Cerebrospinal fluid-administered therapies for leptomeningeal metastases from solid tumors.

Aims/purpose: Leptomeningeal metastases (LM) are associated with substantial morbidity and mortality. Several approaches are used to treat LM, including intrathecally administered therapies. We consolidated current studies exploring intrathecal therapies for LM treatment. Patients & methods: A review of clinical trials using intrathecal agents was conducted with outcomes tabulated and trends described. 48 trials met the inclusion criteria. Initial investigations began with cytotoxic agents; following this were formulations with longer cerebrospinal fluid half-lives, targeted antibodies and radionucleotides. Results & conclusion: Outcomes were not reported consistently. Survival, when reported, remained poor. Intrathecal therapies for LM remain a viable option. Their use can be informed by an understanding of efficacy, safety and toxicity. They may be an important component of future LM treatments.

This paper summarizes the findings from 48 clinical trials conducted since the 1970s about the treatment of leptomeningeal metastases through an intrathecal approach (administering drugs directly into the cerebrospinal fluid ­ a fluid that surrounds the brain and spinal cord). The results of these studies suggest that although these therapies show promise for the future, they currently do not clearly and consistently report a benefit. Further work is needed to explore the possible use of these treatments.

Cytopathological differential diagnosis of malignant tumor cells in the cerebrospinal fluid: A retrospective analysis.

Leptomeningeal metastasis is the spread of cancer to the leptomeninges and subarachnoid space and represents a dreadful complication of cancer. The most commonly responsible neoplasms are high-grade lymphomas, leukemias, and some solid tumors, chiefly breast and lung cancer as well as melanoma. Herein we report our ten-year retrospective experience on 715 cases of cerebrospinal fluid cytology, 21 (2.9%) of which were positive for leptomeningeal metastasis. Sample collection and processing, clinical history, interdisciplinary dialog, and ancillary techniques such as immunocytochemistry and flow cytometry are all fundamental in reaching the correct diagnosis and thus optimally caring for patients with leptomeningeal metastasis.

Intrathecal trastuzumab versus alternate routes of delivery for HER2-targeted therapies in patients with HER2+ breast cancer leptomeningeal metastases.

BACKGROUND: Patients with HER2+ breast cancer (BC) frequently develop leptomeningeal metastases (LM). While HER2-targeted therapies have demonstrated efficacy in the neoadjuvant, adjuvant, and metastatic settings, including for parenchymal brain metastases, their efficacy for patients with LM has not been studied in a randomized controlled trial. However, several single-armed prospective studies, case series and case reports have studied oral, intravenous, or intrathecally administered HER2-targeted therapy regimens for patients with HER2+ BC LM. METHODS: We conducted a systematic review and meta-analysis of individual patient data to evaluate the efficacy of HER2-targeted therapies in HER2+ BC LM in accordance with PRISMA guidelines. Targeted therapies evaluated were trastuzumab (intrathecal or intravenous), pertuzumab, lapatinib, neratinib, tucatinib, trastuzumab-emtansine and trastuzumab-deruxtecan. The primary endpoint was overall survival (OS), with CNS-specific progression-free survival (PFS) as a secondary endpoint. RESULTS: 7780 abstracts were screened, identifying 45 publications with 208 patients, corresponding to 275 lines of HER2-targeted therapy for BC LM which met inclusion criteria. In univariable and multivariable analyses, we observed no significant difference in OS and CNS-specific PFS between intrathecal trastuzumab compared to oral or intravenous administration of HER2-targeted therapy. Anti-HER2 monoclonal antibody-based regimens did not demonstrate superiority over HER2 tyrosine kinase inhibitors. In a cohort of 15 patients, treatment with trastuzumab-deruxtecan was associated with prolonged OS compared to other HER2-targeted therapies and compared to trastuzumab-emtansine. CONCLUSIONS: The results of this meta-analysis, comprising the limited data available, suggest that intrathecal administration of HER2-targeted therapy for patients with HER2+ BC LM confers no additional benefit over oral and/or IV treatment regimens. Although the number of patients receiving trastuzumab deruxtecan in this cohort is small, this novel agent offers promise for this patient population and requires further investigation in prospective studies.

