Category: Statistics

J Clin Oncol. 2025 Dec 7:JCO2502477. doi: 10.1200/JCO-25-02477. Online ahead of print.

ABSTRACT

PURPOSE: Pirtobrutinib, a highly selective, noncovalent Bruton tyrosine kinase inhibitor (BTKi), has shown efficacy and safety in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who received prior covalent BTKi. We report results, to our knowledge, from the first randomized head-to-head comparison of pirtobrutinib versus ibrutinib in BTKi-naïve CLL/SLL in both treatment-naïve (TN) patients and patients with relapsed/refractory (R/R) disease.

PATIENTS AND METHODS: Patients (N = 662) were randomly assigned 1:1 to receive pirtobrutinib or ibrutinib. All patients were BTKi-naïve. Primary end points were overall response rate (ORR) by independent review committee (IRC) among all randomly assigned patients (intention to treat [ITT]) and in patients with R/R disease.

RESULTS: The study met its primary end points, demonstrating statistically significant noninferiority (NI) of IRC-ORR for pirtobrutinib versus ibrutinib in both the ITT (87.0% [95% CI, 82.9 to 90.4] v 78.5% [95% CI, 73.7 to 82.9]; ORR ratio = 1.11 [95% CI, 1.03 to 1.19]; two-sided P < .0001) and R/R populations (n = 437; 84.0% [95% CI, 78.5 to 88.6] v 74.8% [95% CI, 68.5 to 80.4]; ORR ratio = 1.12 [95% CI, 1.02 to 1.24]; two-sided P < .0001). In TN patients (n = 225), IRC-ORR was 92.9% (95% CI, 86.4 to 96.9) with pirtobrutinib versus 85.8% (95% CI, 78.0 to 91.7) with ibrutinib. Investigator assessed ORR results were consistent. Investigator-assessed progression-free survival (PFS) favored pirtobrutinib in the ITT (hazard ratio [HR], 0.57 [95% CI, 0.39 to 0.83]), R/R (HR, 0.73 [95% CI, 0.47 to 1.13]), and TN (HR, 0.24 [95% CI, 0.10 to 0.59]) populations. Cardiac adverse event rates of atrial fibrillation/flutter and hypertension were lower with pirtobrutinib.

CONCLUSION: Pirtobrutinib demonstrated NI of ORR versus ibrutinib, with a favorable early PFS trend, particularly in TN patients, and a favorable safety profile including low rates of atrial fibrillation and hypertension.

PMID:41353787 | DOI:10.1200/JCO-25-02477

J Chem Inf Model. 2025 Dec 7. doi: 10.1021/acs.jcim.5c01597. Online ahead of print.

ABSTRACT

Uncertainty quantification (UQ) has been recognized as a prerequisite for reliable and trustworthy computational modeling in drug discovery. Two widely considered paradigms, Bayesian methods (deep ensemble and MC dropout) and evidential learning, differ in their computational demands and expressivity of uncertainties, excelling in complementary settings. Here, we propose hybrid approaches that combine both paradigms and benchmark them on the Papyrus++ data set across two end points (xC₅₀, K_x) and multiple split strategies. Our ensemble of evidential models (EOE) consistently achieves the best overall performance, yielding the lowest RMSE and leading CRPS and interval scores, including under the most challenging distributional shifts. While large ensembles often excel in rejection-based utility, EOE matches or surpasses them at a fraction of the computational cost. Statistical tests confirm its advantage, and a hardware-agnostic compute analysis highlights favorable performance-efficiency trade-offs. These results demonstrate that combining evidential and Bayesian principles yields more accurate and informative uncertainties for bioactivity modeling, with EOE offering a robust─and computationally practical─default for uncertainty-aware decision-making in drug discovery.

PMID:41353755 | DOI:10.1021/acs.jcim.5c01597

Knee Surg Sports Traumatol Arthrosc. 2025 Dec 7. doi: 10.1002/ksa.70218. Online ahead of print.

ABSTRACT

PURPOSE: To evaluate the effect of medial patellofemoral ligament (MPFL) reconstruction with or without lateral retinacular release (LRR) on patellar height in patients with recurrent patellar dislocation (RPD). It was hypothesised that the addition of LRR would not significantly modify patellar height compared with isolated MPFL reconstruction.

