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Abstract The clinical significance of FOLFOXIRI (5-FU, leucovorin, oxaliplatin, and irinotecan) plus anti-EGFR monoclonal antibody using cetuximab for metastatic colorectal cancer (mCRC) remains controversial. We report results from a randomized phase 2 DEEPER trial (UMIN000018217, jRCTs061180022) to test the superiority of modified (m)-FOLFOXIRI plus weekly cetuximab over bevacizumab in patients with RAS wild-type (wt) mCRC. Primary endpoint was depth of response (DpR). Secondary endpoints included objective response rate (ORR), early tumor shrinkage (ETS) at week 8, progression-free survival (PFS), overall survival (OS), time to tumor growth (TTG), time to treatment failure (TTF), association between tumor shrinkage and prognosis, association between TTG and prognosis, R0 resection rate, and safety. In 359 enrolled patients with RAS wt mCRC, median DpR was significantly better in cetuximab (57.3% vs 46.0%, p = 0.0029); however, ORR, ETS, R0 resection rate, TTG, TTF, PFS and OS were similar between 2 treatments. There was a weak association between DpR and survival time in both treatments. The correlation between TTG and OS was slightly stronger in cetuximab. The post-hoc exploratory analysis showed that cetuximab produced greater PFS (15.3 vs 11.7 months; HR 0.68) and OS (53.6 vs 40.2 months; HR 0.54) in patients with left-sided and RAS/BRAF wt tumors. m-FOLFOXIRI plus cetuximab has clinical benefit for tumor shrinkage in RAS wt mCRC. The survival benefit for RAS/BRAF wt and left-sided mCRC needs further investigation.

Objectives: The present study examined the incidence of incisional hernia by comparing patients from whom a specimen was extracted either through a Pfannenstiel incision (PI) with an intracorporeal anastomosis or via a midline incision (MI) with an extracorporeal anastomosis. Methods: The records of 370 consecutive patients who underwent a laparoscopic or robotically-assisted colectomy were retrospectively analyzed. Regardless of the clinical symptoms, incisional hernia was objectively diagnosed based on abdominal computed tomography findings. The surgical outcomes and incisional hernia incidence were retrospectively compared between the groups. Propensity score matching (PSM) was used to balance background differences between the groups. Results: Eighty-seven and 283 patients were in the PI group and MI group, respectively. After PSM, 71 patients were selected from each group. The median observation time was 572 and 1110 days in the PI and MI group, respectively. The PI group had no incidence of incisional hernia whereas the MI group had a 14% incidence, demonstrating that the former had significantly fewer incisional hernias (p=0.0014). The median interval from surgery to incisional hernia development was 295 days. The PI with an intracorporeal anastomosis was not associated with an increased complication rate. Conclusions: The PI was preferable for intraoperative specimen extraction owing to the low, associated incidence of incisional hernia.

Objectives: Serrated polyposis syndrome (SPS) is a rare condition associated with an increased risk of colorectal cancer. However, the genetic basis of SPS in Japanese patients remains unclear. The present study therefore aimed to address this omission by identifying candidate causative genes of SPS in Japanese patients. Methods: The present study performed next-generation sequencing using a multigene panel to identify the causative genes in SPS. Whenever a candidate gene was detected, whole exome sequencing of the tumor tissue was performed. Results: An analysis of 11 patients with SPS identified a germline pathogenic variant of BUB1 (c.1543G>T/p.Gly515Ter) in a 47-year-old, female patient with transverse colon cancer with more than 50 serrated polyps. She had no history of smoking. None of the canonical, causative genes in common colorectal cancer, such as APC, KRAS and TP53, were detected in her lesion. Most of the somatic variants detected in the cancer were transition substitutions (C>T). Conclusions: BUB1 was identified as a candidate causative gene in SPS in a non-smoker with the disease. These findings will hopefully contribute to understanding the genetic basis of SPS.

Abstract Introduction In Japanese patients with familial adenomatous polyposis (FAP), colectomy tends to be postponed or avoided. Aim This study aimed to clarify the current clinical practice from a Japanese multicenter cohort study database. Methods We analyzed the records of 250 patients with non‐dense FAP who did not require colorectal cancer removal. The clinical outcomes were compared between patients who received colectomy (n = 142) (Group A) and those who did not receive colectomy (n = 108) (Group B). Results The colectomy rate based on the age at the final follow‐up examination was 46%, 60%, 54%, 65%, at ≤29, 30–39, 40–49, and ≥ 50 years, respectively (P = .11). The development of colorectal cancer did not differ between Groups A and B (25% vs 22% P = .67); however, colorectal cancer was diagnosed at the Tis stage in 88% of the patients with colorectal cancer in Group B, and 34% of the patients with colorectal cancer in Group A (P 30 years of age, and patients who managed without colectomy showed acceptable survival with the early diagnosis of colorectal cancer, and a very low incidence of desmoid tumor development, indicating that this approach represents a potential option for the management of selected non‐dense FAP patients.

