Rimas Lukas

• MD
• Managing Director at Northwestern University

Background In 2021, the World Health Organization reclassified glioblastomas to include only gliomas with wild-type isocitrate dehydrogenase (IDHwt). Reclassification has created a challenge for retrospective identification of patients with GBM, as many were classified with outdated definitions. This study aims to address this challenge by using na...

Background Determining appropriate suitability and goals for inpatient rehabilitation of patients with glioblastoma, isocitrate dehydrogenase‐wildtype (GBM) requires real‐time prognostic information. Functional measures, such as bed mobility, are standardized scores that can be assessed by members of the care team at the bedside and may aid medical...

Objective This study aimed to determine how age and IDO1 interact to affect the gut microbiome, microbial metabolite levels, and survival outcomes in subjects undergoing IDO1-targeted immunotherapy against glioblastoma (GBM). Methods Serum and colon contents from younger 16-20- or older 92-118-week-old wild-type (WT), IDO1 knockout (IDO1-KO), and...

Background Glioblastoma (GBM), the most common primary brain tumor in adults with a devastating median overall survival time of 12 months, was reclassified by the World Health Organization in 2021 to only include gliomas with wild-type isocitrate dehydrogenase (IDHwt). This presents a challenge in studying retrospective cohorts of patients diagnose...

Gliomas are the most common primary malignant brain tumors. Their electrobiologic properties drive disease development, and in select tumors, aberrant neurosignaling is situated at the crux of gliomagenesis and glioma-related epilepsy (GRE). Tumor microtubes and the neuronal-glioma synapse are defined components of the glioma circuitry. The nidus o...

Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive protein that inhibits antitumor immunity through both tryptophan metabolism and nonenzymatic functions. Drugs targeting IDO1 enzyme activity have failed to improve the overall survival of patients with cancer. Developing new therapeutics that neutralize both enzyme- and nonenzyme-derived...

Advances in molecular biology, genetics, and epigenetics have refined our understanding of metastatic brain cancer and underscored the need for better classification and targeted approaches. The heterogeneity of brain metastases highlights the differences from their primary source of origin and contributes to therapeutic resistance. Before colonisi...

Background Cachexia is a complex syndrome that impacts up to half of patients with cancer. Criteria systems have been developed for the purpose of diagnosing and grading cachexia severity in clinical settings. One of the most widely known is those developed by Fearon et al. in 2011, which utilizes body mass loss and body mass index (BMI) to determi...

Seizures are a frequent complication in glioma. Incidence of brain tumor-related epilepsy (BTRE) in high-grade glioma (HGG) is an estimated > 25% and in low-grade glioma (LGG) is approximately 72%. Two first-line antiseizure medications (ASMs) for BTRE include levetiracetam (LEV) and valproic acid (VPA). Use of VPA has decreased because of a broade...

Indoleamine 2,3-dioxygenase 1 (IDO1) is a potently immunosuppressive protein that inhibits antitumor immunity through both tryptophan metabolism and non-enzymatic functions. Pharmacological therapies targeting IDO1 enzyme activity have generally failed to improve the overall survival of patients with cancer. Developing new therapeutic agents that a...

Importance Molecular techniques, including next-generation sequencing, genomic copy number profiling, fusion transcript detection, and genomic DNA methylation arrays, are now indispensable tools for the workup of central nervous system (CNS) tumors. Yet there remains a great deal of heterogeneity in using such biomarker testing across institutions...

STING (stimulator of interferon genes) activation triggers interferon (IFN) release within the tumor microenvironment from myeloid cells and other cell types, inducing proinflammatory anti-tumor immune responses. The small molecule STING agonist, 8803, elicits long-term survival in 56% (QPP4; p=0.0003) to 100% (QPP8; p<0.0001) of mice with orthotop...

Despite being the leading cause of childhood mortality, pediatric gliomas have been relatively understudied. Repurposing of adult brain tumor immunotherapies in pediatric patients has not been successful, highlighting the need for pediatric-specific immunotherapies. Pilocytic astrocytomas (PA) are the most common pediatric glioma. While surgical re...

