A qualitative evaluation of factors influencing Tumor Treating fields (TTFields) therapy decision making among brain tumor patients and physicians.

BACKGROUND: Tumor Treating Fields (TTFields) Therapy is an FDA-approved therapy in the first line and recurrent setting for glioblastoma. Despite Phase 3 evidence showing improved survival with TTFields, it is not uniformly utilized. We aimed to examine patient and clinician views of TTFields and factors shaping utilization of TTFields through a unique research partnership with medical neuro oncology and medical social sciences. METHODS: Adult glioblastoma patients who were offered TTFields at a tertiary care academic hospital were invited to participate in a semi-structured interview about their decision to use or not use TTFields. Clinicians who prescribe TTFields were invited to participate in a semi-structured interview about TTFields. RESULTS: Interviews were completed with 40 patients with a mean age of 53 years; 92.5% were white and 60% were male. Participants who decided against TTFields stated that head shaving, appearing sick, and inconvenience of wearing/carrying the device most influenced their decision. The most influential factors for use of TTFields were the efficacy of the device and their clinician's opinion. Clinicians (N = 9) stated that TTFields was a good option for glioblastoma patients, but some noted that their patients should consider the burdens and benefits of TTFields as it may not be the desired choice for all patients. CONCLUSIONS: This is the first study to examine patient decision making for TTFields. Findings suggest that clinician support and efficacy data are among the key decision-making factors. Properly understanding the path to patients' decision making is crucial in optimizing the use of TTFields and other therapeutic decisions for glioblastoma patients.

Deep-learning-based reconstruction of undersampled MRI to reduce scan times: a multicentre, retrospective, cohort study.

BACKGROUND: The extended acquisition times required for MRI limit its availability in resource-constrained settings. Consequently, accelerating MRI by undersampling k-space data, which is necessary to reconstruct an image, has been a long-standing but important challenge. We aimed to develop a deep convolutional neural network (dCNN) optimisation method for MRI reconstruction and to reduce scan times and evaluate its effect on image quality and accuracy of oncological imaging biomarkers. METHODS: In this multicentre, retrospective, cohort study, MRI data from patients with glioblastoma treated at Heidelberg University Hospital (775 patients and 775 examinations) and from the phase 2 CORE trial (260 patients, 1083 examinations, and 58 institutions) and the phase 3 CENTRIC trial (505 patients, 3147 examinations, and 139 institutions) were used to develop, train, and test dCNN for reconstructing MRI from highly undersampled single-coil k-space data with various acceleration rates (R=2, 4, 6, 8, 10, and 15). Independent testing was performed with MRIs from the phase 2/3 EORTC-26101 trial (528 patients with glioblastoma, 1974 examinations, and 32 institutions). The similarity between undersampled dCNN-reconstructed and original MRIs was quantified with various image quality metrics, including structural similarity index measure (SSIM) and the accuracy of undersampled dCNN-reconstructed MRI on downstream radiological assessment of imaging biomarkers in oncology (automated artificial intelligence-based quantification of tumour burden and treatment response) was performed in the EORTC-26101 test dataset. The public NYU Langone Health fastMRI brain test dataset (558 patients and 558 examinations) was used to validate the generalisability and robustness of the dCNN for reconstructing MRIs from available multi-coil (parallel imaging) k-space data. FINDINGS: In the EORTC-26101 test dataset, the median SSIM of undersampled dCNN-reconstructed MRI ranged from 0·88 to 0·99 across different acceleration rates, with 0·92 (95% CI 0·92-0·93) for 10-times acceleration (R=10). The 10-times undersampled dCNN-reconstructed MRI yielded excellent agreement with original MRI when assessing volumes of contrast-enhancing tumour (median DICE for spatial agreement of 0·89 [95% CI 0·88 to 0·89]; median volume difference of 0·01 cm3 [95% CI 0·00 to 0·03] equalling 0·21%; p=0·0036 for equivalence) or non-enhancing tumour or oedema (median DICE of 0·94 [95% CI 0·94 to 0·95]; median volume difference of -0·79 cm3 [95% CI -0·87 to -0·72] equalling -1·77%; p=0·023 for equivalence) in the EORTC-26101 test dataset. Automated volumetric tumour response assessment in the EORTC-26101 test dataset yielded an identical median time to progression of 4·27 months (95% CI 4·14 to 4·57) when using 10-times-undersampled dCNN-reconstructed or original MRI (log-rank p=0·80) and agreement in the time to progression in 374 (95·2%) of 393 patients with data. The dCNN generalised well to the fastMRI brain dataset, with significant improvements in the median SSIM when using multi-coil compared with single-coil k-space data (p<0·0001). INTERPRETATION: Deep-learning-based reconstruction of undersampled MRI allows for a substantial reduction of scan times, with a 10-times acceleration demonstrating excellent image quality while preserving the accuracy of derived imaging biomarkers for the assessment of oncological treatment response. Our developments are available as open source software and hold considerable promise for increasing the accessibility to MRI, pending further prospective validation. FUNDING: Deutsche Forschungsgemeinschaft (German Research Foundation) and an Else Kröner Clinician Scientist Endowed Professorship by the Else Kröner Fresenius Foundation.

