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Abstract Background Advanced hepatobiliary–pancreatic cancer often invades critical blood vessels, including the portal vein (PV) and hepatic artery. Resection with tumor-free resection margins is crucial to achieving a favorable prognosis in these patients. Herein, we present our cases and surgical techniques for PV wedge resection with patch venoplasty using autologous vein grafts during surgery for pancreatic ductal adenocarcinoma (PDAC) and perihilar cholangiocarcinoma (PhCC). Case presentation Case 1: 73-year-old female patient with PDAC; underwent subtotal stomach-preserving pancreatoduodenectomy, with superior mesenteric vein wedge resection and venoplasty with the right gonadal vein. Case 2: 67-year-old male patient with PDAC; underwent distal pancreatectomy and celiac axis resection, with PV wedge resection and venoplasty with the middle colic vein. Case 3: 51-year-old female patient with type IV PhCC; underwent left hepatectomy with caudate lobectomy and bile duct resection, with hilar PV wedge resection and venoplasty with the inferior mesenteric vein (IMV). Case 4: 69-year-old male patient with type IIIA PhCC; underwent right hepatopancreatoduodenectomy, with hilar PV resection and patch venoplasty with the IMV. All patients survived for over 12 months after the surgery, without local recurrence. Conclusions PV wedge resection and patch venoplasty is a useful technique for obtaining tumor-free margins in surgeries for hepatobiliary–pancreatic cancer.

Abstract Circulating tumor cells (CTCs) play an important role in metastasis and recurrence. However, which cells comprise the complex tumor lineages in recurrence and are key in metastasis are unknown in colorectal cancer (CRC). CRC with high expression of POU5F1 has a poor prognosis with a high incidence of liver metastatic recurrence. We aim to reveal the key cells promoting metastasis and identify treatment-resistant lineages with established EGFP-expressing organoids in two-dimensional culture (2DOs) under the POU5F1 promotor. POU5F1-expressing cells are highly present in relapsed clinical patients’ blood as CTCs. Sorted POU5F1-expressing cells from 2DOs have cancer stem cell abilities and abundantly form liver metastases in vivo. Single-cell RNA sequencing of 2DOs identifies heterogeneous populations derived from POU5F1-expressing cells and the Wnt signaling pathway is enriched in POU5F1-expressing cells. Characteristic high expression of CTLA4 is observed in POU5F1-expressing cells and immunocytochemistry confirms the co-expression of POU5F1 and CTLA4. Demethylation in some CpG islands at the transcriptional start sites of POU5F1 and CTLA4 is observed. The Wnt/β-catenin pathway inhibitor, XAV939, prevents the adhesion and survival of POU5F1-expressing cells in vitro. Early administration of XAV939 also completely inhibits liver metastasis induced by POU5F1-positive cells.

Abstract Background Anorectal fistula cancer is often diagnosed in an advanced state, and radical resection is difficult when invasion of the pelvic wall is observed. In addition, there is currently no clear evidence for perioperative treatment of locally advanced cases. We report a case of anorectal fistula cancer with widespread infiltration diagnosed during the course of Crohn’s disease, which was curatively resected after preoperative chemoradiotherapy. Case presentation A 49-year-old man who had been diagnosed with Crohn’s disease (ileocolonic type) at the age of 25 and was found to have an anorectal fistula and perianal abscess at the age of 44 was referred to our department with complaints of abdominal pain and diarrhea. Computed tomography (CT) showed anal stenosis due to a pelvic mass. Pathological analysis of a biopsy taken under general anesthesia indicated mucinous carcinoma. Magnetic resonance imaging (MRI) revealed infiltration into the prostate, seminal vesicles, levator ani muscle, and left internal obturator muscle, and the patient was diagnosed with cT4N0M0 cStage IIIB anorectal fistula cancer (UICC TNM classification 8th edition). After performing a laparoscopic sigmoid colostomy, chemoradiation therapy (capecitabine + oxaliplatin, 50.4 Gy/28fr) was initiated. The patient then underwent laparoscopic total pelvic exenteration, colonic conduit diversion, extensive perineal resection, and reconstruction using bilateral gluteus maximus flaps and a right rectus abdominis musculocutaneous flap. The pathological diagnosis was mucinous adenocarcinoma, pT4, and all margins were negative. No recurrence was evident 6 months after the operation without adjuvant chemotherapy. Conclusion We described a case of curative resection after preoperative chemoradiotherapy for anorectal fistula cancer with extensive invasion that was diagnosed during the course of Crohn’s disease.An accumulation of cases is needed to determine the usefulness of preoperative chemoradiation therapy for local control of anorectal fistula cancer associated with Crohn’s disease.

Abstract Background As the number of patients with inflammatory bowel disease (IBD) increases, the incidence of IBD-related colorectal cancer (CRC) is also on the rise. Crohn’s disease (CD)-related CRC has been reported to have a poorer prognosis than sporadic CRC, and the early detection of CD-related CRC is difficult. Japanese patients with CD are reported to have a higher frequency of anorectal cancer than the Western population; however, methods for early diagnosis have not yet been established because of perianal pain during the examination. Case presentation We report a case of CD-related anal fistula cancer that was detected early by surveillance examination under anesthesia (EUA). The patient was a 37-year-old man, diagnosed with CD at the age of 15 years and started medical treatment. However, due to poor disease control, the intestinal tract remained highly inflamed and the patient continued to have over 10 bowel movements per day. He was referred to our hospital for surgical treatment after a colonoscopy (CS), which revealed multiple active ulcers and stenoses. Since three perianal seton drainage tubes had been placed around his anus since the age of 33 years, we decided to perform an EUA to rule out cancer coexistence in the anorectal region. After a random biopsy of the rectum by CS under general anesthesia, we resected and curetted multiple perianal fistulas as much as possible and reinserted the seton drainage tubes. Pathological examination of the fistula tract revealed adenocarcinoma in one tract, indicating the coexistence of anal fistula cancer. Based on the diagnosis of multiple intestinal stenoses and anal fistula cancer due to CD, we performed hand-assisted laparoscopic total colectomy, rectal amputation, extensive perineal resection, and reconstruction using a left rectus abdominis flap. Conclusion In a long-term CD patient with anorectal lesions, we performed an EUA to diagnose the coexistence of anal fistula cancer at an early stage, and surgical resection was achieved. EUA is effective for the early detection and treatment of CD-related CRC and may contribute to an improved prognosis.

Abstract Aims Risk‐scoring systems for colorectal liver metastasis (CRLM) after hepatectomy allow prognoses to be predicted preoperatively. We investigated the clinical outcomes of neoadjuvant chemotherapy for resectable CRLM according to patient risk status, aiming to determine the subgroup of patients who could benefit from neoadjuvant chemotherapy. Methods In this multi‐institutional retrospective analysis, the preoperative risk score was calculated from six previously reported factors: synchronous metastases, primary lymph node positivity, tumor number, largest tumor diameter, extrahepatic metastasis, and the preoperative carbohydrate antigen 19–9 level. Patients were divided into three groups according to their risk scores: low risk (score = 0), intermediate risk (score 1–10), and high risk (score ≥11). Overall and recurrence‐free survival curves were calculated using the Kaplan–Meier method. After propensity‐score matching in the intermediate‐risk group, we compared clinicopathological features and outcomes. Results There were 318 cases, from 20 institutions. The preoperative risk score could be calculated in 277 cases. There were 34, 192, and 51 patients in the low‐, intermediate‐, and high‐risk groups, respectively. Intermediate‐risk group patients who received neoadjuvant chemotherapy had significantly better recurrence‐free survival than that of patients without neoadjuvant chemotherapy (P = .0453). After propensity‐score matching in the intermediate‐risk group, the recurrence‐free survival rate was better in patients who received neoadjuvant chemotherapy (P = .0261). But the overall survival rate was not improved after the matching. Conclusion Neoadjuvant chemotherapy for resectable CRLM might prolong the recurrence‐free survival period for intermediate‐risk patients with preoperative risk scores in the range of 1–10, but the overall survival was not improved by neoadjuvant chemotherapy.

