bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessment of electronic health record (EHR) –based machine learning (ML) in predicting risk of brain metastasis among patients with early-stage non–small-cell lung cancer (eNSCLC).
Authors: Honarvar Hossein , Hathi Deep K , Parikh Ravi Bharat , Das Rahul K 
Published: June 2023

2036 Background: Among patients (pts) with eNSCLC, development ofbrain metastasis (BM) is a poor prognostic sign, but routine surveillance for BM is not recommended post-therapy. EHR-based ML algorithms may identify pts who would benefit from active brain MRI surveillance and/or treatment intensification in the early-stage setting. Methods: ConcertAI Patient360 database, consisting of structured and curated EHR records from pts receiving care in ~900 US oncology clinics, was used to identify pts diagnosed with stage IB-IIIA NSCLC without prior evidence of BM between Jan 2010 – December 2021. Presence of BM was identified from human curation of patient documents. Gradient boosting (GB), random forest (RF), and logistic regression (LR) algorithms with 3-fold cross-validation were trained and compared to predict risk of BM at two landmarks: 18 and 24 months (mos) from initial diagnosis (index). Pts who did not develop BM and either died or were lost to follow-up prior to landmark times were removed. Feature importance was defined using Shapley Additive Explanation (SHAP)-derived marginal odds ratios (OR). Due to low prevalence of BM, AUPRC was used as performance metric. Pts in the 1st and 4th quartiles of predicted probabilities from GB model were flagged as low-risk vs. high-risk. Results: Among 7473 pts in 18 mos model, median age was 68.4 years (IQR 13.2), 50.5% were female, and 10.9% were black. Demographics were similar for 6863 pts in 24 mos model. 6.4% and 8.3% developed BM at 18 and 24 mos. Ability of GB, RF, and LR models to predict BM was similar with validation AUPRC of 0.109 at 18 mos and 0.137 at 24 mos. In the GB model, BM prevalence in high-risk vs. low-risk group was 10.3% vs. 3.1% at 18 mos and 13.4% vs. 4.4% at 24 mos. In both landmark models, N0 stage and surgery within 90 days after index diagnosis were protective against BM, while presence of EGFR targetable mutations, adenocarcinoma (AD) histology, higher platelets (PLT), and history of pneumonia were risk factors. A glucose-by-histology interaction was found: For pts with normal blood glucose (GLU), risk of BM was independent of histology, for pts with high GLU, AD conferred greater risk of BM. Conclusions: An EHR-based ML model identified risk factors for developing BM among pts with eNSCLC and may identify pts who would benefit from active brain MRI surveillance and treatment intensification. [Table: see text]
Surgically targeted radiation therapy (STaRT) for recurrent glioblastoma: Initial outcomes from a prospective multicenter registry.
Authors: Ozair Ahmad , Brachman David , Campbell Lisa , Chen Clark C , Patel Toral R. , Floyd John , Hayden Devon H , Nowlan Adam W , Wasilewski Andrea C , Wanebo John , Shah Mitesh , Richardson Angela , Hanft Simon , Choutka Ondrej , Shen Colette , Wardak Zabi , Lee Stuart , Ranjan Tulika , Khosla Atulya Aman , Ahluwalia Manmeet Singh ,   STaRT Investigators' Group
Published: June 2023

2038 Background: Surgically targeted radiation therapy (STaRT), using a novel bioresorbable collagen brachytherapy device containing 4 Cesium-131 sources, is FDA-cleared for use as adjuvant radiation therapy (RT) post-resection in both newly diagnosed and recurrent intracranial neoplasms. Intraoperative initiation of brachytherapy potentially minimizes post-resection tumor regrowth with a favorable dosimetric profile compared to external beam radiation. This work sought to determine early patterns of care and the safety of this approach in recurrent GBM. Methods: This prospective multi-institutional observational study (NCT04427384) included recurrent GBM patients who underwent maximum safe resection (MSR) and permanent implantation of the device(s) (GammaTile, GT Medical Technologies, Tempe, AZ, US). Descriptive and comparative analyses regarding patient characteristics and early clinical outcomes were performed. Toxicities were categorized using the CTCAE v5.0 adverse event (AE) criteria. Results: During 10/2020–01/2023, 14 participating sites enrolled 45 patients with recurrent GBM for STaRT; 2 patients had two sites treated for a total of 47 implants. 67% of patients were treated at the first recurrence, 24% at the second, and 13% at the third, respectively. The median age was 61 (range 28-75), 36% were female, and 23% were > 65 years. 85% of patients received prior same-site RT with the median time from last RT to implantation of 14.6 months (range 3.5-57). The median maximum preoperative size was 4.2 cm (range 1.6-7.0) and the median volume was 20.8 cm3 (range 0.8-130). 68% of resections were gross-total, 17% near-total, and 15% sub-total; the median time needed for device implantation was 5 minutes (range 1.0-13). Median follow-up was 5.2 months (range 0.6-23.2). Median Karnofsky performance status (KPS) at screening, at initial postoperative assessment, and 3 months were all 80 (range 40-100). 7 attributed AEs occurred in 13% (6/45) of patients, all grade 3 AEs: 2 CSF leaks, 2 seizures, 1 cerebral edema, 1 pseudomeningocele, and 1 left hemiparesis. All except one were coded as related to both radiation and surgery; the patient with pseudomeningocele experienced a seizure at 47 days that was considered related to radiation alone. Conclusions: Early data from this prospective registry demonstrate the feasibility and safety of STaRT in recurrent GBM. Data on 6-month progression-free survival will be presented at the conference. A prospective randomized trial of adjuvant systemic therapy (AST) +MSR+STaRT versus MSR+AST is planned for initiation in 2023.