BACKGROUND Glioblastoma (GBM) is the most common aggressive primary malignant brain tumor in adults with a poor median survival rate. Despite the aggressive standard of care treatment combining surgical resection, chemo-, and radio-therapy, the median overall survival (OS) is only ~15-18 months. Progressively increasing subject age is inversely ass...

The field of immunology has traditionally focused on immune checkpoint modulation of adaptive immune cells. However, many malignancies such as glioblastoma are mostly devoid of T cells and rather are enriched with immunosuppressive myeloid cells of the innate immune system. While some immune checkpoint targets are shared between adaptive and innate...

Despite being the leading cause of cancer-related childhood mortality, pediatric gliomas have been relatively understudied, and the repurposing of immunotherapies has not been successful. Whole-transcriptome sequencing, single-cell sequencing, and sequential multiplex immunofluorescence were used to identify an immunotherapeutic strategy that could...

Background Report our institutional experience with pleomorphic xanthoastrocytoma (PXA) to contribute to limited data on optimal management. Methods Patients with pathologically confirmed PXA treated at our institution between 1990 and 2019 were identified. Demographic information, tumor grade, treatment variables, and clinical outcomes were colle...

Background Tumor Treating Fields (TTFields) are alternating electric fields that disrupt cancer cell processes. TTFields therapy is approved for recurrent glioblastoma (rGBM), and newly-diagnosed (nd) GBM (with concomitant temozolomide for ndGBM; US), and for grade IV glioma (EU). We present an updated global, post-marketing surveillance safety ana...

STING agonists can reprogram the tumor microenvironment to induce immunological clearance within the central nervous system. Using multiplexed sequential immunofluorescence (SeqIF) and the Ivy Glioblastoma Atlas, STING expression was found in myeloid populations and in the perivascular space. The STING agonist 8803 increased median survival in mult...

Introduction Central Neurocytoma (CN) is a rare, WHO grade 2 brain tumor that predominantly affects young adults. Gross total resection (GTR) is often curative for CNs, but the optimal treatment paradigm including incorporation of RT, following subtotal resection (STR) and for scarcer pediatric cases has yet to be established. Methods Patients bet...

Given the marginal penetration of most drugs across the blood-brain barrier, the efficacy of various agents remains limited for glioblastoma (GBM). Here we employ low-intensity pulsed ultrasound (LIPU) and intravenously administered microbubbles (MB) to open the blood-brain barrier and increase the concentration of liposomal doxorubicin and PD-1 bl...

Patients with solid tumor brain metastases that progress after whole-brain radiation have limited options. This prospective trial investigated the efficacy, safety, and tolerability of bevacizumab as salvage therapy in this population. Eligible patients received bevacizumab 10 mg/kg intravenously every 2 weeks until progression. The primary endpoin...

Introduction Solitary fibrous tumors (SFTs) of the central nervous system represent a unique entity with limited data on best treatment practices. Case Report Here, we present a case of multiply recurrent central nervous system SFT treated with radiation and immunotherapy. Immunotherapy was chosen based on mutations of genes encoding DNA repair en...

Macrophages and microglia are professional phagocytes that sense and migrate toward “eat-me” signals. The role of phagocytic cells is to maintain homeostasis by engulfing senescent or apoptotic cells, debris, and abnormally aggregated macromolecules. Usually, dying cells send out “find-me” signals, facilitating the recruitment of phagocytes. Health...

Simple Summary Meningiomas are the most common intracranial tumors, and significant advances have been made in our understanding of the biology that leads to meningioma growth and aggressiveness. This review summarizes molecular advances and the historical contexts that led to them. Abstract Meningioma classification and treatment have evolved ove...

Background Tumor Treating Fields (TTFields) Therapy is an FDA-approved therapy in the first line and recurrent setting for glioblastoma. Despite Phase 3 evidence showing improved survival with TTFields, it is not uniformly utilized. We aimed to examine patient and clinician views of TTFields and factors shaping utilization of TTFields through a uni...

INTRODUCTION The limited drug penetration across the blood-brain barrier (BBB) represents a challenge for the treatment of glioblastoma patients. A novel drug delivery technology based on low-intensity pulsed ultrasound combined with intravenous microbubbles (LIPU/MB) overcomes this challenge by opening the BBB. In this study, we hypothesize that L...

