Multimodal management of surgery- and radiation-refractory meningiomas: an analysis of the French national tumor board meeting on meningiomas cohort.

PURPOSE: Meningiomas represent the most frequent tumor of the central nervous system in adults. While most meningiomas are efficiently treated by surgery and radiotherapy/radiosurgery, there is a small portion of radiation- and surgery-refractory tumors for which there is no clear recommendation for optimal management. The French National Tumor Board Meeting on Meningiomas (NTBM) offers a glimpse on the current management of such patients. METHODS: We retrospectively reviewed the charts of patients presented to the multidisciplinary Meeting between 2016 and 2019. We selected patients with a progressive disease after at least two treatments, including surgery and radiotherapy. RESULTS: In this multicentric cohort of 86 cases, patients harbored 17 (19.8%) WHO Grade I, 48 (55.8%) WHO Grade II and 21 (24.4%) WHO Grade III tumors. The median number of treatments received before inclusion was 3 (range: 2 - 11). Following the Board Meeting, 32 patients (37.2%) received chemotherapy, 11 (12.8%) surgery, 17 (19.8%) radiotherapy, 14 (16.3%) watchful observation and 12 (13.9%) palliative care. After a mean follow-up of 13 months post-inclusion, 32 patients (37.2%) had died from their disease. The mean progression free survival was 27 months after radiotherapy, 10 months after surgery, 8.5 months after chemotherapy (Bevacizumab: 9 months - Octreotide/Everolimus: 8 months). CONCLUSIONS: Surgery- and radiation-refractory meningiomas represent a heterogeneous group of tumors with a majority of WHO Grade II cases. If re-irradiation and redo-surgery are not possible, bevacizumab and octreotide-everolimus appear as a valuable option in heavily pre-treated patients considering the current EANO guidelines.

Long survival of patients with metastatic clear cell renal cell carcinoma. Results of real life study of 344 patients.

The treatment landscape in metastatic renal cell carcinoma has changed fundamentally over the last decade by the development of antiangiogenic agents, mammalian target of rapamycin inhibitors and immunotherapy. Outside of the context of a clinical trial, the treatments are used sequentially. We describe results under real-life conditions of a sequential treatment strategy, before the era of immunotherapy. All patients were treated according to their prognostic score (either Memorial Sloan Kettering Cancer Center or International Metastatic Renal Cell Carcinoma Database Consortium) for advanced renal cell carcinoma. A treatment strategy involving 1 to 4 lines was determined including a rechallenge criterion for the repeat use of a treatment class. Three hundred forty-four patients were included over 3 years. Overall survival was 57 months in patients with good or intermediate prognosis and 19 months in patients with poor prognosis. In the former group, the proportions of patients treated with 2 to 4 treatment lines were 70%, 38% and 16%, respectively. The best objective response rates for lines 1 to 4 were 46%, 36%, 16% and 17%, respectively. Grade III/IV toxicity did not appear to be cumulative. The recommended strategy was followed in 68% of patients. A large proportion of patients with good or intermediate prognosis who progress after two lines of treatment still have a performance status good enough to receive a systemic treatment, which justifies such a strategy. Overall survival of patients with good and intermediate prognosis was long, suggesting a benefit from the applied approach. These results might be used as selection criterion for the treatment of patients in the era of immune checkpoint inhibitors.

Absolute numbers of regulatory T cells and neutrophils in corticosteroid-free patients are predictive for response to bevacizumab in recurrent glioblastoma patients.

