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IntroductionThe ERAS protocol (Enhanced Recovery After Surgery) is a multimodal pathway aimed to reduce surgical stress and to allow a rapid postoperative recovery. Application of the ERAS protocol to colorectal cancer surgery has been limited to a minority of hospitals in Italy. To promote the systematic adoption of ERAS in the entire regional hospital network in Piemonte an Audit and Feedback approach (A&F) has been adopted together with a cluster randomised trial to estimate the true impact of the protocol on a large, unselected population.MethodsA multicentre stepped wedge cluster randomised trial is designed for comparison between standard perioperative management and the management according to the ERAS protocol. The primary outcome is the length of hospital stay (LOS). Secondary outcomes are: incidence of postoperative complications, time to patients’ recovery, control of pain and patients’ satisfaction. With an A&F approach the adherence to the ERAS items is monitored through a dedicated area in the study web site. The study includes 28 surgical centres, stratified by activity volume and randomly divided into four groups. Each group is randomly assigned to a different activation period of the ERAS protocol. There are four activation periods, one every 3 months. However, the planned calendar and the total duration of the study have been extended by 6 months due to the COVID-19 pandemic.The expected sample size of about 2200 patients has a high statistical power (98%) to detect a reduction of LOS of 1 day and to estimate clinically meaningful changes in the other endpoints.Ethics and disseminationThe study protocol has been approved by the Ethical Committee of the coordinating centre and by all participating centres. Study results will be timely circulated within the hospital network and published in peer-reviewed journals.Trial registration numberNCT04037787.

Background: In 2019, the Enhanced Recovery After Surgery (ERAS) protocol for colorectal cancer surgery was adopted by a minority of hospitals in Piemonte (4.3 million inhabitants, north-west Italy). The present analysis aims to compare the level of application of the ERAS protocol between hospitals already adopting it (ERAS, N = 3) with the rest of the regional hospitals (non-ERAS, N = 28) and to identify possible obstacles to its application. Methods: All patients surgically treated for a newly diagnosed colorectal cancer during September–November 2019, representing the baseline period of a randomized controlled trial with a cluster stepped-wedge design, were included. Indicators of compliance to the ERAS items were calculated overall and for groups of items (preoperative, intraoperative and postoperative) and analyzed with a multilevel linear model adjusting for patients’ characteristics, considering centers as random effects. Results: Overall, the average level of compliance to the ERAS protocol was 56% among non-ERAS centers (N = 364 patients) and 80% among ERAS ones (N = 79), with a difference of 24% (95% CI: −41.4; −7.3, p = 0.0053). For both groups of centers, the lowest level of compliance was recorded for postoperative items (42% and 66%). Sex, age, presence of comorbidities and American Society of Anesthesiologists (ASA) score were not associated with a different probability of compliance to the ERAS protocol. Conclusions: Several items of the ERAS protocol were poorly adopted in colorectal surgery units in the Piemonte region in the baseline period of the ERAS Colon-Rectum Piemonte study and in the ERAS group. No relevant obstacles to the ERAS protocol implementation were identified at patient level.

Background and Aim Although colorectal laterally spreading tumors (LSTs) can be classified into four subtypes, the histopathological characteristics are known to differ among these subtypes. We therefore performed a logistic regression analysis to determine whether the risk of pathological T1 cancer of large colorectal LSTs can be predicted based on factors such as endoscopic findings in a large group of patients enrolled in a multicenter study in Japan. Methods In the main study, we assessed 1236 colorectal adenomas or early cancers that were classified as LSTs measuring 20 mm or more in diameter and treated endoscopically. Logistic regression analysis was performed to determine whether factors such as the subtype of LST could be used to predict the risk of pathological T1 cancer. A validation study of 356 large colorectal LSTs was conducted to confirm the validity of the results obtained in the main study. Results The locations and tumor diameter of the LSTs in the main study were found to differ significantly according to the LST subclassification (P, We performed a logistic regression analysis to determine whether the risk of invasive cancer of large colorectal laterally spreading tumors (LSTs) measuring 20 mm or greater and treated endoscopically can be predicted based on factors such as endoscopic findings in a large group of patients enrolled in a multicenter study in Japan. The locations and tumor diameters of the LSTs were found to differ significantly according to the LST subclassification. The risk of pathological T1 cancer was significantly associated with LST subclassification and tumor diameter.

