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An 82-year-old man with fever and back pain was referred to our hospital and was thus found to be thrombocytopenic. A bone marrow biopsy revealed the diffuse infiltration of poorly differentiated neuroendocrine carcinoma (NEC). Computed tomography revealed a large hepatic mass. Considering the risk of bleeding due to thrombocytopenia, a needle biopsy was not performed. The patient rapidly deteriorated and died 10 days after presentation. An autopsy confirmed the diagnosis of primary hepatic NEC, with diffuse metastasis to the spleen, bone marrow, and systemic lymph nodes. This is an extremely rare case of NEC presenting with thrombocytopenia due to extensive bone marrow and splenic infiltration.

Although the use of a long metal stent is favored for EUS-guided hepaticogastrostomy (EUS-HGS) for the relief of malignant biliary obstruction (MBO), endoscopic reintervention (E-RI) at the time of recurrent biliary obstruction (RBO) is challenging due to a long intragastric portion. This study evaluated the feasibility and safety of E-RI after a long partially covered metal stent (L-PCMS) placement during EUS-HGS.We performed a multicenter retrospective study between January 2015 and December 2019 examining patients with MBO who underwent E-RI for RBO through the EUS-HGS route after the L-PCMS placement. Technical and clinical success rates, details of E-RI, adverse events (AEs), stent patency, and survival time were evaluated.Thirty-three patients at eight referral centers in Japan who underwent E-RI through the EUS-HGS route were enrolled. The location of MBO was distal in 54.5%. The median intragastric length of the L-PCMS was 5 cm. As the first E-RI attempt, E-RI via the distal end of the existing L-PCMS was successful in 60.6%. The overall technical and clinical success rates of E-RI were 100% and 81.8%, respectively. Liver abscess was noted in one patient. A proximal biliary stricture was associated with the clinical ineffectiveness of E-RI in multivariable analysis (odds ratio, 12.5, P = 0.04). The median survival and stent patency duration after E-RI were 140 and 394 days, respectively.Our study findings suggest that E-RI for RBO after EUS-HGS with a L-PCMS is technically feasible and clinically effective, without any severe AEs, especially for patients with distal MBO.

Background and Aim: Whether administration of antispasmodics as a component of premedication contributes to detection of lesions by screening esophagogastroduodenoscopy (EGDS) remains unclear. Our primary aim was to investigate this possibility.Methods: The cohort of this retrospective study comprised consecutive cases who had undergone screening EGDS at the Japanese Red Cross Wakayama Medical Center from October 2015 to September 2020. The investigated lesions comprised esophageal squamous cell carcinoma or adenocarcinoma, gastric adenoma or adenocarcinoma, and duodenal adenoma or adenocarcinoma.Results: Targeted lesions were detected in 72 of 31484 participants (0.23%), 18260 and 13224 of whom had received and not received pre-procedure antispasmodic agents, respectively. The rates of detection of lesions in these groups were 0.21% (38/18260) and 0.26% (34/13224), respectively (P = 0.40). Multivariate logistic regression analysis showed no association between administration of antispasmodics and rates of detection of targeted lesions (P = 0.12). Conclusions: Antispasmodics, which were administered to more than half of the study cohort, did not improve the rate of detection of targeted lesions.

Background and aims Endoscopic resection of nonampullary duodenal adenoma is often challenging, and its technique has not yet been standardized. To overcome the practical difficulty of conventional endoscopic mucosal resection, underwater endoscopic mucosal resection (UEMR) was recently developed; therefore, we investigated the effectiveness and safety of UEMR for nonampullary duodenal adenoma. Methods A multicenter, prospective cohort study was conducted at 21 institutions in Japan. We enrolled patients with no more than 2 nonampullary duodenal adenomas ≤20 mm in size, who were scheduled to undergo UEMR. After UEMR, follow-up endoscopies were scheduled at 2 and 12 months after the procedure, and biopsy specimens were taken from the post-UEMR scars. The primary endpoint was the proportion of patients with histologically proven nonrecurrence at follow-up endoscopy and biopsy. Results A total of 155 patients with 166 lesions underwent UEMR. One patient with a non-neoplastic lesion in the resected specimen and 10 patients with 10 lesions who were lost to follow-up were excluded. Finally, 144 patients with 155 lesions who received all follow-up endoscopies were analyzed for the primary endpoint. The proportion of patients with proven nonrecurrence was 97.2% (n = 140 of 144; 95% confidence interval, 92.8%–99.1%) which exceeded the predefined threshold value (92%). Two cases of delayed bleeding (1.2%) occurred and they were successfully managed by clips. All recurrences were successfully treated by additional endoscopic treatment. Conclusions This multicenter, prospective cohort study demonstrated effectiveness and safety of UEMR for nonampullary duodenal adenomas ≤20 mm in size. (University Hospital Medical Network Clinical Trials Registry, Number: UMIN000030414 ).

