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Background: Available data on Mismatch Repair system (MMR) deficiency are conflicting and derived from small studies. Our study aimed to evaluate the therapeutic implications of MMR status in patients with locally advanced rectal cancer (LARC)., Methods: We retrospectively collected data from 318 patients affected by LARC treated in Italy at the Medical Oncology Units of the University Hospital of Cagliari, Istituto Nazionale dei Tumori Milan, and AOU Ospedali Riuniti Ancona. All patients underwent neoadjuvant chemoradiotherapy. The primary objective was major TRG while secondary objectives were pathological complete response, disease-free survival (DFS) and overall survival (OS)., Results: One hundred sixty patients (148 pMMR and 12 dMMR) were included in the exploratory cohort and 158 (146 pMMR and 12 dMMR) were included in the validation cohort. A major TRG has been shown in 42.6% and 43.1% patients with pMMR in exploratory and validation cohort, respectively; while no major TRG have been shown in dMMR patients in both cohorts. Exploratory and validation cohorts showed a statistically significant higher mDFS in pMMR patients compared to dMMR: NR vs. 14 months and NR vs. 17 months, respectively., Conclusion: Our results indicated an association between dMMR and poor response to preoperative chemoradiotherapy and they represent a hypothesis-generating data for new neoadjuvant strategies., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Accurate clinical restaging is required to select patients who respond to neoadjuvant chemoradiotherapy for locally advanced rectal cancer and who may benefit from an organ preservation strategy., Objective: The purpose of this study was to review our experience with the clinical restaging of rectal cancer after neoadjuvant therapy to assess its accuracy in detecting major and pathological complete response to treatment., Design: This was a retrospective cohort study., Setting: This study was conducted at 2 high-volume Italian centers for Colorectal Surgery., Patients: Data were included from all consecutive patients who underwent neoadjuvant therapy and surgery for locally advanced rectal cancer from January 2012 to July 2020. Criteria to define clinical response were no palpable mass, a superficial ulcer <2 cm (major response), or no mucosal abnormality (complete response) at endoscopy and no metastatic nodes at MRI., Main Outcome Measures: The main outcome measures were sensitivity, specificity, positive predictive values, and negative predictive values of clinical restaging in detecting pathological complete response (ypT0) or major pathological response (ypT0-1) after neoadjuvant therapy., Results: A total of 333 patients were included; 81 (24.3%) had a complete response whereas 115 (34.5%) had a pathological major response. Accuracy for clinical complete response was 80.8% and for major clinical response was 72.9%. Sensitivity was low for both clinical complete response (37.5%) in detecting ypT0 and clinical major response (59.3%) in detecting ypT0-1. Positive predictive value was 68.2% for ypT0 and 60.4% for ypT0-1., Limitations: The main limitation of the study its retrospective nature., Conclusion: Accuracy of actual clinical criteria to define pathological complete response or pathological major response is poor. Failure to achieve good sensitivity and precision is a major limiting factor in the clinical setting. Current clinical assessments need to be revised to account for indications for rectal preservation after neoadjuvant chemoradiotherapy. See Video Abstract at http://links.lww.com/DCR/C63 ., Lmites De La Reestadificacin Clnica En La Deteccin De Respondedores Despus De Terapias Neoadyuvantes Para El Cncer De Recto: ANTECEDENTES:Se requiere una nueva reestadificación clínica precisa para seleccionar pacientes que respondan a la quimiorradioterapia neoadyuvante para el cáncer de recto localmente avanzado y que puedan beneficiarse de una estrategia de preservación de órganos.OBJETIVO:El propósito de este estudio fue revisar nuestra experiencia con la reestadificación clínica del cáncer de recto después de la terapia neoadyuvante para evaluar su precisión en la detección de una respuesta patológica importante y completa al tratamiento.DISEÑO:Estudio de cohorte retrospectivo.AJUSTE:Este estudio se realizó en dos centros italianos de alto volumen para cirugía colorrectal.PACIENTES:Incluimos datos de todos