cancer. Forty-four patients with locally advanced gastric cancer were analyzed in this study from January 2000 to December 2008. Clinicopathological parameters, expression and mutation/polymorphism of p21 and Her-2 results were used to predict disease-free survival and overall survival. The positive expression of p21 and Her-2 was observed in 61.4 % (n = 27) and 9.1 % (n = 4) of all 44 tumors, respectively. p21 gene mutation and Her-2 gene polymorphism were detected in 20 % (n = 11) and 2.3 % (n = 1, II phenotype) of cases, respectively. The negative expression of p21 was correlated significantly with diffuse and undifferential type histologies, whole gastric involvement and positive vascular/neural invasion. The median survival rate of patients with negative expression was significantly poorer than that of patients with positive expression of p21 (17 vs. 27 months, p = 0.01, cox regression). p21 mutation was significantly higher in patients with diffuse (p = 0.03) and undifferential (p = 0.02) type histologies. There was no statistically significant association between histopathological parameters and Her-2 gene polymorphism/expression. The negative expression of p21 correlates with disease survival and may be a poor prognostic factor in patients with resected gastric cancer treated with adjuvant chemotherapy.




TÍTULO / TITLE:  - Network-based approach identified cell cycle genes as predictor of overall survival in lung adenocarcinoma patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Lung Cancer. 2013 Jan 25. pii: S0169-5002(13)00005-6. doi: 10.1016/j.lungcan.2012.12.022.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.lungcan.2012.12.022

AUTORES / AUTHORS:  - Li Y; Tang H; Sun Z; Bungum AO; Edell ES; Lingle WL; Stoddard SM; Zhang M; Jen J; Yang P; Wang L

INSTITUCIÓN / INSTITUTION:  - Department of Epidemiology, College of Preventive Medicine, Third Military Medical University, Chongqing, People’s Republic of China; Department of Health Sciences Research, Mayo Clinic, College of Medicine, Rochester, MN, USA.

RESUMEN / SUMMARY:  - Lung adenocarcinoma is the most common type of primary lung cancer. The purpose of this study was to delineate gene expression patterns for survival prediction in lung adenocarcinoma. Gene expression profiles of 82 (discovery set) and 442 (validation set 1) lung adenocarcinoma tumor tissues were analyzed using a systems biology-based network approach. We also examined the expression profiles  of 78 adjacent normal lung tissues from 82 patients. We found a significant correlation of an expression module with overall survival (adjusted hazard ratio  or HR=1.71; 95% CI=1.06-2.74 in discovery set; adjusted HR=1.26; 95% CI=1.08-1.49 in validation set 1). This expression module contained genes enriched in the biological process of the cell cycle. Interestingly, the cell cycle gene module and overall survival association were also significant in normal lung tissues (adjusted HR=1.91; 95% CI, 1.32-2.75). From these survival-related modules, we further defined three hub genes (UBE2C, TPX2, and MELK) whose expression-based risk indices were more strongly associated with poor 5-year survival (HR=3.85, 95% CI=1.34-11.05 in discovery set; HR=1.72, 95% CI=1.21-2.46 in validation set 1; and HR=3.35, 95% CI=1.08-10.04 in normal lung set). The 3-gene prognostic result was further validated using 92 adenocarcinoma tumor samples (validation set 2); patients with a high-risk gene signature have a 1.52-fold increased risk  (95% CI, 1.02-2.24) of death than patients with a low-risk gene signature. These  results suggest that a network-based approach may facilitate discovery of key genes that are closely linked to survival in patients with lung adenocarcinoma.




TÍTULO / TITLE:  - Is ATP7B a Predictive Marker in Patients With Ovarian Carcinoma Treated With Platinum-Taxane Combination Chemotherapy?

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Gynecol Cancer. 2013 Jan;23(1):60-4. doi: 10.1097/IGC.0b013e318275afef.

            ●● Enlace al texto completo (gratuito o de pago) 1097/IGC.0b013e318275afef

AUTORES / AUTHORS:  - Katagiri H; Nakayama K; Rahman MT; Rahman M; Katagiri A; Ishibashi T; Ishikawa M; Iida K; Nakayama S; Otsuki Y; Miyazaki K

INSTITUCIÓN / INSTITUTION:  - *Department of Obstetrics and Gynecology, Shimane University School of Medicine,  Izumo, Japan; daggerDepartment of Obstetrics and Gynecology, and double daggerDepartment of Pathology, Seirei Hamamatsu General Hospital, Hamamatsu, Japan.

RESUMEN / SUMMARY:  - OBJECTIVE: This study examined the prognostic significance of copper-transporting P-type adenosine triphosphatase (ATP7B) expression in patients with ovarian carcinoma treated with platinum-taxane combination chemotherapy. METHODS: Expression of ATP7B in ovarian carcinoma was assessed by immunohistochemistry and clinical data collected by retrospective review of medical charts. RESULTS: Overexpression of ATP7B was identified in 25 (29.1%) of 86 ovarian carcinomas. The frequency of ATP7B expression in clear cell carcinomas was significantly higher than that in serous high-grade carcinomas (P < 0.05). We observed no statistically significant correlations between high ATP7B protein expression and  either disease-free survival (P = 0.722) or overall survival (P = 0.389). CONCLUSIONS: Our study is the first to demonstrate a lack of statistically significant differences between ATP7B positive and negative cases with respect to prognosis of patients with ovarian carcinoma treated with a platinum-taxane combination regimen. However, that ATP7B expression in clear cell carcinomas was  significantly higher than that in serous carcinomas may partially explain the difference in chemotherapeutic response and prognosis between patients with these 2 types of carcinomas.




TÍTULO / TITLE:  - Androgen receptor phosphorylation at serine 515 by Cdk1 predicts biochemical relapse in prostate cancer patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Br J Cancer. 2013 Jan 15;108(1):139-48. doi: 10.1038/bjc.2012.480. Epub 2012 Dec  4.

            ●● Enlace al texto completo (gratuito o de pago) 1038/bjc.2012.480

AUTORES / AUTHORS:  - Willder JM; Heng SJ; McCall P; Adams CE; Tannahill C; Fyffe G; Seywright M; Horgan PG; Leung HY; Underwood MA; Edwards J

INSTITUCIÓN / INSTITUTION:  - 1] Institute of Cancer, University of Glasgow, McGregor Building, Western Infirmary, Glasgow G11 6NT, UK [2] Academic Department of Surgery, School of Medicine, University of Glasgow, Walton Building, Glasgow Royal Infirmary, 84 Castle Street, Glasgow, G4 0SF, UK.

RESUMEN / SUMMARY:  - Background:Prostate cancer cell growth is dependent upon androgen receptor (AR) activation, which is regulated by specific kinases. The aim of the current study  is to establish if AR phosphorylation by Cdk1 or ERK1/2 is of prognostic significance.Methods:Scansite 2.0 was utilised to predict which AR sites are phosphorylated by Cdk1 and ERK1/2. Immunohistochemistry for these sites was then  performed on 90 hormone-naive prostate cancer specimens. The interaction between  Cdk1/ERK1/2 and AR phosphorylation was investigated in vitro using LNCaP cells.Results:Phosphorylation of AR at serine 515 (pAR(S515)) and PSA at diagnosis were independently associated with decreased time to biochemical relapse. Cdk1 and pCdk1(161), but not ERK1/2, correlated with pAR(S515). High expression of pAR(S515) in patients with a PSA at diagnosis of </=20 ng ml(-1) was associated with shorter time to biochemical relapse (P=0.019). This translated into a reduction in disease-specific survival (10-year survival, 38.1% vs 100%, P<0.001). In vitro studies demonstrated that treatment with Roscovitine  (a Cdk inhibitor) caused a reduction in pCdk1(161) expression, pAR(S515)expression and cellular proliferation.Conclusion:In prostate cancer patients with PSA at diagnosis of </=20 ng ml(-1), phosphorylation of AR at serine 515 by Cdk1 may be an independent prognostic marker.




TÍTULO / TITLE:  - REG Ialpha is a biomarker for predicting response to chemotherapy with S-1 plus cisplatin in patients with unresectable stage IV gastric cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Br J Cancer. 2013 Jan 15. doi: 10.1038/bjc.2012.572.

            ●● Enlace al texto completo (gratuito o de pago) 1038/bjc.2012.572

AUTORES / AUTHORS:  - Sekikawa A; Fukui H; Zhang X; Maruo T; Tsumura T; Okabe Y; Wakasa T; Osaki Y; Chiba T; Tomita T; Oshima T; Watari J; Miwa H

INSTITUCIÓN / INSTITUTION:  - Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan.

RESUMEN / SUMMARY:  - Background:The regenerating gene Ialpha (REG Ialpha) is involved in gastric carcinogenesis as an antiapoptotic factor. Therefore, we investigated whether REG Ialpha confers resistance to chemotherapeutic drugs in gastric cancer (GC) cells  and whether REG Ialpha expression is useful for predicting the response to chemotherapy and outcome in patients with GC.Methods:A total of 70 patients with  unresectable stage IV GC received first-line chemotherapy with S-1 and cisplatin  (S-1/CDDP). The expression of REG Ialpha was evaluated immunohistochemically using biopsy samples obtained before chemotherapy, and its relationship to clinicopathological parameters was analysed statistically. The effects of REG Ialpha gene induction on resistance to 5-FU or CDDP treatment were examined by cell survival assay and flow cytometry.Results:Of the 70 patients with unresectable stage IV GC, 19 (27%) were positive for REG Ialpha expression. The expression of REG Ialpha was independently predictive of poorer progression-free  and overall survival in such patients (hazard ratio (HR) 2.46; P=0.002 and HR 1.89; P=0.037, respectively). The gene induction of REG Ialpha conferred resistance to cell death induced by 5-FU or CDDP in GC cells.Conclusion:In patients with stage IV GC, REG Ialpha, which confers resistance to chemotherapeutic drugs in GC cells, is a potential biomarker for predicting resistance to S-1/CDDP treatment.British Journal of Cancer advance online publication, 15 January 2013; doi:10.1038/bjc.2012.572 www.bjcancer.com.




TÍTULO / TITLE:  - Is the immunohistochemical expression of proliferation (Ki-67) and apoptosis (Bcl-2) markers and cyclooxigenase-2 (COX-2) related to carcinogenesis in postmenopausal endometrial polyps?

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Anal Quant Cytol Histol. 2012 Oct;34(5):264-72.

AUTORES / AUTHORS:  - Antunes A Jr; Andrade LA; Pinto GA; Leao R; Pinto-Neto AM; Costa-Paiva L

INSTITUCIÓN / INSTITUTION:  - Department of Obstetrics and Gynecology, State University of Campinas-UNICAMP School of Medicine, 13083-970 Campinas, SP, Brazil.

RESUMEN / SUMMARY:  - OBJECTIVE: To evaluate the pattern of Ki-67, Bcl-2 and COX-2 expression in the glandular epithelium and stroma of malignant and benign endometrial polyps in postmenopause. STUDY DESIGN: A total of 390 postmenopausal women underwent surgical hysteroscopy; women with endometrial polyps were included. Polypoid lesions were histologically classified as benign, premalignant or malignant lesions. Ki-67, Bcl-2 and COX-2 expression were evaluated by immunohistochemistry according to percentage of stained cells, staining intensity, and final score. RESULTS: The prevalence of malignancy in endometrial polyps was 7.1% and was associated with postmenopausal bleeding. The final score showed that only mean COX-2 expression was higher in malignant polyps both in the glandular epithelium  (6.1 +/- 2.5) (p < 0.001) and stroma (2.4 +/- 3.0) (p < 0.01). There was a higher Bcl-2 expression, especially in the glandular epithelium, with no differences between benign polyps and premalignant/malignant polyps. Ki-67 expression was low in both benign polyps and premalignant/malignant polyps. CONCLUSION: Polyps in postmenopause have a high COX-2 expression that is higher in malignant polyps than in benign polyps. There was no difference in Ki-67 and Bcl-2 expression between malignant polyps and premalignant/malignant polyps.




TÍTULO / TITLE:  - Prognosis in patients with non-small cell lung cancer who received erlotinib treatment and subsequent dose reduction due to skin rash.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Onkologie. 2012;35(12):747-52. doi: 10.1159/000345039. Epub 2012 Nov 20.

            ●● Enlace al texto completo (gratuito o de pago) 1159/000345039

AUTORES / AUTHORS:  - Takashima N; Kimura T; Watanabe N; Umemura T; Katsuno S; Arakawa K; Fukatsu M; Nakamura N; Nishiyama O; Kataoka K; Kondoh Y; Taniguchi H

INSTITUCIÓN / INSTITUTION:  - Department of Pharmacy, Tosei General Hospital, Seto, Aichi, Japan.

RESUMEN / SUMMARY:  - BACKGROUND: Severe skin rash as toxicity of erlotinib has been reported in relation to better response and survival. However, some patients require dose reduction due to skin toxicities, and their prognosis remains uncertain. We retrospectively evaluated the clinical course of non-small cell lung cancer patients receiving erlotinib at a reduced dose because of skin rash. PATIENTS AND METHODS: Among 76 patients treated with erlotinib, 55 patients who developed skin rash severer than grade 2 were divided into 2 groups: 24 patients treated with erlotinib with dose reduction because of skin rash (dose reduction group) and 31  patients without any dose reduction (non-dose reduction group). RESULTS: The median progression-free survival in the dose reduction and non-dose reduction groups was 341 and 70 days, respectively, and the median overall survival was 566 and 202 days, respectively (p < 0.001). In the dose reduction group, no smoking history, female sex, epidermal growth factor receptor gene mutation, and grade 3  skin rash were significant baseline factors. CONCLUSIONS: Patients who received erlotinib at a reduced dose following skin rash showed better survival than those without reduction. In cases of intolerable skin rash, patients may benefit from continuous treatment with a reduced dose of erlotinib.




TÍTULO / TITLE:  - Application of a Proapoptotic Peptide to Intratumorally Spreading Cancer Therapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Res. 2012 Dec 17.

            ●● Enlace al texto completo (gratuito o de pago) 1158/0008-5472.CAN-12-1979

AUTORES / AUTHORS:  - Chen R; Braun G; Luo X; Sugahara KN; Teesalu T; Ruoslahti E

INSTITUCIÓN / INSTITUTION:  - Center for Nanomedicine, Sanford-Burnham Medical Research Institute (at UCSB).

RESUMEN / SUMMARY:  - Bit1 is a pro-apoptotic mitochondrial protein associated with anoikis. Upon cell  detachment, Bit1 is released into the cytoplasm and triggers caspase-independent  cell death. Bit1 consists of 179 amino acids; the C-terminal two thirds of the molecule functions as a peptidyl-tRNA hydrolase, while the N-terminus contains a  mitochondrial localization signal. Here, we localize the cell death domain (CDD)  to the N-terminal 62 amino acids of Bit1 by transfecting cells with truncated Bit1 cDNA constructs. CDD was more potent in killing cells than the full-length Bit1 protein when equivalent amounts of cDNA were transfected. To develop Bit1 CDD into a cancer therapeutic we engineered a recombinant protein consisting of the CDD fused to iRGD, which is a tumor-specific peptide with unique tumor-penetrating and cell internalizing properties. iRGD-CDD internalized into cultured tumor cells through a neuropilin-1-activated pathway and triggered cell  death. Importantly, iRGD-CDD spread extensively within the tumor when injected intratumorally into orthotopically implanted breast tumors in mice. Repeated treatment with iRGD-CDD strongly inhibited tumor growth, resulting in an average  reduction of 77% in tumor volume and eradication of some tumors. The caspase independence of Bit1-induced cell death makes CDD a potentially attractive anti-cancer agent because tumor resistance to the main mechanisms of apoptosis is circumvented. Using iRGD to facilitate the spreading of a therapeutic agent throughout the tumor mass may be a useful adjunct to local therapy of tumors that are surgically inoperable or difficult to treat systemically.




TÍTULO / TITLE:  - Sequential azacitidine plus lenalidomide combination for elderly patients with untreated acute myeloid leukemia.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Haematologica. 2012 Dec 14.

            ●● Enlace al texto completo (gratuito o de pago) 3324/haematol.2012.076414

AUTORES / AUTHORS:  - Pollyea DA; Zehnder J; Coutre S; Gotlib J; Gallegos L; Abdel-Wahab O; Greenberg P; Zhang B; Liedtke M; Berube C; Levine R; Mitchell BS; Medeiros BC


RESUMEN / SUMMARY:  - Background There are limited treatment options for older patients with acute myeloid leukemia (AML) and prognosis remains poor, thereby warranting development of novel therapies. We evaluated the efficacy and safety of azacitidine in combination with lenalidomide as front-line therapy for older AML patients. Design and methods Patients >60 years of age with untreated AML received azacitidine 75mg/m2 for 7 days followed by escalating doses of lenalidomide daily for 21 days starting on day 8 of each cycle every 6 cycles. Patients received continued therapy until disease progression, unacceptable toxicity, or completion of 12 cycles. Results Forty-two patients (median age, 74 years) were enrolled with equal distribution according to ELN risk. Overall response rate was 40% (CR+CRi rate = 28%). The median time to CR/CRi was 12 weeks, and duration of CR/CRi was 28 weeks (range, 4- >104 weeks). Therapy-related AML and high hematopoietic cell transplantation comorbidity index were negative predictors of  response. Early death was noted in 17% of patients. Grades >/= 3 toxicities were  uncommon and most adverse events were gastrointestinal, fatigue and myelosupression. Conclusions Sequential combination of azacitidine plus lenalidomide has clinical activity in older AML patients, and further studies of  this combination are underway. This study is registered at www.clinicaltrials.gov as # NCT00890929.




TÍTULO / TITLE:  - Early Viral Suppression Predicts Good Postoperative Survivals in Patients with Hepatocellular Carcinoma with a High Baseline HBV-DNA Load.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Ann Surg Oncol. 2012 Dec 18.

            ●● Enlace al texto completo (gratuito o de pago) 1245/s10434-012-2803-7

AUTORES / AUTHORS:  - Huang G; Yang Y; Shen F; Pan ZY; Fu SY; Lau WY; Zhou WP; Wu MC

INSTITUCIÓN / INSTITUTION:  - The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital,  Second Military Medical University, Shanghai, China.

RESUMEN / SUMMARY:  - PURPOSE: To correlate early HBV-DNA suppression by antiviral treatment with posthepatectomy long-term survivals in patients with HBV-related hepatocellular carcinoma (HCC). METHODS: A retrospective study was conducted on patients with a  baseline HBV-DNA load of >2,000 IU/ml. The cumulative rates of HBV-DNA undetectability at weeks 24 and 48, as well as long-term tumor recurrence and overall survivals were determined. RESULTS: Of 1,040 patients with a high baseline HBV-DNA load, 865 patients received antiviral treatment. At a median follow-up of 42 months, 616 patients (59.2 %) had developed HCC recurrence and 482 patients (46.3 %) had died. The median time to recurrence was 25 months. In patients who received antiviral treatment, the cumulative rates of HBV-DNA undetectability (<200 IU/ml) were 54.3 and 88.1 % at weeks 24 and 48, respectively. There was no significant difference between the two groups of patients who received antiviral treatment or not for disease-free survival. On multivariate analyses, tumor size >5 cm, blood transfusion, surgical margin <1 cm, presence of satellite nodules, presence of portal vein tumor thrombus and high Ishak inflammation score were significant risk factors of HCC recurrence. Also, tumor size >5 cm, surgical margin <1 cm, presence of satellite nodules, presence of portal vein tumor thrombus and high Ishak fibrosis score were significant factors associated with poor postoperative overall survival. On the other hand, an undetectable HBV-DNA level before week 24 was a significant protective factor of disease-free survival and overall survival. CONCLUSIONS: Early HBV-DNA suppression with antiviral treatment improved prognosis of patients with HBV-related HCC.




TÍTULO / TITLE:  - Biodistribution, tumor detection, and radiation dosimetry of 18F-DCFBC, a low-molecular-weight inhibitor of prostate-specific membrane antigen, in patients with metastatic prostate cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Nucl Med. 2012 Dec;53(12):1883-91. doi: 10.2967/jnumed.112.104661.

            ●● Enlace al texto completo (gratuito o de pago) 2967/jnumed.112.104661

AUTORES / AUTHORS:  - Cho SY; Gage KL; Mease RC; Senthamizhchelvan S; Holt DP; Jeffrey-Kwanisai A; Endres CJ; Dannals RF; Sgouros G; Lodge M; Eisenberger MA; Rodriguez R; Carducci MA; Rojas C; Slusher BS; Kozikowski AP; Pomper MG

INSTITUCIÓN / INSTITUTION:  - Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland 21287-0014, USA.

RESUMEN / SUMMARY:  - Prostate-specific membrane antigen (PSMA) is a type II integral membrane protein  expressed on the surface of prostate cancer (PCa) cells, particularly in androgen-independent, advanced, and metastatic disease. Previously, we demonstrated that N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-(18)F-fluorobenzyl-L-cysteine ((18)F-DCFBC) could image an experimental model of PSMA-positive PCa using PET. Here, we describe the initial clinical experience and radiation dosimetry of (18)F-DCFBC in men with metastatic PCa. METHODS: Five patients with radiologic evidence of metastatic PCa were studied after the intravenous administration of 370 MBq (10 mCi) of (18)F-DCFBC. Serial PET was performed until 2 h after administration. Time-activity curves were generated for selected normal tissues and metastatic foci. Radiation dose estimates were calculated using OLINDA/EXM 1.1. RESULTS: Most vascular organs demonstrated a slow decrease in radioactivity  concentration over time consistent with clearance from the blood pool, with primarily urinary radiotracer excretion. Thirty-two PET-positive suspected metastatic sites were identified, with 21 concordant on both PET and conventional imaging for abnormal findings compatible with metastatic disease. Of the 11 PET-positive sites not identified on conventional imaging, most were within the bone and could be considered suggestive for the detection of early bone metastases, although further validation is needed. The highest mean absorbed dose per unit administered radioactivity (muGy/MBq) was in the bladder wall (32.4), and the resultant effective dose was 19.9 +/- 1.34 muSv/MBq (mean +/- SD). CONCLUSION: Although further studies are needed for validation, our findings demonstrate the potential of (18)F-DCFBC as a new positron-emitting imaging agent for the detection of metastatic PCa. This study also provides dose estimates for  (18)F-DCFBC that are comparable to those of other PET radiopharmaceuticals such as (18)F-FDG.




TÍTULO / TITLE:  - Sunitinib, a tyrosine kinase inhibitor, induces cytochrome P450 1A1 gene in human breast cancer MCF7 cells through ligand-independent aryl hydrocarbon receptor activation.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Arch Toxicol. 2013 Jan 4.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00204-012-0996-y

AUTORES / AUTHORS:  - Maayah ZH; El Gendy MA; El-Kadi AO; Korashy HM

INSTITUCIÓN / INSTITUTION:  - Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2529, Riyadh, 11461, Kingdom of Saudi Arabia.

RESUMEN / SUMMARY:  - Sunitinib (SUN) is a new multi-targeted oral tyrosine kinase inhibitor that has both anti-angiogenic and anti-tumor activities. However, information reported in  the literature on the effects of SUN on the constitutive expression of cytochrome P450 1A1 (CYP1A1) gene in cells from mammalian species remains unclear. Therefore, the main objectives of the current work were to investigate the potentiality of SUN to induce CYP1A1 gene expression in human breast cancer MCF7  cells and to explore the molecular mechanisms involved. Our results showed that SUN induced the CYP1A1 mRNA, protein, and activity levels in a concentration-dependent manner in MCF7 cells. The increase in CYP1A1 mRNA by SUN  was completely blocked by the transcriptional inhibitor, actinomycin D; implying  that SUN increased de novo RNA synthesis. Furthermore, the ability of SUN to increase luciferase reporter gene expression suggests an aryl hydrocarbon receptor (AhR)-dependent transcriptional control and excludes the possibility of  any posttranscriptional mechanisms. In addition, blocking of AhR activation by resveratrol, a well-known AhR antagonist, prevented the SUN-induced CYP1A1 gene expression, further confirms the involvement of AhR. Interestingly, this was associated with the inability of SUN to directly bind to and induce transformation of cytosolic AhR to its DNA-binding form in vitro, suggesting that the effect of SUN does not involve direct binding to AhR. The current manuscript  provides the first evidence for the ability of SUN to induce CYP1A1 gene expression in MCF7 cells through AhR ligand-independent mechanisms.




TÍTULO / TITLE:  - Systems Analysis of BCL2 Protein Family Interactions Establishes a Model to Predict Responses to Chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Res. 2013 Jan 15;73(2):519-28. doi: 10.1158/0008-5472.CAN-12-2269.

            ●● Enlace al texto completo (gratuito o de pago) 1158/0008-5472.CAN-12-2269

AUTORES / AUTHORS:  - Lindner AU; Concannon CG; Boukes GJ; Cannon MD; Llambi F; Ryan D; Boland K; Kehoe J; McNamara DA; Murray F; Kay EW; Hector S; Green DR; Huber HJ; Prehn JH

INSTITUCIÓN / INSTITUTION:  - Authors’ Affiliations: Centre for Systems Medicine, Department of Physiology and  Medical Physics, Royal College of Surgeons in Ireland; Departments of Surgery, Pathology, and Gastroenterology, Beaumont Hospital, Dublin, Ireland; and Department of Immunology, St. Jude Children’s Research Hospital, Memphis, Tennessee.

RESUMEN / SUMMARY:  - Apoptotic desensitization is a hallmark of cancer cells, but present knowledge of molecular systems controlling apoptosis has yet to provide significant prognostic insights. Here, we report findings from a systems study of the intrinsic pathway  of apoptosis by BCL2 family proteins and clinical translation of its findings into a model with applications in colorectal cancer (CRC). By determining absolute protein quantifications in CRC cells and patient tumor samples, we found that BAK and BAX were expressed more highly than their antiapoptotic inhibitors.  This counterintuitive finding suggested that sole inhibition of effector BAX and  BAK could not be sufficient for systems stability in nonstressed cells. Assuming  a model of direct effector activation by BH3-only proteins, we calculated that the amount of stress-induced BH3-only proteins required to activate mitochondrial apoptosis could predict individual death responses of CRC cells to 5-fluorouracil/oxaliplatin. Applying this model predictor to protein profiles in  tumor and matched normal tissue samples from 26 patients with CRCs, we found that differences in protein quantities were sufficient to model the increased tumor sensitivity to chemotherapy compared with normal tissue. In addition, these differences were sufficient to differentiate clinical responders from nonresponders with high confidence. Applications of our model, termed DR_MOMP, were used to assess the impact of apoptosis-sensitizing dugs in lowering the necessary dose of state-of-the-art chemotherapy in individual patients. Together, our findings offer a ready clinical tool with the potential to tailor chemotherapy to individual patients. Cancer Res; 73(2); 519-28. ©2012 AACR.




TÍTULO / TITLE:  - Loss of phosphatase and tensin homolog expression is associated with recurrence and poor prognosis in patients with pancreatic ductal adenocarcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Hum Pathol. 2012 Dec 19. pii: S0046-8177(12)00329-2. doi: 10.1016/j.humpath.2012.09.001.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.humpath.2012.09.001

AUTORES / AUTHORS:  - Foo WC; Rashid A; Wang H; Katz MH; Lee JE; Pisters PW; Wolff RA; Abbruzzese JL; Fleming JB; Wang H

INSTITUCIÓN / INSTITUTION:  - Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

RESUMEN / SUMMARY:  - Phosphatase and tensin homolog (PTEN) is a tumor suppressor in the AKT/mTOR pathway. Animal model studies have shown that loss of PTEN function is involved in the progression of pancreatic cancer. However, the prognostic significance of  loss of PTEN expression in pancreatic cancer is unclear. PTEN expression was evaluated by immunohistochemistry on tissue microarrays consisting of multiple cores of 133 resected stage II pancreatic ductal adenocarcinomas. A PTEN expression score was calculated as the product of the percentage of positive tumor cells and the intensity of PTEN staining. We categorized PTEN expression for each tumor as retained (PTEN score >5) or lost (PTEN score </=5). Thirty-four (25.6%) patients had tumors with loss of PTEN expression, and 99 (74.4%) had tumors with retained PTEN expression. Recurrence/Metastasis was observed in 88.2% (30/34) of patients whose tumors showed loss of PTEN compared with 68.7% (68/99)  of patients whose tumors showed retained PTEN (P = .03). Patients whose tumors showed loss of PTEN had a shorter overall survival (median, 19.9 +/- 3.6 months)  than did patients whose tumors had retained PTEN (32.7 +/- 5.0 months, P = .03).  In a multivariate analysis, loss of PTEN expression was an independent prognostic factor for poor overall survival in patients with stage II pancreatic ductal adenocarcinoma. No significant correlations between loss of PTEN expression and other clinicopathologic parameters were observed (P > .05). Assessment of PTEN expression may be used as a prognostic marker for patients with resected pancreatic ductal adenocarcinoma.




