Prognosis of pancreatic cancer is poor with a 5-year survival rate of only 7%. Although several new chemotherapy treatments have shown promising results, all patients will eventually progress, and we ...need to develop newer chemotherapy treatments to improve response rates and overall survival (OS). HF10 is a spontaneously mutated oncolytic virus derived from a herpes simplex virus-1, and it has potential to show strong antitumor effect against malignancies without damaging normal tissue. We aimed to evaluate the safety and anti-tumor effectiveness in phase I dose-escalation trial of direct injection of HF10 into unresectable locally advanced pancreatic cancer under endoscopic ultrasound (EUS)-guidance in combination with erlotinib and gemcitabine administration. The mid-term results have been previously reported and here we report the final results of our study.
This was a single arm, open-label Phase I trial. HF10 was injected once every 2 weeks and continued up to four times in total unless dose-limiting toxicity (DLT) appears. A total of nine subjects in three Cohorts with dose-escalation were planned to be enrolled in this trial. The primary endpoint was the safety assessment and the secondary endpoint was the efficacy assessment.
Twelve patients enrolled in this clinical trial, and ten subjects received this therapy. Five patients showed Grade III myelosuppression and two patients developed serious adverse events (AEs) (perforation of duodenum, hepatic dysfunction). However, all of these events were judged as AEs unrelated to HF10. Tumor responses were three partial responses (PR), four stable diseases (SD), and two progressive diseases (PD) out of nine subjects who completed the treatment. Target lesion responses were three PRs and six SDs. The median progression free survival (PFS) was 6.3 months, whereas the median OS was 15.5 months. Two subjects from Cohort 1 and 2 showed downstaging and finally achieved surgical complete response (CR).
HF10 direct injection under EUS-guidance in combination with erlotinib and gemcitabine was a safe treatment for locally advanced pancreatic cancer. Combination therapy of HF10 and chemotherapy should be explored further in large prospective studies.
This study was prospectively registered in UMIN-CTR (UMIN000010150) on March 4th, 2013.
In obese and diabetic patients, plasma free fatty acid (FFA) levels are often elevated and may play a causal role in insulin resistance and reactive oxygen species (ROS) production. We have ...previously shown that ursodeoxycholic acid (UDCA) has antioxidative activity through the phosphatidylinositol 3-kinase (PI3K)/Akt signaling-mediated glutathione production. In this study, we investigated the effects of UDCA on insulin response by analyzing intracellular ROS and the activation of the PI3K/Akt signaling pathway in HepG2 cells treated with palmitate. The level of ROS was quantified using 2′,7′-dichlorodihydrofluorescein diacetate (H2DCFDA), and the activation of the PI3K/Akt signaling pathway was determined by Western blotting assay using appropriate antibodies. The intracellular ROS levels were increased by palmitate but were reduced by treatment with UDCA and insulin. Furthermore, insulin significantly stimulated the phosphorylation of Akt. When the cells were pre-treated with palmitate, insulin-induced Akt-phosphorylation was markedly inhibited. However, when the cells were treated with palmitate and UDCA, the effects of insulin were partially restored. UDCA may have protective effects against palmitate-induced decreases in responsiveness to insulin.
Background and Aims In the International Consensus Diagnostic Criteria (ICDC), autoimmune pancreatitis (AIP) is classified into types 1 and 2, and its definite histopathology diagnosis can be made ...based only on surgical or core biopsy specimens. Although EUS-guided FNA (EUS-FNA) biopsy is a safe technique for the collection of pancreatic tissue, no consensus viewpoint has been reached with regard to the role of EUS-FNA biopsy in the diagnosis of AIP. This study investigated the utility of pancreatic tissue collected by EUS-FNA biopsy by using a standard 22-gauge aspiration needle in the diagnosis of AIP. Methods Patients with suspected AIP were prospectively enrolled in Nagoya University Hospital and Nagoya University–affiliated institutions. Pancreatic tissue was collected from each by EUS-FNA biopsy with a standard 22-gauge aspiration needle. Results Fifty patients were registered, including 45 with a final diagnosis of AIP. Lymphoplasmacytic infiltration and abundant immunoglobulin G4 –positive plasmacyte infiltration (>10/high-power field) were detected in 36 (72%) and 27 (54%) patients, respectively. Obliterative phlebitis and storiform fibrosis were not detected in our study. Granulocytic epithelial lesions (GEL) were observed in 3 patients. The sensitivity, specificity, positive predictive value, and negative predictive value of EUS-FNA biopsy to definitively diagnose AIP were 7.9% (3/38), 100% (12/12), 100% (3/3), and 25.5% (12/47), respectively. Pathology evaluation of pancreatic tissue collected by EUS-FNA biopsy improved the diagnostic accuracy in 8 (16%) of the 50 patients. Conclusions In this study, EUS-FNA biopsy by using a standard 22-gauge aspiration needle is not an effective diagnostic method for most patients with AIP. The combination of level 2 histology diagnosis of AIP with other findings specified in the ICDC slightly improved the diagnostic accuracy, although it still remains insufficiently accurate for routine clinical use.(Clinical trial registration number: 000006297.)
