Diagnosis Of Leptomeningeal Metastasis Research Articles

Real-world use of a CSF circulating tumor cell assay in the diagnosis and management of leptomeningeal metastasis.

2029 Background: The diagnosis of leptomeningeal metastasis (LM) can be challenging due to variability in clinical symptoms, radiographic, and cerebrospinal fluid (CSF) findings. The National Comprehensive Cancer Network (NCCN) guidelines recommend assessment of circulating tumor DNA (ctDNA) to increase sensitivity of tumor cell detection and assess the response to treatment. We hypothesize that the real-world use of an assay for the direct detection and enumeration of circulating tumor cells (CTCs) in the CSF is clinically useful for accurate diagnosis of LM, particularly in an early stage of disease. Methods: We report a series of 55 patients treated at our institution with a cancer diagnosis and either neurological symptoms or radiographic findings that suggested LM. All patients underwent a lumbar puncture, assessment for CSF CTCs, and conventional hospital-based cytology testing between 6/1/2020 and 8/1/2023. Survival data cutoff was 12/31/2023. Patient outcomes are reported. Results: 55 patients were tested, and 30 patients were found to be positive for CTCs and diagnosed with LM. Only 10 patients were concurrently positive for CTCs and cytology at our institution, whereas 20 patients with positive CTCs had a negative or ambiguous cytology. No patients with a negative CTC result (25 patients) were subsequently diagnosed with LM, whereas 4 patients with a positive CTC result remained without progressive neurological symptoms. 5 patients diagnosed with LM were alive at the time of data cutoff. The histologic breakdown for LM was: breast (11), non-small cell lung cancer (NSCLC) (16), gastrointestinal (GI) (3). Median overall survival (OS) was longer in patients with a positive CTC and negative cytology result compared to patients with concurrent positive CTC and cytology (172 vs. 63 days, p = 0.06). Median OS was also longer in breast cancer LM compared to NSCLC LM (235 vs. 63 days, p = 0.008). Most patients diagnosed with LM received therapies including Ommaya reservoir placement, intrathecal chemotherapy, and/or radiation. Conclusions: The use of a CSF circulating tumor cell assay aided the diagnosis of LM and led to timely initiation of treatment. A negative result of the CTC assay was associated with ruling out LM. Diagnosis of LM with the CTC assay and negative cytology was associated with longer survival, possibly due to earlier treatment initiation, and not solely a lead time bias. Breast cancer LM patients had improved survival compared to NSCLC and GI cancer patients, possibly due to more effective treatment options.

Leptomeningeal Metastases in IDH-wildtype Glioblastomas Revisited: Comprehensive Analysis of Incidence, Risk Factors, and Prognosis Based on Post-contrast FLAIR.

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 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 = 0.014), shorter distance between tumor and SVZ (OR = 0.94, P = 0.010), and larger contrast-enhancing tumor volume (OR = 1.02, P < 0.001) were significantly associated with LM. The overall survival (OS) was significantly shorter in patients with LM than in those without (log-rank test; P < 0.001), with median OS of 12.2 and 18.5 months, respectively. Presence of LM remained an independent prognostic factor for OS in IDH-wildtype glioblastoma (hazard ratio = 1.42, P = 0.011), 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 acknowledgement of post-contrast FLAIR as a reliable diagnostic tool for clinicians.

Diagnosis and genetic characterization of CNS metastases in lung cancer via shallow whole-genome sequencing of CSF cell-free DNA.

e14013 Background: The genetic characterization of CNS metastases in lung cancer is hindered by the limited sampling opportunities and genetic heterogeneity between intracranial and extracranial lesions. To address these challenges, this study uses cerebrospinal fluid (CSF) and blood samples, to detect and characterize CNS metastasis variants through shallow whole-genome sequencing (sWGS). Methods: From Dec. 2021 to Aug. 2023, 57 lung cancer patients were recruited, comprising 29 with leptomeningeal metastases (LMs) and 28 with only parenchymal brain metastases (PMs). A total of 66 blood and 112 CSF samples were collected for cfDNA sWGS to analyze chromosomal arm CNVs, focal amplifications (CN &gt; 5) and SNV/InDels. Cytology was also conducted on 95 of these CSF samples. Variant differences between PMs and extracranial metastases (EMs) were analyzed using the MSK-MET database. Results: CSF cfDNA concentration was significantly lower than that in plasma (p &lt; 0.0001), with 41.7% of samples unquantifiable, yet all samples successfully completed sWGS. The cfDNA tumor fraction in CSF was significantly higher than in paired plasma (p &lt; 0.0001), and most arm CNVs and gene amplifications exclusively detected in CSF. Cytology, as the gold standard for LM diagnosis, had a sensitivity of 0.76. The sensitivity for LM diagnosis based on aneuploidy and genomic amplification fraction (GAF) were 0.51 and 0.80, respectively, without compromising specificity. Gains in 1p, 7p, 11q, 16p, and 17q, as well as losses in 9p and 9q, were significantly more frequent in PMs compared to EMs and further increased in the LMs (p &lt; 0.05). Notably, losses in 1p, 4p, 5q, and 11p, significantly more frequent in PMs than in extracranial metastases, but showed a significant increase in gain frequency in LMs (p &lt; 0.05). In the LM group, the frequency of EGFR L858R and amplification of nearly the entire 7p where the EGFR located, were significantly increased, whereas KRAS G12D frequency significantly decreased (p &lt; 0.05). Conclusions: The characteristics of extremely low concentration but high tumor fraction of CSF cfDNA make it suitable for sWGS, enhancing LM diagnostic sensitivity without compromising specificity, and identifying molecular characteristics of CNS metastasis. These molecular features require further validation in larger prospective clinical cohorts, offering potential for personalized diagnosis and treatment of CNS metastases.

