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Abstract The 1997/1998 El Niño event caused mass coral bleaching and mortality in many tropical and subtropical regions, including corals on Green Island, Taiwan, in the northwestern Pacific Ocean. This study analyzed coral carbon isotope ratios (δ13C), oxygen isotope ratios (δ18O), and Sr/Ca ratios for 29 years, including the 1997/1998 El Niño period, to examine how high water temperature events are recorded in coral geochemical indicators. Sr/Ca ratios in coral skeletons from Green Island show the lowest peak, means the highest temperature during the 1997/1998 El Niño period. However, we couldn’t observe high-temperature events on δ18O. Furthermore, a negative δ13C shift was observed after El Niño events. The regime shift of δ13C might have been caused by temporal bleaching and/or a decrease in symbiotic algae due to high water temperature stress under the continuous decrease in δ13C in DIC due to the Suess effect.

Abstract Background Laparoscopic rectopexy is an established treatment option for full-thickness rectal prolapse. Recently, reduced port surgery (RPS) has emerged as a novel concept, offering reduced postoperative pain and improved cosmetic outcomes compared with conventional multiport surgery (MPS). This study aimed to evaluate the feasibility and safety of RPS for full-thickness rectal prolapse. Methods From October 2012 to December 2018, 37 patients (MPS: 10 cases, RPS: 27 cases) underwent laparoscopic rectopexy for full-thickness rectal prolapse. Laparoscopic posterior mesh rectopexy (Wells procedure) is the standard technique for full-thickness rectal prolapse at our hospital. RPS was performed using a multi-channel access device, with an additional 12-mm right-hand port. Short-term outcomes were retrospectively compared between MPS and RPS. Results No significant differences were observed between MPS and RPS in the median operative time, the median blood loss volume, the postoperative complication rates, and median hospital stay duration after surgery. Conclusion Reduced port laparoscopic posterior mesh rectopexy may serve as an effective therapeutic option for full-thickness rectal prolapse. However, to establish the superiority of RPS over MPS, a prospective, randomized, controlled trial is warranted.

Background: The survival benefit of adjuvant chemotherapy after surgical resection of oligometastases from colorectal cancer (CRC) remains unclear. The prognostic role of circulating-tumor DNA (ctDNA) was reported recently and a risk stratification strategy based on monitoring minimal/molecular residual disease (MRD) has been proposed, however, which drug regimen is most effective for ctDNA-positive patients is unknown. Methods/Design: Oligometastatic CRC patients planning to undergo surgery were registered in this study. After metastasectomy, the registered patients were enrolled in the treatment arm, in which 8 courses of modified-FOLFOXIRI (mFOLFOXIRI; irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, l-leucovorin (l-LV) 200 mg/m2, and 46-h continuous infusion of 5-fluorouracil (5-FU) 2400 mg/m2 every 2 weeks) followed by 4 courses of 5-FU/l-LV are administered. The patients who did not meet the eligibility criteria for the treatment arm or did not consent to mFOLFOXIRI enrolled in the observation arm in which standard of care treatment is provided. Prospective blood collections for retrospective ctDNA analysis are scheduled pre-surgery, and at 28 days, 4 and 7 months after surgery. The primary endpoint is treatment compliance at 8 courses of mFOLFOXIRI and the key secondary endpoints are the ctDNA-positivity rate and survival outcomes in ctDNA-positive and -negative groups. A total of 85 patients will be enrolled from 11 institutions. First patient-in was on July 2020. Accrual completed in February 2024. Discussion: This study will potentially identify a better treatment strategy for patients with resectable oligometastatic CRC having postsurgical ctDNA positivity, compared to the current standard of care approaches.

Background: Spatial and temporal heterogeneities of RAS and other molecular genes should be considered in the treatment of metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs); acquired RAS mutation is sometimes observed at disease progression of treatment with the anti-EGFR mAb. At the same time, discrepancy of RAS status from tissues and circulating tumor DNA (ctDNA) in the same patient is sometimes observed. Based on this, we commenced two observational studies to clarify these heterogeneities of RAS and BRAF in mCRC, using next generation sequencing from liquid biopsy. Methods/Design: RAS-trace study is an observational study to monitor ctDNA RAS/BRAF/PIK3CA status every 4-12 weeks using the Plasma-SeqSensei™ CRC RUO Kit (Sysmex Inostics GmbH) in mCRC with RAS/BRAF wild-type (wt) on tumor tissue. The primary endpoint was the time to the acquired RAS mutations. A total of 42 patients has been accrued. RAS-trace-2 study is also an observational study aimed at comparing the efficacy of the anti-EGFR mAb in ctDNA RAS/BRAF wt with ctDNA RAS or BRAF mutant mCRC patients, whose RAS/BRAF are wt in tumor tissue. The primary endpoint was progression-free survival in patients with ctDNA RAS/BRAF wt and RAS or BRAF mutant. A total of 240 patients will be accrued over 2 years. Discussion: These trials will help us understanding the clinical significance of spatial and temporal heterogeneities of RAS, BRAF and other genes, while optimizing the anti-EGFR mAb treatment strategies in mCRC.

