Brady, Justin T.

ABSTRACT Human intestinal diseases, including inflammatory bowel disease (IBD), are difficult to model because existing animal and in vitro systems do not capture the intestine’s integrated vascular, immune, and metabolic complexity. Here, we establish a custom normothermic machine perfusion platform that maintains surgically resected human intestinal tissue for up to 72 hours under near-physiological conditions. Discarded specimens from patients with nonmalignant intestinal diseases, including IBD and diverticulitis, were continuously perfused at 37°C with real-time hemodynamic and metabolic monitoring. Perfusion preserved tissue viability, mucosal architecture, epithelial integrity, oxygen consumption, metabolic activity, and vascular patency. Daily perfusate sampling enabled longitudinal profiling and experimental modulation of inflammatory mediators, revealing patient-specific immune states. This long-duration platform bridges reductionist in vitro models and clinical disease, enabling mechanistic studies of intestinal inflammation and future testing of personalized therapies in intact patient-derived tissue.

Abstract Background Presacral tumours are rare, heterogeneous lesions. Historical classification systems for presacral tumours have provided a valuable framework, but were based on limited available data. This study aimed to develop a contemporary classification aligned with current tumour entities and clinical practice. Methods A prospectively registered systematic review of surgically managed presacral tumours published from 1975 to 2025 was combined with a retrospective multisite institutional surgical pathology review from 1986 to 2025. Pathological descriptors were extracted, cross-referenced, harmonized to current terminology, and organized through multidisciplinary expert review to obtain a new classification. Results The systematic review identified 5997 records, of which 203 studies met the inclusion criteria and contributed 181 pathological terms after generic and unclassifiable diagnoses were removed. Review of 3606 pathology reports identified 19 additional terms, bringing the total to 200 pathological terms. After harmonization to current terminology and exclusion of non-neoplastic processes, a contemporary classification was developed using biological descriptors: developmental versus acquired origin; tissue lineage (neurogenic, osseous/haematopoietic, soft tissue, or miscellaneous); and tumour behaviour (benign, locally recurrent without metastatic potential, locally recurrent with low metastatic potential, malignant non-sarcoma, or malignant sarcoma). Conclusion The Mayo Clinic classification of presacral tumours updates historical systems by reflecting the broader, more modern spectrum of neoplasms and distinguishing lesions by lineage and biological behaviour. It may improve diagnostic clarity, communication, and selection of appropriate observation, multidisciplinary assessment, and treatment pathways.

BACKGROUND: Surgeons and ostomy nurses receive a high volume of stoma photos from patients. OBJECTIVE: This study aimed to develop and validate an automated and scalable artificial intelligence pipeline for identification and triage of patient-submitted intestinal ostomy photos. DESIGN: Retrospective derivation and validation study with stakeholder engagement to guide model design. Clinical teams reviewed photos in duplicate and categorized them into: (a) obstructed view, (b) healthy stoma, (c) suitable for conservative management, or (d) requiring in-person review. Pre-trained neural networks including MobileNetV4, ResNet50, ViT and CLIP-ViT were fine-tuned with 5-fold cross-validation. SETTINGS: Nine Mayo Clinic hospitals (2019–2022). PATIENTS: Adult patients (≥18 years) undergoing surgery who submitted images within 30 days after surgery. MAIN OUTCOME MEASURES: Model performance was evaluated with area under the receiver operator curve, precision, recall, and F1-scores. RESULTS: In this study, 538 photos of abdominal ostomies were sent in by 191 patients (median age 52 years, IQR 40–63; 60.4% female). Expert consensus triaged 236 (43.9%) photos as having an obstructed view, 30 (5.6%) as healthy, 177 (32.9%) for conservative management, and 95 (17.7%) for in-person review. All models achieved area under the receiver operator curve >0.97 for identifying stomas. The CLIP-ViT model performed best at triage (macro- area under the receiver operator curve 0.94 ± 0.06; F1 0.77 ± 0.10). End-to-end detection and triage using CLIP-ViT achieved area under the receiver operator curve of 0.99 ± 0.01, precision of 0.87 ± 0.08, recall of 0.93 ± 0.04, and F1 of 0.89 ± 0.07. Attention maps showed that models focused on stomas to determine classification. LIMITATIONS: Low sample size and lack of prospective validation. CONCLUSIONS: A vision language model pipeline accurately detected and triaged patient-submitted ostomy photos. Prospective evaluation is now needed to support integration into multidisciplinary digital workflows. See Video Abstract .

