Intravesical Ad-IFNalpha causes marked regression of human bladder cancer growing orthotopically in nude mice and overcomes resistance to IFN-alpha protein.

We have produced prolonged, high local concentrations of interferon in vivo by intravesical instillation of adenoviruses encoding interferon-alpha (Ad-IFNalpha) together with the gene transfer-enhancing agent Syn3. We found sustained interferon protein levels for days, both in normal mouse urothelium and in human bladder cancer cells growing as superficial bladder tumors in nude mice using an orthotopic bladder model developed by us. Tumor burden in the bladder was determined utilizing cancer cells containing the green fluorescent protein. Marked tumor regression was observed following two 1-h exposures of Ad-IFNalpha/Syn3 and little or no cytotoxicity was detected in normal cells. Similar intravesical instillation of clinically relevant concentrations of IFN protein alone or Ad-IFNalpha without Syn3 was ineffective. Surprisingly, in vitro, Ad-IFNalpha also caused caspase-dependent death of bladder cancer cell lines that were resistant to high concentrations of IFN-alpha protein, including the cell line used in vivo. These findings demonstrate that Ad-IFNalpha can overcome resistance to IFN-alpha protein both in vitro and in vivo and support evaluation of intravesical Ad-IFNalpha/Syn3 for the treatment of superficial bladder cancer.     

Effect of necrosis modulator necrox-7 on hepatic ischemia-reperfusion injury in beagle dogs

Objective

The liver is susceptible to ischemia-reperfusion (IR) injury during inflow occlusion for hepatectomy. There is no effective pharmacologic agent available to prevent the release of high-mobility-group box 1 (HMGB1) or to ameliorate IR injury. This pilot study sought to develop a model in beagle dogs for the purpose of testing the efficacy of a necrosis modulator, necrox-7, to prevent hepatic IR injury in beagle dogs.

Methods

Six male beagle dogs were randomly assigned to the control group (group A; n = 3) or the treatment group (group B; n = 3). Under general anesthesia, group B received intravenous infusion of necrox-7 (13 mg/kg over 20 minutes) followed by 60 minutes of left hepatic inflow occlusion and 60 minutes of reperfusion. Both groups were tested for serum biochemicals, hematology values, liver biopsies, and plasma HMGB1 levels over a 48-hour period.

Results

The maximum alanine transferase (ALT), aspartate transferase (AST), and lactate dehydrogenase (LDH) levels among group A versus group B were: ALT 868.3 ± 337.4 IU/L vs 274.3 ± 72.6 IU/L (P = .041); AST 1,024.7 ± 246.5 IU/L vs 505.3 ± 66.7 IU/L (P = .024); and LDH 962.7 ± 226.2 IU/L vs 552.7 ± 62.4 IU/L (P = .039). Liver biopsy demonstrated marked necrosis and inflammatory infiltrates in group A, whereas group B showed little evidence of IR injury. The plasma HMGB1 concentration was significantly lower among group B versus A.

Conclusion

This pilot study developed a hepatic IR injury model, demonstrating that necrox-7 reduced hepatic necrosis secondary to IR injury in a large animal setting.     

Prospective validation of P2/MS noninvasive index using complete blood counts for detecting oesophageal varices in B‐viral cirrhosis

Backgrounds: Periodic endoscopic screening for oesophageal varices (OVs) and prophylactic treatment for high‐risk OVs (HOVs; medium/large OVs or small OVs plus red sign/decompensation) are currently recommended for all cirrhotic patients. However, if a simple, noninvasive test is available, many low‐risk patients may reliably avoid endoscopy. Aims: We conducted a large‐scale validation study of a simple, noninvasive test called P2/MS based on complete blood counts, (platelet count)²/[monocyte fraction (%) × segmented neutrophil fraction (%)], and compared it with other predictive tests for HOVs in B‐viral cirrhotic patients. Methods: From 2008 to 2009, we prospectively enrolled 318 consecutive B‐viral cirrhotic patients. All underwent endoscopy and laboratory evaluation. Results: An area under the receiver operating characteristic curve of P2/MS was 0.941 for HOVs, comparable with those of the age–spleen platelet ratio index (0.922, P=0.317) and spleen–platelet ratio index (0.922, P=0.324), and better than those of age–platelet index (0.653, P<0.001), aspartate aminotransferase (AST)–platelet ratio index (0.871, P<0.006) and AST‐alanine aminotransferase ratio (0.644, P<0.001). P2/MS<11 reliably identified 83 patients as having HOVs (94.0% positive predictive value), while at a cutoff of 25 and 179 as not having HOVs (94.4% negative predictive value). Overall, P2/MS reliably determined the likelihood of HOVs in 262 patients (82.4%). These cutoffs were validated internally using bootstrap resampling methods, which showed good agreement. Conclusions: P2/MS is a simple, accurate and economical method, reducing the need for endoscopy in B‐viral cirrhosis. Patients with P2/MS<11 should be considered for appropriate prophylactic treatments, while those with P2/MS>25 may avoid endoscopy reliably.     

