Citations

ABSTRACT Background Sunlight has profound impacts on physical and mental health, beyond vision, including effects on circadian rhythms, alertness, mood, and sleep. A family history of any mood disorders is strongly associated with psychiatric disorders including bipolar disorder. The purpose of this study was to evaluate the association between a family history of any mood disorder in patients with bipolar I disorder and solar insolation at varied international onset locations. Methods Data for this analysis were available from 5842 patients with a diagnosis of bipolar I disorder obtained at 83 collection sites in both hemispheres. This included 4752 patients from 71 collection sites in the northern hemisphere and 1090 patients from 12 collection sites in the southern hemisphere. Patient data variables were obtained from records or interviews. Solar insolation data were obtained from The National Aeronautics and Space Administration (NASA) Power database for each onset location, and the ratio of the mean monthly minimum/mean monthly maximum solar insolation was calculated. Typically, the ratio is largest near the equator (little yearly change in solar insolation) and smallest near the poles (large yearly change in solar insolation). Results A significant relationship was found between a family history of any mood disorder, the ratio of the mean monthly minimum/mean monthly maximum solar insolation, and gender. The odds of a family history of mood disorder increased as patient location nears the poles and decreased near the equator. Female gender also increased the odds of having a family history of a mood disorder. Conclusions This study highlighted the association between family history, solar insolation, and gender in international patients with bipolar I disorder. Given the profound effects of sunlight on human health, the family of patients with bipolar disorder who live in the same location with the same solar insolation, and especially females, may be at increased risk for a mood disorder.

Integration of the high-risk human papillomavirus 16 (HPV16) genome into the host chromosome, frequently driven by microhomology-mediated end joining (MMEJ), is a critical step in the carcinogenesis of HPV-associated tumors. However, the mechanisms by which viral oncoproteins manipulate the error-prone MMEJ pathway remain poorly defined. Here, we demonstrate that the HPV16 E6 oncoprotein upregulates MMEJ to facilitate viral genome integration. This heightened MMEJ activity is driven by a marked increase in the protein levels of DNA polymerase theta (PolΘ), a central enzyme of the MMEJ pathway. Mechanistically, we show that the elevation of PolΘ levels in response to HPV16 E6 expression is dependent on the host E3 ubiquitin ligase UBE3A/E6AP but is independent of p53 degradation. E6 redirects UBE3A to enhance the ubiquitination and degradation of RAD23A, a shuttle protein required for delivering polyubiquitinated PolΘ to the proteasome. Consequently, the loss of functional RAD23A phenocopies the effect of HPV16 E6, leading to PolΘ protein stabilization and increased MMEJ activity. By elucidating the E6-UBE3A-RAD23A-PolΘ axis, our findings reveal a mechanism through which HPV manipulates the host DNA repair machinery to promote its integration and oncogenic potential.

776 Background: There continues to be a significant unmet need for safe, effective, and bladder sparing treatment options for patients with non-muscle invasive bladder cancer (NMIBC). TARA-002 is a lyophilized biological preparation for intravesical instillation containing inactivated cells of Streptococcus pyogenes (Group A, type 3) Su strain. TARA-002 rapidly enters cancer cells, activating TLR2 and NOD2 to trigger innate immunity, inflammation, and potential immunogenic cell death. ADVANCED-2 (NCT05951179) is an ongoing Phase 2, open-label study to evaluate the safety and efficacy of intravesical TARA-002 in adults ≥ 18 years with high-grade (HG)-NMIBC CIS (± Ta/T1). Preliminary results showed promising complete response (CR) rates and durable responses in patients with HG NMIBC treated with TARA-002 (Jayram et al. AUA 2025). This abstract presents pooled safety data of TARA-002 from the BCG-naïve cohort and BCG-unresponsive cohort of the ADVANCED-2 study. Methods: The ADVANCED-2 study includes 2 cohorts of BCG-naïve (Cohort A) and BCG-unresponsive (Cohort B) participants. Key exclusion criteria include penicillin allergy; history of ≥ T2 bladder cancer, nodal, or metastatic disease; and concomitant prostatic or upper tract urothelial involvement. Each participant is treated with TARA-002 to receive induction (6 weekly doses), reinduction (if persistent disease at 3 months), and maintenance (through 24 months). Response is assessed every 3 months for 2 years. Long-term follow-up is conducted up to 60 months. Safety is monitored throughout the study. Results: As of 07-October-2025, 60 participants (median age: 74; range: 45 to 92), have been enrolled and exposed to TARA-002: 31 BCG-naïve (Cohort A) and 29 BCG-unresponsive (Cohort B). In both cohorts, 18/60 (30.0 %) participants reported drug-related treatment emergent adverse events (TEAEs). Related TEAEs were Grade 1 (18/60; 30.0%) and Grade 2 (3/60; 5.0%), with no reported Grade 3-5 related TEAEs. Commonly reported related TEAEs (≥ 5%) included bladder spasm (10.0%), dysuria (13.3%), fatigue (6.7%), and micturition urgency (6.7%). Most TEAEs were mild and transient. In both cohorts, 10/60 (16.7%) experienced serious AEs (SAEs); 4/60 (6.7%) were Grade 2 and 9/60 (15.0%) were Grade 3. No participants experienced drug-related SAEs or drug-related TEAEs leading to withdrawal or death. Conclusions: TARA-002 monotherapy was well tolerated, thus demonstrating a favorable tolerability profile to date for the treatment of BCG-naïve and BCG-unresponsive HG NMIBC with CIS (±Ta/T1). TARA-002 has a promising safety profile as a bladder-sparing treatment in HG NMIBC across BCG exposure status. Updated safety data will be provided based on evaluable time points at the time of the presentation. Clinical trial information: NCT05951179 .

