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Satoshi Tanida, Keiji Ozeki, Tsutomu Mizoshita, Hironobu Tsukamoto, Takahito Katano, Hiromi Kataoka, Takeshi Kamiya, Takashi Joh Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Aichi Prefecture, Japan Abstract: The goals of treatment for active Crohn's disease (CD) are to achieve clinical remission and improve quality of life. Conventional therapeutics for moderate-to-severe CD include 5-aminosalicylic acid, corticosteroids, purine analogs, azathioprine, and 6-mercaptopurine. Patients who fail to respond to conventional therapy are treated with tumor necrosis factor (TNF)-α inhibitors such as infliximab and adalimumab, but their efficacy is limited due to primary nonresponse or loss of response. It is suggested that this requires switch to another TNF-α inhibitor, a combination therapy with TNF-α blockade plus azathioprine, or granulocyte and monocyte adsorptive apheresis, and that other therapeutic options having different mechanisms of action, such as blockade of inflammatory cytokines or adhesion molecules, are needed. Natalizumab and vedolizumab are neutralizing antibodies directed against integrin a4 and a4ß7, respectively. Ustekinumab is a neutralizing antibody directed against the receptors for interleukin-12 and interleukin-23. Here, we provide an overview of therapeutic treatments that are effective and currently available for CD patients, as well as some that likely will be available in the near future. We also discuss the advantages of managing patients with refractory CD using a combination of TNF-α inhibitors plus azathioprine or intensive monocyte adsorptive apheresis. Keywords: adalimumab, granulocyte and monocyte adsorptive apheresis, combination therapy, complete remission

Shunsuke Nojiri,1 Atsunori Kusakabe,1 Kei Fujiwara,1 Noboru Shinkai,1 Kentaro Matsuura,1 Etsuko Iio,1 Tomokatsu Miyaki,1 Tomoyuki Nomura,2 Satoshi Sobue,3 Hitoshi Sano,4 Izumi Hasegawa,5 Tomoyoshi Ohno,5 Yoshitsugu Takahashi,6 Etsuro Orito,7 Takashi Joh11Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, 2Inabe General Hospital, Inabe, 3Kasugai Municipal Hospital, Kasugai, 4Tajimi Prefectural Hospital, Tajimi, 5Social Chukyo Insurance Hospital, Nagoya, 6Chita Kousei Hospital, Aichi-ken, 7Nagoya Daini Red Cross Hospital, Showa-ku, JapanBackground: Sorafenib has been approved in the indication of unresectable hepatocellular carcinoma, but there are many cases in which administration of the drug is discontinued due to severe side effects. In this study, we compared the characteristics of patients who continued and discontinued sorafenib.Methods: Ninety-six patients (75 men and 21 women) were initiated on sorafenib from July 2009 through September 2011. The patient characteristics of interest included gender, age, etiology, Child-Pugh classification, treatment history and frequency, and levels of α-fetoprotein, des-gamma-carboxy prothrombin, aspartate amino acid transferase, and alanine aminotransferase. Duration of administration of sorafenib and reasons for its discontinuation were compared.Results: Median overall survival was 11.8 months. Discontinuation of sorafenib within 90 days was identified as an independent prognostic factor for overall survival on multivariate analysis (P < 0.0001). Transarterial chemoembolization performed six times or more (P = 0.013) was also identified as an independent factor contributing to discontinuation of sorafenib within 90 days in multivariate analysis. Patients who received sorafenib for ≥90 days had significantly longer overall survival than those who discontinued it (P < 0.0001).Conclusion: Prolonged treatment with sorafenib is an important factor in achieving extended overall survival. We recommend starting sorafenib before latent liver damage has occurred as a result of too many transarterial chemoembolization procedures.Keywords: sorafenib, hepatocellular continuation, discontinuation, efficacy

Shunsuke Nojiri, Atsunori Kusakabe, Noboru Shinkai, Kentaro Matsuura, Etsuko Iio, Tomokatsu Miyaki, Takashi JohDepartment of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, JapanBackground: The purpose of this study was to clarify important risk factors for distant recurrence of hepatocellular carcinoma in patients positive for hepatitis C and without local recurrence.Methods: A total of 212 patients (145 males and 67 females) underwent radiofrequency ablation and transcatheter arterial embolization or transcatheter arterial chemoembolization at initial development of hepatocellular carcinoma. All patients were positive for hepatitis C. Child–Pugh classification was A in 115 and B in 97. The indication for radiofrequency ablation was the presence of up to three tumors ≤ 3 cm. The distant recurrence rate was analyzed using the Kaplan–Meier method and tested by Wilcoxon’s method.Results: Cumulative distant recurrence rates at years 1, 3, and 5 were 19%, 62%, and 79%, respectively. On univariate analysis, a ≥ 3 cm tumor, ≥ 50 ng/mL α-fetoprotein level, and < 3.6 g/dL serum albumin level were significant risk factors for distant recurrence, but only a serum albumin level < 3.6 g/dL (P = 0.004) was identified as significant on multivariate analysis. In the group with a pretreatment albumin level ≥ 3.6 g/dL, the distant recurrence rate was compared between patients in whom the albumin level rose, remained unchanged, or decreased by < 0.3 g/dL, and those in whom the level decreased by ≥ 0.3 g/dL. The rate was significantly higher in the latter, with a one-year recurrence rate of 7% versus 15% (P = 0.04).Conclusion: Distant recurrence was significantly decreased in patients with a high serum albumin level. Distant recurrence was more likely to occur in patients with a decreased albumin level, although the pretreatment level was high. Thus, strict follow-up after treatment for hepatocellular carcinoma is necessary in patients with low serum albumin levels.Keywords: distant recurrence, hepatocellular carcinoma, radiofrequency ablation

It is strongly suspected that cytokine-induced gene expression in inflammation is oxidant mediated; however, the intracellular sources of signaling oxidants remain controversial. In inflammatory bowel disease (IBD) proinflammatory cytokines, such as TNF-[alpha], trigger gene expression of endothelial adhesion molecules including mucosal addressin cell adhesion molecule-1 (MAdCAM-1). MAdCAM-1 plays an essential role in gut inflammation by governing the infiltration of leukocytes into the intestine. Several groups suggest that endothelial-derived reduced NADP (NADPH) oxidase produces signaling oxidants that control the expression of adhesion molecules (E-selectin, ICAM-1, VCAM-1). In addition to NADPH oxidase, cytochrome P-450 (CYP450) monooxygenases have also been shown to trigger cytokine responses. We found that in high endothelial venular cells (SVEC4-10), multiple inhibitors of CYP450 monooxygenases (SKF-525a, ketoconazole, troleandomycin, itraconazole) attenuated TNF-[alpha] induction of MAdCAM-1, whereas NADPH oxidase inhibition (PR-39) did not. Conversely, E-selectin, ICAM-1, and VCAM-1 induction requires both NADPH oxidase and CYP450-derived oxidants. We show here that MAdCAM-1 induction may depend exclusively on CYP450-derived oxidants, suggesting that CYP450 blockers might represent a possible novel therapeutic treatment for human IBD. cytochrome P-450 monooxygenase; reduced nicotinamide adenine dinucleotide phosphate oxygenase; mucosal addressin cell adhesion molecule-1; inflammatory bowel disease; endothelial cell adhesion molecules