Iatrogenic immunodeficiency-associated lymphoproliferative disorders of the central nervous system: a treatment paradox.

Background: Primary central nervous system lymphomas (PCNSLs) have historically had dismal survival rates until the advent of high-dose methotrexate (HD-MTX) based chemotherapy regimens. With increasing prevalence of autoimmune disease and development of new immunosuppressants, a genetically distinct entity known as iatrogenic immunodeficiency-associated lymphoproliferative disorder (LPD) has emerged. Many of these cases arise following methotrexate use, challenging feasibility of standard HD-MTX regimens. The aim of this study was to further characterize this disorder and determine the optimal management strategy. Methods: We describe a case of a 76-year-old female with iatrogenic immunodeficiency-associated PCNSL successfully treated with surgical resection followed by an antiviral and rituximab based regimen. We then performed a systematic literature review and identified 58 cases of non-transplant iatrogenic immunodeficiency-associated LPD involving the CNS. We used a linear probability statistical model to determine correlations with outcome. Results: Natalizumab was associated with EBV negative tumors (P = .023), and EBV positive tumors were associated with improved outcomes (P = .016). Surgical resection was associated with improved outcomes (P = .032), although limited by potential confounding effect. Antiviral treatment (P = .095), rituximab (P = .111), and stem cell transplant (SCT) (P = .198) showed a trend toward improved outcomes. The remaining treatments including methotrexate showed no improvement. Conclusion: We propose that surgical resection, rituximab, and antiviral treatment may be considered as an alternative to standard HD-MTX based regimens when managing iatrogenic immunodeficiency-associated LPD of the CNS. Further study through prospective cohort studies or randomized clinical trials is warranted.

Larotrectinib in NTRK Fusion-Positive High-Grade Glioneuronal Tumor: A Case Report.

Glioneuronal tumors are rare central nervous system tumors with heterogeneous histological and molecular features. While the majority are low grade, a small percentage can behave aggressively. Due to the rarity of these tumors, there is no consensus on how to treat high-grade glioneuronal tumors, and they are often managed similarly to glial tumors. With the advent of molecular profiling, management decisions are increasingly determined by molecular alterations in the tumor rather than the tumor type, which can be a useful approach for tumor types that do not have robust supportive clinical trial data due to low prevalence. We present a case of an 18-year-old patient with a high-grade glioneuronal neoplasm initially treated with craniospinal irradiation, vincristine, and cyclophosphamide. He presented eight years later with a recurrent tumor and was found to be positive for MEF2D-NTRK1 fusion. He was treated with surgical resection and postoperative intensity-modulated radiation therapy (IMRT; 55.8 Gy) with concurrent temozolomide, followed by the NTRK inhibitor larotrectinib. He achieved a radiographic response, with a decrease in residual enhancement and radiographic improvement over the course of treatment. He remained in clinical and radiographic remission for six months. This demonstrates the successful treatment of a high-grade glioneuronal NTRK fusion-positive tumor with larotrectinib, which has only been previously reported once in the literature.

A Single-Center Experience of Dopamine Antagonist ONC201 for Recurrent Histone H3 Lysine 27-to-Methionine (H3K27M)-Mutant Glioblastoma in Adults.

This study aimed to report a single-center experience of three adult subjects receiving ONC201 as part of the ONC018-expanded access clinical trial (NCT03134131). ONC201 is an oral investigational antagonist against the D2 dopamine receptor that has shown encouraging results for malignant gliomas harboring the histone H3 lysine 27-to-methionine (H3K27M) mutation in the H3 histone complex. Responses have been reported in pediatric subjects with such tumors. An expanded access clinical trial (ONC018) was available to eligible patients allowing them access to this agent pending FDA review. Our site enrolled three subjects in the ONC018 trial. We present the demographic, clinical, and molecular characteristics of our enrolled subjects. We report the tolerability, adverse events, and outcome measures including survival, Karnofsky Performance Status (KPS), and quality-of-life measured by the MD Anderson symptom inventory instrument (MDASI). Three subjects were registered at our site onto ONC018 with the age range of 18-44 years, two of three were female, residing in Norway, India, and the United States. Tumor locations were brainstem, corpus callosum, and thalamus. Pathology includes glioblastoma (3/3), methylguanine-DNA methyltransferase (MGMT) methylated (2/3), isocitrate dehydrogenase 1 (IDH1) mutant (0/3), epidermal growth factor receptor (EGFR) amplification (0/3), and α thalassemia/mental retardation syndrome X­linked (ATRX) (3/3). Median change from baseline KPS ≤20% decrease; MDASI of 2/3 experienced decrease from baseline (median 6%), consistent with improved quality of life. No clinically significant laboratory abnormalities were found. All adverse events were grades I-II. We found that the study drug was quite tolerable. No serious adverse events nor radiographic responses were seen. Analyses of the larger study cohort and additional randomized controlled trials are necessary to provide insight into the safety and efficacy.

