Search

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.

PDF file - 90K, EGF and IGF-1 Together Modulate Viability and Expression Profile of Responder Cells.

PDF file - 279K, EGFR/IGFR Inhibitors do not Affect the Phenotype of Responding Tumor Cells in Animals Bearing Control Matrigel.

PDF file - 159K, Identification of Instigating Human Breast Tumor Surgical Specimens.

PDF file - 508K, Tumor Microenvironment of Hosts with TNBC Expresses EGF and IGF-1 and Supports Responding Tumor Cell Malignancy.

PDF file - 220K, Response to the Pro-Tumorigenic TNBC Environment is Not Oncotype Specific.

PDF file - 181K, Instigating Tumors Facilitate Responder Growth in the Absence of "Self-seeding".

PDF file - 51K, EGF and IGF-1 Together Modulate Tumorogenicity of Responder Cells in vitro.

PDF file - 125K, Supplemental Table 1: PCR Oligonucleotide Primers. Supplemental Table 2: Antibodies.

PDF file - 174K, Activation of EGF and IGF1 Receptors.

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 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.

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.

OBJECTIVE To report single center experience of three adult subjects receiving ONC-201 as part of the ONC018 expanded access clinical trial [NCT03134131]. BACKGROUND ONC-201 is an oral investigational antagonist against the D2 dopamine receptor that has shown encouraging results for malignant gliomas harboring the 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. Design/ METHODS Our site enrolled three subjects on the ONC018 trial. We present the demographic, clinical, and molecular characteristics for 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]. RESULTS Three subjects were registered at our site onto ONC018 with age range 18–44yrs, 2/3 female, residing in Norway, India, and United states. Tumor locations: brainstem, corpus callosum and thalamus. Pathology: Glioblastoma (3/3), MGMT methylated (2/3), IDH1 mutant (0/3), EGFR amplification (0/3) and ATRX (3/3). Median change from baseline KPS: ≤20 % decrease; MDASI:2/3 experienced decrease from baseline [median 6%], consistent with improved quality of life. No clinically significant laboratory abnormalities. All adverse events were grade I–II. CONCLUSIONS 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.

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.

BACKGROUND Tectal gliomas (TG) are rare tumors occurring primarily in children but also found in adults during workup of various neurological symptoms. Surgery is not required in asymptomatic cases, so histopathological information is sparse. No consensus on timing of imaging surveillance or management has been established. OBJECTIVE We seek to standardize neuroimaging, including MRI protocol and surveillance time intervals, and clinical management of symptoms and disease progression, including surgery, radiotherapy, and chemotherapy. METHODS At our institution, patients with TG were identified through a search of radiology reports and clinic notes between 1989 and 2020. Initial and serial MRI exams were evaluated for tumor size, enhancement, edema, hydrocephalus, and other radiographic features. When tissue was available, cellularity, mitotic activity, and morphology were described. We documented neurological symptoms and signs potentially related to the tumor. RESULTS 37 cases were identified: 22 female, 15 male; 5 children, 32 adults. Age of diagnosis ranged from 7 to 69 years. Presenting symptoms included headache (59%), visual symptoms (35%), and imbalance (14%), less commonly: seizure, weakness, nausea/vomiting, and dizziness. Surgical procedures included biopsy (9), resection (7), endoscopic third ventriculostomy (15), and shunt placement (11). Eight patients received radiotherapy, including IMRT, CyberKnife, GammaKnife, and Zap-X (all adults; 4 at diagnosis, 3 at progression, 1 at diagnosis and again at progression). Four patients received chemotherapy (all adults; 1 at diagnosis, 3 at progression), all with temozolomide. One additionally received bevacizumab for radionecrosis. Three patients died with progressive disease, two following treatment and one without. Of interest, 5 adult patients developed signs of parkinsonism during their follow-up period. CONCLUSION Management of TG encompasses both neoplastic progression and symptom control, either from local compression or infiltrative disease. We have developed an algorithm for imaging surveillance and treatment, including MRI protocol, definition of progressive disease, and indications for antineoplastic therapies.

