Showing papers in "Journal of Neuro-oncology in 2021"

Immune suppression in gliomas

Abstract: The overall survival in patients with gliomas has not significantly increased in the modern era, despite advances such as immunotherapy. This is in part due to their notorious ability to suppress local and systemic immune responses, severely restricting treatment efficacy. We have reviewed the preclinical and clinical evidence for immunosuppression seen throughout the disease process in gliomas. This review aims to discuss the various ways that brain tumors, and gliomas in particular, co-opt the body’s immune system to evade detection and ensure tumor survival and proliferation. A multitude of mechanisms are discussed by which neoplastic cells evade detection and destruction by the immune system. These include tumor-induced T-cell and NK cell dysfunction, regulatory T-cell and myeloid-derived suppressor cell expansion, M2 phenotypic transformation in glioma-associated macrophages/microglia, upregulation of immunosuppressive glioma cell surface factors and cytokines, tumor microenvironment hypoxia, and iatrogenic sequelae of immunosuppressive treatments. Gliomas create a profoundly immunosuppressive environment, both locally within the tumor and systemically. Future research should aim to address these immunosuppressive mechanisms in the effort to generate treatment options with meaningful survival benefits for this patient population.

A review of glioblastoma immunotherapy

Abstract: Glioblastoma is a very aggressive cancer with dismal prognosis despite standard of care including surgical resection, radiation therapy, and chemotherapy. There is interest in applying immunotherapy to glioblastoma as this modality has demonstrated remarkable improvements in the management of several solid tumors including melanoma, renal cell carcinoma, and non-small cell lung cancer. This review aims to provide an overview of the current state of glioblastoma immunotherapy. Literature search was performed on PubMed between 1961 and 2020. Initial clinical trials of checkpoint inhibitors and vaccine therapy for glioblastoma have largely been disappointing for both primary and recurrent glioblastoma. This failure has been attributed to glioblastoma’s highly immunosuppressive environment and multiple mechanisms of therapy resistance including high tumor heterogeneity, low mutational burden, systemic immunosuppression, and local immune dysfunction. Current clinical trials are exploring combination therapy and novel treatment strategies beyond immune checkpoint therapies and vaccine therapy such as CAR T cells. There is also an effort to establish synergy between immunotherapy and current standard of care. Furthermore, recent advances in personalized neoantigen vaccines suggest a shift towards personalized, patient-specific GBM treatment.

Temozolomide treatment outcomes and immunotherapy efficacy in brain tumor

Abstract: Glioblastoma (GBM) has a survival rate of around 2 years with aggressive current standard of care. While other tumors have responded favorably to trials combining immunotherapy and chemotherapy, GBM remains uniformly deadly with minimal increases in overall survival. GBM differ from others due to being isolated behind the blood brain barrier, increased heterogeneity and mutational burden, and immunosuppression from the brain environment and tumor itself. We have reviewed clinical and preclinical studies investigating how different doses (dose intense (DI) and metronomic) and timing of immunotherapy following TMZ treatment can eradicate tumor cells, alter tumor mutational burden, and change immune cells. Recent clinical trials with standard of care (SoC), DI and metronomic TMZ regimes are no able to completely eradicate GBM. Elevated TMZ levels in DI treatment can overcome MGMT resistance but may result in hypermutation of surviving tumor cells. Higher levels of TMZ will also generate a higher degree of lymphopenia compared to SoC and metronomic regimes in preclinical studies. The different levels of lymphopenia and tumor eradication discussed in this review suggest possible beneficial pairings between immunotherapy and TMZ treatment. Treatments resulting in profound lymphopenia will allow for expansion of vaccine specific T cells or of CAT T cells. Clinical and preclinical studies are currently comparing different combinations of TMZ and immunotherapy timing to treat GBM through a balance between tumor killing and immune cell expansion. More frequent immune monitoring time points in ongoing clinical trials are crucial for further development of these combinations.

Convection-enhanced drug delivery for glioblastoma: a review

Abstract: Convection-enhanced delivery (CED) is a method of targeted, local drug delivery to the central nervous system (CNS) that bypasses the blood-brain barrier (BBB) and permits the delivery of high-dose therapeutics to large volumes of interest while limiting associated systemic toxicities. Since its inception, CED has undergone considerable preclinical and clinical study as a safe method for treating glioblastoma (GBM). However, the heterogeneity of both, the surgical procedure and the mechanisms of action of the agents studied—combined with the additional costs of performing a trial evaluating CED—has limited the field’s ability to adequately assess the durability of any potential anti-tumor responses. As a result, the long-term efficacy of the agents studied to date remains difficult to assess. We searched PubMed using the phrase “convection-enhanced delivery and glioblastoma”. The references of significant systematic reviews were also reviewed for additional sources. Articles focusing on physiological and physical mechanisms of CED were included as well as technological CED advances. We review the history and principles of CED, procedural advancements and characteristics, and outcomes from key clinical trials, as well as discuss the potential future of this promising technique for the treatment of GBM. While the long-term efficacy of the agents studied to date remains difficult to assess, CED remains a promising technique for the treatment of GBM.

Combination immunotherapy strategies for glioblastoma.

