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Introduction/Background: Craniopharyngiomas are the most common neoplasms of the central nervous system of non-glial origin in childhood. Therapeutic options for proper management include total surgical resection, partial surgical resection associated with radiotherapy, and use of drugs such as bleomycin and alpha interferon (INFα) via Ommaya reservoir. The scope of this article is to report the case of a child with successive recurrence of craniopharyngioma who progressed to endocrine and neurological complications after bleomycin administration. Case presentation: A 9-year-old boy underwent partial resections of craniopharyngioma followed by radiotherapy. Due to the increase in the cystic portion of the lesion, he underwent a complete treatment protocol with INFα. Two years after finishing the treatment, a new increase in the cystic portion of the craniopharyngioma was detected and bleomycin was administered in an attempt to control the disease. The boy was hospitalized on an urgent basis due to decreased level of consciousness, drowsiness, ataxia, and hyponatremia. Magnetic resonance imaging findings of the brain showed edema in the vicinity of the tumor suggestive of injury due to pharmacological toxicity. The child presented complete remission of symptoms with the use of systemic corticosteroids. Conclusion: Neurotoxicity is a complication following bleomycin administration via Ommaya reservoir. Immediate discontinuation associated with the introduction of systemic corticosteroids and support in a specialized care unit can reverse the initial clinical picture [ABSTRACT FROM AUTHOR]

Background: HeberFERON is a co-formulation of α2b and γ interferons, based on their synergism, which has shown its clinical superiority over individual interferons in basal cell carcinomas. In glioblastoma (GBM), HeberFERON has displayed promising preclinical and clinical results. This led us to design a microarray experiment aimed at identifying the molecular mechanisms involved in the distinctive effect of HeberFERON compared to the individual interferons in U-87MG model. Methods: Transcriptional expression profiling including a control (untreated) and three groups receiving α2b-interferon, γ-interferon and HeberFERON was performed using an Illumina HT-12 microarray platform. Unsupervised methods for gene and sample grouping, identification of differentially expressed genes, functional enrichment and network analysis computational biology methods were applied to identify distinctive transcription patterns of HeberFERON. Validation of most representative genes was performed by qPCR. For the cell cycle analysis of cells treated with HeberFERON for 24 h, 48 and 72 h we used flow cytometry. Results: The three treatments show different behavior based on the gene expression profiles. The enrichment analysis identified several mitotic cell cycle related events, in particular from prometaphase to anaphase, which are exclusively targeted by HeberFERON. The FOXM1 transcription factor network that is involved in several cell cycle phases and is highly expressed in GBMs, is significantly down regulated. Flow cytometry experiments corroborated the action of HeberFERON on the cell cycle in a dose and time dependent manner with a clear cellular arrest as of 24 h post-treatment. Despite the fact that p53 was not down-regulated, several genes involved in its regulatory activity were functionally enriched. Network analysis also revealed a strong relationship of p53 with genes targeted by HeberFERON. We propose a mechanistic model to explain this distinctive action, based on the simultaneous activation of PKR and ATF3, p53 phosphorylation changes, as well as its reduced MDM2 mediated ubiquitination and export from the nucleus to the cytoplasm. PLK1, AURKB, BIRC5 and CCNB1 genes, all regulated by FOXM1, also play central roles in this model. These and other interactions could explain a G2/M arrest and the effect of HeberFERON on the proliferation of U-87MG. Conclusions: We proposed molecular mechanisms underlying the distinctive behavior of HeberFERON compared to the treatments with the individual interferons in U-87MG model, where cell cycle related events were highly relevant. [ABSTRACT FROM AUTHOR]

