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Objectives This study aimed to explore the risk factors associated with cancer cell exfoliation in Stage II and III colorectal cancer (CRC). Methods This multicenter, prospective, observational study targeted 1,698 patients with cStage II and III CRC who underwent R0 resection between 2013 and 2017. Clinicopathological variables were analyzed for correlations with positive peritoneal lavage cytology (PLC). Results The positive PLC rate was 2.7% (46/1,694 cases) at laparotomy and 1.6% (25/1,590 cases) after tumor resection. Logistic regression analyses identified that undifferentiated histologies diagnosed by preoperative biopsy specimen, cT4, and pN+ were independent factors that affected the positive PLC at laparotomy. The positive PLC rate at laparotomy was 4.5% (33/736 cases) among the patients with undifferentiated histology and/or cT4. Logistic regression analyses revealed that the presence of ascites and undifferentiated histology by biopsy independently affected positive PLC after tumor resection. Conclusions The undifferentiated histology and/or T4 indicated by preoperative diagnosis were identified as factors affecting PLC at laparotomy. Furthermore, ascites and preoperative histological type were identified as factors affecting positive PLC after tumor resection. As factors affecting positive PLC, these preoperative findings were found to be equivalent to pathological findings.

The purpose of the study was to compare staging of stage II colon cancer using the number of retrieved lymph nodes (RN) to current TNM staging for stratification of prognosis. The subjects were 6307 patients with stage II colon cancer who underwent curative resection at 24 Japanese institutions. The cutoff for the number of RN was established using Akaike information criterion (AIC) values for relapse-free survival (RFS) and overall survival (OS). Comparison of survival using TNM and T + RN (TRN) staging was performed using a Cox proportional hazards regression model. AIC was lowest for 14 retrieved lymph nodes for RFS and OS. This number was used as the cutoff. In multivariate analysis, age (≥ 69), male gender, V1, CEA (> 5), pT (T4a, T4b), and RN-L were independent factors associated with RFS and OS. Six combinations of pT and RN categories were used to establish three subgroups: TRN stages IIA, IIB, and IIC. The 5-year RFS was 83.9%, 72.3%, and 71.8% in TNM stages IIA, IIB, and IIC; and 86.0%, 76.9%, and 60.3% in TRN stages IIA, IIB, and IIC. The 5-year OS was 90.0%, 81.3%, and 82.6% for the TNM stages; and 91.6%, 85.0%, and 71.9% for the TRN stages. The AIC for RFS was lower for TRN (22,318.2) than for TNM (22,390.6), and that for OS was also lower for TRN (16,285.3) than for TNM (16,355.1). Stage II colon cancer staging using the number of retrieved lymph nodes may be superior to current TNM staging for prognosis stratification.

Lynch syndrome is a hereditary disease characterized by an increased risk of colorectal and other cancers. Germline variants in the mismatch repair (MMR) genes are responsible for this disease. Previously, we screened the MMR genes in colorectal cancer patients who fulfilled modified Amsterdam II criteria, and multiplex ligation-dependent probe amplification (MPLA) identified 11 structural variants (SVs) of MLH1 and MSH2 in 17 patients. In this study, we have tested the efficacy of long read-sequencing coupled with target enrichment for the determination of SVs and their breakpoints. DNA was captured by array probes designed to hybridize with target regions including four MMR genes and then sequenced using MinION, a nanopore sequencing platform. Approximately, 1000-fold coverage was obtained in the target regions compared with other regions. Application of this system to four test cases among the 17 patients correctly mapped the breakpoints. In addition, we newly found a deletion across an 84 kb region of MSH2 in a case without the pathogenic single nucleotide variants. These data suggest that long read-sequencing combined with hybridization-based enrichment is an efficient method to identify both SVs and their breakpoints. This strategy might replace MLPA for the screening of SVs in hereditary diseases.

This study aimed to elucidate the benefits and limitations of preoperative chemoradiotherapy (CRT) in rectal cancer treatment, specifically in T4b rectal cancer. This retrospective cohort study reviewed 1014 consecutive patients with clinical T3/4a/T4b adenocarcinomas of the lower rectum, who underwent total mesorectal excision at the Department of Surgical Oncology of the University of Tokyo Hospital and 22 referral institutions affiliated with the Japanese Study Group for Postoperative Follow-up of Colorectal Cancer. Patients were divided into two cohorts: cohort 1 comprised 298 consecutive patients who underwent CRT followed by radical surgery and cohort 2 comprised 716 consecutive patients who underwent curative surgery without preoperative therapy. We assessed the prognostic differences between the two cohorts, focusing particularly on T stages. In T3/4a patients, cohort 1 showed a significantly lower local recurrence rate than cohort 2 (4.8% vs. 9.4%, p=0.024), but not in T4b patients (23.5% vs. 16.0%, p=0.383). In contrast, no significant differences in survival were observed between T3/4a and T4b patients. T4b classification was found to be an independent predictive factor of local recurrence in cohort 1, but not in cohort 2. In T4b rectal cancer, preoperative CRT demonstrated a limited benefit for local control and survival. In cases of suspected T4b rectal tumors, additional therapies such as induction chemotherapy to conventional CRT may contribute to better outcomes.

Aim Neuroendocrine tumors (NETs) are one of the subtypes of neuroendocrine neoplasms and are defined as epithelial neoplasms with predominant neuroendocrine differentiation. The aim of this study was to clarify the clinicopathological characteristics of colorectal NETs through a nationwide retrospective study in Japan. Methods This multicenter retrospective cohort study of NETs in Japan was conducted by the study group of the Japanese Society for Cancer of the Colon and Rectum. In this study, we aimed to clarify the characteristics of Japanese patients with colorectal NETs. This cohort study included patients with colorectal NETs who were treated from January 2011 to December 2015. Results Most NETs developed in the lower rectum. Predictive factors of lymph node metastasis included size (>10 mm), depth of invasion (muscular propria or greater), NET grade (NET G2), depressed lesion of the tumor, and lymphovascular infiltration. In particular, depressed lesion of the tumor and lymphovascular infiltration were independent predictive factors of lymph node metastasis. The presence of an increased number of these predictive factors increased the lymph node metastasis rate. Conclusion Surgical resection with lymph node dissection is considered in the colorectal NETs patients with predictive factors of lymph node metastasis, the number of which is correlated with incidence of lymph node metastasis., This Japanese multicenter retrospective study revealed clinicopathological characteristics and the risk factors of lymph node metastasis in colorectal neuroendocrine tumors.

Objectives In Japan, there are three grades of peritoneal metastasis from colorectal cancer. The grade depends on the extent and number of lesions (P classification). The P classification is useful for its simplicity but lacks objectivity. On the other hand, the peritoneal cancer index (PCI) objectively indicates the peritoneal metastasis grade. However, the evaluation process is complicated clinically. In this study, we compared these two methods and investigated how to improve the P classification's objectivity by referring to PCI. Methods We investigated 150 cases of synchronous peritoneal metastasis from colorectal cancer. We inspected the correlation between the P classification and the PCI and pointed out the problems which prevented objective evaluation when using the P classification. We also estimated new criteria for extent and number in the P classification. Results We found the ideal definition for the best alignment between the P classification and the PCI was: ・P1 is metastases confined to one peritoneal region, ・P2 is 19 or fewer peritoneal metastases in two or more regions, and ・P3 is 20 or more metastases in two or more regions. This revision improved the P classification's objectivity and correlated with the PCI. Conclusions Grading using the P classification was both imprecise and subjective. We propose a new standard value of extent and number in the P classification based on the PCI. This improvement would provide an objective, simple method of grading for peritoneal metastasis from colorectal cancer.

Aim To investigate the usefulness of resection for synchronous peritoneal metastasis from colorectal cancer. Methods The patients who underwent surgery for stage IV colorectal cancer at 16 hospitals between 1991 and 2007 were enrolled in this study. The overall survival rates of patients with synchronous peritoneal metastasis from colorectal cancer with and without R0 resection were compared using a propensity score‐matched analysis. Results Among the 3965 patients with stage IV colorectal cancer, 1169 had synchronous peritoneal metastasis (28.5%). No patients received hyperthermic intraperitoneal chemotherapy (HIPEC) in this study. Among the 1169 patients, 783 had enough clinicopathologic information and went through further analysis. Out of 783 patients, 204 underwent R0 resection. A multivariate analysis revealed that severity of peritoneal metastasis according to the Japanese classification (P, A propensity score‐matched analysis disclosed that the outcomes of patients with R0 resection for colorectal cancer with synchronous peritoneal metastasis were better than those without R0 resection.

