Non-Pure Intestinal Phenotype as an Indicator of Progression in Sporadic Nonampullary Duodenal Adenomas: A Multicenter Retrospective Cohort Study.

INTRODUCTION: We aimed to evaluate the natural course of sporadic nonampullary duodenal adenomas (SNDAs) and determine the risk factors of progression. METHODS: We retrospectively analyzed the follow-up outcomes of patients with biopsy-diagnosed SNDA between April 2010 and March 2016 at 13 institutions. All initial biopsy specimens were centrally evaluated. Only those diagnosed with adenomas were included. Mucinous phenotypes were classified into pure intestinal and non-pure intestinal phenotypes. Cumulative incidence rates of carcinoma and tumor enlargement were evaluated. Tumor enlargement was defined as a ≥25% or 5-mm increase in tumor size. RESULTS: Overall, 121 lesions were analyzed. Within a median observation period of 32.7 months, 5 lesions were diagnosed as carcinomas; the cumulative 5-year incidence of carcinoma was 9.5%. Male sex ( P = 0.046), initial lesion size ≥10 mm ( P = 0.044), and non-pure intestinal phenotype ( P = 0.019) were significantly associated with progression to carcinoma. Tumor enlargement was observed in 22 lesions, with a cumulative 5-year incidence of 33.9%. Initial lesion size ≥10 mm ( P < 0.001), erythematous lesion ( P = 0.002), high-grade adenoma ( P = 0.002), Ki67 negative ( P = 0.007), and non-pure intestinal phenotype ( P = 0.001) were risk factors of tumor enlargement. In a multivariate analysis, an initial lesion size ≥10 mm ( P = 0.010) and non-pure intestinal phenotype ( P = 0.046) were independent and significant risk factors of tumor enlargement. DISCUSSION: Lesion size ≥10 mm and non-pure intestinal phenotype on initial biopsy are risk factors of cancer progression and tumor enlargement in cases with SNDA. Thus, management effectiveness may be improved by focusing on lesion size and the mucinous phenotype.

Effect of anticoagulants on the risk of delayed bleeding after colorectal endoscopic submucosal dissection.

Background and study aims In patients receiving antithrombotic therapy, the risks of delayed bleeding after endoscopic procedures for gastrointestinal neoplasms become a major problem. Few reports have shown the effects of delayed bleeding in patients taking anticoagulants after colorectal endoscopic submucosal dissection (ESD). This study aimed to evaluate the delayed bleeding events after colorectal ESD in patients receiving anticoagulant therapy. Patients and methods We retrospectively analyzed 87 patients taking anticoagulants who underwent colorectal ESD from April 2012 to December 2017 at 13 Japanese institutions participating in the Osaka Gut Forum. Among these patients, warfarin users were managed with heparin bridge therapy (HBT), continued use of warfarin, a temporary switch to direct oral anticoagulation (DOAC), or withdrawal of warfarin, and DOAC users were managed with DOAC discontinuation with or without HBT. We investigated the occurrence rate of delayed bleeding and compared the rates between warfarin and DOAC users. Results The delayed bleeding rate was 17.2 % among all patients. The delayed bleeding rate was higher in DOAC users than in warfarin users (23.3 % vs. 11.4 %, P  = 0.14), although no statistically significant difference was observed. In DOAC users, the delayed bleeding rates for dabigatran, rivaroxaban, apixaban, and edoxaban users appeared similar (30 %, 18.2 %, 22.2 %, and 25 %, respectively). The onset of delayed bleeding in both warfarin and DOAC users was late, averaging 6.9 and 9.4 days, respectively. Conclusions Among patients taking anticoagulants, the risk of delayed bleeding after colorectal ESD was relatively high and the onset of delayed bleeding was late.

Efficacy of chemotherapy for older patients with gastric cancer: a multicenter retrospective cohort study.

