Genotype C hepatitis B virus infection is associated with an increased risk of hepatocellular carcinoma

BACKGROUND: Identification of risk factors for the development of hepatocellular carcinoma (HCC) is important for HCC surveillance in chronic hepatitis B virus (HBV) infection. Our aim was to study the independent risk factors and effect of HBV genotypes on HCC development in a prospective longitudinal cohort of chronic hepatitis B patients. PATIENTS AND METHODS: Chronic hepatitis B patients recruited since 1997 were prospectively followed up for the development of HCC. HCC was diagnosed by a combination of alpha fetoprotein, imaging, and histology. Liver cirrhosis was defined as ultrasonic features of cirrhosis together with hypersplenism, ascites, varices, and/or encephalopathy. RESULTS: In total, 426 patients were followed up for 1664 person years; median 225 (range 12-295) weeks. Forty nine (11%) patients had underlying clinical liver cirrhosis. A total of 242 (57%) and 179 (42%) patients had HBV genotypes C and B, respectively. Twenty five patients developed HCC in a median follow up of 121 (range 14-236) weeks. The overall incidence of HCC was 1502 cases per 100 000 person years. On multivariate analysis, clinical liver cirrhosis and HBV genotype C infection were independently associated with HCC development, with an adjusted relative risk of 10.24 (95% confidence interval (CI) 4.39-23.89; p<0.001) and 2.84 (95% CI 1.05-7.72; p = 0.040), respectively. Patient age, sex, hepatitis B e antigen (HBeAg) status, alanine aminotransferase (ALT) levels, and basal core promoter mutations did not predict HCC development. Patients infected with HBV genotype C tended to have persistently positive HBeAg or fluctuating HBeAg status and higher ALT levels during the follow up period. CONCLUSION: Genotype C HBV infection is an independent risk factor for HCC development in addition to liver cirrhosis.     

A critical role for transforming growth factor-beta in donor transfusion-induced allograft tolerance.

Donor-specific (DST) or nonspecific blood transfusions administered before transplantation can enhance survival of vascularized allografts both in humans and animals but the immunological mechanisms of this effect remain unclear. We have analyzed the expression and the role of endogenous TGF-beta1 in a model of heart allograft tolerance, induced by pregraft DST in adult rats. We reported previously that this tolerance occurs despite a strong infiltration of leukocytes into the graft that are unable to produce both Th1- and Th2-related cytokines in vivo. Allografts from DST-treated rats express high levels of TGF-beta1 mRNA and active protein. This phenomenon is correlated with the rapid infiltration of leukocytes producing high amounts of TGF-beta1. TGF-beta1-producing cells are virtually absent among early infiltrating cells in rejected grafts but are found at a later time point. The induction of allograft tolerance in vivo is abrogated by administration of neutralizing anti-TGF-beta mAb. Moreover, overexpression of active TGF- beta1 in heart allografts using a recombinant adenovirus leads to prolonged graft survival in unmodified recipients. Taken together, our results identify TGF-beta as a critical cytokine involved in the suppression of allograft rejection induced by DST and suggest that TGF-beta-producing regulatory cells are also involved in allograft tolerance.     

Non-surgical treatment for afferent loop syndrome in recurrent gastric cancer complicated by peritoneal carcinomatosis: percutaneous transhepatic duodenal drainage followed by 24-hour infusion of high-dose fluorouracil and leucovorin.

Afferent loop syndrome (ALS) is a debilitating complication of recurrent gastric cancer. Surgical intervention is usually not feasible in the face of poor general performance, presence of advanced peritoneal carcinomatosis and limited survival of the patients. Non-surgical approaches include internal drainage by stenting at the stenotic or anastomotic site and external drainage via the percutaneous routes. Percutaneous transhepatic duodenal drainage (PTDD) has been shown to provide effective palliation for ALS, but long-term catheterization is usually inevitable. We hereby present two cases of recurrent gastric cancer whose ALS was successfully treated with PTDD followed by weekly 24-h infusion of high-dose 5-fluorouracil and leucovorin (HDFL). PTDD rapidly ameliorated the incapacitating symptoms of ALS, and the effective, low-toxicity chemotherapy subsequently led to tumor regression, restoration of bowel patency and removal of the drainage tube. At present, both patients have remained ALS-free and drainage-free for 16 and 17 months, respectively. Our results indicate that this non-surgical approach with PTDD followed by weekly HDFL could serve as a safe and effective treatment for ALS in recurrent gastric cancer complicated by peritoneal carcinomatosis.     