TÍTULO / TITLE:  - Genome-wide single-nucleotide polymorphism array-based karyotyping in myelodysplastic syndrome and chronic myelomonocytic leukemia and its impact on treatment outcomes following decitabine treatment.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Ann Hematol. 2012 Dec 23.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00277-012-1635-7

AUTORES / AUTHORS:  - Yi JH; Huh J; Kim HJ; Kim SH; Kim SH; Kim KH; Do YR; Mun YC; Kim H; Kim MK; Kim HJ; Kim T; Kim DD

INSTITUCIÓN / INSTITUTION:  - Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center,  Sungkyunkwan University School of Medicine, Irwon-dong 50, Gangnam-gu, Seoul, 135-710, South Korea.

RESUMEN / SUMMARY:  - Decitabine is a hypomethylating agent with proven clinical efficacy in myelodysplastic syndrome (MDS). The current study analyzed the role of single nucleotide polymorphism array (SNP-A)-based karyotyping in prediction of clinical outcome in MDS or chronic myelomonocytic leukemia (CMML) patients following decitabine therapy. A total of 61 MDS/CMML patients treated with decitabine were  evaluated with Genome-Wide Human SNP 6.0 Array using DNAs derived from marrow samples. The primary endpoint was the best response rate including complete (CR)  and partial response (PR) with overall (OS) and event-free survival (EFS) as secondary endpoints. Best response was noted in 14 patients (26.4 %) out of 53 evaluated patients including 12 CR and two PR with median follow-up of 21.6 months. A total of 81 abnormal SNP lesions were found in 25 out of 61 patients (41.0 %). The patients carrying abnormal SNP lesions showed an inferior CR/PR rate (p = 0.002) and showed a trend of worse OS (p = 0.02 in univariate, p = 0.09 in multivariate) compared to those without SNP lesions, but not were associated with inferior EFS. The presence of abnormal SNP lesions in MDS was associated with adverse outcomes following decitabine therapy. Further study is strongly warranted to establish the role of SNP-A karyotyping in MDS.




TÍTULO / TITLE:  - Health Behaviors Predict Higher Interleukin-6 levels Among Patients Newly Diagnosed with Head and Neck Squamous Cell Carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Epidemiol Biomarkers Prev. 2013 Jan 8.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1055-9965.EPI-12-0987

AUTORES / AUTHORS:  - Duffy SA; Teknos T; Taylor JM; Fowler K; Islam M; Wolf GT; McLean SA; Ghanem TA; Terrell JE

INSTITUCIÓN / INSTITUTION:  - 1Otolaryngology & Nursing, University of Michigan.

RESUMEN / SUMMARY:  - BACKGROUND: Health behaviors have been shown to be associated with recurrence risk and survival rates in cancer patients and are also associated with Interleukin-6 levels, but few epidemiologic studies have investigated the relationship of health behaviors and Interleukin-6 among cancer populations. The  purpose of the study is to look at the relationship between five health behaviors: smoking, alcohol problems, body mass index (a marker of nutritional status), physical activity, and sleep and pretreatment Interleukin-6 levels in persons with head and neck cancer. METHODS: Patients (N=409) were recruited in otolaryngology clinic waiting rooms and invited to complete written surveys. A medical record audit was also conducted. Descriptive statistics and multivariate  analyses were conducted to determine which health behaviors were associated with  higher Interleukin-6 levels controlling for demographic and clinical variables among newly diagnosed head and neck cancer patients. RESULTS: While smoking, alcohol problems, body mass index, physical activity, and sleep were associated with Interleukin-6 levels in bivariate analysis, only smoking (current and former) and decreased sleep were independent predictors of higher Interleukin-6 levels in multivariate regression analysis. Covariates associated with higher Interleukin-6 levels were age and higher tumor stage, while comorbidities were marginally significant. CONCLUSION: Health behaviors, particularly smoking and sleep disturbances, are associated with higher Interleukin-6 levels among head and neck cancer patients. Impact: Treating health behavior problems, especially smoking and sleep disturbances, may be beneficial to decreasing Interleukin-6 levels which could have a beneficial effect on overall cancer treatment outcomes.




TÍTULO / TITLE:  - Instability of mRNA expression signatures of drug transporters in chronic myeloid leukemia patients resistant to imatinib.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Rep. 2013 Feb;29(2):741-50. doi: 10.3892/or.2012.2153. Epub 2012 Nov 28.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2012.2153

AUTORES / AUTHORS:  - Gromicho M; Magalhaes M; Torres F; Dinis J; Fernandes AR; Rendeiro P; Tavares P; Laires A; Rueff J; Sebastiao Rodrigues A

INSTITUCIÓN / INSTITUTION:  - Human Molecular Genetics Research Centre, Department of Genetics, New University  of Lisbon, Lisbon, Portugal. marta.gromicho@fcm.unl.pt

RESUMEN / SUMMARY:  - Despite the success of imatinib mesylate (IM) in the treatment of chronic myeloid leukemia (CML), approximately 30% of patients are resistant to therapy, mostly due to unknown causes. To profile the expression signatures of drug transporters  throughout IM therapy and correlate them with resistance, we quantified mRNA expression levels of the SLC22A12, ABCB1, ABCC1, ABCG2 and MVP genes in consecutive samples from peripheral blood or bone marrow of CML patients who were either responsive or resistant to IM. Additionally we identified and quantified BCR-ABL1 transcript variants and analyzed 1236T>C ABCB1 and 480G>C SLC22A1 polymorphisms. A relationship between the type of BCR-ABL1 transcript or ABCB1 or SLC22A1 genotype and response to treatment was not discovered. However, the studied genes had higher expression levels in follow-up compared to the diagnostic samples, demonstrating a possible induction in expression. IM-sensitive patients presented significantly higher values of SLC22A1 expression, suggesting higher drug influx. Most importantly, while responding patients demonstrated stable expression signatures in consecutive samples, there  was considerable variation in IM-resistant patients, indicating that single point sampling expression signatures are not reliable in predicting clinical outcomes or prognostic features in these patients. Studies that assessed consecutive samples from CML patients in order to evaluate the variation in expression levels of transporter genes are limited yet our study emphasizes the importance of such  approaches.




TÍTULO / TITLE:  - Critical role of presenilin-dependent gamma-secretase activity in DNA damage-induced promyelocytic leukemia protein expression and apoptosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cell Death Differ. 2013 Jan 11. doi: 10.1038/cdd.2012.162.

            ●● Enlace al texto completo (gratuito o de pago) 1038/cdd.2012.162

AUTORES / AUTHORS:  - Song H; Hyun Boo J; Ho Kim K; Kim C; Kim YE; Ahn JH; Sun Jeon G; Ryu H; Kang DE; Mook-Jung I

INSTITUCIÓN / INSTITUTION:  - Department of Biochemistry and Biomedical Sciences, WCU neurocytomics, College of Medicine, Seoul National University, Seoul, Korea.

RESUMEN / SUMMARY:  - Promyelocytic leukemia (PML) is a major component of macromolecular multiprotein  complexes called PML nuclear-bodies (PML-NBs). These PML-NBs recruit numerous proteins including CBP, p53 and HIPK2 in response to DNA damage, senescence and apoptosis. In this study, we investigated the effect of presenilin (PS), the main component of the gamma-secretase complex, in PML/p53 expression and downstream consequences during DNA damage-induced cell death using camptothecin (CPT). We found that the loss of PS in PS knockout (KO) MEFs (mouse embryonic fibroblasts)  results in severely blunted PML expression and attenuated cell death upon CPT exposure, a phenotype that is fully reversed by re-expression of PS1 in PS KO cells and recapitulated by gamma-secretase inhibitors in hPS1 MEFs. Interestingly, the gamma-secretase cleavage product, APP intracellular domain (AICD), together with Fe65-induced PML expression at the protein and transcriptional levels in PS KO cells. PML and p53 reciprocally positively regulated each other during CPT-induced DNA damage, both of which were dependent  on PS. Finally, elevated levels of PML-NB, PML protein and PML mRNA were detected in the brain tissues from Alzheimer’s disease (AD) patients, where gamma-secretase activity is essential for pathogenesis. Our data provide for the  first time, a critical role of the PS/AICD-PML/p53 pathway in DNA damage-induced  apoptosis, and implicate this pathway in AD pathogenesis.Cell Death and Differentiation advance online publication, 11 January 2013; doi:10.1038/cdd.2012.162.




TÍTULO / TITLE:  - Low expression of nucleus accumbens-associated protein 1 predicts poor prognosis  for patients with pancreatic ductal adenocarcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Pathol Int. 2012 Dec;62(12):802-10. doi: 10.1111/pin.12020.

            ●● Enlace al texto completo (gratuito o de pago) 1111/pin.12020

AUTORES / AUTHORS:  - Nishi T; Maruyama R; Urano T; Nakayama N; Kawabata Y; Yano S; Yoshida M; Nakayama K; Miyazaki K; Takenaga K; Tanaka T; Tajima Y

INSTITUCIÓN / INSTITUTION:  - Department of Digestive and General Surgery, Shimane University Faculty of Medicine, Izumo, Japan.

RESUMEN / SUMMARY:  - Nucleus accumbens-associated protein 1 (NAC1) is overexpressed in various carcinomas including ovarian, cervical, breast, and pancreatic carcinomas. High expression of NAC1 is considered to have adverse effects on prognosis through negative regulation of growth arrest and DNA-damage-inducible 45-gamma interacting protein 1 (GADD45GIP1) in ovarian and cervical carcinomas. In the present study, the expression of NAC1 in pancreatic ductal adenocarcinoma (PDA) was measured using immunohistochemistry and computer-assisted image analysis in order to investigate its correlation with various clinicopathological parameters  and prognosis. Patients with low-NAC1 PDA had worse overall survival (P = 0.0010) and a shorter disease-free survival (P = 0.0036) than patients with high-NAC1 PDA. This was a clinical effect opposite to that reported in ovarian and cervical carcinomas. Furthermore, knockdown of NAC1 in pancreatic carcinoma cell lines did not increase expression of the GADD45GIP1 protein. These results indicate that the gene(s) regulated by NAC1 vary depending on the types of carcinoma or originating tissue, and that low expression of NAC1 predicts poor prognosis for patients with PDA.




TÍTULO / TITLE:  - Neurosarcoidosis in a patient treated with tumor necrosis factor alpha inhibitors.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Neurol. 2013 Jan 10.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00415-012-6726-9

AUTORES / AUTHORS:  - Mao-Draayer Y; Cash T

INSTITUCIÓN / INSTITUTION:  - Neurology Department, University of Michigan, Ann Arbor, MI, 48103, USA, maodraay@med.umich.edu.




TÍTULO / TITLE:  - Plasma DNA integrity indicates response to neoadjuvant chemotherapy in patients with locally confined breast cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Clin Pharmacol Ther. 2013 Jan;51(1):59-62.

AUTORES / AUTHORS:  - Lehner J; Stotzer OJ; Fersching DM; Nagel D; Holdenrieder S

INSTITUCIÓN / INSTITUTION:  - Institute of Clinical Chemistry, University Hospital Munich-Grosshadern, Hematology/Oncology Outpatient Center Munich, Munich and Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.




TÍTULO / TITLE:  - Perihepatic lymph node enlargement is a negative predictor for sustained responses to pegylated interferon-alpha and ribavirin therapy for Japanese patients infected with hepatitis C virus genotype 1.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Hepatol Res. 2013 Jan 3. doi: 10.1111/hepr.12061.

            ●● Enlace al texto completo (gratuito o de pago) 1111/hepr.12061

AUTORES / AUTHORS:  - Hikita H; Enooku K; Satoh Y; Yoshida H; Nakagawa H; Masuzaki R; Tateishi R; Soroida Y; Sato M; Suzuki A; Gotoh H; Iwai T; Yokota H; Koike K; Yatomi Y; Ikeda H

INSTITUCIÓN / INSTITUTION:  - Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan.

RESUMEN / SUMMARY:  - AIM: Although perihepatic lymph node enlargement (PLNE) is reportedly associated  with the negative outcome of interferon therapy for chronic hepatitis C, there were limitations in that the results were obtained in patients with various genotypes, viral loads and treatment regimens. We aimed to precisely clarify the  significance of PLNE in interferon therapy for chronic hepatitis C. METHODS: Between December 2004 and June 2005, 112 patients with hepatitis C virus (HCV) genotype 1 and HCV RNA of more than 100 KIU/mL were enrolled, who underwent pegylated interferon-alpha plus ribavirin therapy thereafter. PLNE was defined as a perihepatic lymph node of more than 1 cm in the longest axis by ultrasonography. RESULTS: The sustained virological response (SVR) rate was lower in patients with PLNE (4/22, 18.2%) than in those without (37/90, 41.1%; P = 0.045) and viral load decline was smaller in patients with PLNE than in those without (P = 0.028). The proportion of PLNE positive patients was the smallest in the SVR group (P = 0.033) among the patient groups divided by the treatment outcome. PLNE was retained as a negative predictor for SVR by multivariate logistic regression analysis (P = 0.012). Furthermore, PLNE was not significantly associated with the mutations at HCV core protein and at interferon sensitivity-determining region, or interleukin-28B polymorphism in 45 patients with HCV genotype 1, enrolled between December 2011 and March 2012. CONCLUSION: PLNE is a negative predictor for SVR in patients with HCV genotype 1 and HCV RNA  of more than 100 KIU/mL treated with pegylated interferon-alpha plus ribavirin, independent of other known predictors for SVR.




TÍTULO / TITLE:  - SP600125, a JNK inhibitor, suppresses growth of JNK-inactive glioblastoma cells through cell-cycle G2/M phase arrest.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Pharmazie. 2012 Nov;67(11):942-6.

AUTORES / AUTHORS:  - Li JY; Huang JY; Xing B; Ren KW; Li M; Wei D; Gu PY; Chen G; Gu B; Zhang GF; Hu WX

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing City, Nanjing, China.

RESUMEN / SUMMARY:  - SP600125 is a well studied inhibitor of c-Jun N-terminal kinase (JNK). Its direct biochemical effects on JNK-inactive tumor cells are usually ignored. In this study, we investigated the effects of SP600125 on JNK-inactive U251 human glioblastoma cells. Our results demonstrate that, 20 microM or more SP600125 can  induce significant cell growth inhibition and cell-cycle G2/M phase arrest in U251 cells. Interestingly, we also found that SP600125 can stop the duplicated chromosomes from separating into two cells and the karyokinesis progression. Our  study opened up a new perspective for further studies involved in JNK inhibitors  or anti-glioma therapy.




TÍTULO / TITLE:  - Pro-adrenomedullin as a Novel Biomarker for Predicting Infections and Response to Antimicrobials in Febrile Patients With Hematologic Malignancies.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Infect Dis. 2013 Jan 29.

            ●● Enlace al texto completo (gratuito o de pago) 1093/cid/cis1029

AUTORES / AUTHORS:  - Al Shuaibi M; Bahu RR; Chaftari AM; Al Wohoush I; Shomali W; Jiang Y; Debiane L; Raad S; Jabbour J; Al Akhrass F; Hachem RY; Raad I

INSTITUCIÓN / INSTITUTION:  - Department of Infectious Diseases, University of Texas MD Anderson Cancer Center, Houston.

RESUMEN / SUMMARY:  - Background. Health professionals and researchers have become increasingly interested in biomarkers that help them in diagnosis of infections with recent growing attention to procalcitonin (PCT) and pro-adrenomedullin (proADM).Methods. This study compares proADM to PCT as diagnostic and prognostic biomarkers of infection in febrile patients with hematologic malignancies (HMs). From June 2009 to December 2010, 340 febrile HM patients were evaluated for presence of sepsis,  systemic inflammatory response syndrome (SIRS), documented infections, and response to antimicrobial therapy.Results. ProADM and PCT levels were measured at onset of fever and then on days 4-7 afterward. Of the 340 patients, 103 had definite sepsis, and 159 had SIRS. Only proADM initial levels were significantly  higher in patients with localized bacterial infections than in those with no documented infection (P = .019) and in patients with definite sepsis than those with SIRS (P = .023). The initial proADM and PCT levels were significantly higher in neutropenic patients with BSIs than in those without documented infections (P  = .010 and P = . 011, respectively). Follow-up, proADM, and PCT levels decreased  significantly in response to antimicrobial therapy in patients with bacterial infections (BSIs or localized; P = .007 and P = .002, respectively).Conclusions.  ProADM and PCT have promising roles in assisting clinicians in managing febrile HM patients. However, proADM appears to have the advantage of predicting localized bacterial infection and differentiating sepsis from SIRS.




TÍTULO / TITLE:  - Sense and nonsense of high-dose cytarabine for acute myeloid leukemia.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Blood. 2013 Jan 3;121(1):26-8. doi: 10.1182/blood-2012-07-444851.

            ●● Enlace al texto completo (gratuito o de pago) 1182/blood-2012-07-444851

AUTORES / AUTHORS:  - Lowenberg B

INSTITUCIÓN / INSTITUTION:  - Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.

RESUMEN / SUMMARY:  - High-dose cytarabine applied during remission induction or as consolidation after attainment of a complete remission has become an established element in the treatment of adults with acute myeloid leukemia. Recent evidence has challenged the need for these exceptionally high-dose levels of cytarabine. In this review,  we present a reappraisal of the usefulness of high-dose cytarabine for acute myeloid leukemia treatment.




TÍTULO / TITLE:  - BTB/POZ domain-containing protein 7: Epithelial-mesenchymal transition promoter and prognostic biomarker of hepatocellular carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Hepatology. 2013 Jan 16. doi: 10.1002/hep.26268.

            ●● Enlace al texto completo (gratuito o de pago) 1002/hep.26268

AUTORES / AUTHORS:  - Tao YM; Huang JL; Zeng S; Zhang S; Fan XG; Wang ZM; Yang HX; Yuan XH; Wang P; Wu F; Luo J; Zeng DY; Shen H

INSTITUCIÓN / INSTITUTION:  - Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan, China.

RESUMEN / SUMMARY:  - Epithelial-mesenchymal transition (EMT) is a critical step in the metastasis of hepatocellular carcinoma (HCC). BTB/POZ domain-containing protein 7 (BTBD7) regulates EMT-associated proteins implicated in HCC progression. However, the role(s) of BTBD7 in HCC have not been identified. Using highly metastatic HCC HCCLM3 cells, immortalized L02 hepatocytes, metastatic HCC animal models and three independent cohorts of HCC patient specimens, we aimed to determine the involvement of BTBD7 in HCC metastasis. We show that BTBD7 mRNA and protein was highly expressed in HCC cells and tumor tissues, with such expression being associated with: enhanced cell motility, venous invasion, and poor prognosis. BTBD7 promoted HCC angiogenesis and metastasis in vitro and in vivo, but did not  influence cell proliferation or colony formation. BTBD7 enhancement of HCC invasion and EMT phenotype occurred via activation of a RhoC-Rock2-FAK signaling  pathway resulting in MMP-2/9 production and microvessel formation. Applying a predictive risk score model, Cox regression analysis revealed that high BTBD7 expression integrated with high microvessel density was a powerful independent predictive factor of HCC clinical outcome. Conclusion: The present study identifies BTBD7 as a novel candidate prognostic factor and a potential therapeutic target of HCC. (HEPATOLOGY 2013.).




TÍTULO / TITLE:  - Prediction of response to chemotherapy in anaplastic glioma: how many markers does it take?

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Clin Oncol. 2013 Jan 20;31(3):297-8. doi: 10.1200/JCO.2012.46.9627. Epub 2012 Dec 26.

            ●● Enlace al texto completo (gratuito o de pago) 1200/JCO.2012.46.9627


INSTITUCIÓN / INSTITUTION:  - The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 431,  Houston, TX 77030; jdegroot@mdanderson.org.




TÍTULO / TITLE:  - The glucocorticoid receptor gene polymorphism N363S predisposes to more severe toxic side effects during pediatric acute lymphoblastic leukemia (ALL) therapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Hematol. 2013 Jan 26.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12185-012-1236-1

AUTORES / AUTHORS:  - Eipel OT; Nemeth K; Torok D; Csordas K; Hegyi M; Ponyi A; Ferenczy A; Erdelyi DJ; Csoka M; Kovacs GT

INSTITUCIÓN / INSTITUTION:  - 2nd Department of Paediatrics, Semmelweis University, Faculty of Medicine, Tuzolto u.7-9, Budapest, 1094, Hungary.

RESUMEN / SUMMARY:  - The survival rates in childhood acute lymphoid leukemia (ALL) have improved dramatically; however, patients still suffer from a variety of drug-related toxicities. Individualized therapy regimens promise the least toxic therapy regimen with the best hematologic outcome. Our aim was to investigate whether increased individual glucocorticoid sensitivity due to the N363S polymorphism of  the glucocorticoid receptor increased susceptibility to steroid-related toxicities during ALL therapy. A total of 346 pediatric ALL patients were involved in the present study. N363S carrier status was investigated by allele-specific PCR. Clinical and laboratory signs of glucocorticoid-related toxicities, Day 8 prednisone response, and 5-year event-free survival were analyzed and compared retrospectively. Thirty-two of the 346 patients were heterozygous carriers (9.2 %). Hepatotoxicity (31.3 vs. 11.2 %, p = 0.004, carriers and non-carriers, respectively) and glucose metabolism abnormalities (18.8 vs. 3.8 %, p = 0.001, carriers and non-carriers, respectively) were significantly more frequent among carriers. There was no difference in the incidence of hypertension and encephalopathy/psychosis among carriers and non-carriers. Carriers were also more prone to have a combination of toxicities.  All 363S carriers were good prednisone responders (100 %) and had significantly better 5-year event-free survival rates (93.1 vs. 71.86 %, p = 0.012), whereas among non-carriers there were more poor prednisone responders (8.28 %) and worse  5-year event-free survival rates. Patients with the N363S polymorphism in the glucocorticoid receptor are more prone to steroid-related toxicity during ALL therapy and should be monitored more closely. Patients with N363S polymorphism of the glucocorticoid receptor may be appropriate candidates for inclusion in the design of individualized therapies.




TÍTULO / TITLE:  - Hypertension as a predictive biomarker in bevacizumab treatment for colorectal cancer patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Med Oncol. 2013 Mar;30(1):327. doi: 10.1007/s12032-012-0327-4. Epub 2012 Dec 20.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12032-012-0327-4

AUTORES / AUTHORS:  - Tahover E; Uziely B; Salah A; Temper M; Peretz T; Hubert A

INSTITUCIÓN / INSTITUTION:  - Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, POB 12000, Jerusalem, 91120, Israel, esthert@hadassah.org.il.

RESUMEN / SUMMARY:  - Bevacizumab treatment is associated with an increased risk of hypertension (HTN), a potential marker for effectiveness. We aimed to assess whether grades 2-3 HTN during bevacizumab treatment was associated with increased overall survival (OS)  or progression-free survival (PFS). One hundred and eighty-one patients with metastatic colorectal cancer (CRC), who were treated in our Department from January 2009-February 2011 were included. Bevacizumab was administered jointly with standard first- or second-line chemotherapy protocols. Blood pressure was measured before each treatment. HTN was graded using common toxicity criteria. There were 181 CRC patients. Grades 2-3 HTN developed in 81 patients (44.75 %) but not in 100 patients (55.25 %); no patient developed grades 4-5 HTN. Median follow-up was 15.2 months. HTN was associated with better OS in HTN-positive versus HTN-negative patients (median not reached vs. 36.8 months, p = 0.029) and  better PFS (29.9 vs. 17.2 months, p = 0.024, respectively). Bevacizumab-related HTN may represent a biomarker for clinical benefit in metastatic colorectal cancer patients.




TÍTULO / TITLE:  - Impairment of Glioma Stem Cell Survival and Growth by a Novel Inhibitor for Survivin-Ran Protein Complex.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Jan 18.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-0647

AUTORES / AUTHORS:  - Guvenc H; Pavlyukov MS; Joshi K; Kurt H; Banasavadi-Siddegowda YK; Mao P; Hong C; Yamada R; Kwon CH; Bhasin D; Chettiar S; Kitange G; Park IH; Sarkaria JN; Li C; Shakhparonov MI; Nakano I

INSTITUCIÓN / INSTITUTION:  - Authors’ Affiliations: Department of Neurological Surgery; Division of Medicinal  Chemistry and Pharmacognosy, College of Pharmacy; James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota; Shemiakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia; and Department of Neurosurgery, The First Affiliated Hospital, School of Medicine, Xi’an, Jiaotong University, Xi’an, China.

RESUMEN / SUMMARY:  - PURPOSE: Glioblastoma multiforme (GBM) is a devastating disease. Recent studies suggest that the stem cell properties of GBM contribute to the development of therapy resistance.EXPERIMENTAL DESIGN: The expression of Survivin and Ran was evaluated by immunohistochemistry with GBM tissues, and quantitative reverse transcriptase (qRT)-PCR and immunocytochemistry with patient-derived GBM sphere cultures. With a computational structure-based drug design, 11 small-molecule compounds were designed, synthesized, and evaluated as inhibitor candidates for the molecular interaction of Survivin protein. The molecular mechanism of the lead compound, LLP-3, was determined by Western blot, ELISA, in situ proximity ligation assay, and immunocytochemistry. The effects of LLP-3 treatment on GSCs were evaluated both in vitro and in vivo. Quantitative immunohistochemistry was carried out to compare Survivin expression in tissues from 44 newly diagnosed and 31 recurrent post-chemoradiation GBM patients. Lastly, the sensitivities of temozolomide-resistant GBM spheres to LLP-3 were evaluated in vitro.RESULTS: Survivin and Ran were strongly expressed in GBM tissues, particularly in the perivasculature, and also in patient-derived GSC cultures. LLP-3 treatment disrupted the Survivin-Ran protein complex in cancer cells and abolished the growth of patient-derived GBM spheres in vitro and in vivo. This inhibition was dependent on caspase activity and associated with p53 status of cells. Immunohistochemistry showed that Survivin expression is significantly increased in recurrent GBM compared with newly diagnosed tumors, and temozolomide-resistant GBM spheres exhibited high sensitivities to LLP-3 treatment.CONCLUSIONS: Disruption of the Survivin-Ran complex by LLP-3 abolishes survival and growth of  GSCs both in vitro and in vivo, indicating an attractive novel therapeutic approach for GBM. Clin Cancer Res; 19(3); 1-12. ©2012 AACR.




TÍTULO / TITLE:  - Polymorphisms of the UDP-Glucuronosyl Transferase 1A Genes Are Associated with Adverse Events in Cancer Patients Receiving Irinotecan-Based Chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Tohoku J Exp Med. 2013;229(2):107-14.

AUTORES / AUTHORS:  - Inoue K; Sonobe M; Kawamura Y; Etoh T; Takagi M; Matsumura T; Kikuyama M; Kimura M; Minami S; Utsuki H; Yamazaki T; Suzuki T; Tsuji D; Hayashi H; Itoh K

INSTITUCIÓN / INSTITUTION:  - Department of Clinical Pharmacology and Genetics, School of Pharmaceutical Sciences, University of Shizuoka.

RESUMEN / SUMMARY:  - A prodrug, irinotecan (CPT-11), is a semisynthetic derivative of camptothecin. It inhibits topoisomerase I and is used for treatment of lung, stomach, and colon cancers in Japan. The active form of CPT-11, SN-38, causes the adverse events such as neutropenia and diarrhea. Since SN-38 is metabolized to non-toxic SN-38-glucuronide by hepatic uridine diphosphate glucuronosyl transferase (UGT) 1A enzymes, UGT1A enzyme activities may influence adverse events of CPT-11. UGT1A enzymes consist of three isozymes (1A1, 1A7, 1A9), and their genes are characterized by polymorphisms. Here, to identify the genetic factors that affect the adverse events of CPT-11, we determined the polymorphism in three UGT 1A isozyme genes in 45 inpatients with lung, colon, or stomach cancer. The univariate and multivariate analysis of patients’ physiological and genetic factors revealed that one or more genotypes of UGT1A1*6/*28, UGT1A7*3/*3, and UGT1A9*1/*1 may enhance the adverse events. Each of the first two genotypes is expected to generate the enzyme with low catalytic activity. The UGT1A9*1 represents the wild-type allele, which however provides the lower catalytic activity, compared to the UGT1A9*22 variant that is common in this study population. Indeed, four (67%) out of six patients who carry one or more of the above-mentioned genotypes suffered from adverse events, leading to the discontinuation of chemotherapy or the decreased dose of CPT-11. By contrast, only six (15%) out of 39 patients with other genotypes suffered from adverse events. In conclusion, UGT1A1*6/*28, UGT1A7*3/*3, and UGT1A9*1/*1 should be taken into consideration as markers for preventing severe adverse events of CPT-11 administration.




TÍTULO / TITLE:  - Successful azacitidine treatment with increase of regulatory T cells for relapsed acute myeloid leukemia after allogeneic stem cell transplantation.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Leuk Lymphoma. 2013 Jan 9.

            ●● Enlace al texto completo (gratuito o de pago) 3109/10428194.2013.764420

AUTORES / AUTHORS:  - Yamamoto W; Tachibana T; Ogusa E; Matsumoto K; Maruta A; Ishigatsubo Y; Kanamori H




TÍTULO / TITLE:  - Erratum to: The use of the (13)C-dextromethorphan breath test for phenotyping CYP2D6 in breast cancer patients using tamoxifen: association with CYP2D6 genotype and serum endoxifen levels.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Chemother Pharmacol. 2013 Jan 12.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00280-012-2065-x

AUTORES / AUTHORS:  - Opdam FL; Dezentje VO; den Hartigh J; Modak AS; Vree R; Batman E; Smorenburg CH; Nortier JW; Gelderblom H; Guchelaar HJ

INSTITUCIÓN / INSTITUTION:  - Department of Clinical Oncology, K-1, Leiden University Medical Center, P.O. box  9600, 2300 RC, Leiden, The Netherlands, f.l.opdam@lumc.nl.