The feasibility of laparoscopic surgery for primary appendiceal tumors compared to that of open surgery has not been demonstrated to date because primary appendiceal tumors are rare. This study aimed to compare the long-term outcomes between laparoscopic and open surgeries for primary appendiceal tumors. In this multicenter retrospective cohort study, the data of patients who had been histologically diagnosed with primary appendiceal tumors at 43 tertiary hospitals in Japan between 2000 and 2017 were analyzed. In total, 922 patients were assessed, and 679 cases were eligible for analysis. Using propensity scores, the baseline characteristics were matched for 114 open surgery cases and 114 laparoscopic surgery cases. The primary endpoints were recurrence-free survival (excluding patients with stage IV disease with distant metastasis) and overall survival. The rate of conversion from laparoscopic to open surgery was 1.5%. The 5-year recurrence-free survival rates were 80.4% (95% confidence interval: 71.0–89.7) and 78.2% (95% confidence interval: 69.0–87.3) in the laparoscopic and open surgery groups, respectively, with no significant difference (p = 0.57). No significant difference was observed in the 5-year overall survival rates between the laparoscopic [83.5% (95% confidence interval: 74.4–92.7)] and open surgery [72.7% (95% confidence interval: 62.3–83.0); p = 0.09] groups. In multivariate analysis, laparoscopic surgery was not identified as an independent prognostic factor for overall survival [hazard ratio: 0.49 (95% confidence interval: 0.23–1.06), p = 0.0707]. Laparoscopic surgery is comparable to open surgery and can be considered a treatment option for primary appendiceal tumors.

The recurrent risk of stage I colorectal cancer (CRC) is not clear, and the data regarding appropriate post-operative surveillance schedules in stage I CRC are scarce. We aimed to stratify stage I CRC based on the recurrence risk and evaluate optimal post-operative surveillance durations based on this stratification. We retrospectively analyzed the cases of 6607 stage I CRC patients from 24 institutions. To assess the patients’ clinicopathological factors that impact recurrence-free survival (RFS), we performed univariate and multivariate analyses using Cox proportional hazards models. We divided the patients into classes based on their numbers of factors that were associated with poor RFI in the multivariate analysis. Recurrence occurred in 3.9% patients. The multivariate analysis revealed the independent factors for poor RFS: rectal cancer, T2 depth, presence of lymphatic invasion, high level of pre-operative carcinoembryonic antigen, and absence of D2–3 lymphadenectomy. We also divided the patients into three classes based on their numbers of these risk factors; the 3-year and 5-year RFS rates were 99.3% and 99.1% in the no-risk patients, 97.4% and 96.5% in the patients with 1–2 risks, and 92.1% and 90.0% in the patients with 3–5 risks, respectively. In the patients with no risk and in the patients with 1–2 risks after 3 years post-surgery, ≤ 1% recurrence occurred. Thus, post-operative surveillance may be omitted in these populations. Our new classification properly stratified the recurrence risks of stage I CRC patients, and may help reduce unnecessary post-operative surveillance.

Mechanisms accounting for sex differences in the incidence of adverse events caused by fluoropyrimidine treatments, and histologic differences in efficacy are insufficiently understood. We determined differences between the sexes in terms of the safety of S-1 plus oxaliplatin (SOX)/bevacizumab-versus-l-leucovorin, 5-fluorouracil (5-FU) and oxaliplatin (FOLFOX)/bevacizumab, and the impact of histology on their therapeutic effects, in 512 unresectable metastatic colorectal cancer patients from the SOFT phase III study. Nausea (OR: 2.88, P < 0.001) and vomiting (OR: 3.04, P = 0.005) occurred more frequently in females than males treated with SOX/bevacizumab, while nausea (OR: 2.12, P = 0.006), vomiting (OR: 3.26, P = 0.004), leukopenia (OR: 2.61, P < 0.001), neutropenia (OR: 2.92, P < 0.001), and alopecia (OR: 4.13, P < 0.001) were higher in females on FOLFOX/bevacizumab. Mean relative dose intensities (RDIs) of S-1 during all cycles of SOX/bevacizumab were significantly lower in females (73.9%) than males (81.5%) (P < 0.001), while RDIs of continuous infusion of 5-FU in the FOLFOX/bevacizumab regimen were 75.0% in females and 80.5% in males (P = 0.005). No significant differences in efficacy with regard to overall survival (OS) and progression-free survival (PFS) were identified between the sexes for either SOX/bevacizumab or FOLFOX/bevacizumab treatment. Patients with poorly-differentiated adenocarcinoma had significantly worse OS (HR: 2.72, 95% CI: 1.67-4.44, P < 0.0001) and PFS (HR: 1.89, 95% CI: 1.18-3.02, P = 0.0079) than patients with well- or moderately-differentiated adenocarcinoma. Female patients experienced more frequent and severe adverse reactions to SOX/bevacizumab and FOLFOX/bevacizumab and a worse prognosis for poorly-differentiated adenocarcinoma were confirmed in this phase III study. This warrants further translational research to identify the responsible mechanisms.

Supplemental Digital Content is available in the text., Grade 3 (G3, poorly differentiated) is an important treatment-decision factor in stage II colon cancer, but no unified diagnostic criteria are established. According to previous studies, an intratumoural poorly differentiated area with no glandular formation (POR) that fills the microscopic field of a ×40 objective lens was an essential factor that defined G3. We aimed to prospectively validate this in a randomized controlled study of adjuvant chemotherapy (SACURA trial). We enrolled 991 patients with stage II colon cancer. POR was graded according to the ×40 objective lens rule and the intensity of poorly differentiated clusters (GradePOR), and its prognostic power was compared with that of the conventional tumor grade on the basis of predominant histology rule (Gradeconv). According to GradePOR, 313, 526, and 152 tumors were classified as G1POR, G2POR, and G3POR, respectively, and the 5-year relapse-free survival (RFS) rates were 91.1%, 82.9%, and 74.7%, respectively (P

Aim The prognostic value of the stage III subclassification system based on the Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma has not yet been clarified. This study aimed to develop a modified system with optimal risk stratification and compare its performance with the current staging systems. Methods Clinicopathological data from 6855 patients with stage III colorectal cancers who underwent D3 dissection were collected from a nationwide multicenter database. After determining patient survival rates across 13 divisions based on pathological N stage (N1, N2a, and N2b/N3) and tumor depth (T1, T2, T3, T4a, and T4b), except for T1N2a and T1N2b/N3 due to the small number, we categorized patients into three groups and developed a trisection staging system according to the Akaike information criterion. We then compared the Akaike information criterion of the developed system with those of the current staging systems. Results The T1N1[rank, 1] division (98.5%) had the most favorable prognosis in terms of 5‐year cancer‐specific survival, followed by T2N1[2] (93.9%), T2N2a[3] (92.0%), T3N1[4] (87.0%), T3N2a[5] (78.8%), T4aN1[6] (78.7%), T2N2b/N3[7] (77.8%), T4aN2a[8] (75.2%), T4bN1[9] (73.5%), T3N2b/N3[10] (64.7%), T4aN2b/N3[11] (61.5%), T4bN2b/N3[12] (43.0%), and T4bN2a[13] (42.5%). Compared to the categorizations of the Japanese and tumor‐node‐metastasis systems (Akaike information criterion, 22 684.6 and 22 727.1, respectively), the following stage categorizations were proven to be the most clinically efficacious: T1N1[1 ]‐T3N1[4], T3N2a[5 ]‐T4bN1[9], and T3N2b/N3[10 ]‐T4bN2a[13] (Akaike information criterion, 22 649.2). Conclusion The proposed modified system may be useful in the risk stratification of patients with stage III colorectal cancer who had undergone D3 dissection., The present study retrospectively analyzed data from 6855 patients with colorectal cancer who underwent resection with D3 dissection and showed the presence of prognostic heterogeneity in each subclassification category (i.e. stage IIIa, IIIb, and IIIc). Subsequently, we created a modified staging system primarily considering prognostic stratification power.