Abstract The optimal management of diverticulitis in young and immunocompromised patients remains controversial, particularly regarding whether these groups warrant a lower threshold for surgery. Historically, young patients were often offered elective colectomy after the first episode of diverticulitis because of concerns regarding recurrence and more aggressive disease. However, contemporary evidence shows that although younger patients may experience higher recurrence rates, they are not at increased risk for complicated recurrence, emergency surgery, or mortality compared with older adults. Nonoperative management is successful in most cases, supporting an individualized rather than age-based surgical approach. Immunocompromised patients, including those with solid organ transplantation, malignancy, chemotherapy exposure, chronic steroid use, or autoimmune disease requiring immunosuppression, represent a higher-risk population. These patients more commonly present with complicated diverticulitis, perforation, sepsis, and atypical symptoms that may delay diagnosis. Although uncomplicated disease can often be managed nonoperatively, immunocompromised patients experience higher rates of emergent surgery, stoma creation, postoperative complications, and mortality, particularly when surgery is performed in a non-elective setting. Current evidence does not support lowering the surgical threshold solely on the basis of young age or immunosuppression status. Instead, management should remain individualized, incorporating disease severity, recurrence pattern, comorbidities, operative risk, and patient preferences. Further research is needed to better define optimal surgical timing and patient selection in these two populations.

Background: ASCO recommends extended venous thromboembolism (VTE) prophylaxis with low-molecular-weight heparin (LMWH) or direct oral anticoagulants (DOACs) following cancer surgery. However, these recommendations were based on trials using routine venography, which detects asymptomatic VTEs, and real-life efficacy is not well studied. We aimed to assess the association of extended VTE prophylaxis with the incidence of clinically significant VTE after elective cancer surgery. Patients and Methods: In this retrospective, population-based cohort study, we identified patients who underwent surgical resection for lung, breast, esophageal, gastric, pancreas, and colon cancer from 2010 to 2017 using the SEER–Medicare linked dataset. Patients were divided into 1 of 2 main groups for comparative analyses: those who received extended VTE prophylaxis after cancer surgery and those who did not. Patients who received extended VTE prophylaxis after cancer surgery were identified as those prescribed prophylactic doses of LMWH or a DOAC within 7 days of discharge, as captured in Medicare Part D files. Results: A total of 113,739 Medicare beneficiaries were identified, of whom 1,570 (1.4%) received extended VTE prophylaxis. There was a year-over-year increase in the use of extended VTE prophylaxis during the study period, rising from 0.6% in 2010 to 3.3% in 2017. The overall incidence of VTE was 1.6% at 1 month, 4.3% at 6 months, 5.7% at 12 months, with significant differences observed across cancer types ( P <.001). However, patients who received extended VTE prophylaxis had a higher 1-year cumulative incidence of postoperative VTE compared with those who did not (11.4% vs 5.3%; P <.001), an association that was consistent across cancer sites. In adjusted analyses, extended VTE prophylaxis was independently associated with an increased risk of VTE (hazard ratio, 1.6; 95% CI, 1.3–2.0; P <.001). Extended prophylaxis was also associated with a higher 1-year incidence of bleeding events compared with patients who did not receive prophylaxis (12.0% vs 8.5%; P <.001). Conclusions: The utilization of extended VTE prophylaxis after cancer surgery remains low, although it has increased every year. Paradoxically, patients who received extended VTE prophylaxis had higher incidences of clinically significant VTE and bleeding compared with those who did not, likely reflecting patient selection and surveillance bias after surgery. In light of these findings, national guidelines recommending postoperative extended VTE prophylaxis, and its use as a surrogate for quality of care, should continue to be re-examined.

