Genetic architecture of alcohol consumption identified by a genotype-stratified GWAS and impact on esophageal cancer risk in Japanese people.

An East Asian-specific variant on aldehyde dehydrogenase 2 (ALDH2 rs671, G>A) is the major genetic determinant of alcohol consumption. We performed an rs671 genotype-stratified genome-wide association study meta-analysis of alcohol consumption in 175,672 Japanese individuals to explore gene-gene interactions with rs671 behind drinking behavior. The analysis identified three genome-wide significant loci (GCKR, KLB, and ADH1B) in wild-type homozygotes and six (GCKR, ADH1B, ALDH1B1, ALDH1A1, ALDH2, and GOT2) in heterozygotes, with five showing genome-wide significant interaction with rs671. Genetic correlation analyses revealed ancestry-specific genetic architecture in heterozygotes. Of the discovered loci, four (GCKR, ADH1B, ALDH1A1, and ALDH2) were suggested to interact with rs671 in the risk of esophageal cancer, a representative alcohol-related disease. Our results identify the genotype-specific genetic architecture of alcohol consumption and reveal its potential impact on alcohol-related disease risk.

Adult Height and Risk of Colorectal Cancer: A Pooled Analysis of 10 Population-based Cohort Studies in Japan.

BACKGROUND: While tall stature has been linked to an increase in the risk of colorectal cancer (CRC), its association with cancer in the colorectum and its subsites remains unclear among Asians. METHODS: We conducted a pooled analysis of 10 population-based cohort studies among adults in Japan. Each study estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for CRC incidence associated with adult height were estimated using Cox proportional hazards regression with adjustment of the same set of covariates were then pooled to estimate summary HRs incidence using random-effect models. RESULTS: We identified 9,470 CRC incidences among 390,063 participants during 5,672,930 person-years of follow-up. Men and women with tall stature had a higher risk of CRC and colon cancer. HRs for CRC, colon cancer, and distal colon cancer for the highest versus lowest height categories were 1.23 (95% CI, 1.07-1.40), 1.22 (95% CI, 1.09-1.36), and 1.27 (95% CI, 1.08-1.49), respectively, in men and 1.21 (95% CI, 1.09-1.35), 1.23 (95% CI, 1.08-1.40), and 1.35 (95% CI, 1.003-1.81), respectively, in women. The association with proximal colon cancer and rectal cancer was less evident in both sexes. CONCLUSION: This pooled analysis confirms the link between tall stature and a higher risk of CRC and colon cancer (especially distal colon) among the Japanese and adds evidence to support the use of adult height to identify those at a higher risk of CRC.

Mediation analysis unveils a carcinogenic effect of ADH1B rs1229984 through mechanisms other than change in drinking intensity: oesophageal cancer case-control study.

BACKGROUND: Ingested alcohol is predominantly oxidized to acetaldehyde by alcohol dehydrogenase 1B (ADH1B), and acetaldehyde is further oxidized to acetate mainly by aldehyde dehydrogenase 2 (ALDH2). Although alcohol consumption is a convincing risk factor for oesophageal cancer, the role of ADH1B rs1229984 (His48Arg), the single-nucleotide polymorphism associated with slow alcohol metabolism, in oesophageal cancer development is unclear. Because this single-nucleotide polymorphism is associated with both increased risk of oesophageal cancer and drinking intensity, its association with oesophageal cancer might operate either through a direct pathway independently of drinking intensity, via an indirect pathway mediated by drinking intensity, or both. METHODS: To disentangle these different pathways, we applied a mediation analysis to an oesophageal cancer case-control study (600 cases and 865 controls) by defining the ADH1B Arg allele and alcohol consumption as exposure and mediator, respectively, and decomposed the total-effect odds ratio of the ADH1B Arg allele into direct- and indirect-effect odds ratio. RESULTS: The ADH1B Arg allele was associated with oesophageal cancer risk through pathways other than change in drinking intensity (direct-effect odds ratio, 2.03; 95% confidence interval, 1.41-2.92), in addition to the indirect pathway mediated by drinking intensity (indirect-effect odds ratio, 1.27; 95% confidence interval, 1.05-1.53). Further analyses by stratifying genotypes of ALDH2 rs671 (Glu504Lys), the functional single-nucleotide polymorphism that strongly attenuates the enzymatic activity, showed significant direct-effect odds ratio within each stratum. CONCLUSIONS: These results indicate that ADH1B Arg allele contributes to oesophageal cancer risk by slowing alcohol breakdown, in addition to its effect on the amount of alcohol consumed.