Repeated blood-brain barrier opening with a nine-emitter implantable ultrasound device in combination with carboplatin in recurrent glioblastoma: a phase I/II clinical trial.

Here, the results of a phase 1/2 single-arm trial (NCT03744026) assessing the safety and efficacy of blood-brain barrier (BBB) disruption with an implantable ultrasound system in recurrent glioblastoma patients receiving carboplatin are reported. A nine-emitter ultrasound implant was placed at the end of tumor resection replacing the bone flap. After surgery, activation to disrupt the BBB was performed every four weeks either before or after carboplatin infusion. The primary objective of the Phase 1 was to evaluate the safety of escalating numbers of ultrasound emitters using a standard 3 + 3 dose escalation. The primary objective of the Phase 2 was to evaluate the efficacy of BBB opening using magnetic resonance imaging (MRI). The secondary objectives included safety and clinical efficacy. Thirty-three patients received a total of 90 monthly sonications with carboplatin administration and up to nine emitters activated without observed DLT. Grade 3 procedure-related adverse events consisted of pre syncope (n = 3), fatigue (n = 1), wound infection (n = 2), and pain at time of device connection (n = 7). BBB opening endpoint was met with 90% of emitters showing BBB disruption on MRI after sonication. In the 12 patients who received carboplatin just prior to sonication, the progression-free survival was 3.1 months, the 1-year overall survival rate was 58% and median overall survival was 14.0 months from surgery.

A multi-institutional phase I study of acetazolamide with temozolomide in adults with newly diagnosed MGMT-methylated malignant glioma.

Background: A significant unmet need exists for the treatment of glioblastoma, IDH-wildtype (GBM). Preclinical work shows that acetazolamide sensitizes GBM to temozolomide (TMZ) by overcoming TMZ resistance due to BCL-3-dependent upregulation of carbonic anhydrase. Acetazolamide is Food and Drug Administration-approved for the treatment of altitude sickness. Drug repurposing enables the application of drugs to diseases beyond initial indications. This multi-institutional, open-label, phase I trial examined a combination of acetazolamide and TMZ in patients with MGMT promoter-methylated high-grade glioma. Methods: A total of 24 patients (GBM, IDH-wildtype = 22; Grade 4 astrocytoma, IDH-mutant = 1; Grade 3 astrocytoma, IDH-mutant = 1) were accrued over 17 months. All patients received oral acetazolamide (250 mg BID for 7 days increased to 500 mg BID for Days 8-21 of each 28-day cycle) during the adjuvant phase of TMZ for up to 6 cycles. Results: No patient had a dose-limiting toxicity. Adverse events were consistent with known sequelae of acetazolamide and TMZ. In the 23 WHO Grade 4 patients, the median overall survival (OS) was 30.1 months and the median progression-free survival was 16.0 months. The 2-year OS was 60.9%. In total 37% of the study population had high BCL-3 staining and trended toward shorter OS (17.2 months vs N.R., P = .06). Conclusions: The addition of acetazolamide is safe and tolerable in GBM patients receiving standard TMZ. Survival results compare favorably to historical data from randomized trials in patients with MGMT promoter-methylated GBM and support examination of acetazolamide in a randomized trial. BCL-3 expression is a potential biomarker for prognosis in GBM or for patients more likely to benefit from TMZ.

Paclitaxel and Carboplatin in Combination with Low-intensity Pulsed Ultrasound for Glioblastoma.

