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Supplementary Data from The Expression of Three Genes in Primary Non–Small Cell Lung Cancer Is Associated with Metastatic Spread to the Brain

Purpose: Tumor-treating fields (TTFields) are an antimitotic treatment modality that interfere with glioblastoma (GBM) cell division and organelle assembly by delivering low-intensity, alternating electric fields to the tumor. A previous analysis from the pivotal EF-14 trial demonstrated a clear correlation between TTFields dose density at the tumor bed and survival in patients treated with TTFields. This study tests the hypothesis that the antimitotic effects of TTFields result in measurable changes in the location and patterns of progression of newly diagnosed GBM. Methods and Materials: Magnetic resonance images of 428 newly diagnosed GBM patients who participated in the pivotal EF-14 trial were reviewed, and the rates at which distant progression occurred in the TTFields treatment and control arm were compared. Realistic head models of 252 TTFields-treated patients were created, and TTFields intensity distributions were calculated using a finite element method. The TTFields dose was calculated within regions of the tumor bed and normal brain, and its relationship with progression was determined. Results: Distant progression was frequently observed in the TTFields-treated arm, and distant lesions in the TTFields-treated arm appeared at greater distances from the primary lesion than in the control arm. Distant progression correlated with improved clinical outcome in the TTFields patients, with no such correlation observed in the controls. Areas of normal brain that remained normal were exposed to higher TTFields doses compared with normal brain that subsequently exhibited neoplastic progression. Additionally, the average dose to areas of the enhancing tumor that returned to normal was significantly higher than in the areas of the normal brain that progressed to enhancing tumor. Conclusions: There was a direct correlation between TTFields dose distribution and tumor response, confirming the therapeutic activity of TTFields and the rationale for optimizing array placement to maximize the TTFields dose in areas at highest risk of progression, as well as array layout adaptation after progression.

PURPOSE: Non-small cell lung cancer (NSCLC), the most prevalent subtype of lung cancer, tends to metastasize to the brain. Between 10-60% of NSCLCs harbor an activating mutation in the epidermal growth factor receptor (EGFR), which may be targeted with selective EGFR inhibitors. However, due to a high discordance rate between the molecular profile of the primary tumor and the brain metastases (BMs), identifying an individual patient’s EGFR status of the BMs necessitates tissue diagnosis via an invasive surgical procedure. We employed a deep learning (DL) method with the aim of noninvasive detection of the EGFR mutation status in NSCLC BM. METHODS: We retrospectively collected clinical, radiological, and pathological-molecular data of all the NSCLC patients who had been diagnosed with BMs and underwent resection of their BM during 2006-2019. The study population was then divided into 2 groups based upon EGFR mutational status. We further employed a DL technique to classify the 2 groups according to their preoperative magnetic resonance imaging features. Finally, we established the accuracy of our model in predicting EGFR mutation status of BM of NSCLC. RESULTS: Fifty-nine patients were included in the study, 16 patients harbored EGFR mutations. Our model predicted mutational status with mean accuracy of 89.8%, sensitivity of 68.7%, specificity of 97.7%, and a receiver operating characteristic curve )ROC( value of 0.91 across the 5 validation datasets.CONCLUSION: DL based noninvasive molecular characterization is feasible, has high accuracy and should be further validated in large prospective cohorts.

Gliadel occasionally induces edema following its implantation. We aimed to correlate such post-surgical radiological changes to its efficacy and subsequent survival. Fifty-six patients with recurrent high grade glioma were treated between 2005 and 2016 with Gliadel implantation. Volumetric measurements of MRI features, including FLAIR abnormalities, tumor bulk (volume of gadolinium enhancement on T1) and resection cavity volumes over time were conducted. To assess dynamics over time, linear regression trendlines for each of these were calculated and examined to correlate with survival. Median follow-up after resection was 21.5 months. Median survival post-Gliadel implantation and overall survival since diagnosis were 12 months and 22 months, respectively. A subgroup of patients (n = 6) with a transient increase in FLAIR changes volume over time survived significantly longer post-Gliadel compared to those who did not demonstrate such change (36 vs 12 months, p = .03). Positive trends, representing overall growth in volume over time, of tumor bulk and resection cavity predicted survival in multivariate analyses (hazard ratios 7.9 and 84, p = .003 and .002, respectively). Increase in tumor bulk and resection cavity over time were associated with decreased survival, while transient FLAIR increase was a favorable prognostic factor. This may represent a transient inflammatory process in the tumor, possibly stemming from a presumed immune-mediated anti-tumor response.

Surgery-related strokes are an important cause of morbidity following resection of high-grade glioma (HGG). We explored the incidence, risk factors and clinical consequences of intra-operative ischemic strokes in surgeries for resection of HGG. We retrospectively followed a cohort of 239 patients who underwent surgical resection of HGG between 2013 and 2017. Tumor types included both isocitrate dehydrogenase (IDH) wildtype glioblastoma and IDH-mutant WHO grade 4 astrocytoma. We analyzed pre- and post-operative demographic, clinical, radiological, anesthesiology and intraoperative neurophysiology data, including overall survival and functional outcomes. Acute ischemic strokes were seen on postoperative diffusion-weighted imaging (DWI) in 30 patients (12.5%), 13 of whom (43%) developed new neurological deficits. Infarcts were more common in insular (23%, p = 0.019) and temporal surgeries (57%, p = 0.01). Immediately after surgery, 35% of patients without infarcts and 57% of those with infarcts experienced motor deficits (p = 0.022). Six months later, rates of motor deficits decreased to 25% in the non-infarcts group and 37% in the infarcts group (p = 0.023 and 0.105, respectively) with a significantly lower Karnofsky-Performance Score (KPS, p = 0.001). Intra-operative language decline in awake procedures was a significant indicator of the occurrence of intra-operative stroke (p = 0.029). In conclusion, intraoperative ischemic events are more common in insular and temporal surgeries for resection of HGG and their intra-operative detection is limited. These strokes can impair motor and speech functions as well as patients’ performance status.

OBJECTIVEPrimary central nervous system lymphoma (PCNSL) is a rare CNS tumor with a poor prognosis. It is usually diagnosed by needle biopsy and treated mainly with high-dose chemotherapy. Resection is currently not considered a standard treatment option. A possible prolonged survival after resection of PCNSL lesions in selected patients has been suggested, but selection criteria for surgery, especially for solitary lesions, have never been established.METHODSThe authors retrospectively searched their patient database for records of adult patients (≥ 18 years) who were diagnosed and treated for a solitary PCNSL between 2005 and 2019. Patients were divided into groups according to whether they underwent resection or needle biopsy. Statistical analyses were performed in an attempt to identify variables affecting outcome and possible survival advantage and to characterize subgroups of patients who would benefit from resection of their tumor compared with undergoing biopsy only.RESULTSA total of 113 patients with a solitary lesion of PCNSL were identified; 36 patients underwent resection, and 77 had a diagnostic stereotactic biopsy only. The statically significant preoperative risk factors included age ≥ 70 years (adjusted HR 9.61, 95% CI 2.42–38.11; p = 0.001), deep-seated lesions (adjusted HR 3.33, 95% CI 1.13–9.84; p = 0.030), and occipital location (adjusted HR 4.26, 95% CI 1.08–16.78; p = 0.039). Having a postoperative Karnofsky Performance Scale (KPS) score < 80 (adjusted HR 3.21, 95% CI 1.05–9.77; p = 0.040) and surgical site infection (adjusted HR 4.27, 95% CI 1.18–15.47; p = 0.027) were significant postoperative risk factors after the adjustment and selection by means of other possible risk factors. In a subgroup analysis, patients younger than 70 years who underwent resection had a nonsignificant trend toward longer survival than those who underwent needle biopsy (median survival 35.0 months vs 15.2 months, p = 0.149). However, patients with a superficial tumor who underwent resection had significantly longer survival times than those who underwent needle biopsy (median survival 34.3 months vs 8.9 months, p = 0.014). Patients younger than 70 years who had a superficial tumor and underwent resection had significantly prolonged survival, with a median survival of 35.0 months compared with 8.9 months in patients from the same group who underwent needle biopsy (p = 0.007).CONCLUSIONSSpecific subgroups of patients with a solitary PCNSL lesion might gain a survival benefit from resection compared with undergoing only a diagnostic biopsy.

