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

Cancer Pharmacogenomics.

February - March 2013

 

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[1]

TÍTULO / TITLE:  - ERCC1 isoform expression and DNA repair in non-small-cell lung cancer.

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

REVISTA / JOURNAL:  - N Engl J Med. 2013 Mar 21;368(12):1101-10. doi: 10.1056/NEJMoa1214271.

            ●● Enlace al texto completo (gratuito o de pago) 1056/NEJMoa1214271

AUTORES / AUTHORS:  - Friboulet L; Olaussen KA; Pignon JP; Shepherd FA; Tsao MS; Graziano S; Kratzke R; Douillard JY; Seymour L; Pirker R; Filipits M; Andre F; Solary E; Ponsonnailles F; Robin A; Stoclin A; Dorvault N; Commo F; Adam J; Vanhecke E; Saulnier P; Thomale J; Le Chevalier T; Dunant A; Rousseau V; Le Teuff G; Brambilla E; Soria JC

INSTITUCIÓN / INSTITUTION:  - INSERM Unite 981, and Departement Hospitalo-Universitaire Thorax Innovation, Institut Gustave-Roussy, Villejuif, France.

RESUMEN / SUMMARY:  - BACKGROUND: The excision repair cross-complementation group 1 (ERCC1) protein is  a potential prognostic biomarker of the efficacy of cisplatin-based chemotherapy  in non-small-cell lung cancer (NSCLC). Although several ongoing trials are evaluating the level of expression of ERCC1, no consensus has been reached regarding a method for evaluation. METHODS: We used the 8F1 antibody to measure the level of expression of ERCC1 protein by means of immunohistochemical analysis in a validation set of samples obtained from 494 patients in two independent phase 3 trials (the National Cancer Institute of Canada Clinical Trials Group JBR.10 and the Cancer and Leukemia Group B 9633 trial from the Lung Adjuvant Cisplatin Evaluation Biology project). We compared the results of repeated staining of the entire original set of samples obtained from 589 patients in the  International Adjuvant Lung Cancer Trial Biology study, which had led to the initial correlation between the absence of ERCC1 expression and platinum response, with our previous results in the same tumors. We mapped the epitope recognized by 16 commercially available ERCC1 antibodies and investigated the capacity of the different ERCC1 isoforms to repair platinum-induced DNA damage. RESULTS: We were unable to validate the predictive effect of immunostaining for ERCC1 protein. The discordance in the results of staining for ERCC1 suggested a change in the performance of the 8F1 antibody since 2006. We found that none of the 16 antibodies could distinguish among the four ERCC1 protein isoforms, whereas only one isoform produced a protein that had full capacities for nucleotide excision repair and cisplatin resistance. CONCLUSIONS: Immunohistochemical analysis with the use of currently available ERCC1 antibodies did not specifically detect the unique functional ERCC1 isoform. As a result, its usefulness in guiding therapeutic decision making is limited. (Funded by Eli Lilly and others.).

 

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[2]

TÍTULO / TITLE:  - Ten-year analysis of the prospective multicentre Chemo-N0 trial validates American Society of Clinical Oncology (ASCO)-recommended biomarkers uPA and PAI-1 for therapy decision making in node-negative breast cancer patients.

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

REVISTA / JOURNAL:  - Eur J Cancer. 2013 Mar 13. pii: S0959-8049(13)00045-2. doi: 10.1016/j.ejca.2013.01.007.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ejca.2013.01.007

AUTORES / AUTHORS:  - Harbeck N; Schmitt M; Meisner C; Friedel C; Untch M; Schmidt M; Sweep CG; Lisboa BW; Lux MP; Beck T; Hasmuller S; Kiechle M; Janicke F; Thomssen C

INSTITUCIÓN / INSTITUTION:  - Brustzentrum, Frauenklinik Maistrasse, Universitaet Munchen, 80337 Munich, Germany. Electronic address: nadia.harbeck@med.uni-muenchen.de.

RESUMEN / SUMMARY:  - AIM: Final 10-year analysis of the prospective randomised Chemo-N0 trial is presented. Based on the Chemo-N0 interim results and an European Organisation for Research and Treatment of Cancer (EORTC) pooled analysis (n=8377), American Society of Clinical Oncology (ASCO) and Arbeitsgemeinschaft Gynakologische Onkologie (AGO) guidelines recommend invasion and metastasis markers urokinase-type plasminogen activator (uPA)/plasminogen activator inhibitor-1 (PAI-1) for risk assessment and treatment decision in node-negative (N0) breast cancer (BC). METHODS: The final Chemo-N0 trial analysis (recruitment 1993-1998; n=647; 12 centres) comprises 113 (5-167) months of median follow-up. Patients with low-uPA and PAI-1 tumour tissue levels (n=283) were observed. External quality assurance guaranteed uPA/PAI-1 enzyme-linked immunosorbent assay (ELISA)  standardisation. Of 364 high uPA and/or PAI-1 patients, 242 agreed to randomisation for CMF chemotherapy (n=117) versus observation (n=125). RESULTS: Actuarial 10-year recurrence rate (without any adjuvant systemic therapy) for high-uPA/PAI-1 observation group patients (randomised and non-randomised) was 23.0%, in contrast to only 12.9% for low-uPA/PAI-1 patients (plog-rank=0.011). High-risk patients randomised to cyclophosphamide-methotrexate-5-fluorouracil (CMF) therapy had a 26.0% lower estimated probability of disease recurrence than  those randomised for observation (intention-to-treat (ITT)-analysis: hazard ratio (HR) 0.74 (0.44-1.27); plog-rank=0.28). Per-protocol analysis demonstrated significant treatment benefit: HR 0.48 (0.26-0.88), p=0.019, disease-free survival (DFS) Cox regression, adjusted for tumour stage and grade. CONCLUSIONS:  Chemo-N0 is the first prospective biomarker-based therapy trial in early BC defining patients reaching good long-term DFS without adjuvant systemic therapy.  Using a standardised uPA/PAI-1 ELISA, almost half of N0-patients could be spared  chemotherapy, while high-risk patients benefit from adjuvant chemotherapy. These  10-year results validate the long-term prognostic impact of uPA/PAI-1 and the benefit from adjuvant chemotherapy in the high-uPA/PAI-1 group at highest level of evidence. They thus support the guideline-based routine use of uPA/PAI-1 for risk-adapted individualised therapy decisions in N0 breast cancer.

 

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[3]

TÍTULO / TITLE:  - Efficacy of tamoxifen+/-aminoglutethimide in normal weight and overweight postmenopausal patients with hormone receptor-positive breast cancer: an analysis of 1509 patients of the ABCSG-06 trial.

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

REVISTA / JOURNAL:  - Br J Cancer. 2013 Mar 19. doi: 10.1038/bjc.2013.114.

            ●● Enlace al texto completo (gratuito o de pago) 1038/bjc.2013.114

AUTORES / AUTHORS:  - Pfeiler G; Stoger H; Dubsky P; Mlineritsch B; Singer C; Balic M; Fitzal F; Moik M; Kwasny W; Selim U; Renner K; Ploner F; Steger GG; Seifert M; Hofbauer F; Sandbichler P; Samonigg H; Jakesz R; Greil R; Fesl C; Gnant M

INSTITUCIÓN / INSTITUTION:  - Division of Gynecology and Gynecological Oncology, Department of Obstetrics and Gynecology, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.

RESUMEN / SUMMARY:  - Background:There exists evidence that body mass index (BMI) impacts on the efficacy of aromatase inhibitors in patients with breast cancer. The relationship between BMI and the efficacy of tamoxifen is conflicting. We investigated the impact of BMI on the efficacy of single tamoxifen and tamoxifen plus an aromatase inhibitor in the well-defined prospective study population of the ABCSG-06 trial.Methods:ABCSG-06 investigated the efficacy of tamoxifen vs tamoxifen plus aminoglutethimide in postmenopausal women with hormone receptor-positive breast cancer. Taking BMI at baseline, patients were classified as normal weight (BMI=18.5-24.9 kg m-2), overweight (BMI=25-29.9 kg m-2), and obese (30 kg m-2) according to WHO criteria.Results:Overweight+obese patients had an increased risk for distant recurrences (hazard ratio (HR): 1.51; Cox P=0.018) and a worse overall survival (OS; HR: 1.49; Cox P=0.052) compared with normal weight patients. Analysing patients treated with single tamoxifen only, no difference between overweight+obese patients and normal weight patients regarding distant recurrence-free survival (HR: 1.35; Cox P=0.24) and OS (HR: 0.99; Cox P=0.97) could be observed. In contrast, in the group of patients treated with the combination of tamoxifen plus aminoglutethimide, overweight+obese patients had an increased risk for distant recurrences (1.67; Cox P=0.03) and a worse OS (1.47; Cox P=0.11) compared with normal weight patients.Conclusion:BMI impacts on the efficacy of aromatase inhibitor-based treatment but not single tamoxifen.British  Journal of Cancer advance online publication, 19 March 2013; doi:10.1038/bjc.2013.114 www.bjcancer.com.

 

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[4]

TÍTULO / TITLE:  - Multicenter Phase I Trial of the Mitogen-Activated Protein Kinase ½ Inhibitor BAY 86-9766 in Patients with Advanced Cancer.

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

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Mar 1;19(5):1232-43. doi: 10.1158/1078-0432.CCR-12-3529. Epub 2013 Feb 22.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-3529

AUTORES / AUTHORS:  - Weekes CD; Von Hoff DD; Adjei AA; Leffingwell DP; Eckhardt SG; Gore L; Lewis KD; Weiss GJ; Ramanathan RK; Dy GK; Ma WW; Sheedy B; Iverson C; Miner JN; Shen Z; Yeh LT; Dubowy RL; Jeffers M; Rajagopalan P; Clendeninn NJ

INSTITUCIÓN / INSTITUTION:  - Authors’ Affiliations: University of Colorado Cancer Center, Aurora, Colorado; Translational Genomics Research Institute (TGen); Virginia G. Piper Cancer Center at Scottsdale Healthcare, Scottsdale, Arizona; Roswell Park Cancer Institute, Buffalo, New York; Ardea Biosciences, Inc., San Diego, California; and Bayer HealthCare Pharmaceuticals, Montville, New Jersey.

RESUMEN / SUMMARY:  - PURPOSE: To evaluate the safety, pharmacokinetics, and pharmacodynamics of BAY 86-9766, a selective, potent, orally available, small-molecule allosteric inhibitor of mitogen-activated protein kinase ½ in patients with advanced solid tumors. EXPERIMENTAL DESIGN: BAY 86-9766 was administered orally daily in 28-day  courses, with doses escalated to establish the maximum-tolerated dose (MTD). An expanded cohort was evaluated at the MTD. Pharmacokinetic and pharmacodynamic parameters were assessed, with extracellular signal-regulated kinase (ERK) phosphorylation evaluated in paired biopsies from a subset of the expanded MTD cohort. Tumor specimens were evaluated for mutations in select genes. RESULTS: Sixty-nine patients were enrolled, including 20 patients at the MTD. The MTD was  100 mg given once-daily or in two divided doses. BAY 86-9766 was well-tolerated.  The most common treatment-related toxicities were acneiform rash and gastrointestinal toxicity. BAY 86-9766 was well-absorbed after oral administration (plasma half-life approximately 12 hours), and displayed dose proportional pharmacokinetics throughout the tested dose range. Continuous daily  dosing resulted in moderate accumulation at most dose levels. BAY 86-9766 suppressed ERK phosphorylation in biopsied tissue and tetradecanoylphorbol acetate-stimulated peripheral blood leukocytes. Of 53 evaluable patients, one patient with colorectal cancer achieved a partial response and 11 patients had stable disease for 4 or more courses. An ocular melanoma specimen harbored a GNAQ-activating mutation and exhibited reduced ERK phosphorylation in response to therapy. CONCLUSION: This phase I study showed that BAY 86-9766 was well-tolerated, with good oral absorption, dose proportional pharmacokinetics, target inhibition at the MTD, and some evidence of clinical benefit across a range of tumor types. Clin Cancer Res; 19(5); 1232-43. ©2012 AACR.

 

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[5]

TÍTULO / TITLE:  - Predictors of long-term outcome in multiple sclerosis patients treated with interferon beta.

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

REVISTA / JOURNAL:  - Ann Neurol. 2013 Jan;73(1):95-103. doi: 10.1002/ana.23758.

            ●● Enlace al texto completo (gratuito o de pago) 1002/ana.23758

AUTORES / AUTHORS:  - Bermel RA; You X; Foulds P; Hyde R; Simon JH; Fisher E; Rudick RA

INSTITUCIÓN / INSTITUTION:  - Neurological Institute, Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, OH, USA. bermelr@ccf.org

RESUMEN / SUMMARY:  - OBJECTIVE: To identify early predictors of long-term outcomes in patients with relapsing-remitting multiple sclerosis (RRMS) treated with intramuscular (IM) interferon beta-1a (IFNbeta-1a). METHODS: A multicenter, observational, 15-year follow-up study of patients who completed >/=2 years in the pivotal trial of IM IFNbeta-1a for RRMS was conducted. One hundred thirty-six patients participated in the 15-year follow-up (69 originally randomized to IM IFNbeta-1a and 67 to placebo). After the 2-year clinical trial, treatment was not regulated by study protocol. Disease activity during the 2-year trial was defined as: >/=2 gadolinium-enhancing lesions (cumulative) on year 1 and/or year 2 magnetic resonance imaging (MRI); >/=3 new T2 lesions on year 2 MRI compared to baseline;  and >/=2 relapses over 2 years. Odds ratios were calculated for early disease activity predicting severe Expanded Disability Status Scale (EDSS) worsening (worst quartile of change, >/=4.5 EDSS points) during the 15-year interval. RESULTS: The proportion of patients experiencing early disease activity was lower in patients on IM IFNbeta-1a than placebo for all disease activity markers (range, 23.5-29.0% vs 41.0-45.5%). In the IM IFNbeta-1a group, persistent disease activity predicted severe EDSS worsening: gadolinium-enhancing lesions (odds ratio [OR], 8.96; p < 0.001); relapses (OR, 4.44; p = 0.010); and new T2 lesions  (OR, 2.90; p = 0.080). In placebo patients, early disease activity was not as strongly associated with long-term outcomes (OR range, 1.53-2.62; p = 0.069-0.408). INTERPRETATION: Disease activity despite treatment with IFNbeta is  associated with unfavorable long-term outcomes. Particular attention should be paid to gadolinium-enhancing lesions on IFNbeta therapy, as their presence strongly correlates with severe disability 15 years later. The results provide rationale for monitoring IFNbeta-treated patients with MRI, and for changing therapy in patients with active disease.

 

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[6]

TÍTULO / TITLE:  - Prognosis of early breast cancer by immunohistochemistry defined intrinsic sub-types in patients treated with adjuvant chemotherapy in the NEAT/BR9601 trial.

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

REVISTA / JOURNAL:  - Int J Cancer. 2013 Mar 9. doi: 10.1002/ijc.28150.

            ●● Enlace al texto completo (gratuito o de pago) 1002/ijc.28150

AUTORES / AUTHORS:  - Ali A; Provenzano E; Bartlett JM; Abraham J; Driver K; Munro AF; Twelves C; Poole CJ; Hiller L; Dunn J; Earl HM; Caldas C; Pharoah P

INSTITUCIÓN / INSTITUTION:  - Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; Department of Biostatistics and Cancer Epidemiology, South Egypt Cancer Institute, University of Assiut, Egypt.

RESUMEN / SUMMARY:  - Breast cancer can be classified into molecular sub-types that have distinct survival patterns. We evaluated the prognostic significance of breast cancer sub-types in a cohort of women taking part in the NEAT and BR9601 clinical trials comparing cyclophosphamide, methotrexate, and fluorouracil (CMF) with ECMF (epirubicin and CMF). Furthermore we evaluated whether the sub-types were predictive of the added benefit of epirubicin in these trials. Tumour tissue microarrays were stained and scored for ER, PR, HER2, EGFR and CK5/6. These were  used to classify the tumours into six intrinsic sub-types. We used Cox regression to compare overall survival (OS), breast cancer-specific survival (BCSS) and relapse-free survival (RFS) in the different sub-groups. We also compared the effect of ECMF with CMF by sub-group. Immunohistochemistry data were available for 1,725 cases of whom 805 were luminal 1-basal negative. Median follow-up time  was 7 years. The luminal 1-basal negative tumours were associated with the best prognosis in five years after surgery and the HER2-like tumours were associated with the poorest prognosis. There was little evidence for significant heterogeneity of this effect by tumour sub-type (OS P =0.40, BCSS P=0.53 RFS P=0.50) - the largest additional benefit of epirubicin was in women with tumours  of the 5-negative phenotype (OS HR=0.39 95% CI:0.21-0.73) and the smallest was in Luminal 1-basal negative tumours (OS HR=0.86 95% CI:0.64-1.16). We confirmed that breast cancer sub-types show distinct behaviour with differences in short- and long-term survival. The benefit of ECMF over CMF was statistically similar in all disease sub-types. © 2013 Wiley Periodicals, Inc.

 

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[7]

TÍTULO / TITLE:  - Progression-free Survival Is Accurately Predicted in Patients Treated with Chemotherapy for Epithelial Ovarian Cancer by the Histoculture Drug Response Assay in a Prospective Correlative Clinical Trial at a Single Institution.

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

REVISTA / JOURNAL:  - Anticancer Res. 2013 Mar;33(3):1029-34.

AUTORES / AUTHORS:  - Jung PS; Kim DY; Kim MB; Lee SW; Kim JH; Kim YM; Kim YT; Hoffman RM; Nam JH

INSTITUCIÓN / INSTITUTION:  - Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 139-736, Korea. kdyog@amc.seoul.kr.

RESUMEN / SUMMARY:  - This study aimed to prospectively correlate clinical outcomes of advanced epithelial ovarian cancer (AEOC), with the results of in vitro chemosensitivity testing of taxol and carboplatin using the in vitro histoculture drug response assay (HDRA). A total of 104 patients with AEOC were treated with combination chemotherapy of taxol and carboplatin after primary cytoreductive surgery between 2007 and 2012 at the Asan Medical Center, Seoul, Korea. To compare chemosensitivity in the HDRA with clinical response, all patients were first categorized into two groups as either sensitive to both taxol and carboplatin (SS), or not sensitive to one or both drugs ® based on HDRA results. The recurrence rate was much lower in the SS group compared to the R group; 29.2% vs  69.8%, respectively (p=0.02). The SS group had a significantly longer progression-free survival compared to the R group, 34.0 months vs 16.0 months, respectively (p=0.025). These results demonstrate that the HDRA prospectively correlates to clinical outcome from chemotherapy and that treatment regimens can  be individualized based on the HDRA.

 

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[8]

TÍTULO / TITLE:  - Phase III Randomized Study of Rituximab/Carmustine, Etoposide, Cytarabine, and Melphalan (BEAM) Compared With Iodine-131 Tositumomab/BEAM With Autologous Hematopoietic Cell Transplantation for Relapsed Diffuse Large B-Cell Lymphoma: Results From the BMT CTN 0401 Trial.

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

REVISTA / JOURNAL:  - J Clin Oncol. 2013 Mar 11.

            ●● Enlace al texto completo (gratuito o de pago) 1200/JCO.2012.45.9453

AUTORES / AUTHORS:  - Vose JM; Carter S; Burns LJ; Ayala E; Press OW; Moskowitz CH; Stadtmauer EA; Mineshi S; Ambinder R; Fenske T; Horowitz M; Fisher R; Tomblyn M

INSTITUCIÓN / INSTITUTION:  - Julie M. Vose, University of Nebraska Medical Center, Omaha, NE; Shelly Carter, EMMES, Rockville; Richard Ambinder, Johns Hopkins Medical Center, Baltimore, MD;  Linda J. Burns, University of Minnesota, Minneapolis, MN; Ernesto Ayala and Marcie Tomblyn, H. Lee Moffitt Cancer Center, Tampa, FL; Oliver W. Press, Fred Hutchinson Cancer Center, Seattle, WA; Craig H. Moskowitz, Memorial Sloan-Kettering Cancer Center, New York; Richard Fisher, University of Rochester, Rochester, NY; Edward A. Stadtmauer, Abramson Cancer Center, The University of Pennsylvania, Philadelphia, PA; Shin Mineshi, University of Michigan; Richard Fisher, Southwest Oncology Group, Ann Arbor, MI; Timothy Fenske and Mary Horowitz, Medical College of Wisconsin, Milwaukee, WI.

RESUMEN / SUMMARY:  - PURPOSEThis clinical trial evaluated standard-dose radioimmunotherapy with a chemotherapy-based transplantation regimen followed by autologous hematopoietic cell transplantation versus rituximab with the same regimen in patients with relapsed diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODSPatients with chemotherapy-sensitive persistent or relapsed DLBCL were randomly assigned to receive iodine-131 tositumomab (dosimetric dose of 5 mCi on day -19 and therapeutic dose of 0.75 Gy on day -12), carmustine 300 mg/m2 (day -6), etoposide 100 mg/m2 twice daily (days -5 to -2), cytarabine 100 mg/m2 twice daily (days -5  to -2), and melphalan 140 mg/m2 (day -1; B-BEAM) or rituximab 375 mg/m2 on days -19 and -12 and the same chemotherapy regimen (R-BEAM).ResultsTwo hundred twenty-four patients were enrolled, with 113 patients randomly assigned to R-BEAM and 111 patients assigned to B-BEAM. Two-year progression-free survival (PFS) rates, the primary end point, were 48.6% (95% CI, 38.6% to 57.8%) for R-BEAM and  47.9% (95% CI, 38.2% to 57%; P = .94) for B-BEAM, and the 2-year overall survival (OS) rates were 65.6% (95% CI, 55.3% to 74.1%) for R-BEAM and 61% (95% CI, 50.9%  to 69.9%; P = .38) for B-BEAM. The 100-day treatment-related mortality rates were 4.1% (95% CI, 0.2% to 8.0%) for R-BEAM and 4.9% (95% CI, 0.8% to 9.0%; P = .97) for B-BEAM. The maximum mucositis score was higher in the B-BEAM arm (0.72) compared with the R-BEAM arm (0.31; P < .001). CONCLUSIONThe B-BEAM and R-BEAM regimens produced similar 2-year PFS and OS rates for patients with chemotherapy-sensitive relapsed DLBCL. No differences in toxicities other than mucositis were noted.

 

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[9]

TÍTULO / TITLE:  - Cytotoxic T cells induce proliferation of chronic myeloid leukemia stem cells by  secreting interferon-gamma.

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

REVISTA / JOURNAL:  - J Exp Med. 2013 Mar 11;210(3):605-21. doi: 10.1084/jem.20121229. Epub 2013 Feb 11.

            ●● Enlace al texto completo (gratuito o de pago) 1084/jem.20121229

AUTORES / AUTHORS:  - Schurch C; Riether C; Amrein MA; Ochsenbein AF

INSTITUCIÓN / INSTITUTION:  - Tumor Immunology, Department of Clinical Research, 2 Institute of Pathology, and  3 Department of Medical Oncology, University of Bern, 3010 Bern, Switzerland.

RESUMEN / SUMMARY:  - Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasia arising from the oncogenic break point cluster region/Abelson murine leukemia viral oncogene homolog 1 translocation in hematopoietic stem cells (HSCs), resulting in a leukemia stem cell (LSC). Curing CML depends on the eradication of LSCs. Unfortunately, LSCs are resistant to current treatment strategies. The host’s immune system is thought to contribute to disease control, and several immunotherapy strategies are under investigation. However, the interaction of the immune system with LSCs is poorly defined. In the present study, we use a murine  CML model to show that LSCs express major histocompatibility complex (MHC) and co-stimulatory molecules and are recognized and killed by leukemia-specific CD8 effector CTLs in vitro. In contrast, therapeutic infusions of effector CTLs into  CML mice in vivo failed to eradicate LSCs but, paradoxically, increased LSC numbers. LSC proliferation and differentiation was induced by CTL-secreted IFN-gamma. Effector CTLs were only able to eliminate LSCs in a situation with minimal leukemia load where CTL-secreted IFN-gamma levels were low. In addition,  IFN-gamma increased proliferation and colony formation of CD34 stem/progenitor cells from CML patients in vitro. Our study reveals a novel mechanism by which the immune system contributes to leukemia progression and may be important to improve T cell-based immunotherapy against leukemia.

 

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[10]

TÍTULO / TITLE:  - Rates of peripheral arterial occlusive disease in patients with chronic myeloid leukemia in the chronic phase treated with imatinib, nilotinib, or non-tyrosine kinase therapy: a retrospective cohort analysis.

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

REVISTA / JOURNAL:  - Leukemia. 2013 Mar 5. doi: 10.1038/leu.2013.69.

            ●● Enlace al texto completo (gratuito o de pago) 1038/leu.2013.69

AUTORES / AUTHORS:  - Giles FJ; Mauro MJ; Hong F; Ortmann CE; McNeill C; Woodman RC; Hochhaus A; le Coutre PD; Saglio G

INSTITUCIÓN / INSTITUTION:  - HRB Clinical Research Facility, National University of Ireland Galway and Trinity College Dublin, Dublin, Ireland.

RESUMEN / SUMMARY:  - Peripheral arterial occlusive disease (PAOD) occurs in patients with chronic phase chronic myeloid leukemia (CML-CP) treated with tyrosine kinase inhibitors (TKIs). The risk of developing PAOD on TKI therapy is unknown and causality has not been established. Patients with CML-CP from three randomized phase III studies (IRIS, TOPS and ENESTnd) were divided into three cohorts: no TKI (cohort  1; n=533), nilotinib (cohort 2; n=556) and imatinib (cohort 3; n=1301). Patients  with atherosclerotic risk factors were not excluded. Data were queried for terms  indicative of PAOD. Overall, 3, 7 and 2 patients in cohorts 1, 2 and 3, respectively, had PAOD; 11/12 patients had baseline PAOD risk factors. Compared with that of cohort 1, exposure-adjusted risks of PAOD for cohorts 2 and 3 were 0.9 (95% CI, 0.2-3.3) and 0.1 (95% CI, 0.0-0.5), respectively. Multivariate logistic regression revealed that nilotinib had no impact on PAOD rates compared  with no TKI, whereas imatinib had decreased rates of PAOD compared with no TKI. Nilotinib was associated with higher rates of PAOD versus imatinib. Baseline assessments, preferably within clinical studies, of PAOD and associated risk factors should occur when initiating TKI therapy in CML; patients should receive  monitoring and treatment according to the standard of care for these comorbidities.Leukemia advance online publication, 5 April 2013; doi:10.1038/leu.2013.69.

 

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[11]

TÍTULO / TITLE:  - Prognostic model for predicting survival of patients with metastatic urothelial cancer treated with Cisplatin-based chemotherapy.

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

REVISTA / JOURNAL:  - J Natl Cancer Inst. 2013 Apr 3;105(7):499-503. doi: 10.1093/jnci/djt015. Epub 2013 Feb 14.

            ●● Enlace al texto completo (gratuito o de pago) 1093/jnci/djt015

AUTORES / AUTHORS:  - Apolo AB; Ostrovnaya I; Halabi S; Iasonos A; Philips GK; Rosenberg JE; Riches J; Small EJ; Milowsky MI; Bajorin DF

INSTITUCIÓN / INSTITUTION:  - Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065. bajorind@mskcc.org.

RESUMEN / SUMMARY:  - A prognostic model that predicts overall survival (OS) for metastatic urothelial  cancer (MetUC) patients treated with cisplatin-based chemotherapy was developed,  validated, and compared with a commonly used Memorial Sloan-Kettering Cancer Center (MSKCC) risk-score model. Data from 7 protocols that enrolled 308 patients with MetUC were pooled. An external multi-institutional dataset was used to validate the model. The primary measurement of predictive discrimination was Harrell’s c-index, computed with 95% confidence interval (CI). The final model included four pretreatment variables to predict OS: visceral metastases, albumin, performance status, and hemoglobin. The Harrell’s c-index was 0.67 for the four-variable model and 0.64 for the MSKCC risk-score model, with a prediction improvement for OS (the U statistic and its standard deviation were used to calculate the two-sided P = .002). In the validation cohort, the c-indices for the four-variable and the MSKCC risk-score models were 0.63 (95% CI = 0.56 to 0.69) and 0.58 (95% CI = 0.52 to 0.65), respectively, with superiority of the four-variable model compared with the MSKCC risk-score model for OS (the U statistic and its standard deviation were used to calculate the two-sided P = .02).

 

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[12]

TÍTULO / TITLE:  - Randomized Trial of Lapatinib Versus Placebo Added to Paclitaxel in the Treatment of Human Epidermal Growth Factor Receptor 2-Overexpressing Metastatic Breast Cancer.

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

REVISTA / JOURNAL:  - J Clin Oncol. 2013 Mar 18.

            ●● Enlace al texto completo (gratuito o de pago) 1200/JCO.2011.40.5241

AUTORES / AUTHORS:  - Guan Z; Xu B; Desilvio ML; Shen Z; Arpornwirat W; Tong Z; Lorvidhaya V; Jiang Z; Yang J; Makhson A; Leung WL; Russo MW; Newstat B; Wang L; Chen G; Oliva C; Gomez H

INSTITUCIÓN / INSTITUTION:  - Zhongzhen Guan, Sun Yat-Sen University Cancer Center, Guangzhou; Binghe Xu, Chinese Academy of Medical Sciences Cancer Hospital; Zefei Jiang, Military Medical Science Academy Hospital; Junlan Yang, Beijing 301 People’s Liberation Army Hospital; George Chen, BeiGene (Beijing) Company, Beijing; Zhenzhou Shen, Fudan University Cancer Hospital; Li Wang, Eli Lilly, Shanghai; Zhongsheng Tong,  Tianjin Cancer Hospital, Tianjin, People’s Republic of China; Michelle L. DeSilvio, Mark W. Russo, and Beth Newstat, Medicine Development Center Oncology,  GlaxoSmithKline, Collegeville, PA; Wichit Arpornwirat, National Cancer Institute, Bangkok; Vicharn Lorvidhaya, Maharaj Nakorn Chiangmai Hospital, Chiang Mai University, Chiang Mai, Thailand; Anatoly Makhson, State Healthcare Institution of Moscow, Moscow, Russian Federation; Wai Lim Leung, Queen Elizabeth Hospital, Kowloon, Hong Kong; Cristina Oliva, Takeda Pharmaceutical, London, United Kingdom; and Henry Gomez, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru.

RESUMEN / SUMMARY:  - PURPOSELapatinib is an oral small-molecule tyrosine kinase inhibitor of both epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2). This study is designed to test whether the addition of lapatinib to paclitaxel improves overall survival (OS) compared with placebo plus paclitaxel in patients with HER2-overexpressing metastatic breast cancer (MBC).Patients And  methodsThis phase III, randomized, double-blind study assessed the efficacy and safety of lapatinib plus paclitaxel compared with placebo plus paclitaxel in patients with newly diagnosed HER2-positive MBC. The primary end point was OS. Secondary end points included progression-free survival (PFS), overall response rate (ORR), clinical benefit rate, and safety.ResultsThe addition of lapatinib to paclitaxel significantly improved OS versus paclitaxel (treatment hazard ratio [HR], 0.74; 95% CI, 0.58 to 0.94; P = .0124); median OS was 27.8 versus 20.5 months, respectively. Median PFS was prolonged by 3.2 months, from 6.5 months with placebo plus paclitaxel to 9.7 months with lapatinib plus paclitaxel (HR, 0.52; 95% CI, 0.42 to 0.64; stratified log-rank P < .001). ORR was significantly  higher with lapatinib plus paclitaxel compared with placebo plus paclitaxel (69%  v 50%, respectively; P < .001). The incidence of grades 3 and 4 diarrhea and neutropenia was higher in the lapatinib plus paclitaxel arm. Only 4% of patients  in this group reported febrile neutropenia. Cardiac events were low grade, asymptomatic, and mostly reversible. The incidence of hepatic events was similar  in both arms. There were no fatal adverse events in the lapatinib plus paclitaxel arm. CONCLUSIONThis trial demonstrated that lapatinib combined with paclitaxel offers a significant and clinically meaningful survival advantage over paclitaxel alone in patients with HER2-positive MBC.

 

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[13]

TÍTULO / TITLE:  - Immune thrombocytopenia in patients with chronic lymphocytic leukemia treated with cladribine-based regiments or chlorambucil - follow-up of PALG-CLL randomized trials.

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

REVISTA / JOURNAL:  - Eur J Haematol. 2013 Mar 23. doi: 10.1111/ejh.12112.

            ●● Enlace al texto completo (gratuito o de pago) 1111/ejh.12112

AUTORES / AUTHORS:  - Blonski JZ; Robak T; Chojnowski K; Gora-Tybor J; Warzocha K; Ceglarek B; Seferynska I; Calbecka M; Kostyra A; Stella-Holowiecka B; Kloczko J; Dmoszynska A; Kowal M; Lewandowski K; Dwilewicz-Trojaczek J; Wiater E; Kuliczkowski K; Potoczek S; Hellmann A; Mital A; Skotnicki A; Nowak W; Sulek K; Zawilska K; Trelinski J

INSTITUCIÓN / INSTITUTION:  - Department of Hematology, Medical University of Lodz, Lodz.

RESUMEN / SUMMARY:  - OBJECTIVES: The relationship between treatment of Chronic lymphocytic leukemia (CLL) with cladribine (2 - CdA) or chlorambucil and immune thrombocytopenia (IT)  have not been yet determined. Methods:The records of 777 patients in two randomized PALG (Polish Adult Leukemia Group) CLL programs treated with these agents were retrospectively analyzed. RESULTS: Immune thrombocytopenia occurred in 55 of 777 (7.1%) patients. No significant differences in IT prevalence was seen between patients on chlorambucil or 2-CdA - based regiments (p=0.33). IT developed at a median time of 0.499 years (0,06 - 4.8) from the start of CLL therapy. This time was significantly longer in patients treated with chlorambucil (2.03 yrs, 95%CI: 0.06-4.22) in relation to patients treated with 2- CdA- based regiments (0.52 yrs, 95%CI: 0.34-0.69, p=0,049). Overall survival (OS) of patients with IT and those without IT were similar (2.65 yrs. vs. 3.2 yrs. p=0.23) but the severity of bleeding was more pronounced in the 2- CdA group. The responses to IT therapy was 35%, 54% and 75% for steroids, chemotherapy and splenectomy respectively. CONCLUSIONS: In this study, an unexpectedly high percentage of IT incidence was demonstrated in patients with CLL requiring chemotherapy. Although no marked differences were seen in IT frequency in patients treated with 2 - CdA-based regiments compared to chlorambucil regimen the clinical course of haemorrhagic diathesis was more severe in 2 - CdA group. Also the time elapsed from study screening to IT diagnosis was significantly shorter in the 2-CdA group than in the chlorambucil group suggesting a causative  relationship. The appearance of IT did not influence the median time of OS. © 2013 John Wiley & Sons A/S.

 

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[14]

TÍTULO / TITLE:  - Translational Phase I Trial of Vorinostat (Suberoylanilide Hydroxamic Acid) Combined with Cytarabine and Etoposide in Patients with Relapsed, Refractory, or  High-Risk Acute Myeloid Leukemia.

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

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Apr 1;19(7):1838-1851. Epub 2013 Feb 12.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-3165

AUTORES / AUTHORS:  - Gojo I; Tan M; Fang HB; Sadowska M; Lapidus R; Baer MR; Carrier F; Beumer JH; Anyang BN; Srivastava RK; Espinoza-Delgado I; Ross DD

INSTITUCIÓN / INSTITUTION:  - Authors’ Affiliations: University of Maryland Marlene and Stewart Greenebaum Cancer Center (UMGCC), Department of Medicine, Division of Biostatistics, University of Maryland School of Medicine, Translational Laboratory Shared Service, UMGCC; Department of Medicine, Division of Hematology and Oncology, Departments of Epidemiology and Public Health and Radiation Oncology, University  of Maryland School of Medicine; The Baltimore Veterans Affairs Medical Center, Baltimore; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland; Molecular Therapeutics/Drug Discovery Program, University of  Pittsburgh Cancer Institute (UPCI); Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania; and University of Kansas Medical Center, Kansas City, Kansas.

RESUMEN / SUMMARY:  - PURPOSE: To determine the maximum-tolerated dose (MTD) of the histone deacetylase inhibitor vorinostat combined with fixed doses of cytarabine (ara-C or cytosine arabinoside) and etoposide in patients with poor-risk or advanced acute leukemia, to obtain preliminary efficacy data, describe pharmacokinetics, and in vivo pharmacodynamic effects of vorinostat in leukemia blasts. EXPERIMENTAL DESIGN: In this open-label phase I study, vorinostat was given orally on days one to seven at three escalating dose levels: 200 mg twice a day, 200 mg three times a day, and 300 mg twice a day. On days 11 to 14, etoposide (100 mg/m2) and cytarabine (1 or 2 g/m2 twice a day if >/=65 or <65 years old, respectively) were given. The study used a standard 3+3 dose escalation design. RESULTS: Eighteen of 21 patients with acute myelogenous leukemia (AML) treated on study completed planned therapy. Dose-limiting toxicities [hyperbilirubinemia/septic death (1) and anorexia/fatigue (1)] were encountered at the 200 mg three times a day level; thus, the MTD was established to be vorinostat 200 mg twice a day. Of 21 patients enrolled, seven attained a complete remission (CR) or CR with incomplete platelet recovery, including six of 13 patients treated at the MTD. The median remission duration was seven months. No differences in percentage S-phase cells or multidrug resistance transporter (MDR1 or BCRP) expression or function were observed in vivo in leukemia blasts upon vorinostat treatment. CONCLUSIONS: Vorinostat 200 mg twice a day can be given safely for seven days before treatment with cytarabine and etoposide. The relatively high CR rate seen at the MTD in this poor-risk group of patients with AML warrants further studies to confirm these findings. Clin Cancer Res; 19(7); 1838-51. ©2013 AACR.

 

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[15]

TÍTULO / TITLE:  - A dual-center randomized controlled double blind trial assessing the effect of acupuncture in reducing musculoskeletal symptoms in breast cancer patients taking aromatase inhibitors.

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

REVISTA / JOURNAL:  - Breast Cancer Res Treat. 2013 Feb;138(1):167-74. doi: 10.1007/s10549-013-2427-z.  Epub 2013 Feb 8.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10549-013-2427-z

AUTORES / AUTHORS:  - Bao T; Cai L; Giles JT; Gould J; Tarpinian K; Betts K; Medeiros M; Jeter S; Tait N; Chumsri S; Armstrong DK; Tan M; Folkerd E; Dowsett M; Singh H; Tkaczuk K; Stearns V

INSTITUCIÓN / INSTITUTION:  - University of Maryland Greenebaum Cancer Center, Baltimore, MD, 20201, USA, tbao@umm.edu.

RESUMEN / SUMMARY:  - Up to 50 % of women receiving aromatase inhibitor (AI) complain of AI-associated  musculoskeletal symptoms (AIMSS) and 15 % discontinue treatment. We conducted a randomized, sham-controlled trial to evaluate whether acupuncture improves AIMSS  and to explore potential mechanisms. Postmenopausal women with early stage breast cancer, experiencing AIMSS were randomized to eight weekly real or sham acupuncture sessions. We evaluated changes in the Health Assessment Questionnaire Disability Index (HAQ-DI) and pain visual analog scale (VAS) following the intervention compared to baseline. Serum estradiol, beta-endorphin, and proinflammatory cytokine concentrations were measured pre and post-intervention.  We enrolled 51 women of whom 47 were evaluable, including 23 randomized to real and 24 to sham acupuncture. Baseline characteristics were balanced between groups with the exception of a higher HAQ-DI score in the real acupuncture group (p = 0.047). We did not observe a statistically significant difference in reduction of HAQ-DI (p = 0.30) or VAS (p = 0.31) between the two groups. Following eight weekly treatments, we observed a statistically significant reduction of IL-17 (p  </= 0.009) in both groups. No significant modulation was seen in estradiol, beta-endorphin, or other proinflammatory cytokine concentrations in either group. We did not observe a significant difference in AIMSS changes between real and sham acupuncture. As sham acupuncture used in this study may not be equivalent to placebo, further studies with a non-acupuncture arm may be required to establish  whether acupuncture is beneficial for the treatment of AIMSS.

 

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[16]

TÍTULO / TITLE:  - Post-transplant T cell chimerism predicts graft versus host disease but not disease relapse in patients undergoing an alemtuzumab based reduced intensity conditioned allogeneic transplant.

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

REVISTA / JOURNAL:  - Leuk Res. 2013 Feb 5. pii: S0145-2126(13)00024-6. doi: 10.1016/j.leukres.2013.01.010.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.leukres.2013.01.010

AUTORES / AUTHORS:  - Nikolousis E; Robinson S; Nagra S; Brookes C; Kinsella F; Tauro S; Jeffries S; Griffiths M; Mahendra P; Cook M; Paneesha S; Lovell R; Kishore B; Chaganti S; Malladi R; Raghavan M; Moss P; Milligan D; Craddock C

INSTITUCIÓN / INSTITUTION:  - Department of Haematology, Heart of England NHS Foundation Trust, Birmingham, UK. Electronic address: emelni@hotmail.com.

RESUMEN / SUMMARY:  - In this multicentre retrospective study we have studied the impact of T cell chimerism on the outcome of 133 patients undergoing an alemtuzumab based reduced  intensity conditioning allograft (RIC). The median age of the patients was 50 years (range 42-55 years). 77 patients were transplanted using an HLA identical sibling donor while 56 patients received a fully matched volunteer unrelated donor graft. 64 patients had a lymphoid malignancy and 69 were transplanted for a myeloid malignancy. 38 patients (29%) relapsed with no significant difference in  risk of relapse between patients developing full donor and mixed donor chimerism  in the T-cell compartment on D+90 and D+180 post transplant. Day 90 full donor T  cell chimerism correlated with an increased incidence of acute GVHD according to  NIH criteria (p=0.0004) and the subsequent development of chronic GVHD. Consistent with previous observations, our results confirmed a correlation between the establishment of T cell full donor chimerism and acute GVHD in T deplete RIC allografts. However our study failed to identify any correlation between T cell chimerism and relapse risk and challenge the use of pre-emptive donor lymphocyte infusions (DLI) in patients with mixed T cell chimerism transplanted using an alemtuzumab based RIC regimen.

 

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[17]

TÍTULO / TITLE:  - A potentially neuroprotective role for erythropoietin with paclitaxel treatment in ovarian cancer patients: a prospective phase II GINECO trial.

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

REVISTA / JOURNAL:  - Support Care Cancer. 2013 Feb 19.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00520-013-1748-0

AUTORES / AUTHORS:  - Weber B; Largillier R; Ray-Coquard I; Yazbek G; Meunier J; Alexandre J; Dauba J; Spaeth D; Delva R; Joly F; Pujade-Lauraine E; Copel L

INSTITUCIÓN / INSTITUTION:  - Centre Alexis Vautrin, 6 Avenue de Bourgogne Brabois, Vandoeuvre-les-Nancy, France.

RESUMEN / SUMMARY:  - PURPOSE: A prospective phase II multicenter study was performed in two steps in paclitaxel-treated ovarian cancer patients in France. A French version of the four-item Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) questionnaire was validated. This was then used to evaluate neurotoxicity in relation to erythropoietin treatment. METHODS:  Patients received standard second-line paclitaxel-based chemotherapy and erythropoietin for anemia. Neurotoxicity and hemoglobin levels were evaluated every cycle with the FACT/GOG-Ntx and NCI-CTCAE. The translated questionnaire was tested in 20 patients to confirm the translation accuracy. The final questionnaire was validated in 98 patients with internal consistency (Cronbach’s  coefficient) and item correlation (Pearson’s r coefficient) tests. Neurotoxicity  severity was analyzed according to erythropoietin intake (first three cycles versus no or late intake) and correlated with anemia. RESULTS: Patients received  a median of six paclitaxel cycles (range 1-9). Neurotoxicity was validated in 484 questionnaires. Internal consistency was excellent with Cronbach’s coefficients of >/=0.89 at inclusion, after 3 cycles and at study end. Inter-question correlation was high with Pearson’s coefficients of 0.65-0.85. FACT/GOG-Ntx and NCI-CTCAE severity scoring was similar. Globally, the incidence of severe neurotoxicity (FACT/GOG-Ntx and NCI-CTCAE) was found significantly higher in patients with severe anemia. Of 98 evaluable patients, 31 received erythropoietin during the first three cycles. Mean hemoglobin level was significantly lower in this group from baseline to cycle 4; however, these anemic patients with early EPO intake did not develop an increase rate of severe neurotoxicity. CONCLUSIONS: The French FACT/GOG-Ntx questionnaire is a reliable and valid tool for assessing  chemotherapy-induced neuropathy. This study raises the possibility that erythropoietin might play a neuroprotective role when administered with paclitaxel.

 

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TÍTULO / TITLE:  - Words of wisdom: re: prognostic or predictive plasma cytokines and angiogenic factors for patients treated with pazopanib for metastatic renal-cell cancer: a retrospective analysis of phase 2 and phase 3 trials.

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

REVISTA / JOURNAL:  - Eur Urol. 2013 Apr;63(4):769. doi: 10.1016/j.eururo.2012.12.055.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.eururo.2012.12.055

AUTORES / AUTHORS:  - Karam JA; Wood CG

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

 

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[19]

TÍTULO / TITLE:  - Long-term Follow-up of a Phase II Trial of Chemotherapy Plus Hormone Therapy for  Biochemical Relapse After Definitive Local Therapy for Prostate Cancer.

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

REVISTA / JOURNAL:  - Urology. 2013 Mar;81(3):611-6. doi: 10.1016/j.urology.2012.12.025.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.urology.2012.12.025

AUTORES / AUTHORS:  - Nakabayashi M; Xie W; Buckle G; Bubley G; Ernstoff MS; Walsh W; Morganstern DE; Kantoff PW; Taplin ME

INSTITUCIÓN / INSTITUTION:  - Division of Medical Oncology, Department of Medicine, Lank Center for Genitourinary Oncology, Boston, MA.

RESUMEN / SUMMARY:  - OBJECTIVE: To evaluate long-term follow-up of a phase II trial of chemohormonal therapy in 62 men with prostate cancer biochemical relapse (BR). METHODS: Treatment was 4 cycles of docetaxel (70 mg/m) every 3 weeks and estramustine 280  mg three times a day (days 1-5) followed by 15 months of goserelin acetate/bicalutamide. The primary endpoint was the proportion with prostate-specific antigen (PSA) <0.1 with recovered testosterone 5 years after completion of therapy. Secondary endpoints included time to progression (TTP), time to reinitiate androgen deprivation therapy (ADT), the proportion with castration-resistant prostate cancer (CRPC), and overall survival (OS). RESULTS:  Median follow-up was 8.6 years (range 1.3-11.1 years). At 5 year follow-up, 7 patients (11%) had PSA <0.1 (5 undetectable); 8 (13%) had PSA >0.1 but without reinitiation of ADT (median PSA 0.37). Of the 15 (24%) men without reinitiation of ADT, and 14 have recovered testosterone to normal range. Median TTP for the complete cohort was 35.0 months (95% confidence interval [CI] 31.7-39.2). Baseline PSA <3.0 ng/dL, no prior ADT, and prostatectomy (vs radiation) were associated with longer TTP (P = .0001, P = .0055, and P = .0398, respectively). At the time of analysis, 42 men (68%) had restarted ADT, 23 men had CRPC (37%), and 11 (18%) had chemotherapy. Median time to reinitiation of ADT was 32.6 months (range 0-107.6 months). Median OS has not been reached; there were 15 deaths. CONCLUSION: Chemotherapy plus ADT for BR resulted in durable (>5 years) complete  responses (<0.1 ng/mL) in 7 men (11%). Twenty-four percent of men have not re-initiated ADT 5 years from completion of protocol therapy.

 

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[20]

TÍTULO / TITLE:  - Clinical Significance of CD33 Nonsynonymous Single-Nucleotide Polymorphisms in Pediatric Patients with Acute Myeloid Leukemia Treated with Gemtuzumab-Ozogamicin-Containing Chemotherapy.

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

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Mar 15;19(6):1620-1627. Epub 2013 Feb 26.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-3115

AUTORES / AUTHORS:  - Mortland L; Alonzo TA; Walter RB; Gerbing RB; Mitra AK; Pollard JA; Loken MR; Hirsch B; Raimondi S; Franklin J; Pounds S; Cao X; Rubnitz JE; Ribeiro RC; Gamis A; Meshinchi S; Lamba JK

INSTITUCIÓN / INSTITUTION:  - Authors’ Affiliations: Departments of Hematology and Oncology and Department of Lab Medicine and Pathology, PUMA-Institute of Personalized Medicine, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota; Department of Experimental and Clinical Pharmacology, Clinical Research Division, Fred Hutchinson Cancer Research Center; Department of Medicine, Division of Hematology, Department of Pediatrics, University of Washington; Hematologics, Inc, Seattle, Washington; Department of Biostatistics, University of Southern California, Los Angeles; Children’s Oncology Group, Arcadia; University of Southern California and Amgen Incorporated, Thousand Oaks, California; Departments of Pathology, Biostatistics, and Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee; and Division of Hematology/Oncology/Bone Marrow Transplantation, Children’s Mercy Hospitals & Clinics, Kansas City, Missouri.

RESUMEN / SUMMARY:  - PURPOSE: The purpose of this study was to evaluate clinical implications of CD33  single-nucleotide polymorphisms (SNP) in pediatric patients with acute myeloid leukemia (AML) treated with gemtuzumab-ozogamicin (GO)-based therapy. EXPERIMENTAL DESIGN: We genotyped four CD33 SNPs: rs35112940 (G>A; Arg304Gly), rs12459419 (C>T; Ala14Val), rs2455069 (A>G; Arg69Gly), and rs1803254 (G>C; 3’UTR) in pediatric patients undergoing induction chemotherapy containing GO (COG-AAML03P1 trial; n = 242) or not containing GO (St. Jude AML02 trial; n = 172). RESULTS: CD33 SNPs were correlated significantly with clinical characteristics and treatment outcome. The coding SNPs, rs35112940 and rs12459419, were significantly associated with clinical endpoints in COG-AAML03P1 but not in the St. Jude AML02 trial. Specifically, among white patients in COG-AAML03P1, the 3-year overall survival (OS) rate from remission was 84% +/- 8% for those homozygous (GG) for rs35112940 versus 68% +/- 15% for the other genotypes (P = 0.018); these patients also had a lower relapse risk and superior  disease-free survival. Likewise, patients homozygous for variant allele (TT) for  rs12459419 were more likely to have favorable risk disease than CC and CT genotypes (52% vs. 31%, P = 0.034) and significantly lower diagnostic blast CD33  expression than other genotypes (P < 0.001). CONCLUSION: Our data suggest that genetic variations in CD33 could impact clinical outcome of GO-based therapy in pediatric AMLs. Clin Cancer Res; 19(6); 1620-7. ©2013 AACR.

 

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[21]

TÍTULO / TITLE:  - Geriatric Factors Predict Chemotherapy Feasibility: Ancillary Results of FFCD 2001-02 Phase III Study in First-Line Chemotherapy for Metastatic Colorectal Cancer in Elderly Patients.

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

REVISTA / JOURNAL:  - J Clin Oncol. 2013 Mar 4.

            ●● Enlace al texto completo (gratuito o de pago) 1200/JCO.2012.42.9894

AUTORES / AUTHORS:  - Aparicio T; Jouve JL; Teillet L; Gargot D; Subtil F; Le Brun-Ly V; Cretin J; Locher C; Bouche O; Breysacher G; Charneau J; Seitz JF; Gasmi M; Stefani L; Ramdani M; Lecomte T; Mitry E

INSTITUCIÓN / INSTITUTION:  - Thomas Aparicio, Avicenne Hospital, Assistance Publique-Hopitaux de Paris (AP-HP), Universite Paris 13, Sorbonne Paris Cite, Bobigny; Laurent Teillet, Sainte Perine Hospital, AP-HP; Emmanuel Mitry, Institut Curie, Versaille Saint Quentin University, Paris; Jean-Louis Jouve, Centre Hospitalier Universitaire (CHU) Dijon; Fabien Subtil, Federation Francophone de Cancerologie Digestive, Dijon; Dany Gargot, Centre Hospitalier (CH) Blois, Blois; Valerie Le Brun-Ly, CHU Limoges, Limoges; Jacques Cretin, CH Ales, Ales; Christophe Locher, CH Meaux, Meaux; Olivier Bouche, CHU Robert Debre, Reims; Gilles Breysacher, CH Colmar Colmar; Jacky Charneau, CH Boulogne-sur-Mer, Boulogne-sur-Mer; Jean-Francois Seitz, Timone Hospital, Assistance Publique-Hopitaux de Marseille (AP-HM); Mohamed Gasmi, Hopital Nord, AP-HM, Marseille; Laetitia Stefani, CH Pringy, Pringy; Mohamed Ramdani, CH Bezier, Bezier; and Thierry Lecomte, CHU Trousseau, Universite Francois-Rabelais, Tours, France.