Anatomical and surgical characteristics correlate with pachymeningeal failure in patients with brain metastases after neurosurgical resection and adjuvant stereotactic radiosurgery.

PURPOSE: Neurosurgery (NS) is an essential modality for large brain metastases (BM). Postoperative stereotactic radiosurgery (SRS) is the standard of care adjuvant treatment. Pachymeningeal failure (PMF) is a newly described entity, distinct from classical leptomeningeal failure (LMF), that is uniquely observed in postoperative patients treated with adjuvant SRS. We sought to identify risk factors for PMF in patients treated with NS + SRS. METHODS: From a prospective registry (2009 to 2021), we identified all patients treated with NS + SRS. Clinical, imaging, pathological, and treatment factors were analyzed. PMF incidence was evaluated using a competing risks model. RESULTS: 144 Patients were identified. The median age was 62 (23-90). PMF occurred in 21.5% (31/144). Female gender [Hazard Ratio (HR) 2.65, p = 0.013], higher Graded Prognostic Assessment (GPA) index (HR 2.4, p < 0.001), absence of prior radiation therapy (HR N/A, p = 0.018), controlled extracranial disease (CED) (HR 3.46, p = 0.0038), and pia/dura contact (PDC) (HR 3.30, p = 0.0053) were associated with increased risk for PMF on univariate analysis. In patients with PDC, wider target volumes correlated with reduced risk of PMF. Multivariate analysis indicated PDC (HR 3.51, p = 0.0053), piecemeal resection (HR 2.38, p = 0.027), and CED (HR 3.97, p = 0.0016) independently correlated with PMF risk. PMF correlated with reduced OS (HR 2.90, p < 0.001) at a lower rate compared to LMF (HR 10.15, p < 0.001). CONCLUSION: PMF correlates with tumor PDC and piecemeal resection in patients treated with NS + SRS. For unclear reasons, it is also associated with CED. In tumors with PDC, wider dural radiotherapy coverage was associated with a lower risk of PMF.

Leptomeningeal dissemination in pediatric brain tumors.

Leptomeningeal disease (LMD) in pediatric brain tumors (PBTs) is a poorly understood and categorized phenomenon. LMD incidence rates, as well as diagnosis, treatment, and screening practices, vary greatly depending on the primary tumor pathology. While LMD is encountered most frequently in medulloblastoma, reports of LMD have been described across a wide variety of PBT pathologies. LMD may be diagnosed simultaneously with the primary tumor, at time of recurrence, or as primary LMD without a primary intraparenchymal lesion. Dissemination and seeding of the cerebrospinal fluid (CSF) involves a modified invasion-metastasis cascade and is often the result of direct deposition of tumor cells into the CSF. Cells develop select environmental advantages to survive the harsh, nutrient poor and turbulent environment of the CSF and leptomeninges. Improved understanding of the molecular mechanisms that underlie LMD, along with improved diagnostic and treatment approaches, will help the prognosis of children affected by primary brain tumors.

VLA-4 suppression by senescence signals regulates meningeal immunity and leptomeningeal metastasis.

Leptomeningeal metastasis is associated with dismal prognosis and has few treatment options. However, very little is known about the immune response to leptomeningeal metastasis. Here, by establishing an immunocompetent mouse model of breast cancer leptomeningeal metastasis, we found that tumor-specific CD8+ T cells were generated in deep cervical lymph nodes (dCLNs) and played an important role in controlling leptomeningeal metastasis. Mechanistically, T cells in dCLNs displayed a senescence phenotype and their recruitment was impaired in mice bearing cancer cells that preferentially colonized in leptomeningeal space. Upregulation of p53 suppressed the transcription of VLA-4 in senescent dCLN T cells and consequently inhibited their migration to the leptomeningeal compartment. Clinically, CD8+ T cells from the cerebrospinal fluid of patients with leptomeningeal metastasis exhibited senescence and VLA-4 downregulation. Collectively, our findings demonstrated that CD8+ T cell immunosenescence drives leptomeningeal metastasis.

