Biphasic clinical course of a ruptured right gastric artery aneurysm caused by segmental arterial mediolysis: a case report.

BACKGROUND: Gastric artery aneurysms are rarely caused by segmental arterial mediolysis (SAM), a condition that often involves multiple vessels. The clinical course of SAM after vessel rupture may vary depending on the involved vessels. For example, the "double-rupture phenomenon" observed following the rupture of the splenic artery aneurysm manifests as a biphasic and relatively slow clinical course. Even in cases of rupture of gastric artery aneurysm, the double-rupture phenomenon has only been reported in two cases so far. However, the rupture was not caused by SAM in either case. Herein, we present the apparent first case of a right gastric artery (RGA) aneurysm rupture caused by SAM that presented with a biphasic clinical course, possibly due to the double-rupture phenomenon. CASE PRESENTATION: A 54-year-old woman was transferred to the emergency department with severe abdominal pain and a cold sweat for a duration of 3 h. She had developed mild abdominal pain and nausea 3 days earlier. Her vital signs were stable. Physical examination revealed tenderness in the epigastric area. Abdominal contrast-enhanced computed tomography revealed an RGA aneurysm with contrast media extravasation. A diagnosis of hemoperitoneum following a ruptured RGA aneurysm was made, and the patient underwent angiography. However, this modality did not reveal any extravasation from the RGA due to an interruption in the peripheral branch of the artery. Nevertheless, to prevent major bleeding, we performed coil embolization at the point of interruption in the RGA, which we suspected to be a ruptured aneurysm. A distal gastrectomy with Roux-en-Y reconstruction for aneurysm resection was performed the following day. There were no postoperative complications, and the patient was discharged 17 days after surgery. Histologically, the RGA demonstrated multiple vacuoles in the medial muscle layer, which were characteristic of SAM. CONCLUSIONS: An RGA aneurysm rupture should be considered a differential diagnosis in patients presenting with hemoperitoneum with a slow or biphasic clinical course.

Clinical and endoscopic evaluations of sessile serrated adenoma/polyps with cytological dysplasia.

BACKGROUND AND AIM: Although sessile serrated adenoma/polyps (SSA/Ps) are considered to be premalignant lesions and rapidly progress to carcinomas after they develop cytological dysplasia (CD), a treatment strategy for SSA/Ps in Asian countries is still being debated and has not yet been established. The present study aimed to propose a treatment strategy for SSA/Ps. METHODS: Histopathological data of patients, who underwent colonoscopy at our center between January 2011 and December 2016, were reviewed. Data of patients with ≥ 1 SSA/P were retrieved, and clinicopathological characteristics were retrospectively analyzed. RESULTS: A total of 281 patients with 326 SSA/Ps, including 258 patients who had 300 SSA/Ps without CD (SSA/Ps-CD[-]) and 23 patients who had 26 SSA/Ps with CD (SSA/Ps-CD[+]), were evaluated in this study. Although SSA/Ps-CD(+) were often found in older female patients and in the proximal colon, there were no significant differences between SSA/Ps-CD(-) and SSA/Ps-CD(+). Endoscopic morphological findings, such as large or small nodules on the surface and partial protrusion of the lesions, were significantly more common in SSA/Ps-CD(+) than in SSA/Ps-CD(-). Although the diagnostic ability of nodule/protrusion in lesions to predict CD within SSA/Ps was very high with an accuracy of 93.9% and a negative predictive value of 95.4%, sensitivity was low at 46.2%. SSA/Ps-CD(+) were significantly larger than SSA/Ps-CD(-), and the rate of CD within SSA/Ps significantly increased with lesion size (≤ 5 mm, 0%; 6-9 mm, 6.0%; ≥ 10 mm, 13.6%). CONCLUSION: The study proposes removing all SSA/Ps ≥ 6 mm in order to remove high-risk SSA/Ps-CD(+), with high sensitivity.

Additional chromoendoscopy for colorectal lesions initially diagnosed with low confidence by magnifying narrow-band imaging: Can it improve diagnostic accuracy?

