bluuebunny/crossref_metadata_2025 huggingface dataset:
SDPS-05 ASSESSING SURVIVAL OUTCOMES AND COMPLICATION PROFILES FOLLOWING SURGICAL EXCISION OF SKULL BASE CHORDOMA: A COMPREHENSIVE SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Brown Nolan , Kuo Cathleen , Gendreau Julian
Published: August 2023

Despite their precarious behavioral classification (histopathologically benign (low-grade), behaviorally malignant), great strides have been taken to improve prognostication and treatment paradigms for patients with skull base chordoma. However, due to the rarity of this tumor, prior investigations remain limited to small retrospective series. Accordingly, we performed a systematic review and meta-analysis in order to profile surgical and survival outcomes for skull base chordoma. Fixed and random-effect meta-analyses were performed for categorial variables including number of males, GTR, STR, 5-year OS, 10-year OS, 5-year PFS, and 10-year PFS. Following the systematic search and screen, 47 studies published between 1993-2020 reporting data for 2204 patients remained eligible for analysis. Sex distribution was comparable between males and females, with a slight predominance of male-identifying patients (0.5625 [0.5418;0.3909]). Average age at diagnosis was 42.4 ± 12.5 years, while average age of treatment initiation was 43.0 ± 10.6 years. Overall, there was a substantial degree of heterogeneity across the 47 studies (I^2=56.3% [44.0%; 65.9%]). With respect to operative margins, the rate of GTR was 0.3323 [0.2824; 0.3909], I^2 = 91.9% [90.2%; 93.4%], while the rate of STR was significantly higher at 0.5167 [0.4596; 0.5808], I^2 = 93.1% [91.6%; 94.4%]. Interestingly, 5-year OS rate was 0.7113 [0.6685; 0.7568], I^2 = 91.9% [90.0%; 93.5%]. Furthermore, 10-year OS rate was 0.4957 [0.4230; 0.5809], I^2 = 92.3% [89.2%; 94.4%], which was comparable to both 5-year PFS rate of 0.5054 [0.4394; 0.5813], I^2 = 84.2% [77.6%; 88.8%] and 10-yr PFS rate of 0.4949 [0.4075; 0.6010], I^2 = 14.9% [0.0%; 87.0%]. There were 55 reported deaths for a perioperative mortality rate of 2.5%. The most common complication was CSF leak(5.4%). Overall, these results indicate good 5-year outcomes; however, 10-year prognosis for skull base chordoma remains poor due to its radiotherapeutic resistance and high recurrence rate.
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

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<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

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<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<0.0001). OS differs in ST vs BC cohorts overall (p<0.0001; median OS 1.7 vs 18.5y) and in patients with metastatic disease at diagnosis (p<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

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

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

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

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

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<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<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

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

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

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.
SYST-28 FUNCTIONAL MAPPING REVEALS WIDESPREAD REMODELLING AND A NOVEL TARGETABLE PTP4A2-ROBO1 SIGNALING AXIS AT GLIOBLASTOMA RECURRENCE
Authors: Chokshi Chirayu , Shaikh Vaseem , Tieu David , Brakel Benjamin , Brown Kevin , chan Katherine , rossotti Martin , Maich William , Venugopal Chitra , Anand Alisha , Lazo John , Kislinger Thomas , Lu Jian , Provias John , Henry Kevin , Moffat Jason , Singh Sheila
Published: August 2023

