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1.
The pathogenesis, diagnosis and management of congenital dyserythropoietic anaemia type I.
Roy, NBA, Babbs, C
British journal of haematology. 2019;(3):436-449
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Abstract
Congenital dyserythropoietic anaemia type I (CDA-I) is one of a heterogeneous group of inherited anaemias characterised by ineffective erythropoiesis. CDA-I is caused by bi-allelic mutations in either CDAN1 or C15orf41 and, to date, 56 causative mutations have been documented. The diagnostic pathway is reviewed and the utility of genetic testing in reducing the time taken to reach an accurate molecular diagnosis and avoiding bone marrow aspiration, where possible, is described. The management of CDA-I patients is discussed, highlighting both general and specific measures which impact on disease progression. The use of interferon alpha and careful management of iron overload are reviewed and suggest the most favourable outcomes are achieved when CDA-I patients are managed with a holistic and multidisciplinary approach. Finally, the current understanding of the molecular and cellular pathogenesis of CDA-I is presented, highlighting critical questions likely to lead to improved therapy for this disease.
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2.
Minimal residual disease or cure in MPNs? Rationales and perspectives on combination therapy with interferon-alpha2 and ruxolitinib.
Bjørn, ME, Hasselbalch, HC
Expert review of hematology. 2017;(5):393-404
Abstract
The therapeutic landscape of the Philadelphia-negative myeloproliferative neoplasms (MPNs) is markedly changing consequent to the development of JAK-inhibitors and the use of ruxolitinib (RUX) in patients with myelofibrosis (MF) and patients with polycythemia vera (PV) who develop refractoriness or intolerance to hydroxyurea. The use of Interferon-alpha2 (IFN) is rapidly expanding in several countries, based upon favourable safety and efficacy profiles in several single-arm studies during the last 30 years, displaying complete hematological remissions in a large proportion of patients, a reduction in the JAK2V617 F and CALR mutational burden and in a subset of patients with PV with normalisation of the bone marrow after long-term treatment - even being sustained for several years after discontinuation of IFN. To this end the concept of chronic inflammation as the driving force for MPN disease progression is being increasingly recognized. This novel concept has initiated phase II studies in patients with PV and MF of combination therapy with IFN and RUX. Areas covered and Expert commentary: Herein we highlight the background, the rationales and perspectives for this novel combinatorial approach which is foreseen as the most encouraging and promising treatment for patients with MPNs - hopefully with the potential of cure - at least operational cure - in a subset of patients.
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Overview of Targeted Therapies for Adult T-Cell Leukemia/Lymphoma.
Nasr, R, Marçais, A, Hermine, O, Bazarbachi, A
Methods in molecular biology (Clifton, N.J.). 2017;:197-216
Abstract
Adult T-Cell Leukemia/lymphoma (ATL) is the first human malignancy associated with a chronic infection by a retrovirus, the human T-cell lymphotropic virus type I (HTLV-I). ATL occurs, after a long latency period, only in about 5% of 10-20 millions infected individuals. ATL has a dismal prognosis with a median survival of less than 1 year, mainly due to its resistance to chemotherapy and to a profound immunosuppression. The viral oncoprotein, Tax, plays a major role in ATL oncogenic transformation by interfering with cell proliferation, cell cycle, apoptosis, and DNA repair. The diversity in ATL clinical features and prognosis led to Shimoyama classification of ATL into four clinical subtypes (acute, lymphoma, chronic, and smoldering) requiring different therapeutic strategies. Clinical trials, mainly conducted in Japan, demonstrated that combination of chemotherapy could induce acceptable response rate in the lymphoma subtype but not in acute ATL. However, long-term prognosis remains poor for both subtypes, due to a high relapse rate. Similarly, whether managed by a watchful waiting or treated with chemotherapy, the indolent forms (smoldering and chronic) have a poor long-term outcome. An international meta-analysis showed improved survival in the leukemic subtypes of ATL (chronic, smoldering as well as a subset of the acute subtype) with the use of two antiviral agents, zidovudine and interferon-alpha, and accordingly, this combination should be considered the standard first-line treatment in this context. ATL patients with lymphoma subtype benefit from induction chemotherapy, given simultaneously or sequentially with an antiviral combination of zidovudine and interferon-alpha. Allogeneic hematopoietic stem cells transplantation remains a promising and potentially curative approach but is limited to a small number of patients. Novel drugs such as arsenic trioxide in combination with interferon-alpha or monoclonal antibodies such as anti-CXCR4 have shown promising results and warrant further investigation.