BACKGROUND AND AIM: Magnifying chromoendoscopy has been one of the most reliable diagnostic methods for distinguishing neoplastic from non-neoplastic lesions. The aim of this prospective study was to clarify the clinical usefulness of magnifying chromoendoscopy for colorectal polyps initially diagnosed with low confidence (LC) by magnifying narrow-band imaging (NBI). METHODS: Consecutive adult patients who underwent total colonoscopic examination with magnifying NBI between July and December 2016 at Sano Hospital were prospectively recruited. Endoscopists were asked to carry out additional magnifying chromoendoscopy for cases that had been initially diagnosed as Japan NBI Expert Team (JNET) Type 1 or 2A with LC by magnifying NBI. We investigated the diagnostic performance of magnifying NBI for polyps diagnosed as JNET Type 1 or 2A with LC (first phase) and that of subsequent magnifying chromoendoscopy (second phase) in differentiating neoplasia from non-neoplasia. RESULTS: In 50 patients, we analyzed 53 polyps classified as JNET Type 1 or 2A with LC prediction. Accuracy and negative predictive value of magnifying NBI (first phase) were 58.5% (95% CI, 44.1-71.9%) and 66.0% (95% CI, 36.6-77.9%), and those of magnifying chromoendoscopy (second phase) were 66.0% (95% CI, 51.7-78.5%) and 61.1% (95% CI, 43.5-76.9%), respectively. CONCLUSION: Regardless of the findings of additional chromoendoscopy, all polyps should be resected and submitted for histopathological examination when the confidence level in differentiating adenomatous from hyperplastic polyps by magnifying NBI is low.

[An Elderly Patient with Local Recurrence of Gastric Cancer Responding Completely to S-1 Monotherapy].

An 80-year-old man with a local recurrence of gastric cancer was treated with S-1 monotherapy leading to a complete response(CR).The patient was diagnosed with gastric cancer and underwent a distal gastrectomy with lymph node dissection. Pathological findings showed tub2>por1, pT3 (SS), pN2, pStage III A.Five months after surgery, the patient presented with redness of the abdominal skin.Computed tomography (CT) revealed massive tumors in the abdominal cavity with invasion to the abdominal wall. He was administered S-1, 80 mg/body/day for 14 days, followed by a 7-day rest.After 2 courses of treatment, CT showed a dramatic reduction of the tumors. After 6 months, the tumor tissue completely disappeared and he had a CR.Administration of S-1 was continued for 2 years and 6 months.There was no relapse for 3 years after discontinuation.S -1 monotherapy appears to be a feasible and effective therapy for elderly patients with recurrent gastric cancer.

Effect of skip lymphovascular invasion on hepatic metastasis in colorectal carcinomas.

BACKGROUND: "Skip" lymphovascular invasion presenting as discontinuous foci of tumor cells within the colon wall is now excluded from consideration when determining T stage in the TNM classification. The purpose of this study was to assess the clinicopathological characteristics of colorectal cancer (CRC) patients with such skip lymphovascular invasion. METHODS: First, a retrospective questionnaire survey of the incidence of skip lymphovascular invasion was performed for a total of 1,868 patients with CRCs at ten institutions. Next, we comparatively assessed clinicopathological data for 896 CRC patients with or without skip lymphovascular invasion. RESULTS: The incidence of skip lymphovascular invasion was 1.1 % (20 out of 1,868). Most of the affected cases were rectal, pT2, and node negative, with moderately differentiated histology. Skip lymphovascular invasion was present in the muscularis propria and subserosa, with the tumors directly invading submucosa (pT1) or muscularis propria (pT2). Hepatic metastasis was greater in CRC with skip lymphovascular invasion (25 %) than in pT1/2 CRC (0 %; P < 0.001) or pT3 CRC without such invasion (13.8 %; P = 0.185). CONCLUSIONS: Our study suggests that skip lymphovascular invasion is associated with hepatic metastasis in CRC cases. Thus, definition of a T category including such invasion would be useful for clinical practice.

Analysis of KRAS mutations in cases of metastatic colorectal cancer at a single institution in Tochigi, Japan.

