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The prevalence of Lynch syndrome (LS)-associated DNA mismatch repair (MMR)-deficient bladder cancer (BC) has scarcely been investigated. Immunohistochemistry for four MMR proteins (MLH1, MSH2, MSH6, and PMS2) was performed in formalin-fixed paraffin-embedded (FFPE) sections prepared from the resected specimens of 618 consecutive newly diagnosed BC cases. Genetic/epigenetic analyses were performed in patients displaying the loss of any MMR proteins in the tumor. Of the 618 patients, 9 (1.5%) showed the loss of MMR protein expression via immunohistochemistry; specifically, 3, 3, 2, and 1 patients displayed the loss of MLH1/PMS2, PMS2, MSH6, and MSH2/MSH6, respectively. All nine patients were male with a median age of 68 years (63–79 years). One had been previously diagnosed as having LS with an MSH2 variant. Genetic testing demonstrated the presence of a pathogenic PMS2 variant (n = 1), a variant of uncertain significance in MSH2 (n = 1), and no pathogenic germline variants of the MMR genes (n = 1). One patient with MSH6-deficient BC did not complete the genetic testing because of severe degradation of DNA extracted from the FFPE specimen, but the patient was strongly suspected to have LS because of their history of colon cancer and MSH6-deficient upper urinary tract cancer. There remained a possibility that the remaining four patients who refused genetic testing had LS. The prevalence of LS-associated MMR-deficient BC was estimated to be 0.6–1.1% among unselected BC cases.

Background/aim DNA mismatch repair (MMR) deficiency has received increasing attention as a biomarker of anti-PD-1 treatments of solid tumors including gastric cancer (GC). However, efficient screening has not been established. Patients and methods A total of 513 patients were tested for the expression of MMR proteins by immunohistochemistry to identify MMR deficient GC. Development of a prediction model was attempted using the common clinicopathological features. Results In total, 11% (57/513) of the patients showed loss of expression of either one or more MMR proteins (MMR protein deficiency; MMR-D). Multivariate analysis demonstrated that age (≥70 years), sex (female), tumor location (lower 1/3), depth invasion (low, T1/T2/T3), and absence of distant metastasis were significantly independent predictive factors of MMR-D GCs. The MMR-D GC probability estimated by the prediction model ranged from 0.4% to 62.2%, and the area under the curve of the receiver operating characteristics curve was 0.82 (95% confidence interval=0.75-0.87). Conclusion Our prediction model can sufficiently and efficiently identify MMR-D GCs using clinical features.

Background The prevalence and molecular characteristics of deficient mismatch repair prostate cancer in the Japanese population have scarcely been investigated. Methods Immunohistochemistry for mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2) was performed in formalin-fixed paraffin-embedded sections prepared from resected primary prostate cancers in patients who underwent prostatectomy at our institution between January 2001 and May 2016. Genetic and/or epigenetic alterations of mismatch repair genes were investigated in patients with any loss of mismatch repair protein expression in the tumour. Results Of the 337 patients, four (1.2%) showed loss of mismatch repair protein expression on immunohistochemistry. All four patients showed loss of both MSH2 and MSH6 protein expression. Genetic testing was performed in two of the four patients, demonstrating no pathogenic germline alterations were present. In each of these two patients, at least one somatic alteration inactivating MSH2 without MSH2 hypermethylation was identified, leading to the diagnosis of supposed ‘Lynch-like syndrome’. Patients with deficient mismatch repair prostate cancer were at a significantly higher stage (pT2pN0 vs. pT3-4pN0/pTanypN1, P = 0.02) and had a greater Gleason score ( Conclusions The prevalence of deficient mismatch repair prostate cancer in the Japanese hospital-based prostatectomized population was extremely low. To improve screening efficacy for deficient mismatch repair prostate cancer, screening candidates can be limited to patients with locally advanced, node-positive and/or Gleason score of 8 or greater prostate cancer. Universal tumour screening for Lynch syndrome seems ineffective in patients with prostate cancer.

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.

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 proband was a 39-year-old Japanese woman with stage I triple negative breast cancer. Germline BRCA1 and BRCA2 genetic testing revealed the presence of a BRCA1 c.5332G>A (p.Asp1778Asn) variant classified as a VUS in the heterozygous state. She underwent curative surgery and adjuvant chemotherapy for her TNBC, but no intensive follow-up or risk-reducing surgery was performed in contrast to normal practice in a patient with hereditary breast and ovarian cancer syndrome. At postoperative 2 years 6 months, elevation of CA15-3 led to the diagnosis of Stage III high-grade serous ovarian cancer. Studies and information in public databases at the time of the patient’s genetic testing showed only VUS results for c.5332G>A; within the next few years, one pathogenic and one likely pathogenic result were confirmed. Thus, according to a joint consensus recommendation of the ACMG/AMP, c.5332G>A is considered ‘likely pathogenic’. The public database should be checked regularly for VUS results, and practical management should be considered if reliable likely pathogenic or pathogenic reports were added.

Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (p 0 center dot 0001 for each of the three three continents). These familial risk factors resulted in a wide within-gene variation in the risk of colorectal cancer for men and women from each continent who all carried pathogenic variants in the same gene or the MSH2 c.942+3A T variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and onlyBackground Existing clinical practice guidelines for carriers of pathogenic variants of DNA mismatch repair genes (Lynch syndrome) are based on the mean age-specific cumulative risk (penetrance) of colorectal cancer for all carriers of pathogenic variants in the same gene. We aimed to estimate the variation in the penetrance of colorectal cancer between carriers of pathogenic variants in the same gene by sex and continent of residence. Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero. Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (pT variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and only 10-19% having a penetrance of 40-60%. Interpretation Our study findings highlight the important role of risk modifiers, which could lead to personalised risk assessments for precision prevention and early detection of colorectal cancer for people with Lynch syndrome. Funding National Health and Medical Research Council, Australia. Copyright (c) 2021 Elsevier Ltd. All rights reserved.Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero.

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.

