bluuebunny/crossref_metadata_2025_split huggingface dataset:
SDPS-09 MIXED RESPONSE OF BRAIN METASTASES TREATED WITH OSIMERTINIB PREDICTS INFERIOR SURVIVAL OUTCOMES: AN ARTIFICIAL INTELLIGENCE-BASED LESION-LEVEL ASSESSMENT FOR CRANIAL CONTROL OF EGFRMUTANT NONSMALL CELL LUNG CANCER
Authors: Lu Shao-Lun , Chang Yu-Cheng , Hui Caressa , Liang Chih-Hung , Chiang Po-Lin , Lin Vicki , Lu Jen-Tang , Pollom Erqi 
Published: August 2023

Abstract
Osimertinib has been found to be effective for intracranial control in patients with metastatic EGFR-mutant non-small cell lung cancer (NSCLC). However, the lesion-level response of brain metastases to osimertinib has not been thoroughly evaluated. This retrospective study included 73 patients with EGFR-mutant NSCLC and brain metastases who were treated with osimertinib at a single institution from 2016 to 2021. Patients with the leptomeningeal disease were excluded. The study used an FDA-approved brain tumor management artificial intelligence (AI) platform, VBrain, to identify, track, and measure brain metastases on the baseline and follow-up MRI brain scans. Mixed response (MiR) was defined as the occurrence of progressive or new lesions along with synchronous responsive shrinking intracranial lesions at the first follow-up scan. K-means grouping was used to partition patients into two clusters according to their response heterogeneity. With a median follow-up of 23.8 months, a high MiR score (higher than 103%, n=25) was associated with worse cranial-progression-free survival (3.2 vs. 17.9 months, p&lt;0.0001) and significantly inferior overall survival (12.4 vs. 30.1 months, HR=2.35, p=0.016). This poses a similar negative impact on the survivals of 18 patients with pure RANO-BM progression (HR=2.52, p=0.025). Eight patients had the highest MiR score (MiRmax), in whom synchronous new lesions and completely responsive tumors were observed. In a multivariate Cox proportional-hazards regression involving performance status, extracranial failure, tumor volume, lesion number, and RANO-BM classification as variables, MiRmax remained an independent prognosticator for inferior survival (HR=5.20, 95%CI; 2.21–12.23, p=0.002). Our study demonstrates that MiR in brain metastases from EGFR-mutant NSCLC treated with osimertinib is associated with inferior survival outcomes and a higher risk of local progression. Lesion-level response assessment using AI may provide important prognostic information and aid in treatment decision-making for these patients.
SDPS-10 DISPARITIES IN THE RISK OF CNS METASTASIS AND CLINICAL OUTCOMES IN PATIENTS WITH HER2- MUTATION POSITIVE (HER2+) NON-BREAST VERSUS HER2+ BREAST CANCERS
Authors: Elghawy Omar , Horton Bethany , Shen Shiyi , Kaur Varinder 
Published: August 2023

Abstract

BACKGROUND
Risk of CNS metastases is well characterized for patients (pts) with HER2+ breast cancer (BC), however, poorly defined for pts with HER2+ non-breast solid tumors (ST).

METHODS
We performed a retrospective cohort analysis to characterize the frequency of CNS metastasis and clinical outcomes in pts with Her2+ ST treated at the University of Virginia Emily Couric Cancer Center between 01/2010- 01/2022. Risk of CNS metastasis, time to CNS metastasis, progression free survival (PFS) and overall survival (OS) were analyzed for each cohort and stage IV subgroups. The outcomes were further compared between HER2+ ST vs BC cohorts.