Clinical features and prognosis of hepatocellular carcinoma with respect to pre-S deletion and basal core promoter mutations of hepatitis B virus Genotype C2

Few studies have reported on the clinical characteristics of hepatocellular carcinoma (HCC) at the time of diagnosis with regard to pre-S and basal core promoter (BCP) mutations. In this study, the clinical features and prognosis of 126 Korean HCC patients were examined with respect to pre-S deletion and BCP mutations of hepatitis B virus. The proportion of HCC patients according to tumor-node-metastasis stage are as follows: 8.7% in stage I, 31% in stage II, 30.2% in stage III, 21.4% in stage IV-A, and 8.7% in stage IV-B. Overall, 40.5% of HCC patients were treated by surgery or ablation, 59.5% by other methods. Patients were divided according to pre-S deletion and BCP mutations (103 without pre-S deletion, 23 with pre-S deletion; 44 without BCP mutation, 82 with BCP mutation). The tumor characteristics and prognosis were evaluated between the groups, including size, number, type, vessel invasion, portal vein thrombosis, and metastasis. No significant difference in tumor characteristics between the HCC patients with pre-S deletion was observed, compared with the HCC patients without pre-S deletion. In contrast, the survival rate was lower in those with pre-S deletion than in those without it (P = 0.024). No difference in tumor characteristics was found in non-BCP and BCP mutation patients. Unlike the pre-S deletion group, no difference was observed in survival rate between the non-BCP and BCP patients. In conclusion, pre-S deletion and BCP mutations did not affect the initial tumor features. However, pre-S deletion was an independent risk factor affecting HCC survival.     

Gender Difference in the Prodromal Symptoms of First-episode Schizophrenia

To investigate the gender difference of early symptoms appearing before the onset of the psychotic symptoms in patients with first-episode schizophrenia, we reviewed the medical records of 63 patients (38 males, 25 females), who were hospitalized for first-episode schizophrenia. The frequency and duration of prodromal and psychotic symptoms, Clinical Global Impression scale scores, Global Assessment of Functioning (GAF) scale scores at admission, and other clinical characteristics were recorded for all patients. Overall, the most common prodromal symptoms were attenuated positive symptoms (89%), followed by mood symptoms (86%). Negative symptoms were the most common in male patients (97.4%), whereas attenuated positive symptoms were the most common in female patients (84%). Male patients demonstrated more frequent negative, cognitive, and obsessive-compulsive symptoms than female patients did and also showed a tendency of having negative symptoms for the longer period. Correlational analysis showed a significant negative correlation between the duration of negative symptoms and GAF scores at admission in male patients. Our findings suggest that different patterns of prodromal symptoms between male and female begin before the onset of the psychosis. Further prospective studies should be needed.     

Clevudine is highly efficacious in hepatitis B e antigen-negative chronic hepatitis B with durable off-therapy viral suppression

Clevudine is a pyrimidine analog with potent and sustained antiviral activity against HBV. In the present study, we evaluated the safety and efficacy of clevudine 30 mg daily for 24 weeks and assessed the durability of antiviral response for 24 weeks after cessation of dosing in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (e-CHB). We randomized a total of 86 patients (3:1) to receive clevudine 30 mg (n = 63) or placebo (n = 23) daily for 24 weeks. We followed patients for an additional 24 weeks after withdrawal of treatment. The median changes in HBV DNA from baseline were -4.25 and -0.48 log(10) copies/mL at week 24 in the clevudine and placebo groups, respectively (P < 0.0001). Viral suppression in the clevudine group was sustained after withdrawal of therapy, with 3.11 log(10) reduction at week 48. At week 24 and week 48, 92.1% and 16.4% of patients in the clevudine group had undetectable serum HBV DNA levels by Amplicor PCR assay (<300 copies/mL). The proportion of patients who achieved ALT normalization was 74.6% and 33.3% in the clevudine and placebo groups at week 24, respectively (P = 0.0006). ALT normalization in the clevudine group was well-maintained during the post-treatment follow-up period. The incidence of adverse events was similar in the 2 groups. No resistance to clevudine was detected during treatment. CONCLUSION: A 24-week clevudine therapy was well-tolerated and showed potent and sustained antiviral effect without evidence of viral resistance in e-CHB patients. However, treatment for longer than 24 weeks would be needed to achieve durable remission.     

Comparison of two- and three-dimensional transthoracic echocardiography in the assessment of trabeculations and trabecular mass in left ventricular noncompaction

Twenty-one patients (mean age 47.5 years, 9 females) with left ventricular noncompaction (LVNC) diagnosed by both two-dimensional transthoracic echocardiography (2DTTE) and live/real time three-dimensional transthoracic echocardiography (3DTTE) were included in the study. Left ventricular (LV) mass was calculated with epicardial and endocardial border tracings first including the LV trabeculations and then excluding them. LV trabecular mass was then derived as the difference between the two measurements. This was done by 2DTTE using the modified biplane Simpson's method and by live/real time 3DTTE using the Tom Tec imaging system. The number of trabeculations arising from each segment of LV walls as well as the segmental distribution of trabeculations were also assessed by both 2DTTE and 3DTTE. The calculated LV trabecular mass by 3DTTE (mean 11.8 +/- 5.5 g) was significantly greater than 2DTTE (mean 7.3 +/- 4.3 g, P = 0.005). The total number of trabeculations assessed by 3DTTE (mean 11.2 +/- 3.3) was also significantly greater than 2DTTE (mean 3.76 +/- 1.2, P < 0.0001). The values for inter- and intraobserver variability were lower for 3DTTE than 2DTTE. In conclusion, both LV trabecular mass as well as the total number of trabeculations in patients with LVNC were significantly underestimated by 2DTTE as compared to 3DTTE.