Effects of intrathecal pemetrexed on the survival of patients with leptomeningeal metastasis from lung adenocarcinoma: a propensity score matching analysis.

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.

Leptomeningeal dissemination as a first sign of progression in metastatic melanoma: a diagnostic lesson.

One of the most serious complications of advanced melanoma is the diffusion of cancer cells to the central nervous system. The diagnosis of leptomeningeal metastasis (LMM) is notoriously challenging and requires a combination of consistent MRI and cerebrospinal fluid (CSF) cytology. In ambiguous cases, mutations like BRAF V600E in CSF-cell-free (cf)DNA may help to clarify diagnosis of LMM. Here we present the case of a young woman who developed isolated LMM after the diagnosis of a node-positive primary melanoma with normal LDH. The CSF was negative for tumour cells by cytology but positive for cfDNA BRAF V600E mutation, thus allowing us to diagnose LMM. To our knowledge, this is the first case where CSF sampling for the detection of BRAF mutation was used to identify leptomeningeal disease in the presence of negative MRI and without involvement of any other distant sites.

Under-recognized toxicities of cranial irradiation.

Cranial irradiation of primary or metastatic lesions is frequent, historically with 3D-conformal radiation therapy and now with stereotactic radiosurgery and intensity modulation. Evolution of radiotherapy technique is concomitant to systemic treatment evolution permitting long time survival. Thus, physicians have to face underestimated toxicities on long-survivor patients and unknown toxicities from combination of cranial radiotherapy to new therapeutics as targeted therapies and immunotherapies. This article proposes to develop these toxicities, without being exhaustive, to allow a better apprehension of cranial irradiation in current context.

Cerebrospinal Fluid Spread in a Child with Pleomorphic Xanthoastrocytoma: Report with Cytopathologic Evidence.

BACKGROUND: Pleomorphic xanthoastrocytoma (PXA), a relatively uncommon, World Health Organization grade II tumor of astrocytic origin, occurs in children and in general carries good prognosis. The recently identified anaplastic PXA (grade III) type shows poor outcome. Rarely, these said tumors can display an aggressive clinical course with features of leptomeningeal spread. Such cases are mostly seen in adults, with rare instances reported in the pediatric age group. CASE DESCRIPTION: In this report, we describe an 8-year-old child with anaplastic PXA with a rapid downhill course due to cerebrospinal fluid spread. This child is perhaps the first pediatric report in which the cerebrospinal fluid dissemination was established on cytology. CONCLUSIONS: The case is an indicator of the need for craniospinal screening protocol in patients with PXA, especially the anaplastic variety, both at the time of initial diagnosis and follow-up.

Whole-brain Radiation and Pembrolizumab Treatment for a Non-small-cell Lung Cancer Patient with Meningeal Carcinomatosis Lacking Driver Oncogenes Led to a Long-term Survival.

We herein report a 66-year-old woman with advanced lung adenocarcinoma [programmed cell death and its ligand 1 (PD-L1) tumor proportion score 60%] lacking driver oncogenes in whom meningeal carcinomatosis, along with sudden onset dizziness, deafness, and consciousness disturbance, appeared after second-line chemotherapy. Whole-brain radiation therapy (WBRT) and Pembrolizumab were subsequently administered, and third-line chemotherapy with Pembrolizumab is now ongoing. At the time of writing, the patient has achieved a 23-month survival without disease progression. Our findings suggest that the combination of WBRT and an immune checkpoint inhibitor is effective for non-small-cell lung cancer patients lacking driver oncogenes who develop meningeal carcinomatosis.

Full-width postlaminar optic nerve tumor invasion of retinoblastoma as risk-factor for leptomeningeal spread of retinoblastoma. A case report and review of the literature.

We present a 6-year-old boy with unilateral retinoblastoma of the left eye. MRI showed an intraocular tumor that extended into the optic nerve beyond the lamina cribrosa. The affected eye was enucleated and the optic nerve resection margin proved to be free. Following protocol, this patient received six courses of adjuvant systemic chemotherapy. Unfortunately, after 5 months this patient returned with the leptomeningeal spread of the tumor and died quickly thereafter.Histopathologic analysis of the enucleated eye and distal optic nerve revealed that the postlaminar tumor cells occupied the entire width of the optic nerve, extending all the way up to the pia mater, whereas, more often the tumor invasion is restricted to the center of the optic nerve. This was also visible on the MR images where contrast enhancement occupied the entire nerve width. A resection margin with tumor cells is recognized as a risk factor for metastasis, but perhaps the proximity of tumor cells to the leptomeninges should also be judged with caution as a potential increased risk for metastatic spread.

