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BACKGROUND: Stoma-free survival represents a key quality-of-life outcome after surgery for locally advanced rectal cancer. Despite advances in neoadjuvant and surgical management, up to 30% of patients ultimately require a permanent fecal diversion. OBJECTIVE: To evaluate stoma-free survival and identify factors associated with permanent stoma formation in patients with locally advanced rectal cancer undergoing coloanal anastomosis. DESIGN: Retrospective cohort study. SETTINGS: Single tertiary referral center (2017–2021). PATIENTS: A total of 126 patients with clinical stage II and III rectal adenocarcinoma who received neoadjuvant therapy and underwent curative-intent resection with coloanal anastomosis were included. INTERVENTION: Curative-intent resection with coloanal anastomosis. MAIN OUTCOME MEASURES: The primary outcome was stoma-free survival. Secondary analyses examined factors associated with permanent fecal diversion. RESULTS: The medical records of 126 patients were analyzed, comprising 62.5% men, with a mean age of 54 ± 10 years and a median BMI of 27.7 (interquartile range 24.5–31.4). At a median follow-up of 53.0 months, the 5-year stoma-free survival rate was 88.9%. Univariate Cox regression analysis showed that BMI ≥35 (HR 3.80; 95% CI, 1.04–13.91, p = 0.044) and handsewn coloanal anastomosis with mucosectomy compared to stapled coloanal anastomosis without mucosectomy (HR 5.58; 95% CI, 1.71–18.14, p = 0.004), as well as local recurrence (HR 6.51; 95% CI, 1.44–29.46), were associated with worse stoma-free survival. The 30-day major morbidity rate was 7.9% after the index surgery. Sixteen patients required permanent fecal diversion due to bowel dysfunction (n = 11), disease recurrence (n = 4), or bowel obstruction (n = 1). LIMITATIONS: Retrospective, single-institution design with limited generalizability. CONCLUSIONS: Coloanal anastomosis in the era of total neoadjuvant therapy resulted in favorable 5-year stoma-free survival. BMI ≥35, handsewn coloanal anastomosis with mucosectomy, and local recurrence were associated with worse stoma-free survival. See Video Abstract . SUPERVIVENCIA SIN ESTOMA TRAS UNA RESECCIÓN ANTERIOR BAJA CON ANASTOMOSIS COLOANAL PARA EL CÁNCER RECTAL EN ESTADIO II-III ANTECEDENTES: La supervivencia sin estoma representa un resultado clave para la calidad de vida tras la cirugía de cáncer rectal localmente avanzado. A pesar de los avances en el tratamiento neoadyuvante y quirúrgico, hasta un 30 % de los pacientes requieren finalmente una derivación fecal permanente. OBJETIVO: Evaluar la supervivencia sin estoma e identificar los factores asociados con la formación de un estoma permanente en pacientes con cáncer rectal localmente avanzado sometidos a anastomosis coloanal. DISEÑO: Estudio de cohorte retrospectivo. ENTORNO: Centro terciario de referencia único, 2017-2021. PACIENTES: Se incluyó a un total de 126 pacientes con adenocarcinoma rectal en estadio clínico II-III que recibieron terapia neoadyuvante y se sometieron a una resección con intención curativa con anastomosis coloanal. INTERVENCIÓN: Resección con intención curativa con anastomosis coloanal. PRINCIPALES MEDIDAS DE RESULTADO: El resultado principal fue la supervivencia sin estoma. Los análisis secundarios examinaron los factores asociados con la derivación fecal permanente. RESULTADOS: Se analizaron 126 pacientes, de los cuales el 62,5 % eran hombres, con una edad media de 54 ± 10 años y un índice de masa corporal medio de 27,7 kg/m 2 (rango intercuartílico: 24,5-31,4 kg/m 2 ). Con una mediana de seguimiento de 53,0 meses, la tasa de supervivencia sin estoma a 5 años fue del 88,9 %. El análisis de regresión de Cox univariante mostró que el índice de masa corporal ≥ 35 kg/m 2 (razón de riesgo = 3,80, intervalo de confianza del 95 %: 1,04-13,91, p = 0,044) y la anastomosis coloanal cosida a mano con mucosectomía, en comparación con la anastomosis coloanal grapada sin mucosectomía (razón de riesgo = 5,58, intervalo de confianza del 95 %: 1,71-18,14, p = 0,004), así como la recurrencia local (razón de riesgo = 6,51, intervalo de confianza del 95 %: 1,44-29,46) se asociaron con una peor supervivencia sin estoma. La tasa de morbilidad grave a los 30 días fue del 7,9 % tras la cirugía índice. Dieciséis pacientes requirieron una derivación fecal permanente debido a disfunción intestinal (n = 11), recurrencia de la enfermedad (n = 4) u obstrucción intestinal (n = 1). LIMITACIONES: Diseño retrospectivo, de una sola institución, con una generalización limitada. CONCLUSIONES: La anastomosis coloanal en la era de la terapia neoadyuvante total dio lugar a una supervivencia sin estoma favorable a los 5 años. El índice de masa corporal ≥ 35 kg/m2, la anastomosis coloanal cosida a mano con mucosectomía y la recurrencia local se asociaron con una peor supervivencia sin estoma. (AI-generated translation )