Introduction: Laparoscopic surgery (LAP) is now recognized as the standard procedure for colorectal surgery. However, the standard surgery for ulcerative colitis (UC) is total proctocolectomy with ileal pouch anal anastomosis (IPAA), which may be an overly complex procedure to complete laparoscopically. We conducted this systematic review and meta-analysis to evaluate the efficacy as well as the advantages and disadvantages of LAP-IPAA in patients with UC stratified by the outcome of interest. Method: We performed a systematic literature review by searching the PubMed/MEDLINE, the Cochrane Library, and the Japan Centra Reuvo Medicina databases from inception until January 2023. Meta-analyses were performed for surgical outcomes, including morbidity and surgical course, to evaluate the efficacy of LAP-IPAA. Results: A total of 707 participants, including 341 LAP and 366 open surgery (OPEN) patients in 9 observational studies and one randomized controlled study, were included. From the results of the meta-analyses, the odds ratio (OR) of total complications in LAP was 1.12 (95% CI: 0.58–2.17, p = 0.74). The OR of mortality for LAP was 0.38 (95% CI: 0.08–1.92, p = 0.24). Although the duration of surgery was extended in LAP (mean difference (MD) 118.74 min (95% CI: 91.67–145.81), p < 0.01) and hospital stay were not shortened, the duration until oral intake after surgery was shortened in LAP (MD −2.10 days (95% CI: −3.52–0.68), p = 0.004). Conclusions: During IPAA for UC, a similar morbidity rate was seen for LAP and OPEN. Although LAP necessitates extended surgery, there may be certain advantages to this procedure, including easy visibility during the surgical procedure or a shortened time to oral intake after surgery.

Abstract Purpose The aim of this study was to compare the clinical characteristics of ulcerative colitis (UC) patients who underwent surgery for cancer/dysplasia with those who underwent surgery for refractory disease and to discuss the preoperative preparation for successful hand-sewn IPAA. Methods Patients who underwent surgery for UC between January 2014 and December 2021 at Hyogo Medical University were included in the study. A total of 443 UC surgical cases were included in the study, which comprised 188 cancer/dysplasia patients and 255 refractory patients. Clinical records were compared retrospectively. Results The proportion of surgical UC cases with cancer/dysplasia has been on the rise, accounting for approximately 40% in recent years. The duration of disease (months) was 186 (2–590) in the cancer/dysplasia group and 48 (1–580) in the refractory group (p = 0.02). UC severity (mild/moderate/severe) was 119/69/0 in the cancer/dysplasia group and 18/157/80 in the refractory group (p

Objectives: Anatomical understanding of the internal iliac vessels is important with the increasing frequency of minimally-invasive pelvic surgery. We aimed to investigate the branch patterns of internal iliac vessels, especially the veins. Methods: This study included 30 patients with 60 half-pelvises who underwent minimally-invasive pelvic surgery. Branch patterns were assessed on surgical videos with a multi-detector computed tomography-based three-dimensional simulation. Branch patterns of the superior gluteal artery and vein (SGA and SGV), inferior gluteal artery and vein (IGA and IGV), internal pudendal artery and vein (IPA and IPV), and obturator artery and vein (ObA and ObV) were investigated. Results: In the most frequent internal iliac vein (IIV) branch pattern, 67% of SGV branched from the IIV, 95% of the IGV branched from the IPV and 82% of the ObV branched from the IPV. According to Adachi's classification, 62% of IIVs were Type I and 33% Type IV. Although IIV branch patterns are heterogeneous, in individual patients with the most frequent branch patterns, good correlation (75-100%) of the branch patterns was observed between the internal iliac artery (IIA) and IIV, and between the right and left IIVs. Conclusions: This study clarified the branch patterns of IIV. In patients with the most frequent branch patterns, good correlation of the branch patterns was observed between the IIA and IIV, and between right and left IIV. We believe this helps secure the safety and standardization of minimally-invasive pelvic surgery.

Background Ferroptosis, an iron‐dependent form of regulated cell death, is a major cell death mode in myocardial ischemia reperfusion (I/R) injury, along with mitochondrial permeability transition‐driven necrosis, which is inhibited by cyclosporine A (CsA). However, therapeutics targeting ferroptosis during myocardial I/R injury have not yet been developed. Hence, we aimed to investigate the therapeutic efficacy of deferasirox, an iron chelator, against hypoxia/reoxygenation‐induced ferroptosis in cultured cardiomyocytes and myocardial I/R injury. Methods and Results The effects of deferasirox on hypoxia/reoxygenation‐induced iron overload in the endoplasmic reticulum, lipid peroxidation, and ferroptosis were examined in cultured cardiomyocytes. In a mouse model of I/R injury, the infarct size and adverse cardiac remodeling were examined after treatment with deferasirox, CsA, or both in combination. Deferasirox suppressed hypoxia‐ or hypoxia/reoxygenation‐induced iron overload in the endoplasmic reticulum, lipid peroxidation, and ferroptosis in cultured cardiomyocytes. Deferasirox treatment reduced iron levels in the endoplasmic reticulum and prevented increases in lipid peroxidation and ferroptosis in the I/R‐injured myocardium 24 hours after I/R. Deferasirox and CsA independently reduced the infarct size after I/R injury to a similar degree, and combination therapy with deferasirox and CsA synergistically reduced the infarct size (infarct area/area at risk; control treatment: 64±2%; deferasirox treatment: 48±3%; CsA treatment: 48±4%; deferasirox+CsA treatment: 37±3%), thereby ameliorating adverse cardiac remodeling on day 14 after I/R. Conclusions Combination therapy with deferasirox and CsA may be a clinically feasible and effective therapeutic approach for limiting I/R injury and ameliorating adverse cardiac remodeling after myocardial infarction.