TÍTULO / TITLE:  - The use of the (13)C-dextromethorphan breath test for phenotyping CYP2D6 in breast cancer patients using tamoxifen: association with CYP2D6 genotype and serum endoxifen levels.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Chemother Pharmacol. 2012 Dec 11.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00280-012-2034-4

AUTORES / AUTHORS:  - Opdam FL; Dezentje VO; den Hartigh J; Modak AS; Vree R; Batman E; Smorenburg CH; Nortier JW; Gelderblom H; Guchelaar HJ

INSTITUCIÓN / INSTITUTION:  - Department of Clinical Oncology, K-1, Leiden University Medical Center, P.O. box  9600, 2300 RC, Leiden, The Netherlands, f.l.opdam@lumc.nl.

RESUMEN / SUMMARY:  - PURPOSE: Adjuvant therapy with tamoxifen significantly reduces breast cancer recurrence and mortality in estrogen receptor positive disease. CYP2D6 is the main enzyme involved in the activation of the prodrug tamoxifen into the anti-estrogen endoxifen. Endoxifen is thought to be a main determinant for clinical efficacy in breast cancer patients using tamoxifen. As the large interindividual variation in endoxifen levels is only partly explained by CYP2D6  genotype, we explored the use of the (13)C-dextromethorphan breath test (DM-BT) for phenotyping CYP2D6 and to predict serum steady-state endoxifen levels as a marker for clinical outcome in breast cancer patients using tamoxifen. METHODS: In 65 patients with early breast cancer using tamoxifen, CYP2D6 phenotype was assessed by DM-BT. CYP2D6 genotype using Amplichip and serum steady-state levels  of endoxifen were determined. Genotype was translated into the gene activity score and into ultrarapid, extensive, heterozygous extensive, intermediate or poor metabolizer CYP2D6 predicted phenotype. RESULTS: CYP2D6 phenotype determined by the DM-BT explained variation in serum steady-state endoxifen levels for 47.5  % (R (2) = 0.475, p < 0.001). Positive and negative predictive values for a recently suggested threshold serum level of endoxifen (5.97 ng/mL) for breast cancer recurrence rate were 100 and 90 %, respectively, for both CYP2D6 phenotype by DM-BT (delta-over-baseline at t = 50 min (DOB(50)) values of 0.7-0.9) and genotype (CYP2D6 gene activity score of 1.0). CONCLUSION: DM-BT might be, along with CYP2D6 genotyping, of value in selection of individualized endocrine therapy in patients with early breast cancer, especially when concomitant use of CYP2D6 inhibiting medication alters the phenotype.




TÍTULO / TITLE:  - Cystine/glutamic acid transporter is a novel marker for predicting poor survival  in patients with hepatocellular carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Rep. 2013 Feb;29(2):685-9. doi: 10.3892/or.2012.2162. Epub 2012 Nov 30.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2012.2162

AUTORES / AUTHORS:  - Kinoshita H; Okabe H; Beppu T; Chikamoto A; Hayashi H; Imai K; Mima K; Nakagawa S; Ishimoto T; Miyake K; Yokoyama N; Ishiko T; Baba H

INSTITUCIÓN / INSTITUTION:  - Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.

RESUMEN / SUMMARY:  - Cystine/glutamic acid transporter (xCT) plays a role in tumor progression by regulating the redox status in several types of cancers. To demonstrate the importance of xCT expression for predicting the prognosis of hepatocellular carcinoma (HCC), we analyzed xCT gene expression in 130 paired HCC and non-cancerous tissues. xCT protein expression was confirmed using 7 HCC cell lines and samples from human subjects. xCT mRNA expression was detected in 34 (26%) tumor tissues. Expression of xCT was higher in HCC tissues compared to the  corresponding normal tissues according to quantitative reverse transcriptase-polymerase chain reaction findings (P<0.0001). Patients in the group presenting with xCT mRNA expression showed poorer overall and disease-free  survival than did those with an absence of xCT mRNA (P=0.0130 and 0.0416, respectively). xCT mRNA expression proved to be an independent factor for poor prognosis in a multivariate analysis of overall survival (hazard ratio, 1.68; 95% CI, 1.03-2.92). We observed xCT protein expression in both the HCC cell lines and in human tissue samples. In conclusion, the findings of the present study suggest that xCT is useful as a predictive marker for patient prognosis and that it may be a novel therapeutic target for HCC.




TÍTULO / TITLE:  - Collections of simultaneously altered genes as biomarkers of cancer cell drug response.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Res. 2013 Jan 21.

            ●● Enlace al texto completo (gratuito o de pago) 1158/0008-5472.CAN-12-3122

AUTORES / AUTHORS:  - Masica DL; Karchin R

INSTITUCIÓN / INSTITUTION:  - Biomedical Engineering/Institute of Computational Medicine, Johns Hopkins University.

RESUMEN / SUMMARY:  - Abstract Computational analysis of cancer pharmacogenomics data has resulted in biomarkers predictive of drug response, but the majority of response is not captured by current methods. Methods typically select single biomarkers or groups of related biomarkers, but do not account for response that is strictly dependent on many simultaneous genetic alterations. This shortcoming reflects the combinatorics and multiple-testing problem associated with many-body biological interactions. We developed a novel approach, MOCA (Multivariate Organization of Combinatorial Alterations), to partially address these challenges. Extending on previous work that accounts for pairwise interactions, the approach rapidly combines many genomic alterations into biomarkers of drug response, using Boolean set operations coupled with optimization; in this framework the union, intersection, and difference Boolean set operations are proxies of molecular redundancy, synergy, and resistance, respectively. The algorithm is fast, broadly applicable to cancer genomics data, is of immediate utility for prioritizing cancer pharmacogenomics experiments, and recovers known clinical findings without bias. Furthermore, the results presented here connect many important, previously  isolated observations. Major Findings When applied to 416 pharmacogenomically characterized cancer cell lines, MOCA identifies many known and potential markers of drug response. For instance, correlation with ERBB inhibitor response drastically increased when considering EGFR (ERBB1), ERBB2, ERBB3, ERBB4, and KRAS alterations in a single feature. Similarly, a feature combining IGF1, IGF1R, and RAD51 drastically increased correlation with IGF1R inhibitor response, relative to any of these three genetic markers considered in isolation. This approach is also powerful for determining subsets of site-specific mutations, for a particular gene, that increase correlation with drug response. For example, MOCA captures the differential EGFR inhibitor response conferred by common EGFR mutations. Similarly, we find specific HDAC1 mutations cooperate with HDAC5 overexpression to potentiate cells to the HDAC inhibitor panobinostat. Additionally, considering all pairwise gene-drug interactions, MOCA recovers known and compelling correlations, including: RTK inhibitor resistance via c-MET, EGFR, ERBB2, and PDGFRB kinase switching; mutual exclusivity of TP53 mutation and response to the MDM2 inhibitor nutlin-3; greater nutilin-3 potentiation via MDM4, rather than MDM2, overexpression; MEK and RAF inhibitor response in BRAF mutated  cell lines; and, MEK inhibitor potentiating NRAS mutations.




TÍTULO / TITLE:  - IgD cross-linking induces gene expression profiling changes and enhances apoptosis in chronic lymphocytic leukemia cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Leuk Res. 2013 Jan 18. pii: S0145-2126(12)00504-8. doi: 10.1016/j.leukres.2012.12.019.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.leukres.2012.12.019

AUTORES / AUTHORS:  - Tavolaro S; Peragine N; Chiaretti S; Ricciardi MR; Raponi S; Messina M; Santangelo S; Marinelli M; Di Maio V; Mauro FR; Del Giudice I; Foa R; Guarini A

INSTITUCIÓN / INSTITUTION:  - Division of Hematology, Department of Cellular Biotechnologies and Hematology, “Sapienza” University, Rome, Italy.

RESUMEN / SUMMARY:  - Gene profile and functional changes upon IgD cross-linking were evaluated in chronic lymphocytic leukemia (CLL). Microarrays highlighted responsiveness to IgD in all cases, independently of clinico-biological characteristics. Stimulated samples exhibited the down-regulation of transcripts of B-cell receptor signaling and cell-adhesion at 24h and the up-modulation of differentiation and apoptosis genes at 48h. A significant increase in apoptosis upon ligation was also documented. Furthermore, comparison between IgD and IgM stimulation displayed a differential transcriptional/functional response. In conclusion, CLL respond to IgD displaying expression changes and cell-death enhancement, indicating the apoptosis induction via-IgD as an alternative approach for CLL management.




TÍTULO / TITLE:  - Aryl Hydrocarbon Receptor is a Target of 17-allylamino-17-demethoxygeldanamycin and Enhances its Anticancer Activity in Lung Adenocarcinoma Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Pharmacol. 2012 Dec 10.

            ●● Enlace al texto completo (gratuito o de pago) 1124/mol.112.081646

AUTORES / AUTHORS:  - Chen PH; Chang JT; Li LA; Tsai HT; Shen MY; Lin PP

INSTITUCIÓN / INSTITUTION:  - 1 National Health Research Institutes;

RESUMEN / SUMMARY:  - We have demonstrated that aryl hydrocarbon receptor (AhR) is overexpressed in lung adenocarcinoma (AD). AhR is usually associated with heat shock protein 90 (Hsp90) in the cytoplasm. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), an Hsp90 inhibitor, is currently under evaluation for its anticancer activity in clinical trials. Here, we investigated whether AhR plays a role in 17-AAG-mediated anticancer activity by functioning as a downstream target or by modulating its anticancer efficacy. AhR expression in lung AD cells was modulated by siRNA interference or overexpression. Tumor growth was determined with colony  formation in vitro or in vivo. Anticancer activity of 17-AAG was determined by measuring cell viability, cell cycle distribution and expression of cell cycle regulators. Proteins and mRNA levels were examined by immunoblotting and the real-time reverse transcription-polymerase chain reaction, respectively. In this  study, AhR overexpression positively modulated growth of lung AD cells, at least  partially, via RelA-dependent mechanisms. Although treatment with 17-AAG reduced  AhR levels and AhR-regulated gene expression in lung AD cells, AhR expression increased anticancer activity of 17-AAG. In addition, 17-AAG treatment reduced cell viability, CDK2, CDK4, cyclin E, cyclin D1 and phosphorylated Rb levels in AhR-expressing lung AD cells. NAD(P)H:quinone oxidoreductase (NQO1), which is regulated by AhR, was shown to increase anticancer activity of 17-AAG in cells. Knockdown of NQO1 expression attenuated the reduction of cell cycle regulators by 17-AAG treatment in AhR overexpressed cells. We demonstrated that AhR protein not only functions as a downstream target of 17-AAG, but also enhances anticancer activity of 17-AAG in lung AD cells.




TÍTULO / TITLE:  - Sodium orthovanadate associated with pharmacological doses of ascorbate causes an increased generation of ROS in tumor cells that inhibits proliferation and triggers apoptosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochem Biophys Res Commun. 2013 Jan 18;430(3):883-888. doi: 10.1016/j.bbrc.2012.12.061. Epub 2012 Dec 19.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bbrc.2012.12.061

AUTORES / AUTHORS:  - Gunther TM; Kviecinski MR; Baron CC; Felipe KB; Farias MS; da Silva FO; Bucker NC; Pich CT; Ferreira EA; Filho DW; Verrax J; Calderon PB; Pedrosa RC

INSTITUCIÓN / INSTITUTION:  - Departamento de Bioquimica, Universidade Federal de Santa Catarina, Florianopolis, Brazil.

RESUMEN / SUMMARY:  - Pharmacological doses of ascorbate were evaluated for its ability to potentiate the toxicity of sodium orthovanadate (Na(3)VO(4)) in tumor cells. Cytotoxicity, inhibition of cell proliferation, generation of ROS and DNA fragmentation were assessed in T24 cells. Na(3)VO(4) was cytotoxic against T24 cells (EC(50)=5.8muM  at 24h), but in the presence of ascorbate (100muM) the EC(50) fell to 3.3muM. Na(3)VO(4) plus ascorbate caused a strong inhibition of cell proliferation (up to 20%) and increased the generation of ROS (4-fold). Na(3)VO(4) did not directly cleave plasmid DNA, at this aspect no synergism was found occurring between Na(3)VO(4) and ascorbate once the resulting action of the combination was no greater than that of both substances administered separately. Cells from Ehrlich  ascites carcinoma-bearing mice were used to determine the activity of antioxidant enzymes, the extent of the oxidative damage and the type of cell death. Na(3)VO(4) alone, or combined with ascorbate, increased catalase activity, but only Na(3)VO(4) plus ascorbate increased superoxide dismutase activity (up to 4-fold). Oxidative damage on proteins and lipids was higher due to the treatment  done with Na(3)VO(4) plus ascorbate (2-3-fold). Ascorbate potentiated apoptosis in tumor cells from mice treated with Na(3)VO(4). The results indicate that pharmacological doses of ascorbate enhance the generation of ROS induced by Na(3)VO(4) in tumor cells causing inhibition of proliferation and apoptosis. Apoptosis induced by orthovanadate and ascorbate is closer related to inhibition  on Bcl-xL and activation of Bax. Our data apparently rule out a mechanism of cell demise p53-dependent or related to Cdk2 impairment.




TÍTULO / TITLE:  - Interleukin-17 enhances the production of interferon-gamma and tumour necrosis factor-alpha by bone marrow T lymphocytes from patients with lower risk myelodysplastic syndromes.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur J Haematol. 2013 Jan 19. doi: 10.1111/ejh.12074.

            ●● Enlace al texto completo (gratuito o de pago) 1111/ejh.12074

AUTORES / AUTHORS:  - Zhang Z; Li X; Guo J; Xu F; He Q; Zhao Y; Yang Y; Gu S; Zhang Y; Wu L; Chang C

INSTITUCIÓN / INSTITUTION:  - The Sixth People’s Hospital affiliated with Shanghai Jiaotong University, Shanghai Jiaotong University School of Medicine, Shanghai, China.

RESUMEN / SUMMARY:  - INTRODUCTION: Lower risk myelodysplastic syndromes (MDSs) are characterised by increased apoptosis of haematopoietic cells in the bone marrow (BM). The mechanism driving this excessive apoptosis involves multiple immune molecules, including inflammatory cytokines such as interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) and interleukins (ILs). Interleukin-17(IL-17) is the hallmark cytokine produced by CD4+ Th17 cells, and IL-17 mediates activation of the adaptive T cell response, inducing an inflammatory cytokine environment. However, little is known about the role of IL-17 in MDS-associated immune dysfunction. METHODS: A total of 47 patients with myelodysplastic syndromes were enrolled in this study, and the levels of IL-17 and IL-17 receptor (IL-17R) in BM mononuclear cells (BMNCs) were detected by real-time polymerase chain reaction (RQ-PCR) and enzyme-linked immunosorbent assay (ELISA). Then, BMNCs were stimulated with recombinant human IL-17 (rhIL-17), and flow cytometry  was used to analyse the production of IFN-gamma and TNF-alpha by CD4+ and CD8+ T  lymphocytes from lower risk MDS patients. Characterisation of IL-17 expression in patients with the HLA-DR15 allele or hypocellularity was also performed. RESULTS: mRNA levels for both IL-17 and the IL-17R subunits in BMNCs and for IL-17 in the  BM and plasma were higher in patients with lower risk MDS as compared to patients with higher risk MDS and normal controls. The production of IFN-gamma and TNF-alpha by CD4+ and CD8+ T lymphocytes from lower risk MDS patients could be enhanced by recombinant human IL-17 (rhIL-17) treatment. Furthermore, increased IL-17 expression was associated with more severe anaemia in MDS patients. CONCLUSION: Elevated IL-17 levels and IL-17-induced IFN-gamma and TNF-alpha overproduction may be involved in the pathogenesis of lower risk MDS. © 2013 John Wiley & Sons A/S.




TÍTULO / TITLE:  - The phosphatidylinositol-3 kinase I inhibitor BKM120 induces cell death in B-chronic lymphocytic leukemia cells in vitro.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Cancer. 2012 Dec 12. doi: 10.1002/ijc.27989.

            ●● Enlace al texto completo (gratuito o de pago) 1002/ijc.27989

AUTORES / AUTHORS:  - Amrein L; Shawi M; Grenier J; Aloyz R; Panasci L

INSTITUCIÓN / INSTITUTION:  - Department of Oncology, Faculty of Medicine, McGill University, Lady Davis Institute-Segal Cancer Center from the Jewish General Hospital, Montreal, Quebec, Canada.

RESUMEN / SUMMARY:  - BKM120, a pan class I PI3K inhibitor, was cytotoxic in the majority of primary B-chronic lymphocytic leukemia (CLL) lymphocytes, including samples from patients who have a high-risk for poor response to treatment (patient with del11 and del17) at clinically obtainable concentrations. The PI3Kdelta inhibitor Cal-101 is cytotoxic in B-CLL lymphocytes in vitro and is active in the treatment of CLL  in vivo. Interestingly, we demonstrated that BKM120 is 3.6 fold more toxic than Cal-101 in malignant B-CLL lymphocytes in vitro. BKM120 cytotoxicity correlated with the basal expression of proteins involved in the PI3K/Akt pathway. A protein signature of PI3K pathway proteins predicts the response to BKM120 treatment. In  the primary B-CLL lymphocytes tested in vitro, BKM120 decreased the phosphorylation status of molecular biomarkers used as indicators of PI3K pathway inhibition in vivo. Also, BKM120 induced apoptosis in primary B-CLL cells culture in the presence and absence of stromal cell support. Our findings suggest that BKM120 should be tested clinically in CLL.




TÍTULO / TITLE:  - Research resource: nuclear receptors as transcriptome: discriminant and prognostic value in breast cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Endocrinol. 2013 Feb;27(2):350-65. doi: 10.1210/me.2012-1265. Epub 2013 Jan 4.

            ●● Enlace al texto completo (gratuito o de pago) 1210/me.2012-1265

AUTORES / AUTHORS:  - Muscat GE; Eriksson NA; Byth K; Loi S; Graham D; Jindal S; Davis MJ; Clyne C; Funder JW; Simpson ER; Ragan MA; Kuczek E; Fuller PJ; Tilley WD; Leedman PJ; Clarke CL

INSTITUCIÓN / INSTITUTION:  - Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia. G.Muscat@uq.edu.au; or Christine L. Clarke, Westmead Millennium Institute, Sydney Medical School, Westmead, University of Sydney, New  South Wales, Australia. E-mail: christine.clarke@sydney.edu.au.

RESUMEN / SUMMARY:  - To identify biologically relevant groupings or clusters of nuclear receptors (NR) that are associated with breast neoplasia, with potentially diagnostic, discriminant or prognostic value, we quantitated mRNA expression levels of all 48 members of the human NR superfamily by TaqMan low-density array analysis in 116 curated breast tissue samples, including pre- and postmenopausal normal breast and both ERalpha(+) and ERalpha(-) tumor tissue. In addition, we have determined  NR levels in independent cohorts of tamoxifen-treated ERalpha(+) and ERalpha(-) tissue samples. There were differences in relative NR mRNA expression between neoplastic and normal breast, and between ER(+) and ER(-) tumors. First, there is overexpression of the NUR77 subgroup and EAR2 in neoplastic breast. Second, we identify a signature of five NR (ERalpha, EAR2, NUR77, TRalpha, and RARgamma) that classifies breast samples with more than 97% cross-validated accuracy into normal or cancer classes. Third, we find a novel negative association between five NR (TRbeta, NUR77, RORgamma, COUP-TFII, and LRH1) and histological grade. Finally, four NR (COUP-TFII, TRbeta, PPARgamma, and MR) are significant predictors of metastasis-free survival in tamoxifen-treated breast cancers, independent of ER expression. The present study highlights the discriminant and prognostic value of NR in breast cancer; identifies novel, clinically relevant, NR signatures; and highlights NR signaling pathways with potential roles in breast cancer pathophysiology and as new therapeutic targets.




TÍTULO / TITLE:  - Vaccination for the prevention and treatment of breast cancer with special focus  on Her-2/neu peptide vaccines.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Breast Cancer Res Treat. 2013 Jan 23.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10549-013-2410-8

AUTORES / AUTHORS:  - Wiedermann U; Davis AB; Zielinski CC

INSTITUCIÓN / INSTITUTION:  - Institute of Specific Prophylaxis and Tropical Medicine, Center for Pathophysiology, Immunology & Infectiology, Medical University of Vienna, Kinderspitalgasse 15, 1090, Vienna, Austria, ursula.wiedermann@meduniwien.ac.at.

RESUMEN / SUMMARY:  - Immunologic interventions in a subset of breast cancer patients represent a well-established therapeutic approach reflecting individualized treatment modalities. Thus, the therapeutic administration of monoclonal antibodies targeting tumor-associated antigens (TAA), such as Her-2/neu, represents a milestone in cancer treatment. However, passive antibody administration suffers from several drawbacks, including frequency and long duration of treatment. These undesirables may be avoidable in an approach based on generating active immune responses against these same targets. Only recently has the significance of tumors in relation to their microenvironments been understood as essential for creating an effective cancer vaccine. In particular, the immune system plays an important role in suppressing or promoting tumor formation and growth. Therefore, activation of appropriate triggers (such as induction of Th1 cells, CD8+ T cells, and suppression of regulatory cells in combination with generation of antibodies  with anti-tumor activity) is a desirable goal. Current vaccination approaches have concentrated on therapeutic vaccines using certain TAA. Many cancer antigens, including breast cancer antigens, have been described and also given priority ranking for use as vaccine antigens by the US National Cancer Institute. One of the TAA antigens which has been thoroughly examined in numerous trials is  Her-2/neu. This review will discuss delivery systems for this antigen with special focus on T and B cell peptide vaccines. Attention will be given to their  advantages and limitations, as well as the use of certain adjuvants to improve anti-cancer responses.




TÍTULO / TITLE:  - Molecular Pathways: Toll-like Receptors in the Tumor Microenvironment: Poor Prognosis or New Therapeutic Opportunity.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Cancer Res. 2012 Dec 27.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-0408

AUTORES / AUTHORS:  - Ridnour LA; Cheng RY; Switzer CH; Heinecke JL; Ambs S; Glynn SA; Young HA; Trinchieri G; Wink DA

INSTITUCIÓN / INSTITUTION:  - Radiation Biology Branch, National Cancer Institute, NIH.

RESUMEN / SUMMARY:  - Numerous reports have described toll-like receptor (TLR) expression in the tumor  microenvironment as it relates to cancer progression, as well as their involvement in inflammation. While TLRs mediate immune surveillance, clinical studies have associated TLR expression in the tumor with poor patient survival, indicating that TLR expression may affect cancer treatment and survival. This review will examine mechanisms where TLR activation up-regulates pro-tumorigenic  pathways including the induction of inducible nitric oxide synthase (NOS2) and cyclooxygenase-2 (COX2), which in turn increase TLR expression and promotes a feed forward loop leading to tumor progression and the development of more aggressive tumor phenotypes. These propagating loops involve cancer cell, stroma  and/or immune cell TLR expression. Because of abundant TLR expression in many human tumors, several TLR agonists are now in clinical and preclinical trials and some have shown enhanced efficacy when used as adjuvant with radiation, chemotherapy or cancer vaccines. These findings suggest that TLR expression influences cancer biology and therapeutic response, which may involve specific interactions within the tumor microenvironment including mediators of inflammation like nitric oxide and the arachidonic acid signaling pathways.




TÍTULO / TITLE:  - DNA Index as a Strong Prognostic Factor in Patients With Adenocarcinoma of the Pancreatic Head: Results of a 5-Year Prospective Study.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Pancreas. 2012 Dec 26.

            ●● Enlace al texto completo (gratuito o de pago) 1097/MPA.0b013e3182773eb6

AUTORES / AUTHORS:  - Kamphues C; Al-Abadi H; Durr A; Al-Abadi N; Schricke D; Bova R; Muller V; Stenzinger A; Klauschen F; Seehofer D; Neuhaus P; Bahra M

INSTITUCIÓN / INSTITUTION:  - From the *Department of General, Visceral and Transplantation Surgery, Charite University Hospital, Berlin, Germany; daggerInstitute of Pathology, University Hospital, Heidelberg, Germany; and double daggerInstitute of Pathology, Charite University Hospital, Berlin, Germany.

RESUMEN / SUMMARY:  - OBJECTIVES: To improve the devastating prognosis of pancreatic cancer; the identification of reliable predictive factors is crucial. The aim of the present  study was to prospectively assess the prognostic value of DNA index determined by image cytometry as an predictive factor in pancreatic head cancer. METHODS: The DNA ploidy and the DNA index of 61 patients were evaluated by DNA image cytometry and were found to be correlated, as well as standard histopathologic parameters,  with patient survival. RESULTS: Through the DNA image cytometry, 15 tumors (24.6%) were identified as diploid and 46 (75.6%) as nondiploid. The median DNA index in the entire cohort was 1.9 (range, 1.0-2.5). Tumor stage, lymph node status, lymph node index, lymphatic invasion, and DNA index were identified as prognostic factors in the univariate analysis, but only DNA index (hazard ratio,  3.137; 95% confidence interval, 1.149-8.566; P = 0.026) and lymph node status (hazard ratio, 0.377; 95% confidence interval, 0.186-0.765; P = 0.007) were identified as independent predictive factors in the multivariate analysis. CONCLUSIONS: The DNA index represents an independent predictive marker in patients with pancreatic head cancer and a potential tool in designing specific treatment strategies for patients with pancreatic cancer.




TÍTULO / TITLE:  - Outcome and predictors of mortality in patients requiring invasive mechanical ventilation due to acute respiratory failure while undergoing ambulatory chemotherapy for solid cancers.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Support Care Cancer. 2013 Jan 12.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00520-012-1709-z

AUTORES / AUTHORS:  - Park SY; Lim SY; Um SW; Koh WJ; Chung MP; Kim H; Kwon OJ; Park HK; Kim SJ; Im YH; Ahn MJ; Suh GY

INSTITUCIÓN / INSTITUTION:  - Division of Pulmonary and Critical Care Medicine, Department of Medicine, Chuncheon Sacred Heart Hospital, Hallym University Medical Center, Chuncheon, Gangwon-do, Republic of Korea.

RESUMEN / SUMMARY:  - PURPOSE: Acute respiratory failure that requires invasive mechanical ventilation  is a leading cause of death in critically ill cancer patients. The aim of this study was to evaluate the outcome and prognostic factors of patients requiring invasive mechanical ventilator for acute respiratory failure, within 1 month of ambulatory chemotherapy for solid cancer. METHODS: A retrospective observational  study of patients who underwent ambulatory chemotherapy at Samsung Medical Center, between January of 2007 and April of 2009, was employed for this study. RESULTS: A total of 51 patients met the inclusion criteria and were included in the study. The median age was 65 years (25-87) and the majority of the patients were male (n = 38, 74.5 %). There were 42 patients (82.3 %) with lung cancer. The most common cause of acute respiratory failure was pneumonia (n = 24, 47.1 %), followed by acute respiratory failure due to extra-pulmonary infection, drug-induced pneumonitis, alveolar hemorrhage, and cancer progression. The intensive care unit (ICU) mortality was 68.6 % and the most common cause of death in the ICU was uncorrected cause of acute respiratory failure. Before adjustment  for others factors, prechemotherapy Eastern Cooperative Oncology Group (ECOG) Performance Scale (PS) (P = 0.03), Sequential Organ Failure Assessment score (P = 0.01), and anemia (P = 0.04) were significantly associated with ICU mortality. However, when adjusted for age, sex, and Acute Physiologic and Chronic Health Evaluation II score, only poor ECOG PS (>/=2) was significantly associated with ICU mortality [OR 6.36 (95 % CI (1.02-39.5))]. CONCLUSIONS: The outcome of patients with acute respiratory failure needing invasive mechanical ventilation during ambulatory chemotherapy for solid cancer is poor. Prechemotherapy performance status is an independent predictor of mortality.




TÍTULO / TITLE:  - Lapatinib-mediated COX-2 Expression Via EGFR/HuR Interaction Enhances the Aggressiveness of Triple-negative Breast Cancer Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Pharmacol. 2013 Jan 25.

