Weight-based high- and low-dose ribavirin in combination with peginterferon α-2b therapy for genotype 2 chronic hepatitis C: A randomized trial

Aim: The optimal ribavirin dose in the treatment of patients infected with hepatitis C virus (HCV) genotype 2 remains to be elucidated. We aimed to seek the optimal ribavirin dose required for this genotype in a randomized trial. Methods: We compared the efficacy and tolerability of the 24‐week peginterferon α‐2b (1.5 µg/kg/week) therapy in combination with a weight‐based higher dose (600–1000 mg) and lower dose (400–800 mg) of ribavirin for genotype 2 patients. Noninferior margin was set at 10%. Results: A total of 120 patients were randomized to a higher‐dose or a lower‐dose group. Sustained virological response (SVR) by intention‐to‐treat analysis was achieved in 47/58 (81.0%, 90% confidential interval [CI]: 72.6–89.5) patients in the higher‐dose group and 41/60 (68.3%, 90% CI: 58.5–78.2) patients in the lower‐dose group (difference, ?12.7%; 90% CI, ?25.7 to 0.3). Relapse rates were 10% and 21.6% in the higher‐dose and the lower‐dose groups, respectively. Multiple logistic regression analysis showed that ribavirin dose/kg body weight was the only significant predictor of SVR (≥9.5 mg/kg per day vs <9.5 mg/kg per day; odds ratio = 3.34; 95% CI, 1.41–7.92; P = 0.006). Twenty‐one (36.2%) in the higher‐dose group required ribavirin dose reduction because of anemia, whereas seven patients (11.7%) did in the lower‐dose group (P < 0.01). Three of the higher‐dose group and two of the lower‐dose group required premature termination of therapy. Conclusions: Weight‐based lower‐dose ribavirin regimen was not equivalent to the higher‐dose counterpart in the treatment of HCV genotype 2. We discourage treating these patients with low‐dose ribavirin regimens. The peginterferon therapy in combination with ribavirin at a weight‐based higher dose (600–1000 mg) remains the standard‐of‐care treatment for this genotype.     

Phase I clinical trial of vaccination with URLC10-derived peptide for patients with advanced esophageal cancer

Background

Up-regulated gene in lung cancer 10 (URLC10), confirmed to be lymphocyte antigen 6 complex locus K and defined as an oncoantigen, has been identified as a tumor-associated antigen by systematic analysis of expression levels of thousands of genes in lung cancer tissues and esophageal squamous cell carcinoma tissues, which were compared with those of normal human tissues by use of cDNA microarray analysis. Human leukocyte antigen (HLA)-A*2402-positive dendritic cells pulsed with URLC10-derived epitope peptide induced CD8⁺ cytotoxic T lymphocytes to exert specific cytotoxicity against the HLA-A*2402-positive URLC10-expressing esophageal carcinoma cell lines.

Methods

In a phase I clinical trial we evaluated the safety and immunogenicity of a URLC10-177 peptide vaccine emulsified with Montanide ISA51 for patients with unresectable advanced esophageal cancer. One milligram of URLC10-177 peptide in 1 mL sterile saline was emulsified with 1 mL incomplete Freund’s adjuvant and administered subcutaneously to the inguinal region or axilla of the patients. One course of treatment comprised four vaccinations, which were performed every week in the first and second treatment courses and subsequently every 2 weeks after the first vaccination in the third treatment course.

Results

Redness and induration of the skin were the only adverse events at the injection site and were believed to be a delayed-type hypersensitivity (DTH) reaction against the peptide vaccine. A URLC10-177-specific immune reaction in the enzyme-linked immunospot assay was detected in three of four DTH-positive patients (75 %) and in one of three DTH-negative patients (33 %). Furthermore, patients who had a DTH reaction seemed to survive longer than those who had no DTH reaction.

Conclusion

URLC10-177 peptide/Montanide vaccine therapy was well tolerated and induced a URLC10-177 peptide-specific immune response. Therapeutic URLC10-177 peptide vaccination is expected to have clinical benefit in prolonging the survival of patients with unresectable advanced esophageal cancer.     

Nationwide survey of neonatal transportation practices in Japan

Rapid resuscitation and appropriate transportation of sick infants can greatly improve infant survival and neurological prognosis. To gain an understanding of the status of neonatal transport in Japan, we conducted a survey of neonatal transportation capabilities at perinatal medical centers across the country. Survey content included the number of neonatal transportation cases and the method of transportation. Twenty percent of infants admitted to neonatal intensive care units were transported to the medical centers from other institutions. Half of the level III perinatal medical centers owned an ambulance specialized for neonatal transport. A total of 36% of sick newborns, however, were transported by fire department ambulances that are ill‐equipped to care for infants. Thirteen percent of centers reported problems with the emergency transportation of newborns in fire department ambulances. Centers lacked specialized ambulances primarily because of financial constraints. Adequate medical insurance coverage is needed to increase the number of specialized ambulances at perinatal medical centers.     