Hurdles to effective treatments for glioblastoma multiforme (GBM), the most aggressive form of brain cancer, are resistance to chemotherapy, radiation, and immune checkpoint inhibitors. GBMs, like other “difficult to treat” tumors, often over-utilize the phosphatidyl inositol 3 kinase (PI3K) pathway for survival, cell growth, and cell division, conferring both chemotherapy and radiation resistance. Furthermore, the PI3K pathway has been shown to modulate expression of Major Histocompatibility Complex (MHC) molecules, key components of immune recognition. Based on these observations, we examined the potential of a novel, small molecule PI3K inhibitor GCT.Glio.1 (NPT520-337), which was designed to cross the blood brain barrier, to increase the sensitivity of GBM to immune based therapies and radiation. We hypothesized that targeting PI3K would result in growth arrest and increase cell surface expression of MHC molecules and the PD-L1 checkpoint target. Treatment of GL261 mouse and human U251 GBM cell lines with GCT.Glio.1 caused growth arrest at the G2/M checkpoint, increased the cell surface expression of PD-L1 and MHC class II, and synergized with radiation to cause growth arrest and cell death. Based on these results we designed and performed in vivo animal studies, implanting luciferase-flagged GL261 into the caudate nucleus of C57BL6 mice. We treated the animals orally with GCT.Glio.1 followed 24 hours later by anti-PD1 therapy in repeating cycles. The treatments significantly delayed progression of the tumor when compared to no treatment or either treatment alone, with several animals exhibiting complete regression as measured by MRI and bioluminescence. In conclusion, these results indicate that GCT.Glio.1 may sensitize GBM to immune checkpoint inhibitor and/or radiation therapies. Based on our encouraging pre-clinical data and early results from pre-clinical pharmacology and safety studies, we anticipate filing a pre-Investigational New Drug application (pre-IND) as the next step toward our goal of a clinical trial using this combination therapy.

INTRODUCTION Virtual tumor board [VTB] platforms are an important aspect of cancer management. They enable easier access to a multidisciplinary team of experts. In order to deliver high-quality cancer care, it is necessary to coordinate numerous therapies and providers, and maintain open lines of communication among all professionals involved. Design/ METHODS We performed a systematic search of all VTBs incorporating a platform designed for this specific role. We reviewed the records of Genomet, Medical University of South Carolina[MUSC] and Xcures virtual tumor boards. Summary data examined include year of launch, demographics, characteristics of cases, average response time, advantages, and how they handle protected health information. RESULTS 30% of VTBs examined launched in 2017. All had a HIPAA compliant online environment. Xcures records reveals median age of female patients was 57yrs and the median age of male patients was 55 years. The data showed that 44% with a confirmed treatment preferred VTB integrated option. 76% of patients in Xcures registry consist of primary CNS tumors. There are at least 556 patients in the tumor registry which included 46% Glioblastoma cases [96% primary, 4% secondary]. MUSC VTB shows 112 thoracic tumor cases and 9 neuro-Oncology cases. Genomet VTB data shows age range from 6 months to 84 years [mean age 44.5 years] with 69.6% males and 30.4% females, 43.5% glioblastoma, 8.7% adenocarcinoma, 8.7% infratentorial tumor. Average response time observed in all cases was ≤ 24 hours. CONCLUSION VTBs allow for quicker expert analysis of cases. More studies are needed to gain additional insight into user engagement metrics.

OBJECTIVE The purpose of this systematic review and meta-analysis is to evaluate the various innovative approaches to diagnosing and treating patients presenting with brain tumor-related pain. BACKGROUND Brain tumors make up for lower than 2% of all cancers, which is heavily linked to high morbidity, deteriorated quality of life, and the death of the affected patients. Glioblastoma (GBM) makes up 38% of the malignant brain glioma.The main treatment approaches for gliomas are widely dependent on chemotherapy and radiation therapy. However, these methods have been associated with vast side effects which constitute the quality of life of the patient. METHODS This systematic review and meta-analysis conformed to PRISMA guidelines. A total of 3025 studies were assessed through the eligibility criteria to remain with twenty eligible studies. The included studies were then grouped into two categories; group one comprised 14 studies that focused on an innovative approach to diagnosis and treatment of gliomas, and six studies comprised of studies that focused on health-related quality of life (HRQoL) of patients with brain tumors. RESULTS Twenty studies that met the inclusion criteria were analyzed independently and in two groups: diagnosis and treatment and quality of life issues of brain tumor patients. In one group, one study revealed a relatively progression-free survival (PFS) going up to 57 weeks and overall survival (OS) time of more than 20 weeks after the initial surgery. Group two indicated HRQoL issues associated with symptoms such as headaches, fatigue, trauma, cognitive and personality dysfunction, leg weakness, and neurological deficits. CONCLUSION Timely diagnosis of the gliomas has significant improvements to the overall survival. Treatment approaches explored in the studies include Temozolomide (TZ), Gliadel Wafer, immunogeno-type, peptide vaccination, Bevacizumab, chemotherapy, radiation therapy, and Temsirolimus. Chemotherapy and radiation therapy have been linked to a deteriorated quality of life of the patients