            ●● Enlace al texto completo (gratuito o de pago) 1124/mol.112.082743

AUTORES / AUTHORS:  - Hsia TC; Tu CY; Chen YJ; Wei YL; Yu MC; Hsu SC; Tsai SL; Chen WS; Yeh MH; Yen CJ; Yu YL; Huang TC; Huang CY; Hung MC; Huang WC

INSTITUCIÓN / INSTITUTION:  - 1 China Medical University and Hospital;

RESUMEN / SUMMARY:  - Lapatinib, a dual EGFR/HER2 kinase inhibitor, showed clinical benefits in advanced HER2-positive breast cancer patients. Because some triple-negative breast cancers (TNBCs) frequently overexpress EGFR, the anti-tumor activity of lapatinib in such diseases was also tested. However, the results showed a worse event-free survival rate. It remains unknown whether and how lapatinib elicits the aggressiveness of such cancer cells. In this study, our results demonstrated  that lapatinib facilitated axillary and lung metastases of triple-negative MDA-MB-231 breast cancer cells without affecting their viability, leading to worse survival in orthotopic xenograft mice. The lapatinib-increased motility was attributed by the elevation of EGFR through the downregulation of microRNA-7 and  by the subsequent overexpression of cyclooxygenase-2 (COX-2). Strikingly, independent of its kinase activity, the elevated EGFR at least partly stabilized  COX-2 expression by enhancing the binding of HuR to COX-2 mRNA. Our results suggest that lapatinib may increase the migration and invasion of MDA-MB-231 cells by upregulating EGFR and COX-2 through the downregulation of microRNA-7, providing a potential explanation for the worse clinical outcome of TNBC patients who receive lapatinib-based treatment. These findings also shed new light on the  molecular mechanism of COX-2 mRNA stabilization by EGFR in a kinase-independent manner.




TÍTULO / TITLE:  - A Novel Semisynthetic Inhibitor of the FRB Domain of Mammalian Target of Rapamycin Blocks Proliferation and Triggers Apoptosis in Chemoresistant Prostate  Cancer Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Pharmacol. 2013 Feb;83(2):531-41. doi: 10.1124/mol.112.081349. Epub 2012 Dec  3.

            ●● Enlace al texto completo (gratuito o de pago) 1124/mol.112.081349

AUTORES / AUTHORS:  - Morad SA; Schmid M; Buchele B; Siehl HU; El Gafaary M; Lunov O; Syrovets T; Simmet T

INSTITUCIÓN / INSTITUTION:  - Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Helmholtzstr. 20, D-89081 Ulm, Germany. thomas.simmet@uni-ulm.de.

RESUMEN / SUMMARY:  - The mammalian target of rapamycin (mTOR) is a key regulator of cell growth and its uncontrolled activation is a hallmark of cancer. Moreover, mTOR activation has been implicated in the resistance of cancer cells to many anticancer drugs, rendering this pathway a promising pharmacotherapeutic target. Here we explored the capability of a semisynthetic compound to intercept mTOR signaling. We synthesized and chemically characterized a novel, semisynthetic triterpenoid derivative, 3-cinnamoyl-11-keto-beta-boswellic acid (C-KbetaBA). Its pharmacodynamic effects on mTOR and several other signaling pathways were assessed in a number of prostate and breast cancer cell lines as well as in normal prostate epithelial cells. C-KbetaBA exhibits specific antiproliferative and proapoptotic effects in cancer cell lines in vitro as well as in PC-3 prostate cancer xenografts in vivo. Mechanistically, the compound significantly inhibits the cap-dependent transition machinery, decreases expression of eukaryotic translation initiation factor 4E and cyclin D1, and induces G(1) cell-cycle arrest. In contrast to conventional mTOR inhibitors, C-KbetaBA downregulates the phosphorylation of p70 ribosomal S6 kinase, the major downstream target of mTOR complex 1, without concomitant activation of mTOR complex 2/Akt and extracellular signal-regulated kinase pathways, and independently of protein phosphatase 2A, liver kinase B1/AMP-activated protein kinase/tuberous sclerosis complex, and F12-protein binding. At the molecular level, the compound binds to the FKBP12-rapamycin-binding domain of mTOR with high affinity, thereby competing with the endogenous mTOR activator phosphatidic  acid. C-KbetaBA represents a new type of proapoptotic mTOR inhibitor that, due to its special mechanistic profile, might overcome the therapeutic drawbacks of conventional mTOR inhibitors.




TÍTULO / TITLE:  - Cumulative Number of Altered Biomarkers in Mammalian Target of Rapamycin Pathway  Is an Independent Predictor of Outcome in Patients With Clear Cell Renal Cell Carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Urology. 2013 Jan 3. pii: S0090-4295(12)01422-7. doi: 10.1016/j.urology.2012.11.030.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.urology.2012.11.030

AUTORES / AUTHORS:  - Darwish OM; Kapur P; Youssef RF; Bagrodia A; Belsante M; Alhalabi F; Sagalowsky AI; Lotan Y; Margulis V

INSTITUCIÓN / INSTITUTION:  - Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.

RESUMEN / SUMMARY:  - OBJECTIVE: To evaluate the association of the altered expression of the mammalian target of rapamycin (mTOR) pathway components with oncologic outcomes in patients with nonmetastatic clear cell renal cell carcinoma (ccRCC). MATERIALS AND METHODS: Immunohistochemistry for phosphorylated-S6, phosphorylated-mTOR, mTOR, phosphorylated-AKT, hypoxia inducible factor-1alpha, Raptor, phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K), and phosphorylated 4E-binding protein-1 was performed on tissue microarray constructs of patients treated for nonmetastatic kidney cancer from 1997 to 2010. The relationship between individual altered marker expression and a prognostic marker score (low,  intermediate, and high, defined as </=3, 4-5, >5 altered biomarkers, respectively) and oncologic outcome was assessed. RESULTS: The study included 419 patients with nonmetastatic ccRCC, with a median follow-up period of 26 months (range 6-150). The tumors were nonorgan confined (pT3-T4) in 86 (20.5%) and high  Fuhrman nuclear grade (3-4) in 131 (31%). A low, intermediate, and high prognostic marker score was found in 214 (51%), 152 (36%), and 53 (13%) patients, respectively. Kaplan-Meier analysis demonstrated a statistically significant correlation between the risk groups and disease recurrence and cancer-specific survival. In a multivariate Cox regression analysis controlling for tumor stage and grade, a high marker score was an independent predictor of disease recurrence (hazard ratio 3.3, 95% confidence interval 1.33-8.39, P = .01), and a combination of a high and an intermediate score was an independent predictor of survival (hazard ratio 4.8, 95% confidence interval 1.27-4.78, P = .008). CONCLUSION: The  cumulative number of aberrantly expressed biomarkers correlated with aggressive tumor biology and inferior oncologic outcomes in patients with ccRCC. Our data support prospective pathway-based exploration of the mTOR signaling cascade to augment current clinicopathologic predictors of oncologic outcomes in patients with ccRCC.




TÍTULO / TITLE:  - Pharmacokinetic and myocardial enzyme profiles of two administration routes of epirubicin in breast cancer patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Arzneimittelforschung. 2012 Dec;62(12):677-81. doi: 10.1055/s-0032-1331166. Epub  2012 Nov 30.

            ●● Enlace al texto completo (gratuito o de pago) 1055/s-0032-1331166

AUTORES / AUTHORS:  - Yang RX; Ren HX; Zhuang L; Gao CL; Dong C; Luo CX; Wang XN; Feng EF; He JC

INSTITUCIÓN / INSTITUTION:  - Chemotherapy Research Center, Kunming Medical University, Kunming, China.

RESUMEN / SUMMARY:  - To evaluate the changes in myocardial enzymes and plasma epirubicin concentration following administration by micro-pump (MP) and intravenous drip (ID) in breast cancer patients.11 self-controlled breast cancer patients were recruited for a trial with epirubicin administration by MP for 48 h and by ID for 1 h during 2 cycles of treatment. Plasma concentration of epirubicin at different time points  was determined using LC-MS/MS. The levels of myocardial enzymes before and after  chemotherapy were compared. Another group of patients receiving epirubicin by ID  (n=4) or MP (n=9) were monitored for 4 months.8 patients completed the self-controlled study. The peak concentration of epirubicin in the MP group and the ID group were 21.84+/-18.85 ng/mL and 294.80+/-225.54 ng/mL, respectively. The MP group had a longer duration (54~60 h) of plasma concentration of epirubicin not less than 10 ng/mL than that of the ID group (8~14 h). There was significant difference for the alteration of myocardial enzymes before and after  chemotherapy (p<0.05) in the ID group, whereas the MP group showed no significant difference (p>0.05). The increased range of myocardial enzymes after chemotherapy in the ID group was larger than that of the MP group and the difference was significant (p<0.05). There is an increased cardiotoxicity in patients receiving  epirubicin by ID during the 4-month trial.Administration of epirubicin by MP maintained an effective drug concentration for a longer period of time than by ID. The higher peak plasma concentration observed following epirubicin administration by ID may lead to cardiac toxicity.




TÍTULO / TITLE:  - Soluble receptor of advanced glycation end products (sRAGE) indicates response to chemotherapy in pancreatic cancer patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Clin Pharmacol Ther. 2013 Jan;51(1):67-9.

AUTORES / AUTHORS:  - Wittwer C; Boeck S; Heinemann V; Haas M; Stieber P; Nagel D; Holdenrieder S

INSTITUCIÓN / INSTITUTION:  - University Hospital Munich, Institute of Clinical Chemistry, University Hospital  Munich, Department of Internal Medicine III and Comprehensive Cancer Center, Munich, and University Hospital Bonn, Institute of Clinical Chemistry and Clinical Pharmacology, Bonn, Germany.




TÍTULO / TITLE:  - Metformin-mediated downregulation of p38 mitogen-activated protein kinase-dependent excision repair cross-complementing 1 decreases DNA repair capacity and sensitizes human lung cancer cells to paclitaxel.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochem Pharmacol. 2013 Feb 15;85(4):583-94. doi: 10.1016/j.bcp.2012.12.001. Epub 2012 Dec 7.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bcp.2012.12.001

AUTORES / AUTHORS:  - Tseng SC; Huang YC; Chen HJ; Chiu HC; Huang YJ; Wo TY; Weng SH; Lin YW

INSTITUCIÓN / INSTITUTION:  - Molecular Oncology Laboratory, Department of Biochemical Science and Technology,  National Chiayi University, 300 Syuefu Road, Chiayi 600, Taiwan.

RESUMEN / SUMMARY:  - Metformin, an extensively used and well-tolerated drug for treating individuals with type 2 diabetes, has recently gained significant attention as an anticancer  drug. On the other hand, paclitaxel (Taxol) is a new antineoplastic drug that has shown promise in the treatment of non-small cell lung cancer (NSCLC). High expression levels of excision repair cross-complementary 1 (ERCC1) in cancers have been positively associated with the DNA repair capacity and a poor prognosis in NSCLC patients treated with platinum-containing chemotherapy. In this current  study, paclitaxel was found to increase phosphorylation of mitogen-activated protein kinase (MAPK) kinase 3/6 (MKK3/6)-p38 MAPK as well as protein and mRNA levels of ERCC1 in H1650 and H1703 cells. Moreover, paclitaxel-induced ERCC1 protein and mRNA levels significantly decreased via the downregulation of p38 activity by either a p38 MAPK inhibitor SB202190 or p38 knockdown with specific small interfering RNA (siRNA). Specific inhibition of ERCC1 with siRNA was found  to enhance the paclitaxel-induced cytotoxic effect and growth inhibition. Furthermore, metformin was able to not only decrease the paclitaxel-induced p38 MAPK-mediated ERCC1 expression, but also augment the cytotoxic effect induced by  paclitaxel. Finally, expression of constitutive activate MKK6 or HA-p38 MAPK vectors in lung cancer cells was able to abrogate ERCC1 downregulation by metformin and paclitaxel as well as cell viability and DNA repair capacity. Overall, our results suggest that inhibition of the p38 MAPK signaling by metformin coupled with paclitaxel therapy in human NSCLC cells may be a clinically useful combination, which however will require further validation.




TÍTULO / TITLE:  - Antitumor Activity of Cell-Permeable RUNX3 Protein in Gastric Cancer Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Jan 15.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-2692

AUTORES / AUTHORS:  - Lim J; Duong T; Do N; Do P; Kim J; Kim H; El-Rifai W; Ruley HE; Jo D

INSTITUCIÓN / INSTITUTION:  - Authors’ Affiliations: ProCell R&D Institute, ProCell Therapeutics, Inc., Seoul;  Department of Biomedical Sciences, Chonnam National University Medical School, Kwangju; Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul; Interdisciplinary Program of Integrated Biotechnology, Sogang  University, Seoul, Korea; and Departments of Surgery and Cancer Biology; Department of Pathology, Microbiology & Immunology, Vanderbilt University School  of Medicine, Nashville, Tennessee.

RESUMEN / SUMMARY:  - PURPOSE: Gastric cancer is a leading cause of cancer death worldwide. Limited therapeutic options highlight the need to understand the molecular changes responsible for the disease and to develop therapies based on this understanding. The goal of this study was to develop cell-permeable (CP-) forms of the RUNT-related transcription factor 3, RUNX3-a candidate tumor suppressor implicated in gastric and other epithelial cancers-to study the therapeutic potential of RUNX3 in the treatment of gastric cancer.EXPERIMENTAL DESIGN: We developed novel macromolecule transduction domains (MTD) which were tested for the ability to promote protein uptake by mammalian cells and tissues and used to  deliver of biologically active RUNX3 into human gastric cancer cells. The therapeutic potential CP-RUNX3 was tested in the NCI-N87 human tumor xenograft animal model.RESULTS: RUNX3 fusion proteins, HM(57)R and HM(85)R, containing hydrophobic MTDs enter gastric cancer cells and suppress cell phenotypes (e.g., cell-cycle progression, wounded monolayer healing, and survival) and induce changes in biomarker expression (e.g., p21(Waf1) and VEGF) consistent with previously described effects of RUNX3 on TGF-beta signaling. CP-RUNX3 also suppressed the growth of subcutaneous human gastric tumor xenografts. The therapeutic response was comparable with studies augmenting RUNX3 gene expression in tumor cell lines; however, the protein was most active when administered locally, rather than systemically (i.e., intravenously).CONCLUSIONS: These results provide further evidence that RUNX3 can function as a tumor suppressor and suggest that practical methods to augment RUNX3 function could be useful in treating of some types of gastric cancer. Clin Cancer Res; 1-11. ©2012 AACR.




TÍTULO / TITLE:  - Effects of iodonium-class flavin dehydrogenase inhibitors on growth, reactive oxygen production, cell cycle progression, NADPH oxidase 1 levels, and gene expression in human colon cancer cells and xenografts.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Free Radic Biol Med. 2013 Jan 11. pii: S0891-5849(13)00003-8. doi: 10.1016/j.freeradbiomed.2013.01.002.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.freeradbiomed.2013.01.002

AUTORES / AUTHORS:  - Doroshow JH; Gaur S; Markel S; Lu J; van Balgooy J; Synold TW; Xi B; Wu X; Juhasz A

INSTITUCIÓN / INSTITUTION:  - Center for Cancer Research; Division of Cancer Treatment and Diagnosis, National  Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: doroshoj@mail.nih.gov.

RESUMEN / SUMMARY:  - Iodonium-class flavoprotein dehydrogenase inhibitors have been demonstrated to possess antiproliferative potential and to inhibit reactive oxygen production in  human tumor cells, although the mechanism(s) that explains the relationship between altered cell growth and the generation of reactive oxygen species (ROS) remains an area of active investigation. Because of the ability of these compounds to inhibit the activity of flavoprotein-containing epithelial NADPH oxidases, we chose to examine the effects of several iodonium-class flavoprotein  inhibitors on human colon cancer cell lines that express high, functional levels  of a single such oxidase (NADPH oxidase 1, or Nox1). We found that diphenyleneiodonium (DPI), di-2-thienyliodonium (DTI), and iodonium diphenyl inhibited the growth of Caco2, HT-29, and LS-174T colon cancer cells at concentrations (10-250nM for DPI, 0.5-2.5muM for DTI, and 155nM to 10muM for iodonium diphenyl) substantially lower than needed for DU145 human prostate cancer cells, which do not possess functional NADPH oxidase activity. Drug treatment was associated with decreased H(2)O(2) production and diminished intracellular ROS levels, lasting up to 24h, after short-term (1-h) exposure to the iodonium analogs. Decreased tumor cell proliferation was caused, in part, by  a profound block in cell cycle progression at the G(1)/S interface in both LS-174T and HT-29 cells exposed to either DPI or DTI; and the G(1) block was produced, for LS-174T cells, by upregulation of p27 and a drug concentration-related decrease in the expression of cyclins D1, A, and E that was partially prevented by exogenous H(2)O(2). Not only did DPI and DTI decrease intracellular ROS, they both also significantly decreased the mRNA expression levels of Nox1, potentially contributing to the prolonged reduction in tumor cell reactive oxygen levels. We also found that DPI and DTI significantly decreased the growth of both HT-29 and LS-174T human tumor xenografts, at dose levels that  produced peak plasma concentrations similar to those utilized for our in vitro experiments. These findings suggest that iodonium analogs have therapeutic potential for NADPH oxidase-containing human colon cancers in vivo and that at least part of their antineoplastic mechanism of action may be related to targeting Nox1.




TÍTULO / TITLE:  - Epigallocatechin gallate and sulforaphane combination treatment induce apoptosis  in paclitaxel-resistant ovarian cancer cells through hTERT and Bcl-2 down-regulation.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Exp Cell Res. 2013 Jan 16. pii: S0014-4827(13)00014-1. doi: 10.1016/j.yexcr.2012.12.026.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.yexcr.2012.12.026

AUTORES / AUTHORS:  - Chen H; Landen CN; Li Y; Alvarez RD; Tollefsbol TO

INSTITUCIÓN / INSTITUTION:  - Department of Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

RESUMEN / SUMMARY:  - The cellular development of resistance to chemotherapy contributes to the high mortality noted in patients affected by ovarian cancer. Novel compounds that specifically target cellular drug resistance in ovarian cancer are therefore highly desired. Previous epidemiological studies indicate that consumption of green tea and cruciferous vegetables is inversely associated with occurrence of ovarian cancer. Therefore revealing the effects and mechanisms of major components of green tea (epigallocatechin gallate, EGCG) and cruciferous vegetables (sulforaphane, SFN) on ovarian cancer cells will provide necessary knowledge for developing potential novel treatments for the disease. In this study, EGCG or SFN was used to treat both paclitaxel-sensitive (SKOV3-ip1) and -resistant (SKOV3TR-ip2) ovarian cancer cell lines alone or in combination. We found that SFN inhibits cell viability of both ovarian cancer cell lines time- and dose-dependently and that EGCG potentiates the inhibiting effect of SFN on ovarian cancer cells. Cell cycle analysis indicates SFN can arrest ovarian cancer cells in G2/M phase, while EGCG and SFN co-treatment can arrest cells in both G2/M and S phase. Combined EGCG and SFN treatment increases apoptosis significantly in paclitaxel-resistant SKOV3TR-ip2 cells after 6 days of treatment, while reducing the expression of hTERT, the main regulatory subunit of telomerase. Western blotting also indicates that SFN can down-regulate Bcl-2 (a gene involved in anti-apoptosis) protein levels in both cell types. Cleaved poly(ADP-ribose) polymerase (PARP) becomes up-regulated by 6 days of treatment with SFN and this is more pronounced for combination treatment indicating induction of apoptosis. Furthermore, phosphorylated H2AX is up-regulated after 6  days of treatment with SFN alone, and EGCG can potentiate this effect, suggesting that DNA damage is a potential cellular mechanism contributing to the inhibiting  effect of EGCG and SFN combination treatment. Taken together, these results indicate that EGCG and SFN combination treatment can induce apoptosis by down-regulating of hTERT and Bcl-2 and promote DNA damage response specifically in paclitaxel-resistant ovarian cancer cell lines and suggest the use of these compounds for overcoming paclitaxel resistance in ovarian cancer treatment.




TÍTULO / TITLE:  - Computed Tomography RECIST Assessment of Histopathologic Response and Prediction  of Survival in Patients with Resectable Non-Small-Cell Lung Cancer after Neoadjuvant Chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Thorac Oncol. 2013 Feb;8(2):222-228.

            ●● Enlace al texto completo (gratuito o de pago) 1097/JTO.0b013e3182774108

AUTORES / AUTHORS:  - William WN Jr; Pataer A; Kalhor N; Correa AM; Rice DC; Wistuba II; Heymach J; Lee JJ; Kim ES; Munden R; Gold KA; Papadimitrakopoulou V; Swisher SG; Erasmus JJ

INSTITUCIÓN / INSTITUTION:  - *Departments of Thoracic/Head and Neck Medical Oncology, daggerThoracic and Cardiovascular Surgery, double daggerPathology, section signBiostatistics, and ||Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina; and paragraph signDepartment of Diagnostic Imaging, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.

RESUMEN / SUMMARY:  - INTRODUCTION:: This study’s objectives were to determine whether tumor response measured by computed tomography (CT) and evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) correlated with overall survival (OS) in patients with non-small-cell lung cancer (NSCLC) after neoadjuvant chemotherapy and surgical resection. METHODS:: We measured primary tumor size on CT before and after neoadjuvant chemotherapy in 160 NSCLC patients who underwent surgical resection. The relationship between CT-measured response (RECIST) and histopathologic response (</= 10% viable tumor) and OS were assessed by Kaplan-Meier survival, univariable, and multivariable Cox proportional hazards regression. RESULTS:: There was a statistically significant association between CT-measured response (RECIST) and OS (p = 0.03). However, histopathologic response was a stronger predictor of OS (p = 0.002), with a more pronounced separation of the survival curves when compared with CT-measured response. In multivariable Cox regression analysis, only pathologic stage and histopathologic  response were significant predictors of OS. A 41% overall discordance rate was noted between CT RECIST response and histopathologic response. CT RECIST classified as nonresponders a subset of patients with histopathologic response (8 out of 30 points, 27%) who demonstrated prolonged survival after neoadjuvant chemotherapy. CONCLUSION:: We were unable to show that CT RECIST is a reliable predictor of OS in patients with NSCLC undergoing surgical resection after neoadjuvant chemotherapy. The failure of CT RECIST to predict long-term outcome may be because of the inability of CT imaging to consistently identify patients with histopathologic response. CT RECIST may have only a limited role as an efficacy endpoint after neoadjuvant chemotherapy in patients with resectable NSCLC.




TÍTULO / TITLE:  - Association of thymidylate synthase gene 3’-untranslated region polymorphism with sensitivity of non-small cell lung cancer to pemetrexed treatment: TS gene polymorphism and pemetrexed sensitivity in NSCLC.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Biomed Sci. 2013 Jan 25;20(1):5.

            ●● Enlace al texto completo (gratuito o de pago) 1186/1423-0127-20-5

AUTORES / AUTHORS:  - Wang X; Wang Y; Wang Y; Cheng J; Wang Y; Ha M

RESUMEN / SUMMARY:  - ABSTRACT: BACKGROUND: Thymidylate synthase (TS) is a key enzyme responsible for DNA synthesis and repair. Altered expression of TS protein or TS gene polymorphisms has been associated with cancer progression and treatment response. This study investigated the expressions of TS and its gene SNPs in non-small cell lung cancer (NSCLC), and then its association with sensitivity to pemetrexed treatment. Immunohistochemistry and qRT-PCR were performed on 160 resected NSCLC  specimens and corresponding normal tissues to assess the expressions of TS protein and TS mRNA, and for associations with clinicopathological data. Blood samples of 106 lung adenocarcinoma patients were examined for polymorphisms of the TS gene 3’-UTR 1494del 6 bp, which was then investigated for associations with responses of the patients to pemetrexed treatment and survival. RESULTS: Expression of both TS protein and its mRNA was elevated in NSCLC tissues compared with matched normal tissues, and significantly higher in lung squamous cell carcinoma than in lung adenocarcinoma. TS expression was associated with poor tumor differentiation. Furthermore, the genotyping data showed that 56% of lung adenocarcinoma patients had the TS gene 3’-UTR 1494 bp (-6 bp/-6 bp) genotype and the rest had TS gene 3’-UTR 1494 bp (-6 bp/+6 bp). There was no TS 3’-UTR 1494 bp (+6 bp/+6 bp) genotype in any patients. Statistical analysis revealed that gender, tumor stage, and TS 3’-UTR 1494del 6 bp polymorphism were significant prognostic factors after short-term pemetrexed treatment. Log-rank analysis revealed that patients with the (-6 bp/-6 bp) genotype had significantly better progression-free and overall survival than patients with (-6 bp/+6 bp). CONCLUSIONS: This study showed that TS protein is highly expressed in NSCLC and that polymorphisms of TS 3’-UTR 1494del 6 bp are associated with sensitivity of lung adenocarcinoma patients to pemetrexed treatment. This suggests that TS gene  polymorphisms should be further evaluated as prognostic markers for personalized  therapy in lung adenocarcinoma.




TÍTULO / TITLE:  - miR-9 modulates the expression of interferon-regulated genes and MHC class I molecules in human nasopharyngeal carcinoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochem Biophys Res Commun. 2013 Jan 4. pii: S0006-291X(12)02457-6. doi: 10.1016/j.bbrc.2012.12.097.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bbrc.2012.12.097

AUTORES / AUTHORS:  - Gao F; Zhao ZL; Zhao WT; Fan QR; Wang SC; Li J; Zhang YQ; Shi JW; Lin XL; Yang S; Xie RY; Liu W; Zhang TT; Sun YL; Xu K; Yao KT; Xiao D

INSTITUCIÓN / INSTITUTION:  - Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.

RESUMEN / SUMMARY:  - The functions of miR-9 in some cancers are recently implicated in regulating proliferation, epithelial-mesenchymal transition (EMT), invasion and metastasis,  apoptosis, and tumor angiogenesis, etc. miR-9 is commonly down-regulated in nasopharyngeal carcinoma (NPC), but the exact roles of miR-9 dysregulation in the pathogenesis of NPC remains unclear. Therefore, we firstly used miR-9-expressing  CNE2 cells to determine the effects of miR-9 overexpression on global gene expression profile by microarray analysis. Microarray-based gene expression data  unexpectedly demonstrated a significant number of up- or down-regulated immune- and inflammation-related genes, including many well-known interferon (IFN)-induced genes (e.g., IFI44L, PSMB8, IRF5, PSMB10, IFI27, PSB9_HUMAN, IFIT2, TRAIL, IFIT1, PSB8_HUMAN, IRF1, B2M and GBP1), major histocompatibility complex (MHC) class I molecules (e.g., HLA-B, HLA-C, HLA-F and HLA-H) and interleukin (IL)-related genes (e.g., IL20RB, GALT, IL7, IL1B, IL11, IL1F8, IL1A, IL6 and IL7R), which was confirmed by qRT-PCR. Moreover, the overexpression of miR-9 with the miRNA mimics significantly up- or down-regulated the expression of above-mentioned IFN-inducible genes, MHC class I molecules and IL-related genes;  on the contrary, miR-9 inhibition by anti-miR-9 inhibitor in CNE2 and 5-8F cells  correspondingly decreased or increased the aforementioned immune- and inflammation-related genes. Taken together, these findings demonstrate, for the first time, that miR-9 can modulate the expression of IFN-induced genes and MHC class I molecules in human cancer cells, suggesting a novel role of miR-9 in linking inflammation and cancer, which remains to be fully characterized.




TÍTULO / TITLE:  - Validation of the IASLC/ATS/ERS lung adenocarcinoma classification for prognosis  and association with EGFR and KRAS gene mutations: analysis of 440 Japanese patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Thorac Oncol. 2013 Jan;8(1):52-61. doi: 10.1097/JTO.0b013e3182769aa8.

            ●● Enlace al texto completo (gratuito o de pago) 1097/JTO.0b013e3182769aa8

AUTORES / AUTHORS:  - Yoshizawa A; Sumiyoshi S; Sonobe M; Kobayashi M; Fujimoto M; Kawakami F; Tsuruyama T; Travis WD; Date H; Haga H

INSTITUCIÓN / INSTITUTION:  - Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan. akyoshi@shinshu-u.ac.jp

RESUMEN / SUMMARY:  - INTRODUCTION: This study aimed to validate the utility of the new histological classification proposed by the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS) for identifying the prognostic subtypes of adenocarcinomas in Japanese patients; correlations between the classification and the presence of EGFR or KRAS mutation status were also investigated. METHODS: We retrospectively reviewed 440 patients with lung adenocarcinoma, who underwent resection. The tumors were classified according to the IASLC/ATS/ERS classification. EGFR and KRAS mutations were detected using the established methods. RESULTS: Five-year disease-free survival rates were: 100% for adenocarcinoma in situ (n = 20) and minimally invasive adenocarcinoma (n = 33), 93.8% for lepidic-predominant adenocarcinoma (n = 36), 88.8% for invasive mucinous adenocarcinoma (n = 10), 66.7% for papillary-predominant adenocarcinoma (n = 179), 69.7% for acinar-predominant adenocarcinoma (n = 61), 43.3% for solid-predominant adencoarcinoma (n = 78), and 0% for micropapillary-predominant adenocarcinoma (n = 19). Multivariate analysis  revealed that the new classification was an independent predictor of disease-free survival. EGFR and KRAS mutations were detected in 90 cases (53.9%) and 21 cases  (13.3%), respectively; EGFR mutations were significantly associated with adenocarcinoma in situ, minimally invasive adenocarcinoma, lepidic- and papillary-predominant adenocarcinoma, and KRAS mutations adenocarcinomas with mucinous tumor subtypes. CONCLUSIONS: We found that the IASLC/ATS/ERS classification identified prognostic histologic subtypes of lung adenocarcinomas  among Japanese patients. Histologic subtyping and molecular testing for EGFR and  KRAS mutations can help predict patient prognosis and select those who require adjuvant chemotherapy.