Abstract Objective To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. Methods CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. Results In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. Conclusions Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so.

Abstract Objectives Colonoscopy surveillance reduces the incidence of colorectal cancer through the detection and endoscopic removal of adenomas. Current guidelines recommend that patients with Lynch syndrome should have colonoscopy surveillance every 1–2 years starting at the age of 20–25. However, insufficient data are available to evaluate the quality and safety of colonoscopy surveillance for patients with Lynch syndrome nationwide in Japan. Methods Patients with Lynch syndrome (n = 309) from 13 institutions who underwent one or more colonoscopy procedures were enrolled in this retrospective analysis. Colonoscopy completion rate, colonoscopy‐related complication rate, proportion with an adequate colonoscopy interval, and adenoma detection rate were reviewed. Results The colonoscopy completion rate was 98.8% and a history of previous colorectal cancer surgery was significantly associated with a higher completion rate. All complications were associated with endoscopic treatment and the rate of bleeding needing hemostasis and perforation needing surgical repair were both 0.16% after colonoscopy with polypectomy. The adenoma detection rate at the first colonoscopy was 25%. Although there was no difference in the completion and complication rates based on differences in the colonoscopy experience of the endoscopist, the detection rate of adenomas and intramucosal cancers was significantly higher with more experienced endoscopists. The proportion of patients developing cancer was significantly higher with a >24 months than a ≤24 months interval. Conclusion High‐volume experienced endoscopists and appropriate surveillance intervals may minimize the risk of developing colorectal cancers in patients with Lynch syndrome.

Objectives: This retrospective study was conducted to clarify the morphological characteristics of colorectal cancer (CRC) in Japanese familial adenomatous polyposis (FAP) patients. Methods: This study was carried out by the study group for FAP of the Japanese Society for Cancer of the Colon and Rectum. FAP patients who underwent surgical resection between 2000 and 2012 were included in the study. Results: Of the 303 patients enrolled, 119 patients without CRC were excluded. Of 523 lesions, 49 lesions with missing morphological information were excluded; hence, only 474 CRC lesions in 178 patients (328 superficial lesions in 122 patients and 146 non-superficial lesions in 92 patients) were included in the study. Depressed lesions accounted for 3.0% of superficial lesions and ulcerated lesions accounted for 84.9% of non-superficial lesions. The depressed superficial lesions were observed only in patients with sparse and attenuated FAP (P = 0.003). The age of the patients at surgery differed between the two groups, with patients with depressed superficial lesions being significantly older than those with non-depressed superficial lesions (P = 0.009). Moreover, the age of the patients at FAP diagnosis differed between the two groups, with patients with ulcerated non-superficial lesions being significantly older than those with protruded non-superficial lesions (P = 0.006). Conclusions: In patients with FAP, depressed superficial CRC lesions rarely developed but were detected in our study group, and ulcerated non-superficial CRC lesions were also present with similar ratios. Clinicians should pay attention to depressed superficial lesions during endoscopic surveillance of FAP patients.

Abstract We identified a Japanese patient with Lynch syndrome with a novel large germline deletion of chromosome 2p16-21, including the EPCAM, MSH2, and KCNK12 genes. The proband was a 46-year-old man with ascending colon cancer. The clinical significance of germline KCNK12 gene deletion, which encodes one of the subfamilies of two-pore-domain potassium channels, is still unknown.

Abstract 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.

BackgroundMicrosatellite instability (MSI) is a clonal change in the number of repeated DNA nucleotide units in microsatellites. High-frequency MSI (MSI-H) colorectal cancers (CRCs) are known to have different clinicopathological features compared with microsatellite stable (MSS) CRCs. In addition, previous studies have shown that type2 diabetes mellitus (T2DM) is a risk factor for malignant tumors including CRCs. The aim of this study was to investigate the relationship between T2DM and MSI-H colorectal cancer.MethodsThe study design is a single center, cross-sectional study. Data from a series of 936 patients with CRCs were collected and MSI status was assessed.ResultsIn total, 29 (3.1%) and 907 (96.9%) tumors were classified as having MSI-H and low-frequency microsatellite instability or being MSS (MSS), respectively. Of the 936 patients, 275 (29.6%) were associated with T2DM. One (3.4%) of the 29 MSI-H patients and 274 (30.2%) of the 907 MSS patients had T2DM. Thus, the incidence of T2DM was significantly less frequent in MSI-H compared with MSS patients (Fisher's exact test: p = 0.0007).ConclusionsWe conclude that MSS tumors are significantly more common than MSI-H tumors among individuals with T2DM.