Objective: Gliadel® occasionally induces edema following its implantation. We aimed to correlate such post-surgical radiological changes to its efficacy and subsequent survival.Methods: Fifty-six patients with recurrent glioblastoma were treated between 2005-2016 with Gliadel® implantation. Volumetric measurements of MRI features, including FLAIR abnormalities, tumor bulk (volume of gadolinium enhancement on T1) and resection cavity volumes over time were conducted. To assess dynamics over time, linear regression trendlines for each of these were calculated and examined to correlate with survival.Results: Median follow-up after resection was 21.5 months. Median survival post-Gliadel® implantation and overall survival since diagnosis were 12 months and 22 months, respectively. A subgroup of patients (n=6) with a transient increase in FLAIR changes volume over time survived significantly longer post-Gliadel® compared to those who did not demonstrate such change (36 vs 12 months, p=.03). Positive trends, representing overall growth in volume over time, of tumor bulk and resection cavity predicted survival in multivariate analyses (hazard ratios 7.9 and 84, p=.003 and .002, respectively).Conclusions: Increase in tumor bulk and resection cavity over time were associated with decreased survival, while transient FLAIR increase was a favorable prognostic factor. This may represent a transient inflammatory process in the tumor, possibly stemming from a presumed immune-mediated anti-tumor response.

Tumor-treating fields (TTFields) are a localized, antitumoral therapy using alternating electric fields, which impair cell proliferation. Combining TTFields with tumor immunotherapy constitutes a rational approach; however, it is currently unknown whether TTFields’ locoregional effects are compatible with T cell functionality. Healthy donor PBMCs and viably dissociated human glioblastoma samples were cultured under either standard or TTFields conditions. Select pivotal T cell functions were measured by multiparametric flow cytometry. Cytotoxicity was evaluated using a chimeric Ag receptor (CAR)–T–based assay. Glioblastoma patient samples were acquired before and after standard chemoradiation or standard chemoradiation + TTFields treatment and examined by immunohistochemistry and by RNA sequencing. TTFields reduced the viability of proliferating T cells, but had little or no effect on the viability of nonproliferating T cells. The functionality of T cells cultured under TTFields was retained: they exhibited similar IFN-γ secretion, cytotoxic degranulation, and PD1 upregulation as controls with similar polyfunctional patterns. Glioblastoma Ag–specific T cells exhibited unaltered viability and functionality under TTFields. CAR-T cells cultured under TTFields exhibited similar cytotoxicity as controls toward their CAR target. Transcriptomic analysis of patients’ glioblastoma samples revealed a significant shift in the TTFields-treated versus the standard-treated samples, from a protumoral to an antitumoral immune signature. Immunohistochemistry of samples before and after TTFields treatment showed no reduction in T cell infiltration. T cells were found to retain key antitumoral functions under TTFields settings. Our data provide a mechanistic insight and a rationale for ongoing and future clinical trials that combine TTFields with immunotherapy.

Introduction Pituitary surgery has shifted in recent years from microscopic surgery(MS) to endoscopic endonasal surgery (EES). However, the comparative long-term outcome of these surgical approaches, including the need for subsequent re-operation has never been reported. We present our experience in a high-volume referral center experienced in both endoscopic and microscopic approaches to compare the need for re-operation after initial resection of non-functioning pituitary macroadenomas using these surgical approaches. Methods 684 patients (398 with NF adenomas) underwent trans-sphenoidal pituitary surgery in our institution between 2006 and 2017. Complete follow-up (mean 72 months, minimum two years) was available in 87 newly diagnosed patients with non-functioning pituitary macroadenomas (NFPMA; 48-microscopic and 39-endoscopic). The EES approach has been used almost exclusively since 2012. The need for repeat operation for tumor resection during the follow-up period was assessed as the primary end-point of the study. Extracted data included various demographic and clinical parameters, radiographic findings as well as the extent of resection (EOR). Results The EOR was similar for both groups, with a trend towards better EOR in the EES group. The rate of surgical complications was also similar for both groups. There was a strong trend towards lower need for re-operation in the EES group compared to the MS group (12.8% vs. 29.2%, p = 0.056). In a multivariate analysis, only EOR and Knosp grade were independently associated with the need for re-operation surgery. Conclusion Our data indicate that EES in NFPMA tends to be associated with a lower need for re-operation compared to the MS approach, with a similar rate of EOR and complications.

Introduction Endoscopic endonasal surgery (EES) has become the preferred approach for pituitary tumor resection. Nevertheless, research on quality of life related to pituitary adenoma surgery is scarce. Objective The aim of the study is to evaluate short-term quality of life in patients after endoscopic endonasal resection of pituitary tumors and to find predictors for poor quality of life (QOL) outcome. Materials and Methods A prospective cohort study was conducted, including all patients who underwent EES for pituitary tumors in a tertiary medical referral center. Recruited patients completed the Anterior Skull Base Disease-Specific QOL (ASBS-Q) questionnaire and the Sinonasal Outcome Test 22 (SNOT-22) questionnaire before surgery, 2 and 4 to 6 months after surgery. Demographic and clinical data was collected. Results Our study included 49 patients. The overall ASBS-Q scores significantly improved 4 to 6 months after surgery (4.46 vs. 4.2, p Conclusion We found that patients after EES reported improved QOL 4 to 6 months post surgery. Specific improvement was noted in the QOL related to pain and vitality.

Purpose Tumor Treating Fields (TTFields) therapy, a noninvasive, anti-mitotic treatment modality, is approved for recurrent glioblastoma (rGBM) and newly diagnosed GBM based on phase III, EF-11 (NCT00379470) and EF-14 (NCT00916409) studies, respectively. The EF-19 study aimed to evaluate efficacy and safety of TTFields monotherapy (200 kHz) vs physicians’ choice standard of care (PC-SOC; EF-11 historical control group) in rGBM. Methods A prospective, post-marketing registry study of adults with supratentorial rGBM treated with TTFields therapy was conducted. Primary endpoint was overall survival (OS; intent-to-treat [ITT] population) and secondary endpoint was OS per-protocol (PP). Subgroup and toxicity analyses were conducted. Results Median OS (ITT population) was comparable with TTFields monotherapy vs PC-SOC (7.4 vs 6.4 months, log-rank test P = 0.053; Cox test hazard ratio [HR] [95% CI], 0.66 [0.47–0.92], P = 0.016). The upper-bound HR (95% CI) was lower than pre-defined noninferiority (1.375 threshold). In the PP population, median OS was significantly longer for TTFields monotherapy vs PC-SOC (8.1 vs 6.4 months; log-rank test P = 0.017; Cox test HR [95% CI], 0.60 [0.42–0.85], P = 0.004). TTFields therapy showed increased benefit with extended use (≥ 18 h/day [averaged over 28 days]). TTFields therapy-related adverse events (AEs) by body system were lower vs PC-SOC: mainly mild-to-moderate skin AEs. Conclusion In the real-world setting, TTFields monotherapy showed comparable (ITT population) and superior (PP population) OS vs PC-SOC in rGBM. In line with previous results, TTFields therapy showed a favorable safety profile vs chemotherapy, without new safety signals/systemic effects. Trial registration: NCT01756729, registered December 20, 2012. Graphical Abstract

To follow the revision of the fourth edition of WHO classification and the recent progress on the management of diffuse gliomas, the joint guideline committee of Chinese Glioma Cooperative Group (CGCG), Society for Neuro-Oncology of China (SNO-China) and Chinese Brain Cancer Association (CBCA) updated the clinical practice guideline. It provides recommendations for diagnostic and management decisions, and for limiting unnecessary treatments and cost. The recommendations focus on molecular and pathological diagnostics, and the main treatment modalities of surgery, radiotherapy, and chemotherapy. In this guideline, we also integrated the results of some clinical trials of immune therapies and target therapies, which we think are ongoing future directions. The guideline should serve as an application for all professionals involved in the management of patients with adult diffuse glioma and also a source of knowledge for insurance companies and other institutions involved in the cost regulation of cancer care in China and other countries.

