Citations

According to the current WHO classification, noninvasive germ cell neoplasia of the testis comprises germ cell neoplasia in situ (GCNIS), specific forms of intratubular germ cell neoplasia, and gonadoblastoma. Because type II germ cell tumors (GCT, type II) arise from GCNIS, accurate detection of precursor lesions is diagnostically important. In preparation for the 2024 International Society of Urological Pathology (ISUP) Consensus Conference on genitourinary precursor lesions, which took place in Florence, Italy, an anonymous survey was distributed to ISUP members to assess current diagnostic practices regarding testicular precursor lesions. The literature and current WHO classification affirm the significance of precursor lesions in testicular tumours. Working Group 4—Precursor Lesions of the Testis—focused on their practical application by individual pathologists rather than establishing consensus from scientific data. There is strong agreement that GCNIS is the preferred and appropriate term for GCT precursor lesions and that its presence should be reported in cases of invasive GCT. Respondents also agree that “seminoma with intratubular nonseminoma” is the appropriate terminology for seminoma with an associated noninvasive nonseminomatous (embryonal carcinoma, yolk sac tumor, trophoblasts, or teratoma) component. Most pathologists prefer to use OCT3/4 as the primary immunohistochemical marker, and a panel was generally not considered necessary. No consensus is reached regarding the requirement for immunohistochemistry to confirm GCT precursor lesions in the testis. Three questions remain open: the value of subtyping intratubular lesions, the immunohistochemical approach to gonadoblastoma, and the criteria distinguishing Sertoli cell nodules from Sertoli cell tumors.

Abstract Objectives: In the RadComp randomized trial, we compared radiation dose to cardiac substructures in patients treated with proton versus photon radiation therapy (RT) ; evaluated changes in cardiac-specific health-related quality of life (HRQOL) outcomes from baseline to 6 months following RT; and determined associations between radiation dose volume histogram (DVH) parameters and changes in cardiac-specific HRQOL. Methods: The study cohort included patients with locally advanced breast cancer enrolled on RadComp who completed treatment per protocol, had available radiation DVH metrics for all cardiac substructures, and completed both the baseline and at least one follow-up cardiac-specific HRQOL over the 6 months post-RT. Cardiac-specific HRQOL measures included PROMIS fatigue, PRO-CTCAE shortness of breath (SOB) (severity and interference with daily activities), and PRO-CTCAE chest pain, chest tightness, and angina (frequency, severity, and interference). Detailed dose volume histograms (DVH) for cardiac substructures included the whole heart, left ventricle (LV), right ventricle (RV), left atrium (LA), right atrium (RA), and left anterior descending artery (LAD) were derived. The Wilcoxon rank-sum test was used to compare dose distributions between photon and proton RT. Associations between DVH metrics and HRQOL outcomes were evaluated using repeated-measures linear regression via generalized estimating equations with an independent working correlation structure. All models were adjusted for RT type, age, cardiovascular risk factors, surgery type, laterality, ethnicity, education, timepoint, and race. Additional stratified analyses was performed according to laterality (right versus left + bilateral). Results: Across 1160 RadComp participants, RT exposure to cardiac substructures differed significantly between proton and photon RT and by laterality. Median mean heart dose was lower with protons, 0.9 Gy (Q1, Q3 0.49, 1.46), compared to photons 2.83 Gy (Q1, Q3 1.49, 4.52) (p< 0.001), and lower for right-sided disease, 0.91 Gy (Q1, Q3 0.44, 1.55), compared to left and bilateral 1.99 Gy (Q1, Q3 1.11, 3.63) (p<0.001). Similarly, for the LAD, LA, LV, and RA, mean proton dose was significantly lower (p<0.001). However, for the whole heart, RA, and RV, maximum doses to small-volume parameters and dose to 0.03cc were higher with proton RT. PRO-CTCAE measures of HRQOL were generally favorable at all timepoints across all participants, and grade ≥3 toxicity was rare (≤5.5%) for all measures. The PROMIS Fatigue T-Score increased from baseline (median 49 [Q1, Q3 46, 57]) to end of RT (55 [Q1, Q3 49, 63]), and returned to baseline levels at 6 months (p<0.001). While there were no significant differences in PRO-CTCAE SOB severity (p=0.24) and interference (p=0.11) over time, PRO-CTCAE chest pain worsened compared to pre-RT with respect to frequency (p<0.001), severity (p<0.001), and interference (p=0.008). However, the absolute changes were small. No DVH metrics were significantly associated with any cardiac-specific HRQOL outcomes. Stratification by laterality yielded similar results. Conclusions: Proton RT generally conferred significantly lower doses to the heart and cardiac substructures compared to photon RT. HRQOL outcomes were favorable across all participants, with fatigue returning to baseline, no change in SOB parameters, and a slight worsening of chest pain outcomes over 6 months following RT. Cardiac-specific HRQOLs appear not to be significantly affected by RT dose to cardiac substructures within the first 6 months post-RT. Other organs at risk that could also impact cardiac HRQOL endpoints, longer follow-up, and major cardiac events will be evaluated in future analyses. Citation Format: J. L. Wright, K. Ko, W. Kenworthy, W. Bosch, L. Braunstein, G. Freedman, E. Gillespie, R. Jimenez, S. Pugh, H. Lu, M. Pankuch, N. Remmes, W. Straube, W. Zou, E. Berlin, L. Fang, S. MacDonald, N. Taunk, J. Kim, A. Thukral, A. Taghian, M. Mishra, R. Mutter, V. Croog, D. Boggs, J. Urbanic, N. Ohri, A. Chawla, T. Meier, L. Rosen, M. Fegundes, O. Cahlon, K. Hoffman, A. Ferriozzi, J. Bekelman, A. Lin, B. Ky. Associations Between Cardiac Radiation Dose Volume Metrics and Cardiac Specific Health Related Quality of Life for Patients with Breast Cancer Randomized to Proton versus Photon Radiation on the RadComp Trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr RF6-04.

