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Background/purpose Glioblastoma (GBM) is the most common primary malignant brain tumor. Sex has been shown to be an important prognostic factor for GBM. The purpose of this study was to develop and independently validate sex-specific nomograms for estimation of individualized GBM survival probabilities using data from 2 independent NRG Oncology clinical trials. Methods This analysis included information on 752 (NRG/RTOG 0525) and 599 (NRG/RTOG 0825) patients with newly diagnosed GBM. The Cox proportional hazard models by sex were developed using NRG/RTOG 0525 and significant variables were identified using a backward selection procedure. The final selected models by sex were then independently validated using NRG/RTOG 0825. Results Final nomograms were built by sex. Age at diagnosis, KPS, MGMT promoter methylation and location of tumor were common significant predictors of survival for both sexes. For both sexes, tumors in the frontal lobes had significantly better survival than tumors of multiple sites. Extent of resection, and use of corticosteroids were significant predictors of survival for males. Conclusions A sex specific nomogram that assesses individualized survival probabilities (6-, 12- and 24-months) for patients with GBM could be more useful than estimation of overall survival as there are factors that differ between males and females. A user friendly online application can be found here—https://npatilshinyappcalculator.shinyapps.io/SexDifferencesInGBM/.

PURPOSE Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. PATIENTS AND METHODS Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation. RESULTS A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically ( P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively ( P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance ( P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. CONCLUSION Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.

BackgroundTumor-Treating Fields (TTFields) is an emerging treatment modality for glioblastoma (GBM). Studies have shown a good safety profile alongside improved efficacy in newly diagnosed GBM (ndGBM), while a less clear effect was shown for recurrent GBM (rGBM). Despite regulatory support, sectors of the neuro-oncology community have been reluctant to accept it as part of the standard treatment protocol. To establish an objective understanding of TTFields’ mechanism of action, safety, efficacy, and economical implications, we conducted a systematic literature review and meta-analysis.MethodsA systematic search was conducted in PubMed, Scopus, and Cochrane databases. Twenty studies met the pre-defined inclusion criteria, incorporating 1636 patients (542 ndGBM and 1094 rGBM), and 11 558 patients (6403 ndGBM and 5155 rGBM) analyzed for the clinical outcomes and safety endpoints, respectively.ResultsThis study demonstrated improved clinical efficacy and a good safety profile of TTFields. For ndGBM, pooled median overall survival (OS) and progression-free survival (PFS) were 21.7 (95%CI = 19.6-23.8) and 7.2 (95%CI = 6.1-8.2) months, respectively. For rGBM, pooled median OS and PFS were 10.3 (95%CI = 8.3-12.8) and 5.7 (95%CI = 2.8-10) months, respectively. Compliance of ≥75% was associated with an improved OS and the predominant adverse events were dermatologic, with a pooled prevalence of 38.4% (95%CI = 32.3-44.9). Preclinical studies demonstrated TTFields’ diverse molecular mechanism of action, its potential synergistic efficacy, and suggest possible benefits for certain populations.ConclusionsThis study supports the use of TTFields for GBM, alongside the standard-of-care treatment protocol, and provides a practical summary, discussing the current clinical and preclinical aspects of the treatment and their implication on the disease course.

Primary central nervous system lymphoma (PCNSL) is a rare disease with a dismal prognosis compared to its systemic large B-cell lymphoma counterpart. Real world data are limited, when considering a uniform backbone treatment. A retrospective study of all adult patients treated sequentially with a high-dose methotrexate (HD MTX)-based regimen in a single tertiary medical center between 2003 and 2019. The 2015–2019 period differed from its predecessor in that most patients were treated with an HD MTX-based polychemotherapy regimen as opposed to HD MTX monotherapy (81% vs. 13%, P

Background There is evidence for an inherited contribution to primary brain cancer. Linkage analysis of high-risk brain cancer pedigrees has identified candidate regions of interest in which brain cancer predisposition genes are likely to reside. Methods Genome-wide linkage analysis was performed in a unique set of 11 informative, extended, high-risk primary brain cancer pedigrees identified in a population genealogy database, which include from 2 to 6 sampled, related primary brain cancer cases. Access to formalin-fixed paraffin embedded tissue samples archived in a biorepository allowed analysis of extended pedigrees. Results Individual high-risk pedigrees were singly informative for linkage at multiple regions. Suggestive evidence for linkage was observed on chromosomes 2, 3, 14, and 16. The chromosome 16 region in particular contains a promising candidate gene, pyridoxal-dependent decarboxylase domain-containing 1 (PDXDC1), with prior evidence for involvement with glioblastoma from other previously reported experimental settings, and contains the lead single nucleotide polymorphism (rs3198697) from the linkage analysis of the chromosome 16 region. Conclusions Pedigrees with a statistical excess of primary brain cancers have been identified in a unique genealogy resource representing the homogeneous Utah population. Genome-wide linkage analysis of these pedigrees has identified a potential candidate predisposition gene, as well as multiple candidate regions that could harbor predisposition loci, and for which further analysis is suggested.

In recent years, several automatic methods have been proposed to differentiate between brain tumor recurrence and treatment-related changes following radiotherapy, based on conventional and advanced MRI methods. Vascular parameters extracted from dynamic contrast-enhanced (DCE) were suggested as potential markers for disease progression. Yet, most studies that proposed machine-learning methods or relayed on threshold values of DCE for classification, did not analyze separately Glioblastoma (GBM) and brain metastasis, and often offer the same method/threshold values, neglecting the different vascularity of these two tumor types. Understanding and quantifying the differences between tumors type can improve early diagnosis of recurrence and may improve the reliability of identifying treatment-related changes. The aim of this study was to quantify vascular parameters of tumor recurrence and to assess differences between GBM and brain metastasis, specifically metastasis of breast cancer. METHOD: 41 MRI scans were included: 24 from patients with GBM: 20 with recurrence and 4 with treatment-related changes, and 17 scans from patients with brain metastasis of breast cancer: 10 with recurrence and 7 with treatment-related changes (diagnosis were based on radiological follow-up/histopathology, when available). MRIs were performed on a 3.0 Tesla MRI scanner (Siemens MAGNETOM Prisma) and included T1, T1+contrast, and DCE images. DCE analysis was performed using DUSTER and Ktrans, Vp and Kep pharmacokinetic parameters were compared between groups. RESULTS: Patients with GBM often demonstrated both tumor recurrence and areas with treatment-related changes. Significantly differences were detected between tumor recurrence and treatment-related changes, and higher Vp and Ktrans were detected in recurrent GBM as compared to recurrent breast cancer metastasis. Cutoff for differentiation between tumor recurrence and treatment-related changes will be presented specifically for each tumor type. To conclude, when defining quantitative threshold values for clinical decision-making, the inherent differences between primary and metastatic brain tumors should be taken into account.