AIM The TRICOLORE trial previously demonstrated that S-1 and irinotecan plus bevacizumab was non-inferior, based on progression-free survival (PFS), to 5-fluorouracil, leucovorin and oxaliplatin (mFOLFOX6)/capecitabine and oxaliplatin (CapeOX) plus bevacizumab as first-line chemotherapy for metastatic colorectal cancer (mCRC). Overall survival (OS) data were immature at the time of the primary analysis. METHODS In total, 487 patients from 53 institutions with previously untreated mCRC were randomly assigned (1:1) to receive either mFOLFOX6/CapeOX plus bevacizumab (control group) or S-1 and irinotecan plus bevacizumab (experimental group; 3- or 4-week regimen). The final OS data were analysed from follow-up data collected until 30th September 2017. RESULTS With a median follow-up period of 48.7 months, median survival times were 32.6 and 34.3 months (hazard ratio [HR]: 0.89, 95% confidence interval [CI]: 0.72-1.10, P = 0.293) and median PFS durations were 10.8 and 14.0 months in the control and experimental groups, respectively (HR: 0.86, 95% CI: 0.71-1.04, P

Oxaliplatin (OX) and irinotecan (IRI) are used as key drugs for the first‐line treatment of metastatic colorectal cancer (mCRC). However, no biomarkers have been identified to decide which of the drugs is initially used. In this translational research (TR) of the TRICOLORE trial, the advanced colorectal cancer subtype (aCRCS) was analyzed as a potential biomarker for the selection of OX or IRI. We collected 335 (68.8%) formalin‐fixed, paraffin‐embedded (FFPE) primary tumor specimens from 487 patients registered in the TRICOLORE trial and performed direct sequencing and immunohistochemical staining of CRC‐related genes, comprehensive gene‐expression analysis, and genome‐wide methylation analysis. The progression‐free survival (PFS) of the IRI group was significantly better compared with the OX group in BRAF wild‐type (WT), PTEN‐positive, and aCRCS A1 patients. Among the molecular factors, aCRCS were only associated with the PFS of OX and IRI groups. The PFS of the IRI group was significantly better compared with the OX group in aCRCS A1 + B1 (hazard ratio [HR] = 0.58; 95% confidence interval [CI] = 0.41‐0.82; P = .0023). In contrast, the OX group had better PFS compared with the IRI group in aCRCS B2, although this was not statistically significant (HR = 1.66; 95% CI = 0.94‐2.96; P = .083). Nearly half of patients with mCRC (46.8%, aCRCS A1 + B1) respond well to IRI, while only about 18.5% (aCRCS B2) of patients with mCRC responded well to OX. In conclusion, the aCRCS might be a predictive factor for the clinical outcomes of OX‐based and IRI‐based therapies., From translational research of TRICOLORE trail, the advanced colorectal cancer subtypes (aCRCS) can help to select oxaliplatin‐based or irinotecan‐based therapy for first‐line metastatic colorectal cancer treatment.

The clinical and pathological features of sporadic microsatellite instability-high (MSI) colorectal cancer (CRC) are still unclear. The present study aimed to clarify the clinicopathological features of sporadic MSI CRC in comparison with those of Lynch syndrome (LS) exploratorily. The present study was a single-center, retrospective cohort study. Sporadic MSI CRC was defined as MSI CRC with aberrant promoter hypermethylation of the MLH1 gene, while hereditary MSI CRC was defined colorectal cancer in patients with LS. In total, 2653 patients were enrolled; of these, 120 (4.5%) had MSI CRC, 98 had sporadic MSI CRC, and 22 had LS. Patients with sporadic MSI CRC were significantly older (p

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 The attention on mismatch repair-deficient (dMMR) gastric cancer has increased in this era of anti-PD-1 blockade therapy; however, the prevalence and molecular genetics of patients with dMMR gastric cancer have not been completely investigated. Methods Immunohistochemistry of MMR proteins (MLH1, MSH2, MSH6 and PMS2) was performed on formalin-fixed paraffin-embedded sections prepared from resected primary gastric cancers of 513 consecutive patients. Genetic and/or epigenetic alterations of the MMR genes were also investigated. Results Loss of expression of one or more MMR proteins was observed in 58 patients (11.3%); 54 patients showed loss of MLH1/PMS2, 3 patients showed loss of MLH1/PMS2/MSH6 and 1 patient showed loss of PMS2 alone. Among these 58 patients, 55 showed hypermethylation of the promoter region of MLH1. Genetic testing revealed that the remaining three patients had Lynch syndrome (n = 1) or Lynch-like syndrome (n = 2). A total of 15 patients (25.9% of all patients with dMMR gastric cancer and 2.9% of all patients with gastric cancer), including 11 patients with stage I–III dMMR gastric cancer who had recurrence and 4 patients with stage IV dMMR gastric cancer, are potential candidates for the use of anti-PD-1 blockades. Conclusions This is the first study to investigate the frequency and molecular genetic mechanisms of dMMR gastric cancer comprehensively, focusing on the benefit of using PD-1 blockades. Our observations will be beneficial in the clinical practice of metastatic gastric cancer.

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/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.

BackgroundThe prevalence and molecular characteristics of defective DNA mismatch repair endometrial cancers in the Japanese population have been underexplored. Data supporting clinical management of patients with Lynch-like syndrome and germline variant of uncertain significance of mismatch repair genes are still lacking.MethodsImmunohistochemistry of mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2) was performed on formalin-fixed paraffin-embedded sections prepared from resected primary endometrial cancers in 395 women with a median age of 59 years. Genetic and/or epigenetic alterations of the mismatch repair genes were also investigated.ResultsLoss of expression of one or more mismatch repair proteins was observed in 68 patients (17.2%). A total of 17 out of 68 patients (25%, 4.3% of all cases) were identified as candidates for genetic testing for Lynch syndrome after excluding 51 patients with MLH1 hypermethylated cancer. Fourteen of these 17 patients subjected to genetic testing were found to have Lynch syndrome (n = 5), germline variant of uncertain significance (n = 2) or Lynch-like syndrome (n = 7). Compared with patients with Lynch syndrome, those with germline variant of uncertain significance and Lynch-like syndrome tended to demonstrate an older age at the time of endometrial cancer diagnosis (P = 0.07), less fulfillment of the revised Bethesda guidelines (P = 0.09) and lower prevalence of Lynch syndrome-associated tumors in their first-degree relatives (P = 0.01).ConclusionsThis study provides useful information for management in patients with DNA mismatch repair endometrial cancer. Specifically, cancer surveillance as recommended in patients with Lynch syndrome might not be necessary in patients with germline variant of uncertain significance and Lynch-like syndrome and their relatives.

To date, various testings to screen for Lynch syndrome have been proposed. Classically, Amsterdam criteria I/II and Bethesda guideline were developed as clinical screening testing using family history and cancer history. Since these screening testings do not detect all colorectal cancer with microsatellite instability, the universal tumor screening for Lynch syndrome using microsatellite instability testing or immunohistochemistry of mismatch repair proteins in all colorectal cancer and endometrial cancer is recommended. The effectiveness of immunohistochemical analysis of the mismatch repair proteins is similar to that of microsatellite instability; however, immunohistochemistry is more readily available and helps to direct gene testing. The universal genetic testing is reported from some groups; however, it is still premature to generalize the universal genetic testing as a screening test for Lynch syndrome.

