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Incidental gallbladder cancers （IGBCs） refer to gallbladder cancers （GCs） that are not preoperatively diagnosed but are diagnosed only after cholecystectomy for benign gallbladder diseases. This exploratory study aimed to investigate the diagnostic performance of bile cytology with percutaneous transhepatic gallbladder drainage （PTGBD） and tumor markers in preoperatively detecting IGBC. Data on consecutive acute cholecystitis cases between January 2018 and March 2020 at the Showa University Hospital in Tokyo, Japan, were retrospectively analyzed. Patient characteristics, bile cytology results, collection date, and blood test results were assessed. Concerning the bile cytology results, classes I–III were categorized as negative, whereas classes IV and V were positive. Bile cytology was performed in 102 patients; of these, 2 cases were diagnosed as GC. The bile cytology results were as follows: class I in 15 cases; class II in 84; class III in 2; class IV in 1; and class V in 0. Therefore, 101 and 1 cases were judged as negative and positive, respectively. Bile cytology had a sensitivity of 50％, specificity of 100％, positive predictive value of 100％, and negative predictive value of 99％. Among 47 patients in whom carcinoembryonic antigen （CEA） and carbohydrate antigen 19-9 （CA19-9） levels were measured, 3 and 12 patients exhibited elevated CEA and CA19-9 levels, respectively. Tumor markers were elevated in IGBC cases; however, several false-positive results were present in cases without GC. Bile cytology from PTGBD may be useful for the preoperative diagnosis of IGBC with acute cholecystitis. Measurement of CEA and CA19-9 levels as tumor markers should be performed with caution, as false-positive results due to inflammation would be included.

To identify the risk factors and clinical results for acute cholecystitis after covered self-expandable metal stent （SEMS） placement for distal malignant biliary obstruction （MBO）, we have retrospectively examined the clinical outcomes in patients with acute cholecystitis after endoscopic biliary SEMS placement for distal MBO. This was a retrospective study. Between January 2014 and June 2017, 90 patients who were identified to have underwent endoscopic covered SEMS placement for distal MBO at our institution were included in this analysis. Patients with benign biliary strictures after cholecystectomy were excluded. After covered SEMS placement, we followed up with physical examination and laboratory data and continued with the follow-up for as long as possible. The risk factors for acute cholecystitis after covered SEMS placement were then evaluated. Acute cholecystitis was observed in 15 patients （17％） after covered SEMS placement. The median time to the onset of acute cholecystitis after covered SEMS placement was 19 days （interquartile range, 5-127 days）. Cholecystitis was initially treated with percutaneous gallbladder aspiration （PTGBA） in 11 patients, percutaneous gallbladder drainage （PTGBD） in 2 patients, and antimicrobial therapy alone in 2 patients. Five patients （including four patients treated with PTGBA and one patient treated with antimicrobial therapy alone） had cholecystitis recurrence. In a multivariate analysis of the risk factors for cholecystitis after covered SEMS placement, bile duct cancer （odds ratio （OR）, 12; P＝0.028）, thin bile duct diameter （≤8mm） （OR, 5.2; P＝0.048）, and chemotherapy （OR, 12.6; P＝0.008） were identified as the significant risk factors. Bile duct cancer, thin bile duct diameter, and chemotherapy were identified as risk factors for acute cholecystitis after endoscopic covered SEMS placement for distal MBO. PTGBA is useful as the initial treatment for acute cholecystitis after covered SEMS placement for distal MBO; however, cholecystitis recurrence should be taken into consideration.

Surgical resection for colorectal cancer（CRC）that deeply invades the submucosa（≥1,000µm）（T1b）has been recommended to reduce the potential risk of lymph node metastasis. In clinical settings, cases of pathological T1b exist, and these cases are treated with endoscopic resection（ER）for various reasons. However, factors that influence the choice of ER to treat T1b CRC remain unknown. Therefore, in this study, we investigated the factors associated with the choice of endoscopic treatments in patients diagnosed with pathological T1b or a more deeply invading CRC. To achieve this aim, we conducted a case series investigation of the previously conducted endoscopic diagnoses, after which we selected treatments for colorectal lesions. The case series comprised 83 lesions endoscopically diagnosed as early CRC, which was subsequently reviewed by eight endoscopists with various levels of experience in magnifying colonoscopy at Showa University Hospital. Then, pathological T1b or T2 lesions were extracted from the case series. We also assessed factors related to ER selection for these lesions using multiple logistic regression and analyzed their contributions using decision tree analysis. Eighteen cases with pathological T1b or more deeply invading lesions were extracted, and the analyses were conducted using 144 data obtained from these 18 lesions as interpreted by the eight reviewers. With multivariate logistic regression, a low estimation level for T1b and high confidence to perform ER were identified as independent factors affecting the selection of ER for T1b. The decision tree analysis further indicated that confidence levels to perform ER influenced treatment selection, especially in lesions diagnosed as probable T1b. Our study therefore demonstrated that factors affecting the selection of ER to treat T1b CRCs were low estimations during endoscopic diagnosis and high confidence to conduct the ER procedure.