Cancers arising from germline DNA mismatch-repair or polymerase-proofreading deficiencies (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion/deletion (MS-indel) burden in humans and are lethal due to inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICI) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI in these patients. ICI treatment of 45 progressive/recurrent tumours from 38 patients revealed durable objective responses in the majority, culminating in 3-year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations/Mb) enriched for combined MMRD+PPD, while MS-indels predicted response in MMRD tumours with lower mutation burden (10-100 mutations/Mb). Further, both mechanisms were associated with increased immune infiltration even in “immunologically-cold” tumours such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and associated with immune activation in both the tumour microenvironment and systemically. Further, patients with flare continuing ICI treatment achieved durable responses. Our study demonstrates improved survival for patients with tumours not previously known to respond to ICI, including CNS and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained responses to immunotherapy.

Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion–deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10–100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in ‘immunologically cold’ tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy., Hypermutation and microsatellite burden determine responses and long-term survival following PD-1 blockade in children and young adults with refractory cancers resulting from germline DNA replication repair deficiency.

Introduction Tumor Treating Fields (TTFields; antimitotic treatment) delivers low-intensity, intermediate-frequency, alternating electric fields through skin-applied transducer arrays. TTFields (200 kHz) was FDA-approved in glioblastoma (GBM), based on the phase 3 EF-11 (recurrent GBM, rGBM) and EF-14 (newly diagnosed GBM, ndGBM) trials. The most common TTFields-related adverse event (AE) in both trials was array-associated skin irritation. We now report on TTFields-related AEs in the real-world, clinical practice setting. Methods Unsolicited, post-marketing surveillance data from TTFields-treated patients (October 2011–February 2019) were retrospectively analyzed using MedDRA v21.1 preferred terms, stratified by region (US, EMEA [Europe, Middle East, Africa], Japan), diagnosis (ndGBM, rGBM, anaplastic astrocytoma/oligodendroglioma, other brain tumors), and age ( Results Of 11,029 patients, 53% were diagnosed with ndGBM and 39% were diagnosed with rGBM at any line of disease recurrence. Most were adults (73%), 26% were elderly, and the male-to-female ratio was ~ 2:1 (close to published ratios of typical GBM populations). The most commonly reported TTFields-related AE was array-associated skin reaction, occurring in patients with ndGBM (38%), rGBM (29%), anaplastic astrocytoma/oligodendroglioma (38%), and other brain tumors (31%); as well as 37% of pediatric, 34% of adult, and 36% of elderly patients. Most skin AEs were mild/moderate and manageable. Other TTFields-related AEs in patients with ndGBM/rGBM included under-array heat sensation (warmth; 11%, 10%, respectively) and electric sensation (tingling; 11%, 9%, respectively), and headache (7%, 6%, respectively). Conclusions This TTFields safety surveillance analysis in > 11,000 patients revealed no new safety concerns, with a favorable safety profile comparable with published TTFields/GBM trials. The safety profile remained consistent among subgroups, suggesting feasibility in multiple populations, including elderly patients. Graphic abstract

Background VB-111 is a non-replicating adenovirus carrying a Fas-chimera transgene, leading to targeted apoptosis of tumor vascular endothelium and induction of a tumor-specific immune response. This phase I/II study evaluated the safety, tolerability, and efficacy of VB-111 with and without bevacizumab in recurrent glioblastoma (rGBM). Methods Patients with rGBM (n = 72) received VB-111 in 4 treatment groups: subtherapeutic (VB-111 dose escalation), limited exposure (LE; VB-111 monotherapy until progression), primed combination (VB-111 monotherapy continued upon progression with combination of bevacizumab), and unprimed combination (upfront combination of VB-111 and bevacizumab). The primary endpoint was median overall survival (OS). Secondary endpoints were safety, overall response rate, and progression-free survival (PFS). Results VB-111 was well tolerated. The most common adverse event was transient mild-moderate fever. Median OS time was significantly longer in the primed combination group compared with both LE (414 vs 223 days; hazard ratio [HR], 0.48; P = 0.043) and unprimed combination (414 vs 141.5 days; HR, 0.24; P = 0.0056). Patients in the combination phase of the primed combination group had a median PFS time of 90 days compared with 60 in the LE group (HR, 0.36; P = 0.032), and 63 in the unprimed combination group (P = 0.72). Radiographic responders to VB-111 exhibited characteristic, expansive areas of necrosis in the areas of initial enhancing disease. Conclusions Patients with rGBM who were primed with VB-111 monotherapy that continued after progression with the addition of bevacizumab showed significant survival and PFS advantage, as well as specific imaging characteristics related to VB-111 mechanism of action. These results warrant further assessment in a randomized controlled study.

2542 Background: Tumor Treating Fields (TTFields) are an antineoplastic treatment delivering low intensity, intermediate frequency, alternating electric fields through two pairs of transducer arrays locoregionally applied to tumor bed. TTFields are FDA-approved for glioblastoma (GBM; 200 kHz) and mesothelioma (150 kHz). Safety and effectiveness were demonstrated in the phase III EF-11 and EF-14 trials in recurrent GBM (rGBM) and in newly diagnosed GBM (ndGBM), respectively. The main TTFields-related adverse event (AE) was array-associated manageable skin irritation. We report AEs from TTFields-treated patients in the real-world, clinical practice setting. Methods: Unsolicited, global, post-market surveillance data from TTFields-treated patients (October 2011–February 2019) were retrospectively analyzed using MedDRA v21.1, stratified by region (US, EMEA [Europe, Middle East, Africa], or Japan), diagnosis (ndGBM, rGBM, anaplastic astrocytoma and anaplastic oligodendroglioma, or other brain tumors that includes brain metastases from different cancer types), and years of age (

To study the repeatability of plasma volume (vp) extracted from dynamic-contrast-enhanced (DCE) MRI in order to define threshold values for significant longitudinal changes, and to assess changes in patients with high-grade-glioma (HGG). Twenty eight healthy subjects, of which eleven scanned twice, were used to assess the repeatability of vp within the normal-appearing brain tissue and to define threshold values for significant changes based on least-detected-differences (LDD) of mean vp values and histogram comparisons using earth-mover’s-distance (EMD). Sixteen patients with HGG were scanned longitudinally with eight patients scanned before and following bevacizumab therapy. Longitudinal changes were assessed based on defined threshold values in comparison to RANO criteria. The threshold values for significant changes were: LDD = 0.0024 (ml/100 ml, 21%) for mean vp and EMD = 4.14. In patients, in 20/24 comparisons, no significant longitudinal changes were detected for vp within the normal-appearing brain tissue. Concurring results were obtained between changes in lesion volume (RANO criteria) and LDD or EMD values in cases diagnosed with progressive-disease, yet in about 50% of cases diagnosed with partial-response preliminary results demonstrated significant increase in vp despite significant reductions in lesion volume. In two patients, these changes preceded progression detected at follow-up scans. In general, a good concordance was obtained between LDD and EMD. This study shows high repeatability of vp and provides threshold values for significant changes in longitudinal assessment of patients with brain tumors. Preliminary results suggest the use of vp-DCE parameter to improve assessment of therapy response in patients with high-grade-glioma.

