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- Clinical trials of investigational agents for IPF: a review of a Cochrane report. [Journal Article]
- Respir Res 2013 Apr 16.:S4.
The magnitude of treatment effect can be assessed by a number of methods. One reliable method of collectively analysing data from randomised clinical trials is that used in Cochrane reviews. These systematic reviews identify and analyse the available evidence using the reliable method of meta-analysis. These often combine data from studies to provide robust evaluations of overall treatment effects. In 2003, a review of data from studies of corticosteroid use in IPF patients found no evidence of a treatment effect. Similarly, very little evidence was found to support the use of immunomodulatory agents. A recent update of these Cochrane reviews failed to identify any new evidence supporting the use of corticosteroids in IPF. However, a review of non-steroid agents for the treatment of IPF identified data from 15 RCTs that was suitable for analysis. Two trials of interferon gamma-1b were pooled and analysed, but no treatment effect was observed in terms of survival. Meta-analysis of three Phase III studies of pirfenidone treatment in IPF patients suggested that progression-free survival was significantly increased by 30%, demonstrating a reduction in the decline of lung function in IPF patients. In addition, there are numerous ongoing trials investigating potential therapeutic agents which provides hope for IPF patients and their doctors.
- Evidence-based treatment strategies in idiopathic pulmonary fibrosis. [Journal Article]
- Eur Respir Rev 2013 Jun 1; 22(128):163-8.
Recently updated guidelines have provided revised recommendations, based on the GRADE criteria, for the diagnosis and pharmacological and non-pharmacological management of patients with idiopathic pulmonary fibrosis (IPF). Cochrane reviews are also a highly respected and reliable source of evidence-based information that identify and analyse all available data of overall treatment effects from appropriate studies. A recent update of one Cochrane review failed to identify any new evidence supporting the use of corticosteroids in IPF. Another review of data from 15 randomised controlled studies of non-steroid agents for the treatment of IPF identified two trials of interferon-γ-1b suitable for analysis. However, the pooled analysis revealed no treatment effect in terms of survival. A further meta-analysis of three phase III studies of pirfenidone treatment in IPF patients suggested a significant increase in progression-free survival. The interpretation of recent international and national European guideline updates and treatment recommendations, available clinical data from published and ongoing trials investigating potential pharmacological agents, and the individual patient's preferences, must be considered in the clinical management of this disease.
- Loss of protein tyrosine phosphatase nonreceptor type 22 regulates interferon-γ-induced signaling in human monocytes. [Comparative Study, Journal Article, Research Support, Non-U.S. Gov't]
- Gastroenterology 2013 May; 144(5):978-988.e10.
A gain-of-function variation within the locus that encodes protein tyrosine phosphatase nonreceptor type (PTPN)22 is associated with a reduced risk for Crohn's disease (CD), whereas a loss-of-function variant seems to promote autoimmune disorders. We investigated how loss of PTPN22 could contribute to chronic inflammation of the intestine.Intestinal tissue samples from patients with or without inflammatory bowel disease (controls) were analyzed for levels of PTPN22 messenger RNA (mRNA) and protein. In human THP-1 monocytes, protein levels were analyzed by immunoblotting, mRNA levels by real-time polymerase chain reaction, and cytokine release by enzyme-linked immunosorbent assay.Intestinal tissue samples from patients with CD had reduced levels of PTPN22 mRNA and protein, compared with samples from controls. In human THP-1 monocytes, interferon-γ (IFN-γ) induced expression and activity of PTPN22. Loss of PTPN22 increased levels of p38-mitogen-activated protein kinase, but reduced phosphorylation of nuclear factor-κB subunits. Increased activity of suppressor of cytokine signaling-1 was accompanied by reduced phosphorylation of signal-transducer and activator of transcription protein 1 and signal-transducer and activator of transcription protein 3 in PTPN22-deficient cells incubated with cytokines. PTPN22 knockdown increased secretion of the inflammatory cytokines interleukin (IL)-6 and IL-17, but reduced expression or secretion of T-bet, intercellular adhesion molecule-1, nucleotide-binding oligomerization domain containing-2, monocyte chemoattractant protein-1, IL-2, and IL-12p40 in response to IFN-γ.PTPN22 expression is reduced in intestinal tissues of patients with active CD. PTPN22 regulates intracellular signaling events and is induced by IFN-γ in human monocytes. Knockdown of PTPN22 alters activation of inflammatory signal transducers, increasing secretion of T-helper 17-related inflammatory mediators. Genetic variants that reduce PTPN22 activity might contribute to the pathogenesis of CD by these mechanisms.