Background Bleomycin-induced chromosomal breaks (CB) and sister chromatid exchange (SCE) in peripheral blood lymphocytes have been shown to be sensitive cytological markers for susceptibility to DNA damage in patients with various types of cancer and in healthy controls. Factors such as age, sex, smoking, and alcohol consumption could affect the values of some of these biomarkers and should be considered as covariates when analyzing cytogenetic biomarkers because these factors can affect the frequency of CB and SCE. Methods We propose a statistical method using negative binomial (NB) distribution to evaluate the numbers of CB and SCE. In order to determine the best model to represent the frequency of CB and SCE, we compared the NB model with the widely used Poisson model and log-transformed normal model by using generalized linear models. To demonstrate the better fit of the NB model, we analyzed three different data sets from studies conducted at The University of Texas M.D. Anderson Cancer Center. The first set was a case-control study of lung cancer in a population of African Americans and Mexican Americans (286 cases and 156 con-trols), the second set consisted of 311 head and neck cancer patients, and the third set consisted of 105 Hodgkin's disease patients. Results For CB, the estimates of the variability for Hodgkin's disease, head and neck, and lung cancers were 487.24, 502.82, and 520.15, respectively. For SCE, the esti-mates of the variability for Hodgkin's disease was 9777.01. For CB, the dispersion estimates under the three models (Poisson, NB, and Normal) for Hodgkin's disease, head and neck, and lung cancers were: 12.30, 1.20, 0.85; 8.94, 1.05, 0.22; and 10.10, 1.05, 0.25, respectively. For SCE (Hodgkin's disease only), the dispersion estimates under the three models (Poisson, NB, and Normal) were 30.91, 1.11, 0.10, respec-tively. Conclusions Our results demonstrate that the NB model provides a better interpretation and fit for the frequency of CB and SCE in different cancer types. Therefore, we recom-mend it as a model for the analysis of cytogenetic biomarkers.

Abstract Motivation The American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines represent the gold standard for clinical variant interpretation. Despite the widespread adoption of ACMG/AMP guidelines, a comprehensive comparison of the software tools designed to implement them has been lacking. This represents a significant gap, as clinicians require evidence-based guidance on which tools to use in their practice. Results We benchmarked four ACMG/AMP-based tools (Franklin, InterVar, TAPES, Genebe) selected from 22 tools, and compared their performance with LIRICAL, a top-performing phenotype-driven tool, using 151 expert-curated datasets from Mendelian disorders. Selection criteria included free availability, VCF compatibility, operational reliability, and not being disease-specific. Our evaluation framework assessed top-N accuracy (N = 1, 5, 10, 20, 50), retention rates, precision, recall, F1 scores, and area under the curve (AUC). Statistical validation employed bootstrap confidence intervals (n = 1000) and Friedman tests. LIRICAL (68.21%) and Franklin (61.59%) demonstrated superior top-10 variant prioritization accuracy in Mendelian disorders, significantly outperforming other tools (P = .0000). Results demonstrate that tools with advanced phenotypic integration significantly outperform those relying primarily on genomic features. Availability and implementation All data and source code required to reproduce the findings of this study are openly available in the Code Ocean repository at https://doi.org/10.24433/CO.6562438.v1.