Spontaneous acute bleeding within subdural effusion from dural metastasis of gastric cancer: A case report / Sangrado subdural agudo en el seno de una efusión subdural causada por una metástasis de cáncer gástrico: un caso clínico

Dural metastases are uncommon findings and at diagnosis normally appear in disseminated stages of malignant tumors. Usually clinically silent, these could become symptomatic due to mass effect or after developing subdural collections. We present the case of a young woman recently operated from gastric cancer who presented consciousness deterioration and hemiparesis caused by subdural collection. During examination, the patient drastically worsens his neurological status due to an acute subdural bleeding within the subdural collection, which after pathological analysis was diagnosed of dural metastasis of gastric cancer. In malignancies associated with subdural collections it is important to suspect the coexistence of dural metastases and performing a contrast enhanced CT scan or Magnetic Resonance Imaging (MRI) may help in the diagnosis. If surgery is indicated, it is mandatory to evacuate the tumor and involved dura which causes the accumulation of fluid and to coagulate the external tumor membrane to avoid re-bleeding (AU)

Las metástasis durales son hallazgos infrecuentes, y al diagnosticarse, normalmente se encuentran en estadios diseminados de tumores malignos. Generalmente, son clínicamente silentes, pero pueden dar síntomas debido al efecto de masa o tras desarrollar colecciones subdurales. Presentamos el caso de una mujer joven, recientemente intervenida de cáncer gástrico, que presentó deterioro de la conciencia y hemiparesia por colección subdural. Durante la exploración, la paciente empeoró neurológicamente debido a un sangrado subdural agudo dentro de la colección subdural, que tras análisis patológico fue diagnosticada de metástasis dural de cáncer gástrico. En las neoplasias asociadas con colecciones subdurales es importante sospechar la coexistencia de metástasis durales y realizar una tomografía computarizada con contraste o una resonancia magnética puede ayudar en el diagnóstico. Si está indicada la cirugía es obligatorio evacuar el tumor y la duramadre afectada que provoca la acumulación de líquido y coagular la membrana tumoral externa para evitar el resangrado (AU)

Leptomeningeal Metastases of the Spine: A Systematic Review.

BACKGROUND/AIM: Leptomeningeal metastases (LMs) of the spine have complex management. We reviewed the literature on spine LMs. MATERIALS AND METHODS: PubMed, EMBASE, Scopus, Web-of-Science, and Cochrane were searched following the PRISMA guidelines to include studies of spine LMs. RESULTS: We included 46 studies comprising 72 patients. The most frequent primary tumors were lung (19.4%) and breast cancers (19.4%). Median time from primary tumors was 12 months (range=0-252 months). Cauda equina syndrome occurred in 34 patients (48.6%). Nodular spine LMs (63.6%) were more frequent. Concurrent intracranial LMs were present in 27 cases (50.9%). Cerebrospinal fluid cytology was positive in 31 cases (63.6%). Cases were managed using palliative steroids (73.6%) with locoregional radiotherapy (55.6%) chemotherapy (47.2%), or decompressive laminectomy (8.3%). Post-treatment symptom improvement (32%) and favorable radiological response (28.3%) were not different based on treatment (p=0.966; p=0.727). Median overall-survival was 3 months (range=0.3-60 months), not significantly different between radiotherapy and chemotherapy (p=0.217). CONCLUSION: Spine LMs have poor prognoses. Radiotherapy, chemotherapy, and surgery are only palliative, as described for intracranial LMs.

Pediatric Malignant Peritoneal Mesothelioma With Meningeal Metastasis.