This study is aimed at investigating the relationship between the polymeric immunoglobulin receptor （pIgR） expression and clinicopathological factors in advanced colorectal cancer （CRC） patients. The study involved 47 advanced CRC patients who were surgically resected and underwent KRAS gene test. The pIgR expression was analyzed by immunohistochemistry, and the patients were classified into high and low （pIgR-H and pIgR-L, respectively） groups based on the staining intensity and range. A total of 13 cases was classified under the pIgR-H group, and the remaining 34 were classified under the pIgR-L group. Results suggest no significant differences in most clinicopathological factors between the pIgR-H and pIgR-L groups, although the pIgR-L group had a significantly higher frequency of venous invasion than the pIgR-H group, whereas the frequency of KRAS gene mutation was significantly higher in the pIgR-H group than that in the pIgR-L group. The findings in this study showed little significant correlation between the pIgR expression and clinicopathological factors in advanced CRC patients. Further research on the biological behavior of pIgR as a drug treatment option for KRAS-mutated advanced CRCs is also warranted.

Serum levels of tumor markers, such as carcinoembryonic antigen （CEA） and carbohydrate antigen 19-9 （CA19-9）, are often measured to detect potential malignancy. When these levels are high, the presence or absence of malignancy is confirmed via a more detailed examination using gastrointestinal （GI） endoscopy and computed tomography. The rate of confirmation of malignancy upon such a follow-up is unknown. This study aimed to investigate the malignancy detection rate via GI endoscopy for patients with high levels of serum CEA and CA19-9. All patients who underwent such GI endoscopy between January 2018 and February 2019 at Showa University Hospital were included in this study. The patients were divided into a follow-up group and a screening group, depending on the purpose of measuring their serum CEA/CA19-9 levels. There were 156 patients who underwent GI endoscopy because of high CEA/CA19-9 levels within the study period. Advanced malignant lesions were detected in 10 patients （6.4％）, including seven cases of colorectal cancer and three cases of upper GI malignancies. In the screening group, six cases （5.7％） of GI malignancies were detected, none of which were found in asymptomatic patients without anemia. In the follow-up group, four cases （7.8％） of GI malignancies were detected; three patients were asymptomatic, and one patient had anemia. Our findings suggest that high serum CEA/CA19-9 levels in asymptomatic patients without anemia and without a history of malignancy do not indicate the presence of malignancy. However, high serum CEA/CA19-9 levels may indicate the potential presence of GI malignancies for patients with a history of malignant tumors, even if they are asymptomatic and do not have anemia.

Reports on surveillance systems useful for determining the risk of developing hepatocellular carcinoma （HCC） after direct-acting antiviral （DAA） treatment for hepatitis C have been published. Liver cirrhosis （LC） is a high-risk factor for HCC, but the evaluation frequency necessary for patients with chronic hepatitis （CH） remains unknown. Here, we aimed to identify how frequent CH patients should be evaluated for HCC, with particular emphasis on patients achieving a sustained virological response （SVR） with DAA treatment. Data were collected pre-treatment （Pre） and at the time of SVR for 141 patients with hepatitis C receiving DAA treatment. We defined LC by a platelet （PLT） count ≤10×104/µl, and CH was defined by a PLT count of ＞10×104/µl. The incidence of HCC in patients with CH after achieving SVR was retrospectively evaluated. In total, 128 patients （CH, n＝102; LC, n＝26） achieved SVR, and 13 developed HCC after SVR during the follow-up period （mean, 748 days）. Although fibrosis-4 （FIB-4） index, the presence of α-fetoprotein, and prothrombin time were significant risk factors for HCC in patients with CH in the univariate analysis, only the Pre-FIB-4 index was an independent predictive factor for HCC development in the multivariate analysis （p＝0.04）. An FIB-4 index ≥3 was a significant risk factor for HCC （p＝0.005）. The cumulative risk for HCC at 1000 days was 2.6％ and 24.2％ in the FIB-4 index ＜3 and FIB-4 index ≥3 groups, respectively （p＝0.004）. Frequent HCC examination is recommended for FIB-4 index ≥3 CH patients who obtain SVR after DAA treatment.