Cranial nerve palsies in patients with hematological malignancies: a case series.

Objectives: Cranial neuropathies (CNs) can be due to a wide spectrum of causes, and the differential diagnosis is particularly challenging in patients with positive history of hematological malignancies, when neoplastic meningitis (NM) must be excluded.Patients and Methods: We retrospectively selected a series of twelve haematological patients with isolated cranial neuropathies (ICNs) or multiple cranial neuropathies (MCNs). among 71 patients that developed neurologic symptoms during different stages of the cancer, between 1 January, 2010 and 31 December, 2017. Brain and cauda equina magnetic resonance imaging (MRI) with gadolinium, cerebrospinal fluid (CSF) analysis, including flow cytometry for cell immunophenotyping and microbiological exams were performed in all patients.Results: Patients developed signs and symptoms of involvement of isolated (n = 11) or multiple (n = 1) cranial nerves, at different stages of the primary disease, and, in 5 of these cases in complete remission after hematopoietic stem cell transplantation. Among the 5 cases that eventually were diagnosed as having NM, cerebrospinal fluid was positive for neoplastic cells in 3, and MRI gadolinium-enhancement was present in 3. The other episodes were attributed to heterogeneous pathologies that were unrelated to meningeal infiltration by neoplastic cells.Conclusions: Our observations confirm that NM in haematological malignancies can yield insidious isolated signs of cranial nerves. Only a multidisciplinary approach allows prompt recognition of these conditions through a challenging process of differential diagnosis, and proper therapies.

Prognostic significance of molecular characteristics of cerebrospinal fluid for non-small cell lung cancer patients with leptomeningeal metastasis.

BACKGROUND: Studies in EGFR+ non-small cell lung cancer (NSCLC) patients with leptomeningeal metastasis (LM) comparing survival rates and gene mutation detection with matched cerebrospinal fluid (CSF) and plasma are relatively scarce. We evaluated gene mutations, treatment strategies, and clinical outcomes in EGFR+ NSCLC patients with LM. METHODS: We retrospectively reviewed gene mutation status in the CSF and plasma of 32 EGFR+ NSCLC patients with LM for prognostic significance. RESULTS: The rate of LM disease control was significantly higher in patients that switched EGFR-tyrosine kinase inhibitor (TKI) treatments, initiated EGFR-TKIs, or received high-dose EGFR-TKI treatment than those who continued their current EGFR-TKI treatment, received chemotherapy, or were not administered antitumor treatment (24/24, 100.0% vs. 1/8, 12.5%; P = 0.000). Overall survival was 27.0 months (95% confidence interval [CI] 19.0-37.5), median survival after LM was 7.0 months (95% CI 5.0-11.0), and median survival before LM was 17.0 months (95% CI 12-25.5). Median survival after LM was significantly shorter in patients with "worse" status (n = 7) than in those with "improved/stable" status (n = 25; 4.2 [95% CI 2.2-6.1] vs. 33.7 [95% CI 25.5-41.8] months, HR 10.114, 95% CI 0.29-1.37; P = 0.008). CONCLUSIONS: EGFR-TKIs should be the priority course of treatment in EGFR+ NSCLC patients after a diagnosis of LM. Liquid biopsy in both plasma and CSF, as well as dynamic detection, play important roles in the direction of treatment for such patients.

Association of MRI findings with clinical characteristics and prognosis in patients with leptomeningeal carcinomatosis from non-small cell lung cancer.

PURPOSE: Magnetic resonance imagining (MRI) is helpful for diagnosis of leptomeningeal carcinomatosis (LMC) and localizing LMC symptoms. Goal of this study is how MRI findings of LMC are associated with clinical characteristics or prognosis in patients with non-small cell lung cancer (NSCLC). METHODS: We retrospectively collected data on 283 patients with LMC from NSCLC, adenocarcinoma based on cerebrospinal fluid cytology. All patients had brain MRI with gadolinium enhancement at LMC diagnosis, and spinal MRI was performed at the physician's discretion. We evaluated the prognostic factors for overall survival (OS) of all patients and subgroup of patients with central nervous system cause of death. RESULTS: Two-hundred sixteen patients (76%) had definite or suggestive LMC findings and 67 had negative findings on brain MRI. Of the 37 patients who presented with cauda equina syndrome, 35 (95%) exhibited typical spinal MRI findings. Median OS of all patients was 3.65 months (95% confidence interval, 3.06-4.18). There was no significant difference in median OS between MRI-negative and MRI-positive groups (4.31 vs. 3.48 months, p = 0.711), whereas negative MRI finding showed longer median OS significantly in a subgroup of 77 patients with a central nervous system cause of death (p = 0.035). Considering clinical characteristics, progressive systemic disease, and altered mentality were significant prognostic factors associated with poor OS, whereas presenting symptom of headache with nausea/vomiting, intra-CSF chemotherapy, WBRT after LMC diagnosis, and concurrent RTKi treatment were significant for favorable OS in multivariable analysis. CONCLUSIONS: Positive MRI findings suggests heavier disease burden than negative MRI findings in patients with LMC who died of a central nervous system cause. Spinal MRI findings in patients with LMC correlate with cauda equina symptoms.