NSCLC extracellular vesicles containing miR-374a-5p promote leptomeningeal metastasis by influencing blood‒brain barrier permeability.

Leptomeningeal metastasis (LM) is a devastating complication of advanced non-small cell lung cancer (NSCLC). Diagnosis and monitoring of LM can be challenging. Extracellular vesicles (EVs) microRNAs (miRNAs) have become a new noninvasive diagnostic biomarker. The purpose of this study was to examine the clinical value and role of EVs miRNAs in NSCLC-LM. According to next-generation sequencing (NGS), miRNAs with differential expression of EVs in serum of NSCLC patients with LM and non-LM were detected to find biological markers for the diagnosis of LM. Cellular and in vivo experiments were conducted to explore the pathogenesis of EVs miRNA promoting LM in NSCLC. In the present study, we first demonstrated the serum level of EV-associated miR-374a-5p in patients with LM of lung cancer was much higher than that in patients without LM and was correlated with the survival time of patients with LM. Further studies showed that EVs miR-374a-5p efficiently destroys tight junctions and the integrity of the cerebral microvascular endothelial cell barrier, resulting in increased blood-brain barrier (BBB) permeability. Mechanistically, miR-374a-5p regulates the distribution of ZO-1 and occludin in endothelial cells by targeting ADD3, increasing vascular permeability and promoting LM. Implications: These results suggest that serum NSCLC-derived EVs miR-374a-5p is involved in premetastatic niche formation by regulating the permeability of BBB to promote NSCLC-LM, and can be used as a blood biomarker for the diagnosis and prognosis of NSCLC-LM.

Abstract A051: Treatment outcome of leptomeningeal metastasis from breast cancer

Abstract Purpose: Leptomeningeal metastasis (LM) is well-known for its dismal prognosis. Despite various treatment approaches, there has been minimal improvement in survival, and the optimal treatment for leptomeningeal metastasis remains uncertain. Our study aimed to report treatment outcomes using different modalities for LM and to identify prognostic factors. Materials and Methods: We analyzed 111 breast cancer patients with LM, who were treated at Seoul National University and Seoul Metropolitan Government Seoul National University Boramae Medical Center between January 2010 and December 2022. The median follow-up period was 4.4 months (range, 0.2 – 125.4 months). Results: The median age was 48 years, with the majority having a Karnofsky performance status below 60 (n = 100, 90.1%). Among the 111 patients, intrathecal chemotherapy was the most commonly used treatment modality (n = 89, 80.2%), followed by radiotherapy (n = 74, 66.7%), and systemic chemotherapy (n = 56, 50.5%). The median freedom from progression was 3.4 months. In multivariate analysis, patients who underwent more than 2 treatment modalities experienced significantly longer progression-free interval (1.8 months vs. 7.4 months, HR = 0.20, p = 0.038). Additionally, patients who underwent excision of the primary breast tumor displayed a tendency for longer progression-free interval (3.1 months vs. 3.4 months, HR = 0.33, p = 0.084). Patients with systemic inflammation index greater than 500 × 103/mm3 at the time of the diagnosis of LM exhibited shorter progression-free interval (3.5 months vs. 2.9 months, HR = 2.88, p = 0.056). There was no difference of progression-free interval according to treatment modalities. Conclusions: The freedom from progression of LM originating from breast cancer was found to be poor, exhibiting less than 4 months. A multimodal approach upon LM and high systemic inflammation index at the time of the diagnosis of LM demonstrated significant difference in prognosis. Further research is warranted to elucidate the clinical implications and develop optimized treatment strategie Citation Format: Suzy Kim, Choong-won Lee. Treatment outcome of leptomeningeal metastasis from breast cancer [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A051.

