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BMC Neurology Sep 2023Spinal neuraxis leptomeningeal metastasis (LM) relapse in glioblastoma is an uncommon event that is challenging to manage. This study aims to determine the incidence,...
BACKGROUND
Spinal neuraxis leptomeningeal metastasis (LM) relapse in glioblastoma is an uncommon event that is challenging to manage. This study aims to determine the incidence, associated factors, and outcome of LM relapse in patients with glioblastoma managed with radical intent.
METHODS
Patients managed for glioblastoma using the EORTC-NCIC (Stupp) Protocol from 2007 to 2019 were entered into a prospective ethics-approved database. Follow-up included routine cranial MRI surveillance with further imaging as clinically indicated. LM relapse was determined by MRI findings and/or cerebrospinal fluid analysis. The chi-square test of independence was used to evaluate clinico-pathologic factors associated with increased risk of subsequent LM relapse. Median survival post-LM relapse was calculated using Kaplan-Meier technique.
RESULTS
Four-hundred-and-seven patients were eligible, with median follow-up of 60 months for surviving patients. Eleven (2.7%) had LM at first relapse and in total 21 (5.1%) experienced LM in the entire follow-up period. Sites of LM relapse were 8 (38%) focal spinal, 2 (10%) focal brainstem medulla and 11 (52%) diffuse spinal. Median overall survival from initial diagnosis for the entire cohort was 17.6 months (95% CI 16.7-19.0). Median survival from LM relapse to death was 39 days (95% CI: 19-107). Factors associated with LM relapse were age less than 50 years (p < 0.01), initial disease located in the temporal lobe (p < 0.01) and tumours lacking MGMT promoter methylation (p < 0.01).
CONCLUSIONS
LM relapse is an uncommon but not rare event in patients managed radically for glioblastoma. It is associated with poor outcome with the majority of patients deceased within two months of recognition.
Topics: Humans; Middle Aged; Glioblastoma; Prospective Studies; Meningeal Carcinomatosis; Brain Stem; Chronic Disease
PubMed: 37715122
DOI: 10.1186/s12883-023-03378-1 -
Journal of Breast Cancer Dec 2023Most oncological treatments for leptomeningeal metastasis (LM) do not cross the blood-brain barrier (BBB). One therapeutic option is intrathecal (IT) chemotherapy. Both...
PURPOSE
Most oncological treatments for leptomeningeal metastasis (LM) do not cross the blood-brain barrier (BBB). One therapeutic option is intrathecal (IT) chemotherapy. Both the brain-implanted Omaya reservoir and lumbar puncture (LP) are classic routes for IT chemotherapy delivery. An intrathecal catheter (IC) connected to a subcutaneous port is a recently developed option for the management of chemotherapy infusions. It is essential to evaluate the efficacy and safety of chemotherapy infusion using such device.
METHODS
We conducted a retrospective monocentric study within Institut de cancerologie de l'Ouest at Angers, including all patients with advanced breast cancer (aBC) with LM implanted with an IT device for IT chemotherapy between January 2013 and May 2020. The primary endpoint was overall survival (OS) and secondary endpoints included surgical feasibility, patient safety, and progression-free survival (PFS). The catheter was inserted through an LP, the tip was positioned at the right level and connected to a subcutaneous port implanted under the skin of the anterior thoracic wall. IT chemotherapy is painless and easy for qualified nurses to administer on an outpatient basis.
RESULTS
Thirty women underwent the implantation. No failures occurred during the procedure. A total of 77% of patients reported no complications after implantation. Only three complications required surgical treatment. The median number of IT chemotherapy courses per patient was 8 (range, 2-27). The tolerance profile for iterative IT chemotherapy was manageable in ambulatory care. With a median follow-up of 76.5 months (95% confidence interval [CI], 11.6-not available), the median OS was 158 days (95% CI, 87-235), and the median PFS was 116 days (95% CI, 58-174).
CONCLUSION
Infusing chemotherapy using an implanted catheter is an efficient option for managing IT chemotherapy with a good tolerance profile. Patient-reported outcomes for the evaluation of IT chemotherapy toxicity are currently being developed.
PubMed: 37704384
DOI: 10.4048/jbc.2023.26.e40 -
Journal of Neuro-oncology Sep 2023Leptomeningeal carcinomatosis (LC) is a rare complication of non-small cell lung cancer (NSCLC) with highly mortality. Cerebrospinal fluid (CSF) as a special kind of...
PURPOSE
Leptomeningeal carcinomatosis (LC) is a rare complication of non-small cell lung cancer (NSCLC) with highly mortality. Cerebrospinal fluid (CSF) as a special kind of tumor microenvironment (TME) better represents alterations than plasma. However, the clinical value of protein profiles of exosome in CSF as liquid biopsy remains unclear.
