Incidence Of Leptomeningeal Metastasis Research Articles

Leptomeningeal metastases in isocitrate dehydrogenase-wildtype glioblastomas revisited: Comprehensive analysis of incidence, risk factors, and prognosis based on post-contrast fluid-attenuated inversion recovery.

The incidence of leptomeningeal metastases (LM) has been reported diversely. This study aimed to investigate the incidence, risk factors, and prognosis of LM in patients with isocitrate dehydrogenase (IDH)-wildtype glioblastoma. A total of 828 patients with IDH-wildtype glioblastoma were enrolled between 2005 and 2022. Baseline preoperative MRI including post-contrast fluid-attenuated inversion recovery (FLAIR) was used for LM diagnosis. Qualitative and quantitative features, including distance between tumor and subventricular zone (SVZ) and tumor volume by automatic segmentation of the lateral ventricles and tumor, were assessed. Logistic analysis of LM development was performed using clinical, molecular, and imaging data. Survival analysis was performed. The incidence of LM was 11.4%. MGMTp unmethylation (odds ratio [OR] = 1.92, P = .014), shorter distance between tumor and SVZ (OR = 0.94, P = .010), and larger contrast-enhancing tumor volume (OR = 1.02, P < .001) were significantly associated with LM. The overall survival (OS) was significantly shorter in patients with LM than in those without (log-rank test; P < .001), with median OS of 12.2 and 18.5 months, respectively. The presence of LM remained an independent prognostic factor for OS in IDH-wildtype glioblastoma (hazard ratio = 1.42, P = .011), along with other clinical, molecular, imaging, and surgical prognostic factors. The incidence of LM is high in patients with IDH-wildtype glioblastoma, and aggressive molecular and imaging factors are correlated with LM development. The prognostic significance of LM based on post-contrast FLAIR imaging suggests the acknowledgment of post-contrast FLAIR as a reliable diagnostic tool for clinicians.

Single-cell landscape of the immune microenvironment of leptomeningeal metastases in non-small cell lung cancer treated with pemetrexed sheath injection.

e20026 Background: The incidence of leptomeningeal metastasis (LM) is increasing in non-small cell lung cancer (NSCLC) and pemetrexed injection is an important treatment for LM. Here, we used single-cell RNA sequencing (scRNA-seq) to define the immune landscape of LM in NSCLC treated with pemetrexed sheath injection. Methods: scRNA-seq was utilized on 27 cerebrospinal fluid (CSF) samples from 20 patients, including 7 pairs of pre- and post-treatment samples. Detailed immune landscapes were mapped, and key results were confirmed by flow cytometry and IHC. Biomarkers for the efficacy of pemetrexed sheath injection was analyzed. Results: The LM microenvironment was characterized by macrophages and cancer cells with decreased significantly after pemetrexed injection. The cancer cells in LM was highly expressed CEACAM6, SFTPB and NAPSA, and chemokines liked CXCL16 in macrophages decreased significantly after receiving pemetrexed sheath treatment than pre- treatment, which was validated by flow cytometry and IHC. In the signal pathway enrichment analysis, significant changes of metabolism and cell cycle genes occurred before and after pemetrexed injection. Moreover, the analysis of tumor cells and immune cells interaction showed that CSF1-CSF1R, AREG/HBEGF-EGFR, FD1-Intergrin_a2B1_complex, CCL5-CCR1, CD55_ADGRE play a key role in tumor cells recruiting monocytes and inhibiting macrophages. Gene set based on the efficacy of pemetrexed sheath injection was enriched, including C15orf48, CCL5, DUSP6, FLNA, TXNIP, TNNT1, was confirmed associating with increased overall survival. Conclusions: Our study characterizes the immune cell landscape of LM from NSCLC, and provided the biomarkers for the efficacy of pemetrexed injection.

Long-term response to sequential anti-HER2 therapies including trastuzumab-deruxtecan in a patient with HER2-positive metastatic breast cancer with leptomeningeal metastases: a case report and review of the literature.

The incidence of leptomeningeal metastases (LM) is increasing among breast cancer patients, but their prognosis remains dismal. Many therapeutic options are now available to treat HER2-positive (HER2+) metastatic breast cancer (MBC) involving the central nervous system (CNS). This case report illustrates a long-lasting response of more than 2 years in a patient with HER2+ MBC with LM after sequential administration of systemic and intrathecal (IT) anti-HER2 therapies and highlights that an appropriate treatment of HER2+ LM can result in durable survival.