Abstract Aim The National Clinical Database (NCD) of Japan is a nationwide data entry system for surgery, and it marked its 10th anniversary in 2020. The aim was to present the 2020 annual report of gastroenterological surgery of the NCD. Methods The data of the surgical procedures stipulated by the training curriculum for board‐certified surgeons of the Japanese Society of Gastroenterological Surgery in the NCD from 2011 to 2020 were summarized. Results In total, 5 622 845 cases, including 593 088 cases in 2020, were extracted from the NCD. The total number of gastroenterological surgeries increased gradually in these 10 years, except for the year 2020 due to the COVID‐19 pandemic. The annual number of surgeries of each organ, except the pancreas and liver, decreased by 0.4%–13.1% in 2020 compared to 2019. The surgical patients were consistently aging, with more than 20% of all gastroenterological surgeries in 2020 involving patients aged 80 years or older. The participation of board‐certified surgeons increased for each organ (75.9%–95.7% in 2020). The rates of endoscopic surgery also increased constantly. Although the incidences of postoperative complications of each organ increased by 0.7%–7.9% in these 10 years, postoperative mortality rates decreased by 0.2%–1.5%. Conclusions We present here the short‐term outcomes of each gastroenterological operative procedure in 2020. This review of the 10‐years of NCD data of gastroenterological surgery revealed a consistent increase of the number of surgeries (except for in 2020), especially endoscopic procedures, and aging of the Japanese population. The good safety of Japanese gastroenterological surgeries was also indicated.

Abstract Objective Dihydropyrimidine dehydrogenase (DPYD) genotype is closely associated with fluoropyrimidine (FP)‐induced toxicities in Caucasian population and European Medicines Agency now recommends DPYD genotype‐based FP dosing strategy. Patients and Methods The current study aimed to investigate their impact on FP‐related toxicities in an Asian population using genome‐wide association study (GWAS) data set from 1364 patients with colon cancer. Results Among 82 variants registered in the Clinical Pharmacogenetics Implementation Consortium, 74 DPYD variants were directly genotyped in GWAS cohort; however, only 7 nonsynonymous DPYD variants (CPIC variants) were identified and none of the four recurrent DPYD variants (DPYD*2A, c.2846A>T, c.1679T>G, c.1236G>A) were included. Seven CPIC variants were investigated for their association with the incidence of FP‐related toxicities; however, none of these variants revealed a significant correlation with FP‐related toxicities. Conclusion These data suggested that the DPYD genotype registered in CPIC plays a minor role in FP‐related toxicities in an Asian population.

Abstract Numerous studies have investigated the various cellular responses against genotoxic stress, including those mediated by focal adhesions. We here identified a novel type of focal adhesion remodelling that occurs under genotoxic stress conditions, which involves the replacement of active focal adhesion kinase (FAK) with FAK-related non-kinase (FRNK). FRNK stabilized focal adhesions, leading to strong cell-matrix adhesion, and FRNK-depleted cells were easily detached from extracellular matrix upon genotoxic stress. This remodelling occurred in a wide variety of cells. In vivo, the stomachs of Frnk-knockout mice were severely damaged by genotoxic stress, highlighting the protective role of FRNK against genotoxic stress. FRNK was also found to play a vital role in cancer progression, because FRNK depletion significantly inhibited cancer dissemination and progression in a mouse cancer model. Furthermore, in human cancers, FRNK was predominantly expressed in metastatic tissues and not in primary tissues. We hence conclude that this novel type of focal adhesion remodelling reinforces cell adhesion and acts against genotoxic stress, which results in the protection of normal tissues, but in turn facilitates cancer progression.

Abstract Regorafenib has shown significant survival benefit as a salvage therapy for colorectal cancer; however, its starting dose has been controversial in recent studies. Therefore, we conducted a prospective study on the efficacy and safety of the dose reduction of regorafenib to 120 mg. Patients received 120 mg regorafenib once per day for 3 weeks, followed by a 1-week off-treatment period. The primary endpoint was the investigator-assessed disease control rate (DCR). Sixty patients were registered, and the DCR was 38.3% with a median progression-free survival of 2.5 months (95% confidence interval [CI] 1.9–3.7) and median overall survival of 10.0 months (95% CI 6.9–15.2). Common grade 3–4 adverse events were hand-foot skin reaction and hypertension (20.0% each). The results of administration of 120 mg regorafenib as the starting dose are consistent with reports from prior phase III trials, which used starting doses of 160 mg. This lower initiating dose of regorafenib may be beneficial to certain patient populations. This clinical trial was registered in the UMIN Clinical Trials Registry (UMIN-CTR number UMIN000018968, registration date: 10/09/2015).

Abstract Approximately 10% of patients with colorectal cancer with submucosal invasion have lymph node metastasis. Pathological risk factors for lymph node metastasis have varying sensitivities and specificities. To predict the risk of lymph node metastasis, the identification of new risk factors is vital. Tumor-infiltrating T cells have been reported to improve the prognosis of many solid tumors. Therefore, the purpose of this study was to examine the relationship between lymph node metastasis and tumor-infiltrating T cells in patients with colorectal cancer with submucosal invasion. We examined CD8+ tumor-infiltrating T cells level as a risk factor for lymph node metastasis in patients with colorectal cancer with submucosal invasion. Using immunohistochemical staining, we identified CD8 + T cells in surgically resected specimens from 98 patients with SM-CRC. We showed that low CD8+ tumor-infiltrating T cells levels are positively correlated with lymph node metastasis. Furthermore, by combining the number of CD8+ tumor-infiltrating T cell and the number of CD103+ tumor-infiltrating T cells, the results showed a high positive predictive value for lymph node metastasis in cases with low numbers of both types of tumor-infiltrating T cells and a high negative predictive value in cases with high numbers of both types of tumor-infiltrating T cells.

Abstract Purpose Addition of perioperative multi‐agent chemotherapy to the treatment strategy for locally advanced rectal cancer (LARC) may be a promising option. We conducted a phase II study to evaluate the safety and efficacy of capecitabine combined with oxaliplatin and irinotecan (XELOXIRI) as triplet neoadjuvant chemotherapy in patients with LARC. Methods Patients received neoadjuvant irinotecan and oxaliplatin and capecitabine and then underwent total mesorectal excision. The primary study endpoint was the pathological complete response (pCR) rate. Results Between June 2013 and December 2016, 55 patients were enrolled in the study. Forty‐two (77.8%) of 54 completed the study protocol. The pCR rate was 7.7% (95% CI 3.0% to 18.2%). The 3‐year local recurrence rate was 3.9%, the 3‐year disease‐free survival (DFS) rate was 77.3, and the 3‐year overall survival rate was 96.0%. Conclusion XELOXIRI neoadjuvant chemotherapy appears to be feasible and efficacious for patients with LARC. Although neoadjuvant XELOXIRI alone did not yield our expected pCR rate, the local recurrence rate, 3‐year DFS, and measures of safety met current standards.

