Hot off the presses! Jan 01 Neuro Oncol

The Jan 01 issue of the Neuro Oncol is now up on Pubget (About Neuro Oncol): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Stem Cells for Treating Glioblastoma: How Close to Reality?
  James CD Cavenee WK - Neuro Oncol 11(2):101 (2009)
  
• In vivo gene delivery by embryonic-stem-cell-derived astrocytes for malignant gliomas
  Uzzaman M Keller G Germano IM - Neuro Oncol 11(2):102-108 (2009)
  The treatment of malignant gliomas with current therapies remains a challenge in neurooncology. Our recent work showed that embryonic stem cell (ESC)-derived astrocytes conditionally expressing genes can be used to induce apoptosis in malignant glioma cells in vitro. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene has been shown to induce apoptosis in a variety of tumor cells, including gliomas. The aim of this study was to assess the proapoptotic effects of transgenic TRAIL delivered by ESC-derived astrocytes on malignant gliomas in vivo. Malignant glioma A172 cells were used to induce heterotopic xenografts in nude mice. ESC-derived astrocytes conditionally expressing TRAIL were injected into the xenografts. TRAIL expression was documented in the malignant glioma xenografts by reverse transcription PCR and immunohistochemistry after external gene induction. A significant reduction in tumor volume occurred 48 h after a single injection (14%) a! nd double injections (31%) in the experimental groups. Terminal dUTP nick end labeling (TUNEL) revealed abundant apoptotic tumor cells in the experimental groups. Seven days after injection, the tumor had undergone severe necrosis, with only scattered residual tumor cells at the periphery. Death receptor DR4 expression increased significantly in the experimental groups compared with controls. Our data suggest that ESC-derived astrocytes conditionally expressing TRAIL should be considered as vectors to deliver gene therapy for malignant gliomas.
• Efficacy of the HSP90 inhibitor 17-AAG in human glioma cell lines and tumorigenic glioma stem cells
  Sauvageot CM Weatherbee JL Kesari S Winters SE Barnes J Dellagatta J Ramakrishna NR Stiles CD Kung AL Kieran MW Wen PY - Neuro Oncol 11(2):109-121 (2009)
  Glioblastoma multiforme (GBM) arises from genetic and signaling abnormalities in components of signal transduction pathways involved in proliferation, survival, and the cell cycle axis. Studies to date with single-agent targeted molecular therapy have revealed only modest effects in attenuating the growth of these tumors, suggesting that targeting multiple aberrant pathways may be more beneficial. Heat-shock protein 90 (HSP90) is a molecular chaperone that is involved in the conformational maturation of a defined group of client proteins, many of which are deregulated in GBM. 17-allylamino-17-demethoxygeldanamycin (17-AAG) is a well-characterized HSP90 inhibitor that should be able to target many of the aberrant signal transduction pathways in GBM. We assessed the ability of 17-AAG to inhibit the growth of glioma cell lines and glioma stem cells both in vitro and in vivo and assessed its ability to synergize with radiation and/or temozolomide, the standard therapies fo! r GBM. Our results reveal that 17-AAG is able to inhibit the growth of both human glioma cell lines and glioma stem cells in vitro and is able to target the appropriate proteins within these cells. In addition, 17-AAG can inhibit the growth of intracranial tumors and can synergize with radiation both in tissue culture and in intracranial tumors. This compound was not found to synergize with temozolomide in any of our models of gliomas. Our results suggest that HSP90 inhibitors like 17-AAG may have therapeutic potential in GBM, either as a single agent or in combination with radiation.