Background More extensive lymphadenectomy may improve survival after resection of colonic cancer. Nomograms were created predicting overall survival and recurrence for patients who undergo D2-D3 lymph node dissection, and their validity determined. Methods This was a multicentre study of patients with colonic cancer who underwent resection with D2-D3 lymph node dissection in Japan. Inclusion criteria included R0 resection. A training cohort of patients operated on from 2007 to 2008 was analysed to construct prognostic models predicting survival and recurrence. Discrimination and calibration were performed using an external validation cohort from the Japanese colorectal cancer registry (procedures in 2005-2006). Results The training cohort consisted of 2746 patients. Predictors of survival were: age (hazard ratio (HR) 1·04), female sex (HR 0·71), depth of tumour invasion (HR 1·15, 1·22, 2·96 and 3·14 for T2, T3, T4a and T4b respectively versus T1), lymphatic invasion (HR 1·11, 1·15 and 2·95 for ly1, ly2 and ly3 versus ly0), preoperative carcinoembryonic antigen (CEA) level (HR 1·21, 1·59 and 1·99 for 5·1-10·0, 10·1-20·0 and 20·1 and over versus 0-5·0 ng/ml), number of metastatic lymph nodes (HR 1·07), number of lymph nodes examined (HR 0·98) and extent of lymphadenectomy (HR 0·23, 0·13 and 0·11 for D1, D2 and D3 versus D0). Predictors of recurrence were: female sex (HR 0·82), macroscopic type (HR 3·82, 4·56, 6·66, 7·74 and 3·22 for types I, II, III, IV and V versus type 0), depth of invasion (HR 1·25, 2·66, 5·32 and 6·43 for T2, T3, T4a and T4b versus T1), venous invasion (HR 1·43, 3·05 and 4·79 for v1, v2 and v3 versus v0), preoperative CEA level (HR 1·39, 1·43, 1·56 and 1·85 for 5·1-10·0, 10·1-20·0, 20·1-40·0 and 40·1 or more versus 0-5 ng/ml), number of metastatic lymph nodes (HR 1·07) and number of lymph nodes examined (HR 0·98). The validation cohort comprised 4446 patients. The internal and external validated Harrell's C-index values for the nomogram predicting survival were 0·75 and 0·74 respectively. Corresponding values for recurrence were 0·78 and 0·75. Conclusion These nomograms could predict survival and recurrence after curative resection of colonic cancer.

Peritoneal metastasis is recognized as a predictor of poor prognosis in patients with colorectal cancer, and whether surgical intervention for peritoneal metastasis has any clinical benefit has remained controversial. The purposes of this study were to identify prognostic factors in cases of unresectable colorectal cancer with synchronous peritoneal metastasis and to clarify the impacts of primary tumor resection with high tie lymph node dissection. A multi-institutional retrospective analysis was conducted of 579 patients who underwent resection of the primary tumor for unresectable colorectal cancer with peritoneal metastasis between 1991 and 2007. For these 579 patients, clinicopathological variables were analyzed for prognostic significance using Cox proportional hazards model and propensity score analysis to mitigate the selection bias. Multivariate analysis revealed hematogenous metastasis (p