Purpose Multidisciplinary tumor boards (MTBs) integrate clinical, molecular, and radiological information and facilitate coordination of neuro-oncology care. During the COVID-19 pandemic, our MTB transitioned to a virtual and multi-institutional format. We hypothesized that this expansion would allow expert review of challenging neuro-oncology case...

Background Increased age is a strong and unfavorable prognostic factor for patients with glioblastoma (GBM). However, the relationships between stratified patient age, comorbidities, and medications have yet to be explored in GBM patient survival analyses. Objective To evaluate co-morbid conditions, tumor-related symptoms, medication prescriptions...

Background A significant unmet need exists for the treatment of glioblastoma, IDH-wildtype (GBM). Preclinical work shows that acetazolamide sensitizes GBM to temozolomide (TMZ) by overcoming TMZ resistance due to BCL-3-dependent upregulation of carbonic anhydrase. Acetazolamide is Food and Drug Administration-approved for the treatment of altitude...

OBJECTIVE Whether obesity is associated with meningioma and the impact of obesity by gender has been debated. The primary objective of this study was to investigate differences in BMI between male and female patients undergoing craniotomy for meningioma and compare those with patients undergoing craniotomy for other intracranial tumors. The seconda...

Meningiomas are the most frequent type of Central Nervous System tumor. They are dural-based tumors, that most commonly occur intracranially. They are often diagnosed based on imaging features and may come to attention due to symptoms or are found incidentally on imaging. The majority of meningiomas are slow-growing and not life-threatening but som...

BACKGROUND Glioblastoma (GBM) is an aggressive central nervous system (CNS) malignancy with poor prognosis. TTFields are electric fields that exert physical forces to disrupt cellular processes critical for cancer cell viability. TTFields therapy is approved for recurrent and newly diagnosed GBM, and pleural mesothelioma. We report long-term safety...

INTRODUCTION Central Neurocytoma (CN) is a rare, WHO grade 2 brain tumor that predominantly affects young adults. Gross total resection (GTR) is often curative for CN, but the optimal treatment paradigm following subtotal resection (STR) and or scarcer pediatric cases has yet to be established—including the role of radiation therapy (RT). Herein, w...

Using an in vivo CRISPR screen approach, we demonstrated the contribution of glioma cell intrinsic checkpoint kinase 2 (Chek2) in the evasion of tumor cells from CD8+ T cell recognition. Genetic depletion or pharmacological inhibition of Chek2 with blood-brain-barrier permeable drugs that are being evaluated in clinical trials, in combination with...

Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive rate-limiting enzyme that metabolizes the essential amino acid, tryptophan (Trp), into the downstream catabolite, kynurenine. IDO1 is expressed in >90% of patient-resected glioblastoma (GBM). We recently validated that IDO1 can suppress the anti-brain tumor immune response and ablate immu...

BACKGROUND New therapies are especially needed for uMGMT nGBM. NRG Oncology BN002 (phase I) demonstrated safety and preliminary efficacy of Ipi+Nivo for nGBM, leading to BN007 as phase II/III. METHODS Adults with uMGMT nGBM (WHO 2016) and KPS ≥ 70 were randomized to RT and concurrent and adjuvant Ipi+Nivo or TMZ, stratified by glioma-recursive par...

MGMT promoter methylation predicts favorable temozolomide (TMZ) response in gliomas. Accurate test results depend on adequate tumor cellularity in analyzed samples, which is usually estimated (with sub-optimal accuracy) via light microscopy. We evaluated driver mutation variant allelic frequency (VAF) as a quantitative metric for tumor cellularity...

Checkmate 498 is a large, randomized, phase 3 clinical trial that demonstrated an improved hazard ratio for younger but not older adults with MGMT unmethylated GBM treated with RT + PD-1 mAb. In an effort to better understand the biological determinant, indoleamine 2,3 dioxygenase 1 (IDO1), and its relationship with reducing RT + PD-1 mAb treatment...

