bluuebunny/crossref_metadata_2025_split huggingface dataset:
LMAP-17 FEASIBILITY OF COGNITIVE-SPARING STEREOTACTIC RADIOSURGERY FOR BRAIN METASTASES: INITIAL REPORT OF PHASE II COG-SRS TRIAL
Authors: Hopper Austin , Connor Michael , Karunamuni Roshan , Sanghvi Parag , Kim Grace , Bruggeman Andrew , Moiseenko Vitali , Farid Nikdokht , McDonald Carrie , Hattangadi-Gluth Jona 
Published: August 2023

Abstract
Radiotherapy at high doses leads to white matter (WM) and hippocampal injury which can cause cognitive decline. We designed the first, to our knowledge, evidence-based cognitive-sparing brain SRS trial for patients with limited brain metastases. In this report we analyze feasibility of cognitive-sparing SRS, utilizing dose constraints for eloquent WM tracts and bilateral hippocampi. Patients underwent high-resolution quantitative diffusion and volumetric MRI at baseline and post-SRS follow-up. Comprehensive neurocognitive assessment was performed at baseline and 3 months post-SRS evaluating multiple neurocognitive domains. Clinical workflow was largely automated with robust, validated segmentation of eloquent WM tracts and the hippocampi. Single fraction max dose constraints to WM tracts and hippocampi were 12 Gy and 8.4 Gy, respectively, with 3 and 5 fraction equivalent doses based on our prior NTCP studies. Patient accrual, follow-up imaging and neurocognitive testing is still active. To date, 59 patients and 114 lesions have been treated with cognitive-sparing linac-based SRS on trial. Median age is 63 years. Patients had 1-4 brain metastases; median prescription dose was 24Gy/1, 27Gy/3, or 30Gy/5 depending on target volume. Most patients were treated &lt;7 business days from MRI. Cognitive endpoints have been collected on 89.5% of patients. Cognitive-sparing constraints were met in 79.3% of plans while maintaining standard clinical SRS plan indices and coverage benchmarks. Plans going over constraints had tumors overlying or within 1 mm of eloquent ROIs. Local control for treated lesions at 6 months was 97.9% and 95.7% at 12 months. Distant intracranial control was 68.1% at 6 and 12 months. Median OS was 18 months. Cognitive-sparing SRS treatment planning was successfully implemented for the majority of treated lesions with excellent local control. Mitigation of damage to eloquent structures has potential to further reduce cognitive decline after SRS. Full neurocognitive outcomes will be reported after accrual and testing are complete.
NEIM-02 CHARACTERIZATION OF LARGE BRAIN METASTASES WITH18F-FLUCICLOVINE PET/CT TREATED WITH STAGED STEREOTACTIC RADIOSURGERY (SSRS): INTERIM ANALYSIS OF A PILOT STUDY
Authors: Rosa Alonso La , Chundru Surya , Vuong Hao , Tom Martin , Kutuk Tugce , Wieczorek D Jay , Lee Yongsook , Avendano Maria Carolina , Rubens Muni , Tolakanahalli Ranjini , McDermott Michael , Hall Matthew , Gutierrez Alonso , Ahluwalia Manmeet , Mehta Minesh , Kotecha Rupesh 
Published: August 2023

