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Objective The effectiveness of everolimus for the management of pancreatic neuroendocrine neoplasms (PNENs), including the G3/NEC types, remains unclear. We therefore investigated the effectiveness of the drug for the management of PNENs. Methods We analyzed the progression-free survival (PFS) and overall survival (OS) associated with everolimus and factors influencing the PFS and OS. Results One hundred patients were evaluated. The PFS associated with the G1/G2 types tended to be significantly longer than that associated with the G3/NEC types (hazard ratio [HR], 0.45; p =0.005). A multivariate analysis showed that the significant factors influencing the PFS were age (65 years old; HR, 0.44; p =0.002), grade (G1/G2; HR, 0.42; p =0.006), everolimus treatment line (≤2nd; HR, 0.55; p =0.031), and presence of treatment with metformin (yes; HR, 0.29; p =0.044). The median OS was 63.8 months. In the multivariate analysis, the significant factors influencing the OS were grade (G1/G2; HR, 0.21; p0.001), volume of liver metastasis (≤25%; HR, 0.27; p0.001), everolimus treatment line (≤2nd; HR, 0.27; p0.001), and presence of primary tumor resection (yes; HR, 0.33; p =0.005). Conclusions The effectiveness of everolimus in the management of G3/NEC types and prognoses tended to be poorer than those associated with the G1/G2 types. Everolimus combined with metformin and early-line treatment with everolimus may be effective for managing advanced PNENs.

Background There are several types of pancreatic mass, so it is important to distinguish between them before treatment. Artificial intelligence (AI) is a mathematical technique that automates learning and recognition of data patterns. This study aimed to investigate the efficacy of our AI model using endoscopic ultrasonography (EUS) images of multiple types of pancreatic mass (pancreatic ductal adenocarcinoma [PDAC], pancreatic adenosquamous carcinoma [PASC], acinar cell carcinoma [ACC], metastatic pancreatic tumor [MPT], neuroendocrine carcinoma [NEC], neuroendocrine tumor [NET], solid pseudopapillary neoplasm [SPN], chronic pancreatitis, and autoimmune pancreatitis [AIP]). Methods Patients who underwent EUS were included in this retrospective study. The included patients were divided into training, validation, and test cohorts. Using these cohorts, an AI model that can distinguish pancreatic carcinomas from noncarcinomatous pancreatic lesions was developed using a deep-learning architecture and the diagnostic performance of the AI model was evaluated. Results 22 000 images were generated from 933 patients. The area under the curve, sensitivity, specificity, and accuracy (95 %CI) of the AI model for the diagnosis of pancreatic carcinomas in the test cohort were 0.90 (0.84–0.97), 0.94 (0.88–0.98), 0.82 (0.68–0.92), and 0.91 (0.85–0.95), respectively. The per-category sensitivities (95 %CI) of each disease were PDAC 0.96 (0.90–0.99), PASC 1.00 (0.05–1.00), ACC 1.00 (0.22–1.00), MPT 0.33 (0.01–0.91), NEC 1.00 (0.22–1.00), NET 0.93 (0.66–1.00), SPN 1.00 (0.22–1.00), chronic pancreatitis 0.78 (0.52–0.94), and AIP 0.73 (0.39–0.94). Conclusions Our developed AI model can distinguish pancreatic carcinomas from noncarcinomatous pancreatic lesions, but external validation is needed.

Based on the results of the JCOG1109 trial, docetaxel + cisplatin + 5-fluorouracil (DCF) may be a standard neoadjuvant chemotherapy (NAC), in addition to the conventional 5-fluorouracil and cisplatin (FP) therapy. We examined whether the nutritional therapy should be modified when a different NAC is used based on the changes in body composition. The study included 215 patients with advanced esophageal cancer who underwent surgery after receiving NAC at our hospital between 2013 and 2019, and those who underwent abdominal computed tomography before and after NAC. The skeletal muscle mass index (SMI) was calculated using the following formula: total skeletal muscle mass at the third lumbar level/height2. The visceral and subcutaneous fat masses were assessed at the umbilical level. The lower 25% of men and women were defined as the low visceral fat and low subcutaneous fat groups, respectively. The DCF group was significantly younger (p

Supplementary Figure S1 presents the distribution (%) of first-visit hospital units among controls in each study.

Supplementary Table S1 shows the first-visit hospital unit among controls in each study. Supplementary Table S2 shows the baseline characteristics of case and control subjects. Supplementary Table S3 contains the frequencies of never/ever drinkers and median (IQR) values of alcohol intake (g/day) among ever drinkers across ALDH2 genotypes in control subjects. Supplementary Table S4 presents the sample size (n cases/n controls) for each group for both the exposure and mediator association, and the mediator and outcome association. Supplementary Table S5 shows the total-effect odds ratios (ORs) of ALDH2 Lys allele in each cancer risk. Supplementary Table S6 shows the direct- and indirect-effect odds ratios (ORs) in stomach cancer for ALDH2 Lys allele with further adjustment for Helicobacter pylori [H.pylori] infection and atrophic gastritis statuses. Supplementary Table S7 shows the direct- and indirect-effect odds ratios (ORs) on each cancer for ALDH2 Glu/Lys and Lys/Lys. Supplementary Table S8 presents the results for smoking-drinking interaction analyses on each cancer risk. Supplementary Table S9 shows the direct- and indirect-effect odds ratios (ORs) on each cancer for ALDH2 Lys allele in strata of cumulative smoking exposure (pack-years).