Abstract Background Common genetic variation has been linked to an increased risk of developing dilated cardiomyopathy (DCM) in case-control studies. However, the phenotypic profile and biological mechanisms by which genetic background may predispose individuals to DCM and outcomes in the general population remain unclear. Aim The primary objectives of this study were twofold: (1) to validate a DCM polygenic score (PRS-1) based on a prior meta-analysis of case–control genetic association studies [Tadros R et al. Nat Genet (2021)]; and (2) To apply this PRS, along with two recently developed PRSs for DCM [PRS-2 from Zheng SL et al. Nat Genet (2024) and PRS-3 from Jurgens SJ et al. Nat Genet (2024)] to a general population that underwent comprehensive longitudinal phenotypic assessments and had long-term outcomes available. Methods While the PRS-1 was derived from only 13 SNPs, PRS-2 and PRS-3 were generated from 709,534 and 1,072,247 SNPs, respectively with significant overlap between them. These DCM-PRSs were applied to an unselected community-based cohort (n=1897) aged >45 years, who underwent a physical examination, echocardiogram, and blood sample at baseline. Subsequent clinical outcomes were collected over a median 16 year follow-up (IQR: 15-17). Results No significant differences between the quartiles were present in terms of age, sex (48% male), and cardiovascular risk factors (CV-RF) (such as hypertension, diabetes, and coronary artery disease). However, linear regression models demonstrated a significant correlation between all DCM-PRSs and left ventricular (LV) parameters, including LV ejection fraction, LV end-systolic diameter, and LV end-diastolic diameter (Table). Multivariable regression analysis confirmed that these correlations were independent of age, sex, CV-RF, and population stratification (adjusted for the first 10 principal components [PCs]). During follow-up, 47 individuals developed DCM. A logistic regression analysis, using a 3:1 matched cohort of non-DCM vs. DCM individuals based on age and sex and adjusted for the same 10 PCs, found a significant correlation between DCM development and both PRS-1 [OR=2.27 (1.06–4.85), p=0.03] and PRS-3 [OR=2.63 (1.20–5.75), p=0.02], while PRS-2 did not show a significant association [OR=1.85 (0.84–4.06), p=0.12]. No association was found between the DCM-PRSs and heart failure (HF) biomarkers (aldosterone, natriuretic peptides, ST2, Galectin-3) or HF outcomes (all-cause mortality/HF hospitalization). Conclusion PRS-1 for DCM despite being derived from only 13 risk alleles, performs at least as well as the newer and more extensive PRSs, in its correlation with LV function, dimensions, and DCM development (except for PRS-2) in a general population. The absence of correlation between these DCM-PRSs and the renin-angiotensin-aldosterone system or natriuretic peptides suggests that genetic background influences LV traits through mechanisms independent of these biological pathways.