Previous studies investigating the impact of tumor location on colorectal cancer prognosis only compared two groups by location, e.g., ‘right-sided colon vs. left-sided colon,’ ‘colon vs. rectum,’ and ‘right-sided (right-sided colon) vs. left-sided (left-sided colon and rectum).’ This nationwide multicenter retrospective study aimed to clarify the prognostic impact of tumor location in patients with stage III colorectal cancer by classifying tumors into three groups: right-sided colon, left-sided colon, and rectum. Subjects were 9194 patients with stage III colorectal cancer who underwent curative surgery from 1997 to 2012. Relapse-free survival (RFS) after primary surgery and overall survival (OS) after recurrence were examined. Rectal cancer (n = 2922) was associated with worse RFS compared to right-sided colon cancer (n = 2362) (hazard ratio (HR) 0.65; 95% CI 0.59–0.72; p

To collect large-scale data for further research to improve treatment outcomes in patients with colorectal liver metastasis (CRLM), the Joint Committee for Nationwide Survey on CRLM was established by the Japanese Society for Cancer of the Colon and Rectum and the Japanese society of Hepato-Biliary-Pancreatic Surgery. The joint committee was initiated to collect data since 2014 and has already reported data including the prognostic data of 3820 patients newly diagnosed with CRLM between 2005 and 2007.The data of patients newly diagnosed with CRLM after 2013 are continuously being registered prospectively, and herein, we report the data of the patients newly diagnosed with CRLM in 2013 and 2014.The data of 3839 patients newly diagnosed with CRLM in 2013 and 2014 were registered from 156 departments (75%) of 152 institutions among 209 departments (from 201 institutions) that agreed to participate in this database system at its initiation. Finally, 3525 patients were enrolled in this study after a quality management process conducted by the joint committee. We report the comprehensive data obtained from 3525 patients, including clinicopathological findings, treatment strategies, and implementation status of chemotherapy.The joint committee will provide these raw data while updating prognostic data to researchers who will conduct meaningful studies that meet the aim of the joint committee.

Tumour-Node-Metastasis (TNM) staging of colorectal cancer (CRC) needs further classification for better treatment because of disease heterogeneity. Although molecular classifications which are expensive and laborious are under study, cost and labour efficient subtyping is desirable. We assessed the combinations of preoperative tumour marker (TM) elevation and tumour lymphovascular invasion (LVI) as a solution. We used the pooled data of 7151 colon cancer (CC) patients and 4620 rectal cancer (RC) patients who received curative surgery between 2004 and 2008 in Japan. The best-matched subtyping for predicting relapse-free survival (RFS) was statistically selected using the c-index and Akaike’s information criterion. This subtyping (TM-LVI), which consisted of three categories by TM elevation status and severity of LVI status, was an independent prognostic factor for RFS of CC (stage IIa, IIIb, and IIIc) and RC (stage I, IIa, IIb, IIIa, and IIIb) and also for disease specific survival of CC (stage IIa, IIb, IIIb, and IIIc) and RC (all stage except for IIc). Although TM-LVI classified CRC patients into low and high recurrence risk groups, the application of adjuvant therapy was not accordance with the TM-LVI status. TM-LVI may be a cost and labour efficient subtyping of colorectal cancer for better treatment strategy.

Whether tumour side affects the anatomical extent and distribution of lymph node metastasis in colon cancer is unknown. The impact of tumour side on the anatomical pattern of lymphatic spread in colon cancer was assessed.Patients with stage III colon cancer from a Japanese multi-institutional database who underwent extensive (D3) lymphadenectomy, which is similar in concept to complete mesocolic excision with central venous ligation, were divided into groups with right- and left-sided tumours. Based on location, mesenteric lymph nodes were categorized as paracolic (L1), intermediate (L2) or central (L3). The Kaplan-Meier method was used to evaluate disease-free survival (DFS) and overall survival (OS), and multivariable Cox models were used to evaluate the association between anatomical lymph node level, metastatic pattern and outcome.A total of 4034 patients with stage III colon cancer (right 1618, left 2416) were included. Unadjusted OS was worse in patients with right colon cancer (hazard ratio 1·23, 95 per cent c.i. 1·08 to 1·40; P = 0·002), but DFS was similar. Right-sided tumours more frequently invaded L3 nodes than left-sided lesions (8·5 versus 3·7 per cent; P 0·001). The proportion of patients with a skipped pattern of lymphatic spread was higher in right than in left colon cancer (13·7 versus 9·0 per cent; P 0·001). In multivariable analysis, invasion of L3 nodes was associated with worse OS in left but not in right colon cancer. The presence of skipped metastasis was associated with worse DFS in left, but not right, colon cancer.There are significant differences in the pattern of lymph node invasion between right- and left-sided stage III colon cancer, and in their prognostic significance, suggesting that tumour side may dictate the operative approach.Se desconoce si la lateralidad del tumor influye en la extensión anatómica y en la distribución de las metástasis en los ganglios linfáticos (lymph node metastasis, LN) en el cáncer de colon. Se evaluó el impacto de la lateralidad del tumor en el patrón anatómico de diseminación linfática en el cáncer de colon. MÉTODOS: Los pacientes con cáncer de colon en estadio III recogidos en una base de datos japonesa multicéntrica, que se sometieron a una linfadenectomía ampliada (D3), conceptualmente similar a la escisión completa del mesocolon con ligadura venosa central, se dividieron en cáncer de colon del lado derecho y cáncer de colon del lado izquierdo. Según la ubicación, las LN mesentéricas se clasificaron como paracólicas (L1), intermedias (L2) o centrales (L3). Se utilizó el método de Kaplan-Meier para evaluar la supervivencia libre de enfermedad (disease-free survival, DFS) y la supervivencia global (overall-survival, OS), y se utilizaron modelos de Cox multivariados para evaluar la asociación entre el nivel L y el patrón metastásico con el resultado.Se incluyeron 4.034 pacientes con cáncer de colon en estadio III (cáncer de colon derecho: n = 1.618, cáncer de colon izquierdo: n = 2.416). La OS no ajustada fue peor en el cáncer de colon derecho (cociente de riesgos instantáneos, hazard ratio, HR 1,23, i.c. del 95%: 1,08-1,4; P = 0,002), pero la DFS fue similar. La afectación de los ganglios L3 fue más frecuente en pacientes con cáncer de colon derecho que izquierdo (8,5% versus 3,7%, P 0,001). En el cáncer de colon derecho, la proporción de pacientes con patrón de diseminación linfática discontinuo, con salto entre niveles, fue mayor en comparación con el cáncer de colon izquierdo (13,7% versus 9%; P 0,001). En el análisis multivariante, la invasión de los ganglios L3 se asoció con una peor OS en el cáncer de colon izquierdo, pero no en el cáncer de colon derecho. La presencia de metástasis discontinuas se asoció con una peor DFS en el cáncer de colon izquierdo, pero no en el cáncer de colon derecho. CONCLUSIÓN: Existen diferencias significativas en el patrón de invasión de los LN entre el cáncer de colon derecho e izquierdo en estadio III, así como en su importancia pronóstica, lo que sugiere que la lateralidad del tumor puede determinar el abordaje quirúrgico.

Objectives: The necessary and sufficient length of the distal resection margin (l-DRM) for rectosigmoid cancer remains controversial. This study evaluated the validity of the 3-cm l-DRM rule for rectosigmoid cancer in the Japanese classification of colorectal cancer. Methods: We retrospectively reviewed 1,443 patients with cT3 and cT4 rectosigmoid cancer who underwent R0 resection in Japanese institutions between 1995 and 2004. We identified the optimal cutoff point of the l-DRM affecting overall survival (OS) rate using a multivariate Cox regression analysis model. Using this cutoff point, the patients were divided into two groups after balancing the potential confounding factors of the l-DRM using propensity score matching, and the OS rates of the two groups were compared. Results: A multivariate Cox regression analysis model revealed that the l-DRM of 4 cm was the best cutoff point with the greatest impact on OS rate (hazard ratio [HR], 1.37; 95% confidence interval [CI], 1.00-1.84; P = 0.0452) and with the lowest Akaike information criterion value. In the matched cohort study, the OS rate of patients who had l-DRM of 4 cm or more was significantly higher than that of patients who had l-DRM < 4 cm (n = 402; 5-year OS rates, 87.6% vs. 80.3%, respectively; HR, 1.60; 95% CI, 1.09-2.31; P = 0.0136). Conclusions: For cT3 and cT4 rectosigmoid cancer, l-DRM of 4 cm may be an appropriate landmark for a curative intent surgery, and we were unable to definitively confirm the validity of the Japanese 3-cm l-DRM rule.