Prognostic impact of clinical and radiological factors on leptomeningeal metastasis from solid cancers.

The number of leptomeningeal metastasis (LM) patients has increased in recent years, as the cancer survival rates increased. An optimal prediction of prognosis is essential for selecting an appropriate treatment. The European Association of Neuro-Oncology-European Society for Medical Oncology (EANO-ESMO) guidelines for LM proposed a classification based on the cerebrospinal fluid cytological findings and contrast-enhanced magnetic resonance imaging (MRI) pattern. However, few studies have validated the utility of this classification. This study aimed to investigate the prognostic factors of LM, including the radiological and cytological types. We retrospectively analyzed the data of 240 adult patients with suspected LM who had undergone lumbar puncture between April 2014 and September 2021. The most common primary cancer types were non-small-cell lung cancer (NSCLC) (143 (60%)) and breast cancer (27 (11%)). Positive cytology results and the presence of leptomeningeal lesions on contrast-enhanced MRI correlated with decreased survival in all patients. Nodular lesions detected on contrast-enhanced magnetic resonance were a poor prognostic factor in cytology-negative patients, while contrast-enhanced patterns had no prognostic significance in cytology-positive patients. Systemic therapy using cytotoxic agents and molecular-targeted therapy after LM diagnosis correlated with prolonged survival, regardless of the cytology results. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor treatment and systemic chemotherapy after LM improved the survival of EGFR-mutated and wild-type NSCLC patients with positive cytology results. This study validated the efficacy of prognostication according to the EANO-ESMO guidelines for LM. Systemic therapy after LM diagnosis improves the survival of NSCLC patients.

Diagnostic value of cerebrospinal fluid human epididymis protein 4 for leptomeningeal metastasis in lung adenocarcinoma.

The diagnosis of lung adenocarcinoma (LUAD) leptomeningeal metastasis (LM) remains a clinical challenge. Human epididymis protein 4 (HE4) functions as a novel tumor biomarker for cancers. This study aimed to assess the diagnostic value of cerebrospinal fluid (CSF) HE4, and combined with CEACAM6, for LUAD LM. The CSF HE4 protein level was measured in two independent cohorts by electrochemiluminescence. Test cohort included 58 LUAD LM patients, 22 LUAD patients without LM (Wiot-LM), and 68 normal controls. Validation cohort enrolled 50 LUAD LM patients and 40 normal controls, in parallel with Wiot-LM patients without brain metastases (19 Wiot-LM/BrM patients) or with BrM (26 BrM patients). The CSF level of CEA, CA125, CA153, CA199, CA724, NSE and ProGRP of these samples was measured by electrochemiluminescence, whereas the CSF CEACAM6 level was detected by enzyme-linked immunosorbent assay (ELISA). In addition, the serum level of these biomarkers was detected by same method as CSF. The level of HE4 or CEACAM6 in CSF samples from LUAD LM patients was significantly higher than those from normal controls and Wiot-LM patients. The HE4 or CEACAM6 level in CSF was higher than that in serum of LM patient. The CSF HE4 or CEACAM6 level for distinguished LM from Wiot-LM showed good performance by receiver-operating characteristic analysis. The better discriminative power for LM was achieved when HE4 was combined with CEACAM6. In addition, the CSF HE4 and CEACAM6 level showed little or no difference between Wiot-LM/BrM and BrM patients, the BrM would not significantly influence the HE4 or CEACAM6 level in CSF. The diagnostic power of CSF CA125, CA153, CA199, CA724, NSE and ProGRP for LUAD LM were not ideal. The combination with HE4 and CEACAM6 has the promising application for the diagnosis of LUAD LM.

10060-MET-5 LEPTOMENINGEAL METASTASES FROM HER2 POSITIVE SALIVARY GLAND CARCINOMATREATED WITH CRANIOSPINAL IRRADIATION FOLLOWED BY INTRATHECAL TRASTUZUMAB

Abstract We report our experience with a case of intrathecal trastuzumab (Tmab) after craniospinal irradiation for leptomeningeal metastases (LM) of HER2-positive salivary gland carcinoma. The patient was a 46-year-old male with postoperative extensive cervical recurrence of left parotid carcinoma (salivary gland conduit carcinoma, HER2 positive) treated with intravenous Tmab and docetaxel. He was hospitalized for headache and nausea, and diagnosed as LM by MRI and CSF cytology. He received whole brain irradiation of 30Gy/10Fr and whole spinal cord irradiation of 30Gy/10Fr. Because of HER2 positive cancer, we applied to the ethics committee and started Tmab intrathecal treatment(IT) . The initial dose was 20 mg, which was administered intrathecally once every 3 weeks, and the dose was increased by 20 mg in 20 mg increments up to 60 mg while checking for post-dose side effects. The side effect was discomfort in the extremities during IT, which resolved by slowing down the administration rate. The time from diagnosis of LM to CNS deterioration was 9 months. Tmab IT may be effective in treating LM in HER2-positive salivary gland carcinoma. Further clinical studies are needed to evaluate efficacy and safety.

