PURPOSE:Incorporating Cherenkov imaging can improve radiation therapy treatment verification through both real-time monitoring and retrospective analysis of beam delivery. In bilateral breast radiation therapy, a medial gap between opposing beams is intentionally planned to avoid unwanted overlap in the midline region. We present the first in vivo analysis of Cherenkov images from bilateral breast radiation therapy. METHODS AND MATERIALS:All patients were treated with a single-isocenter, 3-dimensional conformal plan using a deep-inspiration breath-hold technique. Cherenkov emissions were recorded with a ceiling-mounted camera. Optical phantom experiments were conducted to identify an appropriate imaging thresholding method. The minimum distance across the medial gap was measured using the Cherenkov imaging data for 3 patients recorded across a total of 23 treatment fractions. RESULTS:Analysis of the Cherenkov beam footprints demonstrated a discernible gap for all delivered fractions. The average minimum gap size computed in each of the patient treatment plans was 1.1 cm, 1.0 cm, and 2.0 cm. The average minimum gap size for each patient during radiation therapy measured with Cherenkov imaging was 1.0 ± 0.4 cm, 0.9 ± 0.2 cm, and 2.0 ± 0.6 cm, respectively. Intrapatient gap size variability is thought to be because of patient breath-hold differences across sessions. CONCLUSIONS:This study provides the use of Cherenkov imaging to verify the daily medial field gap in bilateral breast radiation therapy patients. Regular offline review of these images could enable direct feedback to the treatment team in cases of potential field overlap, while also reducing the need for radiochromic film or detector-based in vivo dosimetry.

e13101 Background: As systemic therapy improves, the prevalence of breast cancer brain metastases(BCBM) is increasing. Current National Comprehensive Cancer Network(NCCN) guidelines do not recommend breast cancer brain MRI surveillance unless suspicious central nervous system(CNS) symptoms are present. We sought to understand the presentation and outcomes of BCBM by subtype. Methods: Breast cancer patients who developed brain metastases(BM) at our institution between 2015 and 2025 were identified. Details of initial presentation, treatments delivered and overall survival(OS) were assessed. Kruskal-Wallis and Pearsons's chi-square tests were used to test differences between subtypes. OS was calculated from dates of initial BM diagnosis using the Kaplan-Meier method. The Cox proportional hazards model was used for multivariate analysis (MVA) to identify variables prognostic for OS. Results: A total of 426 patients were identified including 176(41%) hormone receptor (HR)+/HER2-, 133(31%) HER2+, and 117(27%) triple negative (TN). HER2+ patients were younger at initial presentation (HER2+ median age: 55, TN: 56, HR+/HER2-: 57, p = 0.03). TN patients had the shortest interval from stage IV diagnosis to BM diagnosis (TN median: 10.4 months, HER2+:12.6 months, and HR+/HER2-: 16 months, p = 0.0005) and cancer diagnosis to BM diagnosis (TN median: 26.8 months, HER2+: 27.8 months, and HR+/HER2-: 54.7 months, p < 0.0001). The median lines of therapy in the stage IV setting at BM diagnosis were HER2+:1, TN:2, and HR+/HER2-:3, p < 0.0001. TN patients were most likely to present without evidence of systemic metastases (TN:25.6%, HER2+:19.6% and HR+/HER2-:13.1%, p = 0.02). TN patients were less likely to have liver metastases at the time of their diagnosis (TN:19%, HER2+:44% and HR+/HER2-:44%, p < 0.0001). TN patients were more likely to undergo surgical resection at the time of their BM diagnosis(TN: 28%, HER2+:22%, HR+/HER2-:16%, p = 0.05) while HER2+ patients were more likely to present with > 20 BM at diagnosis (HER2+:21%, TN:11%, HR+/HER2-:10%, p = 0.04). Median OS following BM diagnosis was 38.1, 11.6 and 9.1 months, p < 0.0001, for HER2+, HR+/HER2- and TN subtypes. On MVA, TN subtype(p < 0.0001), presence of leptomeningeal disease(p = 0.0007), presence of > 20 BM(p = 0.0013), > 2 lines of systemic therapy (p < 0.0001), and symptomatic intracranial presentation(p = 0.004) were significant for worse OS following BM diagnosis. Conclusions: Our institutional analysis found significant differences in presentation of brain metastases by breast cancer subtypes, with TN patients presenting earlier in their diagnosis and undergoing surgical resection more commonly. On MVA, > 20 brain metastases, leptomeningeal disease, and symptomatic presentation predicted for worse OS. These findings potentially support early brain MRI surveillance to facilitate detection.

