A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases.
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ABSTRACT:
SUBMITTER: Garzia L
PROVIDER: S-EPMC6346737 | biostudies-literature | 2018 Feb
REPOSITORIES: biostudies-literature
Publications
A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases.
Garzia Livia L Kijima Noriyuki N Morrissy A Sorana AS De Antonellis Pasqualino P Guerreiro-Stucklin Ana A Holgado Borja L BL Wu Xiaochong X Wang Xin X Parsons Michael M Zayne Kory K Manno Alex A Kuzan-Fischer Claudia C Nor Carolina C Donovan Laura K LK Liu Jessica J Qin Lei L Garancher Alexandra A Liu Kun-Wei KW Mansouri Sheila S Luu Betty B Thompson Yuan Yao YY Ramaswamy Vijay V Peacock John J Farooq Hamza H Skowron Patryk P Shih David J H DJH Li Angela A Ensan Sherine S Robbins Clinton S CS Cybulsky Myron M Mitra Siddhartha S Ma Yussanne Y Moore Richard R Mungall Andy A Cho Yoon-Jae YJ Weiss William A WA Chan Jennifer A JA Hawkins Cynthia E CE Massimino Maura M Jabado Nada N Zapotocky Michal M Sumerauer David D Bouffet Eric E Dirks Peter P Tabori Uri U Sorensen Poul H B PHB Brastianos Priscilla K PK Aldape Kenneth K Jones Steven J M SJM Marra Marco A MA Woodgett James R JR Wechsler-Reya Robert J RJ Fults Daniel W DW Taylor Michael D MD
Cell 20180201 5
While the preponderance of morbidity and mortality in medulloblastoma patients are due to metastatic disease, most research focuses on the primary tumor due to a dearth of metastatic tissue samples and model systems. Medulloblastoma metastases are found almost exclusively on the leptomeningeal surface of the brain and spinal cord; dissemination is therefore thought to occur through shedding of primary tumor cells into the cerebrospinal fluid followed by distal re-implantation on the leptomeninge ...[more]
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Project description:BackgroundDiagnosis of leptomeningeal metastasis (LM) has become increasingly frequent. The diagnostic gold standard has been CSF cytology, but MRI is now used routinely for diagnosis. Diagnosis and prognosis of LM has not been studied in the MRI era.MethodsPatients with LM from 2002 through 2004 were identified through a neurology database, as well as by reviewing all abnormal CSF cytologies from a pathology database. Diagnosis was made by malignant cytology or imaging; suspicious cases treated as LM were also included.ResultsA total of 187 patients with LM were analyzed in this retrospective review. Of these, 150 had solid and 37 had hematopoietic malignancies. Median age was 56.4 years, and median Karnofsky performance status (KPS) was 70. The most common types of solid tumor were breast (65 patients), lung (47), gastrointestinal (11), and melanoma (9). Of the hematopoietic tumors, 21 were lymphoma and 15 were leukemia. Fifty-three percent of patients were diagnosed by imaging, 23% by cytology, and 24% by both. Treatment included radiation therapy in 55%, intrathecal chemotherapy in 29%, and systemic chemotherapy in 18%; 21% received supportive care alone. Median overall survival was 2.4 (95% confidence interval 1.9-3.1) months. Median survival for patients with hematopoietic tumors was 4.7 months and for solid tumors was 2.3 months (p = 0.0006). In multivariate analysis, initial KPS and tumor type (solid vs hematopoietic) were significant predictors of survival.ConclusionsDespite enhanced diagnosis with MRI, prognosis remains poor in leptomeningeal metastasis. Those with hematopoietic tumors continue to fare better than those with solid tumors.
| S-EPMC2871005 | biostudies-literature
Project description:The goal of treatment of leptomeningeal metastasis is to improve survival and to maintain quality of life by delaying neurological deterioration. Tumour-specific therapeutic options include intrathecal pharmacotherapy, systemic pharmacotherapy and focal radiotherapy. Recently, improvement of leptomeningeal disease-related progression-free survival by adding intrathecal liposomal cytarabine to systemic treatment versus systemic treatment alone has been observed in a randomised phase III trial for patients with breast cancer with newly diagnosed leptomeningeal metastasis. Safety and efficacy of intrathecal administration of new agents such as trastuzumab are under evaluation. Systemic therapy using targeted agents and immunotherapy has also improved outcome in patients with brain metastasis, and its emerging role in the management of leptomeningeal metastasis needs to better studied in prospective series. Focal radiotherapy is commonly indicated for the treatment of macroscopic disease such as meningeal nodules or clinically symptomatic central nervous system structures, for example, base of skull with cranial nerve involvement or cauda equine syndrome. The role of whole brain radiotherapy is decreasing. An individualised combination of different therapeutic options should be used considering the presentation of leptomeningeal metastasis, as well as the histological and molecular tumour characteristics, the presence of concomitant brain and systemic metastases, and prior cancer-directed treatments.