Multi-cancer brain metastasis risk score development and validation using 220,246 whole transcriptomes and machine learning.
Authors: Abraham Jim , Anders Carey K. , Brufsky Adam , Glantz Michael J. , Brastianos Priscilla Kaliopi , Pike Luke Roy George , Heimberger Amy B. , Sledge George W. , Oberley Matthew James , Spetzler David 
Published: June 2023

2039 Background: Brain metastases occur in multiple cancer types with higher prevalence in lung, breast, melanoma, and GI cancers. The prognoses of patients who develop brain metastases are very poor and identification of brain metastasis risk could be useful for prognostication, monitoring, and therapy selection. Methods: Data from the whole transcriptome of 220,246 tumor profiles were analyzed and multiple machine learning models were trained on various molecular subtypes. The dataset was split 50% for training and the other 50% for testing, UMAP was employed for dimensionality reduction and the patterns learned across the entirety of the training dataset irrespective of brain metastasis were leveraged on the testing data set. Patients with brain metastasis were identified using the presence of ICD-10 code C79.31 (Secondary malignant neoplasm of the brain). As the absence of C79.31 could be due to the event not happening yet, patients without brain metastasis were stratified into groups based on 3, 4 or greater than 5 years without a C79.31 ICD-10 code. The brain metastasis risk score was defined by empirical evaluation of the positive predictive value in 7 groups of risk probabilities. The validation set contained 1,217 patients with brain metastasis and 4,631 without an observed brain metastasis within 3 years. Results: In the validation set, the prevalence of brain metastases within the risk scores across all cancer types ranged from 4% with the lowest risk score to 94% in the highest with 71% of cases receiving the lowest 2 risk scores, 15% the 2 intermediate risk scores, and 14% the 3 highest risk scores. For breast, lung and colon cancers, the prevalence of brain metastasis ranged from 4-10% in patients with the lowest risk scores to 92-100% in patients with the highest however the distribution of cases with each risk score was markedly different across cancer type. Breast cancer had 62% of cases receiving the lowest 2 risk scores versus 27% in lung, and 92% in colon. Breast cancer had 18% of cases receiving the 3 highest risk scores while lung had 42% and colon only 2% of cases with those 3 highest scores. Conclusions: Whole transcriptome data can be leveraged by a machine learning platform that employs dimensionality reduction techniques along with transfer learning to predict the risk of brain metastasis. This tool can be used to augment the clinical picture of cancer patients an unmet clinical opportunity to inform prognosis, monitoring, and therapeutic selection.
Cerebrospinal fluid immunological cytokines to predict intracranial tumor response to immunotherapy in non-small cell lung cancer patients with brain metastases: GASTO 1060.