Clinical Safety and Efficiency of the H-Port for Treatment of Leptomeningeal Metastasis.

To evaluate the usefulness of a cranial implantable chemoport, the H-port, as an alternative to the Ommaya reservoir for intraventricular chemotherapy/cerebrospinal fluid (CSF) access in patients with leptomeningeal metastasis (LM). One hundred fifty-two consecutive patients with a diagnosis of LM and who underwent H-port installation between 2015 and 2021 were evaluated. Adverse events associated with installation and intraventricular chemotherapy, and the rate of increased intracranial pressure (ICP) control via the port were evaluated for safety and efficacy. These indices were compared with published data of Ommaya (n=89), from our institution. Time-to-install and installation-related complications of intracranial hemorrhage (n=2) and catheter malposition (n=5) were not significantly different between the two groups. Intraventricular chemotherapy-related complications of CSF leakage occurred more frequently in the Ommaya than in the H-port group (13/89 vs. 3/152, respectively, p<0.001). Intracranial hemorrhage during chemotherapy occurred only in the Ommaya group (n=4). The CSF infection rate was not statistically different between groups (14/152 vs. 12/89, respectively). The ICP control rate according to reservoir type revealed a significantly higher ICP control rate with the H-port (40/67), compared with the Ommaya result (12/58, p<0.001). Analyzing the ICP control rate based on the CSF drainage method, continuous extraventricular drainage (implemented only with the H-port), found a significantly higher ICP control rate than with intermittent CSF drainage (33/40 vs. 6/56, respectively, p<0.0001). The H-port for intraventricular chemotherapy in patients with LM was superior for ICP control; it had equal or lower complication rates than the Ommaya reservoir.

EPID-04. EVOLVING SURVIVAL IN PATIENTS WITH LEPTOMENINGEAL METASTASES FROM SOLID TUMORS

Abstract BACKGROUND The prognosis for patients with leptomeningeal metastases (LM) has been historically bleak, with an average survival &amp;lt; 4 months and limited treatment options. As modern therapeutics prolong the lives of cancer patients, the life expectancy of those with LM may also improve. This study aims to demonstrate survival trends in patients with LM over a 20-year time span. METHODS This is a single-institution retrospective analysis of patients diagnosed with solid tumor LM, excluding primary brain tumors, between 2002-2022. LM diagnosis was determined via unequivocal radiographic enhancement, CSF cytology, and CSF circulating tumor cell enumeration (CSF-CTC, cells/3mL). Patient characteristics, CSF-CTC enumeration at diagnosis, and therapeutic interventions post-LM were collected. Median overall survival (OS) with IQRs were calculated. RESULTS A total of 626 patients with LM were identified. The median age at LM diagnosis was 59 years (range, 13-86) with a female predominance (72.5%). Primary malignancy consisted of lung (45.2%), breast (35.7%), melanoma (4.0%), and other (15.1%). The 20-year median OS in patients with lung cancer was 4.8 months (1.9-13.0), breast cancer was 6.1 months (2.0-13.7), and melanoma was 7.1 months (2.8-14.5). Median OS was prolonged in patients with a CSF-CTC count ≤ 50 versus &amp;gt; 50 (8.9 vs 3.4 months, p&amp;lt; 0.0001). Patients who received LM-directed proton craniospinal irradiation (17.1%), photon involved-field radiation (45.5%), and no radiation (37.4%) had a median OS of 8.7 months (4.3-20.2), 4.3 months (1.5-9.1), and 3.4 months (1.2-12.5), respectively. Patients diagnosed with LM between 2017-2022 trended towards superior median OS (6.2 months, 2.2-14.0) compared to those diagnosed between 2002-2016 (5.3 months, 2.2-12.2). CONCLUSION In this largest known series of patients with LM, outcomes show signs of improvement. Superior survival trends emerge based on primary malignancy, early detection, and modern treatment modalities. Further analyses will define survival trends by patient characteristics, cancer subtypes, and systemic therapies.

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.

Validation of targeted next-generation sequencing of cell-free DNA from archival cerebrospinal fluid specimens for the detection of somatic variants in cancer involving the leptomeninges: Cytopathologic and radiographic correlation.