• Quercetin promotes degradation of survivin and thereby enhances death-receptor-mediated apoptosis in glioma cells
  Siegelin MD Reuss DE Habel A Rami A von Deimling A - Neuro Oncol 11(2):122-131 (2009)
  The flavonoid quercetin has been reported to inhibit the proliferation of cancer cells, whereas it has no effect on nonneoplastic cells. U87-MG, U251, A172, LN229, and U373 malignant glioma cells were treated with quercetin (50-200 {micro}M). Quercetin did not cause cytotoxicity 24 h after treatment. Combining quercetin with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) strongly augmented TRAIL-mediated apoptosis in U87-MG, U251, A172, and LN229 glioma cells; U373 cells could not be sensitized by quercetin to TRAIL-mediated apoptosis. TRAIL-induced apoptosis was enhanced by quercetin-induced reduction of survivin protein levels. Upon treatment with quercetin, the protein level of survivin was strongly suppressed in U87-MG, U251, and A172 but not in U373 glioma cells. Quercetin exposure resulted in proteasomal degradation of survivin. TRAIL-quercetin-induced apoptosis was markedly reduced by overexpression of survivin. In addition, upon treatment with ! quercetin, downregulation of survivin was also regulated by the Akt pathway. Taken together, the results of the present study suggest that quercetin sensitizes glioma cells to death-receptor-mediated apoptosis by suppression of inhibitor of the apoptosis protein survivin.
• Promyelocytic leukemia protein induces apoptosis due to caspase-8 activation via the repression of NF{kappa}B activation in glioblastoma
  Kuwayama K Matsuzaki K Mizobuchi Y Mure H Kitazato KT Kageji T Nakao M Nagahiro S - Neuro Oncol 11(2):132-141 (2009)
  Promyelocytic leukemia (PML) protein plays an essential role in the induction of apoptosis; its expression is reduced in various cancers. As the functional roles of PML in glioblastoma multiforme (GBM) have not been clarified, we assessed the expression of PML protein in GBM tissues and explored the mechanisms of PML-regulated cell death in GBM cells. We examined the PML mRNA level and the expression of PML protein in surgical GBM specimens. PML-regulated apoptotic mechanisms in GBM cells transfected with plasmids expressing the PML gene were examined. The protein expression of PML was significantly lower in GBM than in non-neoplastic tissues; approximately 10% of GBM tissues were PML-null. The PML mRNA levels were similar in both tissue types. The overexpression of PML activated caspase-8 and induced apoptosis in GBM cells. In these cells, PML decreased the expression of transactivated forms of NF{kappa}B/p65, and c-FLIP gene expression was suppressed. Therefore, PML-! induced apoptosis resulted from the suppression of the transcriptional activity of NF{kappa}B/p65. PML overexpression decreased phosphorylated I{kappa}B{alpha} and nuclear NF{kappa}B/p65 and increased the expression of the suppressor of cytokine signaling (SOCS-1). A proteasome inhibitor blocked the reduction of activated p65 by PML. The reduction of PML is associated with the pathogenesis of GBM. PML induces caspase-8-dependent apoptosis via the repression of NF{kappa}B activation by which PML facilitates the proteasomal degradation of activated p65 and the sequestration of p65 with I{kappa}B{alpha} in the cytoplasm. This novel mechanism of PML-regulated apoptosis may represent a therapeutic target for GBM.
