Supratentorial Glioblastoma Multiforme Research Articles

H3K27M/I Mutations Promote Context-Dependent Transformation in Acute Myeloid Leukemia with RUNX1 Alterations

Neomorphic missense mutations in histone H3 genes (most notably K27M and K36M) are frequent in solid cancers such as diffuse intrinsic pontine gliomas (DIPG), supratentorial glioblastoma multiforme (GBM) or chondroblastomas. Despite high incidences of these mutations and their profound impact on global histone H3 lysine methylation, their relevance has not been studied in hematologic cancers.Here, we report the first identification of histone H3 mutations in AML. We find that two of 415 AML patients in the Leucegene cohort and one of 200 patients in the TCGA cohort carry either K27M (n=2) or K27I (n=1) mutations in one of twelve canonical H3 genes. No K36M or other lysine-to-methionine mutations on any of the H3 genes, and no K27M mutation on any of the replication-independent H3.3 variant genes were detected in the same cohorts. H3K27 mutations invariably occurred in the context of either truncating RUNX1 mutations or t(8;21)(q22;q22), suggesting an association with altered RUNX1 function (p < 0.003; Fisher exact test). Characterization of two of the identified H3K27 mutant patient specimens revealed that both samples contained major sub-clones with markedly reduced H3K27me2/3 levels. The H3K27 mutants but not co-occurring mutant ASXL2 or USP7 alleles were only detectable in the H3K27me2/3-low sub-clones, demonstrating that the H3K27 mutations had the most profound impact on H3K27me2/3 in these patients. Moreover, although a heterozygous TET2S1203R mutation was equally present in both H3K27me2/3-high and low sub-fractions, a homozygous RUNX1L98Sfs*22 mutation was restricted to the H3K27me2/3-low sub-clone, further strengthening the possibility that impaired RUNX1 function and reduced H3K27me2/3 associate with each other.We tested the possibility that H3K27 mutants may specifically collaborate with the product of the t(8;21) translocation (AML1-ETO-9a ; AE9a) in transduced mouse hematopoietic stem and progenitor cells (HSPCs). Selectivity of this collaboration was assessed using the combination of the H3K27 mutant gene with the MLL-AF9 fusion product. Whereas expression of H3 WT resulted in a mild competitive proliferation disadvantage in both AE9a and MLL-AF9 cells, expression of H3.3K27I/M conferred a proliferative advantage in AE9a cells in three of four H3K27I -infected and in all H3K27M- infected cultures. This was not observed in MLL-AF9 cells, where H3K27I/M expressing cells were progressively outcompeted in the same culture period. H3K27I/M -infected AE9a cells exhibited significant reductions in H3K27me2/3 and elevated levels of H3K27 acetylation (H3K27ac) compared to H3WT -infected control cells despite undiminished Ezh1, Ezh2 and Suz12 protein levels. In the context of AE9a driven AML in vivo, expression of H3K27M caused a striking disease acceleration leading to all mice reaching end stage disease with a median of 88 days, in contrast to recipients of AE9a ; empty vector or AE9a ; H3WT cells, of which none or only two of nine transplanted mice succumbed to AML within 330 days, respectively (p<0.0001, Log-rank test). Seven of nine AE9a ; H3.3K27I transplanted mice developed AML with a median latency of 208 days (p=0.0004, Log-rank test, compared to controls). Importantly, combined expression of H3K27I or H3K27M with MLL-AF9 did not change disease latencies compared to control groups, indicating selectivity.We next tested the influence of the H3K27M mutation on the differentiation and proliferation of human cord blood CD34+ HSPCs ex vivo . Relative to controls, H3.3K27M expression led to an 8-fold net expansion of a phenotypically primitive CD34+/CD45RA-/CD90+ cell population, which surprisingly lacked expression of the CD133 stem cell marker. Interestingly, granulocytic/granulo-monocytic colony-forming cells (CFU-G/GM) but not multipotent colony-forming cells (granulo/erythroid/monocytic/megakaryocytic; CFU-GEMM) were expanded in 14d cultures initiated with H3K27M transduced CD34+ CB cells when compared to controls. Xenografts of transduced CD34+ CB cells indicated a marginal loss in in vivo reconstitution activity by K27M-transduced cells, mostly at 6 and 12-week time-points.Taken together, our results represent the first description of neomorphic H3K27M/I mutations in AML. We demonstrate that these mutations have a profound impact on H3K27me2/3 and provide evidence that they selectively collaborate with impaired RUNX1 function. DisclosuresNo relevant conflicts of interest to declare.