OBJECTIVE: Colorectal cancer patients bearing wild-type KRAS benefit from anti-epidermal growth factor receptor (EGFR) antibody treatment. Since clinical studies showed the efficacy of anti-EGFR antibody treatment for metastatic colorectal cancer (mCRC), we analyzed KRAS mutations in mCRC to gain insight into the association between these mutations and clinicopathological characteristics. METHODS: KRAS mutations were analyzed in 109 tissue samples of mCRC using amplification refractory mutation system-Scorpion (ARMS/S) assay (68 samples) and direct sequencing (41 samples). RESULTS: In the ARMS/S assay, 36.5 and 7.4% of mCRCs harbored mutations at codons 12 and 13, respectively. In direct sequencing, corresponding values were 24.4 and 19.5%. Overall, 37.6% (codon 12/13, 25.7/11.9%) of mCRCs harbored KRAS mutations. No significant differences were found between KRAS mutations and clinicopathological variables. Among mCRC patients <65 years of age, the incidence of KRAS mutations at codon 13 was significantly higher in female than male patients (p = 0.035). CONCLUSION: The incidence of KRAS mutations in mCRC was similar to that of non-mCRC as previously reported. KRAS codon 13 mutations might be associated with younger female patients with mCRC, but further investigation is necessary to clarify the association between this type of mutation and metastatic potential in female CRC patients.

[The brand new trend of colorectal carcinoma pathology].

Japanese classification of colorectal carcinoma continues to develop several decades. In 2015, the Japanese Society for Cancer of the Colon and Rectum published the eighth edition of the general rules for clinical and pathological studies on cancer of the colon, rectum, and anus. The new Japanese classification of colorectal carcinoma based on new evidences including sessile serrated adenoma/polyp (SSA/P) of serrated polyp, budding, desmoplastic reaction, head/stalk invasion, submucosal invasion depth for early cancer, EX (extramural cancer deposit), and PN (perineural invasion) for advanced cancer. And recently molecular targeted therapy for anti EGFR has made rapidly progress in refractory advanced cancer. However, some issues still remain to be resolved in pathological diagnosis. We describe and discuss about assessment of pathological diagnosis for new therapy for colorectal carcinoma.

Digestive disease management in Japan: a report on the 6th diagnostic pathology summer fest in 2012.

The 6th Diagnostic Pathology Summer Fest, held in Tokyo on August 25-26, 2012, opened its gates for everyone in the medical profession. Basic pathology training can contribute to the improvement of algorithms for diagnosis and treatment. The 6th Summer Fest with the theme 'Pathology and Clinical Treatment of Gastrointestinal Diseases' was held at the Ito International Research Center, The University of Tokyo. On August 25, 'Treatment of Early Gastrointestinal Cancer and New Guidelines' was discussed in the first session, followed by 'Biopsy Diagnosis of Digestive Tract: Key Points of Pathological Diagnosis for Inflammation and Their Clinical Significance' in the second session. On August 26, cases were discussed in the third session, and issues on pathological diagnosis and classification of neuroendorcrine tumor in the fourth session. The summaries of speeches and discussions are introduced along with the statements of each speaker. This meeting was not a formal evidence-based consensus conference, and 20 experts gave talks on their areas of specialty. Discussion was focused on how the management strategy should be standardized on the algorithm of patient care.

Histological assessment of intra- and inter-institutional reliabilities in detection of desmoplastic reaction in biopsy specimens of early colorectal carcinomas.

We previously reported a relationship between depth of submucosal invasion of early colorectal carcinomas and desmoplastic reaction (DR). However, poor inter-observer agreement on the histopathological diagnosis of DR in biopsy specimens with hematoxylin and eosin (H&E) staining has been the major critique of this tool. In this study, reproducibility of the histopathological diagnosis of DR was evaluated. Furthermore, we investigated the possible improvement of the reproducibility after education about histological characteristics and tried to identify histological characteristics that are most important in the recognition of DR. A total of 34 H&E stained slides were included in this study and analyzed by three pathologists. Slides were reviewed before and after education about histological characteristics of DR. Kappa statistics were used to compare the inter-observer variability. We investigated the relationship between DR and histopathological factor. The inter-observer agreement during the first session varied between 0.30 and 0.63, which improved during the second session toward an agreement between 0.58 and 0.71. Myofibroblast proliferation associated with cancer invasion was found to be the most useful in the diagnosis of DR. In conclusion, the correct detection of myofibroblasts may facilitate the standardization of diagnosis of DR.

Immunohistochemical analysis of the DNA methyltransferase 3b expression is associated with significant improvements in the discrimination of ulcerative colitis-associated neoplastic lesions.