Abstract Background Single incision laparoscopic surgery (SILS) is a recent advancement in minimally invasive techniques for colorectal cancer (CRC). However, SILS is a technically challenging procedure for novice surgeons. The aim of this study was to evaluate clinical outcomes of SILS for CRC performed by novice surgeons compared with those performed by well‐experienced surgeons. Methods We retrospectively analyzed 1004 consecutive patients with stage I‐IV CRC who underwent SILS between May 2009 and December 2018, using propensity score‐matched analysis. Results After propensity score‐matching, we enrolled 344 patients (n = 172 in each group). Before matching, significant group‐dependent differences were observed in terms of age (P = 0.034) and tumor location (P

Abstract Aim Due to the overwhelming spread of SARS‐CoV‐2 and its disruption of the healthcare system, delays and reduced numbers were reported for colorectal cancer screening, colonoscopies, and surgery during the COVID‐19 pandemic. This multicenter retrospective study investigated the still poorly understood impact of the COVID‐19 pandemic on colorectal cancer treatment in Japan. Methods This study was organized by the Clinical Study Group of Osaka University, which comprised 32 major institutions in Osaka. We retrospectively analyzed the number of surgeries and colonoscopies performed and the characteristics of patients who underwent surgery for colorectal cancer between March 2019 and February 2021. We compared data collected before and during the COVID‐19 pandemic. We also assessed the methods used for detecting colorectal cancer, including fecal occult blood test, abdominal symptoms, and anemia. Results The COVID‐19 pandemic caused reductions in the annual numbers of surgeries (3569 vs 3198) and colonoscopies (67 622 vs 58 183) performed in the 2020 fiscal year, compared to the 2019 fiscal year. During the COVID‐19 pandemic, a significantly lower proportion of patients were treated for clinical stages ≤I (24.2% vs 26.9%; P = .011), compared to the proportion treated before the pandemic. Fecal occult blood tests for detecting colorectal cancer were used significantly less frequently during the COVID‐19 pandemic (26.2% vs 29.6%; P = .002). These trends were more significant in larger institutions. Conclusion The COVID‐19 pandemic reduced the number of colonoscopies and surgeries performed for colorectal cancer and hindered the detection of asymptomatic early‐stage cancers, and its impact varied by hospital size.

Abstract Background The clinical impact of single-incision laparoscopic surgery (SILS) for descending colon cancer (DCC) is unclear. The aim of this study was to evaluate the clinical outcomes of SILS for DCC compared with multi-port laparoscopic surgery (MPLS). Methods We retrospectively analyzed 137 consecutive patients with stage I–III DCC who underwent SILS or MPLS at two high-volume multidisciplinary tertiary hospitals between April 2008 and December 2018, using propensity score-matched analysis. Results After propensity score-matching, we enrolled 88 patients (n = 44 in each group). SILS was successful in 97.7% of the matched cohort. Compared with the MPLS group, the SILS group showed significantly less blood loss and a greater number of harvested lymph nodes. Morbidity rates were similar between groups. Recurrence pattern did not differ between groups. No significant differences were found between groups in terms of 3-year disease-free and overall survivals. Conclusion SILS appears safe and feasible and can provide satisfactory oncological outcomes for patients with DCC.

Abstract Anal canal cancer (ACC) has been reported to be an uncommon cancer in Japan, as in the USA, Europe, and Australia. This retrospective multi‐institutional study was conducted to clarify the characteristics of ACC in Japan. First, the histological ACC type cases treated between 1991 and 2015 were collected. A detailed analysis of the characteristics of anal canal squamous cell carcinoma (SCC) cases was then conducted. The results of the histological types revealed that of the 1781 ACC cases, 435 cases (24.4%) including seven cases of adenosquamous cell carcinomas were SCC and 1260 cases (70.7%) were adenocarcinoma. However, the most common histological type reported in the USA, Europe, and Australia is SCC. Most ACC cases are adenocarcinomas and there is a low incidence of SCC in Japan which is different from the above‐mentioned countries. Moreover, we reclassified T4 into the following two groups based on tumor size: T4a (tumor diameter of 5 cm or less) and T4b (tumor diameter of more than 5 cm). The results of the TNM classification of SCC revealed that the hazard ratio (HR) to T1 of T2, T3, T4a, and T4b was 2.45, 2.28, 2.89, and 4.97, respectively. As T4b cases had a worse prognosis than T4a cases, we propose that T4 for anal canal SCC in Japan be subclassified into T4a and T4b.

Summary: Somatic cell reprogramming using the microRNAs miR-200c, miR-302s, and miR-369s leads to increased expression of cyclin-dependent kinase inhibitors in human colorectal cancer (CRC) cells and suppressed tumor growth. Here, we investigated whether these microRNAs inhibit colorectal tumorigenesis in CPC;Apc mice, which are prone to colon and rectal polyps. Repeated administration of microRNAs inhibited polyp formation. Microarray analysis indicated that c-MAF, which reportedly shows oncogene-like behavior in multiple myeloma and T cell lymphoma, decreased in tumor samples but increased in microRNA-treated normal mucosa. Immunohistochemistry identified downregulation of c-MAF as an early tumorigenesis event in CRC, with low c-MAF expression associated with poor prognosis. Of note, c-MAF expression and p53 protein levels were inversely correlated in CRC samples. c-MAF knockout led to enhanced tumor formation in azoxymethane/dextran sodium sulfate–treated mice, with activation of cancer-promoting genes. c-MAF may play a tumor-suppressive role in CRC development.

Abstract Background The standard treatment for locally advanced rectal cancer (LARC) is preoperative chemoradiotherapy (CRT) followed by surgery and adjuvant chemotherapy. However, it has been suggested that intensification of neoadjuvant treatment with polychemotherapy in addition to CRT instead of as an adjuvant chemotherapy is better tolerated and associated with a higher pathological complete response (pCR) rate. This concept is known as total neoadjuvant therapy (TNT). Recently, the addition of immunotherapy to preoperative CRT has been reported to be useful in LARC patients with mismatch-repair-deficiency and high levels of microsatellite instability (MSI-H), but there are no reports showing the therapeutic effect of nivolumab in combination with TNT. Case presentation A 23-year-old man had frequent diarrhea. Preoperative examination revealed two adenocarcinomas in the rectum. His maternal grandmother had a rectal cancer patient who developed the disease at age 70s. The larger tumor was located at the peritoneal reflection, and its anterior border close to the prostate (

Abstract Background Low anterior resection syndrome (LARS) is the most common complication after rectal cancer resection. We aimed to identify LARS' predictive factors and construct and evaluate a predictive model for LARS. Methods This retrospective study included patients with rectal cancer more than 1 year after laparoscopic or robotic-assisted surgery. We administered a questionnaire to evaluate the degree of LARS. In addition, we examined clinical characteristics with univariate and multivariate analysis to identify predictive factors for major LARS. Finally, we divided the obtained data into a learning set and a validation set. We constructed a predictive model for major LARS using the learning set and assessed the predictive accuracy of the validation set. Results We reviewed 160 patients with rectal cancer and divided them into a learning set (n = 115) and a validation set (n = 45). Univariate and multivariate analyses in the learning set showed that male (odds ratio [OR]: 2.88, 95% confidence interval [95%CI] 1.11–8.09, p = 0.03), age

Abstract Background Despite advances in medical treatments, most patients with Crohn's disease (CD) will still require surgery, with 20%‐50% needing redo surgery within 10 years after the primary procedure. There is no consensus on the application of laparoscopic redo surgery for recurrent CD. Methods This study included 107 patients with CD who underwent surgery from 2012 to 2020 at Osaka University Hospital. All procedures were laparoscopic. Patients were grouped based on whether the surgery was redo or primary for evaluation of the safety and feasibility of laparoscopic redo surgery. Results The study included 40 patients undergoing redo surgery and 67 having primary surgery. The median age at the time of the procedure was higher for those undergoing redo surgery (43 years vs 34 years, P

Abstract Aim Early detection of surgical site infection (SSI) allows for appropriate management after Crohn's disease (CD) surgery. The aim of this study was to evaluate the usefulness of bacterial culture of postoperative drainage fluid after CD surgery. Methods This study included 110 patients with CD who underwent surgery with bowel resection between January 2010 and March 2020 at Osaka University Hospital. Patients with only perianal surgery or incomplete records were excluded. Risk factors for SSI were evaluated in the context of clinical findings, including bacterial culture of postoperative drainage fluid, and bacterial species related to SSI were also examined. Results Of 110 patients, 18 (16.4%) developed SSI. Organ/space SSI developed in six, and a positive bacterial culture of drainage fluid (D‐Posi) was found in five (83.3%). Of 104 patients without organ/space SSI, 31 (29.8%) were D‐Posi (P = .027). Similarly, 68.8% with incisional SSI were D‐Posi, whereas 26.6% without incisional SSI were D‐Posi (P = .0021). Multivariate analysis revealed that D‐Posi was an independent risk factor in both organ/space and incisional SSI. Bacterial examination showed that Pseudomonas aeruginosa and Enterococcus faecalis were significantly detected in patients with SSI. Conclusion This study suggests the usefulness of postoperative drainage fluid bacterial culture for early diagnosis of SSI after CD surgery.

