Metabolic dysfunction and neurocognitive decline share inflammatory pathways that may be amplified in people with HIV (PWH). Prior studies suggest insulin resistance correlates with cognitive decline, while gut-related metabolites, such as betaine, may be protective through metabolic regulation and anti-inflammatory effects. We investigated whether metabolic markers differentially associate with cognitive performance in PWH versus people without HIV (PWoH).

We enrolled 200 participants, equally stratified by HIV and diabetes mellitus status, into four groups of 50. All completed neuropsychological testing yielded demographically corrected global T-scores (higher indicates better performance). Biomarkers included GlycA, Diabetes Risk Index (DRI), Lipoprotein Insulin Resistance Index (LP-IR), branched-chain amino acids, and betaine. Multiple linear regression examined associations between metabolic markers and T-scores, adjusting for covariates.

Participants had a mean age of 55.7 years (71.0% male). GlycA levels were higher in individuals with diabetes (p = 0.001). Higher DRI levels were associated with worse global T-scores (standardized β = -0.27, p = 0.009). Higher LP-IR was associated with worse cognitive performance in PWH, but not in PWoH (interaction p = 0.007). HIV moderated the association between betaine and global T-scores (interaction p = 0.01); higher betaine was associated with better cognitive performance (standardized β = 0.24, p = 0.02). Higher betaine correlated with lower LP-IR in PWH (standardized β = -0.47, p < 0.01) and lower DRI in all participants (ps < 0.05).

Insulin resistance might play a prominent role in cognitive health in PWH than PWoH, suggesting HIV-related metabolic vulnerability is affecting brain health. Associations between betaine, which has immunomodulatory effects, and improved metabolic profiles suggest potential therapeutic targets to preserve cognitive function in PWH. These observational findings may reflect metabolic, dietary, or lifestyle-related factors and require confirmation in studies with detailed nutritional assessment.

Pathogenic variants in BRCA1 and BRCA2 confer substantial risks of breast and ovarian cancer; however, risk for female individuals undergoing testing, particularly those with variants of uncertain significance (VUS) or negative results, remain poorly defined.

To estimate lifetime incidence of breast and ovarian cancer among female individuals undergoing BRCA1 or BRCA2 testing across all result categories and evaluate the modifying association of family history.

This retrospective cohort study was conducted as part of the What Comes Next Cohort Study, a near-population-based cohort in Ontario, Canada, established through linkage with administrative databases. Female participants who underwent BRCA1 or BRCA2 testing from 2007 to 2016 were matched 1:5 to females from the general population. Participants were followed up to September 2024. Data were analyzed from May to December 2025.

The outcome of interest was the cumulative incidence of breast and ovarian cancer to age 80 years, stratified by genetic test result and family history.

Of 15 986 individuals in the What Comes Next Cohort Study cohort, 6966 individuals eligible for breast cancer analyses (median [IQR] age, 49 [38-60] years) were matched to 34 830 individuals from the general population and 13 276 individuals eligible for ovarian cancer analyses (median [IQR] age, 51 [41-61] years) were matched to 66 380 individuals from the general population. Cumulative breast cancer incidence to age 80 years was 62.1% (95% CI, 52.2%-69.9%) for BRCA1 pathogenic variant carriers and 66.1% (95% CI, 57.5%-72.9%) for BRCA2 pathogenic variant carriers, compared with 12.0% (95% CI, 11.2%-12.8%) in the general population; corresponding ovarian cancer incidence was 56.0% (95% CI, 40.0%-67.7%) for BRCA1 pathogenic variant carriers and 29.3% (95% CI, 14.2%-41.7%) for BRCA2 pathogenic variant carriers, compared with 1.5% (95% CI, 1.3%-1.7%) in the general population. Family history modified breast cancer risk, reaching a cumulative incidence of 86.3% (95% CI, 70.9%-93.5%) in carriers with at least 2 affected first-degree relatives vs 55.8% (95% CI, 45.4%-64.2%) in carriers without a family history of breast cancer. Among individuals with test results positive for pathogenic variants, lifetime risk of ovarian cancer was similarly modified by family history, reaching 64.2% (95% CI, 37.0%-79.7%) in those with vs 38.2% (95% CI, 25.8%-48.4%) in those without a family history of ovarian cancer. Individuals with VUS and negative test results also had increased lifetime breast cancer risks (31.2% [95% CI, 19.2%-41.4%] and 26.3% [95% CI, 23.0%-29.4%], respectively) but no increase in ovarian cancer risk. Individuals with test results negative for a known familial variant had risks similar to the general population.