Changes in survival of patients with non-small cell lung cancer in Japan: An interrupted time series study.

The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) gefitinib and erlotinib were approved for metastatic or relapsed non-small cell lung cancer (NSCLC) in Japan in 2002 and 2007, respectively. EGFR mutation testing was also approved in 2007. Although clinical trials showed efficacy in NSCLC patients harboring activating EGFR mutations, these effects have rarely been reported in real-world practice. We evaluated changes in survival in NSCLC patients following introduction of these agents and EGFR mutation testing by extracting patients diagnosed with NSCLC from 1993 through 2011 from six prefectural population-based cancer registries in Japan. Relative survival (RS) was calculated by sex, histological subtype, and cancer stage. We conducted interrupted time series analysis to assess survival changes following introduction of EGFR-TKIs and EGFR mutation testing. 120,068 patients with NSCLC were analyzed. One- and three-year RS gradually increased in overall NSCLC for men and women. For adenocarcinoma, among men, slopes of 1- and 3-year RS increased steeply in patients diagnosed from 2007 through 2011; among women, significant level increases were seen in 1-year RS in patients diagnosed in 2002 (4.55% [95% confidence interval: 1.76-7.33]) and 2007 (3.40% [1.27-5.52]). These significant level increases were particularly obvious in women with adenocarcinoma at an advanced stage. Our results suggest that recent improvements in survival in men and women with adenocarcinoma are due at least partly to introduction of EGFR-TKIs into real-world practice, and to prescription based on appropriate patient selection following introduction of EGFR mutation testing into real-world practice in Japan.

New insights into the genetic contribution of ALDH2 rs671 in pancreatic carcinogenesis: Evaluation by mediation analysis.

A functional variant on ALDH2 rs671 (G>A) confers a protective effect against alcohol-induced carcinogenesis through an indirect pathway mediated by decreased alcohol consumption. Conversely, this variant also contributes to the accumulation of carcinogenic agents, resulting in a direct carcinogenic effect. This study aimed to separately quantify these two opposing effects of the rs671 A allele on pancreatic cancer risk and explore the impact of the rs671 A allele and alcohol consumption on pancreatic carcinogenesis. We included 426 cases and 1456 age- and sex-matched controls. Odds ratio (OR) and 95% confidence interval (CI) for alcohol consumption were estimated using a conditional logistic regression model. By defining rs671 A allele and alcohol consumption as exposure and mediator, respectively, we used mediation analysis to decompose the total-effect OR of the rs671 A allele into direct- and indirect-effect ORs. Alcohol consumption (10 g/d) was associated with pancreatic cancer risk (OR, 1.05; 95% CI, 1.01-1.10), but tests for interaction between the rs671 A allele and alcohol consumption were nonsignificant, indicating that the effect of alcohol consumption did not vary by genotype. Mediation analysis showed that the nonsignificant total effect (OR, 1.15; 95% CI, 0.92-1.44) can be decomposed into the carcinogenic direct (OR, 1.34; 95% CI, 1.04-1.72) and protective indirect effect (OR, 0.86; 95% CI, 0.77-0.95). This study supports the association between alcohol consumption and pancreatic cancer risk and indicates the potential contribution of the rs671 A allele to pancreatic carcinogenesis through impaired metabolism of known or unknown ALDH2 substrates.

Risk Prediction for Gastric Cancer Using GWAS-Identifie Polymorphisms, Helicobacter pylori Infection and Lifestyle-Related Risk Factors in a Japanese Population.

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.

Association between Socioeconomic Status and Digestive Tract Cancers: A Case-Control Study.