Abstract Background Stoma outlet obstruction (SOO) is much more common after total proctocolectomy (TPC) and ileal‐pouch anal anastomosis (IPAA) for ulcerative colitis (UC) compared to after rectal surgery for cancer. Few prior reports have evaluated anatomical risk factors for SOO. In this study we aimed to clarify the risk factors for SOO after IPAA, focusing on the anatomical perspective. Methods This study included 68 UC patients who underwent IPAA with diverting ileostomy. These cases were analyzed based on clinicopathological factors and computed tomography (CT)‐based anatomical factors. Results SOO was identified in 18 patients (26.5%). We compared this SOO group with the non‐SOO group. The two groups significantly differed in sex distribution, and patients in the SOO group tended to have a longer postoperative hospital stay. Regarding surgery‐related factors, patients who underwent two‐stage surgery and experienced high‐output syndrome tended to develop SOO. Analysis of anatomical risk factors revealed that SOO was more common in patients with a longer distance between the root of their superior mesenteric artery and the bottom of the external anal sphincter (rSMA‐bEAS). This tendency remained significant even with adjustment for patient height. In multivariate analyses, adjusted rSMA‐bEAS (>191.0 mm/m) and male sex were independent risk factors associated with SOO. Conclusion A long rSMA‐bEAS distance suggests that the mesentery is likely to be under tension. In such cases, surgeons should endeavor to avoid tension in the mesentery as much as possible.

Abstract Background The incidence of fecal incontinence is ~2%, and the associated symptoms significantly impact daily life. New treatment methods including electrical stimulation and regenerative therapy using stem cells for fecal incontinence have been reported. We explored the usefulness of an anal sphincter injury mouse model by means of a balloon catheter and focused on the defecation status of mice as a novel method for evaluating anal function. We examined the utility of the mouse model of anal sphincter injury and the efficacy of electrical stimulation as a treatment modality using this model. Methods A 10‐mm balloon catheter was used to create an anal sphincter injury model in mice. Sphincter function was evaluated in the noninjured (n = 4), injured (n = 4), noninjured electrical stimulation (n = 4), and injured electrical stimulation (n = 4) groups. Defecation status (defecation frequency in 24 h and fecal weight per stool) and pathological evaluation were used for comparison. Results The defecation frequency increased and the fecal weight per stool decreased significantly in the anal sphincter injury model. Pathological evaluation revealed that anal sphincter tears occurred the day after the injury. Meanwhile, the defecation frequency improved on d 7, and the fecal weight per stool gradually normalized to that of the control group and exhibited significant sphincter muscle hypertrophy in the electrical stimulation group. Conclusion Anal sphincter injury using a balloon catheter in mice allowed us to create a uniform model. The evaluation of defecation status in mice is a useful method for comparatively evaluating anal function.

The novel coronavirus disease 2019 (COVID-19) caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread at a very fast rate, overwhelming and disrupting healthcare systems around the world since its outbreak in December 2019 in China. As of October 2021, the total number of COVID-19 cases exceeds 240,000,000, and the total number of deaths is close to 5,000,000. In the situation of widespread SARS-CoV-2 infection, restrictions on the medical system due to shifts in medical care to accommodate the pandemic will occur, and its impact on surgical and endoscopic treatment for colorectal cancer is inevitable. Therefore, it is necessary to satisfy all of the following requirements: patient safety, prevention of exposure of healthcare workers including surgeons, prevention of nosocomial infection, and a decision on how to treat the primary disease. Surgical triage is also required, based on comprehensive consideration of the patient's condition, the severity of the disease, the SARS-CoV-2 infection situation in the region, and the medical supply system at each facility, including medical resources, human resources, and the availability of medical equipment. Understanding the diagnostic and treatment environment that the COVID-19 pandemic has dramatically changed is important in providing appropriate surgical care to patients who require surgery while taking utmost care to prevent the spread of COVID-19.

Abstract Background Locally recurrent rectal cancer (LRRC) remains a major problem after curative resection of primary rectal cancer. A noninvasive, prognostic biomarker with which to accurately evaluate disease status and assess the treatment response is critically needed to optimize treatment plans. This study assesses the effectiveness of PET/CT evaluation of preoperative chemoradiation therapy (CRT) in patients with LRRC. Methods Since 2004, we have been performing preoperative CRT to improve local tumor control and survival. Between 2004 and 2013, 40 patients with LRRC underwent preoperative CRT (radiation: 50 Gy/25 fractions; chemotherapy: irinotecan plus UFT [tegafur and uracil]/leucovorin) and radical surgery, and underwent 18F-FDG-PET/CT before and 3 weeks after the completion of CRT. The maximum standardized uptake values (SUVmax) of the pre-CRT scan (Pre-SUV) and the post-CRT scan (Post-SUV) were measured. The predictive value of the 18F-FDG-PET and CT/MRI response assessments was evaluated. Results The mean Pre-SUV was significantly higher than the Post-SUV (8.2 ± 6.1, vs. 3.8 ± 4.0; P 0.9999) or MRI (P > 0.9999). Multivariate regression analysis identified Post-SUV as an independent predictor of local re-recurrence-free survival (P = 0.0383) and for overall survival (P = 0.0195). Conclusions PET/CT is useful in assessing tumor response to preoperative CRT for LRRC and predicting prognosis after surgery.

Abstract Background Although chemotherapy for metastatic colorectal cancer (mCRC) has improved, the standard chemotherapy regimens for patients with RAS wild-type mCRC remain debated. This study aimed to compare S-1 and oxaliplatin (SOX) + bevacizumab (B-mab) with SOX + cetuximab (C-mab) in patients with previously untreated recurrent advanced CRC with wild-type KRAS. Methods This randomized phase II, open-label, multicenter study compared the efficacy and safety of SOX+B-mab with SOX+C-mab in patients with previously untreated advanced CRC with wild-type KRAS. Between February 2012 and October 2016, 45 patients were enrolled. Results Overall response rates were 59.1 and 43.5% (p = 0.29) and disease control rates were 90.9 and 91.3% (p = 0.96) in the SOX+B-mab and SOX+C-mab groups, respectively. Median overall survival (OS) was 25.3 and 15.5 months (HR = 0.607, p = 0.167) and median progression-free survival (PFS) were 11.7 and 5.5 months (HR = 0.558, p = 0.077) in the SOX+B-mab and SOX+C-mab groups, respectively. The OS and PFS of patients with early tumor shrinkage (ETS) were not significantly different in the SOX+B-mab group. However, they were significantly better when ETS was ≥20 in the SOX+C-mab group (p = 0.032 and p = 0.003, respectively). Conclusions The efficacy and safety of SOX+B-mab and SOX+C-mab for wild-type KRAS recurrent advanced CRC as first-line chemotherapy were almost the same. Consideration of the treatment strategy based on ETS may improve patient prognosis, especially in patients receiving the SOX+C-mab regimen. Trial registration UMIN Clinical Trials Registry ( UMIN000006706 ). Date of registration: NOV/11/2011. URL of trial registry record: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000007920