TPS1160 Background: The incidence and prevalence of breast cancer patients who develop brain metastasis is increasing. Intracranial surveillance of asymptomatic stage IV breast cancer patients with brain MRIs is not currently recommended by the National Comprehensive Cancer Network (NCCN) Guidelines. In a previously conducted phase II brain MRI surveillance trial, approximately 25% of patients with stage IV breast cancer, independent of tumor subtype, were found to have newly detected brain metastases on the 6-month follow-up MRI from study entry. Methods: The study is designed as a randomized phase III, multi-institutional prospective trial evaluating the role of surveillance brain MRIs in neurologically asymptomatic patients with metastatic breast cancer, based on subtypes (triple negative (TN), HER2+, and hormone receptor (HR)+ breast cancer). Following study enrollment, patients will be randomized in a 1:1 fashion to surveillance brain MRIs at baseline and q6 months for 24 months compared to a baseline MRI followed by standard-of-care brain MRI surveillance for symptomatic presentation. Newly diagnosed stage IV patients (within ≤ 60 days of starting systemic therapy for HER2+ or TN or within ≤ 60 days of initiating 1 st or 2 nd line therapy for HR+/HER2- disease) with an ECOG ≤ 2 and life expectancy ≥ 6 months are eligible. The primary objective is to evaluate the treatment characteristics of brain metastases diagnosed via brain MRI surveillance or standard of care imaging. Secondary objectives include the frequency of asymptomatic brain metastases and leptomeningeal disease, the number and size of brain metastases at diagnosis, quality of life, and overall and brain metastases specific survival following brain metastasis diagnosis in patients randomized to brain MRI surveillance compared to standard of care imaging. A total of 156 patients will be enrolled with an equal distribution of TN, HER2+, and HR+/HER2- subtypes, respectively. Funding: Florida Department of Health. Clinical trial information: NCT07357298 .

Meningiomas are the most common primary tumors of the central nervous system. While standard-of-care treatment—surgical resection and/or radiotherapy—is effective for most patients, a subset of tumors progress despite these interventions. To identify novel therapeutic targets, we generated single-cell transcriptomic atlases of WHO grade 1 and 2 meningiomas. This analysis revealed multiple tumor cell states and highlighted robust activation of the Insulin-like Growth Factor 2–Insulin-like Growth Factor 1 Receptor (IGF2–IGF1R) signaling axis, a key regulator of cell metabolism and growth. Inhibition of IGF1R in fresh patient-derived 2D cultures and ex vivo explant models suppressed tumor cell proliferation. Based on these findings, a patient with a rapidly progressing, IGF2–IGF1R–expressing grade 2 meningioma—previously treated with radiotherapy—was administered Ceritinib, an IGF1R inhibitor. While the tumor had been growing at a rate exceeding 1 mm/month prior to treatment, no further growth was observed after two months of Ceritinib therapy. In summary, we identified IGF2–IGF1R signaling as an active and targetable pathway in meningioma. Ceritinib demonstrated both preclinical efficacy and promising early clinical activity in a case of radiotherapy-resistant recurrent meningioma. To our knowledge, this represents the first report of clinical efficacy of Ceritinib in meningioma.