Resistance to genotoxic therapies and tumor recurrence are hallmarks of glioblastoma (GBM), an aggressive brain tumor. Here, we explore the functional drivers of post-treatment recurrent GBM. By conducting genome-wide CRISPR-Cas9 screens in patient-derived GBM models, we uncover distinct genetic dependencies in recurrent tumor cells that were absent in their patient-matched primary predecessors, accompanied by increased mutational burden and differential transcript and protein expression. These analyses map a multilayered genetic response to drive tumor recurrence, identifying protein tyrosine phosphatase 4A2 (PTP4A2) as a novel modulator of self-renewal, proliferation and tumorigenicity at GBM recurrence. Mechanistically, genetic perturbation or small molecule inhibition of PTP4A2 represses axon guidance activity through a dephosphorylation axis with roundabout guidance receptor 1 (ROBO1), exploiting a functional dependency on ROBO signaling. Roundabout guidance receptor 1 (ROBO1) protein is involved in axonal guidance during neurodevelopment and aberrant ROBO1 signaling axis is associated with higher tumorigenicity in GBM. ROBO1 was highly expressed on the surface of malignant and treatment-refractory brain tumor initiating cells (BTICs) in rGBM, brain metastasis (BM) and medulloblastoma (MB). Importantly, engineered anti-ROBO1 single-domain antibodies also mimic the effects of PTP4A2 inhibition. We therefore developed and validated second-generation CAR-T cells against ROBO1, which demonstrated upregulation of activation markers, enhanced cytokine release, markedly increased proliferation, and induction of potent and specific tumor cell death compared to untransduced cells in all the three brain cancers. These findings were further validated in vivo in rGBM, MB and BM models, where ROBO1 CAR-T cells showed significant reduction in tumor burden and increase in survival of treated mice. We conclude that functional reprogramming drives tumorigenicity and dependence on a multi-targetable PTP4A2-ROBO1 signaling axis at GBM recurrence.
SYST-31 PROBIOTIC DELIVERY TO ORTHOTOPIC GLIOBLASTOMA MULTIFORME MODELS AS AN IMMUNOTHERAPY
Authors: Windemuth Sophia , Ali Alessandra , Molotkov Andrei , Hahn Jaeseung , Danino Tal , Leong Kam , Mintz Akiva
Published: August 2023

Therapeutic bacteria have been shown to be effective as an immunotherapy in several types of solid tumors because of their inherent immunogenicity and ability to target tumor tissue with systemic administration. Furthermore, advances in synthetic biology enable production and release of cancer therapeutics from bacteria. However, there is little work describing therapeutic probiotics in brain cancers such as glioblastoma multiforme (GBM). To bridge this gap, we tested different routes of administration for delivery of engineered strains of E. coli Nissle (EcN), and observed the colonization of orthotopic GBM tumors in immunocompetent mouse models. In these models, we successfully colonized tumors using both intratumoral and intravenous injection with little to no observable off-target colonization. This specificity in both delivery methods demonstrates that systemic delivery of wild-type EcN is sufficient to achieve targeted colonization of the tumor. After systemic delivery of bacteria was established in GBM, we sought to reduce edema reactions to the bacteria that occurred after colonization. To reduce the inflammatory response, we treated the edema with antibodies against vascular endothelial growth factor (VEGF), which are a clinical standard treatment for high intracranial pressure. Injecting anti-VEGF antibodies prior to bacteria administration substantially increased the survival rate compared to the mice not given anti-VEGF, suggesting that anti-VEGF significantly reduces the toxicity resulting from the bacteria that has been observed in our work and that of other works. This work therefore opens up the possibility of further work in optimizing the engineered strains for treating GBM.
TIPS-05 ADJUVANT TEMOZOLOMIDE CHEMOTHERAPY FOLLOWING RADIOTHERAPY IN NEWLY DIAGNOSED LOW-GRADE GLIOMA PATIENT WITH RESIDUE TUMORS: A MULTICENTER, OPEN LABEL, RANDOMIZED TRIAL
Authors: Chen Zhongping , Sai Ke , Yang Qunying , Guo Chengcheng , Wu Shaoxiong , Xia Yunfei , Xi Shaoyan , Liao Yixiang
Published: August 2023

