Citations

Abstract The aim of this international meta-analysis was to quantify the predictive value of BMI for incident fracture and relationship of this risk with age, sex, follow-up time, and BMD. A total of 1 667 922 men and women from 32 countries (63 cohorts), followed for a total of 16.0 million person-years were studied. 293 325 had FN BMD measured (2.2 million person-years follow-up). An extended Poisson model in each cohort was used to investigate relationships between WHO-defined BMI categories (Underweight: <18.5 kg/m2; Normal: 18.5-24.9 kg/m2; Overweight: 25.0-29.9 kg/m2; Obese I: 30.0-34.9 kg/m2; Obese II: ≥35.0 kg/m2) and risk of incident osteoporotic, major osteoporotic and hip fracture (HF). Inverse-variance weighted β-coefficients were used to merge the cohort-specific results. For the subset with BMD available, in models adjusted for age and follow-up time, the hazard ratio (95% CI) for HF comparing underweight with normal weight was 2.35 (2.10-2.60) in women and for men was 2.45 (1.90-3.17). Hip fracture risk was lower in overweight and obese categories compared to normal weight [obese II vs normal: women 0.66 (0.55-0.80); men 0.91 (0.66-1.26)]. Further adjustment for FN BMD T-score attenuated the increased risk associated with underweight [underweight vs normal: women 1.69 (1.47-1.96); men 1.46 (1.00-2.13)]. In these models, the protective effects of overweight and obesity were attenuated, and in both sexes, the direction of association reversed to higher fracture risk in Obese II category [Obese II vs Normal: women 1.24 (0.97-1.58); men 1.70 (1.06-2.75)]. Results were similar for other fracture outcomes. Underweight is a risk factor for fracture in both men and women regardless of adjustment for BMD. However, while overweight/obesity appeared protective in base models, they became risk factors after additional adjustment for FN BMD, particularly in the Obese II category. This effect in the highest BMI categories was of greater magnitude in men than women. These results will inform the second iteration of FRAX®.

Abstract Background Cone‐beam computed tomography (CBCT) is essential for image‐guided particle therapy (IGPT), providing daily patient positioning, anatomical monitoring, and treatment verification. However, conventional single‐detector CBCT suffers from poor soft‐tissue contrast, long acquisition times, and motion artifacts, reducing its effectiveness for adaptive radiotherapy workflows. Addressing these challenges requires an advanced CBCT reconstruction approach capable of enhancing image quality while reducing scan time and radiation exposure. Purpose This study introduces a Dual Detector Combined Scanning (DDCS) CBCT reconstruction algorithm to overcome conventional CBCT limitations. By integrating a dual‐source, orthogonal imaging setup, DDCS significantly reduces scanning time and imaging artifacts. A modified Parker‐weighting algorithm further improves image reconstruction accuracy, ensuring high‐fidelity visualization. The goal is to enhance adaptive radiotherapy by improving real‐time patient positioning, dose verification, and motion management. Methods A dual‐detector CBCT system was designed to acquire orthogonal projections simultaneously, reducing scan time and improving data completeness. A modified Parker‐weighting algorithm corrected angular overlap distortions, ensuring better reconstruction accuracy. The system was evaluated using numerical and physical phantom studies to assess spatial resolution, contrast‐to‐noise ratio (CNR), and artifact reduction. Additionally, a dynamic phantom simulated respiratory motion, validating motion robustness for adaptive radiotherapy. Performance was compared against single‐detector CBCT, focusing on image fidelity, noise suppression, and computational efficiency. Results DDCS‐CBCT demonstrated higher CNR, reduced motion artifacts, and improved spatial resolution, leading to more accurate anatomical visualization. The system's efficiency enables faster, more reliable patient setup in IGPT while maintaining a lower imaging dose. Conclusion The proposed DDCS‐CBCT approach significantly improves imaging accuracy, reduces scan time, and enhances real‐time volumetric guidance in IGRT/IGPT. These findings support the clinical feasibility of the DDCS system and its integration into online adaptive radiotherapy workflows.