PURPOSE: We recently reported on clinical trials for patients with recurrent glioblastoma where low-intensity pulsed ultrasound and microbubbles (LIPU/MB) improved paclitaxel or carboplatin delivery into the brain. Here, we report variable local tumor control with paclitaxel at the maximal/target dose in our phase I trial (NCT04528680). To address this, we investigated the combination of paclitaxel with carboplatin in preclinical glioma models. EXPERIMENTAL DESIGN: We performed MRI-based analysis to evaluate disease control in patients from our trial. We studied the cytotoxicity of paclitaxel and carboplatin against 11 human glioma lines as monotherapy and in combination at concentrations derived from human intraoperative studies. Synergy was assessed with the Loewe model and the survival benefit evaluated in two xenografts. We examined the effects on cell cycle progression, DNA damage, and apoptosis. RESULTS: Patients treated with paclitaxel and LIPU/MB exhibited variable local tumor control, which correlated with overall survival. We observed limited cross-resistance to paclitaxel and carboplatin in glioma lines, with almost a third of them being exclusively susceptible to one drug. This combination led to susceptibility of 81% of lines and synergy in 55% of them. The combination proved more efficacious in two intracranial xenografts when administered with LIPU/MB, leading to complementary effects on cell cycle arrest. CONCLUSIONS: Combining paclitaxel and carboplatin in gliomas may be more efficacious than monotherapy, as in other cancers, due to synergy and independent susceptibility to each drug. These results form the basis for an ongoing phase II trial (NCT04528680) where we investigate this combination with LIPU/MB.

ERK1/2 Phosphorylation Predicts Survival in Recurrent Glioblastoma Following Intracerebral and Adjuvant PD-1/CTLA-4 Immunotherapy: A REMARK-guided Analysis.

PURPOSE: Evidence suggests that MAPK pathway activation, as measured by ERK1/2 phosphorylation (p-ERK), predicts overall survival (OS) in patients with recurrent glioblastoma receiving anti-PD-1 therapy. We aimed to validate these findings in independent cohorts. EXPERIMENTAL DESIGN: In a 24-patient clinical trial on recurrent glioblastoma and high-grade gliomas, we examined the link between p-ERK levels and OS. Patients received intravenous nivolumab, followed by maximal safe resection and an intracerebral injection of either ipilimumab alone or combined with nivolumab. Biweekly adjuvant nivolumab was then administered up to five times (NCT03233152). Using REporting recommendations for tumor MARKER prognostic studies (REMARK) criteria, we conducted independent analyses for p-ERK quantification and statistical evaluations. Additional comparative analysis included prior cohorts, totaling 65 patients. Cox proportional hazards models and meta-analysis were employed to assess p-ERK as a predictive biomarker after immunotherapy. RESULTS: Lower median p-ERK+ cell density was observed compared with prior studies, likely due to variable tissue processing across cohorts. Nonetheless, high p-ERK was associated with prolonged OS, particularly in isocitrate dehydrogenase wild-type glioblastomas (P = 0.036). Median OS for high and low p-ERK patients were 55.6 and 30 weeks, respectively. Multivariable analysis reinforced p-ERK's significance in survival prediction (P = 0.011). Upon p-ERK normalization across cohorts (n = 65), meta-analysis supported the survival benefit of elevated tumor p-ERK levels (P = 0.0424). CONCLUSIONS: This study strengthens the role of p-ERK as a predictive biomarker for OS in patients with glioblastoma on immune checkpoint blockade. Future research should focus on further validation in prospective trials and the standardization of preanalytical variables influencing p-ERK quantification.

Variant allelic frequencies of driver mutations can identify gliomas with potentially false-negative MGMT promoter methylation results.

MGMT promoter methylation testing is required for prognosis and predicting temozolomide response in gliomas. Accurate results depend on sufficient tumor cellularity, but histologic estimates of cellularity are subjective. We sought to determine whether driver mutation variant allelic frequency (VAF) could serve as a more objective metric for cellularity and identify possible false-negative MGMT samples. Among 691 adult-type diffuse gliomas, MGMT promoter methylation was assessed by pyrosequencing (N = 445) or DNA methylation array (N = 246); VAFs of TERT and IDH driver mutations were assessed by next generation sequencing. MGMT results were analyzed in relation to VAF. By pyrosequencing, 56% of all gliomas with driver mutation VAF ≥ 0.325 had MGMT promoter methylation, versus only 37% with VAF < 0.325 (p < 0.0001). The mean MGMT promoter pyrosequencing score was 19.3% for samples with VAF VAF ≥ 0.325, versus 12.7% for samples with VAF < 0.325 (p < 0.0001). Optimal VAF cutoffs differed among glioma subtypes (IDH wildtype glioblastoma: 0.12-0.18, IDH mutant astrocytoma: ~0.33, IDH mutant and 1p/19q co-deleted oligodendroglioma: 0.3-0.4). Methylation array was more sensitive for MGMT promoter methylation at lower VAFs than pyrosequencing. Microscopic examination tended to overestimate tumor cellularity when VAF was low. Re-testing low-VAF cases with methylation array and droplet digital PCR (ddPCR) confirmed that a subset of them had originally been false-negative. We conclude that driver mutation VAF is a useful quality assurance metric when evaluating MGMT promoter methylation tests, as it can help identify possible false-negative cases.