los pacientes consecutivos que se sometieron a terapia neoadyuvante y cirugía por cáncer de recto localmente avanzado desde enero de 2012 hasta julio de 2020. Los criterios para definir la respuesta clínica fueron ausencia de masa palpable, úlcera superficial <2 cm (respuesta mayor) o ausencia de anomalías en la mucosa. (respuesta completa) en la endoscopia, y sin ganglios metastásicos en la resonancia magnética.PRINCIPALES MEDIDAS DE RESULTADO:Exploramos la sensibilidad, la especificidad, los valores predictivos positivos y negativos de la reestadificación clínica para detectar una respuesta patológica completa (ypT0) o mayor (ypT0-1) después de la terapia neoadyuvante.RESULTADOS:Se incluyeron 333 pacientes; 81 (24,3%) tuvieron una respuesta completa mientras que 115 (34,5%) tuvieron una respuesta patológica mayor. La precisión de la respuesta clínica completa y la respuesta clínica importante fue del 80,8 % y el 72,9 %, respectivamente. La sensibilidad fue baja tanto para la respuesta clínica completa (37,5 %) en la detección de ypT0 como para la respuesta clínica mayor (59,3 %) en la detección de ypT0-1. El valor predictivo positivo fue del 68,2 % para ypT0 y del 60,4 % para ypT0-1.LIMITACIONES:Nuestro estudio tiene como principal limitación su carácter retrospectivo.CONCLUSIÓNES:La precisión de los criterios clínicos reales para definir una respuesta patológica completa o mayor es pobre. El hecho de no lograr una buena sensibilidad y precisión es un factor limitante importante en el entorno clínico. La indicación para la preservación rectal después de la quimiorradioterapia neoadyuvante necesita una mejora de la evaluación clínica actual. Consulte Video Resumen en http://links.lww.com/DCR/C63 . (Traducción-Dr. Mauricio Santamaria )., (Copyright © The ASCRS 2023.)

Importance: Extending the interval between the end of neoadjuvant chemoradiotherapy (CRT) and surgery may enhance tumor response in patients with locally advanced rectal cancer. However, data on the association of delaying surgery with long-term outcome in patients who had a minor or poor response are lacking., Objective: To assess a large series of patients who had minor or no tumor response to CRT and the association of shorter or longer waiting times between CRT and surgery with short- and long-term outcomes., Design, Setting, and Participants: This is a multicenter retrospective cohort study. Data from 1701 consecutive patients with rectal cancer treated in 12 Italian referral centers were analyzed for colorectal surgery between January 2000 and December 2014. Patients with a minor or null tumor response (ypT stage of 2 to 3 or ypN positive) stage greater than 0 to neoadjuvant CRT were selected for the study. The data were analyzed between March and July 2020., Exposures: Patients who had a minor or null tumor response were divided into 2 groups according to the wait time between neoadjuvant therapy end and surgery. Differences in surgical and oncological outcomes between these 2 groups were explored., Main Outcomes and Measures: The primary outcomes were overall and disease-free survival between the 2 groups., Results: Of a total of 1064 patients, 654 (61.5%) were male, and the median (IQR) age was 64 (55-71) years. A total of 579 patients (54.4%) had a shorter wait time (8 weeks or less) 485 patients (45.6%) had a longer wait time (greater than 8 weeks). A longer waiting time before surgery was associated with worse 5- and 10-year overall survival rates (67.6% [95% CI, 63.1%-71.7%] vs 80.3% [95% CI, 76.5%-83.6%] at 5 years; 40.1% [95% CI, 33.5%-46.5%] vs 57.8% [95% CI, 52.1%-63.0%] at 10 years; P < .001). Also, delayed surgery was associated with worse 5- and 10-year disease-free survival (59.6% [95% CI, 54.9%-63.9%] vs 72.0% [95% CI, 67.9%-75.7%] at 5 years; 36.2% [95% CI, 29.9%-42.4%] vs 53.9% [95% CI, 48.5%-59.1%] at 10 years; P < .001). At multivariate analysis, a longer waiting time was associated with an augmented risk of death (hazard ratio, 1.84; 95% CI, 1.50-2.26; P < .001) and death/recurrence (hazard ratio, 1.69; 95% CI, 1.39-2.04; P < .001)., Conclusions and Relevance: In this cohort study, a longer interval before surgery after completing neoadjuvant CRT was associated with worse overall and disease-free survival in tumors with a poor pathological response to preoperative CRT. Based on these findings, patients who do not respond well to CRT should be identified early after the end of CRT and undergo surgery without delay.