The Emergence of Virtual Tumor Boards in Neuro-Oncology: Opportunities and Challenges.

Background Virtual tumor board (VTB) platforms are an important aspect of cancer management. They enable easier access to a multidisciplinary team of experts. To deliver high-quality cancer care, it is necessary to coordinate numerous therapies and providers, share technical knowledge, and maintain open lines of communication among all professionals involved. The VTB is an essential tool in the diagnosis and treatment of brain cancer. For patients with glioma and brain metastases, multidisciplinary tumor board guidelines should guide diagnosis and therapy throughout the course of the illness. VTBs are an emerging resource across various cancer care networks in the United States. Methodology We performed a systematic search of all VTBs incorporating a platform designed for this specific role. We reviewed the records of the Genomet VTB, the Medical University of South Carolina (MUSC) VTB, and Xcures VTB. Summary data examined included the year of launch, demographics, characteristics of cases, average response time, advantages, and how they handle protected health information. Results Overall, 30% of VTBs examined were launched in 2017. All had a Health Insurance Portability and Accountability Act-compliant online environment. On a review of Xcures records, the median age of the female patients was 57 years and the median age of the male patients was 55 years. The data showed that 44% (4.4 out of every 10 patients) with a confirmed treatment chose the VTB integrated option. Overall, 76% of patients in the Xcures registry had primary central nervous system tumors, with at least 556 patients in the tumor registry which included 46% glioblastoma cases (96% primary, 4% secondary). In the MUSC VTB project, 112 thoracic tumor cases and nine neuro-oncology cases were reviewed. The tumor board met weekly, and the average response time was within 24 hours of case review and presentation. The Genomet VTB de-identifies all patient information; this is a virtual platform primarily focused on neuro-oncology cases. Cases involved a median of five specialists most commonly neuro-oncologists, neurosurgeons, radiation oncologists, molecular pathologists, and neuroradiologists. The case review revealed an age range of six months to 84 years (mean age = 44.5 years), with 69.6% males and 30.4% females, 43.5% glioblastomas, 8.7% adenocarcinomas, and 8.7% infratentorial tumors. The average response time observed in all cases was ≤24 hours. Conclusions VTBs allow for quicker expert analysis of cases. This has resulted in an accelerated number of cases reviewed with a shortened communication time. More studies are needed to gain additional insights into user engagement metrics.

A Rare Case of Burkitt's Lymphoma Presenting With Features Mimicking Vogt-Koyanagi-Harada Disease.

Here, we report a case of Burkitt's lymphoma in an HIV-positive patient presenting with features suggestive of Vogt-Koyanagi-Harada disease (VKHD), which in retrospect was likely a misdiagnosis. We hope to describe a rare presentation of lymphoma in order to prevent misdiagnosis and promote early recognition. The patient was a 25-year-old male who initially presented with right eye pain and blurry vision. He was found to have bilateral serous retinal detachments and was diagnosed with VKHD and started on prednisone. He stopped taking the prednisone, and his vision worsened. He then developed right eye ptosis, restricted eye movements, nausea, vomiting, headache, dysphagia, tongue deviation, and slurred speech. MRI showed diffuse cranial nerve enhancement. He was found to be positive for HIV and Hepatitis A with CD4 count of 41. Lumbar puncture showed WBC 83 (94% lymphocytes), RBC 1460, glucose 62, and protein 195, with Epstein-Barr virus (EBV) positivity and negative cytology. Gd1a antibody was positive (72). He underwent empiric treatment with IV solumedrol for possible VKHD exacerbation, followed by empiric intravenous immune globulin (IVIG) for possible acute inflammatory demyelinating polyneuropathy (AIDP). He subsequently developed diffuse limb weakness and loss of reflexes, and he was treated with plasma exchange (PLEX). He demonstrated minimal response to treatment. Electromyography (EMG) was unrevealing, and the MRI of the cervical and lumbar spine showed diffuse nerve root thickening and enhancement. He underwent an esophagogastroduodenoscopy (EGD) for continued dysphagia, and the biopsy was positive for an aggressive B-cell lymphoma strongly favoring Burkitt's lymphoma. VKHD is a rare condition diagnosed based on retinal exam findings. Few cases of lymphoma report findings suggestive of VKHD. This is a rare case of lymphoma initially presenting with these retinal findings. Understanding this potential presentation of lymphoma is essential for early diagnosis and treatment and for optimizing patient outcomes.