Background: For most patients who undergo lumpectomy, adjuvant radiation therapy is standard of care (SOC) following surgery. There is an increasing emphasis on de-escalation or omission of radiotherapy, for which achieving the most complete tumor resection is particularly critical to minimize the risk of recurrence. When used as an adjunct to standard lumpectomy, the LumiSystem has been shown to remove residual cancer missed by the initial surgery and reduce the rate of positive margins. We evaluated whether eligibility for de-scalation or omission of radiotherapy changed based on the LumiSystem intervention. Methods: In this prospective trial, we assessed margin status with and without LumiSystem-guided surgery for patients with stage 0-3 breast cancer. After surgeons completed their standard lumpectomy procedure, patients were randomly assigned 10:1 to receive further LumiSystem-guided surgery for positive signal or not. For patients randomized to the LumiSystem intervention, eligibility for de-escalation or omission of radiotherapy, both after standard lumpectomy and after LumiSystem intervention, were retrospectively determined based on eligibility criteria from RTOG 9804, CALGB 9343, PRIME II, LUMINA, IDEA, BR007/DEBRA and the 2024 ASTRO Partial Breast Irradiation Guidelines. According to these criteria, the population of interest included only patients >49 yr. with various tumor characteristics intended to identify lower risk patients. Results: 357 patients received LumiSystem-guided surgery, and a retrospective chart review was performed by two independent breast specialized radiation oncologists for the 166/357 (46.5%) patients that had additional LumiSystem-guided excisions taken after standard lumpectomy. 133/166 (80.1%) patients reviewed had negative margins after standard lumpectomy and 77/166 (46.4%) patients (age: median - 66 yr., range - 51-82 yr.) were eligible for omission of radiotherapy after standard lumpectomy based on the aforementioned eligibility criteria. 9/77 (11.7%) patients (age: median 51 yr., range 51-77 yr.) who were eligible for omission of radiotherapy following standard lumpectomy had residual tumor removed in subsequent LumiSystem-guided excisions. These residual tumor deposits included grade 3 histology and ranged from 1-11mm in size. 33/166 (19.9%) patients had a positive margin after standard lumpectomy, and 9/33 (27.3%) of these patients were converted to negative margins intraoperatively by LumiSystem-guided wider negative margins. 3/33 (9.1%) of these patients (age: median - 57 yr., range 54-73 yr.) with positive margins after standard lumpectomy had a change in eligibility for omission of radiotherapy based on LumiSystem-guided wider negative margins, and 2/33 (6.1%) patients also became eligible for smaller volumes of accelerated partial breast irradiation. Discussion: LumiSystem-guided surgery altered radiation therapy recommendations in a subset of patients. Among patients eligible for omission of adjuvant radiotherapy based on SOC negative margins, identification of fluorescence in the lumpectomy cavity resulted in removal of unsuspected residual tumor. These findings support the notion that those patients who historically have recurred without radiotherapy may have had residual disease left behind after standard lumpectomy. Using LumiSystem as an adjunct to standard lumpectomy may lead to the potential of the reducing targeted volume of radiation therapy and the option to omit radiation in additional patients. Long-term follow-up data is needed to determine if the risk of local recurrence is lower in patients undergoing LumiSystem-guided surgery, particularly in those who are candidates for radiation omission. Citation Format: Simona Shaitelman, Roberto Diaz, Brian Schlossberg, Manna Chang, Kate Smith, Jorge Ferrer, Kelly K. Hunt, David Carr, Peter Blumencranz, E. Shelley Hwang, Irene Wapnir, Barbara L. Smith. LumiSystem-guided lumpectomy enables informed customization of radiation therapy in select patients with breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-09-13.

