Prophylactic tenofovir alafenamide for hepatitis B virus reactivation and reactivation-related hepatitis.

No prospective study on the efficacy of tenofovir alafenamide (TAF), a novel tenofovir prodrug, in preventing hepatitis B virus (HBV) reactivation has yet been reported. This multicenter prospective study enrolled HBV-carriers who received TAF to prevent HBV reactivation before antitumor or immunosuppressive therapy, and patients with resolved HBV infection who experienced HBV-reactivation and received TAF to prevent HBV reactivation-related hepatitis. The efficacy of prophylactic TAF in preventing HBV reactivation and HBV reactivation-related hepatitis was evaluated at 6 and 12 months after initiating TAF. Overall, 110 patients were administered TAF to prevent HBV reactivation or HBV reactivation-related hepatitis. Three patients died owing to primary disease, whereas one patient was transferred to another hospital within 6 months after initiating TAF. Seven patients died due to primary disease, and five patients were transferred to another hospital within 12 months after initiating TAF. Therefore, 106 and 94 (77 patients with HBV infection, 17 with previous-HBV infection) patients were evaluated at 6 and 12 months after initiating TAF, respectively. No patient experienced HBV reactivation, HBV reactivation-related hepatitis, or treatment discontinuation due to HBV reactivation or adverse events of TAF after 6 and 12 months. TAF could effectively prevent HBV reactivation and HBV reactivation-related hepatitis.

Recent prevalence and characteristics of patients with hepatitis delta virus in Hokkaido, Japan.

AIM: Although hepatitis delta virus (HDV) coinfection with hepatitis B virus (HBV) is a global health concern, the global prevalence of HDV infections remains unknown due to insufficient data in many countries. In Japan, HDV prevalence has not been updated for over 20 years. We aimed to investigate the recent prevalence of HDV infections in Japan. METHODS: We screened 1264 consecutive patients with HBV infection at Hokkaido University Hospital between 2006 and 2022. Patients' serums were preserved and subsequently tested for HDV antibody (immunoglobulin-G). Available clinical information was collected and analyzed. We compared the changes in liver fibrosis using the Fibrosis-4 (FIB-4) index between propensity-matched patients with and without the evidence of anti-HDV antibodies and corrected for baseline FIB-4 index, nucleoside/nucleotide analog treatment, alcohol intake, sex, HIV coinfection, liver cirrhosis, and age. RESULTS: After excluding patients without properly stored serums and those lacking appropriate clinical information, 601 patients with HBV were included. Of these, 1.7% of patients had detectable anti-HDV antibodies. Patients with anti-HDV antibody serum positivity had a significantly higher prevalence of liver cirrhosis, significantly lower prothrombin time, and a higher prevalence of HIV coinfection than those who demonstrated serum anti-HDV antibody negativity. A propensity-matched longitudinal analysis revealed that liver fibrosis (FIB-4 index) progressed more rapidly in patients with positive results for anti-HDV antibody tests. CONCLUSIONS: The recent prevalence of HDV infections in Japanese patients with HBV was 1.7% (10/601). These patients experienced rapid liver fibrosis progression, highlighting the importance of routine HDV testing.

Hepatitis C virus eradication by direct-acting antivirals causes a simultaneous increase in the prevalence of fatty liver and hyper low-density lipoprotein cholesterolemia without an increase in body weight.