Tumor-induced mortality in adult primary supratentorial glioblastoma multiforme with different age subgroups.

To assess the independent determinants of tumor-induced mortality in different age subgroups after considering competing risk (CR). Data were extracted from the SEER database. The independent determinants of tumor-induced mortality were defined by CR analysis and validated by conditional inference trees. A CR nomogram was created based on the proportional subdistribution hazard model. The different age subgroups had their own independent determinants of tumor-induced mortality. Using these variables, a CR nomogram was built with good discrimination and calibration. When conducting population-based cohort studies, a CR analysis is recommended for cancers with short survival and high mortality. A CR nomogram represents the first attempt at a predictive model for quantifying tumor-induced mortality.

TM1-3 Improved prediction of surgical resectability in patients with glioblastoma multiforme using an artificial neural network

ObjectivesIn managing a patient with glioblastoma multiforme (GBM), a surgeon must weigh up whether sufficient tumour can be removed so that the patient can enjoy the benefits of decompression and cytoreduction, without impacting on the patient’s neurological status. In a previous study we identified the five most important anatomical features on a pre-operative MRI that are predictive of surgical resectability and used them to develop a grading system. The aim of this study was to apply an artificial neural network (ANN) to improve the prediction of surgical resectability.MethodsA prospectively maintained database was searched between February and August 2017 to identify all adult patients with supratentorial GBM that underwent resection. Pre-operative MRI scans were scored using the aforementioned grading system and post-operative scans assessed to determine the extent of resection. Performance of the standard grading system and ANN were then evaluated by analysing their Receiver Operator Characteristic curves; Area Under Curve (AUC) and accuracy were calculated and compared using the t-­test with a value of p&lt;0.05 considered significant.ResultsIn all, 47 patients were included, of which 18 (38.3%) were found to have complete excision. The AUC and accuracy were significantly greater using the ANN compared to the standard grading system (0.87 vs. 0.79 and 0.81 vs. 0.77 respectively; p&lt;0.01 in both cases).ConclusionsAn ANN allows for improved prediction of surgical resectability in patients with GBM.

Efficacy and safety of nimotuzumab in addition to radiotherapy and temozolomide for cerebral glioblastoma: a phase II multicenter clinical trial

Background: Nimotuzumab is a humanized anti-epidermal growth factor receptor (EGFR) antibody that has shown preclinical and clinical anticancer activity in cerebral glioblastoma multiforme (GBM). We conducted a phase II, single-arm, multicenter clinical trial to evaluate the benefit of adding nimotuzumab to current standard chemo-radiotherapy for patients with GBM with positive EGFR expression.Methods: Newly diagnosed patients with histologically proven single supratentorial GBM and epidermal growth factor receptor (EGFR) positive expressions were recruited. All patients were treated with nimotuzumab, administered once a week intravenously for 6 weeks in addition to radiotherapy with concomitant and adjuvant temozolomide after surgery. The primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary objectives included objective response rate (ORR) and toxicity.Results: A total of 39 patients were enrolled and 36 patients were evaluated for efficacy. The ORR at the end of RT was 72.2%. Median OS and PFS were 24.5 and 11.9 months. The 1-year OS and PFS rates were 83.3% and 49.3%. The 2-year OS and PFS rates were 51.1% and 29.0%. O (6)-methylquanine DNA methyl-tranferase (MGMT) expression is known to affect the efficacy of chemotherapy and status of its expression is examined. No significant correlation between treatment outcomes and MGMT status was found. Most frequent treatment-related toxicities were mild to moderate and included constipation, anorexia, fatigue, nausea, vomiting, and leucopenia.Conclusions: Our study show that nimotuzumab in addition to standard treatment is well tolerable and has increased survival in newly diagnosed GBM patients with EGFR positive expression.

