Mrugała, Maciej M.

Abstract INTRODUCTION Leptomeningeal carcinomatosis (LC) is an end-stage sequela of metastatic cancer that commonly leads to severe neurological symptoms due to hydrocephalus and commonly treated with surgery or radiation. As these procedures are invasive and have associated risks, chemotherapy could be a great alternative. We report a case of a hydrocephalus related to LC in a patient with Stage IV breast cancer that resolved after the administration of HD-MTX and intrathecal cytarabine. CASE A 64-year-old right-handed woman with Stage IV ER positive, PR positive, HER2 negative invasive lobular carcinoma of the left breast on chemotherapy with palbociclib and alpelisib who presented with mild occipital headaches, diplopia and imbalance. Imaging revealed an extensive abnormal leptomeningeal enhancement withing the posterior fossa compatible with leptomeningeal carcinomatosis. CSF cytology was consistent with metastatic adenocarcinoma. Liquid biopsy detected circulating tumor cells. During the admission for the cycle 1 of systemic chemotherapy with HD-MTX and intrathecal cytarabine, neurological status deteriorated as she became stuporous due to the newly developed moderate obstructive and communicating hydrocephalus. Surgical innervation was considered but given her response to serial Ommaya taps and dexamethasone, we proceeded with observation. Symptomatic improvement was noted within few days and confirmed on imaging showing the resolution of previously seen hydrocephalus. DISCUSSION This case highlights the role of non-invasive combination of systemic and intrathecal chemotherapy in patients with LC-related hydrocephalus aimed to preserve patient’s quality of life. No relevant disclosures.

Abstract Background Advanced age is a major risk factor for the development of many diseases including those affecting the central nervous system. Wild-type isocitrate dehydrogenase glioblastoma (IDHwt GBM) is the most common primary malignant brain cancer and accounts for ≥90% of all adult GBM diagnoses. Patients with IDHwt GBM have a median age of diagnosis at 68–70 years of age, and increasing age is associated with an increasingly worse prognosis for patients with this type of GBM. Methods The Surveillance, Epidemiology, and End Results, The Cancer Genome Atlas, and the Chinese Glioma Genome Atlas databases were analyzed for mortality indices. Meta-analysis of 80 clinical trials was evaluated for log hazard ratio for aging to tumor survivorship. Results Despite significant advances in the understanding of intratumoral genetic alterations, molecular characteristics of tumor microenvironments, and relationships between tumor molecular characteristics and the use of targeted therapeutics, life expectancy for older adults with GBM has yet to improve. Conclusions Based upon the results of our analysis, we propose that age-dependent factors that are yet to be fully elucidated, contribute to IDHwt GBM patient outcomes.

Background: High-dose chemotherapy followed by autologous stem cell transplantation (HD-ASCT) is a promising alternative to whole brain radiation therapy (WBRT) in the treatment of primary central nervous system lymphoma (PCNSL). The objective of this study was to critically assess current evidence supporting the use of HD-ASCT as first-line consolidative therapy in PCNSL. Methods: The objective was addressed through the development of a critically appraised topic that included a clinical scenario, structured question, literature search strategy, critical appraisal, assessment of results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and a content expert in the field of neuro-oncology. Results: A recent, open-label, noncomparative randomized phase II trial was selected for critical appraisal. This trial evaluated the efficacy and toxicity of consolidative therapy with HD-ASCT and WBRT in PCNSL in 2 separate treatment arms. A total of 140 patients with newly diagnosed PCNSL between the ages of 18 and 60 years were included. The primary endpoint of 2-year progression-free survival was met in 63% of patients in the WBRT arm and 87% in the HD-ASCT arm. Notably, an overall improvement in neurocognitive scores was observed following HD-ASCT, while WBRT was associated with worsened cognitive outcomes. Conclusions: In young patients with newly diagnosed PCNSL, consolidative therapy with HD-ASCT appears to be associated with less neurocognitive toxicity and may be more effective than WBRT at preventing relapses, however, at the cost of a higher treatment-related mortality.

AbstractBackgroundIt remains unknown how the COVID-19 pandemic has changed neuro-oncology clinical practice, training, and research efforts.MethodsWe performed an international survey of practitioners, scientists, and trainees from 21 neuro-oncology organizations across 6 continents, April 24–May 17, 2020. We assessed clinical practice and research environments, institutional preparedness and support, and perceived impact on patients.ResultsOf 582 respondents, 258 (45%) were US-based and 314 (55%) international. Ninety-four percent of participants reported changes in their clinical practice. Ninety-five percent of respondents converted at least some practice to telemedicine. Ten percent of practitioners felt the need to see patients in person, specifically because of billing concerns and pressure from their institutions. Sixty-seven percent of practitioners suspended enrollment for at least one clinical trial, including 62% suspending phase III trial enrollments. More than 50% believed neuro-oncology patients were at increased risk for COVID-19. Seventy-one percent of clinicians feared for their own personal safety or that of their families, specifically because of their clinical duties; 20% had inadequate personal protective equipment. While 69% reported increased stress, 44% received no psychosocial support from their institutions. Thirty-seven percent had salary reductions and 63% of researchers temporarily closed their laboratories. However, the pandemic created positive changes in perceived patient satisfaction, communication quality, and technology use to deliver care and mediate interactions with other practitioners.ConclusionsThe pandemic has changed treatment schedules and limited investigational treatment options. Institutional lack of support created clinician and researcher anxiety. Communication with patients was satisfactory. We make recommendations to guide clinical and scientific infrastructure moving forward and address the personal challenges of providers and researchers.