NIMG-69. LEPTOMENINGEAL METASTASES IN IDH-WILDTYPE GLIOBLASTOMAS REVISITED: COMPREHENSIVE ANALYSIS OF INCIDENCE, RISK FACTORS, AND PROGNOSIS BASED ON POSTCONTRAST FLAIR IMAGING

Abstract BACKGROUND To comprehensively investigate the incidence, risk factors, and prognosis of leptomeningeal metastases (LM) in isocitrate dehydrogenase (IDH)-wildtype glioblastoma patients. METHODS Total 913 IDH-wildtype glioblastoma patients with complete molecular information on IDH mutation and MGMT promoter methylation status were enrolled between 2004 and 2022. LM diagnosis was performed with MRI including postcontrast FLAIR and CSF cytology. Logistic regression analysis for LM development at initial diagnosis and recurrence was performed with clinical, surgical, imaging, and molecular data. The overall survival (OS) was compared between patients with and without LM. RESULTS The incidence of LM was 21.8% (199 patients) among patients with IDH-wildtype glioblastoma, with 11.5% (105 patients) at initial diagnosis, and 10.3% (94 patients) at recurrence. Male sex (odds ratio [OR]: 1.74, P = 0.017), MGMT promoter unmethylation (OR: 1.48, P = 0.048), nonlobar location (OR: 2.27, P &amp;lt; 0.001), and presence of necrosis (OR: 3.64, P &amp;lt; 0.001) were independent predictors of LM at initial diagnosis, whereas ventricular opening during surgery (OR: 2.96, P &amp;lt; 0.001) was the only independent predictor of LM at recurrence. The median OS was 16.2 months (interquartile range [IQR]: 9.6-30.4) in patients with LM and 19.3 months (IQR: 12.1-38.5) in patients without LM (log-rank test; P = 0.001). CONCLUSION The incidence of LM is high in patients with IDH-wildtype glioblastoma. Aggressive clinical, imaging, and molecular factors are correlated with LM at initial diagnosis, whereas ventricular entry warrant imaging surveillance for LM at recurrence. The prognosis of LM is not discouraging as expected, and promote reconsideration of focused clinical trials.

Leptomeningeal Metastases in Carcinoma Rectum with Extensive Skeletal Metastasis - A Case Report

Incidence of rectal carcinoma has been rising in younger people in recent decades. Skeletal metastasis without other organ metastasis from primary rectal carcinoma is very rare, spine and the pelvis are the first sites of bony metastasis. Leptomeningeal Metastases (LM) is a very rare complication of solid tumour progression and its incidence in colorectal carcinoma is far less. A nineteen-year-old male presented in the OPD with rectal bleeding and low back pain with colonoscopic biopsy proving rectal carcinoma. MRI of pelvis revealed multiple osseous metastases to vertebrae and pelvic bones. After four cycles of palliative chemotherapy, he developed lower back pain. Repeat MRI revealed multiple lesions in the vertebrae and long bones for which he received palliative external beam radiation therapy (EBRT). Subsequently seven months later he developed meningeal metastases and received whole brain radiation and supportive care. LM in patients with primary colorectal cancer (CRC) remains an exceedingly rare complication of metastatic disease progression in CRC.&#x0D; Colorectal cancer (CRC) is the third most common cancer diagnosed in both men and women.[1] The incidence of it has been rising in young adults.[2] The common metastatic sites of CRC include the liver (57.6%), abdominal lymph nodes (48.3%), lungs (37.6%) and Peritoneum.[3,4,5] Skeletal metastasis without other organ metastasis is very rare. Bone metastasis is seen in 4.7% to 10.9% in clinical cases and often indicates advanced disease with a poor prognosis with 5-year survival rate less than 5%,[6] leading to significantly high rate of morbidity and mortality.&#x0D; Leptomeningeal Metastases (LM) or neoplastic meningitis, is an uncommon metastatic complication of solid tumour progression. Most commonly arising from breast, non-small-cell lung cancer, and melanoma with a frequency of 5% to 25%.[7] The incidence of LM in colorectal cancer (CRC) is far less than 1%.[8]&#x0D; Here we report a case of rectal carcinoma, with extensive skeletal metastases and their pattern of bone involvement, who later presented with meningeal metastases.