A Phase 1/2 Trial of 5 Fraction Stereotactic Radiosurgery With 5 mm Margins With Concurrent and Adjuvant Temozolomide in Newly Diagnosed Supratentorial Glioblastoma Multiforme: Pattern of Recurrence Analysis

We sought to determine the pattern of recurrence of tumors treated with 5 fractions of stereotactic radiosurgery (SRS) with 5 mm margins delivered with concurrent and adjuvant temozolomide (TMZ) in newly diagnosed glioblastoma (GBM). Thirty adult patients with newly diagnosed supra-tentorial GBM were enrolled on an institutional review board approved protocol of 5 consecutive days of SRS in escalating doses in a 3+3 design on 4 dose levels: 25 Gy, 30 Gy, 35 Gy, and 40 Gy targeting the GTV of the resection cavity/residual tumor with a 5 mm CTV margin and 0 mm PTV margin. MRI T2 edema signal was not purposely targeted. In-field recurrences were scored if the initial site of recurrence was contained within the 95% prescription isodose line (IDL), which corresponds to 5 mm margin on the cavity/residual or if contiguous with tumors within the 95% IDL. Recurrent tumor located outside of the 95% IDL, between 5 and 20 mm from the cavity (and otherwise covered with typical 2 cm margins for IMRT), were scored as marginal. Recurrences presenting more than 20 mm away from the cavity were considered distal. From 2010 to 2016, 26 patients had progressed and were eligible for pattern of recurrence analysis, with a median follow-up of 14 months (range 2-53). Seventeen out of 26 cases (65%) showed in-field recurrence within the 95% IDL, including one patient who also presented with a distal recurrence. Six patients (23%) showed purely distal recurrences, and 3 patients developed marginal failures (12%). Eight out of the 10 patients in the highest 40 Gy dose level recurred locally. Looking at marginal failures, 2 out of the 3 cases received doses above 30 Gy, including one who received 38 Gy to the failure region. The median time to progression was 3.5 months (range 0.5-17) for infield failures, 9 months (range 5-33) for marginal failures, and 17 months (range 6-22) for distal failures. Median OS was 12 months in patients with in-field recurrence vs. 21 months for distal recurrence (median OS not reached for marginal recurrence). On univariate analysis, pattern of failure was not associated with the dose level received (P = 0.422), with the MGMT methylation status of the tumor (P = 0.820), or with the extent of resection (P = 0.1051). Four out of the 6 patients who developed radionecrosis showed a distal pattern of recurrence compared to those who did not develop radionecrosis (P = 0.0245). Despite dose escalation up to 40 Gy in 5 fractions with concurrent TMZ, the dominant pattern of failure for GBM was in-field. Tumor Control Probability analyses are ongoing to determine the 2 Gy equivalent dose delivered to the 12% of tumors that progressed between 5 and 20 mm. Radionecrosis, but not total dose or MGMT status, correlated with in-field tumor control.

Glioblastoma Multiforme: an Advanced Analysis of 153 Patients and Review of the Literature

Objective Glioblastoma multiforme (GBM) is an aggressive primary tumor with frequent recurrences that leaves patients with a short survival time and a low quality of life. The aim of this study was to review the prognostic factors in patients with glioblastoma multiforme. Material and Methods The focus of this retrospective study was a group of 153 patients with supratentorial GBM tumors, who were admitted to a tertiary-care referral academic center from 2005 to 2013. The factors associated with survival and local recurrence were assessed using the hazard ratio (HR) function of Cox proportional hazards regression and neural network analysis. Results Out of the 153 patients, 99 (64.7%) were male. The average age of the patients was 55.69 ± 15.10 years. The median overall survival (OS) and progression-free survival (PFS) rates were 14.0 and 7.10 months respectively. In the multivariate analysis, age (HR = 2.939, p &lt; 0.001), operative method (HR = 7.416, p &lt; 0.001), temozolomide (TMZ, HR = 11.723, p &lt; 0.001), lomustine (CCNU, HR = 8.139, p &lt; 0.001), occipital lobe involvement (HR = 3.088, p &lt; 0.001) and Karnofsky Performance Status (KPS, HR = 4.831, p &lt; 0.001) scores were shown to be significantly associated with a higher OS rate. Furthermore, higher KPS (HR = 7.292, p &lt; 0.001) readings, the operative method (HR = 0.493, p = 0.005), the use of CCNU (HR = 2.047, p = 0.003) and resection versus chemotherapy (HR = 0.171, p &lt; 0.001) were the significant factors associated with the local recurrence of the tumor. Conclusion Our findings suggest that the use of CCNU and TMZ, the operative method and higher KPS readings are associated with both higher survival and lower local recurrence rates.