BACKGROUND The MET pathway is a key oncogenic pathway in gliomas and is involved in tumor survival, angiogenesis, and invasion. MET alterations have been increasingly identified as a potential therapeutic target. METHODS Our objective was to further characterize the natural history of gliomas which harbor MET alterations and study outcomes as determined by progression free survival (PFS) and overall survival (OS). RESULTS We identified 22 glioma patients seen at our institution between 2015 and 2021 who had a MET alteration confirmed through comprehensive molecular profiling. There were 18 grade 4 astrocytomas/glioblastomas, 3 grade 3 gliomas (2 astrocytomas, 1 oligodendroglioma), and 1 grade 2 glioma (oligodendroglioma). MET amplification was observed in 13 patients and fusion in 16 patients , with 7 patients carrying both amplification and fusion alterations. MET fusion partners included PTPRZ1 (8 patients), CAPZA2 (6 patients), and ST7 (3 patients). Median OS was 12.8 months, and median PFS was 8.47 months. IDH1/2 mutation was associated with significantly improved survival, with an estimated OS of 146 months for IDH1/2 mutant tumors and 17.9 months for IDH1/2 wildtype tumors (p< 0.001), MGMT methylation status had no significant survival impact. No significant survival differences were observed between the fusion only, amplification only, and combined fusion and amplification groups. No therapy was predictive of improved outcomes. CONCLUSION MET amplification and fusion alterations were observed in both low and high grade gliomas, suggesting that they may be involved in early tumorigenesis. Survival outcomes were poor compared with historical data, with no differences observed between treatment groups, suggesting that current therapeutic modalities may be inadequate. This study indicates that MET may be an appropriate therapeutic target, laying the groundwork for clinical trials investigating MET-targeted agents.

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 = 0.023), and EBV positive tumors were associated with improved outcomes (p = 0.016). Surgical resection was associated with improved outcomes (p = 0.032), although limited by potential confounding effect. Antiviral treatment (p = 0.095), rituximab (p = 0.111), and SCT (p = 0.198) 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.

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.

OBJECTIVE To report a summary of a systematic review of virtual tumor boards and their implementation in neuro- oncology. BACKGROUND Virtual tumor board [VTB] platforms are an important aspect of cancer management. They enable easier access to a multidisciplinary team of experts. VTBs are an emerging resource across various cancer care networks in the United States. DESIGN/METHODS We performed a systematic search of all VTBs incorporating a platform designed for this specific role. We reviewed UC Davis Health Care Center VTB, Genomet, Oncolens, Navify Tumor Board, Medical University of South Carolina Virtual Tumor Board, Precision Oncology, Cancer Commons, Virtual Tumor Board, Virtual Tumor Board Tahoe Forest Cancer Center and MassiveBio. Summary data examined include year of launch, demographics, characteristics of cases, average response time, advantages, and how they handle protected health information. RESULTS 30% of all VTBs examined launched in 2017. All had a HIPAA compliant online environment. Genomet VirtualBoard de-identifies all patient information; this is a virtual platform primarily focused on neuro-oncology cases. Cases involved a median of 5 specialists most commonly neuro-oncologists, neurosurgeons, radiation oncologists, molecular pathologists and neuroradiologists. Participants had an average of 23 cases reviewed. Case review revealed an age range from 6 months to 84 years [mean age 44.5 years] with 69.6% males and 30.4% females, 43.5% glioblastoma, 8.7% adenocarcinoma, 8.7% infratentorial tumor, CONCLUSIONS VTBs have allowed 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 insight into user engagement metrics.