PURPOSE: Making a clinicopathological diagnosis of dysplasia is crucial. We herein assess the significance of the DNA methyltransferase 3b (DNMT3b) expression as a diagnostic marker of ulcerative colitis (UC)-associated neoplasia. METHODS: Thirty-one patients with long-standing and extensive UC were included in this study. The expression of DNMT3b in non-neoplastic rectal epithelium (non-dysplasia in 31 patients) and colorectal neoplasia (dysplasia in 43 patients and invasive cancer in 34 patients) was determined using immunohistochemistry. The presence of immunoreactive DNMT3b was assessed in the areas with the highest density of cells with positively staining nuclei. DNMT3b was expressed as the percentage of positive cells relative to the total number of cells counted under high power magnification. RESULTS: The DNMT3b expression in neoplastic rectal epithelium (0.76, range 0.59-0.84) was increased compared to that observed in non-neoplastic epithelium (0.32, range 0.18-0.67, P < 0.001). A ROC curve analysis confirmed 0.68 to be the best diagnostic cut-off value for the DNMT3b expression in neoplastic epithelium (area under the curve = 0.810). The sensitivity of the diagnostic test was 66.2 %, the specificity was 86.7 %, the positive predictive value was 95.7 % and the negative predictive value was 36.1 %. The positive likelihood ratio was 4.98 and the negative likelihood ratio was 0.20. The accuracy was 69.9 %. CONCLUSIONS: An immunohistochemical analysis of the DNMT3b expression was associated with significant improvements in the discrimination of UC-associated neoplastic lesions.

Diagnosis of desmoplastic reaction by immunohistochemical analysis, in biopsy specimens of early colorectal carcinomas, is efficacious in estimating the depth of invasion.

The aim of our study was to evaluate the diagnosis of desmoplastic reaction (DR) by immunostaining for α-smooth muscle actin (αSMA) and desmin, for predicting the depth of submucosal invasion in biopsy specimens of early colorectal carcinomas (CRCs). Thirty-eight cases of non-pedunculated early CRCs were included in this study. Positive for DR was defined as αSMA-positive and desmin-negative stroma in the CRC. The depth of submucosal invasion was measured in endoscopically or surgically resected specimens and the lesions were subsequently divided into two groups: Group A (carcinoma in situ/intramucosal carcinoma and submucosal invasive carcinoma with a depth <1000 µm) and Group B (submucosal invasion with a depth ≥1000 µm). Twenty-one cases were DR-positive and 17 were DR-negative. No statistical significance was found between the DR with regard to tumor size, location and histological type. All DR-positive cases belonged to Group B whereas 14 (82.4%) DR-negative lesions belonged to Group A (p < 0.001). The sensitivity, specificity, positive and negative predictive values and accuracy of DR positivity for diagnosis of Group B were 87.5%, 100%, 100%, 82.4% and 92.1%, respectively. Conclusively, detection of DR in biopsy specimens with ancillary immunohistochemistry (αSMA/desmin) would help in preoperative diagnosis for the depth of submucosal invasion of early CRC.

Clinicopathological features of serrated adenocarcinoma defined by Mäkinen in dukes' B colorectal carcinoma.

OBJECTIVE: Serrated adenocarcinoma (SAC), proposed as a new pathologic type, arises predominantly in the right side of the colon and has a poorer prognosis than conventional colorectal carcinoma. The prognosis of colorectal carcinoma is variable in Dukes' B, so the aim of this study was to determine whether or not SAC has a poor prognosis in Dukes' B. METHODS: The study group comprised 64 patients who underwent surgery for colorectal carcinoma. We undertook a statistical analysis of the association of SAC and non-SAC with sex, age, histologic type, depth of tumor, location of tumor, venous invasion and lymphatic invasion. RESULTS: SACs were encountered in 17.5% of cases (n = 11). SAC had a less favorable 5-year survival than non-SAC (p = 0.0396 log-rank, Kaplan-Meier). The factors that achieved statistical significance in the univariate analysis were subsequently included in a multivariate analysis and we found that SAC was an independent factor (p = 0.027). CONCLUSIONS: SAC has a poor prognosis and is not affected by other factors confirming that SAC is an independently less favorable prognostic factor.