Bevacizumab (Bv) remains frequently prescribed in glioblastoma (GBM) patients, especially at recurrence. We conducted a prospective clinical trial with 29 recurrent GBM patients treated with Bv alone with a longitudinal follow-up of different circulating immune cells [complete blood count, myeloid-derived suppressor cells (MDSCs), classical, intermediate, non-classical and Tie2 monocytes, VEGFR1+ and regulatory T cells (Treg)]. We observed a significant increase for leucocytes, neutrophils, eosinophils and classical monocytes and a decrease for the fraction of Treg during the treatment. The best prognostic values for survival under Bv were obtained for basal neutrophils and Treg. Counts below 3.9 G/L for neutrophils and above 0.011 G/L for Treg were associated with an overall survival of 17.5 and 19.9 months, respectively, as compared with 5.4 and 5.6 months, respectively, for counts above and below these cutoffs (p = 0.004 and p < 0.001). No prognostic impact was observed for neutrophils in a retrospective cohort of 26 patients treated with nitrosoureas alone. In another retrospective validation cohort of 61 GBM patients treated at recurrence with a Bv-containing regimen, an interaction was observed between neutrophils and corticosteroid intake. The predictive value of neutrophils on survival under Bv was lost in patients treated with corticosteroids, when steroid-free patients with a low neutrophil count had a particularly long median survival of 3.4 years. These two simply accessible criteria (basal neutrophils and steroid intake) could be used to reserve this relatively costly treatment for patients likely to be the most responsive to Bv and prevent unnecessary side effects in others.

The DNA methylome of DDR genes and benefit from RT or TMZ in IDH mutant low-grade glioma treated in EORTC 22033.

The optimal treatment for patients with low-grade glioma (LGG) WHO grade II remains controversial. Overall survival ranges from 2 to over 15 years depending on molecular and clinical factors. Hence, risk-adjusted treatments are required for optimizing outcome and quality of life. We aim at identifying mechanisms and associated molecular markers predictive for benefit from radiotherapy (RT) or temozolomide (TMZ) in LGG patients treated in the randomized phase III trial EORTC 22033. As candidate biomarkers for these genotoxic treatments, we considered the DNA methylome of 410 DNA damage response (DDR) genes. We first identified 62 functionally relevant CpG sites located in the promoters of 24 DDR genes, using the LGG data from The Cancer Genome Atlas. Then we tested their association with outcome [progression-free survival (PFS)] depending on treatment in 120 LGG patients of EORTC 22033, whose tumors were mutant for isocitrate dehydrogenase 1 or 2 (IDHmt), the molecular hallmark of LGG. The results suggested that seven CpGs of four DDR genes may be predictive for longer PFS in one of the treatment arms that comprised MGMT, MLH3, RAD21, and SMC4. Most interestingly, the two CpGs identified for MGMT are the same, previously selected for the MGMT-STP27 score that is used to determine the methylation status of the MGMT gene. This score was higher in the LGG with 1p/19q codeletion, in this and other independent LGG datasets. It was predictive for PFS in the TMZ, but not in the RT arm of EORTC 22033. The results support the hypothesis that a high score predicts benefit from TMZ treatment for patients with IDHmt LGG, regardless of the 1p/19q status. This MGMT methylation score may identify patients who benefit from first-line treatment with TMZ, to defer RT for long-term preservation of cognitive function and quality of life.

Transformation From Atypical to Anaplastic Metastatic Meningioma: Evolutionary Turning Point Marked by Strong 18 F-FDG Avidity and Uptake Collapse From 68 GA-DOTATOC.

ABSTRACT: World Health Organization (WHO) grade III anaplastic meningioma is scarce. In this way, most studies compared WHO grade I and II. Otherwise, some authors are uncertain about using 18 F-FDG as a diagnostic tool to estimate the WHO grade, especially high. We report the case from a man with a grading tumor evolution from WHO grade II atypical to grade III anaplastic metastatic meningioma. This turning point was imaged using 68 Ga-DOTATOC and 18 F-FDG. Diagnostic was confirmed by histology. The case underlines the unparalleled power of molecular imaging characterized by high sensitivity staging and spectacular avidity changing relationship with grading tumor evolution.

Evolution of parenteral nutrition practices in a comprehensive cancer center: Comparative audits.

