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The different molecular profiles of cerebrospinal fluid (CSF) between ventricular and lumbar compartments remain elusive, especially in the context of leptomeningeal metastasis (LM), which affects CSF flow. We evaluated CSF metabolomic and proteomic profiles based on the compartments and the diagnosis of spinal LM, proved by MRI from 20 paired ventricular and lumbar CSF samples of LM patients, including 12 spinal LM (+) samples. In metabolome analysis, 9512 low-mass ions (LMIs) were identified—7 LMIs were abundant in all lumbar versus paired ventricular CSF samples, and 3 LMIs were significantly abundant in all ventricular CSF. In comparisons between spinal LM (+) CSF and LM (−) CSF, 105 LMIs were discriminative for spinal LM (+) CSF. In proteome analysis, a total of 1536 proteins were measured. A total of 18 proteins, including complement C3, were more highly expressed in all lumbar CSF, compared with paired ventricular CSF, while 82 proteins, including coagulation factor V, were higher in the ventricular CSF. Of 37 discriminative proteins, including uteroglobin and complement component C8 gamma chain, 4 were higher in all spinal LM (+) CSF versus spinal LM (−) CSF. We further evaluated metabolic pathways associated with these discriminative proteins using the Gene Ontology database. We found that 16/17 spinal LM (+) pathways, including complement activation, were associated with lumbar discriminative proteins, whereas only 2 pathways were associated with ventricular-discriminative proteins. In conclusion, we determined that metabolite and protein profiles differed between paired lumbar and ventricular CSF samples. The protein profiles of spinal LM (+) CSF showed more similarity with the lumbar CSF than the ventricular CSF. Thus, we suggest that CSF LMIs and proteins could reflect LM disease activity and that LM-associated differences in CSF are more likely to be present in the lumbar compartment.

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.

Objectives To explore the diagnostic accuracy of ultrasound measurement of optic nerve sheath diameter (ONSD) and optic disc height (ODH) in detecting intracranial hypertension in non‐small‐cell lung cancer (NSCLC) patients with leptomeningeal metastases (LM). Methods Seventy‐two patients with NSCLC‐LM and 65 patients with NSCLC were enrolled. The ONSD, ODH, eyeball transverse diameter (ETD), and eyeball vertical diameter (EVD) were measured by ultrasound. Subsequently, lumbar puncture was performed in NSCLC‐LM patients to measure cerebrospinal fluid pressure (CSFP), and intrathecal chemotherapy was regularly implemented. Pearson's correlation analysis was used to analyze the relationship between CSFP and ultrasound findings. The diagnostic accuracy of ONSD, ODH, and combined ONSD and ODH was evaluated by receiver operating characteristic (ROC) curve analysis and the corresponding area under the ROC curve (AUC). Results The ONSD, ODH, ONSD/ETD, and ONSD/EVD values were higher in the NSCLC‐LM group (all p < 0.05). The ONSD, ODH, ONSD/ETD, and ONSD/EVD values were all elevated in the abnormally elevated CSFP group (all p < 0.05). ONSD, ODH, ONSD/ETD, and ONSD/EVD were positively correlated with CSFP (r = 0.531, 0.383, 0.534, and 0.535, all p < 0.0001). The AUCs for ONSD, ODH, ONSD/ETD, and ONSD/EVD to detect CSFP >280 mmH2O were 0.787 (95% CI: 0.64–0.93, sensitivity 68.75%, specificity 91.07%), 0.885 (95% CI: 0.81–0.96, sensitivity 100%, specificity 69.64%), 0.765 (95% CI: 0.64–0.89, sensitivity 81.25%, specificity 64.29%), and 0.788 (95% CI: 0.64–0.93, sensitivity 56.25%, specificity 91.07%), respectively. When ONSD was combined with ODH, the AUC was 0.913 (95% CI: 0.83–0.99, sensitivity 87.85%, specificity 85.70%). Furthermore, intrathecal chemotherapy was associated with a downtrend in CSFP and ultrasound findings. Conclusion There are important advantages of using bedside ultrasonography for detecting elevated CSFP in NSCLC‐LM patients. Further research should be performed to evaluate the clinical significance of an enlarged ONSD and increased ODH in NSCLC‐LM. Bedside ocular ultrasonography is a noninvasive, bedside and easy‐to‐use way for detecting increased intracranial pressure in patients with leptomeningeal metastases from non‐small‐cell lung cancer. The measurement of combined ONSD and ODH may be a promising technique to detect elevated CSF pressure..