- Interventions to improve symptoms and quality of life of patients with fibrotic interstitial lung disease: a systematic review of the literature. [JOURNAL ARTICLE]
- Thorax 2012 Dec 1.
BACKGROUND:Patients with fibrotic interstitial lung disease have symptom control and quality of life (QoL) needs. This review aims to evaluate the evidence for the use of interventions in improving dyspnoea, other symptoms and QoL.
METHODS:Eleven databases, relevant websites and key journals were hand-searched. Studies were assessed and data extracted independently by two researchers using standardised proformas. Meta-analyses were performed where possible with 95% CI.
RESULTS:34 papers with 19 interventions in 3635 patients were included. Meta-analyses showed no significant effect of interferon γ-1b or sildenafil on 6-minute walking distance (6MWD) or dyspnoea. Pulmonary rehabilitation and pirfenidone had a positive effect on 6MWD (mean difference (95% CI) 27.4 (4.1 to 50.7)) and 24.0 (4.3 to 43.7), respectively), and pulmonary rehabilitation had a mixed effect on dyspnoea. Both pulmonary rehabilitation and sildenafil showed a trend towards significance in improving QoL. There was weak evidence for the improvement of 6MWD using oxygen; dyspnoea using prednisolone, diamorphine, D-pencillamine and colchicine; cough using interferon α and thalidomide; anxiety using diamorphine; fatigue using pulmonary rehabilitation; and QoL using thalidomide and doxycycline. A wide range of outcome scales was used and there were no studies with economic evaluation.
CONCLUSIONS:There is strong evidence for the use of pulmonary rehabilitation and pirfenidone to improve 6MWD and moderate evidence for the use of sildenafil and pulmonary rehabilitation to improve QoL. Future recommendations for research would include careful consideration of the dichotomy of radical and palliative treatments when deciding on how symptom and QoL outcome measures are used and data presented.
- Interferon-gamma with peginterferon alpha-2a and ribavirin in nonresponder patients with chronic hepatitis C (ANRS HC16 GAMMATRI). [Journal Article, Research Support, Non-U.S. Gov't]
- J Gastroenterol Hepatol 2013 Feb; 28(2):329-34.
Interferon-gamma-1b (IFN-γ-1b) improves alpha interferon (IFN-α) inhibition of hepatitis C virus (HCV) replication in replicon system. We described virological response after addition of IFN-γ to a combination of ribavirin/peginterferon (PEG-IFN)-α-2a or α-2b.In this non-comparative, multicenter trial, patients chronically infected by HCV who were nonresponders to a previous treatment by PEG-IFN and ribavirin were restarted on a regimen of PEG-IFN-α-2a (180 μg/week) + ribavirin (1000-1200 mg/day) for 16 weeks. If HCV-RNA decreased less than 2 log(10) copies/mL (nonresponders), and if PEG-IFN-α-2a and ribavirin dosages were unchanged while tolerance was good, IFNγ-1b (100 μg three times per week) was added for the last 32 weeks of treatment. Virological response was evaluated at week 28 (12 weeks after initiation of IFN-γ-1b).Among the 48 patients started on dual therapy, 23 patients (47%) were nonresponders at week 12 and received IFN-γ-1b from week 16 onward. Their mean HCV-RNA (log(10) IU/mL) was 6.83 at baseline, 5.81 at week 12, and 5.63 at week 28. No patient reached undetectable HCV-RNA at week 28 (upper bound of 95% confidence interval: 14.8%); none had a decrease > 1 log(10) IU/mL. One case of grade 4 neutropenia was reported.Among the strictly selected nonresponders, IFN-γ-1b (at a dosage of 100 μg thrice a week) in combination with PEG-IFN-α-2a and ribavirin failed to show virological efficacy.