RANO 2.0: Update to the Response Assessment in Neuro-Oncology Criteria for High- and Low-Grade Gliomas in Adults.

PURPOSE: The Response Assessment in Neuro-Oncology (RANO) criteria for high-grade gliomas (RANO-HGG) and low-grade gliomas (RANO-LGG) were developed to improve reliability of response assessment in glioma trials. Over time, some limitations of these criteria were identified, and challenges emerged regarding integrating features of the modified RANO (mRANO) or the immunotherapy RANO (iRANO) criteria. METHODS: Informed by data from studies evaluating the different criteria, updates to the RANO criteria are proposed (RANO 2.0). RESULTS: We recommend a standard set of criteria for both high- and low-grade gliomas, to be used for all trials regardless of the treatment modalities being evaluated. In the newly diagnosed setting, the postradiotherapy magnetic resonance imaging (MRI), rather than the postsurgical MRI, will be used as the baseline for comparison with subsequent scans. Since the incidence of pseudoprogression is high in the 12 weeks after radiotherapy, continuation of treatment and confirmation of progression during this period with a repeat MRI, or histopathologic evidence of unequivocal recurrent tumor, are required to define tumor progression. However, confirmation scans are not mandatory after this period nor for the evaluation of treatment for recurrent tumors. For treatments with a high likelihood of pseudoprogression, mandatory confirmation of progression with a repeat MRI is highly recommended. The primary measurement remains the maximum cross-sectional area of tumor (two-dimensional) but volumetric measurements are an option. For IDH wild-type glioblastoma, the nonenhancing disease will no longer be evaluated except when assessing response to antiangiogenic agents. In IDH-mutated tumors with a significant nonenhancing component, clinical trials may require evaluating both the enhancing and nonenhancing tumor components for response assessment. CONCLUSION: The revised RANO 2.0 criteria refine response assessment in gliomas.

Building Team Medicine in the Management of CNS Metastases.

CNS metastases are often terminal for cancer patients and occur at an approximately 10-fold higher rate than primary CNS tumors. The incidence of these tumors is approximately 70,000-400,000 cases annually in the US. Advances that have occurred over the past two decades have led to more personalized treatment approaches. Newer surgical and radiation techniques, as well as targeted and immune therapies, have enanled patient to live longer, thus increasing the risk for the development of CNS, brain, and leptomeningeal metastases (BM and LM). Patients who develop CNS metastases have often been heavily treated, and options for future treatment could best be addressed by multidisciplinary teams. Studies have indicated that patients with brain metastases have improved survival outcomes when cared for in high-volume academic institutions using multidisciplinary teams. This manuscript discusses a multidisciplinary approach for both parenchymal brain metastases as well as leptomeningeal metastases implemented in three academic institutions. Additionally, with the increasing development of healthcare systems, we discuss optimizing the management of CNS metastases across healthcare systems and integrating basic and translational science into our clinical care to further improve outcomes. This paper summarizes the existing therapeutic approaches to the treatment of BM and LM and discusses novel and emerging approaches to optimizing access to neuro-oncologic care while simultaneously integrating multidisciplinary teams in the care of patients with BM and LM.

Repeated blood-brain barrier opening with an implantable ultrasound device for delivery of albumin-bound paclitaxel in patients with recurrent glioblastoma: a phase 1 trial.