INTRODUCTION: Malnutrition affects 20% to 70% of oncology patients depending on the patient's age, type and stage of cancer. Two audits were carried out in 2016 and 2019 to evaluate the practice of Parenteral Nutrition (PN). METHODS: Records of adult medical inpatients who received PN between January 1, 2018 and April 30, 2019 were retrospectively analysed. Twenty criteria were defined. We conducted a statistical analysis to compare the two audit data. RESULTS: Between January 1, 2018 and April 30, 2019, 86 hospitalizations with a PN prescription were analysed. Of the 69 patients, 66% were female, the mean and median age was 60 years. These were most often medical oncology patients in palliative care. Gynecological and digestive tumors were the two main tumor localization. Bowel obstruction and palliative care management were the two main reasons for hospitalization. Nutritional assessment, amount of energy prescribed, monitoring, and duration of PN remain with poor results. CONCLUSION: Our study seems to show improvements in the relevance of PN indications, the prescription, and monitoring in patients due to the computerization of prescription and training of professionals. PN remains often prescribed in exclusive palliative situations. We need to continue our improvements, particularly for the initial clinical and biological assessment, and the monitoring. It requires a referral team to improve management of patients treated with PN.

Afatinib maintenance therapy following post-operative radiochemotherapy in head and neck squamous cell carcinoma: Results from the phase III randomised double-blind placebo-controlled study BIB2992ORL (GORTEC 2010-02).

OBJECTIVE: We investigated the efficacy and safety of afatinib maintenance therapy in patients with head and neck squamous cell carcinoma (HNSCC) with macroscopically complete resection and adjuvant radiochemotherapy (RCT). METHODS: This French multicentric randomised phase III double-blind placebo-controlled study included adult patients with ECOG-PS≤2, normal haematological, hepatic and renal functions, and non-metastatic, histologically confirmed HNSCC of the oral cavity, oropharynx, larynx or hypopharynx, with macroscopically complete resection and adjuvant RCT (≥2 cycles of cisplatin 100 mg/m2 J1, J22, J43 and 66Gy (2Gy/fraction, 5 fractions/week, conventional or intensity modulated radiotherapy ≥60Gy). Randomised patients were planned to receive either afatinib (afa arm) or placebo (control arm (C)) as maintenance therapy for one year. Primary endpoint was disease free survival (DFS). A 15% improvement in DFS was expected at 2 years with afatinib (from 55 to 70%). RESULTS: Among the 167 patients with resected HNSCC included in 19 cancer centres and hospitals from Dec 2011, 134 patients were randomised to receive one-year maintenance afatinib or placebo (afa:67; C:67). Benefit/risk ratio was below assumptions and independent advisory committee recommended to stop the study in Feb 2017, the sponsor decided premature study discontinuation, with a 2-year follow-up for the last randomised patient. 2y-DFS was 61% (95% CI 0.48-0.72) in the afatinib group and 64% (95% CI 0.51-0.74) in the placebo group (HR 1.12, 95% CI 0.70-1.80). CONCLUSION: Maintenance therapy with afatinib compared with placebo following post-operative RCT in patients with HNSCC did not significantly improve 2y-DFS and should not be recommended in this setting outside clinical trials. CLINICALTRIALS: gov identifier NCT01427478.

Incidence and characteristics of pseudoprogression in IDH-mutant high-grade gliomas: A POLA network study.

BACKGROUND: Incidence and characteristics of pseudoprogression in isocitrate dehydrogenase-mutant high-grade gliomas (IDHmt HGG) remain to be specifically described. METHODS: We analyzed pseudoprogression characteristics and explored the possibility of pseudoprogression misdiagnosis in IDHmt HGG patients, treated with radiotherapy (RT) (with or without chemotherapy [CT]), included in the French POLA network. Pseudoprogression was analyzed in patients with MRI available for review (reference cohort, n = 200). Pseudoprogression misdiagnosis was estimated in this cohort and in an independent cohort (control cohort, n = 543) based on progression-free survival before and after first progression. RESULTS: In the reference cohort, 38 patients (19%) presented a pseudoprogression after a median time of 10.5 months after RT. Pseudoprogression characteristics were similar across IDHmt HGG subtypes. In most patients, it consisted of the appearance of one or several infracentimetric, asymptomatic, contrast-enhanced lesions occurring within 2 years after RT. The only factor associated with pseudoprogression occurrence was adjuvant PCV CT. Among patients considered as having a first true progression, 7 out of 41 (17%) in the reference cohort and 35 out of 203 (17%) in the control cohort were retrospectively suspected to have a misdiagnosed pseudoprogression. Patients with a misdiagnosed pseudoprogression were characterized by a time to event and an outcome similar to that of patients with a pseudoprogression but presented with larger and more symptomatic lesions. CONCLUSION: In patients with an IDHmt HGG, pseudoprogression occurs later than in IDH-wildtype glioblastomas and seems not only frequent but also frequently misdiagnosed. Within the first 2 years after RT, the possibility of a pseudoprogression should be carefully considered.