Development of the Positive Automatic Thoughts List (PAL)

The present study developed and evaluated the Positive Automatic Thoughts List (PAL) to explore the roles and function of self-talk in a Japanese population in positive situations. In Study 1, 22 items were chosen to construct the PAL. Five factors were identified, I . Expressions of Positive Emotion, II. Positive Expectations of Future and Self, III. Positive Self-Evaluation, IV. Having Social Support, and V. Hope for Maintaining Positive Mood. All these factors had high degrees of internal consistency. Factors I and V have never been identified in previous studies, these factors may characterized Japanese positive automatic thoughts. In Study 2, the concurrent validity of the PAL was examined. The results showed that the PAL total scores were significantly correlated with the Self-rating Depression Scale (r= -.29) and the Automatic Thoughts Questionnaire-Revised (Positive: r=.46, Negative: r= -.16). Study 3 confirmed the clinical validity of the PAL, discriminating between healthy undergraduates and depressed outpatients. We discussed that Factor I could be closely related to the increase of positive affect and to the maintenance of depressive states.     

Low frequency of promoter methylation of O6-methylguanine DNA methyltransferase and hMLH1 in ulcerative colitis-associated tumors: comparison with sporadic colonic tumors

To cast light on the contribution of methylation to genesis of ulcerative colitis (UC)-associated tumors, promoter methylation and expression of O6-methylguanine DNA methyltransferase (MGMT), hMLH1, p16INK4, and E-cadherin were examined in 14 low-grade dysplasias (LGDs), 15 high-grade dysplasias (HGDs), and 14 adenocarcinomas associated with UC and, for comparison, in 30 sporadic adenomas with LGD, 30 adenomas with HGD, and 60 adenocarcinomas, using methylation-specific polymerase chain reaction and immunohistochemical analysis. The frequency of MGMT and hMLH1 methylation in UC-associated tumors was low, with a significant difference between HGD and sporadic adenomas with HGD of the left hemicolon. The methylation frequency of p16INK4 in UC-associated tumors was also relatively low compared with sporadic colonic tumors. For E-cadherin, methylation was limited in both types of tumor. Decrease of expression of MGMT, hMLH1, and p16INK4 was significantly correlated with methylation. Thus, compared with the sporadic type, contribution of methylation to UC-associated tumorigenesis seems to be low.     

Detection of peripheral blood and bronchoalveolar lavage fluid lymphocytes in rat lung transplantation for early diagnosis of rejection

Left lung transplantation was performed in two combinations of rat strains. In group 1, lung grafts were rejected within 7 day postoperatively, and in group 2, grafts were rejected within 18 day postoperatively. The histological appearance of rejection was classified into 4 stages, and lymphocytes from peripheral blood (PB) and bronchoalveolar lavage fluid (BALF) were collected at each stage. In group 1, a significant decrease in the number of lymphocytes in PB was observed as the rejection progressed, whereas the number of lymphocytes in PB increased slightly in group 2. The number of total cells in BALF increased significantly as the rejection progressed in both groups. A marked increase in the value of spontaneous blastogenesis (SB) was observed in stage 2 in BALF lymphocytes, whereas that in PB lymphocytes was found to increase after stage 3 in both groups. The ratio of T-helper/T-nonhelper did not change significantly in PB lymphocytes in both groups. On the other hand, a significant decrease in the value of T-helper/T-nonhelper (less than 1.0) was observed in BALF at stage 3 and 4 in both groups. These results show that the studies of BALF lymphocytes were very useful for early diagnosis of rejection in lung transplantation.     

Prognostic Significance of Hiatal Hernia in Patients with Gastric Cancer Located within the Upper-Third of the Stomach

World Journal of Surgery - Gastric cancers located within the upper-third of the stomach (UGC), especially the esophagogastric junction GC (EGJGC), have distinct clinicopathological features due to...     

In vitro performance of trans-valve left ventricular assist device installed at aortic valve position

In this study, we developed a trans-valve left ventricular assist device (LVAD) that unites a rear-impeller axial-flow blood pump (AFBP) and a polymer membrane valve placed at the aortic valve position. The diameter and length of the rear impeller AFBP was 12 and 63 mm, respectively. The polymer membrane valve was similar to the jelly-fish valve consisting of a valve leaflet made of silicone rubber (thickness 0.5 mm), valve ring (diameter: 25 mm), and valve spokes. The trans-valve LVAD was examined in a mock circulation. An implantable pulsatile flow (PF) VAD was connected to an atrial reservoir to simulate the left ventricle (LV), and the Hall valve was worn in the inflow port, and the trans-valve LVAD was placed in the outflow port as an outflow valve. When the motor rotational speed increased to 26 400 rpm, the mean aortic flow increased from 4.2 to 5.3 L/min, mean aortic pressure increased from 83.4 to 100 mm Hg, and mean motor current of the implantable PF VAD decreased from 1.18 to 0.94 A (unloading effect on LV −21%). The energy equivalent pressure increased from 85.2 to 102 mm Hg, and surplus hemodynamic energy (SHE) decreased by −15.4% from the baseline. In conclusion, the trans-valve LVAD has an advantage of preserving pulsatility without any complicated mechanism and is a novel and promising LV support device.