Despite preoperative chemoradiotherapy (CRT) and total mesorectal excision improving the local control for locally advanced rectal cancer (LARC), oncologic outcomes and survival were not significantly improved because the main prognostic factor is distant metastasis. Thus, total neoadjuvant chemotherapy (TNT) as a novel approach has been proposed to improve chemotolerance. Since the first randomized phase II trial of TNT versus standard CRT demonstrated in 2012, many prospective and retrospective studies have been published. The initial consensus from TNT studies was that pathological complete response, pathological response of the main tumor, and local control are more favorable at TNT than at CRT. Furthermore, recent studies such as the PAPIDO trial and PRODIGE 23 trial made a major breakthrough of the treatment of TNT, showing that TNT improves the disease-free survival compared to standard treatment with long-course CRT. In addition, several innovative findings of TNT were clarified by prospective phase II trial. In this review, we summarize the most recent advances in TNT based on the findings of pivotal clinical trials for patients with LARC.

Abstract Aim In Japan, we have not been able to validate the results of laparoscopic surgery for locally advanced rectal cancer using the universal index “circumferential resection margin (CRM).” Previously, we established a semi‐opened circular specimen processing method and validated its feasibility. In the PRODUCT trial, we aimed to assess CRM in patients with locally advanced rectal cancer who underwent laparoscopic rectal resection. Methods This was a multicenter, prospective, observational study. Eligible patients had histologically confirmed rectal adenocarcinoma located at or below 12 cm above the anal verge with clinical stage II or III and were scheduled for laparoscopic or robotic surgery. The primary endpoint was pathological CRM. CRM ≤1 mm was defined as positive. Results A total of 303 patients operated on between August 2018 and January 2020 were included in the primary analysis. The number of patients with clinical stage II and III was 139 and 164, respectively. Upfront surgery was performed for 213 patients and neoadjuvant therapy for 90 patients. The median CRM was 4.0 mm (IQR, 2.1‐8.0 mm), and CRM was positive in 26 cases (8.6%). Univariate and multivariate analyses demonstrated that a predicted CRM from the mesorectal fascia of ≤1 mm on MRI was the significant factor for positive CRM (P = .0012 and P = .0045, respectively). Conclusion This study showed the quality of laparoscopic rectal resection based on the CRM in Japan. Preoperative MRI is recommended for locally advanced rectal cancer to prevent CRM positivity.

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

Oxidative stress is hypothesized to drive the progression of age-related macular degeneration (AMD). Retinal pigment epithelial (RPE) cell layer is important for supporting the function of retina and is particularly susceptible to oxidative stress-induced cell death. How RPE cells die in AMD, especially in geographic atrophy (GA), a late stage of dry AMD, is still controversial. The goal of this study is to compare the features and mechanisms of RPE cell death induced by different oxidative stresses, to identify potential universal therapeutic targets for GA. RPE cell death was induced both in vitro and ex vivo by 4-Hydroxynonenal (4-HNE), a major product of lipid peroxidation, sodium iodate (NaIO3) that has been widely used to model RPE cell death in dry AMD, a ferroptosis inducer RAS-selective lethal 3 (RSL3) or a necroptosis inducer shikonin. We found that RPE necroptosis and ferroptosis show common and distinct features. Common features include receptor-interacting protein kinase (RIPK)1/RIPK3 activation and lipid reactive oxygen species (ROS) accumulation, although lipid ROS accumulation is much milder during necroptosis. This supports cross talk between RPE ferroptosis and necroptosis pathways and is consistent with the rescue of RPE necroptosis and ferroptosis by RIPK1 inhibitor Necrostatin-1 (Nec-1) or in Ripk3−/− RPE explants. Distinct feature includes activated mixed lineage kinase domain like pseudokinase (MLKL) that is translocated to the cell membrane during necroptosis, which is not happening in ferroptosis. This is consistent with the failure to rescue RPE ferroptosis by MLKL inhibitor necrosulfonamide (NSA) or in Mlkl−/− RPE explants. Using this framework, we found that 4-HNE and NaIO3 induced RPE cell death likely through necroptosis based on the molecular features and the rescuing effect by multiple inhibitors. Our studies suggest that multiple markers and inhibitors are required to distinguish RPE necroptosis and ferroptosis, and that necroptosis inhibitor Nec-1 could be a potential therapeutic compound for GA since it inhibits RIPK1/RIPK3 activation and lipid ROS accumulation occurred in both necroptosis and ferroptosis pathways.