OBJECTIVE To report the single center experience of three adult subjects receiving ONC-201 as part of the ONC018 expanded access clinical trial [NCT03134131]. BACKGROUND ONC-201 is an oral investigational antagonist against the D2 dopamine receptor that has shown encouraging results for malignant gliomas harboring the H3K27M mutation in the H3 histone complex. Responses have been reported in pediatric subjects with such tumors. H3K27M tumors are generally located in the midline of the central nervous system which co-localize, for unknown reasons, with key dopaminergic pathways. An expanded access clinical trial (ONC018) was available to eligible patients allowing them access to this agent pending FDA review. DESIGN/METHODS Our site enrolled three subjects on the ONC018 trial. We present the demographic, clinical, and molecular characteristics for our enrolled subjects. We report the tolerability, adverse events, and outcome measures including survival, time-to-progression, response, Karnofsky Performance Status [KPS] and quality-of-life measured by the MD Anderson symptom inventory instrument [MDASI]. RESULTS Three subjects were registered at our site onto ONC018 with age range 18-44yrs, 2/3 female, residing in Norway, India and United states. Tumor locations: brainstem, corpus callosum and thalamus. Pathology: glioblastoma(3/3), MGMT methylated (2/3), IDH1 mutant (0/3), EGFR amplification (0/3) and ATRX (3/3). Median change from baseline KPS: ≤20% decrease; MDASI:2/3 experienced decrease from baseline [median 6%],consistent with improved quality of life. No clinically significant laboratory abnormalities. No serious adverse events observed in any cases. All adverse events grade I-II. CONCLUSIONS In three subjects with H3K27M-mutant malignant glioma that received ONC201 as part of this expanded access clinical trial, we found that study drug was quite tolerable. No serious adverse events nor radiographic responses were seen. Analyses of larger study cohort and additional randomized controlled trials are necessary to provide insight into the safety and efficacy of this agent for this patient population.

e14043 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 additional survival benefit gained by CD-20 targeting with rituximab. With increasing prevalence of autoimmune disease and a corresponding rapid rate of development and approval of new immunosuppressant medications, a new type of lymphoproliferative disorder (LPD) has been described, known as iatrogenic immunodeficiency associated LPD. These disorders are typically EBV positive and have distinct histologic and genetic features. Furthermore, many of them arise in the setting of prior methotrexate use, raising the question of whether standard HD-MTX based regimens would still be effective. Our objective was to further characterize this disorder, with a focus on cases with central nervous system involvement, and to determine the optimal management strategy. Methods: We describe a case of a 76-year-old female with iatrogenic immunodeficiency associated PCNSL following 10 years of mercaptopurine, which was 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 central nervous system (CNS). We used a linear probability statistical model to determine correlations with outcome. Results: While the majority of immunosuppressants were associated with EBV positive tumors, natalizumab was associated with EBV negative tumors (95% CI -0.951, -0.076), and EBV positive tumors were associated with improved outcomes (95% CI 0.074, 0.687). Surgical resection (95% CI 0.028, 0.574) was associated with improved outcomes, although limited by potential confounding effect. Although they did not reach statistical significance, antiviral treatment (95% CI -0.039, 0.459) and rituximab (95% CI -0.073, 0.524) showed a trend toward improved outcomes. The remaining treatments including methotrexate showed no improvement. Conclusions: Based on this data, 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. However, further study through randomized clinical trials is warranted.