Although socioeconomic status (SES) has been associated with cancer risk, little research on this association has been done in Japan. To evaluate the association between SES and digestive tract cancer risk, we conducted a case-control study for head and neck, esophageal, stomach, and colorectal cancers in 3188 cases and the same number of age- and sex-matched controls within the framework of the Hospital-based Epidemiological Research Program at Aichi Cancer Center III (HERPACC III). We employed the education level and areal deprivation index (ADI) as SES indicators. The association was evaluated with odds ratios (ORs) and 95% confidence intervals (CIs) by conditional logistic models adjusted for potential confounders. Even after allowance for known cancer risk factors, the education level showed linear inverse associations with head and neck, stomach, and colorectal cancers. Compared to those educated to junior high school, those with higher education showed statistically significantly lower risks of cancer (0.43 (95% CI: 0.27-0.68) for head and neck, 0.52 (0.38-0.69) for stomach, and 0.52 (0.38-0.71) for colorectum). Consistent with these results for the educational level, the ADI in quintiles showed positive associations with head and neck, esophageal, and stomach cancers (p-trend: p = 0.035 for head and neck, p = 0.02 for esophagus, and p = 0.013 for stomach). Interestingly, the positive association between ADI and stomach cancer risk disappeared in the additional adjustment for Helicobacter pylori infection and/or atrophic gastritis status. In conclusion, a lower SES was associated with an increased risk of digestive cancers in Japan and should be considered in cancer prevention policies for the target population.

IgG4-related Autoimmune Hepatitis with a Suspected Drug-induced Etiology.

A 69-year-old man was referred to our department with acute hepatitis. He had been newly treated with benidipine hydrochloride for two months. His blood test results were as follows: aspartate aminotransferase, 1,614 IU/L; alanine aminotransferase, 1,091 IU/L and anti-smooth muscle antibody, ×80. Needle liver biopsy specimen showed interface hepatitis with mainly lymphocytic infiltration and bridging fibrosis in the periportal area. Immunohistochemistry revealed lymphocytic infiltration positive for IgG4. We diagnosed him with IgG4-related AIH with an etiology that was suspected of being drug-induced. Oral prednisolone was started and then tapered after achieving biochemical remission. Hepatitis recurred after the cessation of steroids; however, remission was achieved with ursodeoxycholic acid.

Across-Site Differences in the Mechanism of Alcohol-Induced Digestive Tract Carcinogenesis: An Evaluation by Mediation Analysis.

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.

A rare case of Goodpasture syndrome concomitant with bleeding jejunal Dieulafoy's lesion.

An 81-year-old man was diagnosed with Goodpasture syndrome (GS) because he met the criteria of positive anti-GBM antibodies, rapid progressive glomerulonephritis and pulmonary hemorrhage. After starting plasmapheresis and steroid pulse therapy, he experienced tarry stool and contrast-enhanced CT revealed an aneurysmal finding in the jejunum. Paroral enteroscopy showed a jejunal Dieulafoy's lesion (DL) with gush-out hemorrhage. Hemostasis was successfully achieved by hemoclipping, and he then experienced no re-bleeding events. GS can present as a jejunal DL, and contrast-enhanced CT is useful for investigating the etiology and site of small intestinal bleeding, which can lead to smooth, effective endoscopic hemostasis.

Prophylactic Biliary Stenting Before Cholecystectomy in Patients With Gallstones and Common Bile Duct Stones.