Hepatitis C virus（HCV）infection can cause chronic liver disease; it has also been associated with lymphoproliferative disorders（LPDs）, such as cryoglobulinemia and B-cell non-Hodgkin’s lymphoma. Our previous studies suggested that cryoglobulinemia, high titer of rheumatoid factor（RF）, and hypocomplementemia are immunological markers of LPDs. In addition, recent therapies with direct-acting antivirals（DAAs）have achieved high rates of sustained virological response（SVR）in patients with chronic hepatitis C（CH-C）. This study analyzed the efficacy of DAA therapy in CH-C patients with cryoglobulinemia, and the association of biochemical and other immune markers for LPDs with persistence of cryoglobulinemia in patients after DAA therapy. Of 226 patients tested, 31（13.7％）had cryoglobulinemia prior to receiving DAAs, and these individuals showed lower complement 4 levels, decreased complement hemolytic activity, and higher IgM than patients without cryoglobulinemia. Of the 24 cryoglobulinemia-positive patients（83％）who could be followed for 24 weeks, 20 became cryoglobulinemia negative after the therapy. The remaining four patients retained the abnormal LPD markers, indicating the possibility of long-term LPD persistence even following successful eradication of HCV in CH-C patients. Thus, long-term follow-up is recommended to avoid exacerbation of extrahepatic manifestations as well as new events.

The present study sought to compare the effectiveness of a proton pump inhibitor （PPI） with that of a histamine H2 receptor antagonist （H2RA） for treating functional dyspepsia （FD） in a real-world setting. A multicenter, open-label, randomized trial was conducted. FD patients were randomly assigned to receive either 20mg, q.d., omeprazole （OPZ; a PPI） or 150mg, b.i.d., ranitidine hydrochloride （RAN; an H2RA） for 4 weeks. Any change in the total Gastrointestinal Symptom Rating Scale （GSRS） score （delta） at week 4 was the primary outcome measure. Secondary outcome measures were reductions in scores for individual items on the GSRS at week 4. As a subanalysis, patients were stratified according to Helicobacter pylori serology and the analyses were repeated. The mean （±SD） deltas in total GSRS score for the OPZ and RAN groups were 0.8±0.7 and 0.6±0.6, respectively （P＝0.098）; however, the delta in reflux score between the OPZ and RAN groups differed significantly （1.1±0.7 vs. 0.5±0.5, respectively; P＝0.001）. There were no significant differences between the two groups in any other scores for individual items on the GSRS. The results of the subanalysis were like those of the main analysis. The PPI and H2RA produced a comparable improvement in symptoms of FD in our patient cohort, thus we propose no advantage would be gained in using a PPI rather than an H2RA.

Some serrated polyps （SPs） are thought to be precursors of colorectal cancers. However, the endoscopic diagnosis of sessile serrated adenoma/polyps （SSA/Ps） has been reported to have a low accuracy. The aim of this study was to clarify the ability to distinguish between SSA/Ps and non-SSA/Ps by using mucosal crypt patterns combined with endoscopic findings. In total, 457 consecutive patients who underwent endoscopic resection for colorectal polyps at the Showa University Hospital from April 2007 to December 2010 were prospectively enrolled in this study. Before treatment, mucosal crypt patterns of the lesions were classified into three types （hyperplastic, adenomatous, and mixed pattern）. When the lesion had an adenomatous pattern with a cerebriform appearance or mixed pattern, it was diagnosed as a traditional serrated adenoma （TSA）. If the lesion had a hyperplastic pattern and was sized 6mm or more in the proximal colon or 10mm or more in the distal colon, it was diagnosed as an SSA/P by the endoscopist. We analyzed 1,151 colorectal polyps in this study. Endoscopically, 117 polyps were diagnosed as SSA/Ps or hyperplastic polyps （HPs）, 998 polyps were conventional adenomas, and 36 polyps were TSAs, with diagnostic accuracies of 94.7％, 94.1％, and 97.3％, respectively. Of the 117 polyps diagnosed as SSA/Ps or HPs, 59 lesions met our criteria for SSA/Ps, with a diagnostic accuracy of 70.9％. Our results indicate that the combination of mucosal crypt patterns and endoscopic findings may be useful for differentiating between SPs and non-SPs. However, additional specific endoscopic features of SSA/Ps are still needed.

