bluuebunny/crossref_metadata_2025_split huggingface dataset:
NIRL-11 3D-FSE IMAGING FOR RADIOSURGERY PLANNING IMPROVES BRAIN METASTASIS DETECTION AND REDUCES INTRACRANIAL RELAPSE
Authors: Akdemir Eyub Y , Press Robert H , Hodgson Lydia C , Rubens Muni B , La Rosa Alonso , Kutuk Tugce , Wieczorek D Jay , Lee Cecillia , Bejarano Tatiana , Tolakanahalli Ranjini , Gutierrez Alonso N , McDermott Michael W , Mehta Minesh P , Kotecha Rupesh 
Published: August 2024

Abstract
INTRODUCTION: Stereotactic radiosurgery (SRS) is an effective treatment for brain metastasis (BM), but patients remain at significant risk for distant intracranial failure (DIF) due to undetected lesions at the time of SRS or subsequent seeding. We implemented dedicated treatment planning imaging with novel MR sequences with the goals of enhancing lesion detection and consequentially increasing time to DIF, correspondingly reducing the need for whole-brain radiotherapy (WBRT). METHODS: Patients treated with SRS for BM between 05/2019-01/2024 were evaluated. MPRAGE sequences were performed for all, and 3D-FSE sequences were added starting in 02/2020. Median times to DIF and WBRT for both cohorts were estimated using the Kaplan–Meier method. RESULTS: 194 patients underwent 310 SRS courses for 1326 BM imaged with both MPRAGE and 3D-FSE (primary cohort), compared to the control cohort (88 patients, 116 SRS courses, 373 BM). MPRAGE sequences detected 1456 lesions in all 282 patients (373 in 88 control patients, 1083 in 194 primary cohort patients). In the primary cohort, an additional 204 lesions were identified with 3D-FSE (18% increase). An additional 39 lesions (3.6% increase) were identified on multidisciplinary review of both MR modalities. Although there was no statistically significant difference in median time to DIF between the cohorts (11.3 vs. 6.7 months, p=0.14), there was a trend towards longer DIF in the 1-4 metastases subgroup (14.6 vs. 7.9 months, p=0.052) and a statistically significant difference in those with a single BM (35.9 vs. 11.8 months, p=0.017). WBRT rates at 2-years were similar between the cohorts, 15% vs. 20%, p=0.2, respectively. CONCLUSIONS: A dual sequence approach at the time of SRS with multidisciplinary review improves lesion detection and lengthens time to DIF and, ultimately, next intervention. This is especially useful in confirming true BM number in those with limited intracranial disease.
NIRL-13 HISTOPATHOLOGIC CONFIRMATION OF TUMOR RECURRENCE IDENTIFIED ON CONTRAST CLEARANCE ANALYSIS MAPS - A VALIDATION STUDY
Authors: Madhugiri Venkatesh , Goulenko Victor , Bregdy Amade , Recker Matthew , Lipinski Lindsay , Fabiano Andrew , Fenstermaker Robert , Plunkett Robert , Abad Ajay , Belal Ahmed , Alberico Ronald , Qiu Jingxin , Prasad Dheerendra 
Published: August 2024

Abstract

BACKGROUND
Stereotactic radiosurgery (SRS) has become a standard modality in the treatment of brain metastases. The differentiation between adverse radiation effects (ARE) and tumor recurrence or progression is important in this setting. The advent of immunotherapy and targeted therapy often makes this distinction difficult to achieve. Contrast clearance analysis (CCA) is a useful technique that can inform clinical decisions but has so far only been histologically validated in the context of high-grade gliomas.

METHODS
Between 2018 and 2023, more than 200 patients who had been treated with SRS for various brain pathologies including brain metastasis, atypical meningiomas, and high-grade gliomas underwent CCA studies. Among these patients, clinical scenarios mandated surgery in 7 patients. Targeted biopsies were taken at the time of surgery in all patients. Histopathology findings were compared with the CCA findings in these patients.

RESULTS
All 7 patients had been treated with gamma knife radiosurgery and were being followed up with periodic MR imaging. All patients underwent CCA when the necessity to distinguish tumor recurrence from ARE/ radiation necrosis arose. Targeted biopsies showed 100% concordance of the pre-surgery CCA findings with histological findings. Viable tumor tissue was identified on pathology in all instances where the CA map indicated the presence of viable tumor represented in blue color.