The need for a central brain tumor registry in Africa: A review of central nervous system tumors in Africa from 1960 to 2017.

BACKGROUND: Central nervous system (CNS) tumors pose a substantial health problem. Although data on specific time periods and regions of Africa have been previously reported, no study has yet to provide a systematic review of CNS tumors for the entire continent of Africa. This study aims to analyze the frequency of CNS tumors in Africa from 1960 to 2017. METHODS: A comprehensive literature search on CNS tumors in Africa was performed using multiple online scientific databases. The following keywords were queried in combination with the phrase "CNS tumors in Africa": incidence, frequency, epidemiology, prevalence, brain, and cancer. A total of 26 articles met the inclusion criteria. Each selected article reported incidence and mortality rates from different regions of Africa in a time period between 1960 and 2017. SPSS21 statistical software was used to analyze the data. RESULTS: Nigeria, Egypt, and Uganda were found to have the most of the cases of CNS tumors in Africa. Males made up 54% of the 5902 cases per 100 000 population. The most common CNS tumors found were astrocytoma (24.70%), meningioma (22.22%), pituitary adenoma (8.4%), medulloblastoma (4.26%), craniopharyngioma (4.07%), and other not specified (25.17%). CONCLUSIONS: Given the large population of Africa, the total reported cases may be underestimated when compared with other continents due to the lack of a central brain tumor registry in Africa. A comprehensive knowledge of CNS tumors in Africa is critical to population-based research and improving the current healthcare system.

Neuro-Oncology Palliative Care Survey of Physicians in Sub-Saharan Africa.

CONTEXT: Early access to palliative care is a critical component of treating patients with advanced cancer, particularly for glioblastoma patients who have low rates of survival despite optimal therapies. Additionally, there are unique considerations for primary brain tumor patients given the need for management of headaches, seizures, and focal neurological deficits. OBJECTIVE: We hoped to determine Sub-Saharan African physicians' level of understanding and skill in providing palliative care, types of palliative care therapies provided, role of cultural beliefs, availability of resources, and challenges faced. METHODS: We conducted a survey of 109 physicians in Sub-Saharan Africa who treat brain tumor patients. RESULTS: Among the participants, 48% felt comfortable in providing palliative care consultations, 52% believed that palliative care is only appropriate when there is irreversible deterioration, 62% expressed having access to palliative care, 49% do not have access to liquid opioid agents, 50% stated that cultural beliefs held by the patient or family prevented them from receiving palliative care, and 23% stated that their own beliefs affected palliative care delivery. Older providers (age > 30) had a clearer understanding of palliative care (P = 0.004), were more comfortable providing consultation (P = 0.052), and were more likely to address mental health (P < 0.001). CONCLUSION: Palliative care delivery to glioblastoma patients in Sub-Saharan Africa is often delayed until late in the disease course. Barriers to adequate palliative care treatment identified in this survey study include lack of training, limited access to liquid opioid agents, and cultural beliefs.

Telemedicine review in neuro-oncology: comparative experiential analysis for Barrow Neurological Institute and Geisinger Health during the 2020 COVID-19 pandemic.

Coronavirus disease 2019 (COVID-19) has grossly affected how we deliver health care and how health care institutions derive value from the care provided. Adapting to new technologies and reimbursement patterns were challenges that had to be met by the institutions while patients struggled with decisions to prioritize concerns and to identify new pathways to care. With the implementation of social distancing practices, telemedicine plays an increasing role in patient care delivery, particularly in the field of neurology. This is of particular concern in our cancer patient population given that these patients are often at increased infectious risk on immunosuppressive therapies and often have mobility limitations. We reviewed telemedicine practices in neurology pre- and post-COVID-19 and evaluated the neuro-oncology clinical practice approaches of 2 large care systems, Barrow Neurological Institute and Geisinger Health. Practice metrics were collected for impact on clinic volumes, institutional recovery techniques, and task force development to address COVID-19 specific issues. Neuro-Oncology divisions reached 67% or more of prepandemic capacity (patient visits and slot utilization) within 3 weeks and returned to 90% or greater capacity within 6 weeks of initial closures due to COVID-19. The 2 health systems rapidly and effectively implemented telehealth practices to recover patient volumes. Although telemedicine will not replace the in-person clinical visit, telemedicine will likely continue to be an integral part of neuro-oncologic care. Telemedicine has potential for expanding access in remote areas and provides a convenient alternative to patients with limited mobility, transportation, or other socioeconomic complexities that otherwise challenge patient visit adherence.