Low-grade glioma (LGG) with infiltrative nature and frequent growth in eloquent area in brain often makes total resection impossible. Although post-radiation adjuvant temozolomide (TMZ) is the standard of care for high-grade gliomas, and radiotherapy and/or TMZ are recommended for the treatment of residue low-grade gliomas, the efficacy of combined radiotherapy with adjuvant TMZ for residue LGG remains to be defined. We have initiated a randomized clinical trial in 2012 to test whether radiotherapy with subsequent TMZ chemotherapy will improve survival of patients with residue LGG compared to radiotherapy alone. This study was approved by the Ethics Committee of the Sun Yat-sen University Cancer Center, Guangzhou, China (approval No. 5010-2012-03) and was registered with ClinicalTrials.gov (NCT01649830). Inclusion Criteria: Patients age of 18 years to 60 years, with incompletely resected supratentorial WHO grade 2 astrocytoma, oligodendroglioma or oligodendroastrocytoma. Enrolled patients were randomized into: radiation therapy alone (RT) or radiotherapy with subsequent TMZ chemotherapy (RC) group. Start Date: July 2012, Estimated Primary Completion Date:August 2025. Radiation therapy will start within 8 weeks after neurosurgical procedures, with a total dose of 54.0 Gy in 27 - 30 fractions over 6 - 7 weeks. Four weeks after radiotherapy, patients in RC group will receive 6 cycle of TMZ dosed at 200 mg/m2 daily for 5 consecutive days, repeated every 28 days. We have completed enrollment on December 2018 with valid cases of 248 patients. Up to last follow-up date of Feb. 2023, 204 cases were analyzed (see table). There is no significant difference between RT group and RC group on both PFS and OS (5-year PFS 68.9% vs 75.2%, p=0.680; 5-year OS 92.0% vs 86.0%, p=0.400). Longer follow-up and molecular subgroup analysis are currently on the way, which could show benefit in special molecular subgroup.
TIPS-06 ADVANCING BEYOND THE HIPPOCAMPUS TO PRESERVE COGNITION FOR PATIENTS WITH BRAIN METASTASES: DOSIMETRIC RESULTS FROM A PHASE 2 TRIAL OF MEMORY-AVOIDANCE WHOLE BRAIN RADIOTHERAPY
Authors: Perlow Haley K , Nalin Ansel P , Ritter Alex R , Addington Mark , Ward Aubrie , Liu Michal , Nappi Collin , Blakaj Dukagjin M , Beyer Sasha J , Thomas Evan M , Grecula John C , Raval Raju R , Kotecha Rupesh , Boulter Daniel , Dawson Erica L , Zoller Wesley , Palmer Joshua D
Published: August 2023

Recent advances to preserve neurocognitive function in patients treated for brain metastases include stereotactic radiosurgery (SRS), hippocampal avoidance whole brain radiation therapy (HA-WBRT), and memantine administration. The hippocampus, corpus callosum, fornix, and amygdala are key neurocognitive substructures with a low propensity for brain metastases. Herein, we report our preliminary experience using a “memory-avoidance” WBRT (MA-WBRT) approach that spares these substructures for patients with >15 brain metastases. Ten consecutive patients treated with MA-WBRT on a phase 2 clinical trial were reviewed. In each patient, the hippocampi, amygdalae, corpus callosum, and fornix were contoured. Patients were not eligible for MA-WBRT if they had metastases in these substructures. A memory- avoidance region created using a 5mm volumetric expansion around these substructures. Hotspots were avoided in the hypothalamus and pituitary gland. Coverage of brain metastases was prioritized over memory avoidance dose constraints. Dose constraints for these avoidance structures included a D100% ≤ 9Gy and D0.03cc ≤ 16Gy (variation acceptable to 20Gy). LINAC-based volumetric modulated arc therapy (VMAT) plans were generated for a prescription dose of 30 Gy in 10 fractions. On average, the memory avoidance structure volume was 37.1 ccs (Range: 25.2-44.6 ccs), occupying 2.5% of the entire whole brain target volume. All treatment plans met the D100% dose constraint, and 8/10 plans met the D0.03cc constraint, with priority given to tumor coverage for the remaining 2 cases. Target coverage (D98% >25Gy) and homogeneity (D2% ≤ 37.5Gy) were achieved for all plans. Modern VMAT techniques allow for sparing of the hippocampus, amygdala, corpus callosum, and fornix with good target coverage and homogeneity. After enrollment is completed, quality of life and cognitive data will be evaluated to assess the efficacy of MA-WBRT to mitigate declines in quality of life and cognition after whole brain radiation.
TIPS-16 A PROSPECTIVE COHORT STUDY ON THE IMPACT OF RADIOTHERAPY ON QUALITY OF LIFE AND DISEASE PROGRESSION IN PATIENTS WITH BRAIN METASTASES AND THEIR CAREGIVERS
Authors: Cialdella Fia , van Grinsven Eva , van der Boog Arthur , Nagtegaal Steven , Smid Ernst , Claes An , Kleynen Karin , Seravalli Enrica , Philippens Marielle , van Zandvoort Martine , Verhoeff Joost
Published: August 2023

INTRODUCTION

Brain metastases (BMs) are diagnosed in 10-30% of all cancer patients, and the incidence is expected to rise due to advancements in primary tumor management. Besides survival, the impact of treatment on quality of life (QoL) and course of disease is highly relevant for patients and their caregivers. The Cohort for patient-reported Outcomes, Imaging and trial inclusion in Metastatic BRAin disease (COIMBRA) study aims to gather data on natural disease progression, treatment response, tumor recurrence, complications, QoL (for both patient and caregiver), cognitive performance and survival of patients with BMs. Additionally, the study evaluates feasibility, performance and added value of new MRI techniques in patients with BMs, while providing an infrastructure for efficient and pragmatic randomized evaluation of new interventions.