Hereditary colorectal cancer accounts for less than 5% of all colorectal cancer cases. Some of the unique characteristics that are commonly encountered in cases of hereditary colorectal cancer include early age at onset, synchronous/metachronous occurrence of the cancer, and association with multiple cancers in other organs, necessitating different management from sporadic colorectal cancer. While the diagnosis of familial adenomatous polyposis might be easy because usually 100 or more adenomas that develop in the colonic mucosa are in this condition, Lynch syndrome, which is the most commonly associated disease with hereditary colorectal cancer, is often missed in daily medical practice because of its relatively poorly defined clinical characteristics. In addition, the disease concept and diagnostic criteria for Lynch syndrome, which was once called hereditary non‐polyposis colorectal cancer, have changed over time with continual research, thereby possibly creating confusion in clinical practice. Under these circumstances, the JSCCR Guideline Committee has developed the "JSCCR Guidelines 2016 for the Clinical Practice of Hereditary Colorectal Cancer (HCRC)," to allow delivery of appropriate medical care in daily practice to patients with familial adenomatous polyposis, Lynch syndrome, or other related diseases. The JSCCR Guidelines 2016 for HCRC were prepared by consensus reached among members of the JSCCR Guideline Committee, based on a careful review of the evidence retrieved from literature searches, and considering the medical health insurance system and actual clinical practice settings in Japan. Herein, we present the English version of the JSCCR Guidelines 2016 for HCRC.

Lynch syndrome (LS) patients have a high risk of developing various tumors. This study aimed to clarify the characteristics of tumors developing in LS patients.This is a retrospective review of 55 LS patients treated at Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital.The median age at the diagnosis of the first malignant tumor and first LS-related tumor was 44 (range, 19-65) and 44 (range, 24-66) years, respectively. Of the 55 LS patients with developing malignant tumors, 45 (93.8%) developed an LS-related tumor as the first malignant tumor. Colorectal cancer (CRC) developed in 47 patients (85.4%), followed by endometrial cancer (n = 13, 56.5%) in females and gastric cancer (n = 10, 18.1%). In 6 gastric cancer patients, Helicobacter pylori was detected in resected specimens. Twenty-nine patients (52.7%) developed CRC and extra-colonic tumors; of these, 15 patients (48.3%) had mutations in MLH1, 10 (58.8%) in MSH2, and 4 (57.1%) in MSH6. At the age of 50, the cumulative incidence was 50.9% [95% confidence interval (CI), 36.9-63.3%] for CRC, 17.4% (95% CI, 5.2-35.6%) for endometrial cancer, and 5.5% (95% CI, 1.4-13.8%) for gastric cancer. Eight gastric cancer, one breast cancer patient, five bladder cancer patients, and one prostate cancer patient demonstrated loss of expression of the mismatch repair (MMR) protein; patients with thyroid cancer, spindle cell sarcoma, and giant cell tumors did not demonstrate this.Gastric cancer incidence was high in Japanese patients with LS and associated with H. pylori infection. MMR protein deficiency caused the development of malignant tumors in LS patients.

A 67-year-old man with a history of low anterior resection and diverting loop transverse colostomy for rectal carcinoma developed fulminant pseudomembranous colitis after stoma closure. Oral administration of vancomycin at 0.5 g every 6 h and colonoscopy with intracolic vancomycin administration was unsuccessful, but continuation of intracolic vancomycin with postural change resulted in dramatic recovery. Postural change may extend the efficacy of intracolic vancomycin, and intracolic vancomycin should be considered as an option between conventional therapy and surgical intervention for pseudomembranous colitis.

Background: The conventional H category-based classification for colorectal liver metastases (CRLM) was created by equal weighting of tumor number and tumor size; however, our previous nomogram to predict postoperative disease-free survival demonstrated that CRLM =5 as a parameter provided 4.5 times greater impact compared with a largest CRLM size >5 cm. Methods: A total of 3815 patients newly diagnosed with CRLM between 2005 and 2007, including 2220 resectable cases, were investigated. Six groups were created based on largest lesion size (= 5 vs >5 cm) and lesion number (1, 2-4, and =5). Results: The novel (n) H1, nH2, and nH3 categories were defined as solitary lesions with a size =5 cm; lesions other than nH1 or nH3; and =5 lesions with any lesion size, respectively. In the resectable cohort, the 5-year cumulative overall survival rates were 64.0%, 53.5%, and 42.6% in the nH1, nH2, and nH3 groups, respectively (P < .001), and no significant differences were observed between the conventional H2 and H3 categories. In the overall cohort, the discrimination ability of the two classifications were comparable. Conclusion: The novel H category-based classification might be beneficial in predicting overall survival in patients with CRLM independent of their resectability. [ABSTRACT FROM AUTHOR]