BACKGROUND AND OBJECTIVES: Myelomeningocele is defined by the presence of a fluid-filled sac that contains the neural placode and cerebrospinal fluid (CSF) at the level of the spinal defect. Alternatively, the term myeloschisis is used when the neural placode is not contained within a CSF-filled sac. While both are eligible for prenatal closure, few studies have characterized the impact of the type of lesion on postnatal outcomes. This study compares the outcomes of these 2 types of open spinal dysraphism using data from the Fetal Myelomeningocele Consortium registry sponsored by the North American Fetal Therapy Network. METHODS: The prospective observational Fetal Myelomeningocele Consortium registry was used to extract deidentified data corresponding to patients who underwent fetal closure of myelomeningocele vs myeloschisis. Demographics, operative characteristics, perioperative complications, and postnatal outcomes were collected. RESULTS: A total of 1327 patients were identified, including 991 (74.7%) with myelomeningocele and 336 (25.3%) with myeloschisis. Compared with myelomeningocele, myeloschisis was associated with lower rates of prenatal talipes (11% vs 24%, P < .001) and higher rates of favorable prenatal movement (94% vs 86%, P < .001). Postnatally, myeloschisis conferred higher rates of leg movement (97% vs 90%, P = .002) and an increased likelihood of ambulation in the household (10.4% vs 4.1%, P = .009) and outside (7.2% vs 1.9%, P = .004) at 1 year. However, myeloschisis was also linked to greater use of skin patches during closure (49% vs 27%, P < .001), higher CSF leak rates among those with wound dehiscence (26% vs 8%, P = .014), and more frequent CSF diversion and tethered cord surgeries at follow-up. CONCLUSION: Myeloschisis and myelomeningocele demonstrate distinct clinical profiles. Although patients with myeloschisis may have favorable motor outcomes, they are also characterized by higher rates of CSF leakage, CSF diversion, and tethered cord surgery. These findings highlight the need for lesion-specific prognostication and may inform surgical planning and parental counseling in the context of prenatal spina bifida closure.

Purpose To explore the relationship between systemic comorbidities and presenting tumor T category in patients with uveal melanoma. Methods Single-center, retrospective cohort study of patients with posterior uveal melanoma initially diagnosed between January 2000 and December 2016. Univariate and multivariate ordinal logistic regression analyses were performed to identify comorbidities associated with presenting tumor T category, as classified by AJCC criteria. Results Initial presenting AJCC T category was T1 in 190 (43%), T2 in 130 (29%), T3 in 89 (20%), and T4 in 38 (9%). The most common comorbidities present were hypertension (250 patients, 56%), hyperlipidemia (211, 47%), obesity (137, 31%), and diabetes mellitus (87, 19%). Of these, obesity ( p = 0.034), hypertension ( p = 0.017), and diabetes mellitus ( p < 0.001) were associated with earlier presenting T category on univariate ordinal logistic regression. After multivariate regression, only diabetes mellitus ( p = 0.01) and obesity ( p = 0.04) remained significantly associated with earlier T category on initial presentation. Conclusion Among patients presenting with uveal melanoma, diabetes mellitus and obesity were associated with earlier presenting T category, which could reflect earlier detection of uveal melanoma in patients undergoing annual diabetic retinopathy screening examinations or having more frequent contact with the healthcare system. Larger studies should further explore this association and examine the utility of increased ocular screening in early detection of uveal melanoma.

Background and Aims: Cholangiocarcinoma (CCA) is a rare but aggressive malignancy with poorly understood genetic susceptibility. To date, genome-wide association studies (GWAS) investigating germline variants associated with CCA risk remain limited. We aimed to identify genetic risk loci for CCA and its clinical subtypes through comprehensive GWAS and post-GWAS analyses. Approach and Results: We conducted a GWAS of 2366 CCA cases and 11,750 controls of European ancestry. Genome-wide significant loci ( p <5×10 −8 ) were identified and further examined through fine-mapping, functional annotation, and HLA imputation. Subgroup analyses were conducted by CCA subtypes and primary sclerosing cholangitis (PSC) status. Cross-trait linkage disequilibrium score regression and Mendelian randomization were employed to investigate the shared genetic architecture and potential causal relationships with a diverse range of traits. We identified 1 new genome-wide significant variant, rs535777 (OR=1.44), near HLA-DRB1/DQA1 associated with CCA, and 2 variants associated with extrahepatic CCA: rs116224263 (OR=0.17) in LINC02506 at 4p15.1 and rs6914950 (OR=1.63) near HLA-DRB1/DQB1 . Stratified analyses revealed rs2395184 (OR=3.51) near HLA-DRA/DRB5 associated with PSC-related CCA, and rs142674434 (OR=2.98) in THSD7A at 7p21.3 associated with non-PSC-related CCA. HLA imputation uncovered new amino acid residues associated with disease risk. Cross-trait analyses identified shared genetic signals between CCA and anthropometric, lipidemic, lifestyle, and medical traits. Mendelian randomization supported putative causal associations for 12 traits with CCA or its subtypes. Conclusions: Our large-scale GWAS highlights new genetic variants and HLA-linked mechanisms underlying CCA susceptibility. Integrating multi-step post-GWAS approaches enhances understanding of CCA pathogenesis and may facilitate the development of risk biomarkers for early detection and precision prevention strategies.

