bluuebunny/crossref_metadata_2025_split huggingface dataset:
Longitudinal single-cell (sc) immune profiling of cerebrospinal fluid (CSF) from melanoma patients (pts) with leptomeningeal disease (LMD) treated with intrathecal (IT) and intravenous (IV) nivolumab (N).
Authors: Morad Golnaz , Yang Yitao , Duncan Sheila , Ferguson Sherise D. , Wargo Jennifer Ann , Burton Elizabeth M. , Tawbi Hussein A. , Davies Michael A. , Liang Han , Glitza Isabella Claudia 
Published: June 2023

2015 Background: LMD is associated with an extremely poor prognosis in melanoma pts, who currently have very limited treatment options. Our group previously reported initial safety and efficacy results from the dose escalation portion of a first in human phase I/IB trial using IT and IV N (NCT03025256) in melanoma LMD pts. Here we present longitudinal sc profiling of immune cells in CSF from a subset of pts in this trial to better understand the immune composition of this unique microenvironment and features associated with treatment and outcomes. Methods: 39 CSF samples were collected longitudinally from 5 long survivors (LS; IT N number of doses received 10-92) and 5 rapid progressors (RP; IT N doses 2-9) and profiled by sc RNA sequencing. Raw FASTQ reads were aligned to the GRCh38 human reference genome using Cell Ranger v6.0.0 to generate the count matrix. All samples were aggregated by Seurat v4.3.0 and data integration was performed using Harmony v0.1.0. Cells were filtered by following criteria: (1) > 20% mitochondrial content, or (2) express < 100 or > 2,500-5,000 genes, according to sample specific distribution. Empty droplets and doublets were identified by EmptyDrops function from the R package DropletUtils v1.18.0 and DoubletFinder v2.0.3, respectively. We applied normalization, FindVariableFeatures (n = 2,000), scaling, PCA, UMAP and FindClusters to summarize the integrated samples and determine cell clusters. Cell types were annotated based on (1) canonical marker genes using FindAllMarkers, (2) published gene expression signatures, and (3) reference-based tool using Symphony v.0.1.0 on published data: GSE164378 and GSE158803. Statistical analysis was conducted using the Wilcoxon rank-sum test. Results: A total of 10 patients were included in this pilot analysis. Five pts were LS (2 males; IT dose 5 mg, 1 pt; 10 mg, 2 pts; 20 mg, 2 pts; 2 BRAF mutant; 5 negative CSF cytology at baseline) and 5 pts were RP (3 males; IT dose 5 mg, 1 pt; 20 mg, 2 pts; 50 mg, 2 pts; 4 BRAF mutant; 4 positive CSF cytology at baseline). At baseline [prior to cycle (C)1 of IT N], LS pts had a higher percentage of NK cells (relative to total immune cells; P = 0.036) and mucosal-associated invariant T cells (relative to total T cells, P = 0.021) than RP pts. Prior to C2, LS had a significantly higher percentage of T cells (relative to all cells; P = 0.036). The abundance of immune cells and tumor cells were not different between the two groups at C3, at which point pts have received two doses of IT N and one dose of IV N. Conclusions: Exploratory sc analysis of longitudinal CSF samples of LMD pts suggest that baseline immune features may predict outcomes with IT N. Analysis of additional pts is ongoing to provide further insights.
Long-term survival with IDH wildtype glioblastoma: First results from the ETERNITY Brain Tumor Funders’ Collaborative Consortium (EORTC 1419).
Authors: Weller Michael , Felsberg Joerg , Gramatzki Dorothee , Le Rhun Emilie , Clarke Jennifer Leigh , Soffietti Riccardo , Wick Wolfgang , Chinot Olivier L. , Ducray Francois , Roth Patrick , Hau Peter , Klein Martin , Preusser Matthias , Bendszus Martin , Golfinopoulos Vassilis , von Deimling Andreas , Gorlia Thierry , Wen Patrick Y. , Reifenberger Guido , Hertler Caroline 
Published: June 2023

2016 Background: Median survival with glioblastoma remains in the range of 12 months on population levels. Only few patients survive for more than 5 years. Patient and disease features associated with long-term survival remain poorly defined. Methods: European Organization for Research and Treatment of Cancer (EORTC) 1419 (ETERNITY) is a registry study supported by the Brain Tumor Funders Collaborative in the US and by the EORTC Brain Tumor Group. Patients with glioblastoma surviving at least 5 years from diagnosis were identified at 24 sites in Europe, US, and Australia. In patients with isocitrate dehydrogenase (IDH) wildtype tumors, prognostic factors were analyzed using the Kaplan-Meier method and the Cox proportional hazards model. A population-based reference cohort was obtained from the Cantonal cancer registry Zurich. Results: At the cut-off of July 2020, 280 patients with histologically centrally confirmed glioblastoma (189 IDH wildtype, 80 IDH mutant, 11 not otherwise specified) had been registered. In the IDH wildtype population, median age was 56 years (range 24-78 years), 96 patients (50.8%) were female, 139 patients (74.3%) had tumors with O6-methylguanine DNA methyltransferase ( MGMT) promoter methylation. Median overall survival was 9.9 years (95% CI 7.9–11.9). Patients without recurrence experienced longer median survival (not reached) than patients with one or more recurrences (8.92 years) (p<0.001) and had a high rate of MGMT promoter unmethylated tumors. Conclusions: Freedom from progression is a powerful predictor of overall survival in long-term survivors with glioblastoma. Never relapsing patients often have MGMT promoter-unmethylated glioblastoma and may represent a distinct subtype of glioblastoma. Clinical trial information: NCT03770468 .
