Mariana Macambira Noronha

Purpose: Skin adnexal carcinomas (SACs) are rare and heterogeneous tumors with no established systemic treatment options and poor long-term survival rates in the advanced disease setting. Here, we aimed to characterize the genomic landscape and clinically actionable alterations across SAC subtypes. Methods: We analyzed next-generation sequencing data from SACs in the American Association for Cancer Research Project GENIE. Mutations, copy number alterations, and structural variants were annotated using OncoKB. Actionable alterations were defined as Level 1-2 alterations or tumor mutational burden (TMB) ≥10 mut/Mb. TMB was compared across subtypes and with melanoma, cutaneous squamous cell carcinoma (CSCC), and basal cell carcinoma (BCC). Results: A total of 224 SACs were analyzed (49% extramammary Paget disease [EMPD], 33% apocrine/eccrine, 17% sebaceous, 1% follicular). In EMPD, the most frequent actionable alterations were in PIK3CA (25.7%) and ERBB2 (22.9%). In sebaceous carcinoma, actionable alterations were mainly in KRAS (10.3%) and PIK3CA (10.3%). Apocrine/eccrine tumors also presented ERBB2 and PIK3CA alterations, but at lower frequencies (5.5% and 8.2%, respectively). TMB-high occurred in 10.1% of EMPD, 28.2% of sebaceous, and 21.9% of apocrine/eccrine tumors, lower than in melanoma (52.1%), CSCC (64.4%), and BCC (63.3%). SAC drivers showed important heterogeneity across subtypes. Overall, 48.2% of SACs harbored at least one potentially actionable alteration. Conclusion: SACs frequently harbor clinically actionable alterations in a histotype-dependent manner. The identification of lineage-specific genomic differences underscores the clinical and translational relevance of integrating histology with genomic profiling for guiding therapeutic decision making.

Antibody-drug conjugates (ADCs) have emerged as a major therapeutic advance in ovarian cancer, particularly when platinum-based chemotherapy is not a treatment option. By selectively delivering potent cytotoxic payloads to tumor cells, ADCs such as mirvetuximab soravtansine (MIRV), targeting FRα, and trastuzumab deruxtecan (T-DXd), targeting HER2, have demonstrated clinically meaningful activity in selected populations. However, resistance to ADCs inevitably develops through diverse mechanisms, including payload resistance and target antigen downregulation. Continued translational research is therefore essential to identify predictive biomarkers and to optimize novel combination strategies. Beyond ADCs, other systemic approaches have demonstrated survival improvements in PROC even in biomarker-unselected populations, including the addition of the glucocorticoid receptor antagonist relacorilant to nab-paclitaxel and immune–chemotherapy combinations such as pembrolizumab plus paclitaxel with or without bevacizumab. Future directions aim to prioritize synergistic combinations to overcome resistance. This includes pairing ADCs with replication stress inhibitors like ATR inhibitors and WEE1 inhibitors or integrating them with next-generation immuno-oncology platforms such as bispecifics, T-cell engagers, and cancer vaccines, as well as the integration of dynamic biomarkers and quantitative tools to define optimal treatment sequencing and improve patient outcomes in this challenging disease setting.

Luspatercept has emerged as a therapeutic option for patients with lower‐risk myelodysplastic neoplasms (MDS). Nonetheless, the performance of luspatercept outside of controlled clinical trials remains unclear. We aimed to synthesize real‐world evidence (RWE) on the effectiveness and safety of luspatercept. This study was conducted following PRISMA guidelines. We searched for studies up to June 2025 evaluating luspatercept in adult MDS patients. Data on hematologic improvement‐erythroid (HI‐E), transfusion independence (TI at 8, 12, and 16 weeks), adverse events, and overall survival (OS) were extracted. Bayesian random‐effects meta‐analyses were performed using priors derived from pooled clinical trials. Seventeen studies were included: five clinical trials (440 patients) and twelve real‐world cohorts (1821 patients). The pooled estimate for HI‐E was 46.6% (95% CrI: 32.5%–63.9%). For TI, pooled rates at 8, 12, and 16 weeks were 44.7% (95% CrI: 28.6%–61.5%), 38.6% (95% CrI: 21.1%–60.0%), and 30.9% (95% CrI: 10.7%–53.9%), respectively. The subgroups with highest TI and HI‐E were patients with positive SF3B1 status (58.5%, at 8 weeks) and Asian patients (54.8%), respectively. Male sex was associated with lower HI‐E, 8, and 12 weeks TI rates. Hypertension and falls were more frequently reported in RWE. We estimated OS rates of 88.9% at 1 year and 74.4% at 2 years following treatment initiation. Real‐world HI‐E were modestly attenuated, likely reflecting selection, adherence, and monitoring differences. The response seems dependent on disease, geographical, and demographical moderators. Such aspects should be taken into account in the design of future studies and in clinical decisions.