Malignant peritoneal mesothelioma (MPM) is an extremely rare entity with a poor prognosis. We report on a 16-year-old boy with ascites and abdominal distension. A computed tomography scan showed peritoneal thickening and a mass adjacent to the transverse colon. Neither repeated cytologic testing of ascitic fluid, nor peritoneal tissue biopsy detected malignant cells. After the patient became progressively comatose, a magnetic resonance imaging scan of the brain showed leptomeningeal enhancement. An autopsy showed MPM infiltrating the pleura and the meninges. This is the first report on meningeal metastasis of MPM in a pediatric patient illustrating the enigmatic behavior of the tumor and highlighting the diagnostic pitfalls.

Advances in targeted therapy in non-small cell lung cancer with actionable mutations and leptomeningeal metastasis.

WHAT IS KNOWN AND OBJECTIVE?: Leptomeningeal metastasis (LM) is a serious complication of advanced non-small cell lung cancer (NSCLC) that is diagnosed in approximately 3%-5% of patients. LM occurs more frequently in patients with NSCLC harbouring epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements and is usually accompanied by a poor prognosis, with a median overall survival (OS) of several months if patients receive conventional treatments. However, tyrosine kinase inhibitor (TKI) therapy after LM diagnosis is an independent predictive factor for extended survival. Here, we aim to summarize the latest advances in targeted therapy for LM and provide patients with better treatment options. METHODS: By reviewing the recent progress of targeted therapy in NSCLC with LM, especially the efficacy of newer generation TKIs, we aim to provide clinicians with a reference to further optimize patient treatment plans. RESULTS AND DISCUSSION: Osimertinib was confirmed to have a several-fold higher CNS permeability than other EGFR-TKIs and was recommended as the preferred choice for patients with EGFR-positive LM whether or not they harboured the T790M mutation. Second-generation ALK-TKIs have a higher rate of intracranial response and can be positioned as front-line drugs in NSCLC with LM. However, the sequence in which ALK-TKIs are administered for effective disease control requires further evaluation. In addition, targeted therapy revealed a potential choice in patients with LM and rare mutations, such as ROS1 and BRAF. WHAT IS NEW AND CONCLUSIONS?: The development of therapeutic agents with greater CNS penetration is vital for the management of CNS metastasis from NSCLC, particularly in the EGFR-mutant and ALK-rearranged subtypes. Systemic therapy with newer generation TKIs is preferred as the initial intervention. This is because newer generation TKIs are designed to penetrate the blood-brain barrier and possess significantly higher intracranial activities. However, their further effectiveness is limited by inadequate blood-brain barrier penetration and acquired drug resistance. Further studies are needed to further understand the mechanisms underlying resistance to treatment.

Complete remission in leptomeningeal metastasis of NSCLC with rare EGFR-SEPT14 fusion treated with osimertinib combined with intrathecal chemotherapy with pemetrexed.

Leptomeningeal metastasis (LM) is one of the most serious complications of non-small cell lung cancer (NSCLC) without standard treatment guidelines and is always accompanied by poor prognosis. Identifying the types of gene mutations is essential to improve the outcome, and an increasing number of rare epidermal growth factor receptor (EGFR) mutations are revealed by next-generation sequencing (NGS). Here, we describe a case of a 56-year-old man who was diagnosed with lung adenocarcinoma and received thoracoscopic resection in May 2015. One year later, LM was confirmed by positive cerebrospinal fluid cytology. Given the existence of EGFR exon 19 deletions, erlotinib was implemented and achieved a short response for 10 months. Then the systemic therapy was changed to osimertinib and obtained clinical remission for 25 months. Owing to the resurgence of violent headache, retching and vomiting, NGS of cerebrospinal fluid was performed and two rare EGFR-SEPT14 fusions were found. Osimertinib combined bevacizumab, chemotherapy (carboplatin and abraxane) and dacomitinib were implemented in turn but ineffective. Thus, osimertinib combined intrathecal chemotherapy with pemetrexed were carried out and gained a complete remission of neurologic symptoms, stable lesions and long-term survival without notable side effects. This study presented the first case of NSCLC-LM harboring particular EGFR-SEPT14 fusions, who showed a durable response to osimertinib and intrathecal pemetrexed, providing a potential therapeutic option for NSCLC-LM patients with this particular mutation.