Abstract
We report the interim analysis of a phase 1, proof-of-concept study (NCT04689048), to assess the potential clinical utility of an amino acid radiotracer, 18F-fluciclovine PET/CT, as a functional integral biomarker for previously untreated patients with large brain metastases [BM] (≥1 lesion; &gt;2cm) treated with staged stereotactic radiosurgery (SSRS). We reviewed the imaging characteristics from static PET images acquired 10-25 minutes after 18F-fluciclovine injection for the first seven enrolled patients (9 lesions) who completed baseline imaging, and five patients (7 lesions) who completed the treatment course (SSRS). Patients underwent a baseline (pre-treatment) 18F-fluciclovine PET/CT and contrast-enhanced treatment planning brain MRI before 1st SSRS (15 Gy), repeated after 4 weeks (interim; before 2nd SSRS [15 Gy]), and 8 weeks after treatment completion (first follow-up after 2nd SSRS). The median age was 72 years and 57% were female. All lesions exhibited baseline increased 18F-fluciclovine uptake compared to normal contralateral brain. The median baseline lesion diameters and volumes were 2.16 cm (1.76-3.22 cm) and 4.71cc (2.24-10.21 cc). The median baseline SUVmax, SUVpeak, and SUVmean values were 5.78 (2.16-8.79), 3.33 (0.5-2.72), and 1.75 (1.22-5.16), respectively. The median relative changes in diameter and volume were both -2% (-23% to +13% and -60% to +30%, respectively) at the interim scans, and -30% (-44% to +0.2%) and -43% (-94% to +13%), respectively, at first follow-up. Corresponding median relative changes values for SUVmax, SUVpeak, and SUVmean at interim scan were -20% (-73% to +174%), -9% (-75% to +99%), and -14% (-69% to +36%), and at first follow-up -59% (-87% to -21%), -41% (-86% to +11%), and -21% (-79% to +44%), respectively. In conclusion, this proof-of-concept interim study reports 18F-fluciclovine metrics for patients with large BMs, demonstrating interval reduction in PET metrics after SSRS, more than anatomical measurements alone, highlighting the potential of this as an imaging biomarker.
NEIM-15 AN EXCEPTION TO THE METASTATIC RULE: A NON-ENHANCING MIDBRAIN LESION DUE TO METASTATIC FIBROMYXOID SARCOMA WITH EXTENSIVEINFLAMMATORY INFILTRATE
Authors: Rogawski David , Wheeler Josh , Nie Esther , Zhu William , Villanueva Eleanor , Coffey Gwen , Ganjoo Kristen , Fischbein Nancy , Iv Michael , Vogel Hannes , Nagpal Seema 
Published: August 2023

Abstract
Metastases from extra-CNS sites typically enhance on MR after the administration of gadolinium-based contrast agents due to disruption of the blood-brain barrier. Fibromyxoid sarcoma involving the brain is extremely rare, with only a few reported cases manifesting as well-circumscribed enhancing masses. Here, we report an extremely rare non-enhancing brain metastasis secondary to an already rare sarcoma. A 44-year-old woman with gluteal fibromyxoid sarcoma metastatic to cervical paraspinal muscles and adrenal gland treated with ipilimumab/nivolumab presented with diplopia and was found to have an 8 mm T2-hyperintense midbrain lesion without enhancement or mass effect. An inflammatory etiology associated with checkpoint inhibitor therapy was suspected, and she was treated with IV methylprednisolone 1 g daily for 3 days followed by an oral prednisone taper, IV immunoglobulin, and plasma exchange without improvement. The midbrain lesion steadily grew over 15 months of follow up, eventually involving the bilateral medial thalami and demonstrating diffusion restriction in the midbrain, but never showing gadolinium enhancement. The imaging was reminiscent of peripheral brainstem non-enhancing band-like lesions reported in leptomeningeal lung cancer, however CSF cytology was repeatedly normal, as was extensive infectious and inflammatory testing. Her neurologic disability continued to progress, with development of bilateral oculomotor nerve palsies, dysarthria, and depressed level of alertness, devolving into non-convulsive status epilepticus requiring intubation. She died six months after onset of neurologic symptoms. At autopsy, histologic and immunohistochemical evaluation revealed fibromyxoid sarcoma (MUC-4 positive, TAOK1-FUS fusion) centered on the periventricular aqueduct with accompanying disseminated single-cell infiltration throughout the midbrain. The background midbrain and periventricular parenchyma were notable for voluminous microglial activation and histiocytic infiltrate. In sum, this case represents a radiographically unique sarcoma brain metastasis which on pathologic exam showed robust inflammatory changes far out of proportion to the tumor present.
SDPS-01 DEVELOPMENT OF A WEB-BASED CALCULATOR APPLICATION FOR PREDICTING SHORT- AND LONG-TERMSURVIVAL IN PEDIATRIC OPTIC PATHWAY GLIOMA: A POPULATION-BASED DATABASE ANALYSIS
Authors: Brown Nolan , Kuo Cathleen , Pennington Zach , Gendreau Julian , Givens Drew , Daniels David 
Published: August 2023