P11.31.B LEPTOMENINGEAL SPREAD AFTER POSTOPERATIVE STEREOTACTIC RADIOTHERAPY FOR BRAIN METASTASES

Abstract BACKGROUND Stereotactic radiotherapy (SRT) is the preferred treatment after surgical resection of brain metastases to improve local tumour control compared to observation. Some recent studies suggest that leptomeningeal metastases (LMM) occur more often after postoperative SRT compared to primary SRT with brain metastases in situ. This may be caused by tumour cells spillage during surgery. The aim of this study was to determine the incidence of LMM after postoperative SRT of brain metastases in our institution. MATERIAL AND METHODS All patients treated with postoperative SRT for brain metastases in our hospital between 2015 and 2020 were included in this retrospective analysis. LMM was diagnosed by a neuro-radiologist (RH) on a cerebral MRI. LMM, overall survival, and time to local recurrence (LR) were estimated from date of SRT, using the Kaplan-Meier method. RESULTS In total, 53 patients with 84 brain metastases were included in the analysis. Median age at SRT was 58 years (range 45 - 75 years). Median survival in this cohort was 16 months (IQR 9 - 26 months). Eight of 53 patients (15%) developed LMM at a median of 9 months after SRT. Using Kaplan-Meyer analysis, the incidence of LMM at 1 and 2 years was 15% and 19%, respectively. Twelve patients (23%) of 53 experienced LR at a median of 9 months. The 1 and 2-year actuarial incidence was 14% and 35%, respectively. CONCLUSION In our cohort, the incidence of LMM after postoperative SRT for brain metastases is comparable to other studies. Studies are needed to determine whether the incidence of LMM after postoperative SRT can be reduced.

Leptomeningeal metastases in glioma revisited: incidence and molecular predictors based on postcontrast fluid-attenuated inversion recovery imaging.

Leptomeningeal metastases (LMs) in glioma have been underestimated given their low incidence and the lack of reliable imaging. Authors of this study aimed to investigate the real-world incidence of LMs using cerebrospinal fluid (CSF)-sensitive imaging, namely postcontrast fluid-attenuated inversion recovery (FLAIR) imaging, and to analyze molecular predictors for LMs in the molecular era. A total of 1405 adult glioma (World Health Organization [WHO] grade 2-4) patients underwent postcontrast FLAIR imaging at initial diagnosis and during treatment monitoring between 2001 and 2021. Collected molecular data included isocitrate dehydrogenase (IDH) mutation, 1p/19q codeletion, H3 K27 alteration, and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. LM diagnosis was performed with MRI including postcontrast FLAIR sequences. Logistic regression analysis for LM development was performed with molecular, clinical, and imaging data. Overall survival (OS) was compared between patients with and those without LM. LM was identified in 228 patients (16.2%), 110 (7.8%) at the initial diagnosis and 118 (8.4%) at recurrence. Among the molecular diagnostics, IDH-wildtype (OR 3.14, p = 0.001) and MGMT promoter unmethylation (OR 1.43, p = 0.034) were independent predictors of LM. WHO grade 4 (OR 10.52, p < 0.001) and nonlobar location (OR 1.56, p = 0.048) were associated with LM at initial diagnosis, whereas IDH-wildtype (OR 5.04, p < 0.001) and H3 K27 alteration (OR 3.39, p = 0.003) were associated with LM at recurrence. Patients with LM had a worse median OS than those without LM (16.7 vs 32.0 months, p < 0.001, log-rank test), which was confirmed as an independent factor on multivariable Cox analysis (p = 0.004). CSF-sensitive imaging aids the diagnosis of LM, demonstrating a high incidence of LM in adult gliomas. Furthermore, molecular markers are associated with LM development in glioma, and patients with aggressive molecular markers warrant imaging surveillance for LM.