ctDNA detection in patients with brain metastases arising from solid tumors.
Authors: Alder Laura , Broadwater Gloria , Green Michelle , Lipp Eric S. , Van Swearingen Amanda E.D. , Clarke Jeffrey Melson , Anders Carey K. , Sammons Sarah 
Published: June 2023

2027 Background: While circulating tumor DNA (ctDNA) is a routine tool for therapeutics in metastatic solid tumors, data in those with stable and active brain metastases (BrMs) is limited. We assessed genomic alterations in ctDNA from patients (pts) with solid tumor BrMs in three groups: isolated BrMs/stable extracranial disease (iCNS), concurrent brain and extracranial progression (cCNS), and extracranial progression with no active BrMs at ctDNA draw (eCNS). We also compared ctDNA alterations between pts with and without BrMs. Methods: Pts with BrMs and a Guardant 360 profile (n=253) from the Duke Molecular Registry of Tumors between 01/2014 – 12/2020 were identified. Intracranial and extracranial disease status were determined via investigator assessment (RECIST and RANO-BM criteria) within 30 days of ctDNA test. Mutant allele fraction (MAF) was defined as the % of mutant alleles divided by total alleles at a given loci. Differences in mean ranks of the MAF % maximum were compared using the Kruskal-Wallis test and pairwise comparisons with the Dwass, Steel, Critchlow-Fligner multiple comparisons post-hoc procedure. We compared differences in MAF >1% using the chi-square test. Results: Among the 253 pts with BrMs: 29 (12%) had iCNS, 160 (63%) cCNS, and 64 (25%) eCNS. The two most common tumor types were breast (BC, 12.0%) and non-small cell lung cancer (NSCLC, 76.4%). Median MAF was lower in the iCNS group (1.6%) vs cCNS (4.8%) p=0.002, but eCNS did not differ (2.6%). In pts with BC BrMs, ESR1 mutations were most frequent in the iCNS group (67%), followed cCNS (54%) then eCNS (18%) (p = 0.09) as were PIK3CA mutations, iCNS(50%), cCNS (46%), and eCNS (27%), p = 0.55. In pts with NSCLC BrMs, EGFR mutations were most frequent in the iCNS followed by cCNS then eCNS (67%, 40% and 37%, p = 0.08). KRAS mutations were more frequent in cCNS followed by eCNS and iCNS (30%, 17% and 6% p = 0.031). Patients with no BrMs (n=449) included 24% breast and 76% NSCLC. In the ctDNA, ESR1 and BRCA2 mutations were more frequent in pts with BC BrMs than those without (60% vs 25%, p< 0.001) and (17% vs 5%, p=0.022), respectively. Mutations in EGFR were more frequent in pts with BrMs vs without (36% vs 17%, p<0.001). Sequencing from both BrMs tissue and ctDNA were available for 8 pts (4cCNS and 4 iCNS). 7 of these (87.5%) had identical mutations in tumor and ctDNA. Conclusions: This study illustrates the feasibility of detecting actionable mutations from ctDNA among pts with BrMs, with and without extracranial disease. A higher frequency of actionable mutations in several targetable genes was observed in ctDNA when comparing pts with and without BrMs, thus providing therapeutic opportunities. Additional studies comparing ctDNA and alterations in BrMs tissue are needed to determine if ctDNA can be considered a surrogate to support treatment decisions.
Evaluating the diagnostic performance of leptomeningeal diagnosis with CNSide compared to standard cytology.