In this cohort study of females who underwent BRCA1 or BRCA2 testing, the lifetime cancer risk varied substantially across BRCA test result groups and was further modified by family history. Elevated breast cancer risk among individuals with VUS or negative results highlights the need for individualized risk assessment and management beyond genetic test results alone.

Aromatase inhibitors (AIs) profoundly suppress estrogen synthesis and accelerate bone loss in postmenopausal women with early breast cancer (EBC). Although body mass index (BMI)-defined obesity has been considered protective for skeletal health, emerging evidence suggests a paradoxical association with fracture risk.

To evaluate whether fat mass percentage (FM%) greater than 40.8%, measured by dual-energy x-ray absorptiometry (DXA), is associated with vertebral fracture (VF) progression in patients with EBC receiving AIs.

This retrospective cohort study included consecutive postmenopausal women with EBC (stages I-III) recruited in a single referral center between September 2014 and June 2024. All patients received adjuvant endocrine therapy and underwent serial DXA assessments. Patients treated with tamoxifen or with major comorbidities affecting skeletal fragility were excluded.

Body composition and bone fragility parameters evaluated by DXA at baseline and at 18, 24, and 30 months.

Adiposity excess was defined as FM% greater than 40.8%, and VF progression was defined as new incident fractures and/or worsening by at least 1 Genant grade at a previously fractured vertebral level. Their association was evaluated using a joint model; time-dependent associations were evaluated using extended Cox regression. Secondary analyses explored associations with bone mineral density, trabecular bone score (TBS), appendicular lean mass index (ALMI), and traditional fracture risk factors.

A total of 769 White women (median [range] age, 63 [30-87] years; median [range] BMI, 24.6 [15.6-46.1]) entered the study. During follow-up, 69 patients (9.0%) experienced VF progression. FM% greater than 40.8% was independently associated with increased VF progression (adjusted hazard ratio [HR], 2.00; 95% CI, 1.44-2.82; P < .001). Higher ALMI (HR, 0.38; 95% CI, 0.22-0.65; P < .001) and BMD (HR, 0.79; 95% CI, 0.66-0.94; P = .01) were associated with lower risk of VF progression.

In this retrospective cohort study of patients with EBC receiving AIs, adiposity excess was identified as a novel fracture risk factor, whereas higher muscle mass was protective. These findings support incorporating body-composition assessment into fracture-risk evaluation and preventive strategies for patients undergoing AI therapy.

Targeted cancer therapies increasingly require platforms that can penetrate poorly perfused tumor regions while minimizing systemic toxicity. Bacteria, owing to their intrinsic tumor tropism, genetic programmability, and immunostimulatory properties, have re-emerged as versatile anticancer agents, ranging from attenuated tumor-colonizing strains to highly engineered "living therapeutics." In this review, we synthesize the mechanistic foundations and therapeutic advances of bacterial-based cancer therapy through four major themes. First, we examine foundational mechanisms, including tumor-selective colonization, direct oncolysis and cytotoxicity, activation of innate and adaptive immunity, and remodeling of the tumor microenvironment. Second, we discuss engineering strategies that enable controllable delivery of therapeutic payloads, such as cytokines, antibodies and nanobodies, enzyme-prodrug systems, toxins, and nucleic-acid therapeutics, while also improving biosafety and biocontainment. Third, we evaluate combination strategies integrating bacteria with chemotherapy, radiotherapy, phototherapy, and immunotherapy, with emphasis on how bacteria complement conventional modalities by targeting hypoxic, necrotic, and immunologically refractory tumor niches. Fourth, we summarize translational progress, including representative early-phase clinical experiences, manufacturing challenges, and major safety constraints. We also highlight emerging microbiome-disease databases and computational resources that may support target selection, biomarker discovery, and therapy-response stratification. Current evidence supports bacteria as a promising precision modality, particularly for immunologically "cold" or hypoxic tumors; however, major challenges remain in the predictability of intratumoral distribution, host clearance, genetic stability, and long-term safety. Addressing these barriers through rigorous engineering, standardized manufacturing, and clinically meaningful endpoints will be essential for the next generation of bacterial therapeutics in oncology.

Genitourinary Syndrome of Menopause (GSM) remains a significant unmet need for postmenopausal breast cancer survivors receiving aromatase inhibitor (AI) therapy.

In this randomized, controlled, open-label clinical trial, ER+ breast cancer survivors receiving adjuvant AI therapy with symptomatic GSM were randomized to receive 24 weeks of a non-hormonal vaginal moisturizer (Replens^®) or vaginal estrogen therapy (either Vagifem^® vaginal tablets or Estring^® vaginal ring). The primary endpoint was change in vaginal dryness. Secondary endpoints included dyspareunia, sexual functioning, vaginal pH, and serum estradiol values.