The Role of Immune Checkpoint Inhibitors in Leptomeningeal Disease: A Systematic Review.

BACKGROUND/AIM: Leptomeningeal disease (LMD) is a debilitating complication of advanced malignancies. Immune-checkpoint inhibitors (ICIs) may alter disease course. We analyzed the role and toxicity of ICIs in LMD. MATERIALS AND METHODS: We systematically reviewed the literature reporting on outcome data of patients with LMD treated with ICIs. RESULTS: We included 14 studies encompassing 61 patients. Lung-cancer (44.3%), breast-cancer (27.9%), and melanoma (23.0%) were the most frequent primary tumors. Median duration of ICI-treatment was 7-months (range=0.5-58.0): pembrolizumab (49.2%), nivolumab (32.8%), ipilimumab (18.0%). Radiological responses included complete response (33.3%), partial response (12.5%), stable disease (33.3%), progressive disease (20.8%). Twenty-two patients developed ICI-related adverse-events, mild (100%) and/or severe (15.6%). Median progression-free and overall survival were 5.1 and 6.3 months, and 12-month survival was 32.1%. Survival correlated with ICI agents (p=0.042), but not with primary tumors (p=0.144). Patients receiving concurrent steroids showed worse survival (p=0.040). CONCLUSION: ICI therapy is well-tolerated in patients with LMD, but concurrent steroids may worsen survival.

CD11c+CD163+ Cells and Signal Transducer and Activator of Transcription 3 (STAT3) Expression Are Common in Melanoma Leptomeningeal Disease.

Leptomeningeal disease (LMD) in melanoma patients is associated with significant neurological sequela and has a dismal outcome, with survival measured typically in weeks. Despite the therapeutic benefit of targeted therapies and immunotherapies for Stage IV melanoma, patients with LMD do not typically benefit. A deeper understanding of the tumor microenvironment (TME) of LMD may provide more appropriate therapeutic selection. A retrospective analysis of subjects who underwent surgical resection with LMD (n=8) were profiled with seven color multiplex staining to evaluate the expression of the global immune suppressive hub - the signal transducer and activator of transcription 3 (STAT3) and for the presence of CD3+ T cells, CD68+ monocyte-derived cells, CD163+ immune suppressive macrophages, and CD11c+ cells [potential dendritic cells (DCs)] in association with the melanoma tumor marker S100B and DAPI for cellular nuclear identification. High-resolution cellular imaging and quantification was conducted using the Akoya Vectra Polaris. CD11c+ cells predominate in the TME (10% of total cells), along with immunosuppressive macrophages (2%). Another potential subset of DCs co-expressing CD11c+ and the CD163+ immunosuppressive marker is frequently present (8/8 of specimens, 8%). Occasional CD3+ T cells are identified, especially in the stroma of the tumor (p=0.039). pSTAT3 nuclear expression is heterogeneous in the various immune cell populations. Occasional immune cluster interactions can be seen in the stroma and on the edge. In conclusion, the TME of LMD is largely devoid of CD3+ T cells but is enriched in immune suppression and innate immunity.

Analysis of intrapatient heterogeneity of circulating tumor cells at the single-cell level in the cerebrospinal fluid of a patient with metastatic gastric cancer.