Objective: In this study, we evaluate the utility of ctDNA analysis in a large cohort of patients for whom ctDNA testing was ordered commercially with real-world application. Summary Background Data: Circulating tumor DNA (ctDNA) has emerged as a prognostic and predictive biomarker for assessing post-surgical molecular residual disease (MRD) and response to treatment. Methods: A real-world data analysis was performed using commercial ctDNA testing (SignateraTM) from patients (N=795, n=5,971 plasma samples) with stage I-III colon cancer treated at multiple US institutions. The association of ctDNA detection within the MRD window, during surveillance, and the impact of ACT was correlated with patient outcomes. Results: ctDNA-positive patients during the MRD window and surveillance showed significantly shorter DFS compared to ctDNA-negative patients (hazard ratio (HR): 9.85, P<0.0001; HR: 26.91, P<0.0001). Multivariate analysis of the MRD window revealed ctDNA-positivity as the most significant factor associated with inferior DFS (adjHR: 7.7, P<0.001). MRD-positive patients who received ACT showed improved DFS compared to patients observed post-surgery (adjHR: 6.1, FDR adj P=0.0007). No ACT benefit was observed in MRD-negative patients (adj HR: 1.20, FDR adj P=0.768). On evaluating ctDNA dynamics from MRD to surveillance, patients who remained ctDNA-positive or converted from negative to positive showed a significantly inferior DFS (HR: 34.40, P<0.0001; HR: 13.65, P<0.0001) compared to persistently ctDNA-negative patients. Conclusions: Postsurgical ctDNA detection is prognostic of relapse and potentially predictive of ACT benefit in patients with resectable colon cancer, which may enable personalized surveillance, intervention, and/or trial options, ultimately improving patient outcomes.

Abstract The treatment patterns and clinical outcomes for patients experiencing progression of disease (POD) following CD19-directed chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (R/R) mantle cell lymphoma (MCL) are undefined. We identified all patients who received CD19-directed CAR T-cell therapy for R/R MCL therapy across 15 international centers, and studied those experiencing POD post–CAR T-cell therapy in detail. We extracted clinical/treatment/pathologic variables, and associated these features with survival outcomes. In total, 384 patients received CAR T-cell therapy, and 135 (35%) experienced POD. POD occurred at a median of 6 months following CAR T-cell therapy infusion, and most (64%) patients with POD had complete response as best response to CAR T-cell therapy. Tumor features at POD included blastoid/pleomorphic morphology in 29 of 78 (37%) patients, and TP53 mutation in 21 of 41 (51%) patients. Following POD, 17 patients received no further therapy, 13 underwent local therapy, and 105 received systemic therapy. The most common first-line systemic therapies were chemo(immuno)therapy (22 patients; overall response rate [ORR], 40%), pirtobrutinib (17 patients; ORR, 36%), and bispecific antibodies (13 patients; ORR, 67%). Among patients experiencing POD, the median progression-free survival and overall survival (OS) were 2.5 months and 5.4 months, respectively, from POD. Lack of response to CAR T-cell therapy and short time from CAR T-cell therapy infusion to POD (&lt;3 vs 3-6 vs &gt;6 months), among other factors, were associated with inferior OS after POD. In conclusion, we confirm the challenging prognosis for patients experiencing POD following CD19 CAR T-cell therapy for R/R MCL, and establish a benchmark for future investigations in this patient population.

The NCCN Clinical Practice Guidelines (NCCN Guidelines) for Wilms Tumor (WT; nephroblastoma) cover strategies for the screening, diagnosis, and treatment of WT, which is the most frequent primary kidney tumor in children. WT can generally be separated into 2 histology types: favorable histology WT and anaplastic WT. Five-year survival is high for children with favorable histology WT who receive appropriate treatment; however, survival rates are much lower for patients who present with higher stage diffuse anaplastic WT. Treatment of WT can range from surgery alone to surgery plus intensive chemotherapy and radiation depending on whether the tumor is unilateral or bilateral, histology, and local stage. The goal of therapy is to maximize cure while minimizing long-term toxicities. The content featured in this issue covers the NCCN panel’s recommendations for overall management of both favorable histology WT and anaplastic WT.