BACKGROUND:Screening of asymptomatic stage IV breast cancer with brain MRIs is currently not recommended by National Comprehensive Cancer Network Guidelines. The incidence of asymptomatic brain metastasis is not well documented. METHODS:The study is designed as a single-arm, phase II trial, with the goal of investigating surveillance brain MRIs in neurologically asymptomatic patients with metastatic breast cancer. Breast cancer patients were classified into triple-negative (TN), HER2+, and hormone receptor (HR)+/HER2-. Patients underwent a surveillance brain MRI and a second brain MRI at 6 months if the baseline MRI was negative. Asymptomatic, stage IV breast cancer patients, ECOG ≤ 2, and life expectancy ≥ 6 months were eligible. The primary objective was to determine the frequency of asymptomatic brain metastasis in metastatic breast cancer. Clinical trial information: NCT05115474. RESULTS:A total of 101 patients completed the surveillance brain MRI including 40 HR+/HER2-, 33 HER2+, and 28 TN patients. The overall frequency of brain metastasis on initial surveillance brain MRI was 14% (n = 14) with rates of 18%, 15%, and 10% in TN, HER2+, and HR+/HER2- patients, respectively. Following the 6-month MRI, the cumulative rates of brain metastasis increased to 25% in TN, 24% in HER2+, and 23% in HR+/HER2- patients. CONCLUSIONS:The highest frequency of brain metastases at baseline was in TN and HER2+ breast cancer. Following the 6-month MRI, the cumulative frequency was approximately a quarter across all subtypes. These results warrant confirmatory trials to refine brain MRI surveillance recommendations for neurologically asymptomatic stage IV breast cancer.

2064 Background: Phase II, propensity-matched trial, to assess feasibility and toxicity of adding Metformin (MTF) to neo-adjuvant, concomitant and adjuvant Temozolomide (TMZ) and hypofractionated accelerated radiotherapy (M-HART), for patients with Glioblastoma (GBM). We compared median survival time (MST), and progression-free-survival (PFS) of M-HART versus a contemporaneous cohort of propensity-score matched controls (PSMC) who received standard of care (SOC). Methods: Eligible patients were ≥ 18 years with newly diagnosed GBM, ECOG score ≤ 2, with known MGMT status, gross total or partial resection, and residual surgical cavity > 15 mm from brainstem, or optic apparatus. Four weeks from surgery, M-HART patients started 2 weeks of neo-adjuvant MTF/TMZ followed by concomitant MTF/TMZ + HART 60 Gy/20 daily fractions, and 6 cycles of adjuvant MTF/TMZ. The PSMC patients received Stupp’s regimen. We used a nearest neighbor matching with a caliper width of 0.2 SD and compared patients’ characteristics using chi-square test (Table). Propensity scores were estimated using logistic regression model, with probability of M-HART treatment as dependent variable. Results: From April 2015 to November 2020, 50 patients participated in the M-HART trial and matched with 50 PSMC cohort treated during the same period, with a median follow up of 24.1 (M-HART) vs 17.6 months PSMC, respectively. M-HART patients had significantly longer MST of 24.1 (95% CI, 15.2- 30.3) vs. 17.7 months for PSMC patients (95% CI, 12-20) (HR, 0.62 [95% CI, 0.40-0.93]; P = 0.02), and significantly longer PFS of 13.7 (95% CI, 11.7 to 18.8) vs. 11.0 months (95% CI, 9-12) (HR, 0.63 [95% CI, 0.42-0.95]; P = 0.02). M-HART treatment was an independent predictor of survival. M-HART patients with methylated-MGMT and gross total resection had significant longer MST of 41.9 vs. 17.8 months for PSMC (95% CI, 15.1-20.5 months) (HR 0.21 [95% CI, 0.09-0.49]; P = 0.001). Conclusions: M-HART protocol is novel, feasible, and well-tolerated approach with significantly longer MST and PFS as compared to propensity-matched SOC controls. These results add to growing evidence for the use of Metformin as an adjunct to HART and TMZ especially in M-MGMT GBM. Clinical trial information: NCT02780024 . Characteristics of M-HART versus propensity-matched standard of care control patients. M-HART N=50 (%) CONTROLS N=50 (%) P-value Age (years)≤ 60> 60 34 (68)16 (32) 27 (54)23 (46) 0.218 SexMaleFemale 22 (44)28 (56) 30 (60)20 (40) 0.161 ECOG-score0-12 43 (84)7 (14) 47 (94)3 (6) 0.318 Surgery Gross Total Subtotal 41 (82)9 (18) 39 (78)11 (22) 0.803 MGMT statusUnmethylatedMethylated 34 (68)16 (32) 29 (58)21 (42) 0.015 Re-operationYesNo 24 (84)26 (52) 18 (36)32 (64) 0.077 Chemotherapy at recurrenceYesNo 14 (28)36 (74) 27 (54)23 (46) <0.001