Radiotherapy combined with nivolumab or temozolomide for newly diagnosed glioblastoma with unmethylated MGMT promoter: An international randomized phase III trial.

BACKGROUND: Addition of temozolomide (TMZ) to radiotherapy (RT) improves overall survival (OS) in patients with glioblastoma (GBM), but previous studies suggest that patients with tumors harboring an unmethylated MGMT promoter derive minimal benefit. The aim of this open-label, phase III CheckMate 498 study was to evaluate the efficacy of nivolumab (NIVO) + RT compared with TMZ + RT in newly diagnosed GBM with unmethylated MGMT promoter. METHODS: Patients were randomized 1:1 to standard RT (60 Gy) + NIVO (240 mg every 2 weeks for eight cycles, then 480 mg every 4 weeks) or RT + TMZ (75 mg/m2 daily during RT and 150-200 mg/m2/day 5/28 days during maintenance). The primary endpoint was OS. RESULTS: A total of 560 patients were randomized, 280 to each arm. Median OS (mOS) was 13.4 months (95% CI, 12.6 to 14.3) with NIVO + RT and 14.9 months (95% CI, 13.3 to 16.1) with TMZ + RT (hazard ratio [HR], 1.31; 95% CI, 1.09 to 1.58; P = .0037). Median progression-free survival was 6.0 months (95% CI, 5.7 to 6.2) with NIVO + RT and 6.2 months (95% CI, 5.9 to 6.7) with TMZ + RT (HR, 1.38; 95% CI, 1.15 to 1.65). Response rates were 7.8% (9/116) with NIVO + RT and 7.2% (8/111) with TMZ + RT; grade 3/4 treatment-related adverse event (TRAE) rates were 21.9% and 25.1%, and any-grade serious TRAE rates were 17.3% and 7.6%, respectively. CONCLUSIONS: The study did not meet the primary endpoint of improved OS; TMZ + RT demonstrated a longer mOS than NIVO + RT. No new safety signals were detected with NIVO in this study. The difference between the study treatment arms is consistent with the use of TMZ + RT as the standard of care for GBM.ClinicalTrials.gov NCT02617589.

Comparison of tumor response by Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST in patients treated with sorafenib for hepatocellular carcinoma.

BACKGROUND: A significant improvement in overall survival (OS) was demonstrated in patients with advanced hepatocellular carcinoma (HCC) who received sorafenib (Sor) in the Sorafenib HCC Assessment Randomized Protocol (SHARP) study, in contrast to a response rate (RR) of 2% assessed according to Response Evaluation Criteria in Solid Tumors (RECIST). Modified RECIST (mRECIST) were developed to assess the response in patients with HCC, based on measurement of viable tumor with arterial enhancement on a computed tomography (CT) scan. In the current study, mRECIST were evaluated and were compared with RECIST in patients who received Sor for advanced HCC. METHODS: The authors retrospectively analyzed 53 patients who received Sor for advanced HCC. Patients must to have undergone a 4-phase CT scan before treatment and repeatedly thereafter. CT scans were analyzed using RECIST 1.1 and mRECIST. RESULTS: The rates of objective response (OR), stable disease (SD), and progressive disease (PD) were 2%, 79%, and 19%, respectively, according to RECIST and 23%, 57%, and 21%, respectively, according to mRECIST (P < .001). Patients who achieved an OR according to mRECIST had a longer OS than nonresponding patients with SD or PD (median OS, 18 months and 8 months, respectively; P = .013). In the 42 patients who achieved SD according to RECIST, OS differed depending on tumor response according to mRECIST, with a median OS of 17 months, 10 months, and 4 months for patients who achieved an OR (n = 11), SD (n = 29), and PD (n = 2), respectively (P = .016). CONCLUSIONS: The current series validated mRECIST in patients who received Sor for advanced HCC. The majority of patients who had SD according to RECIST had a different prognosis according to mRECIST. The results indicated that, for patients with HCC, mRECIST should be used for the standard assessment of treatment efficacy, particularly in patients who are receiving antiangiogenic drugs.