RESUMEN / SUMMARY:  - PURPOSEElderly patients form a heterogeneous population. Evaluation of geriatric  factors may help evaluate a patient’s health status to better adapt treatment. PATIENTS AND METHODSElderly patients with previously untreated metastatic colorectal cancer (mCRC) were randomly assigned to receive fluorouracil (FU) -based chemotherapy either alone or in combination with irinotecan (IRI) in the Federation Francophone de Cancerologie Digestive (FFCD) 2001-02 study. Sites participating in the geriatric substudy completed geriatric screening tools to perform prognostic factor analyses for treatment safety during the first 4 months after treatment initiation.ResultsThe geriatric score was calculated in 123 patients (44%). Median age was 80 years (range, 75 to 91 years). The Charlson comorbidity index was </= 1 in 75%, Mini-Mental State Examination (MMSE) score was </= 27/30 in 31%, and Instrumental Activities of Daily Living (IADL) showed impairment in 34% of the patients. Seventy-one patients (58%) had grade 3 to 4 toxicity, 41 (33%) had a dose-intensity reduction of more than 33%, and 54 (44%)  had at least one unexpected hospitalization during the first 4 months after starting treatment. In multivariate analysis, significant predictive factors for  grade 3-4 toxicity were IRI arm (odds ratio [OR], 5.03), MMSE </= 27/30 (OR, 3.84), and impaired IADL (OR, 4.67); for dose-intensity reduction of > 33%, the significant predictive factors were alkaline phosphates > 2 x upper limit of normal (OR, 4.16) and IRI arm (OR, 6.85); and for unexpected hospitalization, significant predictive factors were MMSE </= 27/30 (OR, 4.56) and Geriatric Depression Scale </= 2 (OR, 5.52). CONCLUSIONGeriatric factors (MMSE and IADL) are predictive of severe toxicity or unexpected hospitalization (MMSE) in a randomized prospective phase III study in mCRC. These results suggest that cognitive function and autonomy impairment should be taken into account when choosing a regimen for chemotherapy.

 

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TÍTULO / TITLE:  - Phase II Randomized Study of Trastuzumab Emtansine Versus Trastuzumab Plus Docetaxel in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer.

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

REVISTA / JOURNAL:  - J Clin Oncol. 2013 Mar 20;31(9):1157-63. doi: 10.1200/JCO.2012.44.9694. Epub 2013 Feb 4.

            ●● Enlace al texto completo (gratuito o de pago) 1200/JCO.2012.44.9694

AUTORES / AUTHORS:  - Hurvitz SA; Dirix L; Kocsis J; Bianchi GV; Lu J; Vinholes J; Guardino E; Song C; Tong B; Ng V; Chu YW; Perez EA

INSTITUCIÓN / INSTITUTION:  - Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224; perez.edith@mayo.edu.

RESUMEN / SUMMARY:  - PURPOSE Trastuzumab emtansine (T-DM1), an antibody-drug conjugate composed of the cytotoxic agent DM1 conjugated to trastuzumab via a stable thioether linker, has  shown clinical activity in single-arm studies enrolling patients with human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer (MBC) whose disease had progressed on HER2-targeted therapy in the metastatic setting. PATIENTS AND METHODS Patients (N = 137) with HER2-positive MBC or recurrent locally advanced breast cancer were randomly assigned to trastuzumab plus docetaxel (HT; n = 70) or T-DM1 (n = 67) as first-line treatment until disease progression or unacceptable toxicity. Primary end points were investigator-assessed progression-free survival (PFS) and safety. Key secondary end points included overall survival (OS), objective response rate (ORR), duration of objective response, clinical benefit rate, and quality of life. Results Median PFS was 9.2 months with HT and 14.2 months with T-DM1 (hazard ratio, 0.59; 95% CI, 0.36 to 0.97); median follow-up was approximately 14 months  in both arms. ORR was 58.0% (95% CI, 45.5% to 69.2%) with HT and 64.2% (95% CI, 51.8% to 74.8%) with T-DM1. T-DM1 had a favorable safety profile versus HT, with  fewer grade >/= 3 adverse events (AEs; 46.4% v 90.9%), AEs leading to treatment discontinuations (7.2% v 40.9%), and serious AEs (20.3% v 25.8%). Preliminary OS  results were similar between treatment arms; median follow-up was approximately 23 months in both arms. CONCLUSION In this randomized phase II study, first-line  treatment with T-DM1 for patients with HER2-positive MBC provided a significant improvement in PFS, with a favorable safety profile, versus HT.

 

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[23]

TÍTULO / TITLE:  - Etoposide in combination with low-dose CAG (cytarabine, aclarubicin, G-CSF) for the treatment of relapsed or refractory acute myeloid leukemia: A multicenter, randomized control trial in southwest China.

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

REVISTA / JOURNAL:  - Leuk Res. 2013 Mar 25. pii: S0145-2126(13)00080-5. doi: 10.1016/j.leukres.2013.03.005.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.leukres.2013.03.005

AUTORES / AUTHORS:  - Zhang X; Li Y; Zhang Y; Chen X; Zhang C; Gao L; Kong P; Liu Y; Wen Q; Zeng Y; Wang Q; Su Y; Wang C; Wang S; Yuan Z; Gao L

INSTITUCIÓN / INSTITUTION:  - Department of Hematology, Xinqiao Hospital, Third Military Medical University, Chongqing, China.

RESUMEN / SUMMARY:  - In a well-controlled multi-center randomized trial in southwestern China, 228 patients with refractory or relapsed AML were received a low-dose CAG regimen either with etoposide (E-CAG) or without etoposide (CAG). The complete remission  (CR) rate, overall survival (OS) and toxicity were evaluated. Patients with E-CAG had a higher CR rate (71.1% vs. CAG 50.9%, P=0.0002). The tolerability appeared to be equivalent. Patients with CR who underwent allogenic hematopoietic stem cell transplantation (allo-HSCT) had a higher five-year OS over those without allo-HSCT (73.8% vs. 10.8%, P=0.000). The E-CAG regimen is expected to become a bridge between relapsed or refractory AML and allo-HSCT.

 

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[24]

TÍTULO / TITLE:  - Phase Ib trial of the Toll-like receptor 9 agonist IMO-2055 in combination with 5-fluorouracil, cisplatin, and cetuximab as first-line palliative treatment in patients with recurrent/metastatic squamous cell carcinoma of the head and neck.

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

REVISTA / JOURNAL:  - Invest New Drugs. 2013 Feb 10.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10637-013-9933-z

AUTORES / AUTHORS:  - Machiels JP; Kaminsky MC; Keller U; Brummendorf TH; Goddemeier T; Forssmann U; Delord JP

INSTITUCIÓN / INSTITUTION:  - Service d’Oncologie Medicale, Centre du Cancer, Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Experimentale (IREC, MIRO), Universite Catholique de Louvain, Bruxelles, Belgium, Jean-Pascal.Machiels@uclouvain.be.

RESUMEN / SUMMARY:  - Background This Phase Ib trial assessed the maximum tolerated dose (MTD) and safety of the Toll-like receptor 9 agonist IMO-2055 combined with 5-fluorouracil, cisplatin, and cetuximab (PFE) as first-line palliative treatment in patients with relapsed and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). Methods A standard 3 + 3 study design was used. Patients were sequentially enrolled to be treated with IMO-2055 (0.16, 0.32, or 0.48 mg/kg/day; days 1, 8, 15), 5-fluorouracil (1,000 mg/m(2)/day; days 1-4), cisplatin (100 mg/m(2)/day; day 1) and cetuximab (400 mg/m(2)/day first dose; then 250 mg/m(2)/day; days 1, 8, 15) every 3 weeks. Results Thirteen patients received IMO-2055. Dose-limiting toxicities (DLTs; ie, any Grade [G]3/4 treatment-related  adverse events [TEAEs] in cycle 1) occurred in 2/4 patients treated with IMO-2055 0.32 mg/kg (G4 hypokalemia and hypomagnesemia [n = 1]; G4 septicemia, hyperthermia, febrile neutropenia, and G3 hypotension [n = 1]). In the IMO-2055 0.16-mg/kg expansion cohort, 1 patient experienced DLTs of G3 sepsis, bacteremia, and hyperthermia. The most common G >/= 3 TEAEs were neutropenia (n = 9; not including febrile neutropenia [n = 1]), hypokalemia (n = 5), and hypomagnesemia (n = 4). Serious adverse events (SAEs) occurred in 8 patients, including 4 with SAEs considered IMO-2055 related; 1 of these patients died. Best response achieved overall was partial response in 3 patients and stable disease in 9 patients. The overall safety profile led to early trial termination; the safety monitoring committee did not confirm the MTD (formally IMO-2055 0.16 mg/kg). Conclusions Regimens combining IMO-2055 and PFE cannot be recommended for further development in R/M SCCHN patients.

 

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[25]

TÍTULO / TITLE:  - Phase II trial of non-pegylated liposomal doxorubicin and low-dose prednisone in  second-line chemotherapy for hormone-refractory prostate cancer.

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

REVISTA / JOURNAL:  - Tumori. 2012 Nov;98(6):696-701. doi: 10.1700/1217.13491.

            ●● Enlace al texto completo (gratuito o de pago) 1700/1217.13491

AUTORES / AUTHORS:  - Montanari M; Fabbri F; Rondini E; Frassineti GL; Mattioli R; Carloni S; Scarpi E; Zoli W; Amadori D; Cruciani G

INSTITUCIÓN / INSTITUTION:  - Oncology Unit, Santa Maria delle Croci Hospital, Viale Randi 5, Ravenna, Italy. marcomontanarimail@libero.it

RESUMEN / SUMMARY:  - AIMS AND BACKGROUND: Non-pegylated liposomal doxorubicin (NPLD) (Myocet) has shown marked in vitro activity in castration-resistant prostate cancer (CRPC) and also in docetaxel-resistant cells, higher than that shown by pegylated liposomal  doxorubicin. Its activity would seem to be due to a high intracellular drug concentration and induction of Golgi-dependent apoptosis. On the basis of these results, a clinical study was designed to assess the activity of NPLD and low-dose prednisone in second-line therapy. METHODS: Fifty-four patients were enrolled and evaluated. Eligibility criteria were histologically confirmed CRPC,  PSA >20 ng/mL or measurable lesions according to the RECIST criteria, previous docetaxel-based chemotherapy, and adequate cardiac function. Patients were treated with weekly intravenous NPLD 25 mg/m2 and daily prednisone 10 mg until progression. RESULTS: Median patient age was 69 years (range, 52-83) and median baseline PSA concentration was 120 ng/mL (range, 5.35-4350). Sixteen (29.6%) patients had measurable lesions. Objective or PSA responses (>50% reduction) were observed in 8 (14.8%) patients. The median time to progression was 2.8 months and the median overall survival was 11.3 months. Toxicity was generally mild (grade 1-2) and infrequent, with grade 3-4 neutropenia in 12.9% of cases. Grade 3 nonhematological toxicities included nausea in 2 patients (3.7%) and fatigue and  stomatitis in 1 case (1.9%). No drug-related serious adverse events were reported. CONCLUSIONS: Weekly administration of NPLD is a well tolerated treatment with proven albeit limited activity.

 

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[26]

TÍTULO / TITLE:  - Safety profile, efficacy, and biodistribution of a bicistronic high-capacity adenovirus vector encoding a combined immunostimulation and cytotoxic gene therapy as a prelude to a phase I clinical trial for glioblastoma.

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

REVISTA / JOURNAL:  - Toxicol Appl Pharmacol. 2013 May 1;268(3):318-30. doi: 10.1016/j.taap.2013.02.001. Epub 2013 Feb 9.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.taap.2013.02.001

AUTORES / AUTHORS:  - Puntel M; A K M GM; Farrokhi C; Vanderveen N; Paran C; Appelhans A; Kroeger KM; Salem A; Lacayo L; Pechnick RN; Kelson KR; Kaur S; Kennedy S; Palmer D; Ng P; Liu C; Krasinkiewicz J; Lowenstein PR; Castro MG

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA; Department of Cell and Developmental Biology, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA; Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

RESUMEN / SUMMARY:  - Adenoviral vectors (Ads) are promising gene delivery vehicles due to their high transduction efficiency; however, their clinical usefulness has been hampered by  their immunogenicity and the presence of anti-Ad immunity in humans. We reported  the efficacy of a gene therapy approach for glioma consisting of intratumoral injection of Ads encoding conditionally cytotoxic herpes simplex type 1 thymidine kinase (Ad-TK) and the immunostimulatory cytokine fms-like tyrosine kinase ligand 3 (Ad-Flt3L). Herein, we report the biodistribution, efficacy, and neurological and systemic effects of a bicistronic high-capacity Ad, i.e., HC-Ad-TK/TetOn-Flt3L. HC-Ads elicit sustained transgene expression, even in the presence of anti-Ad immunity, and can encode large therapeutic cassettes, including regulatory elements to enable turning gene expression “on” or “off” according to clinical need. The inclusion of two therapeutic transgenes within a  single vector enables a reduction of the total vector load without adversely impacting efficacy. Because clinically the vectors will be delivered into the surgical cavity, normal regions of the brain parenchyma are likely to be transduced. Thus, we assessed any potential toxicities elicited by escalating doses of HC-Ad-TK/TetOn-Flt3L (1x10(8), 1x10(9), or 1x10(10) viral particles [vp]) delivered into the rat brain parenchyma. We assessed neuropathology, biodistribution, transgene expression, systemic toxicity, and behavioral impact at acute and chronic time points. The results indicate that doses up to 1x10(9) vp of HC-Ad-TK/TetOn-Flt3L can be safely delivered into the normal rat brain and  underpin further developments for its implementation in a phase I clinical trial  for glioma.

 

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[27]

TÍTULO / TITLE:  - Frequency of ABL gene mutations in chronic myeloid leukemia patients resistant to imatinib and results of treatment switch to second-generation tyrosine kinase inhibitors.

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

REVISTA / JOURNAL:  - Med Clin (Barc). 2013 Feb 21. pii: S0025-7753(13)00014-6. doi: 10.1016/j.medcli.2012.10.028.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.medcli.2012.10.028

AUTORES / AUTHORS:  - Marce S; Zamora L; Cabezon M; Xicoy B; Boque C; Fernandez C; Grau J; Navarro JT; Fernandez de Sevilla A; Ribera JM; Feliu E; Milla F

INSTITUCIÓN / INSTITUTION:  - Hematology Department, ICO Badalona-Hospital Germans Trias i Pujol, Instituto de  Investigacion contra la Leucemia Josep Carreras, Universitat Autonoma de Barcelona, Badalona, Barcelona, España.

RESUMEN / SUMMARY:  - BACKGROUND AND OBJECTIVES: Tyrosine kinase inhibitors (TKI) have improved the management of patients with chronic myeloid leukemia (CML). However, a significant proportion of patients do not achieve the optimal response or are resistant to TKI. ABL kinase domain mutations have been extensively implicated in the pathogenesis of TKI resistance. Treatment with second-generation TKI has produced high rates of hematologic and cytogenetic responses in mutated ABL patients. The aim of this study was to determine the type and frequency of ABL mutations in patients who were resistant to imatinib or had lost the response, and to analyze the effect of second-generation TKI on their outcome. PATIENTS AND METHODS: The presence of ABL mutations in 45 CML patients resistant to imatinib was evaluated by direct sequencing and was correlated with the results of the cytogenetic study (performed in 39 cases). The outcome of these patients after therapy with nilotinib or dasatinib was analyzed. RESULTS: ABL mutations were detected in 14 out of 45 resistant patients. Patients with clonal cytogenetic evolution tended to develop mutations more frequently than those without clonal evolution. Nine out of the 15 patients with ABL mutation responded to a treatment switch to nilotinib (n=4), dasatinib (n=2), interferon (n=1) or hematopoietic stem cell transplantation (n=2). CONCLUSION: The frequency of ABL mutations in CML patients resistant to imatinib is high and is more frequent among those with  clonal cytogenetic evolution. The change to second-generation TKI can overcome imatinib resistance in most of the mutated patients.

 

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[28]

TÍTULO / TITLE:  - A first-in-class, first-in-human, phase I trial of p28, a non-HDM2-mediated peptide inhibitor of p53 ubiquitination in patients with advanced solid tumours.

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

REVISTA / JOURNAL:  - Br J Cancer. 2013 Mar 19;108(5):1061-70. doi: 10.1038/bjc.2013.74. Epub 2013 Feb  28.

            ●● Enlace al texto completo (gratuito o de pago) 1038/bjc.2013.74

AUTORES / AUTHORS:  - Warso MA; Richards JM; Mehta D; Christov K; Schaeffer C; Rae Bressler L; Yamada T; Majumdar D; Kennedy SA; Beattie CW; Das Gupta TK

INSTITUCIÓN / INSTITUTION:  - UIC Department of Surgery, Division of Surgical Oncology, 840 South Wood Street,  #618, MC 820, Chicago, IL 60612, USA.

RESUMEN / SUMMARY:  - Background:This first-in-human, phase I clinical trial of p28 (NSC745104), a 28-amino-acid fragment of the cupredoxin azurin, investigated the safety, tolerability, pharmacokinetics and preliminary activity of p28 in patients with p53(+) metastatic solid tumours.Methods:A total of 15 patients were administered  p28 i.v. as a short infusion three times per week for 4 weeks followed by a 2-week rest under an accelerated titration 3+3 dose escalation design until either a grade 3-related adverse event occurred or the maximum tolerated dose (MTD) was reached. Single-dose and steady-state serum pharmacokinetics were characterised. Assessments included toxicity, best objective response by RECIST 1.1 Criteria, and overall survival.Results:No patients exhibited any dose-limiting toxicities (DLTs), significant adverse events or exhibited an immune response (IgG) to the peptide. The No Observed Adverse Effect Level (NOAEL) and MTD were not reached. Seven patients demonstrated stable disease for  7-61 weeks, three a partial response for 44-125 weeks, and one a complete response for 139 weeks. Three patients are still alive at 158, 140, and 110 weeks post therapy completion.Conclusion:p28 was tolerated with no significant adverse  events. An MTD was not reached. Evidence of anti-tumour activity indicates a highly favourable therapeutic index and demonstrates proof of concept for this new class of non-HDM2-mediated peptide inhibitors of p53 ubiquitination.

 

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[29]

TÍTULO / TITLE:  - Safety analysis of weekly paclitaxel plus S-1 versus paclitaxel plus 5-fluorouracil/calcium folinate as first-line therapy in advanced gastric cancer: a multicenter open random phase II trial.

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

REVISTA / JOURNAL:  - J Chemother. 2013 Feb;25(1):56-9. doi: 10.1179/1973947812Y.0000000057.

            ●● Enlace al texto completo (gratuito o de pago) 1179/1973947812Y.0000000057

AUTORES / AUTHORS:  - Deng T; Xu N; Xiong JP; Yan Z; Zhuang ZX; Yu Z; Wan HP; Zhang Y; Huang DZ; Zheng RS; Guo ZQ; Hu CH; Wang ML; Yu ZH; Yao Y; Meng JC; Ba Y

INSTITUCIÓN / INSTITUTION:  - Department of Gastrointestinal Medical Oncology,Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Cancer Prevention and Therapy of Tianjin, China.

RESUMEN / SUMMARY:  - PURPOSE: To report the results of a safety analysis from a phase II trial comparing administration of weekly paclitaxel plus S-1 (TS) versus paclitaxel plus 5-fluorouracil (5-FU)/calcium folinate (LV) (TLF) as first-line therapy for  advanced gastric cancer. METHODS: Patients (n = 240) with previously untreated advanced gastric cancer were randomly assigned to receive either TS or TLF in a 28-day cycle for six cycles. RESULTS: The clinical features of both sets of patients were similar, with the exception of the incidence of prior chemotherapy  (P>0.05). Most treatment-related adverse events occurred at similar rates in both treatment arms. However, patients receiving TS experienced an increase in all-grade especially grade ¾ neutropenia, with an incidence of 43.7% in the TS  arm and 16.3% in the TLF arm, respectively (P<0.05). Other severe adverse events  were infrequent and not significantly different between the groups. CONCLUSION: The safety and tolerance of weekly paclitaxel plus S-1 or 5-FU/LV is well in untreated advanced gastric cancer patients.

 

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[30]

TÍTULO / TITLE:  - Plasma Epstein-Barr virus DNA predicts outcome in advanced Hodgkin lymphoma: correlative analysis from a large North American co-operative group trial.

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

REVISTA / JOURNAL:  - Blood. 2013 Feb 5.

            ●● Enlace al texto completo (gratuito o de pago) 1182/blood-2012-09-454694

AUTORES / AUTHORS:  - Kanakry JA; Li H; Gellert LL; Lemas MV; Hsieh WS; Hong F; Tan KL; Gascoyne RD; Gordon LI; Fisher RI; Bartlett NL; Stiff P; Cheson BD; Advani R; Miller TP; Kahl BS; Horning SJ; Ambinder RF

INSTITUCIÓN / INSTITUTION:  - Johns Hopkins University, School of Medicine, Baltimore, MD, United States;

RESUMEN / SUMMARY:  - Epstein-Barr virus (EBV) is associated with Hodgkin lymphoma (HL) and can be detected by in situ hybridization (ISH) of viral nucleic acid (EBER) in tumor cells. We sought to determine whether plasma EBV-DNA could serve as a surrogate for EBER-ISH and to explore its prognostic utility in HL. Specimens from a Cancer Cooperative Intergroup Trial (E2496/Stanford V versus ABVD for HL) were used to compare pre-treatment plasma EBV-DNA quantification with EBV tumor status by EBER-ISH. A cut-off of >60 viral copies/100 microL plasma yielded 96% concordance with EBER-ISH. Pre-treatment and month 6 plasma specimens were designated EBV(-)  or EBV(+) by this cut-off. Patients with pre-treatment EBV(+) plasma (n=54) had inferior failure-free survival (FFS) compared to those with pre-treatment EBV(-)  plasma (n=274), log-rank p=0.009. By contrast, no difference in FFS was observed  when patients were stratified by EBER-ISH. Pre-treatment plasma EBV positivity was an independent predictor of treatment failure on multivariate analyses. At month 6, plasma EBV(+) patients (n=7) had inferior FFS compared to plasma EBV(-)  patients (n=125), log-rank p=0.007. These results confirm that plasma EBV-DNA is  highly concordant with EBER-ISH in HL and suggest that it may have prognostic utility at baseline and after 6 months of therapy for HL. (Clinical trial information: NCT00003389).

 

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[31]

TÍTULO / TITLE:  - Three-Gene Immunohistochemical Panel Adds to Clinical Staging Algorithms to Predict Prognosis for Patients With Esophageal Adenocarcinoma.

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

REVISTA / JOURNAL:  - J Clin Oncol. 2013 Mar 18.

            ●● Enlace al texto completo (gratuito o de pago) 1200/JCO.2012.45.9636

AUTORES / AUTHORS:  - Ong CA; Shapiro J; Nason KS; Davison JM; Liu X; Ross-Innes C; O’Donovan M; Dinjens WN; Biermann K; Shannon N; Worster S; Schulz LK; Luketich JD; Wijnhoven BP; Hardwick RH; Fitzgerald RC

INSTITUCIÓN / INSTITUTION:  - Chin-Ann J. Ong, Xinxue Liu, Caryn Ross-Innes, Maria O’Donovan, Susannah Worster, Laura K.E. Schulz, and Rebecca C. Fitzgerald, Hutchison/MRC Research Centre; Nicholas Shannon, Cambridge Research Institute; Richard H. Hardwick, Addenbrooke’s Hospital, Cambridge, United Kingdom; Joel Shapiro, Winand N.M. Dinjens, Katharina Biermann, and Bas P.L. Wijnhoven, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands; and Katie S. Nason, Jon M. Davison, and James D. Luketich, University of Pittsburgh, Pittsburgh, PA.

RESUMEN / SUMMARY:  - PURPOSEEsophageal adenocarcinoma (EAC) is a highly aggressive disease with poor long-term survival. Despite growing knowledge of its biology, no molecular biomarkers are currently used in routine clinical practice to determine prognosis or aid clinical decision making. Hence, this study set out to identify and validate a small, clinically applicable immunohistochemistry (IHC) panel for prognostication in patients with EAC. PATIENTS AND METHODSWe recently identified  eight molecular prognostic biomarkers using two different genomic platforms. IHC  scores of these biomarkers from a UK multicenter cohort (N = 374) were used in univariate Cox regression analysis to determine the smallest biomarker panel with the greatest prognostic power with potential therapeutic relevance. This new panel was validated in two independent cohorts of patients with EAC who had undergone curative esophagectomy from the United States and Europe (N = 666).ResultsThree of the eight previously identified prognostic molecular biomarkers (epidermal growth factor receptor [EGFR], tripartite motif-containing  44 [TRIM44], and sirtuin 2 [SIRT2]) had the strongest correlation with long-term  survival in patients with EAC. Applying these three biomarkers as an IHC panel to the validation cohort segregated patients into two different prognostic groups (P < .01). Adjusting for known survival covariates, including clinical staging criteria, the IHC panel remained an independent predictor, with incremental adverse overall survival (OS) for each positive biomarker (hazard ratio, 1.20; 95% CI, 1.03 to 1.40 per biomarker; P = .02). CONCLUSIONWe identified and validated a clinically applicable IHC biomarker panel, consisting of EGFR, TRIM44, and SIRT2, that is independently associated with OS and provides additional prognostic information to current survival predictors such as stage.

 

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[32]

TÍTULO / TITLE:  - Predictors for the 5-year risk of serious infections in patients with rheumatoid  arthritis treated with anti-tumor necrosis factor therapy: a cohort study in the  Dutch Rheumatoid Arthritis Monitoring (DREAM) registry.

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

REVISTA / JOURNAL:  - Rheumatology (Oxford). 2013 Jan 30.

            ●● Enlace al texto completo (gratuito o de pago) 1093/rheumatology/kes413

AUTORES / AUTHORS:  - van Dartel SA; Fransen J; Kievit W; Dutmer EA; Brus HL; Houtman NM; van de Laar MA; van Riel PL

INSTITUCIÓN / INSTITUTION:  - Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, Department of Rheumatology, Gelderse Vallei Hospital, Ede, Department of Rheumatology, TweeSteden Hospital, Tilburg, Department of Rheumatology, Medical Centre Leeuwarden, Leeuwarden and Department of Rheumatology, Arthritis Centre Twente, Enschede, The Netherlands.

RESUMEN / SUMMARY:  - Objective. The use of TNF inhibitors leads to an increased risk of serious infections in RA. Predicting this risk would facilitate the prevention of serious infections. The objective of this study was to identify which factors are predictive of the increased risk of serious infections in RA patients treated with TNF inhibiting therapy.Methods. Data from the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry of 2044 patients with RA were used for the analyses.  Data were censored at stopping TNF inhibitors or end of observation time up to 5  years. Univariate and multivariate analysis of baseline variables was performed using Cox regression with time to the first serious infection as dependent variable.Results. During a follow-up time of 5 years, 128 of 2044 (6.3%) patients developed a first serious infection with a total of 141 serious infections. The incidence rate in the first year after start of TNF inhibiting therapy was 4.57 first serious infections per 100 patient-years and 2.91 per 100 patient-years over 5 years. Age, corticosteroid use, visual analogue scale (VAS) pain, HAQ, tender joint count 28 joints (TJC28) and the presence of comorbidities were significant predictors for developing a serious infection during TNF inhibiting therapy in the multivariate model.Conclusion. Age, corticosteroid use, VAS pain,  HAQ, TJC28 and the presence of comorbidities all at baseline were significant predictors for developing a serious infection during TNF inhibiting therapy in RA patients.

 

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[33]

TÍTULO / TITLE:  - High-Grade KIT-Negative Sarcoma of the Small Bowel in a Patient With Chronic Myeloid Leukemia Receiving Long-Term Tyrosine Kinase Inhibitors.

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

REVISTA / JOURNAL:  - J Clin Oncol. 2013 Feb 25.

            ●● Enlace al texto completo (gratuito o de pago) 1200/JCO.2012.42.7989

AUTORES / AUTHORS:  - Martz J; Jain S; Vahdat LT; Qin L; Mosquera JM; Antonescu CR; Popa EC

INSTITUCIÓN / INSTITUTION:  - Ludwig-Maximilians Universitat Munich, Munich, Germany.

 

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[34]

TÍTULO / TITLE:  - Neoadjuvant epirubicin, gemcitabine and docetaxel for primary breast cancer: Long-term survival data and major prognostic factors based on two consecutive neoadjuvant phase I/II trials.

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

REVISTA / JOURNAL:  - Int J Cancer. 2013 Feb 7. doi: 10.1002/ijc.28094.

            ●● Enlace al texto completo (gratuito o de pago) 1002/ijc.28094

AUTORES / AUTHORS:  - Marme F; Aigner J; Lorenzo Bermejo J; Sinn P; Sohn C; Jager D; Schneeweiss A

INSTITUCIÓN / INSTITUTION:  - Department of Obstetrics and Gynaecology, University Hospital Heidelberg, Heidelberg, Germany; National Centre for Tumour Diseases, University Hospital, Heidelberg, Germany.

RESUMEN / SUMMARY:  - We previously reported primary endpoints of two consecutive phase I/II trials, evaluating different schedules of neoadjuvant epirubicin (E), gemcitabine (G) and docetaxel (Doc) for primary breast cancer (PBC). Here, we report mature survival  data and prognostic factors. One hundred fifty-one patients were recruited into two consecutive phase I/II trials of neoadjuvant chemotherapy for T2-4 N0-2 M0 PBC. Patients received six cycles of G/E/Doc every 3 weeks with G repeated on d8  (GEDoc, n = 84) or five cycles of G/E followed by four cycles of Doc all given every two weeks (GEsDoc, n = 67). Prognostic factors were investigated using univariate and multivariate analyses. No survival differences by treatment were found. Among reported predictive factors for pathologic complete response (pCR),  oestrogen receptor (ER) status was the only relevant factor in the multivariate analysis. Unexpectedly, pCR resulted in poorer survival (univariate HR for overall survival [OS] 3.11, p = 0.007). Multivariate analyses identified molecular subtype and tumour size as the most relevant prognostic factors for OS. HER2-receptor status and the CPS-EG score (Mittendorf et al., J Clin Oncol 2011;29:1956-62), based on clinical and pathological stage, ER-status and tumour  grade, were particularly relevant in disease-free survival. Our findings cast doubt on the reliability of pCR as single marker for prognosis of this unselected breast cancer cohort, with an abundance of luminal subtypes. These results underline the significance of additional molecular characteristics for breast cancer survival.

 

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[35]

TÍTULO / TITLE:  - The clinical characteristics and prognostic significance of MN1 gene and MN1-associated microRNA expression in adult patients with de novo acute myeloid leukemia.

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

REVISTA / JOURNAL:  - Ann Hematol. 2013 Mar 21.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00277-013-1729-x

AUTORES / AUTHORS:  - Xiang L; Li M; Liu Y; Cen J; Chen Z; Zhen X; Xie X; Cao X; Gu W

INSTITUCIÓN / INSTITUTION:  - Department of Hematology, The First People’s Hospital of Changzhou, Third Affiliated Hospital of Suzhou University, No.185, Juqian Street, Tianning District, Changzhou, 213003, Jiangsu, China.

RESUMEN / SUMMARY:  - This study aimed to determine the clinical characteristics and prognostic significance of the meningioma 1 (MN1) gene and MN1-associated microRNA expression in Chinese adult de novo acute myeloid leukemia (AML) patients. The expression level of MN1, microRNA-20 (miR-20a), and microRNA-181b (miR-181b) in bone marrow mononuclear cells was measured in 158 newly diagnosed AML patients and 20 cases of normal healthy donors by real-time quantitative reverse transcriptase polymerase chain reaction. All AML patients significantly overexpressed MN1 at the level of 0.01983 (P < 0.001) compared with normal controls. High MN1 expression was associated with spleen involvement (P = 0.037), NPM1 wild type (P = 0.001), lower miR-20a expression levels (P = 0.015), and higher miR-181b expression levels (P = 0.035). MiR-20a (P = 0.029) and miR-181b (P = 0.017) overexpressed in the bone marrow cells of patients with certain subtypes of AML compared with healthy donors. High MN1 expressers had lower complete remission (CR) rates and shorter overall survival (OS) within the Southwest Oncology Group classification. In multivariable models, high MN1 expression was associated with worse CR rates (P = 0.01), relapse-free survival (RFS; P = 0.02), and OS (P = 0.02); high miR-20a expression was associated with higher CR rates (P = 0.008) and longer OS (P = 0.04), whereas high miR-181b expression was associated with lower CR rates (P = 0.03), and shorter RFS (P = 0.045) and OS (P = 0.017). High MN1 expression confers worse prognosis in Chinese adult patients with de novo AML. MN1 gene and MN1-associated microRNAs provide clinical prognosis of AML patients and may refine their molecular risk classification.

 

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[36]

TÍTULO / TITLE:  - Validation of serum C-reactive protein (CRP) as an independent prognostic factor  for disease-free survival in patients with localised renal cell carcinoma (RCC).

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

REVISTA / JOURNAL:  - BJU Int. 2013 Mar 15. doi: 10.1111/bju.12067.

            ●● Enlace al texto completo (gratuito o de pago) 1111/bju.12067

AUTORES / AUTHORS:  - de Martino M; Klatte T; Seemann C; Waldert M; Haitel A; Schatzl G; Remzi M; Weibl P

INSTITUCIÓN / INSTITUTION:  - Department of Urology, Medical University of Vienna, Vienna.

RESUMEN / SUMMARY:  - OBJECTIVE: To validate high-sensitivity C-reactive protein (hs-CRP) serum levels  as an independent marker for disease-free survival (DFS) in clinically localised  clear cell renal cell carcinoma (ccRCC). PATIENTS AND METHODS: In all, 403 consecutive patients with clinically localised (T1-3N0M0) ccRCC treated by radical or partial nephrectomy were enrolled. Preoperative serum levels of hs-CRP were evaluated as both a continuous and categorical variables. Associations with  clinical (age, gender) and pathological variables (T classification, grade, tumour necrosis) were assessed with the chi-square and Kruskal-Wallis tests. Univariable and multivariable Cox proportional hazards models were fitted. The prognostic accuracy (PA) was assessed with Harrell’s C-index. RESULTS: The mean hs-CRP level was 1.32 mg/dL. The hs-CRP levels were associated with T classification (P = 0.05), high-grade disease (P < 0.001) and tumour necrosis (P  = 0.003). After a median follow-up of 43 months, 41 patients (10.1%) had developed disease recurrence. With each unit increase in hs-CRP levels, the risk  of recurrence increased by 10% (hazard ratio 1.10, P = 0.015). The thresholds of  0.5 and 0.75 mg/dL showed the best discrimination for stratification of patients  according to the probability of recurrence. These categorically coded hs-CRP levels were identified as independent prognostic factors in multivariable analyses (P < 0.001) and led to a significant increase in the PA of a multivariable base model containing the variables of the ‘Stage, Size, Grade and  Necrosis’ (SSIGN) score. CONCLUSIONS: This study validates preoperative serum hs-CRP levels as independent prognostic factor after surgery for localised ccRCC. Hs-CRP may be included in standard prognostic modelling after surgery and may guide surveillance and inclusion in adjuvant clinical trials.

 

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[37]

TÍTULO / TITLE:  - Immunohistochemically Detected Expression of 3 Major Genes (CDKN2A/p16, TP53, and SMAD4/DPC4) Strongly Predicts Survival in Patients With Resectable Pancreatic Cancer.

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

REVISTA / JOURNAL:  - Ann Surg. 2013 Mar 6.

            ●● Enlace al texto completo (gratuito o de pago) 1097/SLA.0b013e3182827a65

AUTORES / AUTHORS:  - Oshima M; Okano K; Muraki S; Haba R; Maeba T; Suzuki Y; Yachida S

INSTITUCIÓN / INSTITUTION:  - *Departments of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan daggerDepartment of Pathology, Faculty of Medicine, Kagawa University, Kagawa, Japan double daggerDepartment of Laboratory Medicine,  Social Insurance Ritsurin Hospital, Takamatsu, Kagawa, Japan section signDepartment of Surgery, Social Insurance Ritsurin Hospital, Takamatsu, Kagawa, Japan paragraph signDivision of Refractory Cancer Research, National Cancer Center Research Institute, Tokyo, Japan.

RESUMEN / SUMMARY:  - OBJECTIVE:: The goal of this retrospective study was to clarify the clinical implications of the status of the 3 major genes (CDKN2A/p16, TP53, and SMAD4/DPC4). BACKGROUND:: Recent whole-exome sequencing had shown that the landscape of the pancreatic ductal adenocarcinoma (PDAC) genome is notable for 4  frequently mutated genes (KRAS, TP53, CDKN2A/p16, and SMAD4/DPC4). METHODS:: We determined immunohistochemically the status of TP53, CDKN2A/p16, and SMAD4/DPC4 among the 4 genes because the KRAS gene is mutated in virtually all PDAC patients, and analyzed relationships with clinicopathological findings, including survival and patterns of disease progression, in 106 patients with PDAC undergoing radical surgery. RESULTS:: Abnormal immunolabeling of p53 was detected in 81.1% of PDACs and was significantly associated with tumor dedifferentiation (P = 0.022) and the presence of locoregional recurrence (P = 0.020). Loss of p16  and Smad4/Dpc4 immunolabeling was identified in 67.0% and 60.4%, respectively. Loss of p16 immunolabeling was associated with lymphatic invasion (P = 0.012) and postoperative widespread metastases (P < 0.001). A significant correlation was found between Smad4/Dpc4 immunolabeling and tumor size (P = 0.006), lymphatic invasion (P = 0.033), and lymph node metastasis (P = 0.006). Interestingly, all of the 6 patients demonstrating 5-year survival had intact SMAD4/DPC4. Kaplan-Meier survival analysis showed that lymph node metastasis (P = 0.001), lymphatic invasion (P = 0.008), the tumor (T) factor (T3 vs. T1/T2, P = 0.004), loss of p16 immunolabeling (P = 0.029), and loss of Smad4/Dpc4 immunolabeling (P  < 0.001) were significantly associated with shorter overall survival. Multivariate analysis revealed that loss of Smad4/Dpc4 immunolabeling was an independent and significant poor prognostic factor for overall and disease-free survival. On analysis of combinations of the status of these 3 genes, increasing  number of alterations reflected poorer survival. CONCLUSIONS:: Genetic alterations of these 3 genes and their accumulation are strongly associated with  malignant behavior of PDAC. Their immunohistochemical assessment at the time of diagnosis may provide a new prognostic tool, assisting in deciding optimal therapeutic strategies for patients.

 

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[38]

TÍTULO / TITLE:  - Homozygosity for killer immunoglobin-like receptor haplotype a predicts complete  molecular response to treatment with tyrosine kinase inhibitors in chronic myeloid leukemia patients.

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

REVISTA / JOURNAL:  - Exp Hematol. 2013 Feb 1. pii: S0301-472X(13)00011-8. doi: 10.1016/j.exphem.2013.01.008.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.exphem.2013.01.008

AUTORES / AUTHORS:  - La Nasa G; Caocci G; Littera R; Atzeni S; Vacca A; Mulas O; Langiu M; Greco M; Orru S; Orru N; Floris A; Carcassi C

INSTITUCIÓN / INSTITUTION:  - Bone Marrow Transplant Center, R. Binaghi Hospital - ASL 8, Cagliari, Italy; Hematology Unit, Department of Medical Sciences, University of Cagliari, Italy. Electronic address: lanasa@tiscali.it.

RESUMEN / SUMMARY:  - Several recent reports suggest a possible role for killer immunoglobulin-like receptors (KIR) in the onset of chronic myeloid leukemia (CML) and response to therapy with tyrosine kinase inhibitors (TKIs). To explore this hypothesis, we studied KIRs and their human leukocyte antigen class I ligands in 59 consecutive  patients with chronic-phase CML (mean age, 53 years; range, 23-81 years) and a group of 121 healthy control participants belonging to the same ethnic group as the patients. The 2-year cumulative incidence of complete molecular response, obtained after a median of 27 months (range, 4-52 months), was 51.2%. An increased frequency of the activating receptor KIR2DS1 (pm = 0.05) and a reduced  frequency of the KIR-ligand combination KIR2DS2/2DL2 absent/C1 present (pm = 0.001) were significantly associated with CML. Moreover, KIR repertoires in patients appeared to influence response to TKI therapy. Homozygosity for KIR haplotype A (pm = 0.01), a decreased frequency of the inhibitory KIR gene KIR2DL2 (pm = 0.02), and low numbers of inhibitory KIR genes (pm = 0.05) were all significantly associated with achievement of complete molecular remission. These  data suggest that a decrease in properly stimulated and activated NK cells might  contribute to the occurrence of CML and indicate homozygosity for KIR haplotype A as a promising immunogenetic marker of complete molecular response that could help clinicians decide whether to withdraw treatment in patients with CML.

 

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[39]

TÍTULO / TITLE:  - Association between serum levels of C-reactive protein and response to treatment  of chemotherapy-induced anemia in patients with solid tumors: a multicenter, prospective, observational study.

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

REVISTA / JOURNAL:  - Med Oncol. 2013 Mar;30(1):417. doi: 10.1007/s12032-012-0417-3. Epub 2013 Feb 1.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12032-012-0417-3

AUTORES / AUTHORS:  - Esquerdo Galiana G; Cervera JM; Barrajon E; Juarez A; Llorca C; Diaz N; Lopez A; Peiro R

INSTITUCIÓN / INSTITUTION:  - Medical Oncology Service, Hospital Clinica Benidorm, Avda Alfonso Puchades 8, 03501 Benidorm, Alicante, España. gasparesquerdo@yahoo.es

RESUMEN / SUMMARY:  - Our objective was to determine the association between C-reactive protein (CRP) levels at initiation of anemia treatment and response in solid tumor patients with chemotherapy (CT)-induced anemia. This was a multicenter, prospective, observational study which included adult patients with solid tumor initiating treatment for CT-induced anemia. Data were collected up to 16 weeks, or until premature discontinuation. We included 98 patients (median age 62.5 years, 64 % males, 57 % with ECOG 0-1, 85.7 % at stages III-IV and 54.1 % undergoing palliative CT). Mean (SD) Hb levels at baseline were 10.3 (0.9) g/dL (85.7 % < 11 g/dL) and median (Q1; Q3) CRP was 16.4 mg/L (3.9; 77.8) (68 % >/= 5 mg/L). A total of 96 % of patients initiated erythropoiesis-stimulating agents (ESA) and iron supplementation; 4 % initiated iron monotherapy. After a median of 85 days,  65 % of patients had Hb >/= 11 g/dL (in absence of transfusion) (mean change: +0.86 g/dL, 95 % confidence interval (CI) 0.53-1.19). A total of 8 patients required transfusion. A significant correlation (r = -0.39, p = 0.003) was observed between baseline CRP and final Hb levels. In the multivariate linear regression analysis, the independent predictors of higher final Hb levels were a  high baseline Hb (adjusted ss = +0.69 g/dL for each g/dL of baseline Hb, 95 % CI  0.17-1.21) and a low log baseline CRP (-0.62 for each log mg/L, 95 %CI -1.22 to -0.02). Our results suggest that, in patients with solid tumors and CT-induced anemia, high CRP levels at treatment initiation predict a poor response to treatment with ESA and iron, independently from anemia severity at therapy initiation and from other patient and disease characteristics.

 

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[40]

TÍTULO / TITLE:  - Combination of Rituximab, Bendamustine, and Cytarabine for Patients With Mantle-Cell Non-Hodgkin Lymphoma Ineligible for Intensive Regimens or Autologous  Transplantation.

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

REVISTA / JOURNAL:  - J Clin Oncol. 2013 Feb 11.

            ●● Enlace al texto completo (gratuito o de pago) 1200/JCO.2012.45.9842

AUTORES / AUTHORS:  - Visco C; Finotto S; Zambello R; Paolini R; Menin A; Zanotti R; Zaja F; Semenzato G; Pizzolo G; D’Amore ES; Rodeghiero F

INSTITUCIÓN / INSTITUTION:  - Carlo Visco, Silvia Finotto, Andrea Menin, Emanuele S.G. D’Amore, and Francesco Rodeghiero, San Bortolo Hospital, Vicenza; Renato Zambello and Gianpietro Semenzato, Padua University School of Medicine, Padova; Rossella Paolini, Santa Maria della Misericordia Hospital, Rovigo; Roberta Zanotti and Giovanni Pizzolo,  University of Verona, Verona; and Francesco Zaja, Azienda Ospedaliera Universitaria Santa Maria Misericordia, Udine, Italy.

RESUMEN / SUMMARY:  - PURPOSEThe combination of bendamustine (B) and rituximab ® is efficacious, with favorable toxicity in mantle-cell lymphoma (MCL). In this phase II study, we combined cytarabine with R and B (R-BAC) in patients with MCL age >/= 65 years who were previously untreated or relapsed or refractory (R/R) after one prior immunochemotherapy treatment. PATIENTS AND METHODSIn stage one, we established the maximum-tolerated dose (MTD) of cytarabine in R-BAC. In stage two, patients received R (375 mg/m(2) intravenously [IV] on day 1), B (70 mg/m(2) IV on days 2  and 3), and cytarabine (MTD IV on days 2 to 4) every 28 days for four to six cycles. The primary end point (overall response rate [ORR]) was evaluated by positron emission tomography. Secondary end points included safety, progression-free survival (PFS), response duration, and overall survival.ResultsForty patients (median age, 70 years; 20 previously untreated patients) were enrolled; 93% had Ann Arbor stage III/IV disease; 49% had high Mantle Cell International Prognostic Index scores, with 15% blastoid histology. All R/R patients (35% refractory) had previously received R-containing regimens.  The cytarabine MTD used in stage two was 800 mg/m(2), and R-BAC was well tolerated, with an 85% treatment completion rate. The major toxicity was transient grades 3 to 4 thrombocytopenia (87% of patients); febrile neutropenia occurred in 12%. The ORR was 100% (95% complete response [CR]) for previously untreated and 80% (70% CR) for R/R patients. The 2-year PFS rate (+/- standard deviation) was 95% +/- 5% for untreated and 70% +/- 10% for R/R patients. CONCLUSIONR-BAC is well tolerated and active against MCL.

 

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[41]

TÍTULO / TITLE:  - Preferential eradication of acute myelogenous leukemia stem cells by fenretinide.

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

REVISTA / JOURNAL:  - Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):5606-11. doi: 10.1073/pnas.1302352110. Epub 2013 Mar 19.

            ●● Enlace al texto completo (gratuito o de pago) 1073/pnas.1302352110

AUTORES / AUTHORS:  - Zhang H; Mi JQ; Fang H; Wang Z; Wang C; Wu L; Zhang B; Minden M; Yang WT; Wang HW; Li JM; Xi XD; Chen SJ; Zhang J; Chen Z; Wang KK

INSTITUCIÓN / INSTITUTION:  - State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025, China.

RESUMEN / SUMMARY:  - Leukemia stem cells (LSCs) play important roles in leukemia initiation, progression, and relapse, and thus represent a critical target for therapeutic intervention. However, relatively few agents have been shown to target LSCs, slowing progress in the treatment of acute myelogenous leukemia (AML). Based on in vitro and in vivo evidence, we report here that fenretinide, a well-tolerated  vitamin A derivative, is capable of eradicating LSCs but not normal hematopoietic progenitor/stem cells at physiologically achievable concentrations. Fenretinide exerted a selective cytotoxic effect on primary AML CD34(+) cells, especially the LSC-enriched CD34(+)CD38(-) subpopulation, whereas no significant effect was observed on normal counterparts. Methylcellulose colony formation assays further  showed that fenretinide significantly suppressed the formation of colonies derived from AML CD34(+) cells but not those from normal CD34(+) cells. Moreover, fenretinide significantly reduced the in vivo engraftment of AML stem cells but not normal hematopoietic stem cells in a nonobese diabetic/SCID mouse xenotransplantation model. Mechanistic studies revealed that fenretinide-induced  cell death was linked to a series of characteristic events, including the rapid generation of reactive oxygen species, induction of genes associated with stress  responses and apoptosis, and repression of genes involved in NF-kappaB and Wnt signaling. Further bioinformatic analysis revealed that the fenretinide-down-regulated genes were significantly correlated with the existing  poor-prognosis signatures in AML patients. Based on these findings, we propose that fenretinide is a potent agent that selectively targets LSCs, and may be of value in the treatment of AML.

 

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[42]

TÍTULO / TITLE:  - Predictors of depression in breast cancer patients treated with radiation: Role of prior chemotherapy and nuclear factor kappa B.

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

REVISTA / JOURNAL:  - Cancer. 2013 Mar 19. doi: 10.1002/cncr.28003.

            ●● Enlace al texto completo (gratuito o de pago) 1002/cncr.28003

AUTORES / AUTHORS:  - Torres MA; Pace TW; Liu T; Felger JC; Mister D; Doho GH; Kohn JN; Barsevick AM; Long Q; Miller AH

INSTITUCIÓN / INSTITUTION:  - Department of Radiation Oncology, Emory University, Atlanta, Georgia. matorre@emory.edu.

RESUMEN / SUMMARY:  - BACKGROUND: Depression is common during and after breast cancer treatment. However, the role of specific therapeutic modalities and related biologic mechanisms remains unclear. Radiation is an essential component of breast-conserving therapy and may contribute to depression in patients with breast cancer through the activation of inflammatory pathways. METHODS: Depressive symptoms and inflammatory mediators, including nuclear factor kappa B  (NF-kappaB), were assessed at baseline (before radiation), during radiation, and  6 weeks after radiation in 64 women who had stage 0 through IIIA breast cancer. RESULTS: No significant increases in depressive symptoms occurred during or after radiation, although a number of patients exhibited moderate-to-severe depression  throughout the study. Multivariate analyses of baseline factors predictive of depression revealed that educational status, perceived stress, prior chemotherapy, and peripheral blood NF-kappaB DNA binding all were independent predictors of persistent depressive symptoms after radiation (all P < .05). Of these factors, only prior chemotherapy was associated with inflammatory mediators, including NF-kappaB DNA binding, soluble tumor necrosis factor-alpha receptor 2, and interleukin-6, which, in univariate analyses predicted depressive symptoms after radiation (all P < .05). Chemotherapy-treated patients also exhibited an over-representation of gene transcripts regulated by NF-kappaB. CONCLUSIONS: Radiation was not associated with increased depressive symptoms in the current study, but of disease and treatment-related factors, prior chemotherapy predicted significant depression after radiation. Longitudinal studies are warranted to investigate the relationship among prior chemotherapy, inflammation, and persistent depression after breast cancer treatment. Cancer 2013. Esta es una cita bibliográfica que va por delante de la publicación en papel. La fecha indicada en la cita provista, NO corresponde con la fecha o la cita bibliográfica de la publicación en papel. La cita bibliográfica definitiva (con el volumen y su paginación) saldrá en 1 ó 2 meses a partir de la fecha de la emisión electrónica-online. *** This is a bibliographic record ahead of the paper publication. The given date in the bibliographic record does not correspond to the date or the bibliographic citation on the paper publication. The publisher will provide the final bibliographic citation (with the volume, and pagination) within 1 or 2 months from the date the record was published online. © 2013 American Cancer Society.

 

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[43]

TÍTULO / TITLE:  - Impact of HLA-E gene polymorphism on HLA-E expression in tumor cells and prognosis in patients with stage III colorectal cancer.