OBJECTIVE:Synthetic data (SD) is artificially generated information that mimics the statistical characteristics and correlations of real-world data, enabling researchers to simulate variables that are challenging to obtain in routine practice while overcoming confidentiality barriers. This study aims to evaluate the utility, validity, and potential limitations of SD in glioblastoma (GBM) and brain metastases (BM) research. METHODS:Three published neuro-oncology studies focusing on prognostic factors were selected: 2 involving GBM patients and 1 with BM patients. These studies were replicated using the MDClone platform, a healthcare data exploration tool that enables the creation of SD. Real-world data and SD were compared across patient demographic and outcome variables using summary statistics, normality testing, and t-test as required. RESULTS:452 GBM patients and 1320 BM patients were generated with SD. Among GBM patients, longer median overall survival was associated with younger age (age<50: 16.3 months [95% CI: 12.8-19.8]; age 50-59: 15.6 [95% CI: 13.1-18.1]; age 60-69: 13.9 [95% CI: 12.1-15.7]; age>70: 8.8 [95% CI: 7.4-10.2], P < 0.001), greater extent of resection (debulking: 16.8 months [95% CI 14.9-18.7] vs. biopsy: 10.9 months [95% CI: 9.6-12.3], P < 0.001), and higher serum albumin (sAlb) (sAlb<30 g/L: 7.0 months [95% CI: 4.8-9.3]; sAlb 30-40 g/L: 12.9 [95% CI: 11.6-14.1]; sAlb>40: 16.2 [95% CI: 13.4-19.1], P < 0.05). Among BM patients, lower systemic inflammation scores (neutrophil-lymphocyte-ratio, leukocyte-lymphocyte-ratio, platelet-lymphocyte-ratio, monocyte-lymphocyte-ratio, and C-reactive-protein/albumin-ratio) were associated with longer overall survival (P < 0.05). These results aligned with the findings reported in the literature. CONCLUSIONS:Integrating SD into clinical research offers potential for providing accurate predictive insights without compromising patient privacy.

Medulloblastoma (MB), the most common malignant pediatric brain tumor, poses significant therapeutic challenges; current treatments often induce severe long-term morbidities. Sonodynamic therapy (SDT), a non-invasive modality using ultrasound to activate a sonosensitizer for targeted reactive oxygen species (ROS) generation, offers a promising alternative. However, in-vitro SDT models lack standardization and reproducible experimental setups. This study aimed to develop a bench-top model evaluating 5-aminolevulinic acid (5-ALA)-mediated SDT efficacy in the UW426 cell line, assessing ROS production, cell death, and proliferation. UW426 cells (SHH-activated, TP53-mutant) were incubated with 5-ALA (200µg/mL, 24h) to maximize protoporphyrin IX (PpIX) fluorescence. A 1.5MHz focused ultrasound (FUS) transducer (0.91MHz operating) targeted the base of 96-well plates; pressure wave delivery was confirmed by needle hydrophone. Groups included: untreated control, 5-ALA alone, FUS alone, and SDT (5-ALA + FUS). FUS/SDT utilized varied acoustic powers (1W, 3W, 6W) and durations (60s, 90s, 120s). 24h following treatment, intracellular ROS, apoptotic markers, and proliferation were quantified. SDT induced a statistically significant elevation in intracellular ROS levels in UW426 cells versus all controls (p<0.05). This correlated with significantly reduced cell viability and increased apoptotic cell death in the SDT group (p<0.05), demonstrating potent synergistic cytotoxicity. Proliferation was also significantly reduced in the SDT treatment group. Utilizing 6W power and 120s treatment duration yielded the most significant induction of ROS, cell death and decreased proliferation. In this study we demonstrated a reliable bench-top SDT model. The efficacy’s dependence on ultrasound parameters underscores the necessity of optimization and standardization.