TÍTULO / TITLE:  - Inhibition of atypical protein kinase Ciota induces apoptosis through autophagic  degradation of beta-catenin in esophageal cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mol Carcinog. 2013 Jan 28. doi: 10.1002/mc.22003.

            ●● Enlace al texto completo (gratuito o de pago) 1002/mc.22003

AUTORES / AUTHORS:  - Wang BS; Yang Y; Lu HZ; Shang L; Zhang Y; Hao JJ; Shi ZZ; Wang XM; Liu YZ; Zhan QM; Jia XM; Wang MR

INSTITUCIÓN / INSTITUTION:  - State Key Laboratory of Molecular Oncology, Cancer Institute (Hospital), Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.

RESUMEN / SUMMARY:  - Atypical protein kinase Ciota (PKCiota) has been identified as an oncoprotein in  esophageal squamous cell carcinomas. However, the mechanisms underlying the role  of PKCiota in this disease remain unclear. In the present work, we found that inhibition of PKCiota expression by RNAi induced apoptosis via the down-regulation of beta-catenin in esophageal cancer cells. Furthermore, we found that PKCiota regulated beta-catenin in an autophagy dependent way. Since down-regulation of beta-catenin induced by knockdown of PKCiota could be rescued  by autophagy inhibition; knockdown of PKCiota activated autophagy and promoted the recruitment of beta-catenin into autophagosome. These results suggested that  PKCiota positively regulated beta-catenin through negatively regulated autophagy  and depletion of PKCiota promoted apoptosis via autophagic degradation of beta-catenin in esophageal cancer cells. These data provide new insights into PKCiota signaling in human cancer. © 2013 Wiley Periodicals, Inc.




TÍTULO / TITLE:  - Validation study of a prognostic classification in patients with metastatic colorectal cancer who received irinotecan-based second-line chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Cancer Res Clin Oncol. 2012 Dec 19.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00432-012-1349-1

AUTORES / AUTHORS:  - Shitara K; Yuki S; Yamazaki K; Naito Y; Fukushima H; Komatsu Y; Yasui H; Takano T; Muro K

INSTITUCIÓN / INSTITUTION:  - Department of Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan, Kouheis0824@yahoo.co.jp.

RESUMEN / SUMMARY:  - PURPOSE: Five prognostic factors had been previously identified in patients with  metastatic colorectal cancer (MCRC) who received irinotecan-based second-line chemotherapy. Patients were classified into three prognostic groups based on significant differences in median overall survival (OS). This study is conducted  to validate this classification in an external validation cohort. METHODS: This retrospective study included 193 patients of an external validation cohort who received irinotecan-based second-line chemotherapy after first-line oxaliplatin-based chemotherapy, with or without bevacizumab at three institutions. RESULTS: Three of the five predefined factors (poorly differentiated adenocarcinoma, LDH >/=400 IU/L, progression-free survival of first-line therapy <6 months) remained highly significant in the validation cohort, although two (performance status 2 and peritoneal metastasis) were associated with borderline significance. The distribution of the three prognostic groups (low risk = no factors, intermediate risk = 1 factor, high risk = 2 or more factors) was low risk (n = 68; 35 %), intermediate risk (n = 80; 41 %), and  high risk (n = 45; 23 %). The median OS of each group were 19.8, 11.0, and 7.9 months, respectively, with significant differences between groups, as found in the previous cohort. CONCLUSION: The previous prognostic classification of patients with MCRC who received irinotecan-based second-line chemotherapy was validated in another independent cohort. Validation in prospective studies is warranted.




TÍTULO / TITLE:  - Thrombocytosis and immunohistochemical expression of connexin 43 at diagnosis predict survival in advanced non-small-cell lung cancer treated with cisplatin-based chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Chemother Pharmacol. 2013 Jan 26.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00280-013-2080-6

AUTORES / AUTHORS:  - Du G; Yang Y; Zhang Y; Sun T; Liu W; Wang Y; Li J; Zhang H

INSTITUCIÓN / INSTITUTION:  - Institute of Pharmacy, Pharmacy College of Henan University, Jinming street, Kaifeng, 475004, Henan, China, kfdgj@sohu.com.

RESUMEN / SUMMARY:  - PURPOSE: Patients with advanced non-small-cell lung cancer (NSCLC) have poor survival, and platinum-based chemotherapy agents are the standard first-line chemotherapy agents for advanced NSCLC. This study aimed to identify predictive factors associated with the response to chemotherapy and survival in 258 patients with advanced NSCLC treated with platinum-based chemotherapy. METHODS: Stage IIIA-IV NSCLC patients diagnosed in Kaifeng second people’s hospital (Henan, China) between March 2002 and September 2011 were retrospectively reviewed. All of the patients had received platinum-based chemotherapy, and patients were followed up to date of death or last follow-up to obtain data of response to chemotherapy and survival. Potential prognostic factors such as gender, age, tumor size, tumor type, histologic stage, anemia, calcium levels, ECOG performance status (PS), thrombocytosis, TTF-1, p63, and connexin 43 were analyzed. Response to chemotherapy, overall survival (OS) and progression-free survival (PFS) were calculated by the Kaplan-Meier method and Cox regression model. RESULTS: A univariate analysis indicated that thrombocytosis and connexin  43 were found to be significant prognostic factors (p < 0.001) and ECOG PS, Hb levels, and p63 presented a tendency toward association with survival. Kaplan-Meier survival showed that the mean OS and PFS in chemotherapy responders  with connexin 43 >/=+2 were significantly longer than in chemotherapy responders  with connexin 43 </=1+. In contrast, thrombocytosis was associated with increased mortality and resistance to chemotherapy in chemotherapy responders. In addition, all 21 patients of the 5-year OS were from chemotherapy responders with connexin  43 >/=+2 or non-thrombocytosis. CONCLUSIONS: Thrombocytosis and connexin 43 absence may be reliable surrogate markers for the prediction of chemotherapy response and prognosis for patients with advanced NSCLC, and assessment of these  factors may identify a population of patients with advanced NSCLC that is likely  to have a prolonged life expectancy.




TÍTULO / TITLE:  - Risk Factors for Predicting Severe Neutropenia Induced by Amrubicin in Patients with Advanced Lung Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Chemotherapy. 2013 Jan 4;58(6):419-425.

            ●● Enlace al texto completo (gratuito o de pago) 1159/000345617

AUTORES / AUTHORS:  - Watanabe H; Ikesue H; Oshiro M; Nagata K; Mishima K; Takada A; Suetsugu K; Sueyasu M; Egashira N; Harada T; Takayama K; Nakanishi Y; Oishi R

INSTITUCIÓN / INSTITUTION:  - Department of Pharmacy, Kyushu University Hospital, Fukuoka, Japan.

RESUMEN / SUMMARY:  - Background: Neutropenia is one of the most frequent and dose-limiting toxicities  in amrubicin (AMR) therapy. However, the predictive factors for the development of severe neutropenia in AMR therapy remain unknown. Methods: The subjects were 61 advanced lung cancer patients treated with AMR monotherapy. All data were retrospectively collected from the electronic medical record system. A stepwise logistic regression analysis was performed to identify risk factors for grade 3-4 neutropenia. Results: Of a total 61 patients, 50 were male and 11 were female. The median dose of AMR was 35.0 mg/m(2). The incidence of grade 3-4 neutropenia during the first course was 62%. In multivariate analysis, female gender (OR = 6.68; 95% CI 1.01-134.15; p = 0.049), higher AMR doses (40 mg/m(2) or more) (OR = 5.98; 95% CI 1.77-23.74; p = 0.003), and lower hematocrit values (OR = 2.04 per 5% decrease; 95% CI 1.04-4.38; p = 0.036) were significantly associated with severe neutropenia induced by AMR. Conclusion: The present results suggest that female gender, higher doses of AMR, and lower baseline hematocrit values are predictive factors associated with severe neutropenia induced by AMR in patients  with advanced lung cancer. Patients who have these predictive factors should be monitored carefully and considered for early granulocyte colony-stimulating factor support.




TÍTULO / TITLE:  - Mycobacterial Interferon-gamma Release Variations During Longterm Treatment with  Tumor Necrosis Factor Blockers: Lack of Correlation with Clinical Outcome.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Rheumatol. 2012 Dec 1.

            ●● Enlace al texto completo (gratuito o de pago) 3899/jrheum.120688

AUTORES / AUTHORS:  - Scrivo R; Sauzullo I; Mengoni F; Priori R; Coppola M; Iaiani G; Di Franco M; Vullo V; Mastroianni CM; Valesini G

INSTITUCIÓN / INSTITUTION:  - From the Dipartimento di Medicina Interna e Specialita Mediche, Reumatologia, and the Dipartimento di Sanita Pubblica e Malattie Infettive, Sapienza Universita di  Roma, Rome; UOC Malattie Infettive, Fondazione Eleonora Lorillard Spencer Cenci,  Sapienza Universita di Roma (Polo Pontino), Latina, Italy.

RESUMEN / SUMMARY:  - OBJECTIVE: To assess the performance of serial QuantiFeron-TB Gold In-Tube (QFT-GIT) tests in patients with rheumatic diseases during longterm systemic treatment with biologic therapy, evaluating conversions and reversions in relation to the clinical outcome. METHODS: We conducted a prospective study on patients awaiting biologic agents. At baseline, they had chest radiographs, QFT-GIT tests, and tuberculin skin tests (TST); QFT-GIT was repeated at 3, 6, 12, and 18 months after onset of biologic therapy. In patients with no evidence of latent tuberculosis infection (LTBI) at baseline, TST was repeated at 12 months of biologic treatment. RESULTS: Among patients (n = 102; women 65.7%; median age  47 yrs, range 20-82), 14 (13.7%) were considered as having LTBI because of a minimum of 1 abnormal screening test. The agreement between QFT-GIT and TST was 88% (kappa = 0.14). During biologic treatment, both patients with (n = 14) and those without (n = 88) evidence of LTBI at baseline showed conversions and reversions in QFT-GIT results at different timepoints. These fluctuations were not paralleled by significant clinical changes. The TST repeated at 12 months in  patients with no evidence of LTBI at baseline continued to be negative. The median baseline interferon-gamma (IFN-gamma) concentration was not significantly  different from that observed at each subsequent timepoint. CONCLUSION: Dynamic changes occur with serial IFN-gamma release assay testing in patients treated with biologic therapy that do not correlate with clinical outcome. A careful and  integrated evaluation of the patient, including clinical information, should guide the treatment decision. This study was underpowered for definite conclusions and further studies are needed to determine the significance of these findings.




TÍTULO / TITLE:  - Absence of RKIP expression is an independent prognostic biomarker for gastric cancer patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncol Rep. 2013 Feb;29(2):690-6. doi: 10.3892/or.2012.2179. Epub 2012 Dec 10.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2012.2179

AUTORES / AUTHORS:  - Martinho O; Simoes K; Longatto-Filho A; Jacob CE; Zilberstein B; Bresciani C; Gama-Rodrigues J; Cecconello I; Alves V; Reis RM

INSTITUCIÓN / INSTITUTION:  - Life and Health Sciences Research Institute, Health Sciences School, University of Minho, Braga, Portugal.

RESUMEN / SUMMARY:  - Gastric cancer is a leading cause of cancer-related mortality, and the presence of lymph node metastasis an important prognostic factor. Downregulation of RKIP has been associated with tumor progression and metastasis in several types of neoplasms, being currently categorized as a metastasis suppressor gene. Our aim was to determine the expression levels of RKIP in gastric tissues and to evaluate its impact in the clinical outcome of gastric carcinoma patients. RKIP expression levels were studied by immunohistochemistry in a series of gastric tissues. Overall, we analysed 222 non-neoplastic gastric tissues, 152 primary tumors and 42 lymph node metastasis samples. We observed that RKIP was highly expressed in ~83% of non-neoplastic tissues (including normal tissue and metaplasia), was lost in ~56% of primary tumors and in ~90% of lymph node metastasis samples. Loss of RKIP expression was significantly associated with several markers of poor clinical outcome, including the presence of lymph node metastasis. Furthermore, the absence of RKIP protein constitutes an independent prognostic marker for these patients. In conclusion, RKIP expression is significantly lost during gastric carcinoma progression being almost absent in lymph node metastasis samples. Of note, we showed that the absence of RKIP expression is associated with poor outcome features of gastric cancer patients, this being also an independent prognostic marker.




TÍTULO / TITLE:  - Cellular immunotherapy study of prostate cancer patients and resulting IgG responses to peptide epitopes predicted from prostate tumor-associated autoantigens.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Immunother. 2013 Jan;36(1):57-65. doi: 10.1097/CJI.0b013e3182780abc.

            ●● Enlace al texto completo (gratuito o de pago) 1097/CJI.0b013e3182780abc

AUTORES / AUTHORS:  - Hemstreet GP 3rd; Rossi GR; Pisarev VM; Enke CA; Helfner L; Hauke RJ; Tennant L; Ramsey WJ; Vahanian NN; Link CJ

INSTITUCIÓN / INSTITUTION:  - Department of Urology, University of Nebraska Medical Center, Omaha, NE, USA.

RESUMEN / SUMMARY:  - The immunogenicity of a cellular immunotherapy using genetically modified vaccines to express alpha(1,3)galactosyl epitopes (alphaGal) was evaluated in advanced prostate cancer (PC) patients. In this dose escalation phase I study, we report safety, feasibility, and immunologic data of an immunotherapy composed of  2 human PC cell lines engineered to express alphaGal epitopes (HyperAcute-Prostate, HAP, NewLink Genetics). Eight patients received up to 12 biweekly vaccinations with HAP. Enrolled patients (aged range, 53-85 y) had American Joint Committee on Cancer stage IV, any T, any N, M1, Eastern Cooperative Oncology Group PS</=2, at least 1 prior hormonal treatment and <3 prior chemotherapies, adequate bone marrow and organ function, and albumin >/=3.0 g/dL. Serum IgG antibodies to synthetic peptides overexpressed in PC were determined by enzyme-linked immunosorbent assay. Results indicate that HAP immunotherapy induced humoral immune responses to autoantigens in 2 of 8 patients. These patients developed IgG antibody to multiple epitopes overexpressed in PC after immunization. These responding patients received higher doses of the immunotherapy suggesting a dose response. Two immunogenic proteins (prostate-specific membrane antigen, hepsin) belong to the extracellular molecules family participating in malignant cell invasion. Median overall survival for patients was 25.1 months with 1 patient surviving over 70 months with stable PSA and bone metastasis before expiring of other causes. Three of 8 patients showed PSA stabilization (>100 d). In conclusion, HAP immunotherapy induces IgG responses to epitopes from autoantigens overexpressed in PC suggesting dose-dependent effect. HAP represents a viable immunotherapy approach  to induce immune responses against tumor cells and may provide clinical benefit with minimal toxicity.




TÍTULO / TITLE:  - Role of ERCC5 promoter polymorphisms in response to platinum-based chemotherapy in patients with advanced non-small-cell lung cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Anticancer Drugs. 2013 Mar;24(3):300-5. doi: 10.1097/CAD.0b013e32835bd6ce.

            ●● Enlace al texto completo (gratuito o de pago) 1097/CAD.0b013e32835bd6ce

AUTORES / AUTHORS:  - He C; Duan Z; Li P; Xu Q; Yuan Y

INSTITUCIÓN / INSTITUTION:  - Tumor Etiology and Screening Department of Cancer Institute and General Surgery,  the First Affiliated Hospital of China Medical University/Key Laboratory of Cancer Control in Liaoning Province, Shenyang, China.

RESUMEN / SUMMARY:  - The ERCC5 gene plays an important role in the nucleotide excision repair pathway  that recognizes and removes platinum-DNA adducts. We aimed to examine whether ERCC5 promoter polymorphisms contribute toward intervariations in the platinum treatment response in patients with advanced non-small-cell lung cancer (NSCLC).  We evaluated the association between three tag-single nucleotide polymorphisms in the ERCC5 promoter region (rs2094258, rs751402, and rs2296147, respectively) and  the efficacy of chemotherapy in 228 advanced NSCLC patients. We found that the rs751402 AA genotype was associated with a better treatment response [AA vs. AG+GG: odds ratio (OR)=2.74, 95% confidence interval (CI) 1.04-7.26, P=0.036) in  all NSCLC patients, which was more evident in the subgroup of patients with squamous cell carcinoma (AA vs. GG: OR=6.40, 95% CI 1.15-35.50, P=0.043; AA vs. AG+GG: OR=6.12, 95% CI 1.15-32.52, P=0.019). No statistically significant association was found between rs2094258 and rs2296147 polymorphisms and treatment response. Our results suggested that the ERCC5 rs751402 AA genotype increased the chemotherapy response in advanced NSCLC, especially in patients with squamous cell carcinoma. Further and larger scale studies are still required to provide more comprehensive information on ERCC5 promoter variations in the clinical outcome of NSCLC patients treated with platinum regimens.




TÍTULO / TITLE:  - AMPK inhibition enhances apoptosis in MLL-rearranged pediatric B-acute lymphoblastic leukemia cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Leukemia. 2012 Nov 21. doi: 10.1038/leu.2012.338.

            ●● Enlace al texto completo (gratuito o de pago) 1038/leu.2012.338

AUTORES / AUTHORS:  - Accordi B; Galla L; Milani G; Curtarello M; Serafin V; Lissandron V; Viola G; Te Kronnie G; De Maria R; Petricoin EF 3rd; Liotta LA; Indraccolo S; Basso G

INSTITUCIÓN / INSTITUTION:  - Oncohematology Laboratory, Department of Woman and Child Health, University of Padova, Padova, Italy.

RESUMEN / SUMMARY:  - The serine/threonine kinase AMP-activated protein kinase (AMPK) and its downstream effectors, including endothelial nitric oxide synthase and BCL-2, are  hyperactivated in B-cell precursor-acute lymphoblastic leukemia (BCP-ALL) cells with MLL gene rearrangements. We investigated the role of activated AMPK in supporting leukemic cell survival and evaluated AMPK as a potential drug target.  Exposure of leukemic cells to the commercial AMPK inhibitor compound C resulted in massive apoptosis only in cells with MLL gene rearrangements. These results were confirmed by targeting AMPK with specific short hairpin RNAs. Compound C-induced apoptosis was associated with mitochondrial membrane depolarization, reactive oxygen species production, cytochrome c release and caspases cleavage, indicating intrinsic apoptosis pathway activation. Treatment with low concentrations of compound C resulted in a strong antileukemic activity, together with cytochrome c release and cleavage of caspases and poly(ADP-ribose) polymerase, also in MLL-rearranged primary BCP-ALL samples. Moreover, AMPK inhibition in MLL-rearranged cell lines synergistically enhanced the antiproliferative effects of vincristine, daunorubicin, cytarabine, dexamethasone and L-asparaginase in most of the evaluated conditions. Taken together, these results indicate that the activation of the AMPK pathway directly contributes to  the survival of MLL-rearranged BCP-ALL cells and AMPK inhibitors could represent  a new therapeutic strategy for this high-risk leukemia.Leukemia advance online publication, 11 December 2012; doi:10.1038/leu.2012.338.




TÍTULO / TITLE:  - A randomized phase II study of gemcitabine and carboplatin with or without cediranib as first-line therapy in advanced non-small-cell lung cancer: North Central Cancer Treatment Group Study N0528.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Thorac Oncol. 2013 Jan;8(1):79-88. doi: 10.1097/JTO.0b013e318274a85d.

            ●● Enlace al texto completo (gratuito o de pago) 1097/JTO.0b013e318274a85d

AUTORES / AUTHORS:  - Dy GK; Mandrekar SJ; Nelson GD; Meyers JP; Adjei AA; Ross HJ; Ansari RH; Lyss AP; Stella PJ; Schild SE; Molina JR; Adjei AA

INSTITUCIÓN / INSTITUTION:  - Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA.

RESUMEN / SUMMARY:  - INTRODUCTION: The purpose of this study was to assess the safety and efficacy of  gemcitabine and carboplatin with (arm A) or without (arm B) daily oral cediranib  as first-line therapy for advanced non-small-cell lung cancer. METHODS: A lead-in phase to determine the tolerability of gemcitabine 1000 mg/m on days 1 and 8, and carboplatin on day 1 at area under curve 5 administered every 21 days with cediranib 45 mg once daily was followed by a 2 (A):1 (B) randomized phase II study. The primary end point was confirmed overall response rate (ORR) with 6-month progression-free survival (PFS6) rate in arm A as secondary end point. Polymorphisms in genes encoding cediranib targets and transport were correlated with treatment outcome. RESULTS: On the basis of the safety assessment, cediranib 30 mg daily was used in the phase II portion. A total of 58 and 29 evaluable patients were accrued to arms A and B. Patients in A experienced more grade 3+ nonhematologic adverse events, 71% versus 45% (p = 0.01). The ORR was 19% (A) versus 20% (B) (p = 1.0). PFS6 in A was 48% (95% confidence interval: 35%-62%), thus meeting the protocol-specified threshold of at least 40%. The median overall survival was 12.0 versus 9.9 months (p = 0.10). FGFR1 rs7012413, FGFR2 rs2912791, and VEGFR3 rs11748431 polymorphisms were significantly associated with decreased  overall survival (hazard ratio 2.78-5.01, p = 0.0002-0.0095). CONCLUSIONS: The trial did not meet its primary end point of ORR but met its secondary end point of PFS6. The combination with cediranib 30 mg daily resulted in increased toxicity. Pharmacogenetic analysis revealed an association of FGFR and VEGFR variants with survival.




TÍTULO / TITLE:  - Deleted in breast cancer 1 (DBC1) deficiency results in apoptosis of breast cancer cells through impaired responses to UV-induced DNA damage.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Lett. 2013 Jan 22. pii: S0304-3835(13)00058-X. doi: 10.1016/j.canlet.2013.01.026.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.canlet.2013.01.026


INSTITUCIÓN / INSTITUTION:  - Department of PharmacologySchool of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea; Department of Biomedical Science, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.

RESUMEN / SUMMARY:  - DBC1 (deleted in breast cancer 1) participates in the regulation of cell survival and death in response to various stimuli. In particular, DBC1 promotes cell death upon DNA damage through inhibition of SIRT1 deacetylase. However, the SIRT1-independent functions of DBC1 in the regulation of DNA damage response are  less well understood. Therefore, we analyzed the DNA damage response in Hs578T breast cancer cell line in which the DBC1-SIRT1 interaction is barely detectable. DBC1-siRNA transfected cells showed a failure in the DNA damage checkpoint and the accumulation of genomic damage following UV irradiation. In addition, DBC1-deficient cells exhibited less JNK activation. Finally, the interruptions of signaling in DBC1-depeleted cells contributed to cell death in response to UV irradiation. Overall, these data suggest that DBC1 is essential for a fully efficient and effective response to UV irradiation. Therefore, DBC1 plays a critical role in maintaining genomic stability and cellular integrity following UV-induced genotoxic stress.




TÍTULO / TITLE:  - PIN1 Inhibits Apoptosis in Hepatocellular Carcinoma through Modulation of the Antiapoptotic Function of Survivin.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Am J Pathol. 2013 Jan 17. pii: S0002-9440(13)00002-3. doi: 10.1016/j.ajpath.2012.11.034.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ajpath.2012.11.034

AUTORES / AUTHORS:  - Cheng CW; Chow AK; Pang R; Fok EW; Kwong YL; Tse E

INSTITUCIÓN / INSTITUTION:  - Division of Haematology and Medical Oncology, Department of Medicine, University  of Hong Kong, Queen Mary Hospital, Hong Kong.

RESUMEN / SUMMARY:  - PIN1, a peptidyl-prolyl-isomerase, binds a specific motif comprising a phosphorylated serine or threonine preceding a proline (p-Ser/Thr-Pro) residue in proteins. Through cis-trans isomerization, it induces conformational changes and  modulates functions of many proteins that are involved in cell cycle progression, cell proliferation, and oncogenesis. PIN1 is overexpressed in hepatocellular carcinomas (HCC) and contributes to hepatocarcinogenesis. We investigated the role of PIN1 and the significance of its interaction with the inhibitor of apoptosis protein survivin in evading apoptosis in HCC cells. Using cell line and xenograft models, we determined that PIN1 overexpression inhibits apoptosis through suppression of caspase-3 and caspase-9 activity. In addition, down-regulation of survivin in PIN1-overexpressing cells attenuated the antiapoptotic effect induced by PIN1, suggesting that the inhibition of apoptosis is mediated through PIN1-survivin interaction. Coimmunoprecipitation assays showed that PIN1 interacted with survivin via the phosphorylated Thr34-Pro motif  and enhanced binding among survivin phosphorylated at Thr34, hepatitis B X-interacting protein (HBXIP), and pro-caspase-9. Taken together, these results suggest that the inhibition of apoptosis by PIN1 in HCC cells is mediated through modulation of the antiapoptotic function of survivin by increasing its binding to pro-caspase-9 via HBXIP. Such functional interaction between PIN1 and survivin may therefore play an important role in hepatocarcinogenesis and chemoresistance.




TÍTULO / TITLE:  - Fulvestrant radiosensitizes human estrogen receptor-positive breast cancer cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochem Biophys Res Commun. 2013 Jan 10. pii: S0006-291X(13)00042-9. doi: 10.1016/j.bbrc.2013.01.006.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bbrc.2013.01.006

AUTORES / AUTHORS:  - Wang J; Yang Q; Haffty BG; Li X; Moran MS

INSTITUCIÓN / INSTITUTION:  - Department of Breast Surgery, Qilu Hospital, Shandong Univeristy, Wenhua Xi Road  107, Shandong Province, PR China; Department of Oncology, Affiliated Hospital of  Qingdao University Medical College, Shandong Province, PR China. Electronic address: wangstella5@163.com.

RESUMEN / SUMMARY:  - The optimal sequencing for hormonal therapy and radiation are yet to be determined. We utilized fulvestrant, which is showing promise as an alternative to other agents in the clinical setting of hormonal therapy, to assess the cellular effects of concomitant anti-estrogen therapy (fulvestrant) with radiation (F+RT). This study was conducted to assess the effects of fulvestrant alone vs. F+RT on hormone-receptor positive breast cancer to determine if any positive or negative combined effects exist. The effects of F+RT on human breast  cancer cells were assessed using MCF-7 clonogenic and tetrazolium salt colorimetric (MTT) assays. The assays were irradiated with a dose of 0, 2, 4, 6Gy +/- fulvestrant. The effects of F+RT vs. single adjuvant treatment alone on cell-cycle distribution were assessed using flow cytometry; relative expression of repair proteins (Ku70, Ku80, DNA-PKcs, Rad51) was assessed using Western Blot  analysis. Cell growth for radiation alone vs. F+RT was 0.885+/-0.013 vs. 0.622+/-0.029 @2Gy, 0.599+/-0.045 vs. 0.475+/-0.054 @4Gy, and 0.472+/-0.021 vs. 0.380+/-0.018 @6Gy RT (p=0.003). While irradiation alone induced G2/M cell cycle  arrest, the combination of F+RT induced cell redistribution in the G1 phase and produced a significant decrease in the proportion of cells in G2 phase arrest and in the S phase in breast cancer cells (p<0.01). Furthermore, levels of repair proteins DNA-PKcs and Rad51 were significantly decreased in the cells treated with F+RT compared with irradiation alone. F+RT leads to a decrease in the surviving fraction, increased cell cycle arrest, down regulating of nonhomologous repair protein DNA-PKcs and homologous recombination repair protein RAD51. Thus,  our findings suggest that F+RT increases breast cancer cell radiosensitivity compared with radiation alone. These findings have salient implications for designing clinical trials using fulvestrant and radiation therapy.




TÍTULO / TITLE:  - Granocyte-colony Stimulating Factor (G-CSF) Has Significant Efficacy as Secondary Prophylaxis of Chemotherapy-induced Neutropenia in Patients with Solid Tumors: Results of a Prospective Study.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Anticancer Res. 2013 Jan;33(1):301-7.

AUTORES / AUTHORS:  - Freyer G; Jovenin N; Yazbek G; Villanueva C; Hussain A; Berthune A; Rotarski M; Simon H; Boulanger V; Hummelsberger M; Falandry C

INSTITUCIÓN / INSTITUTION:  - Department of Medical Oncology, Lyon-Sud Hospital, 69495 Pierre Benite Cedex, France. gilles.freyer@chu-lyon.fr.

RESUMEN / SUMMARY:  - Aim: To carry out a prospective, multicenter and observational study describing prophylactic strategies [cycle delay, dose-reduction, (G-CSF) prescription] to prevent recurrence of neutropenic events (NE) in patients with solid tumors, and  identify potential predictive factors of NE recurrence. PATIENTS AND METHODS: Patients >/=18 years old with an NE in a previous chemotherapy cycle (cycle A) without G-CSF support, followed for four cycles (B to E) were included in the study. NE was defined as any neutropenia grade 1-4, febrile or not, which impacted on subsequent chemotherapy cycles (cycle delay, or reduction, or prophylactic G-CSF). RESULTS: Data of 548 patients were analyzed, 378 (69%) were  female, with a mean (SD) age of 61.7 (12.3) years. WHO PS: 0-1: 88.3%, incidence  of breast cancer: 40%, metastatic disease: 53.3%. Following the first NE episode, 44.5% of patients had cycle delay, 22.3% dose reduction and 466 (85%) received prophylactic G-CSF. NE recurrence rates were: 21.2% at cycle B, 18.6% at cycle C, 11.5% at cycle D and 12.9% at cycle E. G-CSF support (hazard ratio: 0.32, 0.24-0.43, p<0.001) was associated with lower NE recurrence. Pegfilgrastim seemed to offer the highest protection (hazard ratio; HR=0.23, 95% CI: 0.16-0.32; p<0.001). CONCLUSION: Secondary G-CSF prophylaxis has significant efficacy in reducing the incidence of NE and should be considered as a valuable option.




