Citations

Abstract Background Black women are more likely to develop and die from early‐onset breast cancer. Hereditary breast cancer (HBC) is strongly associated with early age of onset. Accordingly, HBC characteristics in young Black women were evaluated. Methods Black women diagnosed with invasive breast cancer at age 50 years or younger between 2005 and 2018 were recruited through the state cancer registries in Florida and Tennessee. Participants were asked to complete a questionnaire, sign medical records releases, and donate a saliva sample for free genetic testing to identify HBC germline pathogenic or likely pathogenic variant (GPV). Women with sporadic versus hereditary breast cancer were compared, based on age distribution, clinical characteristics, and family cancer history. Results Among 686 participants with confirmed genetic testing, 15.3% had GPVs in breast and/or ovarian cancer predisposition genes, including BRCA1 (7.7%), BRCA2 (4.5%), PALB2 (0.9%), and ATM (0.7%), with 1.5% in other genes. Compared to the sporadic group, triple‐negative breast cancers were overrepresented among BRCA1 carriers (23.6% vs. 75.5%; p < .001), and family history of breast cancer was significantly more frequent among BRCA1 , BRCA2 , and PALB2 carriers (all p < .05). The majority of breast cancers occurred by age 40 years in BRCA1 carriers (52.8%), compared to other genes, where age was more evenly distributed. Conclusion Among unselected young Black women with breast cancer, our findings demonstrate that the highest frequency of HBC GPVs are in BRCA1 , BRCA2, and PALB2, with identification of distinct histopathologic and demographic characteristics across HBC genes, underscoring the critical need for genetic testing in all populations.

Abstract Background Cumulative head trauma, encompassing repetitive head impacts (RHI) and traumatic brain injury (TBI), has been associated with later‐life neurodegenerative disease. Studies on parkinsonism/Parkinson's disease (PD) have evaluated RHI and TBI in isolation, yielding mixed results. Cumulative head trauma may better predict PD risk. Objective To examine independent and cumulative effects of RHI through soccer participation and TBI history on PD diagnosis and age at diagnosis. Methods We used a cross‐sectional cohort design with data from the Fox Insight study. Participants completed self‐report questionnaires on PD diagnosis, TBI (no TBI, TBI with loss of consciousness [LOC], TBI without LOC), and sport participation. Multivariable logistic regressions examined the effects of soccer, TBI group, and their interaction on PD diagnosis. Cox proportional hazards examined associations with time to PD diagnosis. Covariates included age, sex, race, education, income, body mass index, heart disease/diabetes, and family PD history. Results Among 1231 participants (mean[SD] age = 66.12[10.60]), 278 played soccer (953 non–contact and collision sport [CCS] athletes). Participants reported no TBI (390[33%]), TBI without LOC (495[43%]), or TBI with LOC (258[23%]). Overall, 768(62%) reported a PD diagnosis (mean[SD] age at diagnosis = 59.02[9.86]). A significant soccer × TBI interaction indicated that soccer players with TBI with LOC had 2.6× higher odds of PD compared to non‐CCS athletes without TBI (OR [95% CI] = 2.600[1.085–6.305], P = 0.033). Former soccer players with TBI with LOC had a 15.6% higher hazard of early PD diagnosis (HR = 1.469, P = 0.027) compared to non‐CCS athletes with no TBI. Conclusion Cumulative head trauma (RHI + TBI) increased PD risk and lowered age at onset. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

ABSTRACT High dose melphalan (HDM) with autologous stem cell transplant is an established treatment for systemic light chain amyloidosis, but its incremental benefit in the era of effective standard intensity therapy is unknown. We retrospectively analyzed 475 transplant‐eligible patients who completed standard intensity treatment with or without HDM within 12 months at six centers in Europe and the United States between 2010 and 2024 to evaluate outcomes by baseline risk factors, hematologic response, and receipt of HDM. Death was an equally competing risk after the 12‐month landmark chosen to address early non‐proportional hazards and to ensure completion of first‐line therapy. BMPC > 20% was associated with inferior outcomes (HR 1.7), and gain/amp 1q with shorter TTP (HR 2.15), whereas other high‐risk FISH abnormalities were not. In multivariable models, VGPR/CR after standard intensity therapy was associated with longer TTP (HR 0.49/0.29), while gain/amp 1q remained independently associated with shorter TTP (HR 2.18). Receipt of daratumumab and HDM were associated with longer TTP (HR 0.44/0.61). HDM benefited patients who had not achieved CR after standard intensity therapy (mTTP 21.0 vs. 5.7 months without HDM), whereas patients already in CR did not benefit. Higher BMPC at diagnosis was associated with earlier progression in patients not receiving HDM (HR 1.9 for 5%–20% and 4.09 for > 20%), a risk attenuated in the HDM cohort. Gain/amp 1q remained associated with shorter TTP regardless of HDM exposure. These findings support a selective role for HDM, primarily benefiting patients with residual disease after standard intensity therapy or higher BMPC burden at diagnosis.