Abstract: Despite recent advances in treatment for a number of cancers with immune checkpoint blockade (ICB), immunotherapy has had limited efficacy in glioblastoma (GBM). The recent multi-centered CheckMate 143 trial in first time recurrent GBM and the Checkmate 498 trial in newly diagnosed unmethylated GBM showed that antibodies against programmed cell death protein 1 (PD-1) failed to improve overall survival in patients with GBM. Recent preclinical and clinical studies have explored combining ICB with several other therapies including additional ICB against alternative checkpoint molecules, activation of costimulatory checkpoint molecules such as 4-1BB, radiation-induced tumor cell lysis and immunogenic recruitment, local chemotherapy, neoadjuvant ICB therapy, and myeloid cell reactivation. We have reviewed the literature on ICB seminal to the progression of several preclinical studies and clinical trials in order to provide a compendium of the current state of combination immunotherapy for GBM. For ongoing clinical trials without associated publications, we searched clinicaltrials.gov for ongoing studies using the keywords, “GBM” and “glioblastoma”, as well as names of checkpoint molecules. Recent trends from clinical trials demonstrate that despite a variety of different combination strategies involving ICB, GBM remains largely elusive to current immunotherapies. There is a discordance of survival outcomes between GBM pre-clinical models and clinical trials, likely due to the heterogeneity of GBM in patients as well as other adaptive immune mechanisms not otherwise represented in murine models. However, in clinical studies, neoadjuvant ICB in GBM was found to diversify the T cell receptor (TCR) repertoire and increase chemokine mRNA transcripts when comparing pre- and post- surgical time points. Moreover, an increase in peripheral and tumor-infiltrating lymphocyte (TIL) clonotypes were also observed when comparing adjuvant and neoadjuvant cohorts. Despite the lack of clinical survival benefit, immune modulation was observed in multiple different combination strategies for GBM in both preclinical and clinical studies, indicating that ICB combination therapy results in a significant immunological impact on the tumor microenvironment.

Intraoperative MRI for Brain Tumors

Abstract: The use of intraoperative imaging has been a critical tool in the neurosurgeon’s armamentarium and is of particular benefit during tumor surgery. This article summarizes the history of its development, implementation, clinical experience and future directions. We reviewed the literature focusing on the development and clinical experience with intraoperative MRI. Utilizing the authors’ personal experience as well as evidence from the literature, we present an overview of the utility of MRI during neurosurgery. In the 1990s, the first description of using a low field MRI in the operating room was published describing the additional benefit provided by improved resolution of MRI as compared to ultrasound. Since then, implementation has varied in magnetic field strength and in configuration from floor mounted to ceiling mounted units as well as those that are accessible to the operating room for use during surgery and via an outpatient entrance to use for diagnostic imaging. The experience shows utility of this technique for increasing extent of resection for low and high grade tumors as well as preventing injury to important structures while incorporating techniques such as intraoperative monitoring. This article reviews the history of intraoperative MRI and presents a review of the literature revealing the successful implementation of this technology and benefits noted for the patient and the surgeon.

Neuroimmunological adverse events associated with immune checkpoint inhibitor: a retrospective, pharmacovigilance study using FAERS database

Abstract: To investigate the characteristics and risk factors for neurologic adverse events (AEs) induced by immune checkpoint inhibitors (ICIs). An observational, retrospective, and pharmacovigilance study based on the FAERS database collected between January 2014 and December 2019 was conducted. ICI-related AEs were defined as adverse reactions in patients using anti-PD-1 (nivolumab and pembrolizumab), anti-PD-L1 (atezolizumab, avelumab, and durvalumab), and anti-CTLA-4 (ipilimumab and tremelimumab). Neurologic AEs previously reported to be associated with ICI were evaluated in the disproportionality analysis using the reporting odds ratio (ROR). Among 50,406 ICI-related reports, 3619 (7.2%) neurological case was found: 1985 with anti-PD-1, 372 with anti-PD-L1, 366 with anti-CTLA-4, and 896 with the combination of ICIs. In comparison to non-ICI drug use, ICI use demonstrated higher risk for neurologic complication, including hypophysitis/hypopituitarism, myasthenia gravis, encephalitis/myelitis, meningitis, Guillain-Barre syndrome, vasculitis, and neuropathy. The risk of neurologic AEs associated with ICI combination therapy was as high as or even higher than ICI monotherapy, most significantly in hypophysitis/hypopituitarism. The proportion of serious neurological events and death related to combination therapy has been decreasing in recent years. Older age, male and female sex, and metastasis were not significant risk factors for the incidence of neurologic ICI-related AEs. Patients at older age, with melanoma or non-small cell lung cancer, or on dual ICI therapy may be at higher risk of fatal neurologic AEs. ICI use is associated with a higher risk of neurological complications, with dual ICI therapy posing a higher risk, while older age, sex, or metastasis were not. Patients at older age, with certain cancer types, or on dual ICI therapy may be at higher risk of fatal neurologic AEs.

Blood-brain barrier opening with low intensity pulsed ultrasound for immune modulation and immune therapeutic delivery to CNS tumors.

Abstract: Opening of the blood–brain barrier (BBB) by pulsed low intensity ultrasound has been developed during the last decade and is now recognized as a safe technique to transiently and repeatedly open the BBB. This non- or minimally invasive technique allows for a targeted and uniform dispersal of a wide range of therapeutic substances throughout the brain, including immune cells and antibodies. In this review article, we summarize pre-clinical studies that have used BBB-opening by pulsed low intensity ultrasound to enhance the delivery of immune therapeutics and effector cell populations, as well as several recent clinical studies that have been initiated. Based on this analysis, we propose immune therapeutic strategies that are most likely to benefit from this strategy. The literature review and trial data research were performed using Medline/Pubmed databases and clinical trial registry www.clinicaltrials.gov . The reference lists of all included articles were searched for additional studies. A wide range of immune therapeutic agents, including small molecular weight drugs, antibodies or NK cells, have been safely and efficiently delivered to the brain with pulsed low intensity ultrasound in preclinical models, and both tumor control and increased survival have been demonstrated in different types of brain tumor models in rodents. Ultrasound-induced BBB disruption may also stimulate innate and cellular immune responses. Ultrasound BBB opening has just recently entered clinical trials with encouraging results, and the association of this strategy with immune therapeutics creates a new field of brain tumor treatment.

Neurotoxicities associated with immune checkpoint inhibitor therapy.

