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



(Conceptos / Keywords: Gliomas; Glioblastoma multiforme; Oligodendroglioma; Astrocytoma, Ependymoma; Medulloblastoma; etc).

February - March 2013


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TÍTULO / TITLE:  - Loss-of-function mutations in SMARCE1 cause an inherited disorder of multiple spinal meningiomas.

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

REVISTA / JOURNAL:  - Nat Genet. 2013 Mar;45(3):295-8. doi: 10.1038/ng.2552. Epub 2013 Feb 3.

            ●● Enlace al texto completo (gratuito o de pago) 1038/ng.2552

AUTORES / AUTHORS:  - Smith MJ; O’Sullivan J; Bhaskar SS; Hadfield KD; Poke G; Caird J; Sharif S; Eccles D; Fitzpatrick D; Rawluk D; du Plessis D; Newman WG; Evans DG

INSTITUCIÓN / INSTITUTION:  - Genetic Medicine, Manchester Academic Health Sciences Centre (MAHSC), St. Mary’s  Hospital, University of Manchester, Manchester, UK.

RESUMEN / SUMMARY:  - One-third of all primary central nervous system tumors in adults are meningiomas. Rarely, meningiomas occur at multiple sites, usually occurring in individuals with type 2 neurofibromatosis (NF2). We sequenced the exomes of three unrelated individuals with familial multiple spinal meningiomas without NF2 mutations. We identified two individuals with heterozygous loss-of-function mutations in the SWI/SNF chromatin-remodeling complex subunit gene SMARCE1. Sequencing of SMARCE1  in six further individuals with spinal meningiomas identified two additional heterozygous loss-of-function mutations. Tumors from individuals with SMARCE1 mutations were of clear-cell histological subtype, and all had loss of SMARCE1 protein, consistent with a tumor suppressor mechanism. Our findings identify multiple-spinal-meningioma disease as a new discrete entity and establish a key role for the SWI/SNF complex in the pathogenesis of both meningiomas and tumors with clear-cell histology.




TÍTULO / TITLE:  - A phase I/II trial of pazopanib in combination with lapatinib in adult patients with relapsed malignant glioma.

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

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Feb 15;19(4):900-8. doi: 10.1158/1078-0432.CCR-12-1707. Epub 2013 Jan 30.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-1707

AUTORES / AUTHORS:  - Reardon DA; Groves MD; Wen PY; Nabors L; Mikkelsen T; Rosenfeld S; Raizer J; Barriuso J; McLendon RE; Suttle AB; Ma B; Curtis CM; Dar MM; de Bono J

INSTITUCIÓN / INSTITUTION:  - Dana-Farber Cancer Institute, Boston, MA 02215, USA. David_Reardon@DFCI.harvard.edu

RESUMEN / SUMMARY:  - PURPOSE: Increased mitogenic signaling and angiogenesis, frequently facilitated by somatic activation of EGF receptor (EGFR; ErbB1) and/or loss of PTEN, and VEGF overexpression, respectively, drive malignant glioma growth. We hypothesized that patients with recurrent glioblastoma would exhibit differential antitumor benefit based on tumor PTEN/EGFRvIII status when treated with the antiangiogenic agent pazopanib and the ErbB inhibitor lapatinib. EXPERIMENTAL DESIGN: A phase II study evaluated the antitumor activity of pazopanib 400 mg/d plus lapatinib 1,000 mg/d  in patients with grade 4 malignant glioma and known PTEN/EGFRvIII status not receiving enzyme-inducing anticonvulsants (EIAC). The phase II study used a two-stage Green-Dahlberg design for futility. An independent, parallel phase I component determined the maximum-tolerated regimen (MTR) of pazopanib and lapatinib in patients with grade ¾ glioma receiving EIACs. RESULTS: The six-month progression-free survival (PFS) rates in phase II (n = 41) were 0% and  15% in the PTEN/EGFRvIII-positive and PTEN/EGFRvIII-negative cohorts, respectively, leading to early termination. Two patients (5%) had a partial response and 14 patients (34%) had stable disease lasting 8 or more weeks. In phase I (n = 34), the MTR was not reached. On the basis of pharmacokinetic and safety review, a regimen of pazopanib 600 mg plus lapatinib 1,000 mg, each twice  daily, was considered safe. Concomitant EIACs reduced exposure to pazopanib and lapatinib. CONCLUSIONS: The antitumor activity of this combination at the phase II dose tested was limited. Pharmacokinetic data indicated that exposure to lapatinib was subtherapeutic in the phase II evaluation. Evaluation of intratumoral drug delivery and activity may be essential for hypothesis-testing trials with targeted agents in malignant glioma.




TÍTULO / TITLE:  - A prospective randomized trial of perioperative seizure prophylaxis in patients with intraparenchymal brain tumors.

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

REVISTA / JOURNAL:  - J Neurosurg. 2013 Apr;118(4):873-83. doi: 10.3171/2012.12.JNS111970. Epub 2013 Feb 8.

            ●● Enlace al texto completo (gratuito o de pago) 3171/2012.12.JNS111970

AUTORES / AUTHORS:  - Wu AS; Trinh VT; Suki D; Graham S; Forman A; Weinberg JS; McCutcheon IE; Prabhu SS; Heimberger AB; Sawaya R; Wang X; Qiao W; Hess KR; Lang FF

INSTITUCIÓN / INSTITUTION:  - Departments of Neurosurgery.

RESUMEN / SUMMARY:  - Object Seizures are a potentially devastating complication of resection of brain  tumors. Consequently, many neurosurgeons administer prophylactic antiepileptic drugs (AEDs) in the perioperative period. However, it is currently unclear whether perioperative AEDs should be routinely administered to patients with brain tumors who have never had a seizure. Therefore, the authors conducted a prospective, randomized trial examining the use of phenytoin for postoperative seizure prophylaxis in patients undergoing resection for supratentorial brain metastases or gliomas. Methods Patients with brain tumors (metastases or gliomas) who did not have seizures and who were undergoing craniotomy for tumor resection  were randomized to receive either phenytoin for 7 days after tumor resection (prophylaxis group) or no seizure prophylaxis (observation group). Phenytoin levels were monitored daily. Primary outcomes were seizures and adverse events. Using an estimated seizure incidence of 30% in the observation arm and 10% in the prophylaxis arm, a Type I error of 0.05 and a Type II error of 0.20, a target accrual of 142 patients (71 per arm) was planned. Results The trial was closed before completion of accrual because Bayesian predictive probability analyses performed by an independent data monitoring committee indicated a probability of  0.003 that at the end of the study prophylaxis would prove superior to observation and a probability of 0.997 that there would be insufficient evidence  at the end of the trial to choose either arm as superior. At the time of trial closure, 123 patients (77 metastases and 46 gliomas) were randomized, with 62 receiving 7-day phenytoin (prophylaxis group) and 61 receiving no prophylaxis (observation group). The incidence of all seizures was 18% in the observation group and 24% in the prophylaxis group (p = 0.51). Importantly, the incidence of  early seizures (< 30 days after surgery) was 8% in the observation group compared with 10% in the prophylaxis group (p = 1.0). Likewise, the incidence of clinically significant early seizures was 3% in the observation group and 2% in the prophylaxis group (p = 0.62). The prophylaxis group experienced significantly more adverse events (18% vs 0%, p < 0.01). Therapeutic phenytoin levels were maintained in 80% of patients. Conclusions The incidence of seizures after surgery for brain tumors is low (8% [95% CI 3%-18%]) even without prophylactic AEDs, and the incidence of clinically significant seizures is even lower (3%). In contrast, routine phenytoin administration is associated with significant drug-related morbidity. Although the lower-than-anticipated incidence of seizures in the control group significantly limited the power of the study, the low baseline rate of perioperative seizures in patients with brain tumors raises concerns about the routine use of prophylactic phenytoin in this patient population.




TÍTULO / TITLE:  - Inhibition of PRC2 Activity by a Gain-of-Function H3 Mutation Found in Pediatric  Glioblastoma.

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

REVISTA / JOURNAL:  - Science. 2013 Mar 28.

            ●● Enlace al texto completo (gratuito o de pago) 1126/science.1232245

AUTORES / AUTHORS:  - Lewis PW; Muller MM; Koletsky MS; Cordero F; Lin S; Banaszynski LA; Garcia BA; Muir TW; Becher OJ; Allis CD

INSTITUCIÓN / INSTITUTION:  - Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New  York, NY 10065, USA.

RESUMEN / SUMMARY:  - Sequencing of pediatric gliomas has identified missense mutations Lys27Met (K27M) and Gly34Arg/Val (G34R/V) in genes encoding histone H3.3 (H3F3A) and H3.1 (HIST3H1B). We report that human diffuse intrinsic pontine gliomas (DIPGs) containing the K27M mutation display significantly lower overall H3K27me3 levels, and that histone H3K27M transgenes are sufficient to reduce H3K27me3 levels in vitro and in vivo. We find that H3K27M inhibits the enzymatic activity of the Polycomb repressive complex 2 (PRC2) through interaction with the EZH2 subunit. Additionally, transgenes containing lysine-to-methionine substitutions at other known methylated lysines (H3K9 and H3K36) are sufficient to cause specific reduction in methylation levels through inhibition of SET-domain enzymes. We propose that K-to-M substitutions may represent a mechanism to alter epigenetic states in a variety of pathologies.




TÍTULO / TITLE:  - Outcome of infants and young children with newly diagnosed ependymoma treated on  the “Head Start” III prospective clinical trial.

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

REVISTA / JOURNAL:  - J Neurooncol. 2013 Mar 19.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11060-013-1111-9

AUTORES / AUTHORS:  - Venkatramani R; Ji L; Lasky J; Haley K; Judkins A; Zhou S; Sposto R; Olshefski R; Garvin J; Tekautz T; Kennedy G; Rassekh SR; Moore T; Gardner S; Allen J; Shore R; Moertel C; Atlas M; Dhall G; Finlay J

INSTITUCIÓN / INSTITUTION:  - Division of Hematology/Oncology, Children’s Hospital Los Angeles, 4650, Sunset Boulevard, Mailstop 54, Los Angeles, CA, 90027, USA, rvenkatramani@chla.usc.edu.

RESUMEN / SUMMARY:  - This study investigates the outcome of children <10 years old with newly-diagnosed ependymoma treated on the prospective multinational “Head Start”  III clinical trial. Between April 2004 and July 2009, 19 children with newly-diagnosed ependymoma were enrolled. All children were to receive five induction chemotherapy cycles followed by one consolidation cycle of myelo-ablative chemotherapy and autologous hematopoietic cell rescue. Children between 6 and 10 years of age or with residual tumor prior to consolidation were  to receive irradiation thereafter. Median age of 19 children (8 female) was 20 months at diagnosis. Median follow up was 44 months. The primary site was infratentorial in 11 and supratentorial in 8 patients. Gross total resection was  achieved in 10 patients. After induction chemotherapy, all three supratentorial ependymoma patients with residual disease achieved a complete response (CR), while only one of six infratentorial patients with residual disease achieved CR.  Three infratentorial patients developed progressive disease during induction chemotherapy. All four infratentorial patients with residual disease who underwent autologous hematopoietic cell transplant, failed to achieve CR. Four patients received focal irradiation following chemotherapy. The 3-year event free survival (EFS) and overall survival (OS) for supratentorial ependymoma were 86 +/- 13 % and 100 % respectively. The 3-year EFS and OS for infratentorial ependymoma were 27 +/- 13 % and 73 +/- 13 % respectively. The role of intensive induction and consolidation chemotherapy in deferring irradiation should be investigated further in children with supratentorial ependymoma with residual disease following surgery. This approach appears ineffective in children with infratentorial ependymoma in the absence of irradiation.




TÍTULO / TITLE:  - Prospective evaluation of early treatment outcome in patients with meningiomas treated with particle therapy based on target volume definition with MRI and (68)Ga-DOTATOC-PET.

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

REVISTA / JOURNAL:  - Acta Oncol. 2013 Apr;52(3):514-20. doi: 10.3109/0284186X.2013.762996. Epub 2013 Feb 12.

            ●● Enlace al texto completo (gratuito o de pago) 3109/0284186X.2013.762996

AUTORES / AUTHORS:  - Combs SE; Welzel T; Habermehl D; Rieken S; Dittmar JO; Kessel K; Jakel O; Haberkorn U; Debus J

INSTITUCIÓN / INSTITUTION:  - University Hospital of Heidelberg, Department of Radiation Oncology , Heidelberg  , Germany.

RESUMEN / SUMMARY:  - Abstract Purpose. To evaluate early treatment results and toxicity in patients with meningiomas treated with particle therapy. Material and methods. Seventy patients with meningiomas were treated with protons (n = 38) or carbon ion radiotherapy (n = 26). Median age was 49 years. Median age at treatment was 55 years, 24 were male (34%), and 46 were female (66%). Histology was benign meningioma in 26 patients (37%), atypical in 23 patients (33%) and anaplastic in  four patients (6%). In 17 patients (24%) with skull base meningiomas diagnosis was based on the typical appearance of a meningioma. For benign meningiomas, total doses of 52.2-57.6 GyE were applied with protons. For high-grade lesions, the boost volume was 18 GyE carbon ions, with a median dose of 50 GyE applied as  highly conformal radiation therapy. Nineteen patients were treated as re-irradiation. Treatment planning with MRI and 68-Ga-DOTATOC-PET was evaluated.  Results. Very low rates of side effects developed, including headaches, nausea and dizziness. No severe treatment-related toxicity was observed. Local control for benign meningiomas was 100%. Five of 27 patients (19%) developed tumor recurrence during follow-up. Of these, four patients had been treated as re-irradiation for recurrent high-risk meningiomas. Actuarial local control after re-irradiation of high-risk meningiomas was therefore 67% at six and 12 months. In patients treated with primary radiotherapy, only one of 13 patients (8%) developed tumor recurrence 17 months after radiation therapy (photon and carbon ion boost). Conclusion. Continuous prospective follow-up and development of novel study concepts are required to fully exploit the long-term clinical data after particle therapy for meningiomas. To date, it may be concluded that when proton therapy is available, meningioma patients can be offered a treatment at least comparable to high-end photon therapy.




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.




TÍTULO / TITLE:  - Widespread resetting of DNA methylation in glioblastoma-initiating cells suppresses malignant cellular behavior in a lineage-dependent manner.

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

REVISTA / JOURNAL:  - Genes Dev. 2013 Mar 15;27(6):654-69. doi: 10.1101/gad.212662.112.

            ●● Enlace al texto completo (gratuito o de pago) 1101/gad.212662.112

AUTORES / AUTHORS:  - Stricker SH; Feber A; Engstrom PG; Caren H; Kurian KM; Takashima Y; Watts C; Way M; Dirks P; Bertone P; Smith A; Beck S; Pollard SM

INSTITUCIÓN / INSTITUTION:  - Department of Cancer Biology, UCL Cancer Institute, University College London, London WC1E 6BT, United Kingdom;

RESUMEN / SUMMARY:  - Epigenetic changes are frequently observed in cancer. However, their role in establishing or sustaining the malignant state has been difficult to determine due to the lack of experimental tools that enable resetting of epigenetic abnormalities. To address this, we applied induced pluripotent stem cell (iPSC) reprogramming techniques to invoke widespread epigenetic resetting of glioblastoma (GBM)-derived neural stem (GNS) cells. GBM iPSCs (GiPSCs) were subsequently redifferentiated to the neural lineage to assess the impact of cancer-specific epigenetic abnormalities on tumorigenicity. GiPSCs and their differentiating derivatives display widespread resetting of common GBM-associated changes, such as DNA hypermethylation of promoter regions of the cell motility regulator TES (testis-derived transcript), the tumor suppressor cyclin-dependent  kinase inhibitor 1C (CDKN1C; p57KIP2), and many polycomb-repressive complex 2 (PRC2) target genes (e.g., SFRP2). Surprisingly, despite such global epigenetic reconfiguration, GiPSC-derived neural progenitors remained highly malignant upon  xenotransplantation. Only when GiPSCs were directed to nonneural cell types did we observe sustained expression of reactivated tumor suppressors and reduced infiltrative behavior. These data suggest that imposing an epigenome associated with an alternative developmental lineage can suppress malignant behavior. However, in the context of the neural lineage, widespread resetting of GBM-associated epigenetic abnormalities is not sufficient to override the cancer  genome.




TÍTULO / TITLE:  - The etiology of treatment-related lymphopenia in patients with malignant gliomas: modeling radiation dose to circulating lymphocytes explains clinical observations and suggests methods of modifying the impact of radiation on immune cells.

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

REVISTA / JOURNAL:  - Cancer Invest. 2013 Feb;31(2):140-4. doi: 10.3109/07357907.2012.762780.

            ●● Enlace al texto completo (gratuito o de pago) 3109/07357907.2012.762780

AUTORES / AUTHORS:  - Yovino S; Kleinberg L; Grossman SA; Narayanan M; Ford E

INSTITUCIÓN / INSTITUTION:  - Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

RESUMEN / SUMMARY:  - PURPOSE: Severe treatment-related lymphopenia (TRL) occurs in 40% of patients with high grade gliomas (HGG) receiving glucocorticoids, temozolomide, and radiation. This occurs following radiation, persists for months, and is associated with reduced survival. As all three treatment modalities are lymphotoxic, this study was conducted to estimate the radiation dose that lymphocytes receive passing through the radiation field and if this could explain the observed TRL. MATERIALS AND METHODS: A typical glioblastoma plan (8-cm tumor, 60 Gy/30 fractions) was constructed using the Pinnacle radiation planning system. Radiation doses to circulating cells (DCC) were analyzed using MatLab. The primary endpoints were mean DCC and percent of circulating cells receiving >/=0.5 Gy. The model was also used to study how changes in target volumes (PTV), dose rates, and delivery techniques affect DCC. RESULTS: The modeling determined that  while a single radiation fraction delivered 0.5 Gy to 5% of circulating cells, after 30 fractions 99% of circulating blood had received >/=0.5 Gy. The mean DCC  was 2.2 Gy and was similar for IMRT, 3D-conformal techniques, and different dose  rates. Major changes in PTV size affected mean DCC and percent of circulating cells receiving >/=0.5 Gy. CONCLUSIONS: Standard treatment plans for brain tumors deliver potentially lymphotoxic radiation doses to the entire circulating blood pool. Altering dose rates or delivery techniques are unlikely to significantly affect DCC by the end of treatment. Novel approaches are needed to limit radiation to circulating lymphocytes given the association of lymphopenia with poorer survival in patients with HGG.




TÍTULO / TITLE:  - Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma.

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

REVISTA / JOURNAL:  - Cell. 2013 Feb 28;152(5):1065-76. doi: 10.1016/j.cell.2013.01.036.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.cell.2013.01.036

AUTORES / AUTHORS:  - Snuderl M; Batista A; Kirkpatrick ND; Ruiz de Almodovar C; Riedemann L; Walsh EC; Anolik R; Huang Y; Martin JD; Kamoun W; Knevels E; Schmidt T; Farrar CT; Vakoc BJ; Mohan N; Chung E; Roberge S; Peterson T; Bais C; Zhelyazkova BH; Yip S; Hasselblatt M; Rossig C; Niemeyer E; Ferrara N; Klagsbrun M; Duda DG; Fukumura D; Xu L; Carmeliet P; Jain RK

INSTITUCIÓN / INSTITUTION:  - Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA.

RESUMEN / SUMMARY:  - Medulloblastoma is the most common pediatric malignant brain tumor. Although current therapies improve survival, these regimens are highly toxic and are associated with significant morbidity. Here, we report that placental growth factor (PlGF) is expressed in the majority of medulloblastomas, independent of their subtype. Moreover, high expression of PlGF receptor neuropilin 1 (Nrp1) correlates with poor overall survival in patients. We demonstrate that PlGF and Nrp1 are required for the growth and spread of medulloblastoma: PlGF/Nrp1 blockade results in direct antitumor effects in vivo, resulting in medulloblastoma regression, decreased metastasis, and increased mouse survival. We reveal that PlGF is produced in the cerebellar stroma via tumor-derived Sonic  hedgehog (Shh) and show that PlGF acts through Nrp1-and not vascular endothelial  growth factor receptor 1-to promote tumor cell survival. This critical tumor-stroma interaction-mediated by Shh, PlGF, and Nrp1 across medulloblastoma subtypes-supports the development of therapies targeting PlGF/Nrp1 pathway.




TÍTULO / TITLE:  - Increased in vivo angiogenic effect of glioma stromal mesenchymal stem-like cells on glioma cancer stem cells from patients with glioblastoma.

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

REVISTA / JOURNAL:  - Int J Oncol. 2013 Mar 12. doi: 10.3892/ijo.2013.1856.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ijo.2013.1856

AUTORES / AUTHORS:  - Kong BH; Shin HD; Kim SH; Mok HS; Shim JK; Lee JH; Shin HJ; Huh YM; Kim EH; Park EK; Chang JH; Kim DS; Hong YK; Kim SH; Lee SJ; Kang SG

INSTITUCIÓN / INSTITUTION:  - Department of Medical Science, The Catholic University of Korea College of Medicine, Seoul, Republic of Korea.

RESUMEN / SUMMARY:  - The presence of glioma stromal mesenchymal stemlike cells (GS-MSLCs) in tumors from glioma patients has been previously reported. The mechanisms through which these cells function as a part of the glioma microenvironment, however, remain incompletely understood. We investigated the biological effects of GS-MSLCs on glioma cancer stem cells (gCSCs), testing the hypothesis that GS-MSLCs alter the  biological characteristics of gCSCs. GS-MSLCs and gCSCs were isolated from different glioblastoma (GBM) specimens obtained from patients. In in vitro experiments, gCSCs were cultured alone or co-cultured with GS-MSLCs, and gCSCs cell counts were compared between the two groups. In addition, two groups of orthotopic GBM xenografts in mice were created, one using gCSCs from the monoculture group and one using gCSCs isolated from the co-culture group, and tumor volume and survival were analyzed. Furthermore, in vivo proliferation, apoptosis and vessel formation were examined using immunohistochemical analyses.  In vitro cell counts for gCSCs co-cultured with GS-MSLCs increased 3-fold compared to gCSCs cultured alone. In orthotopic xenograft experiments, mice injected with gCSCs isolated from the co-culture group had significantly larger tumor volume, measured on day 40 after injection, and their survival times were shorter. Immunohistochemical analysis showed increased tumor expression of CD31,  indicative of enhanced microvessel formation in mice injected with gCSCs co-cultured with GS-MSLCs compared to mice injected with gCSCs cultured alone. However, proliferation (PCNA) and apoptosis (TUNEL) markers showed no significant difference between the two groups. In conclusion, GS-MSLCs may influence the biological properties of gCSCs, shifting them towards a more aggressive status; moreover, increased angiogenesis may be a critical component of this mechanism.




TÍTULO / TITLE:  - The treatment of glioblastomas: A systematic update on clinical Phase III trials.

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

REVISTA / JOURNAL:  - Crit Rev Oncol Hematol. 2013 Feb 27. pii: S1040-8428(13)00033-4. doi: 10.1016/j.critrevonc.2013.01.007.

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

AUTORES / AUTHORS:  - Yin AA; Cheng JX; Zhang X; Liu BL

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, Xijing Institute of Clinical Neuroscience, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province 710032, PR  China.

RESUMEN / SUMMARY:  - Glioblastomas (GBMs) are invariably associated with unavoidable tumor recurrence  and overall poor prognosis. The present study is to summarize the results of clinical Phase III studies on GBMs over the past seven years. A systematic literature search was performed using major electronic databases and by screening meeting abstracts. Totally, 16 studies of patients with newly diagnosed GBMs, recurrent GBMs, and elderly patients with GBMs were selected for this review. Although the outcomes of the experimental therapies were not encouraging, these studies produced a considerable amount of potentially clinically relevant information. Such aspects as surgical outcomes, radiation schedules, temozolomide (TMZ) schedules, methylation status of the O6-methylguanine DNA methyltransferase (MGMT) gene, combination of therapies, novel drug delivery methods and use of targeted agents have come to light and are being addressed here. In addition, we  discuss the existing controversies of (1) surgical studies, (2) evaluations of recurrence, (3) salvage treatment bias, and (4) studies on elderly patients.




TÍTULO / TITLE:  - Threatening internal carotid artery floating thrombus: left middle cerebral artery stroke in a patient with lymphoma.

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

REVISTA / JOURNAL:  - Circulation. 2013 Feb 26;127(8):e463. doi: 10.1161/CIRCULATIONAHA.112.155689.

            ●● Enlace al texto completo (gratuito o de pago) 1161/CIRCULATIONAHA.112.155689

AUTORES / AUTHORS:  - Delgado MG; Velasco A; Calleja S

INSTITUCIÓN / INSTITUTION:  - Neurology, Hospital Universitario Central de Asturias, Oviedo, España. mglezdelgado@yahoo.es




TÍTULO / TITLE:  - Phase I Trial, Pharmacokinetics, and Pharmacodynamics of Vandetanib and Dasatinib in Children with Newly Diagnosed Diffuse Intrinsic Pontine Glioma.

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

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Mar 27.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-13-0306

AUTORES / AUTHORS:  - Broniscer A; Baker SD; Wetmore C; Pai Panandiker A; Huang J; Davidoff AM; Onar-Thomas A; Panetta JC; Chin TK; Merchant TE; Baker JN; Kaste SC; Gajjar A; Stewart CF

INSTITUCIÓN / INSTITUTION:  - Department of Oncology, St. Jude Children’s Research Hospital.

RESUMEN / SUMMARY:  - PURPOSE: Testing of promising drug combinations is crucial in the treatment of diffuse intrinsic pontine glioma (DIPG). Since the VEGF and PDGF pathways are critical in gliomas, we evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of vandetanib, a VEGFR-2 inhibitor, combined with dasatinib, a potent PDGFR inhibitor, during and after radiotherapy  in children with newly diagnosed DIPG. EXPERIMENTAL DESIGN: Dasatinib was started concurrently with radiotherapy. Vandetanib was started 8 days later. We tested increasing doses of vandetanib (65 and 85 mg/m2 once daily) and dasatinib (65 and 85 mg/m2 twice daily). Dose-limiting toxicities were evaluated during the first six weeks of therapy. Plasma pharmacokinetics was obtained on days 8 and 42+/-3 in all patients and concomitantly with cerebrospinal fluid (CSF) when possible. Inhibition of targets of dasatinib in peripheral blood mononuclear cells (PBMCs)  was evaluated. RESULTS: Twenty-five patients were treated. Treatment was well tolerated. The median duration of treatment was 184 days. Diarrhea was the most significant toxicity. Three patients experienced substantial myelosuppression. The steady-state plasma pharmacokinetics of vandetanib was comparable to previous studies. Although the plasma exposure to dasatinib decreased from days 8 to 42, it remained similar to adult studies. CSF to plasma exposure of vandetanib and dasatinib were approximately 2% in 2 patients. Phosphorylated 70S6K decreased during therapy in PBMCs. CONCLUSIONS: The MTD of vandetanib and dasatinib in combination was 65 mg/m2 for each drug. Other studies are underway to test dasatinib and other PDGFR inhibitors alone or in combination for this deadly cancer.




TÍTULO / TITLE:  - Erratum to: Phase I trial of verubulin (MPC-6827) plus carboplatin in patients with relapsed glioblastoma multiforme.

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

REVISTA / JOURNAL:  - J Neurooncol. 2013 Mar 23.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11060-013-1118-2

AUTORES / AUTHORS:  - Grossmann KF; Colman H; Akerley WA; Glantz M; Matsuoko Y; Beelen AP; Yu M; De Groot JF; Aiken RD; Olson JJ; Evans BA; Jensen RL

INSTITUCIÓN / INSTITUTION:  - Division of Oncology, Huntsman Cancer Institute, University of Utah, 2000 Circle  of Hope Drive, Salt Lake City, UT, 84112, USA.




TÍTULO / TITLE:  - Can Elderly Patients With Newly Diagnosed Glioblastoma be Enrolled in Radiochemotherapy Trials?

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

REVISTA / JOURNAL:  - Am J Clin Oncol. 2013 Feb 5.

            ●● Enlace al texto completo (gratuito o de pago) 1097/COC.0b013e3182868ea2

AUTORES / AUTHORS:  - Fiorentino A; Balducci M; De Bonis P; Chiesa S; De Filippo L; Mangiola A; De Rose F; Autorino R; Rinaldi C; Fersino S; Diletto B; Matteucci P; Ciurlia E; Fusco V; Anile C; Valentini V

INSTITUCIÓN / INSTITUTION:  - *Department of Radiation Oncology, IRCCS/CROB, Rionero in Vulture (PZ) Departments of daggerRadiation Oncology double daggerNeurosurgery, Catholic University of Sacred Heart, Rome, Italy.

RESUMEN / SUMMARY:  - OBJECTIVES:: Age is an unfavorable prognostic factor in glioblastoma multiforme (GBM). To assess the possibility and the advantage of radiotherapy (RT) plus concomitant/sequential temozolomide (TMZ) in patients over 65 years with GBM, we  analyzed 4 prospective trials in terms of compliance and outcomes. METHODS:: Elderly patients with histologically proven GBM, included in 4 prospective phase  II studies with a Karnofsky Performance Status (KPS) >70 and a Charlson Comorbidity Index (CCI) <3, were selected for these analyses. Patients were treated by 3D-conformal RT (60 Gy), fractionated stereotactic conformal-RT (69.4  Gy), or intensity-modulated RT with simultaneous integrated boost (63 Gy). Concomitant (standard modality, first and last week, or from the Monday to Friday) and adjuvant chemotherapy with TMZ was administered. To stratify patients, recursive partitioning analysis was used. Safety and tolerability were  measured by the National Cancer Institute Common Criteria. Progression-free survival (PFS) and overall survival (OS) were calculated by Kaplan-Meier method.  RESULTS:: From 2001 to 2011, 201 patients were enrolled in 4 trials and 111 elderly patients were recruited for this analysis. Compliance was 96.4%: 4/111 patients discontinued treatment, prevalently for disease progression. During radiochemotherapy, acute toxicity was mild. At a median follow-up of 64 months (range, 9 to 122 mo), median PFS and OS were 10 and 13 months, respectively. Extent of surgery (P=0.009) and radiation dose (P=0.01) significantly improved survival. CONCLUSIONS:: Radiochemotherapy is effective and well tolerated by elderly patients when KPS >70 and CCI <3; therefore these criterions should be considered to enroll elderly patients in combined prospective study.




TÍTULO / TITLE:  - Expression of HAUSP in gliomas correlates with disease progression and survival of patients.

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

REVISTA / JOURNAL:  - Oncol Rep. 2013 Mar 12. doi: 10.3892/or.2013.2342.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2013.2342

AUTORES / AUTHORS:  - Cheng C; Niu C; Yang Y; Wang Y; Lu M

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei, Anhui 230001, P.R. China.

RESUMEN / SUMMARY:  - The human herpesvirus-associated ubiquitin-specific protease (HAUSP) deubiquitinating enzyme has been shown to regulate many proteins involved in the  cell cycle, as well as tumor suppressors and oncogenes. However, the expression pattern of HAUSP in glioma patients is still unclear. The purpose of the present  study was to investigate the expression pattern and prognostic significance of HAUSP in patients with glioma. Eighty glioma specimens and 10 normal control samples were obtained. Immunohistochemical assay, quantitative real-time PCR and  western blot analysis were carried out to explore the expression of HAUSP. Additionally, the association of HAUSP expression with clinicopathological parameters and the survival of glioma patients were analyzed. Our results showed  that HAUSP expression levels were increased from grade I to grade IV in the tumors of the glioma patients. Moreover, the survival rate of patients with HAUSP-positive tumors was lower when compared to that of patients with HAUSP-negative tumors. We further confirmed that high expression of HAUSP was a significant and independent prognostic indicator in glioma by multivariate analysis. Our data provide convincing evidence for the first time that the overexpression of HAUSP at the gene and protein levels is correlated with poor outcome in patients with glioma in China. HAUSP may play an important oncogenic role in glioma progression, and it is a potential diagnostic and therapeutic target.




TÍTULO / TITLE:  - Local MEG networks: The missing link between protein expression and epilepsy in glioma patients?

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

REVISTA / JOURNAL:  - Neuroimage. 2013 Mar 16;75C:203-211. doi: 10.1016/j.neuroimage.2013.02.067.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.neuroimage.2013.02.067

AUTORES / AUTHORS:  - Douw L; de Groot M; van Dellen E; Aronica E; Heimans JJ; Klein M; Stam CJ; Reijneveld JC; Hillebrand A

INSTITUCIÓN / INSTITUTION:  - Department of Neurology, VU University Medical Center, Neuroscience Campus Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands; Department of  Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, 149 13th Street, Charlestown, MA 02134, USA; Department of Radiology, Harvard Medical School, Boston, MA, USA. Electronic address: douw@nmr.mgh.harvard.edu.

RESUMEN / SUMMARY:  - Connectivity and network analysis in neuroscience has been applied to multiple spatial scales, but the links between these different scales have rarely been investigated. In tumor-related epilepsy, altered network topology is related to behavior, but the molecular basis of these observations is unknown. We elucidate  the associations between microscopic features of brain tumors, local network topology, and functional patient status. We hypothesize that expression of proteins related to tumor-related epilepsy is directly correlated with network characteristics of the tumor area. Glioma patients underwent magnetoencephalography, and functional network topology of the tumor area was used to predict tissue protein expression patterns of tumor tissue collected during neurosurgery. Protein expression and network topology were interdependent; in particular between-module connectivity was selectively associated with two epilepsy-related proteins. Total number of seizures was related to both the role  of the tumor area in the functional network and to protein expression. Importantly, classification of protein expression was predicted by between-module connectivity with up to 100% accuracy. Thus, network topology may serve as an intermediate level between molecular features of tumor tissue and symptomatology  in brain tumor patients, and can potentially be used as a non-invasive marker for microscopic tissue characteristics.




TÍTULO / TITLE:  - TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal.

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

REVISTA / JOURNAL:  - Proc Natl Acad Sci U S A. 2013 Mar 25.

            ●● Enlace al texto completo (gratuito o de pago) 1073/pnas.1303607110

AUTORES / AUTHORS:  - Killela PJ; Reitman ZJ; Jiao Y; Bettegowda C; Agrawal N; Diaz LA Jr; Friedman AH; Friedman H; Gallia GL; Giovanella BC; Grollman AP; He TC; He Y; Hruban RH; Jallo GI; Mandahl N; Meeker AK; Mertens F; Netto GJ; Rasheed BA; Riggins GJ; Rosenquist TA; Schiffman M; Shih IM; Theodorescu D; Torbenson MS; Velculescu VE; Wang TL; Wentzensen N; Wood LD; Zhang M; McLendon RE; Bigner DD; Kinzler KW; Vogelstein B; Papadopoulos N; Yan H

INSTITUCIÓN / INSTITUTION:  - The Preston Robert Tisch Brain Tumor Center at Duke, Pediatric Brain Tumor Foundation Institute at Duke, and Department of Pathology, Duke University Medical Center, Durham, NC 27710.

RESUMEN / SUMMARY:  - Malignant cells, like all actively growing cells, must maintain their telomeres,  but genetic mechanisms responsible for telomere maintenance in tumors have only recently been discovered. In particular, mutations of the telomere binding proteins alpha thalassemia/mental retardation syndrome X-linked (ATRX) or death-domain associated protein (DAXX) have been shown to underlie a telomere maintenance mechanism not involving telomerase (alternative lengthening of telomeres), and point mutations in the promoter of the telomerase reverse transcriptase (TERT) gene increase telomerase expression and have been shown to occur in melanomas and a small number of other tumors. To further define the tumor types in which this latter mechanism plays a role, we surveyed 1,230 tumors of 60 different types. We found that tumors could be divided into types with low  (<15%) and high (>/=15%) frequencies of TERT promoter mutations. The nine TERT-high tumor types almost always originated in tissues with relatively low rates of self renewal, including melanomas, liposarcomas, hepatocellular carcinomas, urothelial carcinomas, squamous cell carcinomas of the tongue, medulloblastomas, and subtypes of gliomas (including 83% of primary glioblastoma, the most common brain tumor type). TERT and ATRX mutations were mutually exclusive, suggesting that these two genetic mechanisms confer equivalent selective growth advantages. In addition to their implications for understanding  the relationship between telomeres and tumorigenesis, TERT mutations provide a biomarker that may be useful for the early detection of urinary tract and liver tumors and aid in the classification and prognostication of brain tumors.




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.




TÍTULO / TITLE:  - Effects of valganciclovir as an add-on therapy in patients with cytomegalovirus-positive glioblastoma: A randomized, double-blind, hypothesis-generating study.

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

REVISTA / JOURNAL:  - Int J Cancer. 2013 Feb 13. doi: 10.1002/ijc.28111.

            ●● Enlace al texto completo (gratuito o de pago) 1002/ijc.28111

AUTORES / AUTHORS:  - Stragliotto G; Rahbar A; Solberg NW; Lilja A; Taher C; Orrego A; Bjurman B; Tammik C; Skarman P; Peredo I; Soderberg-Naucler C

INSTITUCIÓN / INSTITUTION:  - Department of Neurology, Karolinska University Hospital, Sweden.

RESUMEN / SUMMARY:  - Cytomegalovirus is highly prevalent in glioblastomas. In 2006, we initiated a randomized, double-blind, placebo-controlled, hypothesis-generating study to examine the safety and potential efficacy of Valganciclovir as an add-on therapy  for glioblastoma. Forty-two glioblastoma patients were randomized in double-blind fashion to receive Valganciclovir or placebo in addition to standard therapy for  6 months. Magnetic resonance images were obtained before and immediately and 3 and 6 months after surgery to evaluate treatment efficacy by measuring contrast enhancing tumor volume (primary end point). Survival data were analyzed for patients and controls in explorative analyses to aid the design of future randomized trials. Trends but no significant differences were observed in tumor volumes in Valganciclovir and placebo patients at 3 (3.58 vs. 7.44 cm3 , respectively, p = 0.2881) and 6 (3.31 vs. 13.75 cm3 , p = 0.2120) months. Median  overall survival (OS) was similar in both groups (17.9 vs. 17.4 months, p = 0.430). Patients could take Valganciclovir for compassionate use after the study  phase. Explorative analyses showed an OS of 24.1 months (95% CI, 17.4-40.3) in patients receiving >6 months of Valganciclovir (Val > 6M) versus 13.1 months (95% CI, 7.9-17.7, p < 0.0001) in patients receiving Valganciclovir for 0 or <6 months, and 13.7 months (95% CI, 6.9-17.3, p = 0.0031) in contemporary controls.  OS at 4 years was 27.3% in Val>6M patients versus 5.9% in controls (p = 0.0466).  Prolonged OS in Val>6M patients suggest that future randomized trials are warranted and should evaluate whether continuous antiviral treatment can improve  outcome in glioblastoma patients.




TÍTULO / TITLE:  - TGF-beta Mediates Homing of Bone Marrow-Derived Human Mesenchymal Stem Cells to Glioma Stem Cells.

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

REVISTA / JOURNAL:  - Cancer Res. 2013 Apr 1;73(7):2333-44. doi: 10.1158/0008-5472.CAN-12-3086. Epub 2013 Jan 30.

            ●● Enlace al texto completo (gratuito o de pago) 1158/0008-5472.CAN-12-3086

AUTORES / AUTHORS:  - Shinojima N; Hossain A; Takezaki T; Fueyo J; Gumin J; Gao F; Nwajei F; Marini FC; Andreeff M; Kuratsu J; Lang FF

INSTITUCIÓN / INSTITUTION:  - Authors’ Affiliations: Departments of Neurosurgery Neuro-Oncology, and Molecular  Hematology and Therapy, The Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, Texas; and Department of Neurosurgery, Graduate  School of Life Sciences, Kumamoto University, Kumamoto, Japan.

RESUMEN / SUMMARY:  - Although studies have suggested that bone marrow human mesenchymal stem cells (BM-hMSC) may be used as delivery vehicles for cancer therapy, it remains unclear whether BM-hMSCs are capable of targeting cancer stem cells, including glioma stem cells (GSC), which are the tumor-initiating cells responsible for treatment  failures. Using standard glioma models, we identify TGF-beta as a tumor factor that attracts BM-hMSCs via TGF-beta receptors (TGFbetaR) on BM-hMSCs. Using human and rat GSCs, we then show for the first time that intravascularly administered BM-hMSCs home to GSC-xenografts that express TGF-beta. In therapeutic studies, we show that BM-hMSCs carrying the oncolytic adenovirus Delta-24-RGD prolonged the survival of TGF-beta-secreting GSC xenografts and that the efficacy of this strategy can be abrogated by inhibition of TGFbetaR on BM-hMSCs. These findings reveal the TGF-beta/TGFbetaR axis as a mediator of the tropism of BM-hMSCs for GSCs and suggest that TGF-beta predicts patients in whom BM-hMSC delivery will be effective. Cancer Res; 73(7); 2333-44. ©2012 AACR.




TÍTULO / TITLE:  - Differential molecular genetic analysis in glioblastoma multiforme of long- and short-term survivors: a clinical study in Chinese patients.

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

REVISTA / JOURNAL:  - J Neurooncol. 2013 Mar 15.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11060-013-1102-x

AUTORES / AUTHORS:  - Zhang GB; Cui XL; Sui DL; Ren XH; Zhang Z; Wang ZC; Lin S

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Tiantan Xili 6, Dongcheng District, Beijing, 100050, People’s Republic of China.

RESUMEN / SUMMARY:  - This study was designed to find whether long-term survivors (LTSs) exhibit molecular genetic differences compared with short-term survivors (STSs) in patients with GBM. Tumors from 12 patients initially diagnosed with GBM and survived longer than 36 months (LTSs) were compared with 30 patients with GBM and STSs (survival <18 months) for detecting of MGMT promoter methylation, 1p/19q LOH and IDH1 mutation. IDH1 mutation and MGMT promoter methylation were significantly more frequent in the LTSs group (P = 0.039 and 0.017, respectively). The incidence of 1p/19q co-deletion was not significantly different (P = 1.0). IDH1 mutation and MGMT promoter methylation might be independent, significant, and favorable factors for LTSs with GBM.




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.




TÍTULO / TITLE:  - PML mediates glioblastoma resistance to mammalian target of rapamycin (mTOR)-targeted therapies.

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

REVISTA / JOURNAL:  - Proc Natl Acad Sci U S A. 2013 Mar 12;110(11):4339-44. doi: 10.1073/pnas.1217602110. Epub 2013 Feb 25.

            ●● Enlace al texto completo (gratuito o de pago) 1073/pnas.1217602110

AUTORES / AUTHORS:  - Iwanami A; Gini B; Zanca C; Matsutani T; Assuncao A; Nael A; Dang J; Yang H; Zhu S; Kohyama J; Kitabayashi I; Cavenee WK; Cloughesy TF; Furnari FB; Nakamura M; Toyama Y; Okano H; Mischel PS

INSTITUCIÓN / INSTITUTION:  - Departments of Orthopaedic Surgery and Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.

RESUMEN / SUMMARY:  - Despite their nearly universal activation of mammalian target of rapamycin (mTOR) signaling, glioblastomas (GBMs) are strikingly resistant to mTOR-targeted therapy. We analyzed GBM cell lines, patient-derived tumor cell cultures, and clinical samples from patients in phase 1 clinical trials, and find that the promyelocytic leukemia (PML) gene mediates resistance to mTOR-targeted therapies. Direct mTOR inhibitors and EGF receptor (EGFR) inhibitors that block downstream mTOR signaling promote nuclear PML expression in GBMs, and genetic overexpression and knockdown approaches demonstrate that PML prevents mTOR and EGFR inhibitor-dependent cell death. Low doses of the PML inhibitor, arsenic trioxide, abrogate PML expression and reverse mTOR kinase inhibitor resistance in vivo, thus markedly inhibiting tumor growth and promoting tumor cell death in mice. These results identify a unique role for PML in mTOR and EGFR inhibitor resistance and provide a strong rationale for a combination therapeutic strategy  to overcome it.




TÍTULO / TITLE:  - Headache as a risk factor for neurovascular events in pediatric brain tumor patients.

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

REVISTA / JOURNAL:  - Neurology. 2013 Mar 13.

            ●● Enlace al texto completo (gratuito o de pago) 1212/WNL.0b013e31828cf81e

AUTORES / AUTHORS:  - Kranick SM; Campen CJ; Kasner SE; Kessler SK; Zimmerman RA; Lustig RA; Phillips PC; Beslow LA; Ichord R; Fisher MJ

INSTITUCIÓN / INSTITUTION:  - From the Departments of Neurology (S.M.K., S.E.K., R.I.), Pediatrics (P.C.P., M.J.F.), and Radiation Oncology (R.A.L.), The Perelman School of Medicine at The  University of Pennsylvania, Philadelphia; and the Divisions of Neurology (C.J.C., S.K.K., L.A.B., R.I.), Neuroradiology (R.A.Z.), and Oncology (P.C.P., M.J.F.), Children’s Hospital of Philadelphia, Philadelphia, PA.

RESUMEN / SUMMARY:  - OBJECTIVE: To determine whether severe recurrent headache is a risk factor for neurovascular events in children who received radiation for brain tumors. METHODS: This is a retrospective cohort study of children with brain tumors who received cranial irradiation at a large tertiary care center, aged 0-21 years at  diagnosis, with initial treatment between January 1, 1993 and December 31, 2002,  and 2 or more follow-up visits. Patients were considered to have severe recurrent headache if this appeared as a complaint on 2 or more visits. Headaches attributed to tumor progression, shunt malfunction, or infection, or appearing at the end of life, were excluded. Medical records were reviewed for events of stroke or TIA. RESULTS: Of 265 subjects followed for a median of 6.0 years (interquartile range 1.7-9.2 years), stroke or TIA occurred in 7/37 (19%) with severe headaches compared to 6/228 (3%) without these symptoms (hazard ratio 5.3, 95% confidence interval 1.8-15.9, p = 0.003). Adjusting for multiple variables did not remove the significance of this risk. Median time to first neurovascular  event for the entire cohort was 4.9 years (interquartile range 1.7-5.5 years). CONCLUSIONS: Severe recurrent headache appears to be a risk factor or predictor for subsequent cerebral ischemia in pediatric brain tumor survivors treated with  radiation. This finding has clinical implications for both monitoring survivors and targeting a specific population for primary stroke prevention.




TÍTULO / TITLE:  - Inverse cancer comorbidity: a serendipitous opportunity to gain insight into CNS  disorders.

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

REVISTA / JOURNAL:  - Nat Rev Neurosci. 2013 Apr;14(4):293-304. doi: 10.1038/nrn3464.

            ●● Enlace al texto completo (gratuito o de pago) 1038/nrn3464

AUTORES / AUTHORS:  - Tabares-Seisdedos R; Rubenstein JL

INSTITUCIÓN / INSTITUTION:  - Department of Medicine, University of Valencia, CIBERSAM, INCLIVA, Blasco-Ibez 15, Valencia 46010, España.

RESUMEN / SUMMARY:  - Inverse comorbidity is a lower-than-expected probability of disease occuring in individuals who have been diagnosed with other medical conditions. Emerging evidence points to inverse cancer comorbidity in people with certain CNS disorders. In this Opinion article, we discuss the evidence for this intriguing association and possible underlying mechanisms. We believe that this association  is an invaluable opportunity to gain insight into the pathogenesis of these diseases, and understanding why certain individuals with CNS disorders are protected against many different types of cancer could help to develop new and improved treatments.




TÍTULO / TITLE:  - Central nervous system prophylaxis in patients with aggressive diffuse large B cell lymphoma: an analysis of 3,258 patients in a single center.

