Prolonged complete response to adjuvant tepotinib in a patient with newly diagnosed disseminated glioblastoma harboring mesenchymal-epithelial transition fusion.

The prognosis of patients with glioblastoma (GBM) remains poor despite current treatments. Targeted therapy in GBM has been the subject of intense investigation but has not been successful in clinical trials. The reasons for the failure of targeted therapy in GBM are multifold and include a lack of patient selection in trials, the failure to identify driver mutations, and poor blood-brain barrier penetration of investigational drugs. Here, we describe a case of a durable complete response in a newly diagnosed patient with GBM with leptomeningeal dissemination and PTPRZ1-MET fusion who was treated with tepotinib, a brain-penetrant MET inhibitor. This case of successful targeted therapy in a patient with GBM demonstrates that early molecular testing, identification of driver molecular alterations, and treatment with brain-penetrant small molecule inhibitors have the potential to change the outcome in select patients with GBM.

Collision tumor: Multinodular and vacuolating neuronal tumor with isocitrate dehydrogenase-mutant diffuse astrocytoma.

Herein, we report a case of a collision tumor involving a multinodular and vacuolating neuronal tumor (MVNT) and a diffuse astrocytoma. A collision tumor between these two entities has not previously been reported. The patient is a 35-year-old woman who presented with new-onset hearing loss and ringing in her right ear. Magnetic resonance imaging identified a non-enhancing mass involving the gray matter and subcortical white matter of the left middle frontal gyrus. Additionally, tiny clustered nodules were noted along the underlying subcortical ribbon and superficial subcortical white matter of the left superior frontal gyrus. The patient underwent a left frontal craniotomy and complete resection of the mass. Histologic examination of the resected specimen demonstrated a collision tumor consisting of a diffuse astrocytoma (isocitrate dehydrogenase [IDH] mutant, central nervous system [CNS] World Health Organization [WHO] grade 2) and an MVNT, with the latter demonstrating characteristic morphologic and immunohistochemical features.

Characterization of patients with brain metastases referred to palliative care.

PURPOSE: In this study, we aimed to assess the clinical characteristics, reasons for referral, and outcomes of patients with brain metastases (BM) referred to the supportive care center. METHODS: Equal numbers of patients with melanoma, breast cancer, and lung cancer with (N = 90) and without (N = 90) BM were retrospectively identified from the supportive care database for study. Descriptive statistics were used to analyze demographic, disease, and clinical data. Kaplan Meier method was used to evaluate survival outcomes. RESULTS: While physical symptom management was the most common reason for referral to supportive care for both patients with and without BM, patients with BM had significantly lower pain scores on ESAS at time of referral (p = 0.002). They had greater interaction with acute care in the last weeks of life, with higher rates of ICU admission, emergency room visits, and hospitalizations after initial supportive care (SC) visit. The median survival time from referral to Supportive Care Center (SCC) was 0.90 years (95% CI 0.73, 1.40) for the brain metastasis group and 1.29 years (95% CI 0.91, 2.29) for the group without BM. CONCLUSIONS: Patients with BM have shorter survival and greater interaction with acute care in the last weeks of life. This population also has distinct symptom burdens from patients without BM. Strategies to optimize integration of SC for patients with BM warrant ongoing study.

Association of Emotional Exhaustion With Career Burnout Among Early-Career Medical Oncologists: A Single-Institution Study.