AbstractBackgroundMolecular testing (MT) is utilized in neuro-oncology with increasing frequency. The aim of this study was to determine clinical practice patterns to acquire this information, interpret and utilize MT for patient care, and identify unmet needs in the practical clinical application of MT.MethodsWe conducted a voluntary online survey of providers within the Society for Neuro-Oncology (SNO) membership database between March and April 2019.ResultsWe received 152 responses out of 2022 SNO members (7.5% of membership). 88.8% of respondents routinely order MT for newly diagnosed gliomas. Of those who do not, testing is preferentially performed in younger patients or those with midline tumors. 82.8% use MT in recurrent gliomas. Other common indications included: metastatic tumors, meningioma, and medulloblastoma. Many providers utilize more than one resource (36.0%), most frequently using in-house (41.8%) over commercially available panels. 78.1% used the results for clinical decision-making, with BRAF, EGFR, ALK, and H3K27 mutations most commonly directing treatment decisions. Approximately, half (48.5%) of respondents have molecular tumor boards at their institutions. Respondents would like to see SNO-endorsed guidelines on MT, organized lists of targeted agents available for specific mutations, a database of targetable mutations and clinical trials, and more educational programs on MT.ConclusionThis survey was marked by several limitations including response rate and interpretation of MT. Among respondents, there is routine use of MT in Neuro-Oncology, however, there remains a need for increased guidance for providers to effectively incorporate the expanding genomic data resulting from MT into daily Neuro-Oncology practice.

Abstract Advanced molecular and pathophysiologic characterization of primary central nervous system lymphoma (PCNSL) has revealed insights into promising targeted therapeutic approaches. Medical imaging plays a fundamental role in PCNSL diagnosis, staging, and response assessment. Institutional imaging variation and inconsistent clinical trial reporting diminishes the reliability and reproducibility of clinical response assessment. In this context, we aimed to: (1) critically review the use of advanced positron emission tomography (PET) and magnetic resonance imaging (MRI) in the setting of PCNSL; (2) provide results from an international survey of clinical sites describing the current practices for routine and advanced imaging, and (3) provide biologically based recommendations from the International PCNSL Collaborative Group (IPCG) on adaptation of standardized imaging practices. The IPCG provides PET and MRI consensus recommendations built upon previous recommendations for standardized brain tumor imaging protocols (BTIP) in primary and metastatic disease. A biologically integrated approach is provided to addresses the unique challenges associated with the imaging assessment of PCNSL. Detailed imaging parameters facilitate the adoption of these recommendations by researchers and clinicians. To enhance clinical feasibility, we have developed both “ideal” and “minimum standard” protocols at 3T and 1.5T MR systems that will facilitate widespread adoption.

Abstract OBJECTIVE Glioblastoma (GBM) is the most common malignant primary brain tumor in adults, with males more commonly affected than females(1.6:1). Despite advancements in treatments, prognosis is dismal with a median overall survival of 15 months. Our aim was to investigate sex as a variable in GBM patient survival after receiving incremental levels of standard-of-care treatment regimens – different extents of surgical resection and different numbers of cycles of adjuvant temozolomide chemotherapy. METHODS Drawing from our extensive multi-institutional brain tumor repository, we investigated GBM subjects with overall survival (OS), extent of resection (EOR), number of temozolomide (TMZ) cycles, and sex data (n=620, males: n=387, females: n=233). Cox proportional hazard ratios were computed to investigate the multivariable predictive value of the patient variables with OS. Patients were then divided into groups based on their sex, EOR (either biopsy, subtotal resection (STR) or gross total resection (GTR)), and TMZ cycles (I: < 6 cycles, II: 7-11 cycles and III: >12 cycles). RESULTS We observed that STR was beneficial for females (HR=0.52; CI=0.33-0.83; p-value=0.013), while for males the benefit was not detected (HR=0.73; CI=0.46-1.15; p-value=0.173) for STR but was detectable for GTR (HR=0.58, CI=0.37-0.90; p-value=0.014). Females receiving 7-11 cycles of TMZ showed a survival benefit (HR=0.52; CI=0.12-0.53; p-value=0.048) while males in the same group did not (HR=0.74; CI=0.46-1.19; p-value=0.21), in comparison to those in group I of TMZ cycles. No sex differences were identified in patients receiving < =6 cycles or >=12 cycles. CONCLUSION Together, our results contribute to the growing literature that sex differences exist in GBM patients, even in response to standard-of-care therapies. This should be accounted for when designing clinical trials for GBM so that we may advance our pursuit to deliver personalized medicine.

