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Leptomeningeal disease (LMD) remains a rapidly lethal complication for late-stage melanoma patients. Here, we characterize the tumor microenvironment of LMD and patient-matched extra-cranial metastases using spatial transcriptomics in a small number of clinical specimens (nine tissues from two patients) with extensive in vitro and in vivo validation. The spatial landscape of melanoma LMD is characterized by a lack of immune infiltration and instead exhibits a higher level of stromal involvement. The tumor-stroma interactions at the leptomeninges activate tumor-promoting signaling, mediated through upregulation of SERPINA3. The meningeal stroma is required for melanoma cells to survive in the cerebrospinal fluid (CSF) and promotes MAPK inhibitor resistance. Knocking down SERPINA3 or inhibiting the downstream IGR1R/PI3K/AKT axis results in tumor cell death and re-sensitization to MAPK-targeting therapy. Our data provide a spatial atlas of melanoma LMD, identify the tumor-promoting role of meningeal stroma, and demonstrate a mechanism for overcoming microenvironment-mediated drug resistance in LMD.
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Melanoma , Neoplasias Meníngeas , Células Estromais , Microambiente Tumoral , Melanoma/genética , Melanoma/patologia , Humanos , Microambiente Tumoral/genética , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/patologia , Células Estromais/metabolismo , Células Estromais/patologia , Animais , Linhagem Celular Tumoral , Camundongos , Regulação Neoplásica da Expressão Gênica , Transcriptoma/genética , Perfilação da Expressão Gênica , Meninges/patologia , Meninges/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Transdução de Sinais , FemininoRESUMO
BACKGROUND: EGFR-targeted therapy (ETT) and immune-checkpoint blockade (ICB) have shown promising results in treating NSCLC brain metastases (BM). However, little is known of their effect in treating leptomeningeal disease (LMD). PATIENTS AND METHODS: This is a retrospective review of 80 patients diagnosed with NSCLC LMD from January 2014 to March 2021. Patients were grouped based on initial LMD treatment: radiotherapy (RT) alone, ETT, ICB, and intrathecal chemotherapy (ITC). RESULTS: EGFR mutation was present in 22 patients (28%). Twenty patients had positive cytology in cerebrospinal fluid, while 60 patients were diagnosed based on MRI with clinical correlation. The RT alone group consisted primarily of whole brain radiation (n = 20; 77%), stereotactic radiation (n = 3; 12%), and palliative spine radiation (n = 2; 7%). There were no significant differences amongst the treatment groups in age, performance status, or neurologic symptoms. Overall, the 6-month overall survival (OS) and craniospinal progression free survival (CS-PFS) were 35% and 24%, respectively. The 6-month OS for the ETT, ICB, ITC, and RT alone groups was 64%, 33%, 57%, and 29% respectively (log-rank P = .026). The 6-month CS-PFS for the ETT, ICB, ITC, and RT alone groups was 43%, 33%, 29%, and 19% respectively (log-rank P = .049). Upon univariate analysis, receipt of ETT compared to RT alone reached significance for OS (HR 0.35, P = .006) and CS-PFS (HR 0.39, P = .013). CONCLUSIONS: The prognosis for patients with NSCLC LMD remains poor overall. However, the receipt of ETT for patients with EGFR-positive disease was associated with improved outcomes.
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Carcinoma Pulmonar de Células não Pequenas , Receptores ErbB , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Masculino , Feminino , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/tratamento farmacológico , Estudos Retrospectivos , Pessoa de Meia-Idade , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Idoso , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/administração & dosagem , Injeções Espinhais , Neoplasias Meníngeas/terapia , Neoplasias Meníngeas/patologia , Adulto , Carcinomatose Meníngea/secundário , Carcinomatose Meníngea/tratamento farmacológico , Terapia de Alvo Molecular , Idoso de 80 Anos ou mais , Taxa de Sobrevida , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Prognóstico , Resultado do Tratamento , Seguimentos , MutaçãoRESUMO
This nonrandomized controlled trial examines the safety of radiation therapy (RT) followed by intrathecal trastuzumab and pertuzumab for patients with ERBB2-positive breast leptomeningeal disease (LMD).