A genetic variant on aldehyde dehydrogenase 2 (ALDH2 rs671, Glu504Lys) contributes to carcinogenesis after alcohol consumption. Somewhat conversely, the ALDH2 Lys allele also confers a protective effect against alcohol-induced carcinogenesis by decreasing alcohol consumption due to acetaldehyde-related adverse effects. Here, we applied a mediation analysis to five case–control studies for head and neck, esophageal, stomach, small intestine, and colorectal cancers, with 4,099 cases and 6,065 controls, and explored the potentially heterogeneous impact of alcohol drinking on digestive tract carcinogenesis by decomposing the total effect of the ALDH2 Lys allele on digestive tract cancer risk into the two opposing effects of the carcinogenic effect (direct effect) and the protective effect (indirect effect mediated by drinking behavior). Alcohol was associated with an increased risk of most digestive tract cancers, but significant direct effects were observed only for upper gastrointestinal tract cancer risk, and varied substantially by site, with ORs (95% confidence interval) of 1.83 (1.43–2.36) for head and neck cancer, 21.15 (9.11–49.12) for esophageal cancer, and 1.65 (1.38–1.96) for stomach cancer. In contrast, a significant protective indirect effect was observed on risk for all cancers, except small intestine cancer. These findings suggest that alcohol is a major risk factor for digestive tract cancers, but its impact as a surrogate for acetaldehyde exposure appears heterogeneous by site. Meanwhile, the behavior-related effect of the ALDH2 Lys allele results in a decreased risk of most digestive tract cancers.Significance:These findings support that genetic alcohol avoidance is a factor against alcohol-induced cancers.

Background Endocytoscope systems (ECS) can visualize cellular nuclei of the mucosa of the gastrointestinal tract and are predicted to provide real-time microscopic diagnosis. However, their practical diagnostic performance remains unclear. Therefore, we conducted a multicenter prospective study to evaluate the visualization of superficial esophageal neoplasm in vivo using an ECS, and its diagnostic capability. Methods The study target was histologically confirmed squamous cell carcinoma (SCC) and high-grade intraepithelial neoplasia (HGIN). An integrated ECS was used to obtain ECS images. In each patient, three ECS images of cancerous and corresponding noncancerous regions were selected for evaluation. A pathological review board of five certified pathologists made the final diagnosis of the images. The primary endpoint was the sensitivity of ECS diagnosis by pathologists. Results ECS images of 68 patients were assessed: 42 lesions were mucosal SCC, 13 were submucosal SCC, and 13 were HGIN. The rate of assessable images was 96% (95% CI 87.6–99.1). The sensitivity of ECS diagnosis by pathologists was 88% (95% CI 77.2–94.5). Conclusions ECS can provide high-quality images of cancerous lesions and a high diagnostic accuracy by pathologists, and could be useful for real-time endoscopic histological diagnosis of SCC and HGIN. Trial registration The UMIN Clinical Trials Registry Identification Number: 000004218

A rare case of a squamous cell carcinoma (so-called cloacogenic carcinoma) showing extensive superficial spread to the rectum is presented. A 69-year-old woman had undergone colonoscopy for annual check-up, and a whitish, flat lesion with a central depressed area, 20 mm in size, was identified in the lower rectum. Narrow-band imaging with magnifying observation showed abnormal microvessels without the intrapapillary capillary loop patterns. Endoscopically, the margin of the lesion was unclear. Biopsy was performed, and a histological diagnosis of transitional cell carcinoma was made. Computed tomography showed no evidence of involvement of adjacent organs, lymph nodes or distant sites. Cystoscopy found no abnormality in the bladder mucosa. Owing to difficulty diagnosing this tumor accurately, local excision with transanal endoscopic microsurgery was performed. Cloacogenic carcinoma with submucosal invasion was diagnosed. A human papilloma virus (HPV) polymerase chain reaction test was positive. Judging from the histological findings and the positive HPV test, we hypothesis that the tumor was likely arising from the anal transitional zone with marked superficial spread to the rectum. Clinicians should keep in mind that this variant of squamous cell carcinoma may occur in the rectum, even if no endoscopic findings are seen in the anal transitional zone.

Although definitive chemoradiotherapy (CRT) is recommended for patients with locally advanced unresectable esophageal cancer, the outcome is unsatisfactory. We previously demonstrated the safety and efficacy of induction chemotherapy with docetaxel plus cisplatin and 5-fluorouracil (DCF) and subsequent conversion surgery (CS) for patients with locally advanced unresectable esophageal cancer. However, whether or not induction DCF chemotherapy and subsequent CS improve the long-term outcomes of patients with locally advanced unresectable esophageal cancer is unclear. A total of 177 consecutive patients with locally advanced unresectable esophageal cancer without distant metastasis were included in this study. Of these, 55 patients received DCF induction chemotherapy, of whom 36 underwent CS. We divided these 36 patients into two groups according to clinical response, which was analyzed retrospectively. The toxicities related to DCF chemotherapy were manageable. The response rate to induction DCF chemotherapy was 67%. R0 resection was achieved in 81% of the 36 patients who underwent subsequent CS. No serious postoperative complications were observed. Histopathological CR was achieved in 17% of the 36 patients, and the 3- and 5-year survival rates after CS were 61% and 54%, respectively. The outcomes of the patients who obtained good clinical response was better than the outcomes of patients who did not. Induction DCF chemotherapy and subsequent CS show acceptable toxicity and offer the chance of long-term survival in patients with locally advanced clinically unresectable esophageal cancer.