PURPOSE: Burnout is a psychological occupational syndrome defined by the Maslach Burnout Inventory (MBI) as emotional exhaustion, depersonalization, and a low sense of personal accomplishment. We sought to characterize the prevalence of burnout among early-career medical oncologists at The University of Texas MD Anderson Cancer Center (MDACC). METHODS: For this institutional review board-approved study, an electronic survey was developed for Assistant Professors in the MDACC Division of Cancer Medicine. All participants were involved directly in patient care. Our survey included questions assessing self-reported burnout, nine questions validated in the abbreviated MBI, and 31 questions to assess potential contributors to burnout. Each question was scaled 1-5, with higher scores associated with higher burnout. Descriptive statistics were used to estimate the prevalence of burnout, and logistic regression analyses were performed to identify contributing factors. RESULTS: Among 86 Assistant Professors, 56 (65%) responded to the survey. The mean duration on faculty was 3.1 years. The mean clinical effort was 67% (range, 19-95). Fifty-four percent of respondents self-reported symptoms of burnout including 21% indicating severe burnout. Using the MBI, sentiments of being emotionally drained (54%), fatigued facing another day on the job (45%), and becoming more callous (30%) were especially notable. Twenty-five percent of respondents exhibited severe emotional exhaustion, which was more prevalent (P < .0001) than depersonalization (6%) or lack of personal accomplishment (17%). CONCLUSION: Burnout exists with high prevalence among early-career medical oncologists, with emotional exhaustion being the most common manifestation of burnout. Interventions focusing on reducing emotional exhaustion are needed to reduce burnout among early-career medical oncologists.

Concurrent intrathecal and intravenous nivolumab in leptomeningeal disease: phase 1 trial interim results.

There is a critical need for effective treatments for leptomeningeal disease (LMD). Here, we report the interim analysis results of an ongoing single-arm, first-in-human phase 1/1b study of concurrent intrathecal (IT) and intravenous (IV) nivolumab in patients with melanoma and LMD. The primary endpoints are determination of safety and the recommended IT nivolumab dose. The secondary endpoint is overall survival (OS). Patients are treated with IT nivolumab alone in cycle 1 and IV nivolumab is included in subsequent cycles. We treated 25 patients with metastatic melanoma using 5, 10, 20 and 50 mg of IT nivolumab. There were no dose-limiting toxicities at any dose level. The recommended IT dose of nivolumab is 50 mg (with IV nivolumab 240 mg) every 2 weeks. Median OS was 4.9 months, with 44% and 26% OS rates at 26 and 52 weeks, respectively. These initial results suggest that concurrent IT and IV nivolumab is safe and feasible with potential efficacy in patients with melanoma LMD, including in patients who had previously received anti-PD1 therapy. Accrual to the study continues, including in patients with lung cancer. ClinicalTrials.gov registration: NCT03025256 .

Efficacy of laser interstitial thermal therapy (LITT) for newly diagnosed and recurrent IDH wild-type glioblastoma.

Background: Treatment options for unresectable new and recurrent glioblastoma remain limited. Laser ablation has demonstrated safety as a surgical approach to treating primary brain tumors. The LAANTERN prospective multicenter registry (NCT02392078) data were analyzed to determine clinical outcomes for patients with new and recurrent IDH wild-type glioblastoma. Methods: Demographics, intraprocedural data, adverse events, KPS, health economics, and survival data were prospectively collected and then analyzed on IDH wild-type newly diagnosed and recurrent glioblastoma patients who were treated with laser ablation at 14 US centers between January 2016 and May 2019. Data were monitored for accuracy. Statistical analysis included individual variable summaries, multivariable differences in survival, and median survival numbers. Results: A total of 29 new and 60 recurrent IDH wild-type WHO grade 4 glioblastoma patients were treated. Positive MGMT promoter methylation status was present in 5/29 of new and 23/60 of recurrent patients. Median physician-estimated extent of ablation was 91%-99%. Median overall survival (OS) was 9.73 months (95% confidence interval: 5.16, 15.91) for newly diagnosed patients and median post-procedure survival was 8.97 months (6.94, 12.36) for recurrent patients. Median OS for newly diagnosed patients receiving post-LITT chemo/radiation was 16.14 months (6.11, not reached). Factors associated with improved survival were MGMT promoter methylation, adjuvant chemotherapy within 12 weeks, and tumor volume <3 cc. Conclusions: Laser ablation is a viable option for patients with new and recurrent glioblastoma. Median OS for IDH wild-type newly diagnosed glioblastoma is comparable to outcomes observed in other tumor resection studies when those patients undergo radiation and chemotherapy following LITT.