Background: Thrombotic thrombocytopenic purpura (TTP) is rare and severe thrombotic microangiopathy characterized by thrombocytopenia, hemolytic anemia, and renal dysfunction. In contrast, essential thrombocythemia (ET) is a myeloproliferative disease associated with an abnormal increase in platelet numbers. Previous studies reported several cases of the development of ET in patients with TTP. However, the case of an ET patient complicated with TTP has not been previously reported. In this case study, we present a patient with TTP who was previously diagnosed with ET. Therefore, to the best of our knowledge, this is the first report of TTP in ET. Case presentation: A 31-year-old Chinese female who was previously diagnosed with ET presented with anemia and renal dysfunction. The patient had been on long-term treatment with hydroxyurea, aspirin, and alpha interferon (INF-α) for ten years. The diagnosis of TTP was confirmed by clinical features, schistocytes noted on the peripheral blood smear, and lower ADAMTS13 activity (8.5%), together with the renal biopsy results. INF-α was discontinued, and the patient was then treated with plasma exchange and corticosteroids. After one year of follow-up, the patient had a normal hemoglobin level and platelet numbers, and her ADAMTS13 activity had improved. However, the patient's renal function remains impaired. Conclusions: We report a case of an ET patient complicated with TTP that was possibly due to INF-α, highlighting the potential complications associated with long-term ET therapy. The case also highlights the importance of considering TTP in patients with pre-existing ET who present with anemia and renal dysfunction, extending the spectrum of known studies. [ABSTRACT FROM AUTHOR]

Whooper swan Cygnus cygnus interferon alpha (CyIFN-α) gene was amplified from genomic DNA in the liver of whooper swan, which encodes a 192-amino acid protein containing a 29-amino acid signal peptide. Bioinformatics analysis showed it containes 7 cysteine residues and 5 alpha helices. After expression in prokaryote, purification and renaturation, CyIFN-α was analyzed on its physicochemical property and antiviral activity. In chicken embryo fibroblasts, CyIFN-α exerted more superior anti-vesicular stomatitis virus (VSV), avian influenza virus (AIV), and Newcastle disease virus (NDV) activity than chicken IFN-α, an effective therapeutic agent used for viral infections clinically. Contrarily, these antiviral activities were abrogated by rabbit anti-CyIFN-α in vitro. Moreover, CyIFN-α was shown to be highly sensitive to trypsin, however, it remained stable despite changes in pH and temperature. In addition, CyIFN-α induced the transcription of Mx1, ISG12, and IFIT5 (ISG58) genes, as well as the expression of Mx1 protein, in a time-dependent manner. In conclusion, we first cloned and expressed CyIFN-α and tested its biological activity in vitro. Our findings facilitate further research on the role of type I IFN in antiviral defense responses in whooper swan and other Natatores. [ABSTRACT FROM AUTHOR]

The “rods and rings” (RR) antinuclear antibody (ANA) pattern is believed to be restricted to hepatitis C virus (HCV) infection and related to the treatment. This is a 4-year retrospective study of all patients with RR pattern from the 20 000 serum samples received at the Hospital Universitari de Bellvitge for ANA testing. Two control groups with HCV patients without RR pattern: ANA-positive (n = 74) and ANA negative (n = 75) were included. Eighty-seven patients had samples with the RR pattern. Seventy-three were infected with HCV (prevalence of 15% in the HCV population). The RR pattern could not be related to ribavirin treatment, clinical status, biochemistry data, hepatic fibrosis, IL28B genotype, HCV genotype or the presence of autoantibodies related with autoimmune hepatitis. As 14 cases presented other diseases, mainly of autoimmune origin, the presence of RR antibodies may also be explained by alterations in immune regulation caused by autoimmunity or HCV in a particular genetic background. [ABSTRACT FROM PUBLISHER]