Background FOLFOXIRI (Fluorouracil, folinate, oxaliplatin, and irinotecan) plus bevacizumab improved progression-free survival (PFS) and overall survival in patients with metastatic colorectal cancer (mCRC), compared with FOLFIRI (fluorouracil, folinate, and irinotecan) plus bevacizumab, but significantly increased the incidences of adverse events. The efficacy and safety profiles of FOLFOXIRI plus bevacizumab in ethnic Asian patients have not been established yet. Patients and Methods This study was an open-label, single-arm, multi-centered phase II prospective clinical trial in patients with mCRC who received FOLFOXIRI plus bevacizumab. The primary endpoint was the PFS rate at 10 months. Secondary endpoints included overall survival, response rate, and safety. Results A total of 69 patients received FOLFOXIRI plus bevacizumab as induction therapy and were assessed for efficacy and safety. The PFS rate at 10 months was 75.2% and the median PFS was 13.3 months. Complete response and partial response were achieved in 2 (2.9%) and 47 patients (69.1%), respectively. Grade 3 and 4 adverse events with incidence rates exceeding 20% were neutropenia (72.5%), hypertension (34.8%), leucopenia (33.3%), and febrile neutropenia (21.7%). Significantly more patients with grade 4 neutropenia had single-heterozygous UGT1A1*1/*6 or *1/*28 (46.2%) than UGT1A1 wild-type genotype (*1/*1) (13.3%) (P = .004). Conclusions FOLFOXIRI plus bevacizumab is considered an effective first-line regimen that improves the outcome of patients with mCRC regardless of ethnicity. In Asian patients, utmost attention should be paid to the possible onset of severe neutropenia or febrile neutropenia attributed to different types of UGT1A1*6 and *28 polymorphism, when FOLFOXIRI plus bevacizumab is administered.

Because bone metastasis from colorectal cancer is rare, there are little available data regarding such cases.The study aim was to identify the prognostic factors and characteristics associated with survival in colorectal cancer patients with bone metastasis.This was a retrospective study from a prospectively collected database.The study took place in a multidisciplinary, high-volume tertiary cancer center in Japan.Examined were records from 104 consecutive patients treated between 2004 and 2015 for bone metastasis from colorectal cancer.The primary outcome measure was overall survival.The spine was the most common site of bone metastasis from colorectal cancer. Right colon cancer correlated significantly with long bone metastasis (p = 0.046), whereas left colon cancer correlated significantly with spinal bone metastasis (p = 0.034). Liver metastasis was also significantly correlated with spinal bone metastasis (p = 0.036). The median interval between the primary therapy for colorectal cancer and the metachronous diagnosis of bone metastasis was 20.0 months (quartile 1 to quartile 3, 9.0-46.5 mo). The median survival time from diagnosis of bone metastasis from colorectal cancer was 5.0 months (95% CI, 4.0-9.0 mo), and the 1-year survival rate was 30.0% (95% CI, 21.1%-39.4%). Multivariate analysis revealed that ≥2 extra-bone metastatic organs, hypercalcemia, and pathologic fractures were independent poor prognostic factors (p0.001, 0.001, and 0.033). The number of extra-bone metastatic organs correlated with prognosis.This study was limited by its retrospective, nonrandomized design, as well as selection bias and performance at a single institute.The location of colorectal cancer correlates significantly with the site of bone metastasis; the prognosis of patients with bone metastasis from colorectal cancer is very poor, and the significant prognostic factors are number of extra-bone metastatic organs, hypercalcemia, and pathologic fractures. See Video Abstract at http://links.lww.com/DCR/A589.

The field of immunotherapy has recently focused on cancers with microsatellite instability (MSI). These cancers include both Lynch-syndrome-associated tumors, which are caused by mismatch repair (MMR) germline mutations, and sporadic MSI tumors, which are mainly attributed to MLH1 promoter methylation. The present study aimed to clarify differences in the histological and PD-L1 expression profiles between these two types of MSI cancers in Japanese patients. Among 908 cases of colorectal cancer treated via surgical resection from 2008 to 2014, we identified 64 MSI cancers, including 36 sporadic MSI and 28 Lynch-syndrome-associated cancers, using a BRAF V600E mutation analysis and MLH1 methylation analysis. Of the latter subgroup, 21 (75%) harbored MMR germline mutations. The following were more frequent with sporadic MSI than with Lynch syndrome associated cancers: poor differentiation (50.0 vs. 7.1%, P = 0.0002), especially solid type (30.6 vs. 3.6%, P = 0.0061); medullary morphology (19.4 and 0%, P = 0.015), Crohn-like lymphoid reaction (50.0 vs. 25.0%, P = 0.042), and PD-L1 expression (25.0 vs. 3.6%, P = 0.034). However, the groups did not differ in terms of the mean invasive front and intratumoral CD8-positive cell densities. In a logistic regression analysis, PD-L1 expression correlated with poor differentiation (odds ratio: 7.65, 95% confidence interval: 1.55–37.7, P = 0.012), but not with the difference between sporadic MSI cancer and Lynch-syndrome-associated cancer (odds ratio: 4.74, 95% confidence interval: 0.50–45.0, P = 0.176). Therefore, compared with Lynch-syndrome-associated cancers, sporadic MSI cancers are more frequently solid, poorly differentiated medullary cancers that express PD-L1.

The decrease in carcinoembryonic antigen (CEA) level is faster and greater during cetuximab treatment than bevacizumab treatment and correlates with prolonged survival in patients with metastatic colorectal cancer (mCRC) who receive cetuximab. We investigated if the degree of change in the CEA value can serve as a diagnostic tool for predicting survival, as well as tumor regression in mCRC patients treated with cetuximab combined regimen as first-line treatment. Associations among the CEA decrease, depth of response (DpR), and clinical outcomes were evaluated in 113 patients with mCRC from two phase II trials of first-line therapy: the JACCRO CC-05 trial of cetuximab plus FOLFOX and the CC-06 trial of cetuximab plus SOX. Analysis was performed using Spearman’s rank correlation coefficient. A 75% decrease in the CEA was used as the cut-off value to define the CEA response and discriminate CEA responders on the basis of the results of a previous study. Ninety-two patients were eligible for analyses of both CEA and DpR. The median CEA decrease was 67.4%, and the median time to CEA nadir was 2.8 months, which was similar to the median time to DpR of 3.0 months. The DpR was associated with PFS and OS (rs = 0.56, P