Bihemispheric Cortical Infarcts in an Adult Secondary to Escherichia coli K1 Meningitis.

Cerebral ischemia is a known complication of meningitis. Most Escherichia coli meningitis-induced infarcts have been reported in the neonatal and pediatric population. To the best of our knowledge, there have been no previous reports describing bilateral cortical infarcts in an adult secondary to a K1 strain of E. coli meningitis, and herein we report a case in a 25-year-old female. The challenge in treating this patient was determining the duration of systemic antibiotic treatment and whether or not to use steroids. This study demonstrates the necessity of early diagnosis and treatment of E. coli meningitis to prevent neurological complications, including stroke.

The Role of Immune Checkpoint Inhibitors in Leptomeningeal Disease: A Systematic Review.

BACKGROUND/AIM: Leptomeningeal disease (LMD) is a debilitating complication of advanced malignancies. Immune-checkpoint inhibitors (ICIs) may alter disease course. We analyzed the role and toxicity of ICIs in LMD. MATERIALS AND METHODS: We systematically reviewed the literature reporting on outcome data of patients with LMD treated with ICIs. RESULTS: We included 14 studies encompassing 61 patients. Lung-cancer (44.3%), breast-cancer (27.9%), and melanoma (23.0%) were the most frequent primary tumors. Median duration of ICI-treatment was 7-months (range=0.5-58.0): pembrolizumab (49.2%), nivolumab (32.8%), ipilimumab (18.0%). Radiological responses included complete response (33.3%), partial response (12.5%), stable disease (33.3%), progressive disease (20.8%). Twenty-two patients developed ICI-related adverse-events, mild (100%) and/or severe (15.6%). Median progression-free and overall survival were 5.1 and 6.3 months, and 12-month survival was 32.1%. Survival correlated with ICI agents (p=0.042), but not with primary tumors (p=0.144). Patients receiving concurrent steroids showed worse survival (p=0.040). CONCLUSION: ICI therapy is well-tolerated in patients with LMD, but concurrent steroids may worsen survival.

Aggressiveness of care at end of life in patients with high-grade glioma.

BACKGROUND: Patients with high-grade glioma (HGG) face unique challenges toward the end of life (EoL), given their aggressive trajectory and neurologic deterioration. Aggressiveness of medical care at EoL has been identified as an important quality metric for oncology patients. At this time, limited data exist around the nature of EoL care of patients with HGG. METHODS: Patients with HGG and palliative care (PC) referral seen between 2010 and 2015 were identified (N = 80). Of these, N = 52 met inclusion criteria. Random selections of patients with (1) HGG not referred to PC (n = 80), and (2) non-CNS cancers with PC referral (n = 80) were identified for comparison. A composite score of aggressiveness of medical care at EoL was calculated for each patient from predetermined variables. A time of eligibility for PC was defined for each patient when predetermined criteria based on symptom burden, functional status, and prognosis were met. RESULTS: Among the patients analyzed with HGG referred to PC, 59.6% (N = 31) were referred as inpatients, and 53.8% (N = 28) were referred within the last 12 weeks of life. Patients with HGG had similar aggressiveness of care at EoL regardless of PC referral, and HGG patients had less aggressive care at EoL than patients with non-CNS cancers (p = 0.007). Care was more aggressive at EoL in HGG patients who received late versus early PC referrals (p = 0.012). Motor weakness at time of eligibility (OR = 2.55, p = 0.002) and more disease progressions (OR = 1.25, p = 0.043) were associated with less aggressive care at EoL. CONCLUSIONS: Early clinical- and disease-related features predict the aggressiveness of medical care at EoL in patients with HGG. Formal PC consultation is used infrequently and suboptimally in patients with HGG. Our data suggest that the role of PC in improving EoL outcomes in HGG warrants further evaluation.

Associations of meaning of illness with psychosocial, clinical, and immunological characteristics in patients with Leptomeningeal metastasis.

