Citations

Abstract Recent work on double descent has challenged classical bias–variance tradeoffs, showing that test error can decrease, increase sharply near the interpolation threshold, and then decrease again as model capacity grows. This phenomenon has been documented in regression and classification, but its relevance to survival analysis remains unclear. Survival data are subject to censoring, which obscures true event times, and widely used models such as the Cox proportional hazards model are optimized via partial likelihoods that emphasize ranking rather than calibrated risk estimation. It is therefore unknown whether double descent occurs in this setting, how censoring influences its manifestation, or how it interacts with standard performance metrics.We investigate these questions using synthetic survival data generated from Weibull hazards with controlled censoring, allowing systematic variation of model capacity from under to over parameterized regimes. While we verified double descent occurs in survival models, calibration plateaus and decouples from discrimination, even under strong $\ell_2$ regularization. This decoupling arises because the Cox partial likelihood optimizes rankings rather than magnitudes, producing extreme risk scores that break the Breslow estimator used to estimate survival probabilities. These results highlight limitations of discrimination-based model selection in survival analysis and underscore the need for calibration-aware evaluation in high-capacity prognostic models.

Background: Transanal total mesorectal excision (taTME) facilitates sphincter preservation in low rectal cancer. Preliminary results and functional outcomes from the North American multicenter phase II taTME trial (NCT03144765) have been published. Three-year outcomes are reported. Methods: Patients with stage I to III rectal adenocarcinoma were enrolled across 11 centers (2017–2022). Endpoints included TME grade, 3-year overall survival, disease-free survival, cancer-specific survival, recurrence, late (beyond 90 d) complications, and stoma-free survival. Surveillance followed National Comprehensive Cancer Network guidelines, with pelvic magnetic resonance imaging (MRI) at 3 years to assess for pelvic sidewall recurrence when possible. Kaplan–Meier analysis assessed oncologic outcomes. Results: One hundred patients underwent taTME for tumors at a median of 5.8 cm from the anal verge, with intersphincteric resection in 36% and handsewn anastomosis in 54%. Median follow-up was 50.9 months. Late complications occurred in 32 patients, including 21 severe (Clavien-Dindo ≥3). Late anastomotic complications occurred in 5 patients; one required surgical revision. Estimated 3-year overall survival, cancer-specific survival, and disease-free survival were 93.7%, 96.6%, and 84.6%, respectively. Distant recurrence occurred in 15 patients (median: 17.6 months), most commonly in the lung and liver. Locoregional recurrence occurred in 2 patients. Preoperative N stage, lymph node yield, tumor deposits, and perineural invasion were associated with recurrence. Among 100 patients diverted at taTME, 97% were stoma-free at 3 years; 4 patients later underwent secondary diversion. Conclusions: Three-year outcomes of this multicenter trial support the safety and efficacy of taTME in resectable mid and low rectal tumors, with outcomes comparable to contemporary studies. Longer-term oncologic and functional outcomes are needed.

Abstract Background Clival metastases are a rare and clinically aggressive manifestation of advanced prostate cancer, associated with cranial nerve palsy and poor survival. The molecular features of prostate cancers giving rise to clivus metastases remain unknown. Patients and methods We performed a multi-center retrospective study across six institutions, identifying prostate cancer patients with radiographically confirmed clival metastases and available next-generation sequencing (NGS) data. Baseline characteristics and clinical outcomes were collected. Genomic alterations from tissue- and/or blood-based assays were aggregated at the patient level and compared with a publicly available metastatic castration-resistant prostate cancer (mCRPC) cohort (SU2C/PCF). Results Fifty-nine patients with clival metastases contributed 87 molecular assays. More than half of patients had Gleason grade group 5 cancer and presented with de novo metastatic (M1) disease. The median interval from initial prostate cancer diagnosis to clival metastasis was 71.4 months (95% CI, 42.0-101.7), while median overall survival following clival involvement was only 15.3 months (95% CI, 6.9-22.8). Compared with the SU2C/PCF mCRPC cohort, clival metastases showed significant enrichment of BRAF and CHEK2 alterations as well as homologous recombination repair (HRR) with relative depletion of AR-related, PI3K pathway, and G2–M pathway alterations. Conclusion Prostate cancers giving rise to clival metastases exhibit a distinct molecular profile enriched for DNA damage–repair and RAF kinase alterations, suggesting unique metastatic biology and potential therapeutic vulnerabilities.

PURPOSE BRCA carriers face high risks of developing both breast and ovarian/fallopian tube cancers (hereafter referred to as ovarian ). Among BRCA carriers with ovarian cancer, it is not clear whether the risk of breast cancer is sufficiently high that risk-reducing mastectomy should be offered. This study aimed to assess the risk of breast cancer BRCA carriers after a diagnosis of ovarian cancer. METHODS We included women with a pathogenic/likely pathogenic variant in BRCA1 or BRCA2 , a diagnosis of ovarian cancer, and no other cancer history and no risk-reducing bilateral mastectomy. Women were followed for incident breast cancer from the date of ovarian cancer diagnosis or the date of baseline questionnaire, whichever came last. The 5-, 10-, and 15-year cumulative risks of breast cancer were compared for women with ovarian cancer and an age-matched set of control women without ovarian cancer. RESULTS A total of 960 participants with ovarian cancer were identified (814 BRCA1 and 146 BRCA2 carriers). After a mean follow-up of 4.9 years, 41 women (4.3%) developed breast cancer, at a mean age at diagnosis of 57.5 years (range, 39-74). Actuarial cumulative breast cancer risks after ovarian cancer were 4.4%, 8.9%, and 11.5% at 5, 10, and 15 years, respectively. Only three breast cancer–related deaths occurred. Among 741 age-matched BRCA carriers without ovarian cancer, actuarial cumulative risks of breast cancer were 20.9%, 38.6%, and 47.2% at 5, 10, and 15 years, respectively. The hazard ratio for breast cancer, after an ovarian cancer diagnosis, compared with no ovarian cancer, was 0.18 ([95% CI, 0.12 to 0.27]; P < .0001). CONCLUSION After ovarian cancer, BRCA carriers have a relatively low risk of breast cancer. Risk-reducing mastectomy should not be recommended routinely, but might be considered for long-term survivors. Magnetic resonance imaging surveillance and/or mammography is a realistic alternative.