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

REVISTA / JOURNAL:  - Med Oncol. 2013 Jun;30(2):520. doi: 10.1007/s12032-013-0520-0. Epub 2013 Mar 1.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12032-013-0520-0

AUTORES / AUTHORS:  - Aviles A; Jesus Nambo M; Neri N

INSTITUCIÓN / INSTITUTION:  - Oncology Research Oncology Diseases, Ave. Cuauhtemoc 330, Colonia Doctores, 06725 Mexico, DF, Mexico. aamiranda12@gmail.com

RESUMEN / SUMMARY:  - Central nervous system (CNS) relapse continues to be a frequent and usually fatal complication in patients with diffuse large B cell lymphoma (DLBCL). Multiple factors identify the possibility of relapse and justify neurological prophylaxis; however, most of these have not been confirmed. Thus, the use of prophylaxis has  not been defined. From 1988 to 2008, 3,258 patients with DLBCL with higher clinical risks and multiple extranodal involvement that have been treated with standard anthracycline-based chemotherapy: CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or CHOP-R (CHOP plus rituximab) and that achieve complete response were retrospectively analyzed to assess the efficacy of CNS prophylaxis. One thousand five patients received different schedules for CNS prophylaxis, and 2,253 patients did not receive CNS prophylaxis. CNS relapse was  similar in patients who receive prophylaxis (6 %) compared to patients who did not receive prophylaxis (5.9 %). Overall survival of patients who either receive  or did not receive prophylaxis was not statistically significant: 49 % versus 53  % (p = 0.802). Thus, it seems that CNS prophylaxis did not improve outcome in this special setting of patients, and no prognostic factors to predict the presence of CNS relapse were identified. It is evident that multicentric studies  are necessary to define the role of prophylaxis in order to prevent CNS relapse and that the therapeutic procedure will be carefully revised.




TÍTULO / TITLE:  - Deaths Among Adult Patients with Hypopituitarism: Hypocortisolism During Acute Stress, and De Novo Malignant Brain Tumors Contribute to an Increased Mortality.

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

REVISTA / JOURNAL:  - J Clin Endocrinol Metab. 2013 Mar 1.

            ●● Enlace al texto completo (gratuito o de pago) 1210/jc.2012-4059

AUTORES / AUTHORS:  - Burman P; Mattsson AF; Johannsson G; Hoybye C; Holmer H; Dahlqvist P; Berinder K; Engstrom BE; Ekman B; Erfurth EM; Svensson J; Wahlberg J; Karlsson FA

INSTITUCIÓN / INSTITUTION:  - Department of Endocrinology (P.B., E.M.E.), Skanes University Hospital Malmo/Lund, SE-205 02 Malmo, Sweden; Pfizer Health AB (A.F.M.), Endocrine Care, SE-190 91 Sollentuna, Sweden; Department of Endocrinology (G.J.), and Center for  Bone and Arthritis Research (J.S.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, Sweden; Department of Endocrinology, Metabolism, and Diabetology (C.H., K.B.), Karolinska University Hospital, SE-171 76 Stockholm, Sweden; Department of Internal Medicine (H.H.), Central Hospital, SE-291 85 Kristianstad, Sweden; Department of Public Health and Clinical Medicine (P.D.), Umea University, SE-901 87 Umea, Sweden; Department of  Endocrinology, Diabetes, and Metabolism (B.E.E., F.A.K.), University Hospital, Uppsala University, SE-751 85 Uppsala, Sweden; and Division of Cardiovascular Medicine (B.E., J.W.), Department of Medical and Health Sciences, Faculty of Health Sciences, Linkoping University, SE-581 83 Linkoping, Sweden.

RESUMEN / SUMMARY:  - Context:Patients with hypopituitarism have an increased standardized mortality rate. The basis for this has not been fully clarified.Objective:To investigate in detail the cause of death in a large cohort of patients with hypopituitarism subjected to long-term follow-up.Design and Methods:All-cause and cause-specific  mortality in 1286 Swedish patients with hypopituitarism prospectively monitored in KIMS (Pfizer International Metabolic Database) 1995-2009 were compared to general population data in the Swedish National Cause of Death Registry. In addition, events reported in KIMS, medical records, and postmortem reports were reviewed.Main Outcome Measures:Standardized mortality ratios (SMR) were calculated, with stratification for gender, attained age, and calendar year during follow-up.Results:An excess mortality was found, 120 deaths vs 84.3 expected, SMR 1.42 (95% confidence interval: 1.18-1.70). Infections, brain cancer, and sudden death were associated with significantly increased SMRs (6.32, 9.40, and 4.10, respectively). Fifteen patients, all ACTH-deficient, died from infections. Eight of these patients were considered to be in a state of adrenal crisis in connection with death (medical reports and post-mortem examinations). Another 8 patients died from de novo malignant brain tumors, 6 of which had had a benign pituitary lesion at baseline. Six of these 8 subjects had received prior radiation therapy.Conclusion:Two important causes of excess mortality were identified: first, adrenal crisis in response to acute stress and intercurrent illness; second, increased risk of a late appearance of de novo malignant brain tumors in patients who previously received radiotherapy. Both of these causes may be in part preventable by changes in the management of pituitary disease.




TÍTULO / TITLE:  - Somatic uniparental isodisomy explains multifocality of glomuvenous malformations.

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

REVISTA / JOURNAL:  - Am J Hum Genet. 2013 Feb 7;92(2):188-96. doi: 10.1016/j.ajhg.2012.12.017. Epub 2013 Jan 31.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ajhg.2012.12.017

AUTORES / AUTHORS:  - Amyere M; Aerts V; Brouillard P; McIntyre BA; Duhoux FP; Wassef M; Enjolras O; Mulliken JB; Devuyst O; Antoine-Poirel H; Boon LM; Vikkula M

INSTITUCIÓN / INSTITUTION:  - Laboratory of Human Molecular Genetics, de Duve Institute, Universite catholique  de Louvain, Brussels, Belgium.

RESUMEN / SUMMARY:  - Inherited vascular malformations are commonly autosomal dominantly inherited with high, but incomplete, penetrance; they often present as multiple lesions. We hypothesized that Knudson’s two-hit model could explain this multifocality and partial penetrance. We performed a systematic analysis of inherited glomuvenous malformations (GVMs) by using multiple approaches, including a sensitive allele-specific pairwise SNP-chip method. Overall, we identified 16 somatic mutations, most of which were not intragenic but were cases of acquired uniparental isodisomy (aUPID) involving chromosome 1p. The breakpoint of each aUPID is located in an A- and T-rich, high-DNA-flexibility region (1p13.1-1p12).  This region corresponds to a possible new fragile site. Occurrences of these mutations render the inherited glomulin variant in 1p22.1 homozygous in the affected tissues without loss of genetic material. This finding demonstrates that a double hit is needed to trigger formation of a GVM. It also suggests that somatic UPID, only detectable by sensitive pairwise analysis in heterogeneous tissues, might be a common phenomenon in human cells. Thus, aUPID might play a role in the pathogenesis of various nonmalignant disorders and might explain local impaired function and/or clinical variability. Furthermore, these data suggest that pairwise analysis of blood and tissue, even on heterogeneous tissue, can be used for localizing double-hit mutations in disease-causing genes.




TÍTULO / TITLE:  - Progressive neurolymphomatosis with cutaneous disease: Response in a patient with mycosis fungoides.

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

REVISTA / JOURNAL:  - Skeletal Radiol. 2013 Mar 27.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00256-013-1595-6

AUTORES / AUTHORS:  - Hanna R; Di Primio GA; Schweitzer M; Torres C; Sheikh A; Chakraborty S

INSTITUCIÓN / INSTITUTION:  - Department of Medical Imaging, The Ottawa Hospital - General Campus, 501 Smyth Road, Ottawa, ON, Canada, K1H 8L6, rhanna@toh.on.ca.

RESUMEN / SUMMARY:  - Peripheral neurolymphomatosis is a rare manifestation of advanced lymphoproliferative disorders. It is often associated with B cell lymphomas and rarely with cutaneous T cell lymphomas, such as mycosis fungoides and Sezary syndrome. In this case report, we present a 78-year-old male with a long-standing history of mycosis fungoides. The patient initially presented with chronic peripheral neuropathy in an ulnar nerve distribution. After an unsuccessful ulnar nerve transposition, the ulnar nerve was re-explored and a mass consistent with diffuse lymphomatous infiltration was diagnosed. Magnetic resonance (MR) imaging  of the left brachial plexus and later of the sacral plexus demonstrated diffuse thickening and peripheral nodularity in keeping with neurolymphomatosis. The patient’s clinical course rapidly deteriorated thereafter and the patient succumbed to his disease. Although uncommon, neurolymphomatosis may be considered in patients with chronic peripheral neuropathy and an underlying history of a lymphoproliferative disorder. US and MR may serve as helpful non-invasive adjuncts in making the diagnosis and identifying sites for biopsy.




TÍTULO / TITLE:  - Response classification based on a minimal model of glioblastoma growth is prognostic for clinical outcomes and distinguishes progression from pseudoprogression.

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

REVISTA / JOURNAL:  - Cancer Res. 2013 Feb 11.

            ●● Enlace al texto completo (gratuito o de pago) 1158/0008-5472.CAN-12-3588

AUTORES / AUTHORS:  - Neal ML; Trister AD; Ahn S; Baldock A; Bridge CA; Guyman L; Lange J; Sodt R; Cloke T; Lai A; Cloughesy TF; Mrugala MM; Rockhill JK; Rockne RC; Swanson KR

INSTITUCIÓN / INSTITUTION:  - Pathology, University of Washington.

RESUMEN / SUMMARY:  - Glioblastoma multiforme (GBM) is the most aggressive type of primary brain tumor. GBM growth dynamics vary widely across patients, making it difficult to accurately gauge their response to treatment. We developed a model-based metric of therapy response called Days Gained that accounts for this heterogeneity. Here we demonstrate in 63 newly diagnosed GBM patients that Days Gained scores from a  simple GBM growth model computed at the time of the first post-radiation therapy  MRI scan are prognostic for time to tumor recurrence and overall patient survival. After radiation treatment, Days Gained also distinguished patients with pseudoprogression from those with true progression. Since Days Gained scores can  be easily computed with routinely available clinical imaging devices, it offers immediate potential to be used in ongoing prospective studies.




TÍTULO / TITLE:  - Medulloblastoma: Fuelling the debate.

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

REVISTA / JOURNAL:  - Nat Rev Cancer. 2013 Apr;13(4):222-3. doi: 10.1038/nrc3494. Epub 2013 Mar 14.

            ●● Enlace al texto completo (gratuito o de pago) 1038/nrc3494

AUTORES / AUTHORS:  - Seton-Rogers S




TÍTULO / TITLE:  - GABA deficit in the visual cortex of patients with neurofibromatosis type 1: genotype-phenotype correlations and functional impact.

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

REVISTA / JOURNAL:  - Brain. 2013 Mar;136(Pt 3):918-25. doi: 10.1093/brain/aws368. Epub 2013 Feb 11.

            ●● Enlace al texto completo (gratuito o de pago) 1093/brain/aws368

AUTORES / AUTHORS:  - Violante IR; Ribeiro MJ; Edden RA; Guimaraes P; Bernardino I; Rebola J; Cunha G; Silva E; Castelo-Branco M

INSTITUCIÓN / INSTITUTION:  - IBILI, Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal.

RESUMEN / SUMMARY:  - Alterations in the balance between excitatory and inhibitory neurotransmission have been implicated in several neurodevelopmental disorders. Neurofibromatosis type 1 is one of the most common monogenic disorders causing cognitive deficits for which studies on a mouse model (Nfl(+/-)) proposed increased gamma-aminobutyric acid-mediated inhibitory neurotransmission as the neural mechanism underlying these deficits. To test whether a similar mechanism translates to the human disorder, we used magnetic resonance spectroscopy to measure gamma-aminobutyric acid levels in the visual cortex of children and adolescents with neurofibromatosis type 1 (n = 20) and matched control subjects (n = 26). We found that patients with neurofibromatosis type 1 have significantly lower gamma-aminobutyric acid levels than control subjects, and that neurofibromatosis type 1 mutation type significantly predicted cortical gamma-aminobutyric acid. Moreover, functional imaging of the visual cortex indicated that blood oxygen level-dependent signal was correlated with gamma-aminobutyric acid levels both in patients and control subjects. Our results provide in vivo evidence of gamma-aminobutyric acidergic dysfunction in neurofibromatosis type 1 by showing a reduction in gamma-aminobutyric acid levels in human patients. This finding is relevant to understand the physiological profile of the disorder and has implications for the identification of targets for therapeutic strategies.




TÍTULO / TITLE:  - Inherited Mutations in Pheochromocytoma and Paraganglioma: Why All Patients Should Be Offered Genetic Testing.

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

REVISTA / JOURNAL:  - Ann Surg Oncol. 2013 Mar 20.

            ●● Enlace al texto completo (gratuito o de pago) 1245/s10434-013-2942-5

AUTORES / AUTHORS:  - Fishbein L; Merrill S; Fraker DL; Cohen DL; Nathanson KL

INSTITUCIÓN / INSTITUTION:  - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA,  USA.

RESUMEN / SUMMARY:  - BACKGROUND: Pheochromocytomas (PCC) and paragangliomas (PGL) are neuroendocrine tumors that, although rare, are an important cause of secondary hypertension because of the high morbidity and mortality. PCC/PGL are still thought of as the  “tumor of tens,” with 10 % being hereditary; however, recent population based studies suggest that up to 32 % of patients have a germline mutation in one of the known common susceptibility genes (including NF1, VHL, RET, SDHB, SDHD, and SDHC). Despite this, most patients in the United States are not referred for clinical genetic testing by their physicians. We aimed to examine the mutation prevalence in a clinic-based population in the United States. METHODS: We performed a retrospective chart review of 139 consecutive patients with PCC/PGL from the medical genetics clinic at the hospital of the University of Pennsylvania from January 2004 through February 2012. RESULTS: We found a 41 % overall mutation detection rate. Twenty-six percent of the cohort had a mutation  in the SDHB or SDHD genes. Of patients with at least one PGL tumor outside the adrenal gland, 53 % had an identified mutation. CONCLUSIONS: Forty-one percent of the cohort had a heritable mutation. The most commonly mutated gene was SDHB, which carries the highest risk of malignancy. These data, together with American  Society of Clinical Oncology guidelines suggesting that genetic testing be performed if the risk of a hereditable mutation is at least 10 % or if it will affect medical management, strongly suggest that all patients with PCC/PGL should undergo clinical genetic testing.




TÍTULO / TITLE:  - Central neurocytoma: Radiological and clinico-pathological findings in 18 patients and one additional MRS case.

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

REVISTA / JOURNAL:  - J Neuroradiol. 2013 Feb 11. pii: S0150-9861(12)00198-8. doi: 10.1016/j.neurad.2012.05.007.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.neurad.2012.05.007

AUTORES / AUTHORS:  - Ramsahye H; He H; Feng X; Li S; Xiong J

INSTITUCIÓN / INSTITUTION:  - Department of Radiology, Huashan Hospital, Fudan University, Shanghai 200040, People’s Republic of China.

RESUMEN / SUMMARY:  - OBJECTIVES: To evaluate clinical findings and radiological characteristics of central neurocytoma (CN) in 18patients and magnetic resonance spectroscopy (MRS)  features in one additional case. MATERIALS AND METHODS: Clinical and imaging findings of 18patients (nine female and nine male; age range, 18-37 years old (27.8+/-5.7)) with histopathological diagnosis of CN were evaluated retrospectively. Eight patients underwent CT and eight had MR imaging. Both MR and CT images were acquired for other two patients. We also assessed the tumour NADC values. Clinical data, such as presenting symptoms and medical histories were collected. MRS was also obtained for one additional case. RESULTS: Clinical  symptoms at the time of presentation were headaches (n=11), dizziness (n=6), visual disturbances (n=2), etc. Eight lesions were unilateral ventricle (44%) and ten were located in both lateral ventricles. Three tumours continued towards the  foramen of Monro and one to the third ventricle. The maximum diameter of the CNs  varied from 3.4 to 9.2cm (5.2+/-1.5cm). On CT, diffuse and diverse calcifications were observed in nine cases and cysts varying in sizes were revealed in all. On MRI, the solid parts of the tumours were mainly hypo- to isointense on all T1WI and isointense to grey matter on T2WI. Clusters of cysts gave the tumours a “swiss cheese/soap bubble” inhomogeneous hyperintense appearance on T2WI and FLAIR images. Heterogeneous moderate enhancement (5/8) was present on T1 postcontrast images. On DWI, the tumours had heterogeneous hyperintense appearances and the tumour NADC values were 0.93+/-0.21.On MRS, elevated Cho and  Gly peaks and reduced Cr and NAA peaks were obtained. CONCLUSION: CN is almost exclusively located in the body of lateral ventricle in young adults. It is discovered due to symptoms of raised intracranial pressure. The distinct radiological features such as: (1) diffuse and diverse calcifications on CT images; (2) clusters of cysts of varying sizes resulting in the “swiss cheese/soap bubble” appearance on T2WI and heterogeneous moderate enhancement on  MR images; (3) the incorporation of the septum pellucidum in bilateral tumours and abutting of the septum pellucidum in unilateral tumours together with the attachment of the wall of the ventricles can help in the diagnosis of preoperative central neurocytoma.




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.




TÍTULO / TITLE:  - High-resolution steady-state cerebral blood volume maps in patients with central  nervous system neoplasms using ferumoxytol, a superparamagnetic iron oxide nanoparticle.

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

REVISTA / JOURNAL:  - J Cereb Blood Flow Metab. 2013 Mar 13. doi: 10.1038/jcbfm.2013.36.

            ●● Enlace al texto completo (gratuito o de pago) 1038/jcbfm.2013.36

AUTORES / AUTHORS:  - Varallyay CG; Nesbit E; Fu R; Gahramanov S; Moloney B; Earl E; Muldoon LL; Li X; Rooney WD; Neuwelt EA

INSTITUCIÓN / INSTITUTION:  - Department of Neurology, Oregon Health and Science University, Portland, Oregon,  USA.

RESUMEN / SUMMARY:  - Cerebral blood volume (CBV) measurement complements conventional magnetic resonance imaging (MRI) to indicate pathologies in the central nervous system (CNS). Dynamic susceptibility contrast (DSC) perfusion imaging is limited by low  resolution and distortion. Steady-state (SS) imaging may provide higher resolution CBV maps but was not previously possible in patients. We tested the feasibility of clinical SS-CBV measurement using ferumoxytol, a nanoparticle blood pool contrast agent. SS-CBV measurement was analyzed at various ferumoxytol doses and compared with DSC-CBV using gadoteridol. Ninety nine two-day MRI studies were acquired in 65 patients with CNS pathologies. The SS-CBV maps showed improved contrast to noise ratios, decreased motion artifacts at increasing ferumoxytol doses. Relative CBV (rCBV) values obtained in the thalamus and tumor  regions indicated good consistency between the DSC and SS techniques when the higher dose (510 mg) ferumoxytol was used. The SS-CBV maps are feasible using ferumoxytol in a clinical dose of 510 mg, providing higher resolution images with comparable rCBV values to the DSC technique. Physiologic imaging using nanoparticles will be beneficial in visualizing CNS pathologies with high vascularity that may or may not correspond with blood-brain barrier abnormalities.Journal of Cerebral Blood Flow & Metabolism advance online publication, 13 March 2013; doi:10.1038/jcbfm.2013.36.




TÍTULO / TITLE:  - Bromocriptine-induced Brainstem Angulation in a Patient With Invasive Prolactinoma.

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

REVISTA / JOURNAL:  - J Clin Endocrinol Metab. 2013 Mar;98(3):867-8. doi: 10.1210/jc.2012-3735. Epub 2013 Jan 30.

            ●● Enlace al texto completo (gratuito o de pago) 1210/jc.2012-3735


INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, Beijing Neurosurgical Institute, Capital Medical University, Beijing 100050, China. zyz2004520@163.com.




TÍTULO / TITLE:  - Free and Total Plasma Cortisol Measured by Immunoassay and Mass Spectrometry Following ACTH1-24 Stimulation in the Assessment of Pituitary Patients.

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

REVISTA / JOURNAL:  - J Clin Endocrinol Metab. 2013 Mar 28.

            ●● Enlace al texto completo (gratuito o de pago) 1210/jc.2012-3576

AUTORES / AUTHORS:  - Burt MG; Mangelsdorf BL; Rogers A; Ho JT; Lewis JG; Inder WJ; Doogue MP

INSTITUCIÓN / INSTITUTION:  - Southern Adelaide Diabetes and Endocrine Services (M.G.B., B.L.M., J.T.H., M.P.D.) and Flinders University (M.G.B., A.R., J.T.H., M.P.D.), Adelaide, Australia 5041; Steroid and Immunobiochemistry Laboratory (J.G.L.), Canterbury Health Laboratories, Christchurch, New Zealand 8140; and Department of Endocrinology and Diabetes (W.J.I.), St Vincent’s Hospital, Melbourne, Australia  3065.

RESUMEN / SUMMARY:  - Context:Measurement of plasma cortisol by immunoassay after ACTH1-24 stimulation  is used to assess the hypothalamic-pituitary-adrenal (HPA) axis. Liquid chromatography-tandem mass spectrometry (LCMS) has greater analytical specificity than immunoassay and equilibrium dialysis allows measurement of free plasma cortisol.Objective:We investigated the use of measuring total and free plasma cortisol by LCMS and total cortisol by immunoassay during an ACTH1-24 stimulation test to define HPA status in pituitary patients.Design and Setting:This was a case control study conducted in a clinical research facility.Participants:We studied 60 controls and 21 patients with pituitary disease in whom HPA sufficiency (n = 8) or deficiency (n = 13) had been previously defined.Intervention:Participants underwent 1 mu g ACTH1-24 intravenous and 250 mu g ACTH1-24 intramuscular ACTH1-24 stimulation tests.Main Outcome Measures:Concordance of ACTH1-24-stimulated total and free plasma cortisol with previous HPA assessment.Results:Total cortisol was 12% lower when measured by immunoassay than by LCMS. Female sex and older age were positively correlated with ACTH1-24-stimulated total and free cortisol, respectively. Measurements of total cortisol by immunoassay and LCMS and free cortisol 30 minutes after 1 mu g  and 30 and 60 minutes after 250 mu g ACTH1-24 were concordant with previous HPA axis assessment in most pituitary patients. However, free cortisol had greater separation from the diagnostic cutoff than total cortisol.Conclusions:Categorization of HPA status by immunoassay and LCMS after ACTH1-24 stimulation was concordant with previous assessment in most pituitary patients. Free cortisol may have greater clinical use in patients near the diagnostic threshold.




TÍTULO / TITLE:  - Bone Metastases and Skeletal-Related Events in Patients with Malignant Pheochromocytoma and Sympathetic Paraganglioma.

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

REVISTA / JOURNAL:  - J Clin Endocrinol Metab. 2013 Feb 22.

            ●● Enlace al texto completo (gratuito o de pago) 1210/jc.2012-4231

AUTORES / AUTHORS:  - Ayala-Ramirez M; Palmer JL; Hoffman MC; de la Cruz M; Moon BS; Waguespack SG; Habra MA; Jimenez C

INSTITUCIÓN / INSTITUTION:  - Departments of Endocrine Neoplasia and Hormonal Disorders (M.A.-R., M.-C.H., S.G.W., M.A.H., C.J.), Biostatistics (J.L.P.), Palliative Care and Rehabilitation Medicine (M.d.l.C.), and Orthopaedic Oncology (B.S.M.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.

RESUMEN / SUMMARY:  - Context:Bone metastases (BM) can cause severe pain, spinal cord compression, pathological fractures, and/or hypercalcemia. These skeletal-related events (SREs) may cause immobilization, loss of independence, poor quality of life, and  reduced survival. There is limited information on the clinical effects of BM and  SREs in patients with malignant pheochromocytoma or sympathetic paraganglioma (PHEO/sPGL).Objectives:We studied the prevalence and clinical characteristics of  BM and SREs in patients with PHEO/sPGL and investigated the risk factors for SRE  development.Design:Using a large institutional database, we conducted a retrospective study of 128 patients with malignant PHEO/sPGL at The University of Texas MD Anderson Cancer Center from 1967 through 2011.Results:Of the patients, 91 (71%) had BM, and 57 of these (63%) developed metachronous BM at a median time of 3.4 years (range, 5 months to 23 years) after the primary tumor diagnosis. Metastatic disease was confined exclusively to the skeleton in 26 of 128 (20%) patients. Sufficient information to assess SRE occurrence was available for 67 patients, and 48 of 67 (72%) patients had at least 1 SRE. The median overall survival for the 128 patients was 12 years for patients with only BM, 7.5 years for patients with nonosseous metastases, and 5 years for patients with both BM and nonosseous metastases (log rank test P value = .005). We were unable to identify factors predictive of SRE development, but the occurrence of a first SRE was associated with the development of subsequent SREs in 48% of subjects. In responsive patients, the use of systemic therapy was associated with fewer SREs (P < .0001).Conclusions:BM and SREs are frequent in patients with malignant PHEO/sPGL. SREs often develop shortly after the diagnosis of BM; severe pain is the most frequent SRE. These patients should be followed long-term by a multidisciplinary team to promptly identify the need for medical or surgical intervention.




TÍTULO / TITLE:  - Novel HSP90 inhibitor NVP-HSP990 targets cell cycle regulators to ablate Olig2-positive glioma tumor initiating cells.

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

REVISTA / JOURNAL:  - Cancer Res. 2013 Mar 14.

            ●● Enlace al texto completo (gratuito o de pago) 1158/0008-5472.CAN-12-2033

AUTORES / AUTHORS:  - Fu J; Koul D; Yao J; Wang S; Yuan Y; Colman H; Sulman EP; Lang FF; Yung WK

INSTITUCIÓN / INSTITUTION:  - Brain Tumor Center , Department of Neuro-oncology, M.D.Anderson.Cancer Center.

RESUMEN / SUMMARY:  - Genetic heterogeneity and signaling alterations diminish the effectiveness of single-agent therapies in glioblastoma multiforme (GBM). The heat shock protein HSP90 is a molecular chaperone for several signaling proteins that are deregulated in glioma cells. Thus, HSP90 inhibition may offer an approach to coordinately correct multiple signaling pathways as a strategy for GBM therapy. In this study, we evaluated the effects of a novel HSP90 inhibitor, NVP-HSP990, in glioma tumor initiating cell (GIC, hereafter GIC) populations, which are strongly implicated in the root pathobiology of GBM. In GIC cultures, NVP-HSP990  elicited a dose-dependent growth inhibition with IC50 values in the low nanomolar range. Two GIC subgroups with different responses were observed with an Olig2-expressing subset relatively more sensitive to treatment. We also showed that Olig2 is a functional marker associated with cell proliferation and response to NVP-HSP990, as NVP-HSP990 attenuated cell proliferation in Olig2-high GIC lines. Additionally, NVP-HSP990 disrupted cell cycle control mechanism by decreasing CDK2 and CDK4 and elevating apoptosis-related molecules. Mechanistic investigations revealed molecular interactions between CDK2/CDK4 and Olig2. Inhibition of CDK2/CDK4 activity disrupted Olig2-CDK2/CDK4 interactions and attenuated Olig2 protein stability. In vivo evaluation demonstrated a relative prolongation of median survival in an intracranial model of GIC growth. Our results suggest that GBM characterized by high-expressing Olig2 GIC may exhibit greater sensitivity to NVP-HSP990 treatment, establishing a foundation for further investigation of the role of HSP90 signaling in GBM.




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.




TÍTULO / TITLE:  - Considerable improvement in survival for patients aged 60-84 years with high grade malignant gliomas - Data from the Swedish Brain Tumour Population-based Registry.

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

REVISTA / JOURNAL:  - Acta Oncol. 2013 Feb 11.

            ●● Enlace al texto completo (gratuito o de pago) 3109/0284186X.2012.754993

AUTORES / AUTHORS:  - Asklund T; Malmstrom A; Bjor O; Blomquist E; Henriksson R

INSTITUCIÓN / INSTITUTION:  - Department of Radiation Sciences and Oncology, Norrlands University Hospital , Umea , Sweden.




TÍTULO / TITLE:  - Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics.

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

REVISTA / JOURNAL:  - Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):4009-14. doi: 10.1073/pnas.1219747110. Epub 2013 Feb 14.

            ●● Enlace al texto completo (gratuito o de pago) 1073/pnas.1219747110

AUTORES / AUTHORS:  - Sottoriva A; Spiteri I; Piccirillo SG; Touloumis A; Collins VP; Marioni JC; Curtis C; Watts C; Tavare S

INSTITUCIÓN / INSTITUTION:  - Department of Oncology, University of Cambridge, Cambridge CB2 2XZ, United Kingdom.

RESUMEN / SUMMARY:  - Glioblastoma (GB) is the most common and aggressive primary brain malignancy, with poor prognosis and a lack of effective therapeutic options. Accumulating evidence suggests that intratumor heterogeneity likely is the key to understanding treatment failure. However, the extent of intratumor heterogeneity  as a result of tumor evolution is still poorly understood. To address this, we developed a unique surgical multisampling scheme to collect spatially distinct tumor fragments from 11 GB patients. We present an integrated genomic analysis that uncovers extensive intratumor heterogeneity, with most patients displaying different GB subtypes within the same tumor. Moreover, we reconstructed the phylogeny of the fragments for each patient, identifying copy number alterations  in EGFR and CDKN2A/B/p14ARF as early events, and aberrations in PDGFRA and PTEN as later events during cancer progression. We also characterized the clonal organization of each tumor fragment at the single-molecule level, detecting multiple coexisting cell lineages. Our results reveal the genome-wide architecture of intratumor variability in GB across multiple spatial scales and patient-specific patterns of cancer evolution, with consequences for treatment design.




TÍTULO / TITLE:  - Acute Toxicity Profile of Patients with Low-grade Gliomas and Meningiomas Receiving Proton Therapy.

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

REVISTA / JOURNAL:  - Am J Clin Oncol. 2013 Feb 5.

            ●● Enlace al texto completo (gratuito o de pago) 1097/COC.0b013e31827de86b

AUTORES / AUTHORS:  - Maquilan G; Grover S; Alonso-Basanta M; Lustig RA

INSTITUCIÓN / INSTITUTION:  - Department of Radiation Oncology, Perelman Center for Advanced Medicine, University of Pennsylvania, Philadelphia, PA.

RESUMEN / SUMMARY:  - OBJECTIVES:: Proton therapy is an emerging treatment modality. We studied its acute side effects on patients with low-grade gliomas and meningiomas. MATERIALS  AND METHODS:: Twenty-three patients diagnosed with low-grade gliomas or meningiomas enrolled in an Institutional Review Board-approved prospective proton treatment protocol (NCT01024907) were treated and followed between April 2010 and August 2011. Patients received 54 Gy (relative biological effectiveness) in 1.8 Gy (relative biological effectiveness) per fraction and were assessed at the time of consult, weekly during treatment, and at 1, 3, 6, and 9 months posttreatment.  At each clinic visit, nursing completed a “Symptom Assessment/Grading” table. Symptoms were graded based on National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. RESULTS:: Fatigue: At on-treatment visit (OTV) week 6, 13 patients had grade 1 and 6 patients had grade 2 fatigue. At 1-month follow-up, 3 patients had grade 1 and 1 patient had grade 2 fatigue. At each timepoint, 1 patient had grade 3 fatigue. Nausea: At OTV week 3, 5 patients  experienced grade 1 nausea. At OTV week 6, 3 patients experienced grade 1 nausea. Headache: At OTV week 3, 10 patients had grade 1 headaches. At OTV week 6, 4 patients experienced grade 1 headaches and 1 patient by follow-up month 1. One to 2 patients experienced grade 2 headaches at each timepoint. At OTV week 3, 1 patient experienced a grade 3 headache. CONCLUSIONS:: Our results suggest that proton therapy for patients with low-grade gliomas and meningiomas has a favorable acute toxicity profile-most patients experienced mild fatigue, headache, and insomnia that largely resolved by 1-month posttreatment.




TÍTULO / TITLE:  - In vivo Imaging of the Therapeutic Efficacy and Fate of Bimodal Engineered Stem Cells in Malignant Brain Tumors.

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

REVISTA / JOURNAL:  - Stem Cells. 2013 Feb 6. doi: 10.1002/stem.1355.

            ●● Enlace al texto completo (gratuito o de pago) 1002/stem.1355

AUTORES / AUTHORS:  - Martinez-Quintanilla J; Bhere D; Heidari P; He D; Mahmood U; Shah K

INSTITUCIÓN / INSTITUTION:  - Molecular Neurotherapy and Imaging Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, 02114; Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, 02114.

RESUMEN / SUMMARY:  - Therapeutically engineered stem cells (SC) are emerging as a very effective tumor specific therapeutic approach for different cancer types. However, the assessment of the long-term fate of therapeutic SC post-tumor treatment is critical if such  promising therapies are to be increasingly translated into clinical practice. In  this study, we have developed an efficient stem cell based therapeutic strategy that simultaneously allows killing of tumor cells and assessment and eradication  of SC post highly malignant glioblastoma multiforme (GBM) brain tumor treatment.  Mesenchymal stem cells (MSC) engineered to co-express the prodrug converting enzyme, herpes simplex virus thymidine kinase (HSV-TK) and a potent and secretable variant of tumor necrosis factor apoptosis-inducing ligand (S-TRAIL) induced caspase mediated GBM cell death and showed selective MSC sensitization to the prodrug ganciclovir (GCV). A significant decrease in tumor growth and a subsequent increase in survival were observed when mice bearing a highly aggressive GBM were treated with MSC co-expressing S-TRAIL and HSV-TK. Furthermore, the systemic administration of GCV post-tumor treatment selectively  eliminated therapeutic MSC expressing HSV-TK in vitro and in vivo, which was monitored in real time by positron emission-computed tomography (PET) imaging utilizing 18F-FHBG, a substrate for HSV-TK. These findings demonstrate the development and validation of a novel therapeutic strategy that has implications  in translating stem cell based therapies in cancer patients.




TÍTULO / TITLE:  - Pre-incubation of Pituitary Tumour Cells with the Epidrugs Zebularine and Trichostatin A are Permissive for Retinoic Acid Augmented Expression of the BMP-4 and D2R genes.

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

REVISTA / JOURNAL:  - Endocrinology. 2013 Mar 28.

            ●● Enlace al texto completo (gratuito o de pago) 1210/en.2013-1061

AUTORES / AUTHORS:  - Yacqub-Usman K; Duong CV; Clayton RN; Farrell WE

INSTITUCIÓN / INSTITUTION:  - Institute of Science and Technology in Medicine, Keele University School of Medicine, Stoke-on-Trent, Staffordshire, ST4 7QB. UK.

RESUMEN / SUMMARY:  - Retinoic acid (RA) induced expression of bone morphogenetic protein (BMP-4) inhibits in vitro and in vivo cell proliferation and ACTH synthesis in corticotroph derived tumour cells. Reduced expression of BMP-4 in this adenoma subtype is associated with epigenomic silencing and similar silencing mechanisms  are also associated with the RA responsive dopamine D2 receptor (D2R) in somatolactotroph cells. We now show that pre-incubation with the epidrugs, zebularine and TSA is obligate and permissive for RA induced expression of the BMP-4 and the D2R genes in pituitary tumour cells. Combined epidrug challenges are associated with marginal reduction in CpG island methylation. However, significant change to histone tail modifications toward those associated with expression-competent genes is apparent, whereas RA challenge alone or in combined incubations does not impact on these modifications. Epidrug mediated and RA augmented expression of endogenous BMP-4 increased or decreased cell proliferation and CFE in GH3 and AtT-20 pituitary tumour cells respectively, and  recapitulating recent reports of challenges of these cells with exogenous ligand. The specificity of the BMP-4 mediated effects was further supported by knock-down experiments of the BMP-4 antagonist noggin (siRNA). Knock-down of noggin, in the  absence and the presence of epidrugs, induced and augmented BMP-4 expression respectively. In cell proliferation assays, challenge with either epidrugs or siRNA led to significant increase in cell numbers at the 72hr time point, however, in siRNA treated cells co-incubated with epidrugs a significant increase was apparent at the 48hr time point. These studies show the potential of combined drug challenges as a treatment option, where epidrug renders silenced genes responsive to conventional therapeutic options.




TÍTULO / TITLE:  - “Ghosts in My Body”: Seizure-like Presentation of Hypocalcemic Tetany Secondary to Hypomagnesemia in a Patient Receiving Cetuximab Therapy for Metastatic Medulloblastoma.

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

REVISTA / JOURNAL:  - J Pediatr Hematol Oncol. 2013 Feb 15.

            ●● Enlace al texto completo (gratuito o de pago) 1097/MPH.0b013e318282d99c

AUTORES / AUTHORS:  - Kidwell KS; Kopp WE; Albano EA; Brown AE

INSTITUCIÓN / INSTITUTION:  - *Pediatric Residency Program, University of Colorado Health Sciences Center daggerUniversity of Colorado School of Medicine double daggerCenter for Cancer and Blood Disorders, Children’s Hospital Colorado, Aurora, CO.

RESUMEN / SUMMARY:  - Cetuximab, a monoclonal antibody specific for epidermal growth factor receptor, is increasingly used off-label and in early-phase trials for pediatric malignancies. Here, we report a patient with metastatic medulloblastoma receiving therapy with cyclophosphamide, vinblastine, and cetuximab. During evaluation for  possible seizures, he was noted to be severely hypocalcemic, hypokalemic, and hypomagnesemic, a consequence of the blockade of renal epidermal growth factor receptor expression. His symptoms rapidly abated with intravenous electrolyte repletion. This case highlights the clinical heterogeneity of tetany and the importance of careful laboratory screening for known adverse effects of chemotherapy, particularly when newer biological agents are used off-study in combination chemotherapeutic regimens.




TÍTULO / TITLE:  - Low triiodothyronine syndrome as a predictor of poor outcomes in patients undergoing brain tumor surgery: a pilot study.

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

REVISTA / JOURNAL:  - J Neurosurg. 2013 Mar 12.

            ●● Enlace al texto completo (gratuito o de pago) 3171/2013.1.JNS121696

AUTORES / AUTHORS:  - Bunevicius A; Deltuva V; Tamasauskas S; Tamasauskas A; Laws ER Jr; Bunevicius R

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery and.

RESUMEN / SUMMARY:  - Object A low triiodothyronine (T3) state is highly prevalent and is associated with a poor prognosis in critically ill patients. The authors investigated, in patients undergoing brain tumor surgery, the direct association of a perioperative low T3 syndrome with clinical outcomes and also with symptoms of depression and anxiety. Methods Ninety consecutive patients (71% women, median age 55 years), on admission for brain tumor surgery, were evaluated for sociodemographic and clinical characteristics. Their thyroid function profile was assessed on the morning of brain tumor surgery and on the morning after brain tumor surgery. Patients with free T3 concentrations of 3.1 pmol/L or less were considered to have low T3 syndrome. The patients were evaluated for symptoms of depression and anxiety using the Hospital Anxiety and Depression Scale (HADS) before and after surgery and for clinical outcomes using the Glasgow Outcome Scale (GOS) at discharge. Results After brain tumor surgery, free T3 concentrations decreased (p < 0.001) and the proportion of patients with low T3 levels increased from 38% to 54% (p = 0.02). Lower preoperative (rho = 0.30, p =  0.004) and postoperative (rho = 0.33, p = 0.002) free T3 concentrations correlated with low GOS scores at discharge. Preoperative low T3 syndrome (OR 5.49, 95% CI 1.27-23.69, p = 0.02) and postoperative low T3 syndrome (OR 8.73, 95% CI 1.49-51.21, p = 0.02) both increased risk for unfavorable clinical outcomes (GOS scores < 5) at discharge, after adjusting for age, sex, histological diagnosis of brain tumor, preoperative functional impairment, previous treatment for brain tumor, and depressive symptoms. Preoperative low T3  syndrome increased the risk for preoperative (HADS-depression subscale score >/=  11; OR 4.12, 95% CI 1.16-14.58, p = 0.03) but not postoperative depressive symptoms independently from sociodemographic and clinical factors. Conclusions Low T3 syndrome is a strong independent predictor of unfavorable clinical outcomes and depressive symptoms, and its diagnosis and preoperative management should be considered in patients undergoing neurosurgery for the treatment of brain tumors.




TÍTULO / TITLE:  - Expression of aquaporin 5 and the AQP5 polymorphism A(-1364)C in association with peritumoral brain edema in meningioma patients.

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

REVISTA / JOURNAL:  - J Neurooncol. 2013 Apr;112(2):297-305. doi: 10.1007/s11060-013-1064-z. Epub 2013  Feb 8.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11060-013-1064-z

AUTORES / AUTHORS:  - Lambertz N; Hindy NE; Adler C; Rump K; Adamzik M; Keyvani K; Bankfalvi A; Siffert W; Erol Sandalcioglu I; Bachmann HS

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, Westdeutsches Tumorzentrum WTZ, University Hospital Essen, Hufelandstr. 55, 45147, Essen, Germany, nicole.lambertz@uk-essen.de.

RESUMEN / SUMMARY:  - Aquaporins (AQP) are a growing family of water-channel proteins, numbering 13 to  date. Recent studies have reported AQP1 and AQP4 to be involved in the development and resorption of brain edemas of different origin. Other AQPs have also been detected in brain tissue, but their impact on brain edema remains to be shown. To evaluate a possible role of AQP5 in brain edema, we investigated the association of AQP5 expression and the functional AQP5 promoter polymorphism A(-1364)C with occurrence and intensity of peritumoral edema in meningioma patients. Peritumoral edema was classified in three degrees based on preoperative imaging in 89 meningioma patients treated at the University Hospital Essen between 2003 and 2006. AQP5 expression was assessed immunohistochemically in tumor tissue obtained during neurosurgical tumor resection. Genotypes of the A(-1364)C polymorphism were determined using the “slowdown” polymerase chain reaction. Higher levels of AQP5 expression were significantly correlated with the AQP5-1364 AA genotype (P = 0.02). AQP5 expression was positively correlated with  edema (P = 0.04). AQP5 genotypes were not significantly associated with the occurrence, but with the intensity of peritumoral brain edema (P = 0.04). In our  cohort, 40 % of patients with grade I, 66.7 % with grade II, and 76.5 % with grade III edema possessed at least one A allele. Development and intensity of peritumoral edema in meningiomas are associated with AQP5 expression. The intensity of edema correlates with the AQP5 A(-1364)C genotype. This suggests AQP5 as an interesting new candidate involved in peritumoral brain edema in meningioma patients.




TÍTULO / TITLE:  - Side population in human glioblastoma is non-tumorigenic and characterizes brain  endothelial cells.

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

REVISTA / JOURNAL:  - Brain. 2013 Mar 4.

            ●● Enlace al texto completo (gratuito o de pago) 1093/brain/awt025

AUTORES / AUTHORS:  - Golebiewska A; Bougnaud S; Stieber D; Brons NH; Vallar L; Hertel F; Klink B; Schrock E; Bjerkvig R; Niclou SP

INSTITUCIÓN / INSTITUTION:  - 1 NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Sante (CRP-Sante), L-1526 Luxembourg, Luxembourg.

RESUMEN / SUMMARY:  - The identification and significance of cancer stem-like cells in malignant gliomas remains controversial. It has been proposed that cancer stem-like cells display increased drug resistance, through the expression of ATP-binding cassette transporters that detoxify cells by effluxing exogenous compounds. Here, we investigated the ‘side population’ phenotype based on efflux properties of ATP-binding cassette transporters in freshly isolated human glioblastoma samples  and intracranial xenografts derived thereof. Using fluorescence in situ hybridization analysis on sorted cells obtained from glioblastoma biopsies, as well as human tumour xenografts developed in immunodeficient enhanced green fluorescence protein-expressing mice that allow an unequivocal tumour-stroma discrimination, we show that side population cells in human glioblastoma are non-neoplastic and exclusively stroma-derived. Tumour cells were consistently devoid of efflux properties regardless of their genetic background, tumour ploidy or stem cell associated marker expression. Using multi-parameter flow cytometry we identified the stromal side population in human glioblastoma to be brain-derived endothelial cells with a minor contribution of astrocytes. In contrast with their foetal counterpart, neural stem/progenitor cells in the adult brain did not display the side population phenotype. Of note, we show that CD133-positive cells often associated with cancer stem-like cells in glioblastoma biopsies, do not represent a homogenous cell population and include CD31-positive endothelial cells. Interestingly, treatment of brain tumours with the anti-angiogenic agent bevacizumab reduced total vessel density, but did not affect the efflux properties of endothelial cells. In conclusion our findings contribute to an unbiased identification of cancer stem-like cells and stromal cells in brain neoplasms, and provide novel insight into the complex issue of drug delivery to the brain. Since efflux properties of endothelial cells are likely to compromise drug availability, transiently targeting ATP-binding cassette transporters may be a valuable therapeutic strategy to improve treatment effects in brain tumours.




TÍTULO / TITLE:  - Prognostic Value of Residual Fluorescent Tissue in Glioblastoma Patients After Gross Total Resection in 5-ALA Guided Surgery.

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

REVISTA / JOURNAL:  - Neurosurgery. 2013 Feb 19.

            ●● Enlace al texto completo (gratuito o de pago) 1227/NEU.0b013e31828c3974

AUTORES / AUTHORS:  - Orzaiz GA; Solis ST; Valverde EP; Sanchez MM; Herruzo BB; Idoate Gastearena MA; Valle RD

INSTITUCIÓN / INSTITUTION:  - 1Department of Neurosurgery. Clinica Universidad de Navarra. Pamplona. España 2Department of Pathology. Clinica Universidad de Navarra. Pamplona. España.

RESUMEN / SUMMARY:  - BACKGROUND:: There is evidence in the literature that supports fluorescent tissue signal in fluorescence guided surgery (FGS) extends farther than tissue highlighted in T1Gd MRI, which is the standard to quantify the extent of resection (EOR). OBJECTIVE:: To study whether the presence of residual fluorescent tissue after surgery carries a different prognosis for glioblastoma (GBM) cases with complete resection confirmed by MRI. METHODS:: A retrospective review in our center found 118 consecutive patients with high-grade gliomas operated using 5-aminolevulinic acid (5-ALA) FGS. Within that series, the 52 patients with newly diagnosed GBM and complete resection of enhancing tumor (CRET) in early MRI were selected for analysis. We studied the influence of residual fluorescence in the surgical field on overall survival and neurological  complication rate. Multivariate analysis included potential relevant factors: age, Karnofsky Performance Scale (KPS), MGMT methylation promoter status, tumor eloquent location, preoperative tumor volume, and adjuvant therapy. RESULTS:: The median overall survival was 27.0 months (CI= 22.4-31.6) in patients with non-residual fluorescence (n=25) and 17.5 months (CI= 12.5-22.5) for the group with residual fluorescence (n=27) (p= 0.015). The influence of residual fluorescence was maintained in the multivariate analysis with all covariables, HR= 2.5 (p=0.041).The neurological complication rate was 8% in patients with non-residual fluorescence and 18.5% for the group with residual fluorescence (p=  0.267). CONCLUSION:: GBM patients with CRET in early MRI and no fluorescent residual tissue had longer OS than patients with CRET and residual fluorescent tissue.




TÍTULO / TITLE:  - Cerebral Venous Sinus Thrombosis in Pediatric Cancer Patients: Long-term Neurological Outcomes.

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

REVISTA / JOURNAL:  - J Pediatr Hematol Oncol. 2013 Feb 5.

            ●● Enlace al texto completo (gratuito o de pago) 1097/MPH.0b013e31827e8dbd

AUTORES / AUTHORS:  - Ross CS; Brown TM; Kotagal S; Rodriguez V

INSTITUCIÓN / INSTITUTION:  - Divisions of daggerChild and Adolescent Psychiatry and Psychology double daggerChild and Adolescent Neurology and *Department of Pediatric and Adolescent  Medicine, Mayo Clinic, Rochester, MN.