Abstract: Immune checkpoint inhibitors (ICIs) have emerged as a promising class of cancer immunotherapies. Neurotoxicities are uncommon, but often severe, and potentially fatal complications of ICIs, and clinical experience is limited. The aim of this study is to further define the clinical spectrum and outcome of ICI-mediated neurotoxicities. Patients with ICI-associated neurotoxicities were identified from retrospective review of the quality control database at a single institution. Data regarding demographics, medical history, clinical presentation, diagnosis, management and outcome were recorded. We identified 18 patients with neurotoxicity following ICI therapy with pembrolizumab, nivolumab, atezolizumab, or ipilimumab for a diverse set of malignancies. Neurotoxicities comprised central demyelinating disorder (28%), autoimmune encephalitis predominantly affecting the grey matter (17%), aseptic meningitis (6%), myasthenia gravis (MG) (17%) with concurrent myositis (6%), sensorimotor polyneuropathy (11%) and hypophysitis (17%). Median time to onset of neurotoxicities was 5 weeks (range 1–72). All patients discontinued ICIs and received steroids with additional immunomodulation required in 9 patients, resulting in improvement for 16 of 18 patients. Grade 3–4 neurotoxicity developed in 14 patients, of whom 6 had died at database closure. Grade 3–4 severity negatively impacted overall survival (OS) (p = 0.046). ICI-mediated neurotoxicities present early, are rapidly progressive and include a diverse phenotype affecting the CNS, PNS and neuroendocrine system. A high level of vigilance is warranted, as early diagnosis and targeted treatment can substantially prevent morbidity and mortality. Prospective clinical trials are warranted to assess optimized management of ICI-induced neurotoxicities.

Standardized intraoperative 5-ALA photodynamic therapy for newly diagnosed glioblastoma patients: a preliminary analysis of the INDYGO clinical trial

Abstract: Glioblastoma (GBM) is the most aggressive malignant primary brain tumor. The unfavorable prognosis despite maximal therapy relates to high propensity for recurrence. Thus, overall survival (OS) is quite limited and local failure remains the fundamental problem. Here, we present a safety and feasibility trial after treating GBM intraoperatively by photodynamic therapy (PDT) after 5-aminolevulinic acid (5-ALA) administration and maximal resection. Ten patients with newly diagnosed GBM were enrolled and treated between May 2017 and June 2018. The standardized therapeutic approach included maximal resection (near total or gross total tumor resection (GTR)) guided by 5-ALA fluorescence-guided surgery (FGS), followed by intraoperative PDT. Postoperatively, patients underwent adjuvant therapy (Stupp protocol). Follow-up included clinical examinations and brain MR imaging was performed every 3 months until tumor progression and/or death. There were no unacceptable or unexpected toxicities or serious adverse effects. At the time of the interim analysis, the actuarial 12-months progression-free survival (PFS) rate was 60% (median 17.1 months), and the actuarial 12-months OS rate was 80% (median 23.1 months). This trial assessed the feasibility and the safety of intraoperative 5-ALA PDT as a novel approach for treating GBM after maximal tumor resection. The current standard of care remains microsurgical resection whenever feasible, followed by adjuvant therapy (Stupp protocol). We postulate that PDT delivered immediately after resection as an add-on therapy of this primary brain cancer is safe and may help to decrease the recurrence risk by targeting residual tumor cells in the resection cavity. Trial registration NCT number: NCT03048240. EudraCT number: 2016-002706-39.

Molecular diagnosis of diffuse glioma using a chip-based digital PCR system to analyze IDH, TERT, and H3 mutations in the cerebrospinal fluid.

Abstract: Conventional genetic analyzers require surgically obtained tumor tissues to confirm the molecular diagnosis of diffuse glioma. Recent technical breakthroughs have enabled increased utilization of cell-free tumor DNA (ctDNA) in body fluids as a reliable resource for molecular diagnosis in various cancers. Here, we tested the application of a chip-based digital PCR system for the less invasive diagnosis (i.e., liquid biopsy) of diffuse glioma using the cerebrospinal fluid (CSF). CSF samples from 34 patients with diffuse glioma were collected from the surgical field during craniotomy. Preoperative lumbar CSF collection was also performed in 11 patients. Extracted ctDNA was used to analyze diagnostic point mutations in IDH1 R132H, TERT promoter (C228T and C250T), and H3F3A (K27M) on the QuantStudio® 3D Digital PCR System. These results were compared with their corresponding tumor DNA samples. We detected either of the diagnostic mutations in tumor DNA samples from 28 of 34 patients. Among them, we achieved precise molecular diagnoses using intracranial CSF in 20 (71%). Univariate analyses revealed that the World Health Organization (WHO) grade (p = 0.0034), radiographic enhancement (p = 0.0006), and Mib1 index (p = 0.01) were significant predictors of precise CSF-based molecular diagnosis. We precisely diagnosed WHO grade III or IV diffuse gliomas using lumbar CSF obtained from 6 (87%) of 7 patients with tumors harboring any mutation. We established a novel, non-invasive molecular diagnostic method using a chip-based digital PCR system targeting ctDNA derived from CSF with high sensitivity and specificity, especially for high-grade gliomas.

Characteristics of IDH-mutant gliomas with non-canonical IDH mutation

Abstract: Approximately 10% of IDH-mutant gliomas harbour non-canonical IDH mutations (non-p.R132H IDH1 and IDH2 mutations). The aim of this study was to analyse the characteristics of non-canonical IDH-mutant gliomas. We retrospectively analysed the characteristics of 166 patients with non-canonical IDH mutant gliomas and compared them to those of 155 consecutive patients with IDH1 p.R132H mutant gliomas. The median age at diagnosis was 38 years in patients with non-canonical IDH mutant gliomas and 43 years in glioma patients with IDH1 p.R132H-mutant tumours. Family history of cancer was more frequent among glioma patients harbouring non-canonical IDH mutations than in patients with IDH1 p.R132H mutations (22.2% vs 5.1%; P < 0.05). Tumours were predominantly localised in the frontal lobe regardless of the type of IDH mutation. Compared to IDH1 p.R132H-mutant gliomas, tumours with non-canonical IDH mutations were more frequently found in the infratentorial region (5.5% vs 0%; P < 0.05) and were often multicentric (4.8% vs 0.9%; P < 0.05). Compared to IDH1 P.R132H-mutant gliomas, tumours with non-canonical IDH1 mutations were more frequently astrocytomas (65.6% vs 43%, P < 0.05), while those with IDH2 mutations were more frequently oligodendrogliomas (85% vs 48.3%; P < 0.05). The median overall survival was similar in patients with IDH1 p.R132H-mutant gliomas and patients with non-canonical IDH-mutant gliomas. Gliomas with non-canonical IDH mutations have distinct radiological and histological characteristics. The presence of such tumours seems to be associated with genetic predisposition to cancer development.