Abstract
Optic pathway gliomas (OPG) are generally low-grade lesions arising from the astrocytes of the visual pathway, most commonly of the optic nerves and chiasm. Uncertainty remains regarding the optimal management of this patient population. We sought to leverage population-level data from the Surveillance, Epidemiology, and End Results program database to develop a predictive calculator for overall survival (OS) amongst pediatric patients with OPG. A total of 1,052 patients who had been diagnosed with OPG were included. Multivariate cox proportional hazard model demonstrated patients of “other” race (hazard ratio [HR]=4.109, 95% confidence interval [CI] 1.076-15.694, p=0.039) exhibited a decreased overall survival, while patients with a median household income ≥$55,000 (HR=0.172, 95% CI 0.065-0.457, &lt;0.001) and those who underwent subtotal resection (HR=3.549, 95% CI 1.092-13.364, p=0.047) had a higher overall survival rate. An online, interactive survival prediction tool (https://spine.shinyapps.io/optic_glioma/) was created to estimate 5-, 10-, and 15-year overall survival probability as well as median survival months. C-index was 0.722 (95% CI 0.642-0.776) for the training set and 0.745 (95% CI 0.661-0.790) for the validation set. Good concordance between the predicted probability and the actual probability of the dataset was also observed. This calculator may serve as a useful clinical tool during patient counseling. Further investigations aimed at developing calculators of visual acuity preservation and progression-free survival are merited; progress toward this end will benefit from continued multicenter collaborations.
SDPS-17 COMPREHENSIVE ANALYSIS OF CELL DIVISION CYCLE ASSOCIATED GENE FAMILY EXPRESSION PATTERN AND PROGNOSIS VALUE REVEALS CDCA2 AS A NOVEL ONCOGENE FOR GLIOMA
Authors: Sun Wei , Han Xuetao , Zhou Huandi , Hou Liubing , Xue Xiaoying 
Published: August 2023

Abstract
Glioma is the most common central nervous system tumors. Although many biomarkers have been reported for detecting glioma, the prognosis for the disease remains poor, and therefore, new biomarkers need to be identified. The cell division cycle associated proteins (CDCA) family gene is involved in a wide range of biological functions in human cancers. Nevertheless, the expression characteristics of CDCAs, and prognostic value landscape of glioma are remain unknown. Based on a wide variety of public databases and integrated several bioinformatics analysis methods, we evaluated expression dysregulations, clinical implications, DNA methylation, copy number alterations, prognostic and therapeutic values of CDCA family gene in glioma. Further, we identified crucial biomarker, CDCA2, that influence the progression of malignant glioma and poor prognosis. Thereafter, we disclosed the effect of CDCA2 knockdown on the biological function of glioma cells through various experiments in vitro. We found that the elevated mRNA expression of CDCAs in glioma. The upregulated expression of CDCAs was found to be associated with the tumor grade in glioma. The overexpression of CDCAs mRNA were correlated with the poor prognosis. Moreover, the expression level of CDCA2 was significantly higher in glioma, and the level is correlated with grade, age, IDH1 mutation and 1p19q codeletion states. Further cell experimental results supported that the ability of cell proliferation, migration, invasion and radioresistance of glioma cells was significantly decreased after downregulated CDCA2 expression, and these changes may be achieved through the RAD51 and p21/CDK2/CyclinE1 signaling pathways. These findings provide new insights into CDCAs from a bioinformatics standpoint and highlight the significance of CDCAs in glioma diagnosis and treatment. And knockdown of CDCA2 inhibits glioma cells' proliferation, migration, invasion and radioresistance. Regulation of CDCA2 on malignant progression of glioma cells may be realized through the RAD51 and p21/CDK2/CyclinE1 signaling pathways.
SDPS-18 RHABDOID TUMOR PREDISPOSITION SYNDROME IN TWO INFANT SIBLINGS WITH ATYPICAL TERATOID RHABDOID TUMORS DUE TO A GERMLINE SMARCB1 MUTATION
Authors: Quintero Ana , Hanson Derek , Pedro Helio , Vogel Timothy 
Published: August 2023

Abstract
Atypical teratoid rhabdoid tumors (ATRT) are aggressive, malignant tumors of the central nervous system (CNS) that develop due to a loss-of-function mutation in the SMARCB1 gene. Rhabdoid tumor predisposition syndrome (RTPS) is characterized by familial cases as a result of pathogenic germline variants of this gene and an increased risk of developing ATRT within the first 2 years of life, which carries a poor prognosis. Genetic penetrance is incomplete with variable expressivity but the patient's age at time of diagnosis remains the most significant indicator of survival. We present a case of RTPS in a sibship born to unaffected parents, one of which was a carrier. The first sibling was diagnosed at 8 months of age after presenting with vomiting, developmental regression, and CN VI palsy for 3 months. Imaging revealed a posterior fossa mass, acquired obstructive hydrocephalus, and spinal metastasis. Four years later, her 3-month-old sister was brought in for evaluation due to vomiting, irritability, and macrocephaly for 2 months, along with a new vertical gaze palsy. Imaging findings also showed a posterior fossa mass and acquired obstructive hydrocephalus but without metastasis. Both siblings underwent craniotomy with subtotal tumor resection and ventriculoperitoneal shunt placement. Chemotherapy was promptly initiated but despite active treatment, they had rapid disease progression and ultimately passed away. Whole exome sequencing of both patients revealed an in-frame deletion involving the SNF5 homology domain of SMARCB1, with consistent findings on whole transcriptome sequencing, and evidence of loss of a single copy of chromosome 22. In this case report, we present a family faced with the devastating outcomes of RTPS and emphasize the importance of genetic testing and counseling for these families after diagnosis in the first child. Families should also be streamlined to a fertility specialist prior to subsequent pregnancies as an opportunity for familial screening.
SDPS-30 ANALYSIS OF THE BRAIN TUMOR MATRISOME REVEALS CANCER ASSOCIATED FIBROBLASTS PREDICT POOR IMMUNOTHERAPY RESPONSE IN GLIOBLASTOMA PATIENTS
Authors: Zarodniuk Maksym , Steele Alexander , Lu Xin , Li Jun , Datta Meenal 
Published: August 2023