Primary tumor location is a critical prognostic factor in metastatic colorectal cancer (mCRC); however, it remains unclear whether tumor location is a predictor of the response to cetuximab treatment. It is also uncertain if BRAF mutation contributes to the impact of tumor location on survival. We assessed the prognostic impact of tumor location on clinical outcomes in mCRC patients treated with first-line cetuximab chemotherapy.The associations of tumor location with overall survival and progression-free survival were evaluated in mCRC patients with KRAS exon 2 wild-type tumors who were enrolled onto 2 clinical trials: JACCRO CC-05 of cetuximab plus FOLFOX (n = 57, UMIN000004197) and CC-06 of cetuximab plus SOX (n = 61, UMIN000007022). Tumors proximal or from splenic flexure to rectum were defined as right-sided or left-sided, respectively. In addition, exploratory RAS and BRAF mutation analyses were performed.A total of 110 patients were assessable for tumor location; 90 had left-sided tumors. Left-sided tumors were significantly associated with longer overall survival (36.2 vs. 12.6 months, hazard ratio = 0.28, P .0001) and progression-free survival (11.1 vs. 5.6 months, hazard ratio = 0.47, P = .0041) than right-sided tumors; similar results were obtained in multivariate analysis. A subanalysis showed that the association was evident in the FOLFOX group and that tumor location was an independent prognostic factor irrespective of BRAF status in RAS wild-type patients.Primary tumor location might be a predictor of survival independent of BRAF status in mCRC patients who receive first-line cetuximab combined with oxaliplatin-based chemotherapy.

Familial adenomatous polyposis (FAP)-associated desmoid tumor (DT) is sometimes life threatening. However, the optimal treatment for DTs has not been established. The aim of this study was to analyze the outcomes of surgical and pharmacological treatments for DT in Japanese FAP patients.We retrospectively reviewed the data of 303 patients who underwent colectomy for FAP between 2000 and 2012. We analyzed 41 patients with DTs in which the location was apparent. The selection of treatment for intra-abdominal DTs was also evaluated according to Church's classification.Surgery was frequently used to treat extra-abdominal DTs. Multimodal treatments, including surgery, and the administration of non-steroidal anti-inflammatory drugs, hormonal therapy, and chemotherapy were widely used for intra-abdominal DTs. The most effective pharmacological treatment was cytotoxic chemotherapy, which was associated with a response rate of 45.5% and a disease control rate of 72.7%. After a median follow-up period of 53.0 months, the 5-year DT-specific survival rate in patients with stage IV disease was 71.4%; in contrast, the rate in patients with other stages was 100%. Four-stage IV patients died of DT due to uncontrollable rapid progression. No cytotoxic chemotherapy was administered; however, incomplete resection was performed in three cases.Our findings will provide clues that may help physicians in selecting the optimal strategy for this rare disease.

3608 Background: Circulating tumor DNA (ctDNA) analysis can be used to predict the risk of recurrence by detecting molecular residual disease (MRD) in patients with colorectal cancer (CRC). We are conducting a prospective observational study to monitor MRD status in patients with clinical stage II–IV or relapsed CRC amenable to radical surgical resection (GALAXY study), as part of the CIRCULATE-Japan, a nationwide ctDNA-guided precision adjuvant therapy project. Methods: Analysis of ctDNA is being performed at pre- and post-surgery timepoints and will continue periodically for up to 2 years using Signatera, a personalized, tumor-informed ctDNA assay that is designed to track 16 patient-specific somatic variants based on whole-exome sequencing of tumor tissue. The association of peri-operative ctDNA status with clinicopathological characteristics was investigated. Results: As of January 13, 2021, 941 patients have been enrolled in the GALAXY study, of which 400 patients had their pre-operative ctDNA status evaluated. Of the 400 patients, baseline ctDNA was detected in 92% (367/400) of the patients: consisting of 35 patients with pathological stage (pStage) I, 135 with pStage II, 152 with pStage III, and 78 with pStage IV or relapsed disease (pStage IV/R). Patient-specific Signatera assays targeting 16 variants were designed for 100% of the patients. Out of the 6400 designed variants 99.3% passed quality control in the plasma analysis and produced the final results. Among 4425 genes selected for 400 patients, 3330 genes were selected for only one patient, while TP53 was the most commonly selected in 113 patients (28%). Median ctDNA levels, measured in mean tumor molecules per mL of plasma and ctDNA detection rate, stratified by stage are presented in table. Positive ctDNA status post-surgery was significantly associated with advanced pStage, pT and pN, and lymphovascular invasion. Of the 13 patients with recurrence, 10 were detected with a positive ctDNA at 4-weeks post-surgery, before confirmation of recurrence by the radiological imaging. Conclusions: Preoperative ctDNA detection rates were observed to be in >90% in patients with pStage II–III by personalized ctDNA assay based on unique somatic variants, specific to each patient. ctDNA- based MRD detected post-surgery (4W) was significantly associated with certain known clinicopathological factors for recurrence with ctDNA positivity associated with a very short-term of recurrence. Clinical trial information: 000039205. [Table: see text]

To investigate the incidence of colorectal cancer among familial adenomatous polyposis (FAP) patients by phenotype using the latest modalities. We collected data on 303 patients who underwent surgery for FAP at one of 23 institutions between 2000 and 2012. The incidence of colorectal cancer was investigated by phenotype. Colorectal cancer was diagnosed in 115 (38.0 %) of the 303 patients. Overall, colorectal cancer with the attenuated, sparse, and profuse phenotypes was diagnosed at 30, 31, and 28 years of age, respectively, in 10 % of the patients and at 59, 48, and 41 years of age, respectively, in 50 % of the patients (P = 0.013). The patients with colorectal cancer were older than those without colorectal cancer for all phenotypes. The optimal cut-off age for predicting the development of colorectal cancer in the attenuated, sparse, and profuse phenotypes was 46, 31, and 27 years, respectively. Patients with profuse and sparse phenotypes should undergo prophylactic proctocolectomy before their mid-to-late 20 s. On the other hand, the timing and type of surgery for patients with attenuated FAP (AFAP) should be decided individually with reference to the colonoscopic findings.

The prognostic and predictive value of KRAS gene mutations in stage III colorectal cancer is controversial because many recent clinical trials have not involved a surgery‐alone arm. Additionally, data on the significance of extended RAS (KRAS/NRAS) mutations in stage III cancer are not available. Hence, we undertook a combined analysis of two phase III randomized trials, in which the usefulness of adjuvant chemotherapy with tegafur–uracil (UFT) was evaluated, as compared with surgery alone. We determined the association of extended RAS and mismatch repair (MMR) status with the effectiveness of adjuvant chemotherapy. Mutations in KRAS exons 2, 3, and 4 and NRAS exons 2 and 3 were detected by direct DNA sequencing. Tumor MMR status was determined by immunohistochemistry. Total RAS mutations were detected in 134/304 (44%) patients. In patients with RAS mutations, a significant benefit was associated with adjuvant UFT in relapse‐free survival (RFS) (hazard ratio = 0.49; P = 0.02) and overall survival (hazard ratio = 0.51; P = 0.03). In contrast, among patients without RAS mutations, there was no difference in RFS or overall survival between the adjuvant UFT group and surgery‐alone group. We detected deficient DNA MMR in 23/304 (8%) patients. The MMR status was neither prognostic nor predictive for adjuvant chemotherapy. An interaction analysis showed that there was better RFS among patients treated with UFT with RAS mutations, but not for those without RAS mutations. Extended RAS (KRAS/NRAS) mutations are proposed as predictive indicators with respect to the efficacy of adjuvant UFT chemotherapy in patients with resected stage III colorectal cancer.