Central nervous system (CNS) metastases represent a small portion of pediatric CNS neoplasms and data surrounding this condition with high morbidity is scarce. Single institutional archival institutional pathology records between 1999 and 2022 were searched for patients over 21 years old and younger with CNS, dura, cranial nerve, CSF, or leptomeningeal metastases; 41 cases were identified. We documented primary tumor types and locations, metastasis locations, types of invasion (direct extension vs distant metastasis), times from imaging or pathologic diagnosis to CNS involvement, and outcomes. Distant metastasis was the most common mechanism of metastasis (n = 32, 78%). Interval times to CNS metastasis varied by both tumor type and primary tumor location. In this cohort, osteosarcoma portended the shortest survival following CNS metastasis. This study highlights the diverse mechanisms and locations of CNS involvement in pediatric CNS metastases and illuminates a need for varied monitoring strategies when considering primary tumor type and anatomic location.

Leptomeningeal metastases arise from cancer cell entry into the subarachnoid space, inflicting significant neurologic morbidity and mortality across a wide range of malignancies. The modern era of cancer therapeutics has seen an explosion of molecular-targeting agents and immune-mediated strategies for patients with breast, lung, and melanoma malignancies, with meaningful extracranial disease control and improvement in patient survival. However, the clinical efficacy of these agents in those with leptomeningeal metastases remains understudied, due to the relative rarity of this patient population, the investigational challenges associated with studying this dynamic disease state, and brisk disease pace. Nevertheless, retrospective studies, post hoc analyses, and small prospective trials in the last two decades provide a glimmer of hope for patients with leptomeningeal metastases, suggesting that several cancer-directed strategies are not only active in the intrathecal space but also improve survival against historical odds. The continued development of clinical trials devoted to patients with leptomeningeal metastases is critical to establish robust efficacy outcomes in this patient population, define drug pharmacokinetics in the intrathecal space, and uncover new avenues for treatment in the face of leptomeningeal therapeutic resistance.

BackgroundLeptomeningeal metastasis (LM) occurs in 3–5% of patients with solid metastatic tumors and often portends a severe prognosis including symptomatic hydrocephalus and intracranial hypertension. Cerebrospinal fluid (CSF) shunting can provide symptomatic relief in this patient subset; however, few studies have examined the role of shunting in the palliation, prognosis and overall oncologic care of these patients.ObjectiveTo identify and evaluate risk factors associated with prognosis after CSF diversion and assess surgical, symptomatic and oncologic outcomes in this population.MethodsA retrospective study was conducted on patients with solid-malignancy LM treated with a shunt at a NCI-designated Comprehensive Cancer Center between 2010 and 2019.ResultsOne hundred and ninety patients with metastatic LM underwent CSF diversion. Overall survival was 4.14 months from LM diagnosis (95% CI: 3.29–4.70) and 2.43 months (95% CI: 2.01–3.09) from shunting. Karnofsky performance status (KPS) at time of shunting and brain metastases (BrM) number at LM diagnosis demonstrated significant associations with survival (HR = 0.66; 95% CI [0.51–0.86], p = 0.002; HR = 1.40; 95% CI [1.01–1.93] per 10 BrM, p = 0.04, respectively). Eighty-three percent of patients experienced symptomatic relief, and 79% were discharged home or to rehabilitation facilities post-shunting. Post-shunt, 56% of patients received additional systemic therapy or started or completed WBRT. Complications included infection (5%), symptomatic subdural hygroma/hematoma (6.3%), and shunt externalization/removal/repair (8%). Abdominal seeding was not identified.ConclusionsCSF diversion for LM with hydrocephalus and intracranial hypertension secondary to metastasis can achieve symptomatic relief, hospital discharge, and return to further oncologic therapy, with a complication profile unique to this pathophysiology. However, decision-making in this population must incorporate end-of-life goals of care given limited prognosis.

IntroductionGlioblastoma is an aggressive cancer with a notoriously poor prognosis. Recent advances in treatment have increased overall survival, though this may be accompanied by an increased incidence of leptomeningeal disease (LMD). LMD carries a particularly severe prognosis and remains a late stage manifestation of glioblastoma without satisfactory treatment. The objective of this review is to survey the literature on treatment of LMD in glioblastoma and to more fully characterize the current therapeutic strategies.MethodsThe authors performed a systematic review following PRISMA criteria on PubMed and OVID databases. Articles that included adult patients with LMD from glioblastoma were retrieved and reviewed.ResultsLMD in glioblastoma patients is increasing in incidence, with reports of up to 21%. The overall survival without treatment is alarmingly brief, with patients surviving between 1.6–3.8 months. All studies showed that treatment does improve overall survival significantly, increasing to 11.7 months in one study. However, no one adjuvant or surgical therapy has been shown to improve survival in LMD significantly over another. Direct treatment methods include chemotherapy (standard, anti-angiogenic, intrathecal, immunotherapy), and radiation. Hydrocephalus is a complication in LMD that can be treated with ventriculoperitoneal shunt placement, however treating hydrocephalus and delivering intrathecal chemotherapy is a challenge.ConclusionThough evidence remains lacking and there is no consensus, treatments show a trend towards improving survival and should be considered on a case-by-case basis. Further studies are necessary in the pursuit of a standard of care.