Predicting surgical outcome in patients with glioblastoma multiforme using pre-operative magnetic resonance imaging: development and preliminary validation of a grading system

The lack of a simple, objective and reproducible system to describe glioblastoma multiforme (GBM) represents a major limitation in comparative effectiveness research. The objectives of this study were therefore to develop such a grading system and to validate it on patients who underwent surgical resection. A systematic review of the literature was performed to identify features on pre-operative magnetic resonance imaging (MRI) that predict the surgical outcome of patients with GBM. In all, the five most important features of GBM on pre-operative MRI were as follows: periventricular or deep location, corpus callosum or bilateral location, eloquent location, size and associated oedema. These were then used to develop a grading system. To validate this grading system, a retrospective cohort study of all adult patients with supratentorial GBM who underwent surgical resection between the 1 January 2014 and the 31 June 2015 was performed. There was a substantial agreement between the two neurosurgeons grading GBM (Cohen’s κ was 0.625; standard error 0.066). High-complexity lesions were significantly less likely to result in complete resection of contrast-enhancing tumour than low-complexity lesions (50.0 versus 3.4%; p = 0.0007). The proposed grading system may allow for the standardised communication of anatomical features of GBM identified on pre-operative MRI.

A Phase I/II Trial of 5 Fraction Stereotactic Radiosurgery With 5-mm Margins With Concurrent and Adjuvant Temozolomide in Newly Diagnosed Supratentorial Glioblastoma Multiforme

A Phase I/II Trial of 5 Fraction Stereotactic Radiosurgery With 5-mm Margins With Concurrent and Adjuvant Temozolomide in Newly Diagnosed Supratentorial Glioblastoma Multiforme

37: Results of a Phase I/II Trial of 5 Fraction Stereotactic Radiosurgery with Concurrent and Adjuvant Temozolomide in Newly Diagnosed Supratentorial Glioblastoma Multiforme

37: Results of a Phase I/II Trial of 5 Fraction Stereotactic Radiosurgery with Concurrent and Adjuvant Temozolomide in Newly Diagnosed Supratentorial Glioblastoma Multiforme

Association of the Extent of Resection With Survival in Glioblastoma

Glioblastoma multiforme (GBM) remains almost invariably fatal despite optimal surgical and medical therapy. The association between the extent of tumor resection (EOR) and outcome remains undefined, notwithstanding many relevant studies. To determine whether greater EOR is associated with improved 1- and 2-year overall survival and 6-month and 1-year progression-free survival in patients with GBM. Pubmed, CINAHL, and Web of Science (January 1, 1966, to December 1, 2015) were systematically reviewed with librarian guidance. Additional articles were included after consultation with experts and evaluation of bibliographies. Articles were collected from January 15 to December 1, 2015. Studies of adult patients with newly diagnosed supratentorial GBM comparing various EOR and presenting objective overall or progression-free survival data were included. Pediatric studies were excluded. Data were extracted from the text of articles or the Kaplan-Meier curves independently by investigators who were blinded to each other's results. Data were analyzed to assess mortality after gross total resection (GTR), subtotal resection (STR), and biopsy. The body of evidence was evaluated according to Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria and PRISMA guidelines. Relative risk (RR) for mortality at 1 and 2 years and progression at 6 months and 1 year. The search produced 37 studies suitable for inclusion (41 117 unique patients). The meta-analysis revealed decreased mortality for GTR compared with STR at 1 year (RR, 0.62; 95% CI, 0.56-0.69; P < .001; number needed to treat [NNT], 9) and 2 years (RR, 0.84; 95% CI, 0.79-0.89; P < .001; NNT, 17). The 1-year risk for mortality for STR compared with biopsy was reduced significantly (RR, 0.85; 95% CI, 0.80-0.91; P < .001). The risk for mortality was similarly decreased for any resection compared with biopsy at 1 year (RR, 0.77; 95% CI, 0.71-0.84; P < .001; NNT, 21) and 2 years (RR, 0.94; 95% CI, 0.89-1.00; P = .04; NNT, 593). The likelihood of disease progression was decreased with GTR compared with STR at 6 months (RR, 0.72; 95% CI, 0.48-1.09; P = .12; NNT, 14) and 1 year (RR, 0.66; 95% CI, 0.43-0.99; P < .001; NNT, 26). The quality of the body of evidence by the GRADE criteria was moderate to low. This analysis represents the largest systematic review and only quantitative systematic review to date performed on this subject. Compared with STR, GTR substantially improves overall and progression-free survival, but the quality of the supporting evidence is moderate to low.

Segmentation of peritumoral oedema offers a valuable radiological feature of cerebral metastasis.