METHODS: This prospective, single-blinded randomised controlled trial was conducted between 2011 and 2022. Patients aged 18-45 years with RPD were randomised into two groups: isolated MPFL reconstruction and MPFL reconstruction with associated LRR. Exclusion criteria included previous surgery on the same knee, concomitant bony procedures, or prior contralateral MPFL reconstruction. All patients were evaluated by blinded investigators. The primary outcome was patellar height measured by the Caton-Deschamps Index (CDI) on standardised lateral radiographs obtained at a minimum of 1 year after surgery.

RESULTS: Out of 140 enrolled patients, 107 completed the study, with 59 in the LRR group and 48 in the isolated MPFL group. The preoperative CDI was similar in both groups (1.32 [±0.168] in the LRR group and 1.29 [±0.163] in the isolated MPFL group), and postoperative CDI showed a significant decrease in patellar height in both groups (1.1 [±0.133] in the LRR group and 1.1 [±0.166] in the isolated MPFL group), with a mean follow-up of 12.5 ± 0.3 months, with no significant difference between them. A statistically significant reduction in CDI of 0.2 was observed in both groups.

CONCLUSION: Adding LRR to MPFL reconstruction has no effect on patellar height. Caton Deschamps Index demonstrated a mean decrease of 0.2 after MPFL reconstruction, with or without LRR.

LEVEL OF EVIDENCE: Level II, low-powered randomised clinical trial.

PMID:41353731 | DOI:10.1002/ksa.70218

Knee Surg Sports Traumatol Arthrosc. 2025 Dec 7. doi: 10.1002/ksa.70210. Online ahead of print.

ABSTRACT

PURPOSE: To compare short-term patient-reported outcomes (PROMs) and revision rates between autologous hand-minced cartilage implantation (MCI) and autologous chondrocyte implantation (ACI) for knee cartilage lesions.

METHODS: All patients undergoing MCI or ACI at a single centre were retrospectively analysed from a prospectively maintained database. Propensity score matching was performed based on age, defect localisation, defect size, general health status (ASA class), and prior surgery. PROMs, including the COMI, IKDC score and VAS for pain, were obtained preoperatively and at 6, 12, and 24 months postoperatively. Statistical comparisons were performed for PROM absolute values, improvement from baseline, Patient Acceptable Symptom State (PASS) and Maximum Outcome Improvement (MOI). Postoperative complications and revision surgeries were also compared.

RESULTS: After matching, 25 patients per group were compared. Both groups demonstrated statistically significant improvements in all PROMs when compared against baseline: COMI scores improved from 5.0 ± 1.5 to 2.6 ± 2.0 for ACI and from 5.3 ± 1.7 to 2.0 ± 2.0 for MCI. IKDC scores improved for ACI (49.8 ± 14.0 to 71.3 ± 18.7, p < .001) and MCI (49.4 ± 15.8 to 74.3 ± 15.9, p < 0.001). The VAS score for pain decreased significantly for both ACI (5.0 ± 2.2 to 2.2 ± 2.1, p < 0.001) and MCI (4.2 ± 2.5 to 2.2 ± 2.0, p < 0.001). ACI and MCI differed neither statistically nor clinically in PROMs. Gender, defect localisation, defect size, and concomitant interventions had no substantial influence on outcomes. Overall, 60% and 68% of ACI patients and 68% and 80% of MCI patients achieved PASS for IKDC and COMI scores at 24 months (p = n.s.). Re-operation rates were comparable between both groups.

CONCLUSION: Patients undergoing single-stage MCI or two-stage ACI for medium to large knee chondral defects achieve comparable and favourable short-term outcomes with low rates for adverse event. MCI is an efficient and effective alternative treatment option for patients seeking a single-stage solution or in areas where ACI is inaccessible.

LEVEL OF EVIDENCE: Level III.

PMID:41353730 | DOI:10.1002/ksa.70210

Knee Surg Sports Traumatol Arthrosc. 2025 Dec 7. doi: 10.1002/ksa.70213. Online ahead of print.