142 Background: LuPSMA is a life-prolonging radioligand therapy that is widely considered to have favorable tolerability. SPPADE symptoms (Sleep disturbance, Pain, Physical dysfunction, Anxiety, Depression, low Energy) are common in prostate cancer, yet data on patient-reported outcomes with LuPSMA in real-world settings remain limited. Methods: The E2C2 study (NCT03892967) evaluates the impact of a collaborative care intervention on patient-centered outcomes and healthcare utilization. This analysis includes mCRPC patients who initiated LuPSMA at Mayo Clinic (June 2022-July 2023) and completed at least one symptom survey within 6 weeks before or 2 weeks after the first LuPSMA treatment (baseline survey). SPPADE symptoms were rated on 0-10 scales; scores of 4-6 indicate moderate and 7-10 severe burden. A composite z-score was derived by standardizing each SPPADE domain to the cohort mean and averaging z-scores across domains per patient. Patients were stratified by composite symptom burden using cohort median and upper-tertile cutoffs. Associations with PSA50 response and overall survival (OS, from start of LuPSMA) were assessed using chi-square and Kaplan-Meier methods. In a longitudinal subgroup of patients completing a baseline survey plus at least one additional PRO survey while receiving LuPSMA (≥2 surveys), scores were compared from baseline to best during-treatment using Wilcoxon and Mann-Whitney U tests. Results: Of 373 patients starting LuPSMA, 51 patients met inclusion criteria. Median age was 71 years, 31% had visceral metastases, and median baseline PSA was 42.1 ng/mL. Overall, 85% of patients reported at least one moderate symptom and 46% at least one severe symptom. The most common moderate-to-severe symptoms were low energy (58%), pain (52%), and sleep disturbance (49%). Using an upper-tertile cutoff of the composite SPPADE score, 17 patients had high and 34 had low/moderate symptom burden prior to LuPSMA. PSA50 response was achieved in 17.6% of patients with high vs 47.1% with low/moderate composite symptom scores (p = 0.08). Median OS was 9.2 vs 16.7 months for high vs low symptom groups (p = 0.15, median split). The longitudinal subgroup included 24 patients with serial ePRO assessments while on LuPSMA. Composite SPPADE scores improved from baseline to the best during-treatment assessment in both PSA50 responders (n=10) and non-responders (n=14), with median composite z-score Δ of 0.35 vs 0.20, respectively (p = 0.68). Conclusions: Among patients with mCRPC receiving LuPSMA, baseline SPPADE symptom burden was high. Though not statistically significant in this underpowered cohort, PSA response and OS were numerically inferior in those with higher baseline burden. These findings suggest that ePRO-captured symptom burden may provide prognostic and patient-centered insights beyond traditional clinical variables. Clinical trial information: NCT03892967 .