BACKGROUND: The aims of this study were to detect circulating tumor cells (CTCs) at the single-cell level in cerebrospinal fluid (CSF) and to identify intrapatient heterogeneity of CTCs in a patient with gastric cancer (GC) with leptomeningeal metastasis (LM) using Di-Electro-Phoretic Array technology. MATERIALS AND METHODS: The CSF samples were drawn from a patient who was diagnosed with GC with LM. The CSF samples were centrifuged and stained with antibody cocktail to recognize 4',6-diamidino-2-phenylindole, cytokeratin, and epithelial cell adhesion molecule (EpCAM). Gene sequencing was also conducted to evaluate the status of the gene alteration profile of CSFCTCs as compared with those of the CSF non-CTCs and the primary tumor tissue. RESULTS: Among total 38 cells from the samples, 25 cells represented CK+ (EpCAM+), which boiled down to 0.53 CTCs in 1 mL of CSF. Each CTC was heterogeneous in terms of morphology and degree of marker expression. Some CTCs have a spindle-like shape, whereas others have a round shape. Based on molecular profiling between the 25 CK+ (EpCAM+) CTCs and 13 CK-/EpCAM- cells (i.e., the non-CTCs), CSFCTCs harbored mutations such as MDM2, TP53, KRAS, STK11, and ALK, whereas mutation of these genes was not observed in the CSF non-CTCs. Four genes of nine mutational genes totally observed in the CSFCTCs were also noted in the primary tumor tissue. CONCLUSIONS: We enriched CTCs through a single-cell sorting process in CSF samples of a GC patient with LM. We also demonstrated the intrapatient heterogeneity of the CTCs at the single-cell level.

Application of optic neuro-ophthalmology imaging in latent meningeal metastases of lung cancer.

Latent intracranial meningeal metastases (IMM) of lung cancer is difficult to determine, yet it is critical to do so given that it impacts the treatment agent. Studies on this disease are rare, thus necessitating further investigation. As a case study, we will explore the application of optic neuroimaging in IMM. A 62-year-old female patient was diagnosed with lung adenocarcinoma, which had progressed to osseous metastasis. During the course of chemotherapy, the patient had bilateral vision loss and paralysis of extraocular muscles. Ophthalmologists ruled out disease of the retina and suspected intracranial metastasis; however, brain-enhanced magnetic resonance angiography and magnetic resonance venography were normal. Given the patient's severe osteoarthropathy and poor physical condition, she refused to undergo a lumbar puncture examination. Optic neuro-ophthalmology imaging was ultimately used. Utilizing optical coherence tomography, we found that the basement membrane layer in the papilledema was protruding up towards the vitreous cavity. To assist in visualization, the optic nerve sheath was enhanced with optic magnetic resonance imaging. With these methods, the dural metastasis was identified, the treatment agent was changed for the patient, and she had a successful recovery. Thus, optic neuro-ophthalmology imaging should be recommended for patients who are in the latent course of dural metastasis, and it could also be used to evaluate therapeutic efficacy.

Efficacy of osimertinib for preventing leptomeningeal metastasis derived from advanced EGFR-mutated non-small cell lung cancer: a propensity-matched retrospective study.

BACKGROUND: Leptomeningeal metastasis (LM) is a severe complication of advanced non-small cell lung cancer (NSCLC). This retrospective study aimed to investigate the potential use of osimertinib for preventing LM in patients with advanced epidermal growth factor receptor (EGFR)-mutated NSCLC. METHODS: Patients with advanced NSCLC harboring EGFR mutations who underwent tyrosine kinase inhibitors (TKIs) therapy for at least 8 weeks between September 2016 and September 2019 were eligible for this study. All included patients were divided into two groups based on whether they received osimertinib, the osimertinib group (patients treated with osimertinib) and the control group (patients not treated with osimertinib). Propensity score matching (PSM, ratio of 1:1) was used to account for differences in baseline characteristics. The cumulative incidence of LM and the overall survival (OS) were evaluated. RESULTS: A total of 304 patients were included in the study population. Among them, 116 patients received osimertinib, and 188 did not. A total of 112 patients remained in each group after PSM, and the baseline characteristics were not significantly different between the two cohorts. LM developed in 11 patients (9.82%) in the osimertinib group and 24 patients (21.42%) in the control group (hazard ratio [HR] 0.38, 95% confidence interval [CI] 0.19-0.79, p = 0.009). Multivariate analysis indicated that osimertinib was an independent, statistically significant predictor for determining the risk for LM, with an HR of 0.33 (p = 0.042). At present, the OS rate data are too immature for statistical analysis. CONCLUSION: Real-world data demonstrate that osimertinib can significantly reduce the incidence of LM in patients with advanced NSCLC harboring common EGFR mutations. Given this result, osimertinib should be encouraged in clinical practice for specific patient populations.

