A multi-institutional analysis of clinical outcomes and patterns of care of 1p/19q codeleted oligodendrogliomas treated with adjuvant or salvage radiation therapy Abstract Purpose Practice patterns vary for adjuvant treatment of 1p/19q-codeleted oligodendroglioma patients. This study evaluates the outcomes of adjuvant (aRT) versus salvage radiation therapy (sRT) in a multi-institutional cohort. Methods Oligodendroglioma patients with confirmed 1p/19q codeletion who were treated with RT with or without chemotherapy from 2000 to 2017 at four tertiary centers were retrospectively reviewed. Overall survival (OS), post-RT progression-free survival (PFS), freedom-from-RT (FFRT), and radiation necrosis (RN) rates were determined using Kaplan–Meier analyses. OS1/PFS1 were defined from the initial surgery. OS2/PFS2 were defined from the RT start-date. Multivariable analyses (MVAs) of prognostic factors for OS and PFS were performed with Cox regression. Results One hundred eighty-six patients were identified: 124(67%) received aRT and 62(33%) received sRT; of sRT patients, 58% were observed after surgery while 42% received chemotherapy without aRT. The median time from initial diagnosis to sRT was 61 months, and 74% had reoperations before sRT. sRT had longer OS1 than aRT (94% vs. 69% at 10 years, p = 0.03) and PFS1 (10-year PFS of 80% vs. 68%, p = 0.03), though sRT was not associated with significantly different OS1/PFS1 on MVAs. Chemotherapy did not delay sRT compared to observation and had worse PFS2 (42% vs. 79% at 5 years, p = 0.08). Higher RT dose was not associated with improved clinical outcomes but was associated with higher symptomatic RN rate (15% vs. 0% at 2 years, p = 0.003). Conclusions Delaying RT for selected oligodendroglioma patients appears safe. Adjuvant chemotherapy does not delay sRT longer than observation and may be associated with worse PFS after RT.

EGFR gene amplification in monocentric and multicentric glioblastoma

Radiation chronotherapy—clinical impact of treatment time-of-day: a systematic review Abstract Purpose Many brain tumor patients suffer from radiation-induced toxicities. Chronotherapy is a treatment modality that utilizes circadian rhythms to optimize the effect on tumor while minimizing negative outcomes on healthy tissue. This review aims to systematically examine the literature on the application of a radiation chronotherapeutic for all cancers and determine the possible advantages of incorporating a circadian-based fixed time-of-day for radiotherapy into CNS cancers. Methods A systematic review of the literature was conducted in two electronic databases from inception to February 1, 2019. Primary research manuscripts were screened for those related to adult human subjects exposed to ionizing radiation using the chronotherapy technique. Results Nine manuscripts were included in the review from 79 eligible articles. Three were prospective randomized trails and 6 were retrospective reviews. This survey revealed that overall survival and tumor control do not have consistent effects with only 60% and 55.5% of paper which included the variables having some significance, respectively. Treatment symptoms were the primary endpoint for both the prospective trials and were examined in 3 of the retrospective reviews; effects were observed in sensitive tissue for all 5 studies including mucosal linings and skin basal layer. Conclusions Existing literature suggests that the application of radiation chronotherapy may reduce negative symptom outcome within highly proliferative tissues. Further examination of radiation chronotherapy in well-designed prospective trials and studies in brain tumor patients are merited.

Analysis of CDKN2A gene alterations in recurrent and non-recurrent meningioma Abstract Purpose Assessment of the risk of recurrence is essential to determine the therapeutic strategy of meningioma treatment. Many relapsing or aggressive meningiomas show elevated mitotic and/or Ki67 indices, reflecting cell cycle deregulation. As CDKN2A is a key tumor suppressor gene involved in cell cycle control, we investigated whether CDKN2A alterations may be involved in tumor recurrence. Methods We carried out a comparative analysis of 17 recurrent and 13 non-recurrent meningiomas. CDKN2A single nucleotide variations (SNVs), deletions, methylation status of the promotor, and p16 expression were investigated. Results were correlated with the recurrent or non-recurrent status and clinicopathological data. Results We identified a CDKN2A SNV (NM_000077, exon2, c.G442A, p.Ala148Thr) in five meningiomas that was significantly associated with recurrence (p = 0.03). This mutation, confirmed by Sanger sequencing and referenced in the COSMIC database in various cancers, has not been reported in meningioma. The presence of one of the three following CDKN2A alterations—p.(Ala148Thr) mutation, whole homozygous or heterozygous gene loss, or promotor methylation > 8%—was observed in 13 of the 17 relapsing meningiomas and was strongly associated with recurrence (p < 0.0001) and a Ki67 labeling index > 7% (p = 0.004). Conclusion We report an undescribed p.(Ala148Thr) CDKN2A mutation in meningioma that was only present in relapsing tumors. In our series, CDKN2A gene alterations were only found in recurrent meningiomas. However, our results need to be evaluated on a larger series to ensure that these CDKN2A alterations can be used as biomarkers of recurrence in meningioma.

