Genetic changes of p53,K-ras,and microsatellite instability in gallbladder carcinoma in high-incidence areas of Japan and Hungary

AIM: To disclose geographic differences in genetic changes involved in gallbladder carcinogenesis between two distinct high-incidence areas of Japan and Hungary.METHODS: We examined 42 cases of gallbladder carcinoma: 22 Japanese and 20 Hungarian cases. p53 mutations at exons 5 to 8 and K-ras mutations at codon 12 were tested by direct sequencing. Microsatellite instability was determined from fluorescent dye-labeled PCR amplifications of five-microsatellite markers (BAT-25, BAT-26, D2S123, D5S346, and D17S250).RESULTS: Mutations of p53 were detected in 11 of 22 Japanese cases and 6 of 18 Hungarian cases (11/22 vs 6/18, P = 0.348). Transition at CpG sites was found in none of 11 Japanese cases and 2 of 6 Hungarian cases; the difference was marginally significant (0/11 vs 2/6, P = 0.110). K-ras mutations were detected in only one of the Hungarian cases. Eight of 19 (42.1%) Japanese cases were MSI-high (presence of novel peaks in more than one of the five loci analyzed), whereas only 1 of 15 (6.7%) Hungarian cases was MSI-high (P = 0.047).CONCLUSION: It appears that the p53 mutations and MSI differ in patients with gallbladder carcinoma between two distinct high-incidence areas. Geographic variation might exist in the process of gallbladder carcinogenesis.

Use of entecavir in hepatitis B virus reactivation of a patient with non-Hodgkin's lymphoma

We read with interest the case report by Liu et al and the correspondence by Tuna et al regarding this case. Liu et al described hepatitis B virus(HBV) reactivation in a patient with non-Hodgkin's lymphomaafter withdrawal of lamivudine prophylaxis. When HBV reactivation was observed three months after lamivudine withdrawal, entecavir 0.5 mg daily was started. HBV DNA level was moderately elevated(104 copies/m L) at that time. So, we could not understand why a potent antiviral like entecavir was required for this case. In addition to this, entecavir must be used at a dose of 1 mg in patients with prior prophylactic treatment with lamivudine. As stated by Tuna et al duration of lamivudine prophylaxis in this case might be insufficient and HBV reactivation might have occured for this reason. So, we suppose that resolution of HBV reactivation might also be achieved with lamivudine instead of entecavir in this case.

Is human hepatocellular carcinoma a hormone-responsive tumor?

Before the positive results recently obtained with multitarget tyrosine kinase inhibitor sorafenib,there was no standard systemic treatment for patients with advanced hepatocellular carcinoma(HCC).Sex hormones receptors are expressed in a significant proportion of HCC samples.Following preclinical and epidemiological studies supporting a relationship between sex hormones and HCC tumorigenesis,several randomized controlled trials (RCTs)tested the efficacy of the anti-estrogen tamoxifen as systemic treatment.Largest among these trials showed no survival advantage from the administration of tamoxifen,and the recent Cochrane systematic review produced a completely negative result.This questions the relevance of estrogen receptor-mediated pathways in HCC.However,a possible explanation for these disappointing results is the lack of proper patients selection according to sex hormones receptors expression,but unfortunately the interaction between this expression and efficacy of tamoxifen has not been studied adequately.It has been also proposed that negative results might be explained if tamoxifen acts in HCC via an estrogen receptor-independent pathway,that requires higher doses than those usually administered, but an Asian RCT conducted to assess dose-response effect was completely negative.Interesting,preliminaryresults have been obtained when hormonal treatment (tamoxifen or megestrol)has been selected according to the presence of wild-type or variant estrogen receptors respectively,but no large RCTs are available to support this strategy.Negative results have been obtained also with anti-androgen therapy.In conclusion,there is no robust evidence to consider HCC a hormone-responsive tumor.Hormonal treatments should not be part of the current management of HCC.