Aim We investigated the clinical impact of D3 lymph node dissection preserving left colic artery (LCA) compared to D3 without LCA preservation using data from JCOG0404. LCA preservation is expected to maintain adequate blood supply, which is effective in preventing anastomotic leakage, intestinal paralysis, and bowel obstruction. Whether D3 with LCA preservation (Group A) improves clinical outcomes following resection of sigmoid colon cancer compared to D3 without LCA preservation (Group B) is unclear. Methods Procedure type was identified from photographs of the surgical field collected for central surgical review in JCOG0404. Clinical outcomes were compared between each procedure. Results Among the 1057 randomized patients in JCOG0404, 631 patients receiving sigmoid colectomy or anterior resection were included in the subgroup analysis. Group A comprised of 135 patients and Group B of 496 patients. Patient backgrounds did not differ between groups. Median operative time, blood loss, anastomotic leakage, and intestinal paralysis were not remarkably different (Group A vs Group B: 185 vs 186 minutes, 60 vs 50 mL, 3.0% vs 5.0%, and 2.2% vs 3.8%). More overall postoperative complications occurred in Group B than Group A (21.6% vs 9.6%, P = .022). Five‐year relapse‐free survival (RFS) and overall survival (OS) tended to be better in Group A than Group B (RFS: 83.7% and 80.5%, HR 0.80 [95% CI 0.51‐1.26], OS: 96.3% and 91.1%, HR 0.41 [95% CI 0.19‐0.89]). Conclusions Short‐ and long‐term outcomes tend to be better in Group A than Group B, indicating that preservation of LCA could be an alternative treatment., Our analysis for stage II/III sigmoid and rectosigmoid colon cancer found that short‐ and long‐term outcomes were better in D3 dissection with preservation of the LCA than D3 dissection without preservation of the LCA. We concluded that D3 lymph node dissection with preservation of the LCA could be an alternative treatment for D3 lymph node dissection.

Introduction: The prognosis of adolescent and young adult (AYA) patients with colorectal cancer (CRC) is still unclear. The aim of this study was to investigate the clinical features and prognosis in AYA patients compared with middle- aged patients. Methods: Participants were identified from a clinical database of the multicenter cohort in Japan. The AYA group was defined as those

Suitable lesions for endoscopic treatment include not only early colorectal carcinomas but also several types of precarcinomatous adenomas. It is important to establish practical guidelines wherein preoperative diagnosis of colorectal neoplasia and selection of endoscopic treatment procedures are appropriately outlined and to ensure that actual endoscopic treatment is useful and safe in general hospitals when carried out in accordance with guidelines. In cooperation with the Japanese Society for Cancer of the Colon and Rectum, the Japanese Society of Coloproctology, and the Japanese Society of Gastroenterology, the Japan Gastroenterological Endoscopy Society compiled colorectal endoscopic submucosal dissection/endoscopic mucosal resection guidelines by using evidence-based methods in 2014. The first edition of these guidelines was published 5 years ago. Accordingly, we have published the second edition of these guidelines based on recent new knowledge and evidence.

In the TNM classification 8th edition, colorectal cancer (CRC) with peritoneal metastasis, one of the most poor prognostic factors, is classified as M1c (stage IVC), regardless of the presence/absence of other distant metastasis. Several cases with peritoneal metastasis have been successfully managed by surgical treatment; therefore, there is need to give more consideration for uniform differentiation of peritoneal metastasis. This study was aimed at verifying the classification of M1c in CRC. Data from a multi-institutional retrospective cohort of 2929 CRC patients who were diagnosed as having stage IV CRC from 1997 to 2007 were analyzed. Peritoneal metastasis alone was defined as M1c1 and peritoneal metastasis with other organ metastasis was defined as M1c2. The 3-year OS of patients with M1c1 was significantly higher than that of patients with M1b (25.6% vs. 18.1%; HR 0.77; 95% confidence interval (CI) 0.65–0.92; p = 0.005); in particular, the prognosis of patients with M1c1 with localized peritoneal metastasis and R0 resection was equivalent to that of patients with M1a (3-year OS 40.5% vs. 39.2%, p = 0.41). On the other hand, among the stage IV cases, patients with M1c2 had a low R0 resection rate (5.9%) and the worst prognosis (3-year OS, 9.1%). The prognosis of M1c1 with localized peritoneal metastasis is relatively good, and can be further improved by surgical intervention. Combined evaluation of the M1c1/2 classification with the peritoneal metastasis grade may help in establishing more individualized treatment strategies.

In Japan, R0 resection has been recommended for colorectal cancer patients with peritoneal metastases confined to the adjacent peritoneum and those with a few metastases to the distant peritoneum. R0 resection for M1c disease has drawn attention in Western countries and is currently considered an acceptable therapeutic option in the US National Comprehensive Cancer Network guidelines. However, clinical factors that affect the choice of R0 resection are unknown. This multicenter, prospective, observational study was conducted by the Japanese Society for Cancer of the Colon and Rectum. Colorectal cancer patients with synchronous peritoneal metastases were enrolled at 28 institutions in Japan from October 2012 to December 2016. To determine factors affecting R0 resection and R1 resection with intended R0 resection, stepwise logistic regression analyses were performed on clinical factors including age, sex, performance status (PS), body mass index, peritoneal cancer index (PCI) score, presence of ascites, presence of distant metastases, and primary tumor site. R0/R1 resection was performed in 36 (31/5; 25%) of 146 patients. No distant metastases [odds ratio (OR) 52.9; 95% confidence interval (CI) 13.3–210.1; p

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 Chemotherapy with biologics followed by liver surgery improves the resection rate and survival of patients with colorectal liver metastasis (CRLM). However, no prospective study has compared the outcomes of chemotherapy with bevacizumab (BEV) versus cetuximab (CET). Methods The ATOM study is the first randomised trial comparing BEV and CET for initially unresectable CRLM. Patients were randomly assigned in a 1:1 ratio to receive mFOLFOX6 plus either BEV or CET. The primary endpoint was progression-free survival (PFS). Results Between May 2013 and April 2016, 122 patients were enrolled. Median PFS was 11.5 months (95% CI 9.2–13.3 months) in the BEV group and 14.8 months (95% CI 9.7–17.3 months) in the CET group (hazard ratio 0.803; P = 0.33). Patients with a smaller-number but larger-sized metastases did better in the CET group. In the BEV and CET groups, the response rates were 68.4% and 84.7% and the resection rates were 56.1% and 49.2%, respectively. Conclusion Although CET achieved a better response rate than BEV for patients with a small number of large liver metastases, both biologics had similar efficacy regarding liver resection and acceptable safety profiles. To achieve optimal PFS, biologics should be selected in accordance with patient conditions. Trial registration This trial is registered at ClinicalTrials.gov (number NCT01836653), and UMIN Clinical Trials Registry (UMIN-CTR number UMIN000010209).

The survival benefit of and indications for adjuvant chemotherapy (AC) for colorectal liver metastases (CRLM) remain unclear. Patients who were diagnosed with liver-limited CRLM between 2005 and 2007 and subsequently underwent R0 resection without preoperative chemotherapy were identified in a Japanese nationwide survey. This overall cohort was divided into synchronous and metachronous CRLM cohorts. In each of the three cohorts, the patients that were given AC were matched with those treated with surgery alone via 1:1 propensity score (PS) matching. Recurrence-free survival (RFS) and overall survival (OS) after the initial hepatectomy were compared. The median follow-up period was 79.4 months and the overall, synchronous, and metachronous cohorts included 1145, 498, and 647 patients, respectively. After the PS matching, the patients’ demographics were well balanced. AC was effective in terms of both RFS and OS in the overall cohort (RFS hazard ratio [HR] 0.784, p = 0.045; OS HR 0.716, p = 0.028) and synchronous cohort (RFS HR 0.677, p = 0.027; OS HR 0.642, p = 0.036), whereas AC was not effective in the metachronous cohort (RFS HR 0.875, p = 0.378; OS HR 0.881, p = 0.496). However, in the metachronous cohort, AC was effective in terms of OS in the subgroup that exhibited disease-free intervals of ≤ 1 year after primary tumor resection (RFS HR 0.667, p = 0.068; OS HR 0.572, p = 0.042). Adjuvant chemotherapy has a survival benefit for patients with resected CRLM. Synchronous CRLM is a favorable indication for AC, whereas in metachronous CRLM, the use of AC should be individualized according to each patient’s risk factors.

PURPOSE The International Union Against Cancer highlighted tumor budding as a tumor-related prognostic factor. International assessment criteria for tumor budding were recently defined by the 2016 International Tumor Budding Consensus Conference (ITBCC2016). This study aimed to clarify the prognostic and predictive values of tumor budding in a randomized controlled trial evaluating the superiority of adjuvant chemotherapy with oral tegafur-uracil over surgery alone for stage II colon cancer (SACURA trial; ClinicalTrials.gov identifier: NCT00392899 ). PATIENTS AND METHODS Between 2006 and 2010, we enrolled 991 patients from 123 institutions with stage II colon cancer. Tumor budding was diagnosed by central review on the basis of the criteria adopted in the ITBCC2016. We prospectively recorded all clinical and pathologic data, including the budding grade, and performed prognostic analyses after 5 years of completing the patients’ registration. RESULTS Of 991 tumors, 376, 331, and 284 were classified as BD1, BD2, and BD3, respectively; the 5-year relapse-free survival (RFS) rate was 90.9%, 85.1%, and 74.4%, respectively ( P < .001), and ranged widely in T4 tumors (86.6% to 53.3%). The budding grade significantly correlated with recurrence in the liver, lungs, lymph nodes, and peritoneum ( P < .001 to .01). Multivariable analysis revealed that budding and T stage exerted an independent impact on RFS, and on the basis of the Harrell concordance index, these two factors substantially contributed to the improvement of the Cox model for predicting RFS. Both the BD2 and BD3 groups demonstrated greater improvement in the 5-year recurrence rate in the adjuvant chemotherapy group than the surgery-alone group by approximately 5%, but the difference was statistically nonsignificant. CONCLUSION Tumor budding grade on the basis of the ITBCC2016 criteria should be routinely evaluated in pathologic practice and could improve the benefit of adjuvant chemotherapy for stage II colon cancer.