BACKGROUND: Patients with locally advanced rectal cancer face substantial costs related to multimodal therapy. However, the extent of this burden is poorly characterized. OBJECTIVE: To characterize the prevalence and predictors of patient-reported financial toxicity after treatment for locally advanced rectal cancer. DESIGN: Multicenter retrospective cohort study with a cross-sectional survey administered to assess patients’ financial concerns as well as clinicodemographic data. SETTING: Three high-volume tertiary academic centers. PATIENTS: Patients who completed treatment for pathological stage II to III rectal adenocarcinoma between 2000 and 2019 and were alive. MAIN OUTCOME MEASURES: Patient-reported financial toxicity and risk factors associated with financial toxicity. RESULTS: A total of 523 patients were identified, 190 (36.3%) responded to the survey, and 2 were excluded for incomplete surveys. Of the responders, 163 (86.7%) were identified as having financial toxicity related to their cancer diagnosis, and most (96.8%) had insurance. Patients with financial toxicity were less likely to have fully paid medical leave (39.8% vs 75%; p = 0.03) compared to patients without financial toxicity. They also reported increased difficulty paying bills ( p < 0.001) and decreased monthly household income ( p < 0.001) due to their diagnosis. Furthermore, these patients reported increased difficulty paying for transportation to medical appointments ( p = 0.002) and were less likely to be completely satisfied with their insurance coverage ( p = 0.003). Feeling well informed regarding treatment-related costs was associated with decreased odds of financial toxicity (OR 0.14; 95% CI, 0.02–0.78; p = 0.02), whereas taking unpaid leave for treatment was associated with increased odds of financial toxicity (OR 4.71; 95% CI, 1.36–16.34; p = 0.01). LIMITATIONS: Cross-sectional design and moderate response rate may introduce selection and recall bias. CONCLUSIONS: Patients undergoing treatment for locally advanced rectal cancer, including those insured, are at risk for financial toxicity due to direct and indirect costs. Effective communication between these patients and physicians regarding the economic implications of treatment is essential to reducing financial toxicity. See Video Abstract . TOXICIDAD FINANCIERA TRAS EL TRATAMIENTO DEL CÁNCER RECTAL LOCALMENTE AVANZADO ANTECEDENTES: Los pacientes con cáncer de recto localmente avanzado enfrentan costos sustanciales relacionados con la terapia multimodal. Sin embargo, la magnitud de esta carga está poco caracterizada. OBJETIVO: Caracterizar la prevalencia y los predictores de la toxicidad financiera reportada por los pacientes después del tratamiento para el cáncer de recto localmente avanzado. DISEÑO: Estudio de cohorte retrospectivo multicéntrico con una encuesta transversal para evaluar las preocupaciones financieras de los pacientes, así como datos clínico-demográficos. ESCENARIO: Tres centros académicos terciarios de alto volumen. PACIENTES: Pacientes que completaron el tratamiento para el adenocarcinoma de recto en estadio patológico II-III entre 2000 y 2019 y estaban vivos. PRINCIPALES MEDIDAS DE RESULTADOS: Toxicidad financiera reportada por los pacientes y factores de riesgo asociados con la toxicidad financiera. RESULTADOS: Se identificó a un total de 523 pacientes, 190 (36,3%) respondieron a la encuesta y 2 fueron excluidos por encuestas incompletas. De los encuestados, 163 (86,7 %) presentaron toxicidad financiera relacionada con su diagnóstico de cáncer, y la mayoría (96,8 %) contaba con seguro médico. Los pacientes con toxicidad financiera tuvieron menos probabilidades de tener licencia médica con goce de sueldo completo (39,8 % frente a 75 %; p = 0,03) en comparación con los pacientes sin toxicidad financiera. También informaron mayor dificultad para pagar facturas ( p < 0,001) y una disminución de los ingresos familiares mensuales ( p < 0,001) debido a su diagnóstico. Además, estos pacientes informaron mayor dificultad para pagar el transporte a las citas médicas ( p = 0,002) y menor probabilidad de estar completamente satisfechos con su cobertura médica ( p = 0,003). Sentirse bien informado sobre los costos relacionados con el tratamiento se asoció con una menor probabilidad de toxicidad financiera (OR: 0,14; IC del 95 %: 0,02-0,78; p = 0,02), mientras que tomar una licencia sin sueldo para el tratamiento se asoció con una mayor probabilidad de toxicidad financiera (OR: 4,71; IC del 95 %: 1,36-16,34; p = 0,01). LIMITACIONES: El diseño transversal y la tasa de respuesta moderada pueden introducir sesgos de selección y de recuerdo. CONCLUSIONES: Los pacientes en tratamiento para el cáncer de recto localmente avanzado, incluidos los asegurados, corren el riesgo de sufrir toxicidad financiera debido a los costos directos e indirectos. Una comunicación eficaz entre estos pacientes y los médicos sobre las implicaciones económicas del tratamiento es esencial para reducir la toxicidad financiera. ( AI-generated translation )