TÍTULO / TITLE:  - Prospective Multicentre Evaluation of PCA3 and TMPRSS2-ERG Gene Fusions as Diagnostic and Prognostic Urinary Biomarkers for Prostate Cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur Urol. 2012 Nov 15. pii: S0302-2838(12)01345-0. doi: 10.1016/j.eururo.2012.11.014.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.eururo.2012.11.014

AUTORES / AUTHORS:  - Leyten GH; Hessels D; Jannink SA; Smit FP; de Jong H; Cornel EB; de Reijke TM; Vergunst H; Kil P; Knipscheer BC; van Oort IM; Mulders PF; Hulsbergen-van de Kaa CA; Schalken JA

INSTITUCIÓN / INSTITUTION:  - Radboud University Nijmegen Medical Centre, Department of Urology, Nijmegen, The  Netherlands.

RESUMEN / SUMMARY:  - BACKGROUND: Prostate cancer antigen 3 (PCA3) and v-ets erythroblastosis virus E26 oncogene homolog (TMPRSS2-ERG) gene fusions are promising prostate cancer (PCa) specific biomarkers that can be measured in urine. OBJECTIVE: To evaluate the diagnostic and prognostic value of Progensa PCA3 and TMPRSS2-ERG gene fusions (as individual biomarkers and as a panel) for PCa in a prospective multicentre setting. DESIGN, SETTING, AND PARTICIPANTS: At six centres, post-digital rectal examination first-catch urine specimens prior to prostate biopsies were prospectively collected from 497 men. We assessed the predictive value of Progensa PCA3 and TMPRSS2-ERG (quantitative nucleic acid amplification assay to detect TMPRSS2-ERG messenger RNA [mRNA]) for PCa, Gleason score, clinical tumour  stage, and PCa significance (individually and as a marker panel). This was compared with serum prostate-specific antigen and the European Randomised Study of Screening for Prostate Cancer (ERSPC) risk calculator. In a subgroup (n=61) we evaluated biomarker association with prostatectomy outcome. OUTCOME MEASUREMENTS  AND STATISTICAL ANALYSIS: Univariate and multivariate logistic regression analysis and receiver operating curves were used. RESULTS AND LIMITATIONS: Urine  samples of 443 men contained sufficient mRNA for marker analysis. PCa was diagnosed in 196 of 443 men. Both PCA3 and TMPRSS2-ERG had significant additional predictive value to the ERSPC risk calculator parameters in multivariate analysis (p<0.001 and resp. p=0.002). The area under the curve (AUC) increased from 0.799  (ERSPC risk calculator), to 0.833 (ERSPC risk calculator plus PCA3), to 0.842 (ERSPC risk calculator plus PCA3 plus TMPRSS2-ERG) to predict PCa. Sensitivity of PCA3 increased from 68% to 76% when combined with TMPRSS2-ERG. TMPRSS2-ERG added  significant predictive value to the ERSPC risk calculator to predict biopsy Gleason score (p<0.001) and clinical tumour stage (p=0.023), whereas PCA3 did not. CONCLUSIONS: TMPRSS2-ERG had independent additional predictive value to PCA3 and the ERSPC risk calculator parameters for predicting PCa. TMPRSS2-ERG had prognostic value, whereas PCA3 did not. Implementing the novel urinary biomarker  panel PCA3 and TMPRSS2-ERG into clinical practice would lead to a considerable reduction of the number of prostate biopsies.




TÍTULO / TITLE:  - The Pim kinase inhibitor SGI-1776 decreases cell surface expression of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) and drug transport by Pim-1-dependent and -independent mechanisms.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochem Pharmacol. 2013 Feb 15;85(4):514-24. doi: 10.1016/j.bcp.2012.12.006. Epub 2012 Dec 19.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bcp.2012.12.006

AUTORES / AUTHORS:  - Natarajan K; Bhullar J; Shukla S; Burcu M; Chen ZS; Ambudkar SV; Baer MR

INSTITUCIÓN / INSTITUTION:  - University of Maryland Greenebaum Cancer Center, Baltimore, MD 21201, USA.

RESUMEN / SUMMARY:  - Overexpression of the ATP-binding cassette (ABC) drug efflux proteins P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) on malignant  cells is associated with inferior chemotherapy outcomes. Both, ABCB1 and ABCG2, are substrates of the serine/threonine kinase Pim-1; Pim-1 knockdown decreases their cell surface expression, but SGI-1776, the first clinically tested Pim inhibitor, was shown to reverse drug resistance by directly inhibiting ABCB1-mediated transport. We sought to characterize Pim-1-dependent and -independent effects of SGI-1776 on drug resistance. SGI-1776 at the Pim-1-inhibitory and non-cytotoxic concentration of 1muM decreased the IC(50)s of the ABCG2 and ABCB1 substrate drugs in cytotoxicity assays in resistant cells, with no effect on the IC(50) of non-substrate drug, nor in parental cells. SGI-1776 also increased apoptosis of cells overexpressing ABCG2 or ABCB1 exposed  to substrate chemotherapy drugs and decreased their colony formation in the presence of substrate, but not non-substrate, drugs, with no effect on parental cells. SGI-1776 decreased ABCB1 and ABCG2 surface expression on K562/ABCB1 and K562/ABCG2 cells, respectively, with Pim-1 overexpression, but not HL60/VCR and 8226/MR20 cells, with lower-level Pim-1 expression. Finally, SGI-1776 inhibited uptake of ABCG2 and ABCB1 substrates in a concentration-dependent manner irrespective of Pim-1 expression, inhibited ABCB1 and ABCG2 photoaffinity labeling with the transport substrate [(125)I]iodoarylazidoprazosin ([(125)I]IAAP) and stimulated ABCB1 and ABCG2 ATPase activity. Thus SGI-1776 decreases cell surface expression of ABCB1 and ABCG2 and inhibits drug transport  by Pim-1-dependent and -independent mechanisms, respectively. Decrease in ABCB1 and ABCG2 cell surface expression mediated by Pim-1 inhibition represents a novel mechanism of chemosensitization.




TÍTULO / TITLE:  - Novel Mechanism of Apoptosis Resistance in Cancer Mediated by Extracellular PAR-4.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Res. 2013 Jan 15;73(2):1011-9. doi: 10.1158/0008-5472.CAN-12-3212. Epub 2012 Nov 30.

            ●● Enlace al texto completo (gratuito o de pago) 1158/0008-5472.CAN-12-3212

AUTORES / AUTHORS:  - Burikhanov R; Shrestha-Bhattarai T; Qiu S; Shukla N; Hebbar N; Lele SM; Horbinski C; Rangnekar VM

INSTITUCIÓN / INSTITUTION:  - Authors’ Affiliations: Departments of Radiation Medicine, Pathology, Microbiology, Immunology, and Molecular Genetics; Graduate Center for Toxicology; L.P. Markey Cancer Center, University of Kentucky, Lexington, Kentucky; and University of Nebraska, Omaha, Nebraska.

RESUMEN / SUMMARY:  - Tumor suppressor PAR-4 acts in part by modulating sensitivity to apoptosis, but the basis for its activity is not fully understood. In this study, we describe a  novel mechanism of antiapoptosis by NF-kappaB, revealing that it can block PAR-4-mediated apoptosis by downregulating trafficking of the PAR-4 receptor GRP78 from the endoplasmic reticulum to the cell surface. Mechanistic investigations revealed that NF-kappaB mediated this antiapoptotic mechanism by upregulating expression of UACA, a proinflammatory protein in certain disease settings. In clinical specimens of cancer, a strong correlation existed between NF-kappaB activity and UACA expression, relative to normal tissues. UACA bound to intracellular PAR-4 in diverse cancer cells, where it prevented translocation of  GRP78 from the endoplasmic reticulum to the cell surface. This pathway of antiapoptosis could be inhibited by suppressing levels of NF-kappaB or UACA expression, which enhanced endoplasmic reticulum stress and restored GRP78 trafficking to the cell surface, thereby sensitizing cancer cells to apoptosis by extracellular PAR-4 or GRP78 agonistic antibody. In summary, our results identify a novel intracellular pathway of apoptosis mediated by NF-kappaB through UACA elevation, which by attenuating endoplasmic reticulum stress and GRP78 translocation to the cell surface can blunt the sensitivity of cancer cells to apoptosis. Cancer Res; 73(2); 1011-9. ©2012 AACR.




TÍTULO / TITLE:  - Correction: Cyclin D2-Cyclin-Dependent Kinase 4/6 Is Required for Efficient Proliferation and Tumorigenesis following Apc Loss.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Res. 2013 Jan 1;73(1):469. doi: 10.1158/0008-5472.CAN-12-4285. Epub 2012 Dec 27.

            ●● Enlace al texto completo (gratuito o de pago) 1158/0008-5472.CAN-12-4285




TÍTULO / TITLE:  - Caspase-Independent Cell Death Is Involved in the Negative Effect of EGF Receptor Inhibitors on Cisplatin in Non-Small Cell Lung Cancer Cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Jan 23.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-2621

AUTORES / AUTHORS:  - Yamaguchi H; Hsu JL; Chen CT; Wang YN; Hsu MC; Chang SS; Du Y; Ko HW; Herbst R; Hung MC

INSTITUCIÓN / INSTITUTION:  - Authors’ Affiliations: Departments of Molecular and Cellular Oncology and Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center; Graduate School of Biomedical Sciences, The University of Texas, Houston, Texas; Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University and Asia University, Taichung, Taiwan.

RESUMEN / SUMMARY:  - PURPOSE: Results of multiple clinical trials suggest that EGF receptor (EGFR) tyrosine kinase inhibitors (TKI) exhibit negative effects on platinum-based chemotherapy in patients with lung cancer with wild-type (WT) EGFR, but the underlying molecular mechanisms are still uncertain. Studies that identify the mechanism of how TKIs negatively affect patients with WT EGFR are important for future development of effective strategies to target lung cancer. Thus, we returned to in vitro study to investigate and determine a possible explanation for this phenomenon.EXPERIMENTAL DESIGN: We investigated the effects of TKIs and  cisplatin on caspase-independent cell death (CID) and the role of CID in the efficacy of each drug and the combination. Furthermore, we studied the mechanism  by which EGFR signaling pathway is involved in CID. Finally, on the basis of the  identified mechanism, we tested the combinational effects of cisplatin plus suberoylanilide hydroxamic acid (SAHA) or erastin on CID.RESULTS: We found that gefitinib inhibited cisplatin-induced CID but not caspase-dependent apoptotic cell death. In WT EGFR cells, gefitinib not only inhibited CID but also failed to induce apoptosis, therefore compromising the efficacy of cisplatin. Inhibition of EGFR-ERK/AKT by gefitinib activates FOXO3a, which in turn reduces reactive oxygen species (ROS) and ROS-mediated CID. To overcome this, we showed that SAHA and erastin, the inducers of ROS-mediated CID, strongly enhanced the effect of cisplatin in WT EGFR cells.CONCLUSION: TKI-mediated inhibition of CID plays an important role in the efficacy of chemotherapy. Moreover, FOXO3a is a key factor  in the negative effects of TKI by eliminating cisplatin-induced ROS. Clin Cancer  Res; 1-10. ©2012 AACR.




TÍTULO / TITLE:  - p130Cas acts as survival factor during PMA-induced apoptosis in HL-60 promyelocytic leukemia cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Biochem Cell Biol. 2012 Dec 31;45(3):531-535. doi: 10.1016/j.biocel.2012.12.017.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.biocel.2012.12.017

AUTORES / AUTHORS:  - Kumbrink J; Kirsch KH

INSTITUCIÓN / INSTITUTION:  - Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA.

RESUMEN / SUMMARY:  - Phorbol 12-myristate 13-acetate (PMA) stimulates the differentiation of promyelocytic leukemia HL-60 cells by inducing adhesion followed by cell aggregation and, importantly, apoptosis. p130Cas (Crk-associated substrate) is an adapter molecule that controls cell growth, attachment and apoptotic programs. Notably, elevated p130Cas activity is associated with leukemias and lymphomas. Since p130Cas regulates cell adhesion, we tested the hypothesis that it participates in the differentiation of hematopoietic cells. Here we show that PMA mediates the late induction of p130Cas expression in HL-60 cells, which coincided with cell aggregation and the onset of apoptosis. Ectopic p130Cas expression led  to increased cell adhesion and earlier cell aggregation potentially contributing  to the observed increased cell viability in these transductants. p130Cas expression concurred with the induction of its own regulator the transcription factor EGR1, its coregulator NAB2, and apoptosis. NF-kappaB inhibition in PMA-treated HL-60 cells promoted the loss of cell aggregation and cell death. We  further showed a reduction of p130Cas, EGR1, and NAB2 levels in response to NF-kappaB inhibition during PMA treatment. Hence, p130Cas acts as survival factor by limiting PMA-mediated cell cluster disruption and resulting cell death in HL-60 cells.




TÍTULO / TITLE:  - Phase II study to assess the efficacy, safety and tolerability of the mitotic spindle kinesin inhibitor AZD4877 in patients with recurrent advanced urothelial  cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Invest New Drugs. 2013 Jan 18.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10637-013-9926-y

AUTORES / AUTHORS:  - Jones R; Vuky J; Elliott T; Mead G; Arranz JA; Chester J; Chowdhury S; Dudek AZ; Muller-Mattheis V; Grimm MO; Gschwend JE; Wulfing C; Albers P; Li J; Osmukhina A; Skolnik J; Hudes G

INSTITUCIÓN / INSTITUTION:  - Institute of Cancer Sciences, University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK, r.jones@beatson.gla.ac.uk.

RESUMEN / SUMMARY:  - Background AZD4877 is a potent inhibitor of the mitotic spindle kinesin, Eg5. Early-phase clinical studies in a broad range of cancers showed that AZD4877 is well tolerated. This Phase II study evaluated the efficacy, safety and pharmacokinetics (C(max)) of AZD4877 in patients with previously treated advanced urothelial cancer (ClinicalTrials.gov identifier NCT00661609). Patients and methods AZD4877 25 mg was administered once-weekly for 3 weeks of each 4-week cycle until disease progression, death, unacceptable toxicity or withdrawal. The  primary objective was to determine the objective response rate (RECIST). Recruitment was to be halted if </=2 of the first 20 evaluable patients achieved  an objective tumor response. C(max) was assessed on days 1 and 8 of cycle 1. Results None of the first 20 patients evaluable for efficacy achieved an objective response; enrollment was therefore halted. During this initial analysis, a further 21 patients were recruited. Overall, 39 patients were evaluable for efficacy, including one with confirmed partial response (PR) and seven patients with stable disease for >/=8 weeks (including one unconfirmed PR). The most commonly reported treatment-related adverse events (TRAEs) were neutropenia (22 patients), fatigue (12), leukopenia (7) and constipation (6); the most commonly reported grade >/=3 TRAE was neutropenia (21). Four patients had serious TRAEs. On days 1 and 8, the geometric mean C(max) of AZD4877 was 138 ng/ml (CV = 75 %) and 144 ng/ml (CV = 109 %), respectively. Conclusions AZD4877 was generally tolerable in patients with advanced urothelial cancer. Given the limited clinical efficacy, further development of AZD4877 in urothelial cancer is not planned.




TÍTULO / TITLE:  - Dedifferentiation in Gastrointestinal Stromal Tumor to an Anaplastic KIT-negative Phenotype: A Diagnostic Pitfall: Morphologic and Molecular Characterization of 8  Cases Occurring Either De Novo or After Imatinib Therapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Am J Surg Pathol. 2013 Jan 22.

            ●● Enlace al texto completo (gratuito o de pago) 1097/PAS.0b013e31826c1761

AUTORES / AUTHORS:  - Antonescu CR; Romeo S; Zhang L; Nafa K; Hornick JL; Nielsen GP; Mino-Kenudson M; Huang HY; Mosquera JM; Tos PA; Fletcher CD

INSTITUCIÓN / INSTITUTION:  - *Department of Pathology, Memorial Sloan-Kettering Cancer Center paragraph signWeill Medical College of Cornell University, New York, NY double daggerSurgical Pathology, Brigham & Women’s Hospital section signMassachusetts General Hospital, Boston, MA daggerTreviso General Hospital, Treviso, Italy parallelKaohsiung Chang Gung Memorial Hospital and Chang Gung University College  of Medicine, Kaohsiung, Taiwan, Republic of China.

RESUMEN / SUMMARY:  - Most gastrointestinal stromal tumors (GISTs) can be recognized by their monotonous cytologic features and overexpression of KIT oncoprotein. Altered morphology and loss of CD117 reactivity has been described previously after chronic imatinib treatment; however, this phenomenon has not been reported in imatinib-naive tumors. Eight patients with abrupt transition from a classic CD117-positive spindle cell GIST to an anaplastic CD117-negative tumor were investigated for underlying molecular mechanisms of tumor progression. Pathologic and molecular analysis was performed on each of the 2 components. Genomic DNA polymerase chain reaction for KIT, PDGFRA, BRAF, and KRAS hot spot mutations and  fluorescence in situ hybridization for detecting KIT gene copy number alterations were performed. TP53 mutational analysis was performed in 5 cases. There were 7 men and 1 woman, with an age range of 23 to 65 years. Five of the primary tumors  were located in the stomach, and 1 case each originated in the small bowel, colon, and rectum. In 3 patients, the dedifferentiated component occurred in the  setting of imatinib resistance, whereas the remaining 5 occurred de novo. The dedifferentiated component had an anaplastic appearance, including 1 angiosarcomatous phenotype, with high mitotic activity and necrosis, and showed complete loss of CD117 (8/8) and CD34 (5/8) expression and de novo expression of  either cytokeratin (4/8) or desmin (1/8). There was no difference in the KIT genotype between the 2 components. However, 2 imatinib-resistant tumors showed coexistence of KIT exon 11 and exon 13 mutations. Fluorescence in situ hybridization showed loss of 1 KIT gene in 3 cases and low-level amplification of KIT in 2 other cases in the CD117-negative component, compared with the CD117-positive area. TP53 mutation was identified in 1/5 cases tested, being present in both components. In summary, dedifferentiation in GIST may occur either de novo or after chronic imatinib exposure and can represent a diagnostic  pitfall. This phenomenon is not related to additional KIT mutations, but might be secondary to genetic instability, either represented by loss of heterozygosity or low level of KIT amplification.




TÍTULO / TITLE:  - Lymphotoxin beta receptor mediates caspase-dependent tumor cell apoptosis in vitro and tumor suppression in vivo despite induction of NF-kB activation.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Carcinogenesis. 2013 Jan 24.

            ●● Enlace al texto completo (gratuito o de pago) 1093/carcin/bgt014

AUTORES / AUTHORS:  - Hu X; Zimmerman M; Bardhan K; Yang D; Waller JL; Liles GB; Lee JR; Pollock R; Lev D; Ware CF; Garber E; Bailly V; Browning JL; Liu K

INSTITUCIÓN / INSTITUTION:  - Department of Biochemistry and Molecular Biology, Georgia Health Sciences University, Augusta, GA 30912.

RESUMEN / SUMMARY:  - Ligation of the lymphotoxin beta receptor (LTbetaR) has been shown to induce both tumor growth inhibition and promotion. The functions of LTbetaR in these two contrasting cellular processes require further study. We demonstrated here that mice deficient in LTbetaR ligands, LTalpha, LIGHT, or both LTbeta and LIGHT, exhibit greater susceptibility to methylcholanthrene (MCA)-induced tumor development. LTalpha, LTbeta and LIGHT were expressed in tumor-infiltrating immune cells, and LTbetaR was expressed on human colon carcinoma and soft tissue  sarcoma (STS) cells. Human LTbetaR agonist monoclonal antibody (mAb) BS-1 induced both growth inhibition and NF-B activation in human colon carcinoma, mammary carcinoma and STS cells. Interestingly, BS-1 also significantly inhibited growth  of doxorubicin-resistant and radiation-resistant human STS cells in vitro. In the molecular mechanism level, we demonstrated that BS-1 induces caspases 8 and 3 activation and cytochrome C release in tumor cells, suggesting that the LTbetaR mediates apoptosis at least partially through a caspase-dependent mechanism. Furthermore, mouse LTbetaR mAb ACH6 suppressed colon carcinoma cell metastatic potential in an experimental metastasis mouse model. Although blocking NF-kappaB  activation did not alter tumor cell growth rate and tumor cell response to LTbetaR mAb-induced growth inhibition in vitro, surprisingly, blocking NF-B activation significantly enhanced colon carcinoma cell metastatic potential in vivo, suggesting that the LTbetaR-mediated apoptosis pathway and NF-kappaB signaling pathway might cooperate to suppress tumor growth in vivo. In summary, our findings determine that LTbetaR mediates tumor cell apoptosis in colon carcinoma, mammary carcinoma and sarcoma, and that LTbetaR-activated NF-kappaB potentially functions as a tumor suppressor.




TÍTULO / TITLE:  - Anti-Mullerian hormone as a marker of ovarian reserve in patients with ovarian malignancies who have undergone fertility-preserving surgery and chemotherapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Gynecol Endocrinol. 2013 Jan 10.

            ●● Enlace al texto completo (gratuito o de pago) 3109/09513590.2012.743008

AUTORES / AUTHORS:  - Iwase A; Sugita A; Hirokawa W; Goto M; Nakahara T; Bayasula; Kajiyama H; Shibata K; Nagatomo Y; Kikkawa F

INSTITUCIÓN / INSTITUTION:  - Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine and.

RESUMEN / SUMMARY:  - Abstract With proper and careful selection of patients, fertility-preserving surgery may be feasible in patients with ovarian malignancies. However, the loss  of follicles by oophorectomy and chemotherapy results in decreased ovarian reserve, which consecutively affects reproductive capacity. We evaluated postoperative levels of serum anti-Mullerian hormone (AMH) in women with ovarian  malignancies to assess the impact of the fertility-preserving surgery with or without the administration of chemotherapy on ovarian reserve. In 13 patients who underwent the fertility-preserving surgery with (n = 9) or without (n = 4) the administration of chemotherapy, serum AMH levels were measured and compared with  serum AMH levels measured in patients undergone cystectomy for benign ovarian tumors as a control. We found that the mean AMH level in the treatment group measured 0.9 ng/mL, which was significantly lower than that measured in the control group (4.70 +/- 3.77 ng/mL). The possibility of decreased ovarian reserve occurring in patients with ovarian malignancies following treatment with fertility-preserving surgery with or without the administration of chemotherapy should be considered for fertility planning.




TÍTULO / TITLE:  - Inhibition of cholinergic signaling causes apoptosis in human bronchioalveolar carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Res. 2012 Dec 7.

            ●● Enlace al texto completo (gratuito o de pago) 1158/0008-5472.CAN-12-3190

AUTORES / AUTHORS:  - Lau JK; Brown KC; Thornhill BA; Crabtree CM; Dom AM; Witte TR; Hardman WE; McNees CA; Stover CA; Carpenter AB; Luo H; Chen YC; Shiflett BS; Dasgupta P

INSTITUCIÓN / INSTITUTION:  - Pharmacology, Physiology and Toxicology, Marshall University.

RESUMEN / SUMMARY:  - Recent case-controlled clinical studies show that bronchioalveolar carcinomas (BACs) are correlated with smoking. Nicotine, the addictive component of cigarettes, accelerates cell proliferation through nicotinic acetylcholine receptors (nAChRs). In this study, we show that human BACs produce acetylcholine  (ACh) and contain several cholinergic factors including acetylcholinesterase (AChE), choline acetyltransferase (ChAT), choline transporter 1 (CHT1, SLC5A7), vesicular acetylcholine transporter (VAChT, SLC18A3) and nACh receptors (AChRs, CHRNAs). Nicotine increased the production of ACh in human BACs and ACh acts as a growth factor for these cells. Nicotine-induced ACh production was mediated by alpha7-, alpha3beta2-, and beta3-nAChRs, ChAT and VAChT pathways. We observed that nicotine upregulated ChAT and VAChT. Therefore, we conjectured that VAChT antagonists, such as vesamicol, may suppress the growth of human BACs. Vesamicol  induced potent apoptosis of human BACs in cell culture and nude mice models. Vesamicol did not have any effect on EGF or IGF-II-induced growth of human BAC’s. siRNA-mediated attenuation of VAChT reversed the apoptotic activity of vesamicol. We also observed that vesamicol inhibited Akt phosphorylation during cell death,  and overexpression of constitutively active Akt reversed the apoptotic activity of vesamicol. Taken together, our results suggested that disruption of nicotine-induced cholinergic signaling by agents such as vesamicol may have applications in BAC therapy.




TÍTULO / TITLE:  - Effect of Leuprolide on Serum Amyloid-beta Peptide Levels and Memory in Patients  With Prostate Cancer With Biochemical Recurrence.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Urology. 2013 Jan;81(1):150-4. doi: 10.1016/j.urology.2012.08.066.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.urology.2012.08.066

AUTORES / AUTHORS:  - Tan WW; Heckman MG; Vishnu P; Crook JE; Younkin LH; Covil EG; Ferman TJ; Graff-Radford NR; Younkin SG; Smallridge RC; Wehle MJ; Buskirk SJ

INSTITUCIÓN / INSTITUTION:  - Division of Hematology, Oncology, Cancer Center, GU Oncology, Mayo Clinic, Jacksonville, FL. Electronic address: tan.winston@mayo.edu.

RESUMEN / SUMMARY:  - OBJECTIVE: To investigate whether prostate cancer patients receiving leuprolide demonstrated objective cognitive decline accompanied by a change in plasma levels of amyloid-beta. METHODS: Between November 19, 2003, and July 21, 2008, we prospectively enrolled 50 patients with biochemical recurrence of prostate cancer and measured plasma amyloid-beta peptide 40 and amyloid-beta peptide 42 levels with sandwich enzyme-linked immunosorbent assay at baseline before the first leuprolide injection and at 2, 4, and 12 months. The Mini-Mental State Examination was used to assess 49 patients at baseline and at subsequent visits,  and 24 were also assessed by the California Verbal Learning Test-Short Form. RESULTS: Patients were a median age of 71 years (range, 59-89 years). Compared with baseline levels, plasma amyloid-beta peptide 40 levels were increased at 2 months (P = .04) and 4 months (P = .02). Age was correlated with plasma amyloid-beta peptide 40 levels (P = .003) and likely accounted for this relationship. Plasma amyloid-beta peptide 42 and performance on cognitive tasks did not differ from baseline, but memory measures improved slightly after baseline, most likely due to a practice effect. CONCLUSION: Leuprolide therapy was not associated with a decline in cognition or memory function or with elevated plasma amyloid short-term. Larger studies are needed to confirm these findings.




TÍTULO / TITLE:  - Can mutations of EGFR and KRAS in serum be predictive and prognostic markers in patients with advanced non-small cell lung cancer (NSCLC)?

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Med Oncol. 2013 Mar;30(1):328. doi: 10.1007/s12032-012-0328-3. Epub 2013 Jan 10.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12032-012-0328-3

AUTORES / AUTHORS:  - Kim ST; Sung JS; Jo UH; Park KH; Shin SW; Kim YH

INSTITUCIÓN / INSTITUTION:  - Division of Hematology-Oncology, Department of Medicine, Korea University Anam Hospital, Korea University College of Medicine, 126-1, Anam-dong 5-ga, Seongbuk-gu, Seoul, 136-705, South Korea.

RESUMEN / SUMMARY:  - The status of epidermal growth factor receptor (EGFR) and Kirsten ras (KRAS) mutations has been used widely in management of patients with non-small cell lung cancer (NSCLC). However, it may be difficult to get tumor tissues for analyzing the status of EGFR and KRAS mutation in large proportion of patients with advanced disease. We obtained pairs of tumor and serum samples from 57 patients with advanced NSCLC, between March 2006 and January 2009. EGFR mutation status from tumor samples and KRAS mutation status from serum samples were analyzed by genomic polymerase chain reaction and direct sequence, and EGFR mutation status from serum samples was determined by the peptide nucleic acid-locked nucleic acid PCR clamp. EGFR mutations were detected in the serum samples of 11 patients and in the tumor samples of 12 patients. Fourteen patients revealed (?) KRAS mutation in the serum sample. EGFR mutation status in the serum and tumor samples was consistent in 50 (87.7 %) of the 57 pairs (correlation index 0.62, p < 0.001). Only 5 of 57 (8.7 %) patients showed mutation of both EGFR and KRAS in serum sample. Twenty-two of 57 patients (38.5 %) received EGFR-TKIs as any line therapy. The response for EGFR-TKIs was significantly associated with EGFR mutations in both tumor samples and serum samples (p < 0.05). The status of KRAS  mutation in serum was not predictive for the response of EGFR-TKI (p > 0.05). There was no significant difference in OS according to the status of EGFR mutations in both serum and tumor samples (p > 0.05) and KRAS mutations in serum  samples (p > 0.05). The status of EGFR and KRAS mutation in serum was not prognostic in patients with advanced NSCLC. However, the clinical usefulness of EGFR mutation of serum as a selection marker for EGFR-TKIs sensitivity in NSCLC might be allowed, not KRAS mutation.