Little is known about repeat resection for recurrence exclusive of the liver and lungs and the natural history after the first curative resection in patients with metastatic colorectal cancer.This study aimed to investigate the role of repeat resection for recurrence of metastatic colorectal cancer in a Japanese cohort.This is a multi-institution retrospective observational study.This study was conducted at participating tertiary referral hospitals.Patients with metastatic colorectal cancer who had synchronous distant metastases and underwent simultaneous resection of primary and distant disease or sequential staged resection at short intervals between 1997 and 2007 were included.The primary outcomes measured were patterns of recurrence site, treatments, and survival.A total of 1133 patients were identified, of whom 1073 were eligible. In total, 809 of the 1073 patients developed recurrence after curative resection, and 323 of these underwent repeat resection for recurrence. Of these, 211 developed re-recurrence; 80 of these patients underwent a second repeat resection. When stratified by site of recurrence, the 5-year overall survival rate in patients who underwent repeat resection was 56% in those with recurrence in the liver only, 43% in those with recurrence in the lung only, 30% in those with peritoneal seeding only, and 28% in those with multiple organ involvement. In patients who underwent a second repeat resection, the 5-year overall survival rates were 56%, 46%, 100%, and 50%.This study was limited by its retrospective study design.Repeat surgery could have long-term survival benefit in patients with metastatic colorectal cancer who develop recurrence or re-recurrence in the liver or lung following curative resection. However, repeat surgery should be considered carefully in patients with peritoneal seeding only or recurrence at multiple sites. See Video Abstract at http://links.lww.com/DCR/A838.

Intersphincteric resection (ISR) is the ultimate sphincter-preserving procedure for low rectal cancer. A questionnaire about the standardization of ISR was given to 2125 patients who underwent curative ISR for low rectal cancer between 2005 and 2012 at 127 affiliated institutions of the Japanese Society for Cancer of the Colon and Rectum (JSCCR), and the results were compared with the results of a systematic review. The findings revealed that although mortality and morbidity were relatively low and the survival rate after ISR was good, the rates of local recurrence and postoperative fecal incontinence were relatively high. The radicality of ISR was compared with that of abdominoperineal resection and low anterior resection using the propensity score matching prognosis analysis of patients in the JSCCR nationwide registry. The local recurrence rate was significantly higher after ISR, and especially high in patients with T3 (invasion into the external anal sphincter) and T4 disease. These results provide evidence about the factors related to fecal incontinence after ISR. As measures for the standardization of ISR, it is important to reconfirm that ISR is not indicated for patients with cT3 and cT4 disease and those with poor preoperative defecatory function, based on the ISR indication criteria.

A striking resection rate and survival benefit of first-line cetuximab-containing chemotherapy were demonstrated in patients with mCRC who were classified into the potentially resectable group., Objective We aimed to clarify the clinical practice and outcomes of first-line cetuximab-containing chemotherapy in patients with metastatic colorectal cancer. Efficacy and safety were evaluated in each group classified by the European Society for Medical Oncology Guidelines 2012. Methods This prospective observational study included patients with previously untreated metastatic colorectal cancer from 158 centers in Japan who started first-line cetuximab-containing chemotherapy from January 2012 to June 2013 and were followed for up to 3 years. The resection rates after chemotherapy were calculated and the overall survival was estimated using the Kaplan–Meier method for Group 1 (G1, potentially resectable), Group 2 (G2, not resectable and tumor-related symptoms) and Group 3 (G3, not resectable and asymptomatic). Results Of 578 patients, 562 were classified into G1 (n = 165), G2 (n = 224) or G3 (n = 173). The resection rate of any site was higher in G1 (57.0%) than in G2 (11.2%) and G3 (11.6%). G1, G2 and G3 showed median overall survivals (95% confidence interval) of 45.9 (38.1–not available), 16.7 (14.5–18.8) and 30.6 (23.2–34.8) months, respectively (P < 0.0001). The common tumor-related symptoms in G2 were pain, fatigue and anorexia, from which 31.7, 22.2 and 14.8% of the patients suffered at baseline. Conclusions The expected efficacy and safety of first-line cetuximab-containing chemotherapy were demonstrated in patients with metastatic colorectal cancer under clinical practice in Japan. Registered clinical trial numbers UMIN000007275

The prognostic significance of lymph node ratio (LNR) is not constant among studies. Exploration of appropriate location-specific cutoffs might be necessary because the number of lymph nodes harvested is generally higher in right than in left colon cancer. We aimed to determine appropriate cutoff values of LNR in right and left colon cancer and to clarify its clinical significance. The clinicopathologic data of 5463 patients with stage III colon cancer were collected. The best cutoff for LNR as a prognostic indicator for patients with right and left colon cancer was studied separately. We compared the prognostic impact between LNR and the number of lymph node metastasis using the Akaike information criterion (AIC), and evaluated the prognostic significance of LNR in each stage III subcategory. The best performance was noted when LNR was categorized by cutoffs of 0.16 and 0.22 for right and left colon cancer, respectively. AIC scores were better with these categorizations than with subgrouping by number of positive nodes. LNR-low right colon cancer patients showed better cancer-specific survival than LNR-high in stage IIIA (95.7% vs. 89.3%), IIIB (86.7% vs. 77.2%), and IIIC (71.2% vs. 58.7%). The same results were obtained in left colon cancer patients with stage IIIB (88.3% vs. 80.7%) and IIIC (79.8% vs. 68.4%). We demonstrated the difference in the appropriate cutoffs of LNR between right and left colon cancer. Categorization by location-specific cutoff of LNR may be useful for risk stratification of patients with stage III cancer.

Locally recurrent rectal cancer (LRRC) has a tremendous impact on prognosis as well as the quality of life. Because of the low incidence and various recurrence patterns, the treatment outcome of LRRC is not fully elucidated. The current study aimed to evaluate the prognosis and identify the prognosticators in patients with LRRC. We conducted a multicenter study at 24 hospitals in Japan. Patients with primary rectal cancer who underwent curative resection between 1997 and 2012 and developed local recurrence only as a first recurrent event were recruited. The primary outcome of our study was overall survival (OS) after a diagnosis of LRRC. Four hundred and ninety-eight patients were included in the study. Of these, 213 (42.8%) underwent surgical resection; this was associated with the best 5-year OS rate of 52%, followed by carbon ion/proton therapy (44%). Among LRRC patients, undifferentiated type, T4, high CEA level, and high CA19–9 level were independent prognosticators of OS (hazard ratio (HR) = 1.83, P = 0.008, HR = 1.54, P = 0.004, HR = 1.35, P = 0.03, and HR = 1.58, P = 0.003, respectively). This large-scale cohort study showed that surgical resection led to a favorable prognosis compared to other treatments for LRRC. Therefore, surgical resection should be considered whenever feasible for LRRC patients. In addition, undifferentiated type, T4, and tumor marker (CEA and CA19–9) elevation were identified as independent prognostic factors for OS among patients with LRRC.

Rectal cancer is associated with a worse prognosis than colon cancer in Japan because of its high local recurrence rate [1]. Various surgical options for rectal cancer to reduce local recurrence have been developed since Miles described a method for systematic resection in 1908 [2] and aortopelvic lymphadenectomy was introduced in the USA in the 1950s [3]. Stearns and Deddish [4], however, concluded that aortopelvic lymphadenectomy led to an increase of blood loss and urinary and sexual dysfunction without any survival benefit. Their study included patients with sigmoid colon and rectosigmoid cancers in which paraaortic lymph nodes are not regional lymph nodes. In 1979, Enker reported better survival of patients with rectal cancers who underwent pelvic sidewall dissection [5, 6], but the procedure has not been practised in Western countries as standard surgery because lateral pelvic lymph node metastasis has been considered a part of systemic metastases.