A Japanese multicenter study disclosed four prognostic indicators of colorectal cancer liver metastases: ≥5 hepatic tumors (HT), HT size5 cm, nodal status (N2) of primary cancer, and the presence of extrahepatic metastases (EM). The Japanese classification was then defined as Stage A, HT1 (≤4 lesions and ≤5 cm) and N0/1; Stage B, HT2 (≥5 lesions or5 cm) and N0/1, or HT1 and N2; and Stage C, HT2 and N2, HT3 (≥5 lesions and5 cm) with any N, or EM1 (presence of EM) with any HT/N. This study aimed to validate the prognostic reliability in a recent population and to develop a modified staging system that divided Stage C patients.A total of 1185 patients diagnosed with liver metastases between 2007 and 2008 were enrolled in the study. According to the classification, 358, 257, and 570 patients were categorized as Stages A, B, and C, respectively. Stage C was further divided into two groups: Stage C-I, HT3 and N0/1, HT2 and N2, or HT1 and EM1; and Stage C-II, HT3 and N2, or HT2/3 and EM1.Cumulative overall survival curves for Stages A, B, and C were significantly different between each two stages (p0.0001, p0.0001). The modified system discriminated patients with a relatively better outcome (Stage C-I) from desperate patients (Stage C-II) (p0.0001).The Japanese classification system was adequately validated in a recent population, and the modified system is useful in risk stratification of Stage C cases.

Several studies have shown remarkable differences in colorectal cancer survival across Europe. Most of these studies lacked information about stage and treatment. In this study we compared short-term survival as well as differences in tumour stage and treatment strategies between five European countries: Norway, Sweden, Denmark, Belgium, and the Netherlands. For this retrospective cohort study all patients aged 18 years or older and operated on adenocarcinoma of the rectum without distant metastases and diagnosed in 2008 and 2009 were selected in national audit registries from Norway, Sweden, Denmark, Belgium, and the Netherlands. Differences in pre-operative treatment between the countries were compared using univariable and multivariable logistic regression. One year relative survival and one year relative excess risk of death (RER) were compared between the five countries. Large variation in the use of preoperative radiotherapy and chemoradiation was found between the countries. Even though, there was little variation in relative survival between the countries, except Sweden, which had a significant better one year RER of death among the elderly patients after adjustment. The differences in survival are expected to be caused by differences in peri-operative care, selection of patients, and especially management of elderly patients. The effects of preoperative treatment are expected to be seen on long term follow-up.

Peritoneal metastasis is well-known as a poor prognostic factor in patients with colorectal cancer. It is important to improve the prognosis of patients with colorectal cancer and synchronous peritoneal metastasis. This study aimed to clarify the factors affecting R0 resection and the prognosis of colorectal cancer patients with synchronous peritoneal metastasis. We investigated the data of patients with stage IV colorectal cancer between 1991 and 2007 in 16 hospitals that were members of the Japanese Society for Cancer of the Colon and Rectum. Of the 564 colorectal cancer patients with synchronous peritoneal metastases, 341 also had hematogenous metastases. The 5-year overall survival rates in patients with and without R0 resection were 32.4 and 4.7 %, respectively. A Cox proportional hazards model showed that histologic type of poorly differentiated adenocarcinoma, regional lymph node metastasis, liver metastasis, chemotherapy after surgery, R0 resection, the Japanese classification of peritoneal metastasis, and the size of peritoneal metastases were independent prognostic factors. Of the 564 patients, 28.4 % had R0 resection. The Japanese classification of peritoneal metastasis (P1–P2, p = 0.0024) and absence of hematogenous metastases (p