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

REVISTA / JOURNAL:  - Med Oncol. 2013 Mar;30(1):482. doi: 10.1007/s12032-013-0482-2. Epub 2013 Feb 3.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12032-013-0482-2

AUTORES / AUTHORS:  - Zhen ZJ; Ling JY; Cai Y; Luo WB; He YJ

INSTITUCIÓN / INSTITUTION:  - State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, China. zhenzj@sysucc.org.cn

RESUMEN / SUMMARY:  - Human leukocyte antigen (HLA)-E can contribute to the escape of cancer cells from host immune mechanisms. However, it is unknown whether HLA-E gene polymorphisms might play a role in cancer immune escape. This study aimed to evaluate the correlation between HLA-E gene polymorphisms and HLA-E expression in tumor tissue and determine the effects on clinical outcome of patients with stage III colorectal cancer. Two hundred thirty patients with stage III colorectal cancer were enrolled. HLA-E expression was detected in patient-derived tumor tissues with immunohistochemistry. HLA-E gene alleles in tumor tissues were detected with the polymerase chain reaction-sequence-specific primer method. In colorectal cancer tissue and in the normal tissue adjacent to the tumor, the HLA-E expression rates were 72.2 and 15.1 %, respectively (P < 0.05). Patients with overexpression, low expression, and no expression of HLA-E exhibited disease-free survival of 55.3, 72.9, and 72.1 %, respectively. Patients with HLA-E overexpression exhibited the lowest long-term survival rate. No relationship was  observed between the type of HLA-E gene polymorphism and its expression level in  tumor tissues; moreover, no polymorphisms appeared to affect the long-term survival of patients with colorectal cancer. The type of HLA-E polymorphism did not have an impact on HLA-E expression in tumors or the prognosis in patients with stage III colorectal cancer. However, the level of HLA-E expression in tumor tissue strongly predicted long-term survival in these patients.

 

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[44]

TÍTULO / TITLE:  - Metformin—an adjunct antineoplastic therapy—divergently modulates tumor metabolism and proliferation, interfering with early response prediction by 18F-FDG PET imaging.

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

REVISTA / JOURNAL:  - J Nucl Med. 2013 Feb;54(2):252-8. doi: 10.2967/jnumed.112.107011.

            ●● Enlace al texto completo (gratuito o de pago) 2967/jnumed.112.107011

AUTORES / AUTHORS:  - Habibollahi P; van den Berg NS; Kuruppu D; Loda M; Mahmood U

INSTITUCIÓN / INSTITUTION:  - Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.

RESUMEN / SUMMARY:  - Over the last several years, epidemiologic data have suggested that the antidiabetes drug metformin (MET), an adenosine monophosphate-activated protein kinase (AMPK) activator, improves progression-free survival of patients with multiple cancers; more than 30 clinical trials are under way to confirm this finding. We postulated that the role of AMPK as a central cellular energy sensor  would result in opposite effects on glucose uptake and proliferation, suggesting  different roles for (18)F-FDG and 3’-deoxy-3’-(18)F-fluorothymidine ((18)F-FLT) in assessing its effectiveness as an antineoplastic agent. METHODS: Colon cancer  cell lines HT29 (human) and MC26 (murine) were treated for 24 or 72 h with a range of MET concentrations (0-10 mM). Western blotting was used to study the activation of AMPK after MET treatment. Glucose uptake and cell proliferation were measured by cell retention studies with either (18)F-FDG or (18)F-FLT. EdU (ethynyl deoxyuridine, a thymidine analog) and annexin-propidium iodide flow cytometry was performed to determine cell cycle S-phase and apoptotic changes. In vivo (18)F-FDG and (18)F-FLT PET images were acquired before and 24 h after MET treatment of HT29 tumor-bearing mice. RESULTS: After 24 h of MET incubation, phosphorylated AMPK levels increased severalfold in both cell lines, whereas total AMPK levels remained unchanged. In cell retention studies, (18)F-FDG uptake increased but (18)F-FLT retention decreased significantly in both cell lines. The numbers of HT29 and MC26 cells in the S phase decreased 36% and 33%, respectively, after MET therapy. Apoptosis increased 10.5-fold and 5.8-fold in HT29 and MC26 cells, respectively, after 72 h of incubation with MET. PET imaging revealed increased (18)F-FDG uptake (mean +/- SEM standardized uptake values were 0.71 +/- 0.03 before and 1.29 +/- 0.11 after MET therapy) (P < 0.05) and decreased (18)F-FLT uptake (mean +/- SEM standardized uptake values were 1.18 +/- 0.05 before and 0.89 +/- 0.01 after MET therapy) (P < 0.05) in HT29 tumor-bearing mice. CONCLUSION: MET, through activation of the AMPK pathway, produces a dose-dependent increase in tumor glucose uptake while decreasing cell proliferation in human and murine colon cancer cells. Thus, changes in (18)F-FDG  uptake after MET treatment may be misleading. (18)F-FLT imaging is a promising alternative that correlates with the tumor response.

 

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[45]

TÍTULO / TITLE:  - Identification of a 24-Gene Prognostic Signature That Improves the European LeukemiaNet Risk Classification of Acute Myeloid Leukemia: An International Collaborative Study.

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

REVISTA / JOURNAL:  - J Clin Oncol. 2013 Mar 20;31(9):1172-81. doi: 10.1200/JCO.2012.44.3184. Epub 2013 Feb 4.

            ●● Enlace al texto completo (gratuito o de pago) 1200/JCO.2012.44.3184

AUTORES / AUTHORS:  - Li Z; Herold T; He C; Valk PJ; Chen P; Jurinovic V; Mansmann U; Radmacher MD; Maharry KS; Sun M; Yang X; Huang H; Jiang X; Sauerland MC; Buchner T; Hiddemann W; Elkahloun A; Neilly MB; Zhang Y; Larson RA; Le Beau MM; Caligiuri MA; Dohner K; Bullinger L; Liu PP; Delwel R; Marcucci G; Lowenberg B; Bloomfield CD; Rowley JD; Bohlander SK; Chen J

INSTITUCIÓN / INSTITUTION:  - Department of Medicine, University of Chicago, 900 E. 57th St, Room 7134, Chicago, IL 60637; jchen@medicine.bsd.uchicago.edu.

RESUMEN / SUMMARY:  - PURPOSE To identify a robust prognostic gene expression signature as an independent predictor of survival of patients with acute myeloid leukemia (AML) and use it to improve established risk classification. PATIENTS AND METHODS Four  independent sets totaling 499 patients with AML carrying various cytogenetic and  molecular abnormalities were used as training sets. Two independent patient sets  composed of 825 patients were used as validation sets. Notably, patients from different sets were treated with different protocols, and their gene expression profiles were derived using different microarray platforms. Cox regression and Kaplan-Meier methods were used for survival analyses. Results A prognostic signature composed of 24 genes was derived from a meta-analysis of Cox regression values of each gene across the four training sets. In multivariable models, a higher sum value of the 24-gene signature was an independent predictor of shorter overall (OS) and event-free survival (EFS) in both training and validation sets (P < .01). Moreover, this signature could substantially improve the European LeukemiaNet (ELN) risk classification of AML, and patients in three new risk groups classified by the integrated risk classification showed significantly (P < .001) distinct OS and EFS. CONCLUSION Despite different treatment protocols applied to patients and use of different microarray platforms for expression profiling, a common prognostic gene signature was identified as an independent predictor of survival of patients with AML. The integrated risk classification incorporating this gene signature provides a better framework for risk stratification and outcome prediction than the ELN classification.

 

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[46]

TÍTULO / TITLE:  - Influence of polymorphisms in genes encoding immunoregulatory proteins and metabolizing enzymes on susceptibility and outcome in patients with diffuse large B-cell lymphoma treated with rituximab.

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

REVISTA / JOURNAL:  - Leuk Lymphoma. 2013 Apr 2.

            ●● Enlace al texto completo (gratuito o de pago) 3109/10428194.2013.774392

AUTORES / AUTHORS:  - Yri OE; Ekstrom PO; Hilden V; Gaudernack G; Liestol K; Smeland EB; Holte H

INSTITUCIÓN / INSTITUTION:  - Division for Surgery and Cancer Medicine, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital , Oslo , Norway.

RESUMEN / SUMMARY:  - We analyzed the allelic distribution of 12 candidate polymorphisms in a large retrospective study of 486 patients with diffuse large B-cell lymphoma (DLBCL) treated at Oslo University Hospital with 1056 blood donors serving as controls. Variants in TNFalpha (rs1800629) (GG vs. AG/AA, p < 0.001) and LTA (rs909253) (AA vs. AG/GG, p = 0.02) and deletions in GSTM1 and GSTT1 (undeleted vs. deleted, p = 0.01 and p = 0.01, respectively) were associated with increased susceptibility of developing DLBCL. IL-10 (rs1800896) variants (GG vs. AG/AA, p = 0.03) were associated with decreased susceptibility. In line with several previous reports,  patients carrying the TNFalpha (rs1800629) A allele treated in the pre-rituximab  era had inferior outcome compared to patients carrying the homozygous GG genotype (p = 0.004, n = 33). However, patients receiving at least one dose of rituximab had equal outcome regardless of their TNFalpha genotype (HR = 0.94, p = 0.79, n = 307). Deletion in GSTM1 was associated with inferior outcome for patients with low International Prognostic Index (IPI) score (p = 0.04). Our findings support the suggestions that polymorphisms in genes encoding immunoregulatory proteins and enzymes that metabolize carcinogens and chemotherapeutic drugs influence DLBCL susceptibility and possibly treatment outcome. The influence of polymorphisms in immunoregulatory genes on outcome in DLBCL should be reevaluated in the rituximab era.

 

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[47]

TÍTULO / TITLE:  - Genetic variability in the multidrug resistance associated protein-1 (ABCC1/MRP1) predicts hematological toxicity in breast cancer patients receiving (neo-)adjuvant chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide  (FEC).

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

REVISTA / JOURNAL:  - Ann Oncol. 2013 Feb 7.

            ●● Enlace al texto completo (gratuito o de pago) 1093/annonc/mdt008

AUTORES / AUTHORS:  - Vulsteke C; Lambrechts D; Dieudonne A; Hatse S; Brouwers B; van Brussel T; Neven P; Belmans A; Schoffski P; Paridaens R; Wildiers H

INSTITUCIÓN / INSTITUTION:  - Department of General Medical Oncology and Laboratory of Experimental Oncology, University Hospitals Leuven, Leuven.

RESUMEN / SUMMARY:  - BackgroundTo assess the impact of single-nucleotide polymorphisms (SNPs) on predefined severe adverse events in breast cancer (BC) patients receiving (neo-)adjuvant 5-fluorouracil (FU), epirubicin and cyclophosphamide (FEC) chemotherapy.Patients and methodsTwenty-six SNPs in 16 genes of interest, including the drug transporter gene ABCC1/MRP1, were selected based on a literature survey. An additional 33 SNPs were selected in these genes, as well as in 12 other genes known to be involved in the metabolism of the studied chemotherapeutics. One thousand and twelve female patients treated between 2000 and 2010 with 3-6 cycles of (neo-)adjuvant FEC were genotyped for these SNPs using Sequenom MassARRAY. Severe adverse events were evaluated through an electronic chart review for febrile neutropenia (FN, primary end point), FN first cycle, prolonged grade 4 or deep (<100/microl) neutropenia, anemia grade 3-4, thrombocytopenia grade 3-4 and non-hematological grade 3-4 events (secondary end  points).ResultsCarriers of the rs4148350 variant T-allele in ABCC1/MRP1 were associated with FN relative to homozygous carriers of the G-allele [P = 0.0006; false discovery rate (FDR) = 0.026]. Strong correlations with secondary end points such as prolonged grade 4 neutropenia (P = 0.002, FDR = 0.046) were also observed. Additionally, two other SNPs in ABCC1/MRP1 (rs45511401 and rs246221) correlated with FN (P = 0.007 and P = 0.01, respectively; FDR = 0.16 and 0.19), as well as two SNPs in UGT2B7 and FGFR4 (P = 0.024 and P = 0.04; FDR = 0.28 and 0.38).ConclusionGenetic variability in ABCC1/MRP1 was associated with severe hematological toxicity of FEC.

 

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[48]

TÍTULO / TITLE:  - Whole blood interferon-gamma levels predict the therapeutic effects of adoptive T-cell therapy in patients with advanced pancreatic cancer.

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

REVISTA / JOURNAL:  - Int J Cancer. 2013 Feb 19. doi: 10.1002/ijc.28117.

            ●● Enlace al texto completo (gratuito o de pago) 1002/ijc.28117

AUTORES / AUTHORS:  - Ishikawa T; Kokura S; Sakamoto N; Okayama T; Endo M; Tsuchiya R; Okajima M; Matsuyama T; Adachi S; Kamada K; Katada K; Uchiyama K; Handa O; Takagi T; Yagi N; Ando T; Uno K; Naito Y; Yoshikawa T

INSTITUCIÓN / INSTITUTION:  - Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan; Department of Cancer ImmunoCell Regulation, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

RESUMEN / SUMMARY:  - A core challenge in administering immune-based treatments for cancer is the establishment of easily accessible immunological assays that can predict patients’ clinical responses to immunotherapy. In this study, our aim was to predict the therapeutic effects of adoptive T-cell therapy in patients with advanced pancreatic cancer. To do this, we evaluated whole blood cytokine levels  and peripheral regulatory T cells (Tregs) in 46 patients with unresectable or recurrent pancreatic cancer who received adoptive T-cell therapy at 2-week intervals. To test immune function, venous blood was obtained from patients before the start of therapy and 2 weeks after the 4th treatment. Whole blood interferon (IFN)-alpha levels (after stimulation with the Sendai virus) were evaluated, as well as the levels of 9 cytokines stimulated with phytohemagglutinin [interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12(p70), IL-13, tumor necrosis factor-alpha, IFN-gamma, and granulocyte-monocyte colony-stimulating factor]. Peripheral Tregs were analyzed by flow cytometry. Using the obtained data, we then observed the relationship between these immunological parameters and clinical outcome of patients. We found that the whole blood production of IFN-gamma, IL-2, IL-4, IL-5 and IL-13 significantly increased after adoptive T-cell therapy, whereas the number of peripheral Tregs did not change. Multivariate Cox proportional hazards analyses indicated that the number of peripheral Tregs before receiving adoptive T-cell therapy and the change in IFN-gamma levels after adoptive T-cell therapy were independent variables predicting overall survival. The findings of this study indicate that the assay of whole blood IFN-gamma production offers promise for evaluating the clinical response of patients to cancer immunotherapy.

 

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[49]

TÍTULO / TITLE:  - Survival in patients with newly diagnosed conventional glioblastoma: a modified prognostic score based on a single-institution series.

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

REVISTA / JOURNAL:  - Tumori. 2012 Nov;98(6):756-61. doi: 10.1700/1217.13500.

            ●● Enlace al texto completo (gratuito o de pago) 1700/1217.13500

AUTORES / AUTHORS:  - Bertolini F; Zunarelli E; Baraldi C; Valentini A; Del Giovane C; Depenni R; Falasca A; Giacobazzi P; Malagoli M; Meletti S; Fontana A; Conte P

INSTITUCIÓN / INSTITUTION:  - Division of Oncology, University Hospital, Via del Pozzo 71, Modena, Italy. bertolini.federica@policlinico.mo.it

RESUMEN / SUMMARY:  - AIMS AND BACKGROUND: Recursive partioning analysis (RPA) is commonly used to define the stratification of patients with glioblastoma. Epigenetic silencing of  the O6-methylguanine methyltransferase (MGMT) gene by promoter methylation plays  an important role in regulating MGMT expression in gliomas and this is an established independent prognostic factor. We tested a prognostic scoring system  including all clinical variables used by RPA classification (age, ECOG performance status and type of surgery) and MGMT gene promoter methylation status. METHODS: Seventy-eight consecutive patients with newly diagnosed, histopathologically confirmed conventional glioblastoma were included. Information about MGMT promoter methylation status was available for all of them. Based on the patients’ age (<50 vs >/=50 years), ECOG performance status (0 vs >/=1), type of surgery (gross tumor resection versus partial resection/biopsy) and MGMT promoter methylation status (methylated versus unmethylated), three classes of risk were generated where the prognostic score was defined assigning 1 point to every favorable parameter (Class I: >/=3; Class II: 2; Class III: 0-1).  All classes were correlated with overall survival. RESULTS: The median survival times were 32.4, 8.6 and 8.8 months for Class I, II and III, respectively, corresponding to 2-year survival rates of 69%, 13.5% and <1%. The same analysis was performed on 54 patients treated with postoperative concomitant chemoradiotherapy. The median survival times were 32.5, 13.4 and 8.9 months for Class I, II and III, respectively, corresponding to 2-year survival rates of 68.6%, 26.9% and <1%. In both groups of 78 and 54 patients the differences in survival between Class I and III were statistically significant ( P <0.0001). CONCLUSIONS: The proposed prognostic scoring system including clinical variables  and MGMT promoter methylation status proved valuable in patients with primary conventional glioblastoma, especially those treated with postoperative chemoradiotherapy.

 

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[50]

TÍTULO / TITLE:  - Re: safety and treatment patterns of angiogenesis inhibitors in patients with metastatic renal cell carcinoma: evidence from US community oncology clinics.

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

REVISTA / JOURNAL:  - J Urol. 2013 Mar;189(3):842. doi: 10.1016/j.juro.2012.11.127. Epub 2012 Nov 21.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.juro.2012.11.127

AUTORES / AUTHORS:  - Penson DF

 

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[51]

TÍTULO / TITLE:  - MYC/BCL2 protein co-expression contributes to the inferior survival of activated  B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program Study.

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

REVISTA / JOURNAL:  - Blood. 2013 Feb 28.

            ●● Enlace al texto completo (gratuito o de pago) 1182/blood-2012-10-460063

AUTORES / AUTHORS:  - Hu S; Xu-Monette ZY; Tzankov A; Green T; Wu L; Balasubramanyam A; Liu WM; Visco C; Li Y; Miranda RN; Montes-Moreno S; Dybkaer K; Chiu A; Orazi A; Zu Y; Bhagat G; Richards KL; Hsi ED; Choi WW; Zhao X; van Krieken JH; Huang Q; Huh J; Ai W; Ponzoni M; Ferreri AJ; Zhou F; Slack GW; Gascoyne RD; Tu M; Variakojis D; Chen W; Go RS; Piris MA; Moller MB; Medeiros LJ; Young KH

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

RESUMEN / SUMMARY:  - Diffuse large B-cell lymphoma (DLBCL) is stratified into prognostically favorable germinal center B-cell (GCB)-like and unfavorable activated B-cell (ABC)-like subtypes according to their gene-expression signatures. In this study, we assessed a cohort of 893 de novo DLBCL patients treated with R-CHOP therapy. We show that MYC/BCL2 protein co-expression occurred significantly more commonly in  the ABC subtype. The ABC and GCB subtypes had similar prognoses in DLBCL with MYC/BCL2 co-expression as well as in DLBCL without MYC/BCL2 co-expression. Consistent with the notion that the prognostic difference between the two subtypes was attributable to MYC/BCL2 co-expression, the difference in gene-expression signatures between the two subtypes was dramatically diminished in the absence of MYC/BCL2 co-expression. Furthermore, DLBCL with MYC/BCL2 co-expression demonstrated a signature of marked downregulation of genes encoding extracellular matrix proteins, those involving matrix deposition/remodeling and cell adhesion, and upregulation of proliferation-associated genes. We conclude that MYC/BCL2 co-expression in DLBCL is associated with an aggressive clinical course, is more common in the ABC subtype, and contributes to the overall inferior prognosis of patients with ABC-DLBCL. Furthermore, the data suggest that MYC/BCL2 co-expression, rather than cell of origin classification, is a better predictor of prognosis in patients with DLBCL treated with R-CHOP therapy.

 

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[52]

TÍTULO / TITLE:  - Azacitidine in the treatment of therapy related myelodysplastic syndrome and acute myeloid leukemia (tMDS/AML): A report on 54 patients by the Groupe Francophone Des Myelodysplasies (GFM).

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

REVISTA / JOURNAL:  - Leuk Res. 2013 Mar 14. pii: S0145-2126(13)00068-4. doi: 10.1016/j.leukres.2013.02.014.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.leukres.2013.02.014

AUTORES / AUTHORS:  - Bally C; Thepot S; Quesnel B; Vey N; Dreyfus F; Fadlallah J; Turlure P; de Botton S; Dartigeas C; de Renzis B; Itzykson R; Fenaux P; Ades L

INSTITUCIÓN / INSTITUTION:  - Groupe Francophone des Myelodysplasies, France; Hopital Avicenne et universite Paris 13, APHP, Bobigny, France.

RESUMEN / SUMMARY:  - The effect of azacitidine (AZA) in therapy related MDS and AML (t-MDS/AML) is not well established. 54 patients (42 t-MDS and 12 t-AML), 71% of whom had complex karyotype, received AZA for at least one cycle (median 4 cycles). The overall response rate (ORR) was 39% in the whole cohort and 62% in patients who received  >/=4 cycles. One, 2 and 3 year OS was 36%, 14% and 8% respectively. Female gender (p=0.01) and ECOG 0-1 (p=0.04) were associated with significantly better OS, while karyotype and marrow blast percentage had no significant impact. By comparison with de novo MDS/AML treated in the same program, t-MDS/AML had a similar response rate (38% vs 45% in de novo MDS/AML, p=0.53), but significantly  shorter OS (2 year OS of 14% vs 33.9%, p=0.0005). However, in a multivariate analysis performed in all patients (de novo and therapy related cases), only complex karyotype and high IPSS, and not etiology (i.e. de novo versus therapy related), had a significant impact on OS. Nine (15%) patients received allogeneic stem cell transplantation, 4 of whom were still alive.

 

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[53]

TÍTULO / TITLE:  - Postoperative-stimulated serum thyroglobulin measured at the time of I ablation is useful for the prediction of disease status in patients with differentiated thyroid carcinoma.

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

REVISTA / JOURNAL:  - Surgery. 2013 Mar 8. pii: S0039-6060(12)00756-8. doi: 10.1016/j.surg.2012.12.008.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.surg.2012.12.008

AUTORES / AUTHORS:  - Lee JI; Chung YJ; Cho BY; Chong S; Seok JW; Park SJ

INSTITUCIÓN / INSTITUTION:  - Department of Internal Medicine, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Korea.

RESUMEN / SUMMARY:  - BACKGROUND: This study was conducted to identify the relevant cutoff value and to evaluate the usefulness of postoperative-stimulated serum thyroglobulin (Tg) at the time of 131I ablation for the prediction of disease status in patients with differentiated thyroid carcinoma (DTC) who received high-dose 131I ablation therapy after total thyroidectomy. METHODS: We analyzed 218 consecutively enrolled patients who were diagnosed with DTC and underwent total thyroidectomy.  All patients underwent 131I ablation at doses of 100-200 mCi, and stimulated serum Tg was measured at the time of 131I ablation therapy. To assess disease-free status after 131I ablation therapy, stimulated serum Tg levels, diagnostic whole-body scan (DxWBS) and neck ultrasonography (US) were performed 6-12 months after 131I ablation. RESULTS: The relevant cutoff value of postoperative stimulated Tg for the prediction of disease-free status was 2 ng/mL. A total of 138 patients (63.3%) showed values of <2 ng/mL. Postoperative-stimulated Tg < 2 ng/mL had a negative predictive value of 94.9%, which increased to 97.7% when low Tg was combined with negative neck US findings. CONCLUSIONS: Postoperative-stimulated Tg at the time of 131I remnant ablation is  a useful biochemical marker for the prediction of disease status in patients with DTC. When high-dose 131I remnant ablation is performed after total thyroidectomy, the stimulated Tg measurement and DxWBS that are usually performed 6-12 months after 131I ablation therapy may be skipped, at least in low- and intermediate-risk patients with postoperative stimulated Tg of < 2 ng/mL and negative neck US findings.

 

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[54]

TÍTULO / TITLE:  - Radiotherapy or tamoxifen after conserving surgery for breast cancers of excellent prognosis: British Association of Surgical Oncology (BASO) II trial.

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

REVISTA / JOURNAL:  - Eur J Cancer. 2013 Mar 21. pii: S0959-8049(13)00163-9. doi: 10.1016/j.ejca.2013.02.031.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ejca.2013.02.031

AUTORES / AUTHORS:  - Blamey RW; Bates T; Chetty U; Duffy SW; Ellis IO; George D; Mallon E; Mitchell MJ; Monypenny I; Morgan DA; Macmillan RD; Patnick J; Pinder SE

INSTITUCIÓN / INSTITUTION:  - Nottingham City Hospital, Hucknall Rd., Nottingham NG5 1PB, United Kingdom.

RESUMEN / SUMMARY:  - BACKGROUND: The incidence of local recurrence (LR) after conservative surgery for early breast cancer without adjuvant therapy is unacceptably high even with favourable tumours. The aim of this study was to examine the effect of adjuvant therapies in tumours with excellent prognostic features. METHODS: Patients with primary invasive breast cancer <2cm diameter, grade 1 or good prognosis special type, and node negative, treated by wide local excision (WLE) with clear margins  were randomised into a 2x2 clinical trial of factorial design with or without radiotherapy and with or without tamoxifen. Trial entry was allowed to either comparison or both. FINDINGS: The actuarial breast cancer specific survival in 1135 randomised patients at 10years was 96%. Analysis by intention to treat showed that LR after WLE was reduced in patients randomised to radiotherapy (RT)  (HR 0.37, CI 0.22-0.61 p<0.001) and to tamoxifen (HR 0.33, CI 0.15 - 0.70 p<0.004). Actuarial analysis of patients entered into the four-way randomisation  showed that LR after WLE alone was 1.9% per annum (PA) versus 0.7% with RT alone  and 0.8% with tamoxifen alone. No patient randomised to both adjuvant treatments  developed LR. Analysis by treatment received showed LR at 2.2%PA for surgery alone versus 0.8% for either adjuvant radiotherapy or tamoxifen and 0.2% for both treatments. CONCLUSIONS: Even in these patients with tumours of excellent prognosis, LR after conservative surgery without adjuvant therapy was still very  high. This was reduced to a similar extent by either radiotherapy or tamoxifen but to a greater extent by the receipt of both treatments.

 

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[55]

TÍTULO / TITLE:  - Differential Contributions of STAT5A and STAT5B to Stress Protection and Tyrosine Kinase Inhibitor Resistance of Chronic Myeloid Leukemia Stem/Progenitor Cells.

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

REVISTA / JOURNAL:  - Cancer Res. 2013 Apr 1;73(7):2052-8. doi: 10.1158/0008-5472.CAN-12-3955. Epub 2013 Feb 11.

            ●● Enlace al texto completo (gratuito o de pago) 1158/0008-5472.CAN-12-3955

AUTORES / AUTHORS:  - Casetti L; Martin-Lanneree S; Najjar I; Plo I; Auge S; Roy L; Chomel JC; Lauret E; Turhan AG; Dusanter-Fourt I

INSTITUCIÓN / INSTITUTION:  - Authors’ Affiliations: Inserm U1016, Institut Cochin; Universite Paris Descartes, Sorbonne Paris Cite, Paris; Inserm U1009, Villejuif; Inserm CIC0802, CHU; and Inserm U935, Universite and CHU, Poitiers, France.

RESUMEN / SUMMARY:  - STAT5 fulfills essential roles in hematopoietic stem cell (HSC) self-renewal and  chronic myeloid leukemia (CML), a prototypical stem cell malignancy. However, the specific contributions of the two related genes STAT5A and STAT5B have not been determined. In this study, we used a RNAi-based strategy to establish participation of these genes to CML disease and persistence following targeted therapy. We showed that STAT5A/STAT5B double-knockdown triggers CML cell apoptosis and suppresses both normal and CML HSC long-term clonogenic potential.  STAT5A and STAT5B exhibited similar prosurvival activity, but STAT5A attenuation  alone was ineffective at impairing growth of normal and CML CD34(+) cells isolated at diagnosis. In contrast, STAT5A attenuation was sufficient to enhance  basal oxidative stress and DNA damage of normal CD34(+) and CML cells. Furthermore, it weakened the ability to manage exogenous oxidative stress, increased p53 (TRP53)/CHK-2 (CHEK2) stress pathway activation, and enhanced prolyl hydroxylase domain (PHD)-3 (EGLN3) mRNA expression. Only STAT5A and its transactivation domain-deficient mutant STAT5ADelta749 specifically rescued these activities. STAT5A attenuation was also active at inhibiting growth of CML CD34(+) cells from patients with acquired resistance to imatinib. Our findings show that STAT5A has a selective role in contributing to stress resistance through unconventional mechanisms, offering new opportunities to eradicate the most primitive and tyrosine kinase inhibitor-resistant CML cells with an additional potential to eradicate persistent stem cell populations. Cancer Res; 73(7); 2052-8. ©2013 AACR.

 

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[56]

TÍTULO / TITLE:  - Large genomic aberrations detected by SNP array are independent prognosticators of a shorter time to first treatment in chronic lymphocytic leukemia patients with normal FISH.

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

REVISTA / JOURNAL:  - Ann Oncol. 2013 Jan 31.

            ●● Enlace al texto completo (gratuito o de pago) 1093/annonc/mds646

AUTORES / AUTHORS:  - Mian M; Rinaldi A; Mensah AA; Rossi D; Ladetto M; Forconi F; Marasca R; Uhr M; Stussi G; Kwee I; Cavalli F; Gaidano G; Zucca E; Bertoni F

INSTITUCIÓN / INSTITUTION:  - Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.

RESUMEN / SUMMARY:  - BackgroundGenomic complexity can predict the clinical course of patients affected by chronic lymphocytic leukemia (CLL) with a normal FISH. However, large studies  are still lacking. Here, we analyzed a large series of CLL patients and also carried out the so far largest comparison of FISH versus single-nucleotide polymorphism (SNP) array in this disease.Patients and methodsSNP-array data were  derived from a previously reported dataset.ResultsSeventy-seven of 329 CLL patients (23%) presented with a normal FISH. At least one large (>5 Mb) genomic aberration was detected by SNP array in 17 of 77 patients (22%); this finding significantly affected TTT. There was no correlation with the presence of TP53 mutations. In multivariate analysis, including age, Binet stage, IGHV genes mutational status and large genomic lesion, the latter three factors emerged as independent prognosticators. The concordance between FISH and SNP array varied between 84 and 97%, depending on the specific genomic locus investigated.ConclusionsSNP array detected additional large genomic aberrations not covered by the standard FISH panel predicting the outcome of CLL patients.

 

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[57]

TÍTULO / TITLE:  - Tyrosinase-related protein 1 mRNA expression in lymph node metastases predicts overall survival in high-risk melanoma patients.

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

REVISTA / JOURNAL:  - Br J Cancer. 2013 Mar 21. doi: 10.1038/bjc.2013.115.

            ●● Enlace al texto completo (gratuito o de pago) 1038/bjc.2013.115

AUTORES / AUTHORS:  - El Hajj P; Journe F; Wiedig M; Laios I; Sales F; Galibert MD; Van Kempen LC; Spatz A; Badran B; Larsimont D; Awada A; Ghanem G

INSTITUCIÓN / INSTITUTION:  - Laboratoire d’Oncologie et de Chirurgie Experimentale, Institut Jules Bordet, Universite Libre de Bruxelles, B1000 Brussels, Belgium.

RESUMEN / SUMMARY:  - Background:Clinical outcome of high-risk melanoma patients is not reliably predicted from histopathological analyses of primary tumours and is often adjusted during disease progression. Our study aimed at extending our previous findings in skin metastases to evaluate the prognostic value of tyrosinase-related protein 1 (TYRP1) in lymph node metastases of stages III and IV melanoma patients.Methods:TYRP1 mRNA expression in 104 lymph node metastases was quantified by real-time PCR and normalised to S100 calcium-binding protein B  (S100B) mRNA expression to correct for tumour load. TYRP1/S100B ratios were calculated and median was used as cutoff value. TYRP1/S100B mRNA values were correlated to clinical follow-up and histopathological characteristics of the primary lesion.Results:A high TYRP1/S100B mRNA ratio significantly correlated with reduced disease-free (DFS) and overall survival (OS; Cox regression analysis, P=0.005 and 0.01, respectively), increased Breslow thickness (Spearman’s rho test, P<0.001) and the presence of ulceration (Mann-Whitney test, P=0.02) of the primaries. Moreover, high TYRP1/S100B was of better prognostic value (lower P-value) for OS than Breslow thickness and ulceration. Finally, it was well conserved during disease progression with respect to high/low TYRP1 groups.Conclusion:High TYRP1/S100B mRNA expression in lymph node metastases from  melanoma patients is associated with unfavourable clinical outcome. Its evaluation in lymph node metastases may refine initial prognosis for metastatic patients, may define prognosis for those with unknown or non-evaluable primary lesions and may allow different management of the two groups of patients.British  Journal of Cancer advance online publication, 21 March 2013; doi:10.1038/bjc.2013.115 www.bjcancer.com.

 

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[58]

TÍTULO / TITLE:  - Androgen receptor expression is a predictive marker in chemotherapy-treated patients with endocrine receptor-positive primary breast cancers.

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

REVISTA / JOURNAL:  - J Cancer Res Clin Oncol. 2013 Feb 8.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00432-013-1382-8

AUTORES / AUTHORS:  - Witzel I; Graeser M; Karn T; Schmidt M; Wirtz R; Schutze D; Rausch A; Janicke F; Milde-Langosch K; Muller V

INSTITUCIÓN / INSTITUTION:  - Department of Gynecology, University Medical Center, Martinistrasse 52, 20246, Hamburg, Germany, iwitzel@uke.de.

RESUMEN / SUMMARY:  - PURPOSE: The androgen receptor (AR) is intensively discussed as a prognostic and/or predictive marker in breast cancer patients. METHODS: We evaluated the value of AR mRNA expression with the Affymetrix HG-U 133A array in 3 different cohorts: a cohort of breast cancer patients who received adjuvant treatment (cohort A; n = 165), a cohort of untreated breast cancer patients (cohort B; n =  200) and a cohort of chemotherapy-treated breast cancer patients with estrogen receptor (ER)-positive tumors (cohort C; n = 223). RESULTS: AR mRNA expression was associated with lower grading (Grades 1 and 2) as well as ER and progesterone receptor (PgR) positivity in all cohorts. In the treated cohort (cohort A), low androgen receptor expression was associated with shorter event-free survival (OR  2,34, 95 % CI 1.01-5.43, p = 0.047) which was not seen in the untreated cohort B. Subgroup analysis revealed that shorter survival of patients with low AR mRNA expression was observed mainly in the ER-positive subgroup of patients treated with adjuvant chemotherapy. In the validation cohort C we could confirm a benefit of chemotherapy for the group of tumors with high AR mRNA expression (5-year event-free survival (EFS) 74 % versus 57 %, p = 0.013). In this cohort, low AR mRNA expression was associated with shorter event-free survival also in multivariate analysis (OR 2.86, 95 % CI 1.29-6.35, p = 0.010) adjusted for HER2,  ki-67, tumor size, age and tumor grade. CONCLUSIONS: We provide evidence that AR  expression is associated with chemotherapy responsiveness in ER-positive patients.

 

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[59]

TÍTULO / TITLE:  - Increased expression of metadherin protein predicts worse disease-free and overall survival in laryngeal squamous cell carcinoma.

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

REVISTA / JOURNAL:  - Int J Cancer. 2013 Jan 30. doi: 10.1002/ijc.28071.

            ●● Enlace al texto completo (gratuito o de pago) 1002/ijc.28071

AUTORES / AUTHORS:  - Liu Y; Su Z; Li G; Yu C; Ren S; Huang D; Fan S; Tian Y; Zhang X; Qiu Y

INSTITUCIÓN / INSTITUTION:  - Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China; Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, Hunan, China.

RESUMEN / SUMMARY:  - Metadherin (MTDH) is involved in tumourigenesis and cancer progression in multiple human malignancies. However, the MTDH protein has rarely been reported in laryngeal squamous cell carcinoma (LSCC). The expression pattern of the MTDH protein in 176 primary archival LSCC and 27 corresponding adjacent noncarcinoma specimens was detected by immunohistochemistry and further correlated with clinicopathological parameters. The results demonstrated that 161 (91.48%) primary LSCC samples stained positive for MTDH; however, staining was barely detectable in all adjacent noncarcinoma samples. Moreover, the expression of the  MTDH protein was significantly associated with the primary tumour site (p = 0.021), T classification (p = 0.002), clinical stage (I + II/III + IV; p < 0.001), lymph node metastasis (p < 0.001) and postoperational recurrence (p < 0.001). Kaplan-Meier analysis revealed that MTDH expression was significantly associated with worse disease-free survival (DFS) and overall survival (OS) rates in patients with LSCC (both p < 0.001). When lymph node metastasis and MTDH expression were considered together, patients with lymph node metastasis and high MTDH expression had both poorer DFS and OS rates than others (both p < 0.001). Finally, multivariate analysis demonstrated that MTDH expression was an independent prognostic factor for both DFS and OS rates in patients with LSCC. Strong MTDH expression was negatively correlated with a canonical epithelial-mesenchymal transition molecule E-cadherin (p < 0.001) and positively  associated with proangiogenic protein vascular endothelial growth factor (p < 0.001). MTDH overexpression was tightly associated with more aggressive tumour behaviour and a poor prognosis, indicating that MTDH is a valuable molecular biomarker for LSCC progression.

 

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[60]

TÍTULO / TITLE:  - Coffee prevents early events in tamoxifen-treated breast cancer patients and modulates hormone receptor status.

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

REVISTA / JOURNAL:  - Cancer Causes Control. 2013 Feb 15.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10552-013-0169-1

AUTORES / AUTHORS:  - Simonsson M; Soderlind V; Henningson M; Hjertberg M; Rose C; Ingvar C; Jernstrom H

INSTITUCIÓN / INSTITUTION:  - Department of Oncology, Clinical Sciences, Lund, Lund University, Barngatan 2B, 22185, Lund, Sweden.

RESUMEN / SUMMARY:  - PURPOSE: Whether coffee modulates response to endocrine therapy in breast cancer  patients is currently unknown. The CYP1A2 and CYP2C8 enzymes contribute to tamoxifen and caffeine metabolism. The purpose was to investigate the impact of coffee consumption on tumor characteristics and risk for early events in relation to breast cancer treatment and CYP1A2 and CYP2C8 genotypes. METHODS: Questionnaires regarding lifestyle were completed preoperatively by 634 patients  in southern Sweden. CYP1A2*1F and CYP2C8*3 were genotyped. Clinical data and tumor characteristics were obtained from patients’ charts, population registries, and pathology reports. Coffee consumption was categorized as low (0-1 cups/day),  moderate (2-4 cups/day), or high (5+ cups/day). RESULTS: The proportion of estrogen receptor negative (ER-) tumors increased with increasing coffee consumption (p (trend) = 0.042). Moderate to high consumption was associated with lower frequency of discordant receptor status (ER + PgR-) OR 0.38 (0.23-0.63) compared to low consumption. Median follow-up time was 4.92 (IQR 3.01-6.42) years. Tamoxifen-treated patients with ER+ tumors (n = 310) who consumed two or more cups/day had significantly decreased risk for early events compared to patients with low consumption, adjusted HR 0.40 (0.19-0.83). Low consumption combined with at least one CYP1A2*1F C-allele (n = 35) or CYP2C8*3 (n = 13) was associated with a high risk for early events in tamoxifen-treated patients compared to other tamoxifen-treated patients, adjusted HRs 3.49 (1.54-7.91) and 6.15 (2.46-15.36), respectively. CONCLUSION: Moderate to high coffee consumption  was associated with significantly decreased risk for early events in tamoxifen-treated patients and modified hormone receptor status. If confirmed, new recommendations regarding coffee consumption during tamoxifen treatment may be warranted.

 

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[61]

TÍTULO / TITLE:  - Lenalidomide in International Prognostic Scoring System Low and Intermediate-1 risk myelodysplastic syndromes with del(5q): an Italian phase II trial of health-related quality of life, safety and efficacy.

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

REVISTA / JOURNAL:  - Leuk Lymphoma. 2013 Mar 27.

            ●● Enlace al texto completo (gratuito o de pago) 3109/10428194.2013.778406

AUTORES / AUTHORS:  - Oliva EN; Latagliata R; Lagana C; Breccia M; Galimberti S; Morabito F; Poloni A; Balleari E; Cortelezzi A; Palumbo G; Sanpaolo G; Volpe A; Specchia G; Finelli C; D’Errigo MG; Roda F; Alati C; Alimena G; Nobile F; Aloe Spiriti MA

INSTITUCIÓN / INSTITUTION:  - “Bianchi-Melacrino-Morelli” Hospital , Reggio Calabria , Italy.

RESUMEN / SUMMARY:  - In lower-risk myelodysplastic syndromes (MDS) with del(5q), lenalidomide induces  erythroid responses associated with better survival. In a phase II, single-arm trial, 45 patients with anemia and lower-risk del(5q) MDS received lenalidomide 10 mg/day to evaluate quality of life (QoL) changes, measured by QOL-E, safety, responses and survival. Lenalidomide was well tolerated, with 80% completing >/=  24 weeks of treatment. Earlier study discontinuation was related to disease progression (n = 5), death (n = 1) and withdrawal of consent (n = 3). Within 24 weeks, 82% obtained erythroid responses, durable in 69% at 52 weeks. Cytogenetic  responses occurred in 29 patients (64%), with 10 patients achieving a complete cytogenetic response. QoL-E scores correlated with hemoglobin levels and improved in erythroid responders. Erythroid responders had an 86% reduced risk of disease  progression and an 80% reduction in mortality risk compared with non-responders.  These findings corroborate earlier studies and give further support to the use of lenalidomide in lower-risk MDS and del(5q).

 

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[62]

TÍTULO / TITLE:  - Phase II Trial Assessing Granulocyte-macrophage-Colony Stimulating Factor, Ketoconazole Plus Mitoxantrone in Metastatic Castration-resistant Prostate Cancer Progressing After Docetaxel Treatments.

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

REVISTA / JOURNAL:  - Cancer Invest. 2013 Mar;31(3):177-82. doi: 10.3109/07357907.2013.764564. Epub 2013 Feb 12.

            ●● Enlace al texto completo (gratuito o de pago) 3109/07357907.2013.764564

AUTORES / AUTHORS:  - Amato RJ; Saxena S; Stepankiw M

INSTITUCIÓN / INSTITUTION:  - The University of Texas Health Science Center at Houston, Department of Internal  Medicine, Division of Oncology , Houston, Texas , USA,1.

RESUMEN / SUMMARY:  - Introduction: This study evaluated objective response and safety for the combination of granulocyte macrophage-colony stimulating factor (GM-CSF), ketoconazole, and mitoxantrone in castration-resistant prostate cancer (CRPC) patients who previously failed docetaxel-based chemotherapy. Methods: Treatment consisted of 400 mg TID ketoconazole, 12 mg/m mitoxantrone every 3 weeks, and 250 mug/m GM-CSF. Results: Twenty-nine patients were evaluable for response. Median overall survival (OS) for all patients was 18.03 months. Patients with a higher PSA decrease experienced an increased OS and progression-free survival (PFS). Conclusion: This combination demonstrated significant antitumor activity with reversible toxicity in CRPC patients who previously failed docetaxel-based therapy.

 

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[63]

TÍTULO / TITLE:  - Predictive factors of response and survival among chronic myelomonocytic leukemia patients treated with azacitidine.

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

REVISTA / JOURNAL:  - Leuk Res. 2013 Feb 12. pii: S0145-2126(13)00018-0. doi: 10.1016/j.leukres.2013.01.004.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.leukres.2013.01.004

AUTORES / AUTHORS:  - Ades L; Sekeres MA; Wolfromm A; Teichman ML; Tiu RV; Itzykson R; Maciejewski JP; Dreyfus F; List AF; Fenaux P; Komrokji RS

INSTITUCIÓN / INSTITUTION:  - Groupe Francophone des Myelodysplasies, France. Electronic address: lionel.ades@avc.aphp.fr.

RESUMEN / SUMMARY:  - Treatment of CMML remains a clinical challenge, with no drug demonstrating clear  clinical benefit. Even if azacitidine is approved in the treatment of CMML, its role remains disputed. We report a cohort of 76 CMML patients (according to WHO classification) treated with azacitidine in 3 programs (French AZA compassionate  program, Cleveland Clinic Foundation and H. Lee Moffitt Cancer Center). 45% had CMML2, and 55% had splenomegaly and/or WBC counts >13G/L, which are known to be poor prognostic factors in CMML. All patients received AZA for at least one cycle, and the median number of cycles administered was 6. Thirty-three patients  (43%) achieved a response according to IWG 2006 criteria, including 13 complete remissions (%). Median survival was 29 months. Increased bone marrow blast percentage and proliferative features of the disease, including splenomegaly and  high WBC counts, were significantly associated with shorter survival. By multivariate analysis, only marrow blasts >10% and palpable splenomegaly had prognostic impact on survival. Although promising, the efficacy of azacitidine in advanced CMML needs to be confirmed in a randomized prospective study.

 

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[64]

TÍTULO / TITLE:  - Cetuximab-activated natural killer and dendritic cells collaborate to trigger tumor antigen-specific T-cell immunity in head and neck cancer patients.

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

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Apr 1;19(7):1858-72. doi: 10.1158/1078-0432.CCR-12-2426. Epub 2013 Feb 26.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-2426

AUTORES / AUTHORS:  - Srivastava RM; Lee SC; Andrade Filho PA; Lord CA; Jie HB; Davidson HC; Lopez-Albaitero A; Gibson SP; Gooding WE; Ferrone S; Ferris RL

INSTITUCIÓN / INSTITUTION:  - Authors’ Affiliations: Departments of Otolaryngology, Surgery, Pathology, and Immunology, University of Pittsburgh; Biostatistics Facility and Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.

RESUMEN / SUMMARY:  - PURPOSE: Tumor antigen-specific monoclonal antibodies (mAb) block oncogenic signaling and induce Fcgamma receptor (FcgammaR)-mediated cytotoxicity. However,  the role of CD8(+) CTL and FcgammaR in initiating innate and adaptive immune responses in mAb-treated human patients with cancer is still emerging. EXPERIMENTAL DESIGN: FcgammaRIIIa codon 158 polymorphism was correlated with survival in 107 cetuximab-treated patients with head and neck cancer (HNC). Flow  cytometry was carried out to quantify EGF receptor (EGFR)-specific T cells in cetuximab-treated patients with HNC. The effect of cetuximab on natural killer (NK) cell, dendritic cell (DC), and T-cell activation was measured using IFN-gamma release assays and flow cytometry. RESULTS: FcgammaRIIIa polymorphism did not predict clinical outcome in cetuximab-treated patients with HNC; however, elevated circulating EGFR853-861-specific CD8(+) T cells were found in cetuximab-treated patients with HNC (P < 0.005). Cetuximab promoted EGFR-specific cellular immunity through the interaction of EGFR(+) tumor cells and FcgammaRIIIa on NK cells but not on the polymorphism per se. Cetuximab-activated NK cells induced IFN-gamma-dependent expression of DC maturation markers, antigen processing machinery components such as TAP-1/2 and T-helper cell (TH1) chemokines through NKG2D/MICA binding. Cetuximab initiated adaptive immune responses via NK cell-induced DC maturation, which enhanced cross-presentation to CTL specific for EGFR as well as another tumor antigen, MAGE-3. CONCLUSION: Cetuximab-activated NK cells promote DC maturation and CD8(+) T-cell priming, leading to tumor antigen spreading and TH1 cytokine release through “NK-DC cross-talk.” FcgammaRIIIa polymorphism did not predict clinical response to cetuximab but was necessary for NK-DC interaction and mAb-induced cross-presentation. EGFR-specific T cells in cetuximab-treated patients with HNC  may contribute to clinical response. Clin Cancer Res; 19(7); 1858-72. ©2013 AACR.

 

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[65]

TÍTULO / TITLE:  - A dose finding, safety and pharmacokinetic study of AVE1642, an anti-insulin-like growth factor-1 receptor (IGF-1R/CD221) monoclonal antibody, administered as a single agent and in combination with docetaxel in patients with advanced solid tumours.

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

REVISTA / JOURNAL:  - Eur J Cancer. 2013 Feb 26. pii: S0959-8049(13)00030-0. doi: 10.1016/j.ejca.2013.01.003.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ejca.2013.01.003

AUTORES / AUTHORS:  - Soria JC; Massard C; Lazar V; Ozoux ML; Mery-Mignard D; Deslandes A; Tolcher AW

INSTITUCIÓN / INSTITUTION:  - Universite Paris XI, SITEP (Service des Innovations Therapeutiques Precoces), Departement de Medecine, Institut Gustave Roussy, Villejuif, France. Electronic address: soria@igr.fr.

RESUMEN / SUMMARY:  - PURPOSE: AVE1642, a humanised mAb, binds the human IGF-1R specifically and with high affinity. This study aimed to select the dose of AVE1642 alone and then combined with docetaxel 75mg/m2 (D). MATERIAL AND METHODS: AVE1642 was administered alone at cycle (cy) 1 and then combined with D from cy2, q3w. RESULTS: A total of 27 patients received a median number of 5 cy (range, 1-10). The most common tumour types were sarcoma (18.5%), osseous tumours (11.1%) and colon cancer (11.1%). Two DLTs were reported in cy1 at dose level (DL) 18mg/kg and dose escalation was stopped. No major safety issue was observed. No anti-drug antibodies were detected. The Maximal Tolerated Dose of AVE1642 was 12mg/kg. The  dose selected for further combinations is 6mg/kg, based on PK/PD data. Three objective responses, (two in sarcoma and one breast cancer) were observed but only one was confirmed. Eleven patients appeared to benefit from treatment with prolonged disease stabilisation 4months. CONCLUSION: AVE1642 is well tolerated as a single agent and combined with D. The selected dose of AVE1642 combined with D  is 6mg/kg. Promising activity was seen in sarcoma and breast cancer patients.

 

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[66]

TÍTULO / TITLE:  - Paradoxical activation and RAF inhibitor resistance of BRAF protein kinase fusions characterizing pediatric astrocytomas.

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

REVISTA / JOURNAL:  - Proc Natl Acad Sci U S A. 2013 Mar 26.

            ●● Enlace al texto completo (gratuito o de pago) 1073/pnas.1219232110

AUTORES / AUTHORS:  - Sievert AJ; Lang SS; Boucher KL; Madsen PJ; Slaunwhite E; Choudhari N; Kellet M; Storm PB; Resnick AC

INSTITUCIÓN / INSTITUTION:  - Division of Oncology, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104.

RESUMEN / SUMMARY:  - Astrocytomas are the most common type of brain tumors in children. Activated BRAF protein kinase mutations are characteristic of pediatric astrocytomas with KIAA1549-BRAF fusion genes typifying low-grade astrocytomas and V600EBRAF alterations characterizing distinct or higher-grade tumors. Recently, BRAF-targeted therapies, such as vemurafenib, have shown great promise in treating V600E-dependent melanomas. Like V600EBRAF, BRAF fusion kinases activate  MAPK signaling and are sufficient for malignant transformation; however, here we  characterized the distinct mechanisms of action of KIAA1549-BRAF and its differential responsiveness to PLX4720, a first-generation BRAF inhibitor and research analog of vemurafenib. We found that in cells expressing KIAA1549-BRAF,  the fusion kinase functions as a homodimer that is resistant to PLX4720 and accordingly is associated with CRAF-independent paradoxical activation of MAPK signaling. Mutagenesis studies demonstrated that KIAA1549-BRAF fusion-mediated signaling is diminished with disruption of the BRAF kinase dimer interface. In addition, the KIAA1549-BRAF fusion displays increased binding affinity to kinase  suppressor of RAS (KSR), an RAF relative recently demonstrated to facilitate MEK  phosphorylation by BRAF. Despite its resistance to PLX4720, the KIAA1549-BRAF fusion is responsive to a second-generation selective BRAF inhibitor that, unlike vemurafenib, does not induce activation of wild-type BRAF. Our data support the development of targeted treatment paradigms for BRAF-altered pediatric astrocytomas and also demonstrate that therapies must be tailored to the specific mutational context and distinct mechanisms of action of the mutant kinase.