Desmoplastic reaction in biopsy specimens of early colorectal cancer: a Japanese prospective multicenter study.

We previously reported that detection of desmoplastic reaction (DR) in pretreatment biopsy specimens was useful for predicting the depth of submucosal invasion (SM depth) in nonpedunculated early colorectal cancers (ECRCs) in a retrospective study. Here, we performed a prospective multicenter study for verification of our previous findings. Subjects were diagnosed with ECRC by endoscopy, and with adenocarcinoma from the biopsy specimens. Eleven institutions affiliated with the Japanese Society for Cancer of the Colon and Rectum participated in this collaborative study. A total of 112 patients with ECRC were enrolled. For nonpedunculated ECRCs, presence of DR was significantly correlated with SM depth. The sensitivity and specificity of detection of DR for prediction of pSM2 (tumor invasion ≥1000 µm) in nonpedunculated ECRCs were 68.6% and 92.0%, respectively. Evaluation of DR in pretreatment biopsy specimens may be useful for the clinicopathological diagnosis of colorectal carcinoma with massive invasion into the submucosal layer.

New application of endocytoscope for histopathological diagnosis of colorectal lesions.

BACKGROUND: The endocytoscope with ultra-high magnification (x 520) allows us to observe the cellular structure of the colon epithelium during colonoscopy, known as virtual histopathology. We hypothesized that the endocytoscope could directly observe colorectal histopathological specimens and store them as endocyto-pathological images by the endoscopists without a microscope, potentially saving the burden on histopathologists. AIM: To assess the feasibility of endocyto-pathological images taken by an endoscopist as adequate materials for histopathological diagnosis. METHODS: Three gastrointestinal pathologists were invited and asked to diagnose 40 cases of endocyto-pathological images of colorectal specimens. Each case contained seven endocyto-pathological images taken by an endoscopist, consisting of one loupe image, three low-magnification images, and three ultra-high magnification images. The participants chose hyperplastic polyp or low-grade adenoma for 20 cases of endocyto-pathological images (10 hyperplastic polyps, and 10 Low-grade adenomas in conventional histopathology) in study 1 and high-grade adenoma/ shallow invasive cancer or deep invasive cancer for 20 cases [10 tumor in situ/T1a and 10 T1b] in study 2. We investigated the agreement between the histopathological diagnosis using the endocyto-pathological images and conventional histopathological diagnosis. RESULTS: Agreement between the endocyto-pathological and conventional histopathological diagnosis by the three gastrointestinal pathologists was 100% (95%CI: 94.0%-100%) in studies 1 and 2. The interobserver agreement among the three gastrointestinal pathologists was 100%, and the κ coefficient was 1.00 in both studies. CONCLUSION: Endocyto-pathological images were adequate and reliable materials for histopathological diagnosis.

Immunohistochemical analysis of REG Iα expression in ulcerative colitis-associated neoplastic lesions.

BACKGROUND AND AIMS: The regenerating gene (REG)Iα has been identified by microarray analysis as a gene that is distinctly overexpressed in ulcerative colitis (UC), and its protein product is suggested to play a pivotal role in the development of UC-associated carcinoma. In the present study, we investigated the significance of REG Iα expression as a diagnostic marker of UC-associated neoplasia. METHODS: Tissue samples were obtained from colectomy specimens from 31 patients with long-standing UC (mean disease duration 17.2 years, range 5-29). The lesions were evaluated according to the International Classification for Dysplasia in Inflammatory Bowel Diseases, and the sections were examined using immunohistochemistry for REG Iα and p53. RESULTS: In the 'regenerating atypia' group, REG Iα immunoreactivity was restricted to the lower third of the UC mucosa (grade 1). Lesions classified as 'indefinite for dysplasia' also showed predominantly basal-type staining for REG Iα. However, in 'low-grade dysplasia' and 'high-grade dysplasia' lesions, the localization of REG Iα immunoreactivity expanded to the middle (grade 2) and upper (grade 3) third of the UC mucosa, respectively. The REG Iα immunostaining pattern differed significantly (p < 0.0001) between non-neoplastic and neoplastic lesions, and was significantly (p < 0.0001) associated with p53 overexpression. CONCLUSIONS: Immunohistochemical analysis of REG Iα expression is useful for differential diagnosis of non-neoplastic and neoplastic lesions in UC tissues.