Twenty-three patients were enrolled (vaginal estrogen [VE], n = 11; non-hormonal [NH], n = 12). Vaginal dryness and dyspareunia scores improved significantly in the VE arm compared with the NH arm (p = 0.049, p = 0.048, respectively). Vaginal pH decreased significantly with vaginal estrogen compared to non-hormonal therapy (p = 0.0286). Other domains of sexual function (libido, ability to achieve orgasm, sexual satisfaction, and relationship with partner) were not significantly different between the 2 groups. Serum estradiol levels remained low through the first 12 weeks of therapy. Two participants demonstrated estradiol elevations above threshold at 24 weeks (21.8 pg/mL and 16 pg/mL); both reported non-adherence to AI therapy preceding measurement.

In this randomized study, vaginal estrogen provided greater improvement in vaginal dryness and dyspareunia than non-hormonal therapy in breast cancer survivors. These findings provide prospective evidence supporting symptomatic benefit with minimal systemic estrogen exposure in most patients, although larger studies with longer follow up are needed to define long-term safety and efficacy.

Patients with triple-negative breast cancer (TNBC) are encouraged to consider clinical trials given limited treatment options, yet little is known regarding barriers to trial participation in this population. We examined whether patient-level factors, including disease knowledge, were associated with TNBC patients' participation in trials.

From a prospective multicenter registry of patients with newly-diagnosed TNBC, we identified those with stage I-III tumors who completed at least one survey assessing TNBC knowledge, risk perceptions, treatment rationales, and participation in trials. Accuracy of tumor characteristics reported by patients was verified with medical records. Logistic regression was used to identify factors associated with self-reported trial participation.

TNBC knowledge varied among patients, with many reporting their tumor characteristics incorrectly and/or underestimating their recurrence risk. Among 116 patients with trial participation responses, 55 (47%) reported participating in a trial, including 35% who underwent upfront surgery and 66% who received neoadjuvant systemic therapy. Trial participation was less likely in upfront surgery patients (odds ratio [OR]: 0.41, 95% confidence interval [CI]: 0.20-0.89, p = 0.02) and more likely in stage II versus stage I patients (OR: 2.43, 95% CI: 1.09-5.39; p = 0.03). No associations were found with TNBC knowledge.

Nearly half of patients surveyed reported participating in trials. While not significantly associated with trial participation, many patients demonstrated limited knowledge about TNBC and their prognosis. More research is needed to understand trial participation barriers and improve information delivery in this population to leverage patient engagement in developing more effective TNBC treatments.

Total Neoadjuvant Therapy (TNT) is increasingly replacing standard chemoradiotherapy (sCRT) for the treatment of locally advanced rectal cancer (LARC). Data on the use of personalized TNT (pTNT) regimens tailored to patient disease characteristics remain scarce. Accordingly, this study aimed to assess long-term outcomes of pTNT in patients with LARC.

This was a secondary analysis of a multicentre retrospective cohort study. Patients treated with pTNT between 2019 and 2022 were compared to a historical cohort from the WAIT trial (2012-2014), which included extended chemotherapy during the interval period (xCRT) or sCRT followed by adjuvant chemotherapy. The main outcomes were 4-year disease-free survival (DFS) and overall survival (OS).

Forty patients treated with pTNT were matched with 49 patients from the WAIT trial (25 xCRT, 24 sCRT). All WAIT trial patients underwent surgery, whereas 27 (67.5%) pTNT patients underwent surgery and 13 (32.5%) were managed non-operatively. Median follow-up was 48 months. No significant differences were observed in 4-year DFS (pTNT 70% vs. xCRT 68% vs. sCRT 75%, P = 0.764) or OS (pTNT 82.5% vs. xCRT 80% vs. sCRT 83.3%, P = 0.907). Within the pTNT group, patients with an oCR had significantly higher OS compared to those without oCR (95.2% vs. 68.4%, P = 0.021).

Our findings suggest that pTNT achieves comparable survival outcomes to xCRT and sCRT in patients with LARC, despite higher rates of non-operative management. These findings should be interpreted cautiously given the exploratory nature of the analysis and limited sample size. Larger studies with longer follow-up are required to validate these early data.