High-grade astrocytoma with piloid features (HGAP): the Charité experience with a new central nervous system tumor entity.

Abstract: High-grade astrocytoma with piloid features (HGAP) is a recently described brain tumor entity defined by a specific DNA methylation profile. HGAP has been proposed to be integrated in the upcoming World Health Organization classification of central nervous system tumors expected in 2021. In this series, we present the first single-center experience with this new entity. During 2017 and 2020, six HGAP were identified. Clinical course, surgical procedure, histopathology, genome-wide DNA methylation analysis, imaging, and adjuvant therapy were collected. Tumors were localized in the brain stem (n = 1), cerebellar peduncle (n = 1), diencephalon (n = 1), mesencephalon (n = 1), cerebrum (n = 1) and the thoracic spinal cord (n = 2). The lesions typically presented as T1w hypo- to isointense and T2w hyperintense with inhomogeneous contrast enhancement on MRI. All patients underwent initial surgical intervention. Three patients received adjuvant radiochemotherapy, and one patient adjuvant radiotherapy alone. Four patients died of disease, with an overall survival of 1.8, 9.1, 14.8 and 18.1 months. One patient was alive at the time of last follow-up, 14.6 months after surgery, and one patient was lost to follow-up. Apart from one tumor, the lesions did not present with high grade histology, however patients showed poor clinical outcomes. Here, we provide detailed clinical, neuroradiological, histological, and molecular pathological information which might aid in clinical decision making until larger case series are published. With the exception of one case, the tumors did not present with high-grade histology but patients still showed short intervals between diagnosis and tumor progression or death even after extensive multimodal therapy.

Differential gene expression in peritumoral brain zone of glioblastoma: role of SERPINA3 in promoting invasion, stemness and radioresistance of glioma cells and association with poor patient prognosis and recurrence

Abstract: Glioblastoma (GBM) is a highly invasive tumor. Despite advances in treatment modalities, tumor recurrence is common, seen mainly in the peritumoral brain zone (PBZ). We aimed to molecularly characterize PBZ, to understand the pathobiology of tumor recurrence. We selected eight differentially regulated genes from our previous transcriptome profiling study on tumor core and PBZ. Expression of selected genes were validated in GBM (tumor core and PBZ, n = 37) and control (n = 22) samples by real time quantitative polymerase chain reaction (qPCR). Serine protease inhibitor clade A, member 3 (SERPINA3) was selected for further functional characterization in vitro by gene knockdown approach in glioma cells. Its protein expression by immunohistochemistry (IHC) was correlated with other clinically relevant GBM markers, patient prognosis and tumor recurrence. The mRNA expression of selected genes from the microarray data validated in tumor core and PBZ and was similar to publicly available databases. SERPINA3 knock down in vitro showed decreased tumor cell proliferation, invasion, migration, transition to mesenchymal phenotype, stemness and radioresistance. SERPINA3 protein expression was higher in PBZ compared to tumor core and also was higher in older patients, IDH wild type and recurrent tumors. Finally, its expression showed positive correlation with poor patient prognosis. SERPINA3 expression contributes to aggressive GBM phenotype by regulating pro-tumorigenic actions in vitro and is associated with adverse clinical outcome.

Quantitative CEST and MT at 1.5T for monitoring treatment response in glioblastoma: early and late tumor progression during chemoradiation

Abstract: Quantitative MRI (qMRI) was performed using a 1.5T protocol that includes a novel chemical exchange saturation transfer/magnetization transfer (CEST/MT) approach. The purpose of this prospective study was to determine if qMRI metrics at baseline, at the 10th and 20th fraction during a 30 fraction/6 week standard chemoradiation (CRT) schedule, and at 1 month following treatment could be an early indicator of response for glioblastoma (GBM). The study included 51 newly diagnosed GBM patients. Four regions-of-interest (ROI) were analyzed: (i) the radiation defined clinical target volume (CTV), (ii) radiation defined gross tumor volume (GTV), (iii) enhancing-tumor regions, and (iv) FLAIR-hyperintense regions. Quantitative CEST, MT, T1 and T2 parameters were compared between those patients progressing within 6.9 months (early), and those progressing after CRT (late), using mixed modelling. Exploratory predictive modelling was performed to identify significant predictors of early progression using a multivariable LASSO model. Results were dependent on the specific tumor ROI analyzed and the imaging time point. The baseline CEST asymmetry within the CTV was significantly higher in the early progression cohort. Other significant predictors included the T2 of the MT pools (for semi-solid at fraction 20 and water at 1 month after CRT), the exchange rate (at fraction 20) and the MGMT methylation status. We observe the potential for multiparametric qMRI, including a novel pulsed CEST/MT approach, to show potential in distinguishing early from late progression GBM cohorts. Ultimately, the goal is to personalize therapeutic decisions and treatment adaptation based on non-invasive imaging-based biomarkers.

Surgical strategy for insular glioma.

Abstract: The goal of this article is to review the outcomes of insular glioma surgery and discuss strategies to minimize postoperative morbidity. The authors reviewed the published literature on low- and high-grade insular gliomas with a focus on glioma biology, insular anatomy, and surgical technique. Maximal safe resection of insular gliomas is associated with improved survival and is the primary goal of surgery. Protecting patient speech and motor function during insular glioma resection requires versatile integration of insular anatomy, cortical mapping, and microsurgical technique. Both the transsylvian and transcortical corridors to the insula are associated with low morbidity profiles, but the transcortical approach with intraoperative mapping is more favorable for gliomas within the posterior insular region. Surgical strategy for insular gliomas is dependent on biological, anatomical, and clinical factors. Technical mastery integrated with intraoperative technologies can optimize surgical results.