Hypofractionated radiotherapy with temozolomide in diffuse intrinsic pontine gliomas: a randomized controlled trial Abstract Introduction Diffuse intrinsic pontine glioma (DIPG) is the most common form of brainstem glioma. The present study was performed to assess if hypofractionated radiotherapy completed in < 3 weeks with temozolomide improves survival in DIPG. Material and methods The present study is a phase II open label randomized trial. The study included newly diagnosed patients with DIPG. Patients in arm A received conventional fractionated RT of 60 Gy in 30 fractions over 6 weeks while patients in arm B received hypo-fractionated radiotherapy of 39 Gy in 13 fractions over 2.6 weeks along with concurrent Temozolomide (TMZ) 75 mg/m2 from day 1 to day 17 followed by adjuvant TMZ for six cycles. The survival analysis was performed with modified intention to treat analysis. Results A total of 35 patients were randomized. 33 patients were evaluable. 93% (n = 14) of patients in the conventional arm completed treatment while only 17% (n = 3) of the children could complete planned course of treatment in the experimental arm. The median overall survival (OS) was 11 months (95% CI − 7.5 to 14.5 months) in the conventional arm and 12 months (95% CI − 10.5 to 13.5 months) in the experimental arm (p = 0.208). 28% (n = 5) patients in the experimental arm developed grade 3 or 4 hematological toxicity. Conclusion The above study shows that hypofractionated radiotherapy with concurrent and adjuvant temozolomide does not improve OS and has higher hematological toxicity. Conventional radiotherapy remains the standard of care.

Treatment-induced lesions in newly diagnosed glioblastoma patients undergoing chemoradiotherapy and heat-shock protein vaccine therapy Abstract Objectives Treatment-induced lesions represent a great challenge in neuro-oncology. The aims of this study were (i) to characterize treatment induced lesions in glioblastoma patients treated with chemoradiotherapy and heat-shock protein (HSP) vaccine and (ii) to evaluate the diagnostic accuracy of diffusion weighted imaging for differentiation between treatment-induced lesions and tumor progression. Methods Twenty-seven patients with newly diagnosed glioblastoma treated with HSP vaccine and chemoradiotherapy were included. Serial magnetic resonance imaging evaluation was performed to detect treatment-induced lesions and assess their growth. Quantitative analysis of the apparent diffusion coefficient (ADC) was performed to discriminate treatment-induced lesions from tumor progression. Mann–Whitney U-test and receiver operating characteristic (ROC) curves were used for analysis. Results Thirty-three percent of patients developed treatment-induced lesions. Five treatment-related lesions appeared between end of radiotherapy and the first vaccine administration; 4 lesions within the first 4 months from vaccine initiation and 1 at 3.5 years. Three patients with pathology proven treatment-induced lesions showed a biphasic growth pattern progressed shortly after. ADC ratio between the peripheral enhancing rim and central necrosis showed an accuracy of 0.84 (95% CI 0.63–1) for differentiation between progression and treatment-induced lesions. Conclusion Our findings do not support the iRANO recommendation of a 6-month time window in which progressive disease should not be declared after immunotherapy initiation. A biphasic growth pattern of pathologically proven treatment-induced lesions was associated with a dismal prognosis. The presence of lower ADC values in the central necrotic portion of the lesions compared to the enhancing rim shows high specificity for detection of treatment-induced lesions.

Delay in diagnosing patients with right-sided glioblastoma induced by hemispheric-specific clinical presentation Abstract Purpose Cognitive functions are differentially represented in brain hemispheres. Aphasia is an “easy to recognize” symptom of diseases affecting the left side. In contrast, lesions in the right hemisphere cause subtle neuropsychological deficits such as neglect and anosognosia. We evaluated whether right-sided malignant brain tumors are on average larger at the time of first diagnosis as compared to left-sided tumors, and extrapolated the delay in diagnosing right-sided tumors compared to the left side. Methods All first-ever diagnosed glioblastoma (GBM) patients between 2005 and 2012 were identified using our hospital-based prospective research registry. Baseline data, information on initial clinical presentation and imaging findings (including tumor volume) were collected. Extrapolation of time since tumor initiation was based on an established gompertzian growth model. Results We included 173 patients. Mean age of the study population was 58 ± 13 years. Tumors located in the right hemisphere (n = 96) were larger as compared to tumors located in the left hemisphere (n = 77) (median 36.4 mL [interquartile range 13.0–56.0; minimum 0.2, maximum 140.0] vs. 17.2 mL [7.7–45.1 mL; 0.4, 105.2]; p = 0.011). Right-sided tumors grew longer than left-sided tumors (378 ± 95 days vs. 341 ± 74 days; p = 0.006). Initial neuropsychological symptoms differed depending on the affected hemisphere. Conclusion Right-hemispheric symptoms appear to be less clinically conspicuous resulting in a delayed diagnosis of GBM, which might be improved by raising awareness for the corresponding neuropsychological deficits. Whether our findings have prognostic implications needs to be evaluated in future studies.