RESULTS
50 pts had HER2+ ST and 383 had HER2+ BC. In the ST group, median age was 66.0 years (y), 37 (74.0%) were male, 43 (86.0%) were white and 2(4.0%) were African American. Majority (74%) of patients had gastro-esophageal tumors. Median time to CNS metastasis was 5.8 y and median PFS was 0.7 y (95% CI 0.55-0.98, p&lt;0.05). In those with CNS metastasis 5 (50%) received CNS directed plus HER2 targeted therapy and 3(30%) received CNS directed therapy alone. 24 (48%) pts had baseline CNS imaging in ST group, compared to 11 (2.9%) in the BC group. Rate of CNS metastasis was 20% (n=10) vs 6.8% (n=26) in the ST and BC cohorts (p&lt;0.0001). OS differs in ST vs BC cohorts overall (p&lt;0.0001; median OS 1.7 vs 18.5y) and in patients with metastatic disease at diagnosis (p&lt;0.0001; median OS 1 vs 6.3y). Advanced N (p=0.0445) and smoking (p=0.0868) were associated with early CNS metastasis

CONCLUSIONS
Pts with HER2+ ST have higher risk of CNS metastasis and shorter OS compared to BC pts. Improved understanding of disease characteristics and standardized management approaches are imminently needed to improve outcomes.
SDPS-25 COMPARISON OF MOLECULAR ALTERATIONS BETWEEN SYSTEMIC AND CNS METASTATIC SITES REVEALSMUTATIONAL DISCORDANCES
Authors: Huang David , Bergagnini Isabella , Hajiyeva Sabina , Wong Tamika , D'Amico Randy , Boockvar John , Vojnic Morana 
Published: August 2023

Abstract

INTRODUCTION
Central nervous system (CNS) metastases occur in 10-30% of patients with systemic malignancies and can be genomically distinct from systemic metastases. NGS has revolutionized cancer therapies, providing rapid molecular data to identify therapeutic targets. In this study we compare the genomic profile of matched systemic and CNS tumor samples.

METHODS
Between January 2022 and January 2023, we identified 19 patients who underwent a craniotomy for symptomatic brain metastases (BM) or CSF sampling for leptomeningeal disease (LMD) diagnosis. Results from ten patients are presented (four were excluded due to lack of NGS data or material, sequencing for 5 patients is pending). If systemic tumor NGS was not available, blood-based NGS was used as a surrogate.

RESULTS
9/10 patients had lung adenocarcinoma (LUAD), 1/10 breast adenocarcinoma. 8/10 CNS samples were collected from BM, 2/10 from CSF in patients with LMD. 4/10 patients had received prior systemic therapy. Blood-based NGS was used in 60% (6/10). The mean tumor mutational burden (TMB) in body samples was 3.39 mutations/megabase (SD 3.79, SEM 1.34) compared to CNS samples with mean TMB of 10.94 mutations/megabase (SD 7.08, SEM 2.50), 3.23 times higher. In CNS samples, the driver alterations EGFR Ex19del and KRAS G12D and G12F were retained, however all ten CNS samples had additional mutations (mean of differences 8.9). Interestingly, a patient with previously known osimertinib resistance mutation EGFR C797S, acquired a MET amplification and lost the EGFR C797S mutation in the CNS. A breast cancer patient acquired a HER2 amplification in the CSF.

CONCLUSIONS
With matched NGS of systemic and CNS metastases, we observe substantially higher CNS tumor mutational burden, retention of primary driver alterations, and acquisition of targetable resistance mutations. Our results suggest that sequencing of CNS disease can alter treatment by identifying new therapeutic targets, although larger scale studies are needed.
SDPS-26
UNINTENDED RADIOTHERAPY DOSE ON THE NEUROGENIC NICHES IS ASSOCIATED WITH DECREASED OVERALL SURVIVAL IN PATIENTS WITH LUNG CANCER BRAIN METASTASES
Authors: Cialdella Fia , Bruil Danique , van der Boog Arthur , Nagtegaal Steven , de Vos Filip , Verhoeff Joost , David Szabolcs 
Published: August 2023