Background: Patient-reported outcomes associated with different bowel reconstruction techniques following anterior resection for rectal cancer are still a matter of debate., Objective: This study aimed to assess quality of life and bowel function in patients who underwent colonic J-pouch or straight colorectal anastomosis reconstruction after low anterior resection., Design: Bowel function and quality of life were assessed within a multicenter randomized trial. Questionnaires were administered before the surgery (baseline) and at 6, 12, and 24 months after surgery., Settings: Patients were enrolled by 19 centers. The enrollment started in October 2009 and was stopped in February 2016. The study was registered at www.clinicaltrials.gov (Identifier: NCT01110798)., Patients: Patients who underwent low anterior resection for primary mid-low rectal cancer and who were randomly assigned in a 1:1 ratio to receive either stapled colonic J-pouch or straight colorectal anastomosis were selected., Main Outcome Measures: The primary outcomes measured were quality of life and bowel function., Results: Of the 379 patients who were evaluable, 312 (82.3%) completed the baseline, 259 (68.3%) the 6-month, 242 (63.9%) the 12-month, and 199 (52.5%) the 24-month assessment. Bowel functioning and quality of life did not significantly differ between arms for almost all domains. The total bowel function score, the urgency, and the stool fractionation scores significantly worsened after surgery and remained impaired over time in both arms (p < 0.0032), whereas constipation improved after surgery but recovered to baseline levels from 1 year onward (p < 0.0036). All patients showed a significant and continuous improvement in emotional functioning (p < 0.0013) and future perspective (p < 0.0001) from baseline to the end of the study., Limitations: Limitations of the study include missing data, which increased over time; the possibility that some treatments have slightly changed since the study was conducted; and investigators not blind to treatment allocation., Conclusion: The findings of this study do not support the routine use of colonic J-pouch reconstruction in patients with rectal cancer who undergo a low anterior resection. See Video Abstract at http://links.lww.com/DCR/B328. BOLSA J COLÓNICA O RECONSTRUCCIÓN COLORRECTAL RECTA DESPUÉS DE RESECCIÓN ANTERIOR BAJA PARA CÁNCER RECTAL: IMPACTO EN LA CALIDAD DE VIDA Y LA FUNCIÓN INTESTINAL: UN ESTUDIO ALEATORIZADO PROSPECTIVO MULTICÉNTRICO: Los resultados informados por el paciente asociados con diferentes técnicas de reconstrucción intestinal después de la resección anterior para el cáncer de recto aún son tema de debate.Evaluar la calidad de vida y la función intestinal en pacientes que se sometieron a una bolsa en J colónica o reconstrucción de anastomosis colorrectal recta después de una resección anterior baja.La función intestinal y la calidad de vida se evaluaron en un ensayo aleatorizado multicéntrico. Los cuestionarios se administraron antes de la cirugía (basal) y a los 6, 12 y 24 meses después de la cirugía.Los pacientes fueron incluidos en 19 centros. La inscripción comenzó en Octubre de 2009 y se detuvo en Febrero de 2016. El estudio se registró en www.clinicaltrials.gov (Identificador: NCT01110798).Pacientes que se sometieron a resección anterior baja por cáncer rectal primario medio-bajo y que fueron aleatorizados en una proporción de 1: 1 para recibir bolsa J colónica con grapas o anastomosis colorrectal recta.calidad de vida y función intestinal.De los 379 pacientes que fueron evaluables, 312 (82.3%) completaron la evaluación inicial, 259 (68.3%) a los 6 meses, 242 (63.9%) a los 12 meses y 199 (52.5%) a los 24 meses. . El funcionamiento intestinal y la calidad de vida no difirieron significativamente entre los dos grupos en casi todos los dominios. La puntuación total de la función intestinal, la urgencia y las puntuaciones de fraccionamiento de las heces empeoraron significativamente después de la cirugía y continuaron con el tiempo extra en ambos grupos (p <0.0032), mientras que el estreñimiento mejoró después de la cirugía pero se recuperó a los niveles basales a partir de 1 año en adelante (p <0.0036). Todos los pacientes mostraron una mejora significativa y continua en el funcionamiento emocional (p <0.0013) y la perspectiva futura (<0.0001) desde el inicio hasta el final del estudio.Datos faltantes, que aumentaron con el tiempo; la posibilidad de que algunos tratamientos hayan cambiado ligeramente desde que se realizó el estudio; investigadores no cegados a la asignación del tratamiento.Los hallazgos de este estudio no respaldan el uso rutinario de la reconstrucción de la bolsa J colónica en pacientes con cáncer rectal que se someten a una resección anterior baja. Consulte Video Resumen en http://links.lww.com/DCR/B328. (Traducción-Dr. Yesenia Rojas-Khalil).

