Citations

Abstract Glioblastoma (GBM) is a lethal, treatment-resistant brain cancer characterized by diffuse brain invasion, complex neuron-glioma signaling, and cellular, molecular, and spatial heterogeneity. Surgery is the current mainstay of treatment, aimed at maximizing tumor cytoreduction, decompressing the brain to improve neurological function, and providing material for analyses to inform prognostication and adjuvant treatment selection. To accurately model GBM surgical resection and tissue sampling in preclinical animal models, we developed the Maximal Safe Intracranial Surgery (MSIS) system. MSIS integrated a miniaturized neurosurgical resection device and enabled a safe, tunable, and reproducible approach for intracranial tumor resection, multi-regional biopsy, and longitudinal tissue sampling in murine models, with stereotactic, sterile, and high-viability tissue collection. MSIS was applied across five distinct orthotopic brain tumor models to reproducibly generate histologically and radiologically representative models of post-surgical GBM. Similar to humans, increasing the extent of resection correlated with improved animal survival, and recurrent growth patterns varied significantly by model type. Transcriptional profiles of matched primary vs. post-surgical recurrent tumors revealed enrichment of margin-associated transcriptional states consistent with neuron-glioma signaling. Overall, the MSIS system offers opportunities to model the standard-of-care, dissect the spatial and temporal dynamics of GBM, and pair therapeutic discovery with contextual tumor pathobiology.

Background: Incidental thyroid nodules (ITNs) detected on nonthyroid imaging contribute to thyroid cancer overdiagnosis, largely through downstream evaluation initiated by thyroid ultrasound (TUS). However, TUS follow-up rates for ITNs and their drivers in routine practice remain unclear. We quantified TUS utilization after ITN detection and identified patient, imaging, nodule, and reporting factors associated with this first step in the diagnostic cascade. Methods: We conducted a retrospective cohort study of adults without prior thyroid disease who underwent imaging that incidentally captured the thyroid at Mayo Clinic sites (2017–2023). A validated natural language processing pipeline identified ITNs and extracted nodule characteristics from radiology reports across multiple imaging modalities. The main outcome was the rate of TUS within 180 days after ITN detection. Clinical outcomes, including thyroid biopsy, thyroidectomy, and thyroid cancer diagnosis, were compared between patients who underwent TUS and those who did not. Factors associated with TUS utilization were assessed using multivariable logistic regression with penalized variable selection. Results: Among 115,683 patients who underwent thyroid-capturing imaging, 8426 (7.3%) had an ITN. These patients were predominantly female (64.6%) and White (89.7%), with a mean age of 61.7 years (standard deviation 15.2). Most nodules were detected on computed tomography (80.8%), most commonly from chest imaging (52.3%). Overall, 1677 patients with ITNs (19.9%) underwent TUS. In multivariable analysis, TUS use was independently associated with higher body mass index (odds ratio [OR], 1.20 per 10-unit increase; confidence interval [CI] [1.08–1.33]), nodule size ≥1.5 cm (OR, 1.79; CI [1.52–2.10]), and a radiologist recommendation (OR, 2.51; CI [2.12–2.98]), whereas older age was associated with lower odds of TUS (OR, 0.89 per 10-year increase; CI [0.84–0.93]). Patients undergoing TUS had higher rates of thyroid biopsy, partial thyroidectomy, and total thyroidectomy compared with those without it. All detected thyroid cancers (103 cases) occurred in the TUS group, representing 6.1% of that cohort. Conclusions: One in five patients with ITNs underwent TUS, representing a critical gateway to downstream diagnostic procedures and thyroid cancer detection. Factors associated with TUS utilization highlight opportunities to better define appropriateness of ultrasound after incidental nodule detection and to reduce unnecessary testing and treatment.