| S-EPMC6555600 | biostudies-literature
Project description:Leptomeningeal metastasis (LM) results from metastatic spread of cancer to the leptomeninges, giving rise to central nervous system dysfunction. Breast cancer, lung cancer, and melanoma are the most frequent causes of LM among solid tumors in adults. An early diagnosis of LM, before fixed neurologic deficits are manifest, permits earlier and potentially more effective treatment, thus leading to a better quality of life in patients so affected. Apart from a clinical suspicion of LM, diagnosis is dependent upon demonstration of cancer in cerebrospinal fluid (CSF) or radiographic manifestations as revealed by neuraxis imaging. Potentially of use, though not commonly employed, today are use of biomarkers and protein profiling in the CSF. Symptomatic treatment is directed at pain including headache, nausea, and vomiting, whereas more specific LM-directed therapies include intra-CSF chemotherapy, systemic chemotherapy, and site-specific radiotherapy. A special emphasis in the review discusses novel agents including targeted therapies, that may be promising in the future management of LM. These new therapies include anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors erlotinib and gefitinib in nonsmall cell lung cancer, anti-HER2 monoclonal antibody trastuzumab in breast cancer, anti-CTLA4 ipilimumab and anti-BRAF tyrosine kinase inhibitors such as vermurafenib in melanoma, and the antivascular endothelial growth factor monoclonal antibody bevacizumab are currently under investigation in patients with LM. Challenges of managing patients with LM are manifold and include determining the appropriate patients for treatment as well as the optimal route of administration of intra-CSF drug therapy.
| S-EPMC3656567 | biostudies-literature
Project description: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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Project description:The management of breast cancer (BC) has rapidly evolved in the last 20 years. The improvement of systemic therapy allows a remarkable control of extracranial disease. However, brain (BM) and leptomeningeal metastases (LM) are frequent complications of advanced BC and represent a challenging issue for clinicians. Some prognostic scales designed for metastatic BC have been employed to select fit patients for adequate therapy and enrollment in clinical trials. Different systemic drugs, such as targeted therapies with either monoclonal antibodies or small tyrosine kinase molecules, or modified chemotherapeutic agents are under investigation. Major aims are to improve the penetration of active drugs through the blood-brain barrier (BBB) or brain-tumor barrier (BTB), and establish the best sequence and timing of radiotherapy and systemic therapy to avoid neurocognitive impairment. Moreover, pharmacologic prevention is a new concept driven by the efficacy of targeted agents on macrometastases from specific molecular subgroups. This review aims to provide an overview of the clinical and molecular factors involved in the selection of patients for local and/or systemic therapy, as well as the results of clinical trials on advanced BC. Moreover, insight on promising therapeutic options and potential directions of future therapeutic targets against BBB and microenvironment are discussed.
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Project description:BackgroundLeptomeningeal metastases (LM) are associated with limited survival and treatment options. While involved-field radiotherapy is effective for local palliation, it lacks durability. We evaluated the toxicities of proton craniospinal irradiation (CSI), a treatment encompassing the entire central nervous system (CNS) compartment, for patients with LM from solid tumors.MethodsWe enrolled patients with LM to receive hypofractionated proton CSI in this phase I prospective trial. The primary endpoint was to describe treatment-related toxicity, with dose-limiting toxicity (DLT) defined as any radiation-related grade 3 non-hematologic toxicity or grade 4 hematologic toxicity according to the Common Terminology Criteria for Adverse Events that occurred during or within 4 weeks of completion of proton CSI. Secondary endpoints included CNS progression-free survival (PFS) and overall survival (OS).ResultsWe enrolled 24 patients between June 2018 and April 2019. Their median follow-up was 11 months. Twenty patients were evaluable for protocol treatment-related toxicities and 21 for CNS PFS and OS. Two patients in the dose expansion cohort experienced DLTs consisted of grade 4 lymphopenia, grade 4 thrombocytopenia, and/or grade 3 fatigue. All DLTs resolved without medical intervention. The median CNS PFS was 7 months (95% CI: 5-13) and the median OS was 8 months (95% CI: 6 to not reached). Four patients (19%) were progression-free in the CNS for more than 12 months.ConclusionHypofractionated proton CSI using proton therapy is a safe treatment for patients with LM from solid tumors. We saw durable disease control in some patients.
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Project description:We describe video electroencephalography (video-EEG) correlates of transient neurological attacks due to plateau waves-paroxysmal elevations in intracranial pressure-in patients with leptomeningeal metastases. We identified 3 patients with leptomeningeal metastases, intracranial hypertension, and transient neurological attacks captured on video-EEG without evidence of seizures or epileptiform activity. We identified all clinical events on video and reviewed the corresponding EEG data for evidence of abnormalities. All 3 patients had mild to moderate slowing and 2 had frontal intermittent rhythmic delta activity during background EEG recording. There were 33 clinical events recorded and stereotyped for each patient. All 33 events were associated with an increase in delta range slowing of ?30% compared to the background. This abnormality started ?2 minutes before the onset of clinical symptoms and persisted for minutes after clinical resolution. This study is the first to carefully describe the electrographic correlates of transient neurological attacks due to plateau waves in patients with leptomeningeal metastasis. Clinical attacks were consistently associated with a possible EEG signature of diffuse delta range slowing. Future studies can validate the sensitivity and specificity of these EEG changes as a prognostic and/or response biomarker in patients with leptomeningeal metastases with or without intracranial hypertension.