Abstract In ferroptosis, the roles of mitochondria have been controversial. To explore the role of mitochondrial events in ferroptosis, we employed mitochondrial DNA-depleted ρ0 cells that are resistant to cell death due to enhanced expression of antioxidant enzymes. Expression of mitochondrial-type GPx4 (mGPx4) but no other forms of GPx4 was increased in SK-Hep1 ρ0 cells. Likely due to high mGPx4 expression, SK-Hep1 ρ0 cells were resistant to ferroptosis by erastin inhibiting xCT channel. In contrast, SK-Hep1 ρ0 cells were susceptible to cell death by a high concentration of RSL3 imposing ferroptosis by GPx4 inhibition. Accumulation of cellular ROS and oxidized lipids was observed in erastin- or RSL3-treated SK-Hep1 ρ+ cells but not in erastin-treated SK-Hep1 ρ0 cells. Mitochondrial ROS and mitochondrial peroxidized lipids accumulated in SK-Hep1 ρ+ cells not only by RSL3 but also by erastin acting on xCT on the plasma membrane. Mitochondrial ROS quenching inhibited SK-Hep1 ρ+ cell death by erastin or a high dose of RSL3, suggesting a critical role of mitochondrial ROS in ferroptosis. Ferroptosis by erastin or RSL3 was inhibited by a more than 20-fold lower concentration of MitoQ, a mitochondrial ROS quencher, compared to DecylQ, a non-targeting counterpart. Ferroptosis of SK-Hep1 ρ+ cells by erastin or RSL3 was markedly inhibited by a VDAC inhibitor, accompanied by significantly reduced accumulation of mitochondria ROS, total peroxidized lipids, and mitochondrial peroxidized lipids, strongly supporting the role of mitochondrial events in ferroptotic death and that of VDAC in mitochondrial steps of ferroptosis induced by erastin or RSL3. SK-Hep1 ρ+ cell ferroptosis by sorafenib was also suppressed by mitochondrial ROS quenchers, accompanied by abrogation of sorafenib-induced mitochondrial ROS and mitochondrial peroxidized lipid accumulation. These results suggest that SK-Hep1 ρ0 cells are resistant to ferroptosis due to upregulation of mGPx4 expression and mitochondrial events could be the ultimate step in determining final cell fate.

Abstract Aim Adhesive small bowel obstructions (SBO) are one of the most common complications following abdominal surgery, and they decrease patient quality of life. Since 2000, laparoscopic surgery has been employed with increasing frequency, as has adhesion prevention material (APM). In this study we tried to evaluate whether laparoscopic surgery and APM reduce the incidence of SBO. Methods In Cohort 1, we included patients who developed SBO and received inpatient treatment between 2015 and 2018. We evaluated the elapsed time between precedent surgery and the onset of SBO, and what kind of surgery most often causes SBO. In Cohort 2, we included patients who underwent digestive surgery between 2012 and 2014 and evaluated SBO incidence within 5 y after the precedent surgery. Results In all, 2058 patients were included in Cohort 1. Of these, 164 had experienced no precedent surgery. Among patients with a history of abdominal surgery, 29.7% experienced SBO within 1 y after the precedent surgery and 48.1% within 3 y. Altogether, 18798 patients were analyzed in Cohort 2. The incidence of SBO after laparoscopic colorectal surgery was lower than that of open colorectal surgery (P < .001), and laparoscopic gastroduodenal surgery was also lower (P = .02). However, there were no differences between laparoscopic and open surgery for other types of surgery. The use of APM had no effect on SBO incidence in any type of abdominal surgery. Conclusions Laparoscopic surgery helps to reduce SBO incidence only in colorectal surgery, and possibly in gastroduodenal surgery. APM does not reduce SBO after abdominal surgery.

Abstract Aims Cardiac rehabilitation (CR) is an evidence‐based, secondary preventive strategy that improves mortality and morbidity rates in patients with heart failure (HF). However, the implementation and continuation of CR remains unsatisfactory, particularly for outpatients with physical frailty. This study investigated the efficacy and safety of a comprehensive home‐based cardiac rehabilitation (HBCR) programme that combines patient education, exercise guidance, and nutritional guidance using information and communication technology (ICT). Methods and results This study was a single‐centre, open‐label, randomized, controlled trial. Between April 2020 and November 2020, 30 outpatients with chronic HF (New York Heart Association II–III) and physical frailty were enrolled. The control group (n = 15) continued with standard care, while the HBCR group (n = 15) also received comprehensive, individualized CR, including ICT‐based exercise and nutrition guidance using ICT via a Fitbit® device for 3 months. The CR team communicated with each patient in HBCR group once a week via the application messaging tool and planned the training frequency and intensity of training individually for the next week according to each patient's symptoms and recorded pulse data during exercise. Dietitians conducted a nutritional assessment and then provided individual nutritional advice using the picture‐posting function of the application. The primary outcome was the change in the 6 min walking distance (6MWD). The participants' mean age was 63.7 ± 10.1 years, 53% were male, and 87% had non‐ischaemic heart disease. The observed change in the 6MWD was significantly greater in the HBCR group (52.1 ± 43.9 m vs. −4.3 ± 38.8 m; P

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.

