Citations

Abstract Failure to repair radiation (RT)-induced DNA damage results in cell lethality, and combined treatment with DNA repair inhibitors can markedly enhance tumor control achieved with radiation. These inhibitors also can potentiate acute RT toxicities by suppressing DNA repair. Capitalizing on this normal tissue radiosensitizing effect, we determined effective radiosensitizing dosing regimens in mice for the ATM inhibitor WSD0628 and the DNAPK inhibitor WNC0901 in mice. Drugs were administered via oral gavage prior to each RT dose, and RT was delivered using an anterior/posterior 225 kVp beam. In an initial iteration of this model, various combinations of WSD0628 and RT were administered to cohorts of mice (n=5/group) and body weight was followed for 2 weeks. The resulting data were modeled to define the total dose of radiation estimated to cause 50% of mice to lose >20% body weight (D50). There was an inverse relationship between the WSD0628 and D50 doses: 0 mg/kg WSD0628/24.0 Gy (95% confidence interval (CI) 24.5–24.7); 0.25 mg/kg/19.2 Gy (95% CI 16.7–21.8); 1 mg/kg/13.7 Gy (95% CI 13.2–14.2); 2.5 mg/kg/11.0 Gy (95% CI 10.5–11.5); 5 mg/kg/11.3 Gy (95% CI 6.7–15.9) and 7.5 mg/kg/7.8 Gy (95% CI 7.8–7.9). Histological review of tongues from animals treated with 15 Gy RT (5Gy x 3) + 7.5 mg/kg WSD0628 demonstrated epithelial denudation and acute inflammation consistent with oral mucositis, while these features were not seen with the same dose as RT alone. Similar WSD0628 doses were evaluated in combination with 8 Gy supratentorial RT (via lateral beams) in orthotopic GBM43 PDX tumors. By treatment arm, the median time to a moribund state was: sham (29 days (d)), RT (39d), 1 mg/kg (42d), 2.5 mg/kg (49d), 5 mg/kg (65d), and 10 mg/kg (123d, overall p<0.0001). A second mucositis model was used for evaluation of WNC0901. Cohorts of 5 mice/group were treated with a set dose of RT (4Gy x 3) to the oral cavity alone and in combination with various doses of WNC0901, and the fraction of mice with >20% weight loss within 2 weeks was determined. The results of this study are as follows: placebo (0 of 5 mice with >20% weight loss); 15 mg/kg (3 of 5 mice); 25, 50, or 100 mg/kg (5 of 5 mice). Based on these data, we defined 25 mg/kg WNC0901 as the minimally effective dose and predicted that 50 mg/kg would provide robust radiosensitization. Consistent with this prediction, co-treatment of B16 melanoma flank tumor xenografts with RT (8Gy x 1) and WNC0901 (50 mg/kg) more than doubled the median tumor control duration (median 42 [range 24-45] days; time from implantation for tumor to exceed 1500 mm3) as compared to RT alone (24 [13-30] days) or sham treatment (17 [13-17] days; overall p<0.0001). This study describes how a radiation-induced oral mucositis model can be used to identify effective radiosensitizing regimens faster and with fewer resources than relying on tumor control studies alone. Citation Format: Danielle Burgenske, Darwin Garcia, Jiayan Le, Wenjuan Zhang, Sneha Rathi, Katrina K. Bakken, Lauren L. Ott, Zeng Hu, Brett L. Carlson, Ann Mladek, Jessica L. Abraham, Paul A. Decker, Matthew L . Kosel, Jeanette E. Eckel-Passow, William F. Elmquist, Wei Zhong, Jann N. Sarkaria. Radiation-induced oral mucositis to rapidly determine effective radiosensitizing dosing regimens for ATM and DNAPK inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B090.