Abstract
Excessive deposition of extracellular matrix (ECM) is a hallmark of solid tumors; however, it remains poorly understood which cellular and molecular components contribute to the formation of ECM stroma in central nervous system (CNS) tumors. Here, we undertook a pan-CNS analysis of retrospective gene expression datasets to characterize inter- and intra-tumoral heterogeneity of ECM remodeling signatures. We found that glioblastoma can be divided into two ECM-based subtypes that are influenced by the presence of cells resembling cancer associated fibroblasts (CAFs) and are conserved across a number of CNS lesions. In glioblastoma, CAF-like cells are correlated with unfavorable response to immune checkpoint blockade and poor patient survival across a subset of CNS tumors. We show that CAF-like cells reside in the perivascular niche, activate chemoattractant signaling pathways to recruit tumor-associated macrophages, and promote glioma stem-like cell phenotype. Our analysis provides insights into mechanisms underlying immunotherapy resistance in glioblastoma and suggests that targeting CAF-like cells may provide an effective approach to improve patient survival in a subset of CNS tumors.
SDPS-31 EXTRACELLULAR VESICLES AND THEIR CARGO AS A PHARMACODYNAMIC REPORTER IN GLIOBLASTOMA
Authors: DeLuca Valerie , Tang Nanyun , Hao Yue , Raju Anjali , Shaffer Charles , Riviere-Cazaux Cecile , Burns Terry , Sarkaria Jann , Parney Ian , Pirrotte Patrick , Van Keuren-Jensen Kendall , Berens Michael 
Published: August 2023

Abstract
Glioblastoma (GBM) is a lethal brain tumor with limited treatment options, due in part to the low blood-brain-barrier (BBB) penetrance of many anti-cancer compounds. Development of a non-invasive test that can measure drug delivery and target engagement in GBM represents an opportunity to enhance knowledge during early phase clinical trials of a new compound’s pharmacological suitability and potential efficacy. We present here data supporting that the cargo within extracellular vesicles (EV) can potentially serve as a liquid biopsy that reports on the pharmacodynamics of GBM therapeutics. We treated short-term cell cultures established from four patient-derived xenografts with vehicle, temozolomide, MLN4924, or arsenic trioxide. EVs were isolated from culture supernatants using size exclusion chromatography and then analyzed by RNA sequencing and mass spectrometry (proteomics) to characterize and compare cargo profiles for each condition. We found that depending on treatment, there were shared alterations in EV cargo between models in the expression of long non-coding RNAs, genes that are overrepresented in biological processes such as cytoplasmic translation and cellular macromolecule biosynthesis, and circular RNAs. Mass spectrometry of protein cargo further demonstrated both upregulated and downregulated peptide abundances with treatment compared to vehicle. Thus, our preliminary results indicate that EV cargo post-treatment may be a novel pharmacodynamic reporter in GBM. To allow for the selective interrogation of patient GBM-derived EVs, we have simultaneously pursued the identification of biomarkers to allow for immunoprecipitation of EVs from patient biofluids. Potential biomarkers, including PTPRZ1, B7H3, and IL13RA2, were screened across isolated EVs from both pre-clinical and clinical patient samples. Future efforts are focused on evaluating immunoprecipitated GBM-EVs from longitudinally collected patient biofluids. Overall, we anticipate that the results of this study will lead to development of a clinical test that reflects BBB penetration and tumor response, which will likely aid in novel drug development efforts.
SDPS-34 SCREENING TUMOR INFILTRATING LEUKOCYTES IN GLIOBLASTOMA REVEALS A CORRELATION WITH EGFR POSITIVE TUMOR CELLS WITH PROGNOSTIC IMPLICATIONS
Authors: Goodyke Austin , Arora Sanjana , Orozco Andres Restrepo , Zagorski Joseph , Vitaz Todd 
Published: August 2023