BACKGROUND AND AIMS Although the technique of endoscopic ultrasound-guided choledochoduodenostomy (EUS-CDS) is becoming standardized, its safety issues have not been sufficiently investigated. Therefore, we aimed to identify factors associated with adverse events and stent patency in EUS-CDS. METHODS Consecutive patients who underwent EUS-CDS between September 2003 and July 2017 were included. Technical/clinical success, adverse events and stent dysfunctions were analyzed retrospectively. RESULTS A total of 151 patients underwent EUS-CDS. In nine patients, procedures were discontinued before puncture. Technical and clinical success rates were 96.5% (137/142) and 98.5% (135/137), respectively. The adverse event rate was 20.4% (29/142). As a risk factor for peritonitis, plastic stents (PS) showed a significantly high odds ratio (OR) compared with covered self-expandable metal stents (CSEMS; OR, 4.31; P = 0.030). CSEMS cases showed a significantly longer patency period than PS cases (329 vs 89 days; HR, 0.35; P < 0.001). As a risk factor for early stent dysfunction (within 14 days), stent direction to the oral side showed a significantly high OR (OR, 43.47; P < 0.001). In cases with oblique-viewing EUS, double penetration of the duodenum occurred at significantly higher frequency than in cases with forward-viewing EUS (7.0 vs 0.0%; P = 0.024). CONCLUSIONS Plastic stents and stent direction to the oral side were risk factors for peritonitis and early stent dysfunction, respectively. Using covered self-expandable metal stents and changing stent direction to the anal side seemed appropriate to prevent peritonitis and early stent dysfunction.

Background and aim In chronic pancreatitis (CP) patients, diagnosis of small pancreatic lesions by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is challenging. Thus, the aim of the present study was to investigate whether CP influences the diagnostic ability of EUS-FNA for pancreatic lesions ≤10 mm. Methods One hundred and seventeen patients who underwent EUS-FNA for pancreatic lesions ≤10 mm in size were enrolled. Patients were classified into two groups based on features of CP observed by EUS (EUS-CP features) in accordance with the Rosemont classification. The CP group was defined as cases consistent with CP or suggestive of CP, and the non-CP group was defined as cases indeterminate for CP or normal. Factors influencing the diagnostic accuracy of EUS-FNA and CP status in pancreatic tumors were also investigated. Results Diagnostic ability of EUS-FNA (overall cases, non-CP vs CP) had sensitivity (80.4%, 96.7% vs 57.1%; P 0.05), and accuracy (91.5%, 98.6% vs 80.4%; P = 0.001). In multivariate analysis of factors influencing the accuracy of EUS-FNA, CP significantly lowered the accuracy (P = 0.048; odds ratio [OR] = 9.21). Among pancreatic cancer patients, the number of CP patients was significantly higher than the number of patients with benign lesions (P = 0.023). In multivariate analysis, lobularity without honeycombing was more frequently observed in cases of pancreatic cancer (P = 0.018; OR, 12.65). Conclusion Endoscopic ultrasound-guided FNA offers high accuracy for small pancreatic lesions ≤10 mm. However, in cases with CP, the diagnostic ability of EUS-FNA is significantly reduced.

The detection ability and role of different imaging modalities to detect pancreatic neuroendocrine neoplasms (PNENs) including small lesions is unclear. This study aimed to compare the ability of endoscopic ultrasound (EUS) and computed tomography (CT) to detect PNENs.Data of patients who underwent EUS and contrast-enhanced CT and were diagnosed with PNENs were analyzed. The detection rates of pancreatic lesions with EUS and CT based on tumor size and influencing factors were investigated.For 256 PNEN lesions, the detection rate of EUS was better than that of CT (94.5% vs 86.3%; P .001). EUS was significantly superior to CT for PNENs ≤5 mm (58.3% vs 16.7%; P = .006) and 5-10 mm (97.7% vs 79.5%; P = .008). There was no significant difference in the detection rate between EUS and CT for PNENs10 mm (98.4% vs 96.4%; P = .375). Size (≤5 mm) and insulinoma were independent factors associated with poor EUS and CT detection rates.Endoscopic ultrasound exhibited better detection ability than CT, with an excellent detection rate for PNENs5 mm, except for insulinomas. CT could detect PNENs10 mm, which are amenable to treatment.