Leptomeningeal metastases occur across multiple solid and lymphoid cancers, and patients typically undergo cytopathologic assessment of cerebrospinal fluid (CSF) in this setting. For patients diagnosed with metastatic cancer, the detection of actionable somatic mutations in CSF can provide clinically valuable information for treatment without the need for additional tissue collection. The authors validated a targeted next-generation sequencing assay for the detection of somatic variants in cancer (OncoPanel) on cell-free DNA (cfDNA) isolated from archival CSF specimens in a cohort of 25 patients who had undergone molecular testing of a prior tumor specimen. CSF storage time and volume had no impact on cfDNA concentration or mean target coverage of the assay. Previously identified somatic variants in CSF cfDNA were detected in 88%, 50%, and 27% of specimens diagnosed cytologically as positive, suspicious/atypical, and negative for malignancy, respectively. Somatic variants were identified in 81% of CSF specimens from patients who had leptomeningeal enhancement on magnetic resonance imaging compared with 31% from patients without such enhancement. These data highlight the stability of cfDNA in CSF, which allows for cytopathologic evaluation before triage for next-generation sequencing assays. For a subset of cases in which clinical suspicion is high but cytologic or radiographic studies are inconclusive, the detection of pathogenic somatic variants in CSF cfDNA may aid in the diagnosis of leptomeningeal metastases.

Cerebrospinal fluid circulating tumour DNA genotyping and survival analysis in lung adenocarcinoma with leptomeningeal metastases

PurposeThe prognosis of patients with leptomeningeal metastasis (LM) remains poor. Circulating tumour DNA (ctDNA) has been proven to be abundantly present in cerebrospinal fluid (CSF); hence, its clinical implication as a biomarker needs to be further verified.MethodsWe conducted a retrospective study of 35 lung adenocarcinoma (LUAD) patients with LM, and matched CSF and plasma samples were collected from all patients. All paired samples underwent next-generation sequencing (NGS) of 139 lung cancer-associated genes. The clinical characteristics and genetic profiling of LM were analysed in association with survival prognosis.ResultsLM showed genetic heterogeneity, in which CSF had a higher detection rate of ctDNA (P = 0.003), a higher median mutation count (P < 0.0001), a higher frequency of driver mutations (P < 0.01), and more copy number variation (CNV) alterations (P < 0.001) than plasma. The mutation frequencies of the EGFR, TP53, CDKN2A, MYC and CDKN2B genes were easier to detect in CSF than in LUAD tissue (P < 0.05), possibly reflecting the underlying mechanism of LM metastasis. CSF ctDNA is helpful for analysing the mechanism of EGFR-TKI resistance. In cohort 1, which comprised patients who received 1/2 EGFR-TKIs before the diagnosis of LM, TP53 and CDKN2A were the most common EGFR-independent resistant mutations. In cohort 2, comprising those who progressed after osimertinib and developed LM, 7 patients (43.75%) had EGFR CNV detected in CSF but not plasma. Furthermore, patient characteristics and various genes were included for interactive survival analysis. Patients with EGFR-mutated LUAD (P = 0.042) had a higher median OS, and CSF ctDNA mutation with TERT (P = 0.013) indicated a lower median OS. Last, we reported an LM case in which CSF ctDNA dynamic changes were well correlated with clinical treatment.ConclusionsCSF ctDNA could provide a more comprehensive genetic landscape of LM, indicating the potential metastasis-related and EGFR-TKI resistance mechanisms of LM patients. In addition, genotyping of CSF combined with clinical outcomes can predict the prognosis of LUAD patients with LM.

The sensitivity and specificity of 18F-FDG PET/CT in spinal leptomeningeal metastases: the synergistic effect of the 18F-FDG PET-CT to gadolinium-enhanced MRI.