A Phase I clinical trial of dose-escalated metabolic therapy combined with concomitant radiation therapy in high-grade glioma.

Abstract: Animal brain-tumor models have demonstrated a synergistic interaction between radiation therapy and a ketogenic diet (KD). Metformin has in-vitro anti-cancer activity, through AMPK activation and mTOR inhibition. We hypothesized that the metabolic stress induced by a KD combined with metformin would enhance radiation’s efficacy. We sought to assess the tolerability and feasibility of this approach. A single-institution phase I clinical trial. Radiotherapy was either 60 or 35 Gy over 6 or 2 weeks, for newly diagnosed and recurrent gliomas, respectively. The dietary intervention consisted of a Modified Atkins Diet (ModAD) supplemented with medium chain triglycerides (MCT). There were three cohorts: Dietary intervention alone, and dietary intervention combined with low-dose or high-dose metformin; all patients received radiotherapy. Factors associated with blood ketone levels were investigated using a mixed-model analysis. A total of 13 patients were accrued, median age 61 years, of whom six had newly diagnosed and seven with recurrent disease. All completed radiation therapy; five patients stopped the metabolic intervention early. Metformin 850 mg three-times daily was poorly tolerated. There were no serious adverse events. Ketone levels were associated with dietary factors (ketogenic ratio, p < 0.001), use of metformin (p = 0. 02) and low insulin levels (p = 0.002). Median progression free survival was ten and four months for newly diagnosed and recurrent disease, respectively. The intervention was well tolerated. Higher serum ketone levels were associated with both dietary intake and metformin use. The recommended phase II dose is eight weeks of a ModAD combined with 850 mg metformin twice daily.

Magnetic Hyperthermia as an adjuvant cancer therapy in combination with radiotherapy versus radiotherapy alone for recurrent/progressive glioblastoma: a systematic review

Abstract: Hyperthermia therapy (HT) is a recognized treatment modality, that can sensitize tumors to the effects of radiotherapy (RT) and chemotherapy by heating up tumor cells to 40–45 °C. The advantages of noninvasive inductive magnetic hyperthermia (MH) over RT or chemotherapy in the treatment of recurrent/progressive glioma have been confirmed by several clinical trials. Thus, here we have conducted a systematic review to provide a concise, albeit brief, account of the currently available literature regarding this topic. Five databases, PubMed/Medline, Embace, Ovid, WOS, and Scopus, were investigated to identify clinical studies comparing overall survival (OS) following RT/chemotherapy versus RT/chemotherapy + MH. Eleven articles were selected for this systematic review, including reports on 227 glioma patients who met the study inclusion criteria. The papers included in this review comprised nine pilot clinical trials, one non-randomized clinical trial, and one retrospective investigation. As the clinical trials suggested, MH improved OS in primary glioblastoma (GBM), however, in the case of recurrent glioblastoma, no significant change in OS was reported. All 11 studies ascertained that no major side effects were observed during MH therapy. Our systematic review indicates that MH therapy as an adjuvant for RT could result in improved survival, compared to the therapeutic outcomes achieved with RT alone in GBM, especially by intratumoral injection of magnetic nanoparticles. However, heterogeneity in the methodology of the most well-known studies, and differences in the study design may significantly limit the extent to which conclusions can be drawn. Thus, further investigations are required to shed more light on the efficacy of MH therapy as an adjuvant treatment modality in GBM.

Label-free brain tumor imaging using Raman-based methods.

Abstract: Label-free Raman-based imaging techniques create the possibility of bringing chemical and histologic data into the operation room. Relying on the intrinsic biochemical properties of tissues to generate image contrast and optical tissue sectioning, Raman-based imaging methods can be used to detect microscopic tumor infiltration and diagnose brain tumor subtypes. Here, we review the application of three Raman-based imaging methods to neurosurgical oncology: Raman spectroscopy, coherent anti-Stokes Raman scattering (CARS) microscopy, and stimulated Raman histology (SRH). Raman spectroscopy allows for chemical characterization of tissue and can differentiate normal and tumor-infiltrated tissue based on variations in macromolecule content, both ex vivo and in vivo. To improve signal-to-noise ratio compared to conventional Raman spectroscopy, a second pulsed excitation laser can be used to coherently drive the vibrational frequency of specific Raman active chemical bonds (i.e. symmetric stretching of –CH2 bonds). Coherent Raman imaging, including CARS and stimulated Raman scattering microscopy, has been shown to detect microscopic brain tumor infiltration in fresh brain tumor specimens with submicron image resolution. Advances in fiber-laser technology have allowed for the development of intraoperative SRH as well as artificial intelligence algorithms to facilitate interpretation of SRH images. With molecular diagnostics becoming an essential part of brain tumor classification, preliminary studies have demonstrated that Raman-based methods can be used to diagnose glioma molecular classes intraoperatively. These results demonstrate how label-free Raman-based imaging methods can be used to improve the management of brain tumor patients by detecting tumor infiltration, guiding tumor biopsy/resection, and providing images for histopathologic and molecular diagnosis.

Integration of immuno-oncology with stereotactic radiosurgery in the management of brain metastases.