AIM: Hepatitis C virus (HCV) infection has been reported to cause liver steatosis. Thus, eradicating HCV with direct-acting antivirals (DAAs) is expected to reduce liver steatosis. We aimed to clarify long-term changes in the prevalence of fatty liver and hyper-low-density lipoprotein (LDL) cholesterolemia and their associations in patients who achieve successful HCV eradication using DAAs. METHODS: This retrospective study included patients with HCV who achieved sustained virologic response after interferon-free DAA and analyzed the changes in the prevalence of fatty liver diagnosed with controlled attenuation parameter (CAP), hyper-LDL cholesterolemia, and their relationships at baseline (n = 100) and 24 weeks (SVR24, n = 100), 96 weeks (SVR96, n = 100), and 144 weeks (SVR144, n = 90) after DAA. RESULTS: In 100 participants, the prevalence of fatty liver (19% vs. 32%, p = 0.0349) and hyper-LDL cholesterolemia (6% vs. 15%, p = 0.0379) significantly increased without changes in body weight at SVR96. Median total cholesterol, low-density lipoprotein cholesterol (LDL-C), and small-dense-LDL (sdLDL) levels and CAP values were significantly greater at SVR24, SVR96, and SVR144 than at baseline. Baseline CAP values and changes in CAP values were significantly negatively correlated at every observation point: r = -0.5305, p < 0.0001 at SVR24; r = -0.3617, p = 0.0005 at SVR96; and r = -0.4735, p < 0.0001 at SVR144. A similar relationship was observed in cholesterol levels. Unlike at baseline, CAP values were significantly positively correlated with LDL-C and sdLDL-C levels at all observation points after DAAs. CONCLUSIONS: Direct-acting antivirals may cause an increased prevalence of fatty liver accompanying hyper-LDL cholesterolemia without increased body weight. As post-SVR liver steatosis could cause HCC, careful follow-up may be required.

The potential of soluble CD14 in discriminating nonalcoholic steatohepatitis from nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: Although various noninvasive markers and prediction formulas for nonalcoholic steatohepatitis (NASH) have been reported, they are of value only in the diagnosis of the advanced fibrosis stage of NASH. In this study, we evaluated soluble CD14 (sCD14) as a diagnostic marker for discriminating NASH from nonalcoholic fatty liver disease (NAFLD) using an animal model and clinical specimens. METHODS: Serum sCD14 levels were measured in samples derived from mice with diet-induced NASH and patients using an enzyme-linked immunosorbent assay. Our cohort enrolled 126 patients with liver needle biopsy-proven NAFLD. RESULTS: The intestinal defense mechanism in NASH model mice was altered as a consequence of the unique gut environment. Elevated serum levels of sCD14 were observed in mice with diet-induced NASH, and the condition of the liver was exacerbated as a result of exposure to gut-derived endotoxin. We confirmed that the serum sCD14 levels in NAFL patients significantly differed from those in NASH patients. The area under the curve for distinguishing between NAFL and NASH was 0.891. Moreover, we found that serum sCD14 levels were weakly correlated with the inflammation grade based on the NAFLD activity score (NAS), the grade of fibrosis according to the Brunt fibrosis classification, and a positive correlation with the grade of ballooning based on NAS in patients with NAFLD. CONCLUSION: sCD14 could be a useful pathophysiological marker and diagnostic adjunct distinguishing NASH from NAFLD. The use of sCD14 may allow the screening and identification of high-risk groups for NASH development and support early therapeutic interventions.

Overestimated renal function in patients with liver cirrhosis predicts poor prognosis.

AIM: A high prevalence of overestimated renal function in patients with liver cirrhosis (LC) has been reported; nonetheless, its impact on prognosis remains unclear. We aimed to evaluate the impact of overestimated renal function on prognosis in patients with LC. METHODS: An overestimated renal function was defined as a >20% increase in the creatinine-based estimated glomerular filtration rate (eGFR), compared with cystatin C-based eGFR. LC patients with conserved serum, who were evaluated for muscle atrophy and had proper clinical information were included, and their prognostic factors were analyzed. RESULTS: A total of 215 consecutive patients with LC were included. The prevalence of overestimated renal function was 29.8% (64/215). Kaplan-Meier survival analysis revealed that patients with overestimated renal function had a poorer prognosis than those without overestimated renal function (hazard ratio [HR]: 2.217 95% confidence interval [CI]: 1.290-3.810; p = 0.001). Subgroup analysis showed that overestimated renal function was a significant prognostic factor, irrespective of sex and the presence of hepatocellular carcinoma (HCC). Multivariate Cox regression analyses revealed that overestimated renal function was a significant and independent factor predictive of poor prognosis in the entire cohort (HR: 2.050; 95% CI: 1.041-4.037; p = 0.038) and in subgroups classified by Child-Pugh class A (HR: 2.131; 95% CI: 1.019-4.458; p = 0.044), Model for End-Stage Liver Disease score ≤9 (HR: 2.303; 95% CI: 1.038-5.109; p = 0.04), and presence of HCC (HR: 2.290; 95% CI: 1.128-4.651; p = 0.022). CONCLUSION: Overestimated renal function is a significant and independent prognostic factor in patients with LC.