Magnetic resonance imaging (MRI) plays an important role in the diagnosis of leptomeningeal metastases (LM); however, some sub-centimeter lesions may be missed. Positron emission tomography/computed tomography (PET/CT) has a high sensitivity and may play a synergistic role with MRI in diagnosing spinal LM (SLM). We aimed to retrospectively evaluate the detection of SLM with 18F-fluorodeoxyglucose PET/CT (18F-FDG PET/CT) compared to that of whole spinal cord MRI in a single center. Patients with SLM who had undergone 18F-FDG PET/CT and MRI were enrolled. 18F-FDG PET/CT imaging findings were independently reviewed by 2 nuclear medicine physicians. 18F-FDG PET/CT findings of SLMs were described. A consistency test was conducted to assess the patient-based diagnostic results obtained by the 2 physicians. Patient-based sensitivity, accuracy, and specificity in diagnosing SLM between 18F-FDG PET/CT and MRI of the whole spinal cord were compared using the chi-square or Fisher's exact test. A P value of <0.05 was considered statistically significant. The receiver operating characteristic (ROC) curve was obtained to assess the diagnostic performance of maximum standardized uptake value (SUVmax) to diagnose SLM. A total of 16 patients with SLM were included in this study from October 2010 to April 2022. The primary tumor involved the lungs, liver, ovaries, prostate, esophagus, and unknown primary site. The mean age of patients, including 13 males and 3 females, was 57.8±11.2 (range, 34-73) years. Of 16 patients with SLM, 10 had nodular diseases, 2 had linear diseases, and 4 had mixed diseases. The kappa value of the consistency test of the 2 radiologists' diagnostic results was 0.765. The patient-based sensitivity, specificity, and accuracy of 18F-FDG PET/CT in diagnosing SLM were 87.5%, 89.2%, and 88.7%, respectively and those of whole spinal cord MRI were 75.0%, 100.0%, and 92.5%, respectively. There were no significant differences in sensitivity, specificity, and accuracy between the 2 methods, with P values of 0.654, 0.115, and 0.506, respectively. However, more nodular diseases were observed on PET/CT. The area under the ROC curve (AUC) for the prediction of SLM by SUVmax was 0.907 [95% confidence interval (CI): 0.831-0.983]. When SUVmax ≥2.45, the Youden index was the largest, and the sensitivity and specificity were 89.3% and 75.7%, respectively. 18F-FDG PET/CT is a good choice of imaging modality for assessing SLM. In the diagnosis of SLMs, PET/CT and enhanced MRI can play a better synergistic role.

Clinical characteristics and their influences on the survival of leptomeningeal metastasis derived from lung adenocarcinoma harboring epithelial growth factor receptor mutation

Objective: To analyze the clinical characteristics of leptomeningeal metastasis (LM) patients from epithelial growth factor receptor (EGFR)-mutated lung adenocarcinoma, and their impacts on the survival of the patients. Methods: From July 2018 to July 2022, the clinicopathological data of 81 patients diagnosed as EGFR-mutated lung adenocarcinoma LM by cytopathology who admitted to the Department of Oncology of Xiangya Hospital of Central South University were retrospectively analyzed, including 33 males and 48 females. The age ranged from 31 to 76 years, with a median age of 54 years. All the 81 patients were followed up, with a median follow-up of 21.0 months (95%CI: 12.5 to 29.5 months). The Kaplan Meier method was used to draw survival curve. Cox proportional hazards regression model was used to analyze the impact of the factors on the survival of patients. Results: Among the 81 patients, the interval between the initial diagnosis of lung cancer and the pathological diagnosis of LM in cerebrospinal fluid (CSF) was 0-108 months, with a median interval of 14 months. Fifty-two patients (64.2%) used the third-generation epithelial growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs), while 17 patients (21.0%) used EGFR-TKIs in combination with other drugs, and 12 patients (14.8%) were treated with best supportive care (BSC). Sixty patients (74.1%) had a Kanofsky performance status (KPS) score of less than 60 points, and 71 patients (87.7%) had brain parenchymal metastasis and/or spinal metastasis. Twenty-two patients (27.2%) used pemetrexed through intrathecal CSF, and 17 patients (21.0%) used pemetrexed through the Ommaya sac to the CSF of the ventricle. The incidence of adverse event related to the administration of pemetrexed through CSF was 64.1% (25/39), mainly manifested as myelosuppression, including 22 patients of leukocyte reduction, 25 patients of hemoglobin reduction, and 14 patients of platelet reduction. The median post-leptomeningeal metastasis overall survival (pLM-OS) in 81 patients was 11.0 (95%CI: 7.7-14.3) months. KPS score≥60 points (HR=0.407, 95%CI: 0.170-0.973, P=0.043), CSF cytology negative after treatment (vs persistent positive, HR=0.351, 95%CI: 0.155-0.792, P=0.012), intraventricular administration of pemetrexed (vs non intraventricular administration of pemetrexed, HR=0.319, 95%CI: 0.137-0.745, P=0.008) and the treatment with third-generation EGFR-TKIs after LM (vs EGFR-TKIs in combination with other drugs, HR=0.486, 95%CI: 0.237-0.998, P=0.049) were a factor affecting pLM-OS of patients. Conclusions: Brain parenchyma, or/and spine are the most sites where the LM patients concurrently metastasize. KPS score≥60 points and CSF cytology negative after treatment, intraventricular administration of pemetrexed and the treatment with third-generation EGFR-TKIs are indictors affecting pLM-OS of the patients.