TÍTULO / TITLE:  - Pharmacogenetic analysis of adjuvant FOLFOX for Korean patients with colon cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Chemother Pharmacol. 2013 Jan 13.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00280-013-2075-3

AUTORES / AUTHORS:  - Lee KH; Chang HJ; Han SW; Oh DY; Im SA; Bang YJ; Kim SY; Lee KW; Kim JH; Hong YS; Kim TW; Park YS; Kang WK; Shin SJ; Ahn JB; Kang GH; Jeong SY; Park KJ; Park JG; Kim TY

INSTITUCIÓN / INSTITUTION:  - Department of Internal Medicine, Seoul National University Hospital, 28 Yongon-Dong, 110-744, Chongno-Gu, Seoul, Korea.

RESUMEN / SUMMARY:  - PURPOSE: Ethnic diversity of genetic polymorphism can result in individual differences in the efficacy and toxicity of cancer chemotherapy. METHODS: We analyzed 20 germline polymorphisms in 10 genes (TS, MTHFR, ERCC1, XPD, XRCC1, ABCC2, AGXT, GSTP1, GSTT1 and GSTM1) from prospectively enrolled 292 Korean patients treated with adjuvant oxaliplatin plus leucovorin plus 5-fluorouracil (FOLFOX) for colon cancer. RESULTS: In contrast to previous studies in Caucasians, neutropenia (grade 3-4, 60.5 %) was frequently observed, whereas only 16.4 % experienced grade 2 or more sensory neuropathy. Neutropenia was more frequent in MTHFR 677TT [adjusted odds ratio (OR) 2.32, 95 % confidence interval  (CI) 1.19-4.55] and ERCC1 19007TT (adjusted OR 4.58, 95 % CI 1.20-17.40) genotypes. Patients harboring XRCC1 23885GG experienced less grade 2-4 neuropathy [adjusted OR 0.52, 95 % CI 0.27-0.99]. MTHFR 677TT (p = 0.002) and XRCC1 23885GG  (p = 0.146) genotypes were also more prevalent in Koreans compared to Caucasians. TS ‘low’ genotype (adjusted HR 1.83, 95 % CI 1.003-3.34) was significantly related to shorter disease-free survival. Overall survival was not significantly  different according to the polymorphisms. CONCLUSIONS: Polymorphisms in MTHFR, XRCC1 and TS are related to toxicities and disease-free survival in patients with colon cancer. The ethnic differences in frequencies of genotypes may explain the  ethnic difference in toxicity profile following adjuvant FOLFOX chemotherapy.




TÍTULO / TITLE:  - Induction of p53, p21 and apoptosis by silencing the NF90/NF45 complex in human papilloma virus-transformed cervical carcinoma cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Oncogene. 2012 Dec 3. doi: 10.1038/onc.2012.533.

            ●● Enlace al texto completo (gratuito o de pago) 1038/onc.2012.533

AUTORES / AUTHORS:  - Shamanna RA; Hoque M; Pe’ery T; Mathews MB

INSTITUCIÓN / INSTITUTION:  - 1] Department of Biochemistry and Molecular Biology, New Jersey Medical School, UMDNJ, Newark, NJ, USA [2] Graduate School of Biomedical Sciences, UMDNJ, Newark, NJ, USA.

RESUMEN / SUMMARY:  - The heterodimeric nuclear factor (NF) 90/NF45 complex (NF90/NF45) binds nucleic acids and is a multifunctional regulator of gene expression. Here we report that  depletion of NF90/NF45 restores the expression of the p53 and p21 proteins in cervical carcinoma cells infected with high-risk human papillomaviruses (HPVs). Knockdown of either NF90 or NF45 by RNA interference led to greatly elevated levels of p53 and p21 proteins in HPV-derived HeLa and SiHa cells but not in other cancerous or normal cell lines. In HeLa cells, p21 messenger-RNA (mRNA) increased concomitantly but the level of p53 mRNA was unaffected. RNA interference directed against p53 prevented the induction of both proteins. These results indicated that the upregulation of p21 is due to p53-dependent transcription, whereas p53 is regulated post-transcriptionally. Proteasome-mediated turnover of p53 is accelerated by the HPV E6 and cellular E6AP proteins. We therefore examined the hypothesis that this pathway is regulated by NF90/NF45. Indeed, depletion of NF90 attenuated the expression of E6 RNA and inhibited transcription from the HPV early promoter, revealing a new role for NF90/NF45 in HPV gene expression. The transcription inhibition was largely independent of the reduction of P-TEFb (positive transcription elongation factor  b) levels caused by NF90 depletion. Consistent with p53 derepression, NF90/NF45-depleted HeLa cells displayed elevated poly ADP-ribose polymerase (PARP) cleavage and susceptibility to camptothecin-induced apoptosis. We conclude that high-risk strains of HPV utilize the cellular NF90/NF45 complex for viral E6 expression in infected cervical carcinoma cell lines. Interference with NF90/NF45 function could assist in controlling cervical carcinoma.Oncogene advance online publication, 3 December 2012; doi:10.1038/onc.2012.533.




TÍTULO / TITLE:  - A prospective case series of women with estrogen receptor-positive breast cancer: levels of tamoxifen metabolites in controlled ovarian stimulation with high-dose  tamoxifen.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Hum Reprod. 2013 Jan 18.

            ●● Enlace al texto completo (gratuito o de pago) 1093/humrep/des445

AUTORES / AUTHORS:  - Balkenende EM; Dahhan T; Linn SC; Jager NG; Beijnen JH; Goddijn M

INSTITUCIÓN / INSTITUTION:  - Centre for Reproductive Medicine, Department of Obstetrics and Gynecology, Academic Medical Centre, PO Box 22660, 1100 DD Amsterdam, The Netherlands.

RESUMEN / SUMMARY:  - Controlled ovarian stimulation (COS) in women with estrogen receptor (ER)-positive breast cancer is potentially harmful because of the increase in serum estrogen levels. During COS for cryopreservation of oocytes or embryos, these women may receive high doses of tamoxifen (60 mg) to modulate the ER and prevent extra growth of estrogen responsive tumours during COS. However, it is unknown whether adequate serum concentrations of endoxifen, the most important metabolite of tamoxifen, can be reached. The aim of this study is to evaluate whether the tamoxifen dose used in a tamoxifen-COS combined schedule for women with ER-positive breast cancer is high enough to reach endoxifen levels that are  considered therapeutically effective to inhibit breast cancer growth. The four women with ER-positive breast cancer who underwent COS for cryopreservation of oocytes were prospectively studied at the Academic Medical Centre, Amsterdam, the Netherlands. Throughout COS, blood samples were collected and tamoxifen and endoxifen levels were determined by a validated high-performance liquid chromatography tandem mass spectrometry assay. The four women with ER-positive breast cancer underwent a total of five COS cycles, while additionally using tamoxifen 60 mg daily. The tamoxifen and endoxifen levels showed a large variability between the women, with endoxifen levels during the whole period of ovarian stimulation varying between 3.96 and 41.0 ng/ml. The average number of vitrified oocytes was 11 (5-14). Therapeutically effective endoxifen serum levels can be reached when tamoxifen is used to counteract estrogen levels during COS for fertility preservation, but not in all women. Large variations of tamoxifen and endoxifen levels between the women were observed.




TÍTULO / TITLE:  - Characterization of a novel PERK kinase inhibitor with anti-tumor and anti-angiogenic activity.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Res. 2013 Jan 18.

            ●● Enlace al texto completo (gratuito o de pago) 1158/0008-5472.CAN-12-3109

AUTORES / AUTHORS:  - Atkins C; Liu Q; Minthorn EA; Zhang S; Figueroa DJ; Moss KG; Stanley TB; Sanders B; Goetz A; Gaul N; Choudhry AE; Alsaid H; Jucker BM; Axten JM; Kumar R

INSTITUCIÓN / INSTITUTION:  - Oncology R&D, GlaxoSmithKline Research & Development.

RESUMEN / SUMMARY:  - The unfolded protein response (UPR) is a signal transduction pathway that coordinates cellular adaptation to microenvironmental stresses that include hypoxia, nutrient deprivation, and change in redox status. These stress stimuli are common in many tumors and thus targeting components of the UPR signaling is an attractive therapeutic approach. We have identified a first-in-class, small molecule inhibitor of the eukaryotic initiation factor 2-alpha kinase 3 (EIF2AK3) or PERK, one of the three mediators of UPR signaling. GSK2656157 is an ATP-competitive inhibitor of PERK enzyme activity with an IC50 of 0.9 nM. It is highly selective for PERK with IC50 values >100 nM against a panel of 300 kinases. GSK2656157 inhibits PERK activity in cells with an IC50 in the range of  10-30 nM as shown by inhibition of stress-induced PERK autophosphorylation, eIF2alpha substrate phosphorylation, together with corresponding decreases in ATF4 and CHOP proteins in multiple cell lines. Oral administration of GSK2656157  to mice shows a dose- and time-dependent pharmacodynamic response in pancreas as  measured by PERK auto-phosphorylation. Twice daily dosing of GSK2656157 results in dose dependent inhibition of multiple human tumor xenografts growth in mice. Altered amino acid metabolism, decreased blood vessel density and vascular perfusion are potential mechanisms for the observed anti-tumor effect. However, despite its anti-tumor activity, given the on-target pharmacological effects of PERK inhibition on pancreatic function, development of any PERK inhibitor in human subjects would need to be cautiously pursued in cancer patients.




TÍTULO / TITLE:  - Overexpression of ubiquitin-specific protease 22 predicts poor survival in patients with early-stage non-small cell lung cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur J Histochem. 2012 Nov 30;56(4):e46. doi: 10.4081/ejh.2012.e46.

AUTORES / AUTHORS:  - Ning J; Zhang J; Liu W; Lang Y; Xue Y; Xu S

INSTITUCIÓN / INSTITUTION:  - The Third Affiliated Hospital of Harbin Medical University. shidong_xu@163.com.

RESUMEN / SUMMARY:  - Ubiquitin-specific protease 22 (USP22), a novel ubiquitin hydrolase, has been implicated in oncogenesis and cancer progression in various types of human cancer. However, the clinical significance of USP22 expression in non-small cell  lung cancer (NSCLC) has not been determined. In the present study, USP22 messenger RNA (mRNA) and protein levels were analyzed by quantitative real-time polymerase chain reaction (PCR) and western blot analysis in 30 cases of NSCLC and in corresponding non-tumor tissue samples. Furthermore, immunohistochemistry  was performed to detect USP22 protein expression in 86 primary tumor tissues derived from clinically annotated NSCLC cases at stage I-II. In our analysis we found that both USP22 mRNA and protein levels in NSCLC tissues were significantly higher than those in corresponding non-tumor tissues and that there was a significant correlation between the expression of USP22 mRNA and protein (P=0.000, kappa=0.732). In addition, a high-level of USP22 expression was observed in 53.3% (39 out of 86) cases and it was correlated with large tumor size (P=0.029) and lymph node metastasis (P=0.026). Patients with tumors displaying a high-level of USP22 expression showed significantly shorter survival (P=0.006, log-rank test). Importantly, multivariate analysis showed that high USP22 protein expression was an independent prognostic factor for NSCLC patients  (P=0.003). In sum, our data suggest that USP22 plays an important role in NSCLC progression at the early stage, and that overexpression of USP22 in tumor tissues could be used as a potential prognostic marker for patients with early clinical stage of NSCLC.




TÍTULO / TITLE:  - Molecular subtype and response to dasatinib, a src/abl small molecule kinase inhibitor, in Hepatocellular carcinoma cell lines in vitro.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Hepatology. 2013 Jan 8. doi: 10.1002/hep.26223.

            ●● Enlace al texto completo (gratuito o de pago) 1002/hep.26223

AUTORES / AUTHORS:  - Finn RS; Aleshin A; Dering J; Yang P; Ginther C; Desai A; Zhao D; Euw EV; Busuttil RW; Slamon DJ

INSTITUCIÓN / INSTITUTION:  - Department of Medicine, Division of Hematology/ Oncology, Geffen School of Medicine at UCLA, Los Angeles, CA. Rfinn@mednet.ucla.edu.

RESUMEN / SUMMARY:  - Hepatocellular carcinoma (HCC) is the fifth most common malignancy and is the third leading cause of cancer death worldwide. Recently the multi-targeted kinase inhibitor sorafenib was shown to be the first systemic agent to improve survival  in advanced HCC. Unlike other malignancies such as breast cancer, in which molecular subtypes have been clearly defined (i.e. luminal, HER2 amplified, basal, etc) and tied to effective molecular therapeutics (hormone blockade and trastuzumab, respectively), in HCC this translational link does not exist. Molecular profiling studies of human HCC have identified unique molecular subtypes of the disease. We hypothesized that a panel of human HCC cell lines would maintain molecular characteristics of the clinical disease and could then be used as a model for novel therapeutics. 20 human HCC cell lines were collected and RNA was analyzed using the Agilent microarray platform. Profiles from the cell lines in vitro, recapitulate previously described subgroups from clinical material. Next, we evaluated whether molecular subgroup would have predictive value for response to the Src/ Abl inhibitor dasatinib. Results demonstrate that  sensitivity to dasatinib was associated with a progenitor subtype. Dasatinib was  effective at inducing cell cycle arrest and apoptosis in “progenitor-like” cell lines but not in resistant lines. These findings suggest that cell line models maintain the molecular background of HCC and that subtype may be important for selecting patients for response to novel therapies. In addition, it highlights a  potential role for Src family signaling in this progenitor subtype of HCC. (HEPATOLOGY 2013.).




TÍTULO / TITLE:  - Apoptosis induction of human leukemia U937 cells by 7,8-dihydroxyflavone hydrate  through modulation of the Bcl-2 family of proteins and the MAPKs signaling pathway.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Mutat Res. 2012 Dec 20. pii: S1383-5718(12)00358-0. doi: 10.1016/j.mrgentox.2012.12.002.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.mrgentox.2012.12.002

AUTORES / AUTHORS:  - Park HY; Kim GY; Kwon TK; Hwang HJ; Kim ND; Yoo YH; Choi YH

INSTITUCIÓN / INSTITUTION:  - Department of Pharmacy, Busan National University, Busan 609-735, Republic of Korea.

RESUMEN / SUMMARY:  - The present study investigated possible mechanisms of apoptosis induction of U937 human leukemic cells by 7,8-dihydroxyflavone hydrate (7,8-DHF), a member of the flavonoid family and a recently identified tyrosine kinase receptor B (TrkB) agonist. 7,8-DHF treatment of U937 cells resulted in inhibition of growth and induction of apoptosis as measured by MTT assay, fluorescence microscopy, DNA fragmentation, and flow cytometry analysis. 7,8-DHF-induced apoptosis in U937 cells was correlated with the up-regulation of death receptor related protein levels and down-regulation of anti-apoptotic IAP family proteins. The increase in apoptosis was also associated with proteolytic activation of caspases, Bid cleavage, insertion of pro-apoptotic Bax into the mitochondria and release of cytochrome c from mitochondria to cytosol. Furthermore, it was found that Bcl-2 overexpression markedly protected U937 cells from 7,8-DHF-induced apoptosis by restoring activation of caspases. In addition, 7,8-DHF treatment effectively activated the mitogen-activated protein kinases (MAPK), and inhibitors of extracellular-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), but not p38 MAPK, which significantly reduced 7,8-DHF-induced apoptosis. Taken together,  our results indicate that the JNK and ERK pathways, and modulation of Bcl-2 family proteins were key regulators of apoptosis in response to 7,8-DHF in U937 cells.




TÍTULO / TITLE:  - Chemotherapy, targeted agents, antiemetics and growth-factors in human milk: How  should we counsel cancer patients about breastfeeding?

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Treat Rev. 2012 Nov 28. pii: S0305-7372(12)00209-5. doi: 10.1016/j.ctrv.2012.10.002.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ctrv.2012.10.002

AUTORES / AUTHORS:  - Pistilli B; Bellettini G; Giovannetti E; Codacci-Pisanelli G; Azim HA Jr; Benedetti G; Sarno MA; Peccatori FA

INSTITUCIÓN / INSTITUTION:  - Fertility and Procreation in Oncology Unit, Department of Medicine, European Institute of Oncology, Milan, Italy; Division of Medical Oncology, Ospedale di Macerata, Macerata, Italy.

RESUMEN / SUMMARY:  - An increasing number of women are diagnosed with cancer during pregnancy and lactation. Women are usually advised to interrupt breastfeeding during systemic anticancer treatment for fear of serious adverse effects to the nursed infant. However, the issue is poorly addressed in the literature and very few studies have evaluated the safety of breastfeeding during or after cytotoxic drugs or target agents administration. In this review we will analyze the available evidence that addresses the issue of anticancer drugs, targeted agents, antiemetics and growth-factors excretion in human milk. This could serve as a unique resource that may aid physicians in the management of breastfeeding cancer patients interested in maintaining lactation during treatment.




TÍTULO / TITLE:  - IL-21 gene polymorphism is associated with the prognosis of breast cancer in Chinese populations.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Breast Cancer Res Treat. 2013 Feb;137(3):893-901. doi: 10.1007/s10549-012-2401-1. Epub 2013 Jan 4.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10549-012-2401-1

AUTORES / AUTHORS:  - You Y; Deng J; Zheng J; Hu M; Li N; Wu H; Li W; Lu J; Zhou Y

INSTITUCIÓN / INSTITUTION:  - Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou, 215123, China.

RESUMEN / SUMMARY:  - Interleukin (IL)-21, which is secreted by activated CD4(+) T cells and NKT cells, has been found to be able to influence the humoral and cell-mediated immune responses and have potent antitumor activity in animal models. This study was to  investigate the impact of genetic polymorphisms in IL-21 on survival of breast cancer. Four TagSNPs of IL-21 (rs12508721C>T, rs907715G>A, rs13143866G>A, rs2221903A>G) were selected and then genotyped in 891 patients with breast cancer in Eastern and Southern Chinese populations. We then examined the associations between these SNPs and overall survival. Potential function of rs12508721C>T and  association between this variation and breast cancer prognosis were further studied. Overall, 121 of the patients had died over the followed-up period of 5 years. The IL-21 rs12508721T allele predicted longer five-year survival (HR = 0.347, 95 % CI = 0.187-0.644, P < 0.0001) in the discovery cohort, the independent validation cohort (HR = 0.429, 95 % CI = 0.244-0.755, P = 0.012), and combined group (HR = 0.447, 95 % CI = 0.301-0.667, P < 0.0001). Furthermore, our  luciferase assay revealed that rs12508721T variant allele had a higher transcription activity and the RT-PCR and ELISA assay showed that rs12508721 variant genotypes (CT and TT) carriers have more IL-21 expression than CC carriers (P < 0.05). Our present study established a robust association between the functional polymorphism (rs12508721C>T) in IL-21 and prognosis of breast cancer, indicating that this polymorphism may be a potential biomarker for prognosis of breast cancer.




TÍTULO / TITLE:  - Akt2 expression is associated with good long-term prognosis in oestrogen receptor positive breast cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur J Cancer. 2013 Jan 7. pii: S0959-8049(12)00963-X. doi: 10.1016/j.ejca.2012.12.006.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ejca.2012.12.006

AUTORES / AUTHORS:  - Fohlin H; Perez-Tenorio G; Fornander T; Skoog L; Nordenskjold B; Carstensen J; Stal O

INSTITUCIÓN / INSTITUTION:  - Regional Cancer Center, Southeast Sweden, County Council of Ostergotland, Linkoping, Sweden; Division of Oncology, Department of Clinical and Experimental  Medicine, Faculty of Health Sciences, Linkoping University, Sweden. Electronic address: helena.fohlin@lio.se.

RESUMEN / SUMMARY:  - INTRODUCTION: Akt is a signalling modulator for many cellular processes, including metabolism, cell proliferation, cell survival and cell growth. Three isoforms of Akt have been identified, but only a few studies have concerned the isoform-specific roles in the prognosis of breast cancer patients. The aim of this study was to investigate the prognostic value of v-akt murine thymoma viral  oncogene homologue 1 (Akt1) and v-akt murine thymoma viral oncogene homologue 2 (Akt2) in oestrogen receptor positive (ER+) and oestrogen receptor negative (ER-) breast cancer with long-term follow-up. MATERIAL AND METHODS: The expression of Akt in tumour tissue was analysed with immunohistochemistry in a cohort of 272 postmenopausal patients with stage II breast cancer. The median follow-up time was 19years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using the Cox’s proportional hazards model. RESULTS: The risk of distant recurrence was reduced for patients with ER+ tumours expressing Akt2 compared to patients with no Akt2 expression (HR=0.49, 95% CI 0.29-0.82, p=0.007). When adjusting for important clinical tumour characteristics and treatment, Akt2 was still an independent prognostic factor (HR=0.38, 95% CI 0.21-0.68, p=0.001) and the association remained long-term. The prognostic value  of Akt2 increased with higher oestrogen receptor levels from no effect among patients with ER- tumours to 68% risk reduction for the group with high ER-levels (P for trend=0.042). Akt1 showed no significant prognostic information. CONCLUSION: Our results indicate that Akt2 expression is associated with a lower  distant recurrence rate for patients with ER+ tumours and that this association remains long-term. The prognostic value of Akt2 increases with higher oestrogen receptor expression, motivating further mechanistic studies on the role of Akt2 in ER+ breast cancer.




TÍTULO / TITLE:  - HDAC inhibition by SNDX-275 (Entinostat) restores expression of silenced leukemia-associated transcription factors Nur77 and Nor1 and of key pro-apoptotic proteins in AML.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Leukemia. 2012 Dec 18. doi: 10.1038/leu.2012.366.

            ●● Enlace al texto completo (gratuito o de pago) 1038/leu.2012.366

AUTORES / AUTHORS:  - Zhou L; Ruvolo VR; McQueen T; Chen W; Samudio IJ; Conneely O; Konopleva M; Andreeff M

INSTITUCIÓN / INSTITUTION:  - Molecular Hematology and Therapy, Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.

RESUMEN / SUMMARY:  - Nur77 and Nor1 are highly conserved orphan nuclear receptors. We have recently reported that nur77(-/-)nor1(-/-) mice rapidly develop acute myeloid leukemia (AML) and that Nur77 and Nor1 transcripts were universally down-regulated in human AML blasts. These findings indicate that Nur77 and Nor1 function as leukemia suppressors. We further demonstrated silencing of Nur77 and Nor1 in leukemia stem cells (LSCs). We here report that inhibition of histone deacetylase (HDAC) using the specific class I HDAC inhibitor SNDX-275, restored the expression of Nur77/Nor1 and induced expression of AP1 transcription factors c-Jun and JunB, and of death receptor TRAIL, in AML cells and in CD34+38- AML leukemic stem cells (LSC). Importantly, SNDX-275 induced extensive apoptosis in AML cells, which could be suppressed by silencing nur77 and nor1. In addition, pro-apoptotic proteins Bim and Noxa were transcriptionally up-regulated by SNDX-275 in AML cells and in LSC. Our present work is the first report of a novel mechanism of HDAC inhibitor-induced apoptosis in AML that involves restoration of the silenced nuclear receptors Nur77 and Nor1, activation of AP1 transcription factors, a death receptor and pro-apoptotic proteins.Leukemia accepted article preview online, 18 December 2012; doi:10.1038/leu.2012.366.




TÍTULO / TITLE:  - Sexual outcomes of aromatase inhibitor therapy in women with breast cancer: time  for intervention.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Menopause. 2013 Feb;20(2):128-9. doi: 10.1097/gme.0b013e31828094b0.

            ●● Enlace al texto completo (gratuito o de pago) 1097/gme.0b013e31828094b0

AUTORES / AUTHORS:  - Bradford A

INSTITUCIÓN / INSTITUTION:  - Department of Gynecologic Oncology and Reproductive Medicine University of Texas  MD Anderson Cancer Center Houston, Texas.




TÍTULO / TITLE:  - Preoperative elevation of carcinoembryonic antigen predicts poor tumor response and frequent distant recurrence for patients with rectal cancer who receive preoperative chemoradiotherapy and total mesorectal excision: a multi-institutional analysis in an Asian population.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Colorectal Dis. 2012 Dec 4.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00384-012-1584-6

AUTORES / AUTHORS:  - Lee JH; Kim SH; Jang HS; Chung HJ; Oh ST; Lee DS; Kim JG

INSTITUCIÓN / INSTITUTION:  - Department of Radiation Oncology, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon, South Korea.

RESUMEN / SUMMARY:  - PURPOSE: This study was conducted to evaluate the significance of carcinoembryonic antigen (CEA) level as a predictor for tumor response to chemoradiotherapy (CRT) and a prognosticator for survival in Asian patients with  advanced rectal cancer. MATERIALS AND METHODS: We enrolled 345 patients with primary rectal cancer who had undergone preoperative CRT and total mesorectal excision. We analyzed clinicopathological factors that could be associated with pathologically complete response (ypCR) and disease-free survival (DFS). RESULTS: A cutoff level of 5 ng/mL (p = 0.002) for CEA was found to be significant for prediction of ypCR. Increased CEA level (p = 0.025) was a significant negative predictor of ypCR after CRT in patients with rectal cancer. The 5-year DFS rate was significantly higher in the CEA </=5-ng/mL group than in the CEA >5-ng/mL group (73.2 vs. 60.9 %, p = 0.002). This is mainly due to the higher chance of distant recurrence (p = 0.013), not locoregional recurrence (p = 0.732), in the CEA >5-ng/mL group. CONCLUSIONS: Elevated CEA (>5 ng/mL) is a negative predictor  of ypCR and has a negative impact on DFS in Asian rectal cancer patients who underwent preoperative CRT and surgery due to an increased chance of distant recurrences.




TÍTULO / TITLE:  - Two different formulations with equivalent effect? Comparison of serum estradiol  suppression with monthly goserelin and trimonthly leuprolide in breast cancer patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Med Oncol. 2013 Mar;30(1):354. doi: 10.1007/s12032-012-0354-1. Epub 2012 Dec 29.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12032-012-0354-1

AUTORES / AUTHORS:  - Aydiner A; Kilic L; Yildiz I; Keskin S; Sen F; Kucucuk S; Karanlik H; Muslumanoglu M; Igci A

INSTITUCIÓN / INSTITUTION:  - Department of Medical Oncology, Institute of Oncology, Istanbul University, Capa, Istanbul, Turkey, adnanaydiner@superonline.com.

RESUMEN / SUMMARY:  - Data comparing the efficacy of monthly and trimonthly formulations of LHRH agonists are lacking. The aim of this study was to compare the effects of monthly goserelin and trimonthly leuprolide on estradiol levels. A total of 79 early breast cancer patients receiving LHRH agonists for at least 6 months were enrolled in the study. Serum estradiol, FSH and LH levels were measured before drug injection and at the one-month follow-up visit. Thirty-eight patients were treated with goserelin, and 41 patients were treated with leuprolide. Patient characteristics and histopathological variables did not differ between the groups. A comparison of the mean hormone levels between the two groups revealed no significant differences in FSH or estradiol levels (p = 0.143 and p = 0.683, respectively), but the median LH level was higher in the leuprolide group (p = 0.025). Among the patients who did not receive chemotherapy, LH levels were higher in the leuprolide arm (p = 0.028). Additionally, FSH levels were significantly higher in the patients over 40 years old (p = 0.02) and in those with tumours harbouring cERB-B2 receptor (p = 0.05) in the leuprolide group. Three patients (7.9 %) in the goserelin and five patients (12.2 %) in the leuprolide group failed to achieve postmenopausal estradiol levels (p = 0.707). The effects of monthly goserelin and trimonthly leuprolide on estradiol levels did not differ significantly. Further research is required to interpret the variable effects on gonadotropins in each subgroup and the relationship between LHRH agonists and survival.




TÍTULO / TITLE:  - Aberrations of MET are associated with copy number gain of EGFR and loss of PTEN  and predict poor outcome in patients with salivary gland cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Virchows Arch. 2013 Jan;462(1):65-72. doi: 10.1007/s00428-012-1358-0. Epub 2012 Dec 15.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00428-012-1358-0

AUTORES / AUTHORS:  - Ach T; Zeitler K; Schwarz-Furlan S; Baader K; Agaimy A; Rohrmeier C; Zenk J; Gosau M; Reichert TE; Brockhoff G; Ettl T

INSTITUCIÓN / INSTITUTION:  - Department of Oral and Maxillofacial Surgery, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany, tobias.ach@ukr.de.