• Bevacizumab and carboplatin increase survival and asymptomatic tumor volume in a glioma model
  Jahnke K Muldoon LL Varallyay CG Lewin SJ Kraemer DF Neuwelt EA - Neuro Oncol 11(2):142-150 (2009)
  To evaluate efficacy and MRI findings after intravenous bevacizumab and/or carboplatin in a human glioma animal model, we randomized male nude rats with intracerebral UW28 human glioma xenografts to four groups: (1) controls (n = 9), (2) bevacizumab 10 mg/kg (n = 6), (3) carboplatin 200 mg/m2 (n = 6), and (4) bevacizumab + carboplatin (n = 6). MRI was performed on the day of treatment (day 7-10) and 1 week later, and rats were followed for survival. Dynamic MRI was done in three controls and three rats treated with bevacizumab with or without carboplatin before and 24 h after treatment. Median overall survival (OS) was as follows: group 1, 16 days; group 2, 23 days; group 3, 22 days; group 4, 36 days. OS was significantly longer in group 4 than in group 1 (p = 0.0011), group 2 (p = 0.0014), and group 3 (p = 0.0015), and rats had significantly larger tumors. No objective tumor responses were observed on MR images at 1 week after treatment; however, after bevacizumab, dy! namic MRI showed reduced gadolinium enhancement intensity and increased time to peak, consistent with decreased vascular permeability. Carboplatin + bevacizumab is effective and superior over bevacizumab or carboplatin monotherapy in this animal model. Increased survival concomitant with increased asymptomatic tumor volume is suggestive that vascular targeting with reduced peritumoral edema and mass effect contributes to the efficacy of bevacizumab. The promising survival data warrant future clinical trials using bevacizumab + carboplatin.
• Therapeutic efficacy of a polymeric micellar doxorubicin infused by convection-enhanced delivery against intracranial 9L brain tumor models
  Inoue T Yamashita Y Nishihara M Sugiyama S Sonoda Y Kumabe T Yokoyama M Tominaga T - Neuro Oncol 11(2):151-157 (2009)
  Convection-enhanced delivery (CED) with various drug carrier systems has recently emerged as a novel chemotherapeutic method to overcome the problems of current chemotherapies against brain tumors. Polymeric micelle systems have exhibited dramatically higher in vivo antitumor activity in systemic administration. This study investigated the effectiveness of CED with polymeric micellar doxorubicin (DOX) in a 9L syngeneic rat model. Distribution, toxicity, and efficacy of free, liposomal, and micellar DOX infused by CED were evaluated. Micellar DOX achieved much wider distribution in brain tumor tissue and surrounding normal brain tissue than free DOX. Tissue toxicity increased at higher doses, but rats treated with micellar DOX showed no abnormal neurological symptoms at any dose tested (0.1-1.0 mg/ml). Micellar DOX infused by CED resulted in prolonged median survival (36 days) compared with free DOX (19.6 days; p = 0.0173) and liposomal DOX (16.6 days; p = 0.0007) at th! e same dose (0.2 mg/ml). This study indicates the potential of CED with the polymeric micelle drug carrier system for the treatment of brain tumors.
• Sagopilone crosses the blood-brain barrier in vivo to inhibit brain tumor growth and metastases
  Hoffmann J Fichtner I Lemm M Lienau P Hess-Stumpp H Rotgeri A Hofmann B Klar U - Neuro Oncol 11(2):158-166 (2009)
  The aim of this study was to determine the efficacy of sagopilone (ZK-EPO), a novel epothilone, compared with other anticancer agents in orthotopic models of human primary and secondary brain tumors. Autoradiography and pharmacokinetic analyses were performed on rats and mice to determine passage across the blood-brain barrier and organ distribution of sagopilone. Mice bearing intracerebral human tumors (U373 or U87 glioblastoma, MDA-MB-435 melanoma, or patient-derived non-small-cell lung cancer [NSCLC]) were treated with sagopilone 5-10 mg/kg, paclitaxel 8-12.5 mg/kg (or temozolomide, 100 mg/kg) or control (vehicle only). Tumor volume was measured to assess antitumor activity. Sagopilone crossed the blood-brain barrier in both rat and mouse models, leading to therapeutically relevant concentrations in the brain with a long half-life. Sagopilone exhibited significant antitumor activity in both the U373 and U87 models of human glioblastoma, while paclitaxel showed a lim! ited effect in the U373 model. Sagopilone significantly inhibited the growth of tumors from CNS metastasis models (MDA-MB-435 melanoma and patient-derived Lu7187 and Lu7466 NSCLC) implanted in the brains of nude mice, in contrast to paclitaxel or temozolomide. Sagopilone has free access to the brain. Sagopilone demonstrated significant antitumor activity in orthotopic models of both glioblastoma and CNS metastases compared with paclitaxel or temozolomide, underlining the value of further research evaluating sagopilone in the treatment of brain tumors. Sagopilone is currently being investigated in a broad phase II clinical trial program, including patients with glioblastoma, NSCLC, breast cancer, and melanoma.