Comprehensive Glycomic Approach Reveals Novel Low-Molecular-Weight Blood Group-Specific Glycans in Serum and Cerebrospinal Fluid.

ABO blood antigens on the human red blood cell membrane as well as different cells in various human tissues have been thoroughly studied. Anti-A and -B antibodies of IgM are present in serum/plasma, but blood group-specific glyco-antigens have not been extensively described. In this study, we performed comprehensive and quantitative serum glycomic analyses of various glycoconjugates and free oligosaccharides in all blood groups. Our comprehensive glycomic approach revealed that blood group-specific antigens in serum/plasma are predominantly present on glycosphingolipids on lipoproteins rather than glycoproteins. Expression of the ABO antigens on glycosphingolipids depends not only on blood type but also on secretor status. Blood group-specific glycans in serum/plasma were classified as type I, whereas those on RBCs had different structures including hexose and hexosamine residues. Analysis of free oligosaccharides revealed that low-molecular-weight blood group-specific glycans, commonly containing lacto-N-difucotetraose, were expressed in serum/plasma according to blood group. Furthermore, comprehensive glycomic analysis in human cerebrospinal fluid showed that many kinds of free oligosaccharides were highly expressed, and low-molecular-weight blood group-specific glycans, which existed in plasma from the same individuals, were present. Our findings provide the first evidence for low-molecular-weight blood group-specific glycans in both serum/plasma and cerebrospinal fluid.

Lenvatinib suppresses cancer stem-like cells in HCC by inhibiting FGFR1-3 signaling, but not FGFR4 signaling.

In hepatocellular carcinoma (HCC), a subset of cells defined by high CD44 and CD133 expression has been reported to possess cancer stem-like cell (CSC) characteristics and to be associated with a poor prognosis. Since the approval of the multikinase inhibitor, lenvatinib, for patients with unresectable HCC, two such inhibitors (sorafenib and lenvatinib) have been employed as first-line systemic chemotherapeutics for these patients. Based on differences in the kinase-affinity profiles between these two drugs, evidence has suggested that both exert different effects on HCC, although these differences are not fully characterized. In this study, using in vitro and a preclinical in vivo xenograft mouse model, we showed that lenvatinib alone (not sorafenib or the cytotoxic agent, 5-fluorouracil) diminished CD44High/CD133High CSCs in HCC. Furthermore, western blotting and reverse transcriptase-polymerase chain reaction analysis revealed that the expression of fibroblast growth factor receptor (FGFR)-1-4 differed between CD44High/CD133High CSCs and control cells. Analysis of the effects of selective FGFR inhibitors and FGFR small interfering RNAs on CSCs in HCC revealed that lenvatinib diminished CSCs in HCC by inhibiting FGFR1-3 signaling, however, FGFR4 signaling was not impacted. Finally, we showed that FGF2 and FGF19 were involved in maintaining CD44High/CD133High CSCs in HCC, potentially, via FGFR1-3. The findings provide novel mechanistic insights into the effects of lenvatinib on CSCs in HCC and provide clues for developing effective targeted therapies against CSCs in HCC.

Early response and safety of atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma in patients who do not meet IMbrave150 eligibility criteria.