Abstract: Brain metastases traditionally carried a poor prognosis with treatment being a combination of surgery, whole-brain radiation therapy, and glucocorticoids; however, this treatment paradigm carried a significant amount of morbidity. In recent years, stereotactic radiosurgery (SRS), which involves the delivery of a highly conformal dose of radiation over a single session, has been shown to be an effective alternative to WBRT with excellent rates of local control and improved quality of life; however, a survival benefit has not been demonstrated. Recent developments have challenged the traditional view of the central nervous system being “immunologically privileged” which has led to a greater focus on treating these patients with systemic therapies. Immune checkpoint inhibitors (ICI) have been shown to improve survival in multiple malignancies. As a result, there has been increased utilization in combining these therapies in this setting. We conducted a literature search of medical databases (e.g. PubMed) for articles involving the use of immune checkpoint inhibitors and stereotactic radiosurgery in managing brain metastases. Published evidence utilizing SRS and ICI is largely limited to single institution and retrospective in nature with the most common histology being melanoma. Combination therapy with SRS and ICI appears to improve survival in patients with brain metastases. The available data are largely retrospective; therefore, ongoing and planned prospective studies are needed to further validate these findings.

Sonodynamic therapy for gliomas.

Abstract: Glioma remains incurable and a life limiting disease with an urgent need for effective therapies. Sonodynamic therapy (SDT) involves systemic delivery of non-toxic chemical agents (sonosensitizers) that accumulate in tumor cells or environment and are subsequently activated by exposure to low-frequency ultrasound to become cytotoxic agents. Herein, we discuss proposed mechanisms of action of SDT and provide recommendation for future research and clinical applications of SDT for gliomas. Review of literature of SDT in glioma cell cultures and animal models published in Pubmed/MEDLINE before January, 2021. Different porphyrin and xanthene derivatives have proven to be effective sonosensitizers. Generation of reactive oxygen species and free radicals from water pyrolysis or sonosensitizers, or physical destabilization of cell membrane, have been identified as mechanisms of SDT leading to cell death. Numerous studies across glioma cell lines using various sonosensitizers and ultrasound parameters have documented tumoricidal effects of SDT. Studies in small animal glioma xenograft models have also consistently documented that SDT is associated with improved tumor control and longer survival of animals treated with SDT while avoiding damage of surrounding brain. There are no clinical trials completed to date regarding safety and efficacy of SDT in patients harboring gliomas, but some are beginning. Pre-clinical studies cell cultures and animal models indicate that SDT is a promising treatment approach for gliomas. Further studies should define optimal sonication parameters and sonosensitizers for gliomas. Clinical trials of SDT in patients harboring gliomas and other malignant brain tumors are currently underway.

The effect of surgery on radiation necrosis in irradiated brain metastases: extent of resection and long-term clinical and radiographic outcomes

Abstract: Radiation therapy is a cornerstone of brain metastasis (BrM) management but carries the risk of radiation necrosis (RN), which can require resection for palliation or diagnosis. We sought to determine the relationship between extent of resection (EOR) of pathologically-confirmed RN and postoperative radiographic and symptomatic outcomes. A single-center retrospective review was performed at an NCI-designated Comprehensive Cancer Center to identify all surgically-resected, previously-irradiated necrotic BrM without admixed recurrent malignancy from 2003 to 2018. Clinical, pathologic and radiographic parameters were collected. Volumetric analysis determined EOR and longitudinally evaluated perilesional T2-FLAIR signal preoperatively, postoperatively, and at 3-, 6-, 12-, and 24-months postoperatively when available. Rates of time to 50% T2-FLAIR reduction was calculated using cumulative incidence in the competing risks setting with last follow-up and death as competing events. The Spearman method was used to calculate correlation coefficients, and continuous variables for T2-FLAIR signal change, including EOR, were compared across groups. Forty-six patients were included. Most underwent prior stereotactic radiosurgery with or without whole-brain irradiation (N = 42, 91%). Twenty-seven operations resulted in gross-total resection (59%; GTR). For the full cohort, T2-FLAIR edema decreased by a mean of 78% by 6 months postoperatively that was durable to last follow-up (p < 0.05). EOR correlated with edema reduction at last follow-up, with significantly greater T2-FLAIR reduction with GTR versus subtotal resection (p < 0.05). Among surviving patients, a significant proportion were able to decrease their steroid use: steroid-dependency decreased from 54% preoperatively to 15% at 12 months postoperatively (p = 0.001). RN resection conferred both durable T2-FLAIR reduction, which correlated with EOR; and reduced steroid dependency.

Cyproterone acetate and meningioma: a nationwide-wide population based study.

Abstract: The study the characteristics of surgical meningiomas in female patients who took CPA and to compare this population to a non-CPA control group. We processed the French Systeme National des Donnees de Sante (SNDS) database to retrieve appropriate cases operated between 2007 and 2017. 1 101 female patients (3.8%) who used to take CPA and underwent a meningioma surgery were extracted from a nationwide population based cohort of 28 924 patients. Median age at CPA prescription was 42 years IQR[36.7–48.9]. The median time between CPA start and surgery was 5.5 years IQR[3.1–7.9]. The median age at surgery was significantly lower in patients who were treated by CPA (47 years, IQR[42–54) compared to the non-CPA population (61 years, IQR[51–70], p < 0.001). Median CPA dose was 40 g, IQR[19–72]. There was a strong correlation between CPA dose and duration (r = 0.58, 95%CI[0.54–0.62], p < 0.001). Middle skull base was the most common (39%) location with a anterior skull base insertion being also far more common compared to the usual population with 21.9% of the tumour. This skull base predominance of CPA-associated meningioma is highly significant (p < 0.001). Increased CPA dose raised the risk of having multiple meningioma surgeries (p < 0.001) and multiple meningioma locations (p < 0.001). Tumour grading was not modified by CPA treatment (p = 0.603). Benign or grade I meningioma accounting for 92%, atypical or grade II for 6.1% and malignant or grade III for 1.9%. In the past 10 years, a significant number of CPA-induced meningiomas have been removed, modifying the global pyramid of age at surgery for female patients. These tumours occur well before the usual age and are preferentially located on the anterior and middle skull base.

MRI radiomics to differentiate between low grade glioma and glioblastoma peritumoral region.