Abstract

INTRODUCTION
Radiotherapy is the primary local intervention for cerebral metastases (BMs). Despite decades of advancements in this field, inadvertent collateral irradiation of adjacent healthy tissue in proximity to neoplastic site remains a persistent challenge. Neural stem cells (NSCs), crucial for the establishment and preservation of the nervous system, exhibit heightened sensitivity to radiation. Consequently, radiation-induced damage to NSCs may influence Overall Survival (OS) in patients with BMs. NSCs are primarily located in the subventricular zone (SVZ) and the subgranular zone (SGZ) within the hippocampus (HPC). In this study, our objective is to assess the influence of unintended radiotherapy dose on NSCs and its subsequent effect on OS.

METHODS
In this retrospective study, we incorporated data from 138 Non-Small Cell Lung Cancer (NSCLC) patients with BMs, from a single academic institution. NSC regions were projected on non-enhanced T1 MR images with Computational Anatomy Toolbox 12 and Statistical Parametric Mapping. The association between regional mean doses to the SVZ and HPC and OS was examined using a Cox regression model. Additionally, survival differences between lesion contact and no direct contact with SVZ and HPC were investigated with Kaplan-Meier (KM) analysis.

RESULTS
Multivariable Cox regression analysis of the dose on the SVZ and HPC showed a significant negative correlation, with a hazard ratio (HR) of 1.366 (p = 0.041 [95% (CI) 1.013– 1.842]) and 1.194 (p = 0.037 [95% CI 1.010 – 1.411]), respectively. KM analysis did not identify a relationship between direct lesion contact with NSC-regions and OS.

CONCLUSION
Any unintended dose on the neurogenic niches is correlated with poorer OS in patients with BMs from NSCLC. Interestingly, there was no association between direct contact or invasion of these regions and the OS. We recommend conducting further investigation into the impact on neurocognitive function within this specific group in a prospective study design.
SDPS-27 P16 IMMUNOHISTOCHEMISTRY AS A SCREENING TOOL FOR HOMOZYGOUS CDKN2A DELETIONS IN GLIAL TUMORS
Authors: Zschernack Valentina , Andreiuolo Felipe , Doerner Evelyn , Wiedey Anna , Juenger Stephanie , Pietsch Torsten 
Published: August 2023

Abstract
The 2021 WHO classification of tumors of the central nervous system emphasizes the significance of molecular parameters for an integrated diagnosis. Homozygous deletion of CDKN2A has been associated with an adverse prognosis in IDH-mutant gliomas, supratentorial ependymomas, meningiomas, and MPNST. In this study, we examined the value of p16 protein immunohistochemistry as a screening tool for predicting a homozygous CDKN2A deletion. Genetic analyses for CDKN2A deletion in 30 pleomorphic xanthoastrocytomas, 32 IDH-wildtype high-grade gliomas and 40 supratentorial ependymomas with ZFTA-RELA gene fusion, 10 IDH-mutant astrocytomas, and 10 meningiomas were performed either by a molecular inversion probe assay (MIP), a high-resolution, quantitative technology for the accurate, genome-wide assessment of chromosomal copy number alterations, or by 850k methylation profile-deduced copy number analysis or multiplex ligation-dependent probe amplification analysis. In pleomorphic xanthoastrocytomas and IDH-wildtype high-grade gliomas, p16 immunohistochemistry showed high specificity (100% both), moderate sensitivity (76% and 56%), and a high positive predictive value (PPV; 100% both) for the presence of a homozygous CDKN2A deletion. In supratentorial ependymoma with ZFTA-RELA gene fusion, immunohistochemistry for p16 protein was highly sensitive and specific (90% and 97%) for a homozygous CDKN2A deletion and exhibited a high PPV and NPV (90% and 97%, respectively). For lower-grade meningioma, no correlation between the p16 immunohistochemical status and the CDKN2A deletion status was possible. Therefore, p16 protein expression detected by immunohistochemistry is a useful prescreening tool for detecting a homozygous CDKN2A deletion in glial tumors.
SDPS-32 A CLINICALLY COMPATIBLE IN VITRO DRUG-SCREENING PLATFORM IDENTIFIES THERAPEUTIC VULNERABILITIES IN PRIMARY CULTURES OF BRAIN METASTASES
Authors: Jeising Sebastian , Trübel Johanna , Felsberg Jörg , Picard Daniel , Wolter Marietta , Kaulich Kerstin , Häberle Lena , Esposito Irene , Steinmann Julia , Beez Thomas , Rapp Marion , Sabel Michael , Nickel Ann-Christin , Remke Marc , Reifenberger Guido , Qin Nan 
Published: August 2023