AIM: A clinical trial (IMbrave150) indicated the efficacy and safety of atezolizumab plus bevacizumab for patients with unresectable hepatocellular carcinoma (HCC). In this study, we evaluated this therapeutic combination in a real-world setting, with a focus on patients who did not meet the IMbrave150 eligibility criteria. METHODS: In this multicenter study, patients with unresectable HCC treated with atezolizumab plus bevacizumab between October 2020 and May 2021 were screened. In patients who did not meet IMbrave150 eligibility criteria, treatment responses and safety at 6 and 12 weeks were evaluated. RESULTS: Atezolizumab plus bevacizumab was initiated in 64 patients, including 46 patients (71.9%) who did not meet IMbrave150 eligibility criteria. Most of these patients had a history of systemic therapy (44/46). The objective response rate and disease control rate observed using Response Evaluation Criteria in Solid Tumors 1.1 were 5.2% and 82.8% at 6 weeks and 10.0% and 84.0% at 12 weeks, respectively; these rates were similar between patients who met and did not meet the IMbrave150 criteria. Ten patients experienced progressive disease (PD) at 6 weeks. Portal vein tumor thrombosis was significantly associated with PD (p = 0.039); none of the 15 patients with hepatitis B virus-related HCC experienced PD (p = 0.050). The most common adverse events of grade 3 or higher were aspartate aminotransferase elevation (n = 8, 13.8%) and the safety profile was similar between patients who met and did not meet the IMbrave150 criteria. CONCLUSION: Most patients treated with atezolizumab plus bevacizumab did not meet the IMbrave150 criteria; however, the combination therapy showed good safety and efficacy at the early treatment phase.

Detection of early adenocarcinoma of the esophagogastric junction by spraying an enzyme-activatable fluorescent probe targeting Dipeptidyl peptidase-IV.

BACKGROUND: It is still difficult to detect and diagnose early adenocarcinoma of the esophagogastric junction (EGJ) using conventional endoscopy or image-enhanced endoscopy. A glutamylprolyl hydroxymethyl rhodamine green (EP-HMRG) fluorescent probe that can be enzymatically activated to become fluorescent after the cleavage of a dipeptidyl peptidase (DPP)-IV-specific sequence has been developed and is reported to be useful for the detection of squamous cell carcinoma of the head and neck, and esophagus; however, there is a lack of studies that focuses on detecting EGJ adenocarcinoma by fluorescence molecular imaging. Therefore, we investigated the visualization of early EGJ adenocarcinoma by applying EP-HMRG and using clinical samples resected by endoscopic submucosal dissection (ESD). METHODS: Fluorescence imaging with EP-HMRG was performed in 21 clinical samples resected by ESD, and the fluorescence intensity of the tumor and non-tumor regions of interest was prospectively measured. Immunohistochemistry was also performed to determine the expression of DPP-IV. RESULTS: Fluorescence imaging of the clinical samples showed that the tumor lesions were visualized within a few minutes after the application of EP-HMRG, with a sensitivity, specificity, and accuracy of 85.7, 85.7, and 85.7%, respectively. However, tumors with a background of intestinal metaplasia did not have a sufficient contrast-to-background ratio since complete intestinal metaplasia also expresses DPP-IV. Immunohistochemistry measurements revealed that all fluorescent tumor lesions expressed DPP-IV. CONCLUSIONS: Fluorescence imaging with EP-HMRG could be useful for the detection of early EGJ adenocarcinoma lesions that do not have a background of intestinal metaplasia.

Prevalence, clinical course, and predictive factors of immune checkpoint inhibitor monotherapy-associated hepatitis in Japan.