Abstract: Background The peritumoral region (PTR) of glioblastoma (GBM) appears as a T2W-hyperintensity and is composed of microscopic tumor and edema. Infiltrative low grade glioma (LGG) comprises tumor cells that seem similar to GBM PTR on MRI. The work here explored if a radiomics-based approach can distinguish between the two groups (tumor and edema versus tumor alone). Methods Patients with GBM and LGG imaged using a 1.5 T MRI were included in the study. Image data from cases of GBM PTR, and LGG were manually segmented guided by T2W hyperintensity. A set of 91 first-order and texture features were determined from each of T1W-contrast, and T2W-FLAIR, diffusion-weighted imaging sequences. Applying filtration techniques, a total of 3822 features were obtained. Different feature reduction techniques were employed, and a subsequent model was constructed using four machine learning classifiers. Leave-one-out cross-validation was used to assess classifier performance. Results The analysis included 42 GBM and 36 LGG. The best performance was obtained using AdaBoost classifier using all the features with a sensitivity, specificity, accuracy, and area of curve (AUC) of 91%, 86%, 89%, and 0.96, respectively. Amongst the feature selection techniques, the recursive feature elimination technique had the best results, with an AUC ranging from 0.87 to 0.92. Evaluation with the F-test resulted in the most consistent feature selection with 3 T1W-contrast texture features chosen in over 90% of instances. Conclusions Quantitative analysis of conventional MRI sequences can effectively demarcate GBM PTR from LGG, which is otherwise indistinguishable on visual estimation.

Extent of resection and survival outcomes in World Health Organization grade II meningiomas

Abstract: WHO grade II meningiomas behave aggressively, with recurrence rates as high as 60%. Although complete resection in low-grade meningiomas is associated with a relatively low recurrence rate, the impact of complete resection for WHO grade II meningiomas is less clear. We studied the association of extent of resection with overall and progression-free survivals in patients with WHO grade II meningiomas. A retrospective database review was performed to identify all patients who underwent surgical resection for intracranial WHO grade II meningiomas at our institution between 1995 and 2019. Kaplan–Meier analysis was used to compare overall and progression-free survivals between patients who underwent gross total resection (GTR) and those who underwent subtotal resection (STR). Multivariable Cox proportional-hazards analysis was used to identify independent predictors of tumor recurrence and mortality. Of 214 patients who underwent surgical resection for WHO grade II meningiomas (median follow-up 53.4 months), 158 had GTR and 56 had STR. In Kaplan–Meier analysis, patients who underwent GTR had significantly longer progression-free (p = 0.002) and overall (p = 0.006) survivals than those who underwent STR. In multivariable Cox proportional-hazards analysis, GTR independently predicted prolonged progression-free (HR 0.57, p = 0.038) and overall (HR 0.44, p = 0.017) survivals when controlling for age, tumor location, and adjuvant radiation. Extent of resection independently predicts progression-free and overall survivals in patients with WHO grade II meningiomas. In an era of increasing support for adjuvant treatment modalities in the management of meningiomas, our data support maximal safe resection as the primary goal in treatment of these patients.

The use and efficacy of chemotherapy and radiotherapy in children and adults with pilocytic astrocytoma.

Abstract: The aim of this study was to understand the use of chemotherapy (CMT) and radiotherapy (RT) in pilocytic astrocytoma (PA) and their impact on overall survival (OS). Data from the National Cancer Database (NCDB) for patients with non-metastatic WHO grade I PA from 2004 to 2014 were analyzed. Pearson’s chi-squared test and multivariate logistic regression analyses were performed to assess the distribution of demographic, clinical, and treatment factors. Inverse probability of treatment weighting (IPTW) was used to account for differences in baseline characteristics. Kaplan–Meier analyses and doubly-robust estimation with multivariate Cox proportional hazards modeling were used to analyze OS. Of 3865 patients analyzed, 294 received CMT (7.6%), 233 received RT (6.0%), and 42 (1.1%) received both. On multivariate analyses, decreasing extent of surgical resection was associated with receipt of both CMT and RT. Brainstem tumors were associated with RT, optic nerve tumors were associated with CMT. Cerebellar tumors were inversely associated with both CMT and RT. Younger age was associated with receipt of CMT; conversely, older age was associated with receipt of RT. After IPTW, receipt of CMT and/or RT were associated with an OS decrement compared with matched patients treated with surgery alone or observation (HR 3.29, p < 0.01). This is the largest study to date to examine patterns of care and resultant OS outcomes in PA. We identified patient characteristics associated with receipt of CMT and RT. After propensity score matching, receipt of CMT and/or RT was associated with decreased OS.

PTEN mutations predict benefit from tumor treating fields (TTFields) therapy in patients with recurrent glioblastoma

Abstract: Optimal treatment for recurrent glioblastoma isocitrate dehydrogenase 1 and 2 wild-type (rGBM IDH-WT) is not standardized, resulting in multiple therapeutic approaches. A phase III clinical trial showed that tumor treating fields (TTFields) monotherapy provided comparable survival benefits to physician’s chemotherapy choice in rGBM. However, patients did not equally benefit from TTFields, highlighting the importance of identifying predictive biomarkers of TTFields efficacy. A retrospective review of an institutional database with 530 patients with infiltrating gliomas was performed. Patients with IDH-WT rGBM receiving TTFields at first recurrence were included. Tumors were evaluated by next-generation sequencing for mutations in 205 cancer-related genes. Post-progression survival (PPS) was examined using the log-rank test and multivariate Cox-regression analysis. 149 rGBM patients were identified of which 29 (19%) were treated with TTFields. No significant difference in median PPS was observed between rGBM patients who received versus did not receive TTFields (13.9 versus 10.9 months, p = 0.068). However, within the TTFields-treated group (n = 29), PPS was improved in PTEN-mutant (n = 14) versus PTEN-WT (n = 15) rGBM, (22.2 versus 11.6 months, p = 0.017). Within the PTEN-mutant group (n = 70, 47%), patients treated with TTFields (n = 14) had longer median PPS (22.2 versus 9.3 months, p = 0.005). No PPS benefit was observed in PTEN-WT patients receiving TTFields (n = 79, 53%). TTFields therapy conferred a significant PPS benefit in PTEN-mutant rGBM. Understanding the molecular mechanisms underpinning the differences in response to TTFields therapy could help elucidate the mechanism of action of TTFields and identify the rGBM patients most likely to benefit from this therapeutic option.