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4.
Latest developments in the treatment of hepatitis B.
Dandri, M, Petersen, J
Minerva gastroenterologica e dietologica. 2016;(1):88-102
Abstract
Chronic hepatitis B virus (HBV) infection continues to be a major health burden worldwide. Currently available antiviral treatment options for chronic hepatitis B include pegylated interferon alpha (PEG-IFN) or nucleos(t)ide analogues (NAs). The major advantages of NAs are good tolerance and potent antiviral activity associated with high rates of on-treatment response to therapy. The advantages of PEG-IFN include a finite course of treatment, the absence of drug resistance, and an opportunity to obtain a durable post-treatment response to therapy. The use of these two antiviral agents with different mechanisms of action in combination is theoretically an attractive approach for treatment. Although several studies have confirmed certain virological advantages of combination therapies, pivotal prospective studies demonstrating long-term clinical benefit to patients are still missing and monotherapy with PEG_IFN or NAs remains the therapy of choice. Furthermore, with the current treatment approaches, only a limited number of patients reach the aim HBsAg loss, which is closest to clinical cure. The limited efficacy of current approved therapeutic regimens demands the development of more efficient therapeutic approaches enabling not only suppression of viral replication, but resolution of HBV infection. The unique replication strategy employed by HBV enables its persistence within the infected hepatocytes. As a consequence, relapse of viral activity is commonly observed after cessation of treatment. Both the persistence of the HBV genome, which forms a stable minichromosome, the covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes, as well as the inability of the immune system to resolve chronic HBV infection are believed to be key mechanisms of HBV chronicity. The recent development and availability of innovative in vitro and in vivo systems and sensitive molecular techniques have opened new possibilities to study the complex network of interactions that HBV establishes with the host in the course of infection and to define new targets for antiviral strategies. Several new antiviral or immunomodulatory compounds have reached preclinical or clinical testing with the aim of a clinical cure of chronic HBV with the loss of HBsAg. This review summarizes the most recent therapeutic strategies designed to directly target the virus or to improve immune responses during chronic HBV infection.
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Rhabdomyolysis as a clinical manifestation of association with ciprofibrate, sirolimus, cyclosporine, and pegylated interferon-α in liver-transplanted patients: a case report and literature review.
dos Santos, AG, Guardia, AC, Pereira, TS, Ataíde, EC, Mei, Md, Udo, ME, Boin, IF, Stucchi, RS
Transplantation proceedings. 2014;(6):1887-8
Abstract
BACKGROUND Rhabdomyolysis is a syndrome characterized by impaired metabolic integrity of myocytes, causing the release of intracellular constituents into the circulation, and can be a serious side effect of drug intake. CASE REPORT This report describes a unique case of rabdomyolysis secondary in which ciprofibrate, sirolimus, cyclosporine, and pegylated interferon-α in a liver transplant patient was used. A 47-year-old male liver transplant recipient in 2009, who had hepatitis C and incidental hepatocellular carcinoma, underwent immunosuppressive therapy (cyclosporine and sirolimus). The patient is currently in treatment for viral recurrence with pegylated interferon-α and ribavirin; he had a history of hypertriglyceridemia treated with ciprofibrate. He had development of severe and generalized myalgia and fever after the eighth application of pegylated interferon-α and increasing doses of cyclosporine. Laboratorial tests showed acute renal failure and significant increase in creatine kinase. Rhabdomyolysis secondary to interaction of fibrate-cyclosporine-pegylated interferon-α was postulated. CONCLUSIONS Medical professionals should be aware of possible drug interactions and should monitor patients receiving these drugs.
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6.
Tobacco - a producer of recombinant interferons.