MGMT promoter methylation testing is required for prognosis and predicting temozolomide response in gliomas. Accurate results depend on sufficient tumor cellularity, but histologic estimates of cellularity are subjective. We sought to determine whether driver mutation variant allelic frequency (VAF) could serve as a more objective metric for cellul...

Plain language summary Cancer of the esophagus, the tube that connects the mouth to the stomach, tends to be aggressive. Very rarely, this cancer can spread to the lining that surrounds your brain, called the leptomeninges. Previous reports of patients who have experienced this specific spreading pattern of esophageal cancer to the leptomeninges ar...

Aims/purpose: Leptomeningeal metastases (LM) are associated with substantial morbidity and mortality. Several approaches are used to treat LM, including intrathecally administered therapies. We consolidated current studies exploring intrathecal therapies for LM treatment. Patients & methods: A review of clinical trials using intrathecal agents was...

Treatment of IDH-mutated non-enhancing grade 2 and 3 diffuse gliomas with ivosidenib leads to reduction of tumor size when assessed via volumetric MRI. Isocitrate dehydrogenase inhibition has a therapeutic benefit in patients with these tumors. See related article by Kamson et al., p. XXX

Purpose Glioblastoma (GBM) is the most common aggressive primary malignant brain tumor in adults with a median age of onset of 68 to 70 years old. Although advanced age is often associated with poorer GBM patient survival, the predominant source(s) of maladaptive aging effects remains to be established. Here, we studied intratumoral and extratumora...

AIMS Glioblastoma (GBM) has a poor prognosis, which is compounded by an increase in treatment-related toxicity with age. TTFields are electric fields that exert physical forces to disrupt cellular processes critical for cancer cell viability. Subgroup analysis of the phase 3 EF-14 study demonstrated TTFields therapy to be well-tolerated in patients...

BACKGROUND New therapies are especially needed for uMGMT nGBM. NRG Oncology BN002 (phase I) demonstrated safety and preliminary efficacy of Ipi+Nivo for nGBM, leading to BN007 as phase II/III. METHODS Adults with uMGMT nGBM (WHO 2016) and KPS ≥ 70 were randomized to RT and concurrent and adjuvant Ipi+Nivo or TMZ, stratified by glioma-recursive par...

Simple Summary Despite multi-modal treatment consisting of surgery, chemotherapy, and radiation, glioblastoma inevitably recurs due to its diffuse infiltrative nature. Anti-tumor immune responses, supported by pro-inflammatory cytokines, that can seek out remote cancer vestiges will likely become part of the therapeutic armamentarium but will requi...

This compendium was created to cover the most important subjects in the field of Neuro-Oncology, so that readers will be able to find high-yield information presented in a concise yet comprehensive format. Each chapter highlights information of critical importance by using specifically designed text boxes. In addition, to facilitate consolidation o...

Most of the literature on pineoblastoma consists of case reports and single-institution series. The goal of this systematic review and individual patient data (IPD) analysis was to summarize the existing literature, identify factors associated with overall survival (OS), and provide a contemporary update on prognosis for patients with pineoblastoma...

BACKGROUND TTFields are electric fields that exert physical forces to disrupt cellular processes critical for cancer cell viability and tumor progression. TTFields therapy is approved for adults with recurrent (r) and newly diagnosed (nd) glioblastoma (GBM), based on the phase 3 EF-11 (TTFields 200 kHz) and EF-14 studies (TTFields therapy 200 kHz +...

CNS metastases are often terminal for cancer patients and occur at an approximately 10-fold higher rate than primary CNS tumors. The incidence of these tumors is approximately 70,000–400,000 cases annually in the US. Advances that have occurred over the past two decades have led to more personalized treatment approaches. Newer surgical and radiatio...

2049 Background: Glioblastoma (GBM) has a poor prognosis. Standard treatments are associated with systemic toxicity, further increasing the disease burden in this patient population. Tumor Treating Fields (TTFields) are electric fields that disrupt cancer cell processes which affect cancer cell viability, and are generated by a portable, wearable d...