ABSTRACT

PURPOSE: To compare the patellar tendon-lateral trochlear ridge (PT-LTR) distance and patellar tendon-trochlear groove angle (PT-TGA) between patients with lateral patellar instability (LPI) and those with malalignment-induced patellofemoral pain (PFP), and to evaluate their differential diagnostic validity.

METHODS: Sixty patients with LPI (mean age: 24.2 ± 7.1 years) and 60 patients with malalignment-induced PFP (mean age: 25.3 ± 6.2 years) were included. PT-LTR, PT-TGA, as defined by Dai et al. (PT-TGA1) and Hinckel et al. (PT-TGA2), and additional patellofemoral alignment parameters-including the tibial tubercle-trochlear groove (TT-TG) distance, tibial tubercle-posterior cruciate ligament (TT-PCL) distance, lateral trochlear inclination (LTI) angle, patellar height, valgus deviation, femoral and tibial torsion, knee rotation and leg axis-were measured. The unpaired t tests with Welch’s correction, receiver operating characteristic (ROC) curve analysis via the Youden index, and parametric power analysis were utilized.

RESULTS: PT-LTR, PT-TGA1 and PT-TGA2 values were significantly greater in LPI patients compared to those with PFP (PT-LTR: 8.8 ± 6.7 mm vs. 3.9 ± 5.3 mm; PT-TGA1: 29.1 ± 11.3° vs. 17.3 ± 8.9°; PT-TGA2: 35 ± 9.6° vs. 24.9 ± 8.5°; all p < 0.0001). ROC analysis revealed AUCs of 0.73 (PT-LTR), 0.79 (PT-TGA1) and 0.78 (PT-TGA2). PT-TGA1 demonstrated the highest sensitivity (85%), whereas PT-TGA2 showed the highest specificity (83%). Significant differences were also found for LTI (p < 0.0001), patellar height (p < 0.0001), TT-PCL (p < 0.0001) and valgus deviation (p = 0.004), but not for TT-TG, femur/tibia torsion, or knee rotation. Power analysis confirmed robust statistical validity (Z ≈ 5.60; power = 99.987%).

CONCLUSIONS: While PT-LTR and PT-TGA measurements were significantly greater in patients with LPIs than in those with malalignment-induced PFP, only PT-TGA measurements demonstrated sufficient diagnostic accuracy to identify LPI. The results reinforce the conceptual advantage of angular over linear measurements of the extensor apparatus.

LEVEL OF EVIDENCE: Level III, diagnostic cohort study.

PMID:41353728 | DOI:10.1002/ksa.70213

Otolaryngol Head Neck Surg. 2025 Dec 7. doi: 10.1002/ohn.70076. Online ahead of print.

ABSTRACT

OBJECTIVE: To compare surgical outcomes of patients with Graves’ disease undergoing total thyroidectomy through the transoral endoscopic thyroidectomy vestibular approach versus the transcervical approach.

STUDY DESIGN: Retrospective cohort study.

SETTING: Tertiary care academic institution.

METHODS: Patients were offered a choice of either approach, undergoing surgery between September 2016 (when TOETVA was first offered) and March 2024. Patients were excluded if they were under 18 years old or received a neck dissection or re-operation. Collected data includes demographics, clinical and surgical variables, pathology, and postoperative complications.

RESULTS: In total, 152 transcervical and 81 transoral cases were included. The transoral group was younger (36.1 vs 45.3 years, P < .0001) and had more females (95.1% vs 77.0%, P = .0003) but had comparable body mass index to the transcervical group. There were no significant differences in the median maximum lobe size (5.9 (transcervical) vs 5.6 (transoral) cm, P = .647). Complication rates were similar between groups. Of the minor complications, temporary hypoparathyroidism was the most prevalent with 12 (7.9%) cases in the transcervical and 7 (8.6%) in the transoral groups. There were 2 (1.3%) and 4 (5.0%) cases of major complications in transcervical and transoral groups, respectively. Multivariable regression for age, sex, length of admission, and surgery duration confirmed no significant associations between approach and complication rates.

CONCLUSION: Transcervical and transoral approaches for surgical management of Graves’ disease show statistically comparable rates of minor and major complications, even early in the learning curve. The choice of approach should involve shared decision-making between surgeon and patient, as highly motivated patients may not be excellent candidates.