Peritumoral oedema (PTO) is commonly observed on MRI in malignant brain tumours including brain metastasis (bMET) and glioblastoma multiforme (GBM). This study aimed to differentiate bMET from GBM by comparing the volume ratio of PTO to tumour lesion (Rvol). 56 patients with solitary bMET or GBM were enrolled, and MRI was analyzed by a semi-automatic methodology based on MATLAB (Mathworks, Natick, MA). The PTO volume (Voedema) was segmented for quantification using T2 fluid-attenuated inversion-recovery images, while the tumour volume was quantified with enhanced T1 images. The quantitative volume of the tumour, PTO and the ratio of PTO to tumour were interpreted using SPSS(®) (IBM Corp., New York, NY; formerly SPSS Inc., Chicago, IL) by considering different locations and pathologies. The tumour volumes of supratentorial GBM, supratentorial bMET (supra-bMET) and infratentorial bMET were 32.22 ± 21.9, 18.45 ± 17.28 and 11.40 ± 5.63 ml, respectively. The corresponding Voedema were 44.08 ± 25.84, 73.20 ± 40.35 and 23.74 ± 7.78 ml, respectively. The Voedema difference between supratentorial and infratentorial lesions is significant (p-value = 0.002). Supra-bMET has a smaller tumour volume (p-value = 0.032), but a larger PTO (p-value = 0.007). The ratio of Voedema to the tumour volume in bMET is statistically higher than that in GBM (p-value = 0.015). The cut-off ratio for identifying bMET from GBM is 3.9, with a specificity and sensitivity of 90.0% and 68.8%, respectively. Segmentation is an efficient method to quantify irregular PTO. bMET possesses more extensive oedema with smaller tumour volume than does GBM. The Rvol is a valuable index to distinguish bMET from GBM. This study presents a new method for the quantitation of PTO to differentiate bMET from GBM.

Phase 1/2 Trials of Temozolomide, Motexafin Gadolinium, and 60-Gy Fractionated Radiation for Newly Diagnosed Supratentorial Glioblastoma Multiforme: Final Results of RTOG 0513

The purpose of phase 1 was to determine the maximum tolerated dose (MTD) of motexafin gadolinium (MGd) given concurrently with temozolomide (TMZ) and radiation therapy (RT) in patients with newly diagnosed supratentorial glioblastoma multiforme (GBM). Phase 2 determined whether this combination improved overall survival (OS) and progression-free survival (PFS) in GBM recursive partitioning analysis class III to V patients compared to therapies for recently published historical controls. Dose escalation in phase 1 progressed through 3 cohorts until 2 of 6 patients experienced dose-limiting toxicity or a dose of 5mg/kg was reached. Once MTD was established, a 1-sided 1-sample log-rank test at significance level of .1 had 85% power to detect a median survival difference (13.69 vs 18.48months) with 60 deaths over a 12-month accrual period and an additional 18months of follow-up. OS and PFS were estimated using the Kaplan-Meier method. In phase 1, 24 patients were enrolled. The MTD established was 5mg/kg, given intravenously 5days a week for the first 10 RT fractions, then 3 times a weekfor the duration of RT. The 7 patients enrolled in the third dose level and the 94 enrolled in phase 2 received this dose. Of these 101 patients, 87 were eligible and evaluable. Median survival time was 15.6months (95% confidence interval [CI]: 12.9-17.6months), not significantly different from that of the historical control (P=.36). Median PFS was 7.6months (95% CI: 5.7-9.6months). One patient (1%) experienced a grade 5 adverse event possibly related to therapy during the concurrent phase, and none experience toxicity during adjuvant TMZ therapy. Treatment was well tolerated, but median OS did not reach improvement specified by protocol compared to historical control, indicating that the combination of standard RT with TMZ and MGd did not achieve a significant survival advantage.

Giant pediatric glioblastoma multiforme causing primary calvarial erosion and sutural diastasis presenting with enlarged head

Authors report a rare case of supratentorial glioblastoma multiforme in a 13-year-old boy, who had headache, vomiting and left sided hemiparesis for last 6 months. On evaluation by primary physician he was labeled as hydrocephalus in view of enlarged head with papilledema on fundoscopic evaluation and no imaging was carried out. On current admission, magnetic resonance imaging brain revealed a large heterogeneous mass lesion involving right frontoparietal region associated with massive perilesional edema causing significant mass effect. He underwent right fronto-temporal craniotomy and intraoperatively erosion of parietal bone was observed, unassociated with any extradural deposit of tumor. After surgery, he noticed improvement in headache along with hemiparesis. Primary calvarial erosion in glioblastoma is extremely rare, and there is paucity of literature as evident from the few case reports reported previously and all occurred in elderly, so current case is the first pediatric case having primary calvarial erosion. Management of such case and pertinent literature is briefly discussed.