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Small intestinal neuroendocrine tumors (carcinoids) are the most common neuroendocrine tumor (NET) within the gastrointestinal tract (15-20%). The incidence and prevalence is steadily increasing during the last decade and the estimated incidence is now about 2.5/100 000/year. The majority of the tumors produce peptides and amines giving rise to clinical symptoms related to the hormone production such as the carcinoid syndrome with flushing, diarrhea, bronchial constriction, and carcinoid heart disease. The majority of patients present with metastatic disease (60%) and therefore a surgical cure is not obtainable. The medical treatment consists of somatostatin analogs, alpha interferons, and targeted treatment with mTOR- and tyrosine kinase-inhibitors. Somatostatin analogs are still the gold standard for treatment of carcinoid tumors with hormone-related clinical symptoms. A possible antitumor effect has been debated, but a recent study (PROMID) has demonstrated an antitumor effect of octreotide LAR, 30 mg, every 4 weeks versus placebo. Tyrosine kinase inhibitors have been applied mostly for antiangiogenic purposes with objective responses in 10-20% of the patients and PFS of 10-15 months. The mTOR-inhibitor everolimus have demonstrated an antitumor effect in patients with carcinoid tumors in the RADIANT-2 trial. Cytotoxic treatment has demonstrated a limited efficacy in classical low proliferation well-differentiated neuroendocrine gastrointestinal tumors and should not be considered first-line treatment. The future treatment will be based on tumor biology and molecular genetics taking into account the new classification systems. The treatment will be personalized. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) infects approximately 3% of the world population. The chronicity of hepatitis C seems to depend on the level of genetic variability. We have recently (Torres-Puente et al., J Viral Hepat, 2008; 15: 188) reported genetic variability estimates from a large-scale sequence analysis of 67 patients infected with HCV subtypes 1a (23 patients) and 1b (44 patients) and related them to response, or lack of, to alpha-interferon plus ribavirin treatment.. Two HCV genome regions were analysed in samples prior to antiviral therapy, one compressing the three hypervariable regions of the E2 glycoprotein and another one including the interferon sensitive determining region and the V3 domain of the NS5A protein. Haplotype and nucleotide diversity measures showed a clear tendency to higher genetic variability levels in nonresponder than in responder patients. Here, we have refined the analysis of genetic variability (haplotype and nucleotide diversity, number of haplotypes and mutations) by considering their distribution in each of the biologically meaningful subregions mentioned above, as well as in their surrounding and intervening regions. Variability levels are very heterogeneous among the different subregions, being higher for nonresponder patients. Interestingly, significant differences were detected in the biologically relevant regions, but also in the surrounding regions, suggesting that the level of variability of the whole HCV genome, rather than exclusively that from the hypervariable regions, is the main indicator of the treatment response. Finally, the number of haplotypes and mutations seem to be better discriminators than haplotype and nucleotide diversity, especially in the NS5A region. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) is a major health problem worldwide, infecting an estimated 170 million people. The high genetic variability of HCV contributes to the chronicity of hepatitis C. Here, we report results from a large-scale sequence analysis of 67 patients infected with HCV genotype 1, 23 with subtype 1a and 44 with subtype 1b. Two regions of the HCV genome were analysed in samples prior to combined therapy with alpha interferon plus ribavirin, one compressing the hypervariable regions (HVR1, HVR2 and HVR3) of the E2 glycoprotein and another one including the interferon-sensitive determining region (ISDR) and the V3 domain of the NS5A protein. Genetic diversity measures showed a clear tendency to higher genetic variability levels in nonresponder patients to antiviral treatment than in responder patients, although highly disperse values were present within each response group for both subtypes. A more detailed analysis of amino acid composition revealed the presence of several subtype-specific variants in a few positions, but no discriminating positions between responder and nonresponder patients were detected. Our results also revealed that most amino acid positions were highly conserved, especially for subtype 1a. We conclude that the outcome of the antiviral treatment might depend not only on the nature of one or a few independent positions, but more likely on the combination of several positions along the HCV genome. Moreover, the own host’s ability to generate an appropriate systemic response, in combination with the action of antivirals, is also likely to be essential for treatment outcome. [ABSTRACT FROM AUTHOR]

Objectives The aim of this study was to verify whether intracystic injections of alpha-Interferon (IFN-α) in cystic craniopharyngiomas were able to reduce the tumor by activating the Fas apoptotic pathway. Materials and methods Twenty-one patients with cystic craniopharyngiomas treated at the Pediatric Oncology Institute (IOP/GRAACC) of Federal University of São Paulo were submitted to intracystic chemotherapy with IFN-α. The tumor sizes of all patients were monitored and the apoptotic factor soluble FasL (sFasL) concentration was determined by ELISA (enzyme-linked immunosorbent assay) in tumor fluid samples from eight patients. Results There was a complete reduction in 11 patients, a partial response in seven, and a minor response in three patients. The concentration of sFasL was increased in all the eight patients examined concomitantly with the tumor size reduction. Conclusions Our data demonstrated that the IFN-α was able to induce Fas-mediated apoptosis together with a reduction in the tumor size; such an observation may suggest the importance to investigate still unexplored mechanisms to be exploited in craniopharyngioma therapy. [ABSTRACT FROM AUTHOR]