Medulloblastoma uses GABA transaminase to survive in the cerebrospinal fluid microenvironment and promote leptomeningeal dissemination.

Medulloblastoma (MB) is a malignant pediatric brain tumor arising in the cerebellum. Although abnormal GABAergic receptor activation has been described in MB, studies have not yet elucidated the contribution of receptor-independent GABA metabolism to MB pathogenesis. We find primary MB tumors globally display decreased expression of GABA transaminase (ABAT), the protein responsible for GABA metabolism, compared with normal cerebellum. However, less aggressive WNT and SHH subtypes express higher ABAT levels compared with metastatic G3 and G4 tumors. We show that elevated ABAT expression results in increased GABA catabolism, decreased tumor cell proliferation, and induction of metabolic and histone characteristics mirroring GABAergic neurons. Our studies suggest ABAT expression fluctuates depending on metabolite changes in the tumor microenvironment, with nutrient-poor conditions upregulating ABAT expression. We find metastatic MB cells require ABAT to maintain viability in the metabolite-scarce cerebrospinal fluid by using GABA as an energy source substitute, thereby facilitating leptomeningeal metastasis formation.

[Diagnostic Value of Locally Produced Tumor Markers and Blood Brain Barrier
Integrity in Lung Cancer Patients with Leptomeningeal Metastasis].

BACKGROUND: Tumor markers (TM) in cerebrospinal fluid (CSF) are useful for diagnosing leptomeningeal metastasis (LM). It has not been fully exploited the diagnostic possibilities of the CSF levels since the basic fact that the TM concentration of CSF depends strongly upon the serum levels as well as upon the condition of the blood brain barrier (BBB). To analyze the intrathecal TM synthesis and evaluate the integrity of BBB can be helpful for the definitive diagnosis of LM. Therefore, the aim of this study was to further explore the clinical value of intrathecal TM synthesis and BBB in the diagnosis for the lung cancer patients with LM. METHODS: Twenty-five lung cancer patients with LM and 57 patients with nonmalignant neurological diseases (NMNDs) admitted to Nanjing Drum Tower Hospital from December 2016 to March 2020 were included. We compared the integrity of BBB and intrathecal TM synthesis between two groups, analyzed the correlation of CSF TM between the detection and intrathecal synthesis, and evaluated serial CSF cytology, the integrity of BBB and intrathecal TM synthesis when intrathecal chemotherapy for one patient. RESULTS: Ninety-four percent LM patients showed the dysfunction of BBB, and all LM patients showed at least one intrathecal synthesized TM in CSF. In one patient, the CSF cytology was negative for the first time, but LM was eventually diagnosed based on the the intrathecal TM synthesis and positive CSF cytology of repeated lumbar puncture. In LM group, no correlation was observed between the detection and intrathecal synthesized TM in CSF. In the control group, only 3.5% (2/57) NMNDs patients had the dysfunction of BBB and no patients had intrathecal TM synthesis, both the differences of which were statistically significant (P<0.05). Finally, evaluating the CSF cytology, integrity of BBB and intrathecal TM synthesis can be used to assess the intracranial treatment effect. Moreover, intrathecal TM synthesis changes earlier than cytology. CONCLUSIONS: The evaluation of intrathecal TM synthesis and integrity of BBB are novel clinical diagnostic tools. In addition, serial measurement of intrathecal synthesized TM may play an important role in monitoring efficacy of lung cancer patients with LM, which is worthy of further promotion and clinical application.