BACKGROUND: The usefulness of prophylactic biliary stenting for patients with common bile duct stones (CBDS) and gallstones (GS) to prevent recurrent biliary events after endoscopic sphincterotomy (EST) and CBDS extraction before elective cholecystectomy remains controversial. The aim of this study was to evaluate the risk of recurrent CBDS around the perioperative period and clarify its risk factors. METHODS: The clinical data of all patients who received prophylactic biliary stenting after EST for CBDS and later underwent cholecystectomy for GS followed by stent extraction in our institution were retrospectively reviewed. The numbers of residual CBDS at the end first and second endoscopic retrograde cholangiography (ERC) studies were compared. Univariate and multivariate analyses were performed using a logistic regression model to determine risk factors for recurrent CBDS in the perioperative period. RESULTS: Forty-two consecutive patients received prophylactic biliary stenting and subsequent cholecystectomy for GS. Three of these patients were excluded from this study because the number of residual stones was not confirmed. The median maximum CBDS diameter at second ERC was 0 mm (range, 0 - 10 mm); six patients had multiple CBDS (≥ 5). The number of CBDS at second ERC was increased in comparison to that at the first ERC in 15 patients (38.4%), and was unchanged or decreased in 24 patients. The median minimum cystic duct diameter was 4 mm (range, 1 - 8 mm). The median interval between first ERC and operation was 26 days (range, 2 - 131 days). The median interval between operation and second ERC was 41 days (range, 26 - 96 days). Laparoscopic cholecystectomy (LC) was performed in 38 patients, one of whom was converted from LC to open cholecystectomy. Postoperative complications (transient bacteremia) occurred in one patient. The cystic duct diameter was an independent risk factor for an increased number of CBDS at second ERC in the multivariate analysis (odds ratio 0.611 (95% confidence interval (0.398 - 0.939)), P = 0.03). CONCLUSION: Recurrent CBDS around the perioperative period of cholecystectomy is not a rare complication after EST and the removal of CBDS with concomitant GS. Prophylactic biliary stenting is considered useful for preventing CBDS-associated complications, especially for patients in whom the cystic duct diameter is larger (≥ 5 mm).

A Rare Case of Local Recurrence Following Curative Endoscopic Submucosal Dissection of Intramucosal Differentiated-Type Gastric Cancer.

A 78-year-old man underwent endoscopic submucosal dissection (ESD) of early gastric cancer (EGC) (type 0-IIa) in the anterior wall of the antrum. En bloc resection was achieved. The histopathological examination revealed very well-differentiated tubular adenocarcinoma (tub1) of 30 × 22 mm in size, confined to the mucosa. No lymphovascular invasion or ulceration was observed, and there was no undifferentiated-type component and the margins were tumor-free. Therefore, this lesion fulfilled the eCuraA criteria. Two years after ESD, esophagogastroduodenoscopy revealed an irregular, slightly-depressed lesion within the post-ESD scar. Tubular adenocarcinoma was suspected based on histopathological examination of a biopsy specimen. The tumor was resected by ESD. A histopathological examination revealed well-differentiated tubular adenocarcinoma (tub1) of 6 × 4 mm in size, confined to the mucosa. No lymphovascular invasion was detected and the margins were tumor-free. These findings indicated a curative resection. Recurrence following a curative ESD of an intramucosal differentiated-type EGC which fulfilled the eCuraA criteria is rare. Careful endoscopic observation using magnifying narrow band imaging (NBI) is needed after ESD, even when curative resection is achieved.

Experience of Manual Compression Hemostasis Under Endoscopic Observation for Acute Hemorrhagic Rectal Ulcer.

We experienced two cases in which manual compression hemostasis under endoscopic observation was used in patients with acute hemorrhagic rectal ulcer (AHRU). The patients experienced an episode of massive fresh hematochezia, requiring the blood transfusion. Emergent sigmoidoscopy revealed multiple ulcers with a large protuberant visible vessel or with gush-out hemorrhage on the lower rectum. Endoscopic hemostasis by hemoclips and hypertonic saline-epinephrine injection was attempted; however, mechanical mucosal injury induced by hemoclips and needles caused another gush-out hemorrhage. Thus, the site of bleeding was manually compressed by a forefinger under endoscopic observation. After 5 min, compression hemostasis was achieved, and the postoperative course was uneventful. Manual compression hemostasis under endoscopic observation is useful and worth attempting for AHRU.

[Subcapsular hepatic hematoma due to vessel injury from the rigid portion of a guidewire during endoscopic retrograde cholangiopancreatography].