P16.04.A THE PROGNOSTIC ROLE OF VENTRICULAR SIZE AND ITS DYNAMICS IN PATIENTS WITH LEPTOMENINGEAL METASTASIS FROM SOLID TUMORS

Abstract BACKGROUND Hydrocephalus is a common radiological sign in patients with leptomeningeal metastasis (LM) from solid tumors and can be assessed using the Evans index (EI) with high interrater agreement. Here we explored the prognostic value of ventricular size at diagnosis and during the disease course of LM. METHODS We assembled a cohort of 113 adult patients with a diagnosis of LM from solid extra-CNS tumors and explored the prognostic association of ventricular size assessed by the EI at diagnosis, of its modification between diagnosis and evaluation at first follow-up (&amp;gt;21 days after diagnosis), and at first progression. RESULTS Median age was 58.2 years (interquartile range (IQR) 46.1-65.7), 41 patients (36%) were male, the most frequent cancers were lung cancer (n=39, 35%), breast cancer (n=36, 32%) and melanoma (n=23, 20%). The median EI at baseline was 0.28 (IQR 0.26-0.31) and the EI value was 0.27 or more in 67 patients (59%) and 0.30 or more in 37 patients (33%). Among patients with MRI follow-up, the EI increased by 0.01 or more in 19 patients (40%), including 9 of 29 patients (30%) and 10 of 17 patients (59%), respectively, without and with LM progression at first follow-up. At LM progression, an increase of EI of 0.01 or more was noted in 18 of 34 patients (53%). The median overall survival was 2.9 months (IQR 1-7.2). Patients with a baseline EI of 0.26 or less had a longer survival than those with an EI of 0.27 or more (5.3 months, IQR 2.4-10.8, versus 1.3 months, IQR 0.6-4.1) (p=0.006). Median survival was 3.7 months (IQR 1.4-8.3) with an EI of 0.29 or less versus 1.8 months (IQR 0.8-4.1) with an EI of 0.30 or more (p=0.109). Among patients with follow-up scans available, median overall survival was 9.7 months (IQR 5.6-21.4) for patients with stable or decreased EI at first follow-up as opposed to 6.4 months (IQR 3.2-10.5) for those with an increase in the EI (p=0.292). CONCLUSION The EI at baseline is prognostic in LM. An increase of EI during the follow-up is associated with inferior LM-progression-free survival. An independent validation cohort with larger sample size and evaluation of confounding factors will help to better define the clinical utility of EI assessments in LM.

OS09.6.A A MULTICENTER, PHASE I/II, OPEN-LABEL STUDY OF INTRATHECAL PEMETREXED FOR LEPTOMENINGEAL METASTASES FROM SOLID TUMOR (PMLM, NCT 05289908)

Abstract BACKGROUND There has never been a dose-escalation study on intrathecal pemetrexed (IP) with vitamin supplementation. This phase I/II study was to evaluate the maximum-tolerated dosage (MTD) of IP with vitamin supplementation and the antitumor activity for leptomeningeal metastases (LM) from solid tumors. MATERIAL AND METHODS Phase I study followed the classic 3 + 3 design, with the dose of IP escalated from 15 mg. Phase II followed the Simon 2-stage design with the recommended dose determined in phase I. IP was administered twice per week for 2 weeks (induction therapy), followed by once per week for 4 weeks (consolidation therapy). Clinically stable or improved patients continued IP once a month (maintenance therapy). Vitamin B12 (1000 μg) and folic acid (400 μg, q.d.) were given at the beginning of treatment. Primary end points were MTD in phase I and clinical response rate (CRR) in phase I/II. All patients were assessed to investigate safety, CRR and overall survival (OS). RESULTS Between Feb 2022 and Jan 2023, 34 patients (male: 16; female: 18; age: 45-68 years; median: 56 years) were enrolled, including non-small lung cancer (20), small-cell lung cancer (3), breast cancer (8), others (3). Thirty-three patients had a confirmed LM diagnosis (positive CSF cytology). Remaining one had probable diagnosis (positive neuroimaging with typical clinical signs). Ten patients were enrolled in phase I. Three of 4 patients receiving IP at 15 mg completed induction and consolidation treatment without dose limiting toxicity (DLT). The dose was escalated to 20 mg. Two DLT (1 grade 4 hematologic toxicity and 1 grade 5 arachnoiditis) occurred in 6 patients at 20 mg. The MTD was determined to be 15 mg. Then 24 patients were enrolled in phase II and given 15 mg of IP. 82.4% (28/34) and 58.8% (20/34) patients completed induction and consolidation therapy, respectively. 41.2% (14/34) patients received maintenance therapy. Adverse events (AEs) rate was 73.5% (25/34). 50% (17/34) patients showed grade ≥ 3 AEs, including myelosuppression (11), elevation of hepatic aminotransferases (EHA) (5), elevation of blood bilirubin (EBB) (1), arachnoiditis (1), radiculitis (1), fatigue (1) and nausea (1). The overall CRR was 41.2% (14/34) by neuro-oncology proposal criteria, including 10 (29.4%) with improved neurological dysfunction, 11 (32.4%) with CSF cytological response and 4 (11.8%) with neuroimaging improvement. In a total of 28 patients receiving IP at 15 mg, 50% (14/28) patients showed grade ≥ 3 AEs, including myelosuppression (9), EHA (10), fatigue (1) and nausea (1). The CRR was 46.4% (13/28) in patients at 15 mg IP. Median survival was 7.6 (range 0.3-13.7) months in phase I, while has not yet been achieved in phase II until March 15, 2023. CONCLUSION MTD of IP was 15 mg with folic acid and vitamin B12 supplementation. IP is an optimal therapeutic option for LM from solid tumors.