Abstract The Guardian table is widely utilized for combined hip arthroscopy and periacetabular osteotomy (PAO) due to its postless traction design and the ability to perform both procedures without the need for redraping. This retrospective cohort study reports one surgeon’s use of the Guardian table extension during combined hip arthroscopy and PAO and the occurrence of intraoperative posterior column fractures. Seventy-two consecutive PAO procedures performed at a single institution between February 2023 and January 2025 were analysed. Procedures involving concomitant hip arthroscopy (n = 26) utilized the Guardian table, whereas those without arthroscopy (n = 46) used a conventional radiolucent table. Patient demographics, clinical data, and complications were reviewed. Additionally, mechanical testing quantified table stability by measuring peak absolute acceleration (‘table bounce’) using accelerometry during simulated malleting. The incidence of intraoperative posterior column fractures was significantly higher with the Guardian table (4/26, 15.4%) compared to the conventional table (0/46, 0%; P = .0062). Mechanical testing demonstrated significantly greater table bounce for the Guardian table (69.1 ± 3.4 m/s2 versus 28.2 ± 4.4 m/s2, P < .001). Patient characteristics and surgical complexity did not differ significantly between fracture and non-fracture cases. These findings suggested that the Guardian table extension system was associated with increased risk of posterior column fractures, likely due to lack of distal support and stability. Surgeons should consider alternative table setups or intraoperative support modifications to mitigate this risk during PAO procedures.

Key Points Serum glycerol-3-phosphate (G3P) levels were significantly associated with higher fibroblast growth factor 23 levels in ESKD. Pathway and mediation analyses identified the pentose phosphate pathway as the top mediator of the relationship between serum G3P and fibroblast growth factor 23. The role of G3P in ESKD provides new insights into potential therapeutic targets for CKD-mineral and bone disorder. Background Fibroblast growth factor 23 (FGF23) is a key regulator of mineral metabolism that is independently associated with mortality in patients with ESKD. Glycerol-3-phosphate (G3P), a byproduct of glycolysis that can be derived from injured kidneys, stimulates FGF23 production. We aimed to determine if serum G3P is associated with FGF23 levels in patients with ESKD and identify potential molecular pathways that mediate their relationship. Methods We conducted a cross-sectional study of 99 nondiabetic patients with ESKD on hemodialysis. We used linear regression to examine the association between G3P terciles and log-transformed C-terminal FGF23 levels, adjusting for demographics, coronary artery disease, serum calcium, phosphorus, and parathyroid hormone. Mann–Whitney U tests compared 247 serum metabolite levels between the first and third FGF23 terciles; significant metabolites ( P < 0.01) were selected for pathway enrichment analyses. Top pathway scores were used in mediation analyses. Results The median age of participants was 54 years (interquartile range [IQR], 44–63), 38% were women, 71% self-identified as Black, and 27% had coronary artery disease. The median FGF23 level was 777 (interquartile range, 222–1310) RU/ml. In adjusted analyses, compared with participants with the lowest G3P tercile, those with the highest G3P tercile had a 95% higher FGF23 level (95% Confidence Interval, 6% to 260%; P = 0.04). Of the 27 metabolites significantly associated with FGF23 levels, pathway enrichment analysis identified the pentose phosphate pathway as the top hit (impact score=0.33, false discovery rate-adjusted P value = 0.01). The pentose phosphate pathway mediated the relationship between G3P and FGF23, resulting in a 62% change in the β coefficient. Conclusions In nondiabetic patients with ESKD on hemodialysis, serum G3P positively correlated with serum C-terminal FGF23, and this relationship was mediated by the pentose phosphate pathway. Exploring the pentose phosphate pathway could yield critical mechanistic insights into the regulation of FGF23, enhancing our understanding of its broader biologic functions.

Abstract BRCA2 mutations contribute to the pathogenesis and treatment sensitivity of a subset of ovarian, breast, prostate, and pancreatic cancers. When these cancers become therapy resistant, secondary mutations that restore the BRCA2 open reading frame are found in half the cases, but other causes of resistance remain incompletely understood. Here, we identified translational readthrough of a premature termination codon (PTC) as a cause of resistance to poly(ADP-ribose) polymerase inhibitors (PARPis) and cisplatin in cells derived from the BRCA2-mutated ovarian cancer line PEO1 by PARPi selection. Despite persistence of the signature 4965C &gt; G (p.Y1655X) BRCA2 mutation, low-level expression of full-length BRCA2 protein was detectable in these cells by immunoblotting and tandem mass spectrometry. Either BRCA2 knockdown or gene interruption 5′ or 3′ to the PTC restored treatment sensitivity, implicating BRCA2 in the resistance. Reporter assays demonstrated UAG-selective readthrough in the resistant clones but not parental cells. Moreover, custom searching of global proteomic data indicated readthrough of stop codons, particularly UAGs, in additional proteins in the resistant clones. Finally, multi-omic analysis identified multiple changes in the nonsense-mediated decay and termination machineries that favor readthrough. Accordingly, the present results identify PTC readthrough as a potential mechanism of drug resistance in cells with BRCA2 nonsense mutations.