Background: Low-intensity pulsed ultrasound with concomitant administration of intravenous microbubbles (LIPU-MB) can be used to open the blood-brain barrier. We aimed to assess the safety and pharmacokinetics of LIPU-MB to enhance the delivery of albumin-bound paclitaxel to the peritumoural brain of patients with recurrent glioblastoma. Methods:...

We present three cases of O6-Methylguanine-DNA Methyltransferase (MGMT) methylated high grade gliomas with distant recurrence. All three patients had a radiographic stability of original tumor site at time of distant recurrence indicating impressive local control with Stupp protocol in patients with a MGMT methylated tumors. All patients had a poor...

Seizures are a frequent complication of adult-type diffuse gliomas, and are often difficult to control with medications. Gliomas with mutations in isocitrate dehydrogenase 1 or 2 (IDHmut) are more likely than IDH wild-type (IDHwt) gliomas to cause seizures as part of their initial clinical presentation. However, whether IDHmut is also associated wi...

Objective To characterize neurologic manifestations in post‐hospitalization Neuro‐PASC (PNP) and non‐hospitalized Neuro‐PASC (NNP) patients. Methods Prospective study of the first 100 consecutive PNP and 500 NNP patients evaluated at a Neuro‐COVID‐19 clinic between 5/2020 and 8/2021. Results PNP were older than NNP patients (mean 53.9 vs 44.9 y;...

Background: Primary central nervous system lymphoma (PCNSL) is a rare, often curable neoplasm, often initially presenting in acute care settings by nonneuroscience specialized physicians. Delays in the recognition of specific imaging findings, lack of appropriate specialist consultation, and urgent incorrect medication administration can delay nec...

Patients with glioblastoma (GBM) face poor outcomes; the 5-year survival rate is 7% with standard of care treatments, which are frequently associated with systemic toxicity. Tumor Treating Fields (TTFields) are electric fields that disrupt critical cancer cell processes. The TTFields therapy device consists of a portable electric field generator an...

INTRODUCTION Genome-wide methylation profiling has emerged as a transformative prognostic tool in meningiomas, and has identified discrete epigenetic clusters that share distinct clinical and biological features. The association of these signatures with underlying pathological mechanisms has not been well-explored. METHODS From a collection of ove...

Purpose Report our institutional experience with pleomorphic xanthoastrocytoma (PXA) to contribute to limited data on optimal management. Methods Patients with pathologically confirmed PXA treated at our institution between 1990 and 2019 were identified. Demographic information, tumor grade, treatment variables, and clinical outcomes were collecte...

Tryptophan (Trp) metabolism plays a central role in sleep, mood, and immune system regulation. The kynurenine pathway (KP), which is regulated by the enzymes tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3 dioxygenase (IDO), which catalyze the conversion of Trp to kynurenine (Kyn), facilitates immune regulation and influences neurocognition. N...

Supratentorial non-skull base meningiomas are the most common primary central nervous system tumor subtype. An understanding of their pathophysiology, imaging characteristics, and clinical management options will prove of substantial value to the multi-disciplinary team which may be involved in their care. Extensive review of the broad literature o...

Neuro-oncology encompasses a broad field focusing on an array of neoplasms, many of which can mimic several diseases. Neurologists will often be involved in the initial diagnostic evaluation and management of these patients. Their insight is central to optimizing the diagnostic yield and providing high-level clinical care. Several neuro-oncologic c...

Indoleamine 2,3-dioxygenase 1 (IDO1) is a potent immunosuppressive enzyme that inhibits the antitumor immune response through both tryptophan metabolism and non-enzymatic functions. To date, most IDO1-targeted approaches have focused on inhibiting tryptophan metabolism. However, this class of drugs has failed to improve the overall survival of pati...

Methylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter predicts favorable response to temozolomide in adult-type diffuse gliomas. Accurate MGMT results require adequate tumor cellularity. Too many admixed non-neoplastic cells (which are always MGMT unmethylated) may cause false-negative results. Currently, ~70% tumor cellularity,...

DNA methylation profiling has emerged as a transformative prognostic tool in meningiomas, identifying distinct epigenetic subgroups that share unique clinical and biological features. Hypothesizing that methylation patterns may also reflect underlying pathogenic mechanisms, we investigated if this modality could be informative for the selection of...