Background: There are no standardised criteria for the determination of the ‘regional’ pericolic node in colon cancer surgery, which represents a major cause of the international uncertainty regarding the optimal bowel resection margin. This prospective cohort study aimed to determine ‘regional’ pericolic nodes based on detailed mapping for feeding arteries and lymph nodes. Methods: In all, 2,996 patients with stages I–III colon cancer who underwent curative surgery between June 2013 and December 2017 at 25 institutions in Japan were included. The anatomical distributions of the feeding artery and lymph nodes were determined in resected fresh surgical specimens based on in vivo measurements of the bowel. Findings: The mean number of retrieved pericolic nodes was 20·9 per patient. In all patients except seven (0·2%), the primary feeding artery was distributed within 10 cm of the primary tumour. The metastatic pericolic node location most distant from the primary tumour was within 3 cm in 837 patients, 3–5 cm in 130 patients, 5–7 cm in 39 patients and 7–10 cm in 34 patients. Only four patients (0·1%) had pericolic lymphatic spread beyond 10 cm; all of whom had T3/4 tumours accompanying extensive mesenteric lymphatic spread, and three developed systemic recurrence. The positive pericolic node distance from the primary tumour did not differ depending on the primary tumour location or the distribution of the feeding arteries. Postoperatively, none of the 2996 patients developed recurrence in the remaining pericolic nodes. Interpretation: Based on the distribution of metastatic lymph nodes and prognostic outcomes, the pericolic nodes designated as ‘regional’ were those located within 10 cm of the primary tumours. Despite the fact that surgeons tend to prefer complete mesocolic excision, these findings should be fully considered when determining the bowel resection margin. Funding: Japanese Society for Cancer of the Colon and Rectum Declaration of Interest: All authors declare no competing interests. Ethical Approval: This study was conducted according to the Declaration of Helsinki and comparable Japanese ethical standards. The study was approved by the Institutional Review Boards of the JSCCR and each participating institution. Written informed consent was obtained from all study participants

This is a prospective observational cohort study aiming to include 4000 patients with stages I to III colon cancer treated at 35 specialist institutions in Japan, South Korea, Germany, Russia, Lithuania and Taiwan. The anatomical distribution of lymph nodes and feeding arteries are investigated using surgical specimens according to pre-specified categorizing methods using intraoperative anatomical markings. Primary analyses are performed to identify the general principles of metastatic lymph node distribution in terms of its relation to the location of the primary tumor and feeding arteries. Secondary analyses will be used to estimate prognostic outcomes according to bowel resection length and central radicality and will be used to evaluate the quality of resected surgical specimens. Through in-depth lymph node mapping, standardized criteria for the definite area of ‘regional’ lymph node resection in routine surgical procedures can be identified, which is expected to contribute to international standardization in colon cancer surgery (ClinicalTrials.gov NCT02938481)., The T-REX study is an international initiative to determine standardized criteria for regional lymph node resection in colon cancer surgery using in-depth lymph node mapping.

Hereditary colorectal cancer (HCRC) accounts for

Due to its rarity and biological heterogeneity, guidelines for primary appendiceal tumor (PAT) are based on scarce evidence, resulting in no strong recommendations. The present study explored prognosis-related factors, including the timing of lymph node dissection (LND), in PAT patients after curative resection (CR) to determine the optimal surgical therapies. We retrospectively collected and analyzed data from 404 patients with PATs who underwent CR at 43 tertiary hospitals from 2000 to 2017. This manuscript is based on revised manuscript during review process. Please, change the bold characters to normal characters in the manuscript. After propensity score matching, there were no marked differences in the recurrence-free survival (RFS) or overall survival (OS) between the primary and secondary LND groups (P = 0.993 and 0.728). A multivariate analysis showed that lymph node metastasis (LNM) was an independent factor for the RFS (hazard ratio [HR] 2.59; 95% confidence interval [CI] 1.09–6.13; P = 0.031) and OS (HR 4.70; 95% CI 1.40–15.76; P = 0.012). There were significant associations between the LNM rates and tumor depth (P < 0.0001) and the histological type (P = 0.006). There was no LNM in patients with low-grade appendiceal mucinous neoplasm (LAMN) or well-differentiated mucinous adenocarcinoma (G1) or patients with any Tis or T1 PATs. LNM was an independent prognostic predictor in PATs after CR with LND. Tumor depth and histological type were not prognostic predictors but were LNM predictors. Secondary LND based on the pathological findings of resected specimens is considered an acceptable surgical management without a worse prognosis than primary LND, and it may be omitted in LAMN+G1 or in any Tis and T1 PATs.

Background and objectives An optimal postoperative surveillance protocol for colorectal cancer (CRC) is dependent on understanding the time line of recurrence. By hazard function analysis, this study aimed at evaluating the time of occurrence of metastasis. Methods A total of 21,671 Stage I-III colon cancer patients were retrospectively included from the Japanese study group for postoperative follow-up of colorectal cancer database. Results The 5-year incidence by metastasized organ was 6.3% for liver (right:left = 5.5%:7.0%, p = .0067), 6.0% for lung (right:left:rectum = 3.7%:4.4%:8.8%, p = 7.05E-45), and 2.0% for peritoneal (right:left:rectum = 3.1%:2.0%:1.2%, p = 1.29E-12). The peak of liver metastasis hazard rate (HR) (0.67 years) was earlier and higher than those of other metastases. The peak HR tended to be delayed in early stage CRCs (0.91, 0.76, and 0.52 years; for Stages I, II, and III, respectively). When analyzed as per the primary tumor location (right-sided, left-sided, and rectum), the peak HR for lung metastasis was twice as high for rectal cancer than for colon cancer, and peritoneal metastasis had a high HR in right-sided colon cancers. Conclusion The time course for the risk of recurrence in various metastatic organs based on the primary tumor site was clearly visualized in this study. This will aid in individualizing postoperative surveillance schedules.

Introduction: Recently, “low-grade appendiceal mucinous neoplasms” (LAMNs) have been proposed as one subtype of appendiceal mucinous neoplasms, characterized by a villous or flat proliferation of mucinous epithelium with low-grade cytologic atypia. The aim of this study was to clarify the clinicopathological characteristics of LAMN. Methods: In this multi-institutional cohort study, we retrospectively analyzed the clinicopathological characteristics in appendiceal neoplasms patients who underwent treatment from 2000 to 2017. Results: In total, 922 patients were enrolled, with 279 (30.3%) cases of LAMN, and 93 (10.1%) cases of non-LAMN disease. In comparison with patients with non-LAMN disease, those with LAMN had significantly lower levels of CA19-9 (p = 0.045), a lower frequency of T4 tumors (p < 0.0001), a lower frequency of lymph node metastasis (p < 0.0001), and a lower frequency of distant metastasis (p < 0.0001). Survival analysis revealed that patients with LAMN had a significantly better prognosis than did those with non-LAMN disease (p < 0.001). Among the patients with distant metastasis, those with LAMN had a significantly better prognosis than did those with non-LAMN disease (p = 0.0020), but among the patients without distant metastasis, the difference between the 2 groups was not significant (p = 0.26). However, among patients who underwent complete resection, the difference in prognosis between the 2 groups was not significant (p = 0.10). Conclusions: A multicenter retrospective study revealed that the clinicopathological characteristics of LAMN was different from those of non-LAMN.