INTRODUCTION: This study used the novel C-reactive protein-albumin-lymphocyte (CALLY) index to explore its relationship with the risk of developing gallstones. METHODS: This study conducted a cross-sectional analysis of the National Health and Nutrition Examination Survey data from 2017 to 2020; multivariable logistic regression examined the CALLY-gallstone association. Restricted cubic splines tested nonlinearity. Subgroup and mediation analyses explored population variations and mediating effects (Conicity, lipid accumulation product, and a body shape index). Receiver operating characteristic curves compared CALLY, systemic immune inflammation index, systemic inflammatory response index, and aggregate index of systemic inflammation predictive performance. RESULTS: After comprehensive adjustments, the highest CALLY quartile had significantly lower gallstone risk vs the lowest (odds ratio 0.56, 95% confidence interval 0.34–0.94). Restricted cubic splines revealed a linear inverse correlation. Subgroup analyses generally supported this inverse relationship. Mediation analysis identified the Conicity index as the strongest mediator (21.47%, P < 0.001), followed by lipid accumulation product and a body shape index (10.72% each, P < 0.001). Receiver operating characteristic analysis showed CALLY (area under the curve = 0.604) outperformed systemic immune inflammation index (0.540), systemic inflammatory response index (0.550), and aggregate index of systemic inflammation (0.546). DISCUSSION: A significant inverse association exists between the CALLY index and gallstone prevalence. The CALLY index demonstrates superior predictive ability compared with other indices, suggesting its potential utility as an objective biomarker for early gallstone risk identification.

Abstract Introduction: Underlying tumor biology in metastatic castration-resistant prostate cancer (mCRPC) is highly complex and heterogeneous. To date, mCRPC state biomarker-enriched clinical trial designs incorporating either prognostic or predictive biomarkers are limited to alterations in homologous recombination repair pathway genes. In this study, we use an integrated clinico-molecular prognostic score in mCRPC that combines plasma prognostic proteins with a plasma-based copy number alteration (CNA) risk algorithm (PMID: 40036789; PMID: 36230636) to simulate a biomarker-enriched clinical trial design. Methods: A plasma cell-free DNA (cfDNA) prognostic risk algorithm from eight CNAs (gains in AR, MYC, PIK3CA, PIK3CB; deletions in NKX3-1, TMPRSS2, TP53, ZBTB16) is combined with clinical prognostic proteins (alkaline phosphatase, lactate dehydrogenase) to generate a prognostic risk-score (RS) in three independent treatment-naïve mCRPC cohorts. Using the RS classifier, we estimate the number of high-RS patients (pts) required to be screened from an unselected mCRPC population and the number needed for enrollment to achieve adequate statistical power in a randomized trial for a predefined effect size (Hazard Ratio- 0.70; 80% power). The trial design aims to enrich High-RS pts for targeting lethal mCRPC. Trade-offs are evaluated between number of pts screened and enrolled under varying RS enrichment thresholds and degrees of enrichment. Results: The range of RS distribution in 561 mCRPC pts from three pooled datasets was 0.362-11.737. The median overall survival (OS) (months; 95% Confidence Intervals) based on risk stratification for Low-RS (≤0.8) is 46.2 (38.8-55.4); “Intermediate-risk” (RS: 0.8-2.6) is 27.1(24.3-31.5); High-Risk (RS: &gt;2.6) is 14.9 (11.9-17.6). For a 2-year OS mCRPC endpoint, a biomarker-enriched trial restricted to pts with RS ≥2, which corresponds to the 65th percentile of the RS distribution, would require enrollment of 398 pts, after screening 1,101 mCRPC pts to achieve 80% power to detect a 0.7 treatment vs. control hazard ratio (HR). In contrast, a traditional non-enrichment clinical trial (no molecular classifier) would require 574 pts to achieve to achieve 80% power and still not achieve adequate power to detect strong treatment by risk interactions. As a pragmatic alternative, we evaluated a hybrid enrichment strategy enrolling 50% of pts from the general mCRPC population and 50% of pts with RS ≥1 (41st percentile). This biomarker enriched design which takes 50% pts with a RS of 1.0 (or more) in a trial with 24-month follow-up will require a sample size 525 patients for which 676 pts will be screened to achieve an 80% power to detect a 0.7 treatment vs. control hazard ratio. Conclusion: A plasma-based molecular classifier can be used to design an enrichment trial in biologically defined lethal mCRPC, incorporating 50% of pts with High-RS and yet balance the required sample size and number of pts to be screened enabling an adequately powered molecular classifier-based biomarker-enriched clinical trial. Citation Format: Manish Kohli, Liang Wang, Aik C. Tan, Muhammad Zaki Fadlullah, Anushka Shankar, Sumithra Mandrekar, Benjamin Haaland. Clinico-Genomic Risk Score-Based Biomarker Enrichment Clinical Trial Designs in Poor Prognosis Metastatic Castrate Resistant Prostate Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr B039.