Background Neutrophil-to-lymphocyte ratio (NLR) is used in the prognostication of multiple malignancies. However, the NLR value in glioblastoma (GBM) is controversial. This controversy may be due to the unaccounted effect of dexamethasone on NLR. Using retrospective data from 230 isocitrate dehydrogenase-1 (IDH) wild-type GBM patients, we studied the prognostic value of NLR in relation to dexamethasone treatment in GBM.Methods We retrospectively analyzed 230 patients with GBM. NLR and dexamethasone use were used as dichotomous variables with cutoff values of 9.5 and 8 mg, respectively. Correlations between high NLR, as well as NLR change after surgery, and patient outcome measures, including post-surgical complications and survival, were assessed using Kaplan-Meier curves, logistic, and Cox regression analyses.Results We demonstrate in this study that high perioperative NLR (>= 9.5 NLR) does not associate with survival of GBM patients (274 days, 95% confidence interval [CI] 211-337, vs. 229 days, 95% CI 52-406, P = .9). However, high positive change in NLR (>= 6 units) (higher postoperative NLR relative to preoperative NLR) has a significant association with decreased survival in GBM patients (196 days, 95% CI 121-270, vs. 304 days, 95% CI 223-384, P = .01). High preoperative and perioperative average dexamethasone (>= 8 mg) treatment did not change the perioperative NLR trend and were not associated with decreased survival.Conclusions We demonstrate that an increase in NLR after surgery associates with decreased GBM patient survival. The neutrophil-to-lymphocyte ratio (NLR) is a measure of specific blood cells and has been linked to survival in patients with cancers outside of the brain. The authors of this study wanted to see if NLR was also linked to survival in patients with an aggressive brain cancer, called glioblastoma. To do this, they reviewed the medical records of 230 patients with glioblastoma and looked at their NLR levels before and after surgery. They found that patients whose NLR increased after surgery were more likely to have shorter lifespans.

Background We hypothesized treatment with nivolumab and stereotactic radiosurgery (SRS) would be feasible, well tolerated, and may improve intracranial tumor control over SRS alone for breast cancer brain metastases (BCBM).Methods The study is a phase Ib trial of nivolumab and SRS for BCBM. Clinical trial information: NCT03807765. Key eligibility criteria include BCBM of all subtypes, age ≥18, Eastern Cooperative Oncology Group Performace Status (ECOG-PS)≤2 with ≤10 brain metastases. Treatment was initiated with a dose of nivolumab (480 mg intravenously) that was repeated every 4 weeks. The initial dose of nivolumab was followed 1 week later by SRS. Blood was collected at baseline and every 4 weeks for flow cytometry and cell-free DNA (cfDNA) assessment.Results A total of 12 patients received SRS to 17 brain metastases. Breast cancer subtypes included triple negative (50%), hormone receptor (HR)+/HER2− (33%), and HR−/HER2+ (17%). Median follow-up from start of protocol therapy is 56 months. No cases of radionecrosis were noted. Two lesions were noted to undergo local failure, both pathologically confirmed, for a 12-month local control of 94%. Median distant intracranial control was 7.4 months with a 12-month control rate of 33%. Median systemic progression-free survival was 7.7 months with a 12-month rate of 42%. Median overall survival (OS) was 24.7 months with a 12-month OS of 75%. Most patients were noted to have an increase in cfDNA throughout study treatment, at week 5 compared with baseline (83%), week 25 compared with baseline (89%), and 100% at first follow-up. Intracranial control was associated with lower levels of CD4 regulatory T cells (Treg) (p=0.03) and higher levels of CD4 T effector memory (p=0.04).Conclusions Nivolumab and SRS is a safe and feasible treatment option in BCBM. Long-term follow-up revealed no cases of radiation necrosis.Trial registration number NCT03807765.