RESUMEN / SUMMARY:  - Cerebral venous sinus thrombosis (CVST) is an uncommon but recognized complication of treatment for leukemia. Our goal was to determine the long-term neurocognitive outcomes in childhood cancer survivors who had CVST during therapy. Nine patients were identified from an institutional database. All had experienced CVST in the setting of L-asparaginase therapy in combination with other chemotherapeutic agents. Four patients completed neuropsychological evaluation. Their neurological examinations were normal. Neuropsychological testing showed that the participants performed well, with average to above-average scores on cognitive and behavioral testing. Three exhibited difficulties on a visual-motor integration task and 1 had difficulty with fine-motor dexterity, nonverbal memory, emotional control, shifting attention, and anxiety. Overall, by patient and parent report, the survivors had few problems. CVST is a known complication associated with treatment for leukemia and non-Hodgkin lymphoma, most commonly observed if asparaginase is used in combination with other chemotherapeutic agents. Although subtle difficulties were noted in survivors on neuropsychological testing, survivors themselves were not aware of the deficits. Further evaluation of leukemia survivors with a history of CVST is needed to assess for deficits and to understand whether further intervention is necessary.




TÍTULO / TITLE:  - Reversing the warburg effect as a treatment for glioblastoma.

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

REVISTA / JOURNAL:  - J Biol Chem. 2013 Mar 29;288(13):9153-64. doi: 10.1074/jbc.M112.440354. Epub 2013 Feb 13.

            ●● Enlace al texto completo (gratuito o de pago) 1074/jbc.M112.440354

AUTORES / AUTHORS:  - Poteet E; Choudhury GR; Winters A; Li W; Ryou MG; Liu R; Tang L; Ghorpade A; Wen Y; Yuan F; Keir ST; Yan H; Bigner DD; Simpkins JW; Yang SH

INSTITUCIÓN / INSTITUTION:  - From the Department of Pharmacology and Neuroscience and.

RESUMEN / SUMMARY:  - Glioblastoma multiforme (GBM), like most cancers, possesses a unique bioenergetic state of aerobic glycolysis known as the Warburg effect. Here, we documented that methylene blue (MB) reverses the Warburg effect evidenced by the increasing of oxygen consumption and reduction of lactate production in GBM cell lines. MB decreases GBM cell proliferation and halts the cell cycle in S phase. Through activation of AMP-activated protein kinase, MB inactivates downstream acetyl-CoA  carboxylase and decreases cyclin expression. Structure-activity relationship analysis demonstrated that toluidine blue O, an MB derivative with similar bioenergetic actions, exerts similar action in GBM cell proliferation. In contrast, two other MB derivatives, 2-chlorophenothiazine and promethazine, exert no effect on cellular bioenergetics and do not inhibit GBM cell proliferation. MB inhibits cell proliferation in both temozolomide-sensitive and -insensitive GBM cell lines. In a human GBM xenograft model, a single daily dosage of MB does not  activate AMP-activated protein kinase signaling, and no tumor regression was observed. In summary, the current study provides the first in vitro proof of concept that reversal of Warburg effect might be a novel therapy for GBM.




TÍTULO / TITLE:  - SIOP CNS GCT 96: final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal primary site irradiation for patients with localized disease.

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

REVISTA / JOURNAL:  - Neuro Oncol. 2013 Mar 3.

            ●● Enlace al texto completo (gratuito o de pago) 1093/neuonc/not019

AUTORES / AUTHORS:  - Calaminus G; Kortmann R; Worch J; Nicholson JC; Alapetite C; Garre ML; Patte C; Ricardi U; Saran F; Frappaz D

INSTITUCIÓN / INSTITUTION:  - Department of Radiation Therapy and Radio-oncology, University of Leipzig, Leipzig, Germany (R.K.); Department of Paediatric Hematology/Oncology, University Children’s Hospital, Muenster, Germany (G.C., J.W.); Department of Paediatric Oncology, Addenbrookes Hospital, Cambridge, UK (J.C.N.); Department for Paediatric Hematology/Oncology, Radiation Oncology Department, Paris & Proton Therapy Center, Orsay, Institut Curie, Paris, France (C.A.); Neuro-Oncology Unit, Department of Pedeatric Hematology and Oncol ogy, G. Gaslini Children’s Hospital, Genova, Italy (M.L.G.); Paediatrics Department, Institut Gustave Roussy, Villejuif, France (C.P.); Department of Medical and Surgical Sciences, Radiation  Oncology Unit, University of Turin, Torino, Italy (U.R.); Department of Radiotherapy, Royal Marsden Hospital, Sutton, Surrey, UK (F.S.); Institute d’Hemato-Oncologie Pediatrique, Centre Leon Berard, Lyon, France (D.F.).

RESUMEN / SUMMARY:  - BackgroundWe conducted a nonrandomized international study for intracranial germinoma that compared chemotherapy followed by local radiotherapy with reduced-dose craniospinal irradiation (CSI) alone, to determine whether the combined treatment regimen produced equivalent outcome and avoided irradiation beyond the primary tumor site(s).MethodsPatients with localized germinoma received either CSI or 2 courses of carboplatin and etoposide alternating with etoposide and ifosfamide, followed by local radiotherapy. Metastatic patients received CSI with focal boosts to primary tumor and metastatic sites, with the option to be preceded with chemotherapy.ResultsPatients with localized germinoma  (n = 190) received either CSI alone (n = 125) or combined therapy (n = 65), demonstrating no differences in 5-year event-free or overall survival, but a difference in progression-free survival (0.97 +/- 0.02 vs 0.88 +/- 0.04; P = .04). Seven of 65 patients receiving combined treatment experienced relapse (6 with ventricular recurrence outside the primary radiotherapy field), and only 4 of 125 patients treated with CSI alone experienced relapse (all at the primary tumor site). Metastatic patients (n = 45) had 0.98 +/- 0.023 event-free and overall survival.ConclusionsLocalized germinoma can be treated with reduced dose  CSI alone or with chemotherapy and reduced-field radiotherapy. The pattern of relapse suggests inclusion of ventricles in the radiation field. Reduced-dose craniospinal radiation alone is effective in metastatic disease.




TÍTULO / TITLE:  - Reduced microglial CX3CR1 expression delays neurofibromatosis-1 glioma formation.

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

REVISTA / JOURNAL:  - Ann Neurol. 2013 Feb;73(2):303-8. doi: 10.1002/ana.23813. Epub 2013 Feb 19.

            ●● Enlace al texto completo (gratuito o de pago) 1002/ana.23813

AUTORES / AUTHORS:  - Pong WW; Higer SB; Gianino SM; Emnett RJ; Gutmann DH

INSTITUCIÓN / INSTITUTION:  - Department of Neurology, Washington University School of Medicine, St Louis, MO.

RESUMEN / SUMMARY:  - Although traditional models of carcinogenesis have largely focused on neoplastic  cells, converging data have revealed the importance of non-neoplastic stromal cells in influencing tumor growth and progression. Leveraging a genetically engineered mouse model of neurofibromatosis type 1 (NF1)-associated optic glioma, we now demonstrate that stromal microglia express the CX3CR1 chemokine receptor,  such that reduced CX3CR1 expression decreases optic nerve microglia. Moreover, genetic reduction of Cx3cr1 expression in Nf1 optic glioma mice delays optic glioma formation. Coupled with previous findings demonstrating that microglia maintain optic glioma growth, these new findings provide a strong preclinical rationale for the development of future stroma-directed glioma therapies in children. ANN NEUROL 2013;73:303-308.




TÍTULO / TITLE:  - 68Ga-DOTANOC PET/CT for Baseline Evaluation of Patients with Head and Neck Paraganglioma.

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

REVISTA / JOURNAL:  - J Nucl Med. 2013 Mar 21.

            ●● Enlace al texto completo (gratuito o de pago) 2967/jnumed.112.115485

AUTORES / AUTHORS:  - Sharma P; Thakar A; Suman Kc S; Dhull VS; Singh H; Naswa N; Reddy RM; Karunanithi S; Kumar R; Kumar R; Malhotra A; Bal C

INSTITUCIÓN / INSTITUTION:  - Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi, India; and.

RESUMEN / SUMMARY:  - The purpose of this study was to evaluate the role of 68Ga-labeled DOTANOC PET/CT for baseline evaluation of patients with head and neck paragangliomas (HNPs). METHODS: The data for 26 patients (mean age +/- SD, 34.3 +/- 10.4 y; 50% men) with known or suspected HNPs who underwent 68Ga-DOTANOC PET/CT for staging were retrospectively analyzed. PET/CT was performed after intravenous injection of 132-222 MBq of 68Ga-DOTANOC. The images were evaluated by 2 experienced nuclear medicine physicians in consensus, both qualitatively and quantitatively. The PET/CT findings were grouped as HNPs, paraganglioma at other sites (non-HNPs), and metastatic disease. The size and maximum standardized uptake values (SUVmax)  were measured for all lesions. All of the patients also underwent whole-body 131I-metaiodobenzylgunanidine (131I-MIBG) scintigraphy and conventional imaging (CT/MR imaging) of the head and neck region. Their results were compared with those of 68Ga-DOTANOC PET/CT. RESULTS: 68Ga-DOTANOC PET/CT findings were positive in all 26 patients, and 78 lesions were detected. PET/CT imaging demonstrated 45  HNPS, 10 non-HNPs, and 23 metastatic sites. Fifteen patients (57.6%) had more than one site of disease on PET/CT. Among 45 HNPs, 26 were carotid body tumors (CBTs), 15 glomus jugulare, 3 glomus tympanicum, and 1 laryngeal paraganglioma. A positive correlation was seen between size and SUVmax of HNPs (rho = 0.323; P = 0.030). The SUVmax of the CBTs was higher than that of jugulotympanic paragangliomas (P = 0.026). No correlation was seen between size and SUVmax (rho  = 0.069; P = 0.854) of non-HNPs. The size and SUVmax of non-HNPs were significantly less than those of HNPs (P = 0.029 and 0.047, respectively). 131I-MIBG scintigraphy showed only 30 of the 78 lesions and was inferior to PET/CT (P < 0.0001). Conventional imaging (CT/MR imaging) was positive for 42 of  49 head and neck lesions and was inferior to PET/CT on direct comparison (P = 0.015). A combination of CT/MR imaging and 131I-MIBG scintigraphy detected only 53 of 78 (67.9%) lesions and was also inferior to PET/CT (P < 0.0001). CONCLUSION: 68Ga-DOTANOC PET/CT is useful for the baseline evaluation of patients with HNPs and can demonstrate synchronous paragangliomas at other sites and distant metastases. It is superior to 131I-MIBG scintigraphy and conventional imaging (CT/MR imaging) for this purpose.




TÍTULO / TITLE:  - Vasculogenic mimicry is a prognostic factor for postoperative survival in patients with glioblastoma.

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

REVISTA / JOURNAL:  - J Neurooncol. 2013 Feb 16.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11060-013-1077-7

AUTORES / AUTHORS:  - Wang SY; Ke YQ; Lu GH; Song ZH; Yu L; Xiao S; Sun XL; Jiang XD; Yang ZL; Hu CC

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, Zhujiang Hospital, National Key Clinic Department, Neurosurgery Institute, Key Laboratory on Brain Function Repair and Regeneration  of Guangdong, Southern Medical University, Gongye Road 253, Guangzhou, 510282, China.

RESUMEN / SUMMARY:  - A previous report has confirmed the existence and clinical significance of vasculogenic mimicry (VM) in glioma. However, its conclusions about the negative  clinical significance of VM in glioblastoma are based on a small group of patients and, thus, might be unconvincing. The aim of the present study was to reevaluate the clinical significance of VM in glioblastoma. Patients were classified as VM-positive or VM-negative according to CD34 and periodic acid-Schiff staining. The association between VM and the clinical characteristics of the patients was analyzed. Univariate and multivariate analyses were carried out to identify the independent prognostic factors for overall survival using the Cox regression hazard model. Survival times were estimated using the Kaplan-Meier method and compared using the log-rank test. Of all 86 glioblastomas, 23 were found to have VM. The presence of VM in glioblastoma was not associated with gender, age, Karnofsky performance status, hydrocephalus, tumor burden, microvessel density, tumor relapse, or the extent of tumor resection. The univariate and multivariate analyses revealed that VM is an independent prognostic factor for overall survival. The median survival time for patients with VM was 11.17 months compared with 16.10 months for those without VM (P = 0.017). In addition to VM, an age of 65 years or older, a KPS of 60 or less, a large tumor burden are significant prognostic factors for patient survival. Our data suggest that VM might be an independent adverse prognostic factor in newly diagnosed GBM, further prospective studies are needed to answer this question.




TÍTULO / TITLE:  - Focal Cranial Hyperostosis From Meningioma: A Complication From Previous Radiation Treatment for Childhood T-Cell Acute Lymphoblastic Leukemia.

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

REVISTA / JOURNAL:  - J Pediatr Hematol Oncol. 2013 Mar 1.

            ●● Enlace al texto completo (gratuito o de pago) 1097/MPH.0b013e3182830d56


INSTITUCIÓN / INSTITUTION:  - Fox Chase Cancer Center, Temple University, Philadelphia, PA.

RESUMEN / SUMMARY:  - Nearly 75% of childhood cancer survivors will experience an adverse late effect from previous therapy. In patients previously treated with cranial irradiation, the late effect can manifest as secondary central nervous system tumors. Presented is a case of a 20 year man with a history of T-cell lymphoblastic leukemia diagnosed at age 22 months, treated with chemotherapy and cranial irradiation. He had developed increasing prominence of the top of his head over several months. Plain radiograph showed frontal calvarium thickening with focal “hair-on-end” periosteal reaction. Magnetic resonance imaging revealed an enhancing dural-based mass with transcalvarial extension, confirmed after resection to be meningioma (World Health Organization Grade I). This case illustrates an atypical presentation of a late effect of childhood cancer treatment and highlights the need to be informed about prior treatments received  and potential attendant complications.




TÍTULO / TITLE:  - Preoperative Particle and Glue Embolization of Meningiomas: Indications, Results  and Lessons Learned from 117 Consecutive Patients.

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

REVISTA / JOURNAL:  - Neurosurgery. 2013 Feb 25.

            ●● Enlace al texto completo (gratuito o de pago) 1227/NEU.0b013e31828e1ffd

AUTORES / AUTHORS:  - Borg A; Ekanayake J; Mair R; Smedley T; Brew S; Kitchen N; Samandouras G; Robertson F

INSTITUCIÓN / INSTITUTION:  - 1Victor Horsley Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, London 2Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, London 3Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London.

RESUMEN / SUMMARY:  - BACKGROUND:: Preoperative embolization of meningiomas remains contentious, with persisting uncertainty over the safety and efficacy of this adjunctive technique. OBJECTIVE:: To evaluate the safety of presurgicalembolization of meningiomas and  its impact on subsequent transfusion requirement, with respect to the extent of embolization and technique used. METHODS:: 117 consecutive patients between 2001  and 2010 were referred for embolization of presumed intracranial meningioma prior to surgical resection. Glue and/or particles were used to devascularize the tumor in 107 patients, all of whom went on to operative resection. The extent and nature of embolization-related complications, degree of angiographic devascularization, and the intraoperative blood transfusion requirements were analyzed. RESULTS:: Mean blood transfusion requirement during surgery was 0.8 units per case (range 1-14 units). Blood transfusion was significantly lower in patients whose meningiomas were completely, angiographicallydevascularized (P= .035). Four patients had complications as a direct result of the embolization procedure. These included intratumoral haemorrhage in two, sixth cranial nerve palsy in one, and scalp necrosis requiring reconstructive surgery in a further patient. CONCLUSION:: The complication rate was 3.7%. No relationship between the embolic agent and the degree of devascularization was observed. Achieving a complete devascularization resulted in a lower blood transfusion requirement, considered an indirect measure of operative blood loss. This series demonstrates  that pre-operative meningiomaembolization is safe and may reduce operative blood  loss. We present distal intratumoral injection of liquid embolic as a safe and effective alternative to more established particle embolization techniques.




TÍTULO / TITLE:  - Deciphering the 8q24.21 association for glioma.

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

REVISTA / JOURNAL:  - Hum Mol Genet. 2013 Feb 20.

            ●● Enlace al texto completo (gratuito o de pago) 1093/hmg/ddt063

AUTORES / AUTHORS:  - Enciso-Mora V; Hosking FJ; Kinnersley B; Wang Y; Shete S; Zelenika D; Broderick P; Idbaih A; Delattre JY; Hoang-Xuan K; Marie Y; Di Stefano AL; Labussiere M; Dobbins S; Boisselier B; Ciccarino P; Rossetto M; Armstrong G; Liu Y; Gousias K; Schramm J; Lau C; Hepworth SJ; Strauch K; Muller-Nurasyid M; Schreiber S; Franke A; Moebus S; Eisele L; Forsti A; Hemminki K; Tomlinson IP; Swerdlow A; Lathrop M; Simon M; Bondy M; Sanson M; Houlston RS

INSTITUCIÓN / INSTITUTION:  - Division of Genetics and Epidemiology, Institute of Cancer Research, 15 Cotswold  Road, Sutton, Surrey SM2 5NG, UK+

RESUMEN / SUMMARY:  - We have previously identified tagSNPs at 8q24.21 influencing glioma risk. We have sought to fine-map the location of the functional basis of this association using data from four genome-wide association studies, comprising a total of 4147 glioma cases and 7435 controls. To improve marker density across the 700 kb region, we imputed genotypes using 1000 Genomes Project data and high-coverage sequencing data generated on 253 individuals. Analysis revealed an imputed low-frequency SNP rs55705857 (P = 2.24 x 10(-38)) which was sufficient to fully capture the 8q24.21 association. Analysis by glioma subtype showed the association with rs55705857 confined to non-glioblastoma multiforme (non-GBM) tumours (P = 1.07 x 10(-67)). Validation of the non-GBM association was shown in three additional datasets (625 non-GBM cases, 2412 controls; P = 1.41 x 10(-28)). In the pooled analysis, the odds ratio for low-grade glioma associated with rs55705857 was 4.3 (P = 2.31 x 10(-94)). rs55705857 maps to a highly evolutionarily conserved sequence within the long non-coding RNA CCDC26 raising the possibility of direct functionality. These data provide additional insights into the aetiological basis of glioma development.




TÍTULO / TITLE:  - Higher doses of cabergoline further improve metabolic parameters in patients with prolactinoma regardless of the degree of reduction in prolactin levels.

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

REVISTA / JOURNAL:  - Clin Endocrinol (Oxf). 2013 Mar 18. doi: 10.1111/cen.12204.

            ●● Enlace al texto completo (gratuito o de pago) 1111/cen.12204

AUTORES / AUTHORS:  - Ciresi A; Amato MC; Guarnotta V; Lo Castro F; Giordano C

INSTITUCIÓN / INSTITUTION:  - Section of Endocrinology, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.Mi.S), University of Palermo, Italy.

RESUMEN / SUMMARY:  - OBJECTIVE: Currently available studies that fully analyze the metabolic parameters in patients with prolactinoma are scarce and discordant. The aim of this study was to evaluate the metabolic effects of cabergoline (CAB) treatment in patients with newly diagnosed prolactinoma in relation to disease control and  CAB dosage. DESIGN: This is a retrospective clinical-based therapy analysis. PATIENTS: Forty-three prolactinoma patients (8 men, 35 women), aged 33.65 +/- 11.23 years, were evaluated metabolically at baseline and after 12 months of CAB  treatment. MEASUREMENTS: Body mass index (BMI), systolic and diastolic blood pressure, waist circumference (WC), lipid profile, haemoglobinA1c (HbA1c), glucose and insulin levels (and their areas under the curve, AUC) after an oral glucose tolerance test, homeostasis model assessment of insulin resistance (Homa-IR) index, insulin sensitivity index (ISI) Matsuda, oral disposition index  (DIo) and visceral adiposity index (VAI) were measured at baseline and after 12 months of treatment. RESULTS: 12 months of CAB reduced WC (p<0.001), total (p=0.001), and low-density lipoprotein cholesterol (p<0.001), triglyderides (p=0.024), fasting insulin (p<0.001), AUCINSULIN (p<0.001), HbA1c (p=0.022), Homa-IR (p<0.001) and VAI (p<0.001), with a concomitant increase in high-density  lipoprotein cholesterol (p<0.001) and in ISI-Matsuda (p<0.001), regardless of the degree of reduction in prolactin levels. The patients receiving higher doses (> 0.50 mg/week) of CAB showed lower BMI (p=0.009), fasting insulin (p=0.001), Homa-IR (p<0.001) and VAI (p=0.018) and higher ISI-Matsuda (p=0.002) and DIo (p=0.011), compared to those on lower doses. CONCLUSIONS: A significant metabolic improvement was observed in prolactinoma patients after 12 months of CAB treatment, especially when higher doses were used, highlighting the importance of considering the metabolic profile in these patients and the role of active treatment with high CAB doses. © 2013 Blackwell Publishing Ltd.




TÍTULO / TITLE:  - Management and survival rates in patients with glioma in China (2004-2010): a retrospective study from a single-institution.

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

REVISTA / JOURNAL:  - J Neurooncol. 2013 Mar 13.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11060-013-1103-9

AUTORES / AUTHORS:  - Yang P; Wang Y; Peng X; You G; Zhang W; Yan W; Bao Z; Wang Y; Qiu X; Jiang T

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, No. 6 Tiantan Xili, Dongcheng District, Beijing, 100050, China.

RESUMEN / SUMMARY:  - To analyze the clinical characteristics and prognostic factors in patients with glioma in an academic institute in China. From October 2004 to August 2010, total 1,285 patients were diagnosed as glioma at the Glioma Center of Beijing Tiantan Hospital. Clinical and molecular pathology features and survival rates were analyzed. The median overall survival (OS) times were 78.1, 37.6 and 14.4 months  for low-grade glioma (WHO grade II), anaplastic glioma (WHO grade III) and glioblastoma (WHO grade IV), respectively. In patients with low-grade glioma, age, preoperative Karnofsky performance scale (KPS), pathological type, radiotherapy, O6-methylguanine-DNA methyltransferase (MGMT) expression and Ki-67  expression, were significantly associated with OS in multivariate analyses; and preoperative KPS and radiotherapy were significantly associated with progression-free survival (PFS). For anaplastic gliomas, age, preoperative KPS, pathological type, extent of resection, radiotherapy, p53 expression and phosphatase and tensin homolog (PTEN) expression were associated with OS. For glioblastomas, age, preoperative KPS, pathology type, extent of resection, radiotherapy and chemotherapy were associated with OS; and age, gender, preoperative KPS, extent of resection, radiotherapy and chemotherapy were associated with PFS. This is the largest survey for glioma management in China to date. We found significant differences in age, presenting symptoms and the expression of p53, MGMT, PTEN, and Ki-67 among patients with different types of glioma. Age, preoperative KPS, tumor grades, radiotherapy, chemotherapy and Ki-67 expression were significantly associated with clinical prognosis.




TÍTULO / TITLE:  - Screening for major depressive disorder in adults with glioma using the PHQ-9: a  comparison of patient versus proxy reports.

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

REVISTA / JOURNAL:  - J Neurooncol. 2013 Feb 24.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11060-013-1088-4

AUTORES / AUTHORS:  - Rooney AG; McNamara S; Mackinnon M; Fraser M; Rampling R; Carson A; Grant R

INSTITUCIÓN / INSTITUTION:  - Edinburgh Centre for Neuro-Oncology, Western General Hospital, Edinburgh, Scotland, UK, a.rooney@nhs.net.

RESUMEN / SUMMARY:  - When screening for depression in glioma patients, the utility of proxy carer report is unknown. We studied how patients and proxies differed in the frequency, severity and agreement of reported depressive symptoms, the external validity of  these reports, and whether patient-proxy agreement was associated with cognitive  function. This was a cross-sectional study within a prospective cohort study of depression in glioma. Eligible patients were adults with a new diagnosis of cerebral glioma whose cohabiting partners chose to attend study interviews. Patients completed the Patient Health Questionnaire-9 (PHQ-9, maximum score 27) to screen for major depressive disorder. Proxies independently completed the PHQ-9 ‘for the patient’. A structured clinical interview for MDD was then given.  From 55 couples attending, 41 participated (74 %). Patient-proxy total PHQ-9 score differed by 3 or more points in 26/41 cases (63.4 %). Disagreement within dyads ranged from -7 to +10 points. Proxies observed more individual depressive symptoms than patients reported (mean 2.7 vs 1.8 symptoms respectively, p = 0.013, Wilcoxon Rank Sum Test), and a greater severity of symptom burden (mean PHQ-9 score 8.4 vs 6.8 respectively, p = 0.016, Wilcoxon Rank Sum Test). Proxies  were more reliable than patients on objective behavioural symptoms of depression. Dyadic agreement was not associated with severity of patient cognitive impairment. There was frequent disagreement between glioma patients and proxies reports of depressive symptoms. Proxies reported more depressive symptoms than patients, and were more reliable when reporting observable behavioural symptoms.  When diagnosing depression in glioma, collateral history should be obtained.




TÍTULO / TITLE:  - Tumoral EPAS1 (HIF2A) mutations explain sporadic pheochromocytoma and paraganglioma in the absence of erythrocytosis.

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/ddt069

AUTORES / AUTHORS:  - Comino-Mendez I; de Cubas AA; Bernal C; Alvarez-Escola C; Sanchez-Malo C; Ramirez-Tortosa CL; Pedrinaci S; Rapizzi E; Ercolino T; Bernini G; Bacca A; Leton R; Pita G; Alonso MR; Leandro-Garcia LJ; Gomez-Grana A; Inglada-Perez L; Mancikova V; Rodriguez-Antona C; Mannelli M; Robledo M; Cascon A

INSTITUCIÓN / INSTITUTION:  - Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, España.

RESUMEN / SUMMARY:  - Pheochromocytomas (PCCs) and paragangliomas (PGLs) are chromaffin-cell tumors that arise from the adrenal medulla and extra-adrenal paraganglia, respectively.  The dysfunction of genes involved in the cellular response to hypoxia, such as VHL, EGL nine homolog 1, and the succinate dehydrogenase (SDH) genes, leads to a  direct abrogation of hypoxia inducible factor (HIF) degradation, resulting in a pseudo-hypoxic state implicated in PCC/PGL development. Recently, somatic post-zygotic mutations in EPAS1 (HIF2A) have been found in patients with multiple PGLs and congenital erythrocytosis. We assessed 41 PCCs/PGLs for mutations in EPAS1 and herein describe the clinical, molecular and genetic characteristics of  the 7 patients found to carry somatic EPAS1 mutations; 4 presented with multiple  PGLs (3 of them also had congenital erythrocytosis), whereas 3 were single sporadic PCC/PGL cases. Gene expression analysis of EPAS1-mutated tumors revealed similar mRNA EPAS1 levels to those found in SDH-gene- and VHL-mutated cases and a significant up-regulation of two hypoxia-induced genes (PCSK6 and GNA14). Interestingly, single nucleotide polymorphism array analysis revealed an exclusive gain of chromosome 2p in three EPAS1-mutated tumors. Furthermore, multiplex-PCR screening for small rearrangements detected a specific EPAS1 gain in another EPAS1-mutated tumor and in three non-EPAS1-mutated cases. The finding  that EPAS1 is involved in the sporadic presentation of the disease not only increases the percentage of PCCs/PGLs with known driver mutations, but also highlights the relevance of studying other hypoxia-related genes in apparently sporadic tumors. Finally, the detection of a specific copy number alteration affecting chromosome 2p in EPAS1-mutated tumors may guide the genetic diagnosis of patients with this disease.




TÍTULO / TITLE:  - MR Imaging Assessment of Tumor Perfusion and 3D Segmented Volume at Baseline, during Treatment, and at Tumor Progression in Children with Newly Diagnosed Diffuse Intrinsic Pontine Glioma.

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

REVISTA / JOURNAL:  - AJNR Am J Neuroradiol. 2013 Feb 22.

            ●● Enlace al texto completo (gratuito o de pago) 3174/ajnr.A3421

AUTORES / AUTHORS:  - Sedlacik J; Winchell A; Kocak M; Loeffler RB; Broniscer A; Hillenbrand CM

INSTITUCIÓN / INSTITUTION:  - Departments of Radiological Sciences, Biostatistics, and Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee; and Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.

RESUMEN / SUMMARY:  - BACKGROUND AND PURPOSE:DIPG is among the most devastating brain tumors in children, necessitating the development of novel treatment strategies and advanced imaging markers such as perfusion to adequately monitor clinical trials. This study investigated tumor perfusion and 3D segmented tumor volume as predictive markers for outcome in children with newly diagnosed DIPG.METHODS:Imaging data were assessed at baseline, during, and after RT, and every other month thereafter until tumor progression for 35 patients (ages 2-16 years) with newly diagnosed DIPG enrolled in the phase I clinical study, NCT00472017. Patients were treated with conformal RT and vandetanib, a vascular endothelial growth factor receptor 2 inhibitor.RESULTS:Tumor perfusion increased  and tumor volume decreased during combined RT and vandetanib therapy. These changes slowly diminished in follow-up scans until tumor progression. However, increased tumor perfusion and decreased tumor volume during combined therapy were associated with longer PFS. Apart from a longer OS for patients who showed elevated tumor perfusion after RT, there was no association for tumor volume and  other perfusion variables with OS.CONCLUSIONS:Our results suggest that tumor perfusion may be a useful predictive marker for the assessment of treatment response and tumor progression in children with DIPG treated with both RT and vandetanib. The assessment of tumor perfusion yields valuable information about tumor microvascular status and its response to therapy, which may help better understand the biology of DIPGs and monitor novel treatment strategies in future  clinical trials.




TÍTULO / TITLE:  - Neuregulin 1 enhances cell adhesion molecule l1 expression in human glioma cells  and promotes their migration as a function of malignancy.

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

REVISTA / JOURNAL:  - J Neuropathol Exp Neurol. 2013 Mar;72(3):244-55. doi: 10.1097/NEN.0b013e3182863dc5.

            ●● Enlace al texto completo (gratuito o de pago) 1097/NEN.0b013e3182863dc5

AUTORES / AUTHORS:  - Zhao WJ; Schachner M

INSTITUCIÓN / INSTITUTION:  - Center for Neuroscience, Shantou University Medical College, Shantou, Guandong Province, People’s Republic of China.

RESUMEN / SUMMARY:  - Similar functions of L1, a cell adhesion molecule, and the cytokine neuregulin 1  (Nrg1) have been suggested in tumorigenesis and the promotion of metastasis. We studied the relationships of Nrg1 and L1 expression in human gliomas. Using immunofluorescence staining on a human glioma tissue microarray, we found a positive correlation between levels of L1 and Nrg1alpha or Nrg1beta expression; expression tended to increase with increasing WHO (World Health Organization) tumor grade. L1 was also found to colocalize with either Nrg1 isoform. In cultures of U87-MG human glioblastoma and human U251 and SHG-44 glioma cells, the base levels of full-length L1 expression were increased by the 2 Nrg1 molecules in the nanomolar range, and Nrg1 siRNA downregulated full-length L1 expression in these tumor cell lines. U87-MG cells treated with either Nrg1 isoform also showed enhanced migration when compared with that treated with vehicle control. In addition, administration of either lapatinib (a dual inhibitor of both the epidermal growth factor receptor and ErbB-2) or erlotinib (an inhibitor of the epidermal growth factor receptor) in combination with either Nrg1alpha or Nrg1beta inhibited the L1 expression elicited by these cytokines in U87-MG cells. Together, our data suggest that Nrg1 regulates L1 expression in gliomas, and that Nrg1 may contribute to malignancy by upregulating the L1 expression in glioblastoma cells, thereby enhancing their migration.




TÍTULO / TITLE:  - Seizures during the management of high-grade gliomas: clinical relevance to disease progression.

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

REVISTA / JOURNAL:  - J Neurooncol. 2013 Mar 4.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11060-013-1094-6

AUTORES / AUTHORS:  - Kim YH; Park CK; Kim TM; Choi SH; Kim YJ; Choi BS; Han JH; Lee SH; Kim CY; Kim IA; Heo DS; Kim IH; Kim DG; Jung HW

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, Seoul National University College of Medicine, 101 Daehang-ro Jongno-gu, Seoul, 110-744, South Korea.

RESUMEN / SUMMARY:  - This study was performed to evaluate the incidence of seizures with its implications on disease progression and the diagnostic value of post-ictal magnetic resonance images (MRI) during the management of high-grade gliomas (HGGs). A total of 406 consecutive patients with newly diagnosed HGGs were retrospectively reviewed. The incidence of seizures during the management was investigated. In patients who experienced a seizure, the causality between seizures and disease progression was assessed by pre-ictal, post-ictal (<1 month), and follow-up (<3 months) MRI. After a median follow-up of 17.4 months (range 0.1-88.3), seizures developed in 127 patients (31 %). Of the 127 patients, radiological progression at the post-ictal MRI was found in 83 patients (65 %) and the follow-up MRI confirmed progression in 79 patients (62 %). Four other patients (3 %) were shown to be progression-free. Among those without radiological progression at the post-ictal MRI, the follow-up MRI confirmed progression-free in 31 patients (24 %); however, 13 patients (10 %) revealed eventual progression. In the patients with a seizure, absence of preoperative seizures (p = 0.003), <95 % tumor resection (p = 0.001), and pre-ictal Karnofsky  Performance Scale score </=70 (p = 0.025) were significantly associated with disease progression. During the management of HGG, 31 % of patients experienced seizures; of these patients, 72 % harbored progressive disease. The post-ictal MRI is useful for detecting disease progression; however, there are pitfalls. Clinical settings should be considered together for diagnosing disease progression in patients with seizures.




TÍTULO / TITLE:  - Comparison of glioma-associated antigen peptide-loaded versus autologous tumor lysate-loaded dendritic cell vaccination in malignant glioma patients.

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

REVISTA / JOURNAL:  - J Immunother. 2013 Feb;36(2):152-7. doi: 10.1097/CJI.0b013e3182811ae4.

            ●● Enlace al texto completo (gratuito o de pago) 1097/CJI.0b013e3182811ae4

AUTORES / AUTHORS:  - Prins RM; Wang X; Soto H; Young E; Lisiero DN; Fong B; Everson R; Yong WH; Lai A; Li G; Cloughesy TF; Liau LM

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, USA.

RESUMEN / SUMMARY:  - Dendritic cell (DC) vaccination is emerging as a promising therapeutic option for malignant glioma patients. However, the optimal antigen formulation for loading these cells has yet to be established. The objective of this study was to compare the safety, feasibility, and immune responses of malignant glioma patients on 2 different DC vaccination protocols. Twenty-eight patients were treated with autologous tumor lysate (ATL)-pulsed DC vaccination, whereas 6 patients were treated with glioma-associated antigen (GAA) peptide-pulsed DCs. Safety, toxicity, feasibility, and correlative immune monitoring assay results were compared between patients on each trial. Because of HLA subtype restrictions on the GAA-DC trial, 6/15 screened patients were eligible for treatment, whereas 28/32 patients passed eligibility screening for the ATL-DC trial. Elevated frequencies of activated natural killer cells were observed in the peripheral blood from GAA-DC patients compared with the ATL-DC patients. In addition, a significant correlation was observed between decreased regulatory T lymphocyte (Treg) ratios (postvaccination/prevaccination) and overall survival (P = 0.004) in patients on both trials. In fact, Treg ratios were independently prognostic for overall survival in these patients, whereas tumor pathology was not in multivariate analyses. In conclusion, these results suggest that ATL-DC vaccination is associated with wider patient eligibility compared with GAA-DC vaccination. Decreased postvaccination/prevaccination Treg ratios and decreased frequencies of activated natural killer cells were associated with prolonged survival in patients from both trials, suggesting that these lymphocyte subsets may be relevant immune monitoring endpoints for immunotherapy protocols in malignant glioma patients.




TÍTULO / TITLE:  - Neoadjuvant chemotherapy may optimize the extent of resection of World Health Organization grade II gliomas: a case series of 17 patients.

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

REVISTA / JOURNAL:  - J Neurooncol. 2013 Mar 12.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11060-013-1106-6

AUTORES / AUTHORS:  - Blonski M; Pallud J; Goze C; Mandonnet E; Rigau V; Bauchet L; Fabbro M; Beauchesne P; Baron MH; Fontaine D; Peruzzi P; Darlix A; Duffau H; Taillandier L

INSTITUCIÓN / INSTITUTION:  - Neuro-Oncology Unit, Nancy University Hospital, 29, Avenue du Marechal Lattre de  Tassigny, 54035, Nancy, France, blonski-marie@orange.fr.

RESUMEN / SUMMARY:  - The involvement of eloquent brain areas may preclude the total/subtotal surgical  resection of diffuse low-grade gliomas (DLGGs). The feasibility and functional tolerance of neoadjuvant chemotherapy have been demonstrated in such cases. The present study assesses the clinical and radiological impact of neoadjuvant chemotherapy on the natural course of DLGG. Seventeen patients without feasible surgical resection (infiltration of functional areas and/or large contralateral extension) were retrospectively selected. Temozolomide based neoadjuvant chemotherapy was initiated, inducing a tumor volume decrease and allowing a functional based maximal surgical resection. The median follow-up since initial radiological diagnosis was 5.9 years (range, 1.4-11). The median time to malignant transformation was 5.9 years. Six patients (35 %) had 1p19q codeletion, 12 patients (70 %) with IDH mutation and MGMT promoter methylation, and eight patients (47 %) had p53 overexpression. Chemotherapy reduced tumor volume (median -35.6 %, range -61.6 to -5.1 %) in contralateral hemisphere through the corpus callosum in seven cases (41 %) and in ipsi-lesional functional areas in ten cases (59 %). Chemotherapy significantly decreased the imaging tumor growth (measured by the velocity of diametric expansion VDE) with a median of -3.2 mm/year (range, -29.8 to -0.9 mm/year) (p < 0.001). A tumor volume decrease of more than 20 % was correlated with a lower postoperative residual tumor (median 2 cc, p = 0.04), a greater extent of resection (93.1 vs. 89.5 %), a higher probability of total/subtotal removal. Neoadjuvant chemotherapy with Temozolomide could optimize the surgical resection of DLGGs and could impact their natural history. Further large prospective studies with long-term follow-up are needed.




TÍTULO / TITLE:  - Vaccination for Invasive Canine Meningioma Induces in Situ Production of Antibodies Capable of Antibody-Dependent Cell-Mediated Cytotoxicity.

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

REVISTA / JOURNAL:  - Cancer Res. 2013 Mar 13.

            ●● Enlace al texto completo (gratuito o de pago) 1158/0008-5472.CAN-12-3366

AUTORES / AUTHORS:  - Andersen BM; Pluhar GE; Seiler C; Goulart MR; Santacruz KS; Schutten MM; Meints JP; O’Sullivan G; Bentley RT; Packer RA; Thomovsky SA; Chen AV; Faissler D; Chen W; Hunt MA; Olin MR; Ohlfest JR

INSTITUCIÓN / INSTITUTION:  - Pediatrics, University of Minnesota.

RESUMEN / SUMMARY:  - Malignant and atypical meningiomas are resistant to standard therapies and associated with poor prognosis. Despite progress in the treatment of other tumors with therapeutic vaccines, this approach has not been tested preclinically or clinically in these tumors. Spontaneous canine meningioma is a clinically meaningful but underutilized model for preclinical testing of novel strategies for aggressive human meningioma. We treated 11 meningioma-bearing dogs with surgery and vaccine immunotherapy consisting of autologous tumor cell lysate combined with toll-like receptor ligands. Therapy was well tolerated, and only one dog had tumor growth that required intervention, with a mean follow up of 585 days. Interferon gamma elaborating T cells were detected in the peripheral blood  of two cases, but vaccine-induced tumor-reactive antibody responses developed in  all dogs. Antibody responses were polyclonal, recognizing both intracellular and  cell surface antigens, and heat shock protein 60 was identified as one common antigen. Tumor-reactive antibodies bound allogeneic canine and human meningiomas, demonstrating common antigens across breed and species. Histological analysis revealed robust infiltration of antibody-secreting plasma cells into the brain around the tumor in post-treatment compared to pre-treatment samples. Tumor-reactive antibodies were capable of inducing antibody dependent cell-mediated cytotoxicity to autologous and allogeneic tumor cells. These data demonstrate the feasibility and immunologic efficacy of vaccine immunotherapy for a large animal model of human meningioma and warrant further development towards  human trials.




TÍTULO / TITLE:  - Refining the predictors of risk for central nervous system involvement in patients with mantle cell lymphoma.

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

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

            ●● Enlace al texto completo (gratuito o de pago) 3109/10428194.2013.777839

AUTORES / AUTHORS:  - Cheah CY; Seymour JF

INSTITUCIÓN / INSTITUTION:  - Department of Haematology, Peter MacCallum Cancer Centre , East Melbourne , Australia.




TÍTULO / TITLE:  - Antiproliferative, Antiinvasive, and Proapoptotic Activity of Folate Receptor alpha-Targeted Liposomal Doxorubicin in Nonfunctional Pituitary Adenoma Cells.

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

REVISTA / JOURNAL:  - Endocrinology. 2013 Apr;154(4):1414-23. doi: 10.1210/en.2012-2128. Epub 2013 Mar  5.

            ●● Enlace al texto completo (gratuito o de pago) 1210/en.2012-2128

AUTORES / AUTHORS:  - Liu X; Ma S; Dai C; Cai F; Yao Y; Yang Y; Feng M; Deng K; Li G; Ma W; Xin B; Lian W; Xiang G; Zhang B; Wang R

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, People’s Republic of China. liuxiaohai09@yahoo.com.cn.

RESUMEN / SUMMARY:  - There is an urgent need for novel therapeutic strategies for the treatment of nonfunctional pituitary adenomas (NFPAs), especially those that are invasive. The folate receptor (FR)alpha is overexpressed in several cancers, including NFPA. The aim of this study was to determine the efficacy of FRalpha-targeted liposomes loaded with doxorubicin (F-L-DOX) in the treatment of NFPA. We evaluated targeting, cytotoxicity, antiinvasive, and proapoptotic activity of F-L-DOX in 25 primary cell lines derived from patients with NFPAs. We found that these liposomes effectively targeted NFPA cells through FRalpha and that endocytosis of the liposomes was blocked by 1mM free folic acid. F-L-DOX inhibited proliferation of NFPA cells and promoted apoptosis through activation of caspase-8, caspase-9,  and caspase-3/7 more effectively than L-DOX. Furthermore, F-L-DOX also exerted greater antiinvasive ability in NFPA cells than L-DOX through suppression of the  secretion of matrix metalloproteinase-2 and matrix metalloproteinase-9. Addition  of 1mM free folic acid significantly reduced the pleotropic effects of F-L-DOX in NFPA cells, suggesting that FRalpha plays a critical role in mediating the antitumor effect of F-L-DOX. Our findings warrant further investigation of F-L-DOX as an alternative therapeutic strategy for the treatment of NFPAs that express FRalpha.




TÍTULO / TITLE:  - Protoporphyrin IX fluorescence and photobleaching during interstitial photodynamic therapy of malignant gliomas for early treatment prognosis.

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

REVISTA / JOURNAL:  - Lasers Surg Med. 2013 Mar 26. doi: 10.1002/lsm.22126.

            ●● Enlace al texto completo (gratuito o de pago) 1002/lsm.22126

AUTORES / AUTHORS:  - Johansson A; Faber F; Kniebuhler G; Stepp H; Sroka R; Egensperger R; Beyer W; Kreth FW

INSTITUCIÓN / INSTITUTION:  - Laser-Forschungslabor, University Hospital of Munich, Marchioninistrasse 23, 81377 Munich, Germany.

RESUMEN / SUMMARY:  - BACKGROUND AND OBJECTIVE: Interstitial photodynamic therapy (iPDT) of non-resectable recurrent glioblastoma using 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) has shown a promising outcome. It remained unclear, however, to what extent inter- and intra-tumoural differences of PpIX concentrations influence the efficacy of iPDT. In the current pilot study, we analysed PpIX concentrations quantitatively and assessed PpIX induced fluorescence and photobleaching intraoperatively. MATERIALS AND METHODS: Five patients harbouring non-resectable glioblastomas were included. ALA (20 or 30 mg/kg body weight) was given 5-8 hours before treatment. Stereotactic biopsies were taken throughout the tumour volume for both histological analysis and determination of PpIX concentrations, which were measured by chemical extraction. Cylindrical light diffusors were stereotactically implanted. Prior to and after irradiation, fluorescence measurements were performed. Outcome measurement was based on clinical and neuro-radiological follow up. RESULTS: In three patients, a strong PpIX fluorescence was seen before treatment, which was completely photobleached after iPDT. High concentrations of PpIX could be detected in viable tumour parts of these patients (mean PpIX uptake per tumour: 1.4-3.0 microM). In  the other two patients, however, no or only low PpIX uptake (0-0.6 microM) could  be detected. The patients with strong PpIX uptake showed treatment response and long-term clinical stabilisation (no progression in 29, 30 and 36 months), early  treatment failure was seen in the remaining two patients (death after 3 and 9 months). CONCLUSIONS: Intra-tumoural PpIX concentrations exhibited pronounced inter- and intra-tumoural variations in glioblastoma, which are directly linked to variable degrees of fluorescence intensity. High intra-tumoural PpIX concentrations with strong fluorescence intensity and complete photobleaching after iPDT seem to be associated with favourable outcome. Real-time monitoring of PpIX fluorescence intensity and photobleaching turned out to be feasible and safe and might be employed for early treatment prognosis of iPDT. Lasers Surg. Med. © 2013 Wiley Periodicals, Inc.




TÍTULO / TITLE:  - Atypical Imaging Features of Epstein-Barr Virus—Positive Primary Central Nervous System Lymphomas in Patients without AIDS.

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

REVISTA / JOURNAL:  - AJNR Am J Neuroradiol. 2013 Feb 14.

            ●● Enlace al texto completo (gratuito o de pago) 3174/ajnr.A3429

AUTORES / AUTHORS:  - Lee HY; Kim HS; Park JW; Baek HJ; Kim SJ; Choi CG

INSTITUCIÓN / INSTITUTION:  - Department of Radiology, Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; and Department of Radiology, Inha University Hospital, Inha University School of Medicine, Incheon, Korea.

RESUMEN / SUMMARY:  - BACKGROUND AND PURPOSE:Recent clinical experience with EBV-positive PCNSL in patients without acquired immune deficiency syndrome showed that they tended to have atypical features seen on conventional MR imaging. The purpose of our study  was to evaluate the MR imaging features of EBV-positive PCNSL in patients without AIDS and to compare these imaging findings with those of EBV-negative PCNSL.MATERIALS AND METHODS:MR images were obtained in 55 consecutive patients with pathologically proved EBV-positive (n = 10) or EBV-negative (n = 45) PCNSL.  We statistically analyzed the differences between the patient groups regarding the occurrence of tumor necrosis or hemorrhage and ADC, rCBV(max), rCBV®, and the Cho/NAA ratio in the tumor area.RESULTS:Tumor necrosis and hemorrhage were observed in 9 (90%) and 7 (70%), respectively, of the patients with EBV-positive  PCNSL; necrosis was observed in 8 (18%), and hemorrhage, in 3 (7%) patients with  EBV-negative PCNSL (P < .0001 each). The necrotic core was hyperintense relative  to contralateral white matter, as seen on DWI in 4 patients with EBV-positive PCNSL, though the ADC between the 2 patient groups did not differ significantly.  rCBV(max), rCBV®, and the Cho/NAA ratios did not differ significantly between the 2 groups. The sensitivity and specificity of necrosis and hemorrhage for differentiating the 2 groups were 89.2% and 81.7% and 78.5% and 94.1%, respectively.CONCLUSIONS:Our initial clinical experience with a small number of patients suggests that EBV-positive PCNSL in patients without AIDS tends to present with atypical MR imaging features.




TÍTULO / TITLE:  - Retrospective analysis of the tolerability and activity of lacosamide in patients with brain tumors.