• Phase II trial of preirradiation and concurrent temozolomide in patients with newly diagnosed anaplastic oligodendrogliomas and mixed anaplastic oligoastrocytomas: RTOG BR0131
  Vogelbaum MA Berkey B Peereboom D Macdonald D Giannini C Suh JH Jenkins R Herman J Brown P Blumenthal DT Biggs C Schultz C Mehta M - Neuro Oncol 11(2):167-175 (2009)
  The primary objectives of this phase II study were to evaluate the use of preirradiation temozolomide followed by concurrent temozolomide and radiotherapy (RT) in patients with newly diagnosed anaplastic oligodendroglioma (AO) and mixed anaplastic oligoastrocytoma (MOA). Preirradiation temozolomide (150 mg/m2/day) was given on a 7-day-on/7-day-off schedule for up to six cycles. The primary end point was the response rate during the 6-month, pre-RT chemotherapy. Tumor tissue was analyzed for the presence of chromosomal deletions on 1p and 19q and for MGMT-promoter methylation. Forty-two patients were enrolled; 39 were eligible. The objective response rate was 32% (6% [complete response, CR], 26% [partial response PR]), and the rate of progression during pre-RT chemotherapy was 10%. The worst nonhematological toxicity was grade 4 in three patients (8%). Twenty-two patients completed concurrent chemotherapy and RT. There were no grade 4 nonhematological toxicities during ! the concurrent chemotherapy and RT. Seventeen of 28 (60.7%) evaluable cases had codeletion of 1p/19q; all 17 were free from progression at 6 months. Sixteen of 20 (80%) evaluable cases had MGMT-promoter methylation; all 16 were free from progression at 6 months. In conclusion, the rate of progression of 10% during pre-RT temozolomide chemotherapy for newly diagnosed AO and MAO compared favorably with prior experience with pre-RT PCV chemotherapy (20% in RTOG 9402). The toxicity of the dose-intense pre-RT regimen used in this study may warrant evaluation of other, less intense dosing strategies. Future studies will need to prospectively stratify patients according to the presence of deletions of chromosomes 1p and 19q.
• Prognostic significance of imaging contrast enhancement for WHO grade II gliomas
  Pallud J Capelle L Taillandier L Fontaine D Mandonnet E Guillevin R Bauchet L Peruzzi P Laigle-Donadey F Kujas M Guyotat J Baron MH Mokhtari K Duffau H - Neuro Oncol 11(2):176-182 (2009)
  In this study, we investigated the prognostic value of MRI contrast enhancement (CE) at the time of histological diagnosis specifically in a selected population of WHO grade II gliomas. We reviewed 927 histologically proven WHO grade II gliomas for which contrast-enhanced MR images were available at the time of histological diagnosis. CE patterns were classified into three categories: "patchy and faint," "nodular-like," and "ring-like." CE progression over time was recorded before oncological treatment on successive MR images, when available. CE was present in 143 cases (15.9%), with 93 patchy and faint, 50 nodular-like, and no ring-like patterns. CE areas were time progressive before oncological treatment in 35 of the 56 available cases (62.5%). Regardless of its pattern, the presence of CE was not significantly associated with a worsened prognosis (p = 0.415) by univariate analysis. Only the nodular-like pattern of CE (p < 0.01) and the time-progressive CE (p < 0.001! ) in the available subgroup proved to be statistically associated with survival since first oncological treatment. The present results show the necessity, in cases of WHO grade II gliomas, to study CE at the time of histological diagnosis and, whenever possible, to follow its progression over time before oncological treatment. Nodular-like CE and time-progressive CE are associated with a worsened prognosis, both suggesting malignant transformation, even though histopathological examination cannot initially disclose signs of malignancy in those areas.