Abstract Background The efficacy and safety of bevacizumab-containing chemotherapy for patients with metastatic duodenal and jejunal adenocarcinoma (mDJA) are unclear. The present study aimed to evaluate the efficacy of bevacizumab and to explore immunohistochemical markers that can predict the efficacy of bevacizumab for patients with mDJA. Methods This multicentre study included patients with histologically confirmed small bowel adenocarcinoma who received palliative chemotherapy from 2008 to 2017 at 15 hospitals. Immunostaining was performed for vascular endothelial growth factor-A (VEGF-A), TP53, Ki67, β-catenin, CD10, MUC2, MUC5AC, MUC6, and mismatch repair proteins. Results A total of 74 patients were enrolled, including 65 patients with mDJA and 9 with metastatic ileal adenocarcinoma. Patients with mDJA who received platinum-based chemotherapy with bevacizumab as first-line treatment tended to have a longer progression-free survival and overall survival than those treated without bevacizumab (P = 0.075 and 0.077, respectively). Multivariate analysis extracted high VEGF-A expression as a factor prolonging progression-free survival (hazard ratio: 0.52, 95% confidence interval: 0.30–0.91). In mDJA patients with high VEGF-A expression, those who received platinum-based chemotherapy with bevacizumab as a first-line treatment had significantly longer progression-free survival and tended to have longer overall survival than those treated without bevacizumab (P = 0.025 and P = 0.056, respectively), whereas no differences were observed in mDJA patients with low VEGF-A expression. Conclusion Immunohistochemical expression of VEGF-A is a potentially useful biomarker for predicting the efficacy of bevacizumab-containing chemotherapy for patients with mDJA.

Although common cancer therapies, such as chemotherapy and radiation therapy, have recently improved and yielded good results, evaluated as tumor shrinkage, disease recurrence is still a common event for most cancer patients. This is termed refractory cancer. This tumor regrowth following therapy is generally thought to be caused by a small, specific population of tumor cells called cancer stem cells (CSCs). Similar to other stem cells, CSCs have the capacity for self-renewal and multipotent differentiation, and they have been identified in many tumor types based on cell surface protein expression. This specific cell population has stemness characteristics as examined by serial transplantation in animal models. Previous studies have developed a specific signature of cell surface markers and biological functions that can identify CSCs in many solid tumors. In this review, we summarize the characterization of CSCs using new techniques for identifying and quantifying them in situ. These techniques and concepts could be valuable for evaluating the effects of therapies on this cell population. Finally, we conclude by discussing several unique preclinical treatment strategies to targets CSCs, such as reprogramming CSCs or inducing attack by immune cells. Therapeutic and diagnostic methodologies that can target and quantify CSCs will be valuable tools for eradicating refractory cancer.

Abstract Epithelial–mesenchymal transition (EMT) is a drastic phenotypic change during cancer metastasis and is one of the most important hallmarks of aggressive cancer. Although the overexpression of some specific transcription factors explains the functional alteration of EMT-induced cells, a complete picture of this biological process is yet to be elucidated. To comprehensively profile EMT-related genes in colorectal cancer, we quantified the EMT induction ability of each gene according to its similarity to the cancer stromal gene signature and termed it “mesenchymal score.” This bioinformatic approach successfully identified 90 candidate EMT mediators, which are strongly predictive of survival in clinical samples. Among these candidates, we discovered that the neuronal gene ARC, possibly originating from the retrotransposon, unexpectedly plays a crucial role in EMT induction. Profiling of novel EMT mediators we demonstrated here may help understand the complexity of the EMT program and open up new avenues for therapeutic intervention in colorectal cancer.

Abstract Background The presence of lateral pelvic lymph node (LLN) metastasis is an essential prognostic factor in rectal cancer patients. Thus, preoperative diagnosis of LLN metastasis is clinically important to determine the therapeutic strategy. The aim of this study was to evaluate the efficacy of preoperative positron emission tomography/computed tomography (PET/CT) in the diagnosis of LLN metastasis. Methods Eighty-four patients with rectal cancer who underwent LLN dissection at Osaka University were included in this study. The maximum standardized uptake value (SUVmax) of the primary tumor and LLN were preoperatively calculated using PET/CT. Simultaneously, the short axis of the lymph node was measured using multi-detector row computed tomography (MDCT). The presence of metastases was evaluated by postoperative pathological examination. Results Of the 84 patients, LLN metastases developed in the left, right, and both LLN regions in 6, 7, and 2 patients, respectively. The diagnosis of the metastases was predicted with a sensitivity of 82%, specificity of 93%, positive predictive value of 58%, negative predictive value of 98%, false positive value of 7%, and false negative value of 18% when the cutoff value of the LLN SUVmax was set at 1.5. The cutoff value of the short axis set at 7 mm on MDCT was most useful in diagnosing LLN metastases, but SUVmax was even more useful in terms of specificity. Conclusions The cutoff value of 1.5 for lymph node SUVmax in PET is a reasonable measure to predict the risk of preoperative LLN metastases in rectal cancer patients.

Abstract Aim Many inflammation‐nutrition scores, including the Glasgow Prognostic Score (GPS), have been reported as prognostic biomarkers in patients with colorectal cancer (CRC). We aimed to examine the predictive ability of the GPS and to improve the GPS. Methods We included a total of 438 patients with stage 0‐III CRC who underwent curative surgery from 2010 to 2013. They were divided into a training set comprising 221 patients and a validation set comprising 227 patients, according to the date of surgery. In the training set, the GPS was verified using a Cox regression model, and cut‐off values for C‐reactive protein (CRP) and albumin for relapse‐free survival (RFS) were calculated using receiver operating characteristics (ROC) curves. The improved GPS (iGPS) was developed with additional optimal cut‐off values. We also compared the iGPS with the conventional GPS in the validation set. Results The high GPS (GPS: 1‐2) was correlated with RFS and overall survival (OS) in the training set. Cut‐off values of CRP and albumin for RFS were 1.6 and 3.9, and we modified the GPS accordingly, adding the cut‐off values of 2 and 3.9 to CRP and albumin, respectively. In the validation set, a high iGPS was an independent prognostic factor for RFS (hazard ratio [HR]: 2.273; 95% confidence interval [CI]: 1.212‐4.364; P = .011), although the conventional GPS was not. Conclusion The iGPS was a more accurate prognostic predictor for patients with stage 0‐III CRC.

Abstract POU5F1-expressing cells can self-renew and differentiate, contributing to metastasis formation in colorectal cancer (CRC), but it plays an important role in normal pluripotent stem cells. Here, we identified the CRC-specific gene, HNF1A, which is the downstream of POU5F1. HNF1A associates with fatty acid and glucose metabolism, and CRC cells highly expressed it. In 198 CRC patients, high HNF1A expression was an independent predictor of disease-free (P = 0.031) and overall (P = 0.007) survival. HNF1A-knockdown showed significantly reduced cell growth, increased apoptosis, and improved anticancer drug sensitivity. We revealed that HNF1A regulated controlled GLUT1 expression via HIF1A and multidrug resistance protein function to suppress SRI. HNF1A expression was elevated in persister cells after exposure to anticancer drugs, and anticancer drug sensitivity was also improved in persister cells via the inhibition of HNF1A. In conclusion, HNF1A expression can reflect resistance to anticancer drug treatment, and its suppression improves anticancer drug sensitivity as a new therapeutic target.