BACKGROUND: Gastric cancer is one of the leading causes of malignant disease-related mortality, worldwide. With the use of recently developed anti-tumor agents, the prognoses of patients with unresectable gastric cancer are improving. However, the development of an aggressive treatment strategy for older patients (OPs) remains under debate due to concerns regarding treatment feasibility or patient frailty. We aimed to elucidate whether aggressive chemotherapy has survival benefits for OPs with advanced gastric cancer. METHODS: We analyzed consecutive patients diagnosed with inoperable advanced gastric cancer across seven hospitals from August 2007 to July 2015. We defined OPs as patients aged 75 years or older and compared their survival rates with those of non-older patients (NPs). RESULTS: A total of 256 OPs and 425 NPs were enrolled. Of the OPs, 152 patients received chemotherapy and 104 patients received best supportive care (BSC). In contrast, among the NPs, 375 patients received chemotherapy and 50 patients received BSC. There was no significant difference of the median survival time between OPs and NPs in the response to BSC (61 vs 43 days) or chemotherapy (312 vs 348 days). Combination chemotherapy significantly improved survival compared to monotherapy in both OPs and NPs groups (382 vs 253 days in OPs, 381 vs 209 days in NPs). Good performance status, combination therapy, and male, but not age, were significant independent prognostic factors. CONCLUSION: When the performance status of a gastric cancer patient is good, active chemotherapy may improve survival, regardless of age.

25 mg versus 50†mg dose of rectal diclofenac for prevention of post-ERCP pancreatitis in Japanese patients: a retrospective study.

OBJECTIVES: The aim of the present study was to assess the appropriate administration dose of non-steroidal anti-inflammation drugs to prevent pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). Importantly, the 100 mg dose of diclofenac recommended in Western countries has not been permitted in Japan. DESIGN: A retrospective study. SETTINGS: A single centre in Japan. PARTICIPANTS: This study enrolled patients who underwent ERCP at the Department of Gastroenterology, Osaka Saiseikai Senri Hospital, from April 2011 through June 2013, and who received either a 25 or a 50 mg dose of rectal diclofenac after ERCP. PRIMARY OUTCOME MEASURE: The occurrence of post-ERCP pancreatitis (PEP). A multivariate regression model was used to assess the effect of the 50 mg dose (the 50 mg group) of rectal diclofenac and to compare it to the occurrence of PEP referring to the 25 mg group. RESULTS: A total of 155 eligible patients received either 25 mg (84 patients) or 50 mg (71 patients) doses of rectal diclofenac after ERCP to prevent PEP. The proportion of PEP was significantly lower in the 50 mg group than in the 25 mg group (15.5% (11/71) vs 33.3% (28/84), p=0.018). In a multivariate analysis, the occurrence of PEP was significantly lower in the 50 mg group than in the 25 mg group even after adjusting potential confounding factors (adjusted OR=0.27, 95% CI 0.11 to 0.70). CONCLUSIONS: From this observation, the occurrence of PEP was significantly lower among ERCP patients with the 50 mg dose of rectal diclofenac than among those with the 25 mg dose.

Diagnosis of hepatocellular carcinoma nodules in patients with chronic liver disease using contrast-enhanced sonography: usefulness of the combination of arterial- and kupffer-phase enhancement patterns.

OBJECTIVES: To determine the usefulness of contrast-enhanced sonography using the perfluorobutane contrast agent Sonazoid (Daiichi-Sankyo, Tokyo, Japan) for establishing the diagnosis and cellular differentiation of hepatocellular carcinoma in patients with chronic liver disease. METHODS: Patients with chronic liver disease in whom hepatic nodules were detected during screening for hepatocellular carcinoma were examined by imaging modalities, including contrast-enhanced computed tomography (CT), contrast-enhanced sonography, and contrast-enhanced magnetic resonance imaging. Nodules with negative imaging findings were further investigated with core biopsy or followed at our hospital. Between April 2007 and March 2011, all patients with hepatic nodules who underwent core biopsy of the nodules or hepatic resection for hepatocellular carcinoma were reviewed. Fifty-nine nodules from 47 patients with 42 contrast-enhanced sonographic findings and 41 contrast-enhanced CT findings were examined. Arterial- and Kupffer-phase enhancement patterns of the nodules on contrast-enhanced sonography were compared with the diagnosis and cellular differentiation of hepatocellular carcinoma. Arterial- and late-phase enhancement patterns on contrast-enhanced CT were also compared with histologic findings. RESULTS: The combination of hyperenhancement in the arterial phase and hypoenhancement in the Kupffer phase on contrast-enhanced sonography (n = 11) correlated with moderately differentiated hepatocellular carcinoma (P = .0028, Fisher exact test). The combination of hypoenhancement in the arterial phase and isoenhancement in the Kupffer phase on contrast-enhanced sonography (n = 14) correlated with well-differentiated hepatocellular carcinoma (P = .0006, Fisher exact test). The combination of high density in the arterial phase and low density in the late phase on contrast-enhanced CT (n = 21) correlated with moderately differentiated hepatocellular carcinoma (P = .0059, Fisher exact test), but no enhancement pattern combination on contrast-enhanced CT correlated with well-differentiated hepatocellular carcinoma. CONCLUSIONS: Sonazoid contrast-enhanced sonography is useful for diagnosis of well-differentiated hepatocellular carcinoma.