Adult T-cell leukemia/lymphoma (ATLL) is a malignant lymphoproliferation of mature activated T-cells, mostly CD4, which develops after a long period of latency following Human T cell Lymphotropic virus Type 1 infection. It is characterized by the clonal integration of one or more HTLV-1 proviruses in the tumor cells. There are 4 major subtypes of ATLL: a smoldering type, a chronic type, a lymphoma type and a leukemic/acute type. The survival rate of ATLL patients, especially those who develop the acute leukemic or lymphomas forms, is very poor and such a tumor remains one of the most severe lymphoproliferations. Treatment of ATLL patients using conventional chemotherapy has very limited benefit, since HTLV-1 transformed cells are resistant to most apoptosis-inducing agents. Recently, antiretroviral therapy using the combination of zidovudine (AZT) and interferon alpha (IFN-α) has been shown to induce a high complete remission rate and to prolong the survival of ATLL patients. Based on the current physiopathology, other drugs such as arsenic trioxide combined to IFN-α have also been demonstrated to synergize in vitro for inducing apoptosis in HTLV-1 infected T cells. Such drugs have now been used in vivo for treating ATLL patients. Both in vitro and in vivo data will be discussed. [ABSTRACT FROM AUTHOR]

Alpha interferon (αIFN) therapy is known to induce thyroid autoimmunity in up to 40% of patients. The mechanism is unknown, but Th1 switching has been hypothesized. The aim of our study was to examine whether αIFN accelerated the development of thyroiditis in genetically susceptible mice. We took advantage of NOD-H2h4, a genetically susceptible animal model, which develops thyroiditis when fed a high iodine diet. Six to eight week old male NOD H2h4 mice were injected with mouse αIFN (200 units) or with saline three times a week for 8 weeks. All mice drank iodinated water (0.15%). Mice were sacrificed after 8 weeks of injection. Their thyroids were examined for histology and blood was tested for antithyroglobulin antibody levels. T4 and glucose levels were also assessed. In the IFN-injected group, 6/13 (46.2%) developed thyroiditis and/or thyroid antibodies while in the saline-injected group, only 4/13 (30.8%) developed thyroiditis and/or thyroid antibodies ( p =0.4). The grade of thyroiditis was not different amongst the two groups. None of the mice developed clinical thyroiditis or diabetes mellitus. Our results showed that αIFN treatment did not accelerate thyroiditis in this mouse model. This may imply that αIFN induces thyroiditis in a non-genetically dependent manner, and this would not be detected in a genetically susceptible mouse model if the effect were small. Alternatively, it is possible that αIFN did not induce thyroiditis in mice because, unlike in humans, in mice αIFN does not induce Th1 switching. [ABSTRACT FROM AUTHOR]

Abstract Background : Lamivudine is a new alternative therapeutic agent for chronic hepatitis B, in which alpha interferon (IFN-α) monotherapy is not successful enough. Published reports have revealed no satisfactory data on IFN-α and lamivudine combination therapy in children. The aim of this study is to investigate the efficacy and safety of this combination therapy in children with chronic hepatitis B. Methods : Children with chronic hepatitis B were given either IFN-α and lamuvidine (group 1, n = 47) or IFN-α alone (group 2, n = 30). Alpha interferon was administered as 5 million U/m2 s.c., thrice a week for 6 months and lamivudine 4 mg/kg per day p.o., maximum 100 mg, for 1 year. Clinical examination was performed; blood cell counts and serum alanine aminotransferase (ALT) and amylase were studied at each visit. At the third, sixth and twelfth month, serological markers were determined. Results : End of therapy response was achieved in 19 (40.4%) patients in group 1 and in 14 (46.7%) children in group 2 (P > 0.05). In group 1, pretreatment serum ALT and hepatic activity index (HAI) were statistically higher in children who responded to therapy (P < 0.005). In group 2, mean serum ALT was higher and hepatitis B virus (HBV) DNA was lower in responders. Sustained response rate was 40.4 versus 43.3% in two groups. Conclusion : The response rate of IFN-α and lamivudine combination therapy in children with chronic hepatitis B was similar to that of IFN-α monotherapy. High ALT level and HAI, rather than low HBV-DNA level were found to be important predictors of response. [ABSTRACT FROM AUTHOR]