Metronomic Cyclophosphamide With Cisplatin and Bevacizumab for Refractory Anaplastic Ependymoma: A Retrospective Study.

BACKGROUND/AIM: Anaplastic ependymoma is a rare cancer of the central nervous system. The treatment includes optimal resection with focal radiotherapy. Some case reports or retrospective studies have suggested efficacy of regimens containing platinum or bevacizumab. We describe the feasibility and clinical benefit of the cisplatin-bevacizumab-cyclophosphamide treatment of anaplastic ependymoma. PATIENTS AND METHODS: Patients were identified through the Adolescent and Young Adults (AYAS) brain tumor national Web conference. We estimated the median progression-free (PFS) and overall survival (OS). RESULTS: There were eight patients with anaplastic ependymoma, with a median age of 36 years. The median OS was 19.9 months and median PFS was 12.3 months. Three patients obtained partial response, four stable disease, and one patient had disease progression during induction. Six patients received maintenance with a median duration of 224 days. CONCLUSION: This study confirms the tolerance of bevacizumab-cyclophosphamide-cisplatin treatment of anaplastic ependymoma. The clinical benefit seems even superior to that described in the literature.

Delayed [ 18 F]-FDG PET Imaging Increases Diagnostic Performance and Reproducibility to Differentiate Recurrence of Brain Metastases From Radionecrosis.

PURPOSE: Differentiating brain metastasis recurrence from radiation necrosis can be challenging during MRI follow-up after stereotactic radiotherapy. [ 18 F]-FDG is the most available PET tracer, but standard images performed 30 to 60 minutes postinjection provide insufficient accuracy. We compared the diagnostic performance and interobserver agreement of [ 18 F]-FDG PET with delayed images (4-5 hours postinjection) with the ones provided by standard and dual-time-point imaging. METHODS: Consecutive patients referred for brain [ 18 F]-FDG PET after inconclusive MRI were retrospectively included between 2015 and 2020 in 3 centers. Two independent nuclear medicine physicians interpreted standard (visually), delayed (visually), and dual-time-point (semiquantitatively) images, respectively. Adjudication was applied in case of discrepancy. The final diagnosis was confirmed histologically or after 6 months of MRI follow-up. Areas under the receiver operating characteristic curves were pairwise compared. RESULTS: Forty-eight lesions from 46 patients were analyzed. Primary tumors were mostly located in the lungs (57%) and breast (23%). The median delay between radiotherapy and PET was 15.7 months. The final diagnosis was tumor recurrence in 24 of 48 lesions (50%), with histological confirmation in 19 of 48 lesions (40%). Delayed images provided a larger area under the receiver operating characteristic curve (0.88; 95% confidence interval [CI], 0.75-0.95) than both standard (0.69; 95% CI, 0.54-0.81; P = 0.0014) and dual-time-point imaging (0.77; 95% CI, 0.63-0.88; P = 0.045), respectively. Interobserver agreement was almost perfect with delayed images ( κ = 0.83), whereas it was moderate with both standard ( κ = 0.48) and dual-time-point images ( κ = 0.61). CONCLUSIONS: [ 18 F]-FDG PET with delayed images is an accurate and reliable alternative to differentiate metastasis recurrence from radiation necrosis in case of inconclusive MRI after brain stereotactic radiotherapy.

Characteristics, Patterns of Care and Predictive Geriatric Factors in Elderly Patients Treated for High-Grade IDH-Mutant Gliomas: A French POLA Network Study.