Abstract Background Local recurrence is common after curative resections for rectal cancer. Surgical intervention is among the best treatment choices. However, achieving a negative resection margin often requires extensive pelvic organ resections; thus, the postoperative complication rate is quite high. Recent studies have reported that the inflammatory index could predict postoperative complications. This study aimed to validate the correlation between clinical factors, including inflammatory markers, and severe complications after surgery for local recurrent rectal cancer. Methods This retrospective study included 99 patients that underwent radical resections for local recurrences of rectal cancer. Postoperative complications were graded according to the Clavien-Dindo classification. Grades ≥3 were defined as severe complications. Risk factors for severe complications were identified with univariate and multivariate logistic regression models and assessed with receiver-operating characteristic curves. Results Severe postoperative complications occurred in 38 patients (38.4%). Analyses of correlations between inflammatory markers and severe postoperative complications revealed that the strongest correlation was found between the prognostic nutrition index and severe postoperative complications. The receiver-operating characteristic analysis showed that the optimal prognostic nutrition index cut-off value was 42.2 (sensitivity: 0.790, specificity: 0.508). In univariate and multivariate analyses, a prognostic nutrition index ≤44.2 (Odds ratio: 3.007, 95%CI:1.171–8.255, p = 0.02) and a blood loss ≥2850 mL (Odds ratio: 2.545, 95%CI: 1.044–6.367, p = 0.04) were associated with a significantly higher incidence of severe postoperative complications. Conclusions We found that a low preoperative prognostic nutrition index and excessive intraoperative blood loss were risk factors for severe complications after surgery for local recurrent rectal cancer.

The incidence of inflammatory bowel disease (IBD) is increasing worldwide. It is reported that TGF-β/Smad signal pathway is inactivated in patients with Crohn’s disease by overexpression of Smad 7. With expectation of multiple molecular targeting by microRNAs (miRNAs), we currently attempted to identify certain miRNAs that activate TGF-β/Smad signal pathway and aimed to prove in vivo therapeutic efficacy in mouse model. Through Smad binding element (SBE) reporter assays, we focused on miR-497a-5p. This miRNA is common between mouse and human species and enhanced the activity of TGF-β/Smad signal pathway, decreased Smad 7 and/or increased phosphorylated Smad 3 expression in non-tumor cell line HEK293, colorectal cancer cell line HCT116 and mouse macrophage J774a.1 cells. MiR-497a-5p also suppressed the production of inflammatory cytokines TNF-α, IL-12p40, a subunit of IL-23, and IL-6 when J774a.1 cells were stimulated by lipopolysaccharides (LPS). In a long-term therapeutic model for mouse dextran sodium sulfate (DSS)-induced colitis, systemic delivery of miR-497a-5p load on super carbonate apatite (sCA) nanoparticle as a vehicle restored epithelial structure of the colonic mucosa and suppressed bowel inflammation compared with negative control miRNA treatment. Our data suggest that sCA-miR-497a-5p may potentially have a therapeutic ability against IBD although further investigation is essential.

Abstract Malnutrition has been considered to be associated with the prognosis of cancer. The Geriatric Nutritional Risk Index (GNRI), based on serum albumin levels, present body weight, and ideal body weight, is a simple screening tool to predict the risk of nutrition-related morbidity and mortality in elderly patients. We aimed to evaluate whether preoperative GNRI was associated with postoperative complications and prognosis in elderly patients with colorectal cancer (CRC). We retrospectively enrolled 313 CRC patients aged ≥65 years after curative surgery and classified them into an all-risk GNRI (≤98) group and a no-risk GNRI (>98) group. Kaplan-Meier analysis showed overall survival was significantly worse in the all-risk GNRI group than in the no-risk GNRI group (P = 0.009). Multivariable analyses showed low GNRI (≤98) was an independent risk factor for postoperative complications (P = 0.048) and overall survival (P = 0.001) in the patients. Among the complications, the incidence of surgical site infection, in particular, was significantly higher in the all-risk GNRI group (P = 0.008). In conclusion, low preoperative GNRI (≤98) was associated with increased postoperative complications and poor prognosis. Preoperative GNRI can be used as an identifier for potential high-risk group of morbidity and mortality in elderly CRC patients.

Objectives: We previously reported the feasibility of neoadjuvant capecitabine and oxaliplatin plus bevacizumab as a treatment for locally advanced rectal cancer (UMIN000003219). The aim of this study is to investigate the prognostic relevance of neoadjuvant chemotherapy followed by total mesorectal resection (TME). Methods: Twenty-five patients of our prior multicenter prospective study of neoadjuvant chemotherapy followed by TME enrolled to this study. We analyzed the adjuvant chemotherapy regimen, and the duration between surgery and initial chemotherapy treatment. Five-year progression-free survival and overall survival were estimated using the Kaplan-Meier method. Results: Among survivors, the median follow-up time was 66 months. Recurrence occurred in six patients, all of whom had suboptimal tumor regression after neoadjuvant chemotherapy. Five patients died from other causes. The rate of local recurrence and distant metastasis was 17.4% and 8.7%, respectively. Five-year progression-free survival was 70.0%, and 5 year overall survival was 84.0%. Conclusions: We report the long-term survival of patients who received neoadjuvant chemotherapy without radiation followed by TME, revealing a generally favorable prognosis.

Objectives: The efficacy of negative pressure wound therapy (NPWT) and its application to severely contaminated wounds sustained during surgery remain to be established. Here, we evaluated the efficacy of utilizing NPWT until delayed primary closure (DPC) by assessing the infection rates in patients with lower gastrointestinal perforations. Methods: This prospective multicenter cohort study included 56 patients that underwent abdominal surgery for lower gastrointestinal perforations in eight institutions, from February 2016 to May 2017. All patients received NPWT after surgery before attempting DPC. The extent of peritonitis was categorized according to Hinchey's classification. Patients in stages II-IV were included. Results: Five patients had surgical site infections (SSIs) during NPWT and did not receive a DPC (9%). Of the 51 patients that received DPCs, 44 had no infection (91%) and 7 developed SSIs after the DPC (13.7%). For stages II, III, and IV, the SSI rates were 0%, 22.6%, and 35.7%, respectively; the median (range) times to wound healing were 15 (10-36), 19 (11-99), and 19 (10-53) days, respectively. There were no significant differences between the stages. Conclusions: NPWT followed by DPC resulted in low infection rates in each peritonitis stage. This approach appears promising as an alternative to traditional DPC alone for treating lower gastrointestinal perforations.

Abstract This review outlines current topics on the surgical treatment of benign colorectal diseases, with a focus on inflammatory bowel disease (IBD) and diverticulitis. Treatment options for IBD and diverticulitis have evolved in the last few years as a result of medical advances in technology and new clinical trials. Therefore, treatment options and strategies need to be updated to provide optimal care for patients. The purpose of this review is to elucidate recent global trends and update the surgical treatment strategy for IBD and diverticulitis based on literature published in the past 2 years. Prevalence of IBD, including ulcerative colitis and Crohn's disease, has increased over the last few decades. During this period, many new medical therapies were introduced for the treatment of IBD, including biological therapy, immunomodulators, and leukocyte apheresis therapy. As a result, new surgical strategies for IBD are required. In order to improve surgical outcomes in IBD patients, the influence of preoperative treatment on postoperative complications needs to be considered. The incidence of diverticulitis is also increasing with lifestyle changes and increasing numbers of older people. For diverticulitis with perforation and generalized peritonitis, surgery is the gold standard. Elective surgery after conservative treatment of diverticulitis is also an option because of high recurrence rates. With an increase in diverticulitis, systematic strategies are essential for an appropriate approach to diverticulitis, taking into account various factors, including the patient's background.