Background: Endoscopic treatment for malignant biliary obstruction (MBO) in patients bearing surgically altered anatomy (SAA) is not well-established. Although endoscopic ultrasound-guided biliary drainage (EUS-BD) has emerged as a new treatment option for MBO, limited data are available regarding the efficacy and safety of EUS-BD in patients with SAA. We conducted a multicenter prospective registration study to evaluate the efficacy and safety of EUS-BD in this population. Methods: This study involved 10 referral centers in Japan. Patients with SAA who were scheduled to receive EUS-BD for unresectable MBO between May 2016 and September 2018 were prospectively registered. The primary endpoint was technical success and the secondary outcomes were clinical success, procedure time, procedure-related adverse events (AEs), stent patency, and overall survival. Results: In total, 40 patients were prospectively enrolled. The surgical reconstruction methods were gastrectomy with Roux-en-Y reconstruction (47.5%), gastrectomy with Billroth-II reconstruction (15%), pancreaticoduodenectomy (27.5%), and hepaticojejunostomy with Roux-en-Y reconstruction (10%). EUS-BD was performed for primary biliary drainage in 31 patients and for rescue biliary drainage in nine patients. Transmural stenting alone (60%), antegrade stenting alone (5%), and a combination of the two techniques (35%) were selected for patients treated with EUS-BD. Technical and clinical success rates were 100% (95% confidence interval, 91.2–100.0%) and 95% (95% confidence interval, 83.1–99.4%), respectively. Mean procedure time was 36.5 min. Early AEs were noted in six patients (15%): three self-limited bile leak, one bile peritonitis, and two pneumoperitonea. Late AEs occurred in six patients (15%): one jejunal ulcer and five stent occlusions. Stent patency rate after 3 months of survival was 95.7% (22/23). Median overall survival was 96 days. Conclusion: EUS-BD for MBO in patients with SAA appears to be effective and safe not only as a rescue drainage technique after failed endoscopic retrograde cholangiography but also as a primary drainage technique. Clinical Trial Registration: UMIN000022101

Background and study aims Self-expandable metallic stents (SEMS) have been widely used for left-sided colorectal obstruction. Few studies on SEMS placement for right-sided colonic obstructions have been reported because stenting in the right colon is technically difficult, particularly in the ileocecal region. We present 4 cases of successful bridge-to-surgery stenting for ileocecal cancer. Using an endoscopic retrograde cholangiopancreatography catheter with a movable tip and a decompression tube was effective for stenting. No adverse events occurred during or after SEMS placement in any of these cases. Short-term stenting for ileocecal cancer seems to be effective and safe.

Objectives: This study aimed to evaluate the characteristics and the feasibility of 18-mm-diameter stents for obstructive colorectal cancer, comparing the clinical courses with 22- mm-diameter stents. Methods: We retrospectively compared 33 consecutive cases treated with 18-mm-diameter stents (bridge to surgery [BTS] in 25, palliative therapy [PAL] in 8) with 27 consecutive cases treated with 22-mm-diameter stents (BTS in 21, PAL in 6) for obstructive colorectal cancer between May 2013 and November 2015 in our institution. Results: There were no significant differences between the 18-mm and 22-mm groups in technical success rates (97 and 96%, respectively) and clinical success rates (100 and 100%, respectively). As a BTS, the rates of complications and stoma formation were not significantly different between groups. For PAL, although the rates of complications and stent patency were similar, stent occlusion occurred in 1 patient (12.5%) in the 18-mm group. Conclusions: The 18-mm-diameter stents were similarly effective when compared with 22-mm-diameter stents. Because 18-mm-diameter stents are easy to handle and produce less mechanical stress, they have the potential to decrease the perforation rate and mitigate the stent's impact on the tumors. 18-mm-diameter stents can be useful and safe, especially as a BTS.