Background: Describe the characteristics, patterns of care, and predictive geriatric factors of elderly patients with IDHm high-grade glioma (HGG) included in the French POLA network. Material and Methods: The characteristics of elderly (≥70 years) patients IDHm HGG were compared to those of younger patients IDHm HGG (<70 years) and of elderly patients IDHwt HGG. Geriatric features were collected. Results: Out of 1433 HGG patients included, 119 (8.3%) were ≥70 years. Among them, 39 presented with IDHm HGG. The main characteristics of elderly IDHm HGG were different from those of elderly IDHwt HGG but similar to those of younger IDHm HGG. In contrast, their therapeutic management was different from those of younger IDHm HGG with less frequent gross total resection and radiotherapy. The median progression-free survival (PFS) and overall survival (OS) were longer for elderly patients IDHm HGG (29.3 months and 62.1 months) than elderly patients IDHwt HGG (8.3 months and 13.3 months) but shorter than those of younger patients IDHm HGG (69.1 months and not reached). Geriatric factors associated with PFS and OS were mobility, neuropsychological disorders, body mass index, and autonomy. Geriatric factors associated with PFS and OS were mobility, neuropsychological disorders, and body mass index, and autonomy. Conclusion: the outcome of IDHm HGG in elderly patients is better than that of IDHwt HGG. Geriatric assessment may be particularly important to optimally manage these patients.

Trabectedin for recurrent WHO grade 2 or 3 meningioma: A randomized phase II study of the EORTC Brain Tumor Group (EORTC-1320-BTG).

BACKGROUND: No systemic treatment has been established for meningioma progressing after local therapies. METHODS: This randomized, multicenter, open-label, phase II study included adult patients with recurrent WHO grade 2 or 3 meningioma. Patients were 2:1 randomly assigned to intravenous trabectedin (1.5 mg/m2 every 3 weeks) or local standard of care (LOC). The primary endpoint was progression-free survival (PFS). Secondary endpoints comprised overall survival (OS), objective radiological response, safety, quality of life (QoL) assessment using the QLQ-C30 and QLQ-BN20 questionnaires, and we performed tissue-based exploratory molecular analyses. RESULTS: Ninety patients were randomized (n = 29 in LOC, n = 61 in trabectedin arm). With 71 events, median PFS was 4.17 months in the LOC and 2.43 months in the trabectedin arm (hazard ratio [HR] = 1.42; 80% CI, 1.00-2.03; P = .294) with a PFS-6 rate of 29.1% (95% CI, 11.9%-48.8%) and 21.1% (95% CI, 11.3%-32.9%), respectively. Median OS was 10.61 months in the LOC and 11.37 months in the trabectedin arm (HR = 0.98; 95% CI, 0.54-1.76; P = .94). Grade ≥3 adverse events occurred in 44.4% of patients in the LOC and 59% of patients in the trabectedin arm. Enrolled patients had impeded global QoL and overall functionality and high fatigue before initiation of systemic therapy. DNA methylation class, performance status, presence of a relevant co-morbidity, steroid use, and right hemisphere involvement at baseline were independently associated with OS. CONCLUSIONS: Trabectedin did not improve PFS and OS and was associated with higher toxicity than LOC treatment in patients with non-benign meningioma. Tumor DNA methylation class is an independent prognostic factor for OS.

Impact of previous nivolumab treatment on the response to taxanes in patients with recurrent/metastatic head and neck squamous cell carcinoma.

BACKGROUND: Immune checkpoint inhibitors are widely used in recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC). We aimed to describe response rates to taxanes after progression on nivolumab in R/M HNSCC patients. METHODS: In this multicentric retrospective comparative study, we included patients treated with taxane monotherapy from 2014 to 2020. Patients were divided into two groups depending on whether they received nivolumab before taxanes (post-nivolumab group) or not (control group). The primary end-point was objective response rate (ORR) comparison between the two groups. The secondary end-points included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and PFS ratio (PFSr=PFS associated with taxanes divided by PFS associated with the previous line of treatment), a survival marker used for comparison of different treatment lines. RESULTS: Between July 2014 and August 2020, 185 patients were included (114 in the control group and 71 in the post-nivolumab group). ORR was significantly higher in the post-nivolumab group (39.4% versus 26.3%, p = 0.03) as was DCR (69% versus 50%, P = 0.06). The median OS (7.5 months) and PFS (3.5 months) were not significantly different in the two groups, whereas PFSr was significantly improved in the post-nivolumab group (1.63 versus 1.11, P = 0.004). CONCLUSION: Response and DCRs with taxanes are improved after prior exposure to nivolumab. Thus, taxane monotherapy could be a good choice as third-line therapy after nivolumab following a platinum-based first line. These results currently apply to patients without access to or potential benefit from first-line pembrolizumab.