OBJECTIVES: To assess the long-term outcomes and objective response to pre-radiation chemotherapy and radiation in adult high-risk medulloblastoma. METHODS: In this prospective phase II trial, adults with high-risk medulloblastoma were treated with three cycles of pre-radiation cisplatin, etoposide, cyclophosphamide, and vincristine followed by craniospinal radiation (CSI). Objective response (OR), progression free survival (PFS), overall survival (OS), and toxicities were assessed. RESULTS: Eleven patients were enrolled over a 6 year period. Six (55%) had subarachnoid metastases. Two (18%) had an OR to pre-radiation chemotherapy. Two (18%) progressed while on chemotherapy. Completion of CSI was not compromised. The OR rate after chemotherapy and radiation was 45 % (5/11). Non-evaluable patients at both time points weakened the response data conclusions. Median PFS was 43.8 months. Five year PFS was 27%. Five year OS was 55%. Non-metastatic (M0) and metastatic (M+) patients had similar outcomes. CONCLUSIONS: The OR to this pre-radiation chemotherapy regimen is lower than anticipated from the adult and pediatric literature raising a question about comparative efficacy of chemotherapy in different age groups. The OS achieved is similar to retrospective adult series, but worse than pediatric outcomes. Although this regimen can be administered without compromising delivery of CSI, our results do not provide support for the use of this neoadjuvant chemotherapy for adult medulloblastoma.

Background We previously reported the unexpected finding of significantly improved survival for newly diagnosed glioblastoma in patients when radiation therapy (RT) was initiated later (>4 wk post-op) compared with earlier (≤2 wk post-op). In that analysis, data were analyzed from 2855 patients from 16 NRG Oncology/Radiotherapy Oncology Group (RTOG) trials conducted prior to the era of concurrent temozolomide (TMZ) with RT. We now report on 1395 newly diagnosed glioblastomas from 2 studies, treated with RT and concurrent TMZ followed by adjuvant TMZ. Our hypothesis was that concurrent TMZ has a synergistic/radiosensitizing mechanism, making RT timing less significant. Methods Data from patients treated with TMZ-based chemoradiation from NRG Oncology/RTOG 0525 and 0825 were analyzed. An analysis comparable to our prior study was performed to determine whether there was still an impact on survival by delaying RT. Overall survival (OS) was investigated using the Kaplan-Meier method and Cox proportional hazards model. Early progression (during time of diagnosis to 30 days after RT completion) was analyzed using the chi-square test. Results Given the small number of patients who started RT early following surgery, comparisons were made between >4 and ≤4 weeks delay of radiation from time of operation. There was no statistically significant difference in OS (hazard ratio = 0.93; P = 0.29; 95% CI: 0.80-1.07) after adjusting for known prognostic factors (recursive partitioning analysis and O6-methylguanine-DNA methyltransferase methylation status). Similarly, the rate of early progression did not differ significantly (P = 0.63). Conclusions We did not observe a significant prognostic influence of delaying radiation when given concurrently with TMZ for newly diagnosed glioblastoma. The effects of early (1-3 wk post-op) or late (>5 wk) initiation of radiation tested in our prior study could not be replicated.

Immune checkpoint inhibitors (ICPIs) have recently emerged as a novel treatment for cancer. These agents, transforming the field of oncology, are not devoid of toxicity and cause immune-related side effects which can involve any organ including the nervous system. In this study, we present 9 patients (7 men and 2 women) with neurologic complications secondary to ICPI treatment. These included meningoencephalitis, limbic encephalitis, polyradiculitis, cranial polyneuropathy, myasthenic syndrome and myositis. Four patients received dual ICPI therapy comprised of programmed cell death-1 and cytotoxic lymphocyte associated protein-4 blocking antibodies. Median time to onset of neurologic adverse event during immune checkpoint inhibitor treatment was 8 weeks (range 5 days-19 weeks). In all patients ICPIs were stopped and corticosteroids were initiated, resulting in a marked improvement in seven out of nine patients. Two patients, one with myositis and one with myasthenic syndrome, died. In two patients ICPI therapy was resumed after resolution of the neurological adverse event with no additional neurologic complications. This series highlights the very broad spectrum of neurological complications of ICPIs, emphasizes the need for expedited diagnosis and suggests that withholding treatment early, accompanied with steroid therapy, carries the potential of complete resolution of the neurological immune-mediated condition. Thus, a high level of suspicion and rapid initiation of corticosteroids are mandatory to prevent uncontrolled clinical deterioration, which might be fatal.

BACKGROUND High-grade gliomas (HGGs) induce both vasogenic edema and extensive infiltration of tumor cells, both of which present with similar appearance on conventional MRI. Using current radiological criteria, differentiation between these tumoral and nontumoral areas within the nonenhancing lesion area remains challenging. PURPOSE To use radiomics patch-based analysis, based on conventional MRI, for the classification of the nonenhancing lesion area in patients with HGG into tumoral and nontumoral components. STUDY TYPE Prospective. SUBJECTS In all, 179 MRI scans were obtained from 102 patients: 67 patients with HGG and 35 patients with brain metastases. A subgroup of 15 patients with HGG were scanned before and following administration of bevacizumab. FIELD STRENGTH/SEQUENCE Pre and postcontrast agent T1 -weighted-imaging (WI), T2 WI, FLAIR, diffusion-tensor-imaging (DTI), and dynamic-contrast-enhanced (DCE)-MRI at 3T. ASSESSMENT A total of 225 histograms and gray-level-co-occurrence matrix-based features were extracted from the nonenhancing lesion area. Tumoral volumes of interest (VOIs) were defined at the peritumoral area in patients with HGG; nontumoral VOIs were defined in patients with brain metastasis. Twenty machine-learning algorithms including support-vector-machine (SVM), k-nearest neighbor, decision-trees, and ensemble classifiers were tested. The best classifier was trained on the entire labeled data, and was used to classify the entire data. STATISTICAL TESTS Dimensional reduction was performed on the 225 features using principal component analysis. Classification results were evaluated based on the sensitivity, specificity, and accuracy of each of the 20 classifiers, first based on a training and testing dataset (80% of the labeled data) in a 5-fold manner, and next by applying the best classifier to the validation data (the remaining 20% of the labeled data). Results were additionally evaluated by assessing differences in dynamic-contrast-enhanced plasma-volume (vp ) and volume-transfer-constant (ktrans ) values between the two components using Mann-Whitney U-test/t-test. RESULTS The best classification into tumoral and nontumoral lesion components was obtained using a linear SVM classifier, with average accuracy of 87%, sensitivity 86%, and specificity of 89% (for the training and testing data). Significantly higher vp and ktrans values (P < 0.0001) were detected in the tumoral compared to the nontumoral component. Preliminary classification results in a subgroup of patients treated with bevacizumab demonstrated a reduction mainly in the nontumoral component following administration of bevacizumab, enabling early assessment of disease progression in some patients. DATA CONCLUSION A radiomics patch-based analysis enables classification of the nonenhancing lesion area in patients with HGG. Preliminary results were promising and the proposed method has the potential to assist in clinical decision-making and to improve therapy response assessment in patients with HGG. LEVEL OF EVIDENCE 1 Technical Efficacy Stage 4 J. Magn. Reson. Imaging 2018.