BACKGROUND: Low-intensity pulsed ultrasound with concomitant administration of intravenous microbubbles (LIPU-MB) can be used to open the blood-brain barrier. We aimed to assess the safety and pharmacokinetics of LIPU-MB to enhance the delivery of albumin-bound paclitaxel to the peritumoural brain of patients with recurrent glioblastoma. METHODS: We conducted a dose-escalation phase 1 clinical trial in adults (aged ≥18 years) with recurrent glioblastoma, a tumour diameter of 70 mm or smaller, and a Karnofsky performance status of at least 70. A nine-emitter ultrasound device was implanted into a skull window after tumour resection. LIPU-MB with intravenous albumin-bound paclitaxel infusion was done every 3 weeks for up to six cycles. Six dose levels of albumin-bound paclitaxel (40 mg/m2, 80 mg/m2, 135 mg/m2, 175 mg/m2, 215 mg/m2, and 260 mg/m2) were evaluated. The primary endpoint was dose-limiting toxicity occurring during the first cycle of sonication and albumin-bound paclitaxel chemotherapy. Safety was assessed in all treated patients. Analyses were done in the per-protocol population. Blood-brain barrier opening was investigated by MRI before and after sonication. We also did pharmacokinetic analyses of LIPU-MB in a subgroup of patients from the current study and a subgroup of patients who received carboplatin as part of a similar trial (NCT03744026). This study is registered with ClinicalTrials.gov, NCT04528680, and a phase 2 trial is currently open for accrual. FINDINGS: 17 patients (nine men and eight women) were enrolled between Oct 29, 2020, and Feb 21, 2022. As of data cutoff on Sept 6, 2022, median follow-up was 11·89 months (IQR 11·12-12·78). One patient was treated per dose level of albumin-bound paclitaxel for levels 1 to 5 (40-215 mg/m2), and 12 patients were treated at dose level 6 (260 mg/m2). A total of 68 cycles of LIPU-MB-based blood-brain barrier opening were done (median 3 cycles per patient [range 2-6]). At a dose of 260 mg/m2, encephalopathy (grade 3) occurred in one (8%) of 12 patients during the first cycle (considered a dose-limiting toxicity), and in one other patient during the second cycle (grade 2). In both cases, the toxicity resolved and treatment continued at a lower dose of albumin-bound paclitaxel, with a dose of 175 mg/m2 in the case of the grade 3 encephalopathy, and to 215 mg/m2 in the case of the grade 2 encephalopathy. Grade 2 peripheral neuropathy was observed in one patient during the third cycle of 260 mg/m2 albumin-bound paclitaxel. No progressive neurological deficits attributed to LIPU-MB were observed. LIPU-MB-based blood-brain barrier opening was most commonly associated with immediate yet transient grade 1-2 headache (12 [71%] of 17 patients). The most common grade 3-4 treatment-emergent adverse events were neutropenia (eight [47%]), leukopenia (five [29%]), and hypertension (five [29%]). No treatment-related deaths occurred during the study. Imaging analysis showed blood-brain barrier opening in the brain regions targeted by LIPU-MB, which diminished over the first 1 h after sonication. Pharmacokinetic analyses showed that LIPU-MB led to increases in the mean brain parenchymal concentrations of albumin-bound paclitaxel (from 0·037 µM [95% CI 0·022-0·063] in non-sonicated brain to 0·139 µM [0·083-0·232] in sonicated brain [3·7-times increase], p<0·0001) and carboplatin (from 0·991 µM [0·562-1·747] in non-sonicated brain to 5·878 µM [3·462-9·980] µM in sonicated brain [5·9-times increase], p=0·0001). INTERPRETATION: LIPU-MB using a skull-implantable ultrasound device transiently opens the blood-brain barrier allowing for safe, repeated penetration of cytotoxic drugs into the brain. This study has prompted a subsequent phase 2 study combining LIPU-MB with albumin-bound paclitaxel plus carboplatin (NCT04528680), which is ongoing. FUNDING: National Institutes of Health and National Cancer Institute, Moceri Family Foundation, and the Panattoni family.

Oncolytic DNX-2401 virotherapy plus pembrolizumab in recurrent glioblastoma: a phase 1/2 trial.