PURPOSE Human epidermal growth factor receptor 2 (HER2), a transmembrane receptor with kinase activity involved in cell signaling through the RAS pathway, is expressed in osteosarcoma (OST). Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate with a HER2-targeting monoclonal antibody, trastuzumab, linked to a topoisomerase I inhibitor. We report results of a phase II study of T-DXd in adolescents and young adults with HER2-positive relapsed, unresectable OST (ClinicalTrials.gov identifier: NCT04616560 ). METHODS Patients age 12-39 years with relapsed, unresectable OST were eligible for centrally evaluated HER2 expression screening by immunohistochemistry. Patients with >10% of OST cells with cytoplasmic or membranous HER2 expression of any intensity were eligible to receive T-DXd at 5.4 mg/kg intravenously once every 3 weeks for up to 2 years. The study used a 9 + 15 Simon's optimal two-stage design with a primary end point of event-free survival at 24 weeks. RESULTS Fifty patients were screened for HER2, and 41 met the inclusion criteria of 10% of OST cells having membranous or cytoplasmic HER2 expression. Nine eligible patients, two younger than 18 years, were enrolled and received T-DXd. With a single patient having more than 24 weeks of stable disease (SD) of the nine planned in the first stage, this study did not meet criteria to progress to stage II. The estimated SD rate at 24 weeks is 11.1%. The median (range) number of cycles of therapy was 2 (2-12). Grade 3 and 4 possibly related adverse events occurred in three of nine patients and included nausea, vomiting, tumor hemorrhage, cytopenias (n = 3), wound infection, and hypertension. CONCLUSION T-DXd did not demonstrate sufficient activity to expand enrollment to the planned second stage in patients with OST. No new safety signals were observed.

AimsPeriacetabular osteotomy (PAO) is a complex procedure for treating hip dysplasia by reorienting the acetabulum to slow osteoarthritis progression. This study aimed to assess the types and rates of complications after PAO and provide recommendations for prevention.MethodsA total of 715 consecutive patients underwent unilateral PAO by a single surgeon between December 2006 and January 2024, with at least one year of follow-up. Indications included hip dysplasia, acetabular retroversion, and protrusio. Hip arthroscopy was performed concurrently in 325 cases. Demographic factors, perioperative data, and complications – graded using the modified Clavien-Dindo system – were analyzed. Risk factors and learning curves were also assessed.ResultsOf the 715 patients, 121 (16.6%) experienced 144 complications. There were 68 grade I, 52 grade II, 23 grade III, one grade IV, and 0 grade V complications. The 23 grade III complications requiring reoperations included four revision PAOs for overcorrection, three fixations for posterior column fracture, four neurolysis procedures for symptomatic lateral femoral cutaneous nerve (LFCN) dysesthesias, four heterotopic bone excisions, and eight wound debridements. All type I and II complications were treated without sequelae. The addition of hip arthroscopy did not increase complication rates. Age < 20 years was associated with a lower risk of complications (odds ratio (OR) = 0.53, 95% CI 0.33 to 0.84, p = 0.008), whereas smoking history (OR = 1.72, 95% CI 1.01 to 2.87, p = 0.040) and correction of both acetabular dysplasia and retroversion (OR = 2.46, 95% CI 1.08 to 5.24, p = 0.024) were linked to an increased risk of complications. The operating time and incidence of complications decreased with increasing experience.ConclusionPAO is an effective procedure with an acceptable complication rate. Risk factors should be discussed during preoperative counselling. While patient optimization may help to reduce complications, precise intraoperative technique remains critical for minimizing risk.Cite this article: Bone Jt Open 2025;6(10):2022–2031.