PMID:41353724 | DOI:10.1002/ohn.70076

Knee Surg Sports Traumatol Arthrosc. 2025 Dec 7. doi: 10.1002/ksa.70220. Online ahead of print.

ABSTRACT

PURPOSE: Return to performance (RTPerf) after anterior cruciate ligament (ACL) surgery remains difficult to predict in elite alpine skiers, as general criteria may not fully apply. This study aimed to identify determinants and the time needed to achieve RTPerf at the same competitive level.

METHODS: A prospective cohort of 71 elite alpine skiers (mean age: 23.6 ± 5.2 years; height: 173.0 ± 7.8 cm; weight: 72.0 ± 12.1 kg) who underwent ACL surgery was analysed. Demographic and contextual variables, including sex, age, world ranking and type of injury, were collected. Isokinetic knee muscle strength was assessed six months postsurgery. RTPerf (YES/NO) and time to return were evaluated 2 years postoperatively using the International Ski and Snowboard Federation points system. Associations with categorical and quantitative variables were assessed using χ² and t- or Mann-Whitney U tests. Variables with p < 0.2 were included in multivariable logistic regression. Predictors of return time were analysed using Cox regression and receiving operating characteristic (ROC) curves. Statistical significance was set at p < 0.05.

RESULTS: Seventy-nine percent of skiers returned to preinjury performance within 2 years. Primary ACL injury (vs. revision) (odds ratio [OR]: 6.6; 95% confidence interval [CI]: 1.85-23.6; p = 0.004) and isolated injury (vs. complex) (OR: 5.35; 95% CI: 1.39-20.48; p = 0.014) were significant predictors. Average return time was 348 ± 51.6 days. Greater relative knee extensor strength was associated with earlier return. Limb symmetry in knee extension at 60°/s predicted return within 1 year, while the hamstring-to-quadriceps functional ratio at 90°/s predicted later return (area under the curve [AUC]: 0.78; p < 0.01).

CONCLUSIONS: Primary and isolated ACL injuries were linked to higher RTPerf rates, while greater knee extensor isokinetic strength was associated with shorter time to RTPerf in elite alpine skiers.

LEVEL OF EVIDENCE: Level II.

PMID:41353718 | DOI:10.1002/ksa.70220

Psychooncology. 2025 Dec;34(12):e70354. doi: 10.1002/pon.70354.

ABSTRACT

BACKGROUND: Sarcopenic obesity (SO)-excess adiposity with low muscle strength and mass-is a concern in oncology as it may exacerbate functional decline and cancer-related fatigue (CRF). The European Society for Clinical Nutrition and Metabolism (ESPEN) and the European Association for the Study of Obesity (EASO) recently proposed diagnostic criteria for SO, but these remain untested in breast cancer (BC). We examined associations between SO, CRF, quality of life (QoL), and physical function in women with early BC.

METHODS: Sixty-six patients (48.0 ± 9.9 years; stages I-III) underwent assessments of body mass index (BMI) and composition (DXA), waist circumference (WC), and handgrip strength. Physical function was evaluated using the timed up-and-go (TUG) and the 6-m walk test (6-MWT), while QoL and CRF were assessed using the European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC QLQ-C30) and the Cancer Fatigue Scale (B-CFS). The ESPEN-EASO consensus was applied to classify participants as Eutrophic (normal BMI and WC), Obesity (high BMI and/or WC with preserved muscle strength and mass), or SO (high BMI and/or WC with reduced muscle strength and mass).

RESULTS: Global health/QoL (p = 0.03) was lower in SO (61.6 ± 7.2) and Obesity (60.4 ± 3.7) than Eutrophic (81.1 ± 6.9). Physical functioning scale/QoL was lower in Obesity (84.6 ± 2.2) than Eutrophic (97.0 ± 4.1). Mean physical and overall fatigue in both Obesity (5.3 ± 5.5 and 19.6 ± 9.9) and SO (5.0 ± 4.1 and 18.8 ± 8.6) were not statistically different from Eutrophic (2.0 ± 2.9 and 14.3 ± 7.8). TUG was worse in SO (7.5 ± 0.2 s) than both Eutrophic (6.6 ± 0.2 s) and Obesity (6.8 ± 0.1 s-p < 0.01). Comparisons were adjusted for age, menopausal status, and physical activity. SO-related traits were correlated to physical function and to domains of QoL and CRF.