Down regulation of bcl-2 by p53 in nasopharyngeal carcinoma and lack of detection of its specific t(14;18) chromosomal translocation in fixed tissues

High levels of bcl-2 protein have been found in a wide variety of human cancers. Since p53 gene inactivation occurs in over half of human cancers, it is possible that loss of p53-mediated repression of bcl-2 gene expression accounts, at least in part, for the frequent abnormalities in bcl-2 protein production seen in tumours. By using immunohistochemical methods, we have analysed thirty-three nasopharyngeal carcinomas for p53 and bcl-2 expression. We found an inverse correlation between the expression of these two proteins ( P  < 0.001). Moreover, we utilized universal oligonucelotide primers of a region 5' to the bcl-2 MBR and at the 3' end of J_H segments to initiate a DNA polymerase chain reaction that amplified these bcl-2-J_H junctures. Of the twelve nasopharyngeal carcinomas expressing bcl-2, none showed a t(14;18) chromosome translocation. These findings may indicate potential mechanisms by which bcl-2 regulates apoptosis.     

Negative influence of delayed surgery on survival after preoperative radiotherapy in rectal cancer

OBJECTIVE: In Europe, until recently the standard treatment for locally advanced rectal cancer was preoperative radiotherapy (RT). The objective of this study was to evaluate the influence on survival of intervals between diagnosis and treatment. PATIENTS AND METHODS: The influence on survival of intervals between diagnosis and surgery (Dg-Surg), diagnosis and initiation of RT (Dg-Rad), and completion of RT and surgery (Rad-Surg) was evaluated in a retrospective series of patients treated with preoperative RT. Between 1991 and 1998, 102 patients received treatment with preoperative RT without concomitant chemotherapy at the René Gauducheau Cancer Center. Patients generally received 45 Gy (80%) in 25 fractions over 35 days for T2-T3-T4 N0-N1 M0 rectal adenocarcinoma located mainly (62.7%) in the lower third of the rectum (< or = 5 cm from anal margin). Thirty-five pN1 patients were treated with postoperative chemotherapy. Differences between survival were assessed by the log-rank test, and prognostic factors by the Cox test. RESULTS: Median time was 14.7 weeks for Dg-Surg, 4.6 weeks for Dg-Rad and 5.1 weeks for Rad-Surg. Median follow-up from diagnosis was 57.4 months. Five-year local relapse-free survival was 83.9%, metastasis-free survival 64% and overall survival 60.8%. No factor was predictive of tumour response to RT. Log-rank and multivariate analysis showed that overall survival was significantly influenced by lower-third tumours, pT, pN and Dg-Surg (poorer survival when > or = 16 weeks: OR = 2.59, P = 0.005). Metastasis-free survival correlated significantly with Dg-Surg (> or = 16 weeks: OR = 2.05, P = 0.05). CONCLUSION: An interval of more than 16 weeks between diagnosis and surgery may reduce overall survival of patients treated with preoperative RT for locally advanced rectal cancer. Surgery should be performed shortly after completion of RT for patients with no possibility of sphincter preservation, or a minimal risk of morbidity from an abdominoperineal excision.     

