Short-term outcomes of chemoradiotherapy and local excision versus total mesorectal excision in T2-T3ab,N0,M0 rectal cancer: a multicentre randomised, controlled, phase III trial (the TAU-TEM study).

BACKGROUND: The standard treatment of T2-T3ab,N0,M0 rectal cancers is total mesorectal excision (TME) due to the high recurrence rates recorded with local excision. Initial reports of the combination of pre-operative chemoradiotherapy (CRT) and transanal endoscopic microsurgery (TEM) have shown reductions in local recurrence. The TAU-TEM study aims to demonstrate the non-inferiority of local recurrence and the improvement in morbidity achieved with CRT-TEM compared with TME. Here we describe morbidity rates and pathological outcomes. PATIENTS AND METHODS: This was a prospective, multicentre, randomised controlled non-inferiority trial including patients with rectal adenocarcinoma staged as T2-T3ab,N0,M0. Patients were randomised to the CRT-TEM or the TME group. Patients included, tolerance of CRT and its adverse effects, surgical complications (Clavien-Dindo and Comprehensive Complication Index classifications) and pathological results (complete response in the CRT-TEM group) were recorded in both groups. Patients attended follow-up controls for local and systemic relapse. TRIAL REGISTRATION: NCT01308190. RESULTS: From July 2010 to October 2021, 173 patients from 17 Spanish hospitals were included (CRT-TEM: 86, TME: 87). Eleven were excluded after randomisation (CRT-TEM: 5, TME: 6). Modified intention-to-treat analysis thus included 81 patients in each group. There was no mortality after CRT. In the CRT-TEM group, one patient abandoned CRT, 1/81 (1.2%). The CRT-related morbidity rate was 29.6% (24/81). Post-operative morbidity was 17/82 (20.7%) in the CRT-TEM group and 41/81 (50.6%) in the TME group (P < 0.001, 95% confidence interval 42.9% to 16.7%). One patient died in each group (1.2%). Of the 81 patients in the CRT-TEM group who received the allocated treatment, 67 (82.7%) underwent organ preservation. Pathological complete response in the CRT-TEM group was 44.3% (35/79). In the TME group, pN1 were found in 17/81 (21%). CONCLUSION: CRT-TEM treatment obtains high pathological complete response rates (44.3%) and a high CRT compliance rate (98.8%). Post-operative complications and hospitalisation rates were significantly lower than those in the TME group. We await the results of the follow-up regarding cancer outcomes and quality of life.

Non-inferiority multicenter prospective randomized controlled study of rectal cancer T2-T3s (superficial) N0, M0 undergoing neoadjuvant treatment and local excision (TEM) vs total mesorectal excision (TME).

PURPOSE: The standard treatment of rectal adenocarcinoma is total mesorectal excision (TME), in many cases requires a temporary or permanent stoma. TME is associated with high morbidity and genitourinary alterations. Transanal endoscopic microsurgery (TEM) allows access to tumors up to 20 cm from the anal verge, achieves minimal postoperative morbidity and mortality rates, and does not require an ostomy. The treatment of T2, N0, and M0 cancers remains controversial. Preoperative chemoradiotherapy (CRT) in association with TEM reduces local recurrence and increases survival. The TAU-TEM study aims to demonstrate the non-inferiority of the oncological outcomes and the improvement in morbidity and quality of life achieved with TEM compared with TME. METHODS: Prospective, multicenter, randomized controlled non-inferiority trial includes patients with rectal adenocarcinoma less than 10 cm from the anal verge and up to 4 cm in size, staged as T2 or T3-superficial N0-M0. Patients will be randomized to two areas: CRT plus TEM or radical surgery (TME). Postoperative morbidity and mortality will be recorded and patients will complete the quality of life questionnaires before the start of treatment, after CRT in the CRT/TEM arm, and 6 months after surgery in both arms. The estimated sample size for the study is 173 patients. Patients will attend follow-up controls for local and systemic relapse. CONCLUSIONS: This study aims to demonstrate the preservation of the rectum after preoperative CRT and TEM in rectal cancer stages T2-3s, N0, M0 and to determine the ability of this strategy to avoid the need for radical surgery (TME). TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01308190. Número de registro del Comité de Etica e Investigación Clínica (CEIC) del Hospital universitario Parc Taulí: TAU-TEM-2009-01.