 

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[67]

TÍTULO / TITLE:  - Efficacy of goserelin plus anastrozole in premenopausal women with advanced or recurrent breast cancer refractory to an LH-RH analogue with tamoxifen: Results of the JMTO BC08-01 phase II trial.

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

REVISTA / JOURNAL:  - Oncol Rep. 2013 Feb 27. doi: 10.3892/or.2013.2312.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2013.2312

AUTORES / AUTHORS:  - Nishimura R; Anan K; Yamamoto Y; Higaki K; Tanaka M; Shibuta K; Sagara Y; Ohno S; Tsuyuki S; Mase T; Teramukai S

INSTITUCIÓN / INSTITUTION:  - Department of Breast and Endocrine Surgery, Kumamoto City Hospital, Kumamoto 862-8505, Japan.

RESUMEN / SUMMARY:  - The aim of the present study was to assess the efficacy and tolerability of a luteinizing hormone-releasing hormone (LH-RH) analogue plus an aromatase inhibitor following failure to respond to standard LH-RH analogue plus tamoxifen  (TAM) in premenopausal patients. Premenopausal women with estrogen receptor (ER)-positive and/or progesterone-receptor positive, advanced or recurrent breast cancer refractory to an LH-RH analogue plus TAM received goserelin (GOS) in conjunction with anastrozole (ANA). The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR) and safety. Between September 2008 and November 2010, 37 patients were enrolled. Thirty-five patients (94.6%) had ER-positive tumors, and 36 (97.3%) had human epidermal growth factor  receptor (HER) 2-negative tumors. Thirty-six (97.3%) had measurable lesions and 1 (2.7%) had only bone metastasis. The ORR was 18.9% [95% confidence interval (CI), 8.0-35.2%], the CBR was 62.2% (95% CI, 44.8-77.5%) and the median PFS was 7.3 months. Eight patients had adverse drug reactions but none resulted in discontinuation of treatment. GOS plus ANA is a safe effective treatment for premenopausal women with hormone receptor-positive, recurrent or advanced breast  cancer. The treatment may become viable treatment in the future, particularly when TAM is ineffective or contraindicated. Further studies and discussion are warranted.

 

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[68]

TÍTULO / TITLE:  - High levels of bcl-2 protein expression do not correlate with genetic abnormalities but predict worse prognosis in patients with lymphoblastic lymphoma.

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

REVISTA / JOURNAL:  - Tumour Biol. 2013 Mar 14.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s13277-013-0647-9

AUTORES / AUTHORS:  - Gu Y; Pan Y; Meng B; Guan B; Fu K; Sun B; Zheng F

INSTITUCIÓN / INSTITUTION:  - Department of Clinical Immunology, School of Medical Laboratory, Tianjin Medical  University, Tianjin, 300203, China.

RESUMEN / SUMMARY:  - We aimed to investigate bcl-2, bcl-6, and c-myc rearrangements in patients with lymphoblastic lymphoma (LBL), especially focus on the correlation of protein expression with genetic abnormalities. Moreover, their prognostic significance was further analyzed in LBL. Protein expression and genetic abnormalities of bcl-2, bcl-6, and c-myc were investigated in microarrayed tumors from 33 cases of T cell LBL and eight cases of B cell lineage. Immunohistochemical (IHC) staining  was performed to evaluate protein expression, including bcl-2, bcl-6, c-myc, TdT, CD1alpha, CD34, Ki-67, PAX-5, CD2, CD3, CD4, CD8, and CD20. Genetic abnormalities of bcl-2, bcl-6, and c-myc were detected by dual color fluorescence in situ hybridization (FISH). Bcl-2 protein was positive in 51.2 % (21/41) of the patients, bcl-6 protein in 7.3 % (three out of 41), and c-myc protein in 78.0 % (32/41). Bcl-2 breakpoint was found in two cases by FISH analysis. There was no evidence of bcl-6 or c-myc rearrangement in patients with LBL. However, both gene gain and loss events occurred in bcl-2, bcl-6, and c-myc. A univariate analysis showed that stage III or IV, elevated lactate dehydrogenase (LDH), and positivity for bcl-2 protein were associated with shorter survival (p < 0.05). Enhanced protein expression and detectable genetic abnormalities of bcl-2, bcl-6, and c-myc were observed in patients with LBL. No statistical correlation was found between IHC results and cytogenetic findings. Stage III or IV, elevated LDH, and  positivity for bcl-2 protein were identified as adverse prognostic factors. The patients with more adverse factors would have increasingly worse prognosis.

 

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[69]

TÍTULO / TITLE:  - The Influence of MTHFR Gene Polymorphisms on the Outcome of Pediatric Non-Hodgkin Lymphoma Patients Treated with High-Dose Methotrexate.

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

REVISTA / JOURNAL:  - Leuk Lymphoma. 2013 Mar 14.

            ●● Enlace al texto completo (gratuito o de pago) 3109/10428194.2013.784758

AUTORES / AUTHORS:  - D’Angelo V; Ramaglia M; Iannotta A; Francese M; Pota E; Affinita MC; Pecoraro G; Indolfi C; Di Martino M; Di Pinto D; Buffardi S; Poggi V; Indolfi P; Casale F

RESUMEN / SUMMARY:  - Abstract High-dose Methotrexate (MTX) is a key component of most treatment protocols for childhood and adolescent NHL. Recent studies have suggested that the toxicity of antifolate drugs, such as MTX, is affected by inherited single nucleotide polymorphisms (SNPs) in folate metabolising genes. The aim of our study was to investigate the potential influence of the C677T and A1298C genetic  variants of MTHFR on the clinical toxicity and efficacy of MTX in paediatric NHL  patients (n=95) treated with therapeutic protocols AIEOP NHL 97 and EURO LB-02. We demonstrated that patients with the 677T genotype had an approximately 6-fold  greater risk of developing haematological toxicity compared with wild-type carriers, especially in the 1 g/sq m treatment group (p=0.01). Moreover, we identified a correlation between the risk of relapse and the T genotype; T carriers have a reduced DFS compared with wild-type patients (67% vs. 100%). Our  data suggest a pharmacogenetic influence on the adverse effects of high-dose MTX  in the 1 g/sq m treatment group.

 

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[70]

TÍTULO / TITLE:  - Azacitidine as salvage therapy in elderly patients with relapsed acute myeloid leukemia after autologous transplantation.

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

REVISTA / JOURNAL:  - Ann Hematol. 2013 Mar 20.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00277-013-1732-2

AUTORES / AUTHORS:  - Breccia M; Salaroli A; Serrao A; Alimena G

INSTITUCIÓN / INSTITUTION:  - Department of Cellular Biotechnologies and Hematology, Sapienza University, Via Benevento 6, 00161, Rome, Italy, breccia@bce.uniroma1.it.

 

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[71]

TÍTULO / TITLE:  - Effect of the BCL2 Gene Polymorphism on Survival in Advanced-Stage Non-Small Cell Lung Cancer Patients Who Received Chemotherapy.

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

REVISTA / JOURNAL:  - Oncology. 2013;84(4):214-8. doi: 10.1159/000342854. Epub 2013 Jan 24.

            ●● Enlace al texto completo (gratuito o de pago) 1159/000342854

AUTORES / AUTHORS:  - Masago K; Togashi Y; Fujita S; Nagai H; Sakamori Y; Okuda C; Kim YH; Mishima M

INSTITUCIÓN / INSTITUTION:  - Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

RESUMEN / SUMMARY:  - Introduction: This study aimed to evaluate the association between BCL2 single-nucleotide polymorphisms and survival outcome in advanced non-small cell lung cancer (NSCLC). Methods: One hundred and sixty-eight patients with advanced  NSCLC who were treated with anti-cancer drugs and could be evaluated for therapeutic response between April 2005 and March 2010 at Kyoto University Hospital were enrolled. DNA was extracted from peripheral blood samples. The BCL2 polymorphisms -938 C-->A (rs2279115) and +21 A-->G (rs1801018) were genotyped using the 5’-nuclease assay. The univariate relationship between each independent clinicopathologic variable and BCL2 genotype was examined using Fisher’s exact test. To evaluate risk factors associated with prognosis, a Cox proportional hazards regression model with a step-down procedure was used. Results: The median survival time of patients with the -938 AA and AC genotypes were significantly shorter than those with the -938 CC genotype (p = 0.027 by log-rank test). Based  on multivariate analysis, poor performance status [hazard ratio (HR) 2.424, 95% confidence interval (CI) 1.727-3.262; p < 0.0001], non-adenocarcinoma histology (HR 1.512, 95% CI 1.167-1.938; p = 0.0048) and the BCL2 -938 AA + AC genotype (HR 1.219, 95% CI, 1.024-1.456; p = 0.0256) were significant independent prognostic factors for survival. Conclusions: Polymorphisms in BCL2 may be associated with survival in advanced-stage NSCLC patients who received chemotherapy.

 

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[72]

TÍTULO / TITLE:  - Novel Single-Nucleotide Polymorphism Markers Predictive of Pathologic Response to Preoperative Chemoradiation Therapy in Rectal Cancer Patients.

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

REVISTA / JOURNAL:  - Int J Radiat Oncol Biol Phys. 2013 Mar 9. pii: S0360-3016(12)03914-4. doi: 10.1016/j.ijrobp.2012.12.018.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ijrobp.2012.12.018

AUTORES / AUTHORS:  - Kim JC; Ha YJ; Roh SA; Cho DH; Choi EY; Kim TW; Kim JH; Kang TW; Kim SY; Kim YS

INSTITUCIÓN / INSTITUTION:  - Department of Surgery, University of Ulsan College of Medicine, Seoul, Korea; Institute of Innovative Cancer Research and Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea. Electronic address: jckim@amc.seoul.kr.

RESUMEN / SUMMARY:  - PURPOSE: Studies aimed at predicting individual responsiveness to preoperative chemoradiation therapy (CRT) are urgently needed, especially considering the risks associated with poorly responsive patients. METHODS AND MATERIALS: A 3-step strategy for the determination of CRT sensitivity is proposed based on (1) the screening of a human genome-wide single-nucleotide polymorphism (SNP) array in correlation with histopathologic tumor regression grade (TRG); (2) clinical association analysis of 113 patients treated with preoperative CRT; and (3) a cell-based functional assay for biological validation. RESULTS: Genome-wide screening identified 9 SNPs associated with preoperative CRT responses. Positive  responses (TRG 1-3) were obtained more frequently in patients carrying the reference allele © of the SNP CORO2A rs1985859 than in those with the substitution allele (T) (P=.01). Downregulation of CORO2A was significantly associated with reduced early apoptosis by 27% (P=.048) and 39% (P=.023) in RKO and COLO320DM colorectal cancer cells, respectively, as determined by flow cytometry. Reduced radiosensitivity was confirmed by colony-forming assays in the 2 colorectal cancer cells (P=.034 and .015, respectively). The SNP FAM101A rs7955740 was not associated with radiosensitivity in the clinical association analysis. However, downregulation of FAM101A significantly reduced early apoptosis by 29% in RKO cells (P=.047), and it enhanced colony formation in RKO cells (P=.001) and COLO320DM cells (P=.002). CONCLUSION: CRT-sensitive SNP markers were identified using a novel 3-step process. The candidate marker CORO2A rs1985859 and the putative marker FAM101A rs7955740 may be of value for the prediction of radiosensitivity to preoperative CRT, although further validation is needed in large cohorts.

 

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[73]

TÍTULO / TITLE:  - Changes and prognostic impact of apoptotic and inflammatory cytokines in patients treated with cardiac resynchronization therapy.

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

REVISTA / JOURNAL:  - Cardiology. 2013;124(3):190-8. doi: 10.1159/000346621. Epub 2013 Mar 12.

            ●● Enlace al texto completo (gratuito o de pago) 1159/000346621

AUTORES / AUTHORS:  - Osmancik P; Herman D; Stros P; Linkova H; Vondrak K; Paskova E

INSTITUCIÓN / INSTITUTION:  - Cardiocenter, Department of Cardiology, Third Medical School, Charles University  and University Hospital Kralovske Vinohrady Prague, Prague, Czech Republic.

RESUMEN / SUMMARY:  - Objectives: In patients with heart failure, increased apoptosis, inflammation and activation of the transforming growth factor (TGF)-beta cytokine system have been documented. The aim of the present study was to establish (i) whether cytokine concentrations decrease in patients who respond to cardiac resynchronization therapy (CRT), and (ii) whether pre-implant values have any prognostic value. Methods: Eighty-one CRT candidates were prospectively studied. The success of CRT was assessed based on clinical and echocardiographic improvement 6 months after implantation. Mortality was assessed 2 years after implantation. Blood samples were drawn before and 6 months after implantation. Serum concentrations of Fas, TNF-related apoptosis-inducing ligand, tumor necrosis factor (TNF)-alpha, TNF-receptor 1, TGF-beta1 and interleukin (IL)-6 were measured using ELISA. Results: At 6 months, 46 (56.8%) patients were classified as responders and 35 (43.2%) as nonresponders. Neither group differed with respect to baseline characteristics. In responders, the concentrations of IL-6, TNF-alpha and TGF-beta1 decreased significantly. In nonresponders, the concentration of TGF-beta1 even increased significantly. In multivariate analysis, the concentration of TGF-beta1 was a significant predictor of death during follow-up. Conclusions: The response to CRT implantation was associated with a decrease of TGF-beta1, IL-6 and TNF-alpha. Higher pre-implant concentrations of TGF-1beta were independently associated with a poor prognosis in CRT patients.

 

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[74]

TÍTULO / TITLE:  - The predictive value of BRCA1 and RAP80 mRNA expression in advanced non-small-cell lung cancer patients treated with platinum-based chemotherapy.

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

REVISTA / JOURNAL:  - Ann Oncol. 2013 Apr;24(4):1130-2. doi: 10.1093/annonc/mdt063. Epub 2013 Feb 20.

            ●● Enlace al texto completo (gratuito o de pago) 1093/annonc/mdt063

AUTORES / AUTHORS:  - Bonanno L; Costa C; Majem M; Favaretto A; Rugge M; Rosell R

INSTITUCIÓN / INSTITUTION:  - Second Medical Oncology Unit, Istituto Oncologico Veneto IOV-I.R.C.C.S, Padova, Italy.

 

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[75]

TÍTULO / TITLE:  - Early increase in alpha-fetoprotein for predicting unfavorable clinical outcomes  in patients with advanced hepatocellular carcinoma treated with sorafenib.

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

REVISTA / JOURNAL:  - Eur J Gastroenterol Hepatol. 2013 Feb 11.

            ●● Enlace al texto completo (gratuito o de pago) 1097/MEG.0b013e32835d913b

AUTORES / AUTHORS:  - Nakazawa T; Hidaka H; Takada J; Okuwaki Y; Tanaka Y; Watanabe M; Shibuya A; Minamino T; Kokubu S; Koizumi W

INSTITUCIÓN / INSTITUTION:  - aDepartment of Gastroenterology, Internal Medicine, Kitasato University School of Medicine bNakazawa Medical Clinic, Sagamihara cDepartment of Gastroenterology, Juntendo University Nerima Hospital, Tokyo, Japan.

RESUMEN / SUMMARY:  - BACKGROUND: To determine the value of early alterations of the tumor markers alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) for predicting the outcomes of patients with advanced hepatocellular carcinoma (HCC) who receive sorafenib. MATERIALS AND METHODS: Tumor response, overall survival (OS), and progression-free survival (PFS) were retrospectively analyzed in 59 patients with advanced HCC. Serum AFP and DCP were examined for early elevation within 4 weeks  after the initiation of sorafenib. An increase in AFP was defined as AFP of more  than 20%, and an increase in DCP was defined as more than two-fold higher level than the baseline. The relationship of the clinical characteristics, laboratory data at baseline, and early elevations of AFP and DCP with disease progression was analyzed. RESULTS: The median OS and PFS were 11 and 3.3 months, respectively. The rate of progressive disease (PD) was 54%, and an early increase in AFP was significantly related to PD (P=0.006) and was a significant independent predictor of both poorer OS and PFS (P<0.001, hazard ratio, 4.14; 95% confidence interval, 1.946-8.811; and P=0.001, hazard ratio, 2.852; 95% confidence interval, 1.524-5.337, respectively). There was no association between early increase in DCP and clinical outcomes. CONCLUSION: Early increase in AFP predicted PD and poorer survival and may thus be a useful biomarker in patients with advanced HCC who receive sorafenib.

 

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[76]

TÍTULO / TITLE:  - Biomarker results from the AVADO phase 3 trial of first-line bevacizumab plus docetaxel for HER2-negative metastatic breast cancer.

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

REVISTA / JOURNAL:  - Br J Cancer. 2013 Mar 19;108(5):1052-60. doi: 10.1038/bjc.2013.69. Epub 2013 Feb  19.

            ●● Enlace al texto completo (gratuito o de pago) 1038/bjc.2013.69

AUTORES / AUTHORS:  - Miles DW; de Haas SL; Dirix LY; Romieu G; Chan A; Pivot X; Tomczak P; Provencher L; Cortes J; Delmar PR; Scherer SJ

INSTITUCIÓN / INSTITUTION:  - Mount Vernon Cancer Centre, Rickmansworth Road, Northwood, London, HA6 2RN, UK.

RESUMEN / SUMMARY:  - Background:Combining bevacizumab with first-line chemotherapy significantly improves progression-free survival (PFS) in HER2-negative metastatic breast cancer (mBC). However, identification of patients benefitting most from bevacizumab remains elusive. The AVADO trial included an extensive optional exploratory biomarker programme.Methods:Patients with HER2-negative mBC were randomised to receive docetaxel with placebo or bevacizumab. The primary end point was PFS. Plasma samples were analysed using a multiplex ELISA. Blood mRNA expression was assessed using quantitative PCR. Tumour tissue samples were analysed by immunohistochemistry. Single-nucleotide polymorphisms (SNPs) involved in the VEGF pathway were analysed in germline DNA.Results:Samples for biomarker analysis were available from 24-54% of the 736 treated patients (depending on specimen type). The most consistent potential predictive effect was observed with plasma VEGF-A and VEGFR-2; high baseline concentrations were associated with greater treatment effect. Blood mRNA analyses suggested a greater bevacizumab effect in patients with high VEGF121. No consistent predictive effect was seen for tumour neuropilin or other candidate tumour markers by immunohistochemistry,  or for any of the SNPs investigated.Conclusion:Plasma VEGF-A and VEGFR-2 are potential predictive markers for bevacizumab efficacy, supporting findings in gastric and pancreatic cancers. Plasma VEGF-A is being evaluated prospectively in mBC in the MERiDiAN trial.

 

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[77]

TÍTULO / TITLE:  - Clinical response, drug survival and predictors thereof among 548 switchers of tumor necrosis factor alpha inhibitor therapy in psoriatic arthritis. Results from the Danish nationwide DANBIO registry.

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

REVISTA / JOURNAL:  - Arthritis Rheum. 2013 Mar 4. doi: 10.1002/art.37876.

            ●● Enlace al texto completo (gratuito o de pago) 1002/art.37876

AUTORES / AUTHORS:  - Glintborg B; Ostergaard M; Krogh NS; Andersen MD; Tarp U; Loft AG; Lindegaard HM; Holland-Fischer M; Nordin H; Jensen DV; Olsen CH; Hetland ML

INSTITUCIÓN / INSTITUTION:  - Department of Rheumatology, Gentofte University Hospital, Copenhagen, Denmark; The Danish Rheumatologic Database (DANBIO, Denmark. glintborg@dadlnet.dk.

RESUMEN / SUMMARY:  - OBJECTIVE: To describe switch frequencies and outcomes among patients with psoriatic arthritis switching tumor-necrosis-factor-alpha inhibitor (TNFi) treatment in routine care. METHODS: Observational cohort study based on the Danish nationwide DANBIO registry. Treatment outcomes were evaluated by ACR20/50/70-responses, EULAR-good-response and 28-joint Disease Activity Score (DAS28)-remission. Kaplan-Meier and regression analyses were used for drug survival analyses and to identify predictors of outcome after switching. RESULTS: Of 1,422 patients starting TNFi, 548 patients (39%) switched to a second biological drug during up to 10 years’ follow-up. Median follow-up was 2.3 years  (interquartile-range, IQR 1.0-4.3 years). Switchers were more frequently women (56%/45%), had shorter disease duration (3 years/4 years), higher Health Assessment Questionnaire (HAQ) (1.1(0.6-1.6)/0.9(0.5-1.4) (median(IQR))), DAS28 (4.8(4.0-5.7)/4.4(3.6-5.2)), visual-analogue-scale (VAS) pain (65(46-77)/62(40-75)mm) and fatigue scores (67(50-83)/64(42-80)mm) (all p<0.05 at start of first TNFi). During the first and second treatment HAQ, DAS28, CRP and VAS-scores had decreased after 6 months’ (all p<0.05), median drug survivals were 2.2 vs. 1.3 years (p<0.001). Lower fatigue score increased survival of the second TNFi. After switching, the proportions of patients achieving sustained ACR20/ACR50/ACR70/EULAR-good-response/DAS28-remission after 3-6 months were 22% (number-needed-to-treat, NNT 4.5)/13%(7.9)/5%(20)/19%(5.3)/34%(2.9) respectively. Response rates were lower during the second treatment (compared to first TNFi, all p<0.01). At the 2-year visit, 47% of switchers had achieved ACR20 response. No differences between drug-drug combinations were found. CONCLUSION: 39% of psoriatic arthritis patients switched TNFi. Response rates and drug survivals were lower after switching, however, half of switchers had ACR20 response 2 years after starting the first TNFi.

 

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[78]

TÍTULO / TITLE:  - Insulin-like growth factor 1 and musculoskeletal pain among breast cancer patients on aromatase inhibitor therapy and women without a history of cancer.

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

REVISTA / JOURNAL:  - J Cancer Res Clin Oncol. 2013 Feb 14.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00432-013-1391-7

AUTORES / AUTHORS:  - Gallicchio L; Macdonald R; Helzlsouer KJ

INSTITUCIÓN / INSTITUTION:  - The Prevention and Research Center, The Weinberg Center for Women’s Health and Medicine, Mercy Medical Center, 227 St. Paul Place, 6th Floor, Baltimore, MD, 21202, USA, lgallic@mdmercy.com.

RESUMEN / SUMMARY:  - PURPOSE: Musculoskeletal pain is a common side effect of aromatase inhibitors (AIs), the adjuvant hormonal treatment of choice for postmenopausal estrogen-receptor-positive breast cancer. Although the pain is usually attributed to the estrogen depletion associated with AIs, not all women on AIs experience these symptoms. Thus, the goal of this study was to examine whether changes in the insulin-like growth factor (IGF) axis were associated with pain among women initiating AI therapy or a comparison group of women without a history of cancer. METHODS: Data were analyzed from a cohort study of 52 breast cancer patients for  whom AI therapy was planned and 88 women without a history of cancer. Questionnaire data on pain symptoms were collected, and blood was drawn at baseline (prior to AI therapy for patients) and 6 months after baseline. The blood samples were assayed for IGF-1 and IGF-binding protein-3 (IGFBP-3). RESULTS: While results showed no statistically significant changes in any of the  measures across time for either the breast cancer or the comparison group, increases in both IGF-1 concentrations and the IGF-1/IGFBP-3 ratio over the first 6 months of AI treatment were significantly associated with the onset or increase in musculoskeletal pain among the breast cancer patients. Associations between IGF-1, IGFBP-3, and the IGF-1/IGFBP-3 ratio and pain were not observed in the comparison group. CONCLUSIONS: Although preliminary, findings from this study implicate the IGF axis in the development of AI-associated musculoskeletal pain and represent a first step in developing effective interventions to alleviate this side effect.

 

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[79]

TÍTULO / TITLE:  - Temsirolimus combined with sorafenib in hepatocellular carcinoma: a phase I dose-finding trial with pharmacokinetic and biomarker correlates.

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

REVISTA / JOURNAL:  - Ann Oncol. 2013 Mar 21.

            ●● Enlace al texto completo (gratuito o de pago) 1093/annonc/mdt109

AUTORES / AUTHORS:  - Kelley RK; Nimeiri HS; Munster PN; Vergo MT; Huang Y; Li CM; Hwang J; Mulcahy MF; Yeh BM; Kuhn P; Luttgen MS; Grabowsky JA; Stucky-Marshall L; Korn WM; Ko AH; Bergsland EK; Benson AB 3rd; Venook AP

INSTITUCIÓN / INSTITUTION:  - Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco.

RESUMEN / SUMMARY:  - BackgroundBased upon preclinical evidence for improved antitumor activity in combination, this phase I study investigated the maximum-tolerated dose (MTD), safety, activity, pharmacokinetics (PK), and biomarkers of the mammalian target of rapamycin inhibitor, temsirolimus, combined with sorafenib in hepatocellular carcinoma (HCC).Patients and methodsPatients with incurable HCC and Child Pugh score </=B7 were treated with sorafenib plus temsirolimus by 3 + 3 design. The dose-limiting toxicity (DLT) interval was 28 days. The response was assessed every two cycles. PK of temsirolimus was measured in a cohort at MTD.ResultsTwenty-five patients were enrolled. The MTD was temsirolimus 10 mg weekly plus sorafenib 200 mg twice daily. Among 18 patients at MTD, DLT included  grade 3 hand-foot skin reaction (HFSR) and grade 3 thrombocytopenia. Grade 3 or 4 related adverse events at MTD included hypophosphatemia (33%), infection (22%), thrombocytopenia (17%), HFSR (11%), and fatigue (11%). With sorafenib, temsirolimus clearance was more rapid (P < 0.05). Two patients (8%) had a confirmed partial response (PR); 15 (60%) had stable disease (SD). Alpha-fetoprotein (AFP) declined >/=50% in 60% assessable patients.ConclusionThe  MTD of sorafenib plus temsirolimus in HCC was lower than in other tumor types. HCC-specific phase I studies are necessary. The observed efficacy warrants further study.

 

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[80]

TÍTULO / TITLE:  - Significance of bone marrow reticulin fibrosis in chronic lymphocytic leukemia at diagnosis: A study of 176 patients with prognostic implications.

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

REVISTA / JOURNAL:  - Cancer. 2013 Feb 19. doi: 10.1002/cncr.27930.

            ●● Enlace al texto completo (gratuito o de pago) 1002/cncr.27930

AUTORES / AUTHORS:  - Tadmor T; Shvidel L; Aviv A; Ruchlemer R; Bairey O; Yuklea M; Herishanu Y; Braester A; Levene N; Vernea F; Ben-Ezra J; Bejar J; Polliack A

INSTITUCIÓN / INSTITUTION:  - Hematology Unit, Bnai-Zion Medical Center, Haifa, Israel; The Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. tamar.tadmor@b-zion.org.il.

RESUMEN / SUMMARY:  - BACKGROUND: Bone marrow (BM) biopsies from patients with chronic lymphocytic leukemia (CLL) may show reticulin fibrosis at diagnosis, but its significance remains unclear. This study sought to assess the prognostic impact of BM reticulin fibrosis in patients with previously untreated CLL. METHODS: Data was reviewed from untreated CLL patients in the national Israel CLL database, followed during 1987 to 2012. All bone marrow biopsies were graded for reticulin  fibrosis using a modified scoring system containing 4 grades (0-3), based on the  European consensus report. Grade of reticulin fibrosis was correlated with overall survival (OS), outcome, and a number of well-recognized prognostic factors for CLL. RESULTS: The final cohort included 176 patients (122 males and 51 females). Median age was 63 years (range, 32-86 years) and the 5-year OS was 77.1%. Grade of BM reticulin fibrosis correlated with OS (P < .0001) and mortality (P = .001), and separated patients into 2 groups with different survival curves. Advanced reticulin fibrosis (grades 2-3) was associated with thrombocytopenia (platelet counts of < 100,000/mm(3) ) (P = .025), anemia (P = .018), elevated beta2-microglobulin < 4000 mug/mL (P = .048), and the presence of 11q deletion (P = .0015). CONCLUSIONS: There was a significant correlation between poor survival and grade of BM reticulin fibrosis. This staining procedure is easy to perform and can readily be added routinely when examining BM biopsies  in CLL, because the findings do have prognostic implications. Cancer 2013. Esta es una cita bibliográfica que va por delante de la publicación en papel. La fecha indicada en la cita provista, NO corresponde con la fecha o la cita bibliográfica de la publicación en papel. La cita bibliográfica definitiva (con el volumen y su paginación) saldrá en 1 ó 2 meses a partir de la fecha de la emisión electrónica-online. *** This is a bibliographic record ahead of the paper publication. The given date in the bibliographic record does not correspond to the date or the bibliographic citation on the paper publication. The publisher will provide the final bibliographic citation (with the volume, and pagination) within 1 or 2 months from the date the record was published online. © 2013 American Cancer Society.

 

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[81]

TÍTULO / TITLE:  - Genetic basis for the increased expression of vacuolar H(+) translocating ATPase  genes upon imatinib treatment in human lymphoblastoid cells.

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

REVISTA / JOURNAL:  - Cancer Chemother Pharmacol. 2013 Apr;71(4):1095-100. doi: 10.1007/s00280-013-2110-4. Epub 2013 Feb 19.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00280-013-2110-4

AUTORES / AUTHORS:  - Kulkarni H; Goring HH; Curran JE; Diego V; Dyer TD; Cole S; Walder KR; Collier GR; Blangero J; Carless MA

INSTITUCIÓN / INSTITUTION:  - Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, 78227, USA, hkulkarn@txbiomedgenetics.org.

RESUMEN / SUMMARY:  - PURPOSE: The role of v-ATPases in cancer biology is being increasingly recognized. Yeast studies indicate that the tyrosine kinase inhibitor imatinib may interact with the v-ATPase genes and alter the course of cancer progression.  Data from humans in this regard are lacking. METHODS: We constructed 55 lymphoblastoid cell lines from pedigreed, cancer-free human subjects and treated  them with IC20 concentration of imatinib mesylate. Using these cell lines, we (i) estimated the heritability and differential expression of 19 genes encoding several subunits of the v-ATPase protein in response to imatinib treatment; (ii)  estimated the genetic similarity among these genes; and (iii) conducted a high-density scan to find cis-regulating genetic variation associated with differential expression of these genes. RESULTS: We found that the imatinib response of the genes encoding v-ATPase subunits is significantly heritable and can be clustered to identify novel drug targets in imatinib therapy. Further, five of these genes were significantly cis-regulated and together represented nearly half-log fold change in response to imatinib (p = 0.0107) that was homogenous (p = 0.2598). CONCLUSIONS: Our results proffer support to the growing  view that personalized regimens using proton pump inhibitors or v-ATPase inhibitors may improve outcomes of imatinib therapy in various cancers.

 

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[82]

TÍTULO / TITLE:  - Occurrence and current management of side effects in chronic myeloid leukemia patients treated frontline with tyrosine kinase inhibitors.

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

REVISTA / JOURNAL:  - Leuk Res. 2013 Mar 6. pii: S0145-2126(13)00037-4. doi: 10.1016/j.leukres.2013.01.021.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.leukres.2013.01.021

AUTORES / AUTHORS:  - Breccia M; Alimena G

INSTITUCIÓN / INSTITUTION:  - Department of Cellular Biotechnology and Hematology, Sapienza University, Rome, Italy. Electronic address: breccia@bce.uniroma1.it.

RESUMEN / SUMMARY:  - Tyrosine kinase inhibitors (TKIs) represent the gold standard therapy of chronic  myeloid leukemia and, after being used in imatinib resistant patients, dasatinib  and nilotinib are now also used in frontline. In this article, we review data about occurrence of side effects in several trials testing imatinib or second-generation tyrosine kinase inhibitors first line. Literature data about high-dose imatinib used front-line as single treatment or with different combinations is also examined. A literature search for relevant studies was undertaken mainly in PubMed. This review is aimed to summarize the safety of different treatments and to discuss the current management of most common side effects. Literature evidence supports the fact that side effects associated to TKIs seem to differ between agents, but most of side effects reported occur early within the treatment course. Second generation frontline TKIs reduce the incidence of most of side effects reported with imatinib and peculiar events observed are typically manageable through drug dose reduction or treatment interruption.

 

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[83]

TÍTULO / TITLE:  - Raf kinase inhibitor protein expression combined with peritoneal involvement and  lymphovascular invasion predicts prognosis in Dukes’ B colorectal cancer patients.

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

REVISTA / JOURNAL:  - Histopathology. 2013 Feb;62(3):505-10.

AUTORES / AUTHORS:  - Doyle B; Hagan S; Al-Mulla F; Scott L; Harden S; Paul J; Mulcahy H; Murray GI; Sheahan K; O’Sullivan J; Kolch W

INSTITUCIÓN / INSTITUTION:  - Beatson Institute for Cancer Research, Glasgow, UK.

RESUMEN / SUMMARY:  - AIMS: There is controversy regarding the use of adjuvant therapy in patients with Dukes’ B colorectal cancer (CRC). New markers, identifying high-risk Dukes’ B patients, are needed. Here, we examine the utility of Raf kinase inhibitor protein (RKIP) as such a marker and promoter methylation as a mechanism of RKIP down-regulation. METHODS AND RESULTS: We used a tissue microarray of 220 patients with Dukes’ B CRC to examine the effect of RKIP expression on survival. Pyrosequencing was used to assess RKIP promoter methylation status.RKIP expression correlated inversely with disease-specific survival in this cohort. In multivariate analysis, RKIP was found to be an independent prognostic indicator,  along with peritoneal invasion and lymphovascular invasion (LVI). RKIP promoter hypermethylation was seen in only one of 29 tumours analysed by pyrosequencing. CONCLUSIONS: Raf kinase inhibitor protein, peritoneal invasion and LVI provide independent prognostic information in this cohort of Dukes’ B CRC patients.This demonstrates the potential utility of RKIP in identifying ‘high-risk’ Dukes’ B patients. It is this high-risk group which is most likely to benefit from close postoperative monitoring and may derive the most benefit from adjuvant therapy.

 

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[84]

TÍTULO / TITLE:  - Ganitumab with either exemestane or fulvestrant for postmenopausal women with advanced, hormone-receptor-positive breast cancer: a randomised, controlled, double-blind, phase 2 trial.

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

REVISTA / JOURNAL:  - Lancet Oncol. 2013 Mar;14(3):228-35. doi: 10.1016/S1470-2045(13)70026-3. Epub 2013 Feb 13.

            ●● Enlace al texto completo (gratuito o de pago) 1016/S1470-2045(13)70026-3

AUTORES / AUTHORS:  - Robertson JF; Ferrero JM; Bourgeois H; Kennecke H; de Boer RH; Jacot W; McGreivy J; Suzuki S; Zhu M; McCaffery I; Loh E; Gansert JL; Kaufman PA

INSTITUCIÓN / INSTITUTION:  - Royal Derby Hospital, Derby, UK. Electronic address: john.robertson@nottingham.ac.uk.

RESUMEN / SUMMARY:  - BACKGROUND: Insulin-like growth factors (IGF-1 and IGF-2) bind to the IGF-1 receptor (IGF-1R), increasing cell proliferation and survival. Ganitumab is a monoclonal IgG1 antibody that blocks IGF-1R. We tested the efficacy and safety of adding ganitumab to endocrine treatment for patients with hormone-receptor-positive breast cancer. METHODS: We did this phase 2 trial in outpatient clinics and hospitals. We enrolled postmenopausal women with hormone-receptor-positive, locally advanced or metastatic breast cancer previously treated with endocrine treatment. They were randomly assigned (2:1) with a central randomisation schedule to receive intravenous ganitumab 12 mg per  kg bodyweight or placebo in combination with open-label intramuscular fulvestrant (500 mg on day 1, then 250 mg on days 15, 29, and every 28 days) or oral exemestane (25 mg once daily) on a 28-day cycle. Patients, investigators, study monitors, and the sponsor staff were masked to treatment allocation. Response was assessed every 8 weeks. The primary endpoint was median progression-free survival in the intention-to-treat population. We analysed overall survival as one of our  secondary endpoints. The study is registered at ClinicalTrials.gov, number NCT00626106. FINDINGS: We screened 189 patients and enrolled 156 (106 in the ganitumab group and 50 in the placebo group). Median progression-free survival did not differ significantly between the ganitumab and placebo groups (3.9 months, 80% CI 3.6-5.3 vs 5.7 months, 4.4-7.4; hazard ratio [HR] 1.17, 80% CI 0.91-1.50; p=0.44). However, overall survival was worse in the the ganitumab group than in the placebo group (HR 1.78, 80% CI 1.27-2.50; p=0.025). With the exception of hyperglycaemia, adverse events were generally similar between groups. The most common grade 3 or higher adverse event was neutropenia-reported  by six of 106 (6%) patients in the ganitumab group and one of 49 (2%) in the placebo group. Hyperglycaemia was reported by 12 of 106 (11%) patients in the ganitumab group (with six patients having grade 3 or 4 hyperglycaemia) and none of 49 in the placebo group. Serious adverse events were reported by 27 of 106 (25%) patients in the ganitumab group and nine of 49 (18%) patients in the placebo group. INTERPRETATION: Addition of ganitumab to endocrine treatment in women with previously treated hormone-receptor-positive locally advanced or metastatic breast cancer did not improve outcomes. Our results do not support further study of ganitumab in this subgroup of patients. FUNDING: Amgen.

 

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[85]

TÍTULO / TITLE:  - Preoperative Carcinoembryonic Antigen Level Predicts Prognosis in Patients with Pseudomyxoma Peritonei Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

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

REVISTA / JOURNAL:  - World J Surg. 2013 Mar 7.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00268-013-1988-7

AUTORES / AUTHORS:  - Canbay E; Ishibashi H; Sako S; Mizumoto A; Hirano M; Ichinose M; Takao N; Yonemura Y

INSTITUCIÓN / INSTITUTION:  - NPO Organization to Support Peritoneal Dissemination Treatment, 1-26, Harukimotomachi, Kishiwada City, Osaka, 596-0032, Japan, drecanbay@gmail.com.

RESUMEN / SUMMARY:  - BACKGROUND: Even though management of pseudomyxoma peritonei (PMP) was improved with cytoreductive surgery (CRS) and hyperthermic chemotherapy (HIPEC), several aspects of PMP still need to be optimized, including patient selection for surgery and prognostic factors. We assessed the role of preoperative carcinoembryonic antigen (CEA) levels in PMP patients treated with CRS and HIPEC. METHODS: A total of 449 PMP patients with documented preoperative CEA levels referred to our center between 2005 and 2011 underwent CRS and HIPEC. The association between CEA levels and characteristics of patients with PMP was assessed with chi 2 test, linear correlation, and logistic regression analyses. Survival analysis was performed with Cox proportional hazard model. RESULTS: Median age was 55 (range 19-84) years. There were 245 (54.5 %) females and 204 (45.5 %) males. Preoperative CEA levels were elevated in 328 (73 %, sensitivity)  patients with PMP. Preoperative CEA levels were also related to peritoneal cancer index (P < 0.0001), cytoreductive surgery scores (P < 0.0001), progress free survival (P < 0.001) and overall survival (P < 0.001) in patients with PMP. CONCLUSIONS: Our results indicated that preoperative CEA levels are useful in predicting the extent of disease and surgical success as well as progress-free and overall survival in patients with PMP treated with cytoreductive surgery and  HIPEC.

 

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[86]

TÍTULO / TITLE:  - Androgen receptor-induced tumor suppressor, KLLN, inhibits breast cancer growth and transcriptionally activates p53/p73-mediated apoptosis in breast carcinomas.

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

REVISTA / JOURNAL:  - Hum Mol Genet. 2013 Feb 26.

            ●● Enlace al texto completo (gratuito o de pago) 1093/hmg/ddt077

AUTORES / AUTHORS:  - Wang Y; He X; Yu Q; Eng C

INSTITUCIÓN / INSTITUTION:  - Genomic Medicine Institute.

RESUMEN / SUMMARY:  - Androgen receptor (AR) expression by immunohistochemistry correlates with better  prognosis and survival among breast cancer patients. We and others have shown that AR inhibits proliferation and induces apoptosis in breast cancer cells. However, the mechanism of AR’s anti-tumor effect in breast cancer is still not fully understood. Our recent study indicates that AR upregulates expression of tumor suppressor gene PTEN by promoter activation in breast cancer. KLLN, encoding KLLN protein, is a newly identified gene, which shares a bidirectional promoter with PTEN and is transcribed in the opposite direction. So far, the function of KLLN has never been studied in tumorigenesis. Here, we define KLLN as a tumor suppressor in breast carcinomas, which inhibits tumor growth and invasiveness. After analyzing 188 normal breast and 1247 malignant breast cancer  tissues, we observed the loss of KLLN in multiple breast cancer subtypes and this decreased KLLN expression associates with tumor progression and increasing histological grade in invasive carcinomas. We characterize KLLN, for the first time, as a transcription factor, directly promoting the expression of TP53 and TP73, with consequent elevated apoptosis and cell cycle arrest in breast cancer cells. We demonstrate, in vitro and in murine xenograph models, that both KLLN and PTEN are AR-target genes, mediating androgen-induced growth inhibition and apoptosis in breast cancer cells. Our observations suggest that KLLN might be used as a potential prognostic marker and novel therapy target for breast carcinomas.

 

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[87]

TÍTULO / TITLE:  - Risk factors for recurrence after curative resection of hepatitis C-related hepatocellular carcinoma in patients without postoperative interferon therapy.

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

REVISTA / JOURNAL:  - Hepatol Res. 2013 Mar 27. doi: 10.1111/hepr.12091.

            ●● Enlace al texto completo (gratuito o de pago) 1111/hepr.12091

AUTORES / AUTHORS:  - Yamashita YI; Shirabe K; Toshima T; Tsuijita E; Takeishi K; Harimoto N; Ikegami T; Yoshizumi T; Ikeda T; Soejima Y; Maehara Y

INSTITUCIÓN / INSTITUTION:  - Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka; Department of Surgery, Hiroshima Red Cross Hospital and Atomic Bomb Survivors Hospital, Hiroshima, Japan.

RESUMEN / SUMMARY:  - AIM: Hepatitis C (HC)-related hepatocellular carcinoma (HCC; HC-HCC) is highly recurrent. METHODS: From 1995-2007, 183 curative hepatic resections for primary solitary HC-HCC without postoperative interferon therapy were included in this study. The patients were divided into three groups: (i) 2 cm or less (n = 56); (ii) more than 2 cm to less than 5 cm (n = 79); and (iii) 5 cm or more (n = 48).  Independent risk factors for HC-HCC recurrence for each group were determined. RESULTS: Independent risk factors for recurrence were aspartate aminotransferase  or alanine aminotransferase (AST/ALT) of 80 IU/L or more (hazard ratio [HR], 2.1; P = 0.02) in patients with HCC of 2 cm or less, des-gamma-carboxy prothrombin of  100 mAU/mL or more (HR, 2.5; P = 0.02) and AST/ALT of 80 IU/L or more (HR, 2.1; P = 0.04) in patients with HCC of more than 2 cm to less than 5 cm, and the presence of macroscopic portal vein tumor thrombus (HR, 2.8; P = 0.02) and AST/ALT of 80 IU/L or more (HR, 2.1; P = 0.04) in patients with HCC of 5 cm or more. All 13 late recurrences of 1 year or more after hepatic resection (27.1%) in patients with HCC of 5 cm or more were accompanied by AST/ALT of 80 IU/L or more. CONCLUSION: AST/ALT of 80 IU/L or more is an independent risk factor for the recurrence of primary solitary HC-HCC after curative resection irrespective of the primary HC-HCC size.

 

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[88]

TÍTULO / TITLE:  - Impact of global and gene-specific DNA methylation pattern in relapsed multiple myeloma patients treated with bortezomib.

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

REVISTA / JOURNAL:  - Leuk Res. 2013 Feb 7. pii: S0145-2126(13)00027-1. doi: 10.1016/j.leukres.2013.01.013.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.leukres.2013.01.013

AUTORES / AUTHORS:  - Fernandez de Larrea C; Martin-Antonio B; Cibeira MT; Navarro A; Tovar N; Diaz T; Rosinol L; Monzo M; Urbano-Ispizua A; Blade J

INSTITUCIÓN / INSTITUTION:  - Amyloidosis and Myeloma Unit, Department of Hematology, Hospital Clinic, Barcelona, Institut d’Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Jose Carreras Leukaemia Research Institute, University of Barcelona, Barcelona, España.

RESUMEN / SUMMARY:  - We studied seventy-five patients with relapsed MM treated with bortezomib-based regimens. DNA was isolated from bone marrow samples at the time of relapse. Global methylation was determined by ELISA, and CpG island DNA methylation profile of 30 genes by a DNA methylation PCR system. Patients with more than 3.95% of total DNA methylated achieved better overall survival (OS) (p=0.004). A  relatively low methylation percentage (<1.07%) of NFKB1 was also associated with  longer OS after bortezomib treatment (p=0.015). The combination of highly methylated global genome with low NFKB1 methylation status defined a specific subset of patients with better prognosis.

 

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[89]

TÍTULO / TITLE:  - IgG4 subclass antibodies impair antitumor immunity in melanoma.

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

REVISTA / JOURNAL:  - J Clin Invest. 2013 Mar 1. pii: 65579. doi: 10.1172/JCI65579.

            ●● Enlace al texto completo (gratuito o de pago) 1172/JCI65579

AUTORES / AUTHORS:  - Karagiannis P; Gilbert AE; Josephs DH; Ali N; Dodev T; Saul L; Correa I; Roberts L; Beddowes E; Koers A; Hobbs C; Ferreira S; Geh JL; Healy C; Harries M; Acland KM; Blower PJ; Mitchell T; Fear DJ; Spicer JF; Lacy KE; Nestle FO; Karagiannis SN

RESUMEN / SUMMARY:  - Host-induced antibodies and their contributions to cancer inflammation are largely unexplored. IgG4 subclass antibodies are present in IL-10-driven Th2 immune responses in some inflammatory conditions. Since Th2-biased inflammation is a hallmark of tumor microenvironments, we investigated the presence and functional implications of IgG4 in malignant melanoma. Consistent with Th2 inflammation, CD22+ B cells and IgG4+-infiltrating cells accumulated in tumors, and IL-10, IL-4, and tumor-reactive IgG4 were expressed in situ. When compared with B cells from patient lymph nodes and blood, tumor-associated B cells were polarized to produce IgG4. Secreted B cells increased VEGF and IgG4, and tumor cells enhanced IL-10 secretion in cocultures. Unlike IgG1, an engineered tumor antigen-specific IgG4 was ineffective in triggering effector cell-mediated tumor  killing in vitro. Antigen-specific and nonspecific IgG4 inhibited IgG1-mediated tumoricidal functions. IgG4 blockade was mediated through reduction of FcgammaRI  activation. Additionally, IgG4 significantly impaired the potency of tumoricidal  IgG1 in a human melanoma xenograft mouse model. Furthermore, serum IgG4 was inversely correlated with patient survival. These findings suggest that IgG4 promoted by tumor-induced Th2-biased inflammation may restrict effector cell functions against tumors, providing a previously unexplored aspect of tumor-induced immune escape and a basis for biomarker development and patient-specific therapeutic approaches.

 

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[90]

TÍTULO / TITLE:  - Impact of hyperthermic intraperitoneal chemotherapy on Hsp27 protein expression in serum of patients with peritoneal carcinomatosis.

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

REVISTA / JOURNAL:  - Cell Stress Chaperones. 2013 Mar 19.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12192-013-0415-1

AUTORES / AUTHORS:  - Kepenekian V; Aloy MT; Magne N; Passot G; Armandy E; Decullier E; Sayag-Beaujard A; Gilly FN; Glehen O; Rodriguez-Lafrasse C

INSTITUCIÓN / INSTITUTION:  - EMR3738, Faculte de Medecine Lyon-Sud, Universite Lyon 1, BP12 69921, Oullins Cedex, France.

RESUMEN / SUMMARY:  - Despite the strong rationale for combining cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with peritoneal carcinomatosis, thermotolerance and chemoresistance might result from heat shock  protein overexpression. The aim of the present study was thus to determine whether the heat shock protein 27 (Hsp27), a potential factor in resistance to treatment, could have a higher level in serum from patients under this combined therapy. Patients receiving CRS plus HIPEC for peritoneal carcinomatosis (group 1), patients with cancer or a history of cancer undergoing abdominal surgery (group 2), and patients without malignancies undergoing abdominal surgery (group  3) were included. Hsp27 serum levels were determined before and at different times following CRS and HIPEC using enzyme-linked immunosorbent assay. In group 1 (n = 25), the high Hsp27 levels, observed at the end of surgery compared with before (p < 0.0001), decreased during HIPEC, but remained significantly higher than before surgery (p < 0.0005). In groups 2 (n = 11) and 3 (n = 15), surgery did not significantly increase Hsp27 levels. A targeted molecular strategy, inhibiting Hsp27 expression in tumor tissue, could significantly reduce resistance to the combined CRS plus HIPEC treatment. This approach should be further assessed in a clinical phase I trial.

 

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[91]

TÍTULO / TITLE:  - Arf/p53 module, which induces apoptosis, downregulates histone H2AX to allow normal cells to survive in the presence of anti-cancer drugs.

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

REVISTA / JOURNAL:  - J Biol Chem. 2013 Mar 27.

            ●● Enlace al texto completo (gratuito o de pago) 1074/jbc.M112.402560

AUTORES / AUTHORS:  - Atsumi Y; Inase A; Osawa T; Sugihara E; Sakasai R; Fujimori H; Teraoka H; Saya H; Kanno M; Tashiro F; Nakagama H; Masutani M; Yoshioka KI

INSTITUCIÓN / INSTITUTION:  - National Cancer Center, Japan;

RESUMEN / SUMMARY:  - Anti-cancer drugs generally target cancer cells rather than normal somatic cells. However, the factors that determine this differential sensitivity are poorly understood. Here, we show that Arf/p53-dependent downregulation of H2AX induced the selective survival of normal cells after drug treatment, resulting in the preferential targeting of cancer cells. Treatment with camptothecin, a topoisomerase I inhibitor, caused normal cells to downregulate H2AX and become quiescent, a process mediated by both Arf and p53. By contrast, transformed cells that harbor mutations in either Arf or p53 do not downregulate H2AX and are more  sensitive to drugs unless they have developed drug resistance. Such transformation-associated changes in H2AX expression rendered cancer cells more susceptible to drug-induced damage (by two orders of magnitude); thus, the expression of H2AX and gammaH2AX (phosphorylated form of H2AX at S139) is a critical factor that determines drug sensitivity, and should be considered when administering chemotherapy.

 

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[92]

TÍTULO / TITLE:  - ERCC1, defective mismatch repair status as predictive biomarkers of survival for  stage III colon cancer patients receiving oxaliplatin-based adjuvant chemotherapy.

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

REVISTA / JOURNAL:  - Br J Cancer. 2013 Apr 2;108(6):1238-44. doi: 10.1038/bjc.2013.83. Epub 2013 Mar 12.

            ●● Enlace al texto completo (gratuito o de pago) 1038/bjc.2013.83

AUTORES / AUTHORS:  - Li P; Fang YJ; Li F; Ou QJ; Chen G; Ma G

INSTITUCIÓN / INSTITUTION:  - Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China.

RESUMEN / SUMMARY:  - Background:Excision repair cross-complementation group 1 (ERCC1) expression status has been identified as a candidate marker for predicting efficacy of oxaliplatin (OX) treatment for metastatic colorectal cancer (CRC) in several trials. Also, an association between expression of mismatch repair (MMR) genes and favourable postoperative survival in stage II CRC receiving 5-FU chemotherapy has been identified. It is unknown if the expression of ERCC1 protein and MMR status are associated with survival of stage III colon cancer receiving OX-based  chemotherapy.Methods:Immunohistochemistry (IHC) analysis of the expression of MMR and ERCC1 was performed on tumour tissue of 255 patients with stage III colon cancer. In all, 95 patients received fluoropyrimidine-based chemotherapy and 160  patients received OX-based chemotherapy. A predictive model for 5-year disease-free survival (DFS) and overall survival (OS) was constructed using Kaplan-Meier analysis, logistic and Cox regression.Results:Patients who were treated with OX-based therapy with positive ERCC1 tumours had lower 5-year DFS (54%) and OS (60%) than those with negative ERCC1 tumours (72% and 78%, respectively; DFS HR: 1.98, 95% confidence interval (CI): 1.19-3.31, P=0.009; OS  HR: 2.44, 95% CI: 1.37-4.34, P=0.02). Excision repair cross-complementation group 1 status did not impact DFS or OS in fluorouracil group (DFS HR: 1.16, 95% CI: 0.63-2.14, P=0.62; OS HR: 1.16, 95% CI: 0.63-2.14, P=0.63), whereas MMR status had no impact on DFS or OS in either group.Conclusion:Excision repair cross-complementation group 1 status is highly predictive of which patients will  benefit from the addition of OX to 5-FU for stage III colon cancer. Mismatch repair status had no predictive value in this setting.