Background: Neoadjuvant chemoradiotherapy (CRT) is a standard treatment for locally advanced rectal cancer. CRT leads to a better local control; however, this does not translate into a survival benefit. Long-term survival is mostly affected by the development of distant metastases after surgery. This study aimed to evaluate predictive clinical factors for the development of early metastatic disease after CRT., Methods: Clinical data of patients with stage II/III rectal cancer submitted to CRT between January 2000 and October 2014 were collected from prospectively maintained electronic databases of three Italian institutes. Patients were divided into two groups: those who developed metastasis within 12 months from surgical resection (Group A) and patients without or with late distant relapse (Group B)., Results: Among 635 patients, 86 (13.5%) had early distant relapse within 1 year from surgery (Group A), and 549 (86.5%) did not (Group B). A higher rate of early distant relapse was associated with CEA levels above 3 ng/dL (20% vs. 10%; p <0.001), tumor lying under 5 cm from anal verge (20% vs. 9%; p <0.001), and age under 63 years (17% vs. 11%; p = 0.036). Multivariate analysis confirmed these factors to be independently correlated with a higher risk of early metastasis., Conclusions: Younger age, low tumors, and high serum CEA may be associated with unfavorable early oncological outcomes after CRT and surgery for rectal cancer. These clinical factors could be useful to select patients for more aggressive therapeutic strategies., (© 2020 S. Karger AG, Basel.)

Background: In patients with locally advanced rectal cancer treated by neoadjuvant chemoradiation, pathological complete response in the surgical specimen is associated with favourable long-term oncologic outcome. Based on this observation, nonoperative management is being explored in the subset of patients with clinical complete response. Whereas, patients with poor response have a high risk of local and distant recurrence, and appear to receive no benefit from standard neoadjuvant chemoradiation. Therefore, in order to develop alternative treatment strategies for non responding patients, predictive and prognostic factors are highly needed. Accumulating clinical observations indicate that elevated platelet count is associated with poor outcome in different type of tumors. In this study we investigated the predictive and prognostic impact of elevated platelet count on pathological response and long-term oncologic outcome in patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiation., Methods: A total of 965 patients were selected from prospectively maintained databases of seven Centers within the SICO Colorectal Cancer Network. Patients were divided into two groups based on a pre-neoadjuvant chemoradiation platelet count cut-off value of 300 × 10 9 /L identified by receiver operating characteristic curve considering complete pathological response as the outcome., Results: Complete pathological response rate was lower in patients with elevated platelet count (12.8% vs. 22.1%, p = 0.001). Mean follow-up was 50.1 months. Comparing patients with elevated platelet count with patients with not elevated platelet count, 5-year overall survival was 69.5% vs.76.5% (p = 0.016), and 5-year disease free survival was 63.0% vs. 68.9% (p = 0.019). Local recurrence rate was higher in patients with elevated platelet count (11.1% vs. 5.3%, p = 0.001), as higher was the occurrence of distant metastasis (23.9% vs. 16.4%, p = 0.007). At multivariate analysis of potential prognostic factors EPC was independently associated with worse overall survival (HR 1.40, 95% CI 1.06-1.86), and disease free survival (HR 1.37, 95% CI 1.07-1.76)., Conclusions: In locally advanced rectal cancer elevated platelet count before neoadjuvant chemoradiation is a negative predictive and prognostic factor which might help to identify subsets of patients with more aggressive tumors to be proposed for alternative therapeutic strategies.