Brain metastases are common in patients with advanced melanoma and constitute a major cause of morbidity and mortality. Between 40% and 60% of melanomas harbor BRAF mutations. Selective BRAF inhibitor therapy has yielded improvement in clinical outcome; however, genetic discordance between the primary lesion and the metastatic tumor has been shown to occur. Currently, the only way to characterize the genetic landscape of a brain metastasis is by tissue sampling, which carries risks and potential complications. The aim of this study was to investigate the use of radiomics analysis for non-invasive identification of BRAF mutation in patients with melanoma brain metastases, based on conventional magnetic resonance imaging (MRI) data. We applied a machine-learning method, based on MRI radiomics features for noninvasive characterization of the BRAF status of brain metastases from melanoma (BMM) and applied it to BMM patients from two tertiary neuro-oncological centers. All patients underwent surgical resection for BMM, and their BRAF mutation status was determined as part of their oncological work-up. Their routine preoperative MRI study was used for radiomics-based analysis in which 195 features were extracted and classified according to their BRAF status via a support vector machine. The BRAF status of 53 study patients, with 54 brain metastases (25 positive, 29 negative for BRAF mutation) was predicted with mean accuracy = 0.79 ± 0.13, mean precision = 0.77 ± 0.14, mean sensitivity = 0.72 ± 0.20, mean specificity = 0.83 ± 0.11 and with a 0.78 area under the receiver operating characteristic curve for positive BRAF mutation prediction. Radiomics-based noninvasive genetic characterization is feasible and should be further verified using large prospective cohorts.

BackgroundUnderstudied elderly patients comprise a large segment of high-risk patients with glioblastoma (GBM) that are challenging to treat. Tumor Treating Fields (TTFields) is a locoregional, noninvasive, antimitotic therapy delivering low-intensity, intermediate-frequency alternating electric fields to the tumor. In the phase 3 EF-14 clinical trial, TTFields (200 kHz) improved median progression-free survival (PFS) and median overall survival (OS) in patients with newly diagnosed GBM (ndGBM) when added concomitantly to maintenance temozolomide (TMZ). This EF-14 subgroup analysis evaluated the safety and efficacy of TTFields in elderly patients.MethodsAll 134 patients who are ≥65 years of age were included (TTFields/TMZ combination, n=89; TMZ monotherapy, n=45; 2:1 ratio of randomization). PFS and OS were analyzed using Kaplan–Meier methodology (α=0.05). Health-related quality-of-life (HRQoL) was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire QLQ-C30 supplemented with the brain tumor module (QLQ-BN20). Adverse events (AEs) were evaluated using Common Terminology Criteria for AEs (CTCAE) v4.0.ResultsThe PFS was 6.5 months in patients randomized to the treatment group with TTFields/TMZ combination versus 3.9 months in patients treated with TMZ monotherapy (HR, 0.47; 95% CI, 0.30–0.74; P=0.0236). The OS was 17.4 months in patients treated with TTFields/TMZ combination versus 13.7 months in patients treated with TMZ monotherapy (HR, 0.51; 95% CI, 0.33–0.77; P=0.0204). Annual survival rates with TTFields/TMZ versus TMZ monotherapy were 39% (95% CI, 29–50%) versus 27% (95% CI, 15–41%; P=0.072) at 2 years, 19% (95% CI, 11–29%) versus 11% (95% CI, 4–23%; P=0.135) at 3 years, and 15% (95% CI, 7–25%) versus 0% at 5 years, respectively. There were no significant differences between groups in the preselected items of HRQoL assessment. Grade ≥3 systemic AEs were 46% in the TTFields/TMZ group versus 40% in the TMZ monotherapy group, without statistically significant difference between the two groups. The only TTFields-related AEs were reversible scalp skin reactions, with grades 1–2 and grade 3 skin reactions reported by 51% and 2% of patients, respectively.ConclusionsCombining TTFields with maintenance TMZ significantly improved PFS and OS in elderly patients with ndGBM in the phase 3 EF-14 clinical trial, without significant increases in systemic toxicity or negatively affecting patient HRQoL. TTFields-related skin AEs were low-grade and manageable.Clinical Trial Registrationhttps://clinicaltrials.gov/ct2/show/NCT00916409, identifier: NCT00916409.

Creative thinking represents a major evolutionary mechanism that greatly contributed to the rapid advancement of the human species. The ability to produce novel and useful ideas, or original thinking, is thought to correlate well with unexpected, synchronous activation of several large-scale, dispersed cortical networks, such as the default network (DN). Despite a vast amount of correlative evidence, a causal link between default network and creativity has yet to be demonstrated. Surgeries for resection of brain tumors that lie in proximity to speech related areas are performed while the patient is awake to map the exposed cortical surface for language functions. Such operations provide a unique opportunity to explore human behavior while disrupting a focal cortical area via focal electrical stimulation. We used a novel paradigm of individualized direct cortical stimulation to examine the association between creative thinking and the DN. Preoperative resting-state fMRI was used to map the DN in individual patients. A cortical area identified as a DN node (study) or outside the DN (controls) was stimulated while the participants performed an alternate-uses-task (AUT). This task measures divergent thinking through the number and originality of different uses provided for an everyday object. Baseline AUT performance in the operating room was positively correlated with DN integrity. Direct cortical stimulation at the DN node resulted in decreased ability to produce alternate uses, but not in the originality of uses produced. Stimulation in areas that when used as network seed regions produced a network similar to the canonical DN was associated with reduction of creative fluency. Stimulation of areas that did not produce a default-like network (controls) did not alter creative thinking. This is the first study to causally link the DN and creative thinking.

Meningiomas are the most frequent primary intracranial tumors. They can follow a wide clinical spectrum from benign to highly aggressive clinical course. No specific therapy exists for refractory cases or cases not amenable to resection and radiotherapy. Identification of risk of recurrence and malignant transformation for the individual patients is challenging. However, promising molecular markers and prognostic subgrouping by DNA methylation are emerging. Still, the biological underpinnings of these diagnostic subgroups are elusive, and, consequently, no novel therapeutic options arise thereof. Here we establish robust subgroups across the full landscape of meningiomas, consistent through DNA methylation, mutations, the transcriptomic, proteomic and phospho-proteomic level. Pronounced proliferative stress and DNA damage repair signals in malignant cells and in clusters exclusive to recurrent tumors are in line with their higher mitotic activity, but also provide an explanation for the accumulation of genomic instability in anaplastic meningiomas. Although homozygous deletion of CDKN2A/B is a diagnostic marker of high-grade meningioma, the expression of its gene product increased from low to non-deleted high-grade cases. Differences between subgroups in lymphocyte and myeloid cell infiltration, representing a majority of tumor mass in low-grade NF2 tumors, could be assigned to cluster-specific interaction with tumor cells. Activation to a more proinflammatory phenotype and decreased infiltration of myeloid cells in high-grade cases correlated with lower expression of CSF1, located on chromosome arm 1p, whose deletion is known as prognostic marker, with no proposed mechanism before. Our results demonstrate a robust molecular subclassification of a tumor type across multiple layers, provide insight into heterogeneous growth dynamics despite shared pathognomonic mutations, and highlight immune infiltration modulation as a novel target for meningioma therapy.