Purpose To determine the impact on overall survival with different salvage therapies, including no treatment, reirradiation, systemic therapy, or radiation and systemic therapy, in participants of a phase 3 clinical trial evaluating dose-dense versus standard-dose temozolomide for patients with newly diagnosed glioblastoma. Methods and Materials This analysis of patients from Trial RTOG 0525 investigated the effect of reirradiation or systemic treatment after tumor progression. Survival from first progression was compared between patients receiving no therapy, systemic therapy alone, radiation alone, and both modalities. The Cox proportional hazards model was used to compare the mortality hazard, controlling for potential confounders. Results The analysis included 637 patients who progressed and had information on their management, excluding those who died less than half a month after progression. A total of 267 patients (42%) received neither reirradiation nor systemic treatment at progression, 24 (4%) received radiation alone, 282 (44%) received systemic treatment only, and 64 (10%) received both radiation and systemic therapy. Patients who received no treatment had a median survival of 4.8 months, lower than with radiation treatment alone (8.2 months), systemic therapy alone (10.6 months), and both radiation and systemic therapy (12.2 months). In survival models controlling for potential confounders, those who received radiation alone had modestly better survival (hazard ratio HR 0.74, 95% confidence interval [CI] 0.43-1.28), whereas those who underwent systemic therapy either without (HR 0.42, 95% CI 0.34-0.53) or with radiation therapy (HR 0.44, 95% CI 0.30-0.63) had better survival. There was no significant survival difference between patients who received radiation only and those who received systemic therapy (either with radiation or alone). Conclusions Patients who received no salvage treatment had poorer survival than those who received radiation, chemotherapy, or the combination. However, patient selection for no treatment likely reflects poorer expected prognosis. There was no significant survival difference among those receiving radiation therapy, systemic therapy, or both. Ongoing clinical trials will help define the role of reirradiation after glioblastoma progression.

BACKGROUND Efforts have been directed toward searching for molecular biomarkers predicting response to immunotherapy in glial tumors. Recently, FDA granted accelerated approval of pembrolizumab for treatment patients with solid tumors with high mutational burden (TMB-H; ≥ 10 mut/Mb). There are conflicting results regarding the use of this parameter in glial tumors. OBJECTIVE to review NGS examinations of patients with glial tumors and high TMB and to analyze their response to immunotherapy. METHODS we retrospectively reviewed NGS examinations from patients with glial tumors treated in Tel-Aviv Medical Center from 2016-2021. Cases with TMB-H were retrieved and analyzed. RESULTS We identified nine high-grade glioma patients with TMB-H. The median age was 38 (19-65). There were 4 patients with glioblastoma; three with anaplastic oligodendroglioma; and two with anaplastic astrocytoma. All but one received radiation prior to the biopsy used for NGS examination, and all were treated with temozolomide. The median TMB was 54 (19-252). Only one glioblastoma patient with a family history of Lynch syndrome had microsatellite instability (MSI)-high; all other patients were MSI stable (MSS). Nevertheless, in all cases, mutated mismatch repair (MMR) genes were detected (MSH6 in 3 patients, MSH2 in one patient, MLH1 in one patient, PMS 2 in one patient, and both MSH2 and 6 in one patient). Six patients received immunotherapy. Only one patient with recurrent glioblastoma and the highest TMB in the group (252) demonstrated a near complete response to pembrolizumab and remains on treatment more than three years. All other patients did not respond to immunotherapy. CONCLUSION TMB-H in primary glioma is associated with mutations of MMR genes. It is typically associated with MSS in these patients (MSI-high was seen in only one syndromic patient). In contrast to systemic neoplasms with TMB-H, the majority of our patients did not respond to immunotherapy.

Low-grade gliomas (LGG) are classified into three distinct groups based on their IDH1 mutation and 1p/19q codeletion status, each of which is associated with a different clinical expression. The genomic sub-classification of LGG requires tumor sampling via neurosurgical procedures. The aim of this study was to evaluate the radiomics approach for noninvasive classification of patients with LGG and IDH mutation, based on their 1p/19q codeletion status, by testing different classifiers and assessing the contribution of the different MR contrasts. Preoperative MRI scans of 47 patients diagnosed with LGG with IDH1-mutated tumors and a genetic analysis for 1p/19q deletion status were included in this study. A total of 152 features, including size, location and texture, were extracted from fluid-attenuated inversion recovery images, $$\hbox {T}_{2}$$ -weighted images (WI) and post-contrast $$\hbox {T}_{1}\hbox {WI}$$ . Classification was performed using 17 machine learning classifiers. Results were evaluated by a fivefold cross-validation analysis. Radiomic analysis differentiated tumors with 1p/19q intact ( $$n=21$$ ; astrocytomas) from those with 1p/19q codeleted ( $$n=26$$ ; oligodendrogliomas). Best classification was obtained using the Ensemble Bagged Trees classifier, with sensitivity $$=$$ 92%, specificity $$=$$ 83% and accuracy $$=$$ 87%, and with area under the curve $$=$$ 0.87. Tumors with 1p/19q intact were larger than those with 1p/19q codeleted ( $$46.2\pm 30.0$$ vs. $$30.8\pm 16.8$$ cc, respectively; $$p=0.03$$ ) and predominantly located to the left insula ( $$p=0.04$$ ). The proposed method yielded good discrimination between LGG with and without 1p/19q codeletion. Results from this study demonstrate the great potential of this method to aid decision-making in the clinical management of patients with LGG.