 

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[93]

TÍTULO / TITLE:  - Refining the UGT1A Haplotype Associated with Irinotecan-Induced Hematological Toxicity in Metastatic Colorectal Cancer Patients Treated with 5-Fluorouracil/Irinotecan-Based Regimens.

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

REVISTA / JOURNAL:  - J Pharmacol Exp Ther. 2013 Apr;345(1):95-101. doi: 10.1124/jpet.112.202242. Epub  2013 Feb 5.

            ●● Enlace al texto completo (gratuito o de pago) 1124/jpet.112.202242

AUTORES / AUTHORS:  - Levesque E; Belanger AS; Harvey M; Couture F; Jonker D; Innocenti F; Cecchin E; Toffoli G; Guillemette C

INSTITUCIÓN / INSTITUTION:  - Canada Research Chair in Pharmacogenomics, Pharmacogenomics Laboratory, CHU de Quebec Research Center, T3-48, 2705 Boul. Laurier, Quebec, Canada, G1V 4G2. Chantal.Guillemette@crchul.ulaval.ca.

RESUMEN / SUMMARY:  - Despite the importance of UDP-glucuronosyltransferase (UGT) 1A1*28 in irinotecan  pharmacogenetics, our capability to predict drug-induced severe toxicity remains  limited. We aimed at identifying novel genetic markers that would improve prediction of irinotecan toxicity and response in advanced colorectal cancer patients treated with folic acid (leucovorin), fluorouracil (5-FU), and irinotecan (camptosar)-based regimens. The relationships between UGT1A candidate  markers across the gene (n = 21) and toxicity were prospectively evaluated in 167 patients. We included variants in the 3’untranscribed region (3’UTR) of the UGT1A locus, not studied in this context yet. These genetic markers were further investigated in 250 Italian FOLFIRI-treated patients. Several functional UGT1A variants, including UGT1A1*28, significantly influenced risk of severe hematologic toxicity. As previously reported in the Italian cohort, a 5-marker risk haplotype [haplotype II (HII); UGTs 1A9/1A7/1A1] was associated with severe  neutropenia in our cohort [odds ratio (OR) = 2.43; P = 0.004]. The inclusion of a 3’UTR single-nucleotide polymorphism (SNP) permitted refinement of the previously defined HI, in which HIa was associated with the absence of severe neutropenia in combined cohorts (OR = 0.55; P = 0.038). Among all tested UGT1A variations and upon multivariate analyses, no UGT1A1 SNPs remained significant, whereas three SNPs located in the central region of UGT1A were linked to neutropenia grade 3-4. Haplotype analyses of these markers with the 3’UTR SNP allowed the identification of a protective HI (OR = 0.50; P = 0.048) and two risk haplotypes, HII and HIII,  characterized by 2 and 3 unfavorable alleles, respectively, revealing a dosage effect (ORs of 2.15 and 5.28; P </= 0.030). Our results suggest that specific SNPs in UGT1A, other than UGT1A1*28, may influence irinotecan toxicity and should be considered to refine pharmacogenetic testing.

 

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[94]

TÍTULO / TITLE:  - Osteopontin gene polymorphisms as predictors for the efficacy of interferon therapy in chronic hepatitis C Egyptian patients with genotype 4.

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

REVISTA / JOURNAL:  - Cell Biochem Funct. 2013 Feb 11. doi: 10.1002/cbf.2954.

            ●● Enlace al texto completo (gratuito o de pago) 1002/cbf.2954

AUTORES / AUTHORS:  - Shaker O; El-Shehaby A; Fayez S; Zahra A; Marzouk S; Raziky ME

INSTITUCIÓN / INSTITUTION:  - Departments of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt.

RESUMEN / SUMMARY:  - This study aimed to determine the relationship between osteopontin gene polymorphisms and its protein level and the efficacy of interferon-based therapies in Hepatitis C virus (HCV) patients. Hundreds HCV patients genotype 4,  treated with pegylated interferon alfa-2b plus ribavirin and 60 healthy subjects  were enrolled. All individuals were subjected to clinical and laboratory parameters, including hepatitis markers and HCV quantitation by real-time polymerase chain reaction. Single nucleotide polymorphisms (SNPs) of osteopontin  (OPN) gene (nucleotide -155, -443 and -1748) were analysed by direct sequencing in addition to estimation of serum level of OPN. SNP at -443 (C/C versus C/T, T/T) was found to represent predictors for treatment response by univariate logistic regression analysis. OPN serum level was independent predictors for treatment response by both univariate and multivariate logistic regression analysis. SNP at nucleotide -443 and serum OPN protein levels could be used as useful markers to predict the efficacy of treatment. Copyright © 2013 John Wiley & Sons, Ltd.

 

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[95]

TÍTULO / TITLE:  - HOXA1 drives melanoma tumor growth and metastasis and elicits an invasion gene expression signature that prognosticates clinical outcome.

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

REVISTA / JOURNAL:  - Oncogene. 2013 Feb 25. doi: 10.1038/onc.2013.30.

            ●● Enlace al texto completo (gratuito o de pago) 1038/onc.2013.30

AUTORES / AUTHORS:  - Wardwell-Ozgo J; Dogruluk T; Gifford A; Zhang Y; Heffernan TP; van Doorn R; Creighton CJ; Chin L; Scott KL

INSTITUCIÓN / INSTITUTION:  - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston,  TX, USA.

RESUMEN / SUMMARY:  - Melanoma is a highly lethal malignancy notorious for its aggressive clinical course and eventual resistance to existing therapies. Currently, we possess a limited understanding of the genetic events driving melanoma progression, and much effort is focused on identifying pro-metastatic aberrations or perturbed signaling networks that constitute new therapeutic targets. In this study, we validate and assess the mechanism by which homeobox transcription factor A1 (HOXA1), a pro-invasion oncogene previously identified in a metastasis screen by  our group, contributes to melanoma progression. Transcriptome and pathway profiling analyses of cells expressing HOXA1 reveals upregulation of factors involved in diverse cytokine pathways that include the transforming growth factor beta (TGFbeta) signaling axis, which we further demonstrate to be required for HOXA1-mediated cell invasion in melanoma cells. Transcriptome profiling also shows HOXA1’s ability to potently downregulate expression of microphthalmia-associated transcription factor (MITF) and other genes required for melanocyte differentiation, suggesting a mechanism by which HOXA1 expression  de-differentiates cells into a pro-invasive cell state concomitant with TGFbeta activation. Our analysis of publicly available data sets indicate that the HOXA1-induced gene signature successfully categorizes melanoma specimens based on their metastatic potential and, importantly, is capable of stratifying melanoma patient risk for metastasis based on expression in primary tumors. Together, these validation data and mechanistic insights suggest that patients whose primary tumors express HOXA1 are among a high-risk metastasis subgroup that should be considered for anti-TGFbeta therapy in adjuvant settings. Moreover, further analysis of HOXA1 target genes in melanoma may reveal new pathways or targets amenable to therapeutic intervention.Oncogene advance online publication, 25 February 2013; doi:10.1038/onc.2013.30.

 

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[96]

TÍTULO / TITLE:  - Quality of life (QoL) analyses from OPTIMAL (CTONG-0802), a phase III, randomised, open-label study of first-line erlotinib versus chemotherapy in patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC).

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

REVISTA / JOURNAL:  - Ann Oncol. 2013 Mar 1.

            ●● Enlace al texto completo (gratuito o de pago) 1093/annonc/mdt012

AUTORES / AUTHORS:  - Chen G; Feng J; Zhou C; Wu YL; Liu XQ; Wang C; Zhang S; Wang J; Zhou S; Ren S; Lu S; Zhang L; Hu CP; Hu C; Luo Y; Chen L; Ye M; Huang J; Zhi X; Zhang Y; Xiu Q; Ma J; Zhang L; You C

INSTITUCIÓN / INSTITUTION:  - Tumor Medicine, The Cancer Hospital of Harbin Medical University, Harbin.

RESUMEN / SUMMARY:  - BackgroundThe OPTIMAL study found that erlotinib improved progression-free survival (PFS) versus standard chemotherapy in Chinese patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC). This report describes  the quality of life (QoL) and updated PFS analyses from this study.Patients and methodsChinese patients >/=18 years with histologically confirmed stage IIIB or IV NSCLC and a confirmed activating mutation of EGFR (exon 19 deletion or exon 21 L858R point mutation) received erlotinib (150 mg/day; n = 82) or gemcitabine-carboplatin (n = 72). The primary efficacy end point was PFS; QoL was assessed using the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire, Trial Outcome Index (TOI) and Lung Cancer Subscale (LCS).ResultsPatients receiving erlotinib experienced clinically relevant improvements in QoL compared with the chemotherapy group in total FACT-L, TOI and LCS (P < 0.0001 for all scales). Erlotinib scored better than chemotherapy for all FACT-L subscales from baseline to cycles 2 and 4 (non-significant). In the updated analysis, PFS was significantly longer for erlotinib than chemotherapy (median PFS 13.7 versus 4.6 months; HR = 0.164, 95% CI = 0.105-0.256; P < 0.0001), which was similar to the previously reported primary analysis.ConclusionErlotinib improves QoL compared with standard chemotherapy in  the first-line treatment of patients with EGFR mutation-positive advanced NSCLC.

 

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[97]

TÍTULO / TITLE:  - Indirubin-3’-monoxime promotes autophagic and apoptotic death in JM1 human acute  lymphoblastic leukemia cells and K562 human chronic myelogenous leukemia cells.

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

REVISTA / JOURNAL:  - Oncol Rep. 2013 Mar 6. doi: 10.3892/or.2013.2334.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2013.2334

AUTORES / AUTHORS:  - Lee MY; Liu YW; Chen MH; Wu JY; Ho HY; Wang QF; Chuang JJ

INSTITUCIÓN / INSTITUTION:  - Department of Hematology and Oncology, Ditmanson Medical Foundation ChiaYi Christian Hospital, Chiayi, Taiwan, R.O.C.

RESUMEN / SUMMARY:  - Indirubin is the active component of Dang gui Long hui Wan, a traditional Chinese herbal medicine used as therapy for chronic myelogenous leukemia (CML). In clinical studies, indirubin seldom caused major side-effects. However, the functional effect of indirubin on acute lymphoblastic leukemia (ALL) is unclear.  Therefore, we investigated the effects of indirubin-3’-monoxime (I3M) on the ALL  cell line JM1 and the CML cell line K562 (control). The anti-leukemia effects and mechanisms of I3M were similar on ALL and CML cells. I3M significantly and dose-dependently decreased cell viability. The G2/M cell cycle phase was arrested and the sub-G1 proportion was relatively increased. In addition, caspase-3 activation led to poly(ADP-ribose) polymerase (PARP)-1 cleavage and the progression of apoptosis. Notably, I3M induced autophagy. However, I3M had no effect on necrosis in either cell line. We specifically found that I3M only marginally affected the survival of primary mature lymphocytes, and was not cytotoxic to granulocytes. Since I3M induced apoptosis and autophagy in human lymphocytic leukemia cells and caused few side-effects in healthy lymphocytes and granulocytes, I3M may be useful for clinical anti-ALL therapy.

 

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[98]

TÍTULO / TITLE:  - In vivo RAF signal transduction as a potential biomarker for sorafenib efficacy in patients with neuroendocrine tumours.

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

REVISTA / JOURNAL:  - Br J Cancer. 2013 Apr 2;108(6):1298-305. doi: 10.1038/bjc.2013.64. Epub 2013 Feb  14.

            ●● Enlace al texto completo (gratuito o de pago) 1038/bjc.2013.64

AUTORES / AUTHORS:  - Quintela-Fandino M; Krzyzanowska M; Duncan G; Young A; Moore MJ; Chen EX; Stathis A; Colomer R; Petronis J; Grewal M; Webster S; Wang L; Siu LL

INSTITUCIÓN / INSTITUTION:  - 1] Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre,  University Health Network, University of Toronto, 610 University Avenue, Suite 5-718, Toronto, Ontario, Canada M5G2M9 [2] CNIO - Spanish National Cancer Research Center Clinical Program, Melchor Fernandez Almagro 3, Madrid 28029, España.

RESUMEN / SUMMARY:  - Background:Targeted therapies elicit anticancer activity by exerting pharmacodynamic effects on specific molecular targets. Currently, there is limited use of pharmacodynamic assessment to guide drug administration in the routine oncology setting.Methods:We developed a phosphoshift (pShift) flow cytometry-based test that measures RAF signal transduction capacity in peripheral blood cells, and evaluated it in a phase II clinical trial of oral sorafenib plus low-dose cyclophosphamide in patients with advanced neuroendocrine tumours (NETs), in order to predict clinical course and/or guide individual dose-titration.Results:Twenty-two patients were enrolled. Median progression-free survival (PFS) was 3 months (95% CI 2-10.7), and one patient had a partial response. PFS was longer among five patients who demonstrated an increase in pShift after 7 days of sorafenib compared with those who did not (14.9 months vs  2.8 months; P=0.047). However, pShift did not add value to toxicity-based dose-titration.Conclusion:The pharmacodynamic assessment of RAF transduction may  identify selected patients with advanced NETs most likely to benefit from the combination of sorafenib plus cyclophosphamide. Further investigation of this test as a potential biomarker is warranted.

 

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[99]

TÍTULO / TITLE:  - Prognosis factors for recurrence in patients with locally advanced rectal cancer  preoperatively treated with chemoradiotherapy and adjuvant chemotherapy.

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

REVISTA / JOURNAL:  - Dis Colon Rectum. 2013 Apr;56(4):416-21. doi: 10.1097/DCR.0b013e318274d9c6.

            ●● Enlace al texto completo (gratuito o de pago) 1097/DCR.0b013e318274d9c6

AUTORES / AUTHORS:  - Arredondo J; Baixauli J; Beorlegui C; Arbea L; Rodriguez J; Sola JJ; Chopitea A; Hernandez-Lizoain JL

INSTITUCIÓN / INSTITUTION:  - 1 Department of General Surgery, Clinica Universidad de Navarra, Pamplona, España  2 Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, España 3 Department of Radiation Oncology, Clinica Universidad  de Navarra, Pamplona, España 4 Department of Medical Oncology, Clinica Universidad de Navarra, Pamplona, España 5 Department of Pathology, Clinica Universidad de Navarra, Pamplona, España.

RESUMEN / SUMMARY:  - BACKGROUND: : Neoadjuvant chemoradiotherapy followed by total mesorectal excision has improved the outcome of locally advanced rectal carcinoma. OBJECTIVE: : The aim of this study was to identify independent prognosis factors of disease recurrence in a group of patients treated with this approach. DESIGN AND PATIENTS: : This study was retrospective in design. Data from patients with locally advanced rectal cancer who had completed treatment from 2000 to 2010 were reviewed. SETTINGS: : The analysis was performed in a tertiary referral center. MAIN OUTCOME MEASURES: : The primary outcomes measured were the recurrence risk factors. RESULTS: : The cohort consisted of 228 patients; 69.3% of them were men, and median age was 59 years. Stage III rectal cancer was found in 64.9% of patients. The most frequently administered therapy was concurrent capecitabine, oxaliplatin, and 7-field radiotherapy, followed by 3-field radiotherapy and fluoropyrimidines. After a median follow-up of 49 months, 23.7% of the patients experienced disease recurrence: 2.6% had local recurrence, 21.1% had distant metastases, and 0.5% had both. Factors significantly correlated with recurrence risk in multivariate logistic regression were y-pathological stage (III vs I/II:  OR = 2.51), tumor regression grade (1/2 vs 3+/4: OR = 3.34; 3 vs 3+/4: OR = 1.20), and low rectal location (OR = 2.36). The only independent prognosis factor for liver metastases was tumor regression grade (1/2 vs 3+/4: OR = 4.67; 3 vs 3+/4: OR = 1.41), whereas tumor regression grade (1-2 vs 3+/4: OR = 5.5; 3 vs 3+/4: OR = 1.84), low rectal location (OR = 3.23), and previous liver metastasis  (OR = 7.73) predicted lung recurrence. LIMITATIONS: : This is a single institutional experience, neoadjuvant combined therapy is not homogeneous, and the analysis has been performed in a retrospective manner. CONCLUSIONS: : Patients with low third locally advanced rectal cancer with a poor response to neoadjuvant chemoradiotherapy (high y-pathological stage or low tumor regression  grade) are at high risk of recurrence. Intense surveillance and the design of alternative therapeutic approaches aimed to lower the distant failure rate seem warranted.

 

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[100]

TÍTULO / TITLE:  - Predictive factors for successful imatinib cessation in chronic myeloid leukemia  patients treated with imatinib.

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

REVISTA / JOURNAL:  - Am J Hematol. 2013 Feb 26. doi: 10.1002/ajh.23427.

            ●● Enlace al texto completo (gratuito o de pago) 1002/ajh.23427

AUTORES / AUTHORS:  - Lee SE; Choi SY; Bang JH; Kim SH; Jang EJ; Byeun JY; Park JE; Jeon HR; Oh YJ; Kim HJ; Kim YK; Park JS; Jeong SH; Kim SH; Zang DY; Oh S; Koo DH; Kim H; Do YR; Kwak JY; Kim JA; Kim DY; Mun YC; Mauro MJ; Kim DW

INSTITUCIÓN / INSTITUTION:  - Cancer Research Institute, The Catholic University of Korea, Seoul, Korea.

RESUMEN / SUMMARY:  - Although recent studies have suggested that cessation of imatinib (IM) in chronic myeloid leukemia patients can be associated with sustained response, further validation is needed to explore predictive factors. In a prospective, multicenter study, chronic phase patients were eligible for cessation of IM therapy after more than 3 years if they had no detectable BCR-ABL1 transcript for at least 2 years. A total of 48 patients with a median age of 47 years (19-74 years) were enrolled. Twenty patients received IM for post-transplant relapse. After a median follow-up of 15.8 months (1.4-28.2 months) after IM discontinuation, nine of the  non-transplant group lost undetectable molecular residual disease (UMRD) and major molecular response (MMR), whereas none of the 20 patients in the transplant group experienced UMRD loss. Probabilities for sustained MMR and UMRD were 64.4%  and 66.3% in the non-transplant group, respectively. Of nine patients re-treated  with IM, eight patients re-achieved MMR at a median of 1.7 months (0.9-2.8 months). Seven of these patients re-achieved UMRD at a median of 5.6 months (2.8-12.1 months). Previous transplantation, IM duration, and UMRD duration were  significantly associated with sustained molecular responses. Our data strongly suggest that immunological control contributes to sustained suppression of residual leukemia cell expansion and that IM can be safely discontinued in patients with post-transplant relapse. Am. J. Hematol., 2013. © 2013 Wiley Periodicals, Inc.

 

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[101]

TÍTULO / TITLE:  - Hyperthermic intraperitoneal chemotherapy in patients with peritoneal carcinomatosis: role of heat shock proteins and dissecting effects of hyperthermia.

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

REVISTA / JOURNAL:  - Ann Surg Oncol. 2013 Apr;20(4):1105-13. doi: 10.1245/s10434-012-2784-6. Epub 2013 Mar 2.

            ●● Enlace al texto completo (gratuito o de pago) 1245/s10434-012-2784-6

AUTORES / AUTHORS:  - Pelz JO; Vetterlein M; Grimmig T; Kerscher AG; Moll E; Lazariotou M; Matthes N; Faber M; Germer CT; Waaga-Gasser AM; Gasser M

INSTITUCIÓN / INSTITUTION:  - Department of Surgery I, University of Wuerzburg, Wuerzburg, Germany.

RESUMEN / SUMMARY:  - BACKGROUND: In patients with isolated peritoneal carcinomatosis (PC) of gastrointestinal cancer, hyperthermic intraperitoneal chemotherapy (HIPEC) represents a promising treatment option integrated into multimodal concepts. Heat shock proteins (HSP) seem to play a major role in cellular stress during HIPEC therapy. We analyzed differentially hyperthermic conditions and HSPs responsible  for cell stress-mediated repair mechanisms in tumor tissues from patients who underwent HIPEC therapy and in an in vitro hyperthermic model. METHODS: Tumor tissues from our patient cohort with isolated PC were selected for further analysis when representative material was available before and after HIPEC therapy. To further dissect the role of HSPs under conditions of hyperthermia, gene and protein expression was additionally determined, together with cellular apoptosis and proliferation in human HT-29 colon cancer cells. RESULTS: Differently up-regulated HSP70/72 and HSP90 gene and protein expression was found in all investigated patient tumors. In vitro studies confirmed observations from  clinical tumor analysis as underlying HSP-mediated cell stress mechanisms. Moreover, results from proliferation and apoptosis assays combined with differentiated HSP expression analysis demonstrated the relevance of preselecting specific target temperatures to achieve optimal toxic effects on remaining tumor  cells in vivo. CONCLUSIONS: Therapeutic approaches like HIPEC to achieve antiproliferative and apoptosis-inducing cellular effects in patients with PC are negatively influenced by highly conserved HSP mechanisms in tumor cells. This study shows for the first time that specific hyperthermic conditions are necessary to be established to achieve optimal toxic effects on tumor cells during HIPEC therapy, a finding that opens potentially new therapeutic strategies.

 

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[102]

TÍTULO / TITLE:  - Phase I Trial of Intravesical Recombinant Adenovirus-Mediated Interferon-alpha2b  Formulated in Syn3 for BCG failures in Non-Muscle-Invasive Bladder Cancer.

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

REVISTA / JOURNAL:  - J Urol. 2013 Mar 15. pii: S0022-5347(13)03676-8. doi: 10.1016/j.juro.2013.03.030.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.juro.2013.03.030

AUTORES / AUTHORS:  - Dinney CP; Fisher MB; Navai N; O’Donnell MA; Cutler D; Abraham A; Young S; Hutchins B; Caceres M; Kishnani N; Soder G; Cullen C; Zhang G; Grossman HB; Kamat AM; Gonzales M; Kincaid M; Ainslie N; Maneval DC; Wszolek MF; Benedict WF

INSTITUCIÓN / INSTITUTION:  - Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX 77030. Electronic address: cdinney@mdanderson.org.

RESUMEN / SUMMARY:  - PURPOSE: A Phase l trial of intravesical recombinant adenovirus-mediated interferon-alpha2b gene therapy (rAd-IFNalpha) formulated with the excipient SCH  Syn3 was conducted in patients with non-muscle invasive bladder cancer (NMIBC) who recurred after Bacillus Calmette-Guerin (BCG). The primary objective was to determine the safety of rAd-IFNalpha/Syn3; secondary endpoints were to demonstrate effective rAd-IFNalpha gene expression and preliminary evidence of clinical activity at three months. PATIENTS AND METHODS: Seventeen patients with  recurrent NMIBC after BCG were enrolled. A single treatment of rAd-IFNalpha (3x109 to 3x1011 particles/mL) formulated with the excipient Syn3 was administered. Patient safety was evaluated for >/=12 weeks. Efficacy of gene transfer was determined by urine IFNalpha protein concentrations. Preliminary drug efficacy was determined at 3 months. RESULTS: Intravesical rAd-IFNalpha/Syn3 was well tolerated as no dose limiting toxicity (DLT) was encountered. Urgency was the most common adverse event and all were grade 1 or 2. rAd-IFNalpha DNA was not detected in the blood, however, transient low serum IFNalpha and Syn3 levels  were measured. High and prolonged dose-related urine IFNalpha levels were achieved with the initial treatment. Of the 14 patients treated at doses >/= 1010 particles/mL with detectable urine IFNalpha, 6 (43%) experienced a complete response at 3 months and 2 remained disease free at 29.0 and 39.2 months respectively. CONCLUSION: Intravesical rAd-IFNalpha/Syn3 was well tolerated with  no DLT encountered. Dose dependent urinary IFNalpha concentrations confirmed efficient gene transfer and expression. Intravesical rAd-IFNalpha/Syn3 demonstrated clinical activity in NMIBC recurring after BCG.

 

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[103]

TÍTULO / TITLE:  - PIK3CA mutation is associated with a favorable prognosis among patients with curatively resected esophageal squamous cell carcinoma.

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

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Mar 26.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-3559

AUTORES / AUTHORS:  - Shigaki H; Baba Y; Watanabe M; Murata A; Ishimoto T; Iwatsuki M; Iwagami S; Nosho K; Baba H

INSTITUCIÓN / INSTITUTION:  - Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University.

RESUMEN / SUMMARY:  - PURPOSE: PIK3CA encodes the catalytic subunit of PI3K, p110alpha. Mutant PIK3CA stimulates the AKT pathway and promotes cancer cell proliferation. PIK3CA mutations have been associated with poor prognosis in patients with colorectal or lung cancer. In contrast, the relationship between PIK3CA mutations and favorable prognoses has been shown in breast cancer. However, the influence of PIK3CA mutations on the prognosis of esophageal squamous cell carcinoma (ESCC) patients  remains unclear. EXPERIMENTAL DESIGN: Using a non-biased database of 219 curatively resected ESCCs and eight esophageal cancer cell lines, we evaluated PIK3CA mutational status by pyrosequencing. The expression of p53 and phosphorylated AKT (i.e., AKT activation) was evaluated by immunohistochemistry.  RESULTS: PIK3CA mutations in exon 9 and/or 20 were detected in 46 cases (21%). No ESCC cell line harbored PIK3CA mutations. PIK3CA mutations were significantly associated with phosphorylated AKT expression, but not with p53 expression, sex,  age at surgery, tobacco use, alcohol use, or histological grade. Compared with wild-type PIK3CA cases, patients with PIK3CA mutations in exons 9 and/or 20 experienced significantly better disease-free survival [log-rank P=0.0089; univariate HR= 0.37, 95% confidence interval (CI) 0.15-0.75, P=0.0042; multivariate HR=0.34, 95% CI 0.10-0.86, P=0.021] and overall survival (log-rank P=0.012; univariate HR=0.38, 95% CI 0.16-0.78, P=0.0060; multivariate HR=0.35, 95% CI 0.10-0.90, P=0.028]. CONCLUSIONS: PIK3CA mutations in ESCC are associated  with longer survival, suggesting its role as a prognostic biomarker. Future studies are needed to confirm this association and to elucidate the exact mechanisms by which PIK3CA mutations affect tumor behavior.

 

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[104]

TÍTULO / TITLE:  - Successful treatment by azacitidine therapy of intestinal Behcet’s disease associated with myelodysplastic syndrome.

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

REVISTA / JOURNAL:  - Int J Hematol. 2013 Mar 22.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12185-013-1316-x

AUTORES / AUTHORS:  - Tanaka H; Shimizu N; Tougasaki E; Kawajiri C; Hashimoto S; Takeda Y; Sakai S; Takeuchi M; Ohwada C; Sakaida E; Takagi T; Nakaseko C

INSTITUCIÓN / INSTITUTION:  - Department of Hematology, Oami Municipal Hospital, 884-1 Tomita, Oamishirasato, Chiba, 299-3221, Japan, hiroakitanaka@oami-hp.jp.

RESUMEN / SUMMARY:  - Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic stem cell diseases. It has been reported that several autoimmune diseases are associated with MDS. Recently, the co-occurrence of MDS with trisomy 8 and rare disorders of the immune system, such as Behcet’s disease (BD), has been described. Prognosis in the older-onset group of MDS-associated BD is unfavorable. Here, we report a case of MDS-associated intestinal BD treated successfully by azacitidine therapy. A 59-year-old Japanese male suffering from recurrent high fever, melena, and oral and genital ulcerations was diagnosed with MDS with trisomy 8 and intestinal BD by endoscopic and bone marrow examinations.  Immunosuppressive therapies, including infliximab, were ineffective. Due to his severe emphysema, the patient was considered ineligible for stem cell transplantation, and azacitidine therapy was initiated. With the exception of fever, the symptoms of intestinal BD improved, and severe malnutrition and anemia were ameliorated. Fluorescence in situ hybridization analyses of the bone marrow  before the eighth cycle revealed that the trisomy 8 had not decreased. To our knowledge, this is the first report of azacitidine therapy for MDS-associated BD. We suggest that azacitidine may control intestinal BD by mechanisms other than those responsible for its effect in MDS.

 

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[105]

TÍTULO / TITLE:  - Hepatic interferon-gamma-induced protein-10 expression is more strongly associated with liver fibrosis than interleukin-28B single nucleotide polymorphisms in hepatocellular carcinoma resected patients with chronic hepatitis C.

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

REVISTA / JOURNAL:  - Hepatol Res. 2013 Jan 14. doi: 10.1111/hepr.12070.

            ●● Enlace al texto completo (gratuito o de pago) 1111/hepr.12070

AUTORES / AUTHORS:  - Konishi H; Shirabe K; Yoshiya S; Ikeda T; Ikegami T; Yoshizumi T; Ikawa-Yoshida A; Motomura T; Fukuhara T; Maehara Y

INSTITUCIÓN / INSTITUTION:  - Departments of Surgery and Science, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan.

RESUMEN / SUMMARY:  - AIM: Single nucleotide polymorphisms (SNP) around IL-28B and interferon (IFN)-stimulated gene (ISG) expression are predictors of response to standard therapy involving IFN for chronic hepatitis C virus (HCV) infection. We analyzed  the association between these predictors to improve the prediction of the response to IFN therapy after liver resection for hepatocellular carcinoma (HCC). METHODS: Data were collected from 74 patients with HCV-induced HCC. The IL-28B genotype and hepatic ISG mRNA levels were analyzed to clarify their association,  focusing on the progression of liver fibrosis. RESULTS: Fifty patients were identified as having major alleles (rs8099917 TT) and the remaining 24 patients had minor alleles (rs8099917 TG or GG). Hepatic ISG15 expression was lower in the IL-28B major group than that in the IL-28B minor group (P < 0.005). IP-10 expression was similar between the IL-28B major and minor groups (P = 0.44). IP-10 expression was elevated with advancing stages of liver fibrosis in HCV infected patients (P = 0.005). In patients with mild or no fibrosis, the IL-28B major group had lower IP-10 expression than the IL-28B minor group (P = 0.02). However, in patients with advanced fibrosis, IP-10 expression was not different between the IL-28B major and minor groups (P = 0.66). CONCLUSION: Hepatic ISG15 expression is associated with IL-28B polymorphisms, while IP-10 is strongly affected by liver fibrosis.

 

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[106]

TÍTULO / TITLE:  - Role of epidermal growth factor receptor inhibitors in epidermal growth factor receptor wild-type non-small-cell lung cancer.

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

REVISTA / JOURNAL:  - J Clin Oncol. 2013 Mar 10;31(8):1061-9. doi: 10.1200/JCO.2012.43.4522. Epub 2013  Feb 11.

            ●● Enlace al texto completo (gratuito o de pago) 1200/JCO.2012.43.4522

AUTORES / AUTHORS:  - Laurie SA; Goss GD

INSTITUCIÓN / INSTITUTION:  - FRCPC, Division of Medical Oncology, Ottawa Hospital Cancer Centre, University of Ottawa, 501 Smyth Rd, Ottawa, Ontario, K1H 8L6, Canada; slaurie@toh.on.ca.

RESUMEN / SUMMARY:  - Worldwide, the majority of patients with advanced non-small-cell lung cancer (NSCLC) do not have activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). These wild-type patients comprise a significant proportion of those treated with inhibitors of this pathway, and data from randomized trials suggest that some of these wild-type patients will derive  a modest benefit from these agents. Although the detection of an activating mutation predicts for a greater likelihood of response and longer progression-free survival from an EGFR tyrosine kinase inhibitor, currently there are no biomarkers that consistently and reproducibly predict for lack of benefit  in wild-type patients. Several strategies to increase the efficacy of these inhibitors in wild-type NSCLC are the subject of ongoing investigations.

 

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[107]

TÍTULO / TITLE:  - A Single Nucleotide Polymorphism in Inflammatory Gene RNASEL Predicts Outcome after Radiation Therapy for Localized Prostate Cancer.

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

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Mar 15;19(6):1612-9. doi: 10.1158/1078-0432.CCR-12-2718. Epub 2013 Feb 4.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-2718

AUTORES / AUTHORS:  - Schoenfeld JD; Margalit DN; Kasperzyk JL; Shui IM; Rider JR; Epstein MM; Meisner A; Kenfield SA; Martin NE; Nguyen PL; Kantoff PW; Giovannucci EL; Stampfer MJ; Mucci LA

INSTITUCIÓN / INSTITUTION:  - Authors’ Affiliations: Harvard Radiation Oncology Program; Brigham and Women’s Hospital; Dana-Farber Cancer Institute; and Harvard School of Public Health, Boston, Massachusetts.

RESUMEN / SUMMARY:  - PURPOSE: To study associations between single nucleotide polymorphisms (SNP) in Ribonuclease L (RNASEL), a gene implicated in inflammation and prostate cancer risk, and outcomes after radiation therapy. EXPERIMENTAL DESIGN: We followed participants in the prospective US Health Professionals Follow-Up Study treated with radiation therapy for early-stage prostate cancer. Three SNPs were genotyped based on previously determined functional and biological significance. We used multivariable Cox proportional hazards models to assess per-allele associations with the primary outcome defined as time to a composite endpoint including development of lethal prostate cancer or biochemical recurrence. RESULTS: We followed 434 patients treated with radiation therapy for a median of 9 years. On  multivariate analysis, the rs12757998 variant allele was associated with significantly decreased risk of the composite endpoint [HR: 0.65; 95% confidence  interval (CI), 0.45-0.94%; P = 0.02] driven by decreased biochemical recurrence (HR: 0.60; 95% CI, 0.40-0.89%; P = 0.01) and men treated with external beam (HR:  0.58; 95% CI, 0.36-0.93%; P = 0.02). In contrast, in 516 men from the same cohort treated with radical prostatectomy, we found no significant impact of this variant on outcome. Furthermore, the rs12757998 variant allele significantly modified the association between androgen deprivation therapy and outcomes after  radiation therapy (p-interaction = 0.02). CONCLUSION: We show an association between RNASEL SNP rs12757998 and outcome after radiation therapy for prostate cancer. This SNP is associated with increased circulating C-reactive protein and  interleukin-6, suggesting a potential role for inflammation in the response to radiation. If validated, genetic predictors of outcome may help inform prostate cancer management. Clin Cancer Res; 19(6); 1612-9. ©2013 AACR.

 

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[108]

TÍTULO / TITLE:  - Ursolic acid in cancer prevention and treatment: molecular targets, pharmacokinetics and clinical studies.

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

REVISTA / JOURNAL:  - Biochem Pharmacol. 2013 Mar 13. pii: S0006-2952(13)00187-1. doi: 10.1016/j.bcp.2013.03.006.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bcp.2013.03.006

AUTORES / AUTHORS:  - Shanmugam MK; Dai X; Kumar AP; Tan BK; Sethi G; Bishayee A

INSTITUCIÓN / INSTITUTION:  - Department of Pharmacology, Yong Loo Lin School of Medicine, National University  of Singapore, Singapore.

RESUMEN / SUMMARY:  - Discovery of bioactive molecules and elucidation of their molecular mechanisms open up an enormous opportunity for the development of improved therapy for different inflammatory diseases, including cancer. Triterpenoids isolated several decades ago from various medicinal plants now seem to have a prominent role in the prevention and therapy of a variety of ailments and some have already entered Phase I clinical trials. One such important and highly investigated pentacyclic triterpenoid, ursolic acid has attracted great attention of late for its potential as a chemopreventive and chemotherapeutic agent in various types of cancer. Ursolic acid has been shown to target multiple proinflammatory transcription factors, cell cycle proteins, growth factors, kinases, cytokines, chemokines, adhesion molecules, and inflammatory enzymes. These targets can potentially mediate the chemopreventive and therapeutic effects of ursolic acid by inhibiting the initiation, promotion and metastasis of cancer. This review not only summarizes the diverse molecular targets of ursolic acid, but also provides  an insight into the various preclinical and clinical studies that have been performed in the last decade with this promising triterpenoid.

 

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[109]

TÍTULO / TITLE:  - MYC rearrangements are useful for predicting outcomes following rituximab and chemotherapy: multicenter analysis of Japanese patients with diffuse large B-cell lymphoma.

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

REVISTA / JOURNAL:  - Leuk Lymphoma. 2013 Mar 8.

            ●● Enlace al texto completo (gratuito o de pago) 3109/10428194.2013.771398

AUTORES / AUTHORS:  - Kojima M; Nishikii H; Takizawa J; Aoki S; Noguchi M; Chiba S; Ando K; Nakamura N

INSTITUCIÓN / INSTITUTION:  - Division of Hematology/Oncology, Department of Internal Medicine.

RESUMEN / SUMMARY:  - Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, and it has several morphologic and clinicopathologic variants. The prognosis of DLBCL can vary according to specific genetic and immunophenotypic abnormalities. The aim of this study was to investigate the prognostic impact of  previously identified prognostic factors, such as activated B cell-like immunophenotype, CD5, BCL2 and MYC rearrangement (MYC-R), in patients treated with rituximab. We retrospectively analyzed the prognosis of 100 patients with DLBCL (median age, 66.5 years) treated with rituximab-containing chemotherapy. The 3-year overall survival (OS) and progression-free survival (PFS) were 66% and 62%. Outcomes were significantly worse in patients with MYC-R in 3-year OS (50% vs. 67.8%, p = 0.043) and PFS (30% vs. 57.8%, p = 0.003), and multivariate analysis showed that this finding was independent of the International Prognostic Index (IPI). Immunostaining by Muris algorithm had the highest predictive power among the three algorithms. However, other previously reported prognostic factors, such as BCL2 and CD5, were not good predictors of outcomes in these patients. In conclusion, our data suggest that fluorescence in situ hybridization (FISH) analysis for MYC-R can predict outcomes in response to rituximab-containing chemotherapy in Japanese patients with DLBCL.

 

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[110]

TÍTULO / TITLE:  - Effect of TP53 codon 72 and MDM2 SNP309 polymorphisms on survival of gastric cancer among patients who receiving 5-fluorouracil-based postoperative adjuvant chemotherapy.

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

REVISTA / JOURNAL:  - Cancer Chemother Pharmacol. 2013 Apr;71(4):1073-82. doi: 10.1007/s00280-013-2103-3. Epub 2013 Feb 20.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00280-013-2103-3

AUTORES / AUTHORS:  - Wang S; Chen L; Zhao Q; Rong H; Wang M; Gong W; Zhou J; Wu D; Zhang Z

INSTITUCIÓN / INSTITUTION:  - Department of Environmental Genomics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, 818 East Tianyuan Road, Nanjing, 211166, China.

RESUMEN / SUMMARY:  - PURPOSE: Several studies have examined the prognostic value of the TP53 Arg72Pro  polymorphism (rs1042522) and/or MDM2 SNP309 (rs2279744) in multiple tumors. Our aim was to determine whether these two genetic variants were correlated with clinical outcome of gastric cancer. METHODS: We genotyped the two SNPs, TP53 codon 72 polymorphism and MDM2 SNP309, in 940 gastric cancer patients with complete follow-up information and analyzed the correlation between the SNPs and  gastric cancer survival. RESULTS: The two SNPs were not significantly associated  with gastric cancer survival. However, the TP53 codon 72 polymorphism had a prominent correlation with clinical outcome of patients receiving 5-fluorouracil  (5-Fu)-based postoperative chemotherapy [Arg/Arg + Arg/Pro vs. Pro/Pro, adjusted  hazard ratio (HR) = 1.63, 95 % confidence interval (CI) = 1.08-2.44]. Moreover, the unfavorable effect of Arg allele on survival outcome was more predominant for subgroups of older (age >60 years), male, intestinal histology type, advanced stage (T3/T4), and none metastasis of lymph node (N0) or distant (M0) (adjusted HR = 2.34, 95 % CI = 1.24-4.44 for age >60 years; 1.72, 1.10-2.69 for male; 2.30, 1.10-4.80 for intestinal; 1.62, 1.01-2.59 for T3/T4; 3.42, 1.26-9.24 for N0; and  1.62, 1.06-2.47 for M0). Among multiple chemotherapy regimens, the association was only significant in the subgroup of 5-Fu/calcium folinate plus oxaliplatin (FOLFOX) chemotherapy regimen (adjusted HR = 4.47, 95 % CI = 1.21-16.55). CONCLUSIONS: Our findings showed that TP53 codon 72 polymorphism was associated with survival of gastric cancer patients treated with 5-Fu-based postoperative chemotherapy. The codon 72 polymorphism may be a potential prognostic factor.

 

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[111]

TÍTULO / TITLE:  - Histone deacetylase inhibitors and pancreatic cancer: Are there any promising clinical trials?

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

REVISTA / JOURNAL:  - World J Gastroenterol. 2013 Feb 28;19(8):1173-81. doi: 10.3748/wjg.v19.i8.1173.

            ●● Enlace al texto completo (gratuito o de pago) 3748/wjg.v19.i8.1173

AUTORES / AUTHORS:  - Koutsounas I; Giaginis C; Theocharis S

INSTITUCIÓN / INSTITUTION:  - Ioannis Koutsounas, Constantinos Giaginis, Stamatios Theocharis, Department of Forensic Medicine and Toxicology, Medical School, University of Athens, GR-11527  Athens, Greece.

RESUMEN / SUMMARY:  - Pancreatic cancer, although not very frequent, has an exceptionally high mortality rate, making it one of the most common causes of cancer mortality in developed countries. Pancreatic cancer is difficult to diagnose, allowing few patients to have the necessary treatment at a relatively early stage. Despite a marginal benefit in survival, the overall response of pancreatic cancer to current systemic therapy continues to be poor, and new therapies are desperately  needed. Histone deacetylase (HDAC) enzymes play an important role in the development and progression of cancer and HDAC inhibitors (HDACIs) have been shown to induce differentiation and cell cycle arrest, activate the extrinsic or  intrinsic pathways of apoptosis, and inhibit invasion, migration and angiogenesis in different cancer cell lines. As a result of promising preclinical data, various HDACIs are being tested as either monotherapeutic agents or in combination regimens for both solid and hematological malignancies. Vorinostat was the first HDACI approved by the Food and Drug Administration for patients with cutaneous T-cell lymphoma. The use of HDACIs in clinical trials, in pretreated and relapsed patients suffering from advanced pancreatic cancer is discussed. Unfortunately, clinical data for HDACIs in patients with pancreatic cancer are inadequate, because only a few studies have included patients suffering from this type of neoplasm and the number of pancreatic cancer patients that entered HDACIs phase II/III trials, among others with advanced solid tumors, is very limited. More studies recruiting patients with pancreatic cancer remain to determine the efficiency of these therapies.

 

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[112]

TÍTULO / TITLE:  - Development and validation of a 32-gene prognostic index for prostate cancer progression.

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

REVISTA / JOURNAL:  - Proc Natl Acad Sci U S A. 2013 Mar 26.

            ●● Enlace al texto completo (gratuito o de pago) 1073/pnas.1215870110

AUTORES / AUTHORS:  - Wu CL; Schroeder BE; Ma XJ; Cutie CJ; Wu S; Salunga R; Zhang Y; Kattan MW; Schnabel CA; Erlander MG; McDougal WS

INSTITUCIÓN / INSTITUTION:  - Departments of Pathology and Urology, Massachusetts General Hospital and Harvard  Medical School, Boston, MA 02114.

RESUMEN / SUMMARY:  - The accurate determination of the risk of cancer recurrence is an important unmet need in the management of prostate cancer. Patients and physicians must weigh the benefits of currently available therapies against the potential morbidity of these treatments. Herein we describe the development of a gene expression-based continuous risk index and a validation of this test in an independent, blinded cohort of post-radical prostatectomy (RP) patients. A gene expression signature,  prognostic for prostate-specific antigen (PSA) recurrence, was identified through a bioinformatic analysis of the expression of 1,536 genes in malignant prostate tissue from a training cohort of consecutive patients treated with RP. The assay  was transferred to a real-time RT-PCR platform, and a continuous risk index model was constructed based on the expression of 32 genes. This 32-gene risk index model was validated in an independent, blinded cohort of 270 RP patients. In multivariate analyses, the risk index was prognostic for risk of PSA recurrence and had added value over standard prognostic markers such as Gleason score, pathologic tumor stage, surgical margin status, and presurgery PSA (hazard ratio, 4.05; 95% confidence interval, 1.50-10.94; P = 0.0057). Furthermore, RP patients  could be stratified based on the risk of PSA recurrence and the development of metastatic disease. The 32-gene signature identified here is a robust prognostic  marker for disease recurrence. This assay may aid in postoperative treatment selection and has the potential to impact decision making at the biopsy stage.

 

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[113]

TÍTULO / TITLE:  - Everolimus in Combination with Exemestane: A Review of its Use in the Treatment of Patients with Postmenopausal Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer.

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

REVISTA / JOURNAL:  - Drugs. 2013 Mar 26.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s40265-013-0034-2

AUTORES / AUTHORS:  - Dhillon S

INSTITUCIÓN / INSTITUTION:  - Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore, 0754, Auckland, New Zealand, demail@springer.com.

RESUMEN / SUMMARY:  - Oral everolimus (Afinitor®) in combination with exemestane is indicated for the treatment of hormone receptor-positive, human epidermal growth factor receptor (HER) 2-negative advanced breast cancer in postmenopausal women after failure of  treatment with letrozole or anastrozole (in the USA) or after recurrence of progression following a nonsteroidal aromatase inhibitor (AI) in women without symptomatic visceral disease (in the EU). Everolimus, a selective inhibitor of mammalian target of rapamycin (mTOR), inhibits the downstream signalling events of the mTOR pathway. This review summarizes the pharmacology of everolimus and reviews its efficacy and tolerability when administered in combination with exemestane in postmenopausal women with oestrogen receptor-positive, HER2-negative advanced breast cancer refractory to nonsteroidal AIs. In the well-designed BOLERO-2 study, the addition of everolimus to exemestane was shown  to significantly prolong progression-free survival in this patient population. However, treatment-emergent adverse events and treatment discontinuations occurred more frequently with combination therapy than with exemestane alone, suggesting a need for careful benefit/risk assessment prior to initiating therapy. Mature survival data from this study are awaited and additional studies  would help to further demonstrate the benefit of combination therapy. Nevertheless, current evidence suggests that everolimus plus exemestane combination therapy may be a useful treatment option in patients with postmenopausal hormone receptor-positive, HER2-negative, advanced breast cancer refractory to nonsteroidal AIs.

 

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[114]

TÍTULO / TITLE:  - “NEDD9 depletion destabilizes Aurora A kinase and heightens the efficacy of Aurora A inhibitors: implications for treatment of metastatic solid tumors.”

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

REVISTA / JOURNAL:  - Cancer Res. 2013 Mar 28.

            ●● Enlace al texto completo (gratuito o de pago) 1158/0008-5472.CAN-12-4008

AUTORES / AUTHORS:  - Ice RJ; McLaughlin SL; Livengood RH; Culp MV; Eddy ER; Ivanov AV; Pugacheva EN

INSTITUCIÓN / INSTITUTION:  - Mary Babb Randolph Cancer Center, West Virginia University School of Medicine.

RESUMEN / SUMMARY:  - Aurora A Kinase (AURKA) is overexpressed in 96% of human cancers and is considered an independent marker of poor prognosis. While the majority of tumors  have elevated levels of AURKA protein, few have AURKA gene amplification, implying that posttranscriptional mechanism regulating AURKA protein levels are significant. Here we show that NEDD9, a known activator of AURKA, is directly involved in AURKA stability. Analysis of a comprehensive breast cancer tissue microarray revealed a tight correlation between the expression of both proteins,  significantly corresponding with increased prognostic value. A decrease in AURKA, concomitant with increased ubiquitination and proteasome-dependent degradation, occurs due to depletion or knockout of NEDD9. Re-expression of wild type NEDD9 was sufficient to rescue the observed phenomenon. Binding of NEDD9 to AURKA is critical for AURKA stabilization, as mutation of S296E was sufficient to disrupt  binding and led to reduced AURKA protein levels. NEDD9 confers AURKA stability by limiting the binding of the cdh1-substrate recognition subunit of APC/C ubiquitin ligase to AURKA. Depletion of NEDD9 in tumor cells increases sensitivity to AURKA inhibitors. Combination therapy with NEDD9 shRNAs and AURKA inhibitors impairs tumor growth and distant metastasis in mice harboring xenografts of breast tumors. Collectively, our findings provide rationale for the use of AURKA inhibitors in treatment of metastatic tumors and predict the sensitivity of the patients to AURKA inhibitors based on NEDD9 expression.

 

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[115]

TÍTULO / TITLE:  - The predictive value of soluble biomarkers (CD14 subtype, interleukin-2 receptor, human leucocyte antigen-G) and procalcitonin in the detection of bacteremia and sepsis in pediatric oncology patients with chemotherapy-induced febrile neutropenia.

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

REVISTA / JOURNAL:  - Cytokine. 2013 Apr;62(1):34-7. doi: 10.1016/j.cyto.2013.02.030. Epub 2013 Mar 17.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.cyto.2013.02.030

AUTORES / AUTHORS:  - Urbonas V; Eidukaite A; Tamuliene I

INSTITUCIÓN / INSTITUTION:  - National Research Institute, Center for Innovative Medicine, Department of Immunology, Moletu pl. 29, LT-08409 Vilnius, Lithuania; Klaipeda University Hospital, Diagnostic Department, Molecular Diagnostic Laboratory, Lithuania. Electronic address: v.urbonas@kul.lt.

RESUMEN / SUMMARY:  - BACKGROUND: Prediction of bacteremia/sepsis in childhood oncology patients with febrile neutropenia still remains a challenge for the medical community due to the lack of reliable biomarkers, especially at the beginning of infectious process. The objective of this study was to evaluate diagnostic value of soluble  biomarkers (CD14 subtype, interleukin-2 receptor, HLA-G) and procalcitonin (PCT)  in the identification of infectious process at the beginning of a febrile episode in pediatric oncology patients. METHODS: A total of 62 episodes of febrile neutropenia in 37 childhood oncology patients were enrolled in this study. Serum  samples were collected at presentation after confirmation of febrile neutropenia  and analyzed according to recommendations of manufacturers. Patients were classified into bacteremia/sepsis and fever of unknown origin groups. RESULTS: Median of PCT and sIL-2R were considerably higher in bacteremia/sepsis group compared to fever of unknown origin group, whereas median of sHLA-G and presepsin levels between investigated groups did not differ sufficiently. CONCLUSIONS: PCT  and sIL-2R determination might be used as an additional diagnostic tool for the detection of bacteremia/sepsis in childhood oncology patients with febrile neutropenia.

 

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[116]

TÍTULO / TITLE:  - Restoration of Mannose-Binding Lectin Complement Activity Is Associated With Improved Outcome in Patients With Advanced Pancreatic Cancer Treated With Gemcitabine and Intravenous omega-3 Fish Oil.

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

REVISTA / JOURNAL:  - JPEN J Parenter Enteral Nutr. 2013 Feb 19.

            ●● Enlace al texto completo (gratuito o de pago) 1177/0148607113476304

AUTORES / AUTHORS:  - Arshad A; Chung W; Isherwood J; Steward W; Metcalfe M; Dennison A

INSTITUCIÓN / INSTITUTION:  - Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, Leicester, UK.