Abstract: Background: Acute hepatitis A virus (HAV) infection can cause severe hepatitis especially in patients with underlying chronic liver disease. In patients with pre-existing chronic hepatitis B (HBV) acute HAV infection can suppress HBV replication. The exact mechanism of HBV suppression during acute HAV infection is still a subject of debate. One mechanism may be the production of HAV infection-induced cytokines leading to suppression of HBV replication and viral clearance. Aim: To evaluate cytokine production and HBV-specific lympho-proliferative responses (LPR) during acute HAV infection in a patient with chronic HBV infection-clearing markers of active HBV replication. Design: Early detection of a case of acute HAV infection in an HBeAg-positive, HBV DNA-positive chronic HBV patient treated with lamivudine. Results: At the time of HAV infection a sharp peak in the gamma-interferon (IFN-γ) level occurred just before the rise in serum transaminase activity. This was subsequently followed by a decrease in HBV DNA and HBeAg below the limit of detection of the assay. However the HBV-specific T-cell response was not modified. After resolution of the acute HAV infection and withdrawal of antiviral therapy HBV replication relapsed. Conclusion: The sharp rise in IFN-γ production mediated by the acute HAV infection may be pivotal in the suppression of HBV replication in chronic hepatitis B. [ABSTRACT FROM AUTHOR]

Hepatitis B has been a major challenge within the field of transplantation over the past few decades. Due to aggressive recurrence post-transplant, patients with hepatitis B have been excluded from the benefits of both solid organ and bone marrow transplants. Progress has been made, however, through an improved understanding of the biology of hepatitis B and the development of new antiviral strategies that can reliably suppress the virus. Patients with hepatitis B are now candidates for transplantation in an increasing number of circumstances. Careful pre-transplant evaluation is mandatory, together with a tailored antiviral regimen depending on the replicative status of the virus and the organ being transplanted. Minimizing steroid dose following transplantation is an important part of the strategy to reduce the risk of viral reactivation. Lamivudine has been an important development and it has assumed an increasing role in the management of these patients. As additional antivirals are developed, increasingly effective drug combinations will prevent viral recurrence as well as the emergence of drug-resistant mutants, which plagues the use of single agents. It is a rapidly evolving field and there is every reason for continued optimism. [ABSTRACT FROM AUTHOR]

Objective: This study was designed to investigate any possible pharmacokinetic interaction between lamivudine and alpha interferon as potential candidates for combination therapy for the treatment of hepatitis B virus (HBV). Methods: Nineteen healthy male, Caucasian volunteers, aged 20–41 years and weighing 60.5–83.5 kg completed this open, non-randomised study. They each received a single, abdominal, deep s.c. injection of 10 mIU alpha interferon on day 1, followed by a wash-out period of at least 1 week. Subjects then began a 7-day course of lamivudine (100 mg) followed by a further 10-mIU alpha-interferon injection directly after oral lamivudine dosing. Blood and urine samples were taken pre- and post-dose for alpha-interferon and/or lamivudine assay. Results: Lamivudine was safe and well tolerated in all subjects. No adverse events were reported in subjects on lamivudine, whereas 106 adverse events considered attributable to alpha interferon were recorded. Statistical analysis of pharmacokinetic parameters indicated no significant effect of lamivudine on alpha-interferon pharmacokinetics. There was a small statistically significant reduction (∼10%) in the area under the lamivudine concentration–time curve on co-administration with alpha interferon and a concomitant increase in clearance, which is not considered clinically relevant. Conclusions: Alpha interferon and lamivudine can be co-administered with no requirement for dose modification, as there was no clinically significant difference in the pharmacokinetics of either drug. [ABSTRACT FROM AUTHOR]