• Adult gliosarcoma: epidemiology, natural history, and factors associated with outcome
  Kozak KR Mahadevan A Moody JS - Neuro Oncol 11(2):183-191 (2009)
  The epidemiology and natural history of adult gliosarcomas (GSMs), as well as patient and treatment factors associated with outcome, are ill defined. Patients over 20 years of age with GSM diagnosed from 1988 to 2004 were identified in the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier survival analysis and Cox models were used to examine outcomes. Similar analyses were conducted for patients diagnosed with glioblastoma (GBM) over the same time period. GSM represented 2.2% of the 16,388 patients identified with either GSM or GBM. No significant differences between GSM and GBM were identified with respect to age, gender, race, tumor size, or use of adjuvant radiation therapy (RT). Patients with GSM were more likely to have temporal lobe involvement and undergo some form of tumor resection. The most important analyzed factors influencing GSM overall survival were age, extent of resection, and use of adjuvant RT. After adjusting for factors impa! cting overall survival, the prognosis for GSM appears slightly worse than for GBM (HR = 1.17, 95% CI, 1.05-1.31). GSM is a rare malignancy that presents very similarly to GBM with a slightly greater propensity for temporal lobe involvement. Optimal treatment remains to be defined. However, these retrospective findings suggest tumor excision, as opposed to biopsy only, and adjuvant RT may improve outcome. Despite therapy, prognosis remains dismal and outcomes may be inferior to those seen in GBM patients.
• Presence of 1q gain and absence of 7p gain are new predictors of local or metastatic relapse in localized resectable neuroblastoma
  Pezzolo A Rossi E Gimelli S Parodi F Negri F Conte M Pistorio A Sementa A Pistoia V Zuffardi O Gambini C - Neuro Oncol 11(2):192-200 (2009)
  We have addressed the search of novel genetic prognostic markers in a selected cohort of patients with stroma-poor localized resectable neuroblastoma (NB) who underwent relapse or progression (group 1) or complete remission (group 2) over a minimum follow-up of 32 months from diagnosis. Twenty-three Italian patients with localized resectable NB (stages 1 and 2) diagnosed from 1994 through 2005 were studied. All patients received surgical treatment. Chemotherapy was administered only to the three stage 2 patients who had MYCN-amplified tumors. High-resolution array-comparative genomic hybridization (CGH) DNA copy-number analysis technology was used to identify novel prognostic markers. Chromosome 1p36.22p36.32 loss and 1q22qter gain, detected almost exclusively in group 1 patients, were significantly associated with poor event-free survival (EFS) (p = 0.0024 and p = 0.024, respectively). In contrast, patients with 7p11.2p22 gain, who belonged predominantly to group 2, h! ad a significantly better EFS (p = 0.015). The frequency of 17q gain or 3p and 11q losses did not differ significantly in group 1 versus group 2 NBs. The sensitive technique allowed us to define the smallest region of 1p deletion. In conclusion, 1q22qter gain and 7p11.2p22 gain might represent new prognostic markers in localized resectable NB, but the small study size and the retrospective nature of the findings warrant further validation of the results in larger studies.