Tumor-associated epilepsy (TAE) is a frequent complication of diffusely infiltrative gliomas, and impairs quality-of-life. We previously showed that isocitrate dehydrogenase 1 mutant (IDHmut) gliomas were associated with preoperative seizures, and that D2HG increased synchronized bursts in cultured neurons (PMID: 28404805). But the mechanism whereb...

OBJECTIVE Previous work indicates poorer survival outcomes for older glioblastoma (GBM) patients ≥ 65 years of age as compared to younger patients < 65 years of age. The cellular mechanisms associated with this age-dependent survival difference remain elusive. Here we evaluated the overall survival of young and old immunocompetent mice with intracr...

Tumor Treating Fields therapy (TTFields; 200 kHz) is a noninvasive, locoregional, antimitotic treatment approved for newly diagnosed glioblastoma (ndGBM), recurrent (r) GBM, malignant pleural mesothelioma, and is being investigated in additional solid tumors. Approval in GBM was based on results of the phase 3 EF-11 (TTFields monotherapy; rGBM) and...

OBJECTIVE The median age of onset for glioblastoma (GBM; IDHwt) is 68-70 years. Age is a strong prognostic factor for GBM patient outcomes such that overall survival in older adults is less than their younger counterparts – even after adjustment for MGMT promoter methylation status. Aging is associated with increased levels of senescence in the bra...

INTRODUCTION Indoleamine 2,3-dioxygenase 1 (IDO) is an immunosuppressive enzyme that catabolizes the essential amino acid, tryptophan (Trp), into the metabolite, kynurenine. IDO is expressed in >90% of patient resected GBM. IDO suppresses the anti-brain tumor immune response, in-part, through non-metabolic activities. To determine how IDO non-metab...

Glioblastoma is the most common primary malignant brain tumor in adults. Age is a prognostic factor for grade IV glioma (GIV) survival, where older adults 65 and older, tend to have quicker mortality compared to adults 18-64. This may be due to intrinsic aspects of the aged host, including age-dependent changes to the brain and immune systems. We s...

Glioblastomas are the most common primary malignant brain tumor in adults. Subject age is a strong prognostic factor for survival. We performed a co-morbidity analysis of younger vs. older (greater than 65 years) adults with grade IV gliomas (GIV) to understand inherent differences that vary with subject age. Electronic health records for 1,208 GIV...

Von Hippel Lindau (VHL) disease is a tumor predisposition syndrome caused by mutations in the VHL gene that presents with visceral neoplasms and growths, including clear cell renal cell carcinoma, and central nervous system manifestations, such as hemangioblastomas of the brain and spine. The pathophysiology involves a dysregulation of oxygen sensi...

In the following brief report, we highlight the advances in the neuro-oncology space from the ASCO 2022 annual meeting. We put into context the phase 2 and 3 trials and how these may alter the standard of care going forward. In addition, we highlight some other earlier work that will lead to future and potentially practice changing trials.

Outcomes for glioblastoma (GBM) patients undergoing standard of care treatment remain poor. Here we discuss the portfolio of previously investigated immunotherapies for glioblastoma, including vaccine therapy and checkpoint inhibitors, as well as novel emerging therapeutic approaches. In addition, we explore the factors that potentially influence r...

Background Meningioma is the most common primary intracranial tumor in adults. A subset of these tumors recur and invade the brain, even after surgery and radiation, resulting in significant disability. There is currently no standard-of-care chemotherapy for meningiomas. As genomic DNA methylation profiling can prognostically stratify these lesions...

Background Patients with human epidermal growth factor receptor 2-positive (HER2-positive) cancers have a high incidence of central nervous system (CNS) spread, but unfortunately systemic trastuzumab which targets the HER2 receptor has little CNS penetration. The purpose of this study was to determine the maximum tolerated dose of intrathecal trast...

e14035 Background: Whole genome CpG DNA methylation profiling is proving to be an extremely valuable tool in the diagnostic and prognostic classification of central nervous system (CNS) tumors, and is especially adept at discriminating between very different tumors, or tumor subtypes, that are histologically similar. However, like any bulk assay, r...