RESUMEN / SUMMARY:  - Background: Pancreatic cancer has an extremely poor clinical outcome. Surrogate biomarkers for outcome are scarce. There is mixed evidence for the association of high mannose-binding lectin (MBL) complement activity with cancer outcomes, including reduced survival and increased infectious complications. omega-3-rich fatty acids (omega-3FA) attenuate production of proinflammatory cytokines and potentially manipulate complement activity. Materials and Methods: As part of a single-arm phase II trial in a university hospital, patients with advanced pancreatic adenocarcinoma were treated with weekly omega-3FA-rich intravenous infusion (Lipidem [B. Braun Melsungen AG, Melsungen, Germany]: up to 100 g/wk) plus gemcitabine chemotherapy until withdrawal or tumor progression. Primary outcome measure was objective response rate. Changes in complement activity, which were a secondary outcome measure, were analyzed and relation to clinical outcome determined. Results: Twenty-three patients were assessable for time to progression (TTP), overall survival (OS), and complement activity. No hypoactivity in alternative and classical pathways was demonstrated. Baseline MBL was low in 10 of 23 patients (43.5%). There was no difference in OS or TTP between low- and high-baseline MBL patients. Of these 10 patients, 5 were classified as MBL responders. MBL responders had a tendency toward improved OS over nonresponders (8.9 vs 4.4 months, P = .07). MBL responders had significantly improved TTP over nonresponders (10.6 vs 5.3 months, P = .03). Conclusion: MBL restoration had an association with improved outcome in the cohort of patients with low MBL activity at baseline. The independent contribution of omega-3FA to this effect warrants further investigation in the form of randomized clinical trials.

 

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[117]

TÍTULO / TITLE:  - A neuropharmacokinetic assessment of bafetinib, a second generation dual BCR-Abl/Lyn tyrosine kinase inhibitor, in patients with recurrent high-grade gliomas.

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

REVISTA / JOURNAL:  - Eur J Cancer. 2013 Feb 4. pii: S0959-8049(13)00005-1. doi: 10.1016/j.ejca.2013.01.001.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ejca.2013.01.001

AUTORES / AUTHORS:  - Portnow J; Badie B; Markel S; Liu A; D’Apuzzo M; Frankel P; Jandial R; Synold TW

INSTITUCIÓN / INSTITUTION:  - Department of Medical Oncology, City of Hope/Beckman Research Institute, 1500 East Duarte Road, Duarte, CA 91010, United States. Electronic address: jportnow@coh.org.

RESUMEN / SUMMARY:  - PURPOSE: The primary objective of this study was to use intracerebral microdialysis (ICMD) to determine the neuropharmacokinetics of bafetinib, a dual  BCR-Abl/Lyn tyrosine kinase inhibitor that may have activity against gliomas. METHODS: A microdialysis catheter was placed into either peritumoural or enhancing brain tissue of seven patients at the time of tumour resection or biopsy. Twenty-four hours later, bafetinib was administered, 240 or 360mg po, repeating the same dose 12h later. Dialysate samples were continuously collected  for 24h, with plasma samples obtained in parallel. One to two weeks after finishing ICMD, patients were allowed to resume taking bafetinib continuously while being observed for toxicity and tumour response. RESULTS: Twenty-six dialysate samples per patient were collected (n=6) and analysed for bafetinib by  tandem mass spectrometry. Bafetinib concentrations in the brain were below the lower limit of detection of the assay (0.1ng/ml) in all samples except one from a single subject that was 0.52ng/ml. The mean plasma bafetinib maximum concentrations after dose 1 and 2 were 143+/-99 and 247+/-73ng/ml, respectively.  Only one patient remained on treatment past two cycles, and no radiographic responses were seen. CONCLUSIONS: Bafetinib does not sufficiently cross intact or disrupted blood-brain barrier, and therefore, systemic administration of bafetinib is not recommended when investigating this drug as a treatment for brain tumours. ICMD can be a valuable research tool in early drug development. Lead-in ICMD studies can be performed relatively quickly, requiring only a small  number of patients, and without significantly disrupting standard cancer care.

 

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[118]

TÍTULO / TITLE:  - Transcription factor Nuclear Factor Erythroid-2 mediates expression of the cytokine Interleukin 8, a known predictor of inferior outcome in patients with myeloproliferative neoplasms.

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

REVISTA / JOURNAL:  - Haematologica. 2013 Feb 26.

            ●● Enlace al texto completo (gratuito o de pago) 3324/haematol.2012.071183

AUTORES / AUTHORS:  - Wehrle J; Seeger TS; Schwemmers S; Pfeiffer D; Bullashevska A; Pahl HL

INSTITUCIÓN / INSTITUTION:  - Germany.

RESUMEN / SUMMARY:  - The transcription factor nuclear factor erythroid-2 (NF-E2) is overexpressed in patients with myeloproliferative neoplasms irrespective of the presence of the JAK2V617F mutation. Our NF-E2 transgenic mouse model, which recapitulates many features of myeloproliferative neoplasms including transformation to acute myeloid leukemia, clearly implicates this transcription factor in the pathophysiology of myeloproliferative neoplasms. Because the targets mediating NF-E2 effects are not well characterized, we conducted microarray analysis of CD34+ cells lentivirally transduced to overexpress NF-E2 or to silence NF-E2 via  shRNA, in order to identify novel NF-E2 target genes. Here, we report that the cytokine Interleukin 8 (IL-8) is a novel NF-E2 target gene. NF-E2 directly binds  the IL-8 promoter in vivo, and these binding sites are required for promoter activity. Serum levels of IL-8 are known to be elevated in both polycythemia vera and primary myelofibrosis patients. Recently, increased IL-8 levels have been shown to be predictive of inferior survival in primary myelofibrosis patients in  multivariate analysis. Therefore, one of the mechanisms by which NF-E2 contributes to myeloproliferative neoplasm pathology may constitute increased IL-8 expression.

 

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[119]

TÍTULO / TITLE:  - Cod glycopeptide with picomolar affinity to galectin-3 suppresses T-cell apoptosis and prostate cancer metastasis.

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

REVISTA / JOURNAL:  - Proc Natl Acad Sci U S A. 2013 Mar 26;110(13):5052-7. doi: 10.1073/pnas.1202653110. Epub 2013 Mar 11.

            ●● Enlace al texto completo (gratuito o de pago) 1073/pnas.1202653110

AUTORES / AUTHORS:  - Guha P; Kaptan E; Bandyopadhyaya G; Kaczanowska S; Davila E; Thompson K; Martin SS; Kalvakolanu DV; Vasta GR; Ahmed H

INSTITUCIÓN / INSTITUTION:  - Department of Biochemistry and Molecular Biology, Institute of Marine and Environmental Technology, Department of Otorhinolaryngology, University of Maryland Greenebaum Cancer Center, and Departments of Physiology and Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201.

RESUMEN / SUMMARY:  - Cancer metastasis and immune suppression are critical issues in cancer therapy. Here, we show that a beta-galactoside-binding lectin [galectin-3 (gal3)] that recognizes the Thomsen-Friedenreich disaccharide (TFD, Galbeta1,3GalNAc) present  on the surface of most cancer cells is involved in promoting angiogenesis, tumor-endothelial cell adhesion, and metastasis of prostate cancer cells, as well as evading immune surveillance through killing of activated T cells. To block gal3-mediated interactions, we purified a glycopeptide from cod (designated TFD100) that binds gal3 with picomolar affinity. TFD100 blocks gal3-mediated angiogenesis, tumor-endothelial cell interactions, and metastasis of prostate cancer cells in mice at nanomolar levels. Moreover, apoptosis of activated T cells induced by either recombinant gal3 or prostate cancer patient serum-associated gal3 was inhibited at nanomolar concentration of TFD100. Because the gal3-TFD interaction is a key factor driving metastasis in most epithelial cancers, this high-affinity TFD100 should be a promising antimetastatic agent for the treatment of various cancers, including prostate adenocarcinoma.

 

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[120]

TÍTULO / TITLE:  - Clinicians Versus Nomogram: Predicting Future Technetium-99m Bone Scan Positivity in Patients With Rising Prostate-specific Antigen After Radical Prostatectomy for Prostate Cancer.

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

REVISTA / JOURNAL:  - Urology. 2013 Jan 30. pii: S0090-4295(12)01497-5. doi: 10.1016/j.urology.2012.12.010.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.urology.2012.12.010

AUTORES / AUTHORS:  - Kattan MW; Yu C; Stephenson AJ; Sartor O; Tombal B

INSTITUCIÓN / INSTITUTION:  - Department of Quantitative Health Sciences, Cleveland Clinic Foundation, Cleveland, Ohio. Electronic address: kattanm@ccf.org.

RESUMEN / SUMMARY:  - OBJECTIVE: To compare the ability of clinicians vs a nomogram at predicting future bone scan positivity in patients with prostate cancer. MATERIALS AND METHODS: This investigation was conducted during an advisory board meeting in June 2011. Details of 25 androgen deprivation therapy-naive prostate cancer patients were given to 24 prostate cancer experts, including urologists and oncologists. The clinicians were asked to predict the probability that the patients would have a positive bone scan if left untreated for 1 year. These predictions and those of the Slovin nomogram were compared with the actual occurrence of metastatic disease, and the discrimination ability was quantified using the concordance index (C index). RESULTS: A higher C index value was obtained with the Slovin nomogram (0.812) than with the clinicians (0.628). The nomogram outperformed all of the clinicians; individual clinician C index values  varied between 0.47 and 0.75. The urologists provided superior predictions compared with the oncologists. CONCLUSION: Future bone scan positivity can be predicted more accurately using a nomogram than by expert clinicians. Nomograms should, therefore, become an integral part of the clinical decision-making process in the prostate cancer setting for patients with a rising prostate-specific antigen level after radical prostatectomy.

 

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[121]

TÍTULO / TITLE:  - Insulin growth factor receptor (IGF-1R) antibody cixutumumab combined with the mTOR inhibitor temsirolimus in patients with metastatic adrenocortical carcinoma.

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

REVISTA / JOURNAL:  - Br J Cancer. 2013 Mar 5;108(4):826-30. doi: 10.1038/bjc.2013.46. Epub 2013 Feb 14.

            ●● Enlace al texto completo (gratuito o de pago) 1038/bjc.2013.46

AUTORES / AUTHORS:  - Naing A; Lorusso P; Fu S; Hong D; Chen HX; Doyle LA; Phan AT; Habra MA; Kurzrock R

INSTITUCIÓN / INSTITUTION:  - Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.

RESUMEN / SUMMARY:  - Background:Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy without an available effective systemic chemotherapy. Insulin growth factor 2 (IGF-2) overexpression leading to the activation of the IGF-1 receptor (IGF-1R)/mammalian target of rapamycin (mTOR) pathway is well described in ACC. Cixutumumab, a fully human IgG1 monoclonal antibody directed at IGF-1R was combined with temsirolimus on the basis of preclinical data.Methods:Patients received cixutumumab, 3-6 mg kg intravenously (IV) weekly, and temsirolimus, 25-37.5 mg IV weekly (4-week cycles), with restaging after 8 weeks.Results:Twenty-six patients were enrolled (13 (50%) men); median age, 47 years; median number of prior therapies, 4. Five patients previously received an  IGF-1R inhibitor and one, temsirolimus. The most frequent toxicities, at least possibly drug related, were grade 1-2 thrombocytopenia (38%), mucositis (58%), hypercholesterolaemia (31%), hypertriglyceridemia (35%), and hyperglycaemia (31%). In all, 11 of 26 patients (42%) achieved stable disease (SD) >6 months (duration range=6-21 months) with 3 of the 11 having received a prior IGF-1R inhibitor.Conclusion:Cixutumumab combined with temsirolimus was well tolerated and >40% of patients achieved prolonged SD.

 

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[122]

TÍTULO / TITLE:  - Activation of Triggering Receptor Expressed on Myeloid Cells-1 Protects Monocyte  from Apoptosis through Regulation of Myeloid Cell Leukemia-1.

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

REVISTA / JOURNAL:  - Anesthesiology. 2013 Jan 29.

            ●● Enlace al texto completo (gratuito o de pago) 1097/ALN.0b013e31828744a5

AUTORES / AUTHORS:  - Cai M; Chen Q; Chen C; Liu X; Hou J; Zeng C; Shu Q; Fang X

INSTITUCIÓN / INSTITUTION:  - * Research Assistant, double dagger Resident, vertical line Professor, Department of Thoracic and Cardiovascular Surgery, Children’s Hospital, School of Medicine,  Zhejiang University, and Key Laboratory of Reproductive Genetics, Ministry of Education, Zhejiang University, Hangzhou, People’s Republic of China. dagger Senior Research Assistant, section sign Research Assistant, # Professor, Department of Anesthesiology, the First Affiliated Hospital, School of Medicine,  Zhejiang University, Hangzhou, People’s Republic of China.

RESUMEN / SUMMARY:  - BACKGROUND:: Triggering receptor expressed on myeloid cells-1 (TREM-1) can amplify the proinflammatory response and may contribute to the pathogenesis of inflammatory disease such as sepsis. However, the role of TREM-1 in monocyte fate and the detailed molecular mechanisms evoked by TREM-1 are unknown. METHODS:: Adenoviruses overexpressing TREM-1 were constructed and transfected into a monocytic cell line. After activation of TREM-1 by agonist antibody with or without lipopolysaccharide, apoptosis was induced and assayed using flow cytometry. The signaling pathways downstream of TREM-1 were illustrated by inhibitory experiments. Proapoptotic/antiapoptotic protein levels were measured using immunoblot. In addition, the relationship between the expression levels of  TREM-1 in monocytes and the magnitude of monocyte apoptosis were analyzed in septic patients. RESULTS:: Activation of TREM-1 protected monocytes from staurosporine-induced apoptosis. This characteristic was also obtained under lipopolysaccharide stimulation. The protection of TREM-1 against monocyte apoptosis was abrogated after inhibition of extracellular signal-regulated kinase or v-akt murine thymoma viral oncogene homologue signaling. Cross-linking of TREM-1 remarkably up-regulated myeloid cell leukemia-1 protein level, and inhibition of extracellular signal-regulated kinase or v-akt murine thymoma viral oncogene homologue resulted in the reduction of myeloid cell leukemia-1 expression. Inhibition of myeloid cell leukemia-1 abolished the antiapoptotic effect of TREM-1. Furthermore, in septic patients, TREM-1 levels were inversely correlated to the magnitude of apoptosis in monocyte. CONCLUSIONS:: TREM-1 played an important role in apoptosis in monocytes. Activation of TREM-1 protected monocytic cells from apoptosis through activation of both extracellular signal-regulated kinase and v-akt murine thymoma viral oncogene homologue pathways and increased expression of myeloid cell leukemia-1 protein. These findings provide a novel additional mechanism for TREM-1-mediated hyperinflammatory response in monocytes.

 

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[123]

TÍTULO / TITLE:  - Infliximab-associated psoriasis in children with Crohn’s disease may require withdrawal of anti-tumor necrosis factor therapy.

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

REVISTA / JOURNAL:  - Inflamm Bowel Dis. 2013 Apr;19(5):E75-7. doi: 10.1097/MIB.0b013e3182802c93.

            ●● Enlace al texto completo (gratuito o de pago) 1097/MIB.0b013e3182802c93

AUTORES / AUTHORS:  - Broge T; Nguyen N; Sacks A; Davis M

INSTITUCIÓN / INSTITUTION:  - *Florida State University Pediatric Residency Program Sacred Heart Hospital Pensacola, Florida daggerGastroenterology Nemours Children’s Clinic Pensacola, Florida.

 

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[124]

TÍTULO / TITLE:  - Sorafenib induces apoptosis in endometrial carcinoma cells by inhibiting Elk-1-dependent Mcl-1 gene expression and by inducing Akt/GSK3beta-dependent Mcl-1 protein degradation.

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

REVISTA / JOURNAL:  - J Cell Biochem. 2013 Mar 5. doi: 10.1002/jcb.24530.

            ●● Enlace al texto completo (gratuito o de pago) 1002/jcb.24530

AUTORES / AUTHORS:  - Sun NK; Huang SL; Chang TC; Chao CC

INSTITUCIÓN / INSTITUTION:  - Department of Biochemistry and Molecular Biology, Chang Gung University College of Medicine, Taoyuan 333, Taiwan, Republic of China; Division of Biomedical Sciences, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan, Republic of China.

RESUMEN / SUMMARY:  - Endometrial carcinoma (EC) is one of the main gynecologic malignancies affecting  women, but effective treatments are currently lacking. In the present study, we investigated the effect of sorafenib, a general kinase inhibitor, on several EC cell lines (HEC1A, HEC1B, and RL95-2). Sorafenib induced cell death in EC cells with the following order of sensitivity: HEC1A > HEC1B > RL95-2. Sorafenib suppressed several anti-apoptotic proteins in HEC1A cells, including myeloid cell leukemia 1 (Mcl-1). Ectopic overexpression of Mcl-1 prevented the cell killing effect of sorafenib. Sorafenib suppressed Mcl-1 at the gene transactivation level by inactivating the ERK/Elk-1 pathway. Accordingly, the inhibitory effect of sorafenib on Mcl-1 expression decreased following knockdown of Elk-1 using short-hairpin RNA (shRNA). Elk-1 overexpression rescued both the inhibitory effect of sorafenib on Mcl-1 expression and the cell killing effect of sorafenib. Furthermore, sorafenib reduced the stability of the Mcl-1 protein by enhancing its ubiquitination and degradation by the proteasome via the AKT/GSK3beta and the ERK pathways. Similar results were detected in other EC cell lines. These results indicate that sorafenib induces apoptosis in EC cells by down-regulating the anti-apoptotic protein Mcl-1 via transcriptional inhibition and protein degradation. Our results thus support the notion that sorafenib may be used in endometrial cancer therapy. J. Cell. Biochem. © 2013 Wiley Periodicals, Inc.

 

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[125]

TÍTULO / TITLE:  - Acute lymphoblastic leukaemia.

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

REVISTA / JOURNAL:  - Lancet. 2013 Mar 21. pii: S0140-6736(12)62187-4. doi: 10.1016/S0140-6736(12)62187-4.

            ●● Enlace al texto completo (gratuito o de pago) 1016/S0140-6736(12)62187-4

AUTORES / AUTHORS:  - Inaba H; Greaves M; Mullighan CG

INSTITUCIÓN / INSTITUTION:  - Department of Oncology, St Jude Children’s Research Hospital and University of Tennessee Health Science Center, Memphis, TN, USA. Electronic address: hiroto.inaba@stjude.org.

RESUMEN / SUMMARY:  - Acute lymphoblastic leukaemia occurs in both children and adults but its incidence peaks between 2 and 5 years of age. Causation is multifactorial and exogenous or endogenous exposures, genetic susceptibility, and chance have roles. Survival in paediatric acute lymphoblastic leukaemia has improved to roughly 90%  in trials with risk stratification by biological features of leukaemic cells and  response to treatment, treatment modification based on patients’ pharmacodynamics and pharmacogenomics, and improved supportive care. However, innovative approaches are needed to further improve survival while reducing adverse effects. Prognosis remains poor in infants and adults. Genome-wide profiling of germline and leukaemic cell DNA has identified novel submicroscopic structural genetic changes and sequence mutations that contribute to leukaemogenesis, define new disease subtypes, affect responsiveness to treatment, and might provide novel prognostic markers and therapeutic targets for personalised medicine.

 

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[126]

TÍTULO / TITLE:  - CHFR Protein Expression Predicts Outcomes to Taxane-Based First Line Therapy in Metastatic NSCLC.

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

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Mar 15;19(6):1603-11. doi: 10.1158/1078-0432.CCR-12-2995. Epub 2013 Feb 5.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-2995

AUTORES / AUTHORS:  - Pillai RN; Brodie SA; Sica GL; Shaojin Y; Li G; Nickleach DC; Yuan L; Varma VA; Bonta D; Herman JG; Brock MV; Ribeiro MJ; Ramalingam SS; Owonikoko TK; Khuri FR; Brandes JC

INSTITUCIÓN / INSTITUTION:  - Authors’ Affiliations: Departments of Hematology and Oncology, Pathology, Biostatistics, and Radiology, and Winship Cancer Institute, Emory University; Atlanta VA Medical Center, Atlanta, Georgia; and Sidney Kimmel Comprehensive Cancer Institute, Johns Hopkins University, Baltimore, Maryland.

RESUMEN / SUMMARY:  - PURPOSE: Currently, there is no clinically validated test for the prediction of response to tubulin-targeting agents in non-small cell lung cancer (NSCLC). Here, we investigated the significance of nuclear expression of the mitotic checkpoint  gene checkpoint with forkhead and ringfinger domains (CHFR) as predictor of response and overall survival with taxane-based first-line chemotherapy in advanced stage NSCLC. Methods: We studied a cohort of 41 patients (median age 63  years) with advanced NSCLC treated at the Atlanta VAMC between 1999 and 2010. CHFR expression by immunohistochemistry (score 0-4) was correlated with clinical  outcome using chi-square test and Cox proportional models. A cutoff score of “3”  was determined by receiver operator characteristics analysis for “low” CHFR expression. Results were validated in an additional 20 patients who received taxane-based chemotherapy at Emory University Hospital and the Atlanta VAMC. RESULTS: High expression (score = 4) of CHFR is strongly associated with adverse  outcomes: the risk for progressive disease after first-line chemotherapy with carboplatin-paclitaxel was 52% in patients with CHFR-high versus only 19% in those with CHFR-low tumors (P = 0.033). Median overall survival was strongly correlated with CHFR expression status (CHFR low: 9.9 months; CHFR high: 6.2 months; P = 0.002). After multivariate adjustment, reduced CHFR expression remained a powerful predictor of improved overall survival (HR = 0.24; 95% CI, 0.1-0.58%; P = 0.002). In the validation set, low CHFR expression was associated  with higher likelihood of clinical benefit (P = 0.03) and improved overall survival (P = 0.038). CONCLUSIONS: CHFR expression is a novel predictive marker of response and overall survival in NSCLC patients treated with taxane-containing chemotherapy. Clin Cancer Res; 19(6); 1603-11. ©2013 AACR.

 

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[127]

TÍTULO / TITLE:  - Low RPS14 expression in MDS without 5q- aberration confers higher apoptosis rate  of nucleated erythrocytes and predicts prolonged survival and possible response to lenalidomide in lower-risk non-5q- patients.

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

REVISTA / JOURNAL:  - Eur J Haematol. 2013 Mar 18. doi: 10.1111/ejh.12105.

            ●● Enlace al texto completo (gratuito o de pago) 1111/ejh.12105

AUTORES / AUTHORS:  - Wu L; Li X; Xu F; Zhang Z; Chang C; He Q

INSTITUCIÓN / INSTITUTION:  - Hematology Division, the Sixth Hospital Affiliated to Shanghai Jiaotong University.

RESUMEN / SUMMARY:  - OBJECTIVES: Haploinsufficiency of the ribosomal protein S14 (RPS14) has been identified as a causal factor in myelodysplastic syndrome (MDS) with isolated del (5q). This study was carried out to investigate RPS14 expression in MDS without 5q deletion and the role of lower-expressed RPS14 plays in pathogenesis and the prognosis and lenalidomide-response predicting of non-5q-MDS. PATIENTS AND METHODS: The expression level of RPS14 transcription was detected in 156 MDS patients without 5q-. The apoptosis of bone marrow (BM) nucleated erythrocytes was also analyzed. Furthermore, patient prognosis with lower or normal RPS14 expression was analyzed and the role of RPS14 expression in lenalidomide-response prediction was evaluated. RESULTS: The reduced RPS14 expression occurred in 83 of 156 (53.2%) non- 5q- patients. Patients with RPS14 lower-expression presented higher platelet counts in the peripheral blood compared to RPS14 normal patients  (p=0.012). The lower RPS14 expression status was inversely correlated with increased apoptosis ratio in nucleated erythrocytes from BM (r=-0.54, p=0.013). Patients with lower RPS14 expression have a higher two-year survival probability  than normal RPS14 cases in the international prognosis scoring system (IPSS) lower-risk group (90.8% vs. 71.7%; p = 0.018). A multivariate analysis showed RPS14 expression status was an independent predictor for survival in lower-risk MDS patients without 5q deletion. Twelve patients were treated with lenalidomide. Five of seven patients achieved an erythroid response in the lower RPS14 expression group (5/7, 71.4%), compared to zero responses in the five normal RPS14 patients (p=0.018). CONCLUSION: Lower RPS14 expression in MDS patients without 5q deletion is associated with increased apoptosis of nucleated erythrocytes in lower-risk MDS. Additionally, lower RPS14 predicts prolonged survival and possible response to lenalidomide in lower-risk MDS patients. © 2013 John Wiley & Sons A/S.

 

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[128]

TÍTULO / TITLE:  - The Oncolytic Activity of Newcastle Disease Virus in Clear Cell Renal Carcinoma Cells in Normoxic and Hypoxic Conditions: The Interplay Between VHL and Interferon-beta Signaling.

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

REVISTA / JOURNAL:  - J Interferon Cytokine Res. 2013 Mar 18.

            ●● Enlace al texto completo (gratuito o de pago) 1089/jir.2012.0095

AUTORES / AUTHORS:  - Ch’ng WC; Stanbridge EJ; Yusoff K; Shafee N

INSTITUCIÓN / INSTITUTION:  - 1 Department of Microbiology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia , UPM Serdang, Malaysia .

RESUMEN / SUMMARY:  - Viral-mediated oncolysis is a promising cancer therapeutic approach offering an increased efficacy with less toxicity than the current therapies. The complexity  of solid tumor microenvironments includes regions of hypoxia. In these regions, the transcription factor, hypoxia inducible factor (HIF), is active and regulates expression of many genes that contribute to aggressive malignancy, radio-, and chemo-resistance. To investigate the oncolytic efficacy of a highly virulent (velogenic) Newcastle disease virus (NDV) in the presence or absence of HIF-2alpha, renal cell carcinoma (RCC) cell lines with defective or reconstituted wild-type (wt) von Hippel-Lindau (VHL) activity were used. We show that these RCC cells responded to NDV by producing only interferon (IFN)-beta, but not IFN-alpha, and are associated with increased STAT1 phosphorylation. Restoration of wt VHL expression enhanced NDV-induced IFN-beta production, leading to prolonged STAT1 phosphorylation and increased cell death. Hypoxia augmented NDV oncolytic activity regardless of the cells’ HIF-2alpha levels. These results highlight the potential of oncolytic NDV as a potent therapeutic agent in the killing of hypoxic cancer cells.

 

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[129]

TÍTULO / TITLE:  - KRAS Mutation as the Biomarker of Response to Chemotherapy and EGFR-TKIs in Patients With Advanced Non-Small Cell Lung Cancer: Clues For Its Potential Use in Second-Line Therapy Decision Making.

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

REVISTA / JOURNAL:  - Am J Clin Oncol. 2013 Mar 28.

            ●● Enlace al texto completo (gratuito o de pago) 1097/COC.0b013e318287bb23

AUTORES / AUTHORS:  - Campos-Parra AD; Zuloaga C; Manriquez ME; Aviles A; Borbolla-Escoboza J; Cardona A; Meneses A; Arrieta O

INSTITUCIÓN / INSTITUTION:  - *Laboratory of Experimental Oncology daggerThoracic Oncology Clinic section signDepartment of Pathology #Laboratory of Translational Medicine, Instituto Nacional de Cancerologia (INCan) double daggerDepartment of Pathology, Instituto  Nacional de Enfermedades Respiratorias (INER), Tlalpan, Mexico, D.F parallelBoehringer Ingelheim, Barrio Xaltocan, Xochimilco, Mexico City, Mexico paragraph signClinical and Translational Oncology Group, Institute of Oncology, Fundacion Santa Fe de Bogota, Bogota, Colombia.

RESUMEN / SUMMARY:  - OBJETIVE:: In patients with non-small cell lung cancer (NSCLC), knowledge of the  epidermal growth factor receptor (EGFR) mutation status is fundamental for selecting the treatment involving EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Little information is available regarding the response and progression-free survival (PFS) in platinum-based chemotherapy (CT) versus EGFR-TKIs in the presence or absence of KRAS mutation, particularly in patients without EGFR mutation. METHODS:: From 2007 to 2010, 353 patients with NSCLC were treated with  first-line CT, EGFR-TKIs were used in the second or third line of treatment. Tests were performed for EGFR and KRAS mutation and the results of the mutations  were obtained 3 to 4 months after the start of the treatment. We analyzed clinical characteristics, mutation profile, response and PFS to CT and EGFR-TKIs, and overall survival. The protocol is registered with ClinicalTrials.gov, number  NCT01023828. RESULTS:: Presence of the wild-type (WT) KRAS was independently associated with increased response rate to first-line CT when compared with KRAS  mutation (41.4% vs. 14.7%; P=0.001). The EGFR mutation (57.8% vs. 11.7%; P<0.001) and WT-KRAS (39.6% vs. 3.3%; P=0.001) were associated with the EGFR-TKIs response. PFS of patients with WT-EGFR and KRAS mutation treated with EGFR-TKIs was shorter when compared with patients with WT-EGFR and WT-KRAS (P<0.001). CONCLUSIONS:: KRAS mutation status is a good biomarker for response to EGFR-TKIs  in patients with NSCLC. KRAS mutational status could impact the decision to give  CT or EGFR-TKIs as a second line of treatment to patients with NSCLC, particularly in patients with WT-EGFR.

 

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[130]

TÍTULO / TITLE:  - The Investigational Aurora Kinase A Inhibitor MLN8237 Induces Defects in Cell Viability and Cell-Cycle Progression in Malignant Bladder Cancer Cells In Vitro and In Vivo.

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

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Apr 1;19(7):1717-28. doi: 10.1158/1078-0432.CCR-12-2383. Epub 2013 Feb 12.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-2383

AUTORES / AUTHORS:  - Zhou N; Singh K; Mir MC; Parker Y; Lindner D; Dreicer R; Ecsedy JA; Zhang Z; Teh BT; Almasan A; Hansel DE

INSTITUCIÓN / INSTITUTION:  - Authors’ Affiliations: Pathology and Laboratory Medicine Institute; Lerner Research Institute; Glickman Urological and Kidney Institute; Genomic Medicine Institute; Department of Solid Tumor Oncology, Cleveland Clinic, Cleveland, Ohio; Millennium Pharmaceuticals, Cambridge, Massachusetts; Van Andel Research Institute, Grand Rapids, Michigan; and NCCS-VARI Translational Research Laboratory, National Cancer Center, Singapore, Singapore.

RESUMEN / SUMMARY:  - PURPOSE: Despite more than 70,000 new cases of bladder cancer in the United States annually, patients with advanced disease have a poor prognosis due to limited treatment modalities. We evaluated Aurora kinase A, identified as an upregulated candidate molecule in bladder cancer, as a potential therapeutic target. EXPERIMENTAL DESIGN: Gene expression in human bladder cancer samples was  evaluated using RNA microarray and quantitative reverse transcriptase PCR. Effects of the Aurora kinase A inhibitor MLN8237 (Millennium) on cell dynamics in malignant T24 and UM-UC-3 and papilloma-derived RT4 bladder cells were evaluated  in vitro and in vivo in a mouse xenograft model. RESULTS: A set of 13 genes involved in the mitotic spindle checkpoint, including Aurora kinases A and B, were upregulated in human urothelial carcinoma compared with normal urothelium. The Aurora kinase A inhibitor MLN8237 induced cell-cycle arrest, aneuploidy, mitotic spindle failure, and apoptosis in the human bladder cancer cell lines T24 and UM-UC-3. MLN8237 also arrested tumor growth when administered orally over 4 weeks in a mouse bladder cancer xenograft model. Finally, in vitro sequential administration of MLN8237 with either paclitaxel or gemcitabine resulted in synergistic cytotoxic effects in T24 cells. CONCLUSIONS: Mitotic spindle checkpoint dysfunction is a common characteristic of human urothelial carcinoma and can be exploited with pharmacologic Aurora A inhibition. Given our demonstration of the ability of the Aurora A inhibitor MLN8237 to inhibit growth  of bladder cancer in vitro and in vivo, we conclude that Aurora kinase inhibitors warrant further therapeutic investigation in bladder cancer. Clin Cancer Res; 19(7); 1717-28. ©2013 AACR.

 

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[131]

TÍTULO / TITLE:  - Prognostic Value of High Thymidine Kinase Activity in Previously Untreated Diffuse Large B-Cell Lymphoma Patients Treated by R-CHOP.

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

REVISTA / JOURNAL:  - Leuk Lymphoma. 2013 Mar 14.

            ●● Enlace al texto completo (gratuito o de pago) 3109/10428194.2013.779690

AUTORES / AUTHORS:  - Suzuki K; Terui Y; Yokoyama M; Ueda K; Nishimura N; Mishima Y; Sakajiri S; Tsuyama N; Takeuchi K; Hatake K

RESUMEN / SUMMARY:  - ABSTRACT The purpose of this study was to investigate prognostic factors for overall survival (OS) among previously untreated diffuse large B-cell lymphoma (DLBCL) patients treated with R-CHOP. We evaluated four biological parameters including thymidine kinase activity (TK). This study looked at 183 patients. The  median level of TK was 14.0 IU/L, which we chose as the cut-off. After a median follow-up time of 53.0 months, OS rate at 4 years in the high TK arm and low TK arm were 46.7% and 66.7% (p = .001). By multivariate analysis, OS was significantly worse in high-TK arm (hazard ratio 2.705; p = .045). Complete response (CR) rate among high TK arm was significantly worse than low TK arm. OS  was significantly better in patients who had achieved CR than partial response or less. In conclusion, high TK activity was a strong predictor for short OS and poor response among patients with previously untreated DLBCL treated with R-CHOP.

 

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[132]

TÍTULO / TITLE:  - Does Timing of Cytoreductive Nephrectomy Impact Patient Survival With Metastatic  Renal Cell Carcinoma in the Tyrosine Kinase Inhibitor Era? A Multi-institutional  Study.

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

REVISTA / JOURNAL:  - Urology. 2013 Apr;81(4):805-12. doi: 10.1016/j.urology.2012.10.054. Epub 2013 Feb 13.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.urology.2012.10.054

AUTORES / AUTHORS:  - Stroup SP; Raheem OA; Palazzi KL; Liss MA; Mehrazin R; Kopp RP; Patel N; Cohen SA; Park SK; Patterson AL; Kane CJ; Millard F; Derweesh IH

INSTITUCIÓN / INSTITUTION:  - Division of Urology, Department of Surgery, University of California San Diego School of Medicine, La Jolla, CA.

RESUMEN / SUMMARY:  - OBJECTIVE: To compare outcomes of metastatic renal cell carcinoma (mRCC) patients who underwent primary cytoreductive nephrectomy (CRN), followed by adjuvant sunitinib therapy, vs those who underwent primary sunitinib therapy before planned CRN. METHODS: This was a multi-institutional retrospective analysis of 35 mRCC patients from June 2005 to August 2009 (median follow-up, 28.5 months): 17 underwent primary CRN, followed by adjuvant sunitinib (group 1); 18 underwent primary sunitinib therapy, followed by planned CRN (group 2). Response to therapy was determined using Response Evaluation Criteria in Solid Tumors. Group 2 patients who had partial response (PR)/stable disease (SD) proceeded to CRN (group 2 +CRN). Group 2 patients who progressed were treated with salvage systemic therapy (group 2 no-CRN). Primary and secondary outcomes were disease-specific survival (DSS) and overall survival (OS). RESULTS: Patient demographic and tumor characteristics were similar. The groups had similar rates  of DSS and OS on univariate analysis (P = .318 and P = .181). In group 2, 11 (61%) had PR/DS; 7 (39%) progressed. Mean times to disease-specific death in group 1, group 2 (+CRN), and group 2 (no-CRN) were 29.2, 4.6, and 28.7 months, respectively (P = .025). Kaplan-Meier analysis of DSS and OS demonstrated significant improvement in group 2 (+CRN) vs group 1 vs group 2 (no-CRN; P <.001), which remained significant on multivariate regression. CONCLUSION: Nonresponders to primary sunitinib therapy had a poor prognosis. Offering CRN, if safely feasible, combined with sunitinib, was associated with improved disease-specific outcome in mRCC. Responders to primary sunitinib who underwent CRN had better DSS and OS than patients who underwent primary CRN, followed by sunitinib. Further investigation is required to assess the role, timing, and sequencing of targeted therapy and CRN in treatment of mRCC.

 

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[133]

TÍTULO / TITLE:  - A phase I study of arsenic trioxide (trisenox), ascorbic Acid, and bortezomib (velcade) combination therapy in patients with relapsed/refractory multiple myeloma.

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

REVISTA / JOURNAL:  - Cancer Invest. 2013 Mar;31(3):172-6. doi: 10.3109/07357907.2012.756109. Epub 2013 Feb 13.

            ●● Enlace al texto completo (gratuito o de pago) 3109/07357907.2012.756109

AUTORES / AUTHORS:  - Held LA; Rizzieri D; Long GD; Gockerman JP; Diehl LF; Castro CM; Moore JO; Horwitz ME; Chao NJ; Gasparetto C

INSTITUCIÓN / INSTITUTION:  - Division of Cellular Therapy1.

RESUMEN / SUMMARY:  - Purpose: This Phase I study assessed the feasibility of concomitant arsenic trioxide (ATO), ascorbic acid (AA), and bortezomib (Velcade) (AAV) for patients with relapsed/refractory multiple myeloma. Experimental Design: ATO (0.25 mg/kg)  and AA (1 g) were given with an escalating dose of bortezomib (1 mg/m or 1.3 mg/m IV bolus on days 1 and 8 of a 21-day cycle). Results: Ten patients (median age 62 years), with a median of 3 prior regimens, were enrolled. Four (40%) patients achieved clinical benefit, with one patient achieving a durable partial response. No formal DLTs were encountered. Conclusion: AAV combination was feasible and demonstrated some benefits in this heavily pretreated population.

 

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[134]

TÍTULO / TITLE:  - Assessment of SOX17 DNA methylation in cell free DNA from patients with operable  gastric cancer. Association with prognostic variables and survival.

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

REVISTA / JOURNAL:  - Clin Chem. Acceso gratuito al texto completo a partir de 1 año de la fecha de publicación.

            ●● Enlace a la Editora de la Revista journals.uchicago.edu/ 

            ●● Cita: Clinical Infectious Diseases: <> Lab Med. 2013 Feb 13:1-6. doi: 10.1515/cclm-2012-0320.

            ●● Enlace al texto completo (gratuito o de pago) 1515/cclm-2012-0320

AUTORES / AUTHORS:  - Balgkouranidou I; Karayiannakis A; Matthaios D; Bolanaki H; Tripsianis G; Tentes AA; Lianidou E; Chatzaki E; Fiska A; Lambropoulou M; Kolios G; Kakolyris S

RESUMEN / SUMMARY:  - Abstract Background: DNA methylation represents one of the most common epigenetic changes in human cancer providing important information regarding carcinogenesis. A possible role as a prognostic indicator has also been proposed. The aim of our  study was to evaluate the prognostic significance of SOX17 promoter methylation status in patients with operable gastric cancer. Methods: Using methylation-specific PCR (MSP) we examined the incidence and prognostic significance of SOX17 methylation status in cell free circulating DNA in the serum of 73 patients with operable gastric cancer. Fifty-one patients were male (69.9%), their median age was 65 years, 43 patients (58.9%) had regional lymph node involvement and all had a Performance Status (WHO) of 0-1. Results: SOX17 promoter was found to be methylated in 43 out of 73 gastric cancer serum samples  examined (58.9%). All 20 control serum samples from healthy individuals were negative. Overall survival (OS) was found to be significantly associated with SOX17 methylation (p=0.049). A significant correlation between methylation status and differentiation (p=0.031) was also observed. No other significant associations between different tumor parameters examined and SOX17 methylation status were observed. Conclusions: SOX17 promoter methylation in cell free DNA of patients with operable gastric cancer is a frequent event and may provide important information regarding prognosis in this group of patients.

 

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[135]

TÍTULO / TITLE:  - beta-catenin/POU5F1/SOX2 transcription factor complex mediates IGF-1 receptor signaling and predicts poor prognosis in lung adenocarcinoma.

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

REVISTA / JOURNAL:  - Cancer Res. 2013 Mar 28.

            ●● Enlace al texto completo (gratuito o de pago) 1158/0008-5472.CAN-12-4403

AUTORES / AUTHORS:  - Xu C; Xie D; Yu SC; Yang XJ; He LR; Yang J; Ping YF; Wang B; Yang L; Xu SL; Cui W; Wang QL; Fu WJ; Liu Q; Qian C; Cui YH; Rich JN; Kung HF; Zhang X; Bian XW

INSTITUCIÓN / INSTITUTION:  - Southwest Hospital,Third Military Medical University, Institute of Pathology and  Southwest Cancer Center.

RESUMEN / SUMMARY:  - Cancer stem-like cells (CSLCs) are crucial in tumor initiation and progression, however, the underlying mechanism for the self-renewal of cancer cells remains undefined. In the study, immunohistochemical analysis of specimens freshly excised from patients with lung adenocarcinoma (LAC) showed that high expression  of insulin-like growth factor 1 receptor (IGF-1R) in LAC cells was positively correlated with the expressions of cancer stem cell markers, CD133 and ALDH1A1. IGF-1R activation enhanced POU5F1 expression on human lung adenocarcinoma stem-like cells (LACSLCs) through PI3K/AKT/GSK3beta/beta-catenin cascade. POU5F1  could form a novel complex with beta-catenin and SOX2 to bind Nanog promoter for  transcription to maintain self-renewal of LACSLCs, which was dependent on the functional IGF-1R. Genetic and pharmacological inhibition of IGF-1R abrogated LACSLC capabilities for self-renewal and tumorigenicity in vitro. In an in vivo xenograft tumor model, knockdown of either IGF-1R or POU5F1 impeded tumorigenic potentials of LACSLCs. By analyzing pathological specimens excised from 200 patients with lung adenocarcinoma, we found that co-localization of highly expressed IGF-1R with beta-catenin and POU5F1 predicted poor prognosis. Taken together, we demonstrate that IGF-1R-mediated POU5F1 expression to form a complex with beta-catenin and SOX2 is crucial for the self-renewal and oncogenic potentials of LACSLCs, and the integrative clinical detection of the expressions  of IGF-1R, beta-catenin and POU5F1 is indicatory for predicting prognosis in the  patients of lung adenocarcinoma.

 

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[136]

TÍTULO / TITLE:  - Clinical and MRI predictors of response to interferon-beta and glatiramer acetate in relapsing-remitting multiple sclerosis patients.

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

REVISTA / JOURNAL:  - Eur J Neurol. 2013 Feb 20. doi: 10.1111/ene.12119.

            ●● Enlace al texto completo (gratuito o de pago) 1111/ene.12119

AUTORES / AUTHORS:  - Romeo M; Martinelli-Boneschi F; Rodegher M; Esposito F; Martinelli V; Comi G

INSTITUCIÓN / INSTITUTION:  - Department of Neurology, Division of Neuroscience, Institute of Experimental Neurology (INSPE), San Raffaele Scientific Institute, Milan, Italy.

RESUMEN / SUMMARY:  - BACKGROUND AND PURPOSE: It is still unclear which patients benefit more from available disease-modifying treatments (DMTs) in multiple sclerosis (MS). Our objective is to identify the baseline clinical and magnetic resonance imaging (MRI) predictors of response to first-line DMTs in a cohort of relapsing-remitting (RR) MS patients in a real-world clinical setting. METHODS: Consecutive naive RRMS patients treated with interferon-beta or glatiramer acetate have been included and followed for 2 years. Patients were grouped into responders ® in case of absence of clinical and MRI activity, and non-responders (NR) if the on-treatment annualized relapse rate (ARR) reduction was < 50% of the ARR in the 2 years before treatment or in the presence of MRI activity (>/= 2 active lesions at 1-year MRI or >/= 4 active lesions at 1 + 2-year MRI). RESULTS: At 2-year follow-up, 272 patients were R (34.6%) and 322 NR (40.9%), and multivariate analysis revealed that a later age at onset of the disease (P < 0.0001), a lower disability (P < 0.0001) and a lower number of gadolinium-enhancing lesions at baseline MRI (P = 0.002) were predictors of efficacy of DMTs. Moreover, the first year response had a good predictive power on the second year, as 73.7% of 1-year R had no evidence of clinical and MRI activity within the ensuing year. CONCLUSION: A lower baseline MRI and clinical activity have been identified as predictors of DMT efficacy in patients with RRMS in routine clinical practice. Evaluation of clinical and MRI activity at 1 year is recommended to monitor patients over time.

 

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[137]

TÍTULO / TITLE:  - Millepachine, a novel chalcone, induces G2/M arrest by inhibiting CDK1 activity and causing apoptosis via ROS-mitochondrial apoptotic pathway in human hepatocarcinoma cells in vitro and in vivo.

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

REVISTA / JOURNAL:  - Carcinogenesis. 2013 Apr 1.

            ●● Enlace al texto completo (gratuito o de pago) 1093/carcin/bgt087

AUTORES / AUTHORS:  - Wu W; Ye H; Wan L; Han X; Wang G; Hu J; Tang M; Duan X; Fan Y; He S; Huang L; Pei H; Wang X; Li X; Xie C; Zhang R; Yuan Z; Mao Y; Wei Y; Chen L

INSTITUCIÓN / INSTITUTION:  - State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Keyuan Road 4, Gaopeng Street, Chengdu 610041, China.

RESUMEN / SUMMARY:  - In this study, we reported millepachine (MIL), a novel chalcone compound for the  first time isolated from Millettia pachycarpa Benth (Leguminosae), induced cell cycle arrest and apoptosis in human hepatocarcinoma cells in vitro and in vivo. In in vitro screening experiments, MIL showed strong antiproliferation activity in several human cancer cell lines, especially in HepG2 cells with an IC50 of 1.51 microM. Therefore, we chose HepG2 and SK-HEP-1 cells to study MIL’s antitumor mechanism. Flow cytometry showed that MIL induced a G2/M arrest and apoptosis in a dose-dependent manner. Western blot demonstrated that MIL-induced  G2/M arrest was correlated with the inhibition of cyclin-dependent kinase 1 activity, including a remarkable decrease in cell division cycle (cdc) 2 synthesis, the accumulation of phosphorylated-Thr14 and decrease of phosphorylation at Thr161 of cdc2. This effect was associated with the downregulation of cdc25C and upmodulation of checkpoint kinase 2 in response to DNA damage. MIL also activated caspase 9 and caspase 3, and significantly increased the ratio of Bax/Bcl-2 and stimulated the release of cytochrome c into  cytosol, suggesting MIL induced apoptosis via mitochondrial apoptotic pathway. Associated with those effects, MIL also induced the generation of reactive oxygen species. In HepG2 tumor-bearing mice models, MIL remarkably and dose dependently  inhibited tumor growth. Treatment of mice with MIL (20mg/kg intravenous [i.v.]) caused more than 65% tumor inhibition without cardiac damage compared with 47.57% tumor reduction by 5mg/kg i.v. doxorubicin with significant cardiac damage. These effects suggested that MIL and its easily modified structural derivative might be a potential lead compound for antitumor drug.

 

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[138]

TÍTULO / TITLE:  - Genetic inhibition of vascular endothelial growth factor receptor1 significantly  inhibits the migration and proliferation of leukemia cells and increases their sensitivity to chemotherapy.

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

REVISTA / JOURNAL:  - Oncol Rep. 2013 Mar 13. doi: 10.3892/or.2013.2348.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2013.2348

AUTORES / AUTHORS:  - Xiu B; Zhang W; Huang B; Chen J; Lu H; Fu J; Xiong H; Liang A

INSTITUCIÓN / INSTITUTION:  - Department of Hematology, Tongji Hospital of Tongji University, Putuo, Shanghai 200065, P.R. China.

RESUMEN / SUMMARY:  - Little is known about the role of vascular endothelial growth factor (VEGF) receptor1 (VEGFR-1) in acute leukemia. In this study, using real-time PCR and ELISA, we found that VEGF and VEGFR-1 are highly expressed in U937 leukemia cells and primary leukemia cells (M4/M5 subtypes), which are associated with an increased migration rate and extramedullary disease. In order to elucidate the role of VEGFR-1 in acute leukemia, we used a lentivirus-mediated shRNA expression system to specifically inhibit VEGFR-1 expression in the U937 cell line. In addition, a series of in vitro experiments were conducted, including cell proliferation and migration assays and drug treatments. Our results showed that shRNA reduced the proliferation and migration of U937 cells. RNA interference targeting VEGFR-1 in combination with bevacizumab did not exert synergistic antitumor effects. However, shRNA enhanced the sensitivity of the U937 cells to cytarabine by decreasing the IC50 of cytarabine, reducing the number of cells in  the S phase and suppressing the expression of the survivin gene. Taken together,  these results suggest that VEGFR-1 interference may serve as a novel antitumor therapeutic strategy for the treatment of leukemia.

 

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[139]

TÍTULO / TITLE:  - Markers of cell division cycle in glioblastoma: significance in prediction of treatment response and patient prognosis.

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

REVISTA / JOURNAL:  - Br J Neurosurg. 2013 Mar 11.

            ●● Enlace al texto completo (gratuito o de pago) 3109/02688697.2013.773287

AUTORES / AUTHORS:  - Yousaf J; Hills C; Dixit S; Achawal S; O’Brien D; Greenman J; Scott IS

INSTITUCIÓN / INSTITUTION:  - Departments of Neurosurgery, Hull & East Yorkshire Hospitals NHS Trust , Hull Royal Infirmary, Hull , UK.

RESUMEN / SUMMARY:  - Objective. To investigate whether expression of regulatory components of the cell division cycle can be used independently to predict survival and response to adjuvant therapy in glioblastomas. Method. A tissue micro-array, constructed using glioblastomas (n = 66), was stained using antibodies against minichromosome maintenance protein-2 (Mcm-2), expressed throughout the cell-division cycle; geminin, a protein that prevents re-initiation of DNA replication; and cyclin A,  an S-phase cyclin. A semi-quantitative labelling index (LI) was calculated using  an average of 18 high-power fields (hpf) in three replicate cores. The patients were divided into two groups: Group 1 (n = 50) underwent surgery and radiotherapy with 24 patients receiving temozolomide, and Group 2 (n = 16) received surgical treatment only. Results. The LIs (median +/- IQR) for Group 1 were as follows: Mcm-2, 36.7% (22.9%-51.8%); geminin, 7.8% (5.8%-10.5%); and cyclin A, 4.2% (2.4%-6.9%). Elevated LIs, higher than the median, for geminin and cyclin A correlated with prolonged survival when the tumours received adjuvant therapy (Kaplan-Meier curves, p = 0.0046 and p = 0.0063 for geminin and cyclin A, respectively). Linear regression analysis revealed positive correlations with survival for Mcm-2 (p = 0.0376), geminin (p = 0.0006) and cyclin A (p = 0.004). In Group 2, there was no relationship between the patient survival and the LI for any marker. Conclusions. Geminin and cyclin A, each show potential as independent prognostic markers in glioblastomas receiving adjuvant therapy. This may reflect  the fact that both geminin and cyclin A estimate proliferating tumour cell subpopulations sensitive to radio/chemotherapy. These markers could provide valuable prognostic information, even in small biopsies, especially if combined with O6MGMT expression and 1p;19q deletion status.

 

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[140]

TÍTULO / TITLE:  - Tumor-derived Mutations in the Gene Associated with Retinoid Interferon-induced Mortality (GRIM-19) Disrupt Its Anti-signal Transducer and Activator of Transcription 3 (STAT3) Activity and Promote Oncogenesis.

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

REVISTA / JOURNAL:  - J Biol Chem. 2013 Mar 15;288(11):7930-41. doi: 10.1074/jbc.M112.440610. Epub 2013 Feb 5.

            ●● Enlace al texto completo (gratuito o de pago) 1074/jbc.M112.440610

AUTORES / AUTHORS:  - Nallar SC; Kalakonda S; Lindner DJ; Lorenz RR; Lamarre E; Weihua X; Kalvakolanu DV

INSTITUCIÓN / INSTITUTION:  - From the Department of Microbiology and Immunology, Program in Oncology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201.

