In recent years, novel antidiabetic drugs, particularly sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA), have attracted increasing interest for their effects beyond glycemic control, including potential actions on male reproductive function. This review critically summarizes current evidence regarding the impact of antidiabetic therapies on spermatogenesis, testicular metabolic homeostasis, and male gonadal function, focusing on the underlying molecular and pathophysiological mechanisms. Experimental evidence suggests that metabolic dysfunction, oxidative stress, inflammation, apoptosis, and impaired Sertoli cell metabolism play a central role in diabetes- and obesity-associated male reproductive dysfunction. In this context, SGLT2i and GLP-1 RA appear capable of modulating several of these pathways, improving sperm parameters, preserving testicular architecture, and attenuating oxidative and inflammatory damage in preclinical models. Emerging data also suggest possible direct gonadal effects mediated through intracellular signaling pathways involved in steroidogenesis, autophagy, and cellular energy regulation. However, clinical evidence remains limited and partly conflicting, and it is still unclear whether these findings translate into clinically meaningful reproductive benefits in humans. Preliminary evidence suggests that dual GIP/GLP-1 receptor agonists, such as tirzepatide, may exert beneficial effects on male reproductive health. However, direct evidence regarding their impact on spermatogenesis and fertility remains limited. Overall, well-designed prospective clinical studies incorporating reproductive and hormonal outcomes are warranted to better define the role of these therapies within an integrated andro-metabolic approach to the management of obesity- and diabetes-associated male reproductive dysfunction.

Recent trials in BCG-naïve high-risk non-muscle-invasive bladder cancer (HR-NMIBC) have added immunotherapy to BCG, often using event-free survival (EFS) as the primary endpoint. However, neither EFS nor progression-free survival (PFS) has been validated as a surrogate for overall survival (OS) in this setting.

We retrospectively analyzed data from 18 international centers, including patients with BCG-naïve HR-NMIBC treated between 2001 and 2025. Adequate BCG exposure (International Bladder Cancer Group criteria) was the treatment contrast for its effects on intermediate clinical endpoints (ICEs) and OS, using a 12-month landmark approach and inverse probability of treatment weighting (IPTW). Surrogacy was assessed with: (1) adapted Prentice criteria, with time-varying ICEs in IPTW-adjusted Cox models for OS; and (2) an emulated two-stage meta-analytic framework estimating individual-level association (Kendall's τ) and pseudo-trial-level surrogacy (R²) across 500 random pseudo-trial replications.

Of 3384 patients, 3153 entered the landmark analysis; 2697 (85.5%) received adequate BCG. Median follow-up was 50 months (IQR 17-77). Adequate BCG was associated with improved OS (HR 0.63, 95% CI 0.47-0.83) and lower risks of PFS events (HR 0.46, 95% CI 0.37-0.58) and EFS events (HR 0.48, 95% CI 0.40-0.58). Both ICEs were independently associated with OS, but adjusting for each did not fully attenuate the BCG effect. Individual-level association with OS was strong for PFS (τ = 0.79, 95% CI 0.75-0.83) and EFS (τ = 0.71, 95% CI 0.66-0.75). Pseudo-trial-level surrogacy was moderate, with median R² of 0.60 (PFS) and 0.51 (EFS) and wide dispersion across replications, both below the prespecified threshold for adequate surrogacy (≥ 0.70).

In this exploratory, hypothesis-generating analysis, PFS and EFS were strongly associated with OS at the individual level but failed to demonstrate robust pseudo-trial-level surrogacy. These endpoints may not fully capture treatment effects on OS, warranting caution when interpreting ICE-driven trial results in BCG-naïve HR-NMIBC.

Chimeric Antigen Receptor (CAR) T-cell therapy has transformed the treatment of diffuse large B-cell lymphoma (DLBCL) but carries higher drug acquisition costs than autologous stem cell transplantation (autoSCT), while administration and follow-up costs remain underrepresented in economic evaluations and reimbursement decision-making. This study compares administration-related and subsequent treatment costs of CAR-T and autoSCT for DLBCL from the German statutory health insurance (SHI) perspective.