[A case of hepatocellular carcinoma treated with specific substance of Maruyama resulting in a partial response].

We treated a 41-year-old man with hepatocellular carcinoma and chronic liver disease. He experienced leg edema. Following additional examinations, we diagnosed the patient with hepatocellular carcinoma and ascites with liver cirrhosis. Due to renal dysfunction, he could not undergo treatment with transcatheter arterial chemoembolization(TACE)or transcatheter arterial infusion(TAI). Therefore, he was treated with specific substance of maruyama(SSM), and survived.

[A case in which good quality of life was maintained by stent therapy for duodenal stenosis caused by gallbladder cancer invasion].

We treated an 80-year-old woman with gallbladder cancer. Because of her advanced age, chemotherapy was performed, but obstructive jaundice and duodenal stenosis were caused by invasion of the tumor. We inserted a metallic stent into the common bile duct and duodenum 3 times. As a result, she could eat and live at home with good quality of life.

[A case of partial response achieved by chemotherapy for a duodenal cancer].

We treated a 73-year-old woman with adenocarcinoma of the duodenum. She complained of poor appetite and weight loss. Upon close inspection, we diagnosed duodenal cancer with obstructive jaundice. Curative resection could not be performed because of swelling of the para-aortic lymph nodes. Chemotherapy using mFOLFOX6 was performed, and she survived.

[A clinical case of the esophagogastric malignancy palliated with covered metallic stent with anti-reflux mechanism].

Esohophageal stents are often used in treating malignant stricture. But, when stents are placed across the esophagogastric junction, they may lead to esophagogastric reflux. We report a case of successfully treated esophagogastric strictures using the new stent with anti-reflux mechanism (long cover type Niti-S™ esophageal stent). A 78-year-old man presenting with severe strictures from the lower esophagus to cardiac part of stomach was histopathologically diagnosed as adenocarcinoma. CT scan images showed multiple liver metastatic tumors. However, he refused chemotherapy. Palliation using long cover type Niti-S™ esophageal stent was performed. No adverse effect was occurred. He started solid meals on the 7th postoperative day. He was thereafter able to ingest solid meals without the symptom of esophgogastric reflux and stenosis until he died of the primary disease two month later.

Overexpression of insulin receptor substrate-1 and hepatitis Bx genes causes premalignant alterations in the liver.

UNLABELLED: Activation of the insulin (IN)/insulin receptor substrate-1 (IRS-1)/mitogen-associated protein kinase (MAPK) and the Wnt/beta-catenin signaling cascades occurs frequently in hepatocellular carcinoma (HCC) associated with persistent viral infection. The aims of this study were to provide a chronic proliferative stimulus through IRS-1 in the context of hepatitis Bx (HBx) protein expression in transgenic mice and determine if constitutive expression of these genes is sufficient to cause hepatocyte dysplasia and cellular transformation. We generated transgenic mice in which the HBx (ATX), IRS-1, or both (ATX+/IRS-1) genes were expressed under a liver-specific promoter. We also assessed histology and oxidative damage as well as up-regulation of molecules related to these signal transduction cascades in the liver by quantitative reverse-transcriptase polymerase chain reaction. Whereas mice with a single transgene (ATX or IRS-1) did not develop tumors, ATX+/IRS-1+ double transgenic livers had increased frequency of hepatocellular dysplasia and developed HCC. All three transgenic lines had significantly increased insulin growth factor 1 (IGF-1), Wnt 1 and Wnt 3 mRNA levels, and evidence of DNA damage and oxidative stress. The ATX+/IRS+ double transgenic mice were distinguished by having the highest level of activation of Wnt 3 and Frizzled 7 and selectively increased expression of IGF-II, proliferating cell nuclear antigen, and aspartyl-(asparaginyl)-beta-hydroxylase, a gene associated with increased cell migration. CONCLUSION: These results suggest that continued expression of the ATX or IRS-1 transgenes can contribute to hepatocyte transformation but are not sufficient to trigger neoplastic changes in the liver. However, dual expression that activates both the IN/IRS-1/MAPK and Wnt/beta-catenin cascades is sufficient to cause dysplasia and HCC in a previously normal liver.

Successful multimodal treatment in a patient with thymoma accompanied by hepatic metastasis.