Budzianowski, J
Przeglad lekarski. 2014;(11):639-43
Abstract
The approved therapeutic interferons, which are chiefly indicated for a treatment of hepatitis C or hairy cell leukaemia (IFN-α), relapsingl remitting sclerosis multiplex (IFN-β) and chronic granulomatous disease (IFN-γ), are commercially produced by recombinant DNA technology, mainly in bacteria Escherichia coli (IFN-α, IFN-β1b, IFN-γ), rarely in a mammalian cell line CHO (IFN-βla). A serum half-life time of some non-glycosylated IFN-α products was extended by a chemical attachment of a branched polyethylene glycol (PEG) to give PEGylated IFN-α. The therapy with recombinant interferons proves expensive and hence much hope is concerned with their production in other platforms assumed to be cheaper, like transgenic plants. Currently, tobacco, botanically species Nicotiana tabacum, its cultivars and some related species, especially N. benthamiana, is one of the most important plant expression systems tested for the production of therapeutical polypeptides and proteins (so-called biopharmaceuticals or biologics), especially vaccines, by using either greenhouse or field cultivated plants or cell suspension culture. IFN-α subtypes were expressed in tobacco nuclear genom e (IFN-α2a and 2b), chloroplast genome (IFN-α2b) and by transient expression (IFN-α2b). The IFα-a2b chimera fusions with O-glycosylated protein with O-a-rabinogalactans expressed in tobacco BY-2 cell culture showed increased half-life time similar to that obtained by PEGylation. The production of IFN-α2b (non-glycosydated) in tobacco glasshouse or field cultivation has been also elaborated. One report concerned expression of IFN-β but with low yield. N-glycosylated IFN-γ could be efficiently expressed in tobacco protoplast infected with recombinant brome mosaic virus (BMV) with the yield of 5-10% of total extracted protein. This type interferon (non-glycosylated), when expressed in chloroplast genome, proved unstable and could be obtained with reasonable yield as a fusion with GUS (β-glucuronidase).
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7.
Extended peginterferon plus ribavirin treatment for 72 weeks versus standard peginterferon plus ribavirin treatment for 48 weeks in chronic hepatitis C genotype 1 infected slow-responder adult patients.
Katz, LH, Goldvaser, H, Gafter-Gvili, A, Tur-Kaspa, R
The Cochrane database of systematic reviews. 2012;(9):CD008516
Abstract
BACKGROUND The standard length of peginterferon plus ribavirin treatment for chronic hepatitis C virus (HCV) genotype 1 infected patients is 48 weeks. However, the number of patients demonstrating a sustained virological response is not high. In order to improve sustained virological response, extending the length of the treatment period has been suggested. OBJECTIVES To study the benefits and harms of extended 72-week treatment in comparison with 48-week treatment with peginterferon plus ribavirin in patients with chronic HCV genotype 1 infection who have shown a slow antiviral response. SEARCH METHODS We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, and LILACS until November 2011. We identified further trials by reviewing reference lists and contacting principal authors. SELECTION CRITERIA Trials were eligible for this review if they included patients infected with hepatitis C virus genotype 1 who had a slow antiviral response, and if those patients were randomised to completing 72 weeks versus 48 weeks of treatment with pegylated interferon and ribavirin. DATA COLLECTION AND ANALYSIS Two authors independently assessed the trials for risk of bias, and extracted the data. The primary outcomes were overall mortality, liver-related mortality, and liver-related morbidity. We extracted data separately according to two definitions of slow responders: 1) patients with ≥ 2 log viral reduction but still detectable HCV RNA after 12 weeks of treatment and undetectable HCV RNA after 24 weeks of treatment; 2) patients with detectable HCV RNA after four weeks of treatment. We calculated risk ratios from individual trials as well as in the meta-analyses of trials. MAIN RESULTS We included seven trials with 1369 participants. All trials had high risk of bias. Five trials used our first definition of slow responders, and three other trials (including one that used both definitions) used the second definition. None of the included trials mentioned our primary outcomes. However, regarding the secondary outcomes, extension of the treatment period to 72 weeks increased the sustained virological response according to both definitions (71/217 (32.7%) versus 52/194 (26.8%); risk ratio (RR) 1.43, 95% confidence interval (CI) 1.07 to 1.92, P = 0.02, I(2) = 8%; and 265/499 (53.1%) versus 207/496 (41.7%); RR 1.27, 95% CI 1.07 to 1.50, P = 0.006, I(2) = 38%), with a risk difference of 0.11 and calculated number needed to treat of nine. The end of treatment response was not significantly different between the two treatment groups. The number of participants who relapsed virologically was found to be lower in the groups that had been treated for 72 weeks using both definitions (27/84 (32.1%) versus 46/91 (50.5%); RR 0.59, 95% CI 0.40 to 0.86, P = 0.007, I(2) = 18%, 3 trials; and 85/350 (24.3%) versus 146/353 (41.4%); RR 0.59, 95% CI 0.47, 0.73, P < 0.000001, I(2) = 0%, 3 trials). The length of treatment did not significantly affect the adherence (247/279 (88.5%) versus 252/274 (92.0%); RR 0.95, 95% CI 0.84 to 1.07, P = 0.42, I(2) = 69%, 3 trials). In the single trial that reported adverse events, no significant difference was seen between the two treatment groups. AUTHORS' CONCLUSIONS This review demonstrates higher a proportion of sustained virological response after extension of treatment from 48 weeks to 72 weeks in HCV genotype 1 infected patients in whom HCV RNA was still detectable but decreased by ≥ 2 log after 12 weeks and became negative after 24 weeks of treatment, and in patients with detectable HCV RNA after four weeks of treatment with peginterferon plus ribavirin. The observed intervention effects can be caused by both systematic error (bias) and random errors (play of chance). There was no reporting on mortality and the reporting of clinical outcomes and adverse events was insufficient. More data are needed in order to recommend or reject the policy of extending the treatment period for slow responders.