Abstract
Approximately 20% of cancer patients (including lung, melanoma, breast, renal, and colorectal cancer patients) develop brain metastases. Current systemic therapies often show limited efficacy for brain metastasis treatment and support palliative care only. In this preclinical study, short-term cultured primary cancer cells from brain metastasis patients were molecularly characterized using next-generation sequencing and functionally evaluated using high-throughput in vitro drug screening to identify pharmacological treatment sensitivities. Next-generation sequencing identified matched genetic alterations between brain metastasis tissues and corresponding patient-derived cultured cancer cells. Mutant allele frequencies indicated that short-term cultures of cancer cells reflect the existence of distinct subpopulations of cancer cells within brain metastases. This indicates that our short-term cultured primary brain metastasis cells are suitable models for recapitulating heterogeneity in the sensitivity of tumor cells to anti-cancer drugs. Employing our in-house high-throughput in vitro drug screening platform, we screened the primary cultures from the brain metastasis patients for response to 267 anticancer compounds, and integrated the molecular and high-throughput drug screening data sets. Our preclinical study provides proof-of-concept for combining molecular profiling with in vitro drug screening for improved prediction of therapeutic vulnerabilities in brain metastasis patients. This approach could advance the use of patient-derived cancer cells in clinical practice and might eventually facilitate decision-making for personalized drug treatment.
SDPS-37 IDENTIFICATION OF TIME-COURSE RELATED, TREATMENT-RELATED, AND PATIENT-RELATED PROGNOSTIC FACTORS IN BRAF-MUTANT MELANOMA BRAIN METASTASES.
Authors: Erickson Lily G , Ramaswamy Sahana , Ferguson Sherise D , Long James , Hasanov Merve , Davies Alicia Bea , Sirmans Elizabeth , Saberian Chantal , Posada Eliza L , Malke Jared , Haydu Lauren E , Tawbi Hussein , Chung Caroline 
Published: August 2023

Abstract

PURPOSE
Patients with BRAF-mutant melanoma brain metastases (MBM) continue to have limited overall survival (OS), averaging 4 months, despite advancements in systemic therapies. Our study aims to identify patient-specific and treatment-related prognostic factors in BRAF-mutant MBM to inform treatment sequencing and patient selection in future studies and improve patient outcomes.

METHODS
The following data were manually curated from 100 patients with BRAF-mutant MBM diagnosed from 2009-2018, with primary cutaneous melanoma and who received initial MBM treatment at our institution: clinical and demographic, treatment, and OS outcomes. We compared OS with the log rank test using the Python package kaplanmeier between the various clinical, demographic and treatment (including treatment sequence) related variables.

RESULTS
Both elevated lactase dehydrogenase (LDH) was associated with shorter OS (p=0.023), as was leptomeningeal disease (p&lt;0.001). Gender (male vs. female) and initial treatment modality (BRAFi vs. immunotherapy) did not significantly impact OS, (p=0.911 and 0.578, respectively). Breakthrough brain metastases were associated with shorter OS for patients who received initial systemic therapy for MBM (p&lt;0.001), but breakthrough metastases did not significantly impact OS for the whole cohort (p=0.141). Additionally, patients who received BRAFi before MBM diagnosis had shorter OS (p=0.028).