METHODS
In this study, CSF samples of NSCLC patients with (LC group) or without (NSCLC group) LC were collected and compared to patients without tumors (normal group). CSF exosomes were isolated by ultracentrifugation and protein profiles were performed by label-free proteomics. Differentially expressed proteins (DEPs) were detected by bioinformatics tools and verified by parallel reaction monitoring (PRM).
RESULTS
A total of 814 proteins were detected. Bioinformatics analysis revealed their shared function in the complement activation, extracellular region, and complement and coagulation cascades. Between LC and NSCLC group, 72 DEPs were found among which FN1 demonstrated the highest betweenness centrality (BC) after protein-protein interaction network analysis.
CONCLUSION
We investigated the application of label free and PRM based proteomics to detect key proteins related to LC. FN1 may serve as potential indicator to classify LC and NSCLC. Extracellular matrix (ECM) and epithelial-mesenchymal transition (EMT) are important in the process of LC. These data is promising for early prediction and diagnosis of LC.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Meningeal Carcinomatosis; Proteomics; Liquid Biopsy; Tumor Microenvironment
PubMed: 37656377
DOI: 10.1007/s11060-023-04428-x -
International Journal of Molecular... Jul 2023Leptomeningeal disease (LMD) is a devastating complication of cancer with a particularly poor prognosis. Among solid tumours, malignant melanoma (MM) has one of the... (Review)
Review
Leptomeningeal disease (LMD) is a devastating complication of cancer with a particularly poor prognosis. Among solid tumours, malignant melanoma (MM) has one of the highest rates of metastasis to the leptomeninges, with approximately 10-15% of patients with advanced disease developing LMD. Tumour cells that metastasise to the brain have unique properties that allow them to cross the blood-brain barrier, evade the immune system, and survive in the brain microenvironment. Metastatic colonisation is achieved through dynamic communication between metastatic cells and the tumour microenvironment, resulting in a tumour-permissive milieu. Despite advances in treatment options, the incidence of LMD appears to be increasing and current treatment modalities have a limited impact on survival. This review provides an overview of the biology of LMD, diagnosis and current treatment approaches for MM patients with LMD, and an overview of ongoing clinical trials. Despite the still limited efficacy of current therapies, there is hope that emerging treatments will improve the outcomes for patients with LMD.
Topics: Humans; Meningeal Carcinomatosis; Melanoma; Brain; Skin Neoplasms; Meningeal Neoplasms; Tumor Microenvironment; Melanoma, Cutaneous Malignant
PubMed: 37511202
DOI: 10.3390/ijms241411443 -
Encephalitis (Seoul, Korea) Jan 2023When a patient with encephalopathy has an organic brain lesion, his symptom is easily and often mistakenly attributed to that brain lesion. However, a combination of...
Autoimmune limbic encephalitis combined with leptomeningeal metastases of non-small cell lung cancer: treatment response to osimertinib, immunoglobulin, rituximab, and tocilizumab.
When a patient with encephalopathy has an organic brain lesion, his symptom is easily and often mistakenly attributed to that brain lesion. However, a combination of different conditions is also possible. We present a case of autoimmune limbic encephalitis combined with leptomeningeal carcinomatosis. A 57-year-old female patient was transferred to our institute with a 1-month history of seizure and aggressive behavior. Subacute onset of psychosis with multifocal T2 high signal lesions suggested autoimmune encephalitis, and high-dose steroid pulse and immunoglobulin therapy were started. However, a cerebrospinal fluid study revealed metastatic adenocarcinoma of non-small cell lung cancer, of which she was in complete remission state. Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, was started targeting leptomeningeal metastases while maintaining immunotherapy of rituximab and tocilizumab. Her neurological symptoms showed improvement in response to immunotherapy which lasted approximately 1 month and then deteriorated again. We concluded that her symptoms were more attributable to autoimmune encephalitis than leptomeningeal carcinomatosis, and discontinued osimertinib.
PubMed: 37469717
DOI: 10.47936/encephalitis.2022.00122 -
Annals of Palliative Medicine Nov 2023As novel systemic therapies allow patients to live longer with cancer, the risk of developing central nervous system (CNS) metastases increases and providers will more... (Review)
Review
BACKGROUND AND OBJECTIVE
As novel systemic therapies allow patients to live longer with cancer, the risk of developing central nervous system (CNS) metastases increases and providers will more frequently encounter emergent presentation of brain metastases (BM) and leptomeningeal metastases (LM). Management of these metastases requires appropriate work-up and well-coordinated multidisciplinary care. We set out to perform a review of emergent radiotherapy (RT) for CNS metastases, specifically focusing on BM and LM.