Background: Thyroid eye disease (TED) is a debilitating autoimmune disorder linked to thyroid dysfunction. There is limited knowledge of TED in Asian populations. This multicenter study characterizes the clinical features and treatment response of TED in a large Chinese cohort. Methods: A retrospective multicenter study included 4157 patients with TED from nine Chinese hospitals from February 2016 to July 2023. Disease severity and activity were evaluated according to the European Group on Graves’ Orbitopathy standards. We examined associations of variables including sex, age, smoking status, I 131 treatment, consultation department, and geographical region with clinical outcomes. Logistic regression and nomogram models were developed to examine associations with sight-threatening TED and, in a subgroup analysis ( n = 126), patients’ responsiveness to intravenous glucocorticoid (IVGC) therapy. Results: We included 4157 patients with mean age and standard deviation (SD) 45.96 ± 16.44 years. Of these, 63.6% ( n = 2644) were females. Over half (55.6%, n = 2310) of participants were in the inactive phase, with a mean clinical activity score of 2.19 ± 1.61 (SD) for all patients. TED severity was categorized as mild (9.3%, n = 385), moderate-to-severe (82.5%, n = 3428), and sight-threatening (8.2%, n = 344). The average degree of exophthalmos was 20.04 ± 5.27 mm, and 48.8% ( n = 2029) of patients had diplopia. Patients treated with I 131 had higher disease activity (47.5%, n = 468, vs. 43.5%, n = 1379, p < 0.05). Coastal region patients exhibited more severe TED (sight-threatening cases: 10.1%, n = 195, vs. 7.2%, n = 147) and higher diplopia scores (1.00 ± 1.10 vs. 0.86 ± 1.09, p < 0.001) than inland counterparts. TED severity was also greater in patients treated in Ophthalmology departments (mild cases: 6.0%, n = 213; moderate-to-severe cases: 85.6%, n = 3055) compared with Endocrinology departments (mild cases: 29.3%, n = 172; moderate-to-severe cases: 63.5%, n = 373). Nomograms had an area under the receiver operating curve of 0.742 (confidence interval [CI] 0.716–0.768) for sight-threatening TED and 0.759 (CI 0.674–0.843) for IVGC therapy responsiveness. Conclusions: We characterized the clinical features and treatment response of TED in a large Chinese cohort. These findings offer valuable insights informing TED risk stratification in Asian patients and forming a foundation for future prospective studies.

Abstract Objectives To implementation an automated multi-institutional pipeline that delivers breast-cancer risk integrated with polygenic risk scores, monogenic variants, family history, and clinical factors, emphasizing operational challenges and their solutions. Materials and Methods A five-stage process was executed at ten sites. Data streams from REDCap surveys, PRS and monogenic reports, and MeTree pedigrees were normalized and forwarded through a REDCap plug-in to the CanRisk API. Results Integrated risk was returned to &gt;10 000 women; 3.6% were ≥25 % lifetime risk and 0.9% carried pathogenic variants. Pipeline generated score aligns well with manual generated ones. Major barriers such as heterogeneous pedigree formats, missing data, edge-case handling, and evolving model versions were identified and resolved through mapping rules, imputations, and iterative testing. Discussion Cross-platform data harmonization and stakeholder alignment were decisive for success. Borderline-risk communication and model-version drift remain open issues. Conclusion Large-scale PRS-integrated breast-cancer risk reporting is feasible but requires robust interoperability standards and iterative governance.