CONCLUSIONS
Based on prior studies on GBM and the surgical findings in our series, delayed contrast extravasation MRI findings correlate well with histopathology. CCA can provide a quick diagnosis and have a direct impact on patient treatment and outcomes.
NVTG-02 CIRCULAR RNAS AS NOVEL TARGETS IN BREAST-TO-BRAIN CANCER METASTASIS
Authors: Szczepaniak Adrian , Bronisz Agnieszka , Godlewski Jakub 
Published: August 2024

Abstract
Breast-to-brain metastatic (BTB met) cancer constitutes a great challenge for modern medicine and science, and thus, a quest for the discovery of novel therapeutic targets is underway. As the research on protein-coding genes has brought only incremental progress in discovering such targets, much attention is currently devoted to understanding the role of non-coding RNAs, including a relatively recently discovered group of circular RNAs. These non-coding RNAs, which arise from linear RNA transcripts, possess a covalently closed structure that renders them resistant to RNA turnover and a specific circularization site sequence that allows their precise suppression while keeping the linear parental transcript intact. These features thus make them promising candidates for biomarkers and therapeutic targets. This project aimed to map the circular RNA landscape in a comprehensive model of BTB met cancer cells, primary breast carcinoma, primary brain tumor cells, and relevant non-malignant breast and brain cell controls. Despite different tissue-of-origin, the analysis of global circRNAomes showed striking similarities between BTB mets and glioblastoma stem-like cells (GSCs) and allowed the selection of reliable candidates for mechanistic studies. Interestingly, the circRNAome of BTB mets clustered particularly closely with mesenchymal GSC, the most aggressive and therapy-resistant subtype of GSCs. Efficient knockdown of candidate circular RNAs in BTB met cells by antisense oligonucleotides resulted in molecular and phenotypic alterations such as diminished viability and clonality, arrested cell cycle concurrent with increased expression of cyclin-dependent kinase inhibitors, and changed expression of epithelial-mesenchymal transition markers. These results thus demonstrated the role of circular RNAs in shaping the oncogenic traits of BTB met cells. Further research focuses on circular RNA-dependent chemotherapy resistance, stemness/differentiation balance, and relevant models of metastatic progression (primary site/pleural effusion/brain). Therefore, circular RNAs can serve as valuable biomarkers and promising novel mechanistic candidates whose modulation may become a paradigm-shifting therapeutic approach.
NVTG-07 SAFETY, TOLERABILITY, AND ANTITUMOR ACTIVITY OF TRASTUZUMAB DERUXTECAN (T-DXD) IN PATIENTS WITH HER2+ METASTATIC BREAST CANCER (MBC) AND ACTIVE BRAIN METASTASES (BMS) IN DESTINY-BREAST07 (DB-07)
Authors: Anders Carey , Loi Sherene , Hamilton Erika , Jhaveri Komal , Schmid Peter , Gökmen Erhan , Im Seock-Ah , Karaçin Cengiz , Barrios Carlos , Park Yeon Hee , Topaloğlu Sernaz , Boston Sarice , Konpa Adam , Mondal Shoubhik , André Fabrice 
Published: August 2024

Abstract

BACKGROUND
DEBBRAH, ROSET-BM, TUXEDO-1, and a pooled DB-01, -02, -03 analysis indicate robust efficacy of T-DXd in patients with stable/active BMs; however, efficacy in active BMs is not yet fully established. DB-07 is a Phase 1b/2, multicenter, open-label study exploring the safety, tolerability, and antitumor activity of T-DXd alone or in combination with other anticancer agents (NCT04538742). Results are from an interim analysis of the dose-expansion phase of T-DXd monotherapy in patients with active BMs.

METHODS
Patients had locally assessed HER2+ mBC with measurable disease. No or one prior line of therapy for mBC was allowed; a ≥12-month disease-free interval from (neo)adjuvant HER2-directed therapy or chemotherapy was required. Patients had untreated BMs not requiring local therapy or progressing BMs after local therapy. Ongoing use of systemic corticosteroids (&gt;2 mg dexamethasone daily or equivalent) for control of BMs symptoms was exclusionary. Patients received T-DXd 5.4 mg/kg intravenously every 3 weeks. Primary objectives were safety and tolerability; additional endpoints included objective response rate (ORR) and progression-free survival (PFS) per RECIST 1.1 and Response Assessment in Neuro-Oncology (RANO)-BM.