Authors: Chen Likun , Li Meichen , Chen Jing , Yu Hui , Zhang Baishen , Hou Xue 
Published: June 2023

2040 Background: Immunotherapy has been the standard first-line therapy in patients with advanced non-small cell lung cancer (NSCLC), and shown a certain efficacy for patients with brain metastases. however, the appropriate predictive biomarkers for intracranial tumor response to immunotherapy are unclear. We conducted this prospective study to explore the immunological cytokines in cerebrospinal fluid (CSF) to predict intracranial tumor response to immunotherapy in NSCLC patients with brain metastases. Methods: We prospectively enrolled treatment-naive, EGFR/ALK wild-type NSCLC patients with brain metastases in this study. Patients received chemotherapy plus camrelizumab (a humanized anti-PD-1 monoclonal antibody) as first-line treatment, and paired plasma and cerebrospinal fluid (CSF) samples were collected at baseline and first treatment evaluation (8-week). All samples were detected for 92 Immuno-Oncology cytokines using the Olink panels, and were explored for predictive biomarkers to immunotherapy. The Mann-Whitney U test was performed to compare the immunological cytokine expression between intracranial response and non-response groups. And logistic LASSO regression model was used to variate selection and develop a CSF immuno-cytokine model to predict intracranial tumor response. Results: Between April 2020 and May 2022, a total of 28 patients were enrolled this study.At baseline, most immunological cytokines were significantly lower in paired CSF than in plasma, whereas a subset including CD83, PTN, TNFRSF21, TWEAK, ICOSLG, DCN, IL-18 and MCP-1 were increasing expressed in CSF samples. For patients with objective intracranial tumor response compared to patients with non-response, the baseline CSF levels of LAMP3 were significantly higher, whereas the CXCL10, IL-12, CXCL11, IL-18, TIE2, HGF and PDCD1 levels were significantly lower. And patients with lower HGF, IL-18 or PDCD1 levels had significantly longer intracranial progression-free survival to immunotherapy. The above CSF immunological cytokines were significantly decreased at first treatment evaluation in patients with intracranial tumor response. Our logistic CSF immuno-cytokine model selected TIE2, IL-18, LAMP3, PDCD1 and IL-12 that were significantly associated with intracranial tumor response, and yielded a mean AUC of 0.91, compared to PD-L1 expression (mean AUC of 0.72). Conclusions: Immunological cytokines in CSF could predict intracranial tumor response to immunotherapy in NSCLC patients with brain metastases, and findings require validation in a larger prospective cohort.
Analysis of tumor progression among patients with glioma after COVID-19 infection.
Authors: Gregory Tim , Knight Stephanie , Aaroe Ashley , O'Brien Barbara Jane , Patel Chirag B , Weathers Shiao-Pei S. , Majd Nazanin , Puduvalli Vinay K. , Kamiya-Matsuoka Carlos 
Published: June 2023

2041 Background: As of January 2023, there have been 6.7 million worldwide deaths attributed to SARS-CoV-2 COVID-19, which has impacted outcomes and medical care for all patients. Relatively little is known about the direct effects mediated by the virus on CNS tumor biology, despite the fact that viral neurotropism is well described, various coronavirus receptors have been observed in glioblastoma (GBM) tissues, and differential monocytic infiltration has been proposed to dysregulate the immune microenvironment. We detected a trend of rapid progression following COVID-19 infection among several patients with primary brain tumor patients and sought to systematically evaluate the pace of progression among infected patients in our institution. Methods: A single-institutional database of COVID-19 patients and an electronic medical record (EMR) search tool were used to identify a total cohort of 67 patients with glioma for retrospective analysis. This included 38 GBMs, 18 IDH-mutant gliomas, 5 ependymomas, 2 pilocytic astrocytomas, 1 diffuse midline glioma, 1 diffuse hemispheric glioma, and 1 ganglioglioma patients, each of whom had a documented COVID-19 infection between June 2020-December 2022. Hyperprogression was defined as tumor increase ≥40% compared to previous scan using RECIST size criteria. Results: Thirty-nine (58%) patients experienced tumor progression following COVID-19 infection at a median of 34 days (range=1-734 days) after testing positive for COVID-19. Twenty-two (56%) had received COVID-19 vaccine before their infection and 5 (13%) had asymptomatic infections. Twenty-two patients had measurably increased tumor area by a median of 63% (range=10-2,900%), 18 of which constituted hyperprogression;16 patients developed multifocal disease, 8 developed new nodular enhancement, 3 developed leptomeningeal disease (LMD), and 2 experienced increased infiltrative disease alone. Ten patients’ presentation with new glioma was preceded by COVID-19 infection by a median of 31 days. GBM patients represented the majority of progression events, among whom 59% progressed within 60 days of documented infection (median 25 days). This subgroup of GBM with rapid progression within 60 days had a mOS from infection of 5.2 months; 89% had TERT promotor mutations and 42% had MGMT promoter methylation. Conclusions: Glioma patients appear to have disease progression at an accelerated pace in the first two months after COVID-19 infection. This suggests that glioma patients should continue observing strict precautions to prevent infection and should be clinically monitored vigilantly after infection, with consideration for short interval imaging during treatment. These preliminary data warrant further investigation exploring changes of immune cell infiltration in the tumor microenvironment and the possible correlation between tumor progression and COVID-19.
