Hepatitis C Treatment in Elderly Patients

The patients with chronic hepatitis C (CHC) are getting older and the demands for treatment to those patients are increasing due to the high risk of development of hepatocellular carcinoma. Elderly patients were previously defined as 60 years and over, however definition of the elderly patients shifted to be older year to year. Interferon (IFN) and ribavirin combination therapy was significantly improved efficacy of treatment, however ribavirin induces anemia, resulted in lower efficacy due to reduction of ribavirin for the elderly patients. And efficacy of over 60 years old was comparable to the patients under 60 years. In the CHC patients with genotype 1, the efficacy of elderly patient was significantly lower than that of younger patients, especially in female. Direct-acting antivirals (DAAs) therapy makes treatment efficacy improved to over 90% and side effect of treatment was dramatically reduced compared to IFN-based therapy. The efficacy of dual oral therapy by using asunaprevir (ASV) and daclatasvir (DCA) for elderly patients with hepatitis C virus (HCV) genotype 1b has not been fully clarified. In this article we would like to show the efficacy of elderly patients with CHC, especially patients infected with genotype 1b, from the era of IFN monotherapy to the era of new DAAs

Impact of HBV Infection on Outcomes of Direct-Acting Antiviral Therapy of Chronic Hepatitis C

Background: Most clinical trials of direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection have excluded hepatitis B virus (HBV) coinfection, and little is known about the effects of DAA on chronic hepatitis C patients with HBV coinfection. Recent studies have reported that DAA therapy for HCV can also cause HBV reactivation in patients with HBV and HCV coinfection. The aim of this study was to assess the effects of DAA on sustained virologic response (SVR) and HBV reactivation in patients with chronic hepatitis C. Methods: Participants comprised 199 chronic hepatitis C patients who received DAA therapy (96 men, 103 women; mean age, 66.7 ± 12.0 years). Results: Twelve patients were coinfected with HCV and HBV. Sixty patients were HBV surface antigen negative but positive for hepatitis B core antibody and/or hepatitis B surface antibody, and one hundred and twenty-seven patients had not been exposed to HBV. Rates of SVR in HBV and HCV coinfected patients, HBV prior infection, and no exposure to HBV were 100, 95, and 97%, respectively. Significant differences were seen between each group. No case showed HBV reactivation. Conclusions: DAA treatments were effective in patients with HBV coinfection or HBV prior infection, as well as HCV monoinfection. As the number of cases was small, we still suggest caution regarding HBV reactivation in HCV and HBV coinfected patients undergoing treatment with DAA

The first Japanese biobank of patient‐derived pediatric acute lymphoblastic leukemia xenograft models

A lack of practical resources in Japan has limited preclinical discovery and testing of therapies for pediatric relapsed and refractory acute lymphoblastic leukemia (ALL), which has poor outcomes. Here, we established 57 patient-derived xenografts (PDXs) in NOD.Cg-Prkdcscidll2rgtm1Sug/ShiJic (NOG) mice and created a biobank by preserving PDX cells including three extramedullary relapsed ALL PDXs. We demonstrated that our PDX mice and PDX cells mimicked the biological features of relapsed ALL and that PDX models reproduced treatment-mediated clonal selection. Our PDX biobank is a useful scientific resource for capturing drug sensitivity features of pediatric patients with ALL, providing an essential tool for the development of targeted therapies

Seven-Signal Proteomic Signature for Detection of Operable Pancreatic Ductal Adenocarcinoma and Their Discrimination from Autoimmune Pancreatitis

There is urgent need for biomarkers that provide early detection of pancreatic ductal adenocarcinoma (PDAC) as well as discrimination of autoimmune pancreatitis, as current clinical approaches are not suitably accurate for precise diagnosis. We used mass spectrometry to analyze protein profiles of more than 300 plasma specimens obtained from PDAC, noncancerous pancreatic diseases including autoimmune pancreatitis patients and healthy subjects. We obtained 1063 proteomic signals from 160 plasma samples in the training cohort. A proteomic signature consisting of 7 mass spectrometry signals was used for construction of a proteomic model for detection of PDAC patients. Using the test cohort, we confirmed that this proteomic model had discrimination power equal to that observed with the training cohort. The overall sensitivity and specificity for detection of cancer patients were 82.6% and 90.9%, respectively. Notably, 62.5% of the stage I and II cases were detected by our proteomic model. We also found that 100% of autoimmune pancreatitis patients were correctly assigned as noncancerous individuals. In the present paper, we developed a proteomic model that was shown able to detect early-stage PDAC patients. In addition, our model appeared capable of discriminating patients with autoimmune pancreatitis from those with PDAC

A functional polymorphism in the epidermal growth factor gene predicts hepatocellular carcinoma risk in Japanese hepatitis C patients