BACKGROUND Recent advances in endoscopic technology, especially magnifying endoscopy with narrow band imaging (ME-NBI) enable us to detect superficial esophageal squamous cell carcinoma (ESCC), but determining the appropriate method of resection, endoscopic resection (ER) vs surgical resection, is often challenging. Recently, several studies have reported that 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is a useful indicator for decision-making regarding treatment for superficial ESCC. Although, there are not enough reports on association between FDG-PET uptake and clinicopathological characteristics of superficial ESCC. And, there are not enough reports on evaluating the usefulness of combination of FDG-PET and ME-NBI for determining the treatment strategy for superficial ESCC. This study evaluated clinical relevance of FDG-PET and ME-NBI in decision-making regarding the treatment strategy for ESCC. AIM To investigate the association between FDG uptake and the clinicopathological characteristics of superficial ESCC and its usefulness of combination of FDG-PET and ME-NBI for determining the treatment strategy for superficial ESCC. METHODS A database of all patients with superficial ESCC who had undergone both ME-NBI and FDG-PET for pre-treatment staging at Aichi Cancer Center Hospital between January 2008 and November 2018 was retrospectively analyzed. FDG uptake was defined positive or negative whether the primary lesion was visualized or could be distinguished from the background, or not. The invasion depth of ESCC was classified according to the Japan Esophageal Society. Primary endpoint is to evaluate the association between FDG uptake and clinicopathological characteristics of superficial ESCC. Secondary endpoint is to investigate the efficacy of combination of FDG-PET and ME-NBI for determining the treatment strategy for superficial ESCC. RESULTS A total of 82 lesions in 82 patients were included. FDG-PET showed positive uptake in 29 (35.4%) lesions. Univariate analysis showed that uptake of FDG-PET had significant correlations with circumferential extension (P = 0.014), pathological depth of tumor invasion (P < 0.001), infiltrative growth pattern (P < 0.001), histological grade (P = 0.002), vascular invasion (P = 0.001), and lymphatic invasion (P < 0.001). On multivariate analysis, only depth of tumor invasion was independently correlated with FDG-PET/computed tomography visibility (P = 0.018). The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of Type B2 in ME-NBI for the invasion depth of T1a muscularis mucosae and T1b upper submucosal layer were 68.4%/79.4%/50.0%/89.3%/76.8%, respectively, and those of Type B3 for the depth of T1b middle and deeper submucosal layers (SM2 and SM3) were 46.7%/100%/100%/89.3%/90.2%, respectively. On the other hand, those of FDG-PET for SM2 and SM3 were 93.3%/77.6%/48.2%/98.1%/80.5%, respectively, whereas, if the combination of positive FDG uptake and type B2 and B3 was defined as an indicator for radical esophagectomy or definitive chemoradiotherapy, the sensitivity, specificity, PPV, NPV, and accuracy were 78.3%/91.5%/78.3%/91.5%/87.8%, respectively. CONCLUSION FDG uptake was correlated with the invasion depth of superficial ESCC. Combined use of FDG-PET and ME-NBI, especially with the microvascular findings of Type B2 and B3, is useful to determine whether ER is indicated for the lesion.

Effects of changes in body composition during neoadjuvant chemotherapy (NAC) on perioperative complications and prognosis are unknown in patients with esophageal squamous cell carcinoma (ESCC). A total of 175 patients who underwent surgery for ESCC in our hospital between 2016 and 2019 were examined. The psoas muscle index (PMI) was calculated from the total psoas muscle area, and the visceral fat mass (VFM) at the umbilical level was measured. We defined body composition change (BCC) group as those with increased VFM of ≥ 3% and decreased PMI of ≥ 3% during NAC. Sarcopenia (S) was defined as PMI < 5.89 (male) and

Simple Summary Gastric cancer remains the major cancer in Japan and worldwide. It is expected that practical intervention strategies for prevention, such as personalized approaches based on genetic risk models, will be developed. Here, we developed and validated a risk prediction model for gastric cancer using genetic, biological, and lifestyle-related risk factors. Results showed that the combination of selected GWAS-identified SNP polymorphisms and other predictors provided high discriminatory accuracy and good calibration in both the derivation and validation studies; however, the contribution of genetic factors to risk prediction was limited. The greatest contributor to risk prediction was ABCD classification (Helicobacter pylori infection-related factor). Abstract Background: As part of our efforts to develop practical intervention applications for cancer prevention, we investigated a risk prediction model for gastric cancer based on genetic, biological, and lifestyle-related risk factors. Methods: We conducted two independent age- and sex-matched case–control studies, the first for model derivation (696 cases and 1392 controls) and the second (795 and 795) for external validation. Using the derivation study data, we developed a prediction model by fitting a conditional logistic regression model using the predictors age, ABCD classification defined by H. pylori infection and gastric atrophy, smoking, alcohol consumption, fruit and vegetable intake, and 3 GWAS-identified polymorphisms. Performance was assessed with regard to discrimination (area under the curve (AUC)) and calibration (calibration plots and Hosmer–Lemeshow test). Results: A combination of selected GWAS-identified polymorphisms and the other predictors provided high discriminatory accuracy and good calibration in both the derivation and validation studies, with AUCs of 0.77 (95% confidence intervals: 0.75–0.79) and 0.78 (0.77–0.81), respectively. The calibration plots of both studies stayed close to the ideal calibration line. In the validation study, the environmental model (nongenetic model) was significantly more discriminative than the inclusive model, with an AUC value of 0.80 (0.77–0.82). Conclusion: The contribution of genetic factors to risk prediction was limited, and the ABCD classification (H. pylori infection-related factor) contributes most to risk prediction of gastric cancer.

