Hitoshi Setoyama

Safety and pharmacokinetics of recombinant human hepatocyte growth factor (rh-HGF) in patients with fulminant hepatitis: a phase I/II clinical trial, following preclinical studies to ensure safety

BackgroundHepatocyte growth factor (HGF) stimulates hepatocyte proliferation, and also acts as an anti-apoptotic factor. Therefore, HGF is a potential therapeutic agent for treatment of fatal liver diseases. We performed a translational medicine protocol with recombinant human HGF (rh-HGF), including a phase I/II study of patients with fulminant hepatitis (FH) or late-onset hepatic failure (LOHF), in order to examine the safety, pharmacokinetics, and clinical efficacy of this molecule.MethodsPotential adverse effects identified through preclinical safety tests with rh-HGF include a decrease in blood pressure (BP) and an increase in urinary excretion of albumin. Therefore, we further investigated the effect of rh-HGF on circulatory status and renal toxicity in preclinical animal studies. In a clinical trial, 20 patients with FH or LOHF were evaluated for participation in this clinical trial, and four patients were enrolled. Subjects received rh-HGF (0.6 mg/m2/day) intravenously for 12 to 14 days.ResultsWe established an infusion method to avoid rapid BP reduction in miniature swine, and confirmed reversibility of renal toxicity in rats. Although administration of rh-HGF moderately decreased BP in the participating subjects, this BP reduction did not require cessation of rh-HGF or any vasopressor therapy; BP returned to resting levels after the completion of rh-HGF infusion. Repeated doses of rh-HGF did not induce renal toxicity, and severe adverse events were not observed. Two patients survived, however, there was no evidence that rh-HGF was effective for the treatment of FH or LOHF.ConclusionsIntravenous rh-HGF at a dose of 0.6 mg/m2 was well tolerated in patients with FH or LOHF; therefore, it is desirable to conduct further investigations to determine the efficacy of rh-HGF at an increased dose.

Effect of Endoscopic Submucosal Dissection for Superficial Esophageal Neoplasms and Risk Factors for Postoperative Stricture

AbstractEndoscopic submucosal dissection (ESD) enables wider tumor resection compared with endoscopic mucosal resection and en bloc resection of superficial esophageal neoplasms. However, ESD may cause difficult-to-treat stricture of the esophagus, and therefore, prediction of and measures against postoperative esophageal stricture are critical. The aim of this study was to evaluate the effect of ESD on superficial esophageal neoplasms and identify risk factors associated with esophageal stricture after ESD.This study included 165 lesions in 120 patients with superficial esophageal neoplasms, including cancer and neoplasia, who underwent ESD from 2009 to 2013.The complete resection rate of superficial esophageal neoplasms by ESD was 90.9%. After ESD, 22 subjects (18.3%) had symptomatic esophageal stricture, 12 (10.0%) had aspiration pneumonia of grade 2, and 7 (5.8%) had mediastinal emphysema of grade 2. Comparison of the 22 subjects with stricture with the 98 subjects without stricture showed significant differences in the rate of resection of >75% of the esophageal circumference, rate of whole circumference resection, and the required time for resection. The tumor size and the size of the resected tissue sample also differed between the 2 groups. The groups did not differ in age, sex, alcohol intake, and smoking; location, macroscopic, and histological tumor findings; chest pain; or use of anticoagulants for comorbidities. In multivariate analysis, tumor size and whole circumference resection were independent risk factors for stricture. Furthermore, in 45 subjects with resection of >75% of the esophageal circumference, whole resection of the esophagus was the only independent risk factor for stricture.This study suggests that ESD has a strong therapeutic effect on superficial esophageal neoplasms; however, a greater extent of resection of the esophagus increases the risk of postoperative esophageal stricture. Preventive measures against development of postoperative stricture require further study.

Translational research on HGF: A phase I/II study of recombinant human HGF for the treatment of fulminant hepatic failure

Hepatocyte growth factor (HGF) is a potential therapeutic agent for fatal liver diseases, including fulminant hepatic failure (FHF). After performing a number of preclinical tests with recombinant human HGF (rh‐HGF), we started a phase I/II study in September 2005 of patients with FHF or late‐onset hepatic failure (LOHF), to examine the safety and clinical efficacy of rh‐HGF. We first administered rh‐HGF (0.6 mg/m2/day) for 13 days to a 67‐year‐old Japanese man with FHF. All data from this patient were reviewed by the independent data monitoring committee, and the safety of rh‐HGF was recognized. Finally, a clinical trial of rh‐HGF was approved to be continued. As of August 2007, we have administered rh‐HGF to four patients with FHF or LOHF. All patients showed a moderate decrease in systolic blood pressure during rh‐HGF administration, while the urinary excretion of albumin did not increase in all cases. In the first and third patients, hepatic failure gradually progressed, and they died 66 and 29 days, respectively, after encephalopathy occurred. The second and fourth patients are presently still alive. In conclusion, we started a clinical trial that examined the effects of rh‐HGF in patients with FHF or LOHF, and in the four patients with FHF or LOHF enrolled in this study, repeated doses of rh‐HGF did not produce any severe side effects.

