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American Family Physician Apr 2021Cerebrospinal fluid (CSF) analysis is a diagnostic tool for many conditions affecting the central nervous system. Urgent indications for lumbar puncture include... (Review)
Review
Cerebrospinal fluid (CSF) analysis is a diagnostic tool for many conditions affecting the central nervous system. Urgent indications for lumbar puncture include suspected central nervous system infection or subarachnoid hemorrhage. CSF analysis is not necessarily diagnostic but can be useful in the evaluation of other neurologic conditions, such as spontaneous intracranial hypotension, idiopathic intracranial hypertension, multiple sclerosis, Guillain-Barré syndrome, and malignancy. Bacterial meningitis has a high mortality rate and characteristic effects on CSF white blood cell counts, CSF protein levels, and the CSF:serum glucose ratio. CSF culture can identify causative organisms and antibiotic sensitivities. Viral meningitis can present similarly to bacterial meningitis but usually has a low mortality rate. Adjunctive tests such as CSF lactate measurement, latex agglutination, and polymerase chain reaction testing can help differentiate between bacterial and viral causes of meningitis. Immunocompromised patients may have meningitis caused by tuberculosis, neurosyphilis, or fungal or parasitic infections. Subarachnoid hemorrhage has a high mortality rate, and rapid diagnosis is key to improve outcomes. Computed tomography of the head is nearly 100% sensitive for subarachnoid hemorrhage in the first six hours after symptom onset, but CSF analysis may be required if there is a delay in presentation or if imaging findings are equivocal. Xanthochromia and an elevated red blood cell count are characteristic CSF findings in patients with subarachnoid hemorrhage. Leptomeningeal carcinomatosis can mimic central nervous system infection. It has a poor prognosis, and large-volume CSF cytology is diagnostic.
Topics: Central Nervous System Bacterial Infections; Central Nervous System Fungal Infections; Central Nervous System Infections; Central Nervous System Parasitic Infections; Central Nervous System Viral Diseases; Cerebrospinal Fluid; Cerebrospinal Fluid Proteins; Culture Techniques; Eosinophils; Glucose; Humans; Leukocytes; Lymphocytes; Meningeal Carcinomatosis; Meningitis, Cryptococcal; Neurosyphilis; Neutrophils; Polymerase Chain Reaction; Reference Values; Spinal Puncture; Subarachnoid Hemorrhage; Tuberculosis, Central Nervous System
PubMed: 33788511
DOI: No ID Found -
Clinical Cancer Research : An Official... Jan 2023Leptomeningeal metastasis (LM), also known as leptomeningeal carcinomatosis (LC), is a devastating complication of metastatic cancer that occurs when neoplastic cells... (Review)
Review
Leptomeningeal metastasis (LM), also known as leptomeningeal carcinomatosis (LC), is a devastating complication of metastatic cancer that occurs when neoplastic cells invade the meningeal space. Diagnosis of LM remains challenging given the heterogeneous signs and symptoms at presentation and requires thorough neurological examination, cerebrospinal fluid (CSF) analysis, and MRI of the brain and spine with gadolinium. Detecting neoplastic cells in the CSF is the gold standard for diagnosing leptomeningeal metastases; however, it has low sensitivity and may require multiple CSF samples. New emerging technologies, such as liquid biopsy of CSF, have increased sensitivity and specificity for detecting circulating tumor cells in CSF. The management of LM in patients with NSCLC requires an individualized multidisciplinary approach. Treatment options include surgery for ventricular shunt placement, radiation therapy to bulky or symptomatic disease sites, systemic or intrathecal chemotherapy, molecularly targeted agents, and, more recently, immunotherapy. Targeting actionable mutations in LM from NSCLC, such as EGFR tyrosine kinase inhibitors or anaplastic lymphoma kinase gene rearrangement inhibitors, has shown encouraging results in terms of disease control and survival. Although there are limited data regarding the use of immunotherapy in LM, immunotherapy has produced promising results in several case reports. In this review, we focused on the epidemiology, pathophysiology, clinical presentation, diagnosis, and current treatment strategies, with a special emphasis on novel agents, including targeted therapies and immunotherapy of LM in patients with NSCLC.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Meningeal Carcinomatosis; Antineoplastic Agents; Prognosis
PubMed: 35972437
DOI: 10.1158/1078-0432.CCR-22-1585 -
Journal of Clinical Oncology : Official... Nov 2022Photon involved-field radiotherapy (IFRT) is the standard-of-care radiotherapy for patients with leptomeningeal metastasis (LM) from solid tumors. We tested whether... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Photon involved-field radiotherapy (IFRT) is the standard-of-care radiotherapy for patients with leptomeningeal metastasis (LM) from solid tumors. We tested whether proton craniospinal irradiation (pCSI) encompassing the entire CNS would result in superior CNS progression-free survival (PFS) compared with IFRT.