Background: Leptomeningeal metastasis (LM) creates symptoms related to both the disease within the nervous system and treatment toxicities. Biologic processes, such as inflammation and behavioral processes, such as the meaning ascribed to illness (Meaning of Illness: MoI), can impact physical and psychosocial symptoms. The aim of this study was to understand the relationships among MoI, physical and psychosocial symptoms, and inflammation in patients with LM. Methods: Thirty enrolled participants completed the MD Anderson Symptom Inventory-Brain Tumor with spine experimental symptoms added. Meaning of illness, quality of life (QoL), and depression were captured by validated instruments. Interleukin (IL)-6 and tumor necrosis factor (TNF)-α in serum and cerebrospinal fluid (CSF) were measured by ELISA. Correlations were performed to assess relationships among the variables. Results: Participants were primarily white (73%), female (63%). Median age was 54 years (34-83). Breast (50%) and lung (20%) were most common diagnosis. Higher MoI scores were associated with better QoL (p < .01) and fewer depressive symptoms (p < .01). All CSF samples contained IL-6 and all but one sample had elevated IL-6. Higher levels of IL-6 in the CSF were associated with greater symptom burden (p < .01) and interference of symptoms in daily life (p = .02) but not MoI. Conclusions: MoI was associated with QoL and depression. High levels of IL-6 in the CSF were associated with more severe symptoms. This study provides the groundwork for future research, including interventional studies to improve QoL in patients with LM.

Targeting the Tumor Microenvironment in Brain Metastasis.

Dynamic interplay between cancer cells and the surrounding microenvironment is a feature of the metastatic process. Successful metastatic brain colonization requires complex mechanisms that ultimately allow tumor cells to adapt to the unique microenvironment of the central nervous system, evade immune destruction, survive, and grow. Accumulating evidence suggests that components of the brain tumor microenvironment (TME) play a vital role in the metastatic cascade. In this review, the authors summarize the contribution of the TME to the development and progression of brain metastasis. They also highlight opportunities for TME-directed targeted therapy.

Glioblastoma-mediated Immune Dysfunction Limits CMV-specific T Cells and Therapeutic Responses: Results from a Phase I/II Trial.

PURPOSE: Cytomegalovirus (CMV) antigens occur in glioblastoma but not in normal brains, making them desirable immunologic targets. PATIENTS AND METHODS: Highly functional autologous polyclonal CMV pp65-specific T cells from patients with glioblastoma were numerically expanded under good manufacturing practice compliant conditions and administered after 3 weeks of lymphodepleting dose-dense temozolomide (100 mg/m2) treatment. The phase I component used a 3+3 design, ascending through four dose levels (5 × 106-1 × 108 cells). Treatment occurred every 6 weeks for four cycles. In vivo persistence and effector function of CMV-specific T cells was determined by dextramer staining and multiparameter flow cytometry in serially sampled peripheral blood and in the tumor microenvironment. RESULTS: We screened 65 patients; 41 were seropositive for CMV; 25 underwent leukapheresis; and 20 completed ≥1 cycle. No dose-limiting toxicities were observed. Radiographic response was complete in 1 patient, partial in 2. Median progression-free survival (PFS) time was 1.3 months [95% confidence interval (CI), 0-8.3 months]; 6-month PFS was 19% (95% CI, 7%-52%); and median overall survival time was 12 months (95% CI, 6 months to not reached). Repeated infusions of CMV-T cells paralleled significant increases in circulating CMV+ CD8+ T cells, but cytokine production showing effector activity was suppressed, especially from T cells obtained directly from glioblastomas. CONCLUSIONS: Adoptive infusion of CMV-specific T cells after lymphodepletion with dose-dense temozolomide was well tolerated. But apparently CMV seropositivity does not guarantee tumor susceptibility to CMV-specific T cells, suggesting heterogeneity in CMV antigen expression. Moreover, effector function of these T cells was attenuated, indicating a requirement for further T-cell modulation to prevent their dysfunction before conducting large-scale clinical studies.