Background Corticosteroid injections (CSIs) are widely employed for chronic pain. These injections include peripheral nerve blocks and trigger point injections, injections of large appendicular joints, the axial facet and sacroiliac joints, and the epidural space. These injections may be performed in patients who have been recently vaccinated or plan to be vaccinated. This multisociety multispecialty position statement aims to develop evidence-based statements and recommendations (SRs) on the safe interval between CSIs and COVID-19 and influenza vaccine administration. Methods Development of the position statement was approved by the American Society of Regional Anesthesia and Pain Medicine Board of Directors and several other societies that agreed to participate. The scope of the SRs was agreed on to include the efficacy of COVID-19 and influenza vaccines, adverse events related to the CSIs, specifically the effect of CSIs on the hypothalamic–pituitary axis, incidence of COVID-19 in patients who had CSIs during the pandemic, incidence of influenza in patients who had CSIs during the influenza season, and recommend a reasonable interval between CSIs and COVID-19 and influenza vaccination 20 mg/day of prednisone s. Experts were assigned topics to perform a comprehensive literature review and draft SRs, which were refined and voted for consensus (≥75% agreement) using a modified Delphi process. A modified version of the US Preventive Services Task Force grading of evidence and strength of recommendation was followed. Results All SRs were approved by all participants after four rounds of discussion. The Practice Guidelines Committees and Boards of Directors of the participating societies also approved all SRs. If a vaccine has been recently administered or planned, then for non-urgent indications, the CSI should be offered at least 1 week before or after vaccine administration. For healthy patient(s), CSI, or vaccine administration may be performed without a 7-day interval after informed discussion with the patient and consent regarding the risk of blunted vaccine efficacy. For non-healthy patients, shared decision-making should include discussion of diminished vaccine effectiveness and the possibility of influenza or COVID-19 infection. Conclusions In this position statement, we provide recommendations on the optimal timing between CSIs and COVID-19 or influenza vaccine.

PURPOSE The continuous development of new imaging approaches, molecular phenotyping, genetic subtypes, prognosis assessments, and effective therapies across a range of disease states has created a need to redefine terminology and best practices for clinical trial conduct in patients with advanced prostate cancer. Methods We convened an international expert committee of diverse working groups, the Prostate Cancer Working Group 4 (PCWG4), between 2016 and 2025. Our objective was to formulate updated criteria based on emerging evidence and clinical trial data in a biomarker context to provide guidance for clinical trial design, eligibility, and end point assessments for patients with advanced prostate cancer. RESULTS PCWG4 redefines terminology around the disease state and previous therapies in a patient-centric context and terminology focused on androgen pathway modulation. We consider imaging, with a particular focus on positron emission tomography (PET)–defined disease. New recommendations are provided for disease state terminology, defining eligibility criteria, response and delay/prevent end points, intervals for reassessments including imaging, and patient-reported outcome determination. We provide recommendations in a biomarker-based context of use for the intended indication, reflective of patient benefit for specific interventions. We emphasize the need for development of validated PET imaging and molecular and phenotypic criteria as well as trial designs to appropriately risk stratify patients, predict and assess benefit, and measure post-treatment outcomes reliably in a trial framework. CONCLUSION PCWG4 updates recommendations on patient and tumor characterization, therapy development, and imaging criteria and extends guidance into earlier androgen pathway modulator–naïve/sensitive disease states to reflect an evolving, heterogeneous, and diverse patient population to optimize treatment benefits for all patients.

The expanding application of spinal stimulation therapies in spinal cord injury (SCI) rehabilitation necessitates a critical reexamination of cardiovascular (CV) responses to these interventions. A key question arises: How should blood pressure (BP) responses to stimulation be interpreted, and does the conventional definition of autonomic dysreflexia (AD) adequately capture these phenomena? Researchers remain divided—some classify BP elevations during stimulation as AD, while others attribute them to intentional neuromodulation targeting sympathetic preganglionic neurons. This review scrutinizes the various AD definitions in the literature, including the conventional threshold (systolic BP increase >20 mmHg), revealing substantial limitations in research contexts. While symptomatic AD occurs in only 4-7% of stimulation study participants, asymptomatic BP increases are considerably more frequent. This established threshold lacks robust physiological rationale and creates significant interpretive challenges, particularly when evaluating interventions designed to modulate BP responses. The current limitations of guideline-based definitions of AD challenge research interpretation and clinical translation. Although several publications describe AD as “unregulated” or “uncontrolled,” it has not yet been incorporated into formal guideline definitions. This review underscores the need for a collaborative effort to refine AD definitions in research, particularly in the context of spinal stimulation. Future consensus development should address whether uniform thresholds should apply across different contexts, how to integrate heart rate dynamics and absolute BP values alongside symptomatic status, and how to meaningfully distinguish therapeutic BP modulation from adverse autonomic responses. This is essential for standardizing research approaches, optimizing stimulation parameters, and ensuring efficacy and safety as spinal stimulation technologies advance clinically.