Data regarding the outcome of children with chronic hepatitis B after seroconversion are scarce. We describe the long-term evolution of these patients. One hundred and three children with antibody against hepatitis B e antigen and normal alanine aminotransferase (ALT) levels were followed for 0.6 to 12.5 years (mean, 6.3 years). Paired liver biopsies (before and after seroconversion) were available in 83 cases. Final biopsies were obtained 0.5 to 12.5 years (mean, 4.5 years) after seroconversion. ALT levels remained normal in most of the children (79%) throughout the follow-up. All children, except five who lost hepatitis B surface antigen, had serum viral DNA detected by polymerase chain reaction. When comparing baseline and final liver biopsies, a significant improvement (P F .001) was found in the histological activity index and in the necrosis, cytolysis, inflammation, and fibrosis scores. The histological diagnosis improvement in the final biopsy was significantly related (P F .001) to the time from seroconversion to the biopsy performance. All children had viral DNA on their final liver biopsy. In summary, seroconversion and ALT normalization are quite stable findings in children, and no differences in the long-term outcome between treated and untreated children were found. In light of the histological outcome, it seems unnecessary to perform a follow-up liver biopsy in these cases.(HEPATOLOGY 1999;29:572-575.)Although the long-term outcome of patients with chronic hepatitis B (HBV) after hepatitis B e antigen to antibody (anti-HBe) seroconversion and normalization of serum alanine aminotransferase (ALT) levels has already been reported, 1-6 these reports include a relatively small number of liver biopsies. Thus, the information about the liver histological activity and hepatitis B virus DNA (HBV-DNA) status is scarce. In addition, the time when a liver biopsy should be taken after seroconversion to anti-HBe, to definitively establish the histological status, has not yet been defined. Furthermore, differences in the long-term outcome between hepatitis B surface antigen (HBsAg)-carriers who seroconvert to antiHBe spontaneously and those who do so because of interferon-␣ treatment have not been conclusively shown, especially in children with chronic HBV.We studied the long-term outcome of children with chronic HBV who had seroconverted to anti-HBe, either spontaneously or as a result of interferon-␣ treatment, by comparing the baseline and final liver biopsies obtained at different time periods after ALT normalization and by determining the liver HBV-DNA status. PATIENTS AND METHODS Patients.Patients with chronic HBV under 18 years of age who attended our pediatrics department between 1978 and 1996 were retrospectively eligible if the following inclusion criteria were fulfilled: (1) Strictly documented seroconversion to anti-HBe with serum HBV-DNA clearance (as detected by dot-blot hybridization) and normal ALT levels on two consecutive occasions, 6 months apart; (2) Histologic evidence of chronic hepatitis ...

virus infects patients with chronic viral hepatitis, intraveThe aim of this work was to study the presence of the nous drug abusers, and organ or blood recipients. 2,4,5 To our hepatitis GB virus type C (HGBV-C) in liver and serum knowledge, the presence of HGBV-C RNA in children with samples of children with chronic viral hepatitis, the time chronic viral hepatitis has not yet been reported. course of changes in viral RNA, and the possible acquisi-We have retrospectively analyzed the presence of HGBVtion routes of infection. Frozen serum and liver samples C RNA in paired serum and liver samples from 58 children from 58 children with chronic hepatitis B (n Å 33) or C with chronic hepatitis B or C. We have also studied the time (n Å 25) were analyzed using polymerase chain reaction.course of changes in serum HGBV-C RNA in both treated Twenty-seven children had been included in different and untreated children with chronic viral hepatitis as well interferon trials. Two additional serum samples from the as the possible routes of HGBV-C transmission in infected HGBV-C-positive children as well as serum samples from children. properly stored at 020ЊC (serum samples) or in liquid nitrogen (liver mother. In the 3 children receiving alpha-interferon, samples). The mean age of the children was 12.1 { 3.9 years (range: HGBV-C RNA became undetectable during treatment al-2-16 years). Forty-six of 58 children had had abnormal alanine amithough it reappeared in 2 of them after therapy. In con-notransferase (ALT) levels for at least 1 year before the study start clusion, we found that 15% of children with chronic viral ( 21. Twenty-seven children had been included in different interferon Studies of HGBV-C RNA prevalence have shown that this (IFN) trials; in these cases, the first sample analyzed corresponded to the baseline sample of the trial.In the HGBV-C RNA-positive children two additional serum samples, apart from the baseline sample, were analyzed. In the treated Abbreviations: HGBV-C, hepatitis GB virus type C; ALT, alanine aminotransferase; children, serum samples were taken at the end of treatment (range:anti-HBe, antibodies to hepatitis B e antigen; HCV, hepatitis C virus; HBV, hepatitis B 6-9 months) and follow-up period (range: 12-18 months after the virus; IFN, interferon; HBeAg, hepatitis B e antigen; RT-PCR, reverse transcription-nested end of treatment). In the untreated children, two additional serum polymerase chain reaction.samples taken 12 months and 18-30 months after the first sample infection.