• Treatment of early childhood medulloblastoma by postoperative chemotherapy and deferred radiotherapy
  - Neuro Oncol 11(2):201-210 (2009)
  To investigate the utility of postoperative chemotherapy in delaying radiotherapy and to identify prognostic factors in early childhood medulloblastoma, we studied children younger than 3 years of age registered to the HIT-SKK'87 (Therapieprotokoll fur Sauglinge und Kleinkinder mit Hirntumoren [Brain Tumor Radiotherapy for Infants and Toddlers with Medulloblastoma] 1987) trial who received systemic interval chemotherapy until craniospinal radiotherapy was applied at 3 years of age or at relapse, from 1987 to 1993. Children with postoperative residual tumor or metastatic disease received systemic induction chemotherapy prior to interval chemotherapy. Twenty-nine children were eligible for analyses (median age, 1.7 years; median follow-up, 12.6 years). In children without macroscopic metastases, rates ({+/-}SEM) for 10-year progression-free survival (PFS) and overall survival (OS) were 52.9% {+/-} 12.1% and 58.8% {+/-} 11.9% (complete resection), and 55.6% {+/-} 16.6% an! d 66.7% {+/-} 15.7% (incomplete resection), compared with 0% and 0% in children with macroscopic metastases. Survival was superior in nine children with desmoplastic or extensive nodular histology compared with 20 children with classic medulloblastoma (10-year PFS, 88.9% {+/-} 10.5% and 30.0% {+/-} 10.3%, p = 0.003; OS, 88.9% {+/-} 10.5% and 40.0% {+/-} 11.0%, p = 0.006). Eleven of 12 children with tumor progression during chemotherapy had classic medulloblastoma. After treatment, IQ scores were inferior compared with nonirradiated children from the subsequent study, HIT-SKK'92. Classic histology, metastatic disease, and male gender were independent adverse risk factors for PFS and OS in 72 children from HIT-SKK'87 and HIT-SKK'92 combined. In terms of survival, craniospinal radiotherapy was successfully delayed especially in young children with medulloblastoma of desmoplastic/extensive nodular histology, which was a strong independent favorable prognostic factor. Because of! the neurocognitive deficits of survivors, the emerging concep! ts to avoid craniospinal radiotherapy should rely on the histological medulloblastoma subtype.
• High-dose methotrexate for elderly patients with primary CNS lymphoma
  Zhu JJ Gerstner ER Engler DA Mrugala MM Nugent W Nierenberg K Hochberg FH Betensky RA Batchelor TT - Neuro Oncol 11(2):211-215 (2009)
  The introduction of methotrexate (MTX)-based chemotherapy has improved median survival for patients with primary CNS lymphoma (PCNSL). Older age is a negative prognostic marker in patients with PCNSL and may increase the likelihood of MTX toxicity. We studied the response and adverse effects of intravenous high-dose MTX in patients who were 70 or more years of age at the time of diagnosis. We identified 31 patients at our institution diagnosed with PCNSL at age [>=]70 years (median, 74 years) who were treated with high-dose MTX (3.5-8 g/m2) as initial therapy from 1992 through 2006. The best response to MTX was determined by contrast-enhanced MRI. Toxicity was analyzed by chart review. These 31 patients received a total of 303 cycles of MTX (median, eight cycles per patient). Overall, 87.9% of the cycles required dose reduction because of impaired creatinine clearance. In 30 evaluable patients, the overall radiographic response rate was 96.7%, with 18 complete respo! nses (60%) and 11 partial responses (36.7%). Progression-free survival and overall survival were 7.1 months and 37 months, respectively. Grade I-IV toxicities were observed in 27 of 31 patients and included gastrointestinal disturbances in 58% (3.2% grade III), hematological complications in 80.6% (6.5% grade III), and renal toxicity in 29% (0% grade III/IV). High-dose MTX is associated with a high proportion of radiographic responses and a low proportion of grade III/IV toxicity in patients 70 or more years of age. High-dose MTX should be considered as a feasible treatment option in elderly patients with PCNSL.
• Abstracts from the 17th International Conference on Brain Tumor Research and Therapy June 9-12, 2008 Tokyo, Japan
  - Neuro Oncol 11(2):217-235 (2009)
  
• LETTER TO THE EDITOR
  Roesler R Schröder N Schwartsmann G - Neuro Oncol 11(2):236-237 (2009)
  
• SOCIETY NEWS
  - Neuro Oncol 11(2):238-239 (2009)