METHODS
We review the appropriate pathways for workup and initial management of BM and LM, while reviewing the literature supporting emergent treatment of these entities with surgery, systemic anti-cancer therapy, and RT. To inform this narrative review, literature searches in PubMed and Google Scholar were conducted, with preference given to articles employing modern RT techniques, when applicable. Due to the paucity of high-quality evidence for management of BM and LM in the emergent setting, discussion was supplemented by the authors' expert commentary.
KEY CONTENT AND FINDINGS
This work highlights the importance of surgical evaluation, particularly for patients presenting with significant mass effect, hemorrhagic metastases, or increased intracranial pressure. We review the rare situations where emergent initiation of systemic anti-cancer therapy is indicated. When defining the role of RT, we review factors guiding selection of appropriate modality, treatment volume, and dose-fractionation. Generally, 2D- or 3D-conformal treatment techniques prescribed as 30 Gy in 10 fractions or 20 Gy in 5 fractions, should be employed in the emergent setting.
CONCLUSIONS
Patients with BM and LM present from a diverse array of clinical situations, requiring well-coordinated multidisciplinary management, and there is a paucity of high-quality evidence guiding such management decisions. This narrative review aims to more thoroughly prepare providers for the challenging situation of emergent management of BM and LM.
Topics: Humans; Meningeal Carcinomatosis; Brain Neoplasms; Brain
PubMed: 37431225
DOI: 10.21037/apm-22-1276 -
Current Oncology (Toronto, Ont.) Jun 2023The present review aimed to establish an understanding of the pathophysiology of leptomeningeal disease as it relates to late-stage development among different cancer... (Review)
Review
The present review aimed to establish an understanding of the pathophysiology of leptomeningeal disease as it relates to late-stage development among different cancer types. For our purposes, the focused metastatic malignancies include breast cancer, lung cancer, melanoma, primary central nervous system tumors, and hematologic cancers (lymphoma, leukemia, and multiple myeloma). Of note, our discussion was limited to cancer-specific leptomeningeal metastases secondary to the aforementioned primary cancers. LMD mechanisms secondary to non-cancerous pathologies, such as infection or inflammation of the leptomeningeal layer, were excluded from our scope of review. Furthermore, we intended to characterize general leptomeningeal disease, including the specific anatomical infiltration process/area, CSF dissemination, manifesting clinical symptoms in patients afflicted with the disease, detection mechanisms, imaging modalities, and treatment therapies (both preclinical and clinical). Of these parameters, leptomeningeal disease across different primary cancers shares several features. Pathophysiology regarding the development of CNS involvement within the mentioned cancer subtypes is similar in nature and progression of disease. Consequently, detection of leptomeningeal disease, regardless of cancer type, employs several of the same techniques. Cerebrospinal fluid analysis in combination with varied imaging (CT, MRI, and PET-CT) has been noted in the current literature as the gold standard in the diagnosis of leptomeningeal metastasis. Treatment options for the disease are both varied and currently in development, given the rarity of these cases. Our review details the differences in leptomeningeal disease as they pertain through the lens of several different cancer subtypes in an effort to highlight the current state of targeted therapy, the potential shortcomings in treatment, and the direction of preclinical and clinical treatments in the future. As there is a lack of comprehensive reviews that seek to characterize leptomeningeal metastasis from various solid and hematologic cancers altogether, the authors intended to highlight not only the overlapping mechanisms but also the distinct patterning of disease detection and progression as a means to uniquely treat each metastasis type. The scarcity of LMD cases poses a barrier to more robust evaluations of this pathology. However, as treatments for primary cancers have improved over time, so has the incidence of LMD. The increase in diagnosed cases only represents a small fraction of LMD-afflicted patients. More often than not, LMD is determined upon autopsy. The motivation behind this review stems from the increased capacity to study LMD in spite of scarcity or poor patient prognosis. In vitro analysis of leptomeningeal cancer cells has allowed researchers to approach this disease at the level of cancer subtypes and markers. We ultimately hope to facilitate the clinical translation of LMD research through our discourse.
Topics: Humans; Female; Positron Emission Tomography Computed Tomography; Meningeal Carcinomatosis; Breast Neoplasms; Magnetic Resonance Imaging; Hematologic Neoplasms
PubMed: 37366925
DOI: 10.3390/curroncol30060442 -
CNS Oncology Sep 2023We recently reported the largest trial of breast cancer patients with HER2 positive leptomeningeal metastases (LM) treated with trastuzumab. An additional treatment...
We recently reported the largest trial of breast cancer patients with HER2 positive leptomeningeal metastases (LM) treated with trastuzumab. An additional treatment indication was explored as part of a single institution retrospective case series of HER2 positive esophageal adenocarcinoma LM (n = 2). One patient received intrathecal trastuzumab (80 mg twice weekly) as part of their treatment regimen with durable long-term response and clearance of circulating tumor cells in the cerebral spinal fluid. The other patient demonstrated rapid progression and death as previously described in the literature. Intrathecal trastuzumab is a well-tolerated and reasonable therapeutic option worthy of further exploration for patients with HER2 positive esophageal carcinoma LM. An associative, but not a causal relationship, can be made regarding therapeutic intervention.