RESULTS
Thirty-five patients with active BMs were treated. As of August 1, 2023, median follow up was 11.5 months (range 5.3–24.6). The most common any-grade adverse events (AEs) were nausea (74.3%; Grade 3, 5.7%) and vomiting (45.7%; Grade 3, 2.9%); AEs Grade ≥3 occurred in 18 patients (51.4%). By RECIST 1.1, confirmed ORR was 77.1% (80% CI 65.5, 86.2), and 12-month PFS rate was 84.5% (80% CI 74.1, 91.0). By RANO-BM, confirmed ORR was 57.1% (80% CI 44.9, 68.7) and 12-month PFS rate was 74.6% (80% CI 59.4, 84.8).

CONCLUSION
The safety profile is consistent with the known profile for T-DXd, and data confirm promising efficacy in patients with active BMs. Ongoing analyses will provide more mature data.
NVTG-08 PERSONALIZED TREATMENT OF MELANOMA BRAIN METASTASES THROUGH HIGH THROUGHPUT DRUG SCREENING
Authors: Doonan Bently , Spicer Timothy , Rahman Maryam , Scampavia Louis , Vega Virneliz Fernandez , Benslimane Nesrine , Mctiernan Raquel , Von Roemeling Christina , Mitchell Duane 
Published: August 2024

Abstract
Melanoma is an increasing clinical concern, with an expected increase in incidence over the next 20 years. Compounding this problem, as many as 70% of all metastatic patients will develop brain metastases as a manifestation of their disease. Current strategies including immunotherapy, targeted therapy, and local therapies (surgery, SRS, and LITT) have greatly improved patient outcomes yet fail to cure the majority of patients, with intracranial progression a major driver of mortality. Novel treatment strategies are needed to provide immediate options for our patients. To combat this issue, we have developed a pipeline of high throughput drug screening of patient derived tumor microspheres, capable of screening over 100,000 compounds rapidly for potential therapeutic options for patient at time of progression following standard of care. These high throughput results are further paired with tumor derived genomic sequencing to identify potential biomarkers of drug responsiveness. Through this work we will identify potential patient specific therapy options for use in compassionate care trials and through utilization of blood brain barrier permeabilization strategies (LITT or low frequency ultrasound) we plan to expand the pool of available therapies to include those therapies traditionally not capable of reaching drug concentration intracranially. If successful, this strategy has the potential for reshaping both individual patient outcomes, but identifying novel candidate therapies for future clinical trial design.
NVTG-09 TARGETING TRKB IN LUNG-TO-BRAIN METASTATIC PROGRESSION
Authors: Contreras-Zárate Maria J , Koliavas Stella , Heasley Lynn , Pine Sharon , Nemenoff Raphael , Camidge D Ross , Cittelly Diana 
Published: August 2024

Abstract

Brain metastases (BM) are a common site of metastasis for both non-small cell (NSCLC) and small cell lung cancer, affecting 20-56% of advanced lung cancer (LC) patients. In breast cancer models, we have shown that astrocytes secrete brain-derived neurotrophic factor (BDNF), which, in a paracrine manner, activates its receptor tropomyosin-related kinase B (TrkB, also called NTRK2) in a subset of cancer cells, promoting BM. Although NTRK gene rearrangements are known to function as primary oncogenic drivers in a subset of NSCLC, wildtype TrkB has been shown to promote lung adenocarcinoma metastases and TrkB expression was associated with worse survival in multiple LC subtypes. Thus, we

HYPOTHESIZE
that paracrine BDNF/TRKB activation is also a mechanism whereby subsets of non-NTRK rearranged LC cells can colonize the brain. We investigated TrkB expression levels in murine (CMT167) and human (LU65, H358, PC9BR3, H2030BR3) LC cell lines and their ability to form BM in mouse models. TrkB expression varied among cell lines, with brain metastases incidence of 20% (CMT167), 50% (PC9BR3), 64% (H358) and 75% for H2030BR3. While all cells responded to BDNF stimulation activating AKT, ERK and PLCg signaling, H358 and H2030BR3 cells showed faster and stronger TRKB activation. Stimulation with astrocyte-conditioned media (Ast-CM) or coculture with astrocytes, activated TrkB and promoted proliferation and invasion of LC cells. Entrectinib, an FDA-approved drug for NTRK fusion-positive solid tumors, decreased BDNF and Ast-CM-induced TrkB activation and proliferation, particularly in models with increased BDNF-dependency. Importantly, co-culture of a subset of LC cells with astrocytes renders them less sensitive to Entrectinib, suggesting that additional survival mechanisms contribute to LC cell fitness in the brain niche. Ongoing studies interrogate the effectiveness of Entrectinib to decrease early and late brain metastatic progression in LC. These studies suggest that targeting TrkB could impact LC therapy even in tumors lacking NTRK rearrangements
OCTS-04 TRIAL IN PROGRESS: PHASE II STUDY OF PRE-OPERATIVE HYPOFRACTIONATED STEREOTACTIC RADIOSURGERY FOR RESECTABLE BRAIN METASTASES
Authors: Oliver Daniel , Tran Nam , Ahmed Kamran , DeJesus Michelle , Liu James , Furlan Andre Beer , Kim Jongphil , Farinhas Joaquim , Vogelbaum Michael , Booth-Jones Margaret , Etame Arnold , Yu Michael 
Published: August 2024