Background Colloid cysts (CC) have been associated with neurocognitive function (NCF) decline, both preoperatively and after resection. Factors such as local pressure on the fornix and hydrocephalus are thought to contribute to preoperative NCF decline. The potential cause of postoperative decline is thought to be forniceal injury during surgery. In the current series, we describe NCF outcomes amongst patients with CC, both nonoperated and operated. Methods A total of 36 patients (23 operated, 13 nonoperated) were included in this retrospective study. All patients underwent at least 1 NCF evaluation battery. Of the 13 nonoperated cases, 5 had follow-up tests too. Of the 23 operated, 14 had both pre- and postoperative tests, and 8 had early and late postoperative tests. Results There was no significant difference in baseline NCF between nonoperated and operated cases (as evaluated preoperatively). Nonoperated patients had a stable NCF test over time. Patients who were operated showed a significant improvement after surgery in several NCF variables. There was no significant change in NCF between early and late postoperative evaluation. None of the operated patients had a postoperative NCF decline. Conclusions Patients with CC should undergo routine NCF testing with a standardized protocol, whether they are operated or followed. Surgery has a positive impact on NCF; however, it remains to be determined if the improvement is solely secondary to treatment of hydrocephalus, or to a reduction of local pressure on the fornices. It remains to be determined whether the surgical technique, that is, endoscopic, interhemispheric, or transcortical, has an impact on NCF outcome.

OBJECTIVECognition is a key component in health-related quality of life (HRQoL) and is currently incorporated as a major parameter of outcome assessment in patients treated for brain tumors. The effect of surgery on cognition and HRQoL remains debatable. The authors investigated the impact of resection of low-grade gliomas (LGGs) on cognition and the correlation with various histopathological markers.METHODSA retrospective analysis of patients with LGG who underwent craniotomy for tumor resection at a single institution between 2010 and 2014 was conducted. Of 192 who underwent resective surgery for LGG during this period, 49 had complete pre- and postoperative neurocognitive evaluations and were included in the analysis. These patients completed a full battery of neurocognitive tests (memory, language, attention and working memory, visuomotor organization, and executive functions) pre- and postoperatively. Tumor and surgical characteristics were analyzed, including volumetric measurements and histopathological markers (IDH, p53, GFAP).RESULTSPostoperatively, significant improvement was found in memory and executive functions. A subgroup analysis of patients with dominant-side tumors, most of whom underwent intraoperative awake mapping, revealed significant improvement in the same domains. Patients whose tumors were on the nondominant side displayed significant improvement only in memory functions. Positive staining for p53 testing was associated with improved language function and greater extent of resection in dominant-side tumors. GFAP positivity was associated with improved memory in patients whose tumors were on the nondominant side. No correlation was found between cognitive outcome and preoperative tumor volume, residual volume, extent of resection, or IDH1 status.CONCLUSIONSResection of LGG significantly improves memory and executive function and thus is likely to improve functional outcome in addition to providing oncological benefit. GFAP and pP53 positivity could possibly be associated with improved cognitive outcome. These data support early, aggressive, surgical treatment of LGG.

Background Tumor treating fields (TTFields) is a non-invasive, antimitotic therapy. In the EF-14 phase 3 trial in newly diagnosed glioblastoma, TTFields plus temozolomide (TTFields/TMZ) improved progression free (PFS) and overall survival (OS) versus TMZ alone. Previous data indicate a ≥ 75% daily compliance improves outcomes. We analyzed compliance data from TTFields/TMZ patients in the EF-14 study to correlate TTFields compliance with PFS and OS and identify potential lower boundary for compliance with improved clinical outcomes. Methods Compliance was assessed by usage data from the NovoTTF-100A device and calculated as percentage per month of TTFields delivery. TTFields/TMZ patients were segregated into subgroups by percent monthly compliance. A Cox proportional hazard model controlled for sex, extent of resection, MGMT methylation status, age, region, and performance status was used to investigate the effect of compliance on PFS and OS. Results A threshold value of 50% compliance with TTFields/TMZ improved PFS (HR 0.70, 95% CI 0.47–1.05) and OS (HR 0.67, 95% CI 0.45–0.99) versus TMZ alone with improved outcome as compliance increased. At compliance > 90%, median survival was 24.9 months (28.7 months from diagnosis) and 5-year survival rate was 29.3%. Compliance was independent of gender, extent of resection, MGMT methylation status, age, region and performance status (HR 0.78; p = 0.031; OS at compliance ≥ 75% vs. Conclusion A compliance threshold of 50% with TTFields/TMZ correlated with significantly improved OS and PFS versus TMZ alone. Patients with compliance > 90% showed extended median and 5-year survival rates. Increased compliance with TTFields therapy is independently prognostic for improved survival in glioblastoma.

BACKGROUND Tumor Treating Fields (TTFields) are an anti-mitotic therapy of alternating electric fields delivered non-invasively to the tumor. In phase 3 studies leading to FDA-approvals, TTFields plus temozolomide (TMZ) significantly extended survival in newly diagnosed GBM, and achieved comparable survival to best standard of care (BSC) as monotherapy in recurrent GBM (rGBM). The EF-19 study evaluated efficacy of TTFields vs BSC in rGBM in post-approval real-life setting. METHODS This registry trial (192 rGBM patients, >21 yrs, KPS > 70) were treated with TTFields (200 kHz, >18h/day). Primary endpoint was overall survival (OS); secondary endpoints were OS in the per protocol (PP) population, time to treatment failure and adverse events (AEs). The registry data were compared to OS of all 117 patients in EF-11 BSC group (Stupp EJC 2012). The sample size (N=192) was based on non-inferiority log-rank test with two-sided alpha (0.05), 80% power, HR of 1.0 comparing TTFields to control with an upper one-sided 95% CI of HR < 1.375. RESULTS Median OS with TTFields versus EF-11 BSC was 7.4 versus 6.4 months, p=0.053; HR = 0.64 (95%CI 0.46–0.91, Cox-test P=0.012). Median OS (PP) with TTFields versus EF-11 BSC was 8.1 months versus 6.5 months; p=0.045; HR 0.65. OS was significantly higher TTFields as the 95% CI upper limit of HR was lower than the pre-defined threshold of 1.375. The overall incidence of AEs was lower with TTFields than EF-11 BSC (67% vs. 95%). The median time to treatment failure was longer in the TTFields arm (3.3 months (95% CI 2.6, 3.9) versus BSC arm (1.6 months; 95% CI 1.1, 1.9); HR=0.53 (95% CI 0.41, 0.68, p< 0.0001). Skin AE was the most common AE in the TTFields arm. CONCLUSION The results of the EF-19 registry study confirm the effectiveness and safety of TTFields monotherapy in rGBM.

Background Maximal, aggressive resection of diffuse low-grade gliomas (DLGG) is well established as the standard of care in neuro-oncology. The role of repeat resection for tumor progression is unclear. Objective To assess the role of repeated operation for DLGG, and the effect on malignant transformation and survival. Methods We conducted a historical cohort study in which all patients undergoing multiple resections of DLGG between the years 1995–2019 were evaluated for overall survival (OS) and time to transformation (TTT). We then compared the outcome of this group with that of a matched control group comprised of patients who underwent only one operation despite being eligible for repeat surgery at tumor progression, but had received non-surgical oncological therapy or declined additional treatment. Results Of 607 patients in our departmental DLGG database, 93 patients underwent 2 or more surgeries and had sufficient follow-up and imaging data to be included in the study group. Thirty-eight patients were included in the matched control group. Early (less than 1 year) progression was associated with decreased survival and shorter TTT in the study group. Patients undergoing multiple resections had significantly longer TTT and OS compared to patients who underwent a single surgery. This effect was especially noted in patients who had radiological evidence of tumor transformation. Conclusions Repeated resections of LGG are safe and offer survival benefit in select patients. Early progression following resection is associated with worse prognosis. Patients with evidence of radiological transformation may benefit the most from re-resection.