BIOL-08. RADIATION DRIVES METASTASIS IN MEDULLOBLASTOMA THROUGH AN INFLAMMATORY PROCESS

Abstract Current treatment for medulloblastoma is comprised of surgery, radiotherapy (RT) and/or chemotherapy. Although the primary tumor is controlled with this approach, recurrent metastatic disease is ubiquitously fatal. However, little is known about the biology of metastatic recurrences in medulloblastoma. In the present study, we observe across 3 non-overlapping cohorts of infant medulloblastoma that patients recur locally without focal RT and metastatically after focal RT. Using 3 independent murine flank xenograft medulloblastoma models, we found that the incidence of leptomeningeal metastasis was significantly increased in mice that received RT compared to sham controls. We have also found a significant increase in viable circulating tumor cells after RT. Our multi-omics (bulk RNA-seq, scRNA-seq and proteo/phosphoproteomics) approach using immunocompetent sporadic medulloblastoma models treated with RT showed activation of the innate inflammatory response through the overexpression of chemokines, cytokines and activation of immune cell types. In situ analysis of protein expression after RT showed a gradual increase in the abundance of macrophages, neutrophils and dendritic cells after RT, suggesting increased permeability and cell trafficking across the blood brain barrier. Applying live intravital microscopy using a low molecular weight vascular dye (150kDa), we observed a striking increase in blood vessel permeability in RT vs sham-treated brain tumors. Our observations support a model where RT drives metastasis through inflammation. To test this, we applied lipopolysaccharide (LPS), an inflammation inducing treatment, to a sporadic murine medulloblastoma model which significantly increased the metastatic burden. We then treated a xenograft model with dexamethasone in combination with RT, which resulted in total abrogation of metastatic dissemination compared to RT alone. Collectively, our findings suggest that while external beam irradiation is an effective and essential treatment for medulloblastoma, it may facilitate metastatic dissemination through an inflammation-induced process. These findings can help inform potential approaches to prevent disseminated relapsed disease.

Baseline characteristics, hospital outcomes, and palliative care utilization in leptomeningeal disease: A nationwide analysis.

e14004 Background: Leptomeningeal metastasis (LM) is a rare but devastating manifestation of cancer metastasis. Most solid tumors are known to cause LM, but the most common etiology is breast cancer and lung cancer. The incidence of LM has been increasing due to increased survival rates secondary to the improved systemic cancer treatment. Here we aim to explore the baseline characteristics, epidemiologic differences, palliative care utilization. and hospital outcomes of LM. Methods: Nationwide Inpatient Sample (NIS) database 2016-2019 was queried to determine adult hospitalized patients with LM and relevant cancers by using ICD-10 codes. We studied the racial and socioeconomic differences, palliative care utilization, length of stay (LOS), total hospital charges (THC), and all-cause mortality in cancer patients with and without LM. Multivariate logistic regression analysis was conducted to adjust for confounders. Results: There were 15,325 admissions with LM, 20% had lung cancer (LC) and 20.4% had breast cancer (BC). The prevalence of LM was 1.9% and 0.5%, respectively, in LC and BC patients. LM patients were younger (LC 63 vs 69; BC 56 vs 64 p&lt;0.001), more likely to be non-White, and more likely to have private insurance (37% vs. 19%, p&lt;0.001). LM admissions had significantly increased LOS and higher THC compared to other cohorts. BC or LC with LM was associated with significantly increased Palliative care consult rate ( LC 31% vs 16%; BC 29% vs 10% p&lt;0.001) compared to BC and LC without LM. Palliative care use was more common in the African American race. The all-cause mortality rate in hospitalizations with LM was increased compared to cancer without LM (LC 11% vs 8.6% p=0.008 aOR 1.41; BC 12.8% vs 4.5% p&lt;0.001 aOR 3.39). The white race (OR 0.6, p&lt;0.001) and Medicare (OR 0.58 p&lt;0.001) were associated with lower odds of mortality, while the Hispanic race (OR 1.43, p=0.042) and Medicaid (OR 1.39, p=0.041) were associated with higher odds of mortality among LM hospitalizations. Conclusions: While actionable mutations and targeted therapies are developing rapidly, therapeutic options for LM remain limited, with a median survival of 4-5 months. Palliative care remains essential for a better quality of life; hence further studies should be conducted to improve the utilization of palliative care and investigate racial and economic disparities in the utilization of such.

The Riddle of the Sphinx: Progress in Leptomeningeal Metastasis of Non-Small Cell Lung Cancer.