The Japanese Society of Gastroenterology (JSGE) revised the evidence-based clinical practice guidelines for peptic ulcer disease in 2014 and has created an English version. The revised guidelines ...consist of seven items: bleeding gastric and duodenal ulcers,
Helicobacter pylori
(
H. pylori
) eradication therapy, non-eradication therapy, drug-induced ulcer, non-
H. pylori
, non-nonsteroidal anti-inflammatory drug (NSAID) ulcer, surgical treatment, and conservative therapy for perforation and stenosis. Ninety clinical questions (CQs) were developed, and a literature search was performed for the CQs using the Medline, Cochrane, and Igaku Chuo Zasshi databases between 1983 and June 2012. The guideline was developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Therapy is initially provided for ulcer complications. Perforation or stenosis is treated with surgery or conservatively. Ulcer bleeding is first treated by endoscopic hemostasis. If it fails, surgery or interventional radiology is chosen. Second, medical therapy is provided. In cases of NSAID-related ulcers, use of NSAIDs is stopped, and anti-ulcer therapy is provided. If NSAID use must continue, the ulcer is treated with a proton pump inhibitor (PPI) or prostaglandin analog. In cases with no NSAID use,
H. pylori
-positive patients receive eradication and anti-ulcer therapy. If first-line eradication therapy fails, second-line therapy is given. In cases of non-
H. pylori
, non-NSAID ulcers or
H. pylori
-positive patients with no indication for eradication therapy, non-eradication therapy is provided. The first choice is PPI therapy, and the second choice is histamine 2-receptor antagonist therapy. After initial therapy, maintenance therapy is provided to prevent ulcer relapse.
Background
Although obscure gastrointestinal bleeding cannot be detected by colonoscopy or upper endoscopy, wireless video capsule endoscopy (VCE) is capable of imaging it. Few data are available on ...medical therapy for patients with nonsteroidal anti-inflammatory drug (NSAID)-induced small-intestinal mucosal injuries. The aim of this study was to compare prevention by rebamipide and placebo of NSAID-induced smallintestinal injury in healthy subjects.
Methods
Ten healthy subjects who provided written informed consent were enrolled. Rebamipide or placebo plus diclofenac was administered with omeprazole for 7 days, and for an additional 7-day period with treatments reversed in the same subjects, with a 4-week washout period between treatments. VCE of the small intestine was performed four times, before and after each of the two study periods.
Results
The number of subjects with small-intestinal mucosal injuries was higher in the placebo group (8/10) than in the rebamipide group (2/10) (
P
= 0.023). Two cases of ulcer and one of bleeding were observed in the placebo group, while no ulcer or bleeding was observed in the rebamipide group.
Conclusions
Rebamipide had significantly higher efficacy than placebo in preventing NSAID-induced small-intestinal mucosal injury.
Abstract Background For successful treatment for nonalcoholic steatohepatitis (NASH), it may be important to treat the individual causative factors. At present, however, there is no established ...treatment for this disease. Branched-chain amino acids (BCAAs) have been used to treat patients with decompensated cirrhosis. Aim In order to elucidate the mechanisms responsible for the effects of BCAAs on hepatic steatosis and disease progression, we investigated the effects of BCAA supplementation in mice fed a choline-deficient high-fat diet (CDHF), which induces NASH. Methods Male mice were divided into four groups that received (1) choline-sufficient high fat (HF) diet (HF-control), (2) HF plus 2% BCAA in drinking water (HF-BCAA), (3) CDHF diet (CDHF-control), or (4) CDHF-BCAA for 8 weeks. We monitored liver injury, hepatic steatosis and cholesterol, gene expression related to lipid metabolism, and hepatic fat accumulation. Results Serum alanine aminotransferase (ALT) levels and hepatic triglyceride (TG) were significantly elevated in CDHF-control relative to HF-control. Liver histopathology revealed severe steatosis, inflammation, and pericellular fibrosis in CDHF-control, confirming the NASH findings. Serum ALT levels and hepatic TG and lipid droplet areas were significantly lower in CDHF-BCAA than in CDHF-control. Gene expression and protein level of fatty acid synthase (FAS), which catalyzes the final step in fatty acid biosynthesis, was significantly decreased in CDHF-BCAA than in CDHF-control ( P < 0.05). Moreover, hepatic total and free cholesterol of CDHF-BCAA was significantly lower than those of CDHF-control. Conclusions BCAA can alleviate hepatic steatosis and liver injury associated with NASH by suppressing FAS gene expression and protein levels.