Isocitrate dehydrogenase 1 (IDH1)-wild type glioblastoma (GBM) constitutes about 12-15% of primary central nervous system tumors. The 5-year survival remains dismal at less than 5% due to the limited options available in the management of GBM patients. Metformin (N, N-dimethyl biguanide), a medication used primarily in the management of patients with type 2 diabetes mellitus, showed anti-proliferative actions in the management of various tumor cells, including GBM. The temozolomide (TMZ)-based genotoxic management of GBM patients elicits DNA damage response (DDR) pathways that limit the efficacy of TMZ and induce resistance. Tumors with a methylated O6-methylguanine-DNA-methyltransferase (MGMT) promoter status may be more dependent on DDR pathways due to the reduced DNA repair capability. Metformin can reinforce an integrative approach in GBM management in conjunction with TMZ by inhibiting several key DDR pathways of metabolism and growth. In addition to inhibition of the mitochondrial complex I, uncoupling glycolysis from oxidative phosphorylation, metformin AMP-activated Protein Kinase (AMPK)-mediated inhibition of Akt signaling can manipulate multiple key metabolic cellular processes. Our commentary proposes that metformin may exert an asymmetrical effect, preferentially inhibiting GBM cells with MGMT promoter methylation, by exploiting differences in metabolism that extend to glycolysis, oxidative phosphorylation, lipolysis, sphingolipid metabolism, and amino acid transport and sensing. We also highlight an emerging role for metformin in epigenetic modification through regulation of homocysteine metabolism and 2-Hydroxyglutarate bioavailability. In this commentary, expanding on our recent study showing that metformin treatment is associated with improved survival in GBM patients with a methylated MGMT promoter, we explore how the targets of metformin in GBM may differ depending on the MGMT methylation status. Our commentary invites a better examination of the action of metformin in GBM and highlights its therapeutic potential in conjunction with the molecular signature of GBM.

Abstract BACKGROUND In-vitro studies have demonstrated that low frequency sound waves can interact with hemo-porphyrin molecule to induce the production of reactive oxygen species. This biophysical phenomenon can induce tumour cell death in glioblastoma cells in-vitro. The purpose of this study was to evaluate the production of reactive oxygen species and expression of apoptotic markers in glioblastoma cells in response to varying total treatment time and ultrasound power using a bench-top focused ultrasound (FUS) device. METHODS U251 cells were exposed to 5-Aminolevulenic Acid (5-ALA) at varying concentrations for up to 24 hours. The time point with peak proto-porphyrin IX (PPIX) fluorescence was established using fluorescence activated cell sorting (FACS). A transducer utilized at 0.91MHz was placed on an inverted stage with the focus targeted to the bottom of a standard 96-well cell culture plate. Pressure wave delivery was confirmed using a hydrophone. GBM cells were treated with 5-ALA alone, FUS alone, or 5-ALA + FUS and the cells were incubated for 24 hours prior to measuring ROS induction and cell death. ROS was measured using FACS with the CellROX Green Kit for Oxidative Stress Detection and Annexin-V was measured using the Dead Cell Stain Kit. RESULTS Peak fluorescence intensity for PPIX in the U251 cell line was found to be induced through incubation with 5-ALA for 24 hours with a concentration 200mg/mL. The fluorescence intensity of PPIX was found to be 313% greater in the treated group compared to the control group. Peak ROS was observed using a 0.91MHz transducer frequency for a total time of 120s with 6W average power. ROS was 61% and 66% greater in the SDT group compared to the FUS and 5-ALA group respectively. CONCLUSION Using this bench-top set up we successfully induced ROS and apoptosis in U251 cells. Establishing a reliable in-vitro model will allow us to further investigate the effects of other sonication parameters such as burst length.