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

REVISTA / JOURNAL:  - J Neurosurg. 2013 Mar 1.

            ●● Enlace al texto completo (gratuito o de pago) 3171/2013.1.JNS12397

AUTORES / AUTHORS:  - Saria MG; Corle C; Hu J; Rudnick JD; Phuphanich S; Mrugala MM; Crew LK; Bota DA; Dan Fu B; Kim RY; Brown T; Feely H; Brechlin J; Brown BD; Drappatz J; Wen PY; Chen CC; Carter B; Lee JW; Kesari S

INSTITUCIÓN / INSTITUTION:  - Departments of Neurosciences and.

RESUMEN / SUMMARY:  - Object The object of this study was to determine the tolerability and activity of lacosamide in patients with brain tumors. Methods The authors reviewed the medical records at 5 US academic medical centers with tertiary brain tumor programs, seeking all patients in whom a primary brain tumor had been diagnosed and who were taking lacosamide. Results The authors identified 70 patients with primary brain tumors and reviewed seizure frequency and toxicities. The majority  of the patients had gliomas (96%). Fifty-five (78%) had partial seizures only, and 12 (17%) had generalized seizures. Most of the patients (74%) were started on lacosamide because of recurrent seizures. Forty-six patients (66%) reported a decrease in seizure frequency, and 21 patients (30%) reported stable seizures. Most of the patients (54 [77%]) placed on lacosamide did not report any toxicities. Conclusions This retrospective analysis demonstrated that lacosamide  was both well tolerated and active as an add-on antiepileptic drug (AED) in patients with brain tumors. Lacosamide’s novel mechanism of action will allow for concurrent use with other AEDs, as documented by its activity across many different types of AEDs used in this patient population. Larger prospective studies are warranted.




TÍTULO / TITLE:  - Genetic expression profiles of adult and pediatric ependymomas: Molecular pathways, prognostic indicators, and therapeutic targets.

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

REVISTA / JOURNAL:  - Clin Neurol Neurosurg. 2013 Apr;115(4):388-99. doi: 10.1016/j.clineuro.2012.12.006. Epub 2013 Jan 29.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.clineuro.2012.12.006

AUTORES / AUTHORS:  - Nagasawa DT; Trang A; Choy W; Spasic M; Yew A; Zarinkhou G; Garcia HM; Yang I

INSTITUCIÓN / INSTITUTION:  - UCLA Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, United States.

RESUMEN / SUMMARY:  - Ependymomas are tumors that can present within either the intracranial or spinal  regions. While 90% of all pediatric ependymomas are intracranial, spinal cord ependymomas are more commonly found in patients 20-40 years old. Treatment for spinal lesions has achieved local control rates up to 100% following gross total  resection, while pediatric intracranial tumors have 40-60% mortality. Given the inability to effectively treat ependymomas with current standard practices, researchers have focused their efforts on evaluating chromosomal alterations, genetic expression profiles, epigenetic events, and molecular pathways. While these studies have provided critical insight into the potential mechanisms underlying ependymoma pathogenesis, understanding of the intricate interplay between the various pathways involved in tumor initiation, development, and progression will require deeper investigation. However, several potential prognostic markers and therapeutic targets have been identified, providing key areas of focus for future research. The utilization of unique genetic expression  profiles based upon patient age, tumor location, tumor grade, and subtype has revealed a multitude of findings warranting further study. Inspection of various  molecular pathways associated with ependymomas may establish the foundation for developing novel therapies capable of achieving significant clinical improvements with individualized regimens specifically designed for personalized treatment strategies.




TÍTULO / TITLE:  - ‘Elderly’ patients with newly diagnosed glioblastoma deserve optimal care.

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

REVISTA / JOURNAL:  - J Neurooncol. 2013 Mar 23.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11060-013-1113-7

AUTORES / AUTHORS:  - Holdhoff M; Rosner GL; Alcorn S; Grossman SA

INSTITUCIÓN / INSTITUTION:  - Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1550 Orleans Street, 1M16, Baltimore, MD, 21287, USA, mholdho1@jhmi.edu.




TÍTULO / TITLE:  - Noninvasive language mapping in patients with epilepsy or brain tumors.

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

REVISTA / JOURNAL:  - Neurosurgery. 2013 Apr;72(4):555-65. doi: 10.1227/NEU.0b013e318282cdad.

            ●● Enlace al texto completo (gratuito o de pago) 1227/NEU.0b013e318282cdad

AUTORES / AUTHORS:  - Genetti M; Grouiller F; Vulliemoz S; Spinelli L; Seeck M; Michel CM; Schaller K

INSTITUCIÓN / INSTITUTION:  - double daggerDepartment of Neurology and Fundamental Neurosciences, Geneva University Hospitals, Geneva, Switzerland section signDepartment of Radiology and Medical Informatics, Geneva University Hospitals, Geneva, Switzerland ||Department of Neurology, Geneva University Hospitals, Geneva, Switzerland paragraph signDepartment of Neurosurgery, Geneva University Hospitals, Geneva, Switzerland.

RESUMEN / SUMMARY:  - BACKGROUND: : Functional magnetic resonance imaging (fMRI) has become part of routine brain mapping in patients with epilepsy or tumor undergoing resective surgery. However, robust localization of crucial functional areas is required. OBJECTIVE: : To establish a simple, short fMRI task that reliably localizes crucial language areas in individual patients who undergo respective surgery. METHODS: : fMRI was measured during an 8-minute auditory semantic decision task in 28 healthy controls and 35 consecutive patients who had focal epilepsy or a brain tumor. Nineteen underwent resective surgery. Group and individual analyses  were performed. Results in patients were compared with postsurgical language outcome and electrocortical stimulation when available. RESULTS: : fMRI activations concordant with the anterior and posterior language areas were found  in 96% and 89% of the controls, respectively. The anterior and posterior language areas were both activated in 93% of the patients. These results were concordant with electrocortical stimulation results in 5 patients. Transient postsurgical language deficits were found in 2 patients in whom surgery was performed in the vicinity of the fMRI activations or who had postsurgical complications implicating areas of fMRI activations. CONCLUSION: : The proposed fast fMRI language protocol reliably localized the most relevant language areas in individual subjects. It appears to be a valuable complementary tool for surgical  planning of epileptogenic foci and of brain tumors. ABBREVIATIONS: : ECS, electrocortical stimulationFLI, frontal lateralization indexfMRI, functional magnetic resonance imagingFWE, family-wise errorLI, lateralization indexMNI, Montreal Neurological InstituteSD, standard deviationSEM, standard error of the meanTPLI, temporoparietal lateralization index.




TÍTULO / TITLE:  - Early Clinical Outcomes Using Proton Radiation for Children With Central Nervous  System Atypical Teratoid Rhabdoid Tumors.

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

REVISTA / JOURNAL:  - Int J Radiat Oncol Biol Phys. 2013 Mar 13. pii: S0360-3016(12)03900-4. doi: 10.1016/j.ijrobp.2012.12.004.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ijrobp.2012.12.004

AUTORES / AUTHORS:  - De Amorim Bernstein K; Sethi R; Trofimov A; Zeng C; Fullerton B; Yeap BY; Ebb D; Tarbell NJ; Yock TI; Macdonald SM

INSTITUCIÓN / INSTITUTION:  - Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

RESUMEN / SUMMARY:  - PURPOSE: Atypical teratoid/rhabdoid tumor (AT/RT) is an uncommon and aggressive tumor that often affects infants. Irradiation improves survival but has traditionally been avoided in patients under the age of 3 due to the increasing risk of neurocognitive side effects. We report the first cohort of AT/RT patients treated with proton therapy. METHODS AND MATERIALS: All patients with AT/RT treated at Massachusetts General Hospital (MGH) Frances H. Burr Proton Beam Therapy Benter between July 2004 and November 2011 were included in this study. All patients were treated with 3-dimensional conformal proton therapy (3D-CPT). RESULTS: Ten consecutive patients of a median 2.3 years of age and with a median  follow-up of 27.3 months (range, 11.3-99.4 months) were identified. Two patients  suffered distant relapse; 1 patient was successfully treated with involved field  irradiation and chemotherapy, while the second patient died of disease. At last follow-up, 9 patients were alive without evidence of disease. Proton radiation demonstrated increasing sparing of the cerebrum, temporal lobe, cochlea, and hypothalamus. CONCLUSIONS: Initial clinical outcomes with proton therapy are favorable. The advantages of proton therapy are particularly suited to the treatment of AT/RT, a tumor that often requires irradiation treatment at an age when avoiding irradiation to healthy tissues is most desirable.




TÍTULO / TITLE:  - Dental X-rays and Risk of Meningioma: Anatomy of a Case-Control Study.

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

REVISTA / JOURNAL:  - J Dent Res. 2013 Mar 28.

            ●● Enlace al texto completo (gratuito o de pago) 1177/0022034513484338

AUTORES / AUTHORS:  - Dirksen D; Runte C; Berghoff L; Scheutzel P; Figgener L

INSTITUCIÓN / INSTITUTION:  - Department of Prosthetic Dentistry and Biomaterials, University of Muenster, Waldeyerstr. 30 D-48149 Muenster, Germany.




TÍTULO / TITLE:  - Steroid-sparing effect of corticorelin acetate in peritumoral cerebral edema is associated with improvement in steroid-induced myopathy.

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

REVISTA / JOURNAL:  - J Clin Oncol. 2013 Mar 20;31(9):1182-7. doi: 10.1200/JCO.2012.43.9455. Epub 2013  Feb 4.

            ●● Enlace al texto completo (gratuito o de pago) 1200/JCO.2012.43.9455

AUTORES / AUTHORS:  - Recht L; Mechtler LL; Wong ET; O’Connor PC; Rodda BE

INSTITUCIÓN / INSTITUTION:  - Department of Neurology, Advanced Medicine Clinic, Stanford University School of  Medicine, 875 Blake Wilbur Dr, Stanford, CA 94305; LRecht@stanford.edu.

RESUMEN / SUMMARY:  - PURPOSE To compare the safety and efficacy of corticorelin acetate (CrA) and placebo in patients with malignant brain tumors requiring chronic administration  of dexamethasone (DEX) to control the signs and symptoms of peritumoral brain edema (PBE). PATIENTS AND METHODS Prospective, randomized, double-blind study of  200 patients with PBE on a stable dose of DEX. Initially, DEX dose was decreased  by 50% over a 2-week period and then held at this level for 3 weeks. The primary  end point was the proportion of patients who responded to treatment-patients who  achieved a >/= 50% DEX reduction from baseline and achieved stable or improved neurologic examination score and Karnofsky performance score at week 2, and then  continued to respond at week 5. Results One hundred patients received subcutaneous injections of 1 mg twice per day of CrA and 100 patients received placebo for the duration of the study period. Although results did not attain statistical significance (at the P < .05 level), a clinically important difference in the proportion of responders between the CrA group (57.0%) and the  placebo group (46.0%; P = .12) was observed. In addition, the maximum percent reduction in DEX dose achieved during the double-blind 12-week study was significantly greater in the CrA group (62.7%) than in placebo group (51.4%; P <  .001). Patients receiving CrA demonstrated an improvement in myopathy and were less likely to develop signs of Cushing syndrome. CONCLUSION CrA enables a reduction in steroid requirement for patients with PBE and is associated with a reduction in the incidence and severity of common steroid adverse effects, including myopathy.




TÍTULO / TITLE:  - New Syndrome of Paraganglioma and Somatostatinoma Associated With Polycythemia.

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.2012.47.1912

AUTORES / AUTHORS:  - Pacak K; Jochmanova I; Prodanov T; Yang C; Merino MJ; Fojo T; Prchal JT; Tischler AS; Lechan RM; Zhuang Z

INSTITUCIÓN / INSTITUTION:  - Karel Pacak, Ivana Jochmanova, and Tamara Prodanov, Eunice Kennedy Shriver National Institute of Child Health and Human Development; Maria J. Merino and Tito Fojo, National Cancer Institute; Chunzhang Yang and Zhengping Zhuang, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD; Josef T. Prchal, University of Utah School of Medicine and  VA Hospital, Salt Lake City, UT; and Arthur S. Tischler and Ronald M. Lechan, Tufts Medical Center, Boston, MA.

RESUMEN / SUMMARY:  - PURPOSEThe occurrence of >/= two distinct types of tumors, one of them paraganglioma (PGL), is unusual in an individual patient, except in hereditary cancer syndromes. PATIENTS AND METHODSFour unrelated patients were investigated,  with thorough clinical evaluation. Plasma and tissue catecholamines and metanephrines were measured by high-performance liquid chromatography. Anatomic and functional imaging were performed for tumor visualization. Germline and tumor tissue DNA were analyzed for hypoxia-inducible factor 2 alpha (HIF2A) mutations.  The prolyl hydroxylation and stability of the mutant HIF2alpha protein, transcriptional activity of mutant HIF2A, and expression of hypoxia-related genes were also investigated. Immunohistochemical staining for HIF1/2alpha was performed on formalin-fixed, paraffin-embedded tumor tissue.ResultsPatients were  found to have polycythemia, multiple PGLs, and duodenal somatostatinomas by imaging or biochemistry with somatic gain-of-function HIF2A mutations. Each patient carried an identical unique mutation in both types of tumors but not in germline DNA. The HIF2A mutations in these patients were clustered adjacent to an oxygen-sensing proline residue, affecting HIF2alpha interaction with the prolyl hydroxylase domain 2-containing protein, decreasing the hydroxylation of HIF2alpha, and reducing HIF2alpha affinity for the von Hippel-Lindau protein and  its degradation. An increase in the half-life of HIF2alpha was associated with upregulation of the hypoxia-related genes EPO, VEGFA, GLUT1, and END1 in tumors.  CONCLUSIONOur findings indicate the existence of a new syndrome with multiple PGLs and somatostatinomas associated with polycythemia. This new syndrome results from somatic gain-of-function HIF2A mutations, which cause an upregulation of hypoxia-related genes, including EPO and genes important in cancer biology.




TÍTULO / TITLE:  - The impact of sequential vs. combined radiochemotherapy with temozolomide, resection and MGMT promoter hypermethylation on survival of patients with primary glioblastoma- a single centre retrospective study.

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

REVISTA / JOURNAL:  - Br J Neurosurg. 2013 Feb 18.

            ●● Enlace al texto completo (gratuito o de pago) 3109/02688697.2013.767317

AUTORES / AUTHORS:  - Rapp M; Goeppert M; Felsberg J; Steiger HJ; Sabel M

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, University of Duesseldorf , Duesseldorf , Germany.

RESUMEN / SUMMARY:  - Background. The benefit of the introduction of alkylating chemotherapy in the treatment of glioblastoma multiforme (GBM) patients has been demonstrated by comparing radiotherapy with concomitant plus intermittent temozolomide (iTMZ) to  radiation therapy. The isolated impact of the concomitant part of this protocol on survival was not investigated. We were therefore interested in the impact of the effect of the concomitant therapy part on survival. Hence, we compared patients treated with open surgery followed by radiotherapy and iTMZ with patients treated with concomitant plus iTMZ chemotherapy regarding overall (OS) and progression-free survival (PFS). Methods. We performed a retrospective database search for the period between 2002 and 2007 and aimed at the identification of patients with primary GBM treated by open resection, radiotherapy (only radiotherapy = Group A and plus concomitant TMZ = Group B) and at least two cycles of TMZ. Patients were stratified for established prognostic markers like extent of resection, MGMT promoter methylation, Karnofsky Performance Scale (KPS), and age. Results. Eighty-five patients were analysed, among which 42 patients (49%) were affiliated with Cohort A and 43 patients (51%) with Cohort B. Between both cohorts there was no significant difference regarding MGMT methylation status (p = 0.929), extend of resection (p = 0.102), KPS (p = 0.197) and age (p = 0.327). For the entire patient population, median OS was 18.6 months and PFS was 5.6 months. The extent of resection was significantly correlated with survival (OS: 21.5 vs. 16.1 months (p = 0.001) and PFS: 11.0 vs.  3.9 months (p = 0.044)). MGMT methylation status revealed a significant impact on OS (p = 0.008). Affiliation to Cohort A or B was neither correlated with PFS (p = 0.168) nor with OS (p = 0.343). Conclusion. Our study demonstrates that PFS and OS are strongly determined by the MGMT status and the extent of resection. Interestingly, concomitant radiochemotherapy was not superior to radiotherapy followed by iTMZ chemotherapy regarding OS and PFS.




TÍTULO / TITLE:  - Initial Contact of Glioblastoma Cells with Existing Normal Brain Endothelial Cells Strengthen the Barrier Function via Fibroblast Growth Factor 2 Secretion: A New In Vitro Blood-Brain Barrier Model.

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

REVISTA / JOURNAL:  - Cell Mol Neurobiol. 2013 Feb 6.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10571-013-9913-z

AUTORES / AUTHORS:  - Toyoda K; Tanaka K; Nakagawa S; Thuy DH; Ujifuku K; Kamada K; Hayashi K; Matsuo T; Nagata I; Niwa M

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.

RESUMEN / SUMMARY:  - Glioblastoma multiforme (GBM) cells invade along the existing normal capillaries  in brain. Normal capillary endothelial cells function as the blood-brain barrier  (BBB) that limits permeability of chemicals into the brain. To investigate whether GBM cells modulate the BBB function of normal endothelial cells, we developed a new in vitro BBB model with primary cultures of rat brain endothelial cells (RBECs), pericytes, and astrocytes. Cells were plated on a membrane with 8  mum pores, either as a monolayer or as a BBB model with triple layer culture. The BBB model consisted of RBEC on the luminal side as a bottom, and pericytes and astrocytes on the abluminal side as a top of the chamber. Human GBM cell line, LN-18 cells, or lung cancer cell line, NCI-H1299 cells, placed on either the RBEC monolayer or the BBB model increased the transendothelial electrical resistance (TEER) values against the model, which peaked within 72 h after the tumor cell application. The TEER value gradually returned to baseline with LN-18 cells, whereas the value quickly dropped to the baseline in 24 h with NCI-H1299 cells. NCI-H1299 cells invaded into the RBEC layer through the membrane, but LN-18 cells did not. Fibroblast growth factor 2 (FGF-2) strengthens the endothelial cell BBB  function by increased occludin and ZO-1 expression. In our model, LN-18 and NCI-H1299 cells secreted FGF-2, and a neutralization antibody to FGF-2 inhibited  LN-18 cells enhanced BBB function. These results suggest that FGF-2 would be a novel therapeutic target for GBM in the perivascular invasive front.




TÍTULO / TITLE:  - Overexpression of SLC7A7 predicts poor progression-free and overall survival in patients with glioblastoma.

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

REVISTA / JOURNAL:  - Med Oncol. 2013 Mar;30(1):384. doi: 10.1007/s12032-012-0384-8. Epub 2013 Feb 14.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12032-012-0384-8

AUTORES / AUTHORS:  - Fan S; Meng D; Xu T; Chen Y; Wang J; Li X; Chen H; Lu D; Chen J; Lan Q

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, Second Affiliated Hospital of Soochow University, Suzhou, China.

RESUMEN / SUMMARY:  - The clinical significance of SLC7A7 expression remains unclear. In this study, we aimed to explore whether SLC7A7 expression in tumor tissues could be used to assess subsequent prognosis in patients with glioblastoma (GBM). A total of 119 patients with pathologically confirmed GBM and 16 normal controls were recruited  for this study. The expression of SLC7A7 in GBM and normal tissues was evaluated  by immunohistochemistry in tissue microarrays and quantitative real-time PCR. Kaplan-Meier method and Cox’s proportional hazards model were used in survival analysis. Compared with normal tissues, GBM specimens had significantly increased expression of SLC7A7 at both mRNA and protein levels (both P < 0.05). Moreover, multivariate analysis confirmed that overexpression of SLC7A7 was a significant and independent indicator for predicting poor prognosis. Our results suggest, for the first time, that overexpression of SLC7A7 is correlated with worse outcomes in patients with GBM. SLC7A7 plays a critical role in GBM carcinogenesis and may  be a potential prognosis predictor of GBM.




TÍTULO / TITLE:  - Central pontine myelinolysis in a patient with non-Hodgkin lymphoma.

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

REVISTA / JOURNAL:  - Br J Haematol. 2013 Apr;161(2):156. doi: 10.1111/bjh.12241. Epub 2013 Feb 6.

            ●● Enlace al texto completo (gratuito o de pago) 1111/bjh.12241

AUTORES / AUTHORS:  - Zhou AY; Barnes C; Razzaq R

INSTITUCIÓN / INSTITUTION:  - Department of Haematology, Royal Bolton Hospital, Manchester, UK. anlizhou89@doctors.org.uk.




TÍTULO / TITLE:  - Do severe headaches portend greater stroke risk following CRT for childhood brain tumor?

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

REVISTA / JOURNAL:  - Neurology. 2013 Mar 13.

            ●● Enlace al texto completo (gratuito o de pago) 1212/WNL.0b013e31828cfaf5


INSTITUCIÓN / INSTITUTION:  - From the Division of Child Neurology (G.L.H.), Nationwide Children’s Hospital and the Ohio State University, Columbus, OH; and Division of Child Neurology (K.J.M.), Mayo Clinic, Rochester, MN.

RESUMEN / SUMMARY:  - Children with brain tumors are more likely to survive, with survival rates improving consistently over several decades and well over 70% of patients now surviving 5 years from diagnosis.1 The vast majority of these children will become long-term survivors. As cure rates improve, a greater focus has been placed on enduring patient health after cancer treatment.




TÍTULO / TITLE:  - Unclear standard of care for pediatric high grade glioma patients.

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

REVISTA / JOURNAL:  - J Neurooncol. 2013 Mar 8.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11060-013-1104-8

AUTORES / AUTHORS:  - Fangusaro J; Warren KE

INSTITUCIÓN / INSTITUTION:  - Pediatric Neuro-Oncology, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, 60611, USA, jfangusaro@luriechildrens.org.




TÍTULO / TITLE:  - Spontaneous and therapeutic prognostic factors in adult hemispheric World Health  Organization Grade II gliomas: a series of 1097 cases.

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

REVISTA / JOURNAL:  - J Neurosurg. 2013 Mar 15.

            ●● Enlace al texto completo (gratuito o de pago) 3171/2013.1.JNS121

AUTORES / AUTHORS:  - Capelle L; Fontaine D; Mandonnet E; Taillandier L; Golmard JL; Bauchet L; Pallud J; Peruzzi P; Baron MH; Kujas M; Guyotat J; Guillevin R; Frenay M; Taillibert S; Colin P; Rigau V; Vandenbos F; Pinelli C; Duffau H

INSTITUCIÓN / INSTITUTION:  - Departments of Neurosurgery.

RESUMEN / SUMMARY:  - Object The spontaneous prognostic factors and optimal therapeutic strategy for WHO Grade II gliomas (GIIGs) have yet to be unanimously defined. Specifically, the role of resection is still debated, most notably because the actual amount of resection has seldom been assessed. Methods Cases of GIIGs treated before December 2007 were extracted from a multicenter database retrospectively collected since January 1985 and prospectively collected since 1996. Inclusion criteria were a patient age >/= 18 years at diagnosis, histological diagnosis of  WHO GIIG, and MRI evaluation of tumor volume at diagnosis and after initial surgery. One thousand ninety-seven lesions were included in the analysis. The mean follow-up was 7.4 years since radiological diagnosis. Factors significant in a univariate analysis (with a p value </= 0.1) were included in the multivariate  Cox proportional hazard regression model analysis. Results At the time of radiological diagnosis, independent spontaneous factors of a poor prognosis were  an age >/= 55 years, an impaired functional status, a tumor location in a nonfrontal area, and, most of all, a larger tumor size. When the study starting point was set at the time of first treatment, independent favorable prognostic factors were limited to a smaller tumor size, an epileptic symptomatology, and a  greater extent of resection. Conclusions This large series with its volumetric assessment refines the prognostic value of previously stressed clinical and radiological parameters and highlights the importance of tumor size and location. The results support additional arguments in favor of the predominant role of resection, in accordance with recently reported experiences.




TÍTULO / TITLE:  - Multifunctional mesoporous silica-coated graphene nanosheet used for chemo-photothermal synergistic targeted therapy of glioma.

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

REVISTA / JOURNAL:  - J Am Chem Soc. 2013 Mar 27;135(12):4799-804. doi: 10.1021/ja312221g. Epub 2013 Mar 15.

            ●● Enlace al texto completo (gratuito o de pago) 1021/ja312221g

AUTORES / AUTHORS:  - Wang Y; Wang K; Zhao J; Liu X; Bu J; Yan X; Huang R

INSTITUCIÓN / INSTITUTION:  - Department of Pharmaceutics, School of Pharmacy, Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, Fudan University , Shanghai 201203, China.

RESUMEN / SUMMARY:  - Current therapy of malignant glioma in clinic is unsatisfactory with poor patient compliance due to low therapeutic efficiency and strong systemic side effects. Herein, we combined chemo-photothermal targeted therapy of glioma within one novel multifunctional drug delivery system. A targeting peptide (IP)-modified mesoporous silica-coated graphene nanosheet (GSPI) was successfully synthesized and characterized, and first introduced to the drug delivery field. A doxorubicin (DOX)-loaded GSPI-based system (GSPID) showed heat-stimulative, pH-responsive, and sustained release properties. Cytotoxicity experiments demonstrated that combined therapy mediated the highest rate of death of glioma cells compared to that of single chemotherapy or photothermal therapy. Furthermore, the IP modification could significantly enhance the accumulation of GSPID within glioma  cells. These findings provided an excellent drug delivery system for combined therapy of glioma due to the advanced chemo-photothermal synergistic targeted therapy and good drug release properties of GSPID, which could effectively avoid  frequent and invasive dosing and improve patient compliance.




TÍTULO / TITLE:  - Prolonged survival associated with the use of intraoperative carmustine (Gliadel(®)) in a paediatric patient with recurrent Grade III astrocytoma.

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

REVISTA / JOURNAL:  - Br J Neurosurg. 2013 Feb 8.

            ●● Enlace al texto completo (gratuito o de pago) 3109/02688697.2013.764970

AUTORES / AUTHORS:  - Pizer B; Salehzadeh A; Brodbelt A; Mallucci C

INSTITUCIÓN / INSTITUTION:  - Department of Oncology, Alder Hey Children’s NHS Foundation Trust , Liverpool , UK.

RESUMEN / SUMMARY:  - A 15-year-old female presented with a middle cranial fossa anaplastic astrocytoma that was completely excised. She received local radiotherapy (54 Gy) and oral temozolomide. Five months after therapy, MRI showed local relapse. She underwent  resection of the tumour with implantation of seven carmustine-impregnated wafers  (Gliadel(®)). She then received six cycles of procarbazine and lomustine therapy. Three years later, she is well and disease free. This case supports the  further investigation of Gliadel(®) in children and young people with relapsed  high-grade glioma, particularly in the setting of a second complete resection.




TÍTULO / TITLE:  - MR Imaging Predictors of Molecular Profile and Survival: Multi-institutional Study of the TCGA Glioblastoma Data Set.

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

REVISTA / JOURNAL:  - Radiology. 2013 Feb 7.

            ●● Enlace al texto completo (gratuito o de pago) 1148/radiol.13120118

AUTORES / AUTHORS:  - Gutman DA; Cooper LA; Hwang SN; Holder CA; Gao J; Aurora TD; Dunn WD Jr; Scarpace L; Mikkelsen T; Jain R; Wintermark M; Jilwan M; Raghavan P; Huang E; Clifford RJ; Mongkolwat P; Kleper V; Freymann J; Kirby J; Zinn PO; Moreno C; Jaffe C; Colen R; Rubin DL; Saltz J; Flanders A; Brat DJ

INSTITUCIÓN / INSTITUTION:  - Departments of Biomedical Informatics, 36 Eagle Row, Room 572 PAIS, Emory University Hospital, Atlanta, GA 30322; Hermelin Brain Tumor Center, Henry Ford Hospital, Detroit, Mich; Department of Radiology, University of Virginia, Charlottesville, Va; National Cancer Institute, Bethesda, Md; Department of Radiology, Northwestern University, Chicago, Ill; SAIC-Frederick Inc, Frederick,  Md; Department of Genetics, MD Anderson Cancer Center, Houston, Tex; Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Ga; Department of Radiology, Boston University School of Medicine, Boston, Mass; Department of Radiology, Brigham & Women’s Hospital, Harvard University, Boston, Mass; Department of Radiology, Thomas Jefferson University Hospital, Philadelphia, Pa.

RESUMEN / SUMMARY:  - Purpose:To conduct a comprehensive analysis of radiologist-made assessments of glioblastoma (GBM) tumor size and composition by using a community-developed controlled terminology of magnetic resonance (MR) imaging visual features as they relate to genetic alterations, gene expression class, and patient survival.Materials and Methods:Because all study patients had been previously deidentified by the Cancer Genome Atlas (TCGA), a publicly available data set that contains no linkage to patient identifiers and that is HIPAA compliant, no institutional review board approval was required. Presurgical MR images of 75 patients with GBM with genetic data in the TCGA portal were rated by three neuroradiologists for size, location, and tumor morphology by using a standardized feature set. Interrater agreements were analyzed by using the Krippendorff alpha statistic and intraclass correlation coefficient. Associations between survival, tumor size, and morphology were determined by using multivariate Cox regression models; associations between imaging features and genomics were studied by using the Fisher exact test.Results:Interrater analysis  showed significant agreement in terms of contrast material enhancement, nonenhancement, necrosis, edema, and size variables. Contrast-enhanced tumor volume and longest axis length of tumor were strongly associated with poor survival (respectively, hazard ratio: 8.84, P = .0253, and hazard ratio: 1.02, P  = .00973), even after adjusting for Karnofsky performance score (P = .0208). Proneural class GBM had significantly lower levels of contrast enhancement (P = .02) than other subtypes, while mesenchymal GBM showed lower levels of nonenhanced tumor (P < .01).Conclusion:This analysis demonstrates a method for consistent image feature annotation capable of reproducibly characterizing brain  tumors; this study shows that radiologists’ estimations of macroscopic imaging features can be combined with genetic alterations and gene expression subtypes to provide deeper insight to the underlying biologic properties of GBM subsets.© RSNA, 2013.




TÍTULO / TITLE:  - Valproic Acid Use During Radiation Therapy for Glioblastoma Associated With Improved Survival.

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

REVISTA / JOURNAL:  - Int J Radiat Oncol Biol Phys. 2013 Mar 19. pii: S0360-3016(13)00180-6. doi: 10.1016/j.ijrobp.2013.02.012.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ijrobp.2013.02.012

AUTORES / AUTHORS:  - Barker CA; Bishop AJ; Chang M; Beal K; Chan TA

INSTITUCIÓN / INSTITUTION:  - Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York. Electronic address: barkerc@mskcc.org.

RESUMEN / SUMMARY:  - PURPOSE: Valproic acid (VA) is an antiepileptic drug (AED) and histone deacetylase (HDAC) inhibitor taken by patients with glioblastoma (GB) to manage seizures, and it can modulate the biologic effects of radiation therapy (RT). We  investigated whether VA use during RT for GB was associated with overall survival (OS). METHODS AND MATERIALS: Medical records of 544 adults with GB were retrospectively reviewed. Analyses were performed to determine the association of Radiation Therapy Oncology Group recursive partitioning analysis (RTOG RPA) class, seizure history, and concurrent temozolomide (TMZ) and AED use during RT with OS. RESULTS: Seizures before the end of RT were noted in 217 (40%) patients, and 403 (74%) were taking an AED during RT; 29 (7%) were taking VA. Median OS in  patients taking VA was 16.9 months (vs 13.6 months taking another AED, P=.16). Among patients taking an AED during RT, OS was associated with VA (P=.047; hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.27-1.07), and RTOG RPA class (P<.0001; HR, 1.49; 95% CI, 1.37-1.61). Of the 5 most common AEDs, only VA was associated with OS. Median OS of patients receiving VA and TMZ during RT was 23.9 months (vs 15.2 months for patients taking another AED, P=.26). When the analysis was restricted to patients who received concurrent TMZ, VA use was marginally associated with OS (P=.057; HR, 0.54; 95% CI, -0.09 to 1.17), independently of RTOG RPA class and seizure history. CONCLUSIONS: VA use during RT for GB was associated with improved OS, independently of RTOG RPA, seizure history, and concurrent TMZ use. Further studies of treatment that combines HDAC inhibitors and RT are warranted.




TÍTULO / TITLE:  - The caregivers’ perspective on the end-of-life phase of glioblastoma patients.

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

REVISTA / JOURNAL:  - J Neurooncol. 2013 Feb 15.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11060-013-1069-7

AUTORES / AUTHORS:  - Flechl B; Ackerl M; Sax C; Oberndorfer S; Calabek B; Sizoo E; Reijneveld J; Crevenna R; Keilani M; Gaiger A; Dieckmann K; Preusser M; Taphoorn MJ; Marosi C

INSTITUCIÓN / INSTITUTION:  - Department of Medicine I, Medical University of Vienna, Austria Comprehensive Cancer Center, Central Nervous System Tumors Unit (CCC-CNS), Wahringer Gurtel 18-20, 1090, Vienna, Austria, birgit.flechl@gmx.at.

RESUMEN / SUMMARY:  - Glioblastoma multiforme (GBM) still harbors a fatal prognosis. The involvement of the neurocognition and psyche poses unique challenges for care provision by relatives. We lack data about the caregivers’ perspective on the end-of-life (EOL) phase of GBM patients to improve counseling and support. In this study we investigated the experiences of 52 caregivers of deceased GBM patients treated in Austria. We used a questionnaire developed by the University Medical Centre of Amsterdam for exploration of the EOL-phase in glioma patients. The caregivers (17 men, 34 women) completed the questionnaire in median three years after the patients’ death. 29 % of caregivers reported that they felt incompletely prepared for their tasks, however, those with higher education levels felt significantly better informed. 29 % suffered from financial difficulties, which was associated  with burnout (60 %) and reduced quality of life (QOL). The patients’ most common  symptoms reported by caregivers were fatigue (87 %), reduced consciousness (81 %) and aphasia (77 %). 22 % of patients were bedbound during their last three months increasing to 80 % in the last week of life. The reported QOL of caregivers was very low and did not differ between caregivers of patients, who died at home (40  %) and caregivers of patients, who died in hospital (46 %). The caregiver reported that their QOL was only slightly better than the QOL they attributed to  the patients. Furthermore, the high frequency of financial difficulties, burnout  symptoms and feelings of insufficient information emphasize the urgent need for support and training dedicated to caregivers.




TÍTULO / TITLE:  - AMPK activation by oncogenesis is required to maintain cancer cell proliferation  in astrocytic tumors.

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

REVISTA / JOURNAL:  - Cancer Res. 2013 Jan 31.

            ●● Enlace al texto completo (gratuito o de pago) 1158/0008-5472.CAN-12-0861

AUTORES / AUTHORS:  - Rios M; Foretz M; Viollet B; Prieto A; Fraga M; Costoya JA; Senaris R

INSTITUCIÓN / INSTITUTION:  - Physiology, University of Santiago de Compostela.

RESUMEN / SUMMARY:  - AMPK is an energy sensor that controls cell metabolism, and it has been related with apoptosis and cell cycle arrest. Although its role in metabolic homeostasis  is well documented, its function in cancer is much less clear. In this study, we  examined the role of AMPK in a mouse model of astrocytoma driven by oncogenic H-RasV12 and/or with PTEN deletion, based upon the common constitutive activation of the Raf/MEK/ERK and PI3K/AKT cascades in human astrocytomas. We also evaluated the activity and role of AMPK in human glioblastoma cells and xenografts. AMPK was constitutively activated in astrocytes expressing oncogenic H-RasV12 in parallel with high cell division rates. Genetic deletion of AMPK or attenuation of its activity in these cells was sufficient to reduce cell proliferation. The levels of pAMK were always related to the levels of phosphorylated Rb at Ser804,  which might indicate an AMPK mediated phosphorylation of Rb. We confirmed this AMPK-Rb relationship in human glioblastoma cell lines and xenografts. In clinical specimens of human glioblastoma, elevated levels of activated AMPK appeared especially in areas of high proliferation surrounding the blood vessels. Together, our findings indicate that the initiation and progression of astrocytic tumours relies upon AMPK-dependent control of the cell cycle, thereby identifying AMPK as a candidate therapeutic target in this setting.




TÍTULO / TITLE:  - Adenomatous polyposis coli regulates oligodendroglial development.

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

REVISTA / JOURNAL:  - J Neurosci. 2013 Feb 13;33(7):3113-30. doi: 10.1523/JNEUROSCI.3467-12.2013.

            ●● Enlace al texto completo (gratuito o de pago) 1523/JNEUROSCI.3467-12.2013

AUTORES / AUTHORS:  - Lang J; Maeda Y; Bannerman P; Xu J; Horiuchi M; Pleasure D; Guo F

INSTITUCIÓN / INSTITUTION:  - Institute for Pediatric Regenerative Medicine, University of California, Davis, School of Medicine and Shriners Hospital, Sacramento, California 95817, USA.

RESUMEN / SUMMARY:  - The expression of the gut tumor suppressor gene adenomatous polyposis coli (Apc)  and its role in the oligodendroglial lineage are poorly understood. We found that immunoreactive APC is transiently induced in the oligodendroglial lineage during  both normal myelination and remyelination following toxin-induced, genetic, or autoimmune demyelination murine models. Using the Cre/loxP system to conditionally ablate APC from the oligodendroglial lineage, we determined that APC enhances proliferation of oligodendroglial progenitor cells (OPCs) and is essential for oligodendrocyte differentiation in a cell-autonomous manner. Biallelic Apc disruption caused translocation of beta-catenin into the nucleus and upregulated beta-catenin-mediated Wnt signaling in early postnatal but not adult oligodendroglial lineage cells. The results of conditional ablation of Apc  or Ctnnb1 (the gene encoding beta-catenin) and of simultaneous conditional ablation of Apc and Ctnnb1 revealed that beta-catenin is dispensable for postnatal oligodendroglial differentiation, that Apc one-allele deficiency is not sufficient to dysregulate beta-catenin-mediated Wnt signaling in oligodendroglial lineage cells, and that APC regulates oligodendrocyte differentiation through beta-catenin-independent, as well as beta-catenin-dependent, mechanisms. Gene ontology analysis of microarray data suggested that the beta-catenin-independent  mechanism involves APC regulation of the cytoskeleton, a result compatible with established APC functions in neural precursors and with our observation that Apc-deleted OPCs develop fewer, shorter processes in vivo. Together, our data support the hypothesis that APC regulates oligodendrocyte differentiation through both beta-catenin-dependent and additional beta-catenin-independent mechanisms.




TÍTULO / TITLE:  - LOH in the HLA Class I Region at 6p21 Is Associated with Shorter Survival in Newly Diagnosed Adult Glioblastoma.

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

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Apr 1;19(7):1816-26. doi: 10.1158/1078-0432.CCR-12-2861. Epub 2013 Feb 11.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-2861

AUTORES / AUTHORS:  - Yeung JT; Hamilton RL; Ohnishi K; Ikeura M; Potter DM; Nikiforova MN; Ferrone S; Jakacki RI; Pollack IF; Okada H

INSTITUCIÓN / INSTITUTION:  - Authors’ Affiliations: Departments of Neurological Surgery, Pathology, Surgery and Immunology, and Pediatrics, University of Pittsburgh School of Medicine; Department of Biostatistics, Graduate School of Public Health; and Brain Tumor Program and Biostatistics Facility, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.

RESUMEN / SUMMARY:  - PURPOSE: Glioblastoma (GBM) shows downregulated expression of human leukocyte antigen (HLA) class I, thereby escaping from cytotoxic T cells and limiting the efficacy of immunotherapy. Loss of heterozygosity (LOH) of HLA class I (6p21) and/or beta-2 microglobulin (B2m) (15q21) regions represents irreversible downregulation. In this study, we examined the prevalence of these LOH events and their relations with overall survival in GBM. EXPERIMENTAL DESIGN: In a cross-sectional analysis on 60 adult patients with GBM, DNA from formalin-fixed,  paraffin-embedded specimens were evaluated for 10 microsatellite regions of HLA class I, B2m, HLA class II, HLA class III, and 6q by PCR as well as immunohistochemical evaluation of HLA class I expression and CD8(+) T-cell infiltration. RESULTS: LOH in HLA class I, B2m, HLA class II, HLA class III, and  6q regions was present in 41.4%, 18.2%, 9.4%, 77.8%, and 36.0% of informative cases, respectively. LOH of HLA class I was associated with shorter overall survival (HR = 4.89, P = 0.0078). HLA class I was downregulated in 22% to 43% of  cases based on immunohistochemistry. Cases that displayed negative staining were  significantly younger. HLA class I expression correlated with intratumoral CD8(+) T-cell infiltration. CONCLUSION: LOH in the HLA class I region is frequent in adult GBMs. The association of shorter survival with LOH in this region suggests  a crucial role for these genes in immunosurveillance. Clin Cancer Res; 19(7); 1816-26. ©2013 AACR.




TÍTULO / TITLE:  - Human Glioma-Initiating Cells Show a Distinct Immature Phenotype Resembling but Not Identical to NG2 Glia.

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

REVISTA / JOURNAL:  - J Neuropathol Exp Neurol. 2013 Apr;72(4):307-24. doi: 10.1097/NEN.0b013e31828afdbd.

            ●● Enlace al texto completo (gratuito o de pago) 1097/NEN.0b013e31828afdbd

AUTORES / AUTHORS:  - Barrantes-Freer A; Kim E; Bielanska J; Giese A; Mortensen LS; Schulz-Schaeffer WJ; Stadelmann C; Bruck W; Pardo LA

INSTITUCIÓN / INSTITUTION:  - Max-Planck-Institute of Experimental Medicine, Molecular Biology of Neuronal Signals, AG Oncophysiology, Gottingen (AB-F, JB, LSM, LAP); Universitatsmedizin Johannes Gutenberg University, Department of Neurosurgery,Translational Neurooncology Research Group, Mainz (EK, AG); and Institute of Neuropathology, University Medical Center, Gottingen (AB-F, WJS-S, CS, WB), Germany.

RESUMEN / SUMMARY:  - Glioma-initiating cells (GICs) represent a potential important therapeutic target because they are likely to account for the frequent recurrence of malignant gliomas; however, their identity remains unsolved. Here, we characterized the cellular lineage fingerprint of GICs through a combination of electrophysiology,  lineage marker expression, and differentiation assays of 5 human patient-derived  primary GIC lines. Most GICs coexpressed nestin, NG2 proteoglycan, platelet-derived growth factor receptor-alpha, and glial fibrillary acidic protein. Glioma-initiating cells could be partially differentiated into astrocytic but not oligodendroglial or neural lineages. We also demonstrate that  GICs have a characteristic electrophysiologic profile distinct from that of well-characterized tumor bulk cells. Together, our results suggest that GICs represent a unique type of cells reminiscent of an immature phenotype that closely resembles but is not identical to NG2 glia with respect to marker expression and functional membrane properties.




TÍTULO / TITLE:  - Treatment of primary CNS lymphoma (PCNSL) following successful treatment of systemic non-Hodgkin’s lymphoma (NHL): a case series.

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

REVISTA / JOURNAL:  - J Neurooncol. 2013 Mar 1.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11060-013-1085-7

AUTORES / AUTHORS:  - Chamberlain MC

INSTITUCIÓN / INSTITUTION:  - Division of Neuro-Oncology, Department of Neurology and Neurological Surgery, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, University  of Washington, 825 Eastlake Ave E, MS G-4940, Seattle, WA, 98109, USA, chambemc@u.washington.edu.

RESUMEN / SUMMARY:  - Management of PCNSL occurring after successful treatment of systemic non-Hodgkin’s lymphoma (NHL) is poorly defined. Illustrate a treatment approach for PCNSL following prior treatment of a systemic NHL. A retrospective case series of 6 patients (mean age 60 years; range 46-65) diagnosed with a diffuse large B cell lymphoma of the CNS following prior successful treatment of a systemic NHL (low-grade in 2; high-grade in 4). Mean interval to diagnosis of PCNSL after diagnosis of systemic NHL was 12 months (range 7-18). In 4/6 patients in whom genetic analysis could be performed, the PCNSL and NHL differed. Treatment utilized high-dose methotrexate and rituximab (immunochemotherapy) followed in patients with a radiographic complete response by autologous peripheral stem cell transplant (ASCT) with total body irradiation (TBI) and multi-agent conditioning chemotherapy (BEAM: carmustine, etoposide, cytarabine, melphalan). 5/6 patients had a radiographic complete response to immunochemotherapy and were treated with ASCT. 4/5 patients were free of disease  following ASCT with a mean follow-up of 3 years (range 0.5-4 years). There were no toxic deaths and all patients transplanted successfully engrafted within 28 days (mean 18). Using a treatment paradigm similar to that utilized for recurrent systemic NHL (induction chemotherapy followed by ASCT) for PCNSL occurring metachronously after successful treatment of systemic NHL appears safe and effective.




TÍTULO / TITLE:  - DNA Mismatch Repair Protein (MSH6) Correlated With the Responses of Atypical Pituitary Adenomas and Pituitary Carcinomas to Temozolomide: The National Cooperative Study by the Japan Society for Hypothalamic and Pituitary Tumors.

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

REVISTA / JOURNAL:  - J Clin Endocrinol Metab. 2013 Mar;98(3):1130-6. doi: 10.1210/jc.2012-2924. Epub 2013 Jan 30.

            ●● Enlace al texto completo (gratuito o de pago) 1210/jc.2012-2924

AUTORES / AUTHORS:  - Hirohata T; Asano K; Ogawa Y; Takano S; Amano K; Isozaki O; Iwai Y; Sakata K; Fukuhara N; Nishioka H; Yamada S; Fujio S; Arita K; Takano K; Tominaga A; Hizuka N; Ikeda H; Osamura RY; Tahara S; Ishii Y; Kawamata T; Shimatsu A; Teramoto A; Matsuno A

INSTITUCIÓN / INSTITUTION:  - MD, Department of Neurosurgery, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku,  Tokyo 113-8655, Japan. hirohata-tky@umin.ac.jp.

RESUMEN / SUMMARY:  - Context: Temozolomide (TMZ) is an alkylating agent and was a first-line chemotherapeutic agent for malignant gliomas. Recently, TMZ has been documented to be effective against atypical pituitary adenomas (APAs) and pituitary carcinomas (PCs). Objective: The clinical and pathological characteristics of APAs and PCs treated with TMZ in Japan were surveyed and analyzed retrospectively. Design: Members of the Japan Society of Hypothalamic and Pituitary Tumors were surveyed regarding the clinical characteristics of APAs and PCs treated with TMZ. Stored tumor samples were gathered from the responders and  were assessed by the immunohistochemistry of Ki-67, O-methyl-guanine-DNA methyltransferase, p53, MSH6, and anterior pituitary hormones. Responses to TMZ treatment were defined as complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD) according to RECIST (Response Evaluation Criteria in Solid Tumors) version 2.0. Subjects: Three samples from 3  subjects with APA and 11 samples from 10 subjects with PC were available. Results: The 13 subjects had APAs and PCs consisting of 5 prolactin-producing tumors, 5 ACTH-producing tumors, and 3 null cell adenomas. The clinical response  to TMZ treatment was as follows: 4 cases of CR and PR (31%), 2 cases of SD (15%), 6 cases of recurrence after CR and PR (46%), and 1 case of PD (8%). However, considerable subjects had recurrent disease after a response to TMZ. The immunohistochemical findings of Ki-67, O-methyl-guanine-DNA methyltransferase, and p53 did not show any significant correlation with the efficacy of TMZ. However, the immunopositivity of MSH6 was positively correlated with TMZ response (P = .015, Fisher’s exact test). Conclusions: This study showed that preserving MSH6 function was contributory to the effectiveness of TMZ in malignant pituitary neoplasms. It is necessary to survey more cases and evaluate multifactor analyses.