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Anticorpos Monoclonais Humanizados , Neoplasias da Mama , Injeções Espinhais , Receptor ErbB-2 , Trastuzumab , Humanos , Trastuzumab/administração & dosagem , Trastuzumab/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/radioterapia , Neoplasias da Mama/patologia , Feminino , Receptor ErbB-2/metabolismo , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Pessoa de Meia-Idade , Neoplasias Meníngeas/secundário , Neoplasias Meníngeas/radioterapia , Neoplasias Meníngeas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Adulto , IdosoRESUMO
BACKGROUND: Breast cancer-related leptomeningeal disease (BC-LMD) is a dire diagnosis for 5-8% of patients with breast cancer (BC). We conducted a retrospective review of BC-LMD patients diagnosed at Moffitt Cancer Center from 2011 to 2020, to determine the changing incidence of BC-LMD, factors which are associated with the progression of BC CNS metastasis to BC-LMD, and factors which are associated with OS for patients with BC-LMD. METHODS: Patients with BC and brain/spinal metastatic disease were identified. For those who eventually developed BC-LMD, we used Kaplan-Meier survival curve, log-rank test, univariable, and multivariate Cox proportional hazards regression model to identify factors affecting time from CNS metastasis to BC-LMD and OS. RESULTS: 128 cases of BC-LMD were identified. The proportion of BC-LMD to total BC patients was higher between 2016 and 2020 when compared to 2011-2015. Patients with HR+ or HER2 + BC experienced longer times between CNS metastasis and LMD than patients with triple-negative breast cancer (TNBC). Systemic therapy and whole-brain radiation therapy (WBRT) was associated with prolonged progression to LMD in all patients. Hormone therapy in patients with HR + BC were associated with a delayed BC-CNS metastasis to LMD progression. Lapatinib treatment was associated with a delayed progression to LMD in patients with HER2 + BC. Patients with TNBC-LMD had shorter OS compared to those with HR + and HER2 + BC-LMD. Systemic therapy, intrathecal (IT) therapy, and WBRT was associated with prolonged survival for all patients. Lapatinib and trastuzumab therapy was associated with improved OS in patients with HER2 + BC-LMD. CONCLUSIONS: Increasing rates of BC-LMD provide treatment challenges and opportunities for clinical trials. Prospective trials testing lapatinib and/or similar tyrosine kinase inhibitors, IT therapies, and combination treatments are urgently needed.
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Neoplasias Encefálicas , Doenças Mamárias , Neoplasias da Mama , Neoplasias do Sistema Nervoso Central , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Neoplasias da Mama/complicações , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/terapia , Neoplasias Encefálicas/secundário , Lapatinib , Estudos Retrospectivos , Estudos Prospectivos , Irradiação Craniana , Doenças Mamárias/complicações , Receptor ErbB-2RESUMO
Patients with primary central nervous system lymphoma (PCNSL) typically present with non-focal neurological symptoms, including disorientation, poor balance and memory loss with unifocal or multifocal periventricular lesions seen on MRI. Deviations from these characteristic findings can delay diagnosis and lead to additional diagnostic tests being needed. The present study reports a 68-year-old man with a recent varicella zoster infection and history of acetylcholine receptor antibody-positive myasthenia gravis who received mycophenolate mofetil for 22 years. He presented with left eye vision changes and cognitive memory deficits. A brain MRI showed an enhancing lesion within his left medulla extending to the cerebellum. Cerebrospinal fluid analysis was positive for Epstein-Barr virus (EBV) and negative for malignancy. He was diagnosed with varicella zoster virus vasculopathy. At 3 months later, a repeat brain MRI showed multiple new enhancing lesions developing bilaterally along the periventricular white matter. Soon after, he presented to a local ER with acute left-sided blurry vision and worsening memory loss, and he began receiving steroids. Because of rapid symptom progression, he underwent resection of the left frontal lesion, which showed EBV-induced diffuse large B-cell lymphoma (DLBCL). Mycophenolate mofetil was discontinued, and within 24 h of one dose of intravenous 500 mg/m2 rituximab, he had a dramatic improvement in left eye vision and memory loss. He experienced mixed responses to rituximab after 3 cycles. Following one dose of high-dose methotrexate, he developed subsequent chronic kidney disease and required dialysis. He received whole-brain radiation therapy with craniospinal radiation and is currently in complete remission. An EBV-induced DLBCL diagnosis should be highly considered for patients with periventricular lesions and EBV-positive cerebrospinal fluid. Misdiagnosis or delay in PCNSL diagnosis because of atypical features in disease presentation and radiographic findings could lead to PCNSL progression and worsening neurological deficits.