Abstract Background: Our group has previously developed the radiosensitivity index (RSI) using a multigene expression model that is directly proportional to tumor radioresistance (high RSI = increased radioresistance). RSI has been previously validated in two datasets of patients with triple negative breast cancer (TNBC). In this study, we will run a selective dose personalization study in TNBC patients undergoing breast conservation therapy (BCT). Based on patients RSI scores, they will either receive a radiation therapy (RT) boost of 10 Gy to the tumor cavity or not. Given our data in two independent datasets, the current study will reveal the feasibility and benefit of selective genomic dose personalization in TNBC following BCT. Trial Design: The study is designed as a prospective, nonrandomized, phase II trial of genomically guided RT in the management of TNBC undergoing BCT. Patients will be allocated to one of two groups based on their RSI determination from fresh frozen tissue collected by biopsy or at the time of BCT. These groups will be Group A, RSI optimized whole breast radiotherapy alone or with a 10 Gy boost or Group B, RSI not optimized whole breast radiotherapy with a boost of 10 Gy to tumor cavity. Patients will receive standard of care chemotherapy, neoadjuvant or adjuvant. Eligibility: TNBC patients undergoing BCT. Specific Aims: To determine the three-year local control following genomically guided dose personalization in the management of TNBC following BCT. Secondary objectives include determination of overall survival (OS), progression free survival (PFS), and quality of life (QOL) following genomically guided dose personalization. Statistical Methods: The primary hypothesis is the three-year local control rates differ for groups A and B, against the null hypothesis that the two rates are identical. Patients will allocate approximately 78% in group A and 22% in group B and local control rates are expected to be 96% and 75%, respectively. Assuming 80% power and 10% type I error for a log-rank test, 86 patients are needed. An interim analysis will be completed when 4 disease progression events are observed. There will be approximately 43 patients at the time of interim analysis. Patient Accrual: This study is open with 1 patient enrolled at the time of submission. A total of 86 patients will be enrolled. Contact Information: Kamran A. Ahmed MD, Moffitt Cancer Center, email: kamran.ahmed@moffitt.org, Clinical trial information: NCT05115474. Funding: Moffitt and Morton Plant Mease Foundations. Citation Format: Kamran Ahmed, Iman Washington, Matthew Mills, Michelle DeJesus, Youngchul Kim, Ronica Nanda, Javier Torres-Roca, Steven Eschrich, Janis De La Iglesia, John Puskas, Marilin Rosa, Jason Wilson, Paula Lundgren, Negar Golesorkhi, Nazanin Khakpour, Susan Hoover, Marie Lee, John Kiluk, Melissa Mallory, Christine Laronga, Laura Kruper, Brian Czerniecki, Roberto Diaz. Phase II Study of Genomically Guided Radiation Dose Personalization in the Management of Triple Negative Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-20-05.

Background: Synthetic data has garnered heightened attention in contemporary research due to confidentiality barriers and its capacity to simulate variables challenging to obtain. This study aimed to evaluate the reliability and validity of synthetic data in the context of neuro-oncology research, comparing findings from two published studies with results from synthetic datasets. Methods: Two published neuro-oncology studies focusing on prognostic factors such as serum albumin and systemic inflammation scores were selected, and their methodologies were replicated using MDClone Platform to generate five synthetic datasets for each. We used Chi-Square test to assess inter-variability between synthetic datasets. Survival outcomes were evaluated using Kaplan-Meier and t-test was used to determine statistical significance. Results: Findings from synthetic data consistently matched outcomes from both original articles, with serum albumin and systemc inflammation scores correlating with survival prognosis in glioblastoma and metastasis patients (p<0.05) Reported findings, demographic trends and survival outcomes showed significant similarity (P > 0.05) with synthetic datasets. Conclusions: Synthetic data consistently reproduced the statistical attributes of real patient data. Integrating synthetic data into clinical research offers excellent potential for providing accurate predictive insights without compromising patient privacy. In neuro-oncology, where patient follow-up pose challenges, the adoption of synthetic datasets can be transformative.