Purpose To explore the impact of intrathecal pemetrexed (IP) on the survival of lung adenocarcinoma (LUAC) patients with leptomeningeal metastasis (LM). Methods We analyzed patients with LUAC and LM who received systemic therapy after LM diagnosis at the Fujian Cancer Hospital between July 2018 and March 2022. Patients who underwent IP were assigned to the IP group; those without IP treatment were designated as the non-IP group. Propensity score matching (PSM) was performed between the two groups. Results 165 patients were enrolled: 83 and 82 in the IP and non-IP groups, respectively. After 1:1 PSM, we included 114 patients in the matched cohort. Median overall survival (OS) was 13.2 months (95% CI 10.8–15.6 months) in the IP group versus 10.1 months (95% CI 5.3–14.9 months) in the non-IP group (P = 0.488). Only Eastern Cooperative Oncology Group Performance Status (ECOG PS) was confirmed as an independent predictor for OS in the matched cohort (hazard ratio (HR) 2.03; P = 0.023). Multivariate competing-risks analysis showed that IP significantly correlated with central nervous system-related death (HR 0.31; P = 0.046). When stratified by ECOG PS, IP improved survival in patients with poor ECOG PS (PS = 2) (14.3 months vs. 1.6 months; P = 0.003). Conclusions Intrathecal pemetrexed did not enhance OS for the entire LUAC patient with LM compared to non-intrathecal chemotherapy. However, it exhibited the potential to reduce the risk of central nervous system-related mortality and improve survival in patients with poor ECOG PS.

PurposeThe treatment of leptomeningeal metastasis (LM), a serious complication of advanced non-small cell lung cancer (NSCLC), presents challenges, particularly in patients with EGFR exon 20 insertion (ex20ins) mutations.MethodsThis study retrospectively analyzed data from 10 EGFR ex20ins-mutated NSCLC patients with LM admitted at our institution from May 2011 to June 2023. Circulating tumor DNA (ctDNA) from cerebrospinal fluid (CSF) and matched plasma samples was analyzed using next-generation sequencing. All patients received high-dose furmonertinib combined with intraventricular chemotherapy (IVC) as salvage therapy. Data on patient demographics, treatment efficacy, and safety outcomes were collected.ResultsThe most common insertion mutation identified in this study was p.A767_V769dup (n = 4, 40%), followed by D770-N771insY (n = 2, 20%). Nine patients had EGFR ex20ins occurring in the EGFR loop region following the C-helix, whereas only one patient had an EGFR ex20ins (A763_Y764insFQEA) occurring in the C-helix of the tyrosine kinase domain. LM response assessment using the RANO-LM criteria revealed that 6 patients (60%, 95% CI 26.2–87.8%) achieved a response, 3 had stable disease, and 1 had progressive disease. The median progression-free survival and overall survival were estimated to be 6.5 months and 8.8 months, respectively. The most commonly reported treatment-related adverse events were rash (n = 7) and diarrhea (n = 7), with no treatment-related deaths occurring.ConclusionsThe current study demonstrated that high-dose furmonertinib plus IVC as salvage treatment for patients with LM harboring EGFR ex20ins mutations had promising clinical benefits and a manageable safety profile.

Leptomeningeal disease (LMD) refers to the infiltration of cancer cells into the leptomeningeal compartment. Leptomeninges are the two membranous layers, called the arachnoid membrane and pia mater. The diffuse nature of LMD poses a challenge to its effective diagnosis and successful management. Furthermore, the predominant phenotype; solid masses or freely floating cells, has altering implications on the effectiveness of drug delivery systems. The standard of care is the intrathecal delivery of chemotherapy drugs but it is associated with increased instances of treatment-related complications, low patient compliance, and suboptimal drug distribution. An alternative involves administering the drugs systemically, after which they must traverse fluid barriers to arrive at their destination within the leptomeningeal space. However, this route is known to cause off-target effects as well as produce subtherapeutic drug concentrations at the target site within the central nervous system. The development of new drug delivery systems such as liposomal cytarabine has improved drug delivery in leptomeningeal metastatic disease, but much still needs to be done to effectively target this challenging condition. In this review, we discuss about the anatomy of leptomeninges relevant for drug penetration, the conventional and advanced drug delivery methods for LMD. We also discuss the future directions being set by different clinical trials.