CONCLUSION
In conclusion, we have identified some interesting relationships between OS and the sequencing of treatment modalities, as well as the timing of MBM presentation. These findings support further investigation of treatment sequencing to improve outcomes and the consideration of clinical variables, disease presentation, and treatment history to help refine patient selection for future trials for patients with BRAF-mutant MBM.
SDPS-39 AN UPDATED VALIDATION OF PREDICTIVE ALGORITHMS FOR BRAIN METASTASES IN NON-SMALL CELL LUNG CANCER: SYSTEMATIC REVIEW AND INDEPENDENT COHORTVALIDATION ANALYSIS
Authors: Wilding Hannah , Mikolajewicz Nicholas , Bhanja Debarati , Moeckel Camille , Hamidi Nima , Tankam Cyril , Stoltzfus Mason , Baroz Angel , Stahl Caleb , Trifoi Mara , Dudek Cain , Mansouri Alireza 
Published: August 2023

Abstract

INTRODUCTION
Many non-small cell lung cancer (NSCLC) patients eventually develop brain metastases (BM). Reliable risk stratification with predictive algorithms can lead to early intervention. Here, we evaluated the performance of published BM risk-stratification algorithms using an independent cohort of NSCLC patients.

METHODS
We evaluated statistical models predicting BM in NSCLC by systematically reviewing relevant studies and testing them on an independent cohort of NSCLC patients in electronic medical records (2011-2020) from Penn State Health. Patient data was randomly split into 70% training and 30% testing for modeling using L1-regularized logistic regression, and we assessed the models' performance using ROC analyses.

RESULTS
Out of 1,643 publications, 22 met our criteria, and 12 of those studies (527,258 patients) included variables consistently available in patient charts. Our validation cohort included 1,699 NSCLC patients, with a median age at diagnosis of 68 and 20.4% developing BM. Among feasible models, Zhang 2021 had the highest performance in our cohort (AUROC [95% CI]: 0.89 [0.85-0.93]) and was comprised of the following predictors: age at diagnosis; surgical, chemotherapy, and radiation status; T and N stage; histological grade; and number of organs with metastases. Within our independent cohort, logistic regression revealed that the most informative predictors were the number of organs with metastases (OR [95% CI]: 3.25 [2.70, 3.92]), age at NSCLC diagnosis (OR [95% CI]: 0.98 [0.96, 0.99]), N-stage 1 at diagnosis (OR [95% CI]: 1.83 [1.08, 3.11]), and non-carcinoid or -carcinoma histology (OR [95% CI]: 0.29 [0.10, 0.84]).

CONCLUSION
Our robust approach, including systematic review and one of the largest-to-date independent institutional datasets, proposes a clinically feasible, novel algorithm for stratifying NSCLC patients based on risk of developing BM. This work can inform pragmatic screening and surveillance guidelines to facilitate early detection of BM in NSCLC patients.
SDPS-43 OUTCOMES OF SUPRATENTORIAL FOCAL ENHANCING LESIONS CONCERNING FOR LEPTOMENINGEAL METASTASES
Authors: Rodriguez Andrew , Wang Chenyang , Loghin Monica , Guha-Thakurta Nandita , O'Brien Barbara 
Published: August 2023