Sessile serrated adenoma/polyps (SSA/Ps) are thought to be precursors of colorectal cancers. However, current endoscopic techniques for differentiating SSA/Ps from conventional hyperplastic polyps (HPs) have low diagnostic accuracy. The aim of the present study was to assess the ability of mucosal crypt patterns to distinguish SSA/Ps from HPs. We examined 140 lesions from 93 patients that had been diagnosed histologically as SSA/Ps or HPs at the Showa University Hospital between June 2010 and May 2012. Three experienced colonoscopists reviewed the endoscopic findings of magnifying colonoscopy. Type II open-shape (Type II-O) pit patterns and varicose microvascular vessels (VMVs) were identified according to previously proposed definitions. Although 140 lesions were initially identified for the study, 27 lesions were excluded from analysis because of insufficient endoscopic findings. Thus, endoscopic findings from a total of 113 lesions (68 SSA/Ps and 45 HPs) were evaluated. Of 113 serrated polyps, 51 lesions (44 SSA/Ps and 7 HPs; P

Doripenem (DRPM) is a relatively new drug belonging to the carbapenem antibiotic group. We hypothesized that the pharmacological characteristics of DRPM could make it useful in the treatment of severe acute pancreatitis (SAP). We investigated the usefulness of continuous regional arterial infusion (CRAI) with DRPM and protease inhibitors for SAP. Two hundred and forty-two patients with SAP were admitted to Showa University Hospital between November 2002 and June 2013. Of these, 53 patients were treated with CRAI with carbapenem antibiotics and nafamostat mesilate (NM), a serine protease inhibitor, via the celiac and superior mesenteric arteries. Clinical outcomes were evaluated retrospectively in 34 patients treated with DRPM and 19 patients undergoing non-DRPM therapy (meropenem n=11, imipenem n=6; biapenem n=2). The median time to commencement of oral intake was significantly shorter in the DRPM than non-DRPM group (9 vs 14 hospital days, respectively; P

We investigated the safety and utility of endoscopic removal of common bile duct stones (CBDS) in the elderly. In all, 253 patients with CBDS who underwent endoscopic retrograde cholangiopancreatography (ERCP) between January 2007 and December 2011 at Showa University Hospital were evaluated retorspectively. The median age of the patients was 75 years ; thus, we divided patients into two groups, those aged ≥ 75 years (Group A ; n ＝ 134) and those aged ＜75 years (Group B ; n ＝ 119). Patients in Group A had significantly higher rates of endoscopic sphincterotomy in palliative ERCP (24.8% vs. 10.7%; p ＝ 0.008) and palliative removal of CBDS (34.8% vs. 20.9%; p ＝ 0.015) than patients in Group B. However, the median dose of flunitrazepam was significantly lower for patients in Group A than Group B (1 vs. 1.4 mg, respectively ; p ＜ 0.001). The rate of use of pentazocine (18.5% vs. 54.7%; p ＜ 0.001) and scopolamine butylbromide (6.2% vs. 23.9%; p ＜ 0.01) was significantly lower in Group A patients, whereas the use of glucagon was significantly higher in this group (43.8 vs. 15.4%; p ＜ 0.001). There were no significant differences in the rate of successful endoscopic removal of CBDS, treatment time, complications, and the recurrence of CBDS between the two groups. Endoscopic removal of CBDS in the elderly is a safe procedure with good outcomes if the appropriate treatment is selected.