RESUMEN / SUMMARY:  - The signal transducer and activator of transcription 3 (STAT3) protein is critical for multiple cytokine and growth factor-induced biological responses in  vivo. Its transcriptional activity is controlled by a transient phosphorylation of a critical tyrosine. Constitutive activation of STAT3 imparts resistance to apoptosis, promotes cell proliferation, and induces de novo micro-angiogenesis, three of the six cardinal hallmarks of a typical cancer cell. Earlier we reported the isolation of GRIM-19 as a growth suppressor using a genome-wide expression knockdown strategy. GRIM-19 binds to STAT3 and suppresses its transcriptional activity. To understand the pathological relevance of GRIM-19, we screened a set  of primary head and neck tumors and identified three somatic mutations in GRIM-19. Wild-type GRIM-19 suppressed cellular transformation by a constitutively active form of STAT3, whereas tumor-derived mutants L71P, L91P and A95T significantly lost their ability to associate with STAT3, block gene expression,  and suppress cellular transformation and tumor growth in vivo. Additionally, these mutants lost their capacity to prevent metastasis. These mutations define a mechanism by which STAT3 activity is deregulated in certain human head and neck tumors.

 

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[141]

TÍTULO / TITLE:  - Thymidylate synthase and ERCC1 as predictive markers in patients with pulmonary adenocarcinoma treated with pemetrexed and cisplatin.

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

REVISTA / JOURNAL:  - Lung Cancer. 2013 Mar 21. pii: S0169-5002(13)00107-4. doi: 10.1016/j.lungcan.2013.03.002.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.lungcan.2013.03.002

AUTORES / AUTHORS:  - Lee SH; Noh KB; Lee JS; Lee EJ; Min KH; Hur GY; Lee SH; Lee SY; Kim JH; Lee SY; Shin C; Shim JJ; Kim CH; Kang KH; In KH

INSTITUCIÓN / INSTITUTION:  - Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Korea University, 126-1, Anam-dong 5-ga, Seongbuk-gu, Seoul 136-705, Republic of Korea. Electronic address: humanmd04@hanmail.net.

RESUMEN / SUMMARY:  - Increased expression of thymidylate synthase (TS) is thought to be associated with resistance to antifolate drugs such as pemetrexed. Excision repair cross-complementation group 1 (ERCC1) is a predictive marker for platinum-based chemotherapy. This study evaluated whether the expression of TS and ERCC1 proteins is associated with clinical outcomes of the patients with pulmonary adenocarcinoma who were treated with pemetrexed/cisplatin as first-line chemotherapy. The expressions of TS and ERCC1 were evaluated by immunohistochemistry in biopsy specimens obtained from patients with pulmonary adenocarcinoma who had received pemetrexed/cisplatin as first-line treatment. Patients were categorized according to median H-score. Response rate (RR), progression-free survival (PFS) and overall survival (OS) were analyzed retrospectively. Both low TS and ERCC1 expressions were significantly associated  with better RR (p=0.037 and p=0.015, respectively) and longer PFS (p<0.001 and p=0.004, respectively). Low ERCC1 expression was also associated with longer OS (p=0.003) while TS only showed a trend (p=0.105). TS expression was independent predictor for the better PFS in multivariate analysis (hazard ratio [HR]=0.32, 95% confidence interval [CI]: 0.14-0.76). Combining the two markers, the low TS/low ERCC1 group showed significantly longer PFS (HR=0.48, 95% CI: 0.26-0.75) and OS (HR=0.57, 95% CI: 0.36-0.89) compared with high TS/high ERCC1 group. Protein expressions of TS and ERCC1 were associated with clinical outcomes in patients with pulmonary adenocarcinoma who were treated with pemetrexed/cisplatin as first-line chemotherapy. TS and ERCC1 protein expressions can be potential predictive markers in this setting.

 

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[142]

TÍTULO / TITLE:  - Inactivation of 9q22.3 tumor suppressor genes predict outcome for patients with head and neck squamous cell carcinoma.

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

REVISTA / JOURNAL:  - Anticancer Res. 2013 Mar;33(3):1215-20.

AUTORES / AUTHORS:  - Ghosh A; Maiti GP; Bandopadhyay MN; Chakraborty J; Biswas J; Roychoudhury S; Panda CK

INSTITUCIÓN / INSTITUTION:  - Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata 700026, India. ckpanda@vsnl.net, ckpanda.cnci@gmail.com.

RESUMEN / SUMMARY:  - Aim: This study examined the prognostic significance of candidate tumor suppressor genes (TSGs) PHD finger protein-2 (PHF2), Fanconi anaemia complementation group C (FANCC) and human homologue of Drosophila patched gene (PTCH1), in head and neck squamous cell carcinoma (HNSCC) treated primarily with  surgery, or surgery followed by adjuvant radiotherapy. PATIENTS AND METHODS: Eighty-four patients with HNSCC were followed-up for recurrence/death for up to five years after diagnosis. Molecular alterations (deletion/methylation) of TSGs  and human papilloma virus (HPV) status were determined in previous studies of our group. Statistical analyses of correlation of genetic alterations with treatment  response and survival were carried out. RESULTS: Alterations of FANCC and PTCH1 were significantly associated with locoregional recurrence/death. In the surgery  with adjuvant radiotherapy-group (n=56), patients showing alterations in FANCC and in PTCH1 were seven- and six-times, respectively, more likely to have locoregional recurrence compared to those with no alterations. In addition, the presence of alterations of both FANCC and PTCH1 had remarkable prognostic significance. CONCLUSION: FANCC and PTCH1 alterations might be used as molecular  markers for prognosis and to develop strategies for effective treatment planning.

 

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[143]

TÍTULO / TITLE:  - Prognostic impact of atypical chemokine receptor expression in patients with gastric cancer.

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

REVISTA / JOURNAL:  - J Surg Res. 2013 Feb 4. pii: S0022-4804(13)00021-8. doi: 10.1016/j.jss.2013.01.023.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.jss.2013.01.023

AUTORES / AUTHORS:  - Zhu Z; Sun Z; Wang Z; Guo P; Zheng X; Xu H

INSTITUCIÓN / INSTITUTION:  - Department of Surgical Oncology, Department of General Surgery, First Affiliated  Hospital, China Medical University, Shenyang, Liaoning Province, China.

RESUMEN / SUMMARY:  - BACKGROUND: Atypical chemokine receptors (ACRs), which serve as a decoy receptor  to attract chemokines, including DARC, D6, and CCX-CKR, have an important role in inhibiting invasion and metastasis of cancer cells; however, their expression in  gastric cancer has not been characterized. The purpose of this study was to determine the predictive value of ACRs for overall survival in gastric cancer. METHODS: We performed immunohistochemical analysis on formalin-fixed, paraffin-embedded cancer tissue and used Western blot analysis on cell lines with an antibody against ACR protein. We investigated tumor material from total of 282 consecutive gastric specimens, composed of 101 normal gastric tissues, 181 peri-carcinoma tissues (2 cm away from the carcinoma), and their relationships to clinicopathologic features and survival, using a tissue micro-array. RESULTS: We  found the expression of ACRs to be lower in gastric cancer cell lines or tissues  than in normal cell line, peri-carcinoma, or normal tissues, respectively (P < 0.05). In univariate analysis, the three proteins and their co-expression were significantly associated with higher overall survival. In multivariate analysis,  each of these molecules was not favorable for overall survival; however, their co-expression was an independently prognostic factor for overall survival (hazard ratio, 0.276; 95% confidence interval, 0.173-0.444; P < 0.001). CONCLUSIONS: These findings highlight the possibility that the multiple loss of ACRs may occur during the development of tumorigenesis, and their co-expression in gastric cancer may be predictive of favorable outcomes.

 

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[144]

TÍTULO / TITLE:  - Cytokine-induced killer cells co-cultured with complete tumor antigen-loaded dendritic cells, have enhanced selective cytotoxicity on carboplatin-resistant retinoblastoma cells.

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

REVISTA / JOURNAL:  - Oncol Rep. 2013 Feb 28. doi: 10.3892/or.2013.2315.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2013.2315

AUTORES / AUTHORS:  - Wang YF; Kunda PE; Lin JW; Wang H; Chen XM; Liu QL; Liu T

INSTITUCIÓN / INSTITUTION:  - Graduate Division, Xinxiang Medical University, Xinxiang, He’nan 453003, P.R. China.

RESUMEN / SUMMARY:  - Retinoblastoma (RB) is a challenging disease that affects mostly young children.  Chemical therapy has been shown to have limitations during clinical practice, principally because of the ability of RB to become resistant to the treatment. Nevertheless, chemotherapy is still the main treatment for RB, and immunotherapy  has become a promising treatment for most solid tumors with fewer side effects than traditional therapies. In this study, we explored the antitumor effects of cytokine-induced killer (CIK) cells co-cultured with dendritic cells (DCs) pulsed with complete tumor antigens (DC-Ag). Cytotoxicity and specificity were evaluated on an RB cell line (RB-Y79), on a human normal retina cell line (hTERT-RPE1) and  a carboplatin-resistant RB cell line. Our results showed that CIK differentiation and cytotoxicity were enhanced by co-culturing CIKs with DC-Ag. Moreover, the co-culture improved the CIK proliferation rate by increasing IL-6 and decreasing  IL-10 levels in the culture medium. Furthermore, the use of DC-Ag-CIK cells had little effect on normal retinal cells but high cytotoxicity on RB cells even on carboplatin-resistant retinoblastoma cells. This is the first study showing that  DC cells pulsed with the complete tumor antigen improve proliferation, differentiation and cytotoxic activity of CIKs specific not only for RB but also  for the chemotherapy-resistant form of the malady. Thus highly efficient immunotherapy based on DC-Ag-CIK cells may be a potential effective and safe mean of treating RB especially to patients where traditional chemical therapy has failed.

 

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[145]

TÍTULO / TITLE:  - Overcoming chemotherapy resistance of ovarian cancer cells by liposomal cisplatin: Molecular mechanisms unveiled by gene expression profiling.

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

REVISTA / JOURNAL:  - Biochem Pharmacol. 2013 Apr 15;85(8):1077-90. doi: 10.1016/j.bcp.2013.01.028. Epub 2013 Feb 8.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bcp.2013.01.028

AUTORES / AUTHORS:  - Koch M; Krieger ML; Stolting D; Brenner N; Beier M; Jaehde U; Wiese M; Royer HD; Bendas G

INSTITUCIÓN / INSTITUTION:  - Pharmaceutical Institute, Rheinische Friedrich Wilhelms University Bonn, An der Immenburg 4, 53121 Bonn, Germany.

RESUMEN / SUMMARY:  - Previously we reported that liposomal cisplatin (CDDP) overcomes CDDP resistance  of ovarian A2780cis cancer cells (Krieger et al., Int. J. Pharm. 389, 2010, 10-17). Here we find that the cytotoxic activity of liposomal CDDP is not associated with detectable DNA platination in resistant ovarian cancer cells. This suggests that the mode of action of liposomal CDDP is different from the free drug. To gain insight into mechanisms of liposomal CDDP activity, we performed a transcriptome analysis of untreated A2780cis cells, and A2780cis cells in response to exposure with IC50 values of free or liposomal CDDP. A process network analysis of upregulated genes showed that liposomal CDDP induced  a highly different gene expression profile in comparison to the free drug. p53 was identified as a key player directing transcriptional responses to free or liposomal CDDP. The free drug induced expression of essential genes of the intrinsic (mitochondrial) apoptosis pathway (BAX, BID, CASP9) most likely through p38MAPK activation. In contrast, liposomal CDDP induced expression of genes from  DNA damage pathways and several genes of the extrinsic pathway of apoptosis (TNFRSF10B-DR5, CD70-TNFSF7). It thus appears that liposomal CDDP overcomes CDDP  resistance by inducing DNA damage and in consequence programmed cell death by the extrinsic pathway. Predictions from gene expression data with respect to apoptosis activation were confirmed at the protein level by an apoptosis antibody array. This sheds new light on liposomal drug carrier approaches in cancer and suggests liposomal CDDP as promising strategy for the treatment of CDDP resistant ovarian carcinomas.

 

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[146]

TÍTULO / TITLE:  - Mechanisms of the Antitumor Activity of Human Vgamma9Vdelta2 T Cells in Combination With Zoledronic Acid in a Preclinical Model of Neuroblastoma.

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

REVISTA / JOURNAL:  - Mol Ther. 2013 Mar 12. doi: 10.1038/mt.2013.38.

            ●● Enlace al texto completo (gratuito o de pago) 1038/mt.2013.38

AUTORES / AUTHORS:  - Di Carlo E; Bocca P; Emionite L; Cilli M; Cipollone G; Morandi F; Raffaghello L; Pistoia V; Prigione I

INSTITUCIÓN / INSTITUTION:  - 1] Anatomic Pathology and Molecular Medicine, Department of Medicine and Sciences of Aging, “G. d’Annunzio” University, Chieti, Italy [2] Ce.S.I. Aging Research Center, “G. d’Annunzio” University Foundation, Chieti, Italy.

RESUMEN / SUMMARY:  - Low expression of surface major histocompatibility complex (MHC) class I molecules and defects in antigen processing machinery make human neuroblastoma (NB) cells appropriate targets for MHC unrestricted immunotherapeutic approaches. Human T-cell receptor (TCR) Vgamma9Vdelta2 lymphocytes exert MHC-unrestricted antitumor activity and are activated by phosphoantigens, whose expression in cancer cells is increased by aminobisphosphonates. With this background, we have  investigated the in vivo anti-NB activity of human Vgamma9Vdelta2 lymphocytes and zoledronic acid (ZOL). SH-SY-5Y human NB cells were injected in the adrenal gland of immunodeficient mice. After 3 days, mice received ZOL or human Vgamma9Vdelta2  T cells or both agents by intravenous administration once a week for 4 weeks. A significantly improved overall survival was observed in mice receiving Vgamma9Vdelta2 T cells in combination with ZOL. Inhibition of tumor cell proliferation, angiogenesis and lymphangiogenesis, and increased tumor cell apoptosis were detected. Vgamma9Vdelta2 T lymphocytes were attracted to NB-tumor  masses of mice receiving ZOL where they actively modified tumor microenvironment  by producing interferon-gamma (IFN-gamma), that in turn induced CXCL10 expression in NB cells. This study shows that human Vgamma9Vdelta2 T cells and ZOL in combination inhibit NB growth in vivo and may provide the rationale for a phase I clinical trial in patients with high-risk NB.Molecular Therapy (2013); doi:10.1038/mt.2013.38.

 

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[147]

TÍTULO / TITLE:  - Keratin 8 and 18 loss in epithelial cancer cells increases collective cell migration and cisplatin sensitivity through claudin1 up-regulation.

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

REVISTA / JOURNAL:  - J Biol Chem. 2013 Feb 28.

            ●● Enlace al texto completo (gratuito o de pago) 1074/jbc.M112.428920

AUTORES / AUTHORS:  - Fortier AM; Asselin E; Cadrin M

INSTITUCIÓN / INSTITUTION:  - Universite du Quebec a Trois-Rivieres, Canada.

RESUMEN / SUMMARY:  - Keratins 8 and 18 (K8/18) are simple epithelial-specific intermediate filament proteins. Keratins are essential for tissues integrity and are involved in intracellular signaling pathways which regulate cell response to injuries, cell growth and death. K8/18 expression are maintained during tumorigenesis, hence their use as diagnostic marker in tumor pathology. In recent years, studies provided evidence that keratins should not be considered only as markers but also as regulators of cancer cell signaling. The loss of K8/18 expression during epithelial-mesenchymal transition (EMT) is associated with metastasis and chemoresistance. In the present study, we investigated whether K8/18 expression play an active role in EMT. We show that K8/18 stable knockdown using shRNA increases collective migration and invasiveness of epithelial cancer cells without modulating EMT markers. K8/18-depleted cells show PI3K/Akt/NF-kappaB hyperactivation and increased MMP2 and MMP9 expression. K8/18 deletion also increases cisplatin-induced apoptosis. Increased FasR membrane targeting suggest  that apoptosis is enhanced via the extrinsic pathway. Interestingly, we identified the tight junction protein claudin1 as a regulator of these processes. This is the first indication that modulation of K8/18 expression can influence the phenotype of epithelial cancer cells at a transcriptional level and support the hypothesis that keratins play an active role in cancer progression.

 

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[148]

TÍTULO / TITLE:  - Angiopoietin-2: an attractive target for improved antiangiogenic tumor therapy.

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

REVISTA / JOURNAL:  - Cancer Res. 2013 Mar 15;73(6):1649-57. doi: 10.1158/0008-5472.CAN-12-4697. Epub 2013 Mar 6.

            ●● Enlace al texto completo (gratuito o de pago) 1158/0008-5472.CAN-12-4697

AUTORES / AUTHORS:  - Gerald D; Chintharlapalli S; Augustin HG; Benjamin LE

INSTITUCIÓN / INSTITUTION:  - Authors’ Affiliations: ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company, New York, New York; Eli Lilly and Company, Indianapolis, Indiana; Department of Vascular Biology and Tumor Angiogenesis, Medical Faculty Mannheim,  Heidelberg University; and Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany.

RESUMEN / SUMMARY:  - Anti-VEGF pathway therapies primarily target immature blood vessels in tumors. However, emerging approaches to combine with targeted therapies impacting the later stages of remodeling and vessel maturation are expected to improve clinical efficacy by expanding the target vessel population. The angiopoietin/Tie ligand/receptor system is a prototypic regulator of vessel remodeling and maturation. Angiopoietin-2 (Ang2) appears to be a particularly attractive therapeutic target. In fact, the experimental proof-of-concept showing improved efficacy when VEGF and Ang2-targeting therapies are combined has been solidly established in preclinical models, and several Ang2-targeting drugs are in clinical trials. However, rational development of these second-generation combination therapies is hampered by a limited understanding of the biological complexity that is generated from agonistic and antagonistic Ang/Tie signaling. This review discusses recent mechanistic advances in angiopoietin signaling, particularly in light of the recent study published on REGN910 and summarizes the status quo of Ang2-targeting therapies. In light of the clarified partial agonist function of Ang2, we propose that clarity on the expression profile of the angiopoietin ligands and Tie1 and Tie2 receptors in subsets of cancer vessels and cancer cells will provide clearer hypotheses for more focused rational clinical trials to exploit this seminal pathway and improve current antiangiogenic therapies. Cancer Res; 73(6); 1649-57. ©2013 AACR.

 

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[149]

TÍTULO / TITLE:  - Hyaluronic Acid as a Marker of Hepatic Sinusoidal Obstruction Syndrome Secondary  to Oxaliplatin-Based Chemotherapy in Patients with Colorectal Liver Metastases.

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

REVISTA / JOURNAL:  - Ann Surg Oncol. 2013 Mar 6.

            ●● Enlace al texto completo (gratuito o de pago) 1245/s10434-013-2915-8

AUTORES / AUTHORS:  - van den Broek MA; Vreuls CP; Winstanley A; Jansen RL; van Bijnen AA; Dello SA; Bemelmans MH; Dejong CH; Driessen A; Olde Damink SW

INSTITUCIÓN / INSTITUTION:  - Department of Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands, m.vandenbroek@maastrichtuniversity.nl.

RESUMEN / SUMMARY:  - BACKGROUND: A considerable number of patients develop sinusoidal obstruction syndrome (SOS) after oxaliplatin-based chemotherapy for colorectal liver metastases (CLMs). SOS is associated with adverse outcomes after major hepatectomy. Hyaluronic acid (HA) is a marker of hepatic sinusoidal endothelial cell function and may serve as an accurate marker of SOS. This study aimed to assess the value of systemic HA levels and fractional extraction (FE) of HA by the splanchnic area and liver as markers of SOS after oxaliplatin-based chemotherapy for CLMs. METHODS: Forty patients were studied. The presence of SOS  was assessed histopathologically. Blood samples from the radial artery and portal and hepatic veins were collected. HA levels were determined by ELISA and the FE of HA was estimated. RESULTS: SOS was present in 23 patients, 11 of whom demonstrated moderate or severe SOS. Preoperative HA levels were significantly higher in patients with moderate or severe SOS (group B, n = 11) compared to patients with no or mild SOS (group A, n = 29) (51.6 +/- 10.2 ng/mL vs. 32.1 +/-  3.5 ng/mL, p = 0.030). A cutoff HA level of 44.1 ng/mL yielded a sensitivity of 67 % and specificity of 83 % for detection of SOS. The positive predictive value  was 50 % and the negative predictive value 91 %. Both groups exhibited a similar  FE of HA by the splanchnic area (-7.9 +/- 8.5 % in Group A vs. 7.3 +/- 3.6 % in Group B, p = 0.422) and liver (-10.7 +/- 6.2 % in Group A vs. 4.6 +/- 2.3 % in Group B, p = 0.265). CONCLUSIONS: Systemic HA levels can be used to detect patients at risk of SOS after oxaliplatin-based chemotherapy for CLMs. Additional investigations into the presence of SOS are indicated in patients with elevated HA levels.

 

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[150]

TÍTULO / TITLE:  - Wwox expression may predict benefit from adjuvant tamoxifen in randomized breast  cancer patients.

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

REVISTA / JOURNAL:  - Oncol Rep. 2013 Apr;29(4):1467-74. doi: 10.3892/or.2013.2261. Epub 2013 Jan 31.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2013.2261

AUTORES / AUTHORS:  - Gothlin Eremo A; Wegman P; Stal O; Nordenskjold B; Fornander T; Wingren S

INSTITUCIÓN / INSTITUTION:  - School of Health and Medical Sciences, Orebro University, SE-70182 Orebro, Sweden. anna.gothlin-eremo@oru.se

RESUMEN / SUMMARY:  - Reduced or absent Wwox expression has recently been associated with tamoxifen resistance in breast cancer and has also been proposed as a candidate predictive  marker for treatment. We aimed to investigate the correlation of Wwox expression  with the outcome of tamoxifen treatment by examining tissues from 912 randomized  breast cancer patients. Paraffin-embedded tissues from patient tumors were arranged on tissue microarray, and Wwox protein was stained using immunohistochemistry. After microscopic examination, the results were analyzed with Cox regression, Kaplan-Meier survival curves and the log-rank test. In the group of cases having a tumor absent for Wwox expression, there was no difference in recurrence-free survival between treated and untreated patients (P=0.81). For  treated cases with a tumor expressing moderate or strong Wwox protein, recurrence-free survival was improved (P=0.001 and P=0.003, respectively). The test for interaction between Wwox and treatment response demonstrated a decreased risk of recurrence for treated patients with a moderate or strong Wwox expression (HR=0.31, 95% CI 0.10-0.98 and HR=0.28, 95% CI 0.08-0.97, respectively). Our results indicate that patients with high expression of Wwox may gain more benefit from treatment with tamoxifen.

 

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[151]

TÍTULO / TITLE:  - KRAS mutation status is not predictive for objective response to anti-EGFR treatment with erlotinib in patients with advanced pancreatic cancer.

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

REVISTA / JOURNAL:  - J Gastroenterol. 2013 Feb 23.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00535-013-0767-4

AUTORES / AUTHORS:  - Boeck S; Jung A; Laubender RP; Neumann J; Egg R; Goritschan C; Ormanns S; Haas M; Modest DP; Kirchner T; Heinemann V

INSTITUCIÓN / INSTITUTION:  - Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Marchioninistr. 15, 81377,  Munich, Germany, stefan.boeck@med.uni-muenchen.de.

RESUMEN / SUMMARY:  - BACKGROUND: It has not yet been defined if KRAS has a prognostic value or is a predictive biomarker for the efficacy of erlotinib in advanced pancreatic cancer  (PC). METHODS: AIO-PK0104 was a phase III trial comparing gemcitabine/erlotinib followed by capecitabine with capecitabine/erlotinib followed by gemcitabine in advanced PC. For this post hoc subgroup analysis, biomarker data on the KRAS exon 2 mutation status were correlated with objective response to 1st-line therapy and with overall survival after start of 2nd-line chemotherapy (OSc). RESULTS: KRAS codon 12 was mutated in 121 of 173 (70 %) patients. The KRAS status showed no association with objective response (p = 0.40), but KRAS wildtype patients had an improved OS (HR 1.68, p = 0.005). A trend for a survival benefit was also observed during (non-erlotinib containing) 2nd-line chemotherapy, with a HR of 1.47 (p = 0.10) for the OSc. CONCLUSION: This post hoc analysis of AIO-PK0104 supports the assumption that KRAS is rather a prognostic than a predictive biomarker in PC.

 

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[152]

TÍTULO / TITLE:  - Interaction with Cyclin H/Cyclin-dependent Kinase 7 (CCNH/CDK7) Stabilizes C-terminal Binding Protein 2 (CtBP2) and Promotes Cancer Cell Migration.

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

REVISTA / JOURNAL:  - J Biol Chem. 2013 Mar 29;288(13):9028-34. doi: 10.1074/jbc.M112.432005. Epub 2013 Feb 7.

            ●● Enlace al texto completo (gratuito o de pago) 1074/jbc.M112.432005

AUTORES / AUTHORS:  - Wang Y; Liu F; Mao F; Hang Q; Huang X; He S; Wang Y; Cheng C; Wang H; Xu G; Zhang T; Shen A

INSTITUCIÓN / INSTITUTION:  - From the Department of Pathogen and Immunology, Medical College, Nantong University, Nantong 226001, China.

RESUMEN / SUMMARY:  - CtBP2 has been demonstrated to possess tumor-promoting capacities by virtue of up-regulating epithelial-mesenchymal transition (EMT) and down-regulating apoptosis in cancer cells. As a result, cellular CtBP2 levels are considered a key factor determining the outcome of oncogenic transformation. How pro-tumorigenic and anti-tumorigenic factors compete for fine-tuning CtBP2 levels is incompletely understood. Here we report that the cyclin H/cyclin-dependent kinase 7 (CCNH/CDK7) complex interacted with CtBP2 in vivo and in vitro. Depletion of either CCNH or CDK7 decreased CtBP2 protein levels by accelerating proteasome-dependent CtBP2 clearance. Further analysis revealed that CCNH/CDK7 competed with the tumor repressor HIPK2 for CtBP2 binding and consequently inhibited phosphorylation and dimerization of CtBP2. Phosphorylation-defective CtBP2 interacted more strongly with CCNH/CDK7 and was more resistant to degradation. Finally, overexpression of CtBP2 increased whereas depletion of CtBP2 dampened the invasive and migratory potential of breast cancer cells. CtBP2 promoted the invasion and migration of breast cancer cells in a CCNH-dependent manner. Taken together, our data have delineated a novel pathway that regulates CtBP2 stability, suggesting that targeting the CCNH/CDK7-CtBP2 axis may yield a viable anti-tumor strategy.

 

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[153]

TÍTULO / TITLE:  - Inclusion of hemoglobin level in prognostic score provides better prognostic stratification in patients with acute promyelocytic leukemia (APL).

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

REVISTA / JOURNAL:  - Int J Hematol. 2013 Mar;97(3):388-96. doi: 10.1007/s12185-013-1276-1. Epub 2013 Feb 9.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12185-013-1276-1

AUTORES / AUTHORS:  - Park S; Lee SJ; Kim K; Jang JH; Kim DH; Lee KH; Lee JH; Lee JH; Kim DY; Jang DY; Kim H; Park JH; Ryoo HM; Bae SH; Kim MK; Hyun MS; Joo YD; Lee WS; Lee SM; Jung CW

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

RESUMEN / SUMMARY:  - The clinical outcomes of acute promyelocytic leukemia (APL) have improved greatly, but treatment failure still occurs. Identification of patients with poor prognosis is fundamental, and we propose a new clinical prognostic system (CBC-score) consisting of WBC, platelet count, and hemoglobin level. Between 1995 and 2009, 156 patients with APL from seven institutes in Korea were retrospectively reviewed. In the new CBC-score system, each of the following (WBC >/=10 x 109/L, platelet <40 x 109/L, hemoglobin <8.0 g/dL) was considered as a risk factor; the sum of each was designated as the CBC-score. With a median follow-up of 8.4 years, the complete remission (CR) rate was 81.4 % (127/156), while 24 (15.4 %) were considered as treatment failures due to early death (ED).  The 5-year overall survival (OS), leukemia-free survival, and cumulative incidence of relapse were 73.8, 82.8, and 13.5 %, respectively. Compared to the individual CBC parameters, combined prognostic systems such as PETHEMA or CBC-score provided better prognostic stratification. Compared to PETHEMA stratification, the proposed prognostic CBC-score system showed better stratification of APL patients in terms of CR rates (p = 0.004), OS (p = 0.004),  and ED (p = 0.008). This retrospective study suggests that the proposed CBC-score may provide better prognostic stratification of APL patients.

 

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[154]

TÍTULO / TITLE:  - Bitter melon juice activates cellular energy sensor AMP-activated protein kinase  causing apoptotic death of human pancreatic carcinoma cells.

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

REVISTA / JOURNAL:  - Carcinogenesis. 2013 Mar 14.

            ●● Enlace al texto completo (gratuito o de pago) 1093/carcin/bgt081

AUTORES / AUTHORS:  - Kaur M; Deep G; Jain AK; Raina K; Agarwal C; Wempe MF; Agarwal R

INSTITUCIÓN / INSTITUTION:  - Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences and.

RESUMEN / SUMMARY:  - Prognosis of pancreatic cancer is extremely poor, suggesting critical needs for additional drugs to improve disease outcome. In this study, we examined efficacy  and associated mechanism of a novel agent bitter melon juice (BMJ) against pancreatic carcinoma cells both in culture and nude mice. BMJ anticancer efficacy was analyzed in human pancreatic carcinoma BxPC-3, MiaPaCa-2, AsPC-1 and Capan-2  cells by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide, cell death enzyme-linked immunosorbent assay and annexin/propidium iodide assays. BMJ  effect on apoptosis regulators was assessed by immunoblotting. In vivo BMJ efficacy was evaluated against MiaPaCa-2 tumors in nude mice, and xenograft was analyzed for biomarkers by immunohistochemistry (IHC). Results showed that BMJ (2-5% v/v) decreases cell viability in all four pancreatic carcinoma cell lines by inducing strong apoptotic death. At molecular level, BMJ caused caspases activation, altered expression of Bcl-2 family members and cytochrome-c release into the cytosol. Additionally, BMJ decreased survivin and X-linked inhibitor of  apoptosis protein but increased p21, CHOP and phosphorylated mitogen-activated protein kinases (extracellular signal-regulated kinase ½ and p38) levels. Importantly, BMJ activated adenosine monophosphate-activated protein kinase (AMPK), a biomarker for cellular energy status, and an AMPK inhibitor (Compound C) reversed BMJ-induced caspase-3 activation suggesting activated AMPK involvement in BMJ-induced apoptosis. In vivo, oral administration of lyophilized BMJ (5mg in 100 microl water/day/mouse) for 6 weeks inhibited MiaPaCa-2 tumor xenograft growth by 60% (P < 0.01) without noticeable toxicity in nude mice. IHC  analyses of MiaPaCa-2 xenografts showed that BMJ also inhibits proliferation, induces apoptosis and activates AMPK in vivo. Overall, BMJ exerts strong anticancer efficacy against human pancreatic carcinoma cells, both in vitro and in vivo, suggesting its clinical usefulness.

 

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[155]

TÍTULO / TITLE:  - Apoptosis in chronic myeloid leukemia cells transiently treated with imatinib or  dasatinib is caused by residual BCR-ABL kinase inhibition.

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

REVISTA / JOURNAL:  - Am J Hematol. 2013 Feb 18. doi: 10.1002/ajh.23419.

            ●● Enlace al texto completo (gratuito o de pago) 1002/ajh.23419

AUTORES / AUTHORS:  - Simara P; Stejskal S; Koutna I; Potesil D; Tesarova L; Potesilova M; Zdrahal Z; Mayer J

INSTITUCIÓN / INSTITUTION:  - CBIA-Centre for Biomedical Image Analysis, Faculty of Informatics, Masaryk University, Brno, Czech Republic.

RESUMEN / SUMMARY:  - Transient, potent BCR-ABL inhibition with tyrosine kinase inhibitors (TKIs) was recently demonstrated to be sufficient to commit chronic myeloid leukemia (CML) cells to apoptosis irreversibly. This mechanism explains the clinical efficacy of once-daily dasatinib treatment, despite the rapid clearance of the drug from the  plasma. However, our in vitro data suggest that apoptosis induction after transient TKI treatment, observed in the BCR-ABL-positive cell lines K562, KYO-1, and LAMA-84 and progenitor cells from chronic phase CML patients, is instead caused by a residual kinase inhibition that persists in the cells as a consequence of intracellular drug retention. High intracellular concentrations of imatinib and dasatinib residues were measured in transiently treated cells. Furthermore, the apoptosis induced by residual imatinib or dasatinib from transient treatment could be rescued by washing out the intracellularly retained  drugs. The residual kinase inhibition was also undetectable by the phospho-CRKL assay. These findings confirm that continuous target inhibition is required for the optimal efficacy of kinase inhibitors. Am. J. Hematol., 2013. © 2013 Wiley  Periodicals, Inc.

 

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[156]

TÍTULO / TITLE:  - Inhibition of NF-kappaB-mediated signaling by the CDK inhibitor CR8 overcomes pro-survival stimuli to induce apoptosis in chronic lymphocytic leukemia cells.

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

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Mar 26.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-2170

AUTORES / AUTHORS:  - Cosimo E; McCaig AM; Carter-Brzezinski LJ; Wheadon H; Leach MT; Le Ster K; Berthou C; Durieu E; Oumata N; Galons H; Meijer L; Michie AM

INSTITUCIÓN / INSTITUTION:  - Experimental Haematology, University of Glasgow.

RESUMEN / SUMMARY:  - Background: Chronic lymphocytic leukemia (CLL) is currently incurable with standard chemotherapeutic agents, highlighting the need for novel therapies. Overcoming proliferative and cytoprotective signals generated within the microenvironment of lymphoid organs is essential for limiting CLL progression and ultimately developing a cure. EXPERIMENTAL DESIGN: We assessed the potency of cyclin-dependent kinase (CDK) inhibitor CR8, a roscovitine analog, to induce apoptosis in primary CLL from distinct prognostic subsets using flow cytometry based assays. CLL cells were cultured in in vitro pro-survival and pro-proliferative conditions to mimic microenvironmental signals in the lymphoid  organs, to elucidate the mechanism of action of CR8 in quiescent and proliferating CLL cells utilising flow cytometry, western blotting, and quantitative real-time PCR. RESULTS: CR8 was 100-fold more potent at inducing apoptosis in primary CLL cells than roscovitine, both in isolated culture and stromal-co-culture conditions. Importantly, CR8 induced apoptosis in CD40-ligated CLL cells and preferentially targeted actively proliferating cells within these cultures. CR8 treatment induced downregulation of the anti-apoptotic proteins Mcl-1 and XIAP, through inhibition of RNA polymerase II, and inhibition of NF-kappaB signaling at the transcriptional level and through inhibition of the IKK complex, resulting in stabilisation of IkappaBalpha expression. CONCLUSIONS:  CR8 is a potent CDK inhibitor that subverts pivotal pro-survival and pro-proliferative signals present in the tumor microenvironment of CLL patient lymphoid organs. Our data support the clinical development of selective CDK inhibitors as novel therapies for CLL.

 

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[157]

TÍTULO / TITLE:  - Lung Resistance-Related Protein (LRP) Expression in Malignant Ascitic Cells as a  Prognostic Marker for Advanced Ovarian Serous Carcinoma.

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

REVISTA / JOURNAL:  - Ann Surg Oncol. 2013 Mar 24.

            ●● Enlace al texto completo (gratuito o de pago) 1245/s10434-013-2878-9

AUTORES / AUTHORS:  - Kerr EH; Frederick PJ; Egger ME; Stockard CR; Sellers J; Dellamanna D; Oelschlager DK; Amm HM; Eltoum IE; Michael Straughn J; Buchsbaum DJ; Grizzle WE; McNally LR

INSTITUCIÓN / INSTITUTION:  - Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.

RESUMEN / SUMMARY:  - PURPOSE: Ovarian serous carcinoma is an aggressive cancer that often presents with metastatic disease. Although primary tumor and established metastatic foci in the omentum are generally compared to identify proteins involved in drug resistance, we investigated a potential bridge, the malignant cells from ascites, as facilitator of drug resistance and recurrence. METHODS: We evaluated the expression of drug resistance markers P-glycoprotein (P-gp), canalicular multispecific organic anion transporter (MRP2), and lung resistance-related protein (LRP) in malignant cells from ascites and matched omental metastasis from 25 patients with advanced-stage ovarian serous carcinoma who were chemotherapeutic naive and undergoing initial cytoreductive surgery. Cell viability in vitro, patient response to chemotherapy, and patient survival were correlated with these biomarkers. RESULTS: Of the 25 patients evaluated for a correlation of LRP to 1-year recurrence, we correctly predicted the 1-year recurrence of 24 patients based solely on the presence of LRP in ascitic tumor cells (p = 0.01). P-gp and MRP2 were not expressed in malignant cells of ascites  or omental metastases. Malignant cells from ascites had higher expression of LRP  and were found to be more resistant to carboplatin treatment than cells from omental metastasis (p = 0.00375) by in vitro assay. LRP expression in the malignant cells of ascites correlated with carboplatin resistance (p = 0.001) by  in vitro assay and recurrence at 1 year (p = 0.0125). CONCLUSIONS: LRP expression in malignant cells of ascites is a promising marker to predict response to first-line chemotherapy in patients with advanced ovarian serous carcinoma.

 

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[158]

TÍTULO / TITLE:  - Protein kinase Cdelta is required for ErbB2-driven mammary gland tumorigenesis and negatively correlates with prognosis in human breast cancer.

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

REVISTA / JOURNAL:  - Oncogene. 2013 Mar 11. doi: 10.1038/onc.2013.59.

            ●● Enlace al texto completo (gratuito o de pago) 1038/onc.2013.59

AUTORES / AUTHORS:  - Allen-Petersen BL; Carter CJ; Ohm AM; Reyland ME

INSTITUCIÓN / INSTITUTION:  - Program in Cell Biology, Stem Cells and Development, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.

RESUMEN / SUMMARY:  - Protein kinase C delta (PKCdelta) regulates apoptosis in the mammary gland, however, the functional contribution of PKCdelta to the development or progression of breast cancer has yet to be determined. Meta-analysis of ErbB2-positive breast cancers shows increased PKCdelta expression, and a negative correlation between PKCdelta expression and prognosis. Here, we present in-vivo evidence that PKCdelta is essential for the development of mammary gland tumors in a ErbB2-overexpressing transgenic mouse model, and in-vitro evidence that PKCdelta is required for proliferative signaling downstream of the ErbB2 receptor. Mouse mammary tumor virus (MMTV)-ErbB2 mice lacking PKCdelta (deltaKO)  have increased tumor latency compared with MMTV-ErbB2 wild-type (deltaWT) mice, and the tumors show a dramatic decrease in Ki-67 staining. To explore the relationship between PKCdelta and ErbB2-driven proliferation more directly, we used MCF-10A cells engineered to express a synthetic ligand-inducible form of the ErbB2 receptor. Depletion of PKCdelta with short hairpin RNA inhibited ligand-induced growth in both two-dimensional (2D) (plastic) and three-dimensional (3D) (Matrigel) culture, and correlated with decreased phosphorylation of the ErbB2 receptor and reduced activation of Src and MAPK/ERK  pathways. Similarly, in human breast cancer cell lines in which ErbB2 is overexpressed, depletion of PKCdelta suppresses proliferation, Src and ERK activation. PKCdelta appears to drive proliferation through the formation of an active ErbB2/PKCdelta/Src signaling complex, as depletion of PKCdelta disrupts association of Src with the ErbB2 receptor. Taken together, our studies present the first evidence that PKCdelta is a critical regulator of ErbB2-mediated tumorigenesis, and suggest further investigation of PKCdelta as a target in ErbB2-positive breast cancer.Oncogene advance online publication, 11 March 2013;  doi:10.1038/onc.2013.59.

 

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[159]

TÍTULO / TITLE:  - Sarcopenia and body mass index predict sunitinib-induced early dose-limiting toxicities in renal cancer patients.

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

REVISTA / JOURNAL:  - Br J Cancer. 2013 Mar 19;108(5):1034-41. doi: 10.1038/bjc.2013.58. Epub 2013 Mar  5.

            ●● Enlace al texto completo (gratuito o de pago) 1038/bjc.2013.58

AUTORES / AUTHORS:  - Huillard O; Mir O; Peyromaure M; Tlemsani C; Giroux J; Boudou-Rouquette P; Ropert S; Delongchamps NB; Zerbib M; Goldwasser F

INSTITUCIÓN / INSTITUTION:  - CERIA (Centre for Research on Angiogenesis Inhibitors), Department of Medical Oncology, Teaching Hospital Cochin, AP-HP, University Paris Descartes, 27, rue du Faubourg Saint Jacques, Paris F75014, France.

RESUMEN / SUMMARY:  - Background:Little is known on factors predicting sunitinib toxicity. Recently, the condition of low muscle mass, named sarcopenia, was identified as a significant predictor of toxicity in metastatic renal cell cancer (mRCC) patients treated with sorafenib. We investigated whether sarcopenia could predict early dose-limiting toxicities (DLTs) occurrence in mRCC patients treated with sunitinib.Methods:Consecutive mRCC patients treated with sunitinib were retrospectively reviewed. A DLT was defined as any toxicity leading to dose reduction or treatment discontinuation. Body composition was evaluated using CT scan obtained within 1 month before treatment initiation.Results:Among 61 patients eligible for analysis, 52.5% were sarcopenic and 32.8% had both sarcopenia and a body mass index (BMI)<25 kg m(-2). Eighteen patients (29.5%) experienced a DLT during the first cycle. Sarcopenic patients with a BMI<25 kg m(-2) experienced more DLTs (P=0.01; odds ratio=4.1; 95% CI: (1.3-13.3)), more cumulative grade 2 or 3 toxicities (P=0.008), more grade 3 toxicities (P=0.04) and more acute vascular toxicities (P=0.009).Conclusion:Patients with sarcopenia  and a BMI<25 kg m(-2) experienced significantly more DLTs during the first cycle  of treatment.

 

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[160]

TÍTULO / TITLE:  - Phase 2 study of subcutaneous omacetaxine mepesuccinate for chronic-phase chronic myeloid leukemia patients resistant to or intolerant of tyrosine kinase inhibitors.

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

REVISTA / JOURNAL:  - Am J Hematol. 2013 Feb 8. doi: 10.1002/ajh.23408.

            ●● Enlace al texto completo (gratuito o de pago) 1002/ajh.23408

AUTORES / AUTHORS:  - Cortes J; Digumarti R; Parikh PM; Wetzler M; Lipton JH; Hochhaus A; Craig AR; Benichou AC; Nicolini FE; Kantarjian HM

INSTITUCIÓN / INSTITUTION:  - Department of Leukemia, UT MD Anderson Cancer Center, Houston, Texas.

RESUMEN / SUMMARY:  - Omacetaxine mepesuccinate (omacetaxine) is a first-in-class cephalotaxine with a  unique mode of action, independent of BCR-ABL, that has shown promising activity  in patients with chronic myeloid leukemia (CML). This multicenter, noncomparative, open-label phase 2 study evaluated the efficacy and safety of subcutaneous omacetaxine in CML patients with resistance or intolerance to two or more tyrosine kinase inhibitors (TKIs); results in patients in chronic phase are  reported here. Patients received subcutaneous omacetaxine 1.25 mg/m2 twice daily  days 1-14 every 28 days until hematologic response (up to a maximum of six cycles), then days 1-7 every 28 days as maintenance. Primary endpoints were rates of hematologic response lasting >8 weeks and major cytogenetic response (MCyR). Forty-six patients were enrolled: all had received imatinib, 83% had received dasatinib, and 57% nilotinib. A median 4.5 cycles of omacetaxine were administered (range, 1-36). Hematologic response was achieved or maintained in 31 patients (67%); median response duration was 7.0 months. Ten patients (22%) achieved MCyR, including 2 (4%) complete cytogenetic responses. Median progression-free survival was 7.0 months [95% confidence interval (CI), 5.9-8.9 months], and overall survival was 30.1 months (95% CI, 20.3 months-not reached).  Grade ¾ hematologic toxicity included thrombocytopenia (54%), neutropenia (48%), and anemia (33%). Nonhematologic adverse events were predominantly grade ½ and included diarrhea (44%), nausea (30%), fatigue (24%), pyrexia (20%), headache (20%), and asthenia (20%). Subcutaneous omacetaxine may offer clinical benefit to patients with chronic-phase CML with resistance or intolerance to multiple TKI therapies. Am. J. Hematol., 2013. © 2013 Wiley Periodicals, Inc.

 

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[161]

TÍTULO / TITLE:  - KIR gene variability in cutaneous malignant melanoma: influence of KIR2D/HLA-C pairings on disease susceptibility and prognosis.

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

REVISTA / JOURNAL:  - Immunogenetics. 2013 Jan 31.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00251-013-0682-0

AUTORES / AUTHORS:  - Campillo JA; Legaz I; Lopez-Alvarez MR; Bolarin JM; Las Heras B; Muro M; Minguela A; Moya-Quiles MR; Blanco-Garcia R; Martinez-Banaclocha H; Garcia-Alonso AM; Alvarez-Lopez MR; Martinez-Escribano JA

INSTITUCIÓN / INSTITUTION:  - Immunology Department, Virgen de la Arrixaca University Hospital, Ctra. Madrid-Cartagena, 30120, El Palmar, Murcia, España, jcampillo68@hotmail.com.

RESUMEN / SUMMARY:  - Natural killer and CD8(+) T cells are believed to be involved in the immune protection against melanoma. Their function may be regulated by a group of receptors defined as killer immunoglobulin-like receptors (KIRs) and their cognate HLA class I ligands. In this study, we analyzed the influence of KIR genes and KIR/HLA-I combinations on melanoma susceptibility and/or prognosis in a Spanish Caucasian population. For this purpose, KIR genotyping by PCR-SSP and HLA-C genotyping by reverse PCR-SSO were performed in 187 melanoma patients and 200 matched controls. We found a significantly low frequency of KIR2DL3 in nodular melanoma (NM) patients (P = 0.001) and in ulcerated melanoma patients (P  < 0.0001). Similarly, the KIR2DL3/C1 combination was significantly decreased in melanoma patients (P © = 0.008) and in patients with sentinel lymph node (SLN)  melanoma metastasis (P © = 0.002). Multivariate logistic regression models showed that KIR2DL3 behaves as a protective marker for NM and ulcerated melanoma  (P = 0.02, odds ratio (OR) = 0.14 and P = 0.04, OR = 0.28, respectively), whereas the KIR2DL3/C1 pair acts as a protective marker for melanoma (P = 0.017, OR = 0.54), particularly superficial spreading melanoma (P = 0.02, OR = 0.52), and SLN metastasis (P = 0.0004, OR = 0.14). In contrast, the KIR2DL3(-)/C1C2 genotype seems to be correlated with NM and ulceration. We also report that the KIR2DL1(+)/S1(-)/C2C2 genotype is associated with susceptibility to melanoma and  SLN metastasis. Altogether, the study of KIR2D genes and HLA-C ligands may help in assessing cutaneous melanoma risk and prognosis.

 

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[162]

TÍTULO / TITLE:  - BRAF(V600E) protein expression and outcome from BRAF inhibitor treatment in BRAF(V600E) metastatic melanoma.

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

REVISTA / JOURNAL:  - Br J Cancer. 2013 Mar 5;108(4):924-31. doi: 10.1038/bjc.2013.29. Epub 2013 Feb 12.

            ●● Enlace al texto completo (gratuito o de pago) 1038/bjc.2013.29

AUTORES / AUTHORS:  - Wilmott JS; Menzies AM; Haydu LE; Capper D; Preusser M; Zhang YE; Thompson JF; Kefford RF; von Deimling A; Scolyer RA; Long GV

INSTITUCIÓN / INSTITUTION:  - 1] Melanoma Institute Australia, Sydney, New South Wales, Australia [2] Discipline of Pathology, The University of Sydney, Sydney, New South Wales, Australia.

RESUMEN / SUMMARY:  - Background:To examine the association between level and patterns of baseline intra-tumoural BRAF protein expression and clinical outcome of BRAF melanoma patients treated with selective BRAF inhibitors.Methods:Fifty-eight BRAF metastatic melanoma patients treated with dabrafenib or vemurafenib on clinical trials had pre-treatment tumour BRAF protein expression immunohistochemically (IHC) assessed using the BRAF V600E mutant-specific antibody VE1. Sections were examined for staining intensity (score 1-3) and percentage of immunoreactive tumour cells, and from this an immunoreactive score (IRS) was derived (intensity  x per cent positive/10). The presence of intra-tumoural heterogeneity for BRAF protein expression was also assessed. BRAF expression was correlated with RECIST  response, time to best response (TTBR), progression-free survival (PFS) and overall survival (OS).Results:Expression was generally high (median IRS 28 (range 5-30)) and homogeneous (78%). Expression of mutated protein BRAF as measured by intensity, per cent immunoreactive cells, or IRS did not correlate with RECIST response, TTBR, PFS or OS, including on multivariate analysis. Heterogeneity of staining was seen in 22% of cases and did not correlate with outcome.Conclusion:In the current study population, IHC-measured pre-treatment BRAF protein expression does not predict response or outcome to BRAF inhibitor therapy in BRAF metastatic melanoma patients.

 

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[163]

TÍTULO / TITLE:  - Phase II Open Label Study of the oral VEGF-Receptor inhibitor PTK787/ZK222584 (Vatalanib) in Adult Patients with Refractory or Relapsed Diffuse Large B Cell Lymphoma.

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

REVISTA / JOURNAL:  - Leuk Lymphoma. 2013 Mar 14.

            ●● Enlace al texto completo (gratuito o de pago) 3109/10428194.2013.784969

AUTORES / AUTHORS:  - Brander D; Rizzieri D; Gockerman J; Diehl L; Shea TC; Decastro C; Moore JO; Beaven A

RESUMEN / SUMMARY:  - ABSTRACT PTK787/ZK222584 (Vatalanib), an orally active inhibitor of vascular endothelial growth factor receptors (VEGF-Rs), was evaluated in this phase II study of 20 patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Patients received once daily PTK787/ZK222584 at a target dose of 1250mg. Eighteen patients were evaluable for response: 1 patient had a complete response  (CR), 6 patients had stable disease but subsequently progressed, 10 patients had  progressive disease by 3 cycles, and 1 subject withdrew before response evaluation. The patient who attained a CR underwent autologous stem cell transplantation and remains disease free 76 months after study completion. There  were no grade 4 toxicities. Grade 3 thrombocytopenia occurred in 20% and grade 3  hypertension occurred in 10%. There were no episodes of grade 3 proteinuria. In conclusion, PTK787/ZK222584 was well tolerated in a heavily pretreated population of DLBCL patients, though its therapeutic potential as a single agent in DLBCL appears limited.

 

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[164]

TÍTULO / TITLE:  - FGF-2 Prevents Cancer Cells from ER Stress-Mediated Apoptosis via Enhancing Proteasome-mediated Nck Degradation.

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

REVISTA / JOURNAL:  - Biochem J. 2013 Mar 1.

            ●● Enlace al texto completo (gratuito o de pago) 1042/BJ20121671

AUTORES / AUTHORS:  - Li B; Pi Z; Liu L; Zhang B; Huang X; Hu P; Chevet E; Yi P; Liu J

RESUMEN / SUMMARY:  - Induction of Endoplasmic Reticulum (ER) stress-mediated apoptosis in cancer cells represents an alternative approach for cancer therapy. Whether fibroblast growth  factor 2 (FGF-2)-induced survival signals may interact with ER stress signalling  in cancer cells remains elusive. In this work, we showed that pretreatment with FGF-2 decreased the inhibition of DNA synthesis and induction of apoptosis by two different ER stress inducers, tunicamycin ™ and thapsigargin (TG), in both human hepatoblastoma HepG2 cells and breast cancer MCF-7 cells. Pretreatment with FGF-2 prevented ER stress-mediated apoptosis by decreasing ER stress-induced CCAAT/-enhancer-binding protein homologous protein (CHOP) expression. We further  demonstrated that pretreatment with FGF-2 mediated decrease of TM-induced CHOP expression and apoptosis through extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathway. Finally, we demonstrated that FGF-2 promoted proteasome-mediated degradation of Non-catalytic region of tyrosine kinase adaptor protein (Nck), a SH2/SH3-containing adaptor protein. Whereas overexpression of Nck1 decreased FGF-2-induced ERK1/2 phosphorylation to inhibit  the effect of FGF-2 on TM-induced CHOP expression and apoptosis, and decrease of  Nck expression prevented TM-induced CHOP expression and apoptosis. In all, our findings provide the first evidence that Nck plays a pivotal role in integrating  FGF-2 and ER stress signals to counteract ER stress deleterious impact on cancer  cell survival.