TÍTULO / TITLE:  - Chronic Residual Lesions in Metastatic Medulloblastoma Patients.

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

REVISTA / JOURNAL:  - J Pediatr Hematol Oncol. 2013 Mar 21.

            ●● Enlace al texto completo (gratuito o de pago) 1097/MPH.0b013e3182843b40

AUTORES / AUTHORS:  - Fried I; Huang A; Bartels U; Tabori U; Laperriere N; Dirks P; Bouffet E

INSTITUCIÓN / INSTITUTION:  - *Neuro-Oncology Program, Division of Paediatric Haematology and Oncology, The Hospital for Sick Children, University of Toronto double daggerDepartment of Radiation Oncology, Princess Margaret Hospital section signDepartment of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada daggerDepartment of Pediatrics, Hadassah Medical Center, Division of Pediatric Hematology and Oncology, Jerusalem, Israel.

RESUMEN / SUMMARY:  - In a retrospective review of 24 metastatic medulloblastoma patients whose treatment included craniospinal irradiation, 5 patients presented with gross residual abnormalities at completion of therapy. This report describes 2 medulloblastoma patients with persistent residual abnormalities on serial follow-up imaging studies. The patients aged 2 and 2.5 years old at the time of diagnosis underwent surgery followed by multiagent chemotherapy. One patient progressed on therapy and underwent salvage craniospinal radiation. The second showed residual tumor on end of treatment imaging and received low-dose craniospinal irradiation. Despite persistent magnetic resonance imaging findings, the patients are alive and well 13 and 7 years after diagnosis with no further treatment applied. The nature of these residual abnormalities is discussed.




TÍTULO / TITLE:  - First Report of Bilateral Pheochromocytoma in the Clinical Spectrum of HIF2A-Related Polycythemia-Paraganglioma Syndrome.

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

REVISTA / JOURNAL:  - J Clin Endocrinol Metab. 2013 Mar 28.

            ●● Enlace al texto completo (gratuito o de pago) 1210/jc.2013-1217

AUTORES / AUTHORS:  - Taieb D; Yang C; Delenne B; Zhuang Z; Barlier A; Sebag F; Pacak K

INSTITUCIÓN / INSTITUTION:  - Department of Nuclear Medicine (D.T.), La Timone University Hospital, Centre Europeen de Recherche en Imagerie Medicale, Aix-Marseille University, 13005 Marseille, France; Surgical Neurology Branch (C.Y., Z.Z.), National Institute of  Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892; Department of Endocrinology (B.D.), Aix-en-Provence General Hospital, 13616 Aix-en-Provence France; Laboratory of Biochemistry and Molecular  Biology (A.B.), Conception Hospital, Aix-Marseille University, 13005 Marseille, France; Department of Endocrine Surgery (F.S.), La Timone University Hospital, Aix-Marseille University, 13005 Marseille, France; and Program in Reproductive and Adult Endocrinology (K.P.), Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health, Bethesda, Maryland 20892.

RESUMEN / SUMMARY:  - Context:Molecular genetic research has so far resulted in the identification of 10 well-characterized susceptibility genes for hereditary pheochromocytoma (PHEO) or paraganglioma (PGL). Recently, a new syndrome characterized by multiple PGLs and somatostatinomas associated with congenital polycythemia due to somatic mutations in HIF2A has been reported.Objective:The aim of the study was to define the genetic defect in a new case of bilateral PHEO and multiple PGLs associated with congenital polycythemia.Patient:A female patient presented with neonatal polycythemia (treated by phlebotomies, 1 session approximately every 4 mo), mildly enlarged cerebral ventricles, and bilateral PHEO and multiple PGLs. There  was no family history of any neuroendocrine tumor or polycythemia. Surgical removal of the tumors only temporarily normalized plasma erythropoietin (Epo) levels and discontinued phlebotomies. No germline mutations were initially detected in the SDHB, SDHC, SDHD, VHL, and PHD2 genes, known to be associated with polycythemia. The PHEOs presented with a typical noradrenergic biochemical phenotype.Results:A heterozygous missense mutation (c.1589C>T) was identified in  exon 12 of HIF2A, resulting in an alanine 530 substitution in the HIF-2alpha protein with valine (A530V). This somatic mutation was detected in the tissue from 1 PHEO and 1 PGL, with no HIF2A germline mutation found. This mutation led to stabilization of HIF-2alpha and hence a gain-of-function phenotype, as in previously published studies.Conclusion:This case represents the first association of a somatic HIF2A gain-of-function mutation with PHEO and congenital polycythemia, and it alerts physicians to perform proper genetic screening in patients presenting with multiple norepinephrine-producing PHEOs and polycythemia. This report also extends the previous findings of a new syndrome of only multiple PGLs, somatostatinomas, and polycythemia to multiple PHEOs.




TÍTULO / TITLE:  - GC/MS-based metabolomic analysis of cerebrospinal fluid (CSF) from glioma patients.

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

REVISTA / JOURNAL:  - J Neurooncol. 2013 Mar 1.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11060-013-1090-x

AUTORES / AUTHORS:  - Nakamizo S; Sasayama T; Shinohara M; Irino Y; Nishiumi S; Nishihara M; Tanaka H; Tanaka K; Mizukawa K; Itoh T; Taniguchi M; Hosoda K; Yoshida M; Kohmura E

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.

RESUMEN / SUMMARY:  - Metabolomics has recently undergone rapid development; however, metabolomic analysis in cerebrospinal fluid (CSF) is not a common practice. We analyzed the metabolite profiles of preoperative CSF samples from 32 patients with histologically confirmed glioma using gas chromatography/mass spectrometry (GC/MS). We assessed how alterations in the metabolite levels were related to the World Health Organization (WHO) tumor grades, tumor location, gadolinium enhancement on magnetic resonance imaging (MRI), and the isocitrate dehydrogenase (IDH) mutation status. Sixty-one metabolites were identified in the CSF from glioma patients using targeted, quantitative and non-targeted, semi-quantitative  analysis. The citric and isocitric acid levels were significantly higher in the glioblastoma (GBM) samples than in the grades I-II and grade III glioma samples.  In addition, the lactic and 2-aminopimelic acid levels were relatively higher in  the GBM samples than in the grades I-II glioma samples. The CSF levels of the citric, isocitric, and lactic acids were significantly higher in grade I-III gliomas with mutant IDH than in those with wild-type IDH. The tumor location and  enhancement obtained using MRI did not significantly affect the metabolite profiles. Higher CSF levels of lactic acid were statistically associated with a poorer prognosis in grades III-IV malignant gliomas. Our study suggests that the  metabolomic analysis of CSF from glioma patients may be useful for predicting the glioma grade, metabolic state, and prognosis of gliomas.




TÍTULO / TITLE:  - Single-nucleotide polymorphisms of allergy-related genes and risk of adult glioma.

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

REVISTA / JOURNAL:  - J Neurooncol. 2013 Mar 25.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11060-013-1122-6

AUTORES / AUTHORS:  - Backes DM; Siddiq A; Cox DG; Calboli FC; Gaziano JM; Ma J; Stampfer M; Hunter DJ; Camargo CA; Michaud DS

INSTITUCIÓN / INSTITUTION:  - Department of Epidemiology, Brown Public Health, Brown University, PO Box G-S121-2, Providence, RI, 02912, USA.

RESUMEN / SUMMARY:  - Previous studies have shown an inverse association between allergies and glioma risk; however, results for associations between single nucleotide polymorphisms (SNPs) of allergy-related genes and glioma risk have been inconsistent and restricted to a small number of SNPs. The objective of this study was to examine  the association between 166 SNPs of 21 allergy-related genes and glioma risk in a nested case-control study of participants from three large US prospective cohort  studies. Blood collection took place between 1982 and 1994 among the 562 included Caucasian participants (143 cases and 419 matched controls) prior to case diagnosis. Custom Illumina assay chips were used for genotyping. Logistic regression analyses, controlling for age and study cohort, were used to determine associations between each SNP and glioma risk. Statistically significant associations were found between rs2494262 and rs2427824 of the FCER1A gene, which encodes the alpha chain of the high affinity immunoglobulin E receptor, and glioma risk (nominal trend p values 0.01 and 0.03, respectively). Significant associations were also found between SNPs in IL10, ADAM33, NOS1 and IL4R and glioma risk. However, our analyses were not corrected for multiple comparisons and need to be interpreted with caution. Our findings with FCER1A SNPs provide further support for the link between allergies and risk of glioma.




TÍTULO / TITLE:  - Surgical management of multicentric diffuse low-grade gliomas: functional and oncological outcomes.

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

REVISTA / JOURNAL:  - J Neurosurg. 2013 Mar 15.

            ●● Enlace al texto completo (gratuito o de pago) 3171/2013.2.JNS121747

AUTORES / AUTHORS:  - Terakawa Y; Yordanova YN; Tate MC; Duffau H

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, Gui de Chauliac Hospital, Montpellier University Medical Center, Montpellier;

RESUMEN / SUMMARY:  - Object Multicentric diffuse low-grade gliomas (DLGGs) are defined as widely separated lesions in different lobes or hemispheres where there is no anatomical  continuity between lesions. This condition is rare and its clinicopathological characteristics have been scarcely described in the literature. Here, the authors report the first consecutive surgical series of multicentric DLGGs with functional and oncological outcomes. Methods A retrospective review of patients surgically treated for histopathologically confirmed multicentric DLGGs between 2000 and 2012 was performed. Information regarding clinical features, surgical procedures, histopathological results, and clinical outcomes was collected and analyzed. Results Five consecutive patients were included in this study. There were 3 men and 2 women, whose mean age was 27.4 years (range 23-35 years). The mean follow-up period after surgery was 46 months (range 11-138 months). Gross-total or subtotal resection was achieved in all cases, using a single surgery in 3 patients and a 2-stage surgery in 2 patients. There was no mortality or permanent morbidity associated with surgery. The Karnofsky Performance Scale score ranged between 90 and 100 in all cases. Adjuvant chemotherapy was administered in 2 patients because of tumor regrowth with no malignant transformation. Conclusions Multicentric DLGGs can be removed safely without inducing severe permanent neurological deficits. Interestingly, a single-stage resection of multiple lesions within different lobes may be performed if tumors are located in the same hemisphere. Therefore, the authors suggest considering surgery as the first therapeutic option for multicentric DLGGs, as in solitary DLGGs.




TÍTULO / TITLE:  - Evaluation of High Ipsilateral Subventricular Zone Radiation Therapy Dose in Glioblastoma: A Pooled Analysis.

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

REVISTA / JOURNAL:  - Int J Radiat Oncol Biol Phys. 2013 Feb 22. pii: S0360-3016(13)00072-2. doi: 10.1016/j.ijrobp.2013.01.009.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ijrobp.2013.01.009

AUTORES / AUTHORS:  - Lee P; Eppinga W; Lagerwaard F; Cloughesy T; Slotman B; Nghiemphu PL; Wang PC; Kupelian P; Agazaryan N; Demarco J; Selch MT; Steinberg M; Kang JJ

INSTITUCIÓN / INSTITUTION:  - Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California; UCLA Jonsson Comprehensive Cancer Center, Los Angeles, California. Electronic address: percylee@mednet.ucla.edu.

RESUMEN / SUMMARY:  - PURPOSE: Cancer stem cells (CSCs) may play a role in the recurrence of glioblastoma. They are believed to originate from neural stem cells in the subventricular zone (SVZ). Because of their radioresistance, we hypothesized that high doses of radiation (>59.4 Gy) to the SVZ are necessary to control CSCs and improve progression-free survival (PFS) or overall survival (OS) in glioblastoma. METHODS AND MATERIALS: 173 patients with glioblastoma pooled from 2 academic centers were treated with resection followed by chemoradiation therapy. The SVZ was segmented on computed tomography to calculate radiation doses delivered to the presumptive CSC niches. The relationships between high SVZ doses and PFS and  OS were examined using Cox proportional hazards models. Five covariates were included to estimate their impact on PFS or OS: ipsilateral and contralateral SVZ doses, clinical target volume dose, age, and extent of resection. RESULTS: Median PFS and OS were 10.4 and 19.6 months for the cohort. The mean ipsilateral SVZ, contralateral SVZ, and clinical target volume doses were 49.2, 35.2, and 60.1 Gy, respectively. Twenty-one patients who received high ipsilateral SVZ dose (>59.4 Gy) had significantly longer median PFS (12.6 vs 9.9 months, P=.042) and longer OS (25.8 vs 19.2 months, P=.173). On multivariate analysis, high radiation therapy doses to ipsilateral SVZ remained a statistically significant independent predictor of improved PFS but not of OS. The extent of surgery affected both PFS  and OS on multivariate analysis. CONCLUSION: High radiation therapy doses to ipsilateral CSC niches are associated with improved PFS in glioblastoma.




TÍTULO / TITLE:  - Pituitary Tumor With Gigantism, Acromegaly and Preclinical Cushing’s Disease Diagnosed from the 10th Row.

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

REVISTA / JOURNAL:  - Am J Med Sci. 2013 Mar 4.

            ●● Enlace al texto completo (gratuito o de pago) 1097/MAJ.0b013e3182831919

AUTORES / AUTHORS:  - Tourtelot JB; Vesely DL

INSTITUCIÓN / INSTITUTION:  - Division of Endocrinology (JBT), H. Lee Moffitt Cancer Center, Tampa, Florida; Division of Endocrinology (DLV), James A. Haley Veterans Administration Hospital, Tampa, Florida; and Department of Medicine (JBT, DLV), School of Medicine, University of South Florida Morsani, Tampa, Florida.

RESUMEN / SUMMARY:  - : A 7’3” basketball player was noted to have 2 to 3 times thicker tissue in his  hands than 6’10” players by an endocrinologist sitting 10 rows above the player  in a basketball arena. This led to the diagnosis of pituitary gigantism where the history revealed that he was 7’3” at 15 years of age. At age 19 when the acryl enlargement was noted, a diagnostic workup revealed elevated growth hormones and  insulin-like growth factor 1 (IGF-1) with a 2 x 1.3 cm pituitary tumor. His history suggested that his epiphyseal plates had closed at age 15, and because he continued to produce IGF-1, he now has acromegaly. His elevated adrenocorticotropic hormone (ACTH) before surgery suggests that he also had preclinical Cushing’s disease. After pituitary transsphenoidal surgery, all acryl enlargement in hands and ligaments disappeared. His growth hormone, IGF-1 and ACTH returned to normal 2 weeks after surgery.




TÍTULO / TITLE:  - miR-26a Plays an Important Role in Cell Cycle Regulation in ACTH-Secreting Pituitary Adenomas by Modulating Protein Kinase Cdelta

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

REVISTA / JOURNAL:  - Endocrinology. 2013 Mar 22.

            ●● Enlace al texto completo (gratuito o de pago) 1210/en.2012-2070

AUTORES / AUTHORS:  - Gentilin E; Tagliati F; Filieri C; Mole D; Minoia M; Rosaria Ambrosio M; Degli Uberti EC; Zatelli MC

INSTITUCIÓN / INSTITUTION:  - Section of Endocrinology (E.G., F.T., C.F., D.M., M.M., M.R.A., E.C.d.U., M.C.Z.), Department of Medical Sciences, and Laboratorio in rete del Tecnopolo “Tecnologie delle terapie avanzate” (E.G., E.d.U., M.C.Z.), University of Ferrara, 44100 Ferrara, Italy.

RESUMEN / SUMMARY:  - The functional aftermath of microRNA (miRNA) dysregulation in ACTH-secreting pituitary adenomas has not been demonstrated. miRNAs represent diagnostic and prognostic biomarkers as well as putative therapeutic targets; their investigation may shed light on the mechanisms that underpin pituitary adenoma development and progression. Drugs interacting with such pathways may help in achieving disease control also in the settings of ACTH-secreting pituitary adenomas. We investigated the expression of 10 miRNAs among those that were found as most dysregulated in human pituitary adenoma tissues in the settings of a murine ACTH-secreting pituitary adenoma cell line, AtT20/D16v-F2. The selected miRNAs to be submitted to further investigation in AtT20/D16v-F2 cells represent  an expression panel including 5 up-regulated and 5 down-regulated miRNAs. Among these, we selected the most dysregulated mouse miRNA and searched for miRNA targets and their biological function. We found that AtT20/D16v-F2 cells have a specific miRNA expression profile and that miR-26a is the most dysregulated miRNA. The latter is overexpressed in human pituitary adenomas and can control viable cell number in the in vitro model without involving caspase 3/7-mediated apoptosis. We demonstrated that protein kinase Cdelta (PRKCD) is a direct target  of miR-26a and that miR26a inhibition delays the cell cycle in G1 phase. This effect involves down-regulation of cyclin E and cyclin A expression via PRKCD modulation. miR-26a and related pathways, such as PRKCD, play an important role in cell cycle control of ACTH pituitary cells, opening new therapeutic possibilities for the treatment of persistent/recurrent Cushing’s disease.




TÍTULO / TITLE:  - A treatment planning comparison of highly conformal radiation therapy for pediatric low-grade brainstem gliomas.

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

REVISTA / JOURNAL:  - Acta Oncol. 2013 Apr;52(3):594-9. doi: 10.3109/0284186X.2013.767474. Epub 2013 Feb 20.

            ●● Enlace al texto completo (gratuito o de pago) 3109/0284186X.2013.767474

AUTORES / AUTHORS:  - Brower JV; Indelicato DJ; Aldana PR; Sandler E; Rotondo R; Mendenhall NP; Marcus RB; Su Z

INSTITUCIÓN / INSTITUTION:  - University of Florida Proton Therapy Institute , Jacksonville, Florida , USA.




TÍTULO / TITLE:  - Hypo-fractionated IMRT for patients with newly diagnosed glioblastoma multiforme: A 6 year single institutional experience.

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

REVISTA / JOURNAL:  - Clin Neurol Neurosurg. 2013 Feb 26. pii: S0303-8467(13)00054-1. doi: 10.1016/j.clineuro.2013.02.001.

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

AUTORES / AUTHORS:  - Ciammella P; Galeandro M; D’Abbiero N; Podgornii A; Pisanello A; Botti A; Cagni E; Iori M; Iotti C

INSTITUCIÓN / INSTITUTION:  - Radiation Therapy Unit, Department of Oncology and Advanced Technology, Azienda Ospedaliera ASMN, Istituto di Ricovero e Cura a Carattere Scientifico, Reggio Emilia, Italy. Electronic address: patrizia.ciammella@asmn.re.it.

RESUMEN / SUMMARY:  - OBJECTIVES: Glioblastoma (GBM) is the most common malignant primary brain tumour  in adults. Surgery and radiotherapy constitute the cornerstones for the therapeutic management of GBM. The standard treatment today is maximal surgical resection followed by concomitant chemo-radiation therapy followed by adjuvant TMZ according to Stupp protocol. Despite the progress in neurosurgery, radiotherapy and oncology, the prognosis still results poor. In order to reduce the long time of standard treatment, maintaining or improving the clinical results, in our institute we have investigated the effects of hypo-fractionated radiation therapy for patients with GBM. PATIENTS AND METHODS: Sixty-seven patients affected by GBM who had previously undergone surgical resection (total,  subtotal or biopsy) were enrolled between October 2005 and December 2011 in a single institutional study of hypo-fractionated intensity modulated radiation therapy (IMRT) followed or not by adjuvant chemotherapy with TMZ (6-12 cycles). The most important eligibility criteria were: biopsy-proven GBM, KPS>/=60, age>/=18 years, no previous brain irradiation, informed consensus. Hypo-fractionated IMRT was delivered to a total dose of 25Gy in 5 fractions prescribed to 70% isodose. Response to treatment, OS, PFS, toxicity and patterns  of recurrence were evaluated, and sex, age, type of surgery, Karnofsky performance status, Recursive Partitioning Analysis (RPA) classification, time between surgery and initiation of radiotherapy were evaluated as potential prognostic factors for survival. RESULTS: All patients have completed the treatment protocol. Median age was 64.5 years (range 41-82 years) with 31 females (46%) and 36 males (54%). Median KPS at time of treatment was 80. The surgery was gross total in 38 patients and subtotal in 14 patients; 15 patients underwent only biopsy. No grade 3-4 acute or late neurotoxicity was observed. With median follow-up of 14.9 months, the median OS and PFS were 13.4 and 7.9 months, respectively. CONCLUSIONS: The hypo-fractionated radiation therapy can be used for patients with GBM, resulting in favourable overall survival, low rates of toxicity and satisfying QoL. Future investigations are needed to determine the optimal fractionation for GBM.




TÍTULO / TITLE:  - Fronto-cerebellar fiber tractography in pediatric patients following posterior fossa tumor surgery.

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

REVISTA / JOURNAL:  - Childs Nerv Syst. 2013 Mar 19.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00381-013-2070-3

AUTORES / AUTHORS:  - Gudrunardottir T; Sehested A; Juhler M; Schmiegelow K

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, The University Hospital Rigshospitalet, 2100, Copenhagen, Denmark.




TÍTULO / TITLE:  - Spontaneous speech of patients with gliomas in eloquent areas before and early after surgery.

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

REVISTA / JOURNAL:  - Acta Neurochir (Wien). 2013 Apr;155(4):685-92. doi: 10.1007/s00701-013-1638-8. Epub 2013 Feb 26.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00701-013-1638-8

AUTORES / AUTHORS:  - Satoer D; Vincent A; Smits M; Dirven C; Visch-Brink E

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, Erasmus MC-University Medical Center, Dr. Molewaterplein 50-60, PO Box 2040, 3015 GE, Rotterdam, The Netherlands, d.satoer@erasmusmc.nl.

RESUMEN / SUMMARY:  - BACKGROUND: Glioma patients often complain about problems in daily conversation.  A detailed spontaneous speech analysis could provide more insight in these communicative problems; no previous studies are reported. OBJECTIVE: To select sensitive parameters in spontaneous speech pre- and post-operatively in patients  with gliomas in eloquent areas. METHODS: We included 27 patients and 21 healthy controls. In addition to a naming and category fluency test, spontaneous speech was collected 1 month pre-operatively and 3 months post-operatively, and analysed with the variables: Self-corrections, Repetitions, Lexical Diversity, Incomplete  Sentences and Mean Length of Utterance (MLUw). A correlation analysis was performed between the linguistic variables and tumour characteristics (grade, localisation and volume), treatment related factors, and between the linguistic variables and the language tasks. RESULTS: Pre-operatively, patients produced more Incomplete Sentences than the controls (p < 0.001). Post-operatively, patients’ utterance length (MLUw) (p < 0.05) was also deviant. The quality of the spontaneous speech was influenced by tumour grade and localisation. There was no  influence of tumour volume or treatment-related factors. Pre- and post-operatively, patients’ performance on the naming and the fluency task deviated from normal (p < 0.001). The majority of the linguistic variables did not correlate with the language tasks, pointing to a measurement of distinct linguistic aspects. CONCLUSION: Pre- and post-operatively there was a disorder in naming, category fluency and spontaneous speech, partly influenced by tumour characteristics. A spontaneous speech analysis appeared to be a valuable addition to standardised language tasks. Both measurements are important tools to obtain a complete linguistic profile.




TÍTULO / TITLE:  - PDGFRA Amplification is Common in Pediatric and Adult High-Grade Astrocytomas and Identifies a Poor Prognostic Group in IDH1 Mutant Glioblastoma.

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

REVISTA / JOURNAL:  - Brain Pathol. 2013 Feb 25. doi: 10.1111/bpa.12043.

            ●● Enlace al texto completo (gratuito o de pago) 1111/bpa.12043

AUTORES / AUTHORS:  - Phillips JJ; Aranda D; Ellison DW; Judkins AR; Croul SE; Brat DJ; Ligon KL; Horbinski C; Venneti S; Zadeh G; Santi M; Zhou S; Appin CL; Sioletic S; Sullivan LM; Martinez-Lage M; Robinson AE; Yong WH; Cloughesy T; Lai A; Phillips HS; Marshall R; Mueller S; Haas-Kogan DA; Molinaro AM; Perry A

INSTITUCIÓN / INSTITUTION:  - Department of Pathology, University of California San Francisco, San Francisco, CA; Department of Neurological Surgery, University of California San Francisco, San Francisco, CA; Department of Brain Tumor Research Center, University of California San Francisco, San Francisco, CA.

RESUMEN / SUMMARY:  - High-grade astrocytomas (HGAs), corresponding to World Health Organization grades III (anaplastic astrocytoma) and IV (glioblastoma; GBM), are biologically aggressive, and their molecular classification is increasingly relevant to clinical management. PDGFRA amplification is common in HGAs, although its prognostic significance remains unclear. Using fluorescence in situ hybridization (FISH), the most sensitive technique for detecting PDGFRA copy number gains, we determined PDGFRA amplification status in 123 pediatric and 263 adult HGAs. A range of PDGFRA FISH patterns were identified and cases were scored as non-amplified (normal and polysomy) or amplified (low-level and high-level). PDGFRA amplification was frequent in pediatric (29.3%) and adult (20.9%) tumors.  Amplification was not prognostic in pediatric HGAs. In adult tumors diagnosed initially as GBM, the presence of combined PDGFRA amplification and isocitrate dehydrogenase 1 (IDH1)R132H mutation was a significant independent prognostic factor (P = 0.01). In HGAs, PDGFRA amplification is common and can manifest as high-level and focal or low-level amplifications. Our data indicate that the latter is more prevalent than previously reported with copy number averaging techniques. To our knowledge, this is the largest survey of PDGFRA status in adult and pediatric HGAs and suggests PDGFRA amplification increases with grade and is associated with a less favorable prognosis in IDH1 mutant de novo GBMs.




TÍTULO / TITLE:  - Development of Dual PLD1/2 and PLD2 Selective Inhibitors from a Common 1,3,8-Triazaspiro[4.5]decane Core: Discovery of ML298 and ML299 That Decrease Invasive Migration in U87-MG Glioblastoma Cells.

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

REVISTA / JOURNAL:  - J Med Chem. 2013 Mar 28;56(6):2695-9. doi: 10.1021/jm301782e. Epub 2013 Mar 13.

            ●● Enlace al texto completo (gratuito o de pago) 1021/jm301782e

AUTORES / AUTHORS:  - O’Reilly MC; Scott SA; Brown KA; Oguin TH 3rd; Thomas PG; Daniels JS; Morrison R; Brown HA; Lindsley CW

INSTITUCIÓN / INSTITUTION:  - Department of Pharmacology and double daggerVanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.

RESUMEN / SUMMARY:  - An iterative parallel synthesis effort identified a PLD2 selective inhibitor, ML298 (PLD1 IC50 > 20 000 nM, PLD2 IC50 = 355 nM) and a dual PLD1/2 inhibitor, ML299 (PLD1 IC50 = 6 nM, PLD2 IC50 = 20 nM). SAR studies revealed that a small structural change (incorporation of a methyl group) increased PLD1 activity within this classically PLD2-preferring core and that the effect was enantiospecific. Both probes decreased invasive migration in U87-MG glioblastoma  cells.




TÍTULO / TITLE:  - Glioblastoma Resistance to Anti-VEGF Therapy: Has the Challenge Been MET?

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

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Apr 1;19(7):1631-3. doi: 10.1158/1078-0432.CCR-13-0051. Epub 2013 Feb 12.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-13-0051


INSTITUCIÓN / INSTITUTION:  - Author’s Affiliation: Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas.

RESUMEN / SUMMARY:  - In glioblastoma cells the receptor tyrosine kinase c-Met is upregulated in response to bevacizumab and plays an important role in promoting invasion and tumor recurrence. These data support novel links between VEGF-A and hepatocyte growth factor and suggest that c-Met and its signaling effectors may be effective targets for anti-invasive therapies. Clin Cancer Res; 19(7); 1631-3. ©2013 AACR.




TÍTULO / TITLE:  - Anaplastic astrocytomas with abundant Rosenthal fibers in elderly patients: A diagnostic pitfall of high-grade gliomas.

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

REVISTA / JOURNAL:  - Neuropathology. 2013 Feb 25. doi: 10.1111/neup.12025.

            ●● Enlace al texto completo (gratuito o de pago) 1111/neup.12025

AUTORES / AUTHORS:  - Sugita Y; Nakashima S; Ohshima K; Terasaki M; Morioka M

INSTITUCIÓN / INSTITUTION:  - Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan.

RESUMEN / SUMMARY:  - To investigate the clinicopathological features of anaplastic astrocytoma (AA) with abundant Rosenthal fibers (RFs), this study assessed four cases of AA (elderly patients; age >/=70 years). Histologically, these tumors were composed of diffusely infiltrating astrocytomas with brightly eosinophilic cytoplasmic granules or cork-screw or beaded bundles. Tumor cells showed pleomorphism, bizarre giant cells, and mitotic activity, but no necrosis. The cytoplasmic granules showed negativity on PAS staining. Immunohistochemically, the tumor cells with cytoplasmic granular cells showed a positive reaction for GFAP. The cytoplasmic eosinophilic granules or bundles were positive for alphaB-crystallin, ubiquitin and HSP27. In addition, tumor cells showed strong cytoplasmic positivity for isocitrate dehydrogenase 1 (IDH1)-R132H protein in all cases. The  MIB-l labeling index of these cases ranged from 7% to 10%. In cases 1 and 2, ultrastructurally, the tumor cells had electron-dense, amorphous structures in the cytoplasm and in the processes. These structures were bound to glial intermediate filaments. Based on these microscopic, immunohistochemical and ultrastructural findings, case 1 was diagnosed as AA with abundant, mixed, common type of RFs and miniature (m) RFs, and cases 2,3, and 4 were diagnosed as AA with abundant mRFs. These results indicate that the presence of RFs in astrocytic tumors does not necessarily exclude a diagnosis of high-grade astrocytoma. In addition, AAs with abundant mRFs in elderly patients should be classified as a peculiar variant of AA.




TÍTULO / TITLE:  - Malignant Emboli on Transcranial Doppler During Carotid Stenting Predict Postprocedure Diffusion-Weighted Imaging Lesions.

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

REVISTA / JOURNAL:  - Stroke. 2013 Mar 26.

            ●● Enlace al texto completo (gratuito o de pago) 1161/STROKEAHA.111.000659

AUTORES / AUTHORS:  - Almekhlafi MA; Demchuk AM; Mishra S; Bal S; Menon BK; Wiebe S; Clement FM; Wong JH; Hill MD; Goyal M

INSTITUCIÓN / INSTITUTION:  - From the Departments of Clinical Neurosciences.

RESUMEN / SUMMARY:  - BACKGROUND AND PURPOSE: Carotid angioplasty and stenting (CAS) has a higher incidence of periprocedural stroke compared with endarterectomy. Identifying CAS  steps with the highest likelihood of embolization may have important implications. We evaluated CAS safety by correlating the findings of procedural transcranial Doppler with postprocedure diffusion-weighted imaging (DWI) lesions. METHODS: In this prospective study, transcranial Doppler monitoring was performed during CAS procedures, which were divided into 11 steps. Embolic signals on transcranial Doppler were counted and classified based on the relative energy index of microembolic signals into microemboli </=1 or malignant macroemboli >1.  Poststenting MRI was performed in all cases. A negative binomial regression model was used to evaluate the predictive value of transcranial Doppler emboli for new  DWI lesions. RESULTS: Thirty subjects were enrolled. Seven of 30 subjects (23.3%) were asymptomatic. The median embolic signal count was 212.5 (108 microemboli and 80 malignant macroemboli). Stent deployment phase showed the highest median embolic signals count at 58, followed by protection device deployment at 30 (P=0.0006). Twenty-four of 30 (80%) had new DWI lesions on post-CAS MRI. The median DWI count was 4 (interquartile range 7). Two of 30 (6.7%) had new or worsening clinical deficits post-CAS. For every malignant embolus, the expected count of DWI lesions increases by 1% ( 95% confidence interval, 0%-2%; P=0.032).  CONCLUSIONS: We observed a high incidence of embolic signals during CAS procedure, especially, when devices were deployed. Most subjects developed new DWI lesions, but only 6.7% had deficits. Malignant macroemboli predicted new DWI  lesions.




TÍTULO / TITLE:  - Familial Isolated Pituitary Adenomas (FIPA) and the Pituitary Adenoma Predisposition due to Mutations in the Aryl Hydrocarbon Receptor Interacting Protein (AIP) Gene.

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

REVISTA / JOURNAL:  - Endocr Rev. 2013 Jan 31.

            ●● Enlace al texto completo (gratuito o de pago) 1210/er.2012-1013

AUTORES / AUTHORS:  - Beckers A; Aaltonen LA; Daly AF; Karhu A

INSTITUCIÓN / INSTITUTION:  - Department of Endocrinology (A.B., A.F.D.), Centre Hospitalier Universitaire de Liege, University of Liege, 4000 Liege, Belgium; and Genome-Scale Biology Research Program (L.A.A., A.K.), Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, 00530 Helsinki, Finland.

RESUMEN / SUMMARY:  - Pituitary adenomas are one of the most frequent intracranial tumors and occur with a prevalence of approximately 1:1000 in the developed world. Pituitary adenomas have a serious disease burden, and their management involves neurosurgery, biological therapies, and radiotherapy. Early diagnosis of pituitary tumors while they are smaller may help increase cure rates. Few genetic predictors of pituitary adenoma development exist. Recent years have seen two separate, complimentary advances in inherited pituitary tumor research. The clinical condition of familial isolated pituitary adenomas (FIPA) has been described, which encompasses the familial occurrence of isolated pituitary adenomas outside of the setting of syndromic conditions like multiple endocrine neoplasia type 1 and Carney complex. FIPA families comprise approximately 2% of pituitary adenomas and represent a clinical entity with homogeneous or heterogeneous pituitary adenoma types occurring within the same kindred. The aryl hydrocarbon receptor interacting protein (AIP) gene has been identified as causing a pituitary adenoma predisposition of variable penetrance that accounts for 20% of FIPA families. Germline AIP mutations have been shown to associate with the occurrence of large pituitary adenomas that occur at a young age, predominantly in children/adolescents and young adults. AIP mutations are usually associated with somatotropinomas, but prolactinomas, nonfunctioning pituitary adenomas, Cushing disease, and other infrequent clinical adenoma types can also occur. Gigantism is a particular feature of AIP mutations and occurs in more than one third of affected somatotropinoma patients. Study of pituitary adenoma patients with AIP mutations has demonstrated that these cases raise clinical challenges to successful treatment. Extensive research on the biology of AIP and  new advances in mouse Aip knockout models demonstrate multiple pathways by which  AIP may contribute to tumorigenesis. This review assesses the current clinical and therapeutic characteristics of more than 200 FIPA families and addresses research findings among AIP mutation-bearing patients in different populations with pituitary adenomas.




TÍTULO / TITLE:  - Pilocytic Astrocytoma: A Disease With Evolving Molecular Heterogeneity.

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

REVISTA / JOURNAL:  - J Child Neurol. 2013 Feb 25.

            ●● Enlace al texto completo (gratuito o de pago) 1177/0883073813476141

AUTORES / AUTHORS:  - Sadighi Z; Slopis J

INSTITUCIÓN / INSTITUTION:  - 1St. Jude Children’s Research Hospital, Memphis, TN, USA.

RESUMEN / SUMMARY:  - Pilocytic astrocytoma, the most common pediatric brain tumor, is a clinically and molecularly heterogeneous disease that occurs most often in the cerebellum and hypothalamic and chiasmatic regions. Classically, pilocytic astrocytomas are driven by the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway. Recently described genetic aberrations involving this pathway are critical for tumorigenesis. Tandem duplication of 7q34 encodes BRAF and produces  several KIAA1549-BRAF novel oncogenic fusions. Activating point mutations of BRAF, such as BRAF(V600E), also lead to pilocytic astrocytoma. Loss of the NF1 gene allows hyperactivation of the oncogene KRAS. In this review, we discuss the  current understanding of the novel molecular aberrations described in pilocytic astrocytomas and their clinical relevance for prognosis and treatment. The prognostic indications of these aberrations are discussed with regard to tumor location, tumor pathology, and patient age. A better understanding of the evolving molecular heterogeneity of pilocytic astrocytomas offers hope for developing molecularly targeted therapeutic armamentariums.




TÍTULO / TITLE:  - Cardiac paraganglioma.

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

REVISTA / JOURNAL:  - J Am Coll Cardiol. 2013 Mar 7. pii: S0735-1097(13)00931-5. doi: 10.1016/j.jacc.2012.10.061.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.jacc.2012.10.061


INSTITUCIÓN / INSTITUTION:  - Department of Ultrasound, Second Affiliated Hospital, the Third Military Medical  University, Chongqing, 400037 China. Electronic address: digitalheart@163.com.




TÍTULO / TITLE:  - Double, Synchronous Pituitary Adenomas Causing Acromegaly and Cushing’s Disease.  A Case Report and Review of Literature.

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

REVISTA / JOURNAL:  - Endocr Pathol. 2013 Mar 20.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12022-013-9237-z

AUTORES / AUTHORS:  - Zielinski G; Maksymowicz M; Podgorski J; Olszewski WT

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, Military Institute of Medicine, 128 Szaserow Street., 04-141 Warszawa 44, Warsaw, Poland, gzielinski@wim.mil.pl.

RESUMEN / SUMMARY:  - Double pituitary adenomas are very rare and present up to 1 % of pituitary adenomas in unselected autopsy series and up to 2 % in large surgical series. We  report a case of a 47-year-old man presented slight clinical features of acromegaly with 2 years duration. Endocrine evaluation confirmed active acromegaly and revealed adrenocorticotropin hormone-dependent hypercortisolemia.  Preoperative magnetic resonance imaging of the pituitary demonstrated clearly separated double microadenomas with different intensity. The patient underwent transsphenoidal surgery and both tumors were completely removed and were fixed separately. The histological and ultrastructural examination confirmed coincidence of the double, clearly separated pituitary adenomas in one gland. Postoperative function of the hypothalamo-hypophyseal axis was normalized. We conclude from this case and a literature review that double endocrinologically active pituitary adenomas leading to acromegaly and Cushing’s disease may occur.  Additionally, a review of the literature regarding multiple pituitary adenomas has also been performed.




TÍTULO / TITLE:  - Four Common Polymorphisms in MicroRNAs and the Risk of Adult Glioma in a Chinese  Case-control Study.

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

REVISTA / JOURNAL:  - J Mol Neurosci. 2013 Feb 21.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s12031-013-9980-0

AUTORES / AUTHORS:  - Hu E; Wang D; Zhang X; Li J; Hu Y; Gong H; Liu E

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, First Affiliated Hospital, Harbin Medical University, Number 23 Youzheng Street, Nangang District, Harbin, 150001, Heilongjiang, China.

RESUMEN / SUMMARY:  - Emerging evidence has shown that microRNAs (miRNAs) participate in human carcinogenesis as tumor suppressors or oncogenes. It has been suggested that four common single nucleotide polymorphisms (SNPs; miR-146aG > C, 149C > T, 196a2C > T, and 499A > G) are associated with susceptibility to numerous malignancies. However, published results are inconsistent and inclusive. To further investigate the role of these loci, we examined the association of the miRNA polymorphisms with the risk of gliomas in a Han population in northeastern China. Both miR-146aG > C and 196a2C > T showed allelic differences between glioma patients and healthy controls in the studied population, with an OR of 1.30 (P = 0.0006) and an odds ratio (OR) of 1.25 (P = 0.003), respectively. Logistic regression analysis also revealed that the 146aG > C and 196a2C > T wild-type homozygous carriers had an increased glioma risk compared to the variant carriers. Besides,  in pairwise comparisons two SNP combinations were associated with the risk of glioma. Among others, carriers of both homozygous risk genotypes, i.e., 146aGG and 196a2CC were associated with a nearly 4-fold increased risk of glioma (OR = 3.77, P = 1.3 x 10(-4)). Overall, glioma risk increased with increasing numbers of risk variant alleles. These results suggest that the miR-146aG > C and 196a2C  > T might influence the risk of developing glioma in a northeastern Han Chinese population.




TÍTULO / TITLE:  - Similar pyruvate kinase modifications in glioblastoma cells by 7beta-hydroxycholesterol and glutamine withdrawal.

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

REVISTA / JOURNAL:  - Biochem Pharmacol. 2013 Mar 25. pii: S0006-2952(13)00193-7. doi: 10.1016/j.bcp.2013.03.012.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bcp.2013.03.012

AUTORES / AUTHORS:  - de Weille J; Fabre C; Gaven C; Bakalara N

INSTITUCIÓN / INSTITUTION:  - Institut des Neurosciences de Montpellier, U1051 INSERM, 80 rue Augustin Fliche,  34295 Montpellier cedex 05, France. Electronic address: Jan.de-Weille@INSERM.fr.

RESUMEN / SUMMARY:  - Oxysterols possess anti-proliferative properties that may be used with much effect in the treatment of cancer. We have demonstrated previously that 7 beta-hydroxycholesterol (7b-HC) provokes both metabolic stress, as witnessed by AMPK activation, and changes in lipid raft composition in C6 glioblastoma cells.  These observations suggested that glycolysis might have been changed. Here we will show that 7b-HC increases cell cycle time and that it changes the affinity of pyruvate kinase to its substrate, phosphoenol pyruvate. The latter effect is mimicked by glutamine withdrawal.




TÍTULO / TITLE:  - Use of low-dose aspirin and non-aspirin nonsteroidal anti-inflammatory drugs and  risk of glioma: a case-control study.

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

REVISTA / JOURNAL:  - Br J Cancer. 2013 Mar 19;108(5):1189-94. doi: 10.1038/bjc.2013.87. Epub 2013 Feb  28.

            ●● Enlace al texto completo (gratuito o de pago) 1038/bjc.2013.87

AUTORES / AUTHORS:  - Gaist D; Garcia-Rodriguez LA; Sorensen HT; Hallas J; Friis S

INSTITUCIÓN / INSTITUTION:  - Department of Neurology, Odense University Hospital, Institute of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Sdr Boulevard 29, Odense C 5000, Denmark.

RESUMEN / SUMMARY:  - Background:Few studies have examined the association between use of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs) and risk of glioma and the results have been equivocal. We therefore investigated the influence of NSAID use on glioma risk in a nationwide setting.Methods:We used national registries in Denmark to identify all patients aged 20-85 years with a first diagnosis of histologically verified glioma during 2000-2009. Each case was matched on birth year and sex to eight population controls using risk-set sampling. We used prescription data to assess NSAID use and classified exposure to low-dose aspirin or non-aspirin (NA) NSAIDs into ever use or long-term use, defined as continuous  use for >/=5 years. Conditional logistic regression was used to compute odds ratios (ORs), with 95% confidence intervals (CIs), for glioma associated with NSAID use, adjusted for potential confounders.Results:A total of 2688 glioma cases and 18 848 population controls were included in the study. Ever use of low-dose aspirin (OR=0.90; 95% CI: 0.77-1.04) or NA-NSAIDs (OR=1.05; 95% CI: 0.96-1.14) was not associated with glioma risk. Compared with never use, long-term use of low-dose aspirin or of NA-NSAIDs was associated with ORs of 0.80 (95% CI: 0.53-1.21) and 1.11 (0.57-2.17), respectively. We observed no clear patterns of risk in stratified analysis according to estimated doses of low-dose  aspirin (</=100 mg, 150 mg).Conclusion:We did not find any apparent association between aspirin or NA-NSAID use and risk of glioma, although our results may be consistent with a slight reduction in glioma risk with long-term use of low-dose  aspirin.




TÍTULO / TITLE:  - Transsphenoidal microsurgical results of female patients with prolactinomas.

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

REVISTA / JOURNAL:  - Clin Neurol Neurosurg. 2013 Mar 13. pii: S0303-8467(13)00069-3. doi: 10.1016/j.clineuro.2013.02.016.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.clineuro.2013.02.016

AUTORES / AUTHORS:  - Ikeda H; Watanabe K; Tominaga T; Yoshimoto T

INSTITUCIÓN / INSTITUTION:  - Research Institute for Pituitary Disease, Southern Tohoku General Hospital, Koriyama, Japan. Electronic address: ikeda@nsg.med.tohoku.ac.jp.

RESUMEN / SUMMARY:  - OBJECTIVE: We investigated surgical cure rate and surgical complications of patients with macroprolactinomas who desired pregnancy to evaluate the efficacy of transsphenoidal surgery. METHODS: Surgical cure rate was investigated in 138 female patients who were under 40 years old. RESULTS: We found a significant correlation between serum prolactin levels and adenoma volume (r=0.004; p<0.0001), adenoma volume and age (r=-0.213; p<0.03), and proliferative index of  the adenoma and age (r=-0.15; p<0.007). Seventy-seven out of 81 patients with enclosed macroadenoma were considered cured, and therefore the overall surgical cure rate was 95%. However, during long-term follow-up, recurrence of adenomas with hyperprolactinemia was seen in 5 out of 81 patients (6%), and the long-term  cure rate in patients with enclosed macroadenomas was 89%. Adenomas that did not  invade the cavernous sinus showed a significantly higher surgical curability and  lower serum prolactin levels, and a smaller size than those adenomas that invaded the cavernous sinus. CONCLUSIONS: The long-term surgical cure rate was found to be 89% and this success rate far surpasses the complication rate of 39% during pregnancy by dopamine agonist therapy. Thus, transsphenoidal surgery should be considered as a first-line treatment for female patients who desire pregnancy.




TÍTULO / TITLE:  - The reliability of topographic measurements from navigated transcranial magnetic  stimulation in healthy volunteers and tumor patients.

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

REVISTA / JOURNAL:  - Acta Neurochir (Wien). 2013 Mar 12.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00701-013-1665-5

AUTORES / AUTHORS:  - Zdunczyk A; Fleischmann R; Schulz J; Vajkoczy P; Picht T

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, Charite University Hospital, Augustenburger Platz 1,  13353, Berlin, Germany.

RESUMEN / SUMMARY:  - BACKGROUND: Navigated transcranial magnetic stimulation (nTMS) is increasingly being used for preoperative mapping of the motor cortex. Any new technology should undergo rigorous validation before being widely adopted in routine clinical practice. The aim of this experimental study was to assess the intraexaminer and interexaminer reliability of topographic mapping with nTMS. METHODS: nTMS mapping of the motor cortex for the first dorsal interosseous (FDI) muscle was performed by an expert and a novice examiner, twice in ten healthy volunteers and once in ten tumor patients. The distances between the centers-of-gravity and hotspots were calculated, as were coefficients of variation. This study also compared orthogonal versus variable orientation of the stimulation coil. RESULTS: The mean (range) distance between centers-of-gravity for the expert examiner in the test-retest protocol with healthy volunteers was 4.40 (1.86-7.68) mm. The mean (range) distance between centers-of-gravity for the expert vs. novice examiner was 4.89 (2.39-9.22) mm. There were no significant differences in this result between healthy volunteers and tumor patients. CONCLUSIONS: nTMS is sufficiently reliable for clinical use, but examiners should make efforts to minimize sources of error. The reliability of nTMS in tumor patients appears comparable to healthy subjects.




TÍTULO / TITLE:  - Maze learning in patients with intracranial arachnoid cysts.

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

REVISTA / JOURNAL:  - Acta Neurochir (Wien). 2013 Mar 2.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00701-013-1641-0

AUTORES / AUTHORS:  - Isaksen E; Leet TH; Helland CA; Wester K

INSTITUCIÓN / INSTITUTION:  - Department of Surgical Sciences, University of Bergen, Bergen, Norway, e.isaksen@hotmail.com.