PTT-119, a new synthetic alkylating compound, has shown a marked 'in vitro' inhibitory effect on chronic myeloid leukemia (CML) granulo-monocytic precursors (CFU-GM) at doses greater than 5 µg/ml. Based on previous experiences of synergistic associations between alkylating drugs and biological modifiers, we tested the effects of low doses of PTT-119 (from 0.1 to 1 µg/ml) in concert with alpha, gamma, or alpha + gamma interferons and compared to IFNs alone, in order to investigate an alternative choice for treatment of CML patients in chronic phase. Our results showed a significantly higher CFU-GM cloning inhibition after addition of 100 or 1,000 U/ml of alpha IFN to 0.1 µg/ml PTT-119 (from 39.6% ± 26.6 SD to 80.7% ± 10 SD and 91.5% ± 8 SD, respectively), while gamma IFN resulted in only a slight increase in colony growth inhibition when compared to the drug used alone. The association of alpha plus gamma IFN coupled with PTT-119 treatment did not significantly improve the results observed after exposure of leukemic progenitors to PTT-119 and alpha IFN alone. We conclude that a combined treatment with PTT-119 and IFN is probably worth testing both for purging methods before autologous bone marrow transplantation and for in vivo administration in chronic myeloid leukemia. [ABSTRACT FROM AUTHOR]

Purpose. To identify a suitable nonaqueous, parenterally acceptable suspending vehicle whereby a therapeutic protein is delivered as a stable flowable powder, making it amenable to delivery from sustained delivery systems maintained at body temperature. Methods. Formulations of plasma derived Factor IX (pdFIX) and recombinant human alpha interferon (rhα-lFN) were formulated as dry powders, suspended in various vehicles (perfluorodecalin, perfluorotributylamine, methoxyflurane, polyethylene glycol 400, soybean oil, tetradecane or octanol) and stored at 37°C. Stability was assessed by size exclusion chromatography, reverse phase chromatography, ion exchange chromatography, and bioassay, and was compared to the stability of dry powder formulations stored at 37°C and −80°C. Results. PdFIX was stable when stored at 37°C as a dry powder, or when the dry powder was suspended in the pharmaceutically acceptable vehicles perfluorodecalin or perfluorotributylamine. Suspensions of the powder in other pharmaceutically/parenterally acceptable vehicles such as soybean oil or PEG 400 resulted in aggregation and loss of bioactivity. A dry powder formulation of rhα-lFN suspended in perfluorodecalin was also stable at 37°C. Conclusions. This study shows the potential utility of perfluorinated hydrocarbons as nonaqueous suspending vehicles for long term in-vivo delivery of therapeutic proteins. [ABSTRACT FROM AUTHOR]

Three patients with metastatic malignant melanoma, 2 of whom were males with primary lesion on the shoulder, and a female with primary lesion on the ankle, with Clark's level III-IV, completely responded to interferon-DTIC, but failed in the brain. Radiologically, all the lesions were peripheral in location, and none showed any bleeding tendency. Clinically, these lesions seemed to be resistant to radiotherapy, chemotherapy or steroid treatment, and were the cause of death after a very short survival period. Interferon apparently is inactive against melanoma brain metastases, but does cause CNS symptoms. Because CNS metastases are sometimes the sole site of clinical relapse, and are frequently disabling, prophylactic cranial irradiation (PCI) needs to be studied in high risk patients. [ABSTRACT FROM AUTHOR]

A patient with chronic phase Philadelphia chromosome positive CML, developed severe protracted bone marrow hypoplasia after interferon therapy. This complication did not respond to two courses of immunosuppressive therapy with anti-thymocyte globulin, cyclosporin A and prednisone. The patient continued to be transfusion dependent with persistence of Philadelphia chromosome. Allogeneic BMT restored normal hematopoeisis. [ABSTRACT FROM AUTHOR]

The effects of three doses of interferon alpha (1.5 Mu, 0.5 Mu and 0.1 Mu) on performance were studied. The injection of 1.5 Mu IFN produced symptoms and performance changes which closely resembled those found in volunteers with influenza. Specifically, volunteers were slower at responding when they were uncertain when a target stimulus would appear, but were not impaired on a pursuit tracking task or syntactic reasoning task. The results suggest that interferon-induced changes in CNS function provide a plausible explanation for the selective effects of influenza on performance. [ABSTRACT FROM AUTHOR]

Serum α-interferon levels were analysed in 50 consecutive children admitted with right iliac fossa pain. Serum a-interferon levels were significantly raised in 33% of children without acute appendicitis when compared to 5.7% of children with histologically proven acute appendicitis and 9% of normal controls. This interesting phenomenon needs further investigation. A larger series may show it to be of clinical use in non-specific abdominal pain in childhood. [ABSTRACT FROM AUTHOR]