Objectives: Smoking is a key risk factor for pancreatitis, contributing to pathogenesis and disease progression. Data regarding second-hand smoking, or passive smoking (PS) exposure, are lacking. We therefore aimed to assess the impact of PS exposure across the pancreatitis spectrum. Methods: We analyzed baseline data from the PROCEED study, a multicenter study in the United States including patients with acute (AP), recurrent acute (RAP), and chronic (CP) pancreatitis. Participants detailed their individual smoking history and PS exposure, which was compared between AP, RAP, and CP subgroups. Participant factors and clinical characteristics were compared by level of individual and PS exposure. Results: Among 1369 participants (190 AP, 498 RAP, 681 CP), 346 (25.3%) were current and 409 (29.9%) were former smokers. The CP subgroup had the highest proportion of current smokers (36.7% CP vs 15.1% RAP, 11.1% AP, P < 0.001). PS exposure was also significantly higher in the CP subgroup (68.6% CP vs 58.2% RAP, 55.3% AP, P < 0.001). A minority (16.3%) with CP reported no smoking exposure (by self or passive) while nearly half smoked ≥20 pack-years. The mean PS duration was significantly higher in CP participants (21.8 y) compared with those with AP (17.8 y) or RAP (18.9 y) ( P < 0.0166). Conclusions: In this multicenter study, we affirmed an association with smoking use and intensity with CP-related complications. For the first time, we report a high prevalence of prior exposure to passive smoking in all pancreatitis subtypes, which requires further study to understand the impact on disease outcomes.

Abstract Aims Left bundle branch block (LBBB) is associated with mechanical dyssynchrony, heterogeneous perfusion, and adverse left ventricular (LV) remodeling. However, not all patients with LBBB develop cardiomyopathy, and dyssynchrony can occur without conduction defects. The role of microvascular dysfunction remains uncertain. We aimed to assess how mechanical dyssynchrony and perfusion heterogeneity relate to LV remodeling and function in patients with and without LBBB. Methods and results We retrospectively analyzed 233 patients with isolated LBBB and 932 matched controls who underwent PET myocardial perfusion imaging, assessing mechanical dyssynchrony (phase entropy), myocardial blood flow (MBF), coronary vascular resistance (CVR), myocardial flow reserve (MFR), septal-to-lateral MBF ratio (SLR) for perfusion heterogeneity, LV volumes, and ejection fraction (EF). Compared to controls, patients with LBBB had greater dyssynchrony (56% vs. 40%), larger LV volumes, and lower EF (54% vs. 67%) (all p <0.001), and had higher stress CVR (37 vs. 34 mmHg/mL·min⁻¹·g⁻¹), lower stress MBF (2.4 vs. 2.6 mL/min/g), reduced MFR (2.4 vs. 2.6), and lower SLR (0.95 vs. 1.00) (all p <0.05). Among patients with dyssynchrony, SLR<1.0 identified those with more adverse remodeling. In multivariable regression, phase entropy and SLR independently predicted LV volumes and EF, with adverse effects of SLR reduction amplified in LBBB (interaction p <0.01). In the Cox proportional hazards analysis, phase entropy (HR:1.02, p =0.01), MFR (HR:0.62, p <0.001), and LVEF (HR:0.97, p <0.001) were independently associated with mortality and heart failure hospitalization, whereas LBBB was not. Conclusions Mechanical dyssynchrony and perfusion heterogeneity independently predict adverse LV remodeling, irrespective of LBBB. Integrated imaging enhances cardiomyopathy stratification.

Abstract Background Bedaquiline, pretomanid, and linezolid with or without moxifloxacin (BPaL/M) are recommended oral 6-month treatment regimens for multidrug- or rifampin-resistant (MDR/RR) tuberculosis (TB). Since the US rollout of these regimens in 2019, the US Centers for Disease Control and Prevention (CDC) and partners have identified patients who failed or relapsed on these regimens. Methods Here, we report a case series of US patients with TB treated with BPaL/M-containing regimens, who experienced adverse outcomes during the period 2022‒2024, including drug resistance, relapse, and treatment failure. Results Clinical and public health outcomes were significant for US patients reported. There were 8 patients identified (n = 8). 5 (62.5%) were male, with a median age 57 years, 2 (25%) were previously treated for TB, and 8 (100%) presented with cavitary disease. This included a patient who died from infectious TB with acquired resistance after exposing over 100 healthcare workers, a waitress who was found to have highly infectious TB at the time of her relapse, and a son who contracted Mycobacterium tuberculosis (Mtb) with reduced activity to bedaquiline from his mother in a household transmission event. Conclusions These patients highlight consequences, both for the individual and public health, of relapse and treatment failure in real-life operational settings that may not be readily evident in well-controlled and well-resourced clinical trials. Despite the advent of shorter and better tolerated bedaquiline-based regimens, US clinicians continue to face challenges in managing drug-resistant TB. These data support the need for expert management of these patients beyond routine TB care, as well as the need for close monitoring and follow-up months after treatment completion.