A 58-year-old male receiving two types of antithrombotic medication developed acute obstructive suppressive cholangitis due to choledocholithiasis. During the first endoscopic retrograde cholangiopancreatography (ERCP) procedure, we performed biliary plastic stenting. Seven days after this procedure and with continued antithrombotic treatment, we performed ERCP with endoscopic sphincterotomy and stone extraction. Twelve hours after this procedure, the patient suffered transient unconsciousness and progression of anemia. Sixty hours after the procedure, he experienced right hypochondralgia and hiccups. Ultrasonography and computed tomography revealed a subcapsular hepatic hematoma. Bleeding was successfully arrested with selective arterial embolization. We suspected that the cause of these problems was vessel injury from the rigid portion of the guidewire during the ERCP procedure.

Endoscopic closure of an anastomo-cutaneous fistula: Filling and shielding using polyglycolic acid sheets and fibrin glue with easily deliverable technique.

Background and study aims Recently, endoscopic closure of gastrointestinal fistulas using polyglycolic acid (PGA) sheets with fibrin glue (FG) has been attempted. A 70-year-old woman who had undergone pancreaticoduodenectomy for pancreatic cancer suffered from a refractory anastomo-cutaneous fistula at the site of gastro-jejunostomy. We attempted endoscopic closure with filling and shielding using PGA sheets and FG. After introducing a guidewire into the fistula, a small piece of PGA sheet was skewered onto the guidewire and then pushed using a tapered catheter over the guidewire and delivered into the fistula. A total of 10 sheets were delivered via the same procedure. Next, the mucosa around the fistula was ablated, and the orifice of the fistula along with the surrounding mucosa was shielded with a piece of PGA sheet fixed with hemoclips and FG. After this procedure, the leakage disappeared and the fistula was undetectable on contrast radiograms. Endoscopic closure of anastomo-cutaneous fistula with filling and shielding using PGA sheets and FG is an effective, safe, low-invasive treatment, and the filling technique using a guidewire ensures a safe, smooth procedure.

[Screening for colorectal cancer using immunological fecal occult blood test in inpatients].

We investigated the usefulness of screening for colorectal cancer (CRC) using immunological fecal occult blood test (FOBT) in 472 scheduled inpatients (median age, 68.6 years) who underwent screening for CRC via FOBT (single stool sample) at our hospital. The recall rate for further examination was 26.6% (126/472), and the rate of patients who underwent further examination was only 34.9% (44/126). The overall colorectal neoplasm detection rate, overall CRC detection rate, and positive predictive value for CRC in inpatients were 5.5% (26/472), 1.4% (7/472), and 5.5% (7/126), respectively, which were higher than those of population-based screening for CRC. Screening for CRC using FOBT in inpatients is a non-invasive and efficient method to detect latent CRC.

Intraductal Ultrasonography as a Local Assessment Before Magnetic Compression Anastomosis for Obstructed Choledochojejunostomy.

Magnetic compression anastomosis (MCA) has been developed as a non-surgical alternative treatment for biliary obstruction without serious complications. A 70-year-old woman who had undergone pancreaticoduodenectomy with modified Child reconstruction for pancreatic head cancer suffered from obstructed choledochojejunostomy with no recurrent findings 4 months after the operation. Cholangiography using the percutaneous transhepatic cholangiographic drainage (PTCD) and fluoroscopy revealed complete obstruction of the upper common bile duct, and the length of the obstruction was 7 mm. Intraductal ultrasonography (IDUS) showed fibrous heterogenous hyperechoic appearance without fluid collection, vessels or foreign bodies at the site of the obstruction. We performed choledochojejunostomy using the MCA technique. One magnet was inserted into the obstruction of the hepatic side through the PTCD fistula. Another was delivered endoscopically to the obstruction of the jejunal side. The two magnets were immediately attracted towards each other transmurally, and reanastomosis was confirmed 7 days after starting the compression. The magnets were easily retrieved endoscopically. A 16-Fr indwelling drainage tube was placed in the jejunum through the PTCD. The internal tube is still in place 6 months after reanastomosis, and no MCA-related complications have been observed. In conclusion, MCA is a safe, effective, low-invasive treatment for biliary obstruction, and IDUS is useful for the pretreatment assessment of feasibility and safety.