Treatment results and outcome in elderly patients with glioblastoma multiforme – A retrospective single institution analysis

ObjectiveAlthough glioblastoma multiforme is more common in patients older than 65 years, the elderly population is often excluded from clinical studies. Decision making in this subgroup can be challenging due to the lack of evidence for different neurosurgical and adjuvant treatment strategies. MethodsIn this retrospective study, we evaluated clinical, treatment and survival data of 124 consecutive patients over 65 years of age with supratentorial glioblastoma multiforme. ResultsMedian OS was 6.0 months (std. error 0.783, 95% CI 4.456–7.535). Mean OS was 9.7 months (std. error 0.830, 95% CI 8.073–11.327). In univariate regression analysis, low KPS was of negative prognostic value (p<0.006 for KPS≤80), while greater advanced age did not have any impact on survival (p=0.591 for differences between groups). Gross total resection and subtotal resection led to significantly improved overall survival (median 15.0 and 11.0 months; p<0.02) compared to partial resection or biopsy (both 4.0 months), but complications were more common in subtotal and partial resections. The last observation did not reach statistical significance (p=0.06). Combinations of irradiation and Temozolomide chemotherapy proved to be more effective than other adjuvant therapies. Extent of resection (gross total resection vs. all others) and form of adjuvant treatment were the only factors of independent prognostic value in multivariate analysis (p=0.031 and p<0.001, respectively). ConclusionsIt appears that more aggressive treatment regimens can lead to longer overall survival in elderly glioblastoma multiforme patients. Gross total resection should be offered whenever safely possible; otherwise, biopsy may be preferred. Non-surgical treatment should consist of postoperative radiotherapy and concomitant and/or adjuvant chemotherapy. Possibly higher rates of hematological side effects in concomitant chemotherapy need to be further investigated.

Extended Daily Schedule of Temozolomide in Recurrent Glioblastoma: Single-Institution Report on a Series of 43 Patients

Background: Despite advances in surgical and first-line adjuvant treatment, glioblastoma multiforme (GBM) always recurs as disease natural history. Currently, there is no consensus as to the optimal second-line treatment of recurrent GBM. Patients and Methods: This is a retrospective study of a series of adult patients consecutively treated at a single institution for supratentorial cerebral GBM at first relapse. All patients had previously received the standard concomitant radiochemotherapy protocol as first-line therapy. At recurrence/progression, all patients were treated with a metronomic temozolomide (TMZ) schedule at a daily dosage of 50 mg/m2 of body surface. Radiologic, clinical, and laboratory data were collected for all patients, with a minimum follow-up of 18 months. Results: From January 2010 to June 2011, 43 patients were treated at our facility. A mean of 10 metronomic TMZ cycles (range, 3 - 21) was administered. Radiologically, we observed 2 complete responses (4.6%), 16 partial responses (37.2%), 18 stable disease (41.9%) and 7 progressive disease (16.3%). Steroids administration was safely tapered in 23 patients (53.5%). Karnofsky-Performance-Status (KPS) results improved in 20 patients (46.5%), stabilized in 20 (46.5%), and worsened in 3 patients (7.0%), with a mean KPS score increased from 65.1 at baseline to 75.3 at follow-up. Six-month progression-free survival was 53.5. One year after recurrence/progression diagnosis, 22 patients were still alive, with a 1-year overall survival rate of 51.6%. Conclusions: The proposed TMZ schedule seems a safe and effective option for patients with recurrent GBM, with high radiologic response rates and good clinical impact. Strict clinical observation of patients may enable obtaining better results than those already present in the literature and further investigation appears auspicable.

Prognostic value of the preoperative immunological profile in patients with glioblastoma.