RESUMEN / SUMMARY:  - BACKGROUND: The temporal lobe is of importance for visuospatial orientation. Intracranial arachnoid cysts have a predilection for the temporal fossa, and might therefore affect visuospatial orientation. The aim was to find out whether  temporal cysts affect maze learning and if surgical cyst decompression improves maze performance. METHODS: Forty-five patients with a temporal arachnoid cyst and 17 control patients with cervical disc disease were tested in a labyrinth route in the hospital corridors the day before surgery and at least 3 months postoperatively. RESULTS: Thirty-five cyst patients (78 %) experienced postoperative improvement of their preoperative complaints. The cyst patients spent significantly longer time than the controls navigating through the maze in  the preoperative test, 161 s and 127 s, respectively, but there was no difference in number of errors between the two groups. However, the cyst patients improved significantly in the postoperative test, both with regards to number of errors they made and time spent, contrary to the control patients, whose postoperative performance equalled that of the preoperative test. For the cyst patients, postoperative improvement in the labyrinth test correlated with the clinical outcome-but not the neuroradiological outcome-after the operation. CONCLUSIONS: Thus, temporal arachnoid cysts may affect visuospatial orientation and learning in a reversible manner.




TÍTULO / TITLE:  - A highly sensitive and specific chemiluminescent enzyme immunoassay for placental alkaline phosphatase in the cerebrospinal fluid of patients with intracranial germinomas.

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

REVISTA / JOURNAL:  - Pediatr Neurosurg. 2012;48(3):141-5. doi: 10.1159/000345632. Epub 2013 Feb 14.

            ●● Enlace al texto completo (gratuito o de pago) 1159/000345632

AUTORES / AUTHORS:  - Watanabe S; Aihara Y; Kikuno A; Sato T; Komoda T; Kubo O; Amano K; Okada Y; Koyamaishi Y

INSTITUCIÓN / INSTITUTION:  - Tokyo PLAP Study Group, Tokyo, Japan.

RESUMEN / SUMMARY:  - Background: Placental alkaline phosphatase (PLAP) in cerebrospinal fluid (CSF) has been proposed as a tumor marker for intracranial germinomas. The purpose of the present study was to develop a sensitive assay for measuring CSF PLAP and to  evaluate the clinical significance of PLAP in patients with germinomas. Methods:  A chemiluminescent enzyme assay for PLAP was developed using an anti-human-PLAP monoclonal antibody. PLAP concentrations were determined in 37 controls, 36 germinomas, 3 nongerminomatous germ cell tumors, 21 gliomas and 12 other brain tumors. Results: The assay detection limit was 5 pg/ml. The median PLAP concentration in the control group was below the detection limit. Significantly higher PLAP levels were detected in all 36 germinoma patients, with values ranging from 16 to 3,700 pg/ml. The high PLAP concentrations of 17 germinoma patients decreased to below the detection limit after complete remission had been achieved with radiochemotherapy. The sensitivity and specificity of PLAP for germinomas were 94 and 97%, respectively, with a cutoff value of 30 pg/ml. Conclusions: The results of this study suggest that the determination of CSF PLAP by the chemiluminescent method described here provides a clinically useful tumor  marker for the diagnosis and monitoring of intracranial germinomas.




TÍTULO / TITLE:  - Sox21 inhibits glioma progression in vivo by forming complexes with Sox2 and stimulating aberrant differentiation.

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

REVISTA / JOURNAL:  - Int J Cancer. 2013 Mar 5. doi: 10.1002/ijc.28147.

            ●● Enlace al texto completo (gratuito o de pago) 1002/ijc.28147

AUTORES / AUTHORS:  - Caglayan D; Lundin E; Kastemar M; Westermark B; Ferletta M

INSTITUCIÓN / INSTITUTION:  - Department of Immunology, Genetics and Pathology, Rudbeck laboratory, Uppsala University, Uppsala, Sweden.

RESUMEN / SUMMARY:  - Sox2 is a transcription factor in neural stem cells and keeps the cells immature  and proliferative. Sox2 is expressed in primary human glioma such as glioblastoma multiforme (GBM), primary glioma cells and glioma cell lines and is implicated in signaling pathways in glioma connected to malignancy. Sox21, the counteracting partner of Sox2, has the same expression pattern as Sox2 in glioma but in general induces opposite effects. In this study, Sox21 was overexpressed by using a tetracycline-regulated expression system (tet-on) in glioma cells. The glioma cells were injected subcutaneously into immunodeficient mice. The control tumors  were highly proliferative, contained microvascular proliferation and large necrotic areas typical of human GBM. Induction of Sox21 in the tumor cells resulted in a significant smaller tumor size, and the effect correlated with the  onset of treatment, where earlier treatment gave smaller tumors. Mice injected with glioma cells orthotopically into the brain survived significantly longer when Sox21 expression was induced. Tumors originating from glioma cells with an induced expression of Sox21 exhibited an increased formation of Sox2:Sox21 complexes and an upregulation of S100beta, CNPase and Tuj1. Sox21 appears to decrease the stem-like cell properties of the tumor cells and initiate aberrant differentiation of glioma cells in vivo. Taken together our results indicate that Sox21 can function as a tumor suppressor during gliomagenesis mediated by a shift in the balance between Sox2 and Sox21. The wide distribution of Sox2 and Sox21 in GBM makes the Sox2/Sox21 axis a very interesting target for novel therapy of gliomas.




TÍTULO / TITLE:  - Successful Treatment of Metastatic Relapse of Medulloblastoma in Childhood With Single Session Stereotactic Radiosurgery: A Report of 3 Cases.

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

REVISTA / JOURNAL:  - J Pediatr Hematol Oncol. 2013 Mar 1.

            ●● Enlace al texto completo (gratuito o de pago) 1097/MPH.0b013e3182830fd4

AUTORES / AUTHORS:  - King D; Connolly D; Zaki H; Lee V; Yeomanson D

INSTITUCIÓN / INSTITUTION:  - Departments of *Paediatric Oncology daggerRadiology double daggerNeurosurgical, Sheffield Children’s Hospital NHS Foundation Trust, Western Bank, Sheffield, UK.

RESUMEN / SUMMARY:  - Stereotactic radiosurgery (SRS) is an increasingly used treatment modality in adults, but its use and effectiveness in pediatric brain tumors is still uncertain. We describe 3 patients with metastatic relapse of medulloblastoma, who were treated with SRS, and achieved prolonged, progression-free survival. Tolerability of the treatment was excellent with no adverse effects reported. This work adds to the growing evidence that SRS may have an important role to play in the treatment of pediatric brain tumors.




TÍTULO / TITLE:  - Longitudinal expression analysis of alphav integrins in human gliomas reveals upregulation of integrin alphavbeta3 as a negative prognostic factor.

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

REVISTA / JOURNAL:  - J Neuropathol Exp Neurol. 2013 Mar;72(3):194-210. doi: 10.1097/NEN.0b013e3182851019.

            ●● Enlace al texto completo (gratuito o de pago) 1097/NEN.0b013e3182851019

AUTORES / AUTHORS:  - Schittenhelm J; Schwab EI; Sperveslage J; Tatagiba M; Meyermann R; Fend F; Goodman SL; Sipos B

INSTITUCIÓN / INSTITUTION:  - Department of Neuropathology, Institute of Pathology and Neuropathology, University of Tubingen, Tubingen, Germany. jens.schittenhelm@med.uni-tuebingen.de

RESUMEN / SUMMARY:  - Integrin inhibitors targeting alphav series integrins are being tested for their  therapeutic potential in patients with brain tumors, but pathologic studies have  been limited by lack of antibodies suitable for immunohistochemistry (IHC) on formalin-fixed, paraffin-embedded specimens. We compared the expression of alphav integrins by IHC in brain tumor and normal human brain samples with gene expression data in a public database using new rabbit monoclonal antibodies against alphavbeta3, alphavbeta5, alphavbeta6, and alphavbeta8 complexes using both manual and automated microscopy analyses. Glial tumors usually shared an alphavbeta3-positive/alphavbeta5-positive/alphavbeta8-positive/alphavbeta6-negati ve phenotype. In 94 WHO (World Health Organization) grade II astrocytomas, 85 anaplastic astrocytomas WHO grade III, and 324 glioblastomas from archival sources, expression of integrins generally increased with grade of malignancy. Integrins alphavbeta3 and alphavbeta5 were expressed in many glioma vessels; the  intensity of vascular expression of alphavbeta3 increased with grade of malignancy, whereas alphavbeta8 was absent. Analysis of gene expression in an independent cohort showed a similar increase in integrin expression with tumor grade, particularly of ITGB3 and ITGB8; ITGB6 was not expressed, consistent with  the IHC data. Parenchymal alphavbeta3 expression and ITGB3 gene overexpression in glioblastomas were associated with a poor prognosis, as revealed by survival analysis (Kaplan-Meier logrank, p = 0.016). Together, these data strengthen the rationale for anti-integrin treatment of glial tumors.




TÍTULO / TITLE:  - Treatment of children with glioblastoma with conformal radiation, temozolomide, and bevacizumab as adjuncts to surgical resection.

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

REVISTA / JOURNAL:  - J Pediatr Hematol Oncol. 2013 Apr;35(3):e123-6. doi: 10.1097/MPH.0b013e318282cd7f.

            ●● Enlace al texto completo (gratuito o de pago) 1097/MPH.0b013e318282cd7f

AUTORES / AUTHORS:  - Friedman GK; Spiller SE; Harrison DK; Fiveash JB; Reddy AT

INSTITUCIÓN / INSTITUTION:  - Departments of *Pediatrics, Division of Hematology and Oncology daggerPathology double daggerRadiation Oncology, University of Alabama at Birmingham, Birmingham, AL.

RESUMEN / SUMMARY:  - Prognosis for children with glioblastoma is unacceptably poor. Modest improvements in progression-free survival were seen in adults with glioblastoma by combining temozolomide and bevacizumab with conformal radiation. We retrospectively reviewed 3 cases of glioblastoma in children treated using upfront bevacizumab and temozolomide during radiation, followed by 12 cycles of maintenance therapy. All patients completed therapy with minimal toxicity and no  delays in treatment. Two patients remain disease free at 38 and 49 months from diagnosis. One patient recurred 14 months off therapy and currently receives salvage therapy 48 months from diagnosis. These results support further investigation of this regimen.




TÍTULO / TITLE:  - Pasireotide, a multi-somatostatin receptor ligand with potential efficacy for treatment of pituitary and neuroendocrine tumors.

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

REVISTA / JOURNAL:  - Drugs Today (Barc). 2013 Feb;49(2):89-103. doi: 10.1358/dot.2013.49.2.1915142.

            ●● Enlace al texto completo (gratuito o de pago) 1358/dot.2013.49.2.1915142

AUTORES / AUTHORS:  - Feelders RA; de Herder WW; Neggers SJ; van der Lely AJ; Hofland LJ

INSTITUCIÓN / INSTITUTION:  - Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands. r.feelders@erasmusmc.nl

RESUMEN / SUMMARY:  - Somatostatin receptors are an important target for medical treatment of pituitary and neuroendocrine tumors. To date, five somatostatin receptor (sst) subtypes have been identified. The currently available somatostatin analogues octreotide and lanreotide have predominantly affinity for sst. Pasireotide is a sst multireceptor ligand with affinity for sst, sst, sst and sst and this broader binding profile may translate into a higher efficacy with respect to suppression  of hormone production and cell growth in certain tumors. Experimental animal studies and in vitro studies with cultured tumor cells have shown that pasireotide strongly suppresses growth hormone and adrenocorticotropin production. In addition, pasireotide can influence tumor cell growth via effects  on apoptosis and angiogenesis. In this review, the role of somatostatin receptors in pituitary and neuroendocrine tumors is briefly discussed followed by an overview of possible applications of pasireotide based on recent trials in patients with acromegaly, Cushing’s disease and neuroendocrine tumors.




TÍTULO / TITLE:  - Chromatin remodeling defects in pediatric and young adult glioblastoma: a tale of a variant histone 3 tail.

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

REVISTA / JOURNAL:  - Brain Pathol. 2013 Mar;23(2):210-6. doi: 10.1111/bpa.12023.

            ●● Enlace al texto completo (gratuito o de pago) 1111/bpa.12023

AUTORES / AUTHORS:  - Fontebasso AM; Liu XY; Sturm D; Jabado N

INSTITUCIÓN / INSTITUTION:  - Division of Experimental Medicine, McGill University and McGill University Health Centre, Montreal, QC, Canada.

RESUMEN / SUMMARY:  - Primary brain tumors occur in 8 out of 100 000 people and are the leading cause of cancer-related death in children. Among brain tumors, high-grade astrocytomas  (HGAs) including glioblastoma multiforme (GBM) are aggressive and are lethal human cancers. Despite decades of concerted therapeutic efforts, HGAs remain essentially incurable in adults and children. Recent discoveries have revolutionized our understanding of these tumors in children and young adults. Recurrent somatic driver mutations in the tail of histone 3 variant 3 (H3.3), leading to amino acid substitutions at key residues, namely lysine (K) 27 (K27M)  and glycine 34 (G34R/G34V), were identified as a new molecular mechanism in pediatric GBM. These mutations represent the pediatric counterpart of the recurrent mutations in isocitrate dehydrogenases (IDH) identified in young adult  gliomas and provide a much-needed new pathway that can be targeted for therapeutic development. This review will provide an overview of the potential role of these mutations in altering chromatin structure and affecting specific molecular pathways ultimately leading to gliomagenesis. The distinct changes in chromatin structure and the specific downstream events induced by each mutation need characterizing independently if progress is to be made in tackling this devastating cancer.




TÍTULO / TITLE:  - Oligodendroglioma (WHO grade I) in a young epilepsy patient: A specific entity lying within the spectrum of dysembryoplastic neuroepithelial tumor?

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

REVISTA / JOURNAL:  - Neuropathology. 2013 Feb 24. doi: 10.1111/neup.12026.

            ●● Enlace al texto completo (gratuito o de pago) 1111/neup.12026

AUTORES / AUTHORS:  - Takahashi H; Kakita A; Tomikawa M; Okamoto K; Kameyama S

INSTITUCIÓN / INSTITUTION:  - Department of Pathology, Brain Research Institute, University of Niigata, Niigata, Japan.

RESUMEN / SUMMARY:  - We studied a frontal lobe subcortical cystic tumor that had been resected from a  13-year-old girl with a 3-year history of intractable partial seizure. Currently, more than 13 years after surgery, the patient remains recurrence-free and has no  neurological deficits. Histological examination showed that the tumor was non-infiltrating and paucicellular with a mucinous matrix, and consisted of fairly uniform small cells with round to oval nuclei. Within the mucinous matrix, the tumor cells were often arranged in pseudorosettes around small blood vessels. Mitotic activity and necrosis were absent, with a Ki-67 labeling index of <1%. Based on the immunohistochemical and ultrastructural findings, the constituent tumor cells were considered to be those of oligodendroglioma, including mini-gemistocytes and gliofibrillary oligodendrocytes. No neuronal elements were  identified. Features of cortical dysplasia (FCD Type 1) were evident in the cortex covering the lesion. The surrounding white matter also contained a significant number of ectopic neurons. The entire pathological picture appeared to differ somewhat from that of ordinary oligodendroglioma (WHO grade II). Considering the clinical and pathological features, the present unusual oligodendroglioma appeared to represent a previously undescribed form of oligodendroglioma (WHO grade I) lying within the spectrum of dysembryoplastic neuroepithelial tumor (DNT; WHO grade I). Simultaneously, the present oligodendroglioma also raises the question of whether or not oligodendrocyte-like cells of DNTs truly show neurocytic differentiation.




TÍTULO / TITLE:  - Optic nerve seeding of atypical meningiomas presenting with subacute visual loss: 2 case reports with genetic characterization.

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

REVISTA / JOURNAL:  - J Neurosurg. 2013 Feb 22.

            ●● Enlace al texto completo (gratuito o de pago) 3171/2013.1.JNS121533

AUTORES / AUTHORS:  - Kitamura Y; Akiyama T; Sasaki H; Hayashi Y; Yoshida K

INSTITUCIÓN / INSTITUTION:  - Departments of Neurosurgery and.

RESUMEN / SUMMARY:  - Meningiomas rarely cause CSF dissemination, and CSF seeding to the optic nerve (ON) is extremely rare. This is the first report of 2 cases of atypical meningioma with subacute visual loss due to ON seeding. The authors present the genetic characteristics of these atypical meningiomas with CSF dissemination. The patient in Case 1 was a 36-year-old woman with a 1.5-cm mass within the left ON,  and the patient in Case 2 was a 70-year-old woman with a 0.9-cm mass around the right ON. Both individuals had undergone multiple surgeries for primary lesions and local recurrent lesions. They presented with subacute visual loss, and both tumors were completely resected. The pathological diagnosis was atypical meningioma with high MIB-1 indices and p53-positive cell ratios in each case. Comparative genomic hybridization showed significant chromosomal copy number alterations similar to the results of previous surgeries, confirming that the tumors were disseminated lesions. The present findings suggest that genetic characteristics, such as 1p and 10qcen-23 losses and 17q and 20 gains, shared by  the 2 cases might be associated with CSF dissemination of meningiomas.




TÍTULO / TITLE:  - Dysembryoplastic Neuroepithelial Tumors Share with Pleomorphic Xanthoastrocytomas and Gangliogliomas BRAF Mutation and Expression.

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

REVISTA / JOURNAL:  - Brain Pathol. 2013 Feb 26. doi: 10.1111/bpa.12048.

            ●● Enlace al texto completo (gratuito o de pago) 1111/bpa.12048

AUTORES / AUTHORS:  - Chappe C; Padovani L; Scavarda D; Forest F; Nanni-Metellus I; Loundou A; Mercurio S; Fina F; Lena G; Colin C; Figarella-Branger D

INSTITUCIÓN / INSTITUTION:  - INSERM, UMR 911, Marseille, France; Medicine School, Aix-Marseille University, Marseille, France.

RESUMEN / SUMMARY:  - Pediatric cortical glioneuronal benign tumors mainly include gangliogliomas (GG)  [differential diagnoses pilocytic astrocytomas (PA) and pleomorphic xanthoastrocytomas (PXA)] and dysembryoplastic neuroepithelial tumor (DNT). DNT include the specific form and the controversial non-specific form that lack the specific glioneuronal element. Our aims were to search for BRAFV600E mutation and CD34 expression in DNT, PXA, GG and PA to correlate BRAFV600E mutation with BRAFV600E expression and to evaluate their diagnostic and prognostic values. Ninety-six children were included. BRAFV600E mutation was studied by sequencing and immunohistochemistry; CD34 expression was analyzed by immunohistochemistry. BRAFV600E mutation was detected in PXA (60%), GG (38.7%), DNT (30%, including 3/11 specific and 3/9 non-specific forms) and PA (12.5%). BRAFV600E expression was recorded in PXA (60%), GG (45.2%) and DNT (30%). CD34 expression was recorded in PXA (60%), GG (58.1%), DNT (25%) and PA (12.5%). Neither CD34 expression nor BRAFV600E status was predictive of prognosis, except for PA tumors where CD34 expression was associated with a shorter overall survival. In conclusion, DNT shared with PXA and GG, BRAFV600E mutation and/or CD34 expression, which represent molecular markers for these tumors, and we recommend searching for CD34 expression and BRAFV600E mutation in all DNT, especially the non-specific forms.




TÍTULO / TITLE:  - Encephalocraniocutaneous Lipomatosis: Magnetic Resonance Imaging Findings in a Child.

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

REVISTA / JOURNAL:  - J Pediatr. 2013 Feb 26. pii: S0022-3476(13)00115-7. doi: 10.1016/j.jpeds.2013.01.040.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.jpeds.2013.01.040

AUTORES / AUTHORS:  - Dhouib A; Hanquinet S; La Scala GC

INSTITUCIÓN / INSTITUTION:  - Pediatric Radiology Unit, Department of Radiology, University of Geneva Children’s Hospital, Geneva, Switzerland.




TÍTULO / TITLE:  - Dopamine D2 receptor activation leads to an up-regulation of glial cell line-derived neurotrophic factor via Gbetagamma-Erk1/2-dependent induction of Zif268.

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

REVISTA / JOURNAL:  - J Neurochem. 2013 Feb 1. doi: 10.1111/jnc.12178.

            ●● Enlace al texto completo (gratuito o de pago) 1111/jnc.12178

AUTORES / AUTHORS:  - Ahmadiantehrani S; Ron D

INSTITUCIÓN / INSTITUTION:  - Gallo Research Center, Emeryville, California, USA; Graduate Program in Pharmaceutical Sciences and Pharmacogenomics, University of California, San Francisco, California, USA.

RESUMEN / SUMMARY:  - Glial cell line-derived neurotrophic factor (GDNF) is a potent growth factor essential to the development, survival, and function of dopaminergic neurons (Airaksinen and Saarma 2002). The molecular mechanisms underlying GDNF expression remain elusive; thus, we set out to identify a signaling pathway that governs GDNF levels. We found that treatment of both differentiated dopaminergic-like SH-SY5Y cells and rat midbrain slices with the dopamine D2 receptor (D2R) agonist, quinpirole, triggered an increase in the expression of GDNF that was temporally preceded by an increase in the levels of zinc-finger protein 268 (Zif268), a DNA-binding transcription factor encoded by an immediate-early gene.  Moreover, the D2R inhibitor raclopride blocked the increase of both GDNF and Zif268 expression following potassium-evoked dopamine release in SH-SY5Y cells. We used adenoviral delivery of small hairpin RNA (shRNA) targeting Zif268 to down-regulate its expression and found that Zif268 is specifically required for the D2R-mediated up-regulation of GDNF. Furthermore, the D2R-mediated induction of GDNF and Zif268 expression was dependent on Gbetagamma-mediated signaling and  activation of extracellular signal-regulated kinase ½. Importantly, using chromatin immunoprecipitation assay, we identified a direct association of Zif268 with the GDNF promoter. These results suggest that D2R activation induces a Gbetagamma- and extracellular signal-regulated kinase ½-dependent increase in the level of Zif268, which functions to directly up-regulate the expression of GDNF.




TÍTULO / TITLE:  - Bevacizumab plus irinotecan in recurrent or progressive malign glioma: a multicenter study of the Anatolian Society of Medical Oncology (ASMO).

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

REVISTA / JOURNAL:  - J Cancer Res Clin Oncol. 2013 Feb 12.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s00432-013-1390-8

AUTORES / AUTHORS:  - Demirci U; Tufan G; Aktas B; Balakan O; Alacacioglu A; Dane F; Engin H; Kaplan MA; Gunaydin Y; Ozdemir NY; Tugba Unek I; Karaca H; Akman T; Sonmez OU; Coskun U; Harputluoglu H; Sevinc A; Tonyali O; Buyukberber S; Benekli M

INSTITUCIÓN / INSTITUTION:  - Department of Medical Oncology, Ataturk Training and Research Hospital, Bilkent,  Ankara, 0906800, Turkey, drumutdemirci@gmail.com.

RESUMEN / SUMMARY:  - PURPOSES: The overall prognosis for recurrent malignant glioma (MG) is extremely  poor, and treatment options are limited. We evaluated our multicenter retrospective experience for patients with recurrent MG administering bevacizumab and irinotecan in combination therapy. METHODS: A total of 115 patients with grade IV glial tumor (n = 93) and grade III glial tumor (n = 22) were retrospectively evaluated at 14 centers in Turkey. Primary objectives of the study were to evaluate the efficacy and toxicity of the bevacizumab and irinotecan as salvage treatment based on response to therapy, progression-free survival (PFS), 6 months of PFS, overall survival (OS), and 6 months of OS (OS6). RESULTS: Bevacizumab and irinotecan were performed as second line (79.1 %) and third line treatment (20.9 %). Median chemotherapy cycle was 6 (range 1-37), and  median follow-up was 6 months (range 1-36 months). Objective response rate was 39.1 %. Six-month PFS and OS6 were 46.3 % and 67.5 %, respectively. Median PFS was 6 months (95 % CI 2.5-9.5) and 6 months (95 % CI 4.9-7.1) in the grade III and IV groups, respectively (p = 0.773). Median OS was 9 months (95 % CI 7.1-10.9) and 8 months (95 % CI 6.6-9.4) in the grade III and IV groups, respectively (p = 0.450). Serious toxicities were observed in 7.8 % of patients.  Treatment-related toxic death was observed in 3 patients. There was no treatment  related to central nervous system hemorrhage or other serious hemorrhages. CONCLUSIONS: Present study results were consistent with previous studies. In addition, we detected similar outcomes in grade III and IV glial tumors.




TÍTULO / TITLE:  - Inhibition of BET Bromodomain Targets Genetically Diverse Glioblastoma.

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

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Apr 1;19(7):1748-59. doi: 10.1158/1078-0432.CCR-12-3066. Epub 2013 Feb 12.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-3066

AUTORES / AUTHORS:  - Cheng Z; Gong Y; Ma Y; Lu K; Lu X; Pierce LA; Thompson RC; Muller S; Knapp S; Wang J

INSTITUCIÓN / INSTITUTION:  - Authors’ Affiliations: Departments of Neurological Surgery and Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee; Departments of Oncology and Geriatrics, the Second Affiliated Hospital, Department of Oncology,  the First Affiliated Hospital, Nanjing Medical University, Nanjing, China; and Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Oxford, United Kingdom.

RESUMEN / SUMMARY:  - PURPOSE: Glioblastoma is refractory to conventional therapies. The bromodomain and extraterminal domain (BET) proteins are epigenetic readers that selectively bind to acetylated lysine residues on histone tails. These proteins recently emerged as important therapeutic targets in NUT midline carcinoma and several types of hematopoietic cancers. In this study, the therapeutic potential of a novel BET bromodomain inhibitor, JQ1, was assessed in a panel of genetically heterogeneous glioblastoma samples. EXPERIMENTAL DESIGN: The antineoplastic effects of JQ1 were shown using ex vivo cultures derived from primary glioblastoma xenograft lines and surgical specimens of different genetic background. The in vivo efficacy was assessed in orthotopic glioblastoma tumors.  RESULTS: We showed that JQ1 induced marked G1 cell-cycle arrest and apoptosis, which was phenocopied by knockdown of individual BET family members. JQ1 treatment resulted in significant changes in expression of genes that play important roles in glioblastoma such as c-Myc, p21(CIP1/WAF1), hTERT, Bcl-2, and  Bcl-xL. Unlike the observations in some hematopoietic cancer cell lines, exogenous c-Myc did not significantly protect glioblastoma cells against JQ1. In  contrast, ectopically expressed Bcl-xL partially rescued cells from JQ1-induced apoptosis, and knockdown of p21(CIP1/WAF1) attenuated JQ1-induced cell-cycle arrest. Cells genetically engineered for Akt hyperactivation or p53/Rb inactivation did not compromise JQ1 efficacy, suggesting that these frequently mutated signaling pathways may not confer resistance to JQ1. Furthermore, JQ1 significantly repressed growth of orthotopic glioblastoma tumors. CONCLUSION: Our results suggest potentially broad therapeutic use of BET bromodomain inhibitors for treating genetically diverse glioblastoma tumors. Clin Cancer Res; 19(7); 1748-59. ©2013 AACR.




TÍTULO / TITLE:  - Integrin control of the transforming growth factor-beta pathway in glioblastoma.

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

REVISTA / JOURNAL:  - Brain. 2013 Feb;136(Pt 2):564-76. doi: 10.1093/brain/aws351. Epub 2013 Jan 31.

            ●● Enlace al texto completo (gratuito o de pago) 1093/brain/aws351

AUTORES / AUTHORS:  - Roth P; Silginer M; Goodman SL; Hasenbach K; Thies S; Maurer G; Schraml P; Tabatabai G; Moch H; Tritschler I; Weller M

INSTITUCIÓN / INSTITUTION:  - Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, 8091 Zurich, Switzerland. patrick.roth@usz.ch

RESUMEN / SUMMARY:  - Transforming growth factor-beta is a central mediator of the malignant phenotype  of glioblastoma, the most common and malignant form of intrinsic brain tumours. Transforming growth factor-beta promotes invasiveness and angiogenesis, maintains cancer cell stemness and induces profound immunosuppression in the host. Integrins regulate cellular adhesion and transmit signals important for cell survival, proliferation, differentiation and motility, and may be involved in the activation of transforming growth factor-beta. We report that alphavbeta3, alphavbeta5 and alphavbeta8 integrins are broadly expressed not only in glioblastoma blood vessels but also in tumour cells. Exposure to alphav, beta3 or beta5 neutralizing antibodies, RNA interference-mediated integrin gene silencing  or pharmacological integrin inhibition using the cyclic RGD peptide EMD 121974 (cilengitide) results in reduced phosphorylation of Smad2 in most glioma cell lines, including glioma-initiating cell lines and reduced transforming growth factor-beta-mediated reporter gene activity, coinciding with reduced transforming growth factor-beta protein levels in the supernatant. Time course experiments indicated that the loss of transforming growth factor-beta bioactivity due to integrin inhibition likely results from two distinct mechanisms: an early effect  on activation of preformed inactive protein, and second, major effect on transforming growth factor-beta gene transcription as confirmed by decreased activity of the transforming growth factor-beta gene promoter and decreased transforming growth factor-beta(1) and transforming growth factor-beta(2) messenger RNA expression levels. In vivo, EMD 121974 (cilengitide), which is currently in late clinical development as an antiangiogenic agent in newly diagnosed glioblastoma, was a weak antagonist of pSmad2 phosphorylation. These results validate integrin inhibition as a promising strategy not only to inhibit  angiogenesis, but also to block transforming growth factor-beta-controlled features of malignancy including invasiveness, stemness and immunosuppression in  human glioblastoma.




TÍTULO / TITLE:  - MiR-134 regulates the proliferation and invasion of glioblastoma cells by reducing Nanog expression.

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

REVISTA / JOURNAL:  - Int J Oncol. 2013 Mar 4. doi: 10.3892/ijo.2013.1844.

            ●● Enlace al texto completo (gratuito o de pago) 3892/ijo.2013.1844

AUTORES / AUTHORS:  - Niu CS; Yang Y; Cheng CD

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei, Anhui 230001, P.R. China.

RESUMEN / SUMMARY:  - MiR-134 is a brain-enriched miRNA that plays an essential role in the development of the embryonic stem cell-orientated differentiation to central nervous system by suppression of Nanog and neural development (including neurons, cylindraxile and dendrites) and has been shown to be downregulated in oligodendrogliomas (ODG) and glioblastomas (GBM), suggesting its possible involvement in brain tumor progression. In this study, we defined the expression and function of miR-134, which we found to be downregulated in glioma samples and the glioblastoma cell line U87 by SYBR green real-time quantitative reverse transcription-PCR (real-time PCR). Early reports have characterized Nanog as a direct target of miR-134 by a dual-luciferase reporter assay in 293T cells. In our study, overexpression of miR-134 in U87 glioblastoma cells resulted in significant downregulation of Nanog mRNA levels as well as protein levels. miR-134 overexpression reduced the proliferation, invasiveness and migration capability of U87 cells while promoted apoptosis of these cells in vitro and suppressed the  growth of tumor xenografts in vivo. These findings demonstrated that miR-134 deregulation is common in human gliomas. Restoration of its function inhibits cell proliferation, invasion and migration capability and promotes apoptosis, which could be partly due to its inhibitory effect on Nanog protein expression in glioblastoma cells. MiR-134 could play an important role as a tumor suppressor relying on its direct translational attenuation of Nanog.




TÍTULO / TITLE:  - A comprehensive analysis of 41 patients with rosette-forming glioneuronal tumors  of the fourth ventricle.

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

REVISTA / JOURNAL:  - J Clin Neurosci. 2013 Mar;20(3):335-41. doi: 10.1016/j.jocn.2012.09.003. Epub 2013 Jan 30.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.jocn.2012.09.003

AUTORES / AUTHORS:  - Zhang J; Babu R; McLendon RE; Friedman AH; Adamson C

INSTITUCIÓN / INSTITUTION:  - Division of Neurosurgery, Department of Surgery, Duke University Medical Center,  DUMC 2624, Durham, NC 27710, USA.

RESUMEN / SUMMARY:  - The rosette-forming glioneuronal tumor (RGNT) of the fourth ventricle is a recently described, rare, and distinct tumor of the glioneuronal family. The presentation, natural history, and treatment response of these tumors has been unclear as there are no significant series of a sizeable population with long-term follow-up. We report a comprehensive analysis of 41 patients with RGNT  to provide the most current understanding of this rare tumor. Treatment of these  patients has consisted of resection via the transvermian and telovelar approaches, with one patient requiring radiotherapy due to tumor recurrence. Various unique imaging characteristics may allow for the preoperative identification of these tumors. Resection via the telovelar approach should be considered for symptomatic tumors and those that pose a risk of obstructive hydrocephalus. Due to their benign nature and low propensity for recurrence, subtotal resection may be appropriate for those that are adherent to the brainstem. Radiotherapy may be considered for patients with tumor recurrence.




TÍTULO / TITLE:  - Poly(amido amine) is an ideal carrier of miR-7 for enhancing gene silencing effects on the EGFR pathway in U251 glioma cells.

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

REVISTA / JOURNAL:  - Oncol Rep. 2013 Apr;29(4):1387-94. doi: 10.3892/or.2013.2283. Epub 2013 Feb 11.

            ●● Enlace al texto completo (gratuito o de pago) 3892/or.2013.2283

AUTORES / AUTHORS:  - Liu X; Li G; Su Z; Jiang Z; Chen L; Wang J; Yu S; Liu Z

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, The Fifth Central Hospital of Tianjin, Tianjin, PR China.

RESUMEN / SUMMARY:  - microRNAs are regarded as promising drugs for glioma gene therapy. However, conventional administration routes, such as oral administration and intravenous infusion, present low efficiency due to the blood-brain barrier and intercellular retention, thereby limiting their application. Recent studies showed poly(amido amine) (PAMAM) was a candidate carrier due to its high solubilization, delayed release and low toxicity. In the present study, U251 human brain glioma cells were transfected with the miR-7 gene using PAMAM as the vector to determine the transfection efficiency and therapeutic effects in vivo and in vitro. We found that PAMAM exhibited higher transfection efficiency and longer duration of action compared with liposome delivery, and miR-7 efficiently silenced some genes involved in the epidermal growth factor receptor (EGFR) pathway and achieved favorable effects in treating glioma in vivo and in vitro. These investigations provide a basis for developing high-efficiency micromolecular drug delivery.




TÍTULO / TITLE:  - Anti-PD-1 Blockade and Stereotactic Radiation Produce Long-Term Survival in Mice  With Intracranial Gliomas.

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

REVISTA / JOURNAL:  - Int J Radiat Oncol Biol Phys. 2013 Feb 22. pii: S0360-3016(13)00004-7. doi: 10.1016/j.ijrobp.2012.12.025.

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

AUTORES / AUTHORS:  - Zeng J; See AP; Phallen J; Jackson CM; Belcaid Z; Ruzevick J; Durham N; Meyer C; Harris TJ; Albesiano E; Pradilla G; Ford E; Wong J; Hammers HJ; Mathios D; Tyler B; Brem H; Tran PT; Pardoll D; Drake CG; Lim M

INSTITUCIÓN / INSTITUTION:  - Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins  Medical Institutes, Baltimore, Maryland.

RESUMEN / SUMMARY:  - PURPOSE: Glioblastoma multiforme (GBM) is the most common primary brain tumor in  adults, and radiation is one of the main treatment modalities. However, cure rates remain low despite best available therapies. Immunotherapy is a promising modality that could work synergistically with radiation, which has been shown to  increase antigen presentation and promote a proinflammatory tumor microenvironment. Programmed-death-1 (PD-1) is a surface receptor expressed on activated and exhausted T cells, which mediate T cell inhibition upon binding with its ligand PD-L1, expressed on many tumor types including human GBMs. We tested the combination of anti-PD-1 immunotherapy with stereotactic radiosurgery  in a mouse orthotopic GBM model. METHODS AND MATERIALS: We performed intracranial implantation of mouse glioma cell line GL261 transfected with luciferase into C57BL/6 mice. Mice were stratified into 4 treatment groups: (1) control; (2) radiation only; (3) anti-PD-1 antibody only; and (4) radiation plus anti-PD-1 antibody. Overall survival was quantified. The mice were killed on day 21 after implantation to assess immunologic parameters in the brain/tumor, cervical lymph  nodes, and spleen. RESULTS: Improved survival was demonstrated with combination anti-PD-1 therapy plus radiation compared with either modality alone: median survival was 25 days in the control arm, 27 days in the anti-PD-1 antibody arm, 28 days in the radiation arm, and 53 days in the radiation plus anti-PD-1 therapy arm (P<.05 by log-rank Mantle-Cox). Long-term survival was seen only in the combined treatment arm, with a fraction (15%-40%) of animals alive at day 180+ after treatment. Immunologic data on day 21 after implantation showed increased tumor infiltration by cytotoxic T cells (CD8+/interferon-gamma+/tumor necrosis factor-alpha+) and decreased regulatory T cells (CD4+/FOXP3) in the combined treatment group compared with the single modality arms. CONCLUSIONS: The combination of PD-1 blockade and localized radiation therapy results in long-term survival in mice with orthotopic brain tumors. These studies provide strong preclinical evidence to support combination trials in patients with GBM.




TÍTULO / TITLE:  - Detection of remote neuronal reactions in the Thalamus and Hippocampus induced by rat glioma using the PET tracer cis-4-[(18)F]fluoro-D-proline.

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

REVISTA / JOURNAL:  - J Cereb Blood Flow Metab. 2013 Feb 6. doi: 10.1038/jcbfm.2013.8.

            ●● Enlace al texto completo (gratuito o de pago) 1038/jcbfm.2013.8

AUTORES / AUTHORS:  - Geisler S; Willuweit A; Schroeter M; Zilles K; Hamacher K; Galldiks N; Shah NJ; Coenen HH; Langen KJ

INSTITUCIÓN / INSTITUTION:  - Institute of Neuroscience and Medicine, INM-4-Medical Imaging Physics, Research Centre Julich, Julich, Germany.

RESUMEN / SUMMARY:  - After cerebral ischemia or trauma, secondary neurodegeneration may occur in brain regions remote from the lesion. Little is known about the capacity of cerebral gliomas to induce secondary neurodegeneration. A previous study showed that cis-4-[(18)F]fluoro-D-proline (D-cis-[(18)F]FPro) detects secondary reactions of  thalamic nuclei after cortical infarction with high sensitivity. Here we investigated the potential of D-cis-[(18)F]FPro to detect neuronal reactions in remote brain areas in the F98 rat glioma model using ex vivo autoradiography. Although the tumor tissue of F98 gliomas showed no significant D-cis-[(18)F]FPro  uptake, we observed prominent tracer uptake in 7 of 10 animals in the nuclei of the ipsilateral thalamus, which varied with the specific connectivity with the cortical areas affected by the tumor. In addition, strong D-cis-[(18)F]FPro accumulation was noted in the hippocampal area CA1 in two animals with ipsilateral F98 gliomas involving hippocampal subarea CA3 rostral to that area. Furthermore, focal D-cis-[(18)F]FPro uptake was present in the necrotic center of the tumors. Cis-4-[(18)F]fluoro-D-proline uptake was accompanied by microglial activation in the thalamus, in the hippocampus, and in the necrotic center of the tumors. The data suggest that brain tumors induce secondary neuronal reactions in remote brain areas, which may be detected by positron emission tomography (PET) using D-cis-[(18)F]FPro.Journal of Cerebral Blood Flow & Metabolism advance online publication, 6 February 2013; doi:10.1038/jcbfm.2013.8.




TÍTULO / TITLE:  - Postoperative ischemic changes following resection of newly diagnosed and recurrent gliomas and their clinical relevance.

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

REVISTA / JOURNAL:  - J Neurosurg. 2013 Apr;118(4):801-8. doi: 10.3171/2012.12.JNS12125. Epub 2013 Feb  1.

            ●● Enlace al texto completo (gratuito o de pago) 3171/2012.12.JNS12125

AUTORES / AUTHORS:  - Gempt J; Forschler A; Buchmann N; Pape H; Ryang YM; Krieg SM; Zimmer C; Meyer B; Ringel F

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery and.

RESUMEN / SUMMARY:  - Object The aim of surgical treatment of glioma is the complete resection of tumor tissue with preservation of neurological function. Inclusion of diffusion-weighted imaging (DWI) in the postoperative MRI protocol could improve  the delineation of ischemia-associated postoperative neurological deficits. The present study aims to assess the incidence of infarctions following resection of  newly diagnosed gliomas in comparison with recurrent gliomas and the influence on neurological function. Methods Patients who underwent glioma resection for newly  diagnosed or recurrent gliomas had early postoperative MRI, including DWI and apparent diffusion coefficient (ADC) maps. Postoperative areas of restricted diffusion were classified as arterial territorial infarctions, terminal branch infarctions, or venous infarctions. Tumor entity, location, and neurological function were recorded. Results New postoperative ischemic lesions were identified in 26 (31%) of 84 patients with newly diagnosed gliomas and 20 (80%) of 25 patients with recurrent gliomas (p < 0.01). New permanent and transient neurological deficits were more frequent in patients with recurrent gliomas than  in patients with newly diagnosed tumors. Patients with neurological deficits had  a significantly higher rate of ischemic lesions. Conclusions Postoperative infarctions occur frequently in patients with newly diagnosed and recurrent gliomas and do have an impact on postoperative neurological function. In this patient cohort there was a higher risk for ischemic lesions and for deterioration of neurological function after resection of recurrent tumors. Radiogenic and postoperative tissue changes could contribute to the higher risk of an ischemic infarction in patients with recurrent tumors.




TÍTULO / TITLE:  - Folate receptor-mediated drug targeting: a possible strategy for nonfunctioning pituitary adenomas?

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

REVISTA / JOURNAL:  - Endocrinology. 2013 Apr;154(4):1387-9. doi: 10.1210/en.2013-1182.

            ●● Enlace al texto completo (gratuito o de pago) 1210/en.2013-1182

AUTORES / AUTHORS:  - Lee M; Pellegata NS

INSTITUCIÓN / INSTITUTION:  - PhD, Helmholtz Zentrum Munchen-German Research Center, for Environmental Health,  Institute of Pathology, Ingolstadter Landstrasse 1, Neuherberg, D-85764, Germany. natalia.pellegata@helmholtz-muenchen.de.




TÍTULO / TITLE:  - GOLPH3 regulates the migration and invasion of glioma cells though RhoA.

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

REVISTA / JOURNAL:  - Biochem Biophys Res Commun. 2013 Mar 13. pii: S0006-291X(13)00394-X. doi: 10.1016/j.bbrc.2013.03.003.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bbrc.2013.03.003

AUTORES / AUTHORS:  - Zhou X; Zhan W; Bian W; Hua L; Shi Q; Xie S; Yang D; Li Y; Zhang X; Liu G; Yu R

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China; Lab of Neurosurgery, Xuzhou Medical College, Xuzhou, Jiangsu, China; Key Laboratory of Brain Disease Biology, Affiliated Hospital of Xuzhou Medical College, Jiangsu, China. Electronic address: xpzhou@xzmc.edu.cn.

RESUMEN / SUMMARY:  - Golgi phosphoprotein 3 (GOLPH3) has been reported to be involved in the development of several human cancers. However, the biological significance of GOLPH3 in glioma progression remains largely unknown. In this study, we report, for the first time, that downregulation of GOLPH3 led to clear reductions in glioma cell migration and invasion. In addition, downregulation of GOLPH3 inhibited the expression of the small GTPase RhoA as well as cytoskeletal reorganization, which are both required for glioma cell migration. Furthermore, we found that the observed reductions in glioma cell migration and RhoA level could be rescued by RhoA overexpression. Taken together, these results show that  GOLPH3 contributes to the motility of glioma cells by regulating the expression of RhoA.




TÍTULO / TITLE:  - Cell surface Nestin is a biomarker for glioma stem cells.

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

REVISTA / JOURNAL:  - Biochem Biophys Res Commun. 2013 Mar 21. pii: S0006-291X(13)00434-8. doi: 10.1016/j.bbrc.2013.03.021.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.bbrc.2013.03.021

AUTORES / AUTHORS:  - Jin X; Jin X; Jung JE; Beck S; Kim H

INSTITUCIÓN / INSTITUTION:  - School of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Republic of Korea.

RESUMEN / SUMMARY:  - Cancer stem cells (CSCs) are the most aggressive cell type in many malignancies.  Cell surface proteins are generally used to isolate and characterize CSCs. Therefore, the identification of CSC-specific cell surface markers is very important for the diagnosis and treatment of malignancies. We found that Nestin (a type VI intermediate filament protein), like the glioma stem cell (GSC) markers CD133 and CD15, exhibited different levels of expression in primary human glioblastoma specimens. Similar to our previous finding that cytoplasmic Nestin is expressed as a cell surface form in mouse GSCs, the cell surface form of Nestin was also expressed at different levels in human GSCs. We isolated cell surface Nestin-positive cell populations from human GSCs by fluorescence-activated cell sorting FACS analysis, and observed that these populations exhibited robust CSC properties, such as increased tumorsphere-forming ability and tumorsphere size. Mechanistically, we found that  DAPT, a gamma-secretase (a multi-subunit protease complex) inhibitor, reduced the proportion of cell surface Nestin-positive cells in human GSCs in a time- and dose-dependent manner, without significant changes in total Nestin expression, implying that a post-translational modification was involved in the generation of cell surface Nestin. Taken together, our data provides the first evidence that cell surface Nestin may serve as a promising GSC marker for the isolation and characterization of heterogeneous GSCs in glioblastomas.




TÍTULO / TITLE:  - Advanced Intimal Hyperplasia Without Luminal Narrowing of Leptomeningeal Arteries in CADASIL.

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

REVISTA / JOURNAL:  - Stroke. 2013 Mar 12.

            ●● Enlace al texto completo (gratuito o de pago) 1161/STROKEAHA.111.000721

AUTORES / AUTHORS:  - Dong H; Ding H; Young K; Blaivas M; Christensen PJ; Wang MM

INSTITUCIÓN / INSTITUTION:  - From the Departments of Neurology, Pathology, Medicine, and Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI; Departments of Neurology and Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; and Departments of Medicine and Neurology, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI.

RESUMEN / SUMMARY:  - BACKGROUND AND PURPOSE: Leptomeningeal artery abnormalities in Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) have not been extensively characterized. We quantified substructure and diameter of leptomeningeal arteries in CADASIL compared with age-matched controls and the very old; in addition, we characterized intimal thickening in CADASIL using immunohistochemistry. METHODS: Frontal and temporal cortex of 6 genetically proven CADASIL brains (average age, 66 years), 6 controls without symptoms of cerebrovascular disease, and 6 very old brains (average age, 89 years) were examined for leptomeningeal artery intimal, medial, and adventitial thickness; inner diameter; and sclerotic index and for smooth muscle markers. RESULTS: The intima of CADASIL arteries was thickened 5-fold compared with controls and the very aged (P<0.0001). Medial thickness was lower in CADASIL compared with controls and the very old (P<0.01). The adventitia was not significantly increased in CADASIL compared with age-matched controls. Arterial diameters were  not smaller in CADASIL compared with controls. Sclerotic index was significantly  increased in CADASIL compared with other groups (P<0.00001). Intimal cells in CADASIL expressed smooth muscle actin, S100A4, and vimentin but not desmin. CONCLUSIONS: Principle changes of leptomeningeal arteries in CADASIL include intimal thickening and medial thinning, but not luminal narrowing. Smooth muscle-like cells participate in neointimal thickening of CADASIL arteries.




TÍTULO / TITLE:  - Effect of lomeguatrib-temozolomide combination on MGMT promoter methylation and expression in primary glioblastoma tumor cells.

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

REVISTA / JOURNAL:  - Tumour Biol. 2013 Mar 22.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s13277-013-0738-7

AUTORES / AUTHORS:  - Taspinar M; Ilgaz S; Ozdemir M; Ozkan T; Oztuna D; Canpinar H; Rey JA; Sunguroglu A; Castresana JS; Ugur HC

INSTITUCIÓN / INSTITUTION:  - Department of Medical Biology, Ankara University School of Medicine, Ankara, Turkey, mtaspinartr@gmail.com.