Predictors of postoperative biochemical remission in acromegaly

Abstract: Acromegaly is a rare neuroendocrine condition that can lead to significant morbidity. Despite China’s vast population size, studies on acromegaly remain sparse. This study aimed to investigate the clinical characteristics and predictors of biochemical remission after surgery for acromegaly using the China Acromegaly Patient Association (CAPA) database. A retrospective nationwide study was conducted using patient-reported data from CAPA database between 1998 and 2018. The principal component analysis (PCA) and logistic regression analysis were employed to determine independent predictors of biochemical remission at 3 months in patients after surgery. Of the 546 surgical cases (mean age: 36.8 years; 59.5% females), macroadenomas and invasive tumors (Knosp score 3–4) were 83.9% and 64.1%, respectively. Ninety-five percent of patients were treated with endonasal surgery and 36.8% exhibited biochemical remission at 3-months postoperatively. The following independent predictors of biochemical remission were identified: preoperative growth hormone (GH) levels between 12 and 28 μg/L [odds ratio (OR) = 0.58; 95% confidence interval (CI), 0.37–0.92; p = 0.021], preoperative GH levels > 28 μg/L (OR = 0.55; 95% CI, 0.34–0.88; p = 0.013), macroadenoma (OR = 0.56; 95% CI, 0.32–0.96; p = 0.034), giant adenomas (OR = 0.14; 95% CI, 0.05–0.38; p < 0.001), Knosp score 3–4 (OR = 0.37; 95% CI, 0.24–0.57; p < 0.001), and preoperative medication usage (OR = 2.32; 95% CI, 1.46–3.70; p < 0.001). In this nationwide study spanning over two decades, we highlight that higher preoperative GH levels, large tumor size, and greater extent of tumor invasiveness are associated with a lower likelihood of biochemical remission at 3-months after surgery, while preoperative medical therapy increases the chance of remission.

Association of baseline frailty status and age with postoperative morbidity and mortality following intracranial meningioma resection

Abstract: Although numerous studies have established advanced patient age as a risk factor for poor outcomes following intracranial meningioma resection, large-scale evaluation of frailty for preoperative risk assessment has yet to be examined. Weighted discharge data from the National Inpatient Sample were queried for adult patients undergoing benign intracranial meningioma resection from 2015 to 2018. Complex samples multivariable logistic regression models and receiver operating characteristic curve analysis were performed to evaluate adjusted associations and discrimination of frailty, quantified using the 11-factor modified frailty index (mFI), for clinical endpoints. Among 20,250 patients identified (mean age 60.6 years), 35.4% (n = 7170) were robust (mFI = 0), 34.5% (n = 6985) pre-frail (mFI = 1), 20.1% (n = 4075) frail (mFI = 2), and 10.0% (n = 2020) severely frail (mFI ≥ 3). On univariable analysis, these sub-cohorts stratified by increasing frailty were significantly associated with the development of Clavien–Dindo grade IV (life-threatening) complications (inclusive of those resulting in mortality) (1.3% vs. 3.1% vs. 6.5% vs. 9.4%, p < 0.001) and extended length of stay (eLOS) (15.4% vs. 22.5% vs. 29.3% vs. 37.4%, p < 0.001). Following multivariable analysis, increasing frailty (aOR 1.40, 95% CI 1.17, 1.68, p < 0.001) and age (aOR 1.20, 95% CI 1.05, 1.38, p = 0.009) were both independently associated with development of life-threatening complications or mortality, whereas increasing frailty (aOR 1.20, 95% CI 1.10, 1.32, p < 0.001), but not age, was associated with eLOS. Frailty (by mFI-11) achieved superior discrimination in comparison to age for both endpoints (AUC 0.69 and 0.61, respectively). Frailty may be more accurate than advanced patient age alone for prognostication of adverse events and outcomes following intracranial meningioma resection.

Bevacizumab vs laser interstitial thermal therapy in cerebral radiation necrosis from brain metastases: a systematic review and meta-analysis

Abstract: Radiation necrosis (RN) represents a serious post-radiotherapy complication in patients with brain metastases. Bevacizumab and laser interstitial thermal therapy (LITT) are viable treatment options, but direct comparative data is scarce. We reviewed the literature to compare the two treatment strategies. PubMed, EMBASE, Scopus, and Cochrane databases were searched. All studies of patients with RN from brain metastases treated with bevacizumab or LITT were included. Treatment outcomes were analyzed using indirect meta-analysis with random-effect modeling. Among the 18 studies included, 143 patients received bevacizumab and 148 underwent LITT. Both strategies were equally effective in providing post-treatment symptomatic improvement (P = 0.187, I2 = 54.8%), weaning off steroids (P = 0.614, I2 = 25.5%), and local lesion control (P = 0.5, I2 = 0%). Mean number of lesions per patient was not statistically significant among groups (P = 0.624). Similarly, mean T1-contrast-enhancing pre-treatment volumes were not statistically different (P = 0.582). Patterns of radiological responses differed at 6-month follow-ups, with rates of partial regression significantly higher in the bevacizumab group (P = 0.001, I2 = 88.9%), and stable disease significantly higher in the LITT group (P = 0.002, I2 = 81.9%). Survival rates were superior in the LITT cohort, and statistical significance was reached at 18 months (P = 0.038, I2 = 73.7%). Low rates of adverse events were reported in both groups (14.7% for bevacizumab and 12.2% for LITT). Bevacizumab and LITT can be safe and effective treatments for RN from brain metastases. Clinical and radiological outcomes are mostly comparable, but LITT may relate with superior survival benefits in select patients. Further studies are required to identify the best patient candidates for each treatment group.