BACKGROUND AND PURPOSE: Current imaging assessment of high-grade brain tumors relies on the Response Assessment in Neuro-Oncology criteria, which measure gross volume of enhancing and nonenhancing lesions from conventional MRI sequences. These assessments may fail to reliably distinguish tumor and nontumor. This study aimed to classify enhancing and nonenhancing lesion areas into tumor-versus-nontumor components. MATERIALS AND METHODS: A total of 140 MRI scans obtained from 32 patients with high-grade gliomas and 6 patients with brain metastases were included. Classification of lesion areas was performed using a support vector machine classifier trained on 4 components: enhancing and nonenhancing, tumor and nontumor, based on T1-weighted, FLAIR, and dynamic-contrast-enhancing MRI parameters. Classification results were evaluated by 2-fold cross-validation analysis of the training set and MR spectroscopy. Longitudinal changes of the component volumes were compared with Response Assessment in Neuro-Oncology criteria. RESULTS: Normalized T1-weighted values, FLAIR, plasma volume, volume transfer constant, and bolus-arrival-time parameters differentiated components. High sensitivity and specificity (100%) were obtained within the enhancing and nonenhancing areas. Longitudinal changes in component volumes correlated with the Response Assessment in Neuro-Oncology criteria in 27 patients; 5 patients (16%) demonstrated an increase in tumor component volumes indicating tumor progression. These changes preceded Response Assessment in Neuro-Oncology assessments by several months. Seven patients treated with bevacizumab showed a shift to an infiltrative pattern of progression. CONCLUSIONS: This study proposes an automatic classification method: segmented Response Assessment in Neuro-Oncology criteria based on advanced imaging that reliably differentiates tumor and nontumor components in high-grade gliomas. The segmented Response Assessment in Neuro-Oncology criteria may improve therapy-response assessment and provide earlier indication of progression.

BACKGROUND Constitutional mismatch repair deficiency syndrome (CMMRD) is a severe cancer predisposition syndrome resulting in early onset central nervous system (CNS) and other cancers. International guidelines for surveillance exist but no study has systematically evaluated the efficacy of this protocol. METHODS We surveyed all confirmed CMMRD patients in the International Replication Repair Deficiency Consortium. A surveillance protocol consisting of frequent biochemical, endoscopic and imaging (CNS and total body MRI) studies were employed. Survival analyses and efficacy of each method were assessed. RESULTS Surveillance data were collected from 105 CMMRD individuals from 41 countries. Of the 193 malignant tumors, CNS malignancies were the most common (44%). The surveillance protocol uncovered 49 asymptomatic tumors including 16 glioblastomas and medulloblastomas. Five-year overall survival was 89% for tumors discovered by surveillance, and 61% for symptomatic tumors (p6 months as per protocol. Finally, of the low grade tumors identified asymptomatically, 5 were low grade gliomas. All of the low grade gliomas, which were not resected transformed to high grade tumors at a median of 1.6 ± 0.9 years. CONCLUSION These data support a survival benefit in CMMRD patients undergoing a surveillance protocol. Adherence to protocol and resection of lower grade lesions may improve survival for patients with CNS tumors.

BACKGROUND Previous studies examining the time to initiate chemoradiation (CRT) after surgical resection of glioblastoma have been conflicting. To better define the effect that the timing of adjuvant treatment may have on outcomes, the authors examined patients within the National Cancer Database (NCDB) stratified by a validated prognostic classification system. METHODS Patients with glioblastoma in the NCDB who underwent surgery and CRT from 2004 through 2013 were analyzed. Radiation Therapy Oncology Group recursive partitioning analysis (RPA) class (III, IV, V) was extrapolated for the cohort. Time intervals were grouped weekly, with weeks 4 to 5 serving as the reference category for analyses. Kaplan-Meier analysis, log-rank testing, and multivariate (MVA) Cox proportional hazards regression were performed. RESULTS In total, 30,414 patients were included. RPA classes III, IV, and V contained 5250, 20,855, and 4309 patients, respectively. On MVA, no time point after week 5 was associated with a change in overall survival for the entire cohort or for any RPA class subgroup. The periods of weeks 0 to 1 (hazard ratio [HR], 1.18; 95% CI, 1.02-1.36), >1 to 2 (HR, 1.23; 95% CI, 1.16-1.31), and >2 to 3 (HR, 1.11; 95% CI, 1.07-1.15) demonstrated slightly worse overall survival (all P

Pediatric brain tumors with replication repair deficiency (RRD) are hypermutant and may respond favorably to immune checkpoint inhibition (ICI). We are collecting ongoing clinical and molecular data from patients with RRD hypermutant cancers treated with ICI as a part of our consortium registry study. Companion biomarkers include tumor mutational burden (TMB), neoantigens and genetic signatures obtained from whole genome and exome sequencing. Immune inference is obtained from RNAseq. Additionally, T-cell receptor rearrangement data are collected from the tumor and blood throughout treatment. From 2015–2018, 53 patients were treated with ICI and combination therapies. Of these 39 had brain tumors, with 93% having high grade gliomas. Two-year overall survival for the entire cohort is 47+/-8%, which compares favorably with historical controls. Tumor location had major impact on outcome. Non-CNS solid tumor patients have 2-year OS of 78+/-11%, all failures occurring within the first 2 months, and sustained responses are observed for 3 years. In contrast, OS for brain tumors is 39+/-10% with late recurrences observed even after 2 years of therapy (p=0.02). Large tumor size and total tumor burden are associated with higher rates of “flare” and poor outcome throughout all cancers. While all tumors are hypermutant, TMB and predicted neoantigens do not correlate with response. However, specific signatures extracted from SNVs and indels are significantly associated with response to ICI and favorable outcome (p=0.005). Notably, RRD IDH1 mutant glioblastomas have particularly poor response to ICI. Interestingly, glioblastomas (n=8) which failed single agent ICI had favorable responses to combination immunotherapies with prolonged survival of 65%+/-8% one year after failure vs 0 for untreated patients (p=0.01). The favorable outcome and responses to ICI are encouraging. Since brain tumors respond less favorably to ICI than other solid tumors, combination therapies based on tumor and immune signatures of these cancers may be beneficial.

e18725 Background: Healthcare data sharing is important for the creation of diverse and large data sets, supporting clinical decision making, and accelerating efficient research to improve patient outcomes. This is especially vital in the case of real world data analysis. However, stakeholders are reluctant to share their data without ensuring patients’ privacy, proper protection of their data sets and the ways they are being used. Homomorphic encryption is a cryptographic capability that can address these issues by enabling computation on encrypted data without ever decrypting it, so the analytics results are obtained without revealing the raw data. The aim of this study is to prove the accuracy of analytics results and the practical efficiency of the technology. Methods: A real-world data set of colorectal cancer patients’ survival data, following two different treatment interventions, including 623 patients and 24 variables, amounting to 14,952 items of data, was encrypted using leveled homomorphic encryption implemented in the PALISADE software library. Statistical analysis of key oncological endpoints was blindly performed on both the raw data and the homomorphically-encrypted data using descriptive statistics and survival analysis with Kaplan-Meier curves. Results were then compared with an accuracy goal of two decimals. Results: The difference between the raw data and the homomorphically encrypted data results, regarding all variables analyzed was within the pre-determined accuracy range goal, as well as the practical efficiency of the encrypted computation measured by run time, are presented in table. Conclusions: This study demonstrates that data encrypted with Homomorphic Encryption can be statistical analyzed with a precision of at least two decimal places, allowing safe clinical conclusions drawing while preserving patients’ privacy and protecting data owners’ data assets. Homomorphic encryption allows performing efficient computation on encrypted data non-interactively and without requiring decryption during computation time. Utilizing the technology will empower large-scale cross-institution and cross- stakeholder collaboration, allowing safe international collaborations. Clinical trial information: 0048-19-TLV. [Table: see text]

The graphic abstract was missing in the original online publication. The original article has been corrected.