The histogenesis of the pattern of cancer spread along Auerbach's plexus (myenteric spread: MS) remains unclear and its prognostic value in colorectal cancer (CRC) has not been thoroughly investigated.Pathology slides of 2845 pT2/pT3/pT4 CRCs stained with hematoxylin-eosin (HE) were reviewed at 10 institutions. MS was classified into 2 groups depending on whether it was accompanied by the finding of perineural invasion (PN) within the lesion. In addition, immunohistochemical staining (D2-40, S100, CD56, synaptophysin) was performed for serially sectioned specimens from 50 CRCs diagnosed as having PN-negative MS.MS was observed in 504 patients (17.7 %); 360 patients were classified as having PN-positive MS and 144 as having PN-negative MS. The 5-year disease-free survival rate of patients with MS was lower than that of patients without MS (63.3 vs 82.7 %, P0.0001); however, there was no significant difference in survival outcome according to the presence or absence of intralesion PN in MS. Multivariate analysis showed that the prognostic impact of MS was independent of conventional prognosticators including T and N stages, vascular invasion and extramural PN. In all the tumors having PN-negative MS, remnants of neural tissue were identified within or around cancer nests located at the leading edge of MS.MS is an important prognostic factor for CRC. This feature is the result of cancer development with replacement of Auerbach's plexus and can be classified as intramural PN. The clinical significance of "Pn1" in the UICC/AJCC TNM classification could be enhanced by individual assessment both intramurally and extramurally.

Background In rectal cancer, anastomotic leakage was reported to have a negative impact on both short- and long-term outcomes. However, there is limited data on the impact of anastomotic leakage on oncologic outcomes in patients with colon cancer. We aimed to evaluate the impact of anastomotic leakage on disease recurrence and long-term survival after curative resection of colon cancer. Methods This multicenter, retrospective cohort study of 4,919 consecutive patients utilized data from the Japanese Society for Cancer of the Colon and Rectum. Multivariable Cox regression analysis was used to adjust for confounding. Results The incidence of anastomotic leakage was 2.5% and 30-day mortality was 0.21%. The 5-year overall survival rate was 80.8% in the anastomotic leakage group, compared with 90.3% in the no leak group (P = .001). In the multivariable analysis, anastomotic leakage was significantly associated with reduced overall survival rate (hazard ratio = 1.84; 95% confidence interval, 1.06–2.96). Overall disease recurrence rate was 14.1%: 21.2% in the anastomotic leakage group and 13.9% in the no leak group. There was a significant association between anastomotic leakage and local recurrence (hazard ratio = 4.63; 95% confidence interval, 1.60–10.6). In contrast, anastomotic leakage was not significantly associated with total distant recurrence. However, anastomotic leakage did show a tendency toward increasing peritoneal recurrence, although it did not reach statistical significance (hazard ratio = 2.59; 95% confidence interval, 0.79–6.29). Conclusion In our study population, anastomotic leakage was associated with reduced overall survival and with increased rate of local recurrence after curative resection for colon cancer.

The prognostic impact of isolated lymphovascular invasion (LVI) after radical resection of rectal cancer is controversially discussed. However, it could be relevant to decide for an adjuvant treatment.The aim of the analysis was, based on the data of an observational study, to determine the prognostic relevance of the isolated LVI.Patients after radical resection of rectal cancer with no hemangioinvasion were subdivided in three groups: I-no LVI, no lymph node metastases (LNM); II-positive LVI, no LNM; III-positive LNM. Five-year local recurrence rate, distant metastases-free and disease-free survival were determined uni- and multivariate.Patients, n = 846, were studied (I, n = 471; II, n = 75; III, n = 300). The univariate comparison between the groups revealed the following 5-year results: local recurrence rate: 9.4 vs 10.0 vs 14.0%; distant metastases-free survival: 84.1 vs 82.5 vs 49.3%; disease-free survival: 83.2 vs 80.7 vs 45.5%. The differences between groups I and III were significant, but not between groups I and II. The determined higher disease-free survival rate in group II vs group III was significant (P = 0.041), but the differences in local recurrence rate and rate of distant metastases did not reach statistical significance. The multivariate analysis revealed no impact of the isolated LVI on the oncological outcome.The isolated LVI has no independent prognostic impact on the local recurrence rate and long-term survival after radical resection of rectal cancer. Based on this finding, no indication for an adjuvant treatment in these patients can be derived.