A two-step analysis based on two German databases was performed. In step 1, SHI billing data (representing 5 million insured individuals, ≙ 8% of SHI) from 2020-2022 were analyzed longitudinally. Costs were divided into initial regime (IR) (all services except CAR-T drug acquisition) and a following regime (FR). In step 2, a cross-sectional analysis of all German inpatient cases from 2020-2023 (17 million cases/year) assessed inpatient costs.

Step 1 included 12 CAR-T and 59 autoSCT patients. Median IR costs per patient were €61,703 (CAR-T) versus €55,802 (autoSCT), while FR costs were lower for CAR-T (€44,832 versus €69,453). Most frequently reported adverse events (any grade) for CAR-T versus autoSCT were: B-cell aplasia/neutropenia (77% versus 64%), thrombocytopenia (38% versus 64%). Step 2 included 1,229 CAR-T and 2,239 autoSCT inpatient cases (2020-2023). Average LOS was comparable (27.3 versus 27.8 days), and average inpatient costs were lower for CAR-T (€13,991 versus €29,432).

Although associated with higher IR costs, CAR-T therapy in DLBCL demonstrated lower inpatient and FR costs compared to autoSCT. This analysis focused on administration and follow-up costs, excluding drug acquisition costs, characterizing the economic burden beyond drug pricing.

Esophageal cancer is a major contributor to the global cancer burden, yet comprehensive global assessments of its burden across subtypes are lacking. This study examines the incidence, risk factors, and trends of esophageal cancer by histological and anatomical subtypes, with stratification by sex and age across different countries, using GLOBOCAN 2022 estimates, Cancer Incidence in Five Continents data, and country-level socioeconomic, lifestyle, and metabolic risk-factor indicators. Here we show that Eastern Asia has the highest age-standardized rate (ASR) of incidence of esophageal squamous cell carcinoma (ESCC) (7.2 per 100,000 population) and upper- and middle-third esophageal cancer (6.0), whereas Northern Europe exhibits the highest ASR of incidence of esophageal adenocarcinoma (EAC) (3.2) and lower‑third esophageal cancer (3.6). EAC and lower‑third esophageal cancer generally share risk factors and exhibit increasing trends; in contrast, ESCC and the upper- and middle-third esophageal cancer share a different risk profile and show an overall decreasing trend. In developed regions, EAC and lower‑third esophageal cancer are more common, whereas in developing regions, ESCC and upper- and middle-third esophageal cancer predominate. Our findings may assist the development of tailored prevention strategies based on locally emerging patterns of esophageal cancer subtypes and relevant risk factors.

The combination of azacitidine and venetoclax (Aza/Ven) is an effective treatment for acute myeloid leukemia (AML); however, biological factors underlying heterogeneous treatment responses across diverse genetic backgrounds remain incompletely defined. We analyzed 97 AML patients treated with Aza/Ven in the prospective HM-SCREEN-Japan 02 study using targeted next-generation sequencing (NGS) of 53 genes, cytogenetic analyses, and clinical variables. Somatic mutations were categorized into type 1 (FLT3, PTPN11, WT1, IDH1/2, NPM1, NRAS) and type 2 (GATA2, KRAS, TP53, RUNX1, STAG2, ASXL1, ZRSR2, TET2) groups based on a previously proposed framework describing clonal characteristics. Complete remission (CR) or CR with incomplete hematologic recovery (CRi) was achieved in 53.8%, 52.1%, and 50.0% of patients treated in the first-, second-, and ≥third-line settings, respectively. Among 53 first-line patients with pre-treatment NGS data, type 1-only mutations were more frequently observed in responders (CR/CRi 72%), whereas type 2-only mutations were enriched in non-responders (CR/CRi 33%). In the first-line setting, achievement of CR/CRi following Aza/Ven was associated with improved overall survival. In addition, an exploratory mathematical model integrating baseline clinical variables demonstrated strong discriminatory performance for treatment response, including in cases without established prognostic mutations. In conclusion, Aza/Ven demonstrated consistent clinical activity across treatment lines in this real-world cohort. Mutational patterns classified by a type 1/type 2 framework were associated with differential response patterns in the first-line setting. Integrative modeling approaches may support the interpretation of response heterogeneity, particularly in genetically uninformative AML.