Despite a benign histologic appearance, thymomas have metastatic potential. Here we report a case of a patient with a Masaoka stage IVb thymoma who was successfully treated using a multimodal strategy including systemic chemotherapy, radiofrequency ablation, and thoracic surgery. Despite complete remission after treatment, the patient developed myasthenia gravis with ptosis and neck drop symptoms. Hepatic metastasis of thymoma is a relatively rare occurrence and, to the best of our knowledge, this is the first report about the application of radiofrequency ablation to thymoma.

Ninjurin1 increases p21 expression and induces cellular senescence in human hepatoma cells.

BACKGROUND/AIMS: Ninjurin1 is a novel adhesion molecule that has a role in promoting nerve regeneration. Although ninjurin1 is ubiquitously expressed in various human tissues, including the liver, the biologic functions of ninjurin1 in tissues other than the nervous system remain unknown. The aim of this study was to investigate the function of ninjurin1 in hepatocytes. METHODS: The effect of ninjurin1 overexpression was examined in Huh-7 hepatoma cells. Ninjurin1 expression was examined by Western blot in human hepatocellular carcinoma tissues as well as their adjacent liver tissues. RESULTS: Ninjurin1-overexpressing clones exhibited strong growth inhibition due to G1 cell cycle arrest, which is associated with a posttranscriptional increase in p21WAF1/Cip1, a decrease of cyclin-dependent kinase 2 activity and the hypophosphorylation of Rb. The ninjurin1-overexpressing clones had increased senescence-associated beta-galactosidase activity and autofluorescent pigment, characteristic features of cellular senescence. The levels of ninjurin1 expression were higher in hepatocellular carcinoma tissues than those in adjacent liver tissues. CONCLUSIONS: The present study provides the first evidence that ninjurin1 is able to induce the senescence program. Ninjurin1 may be involved in the regulation of cellular senescence in the liver during carcinogenesis.

Expression of uncoupling protein-2 in human colon cancer.

PURPOSE: Cancer cell survival depends on adaptive mechanisms that include modulation of oxidative stress. One such mechanism may be via up-regulation of uncoupling protein-2 (UCP2), a mitochondrial inner membrane anion carrier recently found to provide cytoprotection in nontumor cells by acting as a sensor and negative regulator of reactive oxygen species production. We hypothesized that UCP2 expression may be increased in colon cancer as part of tumor adaptation. EXPERIMENTAL DESIGN: UCP2 expression was characterized by real-time polymerase chain reaction and Western blotting using paired human colon adenocarcinoma and peritumoral specimens. Oxidant production was characterized by tissue malondialdehyde levels. Tissue microarrays constructed of 107 colon adenocarcinomas as well as representative specimens of hyperplastic polyps and tubular adenomas were used for UCP2 immunohistochemistry. RESULTS: UCP2 mRNA and protein levels were 3- to 4-fold higher in adenocarcinomas, and UCP2 mRNA levels showed significant correlation with increased tumor tissue malondialdehyde contents. Immunohistochemistry on tissue microarrays showed positive staining for UCP2 in most adenocarcinomas (86.0%); positive staining for UCP2 was seen less often in tubular adenomas (58.8%) and rarely seen in hyperplastic polyps (11.1%). CONCLUSIONS: UCP2 expression is increased in most human colon cancers, and the level of expression appears to correlate with the degree of neoplastic changes. These findings may foster the idea that UCP2 is part of a novel adaptive response by which oxidative stress is modulated in colon cancer.

Uncoupling protein-2 deficiency promotes oxidant stress and delays liver regeneration in mice.

The control of liver regeneration remains elusive. Because reactive oxygen species (ROS) are able to mediate cell growth arrest and activate proteins that inhibit the cell cycle, ROS production may have a negative impact on liver regeneration. We examined how liver regeneration is affected by uncoupling protein-2 (UCP2), an inner mitochondrial membrane carrier that senses and negatively regulates superoxide production. Liver regeneration was monitored up to 5 days and was found to be significantly delayed in UCP2(-/-) mice after partial hepatectomy. Apoptosis rates in UCP2(+/+) and UCP2(- /-) liver remnants were similar, while parameters of cell proliferation indicated a diminished response in UCP2(- /-) mice with corresponding changes in the expression of key cell cycle regulatory proteins and prolonged activation of stress-responsive protein kinase p38. Levels of malondialdehyde, a marker of ROS generation and oxidant stress, were elevated in UCP2(- /-) livers at every examined time point. Liver remnants of UCP2(+ /+) mice 48 hours post-hepatectomy showed a fourfold increase in the expression of UCP2 protein primarily detected in hepatocytes. In conclusion, our results suggest that absent or insufficient UCP2 function in the regenerating liver results in increased ROS production and negatively modulates the control of cell cycle.