TPS890 Background: Although first-line (1L) EV + pembrolizumab has improved outcomes for patients with la/mUC, most experience disease progression, highlighting an unmet need for novel therapies. TROP2 is a glycoprotein highly expressed in several epithelial tumors, including UC. Dato-DXd is a TROP2-directed antibody–drug conjugate comprising an anti-TROP2 monoclonal antibody, a tetrapeptide-based cleavable linker, and a topoisomerase I inhibitor payload (DXd), designed to induce selective tumor-cell death and reduce systemic exposure to the payload. Dato-DXd has demonstrated durable efficacy and a manageable safety profile in patients with la/mUC both as monotherapy (TROPION-PanTumor01 [NCT03401385]) and in combination with immunotherapy (TROPION-PanTumor03 [NCT05489211]). We describe a phase 2/3 trial comparing the efficacy and safety of Dato-DXd + platinum CT (carboplatin or cisplatin) vs gemcitabine + platinum CT in participants with la/mUC with disease progression on or after EV + pembrolizumab. Methods: TROPION-Urothelial03 (NCT07129993) is a global, multicenter, randomized, open-label, phase 2/3 trial. In part A (phase 2), ~60 participants will be randomized 1:1 to receive Dato-DXd 4 or 6 mg/kg + platinum CT. In part B (phase 3), ~570 participants will be randomized 1:1 to receive Dato-DXd at the recommended phase 3 dose (determined using part A data) + platinum CT vs gemcitabine + platinum CT. Randomization in part A is stratified by assignment of platinum CT (carboplatin vs cisplatin), and in part B, by assignment of platinum CT, presence vs absence of liver metastasis at screening, and time to progression on 1L EV + pembrolizumab ( < 6 vs ≥6 months). Study treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, death, loss to follow-up, or other reasons per protocol. Radiographic tumor assessments occur every 6 weeks for 54 weeks, then every 12 weeks. The primary endpoint of part A is objective response rate (ORR) by investigator per Response Evaluation Criteria in Solid Tumours, version 1.1 (RECIST 1.1). The dual primary endpoints of part B are progression-free survival (PFS) by blinded independent central review (BICR) per RECIST 1.1 and overall survival (OS). Secondary endpoints include duration of response by investigator per RECIST 1.1 (part A), and PFS by investigator per RECIST 1.1 and ORR by BICR and investigator per RECIST 1.1 (part B). In part A, ORR will be summarized with 2-sided 95% exact confidence intervals using the Clopper–Pearson method by trial group. In part B, PFS and OS will be compared between trial groups using a log-rank test stratified by randomization stratification factors, with hazard ratios from the stratified Cox regression model. Clinical trial information: NCT07129993 .

743 Background: Although patients with Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) have several emerging therapeutic options, there remains a clinical unmet need to improve efficacy, durability of response, and tolerability while obviating the need for radical cystectomy. TARA-002 is a lyophilized biological preparation for intravesical instillation containing inactivated cells of Streptococcus pyogenes (Group A, type 3) Su strain. TARA-002 rapidly enters cancer cells, activating TLR2 and NOD2 to trigger the innate immune response, inflammation, and potential immunogenic cell death. Herein we present interim safety and efficacy data of TARA-002 from the BCG-unresponsive cohort of the ongoing ADVANCED-2 study (NCT05951179). Methods: ADVANCED-2 (Cohort B) is a Phase 2, open-label study to evaluate the safety and efficacy of intravesical TARA-002 in BCG-unresponsive adults ≥ 18 years with high-grade NMIBC CIS (± Ta/T1). Key exclusion criteria include penicillin allergy; history of ≥ T2 bladder cancer, nodal, or metastatic disease; or concomitant prostatic or upper tract urothelial involvement. TARA-002 is delivered intravesically for 2 hours and includes induction (6 weekly doses), reinduction (if persistent disease at 3 months), and maintenance (through 24 months). Response is assessed every 3 months for 2 years. Biopsy is mandated at Month 3. Long-term follow-up is conducted up to 60 months. Safety is monitored throughout the study. The primary endpoint is complete response (CR) at any time defined by the absence of any high-grade recurrence. The key secondary endpoint is duration of response. Results: As of 07-October-2025, 32 BCG-unresponsive participants have been enrolled. Majority of participants were White (84.4%, 27 of 32), non-Hispanic (93.8%, 30 of 32), and male (68.8%, 22 of 32). The median age was 74 years (range: 47 to 92). The majority of participants had a baseline diagnosis of CIS only ie, without concomitant Ta/T1 (75.0%, 24 of 32). TARA-002 demonstrated a 68.4% (13 of 19) CR at any time in evaluable participants. The 6-month CR was 75.0% (9 of 12), the 9-month CR was 50.0% (4 of 8), and the 12-month CR was 37.5% (3 of 8). The salvage rate was 75.0% (6 of 8) with reinduction therapy. Most treatment-emergent adverse events (TEAEs) were mild (CTCAE Grades 1-2) and transient; no participants experienced higher than Grade 3 TEAEs. No participants experienced drug-related serious adverse events (SAEs) or drug-related TEAEs leading to withdrawal or death. Conclusions: In participants with BCG-unresponsive high-risk NMIBC with CIS ± Ta/T1, TARA-002 appears to be well tolerated and demonstrated encouraging efficacy, supporting ongoing accrual of the ADVANCED-2 study. Further follow-up will inform durability of response, and data will be updated based on evaluable time points at the time of the presentation. Clinical trial information: NCT05951179 .