[A Case of Carcinomatous Meningitis Due to Gastric Cancer].

A 43-year-old man was diagnosed with gastric cancer with diaphragm invasion and multiple lymph node metastases and underwent total gastrectomy. The histological diagnosis was por2>tub2, ypT4b(diaphragm), int, INF c, ly1, v1, ypN3, yp Stage ⅢC. Three months postoperatively, computed tomography showed recurrence in the peritoneum and multiple lymph nodes, and he received chemotherapy(RAM plus PTX). After initiating the third course of chemotherapy, he was hospitalized due to loss of appetite and fatigue. On the third day of hospitalization, he lost consciousness and had a temporary convulsion seizure. Thereafter, he complained of headache and nausea. Brain magnetic resonance imaging and cerebrospinal fluid examination lead to a diagnosis of carcinomatous meningitis due to gastric cancer. An Ommaya reservoir was placed, and intrathecal infusion with methotrexate(MTX)and cytarabine(Ara-C)was planned; however, intrathecal infusion could not be administered because of hepatic injury due to acute obstructive cholangitis. He died 6 months postoperatively. Carcinomatous meningitis has a rapidly progressive course with very poor prognosis. Early diagnosis is important, and the treatment should be initiated as soon as possible. Moreover, an effective standard treatment for carcinomatous meningitis needs to be established.

Leptomeningeal Carcinomatosis After Neoplastic Cerebral Aneurysm Rupture.

BACKGROUND: Several possible mechanisms exist for the spread of a primary tumor to the leptomeninges in leptomeningeal carcinomatosis. This report describes a case caused by direct bleeding in the subarachnoid space from a neoplastic cerebral aneurysm rupture. CASE DESCRIPTION: A 48-year-old Japanese woman, who was diagnosed with breast carcinoma (pT3 pN2 M0) at the age of 45 years and underwent mastectomy and chemotherapy, was admitted in a coma following a sudden-onset severe headache. Computed tomography revealed diffuse hemorrhage in the subarachnoid space, and angiography revealed an aneurysm at the distal middle cerebral artery. Superficial temporal artery-middle cerebral artery bypass, aneurysmal trapping, and aneurysm resection were performed within 24 hours of admission. Staining for AE1/AE3 revealed accumulation of atypical cells with a high nuclear-cytoplasmic ratio in the aneurysmal wall. After showing initial improvement, she developed disturbed consciousness due to complicated ventricular enlargement on day 45. Although the cerebrospinal fluid in the acute phase had no atypical cells, subsequent testing revealed atypical cells, which supported a diagnosis of leptomeningeal carcinomatosis due to breast cancer dissemination. The patient died on day 78 after receiving standard endocrine therapy and radiation therapy. CONCLUSIONS: Tumor cells reach the leptomeninges via hematogenous spread or direct extension from preexisting lesions and can undergo neuraxis dissemination via the cerebrospinal fluid. Subarachnoid hemorrhage and leptomeningeal carcinomatosis are both devastating conditions with extremely poor prognoses. This patient experienced delayed disturbed consciousness leptomeningeal carcinomatosis with decreased performance status, which made it difficult to justify aggressive treatment on the basis of her poor prognosis.

Management of leptomeningeal metastasis in breast cancer.

Leptomeningeal metastasis (LM), which occurs when malignant cells spread to the central nervous system, is becoming an increasingly common complication in patients with breast cancer. Diagnosis and treatment of LM is challenging. Moreover, prognosis of patients with LM is poor, with a median survival of 6 months after diagnosis. This review highlights the strengths and limitations of currently available diagnostic tools and therapies for LM. The current treatments for LM, including radiotherapy, systemic therapy, and intrathecal treatment, aim to maintain the quality of life of patients by correcting neurological deficits and arresting neurological degeneration. However, there is no standardized therapy for LM because of a lack of randomized trials on this condition.

Embryonal brain tumor with unknown primary lesion and massive cerebrospinal fluid dissemination: A case report.