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Síndrome de Bronquiolite Obliterante , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Sistema Nervoso Central , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Doença CrônicaRESUMO
Background: Breast cancer-related leptomeningeal disease (BC-LMD) is a dire diagnosis for 5-8% of patients with breast cancer (BC). We conducted a retrospective review of BC-LMD patients diagnosed at Moffitt Cancer Center (MCC) from 2011-2020, to determine the changing incidence of BC-LMD, which factors impact progression of BC CNS metastasis to BC-LMD, and which factors affect OS for patients with BC-LMD. Methods: Patients with BC and brain/spinal metastatic disease were identified. For those who eventually developed BC-LMD, we used Kaplan-Meier survival curve, log-rank test, univariable, and multivariate Cox proportional hazards regression model to identify factors affecting time from CNS metastasis to BC-LMD and OS. Results: 128 cases of BC-LMD were identified. The proportion of BC-LMD to total BC patients was higher between 2016-2020 when compared to 2011-2015. Patients with HR + or HER2 + BC experienced longer times between CNS metastasis and LMD than patients with triple-negative breast cancer (TNBC). Systemic therapy and whole-brain radiation therapy (WBRT) prolonged progression to LMD in all patients. Hormone therapy in patients with HR + BC delayed BC-CNS metastasis to LMD progression. Lapatinib delayed progression to LMD in patients with HER2 + BC. Patients with TNBC-LMD had shorter OS compared to those with HR + and HER2 + BC-LMD. Systemic therapy, intrathecal (IT) therapy, and WBRT prolonged survival for all patients. Lapatinib and trastuzumab improved OS in patients with HER2 + BC-LMD. Conclusions: Increasing rates of BC-LMD provide treatment challenges and opportunities for clinical trials. Trials testing lapatinib and/or similar tyrosine kinase inhibitors, IT therapies, and combination treatments are urgently needed.
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Leptomeningeal disease (LMD) is a devastating complication caused by seeding malignant cells to the cerebrospinal fluid (CSF) and the leptomeningeal membrane. LMD is diagnosed in 5-15% of patients with systemic malignancy. Management of LMD is challenging due to the biological and metabolic tumor microenvironment of LMD being largely unknown. Patients with LMD can present with a wide variety of signs and/or symptoms that could be multifocal and include headache, nausea, vomiting, diplopia, and weakness, among others. The median survival time for patients with LMD is measured in weeks and up to 3-6 months with aggressive management, and death usually occurs due to progressive neurologic dysfunction. In melanoma, LMD is associated with a suppressive immune microenvironment characterized by a high number of apoptotic and exhausted CD4+ T-cells, myeloid-derived suppressor cells, and a low number of CD8+ T-cells. Proteomics analysis revealed enrichment of complement cascade, which may disrupt the blood-CSF barrier. Clinical management of melanoma LMD consists primarily of radiation therapy, BRAF/MEK inhibitors as targeted therapy, and immunotherapy with anti-PD-1, anti-CTLA-4, and anti-LAG-3 immune checkpoint inhibitors. This review summarizes the biology and anatomic features of melanoma LMD, as well as the current therapeutic approaches.