Mice with CCl4‐induced liver fibrosis that were treated with a single intravenous dose of serum‐free conditioned medium (CM) derived from stem cells from human deciduous teeth (SHEDs) exhibited ...remarkable recovery. The data suggest that SHED‐CM provides multifaceted therapeutic benefits for the treatment of liver fibrosis.
Chronic liver injury from various causes often results in liver fibrosis (LF). Although the liver possesses endogenous tissue‐repairing activities, these can be overcome by sustained inflammation and excessive fibrotic scar formation. Advanced LF leads to irreversible cirrhosis and subsequent liver failure and/or hepatic cancer. Here, using the mouse carbon tetrachloride (CCl4)‐induced LF model, we showed that a single intravenous administration of stem cells derived from human exfoliated deciduous teeth (SHEDs) or of SHED‐derived serum‐free conditioned medium (SHED‐CM) resulted in fibrotic scar resolution. SHED‐CM suppressed the gene expression of proinflammatory mediators, such as TNF‐α, IL‐1β, and iNOS, and eliminated activated hepatic stellate cells by inducing their apoptosis, but protected parenchymal hepatocytes from undergoing apoptosis. In addition, SHED‐CM induced tissue‐repairing macrophages that expressed high levels of the profibrinolytic factor, matrix metalloproteinase 13. Furthermore, SHED‐CM suppressed the CCl4‐induced apoptosis of primary cultured hepatocytes. SHED‐CM contained a high level of hepatocyte growth factor (HGF). Notably, HGF‐depleted SHED‐CM (dHGF‐CM) did not suppress the proinflammatory response or resolve fibrotic scarring. Furthermore, SHED‐CM, but not dHGF‐CM, inhibited CCl4‐induced hepatocyte apoptosis. These results suggest that HGF plays a central role in the SHED‐CM‐mediated resolution of LF. Taken together, our findings suggest that SHED‐CM provides multifaceted therapeutic benefits for the treatment of LF.
Significance
This study demonstrated that a single intravenous administration of stem cells from human exfoliated deciduous teeth (SHEDs) or of the serum‐free conditioned medium (CM) derived from SHEDs markedly improved mouse liver fibrosis (LF). SHED‐CM suppressed chronic inflammation, eliminated activated hepatic stellate cells by inducing their apoptosis, protected hepatocytes from undergoing apoptosis, and induced differentiation of tissue‐repairing macrophages expressing high levels of the profibrinolytic factor matrix metalloproteinase 13. Furthermore, hepatocyte growth factor played a central role in the SHED‐CM‐mediated resolution of LF. This is the first report demonstrating the multifaceted therapeutic benefits of secreted factors derived from SHEDs for LF.
Chemotherapy‐induced peripheral neurotoxicity (CIPN) seriously impairs patients’ quality of life cumulatively and dose‐dependently. Because assessment of CIPN usually depends on patients’ subjective ...evaluation of symptoms, objective and quantitative measures are needed. We evaluated a point‐of‐care nerve conduction device (POCD), previously validated for the assessment of diabetic peripheral neuropathy. Sensory nerve action potential (SNAP) amplitude and sensory nerve conduction velocity (SNCV) of the sural nerve were measured using a portable, automated POCD (DPNCheck; NeuroMetrix Inc., Waltham, MA, USA) in patients with a clinical diagnosis of CIPN of grade 1 or higher. We compared SNAP and SNCV among patients with different grades of CIPN according to the Common Terminology Criteria for Adverse Events. A total of 50 patients (22 men, 28 women; median age, 64 years; grade 1/2/3, 21/18/11) were evaluated. Anticancer drugs responsible for CIPN were cisplatin in five patients, oxaliplatin in 15, carboplatin in 5, paclitaxel in 16, docetaxel in 14, nab‐paclitaxel in 7, vincristine in 6, and bortezomib in 3. Unadjusted SNAP was 8.45 ± 3.67 μV (mean ± SD) in patients with grade 1 CIPN, 5.42 ± 2.68 μV with grade 2, and 2.45 ± 1.52 μV with grade 3. Unadjusted SNCV was 49.71 ± 4.77 m/s in patients with grade 1 CIPN, 48.78 ± 6.33 m/s with grade 2, and 44.14 ± 7.31 m/s with grade 3. The adjusted SNAP after controlling for age significantly differed between each CTCAE grade (P < 0.001, ancova). The adjusted SNCV after controlling for age and height also differed significantly (P = 0.027). Differences in the severity of CIPN could be detected objectively and quantitatively using this POCD.