RESUMEN / SUMMARY:  - Temozolomide (TMZ) is commonly used in the treatment of glioblastoma (GBM). The MGMT repair enzyme (O 6-methylguanine-DNA methyltransferase) is an important factor causing chemotherapeutic resistance. MGMT prevents the formation of toxic  effects of alkyl adducts by removing them from the DNA. Therefore, MGMT inhibition is an interesting therapeutic approach to circumvent TMZ resistance. The aim of the study was to investigate the effect of the combination of lomeguatrib (an MGMT inactivator) with TMZ, on MGMT expression and methylation. Primary cell cultures were obtained from GBM tumor tissues. The sensitivity of primary GBM cell cultures and GBM cell lines to TMZ, and to the combination of TMZ and lomeguatrib, was determined by a cytotoxicity assay (MTT). MGMT and p53 expression, and MGMT methylation were investigated after drug application. In addition, the proportion of apoptotic cells and DNA fragmentation was analyzed. The combination of TMZ and lomeguatrib in primary GBM cell cultures and glioma cell lines decreased MGMT expression, increased p53 expression, and did not change MGMT methylation. Moreover, apoptosis was induced and DNA fragmentation was increased in cells. In addition, we also showed that lomeguatrib-TMZ combination did not have any effect on the cell cycle. Finally, we determined that the sensitivity of each primary GBM cells and glioma cell lines to the lomeguatrib-TMZ combination was different and significantly associated with the structure of MGMT methylation. Our study suggests that lomeguatrib can be used with TMZ for GBM treatment, although further clinical studies will be needed so as to determine the feasibility of this therapeutic approach.




TÍTULO / TITLE:  - Adenovirus-mediated expression of BmK CT suppresses growth and invasion of rat C6 glioma cells.

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

REVISTA / JOURNAL:  - Biotechnol Lett. 2013 Feb 27.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s10529-013-1167-9

AUTORES / AUTHORS:  - Du J; Fu Y; Wang J; Liang A

INSTITUCIÓN / INSTITUTION:  - Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Institute of Biotechnology, Shanxi University, Taiyuan, 030006, People’s Republic of China.

RESUMEN / SUMMARY:  - BmK CT, one of the key toxins in the venom of the scorpion, Buthus martensii Karsch, can interact specifically with glioma cells as a chloride channel blocker and inhibit the invasion and migration of those cells via MMP-2. A recombinant adenovirus, Ad-BmK CT, was constructed and characterized by in vitro and in vivo  studies, using MTT cytotoxicity assay and the glioma C6/RFP (red fluorescence protein)/BALB/c allogeneic athymic nude mice model, respectively. The adenovirus-mediated expression of BmK CT displayed a high activity in suppressing rat C6 glioma cells growth and invasion thereby suggesting that this recombinant  adenovirus may be a powerful method for treating glioblastoma.




TÍTULO / TITLE:  - Dental diagnostic X-ray exposure and risk of benign and malignant brain tumors.

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

REVISTA / JOURNAL:  - Ann Oncol. 2013 Feb 13.

            ●● Enlace al texto completo (gratuito o de pago) 1093/annonc/mdt016

AUTORES / AUTHORS:  - Lin MC; Lee CF; Lin CL; Wu YC; Wang HE; Chen CL; Sung FC; Kao CH

INSTITUCIÓN / INSTITUTION:  - Department of Nuclear Medicine, E-DA Hospital, I-Shou University, Kaohsiung.

RESUMEN / SUMMARY:  - BackgroundThis study evaluates the risk of benign brain tumors (BBTs) and malignant brain tumors (MBTs) associated with dental diagnostic X-ray, using a large population-based case-control study.Materials and methodsWe identified 4123 BBT cases and 16 492 controls without BBT (study 1) and 197 MBT cases and 788 controls without MBT (study 2) from Taiwan National Health Insurance claim data.  The risks of both types of tumor were estimated in association with the frequency of received dental diagnostic X-ray.ResultsThe mean ages were approximately 44.2  years in study 1 and 40.6 years in study 2. Multivariable unconditional logistic  regression analysis showed that the risk of BBT increases as the frequency of received dental diagnostic X-ray increases. The BBT odds ratio increased from 1.33 [95% confidence interval (CI) 1.22-1.44] for those with annual mean X-ray examination of less than one to 1.65 (95% CI 1.37-1.98) for those with three or more X-ray examinations, after controlling for comorbidities. No significant association was found between MBTs and dental diagnostic X-ray exposure.ConclusionsExposure to dental diagnostic X-rays in oral and maxillofacial care increases the risk of BBTs, but not MBTs.




TÍTULO / TITLE:  - Histological Predictors of Outcome in Ependymoma are Dependent on Anatomic Site Within the Central Nervous System.

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

REVISTA / JOURNAL:  - Brain Pathol. 2013 Mar 4. doi: 10.1111/bpa.12050.

            ●● Enlace al texto completo (gratuito o de pago) 1111/bpa.12050

AUTORES / AUTHORS:  - Raghunathan A; Wani K; Armstrong TS; Vera-Bolanos E; Fouladi M; Gilbertson R; Gajjar A; Goldman S; Lehman NL; Metellus P; Mikkelsen T; Necesito-Reyes MJ; Omuro A; Packer RJ; Partap S; Pollack IF; Prados MD; Robins HI; Soffietti R; Wu J; Miller CR; Gilbert MR; Aldape KD

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

RESUMEN / SUMMARY:  - Ependymomas originate in posterior fossa (PF), supratentorial (ST) or spinal cord (SC) compartments. At present, grading schemes are applied independent of anatomic site. We performed detailed histological examination on 238 World Health Organization grade II and III ependymomas. Among PF ependymomas, the presence of  hypercellular areas, necrosis, microvascular proliferation and elevated mitotic rate (all P < 0.01) were significantly associated with worse progression-free survival (PFS), while extensive ependymal canal formation was not (P = 0.89). Similar to the PF tumors, microvascular proliferation (P = 0.01) and elevated mitotic rate (P = 0.03) were significantly associated with worse PFS in the ST tumors. However, in contrast to PF tumors, extensive ependymal canals (P = 0.03)  were associated with worse clinical outcome in ST ependymomas, but hypercellularity (P = 0.57) and necrosis (P = 0.47) were not. On multivariate Cox regression, after adjusting for relevant clinical variables, individual histological factors and a composite histological score remained significant among ST and PF ependymoma. In contrast to both PF and ST ependymoma, histological features were not found to be associated with PFS in SC tumors. Taken together, the clinical relevance of specific histological features in ependymoma appears to be related to the anatomic site of origin and suggests that site-specific grading criteria be considered in future classification systems.




TÍTULO / TITLE:  - Inhibition of PI3K/AKT/mTOR pathway enhances temozolomide-induced cytotoxicity in pituitary adenoma cell lines in vitro and xenografted pituitary adenoma in female nude mice.

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

REVISTA / JOURNAL:  - Endocrinology. 2013 Mar;154(3):1247-59. doi: 10.1210/en.2012-1908. Epub 2013 Feb  5.

            ●● Enlace al texto completo (gratuito o de pago) 1210/en.2012-1908

AUTORES / AUTHORS:  - Dai C; Zhang B; Liu X; Ma S; Yang Y; Yao Y; Feng M; Bao X; Li G; Wang J; Guo K; Ma W; Xing B; Lian W; Xiao J; Cai F; Zhang H; Wang R

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, Peking Union Medical College Hospital, Beijing 100730, China.

RESUMEN / SUMMARY:  - Invasive pituitary adenomas (PAs) are often refractory to standard therapy and salvage treatment with temozolomide (TMZ). Hyperactivation of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway contributes to chemotherapy resistance in many cancers. XL765, a novel dual-PI3K/mTOR inhibitor, has recently shown its efficacy as a monotherapy and in combination with conventional therapeutics in many cancers. The hyperactive PI3K/AKT/mTOR pathway frequently occurs in invasive PAs. In this study, we investigated whether XL765 sensitizes PA cells to TMZ in vitro and in vivo. Experiments were carried out to evaluate the effect of XL765 and TMZ alone or in  combination on cell proliferation and apoptosis of PA cell lines (alphaT3-1, GH3, and MMQ) in vitro as well as the tumor growth and serum GH and prolactin secretions in a GH3 xenograft tumor model of female nude mice. XL765 and TMZ synergistically inhibited the growth of PA cell lines and induced apoptosis. Combination of XL765 and TMZ synergistically inhibited tumor growth, decreased serum GH and prolactin levels, and reduced the sacrifice rate of GH3 xenograft tumor models without increased systemic side effects. In addition, XL765 in combination with TMZ dramatically decreased phosphorylation of AKT and mTOR as well as the expression of Bcl-2. The increased expression of cleaved poly (ADP-ribose) polymerase and Bcl-2-associated X protein along with elevated caspase-3/7 activity were also observed in the combination group. Therefore, dual inhibitors of PI3K and mTOR may enhance alkylating agent-mediated cytotoxicity and provide a novel regimen in the treatment of invasive PAs.




TÍTULO / TITLE:  - Cellular Plasticity Confers Migratory and Invasive Advantages to a Population of  Glioblastoma-initiating Cells that Infiltrate Peritumoral Tissue.

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

REVISTA / JOURNAL:  - Stem Cells. 2013 Feb 8. doi: 10.1002/stem.1349.

            ●● Enlace al texto completo (gratuito o de pago) 1002/stem.1349

AUTORES / AUTHORS:  - Ruiz-Ontanon P; Orgaz JL; Aldaz B; Elosegui-Artola A; Martino J; Berciano MT; Montero JA; Grande L; Nogueira L; Diaz-Moralli S; Esparis-Ogando A; Vazquez-Barquero A; Lafarga M; Pandiella A; Cascante M; Segura V; Martinez-Climent JA; Sanz-Moreno V; Fernandez-Luna JL

INSTITUCIÓN / INSTITUTION:  - Molecular Genetics Unit, Hospital Universitario Marques de Valdecilla and Instituto de Formacion e Investigacion Marques de Valdecilla (IFIMAV), Av. Cardenal Herrera Oria s/n, 39011 Santander, España.

RESUMEN / SUMMARY:  - Glioblastoma (GBM) is associated with infiltration of peritumoral parenchyma by isolated tumor cells that leads to tumor regrowth. Recently, GBM stem-like or initiating cells (GICs) have been identified in the peritumoral (PT) area, but whether these GICs have enhanced migratory and invasive capabilities compared with GICs from the tumor mass ™ is presently unknown. We isolated GICs from the infiltrated PT tissue and the TM of three patients and found that PT cells have an advantage over TM cells in 2D and 3D migration and invasion assays. Interestingly, PT cells display a high plasticity in protrusion formation and cell shape and their migration is insensitive to substrate stiffness, which represent advantages to infiltrate microenvironments of different rigidity. Furthermore, mouse and chicken embryo xenografts revealed that only PT cells showed a dispersed distribution pattern, closely associated to blood vessels. Consistent with cellular plasticity, simultaneous Rac and RhoA activation is required for the enhanced invasive capacity of PT cells. Moreover, Rho GTPase signaling modulators alphaVbeta3 and p27 play key roles in GIC invasiveness. Of note, p27 is upregulated in TM cells and inhibits RhoA activity. Gene silencing of p27 increased the invasive capacity of TM GICs. Additionally, beta3 integrin is upregulated in PT cells. Blockade of dimeric integrin alphaVbeta3, a Rac activator, reduced the invasive capacity of PT GICs in vitro and abrogated the spreading of PT cells into chicken embryos. Thus, our results describe the invasive features acquired by a unique subpopulation of GICs that infiltrate neighbouring tissue.




TÍTULO / TITLE:  - Mass spectrometric peptide analysis of 2DE-separated mouse spinal cord and rat hippocampus proteins suggests an NGxG motif of importance for in-vivo deamidation.

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

REVISTA / JOURNAL:  - Electrophoresis. 2013 Mar 20. doi: 10.1002/elps.201200682.

            ●● Enlace al texto completo (gratuito o de pago) 1002/elps.201200682

AUTORES / AUTHORS:  - Mikkat S; Kischstein T; Kreutzer M; Glocker MO

INSTITUCIÓN / INSTITUTION:  - Core Facility Proteome Analysis, University Medicine Rostock, Rostock, Germany; Proteome Center Rostock, University Medicine Rostock, Rostock, Germany.

RESUMEN / SUMMARY:  - Asparagine deamidation is a common nonenzymatic posttranslational modification comprising the conversion of asparaginyl residues to aspartyl and isoaspartyl residues, respectively. As a result an additional negative charge is introduced that can affect the tertiary structure as well as the biological activity of a protein. Since deamidation reduces the protein’s pI value, differentially deamidated forms of a protein can be separated in 2D gels. We have analyzed a dataset of 430 protein spots from 2D gels that contained mouse spinal cord proteins and estimated that roughly 10% of the spots in a Coomassie-stained gel derive from in-vivo deamidation at particular asparaginyl residues. Several of the deamidated protein forms, e.g. tropomodulin-2, V-type proton ATPase subunit B, and protein disulfide-isomerase A3 were also found in 2D gels of proteins extracted from rat hippocampus. All identified deamidation sites contained a glycine residue on the carboxyl side of the asparaginyl residue. Strikingly, a second glycine residue at the +3 position was found in the majority of the deamidated peptides. We propose that the NGxG motif confers exceptional susceptibility to in-vivo asparagine deamidation.




TÍTULO / TITLE:  - NK1 receptor antagonists and dexamethasone as anticancer agents in vitro and in a model of brain tumours secondary to breast cancer.

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

REVISTA / JOURNAL:  - Anticancer Drugs. 2013 Apr;24(4):344-54. doi: 10.1097/CAD.0b013e32835ef440.

            ●● Enlace al texto completo (gratuito o de pago) 1097/CAD.0b013e32835ef440

AUTORES / AUTHORS:  - Lewis KM; Harford-Wright E; Vink R; Ghabriel MN

INSTITUCIÓN / INSTITUTION:  - Adelaide Centre for Neuroscience Research, School of Medical Sciences, The University of Adelaide, Adelaide, South Australia, Australia.

RESUMEN / SUMMARY:  - Emend, an NK1 antagonist, and dexamethasone are used to treat complications associated with metastatic brain tumours and their treatment. It has been suggested that these agents exert anticancer effects apart from their current use. The effects of the NK1 antagonists, Emend and N-acetyl-L-tryptophan, and dexamethasone on tumour growth were investigated in vitro and in vivo at clinically relevant doses. For animal experiments, a stereotaxic injection model  of Walker 256 rat breast carcinoma cells into the striatum of Wistar rats was used. Emend treatment led to a decrease in tumour cell viability in vitro, although this effect was not replicated by N-acetyl-L-tryptophan. Dexamethasone did not decrease tumour cell viability in vitro but decreased tumour volume in vivo, likely to be through a reduction in tumour oedema, as indicated by the increase in tumour cell density. None of the agents investigated altered tumour cell replication or apoptosis in vivo. Inoculated animals showed increased glial  fibrillary acidic protein and ionized calcium-binding adapter molecule 1 immunoreactivity indicative of astrocytes and microglia in the peritumoral area,  whereas treatment with Emend and dexamethasone reduced the labelling for both glial cells. These results do not support the hypothesis that NK1 antagonists or  dexamethasone exert a cytotoxic action on tumour cells, although these conclusions may be specific to this model and cell line.




TÍTULO / TITLE:  - Teaching NeuroImages: Pseudo-abnormal DaTscan findings in meningioma-induced parkinsonism.

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

REVISTA / JOURNAL:  - Neurology. 2013 Mar 26;80(13):e147. doi: 10.1212/WNL.0b013e318289709d.

            ●● Enlace al texto completo (gratuito o de pago) 1212/WNL.0b013e318289709d

AUTORES / AUTHORS:  - Erro R; Pappata S; Picillo M; Rocco M; Santangelo G; Barone P; Vitale C

INSTITUCIÓN / INSTITUTION:  - From the University of Naples (R.E., M.P., M.R.), Federico II, Naples; Institute  of Biostructure and Bioimaging (S.P.), CNR, Naples; Istituto di Diagnosi e Cura Hermitage Capodimonte (G.S., P.B., C.V.), Naples; Department of Psychology (G.S.), Second University of Naples, Caserta; University of Salerno (P.B.), Center for Neurodegenerative Diseases, Salerno; and University Parthenope (C.V.), Naples, Italy.

RESUMEN / SUMMARY:  - A 71-year-old man presented with a 6-month history of rest tremor and slowness in his left hand. Apart from mild left parkinsonism, neurologic examination was unremarkable. Because response to l-dopa, up to 600 mg/d, was lacking, [(123)I]FP-CIT ((123)I-N-omega-fluoropropyl-2beta-carbomethoxy-3beta-[4-iodophenyl]nortropane) SPECT was prescribed with unexpected results: transverse and coronal slices showed the right striatum to be moved upward and medially, suggesting a structural compression rather than degenerative damage (figure). Brain MRI revealed the presence of a frontal meningioma. Caution is required when interpreting DaTscan findings,(1,2) and morphologic imaging should always be performed first.




TÍTULO / TITLE:  - Exosomes from marrow stromal cells expressing miR-146b inhibit glioma growth.

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

REVISTA / JOURNAL:  - Cancer Lett. 2013 Feb 16. pii: S0304-3835(13)00131-6. doi: 10.1016/j.canlet.2013.02.019.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.canlet.2013.02.019

AUTORES / AUTHORS:  - Katakowski M; Buller B; Zheng X; Lu Y; Rogers T; Osobamiro O; Shu W; Jiang F; Chopp M

INSTITUCIÓN / INSTITUTION:  - Department of Neurology, Henry Ford Hospital, Detroit, MI, USA.

RESUMEN / SUMMARY:  - Exosomes are 30-150nm vesicles secreted by a wide range of mammalian cells that can contain microRNA (miRNA). To test if marrow stromal cell (MSC) exosomes could be used as a vehicle for delivery of anti-tumor miRNAs, we transfected MSCs with  a miR-146b expression plasmid, and harvested exosomes released by the MSCs. Intra-tumor injection of exosomes derived from miR-146-expressing MSCs significantly reduced glioma xenograft growth in a rat model of primary brain tumor.




TÍTULO / TITLE:  - mTORC1 Inhibitors Suppress Meningioma Growth in Mouse Models.

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

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Mar 1;19(5):1180-9. doi: 10.1158/1078-0432.CCR-12-1904. Epub 2013 Feb 13.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-1904

AUTORES / AUTHORS:  - Pachow D; Andrae N; Kliese N; Angenstein F; Stork O; Wilisch-Neumann A; Kirches E; Mawrin C

INSTITUCIÓN / INSTITUTION:  - Authors’ Affiliations: Departments of Neuropathology and Genetics & Molecular Neurobiology, Institute of Biology, Otto-von-Guericke University; and Laboratory  for Non-Invasive Imaging, Leibniz Institute for Neurobiology, Magdeburg, Germany.

RESUMEN / SUMMARY:  - PURPOSE: To evaluate the mTORC1 (mammalian target of rapamycin complex 1) pathway in meningiomas and to explore mTORC1 as a therapeutic target in meningioma cell lines and mouse models. EXPERIMENTAL DESIGN: Tissue microarrays (53 meningiomas of all WHO grades) were stained for phosphorylated polypeptides of mTOR, Akt, and the mTORC1 targets 4EBP1 and p70S6K, the latter being the consensus marker for mTORC1 activity. Expression of proteins and mRNAs was assessed by Western blotting and real-time PCR in 25 tumors. Cell lines Ben-Men-1 (benign), IOMM-Lee  and KT21 (malignant), and pairs of merlin-positive or -negative meningioma cells  were used to assess sensitivity toward mTORC1 inhibitors in methyl-tetrazolium and bromodeoxyuridine (BrdUrd) assays. The effect of temsirolimus (20 mg/kg daily) on tumor weight or MRI-estimated tumor volume was tested by treatment of eight nude mice (vs. 7 controls) carrying subcutaneous IOMM-Lee xenografts, or of eight (5) mice xenotransplanted intracranially with IOMM-Lee (KT21) cells in comparison to eight (5) untreated controls. RESULTS: All components of the mTORC1 pathway were expressed and activated in meningiomas, independent of their WHO grade. A significant dosage-dependent growth inhibition by temsirolimus and everolimus was observed in all cell lines. It was slightly diminished by merlin loss. In the orthotopic and subcutaneous xenograft models, temsirolimus treatment resulted in about 70% growth reduction of tumors (P < 0.01), which was paralleled by reduction of Ki67 mitotic index (P < 0.05) and reduction of mTORC1 activity (p70S6K phosphorylation) within the tumors. CONCLUSION: mTORC1 inhibitors suppress meningioma growth in mouse models, although the present study did not measure survival. Clin Cancer Res; 19(5); 1180-9. ©2012 AACR.




TÍTULO / TITLE:  - Gene expression changes associated with erlotinib response in glioma cell lines.

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

REVISTA / JOURNAL:  - Eur J Cancer. 2013 Jan 29. pii: S0959-8049(13)00006-3. doi: 10.1016/j.ejca.2013.01.002.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ejca.2013.01.002

AUTORES / AUTHORS:  - Garcia-Claver A; Lorente M; Mur P; Campos-Martin Y; Mollejo M; Velasco G; Melendez B

INSTITUCIÓN / INSTITUTION:  - Molecular Pathology Research Unit, Virgen de la Salud Hospital, Toledo, España.

RESUMEN / SUMMARY:  - Erlotinib (ERL), a tyrosine kinase inhibitor that acts on the epidermal growth factor receptor (EGFR), is used as a second line treatment for glioma therapy, with controversial findings regarding its response. Here, we analysed the gene expression profiles of a series of human glioma cell lines with differing sensitivities to ERL to identify the gene expression changes associated with ERL  response. The varying responses to ERL were associated with different expression  levels of specific genes (HRAS, CTFG, ERCC5 and HDAC3) and genes associated with  specific pathways (apoptosis and cell death). PI3K pathway genes were primarily affected by ERL, as we found that PIK3R3 was repressed by ERL treatment in sensitive glioma cell lines. The cell cycle and ubiquitin pathways were also affected by EGFR inhibition, as GAS5, PLK1 and BIRC5 were the most significantly  affected genes. In this study we have identified several genes such as PIK3R3 and GAS5, that can be targeted in order to enhance the response to ERL therapy.




TÍTULO / TITLE:  - Pituitary tumor-transforming gene 1 as a proliferation marker lacking prognostic  value in cutaneous squamous cell carcinoma.

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

REVISTA / JOURNAL:  - Exp Dermatol. 2013 Feb 15. doi: 10.1111/exd.12118.

            ●● Enlace al texto completo (gratuito o de pago) 1111/exd.12118

AUTORES / AUTHORS:  - Ishitsuka Y; Kawachi Y; Taguchi S; Maruyama H; Nakamura Y; Fujisawa Y; Furuta JI; Nakamura Y; Ishii Y; Otsuka F

INSTITUCIÓN / INSTITUTION:  - Department of Dermatology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.

RESUMEN / SUMMARY:  - Non-melanoma skin cancer is the most frequently occurring type of cancer worldwide and is caused by epidermal carcinogenesis and malignant progression that involve dysregulated expression of proto-oncogenes and tumor suppressor genes. The proto-oncogene pituitary tumor-transforming gene 1 (PTTG1) is a ubiquitously expressed transcription factor that can promote enhanced proliferation of cultured epidermal keratinocytes. To investigate the potential roles of PTTG1 in epidermal carcinogenesis and malignant progression, the expression of PTTG1 was analysed by immunohistochemistry along with Ki67, keratin 10 (K10) and p53 in tissue samples of cutaneous squamous cell carcinomas (SCC), actinic keratoses (AK) and Bowen’s disease (BD). Expression levels of PTTG1 were  compared among these disease groups to test for correlations with proliferation,  differentiation capacity or the existence of mutated tumor suppressor genes in each disease group. In each disease group, the expression levels of PTTG1 correlated positively with those of Ki67, although the differentiation status, measured by K10 expression, did not show any correlation. In contrast, the existence of mutated p53 proteins showed a positive correlation only in the SCC group. Moreover, the expression levels of PTTG1 in SCC did not correlate with known prognostic factors such as TNM staging or tumor thickness. These results suggest that PTTG1 may represent a proliferation marker associated with mutated p53 proteins but is not an informative predictor of poor clinical outcomes in SCC.




TÍTULO / TITLE:  - Mechanisms of intracerebral lymphoma growth delineated in a syngeneic mouse model of central nervous system lymphoma.

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

REVISTA / JOURNAL:  - J Neuropathol Exp Neurol. 2013 Apr;72(4):325-36. doi: 10.1097/NEN.0b013e31828b7a98.

            ●● Enlace al texto completo (gratuito o de pago) 1097/NEN.0b013e31828b7a98

AUTORES / AUTHORS:  - Montesinos-Rongen M; Sanchez-Ruiz M; Brunn A; Hong K; Bens S; Perales SR; Cigudosa JC; Siebert R; Deckert M

INSTITUCIÓN / INSTITUTION:  - From the Institute for Neuropathology, University Hospital of Cologne, Cologne (MM-R, MS-R, AB, KH, MD); and Institute for Human Genetics, Christian-Albrechts-University Kiel (SB, RS); and University Hospital Schleswig Holstein, Campus Kiel, Kiel (SB, RS), Germany; and Molecular Cytogenetics Group,  Centro Nacional de Investigaciones Oncologicas, Madrid, España (SRP, JCC).

RESUMEN / SUMMARY:  - Primary lymphoma of the central nervous system (PCNSL) is defined as lymphoma of  the diffuse large B-cell type confined to the CNS. To understand the effects of the CNS microenvironment on the malignant B cells and their interactions with the cells of the target organ, we analyzed a syngeneic mouse model. Transplantation of BAL17 cells into the frontal white matter of syngeneic BALB/c mice induced lymphomas with major clinical and neuropathologic features that parallel those of human PCNSL, including an angiocentric growth pattern in the brain parenchyma and tropism for the inner and outer ventricular system. Seven cycles of repeated isolation of lymphoma cells from the CNS and their intracerebral reimplantation induced genotypic and phenotypic alterations in resulting BAL17VII cells; the affected genes regulate apoptosis and are of the JAK/STAT pathway. Because lymphoma growth of BAL17VII cells was significantly accelerated, that is, shortening the time to death of the mice, these data indicate that prolonged stay of the lymphoma cells in the CNS was associated with worse outcome. These findings suggest that the CNS microenvironment fosters aggressiveness of lymphoma cells, thereby accelerating the lethal course of PCNSL.




TÍTULO / TITLE:  - Pleomorphic xanthoastrocytoma: Long-term results of surgical treatment and analysis of prognostic factors.

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

REVISTA / JOURNAL:  - Br J Neurosurg. 2013 Mar 20.

            ●● Enlace al texto completo (gratuito o de pago) 3109/02688697.2013.776666

AUTORES / AUTHORS:  - Gallo P; Cecchi PC; Locatelli F; Rizzo P; Ghimenton C; Gerosa M; Pinna G

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, University Hospital , Verona , Italy.

RESUMEN / SUMMARY:  - Background. Pleomorphic Xanthoastrocytoma (PXA) is a rare brain tumour, most commonly affecting children and young adults. To date, only few data regarding the long-term follow-up of these patients after surgery are available. The aim of this study is to describe our single-institution experience in the surgical management of this particular glioma over a period of over 18 years. Methods. We  performed a retrospective review of all cases of PXA (40 patients) operated upon  at the Department of Neurosurgery of Verona, Italy, between 1990 and 2008. The impact of clinical, radiological, surgical and histological factors on overall survival (OS) and progression-free survival (PFS) was analysed by means of univariate and multivariate models. Findings. We achieved a gross total resection (GTR) in 65% of patients. Histological diagnosis was of grade II in 80%; anaplastic features were present in the remaining 20%. Adjuvant treatment, radiotherapy or chemo-radiotherapy, was administered in 40% of the cases. Median  follow-up was 74 months. OS at 5- and 10 years was 76.32% and 68.24%, respectively. PFS at 5- and 10 years was 71% and 58%, respectively. In the multivariate model, histological grade, extent of resection and age at diagnosis  (</= 30 years vs > 30 years) were the only independent prognostic factors for both OS and PFS. Conclusions. Our retrospective long-term study confirms the relatively favourable prognosis associated with PXA. Young patients with a low-grade tumour (WHO grade II) who underwent GTR carry the longest OS and PFS.




TÍTULO / TITLE:  - Histone 3 Lysine 9 Trimethylation Is Differentially Associated With Isocitrate Dehydrogenase Mutations in Oligodendrogliomas and High-Grade Astrocytomas.

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

REVISTA / JOURNAL:  - J Neuropathol Exp Neurol. 2013 Apr;72(4):298-306.

            ●● Enlace al texto completo (gratuito o de pago) 1097/NEN.0b013e3182898113

AUTORES / AUTHORS:  - Venneti S; Felicella MM; Coyne T; Phillips JJ; Gorovets D; Huse JT; Kofler J; Lu C; Tihan T; Sullivan LM; Santi M; Judkins AR; Perry A; Thompson CB

INSTITUCIÓN / INSTITUTION:  - From the Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York (SV, DG, JTH, CL, CBT); Department of Pathology, University of California, San Francisco, California (MMF, JJP, TT, AP); Departments of Pathology and Laboratory Medicine (TC), and Cancer Biology (CL), University of Pennsylvania, Philadelphia, Pennsylvania; Department of Pathology,  University of Pittsburgh, Pittsburgh, Pennsylvania (JK); Department of Pathology, Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania (LMS, MS); Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern  California, Los Angeles, California (ARJ).

RESUMEN / SUMMARY:  - Trimethylation of histone 3 lysine 9 (H3K9me3) is a marker of repressed transcription. Cells transfected with mutant isocitrate dehydrogenase (IDH) show  increased methylation of histone lysine residues, including H3K9me3, because of inhibition of histone demethylases by 2-hydroxyglutarate. Here, we evaluated H3K9me3 and its association with IDH mutations in 284 gliomas. Trimethylation of  H3K9 was significantly associated with IDH mutations in oligodendrogliomas. Moreover, 72% of World Health Organization grade II and 65% of grade III oligodendrogliomas showed combined H3K9me3 positivity and 1p19q codeletion. In astrocytic tumors, H3K9me3 positivity was found in all grades of tumors; it showed a significant relationship with IDH mutational status in grade II astrocytomas but not in grade III astrocytomas or glioblastomas. Finally, H3K9me3-positive grade II oligodendrogliomas, but not other tumor subtypes, showed improved overall survival compared with H3K9me3-negative cases. These results suggest that repressive trimethylation of H3K9 in gliomas may occur in a  context-dependent manner and is associated with IDH mutations in oligodendrogliomas but may be differently regulated in high-grade astrocytic tumors. Furthermore, H3K9me3 may define a subset of grade II oligodendrogliomas with better overall survival. Our results suggest variable roles for IDH mutations in the pathogenesis of oligodendrogliomas versus astrocytic tumors.




TÍTULO / TITLE:  - Human cytomegalovirus infection levels in glioblastoma multiforme are of prognostic value for survival.

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

REVISTA / JOURNAL:  - J Clin Virol. 2013 May;57(1):36-42. doi: 10.1016/j.jcv.2012.12.018. Epub 2013 Feb 4.

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

AUTORES / AUTHORS:  - Rahbar A; Orrego A; Peredo I; Dzabic M; Wolmer-Solberg N; Straat K; Stragliotto G; Soderberg-Naucler C

INSTITUCIÓN / INSTITUTION:  - Department of Medicine Solna, Experimental Cardiovascular Research Unit, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden.

RESUMEN / SUMMARY:  - BACKGROUND: Patients with glioblastoma multiforme (GBM) generally live 12-15 months after diagnosis, despite maximal surgical resection, adjuvant radiotherapy, and chemotherapy. HCMV has been detected in 90-100% of GBMs. We recently found that low grade HCMV infection in GBM tumours was highly associated with survival over 18 months (case-control study). Here, we sought to determine whether low-grade HCMV infection in GBMs is associated with prolonged survival in a consecutive patient cohort, analysed retrospectively. STUDY DESIGN: Tumour samples from 75 consecutive GBM patients treated surgically at Karolinska University Hospital in 2004-2005 were examined by immunohistochemistry (IHC) and  in situ hybridization for HCMV proteins and DNA, respectively. Tumours were graded 1-4, depending on the percentage of positive cells by IHC. Low-grade HCMV  was defined as grade 1 (<25% of HCMV infected tumour cells). Time to tumour progression (TTP) and survival data were analysed with Cox regression and Kaplan-Meier models. RESULTS: HCMV infection was detected in 74 of 75 tumours (99%). In patients with low-grade HCMV infection, median survival was 20 months longer than in patients with high-grade infections (P=0.036, HR: 2.2), and TTP was 8 months longer (P=0.1, HR: 1.8). Two-year survival was much higher in patients with low-grade HCMV infection (63.6% vs. 17.2%, P=0.003). CONCLUSION: The longer survival in patients whose tumours had low-grade HCMV infection suggests that the level of HCMV infection in GBMs has a prognostic value and that HCMV may contribute to the pathogenesis of GBM.




TÍTULO / TITLE:  - Interstitial brachytherapy with iodine-125 seeds for low grade brain stem gliomas in adults: Diagnostic and therapeutic intervention in a one-step procedure.

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

REVISTA / JOURNAL:  - Clin Neurol Neurosurg. 2013 Feb 25. pii: S0303-8467(13)00039-5. doi: 10.1016/j.clineuro.2013.01.012.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.clineuro.2013.01.012

AUTORES / AUTHORS:  - Lopez WO; Trippel M; Doostkam S; Reithmeier T

INSTITUCIÓN / INSTITUTION:  - Division of Stereotactic Neurosurgery, Department of General Neurosurgery, University Medical Center Freiburg, Freiburg, Germany. Electronic address: william.contreras@uniklinik-freiburg.de.

RESUMEN / SUMMARY:  - PURPOSE: To report on iodine-125 (I125) interstitial irradiation in the treatment of low grade brain stem gliomas in adults. PATIENTS AND METHODS: Ten patients with well-circumscribed lesions of the brainstem and histological confirmation of low grade glioma treated with stereotactically implanted I-125 seed in our department between 1995 and 2012 were retrospectively analyzed. RESULTS: In 9 patients the lesion was treated with one I-125 seed and in one patient, 2 spatial separated lesions were implanted, therefore a total of 11 I-125 seeds were implanted. The mean volume of the 11 lesions was 2.76ml (range: 0.5-7.2ml), mean  activity of the seeds was 6.23mCi (range: 1.5-11.1mCi), mean duration of irradiation was 28.5 days (range: 21-41 days) and mean effective dose rate was 9.16cGy/h (range: 6.2-12cGy/h). The 30 days perioperative morbidity and mortality rate was 0%. Median follow up was 72.5 month (range 5-168 months). Six of ten patients were free of progression until last follow up. CONCLUSION: In our experience at the University Clinic in Freiburg Germany, interstitial radiosurgery based on MRI is a safe and effective method to diagnose and treat low grade gliomas of the brain stem. Furthermore randomized studies are needed to confirm the therapeutic impact of this method in comparison to external beam radiation of brain stem gliomas.




TÍTULO / TITLE:  - Combined temozolomide and sunitinib treatment leads to better tumour control but  increased vascular resistance in O-methylguanine methyltransferase-methylated gliomas.

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

REVISTA / JOURNAL:  - Eur J Cancer. 2013 Mar 14. pii: S0959-8049(13)00149-4. doi: 10.1016/j.ejca.2013.02.019.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ejca.2013.02.019

AUTORES / AUTHORS:  - Czabanka M; Bruenner J; Parmaksiz G; Broggini T; Topalovic M; Bayerl SH; Auf G; Kremenetskaia I; Nieminen M; Jabouille A; Mueller S; Harms U; Harms C; Koch A; Heppner FL; Vajkoczy P

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, Universitatsmedizin Charite, Berlin, Germany.

RESUMEN / SUMMARY:  - INTRODUCTION: Combined antiangiogenic and cytotoxic treatment represents an appealing treatment approach for malignant glioma. In this study we characterised the antitumoural and microvascular consequences of sunitinib (Su) and temozolomide (TMZ) therapy and verified the ideal treatment protocol, with special focus on a potential therapeutic window for combined scheduling. MATERIALS AND METHODS: O6-Methylguanine methyltransferase (MGMT) status was analysed by pyrosequencing. Tumour growth of subcutaneous xenografts was assessed under different treatment protocols (TMZ, SU, SU followed by TMZ, TMZ followed by SU, combined TMZ/SU). Intravital microscopy (dorsal skinfold chamber model) assessed microvascular consequences. Immunohistochemistry included tumour and endothelial cell proliferation, apoptosis and vascular pericyte coverage. Real-time polymerase chain reaction (RT-PCR) analysed the expression of angiogenesis-related pathways in response to therapy. RESULTS: Combined TMZ/SU resulted in significantly reduced tumour growth compared to either monotreatment  (TMZ: 106+/-13mm3; SU: 114+/-53mm3; TMZ/SU: 34+/-7mm3) by additional antiangiogenic effects and synergistic induction of apoptosis versus TMZ monotreatment. Sequential treatment protocols did not show additive antitumour responses. TMZ/SU aggravated vascular resistance mechanisms characterised by significantly higher blood flow rate (TMZ: 74+/-34mul/s; SU: 164+/-36mul/s; TMZ/SU: 254+/-95mul/s), reduced permeability (TMZ: 1.05+/-0.02; SU: 0.99+/-0.07;  TMZ/SU: 0.89+/-0.05) and recovery of pericyte-endothelial interactions (TMZ: 89+/-7%; SU: 67+/-9%, TMZ/SU:80+/-10%) versus either monotreatment. Vascular resistance was paralleled by an increase in Ang-1 and Tie-2 and by the downregulation of Dll4. CONCLUSION: Sequential application of TMZ and SU in the angiogenic window does not add antitumour efficacy to monotherapy. Simultaneous application yields beneficial tumour control due to additive antiangiogenic and proapoptotic effects. Combined treatment may aggravate pericyte-mediated vascular resistance mechanisms by altering Ang-1-Tie-2 and Dll4/Notch pathways.




TÍTULO / TITLE:  - Bcl-2 proapoptotic proteins distribution in U-87 MG glioma cells before and after hypericin photodynamic action.

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

REVISTA / JOURNAL:  - Gen Physiol Biophys. 2013 Mar 11.

            ●● Enlace al texto completo (gratuito o de pago) 4149/gpb_2013021

AUTORES / AUTHORS:  - Balogova L; Maslanakova M; Dzurova L; Miskovsky P; Stroffekova K

INSTITUCIÓN / INSTITUTION:  - Department of Biophysic, Institute of Physical Sciences, P. J. Safarik University, Kosice, Slovak Republic.

RESUMEN / SUMMARY:  - Apoptosis is a key process in the development and maintenance of tissue homeostasis. This process of controlled cell death is tightly regulated by a balance between cell survival and damage signals. We focused our attention towards one apoptotic pathway, the intrinsic mitochondrial one where Bcl-2 family of proteins plays the major role. We are particularly interested in two pro-apoptotic players Bak and Bax from this family. Here we investigated their role in apoptosis triggered by photodynamic action. Targeted photodynamic therapy (PDT) is a promising approach to diagnose and treat different types of cancer. We show the localization of Bax and Bak in U-87 MG human glioma cells incubated with photosensitizer hypericin (Hyp) before and after photodynamic action. Apoptotic stimulus by Hyp photodynamic action causes Bax translocation into mitochondria. However our results suggest that under these conditions there are two populations of mitochondria: one which contains Bax and Bak simultaneously, and is almost exclusively localized near the plasma membrane; the other which contains Bax only and is distributed throughout the cell. The different protein content and spatial distribution of these two populations suggest that they can play different roles  in response to apoptotic stimuli.




TÍTULO / TITLE:  - Retrospective analysis of treatment outcome of pediatric ependymomas in Korea: analysis of Korean multi-institutional data.

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

REVISTA / JOURNAL:  - J Neurooncol. 2013 Mar 6.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11060-013-1087-5

AUTORES / AUTHORS:  - Kim YJ; Kim JY; Lim DH; Park HJ; Joo J; Sung KW; Shin HJ; Kim SK; Phi JH; Kim IH; Park KD; Ahn SD; Jung J; Rha YS; Kim DS; Suh CO

INSTITUCIÓN / INSTITUTION:  - Research Institute and Hospital, National Cancer Center, Goyang, South Korea.

RESUMEN / SUMMARY:  - We analyzed the treatment outcomes of intracranial ependymomas in Korean children aged <18 years. Data for 96 patients were collected from five hospitals. Survival rates were calculated using the Kaplan-Meier method. Log-rank tests for univariate analyses and Cox regression model for multivariate analysis were conducted to identify prognostic factors for survival. The median age of the patients was 4 years (range, 0.3-17.9 years). The median follow-up was 55 months  (range, 2-343 months). Age <3 years was an important factor for selecting adjuvant therapy after surgery. Among children aged <3 and >/=3 years, adjuvant radiotherapy (RT) was applied to 55 and 84 %, respectively, and adjuvant chemotherapy to 52 and 10 %, respectively. The 5 year local progression-free survival (LPFS), disease-free survival (DFS), and overall survival (OS) rates were 54, 52, and 79 %, respectively. Gross total resection was the most significant prognostic factor for all survival endpoints. Age >/=3 years and RT were significant prognostic factors for superior LPFS and DFS. However, the significance of age was lost in multivariate analysis for DFS. LPFS, DFS, and OS  were superior in patients who started RT within 44 days after surgery (the median time) than in patients who started RT later in the patients aged >/=3 years. Postoperative RT was a strong prognostic factor for intracranial ependymomas. Our results suggest that early use of RT is an essential component of treatment, and  should be considered in young children.




TÍTULO / TITLE:  - Evaluation of Histone 3 Lysine 27 Trimethylation (H3K27me3) and Enhancer of Zest  2 (EZH2) in Pediatric Glial and Glioneuronal Tumors Shows Decreased H3K27me3 in H3F3A K27M Mutant Glioblastomas.

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

REVISTA / JOURNAL:  - Brain Pathol. 2013 Feb 18. doi: 10.1111/bpa.12042.

            ●● Enlace al texto completo (gratuito o de pago) 1111/bpa.12042

AUTORES / AUTHORS:  - Venneti S; Garimella MT; Sullivan LM; Martinez D; Huse JT; Heguy A; Santi M; Thompson CB; Judkins AR

INSTITUCIÓN / INSTITUTION:  - Cancer biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New  York, NY.

RESUMEN / SUMMARY:  - H3F3A mutations are seen in approximately 30% of pediatric glioblastoma (GBMs) and involve either the lysine residue at position 27 (K27M) or glycine at position 34 (G34R/V). Sixteen genes encode histone H3, each variant differing in  only a few amino acids. Therefore, how mutations in a single H3 gene contribute to carcinogenesis is unknown. H3F3A K27M mutations are predicted to alter methylation of H3K27. H3K27me3 is a repressive mark critical to stem cell maintenance and is mediated by EZH2, a member of the polycomb-group (PcG) family. We evaluated H3K27me3 and EZH2 expression using immunohistochemistry in 76 pediatric brain tumors. H3K27me3 was lowered/absent in tumor cells but preserved  in endothelial cells and infiltrating lymphocytes in six out of 20 GBMs. H3K27me3 showed strong immunoreactivity in all other tumor subtypes. Sequencing of GBMs showed H3F3A K27M mutations in all six cases with lowered/absent H3K27me3. EZH2 expression was high in GBMs, but absent/focal in other tumors. However, no significant differences in EZH2 expression were observed between H3F3A K27M mutant and wild type GBMs, suggesting that EZH2 mediated trimethylation of H3K27  is inhibited in GBM harboring K27M mutations. Our results indicate that H3F3A K27M mutant GBMs show decreased H3K27me3 that may be of both diagnostic and biological relevance.




TÍTULO / TITLE:  - Bereaved Parents’ Intentions and Suggestions about Research Autopsies in Children with Lethal Brain Tumors.

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

REVISTA / JOURNAL:  - J Pediatr. 2013 Feb 19. pii: S0022-3476(13)00039-5. doi: 10.1016/j.jpeds.2013.01.015.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.jpeds.2013.01.015

AUTORES / AUTHORS:  - Baker JN; Windham JA; Hinds PS; Gattuso JS; Mandrell B; Gajjar P; West NK; Hammarback T; Broniscer A

INSTITUCIÓN / INSTITUTION:  - Division of Quality of Life and Palliative Care, Departments of Pediatric Medicine and Oncology, St. Jude Children’s Research Hospital, Memphis, TN. Electronic address: justin.baker@stjude.org.

RESUMEN / SUMMARY:  - OBJECTIVE: To determine bereaved parents’ perceptions about participating in autopsy-related research and to elucidate their suggestions about how to improve  the process. STUDY DESIGN: A prospective multicenter study was conducted to collect tumor tissue by autopsy of children with diffuse intrinsic pontine glioma. In the study, parents completed a questionnaire after their child’s death to describe the purpose for, hopes (ie, desired outcomes of), and regrets about their participation in autopsy-related research. Parents also suggested ways to improve autopsy-related discussions. A semantic content analytic method was used  to analyze responses and identify themes within and across parent responses. RESULTS: Responses from 33 parents indicated that the main reasons for participating in this study were to advance medical knowledge or find a cure, a desire to help others, and choosing as their child would want. Parents hoped that participation would help others or help find a cure as well as provide closure. Providing education/anticipatory guidance and having a trusted professional sensitively broach the topic of autopsy were suggestions to improve autopsy discussions. All parents felt that study participation was the right decision, and none regretted it; 91% agreed that they would make the choice again. CONCLUSION: Because autopsy can help advance scientific understanding of the disease itself and because parents reported having no regret and even cited benefits, researchers should be encouraged to continue autopsy-related research.  Parental perceptions about such studies should be evaluated in other types of pediatric diseases.




TÍTULO / TITLE:  - Modern surgical outcomes following surgery for sphenoid wing meningiomas.

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

REVISTA / JOURNAL:  - J Neurosurg. 2013 Feb 22.

            ●● Enlace al texto completo (gratuito o de pago) 3171/2012.12.JNS11539

AUTORES / AUTHORS:  - Sughrue ME; Rutkowski MJ; Chen CJ; Shangari G; Kane AJ; Parsa AT; Berger MS; McDermott MW

INSTITUCIÓN / INSTITUTION:  - Brain Tumor Research Center, Department of Neurological Surgery, University of California, San Francisco, California.

RESUMEN / SUMMARY:  - Object Cushing and Eisenhardt were the first to describe sphenoid wing meningiomas in detail, categorizing globoid tumors into 3 groups: 1) medial; 2) middle; and 3) lateral. The authors review their experience with resection of sphenoid wing meningiomas at a single center, to examine whether this classification predicts clinical presentation and postsurgical outcome. Methods All patients undergoing resection of sphenoid wing meningioma at the authors’ institution over a 9-year period were identified. Clinical data were compared from patients with tumors arising at different points along the sphenoid wing to  determine if these tumors behaved differently in terms of symptoms, radiographic  characteristics, and postsurgical outcome. Results A total of 56 patients underwent microsurgical resection for sphenoid wing meningioma during this period. The rates of optic canal invasion (medial 50% vs middle 5% vs lateral 0%; p < 0.0001, chi-square test), supraclinoid internal carotid artery encasement (medial 32% vs middle 5% vs lateral 0%; p < 0.01, chi-square test), and middle cerebral artery encasement (medial 45% vs middle 24% vs lateral 0%; p < 0.01, chi-square test) were all highest with medial-third tumors. New or worsened neurological deficits occurred in 10 (19%) of 56 patients. Of all the imaging characteristics studied, only location of the tumor along the medial third of the sphenoid wing significantly predicted an increased rate of new or worsened neurological deficit (OR 2.7, p < 0.05). Conclusions The authors report outcomes  in a large series of sphenoid wing meningiomas that were treated using modern surgical techniques.