BACKGROUND AND AIM: Immune checkpoint inhibitors (ICI) have revolutionized anti-malignancy therapy and thus have been increasingly used. Although ICI may cause immune-related adverse events (irAE) in various organs, including the liver, the prevalence and predictive factors of irAE have not been clarified. METHODS: In this retrospective study, consecutive patients who had malignancies and were treated with ICI without other chemotherapeutic agents at Hokkaido University Hospital between 2014 and 2019 were screened. Patients were excluded if they were < 20 years old and had insufficient clinical data. RESULTS: Of the 233 patients screened, 202 patients met the inclusion criteria and were included in the analysis. The patients were aged 25-92 years, and 60.9% were male. The patients received nivolumab (n = 137), pembrolizumab (n = 45), ipilimumab (n = 17), atezolizumab (n = 2), and avelumab (n = 1). The prevalence of any grade and grade ≥ 3 irAE hepatitis was 8.4% (17/202) and 4.0% (8/202), respectively. irAE hepatitis occurred at a median duration of 42 days in any grade and 36 days in grade ≥ 3 after ICI initiation. The clinical course of grade ≥ 3 irAE hepatitis was generally favorable; however, 50% required corticosteroid treatment and two patients required additional mycophenolate mofetil. Female sex and history of ICI treatment were significantly associated with the incidence of grade ≥ 3 irAE hepatitis. CONCLUSIONS: Grade ≥ 3 irAE hepatitis was observed in 4.0% of the patients who were treated with ICI. Female sex and history of ICI treatment were significantly associated with the incidence of grade ≥ 3 irAE hepatitis.

Preventive effect of mesenchymal stem cell culture supernatant on luminal stricture after endoscopic submucosal dissection in the rectum of pigs.

BACKGROUND: Mesenchymal stem cells (MSCs) are valuable in regenerative medicine, and MSC culture supernatant (MSC-CS) reportedly inhibits inflammation and fibrosis. We investigated whether colorectal luminal stricture develops after circumferential endoscopic submucosal dissection (ESD) in the colorectum, and whether the development of luminal stricture could be prevented by using MSC-CS enema. METHODS: In the first experiment, we performed circumferential ESD in the rectums or distal colons of pigs (n = 4 in each group). We sacrificed the pigs on Day 22 and measured the degree of luminal stricture. In the second experiment, we performed circumferential ESD in the rectums of pigs and administered an MSC-CS gel or a control gel enema after ESD for 4 days. We sacrificed the pigs on Day 8 (n = 3 in each group) or 22 (n = 3 in each group) to measure the degree of luminal stricture, and performed histological analysis. RESULTS: Severe luminal stricture was observed in the rectum but not in the distal colon. Moreover, fiber accumulation in the submucosa and hypertrophy of the muscularis propria were observed in the rectum but not in the distal colon. The degree of luminal stricture in the rectum was significantly lower in the MSC-CS group than in the control group. Furthermore, MSC-CS attenuated myofibroblast activation and hypertrophy of the muscularis propria on Day 22, and reduced inflammatory cell infiltration on Day 8. CONCLUSIONS: Luminal stricture after ESD developed only in the rectum because of the difference in myofibroblast activation and fiber accumulation. In addition, MSC-CS enema prevented luminal stricture after ESD, possibly by inhibiting the inflammatory reaction and fibrosis.

Fibroblast growth factor-2-mediated FGFR/Erk signaling supports maintenance of cancer stem-like cells in esophageal squamous cell carcinoma.

In esophageal squamous cell carcinoma (ESCC), a subset of cells defined by high expression of CD44 and low expression of CD24 has been reported to possess characteristics of cancer stem-like cells (CSCs). Novel therapies directly targeting CSCs have the potential to improve prognosis of ESCC patients. Although fibroblast growth factor-2 (FGF-2) expression correlates with recurrence and poor survival in ESCC patients, the role of FGF-2 in regulation of ESCC CSCs has yet to be elucidated. We report that FGF-2 is significantly upregulated in CSCs and significantly increases CSC content in ESCC cell lines by inducing epithelial-mesenchymal transition (EMT). Conversely, the FGFR inhibitor, AZD4547, sharply diminishes CSCs via induction of mesenchymal-epithelial transition. Further experiments revealed that MAPK/Erk kinase (Mek)/extracellular signal-regulated kinases (Erk) pathway is crucial for FGF-2-mediated CSC regulation. Pharmacological inhibition of FGF receptor (FGFR)-mediated signaling via AZD4547 did not affect CSCs in Ras mutated cells, implying that Mek/Erk pathway, downstream of FGFR signaling, might be an important regulator of CSCs. Indeed, the Mek inhibitor, trametinib, efficiently suppressed ESCC CSCs even in the context of Ras mutation. Consistent with these findings in vitro, xenotransplantation studies demonstrated that inhibition of FGF-2-mediated FGFR/Erk signaling significantly delayed tumor growth. Taken together, these findings indicate that FGF-2 is an essential factor regulating CSCs via Mek/Erk signaling in ESCC. Additionally, inhibition of FGFR and/or Mek signaling represents a potential novel therapeutic option for targeting CSCs in ESCC.