Microscopic brain invasion in meningiomas previously classified as WHO grade I is not associated with patient outcome Abstract Purpose For meningiomas, the 2016 revision of the WHO classification introduced brain invasion per se as a sufficient condition to classify as grade II. We analyzed whether meningiomas previously graded as WHO grade I differ in prognosis depending on the presence of microscopic brain invasion. Methods A consecutive series of patients with intracranial meningioma WHO grade I (± brain invasion) at two neurosurgical departments was analyzed retrospectively. Cox regression models on progression-free survival (PFS) and Kaplan–Meier survival estimates were performed. Results 875 adult patients were included. Histological diagnosis of brain invasion was confirmed in 28 patients. Median follow-up was 73 months. In univariate and multivariate models, gross total resection gained favorable prognostic influence for PFS (p < 0.001, HR: 0.237, CI 0.170–0.382). 170 patients with the brain/meningioma interface present in histopathological specimen were separately analyzed as a subgroup. Importantly, presence of brain invasion did not reach significance for PFS, even in the subgroup with available specimen of brain/meningioma interface (p = 0.787, HR: 0.852, CI 0.268–2.710 and p = 0.811, HR: 0.848, CI 0.222–3.246, respectively). Patients with and without brain invasion did not differ in terms of age, tumor location and extent of resection, but were more likely to receive radiotherapy (p = 0.03) of tumor remnants. However, subgroup analysis of non-irradiated tumors revealed no prognostic influence of brain invasion (p = 0.749, HR: 0.772, CI 0.158–3.767). Conclusions In this bi-institutional series, brain invasion was frequent among meningiomas WHO grade I when brain/meningioma interface was available for histology (16.5%). However, brain invasion did not impact early recurrence.

Fractionated stereotactic radiosurgery for malignant gliomas: comparison with single session stereotactic radiosurgery Abstract Purpose Stereotactic radiosurgery (SRS) is feasible for malignant glioma; however, delivering the optimal radiation dose with sufficient large-volume coverage is a major concern. We aimed to investigate the clinical efficacy and safety of fractionated SRS (fSRS) versus single-session SRS (sSRS) for malignant gliomas. Methods We retrospectively reviewed 58 malignant glioma patients who underwent gamma knife SRS from January 2015 to December 2018. Forty-one underwent sSRS, and 17 underwent fSRS. Median dose for fSRS was 28 Gy (range 24–35 Gy), with a median dose of 6 Gy per fraction (range 5–7 Gy). Patients received 4 or 5 fractions on consecutive days. Median dose for sSRS was 18 Gy (range 11–25 Gy), with a median isodose of 50% (range 50–65%). Mean target volumes were 5.9 and 19.3 cc for sSRS and fSRS, respectively (p < 0.001, two-sided t test). Results After SRS, median progression-free survival (PFS) was 4.5 and 4.6 months (p = 0.58), and median overall survival (OS) was 12.7 and 12.6 months for sSRS and fSRS (p = 0.41), respectively (log-rank test). The incidence of clinically significant radiation necrosis was 20.5% (8/39) and 18.8% (3/16) for sSRS and fSRS, respectively (p = 1, Fisher’s exact test). Conclusion fSRS for malignant glioma conferred local control and survival comparable with conventional sSRS. The radiation necrosis incidence was comparable between groups when a parallel biological effective dose was administered to the larger target volumes in the fSRS group. fSRS can be a better alternative to sSRS if re-irradiation is considered for large malignant gliomas.

Weak MGMT gene promoter methylation confers a clinically significant survival benefit in patients with newly diagnosed glioblastoma: a retrospective cohort study Abstract Introduction Quantitative methylation specific PCR (qMSP) is a frequently used technique to assess MGMT gene promoter methylation in glioblastoma patients. The optimal technical cut-off value to distinguish methylated from unmethylated samples is nevertheless still undetermined. In literature, a “grey zone” of diagnostic uncertainty has been described. Methods We performed a retrospective analysis of newly diagnosed glioblastoma patients treated according to the Stupp protocol. Epidemiological data were gathered from the individual patient files. MGMT gene promoter methylation status was determined on stored tumour samples using qMSP. A strong, weak or absent promoter methylation was determined based on Cq values (quantification value) of the MGMT and ACTB primers as well as a positive control sample. Results In total, 181 patient files were reviewed and included for statistical analysis. MGMT promoter hypermethylation was detected in 38.7% of glioblastoma patients. The median overall survival of unmethylated and strongly methylated patients was 10.1 months and 19.7 months respectively. Furthermore, 11% of the total patient cohort had a weak MGMT gene promoter methylation. The median OS in this subgroup was 15.4 months, significantly better compared to the unmethylated cohort (P < 0.001). Multivariate Cox regression analysis showed weak MGMT promoter methylation as an independent prognostic parameter for overall survival. Conclusion Glioblastoma patients with weak promoter methylation show a statistically significant longer overall survival when compared to clearly unmethylated patients. Patients with grey zone qMSP test results should receive additional molecular analysis in future to further direct individual therapy strategies.