Update on advances and controversy in rectal cancer treatment.

Changes in the multidisciplinary treatment of rectal cancer have been recently proposed. We performed a comprehensive review of the current data on neoadjuvant and adjuvant treatment of rectal cancer, focussing on chemoradiotherapy treatment and timing of surgery. Six components were proposed as the framework for the treatment of rectal cancer: neoadjuvant therapy and changing patterns in patient selection, long- or short-course radiotherapy, adverse effects of radiotherapy, timing of surgery, non-operative management of rectal cancer and postoperative adjuvant therapy. Lack of a consistent difference in terms of local recurrence has been observed between short-course radiotherapy and long-course chemoradiotherapy. Indications for preoperative radiotherapy have been reconsidered in the last years. An interval of 10-11 weeks seemed to be the optimal timing, with no impact on patient safety. Since assessment criteria of clinical complete response are not well defined, and the basis for non-operative management of rectal cancer is still not clear, further investigations are required. There is controversy about standard treatments for patients with locally advanced rectal cancer that are being analyzed by ongoing studies. Tailored treatments could avoid over-treatment for a large number of patients without any impairment of the oncologic results.

Emergency surgery for perforated diverticulitis in the immunosuppressed patient.

AIM: Immunosuppression is believed to worsen outcomes for patients who require surgery for perforated diverticulitis. The aim of this study was to compare surgical outcomes between immunocompromised and immunocompetent patients undergoing surgery for complicated diverticulitis. METHOD: All patients who underwent emergency surgery for complicated diverticulitis between 2004 and 2012 in a single unit were studied. Patients were classified as immunosuppressed (group I) or immunocompetent (group II). Operation type and postoperative morbidity and mortality were compared between groups. The impact of operating surgeons' specialization and the Peritonitis Severity Score (PSS) were also evaluated to determine their impact on the restoration of gastrointestinal (GI) continuity. RESULTS: One-hundred and sixteen patients (mean age: 63.7 years), 41.4% women, were included. Fifty-three (45.7%) patients were immunosuppressed (group I): 42 underwent Hartmann's procedure (HP) (79.2%), nine (17.0%) underwent resection and primary anastomosis (RPA) with ileostomy (IL) and two (3.8%) underwent RPA without IL. In group II, 15 HP (23.8%), nine RPA with IL (14.3%) and 39 RPA without IL (61.9%) were performed. Postoperative morbidity and mortality were 79.2% and 26.4%, respectively, in group I and 63.5% and 6.3%, respectively, in group II. The overall mean PSS was 9.5, with a mean PSS of 11.1 in group I and of 8.1 in group II. The decision to perform a primary anastomosis differed significantly between colorectal surgeons and general surgeons in the patients with a PSS of 9-10-11. CONCLUSION: In immunocompromised patients, RPA with IL can be a safe surgical option, whereas HP should be reserved for patients with a PSS of > 11. Colorectal surgical specialization is associated with higher rates of restoration of GI continuity in patients with perforated diverticulitis, especially in patients with an intermediate PSS score. Evaluation of each patient's PSS facilitates decision making in surgery for perforated diverticulitis.

Incidence and management of anastomotic bleeding after ileocolic anastomosis.

AIM: Ileocolic anastomosis is performed using a stapled or manual technique, but with either there is a risk of bleeding from the suture line. The aim of this study was to analyse, retrospectively, bleeding after different anastomotic techniques. METHOD: Patients having elective right colectomy were divided, according to the type of ileocolic anastomosis, into Group 1 (circular, double-stapled, end-to-side), Group 2 (linear-stapled, side-to-side) and Group 3 (handsewn, side-to-side). Postoperative lower gastrointestinal bleeding (LGIB) was studied in the three groups. Uni- and multivariate analysis was performed to study risk factors for LGIB and the need for postoperative allogeneic blood transfusion. RESULTS: Three-hundred and fifty patients were included: 174 in Group 1, 59 in Group 2 and 117 in Group 3. The postoperative LGIB rate was 4.9% and occurred exclusively in Group 1. Five patients had severe anastomotic bleeding. Postoperative blood transfusion was indicated in Groups 1, 2 and 3 in 19.0%, 5.1% and 13.7% of patients. In the five patients with severe bleeding, four attempts of colonoscopic arrest were made, achieving bleeding control in one. Angiographic embolization was successful in one patient. There were no procedure-specific complications. CONCLUSION: End-to-side, circular, double-stapling ileocolic anastomosis seems to be related to an increased incidence of anastomotic bleeding and of postoperative blood transfusion compared with patients having other techniques of ileocolic anastomosis.