Abstract Purpose: Inhibitors of the Ataxia telangiectasia and Rad3-related (ATR) protein kinase, a critical component of the DNA damage repair response, have synergistic anti-cancer activity with platinum compounds in preclinical models. We therefore conducted a Phase 2 study of the ATR inhibitor berzosertib+carboplatin vs. docetaxel+carboplatin in metastatic castration-resistant prostate cancer. Patients and Methods: Patients previously treated with at least one androgen receptor pathway inhibitor and taxane underwent mandatory biopsy and were randomized 1:1 to receive Arm A (docetaxel 60 mg/m2+carboplatin AUC4 day 1; or carboplatin AUC5 if not a docetaxel candidate) or Arm B (berzosertib 90 mg/m2 days 2,9+carboplatin AUC5 day 1) every 21 days. The primary endpoint was overall response rate (ORR; ≥50% PSA decline or radiographic response). Results: Of 73 randomized patients, 65 received protocol treatment: 34 on Arm A (26 docetaxel+carboplatin; 8 carboplatin alone) and 31 on Arm B. Thirteen patients (38%) in Arm A and 20 (65%) in Arm B had ≥Grade 3 treatment-related adverse events (TrAEs). ORR was 15% in Arm A (5/34; 5/26[19%] with docetaxel+carboplatin) and 0% in Arm B (0/31). At interim analysis after 65 of planned 130 patients were treated, enrollment was halted due to futility. Homologous recombination repair deficiency status from tissue and blood did not correlate with clinical outcomes, but ATM-deficiency or high levels of phoshpo-KAP1 detected in tissue was associated with clinical benefit across both arms of the trial. Conclusions: Berzosertib+carboplatin demonstrated lower ORR and more frequent ≥grade 3 TrAEs compared to docetaxel+carboplatin in this heavily pre-treated, biomarker-unselected population. NCT03517969

Cardiovascular disease causes the largest number of deaths across the world. The weak regenerative ability of adult hearts originates from limited cell proliferation and polyploidization of postnatal cardiomyocytes, which severely hinders tissue repair after myocardial injury. Fetal development represents a critical window during which maternal physiological and metabolic status can shape long-term offspring cardiac structure and function. Maternal exercise represents a safe nonpharmacological prenatal intervention that confers long-term benefits to offspring health. Available evidence indicates that maternal exercise enhances placental apelin secretion and elevates α-ketoglutarate (α-KG) levels in fetal brown adipose tissue, liver, and skeletal muscle. The apelin and α-KG signaling cascade participates in epigenetic regulation and confers protective effects on offspring metabolic health. Independent animal experiments have further validated that supplementation with either apelin or α-KG alleviates myocardial infarction (MI)-induced cardiac injury in adult mice, with α-KG showing direct evidence of reactivating cardiomyocyte proliferation. Nevertheless, it remains poorly elucidated whether maternal exercise could modulate fetal cardiomyocyte proliferative capacity in offspring through apelin- or α-KG-associated signaling. This narrative review integrates current evidence and proposes a testable framework in which maternal exercise influences fetal cardiac growth and regenerative potential through placental, metabolic, and epigenetic signaling. Because direct evidence remains limited, this model should be regarded as a hypothesis that requires further experimental validation.

Abstract Introduction: Next generation of Theranostics studies are looking at novel combinations with radiation sensitizers to enhance PRRT’s efficacy. Here, we present safety and efficacy data from a multi-center phase 1 study of a [¹⁷⁷Lu]lutetium-dotatate -triapine combination in patients with GEP-NETs. Methods: The study consisted of two phases (dose escalation and expansion) administering the recommended phase 2 doses (RP2D) for the two agents. All patients received 200 mCi of [¹⁷⁷Lu]lutetium-dotatate on day 1 of four 8-week cycles, in combination with oral triapine administered at assigned dose levels (100 mg, 150 mg or 200mg) from days 1 to 14 of each cycle. Results: A total of 31 (A: 15 ; B: 16 ) patients received treatment. Nine patients experienced dose-limiting toxicities; Grade 3 anemia (n=1), Grade 5 cardiac arrest (n=1), and Grade 4 neutropenia (n=7). Based on the overall safety and pharmacokinetics data, a [¹⁷⁷Lu]lutetium-dotatate (200 mCi) plus triapine (150 mg) dose was selected as the RP2D for the expansion phase. Grade ≥3 treatment related adverse events were observed in 77% patients: anemia (23%), nausea and vomiting (3% ), lymphopenia ( 58%), neutropenia ( 35%) and leukopenia ( 39%). The majority of cytopenias were transient and resolved within two weeks. Among the 28 evaluable patients, the objective response rate (ORR) was 21.4% and the median progression-free survival (mPFS) has not been reached (median follow-up period: 23.7 months). Conclusions: The combination of [¹⁷⁷Lu]lutetium-dotatate (200 mCi) and oral triapine (150 mg D1-14) was well tolerated and demonstrated preliminary activity in patients with well-differentiated GEP-NETs. (NCT04234568).