The 2007 World Health Organization Classification of Tumors of the Central Nervous System (CNS) categorized embryonal tumors of the CNS into three classes: medulloblastoma, CNS primitive neuroectodermal tumor, and atypical teratoid/rhabdoid tumor. Due to the lack of specific histological features, it was sometimes difficult to accurately differentiate CNS embryonal tumors pathologically. Here, we report a case of a young man, who presented with headache. Gadolinium-enhanced magnetic resonance imaging demonstrated massive lesions in the cerebrospinal fluid space, which strongly suggested leptomeningeal dissemination of a brain tumor. The histology showed the tumor comprised densely packed, small cells with scant cytoplasm. Immunoreactivities were positive for synaptophysin and chromogranin A, and negative for glial fibrillary acidic protein, S-100, EMA, and CD20. Because the tumors were located in multiple sites and most of them were within the cerebrospinal fluid space, the primary lesion could not be determined. We diagnosed this case as 'CNS primitive neuroectodermal tumor' by the patient age and predominantly supratentorial distribution of the lesions. After the induction therapy, WHO published its updated classification in 2016. Considering the possibility that the diagnosis is medulloblastoma, we performed additional immunohistochemical analyses, and diagnosed Group 3 medulloblastoma because of the expression of natriuretic peptide receptor 3.

Risk of leptomeningeal carcinomatosis in patients with brain metastases treated with stereotactic radiosurgery.

There is limited available literature examining factors that predispose patients to the development of LMC after stereotactic radiosurgery (SRS) for brain metastases. We sought to evaluate risk factors that may predispose patients to LMC after SRS treatment in this case-control study of patients with brain metastases who underwent single-fraction SRS between 2011 and 2016. Demographic and clinical information were collected retrospectively for 19 LMC cases and 30 controls out of 413 screened patients with brain metastases. Risk factors of interest were evaluated by univariate and multivariate logistic regression analyses and overall survival rates were evaluated by Kaplan-Meier survival analysis. About 5% of patients with brain metastases treated with SRS developed LMC. Patients with LMC (median 154 days, 95% CI 33-203 days) demonstrated a poorer overall survival than matched controls (median 417 days, 95% CI 121-512 days, p = 0.002). The most common primary tumor histologies  that lead to the development of LMC were non-small cell lung cancer (36.8%), breast cancer (26.3%), and melanoma (21.1%). No association was found between the risk of LMC and the location of the brain lesion or total volume of brain metastases. Prior surgical resection of brain metastases before SRS was associated with a 6.5 times higher odds (95% CI 1.45-29.35, p = 0.01) of developing LMC post-radiosurgery compared to those with no prior resections of brain metastases. Additionally, adjuvant WBRT may help to reduce the risk of LMC and can be considered in decision-making for patients who have had brain metastasectomy.

[A Case of Cancerous Meningitis in Juvenile Onset Gastric Cancer].

A 30-year-old woman was diagnosed with advanced gastric cancer(MUL, Circ, Type 4, por1+2, T4a, N3a, M1[LYM, P1, CY1, H0], Stage Ⅳ)on delivery. Because of unresectable, she underwent chemotherapy(first-line: S-1 plus CDDP, secondline: PTX plus Rmab, and third-line: Nmab); approximately 10 months later, she started complaining of headache. We performed a close examination, because she also developed resistance to chemotherapy. Contrast-enhanced magnetic resonance imaging of the brain revealed intense and diffuse enhancement on the brain surface, leading to the suspicion of meningeal carcinomatosis. However, hydrocephalus did not occur. She was given steroids to alleviate symptoms, but this treatment did not effective. We used neither intrathecal chemotherapy nor radiation therapy. Her symptoms gradually worsened, and she died approximately 4 weeks after the diagnosis of meningeal carcinomatosis. Meningeal carcinomatosis resulting from gastric cancer is very rare and is often difficult to diagnose. Even though this type of disease is diagnosed correctly, rapid disease progression makes the treatment difficult; therefore, patients with this type of disease have a terribly poor prognosis in daily clinical practice.

[A Case of Lung Adenocarcinoma Presenting with Leptomeningeal Carcinomatosis Successfully Treated with Afatinib after Erlotinib-Induced Hepatotoxicity].

A 65-year-old man was diagnosed with leptomeningeal carcinomatosis based on the findings of cerebrospinal fluid cytology and magnetic resonance imaging(MRI).Treatment with erlotinib and bevacizumab was initiated, and partial improvement in consciousness and MRI findings were obtained.However, it was difficult to continue the treatment because of elevation in levels of liver enzymes and melena.We switched the treatment to afatinib monotherapy, and his consciousness improved immediately.Progression -free survival and overall survival from the initiation of the treatment with afatinib were 7 and 9.4 months, respectively. This clinical course suggests activity of afatinib for central nervous system lesions of EGFRmutated lung cancer.