Anti-adipogenic and antiviral effects of l-carnitine on hepatitis C virus infection.

Hepatitis C virus (HCV) has been reported to hijack fatty acid metabolism in infected hepatocytes, taking advantage of lipid droplets for virus assembly. In this study, we analyzed the anti-HCV activity of l-carnitine, a substance involved in the transport of fatty acids into mitochondria. JFH-1 or HCV replicon-transfected Huh7.5.1 cells were treated with or without l-carnitine to examine its anti-HCV effects. The effects of l-carnitine on HCV entry, HCV-induced adipogenesis and lipid droplet formation, and HCV-induced oxidative stress were examined. Treatment of JFH-1-infected cells with l-carnitine inhibited HCV propagation in a concentration-dependent manner. In contrast, l-carnitine had no anti-HCV activity in the HCV replicon system, which is lacking viral assembly. In addition, l-carnitine did not affect HCV entry. However, l-carnitine treatment decreased intracellular lipid droplets, which are crucial for HCV assembly in JFH-1-infected cells. The expression level of CPT-1 was decreased in JFH-1-infected cells, and l-carnitine treatment restored this expression. HCV-infected cells exhibited increased production of reactive oxygen species and glutathione oxidation. l-carnitine decreased oxidative stress induced by JFH-1-infection, as shown by glutathione/glutathione disulfide assays and MitoSOX staining. l-carnitine exhibited anti-HCV activity, possibly by inhibiting HCV assembly and through its anti-adipogenic activity in HCV-infected cells. Moreover, l-carnitine has antioxidant properties in HCV-infected hepatocytes. Overall, these results indicated that l-carnitine may be an effective adjunctive agent in antiviral therapies to treat chronic hepatitis C. J. Med. Virol. 89:857-866, 2017. © 2016 Wiley Periodicals, Inc.

Oral administration of conditioned medium obtained from mesenchymal stem cell culture prevents subsequent stricture formation after esophageal submucosal dissection in pigs.

BACKGROUND AND AIMS: Endoscopic submucosal dissection (ESD) for esophageal cancer often causes postoperative stricture when more than three fourths of the circumference of the esophagus is dissected. Mesenchymal stem cells are a valuable cell source in regenerative medicine, and conditioned medium (CM) obtained from mesenchymal stem cells reportedly inhibits inflammation. In this study we evaluated whether CM could prevent esophageal stricture after ESD. METHODS: We resected a semi-circumference of pig esophagus by ESD. We prepared CM gel by mixing with 5% carboxymethyl cellulose and endoscopically applied it onto the wound bed immediately after ESD and on days 8 and 15 (weekly CM group) or administered it orally from days 1 to 4 (daily CM group). We also injected triamcinolone acetonide into the remaining submucosa immediately after ESD (steroid group). We killed the pigs on day 8 or day 22 to measure the stricture rate and to perform histologic analysis. RESULTS: Stricture rate in weekly and daily CM groups and steroid groups were significantly lower than in the control group on day 22. Moreover, CM significantly attenuated the number of activated myofibroblasts and fiber thickness on day 22. CM also significantly decreased the infiltration of neutrophils and macrophages compared with the control group on day 8. CONCLUSIONS: CM gel prevents esophageal stricture formation by suppressing myofibroblast activation and fibrosis after the infiltration of neutrophils and macrophages. Oral administration of CM gel is a promising treatment for the prevention of post-ESD stricture.

Fluorescent imaging of superficial head and neck squamous cell carcinoma using a γ-glutamyltranspeptidase-activated targeting agent: a pilot study.