Abstract Cancer outcomes vary widely between individual patients, each accumulating an irregular record of treatments, diagnoses, measurements, and complications. Current prognostic models reduce this complexity into a single snapshot, focus on narrow clinical settings, and rarely generalize across hospitals. Here we introduce Chronicle , an explainable transformer that learns from entire patient trajectories to predict diverse clinical outcomes throughout the disease course while capturing both short- and long-term temporal dependencies. Trained on 53.7 million longitudinal data points from 51,711 patients spanning 67 cancer types, Chronicle operates natively on irregular data without imputation and jointly predicts eight endpoints within a flexible framework adaptable to additional outcomes. Chronicle outperformed cross-sectional models for overall survival prediction (C-index 0.84 vs 0.76-0.79), stratified patients more accurately than established prognostic systems, including TNM stage, and predicted seven adverse event and transfusion endpoints (AUC 0.80-0.92). Applied without retraining to 69,341 patients in Germany, Switzerland, and the United States, Chronicle generalized across healthcare systems and improved further with local fine-tuning. Integrated explainability traced each risk update to patient-specific clinical factors, revealing distinct temporal persistence of prognostic information, with relevance half-lives ranging from weeks for therapies to nearly one year for baseline characteristics. These findings demonstrate that learning from hospital-wide patient trajectories enables interpretable and continuously updated predictions, providing a scalable framework to support individualized treatment decisions.

ABSTRACT Aims Metabolic dysfunction‐associated steatotic liver disease (MASLD) is increasingly linked to cognitive decline, yet the hepatic factors associated with imaging‐derived neurovascular coupling (NVC) remain unclear. This study aimed to investigate whether liver stiffness or liver fat content was more closely associated with resting‐state CBF‐ReHo surrogate measures. Materials and Methods A total of 130 participants including 98 MASLD patients and 32 age‐ and education‐matched healthy controls (HCs) underwent clinical assessment, neuropsychological testing, and multi‐modal MRI. Liver stiffness and fat content were quantified using MR elastography (MRE) and MRI‐proton density fat fraction (PDFF). Imaging‐derived NVC was assessed using global cerebral blood flow (CBF)‐regional homogeneity (ReHo) coupling and voxel‐wise CBF/ReHo ratios, interpreted as resting‐state surrogates rather than direct stimulus‐evoked NVC. Multivariable regression and exploratory mediation analyses were employed. Results Compared to HCs and patients with lower liver stiffness (MASLD_low), those with higher liver stiffness (MASLD_high) showed reduced global CBF‐ReHo coupling and altered CBF/ReHo ratios, primarily localized to the bilateral superior temporal pole/superior temporal gyrus (TPOsup). In multivariable regression, liver stiffness remained independently associated with TPOsup CBF/ReHo ratios ( p < 0.001). Exploratory mediation analysis showed a statistically significant indirect association between hepatocellular injury markers and TPOsup CBF/ReHo ratios involving MRE‐derived liver stiffness (95% CI: 0.0795–0.2790). Conclusions Within this cohort and the observed PDFF range, MRE‐derived liver stiffness was more closely associated with imaging‐derived NVC surrogate measures than liver fat content in MASLD. These findings are hypothesis‐generating and require validation in longitudinal studies.