Seizure burden pre- and postresection of low-grade gliomas as a predictor of tumor progression in low-grade gliomas.

BACKGROUND: Low-grade gliomas (LGGs) are slow-growing, infiltrative tumors frequently associated with seizures. Predicting which patients will develop early tumor recurrence based on clinical indicators following initial surgical intervention remains a challenge. Seizure recurrence following surgery may be an early indicator of tumor recurrence, especially in patients presenting with increase in seizure frequency. METHODS: This study analyzed 148 patients meeting inclusion criteria (age >18 years, LGG diagnosis, at least 1 seizure event recorded before and after initial surgical intervention). All patients were treated at the Brain and Spine Center at The University of Texas MD Anderson Cancer Center from January 2000 to March 2013. Seizure frequency in a 6-month period before and after tumor resection was categorized as none, 1, few (2 to 3 seizures) or several (>3 seizures). Immediately postoperative seizures (up to 48 hours from surgery) were not included in the analysis. RESULTS: A total of 116 (78.4%) patients had seizures at initial presentation and most (95%) were started on antiepileptic drugs (AEDs). We found 2 clinical variables with a significant impact on progression-free survival (PFS): Higher seizure frequency during the 6-month postoperative period and seizure frequency increase between the 6-month pre- and the 6-month postoperative periods were both correlated to higher risk of early tumor recurrence (P = .007 and P = .004, respectively). CONCLUSION: Seizure frequency following surgical resection of LGGs and the seizure frequency change between the 6-month preoperative and postoperative periods may serve as clinical predictors of early tumor recurrence in patients with LGGs who are also afflicted by seizures.

Clinical trial participation of patients with glioblastoma at The University of Texas MD Anderson Cancer Center.

BACKGROUND: It is estimated only 8-11% of patients with glioblastoma (GBM) enrol in clinical trials, limiting treatment development. We analysed the clinical and demographic features of patients with GBM enroled in clinical trials at the University of Texas MD Anderson Cancer Center (MDACC). METHODS: We reviewed the records of adult patients treated for primary GBM between 2007 and 2012 at the MDACC. A total of 755 patients were identified: 133 were deemed non-eligible, 111 were deemed trial eligible but received standard care and 511 participated in a clinical trial (311 for newly diagnosed glioblastoma [nGBM] and 200 for recurrent glioblastoma [rGBM]). Population characteristics were analysed using descriptive statistics, and survival end-points were evaluated with the Kaplan-Meier method. RESULTS: The median age of clinical trial participants and trial eligible patients was 53.2 years (standard deviation 12.1). Most patients (49.4%) were enroled in a clinical trial protocol for nGBM. The majority of nGBM trial participants were male patients (65.1%), white (86.3%), married (84.4%) and in state (59.9%). Employment status, education, symptoms, tumour location, performance status, extent of resection and treatment facility differed between nGBM trial participants and non-participants. Patients who were eligible but did not enrol tended to be older, have worse performance status and live farther away from the MDACC. CONCLUSION: Numerous disease and demographic barriers exist in trial enrolment in patients with GBM. This study highlights some of these obstacles, which require attention to improve patient enrolment to clinical trials. Patient and physician engagement in novel therapeutic strategies is essential to improving outcomes in this disease.

Predictors of survival in metastatic melanoma patients with leptomeningeal disease (LMD).