e13604 Background: Virtual tumor board [VTB] platforms are an important aspect of cancer management. They enable easier access to a multidisciplinary team of experts. VTBs are an emerging resource across various cancer care networks in the United States. Methods: We performed a systematic search of all VTBs incorporating a platform designed for this specific role. We reviewed Xcures, Genomet, Oncolens, Navify Tumor Board, Medical University of South Carolina [MUSC] Virtual Tumor Board, Virtual Tumor Board Tahoe Forest Cancer Center, UC Davis Health Care Center VTB and MassiveBio. Summary data examined include year of launch, demographics, characteristics of cases, average response time, advantages, and how they handle protected health information. Results: 30% of all VTBs examined launched in 2017. All had a HIPAA compliant online environment. Xcures records were reviewed where the median age of female patients was 57yrs and the median age of male patients was 55 years. The data showed that 44% (4.4 out of every 10 patients) with a confirmed treatment chose VTB integrated option. 76% of patients in Xcures registry consist primary CNS tumors. With at least 556 patients in tumor registry which included 46% Glioblastoma cases [96% primary;, 4% secondary], 13% Diffuse midline glioma with H3K27M-mutant cases, 5% Diffuse intrinsic pontine glioma cases, 3% Astrocytoma and Diffuse Astrocytoma cases, 3% Anaplastic astrocytoma cases; Glioma and Diffuse Glioma, 1% Anaplastic Oligodendroglioma cases and < 1% Gliosarcoma, Oligodendroglioma, Pilocytic astrocytoma, Anaplastic pleomorphic Xanthoastrocytoma, Fibrillary astrocytoma, Oligoastrocytoma and Pleomorphic Xanthoastrocytoma cases. In the MUSC VTB, 9 neuro-oncology cases were reviewed. They meet weekly, and average response time was within 24hrs of case review.Patient demographics were not recorded. Genomet Virtual Board de-identifies all patient information; this is a virtual platform primarily focused on neuro-oncology cases. Cases involved a median of 5 specialist most commonly neuro-oncologists, neurosurgeons, radiation oncologists, molecular pathologists and neuroradiologists. Participants had an average of 23 cases reviewed. Case review revealed an age range from 6 months to 84 years [mean age 44.5 years] with 69.6% males and 30.4% females, 43.5% glioblastoma, 8.7% adenocarcinoma, 8.7% infra-tentorial tumor, < 5% each: pineoblastoma, melanoma, hemangioblastoma and pilocytic astrocytoma. Average response time observed in all cases was ≤24 hours. Detailed metrics for number/percentages of brain tumor cases were not available for most other platforms at time of submission. This will be updated at presentation. Conclusions: VTBs have allowed 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 insight into user engagement

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.

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.

BACKGROUND 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. METHODS We conducted a survey of 109 physicians in Sub-Saharan Africa in order to determine 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. Demographic data including age, gender, and prior training was collected and analyzed using ANOVA statistical testing. RESULTS Among the participants, 48% felt comfortable in providing palliative care consultations, 62% have not had prior training, 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). CONCLUSIONS 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. Challenges most often identified by participants were pain management and end-of-life communication skills, but also included patient spirituality and psychological support, anxiety and depression, terminal dyspnea, ethics, and intravenous hydration and non-oral feeding.

Coronavirus disease 2019 (COVID-19) has grossly impacted how we deliver healthcare and how healthcare institutions derive value from the care provided. at increased infectious risk on immunosuppressive therapies and often have mobility limitations. 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-/post-COVID-19 and evaluated the neuro-oncology clinical practice approaches of two 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% of pre-pandemic capacity (patient visits and slot utilization) within 3-weeks and returned to >90% capacity within 6-weeks of initial closures due to COVID-19. The two health systems rapidly and effectively implemented telehealth practices to recover patient volumes. While 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.

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. Significance: Currently, processes that mediate progression of otherwise indolent tumors are not well understood, making it difficult to accurately predict which patients with cancer are likely to relapse. Our findings reveal novel mechanisms of tumor phenotypic and gene expression plasticity that are mandated by microenvironmental factors, identifying novel therapeutic targets for patients with TNBC. Cancer Discov; 3(8); 922–35. ©2013 AACR. This article is highlighted in the In This Issue feature, p. 826

e18766Background: Patients with solid tumors are usually classified as being at low to intermediate risk for developing tumor lysis syndrome (TLS); however, there have been a growing number of case...

By the time metastatic breast cancer is detected, patients are no longer treated with curative intent. Women with triple-negative breast cancer (TNBC) are particularly at risk for early recurrence. Clinical evidence indicates that in women with metastatic TNBC, the primary tumor and disseminated cells co-existed for an indefinite period of time. We demonstrate that outgrowth of distant tumors that would otherwise remain indolent in cancer-free mice is accelerated in mice with TNBC. Systemic signals provided by TNBCs cause formation of a tumor-supportive microenvironment at distant tumor sites. This microenvironment is enriched for EGF and IGF-1, which convert indolent tumors to a malignant state, defined by expression of factors associated with pluripotency, proliferation, and epithelial-mesenchymal transition. Inhibition of both EGFR and IGF1R maintains these tumors in the indolent state. These results suggest that recurrence rates can be dictated by host systemic factors and offer novel therapeutic potential for TNBC patients. Citation Format: Zafira Castano, Tim Marsh, Ramya Tadipatri, Hanna S. Kuznetsov, Fatima Al-Shahrour, Mahanaz Paktinat, April Greene-Colozzi, Bjorn Nilsson, Andrea L. Richardson, Sandra S. McAllister. Systemic and stromal support of triple-negative breast cancer progression is prevented by EGF and IGF-1 inhibitors. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C94.