Cholesterol crystal embolization (CCE) is a rare systemic embolism caused by formation of cholesterol crystals from atherosclerotic plaques. CCE usually occurs during vascular manipulation, such as vascular surgery or endovascular catheter manipulation, or due to anticoagulation or thrombolytic therapy. We report a rare case of intestinal obstruction caused by spontaneous CCE. An 81-year-old man with a history of hypertension was admitted for complaints of abdominal pain, bloating, and anorexia persisting for 4 mo. An abdominal computed tomography revealed intestinal ileus. His symptoms were immediately relieved by an ileus tube insertion, and he was discharged 6 d later. However, these symptoms immediately reappeared and persisted, and partial resection of the small intestine was performed. A histopathological examination indicated that small intestine obstruction was caused by CCE. At the 12-mo follow-up, the patient showed no evidence of CCE recurrence. Thus, in cases of intestinal obstruction, CCE should also be considered.

Cyclooxygenase-2 (COX-2) plays important roles in tumor development. Especially in the early-stage colorectal tumors, COX-2 expression is often observed in the tumor stroma. However, the mechanism regulating such stromal expression of COX-2 remains unknown. In the present study, we simulated the indirect interaction between epithelial cells and stromal cells in the process of colorectal tumor development using an in vitro co-culture model in which NIH3T3 fibroblasts were co-cultured with 'sparsely' or 'densely' populated intestinal epithelial cells, Intestine-407 as a model of premalignant or benign intestinal epithelial cells, and DLD-1 and Caco-2 as models of malignant epithelial cells. COX-2 expression in NIH3T3 fibroblasts was upregulated when co-cultured with the 'dense' epithelial cells regardless of their character. Interestingly, there was pericellular hypoxia in the vicinity of NIH3T3 fibroblasts when co-cultured with 'dense' epithelial cells, and the recovery of the partial pressure of oxygen level resulted in the reduction of enhanced COX-2 expression only in NIH3T3 fibroblasts co-cultured with 'dense' Intestine-407 cells. Furthermore, COX-2 expression was also reduced by the inhibition of transcription factor AP-1. Thus, pericellular hypoxia of the stromal cells caused by densely populated epithelial cells may be one of the potent COX-2 enhancers before completion of malignant transformation during intestinal tumor development.

Signal transduction and activator of transcription 3(STAT3) signaling is constitutively activated in various tumors, and is involved in cell survival and proliferation during oncogenesis. There are few reports, however, on the role of STAT3 signaling in gastric cancer. The aim of the present study was to clarify the role of STAT3 signaling in apoptosis and cellular proliferation in gastric cancer. Here we reported that STAT3 was constitutively activated in various human gastric cancer cells and its inhibition by ectopic dominant-negative STAT3 or Janus kinase inhibitor, tyrphostin AG490, induced apoptosis. Furthermore, STAT3 inhibition markedly decreased survivin expression, and forced expression of survivin rescued AGS cells from apoptosis induced by STAT3 inhibition. Although some reports demonstrated that the PI3K/Akt pathway regulates survivin expression, inhibition of the PI3K/Akt pathway did not affect survivin expression in AGS and MKN1 cells. Finally, activated form of STAT3, Tyr-705 phospho-stat3, was found in the nucleus of cancer cells in 11 of 40 (27.5%) human gastric cancer specimens. These findings suggest that constitutively activated STAT3 signaling supports gastric cancer cell survival in association with survivin expression.2004

We report an extremely rare case of pulmonary lipiodol embolism with acute respiratory distress syndrome (ARDS) after transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). A 77-year-old man who was diagnosed with a huge HCC was admitted for TACE. Immediately after the procedure, this patient experienced severe dyspnea. We suspected that his symptoms were associated with a pulmonary lipiodol embolism after TACE, and we began intensive treatment. However, his condition did not improve, and he died on the following day. A subsequent autopsy revealed that the cause of death was ARDS due to pulmonary lipiodol embolism. No cases have been previously reported for which an autopsy was performed to explain the most probable mechanism of pulmonary lipiodol embolism; thus, ours is the first report for such a rare case.

Activation of tyrosine kinases is an important factor during cancer development. Axl, one of the receptor tyrosine kinases, binds to the specific ligand growth arrest-specific gene 6 (Gas6), which encodes a vitamin K-dependent gamma-carboxyglutamyl protein. Although many receptor tyrosine kinases and their ligands are involved in gastric carcinogenesis, whether Gas6-Axl signaling is involved in gastric carcinogenesis has not been elucidated. The aim of this study was to investigate the expression of Gas6 and Axl in gastric cancer and also their roles during gastric carcinogenesis. mRNA and protein of Gas6 and Axl were highly expressed in a substantial proportion of human gastric cancer tissue and cell lines, and Gas6 expression was significantly associated with lymph node metastasis. With recombinant Gas6 and a decoy-receptor of Axl in vitro, we demonstrated that Gas6-Axl signaling pathway enhanced cellular survival and invasion and suppressed apoptosis via Akt pathway. Our results suggests that Gas6-Axl signaling plays a role during gastric carcinogenesis, and that targeting Gas6-Axl signaling could be a novel therapeutic for gastric cancer.