CONCLUSIONS: Obesity and SO are associated with poorer QoL, while SO is also linked with worse physical function in early BC. Assessing SO traits in clinical settings will improve the management of BC, though confirmation across disease stages is needed.

PMID:41353712 | DOI:10.1002/pon.70354

World J Surg. 2025 Dec 7. doi: 10.1002/wjs.70195. Online ahead of print.

ABSTRACT

BACKGROUND: Access to guideline-concordant global-standard breast cancer care remains limited in many low- and middle-income countries (LMICs), where high-cost technologies for diagnostics, surgical diagnosis and treatment (such as radioisotope mapping, ICG fluorescence, and intraoperative margin assessment) are not widely available. The BRIDGE Course (Breast Surgery Resource Integration & Development for Global Excellence) was designed as a short, virtual educational program to educate and update surgeons with validated, low-cost techniques that ensure oncologic safety while addressing resource constraints.

METHODS: A 7-h online course was designed and conducted in September 2025 with participation from international and national faculty. Content emphasized pragmatic adaptations of global guidelines, including triple assessment, surgical decision-making for mastectomy versus breast conservation, sentinel lymph node biopsy (SLNB) using methylene blue and fluorescein torch, and low-cost oncoplastic approaches. Pre- and post-course surveys assessed baseline practice, perceived barriers, satisfaction, confidence, and intent to implement. Descriptive statistics were analyzed.

RESULTS: Seventy-five participants completed the pre-course survey and 66 completed the post-course survey. At baseline, mastectomy was the most common primary operation (30.7%), whereas only 20% predominantly performed breast-conserving surgery; SLNB was mainly performed using methylene blue (68.5%). Reported barriers included lack of resources, training gaps, and patient mindset. Post-course, ≥ 85% of participants reported improved confidence across all domains: triple assessment (83% strongly agreed), mastectomy versus BCS decision-making (74%), SLNB with low-cost tracers (66%), and complication management (60%). Implementation intent was high, with nearly all (96%) planning to adopt at least one new technique and all intending to share knowledge with colleagues or trainees.

CONCLUSION: The BRIDGE Course successfully enhanced knowledge and confidence in resource-adapted breast cancer surgery, with strong intent to implement and improve practices. Such short, focused virtual programs may serve as a scalable model for narrowing disparities in breast cancer care across LMICs.

PMID:41353710 | DOI:10.1002/wjs.70195

Psychooncology. 2025 Dec;34(12):e70346. doi: 10.1002/pon.70346.

ABSTRACT

PURPOSE: Marriage is associated with better health-related quality of life (HRQOL) among cancer survivors, but it is unclear whether these benefits generalize across sexual orientation and gender identities (SOGI). We examined whether marriage is associated with better HRQOL among cancer survivors with diverse SOGI.

METHODS: We analyzed Behavioral Risk Factor Surveillance System (BRFSS) data from 2014 to 2023 among U.S. adults aged 18 and older who self-reported a cancer diagnosis and completed the optional SOGI module (N = 220,896). HRQOL was assessed using the CDC HRQOL-4, including self-rated general health, frequent mental or physical distress, and activity limitation (each defined as ≥ 14 days in the past 30 days). Logistic regression models estimated adjusted odds ratios for HRQOL outcomes by marital status (married, unmarried couple, not married) within SOGI subgroups, controlling for sociodemographic and healthcare access factors.

RESULTS: Marriage was consistently associated with better HRQOL among heterosexual men and women. Among SGM survivors, gay men and transfeminine individuals showed the clearest marriage-related benefits, including lower odds of mental distress and activity limitation. No consistent benefit was observed among lesbian or bisexual women, bisexual men, or transmasculine individuals. Unmarried couples did not consistently show similar protective effects in any group, though small cell sizes limit precision.

CONCLUSION: The health benefits of marriage vary across SOGI subgroups, challenging assumptions of a universal marriage advantage in survivorship.

IMPLICATIONS FOR CANCER SURVIVORS: Survivorship care should account for relational and structural differences in support networks, especially among SGM individuals who may not benefit equally from legal marital status.

PMID:41353709 | DOI:10.1002/pon.70346