A phase 0 pharmacokinetic trigger trial of infigratinib in patients with recurrent high-grade glioma.
Authors: Sanai Nader , Margaryan Tigran , Molloy Jennifer , DeSantis Anita , Harmon Jocelyn , Hong Amy , Braun Kelly , Wanebo John , Yoo Wonsuk , Tien An-Chi , Tovmasyan Artak , Mehta Shwetal 
Published: June 2023

2051 Background: This Phase 0 trial evaluates tumor pharmacokinetic (PK) and pharmacodynamic (PD) responses of fibroblast growth factor receptor (FGFR) inhibitor, infigratinib, in participants with recurrent high-grade glioma carrying FGFR1 K656E or FGFR3 K650E mutation or FGFR3-TACC3 translocation. Patients with high unbound drug concentrations in the gadolinium-nonenhancing tumor region were graduated to a therapeutic regimen of infigratinib. Methods: Recurrent high-grade glioma patients received 7 days of infigratinib (125 mg QD) prior to planned resection at 7-9 hours following the last dose. Tumor tissue (enhancing and nonenhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound infigratinib concentrations were measured using validated LC-MS/MS methods. A PK ‘trigger’ determined eligibility for the therapeutic expansion phase and was defined as unbound [infigratinib] > 5-fold biochemical IC50 (i.e., 5 nM) in non-enhancing tumor. PD response was assessed by quantification of percentage of positive pERK, MIB-1, and Cleaved Caspase 3 cells in the surgical tissue compared to baseline archival/biopsy tissue. Patients with tumors exceeding the PK threshold for unbound drug concentration were eligible for expansion phase therapeutic dosing of infigratinib. Results: Seven patients were enrolled into the Phase 0 study with 3 patients who met the PK threshold continued to the expansion phase. In non-enhancing tumor region, the mean unbound concentration of infigratinib was 3.5 nM (n=7). The mean non-enhancing tumor-to-plasma coefficient for unbound drug (Kp,uu) was calculated to be 1.4. The suppression of pERK levels and MIB-1 levels was observed in 17% (1/6) and 67% (4/6) of the patients, respectively. At a median follow-up of 16.3 months [range: 2.8-18.7 months], the median progression-free survival (PFS) was 2.8 months (n=3). One patient remains on treatment. No grade 3+ toxicities were observed, and no adverse events resulted in discontinuation of therapy. Conclusions: Despite relatively high unbound tumor-to-plasma (Kp,uu) value, infigratinib achieves sub-optimal unbound drug concentration in the non-enhancing brain tumor tissue. Pharmacodynamic response with archival tissue as comparator did not reveal inhibition of pERK. Clinical trial information: NCT04424966 .
H3.3-K27M neoantigen vaccine elicits anti-tumor T cell immunity against diffuse intrinsic pontine glioma: The phase I ENACTING trial.
Authors: Zhang Yang , Ji Nan , Chen Gang , Wu Haiyang , Wang Yi , Li Xiao’ou , Peng Ling , Xu Wei , Li Tian , Wang Yi , Zhang Li-Feng , Sun Shengjun , Zhao Xiaobin , Li Si , Su Frank , Li Qi-Jing , Zhang Liwei 
Published: June 2023

2052 Background: Diffuse intrinsic pontine glioma (DIPG) harboring H3.3-K27M mutation is a malignant pediatric brain tumor with a >90% mortality rate within two-year of diagnosis. Current therapeutic options for DIPG are limited. Aiming to improve therapeutic outcomes, we herein report the preliminary findings of a phase I trial studying a neoantigen peptide vaccine targeting H3.3-K27M. Methods: ENACTING is an open-label, single center, two-armed phase 1 trial to assess the safety and T cell immunity of a neoantigen peptide vaccine against H3.3-K27M. Patients aged ≥ 5 years old with newly diagnosed DIPG were consented and screened. HLA-A*02+/H3.3-K27M+ patients were enrolled to a two-arm study: Arm A consists of subjects receiving open debulking surgery, and Arm B consists of subjects without surgery eligibilities who received stereotactic biopsy. All patients subsequently received conformal radiotherapy and neoantigen vaccine treatment designed to elicit both CD4+ and CD8+ T cell immune response. Vaccine was administered intramuscularly in combination with polyinosinic-polycytidylic acid-poly-L-Iysine carboxymethylcellulose (Poly-ICLC). The primary objective is to evaluate the safety (AEs graded by CTCAE v4.03) and survival outcomes. Secondary objectives include maximum tolerated dose (MTD) and immunological responses. Results: As of Jan 2023, 11 patients have been treated, with 7 in Arm A and 4 in Arm B. No grade 3-4 treatment-related adverse events have been observed, with fever (81.9%) and injection site pain (54.5%) being the most common AEs. Among 10 efficacy-assessable patients, median progression-free survival (mPFS) and median overall survival (mOS) were 11.4 months (95% CI: 5.8~14.7) and 15.4 months (95% CI: 7.53~not reached), respectively. One-year OS rate was 66.7% (95% CI: 42~100%). One patient was assessed as complete response (CR). T cell responses against neoantigen were detected and H3.3-K27M mutation-specific CD4+ and CD8+ TCR clones were validated. Conclusions: The H3.3-K27M neoantigen vaccine was well tolerated. Initial results from this ongoing study suggest that, compared with other current therapies against DIPG, H3.3-K27M peptide vaccination may provide superior patient survival outcomes. Clinical trial information: NCT04749641 . [Table: see text]
New ESMO scale for clinical actionability of molecular targets (ESCAT) for gliomas based on a multicentric real world data cohort using next-generation sequencing (NGS).