Breast cancer recurrence rates are variable, suggesting that tumor cells disseminate from primary sites at an early stage but remain indolent for extended periods of time before progressing to symptomatic disease. Little is known about mechanisms that cause otherwise dormant tumors to become overt cancers, making it difficult to predict which breast cancer patients are likely to relapse and therefore likely to benefit from preemptive therapy. To address these challenges, we use a human breast tumor xenograft model in which aggressively growing breast cancers (“instigators”) promote the growth of otherwise indolent breast cancers (“responders”) that have disseminated to distant sites. These pro-tumorigenic systemic effects are established by instigating tumors, in large part, through their mobilization of bone marrow cells (BMCs) that are subsequently recruited to the responding breast tumors, where they create a tumor-supportive microenvironment. We report here that the mechanisms of establishing tumor-supportive systemic environments depend upon the molecular-histopathological subtype of the instigating breast cancer. Instigating cell lines and primary tumor surgical specimens, derived from patients with either triple-negative breast cancer (TNBC) or luminal breast cancer (LBC), established different subtype-specific systemic environments that impinged in different ways upon the malignant features of responding tumor cells and their microenvironment. In particular, the TNBC-induced responding tumor microenvironment was characterized by elevated levels of epidermal growth factor (EGF) and insulin-like growth factor 1 (IGF1). EGF and IGF acted on responding tumor cells in a paracrine manner to induce expression of factors that play a role in tumor-initiation, embryonic stem cell maintenance, and epithelial-mesenchymal transition. Pharmacological administration of EGFR and IGF1R inhibitors prevented responding tumors from acquiring the TNBC-induced malignant features, thus maintaining them in an indolent state. Our results demonstrate that microenvironmental composition, as well as tumor cell phenotypic plasticity and molecular properties, are strongly influenced by the host systemic macroenvironment. Our work suggests that the crosstalk between disseminated tumor cells and their microenvironment can be exploited therapeutically to improve outcomes for patients with TNBC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4861. doi:1538-7445.AM2012-4861

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 (TGFβ) 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.

e14029 Background: The MET pathway is a key oncogenic pathway in gliomas and is involved in tumor survival, angiogenesis, and invasion. MET alterations have been increasingly identified as a potential therapeutic target. Methods: Our objective was to further characterize the natural history of gliomas which harbor MET alterations and study outcomes as determined by progression free survival (PFS) and overall survival (OS). Results: We identified 22 glioma patients seen at our institution between 2015 and 2021 who had a MET alteration confirmed through comprehensive molecular profiling. There were 18 grade 4 astrocytomas/glioblastomas, 3 grade 3 gliomas (2 astrocytomas, 1 oligodendroglioma), and 1 grade 2 glioma (oligodendroglioma). MET amplification was observed in 13 patients and fusion in 16 patients, with 7 patients carrying both amplification and fusion alterations. MET fusion partners included PTPRZ1 (8 patients), CAPZA2 (6 patients), and ST7 (3 patients). Median OS was 12.8 months, and median PFS was 8.47 months. IDH1/2 mutation was associated with significantly improved survival, with an estimated OS of 146 months for IDH1/2 mutant tumors and 17.9 months for IDH1/2 wildtype tumors (F2,2 = 38.907, p < 0.001), MGMT methylation status had no significant survival impact. No significant survival differences were observed between the fusion only, amplification only, and combined fusion and amplification groups. No therapy was predictive of improved outcomes. Conclusions: MET amplification and fusion alterations were observed in both low and high grade gliomas, suggesting that they may be involved in early tumorigenesis. Survival outcomes were poor compared with historical data, with no differences observed between treatment groups, suggesting that current therapeutic modalities may be inadequate. This study indicates that MET may be an appropriate therapeutic target, laying the groundwork for clinical trials investigating MET-targeted agents.