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Project description:Diagnosing leptomeningeal metastasis (LM) in medulloblastoma is currently based on positive cerebrospinal fluid (CSF) cytology or magnetic resonance imaging (MRI) finding. However, the relevance of discordant results has not been established. We evaluated the diagnostic potential of CSF metabolomic profiles in the medulloblastoma LM assessment. A total of 83 CSF samples from medulloblastoma patients with documented MRI and CSF cytology results at the time of sampling for LM underwent low-mass ions (LMIs) analysis using liquid chromatography-mass spectrometry. Discriminating LMIs were selected by a summed sensitivity and specificity (>160%) and LMI discriminant equation (LOME) algorithms, evaluated by measuring diagnostic accuracy for verifying LM groups of different MRI/cytology results. Diagnostic accuracy of LM in medulloblastoma was 0.722 for cytology and 0.889 for MRI. Among 6572 LMIs identified in all sample, we identified 27 discriminative LMIs differentiating MRI (+)/cytology (+) from MRI (-)/cytology (-). Using LMI discriminant equation (LOME) analysis, we selected 9 LMIs with a sensitivity of 100% and a specificity of 93.6% for differentiating MRI (+)/cytology (+) from MRI (-)/cytology (-). Another LOME of 20 LMIs significantly differentiated sampling time relative to treatment (p = 0.007) and the presence or absence of LM-related symptoms (p = 0.03) in the MRI (+)/cytology (-) group. CSF metabolomics of medulloblastoma patients revealed significantly different profiles among LM diagnosed with different test results. We suggest that LM patients could be screened by appropriately selected LOME-generated LMIs to support LM diagnosis by either MRI or cytology alone.
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Project description:Intratumoral heterogeneity of breast cancer remains a major challenge in successful treatment. Failure of cancer therapies can also be accredited to inability to systemically eradicate cancer stem cells (CSCs). Recent evidence points to the role of epithelial-mesenchymal transition (EMT) in expanding the pool of tumor cells with CSCs features. Thus, we assessed expression level as well as heterogeneity of CSCs markers in primary tumors (PT), lymph node metastasis (LNM), and circulating tumor cells (CTCs)-enriched blood fractions in order to correlate them with signs of EMT activation as well as clinicopathological data of breast cancer patients. Level of CSCs markers (ALDH1, CD44, CD133, OCT-4, NANOG) and EMT markers was quantified in PT (N=107), LNM (N=56), and CTCs-enriched blood fractions (N=85). Heterogeneity of CSCs markers expression within each PT and LNM was assessed by calculating Gini Index. Percentage of ALDH1-positive cells was elevated in PT in comparison to LNM (P = .005). However, heterogeneity of the four CSCs markers: ALDH1 (P = .019), CD133 (P = .009), OCT-4 (P = .027), and CD44 (P < .001) was decreased in LNM. Samples classified as mesenchymal (post-EMT) showed elevated expression of CSCs markers (OCT-4 and CD44 in PT; OCT-4 in LNM; ALDH1, OCT-4, NANOG, CD44 in CTCs). Patients with mesenchymal-like CTCs had worse prognosis than patients with epithelial-like or no CTCs (P = .0025). CSCs markers are enriched in PT, LNM, and CTCs with mesenchymal features, but their heterogeneity is decreased in metastatic lymph nodes. Mesenchymal CTCs phenotype correlates with poor prognosis of the patients.
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Project description:Leptomeningeal metastasis is an uncommon but devastating complication. The incidence of non-Hodgkin's lymphoma has been increasing in recent decades, due to the poor central nervous system penetration of drugs and the prolonged overall survival of patients, leptomeningeal metastases has gradually increased over time. Patients with leptomeningeal metastases have short survival durations and poor quality of life; there are few studies about non-Hodgkin's lymphoma with leptomeningeal metastases. We investigated characteristics and outcomes of non-Hodgkin's lymphoma patients with leptomeningeal metastases.This study included 27 non-Hodgkin's lymphoma patients with leptomeningeal metastases diagnosed at Tianjin Medical University Cancer Institute and Hospital between 2013 and 2016. Statistical analysis was performed to investigate the overall survival of non-Hodgkin's lymphoma with leptomeningeal metastases.Diffuse large B cell lymphoma was the most common cancer subtype (21/27, 78%), and more than half of the patients showed extranodal involvement (18/27, 67%). Survival analysis has shown extranodal involvement (P?=?0.0205), International Prognostic Index (P?=?0.0112), performance status (P?<?0.0001), parenchymal involvement (P?=?0.0330) and received radiotherapy (P?=?0.0056) were predictive factors of prognosis for these patients with leptomeningeal metastases. Cox regression analysis has shown patients with concurrent parenchymal involvement and received radiotherapy are correlated with good prognosis.Given the small number of patients who were included, this study exhibited limitations with respect to analytical power and the random selection of patients. Nevertheless, this investigation revealed characteristics of non-Hodgkin's lymphoma patients with leptomeningeal metastases and suggested that such patients could benefit from multimodal therapy.
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