Abstract
Glioblastoma (GBM) is a grade IV brain tumor that is difficult to manage and associated with high rates of relapse and mortality. Treatment failures are attributed to the blood-brain barrier, increased tumor vascularity, tumor heterogeneity, numerous molecular mutations, and an immunosuppressive microenvironment. The immune microenvironment is comprised of tumor-infiltrating leucocytes (TILs), including several immunosuppressive cell types such as myeloid derived suppressor cells (MDSCs) (immature TILs of myeloid lineage). These tumor supporting immune cells augment the microenvironment and create conditions for immune suppression, contributing to tumor progression and negatively impacting patient survival. The aim of this study was to characterize the TILs in individual patients and correlate these findings with treatment course and survival. We hypothesized that a higher prevalence of MDSCs in tumors would be associated with lower survival rates. In order to investigate this, tumor specimens were collected from GBM patients who underwent tumor resection at Corewell Health (IRB# 2020-024). Fresh GBM samples were collected into tumor storage solution and immediately dissociated into single cell suspensions using a GentleMACS dissociator. The subsequent single cell suspension was stained with a panel of antibodies for TILs and tumor surface markers EGFR and PDGFRA. Flow cytometric analysis of these specimen revealed that the TILs comprising the tumor microenvironment were primarily dominated by CD11b+ myeloid cells, with prevalent MDSCs negatively associated with survival in our study group. Interestingly, MDSCs were negatively correlated with EGFR+ tumor cells while CD3+ T cells were positively correlated. In addition, patients previously treated with either temozolomide or bevacizumab had significantly different TIL immunophenotypes. Together, these data suggest that screening approaches utilizing these techniques may elucidate how tumor cells and TILs may be interacting and reacting to treatment and may provide additional diagnostic and prognostic avenues ultimately leading to improved outcomes for these patients.
SDPS-46 CENTRAL NERVOUS SYSTEM (CNS)-RELATED MORTALITY IN PATIENTS WITH HER2-POSITIVE METASTATIC BREAST CANCER
Authors: Ferraro Emanuela , Nassif Rabih Bou , Reiner Anne , Tosi Umberto , Panageas Katherine , Dang Chau T , Seidman Andrew D , Moss Nelson 
Published: August 2023

Abstract

BACKGROUND
Approximately one third of patients with HER2-positive (+) metastatic breast cancer (MBC) develop brain metastases (BrM). In light of discordant control of extracranial metastases (ECM) versus BrM for standard-of-care antibody-based therapies for these patients, and the frequent use of radiation and surgical therapies particularly for patients with CNS-centric disease, we sought to determine the proportion of HER2+ MBC patients with BrM who suffered neurologic death in the CNS-only and intracranial-plus-extracranial metastasis settings, and the clinical risk factors of such.

METHODS
Clinicopathologic data for HER2+ MBC patients with BrM treated at an NCI-designated Comprehensive Cancer Center between August 2010 and April 2022 were collected, including disease burden at cancer presentation, the timing and pattern of BrM and ECM, and neurologic complications. CNS-related death was defined as any mortality caused by BrM, leptomeningeal progression, or BrM-associated complication.

RESULTS
275 patients were included. 58/275 (21%) presented with CNS as only and first site of metastasis; the remaining (217/275, 79%) developed BrM synchronously with or subsequent to ECM. 125/275 (45%) had de novo MBC, and nearly all patients were treated with CNS therapies (254/275 [92%] received at least one radiation treatment and 88/275 [32%] underwent BrM resection). After a median follow-up of 2.5 years, 193/275 (70%) patients died, of whom 105 (54%) of CNS-related cause. The median OS was 3 years (95% CI=1.47-5.14) and 2 years (95% CI=1.74-2.34) for patients with CNS-only versus BrM concurrently/subsequent to ECM, respectively (p=0.059). The cumulative incidence of CNS-related death at 5 years was 40% (95%CI=33-46%).

CONCLUSIONS
Almost half of patients with HER2+ BrM suffered neurologic death. Patients with CNS-only disease had better OS than patients with synchronous/preceding ECM, suggesting that overall burden of disease affects mortality. With high rates of durable extracranial control with HER2-directed therapies, new strategies to prevent and eradicate CNS disease are urgent.