169 Background: The TRICOLORE trial previously demonstrated that S-1+IRI+Bmab (Arm B) was non-inferior to mFOLFOX6/CapeOX+Bmab (Arm A) in terms of progression-free survival (PFS) as first-line treatment for mCRC, irrespective of RAS status. CMS was reported to be a prognostic factor for mCRC. Previously, it was reported that the CMS could be a predictive factor for the efficacy of oxaliplatin (OX) and IRI (Okita A, et al. Oncotarget. 2018). In this exploratory study of TRICOLORE trial, we examined if the CMS could be a predictive factor of OX and IRI regimen. Methods: We collected formalin-fixed paraffin-embedded (FFPE) primary tumor tissues and performed gene expression analysis by microarray. The subtype of CMS was determined by the CMS classifier (Guinney et al. Nature Med. 2015). PFS and overall survival (OS) were compared between arm A and B in each subtypes of CMS. Results: Total of 308 FFPE samples from 487 cases who were enrolled in the TRICOLORE study were collected. Number of patients classified into CMS1 to CMS4 were 47, 72, 99 and 90, respectively. Similar to the previous reports, the proportion of RAS mutant cases was highest in CMS3 and the most of BRAF mutant cases were classified into CMS1. The median PFS (mPFS) of arm A and B were almost same in CMS2 (16.1m vs. 17.6m, HR = 1.10, p = 0.79) and CMS3 (10.6 vs. 11.4, HR = 0.95, p = 0.81). In CMS1, mPFS of arm A was worse than that of arm B, although not statistically significant (7.4m vs. 13.2m, HR = 0.73, p = 0.35). In CMS4, mPFS of arm B was better than that of arm A, although not statistically significant again (9.7m vs. 14.1m, HR = 0.72, p = 0.15). The median OS (mOS) of both arm in CMS2-CMS4 and arm B in CMS1 were good and were 29.0m or more. On the other hand, mOS of arm A in CMS1 (18.1m) was worse than the others. Conclusions: From these results, it was not concluded that CMS was a predictor of mFOLFOX6/CapeOX+Bmab and S-1+IRI+Bmab. However, mPFS and mOS of mFOLFOX6/CapeOX+Bmab in CMS1 were poor unlike other CMS subtypes, and these were consistent with a previous report. Whereas S-1+IRI+Bmab was effective in all subtypes of CMS. Clinical trial information: UMIN000007834.

Background Few clinical studies have investigated the association between neutrophil-lymphocyte ratio (NLR) and treatment with cetuximab-based chemotherapy in metastatic colorectal cancer (mCRC). The NLR may reflect immune cells modulating specific cytokine signals in the tumor microenvironment; however, which immune-related genes affect the NLR remain unclear. Patients and Methods In 77 patients with KRAS exon2 wild-type mCRC from prospective trials of first-line chemotherapy with cetuximab, expression levels of 354 immune-related genes were measured in tissue samples obtained from all patients by the HTG EdgeSeq Oncology Biomarker Panel. The association between the NLR and clinical outcomes was evaluated using the Spearman rank correlation coefficient. In addition, 2-sample t tests were performed to investigate which genes among the top 100 genes associated with survival had significantly different expression levels between the NLR-low and NLR-high groups among all measured genes. Results NLR data were available for 71 patients. The NLR was associated with progression-free survival and overall survival (r = −0.24; P = .040 and r = −0.29; P = .010, respectively). When stratified by the median value of the NLR, the Kaplan-Meier curve of NLR-low versus NLR-high differed significantly for both progression-free survival (median, 11.8 vs. 9.1 months; P = .036) and overall survival (median, 42.8 vs. 26.7 months; P = .029). The 2-sample t test revealed that the expression levels of the LYZ, TYMP, and CD68 genes differed significantly between the NLR-low and NLR-high groups (t test P-value Conclusion NLR is significantly associated with survival in patients with mCRC treated with first-line chemotherapy with cetuximab. Genes encoding for activities on macrophages may affect the NLR.

To investigate the recent Japanese prevalence of thyroid cancer and its characteristics in familial adenomatous polyposis (FAP) patients, through the development of surveillance programs. The subjects of this study were 282 (93.1%) FAP patients for whom information on thyroid cancer was available, from among 303 patients registered in “the Retrospective Cohort Study of Familial Adenomatous Polyposis in Japan” database. We evaluated the prevalence and risk factors for thyroid cancer and integrated and/or compared our findings with those of previous reports, using a systematic review, including a meta-analysis. Thyroid cancer was diagnosed in 16 women (11.4%) and 2 men (1.4%), at 17–41 years and 39–57 years of age, respectively. The prevalence of thyroid cancer was 6.4%, with a female-to-male ratio of 8:1, which is comparable to reports from other countries. A young age of

We conducted this study to establish whether drinking alcohol alters the risk of early-onset colorectal cancer (CRC) in Japanese patients with Lynch syndrome (LS). The subjects were 66 LS patients with pathogenic mutation of mismatch repair genes (MLH1, MSH2, and MSH6) from the nationwide Japanese retrospective multicenter study. Cox proportional hazards modeling was used to investigate the factors correlating with early-onset CRC diagnosis, using clinical data such as gender, tobacco use, alcohol consumption, body mass index, gene mutation (MLH1, MSH2 vs MSH6), and family cancer history. Alcohol was significantly correlated with an increased risk of early-onset CRC [HR 2.44, 95% CI 1.13-5.16 (p = 0.02)], but tobacco use was not [HR 0.8, 95%CI 0.38-1.62 (p = 0.53)]. These findings suggest that alcohol consumption is correlated with an earlier onset of CRC in Japanese patients with LS.