Long-term results of surgery plus fibrin sealant for anal fistula.

AIM: The long-term recurrence rate of fibrin glue treatment was analysed in patients with trans-sphincteric cryptoglandular fistula operated by a two-phase procedure: (i) fistulectomy with seton placement; (ii) fibrin sealant (Tissucol Duo®, Baxter) insertion in the track. METHOD: Clinical data were collected prospectively for all patients operated between 2004 and 2010. The statistical association of clinical variables and recurrence was analysed and a disease-free curve was constructed using the Kaplan-Meier method. RESULTS: Twenty-eight consecutive patients (mean age 48.3 ± 13.3 years; 22 men) were enrolled in the study. Middle and high trans-sphincteric fistulae were diagnosed in 20 (71.4%) and eight (28.6%) patients. Seven (25%) had secondary track formation. The mean interval between the first operation and the fibrin sealant treatment was 12.5 ± 7.6 months. There were no complications related to the procedure. Nine (32.1%, 95% CI 17.9-50.7%) patients developed recurrence between 3 and 27 months after fibrin sealant treatment. Disease-free curves showed that the highest probability of recurrence occurred in the first 2 years. No incontinence was found at a mean follow-up of 20.6 (3-60) months among the 67.8% patients with no evidence of recurrence. CONCLUSION: Fibrin sealant is safe and simple. The healing rate is satisfactory without the risk of incontinence.

Differences between proximal and distal obstructing colonic cancer after curative surgery.

AIM: To study any possible differences in morbidity, mortality and overall survival rate after curative surgery for obstructive colon cancer according to tumour location. METHOD: From January 1994 to December 2006, patients with colonic cancer presenting as obstruction were analysed. The two groups were defined as proximal and distal according to the tumour location with respect to the splenic flexure. In relation to the surgeon specialization, patients were operated on by a colorectal surgeon and by a general surgeon. Postoperative morbidity and mortality and cancer-related survival at 3 years were analysed. RESULTS: Of the 377 patients included in the study, there were 173 patients (45.9%) in the proximal group and 204 patients (54.1%) in the distal group. The global morbidity was 54.9% without differences in postoperative morbidity except for anastomotic leakage, which was higher in the proximal group (P < 0.014). No differences in postoperative mortality were observed. After patients were stratified by the tumour node metastasis system, the differences between the groups, with respect to 3-year overall survival, cancer-related survival and probability of being free from recurrence, did not reach statistical significance. The overall survival after radical surgery for colonic obstruction was 57.6%. CONCLUSION: Mortality and morbidity after emergency surgery for obstructing colon cancer are high. Specialization in colorectal surgery influences postoperative results in terms of lower anastomotic dehiscence rate after emergency proximal colon resection. After radical surgery, tumour location does not appear to influence the prognosis of obstructive colon cancer.

Novel mutants of NAB corepressors enhance activation by Egr transactivators.

The NGFI-A binding corepressors NAB1 and NAB2 interact with a conserved domain (R1 domain) within the Egr1/NGFI-A and Egr2/Krox20 transactivators, and repress the transcription of Egr target promoters. Using a novel adaptation of the yeast two-hybrid screen, we have identified several point mutations in NAB corepressors that interfere with their ability to bind to the Egr1 R1 domain. Surprisingly, NAB proteins bearing some of these mutations increased Egr1 activity dramatically. The mechanism underlying the unexpected behavior of these mutants was elucidated by the discovery that NAB conserved domain 1 (NCD1) not only binds to Egr proteins but also mediates multimerization of NAB molecules. The activating mutants exert a dominant negative effect on NAB repression by multimerizing with native NAB proteins and preventing binding of endogenous NAB proteins with Egr transactivators. To examine NAB repression of a native Egr target gene, we show that NAB2 represses Egr2/Krox20-mediated activation of the bFGF/FGF-2 promoter, and that repression is reversed by coexpression of dominant negative NAB2. Because of their specific ability to alleviate NAB repression of Egr target genes, the dominant negative NAB mutants will be useful in elucidating the mechanism and function of NAB corepressors.