NEIM-13 THE PROGNOSTIC ROLE OF VENTRICULAR SIZE AND ITS DYNAMICS IN PATIENTS WITH LEPTOMENINGEAL METASTASIS FROM SOLID TUMORS

Abstract BACKGROUND Hydrocephalus is a common radiological sign in patients with leptomeningeal metastasis (LM) from solid tumors and can be assessed using the Evans index (EI) with high interrater agreement. Here we explored the prognostic value of ventricular size at diagnosis and during the disease course of LM. METHODS We assembled a cohort of 113 adult patients with a diagnosis of LM from solid extra-CNS tumors and explored the association of ventricular size assessed by the EI at diagnosis, of its modification between diagnosis and evaluation at first follow-up and at first progression, with outcome. RESULTS Median age was 58.2 years (interquartile range (IQR) 46.1-65.7), 41 patients (36%) were male, the most frequent cancers were lung cancer (n=39, 35%), breast cancer (n=36, 32%) andmelanoma (n=23, 20%). The median EI at baseline was 0.28 (IQR 0.26-0.31), the EI value was 0.27 or more in 67 patients (59%) and 0.30 or more in 37 patients (33%). At LM progression, an increase of EI of 0.01 or more was noted in 18 of 34 patients (53%). The median overall survival was 2.9 months (IQR 1-7.2). Patients with a baseline EI of 0.26 or less had a longer survival than those with an EI of 0.27 or more (5.3 months, IQR 2.4-10.8, versus 1.3 months, IQR 0.6-4.1) (p=0.006). Among patients with follow-up scans available, median overall survival was 9.7 months (IQR 5.6-21.4) for patients with stable or decreased EI at first follow-up as opposed to 6.4 months (IQR 3.2-10.5) for those with an increase in the EI (p=0.292). CONCLUSION The EI at baseline is prognostic in LM. An increase of EI during the follow-up is associated with inferior LM-PFS. An independent validation cohort with larger sample size and evaluation of confounding factors will help to better define the role of EI assessments in LM.

Leptomeningeal metastasis in patients with non-small cell lung cancer after stereotactic radiosurgery for brain metastasis.

Stereotactic radiosurgery (SRS) is an effective treatment for brain metastases (BMs) in patients with non-small cell lung cancer (NSCLC). However, factors associated with the development of post-SRS leptomeningeal metastasis (LM) remain unclear. The authors analyzed the incidence and risk factors of LM development in patients with NSCLC and BMs after SRS and examined the survival outcomes and prognostic factors after LM development. This retrospective study included patients with NSCLC treated with SRS for MRI-diagnosed BM from 2002 to 2021. The authors recorded various clinical and demographic data, including age, sex, tumor histology, molecular profile of tumors, extracranial disease status, previous craniotomy, Karnofsky Performance Status, systemic treatments, tumor volume, and number of BMs. The management and survival outcomes after LM diagnosis were also recorded. LM developed in 13.7% of patients with NSCLC and BMs after SRS treatment. Large initial tumor volume and more than 5 BM lesions, but not EGFR mutation status and post-SRS treatment, were associated with LM development after SRS. Multivariate analysis revealed that chemotherapy and targeted therapy after LM were associated with better survival in patients with LM after SRS. This study is the first to evaluate the risk factors for LM in a relatively large cohort of patients with NSCLC after SRS. In patients with BMs harboring risk factors for subsequent LM, such as initial tumor volume and number of metastatic lesions, aggressive therapies with high CNS penetrating ability should be considered.

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.