The clinical situation of familial adenomatous polyposis (FAP) in Japan has changed in the period since the last analysis of data of the Japanese Polyposis Center. To reevaluate our data and elucidate the changes we analyzed the records of the 1390 FAP patients in 900 families registered with the Polyposis Committee of the Japanese Society for Cancer of the Colon and Rectum. In the 13-year period 1990-2003, clinical differences between men and women with FAP diminished. The postoperative prognosis was substantially better in patients without advanced colorectal cancer (stageor = T2) than in those with early cancer or no cancer. Mean age at death improved from 42.5 years in the period before 1990 to 46.0 years, and it was a result of a decreased proportion of deaths from colorectal cancer. The distribution of colorectal cancer in FAP patients was similar to that in the general population. Desmoid tumors accounted for about 10% of deaths in the recent 13 years (1990-2003). The cumulative risk of rectal cancer in the preserved rectum was 12% at 10 years and 23% at 15 years. The registry system in Japan revealed a new clinical situation in FAP patients, and the findings of this study will be useful to improve the prognosis of patients with FAP.

“Skip” lymphovascular invasion presenting as discontinuous foci of tumor cells within the colon wall is now excluded from consideration when determining T stage in the TNM classification. The purpose of this study was to assess the clinicopathological characteristics of colorectal cancer (CRC) patients with such skip lymphovascular invasion. First, a retrospective questionnaire survey of the incidence of skip lymphovascular invasion was performed for a total of 1,868 patients with CRCs at ten institutions. Next, we comparatively assessed clinicopathological data for 896 CRC patients with or without skip lymphovascular invasion. The incidence of skip lymphovascular invasion was 1.1 % (20 out of 1,868). Most of the affected cases were rectal, pT2, and node negative, with moderately differentiated histology. Skip lymphovascular invasion was present in the muscularis propria and subserosa, with the tumors directly invading submucosa (pT1) or muscularis propria (pT2). Hepatic metastasis was greater in CRC with skip lymphovascular invasion (25 %) than in pT1/2 CRC (0 %; P

OBJECTIVE Previous studies have reported genetic anticipation, genomic imprinting, and phenotypic concordance of some clinical features in familial cases of Crohn's disease (CD) and ulcerative colitis (UC). The aim of our study was to investigate the phenotypic features of affected members in a large sample of CD and UC Italian families. METHODS In a multicenter study, CD and UC families were recruited. Affected members were questioned about date of birth, gender, age at onset of symptoms and at diagnosis, location and extension of disease, occurrence of extraintestinal manifestations, use of steroids and/or of immunosuppressive drugs, need for resective surgery, and number of relapses per year ( or = 1 yr). Statistical analysis was performed with chi2, Fisher's, Mann-Whitney U, and binomial probability tests, when appropriate. RESULTS A total of 128 families with 270 affected members were studied: 35 were CD, 64 UC, and 29 mixed families (when UC and CD affected different members). In 99 of 128 families (77%), the diagnosis was concordant. In CD families, a high concordance for localization (46%), extraintestinal manifestations (67%), need for steroids (77%), need for immunosuppressive drugs (100%), need for surgery (29%), and relapse rate (36%) was found. In UC families, a high concordance for disease extension (33%), need for steroids (47%), and relapse rate (34%) was disclosed. A higher than expected concordance for ileal localization (p < 0.4) in CD families and extensive colitis (p < 0.05) in UC families was demonstrated. A generation difference of 15-20 yr in mean ages at onset of symptoms and at diagnosis was recorded. No features of more aggressive disease in subsequent generations and no differences in gender of transmitting parents and relatives were found. CONCLUSIONS Our study shows a high rate of concordance for diagnosis and clinical features in UC and, especially, CD families. The disease occurred 15-20 yr earlier than in previous generations without features of increased severity.