Hepatocyte growth factor ameliorates mucosal injuries leading to inhibition of colon cancer development in mice

Hepatocyte growth factor (HGF), which facilitates the repair of injured mucosa, has the potential to be a new therapeutic agent for inflammatory bowel disease (IBD). However, given that the incidence of colorectal cancer increases continuously with disease duration in patients with IBD, the fact that HGF is a potent mitogen for intestinal epithelial cells may further heighten the risk of bowel cancer in this patient population. In this study, we examined the effects of recombinant HGF on colorectal cancer development in mice with or without experimentally induced colitis. Although HGF stimulated proliferation of colonic epithelial cells in normal mucosa, the development of colorectal cancer induced by repeated injection of azoxymethane (AOM) was significantly inhibited by HGF treatment. In a mouse model of colitis-associated cancer, colorectal cancer frequently developed despite only a single injection of AOM prior to three cycles of dextran sulfate sodium administration. However, HGF treatment significantly facilitated the repair of injured mucosa, leading to inhibition of colorectal cancer development in a dose-dependent manner. Thus, HGF-induced repair of injured mucosa inhibits rather than accelerates the development of colorectal cancer, and these results also suggest the importance of blocking the cycles of mucosal injury and repair to prevent colitis-associated colorectal cancer.

Repeated enemas with hepatocyte growth factor selectively stimulate epithelial cell proliferation of injured mucosa in rats with experimental colitis.

AIMS Hepatocyte growth factor (HGF) modulates intestinal epithelial cell proliferation and migration. We previously reported that systemic administration of recombinant human HGF (rh-HGF) ameliorated experimental colitis. However, an increase in serum HGF concentrations may induce undesired systemic effects, limiting the use of rh-HGF. To avoid possible side effects, we investigated the safety and efficacy of rectally administered rh-HGF as a treatment for experimental colitis. MAIN METHODS We measured serum human HGF concentration following a single rectal enema of rh-HGF. Rats with 2,4,6-trinitrobenzene sulfonic acid (TNBS)- or dextran sulfate sodium (DSS)-induced colitis were treated with rectal enemas of rh-HGF once a day for seven days. The degree of mucosal injuries and the proliferative activity of the colon epithelium were examined. KEY FINDINGS Rats administered a rectal enema of rh-HGF at a dose of 0.1 mg/ml or less had no detectable rh-HGF in the serum. Repeated enemas of rh-HGF at this dose significantly reduced mucosal injuries, both with respect to lesion size and inflammatory cell infiltration. This regimen also stimulated proliferation of epithelial cells surrounding injured mucosa; however, the cell proliferation of uninjured mucosa was not affected by this local treatment. SIGNIFICANCE Rectally administered rh-HGF selectively accelerates the repair of injured mucosa in rat experimental colitis without systemic exposure to HGF. Rectal enemas of HGF are thus a potential novel and safe therapy for IBD.

Fecal Human Neutrophil Peptide Levels Correlate with Intestinal Inflammation in Ulcerative Colitis

Background/Aim: Fecal markers have recently been found to provide convenient and noninvasive assessment of intestinal inflammation in inflammatory bowel disease (IBD). In this study, we examined the clinical significance of fecal human neutrophil peptides (F-HNP) in the evaluation of IBD disease activity. Methods: This study enrolled 70 patients with IBD, consisting of 45 patients with ulcerative colitis (UC), 25 patients with Crohns disease (CD), and 11 non-IBD controls. Stools samples were evaluated for the association between F-HNP concentration and disease and endoscopic activity in each group and the correlation between F-HNP and fecal calprotectin (F-CP) concentrations. Results: Median F-HNP levels were as follows: UC: 25.6 ng/ml; CD: 20.1 ng/ml; and non-IBD controls: 4.9 ng/ml. F-HNP levels were significantly higher in each IBD group, especially in the UC group, than in the control group. In the UC group, both F-HNP and F-CP levels were significantly higher during active disease compared to the remission phase. Both markers were significantly correlated with the Mayo endoscopic score, although the correlation was stronger for F-HNP than for F-CP (r = 0.66 vs. r = 0.54). Conclusion: F-HNP is a noninvasive marker that is useful for evaluating UC endoscopic activity.