Topics: Humans; Female; Retrospective Studies; Receptor, ErbB-2; Trastuzumab; Breast Neoplasms; Meningeal Carcinomatosis; Carcinoma; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37219390
DOI: 10.2217/cns-2022-0018 -
Romanian Journal of Internal Medicine =... Sep 2023Leptomeningeal spread with carcinomatous meningitis is a severe complication of glioblastoma, with a poor prognosis. Diagnosis is challenging, as the sensitivity of...
BACKGROUND
Leptomeningeal spread with carcinomatous meningitis is a severe complication of glioblastoma, with a poor prognosis. Diagnosis is challenging, as the sensitivity of classic diagnostic investigations remains low for detecting cerebrospinal fluid (CSF) tumor spread and exclusion of infectious causes is mandatory, especially if unusual clinical findings are present.
CASE PRESENTATION
A 71-year-old woman was admitted to our hospital for recurrent episodes of high fever and xanthochromic meningitis, with subacute onset. Her past medical history was significant for a left temporal glioblastoma, treated with surgical resection and adjuvant chemo- and radiotherapy, with associated systemic immunosuppression secondary to chemotherapy. An extensive workup especially with molecular microbiology testing for exclusion of infectious causes was performed. CSF was analyzed for typical bacterial and viral causes, but also pathogens associated with immunosuppression, such as and A therapeutic trial of standard antituberculous drugs with repeated lumbar punctures were needed in order to exclude and to confirm the diagnosis of carcinomatous meningitis by cytopathological examination of the CSF.
CONCLUSIONS
The case describes an unusual clinical presentation of a patient with glioblastoma associated leptomeningeal dissemination, as high fever and xanthochromic CSF could raise important diagnostic and therapeutic challenges in the clinical practice. The diagnosis of carcinomatous meningitis requires an extensive workup for exclusion of infectious causes which is important for urgent oncologic treatment.
Topics: Female; Humans; Aged; Meningeal Carcinomatosis; Glioblastoma; Spinal Puncture
PubMed: 37148304
DOI: 10.2478/rjim-2023-0010 -
PeerJ 2023Leptomeningeal carcinomatosis (LMC) is a rare type of cancer that settles at the meninges through metastasis of non-small cell lung cancer (NSCLC), breast cancer and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Leptomeningeal carcinomatosis (LMC) is a rare type of cancer that settles at the meninges through metastasis of non-small cell lung cancer (NSCLC), breast cancer and melanoma. The molecular mechanism underlying LMC is not known, therefore molecular studies investigating the development of LMC are needed. Here, we aimed to identify commonly mutated genes in LMC caused by NSCLC, breast cancer, and melanoma using an in-slico approach and their interactions using integrated bioinformatic approaches/tools in this meta-analysis.
METHODS
We conducted a meta-analysis using information from 16 studies that included different sequencing techniques of patients with LMC caused by three different primary cancers: breast cancer, NSCLC, and melanoma. All studies that assessed mutation information from patients with LMC were searched in PubMed, from their inception to February, 16 2022. Studies that performed NGS on LMC patients with NSCLC, breast cancer, or melanoma were included, while studies that did not apply NGS to CSF samples, did not provide information on altered genes, were reviews, editorials, or conference abstracts, or whose main goal was the detection of malignancies were all excluded. We identified commonly mutated genes in all three types of cancer. Next, we constructed a protein-protein interaction network, then performed pathway enrichment analysis. We searched National Institutes of Health (NIH) and Drug-Gene Interaction Database (DGIdb) to find candidate drugs.
RESULTS
We found that , and genes were commonly mutated genes in all three types of cancer our meta-analysis that consisted out of 16 studies. Our pathway enrichment analysis showed that all five genes were primarily associated with regulation of cell communication and signaling, and cell proliferation. Other enriched pathways included regulation of apoptotic processes of leukocytes and fibroblasts, macroautophagy and growth. According to our drug search we found candidate drugs; Everolimus, Bevacizumab and Temozolomide, which interact with these five genes.
CONCLUSION
In conclusion, a total of 96 mutated genes in LMC were investigated meta-analysis. Our findings suggested vital roles of , and , which can provide insight into the molecular basis of LMC development and paving the door to the development of new targeted medicine and will encourage molecular biologists to seek biological evidence.
Topics: United States; Humans; Female; Carcinoma, Non-Small-Cell Lung; Meningeal Carcinomatosis; Lung Neoplasms; Breast Neoplasms; Melanoma
PubMed: 37096065
DOI: 10.7717/peerj.15250