Background. Pancreas transplantation (PT), historically limited to patients with type 1 diabetes (T1D), is currently performed successfully in selected patients with type 2 diabetes (T2D). However, contemporary practice patterns and eligibility criteria for PT in T2D remain incompletely characterized. Methods. The International Pancreas and Islet Transplant Association Pancreas Transplant Interest Group developed an electronic survey to assess center-level approaches to patient phenotyping, candidacy, and peri- and posttransplant management for PT in patients with T2D. The survey was distributed to international transplant professionals during an International Pancreas and Islet Transplant Association Pre-Congress meeting on June 15, 2025. Results. Thirty-seven participants completed the survey. Most respondents’ programs offer PT for T2D only when a kidney transplant is also indicated. Fewer respondents’ programs also offer PT alone (10%), evaluate T2D candidates on a case-by-case basis (3%), or do not offer PT to patients with T2D (10%). Total daily insulin requirement and body mass index (BMI) were the most selected factors in determining eligibility. Considerable variability existed in metabolic thresholds: 62% of programs reported no C-peptide cutoff, whereas nearly half required a BMI of <30 kg/m 2 for C-peptide-positive candidates. Respondents frequently recommend weight-optimization strategies, including lifestyle modification, glucagon-like peptide-1 receptor agonists, and bariatric surgery for candidates exceeding acceptable BMI thresholds. Surgical technique, induction, and maintenance immunosuppression and early posttransplant glycemic management were largely uniform between T2D and T1D recipients. Conclusions. International practice reflects broad but heterogeneous adoption of PT for T2D, with most participants restricting its use to candidates requiring kidney transplantation and emphasizing integrated clinical phenotyping approaches.

ABSTRACT Germline variation shapes cancer risk, yet its influence on the evolutionary dynamics of established tumors remains poorly understood. In multiple myeloma, subclonal diversification drives disease progression and treatment failure, but the heritable factors that modulate this process are unknown. Here, we show that germline variation is associated with tumor evolutionary features, implicating inherited regulation in subclonal expansion. Integrating germline variation with tumor evolutionary parameters identifies variants associated with evolutionary features, with signals enriched in regulatory regions, consistent with a transcriptional basis. We further identify TBKBP1 as a key locus linking germline variation to tumor evolution and clinical outcome. Germline variation at this locus is associated with TBKBP1 expression and subclonal expansion, and TBKBP1 expression correlates with adverse prognosis, consistent across independent cohorts. Functional analyses demonstrate that TBKBP1 promotes proliferation and activates MYC, mTORC1 and non-canonical NF-κB signaling pathway. Together, these findings establish germline regulatory variation as a determinant of tumor evolutionary dynamics and identify TBKBP1 as a mediator linking inherited variation to subclonal expansion and disease progression in multiple myeloma.

Abstract Metabolic vulnerabilities in cancer have been targeted primarily to suppress tumor growth, but less is known about the metabolic requirements for tumor cell invasion. Here we report that lipid catabolism by cytosolic and lysosomal lipases supports pancreatic cancer cell invasion through both overlapping and distinct functional and metabolic mechanisms. Lysosomal acid lipase (LAL)-dependent lipid droplet catabolism promotes invadopodia formation and stabilization, enabling extracellular matrix degradation. In addition to modulating cellular energetics, lipidomics revealed that lipid droplet catabolism regulates cholesterol and membrane phospholipid levels. Using spatially resolved biosensors and cholesterol imaging, we found that lysosomal lipid catabolism occurs at invadopodia and sustains local ATP and membrane cholesterol. These findings identify spatially organized lipid catabolism as a mechanism that couples local energetics and membrane remodeling during the earliest steps of pancreatic cancer cell invasion.

ABSTRACT Although ablation of the greater splanchnic nerve is now being used to treat some patients with heart failure, the anatomical relationships between this nerve and the adjacent posterior intercostal veins used for the procedure are not well elucidated. Therefore, the present anatomical study was performed. The anatomy and relationships of the right GSN and the azygos vein were investigated in 50 adult anatomical donors. In the supine position, the anterior wall of the thorax was removed, and the relationship between the azygos vein and its tributaries and the overlying GSN was observed and documented with quantitation of the distances between these structures. At the T7, T8, and T9 vertebral levels, the mean distance between the GSN and the azygos vein was 3.05, 2.35, and 1.62 cm, respectively. We found that the closest distance between the GSN and the azygos vein was at the T9 vertebral level, with a mean distance of 1.62 cm. Therefore, for the shortest distance between vein and GSN, this level should also be considered for ablation level. Such additional anatomical data can help improve patient outcomes and decrease the complication rates of this procedure.

Abstract Background The current treatment of glioblastoma involves resection followed by radiotherapy (RT) and temozolomide. Rapid early progression (REP) of tumor in the surgery-to-radiotherapy interval (SRI) has been described using categorical or semi-quantitative assessments and is associated with inferior clinical outcomes. This study seeks to establish and validate a quantitative definition for REP and examine how REP could inform future therapy. Methods Volumes of tumor and resection cavity at 3 time points—preoperative, postoperative and RT-planning (pre-RT)—were contoured among patients who had undergone standard of care. A minimal, but clinically appreciable, threshold for defining REP based on change in tumor volume was established, validated, and subsequently used to assess actionable predictors of REP and its prognostic value. Results An increase of &gt;2 cc in volume or a new satellite tumor between the post-operative to planning MRI was found to be a sensitive, pragmatic, and statistically significant cutoff for REP (P = .002). Actionable predictors such as SRI of 6 weeks and a &gt; 5 cc residual immediate post-operative tumor volume were found to be statistically significant predictors of REP. REP was also found to be a statistically significant prognostic indicator for overall survival (P = .002) and progression-free survival. Conclusion These findings support that an increase in tumor volume between post-operative and pre-RT MRI of &gt;2 cc is the ideal working definition of REP in this clinical setting. Furthermore, REP could serve as a prognostic ­biomarker to track treatment response. Additionally, 2 actionable predictors of REP, post-op residual tumor volume and SRI, are identified.