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

Background The aim of this study was to clarify clinicopathological features, frequencies of molecular biomarkers, and prognoses in Japanese colorectal cancer patients and compare them with right-sided colon cancer (RCC) and left-sided colorectal cancer (LCRC). Methods We consecutively selected 575 colorectal cancer patients who underwent surgical resection from 2008 to 2011. RCC was located from the cecum to the transverse colon, and LCRC was located from the splenic flexure to the rectum. Frequencies of KRAS gene mutation, BRAF gene mutation, microsatellite instability (MSI), l18qLOH and CpG island methylator phenotype (CIMP) were statistically analyzed between groups. Results Tumors were located in the RCC in 26.3% of patients and in the LCRC in 73.7%. Elderly patients, females and advanced diseases were significantly more frequent in the RCC group than in the LCRC group. However, venous invasion was significantly more frequent in LCRC than in RCC. Between groups, BRAF mutant type, KRAS mutant type, MSI and CIMP+ were significantly more frequent in RCC, whereas 18qLOH was significantly more frequent in LCRC. In overall survival, RCC demonstrated poor prognosis compared with LCRC; however, age, gender, stage, lymphatic invasion, KRAS status and BRAF status rather than tumor location were independent prognostic factors. In addition, the independent prognostic factors in RCC were different from those in LCRC in each stage. However, the consistency between OS and DFS was not observed in this study, excluding lymphatic invasion in LCRC. Conclusion Comparing RCC with LCRC, RCC is different from LCRC in clinicopathological features, molecular biomarkers and prognostic factors in Japanese colorectal cancer patients. Since the proportions of molecular biomarkers of CRC in this study are different from Western CRCs, further studies are required to clarify the clinicopathological differences between Japanese CRCs and Western CRCs.

Many studies have shown that hospital volume is significantly associated with short- and long-term outcomes in various diseases, including cancer. However, there have been no reports discussing the relationship between hospital volume and familial adenomatous polyposis (FAP). This study aimed to clarify whether hospital volume affects short- and long-term outcomes in FAP patients. We established a retrospectively collected database of FAP patients who underwent initial surgical treatment at 23 Japanese institutions during 2000–2012. Factors associated with short- and long-term outcomes were analyzed. The study cohort included 303 FAP patients. These patients were classified into tertile categories according to hospital volume: low (n = 31), middle (n = 72), and high volume (n = 200). The proportion of only adenoma/stage 0 was comparable among tertile categories. The adoption of operative procedure significantly differed among tertile categories; specifically, high-volume institutions preferred handsewn ileal pouch-anal anastomosis without diverting ileostomy (P

Microsatellite instability (MSI) is an important biomarker for screening for Lynch syndrome, and also of response to immune checkpoint inhibitors. The aim of this study is to create a predictive model to determine which elderly patients with colorectal cancer (CRC) should undergo MSI and/or immunohistochemistry testing on the basis of clinicopathological data. We analyzed a test cohort of CRC patients aged ≥50 years (n = 2219) by multivariate logistic regression analyses to identify predictors of high‐frequency MSI (MSI‐H). The created prediction model was validated in an external cohort (n = 992). The frequency of MSI‐H was 5.5% among CRC patients aged ≥ 50 years. The following five predictors of MSI‐H were identified in the test cohort: female (1 point), mucinous component (2 points), tumor size ≥ 60 mm (2 points), location in proximal colon (3 points), and BRAF mutation (6 points). The area under curve (AUC) in the receiver‐operating characteristic (ROC) analysis of this prediction model was 0.832 (95% confidence interval: 0.790–0.874). The sensitivity and specificity were 74.4% and 77.7%, respectively, for a cut‐off score of 4 points. The receiver‐operating characteristic curve of the validation cohort also showed an AUC of 0.856 (95% CI: 0.806–0.905). This prediction model is useful to select elderly CRC patients who should undergo MSI testing, and who may benefit from treatment with 5‐FU‐based adjuvant chemotherapy and cancer immunotherapy.

Previous reports of the influence of UGT1A1 gene polymorphisms on the pharmacokinetics of irinotecan metabolism have not assessed Asian patients treated with FOLFIRI plus bevacizumab for advanced and recurrent colorectal cancer. Twenty-one Japanese colorectal cancer patients received intravenous FOLFIRI (bolus irinotecan, folinic acid, and fluorouracil followed by 46-hour fluorouracil infusion) followed by bevacizumab (5 mg/kg) in Cycle 1. In Cycle 2, patients received bevacizumab followed by FOLFIRI. The regimen was in 2-week cycles. The area under-the-curves ratio (AUC0-last) (Cycle 2/Cycle 1) was determined from plasma concentrations of irinotecan and metabolites (SN-38, SN-38G). Safety, efficacy, and drug-drug interactions were analyzed. Median observation period was 7.8 months; median number of cycles 15. Drug-drug interactions were evaluated in eight patients without irinotecan dose reduction. Mean AUC0-last ratios (with/without bevacizumab) of irinotecan, SN-38, and SN-38G were 0.959, 0.927, and 0.931 respectively. Response rate was 65%; median progression-free survival 16.4 months. Response occurred in four patients with, and nine without, UGT1A1 polymorphism. No significant differences occurred between efficacy, safety, or polymorphism status. This cohort showed no differences in safety or efficacy compared to previous reports. Bevacizumab did not affect the pharmacokinetics of irinotecan and its metabolites, irrespective of UGT1A1 polymorphism status.

543 Background: We have reported that carcinoembryonic antigen (CEA) response correlated with clinical outcomes of 1st-line cet-based therapy (Target Oncol 2017). Early tumor shrinkage (ETS) is considered to be an on-treatment biomarker for outcomes of chemotherapy; however, clinical biomarkers to predict outcomes earlier are warranted. Methods: This study included 69 pts who were assessable for CEA at baseline and 4 wks, and with observed survival time from 2 phase II trials of 1st-line therapy for KRAS exon2 wild-type mCRC; JACCRO CC-05 of cet plus FOLFOX (UMIN000004197) and CC-06 of cet plus SOX (UMIN000007022). We investigated the influence of baseline age, gender, PS, primary tumor sidedness (PTS), number of tumor sites, as well as the CEA decrease at 4 wks to the patient’s OS and PFS. Results: PTS and the CEA decrease at 4 wks were found to be important predictors to OS and PFS. Baseline CEA and CEA decrease at 4 wks were median of 31.0 (range, 1.0-20920.0) and median of 35% (range, -259%-97%), respectively. The STEP-analysis indicated that CEA response was most significantly associated with OS when a cut-off value of 50% for CEA-responder (HR 0.49, log-rank test p = 0.03). Median OS in responders (n = 25) and non-responders (n = 44) were 36.2 m and 21.5 m, respectively. When the same cut-off value was used, median PFS in responders and non-responders were 11.6 m and 6.5 m, respectively (HR 0.64, log-rank test p = 0.08). In addition, a multivariate Cox Proportional-Hazards Model with both PTS and CEA response as risk factors showed that PTS correlated with both OS and PFS. In pts with left-sided tumors, non-responders (n = 33) had shorter OS and PFS compared to responders (n = 23). In the above 2-covariate Cox proportional hazard model, adjusted HR for CEA 50% decrease is 0.55, p = 0.1; adjusted HR for PTS is 2.66, p = 0.008. Conclusions: Our analysis suggests 50% CEA decrease at 4 wks as an early on-treatment biomarker for 1st-line cet-based therapy in mCRC. It may potentially predict outcomes earlier compared to ETS. Also, CEA response at 4 wks may differentiate pts who receive more benefit from cet treatment in left-sided tumors. Clinical trial information: UMIN000004197 and UMIN000007022.