Authors: Appel Haley , Odia Yazmin , Saxena Anshul , Roy Mukesh , Mohler Alexander , Kotecha Rupesh , Hall Matthew David , Ahluwalia Manmeet Singh , Mehta Minesh P. , Castaneda Serguei A. 
Published: June 2023

2028 Background: Prior reports cited detection rates of leptomeningeal metastases (LM) using CNSide vs standard CSF cytology of 78% vs 55% in NSCLC and 84% vs 52% in various solid tumor cohorts. The objective of this study was to compare the real-world performance of the CNSide assay in diagnosing LM versus CSF cytology from lumbar puncture (LP) and established EANO-ESMD LM diagnostic criteria (EANO). Methods: We retrospectively analyzed all neuro-oncology patients from January, 2020 to December, 2022 with suspected LM who underwent LP with CSF cytology and CNSide. The CNSide assay included tumor cells (CSF-TCs) and cell-free DNA (cfDNA). LM diagnostic probability was defined by EANO criteria. Descriptive statistics and confusion matrix were calculated. Results: 87 patients (66 [76%] women) met eligibility criteria for inclusion with median age of 63 (23-87) years; 35 (40%) had uncontrolled systemic disease. The most common primary histologies were breast (45%) and lung (41%); 33% of primary lung cancers harbored molecular alterations, while primary breast cancers expressed hormone receptors in 69% and HER2 alterations in 10%. Across all primary histologies, 53 (61%) cases harbored molecular alterations, of which 27 (31%) had molecular alterations also detected by CNSide. For 7 (8%) cases with negative cytology and CNSide, CNSide detected alterations by cfDNA assays. LM was diagnosed by CSF cytology in 23 (27%) cases, consistent with confirmed LM by EANO. 36 (41%) cases had confirmed LM by CSF cytology or CNSide; all cytology positive and equivocal cases were detected by CNSide. Patients with negative CSF cytology were further defined as probable (19, 23%), possible (35, 42%), or (7, 8%) lack of evidence by EANO. Modifying EANO criteria to include both standard CSF cytology and CNSide led to 36 (41%) confirmed LM cases, an increase of 13 cases in addition to the 23 cytology positive cases (+56.5%). Compared to CNSide, standard CSF cytology had a sensitivity of 70%, but an expected 100% specificity. Compared to the established higher specificity of CNSide, EANO had 100% sensitivity, but only 18% specificity for diagnosing LM, assuming all EANO possible, probable, or confirmed cases were positive, while specificity improved to 74% with slight decrease sensitivity to 94% if only probable or confirmed cases were considered positive. Conclusions: In the largest, retrospective, single institution, real-world study, implementation of CNSide showed increased sensitivity relative to standard cytology and increased specificity relative to EANO criteria, and provided clinically relevant, cell-based molecular and cell-free DNA analyses. CNSide increased the diagnostic yield by 56.5%.
Leptomeningeal carcinomatosis and brain metastases in gastroesophageal carcinoma: A real-world analysis of outcomes, clinical and pathologic characteristics.
Authors: Megid Thais Baccili Cury , Baskurt Zeynep , Ma Lucy Xiaolu , Barron Carly C. , Saltiel Marie-Philippe , Farooq Abdul Rehman , Jang Raymond Woo-Jun , Chen Eric Xueyu , Wong Rebecca KS , Mesci Aruz , Aoyama Hiroko , Bach Yvonne , Wang Xin , Veit-Haibach Patrick , Wang Ben X , Kalimuthu Sangeetha , Cotton James , Elimova Elena 
Published: June 2023

2029 Background: Brain metastasis (BM) and Leptomeningeal Carcinomatosis (LC) are uncommon complications in gastroesophageal carcinoma (GEC) patients (pts). These patients have a poor prognosis and are challenging to study. We described the clinicopathologic features and outcomes in the largest real-world cohort of CNS metastasis in GEC pts. Methods: We conducted a single-center retrospective study of GEC pts treated at the Princess Margaret Cancer Centre from 2007 to 2021 who developed BM. Clinicopathologic characteristics and treatment modalities were reviewed. Survival was calculated from the date of BM or LC diagnosis until date of death/last follow-up using the Kaplan-Meier method. A multivariable Cox proportional hazards regression model was used to examine the association of baseline covariates and survival. Results: Of 3283 consecutive pts with GEC, 101 (3.08%) were diagnosed with BM and 20 with LC (0.61%). Most pts with BM were male (75.3%), non-Asian (93%), with a primary gastroesophageal junction tumor (47%) and adenocarcinoma histology (86%). Among pts with known HER2 status (N= 48), 60% were HER2 positive (defined as IHC 3+ or IHC 2+/FISH+). All patients with LC had adenocarcinoma histology; most were signet-ring subtype (85%), poorly differentiated (80%) histology and only 15% (2/13) were HER2 positive. Median survival was 0.8; 3.8; and 7.7 months (mo) in BM pts treated with palliative care only, radiation only and surgery followed by radiation, respectively (p< 0.001). In LC, median survival was 0.7 mo in pts who had palliative care only (7/20) and 2.7 mo for those (13/20) who had whole brain radiation therapy (WBRT) (p .008). Multivariate analysis showed a higher probability of death in patients with number of BM ≥4 (p 0.02) and predicted superior survival in patients who received radiation and surgery followed by radiation (p 0.02). Conclusions: This is the most comprehensive summary of clinicopathologic characteristics and survival in patients with GEC and BM and LC disease to date. Biomarker analysis reveals an enriched frequency of HER2 expression in BM, while this is uncommon in pts with LC. BM pts who were treated with surgery followed by radiation had a significantly improved OS. WBRT benefited patients with LC over palliative care alone. These findings add to our understanding for the management of this understudied population with poor survival. [Table: see text]
Risk of brain metastases in metastatic non-small cell lung cancer without baseline brain metastasis: Pooled analysis of individualized patient data from three randomized clinical trials involving first-line atezolizumab treatment.