Involvement of the IL-22/REG Ialpha axis in ulcerative colitis.

The Regenerating gene (REG) Ialpha protein, a trophic and/or anti-apoptotic factor, is important in the pathophysiology of gastrointestinal inflammation. Interleukin (IL)-22 is a recently identified cytokine that is suggested to have pivotal roles in inflammatory bowel diseases. We therefore investigated the involvement of the IL-22/REG Ialpha axis and examined the mechanism of regulation of REG Ialpha expression by IL-22 stimulation in ulcerative colitis (UC) mucosa. Expression of IL-22, IL-22 receptor 1 (IL-22R1), and REG Ialpha in UC mucosa was analyzed by real-time RT-PCR and immunohistochemistry. The effects of IL-22 on REG Ialpha protein expression were examined using a small-interfering RNA for STAT3, an MAPK inhibitor or a PI3K inhibitor. The element responsible for IL-22-induced REG Ialpha promoter activation was determined by a promoter deletion and electrophoretic mobility shift assay. The expression of IL-22 was enhanced in infiltrating inflammatory cells, and that of IL-22R1 and REG Ialpha was concurrently enhanced in the inflamed epithelium in UC mucosa. The levels of REG Ialpha and IL-22 mRNA expression were strongly correlated, and the distributions of REG Ialpha- and IL-22R1-positive epithelial cells were very similar. IL-22 simulation enhanced the expression of REG Ialpha protein through STAT3 tyrosine phosphorylation in colon cancer cells. The IL-22-responsive element was located between -142 and -134 in the REG Ialpha promoter region. REG Ialpha protein may have a pathophysiological role as a biological mediator for immune cell-derived IL-22 in the UC mucosa.

Long-Term Safety and Effectiveness of the Xanthine Oxidoreductase Inhibitor, Topiroxostat in Japanese Hyperuricemic Patients with or Without Gout: A 54-week Open-label, Multicenter, Post-marketing Observational Study.

BACKGROUND AND OBJECTIVES: Topiroxostat, a selective xanthine oxidoreductase inhibitor, is used for the management of hyperuricemic patients with or without gout in Japan. Accumulating evidence has demonstrated the efficacy of topiroxostat for the treatment of hyperuricemia with or without gout. However, the safety and efficacy of topiroxostat in the clinical setting remain unclear, and there is little large-scale clinical evidence. We conducted a post-marketing observational study over 54 weeks. PATIENTS AND METHODS: Patients were centrally enrolled, and case report forms of 4491 patients were collected between April 2014 and March 2019 from 825 medical sites. RESULTS: Overall, 4329 patients were assessed for safety and 4253 patients for effectiveness. The overall incidence of adverse drug reactions was 6.95%, and the incidence rates of adverse drug reactions of gouty arthritis, hepatic dysfunction, and skin disorders, which are of special interest in this study, were 0.79%, 1.73%, and 0.95%, respectively. No case of serious gouty arthritis was observed. Serum urate levels decreased stably over time and showed a significant reduction rate at 54 weeks (21.19% ± 22.07%) and on the final visit (19.91% ± 23.35%) compared to the baseline. The rates for subjects who achieved serum uric acid levels ≤ 6.0 mg/dL at 18 and 54 weeks after administration were 43.80% and 48.28%, respectively. CONCLUSIONS: This study suggests that there is no particular concern about adverse drug reactions or the efficacy of topiroxostat for hyperuricemic patients with or without gout in a post-marketing setting in Japan.

Expression profile of REG family proteins REG Ialpha and REG IV in advanced gastric cancer: comparison with mucin phenotype and prognostic markers.