Retrospective studies have found that early tumor shrinkage (ETS) and depth of response (DpR) are associated with favorable outcomes in patients with metastatic colorectal cancer (mCRC); however, few prospective studies have evaluated ETS and DpR. We performed a phase II study of FOLFOX plus cetuximab as first-line treatment in Japanese patients with KRAS wild-type mCRC. The primary endpoint was response rate (RR), and secondary endpoints included progression-free survival (PFS), overall survival (OS), chronological tumor shrinkage (evaluated every 8 weeks), and safety. The association of ETS and DpR with survival time was analyzed using Spearman’s rank correlation coefficient. In 54 participants, the RR, median PFS, and OS were 66.7 % (95 % CI, 53.4–77.8 %), 11.1 months, and 33.9 months, respectively. There was no unexpected toxicity. Forty (80 %) of 50 assessable patients had ETS, which was associated with prolonged PFS and OS (11.3 vs. 3.7 months, HR 0.26, p = 0.0003; 42.8 vs. 9.0 months, HR 0.40, p = 0.0279, respectively). Median DpR was 56.3 %. The DpR correlated with OS (r s = 0.314, p = 0.027) as well as post-progression survival (PPS) (r s = 0.366, p = 0.017). Interestingly, DpR was moderately associated with OS and PPS (r s = 0.587, r s = 0.570, respectively) in patients harboring tumors with larger target lesions, but was not associated with OS or PPS in patients with smaller target lesions. FOLFOX plus cetuximab was active as a first-line treatment for Japanese mCRC patients, with no unexpected toxicities. Our prospective evaluation of chronological tumor shrinkage showed that ETS and DpR correlate with outcomes in patients with KRAS wild-type mCRC who receive cetuximab-based chemotherapy (UMIN000004197).

We conducted this study to clarify the current clinical practice of prophylactic colectomy for patients with familial adenomatous polyposis (FAP) in Japan. This retrospective multi-center cohort study involved 23 specialized institutions for colorectal disease in Japan. We analyzed the records of 147 patients who underwent prophylactic surgical treatment between 2000 and 2012. Patients were divided into Group 1 (2000–2006) and Group 2 (2007–2012) based on their date of surgery. Age at the time of prophylactic surgery was 27 and 31 years in Groups 1 and 2, respectively. The proportion of attenuated FAP was significantly lower in Group 2 than in Group 1 (1.0 vs. 13 %, respectively). Pathological examination revealed an increased incidence of malignant polyps in the resected specimens from Group 2 patients (10 vs. 23 %, respectively; P = 0.034). Laparoscopic surgery was more frequent in Group 2 than in Group 1 (61 vs. 40 %, respectively). There was no surgical mortality in either group. Prophylactic surgery for FAP results in good short-term surgical outcomes in Japan. The current surgical approach is characterized by limited surgical indications for patients with attenuated FAP, delayed timing of colectomy, and the increasing standardization of laparoscopic surgery.

OBJECTIVE Colorectal cancer is a major cause of death in patients with familial adenomatous polyposis. Despite evidence for prophylactic colectomy, there is no ideal therapy for patients with coexisting familial adenomatous polyposis and colorectal cancer. We evaluated the correlation between surgery for familial adenomatous polyposis and multimodal treatment for colorectal cancer, and clarified prognosis of Japanese patients with familial adenomatous polyposis and colorectal cancer. METHODS We retrospectively reviewed data from 303 patients who underwent colorectal surgery for familial adenomatous polyposis between 2000 and 2012. RESULTS Overall, 172 patients had colorectal cancer. The most common procedure for familial adenomatous polyposis was restorative proctocolectomy with ileal pouch anal anastomosis, irrespective of colorectal cancer. Partial colectomy was more frequent in patients with than without colorectal cancer (8.7% and 0%, respectively). Ileal pouch anal anastomosis was frequently (60.6%) performed in patients with Stage I-III colorectal cancer. Overall, 12 of 20 patients with Stage IV colorectal cancer underwent metastasectomy; six patients simultaneously and six metachronously. There were fewer cases of ileal pouch anal anastomosis, but more total colectomy with ileorectal anastomosis was performed metachronously, compared with simultaneous metastasectomy (P = 0.006). More cytotoxic (P = 0.006) and molecular (P = 0.03) agents were administered to the ileorectal anastomosis/partial colectomy patients, compared with total proctocolectomy/ileal pouch anal anastomosis patients. A 5-year overall survival was 100% in Stage 0/I, 89.8% in Stage II, 87.9% in Stage III and 48.4% in Stage IV. CONCLUSIONS In patients with familial adenomatous polyposis and colorectal cancer, primary surgery, metastasectomy and chemotherapy could be compatible with standard surgical approaches for familial adenomatous polyposis . However, modifying surgical procedures for familial adenomatous polyposis might help multimodality therapy for Stage IV colorectal cancer to prolong survival.

Even during laparoscopic hepatectomy, a technique is often required to expose the major vessels, for example, in anatomical hepatectomy. We have standardized and performed such laparoscopic hepatectomy as successfully as open hepatectomy. We divide the liver parenchyma without pre-coagulation, exposing the major vessels using CUSA. To control the bleeding, we keep the central venous pressure low and often perform Pringle’s maneuver. Over 49 months, we performed totally laparoscopic hepatectomies in 41 patients with the technique of exposing the major vessels. These included major hepatectomy in 7, sectorectomy in 17, segmentectomy in 14, and others in 3. The median operative time was 361 (range 176–605) minutes, with median blood loss of 216 (range 0–1600) g. The conversion rate was 4.9 %. Postoperative morbidity rate was 9.8 % (prolonged ascites in 1, port site infection in 1, peroneal palsy in 2). Mortality was zero. The median length of hospital stay after surgery was 8 (range 5–28) days. No local recurrence was found at the time of writing. By using our standardized procedure exposing the major vessels, we could raise the quality of laparoscopic hepatectomy toward the level of open hepatectomy significantly.