BACKGROUND: Detecting superficial head and neck squamous cell carcinoma (HNSCC) by endoscopy is challenging because of limited morphological hallmarks, and iodine cannot be applied to head and neck lesions due to severe mucosal irritation. γ-glutamyltranspeptidase (GGT), a cell surface enzyme, is overexpressed in several cancers, and it has been reported that γ-glutamyl hydroxymethyl rhodamine green (gGlu-HMRG), a fluorescent targeting agent which can be enzymatically activated and becomes fluorescent after cleavage of a GGT-specific sequence, can be activated within a few minutes after application to animal models. We investigated whether early HNSCC can be detected by applying gGlu-HMRG to clinical samples. METHODS: gGlu-HMRG was applied to four HNSCC cell lines, and fluorescence was observed by fluorescence microscopy and flow cytometry. Immunohistological examination was performed in three recent cases of endoscopic submucosal dissection (ESD) to investigate GGT expression. Fluorescence imaging with gGlu-HMRG in eight clinical samples resected by ESD or surgery was performed, and fluorescence intensity of tumor and normal mucosa regions of interest (ROI) was prospectively measured. RESULTS: All four gGlu-HMRG-applied cell lines emitted green fluorescence. Immunohistological examination demonstrated that GGT was highly expressed in HNSCC of the recent three ESD cases but barely in the normal mucosa. Fluorescence imaging showed that iodine-voiding lesions became fluorescent within a few minutes after application of gGlu-HMRG in all eight resected tumors. Tumor ROI fluorescence intensity was significantly higher than in the normal mucosa five minutes after gGlu-HMRG application. CONCLUSIONS: Fluorescence imaging with gGlu-HMRG would be useful for early detection of HNSCC.

Effects of human amnion-derived mesenchymal stromal cell transplantation in rats with radiation proctitis.

BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) have been reported to be a promising cell source in cell therapy, and large amounts of MSCs can easily be isolated from human amnion. Therapeutic irradiation for intra-pelvic cancer often causes radiation proctitis; however, there is currently no effective treatment. We therefore investigated the effect of transplantation of human amnion-derived MSCs (AMSCs) in rats with radiation proctitis. METHODS: Amnion was obtained at cesarean delivery, and AMSCs were isolated and expanded. Sprague-Dawley rats were γ-irradiated (5 Gy/d) at the rectum for 5 days. On day 5, AMSCs (1 × 10(6) cells) were intravenously transplanted. Rats were killed on day 8. Histological analyses were performed, and messenger RNA expression of inflammatory mediators was measured. In vitro, after γ-irradiation of rat intestinal epithelial cells (IEC-6), the cells were cultured with AMSC-conditioned medium (CM). The effect of AMSC-CM was evaluated by measurement of caspase-3/7 activity, p53 transcription activity and quantitative reverse-transcription-polymerase chain reaction for p53-target genes. RESULTS: Histological examination demonstrated that epithelial injury and infiltration of inflammatory cells in the rectum were significantly suppressed by transplantation of AMSCs. In vitro, the cell injury in IEC-6 cells induced by γ-irradiation was inhibited by AMSC-CM, which also inhibited the upregulation of p53 transcription activity, caspase-3/7 activity and p21 expression. CONCLUSIONS: Transplantation of AMSCs improved radiation proctitis, possibly through inhibition of cell injury and inflammatory reactions. AMSC transplantation should be considered as a new treatment for radiation proctitis.

Serum granulysin levels as a predictor of serious telaprevir-induced dermatological reactions.