Abstract
Leptomeningeal metastasis (LM) is an aggressive cancer complication with poor prognosis. Prompt diagnosis based on clinical findings, neuroaxis imaging, and cerebrospinal fluid (CSF) cytology- critical for appropriate, timely management. However, diagnosis is often challenging- as imaging lacks specificity and CSF cytology lacks sensitivity. Classic LM imaging findings include cerebellar folia, cranial nerve, and cauda equina enhancement. Of 103 patients with solid tumor brain metastasis referred to Neuro-Oncology at MD Anderson Cancer Center from 2016-2022 for evaluation of suspected LM on stereotactic radiosurgery (SRS) planning MRI, 15 had limited (≤5) nodular or linear focal enhancement in supratentorial sulci, without classic LM imaging. Upon initial workup, none had symptoms, neurologic deficits, or spine imaging consistent with LM; 10 underwent ≥1 lumbar puncture (median 1; range, 0-4) of which 2 (13%) had CSF cytology-confirmed disseminated LM. Majority were female (n=10); median age 60 years (range, 29-87). Most had lung (n=6) or breast (n=5) cancer. Five (33%) had history of craniotomy and resection of metastasis, with 1 resection cavity near supratentorial findings subsequently confirmed as LM. Both patients with confirmed LM received whole-brain radiation (WBRT)- instead of planned SRS- and intrathecal chemotherapy. One died 10.5m following diagnosis; the other continues therapy 11.6m later. In the remaining 13, the suspicious LM findings were determined to represent parenchymal/dural metastasis, treatment effect, or vascularity. Six were dispositioned to SRS, 3 to WBRT. One was ultimately diagnosed with LM (cytology-confirmed) 10m following WBRT. Nine subsequently received systemic therapy for intracranial and/or systemic disease. Median OS was 11 months (range, 4-37) from LM suspicion; 6 remain alive. In this small series, a minority of patients with supratentorial focal enhancing lesions without classic imaging findings were diagnosed with disseminated LM. Further study is needed to better stratify patients by LM risk and thus appropriateness of workup and intervention.
SYST-12 LP-184, A NOVEL ACYLFULVENE-DERIVED TUMOR SITE ACTIVATED SMALL MOLECULE INHIBITS ADULT AND PEDIATRIC CNS TUMOR CELL GROWTH
Authors: Kulkarni Aditya , Lal Bachchu , Laterra John , Raabe Eric , Bhatia Kishor , McDermott Joseph , Sharma Panna 
Published: August 2023

Abstract
Blood-brain barrier (BBB) permeable agents effective against recurrent, chemotherapy-resistant central nervous system (CNS) tumors are urgently needed, particularly in Glioblastoma multiforme (GBM) and atypical teratoid/rhabdoid tumors (ATRT). These represent extremely aggressive and lethal types of CNS malignancies. LP-184 is a next-generation acylfulvene class drug candidate and has received FDA orphan drug designations for the treatment of malignant gliomas and ATRT. LP-184 creates covalent DNA adducts that are selectively repaired via nucleotide excision repair (NER). Repair of LP-184-induced DNA damage is mediated by ERCC complexes. Consistent with this, we observed 3-6X decreased cancer cell viability in U87, M1123 and Mayo39 GBM cells treated with LP-184 in combination with the ERCC3 degrader Spironolactone (SP) relative to LP-184 alone. Mice bearing pre-established subcutaneous U87 xenografts were treated with SP alone, LP-184 alone or their combination. Tumors recurred after initial regression in 5/5 animals treated with LP-184 alone whereas tumors showed durable complete regression without recurrence in 4/5 animals treated with LP-184 + SP. Thus, LP-184 likely functions as a synthetically lethal agent in the presence of DNA repair deficiencies. LP-184 inhibited cell growth in CHLA06 and BT37 ATRT cell lines, with IC50s in the 20-25nM range. LP-184 induced apoptosis 96 hours after treatment in these ATRT cell lines as measured by immunofluorescence for cleaved caspase-3 and Western blot for c-PARP. LP-184 intravenous treatment at 4 mg/kg twice weekly for 2 weeks showed tumor regression in mice implanted with CHLA06 ATRT subcutaneous xenografts, with 112% tumor growth inhibition and 2/10 treated mice being tumor-free at study termination. LP-184 further showed favorable intracranial tumor bioavailability along with in vivo BBB permeability comparable to other CNS cancer drugs. These findings identify LP-184 as a promising new agent and support its further development for treating CNS tumors in adult and pediatric populations.