The interstitium-to-plasma rate constant (kep), extracted from dynamic contrast enhancement (DCE-MRI) MRI data, seems to have an important role in the assessment of patients with brain tumors. This parameter is affected by the slow behavior of the system, and thus is expected to be highly dependent on acquisition duration. The aim of this study was to optimize the scan duration and protocol of DCE-MRI for accurate estimation of the kep parameter in patients with high grade brain tumors. The effects of DCE-MRI scan duration and protocol design (continuous vs integrated scanning) on the estimated pharmacokinetic (PK) parameters and on model selection, were studied using both simulated and patient data. Scan duration varied, up to 60min for simulated data, and up to 25min in 25 MRI scans obtained from patients with high grade brain tumors, with continuous and integrated scanning protocols. Converging results were obtained from simulated and real data. Significant effect of scan duration was detected on kep. Scan duration of 9min, with integrated protocol in which the data are acquired continuously for 5min, and additional volumes at 7 and 9min, was sufficient for accurate estimation of even low kep values, with an average error of 3%. Over-estimation of the PK parameters was detected for scan duration 12min. An integrated protocol of 9min is suggested as optimal for clinical use in patients with high grade brain tumors. Lower acquisition time may result in over-estimation of kep when using ETM, and therefore care should be taken using model selection.

Patients with progressive primary brain tumors (PBT) are attracted to promising new treatments, even prior to convincing data. Anti-PD1 immunotherapies have been in the spotlight since publication of groundbreaking results for metastatic melanoma with pembrolizumab (PBL). Our objective was to report on the response and toxicity of PBL in patients with advanced PBT. We retrospectively reviewed the charts of 22 patients (17 adults and 5 children) with recurrent central nervous system tumors treated with PBL. We analyzed prior antineoplastic therapies, steroid usage, and outcomes. Patients received a median of two neoplastic therapies prior to PBL, and a median of three infusions of PBL in adults and four in children. Twelve patients (9 adults and 3 children) started PBL on steroids (median dose in adults 4 mg; range 2-8, and in children 1.5 mg, range 0.5-4) and five patients received steroids later during PBL treatment. Twelve patients (10 adults and 2 children) received concomitant bevacizumab with PBL. Side effects were minimal. All patients showed progressive tumor growth during therapy. Median OS from the start of PBL was 2.6 months in adults and 3.2 months in children. Two GB patients underwent tumor resection following treatment with PBL. Tumor-lymphocytic response in these cases was unremarkable, and PD-L1 immuno-staining was negative. In this series of 22 patients with recurrent primary brain tumors, PBL showed no clinical or histologic efficacy. We do not recommend further use of PBL for recurrent PBT unless convincing prospective clinical trial data are published.

Pediatric brain tumors with replication repair deficiency (RRD) are hypermutant and may respond to immune checkpoint inhibition (ICI). We performed a consortium registry study of ICI in recurrent RRD cancers. Clinical and companion biomarkers were collected longitudinally on all patients. Biomarkers included tumor mutational burden (TMB), neoantigens and genetic signatures obtained from whole genome and exome sequencing. Immune inference was obtained by RNAseq and T cell rearrangement was collected in the tumor and in blood throughout treatment. Of the 46 tumors on the study, 32 were brain tumors with glioblastoma in 96%. Rapid, objective responses (>50%) were observed in 50% of glioblastomas. Three year overall survival for the whole cohort was 48+/-8% which compares favorably with historical controls. Brain tumors fared worse with OS of 39+/-10% and late recurrences observed even after 2 years of therapy (p=0.02). Tumor size and acute “flare” constitute poor outcome throughout all cancers. While all tumors are hypermutant, TMB and predicted neoantigens correlated with response to ICI (p=0.02). Specific signatures extracted from SNVs and total mutations predicted response to ICI and favorable outcome (p=0.005). RNA inference and TCR reveal that the FLARE phenotype is mostly acute nonspecific immune response and not true progression. Finally, glioblastomas (n=8) which failed single agent ICI had favorable responses to combinational immunotherapies with prolonged survival of 65%+/-8% at one year after failure vs 0 for other patients (p=0.01). RRD glioblastomas exhibit favorable outcome and responses to ICI. Combinational therapies based on tumor and immune signatures of these cancers are necessary.

OBJECTIVE In the EF-14 phase 3 trial, TTFields 9200 kHz) added to maintenance TMZ increased median OS to 20.9 months versus 16.0 months with maintenance TMZ (p< 0.001) in ndGBM. Preclinical investigations showed that TTFields/RT have a synergistic effect. A pilot study (N=10) in ndGBM demonstrated the feasibility and safety of TTFields combined with RT/TMZ (Grossman Front Onc 2020). The only TTFields-related adverse event was array-associated skin toxicity. Median PFS was 8.9 months. Based on these encouraging results, this prospective, randomized phase 2 study [NCT03869242] in 60 patients further investigates if the addition of TTFields TMZ/RT treatment in ndGBM patients improves treatment efficacy and delays disease progression. METHODS Following debulking surgery or biopsy, 60 patients (≥18 years) with histologically confirmed GBM, KPS≥70 and life expectancy >3 months will be randomized 1:1 to: i) RT with concomitant TMZ/TTFields (200 kHz) for 6 weeks followed by up to 6 months of maintenance TMZ combined with TTFields (experimental arm) up to 24 months; or ii) RT with concomitant TMZ alone followed by maintenance TMZ combined with TTFields (control arm). Patients with early progressive disease, significant comorbidities precluding maintenance RT or TMZ or with implanted electronic devices will be excluded. The primary endpoint is the rate of progression free survival at 12 months (PFS12). Treatment with TTF will be continued until second progression or 24 months (the earlier of the two). All patients will be followed for survival. All adverse events will graded per CTCAE V5.0. The sample size of 60 patients provides 80% power with two-sided alpha level of 0.05 to detect a PFS12 of 46.5% with RT/TMZ/TTFields compared to 29.4% with RT/TMZ followed, respectively, by maintenance TMZ/TTFields (calculated from the RT/TMZ followed by maintenance TMZ/TTFields arm of the EF-14 trial). Follow-up will continue for >12 months from recruitment of the last patient.