TÍTULO / TITLE:  - HER2-positive breast cancer metastatic to intracranial meningioma: a case report.

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

REVISTA / JOURNAL:  - J Clin Pathol. 2013 Feb 22.

            ●● Enlace al texto completo (gratuito o de pago) 1136/jclinpath-2013-201455

AUTORES / AUTHORS:  - McCormack M; Salinas-La Rosa C; Murphy M; Fox SB

INSTITUCIÓN / INSTITUTION:  - Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.




TÍTULO / TITLE:  - Ultrasound-sensitive siRNA-loaded nanobubbles formed by hetero-assembly of polymeric micelles and liposomes and their therapeutic effect in gliomas.

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

REVISTA / JOURNAL:  - Biomaterials. 2013 Jun;34(18):4532-43. doi: 10.1016/j.biomaterials.2013.02.067. Epub 2013 Mar 19.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.biomaterials.2013.02.067

AUTORES / AUTHORS:  - Yin T; Wang P; Li J; Zheng R; Zheng B; Cheng D; Li R; Lai J; Shuai X

INSTITUCIÓN / INSTITUTION:  - Department of Medical Ultrasonic, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China; PCFM Lab of Ministry of Education, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, China.

RESUMEN / SUMMARY:  - Ultrasound (US)-sensitive nanobubble (NB) which may utilize the physical power of US exposure to improve delivery efficiency to target cells is emerging as one of  the most promising nanocarriers for drug delivery. On the basis of successfully fabricating NBs with the ability of passively accumulating in tumor tissue, in this study we synthesized a US-sensitive NB bearing siRNA (siRNA-NB) for tumor therapy via a hetero-assembling strategy using the siRNA-complexed polymeric micelles and gas-cored liposomes. The US exposure-aided siRNA transfection effectively enhanced the gene silencing effect of siRNA-NBs both in vitro and in  vivo, which resulted in much elevated level of cancer cell apoptosis. Consequently, significantly improved therapeutic effect was achieved in a nude mouse glioma model, using siRNA-NBs bearing siRNA to target the anti-apoptosis gene sirtuin 2 (SIRT2). These results show that, with the aid of US exposure, the US-sensitive siRNA-NB may be an ideal delivery vector to mediate highly effective RNA interference for tumor treatment.




TÍTULO / TITLE:  - Resolution of Mass Effect and Compression Symptoms following Endoluminal Flow Diversion for the Treatment of Intracranial Aneurysms.

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

REVISTA / JOURNAL:  - AJNR Am J Neuroradiol. 2013 Mar 14.

            ●● Enlace al texto completo (gratuito o de pago) 3174/ajnr.A3547

AUTORES / AUTHORS:  - Szikora I; Marosfoi M; Salomvary B; Berentei Z; Gubucz I

INSTITUCIÓN / INSTITUTION:  - Departments of Neurointerventions and Neuroophthalmology, National Institute of Clinical Neurosciences, Budapest, Hungary.

RESUMEN / SUMMARY:  - BACKGROUND AND PURPOSE:Alleviation of aneurysm induced mass effect has been difficult with both conventional endovascular and surgical techniques. Our aim was to study the efficacy of endovascular flow modification on aneurysm-induced mass effect and compression syndrome, as demonstrated by cross-sectional imaging  studies and clinical follow-up.MATERIALS AND METHODS:Thirty aneurysms larger than 10 mm were treated by flow diversion alone and previously had undergone pre- and  posttreatment cross-sectional imaging. Pretreatment MR imaging or contrast CT, follow-up angiography at 6 months, and follow-up MR imaging studies between 6 and 18 months were retrospectively analyzed. The neurologic and neuro-ophthalmologic  statuses of all patients were recorded before treatment and at the time of follow-up cross-sectional imaging.RESULTS:At 6 months, 28 aneurysms were completely occluded, 1 had a neck remnant, and 1 had residual filling on angiography. Between 6 and 18 months, 3 aneurysms decreased in size and 27 completely collapsed as demonstrated on MR imaging. Before treatment, 6 patients  had vision loss, 10 had double vision due to a third or sixth nerve palsy or both, and 1 had hemiparesis due to brain stem compression. On MR imaging follow-up, vision loss had either improved or resolved in all except 1 patient, double vision had resolved completely (7/10) or partially (3/10), and the patient with brain stem compression became asymptomatic. There was no bleeding observed in this series. One parent artery thrombosis resulted in a major infarct.CONCLUSIONS:Endovascular flow diversion is a highly effective technique for resolving radiologic mass effect and clinical compression syndromes.




TÍTULO / TITLE:  - Snail depletes the tumorigenic potential of glioblastoma.

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

REVISTA / JOURNAL:  - Oncogene. 2013 Mar 25. doi: 10.1038/onc.2013.67.

            ●● Enlace al texto completo (gratuito o de pago) 1038/onc.2013.67

AUTORES / AUTHORS:  - Savary K; Caglayan D; Caja L; Tzavlaki K; Bin Nayeem S; Bergstrom T; Jiang Y; Uhrbom L; Forsberg-Nilsson K; Westermark B; Heldin CH; Ferletta M; Moustakas A

INSTITUCIÓN / INSTITUTION:  - Ludwig Institute for Cancer Research, Science for Life Laboratory, Biomedical Center, Uppsala University, Uppsala, Sweden.

RESUMEN / SUMMARY:  - Glioblastoma multiforme (GBM) is an aggressive brain malignancy characterized by  high heterogeneity and invasiveness. It is increasingly accepted that the refractory feature of GBM to current therapies stems from the existence of few tumorigenic cells that sustain tumor growth and spreading, the so-called glioma-initiating cells (GICs). Previous studies showed that cytokines of the bone morphogenetic protein (BMP) family induce differentiation of the GICs, and thus act as tumor suppressors. Molecular pathways that explain this behavior of BMP cytokines remain largely elusive. Here, we show that BMP signaling induces Smad-dependent expression of the transcriptional regulator Snail in a rapid and sustained manner. Consistent with its already established promigratory function in other cell types, we report that Snail silencing decreases GBM cell migration. Consequently, overexpression of Snail increases GBM invasiveness in a mouse xenograft model. Surprisingly, we found that Snail depletes the GBM capacity to form gliomaspheres in vitro and to grow tumors in vivo, both of which are important features shared by GICs. Thus Snail, acting downstream of BMP signaling, dissociates the invasive capacity of GBM cells from their tumorigenic  potential.Oncogene advance online publication, 25 March 2013; doi:10.1038/onc.2013.67.




TÍTULO / TITLE:  - Hepatocyte Growth Factor Sensitizes Brain Tumors to c-MET Kinase Inhibition.

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

REVISTA / JOURNAL:  - Clin Cancer Res. 2013 Mar 15;19(6):1433-44. doi: 10.1158/1078-0432.CCR-12-2832. Epub 2013 Feb 5.

            ●● Enlace al texto completo (gratuito o de pago) 1158/1078-0432.CCR-12-2832

AUTORES / AUTHORS:  - Zhang Y; Farenholtz KE; Yang Y; Guessous F; Dipierro CG; Calvert VS; Deng J; Schiff D; Xin W; Lee JK; Purow B; Christensen J; Petricoin E; Abounader R

INSTITUCIÓN / INSTITUTION:  - Authors’ Affiliations: Departments of Microbiology, Immunology and Cancer Biology, Neurology, and Pathology, and Cancer Center, University of Virginia, Charlottesville; Public Health Sciences; George Mason University, Fairfax; and Pfizer Global Research and Development, Richmond, Virginia.

RESUMEN / SUMMARY:  - PURPOSE: The receptor tyrosine kinase (RTK) c-MET and its ligand hepatocyte growth factor (HGF) are deregulated and promote malignancy in cancer and brain tumors. Consequently, clinically applicable c-MET inhibitors have been developed. The purpose of this study was to investigate the not-well-known molecular determinants that predict responsiveness to c-MET inhibitors and to explore new strategies for improving inhibitor efficacy in brain tumors. EXPERIMENTAL DESIGN: We investigated the molecular factors and pathway activation signatures that determine sensitivity to c-MET inhibitors in a panel of glioblastoma and medulloblastoma cells, glioblastoma stem cells, and established cell line-derived xenografts using functional assays, reverse protein microarrays, and in vivo tumor volume measurements, but validation with animal survival analyses remains to be done. We also explored new approaches for improving the efficacy of the inhibitors in vitro and in vivo. RESULTS: We found that HGF coexpression is a key predictor of response to c-MET inhibition among the examined factors and identified an ERK/JAK/p53 pathway activation signature that differentiates c-MET  inhibition in responsive and nonresponsive cells. Surprisingly, we also found that short pretreatment of cells and tumors with exogenous HGF moderately but statistically significantly enhanced the antitumor effects of c-MET inhibition. We observed a similar ligand-induced sensitization effect to an EGF receptor small-molecule kinase inhibitor. CONCLUSIONS: These findings allow the identification of a subset of patients that will be responsive to c-MET inhibition and propose ligand pretreatment as a potential new strategy for improving the anticancer efficacy of RTK inhibitors. Clin Cancer Res; 19(6); 1433-44. ©2013 AACR.




TÍTULO / TITLE:  - Depressive-like behaviour induced by an intracerebroventricular injection of streptozotocin in mice: the protective effect of fluoxetine, antitumour necrosis  factor-alpha and thalidomide therapies.

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

REVISTA / JOURNAL:  - Behav Pharmacol. 2013 Apr;24(2):79-86. doi: 10.1097/FBP.0b013e32835efc2f.

            ●● Enlace al texto completo (gratuito o de pago) 1097/FBP.0b013e32835efc2f

AUTORES / AUTHORS:  - Souza LC; Filho CB; Fabbro LD; de Gomes MG; Goes AT; Jesse CR

INSTITUCIÓN / INSTITUTION:  - Laboratory of Pharmacological and Toxicological Reviews Applied to Bioactive Molecules - LaftamBio Pampa - Federal University of Pampa, Itaqui, RS, Brazil.

RESUMEN / SUMMARY:  - Information on the effect of an intracerebroventricular (i.c.v.) injection of streptozotocin (STZ) on noncognitive behaviour in rodents such as depression states is scarce. Thus, the aim of this study was to examine the depressive-like  effect of STZ injected by the i.c.v. route in mice and the potential protective effect of fluoxetine, antitumour necrosis factor-alpha (anti-TNF-alpha) and thalidomide. Our results indicated that a single injection of STZ (0.1 mg/site) promoted depressive-like behaviour in the tail suspension and sucrose preference  tests without altering either locomotor activity or plasma glucose levels. We also showed that STZ increased TNF-alpha levels in the hippocampus of mice. Fluoxetine (32 mg/kg, intraperitoneally. 30 min before STZ injection), and the anti-TNF-alpha antibody (0.1 pg/site, i.c.v.) and thalidomide (3 mg/kg, subcutaneously), coadministered with STZ, prevented these effects. This is the first study to report depressive-like effects of STZ using the i.c.v. route in mice. We concluded that fluoxetine, anti-TNF-alpha antibody and thalidomide were  effective in preventing depressive-like behaviour and the increase in TNF-alpha levels in the hippocampus of mice induced by an i.c.v. injection of STZ, reinforcing the involvement of TNF-alpha in the pathophysiology of depression. This model and the mechanisms studied may contribute towards the development of new antidepressant drugs and enhance the options for studying depression.




TÍTULO / TITLE:  - MRI assessment of relapsed glioblastoma during treatment with bevacizumab: Volumetric measurement of enhanced and FLAIR lesions for evaluation of response and progression-A pilot study.

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

REVISTA / JOURNAL:  - Eur J Radiol. 2013 May;82(5):e240-5. doi: 10.1016/j.ejrad.2012.12.018. Epub 2013  Feb 9.

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

AUTORES / AUTHORS:  - Pichler J; Pachinger C; Pelz M; Kleiser R

INSTITUCIÓN / INSTITUTION:  - Wagner Jauregg Weg 15, 4020 Linz, Landesnervenklinik Linz, Austria. Electronic address: josef.pichler@gespag.at.

RESUMEN / SUMMARY:  - PURPOSE: To develop a magnetic resonance imaging (MRI) metric that is useful for  therapy monitoring in patients with relapsed glioblastoma (GBM) during treatment  with the antiangiogenic monoclonal antibody bevacizumab (Bev). We evaluated the feasibility of tumour volume measurement with our software tool in clinical routine and tried to establish reproducible and quantitative parameters for surveillance of patients on treatment with antiangiogenic drugs. MATERIALS AND METHODS: In this retrospective institutional pilot study, 18 patients (11 men, 7  women; mean age 53.5) with recurrent GBM received bevacizumab and irinotecan every two weeks as second line therapy. Follow up scans were assessed every two to four months. Data were collected on a 1.5T MR System (Siemens, Symphony) with  the standard head coil using our standardized tumour protocol. Volumetric measurement was performed with a commercial available software stroketool in FLAIR and T1-c imaging with following procedure: Pre-processing involved cutting  noise and electing a Gaussian of 3x3 to smooth images, selecting a ROI (region of interest) in healthy brain area of the contra lateral side with quantifying the intensity value, adding 20% to this value to define the threshold level. Only values above this threshold are left corresponding to the tumour lesion. For the  volumetric measurement the detected tumour area was circuited in all slices and finally summing up all values and multiplied by slice thickness to get the whole  volume. RESULTS: With McDonalds criteria progression was indicated in 14 out of 18 patients. In contrast, volumetric measurement showed an increase of contrast enhancement of >25%, defined as threshold for progression, in 11 patients (78%) and in 12 patients (85%) in FLAIR volume, respectively. 6 patients revealed that  volumes in MRI increased earlier than the last scan, which was primarily defined  as the date of progression with McDonald criteria, changing PFS after re-evaluation of the tumour volumes from 6.8 to 5.6 months. CONCLUSION: In this pilot study the applied imaging estimates objectively tumour response and progression compared to the bi-dimensional measurement. The quantitative parameters are reproducible and also applicable for the diffuse infiltrating lesions.




TÍTULO / TITLE:  - Tumor blood flow from arterial spin labeling perfusion MRI: A key parameter in distinguishing high-grade gliomas from primary cerebral lymphomas, and in predicting genetic biomarkers in high-grade gliomas.

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

REVISTA / JOURNAL:  - J Magn Reson Imaging. 2013 Feb 6. doi: 10.1002/jmri.24026.

            ●● Enlace al texto completo (gratuito o de pago) 1002/jmri.24026

AUTORES / AUTHORS:  - Yoo RE; Choi SH; Cho HR; Kim TM; Lee SH; Park CK; Park SH; Kim IH; Yun TJ; Kim JH; Sohn CH; Han MH; Chang KH

INSTITUCIÓN / INSTITUTION:  - Department of Radiology, Seoul National University College of Medicine, Seoul, Korea.

RESUMEN / SUMMARY:  - PURPOSE: To evaluate the usefulness of pseudo-continuous arterial spin labeling (pCASL) imaging in differentiating high-grade gliomas from lymphomas and in noninvasively predicting genetic biomarkers in high-grade gliomas. MATERIALS AND  METHODS: Twelve glioblastoma multiforme (GBM), 3 anaplastic astrocytoma (AA), 5 recurred GBM, and 9 lymphoma patients underwent conventional MR and pCASL imaging. On pCASL perfusion map, mean absolute tumor blood flow (mTBF) was calculated from five regions of interest (ROIs) within the enhancing portion of the tumor. Relative TBF (rTBF = mTBF/mBF(gm) x 100) was also calculated. mTBF and rTBF of high-grade gliomas and lymphomas were compared using unpaired Student’s t-test and receiver operating characteristic (ROC) analysis. Additionally, the association of TBF and six immunohistochemically confirmed genetic biomarkers was analyzed by Pearson correlation analysis in the group of high-grade gliomas. RESULTS: Both mTBF and rTBF of the high-grade gliomas were significantly higher than those of the lymphomas: 92.1 +/- 34.7 versus 53.6 +/- 30.5 mL/min/100 mg (P  = 0.008) and 182.3 +/- 69.5 versus 92.5 +/- 44.9 (P = 0.002), respectively. Only  epidermal growth factor receptor (EGFR) expression status showed a significant positive correlation with mTBF(P = 0.015) and rTBF(P = 0.007). CONCLUSION: pCASL  imaging may facilitate differentiation of high-grade gliomas from lymphomas and prediction of EGFR expression status in high-grade gliomas. J. Magn. Reson. Imaging 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 Wiley Periodicals, Inc.




TÍTULO / TITLE:  - Whole-Exome Sequencing Studies of Nonfunctioning Pituitary Adenomas.

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

REVISTA / JOURNAL:  - J Clin Endocrinol Metab. 2013 Feb 28.

            ●● Enlace al texto completo (gratuito o de pago) 1210/jc.2012-4028

AUTORES / AUTHORS:  - Newey PJ; Nesbit MA; Rimmer AJ; Head RA; Gorvin CM; Attar M; Gregory L; Wass JA; Buck D; Karavitaki N; Grossman AB; McVean G; Ansorge O; Thakker RV

INSTITUCIÓN / INSTITUTION:  - Academic Endocrine Unit (P.J.N., M.A.N., R.A.H., C.M.G., R.V.T.), Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7LJ, United Kingdom; Bioinformatics and Statistical Genetics Group (A.J.R., G.M.) and High-Throughput Genomics Group (M.A., L.G., D.B.), Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom; Department  of Endocrinology (J.A.H.W., N.K., A.B.G.), Oxford Centre for Diabetes, Endocrinology, and Metabolism, Oxford University Hospitals Trust, Oxford OX3 7LJ, United Kingdom; and Department of Neuropathology (O.A.), John Radcliffe Hospital, Oxford University Hospitals Trust, Oxford OX3 9DU, United Kingdom.

RESUMEN / SUMMARY:  - Context:The tumorigenic role of genetic abnormalities in sporadic pituitary nonfunctioning adenomas (NFAs), which usually originate from gonadotroph cells, is unknown.Objective:The objective of the study was to identify somatic genetic abnormalities in sporadic pituitary NFAs.Design:Whole-exome sequencing was performed using DNA from 7 pituitary NFAs and leukocyte samples obtained from the same patients. Somatic variants were confirmed by dideoxynucleotide sequencing, and candidate driver genes were assessed in an additional 24 pituitary NFAs.Results:Whole-exome sequencing achieved a high degree of coverage such that  approximately 97% of targeted bases were represented by more than 10 base reads;  24 somatic variants were identified and confirmed in the discovery set of 7 pituitary NFAs (mean 3.5 variants/tumor; range 1-7). Approximately 80% of variants occurred as missense single nucleotide variants and the remainder were synonymous changes or small frameshift deletions. Each of the 24 mutations occurred in independent genes with no recurrent mutations. Mutations were not observed in genes previously associated with pituitary tumorigenesis, although somatic variants in putative driver genes including platelet-derived growth factor D (PDGFD), N-myc down-regulated gene family member 4 (NDRG4), and Zipper sterile-alpha-motif kinase (ZAK) were identified; however, DNA sequence analysis  of these in the validation set of 24 pituitary NFAs did not reveal any mutations  indicating that these genes are unlikely to contribute significantly in the etiology of sporadic pituitary NFAs.Conclusions:Pituitary NFAs harbor few somatic mutations consistent with their low proliferation rates and benign nature, but mechanisms other than somatic mutation are likely involved in the etiology of sporadic pituitary NFAs.




TÍTULO / TITLE:  - Recurrences of ACTH-Secreting Adenomas After Pituitary Adenomectomy Can Be Accurately Predicted by Perioperative Measurements of Plasma ACTH Levels.

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

REVISTA / JOURNAL:  - J Clin Endocrinol Metab. 2013 Feb 28.

            ●● Enlace al texto completo (gratuito o de pago) 1210/jc.2012-3910

AUTORES / AUTHORS:  - Abdelmannan D; Chaiban J; Selman WR; Arafah BM

INSTITUCIÓN / INSTITUTION:  - Division of Clinical and Molecular Endocrinology, Department of Neurological Surgery, University Hospitals Case Medical Center, Louis Stokes Cleveland Veterans Medical Center And Case Western Reserve University, Cleveland, Ohio 44106.

RESUMEN / SUMMARY:  - Background:Adenomectomy is the treatment of choice for ACTH-secreting adenomas. Although the development of ACTH deficiency immediately after adenomectomy suggests surgical success, disease recurrence was reported in patients who developed hypocortisolism postoperatively. In the current study, we examined the  value of measuring perioperative plasma ACTH and cortisol levels in predicting disease recurrence of patients with ACTH-secreting adenomas.Methods:Consecutive patients (n = 55; 41 females, 14 males) with clinical, biochemical, and histological documentation of ACTH-secreting adenomas were investigated after pituitary adenomectomy. All patients were followed with clinical monitoring and frequent measurements of plasma ACTH and serum cortisol levels, and none received glucocorticoids unless or until they developed symptoms of adrenal insufficiency  or when their serum cortisol levels were </=3 mug/dL.Results:Postoperative serum  cortisol levels reached </=3 mug/dL in 46 of 55 and were >/=4 mug/dL in the remaining 9. Simultaneously measured plasma ACTH levels in the latter 9 patients  were >40 ng/L when the serum cortisol reached its nadir. In contrast, among the 46 patients who had serum cortisol levels of </=3 mug/dL, plasma ACTH levels measured simultaneously were </=20 ng/L in 38 of 46 and >20 ng/L in the remaining 8. During a mean follow-up period of nearly 7 years, patients who had a nadir plasma ACTH of >20 ng/L developed recurrences even though their postoperative serum cortisol levels were </=3 mug/dL.Conclusions:Despite profound hypocortisolemia after adenomectomy, a simultaneously measured plasma ACTH level  of >20 ng/L in the perioperative period is highly predictive of future recurrence of ACTH-secreting adenomas.




TÍTULO / TITLE:  - Management of pediatric spinal cord astrocytomas: outcomes with adjuvant radiation.

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

REVISTA / JOURNAL:  - Int J Radiat Oncol Biol Phys. 2013 Apr 1;85(5):1307-11. doi: 10.1016/j.ijrobp.2012.11.022. Epub 2013 Feb 20.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.ijrobp.2012.11.022

AUTORES / AUTHORS:  - Guss ZD; Moningi S; Jallo GI; Cohen KJ; Wharam MD; Terezakis SA

INSTITUCIÓN / INSTITUTION:  - Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins  Hospital, Baltimore, Maryland.

RESUMEN / SUMMARY:  - PURPOSE: Pediatric intramedullary spinal cord tumors are exceedingly rare; in the United States, 100 to 200 cases are recognized annually, of these, most are astrocytomas. The purpose of this study is to report the outcomes in pediatric patients with spinal cord astrocytomas treated at a tertiary care center. METHODS AND MATERIALS: An institutional review board-approved retrospective single-institution study was performed for pediatric patients with spinal cord astrocytomas treated at our hospital from 1990 to 2010. The patients were evaluated on the extent of resection, progression-free survival (PFS), and development of radiation-related toxicities. Kaplan-Meier curves and multivariate regression model methods were used for analysis. RESULTS: Twenty-nine patients were included in the study, 24 with grade 1 or 2 (low-grade) tumors and 5 with grade 3 or 4 (high-grade) tumors. The median follow-up time was 55 months (range, 1-215 months) for patients with low-grade tumors and 17 months (range, 10-52 months) for those with high-grade tumors. Thirteen patients in the cohort received chemotherapy. All patients underwent at least 1 surgical resection. Twelve patients received radiation therapy to a median radiation dose of 47.5 Gy  (range, 28.6-54.0 Gy). Fifteen patients with low-grade tumors and 1 patient with  a high-grade tumor exhibited stable disease at the last follow-up visit. Acute toxicities of radiation therapy were low grade, whereas long-term sequelae were infrequent and manageable when they arose. All patients with low-grade tumors were alive at the last follow-up visit, compared with 1 patient with a high-grade tumor. CONCLUSION: Primary pediatric spinal cord astrocytomas vary widely in presentation and clinical course. Histopathologic grade remains a major prognostic factor. Patients with low-grade tumors tend to have excellent disease  control and long-term survival compared to those with high-grade tumors. This experience suggests that radiation therapy may enhance tumor control with an acceptably low risk of long-term sequelae in this sensitive patient population.




TÍTULO / TITLE:  - Diagnosis and surgical treatment of sporadic meningioangiomatosis.

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

REVISTA / JOURNAL:  - Clin Neurol Neurosurg. 2013 Feb 25. pii: S0303-8467(13)00048-6. doi: 10.1016/j.clineuro.2013.01.021.

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

AUTORES / AUTHORS:  - Feng R; Hu J; Che X; Pan L; Wang Z; Zhang M; Huang F; Xu B; Mao R; Sun A; Bao W; Zhong P; Wang Y

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040,  China.

RESUMEN / SUMMARY:  - OBJECTIVE: To discuss the clinical characteristics, radiological features, surgical treatment and prognosis of sporadic meningioangiomatosis (MA). METHODS:  We retrospectively analyzed the medical records of ten histopathologically confirmed MA patients who were treated in the Department of Neurosurgery of Huashan hospital from 2002 to 2011. All of the patients presented with symptomatic seizure attacks before craniotomy surgeries. Magnetic resonance imaging (MRI) and/or computed tomography (CT) were the main radiological examination for preoperative diagnosis of all cases. RESULTS: All patients underwent craniotomy surgeries with gross total resections (GTRs) of the MA lesions. Postoperative follow-ups range from 8 to 108 months, in average 42.7 months, median 40.5 months. No radiological recurrence can be found in any case.  Eight patients (80.0%) have achieved total symptomatic remission after surgeries  (one of them underwent delayed remission), while two (20.0%) are still suffering  from seizure attacks infrequently under several antiepileptic drugs (AEDs). CONCLUSION: Although MA cases are quite rare and usually misdiagnosed presurgically, a correct preoperative diagnosis, at least a differential diagnosis, can be rationally achieved via a triad of patients’ ages, symptomatic  seizure attacks and radiological features (both CT and MR). MA is curable and the prognosis is excellent since most patients became free of seizure and recurrence  after surgical treatments.




TÍTULO / TITLE:  - Striatal TH-immunopositive fibers recover after an intrastriatal injection of 6-hydroxydopamine in golden hamsters treated with prednisolone: Roles of tumor necrosis factor-alpha and inducible nitric oxide synthase in neurodegeneration.

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

REVISTA / JOURNAL:  - Neurosci Res. 2013 Mar 5. pii: S0168-0102(13)00038-2. doi: 10.1016/j.neures.2013.02.004.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.neures.2013.02.004

AUTORES / AUTHORS:  - Rodriguez S; Uchida K; Nakayama H

INSTITUCIÓN / INSTITUTION:  - Department of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-Ku, Tokyo 113-8657, Japan. Electronic address: sebastian.rodriguez1978@hotmail.com.

RESUMEN / SUMMARY:  - Neuroinflammation has been implicated in the pathology of neurodegenerative processes such as Parkinson’s disease (PD). Using the golden hamster (GH) 6-hydroxydopamine (6-OHDA) model, we investigated whether the attenuation of neuroinflammation influences the onset and progression of dopamine cell degeneration. 6-OHDA-injected GH received a treatment of minocycline (MINO), prednisolone (Pred) or a combination of minocycline and prednisolone (MINO+Pred). Immunohistochemistry for tyrosine hydroxylase (TH), Iba-1 and glial fibrillary acidic protein (GFAP) was used to evaluate lesions in the nigrostriatal axis and  the amount of activated microglia and astroglia, respectively. RT-PCR was used to measure mRNA levels of cytokines and trophic neuroprotective factors. The three anti-inflammatory treatments dramatically reduced activated microglia in the nigrostriatal axis. In addition, TH-immunostaining showed that the positive areas in the ipsilateral striatum of either MINO or Pred groups were higher than that of control. However, only in Pred group this recovery was significant. mRNA measurements demonstrated lower levels of TNF-alpha, iNOS, BDNF and GDNF in Pred  group when compared with controls. The results suggest that TH-immunopositive fibers have the ability to recover after 6-OHDA-induced toxicity of dopaminergic  neurons, and this recovery may be due to a decrease in the microglial production  of TNF-alpha and iNOS.




TÍTULO / TITLE:  - Regulation of Epidermal Growth Factor Receptor Signaling by plasmid-based MicroRNA-7 inhibits human malignant gliomas growth and metastasis in vivo.

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

REVISTA / JOURNAL:  - Neoplasma. 2013;60(3):274-83. doi: 10.4149/neo_2013_036.

            ●● Enlace al texto completo (gratuito o de pago) 4149/neo_2013_036

AUTORES / AUTHORS:  - Wang W; Dai LX; Zhang S; Yang Y; Yan N; Fan P; Dai L; Tian HW; Cheng L; Zhang XM; Li C; Zhang JF; Xu F; Shi G; Chen XL; DU T; Li YM; Wei YQ; Deng HX

RESUMEN / SUMMARY:  - MicroRNAs are endogenous, non-coding RNAs of approximately 20-22 nucleotides that regulate genes expression by binding to the 3’ untranslated region (UTR) of targets mRNAs and play critical roles in cancer pathways. Malignant glioma is the most common and highly lethal central nervous system tumor for which little effective treatment is available over several decades. The purpose of this study  was to explore the therapeutic potential of plasmid-based microRNA-7 (miR-7) for  gliomas in vivo. Enhancing miR-7 levels in vitro could significantly induce cell  apoptosis, and inhibit cell proliferation, cell migration and invasion. Western blotting analysis was performed, which indicated that miR-7 directly inhibited epidermal growth factor receptor (EGFR) and further antagonized the downstream protein kinases including ERK, Akt and Stat3. Furthermore, systemic administration of miR-7 encapsulated in cationic liposome resulted in glioma xenografts growth arrest and the metastatic nodules decrease effectively in asequence-specific manner. In this study, miR-7 was applied in glioma treatment for the first time in vivo. Our findings suggested that the plasmid-mediated gene therapy with miR-7 appeared to be apromising candidate for the development of new antitumor and anti-metastasis treatment for human glioma. Keywords: miR-7, glioma, metastasis, apoptosis, gene therapy.




TÍTULO / TITLE:  - MELK-dependent FOXM1 Phosphorylation is Essential for Proliferation of Glioma Stem Cells.

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

REVISTA / JOURNAL:  - Stem Cells. 2013 Feb 13. doi: 10.1002/stem.1358.

            ●● Enlace al texto completo (gratuito o de pago) 1002/stem.1358

AUTORES / AUTHORS:  - Joshi K; Banasavadi-Siddegowda Y; Mo X; Kim SH; Mao P; Kig C; Nardini D; Sobol RW; Chow LM; Kornblum HI; Waclaw R; Beullens M; Nakano I

INSTITUCIÓN / INSTITUTION:  - Department of Neurological Surgery, The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.

RESUMEN / SUMMARY:  - Glioblastoma multiforme (GBM) is a life-threatening brain tumor. Accumulating evidence suggests that eradication of glioma stem-like cells (GSCs) in GBM is essential to achieve cure. The transcription factor FOXM1 has recently gained attention as a master regulator of mitotic progression of cancer cells in various organs. Here, we demonstrate that FOXM1 forms a protein complex with the mitotic  kinase MELK in GSCs, leading to phosphorylation and activation of FOXM1 in a MELK kinase-dependent manner. This MELK-dependent activation of FOXM1 results in a subsequent increase in mitotic regulatory genes in GSCs. MELK-driven FOXM1 activation is regulated by the binding and subsequent trans-phosphorylation of FOXM1 by another kinase PLK1. Using mouse neural progenitors (NPCs), we found that transgenic expression of FOXM1 enhances, while siRNA-mediated gene silencing diminishes neurosphere formation, suggesting that FOXM1 is required for NPC growth. During tumorigenesis, FOXM1 expression sequentially increases as cells progress from NPCs, to pre-tumorigenic progenitors and GSCs. The antibiotic Siomycin A disrupts MELK-mediated FOXM1 signaling with a greater sensitivity in GSC compared to NSC. Treatment with the first-line chemotherapy agent for GBM, Temozolomide, paradoxically enriches for both FOXM1 (+) and MELK (+) cells in GBM cells, and addition of Siomycin A to Temozolomide treatment in mice harboring GSC-derived intracranial tumors enhances the effects of the latter. Collectively, our data indicate that FOXM1 signaling through its direct interaction with MELK regulates key mitotic genes in GSCs in a PLK1-dependent manner and thus, this protein complex is a potential therapeutic target for GBM.




TÍTULO / TITLE:  - Tumorigenic Potential of miR-18A* in Glioma Initiating Cells Requires NOTCH-1 Signaling.

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

REVISTA / JOURNAL:  - Stem Cells. 2013 Mar 26. doi: 10.1002/stem.1373.

            ●● Enlace al texto completo (gratuito o de pago) 1002/stem.1373

AUTORES / AUTHORS:  - Turchi L; Debruyne DN; Almairac F; Virolle V; Fareh M; Neirijnck Y; Burel-Vandenbos F; Paquis P; Junier MP; Van Obberghen-Schilling E; Chneiweiss H; Virolle T

INSTITUCIÓN / INSTITUTION:  - Universite de Nice-Sophia Antipolis; institut de Biologie Valrose, CNRS UMR7277 - INSERM UMR1091, Nice, France.

RESUMEN / SUMMARY:  - Stem cell-like properties of Glioma initiating Cells (GiCs) fuel glioblastoma (GBM) development by providing the different cell types that comprise the tumor.  It is therefore likely that the molecular circuitries that regulate their decision to self-renew or commit to a more differentiated state may offer targets for future innovative therapies. In previous micro-RNA profiling studies to search for regulators of stem cell plasticity we identified miR-18a* as a potential candidate and its expression correlated with the stemness state. Here,  using human GiCs we found that miR-18a* expression promotes clonal proliferation  in vitro and tumorigenicity in vivo. Mechanistically, ERK-dependent induction of  miR-18a* directly represses expression of DLL3, an autocrine inhibitor of NOTCH,  thus enhancing the level of activated NOTCH-1. Activated NOTCH-1 in turn is required for sustained ERK activation. This feedforward loop, driven by miR-18a*, is required to turn on the SHH-GLI-NANOG network, essential for GiC self-renewal. Hence, by tightly regulating expression of DLL3, miR-18a* constitutes an important signaling mediator for fine tuning the level of GiC self-renewal.




TÍTULO / TITLE:  - Modulation of the Wnt/beta-catenin pathway in human oligodendroglioma cells by Sox17 regulates proliferation and differentiation.

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

REVISTA / JOURNAL:  - Cancer Lett. 2013 Mar 6. pii: S0304-3835(13)00221-8. doi: 10.1016/j.canlet.2013.02.058.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.canlet.2013.02.058

AUTORES / AUTHORS:  - Chen HL; Chew LJ; Packer RJ; Gallo V

INSTITUCIÓN / INSTITUTION:  - Center for Neuroscience Research, Children’s National Medical Center, Washington, DC 20010, USA; Daniel and Jennifer Gilbert Neurofibromatosis Institute, Children’s National Medical Center, Washington, DC 20010, USA.

RESUMEN / SUMMARY:  - Oligodendrogliomas originate from oligodendrocyte progenitor cells (OPCs), whose  development is regulated by the Sonic hedgehog and Wnt/beta-catenin pathways. We  investigated the contribution of these pathways in the proliferation and differentiation of human oligodendroglioma cells (HOG). Inhibition of Hedgehog signaling with cyclopamine decreased cell survival and increased phosphorylated beta-catenin without altering myelin protein levels. Conversely, treatment of HOG with the Wnt antagonist secreted frizzled related protein (SFRP1), led to increased myelin protein levels and reduced cell proliferation, suggesting cell cycle arrest and differentiation. Unlike normal primary human OPCs, beta-catenin  in HOG cells is not associated with endogenous Sox17 protein despite high levels  of both proteins. Retroviral overexpression of recombinant Sox17 increased HOG cell cycle exit and apoptosis, and raised myelin protein levels and the percentage of O4+ cells, indicating increased differentiation. Recombinant Sox17  also increased beta-catenin-TCF4-Sox17 complex formation and decreased total cellular levels of beta-catenin. These changes were associated with increased SFRP1, and reduced expression of Wnt-1 and Frizzled-1, -3 and -7 RNA, indicating  that Sox17 induced a Hedgehog target, and regulated Wnt signaling at multiple levels. Our studies indicate that Wnt signaling regulates HOG cell cycle arrest and differentiation, and that recombinant Sox17 mediates modulation of the Wnt pathway through changes in beta-catenin, SFRP1 and Wnt/Frizzled expression. Our results thus identify Sox17 as a potential molecular target to include in HOG therapeutic strategies.




TÍTULO / TITLE:  - Metabolic modulation of epigenetics in gliomas.

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

REVISTA / JOURNAL:  - Brain Pathol. 2013 Mar;23(2):217-21. doi: 10.1111/bpa.12022.

            ●● Enlace al texto completo (gratuito o de pago) 1111/bpa.12022

AUTORES / AUTHORS:  - Venneti S; Thompson CB

INSTITUCIÓN / INSTITUTION:  - Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New  York, NY 10065, USA.

RESUMEN / SUMMARY:  - Cancer metabolism and epigenetics are two relatively new areas of cancer research. Recent years have seen an explosion of studies implicating either altered tumor metabolism or epigenetic mechanisms in the pathogenesis or maintenance of brain tumors. A new paradigm is emerging in cancer biology that represents a convergence of these themes, the metabolic regulation of epigenetics. We discuss this interrelationship in the context of two metabolic enzymes that can influence the pathogenesis of gliomas by altering the epigenetic state. The first of these enzymes is isocitrate dehydrogenase 1 (IDH1), which is  mutated in secondary glioblastomas and ~70% of grade II/III astrocytomas and oligodendrogliomas. Mutant IDH1 results in the production of a metabolite 2-hydroxyglutarate (2-HG) that can inhibit DNA and histone demethylating enzymes  resulting in the glioma-CpG island phenotype (G-CIMP) and increased histone methylation marks. Pyruvate kinase M2 (PKM2), an enzyme that plays a critical role in the glycolytic pathway, is a second example of a metabolic enzyme that can affect histone modifications. In epidermal growth factor receptor (EGFR)-driven glioblastoma, PKM2 translocates to the nucleus and phosphorylates histone 3 at threonine 11 (H3-T11). This causes dissociation of HDAC3 from the CCND1 (Cyclin D1) and c-MYC promoters and subsequent histone acetylation, leading to transcription of Cyclin-D1 and c-MYC, and subsequent cell proliferation. Modification of the epigenetic state by alterations in metabolic enzymes is a novel phenomenon that contributes to the pathogenesis of gliomas and may help in  the identification of new therapeutic targets.




TÍTULO / TITLE:  - Genistein alleviates the mitochondria-targeted DNA damage induced by beta-amyloid peptides 25-35 in C6 glioma cells.

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

REVISTA / JOURNAL:  - Neurochem Res. 2013 Mar 22.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11064-013-1019-y

AUTORES / AUTHORS:  - Ma WW; Hou CC; Zhou X; Yu HL; Xi YD; Ding J; Zhao X; Xiao R

INSTITUCIÓN / INSTITUTION:  - School of Public Health and Family Medicine, Capital Medical University, No.10 Xitoutiao, No.10 Xitoutiao, You An Men, Beijing, 100069, People’s Republic of China.

RESUMEN / SUMMARY:  - Reactive oxygen species (ROS) are mainly produced by mitochondria which can cause oxidative stress. It has been considered that mitochondrial damage induced by oxidative stress is related to Alzheimer’s disease (AD). Besides, mitochondrial DNA (mtDNA) is more vulnerable to oxidative damage than other biomacromolecules,  causing serious dysfunction to mitochondria. beta-amyloid peptides (Abeta) is a main factor responsible for the occurence and development of AD. Astrocytes is an important target cell for Abeta’ toxicity and can be activated to neglect their normal fountain in the central nervous system. Genistein (Gen), a main active ingredient of soybean isoflavone, has been shown to have neuroprotective effects  by antagonizing oxidative damage induced by Abeta. Thus, in the present study, we evaluated Abeta25-35 induced mitochondrial DNA (mtDNA) damage and the protective  effect of Gen in C6 glioma cells (C6 cells). The study design was consisted of four groups: control group (vehicle), Abeta group treated with Abeta25-35, Gen +  Abeta group treated with Gen + Abeta25-35 and Gen group treated with Gen only. C6 cells were pre-incubated with or without Gen (50 muM) for 2 h followed by the incubation with Abeta25-35 (25 muM) for another 24 h. Then the cells were harvested and processed to perform the analysis according to protocols. The mitochondrial ROS in C6 cells were measured by fluorescence spectrometer. Enzyme-linked immunosorbent assay (ELISA) was used to detect the mitochondrial reduced glutathione (GSH) and oxidized glutathione (GSSG) in C6 cells, then the ratio of GSH and GSSG was calculated. The levels of 8-hydroxydeoxyguanosine (8-OHdG) in C6 cells was also detected by ELISA. In addition, mtDNA deletion was  detected by polymerase chain reaction (PCR). The mRNA and protein expression of 8-oxoguanine DNA glycosylase (OGG1) in both C6 cells and its mitochondria, and manganese superoxide dismutase (MnSOD) in mitochondria were detected by using reverse transcription-PCR and Western blot. The results showed that the increased mitochondrial ROS accumulation in C6 cells induced by Abeta was profoundly reversed by pre-treaded with Gen (p < 0.05). The ratio of GSH and GSSG in mitochondria was significantly increased in both Gen + Abeta group and Gen group  compared with Abeta group (p < 0.05). The levels of 8-OHdG in C6 cells and mtDNA  deletion were decreased after pre-treated with Gen (p < 0.05). Gen could also up-regulate the mRNA and protein expression of OGG1 in both C6 cells and its mitochondria and mitochondrial MnSOD compared with the Abeta group (p < 0.05). These results confirmed that Gen could alleviate the mitochondria-targeted oxidative damage induced by beta-amyloid 25-35 in C6 cells which might be useful  for the treatment of neurodegenerative diseases.




TÍTULO / TITLE:  - PEG2000-DPSE-coated quercetin nanoparticles remarkably enhanced anticancer effects through induced programed cell death on C6 glioma cells.

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

REVISTA / JOURNAL:  - J Biomed Mater Res A. 2013 Mar 25. doi: 10.1002/jbm.a.34607.

            ●● Enlace al texto completo (gratuito o de pago) 1002/jbm.a.34607

AUTORES / AUTHORS:  - Wang G; Wang J; Luo J; Wang L; Chen X; Zhang L; Jiang S

INSTITUCIÓN / INSTITUTION:  - Department of Hospital Pharmacy, Taihe Hospital, Hubei University of Medicine, Shiyan City, Hubei Province, China. 13972481839@163.com, wangan139@163.com.

RESUMEN / SUMMARY:  - In this study, PEGylated nanoparticles quercetin drug delivery vehicles were investigated as carriers for anticancer drugs induced programed cell death (PCD). PEG2000-DPSE-coated quercetin nanoparticles were prepared and tumor cell killing  efficacy was studied on glioma C6 cells and assayed for cell survival, apoptosis, or necrosis. The levels of ROS production and mitochondrial membrane potential (DeltaPsim) were determined. Western blot assayed p53, p-p53, cytochrome C, and caspase proteins expression were also studied. Results indicate that PEG2000-DPSE-QUE-NPS showed dose-dependent cytotoxicity to C6 glioma cells and enhanced ROS accumulation induced upregulation of p53 protein, which was accompanied with an increase in cytochrome c and caspase-3 protein levels. These  results support the hypothesis that quercetin nanoparticles-coated PEG2000-DPSE remarkably enhanced anticancer effect of induced programed cell death on C6 glioma cells. Overall, PEG2000-DPSE-coated quercetin nanoparticles showed promising potential as a drug carrier for cancer therapy. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013.




TÍTULO / TITLE:  - The effect of functionalizing lipid nanocapsules with NFL-TBS.40-63 peptide on their uptake by glioblastoma cells.

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

REVISTA / JOURNAL:  - Biomaterials. 2013 Apr;34(13):3381-9. doi: 10.1016/j.biomaterials.2013.01.068. Epub 2013 Feb 4.

            ●● Enlace al texto completo (gratuito o de pago) 1016/j.biomaterials.2013.01.068

AUTORES / AUTHORS:  - Balzeau J; Pinier M; Berges R; Saulnier P; Benoit JP; Eyer J

INSTITUCIÓN / INSTITUTION:  - Laboratoire Neurobiologie & Transgenese, UPRES-EA3143, Batiment IBS, Centre Hospitalier Universitaire, LUNAM, 49033 Angers, France.

RESUMEN / SUMMARY:  - We previously described a neurofilament derived cell-penetrating peptide, NFL-TBS.40-63, that specifically enters in glioblastoma cells where it disturbs the microtubule network both in vitro and in vivo. The aim of this study is to test whether this peptide can increase the targeted uptake by glioblastoma cells  of lipid nanocapsules filled with Paclitaxel, and thus can increase their anti-proliferation in vitro and in vivo. Here, using the drop tensiometry we show that approximately 60 NFL-TBS.40-63 peptides can bind to one 50 nm lipid nanocapsule. When nanocapsules are filled with a far-red fluorochrome (DiD) and Paclitaxel, the presence of the NFL-TBS.40-63 peptide increases their uptake by glioblastoma cells in culture as evaluated by FACS analysis, and thus reduces their proliferation. Finally, when such nanocapsules were injected in mice bearing a glioma tumour, they are preferentially targeted to the tumour and reduce its progression. These results show that nanocapsules functionalized with  the NFL-TBS.40-63 peptide represent a powerful drug-carrier system for glioma targeted treatment.




TÍTULO / TITLE:  - The value of temozolomide in combination with radiotherapy during standard treatment for newly diagnosed glioblastoma.

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

REVISTA / JOURNAL:  - J Neurooncol. 2013 Apr;112(2):277-83. doi: 10.1007/s11060-013-1060-3. Epub 2013 Feb 2.

            ●● Enlace al texto completo (gratuito o de pago) 1007/s11060-013-1060-3

AUTORES / AUTHORS:  - Park CK; Lee SH; Kim TM; Choi SH; Park SH; Heo DS; Kim IH; Jung HW

INSTITUCIÓN / INSTITUTION:  - Department of Neurosurgery, Seoul National University College of Medicine, Seoul  National University Hospital, Seoul, South Korea.

RESUMEN / SUMMARY:  - The current best standard care for glioblastoma still has limitations and unsatisfactory outcomes in patients with an unmethylated O-6-methylguanine-DNA methyltransferase (MGMT) promoter. Whether the effects of temozolomide are primarily due to its concomitant use with radiotherapy or are also mediated by their independent use in the adjuvant phase remain unclear. To validate the concomitant use of temozolomide in the standard protocol, we compared the overall survival of two prospective patient groups: one treated with radiotherapy alone followed by adjuvant temozolomide (RT --> TMZ group) and the other treated with concomitant radiotherapy and temozolomide followed by adjuvant temozolomide (CCRT-TMZ group). Each patient in the RT --> TMZ group (n = 25) was matched with  two patients in the CCRT-TMZ group (n = 50) with respect to age, extent of resection, MGMT promoter methylation status, and postsurgical performance status  to minimize the influence of confounding factors. In patients with MGMT promoter  methylation, the CCRT-TMZ group showed superior overall survival (OS; median, 41.0 months) and progression-free survival (PFS; median, 24.0 months) compared with the RT --> TMZ group. However, the OS and PFS did not differ between the CCRT-TMZ and the RT --> TMZ groups in the patients without MGMT promoter methylation. Although this data is from a retrospective analysis using small number of patients, the study might indicate that concomitant use of temozolomide with radiotherapy is a crucial step in the standard treatment for glioblastoma patients with MGMT promoter methylation. And the use of temozolomide, either concurrently or by adjuvant after radiotherapy, remains a questionable value for  those with an unmethylated MGMT promoter.