Background: Metastatic colorectal cancer carries a poor prognosis and cannot be cured by currently available therapy. Chemotherapy designed to prolong survival and improve the quality of life (QOL) of patients is the mainstay of treatment. Standard regimens of FOLFOX/bevacizumab and CapeOX/bevacizumab can cause neurotoxicity, potentially disrupting treatment. The results of 3 phase II studies of combination therapy with S-1, irinotecan, and bevacizumab showed comparable efficacy to mFOLFOX6/bevacizumab and CapeOX/bevacizumab, without severe neurotoxicity. Therefore, the establishment and evaluation of S-1-containing irinotecan-based regimens for first-line treatment are expected to become more important.Methods: The TRICOLORE trial is a multicenter, randomized, open-label, controlled phase III study which aims to evaluate the non-inferiority of combination therapy with S-1/irinotecan/bevacizumab (a 3-week regimen [SIRB] or 4-week regimen [IRIS/bevacizumab]) to oxaliplatin-based standard treatment (mFOLFOX6/bevacizumab or CapeOX/bevacizumab) in patients with metastatic colorectal cancer who had not previously received chemotherapy. Patients will be randomly assigned to either the control group (mFOLFOX6/bevacizumab or CapeOX/bevacizumab) or study group (SIRB or IRIS/bevacizumab). The target sample size is 450 patients. The primary endpoint is progression-free survival (PFS), and the secondary endpoints are overall survival (OS), response rate (RR), time to treatment failure (TTF), relative dose intensity (RDI), the incidence and severity of adverse events, quality of life (QOL), quality-adjusted life years (QALY), health care costs, and relations between biomarkers and treatment response (translational research, TR).Discussion: The results of this study will provide important information that will help to improve the therapeutic strategy for metastatic colorectal cancer, and we believe that this study is very meaningful from the perspective of comparative effectiveness research.Trial Registration: UMIN000007834. [ABSTRACT FROM AUTHOR]

BACKGROUND: Capecitabine is used mainly with oxaliplatin to treat metastatic colorectal cancer (mCRC). Results from capecitabine plus irinotecan (XELIRI) with or without bevacizumab (BV) have been reported in Europe but not in Japan. Consequently, the safety and efficacy of XELIRI plus BV in Japanese patients with mCRC were assessed in a single-arm phase II study. METHODS: Eligible patients had had prior chemotherapy containing BV for mCRC and wild-type or heterozygous UGT1A1. Therapy in each 21-day treatment cycle consisted of capecitabine (800 mg/m(2) twice daily on days 1-15), irinotecan (200 mg/m(2) on day 1), and BV (7.5 mg/kg on day 1). The primary endpoint was dose-limiting toxicity in phase I and progression-free survival (PFS) in phase II. RESULTS: A total of 34 patients (6 in phase I, 28 in phase II) were enrolled from May 2010 to June 2011. Baseline characteristics included a median age of 60 years (range: 22-74 years) for 24 men and 10 women. No dose-limiting toxicities appeared in phase I. Median PFS was 240 days (95% confidence interval: 179-311 days). Overall response rate was 18.1%, and the disease-control rate was 90.9%. The incidence of adverse events frequently associated with irinotecan and capecitabine were neutropenia (any grade, 55.9%; grade 3 or 4, 11.8%), diarrhea (any grade, 50%; grade 3 or 4, 5.9%), and hand-foot syndrome (any grade, 61.8%; grade 3 or 4, 5.9%). CONCLUSION: Our results suggest that XELIRI plus BV is well tolerated and effective as a second-line treatment for mCRC in Japanese patients. This regimen could be especially appropriate for patients resistant to oxaliplatin-based regimens. [ABSTRACT FROM AUTHOR]

Abstract  We report the case of a 45-year-old Tokyo man who developed alveolar echinococcosis of the liver, which is an extremely rare disorder in Japan, except for Hokkaido, Japan's northernmost island. The findings of multiple clustered cysts on computed tomography were unlike those of any hepatic tumors we had previously encountered. T2-weighted magnetic resonance imaging revealed the characteristic findings of small cysts with a very high signal intensity. The tumors were successfully removed by a hepatic resection. The patient lives in Tokyo, but has visited Hokkaido many times. The exact route of infection in this patient remains unclear. Sliced raw venison, which he reported eating on every visit to Sapporo in Hokkaido, represented the only potential route of infection we could identify. This meat may have somehow become contaminated with embryonated eggs. Nowadays, even city inhabitants are at risk of developing rare diseases due to the rapid development of transportation systems. [ABSTRACT FROM AUTHOR]