Tyrosine kinase receptors (RTKs) are a heterogeneous group of transmembrane proteins involved in signal transduction. These receptors are expressed in many different cells and regulate cellular growth, differentiation and angiogenesis. Overexpression and/or the structural alteration of different RTKs classes are generally associated to cancer and, when RTKs-mediated signal transduction pathways are abnormally activated, generate cancer growth, angiogenesis and metastatization. Therapeutic intervention targeting RTKs concerns antagonist drugs as little molecules or monoclonal antibodies. Sunitinib malate is a little molecule able to block intracellular tyrosine kinase domain of RTKs, which has both direct anticancer and antiangiogenetic activity. Sunitinib targets selectively vascular endothelial growth factor, KIT, Flt3 and platelet-derived growth factor receptors and the receptor encoded by the ret proto-oncogene. This drug is used in the treatment of gastrointestinal stromal cancer (GIST) resistant to imatinib and metastatic renal cell carcinoma (RCC). In this review, we report preclinical data of sunitinib, even about synergism with chemotherapy and radiotherapy, data relative to phase III trials of sunitinib in the treatment of GIST and RCC, and we try to plan what will be future applications of sunitinib in different types of cancer, even in association to chemotherapy, radiotherapy and monoclonal antibodies.

Little is known about the distribution of precore hepatitis B virus mutants and their influence on the outcome of interferon therapy in children with chronic hepatitis B. In this study, serum samples were analyzed from 60 children with chronic hepatitis B e antigen+ (HBeAg+) hepatitis. Fifty-two of these children underwent different interferon trials, and a second serum sample was taken from 25 of them at the end of therapy. Fifty-six of the original 60 children were simultaneously infected by wild-type and precore mutant hepatitis B virus variants. The remaining four children were infected by the wild type alone. In 50/56 of children with a mixed viral population, the wild-type variant comprised more than 50% of the total viremia. With respect to the influence of precore variants on the outcome of interferon treatment, the prevalence of mixed viral population was similar in responders and nonresponders (96 versus 88%, respectively). However, precore mutant variants were prevalent (> 50% of the viral population) in 21% of the nonresponders, but in none of the responder children (p < 0.05). Viremia levels were significantly higher in nonresponder than in responder children (p < 0.05). No substantial changes in the prevalence of mutants were observed throughout the interferon therapy. In conclusion, mixed viral infection is found in a high percentage of children with chronic B HBeAg+ hepatitis. Response to interferon therapy does not seem to be related to the presence of hepatitis B virus precore mutants, but rather to the levels of viremia.

CINV is still a critical issue in AC-treated patients, despite antiemetic treatment. Non-adherence to antiemetic guidelines may lead to poorer outcomes and indicates the need for strategies to enhance the use of guidelines in clinical practice.

DNA and amino acid sequences of the hepatitis B virus (HBV) genome were studied in serum and liver samples taken from 12 children with chronic hepatitis B before and after interferon (IFN) therapy. The purpose was to discover whether the persistence of low levels of viral replication with normal alanine aminotransferases after the response to IFN treatment is due to the appearance of mutations in the sequence of HB core antigen T and B cell epitopes. The existence of mutants was studied by amplification of precore-core region of the HBV genome by polymerase chain reaction (PCR) and direct sequencing of the PCR products. In addition to the wild type sequence, mutation 1896 in the precore region was detected in the baseline serum and liver samples of five children. No changes in the distribution were found in the final samples, except one case. In the core region, both the wild type sequence and amino acid substitutions were observed in the basal serum and/or liver samples of six patients and most of these remained detectable in the samples after treatment. Sixteen (67%) of 24 changes in the core amino acid sequences were found in the T- or B-cell epitopes. The results suggest that viral persistence after response to IFN therapy in children is not due to the appearance of mutants in the HBV core T- and B-cell epitopes and that the host immune response can control the viral replication.

Important therapeutic advances for patients with advanced non-small cell lung cancer (NSCLC) have recently occurred, and the development of targeted therapy has revolutionized the treatment of these patients. We report the case of an NSCLC patient with unknown EGFR mutation status who developed resistance to erlotinib and was treated with afatinib. After 19 months of therapy with afatinib, the patient is still in treatment and maintains stable disease. Emerging resistance to reversible TKIs is a significant problem. Oral irreversible TKIs such as afatinib may offer an effective treatment option after failure with reversible TKIs.

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