Introduction: Whether the efficacy of vonoprazan–amoxicillin dual therapy (VADT) for Helicobacter pylori eradication is clinically acceptable compared with guideline‐recommended bismuth‐based quadruple therapy (BQT) remains uncertain. Prior analyses have largely relied on superiority frameworks. Methods: PubMed, EMBASE, and CENTRAL were searched through December 23, 2025, for randomized controlled trials (RCTs) comparing VADT with BQT for H. pylori eradication. Intention‐to‐treat and per‐protocol eradication were summarized through Bayesian meta‐analysis as absolute risk differences. Noninferiority margins were prespecified at −10%, −5%, and 0% (superiority). Adverse events (AEs) were evaluated as secondary outcomes. Evidence certainty was assessed using GRADE. Results: Eighteen Asian RCTs (5866 participants) were included. In intention‐to‐treat analyses, VADT achieved an absolute eradication increase of +2.27% compared with BQT (95% credible interval [CrI] −1.34% to +5.71%). The posterior probability of noninferiority exceeded 99% for the −10% and −5% margins but declined to 90.41% at 0%. In per‐protocol analyses, eradication showed an absolute decrease of 0.28% (95% CrI −3.30% to +4.17%), with noninferiority probabilities exceeding 99% for the −10% and −5% margins, but declining to 56.43% at 0%. VADT was associated with significantly lower rates of dysgeusia, dizziness/headache, nausea/vomiting, and overall mild AEs. Evidence certainty was moderate for intention‐to‐treat noninferiority in Eastern populations and low or very low for all other Eastern and Western analyses. Discussion: VADT may be a reasonable alternative in East Asian settings where tolerability or regimen simplicity is a priority, but evidence is insufficient to support generalization to Western or non‐Asian populations.

Background and Aims: Primary sclerosing cholangitis (PSC) is an immune‐mediated cholestatic liver disease. Liver transplantation (LT) remains the only definitive treatment for patients with advanced disease. However, recurrence of PSC (rPSC) after LT is still a significant clinical challenge. The aim of this study was to assess the prevalence and incidence of rPSC following transplantation and to identify factors associated with its occurrence. Methods: We conducted a systematic review and meta‐analysis of observational cohorts by searching PubMed, Embase and Cochrane for studies. Statistical analyses were conducted using R, applying a random‐effects model with 95% confidence intervals. Results: Twenty‐nine studies were included, comprising 4682 patients who underwent LT for PSC (63.7% male). Most data originated from Europe (51.7%) and North America (29.2%), with additional cohorts from Asia (13.7%), South America (2.8%) and Oceania (2.6%). The worldwide pooled prevalence of rPSC was 18.66% (95% CI 15.33–22.52; I ² = 84%) between 1980 and 2024. As for the worldwide pooled incidence, rPSC occurred at 26.04 per 1000 person‐years (95% CI 19.30–32.78; I ² = 76.1%). The continent with the highest rPSC prevalence was Oceania with 30.65% (95% CI 23.17–39.29; I ² = 13.8%) and South America had the highest incidence with 39.97 per 1000 person‐years (95% CI 25.42–54.51). Younger recipient age (mean difference [MD] = 5.16 years, 95% CI 4.13–6.19; I ² = 51.3%), male sex (risk ratio [RR] = 0.92, 95% CI 0.87–0.98; I ² = 0%), post‐LT cyclosporine use (RR = 0.56, 95% CI 0.42–0.76; I ² = 0%), acute rejection (RR = 0.64, 95% CI 0.49–0.83) and de novo IBD (RR = 0.63, 95% CI 0.40–0.99; I ² = 0%) were associated with an increased risk of recurrence. Conclusions: Prevalence and incidence of rPSC post‐LT varied according to continents. Younger recipient age, male sex, de novo IBD, cyclosporine use post‐LT and acute rejection episodes were associated with a higher risk of recurrence. Trial Registration: PROSPERO ID: CRD420250645485