AIM: Telaprevir-based therapy for chronic hepatitis C patients is effective; however, the high prevalence of dermatological reactions is an outstanding issue. The mechanism and characteristics of such adverse reactions are unclear; moreover, predictive factors remain unknown. Granulysin was recently reported to be upregulated in the blisters of patients with Stevens-Johnson syndrome (SJS). Therefore, we investigated the risk factors for severe telaprevir-induced dermatological reactions as well as the association between serum granulysin levels and the severity of such reactions. METHODS: A total of 89 patients who received telaprevir-based therapy and had complete clinical information were analyzed. We analyzed the associations between dermatological reactions and clinical factors. Next, we investigated the time-dependent changes in serum granulysin levels in five and 14 patients with grade 3 and non-grade 3 dermatological reactions, respectively. RESULTS: Of the 89 patients, 57 patients had dermatological reactions, including nine patients with grade 3. Univariate analysis revealed that grade 3 dermatological reactions were significantly associated with male sex. Moreover, serum granulysin levels were significantly associated with the severity of dermatological reactions. Three patients with grade 3 dermatological reaction had severe systemic manifestations including SJS, drug-induced hypersensitivity syndrome, and systemic lymphoid swelling and high-grade fever; all were hospitalized. Importantly, among the three patients, two patients' serum granulysin levels exceeded 8 ng/mL at onset and symptoms deteriorated within 6 days. CONCLUSION: Male patients are at high risk for severe telaprevir-induced dermatological reactions. Moreover, serum granulysin levels are significantly associated with the severity of dermatological reactions and may be a predictive factor in patients treated with telaprevir-based therapy.

[Sensitization to laboratory animal allergens among students and researchers exposed to laboratory rodents in Hokkaido university].

BACKGROUND: Based on a case who developed anaphylaxis after mouse bite which occurred at Hokkaido University, we studied on allergic sensitization prevalence for laboratory animals among students and researchers who are exposed to laboratory rodents and rabbit, for the purpose of allergy prevention, particularly anaphylaxis. METHODS: We carried out the health check-up on laboratory animal allergy (LAA) by questionnaires and specific-IgE antibody test for 555 rodents and/or rabbit handlers from whom informed consent was obtained. RESULT: Prevalence of positive IgE antibody higher than class 1 to mice, rats, hamsters, guinea pigs, and/or rabbits in the examinees was 14.1% (62/441) , 17.9% (50/279) , 18.8% (6/32) , 17.4% (4/23) , and 11.3% (12/106) , respectively. Moreover, among users of mouse, those who had allergic symptoms during contact with animals resulted in significantly higher positive rate for anti-mouse IgE antibody test than the other (38.1% vs 8.8%, p<0.01) . CONCLUSION: Health check-up including measurement of specific-IgE antibody against laboratory animals is useful for understanding allergic sensitization.

Intracerebral transplantation of MRI-trackable autologous bone marrow stromal cells for patients with subacute ischemic stroke.

BACKGROUND: Ischemic stroke is one of the leading causes of death and neurological disability worldwide, and stem cell therapy is highly expected to reverse the sequelae. This phase 1/2, first-in-human study evaluated the safety, feasibility, and monitoring of an intracerebral-transplanted magnetic resonance imaging (MRI)-trackable autologous bone marrow stromal cell (HUNS001-01) for patients with subacute ischemic stroke. METHODS: The study included adults with severe disability due to ischemic stroke. HUNS001-01 cultured with human platelet lysates and labeled with superparamagnetic iron oxide was stereotactically transplanted into the peri-infarct area 47-64 days after ischemic stroke onset (dose: 2 or 5 × 107 cells). Neurological and radiographic evaluations were performed throughout 1 year after cell transplantation. The trial was registered at UMIN Clinical Trial Registry (number UMIN000026130). FINDINGS: All seven patients who met the inclusion criteria successfully achieved cell expansion, underwent intracerebral transplantation, and completed 1 year of follow-up. No product-related adverse events were observed. The median National Institutes of Health Stroke Scale and modified Rankin scale scores before transplantation were 13 and 4, which showed improvements of 1-8 and 0-2, respectively. Cell tracking proved that the engrafted cells migrated toward the infarction border area 1-6 months after transplantation, and the quantitative susceptibility mapping revealed that cell signals at the migrated area constantly increased throughout the follow-up period up to 34% of that of the initial transplanted site. CONCLUSIONS: Intracerebral transplantation of HUNS001-01 was safe and well tolerated. Cell tracking shed light on the therapeutic mechanisms of intracerebral transplantation. FUNDING: This work was supported by the Japan Agency for Medical Research and Development (AMED; JP17bk0104045 and JP20bk0104011).