Introduction: Transanal endoscopic microsurgery (TEM) is a consolidated technique for the excision of rectal tumors. However, many aspects relating to its morbidity, risk of functional alterations, and therapeutic outcomes are still unclear. The aim of this study was to assess the rate of morbidity and fecal incontinence after TEM, and to identify associated risk factors., Methods: We prospectively recorded the clinical data of 157 patients who underwent TEM from 1996 to 2013. Among these, 89 patients answered a questionnaire for the assessment of fecal continence at a median follow-up time of 40 months., Results: Intraoperative and postoperative TEM complication rates were 3.8 and 20.4%. The mortality rate was 0.6%. A distance from the anal verge of more than 6 cm correlated with a higher risk of perforation, while patients with cancer were more likely to have postoperative bleeding. Incontinence was reported by 32 (36%) patients, of which 7 (8%) experienced transitory symptoms only, while 25 (28%) reported persistent symptoms. We found a correlation between patients receiving preoperative radiotherapy (RT) and the development of fecal incontinence. The recurrence rate was 3% (1/32) in pT1, 80% (4/5) in pT2, and 100% (1/1) in pT3. After radiotherapy, 7% (1/9) showed a good response (pT0-1), and 18% (2/7) showed no response (pT2-3)., Conclusions: TEM is associated with low morbidity but the risk of developing functional alterations is not negligible and should be discussed with the patient before the operation. Good oncological outcomes are possible for early invasive cancers and for selected advanced cancers following a good response to preoperative RT.

Background: Recently, many studies have suggested a possible adjuvant role of aspirin in colorectal cancer, reporting a positive prognostic effect with its use in patients with established disease. The aim of this study was to investigate the anticancer effect of aspirin use during preoperative chemoradiation for rectal cancer., Methods: Two hundred and forty-one patients with stage II-III rectal cancer and candidates for chemoradiation (CRT) were selected and assigned to two groups: group 1, patients taking aspirin at the time of diagnosis, and group 2, all others. Treatment and oncological outcomes were explored., Results: Aspirin use was associated with a higher rate of tumour downstaging (67.6% vs 43.6%, P=0.01), good pathological response (46% vs 19%; P<0.001), and a slightly, although not significant, higher rate of complete pathological response (22% vs 13%; P=0.196). Aspirin use was also associated with a better 5-year progression-free survival (86.6% vs 67.1%; hazard rate (HR)=0.20; 95% CI=0.07-0.60) and overall survival (90.6% vs 73.2%; HR=0.21; 95% CI=0.05-0.89). Although chance of local relapse was similar (HR=0.6; 95% CI=0.06-4.5), aspirin use was associated with a lower risk of developing metastasis (HR=0.30; 95% CI=0.10-0.86)., Conclusions: Aspirin might have anticancer activity against rectal cancer during preoperative CRT. This finding could be clinically relevant and should be further investigated with randomised trials.

Background: Endorectal ultrasound (ERUS) is considered reliable in staging rectal cancer, but recently some critics have questioned its accuracy. The aim of this study was to evaluate how often an ERUS-based decision leads to an appropriate treatment., Methods: Two hundred and twenty patients with rectal cancer staged with ERUS who underwent a surgical resection or a local excision without neoadjuvant therapy from 1997 to 2012 were included. According to ERUS, patients were divided into three groups of indication: (a) local excision (Tis-1 N0), (b) direct surgery (T2 N0), (c) preoperative chemoradiation (T3-4 or N+). Accuracy was explored by the correlation established with the final pathology., Results: Accuracy for T and N staging was 65 and 64%, respectively. Indication to local excision and to chemoradiation was correct in 97 and 88% of patients staged by ERUS. Accuracy of indication to direct surgery was poor (37%), and 21% of patients were overtreated in this group., Conclusions: ERUS seems not able to fulfill all the needs of ideal tailored therapeutic strategies. T2 diagnosis needs to be confirmed by an excisional biopsy before a final decision is made because overstaging of early tumors may occur in a not-so-negligible proportion of patients., (© 2015 S. Karger AG, Basel.)