Background:Aim of our study was to determine the predictive impact of certain serum immunological markers on overall survival (OS) in patients with glioblastoma multiforme (GBM).Methods:We assayed prospectively values of interleukin 2 (IL-2), immunoglobulin G (IgG), C4, CD3+, CD4+ and CD8+ cells via flow cytometry, enzyme-linked immunosorbent assay (ELISA) and radial immunodiffusion in preoperative sera of adult patients with de novo histologically confirmed supratentorial GBM. Kaplan-Meier method and Cox proportional hazards models were used to assess clinical, laboratory, and treatment prognostic factors for OS.Results:Twenty-six consecutive patients were identified with a mean age of 59.6 years. Median follow up was 12 months. Lower IL-2 values (<7.97 pg/ml vs. ≥7.97 pg/ml, P = 0.029) und CD4+ counts (<200 cells/μl vs. ≥200 cells/μl, P < 0.001) correlated significantly with a shorter OS. The independent prognostic relevance of CD4 + counts was confirmed by the multivariate analysis (HR = 0.010, 95% CI 0.001-0.226, P = 0.011). Further independent prognostic factors for OS were type of resection (resection vs. biopsy) and administration of radiotherapy (yes/no).Conclusion:Preoperative values IL-2 and CD4+ cells in sera may carry a prognostic impact. Novel diagnostic models prior to histopathological confirmation may be used to predict prognosis of patients with GBM. Future studies should investigate whether targeting immune factors, such as CD4+ and IL-2, may improve the prognosis of patients with GBM.

Adenovirus-mediated gene therapy with sitimagene ceradenovec followed by intravenous ganciclovir for patients with operable high-grade glioma (ASPECT): a randomised, open-label, phase 3 trial

Besides the use of temozolomide and radiotherapy for patients with favourable methylation status, little progress has been made in the treatment of adult glioblastoma. Local control of the disease by complete removal increases time to progression and survival. We assessed the efficacy and safety of a locally applied adenovirus-mediated gene therapy with a prodrug converting enzyme (herpes-simplex-virus thymidine kinase; sitimagene ceradenovec) followed by intravenous ganciclovir in patients with newly diagnosed resectable glioblastoma. For this international, open-label, randomised, parallel group multicentre phase 3 clinical trial, we recruited patients from 38 sites in Europe. Patients were eligible if they were aged 18-70 years, had newly diagnosed supratentorial glioblastoma multiforme amenable to complete resection, and had a Karnofsky score of 70 or more at screening. We used a computer-generated randomisation sequence to allocate patients in a one-to-one ratio (with block sizes of four) to receive either surgical resection of the tumour and intraoperative perilesional injection of sitimagene ceradenovec (1 × 10(12) viral particles) followed by ganciclovir (postoperatively, 5 mg/kg intravenously twice a day) in addition to standard care or resection and standard care alone. Temozolomide, not being standard in all participating countries at the time of the study, was allowed at the discretion of the treating physician. The primary endpoint was a composite of time to death or re-intervention, adjusted for temozolamide use, assessed by intention-to-treat (ITT) analysis. This trial is registered with EudraCT, number 2004-000464-28. Between Nov 3, 2005, and April 16, 2007, 250 patients were recruited and randomly allocated: 124 to the experimental group and 126 to the standard care group, of whom 119 and 117 patients, respectively, were included in the ITT analyses. Median time to death or re-intervention was longer in the experimental group (308 days, 95% CI 283-373) than in the control group (268 days, 210-313; hazard ratio [HR] 1·53, 95% CI 1·13-2·07; p=0·006). In a subgroup of patients with non-methylated MGMT, the HR was 1·72 (95% CI 1·15-2·56; p=0·008). However, there was no difference between groups in terms of overall survival (median 497 days, 95% CI 369-574 for the experimental group vs 452 days, 95% CI 437-558 for the control group; HR 1·18, 95% CI 0·86-1·61, p=0·31). More patients in the experimental group had one or more treatment-related adverse events those in the control group (88 [71%] vs 51 [43%]). The most common grade 3-4 adverse events were hemiparesis (eight in the experimental group vs three in the control group) and aphasia (six vs two). Our findings suggest that use of sitimagene ceradenovec and ganciclovir after resection can increase time to death or re-intervention in patients with newly diagnosed supratentorial glioblastoma multiforme, although the intervention did not improve overall survival. Locally delivered gene therapy for glioblastoma should be further developed, especially for patients who are unlikely to respond to standard chemotherapy. Ark Therapeutics Ltd.