Leptomeningeal metastasis (LM) is a serious complication of advanced non-small cell lung cancer (NSCLC), and the incidence of LM has been increasing yearly in recent times. There is no consensus on the best treatment modality for LM, which underscores a difficult problem in the management of advanced NSCLC patients. The existing treatments include molecular targeted therapy, systemic chemotherapy, local radiotherapy, antivascular tumor therapy, intrathecal chemotherapy, and immunotherapy, but their efficacy is not satisfactory. In this article, we briefly describe the clinical manifestations, diagnosis, and treatment of NSCLC-LM and discuss progress regarding evaluation of the efficacy of LM treatment to better provide a necessary reference for clinical practice and clinical trial evaluation.

EP08.02-069 A Retrospective Study of Aumolertinib Monotherapy or Combination Therapy Treated EGFR-mutated NSCLC Patients with Leptomeningeal Metastases

The incidence of leptomeningeal metastases (LM) is approximately 9% in epidermal growth factor receptor-mutated (EGFRm) NSCLC with extremely poor prognosis. Aumolertinib (formerly almonertinib; HS-10296) is a novel 3rd generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). The preclinical evidence in nonhuman primates shows that aumolertinib has high penetration of the blood-brain barrier and brain exposure compared with other EGFR-TKI. In this study, we researched the efficacy of aumolertinib monotherapy or combination therapy with EGFR-mutated NSCLC leptomeningeal metastases.

Advances in Diagnosis and Treatment of Leptomeningeal Metastasis of Lung Cancer

脑膜转移癌（leptomeningeal metastases, LM）是晚期肺癌中进展迅速、预后差的常见并发症。脑膜转移癌临床诊断率低，治疗手段有限，疗效差，自然生存时间短。脑脊液细胞学作为诊断脑膜转移癌的金标准，但是目前临床症状及影像学阳性的患者脑脊液首次细胞病理学阳性诊断率一般不超过50%，导致脑膜转移癌患者的诊断延迟、治疗延误。随着驱动基因阳性肺癌靶向治疗、驱动基因阴性肺癌免疫治疗的进展，肺癌患者生存期延长，但是脑膜转移癌发病率逐年增加，如何提高诊断率、寻找有效的治疗手段是目前临床研究的热点。本文就肺癌脑膜转移癌诊断及治疗研究进展予以综述。

Leptomeningeal Metastases and Intrathecal Chemotherapy

Leptomeningeal metastases (LM) is a rare but devastating complication of advanced cancer. Advances in cancer treatment has markedly improved the survival, nonetheless, due to the poor penetration of these treatments beyond the blood-brain and blood-CSF barrier for most modalities, creating a sanctuary site in the CNS/CSF space for the disease, and reflecting as increased incidence of LM. Whereas the goal of LM treatment remains to be symptom palliation and not elongation of survival, the optimal treatment, and whom to treat remains to be somewhat controversial. Herein we review the advances in LM treatment focusing on the role of intrathecal chemotherapy.

P47.08 A Phase II, Single-arm, Multicenter, Efficacy of 80 mg Osimertinib in Patients With Leptomeningeal Metastases Associated With EGFR Mutated NSCLC

Leptomeningeal metastases (LM) are severe, an aggressive complication of cancer, characterized by tumor cell spread to the cerebrospinal fluid (CSF) and leptomeninges. The higher incidence of LM in EGFR mutated non-small cell lung cancer (NSCLC) has been observed, especially after treated with 1st or 2nd generation EGFR TKI. The Osimertinib, the third generation irreversible EGFR TKI, has been developed to target T790M mutation. Unlike other EGFR TKIs, Osimertinib showed homogenous distribution to the brain suggesting high penetration of blood-brain barrier, and clinical efficacy in intracranial lesions has been demonstrated from the retrospective analyses.

Microsurgery vs. radiosurgery for the treatment of multiple metastases in the brain: a retrospective cohort study

Objective:Multiple brain metastases are a severe condition for cancer patients. To date, no general consensus exists regarding the optimal treatment procedure for multiple brain metastases. Radiotherapy is the most commonly used treatment option. The role of surgical resection for multiple brain metastases is unclear. The aim of this study was to compare the outcomes of patients with multiple brain metastases treated with either surgery or stereotactic radiosurgery (SRS).Methods:The medical records of 279 consecutive adult patients with multiple brain metastases treated with either surgery (26 patients) or SRS (253 patients) were retrospectively reviewed. Propensity score matching was conducted to correct for discrepancies in the baseline characteristics, and 78 patients (26 receiving surgery and 52 receiving SRS) were chosen for comparison of outcomes, such as overall survival, local tumor control rate, and symptom improvement.Results:The tumor size in the surgery group was significantly greater than that in the SRS group after propensity score matching. However, the neurological recovery rate, incidence of leptomeningeal metastasis after surgery, 1-year local tumor control rate, and overall survival were not significantly different between groups.Conclusions:Our data demonstrate that surgery and radiosurgery have identical overall survival and local tumor control rates in patients with 2 to 4 brain metastases. Although SRS remains the primary and standard option for patients with brain metastasis, surgery offers several distinct advantages, such as establishing a diagnosis or relieving mass effects, and may additionally be beneficial in carefully selected patients with 2–4 brain metastases.