Memory in low-grade glioma patients treated with radiotherapy or temozolomide: a correlative analysis of EORTC study 22033-26033.

BACKGROUND: EORTC study 22033-26033 showed no difference in progression-free survival between high-risk low-grade glioma receiving either radiotherapy (RT) or temozolomide (TMZ) chemotherapy alone as primary treatment. Considering the potential long-term deleterious impact of RT on memory functioning, this study aims to determine whether TMZ is associated with less impaired memory functioning. METHODS: Using the Visual Verbal Learning Test (VVLT), memory functioning was evaluated at baseline and subsequently every 6 months. Minimal compliance for statistical analyses was set at 60%. Conventional indices of memory performance (VVLT Immediate Recall, Total Recall, Learning Capacity, and Delayed Recall) were used as outcome measures. Using a mixed linear model, memory functioning was compared between treatment arms and over time. RESULTS: Neuropsychological assessment was performed in 98 patients (53 RT, 46 TMZ). At 12 months, compliance had dropped to 66%, restricting analyses to baseline, 6 months, and 12 months. At baseline, patients in either treatment arm did not differ in memory functioning, sex, age, or educational level. Over time, patients in both arms showed improvement in Immediate Recall (P = 0.017) and total number of words recalled (Total Recall; P < 0.001, albeit with delayed improvement in RT patients (group by time; P = 0.011). Memory functioning was not associated with RT gross, clinical, or planned target volumes. CONCLUSION: In patients with high-risk low-grade glioma there is no indication that in the first year after treatment, RT has a deleterious effect on memory function compared with TMZ chemotherapy.

DNA methylation in glioblastoma: impact on gene expression and clinical outcome.

BACKGROUND: Changes in promoter DNA methylation pattern of genes involved in key biological pathways have been reported in glioblastoma. Genome-wide assessments of DNA methylation levels are now required to decipher the epigenetic events involved in the aggressive phenotype of glioblastoma, and to guide new treatment strategies. RESULTS: We performed a whole-genome integrative analysis of methylation and gene expression profiles in 40 newly diagnosed glioblastoma patients. We also screened for associations between the level of methylation of CpG sites and overall survival in a cohort of 50 patients uniformly treated by surgery, radiotherapy and chemotherapy with concomitant and adjuvant temozolomide (STUPP protocol). The methylation analysis identified 616 CpG sites differentially methylated between glioblastoma and control brain, a quarter of which was differentially expressed in a concordant way. Thirteen of the genes with concordant CpG sites displayed an inverse correlation between promoter methylation and expression level in glioblastomas: B3GNT5, FABP7, ZNF217, BST2, OAS1, SLC13A5, GSTM5, ME1, UBXD3, TSPYL5, FAAH, C7orf13, and C3orf14. Survival analysis identified six CpG sites associated with overall survival. SOX10 promoter methylation status (two CpG sites) stratified patients similarly to MGMT status, but with a higher Area Under the Curve (0.78 vs. 0.71, p-value < 5e-04). The methylation status of the FNDC3B, TBX3, DGKI, and FSD1 promoters identified patients with MGMT-methylated tumors that did not respond to STUPP treatment (p-value < 1e-04). CONCLUSIONS: This study provides the first genome-wide integrative analysis of DNA methylation and gene expression profiles obtained from the same GBM cohort. We also present a methylome-based survival analysis for one of the largest uniformly treated GBM cohort ever studied, for more than 27,000 CpG sites. We have identified genes whose expression may be tightly regulated by epigenetic mechanisms and markers that may guide treatment decisions.

Overview of cellular immunotherapy for patients with glioblastoma.