Clinically significant anastomotic leakage (AL) after colorectal cancer surgery is associated with substantial postoperative morbidity, but its long-term oncologic impact remains uncertain. We evaluated the association of AL with long-term survival, including stage- and location-specific patterns, after curative colorectal cancer surgery.

We retrospectively reviewed consecutive patients who underwent curative surgery for non-metastatic colorectal adenocarcinoma between 2004 and 2018. Clinically significant AL was defined as grade B or C leakage. Overall survival (OS) and disease-free survival (DFS) were assessed using Kaplan-Meier and multivariable Cox regression analyses. Subgroup and formal interaction analyses were performed according to tumor stage and location.

Among 2,122 patients, 63 (3.0%) developed clinically significant AL. After multivariable adjustment, including treatment era, AL was not independently associated with OS (HR, 1.581; 95% CI, 0.923-2.707; p = 0.095) or DFS (HR, 1.325; 95% CI, 0.812-2.161; p = 0.260). In stage III disease, patients with AL had lower 5-year OS (56.3% vs. 76.3%; p = 0.005) and DFS (43.9% vs. 68.4%; p = 0.007). However, formal interaction testing showed no significant effect modification by tumor stage (OS, p for interaction = 0.132; DFS, p for interaction = 0.141) or tumor location (OS, p for interaction = 0.775; DFS, p for interaction = 0.748).

Clinically significant AL was not independently associated with long-term oncologic outcomes in the overall cohort. Although poorer survival was observed in the stage III subgroup, the absence of significant interaction indicates that these stage- and location-specific findings should be interpreted as exploratory rather than evidence of differential AL effects.

Early-onset colorectal cancer (EOCRC), defined as CRC diagnosed before age 50, is rising globally. The genomic landscape of EOCRC has been characterized in several prior studies, but the reproducibility of findings across independent cohorts, the impact of adjustment for tumor stage and sample type, and the specificity of prognostic biomarkers to the EOCRC subgroup remain incompletely defined. Furthermore, BRAF mutation frequency is strongly modified by tumor location, which is often not considered in prior analyses.

We performed a dual-cohort analysis using two independent, publicly available genomic databases: The Cancer Genome Atlas (TCGA) PanCancer Atlas (discovery cohort) and the MSK-IMPACT 50K Clinical Sequencing Cohort (validation cohort). Patients with any somatic mutation in the four canonical MMR genes (MLH1, MSH2, MSH6, PMS2) were excluded to reduce the influence of MMR-deficient tumors on comparisons. After exclusion, the discovery cohort comprised 536 CRC patients (EOCRC n = 67, LOCRC n = 469) and the validation cohort comprised 4,254 CRC patients (EOCRC n = 1,470, LOCRC n = 2,784). Somatic mutation frequencies for 11 genes and MSI status were compared between EOCRC and LOCRC, with BRAF analyses further stratified by BRAF V600E specifically and by tumor location. Kaplan-Meier overall survival (OS) analyses were performed with number-at-risk tables. Multivariate Cox regression was adjusted for tumor stage (TCGA) or sample type (Primary vs. Metastasis; MSK-IMPACT). An EOCRC-specific multivariate model was also constructed to test whether prognostic effects were specific to the young-onset subgroup.

BRAF total mutations were significantly less frequent in EOCRC in the validation cohort (6.5% vs 10.1%, p < 0.001); BRAF V600E specifically showed a similar pattern (3.3% vs 7.5%, p < 0.001). However, stratification by tumor location attenuated this difference substantially, indicating that BRAF depletion in EOCRC is at least partially explained by differential tumor location distribution. Kaplan-Meier median OS in the TCGA cohort was not reached for EOCRC and 81.4 months for LOCRC (log-rank p = 0.212); in the MSK-IMPACT cohort, EOCRC 49.4 vs LOCRC 44.4 months (p = 0.009). Multivariate Cox regression in the MSK-IMPACT cohort adjusted for sample type identified KRAS (HR = 1.23, p < 0.001), NRAS (HR = 1.38, p = 0.009), and BRAF (HR = 1.29, p = 0.005) as independent adverse prognostic factors; MSI-H was protective (HR = 0.55, p = 0.008); metastatic sample was a strong independent predictor (HR = 1.70, p < 0.001). Age group was not independently prognostic. In the EOCRC-specific analysis, KRAS, NRAS, and BRAF mutations were not independently prognostic within EOCRC.