Background: TTFields are a loco-regional, anti-mitotic treatment comprising low-intensity alternating electric fields. In the EF-14 study of newly diagnosed glioblastoma (ndGBM), TTFields in combination with temozolomide (TMZ) significantly improved survival vs. TMZ alone. In preclinical studies TTFields had a radiosensitizing effect and increased the efficacy of radiation therapy (RT). This study prospectively 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) combined with daily TMZ (75 mg/m2). In the adjuvant phase, patients received monthly TMZ (150-200 mg/m2 for 5 days) plus TTFields. Patients were followed for 24 months or until second disease progression. 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 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 without an increase in RT- or TMZ-related toxicities as a result of combining TTFields with these therapies. Preliminary efficacy results are promising and warrant further investigation of concurrent TTFields/RT/TMZ treatment in ndGBM patients.

The incidence of brain metastases (BM) is increasing to date, mostly due to the actual improvement of cancer patient overall survival (OS) with the advent of targeted therapies. BM management has dramatically evolved over the last 15 years and uses varying strategies including more or less aggressive local treatments, sometimes combined with systemic therapies that led to an improvement of patient’s survival and quality of life. Surgical resection of BM has been shown to be an effective treatment improving overall survival compared to whole brain radiotherapy alone in patients with solitary brain metastasis. Brain metastases resection in patients with oligo metastatic disease especially for large symptomatic lesions with mass effect represent the standard of care. However, surgical resection alone is insufficient to provide a durable local control and recurrence in the surgical bed is common. Recent studies indicate local control could be improved through modern surgical techniques such as neuronavigation, brain mapping, and fluorescence guided surgery. Also, there is a growing body of evidence that molecular documentation of the brain metastatic disease could help to better define the systemic treatment strategy in these patients. Here, we reviewed evidence-based data available in the literature on the actual prognostic impact of surgery in BM patients and provided an overview of new surgical techniques and adjuncts that may improve surgical resection. Finally, we discussed the actual role of the neurosurgeon in the global treatment strategy and management in these BM patients.

BACKGROUND Postoperative neurological deficits may outweigh the benefit conferred by maximal resection of gliomas. We evaluated the incidence of ischemic events in patients undergoing surgery for low-grade gliomas (LGG) and the long-term neurological and cognitive sequelae. METHODS Between 2013–2017, 168 patients underwent surgical resection or biopsy for LGG at our center. A full dataset, including pre- and postoperative magnetic resonance imaging (MRI) and long-term clinical evaluation findings, was available for 82 patients (study group). Ischemic complications, overall and progression-free survival, and functional and neurocognitive outcomes were evaluated. RESULTS The immediate postoperative MRI revealed an acute ischemic stroke adjacent to the tumor resection cavity in 19 patients (23%), 13 of whom developed new neurological deficits due to the ischemic event. Infarcts were more common in patients with recurrent tumors, especially those involving the Sylvian fissure (p< 0.05). Surgery for insular gliomas had the strongest association with postoperative infarcts. Survival of patients w/wo a postoperative infarct was the same. The median Karnofsky-Performance Status was lower for the infarct group vs. the non-infarct group at 3 months post-surgery (p=0.016), with a gradual significant improvement for the former over one year (p=0.04). Immediately after surgery, 27% of the patients without infarcts and 58% of those with infarcts experienced a new motor deficit (p=0.037), decreasing to 16% (p=0.028) and 37% (p=0.001), respectively, at one year. Neurocognitive analysis findings before and 3 months after surgery were unchanged, but patients with an infarct had a significant decrease in naming (p=0.04). Confusion during awake craniotomy was a strong predictor of an ischemic stroke. CONCLUSIONS Intraoperative strokes are more prevalent among patients who undergo recurrent surgeries, especially in the insula. Although they do not affect survival, these strokes negatively impact the patients’ activity and performance status, especially during the first 3 postoperative months, with gradual functional improvement over one year.

Glioblastoma is an aggressive and invasive brain malignancy with high mortality rates despite current treatment modalities. In this study, we show that a 7-gene signature, previously found to govern the switch of glioblastomas from dormancy to aggressive tumor growth, correlates with improved overall survival of patients with glioblastoma. Using glioblastoma dormancy models, we validated the role of 2 genes from the signature, thrombospondin-1 ( TSP-1) and epidermal growth factor receptor ( EGFR), as regulators of glioblastoma dormancy and explored their therapeutic potential. EGFR up-regulation was reversed using EGFR small interfering RNA polyplex, antibody, or small-molecule inhibitor. The diminished function of TSP-1 was augmented via a peptidomimetic. The combination of EGFR inhibition and TSP-1 restoration led to enhanced therapeutic efficacy in vitro, in 3-dimensional patient-derived spheroids, and in a subcutaneous human glioblastoma model in vivo. Systemic administration of the combination therapy to mice bearing intracranial murine glioblastoma resulted in marginal therapeutic outcomes, probably due to brain delivery challenges, p53 mutation status, and the aggressive nature of the selected cell line. Nevertheless, this study provides a proof of concept for exploiting regulators of tumor dormancy for glioblastoma therapy. This therapeutic strategy can be exploited for future investigations using a variety of therapeutic entities that manipulate the expression of dormancy-associated genes in glioblastoma as well as in other cancer types.-Tiram, G., Ferber, S., Ofek, P., Eldar-Boock, A., Ben-Shushan, D., Yeini, E., Krivitsky, A., Blatt, R., Almog, N., Henkin, J., Amsalem, O., Yavin, E., Cohen, G., Lazarovici, P., Lee, J. S., Ruppin, E., Milyavsky, M., Grossman, R., Ram, Z., Calderón, M., Haag, R., Satchi-Fainaro, R. Reverting the molecular fingerprint of tumor dormancy as a therapeutic strategy for glioblastoma.

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.

OBJECTIVE A possible prolonged survival after surgical resection for primary central nervous system lymphoma (PCNSL) lesions in selected patients has been suggested, but selection criteria for surgery, especially for solitary lesions, have never been established. METHODS We retrospectively searched our patient database for records of adult patients (≥18 years) who were diagnosed and treated for a solitary lesion of PCNSL between 2005 and 2019. Patients were divided into groups according to whether they underwent surgical resection or needle biopsy. Statistical analyses were performed in an attempt to identify variables affecting outcome and possible survival advantage and to characterize subgroups of patients who would benefit from resection of their tumor compared to undergoing biopsy only. RESULTS 113 patients with a solitary lesion of PCNSL were identified, 36 underwent surgical resection and 77 a diagnostic stereotaxic biopsy only. Pre-operative risk factors were found to include age > 70 years ([HR] 9.61, 95% [CI] 2.42-38.11, p=0.001) and deep seated lesions (adjusted HR 3.33, 95% CI 1.13-9.84, p=0.030). Having a postoperative Karnofsky Performance Scale (KPS) under 80 (adjusted HR 3.21, 95% CI 1.05-9.77, p=0.040) or surgical-site infections (adjusted HR 4.27, 95% CI 1.18-15.47, p=0.027) were significant postoperative risk factors. In a subgroup analysis, patients with a superficial tumor who underwent surgical resection had significantly longer survival times compared with those who underwent needle biopsy (median survival 34.3 months versus 8.9 months, p=0.014). Patients under 70 years who had a superficial tumor and underwent surgical resection had significantly prolonged survival, with a median survival of 35.0 months versus 8.9 months in patients from the same group who underwent needle biopsy (p=0.007). CONCLUSION Specific subgroups of patients with a solitary PCNSL lesion might gain a survival benefit from surgical resection compared to undergoing only a diagnostic biopsy.