PATIENTS AND METHODS
We conducted a randomized, phase II trial of pCSI versus IFRT in patients with non-small-cell lung cancer and breast cancers with LM. We enrolled patients with other solid tumors to an exploratory pCSI group. For the randomized groups, patients were assigned (2:1), stratified by histology and systemic disease status, to pCSI or IFRT. The primary end point was CNS PFS. Secondary end points included overall survival (OS) and treatment-related adverse events (TAEs).
RESULTS
Between April 16, 2020, and October 11, 2021, 42 and 21 patients were randomly assigned to pCSI and IFRT, respectively. At planned interim analysis, a significant benefit in CNS PFS was observed with pCSI (median 7.5 months; 95% CI, 6.6 months to not reached) compared with IFRT (2.3 months; 95% CI, 1.2 to 5.8 months; < .001). We also observed OS benefit with pCSI (9.9 months; 95% CI, 7.5 months to not reached) versus IFRT (6.0 months; 95% CI, 3.9 months to not reached; = .029). There was no difference in the rate of grade 3 and 4 TAEs ( = .19). In the exploratory pCSI group, 35 patients enrolled, the median CNS PFS was 5.8 months (95% CI, 4.4 to 9.1 months) and OS was 6.6 months (95% CI, 5.4 to 11 months).
CONCLUSION
Compared with photon IFRT, we found pCSI improved CNS PFS and OS for patients with non-small-cell lung cancer and breast cancer with LM with no increase in serious TAEs.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Protons; Craniospinal Irradiation; Lung Neoplasms; Proton Therapy; Meningeal Carcinomatosis; Antineoplastic Combined Chemotherapy Protocols
PubMed: 35802849
DOI: 10.1200/JCO.22.01148 -
Lung Cancer (Amsterdam, Netherlands) Dec 2022Leptomeningeal metastasis (LM) is a rare complication of non-small cell lung cancer (NSCLC) with highly mortality. LM will occur once tumor cells spread to the... (Review)
Review
Leptomeningeal metastasis (LM) is a rare complication of non-small cell lung cancer (NSCLC) with highly mortality. LM will occur once tumor cells spread to the cerebrospinal fluid (CSF) space. Patients may suffer blindness, paralysis, and mental disorders that seriously affect their quality of life. There is a clear unmet need to improve the efficacy of diagnosis and treatment of LM. To better solve this problem, it is helpful to clarify the potential mechanisms of LM. Clinical manifestations, magnetic resonance imaging, and CSF biopsy are the key components in the diagnosis of NSCLC with LM. CSF cytology is insufficient and should be combined with liquid biology. The application of radiotherapy, intrathecal treatment, targeted therapy and immunotherapy provides more options for LM patients. Each treatment has a particular level of efficacy and can be used alone or in combination for individual patients. New technologies in radiotherapy, drug repositioning in intrathecal treatment, and the higher CSF permeability in TKIs have brought new breakthroughs in the treatment of LM. This review focused on clarifying the potential mechanisms, discussing the major clinical challenges, and summarizing recent advances in the diagnosis and treatment of LM from NSCLC. Future research is essential to improve the efficiency of diagnosis, to optimize therapy and to enhance patient prognosis.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Quality of Life; Meningeal Carcinomatosis; Prognosis
PubMed: 36206679
DOI: 10.1016/j.lungcan.2022.09.013 -
Journal of Clinical Oncology : Official... Feb 2020In this phase I study (BLOOM), osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), was evaluated in patients with...