Abstract BACKGROUND Ovarian cancer rarely metastasises to the brain, thus studies reporting the outcomes of affected patients are lacking. Stereotactic radiosurgery (SRS) is now the mainstay of management for patients with brain metastases (BM) from most primary sites, but little evidence of its efficacy in ovarian cancer is available. The current study was undertaken to provide guidance for SRS management using pooled data from multiple institutions. MATERIAL AND METHODS Centers participating in the IRRF (International Radiosurgery Research Foundation) were asked to provide outcome data for patients who had SRS for ovarian cancer brain metastases between 2020 and 2024 and at least one clinical and imaging follow-up after the procedure. Primary endpoints included survival from SRS, local tumor response according to RANO-BM criteria and occurrence of adverse radiation effects (ARE). Cox regression analyses were performed to identify variables impact each endpoint. RESULTS 128 patients had SRS for a total of 532 BM treated. Epithelial histology was the most common (91%). Median age at SRS was 62 years (IQR 56-70). Median KPS was 80% (IQR 80-90%) and 71.9% of patients had neurological symptoms at presentation. Other active systemic metastases were present in 41.4%. The median number of treated BM was 2 (IQR1-3) and the median cumulative treatment volume was 6 cc (IQR 2-12.9). The median margin dose was 18 Gy (IQR 16-20). At last follow-up, 19.5% of patients were still alive. The median overall survival (OS) after SRS was 27 months, and 6-, 12- and 24-month OS was 83.8%, 74.2% and 52.2%, respectively. Multivariate analyses revealed that increasing age at SRS (HR 1.02, p=0.05), active systemic metastases (HR 2, p=0.005) and increasing number of brain metastases (HR 1.05, p=0.04) were associated with worse survival, while repeating SRS (HR 0.4, p=0.002) led to improved survival. Local failure occurred in 12.8% of treated BM. Actuarial progression-free survival (PFS) at 6, 12 and 24 months was 92.3%, 86.6% and 70.3%, respectively. Only prior WBRT (HR 4.36, p=0.03) led to worse local control on multivariate analyses. New remote BM appeared in 49.5% of patients and 14.5% suffered from leptomeningeal dissemination. ARE were seen in 12.1% of BM but were symptomatic in only 3.2%. On multivariate analyses, prior SRS (HR 3.13, p=0.002) was associated with increased risk of ARE. CONCLUSION Ovarian cancer brain metastases can be safely and effectively managed with SRS as the primary treatment modality in most patients.

Abstract Purpose: Isocitrate dehydrogenase (IDH) 1/2–isoform inhibitors have clinical efficacy in IDH1/IDH2-mutated neoplasms. However, primary resistance and secondary resistance limit their therapeutic potential. LY3410738, an oral, brain-penetrant, dual IDH1/IDH2-mutated isoform-selective inhibitor, was designed to overcome resistance. Patients and Methods: This global, multicenter, open-label, phase I study of patients with IDH-mutant solid tumors evaluated LY3410738 as monotherapy (dose escalation) for advanced solid tumors in combination with cisplatin–gemcitabine (CISGEM) for newly diagnosed cholangiocarcinoma or with durvalumab for relapsed/refractory cholangiocarcinoma (dose expansion; NCT04521686). Primary objectives were the maximum tolerated dose, recommended phase II dose, and preliminary antitumor activity. Safety, pharmacokinetics, inhibition of D-2-hydroxyglutarate, and ctDNA were assessed. Results: Overall, 119 patients received LY3410738 alone (N = 94) or in combination with CISGEM (N = 19) or durvalumab (N = 6). No dose-limiting toxicities were observed; the maximum tolerated dose was not determined. Common adverse events included nausea, vomiting, and decreased appetite. Overall response rates of 5.2% and 11.1% and disease control rates of 56.9% and 63.0% were observed for patients with relapsed/refractory IDH1- or IDH2-mutant cholangiocarcinoma or IDH1-mutant glioma, respectively. D-2-hydroxyglutarate normalization was rapid and durable. In dose-expansion cohorts, combination treatments were tolerable, with one dose-limiting toxicity in the durvalumab cohort. LY3410738 plus CISGEM demonstrated a response rate of 42.1%, a median duration of response of 8.1 months, and a median progression-free survival of 10.2 months for patients with newly diagnosed IDH-mutant cholangiocarcinoma. Conclusions: LY3410738 demonstrated largely cytostatic antitumor activity in IDH1- or IDH2-mutated cholangiocarcinoma and IDH1-mutated gliomas. LY3410738 plus CISGEM exhibited favorable antitumor activity in patients with treatment-naïve IDH-mutated cholangiocarcinoma, warranting further exploration as a treatment strategy.