Robotic surgery is increasingly adopted for rectal cancer management, including selected patients with locally advanced disease. We evaluated perioperative safety and medium- to long-term outcomes after robot-assisted rectal cancer surgery with multivisceral resection for cT4 rectal cancer in a single high-volume center. We retrospectively reviewed 45 consecutive patients with locally advanced rectal cancer who underwent robot-assisted surgery with multivisceral resection between April 2021 and June 2025. Demographic and clinical variables, surgical and postoperative outcomes, and pathological findings were extracted from medical records. Recurrence-free survival (RFS), overall survival, and local recurrence were assessed. The study included 45 patients (19 females) with a median age of 72 years. Postoperative complications of Clavien-Dindo grade III or higher occurred in 4 patients (8.8%). Pathologically, 21 patients (46.7%) had pT4 disease (pT4a in 2 and pT4b in 19 [42.2%]), and 39 patients (86.7%) achieved RM0 margins. The median follow-up was 23 months. Across stages I-III, RM0 resection was associated with superior 3-year RFS compared with RM1/RMX resection (74.6% vs. 33.3%, p = 0.03). Robot-assisted rectal cancer surgery combined with multivisceral resection can be performed safely, with acceptable midterm outcomes. RM0 status was linked to improved RFS, supporting complete tumor resection as a prognostic determinant even in locally advanced cases.

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer related death in the United States. While Stage I and II PDAC represent the most treatable and potentially curative stages, most patients do not survive past 5 years of treatment. We sought to understand factors associated with long term survival in early-stage PDAC to improve outcomes and reduce disparities.

The National Cancer Database (NCDB) was queried for Stage I and II PDAC patients treated between 2012 and 2021. Patients were only included if they had a documented survival information. Comparisons between patients alive or deceased at 1, 3 and 5 years were evaluated using Wilcoxon, Chi-square, and Cochran-Armitage trend tests where appropriate. A multivariable Cox proportional hazards model (MVA) was used to evaluate factors associated with overall survival (OS).

We analyzed 43,398 patients with Stage I (n = 21,938) and Stage II (n = 21,460) PDAC. One-, three-, and five-year survival rates were 75.2%, 30.3%, and 12.8% for Stage I, and 68.6%, 23.4%, and 10.5% for Stage II, respectively. Across both stages, improved survival was significantly associated with younger age, lower Charlson-Deyo comorbidity score, Asian race, private insurance, higher income and education levels, and tumor location in the pancreatic body or tail (all p < 0.0001). Higher tumor grade, Black race, Medicaid or uninsured status, and treatment at community-level facilities were associated with significantly worse outcomes. Multivariable analysis confirmed these variables as independent predictors of one-, three-, and five-year survival. Despite early-stage diagnosis, marked disparities in long-term survival persisted based on race, insurance, and socioeconomic status.

Long-term survival for Stage I and II PDAC remains limited, despite diagnosis at an early and potentially curative stage. This highlights the need to not only focus on screening mechanisms for early diagnosis, but to address disparities and expand access to high-quality care that limit long term survival in this cohort. These results support ongoing investment in early detection, equitable treatment delivery, and research into tailored therapeutic strategies.

Helicobacter pylori (H.pylori) eradication contributes to gastric cancer (GC) prevention, yet many subjects are unaware of their infection status. We implemented a workplace-based H.pylori screening.

We implemented a cross-sectional screening with short-term follow-up among hospital workers (HWs), enrolled during occupational health surveillance (OHS). A stool antigen test (SAT) was adopted for H.pylori diagnosis. H.pylori-positive HWs were referred to their general practitioner (GP) or a gastroenterologist and were followed up at three months. Participation, prevalence of infection, participants' experience, and treatment rates were investigated through descriptive and multivariable analyses.

The study was carried out between 2023 and 2025 at S.Orsola University Hospital in Bologna, Italy.

The study targeted HWs aged 40-65 employed at S.Orsola University Hospital.

Of 744 eligible HWs contacted, 550 were enrolled (73.9%), including 399 through OHS and 151 volunteers; the largest proportion of participants were women (74.7%) and nurses (40.2%). Dropout rate was 15.5% (n = 115), leaving 435 HWs with a SAT result. H.pylori prevalence was 16.6%. Men were less likely to participate than women (OR = 0.68, 95% CI = 0.47-0.99). Education was negatively associated with H. pylori infection (OR = 0.41, 95% CI = 0.18-0.93 for the highest educational level vs the lowest). No specific pattern was observed in relation to contact with a physician and treatment prescription. 58/72 H. pylori-positive HWs (80.6%) contacted a physician, 53 (73.6%) being prescribed a treatment and 13 (18.1%) undergoing upper endoscopy. Confirmatory test rate after treatment was suboptimal, while eradication rate was 97.3% when considering those with confirmatory test result (36/37 HWs). Across followed up HWs, the average quality of experience was 8.9/10; 13 had a family member tested following this intervention.

The intervention integrated into OHS was well received and extended to family members of the participants, suggesting that a workplace-based H.pylori screening might contribute to GC prevention. Replications in other workplaces are warranted.