FLAIR hyperintensity along the brainstem surface in leptomeningeal metastases: a case series and literature review

BackgroundThe incidence of leptomeningeal metastasis (LM) is underestimated because of its non-specific signs and the low sensitivity of clinical diagnostic modalities. Cerebrospinal magnetic resonance (MR) imaging with and without contrast enhancement (CE) is a gold standard for the neuroradiological assessment of patients with suspected LM. Previous studies suggested that some LM cases show changes of the brainstem surface on non-contrast MR images without or before the appearance of abnormalities on CE images. We assessed the features of this non-contrast MR finding in a cohort of LM patients in this retrospective single-institution study.MethodsWe reviewed head MR images and clinical data of 142 consecutive patients in whom the final diagnosis was LM.ResultsWe found that 11 of these 142 patients (7.7%) with LM had band-like hyperintensity on the brainstem surface on non-enhanced FLAIR images, which looked like bloomy rind on cheese. Three of seven patients who were examined using diffusion-weighted imaging showed restricted diffusion in the corresponding lesion site. The above-mentioned 11 patients included 10 women and 1 man, with a median age of 61 years. All 11 patients had primary lung adenocarcinoma. Seven patients had symptomatic hydrocephalus. Ten patients had EGFR-mutated and one had ALK-rearrangement adenocarcinomas. Before the diagnosis of LM, 10 patients had undergone systemic therapy with EGFR-TKI or pemetrexed, and 1 patient with ALK inhibitor and bevacizumab.ConclusionsWe present a series of patients with bloomy rind sign that is non-enhancing LM reliably detected by FLAIR hyperintensity on the brainstem surface. This finding is rare, but may reflect the spread of cancer cells in both the leptomeningeal membrane and the surface of the brain parenchyma specifically in patients with lung adenocarcinomas. Further study is needed to determine the clinical significance of this sign, and the pathophysiological factors associated with it may be clarified by analyzing serial MR images in a larger cohort of patients treated for LM.

Leptomeningeal Metastases in Non-small Cell Lung Cancer: Optimal Systemic Management in NSCLC With and Without Driver Mutations

As a devastating complication of non-small cell lung cancer (NSCLC), the incidence of leptomeningeal metastasis (LM) is rising, largely due to overall longer survival of NSCLC, especially in patients with targetable molecular driver mutations. There is no clear consensus on the optimal management of LM. This review will cover recent advances in diagnosis, monitoring, and treatment of LM in NSCLC. In LM without oncogene drivers, systemic chemotherapy, intrathecal therapy, and radiation have modestly improved the clinical outcomes. Emerging data have also suggested encouraging activity of immunotherapy. At the same time, in LM with sensitizing EGFR mutations, osimertinib should be considered regardless of T790M status. Pulse erlotinib, afatinib, and newer agents with improved CNS penetration have also shown benefits. Moreover, accumulating evidences support potential benefits of molecularly targeted therapy in ALK-rearranged and other oncogene-driven NSCLC with LM. Future studies are warranted to better define the underlying mechanism, to optimize the clinical management, and to improve patient outcomes.