Primary hepatocellular carcinoma (HCC) in patients

Simple Summary Although pathologic complete response (pCR) to neoadjuvant chemoradiation (nCRT) in locally advanced rectal cancer (LARC) is associated with better outcomes, a subset of tumors exhibit resistance to nCRT. Therefore, there is a need of biomarkers to predict the nCRT response and increment efforts for personalized therapeutic options. To this end, we analyzed pretreatment plasma proteome of a mouse model of rectal cancer treated with concurrent chemoradiation, resulting in identification and validation of plasma VEGFR3 as a potential predicting biomarker. In addition, plasma levels of EGFR and COX2, previously validated tissue-based predicting biomarkers, were significantly higher in non-pCR than pCR LARC patients, indicating that EGFR and COX2 can also serve as blood-based biomarkers. The performance of the biomarker panel combining VEGFR3, EGFR, and COX2 were significantly improved compared to that of each marker alone, providing a rationale for further integration and refinement of the biomarker panel and validation in the larger sample sets. Abstract The current standard of care for patients with locally advanced rectal cancer (LARC) is neoadjuvant chemoradiation (nCRT) followed by total mesorectal excision surgery. However, the response to nCRT varies among patients and only about 20% of LARC patients achieve a pathologic complete response (pCR) at the time of surgery. Therefore, there is an unmet need for biomarkers that could predict the response to nCRT at an early time point, allowing for the selection of LARC patients who would or would not benefit from nCRT. To identify blood-based biomarkers for prediction of nCRT response, we performed in-depth quantitative proteomic analysis of pretreatment plasma from mice bearing rectal tumors treated with concurrent chemoradiation, resulting in the quantification of 567 proteins. Among the plasma proteins that increased in mice with residual rectal tumor after chemoradiation compared to mice that achieved regression, we selected three proteins (Vascular endothelial growth factor receptor 3 [VEGFR3], Insulin like growth factor binding protein 4 [IGFBP4], and Cathepsin B [CTSB]) for validation in human plasma samples. In addition, we explored whether four tissue protein biomarkers previously shown to predict response to nCRT (Epidermal growth factor receptor [EGFR], Ki-67, E-cadherin, and Prostaglandin G/H synthase 2 [COX2]) also act as potential blood biomarkers. Using immunoassays for these seven biomarker candidates as well as Carcinoembryonic antigen [CEA] levels on plasma collected before nCRT from 34 patients with LARC (6 pCR and 28 non-pCR), we observed that levels of VEGFR3 (p = 0.0451, AUC = 0.720), EGFR (p = 0.0128, AUC = 0.679), and COX2 (p = 0.0397, AUC = 0.679) were significantly increased in the plasma of non-pCR LARC patients compared to those of pCR LARC patients. The performance of the logistic regression model combining VEGFR3, EGFR, and COX2 was significantly improved compared with the performance of each biomarker, yielding an AUC of 0.869 (sensitivity 43% at 95% specificity). Levels of VEGFR3 and EGFR were significantly decreased 5 to 7 months after tumor resection in plasma from 18 surgically resected rectal cancer patients, suggesting that VEGFR3 and EGFR may emanate from tumors. These findings suggest that circulating VEGFR3 can contribute to the prediction of the nCRT response in LARC patients together with circulating EGFR and COX2.

Previous studies have shown sex‐related differences in the incidence of adverse events following treatment with fluoropyrimidines, however the mechanism of this difference is unknown. We examined sex‐related differences in the safety of S‐1 plus oxaliplatin (SOX) and S‐1 plus cisplatin (CS) in 663 metastatic gastric cancer patients taking part in a phase III study. The incidences of leukopenia (odds ratio [OR] 1.9; P = .015), neutropenia (OR 2.2; P = .002), nausea (OR 2.0; P = .009), and vomiting (OR 2.8; P

Background and study aims Restorative proctocolectomy has become the most common surgical option for patients with familial adenomatous polyposis (FAP). However, adenomas and even carcinomas may develop in the ileal pouch over time. The aim of this study was to evaluate the long-term incidence and nature of ileal pouch or distal ileal adenomas and carcinomas in patients with FAP. Patients and methods This was a retrospective study of 47 FAP patients with Kock’s continent ileostomy (Kock) (n = 8), ileorectal anastomosis (IRA) (n = 13), and ileal pouch-anal anastomosis (IPAA) (n = 26). Patients were followed with a standardized protocol including chromoendoscopy and biopsies of visible polyps in the ileal pouch, distal ileum, and rectum every 6 to 12 months. Results Median follow-up was 21.0 years. Overall risk of adenoma development was significantly higher in IRA patients, with incidence rates of 85 % and 100 % at 5 and 10 years’ follow-up, respectively, compared to pouch patients (Kock + IPAA) (P Conclusions There is a significant incidence of adenoma(s) in the ileal pouch of FAP patients on long-term follow-up. Regular endoscopic surveillance is recommended, not only in IRA patients, but also in pouch patients after proctocolectomy.