DESIGN/METHODS

COIMBRA is an observational, prospective cohort for patients with brain metastases and their caregivers that are referred to a tertiary academic radiation oncology department. The study is designed according to the Trials within Cohorts (TwiCs) framework. ClinicalTrials.gov Identifier: NCT05267158.

PRELIMINARY RESULTS

Since April 2019, 419 patients have been included of which 51.2% were men and the majority of the patients had lung cancer (53.6%). Stereotactic radiosurgery (SRS) was administered in 92.4% and 68.1% received any systemic therapy. Median Overall Survival was 18.3 months. Questionnaires available at both baseline and 6 months after radiotherapy showed that 65.3% experienced stability or improvement in QoL measured via the EORTC QLQ-C30 questionnaire. Fewer patients reported anxiety or depression after SRS compared to before (28.4% vs 47.8%). Caregivers’ baseline responses indicated that 59% had to adjust their daily lives due to the patient’s diagnosis.

CONCLUSION

Our study successfully collected clinical and QoL data from a large cohort of patients and their caregivers. The results suggest a modest improvement in anxiety and QoL after radiotherapy.
TIPS-18 TRIAL IN PROGRESS: A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, PLACEBO-CONTROLLED, PHASE 2B STUDY TO ASSESS THE SAFETY AND EFFICACY OF IGV-001, AN AUTOLOGOUS CELL IMMUNOTHERAPY WITH ANTISENSE OLIGONUCLEOTIDE (IMV-001) TARGETING IGF-1R, IN NEWLY DIAGNOSED PATIENTS WITH GLIOBLASTOMA
Authors: Perez-Olle Raul , Diwanji Madhavi , Pennock Gregory , Scott Charles , Andrews David
Published: August 2023

Glioblastoma (GBM) is the most common primary brain malignancy in adults. Standard of care (SOC) for suspected GBM begins with maximal safe resection followed by adjuvant radiotherapy and temozolomide, and maintenance temozolomide. Imvax has developed the Goldspire™ platform to create IGV-001, an autologous biologic-device combination product for the treatment of newly diagnosed GBM (ndGBM). IGV-001 consists of autologous GBM tumor cells and an antisense oligonucleotide against IGF-1R mRNA (IMV-001), irradiated and administered via biodiffusion chambers implanted in the abdomen. Together, these components stimulate immunogenic cell death and antigen release. IGV-001 was well tolerated and multiple efficacy signals were observed in a Phase 1b study in patients with ndGBM, including significant improvements in progression-free survival (PFS), radiographic evidence of tumor response, and changes in immune response biomarkers. A Phase 2b randomized, multicenter, double-blind, placebo-controlled study has been initiated to assess the safety and efficacy of IGV-001 in patients with ndGBM (NCT04485949). After surgical resection, patients will be treated with IGV-001 or placebo followed by SOC. 25 US sites have been selected with a target enrollment of 93 patients (2:1 randomization) and the study is open to enrollment. Key inclusion criteria are 18 to 70 years of age, Karnofsky performance status score ≥ 70, diagnosis of GBM based on the treating neurosurgeon's best clinical judgement, confirmed measurable disease pre-operatively, tumor located in the supratentorial compartment, and adequate bone marrow and organ function. Key exclusioncriteria include bihemispheric disease, multicentric disease, or treatment with Tumor Treating Fields (Optune®) prior to documented progression. The primary outcome is PFS, defined as the time from randomization to first progression, as determined by blinded central radiology review, or death. Secondary outcomes include overall survival, defined as the time from randomization to death due to any cause, and safety.
TIPS-21 PHASE I/II STUDY OF STEREOTACTIC RADIOSURGERY WITH CONCURRENT OLAPARIB FOLLOWED BY ADJUVANT DURVALUMAB AND PHYSICIAN’S CHOICE SYSTEMIC THERAPY IN SUBJECTS WITH BREAST CANCER BRAIN METASTASES (SOLARA)
Authors: Shen Colette , Abdou Yara , Chen Linda , Tan Xianming , Gupta Gaorav , Lynce Filipa , Lobbous Mina , Stringer-Reasor Erica , Anders Carey
Published: August 2023