A view of the epidemiologic landscape: how population-based studies can lend novel insights regarding the pathophysiology of glioblastoma.

Glioblastoma is an aggressive disease that is difficult to treat, in large part due to the high level of molecular heterogeneity that limits the utility of targeted therapies. As such, population studies have been essential in characterizing the factors that promote survival. In this review, we summarize the findings in these studies. Demographic trends, molecular markers (IDH mutation, MGMT promoter methylation, TERT promoter mutation, chromosome 1p19q codeletion, PTEN, and p53 among others), radiographic correlates (peritumoral edema, enhancement, cyst formation, necrosis, and invasion among others), nonsteroidal anti-inflammatory drug (NSAID) and statin use, and ketogenic diet have been assessed. Overall, studies have found that IDH mutation and MGMT promoter methylation are positive prognostic markers and TERT is a negative prognostic marker, although subgroup analysis has revealed differential responses. NSAID and statin use have also suggested improved survival reaching significance in some studies. Ketogenic diet has not yet been adequately assessed. Further studies to characterize the interplay of these and other genetic and environmental factors are warranted.

Stromal EGF and igf-I together modulate plasticity of disseminated triple-negative breast tumors.

The causes for malignant progression of disseminated tumors and the reasons recurrence rates differ in women with different breast cancer subtypes are unknown. Here, we report novel mechanisms of tumor plasticity that are mandated by microenvironmental factors and show that recurrence rates are not strictly due to cell-intrinsic properties. Specifically, outgrowth of the same population of incipient tumors is accelerated in mice with triple-negative breast cancer (TNBC) relative to those with luminal breast cancer. Systemic signals provided by overt TNBCs cause the formation of a tumor-supportive microenvironment enriched for EGF and insulin-like growth factor-I (IGF-I) at distant indolent tumor sites. Bioavailability of EGF and IGF-I enhances the expression of transcription factors associated with pluripotency, proliferation, and epithelial-mesenchymal transition. Combinatorial therapy with EGF receptor and IGF-I receptor inhibitors prevents malignant progression. These results suggest that plasticity and recurrence rates can be dictated by host systemic factors and offer novel therapeutic potential for patients with TNBC.

A novel 3-D mineralized tumor model to study breast cancer bone metastasis.

BACKGROUND: Metastatic bone disease is a frequent cause of morbidity in patients with advanced breast cancer, but the role of the bone mineral hydroxyapatite (HA) in this process remains unclear. We have developed a novel mineralized 3-D tumor model and have employed this culture system to systematically investigate the pro-metastatic role of HA under physiologically relevant conditions in vitro. METHODOLOGY/PRINCIPAL FINDINGS: MDA-MB231 breast cancer cells were cultured within non-mineralized or mineralized polymeric scaffolds fabricated by a gas foaming-particulate leaching technique. Tumor cell adhesion, proliferation, and secretion of pro-osteoclastic interleukin-8 (IL-8) was increased in mineralized tumor models as compared to non-mineralized tumor models, and IL-8 secretion was more pronounced for bone-specific MDA-MB231 subpopulations relative to lung-specific breast cancer cells. These differences were pathologically significant as conditioned media collected from mineralized tumor models promoted osteoclastogenesis in an IL-8 dependent manner. Finally, drug testing and signaling studies with transforming growth factor beta (TGFbeta) confirmed the clinical relevance of our culture system and revealed that breast cancer cell behavior is broadly affected by HA. CONCLUSIONS/SIGNIFICANCE: Our results indicate that HA promotes features associated with the neoplastic and metastatic growth of breast carcinoma cells in bone and that IL-8 may play an important role in this process. The developed mineralized tumor models may help to reveal the underlying cellular and molecular mechanisms that may ultimately enable more efficacious therapy of patients with advanced breast cancer.