Although recent genome-wide association studies (GWASs) have identified genetic variants associated with Helicobacter pylori (HP)-induced gastric cancer, few studies have examined the genetic traits associated with the risk of HP-induced gastric precancerous conditions. This study aimed to elucidate genetic variants associated with these conditions using a genome-wide approach. Data from four sites of the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study were used in the discovery phase (Stage I); two datasets from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center 2 (HERPACC2) study were used in the replication phases (Stages II and III) and SKAT (SNP-set Kernel Association Test) and single variant-based GWASs were conducted for the risks of gastric atrophy (GA) and severe GA defined by serum pepsinogen (PG) levels, and PG1 and PG1/2 ratios. In the gene-based SKAT in Stage I, prostate stem cell antigen (PSCA) was significantly associated with the risks of GA and severe GA, and serum PG1/2 level by linear kernel [false discovery rate (FDR) = 0.011, 0.230 and 7.2 × 10−7, respectively]. The single variant-based GWAS revealed that nine PSCA single nucleotide polymorphisms (SNPs) fulfilled the genome-wide significance level (P < 5 × 10−8) for the risks of both GA and severe GA in the combined study, although most of these associations did not reach genome-wide significance in the discovery or validation cohort on their own. GWAS for serum PG1 levels and PG1/2 ratios revealed that the PSCA rs2920283 SNP had a striking P-value of 4.31 × 10−27 for PG1/2 ratios. The present GWAS revealed the genetic locus of PSCA as the most significant locus for the risk of HP-induced GA, which confirmed the recently reported association in Europeans.

Background and study aims To investigate bleeding risk and thromboembolic risk in patients receiving antithrombotic therapy who underwent endoscopic ultrasound-guided fine-needls aspiration (EUS-FNA). Patients and methods A single-center retrospective study of 908 consecutive patients undergoing EUS-FNA for pancreatic and non-pancreatic lesions patients between March 2013 and March 2017 was performed. Antithrombotic management was classified into three groups: continuous, discontinuation, and heparin replacement. Results A total of 114 patients (12.6 %) were on antithrombotic drugs and 794 (84.6 %) were not. There were six cases of significant bleeding (0.7 %) four in the antithrombotic group (0.4 %) and two (0.2 %) in the non-antithrombotic group, (odds ratio, 9.59; 95 % confidence interval, 2.12 – 43.1; P = 0.006). Of the four cases in the antithrombotic group, two were on continuous treatment, one was on discontinuation treatment and one was on heparin replacement. All cases of non-significant bleeding occurred in the non-antithrombotic group (3 peri-tumoral hematomas, 1 submucosal hematoma, and 1 intraluminal bleed). The sole thromboembolic event (0.9 %) was a cerebral infarction in the antithrombotic group in a patient on thienopyridine who switched to aspirin before the procedure. Conclusions There was a slight increase in risk of bleeding in patients receiving antithrombotic therapy especially postoperative bleeding; however, there were no cases of severe bleeding was seen and only one case of cerebral infarction which occurred in a high-risk thromboembolic patients. We concluded that EUS-FNA in a safe procedure for patients on antithrombotics, even when antithrombotic therapy is not discontinued during EUS-FNA.

In patients with familial adenomatous polyposis (FAP), adenomas and even carcinomas may develop in the rectal remnant and the ileal pouch after surgical treatment. The aim of this study was to evaluate the outcome of endoscopic management in patients with FAP. The main outcome measurements were the appearance of secondary cancer, complications, and the need for additional surgery. Thirty-four FAP patients with Kock’s continent ileostomy (Kock) (n = 3), ileorectal anastomosis (IRA) (n = 12), and ileal pouch-anal anastomosis (IPAA) (n = 19) were identified. The median follow-up period of endoscopic surveillance was 11.5 years for pouch patients (Kock + IPAA) and 21.7 years for IRA. Metachronous adenomas appeared in 32 patients (94.1%). In pouch patients, a total of 120 treatments were given to 20 patients, and 12 sessions of delayed bleeding (10%) occurred, which was significantly higher compared to IRA patients, with 0 sessions (p < 0.001). In IRA patients, a total of 169 treatments were given to 11 patients, with one case of perforation. No adenocarcinoma has developed since the start of endoscopic surveillance. Regular endoscopic surveillance and treatment are feasible and safe. However, in pouch patients, one must be cautious about delayed bleeding in the treatment of adenomas.