High grade gliomas (HGG) including glioblastomas (GBM) are the most common and devastating primary brain tumours. Despite important progresses in GBM treatment that currently includes surgery combined to radio- and chemotherapy, GBM patients' prognosis remains very poor. Immunotherapy is one of the new promising therapeutic approaches that can specifically target tumour cells. Such an approach could also maintain long term antitumour responses without inducing neurologic defects. Since the past 25 years, adoptive and active immunotherapies using lymphokine-activated killer cells, cytotoxic T cells, tumour-infiltrating lymphocytes, autologous tumour cells, and dendritic cells have been tested in phase I/II clinical trials with HGG patients. This paper inventories these cellular immunotherapeutic strategies and discusses their efficacy, limits, and future perspectives for optimizing the treatment to achieve clinical benefits for GBM patients.

Survival and prognostic factors in a series of adults with medulloblastomas.

OBJECT: In this article, the authors report their experience in the management of adult patients with medulloblastoma at their institution to identify prognostic factors important for survival and disease control. METHODS: Between 1977 and 2005, 27 patients who were >or=16 years old and had medulloblastoma were treated consecutively. There were 16 women and 11 men with a median age of 21 years (range 16-54 years). Gross-total resection was performed in 21 patients, subtotal (>or=90%) in 2, incomplete in 1, and biopsy in 3 patients. Six patients had the desmoplastic variant, and 21 patients presented with classic medulloblastoma. Staging according to the Chang classification showed 4 patients with tumors invading the brainstem (2 with Stage T3b and 2 with Stage T4), 3 patients with metastases (2 with Stage M2 and 1 with Stage M3), and 1 patient in whom the stage was unknown (Stage MX) who died 10 days postoperatively. Twenty patients were assigned to the standard-risk group and 7 to the high-risk group. All patients except the one whose status was classified as Stage MX underwent craniospinal radiotherapy at our institution. Seven patients received chemotherapy before radiotherapy. RESULTS: The 5- and 10-year overall survival rates for the present study were 81 and 62%, respectively. The median overall survival time was 17.7 years. The 5- and 10-year event-free survival rates were 72 and 57%, respectively. The median event-free survival time was 17.9 years. Univariate analysis showed that survival was significantly correlated with sex (women had a better prognosis than men) and M stage (patients without metastases had a better outcome). Patient age, duration of symptoms, Karnofsky Performance Scale score at presentation, hydrocephalus, tumor location, brainstem invasion, extent of resection, histological subtype, preradiotherapy chemotherapy, risk group, and period of presentation were not significant variables. Multivariate analysis identified sex and M stage as well as the period of presentation as independent prognostic factors for overall and event-free survival times. Eleven patients suffered tumor recurrence within a median time of 4.2 years. The posterior fossa was not the most common site of recurrence, and delayed recurrence was not rare. All patients in whom the tumor recurred have died despite aggressive treatments. The median survival time after diagnosis of recurrence was 2.5 years. Questionnaires on quality of life and cognition showed high scores in favor of limited negative effects in the perception of mental and physical health after treatment. The authors observed 1 supposed second malignancy (thyroid carcinoma) and no evidence of pituitary dysfunction. CONCLUSIONS: Long-term survival is possible in adults treated for medulloblastoma. Although rare, metastasis seeding at presentation is a poor prognostic factor. The possibility of delayed recurrence necessitates close follow-up of all patients. Tumor recurrences should be treated with aggressive therapies as some patients may have sustained response. Adjuvant chemotherapy should be given to high-risk patients, but its role in reducing recurrences, particularly distant ones, remains unclear in the standard-risk group.

Rethinking Alkylating(-Like) Agents for Solid Tumor Management.

Although old molecules, alkylating agents and platinum derivatives are still widely used in the treatment of various solid tumors. However, systemic toxicity and cellular resistance mechanisms impede their efficacy. Innovative strategies, including local administration, optimization of treatment schedule/dosage, synergistic combinations, and the encapsulation of bioactive molecules in smart, multifunctional drug delivery systems, have shown promising results in potentiating anticancer activity while circumventing such hurdles. Furthermore, questioning of the old paradigm according to which nuclear DNA is the critical target of their anticancer activity has shed light on subcellular alternative and neglected targets that obviously participate in the mediation of cytotoxicity or resistance. Thus, rethinking of the use of these pivotal antineoplastic agents appears critical to improve clinical outcomes in the management of solid tumors.