Glioblastoma (GB) is an aggressive type of brain cancer with high mortality rate. It is a highly angiogenic tumor exhibiting an extremely invasive nature. As such, its brain microenvironment plays a crucial role in its progression. Microglia are the brain resident immune cells which have been shown to facilitate GB cell invasion and immune suppression. The mechanism by which GB cells alter microglia behavior is yet to be fully understood. One proposed mechanism involves adhesion molecules such as the Selectins family of proteins which are expressed on the surface of endothelial and immune cells and are involved in immune modulation and cancer immunity. We have previously shown that P-Selectin (SELP) is expressed by GB cells. Here, we investigated the factional role of SELP in GB-microglia interactions. First, we found that microglia cells facilitate the expression and secretion of SELP by GB cells, and that GB cells facilitate the expression of P-Selectin ligand by microglia. We then showed that SELP mediates microglia-enhanced GB invasion and proliferation in 2D and 3D in vitro models and has a role in microglia activation state. These findings were validated in vivo, showing that inhibition or downregulation of SELP leads to reduced tumor growth, increased overall survival and improved immune response. Single-Cells RNA-seq analysis of the tumors revealed an increase in pro-inflammatory microglia signature, reduction in cancer cell tumorigenesis potential and improved T cell activation. Our results indicated that SELP has an important role in GB progression and microenvironment activation. This work can improve our understanding of tumor-associated microglia function and the mechanisms by which GB cells suppress the immune system and invade the brain tissue. Citation Format: Eilam Yeini, Paula Ofek, Sabina Pozzi, Nitzan Albeck, Dikla Ben-Shushan, Galia Tiram, Sapir Golan, Ron Kleiner, Ron Sheinin, Shlomit Reich-Zeliger, Rachel Grossman, Zvi Ram, Henry Brem, Thomas Hyde, Prerna Magod, Dinorah Friedmann-Morvinski, Asaf Madi, Ronit Satchi-Fainaro. P-selectin axis plays a key role in microglia immunophenotype and glioblastoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2716.

Background: This post hoc analysis of the EF-14 trial (NCT00916409) of tumor-treating fields (TTFields) plus temozolomide versus temozolomide alone in newly diagnosed glioblastoma compared the efficacy of TTFields plus chemotherapy (physician’s choice) versus chemotherapy alone after first recurrence. Methods: Patients on TTFields plus temozolomide continued TTFields plus second-line chemotherapy after first recurrence. Some patients on temozolomide alone crossed over after approval of TTFields for recurrent GBM. The primary efficacy outcome was overall survival (OS). Results: After disease progression, 131 patients received TTFields plus chemotherapy and 73 chemotherapy alone. Thirteen patients in the original temozolomide-alone group crossed over to receive TTFields plus chemotherapy after disease progression, resulting in 144 patients receiving TTFields plus chemotherapy and 60 chemotherapy alone. Median follow-up was 12.6 months. Bevacizumab, alone or with cytotoxic chemotherapy, was the most frequent treatment. Median OS in the TTFields plus chemotherapy group was significantly longer versus chemotherapy alone (11.8 vs 9.2 months; HR: 0.70; 95% CI, 0.48–1.00; p=0.049). TTFields showed a low toxicity safety profile, as previously reported, with no grade 3/4 device-related adverse events. Conclusion: TTFields plus chemotherapy after first disease recurrence on TTFields plus temozolomide or temozolomide alone prolonged OS in patients in the EF-14 trial.

Background Gliomatosis cerebri is a rare diffusely infiltrating malignant glial neoplasm. Presenting symptoms include seizures, neurologic deficits, and frequently symptoms related to increased intracranial pressure (ICP). Surgical intervention, including brain biopsy, may induce worsening of these neurologic symptoms. We reviewed our database to identify prognostic and risk factors for perioperative deterioration specifically associated with elevated ICP. Methods Between 2006 and 2014, 78 patients were treated for gliomatosis cerebri. Ten patients required perioperative emergent treatment for elevated ICP. The clinical course and outcome of these 10 patients (study group) were characterized and compared with the remaining 68 patients. Results The study group patients developed life-threatening symptoms of increased ICP and required urgent decompressive craniectomy ( n = 5 urgent decompressive craniectomy after biopsy, n = 2 urgent decompressive craniectomy on admission) or aggressive medical therapy ( n = 3). Demographic and clinical variables were similar in both groups. In patients with severe symptoms of increased ICP, enhancing tumor volume was significantly greater than in asymptomatic patients. Radiologic evidence of obliteration of the basal cisterns and herniation was more common in symptomatic patients. The proliferation index in the biopsy specimens of tumors was also significantly higher in patients with symptomatic ICP elevation. Conclusions Clinical symptoms and radiologic appearance suggestive of elevated ICP at presentation, volume of contrast enhancement, and high Ki-67 proliferation index may predict the need for aggressive rapid treatment to control ICP in a small but significant subset of patients with GC. Further studies are needed to clarify the biologic basis for the unusual clinical course in these tumors.

OBJECTIVE The aim of this study was to assess in-hospital (immediate) postoperative pain scores and analgesic consumption (primary goals) and preoperative anxiety and sleep quality (secondary goals) in patients who underwent craniotomy and were treated with pregabalin (PGL). Whenever possible, out-of-hospital pain scores and analgesics usage data were obtained as well. METHODS This prospective, randomized, double-blind and controlled study was conducted in consenting patients who underwent elective craniotomy for brain tumor resection at Tel Aviv Medical Center between 2012 and 2014. Patients received either 150 mg PGL (n = 50) or 500 mg starch (placebo; n = 50) on the evening before surgery, 1.5 hours before surgery, and twice daily for 72 hours following surgery. All patients spent the night before surgery in the hospital, and no other premedication was administered. Opioids and nonsteroidal antiinflammatory drugs were used for pain, which was self-rated by means of a numerical rating scale (score range 0–10). RESULTS Eighty-eight patients completed the study. Data on the American Society of Anesthesiologists class, age, body weight, duration of surgery, and intraoperative drugs were similar for both groups. The pain scores during postoperative Days 0 to 2 were significantly lower in the PGL group than in the placebo group (p < 0.01). Analgesic consumption was also lower in the PGL group, both immediately and 1 month after surgery. There were fewer requests for antiemetics in the PGL group, and the rate of postoperative nausea and vomiting was lower. The preoperative anxiety level and the quality of sleep were significantly better in the PGL group (p < 0.01). There were no PGL-associated major adverse events. CONCLUSIONS Perioperative use of twice-daily 150 mg pregabalin attenuates preoperative anxiety, improves sleep quality, and reduces postoperative pain scores and analgesic usage without increasing the rate of adverse effects. Clinical trial registration no.: NCT01612832 (clinicaltrials.gov)

Surgical resection and stereotactic radiosurgery (SRS) are well-established treatment options for selected patients with oligo-brain metastases (BMs). The dynamics of edema resolution with each treatment method have not been well characterized.Of 389 patients treated for BMs between 2012 and 2014, this study retrospectively identified 107 patients (150 metastases) who underwent either surgery or SRS as a single treatment method for BMs. The two groups of patients were matched for clinical parameters. Volumetric assessments of the tumor and associated edema were performed before treatment and then 2-3 months after treatment.In this study, 76 surgical cases were compared with 74 cases treated with SRS. The volume of the tumor and surrounding edema was significantly greater in the surgery group than in the SRS group. However, resolution of edema was significantly more rapid in the surgical group (p 0.0001), accompanied by faster weaning from steroids. After a matching process based on the propensity of a patient to receive SRS, a subgroup cohort was analyzed (mean maximal diameter: 21 mm in the surgical group vs 20.8 mm in the SRS group; p = 0.9). At diagnosis, edema volume, but not tumor volume, was significantly greater in the surgical group. The resolution of edema 2-3 months after treatment was better in the surgical group than in the SRS group (89.6% vs 71.1% of baseline, respectively; p = 0.09), although this difference did not reach the level of significance.Resolution of tumor-associated edema in BMs suitable for either surgery or SRS was significantly faster after surgical resection than after SRS. Accordingly, when both treatment options are suitable, surgery appears to induce faster resolution of the edema.