Inhibition of angiotensin II activity enhanced the antitumor effect of cyclooxygenase-2 inhibitors via insulin-like growth factor I receptor pathway.

Prostaglandin (PG) E(2), a cyclooxygenase (COX) product, and angiotensin II are endogenous and have physiological roles in the body. On the other hand, an inducible isoform of COX (COX-2), insulin-like growth factor (IGF) II, and IGF-I receptor (IGF-IR) are up-regulated in colon carcinoma and might have crucial roles in tumor growth and invasion. The aim of the present study was to investigate the effects of COX-2 inhibitor and drugs blocking the biological activities of angiotensin II [angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs)] on IGF-IR expression and tumor growth in vivo. We also investigated the effects of PGE(2), a major COX-2 product, in cancer cells and the effects of angiotensin II on IGF-IR expression and the underlying mechanism of action. In in vivo studies, tumor growth and IGF-IR expression were investigated in Colon 26 cells inoculated into BALB/c mice. In in vitro studies, the effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on IGF-IR expression were analyzed in three colon cancer cell lines (Colon 26, HCA-7, and LS174T). IGF-II-induced cell growth and invasion were analyzed in Colon 26 cells in the presence and absence of NSAIDs (indomethacin and celecoxib) and angiotensin II. Celecoxib at the lowest effective dose for suppression of PG production (3 mg/kg) or an ACE inhibitor/ARB alone did not have a significant effect as compared with controls, although a high dose of celecoxib (>20 mg/kg) suppressed tumor growth. On the other hand, combination therapy with these two categories of drugs significantly reduced tumor growth in vivo. Treatment with both celecoxib and an ACE inhibitor/ARB decreased IGF-IR expression levels in inoculated tumor cells. In in vitro studies, NSAIDs reduced IGF-IR expression in a dose-dependent manner in all three cell lines. NSAIDs also inhibited IGF-II-stimulated growth and invasion in a dose-dependent manner. PGE(2) or angiotensin II treatment reversed the NSAID-induced down-regulation of IGF-IR expression, growth, and invasion. PGE(2) and angiotensin II induced Akt phosphorylation, and LY294002 or wortmannin inhibited PGE(2)- or angiotensin II-induced IGF-IR expression, indicating that PGE(2) and angiotensin II both regulate IGF-IR expression by the same Akt/phosphatidylinositol-3 pathway. Thus, combination therapy with NSAIDs and ACE inhibitors targeting IGF-IR might be a novel and potentially promising strategy for the chemoprevention of colon cancer.

Involvement of the p38 mitogen-activated protein kinase cascade in hepatocellular carcinoma.

BACKGROUND: The mitogen-activated protein kinase (MAPK) cascade is activated in response to various extracellular stimuli. The authors investigated the involvement of the p38 MAPK, a member of the MAPK superfamily, cascade in hepatoma cell lines and in human hepatocellular carcinoma (HCC) tissue specimens. METHODS: Constitutively active mutant of MAPK kinase 6 (MKK6), which is upstream of p38 MAPK, was transfected into the HepG2 and HuH7 human hepatoma cell lines. The constitutive active mutant was constructed by replacing Ser-189 and Thr-193 with Glu. The growth and death of mutant MKK6-transfected hepatoma cells were analyzed by the WST-1 and sub-G1 assays. The surgically resected livers of 20 HCC patients were divided histologically into tumorous (T) and nontumorous (NT) lesions. p38 MAPK activity was analyzed using in vitro kinase assay and MKK6 activity was measured using Western blot analysis. RESULTS: Mutant MKK6 transfection increased p38 MAPK activity, cytochrome c release from the mitochondria to the cytosol, and caspase-3 activity, accompanied by apoptosis. In contrast, SB203580, a p38 MAPK-specific inhibitor, prevented MKK6-induced apoptosis in hepatoma cell lines. In the T lesions of 20 HCC parients, p38 MAPK and MKK6 activities were significantly lower compared with NT lesions (P < 0.05). There was a significant positive correlation between p38 MAPK and MKK6 activity (r = 0.507, P < 0.05). Larger tumors (> 20 mm) exhibited lower levels of p38 MAPK and MKK6 activity than did smaller tumors (P < 0.05). CONCLUSIONS: These findings suggested that reduction of the p38 MAPK cascade may account, in part, for the resistance to apoptosis, leading to the unrestricted cell growth of human HCC.