Background and aims: Aberrations in telomere length can have important implications in cancer. Using a cohort of 1007 patients, we investigated whether leukocyte telomere length (LTL) in patients with colorectal cancer (CRC) is associated with survival. We also investigated whether some telomere maintenance genes are associated with survival in these patients. Methods: The Biobank for Gastrointestinal Health Research (BGHR), an ongoing project involving collection of biospecimens at the Mayo Clinic, was utilized to obtain data from patients diagnosed with stage II or III CRC. Blood samples were collected prior to chemotherapy/radiation and DNA was extracted for measuring median LTL. The main outcome measures were overall survival (OS) and disease-free survival (DFS) by disease stage. Results: A significant inverse relationship was observed with patient age and LTL (spearman correlation coefficient (r) = −0.48, 95%; p = 1.13 × 10−58). Females had significantly longer LTL than males (p = 3.97 × 10−5). The rs1317082 SNP in the TERC gene was significantly associated with both OS and DFS in combined stage II and stage III patients (p = 0.017 and p = 0.023, respectively). A statistically significant association of the OBFC1 SNP (rs9419958) was observed for OS for the combined stage II and stage III patients (p = 0.016). Importantly, LTL was significantly associated with both OS and DFS (p = 0.008 and 0.044 respectively) in combined stage II and stage III patients. Conclusions: Our results show that LTL is predictive of OS and DFS for stage II and III CRC patients, particularly over a longer follow-up, extending beyond five years after a diagnosis of CRC, and certain SNPs in genes involved in telomere maintenance are significantly associated with patient outcomes, independent of telomere length.

This study uncovers a previously unrecognized role for NAV3 in TGF-β1-driven cardiac fibroblast activation. We show that NAV3 facilitates profibrotic remodeling through noncanonical signaling and cell cycle arrest, independently of SMAD2/3. These findings position NAV3 as a novel regulator of fibroblast phenotype and a potential modulator of cardiac fibrosis.

Background A recent randomized prospective controlled trial demonstrated that atorvastatin for up to 2 years was safe but did not significantly alter rebleeding in cerebral cavernous malformations. However, any consequences of discontinuing atorvastatin remain unknown. We hypothesized that symptomatic hemorrhage (SH) recurs more frequently in cerebral cavernous malformations after discontinuation of atorvastatin than placebo. Methods We conducted a 12‐month posttreatment follow‐up of patients enrolled in the Atorvastatin Therapy in Cavernous Angiomas with Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) trial (41 randomized to atorvastatin, 39 to placebo) to identify potential recurrent SH after trial drug discontinuation. Every SH was adjudicated by review of imaging and corresponding symptoms. Patients were excluded from follow‐up for <90% compliance with study drug, for its discontinuation <3 months after trial enrollment, for statin reinitiation <3 months after discontinuation, or for lack of follow‐up. Cases were censored during follow‐up upon cerebral cavernous malformation resection/radiation or later statin reinitiation. Results Follow‐up included 33 patients who had been randomized to placebo and 32 who had taken atorvastatin. Four SH events occurred at 3, 49, 84, and 225 days after atorvastatin discontinuation, and 1 SH at 395 days after discontinuing placebo. There was significantly lower symptomatic hemorrhage‐free survival in the atorvastatin‐discontinuation group (log‐rank χ 2 =4.136, P =0.042). The hazard ratio was 0.162 (95% CI, 0.027–0.977) for placebo versus atorvastatin discontinuation. Conclusions Discontinuation of atorvastatin was associated with a higher risk of recurrent SH compared with placebo discontinuation. Additional studies are warranted to confirm this hypothesis‐generating observation, examine potential mechanisms, and how best to mitigate this risk. REGISTRATION URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02603328.