The evaluation of leptomeningeal metastases (LM) has long been a complex problem; one which we have not yet solved. Three primary parameters have been traditionally utilized for response assessment of LM. These parameters consist of the clinical assessment, the cerebrospinal fluid (CSF) assessment, and the radiographic assessment. They have been us...

Background Older adults ≥65 years of age represent the majority of new cancer diagnoses and are vulnerable to developing depression-like symptoms. Evaluation and management of depression in older cancer patients is underappreciated despite its high prevalence and impact on health-related quality of life. Although antidepressants are the primary pha...

Sarcomas are neoplasms arising from mesenchymal progenitor cells which differentiates them from other central nervous system (CNS) tumors, such as gliomas, which arise from cells that are ectodermal in origin. Primary tumors arising from these cell types are infrequently seen in the CNS. Many CNS sarcomas, when they do occur, most commonly arise in...

Leptomeningeal metastases (LM) constitute an involvement of cancer which is associated with marked morbidity and mortality. The contemporary diagnostic and therapeutic management of LM from solid tumors is reviewed. Therapeutic modalities including systemic therapies, cerebrospinal fluid (CSF)-directed therapies, and radiation therapy are discussed...

Purpose Survival is dismal for bevacizumab refractory high-grade glioma patients. We prospectively investigated the efficacy of re-irradiation, bevacizumab, and temozolomide in bevacizumab-naïve and bevacizumab-exposed recurrent high-grade glioma, without volume limitations, in a single arm trial. Methods Recurrent high-grade glioma patients were...

Only a subset of recurrent glioblastoma (rGBM) responds to anti-PD-1 immunotherapy. Previously, we reported enrichment of BRAF/PTPN11 mutations in 30% of rGBM that responded to PD-1 blockade. Given that BRAF and PTPN11 promote MAPK/ERK signaling, we investigated whether activation of this pathway is associated with response to PD-1 inhibitors in rG...

Background Veledimex (VDX)-regulatable interleukin-12 (IL-12) gene therapy in recurrent glioblastoma (rGBM) was reported to show tumor infiltration of CD8 + T cells, encouraging survival, but also up-regulation of immune checkpoint signaling, providing the rationale for a combination trial with immune checkpoint inhibition. Methods An open-label,...

WT2725 is a Wilms’ tumor gene 1 (WT1)-derived-oligopeptide vaccine designed to induce WT1-specific cytotoxic T-lymphocytes against WT1 ⁺ tumors in human leukocyte antigen (HLA)-A*0201 ⁺ and/or HLA-A*0206 ⁺ patients. Here, we report the results of a phase I study of WT2725. In this phase I, open-label, dose-escalation and expansion two-part study, t...

Wild-type IDH glioblastoma (wtGBM) represents ≥90% of human GBM patient diagnoses with a median age of onset at 68-70 years of age. We previously found a decline of GBM patient survival with progressive age and that subjects ≥65 years of age had the poorest prognosis. We also showed an age-dependent enhancement of immune suppression in the brain th...

Preclinical studies indicate that up-regulation of carbonic anhydrase (CA) by temozolomide (TMZ), via a mechanism requiring the proto-oncogene BCL-3, promotes resistance to therapy in glioblastoma (GBM) cells. Moreover, the CA inhibitor, acetazolamide (ACZ), sensitizes patient-derived GBM cells and xenografts to TMZ. These findings led to the curre...

INTRODUCTION We previously determined that advanced age plays a negative role in the survival outcome of human recurrent glioblastoma (GBM) patients treated with immune checkpoint blockade. Here we investigate the immunologic “signature” of younger patients who are < 65 years of age and older adult GBM patients who are ≥ 65 years of age that underg...

BACKGROUND IDHwt glioblastoma with unmethylated MGMT gene promoter carries a poor prognosis. Preclinical studies have shown that combination of radiotherapy and dual immunotherapy with nivolumab and IDO inhibition significantly prolongs survival of mice with an orthotopic glioblastoma [Ladomersky, et al. CCR 2018;24(11):2559-2573]. In a clinical tr...