PURPOSE
In this phase I study (BLOOM), osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), was evaluated in patients with leptomeningeal metastases (LMs) from EGFR-mutated (EGFRm) advanced non-small-cell lung cancer (NSCLC) whose disease had progressed on previous EGFR-TKI therapy.
PATIENTS AND METHODS
Patients with cytologically confirmed LM received osimertinib 160 mg once daily. Objectives were to assess confirmed objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), pharmacokinetics (PK), and safety. Additional efficacy evaluations included changes from baseline in CSF cytology and neurologic examination. Measurable lesions were assessed by investigator according to RECIST version 1.1. LMs were assessed by neuroradiologic blinded central independent review (BICR) according to Response Assessment in Neuro-Oncology LM radiologic criteria and by investigator.
RESULTS
Forty-one patients were enrolled. LM ORR and DoR by neuroradiologic BICR were 62% (95% CI, 45% to 78%) and 15.2 months (95% CI, 7.5 to 17.5 months), respectively. Overall, ORR by investigator was 41% (95% CI, 26% to 58%), and median DoR was 8.3 months (95% CI, 5.6 to 16.5 months). Median investigator-assessed PFS was 8.6 months (95% CI, 5.4 to 13.7 months) with 78% maturity; median OS was 11.0 months (95% CI, 8.0 to 18.0 months) with 68% maturity. CSF tumor cell clearance was confirmed in 11 (28%; 95% CI, 15% to 44%) of 40 patients. Neurologic function was improved in 12 (57%) of 21 patients with an abnormal assessment at baseline. The adverse event and PK profiles were consistent with previous reports for osimertinib.
CONCLUSION
Osimertinib showed meaningful therapeutic efficacy in the CNS and a manageable safety profile at 160 mg once daily in patients with EGFRm NSCLC and LM.
Topics: Acrylamides; Adult; Aged; Aniline Compounds; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Female; Humans; Lung Neoplasms; Male; Meningeal Carcinomatosis; Middle Aged; Mutation
PubMed: 31809241
DOI: 10.1200/JCO.19.00457 -
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 -
Journal of Thoracic Oncology : Official... Jun 2020
Topics: Acrylamides; Amphiregulin; Aniline Compounds; Carbazoles; Humans; Lung Neoplasms; Meningeal Carcinomatosis; Piperidines; Receptor Protein-Tyrosine Kinases
PubMed: 32471570
DOI: 10.1016/j.jtho.2020.03.010 -
Clinical and Translational Medicine Jun 2022Leptomeningeal metastases (LM) occur in patients with breast cancer (BC) and lung cancer (LC) showing exceptionally poor prognosis. The cerebrospinal fluid (CSF) tumour...
Leptomeningeal metastases (LM) occur in patients with breast cancer (BC) and lung cancer (LC) showing exceptionally poor prognosis. The cerebrospinal fluid (CSF) tumour microenvironment (TME) of LM patients is not well defined at a single-cell level. Based on the 10× genomics single-cell RNA sequencing (scRNA-seq) data from GEO database including five patient-derived CSF samples of BC-LM and LC-LM, and four patient-derived CSF samples of idiopathic intracranial hypertension (IIH) as controls, we analysed single-cell transcriptome characteristics of CSF TME in LM patients compared to controls simultaneously and comprehensively. In addition, we performed 10× genomics scRNA-seq on CSF cells derived from a BC-LM patient to help generate a solid conclusion. The CSF macrophages in LM patients showing M2-subtype signature and the emergence of regulatory T cells in LM confirmed the direction of tumour immunity toward immunosuppression. Then, the characteristics of CSF circulating tumour cells (CTCs) of breast cancer LM (BC-LM) patients were classified into five molecular subtypes by PAM50 model. The communication between macrophages and five subtype-specific CSF-CTCs showed largest number of ligand-receptor interactions. The five subtypes-specific CSF-CTCs showed great heterogeneities which were manifested in cell proliferation and cancer-testis antigens expression. Gene regulatory networks (GRNs) analysis revealed that transcription factor SREBF2 was universally activated in the five subtypes-specific CSF-CTCs. Our results will provide inspiration on new directions of the mechanism research, diagnosis and therapy of LM.