RESUMEN / SUMMARY:  - Hepatocyte growth factor receptor (MET) is a key driver of oncogenic transformation. Copy number gain and amplification of MET positively enhance tumour growth, invasiveness and metastasis in different cancer types. In the present study, 266 carcinomas of the major and minor salivary glands were investigated for genomic MET status by fluorescence in situ hybridization and for protein expression by immunohistochemistry. Results were matched with clinicopathological parameters, long-term survival and the status of epidermal growth factor receptor (EGFR) and phosphatase and tensin homologue (PTEN). Low polysomy (n = 42), high polysomy (n = 27), amplification (n = 2) and deletion (n  = 18) were found as aberrations of genomic MET in certain subtypes. MET aberrations were associated with increased patient age (>70 years, p = 0.003), male gender (p = 0.01), increased tumour size (p = 0.002), lymph node metastases  (p < 0.001), high-grade malignancy (p < 0.001) and unfavourable overall survival  (p < 0.001). Both copy number gain (p < 0.001) and deletion (p = 0.031) of MET correlated with copy number gain of EGFR. Tumours with genomic loss of PTEN (n =  48) concurrently presented aberration of genomic MET (p < 0.001). MET gene status significantly correlated with protein status (p = 0.038). In conclusion, gain but also loss of genomic MET activity correlates with aggressive tumour growth, nodal metastasis and worse overall survival in salivary gland cancer. Moreover, aberrations of MET are associated with EGFR and PTEN signalling and might possess relevance for targeted therapies of salivary gland carcinomas in the future.




TÍTULO / TITLE:  - Low NDRG1 mRNA expression predicts a poor prognosis in neuroblastoma patients.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Pediatr Surg Int. 2013 Jan 8.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00383-012-3248-6

AUTORES / AUTHORS:  - Matsushita K; Uchida K; Saigusa S; Ide S; Hashimoto K; Koike Y; Otake K; Inoue M; Tanaka K; Kusunoki M

INSTITUCIÓN / INSTITUTION:  - Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.

RESUMEN / SUMMARY:  - PURPOSE: N-myc downstream regulated gene 1 (NDRG1) markedly reduces metastasis of numerous tumors. However, NDRG1’s function in malignant tumors has not been fully determined. Therefore, we investigated the association of NDRG1 expression with clinical outcomes in neuroblastoma (NB) patients. METHODS: We obtained total RNA  from residual cancer cells using microdissection from NB patients. Furthermore, we examined the expression of NDRG1 in NB patients using immunohistochemical staining. RESULTS: Of the 48 patients observed, low NDRG1 expression was associated with poor prognostic factors such as primary tumor size and MYCN amplification. Low expression of NDRG1 was associated with a poor prognosis (p =  0.001) and multivariate analysis identified low expression of NDRG1 as an independent risk factor for predicting poor prognosis in NB patients. Furthermore, in the MYCN non-amplification group (n = 33), low expression of NDRG1 was associated with a poor prognosis (p = 0.001). Immunohistochemical analysis showed NDRG1 expression at the plasma membranes of NB cells. NDRG1 expression levels were also correlated with expression of NDRG1 mRNA. CONCLUSION: We confirmed that low NDRG1 expression is a significant and independent prognostic indicator in NB by multivariate analysis. Furthermore, NDRG1 may be a  novel prognostic marker in MYCN non-amplification NB patients.




TÍTULO / TITLE:  - Honokiol synergizes chemotherapy drugs in multidrug resistant breast cancer cells via enhanced apoptosis and additional programmed necrotic death.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Oncol. 2013 Feb;42(2):721-32. doi: 10.3892/ijo.2012.1739. Epub 2012 Dec 14.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ijo.2012.1739

AUTORES / AUTHORS:  - Tian W; Deng Y; Li L; He H; Sun J; Xu D

INSTITUCIÓN / INSTITUTION:  - Department of Surgical Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China.

RESUMEN / SUMMARY:  - Multidrug resistance (MDR) is a major challenge in cancer therapy. Apoptosis tolerance is one of the key mechanisms of MDR. Honokiol, a small-molecule pharmacologically active component, exhibits competent cytotoxicity in a variety  of human cancer cells through apoptosis and other forms of programmed cell death  (such as programmed necrosis). Although much work has been done on its antitumor  effects, little attention has been paid on systemic evaluation of efficacy of honokiol combined with other chemotherapeutic agents, especially in drugresistant cell lines. Here, we systematically and quantitatively assess its combinational effect with different chemotherapeutic agents using the combination index (CI) equation. We found that honokiol synergized with chemotherapeutic agents both in  sensitive and resistant, solid and non-solid (MCF-7, HL-60, MCF-7/ADR and HL-60/ADR) cell lines. Honokiol (40 microg/ml) induced necrotic cell death in MCF-7/ADR cells with characterized morphological and biochemical features. Co-incubation with honokiol and etoposide (VP-16) activated a complex death modality, which was composed of necrotic cell death and apoptosis. This dual-death pathway was shut down when pretreated with pan-caspase inhibitor (z-VAD-fmk) and cyclophilin D inhibitor (cyclosporin A). Western blot analysis results proved that honokiol also enhanced VP-16-induced apoptosis potentially via blocking nuclear factorkappaB (NF-kappaB) activation. Our data for the first  time quantitatively demonstrate that honokiol synergizes frequently-used chemotherapeutic agents via enhanced apoptosis and additional programmed necrotic death. These findings indicate a promising way to circumvent MDR and apoptosis tolerance.




TÍTULO / TITLE:  - Honokiol induces caspase-independent paraptosis via reactive oxygen species production that is accompanied by apoptosis in leukemia cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Biochem Biophys Res Commun. 2013 Jan 18;430(3):876-82. doi: 10.1016/j.bbrc.2012.12.063. Epub 2012 Dec 21.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bbrc.2012.12.063

AUTORES / AUTHORS:  - Wang Y; Zhu X; Yang Z; Zhao X

INSTITUCIÓN / INSTITUTION:  - West China Hospital Laboratory of Nanomedicine and Institute for Nanobiomedical Technology and Membrane Biology, Sichuan University, Chengdu 610041, Sichuan, China; First Hospital of Xi’an, Shaanxi Provincial Key Lab of Ophthalmology, Shaanxi Institute of Ophthalmology, Xi’an 710002, Shaanxi, China.

RESUMEN / SUMMARY:  - Our previous report has shown that honokiol (HNK), a constituent of Magnolia officinalis, induces a novel form of non-apoptotic programmed cell death in human leukemia NB4 and K562 cells. In this study, we further explored the relationship  between the cell death pathway and cytoplasmic vacuolization and studied the underlying mechanism of leukemia cell death mediated by honokiol. The results showed that low concentrations of honokiol activated an novel alternative cell death fitted the criteria of paraptosis, such as cytoplasmic vacuolization derived from endoplasmic reticulum swelling, lack of caspase activation, and lack of apoptotic morphology. Results further indicated that the cell death was time-  and concentration-dependent. In addition, honokiol-induced paraptosis did not involve membrane blebbing, chromatin condensation and phosphatidylserine exposure at the outer of the plasma membrane. The mechanism of the cell death may be associated, at least in part, with the increased generation of reactive oxygen species. Further analysis showed that honokiol induces cell death predominantly via paraptosis and to a certain extent via apoptosis in NB4 cells, and predominantly via apoptosis and to a certain extent via paraptosis in K562 cells. These observations suggest that cell death occurs via more than one pathway in leukemia cells and targeting paraptosis may be an alternative and promising avenue for honokiol in leukemia therapy.




TÍTULO / TITLE:  - A novel antitumor activity of deguelin targeting the insulin-like growth factor (IGF) receptor pathway via up-regulation of IGF-binding protein-3 expression in breast cancer.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Cancer Lett. 2013 Jan 21. pii: S0304-3835(13)00051-7. doi: 10.1016/j.canlet.2013.01.022.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.canlet.2013.01.022

AUTORES / AUTHORS:  - Suh YA; Kim JH; Sung MA; Boo HJ; Jeong Yun H; Lee SH; Lee HJ; Min HY; Lee HY

INSTITUCIÓN / INSTITUTION:  - Institute for Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-738, Republic of Korea.

RESUMEN / SUMMARY:  - In this study, we investigated the antitumor effects of deguelin in several human breast cancer cells in vitro and in vivo. Deguelin inhibited cell viability and the anchorage-dependent and anchorage-independent colony formation of triple-negative (MDA-MB-231 and MDA-MB-468) and triple-positive (MCF-7) breast cancer cells, and it significantly reduced the growth of MCF-7 cell xenograft tumors. The induction of apoptosis, inhibition of insulin-like growth factor-1 receptor (IGF-1R) signaling activation, and up-regulation of IGF-binding protein-3 (IGFBP-3) expression may be associated with deguelin-mediated antitumor effects. Our findings suggest a potential therapeutic use for deguelin in patients with triple-negative breast cancer and for those with breast cancers who are sensitive to endocrine- and HER2-targeted therapies.




TÍTULO / TITLE:  - Importance of detecting multidrug resistance proteins in acute leukemia prognosis and therapy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Clin Lab Anal. 2013 Jan;27(1):62-71. doi: 10.1002/jcla.21563. Epub 2013 Jan 4.

            ●● Enlace al texto completo (gratuito o de pago) 1002/jcla.21563

AUTORES / AUTHORS:  - de Moraes AC; Maranho CK; Rauber GS; Santos-Silva MC

INSTITUCIÓN / INSTITUTION:  - Programa de Pos-graduacao em Farmacia, Universidade Federal de Santa Catarina, Campus Trindade, Florianopolis - SC, Brazil.

RESUMEN / SUMMARY:  - Multidrug resistance (MDR) is a multifactorial phenomenon and the role of these proteins in generating the MDR phenotype is controversial. With this in mind, this review compiled the current data on the role of ABCB1, ABCC1, and LRP proteins in the prognosis of hematologic neoplasms and their influence on the choice of therapy. Literature showed that the detection of these proteins, mainly ABCB1, is important in the AL prognosis. However, there is controversy regarding  the methodology used for their detection. In summary, the expression and activity profiles of ABCB1, ABCC1, and LRP, proteins capable of promoting the efflux of a  variety of chemotherapeutic agents from the cell cytoplasm represent one of the greatest causes of failure in AL treatment. J. Clin. Lab. Anal. 27:62-71, 2013. © 2012 Wiley Periodicals, Inc.




TÍTULO / TITLE:  - The prognosis of gastric cancer patients with marginally elevated carcinoembryonic antigen (CEA) values after D2 radical gastrectomy.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Surg Oncol. 2013 Jan 7. doi: 10.1002/jso.23300.

            ●● Enlace al texto completo (gratuito o de pago) 1002/jso.23300

AUTORES / AUTHORS:  - Chen S; Feng XY; Li YF; Zhao BW; Zhou ZW; Chen YB

INSTITUCIÓN / INSTITUTION:  - Department of Gastropancreatic Surgery, Sun Yat-Sen University Cancer Center, Guangdong, PR China; State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangdong, PR China.

RESUMEN / SUMMARY:  - AIM: To investigate the clinical significance of the postoperative serum carcinoembryonic antigen (CEA) levels in gastric cancer patients who underwent D2 radical gastrectomy and to identify the prognostic factors for patients with marginally elevated postoperative CEA levels. METHODS: We performed a retrospective study of 480 patients who were histologically diagnosed with gastric cancer and who underwent D2 radical surgery at the Sun Yat-sen University Cancer Center between January 2004 and December 2009. The follow-up lasted until  June 2011. Chi-squared tests and Kaplan-Meier methods were employed to compare the adverse events and prognoses. RESULTS: In this group of gastric cancer patients, the postoperative serum CEA level (P = 0.002) was an independent prognostic factor; the same was true for the histological T and N staging (P < 0.001 and P = 0.045, respectively). In the group of marginally elevated postoperative CEA level gastric cancer patients, univariate analysis demonstrated that tumor position (P = 0.042); histological grade (P = 0.002); and Boarrmann type (P = 0.003) were significant prognostic factors. Multivariate analysis showed that the tumor position (P = 0.003) and histological grade (P = 0.007) were independent prognostic factors for these patients. CONCLUSION: Our study showed that patients with normal postoperative CEA levels have a better prognosis. Furthermore, for marginally elevated postoperative CEA level gastric cancer patients, the tumor position and histological grade were two important factors for predicting the prognosis and the need for aggressive therapy. J. Surg. Oncol © 2013 Wiley Periodicals, Inc.




TÍTULO / TITLE:  - The transcription factor Forkhead box P3 (FoxP3) is expressed in glioma cells and associated with increased apoptosis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Exp Cell Res. 2012 Dec 1. pii: S0014-4827(12)00475-2. doi: 10.1016/j.yexcr.2012.11.018.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.yexcr.2012.11.018

AUTORES / AUTHORS:  - Held-Feindt J; Hattermann K; Sebens S; Krautwald S; Mehdorn HM; Mentlein R

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, University Medical Center Schleswig-Holstein UKSH, Campus Kiel, 24105 Kiel, Germany.

RESUMEN / SUMMARY:  - The forkhead transcription factor FoxP3 is critically involved in the development and function of regulatory T cells (Tregs) that populate tumors and are considered as powerful parts of their immune evasion. However, also tumor cells are reported to express FoxP3. Since gliomas are particularly immunosuppressive tumors, we investigated the occurrence and possible functions of FoxP3 in these malignant cells. By quantitative RT-PCR, immunohistochemistry and FACS analysis,  we detected FoxP3 in glioma cells in situ and in vitro. After exposure of glioma  cell lines to chemotherapeutics, expression of FoxP3 was significantly enhanced,  and it was dislocated from more nuclear to perinuclear localization. Overexpression of FoxP3 in glioma cell lines considerably favored apoptotic damage of nuclei, DNA fragmentation, increased cleavage of the pro-apoptotic enzyme poly(ADP-ribose) polymerase (PARP) and basal activities of effector caspases-3/7. In FoxP3-transfected cells, apoptotic stimuli like Camptothecin, Temozolomide or tumor necrosis factor-alpha synergistically enhanced caspases-3/7-activities over controls. Taking together, FoxP3 occurs in glioma cells, is induced by chemotherapeutics, and its expression is correlated with increased apoptosis of glioma cells, especially when propagated by apoptotic stimuli. Thus, FoxP3 is a novel pro-apoptotic transcription factor in gliomas that is critically involved in the action of apoptotic agents.




TÍTULO / TITLE:  - Des-gamma-carboxy prothrombin identified by P-11 and P-16 antibodies reflects prognosis for patients with hepatocellular carcinoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - J Gastroenterol Hepatol. 2012 Dec 6. doi: 10.1111/jgh.12076.

            ●● Enlace al texto completo (gratuito o de pago) 1111/jgh.12076

AUTORES / AUTHORS:  - Takeji S; Hirooka M; Koizumi Y; Tokumoto Y; Abe M; Ikeda Y; Nadano S; Hiasa Y; Onji M

INSTITUCIÓN / INSTITUTION:  - Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Ehime, 791-0295, Japan.

RESUMEN / SUMMARY:  - BACKGROUND AND AIMS: Serum des-gamma-carboxy prothrombin (DCP) is an established  tumor marker in patients with hepatocellular carcinoma (HCC), which can be identified by using MU-3 antibody. The MU-3 antibody mainly reacts with the 9-10  glutamic acid (Glu) residues of DCP (conventional DCP). Since other variants of DCP with fewer Glu residues can be detected using P-11 and P-16 antibodies (code  name: NX-PVKA), we examined the clinical characteristics associated with NX-PVKA, and whether NX-PVKA is a useful measure in HCC patients. METHODS: Participants comprised 197 HCC patients admitted to our hospital between 2001 and 2010. NX-PVKA, conventional DCP, alpha-fetoprotein (AFP) and L3 fraction of AFP (AFP-L3) were measured prior to initiation of HCC treatment. RESULTS: Of the tumor markers assessed, NX-PVKA was the only significant predictor of prognosis (hazard ratio, 81.32; p < 0.0001). Patients with NX-PVKA level >/= 100 mAU/ml showed significantly lower survival rates (p < 0.0001). NX-PVKA level was also significantly associated with platelet count, prothrombin time, C-reactive protein, sex, maximum tumor size, number of nodules and portal venous invasion by HCC. Finally, using NX-PVKA level and other clinical parameters, we established a prognostic model to estimate patient survival time. CONCLUSIONS: NX-PVKA offers the best marker of tumor prognosis among HCC patients, and is strongly associated with tumor factors and hepatic functional reserve. NX-PVKA could be useful for clinical evaluation of tumor severity, as well as the estimated duration of survival among patients with HCC.




TÍTULO / TITLE:  - PECAM-1 is involved in BCR/ABL signaling and may downregulate imatinib-induced apoptosis of Philadelphia chromosome-positive leukemia cells.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Int J Oncol. 2013 Feb;42(2):419-28. doi: 10.3892/ijo.2012.1729. Epub 2012 Dec 6.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ijo.2012.1729

AUTORES / AUTHORS:  - Wu N; Kurosu T; Oshikawa G; Nagao T; Miura O

INSTITUCIÓN / INSTITUTION:  - Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyoku, Tokyo 113-8519, Japan.

RESUMEN / SUMMARY:  - PECAM-1 (CD31) is an immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing surface glycoprotein expressed on various hematopoietic cells as well as on endothelial cells. PECAM-1 has been shown to play roles in regulation of adhesion, migration and apoptosis. The BCR/ABL fusion tyrosine kinase is expressed in chronic myeloid leukemia and Philadelphia-positive (Ph+) acute lymphoblastic leukemia cells, and its inhibition by the clinically used tyrosine kinase inhibitors imatinib or dasatinib induces apoptosis of these cells. In the present study, we demonstrate that PECAM-1 is tyrosine phospho-rylated in its ITIM motifs in various BCR/ABL-expressing cells including  primary leukemia cells. Studies using imatinib and dasatinib as well as transient expression experiments in 293T cells revealed that PECAM-1 was phosphorylated directly by BCR/ABL, which was enhanced by the imatinib-resistant E255K and T315I mutations, or partly by the Src family tyrosine kinases, including Lyn, which were activated dependently or independently on BCR/ABL. We also demonstrate by using a substrate trapping mutant of SHP2 that tyrosine phosphorylated PECAM-1 binds SHP2 and is a major substrate for this tyrosine phosphatase in BCR/ABL-expressing cells. Overexpression of PECAM-1 in BCR/ABL-expressing cells,  including K562 human leukemia cells, enhanced cell adhesion and partially inhibited imatinib-induced apoptosis involving mitochondria depolarization and caspase-3 cleavage, at least partly, in an ITIM-independent manner. These data suggest that PECAM-1 may play a role in regulation of apoptosis as well as adhesion of BCR/ABL-expressing cells to modulate their imatinib sensitivity and would be a possible candidate for therapeutic target in Ph+ leukemias.




TÍTULO / TITLE:  - Gene expression alterations in doxorubicin resistant MCF7 breast cancer cell line.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Genomics. 2012 Nov 30. pii: S0888-7543(12)00229-7. doi: 10.1016/j.ygeno.2012.11.009.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ygeno.2012.11.009

AUTORES / AUTHORS:  - Abuhammad S; Zihlif M

INSTITUCIÓN / INSTITUTION:  - Department of Pharmacology, Faculty of Medicine, University of Jordan, Amman 11942, Jordan.

RESUMEN / SUMMARY:  - Many molecular mechanisms contribute to the development of doxorubicin resistance and different cancers can express wide and diverse arrays of drug-resistance genes. The aim of this study was to identify the changes in gene expression associated with the development of doxorubicin resistance in MCF7 breast cancer cell line. The doxorubicin resistant MCF7 cell line was developed by stepwise selection of MCF7 cells and was tested using the MTT assay. The alterations in gene expression were examined using the real-time based PCR array. The findings showed an up-regulation of many phase I/II metabolizing genes, specifically, the  CYP1A1 and the CYP1A2 that were up-regulated by 206- and 96-fold respectively. Drug efflux pump genes were also up-regulated profoundly. TOP2A was strongly down-regulated by 202-fold. Many other changes were observed in genes crucial for cell cycle, apoptosis and DNA repair. The findings of this project imply that the development of doxorubicin resistance is a multi-factorial process.




TÍTULO / TITLE:  - Ki-67, mini-chromosome maintenance 2 protein (MCM2) and geminin have no independent prognostic relevance for cancer-specific survival in surgically treated squamous cell carcinoma of the penis.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - BJU Int. 2013 Jan 10. doi: 10.1111/j.1464-410X.2012.11735.x.

            ●● Enlace al texto completo (gratuito o de pago) 1111/j.1464-410X.2012.11735.x

AUTORES / AUTHORS:  - May M; Burger M; Otto W; Hakenberg OW; Wieland WF; May D; Hofstadter F; Gotz S; Niessl N; Fritsche HM; Birnkammer K; Gilfrich C; Peter J; Jain A; Koch S; Lebentrau S; Riedmiller H; Rossler W; Denzinger S; Brookman-May S; Gunia S

INSTITUCIÓN / INSTITUTION:  - Department of Urology, St. Elisabeth Clinic Straubing, Straubing.

RESUMEN / SUMMARY:  - WHAT’S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Only little and partly contradictory data are currently published about the prognostic role of immunohistochemically detectable proliferation-associated biomarkers in surgically treated squamous cell carcinoma of the penis (SCCP), and no data are available at present about their usefulness for refining the delineation between  different Broders’ grading categories (e.g. still G2 or just G3 SCCP?). Moreover, the accuracy of various conventional histopathological parameters for predicting  cancer-specific survival (CSS) in surgically treated SCCP has not been systematically evaluated yet. Based on the so far largest study cohort encompassing 158 consecutive patients with surgically treated PSCCs characterised by means of a central histopathological review, our data add the following to the currently available literature: (i) Ki-67, mini-chromosome maintenance 2 protein  (MCM2), and geminin indicate a more aggressive behaviour in SCPP but do not represent independent prognostic parameters in the multivariable analysis in terms of CSS, (ii) these three biomarkers are not helpful for refining the delineation between different Broders’ grading categories at the immunohistochemical level, and (iii) the conventional histopathological parameters staging, grading, nodal involvement, and lymphovascular invasion are independent prognostic parameters that together achieve a predictive accuracy of  82% for CSS. OBJECTIVE: To assess the role of cell proliferation-associated biomarkers to predict cancer-specific survival (CSS) in patients with surgically  treated squamous cell carcinoma of the penis (SCCP). PATIENTS AND METHODS: A multicentre study enrolling 158 consecutive patients with surgically treated SCCP was performed. After conducting a central histopathological review, the staining  profiles of Ki-67, mini-chromosome maintenance 2 protein (MCM2) and geminin were  evaluated for their correlation with conventional histopathological criteria and  their prognostic relevance for predicting CSS in a multivariable Cox proportional hazards regression model (median [interquartile range] follow-up 33 [6-63] months). RESULTS: Staining evaluation showed high interobserver agreement (92-96%). Ki-67 and MCM2 displayed a significant positive correlation with histological tumour grade, lymphovascular invasion (LVI) and nodal status, whereas geminin expression only correlated with tumour grade. The 5-year CSS for  the entire study cohort was 62%. Univariable analysis showed a significant prognostic impact of Ki-67 (P = 0.026), MCM2 (P = 0.007), and geminin (P = 0.036). In multivariable analysis, only pT (hazard ratio [HR] 1.67; P = 0.003) and pN stage (HR 2.62; P = 0.015) as well as tumour grade (HR 1.89; P = 0.036) and LVI (HR 2.66; P = 0.028) were identified as independent prognostic parameters for CSS. The accuracy of the Cox model for CSS prediction was 0.820 (95% confidence interval 0.741-0.898). CONCLUSIONS: At present, conventional histopathological criteria remain the most powerful predictors of CSS in surgically treated SCCP. Due to overlapping staining profiles, Ki-67, MCM2 and geminin, either singly or in various combinations, failed to immunohistochemically refine the boundaries between Broders’ grading categories.  Ki-67, MCM2 and geminin do not represent independent prognostic parameters but reflect a more aggressive behaviour in surgically treated SCCP. Further studies are needed to clarify the currently contradictory predictive role of proliferation-associated biomarkers in terms of predicting nodal involvement in SCCPs.




TÍTULO / TITLE:  - Serum peptides, represented by complement 3f des-arginine, are useful for prediction of the response to pegylated interferon-alpha plus ribavirin in patients with chronic hepatitis C.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Hepatol Res. 2012 Nov 5. doi: 10.1111/hepr.12018.

            ●● Enlace al texto completo (gratuito o de pago) 1111/hepr.12018

AUTORES / AUTHORS:  - Noguchi Y; Kurokawa MS; Okuse C; Matsumoto N; Nagai K; Sato T; Arito M; Suematsu N; Okamoto K; Suzuki M; Itoh F; Kato T

INSTITUCIÓN / INSTITUTION:  - Clinical Proteomics and Molecular Medicine, St Marianna University Graduate School of Medicine, Japan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, St Marianna University School of Medicine, Japan.

RESUMEN / SUMMARY:  - AIM: Biomarkers predicting sustained virological response (SVR) to pegylated interferon-alpha plus ribavirin (PEG IFN-alpha/RBV) were investigated. METHODS: Peptides in pretreatment sera from 107 patients with hepatitis C virus (HCV) genotype 1 were comprehensively analyzed by mass spectrometry. Ion intensity of the peptides was used to generate discriminant models between the responders who  achieved SVR ® and the non-responders (NR) to PEG IFN-alpha/RBV. RESULTS: In total, 107 peptides were detected in a training set (n = 23). A discriminant model using a peptide, complement 3f des-arginine (C3f-dR), showed sensitivity of 35% and specificity of 94% for SVR prediction in a testing set (n = 68). In all the R and NR (n = 96), an area under the receiver-operator curve (AUROC) of 0.64  in the C3f-dR model was increased to 0.78 by addition of platelet (PLT) counts (C3f-dR/PLT model). Another model using the 107 peptides (AUROC, 0.77) also showed higher AUROC (0.79) by addition of hemoglobin (Hb), body mass index (BMI)  and age (107P/Hb/BMI/Age model). The sensitivity and specificity of the C3f-dR/PLT model were 59% and 88%, and those of the 107P/Hb/BMI/Age model were 70% and 92%, respectively. The C3f-dR/PLT model showed high AUROC (0.82), similar to that of interleukin-28B rs8099917 genotype analysis (0.86) in the 45 tested patients. Prediction by the combination of the C3f-dR/PLT model, the 107P/Hb/BMI/Age model and the rs8099917 genotype analysis was accurate in 44 out  of the 45 patients (AUROC, 0.95). CONCLUSION: Serum peptides, especially C3f-dR,  would be useful predictors for SVR to PEG IFN-alpha/RBV. The complements may be involved in the HCV elimination.




TÍTULO / TITLE:  - Hepatitis A virus cellular receptor 1/kidney injury molecule-1 is a susceptibility gene for clear cell renal cell carcinoma and hepatitis A virus cellular receptor/kidney injury molecule-1 ectodomain shedding a predictive biomarker of tumour progression.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Eur J Cancer. 2013 Jan 23. pii: S0959-8049(12)01029-5. doi: 10.1016/j.ejca.2012.12.020.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ejca.2012.12.020

AUTORES / AUTHORS:  - Cuadros T; Trilla E; Vila MR; de Torres I; Vilardell J; Messaoud NB; Salcedo M; Sarro E; Lopez-Hellin J; Blanco A; Mir C; Ramon Y Cajal S; Itarte E; Morote J; Meseguer A

INSTITUCIÓN / INSTITUTION:  - Fisiopatologia Renal, CIBBIM, VHIR, España.

RESUMEN / SUMMARY:  - AIM OF THE STUDY: To correlate hepatitis A virus cellular receptor (HAVCR)/kidney injury molecule-1 (KIM-1) expression in clear cell renal cell carcinoma (ccRCC) tumours with patient outcome and study the consequences of HAVCR/KIM-1 ectodomain shedding. METHODS: HAVCR/KIM-1 expression in ccRCC, oncocytomes, papillary carcinomas and unaffected tissue counterparts was evaluated. Minimal change disease and pre-clamping normal and ccRCC tissue biopsies were included. Tissue microarrays from 98 ccRCC tumours were analysed. Tumour registry data and patient outcome were retrospectivelly collected. Deletions in HAVCR/KIM-1 ectodomain and  lentiviral infection of 786-O cells with HAVCR/KIM-1 mutated constructs to determine their subcellular distribution and invasive capacity were performed. RESULTS: HAVCR/KIM-1 was expressed in ccRCC, papillary tumours and in tubule cells of adjacent and distal unaffected counterparts of ccRCC tumours. The latest was not related to ischemic or tumour-related paracrine effects since pre-clamping normal biopsies were positive for HAVCR/KIM-1 and unaffected counterparts of papillary tumours were negative. HAVCR/KIM-1 analyses in patients and the invasive capacity of HAVCR/KIM-1 shedding mutants in cell lines demonstrated that: (i) relative low HAVCR/KIM-1 membrane levels correlate with activated shedding in ccRCC patients and mutant cell lines; (ii) augmented shedding directly correlates with higher invasiveness and tumour malignancy. CONCLUDING STATEMENTS: Constitutive expression of HAVCR/KIM-1 in kidney might constitute a susceptibility trait for ccRCC tumour development. Enhanced HAVCR/KIM-1 ectodomain shedding promotes invasive phenotype in vitro and more aggressive tumours in vivo.




TÍTULO / TITLE:  - Sorafenib Inhibits Cell Migration and Stroma-Mediated Bortezomib Resistance by Interfering B-cell Receptor Signaling and Protein Translation in Mantle Cell Lymphoma.

RESUMEN / SUMMARY:  - Enlace al Resumen / Link to its Summary

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Jan 18.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-1935