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Leptomeningeal disease (LMD) remains a rapidly lethal complication for late-stage melanoma patients. The inaccessible nature of the disease site and lack of understanding of the biology of this unique metastatic site are major barriers to developing efficacious therapies for patients with melanoma LMD. Here, we characterize the tumor microenvironment of the leptomeningeal tissues and patient-matched extra-cranial metastatic sites using spatial transcriptomic analyses with in vitro and in vivo validation. We show the spatial landscape of melanoma LMD to be characterized by a lack of immune infiltration and instead exhibit a higher level of stromal involvement. We show that the tumor-stroma interactions at the leptomeninges activate pathways implicated in tumor-promoting signaling, mediated through upregulation of SERPINA3 at the tumor-stroma interface. Our functional experiments establish that the meningeal stroma is required for melanoma cells to survive in the CSF environment and that these interactions lead to a lack of MAPK inhibitor sensitivity in the tumor. We show that knocking down SERPINA3 or inhibiting the downstream IGR1R/PI3K/AKT axis results in re-sensitization of the tumor to MAPK-targeting therapy and tumor cell death in the leptomeningeal environment. Our data provides a spatial atlas of melanoma LMD, identifies the tumor-promoting role of meningeal stroma, and demonstrates a mechanism for overcoming microenvironment-mediated drug resistance unique to this metastatic site.
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PURPOSE: Unique challenges exist in the utilization of telemedicine for neurological and surgical specialties. We examined the differences in patient satisfaction for telemedicine versus in-person visits within a Neuro-Oncology Program to assess whether there was a difference between surgical and medical specialties. We also examined the potential cost savings benefits of utilizing telemedicine. METHODS: 1189 Press Ganey surveys in the Department of Neuro-Oncology (982 in-person and 207 telemedicine) by surgical and medical neuro-oncology patients between 04/01/2020 and 06/30/2021 were reviewed. Survey results were divided into 4 categories (Access, Provider, Technology (telemedicine only), and Overall Satisfaction). Results were analyzed for the impact of telemedicine versus in-person visits, and gender, age, insurance, and specialty. Cost savings were calculated based on potential travel distance and lost productivity. RESULTS: Survey results from telemedicine visits demonstrated that patients with private insurance returned higher scores in the Provider (p = 0.0089), Technology (p = 0.00187), and Overall (p = 0.00382) categories. Surgical patients returned higher scores for Access (p = 0.0015), Technology (p = 0.0002), and Overall (p = 0.0019). When comparing telemedicine to in-person scores, in-person scored higher in Provider (p = 0.0092) for all patients, while in-person scored higher in Access (p = 0.0252) amongst surgical patients. Cost analysis revealed that telemedicine allowed patients to save an average of 4.1 to 5.6 h per visit time and a potential cost savings of up to $223.3 ± 171.4. CONCLUSION: Telemedicine yields equivalent patient satisfaction when employed in surgical as compared to medical Neuro-Oncology patients with the potential to lessen the financial and time burden on neuro-oncology patients.
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Neoplasias , Telemedicina , Humanos , Satisfação do Paciente , Redução de Custos , Telemedicina/métodos , Viagem , Neoplasias/terapiaRESUMO
Leukoencephalopathy in the setting of multiple myeloma (MM) is a rare demyelinating condition, with few reported cases in literature. Daratumumab is a CD38 targeted monoclonal antibody that has been widely used for the management of MM. In the absence of central nervous system (CNS) disease, many medication-induced leukoencephalopathy cases reported with MM, including daratumumab-induced, are associated with progressive multifocal leukoencephalopathy (PML) and John Cunningham (JC) virus. Currently, there are no reported cases of daratumumab-induced leukoencephalopathy among patients without CNS involvement or PML. We discuss 2 patients who developed leukoencephalopathy while receiving daratumumab-based therapy without evidence of PML or CNS disease. Both patients had baseline MRIs without significant white matter changes before daratumumab-based therapy. Patients began experiencing neurological deficits about 6 to 8 months after daratumumab-based therapy initiation. One patient passed away before being assessed for improvement of symptoms with daratumumab cessation. The second patient had some stabilization of symptoms after cessation; however, the leukoencephalopathy remained irreversible. As the class of anti-CD38 monoclonal antibodies expands in MM therapy, we highlight a potential treatment complication and the importance of detecting leukoencephalopathy early among patients receiving anti-CD38 therapy. We recommend vigilant monitoring of any new or worsening neurological symptoms to avoid serious complications of irreversible leukoencephalopathy.