Background Immune checkpoint inhibitors have shown clinically significant antitumor efficacy and have been approved for the treatment of various kinds of advanced malignancies. On the other hand, these immunotherapies show unique adverse events, termed “immune-related adverse events,” which are distinctly associated with conventional cytotoxic chemotherapy. Hepatotoxicity is recognized as an immune-related adverse event; prompt treatment with corticosteroids is recommended. However, some cases are refractory to steroids. Here, we report the first case (to our knowledge) of steroid-refractory immune-related hepatitis that was successfully treated with ursodeoxycholic acid and bezafibrate. Case presentation A 68-year-old Asian man, came to our hospital for the treatment of malignant melanoma involving the gingiva and presenting with multiple lymph node and bone metastases was administered nivolumab as a first-line treatment. Two months into treatment, the patient developed diarrhea as a result of immune-related colitis; the colitis was treated successfully with prednisolone 60 mg/ day, resulting in improvement in the patient’s symptoms. However, when steroids were being tapered, acute elevation of liver enzymes was observed. Autoimmune hepatitis was suspected as an immune-related adverse event, and treatment with intravenous prednisolone 60 mg/ day was reinitiated. However, restoration of the steroid treatment failed to improve the patient’s liver enzymes. On the basis of histological findings from liver biopsy and exclusion of other etiologies such as viral infection and other drug-induced hepatitis, steroid-refractory hepatic immune-related adverse event was deemed the most likely cause of the patient’s acute hepatitis. In general, mycophenolate mofetil or tacrolimus is known to provide benefits in cases of steroid-refractory hepatitis. We therefore decided to add oral ursodeoxycholic acid and bezafibrate in consideration of the patient’s background of repeated aspiration pneumonia. Administration of this regimen resulted in an improvement in liver function, which remained normal even after tapering of prednisolone. Conclusions Ursodeoxycholic acid and bezafibrate may be useful for treatment of steroid-refractory immune-related adverse event hepatitis.

We evaluated the impact of body composition on clinical outcomes after neoadjuvant chemotherapy (NAC) followed by surgery for elderly cStage II/III esophageal squamous cell carcinoma (ESCC). Ninety-one patients &ge, 70 years old and 116 patients &lt, 70 years old with ECSS who underwent NAC between January 2013 and June 2018 at the Aichi Cancer Center were included. Body composition as assessed from computed tomography (CT), American Society of Anesthesiologists physical status (ASA-PS), and subjective global assessment (SGA) was assessed before initiation of NAC. Although elderly patients showed significantly poorer ASA-PS (p &lt, 0.01) and SGA (p &lt, 0.01), and significantly more frequent history of malignancy (p &lt, 0.05), no significant differences were identified in the frequencies of adverse events, postoperative complications, or in cancer-specific survival (p = 0.65, hazard ratio 1.15), or overall survival (p = 0.42, hazard ratio 1.26). However, multivariate analysis identified sarcopenic obesity as the only independent predictor of prognosis in elderly patients. Sarcopenic obesity was associated with higher body mass index (p = 0.04), better SGA (p &lt, 0.01), and lower pre-treatment weight loss (p = 0.03). NAC was as effective and safe for elderly patients without sarcopenic obesity as for young patients. However, diagnosing sarcopenic obesity based on clinical findings is difficult, so the preoperative CT assessment of sarcopenic obesity is important.

While endoscopic submucosal dissection (ESD) is recognized as a minimally invasive standard treatment for differentiated early gastric cancers (EGCs), it has not been indicated for undifferentiated EGC (UD-EGC) because of a relatively high risk of lymph node metastasis (LNM). However, patients with surgically resected mucosal (cT1a) UD-EGC ≤ 2 cm in size with no lymphovascular invasion or ulceration are reported to be at a very low risk of LNM. This multicenter, single-arm, confirmatory trial was conducted to evaluate the efficacy and safety of ESD for UD-EGC. The key eligibility criteria were endoscopically diagnosed cT1a/N0/M0, single primary lesion, size ≤ 2 cm, no ulceration and histologically proven components of undifferentiated adenocarcinoma on biopsy. Based on the histological findings after ESD, additional gastrectomy was indicated if the criteria for curative resection were not satisfied. The subjects of the primary analysis were patients with UD-EGC as the dominant component. The primary endpoint was 5-year overall survival (OS) of patients with UD-EGC. Three hundred 46 patients were enrolled from 49 institutions. The proportion of en bloc resection was 99%. No ESD-related Grade 4 adverse events were noted. Delayed bleeding and intraoperative and delayed perforation occurred in 25 (7.3%), 13 (3.8%), and 6 (1.7%) patients, respectively. Among the 275 patients who were the subjects of the primary analysis, curative resection was achieved in 195 patients (71%), and 5-year OS was 99.3% (95% CI: 97.1–99.8). ESD can be a curative and less invasive treatment for UD-EGC for patients meeting the eligibility criteria of this study.

Objectives A Japanese multicenter prospective cohort study examining endoscopic resection (ER) for early gastric cancer (EGC) has been conducted using a Web registry developed to determine the short-term and long-term outcomes based on absolute and expanded indications. We hereby present the short-term outcomes of this study. Methods All consecutive patients with EGC or suspected EGC undergoing ER at 41 participating institutions between July 2010 and June 2012 were enrolled and prospectively registered into the Web registry. The baseline characteristics were entered before ER, and the short-term outcomes were collected at 6 months following ER. Results Nine thousand six hundred and sixteen patients with 10 821 lesions underwent ER (endoscopic submucosal dissection [ESD]: 99.4%). The median procedure time was 76 min, and R0 resections were achieved for 91.6% of the lesions. Postoperative bleeding and intraoperative perforation occurred in 4.4% and 2.3% of the patients, respectively. Significant independent factors correlated with a longer procedure time (120 min or longer) were as follows: tumor size >20 mm, upper-third location, middle-third location, local recurrent lesion, ulcer findings, gastric tube, male gender, and submucosa. Histopathologically, 10 031 lesions were identified as common-type gastric cancers. The median tumor size was 15 mm. Noncurative resections were diagnosed for 18.3% of the lesions. Additional surgery was performed for 48.6% (824 lesions) of the 1695 noncurative ER lesions with a possible risk of lymph node (LN) metastasis. Among them, 64 (7.8%) exhibited LN metastasis. Conclusions This multicenter prospective study showed favorable short-term outcomes for gastric ESD.