Abstract Background In Japan, Crohn’s disease (CD)-related cancers occur most frequently in the anal canal. Many patients with advanced CD-related cancer require total pelvic exenteration (TPE) based on their medical history, and choosing the most effective method for urinary diversion is a major concern. We herein report the first case of CD-related cancer treatment with urinary diversion using a gastric conduit after TPE in Japan. Case presentation A 51-year-old man with a 25 year history of CD was referred to our institution after having been diagnosed with fistulae between the rectum and urethra. Sigmoidoscopy revealed stenosis of the anal canal, and histological examination of this lesion led to a diagnosis of mucinous adenocarcinoma. Magnetic resonance imaging showed that the tumor had invaded the prostate and left internal obturator muscle, and TPE with left internal obturator muscle resection was planned. Urinary diversion was performed with a gastric conduit. The gastric conduit was created by trimming a gastric tube to a 1.5 cm width via stapled resection of the greater curvature, and the branches of the right gastroepiploic artery were preserved as feeding vessels. The ureters were raised from the mesentery on the right side of the ligament of Treitz. Ureterogastric anastomosis was performed using the Wallace technique, and the entire anastomosis was then retroperitonealized. The anastomotic site had a bleeding tendency, but hemostasis was obtained by proton pump inhibitor administration and discontinuation of enoxaparin, which had been administered to prevent venous thrombosis. No other major complications occurred, and the patient’s quality of life was recovered 6 months after surgery. Conclusion Urinary diversion using a gastric conduit is a feasible treatment option for patients with CD-related anorectal cancer requiring TPE.

Abstract Background The efficacy of adjuvant chemotherapy for high-risk stage II colon cancer (CC) has not been well established. We compared the effects of surgery with and without oral uracil and tegafur plus leucovorin (UFT/LV) in patients with high-risk stage II CC, adjusting for potential risk factors. Methods We enrolled patients with histologically confirmed stage II colon adenocarcinoma with at least one of the following conditions: T4 disease, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, or

Abstract Background Previously, we conducted a randomized controlled trial (JCOG0404) for stage II/III colon cancer patients and reported that the long‐term survival after open surgery (OP) and laparoscopic surgery (LAP) were almost identical; however, JCOG0404 suggested that survival of patients after LAP with tumors located in the rectosigmoid colon, cT4 or cN2 tumors, and high body mass index (BMI) might be unfavorable. Aim To identify the patient subgroups associated with poor long‐term survival in the LAP arm compared with the OP arm. Methods Patients aged 20–75, clinical T3 or deeper lesion without involvement of other organs, clinical N0‐2 and M0 were included. The patients with pathological stage IV and R2 resection were excluded from the current analysis. In each subgroup, the hazard ratio for LAP (vs. OP) in overall survival (OS) from surgery was estimated using a multivariable Cox regression model adjusted for the clinical and pathological factors. Results In total, 1025 patients (OP, 511 and LAP, 514) were included in the current analysis. Adjusted hazards ratios for OS of patients with high BMI (>25 kg/m2), pT4, and pN2 in LAP were 3.37 (95% confidence interval [CI], 1.24–9.19), 1.33 (0.73–2.41), and 1.74 (0.76–3.97), respectively. In contrast, that of rectosigmoid colon tumors was 0.98 (0.46–2.09). Conclusions Although LAP is an acceptable optional treatment for stage II/III colon cancer, the present subgroup analysis suggests that high BMI (>25 kg/m2), pT4, and pN2 except for RS were factors associated with unfavorable long‐term outcomes of LAP in patients with colon cancer who underwent curative resection. (JCOG 0404: NCT00147134/UMIN‐CTR: C000000105.)

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.

Objectives: The appropriate and recommended delivery mode after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC) has not been sufficiently evaluated. This study was designed to compare the delivery outcomes associated with cesarean section (CS) and vaginal delivery (VD) after IPAA. Methods: We conducted a questionnaire-based survey of female patients who underwent IPAA for UC between July 1987 and May 2018. Additionally, we reviewed clinical data and collected information regarding pouch function and postpartum complications. Results: In total, 45 patients had 68 deliveries, including 64 CS deliveries and four VDs. Fecal incontinence worsened in seven patients, including six CS patients and one VD patient. The Wexner scores of these patients before and after delivery were 5.4 ± 0.4 and 14.8 ± 1.0, respectively (p = 0.005). Four patients in the CS group and one in the VD group (p = 0.32) had increased stool frequency. Bowel obstructions developed during 11/64 (17.2%) deliveries, and one patient required surgical intervention. One patient with four VDs (three before IPAA and one after IPAA) developed vaginal fistula 5 months after the final VD. Information on episiotomies could not be obtained. Conclusions: Pouch function can decline even after CS. Notably, bowel obstruction can develop after CS. However, we cannot recommend a particular delivery method after IPAA. Further analyses to elucidate the relationship between CS and postoperative complications or vaginal fistula and episiotomy in VDs should be conducted.