Abstract

BACKGROUND
The current standard of care for limited resectable brain metastases is surgical resection followed by post-operative single-fraction stereotactic radiosurgery (sfSRS) to the resection cavity. Recent retrospective studies showed that pre-operative SRS improves tumor bed control and nodular leptomeningeal disease, but prospective data are lacking. We hypothesize that hypofractionated stereotactic radiosurgery (hfSRS) delivered pre-operatively to resectable brain metastases will result in improved durable local control.

METHODS
This is a single institution phase II study to assess time to local failure in patients with resectable brain metastases (BM) who elect for hfSRS followed by resection. The intervention is hfSRS delivered to a BM designated for resection. The planned target volume for hfSRS is the enhancing tumor + 1-2 mm margin expansion. The dose prescription is 9 Gy per fraction for a total of 3 consecutive daily fractions, to a total of 27 Gy. Surgical resection is planned within 7 days following completion of hfSRS. Other BMs, if present, are treated concurrently with either sfSRS or hfSRS. Key eligibility criteria include patients with at least 1 BM between 1 cm and 6 cm in maximal dimension not previously treated with SRS, deemed resectable by neurosurgery, and are asymptomatic from BM with or without steroids. The primary endpoint is time to local failure at the resection cavity. Other endpoints include time to leptomeningeal disease, changes in neurocognitive function, changes in quality of life (QoL), intracranial distant control, and overall survival. Time-to event outcomes will be analyzed with Kaplan-Meier curves. Changes in neurocognitive function and QoL metrics will be analyzed using descriptive statistics. This study is currently open with 34 patients enrolled at the time of submission. Clinical trial information: NCT05267587
OCTS-08 MRI SCREENING FOR BRAIN METASTASES AMONG PATIENTS WITH TRIPLE NEGATIVE OR HER2+ STAGE II OR III BREAST CANCER: A MULTI-CENTRE, SINGLE ARM PHASE II CLINICAL TRIAL – THE INSIGHT TRIAL
Authors: Fernandes Italo , Watson Geoffrey , Cescon Dave , Mahler Mary , Brezden-Masley Christine , Soliman Hany , Jerzak Katarzyna 
Published: August 2024

Abstract

BACKGROUND
The incidence of asymptomatic brain metastasis (BrM) among patients with early-stage HER2+ and Triple Negative (TN) breast cancer (BC) is not well understood. Our goal is to determine the proportion of patients with stage II or III HER2+ or TN BC who have asymptomatic BrM identified on a screening contrast-enhanced MRI of the brain in a prospective clinical trial.

METHODS
A phase II, single-arm, multi-centre, conducted in Ontario, Canada (NCT06247449). One hundred patients (50 with HER2+ and 50 with TN disease) are being recruited over 24-months. Key inclusion criteria: i) age ≥18; ii) HER2+ or TN BC (2018 ASCO/CAP guidelines); iii) stage II or III disease. Key exclusion criteria: i) symptoms suggestive of BrM which would otherwise require imaging; ii) known asymptomatic BrM; iii) pregnancy. Patients will undergo a contrast-enhanced MRI of the brain (or contrast-enhanced CT if MRI is not possible), blood collection for ctDNA analysis, and completion of the Testing Morbidities Index (TMI) questionnaire within 4 weeks of recruitment. Interventions must be performed within 12 months of original BC diagnosis and within 6 weeks of starting post-operative adjuvant therapy. Co-primary endpoints: i) the proportion of eligible patients with stage II or III HER2+ BC who have asymptomatic BrM, and ii) the proportion of eligible patients with stage II or III TN BC who have asymptomatic BrM. Secondary endpoints: the proportion of patients who are approached about the study who agree to enroll; patients’ acceptability of the brain imaging as evaluated by the TMI; and the proportion of patients who have subsequent brain MRIs after the initial trial MRI. The association of baseline clinical, tissue-based, and ctDNA based biomarkers with the presence of asymptomatic BrM at initial staging and with future development of BrM at 1-year, 2-year and 3-years (captured by chart review) will also be assessed.
RADT-08 IMPACT OF ELEKTA LIGHTENING OPTIMIZER ON DOSIMETRIC AND CLINICAL OUTCOMES FOR INTACT LUNG AND BREAST METASTASES USING GAMMA KNIFE RADIOSURGERY
Authors: Yeoh Desmond , O’Carroll Kyle , Lima Jason , Calugaru Emel , Sreenivasan Sanjeev , Chitti Bhargava , Schulder Michael , Goenka Anuj 
Published: August 2024