Chemotherapy‐induced peripheral neurotoxicity (CIPN) seriously impairs patients’ quality of life. Because assessment of CIPN usually depends on patients’ subjective evaluation of symptoms, objective and quantitative measures are needed. We validated a point‐of‐care nerve conduction device, which has been originally developed for the assessment of diabetic peripheral neuropathy, in patients who had been given a clinical diagnosis of CIPN.
Background
An accurate diagnosis of pancreatic fibrosis is clinically important and may have potential for staging chronic pancreatitis. The aim of this study was to diagnose the grade of pancreatic ...fibrosis through a quantitative analysis of endoscopic ultrasound elastography (EUS-EG).
Methods
From September 2004 to October 2010, 58 consecutive patients examined by EUS-EG for both pancreatic tumors and their upstream pancreas before pancreatectomy were enrolled. Preoperative EUS-EG images in the upstream pancreas were statistically quantified, and the results were retrospectively compared with postoperative histological fibrosis in the same area. For the quantification of EUS-EG images, 4 parameters (mean, standard deviation, skewness, and kurtosis) were calculated using novel software. Histological fibrosis was graded into 4 categories (normal, mild fibrosis, marked fibrosis, and severe fibrosis) according to a previously reported scoring system.
Results
The fibrosis grade in the upstream pancreas was normal in 24 patients, mild fibrosis in 19, marked fibrosis in 6, and severe fibrosis in 9. Fibrosis grade was significantly correlated with all 4 quantification parameters (mean
r
= −0.75, standard deviation
r
= −0.54, skewness
r
= 0.69, kurtosis
r
= 0.67). According to the receiver operating characteristic analysis, the mean was the most useful parameter for diagnosing pancreatic fibrosis. Using the mean, the area under the ROC curves for the diagnosis of mild or higher-grade fibrosis, marked or higher-grade fibrosis and severe fibrosis were 0.90, 0.90, and 0.90, respectively.
Conclusions
An accurate diagnosis of pancreatic fibrosis may be possible by analyzing EUS-EG images.
Objective To assess the prevalence and clinical correlates of non-alcoholic fatty liver disease (NAFLD) identified by computed tomography (CT) in the general population compared with ultrasonography ...(US). Methods Four hundred and fifty-eight subjects who received health checkups at Meijo Hospital in 2021 and underwent CT within a year of US in the past decade were analyzed. The mean age was 52.3±10.1 years old, and 304 were men. Results NAFLD was diagnosed in 20.3% by CT and in 40.4% by the US. The NAFLD prevalence in men was considerably greater in subjects 40-59 years old than in those ≤39 years old and in those ≥60 years old by both CT and US. The NAFLD prevalence in women was substantially higher in the subjects 50-59 years old than in those ≤49 years old or those ≥60 years old on US, while no significant differences were observed on CT. The abdominal circumference, hemoglobin value, high-density lipoprotein cholesterol level, albumin level, and diabetes mellitus were independent predictors of NAFLD diagnosed by CT. The body mass index, abdominal circumference, and triglyceride level were independent predictors of NAFLD diagnosed by the US. Conclusion NAFLD was found in 20.3% of CT cases and 40.4% of US cases among recipients of health checkups. An "inverted U curve" in which the NAFLD prevalence rose with age and dropped in late adulthood was reported. NAFLD was associated with obesity, the lipid profile, diabetes mellitus, hemoglobin values, and albumin levels. Our research is the first in the world to compare the NAFLD prevalence in the general population simultaneously by CT and US.
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