Background: The objective of this study was to evaluate pretreatment clinical parameters as predictive factors for complete pathological response after long-term chemoradiotherapy (RCT) for rectal cancer. Tumor downstaging after RCT for rectal cancer can be obtained in half of cases, whereas a complete pathological response (CPR) is reported to range between 15 and 30%. It is not possible to foresee before therapies who will respond., Methods: Patients with stage II-III rectal cancer that had undergone RCT and rectal resection between January 1995 and October 2010 were considered. Patients were divided in those who achieved a CPR, "CR" group, and those who did not achieve a CPR, "NCR" group. Univariate and multivariate analyses between groups were performed considering the clinical parameters: gender, age, ASA score, preoperative hematic CEA, tumor grading; distance of the tumor from the anal verge, maximum tumor diameter, TNM stage, and neoadjuvant treatment details., Results: Among 260 patients, 43 (16.5%) achieved a CPR. The two groups resulted homogeneous for age, sex, pretreatment status, and tumor stage. A CEA <5 ng/dl and distance from anal verge >5 cm were correlated with CPR at multivariate analysis. Patients with both these conditions presented a significantly higher CPR rate (30.6%) as well as improved 5-year survival. CPR was also correlated with improved survival., Conclusions: Very low tumors with a high serum CEA are very unlikely to reach a CPR. The predictive value of these easily available clinical factors should not be underestimated, and better therapeutic strategies for these tumors are needed.

Background: Complete pathologic response (CPR) after neoadjuvant chemoradiotherapy (combined modality treatment, CMT) for rectal cancer seems associated with improved survival compared to partial or no response (NPR). However, previous reports have been limited by small sample size and single-institution design., Methods: A systematic literature review was conducted to detect studies comparing long-term results of patients with CPR and NPR after CMT for rectal cancer. Variables were pooled only if evaluated by 3 or more studies. Study end points included rates of CPR, local recurrence (LR), distant recurrence (DR), 5-year overall survival (OS), and disease-free survival (DFS)., Results: Twelve studies (1,913 patients) with rectal cancer treated with CMT were included. CPR was observed in 300 patients (15.6%). CPR and NPR patient groups were similar with respect to age, sex, tumor size, distance of tumor from the anus, and stage of disease before treatment. Median follow-up ranged from 23 to 46 months. CPR patients had lower rates of LR [0.7% vs. 2.6%; odds ratio (OR) 0.45, 95% confidence interval (CI) 0.22-0.90, P = 0.03], DR (5.3% vs. 24.1%; OR 0.15, 95% CI 0.07-0.31, P = 0.0001), and simultaneous LR + DR (0.7% vs. 4.8%; OR 0.32, 95% CI 0.13-0.79, P = 0.01). OS was 92.9% for CPR versus 73.4% for NPR (OR 3.6, 95% CI 1.84-7.22, P = 0.002), and DFS was 86.9% versus 63.9% (OR 3.53, 95% CI 1.62-7.72, P = 0.002)., Conclusions: CPR after CMT for rectal cancer is associated with improved local and distal control as well as better OS and DFS.

Background: Accurate preoperative staging is the key to correct selection of rectal tumors for local excision. This study aims to assess the accuracy of endorectal ultrasound (ERUS) at our institution., Patients and Methods: Retrospective analysis was carried out of patients treated by transanal endoscopic microsurgery (TEM) from 1996 to 2008. TEM was considered the treatment of choice for uT0-1/N0 lesions located between 2 and 12 cm from the anal verge. It was also proposed in selected uT2-3 patients. Preoperative staging was compared with histopathologic findings., Results: Eighty-one patients (46 males, mean age 66 years) underwent TEM. Mean distance of the tumor from the anal verge was 6.6 cm (range 2-12 cm). ERUS staged 15 of 27 adenomas (55%) as uT1. Of 54 carcinomas, 5 were pT0 because TEM was performed to remove resection margins of a malign polyp already snared. Five of 19 pTis (26%) were overstaged uT1, while 7 of 17 pT1 (41%) were understaged. Overall, ERUS enabled distinction between early and advanced rectal lesion with 96% sensitivity and 85% specificity, giving accuracy of 94% (65/67). Thirteen patients had advanced lesions (eight pT2 and five pT3). Only in two of them (15%) was depth of invasion underestimated by ERUS (one uT0, one uT1) and thus was subsequent salvage surgery necessary., Conclusions: ERUS is useful to confirm the diagnosis of adenoma and predict depth of mural invasion in early rectal cancer. Differentiation between T0/is and T1 lesions remains challenging, however this does not usually influence surgical strategy.