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The diagnosis of brain metastases has historically been a dreaded, end-stage complication of systemic disease. Additionally, with the increasing effectiveness of systemic therapies that prolong life expectancy and improved imaging tools, the incidence of intracranial progression is becoming more common. Within this context, there has been increasing attention directed at understanding the molecular underpinnings of intracranial progression. Exploring the unique features of brain metastases compared with their extracranial counterparts to identify aberrant signaling pathways, which can be targeted pharmacologically, may help lead to new treatments for this patient population. Additionally, critical discoveries outside the sphere of the central nervous system are increasingly being applied to brain metastases with the emergence of immune checkpoint inhibition, becoming a prevalent treatment option for patients with brain metastases across multiple histologies. As novel treatment strategies are considered, they require thoughtful incorporation of agents that can cross the blood-brain barrier and can synergize with pre-existing agents through rational combinations. Lastly, as clinicians and scientists continue to understand key molecular features of these tumors, they will continue to influence the treatment algorithms that are developing for the management of these patients. Due to the complexity of treatment decisions for patients with brain metastases, an emerging tool is the utilization of multidisciplinary brain metastasis tumor boards to ensure optimal treatment decisions are made and that patients are provided access to applicable clinical trials. Looking to the future, the collective effort to understand the various tumor-intrinsic and tumor-extrinsic factors that promote central nervous system seeding and propagation will have the potential to change the clinical trajectory for these patients.
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Neoplasias Encefálicas , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Humanos , Inibidores de Checkpoint ImunológicoRESUMO
Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer are at a particularly high risk of breast cancer brain metastasis (BCBM) and leptomeningeal disease (LMD). Improvements in systemic therapy have translated to improved survival for patients with HER2-positive BCBM and LMD. However, the optimal management of these cases is rapidly evolving and requires a multidisciplinary approach. Herein, a team of radiation oncologists, medical oncologists, neuro-oncologists, and breast surgeon created a review of the evolving management of HER2-positive BCBM and LMD. We assess the epidemiology, diagnosis, and evolving treatment options for patients with HER2-positive BCBM and LMD, as well as the ongoing prospective clinical trials enrolling these patients. The management of HER2-positive BCBM and LMD represents an increasingly common challenge that involves the coordination of local and systemic therapy. Advances in systemic therapy have resulted in an improved prognosis, and promising targeted therapies currently under prospective investigation have the potential to further benefit these patients.
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Neoplasias Encefálicas , Neoplasias da Mama , Neoplasias Meníngeas , Neoplasias Encefálicas/metabolismo , Neoplasias da Mama/metabolismo , Feminino , Humanos , Neoplasias Meníngeas/terapia , Prognóstico , Estudos Prospectivos , Receptor ErbB-2/metabolismoRESUMO
BACKGROUND: Leptomeningeal disease (LMD) occurs as a late complication of several human cancers and has no rationally designed treatment options. A major barrier to developing effective therapies for LMD is the lack of cell-based or preclinical models that recapitulate human disease. Here, we describe the development of in vitro and in vivo cultures of patient-derived cerebrospinal fluid circulating tumor cells (PD-CSF-CTCs) from patients with melanoma as a preclinical model to identify exploitable vulnerabilities in melanoma LMD. METHODS: CSF-CTCs were collected from melanoma patients with melanoma-derived LMD and cultured ex vivo using human meningeal cell-conditioned media. Using immunoassays and RNA-sequencing analyses of PD-CSF-CTCs, molecular signaling pathways were examined and new therapeutic targets were tested for efficacy in PD-CSF-CTCs preclinical models. RESULTS: PD-CSF-CTCs were successfully established both in vitro and in vivo. Global RNA analyses of PD-CSF-CTCs revealed several therapeutically tractable targets. These studies complimented our prior proteomic studies highlighting IGF1 signaling as a potential target in LMD. As a proof of concept, combining treatment of ceritinib and trametinib in vitro and in vivo demonstrated synergistic antitumor activity in PD-CSF-CTCs and BRAF inhibitor-resistant melanoma cells. CONCLUSIONS: This study demonstrates that CSF-CTCs can be grown in vitro and in vivo from some melanoma patients with LMD and used as preclinical models. These models retained melanoma expression patterns and had signaling pathways that are therapeutically targetable. These novel models/reagents may be useful in developing rationally designed treatments for LMD.