Abstract Aim Rectal prolapse is a full‐thickness intussusception of the rectum beyond the anal canal. It is often mistaken for other anorectal pathologies, leading to inaccurate referrals to colorectal surgeons and inappropriate management. However, the frequency of misdiagnosis is not well characterized. We aimed to assess the diagnostic accuracy of rectal prolapse referrals to three tertiary medical centres. Methods This is a retrospective study of patients referred for rectal prolapse to colorectal surgeons at the Mayo Clinic in Rochester, Jacksonville, and Phoenix from 2020 to 2024. The primary outcome is the accuracy of rectal prolapse diagnosis. The secondary outcomes are factors that correlate with diagnostic accuracy. Results Rectal prolapse was inaccurately diagnosed in 38.7% (186/480) of patients. Among misdiagnosed patients, the correct diagnosis was haemorrhoids (68.0%, n = 134), pelvic floor dysfunction (24.3%, n = 48) and rectocele (18.7%, n = 37). A diagnosis of rectal cancer was found in 3 patients (1.5%). The most common presenting symptoms were protrusion (66.3%, n = 345) and bleeding (33.6%, n = 175). Among the referring physicians, only 50.5% ( n = 227) performed an anorectal examination. Overall, there was significant variability in diagnostic accuracy across different specialties, with the highest accuracy from colorectal practices (84.0%) and the lowest from urologists (50.0%). Internal medicine physicians had a lower diagnostic accuracy with anorectal examination than without, though it did not reach statistical significance (44.0% vs. 59.5%, p = 0.2). Conclusion Over one‐third of rectal prolapse referrals were incorrectly diagnosed. This study highlights the opportunity for further training of referring providers on anorectal pathologies to improve diagnostic accuracy which could reduce treatment delays and optimize clinical outcomes.

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 )

BACKGROUND: Metachronous cancer risk varies by mismatch repair mutation in patients with hereditary nonpolyposis colorectal cancer. Total colectomy offers decreased risk of metachronous colorectal cancers but decreased quality of life compared with segmental colectomy. OBJECTIVE: Compare segmental versus total colectomy for colon cancer via a mutation-specific Markov decision model. DESIGN: Simulated survival and colorectal metachronous occurrence among patients with MLH1, MSH2 , or MSH6 mutations undergoing either segmental or total colectomy. SETTINGS: National databases, literature review. PATIENTS: Simulated patients with hereditary nonpolyposis colorectal cancer. MAIN OUTCOME MEASURES: Overall survival, quality-adjusted life years based on procedure-specific utility states (segmental colectomy 0.99, total colectomy 0.95). RESULTS: Among patients aged 25 years, total colectomy offered less than 1 year of increased mean survival compared with segmental resection across all mutations ( MLH1: 0.8 years, MSH2: 0.9, MSH6: 0.3). This difference in survival decreased with increasing age. Segmental resection offered a small increase in quality-adjusted life years compared with total colectomy across all ages. This difference was highest for MSH6 (0.9 years vs MLH1 : 0.6 and MSH2 : 0.4 at age 25), particularly at younger ages of diagnosis. In a sensitivity analysis, lower total colectomy utility states resulted in greater increases in quality-adjusted life years with segmental colectomy across all mutations. LIMITATIONS: Metachronous cancer risk data do not distinguish between colon and rectal cancers and is extrapolated beyond age 70 years. CONCLUSIONS: Segmental and total colectomy offer similar survival and quality-adjusted life year outcomes. With decreased risk of metachronous cancers, patients with MSH6 mutations across all ages may prefer segmental resection owing to higher quality-adjusted life years and lower survival benefits from total colectomy compared with MLH1 and MSH2 patients. Operative strategy in patients with hereditary nonpolyposis colorectal cancer should be individualized, and this study shows that mutation-specific differences in survival and quality-adjusted life years are small. See Video Abstract . MODELO DE DECISIÓN ESPECÍFICO PARA LA MUTACIÓN EN LA COLECTOMÍA ABDOMINAL SEGMENTARIA FRENTE A LA COLECTOMÍA ABDOMINAL TOTAL EN EL CÁNCER COLORRECTAL HEREDITARIO NO POLIPOSO ANTECEDENTES: El riesgo de cáncer metacrónico varía según la mutación de reparación de desajustes en pacientes con cáncer colorrectal hereditario no poliposo. La colectomía total ofrece un menor riesgo de cánceres colorrectales metacrónicos, pero una menor calidad de vida en comparación con la colectomía segmentaria. OBJETIVO: Comparar la colectomía segmentaria con la colectomía total para el cáncer de colon mediante un modelo de decisión de Markov específico para mutaciones. DISEÑO: Simulación de la supervivencia y la aparición metacrónica de cáncer colorrectal en pacientes con mutaciones MLH1, MSH2 o MSH6 sometidos a colectomía segmentaria o total. ENTORNO: Bases de datos nacionales, revisión de la literatura. PACIENTES: Pacientes simulados con cáncer colorrectal hereditario no poliposo. PRINCIPALES MEDIDAS DE RESULTADO: Supervivencia global, años de vida ajustados por calidad basados en estados de utilidad específicos del procedimiento (colectomía segmentaria 0,99, colectomía total 0,95). RESULTADOS: Entre los pacientes de 25 años, la colectomía total ofreció menos de un año de aumento de la supervivencia media en comparación con la resección segmentaria en todas las mutaciones ( MLH1: 0,8 años, MSH2: 0,9, MSH6: 0,3). Esta diferencia en la supervivencia disminuyó con el aumento de la edad. La resección segmentaria ofreció un pequeño aumento en los años de vida ajustados por calidad en comparación con la colectomía total en todas las edades. Esta diferencia fue mayor para MSH6 (0,9 años frente a MLH1 : 0,6 y MSH2 : 0,4 a los 25 años), especialmente en las edades más jóvenes de diagnóstico. En un análisis de sensibilidad, los estados de utilidad más bajos de la colectomía total dieron lugar a mayores aumentos en los años de vida ajustados por calidad con la colectomía segmentaria en todas las mutaciones. LIMITACIONES: Los datos sobre el riesgo de cáncer metacrónico no distinguen entre cánceres de colon y recto y se extrapolan más allá de los 70 años. CONCLUSIONES: La colectomía segmentaria y la colectomía total ofrecen resultados similares en cuanto a la supervivencia y los años de vida ajustados por calidad. Con la disminución del riesgo de cánceres metacrónicos, los pacientes con mutaciones MSH6 de todas las edades pueden preferir la resección segmentaria debido a los mayores años de vida ajustados por calidad y los menores beneficios de supervivencia de la colectomía total en comparación con los pacientes MLH1 y MSH2 . La estrategia quirúrgica en pacientes con cáncer colorrectal hereditario no poliposo debe individualizarse, y este estudio muestra que las diferencias específicas de la mutación en la supervivencia y los años de vida ajustados por calidad son pequeñas. ( AI-generated translation )