Extensive gastrointestinal surgery surveillance data in Japan were analyzed to examine the differences in the risk factors for surgical site infection (SSI) between laparotomy and laparoscopic abdominal procedures. Surgical procedures investigated in the study were gastrectomy, cholecystectomy, colectomy, rectal resection, and appendectomy. A total of 32,629 patients were included in the study. The study participants were divided into two groups according to the year of surgery, 2003–2009 (first study period) and 2010–2015 (second study period), due to the increase in the number of laparoscopic surgeries in the second study period. The incidence of SSI was stratified by three SSI classifications (superficial incisional, deep incisional, and organ/space SSI). Multiple logistic regression analysis was performed to predict the risk factors for SSI. The percentage of laparoscopic surgeries performed has increased linearly since 2010. Patients in the second study period were significantly older and had a higher prevalence of SSI risk factors compared with those in the first study period. In addition, the predictive factors changed substantially in most surgical procedures between the two study periods. Wound class ≥ 3 was a ubiquitous risk factor for superficial incisional SSI (SI-SSI) and organ/space SSI (OS-SSI) in both open (laparotomy) and laparoscopic procedures in the first study period. Meanwhile, in the second study period, operative duration was a ubiquitous risk factor in both procedures. The risk factors for SI-SSI differed from those for OS-SSI in the five abdominal surgeries investigated in the study. Periodic examination of risk factors for SSI is recommended in an aging society.

This study aimed to analyze circulating tumor cells (CTCs) from patients with colorectal cancer (CRC). We designed a dielectrophoresis-based micropore system and tested its cell capture with HT29 colon cancer cells. Then, blood samples were drawn from 24 patients with stages II-IV CRC. Mononuclear cells were isolated and loaded into the micropore system. Single cells were positioned into small pores with dielectrophoresis. After labeling the cells with the appropriate antibodies, tumor-like cells were collected with an automated micromanipulator. We collected 43 CTCs from 15 out of 24 patient samples. The presence of CTC was significantly associated with ling metastasis. We performed whole genome amplification, followed by PCR and Sanger sequencing, to examine the point mutations in the KRAS, BRAF, and PIK3CA genes. This mutation analysis was successfully performed in 35 cells. Among the 14 cytokeratin (CK)-positive cells, we found PIK3CA mutations in three cells (21%) from two patients. Among the 21 CK-negative cells, we found a KRAS mutation in one cell (5%) from one patient and a PIK3CA mutation in one cell (5%) from one patient. It is noteworthy that these mutations were not detected in the corresponding primary tumors. In conclusion, dielectrophoresis-based capture in a micropore system was useful for detecting both CK-positive and CK-negative CTCs. This simple method could be applied to various tumor types.

Abstract Aim Visceral obesity (VO) reportedly has a stronger association with complications after colorectal surgery than does body mass index. Here, we retrospectively assessed VO as a risk factor for postoperative ileus (POI) after colorectal resection in patients with colorectal cancer. Methods This study included 417 consecutive patients with colorectal cancer who underwent elective surgery at our institute from January 2010 to December 2012. Visceral fat area (VFA) was calculated by image analysis software. VO was defined as VFA ≥100 cm2. We assessed 49 factors, including VO, comorbidities, surgical procedure, and postoperative complications. Data were analyzed using a propensity score‐matching strategy. Results Postoperative ileus occurred in 18 patients (4.3%) from the entire cohort, and in 14 (5.5%) of the 256 matched patients. Multivariate analysis (n = 417 patients) showed that significant risk factors for POI included VO (OR 7.9, 95% confidence interval [CI] 1.9‐32.1, P = .004), open surgery (OR 6.4, 95% CI 1.6‐26.7, P = .010), and pelvic/intra‐abdominal abscess (OR 11.0, 95% CI 1.1‐110.2, P = .041). Propensity score matching showed two independent risk factors in the multivariate analysis: VO (OR 6.2, 95% CI 1.3‐30.4, P = .025) and open surgery (OR 9.1, 95% CI 2.0‐40.5, P = .004). Conclusion Visceral obesity may be an independent risk factor for POI in patients with colorectal cancer.

Abstract Aim To investigate the efficacy and safety of anticoagulant prophylaxis to prevent postoperative venous thromboembolism (VTE) during laparoscopic colorectal cancer (CRC) surgery, which is unknown in Japanese patients. Methods We conducted this randomized controlled trial at nine institutions in Japan from 2011 to 2015. It included 302 eligible patients aged 20 years or older who underwent elective laparoscopic surgery for CRC. Patients were randomly assigned to an intermittent pneumatic compression (IPC) therapy group or to an IPC + anticoagulation therapy group. Anticoagulation therapy comprised fondaparinux or enoxaparin for postoperative VTE prophylaxis. Postoperative VTE was diagnosed based on enhanced multi‐detector helical computed tomography. The primary endpoint was VTE incidence, including asymptomatic cases, the secondary endpoint was incidence of major bleeding, and we conducted an intention‐to‐treat analysis. This study is registered in UMINCTR (UMIN000008435). Results Postoperative VTE incidence was 5.10% with IPC therapy (n = 157) and 2.76% with IPC + anticoagulant therapy (n = 145; P = .293). We identified no symptomatic VTE cases. The major bleeding rates were 1.27% with IPC alone and 1.38% with the combination (P = .936). The overall bleeding rates were 7.69% for enoxaparin and 13.6% for fondaparinux (P = .500), and there were no bleeding‐related deaths. Conclusion Anticoagulant prophylaxis did not reduce the incidence of VTE and the incidence of major bleeding was comparable between the two groups. Usefulness of perioperative anticoagulation was not demonstrated in this study. Pharmacological prophylaxis must be restricted in Japanese patients with higher risk of VTE.

Abstract Background Preoperative 5-FU-based chemoradiation is currently a standard treatment for advanced rectal cancer, particularly in Western countries. Although it reduced the local recurrence, it could not necessarily improve overall survival. Furthermore, it can also produce adverse effects and long-term sphincter function deficiency. Adjuvant oxaliplatin plus capecitabine (XELOX) is a recommended regimen for patients with curatively resected colon cancer. However, the efficacy of postoperative adjuvant therapy for rectal cancer patients who have not undergone preoperative chemoradiation remains unknown. We aimed to evaluate the efficacy of surgery and postoperative XELOX without preoperative chemoradiation for treating rectal cancer. Methods We performed a prospective, multicenter, open-label, single arm phase II study. Patients with curatively resected high-risk stage II and stage III rectal cancer who had not undergone preoperative therapy were treated with a 120 min intravenous infusion of oxaliplatin (130 mg/m2) on day 1 and capecitabine (2000 mg/m2/day) in 2 divided doses for 14 days of a 3-week cycle, for a total of 8 cycles (24 weeks). The primary endpoint was 3-year disease-free survival (DFS). Results Between August 2012 and June 2015, 60 men and 47 women with a median age was 63 years (range: 29–77 years) were enrolled. Ninety-three patients had Eastern Cooperative Oncology Group performance status scores of ‘0’ and 14 had scores of ‘1’. Tumors were located in the upper and lower rectums in 54 and 48 patients, respectively; 8 patients had stage II disease and 99 had stage III. The 3-year DFS was 70.1% (95% confidence interval, 60.8–78.0%) and 33 patients (31%) experienced recurrence, most commonly in the lung (16 patients) followed by local recurrence (9) and hepatic recurrence (7). Conclusions Postoperative XELOX without preoperative chemoradiation is effective for rectal cancer and provides adequate 3-year DFS prospects. Trial registration This clinical trial was registered in the University Hospital Medical Information Network registry system as UMIN000008634 at Aug 06, 2012.