BACKGROUND Appendiceal tumor has recently been treated differently from colorectal cancer. However, obtaining knowledge of this disease is difficult because of its rareness. OBJECTIVE This study aimed to investigate the clinicopathological characteristics of appendiceal tumors in a Japanese cohort. DESIGN This was a nationwide multi-institution retrospective observational study. SETTING This study was conducted at the participating tertiary referral hospitals. PATIENTS Patients with appendiceal tumor who were diagnosed between 2000 and 2017 were included. MAIN OUTCOME MEASURES The primary outcome measured was the total survivability. RESULTS A total of 922 patients from the 43 facilities that participated were identified. Of these, 114 patients were diagnosed with cancer other than adenocarcinomas. The remaining 760 patients, with the exception of 48 patients with unknown survival data, were eligible for the final cohort analysis. Of these 760 patients, 515 (67.8%) had mucinous adenocarcinomas and 245 (32.2%) had nonmucinous adenocarcinomas. Within the mucinous adenocarcinoma group, 267 patients (35.1%) were diagnosed as having low-grade appendiceal mucinous neoplasm. The 5-year survival rate of mucinous adenocarcinoma (83.1%) was superior to that of nonmucinous adenocarcinoma (62.0%; p < 0.01). Regarding mucinous adenocarcinoma, multivariate analysis revealed that high differentiation grade (American Joint Committee on Cancer grade 2/3), distant metastases, and R2 operation were significantly associated with a higher 5-year mortality rate. The 5-year survival rate was significantly better for low-grade appendiceal mucinous neoplasms (93.3%) than for other mucinous adenocarcinomas (72.1%; p < 0.01). LIMITATIONS This study was limited by its retrospective study design. CONCLUSIONS We cumulatively investigated appendiceal tumors in a multicenter retrospective study; this is the first such report from Asia. Grouping the grades as per the American Joint Committee on Cancer was useful as a prognostic indicator of appendiceal mucinous adenocarcinomas, including low-grade appendiceal mucinous neoplasm. See Video Abstract at http://links.lww.com/DCR/B282. ANALISIS DE LAS CARACTERISTICAS CLINICOPATOLOGICAS DE LOS TUMORES APENDICULARES EN JAPON: UN ESTUDIO CLINICO RETROSPECTIVO COLABORATIVO MULTICENTRICO: UNA ENCUESTA NACIONAL JAPONESA: El tumor apendicular recientemente se ha tratado de manera diferente al cancer colorrectal. Sin embargo, obtener conocimiento de esta enfermedad es dificil debido a su rareza.Este estudio tuvo como objetivo investigar las caracteristicas clinicopatologicas de los tumores apendiculares en una cohorte Japonesa.Este fue un estudio observacional retrospectivo de multiples instituciones a nivel nacional.Este estudio se realizo en los hospitales de referencia terciarios participantes.se incluyeron pacientes con tumor apendicular que fueron diagnosticados entre el 2000 y 2017.El resultado primario medido fue la supervivencia total.Se identificaron un total de 922 pacientes de las 43 instalaciones que participaron. De estos, 114 pacientes fueron diagnosticados con cancer distinto de adenocarcinomas. Los 760 pacientes restantes, excepto 48 pacientes con datos de supervivencia desconocidos, fueron elegibles para el analisis de cohorte final. De estos 760 pacientes, 515 (67,8%) tenian adenocarcinomas mucinosos y 245 (32,2%) tenian adenocarcinomas no mucinosos. Dentro del grupo de adenocarcinoma mucinoso, 267 pacientes (35,1%) fueron diagnosticados con neoplasia mucinica apendicular de bajo grado (LAMN). La tasa de supervivencia a 5 anos del adenocarcinoma mucinoso (83.1%) fue superior a la del adenocarcinoma no mucinoso (62,0%) (p

We previously performed a randomized controlled trial (RCT) comparing targeted and random biopsy in neoplasia detection in patients with ulcerative colitis (UC), which showed the short-term effectiveness of targeted biopsy with one-time colonoscopy. In this retrospective cohort study, we investigated the long-term effectiveness of targeted biopsy in tertiary care hospitals, using the follow-up data from patients with UC for &ge, 8 years who had enrolled in the initial RCT. The primary outcome was death from colorectal cancer (CRC). Secondary outcomes were advanced neoplasia (CRC or high-grade dysplasia) and colectomy due to neoplasia after the RCT. We compared these outcomes between target and random groups. Data on 195 of the 221 patients (88.2%) enrolled in the previous RCT were collected from 28 institutions between 2008 and 2019. No patients died of CRC in either group, with a median 8.8-year follow-up demonstrating a robustness for targeted biopsy in terms of CRC death prevention. Advanced neoplasia was detected in four and three patients in the target and random groups, respectively. Colectomy was required due to neoplasia in three patients in each group. The chance of developing CRC in patients with a negative colonoscopy was low, and the targeted biopsy appeared effective in this population. Conversely, patients found with low-grade dysplasia at initial RCT have 10-fold higher risk of progression to high-grade dysplasia and/or CRC. Ten extracolonic malignancies were observed during the follow-up, resulting in four deaths. Panchromoendoscopy was used only in 4.6% and targeted biopsy was only performed in 59.1% of colonoscopies. We recommend targeted biopsy rather than &gt, 33 random biopsies in real-world settings under adequate observation by specialists.

Introduction: Multiple primary malignancies (MPMs) are likely to develop in patients with colorectal cancer (CRC); however, their prognoses are unclear. This study aims to investigate the prognostic impacts and clinicopathological features of multiple CRCs and extracolorectal malignancies (EMs) with CRC. Methods: We retrospectively evaluated a total of 22,628 patients with stage I–III CRC who underwent curative resection at 24 referral institutes in Japan between January 2004 and December 2012. MPMs were classified as synchronous CRCs (SCRCs), metachronous CRCs, synchronous EMs (SEMs), and metachronous EMs. Results: The presence of SCRCs (odds ratio 1.54, p < 0.001) was independently associated with SEMs in the multivariate analyses. SEMs were the strongest poor prognostic factor for OS (hazard ratio [HR] 2.21, p < 0.001) and RFS (HR 1.69, p < 0.001) compared with age, sex, and primary T and N factors. The incidence of stomach cancer was the highest in EMs, followed by lung, breast, and prostate cancers. Multiple CRCs were evenly distributed throughout the right-side colon to the rectum. Discussion/Conclusion: SEMs were a strong poor prognostic factor for patients with stage I–III CRC. Patients with CRC, particularly those with SCRCs, should be surveyed for SEMs, especially for stomach and lung cancers.

Previous studies of stage III colon cancer using the hazard function demonstrated that the risk of recurrence in patients with adjuvant chemotherapy never exceeded that of patients without adjuvant chemotherapy. However, it is unclear whether the same can be said for rectal cancer patients and whether adjuvant chemotherapy reduces recurrence. This study aimed to compare the recurrence hazard of stage III rectal cancer with that of colon cancer by adjuvant chemotherapy status using the hazard function, a method that allows for the assessment of instantaneous risk of recurrence over time. This retrospective nationwide study consisted of 10,356 patients with stage III colorectal cancer who underwent curative resection between January 1997 and December 2012 in Japan. Recurrence hazards of rectal and colon cancers were compared between patients treated with adjuvant chemotherapy and those who were not. Analyses in which recurrence was divided into local and distant recurrence were also performed. The hazard rate of recurrence in rectal cancer patients with adjuvant chemotherapy was consistently lower throughout the follow-up period, and the peak time of recurrence later, compared to patients without adjuvant chemotherapy (peaked at 15.7 vs. 7.1 months). Adjuvant chemotherapy also strongly suppressed distant recurrence but not local recurrence in rectal cancer patients. Similar results were observed in colon cancer patients. Our results using nationwide real-world data in Japan suggest that, similar to what is observed in colon cancer patients, adjuvant chemotherapy delays the peak of recurrence and suppresses distant recurrence in stage III rectal cancer patients.

Objectives: The aim of this study is to examine whether prognosis stratification in staging of Stage III colon cancer using T factor and log odds of positive lymph nodes (LODDS) categories is superior to that of the TNM staging system. Materials and Methods: The subjects were 5,919 patients with Stage III colon cancer who underwent curative resection at 24 Japanese institutions. Univariate analysis of LODDS categories and clinicopathologic factors was conducted using a Cox proportional hazards regression model for cancer-specific survival (CSS). Independent prognostic factors for CSS were extracted in multivariate analysis using factors with significance in univariate analysis. Effect sizes of risk factors for CSS were compared using the LogWorth statistic. Combinations of T factor and LODDS categories were used to create L-stage subgroups A, B and C. Stratification of prognosis with L-stage and TNM was compared using the Akaike information criterion (AIC). Results: In multivariate analysis, LODDS was identified as an independent prognostic factor, together with age, maximum tumor diameter, histopathological grade, L, V, pT, and pN. The LogWorth of LODDS was 17.149, which was the second highest after pT (31.562), and that of pN was 7.434. The 5-year CSS was 96.5%, 88.5%, and 66.6% in TNM stages IIIA, IIIB, and IIIC, respectively, and 96.0%, 87.6%, and 59.3% in L-stage A, B, and C, respectively (p < 0.0001). AICs for TNM and L-stage were 14,795.5 and 14,707.8, respectively. Conclusions: Prognosis stratification of the stage classification for Stage III colon cancer was superior with L-stage compared to TNM stage classification.

Background/purpose The purpose of the present study was to assess long-term outcomes following liver resection for colorectal liver metastases (CRLM) with concurrent extrahepatic disease and to identify the preoperative prognostic factors for selection of operative candidates. Methods In this retrospective, multi-institutional study, 3820 patients diagnosed with CRLM during 2005-2007 were identified using nationwide survey data. Data of identified patients with concurrent extrahepatic lesions were analyzed to estimate the impact of liver resection on overall survival (OS) and to identify preoperative, prognostic indicators. Results Three- and 5-year OS rates after liver resection in 251 CRLM patients with extrahepatic disease (lung, n = 116; lymph node, n = 51; peritoneal, n = 37; multiple sites, n = 23) were 50.2% and 32.0%, respectively. Multivariate analysis revealed that a primary tumor in the right colon, lymph node metastasis from the primary tumor, serum carbohydrate antigen (CA) 19-9 level >37 UI/mL, the site of extrahepatic disease, and residual liver tumor after hepatectomy were associated with higher mortality. We proposed a preoperative risk scoring system based on these factors that adequately discriminated 5-year OS after liver resection in training and validation datasets. Conclusions Performing R0 liver resection for colorectal liver metastases with treatable extrahepatic disease may prolong survival. Our proposed scoring system may help select appropriate candidates for liver resection.