Previous studies have reported genetic anticipation, genomic imprinting, and phenotypic concordance of some clinical features in familial cases of Crohn's disease (CD) and ulcerative colitis (UC). The aim of our study was to investigate the phenotypic features of affected members in a large sample of CD and UC Italian families.In a multicenter study, CD and UC families were recruited. Affected members were questioned about date of birth, gender, age at onset of symptoms and at diagnosis, location and extension of disease, occurrence of extraintestinal manifestations, use of steroids and/or of immunosuppressive drugs, need for resective surgery, and number of relapses per year (1 yr oror = 1 yr). Statistical analysis was performed with chi2, Fisher's, Mann-Whitney U, and binomial probability tests, when appropriate.A total of 128 families with 270 affected members were studied: 35 were CD, 64 UC, and 29 mixed families (when UC and CD affected different members). In 99 of 128 families (77%), the diagnosis was concordant. In CD families, a high concordance for localization (46%), extraintestinal manifestations (67%), need for steroids (77%), need for immunosuppressive drugs (100%), need for surgery (29%), and relapse rate (36%) was found. In UC families, a high concordance for disease extension (33%), need for steroids (47%), and relapse rate (34%) was disclosed. A higher than expected concordance for ileal localization (p0.4) in CD families and extensive colitis (p0.05) in UC families was demonstrated. A generation difference of 15-20 yr in mean ages at onset of symptoms and at diagnosis was recorded. No features of more aggressive disease in subsequent generations and no differences in gender of transmitting parents and relatives were found.Our study shows a high rate of concordance for diagnosis and clinical features in UC and, especially, CD families. The disease occurred 15-20 yr earlier than in previous generations without features of increased severity.

The present study aims to define the prognostic impact of the lymph node ratio (LNR) in patients with stage III distal rectal cancer.We analyzed data from 501 patients who underwent curative resection (total mesorectal excision, TME) for stage III distal rectal cancer at 12 institutions between 1991 and 1998. Patients were divided into four groups according to quartiles based on LNR.Among the 501 patients, 381 underwent TME with pelvic sidewall dissection (PSD). The median numbers of lymph nodes retrieved with and without PSD were 45 and 17, respectively (P0.0001). Forty-nine patients with lymph node retrieved less than 12 were excluded from further analyses. Among various clinicopathological parameters, univariate analysis identified age (P = 0.0059), histological grade (P0.0001), depth of tumor invasion (P = 0.0003), and number of positive nodes (P0.0001) and LNR (P0.0001) as prognostic factors. The Cox proportional hazards model revealed that age (P = 0.014), histological grade (P0.0001), depth of tumor invasion (P = 0.0002), and LNR (group 3, P = 0.0012; group 4, P0.0001) were independent prognostic factors. When the American Joint Committee on Cancer (AJCC) seventh staging system was added as a covariate, both AJCC stage (P0.0001) and LNR (P0.0001) were independent prognostic factors.Adding the LNR concept to the AJCC cancer staging system will improve accuracy in evaluating the nodal status of distal rectal cancer.

Purpose Adjuvant therapy of colorectal cancer with oral fluorinated pyrimidines is attractive because of its ease of administration and good tolerability. The purpose of this meta-analysis is to assess the survival and disease-free survival benefits of treating patients after surgical resection of a primary colorectal tumor with oral fluoropyrimidines for 1 year. Patients and Methods This meta-analysis was performed on individual data from three randomized trials conducted by the Japanese Foundation for Multidisciplinary Treatment for Cancer involving a total of 5,233 patients with stages I to III colorectal cancer. Results The overall hazard ratio in favor of oral therapy was 0.89 for survival (95% CI, 0.80 to 0.99; P = .04), and 0.85 for disease-free survival (95% CI, 0.77 to 0.93; P < .001). Thus oral therapy reduced the risk of death by 11% and the risk of recurrence or death by 15%. There was no significant heterogeneity between trials, nor did the benefit of oral therapy depend on tumor stage (I, II, or III), tumor site (rectum or colon), patient age, or patient sex. Conclusion Oral fluoropyrimidines improve disease-free survival and survival of patients after resection of early-stage colorectal cancer. These observations support the use of these agents alone after resection of early-stage disease, as well as further testing of oral agents in combination with new drugs that have recently shown antitumor activity in advanced colorectal cancer.