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Melanoma , Neoplasias Meníngeas , Células Neoplásicas Circulantes , Meios de Cultivo Condicionados , Humanos , Melanoma/patologia , Neoplasias Meníngeas/patologia , Proteômica , Proteínas Proto-Oncogênicas B-raf/genética , RNARESUMO
PURPOSE OF REVIEW: Melanoma has one of the highest incidences of causing leptomeningeal disease (LMD) among solid tumors. LMD patients have very poor prognosis with a dismal survival despite aggressive management. In this article, we review the current approaches in the management of patients with LMD secondary to melanoma, including updates in diagnosis, treatment, up-to-date clinical studies, and future directions. RECENT FINDINGS: Cerebrospinal fluid (CSF) cytology remains the gold standard for diagnosis, and alternatively, MRI based on clinical presentation can be used. Other approaches such as "liquid biopsies" that detect circulating tumor cells and cell-free DNA have the potential to considerably enhance the diagnosis of LMD from melanoma. As for treatment options, several systemic therapies, involving systemic targeted and immunotherapies have evolved that showed to have possible benefit in LMD patients. Intrathecal chemotherapy, cellular therapy, and immunotherapy are currently under evaluation in Phase I/II clinical trials. In addition, new radiation therapy approaches such as proton cranial-spinal irradiation (CSI) are currently under investigation. LMD management still remains challenging. Future studies are critical to elucidate the pathophysiology of LMD in order to develop new urgently needed diagnostic tools and therapies. Clinical trials ought to be expanded to include patients with LMD. Future clinical studies should also integrate tissue interrogation, scientifically designed therapies, and aggressive, early intervention in patients with suspected LMD.
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Melanoma , Neoplasias Meníngeas , Terapia Combinada , Humanos , Imageamento por Ressonância Magnética , Melanoma/diagnóstico , Melanoma/terapia , Neoplasias Meníngeas/diagnóstico , Neoplasias Meníngeas/terapia , PrognósticoRESUMO
BACKGROUND: Leptomeningeal disease (LMD) is a devastating complication of systemic malignancy, of which there is an unclear etiology. The aim of this study is to determine if surgical or anatomic factors can predict LMD in patients with metastatic melanoma. METHODS: A retrospective chart review was performed of 1162 patients treated at single institution for melanoma brain metastases (MBM). Patients with fewer than 3 months follow-up or lacking appropriate imaging were excluded. Demographic information, surgical, and anatomic data were collected. RESULTS: Eight hundred and twenty-seven patients were included in the final review. On multivariate analysis for the entire cohort, female gender, dural-based and intraventricular metastasis, and tumor bordering CSF spaces were associated with increased risk of LMD. Surgical resection was not significant for risk of LMD. On multivariate analysis of patients who have undergone surgical resection of a metastatic tumor, dural-based and intraventricular metastasis, ventricular entry during surgery, and metastasis in the infratentorial space were associated with increased risk of LMD. On multivariate analysis of patients who did not undergo surgery, chemotherapy after initial diagnosis and metastasis bordering CSF spaces were associated with increased risk of LMD. CONCLUSION: In a single-institution cohort of MBM, we found that surgical resection alone did not result in an increased risk of LMD. Anatomical factors such as dural-based and intraventricular metastasis were significant for developing LMD, as well as entry into a CSF space during surgical resection. These data suggest a strong correlation between anatomic location and tumor cell seeding in relation to the development of LMD.
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Neoplasias Encefálicas , Melanoma , Neoplasias Meníngeas , Radiocirurgia , Neoplasias Encefálicas/secundário , Feminino , Humanos , Melanoma/cirurgia , Neoplasias Meníngeas/etiologia , Neoplasias Meníngeas/cirurgia , Radiocirurgia/efeitos adversos , Estudos RetrospectivosRESUMO
INTRODUCTION: BRAF V600 E mutations have been identified in a subset of patients with primary brain tumors. Combination therapy with BRAF and Mitogen-activated protein kinase (MEK) inhibitors (BRAF/MEKi) targeting sequential steps in the MAPK pathway has replaced BRAFi monotherapy as the standard of care in multiple tumors with BRAF V600 E mutations, and clinical evidence for this strategy continues to grow in primary brain tumors. CASE SERIES: We describe four patients with BRAF V600 E mutated gliomas, including a 21-year-old woman with a ganglioglioma WHO grade I, a 19-year-old man with a pleomorphic xanthoastrocytoma WHO grade III, and 21-year-old and 33-year-old women with epithelioid GBM WHO grade IV, who achieved durable progression-free survival with combination BRAF/MEKi. CONCLUSION: Combination of BRAF/MEK inhibition can be a novel, promising approach as targeted therapy in gliomas with BRAF V600 E mutations, especially those that are resistant to standard therapy. Our cases, along with other early reports utilizing dabrafenib/trametinib, highlight the importance of somatic next-generation sequencing, particularly in younger patients. Interim results from clinical trials utilizing dabrafenib/trametinib have been promising thus far, and our case series suggests that durable clinical benefit is possible, even in the setting of glioblastoma, WHO grade IV.