Background: Grade 3 (G3, poorly differentiated) is an important treatment-decision factor in stage II colon cancer, but no unified diagnostic criteria are established. According to previous studies, an intra-tumoural poorly differentiated area with no glandular formation (POR) that fills the microscopic field of a 40× objective lens was an essential factor that defined G3. We aimed to prospectively validate this in a randomised controlled study of adjuvant chemotherapy (SACURA trial). Methods: Between 2006 and 2010, we enrolled 991 patients with stage II colon cancer from 123 institutions. POR was quantitatively graded according to the 40× objective lens rule and the intensity of poorly differentiated clusters (GradePOR). The prognostic power of GradePOR was compared with that of the conventional tumour grade based on the predominant histology rule (Gradeconv). Findings: According to GradePOR, 313, 526 and 152 tumours were classified as G1POR, G2POR and G3POR, respectively, and the 5-year relapse-free survival (RFS) rates were 91·1%, 82·9%, and 74·7%, respectively (P < 0·0001). When G3POR and G3conv were alternatively added to the standard prognostic model consisting of eight conventional factors, only G3POR was a significant factor for RFS (P = 0·040, Wald test). The adverse impact of G3POR on RFS was greater in the microsatellite stable (MSS)/microsatellite instability (MSI)-low subset (hazard ratio [HR], 2·61; 95% confidence interval [CI], 1·81–3·77) compared with that in the full analysis set (HR, 1·93; 95% CI, 1·34–2·77). In the MSS/MSI-low subset, the 5-year RFS rate of patients with G3POR tumours in the adjuvant chemotherapy group achieved greater improvement (9·1%) than the surgery-alone group (HR, 0·65; 95% CI, 0·34–1·24). Interpretation: The validated prognostic value of the least differentiation policy with the 40× objective lens rule may be highlighted as the diagnostic criterion for G3 in the adjuvant treatment setting for stage II colon cancer, particularly for MSS/MSI-low tumours. Trial Registration: ClinicalTrials.gov NCT00392899 Funding: This study was supported by the Foundation for Biomedical Research and Innovation at Kobe, Translational Research Center for Medical Innovation (TRI), under the funding contract with Taiho Pharmaceutical Co. Ltd., Japan. Declaration of Interests: MI has received consulting fees from Taiho Pharmaceutical Co. Ltd., BristolMyers Squibb and Merck Serono Co. Ltd; honoraria from Taiho, Chugai Pharmaceutical Co. Ltd., and Yakult Honsha Co. Ltd. HM has received consulting fees from Otsuka Pharmaceutical Factory, Inc. and Sysmex Co.; honoraria from Taiho, Chugai, Yakult Honsha, Daiichi Sankyo Co. Ltd., Astellas Pharma Inc. NT has received research funding from Taiho, Chugai, and Yakult Honsha; honoraria from Taiho, Chugai, Takeda Pharmaceutical Co. Ltd., Merck Serono. YS has received honoraria from Taiho, Chugai and Yakult Honsha. KT has received honoraria from Taiho and Takeda. KK has received consulting fees from Taiho and Chugai; honoraria from Taiho, Chugai, Bristol-Myers, Merck Serono and Otsuka. MW has received research funding from Taiho, Chugai, Yakult Honsha, Johnson and Johnson K. K. and Covidien Japan Co. Ltd. YK has received honoraria from Taiho and Chugai. H. Ueno has received honoraria from Taiho, Chugai, Yakult Honsha, BristolMyers and Daiichi Sankyo. TI has received research funding from Taiho; honoraria from Chugai. H. Uetake has received consulting fees, research funding, and honoraria from Taiho, Chugai, Takeda, Bristol-Myers and Merck Serono. SM has no competing interest. ST has received consulting fees from Taiho, Daiichi Sankyo and Solasia Pharma K. K.; research funding from Daiichi Sankyo, Yakult Honsha and Kureha Co. Ltd.; honoraria from Daiichi Sankyo. KS has received consultant fees, research funding and honoraria from Taiho, Chugai, Takeda, Yakult Honsha, Daiichi Sankyo, Bristol-Myers, Merck Serono, and Pfizer Co. Ltd. Ethics Approval Statement: The study protocol was approved by the Institutional Review Boards of each participating institution and was conducted in accordance with the tenets of the Declaration of Helsinki and comparable Japanese ethical standards. Furthermore, written informed consent was obtained from all study participants.

Background Although a number of studies have been conducted to investigate factors affecting colon cancer recurrence and patient overall survival after surgical treatment, no prognostic risk models have been proposed for predicting survival specifically after postsurgical recurrence. Objective We aimed to identify factors affecting the survival of the patients with recurrent colon cancer and to construct a nomogram for predicting their survival. Design This was a retrospective study. Settings This study used the Japanese Study Group for Postoperative Follow-Up of Colorectal Cancer database, which contains retrospectively collected data of all consecutive patients with stage I to III colorectal cancer who underwent surgical curative resection between 1997 and 2008 at 23 referral institutions. Patients A total of 2563 patients with stage I to III colon cancer who experienced recurrence after surgery were included in the present study. Main outcome measures A nomogram predicting survival was constructed using a training cohort composed of patients from 15 hospitals (n = 1721) using a Cox regression hazard model analysis. The clinical applicability of this nomogram was validated in patients from the 8 remaining hospitals (the validation cohort; n = 842). Results Eight factors (age, location of the primary tumor, histopathological type, positive lymph node status, presence of peritoneal metastasis, number of organs involved in the first recurrence, treatment for recurrence, and the interval between initial surgery and recurrence) were identified as nomogram variables. Our nomogram showed good calibration, with concordance indexes of 0.744 in the training cohort and 0.730 in the validation cohort. The survival curves stratified by the risk score calculated by the nomogram were almost identical for the training and validation cohorts. Limitations The study was conducted using the data until 2008, and more advanced chemotherapeutic agents and multidisciplinary therapies that might have improved the outcomes predicted by our nomogram were not available. In addition, treatment strategies for recurrence might differ between countries. Conclusions Our nomogram, which is based on a nationwide multicenter study, is the first statistical model predicting survival after recurrence in patients with stage I to III colon cancer. It promises to be of use in postoperative colon cancer surveillance. See Video Abstract at http://links.lww.com/DCR/A687.

Background The current status and adoption of cancer-related clinical practice guidelines in Japan has not been elucidated yet. The purpose of this study was to propose roles and suggestions to develop future cancer-related clinical guidelines. Methods A questionnaire consisting of four domains with a total of 17 questions was developed. We distributed the questionnaire to 28 specific academic organizations in Japan which have developed any cancer-related clinical practice guidelines and which were funded by the Ministry of Health, Labor, and Welfare. Results Most organizations have investigated nationwide dissemination and adoption of clinical practice guidelines. The rate of adoption in clinical practice was estimated at approximately ≥ 70%. However, organizations with smaller budgets reported surveying approximately 60% of the time, whereas the ones with larger budgets reported approximately 100% success in surveying about their guidelines. The presidents of the organizations agreed that a new organization operated directly by the national government was necessary. Conclusion In Japan, to develop cancer-related clinical practice guidelines, a study of clinical validation is necessary. Sufficient funds must be available to support the project to maintain and revise the guidelines. Furthermore, legal and ethical issues should be solved before establishing any registry system.

AIM Clinical guidelines recommend adjuvant chemotherapy for high-risk patients with Stage II-III colorectal cancer. However, chemotherapeutic administration rates differ significantly between hospitals. We assessed the prognostic benefit of adjuvant chemotherapy in patients with Stage IIb/c colorectal cancer, and the prognostic impact of interhospital variations in the administration of adjuvant chemotherapy for Stage II-III colorectal cancer. METHOD We conducted a multicentre, retrospective study of 17 757 patients with Stage II-III colorectal cancer treated between 1997 and 2008 in 23 hospitals in Japan. Hospitals were classified as high-rate (rate > 42.8%) or low-rate (rate ≤ 42.8%), chemotherapy prescribing clinics. RESULTS The 5-year overall survival (OS) of patients with Stage II-III colorectal cancer receiving adjuvant chemotherapy was significantly higher than for those not receiving adjuvant chemotherapy (85.7% vs 79.2%, P