PURPOSE: Although the survival of most melanoma patients diagnosed with leptomeningeal disease (LMD) is short, some patients can have better outcomes and prolonged survival. A large retrospective cohort of patients was analyzed to identify features associated with survival with LMD from melanoma. METHODS: Clinical characteristics, treatments and survival were collected for melanoma patients diagnosed with LMD from 1999 to 2015. The Kaplan-Meier method was used to estimate overall survival (OS) and Cox proportional hazards regression was used to test statistical significance of associations with survival. Multivariate analysis was performed using Cox proportional regression modeling. RESULTS: 178 melanoma patients with LMD were identified. Median age at LMD diagnosis was 51 years. Most (n = 153) patients received at least one treatment for LMD, including radiation (n = 98), chemotherapy (n = 89), targeted therapy (n = 60), immunotherapy (n = 12), or intrathecal (IT) therapy (n = 64). Median OS from LMD diagnosis was 3.5 months. One-, two-, and five-year OS rates were 22%, 14%, and 9%, respectively. Factors significantly associated with OS on multivariate analysis included Eastern Cooperative Oncology Group [ECOG] performance status > 0 (HR 2.1, P < 0.0001); neurological symptoms (HR 1.6, P < 0.0001); absent systemic disease (HR 0.4, P < 0.0001); and LMD treatment (HR 0.4, P = 0.0024), targeted therapy (HR 0.6, P = 0.0060), or IT therapy (HR 0.5, P = 0.0019). CONCLUSION: Despite their overall poor prognosis a subset of melanoma patients with LMD achieve longer survival. The factors associated with outcomes may be used to guide patient management and to inform the design of future clinical trials for this population.

Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.

Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.

Phase 1 lead-in to a phase 2 factorial study of temozolomide plus memantine, mefloquine, and metformin as postradiation adjuvant therapy for newly diagnosed glioblastoma.

BACKGROUND: Repurposed memantine, mefloquine, and metformin have putative anticancer activity. The objective of this phase 1 study was to determine the maximum tolerated doses (MTDs) of combinations of these agents with temozolomide (TMZ). METHODS: Adults with newly diagnosed glioblastoma who completed chemoradiation were eligible. The patients were assigned to receive doublet, triplet, or quadruplet therapy with TMZ combined with mefloquine, memantine, and/or metformin. Dose-limiting toxicities (DLTs) were determined, using a 3 + 3 study design. RESULTS: Of 85 enrolled patients, 4 did not complete cycle 1 (the DLT observation period) for nontoxicity reasons, and 81 were evaluable for DLT. The MTDs for doublet therapy were memantine 20 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 850 mg twice daily. For triplet therapy, the MTDs were memantine 10 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 850 mg twice daily. For quadruplet therapy, the MTDs were memantine 10 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 500 mg twice daily. DLTs included dizziness (memantine) and gastrointestinal effects (metformin). Lymphopenia was the most common adverse event (66%). From study entry, the median survival was 21 months, and the 2-year survival rate was 43%. CONCLUSIONS: Memantine, mefloquine, and metformin can be combined safely with TMZ in patients with newly diagnosed glioblastoma.

Profiles of brain metastases: Prioritization of therapeutic targets.

We sought to compare the tumor profiles of brain metastases from common cancers with those of primary tumors and extracranial metastases in order to identify potential targets and prioritize rational treatment strategies. Tumor samples were collected from both the primary and metastatic sites of nonsmall cell lung cancer, breast cancer and melanoma from patients in locations worldwide, and these were submitted to Caris Life Sciences for tumor multiplatform analysis, including gene sequencing (Sanger and next-generation sequencing with a targeted 47-gene panel), protein expression (assayed by immunohistochemistry) and gene amplification (assayed by in situ hybridization). The data analysis considered differential protein expression, gene amplification and mutations among brain metastases, extracranial metastases and primary tumors. The analyzed population included: 16,999 unmatched primary tumor and/or metastasis samples: 8,178 nonsmall cell lung cancers (5,098 primaries; 2,787 systemic metastases; 293 brain metastases), 7,064 breast cancers (3,496 primaries; 3,469 systemic metastases; 99 brain metastases) and 1,757 melanomas (660 primaries; 996 systemic metastases; 101 brain metastases). TOP2A expression was increased in brain metastases from all 3 cancers, and brain metastases overexpressed multiple proteins clustering around functions critical to DNA synthesis and repair and implicated in chemotherapy resistance, including RRM1, TS, ERCC1 and TOPO1. cMET was overexpressed in melanoma brain metastases relative to primary skin specimens. Brain metastasis patients may particularly benefit from therapeutic targeting of enzymes associated with DNA synthesis, replication and/or repair.