Authors: Zhou Yue , Ni JianJiao , Zhu Zhengfei , Zhang Zhen 
Published: June 2023

2032 Background: Data on the efficacy of immune checkpoint inhibitors on delaying or preventing the occurrence of brain metastases (BMs) in metastatic NSCLC without initial BMs is limited. We explored the benefit of first-line atezolizumab versus chemotherapy in the occurrence of BMs in patients without baseline BMs. Methods: Individual patient data from IMpower1301, IMpower131, and IMpower150 were pooled. All patients in the intention to treat population were analyzed. Primary endpoints included BM free survival (BMFS) and the cumulative incidence of BM. Patients without baseline BMs were categorized into two groups: patients who received treatment including atezolizumab (atezolizumab group) and patients who received comparator chemotherapies (chemotherapy group). Results: In 2543 patients without baseline BMs, 87 (3.4%) developed BM, including 58 (3.4%) and 29 (3.4%) in the atezolizumab group and the chemotherapy group, respectively. The median BMFS was 8.31 months (95% CI 7.79-8.67). The cumulative incidence of BM at 6 months, 12 months, and 24 months was 1.9%, 3.1%, and 3.8%, respectively. Compared to the chemotherapy group, BMFS was significantly improved in the atezolizumab group (8.6 months versus 7.3 months, p < 0.001). After taking the competing risk events into account, no significant difference of the cumulative incidence of BM was observed between the two groups ( p = 0.671), suggesting that the significantly better BMFS in the atezolizumab group analyzed by Kaplan-Meier method should be due to the lower incidence of extracranial progression or death. Baseline bone metastasis and non-squamous NSCLC were identified as two risk factors for BM. Conclusions: In patients with NSCLC without baseline BMs, first-line atezolizumab improved BMFS but not the cumulative incidence of BM compared to chemotherapy, indicating that atezolizumab could not reduce the intrinsic risk of intracranial tumor spreading. [Table: see text]
Safety, efficacy, and biomarker analysis of response to engineered tumor-infiltrating lymphocytes secreting anti-PD-1 antibody in recurrent glioblastoma: An open-label, two-arms, phase 1 study.