BACKGROUND

Despite progress in the treatment of brain metastasis (BrM) for HER2+ breast cancer (BC), outcomes for patients with HER2-negative BC BrM remain poor. Current standard of care consists of surgery and/or radiotherapy followed by systemic therapy. Preclinical studies show inhibitors of poly(ADP-ribose) polymerase (PARP) are effective together with radiotherapy as DNA damage response inhibitors. Triple-negative BC (TNBC) has higher rates of homologous recombination deficiency compared to other BC subtypes, and together with HER2-negative, BRCA-mutated BC would be particularly sensitive to PARP inhibition. PARP inhibition with immunotherapy has demonstrated promising efficacy in patients with germline BRCA-mutant and metastatic TNBC in clinical trials (MEDIOLA, TOPACIO). In addition, immunotherapy with stereotactic radiosurgery (SRS) is associated with favorable outcomes in patients with BrM. We hypothesize that this biologically-driven combination will enhance local control of SRS-treated BrM through synergy with PARP inhibition, while controlling micrometastatic disease in the brain and extracranial sites by potentiating the immune response.

METHODS

We are conducting a multi-institution, Phase I/II trial of SRS plus olaparib, followed by durvalumab (with physician’s choice systemic therapy), for patients with TNBC (any BRCA status) or HER2-negative with BRCA-mutated (germline or somatic) BC BrM [NCT04711824]. The primary objectives are to evaluate safety and tolerability (Phase I) and intracranial disease control at 6 months (Phase II). Secondary objectives include assessing intracranial and global progression-free survival, overall survival, and intracranial/extracranial response rate. Exploratory objectives will assess potential biomarkers of treatment response, including changes in circulating tumor cells/DNA in blood and cerebrospinal fluid, germline and tumor mutations in DNA repair pathway genes, and PD-L1 expression, as well as quality of life and patient-reported outcomes. A surgical sub-study (n=5) will evaluate olaparib concentration/distribution in resected BrM. As of January 2023, cohort 1 of phase I has been completed without dose-limiting toxicity.
Three consecutive cytosolic glycolysis enzymes modulate autophagic flux
Authors: Lee Du-Hwa , Choi Ilyeong , Park Seung Jun , Kim Sumin , Choi Min-Soo , Lee Ho-Seok , Pai Hyun-Sook
Published: August 2023

Autophagy serves as an important recycling route for the growth and survival of eukaryotic organisms in nutrient-deficient conditions. Since starvation induces massive changes in the metabolic flux that are coordinated by key metabolic enzymes, specific processing steps of autophagy may be linked with metabolic flux-monitoring enzymes. We attempted to identify carbon metabolic genes that modulate autophagy using VIGS screening of 45 glycolysis- and Calvin–Benson cycle-related genes in Arabidopsis (Arabidopsis thaliana). Here, we report that three consecutive triose-phosphate-processing enzymes involved in cytosolic glycolysis, triose-phosphate-isomerase (TPI), glyceraldehyde-3-phosphate dehydrogenase (GAPC), and phosphoglycerate kinase (PGK), designated TGP, negatively regulate autophagy. Depletion of TGP enzymes causes spontaneous autophagy induction and increases AUTOPHAGY-RELATED 1 (ATG1) kinase activity. TGP enzymes interact with ATG101, a regulatory component of the ATG1 kinase complex. Spontaneous autophagy induction and abnormal growth under insufficient sugar in TGP mutants are suppressed by crossing with the atg101 mutant. Considering that triose-phosphates are photosynthates transported to the cytosol from active chloroplasts, the TGP enzymes would be strategically positioned to monitor the flow of photosynthetic sugars and modulate autophagy accordingly. Collectively, these results suggest that TGP enzymes negatively control autophagy acting upstream of the ATG1 complex, which is critical for seedling development.
Gestational Glucose Intolerance and Birth Weight–Related Complications
Authors: Maya Jacqueline , Selen Daryl J. , Thaweethai Tanayott , Hsu Sarah , Godbole Devika , Schulte Carolin C. M. , James Kaitlyn , Sen Sarbattama , Kaimal Anjali , Hivert Marie-France , Powe Camille E.
Published: August 2023

OBJECTIVE:

To evaluate the risks of large-for-gestational-age birth weight (LGA) and birth weight–related complications in pregnant individuals with gestational glucose intolerance, an abnormal screening glucose loading test result without meeting gestational diabetes mellitus (GDM) criteria.