Associations of FcɛRIβ E237G polymorphism with wheezing in Taiwanese schoolchildren

Background The β‐chain of a high‐affinity IgE receptor (Fc?RIβ) has been proposed as a candidate gene for atopic diseases, but previous studies have come to inconsistent conclusions. Because some air pollutants would produce oxidative stress, increase serum IgE, and trigger T‐helper type 2 (Th2)‐type airway inflammation, the associations of Fc?RIβ polymorphism with wheezing illness may vary by their exposures and variants of oxidant defence genes. The purpose of this study was to investigate the association of Fc?RIβ E237G polymorphism with wheezing illness and to determine whether these associations vary with air pollution and glutathione S‐transferase (GST) P1‐105 and M1 genotypes. Methods In 2001, we conducted a case–control study comprised of 214 children with any history of wheezing and 185 non‐wheezing controls, all of whom were selected from 2558 fourth‐ to ninth‐grade schoolchildren in southern Taiwan. We examined differences in associations with ambient air pollution and by GST genotypes. Results Compared with the Fc?RIβ EE genotype, children with the G allele had a significantly reduced risk of lifetime wheezing with low‐ozone exposure [adjusted odds ratio (aOR)=0.25, 95% confidence interval (CI) 0.08–0.69]. The risk was not reduced in children living in high‐ozone communities (aOR=0.98, 95% CI 0.57–1.67). This difference in genotypic effects between low‐ and high‐pollution environments was statistically significant. The reduction of the protective effect from the G allele with higher air pollution was most marked in the GSTP1‐105 Ile/Val or Val/Val and GSTM1 null groups. Conclusion The Fc?RIβ E237G allele may have a protective role in wheezing illness among Taiwanese schoolchildren, depending on airway oxidative stress levels.     

FasL gene therapy: a new therapeutic modality for head and neck cancer

In this study, we investigated the in vitro and in vivo efficacy of Fas ligand (FasL) gene therapy for the treatment of head and neck cancer. Three head and neck squamous cell carcinoma (HNSCC) cell lines (SCC-1, SCC-12, and SCC-14a) were treated with the Fas agonist CH-11, a monoclonal antibody to the Fas receptor, or with a replication-incompetent adenovirus (AdGFPFasL) expressing a modified murine Fas ligand gene fused to green fluorescent protein (GFP). A replication-incompetent adenovirus containing the GFP gene alone was used as a control for viral transduction toxicity (AdGFP). Cell death was quantified using a tetrazolium-based (MTS) assay. Cells were analyzed by flow cytometry to determine the expression of adenoviral and Fas receptors on the surface of the cells. Our results showed that the head and neck cancer cell lines are resistant to cell death induction when treated with the anti-Fas monoclonal antibody CH-11. This resistance can be overcome with AdGFPFasL, which was able to induce cell death in all three cell lines. Apoptosis induction was demonstrated using Western blotting by evaluating poly(ADP-ribose) polymerase, and caspase 9 cleavages. In addition, intratumoral injections of AdGFPFasL into SCC-14a xenografts induced significant growth suppression of tumors, indicating that FasL gene therapy may provide a new efficient therapeutic modality for HNSCC that is worthy of a clinical trial.     

Clinical features and predictors for mortality in patients with infective endocarditis at a university hospital in Taiwan from 1995 to 2003

The clinical features and microbiological characteristics of 315 patients with definite or possible infective endocarditis (IE) from January 1995 to December 2003 were evaluated. There were 187 males and 128 females with a mean age of 51 years (range, 1 month to 92 years). Ninety-three patients (30%) had a diagnosis of valvular heart disease and 24 (8%) had received prosthetic valve replacement. Blood culture was negative in 62 patients (20%). Staphylococci (91 patients, 32%), including methicillin-susceptible Staphylococcus aureus (15%), methicillin-resistant S. aureus (11%), and coagulase-negative staphylococci (6%), were the most commonly encountered pathogens followed by viridans group streptococci (77 patients, 24%). Eight patients (25%) had various neurological, renal, embolic, and cardiac complications. Patients with neurological complications [odds ratio (OR) 8.175, P<0.001], nosocomial IE (OR 6.661, P<0.001), underlying malignancy (OR 4.993, P<0.001), elevated serum creatinine level (OR 3.132, P=0.001), or elevated WBC count (>15000/mm3) (OR 2.537, P=0.007) were at significantly increased risk of mortality. This study found mortality from IE was associated with several factors, among which neurological complications were the most hazardous. Patients with more than one risk factor had poorer prognosis. These results suggest the need for more aggressive management in patients with IE when multiple risk factors for mortality are identified.