Objectives: Few reports are available on post-colectomy enteritis (PCE) with ulcerative colitis (UC), which can be severe and sometimes fatal. The clinical characteristics are unclear, and treatment and diagnosis protocols have not been established. We aimed to investigate the incidence, clinical characteristics, diagnostic criteria, and therapeutic outcomes of PCE in this study. Methods: Patients with UC who underwent colectomy between April 2010 and December 2019 were included in this study. We retrospectively analyzed patients who developed PCE and excluded patients with other forms of enteritis. Results: We performed 829 colectomies because of a preoperative diagnosis of UC. Eleven and four patients were diagnosed with Crohn's disease and indeterminate colitis after surgery, respectively; 22 patients developed enteritis in the perioperative period. We excluded six patients with backwash ileitis, five with prepouch ileitis, three with infectious enteritis, and one with ischemic enteritis. In total, 7/814 (0.8%) patients developed PCE. All patients with PCE had pancolitis. PCE was observed a median of 33 (12-248) days after surgery. Endoscopy showed friable and granular mucosa. The extent of disease included various types such as pan-enteritis with diffuse type, pan-enteritis and mild inflammation in the middle ileum, and only ileitis. Gastroduodenitis-associated UC developed in 6/7 cases. All patients improved with tumor necrosis factor alpha (TNFα) antagonists even if TNFα antagonists had not been effective for colitis. Conclusions: PCE was rare. The mucosal endoscopic findings were similar to those of UC, and the extent of disease varied. TNFα antagonist administration for PCE was effective.

Abstract Aims Individual risk stratification is a fundamental strategy in managing patients with heart failure (HF). Artificial intelligence, particularly machine learning (ML), can develop superior models for predicting the prognosis of HF patients, and administrative claim data (ACD) are suitable for ML analysis because ACD is a structured database. The objective of this study was to analyse ACD using an ML algorithm, predict the 1 year mortality of patients with HF, and finally develop an easy‐to‐use prediction model with high accuracy using the top predictors identified by the ML algorithm. Methods and results Machine learning‐based prognostic prediction models were developed from the ACD on 10 175 HF patients from the Japanese Registry of Acute Decompensated Heart Failure with 17% mortality during 1 year follow‐up. The top predictors for prognosis in HF were identified by the permutation feature importance technique, and an easy‐to‐use prediction model was developed based on these predictors. The c‐statistics and Brier scores of the developed ML‐based models were compared with those of conventional risk models: Seattle Heart Failure Model (SHFM) and Meta‐Analysis Global Group in Chronic Heart Failure (MAGGIC). A voting classifier algorithm (ACD‐VC) achieved the highest c‐statistics among the six ML algorithms. The permutation feature importance technique enabled identification of the top predictors such as Barthel index, age, body mass index, duration of hospitalization, last hospitalization, renal disease, and non‐loop diuretics use (feature importance values were 0.054, 0.025, 0.010, 0.005, 0.005, 0.004, and 0.004, respectively). Upon combination of some of the predictors that can be assessed from a brief interview, the Simple Model by ARTificial intelligence for HF risk stratification (SMART‐HF) was established as an easy‐to‐use prediction model. Compared with the conventional models, SMART‐HF achieved a higher c‐statistic {ACD‐VC: 0.777 [95% confidence interval (CI) 0.751–0.803], SMART‐HF: 0.765 [95% CI 0.739–0.791], SHFM: 0.713 [95% CI 0.684–0.742], MAGGIC: 0.726 [95% CI 0.698–0.753]} and better Brier scores (ACD‐VC: 0.121, SMART‐HF: 0.124, SHFM: 0.139, MAGGIC: 0.130). Conclusions The ML model based on ACD predicted the 1 year mortality of HF patients with high accuracy, and SMART‐HF along with the ML model achieved superior performance to that of the conventional risk models. The SMART‐HF model has the clear merit of easy operability even by non‐healthcare providers with a user‐friendly online interface (https://hfriskcalculator.herokuapp.com/). Risk models developed using SMART‐HF may provide a novel modality for risk stratification of patients with HF.

Summary: The occurrence of diet-induced obesity has been increasing worldwide and has become a major health concern. Mitochondria are densely distributed in brown adipose tissue and are involved in lipid consumption. Therefore, increasing energy expenditure through the activation of brown adipocytes may be a potential therapy for obesity. Our findings showed that mitochondrial transcription factor A (TFAM) homozygous transgenic (TgTg) mice had highly activated brown adipocytes and increased expression of oxidative phosphorylation, leading to resistance to obesity. Transplantation models of TFAM-expressing brown adipocytes could mimic the phenotype of TFAM TgTg mice, and proving their anti-obesity effect. We found that brown adipocytes secrete exosomes which enable self-activation in an autocrine and paracrine manner. The secretion was enhanced in TFAM TgTg brown adipocytes, resulting in a higher activation. These findings may lead to a promising treatment strategy for obesity through selective stimulation of exosome secretion.