Immune-mediated anti-tumoral responses, elicited by oncolytic viruses and augmented with checkpoint inhibition, may be an effective treatment approach for glioblastoma. Here in this multicenter phase 1/2 study we evaluated the combination of intratumoral delivery of oncolytic virus DNX-2401 followed by intravenous anti-PD-1 antibody pembrolizumab in recurrent glioblastoma, first in a dose-escalation and then in a dose-expansion phase, in 49 patients. The primary endpoints were overall safety and objective response rate. The primary safety endpoint was met, whereas the primary efficacy endpoint was not met. There were no dose-limiting toxicities, and full dose combined treatment was well tolerated. The objective response rate was 10.4% (90% confidence interval (CI) 4.2-20.7%), which was not statistically greater than the prespecified control rate of 5%. The secondary endpoint of overall survival at 12 months was 52.7% (95% CI 40.1-69.2%), which was statistically greater than the prespecified control rate of 20%. Median overall survival was 12.5 months (10.7-13.5 months). Objective responses led to longer survival (hazard ratio 0.20, 95% CI 0.05-0.87). A total of 56.2% (95% CI 41.1-70.5%) of patients had a clinical benefit defined as stable disease or better. Three patients completed treatment with durable responses and remain alive at 45, 48 and 60 months. Exploratory mutational, gene-expression and immunophenotypic analyses revealed that the balance between immune cell infiltration and expression of checkpoint inhibitors may potentially inform on response to treatment and mechanisms of resistance. Overall, the combination of intratumoral DNX-2401 followed by pembrolizumab was safe with notable survival benefit in select patients (ClinicalTrials.gov registration: NCT02798406).

Immune checkpoint blockade in glioblastoma: from tumor heterogeneity to personalized treatment.

Immune checkpoint blockade (ICB) has revolutionized modern cancer therapy, arousing great interest in the neuro-oncology community. While several reports show that subsets of patients with glioma exhibit durable responses to immunotherapy, the efficacy of this treatment has not been observed for unselected patient populations, preventing its broad clinical implementation for gliomas and glioblastoma (GBM). To exploit the maximum therapeutic potential of ICB for patients with glioma, understanding the different aspects of glioma-related tumor immune responses is of critical importance. In this Review, we discuss contributing factors that distinguish subsets of patients with glioma who may benefit from ICB. Specifically, we discuss (a) the complex interaction between the tumor immune microenvironment and glioma cells as a potential influence on immunotherapy responses; (b) promising biomarkers for responses to immune checkpoint inhibitors; and (c) the potential contributions of peripheral immune cells to therapeutic responses.

Current status of the preclinical evaluation of alternating electric fields as a form of cancer therapy.

Exposing cancer cells to alternating electric fields of 100-300 kHz frequency and 1-4 V/cm strength has been shown to significantly reduce cancer growth in cell culture and in human patients. This form of anti-cancer therapy is more commonly referred to as tumor treating fields (TTFields), a novel treatment modality that has been approved by the U.S. Food and Drug Administration for use in patients with glioblastoma and malignant pleural mesothelioma. Pivotal trials in other solid organ cancer trials are underway. In regards to overall survival, TTFields alone is comparable to chemotherapy alone in recurrent glioblastoma. However, when combined with adjuvant chemotherapy, TTFields prolong median survival by 4.9 months in newly-diagnosed glioblastoma. TTFields hold promise as a therapeutic approach to numerous solid organ cancers. This review summarizes the current status of TTFields research at the preclinical level, highlighting recent aspects of a relatively complex working hypothesis. In addition, we point out the gaps between limited preclinical in vivo studies and the available clinical data. To date, no customized system for TTFields delivery in rodent models of glioblastoma has been presented. We aim to motivate the expansion of TTFields preclinical research and facilitate the availability of suitable hardware, to ultimately improve outcomes in patients with cancer.

Association of antidepressant drug use with outcome of patients with glioblastoma.

Depressive symptoms are common among patients with glioblastoma, but patients are often not treated with antidepressants. There is only limited evidence on the association of antidepressant drug use with survival in glioblastoma. We performed a pooled analysis of patients treated within the CENTRIC, CORE, AVAglio and ACT-IV trials to explore the relation of antidepressant drug use with progression-free (PFS) and overall survival (OS) at baseline, at the start of maintenance therapy and at the start of maintenance cycle 4. We further assessed the association of antidepressant drugs with seizure, cognition, fatigue and a diagnosis of depression. Among more than 1700 patients, we found no significant association between the use of antidepressants at baseline or at the start of maintenance therapy and PFS or OS. However, we found OS, but not PFS, to be significantly worse in patients using antidepressants at the start of maintenance cycle 4. After adjustment for antiepileptic drug use and despite showing a trend for increased risk, seizures were not significantly associated with antidepressant drug use, nor was there a change in mini mental state examination (MMSE) scores or fatigue by antidepressant drug use at baseline. However, there was a significant positive association between antidepressant use at the start of maintenance treatment and fatigue during maintenance treatment. The association of antidepressant use at the start of maintenance cycle 4 with inferior OS of glioblastoma patients requires independent confirmation and further study. Further prospective trials should evaluate efficacy, side effects and associations with outcome of antidepressants in glioblastoma.