Abstract
In 2022, we incorporated the Lightening optimizer software into our Gamma Knife treatment planning workflow. This allows for the rapid generation of treatment plans based on user selected parameters. We aimed to compare plans used for treatment before and after incorporation of the optimizer on patients with intact breast and lung metastases to identify dosimetric differences (gradient index, selectivity index, and coverage) and clinical outcomes (radionecrosis and local control). We also subdivided lesions by size, defining small as &lt;1cc, medium as 1 to 4 cc, and large as &gt;4 cc. We identified 317 metastases that were treated before Lightening and 284 metastases that were treated after Lightening. Using independent sample t-tests, we found that plans had a higher gradient index (p=&lt;0.001), higher selectivity index (p=0.031), and similar coverage (p=0.082) following incorporation of the Lightening software. ANOVA demonstrated that both tumor size and Lightening influenced the gradient and selectivity indices. After size stratification, we found that only small lesions had different gradient indices and only medium lesions had different selectivity indices between pre- and post-Lightening groups. Before investigating clinical outcomes, we removed lesions that did not have at least a 9 month follow up, reducing pre- and post-Lightening cases to 106 and 90 respectively. Cox regressions showed that there were no significant differences in local failure rates (p=0.871) and radionecrosis (p=0.202) between pre- and post-Lightening plans. Interestingly, there was a marginally insignificant increase in the likelihood of radionecrosis for small lesions planned with Lightening (HR=7.75, p=0.062). Since the gradient index was also increased in small lesions for Lightening plans, this might indicate a clinically valuable correlation. Overall, these results suggest that while there were dosimetric differences between plans, clinical outcomes did not change. However, attention should be placed on small lesions to better understand the impact of gradient index on radionecrosis.
RADT-11 PREDICTING BIOPSY RESULTS OF ENLARGING BRAIN METASTASES FOLLOWING STEREOTACTIC RADIOSURGERY
Authors: Gonzalez Ariel , Haskell-Mendoza Aden , Reason Ellery , Jackson Joshua , Wang Chunhao , Vaios Eugene , Bradbury Claire , Zhao Jingtong , II James Herndon , Fecci Peter 
Published: August 2024

Abstract
Stereotactic radiosurgery (SRS) is the standard of care for initial management of brain metastases (BM) and provides excellent local control with reduced incidence of adverse neurocognitive effects. However, radiographically progressive lesions post-SRS pose a key clinical challenge, as imaging characteristics cannot effectively distinguish between local recurrence (LR) and radiation necrosis (RN). A retrospective analysis was performed on patients receiving SRS treatment for BM between 2011-2022 and who subsequently underwent biopsy alone or in combination with laser interstitial thermal therapy for suspicion of LR vs RN on imaging. Patient demographics, clinicopathologic characteristics, SRS treatment parameters, and biopsy results were collected. The study included 145 patients with 151 progressive lesions biopsied after SRS treatment. The median age at biopsy was 62 (range: 27-92), with lung being the most prevalent primary site (84 cases, 57.9%). Post-SRS biopsy confirmed 92 lesions (61.3%) with RN, 58 (38.7%) with LR, and 1 biopsy result was missing. The median duration from SRS to biopsy was 13 months (range: 3-81), with a median prescribed SRS dose of 20.0 (range: 14.0-30.0) Gy. Of the lesions, 70.3% received unfractionated SRS, while 29.7% received fractionated SRS. Univariate analyses demonstrated that breast primary (vs. lung, P = 0.027, vs. skin, P = 0.012) and receipt of biopsy ≥ 9 months following SRS (P = 0.0062) were associated with lower odds of LR, while fractionation or prescribed SRS dose were not predictive. The association of biopsy timing ≥ 9 months with lower odds of LR remained significant on multivariate analyses (P = 0.0065). The natural history of LR and RN differ such that for patients presenting with an enlarging lesion ≥ 9 months post-SRS, radiation necrosis should be suspected over local tumor recurrence. Multi-disciplinary oncology teams should consider adjusting treatment for lesions progressing prior to this timepoint.