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Dermatomyositis and polymyositis: new treatment targets on the horizon.
Hak, AE, de Paepe, B, de Bleecker, JL, Tak, PP, de Visser, M
The Netherlands journal of medicine. 2011;(10):410-21
Abstract
Polymyositis (PM) and dermatomyositis (DM) are rare idiopathic inflammatory myopathies (IIM) with a presumed autoimmune pathogenesis. Typical features are subacute onset, proximal, symmetric muscle weakness, elevated serum creatine kinase, and mononuclear cell infiltrates in the muscle biopsy. Strong support for an autoimmune pathogenesis comes from histopathological findings in biopsies of affected muscles. Furthermore, the association with autoantibodies supports the notion that immune-mediated inflammation is involved. PM and DM may occur in isolation or in connection with a connective tissue disease or cancer. The current treatment for IIM consists of first-line high-dose steroids and various conventional second-line treatments. Improvements in treatment for IIM are hampered by difficulties in the design of trials and the low incidence and prevalence of the disease. Cytokines and chemokines are factors involved in the inflammatory process in IIM, and are candidates for future therapeutic targets. Preliminary data with anti-tumour necrosis factor therapy are not very promising, but results of blockers of the lymphotoxin signalling pathway are to be awaited. Anti-B cell therapy may be a valuable therapeutic option for treatment of refractory IIM. The effects of anti-interferon-alpha in IIM are to be awaited, as are results of other anti-cytokine therapies and anti-chemokine therapy. Outcome measures to be used in clinical trials in II M include at present the core sets of outcome proposed by the International Myositis Assessment Clinical Study Group (IMACS).
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9.
Does chemotherapy prevent HCV-related hepatocellular carcinoma? Pros.
Masuzaki, R, Yoshida, H, Omata, M
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2010;:S281-6
Abstract
Hepatitis C virus (HCV) infection, which seems to have spread worldwide recently, is now the leading cause of hepatocellular carcinoma (HCC) development in various geographic areas. The primary prevention of HCV-related HCC includes strategies for the prevention of HCV infection and those for viral eradication. Even after HCC development, short-term prognosis of patients has been much improved recently due to advances in early diagnosis and treatment. However, long-term prognosis is as yet far from satisfactory due to frequent recurrence of HCC even after apparently curative treatment, either local ablation or surgical resection. At least theoretically, strategies similar to those of primary prevention may be applicable to HCC recurrence. In this review, we summarized the reported favorable effects of chemotherapy on primary and tertiary prevention of HCC.
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10.
Novel therapies for hypereosinophilic syndromes.
Antoniu, SA
The Netherlands journal of medicine. 2010;(1):304-10
Abstract
BACKGROUND Conventional therapies (corticosteroids, cytotoxic agents or interferon-a) or newer compounds such imatinib are used specifically in subsets of hypereosinophilic syndromes (HES). However other therapies are still needed in this condition. OBJECTIVE To review the novel therapies for HES discussing their advantages and shortcomings. METHODS AND RESULTS Preclinical and clinical data on novel tyrosine kinase inhibitors, anti-IL -5 antibodies or anti-CD52 antibodies (alemtuzumab) are analysed. The former might represent appropriate options in case of imatinib resistance; the efficacy of anti-IL-5 monoclonal antibodies therapy is limited by the occurrence of rebound eosinophilia and alemtuzumab might be a promising anti-eosinophil therapy for all HES subsets. CONCLUSION Some of the novel therapies might become appropriate therapeutic options for HES.