Importance Pathologic complete response (pCR) is increasingly used as a surrogate end point for survival in randomized clinical trials (RCTs) in the field of gastrointestinal oncology. Although this approach has been endorsed by the US Food and Drug Administration, it is still novel and incompletely verified. Objective To evaluate the trial-level association between pCR and survival in rectal cancer RCTs examining the effectiveness of neoadjuvant therapy. Data Sources A meta-analysis was conducted to identify eligible RCTs in PubMed, EMBASE, and Cochrane databases published between database inception to January 3, 2024. Study Selection RCTs evaluating neoadjuvant therapies in patients with rectal cancer who underwent subsequent surgical resection and reported pCR, overall survival (OS), and disease-free survival (DFS) were included. Data Extraction and Synthesis Two investigators extracted the data, which were verified by a third author. The risk of bias and the certainty of the evidence were evaluated using the Cochrane Risk of Bias Tool, version 2, and the Grading of Recommendations Assessment, Development, and Evaluation tool, respectively. Adjusted odds and hazard ratios with their 95% CIs were extracted. Weighted linear regression was used to assess the correlation between pCR and both OS and DFS. Main Outcomes and Measures Trial-level correlation between pCR and both OS and DFS. Results Twenty-five RCTs, including 11 882 patients, met the inclusion criteria. On meta-regression analysis, pCR was not correlated with OS (β = 0.37; 95% CI, −0.98 to 1.71; P = .57). Similarly, pCR was not correlated with DFS (β = −0.84; 95% CI, −2.55 to 0.87; P = .32). Two studies (8%) used in the meta-analysis had high risk of bias. On sensitivity analysis excluding these studies, pCR was still not associated with OS or DFS. Subgroup analysis of RCTs using total neoadjuvant therapies was not possible due to limited sample size. Conclusions and Relevance In this systematic review and meta-analysis of RCTs comparing neoadjuvant therapies in rectal cancer, there was no trial-level association between pCR and survival. These results suggest that the use of pCR as a surrogate end point for survival should be reexamined and used more cautiously.