Cerebrospinal Fluid CYFRA 21-1 as a Diagnostic Indicator for Leptomeningeal Metastasis in Cancer Patients

Background The early and accurate diagnosis of leptomeningeal metastasis (LM) has become important because of introduction of new therapeutic strategies for LM and increasing incidence of LM along with longer survival of cancer patients. We aimed to evaluate the role of cerebrospinal fluid (CSF) CYFRA 21-1 as a diagnostic indicator for LM in patients with cancer. Methods CSF CYFRA 21-1 level was analyzed using electro-chemiluminescent immunoassay. The difference in concentration of CSF CYFRA 21-1 between 91 patients with LM and 339 control groups (patients with other neurological disease or healthy controls) was investigated. The cut-off value of CSF CYFRA 21-1 as a diagnostic indicator for LM and its diagnostic performance were evaluated. Results The CSF CYFRA 21-1 was significantly higher in LM patients than control groups (p<0.001). A cut-off value of diagnosis for LM in patients with cancer was 1.59 ng/mL. The sensitivity, specificity, accuracy, and positive and negative predictive values of CSF CYFRA 21-1 were 80.2%, 96.2%, 92.8%, 84.9%, 94.8% for diagnosis of LM. Conclusions These results suggested that CSF CYFRA 21-1 can be an additional diagnostic indicator for cancer patients with LM. Key Words: Neoplasm metastasis, Diagnosis, Cerebrospinal fluid, CYFRA 21-1

Management of leptomeningeal metastases in non-small cell lung cancer.

In leptomeningeal metastasis (LM), malignant lung cancer cells reach the sanctuary site of the leptomeningeal space through haematogenous or lymphatic route and thrive in the leptomeninges because of restricted access of chemotherapeutic agents across the blood brain barrier. The incidence of LM is 3%-5% in non-small cell lung cancer (NSCLC) patients; the incidence is higher in patients with anaplastic lymphoma kinase (ALK) gene rearrangement or epidermal growth factor receptor (EGFR) mutations. However, the real-world burden of undiagnosed cases may be higher. LM diagnosis is based on clinical, radiological, and cytological testing. Disease management remains a challenge because of low central nervous system penetration of drugs. The prognosis of NSCLC patients with LM is poor with an overall survival (OS) of 3 months with contemporary treatment and <11 months with novel therapies. Therapy goals in this patient population are to improve or stabilize neurologic status, improve quality of life, and prolong survival while limiting the toxicity of chemotherapeutic regimens. We reviewed therapeutic options for management of LM in NSCLC patients with or without genetic mutations. Radiotherapy, systemic, or intrathecal chemotherapy, and personalized molecularly targeted therapy prolong the OS in patients with LM. Newer third generation EGFR-tyrosine kinase inhibitors have considerable brain penetration property and have been vital in increasing the OS especially in patients with EGFR mutations. Sequential or combination therapy third generation EGFR agents with radiotherapy or chemotherapy might be effective in increasing the quality of life and overall survival.

Leptomeningeal metastasis after effective first-generation EGFR TKI treatment of advanced non-small cell lung cancer

ObjectiveTo evaluate the influence of a first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) treatment on the clinical features of leptomeningeal metastasis (LM) progression and outcome in advanced non-small cell lung cancer (NSCLC) patients. MethodsWe retrospectively evaluated advanced NSCLC patients receiving effective first-generation EGFR TKI treatment (e.g., treatment > 6 months) at our institution between January 2008 and February 2014. Incidence, time to progression, and treatment outcome of LM were examined. ResultsIn our cohort, 29/420 patients (6.9%) developed LM. Among the patients harboring L858R or deletion of exon 19 in EGFR, the incidence of LM was 10.7% (21/197) and 3.4% (7/203), respectively (P = 0.006). The median time to LM progression was 16.5 months (95% confidence interval (CI), 11.9–20.8). The median overall survival (OS) after LM diagnosis was 5.2 months (95% CI, 3.2–7.2). In a subgroup analysis, OS was improved in patients with performance status (PS) ≤ 2 vs. PS > 2 (14.2 months vs. 2.3 months, respectively; P < 0.001). OS was also improved among patients who received, rather than did not receive, anti-tumor treatment (6.0 months vs. 1.9 months, respectively; P < 0.001) or whole brain radiotherapy (WBRT) (6.0 months vs. 3.9 months, respectively; P = 0.038). Multivariate analysis indicated that WBRT is a good prognostic factor (P = 0.048), whereas best support care (P = 0.033) and PS > 2 (P = 0.034) were poor prognostic factors. ConclusionA greater incidence of LM was observed in NSCLC patients harboring EGFR mutations after effective EGFR TKI treatment. In particular, the primary mutation, L858R, potentially predicts a higher risk of LM compared with deletion of exon 19. These results highlight the importance of determining mutation status when evaluating the biological behavior of LM in NSCLC patients who positively respond to EGFR TKI treatment.