Background: Tumor Treating Fields (TTFields) are a non-invasive, loco-regional, anti-mitotic treatment comprising low-intensity alternating electric fields. In the phase III EF-14 study in newly diagnosed glioblastoma (ndGBM), TTFields in combination with temozolomide (TMZ) significantly improved survival compared with TMZ alone. In preclinical studies TTFields had a radiosensitizing effect and increased the efficacy of radiation therapy (RT). This pilot study [NCT03780569] evaluated the feasibility and safety of TTFields administered concurrently with RT and TMZ in ndGBM patients. Methods: Patients with histologically confirmed ndGBM were treated with TTFields/RT/TMZ followed by adjuvant TMZ/TTFields. TTFields (200 kHz) were delivered for ≥18 hours/day with transducer arrays removed during RT delivery. RT was administered to the tumor bed in 30 fractions (total dose 60 Gy) in combination with daily TMZ (75 mg/m2). In the adjuvant phase, patients received monthly TMZ (150-200 mg/m2 for 5 days) plus TTFields. The primary outcome was safety of the combined therapies; secondary outcomes included progression-free survival (PFS) and overall survival (OS). Adverse events (AEs) were graded per CTCAE v4.0. Results: Ten patients were enrolled at a single center between April and December 2017. Median age was 60.2 years, median Karnofsky Performance Score was 90.0, and eight (80%) patients were male. Five (50%) patients had undergone tumor resection while the remainder had biopsy only. Eight patients experienced ≥1 RT treatment delay; delays were unrelated to TTFields treatment. All patients experienced ≥1 AE. Three patients suffered from serious AEs (urinary tract infection, confusional state, and decubitus ulcer) that were considered unrelated to TTFields. The most common AE was skin toxicity, reported in eight (80%) patients; all were of low severity (CTCAE grade 1-2) and were reported as related to TTFields treatment. Median PFS from enrollment was 8.9 months; median OS was not reached at the time of study closure. Conclusions: Eighty percent of patients experienced grade 1-2 TTFields-related skin toxicity. No other TTFields-related toxicities were observed and there was no increase in RT- or TMZ-related toxicities as a result of combining TTFields with these therapies. Based on the safety and preliminary efficacy results of this pilot study, a phase 2 randomized trial (N=60; NCT03869242) and the Phase 3 TRIDENT trial have been initiated to further investigate the efficacy of concomitant RT/TMZ/TTFields in ndGBM. Citation Format: Felix Bokstein, Deborah Blumenthal, Dror Limon, Carmit Ben Harosh, Zvi Ram, Rachel Grossman. Concurrent Tumor Treating Fields (TTFields) and radiation therapy for newly diagnosed glioblastoma: A safety and feasibility study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT206.

e14535 Background: Tumor Treating Fields (TTFields), a non-invasive, loco-regional, anti-mitotic treatment comprises low-intensity alternating electric fields. In the phase III EF-14 study in newly diagnosed glioblastoma (ndGBM), TTFields in combination with temozolomide (TMZ) significantly improved survival compared to TMZ alone. In preclinical studies TTFields had a radiosensitizing effect and increased the efficacy of radiation therapy (RT). This pilot study [NCT03780569] evaluated the feasibility and safety of TTFields administered concurrently with RT and TMZ in ndGBM patients. Methods: Patients with histologically confirmed ndGBM were treated with TTFields/RT/TMZ followed by adjuvant TMZ/TTFields. TTFields (200 kHz) were delivered for ≥18 hours/day with transducer arrays removed during RT delivery. RT was administered to the tumor bed in 30 fractions (total dose 60 Gy) in combination with daily TMZ (75 mg/m2). In the adjuvant phase, patients received monthly TMZ (150–200 mg/m2 for 5 days) plus TTFields. The primary outcome was safety of the combined therapies; secondary outcomes included progression-free survival (PFS) and overall survival (OS). Adverse events (AEs) were graded per CTCAE v4.0. Results: Ten patients were enrolled at a single center between April and December 2017. Median age was 60.2 years, median Karnofsky Performance Score was 90.0, and eight (80%) patients were male. Five (50%) patients had undergone tumor resection while the remainder had biopsy only. Eight patients experienced ≥1 RT treatment delay; delays were unrelated to TTFields treatment. All patients experienced ≥1 AE. Three patients suffered from serious AEs (urinary tract infection, confusional state, and decubitus ulcer) that were considered unrelated to TTFields. The most common AE was skin toxicity, reported in eight (80%) patients; all were of low severity (CTCAE grade 1–2) and were reported as related to TTFields treatment. Median PFS from enrollment was 8.9 months; median OS was not reached at the time of study closure. Conclusions: Eighty percent of patients experienced grade 1–2 TTFields-related skin toxicity. No other TTFields-related toxicities were observed and there was no increase in RT- or TMZ-related toxicities as a result of combining TTFields with these therapies. Based on the safety and preliminary efficacy results of this pilot study, a phase 2 randomized trial (N = 60; NCT03869242) and the Phase 3 TRIDENT trial have been initiated to further investigate the efficacy of concomitant RT/TMZ/TTFields in ndGBM. Clinical trial information: NCT03780569.

We report on a series of nine patients with high grade glioma (HGG) who developed punctate contrast-enhancing foci on MRI, several years after tumor treatment. The lesions were considered suspicious for tumor progression at their onset, but were proven over time to be benign in nature. Five of the patients were treated for glioblastoma; 3 for anaplastic astrocytoma, and one for anaplastic oligodendroglioma. Median age of the patients at diagnosis was 48 years (31–62 years). The mean time of onset of “suspicious spots” following treatment was 51 months after diagnosis (6–170 months). Of note, median overall survival of the group is 96 months; with none of the nine patients deceased, and only 2 patients known to have progression. The remainder of the 7 patients are free of active tumor and being followed off treatment. No apparent clinical manifestations of the lesions have been observed. The majority of the punctate lesions were of a dynamic nature; they appeared and spontaneously disappeared over time, without intervention. All lesions developed within the field of radiation treatment; some were contralateral to the tumor. Radiological characteristics of the lesions including analysis of SWI, DWI, and DCE magnetic resonance imaging sequences will be reported. Punctate enhancing foci in the region of radiation treatment are phenomena which may be manifestation of delayed treatment sequelae in HGG. Patients with these lesions are on average of younger age and have a particularly long survival. These lesions appeared several years following oncological treatment. The foci should be initially followed more closely until shown to be of a non-progressive nature; they should not be presumed to be indicative of tumor recurrence. Possible etiology of the lesions may be related to vascular changes induced by radiation.