BACKGROUND TTFields has the ability to induce immunogenic cell death (ICD). As immunotherapy and TTFields have different mechanisms of action (MOA), combining these therapies is a rational approach. Contrarily, TTFields may interfere with immune functions critical for effective T cell function. MATERIAL AND METHODS We cultured T cells from healthy donors’ peripheral blood or from viably dissociated glioblastoma samples under normal or TTFields conditions, with or without superantigen-stimulation. In order to assess T cell responses we used eight-color flow cytometry by monitoring select pivotal antitumoral functions: proliferation (CFSE), IFNγ secretion, cytotoxic degranulation (CD107a), activation/exhaustion (PD1) and viability. Evaluation of direct cytotoxicity was done by using chimeric antigen receptor (CAR) T cells. RESULTS TTFields did not change T cell activation rates for all evaluated functions with the exception of reduced proliferation - in line with TTFields’ MOA. TTFields substantially reduced the viability of activated proliferating T cells, moderately affected activated nonproliferating T cells and had almost no effect on the viability of non-activated cells. Polyfunctionality analysis of T-cells, associated with effective antitumoral responses, demonstrated that under TTFields, the activated non-proliferating T cells retained polyfunctional capabilities. PD1-expressing TILs, a subset containing most of the tumor antigen-specific TILs, exhibited unaltered viability and functionality under TTFields. CAR T-cells, which utilize the same killing machinery as unmodified T cells, exhibited unaltered cytotoxic capability under TTFields. Immunohistochemical evaluation of GBM samples before TTFields treatment and after recurrence showed that some patients had accommodated large increases in their CD8 and CD4 counts. RNA-Seq performed on GBM samples from 6 standardly-treated and 6 TTFields-treated patients before treatment and after recurrence. The data shows differential increases in TTFields-treated patients to controls, in the expression of immune genes associated with favorable prognosis (e.g. t-bet, NKG2D, ICOS-L, CD70) and concurrent decreases in genes associated with poor prognosis (e.g. IL4, TSLP, various complement genes). CONCLUSION The preclinical data showed that all antitumoral T cell functions examined, but proliferation, were unhindered by TTFields. The clinical data showed that TTFields may shift treated tumors to a state more conducive of antitumoral immune responses. Our findings support the further preclinical and clinical investigation into combining TTFields with immunotherapy.

OBJECTIVEIschemic complications are a common cause of neurological deficits following low-grade glioma (LGG) surgeries. In this study, the authors evaluated the incidence, risk factors, and long-term implications of intraoperative ischemic events.METHODSThe authors retrospectively evaluated patients who had undergone resection of an LGG between 2013 and 2017. Analysis included pre- and postoperative demographic, clinical, radiological, and anesthetic data, as well as intraoperative neurophysiology data, overall survival, and functional and neurocognitive outcomes.RESULTSAmong the 82 patients included in the study, postoperative diffusion-weighted imaging showed evidence of acute ischemic strokes in 19 patients (23%), 13 of whom (68%) developed new neurological deficits. Infarcts were more common in recurrent and insular surgeries (p < 0.05). Survival was similar between the patients with and without infarcts. Immediately after surgery, 27% of the patients without infarcts and 58% of those with infarcts experienced motor deficits (p = 0.024), decreasing to 16% (p = 0.082) and 37% (p = 0.024), respectively, at 1 year. Neurocognitive functions before and 3 months after surgery were generally stable for the two groups, with the exception of a decline in verbal rhyming ability among patients with infarcts. Confusion during awake craniotomy was a strong predictor of the occurrence of an ischemic stroke. Mean arterial pressure at the beginning of surgery was significantly lower in the infarct group.CONCLUSIONSRecurrent surgeries and insular tumor locations are risk factors for intraoperative strokes. Although they do not affect survival, these strokes negatively affect patient activity and performance status, mainly during the first 3 postoperative months, with gradual functional improvement over 1 year. Several intraoperative parameters may suggest the impending development of an infarct.

Maximal resection of intrinsic brain tumors is a major prognostic factor for survival. Real-time intraoperative imaging tools, including ultrasound (US), are crucial for maximal resection of such tumors. Microbubbles (MBs) are clinically used in daily practice as a contrast agent for ultrasound and can be further developed to serve combined therapeutic and diagnostic purposes. To achieve this goal, we have developed novel MBs conjugated to specific ligands to receptors which are overexpressed in brain tumors. These MBs are designed to target a tumor tissue, visualize it, and deliver therapeutic molecules into it. The objective of this study was to assess the biodistribution of the test items: We used MBs labeled with indocyanine green (MB-ICG) for visualization and MBs conjugated to a cyclic molecule containing the tripeptide Arg-Gly-Asp (RGD) labeled with ICG (MB-RGD-ICG) to target brain tumor integrins as the therapeutic tools. Male Sprague Dawley rats received a single dose of each MB preparation. The identification of the MB in various organs was monitored by fluorescence microscopy in anesthetized animals as well as real-time US for brain imaging. Equally sized control groups under identical conditions were used in this study. One control group was used to establish fluorescence background conditions (ICG), and two control groups were used to test autofluorescence from the test items (MBs and MB-RGD). ICG with or without MBs (naked or RGD-modified) was detected in the brain vasculature and also in other organs. The pattern, duration, and intensity of the fluorescence signal could not be differentiated between animals treated with ICG alone and animals treated with microbubbles MBs-ICG or MBs-RGD-ICG. Following MB injection, either naked or combined with RGD, there was a sharp rise in the Doppler signal within seconds of injection in the brain. The signal was mainly located at the choroid plexus, septum pellucidum, and the meninges of the brain. The signal subsided within a few minutes. Injection of saline or ICG alone to respective animals did not result in a similar raised signal. Following a single intravenous administration of MB-ICG and MB-RGD-ICG to rats, the MBs were found to be effectively present in the brain.

Real-time intraoperative imaging for brain tumor surgery is crucial for achieving complete resection. We are developing novel lipid-based microbubbles (MBs), engineered with specific ligands, which are able to interact with the integrins overexpressed in the endothelium of the brain tumor vasculature. These MBs are designed to visualize the tumor and to carry therapeutic molecules into the tumor tissue, preserving the ultrasound acoustic properties of the starting plain lipid MBs. The potential toxicity of this novel technology was assessed in rats by intravenous injections of two doses of plain MBs and MBs engineered for targeting and near-infrared fluorescence visualization at two time-points, 10 min and 7 days, for potential acute and chronic responses in rats [(1) MB, (2) MB-ICG, (3) MB-RGD, and (4) MB-ICG-RGD]. No mortality occurred during the 7-day study period in any of the dosing groups. All animals demonstrated a body weight gain during the study period. Minor, mostly reversible changes in hematological and biochemical analysis were observed in some of the treated animals. All changes were reversible by the 7-day time-point. Histopathology examination in the high-dose animals showed development of foreign body granulomatous inflammation. We concluded that the low-dose tested items appear to be safe. The results allow for proceeding to clinical testing of the product.