Topics: Breast Neoplasms; Genomics; Humans; Lung Neoplasms; Male; Meningeal Carcinomatosis; Sequence Analysis, RNA; Tumor Microenvironment
PubMed: 35678121
DOI: 10.1002/ctm2.885 -
Journal of Neuro-oncology Feb 2022Leptomeningeal metastases (LM) constitute an involvement of cancer which is associated with marked morbidity and mortality. The contemporary diagnostic and therapeutic... (Review)
Review
Leptomeningeal metastases (LM) constitute an involvement of cancer which is associated with marked morbidity and mortality. The contemporary diagnostic and therapeutic management of LM from solid tumors is reviewed. Therapeutic modalities including systemic therapies, cerebrospinal fluid (CSF)-directed therapies, and radiation therapy are discussed. This is to provide context for how the field of LM management may evolve in the near term. The future directions currently undergoing investigation for diagnostic, response assessment, and therapeutic purposes are highlighted. This is done within the context of the pathophysiology of the disease. Specifically the role of CSF circulating tumor cells and cell free circulating tumor DNA in diagnosis and response assement are reviewed. Novel therapeutic approaches across a range of modalities are discussed. Numerous ongoing studies which have the potential to alter the management of LM are referenced.
Topics: Humans; Meningeal Carcinomatosis
PubMed: 35048267
DOI: 10.1007/s11060-021-03924-2 -
Neurology India 2021Malignant meningitis (MM) is the diffuse involvement of the leptomeninges by infiltrating cancer cells, most frequently from lung and breast cancers. This review is... (Review)
Review
Malignant meningitis (MM) is the diffuse involvement of the leptomeninges by infiltrating cancer cells, most frequently from lung and breast cancers. This review is aimed to discuss the current advances in the diagnosis and management of MM, along with management of MM-associated hydrocephalus. We reviewed the literature using PubMed and Google Scholar search engines, focusing on various recent randomized controlled trials and clinical trials on MM. Given the hallmark multifocal involvement, the clinical symptoms and signs are also random and asymmetric. There are three important pillars for establishing a diagnosis of MM: clinical examination, neuroimaging, and CSF cytological findings. Several factors should be considered in decision-making, including performance status, neurological findings (clinical, MRI, and CSF flow dynamic), and evaluation of the primary tumor (nature and systemic dissemination). Response Assessment in Neuro-Oncology (RANO) working group recommended the objective assessment of disease for evaluating the progression and response to therapy. Pillars of current management are mainly focal irradiation and intrathecal or systemic chemotherapy. Symptomatic hydrocephalus is managed with a ventriculoperitoneal shunt, lumboperitoneal shunt, or endoscopic third ventriculostomy as palliative procedures, providing significant improvement in performance scores in the limited survival time of patients with MM. Studies using novel therapeutic approaches, such as new biological or cytotoxic compounds, are ongoing. Despite the use of all the combinations, the overall prognosis remains grim; therefore, decision-making for treatment should predominantly be based on attaining an optimal quality of life.
Topics: Breast Neoplasms; Female; Humans; Hydrocephalus; Meningeal Carcinomatosis; Meningitis; Quality of Life
PubMed: 35103001
DOI: 10.4103/0028-3886.332278