Regenerating gene family members 1 (REG Ialpha) and 4 (REG IV) are overexpressed in a subset of gastric cancers. However, comparative characterization of the expression of these family proteins has remained unclear. Therefore, we aimed to elucidate not only the association between REG protein expression and mucin phenotype but also their significance as a prognostic marker for patients with gastric cancer. The expression of REG Ialpha, REG IV, CDX2, MUC2, and MUC5AC in gastric cancer tissues was examined by immunohistochemistry. The relationship between REG protein expression and clinicopathological parameters or mucin phenotype was then analyzed. REG Ialpha and REG IV expression was positive in 33 (52%) and 31 (49%) of 63 gastric cancers examined, respectively. REG Ialpha expression was significantly related to venous invasion and tumor stage, whereas REG IV expression showed no relationship to clinicopathological features. With regard to mucin phenotype, REG IV expression was significantly correlated with MUC2 and CDX2 expression, suggesting an association with the intestinal mucin phenotype of gastric cancer. On the other hand, REG Ialpha expression had no correlation with MUC2, CDX2, or MUC5AC in gastric cancer tissues. Expression of REG Ialpha but not REG IV was an independent predictor of poor outcome in patients with gastric cancer. In addition, patients with gastric cancer negative for both REG Ialpha and REG IV expression had a significantly better outcome than patients positive for either REG Ialpha or REG IV. Profiling of REG protein expression is useful to for prognostication of patients with gastric cancer.

Cholecystoduodenal fistula caused by aggressive mucinous gallbladder carcinoma with a porcelain gallbladder.

Cholecystoduodenal fistula secondary to gallbladder carcinoma (GBC) is extremely rare and develops when the tumor penetrates into the adjacent duodenum. A porcelain gallbladder is also a very rare entity that involves the calcification of the gallbladder wall and can be associated with the development of GBC. Herein, we report an unusual case of a patient with cholecystoduodenal fistula, which has been caused by aggressive mucinous gallbladder carcinoma with a porcelain gallbladder. A 68-year-old man was referred to our department due to significant accumulation near the neck of the gallbladder detected by FDG positron emission tomography/computed tomography (PET/CT), which was performed as a check-up of postpneumonectomy for lung cancer. Abdominal contrast CT and magnetic resonance imaging revealed porcelain-like circumferential calcification of the gallbladder wall and a mass in the region detected by FDG PET/CT. Furthermore, upper endoscopy revealed a submucosal tumor with apical ulceration in the posterior wall of the duodenal bulb. Histopathological examination of its biopsy specimen rendered a diagnosis of adenocarcinoma. The patient was preoperatively diagnosed with either gallbladder cancer or duodenal cancer, and subtotal stomach-preserving pancreatoduodenectomy and radical cholecystectomy with gallbladder bed resection were performed. The resected gallbladder revealed a porcelain gallbladder, which formed the cholecystoduodenal fistula. These specimens were histopathologically diagnosed as mucinous adenocarcinoma of the gallbladder with an abundant mucin production.

REG Ialpha protein mediates an anti-apoptotic effect of STAT3 signaling in gastric cancer cells.

Signal transducer and activator of transcription 3 (STAT3) signaling plays roles in inflammation-associated carcinogenesis. Regenerating gene (REG) Ialpha protein, an interleukin (IL)-6-inducible gene, is suggested to be involved in the gastritis-gastric cancer sequence. We investigated the involvement of IL-6/STAT3 signaling in REG Ialpha protein expression and examined whether REG Ialpha protein mediates an anti-apoptotic effect of STAT3 signaling in gastric cancer cells. The effects of IL-6/STAT3 signaling on REG Ialpha protein expression were examined using a STAT3 small interfering RNA system in gastric cancer cells. The element responsible for IL-6-induced REG Ialpha promoter activation was determined by a promoter deletion assay. The anti-apoptotic effects of STAT3 signaling and its induced REG Ialpha protein were examined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphatase nick-end labeling and caspase assay in vitro. Human gastric cancer specimens were analyzed by immunohistochemistry for phosphorylated signal transducer and activator of transcription 3 (p-STAT3) and REG Ialpha protein. IL-6 treatment enhanced the expression of REG Ialpha protein through STAT3 activation in gastric cancer cells. The IL-6-responsive element was determined to lie in the sequence from -142 to -134 of the REG Ialpha promoter region. REG Ialpha protein mediated the anti-apoptotic effects of STAT3 signaling in gastric cancer cells by enhancing Akt activation, Bad phosphorylation and Bcl-xL expression. The expression of REG Ialpha protein was significantly correlated with that of p-STAT3 in gastric cancer tissues. REG Ialpha protein may play a pivotal role in anti-apoptosis in gastric tumorigenesis under STAT3 activation.