Su1950 Hypertension Exacerbates Hepatic Fibrosis Induced by a Choline-Deficient L-Amino Acid-Defined Diet in Rats

Introduction: Nonalcoholic fatty liver disease (NAFLD) and its subsequent complications create a significant health burden, with an absence of treatment modalities of proven efficacy. Statuses and oxidative stress should be existed to develop the more severe forms of NAFLD. Acai, an amazone palm fruit, is a phytochemical rich berry, with anti inflammatory properties which penetrate and protect cells from oxidative damage In Vitro. Aims: I. To evaluate the effect of freeze-dried acai powder supplementation on steatosis in a fructose enriched diet (FED) model of NAFLD in rats. II. To quantify the reduction in hepatic lipids content following acai supplementation and how it affects the oxidative stress profile. III. To investigate if there is any beneficial effect on NAFL histology. Methods: A total of 46 males Spraue Dawley rats (200-250 gr) were fed by 5 different diets: regular chow (n=5), regular plus 3% of freeze-dried acai powder (n=5), FED (60% fructose) (n=12), FED plus acai from day 21 (n=12) and FED plus aecia from day 1 (n=12). After 6 weeks rats were sacrificed and the liver extracted for evaluation of lipid content, MDA (malondialdehyde), alfa-tocopferol, paraoxonase, total glutathione and glutathione peroxidase. Lipid profile, glucose, transaminases, bilirubin were determined in 1 ml of serum. Results: Acai supplementation to FED rat model tended to decrease liver steatosis and hepatocyte ballooning. Addition of acai from day 21 but not from day 1, decreased significantly hepatic TG level, increased significantly hepatic anti oxidants; alfa-tocopherol, paraoxonase, total glutathione and glutathione peroxidase activity (for each p<0.001), and decreased significantly hepatic MDA level (p<0.001). No significant differences were found in serum glucose level and lipid profile between FED with or without acai supplementation. Conclusions: Supplementation of acai may improve NAFLD in rats by decreasing intra-hepatic TG content, increasing anti oxidants and decreasing oxidative stress, despite having minimal beneficial effect on liver histology. Acai might be an effective therapeutic modality in patients with fatty liver.

T1777 Hepatocyte Growth Factor Stimulates the Migration of Gastric Epithelial Cells by Altering the Intracellular Localization of the Tight Junction Protein ZO-1

Background Hepatocyte growth factor (HGF) is essential for epithelial restitution, a process in which epithelial cells rapidly migrate to cover desquamated epithelium after mucosal injury in the gastrointestinal tract. In this study, we aimed to elucidate the molecular mechanisms of the HGF-mediated reconstitution of gastric epithelial structures by analyzing the expression and subcellular dynamics of tight junction proteins.

W1104 Treatment Strategies for Intestinal Behcet's Disease: A Retrospective Analysis of Infliximab and Other Therapies

assay. Results: Of 113 children with UC, 37 (33%) were anti-CBir1 + and 76 (67%) antiCBir1-. No statistically significant differences between CBir+ and CBirsubjects were noted in terms of age at diagnosis (11±4 vs 12±4 yrs), % < 8yrs at diagnosis (16 vs 15%), % male (46 vs 59%), % pancolitis (81 vs 83%), % moderate/severe UC activity at diagnosis (57 vs 74%) or duration of follow-up (35±20 vs 36±20 months). There were also no statistically significant differences in the rates of pANCA (81 vs 78%), anti-ompC (8 vs 9%), ASCA IgA (8 vs 3%) or ASCA IgG (5 vs 1%). Initial treatments were similar between groups (all comparisons p=NS): 5ASA (68 vs 53%), Steroids (43 vs 55%), 6MP/Azathioprine (3 vs 8%), infliximab (0 vs 3%). UC activity by physicians global assessment at 1 and 2 yrs after diagnosis was inactive or mild in 92-95% of both groups. Two (5%) CBir+ and 9 (12%) CBirsubjects received at least 1 dose of infliximab within 2 yrs of diagnosis (p=NS). Two (5%) CBir+ subjects required colectomy (both treated with infliximab) as did 10 CBir(13%) subjects (6 after infliximab) by 2 yrs after diagnosis (p=NS). Conclusions: Anti-CBir1 is found in a third of children newly diagnosed with UC. However, anti-CBir1 status does not appear to affect disease course or need for infliximab or colectomy in the first 2 years after diagnosis.