INTRODUCTION: Despite the widespread use of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC), many patients remain at risk of progression. Emerging data suggest that normalization of alkaline phosphatase (ALP) and total bilirubin (TB)—particularly when TB < 0.6 times the upper limit of normal (× ULN)—is associated with improved outcomes compared with ALP reduction to < 1.5 × ULN. This study investigated the association between ALP normalization in response to UDCA and long-term clinical outcomes in a real-world cohort of patients with PBC. METHODS: We compared complication-free survival in patients achieving an ALP > ULN and < 1.5 × ULN (adequate response) with those with an ALP ≤ ULN on UDCA monotherapy. Complication-free survival was defined as the absence of serious liver-related clinical events. Restricted mean survival time was used to quantify survival time gained. RESULTS: Patients achieving normal ALP and/or TB ≤ 0.6 × ULN demonstrated significantly improved complication-free survival compared with those with an adequate ALP response. Event-free survival was extended by 1.34 years (95% CI: 0.56, 2.11; P = 0.001) for ALP normalization alone, 3.7 years (95% CI: 3.11, 4.29; P < 0.001) for TB ≤ 0.6 × ULN, and 4.51 years (95% CI: 4.13, 4.88; P < 0.001) for those meeting both criteria. The risk of severe clinical events was reduced in patients achieving ALP normalization (hazard ratio [HR] 0.34; 95% CI: 0.15, 0.80; P = 0.01), TB ≤ 0.6 × ULN (HR 0.23; 95% CI: 0.09, 0.55; P = 0.001), or both (HR 0.14; 95% CI: 0.05, 0.38; P < 0.001). High-risk patients, defined by liver stiffness measurement ≥ 10 kPa or clinical, histological, or laboratory evidence of cirrhosis or portal hypertension, derived the greatest benefit. DISCUSSION: Achieving normal ALP and TB ≤ 0.6 × ULN is associated with significantly improved complication-free survival, particularly in high-risk patients. These findings highlight the potential of biochemical thresholds as a meaningful therapeutic goal in PBC management.

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.

Background Tricuspid regurgitation (TR) is a common valvular disorder that can affect patients’ quality of life and survival. The impact of TR etiology on overall survival and the associated risk factors in each subgroup are not well studied. Methods Multisite, retrospective study evaluating survival based on TR etiology using Kaplan–Meier and Cox regression models. Stepwise approach was used to define TR etiology (≥moderate): primary (PTR; presence of a primary valvular pathology), lead associated (LTR; lead interfering with closure), and secondary TR (STR) in the setting of left‐sided valvular disease, left ventricular disease, other causes of pulmonary hypertension, right ventricular disease, and atrial secondary TR. Results A total of 12 899 patients were included (3% PTR, 90% STR, 7% LTR). The mean age was 68±14, 73±13, and 71±13 years, respectively (44%–55% female patients). Adjusting for age, sex, and TR severity, patients with PTR had better overall survival (PTR: reference; STR hazard ratio [HR], 1.4 [1.2–1.6], LTR HR, 1.5 [1.1–1.7]). On multivariable Cox regression, the Tricuspid Regurgitation Impact on Outcomes score was associated with mortality across all groups ( P <0.05 for all). In addition, other risk factors associated with worse outcomes included pulmonary hypertension and ≥moderate right ventricular enlargement in PTR; left‐sided valvular disease, pulmonary hypertension, and ≥moderate right ventricular dysfunction in STR; and left ventricular disease and ≥moderate right ventricular dysfunction in LTR. Conclusions Patients with PTR have better survival than STR and LTR. Tricuspid Regurgitation Impact on Outcomes score was associated with mortality across etiologies, whereas other risk factors are etiology specific. Improved risk profiling may enhance patient selection, treatment decisions, and outcomes.