BACKGROUND: Tumor Treating Fields (TTFields) are a non-invasive, loco-regional, anti-mitotic treatment comprising low intensity alternating electric fields. In the phase 3 EF14 study in newly diagnosed glioblastoma (ndGBM), TTFields/temozolomide significantly improved survival versus temozolomide alone. TTFields increased glioma cells undergoing cellular death following radiotherapy (RT), suggesting a radiosensitizing effect that enhances RT efficacy. This single center study is the first to investigate TTFields concomitant to RT in ndGBM. METHODS: Enrolled ndGBM patients (N=10), KPS 70 had recovered from maximal debulking surgery or biopsy. Patients started TTFields prior to or at the time of RT, and were on stable/ decreasing corticosteroids doses for 7 days pre-enrollment. Patients received TTFields (200 kHz; 18 hours/day) with daily removal of transducer arrays during RT, temozolomide (75 mg/m2/daily for 6 weeks) and 60 Gy RT. Endpoints included safety of TTFields/RT (primary) and preliminary efficacy. RESULTS: Patients were 59 years (42–71), KPS 90 (80–100) and mostly male (80%). Five patients (50%) underwent gross total resection while rest had biopsy only. Median dose of RT was 60 Gy (range 52–60 Gy). Six patients (60%) reported have an adverse event (AE) to-date. The most common AE was TTFields-related skin toxicity in 4 (40%) patients; none were severe. All other AEs reported occurred in only one patient and be attributed to underlying disease or chemotherapy. Two reported serious AEs (seizures and general deterioration) were considered unrelated to TTFields. Median PFS was 10.5 months (95%CI 2.67–10.5). PFS rate at 6 months was 80% (95%CI 40.9–91.6). CONCLUSION: The proportion of TTFields-related skin toxicity (40%) was similar to that reported in phase III study (52%), where patients started TTFields > 4 weeks after RT. No other TTFields-related toxicities were reported, nor was there an increase in RT- or temozolomide-related toxicities from combining TTFields with these therapies. Preliminary survival data are encouraging.

To study the repeatability of plasma volume (vTwenty eight healthy subjects, of which eleven scanned twice, were used to assess the repeatability of vThe threshold values for significant changes were: LDD = 0.0024 (ml/100 ml, 21%) for mean vThis study shows high repeatability of v

In less than a decade, we have seen a revolution in the fields of hematology and oncology with the advent of immunotherapy, specifically the use of checkpoint inhibitor therapies (anti-PDL, anti-PDL1, and anti-CTLA4). These checkpoint inhibitors have been proven to be a groundbreaking approach for advanced cancers previously thought to be resistant to all other forms of treatments. However, the clinical experience for primary brain tumors is minimal and not yet standard changing. We will review the preclinical data and clinical experience to date for the use of checkpoint inhibitors and novel lymphocytic (T cell) activating immunotherapies for primary brain tumors.

The FDA-approved schedule and dose of bevacizumab (BVZ) for recurrent glioblastoma (rGB) (10 mg/kg q 2 weeks) were adopted from systemic cancer protocols. No dose-defining studies have been performed for glioblastoma. We began using BVZ for the treatment of rGB in 2005 at the dose of 5 mg/kg every 2 weeks combined with irinotecan, and later as single agent. Our previous report of 20 patients treated with BVZ 5 mg/kg every 2 weeks showed similar response rates and overall survival (OS) compared to other BVZ treatment protocols, with less adverse effects. In this study we retrospectively reviewed our 7 year experience with BVZ in 162 rGB patients. Treatment outcomes were analyzed from 87 patients who received BVZ at 5 mg/kg and 75 patients at 10 mg/kg. While median age was similar in both groups, the median KPS was significantly higher in the group treated with 10 mg/kg BVZ (85 versus 60). There was no significant difference in OS or progression free survival (PFS) between the groups treated with BVZ 5 versus 10 mg/kg. Overall survival was significantly improved in the subgroup treated with cytotoxic therapy in addition to BVZ 10 mg/kg. There were more adverse events seen with BVZ 10 mg/kg. There is no significant difference in OS for rGB treated with BVZ 5 mg/kg versus 10 mg/kg when given as monotherapy. The smaller dose was slightly less toxic. Addition of cytotoxic therapy resulted in prolongation of OS in a small subgroup of BVZ 10 mg/kg.

We present a retrospective review of 55 Stereotactic Radiosurgery (SRS) procedures performed in 47 consecutive patients with high-grade glioma (HGG). Thirty-three (70.2%) patients were diagnosed with glioblastoma and 14 (29.8%) with grade III glioma. The indications for SRS were small (up to 30 mm in diameter) locally progressing lesions in 32/47 (68%) or new distant lesions in 15/47 (32%) patients. The median target volume was 2.2 cc (0.2-9.5 cc) and the median prescription dose was 18 Gy (14-24 Gy). Three patients (5.5% incidence in 55 treatments) developed radiation necrosis. In eight cases (17%) patients received a second salvage SRS treatment to nine new lesions detected during follow-up. In 22/55 SRS treatments (40.0%) patients received concurrent chemo- or biological therapy, including temozolamide (TMZ) (15 patients), bevacizumab (BVZ) (6 patients) and carboplatin in one patient. Median time to progression after SRS was 5.0 months (1.0-96.4). Median survival time after SRS was 15.9 months (2.3-109.3) overall median survival (since diagnosis) was 37.4 months (9.6-193.6 months). Long-lasting responses (>12 months) after SRS were observed in 25/46 (54.3%) patients. We compared a matched (histology, age, KPS) cohort of patients with recurrent HGG treated with BVZ alone with the current study group. Median survival was significantly longer for SRS treated patients compared to the BVZ only cohort (12.6 vs. 7.3 months, p = 0.0102). SRS may be considered an effective salvage procedure for selected patients with small volume, recurrent high-grade gliomas. Long-term radiological control was observed in more than 50% of the patients.

Cerebral blood volume (CBV) is an important parameter for the assessment of brain tumors, usually obtained using dynamic susceptibility contrast (DSC) MRI. However, this method often suffers from low spatial resolution and high sensitivity to susceptibility artifacts and usually does not take into account the effect of tissue permeability. The plasma volume (v p) can also be extracted from dynamic contrast enhancement (DCE) MRI. The aim of this study was to investigate whether DCE can be used for the measurement of cerebral blood volume in place of DSC for the assessment of patients with brain tumors. Twenty-eight subjects (17 healthy subjects and 11 patients with glioblastoma) were scanned using DCE and DSC. v p and CBV values were measured and compared in different brain components in healthy subjects and in the tumor area in patients. Significant high correlations were detected between v p and CBV in healthy subjects in the different brain components; white matter, gray matter, and arteries, correlating with the known increased tissue vascularity, and within the tumor area in patients. This work proposes the use of DCE as an alternative method to DSC for the assessment of blood volume, given the advantages of its higher spatial resolution, its lower sensitivity to susceptibility artifacts, and its ability to provide additional information regarding tissue permeability.