Nuclear accumulation of β-catenin is a key event for the development of colorectal cancer. Little is known, however, about the mechanisms underlying translocation of β-catenin from the cytoplasm or the membrane to the nucleus. The present study examined whether signal transducers and activators of transcription 3 (STAT3) activation is involved in the nuclear accumulation of β-catenin in colorectal cancer cells. Of the 90 primary colorectal cancer tissues, 40 (44.4%) were positive for nuclear staining of p-STAT3 and 63 (70.0%) were positive for nuclear staining of β-catenin. The nuclear staining of both p-STAT3 and β-catenin were observed predominantly in the periphery of the cancer tissues. Importantly, of the 40 tumors with p-STAT3 nuclear staining, 37 (92.5%) were also positive for nuclear β-catenin staining and there was a significant correlation between p-STAT3 and β-catenin nuclear staining (P < 0.01). Coexpression of nuclear p-STAT3 and β-catenin was associated with lower patient survival (P < 0.01). In an in vitro study using a human colon cancer cell line, SW480, inhibition of STAT3 by dominant negative STAT3 or the Janus kinase inhibitor, AG490, induced translocation of β-catenin from the nucleus to the cytoplasm or membrane. Luciferase assays revealed that STAT3 inhibition resulted in significant suppression of β-catenin/T-cell factor transcription in association with significant inhibition of cell proliferation (P < 0.05). These findings suggest that in colorectal cancer, STAT3 activation is involved in the nuclear accumulation of β-catenin, resulting in poor patient survival. (Cancer Res 2006; 66(6): 2913-7)

Background and aims: Although regenerating gene (REG) Iα protein may be involved in the inflammation and carcinogenesis in the gastrointestinal tract, its pathophysiological role in ulcerative colitis (UC) and the resulting colitic cancer remains unclear. We investigated expression of the REG Iα gene and its protein in UC and colitic cancer tissues. We examined whether cytokines are responsible for REG Iα gene expression and whether REG Iα protein has a trophic and/or an antiapoptotic effect on colon cancer cells. Methods: Expression of REG Iα mRNA and its gene product in UC tissues was analysed by real time reverse transcription-polymerase chain reaction and immunohistochemistry, respectively. The effects of cytokines on REG Iα promoter activity were examined in LoVo cells by luciferase reporter assay. The effects of REG Iα protein on growth and H2O2 induced apoptosis were examined in LoVo cells by MTT and TUNEL assays, respectively. Results: REG Iα protein was strongly expressed in inflamed epithelium and in dysplasias and cancerous lesions in UC tissues. The level of REG Iα mRNA expression in UC tissues correlated significantly with severity of inflammation and disease duration. REG Iα promoter activity was enhanced by stimulation with interferon γ or interleukin 6. REG Iα protein promoted cell growth and conferred resistance to H2O2 induced apoptosis in LoVo cells. REG Iα protein promoted Akt phosphorylation and enhanced Bcl-xL and Bcl-2 expression in LoVo cells. Conclusions: The REG Iα gene is inducible by cytokines and its gene product may function as a mitogenic and/or an antiapoptotic factor in the UC-colitic cancer sequence.

Mucocele of the appendix due to endometriosis is extremely rare, and there are only 10 previously reported cases in the English literature. We report a case of mucocele of the appendix due to endometriosis and provide the first review of the literature. A 43-year-old woman was admitted to the hospital because of recurrent right lower abdominal pain during her menstrual periods. Colonoscopy revealed submucosal tumor-like elevations of the appendiceal orifice. Computed tomography and magnetic resonance imaging of the abdomen suggested cystic lesions near the appendix. Consequently, mucocele of the appendix was suspected preoperatively. An open ileocecal resection was performed. Multiple cystic lesions were observed around the appendix. The cystic lesions contained mucus. Histopathological examination was consistent with a mucocele of the appendix due to endometriosis. The postoperative course was uneventful. We present the first review of the literature to clarify the clinical features.