In cancer it is assumed that microRNAs recognise and regulate their targets uniformly. Here, the authors show that in gastrointestinal cancers methylation of microRNAs may impact their stability, and that levels of microRNA methylation are distinct in pancreatic cancer patients compared to healthy controls with potential diagnostic implications.

Objectives: It has been reported that there is an association between the nutritional condition and the prognosis of cancer. Here, we evaluated the relation between the prognostic nutritional index (PNI) and colorectal cancer (CRC). Methods: A total of 184 patients with CRC who underwent curative surgery from October 2011 to December 2012 at the Osaka University Hospital were investigated. According to the median PNI value of our data set, patients were classified into a high-PNI (46) group and a low-PNI (

Abstract Aim Appendiceal mucinous neoplasms are rare, and thus the literature is sparse with regard to histological types, staging, and prognosis. In particular, it is unclear how long‐term outcome may differ between mucinous adenocarcinomas and other adenocarcinomas. In the present study, we aimed to investigate the histological types and stages of appendiceal neoplasms, and to evaluate the prognostic impacts of these factors in patients with mucinous adenocarcinomas and non‐mucinous adenocarcinomas. Methods Patients with appendiceal tumors diagnosed between 2007 and 2016 were retrospectively identified from the databases of 19 institutions in the Clinical Study Group of Osaka University, Colorectal Group. Results A total of 266 patients with appendiceal tumors were identified, of whom 130 had pathologically diagnosed adenocarcinomas, including 57 with mucinous adenocarcinomas and 73 with non‐mucinous adenocarcinomas. Five‐year overall survival (OS) rates were 64.5% for mucinous adenocarcinomas, and 49.0% for non‐mucinous adenocarcinomas. OS was significantly shorter among patients with non‐mucinous adenocarcinomas compared to mucinous adenocarcinomas. Among patients with mucinous adenocarcinomas, 5‐year OS rates were 53.6% for stage 0/I, 82.6% for II/III, and 48.4% for IV. Among patients with non‐mucinous adenocarcinomas, 5‐year OS rates were 90.9% for stage 0/I, 68.8% for II/III, and 7.1% for IV. Analysis of patients with stage IV disease revealed significantly shorter OS among patients with non‐mucinous adenocarcinomas compared to mucinous adenocarcinomas. Conclusion Our present findings showed a better prognosis in patients with mucinous adenocarcinomas compared to non‐mucinous adenocarcinomas. In this setting, Union for International Cancer Control staging was associated with prognosis for non‐mucinous adenocarcinomas, but not for mucinous adenocarcinomas.

The incidence of inflammatory bowel disease (IBD) is increasing. Nucleic acid-based medicine has potential as a next-generation treatment, but it is rarely successful with IBD. The aim of this study was to establish a microRNA-based therapy in an IBD model. For this purpose, we used microRNA-29 (miR-29) and a supercarbonate apatite (sCA) nanoparticle as a drug delivery system. Injection of sCA-miR-29a-3p or sCA-miR-29b-3p into mouse tail veins markedly prevented and restored inflammation because of dextran sulfate sodium (DSS)-induced colitis. RNA sequencing analysis revealed that miR-29a and miR-29b could inhibit the interferon-associated inflammatory cascade. Subcutaneous injection of sCA-miR-29b also potently inhibited inflammation, and it efficiently targeted CD11c+ dendritic cells (DCs) among various types of immune cells in the inflamed mucosa. RT-PCR analysis indicated that the miR-29 RNAs in CD11c+ DCs suppressed the production of interleukin-6 (IL-6), transforming growth factor β (TGF-β), and IL-23 subunits in DSS-treated mice. This may inhibit Th17 differentiation and subsequent activation, which is critical in IBD pathogenesis. In vivo experiments using a non-natural artificial microRNA sequence revealed that targeting of DCs in the inflamed colon is an exceptional feature of sCA. This study suggests that sCA-miR-29s may open a new avenue in nucleic acid-based medicine for IBD treatment. Keywords: microRNA-29a, microRNA-29b, DSS colitis, supercarbonate apatite, dendritic cells

Objectives: The aim of this study was to evaluate the feasibility of a protocol for enhanced recovery after surgery (ERAS) for colon cancer in older patients. Methods: One hundred and fifty-nine patients enrolled in the ERAS group of our previous clinical study were divided according to age into an older group (n = 31; ≥80 years old) and a younger group (n = 128;

Summary: Gut epithelial organoids are routinely used to investigate intestinal biology; however, current culture methods are not amenable to genetic manipulation, and it is difficult to generate sufficient numbers for high-throughput studies. Here, we present an improved culture system of human induced pluripotent stem cell (iPSC)-derived intestinal organoids involving four methodological advances. (1) We adopted a lentiviral vector to readily establish and optimize conditioned medium for human intestinal organoid culture. (2) We obtained intestinal organoids from human iPSCs more efficiently by supplementing WNT3A and fibroblast growth factor 2 to induce differentiation into definitive endoderm. (3) Using 2D culture, followed by re-establishment of organoids, we achieved an efficient transduction of exogenous genes in organoids. (4) We investigated suspension organoid culture without scaffolds for easier harvesting and assays. These techniques enable us to develop, maintain, and expand intestinal organoids readily and quickly at low cost, facilitating high-throughput screening of pathogenic factors and candidate treatments for gastrointestinal diseases.

Abstract Multiphoton excitation microscopy (MPM) is regarded as an effective tool that enables the visualization of deep regions within living tissues and organs, with little damage. Here, we report novel non-labeling MPM (NL-MPM) imaging of fresh human colorectal mucosa, which is useful for discriminating cancer lesions from normal tissues quantitatively without any need for resection, fixation, or staining. Using NL-MPM, we visualized three components in human colorectal mucosa, epithelial cells, immune cells, and basement membranes, based on their characteristic patterns of fluorescence. These patterns are characterized by the different auto-fluorescence properties of nicotinamide adenine dinucleotide, nicotinamide adenine dinucleotide phosphate, and flavin adenine dinucleotide and from second harmonic generation (SHG). NL-MPM images were at least as informative to pathologists as were ‘conventional’ images of fixed tissue sections stained with hematoxylin and eosin. Additionally, two quantitative parameters extracted from NL-MPM images – the nucleus diameter (index N) and the intensity of SHG in the basement membrane (index S) – rendered it possible to diagnose cancer regions effectively. In conclusion, NL-MPM is a novel, promising method for real-time clinical diagnosis of colorectal cancers, and is associated with minimal invasiveness.

Objectives: The aim of this phase I study is to identify the maximum tolerated dose (MTD) and recommended dose (RD) of CPT-11 in combination with UFT/LV and radiation in patients with locally recurrent rectal cancer. Methods: Patients with histologically proven rectal cancer with local recurrence were eligible for this study. Escalating doses of CPT-11 (30-60 mg/m2) were administered on days 3, 10, 24, and 31. UFT (300 mg/m2) and LV (75 mg/body) were given on days 1-5, 8-12, 22-26, and 29-33. Radiotherapy doses consisted of 50 Gy in daily fractions of 2.0 Gy each, 5 times per week, for total 5 weeks. Results: We recruited 27 patients, and the MTD of CPT-11 was 60 mg/m2 due to the occurrence of dose-limiting toxicity of grade 3 diarrhea. Major grade 3 adverse events were neutropenia (5/27; 18.5%) and diarrhea (6/27; 22.2%). No grade 4 adverse event was observed throughout this treatment. Conclusions: The combined chemoradiotherapy with oral UFT/LV plus CPT-11 is feasible and promising. The recommended dose for further phase II trials is determined to be 50 mg/m2 of CPT-11.