Outcome and prognostic factors in adult cerebellar glioblastoma

Cerebellar glioblastoma multiforme (GBM) occurs rarely in adults, accounting for 0.4–3.4% of all GBM. Current studies have all involved small patient numbers, limiting the clear identification of prognostic factors. Additionally, while few studies have compared cerebellar GBM to their supratentorial counterparts, there is conflicting data regarding their relative prognosis. To better characterize outcome and identify patient and treatment factors which affect survival, the authors analyzed cases of adult cerebellar GBM from the Surveillance, Epidemiology, and End Results database. A total of 247 adult patients with cerebellar GBM were identified, accounting for 0.67% of all adult GBM. Patients with cerebellar GBM were significantly younger than those with supratentorial tumors (56.6 versus 61.8years, p<0.0001), but a larger percentage of patients with supratentorial GBM were Caucasian (91.7% versus 85.0%, p<0.0001). Overall median survival did not differ between those with cerebellar and supratentorial GBM (7 versus 8months, p=0.24), with similar rates of long-term (greater than 2years) survival (13.4% versus 10.6%, p=0.21). Multivariate analysis revealed age greater than 40years (hazard ratio [HR]: 2.20; 95% confidence interval [CI]: 1.47–3.28; p=0.0001) to be associated with worse patient survival, while the use of radiotherapy (HR: 0.33; 95% CI: 0.24–0.47; p<0.0001) and surgical resection (HR: 0.66; 95% CI: 0.45–0.96; p=0.028) were seen to be independent favorable prognostic factors. In conclusion, patients with cerebellar GBM have an overall poor prognosis, with radiotherapy and surgical resection significantly improving survival. As with supratentorial GBM, older age is a poor prognostic factor. The lack of differences between supratentorial and cerebellar GBM with respect to overall survival and prognostic factors suggests these tumors to be biologically similar.

Temozolomide plus bevacizumab in elderly patients with newly diagnosed glioblastoma and poor performance status: An Anocef phase II trial.

2020 Background: The optimal treatment of glioblastoma multiforme (GBM) in elderly patients (age ≥70 years) with impaired functional status (Karnofsky performance status, KPS&lt;70) remains to be established. A previous study using temozolomide (TMZ) alone suggested an increase in median overall survival (OS) compared to supportive care (25 weeks vs. 12-16 weeks, respectively). Median progression-free survival (PFS) was 16 weeks and 26% of patients became transiently capable of self-care (IK&gt;70) (J Clin Oncol. 2011; 29: 3050-5). The present clinical trial evaluated the efficacy and safety of the combination of TMZ with bevacizumab (BV) as an initial treatment for elderly patients with GBM and KPS&lt;70. Methods: Patients aged ≥ 70 years with KPS &lt; 70 and a newly supratentorial GBM diagnosed by biopsy were eligible for this multicentric, prospective and non-randomised phase II trial. The primary endpoint was the OS and secondary endpoints included median PFS, quality of life, safety and cognition. Treatment consisted of TMZ 130-150 mgs/m2/d for 5 days every 4 weeks plus BV 10mgs/kg every 2 weeks, until 12 cycles or tumoral progression. Neither surgical resection nor radiotherapy was performed. Follow-up included clinical assessment every 2 weeks and brain MRI every 8 weeks. Results: Between October 2010 and March 2012, 66 patients (median age, 77 years; median KPS, 60) were enrolled. Median OS was 24 weeks (95% CI, 19-27.6) and median PFS was 16 weeks (95% CI, 13.1–19.3). Twenty-five patients (38%) became transiently capable of self-care (IK&gt;70). Grade 3 and 4 haematological toxicity occurred in 13(19.6%) cases, whereas non-haematological toxicities were reported in 21(32%), including high blood pressure in 7(10%), thromboembolic events in 3(4.5%), intracerebral haemorrhage in 2(3%) and intestinal perforation in 2(3%) cases. Conclusions: This study confirms that TMZ-based treatment is of help in elderly GBM patients with poor KPS. However, the addition of bevacizumab does not appear to be of benefit in term of PFS and OS.

Unusual Massive Spinal Metastases from a Recurrent Intracranial Glioblastoma Multiforme

Glioblastoma multiforme (GBM) is a highly malignant primary brain tumor and is the most common primary malignancy of the central nervous system (CNS). It is also locally aggressive, invasive, and resistant to therapy. Extracranial seeding of GBM is very rare, but cerebrospinal fluid (CSF) seeding is observed in approximately 15–25 % of supratentorial GBM cases [1–3]. Spinal seeding of GBM metastasis is frequently observed in autopsy series, whilst symptomatic spinal metastases from primary GBM are rarely reported [3–5]. Here, we report the clinical features, radiographic findings, and management of a unique supratentorial GBM case presented with paraplegia secondary to massive spinal metastases.