Mitotic count is prognostic in IDH mutant astrocytoma without homozygous deletion of CDKN2A/B. Results of consensus panel review of EORTC trial 26053 (CATNON) and EORTC trial 22033-26033.

BACKGROUND: Gliomas with IDH1/2 mutations without 1p19q codeletion have been identified as the distinct diagnostic entity of IDH mutant astrocytoma (IDHmut astrocytoma). Homozygous deletion of Cyclin-dependent kinase 4 inhibitor A/B (CDKN2A/B) has recently been incorporated in the grading of these tumors. The question of whether histologic parameters still contribute to prognostic information on top of the molecular classification, remains unanswered. Here we evaluated consensus histologic parameters for providing additional prognostic value in IDHmut astrocytomas. METHODS: An international panel of seven neuropathologists scored 13 well-defined histologic features in virtual microscopy images of 192 IDHmut astrocytomas from EORTC trial 22033-26033 (low-grade gliomas) and 263 from EORTC 26053 (CATNON) (1p19q non-codeleted anaplastic glioma). For 192 gliomas the CDKN2A/B status was known. Consensus (agreement ≥ 4/7 panelists) histologic features were tested together with homozygous deletion (HD) of CDKN2A/B for independent prognostic power. RESULTS: Among consensus histologic parameters, the mitotic count (cut-off of 2 mitoses per 10 high power fields standardized to a field diameter of 0.55 mm and an area of 0.24 mm2) significantly influences PFS (P = .0098) and marginally the OS (P = .07). Mitotic count also significantly affects the PFS of tumors with HD CDKN2A/B, but not the OS, possibly due to limited follow-up data. CONCLUSION: The mitotic index (cut-off 2 per 10 40× HPF) is of prognostic significance in IDHmut astrocytomas without HD CDKN2A/B. Therefore, the mitotic index may direct the therapeutic approach for patients with IDHmut astrocytomas with native CDKN2A/B status.

Modeling Therapy-Driven Evolution of Glioblastoma with Patient-Derived Xenografts.

Adult-type diffusely infiltrating gliomas, of which glioblastoma is the most common and aggressive, almost always recur after treatment and are fatal. Improved understanding of therapy-driven tumor evolution and acquired therapy resistance in gliomas is essential for improving patient outcomes, yet the majority of the models currently used in preclinical research are of therapy-naïve tumors. Here, we describe the development of therapy-resistant IDH-wildtype glioblastoma patient-derived xenografts (PDX) through orthotopic engraftment of therapy naïve PDX in athymic nude mice, and repeated in vivo exposure to the therapeutic modalities most often used in treating glioblastoma patients: radiotherapy and temozolomide chemotherapy. Post-temozolomide PDX became enriched for C>T transition mutations, acquired inactivating mutations in DNA mismatch repair genes (especially MSH6), and developed hypermutation. Such post-temozolomide PDX were resistant to additional temozolomide (median survival decrease from 80 days in parental PDX to 42 days in a temozolomide-resistant derivative). However, temozolomide-resistant PDX were sensitive to lomustine (also known as CCNU), a nitrosourea which induces tumor cell apoptosis by a different mechanism than temozolomide. These PDX models mimic changes observed in recurrent GBM in patients, including critical features of therapy-driven tumor evolution. These models can therefore serve as valuable tools for improving our understanding and treatment of recurrent glioma.

Associations of levetiracetam use with the safety and tolerability profile of chemoradiotherapy for patients with newly diagnosed glioblastoma.

Background: Levetiracetam (LEV) is one of the most frequently used antiepileptic drugs (AED) for brain tumor patients with seizures. We hypothesized that toxicity of LEV and temozolomide-based chemoradiotherapy may overlap. Methods: Using a pooled cohort of patients with newly diagnosed glioblastoma included in clinical trials prior to chemoradiotherapy (CENTRIC, CORE, AVAglio) or prior to maintenance therapy (ACT-IV), we tested associations of hematologic toxicity, nausea or emesis, fatigue, and psychiatric adverse events during concomitant and maintenance treatment with the use of LEV alone or with other AED versus other AED alone or in combination versus no AED use at the start of chemoradiotherapy and of maintenance treatment. Results: Of 1681 and 2020 patients who started concomitant chemoradiotherapy and maintenance temozolomide, respectively, 473 and 714 patients (28.1% and 35.3%) were treated with a LEV-containing regimen, 538 and 475 patients (32.0% and 23.5%) with other AED, and 670 and 831 patients (39.9% and 41.1%) had no AED. LEV was associated with higher risk of psychiatric adverse events during concomitant treatment in univariable and multivariable analyses (RR 1.86 and 1.88, P < .001) while there were no associations with hematologic toxicity, nausea or emesis, or fatigue. LEV was associated with reduced risk of nausea or emesis during maintenance treatment in multivariable analysis (HR = 0.80, P = .017) while there were no associations with hematologic toxicity, fatigue, or psychiatric adverse events. Conclusions: LEV is not associated with reduced tolerability of chemoradiotherapy in patients with glioblastoma regarding hematologic toxicity and fatigue. Antiemetic properties of LEV may be beneficial during maintenance temozolomide.