 

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[165]

TÍTULO / TITLE:  - Combined inhibition of PI3K-related DNA-damage response kinases and mTORC1 induces apoptosis in MYC-driven B-cell lymphomas.

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

REVISTA / JOURNAL:  - Blood. 2013 Feb 12.

            ●● Enlace al texto completo (gratuito o de pago) 1182/blood-2012-08-446096

AUTORES / AUTHORS:  - Shortt J; Martin BP; Newbold A; Hannan KM; Devlin JR; Baker AJ; Ralli R; Cullinane C; Schmitt CA; Reimann M; Hall MN; Wall M; Hannan RD; Pearson RB; McArthur GA; Johnstone RW

INSTITUCIÓN / INSTITUTION:  - Gene Regulation Laboratory, Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia;

RESUMEN / SUMMARY:  - Pharmacological strategies capable of directly targeting MYC are elusive. Previous studies have shown that MYC-driven lymphomagenesis is associated with mammalian target of rapamycin (mTOR) activation and a MYC-evoked DNA damage response (DDR), transduced by phosphatidylinositol-3-kinase (PI3K)-related kinases (DNA-PK, ATM and ATR). Here we report that BEZ235, a multi-targeted pan-PI3K/dual-mTOR inhibitor, potently killed primary Myc-driven B-cell lymphomas and human cell lines bearing IG-cMYC translocations. Using pharmacological and genetic dissection of PI3K/mTOR signaling, dual DDR/mTORC1 inhibition was identified as a key mediator of apoptosis. Moreover, apoptosis was initiated at drug concentrations insufficient to antagonize PI3K/mTORC2-regulated AKT phosphorylation. p53-independent induction of the pro-apoptotic BH3-only protein, BMF, was identified as a mechanism by which dual DDR/mTORC1 inhibition caused lymphoma cell death. BEZ235 treatment induced apoptotic tumor regressions in vivo that correlated with suppression of mTORC1-regulated substrates and reduced H2AX  phosphorylation and also with feedback phosphorylation of AKT. These mechanistic  studies hold important implications for the use of multi-targeted PI3K inhibitors in the treatment of hematological malignancies. In particular the newly elucidated role of PI3K-related DDR-kinases in the response to PI3K inhibitors offers a novel therapeutic opportunity for the treatment of hematological malignancies with a MYC-driven DDR.

 

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[166]

TÍTULO / TITLE:  - The Chromatin Remodeling Gene ARID1A Is a New Prognostic Marker in Clear Cell Renal Cell Carcinoma.

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

REVISTA / JOURNAL:  - Am J Pathol. 2013 Apr;182(4):1163-70. doi: 10.1016/j.ajpath.2013.01.007. Epub 2013 Feb 12.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ajpath.2013.01.007

AUTORES / AUTHORS:  - Lichner Z; Scorilas A; White NM; Girgis AH; Rotstein L; Wiegand KC; Latif A; Chow C; Huntsman D; Yousef GM

INSTITUCIÓN / INSTITUTION:  - Department of Laboratory Medicine and Keenan Research Centre, Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.

RESUMEN / SUMMARY:  - Clear cell renal cell carcinoma (ccRCC) is the most common tumor of the adult kidney, with an increasing rate of incidence. Recently, exome sequencing studies  have revealed that the SWI/SNF (switch/sucrose nonfermentable) members PBRM1 and  ARID1A are mutated in ccRCC, and it has also been suggested that aberrant chromatin regulation is a key step in kidney cancer pathogenesis. Herein, we show that down-regulation of another SW/SNF component, ARID1A, occurs frequently in ccRCC. We detected copy number loss of ARID1A in 16% of patients with ccRCC. Immunohistochemistry indicated that 67% of ccRCC (53 of 79) had significantly lower expression of BAF250a, the protein product of ARID1A, than did the matched  normal kidney cortex. In parallel, we conducted in silico mRNA expression analysis on 404 ccRCC tumors and 167 normal kidney cortex samples using publicly  available databases and confirmed significant down-regulation of ARID1A in 68.8%  of patients. We also show that decreased BAF250a protein and ARID1A mRNA expression correlate with tumor stage and grade. Our results indicate that both the protein and mRNA levels of ARID1A are statistically significant prognostic markers for ccRCC. Even after controlling for other confounders in the multivariate analysis, BAF250 retained its prognostic significance. BAF250a IHC is easy to perform and represents a potential biomarker that could be incorporated in laboratory practice to enhance the accuracy of the existing prognostic models.

 

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[167]

TÍTULO / TITLE:  - Predictive Value of Intratumoral 99mTc-Macroaggregated Albumin Uptake in Patients with Colorectal Liver Metastases Scheduled for Radioembolization with 90Y-Microspheres.

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

REVISTA / JOURNAL:  - J Nucl Med. 2013 Apr;54(4):516-22. doi: 10.2967/jnumed.112.112508. Epub 2013 Feb  27.

            ●● Enlace al texto completo (gratuito o de pago) 2967/jnumed.112.112508

AUTORES / AUTHORS:  - Ulrich G; Dudeck O; Furth C; Ruf J; Grosser OS; Adolf D; Stiebler M; Ricke J; Amthauer H

INSTITUCIÓN / INSTITUTION:  - Department of Radiology and Nuclear Medicine, University of Magdeburg, Magdeburg, Germany; and.

RESUMEN / SUMMARY:  - (90)Y radioembolization is a promising therapy for patients with primary and secondary liver malignancies. Pretherapeutic assessment consists of hepatic angiography and (99m)Tc-macroaggregated albumin ((99m)Tc-MAA) perfusion scintigraphy to estimate the liver-to-lung shunt and exclude extrahepatic (99m)Tc-MAA deposition. However, the predictive value of intratumoral (99m)Tc-MAA uptake remains unclear. METHODS: One hundred four patients with chemotherapy-refractory liver-dominant metastatic colorectal cancer were treated  with (90)Y radioembolization between December 2006 and December 2010. All of the  patients underwent angiographic assessment and perfusion scintigraphy with (99m)Tc-MAA before lobar (90)Y radioembolization. For inclusion, patients must have undergone pretherapeutic and follow-up MR imaging (6 wk and 3 mo after radioembolization, respectively). The degree of intratumoral (99m)Tc-MAA uptake was rated, and liver metastases were classified according to changes in tumor diameter on both an individual and a patient basis using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Response at both time points, MAA uptake,  and catheter position were then statistically analyzed in a linear and generalized linear mixed model at a significance level of 0.05 (P value). RESULTS: Sixty-six patients with a total of 435 colorectal liver metastases (mean number of lesions +/- SD, 6.6 +/- 2.8; mean lesion size +/- SD, 33.8 +/- 21.2 mm; lesion size range, 10-154 mm) were included in this analysis. According to the patient-based analysis, 3 patients had partial response, 49 stable disease, and 6 progressive disease after 6 wk. After 3 mo, 5 patients showed partial response, 26 stable disease, and 17 progressive disease. There was no association of patient-based tumor response with overall (99m)Tc-MAA uptake (P = 0.172) or with  catheter position (P = 0.6456). Furthermore, an interaction effect of (99m)Tc-MAA uptake and catheter position in relation to tumor response was not found (P = 0.512). Moreover, in lesion-based analysis according to RECIST 1.1 there was no association of tumor response with degree of (99m)Tc-MAA uptake, catheter position, or interaction of (99m)Tc-MAA uptake and catheter position (P = 0.339,  0.593, and 0.658, respectively). CONCLUSION: Response to (90)Y radioembolization  was found to be independent of the degree of (99m)Tc-MAA uptake. Therefore, therapy should not be withheld from patients with colorectal liver metastases lacking intratumoral (99m)Tc-MAA accumulation.

 

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[168]

TÍTULO / TITLE:  - Phase I-IIa study of BMS-690514, an EGFR, HER-2 and -4 and VEGFR-1 to -3 oral tyrosine kinase inhibitor, in patients with advanced or metastatic solid tumours.

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

REVISTA / JOURNAL:  - Eur J Cancer. 2013 Mar 8. pii: S0959-8049(13)00120-2. doi: 10.1016/j.ejca.2013.02.012.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ejca.2013.02.012

AUTORES / AUTHORS:  - Soria JC; Baselga J; Hanna N; Laurie SA; Bahleda R; Felip E; Calvo E; Armand JP; Shepherd FA; Harbison CT; Berman D; Park JS; Zhang S; Vakkalagadda B; Kurland JF; Pathak AK; Herbst RS

INSTITUCIÓN / INSTITUTION:  - SITEP, Institut Gustave Roussy, South-Paris University, Villejuif, France. Electronic address: soria@igr.fr.

RESUMEN / SUMMARY:  - PURPOSE: BMS-690514 is a potent, reversible oral inhibitor of epidermal growth factor receptor (EGFR/HER-1), HER-2 and -4, and vascular endothelial growth factor receptors (VEGFRs)-1 to -3 offering targeted inhibition of tumour growth and vascularisation in a single agent. This phase I-IIa study was designed to identify the maximum tolerated dose (MTD) and assess safety, antitumour activity, pharmacokinetics and pharmacodynamics of BMS-690514. PATIENTS AND METHODS: In phase I, patients with advanced solid tumours received escalating doses of once-daily BMS-690514. In phase IIa, erlotinib-naive (cohort A) or erlotinib-resistant (cohort B) patients with advanced non-small-cell lung cancer  (NSCLC) received BMS-690514 once-daily at the MTD. RESULTS: In phase I (n=28), the MTD was determined to be 200mg daily. BMS-690514 was rapidly absorbed and highly metabolised after repeated oral administration with minimum drug accumulation. In phase IIa (n=62), the most frequent treatment-related adverse events were diarrhoea and acneiform rash. Adverse events that led to >1 discontinuation were diarrhoea (n=4; 4%) and rash (n=2; 2%). Disease control (4months) and objective response rates, respectively, were 43.3% and 3.3% (cohort A) and 22.6% and 3.2% (cohort B). Six of 21 (29%) NSCLC patients with wild-type EGFR achieved disease control versus seven of 10 (70%) patients with EGFR mutations (including T790M). At MTD, BMS-690514 modulated pharmacodynamic biomarkers associated with inhibition of VEGFR- and EGFR-signalling pathways. CONCLUSION: This phase I-IIa study suggests that BMS-690514 has manageable safety profile and antitumour activity in patients with NSCLC at 200mg/d, including those with EGFR mutations conferring resistance to erlotinib.

 

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[169]

TÍTULO / TITLE:  - Local therapy with continued EGFR tyrosine kinase inhibitor therapy as a treatment strategy in EGFR-mutant advanced lung cancers that have developed acquired resistance to EGFR tyrosine kinase inhibitors.

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

REVISTA / JOURNAL:  - J Thorac Oncol. 2013 Mar;8(3):346-51. doi: 10.1097/JTO.0b013e31827e1f83.

            ●● Enlace al texto completo (gratuito o de pago) 1097/JTO.0b013e31827e1f83

AUTORES / AUTHORS:  - Yu HA; Sima CS; Huang J; Solomon SB; Rimner A; Paik P; Pietanza MC; Azzoli CG; Rizvi NA; Krug LM; Miller VA; Kris MG; Riely GJ

INSTITUCIÓN / INSTITUTION:  - Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College,  New York, NY 10065, USA.

RESUMEN / SUMMARY:  - BACKGROUND: Development of acquired resistance limits the utility of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) for the treatment  of EGFR-mutant lung cancers. There are no accepted targeted therapies for use after acquired resistance develops. Metastasectomy is used in other cancers to manage oligometastatic disease. We hypothesized that local therapy is associated  with improved outcomes in patients with EGFR-mutant lung cancers with acquired resistance to EGFR TKI. METHODS: Patients who received non-central nervous system local therapy were identified by a review of data from a prospective biopsy protocol for patients with EGFR-mutant lung cancers with acquired resistance to EGFR TKI therapy and other institutional biospecimen registry protocols. RESULTS: Eighteen patients were identified, who received elective local therapy (surgical  resection, radiofrequency ablation, or radiation). Local therapy was well tolerated, with 85% of patients restarting TKI therapy within 1 month of local therapy. The median time to progression after local therapy was 10 months (95% confidence interval [CI]: 2-27 months). The median time until a subsequent change in systemic therapy was 22 months (95% CI: 6-30 months). The median overall survival from local therapy was 41 months (95% CI: 26-not reached). CONCLUSIONS:  EGFR-mutant lung cancers with acquired resistance to EGFR TKI therapy are amenable to local therapy to treat oligometastatic disease when used in conjunction with continued EGFR inhibition. Local therapy followed by continued treatment with an EGFR TKI is well tolerated and associated with long PFS and OS. Further study in selected individuals in the context of other systemic options is required.

 

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[170]

TÍTULO / TITLE:  - Urine of patients with early prostate cancer contains lower levels of light chain fragments of inter-alpha-trypsin inhibitor and saposin B but increased expression of an inter-alpha-trypsin inhibitor heavy chain 4 fragment.

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

REVISTA / JOURNAL:  - Electrophoresis. 2013 Feb 18. doi: 10.1002/elps.201200583.

            ●● Enlace al texto completo (gratuito o de pago) 1002/elps.201200583

AUTORES / AUTHORS:  - Jayapalan JJ; Ng KL; Shuib AS; Razack AH; Hashim OH

INSTITUCIÓN / INSTITUTION:  - University of Malaya Centre for Proteomics Research, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; Department of Molecular Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.

RESUMEN / SUMMARY:  - The present study was aimed at the identification of proteins that are differentially expressed in the urine of patients with prostate cancer (PCa), those with benign prostatic hyperplasia (BPH) and age-matched healthy male control subjects. Using a combination of two-dimensional gel electrophoresis and  tandem mass spectrometry, significantly lower expression of urinary saposin B and two different fragments of inter-alpha-trypsin inhibitor light chain (ITIL) was demonstrated in the PCa patients compared to the controls. However, only one of the ITIL fragments was significantly different between the PCa and BPH patients.  When image analysis was performed on urinary proteins that were transferred onto  nitrocellulose membranes and detected using a lectin that binds to O-glycans, a truncated fragment of inter-alpha-trypsin inhibitor heavy chain 4 was the sole protein found to be significantly enhanced in the PCa patients compared to the controls. Together, these urinary peptide fragments might be useful complementary biomarkers to indicate PCa as well as to distinguish it from BPH, although further epidemiological evidence on the specificity and sensitivity of the protein candidates is required.

 

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[171]

TÍTULO / TITLE:  - Cytarabine, aclarubicin and granulocyte colony-stimulating factor regimen represents an effective and safe salvage regimen for patients with acute myeloid  leukemia refractory to first course of induction chemotherapy.

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

REVISTA / JOURNAL:  - Leuk Lymphoma. 2013 Apr 2.

            ●● Enlace al texto completo (gratuito o de pago) 3109/10428194.2013.776679

AUTORES / AUTHORS:  - Zhu HH; Jiang H; Jiang B; Lu J; Jiang Q; Bao L; Zhang XH; Qin YZ; Huang XJ

INSTITUCIÓN / INSTITUTION:  - Peking University People’s Hospital, Peking University Institute of Hematology ,  Beijing , China.

RESUMEN / SUMMARY:  - There is no consensus regarding the optimal second induction course regimen for patients with acute myeloid leukemia (AML) refractory to an initial course of front-line induction. The CAG regimen (cytarabine, aclarubicin and granulocyte colony-stimulating factor) has shown promise for relapsed/refractory AML. We retrospectively compared the efficacy and toxicity of the CAG regimen (n = 44) with a non-CAG regimen (n = 31) in 75 patients with AML refractory to an initial  induction chemotherapy. The complete remission (CR) rate was higher for the CAG than the non-CAG regimen (63.5% vs. 38.7%, p = 0.038), and this was more pronounced in the subgroup of patients with a lower white blood cell (WBC) count  before first/second induction, better- and intermediate-risk patients, and non-AML-M4/5 (p = 0.019). Although the CAG group demonstrated a higher disease-free survival than the non-CAG group among the intermediate- and poor-risk patients (p = 0.019), no differences in overall survival were observed. The CAG regimen produced hematological and non-hematological side effects similar to those of the non-CAG regimen. The most frequent CAG regimen side effects were  infection (45.5%), fever (50%) and elevated transaminase levels (31.8%). No patients died within 4 weeks after initiating the second induction course in the  CAG regimen. Thus, CAG represents a highly effective and safe salvage regimen for patients with AML who are refractory to the first induction chemotherapy. This regimen may be of specific benefit for CR in patients with low WBC count, better- and intermediate-risk, and non-M4/5 disease.

 

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[172]

TÍTULO / TITLE:  - Transferrin receptor targeting nanomedicine delivering wild-type p53 gene sensitizes pancreatic cancer to gemcitabine therapy.

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

REVISTA / JOURNAL:  - Cancer Gene Ther. 2013 Mar 8. doi: 10.1038/cgt.2013.9.

            ●● Enlace al texto completo (gratuito o de pago) 1038/cgt.2013.9

AUTORES / AUTHORS:  - Camp ER; Wang C; Little EC; Watson PM; Pirollo KF; Rait A; Cole DJ; Chang EH; Watson DK

INSTITUCIÓN / INSTITUTION:  - 1] Department of Surgery, Medical University of South Carolina, Charleston, SC, USA [2] Ralph H Johnson VA Medical Center, Charleston, SC, USA.

RESUMEN / SUMMARY:  - To overcome gene therapy barriers such as low transfection efficiency and nonspecific delivery, liposomal nanoparticles targeted by a single-chain antibody fragment to the transferrin receptor (TfRscFv) delivering wild-type (wt) human p53 (SGT-53) were developed for tumor-specific targeting. We hypothesize that SGT-53 in combination with gemcitabine will demonstrate enhanced therapeutic benefit in an in vivo metastatic pancreatic cancer model. Intrasplenic injection  of 1 x 106 Panc02 murine pancreatic cancer cells was used to generate in vivo hepatic metastatic tumors. Nanoparticle localization was assessed by tail vein injection of TfRscFv with fluorescently labeled oligonucleotides (6-carboxyfluorescein phosphoramidite (6FAM) ODN) imaged by Xenogen IVIS 200 scan. SGT-53 (equivalent to 30 mug of p53 intravenously) and gemcitabine (20 mg/kg intraperitoneally) alone and in combination were administered biweekly and  compared with untreated mice. Survival was determined by blinded daily assessment of morbidity. Human wtp53 expression and transferrin levels in the tumors were assessed by western blot analysis. Tumor burden was quantified by liver weight. Xenogen imaging demonstrated tumor-specific uptake of TfRscFv-6FAM ODN. Exogenous human wtp53 protein was detected in the SGT-53-treated tumors compared with control. Compared with untreated mice with metastatic tumors demonstrating median survival of 20 days, SGT-53, gemcitabine and the combination demonstrated improved median survival of 29, 30 and 37 days, respectively. The combination treatment prolonged median survival when compared with single drug treatment and  decreased tumor burden. The tumor targeting liposomal-based SGT-53 nanoparticle is capable of sensitizing pancreatic cancer to conventional chemotherapy in pancreatic cancer models. This approach has the potential to be translated into a new, more effective therapy for pancreatic cancer. Further optimization is ongoing, moving towards a Phase 1B/2 clinical trial.Cancer Gene Therapy advance online publication, 8 March 2013; doi:10.1038/cgt.2013.9.

 

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[173]

TÍTULO / TITLE:  - Pharmacogenomics in Alzheimer’s disease: a genome-wide association study of response to cholinesterase inhibitors.

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

REVISTA / JOURNAL:  - Neurobiol Aging. 2013 Jun;34(6):1711.e7-1711.e13. doi: 10.1016/j.neurobiolaging.2012.12.008. Epub 2013 Jan 29.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.neurobiolaging.2012.12.008

AUTORES / AUTHORS:  - Martinelli-Boneschi F; Giacalone G; Magnani G; Biella G; Coppi E; Santangelo R; Brambilla P; Esposito F; Lupoli S; Clerici F; Benussi L; Ghidoni R; Galimberti D; Squitti R; Confaloni A; Bruno G; Pichler S; Mayhaus M; Riemenschneider M; Mariani C; Comi G; Scarpini E; Binetti G; Forloni G; Franceschi M; Albani D

INSTITUCIÓN / INSTITUTION:  - San Raffaele Scientific Institute, Division of Neuroscience, Laboratory of Genetics of Complex Neurological Disorders, Institute of Experimental Neurology (INSPE), Milan, Italy; Memory Clinic, Department of Neurology, and Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy. Electronic address: martinelli.filippo@hsr.it.

RESUMEN / SUMMARY:  - We conducted a genome-wide association study in a cohort of 176 Italian Alzheimer’s disease (AD) patients with extreme phenotype of response to cholinesterase inhibitors. Patients were classified into responders in case of positive, stable, or </=1 worsening of mini-mental state examination score and into nonresponders if >3 points worsening during a median follow-up of 0.85 years of treatment. Forty-eight single-nucleotide polymorphisms were selected for replication in 198 additional AD-treated patients. By using the dichotomous response trait and a quantitative trait approach (change of mini-mental state examination), a nominal replication and evidence of association when combining data were achieved for 2 single-nucleotide polymorphisms associated with response to treatment: rs6720975 (p = 2.9 x 10, beta regression coefficient: 1.61) and rs17798800 (p = 6.8 x 10, odds ratio = 0.38, 95% confidence interval = 0.25-0.58). Rs6720975 maps in the intronic region of PRKCE, a protein kinase involved in several cellular functions, whereas rs17798800 is intergenic and, according to expression quantitative trait locus (eQTL) analysis, it acts as a cis-regulator of NBEA, an A kinase-anchoring protein playing a substantial role in the maturation of the nervous system. Despite its limitations, this project paves the way for the application of personalized medicine in AD patients and for collaborative efforts in this field.

 

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[174]

TÍTULO / TITLE:  - Safety and pharmacokinetics of the antisense oligonucleotide (ASO) LY2181308 as a single-agent or in combination with idarubicin and cytarabine in patients with refractory or relapsed acute myeloid leukemia (AML).

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

REVISTA / JOURNAL:  - Invest New Drugs. 2013 Feb 10.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10637-013-9935-x

AUTORES / AUTHORS:  - Erba HP; Sayar H; Juckett M; Lahn M; Andre V; Callies S; Schmidt S; Kadam S; Brandt JT; Van Bockstaele D; Andreeff M

INSTITUCIÓN / INSTITUTION:  - University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA, herba@uabmc.edu.

RESUMEN / SUMMARY:  - Survivin is expressed in tumor cells, including acute myeloid leukemia (AML), regulates mitosis, and prevents tumor cell death. The antisense oligonucleotide sodium LY2181308 (LY2181308) inhibits survivin expression and may cause cell cycle arrest and restore apoptosis in AML. In this study, the safety, pharmacokinetics, and pharmacodynamics/efficacy of LY2181308 was examined in AML  patients, first in a cohort with monotherapy (n = 8) and then post-amendment in a cohort with the combination of cytarabine and idarubicin treatment (n = 16). LY2181308 was administered with a loading dosage of three consecutive daily infusions of 750 mg followed by weekly intravenous (IV) maintenance doses of 750  mg. Cytarabine 1.5 g/m(2) was administered as a 4-hour IV infusion on Days 3, 4,  and 5 of Cycle 1, and idarubicin 12 mg/m(2) was administered as a 30-minute IV infusion on Days 3, 4, and 5 of Cycle 1. Cytarabine and idarubicin were administered on Days 1, 2, and 3 of each subsequent 28-day cycle. Reduction of survivin was evaluated in peripheral blasts and bone marrow. Single-agent LY2181308 was well tolerated and survivin was reduced only in patients with a high survivin expression. In combination with chemotherapy, 4/16 patients had complete responses, 1/16 patients had incomplete responses, and 4/16 patients had cytoreduction. Nine patients died on study: 6 (monotherapy), 3 (combination). LY2181308 alone is well tolerated in patients with AML. In combination with cytarabine and idarubicin, LY2181308 does not appear to cause additional toxicity, and has shown some clinical benefit needing confirmation in future clinical trials.

 

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[175]

TÍTULO / TITLE:  - Transcriptome profiling and genome-wide DNA binding define the differential role  of fenretinide and all-trans RA in regulating the death and survival of human hepatocellular carcinoma Huh7 cells.

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

REVISTA / JOURNAL:  - Biochem Pharmacol. 2013 Apr 1;85(7):1007-17. doi: 10.1016/j.bcp.2013.01.023. Epub 2013 Feb 8.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bcp.2013.01.023

AUTORES / AUTHORS:  - Hu Y; Liu HX; He Y; Fang Y; Fang J; Wan YJ

INSTITUCIÓN / INSTITUTION:  - Department of Medical Pathology and Laboratory Medicine, 4645 2nd Ave, Research Building III, University of California, Davis Health Systems, Sacramento, CA 95817,United States. Electronic address: yinghu0821@gmail.com.

RESUMEN / SUMMARY:  - Fenretinide is significantly more effective in inducing apoptosis in cancer cells than all-trans retinoic acid (ATRA). The current study uses a genome-wide approach to understand the differential role fenretinide and ATRA have in inducing apoptosis in Huh7 cells. Fenretinide and ATRA-induced gene expressions and DNA bindings were profiled using microarray and chromatin immunoprecipitation with anti-RXRalpha antibody. The data showed that fenretinide was not a strong transcription regulator. Fenretinide only changed the expressions of 1 093 genes, approximately three times less than the number of genes regulated by ATRA (2 811). Biological function annotation demonstrated that both fenretinide and ATRA  participated in pathways that determine cell fate and metabolic processes. However, fenretinide specifically induced Fas/TNFalpha-mediated apoptosis by increasing the expression of pro-apoptotic genes i.e., DEDD2, CASP8, CASP4, and HSPA1A/B; whereas, ATRA induced the expression of BIRC3 and TNFAIP3, which inhibit apoptosis by interacting with TRAF2. In addition, fenretinide inhibited the expression of the genes involved in RAS/RAF/ERK-mediated survival pathway. In contrast, ATRA increased the expression of SOSC2, BRAF, MEK, and ERK genes. Most  genes regulated by fenretinide and ATRA were bound by RXRalpha, suggesting a direct effect. This study revealed that by regulating fewer genes, the effects of fenretinide become more specific and thus has fewer side effects than ATRA. The data also suggested that fenretinide induces apoptosis via death receptor effector and by inhibiting the RAS/RAF/ERK pathway. It provides insight on how retinoid efficacy can be improved and how side effects in cancer therapy can be reduced.

 

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[176]

TÍTULO / TITLE:  - Interaction between Interferon-Stimulated Gene 56 and Melanoma Differentiation-Associated Gene 5 in Toll-Like Receptor 3 Signaling in Normal Human Mesangial Cells.

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

REVISTA / JOURNAL:  - Am J Nephrol. 2013;37(2):118-25. doi: 10.1159/000346415. Epub 2013 Jan 29.

            ●● Enlace al texto completo (gratuito o de pago) 1159/000346415

AUTORES / AUTHORS:  - Imaizumi T; Aizawa-Yashiro T; Matsumiya T; Yoshida H; Watanabe S; Tsuruga K; Tatsuta T; Xing F; Hayakari R; Meng P; Tanaka H

INSTITUCIÓN / INSTITUTION:  - Department of Vascular Biology, Hirosaki University Graduate School of Medicine,  Hirosaki, Japan.

RESUMEN / SUMMARY:  - Background/Aims: Toll-like receptor 3 (TLR3) is a pathogen recognition receptor against viral double-stranded RNA. TLR3 signaling is important in antiviral responses, but inappropriate TLR3 signaling may be related with inflammatory renal diseases. Interferon (IFN)-stimulated gene 56 (ISG56) is an IFN-inducible gene that encodes a multifunctional protein with 6 tetratricopeptide motifs and is thought to be involved in antiviral reactions, but the role of ISG56 in TLR3 signaling in mesangial cells is not known well. Methods: Normal human mesangial cells were cultured and treated with a synthetic TLR3 ligand polyinosinic-polycytidylic acid, and the expression of ISG56 was analyzed using real-time RT-PCR and Western blot analyses. Using an RNA-interfering technique, involvement of TLR3, IFN-beta, melanoma differentiation-associated gene 5 (MDA5)  or retinoic acid-inducible gene-I (RIG-I) in ISG56 expression, and of ISG56 in the expression of MDA5, RIG-I, CXCL10 and CCL5 was examined. Results: Treatment of cells with polyinosinic-polycytidylic acid induced ISG56. ISG56 induction was  inhibited by knockdown of TLR3 or IFN-beta, and knockdown of ISG56 resulted in the decreased expression of MDA5, RIG-I, CXCL10 and CCL5. RNA interference against MDA5 decreased ISG56 expression. Conclusion: ISG56 was induced by TLR3 signaling via newly synthesized IFN-beta. ISG56 is involved in the expression of  MDA5, RIG-I, CXCL10 and CCL5, and ISG56 and MDA5 may constitute a positive-feedback loop. ISG56 may play a role in immune and inflammatory reactions induced by TLR3 signaling in human mesangial cells.

 

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[177]

TÍTULO / TITLE:  - Presence of the JAK2 V617F Mutation in a Patient with Chronic Neutrophilic Leukemia and Effective Response to Interferon Alfa-2b.

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

REVISTA / JOURNAL:  - Acta Haematol. 2013 Feb 7;130(1):44-46.

            ●● Enlace al texto completo (gratuito o de pago) 1159/000345851

AUTORES / AUTHORS:  - Zhang X; Pan J; Guo J

INSTITUCIÓN / INSTITUTION:  - Department of Hematology, The Second Affiliated Hospital, Fujian Medical University, Quanzhou, PR China.

RESUMEN / SUMMARY:  - Chronic neutrophilic leukemia (CNL) is a rare type of leukemia characterized by a proliferation mainly of mature neutrophils, elevated neutrophil-alkaline phosphatase activity, and no presence of the Philadelphia chromosome. The prognosis is generally poor and there is no consensus therapeutic strategy for the treatment of this disease. The JAK2 V617F mutation has been detected in patients with classical myeloproliferative disorders (MPD) including polycythemia vera and essential thrombocythemia and idiopathic myelofibrosis. In contrast, this same mutation has been detected in only 4 patients with CNL to date, suggesting that the JAK2 V617F mutation is a rare event in patients with atypical MPD. Here, we report a case of CNL with presence of the JAK2 V617F mutation. After treatment with interferon alfa-2b with 3 million units every other day for  1 month, the patient’s white blood cell count was well controlled below 10.0 x10(9)/l. At present, our patient remains symptomatically well and is maintained  on interferon alfa-2b (3 million units twice a week), and his neutrophil count now averages around 8.0-10.0 x10(9)/l.

 

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[178]

TÍTULO / TITLE:  - Interleukin-10 promoter variants predict HPV-positive tumors and survival of squamous cell carcinoma of the oropharynx.

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

REVISTA / JOURNAL:  - FASEB J. 2013 Feb 21.

            ●● Enlace al texto completo (gratuito o de pago) 1096/fj.12-226803

AUTORES / AUTHORS:  - Jin L; Sturgis EM; Cao X; Song X; Salahuddin T; Wei Q; Li G

INSTITUCIÓN / INSTITUTION:  - *Department of Head and Neck Surgery and daggerDepartment of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA;

RESUMEN / SUMMARY:  - Interleukin-10 (IL-10) plays an important role in a host’s defense against human  papillomavirus (HPV) infection. IL-10 promoter variants may affect its expression level or functional efficiency and, subsequently, susceptibility to and survival  of HPV16-associated squamous cell carcinoma of oropharynx (SCCOP). We determined  tumor HPV16 DNA and genotyped three IL-10 promoter polymorphisms in 309 incident  patients with SCCOP. Compared with the patients with corresponding common homozygous genotypes, patients carrying variant genotypes of IL-10 rs1800871 and  rs1800872 were approximately 2.5 times more likely to have HPV16(+) tumors among  patients with SCCOP. Among HPV16(+) patients with SCCOP only, compared to those with the corresponding variant genotypes, the patients with IL-10 rs1800871 and rs1800872 CC genotypes had significantly better survival and approximately 70-80% reduced risk of death/recurrence after multivariable adjustment. Additionally, functional relevance of these variants was characterized to explore the genotype-phenotype correlation. Our findings indicate that IL-10 genetic variants may be associated with tumor HPV16(+) SCCOP and predict survival of HPV16(+) patients with SCCOP. Larger studies are needed to validate our findings.-Jin, L., Sturgis, E. M., Cao, X., Song, X., Salahuddin, T., Wei, Q., Li, G. Interleukin-10 promoter variants predict HPV-positive tumors and survival of squamous cell carcinoma of the oropharynx.

 

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[179]

TÍTULO / TITLE:  - Hepatitis B reactivation in chronic myeloid leukemia patients receiving tyrosine  kinase inhibitor.

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

REVISTA / JOURNAL:  - World J Gastroenterol. 2013 Feb 28;19(8):1318-21. doi: 10.3748/wjg.v19.i8.1318.

            ●● Enlace al texto completo (gratuito o de pago) 3748/wjg.v19.i8.1318

AUTORES / AUTHORS:  - Lai GM; Yan SL; Chang CS; Tsai CY

INSTITUCIÓN / INSTITUTION:  - Guan-Min Lai, Cheng-Shyong Chang, Chien-Yu Tsai, Division of Hemato-Oncology, Department of Internal Medicine, Changhua Christian Hospital, Changhua 500, Taiwan.

RESUMEN / SUMMARY:  - Hepatitis B virus (HBV) reactivation is a well-recognized complication in patients with chronic HBV infection receiving cytotoxic or immunosuppressive chemotherapy. Imatinib mesylate and nilotinib are selective Bcr/Abl tyrosine kinase inhibitors, which are now widely used in the treatment of patients with chronic myeloid leukemia. Although HBV reactivation induced by imatinib mesylate  has been reported, nilotinib-related HBV reactivation has not been reported in the English literature. We report here 2 cases of HBV reactivation in chronic myeloid leukemia patients receiving imatinib mesylate and a novel case of nilotinib related HBV reactivation.

 

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[180]

TÍTULO / TITLE:  - Verifying Hellstrom-Lindberg score as predictive tool for response to erythropoietin therapy according to the “International Working Group” criteria, in anemic patients affected by myelodysplastic syndrome: a monocentric experience.

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

REVISTA / JOURNAL:  - Int J Hematol. 2013 Mar 19.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12185-013-1305-0

AUTORES / AUTHORS:  - Molteni A; Riva M; Greco R; Nichelatti M; Ravano E; Marbello L; Nosari A; Morra E

INSTITUCIÓN / INSTITUTION:  - Department of Hematology, Niguarda Ca’ Granda Hospital, Milan, Italy, alfredo.molteni@ospedaleniguarda.it.

RESUMEN / SUMMARY:  - The Hellstrom-Lindberg score (HLS) (1997) is designed to predict erythroid response to erythropoietin treatment in myelodysplastic patients. In order to test the validity of this scoring system, 58 patients affected by myelodysplastic syndrome, treated with a “standard dose” approach between 2001 and 2010, were analyzed. The response to erythropoietin treatment was evaluated in accordance with the “international working group” (IWG) criteria. Among the patients only two were scored “poor,” 12 “intermediate,” and 44 “good” (15 of whom were scored  “3” and 29 “4”). Although the system was verified as a predictive tool for response to erythropoietin therapy, we noted that of patients scored as “good,” those with a numerical score of “4” responded more frequently than did those scored “3”, as evaluated under both the 2006- and 2000-IWG (“major response”) criteria. The modest response rate in patients scoring “3” did not show a difference in response rate in comparison to the “intermediate” group. The present data suggest that only patients scoring “4” on the scale may show an adequate response to the standard dose erythropoietin therapy, while frontline high-dose therapy should be offered to other patients. A further analysis considering endogenous erythropoietin as a possible determinant of response revealed the optimal cut-off value of 80 mIU/mL, instead of the value of 100 mIU/mL utilized by the HLS.

 

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[181]

TÍTULO / TITLE:  - CD44v6 expression is related to mesenchymal phenotype and poor prognosis in patients with colorectal cancer.

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

REVISTA / JOURNAL:  - Oncol Rep. 2013 Apr;29(4):1570-8. doi: 10.3892/or.2013.2273. Epub 2013 Feb 5.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2013.2273

AUTORES / AUTHORS:  - Saito S; Okabe H; Watanabe M; Ishimoto T; Iwatsuki M; Baba Y; Tanaka Y; Kurashige J; Miyamoto Y; Baba H

INSTITUCIÓN / INSTITUTION:  - Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.

RESUMEN / SUMMARY:  - CD44 standard isoform (CD44s) is a cancer stem cell marker in many tumors, and is one of the CD44 isoforms.CD44v6 has been reported to correlate with tumor progression and poor prognosis in colorectal cancer. However, the relevance of CD44s and CD44v6 to epithelial-mesenchymal transition (EMT) remains unclear. Immunohistochemistry was performed to investigate the clinical importance of CD44s and CD44v6 and their relevance to EMT in 113 patients with stage II/III colorectal cancer treated by curative resection. The relevance of CD44v6 knockdown to the phenotype of colon cancer cells was examined using small interfering RNA (siRNA) specific for CD44v6 in vitro. CD44v6 expression showed a  significant inverse correlation with E-cadherin expression (P=0.0007) and a positive correlation with vimentin expression (P=0.0096). A multivariate analysis showed that high CD44v6 expression was an independent poor prognostic factor for  disease-free survival (P=0.01, HR=3.05) and overall survival (P=0.025, HR=3.16).  The clinical significance and the relevance of CD44s expression to EMT markers was noted to a lesser extent compared to CD44v6 expression. The knockdown of CD44v6 decreased vimentin expression, cell invasion and HGF-induced cell migration, but conferred only a slight effect on E-cadherin expression in colon cancer cells (HCT116 and LoVo). CD44v6 is related to poor outcome of patients with colorectal cancer via upregulation of the mesenchymal phenotype.

 

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[182]

TÍTULO / TITLE:  - A Health-Care System Perspective on Implementing Genomic Medicine: Pediatric Acute Lymphoblastic Leukemia as a Paradigm.

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

REVISTA / JOURNAL:  - Clin Pharmacol Ther. 2013 Jan 17. doi: 10.1038/clpt.2013.9.

            ●● Enlace al texto completo (gratuito o de pago) 1038/clpt.2013.9

AUTORES / AUTHORS:  - Evans WE; Crews KR; Pui CH

INSTITUCIÓN / INSTITUTION:  - Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA.

RESUMEN / SUMMARY:  - The promise of genomic medicine has received great attention over the past decade, projecting how genomics will soon guide the prevention, diagnosis, and treatment of human diseases. However, this evolution has been slower than forecast, even where evidence is often strong (e.g., pharmacogenomics). Reasons include the requirement for institutional resources and the need for the will to  push beyond barriers impeding health-care changes. Here, we illustrate how genomics has been deployed to advance the treatment of childhood leukemia.Clinical Pharmacology & Therapeutics (2013); advance online publication  6 March 2013. doi:10.1038/clpt.2013.9.

 

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[183]

TÍTULO / TITLE:  - Inhibition of ATP Citrate Lyase Induces an Anticancer Effect via Reactive Oxygen  Species: AMPK as a Predictive Biomarker for Therapeutic Impact.

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

REVISTA / JOURNAL:  - Am J Pathol. 2013 Mar 15. pii: S0002-9440(13)00136-3. doi: 10.1016/j.ajpath.2013.01.048.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ajpath.2013.01.048

AUTORES / AUTHORS:  - Migita T; Okabe S; Ikeda K; Igarashi S; Sugawara S; Tomida A; Taguchi R; Soga T; Seimiya H

INSTITUCIÓN / INSTITUTION:  - Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo; Department of Anti-Aging Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo.

RESUMEN / SUMMARY:  - De novo lipogenesis is activated in most cancers. Inhibition of ATP citrate lyase (ACLY), the enzyme that catalyzes the first step of de novo lipogenesis, leads to growth suppression and apoptosis in a subset of human cancer cells. Herein, we found that ACLY depletion increases the level of intracellular reactive oxygen species (ROS), whereas addition of an antioxidant reduced ROS and attenuated the  anticancer effect. ACLY depletion or exogenous hydrogen peroxide induces phosphorylation of AMP-activated protein kinase (p-AMPK), a crucial regulator of  lipid metabolism, independently of energy status. Analysis of various cancer cell lines revealed that cancer cells with a higher susceptibility to ACLY depletion have lower levels of basal ROS and p-AMPK. Mitochondrial-deficient rho0 cells retained high levels of ROS and p-AMPK and were resistant to ACLY depletion, whereas the replenishment of normal mitochondrial DNA reduced the levels of ROS and p-AMPK and restored the sensitivity to ACLY depletion, indicating that low basal levels of mitochondrial ROS are critical for the anticancer effect of ACLY  depletion. Finally, p-AMPK levels were significantly correlated to the levels of  oxidative DNA damage in colon cancer tissues, suggesting that p-AMPK reflects cellular ROS levels in vitro and in vivo. Together, these data suggest that ACLY  inhibition exerts an anticancer effect via increased ROS, and p-AMPK could be a predictive biomarker for its therapeutic outcome.

 

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[184]

TÍTULO / TITLE:  - Human epidermal growth factor receptor 2 (Her-2) and S-1 adjuvant chemotherapy in stage 2/3 gastric cancer patients who underwent D2 gastrectomy.

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

REVISTA / JOURNAL:  - Surg Today. 2013 Mar 20.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00595-013-0544-2

AUTORES / AUTHORS:  - Aoyama T; Yoshikawa T; Miyagi Y; Kameda Y; Shirai J; Hayashi T; Cho H; Oshima T; Yukawa N; Rino Y; Masuda M; Tsuburaya A

INSTITUCIÓN / INSTITUTION:  - Department of Gastrointestinal Surgery, Kanagawa Cancer Center, 1-1-2 Nakao, Asahi-ku, Yokohama, 241-0815, Japan.

RESUMEN / SUMMARY:  - PURPOSES: The trastuzumab for Gastric Cancer study newly defined tumors that were positive for human epidermal receptor-2 (Her-2) and created a Her-2-oriented treatment strategy that is also applicable in the adjuvant setting for stage 2/3  cancers. However, there is currently no information available on the rate of Her-2 positivity and the relapse-free survival (RFS) stratified by Her-2 status in stage 2/3 patients. METHODS: The Her-2 status, defined by the current standard method, was examined in 100 gastric cancer patients who underwent curative D2 surgery, who were pathologically diagnosed with stage 2/3 cancer, and received adjuvant S-1 chemotherapy between June 2002 and December 2011. RESULTS: Ten of the 100 patients were Her-2 positive. Her-2-positive status was more frequently seen in tumors with a differentiated histology. The 5-year RFS rate was 56.3 % in Her-2-positive cases, and 48.8 % in Her-2 negative cases, which was not significantly different (P = 0.786). CONCLUSIONS: The Her-2-positive rate for stage 2/3 gastric cancer patients was low, at only 10 %. Although the RFS was not significantly different based on the Her-2 status, the low positive rate made interpretation difficult. A multi-center study with a large sample size is necessary to clarify the prognostic impact of Her-2 in stage 2/3 gastric cancer patients.

 

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[185]

TÍTULO / TITLE:  - XBP1 promoter polymorphism modulates platinum-based chemotherapy gastrointestinal toxicity for advanced non-small cell lung cancer patients.

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

REVISTA / JOURNAL:  - Lung Cancer. 2013 Mar 16. pii: S0169-5002(13)00071-8. doi: 10.1016/j.lungcan.2013.02.012.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.lungcan.2013.02.012

AUTORES / AUTHORS:  - Peng J; Chen YY; Yang LX; Zhao XY; Gao ZQ; Yang J; Wu WT; Wang HJ; Wang JC; Qian J; Chen HY; Jin L; Bai CX; Han BH; Lu DR

INSTITUCIÓN / INSTITUTION:  - State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, Institute of Genetics, School of Life Sciences, Fudan  University, Shanghai, China.

RESUMEN / SUMMARY:  - BACKGROUND: The X-box binding protein 1 (XBP1) is a critical transcription factor in the endoplasmic reticulum stress response, which is essential for the maintenance of cellular homeostasis. Here, we investigated whether the regulatory variant rs2269577 of the XBP1 gene influences clinical outcome in advanced non-small cell lung cancer (NSCLC) patients undergoing platinum-based chemotherapy. PATIENTS AND METHODS: We recruited 663 Chinese patients with advanced NSCLC treated with platinum-based regimens and assessed the association  between rs2269577 and clinical outcome. Subsequent functional analyses, including real-time quantitative PCR and dual-luciferase assays, were performed to explore  possible molecular mechanisms. RESULTS: The G/G genotype of rs2269577 was significantly associated with severe gastrointestinal toxicity compared with the  homozygous C/C genotype (P=0.012, odds ratio=2.755), particularly in the female,  performance status 0-1, and adenocarcinoma subgroups. No significant relevance was found between rs2269577 and treatment efficacy. In gastric epithelial cells,  in vitro molecular analyses demonstrated that XBP1 mRNA expression levels decreased after treatment with cisplatin and the G allele of rs2269577 weakened the transcriptional activity of the XBP1 promoter. CONCLUSION: This is the first  study to evaluate the effect of XBP1 polymorphism on severe chemotherapy-related  adverse outcomes in platinum-treated advanced NSCLC patients using both pharmacogenomics and functional molecular analyses.

 

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[186]

TÍTULO / TITLE:  - Prognostic significance of CD44 and c-erb-B2 protein overexpression in patients with gastric cancer.

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

REVISTA / JOURNAL:  - Hepatogastroenterology. 2012 Oct;59(119):2196-201. doi: 10.5754/hge10498.

            ●● Enlace al texto completo (gratuito o de pago) 5754/hge10498

AUTORES / AUTHORS:  - Doventas A; Bilici A; Demirell F; Ersoy G; Turna H; Doventas Y

INSTITUCIÓN / INSTITUTION:  - Department of Geriatrics, Istanbul Education and Research Hospital, Istanbul, Turkey.

RESUMEN / SUMMARY:  - BACKGROUND/AIMS: The aim of the study is to evaluate the correlation between c-erb-B2 and CD44 overexpression and survival of patients with gastric cancer. METHODOLOGY: The paraffin blocks of 48 patients with gastric carcinoma were retrospectively analyzed. The pathological specimens were stained with CD44 and c-erb-B2 by immunohistochemical methods. RESULTS: The positivity of c-erb-B2 was  detected in 9 patients. In six of them, predominantly strong cytoplasmic staining was observed. The remaining three tumors were predominantly membranous stained. No correlation was found between the c-erb-B2 positivity and overall survival (OS). Seventeen specimens (35.4%) were CD44 positive, all localized in cell membrane. The median OS time of CD44 positive patients was worse than that of patients with CD44 negative (11 vs. 17 months, respectively). This difference was statistically significant (p=0.03). In 5 patients both CD44 and c-erb-B2 were detected as positive. However, there were 23 patients with both CD44 negative and c-erb-B2 negative. The median OS time for patients with both CD44 and cerb- B2 negative was better than those of patients with both CD44 and c-erb-B2 positive (37 vs. 11 months, respectively, p=0.03). The relationship between CD44 and c-erb-B2 positivities and clinicopathological factors (p>0.05). CONCLUSIONS: Our  results showed that there was no correlation between c-erb-B2 positivity and OS,  except for CD44. In addition, we found significant association of simultaneous positivities of c-erb-B2 and CD44 with OS of patients with gastric cancer. CD44 alone can be taken as a prognostic factor and also simultaneous overexpression of CD44 and c-erb-B2 may be used as a marker of poor prognosis.

 

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[187]

TÍTULO / TITLE:  - Inhibition of S6K1 enhances glucose deprivation-induced cell death via downregulation of anti-apoptotic proteins in MCF-7 breast cancer cells.

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

REVISTA / JOURNAL:  - Biochem Biophys Res Commun. 2013 Mar 1;432(1):123-8. doi: 10.1016/j.bbrc.2013.01.074. Epub 2013 Jan 29.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bbrc.2013.01.074

AUTORES / AUTHORS:  - Choi HN; Jin HO; Kim JH; Hong SE; Kim HA; Kim EK; Lee JK; Park IC; Noh WC

INSTITUCIÓN / INSTITUTION:  - Division of Radiation Cancer Research, Korea Institute of Radiological & Medical  Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul 139-706, Republic of Korea.

RESUMEN / SUMMARY:  - Nutrient-limiting conditions are frequently encountered by tumor cells in poorly  vascularized microenvironments. These stress conditions may facilitate the selection of tumor cells with an inherent ability to decrease apoptotic potential. Therefore, selective targeting of tumor cells under glucose deprivation conditions may provide an effective alternative strategy for cancer therapy. In the present study, we investigated the effects of S6 kinase 1 (S6K1)  inhibition on glucose deprivation-induced cell death and the underlying mechanisms in MCF-7 breast cancer cells. PF4708671, a selective inhibitor of S6K1, and knockdown of S6K1 with specific siRNA enhanced cell death induced under glucose deprivation conditions. Moreover, inhibition of S6K1 led to apoptosis in  glucose-starved MCF-7 cells via downregulation of the anti-apoptotic proteins, Mcl-1 and survivin. Further experiments revealed that sorafenib, shown to be involved in Mcl-1 and survivin downregulation via mTOR/S6K1 inhibition significantly promotes cell death under glucose deprivation conditions. These findings collectively suggest that S6K1 plays an important role in tumor cell survival under stress conditions, and thus inhibition of S6K1 may be an effective strategy for sensitizing cells to glucose deprivation.

 

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[188]

TÍTULO / TITLE:  - Pharmacodynamic stimulation of thrombogenesis by angiotensin (1-7) in recurrent ovarian cancer patients receiving gemcitabine and platinum-based chemotherapy.

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

REVISTA / JOURNAL:  - Cancer Chemother Pharmacol. 2013 Apr;71(4):965-72. doi: 10.1007/s00280-013-2089-x. Epub 2013 Jan 31.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00280-013-2089-x

AUTORES / AUTHORS:  - Pham H; Schwartz BM; Delmore JE; Reed E; Cruickshank S; Drummond L; Rodgers KE; Peterson KJ; Dizerega GS

INSTITUCIÓN / INSTITUTION:  - Livingston Laboratory, Keck School of Medicine at USC, 1321 N. Mission Rd., Los Angeles, CA, 90033, USA.

RESUMEN / SUMMARY:  - PURPOSE: This randomized, double-blind, placebo-controlled Phase 2 study evaluated safety and efficacy of A(1-7) for reduction in Grade 3-4 thrombocytopenia in patients receiving myelosuppressive chemotherapy. Pharmacodynamic activity of A(1-7) in platelet production and retention of scheduled dose intensity were also determined. METHODS: Thirty-four patients with ovarian, Fallopian tube, or peritoneal carcinoma receiving gemcitabine and carboplatin or cisplatin were evaluated. Patients were randomized to receive study drug subcutaneously at 100 mcg/kg (n = 11), 300 mcg/kg (n = 13), or placebo (n = 10) following chemotherapy for up to six cycles. Hematologic variables were  obtained throughout each treatment cycle. RESULTS: There were no drug-related safety issues. There were no instances of Grade 4 thrombocytopenia in patients who received 100 mcg/kg treatment compared to 6 % of chemotherapy cycles for patients receiving placebo (p = 0.07). The maximal percentage increase in platelet concentration from baseline was higher for patients who received 100 mcg/kg A(1-7) compared to placebo (p = 0.02). This increase was accompanied by a  reduction in the nadir absolute neutrophil count (p = 0.04). Relative dose intensity for the combination chemotherapy was higher for patients who received 100 mcg/kg A(1-7) compared to placebo (p = 0.04). There were no differences in outcomes for patients receiving 300 mcg/kg dose compared to placebo. CONCLUSIONS: A 100 mcg/kg dose of A(1-7) was shown to produce pharmacodynamic effects on peripheral blood platelet counts, preserve planned dose intensity, and reduce Grade 3-4 thrombocytopenia following gemcitabine and platinum chemotherapy. These findings are consistent with A(1-7)-induced stimulation of thrombogenesis in the  bone marrow following marrow-toxic chemotherapy.

 

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