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Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Adulto , Feminino , Humanos , Masculino , Gradação de Tumores , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas B-raf/genética , Adulto JovemRESUMO
Toxin-induced leukoencephalopathy is a rare neurological condition that has been previously associated with intracranial radiation, chemotherapy, drugs of abuse, and environmental exposures. Herein, we present a patient with brain-biopsy proven toxin-induced leukoencephalopathy, likely secondary to multiple environmental offenders including insecticides and non-Food and Drug Administration approved anabolic steroids, opioids, and benzodiazepines. A 60-year-old man presented to our service as a direct transfer from an outside facility for evaluation of a rapidly progressive neuropsychiatric decline. Extensive workup with blood work, cerebrospinal fluid analysis, paraneoplastic panel, serial magnetic resonance imaging brain with and without contrast, and electroencephalograms were unrevealing. Magnetic resonance imaging brain showed diffuse confluent white matter disease, which was non-specific. The patient was treated with high-dose methylprednisolone and trials of intravenous immunoglobulin without any significant improvement. Finally, a brain biopsy was performed, and pathology confirmed a spongiform leukoencephalopathy, favoring a toxin-related etiology. The diagnosis of toxin-induced leukoencephalopathy should be considered in patients with steep neuropsychiatric decline and associated diffuse white matter disease. Diagnosis relies heavily on history of exposure, clinical presentation, imaging findings, and ultimately, histopathology from brain biopsy. The recognition of the clinical presentation is important to pursue the appropriate diagnostic workup and treatment.
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The use of immune checkpoint inhibitors including ipilimumab and nivolumab has expanded for several tumors including melanoma brain metastasis. These have resulted in a growing spectrum of neurologic immune-related adverse events, including ones that are rare and difficult to diagnose and treat. Here, we present a patient with melanoma brain metastasis who was treated with immune checkpoint inhibitors and developed an Acute Motor Axonal Neuropathy. To our knowledge, this is the first case of Acute Motor Axonal Neuropathy as an immune-related adverse event associated with combination treatment of ipilimumab and nivolumab, who was successfully treated. A 28-year-old woman with metastatic BRAF V600E melanoma developed melanoma brain metastasis and was enrolled on Checkmate 204, a Phase 2 clinical trial using ipilimumab (3 mg/kg intravenous) and nivolumab (1 mg/kg intravenous) every 3 weeks for four cycles, followed by monotherapy with nivolumab (240 mg intravenous) every 2 weeks. A few days after Cycle 2 of ipilimumab and nivolumab, she developed a pure motor axonal neuropathy consistent with Acute Motor Axonal Neuropathy. She was treated with several immunosuppressive treatments including high dose methylprednisolone, immune globulin, and infliximab, and her motor neuropathy eventually improved several months after onset of symptoms. Unfortunately, she had progression of her systemic disease and died several months later. This is the first case reported of Acute Motor Axonal Neuropathy associated with ipilimumab and nivolumab, successfully treated with immune-suppressive therapy. As the field of immunotherapy expands with the increasing use of the immune checkpoint inhibitors, it is critical to increase our knowledge and understanding of the neurologic immune-related adverse events associated with immune checkpoint inhibitors. This includes the spectrum of rare neurologic immune-related adverse events, which can be quite difficult to recognize and treat. Early consultations with neurology may expedite a diagnosis and treatment plan in patients with unexplained weakness receiving immune checkpoint inhibitor therapy.