METHODS:

In a retrospective cohort study of 46,989 individuals with singleton pregnancies who delivered after 28 weeks of gestation, those with glucose loading test results less than 140 mg/dL were classified as having normal glucose tolerance. Those with glucose loading test results of 140 mg/dL or higher and fewer than two abnormal values on a 3-hour 100-g oral glucose tolerance test (OGTT) were classified as having gestational glucose intolerance. Those with two or more abnormal OGTT values were classified as having GDM. We hypothesized that gestational glucose intolerance would be associated with higher odds of LGA (birth weight greater than the 90th percentile for gestational age and sex). We used generalized estimating equations to examine the odds of LGA in pregnant individuals with gestational glucose intolerance compared with those with normal glucose tolerance, after adjustment for age, body mass index, parity, health insurance, race and ethnicity, and marital status. In addition, we investigated differences in birth weight–related adverse pregnancy outcomes.

RESULTS:

Large for gestational age was present in 7.8% of 39,685 pregnant individuals with normal glucose tolerance, 9.5% of 4,155 pregnant individuals with gestational glucose intolerance and normal OGTT, 14.5% of 1,438 pregnant individuals with gestational glucose intolerance and one abnormal OGTT value, and 16.0% of 1,711 pregnant individuals with GDM. The adjusted odds of LGA were higher in pregnant individuals with gestational glucose intolerance than in those with normal glucose tolerance overall (adjusted odds ratio [aOR] 1.35, 95% CI 1.23–1.49, P<.001). When compared separately with pregnant individuals with normal glucose tolerance, those with either gestational glucose intolerance subtype had higher adjusted LGA odds (gestational glucose intolerance with normal OGTT aOR 1.21, 95% CI 1.08–1.35, P<.001; gestational glucose intolerance with one abnormal OGTT value aOR 1.77, 95% CI 1.52–2.08, P<.001). The odds of birth weight–related adverse outcomes (including cesarean delivery, severe perineal lacerations, and shoulder dystocia or clavicular fracture) were higher in pregnant individuals with gestational glucose intolerance with one abnormal OGTT value than in those with normal glucose tolerance.

CONCLUSION:

Gestational glucose intolerance in pregnancy is associated with birth weight–related adverse pregnancy outcomes. Glucose lowering should be investigated as a strategy for lowering the risk of these outcomes in this group.
Repurposing Antihypertensive and Statin Medications for Spinal Pain
Authors: Suri Pradeep , Elgaeva Elizaveta E. , Williams Frances M.K. , Freidin Maxim B. , Verzun Dmitrii A. , Tsepilov Yakov A.
Published: August 2023

Study Design.

Mendelian randomization (MR) study.

Objective.

To examine whether antihypertensive medications (beta-blockers, calcium channel blockers, and angiotensin-converting enzyme inhibitors) and statins can be repurposed to prevent or treat spinal pain (back or neck pain).

Summary of Background Data.

Observational studies and a recent MR study have found associations between elevated blood pressure and a greater risk of back pain. Observational studies have found associations between hyperlipidemia and statin use and greater risk of back pain. No prior MR studies have examined the effects of antihypertensives or statins on spinal pain.

Materials and Methods.

This was a two-sample MR study using publicly available summary statistics from large-scale genome-wide association studies (GWAS). Sample sizes in exposure GWASs were n=757,601 (systolic blood pressure) and n=173,082 (low-density lipoprotein cholesterol), and n=1,028,947 for the outcome GWAS of spinal pain defined as health care seeking for any spinal pain-related diagnosis. Genes and cis-acting variants were identified as proxies for the drug targets of interest. MR analyses used inverse-variance weighted meta-analysis. The threshold for statistical significance after correction for multiple testing was P<0.0125.

Results.

No statistically significant associations of these medications with spinal pain were found. However, findings were suggestive of a protective effect of beta-blockers on spinal pain risk (odds ratio [OR] 0.84, 95% confidence interval [CI] 0.72–0.98; P=0.03), and calcium channel blockers on greater spinal pain risk (OR 1.12, 95% CI 1.02–1.24; P=0.02).

Conclusions.

A protective effect of beta-blockers on spinal pain was suggested in the current study, consistent with findings from observational studies of various other pain phenotypes. The detrimental effect of calcium channel blockers on spinal pain suggested in the current study must be interpreted in the context of conflicting directions of effect on nonspinal pain phenotypes in other observational studies.