Treatment-related neuroendocrine-differentiated prostate cancer (NEPC) is a rare tumor entity that transdifferentiates from adenocarcinoma as an adaptive response to androgen receptor pathway inhibition. We report a 79-year-old male with treatment-related NEPC, presenting as rectal bleeding after hormonal therapy. MRI showed a 51 × 52 × 65 mm tumor occupying almost the whole prostate gland and invading the seminal vesicle and rectum as moderately heterogeneous hypointensity on T2-weighted image, restricted diffusion on apparent diffusion coefficient map and diffusion-weighted imaging, and heterogeneous enhancement on Gd-enhanced T1-weighted image. FDG-PET/CT showed strong FDG uptake of the prostate tumor, and somatostatin receptor scintigraphy (SRS) showed mild uptake of the prostate tumor. The surgically resected specimen revealed NEPC. If prostate cancer worsens despite conventional therapy, treatment-related NEPC should be considered, and the benefit of imaging examinations including prostate MRI, FDG-PET/CT, and SRS is in localizing lesions with neuroendocrine differentiation.

Abstract Background Crohn’s disease (CD) recurrence can occur not only at the site of anastomosis but also elsewhere in the bowel following an ileocolic resection (ICR) procedure. The aims of the present study were to assess long-term outcomes of a primary ICR procedure for CD in consecutive patients and examine the location of the reoperation causative lesion. Methods We examined cases of surgery with ICR initially performed at our institution. Those with simultaneous multiple bowel resection or bowel resection with strictureplasty were excluded. Results A total of 169 patients who underwent ICR due to CD were enrolled. The median follow-up period was 12.6 years (range 4–27 years). A reoperation was needed in 45 (26.6%), of whom 14 had lesions causative of the reoperation at other than the anastomotic site. The most common causative lesion location was in the colon rather than the oral side of the small intestine. Furthermore, we investigated the relationship between presence of residual lesions following the initial surgery and lesions causative of reoperation. In the group without residual disease (n = 31), 29.0% (n = 9) had non-anastomotic lesions involved in indications for reoperation, while that was 35.7% (n = 5) in the group with residual disease (n = 14). Conclusions Anastomotic site lesion is not the only causative factor for reoperation following ICR. Regular examinations and applicable treatment with awareness that the cause of reoperation is not limited to the site of anastomosis are important in these cases.

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.

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

Summary: Molecular mechanisms mediating cardiac hypertrophy by glucose metabolism are incompletely understood. Hexosamine biosynthesis pathway (HBP), an accessory pathway of glycolysis, is known to be involved in the attachment of O-linked N-acetylglucosamine motif (O-GlcNAcylation) to proteins, a post-translational modification. We here demonstrate that glutamine-fructose-6-phosphate amidotransferase 2 (GFAT2), a critical HBP enzyme, is a major isoform of GFAT in the heart and is increased in response to several hypertrophic stimuli, including isoproterenol (ISO). Knockdown of GFAT2 suppresses ISO-induced cardiomyocyte hypertrophy, accompanied by suppression of Akt O-GlcNAcylation and activation. Knockdown of GFAT2 does not affect anti-hypertrophic effect by Akt inhibition. Administration of glucosamine, a substrate of HBP, induces protein O-GlcNAcylation, Akt activation, and cardiomyocyte hypertrophy. In mice, 6-diazo-5-oxo-L-norleucine, an inhibitor of GFAT, attenuates ISO-induced protein O-GlcNAcylation, Akt activation, and cardiac hypertrophy. Our results demonstrate that GFAT2 mediates cardiomyocyte hypertrophy by HBP-O-GlcNAcylation-Akt pathway and could be a critical therapeutic target of cardiac hypertrophy.

Background Apoptosis plays a pivotal role in cardiac rupture after myocardial infarction (MI), and p53 is a key molecule in apoptosis during cardiac rupture. Hif‐1α (hypoxia‐inducible factor‐1α), upregulated under hypoxia, is a known p53 inducer. However, the role of Hif‐1α in the regulatory mechanisms underlying p53 upregulation, apoptosis, and cardiac rupture after MI is unclear. Methods and Results We induced MI in mice by ligating the left anterior descending artery. Hif‐1α and p53 expressions were upregulated in the border zone at day 5 after MI, accompanied by apoptosis. In rat neonatal cardiomyocytes, treatment with cobalt chloride (500 μmol/L), which mimics severe hypoxia by inhibiting PHD (prolyl hydroxylase domain‐containing protein), increased Hif‐1α and p53, accompanied by myocyte death with caspase‐3 cleavage. Silencing Hif‐1α or p53 inhibited caspase‐3 cleavage, and completely prevented myocyte death under PHD inhibition. In cardiac‐specific Hif‐1α hetero‐knockout mice, expression of p53 and cleavage of caspase‐3 and poly (ADP‐ribose) polymerase were reduced, and apoptosis was suppressed on day 5. Furthermore, the cleavage of caspase‐8 and IL‐1β (interleukin‐1β) was also suppressed in hetero knockout mice, accompanied by reduced macrophage infiltration and matrix metalloproteinase/tissue inhibitor of metalloproteinase activation. Although there was no intergroup difference in infarct size, the cardiac rupture and survival rates were significantly improved in the hetero knockout mice until day 10 after MI. Conclusions Hif‐1α plays a pivotal role in apoptosis, inflammation, and cardiac rupture after MI, in which p53 is a critical mediator, and may be a prospective therapeutic target for preventing cardiac rupture.