Guidelines on the administration of prophylactic antiepileptic drugs (AED), and specifically levetiracetam, for brain tumor surgery are still lacking. In this two-center matched cohort study, we aim to compare the proportion of postoperative seizures during follow-up after supratentorial tumor surgery in patients receiving no seizure prophylaxis, and those treated with levetiracetam perioperatively. Three hundred sixteen consecutive patients undergoing supratentorial tumor surgery, without history of seizures were included: 207 patients did not receive AED (no AED group), and 109 patients received levetiracetam perioperatively (levetiracetam group). The primary outcome measure was the rate of postoperative seizures. Additionally, uni- and multivariate analyses assessing possible risk factors for postoperative seizures were performed. No statistically significant difference for the occurrence of postoperative seizures was found between the two groups (10.1%, n = 21 in the no AED group vs. 9.2%, n = 10, in the levetiracetam group; p = 0.69, OR 0.9 [0.4–2.0), NNT 103 [12.9–17.1]). After propensity score matching, the primary outcome was observed in 13 patients (12.4%) from the no AED group and in 9 patients (8.6%) from the levetiracetam group (p = 0.50, OR 0.7 [0.3–1.6], NNT 26.3 [8.3–22.4]). Among all analyzed possible risk factors for postoperative seizures, only postoperative infarction showed a statistically significant association with higher seizure rates in multivariate analysis (OR 8.2 [1.1–60.6], p = 0.04). Prophylactic treatment with levetiracetam after brain tumor surgery showed no statistically significant effect in preventing postoperative seizures. However, in case a postoperative infarction occurs, its administration might be indicated.

Thyrotropin (TSH)-secreting pituitary tumors are the rarest functioning pituitary tumors. Nonetheless, they are not infrequently plurihormonal, as they may express/secrete hormones made by other pituitary cells derived from the Pit-1 lineage such as growth hormone (GH), prolactin (PRL), and α-subunit (αSU). However, adrenocorticotropin (ACTH) or gonadotropin secretion by such a tumor is exceptional. Although double pituitary tumors are rare, they often combine ACTH and GH secretion. A 41-year-old presented almost 2 years after delivering her 10th child; she had thyrotoxicosis (goiter and palpitations) masquerading as autoimmune postpartum thyroiditis. She was still breastfeeding and amenorrheic. She proved to have TSH, GH, PRL, and ACTH hypersecretion. Imaging revealed an invasive pituitary macrotumor. She had stigmata neither of Cushing’s disease nor of acromegaly. Prior to surgery, hormonal control was achieved for close to 1 year by combined octreotide and cabergoline treatment with significant shrinking of the tumor. Following surgery, pathology revealed a collision tumor; the dominant lesion was positive for GH, βTSH, βFSH, and αSU and expressed both Pit-1 and SF-1.The smaller lesion was a corticotroph tumor. We report an unusual plurihormonal tumor co-expressing Pit-1 and SF-1 along with hormones made by cells of both lineages. Its simultaneous occurrence adjacent to a corticotroph tumor raises questions regarding the pathogenesis of these tumors. We propose the possibility of a stem cell tumor with multiple lineage differentiation. We hypothesize that pregnancy might have played a permissive role in tumorigenesis.

The endoscopic endonasal approach is increasingly being used for resection and reconstruction of anterior skull base lesions. The vascularized nasoseptal flap (NSF) has become the workhorse for reconstruction of anterior skull base defects, resulting in a significant decrease in the incidence of cerebrospinal fluid (CSF) leak. This study presents a single center’s experience with NSFs and reports associated complications. Patients who underwent endoscopic skull base defect repair with a NSF between 2008 and 2014 were retrospectively evaluated. Complications reviewed were divided into major and minor. Major complications included new-onset and continuing CSF leak and meningitis. Minor complications included long-standing crust formation, synechia, epistaxis, septal perforation, sinusitis and anosmia. Of the 77 patients included in the study, 47 (61%) underwent trans-sphenoidal surgery for pituitary lesions during which CSF leak was observed. The other 30 patients underwent reconstructive surgeries for post-traumatic CSF leaks or extirpation of lesions involving the anterior skull base. A high-flow intra-operative CSF leak was observed in 25 patients (25/77, 32%). The median follow-up was 16 months (range 3–81 months). 9 patients had major complications and 27 patients had minor complications. Only high-flow intra-operative CSF leak correlated with major complications (p = 0.012). NSF is an extremely effective tool for skull base reconstruction. While it is associated with a low rate of major complications, minor complications are frequent and require local treatment, although they tend to resolve in the late postoperative period.

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.

BACKGROUND Tumor Treating Fields (TTFields) are an anti-mitotic, regional treatment that utilizes low intensity alternating electric fields delivered non-invasively to the tumor using a portable medical device. In the EF-14 phase 3 study leading to FDA approval, TTFields significantly extended survival in newly diagnosed GBM when added to maintenance temozolomide (TMZ). Elderly GBM patients usually have worse prognosis and often receive only partial treatment for the disease. This sub-group analysis examined the effects of TTFields in the elderly population (≥65 years of age) enrolled in the EF-14 study. METHODS All 134 elderly patients (≥65 years of age) from the EF-14’s intent-to-treat population were included in the analysis, Overall survival (OS) and progression-free survival (PFS), as well as adverse event frequency and severity were compared between the TMZ/TTFields arm and the TMZ alone arm. RESULTS The median age was 69 (range: 65–83), median KPS was 90%, and 69% were male. Median PFS from randomization was 6.5 months versus 3.9 months in the TMZ/TTFields versus TMZ alone arms, respectively (hazard ratio [HR], 0.47 [95%CI 0.30, 0.74] P< 0.0236). Median OS was 17.4 months versus 13.7 months in the TMZ/TTFields versus TMZ alone arm, respectively (HR 0.51 [CI 0.33, 0.77] P< 0.020). Serious adverse events (SAEs) were reported in 39% of patients treated with TMZ/TTFields and in 33% of patients treated with TMZ alone. None of the SAEs were considered related to TTFields but attributed to TMZ or to the underlying disease. Grades 1–2 skin AEs related to TTFields were observed in 51% of patients. CONCLUSION Consistent with the overall outcome of the EF-14 study, elderly patients treated with TMZ/TTFields showed significantly better OS compared to patients on TMZ alone, and without increase in grade III or IV toxicity.

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.

Objective Clinically nonfunctioning pituitary adenoma (NFPA) remains the only pituitary tumor subtype for which no effective medical therapy is available or recommended. We evaluated dopamine agonist (DA) therapy for preventing growth of postsurgical pituitary tumor remnants. Design The study design included historical cohort analysis of clinical results at two pituitary referral centers with different standard practices for postoperative NFPA management: DA therapy or conservative follow-up. Methods Seventy-nine patients followed for 8.8±6.5 years were treated with DA, initiated upon residual tumor detection on postoperative MRI (preventive treatment (PT) group, n=55), or when tumor growth was subsequently detected during follow-up (remedial treatment (RT) group, n=24). The control group (n=60) received no medication. Tumoral dopamine and estrogen receptor expression assessed by quantitative RT-PCR and immunostaining were correlated with response to treatment. Results Tumor mass decreased, remained stable, or enlarged, respectively, in 38, 49, and 13% of patients in the PT group, and in 0, 53, and 47% of control subjects; shrinkage or stabilization was achieved in 58% of enlarging tumors in the RT group, P < 0.0001. Fifteen-year progression-free survival rate was 0.805, 0.24, and 0.04, respectively, for PT, RT, and control groups (PP=0.002). Outcome measures were not related to NFPA D2R abundance. Conclusions Dopamine agonist therapy in patients with NFPA is associated with decreased prevalence of residual tumor enlargement after transsphenoidal surgical resection.