The NCCN Guidelines for Uterine Neoplasms provide recommendations for diagnostic workup, clinical staging, and treatment options for patients with endometrial cancer and uterine sarcoma. The NCCN Cervical Uterine Panel meets at least annually to review comments from reviewers within their institutions; examine relevant new data from publications, abstracts, and recent FDA approvals; and reevaluate and update recommendations. These NCCN Guidelines Insights summarize the panel’s deliberations on the new FIGO 2023 staging system and updates on the new systemic therapy recommendations for the management of endometrial cancer.

The Dublin ISUP Consensus Conference covered the proceedings on the best practice recommendations on nonurachal glandular lesions of the urinary bladder, bladder diverticular cancers, and molecular features of bladder and urachal glandular lesions. The conference proceedings on urachal neoplasms (except for their molecular features) are published elsewhere. The rationale for convening this conference was the lack of structured and consented pathologic recommendations in these rare lesions. Consensus by participants was reached on the following statements: (1) intestinal metaplasia with dysplasia is considered to be a precursor to primary bladder adenocarcinoma; (2) dysplasia arising from cystitis glandularis should be reported in terms of focality (focal or nonfocal) and grade (low or high); (3) the term “adenocarcinoma” should only be used for carcinomas showing pure (nonurothelial) morphology and should not be used interchangeably in urothelial carcinoma with “glandular differentiation” because of the pathobiological differences and management implications; (4) the different histologic subtypes of bladder adenocarcinoma should be specified in the report; (5) immunohistochemistry has an ancillary role in the work up of bladder adenocarcinoma versus gastrointestinal or Müllerian-type adenocarcinomas; (6) lymphovascular invasion should be included as a parameter when reporting bladder adenocarcinoma; (7) representative or targeted sampling will be sufficient for bladder diverticulum resection specimens; and (8) molecular analysis in genomic profiling should be performed only in advanced or metastatic bladder and urachal adenocarcinomas for targetable therapy. This report on glandular (nonurachal) lesions of the bladder from the Dublin ISUP consensus conference will serve as a best practice recommendation and as a guide for future research on these relatively rare lesions.

Abstract Ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel), 2 B-cell maturation antigen (BCMA)–directed chimeric antigen receptor T-cell (CAR-T) therapies, have transformed outcomes for relapsed/refractory multiple myeloma; however, the 6 to 8 weeks manufacturing time risks disease progression or death in up to 10% of patients. Talquetamab, a G-protein–coupled receptor, family C, group 5, member D (GPRC5D)–targeting bispecific antibody, represents a promising option. We performed a multi-institutional retrospective analysis across 20 centers (18 United States, 2 Germany) evaluating talquetamab as a bridging therapy prior to cilta-cel or ide-cel. Among 134 patients receiving talquetamab, 119 proceeded to CAR-T (n = 98 cilta-cel, n = 21 ide-cel). Reasons for not proceeding (n = 15) included progression (n = 7), manufacturing failure (n = 6), or patient decision (n = 2). Median age was 65 years and had median 5 prior lines of therapy. Notably, 85% would not have met CARTITUDE-1/KarMMa eligibility criteria. Talquetamab was administered for a median 23 days. Toxicity was manageable: no grade ≥3 cytokine release syndrome (CRS), 2% grade 3 immune effector cell–associated neurotoxicity syndrome (ICANS) and grade 1 to 2 talquetamab unique toxicities (70% oral, 38% skin, and 17% nail; 60% resolved). Talquetamab achieved 71% response rate. After CAR-T, 88% responded (54% complete response), with low-grade toxicities (2 grade ≥3 CRS, 1 grade 3 ICANS, and 5% grade ≥3 infections). Two cases of facial palsy and 1 acute myeloid leukemia occurred. Talquetamab correlated with sustained soluble BCMA decline and peak CAR-T expansion around day 14. Talquetamab bridging appears safe, enabling the majority of difficult-to-treat patients to successfully proceed to BCMA CAR-T therapy.