Abstract INTRODUCTION Leptomeningeal disease (LMD) is an aggressive, late-stage complication of systemic cancers that maintains a poor prognosis with an average survival of 3-6 months. Ommaya reservoirs (OR) are an accessible alternative to serial lumbar punctures for the delivery of intrathecal chemotherapy in the treatment of LMD. However, widespread use of OR has been limited by reports of complications, limited physicians trained in their use, and the stigma of brain surgery. Here, we assess survival and complication rates for patients who received intrathecal chemotherapy through OR for LMD treatment. METHODS After IRB approval, chart review of patients who received at least one administration of intrathecal chemotherapy through OR for LMD treatment between 2017- 2020 at Mayo Clinic in Phoenix, Arizona was conducted. Charts were reviewed for demographics, treatment type, complications, and outcomes. RESULTS A total of 10 patients were included. The median overall survival from date of first OR injection was 110.5 days (95% CI: 64 – not estimable). The median time to progression from the first injection was 55.5 days (95% CI: 45 – 753). A total of 82 OR injections were conducted for an average of approximately 8 injections per patient. Two patients (20%) experienced mild adverse events – grade 2 or lower by Common Terminology Criteria for Adverse Events with a single injection. The majority of injections involved no adverse events with the overall risk of any complication at 2.4%. None of the patients experienced infection, a commonly reported complication of OR use. CONCLUSIONS Our results support the inclusion of intrathecal chemotherapy via OR into the treatment paradigm in patients with leptomeningeal malignancies. This approach is feasible, safe, and median survival is comparable with data reported in published series. The overall complication rate in patients receiving intrathecal chemotherapy through OR is very low including the risk of infection.

Abstract BACKGROUND ATRT is a rare primary CNS tumor occurring predominantly in children with the peak age of onset at less than 3 years old. Adult presentations are exceedingly rare, associated with poor prognosis and no standard therapies exist. METHODS Case presentation. RESULTS 61 y old woman presented with headaches, sinus pressure, and cognitive decline. She was found to have a pineal tumor causing obstructive hydrocephalus. The patient underwent gross total resection of the tumor with pathology reported as ATRT. Her CNS staging, including CSF, was negative. She subsequently received radiotherapy to the resection bed. There was no consensus on what should be the next step in her therapy given lack of data in adults. Ultimately, we adopted a pediatric regimen and treated the patient with a combination of high-dose chemotherapy with cisplatin, cyclophosphamide, and vincristine followed by autologous stem cell transplantation (ASCT). This regimen called for up to 4 cycles of chemotherapy with ASCT and we had collected enough cells to complete 3 cycles. The patient completed 2 cycles of therapy with moderate toxicity. Her CNS imaging remained stable with no evidence of recurrence 14-months from the original diagnosis. CONCLUSIONS ATRT continues to be an exceedingly rare diagnosis in adults. No standard therapies exist and treatment decisions are challenging given lack of data and lack of prospective clinical trials. Pediatric regimens can frequently be adopted for adults although high-dose chemotherapy with ASCT can be challenging. Our case exemplifies the feasibility of treating ATRT in an adult in the most aggressive fashion.

Abstract To assess the impact of the pandemic on the field, we performed an international web-based survey of practitioners, scientists, and trainees from 21 neuro-oncology organizations across 6 continents from April 24 through May 17. Of 582 respondents, 258 (45%) were in the US, and 314 (55%) were international. 80.4% were affiliated with academic institutions. 94% respondents reported changes in clinical practice; 95% reported conversion to telemedicine for at least some appointments. However, almost 10% practitioners felt the need to see patients in person specifically because of billing concerns and perceived institutional pressure. Over 50% believed neuro-oncology patients were at increased risk of contracting COVID-19. 67% practitioners suspended enrollment for at least one clinical trial: 53% suspended phase II and 62% suspended phase III trial enrollment. 71% clinicians feared for their or their families’ safety, specifically because of their clinical duties. 20% percent said they did not have enough PPE to work safely; about the same percentage were unhappy with their institutions’ response to the pandemic. 43% believed the pandemic would negatively affect their academic career, and 52% fellowship program directors were worried about losing funding for their training programs. While 69% respondents reported increased stress, 44% were offered no psychosocial support. 37% had their salary reduced. 36% researchers had to temporarily close their laboratories. In contrast, the pandemic created positive changes in perceived patient and family satisfaction, quality of communication, and use of technology to deliver care and interactions with other practitioners. CONCLUSIONS: The pandemic has altered standard treatment schedules and limited investigational treatment options for patients. In some cases, clinicians felt institutional pressure to continue conducting billable in-person visits when telemedicine visits would have sufficed. A lack of institutional support created anxiety among clinicians and researchers. We make specific recommendations to guide clinical and scientific infrastructure moving forward.