Background: A single nucleotide polymorphism (SNP) in the epidermal growth factor (EGF) gene (rs4444903) has been associated with increased risk of cancer, including hepatocellular carcinoma (HCC). The aim of this study was to examine the relationship between the EGF SNP genotype and the development and prognosis of HCC, in a Japanese population. Methods: Restriction fragment-length polymorphism was used to determine the presence of the EGF SNP genotype in 498 patients, including 208 patients with HCC. The level of EGF messenger ribonucleic acid (mRNA) expression in cancerous tissues was measured by quantitative reverse transcription polymerase chain reaction. The correlation between the EGF SNP genotype and prognosis was statistically analyzed in the patients with HCC. Results: The proportion of the A/A, A/G, and G/G genotypes were 5.3%, 42.8%, and 51.9%, respectively, in the patients with HCC, whereas in those without HCC, they were 8.6%, 35.9%, and 55.5%, respectively, revealing that the odds ratio (OR) of developing HCC was higher in patients with a G allele (OR =1.94, P=0.080 for A/G patients and OR =1.52, P=0.261 for G/G patients, as compared with A/A patients). In particular, when the analysis was limited to the 363 patients with hepatitis C, the OR for developing HCC was 3.54 (P=0.014) for A/G patients and was 2.85 (P=0.042) for G/G patients, as compared with A/A patients. Tumoral EGF mRNA expression in G/G patients was significantly higher than that in A/A patients (P=0.033). No statistically significant differences were observed between the EGF SNP genotype and diseasefree or overall survival. Conclusion: The EGF SNP genotype might be associated with a risk for the development of HCC in Japanese patients but not with prognosis. Of note, the association is significantly stronger in patients with hepatitis C, which is the main risk factor for HCC in Japan

Secreted Ectodomain of SIGLEC-9 and MCP-1 Synergistically Improve Acute Liver Failure in Rats by Altering Macrophage Polarity

Effective treatments for acute liver failure (ALF) are still lacking. We recently reported that a single intravenous administration of serum-free conditioned medium from stem cells derived from human exfoliated deciduous teeth (SHED-CM) into the D-galactosamine (D-Gal)-induced rat ALF model improves the liver injury. However, the specific factors in SHED-CM that are responsible for resolving ALF remain unclear. Here we found that depleting SHED-CM of two anti-inflammatory M2 macrophage inducers—monocyte chemoattractant protein-1 (MCP-1) and the secreted ectodomain of sialic acidbinding Ig-like lectin-9 (sSiglec-9)—abolished its ability to resolve rat ALF. Furthermore, treatment with MCP-1/sSiglec-9 alone dramatically improved the survival of ALF rats. This treatment induced anti-inflammatory M2, suppressed hepatocyte apoptosis, and promoted hepatocyte proliferation. Treatment with an M2-depletion reagent (mannosylated clodronate liposomes) suppressed the recovery. In addition, MCP-1 and sSiglec-9 synergistically promoted the M2 differentiation of bone marrow-derived macrophages via CCR2, accompanied by the production of multiple liver-regenerating factors. The conditioned medium from MCP-1/sSiglec-9-activated M2 macrophages, but not from interleukin-4-induced ones, suppressed the D-Gal- and LPS-induced apoptosis of primary hepatocytes and promoted their proliferation in vitro. The unique combination of MCP-1/sSiglec-9 ameliorates rat ALF by inhibiting hepatocellular apoptosis and promoting liver regeneration through the induction of anti-inflammatory/tissue-repairing M2 macrophages

Novel application of low pH-dependent fluorescent dyes to examine colitis

<p>Abstract</p> <p>Background</p> <p>Endoscopy capable of fluorescence observation provides histological information on gastrointestinal lesions. We explored the novel application of low pH-dependent fluorescent dyes for fluorescence observation of crypt structure and inflammatory cell infiltration in the colon.</p> <p>Methods</p> <p>Low pH-dependent fluorescent dyes were applied to the colonic mucosa of normal mice for observation under fluorescence stereomicroscopy system. We also examined mouse models of colitis, which were induced by trinitrobenzenesulfonic acid, dextran sulfate sodium or interleukin-10 deficiency.</p> <p>Results</p> <p>Topical application of low pH-dependent fluorescent dyes revealed crypts as ring-shaped fluorescent stains by visualizing the mucin granules of goblet cells. Because of the minimal fluorescence intensity of the low pH-dependent fluorescent dyes in phosphate-buffered saline, it was not necessary to wash the mucosa before the fluorescence observation. 4-Nitro-7-piperazino-2,1,3-benzoxadiazole (NBD-PZ) was quicker to achieve complete staining (three minutes) than LysoSensor Green DND-153 and DND-189 (20 minutes). In each type of colitis, NBD-PZ revealed the destruction of the crypts as the disappearance of the ring-shaped fluorescent stains and the infiltration of inflammatory cells as the aggregation of punctate fluorescent stains through visualization of lysosomes.</p> <p>Conclusions</p> <p>Low pH-dependent fluorescent dyes, especially NBD-PZ, are suitable for topical application to the colonic mucosa and have characteristics that allow for the histological examination of colitis.</p