Authors: Mirallas Oriol , Velilla Gabriel , Ruiz-Pace Fiorella , Yaringaño Jesús , Hernandez Gonzalez Ainhoa , Lopez Valbuena Daniel , Gómez-Puerto Diego , Gorria Teresa , Vaz Maria Ángeles , Doménech Marta , Martinez-Monino Alvaro , González Macarena , Castro Maria , Martínez-García María , Pineda Estela , Carles Joan , Dienstmann Rodrigo , Balana Carmen , Sepulveda Sanchez Juan Manuel , Vieito Maria 
Published: June 2023

2055 Background: The ESMO ESCAT scale rank molecular alterations (MA) based on the published evidence supporting their clinical use. Building on our proposal for the first ESCAT classification for primary brain tumors (pBT) [Mirallas et al. ESMO 2022], we aim to describe the clinical actionability of NGS in a multicentric glioma cohort and gather clinical factors that enrich patients with MA to justify performing NGS. Methods: A multicentric retrospective study included pts with molecular profiling using NGS methods (Foundation Medicine, local NGS, Caris, Oncomine, and fusion panels). Clinical actionability was classified using the ESCAT scale; Tier 1 (ready for clinical implementation), Tier 2 (alteration-drug match with antitumor activity), Tier 3 (supported in other tumor types), and Tier 4 (preclinical evidence). Clinical factors considered for enrichment were diagnosis of glioblastoma (GBM), sex, and age ≤40 years, differences between groups were determined using Chi-squared test. The overall survival (OS) was calculated through Kaplan-Meier method and cox hazard ratio were fitted. Results: A total of 361 pts with NGS performed between Feb 2018 and Dec 2022 at 4 hospitals in Spain. Median age was 51.5 (range, 3.3-83.8), 77% had ECOG ≥1, 39.2% were women, 23.4% were 40 or younger, 20.8% had IDH1mut, and 73.5% had a diagnosis of GBM. The distribution of MA according to ESCAT was: 10 pts ESCAT 1 (5 BRAFV600E mut, 5 NTRK 1-3 fusions); 75 pts ESCAT 2 (67 IDH1 mut, 6 FGFR-TACC rearrangement, 4 FGFR 1-3 mut, 3 IDH2 mut); 105 pts ESCAT 3 (98 PIK3CA/PTEN mut, 12 PTEN loss, 11 H3K27M mut, 6 BRAF fusion, 2 MET mut, 1 FGFR3 amplification); 93 pts ESCAT 4 (119 TERT mut, 77 EGFR gain, 67 CDKN2A loss, 58 CDKN2B loss, 48 EGFRvIII rearrangement, 46 ATRX mut, 40 EGFR mut, 8 ATM mut). Prevalence of Tier 1-2 MA was 23.6%. In relation to enrichment factors: 12% >40y pts had ESCAT1-2 vs 61% in ≤40y (p<0.001), pts with GBM had a 11% prevalence vs 61% non-GBM (p<0.001), and non-gender differences were seen. The median OS for Tier 1-2 was 135 months (95% CI 166-99) vs Tier 3-4 of 24 months (95% CI 21.5-29.6). Significantly worse OS was observed for Tier 3-4 gliomas (HR: 4.11; 2.84-5.95, p<0.001), and remained significant after adjusting for histology and hospital center (p<0.01). Conclusions: The prevalence of ESCAT Tier 1-2 alterations is high in gliomas suggesting that molecular profiling should be offered, at least, in tertiary centers where these techniques are available. Potential enrichment factors to offer NGS were age and non-GBM pBT, but not gender.