After exclusion of MMR-deficient tumors, tumor location adjustment, and sample type adjustment, BRAF mutation depletion in EOCRC is confirmed but is at least partially explained by tumor location distribution differences. KRAS/NRAS/BRAF and MSI-H are validated as CRC prognostic biomarkers, but these effects are driven by the overall cohort and are not specific to the EOCRC subgroup. These findings support comprehensive NGS profiling in EOCRC while cautioning against interpreting general CRC prognostic biomarkers as EOCRC-specific.

Overadjustment bias occurs when adjusting for a variable increases rather than decreases bias. It commonly arises in studies estimating the total causal effect of an exposure on an outcome due to inappropriate adjustment for a mediator. While such inappropriate mediator adjustment can lead to bias in any direction (towards the null, away from the null, or reverse the direction of effect) even in the absence of other relevant unadjusted variables, this type of overadjustment bias is often described as acting towards the null. Using directed acyclic graphs and a simulated example of adjustment for smoking when estimating the total causal effect of education on the risk of breast cancer, we explain how inappropriately adjusting for a mediator can lead to overadjustment bias in any direction. Correspondingly, we provide general guidance to predict the likely direction of overadjustment bias based on the direction of effect of the relevant paths involved. In general, this bias will be away from the null or in the reverse direction when the mediated pathway being closed by inappropriate adjustment acts in the opposite direction to the combined effect of all remaining pathways between the exposure and the outcome. In contrast, this bias will be towards the null when the effects of these paths act in the same direction.

Colorectal cancer (CRC) screening has contributed to reducing CRC incidence and mortality in Europe. However, inequalities in screening persist, with lower participation among individuals with lower educational attainment. It remains unclear whether screening programmes can mitigate these inequalities. This study examined the impact of mailed faecal immunochemical test (FIT) programmes on screening participation and related educational inequalities.

We analysed repeated cross-sectional data from 202 976 respondents aged 50-74 in 24 European countries from the European Health Interview Survey (2014 and 2019), a nationally administered population-based survey. Outcomes were self-reported stool-based screening uptake (lifetime and past 2 years). Educational attainment was categorized into three levels (lower, middle, higher) based on ISCED-2011. We used a difference-in-differences design to compare changes in screening uptake between 2014 and 2019 in countries that implemented nationwide FIT programmes and countries that did not.

In countries that implemented FIT programmes, lifetime and past-2-year screening uptake increased by 28.3 (95% CI: 12.3-44.3) and 30.2 (95% CI: 13.8-46.6) percentage points (ppts), respectively, compared with countries without programmes. The increase was larger among individuals with middle than higher education, with an additional 8.9 (95% CI: 3.3-14.5) ppts for lifetime and 6.4 (95% CI: 1.5-11.2) ppts for past-2-year uptake, indicating a reduction in inequality between these groups. No reduction in inequality was observed between individuals with lower and higher education.

Mailed FIT programmes increased stool-based screening uptake and reduced inequalities between individuals with middle and higher education. To further promote equity in CRC screening, future initiatives should prioritize individuals with lower educational attainment.

Myoid gonadal stromal tumor is a rare subtype of testicular sex cord-stromal tumor characterized by a mixture of myoid and gonadal spindle cells. We present a 24-year-old man with a two-year history of chronic, intermittent dull pain in the left testicle. Work-up, management, pathology, and follow-up are reviewed. These tumors have demonstrated indolent behavior, typically benign; however, accurate diagnosis is essential to differentiate them from other more dangerous tumor types. Radical orchiectomy alone appears to be sufficient for the treatment of these tumors, with only short-term surveillance appearing adequate due to their indolent nature.