Aberrant pancreas is defined as pancreatic tissue present outside of the pancreas and is often found incidentally during esophagogastroduodenoscopy. Obtaining sufficient tissue to differentiate aberrant pancreas from other subepithelial lesions is sometimes difficult. Due to the lack of a definitive diagnosis, patients often undergo unnecessary surgery. We herein report the first case of aberrant pancreas in which the concomitant use of needle-based probe confocal laser endomicroscopy and fine-needle aspiration supported the final diagnosis. Needle-based probe confocal laser endomicroscopy provides a real-time in vivo histopathology evaluation and may be a feasible means of diagnosing aberrant pancreas.

Summary of Event: Bacterial, mycotic peritonitis and Candida fungemia developed in a patient with moderate ascites who had undergone endoscopic ultrasound-guided biliary drainage (EUS-BD). Antibiotics and antifungal agent were administered and ascites drainage was performed. Although the infection improved, the patient’s general condition gradually deteriorated due to aggravation of the primary cancer and he died.Teaching Point: This is the first report to describe infectious peritonitis after EUS-BD. Ascites carries the potential risk of severe complications. As such, in patients with ascites, endoscopic retrograde cholangiopancreatography (ERCP) is typically preferred over EUS-BD or percutaneous drainage to prevent bile leakage. However, ERCP may not be possible in some patients with tumor invasion of the duodenum or with surgically altered anatomy. Thus, in patients with ascites who require EUS-BD, we recommend inserting the drainage tube percutaneously and draining the ascites before and after the intervention in order to prevent severe infection.

Aldehyde dehydrogenase 2 (ALDH2; rs671, Glu504Lys) and alcohol dehydrogenase 1B (ADH1B; rs1229984, His47Arg) polymorphisms have a strong impact on carcinogenic acetaldehyde accumulation after alcohol drinking. To date, however, evidence for a significant ALDH2–alcohol drinking interaction and a mediation effect of ALDH2/ADH1B through alcohol drinking on gastric cancer have remained unclear. We conducted two case–control studies to validate the interaction and to estimate the mediation effect on gastric cancer. We calculated odds ratios (OR) and 95% confidence intervals (CI) for ALDH2/ADH1B genotypes and alcohol drinking using conditional logistic regression models after adjustment for potential confounding in the HERPACC-2 (697 cases and 1372 controls) and HERPACC-3 studies (678 cases and 678 controls). We also conducted a mediation analysis of the combination of the two studies to assess whether the effects of these polymorphisms operated through alcohol drinking or through other pathways. ALDH2 Lys alleles had a higher risk with increased alcohol consumption compared with ALDH2 Glu/Glu (OR for heavy drinking, 3.57; 95% CI 2.04–6.27; P for trend = 0.007), indicating a significant ALDH2–alcohol drinking interaction (Pinteraction = 0.024). The mediation analysis indicated a significant positive direct effect (OR 1.67; 95% CI 1.38–2.03) and a protective indirect effect (OR 0.84; 95% CI 0.76–0.92) of the ALDH2 Lys alleles with the ALDH2–alcohol drinking interaction. No significant association of ADH1B with gastric cancer was observed. The observed ALDH2–alcohol drinking interaction and the direct effect of ALDH2 Lys alleles may suggest the involvement of acetaldehyde in the development of gastric cancer.

Background and study aims We report a case of amelanotic malignant melanoma of the esophagus (AMME), an exceedingly rare disease. A 77-year-old Japanese woman presented to our hospital with features suggestive of a middle esophageal submucosal tumor, which was diagnosed pathologically as AMME. The patient underwent thoracoscopic resection of the esophagus and laparoscopic gastric tube reconstruction. Three years after surgery, computed tomography showed no recurrence. Generally, the prognosis of malignant melanoma of the esophagus is very poor. However, our patient had no recurrence, and is alive 3 years after surgery and 5 years after the tumor was first detected.

Background The efficacy of intensity-modulated radiotherapy (IMRT) for cervical esophageal cancer has not been determined. Methods Eighty patients with cervical esophageal cancer treated with definitive chemoradiotherapy from 2002 to 2014 were analyzed. Overall survival (OS), failure patterns, and toxicity incidence were compared between the IMRT (N = 32) and 3D conformal radiotherapy (RT; N = 48) groups. Results The median follow-up was 35.9 months. The 3-year OS of the IMRT, 3D conformal RT, and total groups was 81.6%, 57.2%, and 66.6%, respectively. Pulmonary toxicity was not observed with IMRT. Six of 62 cases (9.6%) with nodal involvement developed upper cervical node recurrence outside the prophylactic region. Ten patients in the IMRT group were salvaged, and 60% survived without recurrence; 20% of the 3D conformal RT group was salvaged. Conclusion The IMRT group was comparable with 3D conformal RT group, with a better salvage rate. We recommend extended cervical irradiation for nodal involvement.