Authors: Yao Yu , Chen Di , Tang Chao , Ji Chunxia , Li Zhong , Qian Qijun 
Published: June 2023

2042 Background: Adoptive cell therapy using tumor-infiltrating lymphocytes (TILs) is effective against solid tumors with convincing evidence. But T-cells infused were exhausted when they encountered PD-1-mediated immunosuppression in the microenvironment. Here, we generated a modified autologous TILs secreting antibody targeting PD-1 (PD1-TIL), and conducted a first-in-human, two arms, phase 1 study (NCT03347097) in recurrent glioblastoma who had a poor prognosis with estimated 6-9 months of median overall survival (OS). Methods: Patients were included to be treated with PD1-TIL or TIL cell products intravenously every one month following surgery. The primary endpoint was safety and feasibility. The secondary endpoints were disease control rate (DCR), OS, immunologic responses and biomarker analysis. The clinical response to cell therapy was assessed by MRI according to iRANO criteria. Here, patients with clinical benefit (CR, PR, and SD) were defined as responder. Results: A total of 21 consecutive patients (median age 45 years, range 20–64) received infusions of cell products (7 patients for PD1-TIL with 1 excluded, 14 patients for TIL with 2 excluded). 52% (11/21) and 29% (6/21) of 21 patients had methylated MGMT promoter and IDH1/2 mutant respectively. No significant differences in baseline characteristics between groups were found. Both of PD1-TIL and TIL infusions were well tolerated with no unexpected high-grade adverse events. Of 7 evaluable patients in PD1-TIL group, 1 had PR for more than 26 months, 2 had SD lasting for 7.7 months and 24 months, and 4 had PD after infusion. The DCR, 1-year and 2-years survival rates in PD1-TIL group were 43% (3/7), 86% (6/7) and 29% (2/7) respectively. In TIL group, 3 patients had SD and the others had PD. The DCR, 1-year and 2-years survival rates in TIL group were half of that in PD1-TIL group. Survival analysis showed that patients treated by PD1-TIL had extended OS than those received TIL (16.1 vs. 11.2 months, P = 0.047). Among 21 patients, clinical responders had significantly improved OS (30.9 vs. 10.7 months, P = 0.001) than non-responders. We also found a high capacity for engraftment and persistence of infused TILs in peripheral blood which could be detectable at 6 months after treatment. Existence of neoantigen-reactive T cell clonotypes in cell products may be important for responding because missing of missense mutations predicted to generate a neoantigen after cell therapy was a remarkable signature in responders. Responsive tumors were also associated with tumor microenvironment profiles. Conclusions: This first-in-human study establish the preliminary feasibility, safety and encouraging efficacy of PD1-antibody-secreting TILs, and may constitute a new treatment strategy by T-cell genetic engineering in glioblastoma. Clinical trial information: NCT03347097 .
Post-marketing surveillance safety analysis of patients with CNS malignancies treated with tumor treating fields (TTFields) therapy between 2011–2022.
Authors: Mrugala Maciej M. , Shi Wenyin , Iwamoto Fabio , Lukas Rimas Vincas , Palmer Joshua David , Suh John H. , Glas Martin 
Published: June 2023

2049 Background: Glioblastoma (GBM) has a poor prognosis. Standard treatments are associated with systemic toxicity, further increasing the disease burden in this patient population. Tumor Treating Fields (TTFields) are electric fields that disrupt cancer cell processes which affect cancer cell viability, and are generated by a portable, wearable device which is locoregional and noninvasive. TTFields therapy was approved by the FDA for the treatment of newly diagnosed (nd) and recurrent (r) GBM based on the phase 3 EF-14 (TTFields therapy 200 kHz + temozolomide) and EF-11 (TTFields 200 kHz) studies, respectively. TTFields therapy is also approved for pleural mesothelioma. We report an updated global, post-marketing surveillance (PMS) safety analysis of patients with CNS malignancies treated with TTFields therapy over an 11-year timeframe. This analysis represents the largest dataset of TTFields therapy use to date. Methods: Unsolicited safety data were collected from routine post-marketing activities for patients (N = 25,898) in North America, Europe, Middle East and Africa and Japan, from October 2011 to March 2022. AEs were stratified by diagnosis, age, and sex and categorized using MedDRA version 25.1. Results: Diagnoses were ndGBM (68%), rGBM (26%), anaplastic astrocytoma/oligodendroglioma (4%) and other (2%). Baseline demographics were reflective of real-world practice: median (range) age was 59 (3–103) years; two-thirds of patients were male. Most (69%) patients were 18–65 years; 0.4% were < 18 years, and 30% were > 65 years. All-cause and TTFields-related AEs occurred in 18,798 (73%) and 14,599 (56%), patients, respectively. The most common device-related AE was skin reaction (43% patients overall). There were no major differences in occurrence of this AE between pediatric, adult, and elderly groups (39%, 42%, and 45%, respectively), or between males and females (41% and 46%, respectively). The incidence of device-related skin reactions was higher in ndGBM than rGBM (46% vs 34%, respectively), in line with previous reports. Only 405 (2%) of patients overall reported an AE of treatment-related ‘quality-of-life decreased’. In line with the phase 3 studies, there were no treatment-related systemic AEs. Conclusions: In this updated global PMS safety analysis, TTFields therapy demonstrated a tolerable safety profile in patients with CNS malignancies, with no new safety findings. In line with previous real-world and clinical data, most AEs were localized, non-serious skin events, which were consistent between age groups. Such events can typically be managed easily using prophylaxis and topical therapies, together with optimization of caregiver techniques. Importantly, no TTFields therapy-related systemic AEs were detected.