Colorectal flat-elevated neoplasms can be classified into small-flat adenoma and laterally spreading tumors (LSTs), which can then be sub-categorized into granular-type (LST-G) and nongranular-type (LST-NG) LSTs with possible biological differences between them. We evaluated clinicopathological features and KRAS / BRAF mutations in 24 LST-Gs and 57 LST-NGs. PCR-based pyrosequencing assays were used to determine the presence of activating mutations in codons 12 and 13 of KRAS and in codon 600 of BRAF. Significant differences between LST-Gs and LST-NGs were observed in tumor size (30mm vs. 15mm, P

Hepatitis viruses are causative agents for chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. However these viruses are also associated with lymphoproliferative disorders (LPDs), such as essential mixed cryoglobulinemia and B-cell non-Hodgkin's lymphoma. Indeed, hepatitis C virus infection has been confirmed to be associated with LPDs, but the pathogenic mechanism remains unclear. In this study, we investigated the relationship between hepatitis B virus (HBV) infection and LPDs in 84 patients with chronic hepatitis B (CH-B). LPD markers, such as cryoglobulinemia, high levels of rheumatoid factor (RF), hypocomplementemia, and B cell clonality, were measured and analyzed along with viral factors. Results showed that high levels of RF were observed in 39.5% of patients with CH-B. These high RF levels were not associated with abnormal levels of other LPD markers, but only with the presence of HBV DNA in the sera of these patients. Undergoing therapy with nucleotide analogues was also associated with high RF. In two patients with CH-B, decreasing levels of RF were observed during antiviral therapy. In conclusion, high RF levels are associated with HBV viremia in patients with CH-B. HBV infection also plays an important role in the genesis of LPDs in patients with viral hepatitis.

Gastric cancers (GC) with methylation of multiple CpG islands have a CpG island methylator phenotype (CIMP) and they can have different biological features. The aim of this study was to investigate the DNA methylation status of GCs and its association with their clinicopathological features. We evaluated the methylation status of four genes (MINT1, MINT2, MINT25 and MINT31) in 105 primary GCs using bisulfite-pyrosequencing analysis. We classified tumors as CIMP-high (CIMP-H), CIMP-low (CIMP-L) or CIMP-negative (CIMP-N) based on the methylation of MINT1, MINT2, MINT25, and MINT31. Overall, the prevalence of CIMP-H, CIMP-L and CIMP-N was 22% (23/105), 52% (55/105) and 26% (27/105), respectively. We observed a significant difference in tumor stage (stages I-II vs. stages III-IV) between CIMP-H and CIMP-N tumors (P = 0.0435). No significant differences were observed in clinicopathological characteristics (gender, age, location and tumor differentiation) among the CIMP phenotypes. The prognoses of patients with a CIMP-H tumor is likely to be better than those with CIMP-L or CIMP-N tumors, but these differences are not statistically significant (P = 0.074 and P = 0.200). Our results suggest that CIMP may define a subgroup of GCs with distinct biological features.

Diabetes mellitus (DM) is observed in patients with autoimmune pancreatitis (AIP). The development of DM in AIP is believed to be due to blood flow obstruction of the endocrine gland that accompanies pancreatitis, as well as injury to the islets caused by inflammation. The latter is called insulitis and the detailed mechanisms underlying its development are not yet clear. The aim of the present study was to elucidate the mechanisms involved in the development of insulitis in AIP using aly mice as an animal model of AIP: results in aly/aly male mice, as the AIP group, were compared with those inaly/+ male mice as a control group. Mice in both groups were killed between 16 and 48 weeks of age, and pancreatitis and insulitis were evaluated histologically. Inflammatory and endocrine cells were evaluated by immunofluorescence staining with anti-CD4, anti-CD8, anti-CD11b, and anti-CD11c antibodies, as well as immunohistochemical analyses using insulin and glucagon antibodies. Plasma levels and the pancreatic content of interferon (IFN)-γ (as a Th1-secreted cytokine) and interleukin (IL)-4 (as a Th2-secreted cytokine) were determined. Pancreatitis was seen in aly/aly mice from 16 weeks of age and it developed gradually thereafter. Insulitis also developed gradually and was seen in mice after 24 weeks of age in association with a decrease in the number of islets. CD11c+ cells and CD4+ T cells were seen to infiltrate into the islets. Although the number of β-cells decreased with time, the number of α-cells was maintained until mice were 48 weeks of age. IFN-γ content peaked in mice at 16 weeks of age and declined rapidly from 20 weeks. There were two peaks in IL-4 content, one at 16 weeks and the other at 32 weeks, suggesting an association between IL-4 content and advanced insulitis after 32 weeks. In conclusion, the results suggest that insulitis in AIP is induced predominantly by the infiltration of CD11c+ cells and CD4+ T cells into the islets, and progression is facilitated by the imbalance of the activation of Th2 rather than Th1. Furthermore, insulitis in AIP predominantly involves β-cells rather than α-cells.