Fluorouracil (5-FU) plus irinotecan combined with bevacizumab has significant activity in metastatic colorectal cancer (mCRC), but S-1 has become a substitute for continuous infusion of 5-FU and has a very low incidence of hand-foot syndrome. With the S-1 plus irinotecan regimen (SIR), the response rate was 62.5%, and the progression-free survival was 8.0 months. We report here on an update of efficacy and safety of the SIR plus bevacizumab (SIRB) regimen as first line treatment for mCRC patients. Fifty-one eligible patients with histologically confirmed advanced or recurrent colorectal cancer received this treatment. S-1 was administered orally on days 1-14 of a 21-day cycle. Patients were assigned on the basis of body surface area (BSA) to receive one of the following oral doses twice daily: 40 mg, 50 mg, or 60 mg. Irinotecan (150 mg/m(2)) plus bevacizumab (7.5 mg/kg) were administered by intravenous infusion on day 1. Safety analysis identified a grade 3/4 neutropenia rate of 26%. Other grade 3/4 toxicities were diarrhea (8%), nausea (6%), vomiting (2%), and hypertension (8%). The response rate was 67% and the median progression-free survival time was 373 days. The SIRB regimen appears to be highly active and well tolerated as first-line treatment for mCRC.

Background 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. Methods This is a retrospective review of 55 LS patients treated at Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital. Results 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. Conclusion 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.

The liver is the most common site of metastasis in patients with colorectal cancer (CRC), and this is a determinant of the prognosis. However, no reliable molecular predictors of liver metastasis have yet been identified.Sixty-two surgical specimens of colorectal cancer were studied. The first group included 25 patients who achieved a disease-free survival period of at least 6 years (CRC-M0), and the second group included 37 patients with synchronous (n = 22) or metachronous (n = 15) liver metastasis (CRC-M1). SMAD4, p53, and Ki-67 expression levels were assessed immunohistochemically.The loss of SMAD4 expression and elevated Ki-67 expression were found significantly more frequently in CRC-M1 patients than in CRC-M0 patients (P = 0.0047 and P = 0.013, respectively). Statistically significant differences were also observed between the CRC-M0 group and the metachronous metastasis group. No difference was seen in the overexpression of p53 between the groups. A combination analysis of SMAD4 and Ki-67 revealed no cases with maintained levels of SMAD4 and a low Ki-67 expression had or developed liver metastasis.The loss of SMAD4 expression and elevated Ki-67 expression was therefore found to significantly correlate with liver metastasis, regardless of the time of occurrence, thus indicating these factors to be predictive markers for liver metastasis in patients with CRC.

目的 : 下部直腸癌術後の排便機能および性機能を明らかにする.方法 : 超低位前方切除術後92症例における排便機能の経時的推移を外来診療録から調査した. また術後5年以上経過し, 無再発生存中の直腸癌術後症例を対象に, 排便機能および男性性機能に関するアンケート調査を実施, 術式別に比較検討した.結果 : 超低位前方切除術直後には1日6回以上の頻便を呈する症例が54%を占めていたが, 術後1年では6.5%, 術後3年では3%未満と術後年数の経過とともに改善していた. 前方切除術後あるいは低位前方切除術後と比較すると, 超低位前方切除術後では便意切迫を経験する症例 (22% vs 44%, p=0.03) や便失禁を経験する症例 (18% vs 44%, p

OBJECTIVE The upper gastrointestinal characteristics in Japanese familial adenomatous polyposis patients have not yet been clarified. The aim of the present study was to elucidate these characteristics in Japanese familial adenomatous polyposis patients. METHODS This study was conducted by the study group for familial adenomatous polyposis in the Japanese Society for Cancer of the Colon and Rectum. Familial adenomatous polyposis patients who underwent surgical resection from 2000 to 2012 were included in the study. RESULTS In total, 303 familial adenomatous polyposis patients were enrolled, with 265 cases of classical familial adenomatous polyposis (≥100 adenomas) and 38 cases of attenuated familial adenomatous polyposis (

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 Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1630-1) contains supplementary material, which is available to authorized users.

S-1, a novel oral prodrug of 5-fluorouracil (5-FU), and irinotecan with or without bevacizumab is known to be effective in metastatic colorectal cancer (mCRC). However, it is not clear whether S-1 and irinotecan confers benefits compared to 5-FU and leucovorin plus oxaliplatin (FOLFOX) in patients with mCRC. Our aim was to compare the efficacy and safety of these regimens. We analyzed 187 patients with previously untreated mCRC who were enrolled in four phase II studies: SIR (S-1 and irinotecan, n = 40), SIRB (S-1 and irinotecan with bevacizumab, n = 51), FOLFOX (5-FU and leucovorin plus oxaliplatin, n = 46), and STOX (stop-and-go strategy of modified FOLFOX-6 with bevacizumab, n = 50). We evaluated efficacy and safety between SIR/SIRB and FOLFOX/STOX. Baseline characteristics were similar in the two groups composed of SIR/SIRB (n = 91) and FOLFOX/STOX (n = 96). The overall response rates were not significantly different between the two groups (65 % in SIR/SIRB vs. 52 % in FOLFOX/STOX, p = 0.125). The median progression-free survival was 10.9 months in SIR/SIRB versus 12.1 months in FOLFOX/STOX (p = 0.59). The median overall survival was 27.3 months in SIR/SIRB versus 26.8 months in FOLFOX/STOX (p = 0.97). Gastrointestinal adverse events were the most common toxicities in SIR/SIRB, while neutropenia and sensory neuropathy were the most common toxicities in FOLFOX/STOX. S-1 and irinotecan with or without bevacizumab was well tolerated and showed similar response rates and survival compared to the FOLFOX regimen. This combination should be considered as an experimental first-line treatment for mCRC.

The positive correlation between smoking and cancer risk is well estimated in sporadic colorectal cancer, whereas little is known with regard to Lynch syndrome-associated colorectal cancer. A total of 118 familial colorectal cancer patients from the Hereditary Nonpolyposis Colorectal Cancer Registry and Genetic Testing Project of the Japanese Society for Cancer of the Colon and Rectum, were assessed to determine whether smoking alters the incidence of multiple colorectal cancers. In male patients with Lynch syndrome (n = 29), the incidence of multiple colorectal cancers in patients who had ever smoked (smoking duration: median of 19 years) was higher than that in those who never smoked (58.8% vs. 10.0%, P = 0.02). The cumulative risk for metachronous colorectal cancer was significantly higher in male Lynch syndrome patients who had previously smoked than in those who had never smoked (P = 0.03). Our data suggest that long-term cigarette smoking might be a strong risk factor for the development of multiple colorectal cancers in male Lynch syndrome patients.