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 Aim To investigate the frequency and risk factors of perioperative, symptomatic venous thromboembolism (VTE) after gastroenterological surgery. Methods We assessed the frequency of and risk factors for VTE after eight gastroenterological procedures (total 516 217 cases including, gastrectomy, total gastrectomy, hepatectomy, esophagectomy, right hemicolectomy, low anterior resection, pancreaticoduodenectomy, and acute pan‐peritonitis surgery) based on data from the National Clinical Database. Data collected between 2011 and 2013 (382 124 cases) were used as a test set, and data from 2014 (134 093 cases) were used as a validation set. Results The frequency of deep vein thrombosis (DVT) was 0.3% (382 124 cases), and the incidence of pulmonary embolism (PE) was 0.2% (382 124 cases) ranging from 0.1% to 0.7% for DVT and from 0.1% and 0.3% for PE among eight surgeries, respectively. Analyses using pre‐and intra‐operative factors identified the top three risk factors for VTE as esophagectomy, pancreaticoduodenectomy, and hepatectomy. Using pre‐, intra‐, and postoperative factors, the second through fourth risk factors were sepsis, prolonged ventilation >48 hours and readmission within 30 days. The highest risks factor for PE using pre‐, intra‐, and postoperative factors were any cardiac events. Unplanned intubation was the fourth risk factor. Conclusion The risk for DVT and PE differed for each surgical procedure. VTE and PE risk factors changed after considering postoperative factors. It may be necessary to reconsider the prophylaxis depending on whether the complication occurs after surgery, particularly breathing and cardiac complications.

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.

Circulating microRNAs (miRNAs) are considered promising biomarkers for diagnosis, prognosis, and treatment efficacy of diseases. However, usefulness of circulating miRNAs as biomarkers for hereditary gastrointestinal diseases have not been confirmed yet. We explored circulating miRNAs specific for patients with familial adenomatous polyposis (FAP) as a representative hereditary gastrointestinal disease. Next-generation sequencing (NGS) indicated that plasma miR-143-3p, miR-183-5p, and miR-885-5p were candidate biomarkers for five FAP patients compared to three healthy donors due to moderate copy number and significant difference. MiR-16-5p was considered as an internal control due to minimum difference in expression across FAP patients and healthy donors. Validation studies by real-time PCR showed that mean ratios of maximum expression and minimum expression were 2.2 for miR-143-3p/miR-16-5p, 3.4 for miR-143-3p/miR-103a-3p, 5.1 for miR-183-5p/miR-16-5p, and 4.9 for miR-885-5p/miR-16-5p by using the samples collected at different time points of eight FAP patients. MiR-143-3p/16-5p was further assessed using specimens from 16 FAP patients and 7 healthy donors. MiR-143-3p was upregulated in FAP patients compared to healthy donors (P = 0.04), but not significantly influenced by clinicopathological features. However, miR-143-3p expression in colonic tumors was rare for upregulation, although there was a significant difference by existence of desmoid tumors. MiR-143-3p transfection significantly inhibited colorectal cancer cell proliferation compared to control microRNA transfection. Our data suggested regulation of miR-143-3p expression differed by samples (plasma or colonic tumors) in most FAP patients. Upregulation of plasma miR-143-3p expression may be helpful for diagnosis of FAP, although suppressive effect on tumorigenesis seemed insufficient in FAP patients.

Objective: The aim of this study was to identify risk factors for bleeding complications in patients who receive Venous thromboembolism (VTE) prophylaxis with fondaparinux (FPX) after colorectal cancer surgery. Methods: Records of 546 patients who underwent VTE prophylaxis with intermittent pneumatic compression and FPX after colorectal cancer surgery between January 2009 and May 2014 were reviewed. Patient characteristics, surgical procedures, and patient laboratory data were examined to identify risk factors for bleeding complications using univariate and multivariate logistic regression. Results: We reviewed the records of 324 males and 222 females. Median age and BMI were 68.5 years and 22.7 kg/m2, respectively. The number of laparoscopic surgeries was 366. Median operative time and blood loss were 188.5 min and 20 ml, respectively. The incidence (%) of bleeding events was 5.3%. In univariate analysis, age 80 years, BMI 25.0 kg/m2, hypertension, and antithrombotic therapy were associated with a significantly higher incidence of bleeding events. Multivariate analysis identified age 80 years (odds ratio 5.814; 95% confidence interval 2.502-13.278) as an independent risk factor. Conclusion: Age 80 is a risk factor for bleeding in patients who receive FPX for VTE prophylaxis after colorectal cancer surgery.

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.