Extended resection for potentially operable patients with stage III non-small cell lung cancer after induction treatment.

OBJECTIVE: Surgical treatment of locally advanced non-small cell lung cancer including single or multilevel N2 remains a matter of debate. Several trials demonstrate that selected patients benefit from surgery if R0 resection is achieved. We aimed to assess resectability and outcome of patients with locally advanced clinical T3/T4 (American Joint Committee on Cancer 8th edition) tumors after induction treatment followed by surgery in a pooled analysis of 3 prospective multicenter trials. METHODS: A total of 197 patients with T3/T4 non-small cell lung cancer of 368 patients with stage III non-small cell lung cancer enrolled in the Swiss Group for Clinical Cancer Research 16/96, 16/00, 16/01 trials were treated with induction chemotherapy or chemoradiation therapy followed by surgery, including extended resections. Univariable and multivariable analyses were applied for analysis of outcome parameters. RESULTS: Patients' median age was 60 years, and 67% were male. A total of 38 of 197 patients were not resected for technical (81%) or medical (19%) reasons. A total of 159 resections including 36 extended resections were performed with an 80% R0 and 13.2% pathological complete response rate. The 30- and 90-day mortality were 3% and 7%, respectively, without a difference for extended resections. Morbidity was 32% with the majority (70%) of minor grading complications. The 3-, 5-, and 10-year overall survivals for extended resections were 61% (95% confidence interval, 43-75), 44% (95% confidence interval, 27-59), and 29.5% (95% confidence interval, 13-48), respectively. R0 resection was associated with improved overall survival (hazard ratio, 0.41; P < .001), but pretreatment N2 extension (177/197) showed no impact on overall survival. CONCLUSIONS: Surgery after induction treatment for advanced T3/T4 stage including single and multiple pretreatment N2 disease resulted in 80% R0 resection rate and 7% 90-day mortality. Favorable overall survival for extended and not extended resection was demonstrated to be independent of pretreatment N status.

Translocon-associated Protein Subunit SSR3 Determines and Predicts Susceptibility to Paclitaxel in Breast Cancer and Glioblastoma.

PURPOSE: Paclitaxel (PTX) is one of the most potent and commonly used chemotherapies for breast and pancreatic cancer. Several ongoing clinical trials are investigating means of enhancing delivery of PTX across the blood-brain barrier for glioblastomas. Despite the widespread use of PTX for breast cancer, and the initiative to repurpose this drug for gliomas, there are no predictive biomarkers to inform which patients will likely benefit from this therapy. EXPERIMENTAL DESIGN: To identify predictive biomarkers for susceptibility to PTX, we performed a genome-wide CRISPR knockout (KO) screen using human glioma cells. The genes whose KO was most enriched in the CRISPR screen underwent further selection based on their correlation with survival in the breast cancer patient cohorts treated with PTX and not in patients treated with other chemotherapies, a finding that was validated on a second independent patient cohort using progression-free survival. RESULTS: Combination of CRISPR screen results with outcomes from patients with taxane-treated breast cancer led to the discovery of endoplasmic reticulum (ER) protein SSR3 as a putative predictive biomarker for PTX. SSR3 protein levels showed positive correlation with susceptibility to PTX in breast cancer cells, glioma cells, and in multiple intracranial glioma xenografts models. KO of SSR3 turned the cells resistant to PTX while its overexpression sensitized the cells to PTX. Mechanistically, SSR3 confers susceptibility to PTX through regulation of phosphorylation of ER stress sensor IRE1α. CONCLUSIONS: Our hypothesis generating study showed SSR3 as a putative biomarker for susceptibility to PTX, warranting its prospective clinical validation.