- Organomagnesium suppresses inflammation-associated colon carcinogenesis in male Crj: CD-1 mice. [Journal Article, Research Support, Non-U.S. Gov't]
- Carcinogenesis 2013 Feb; 34(2):361-9.
Magnesium (Mg) deficiency increases genomic instability and Mg intake has been reported to be inversely associated with a risk of colorectal cancer (CRC). This study was designed to determine whether organo-Mg in drinking water suppresses inflammation-associated colon carcinogenesis in mice. Male Crj: CD-1 mice were initiated with a single i.p. injection of azoxymethane (AOM, 10mg/kg body weight) and followed by a 1 week exposure to dextran sulfate sodium (DSS, 1.5%, w/v) in drinking water to induce colonic neoplasms. They were then given the drinking water containing 7, 35 or 175 p.p.m. organo-Mg for 13 weeks. The chemopreventive efficacy of organo-Mg was determined 16 weeks after the AOM exposure. Administration with organo-Mg at all doses caused a significant inhibition of CRC development (P < 0.01 and P < 0.001). Especially, the highest dose of organo-Mg significantly suppressed the occurrence of all the colonic pathological lesions (mucosal ulcer, dysplasia, adenoma and adenocarcinoma). Organo-Mg also significantly reduced the number of mitoses/anaphase bridging, as well as proliferation of CRC. Additionally, at week 4, organo-Mg lowered the messenger RNA expression of certain proinflammatory cytokines, such as interleukin-1β, interleukin-6, interferon-γ and inducible nitric oxide synthase in the lesion-free colorectal mucosa at week 4 but increased the Nrf-2 messenger RNA expression. Our findings that organo-Mg inhibits inflammation-related mouse colon carcinogenesis by modulating the proliferative activities and chromosomal instability of CRC and suppressing colonic inflammation may suggest potential use of organo-Mg for clinical chemoprevention trials of CRC in the inflamed colon.
- PML-IRIS in a patient treated with brentuximab. [Case Reports, Journal Article]
- Neurology 2012 Nov 13; 79(20):2075-7.
A 38-year-old woman was diagnosed with cutaneous anaplastic T-cell lymphoma that proved refractory to methotrexate, bexarotene, denileukin diftitox, interferon γ-1b, interferon α-2b, vorinostat, and pralatrexate. She was therefore started on the newly approved monoclonal anti-CD30 antibody brentuximab vedotin. Treatment with brentuximab 1.8 mg/kg IV every 3 weeks quickly led to disappearance of her cutaneous tumors. The day after her second brentuximab infusion she developed word-finding difficulties and unsteady gait. Due to further neurologic deterioration, she was admitted to an outside hospital. Brain MRI revealed multifocal enhancing white matter lesions throughout bilateral cerebral hemispheres and posterior fossa (figure, A-C). Brain biopsy was performed 15 days after her last brentuximab dose to rule out metastases and she was diagnosed with progressive multifocal leukoencephalopathy (PML) (figure, J). The patient was discharged home with hospice care. Upon discharge, she was started on prednisone 50 mg daily to help treat her eczema. Her family brought her to our clinic for a second opinion.
- Successful salvage therapy of refractory HIV-related cryptococcal meningitis with the combination of liposomal amphotericin B, voriconazole, and recombinant interferon-γ. [Case Reports, Journal Article]
- Diagn Microbiol Infect Dis 2012 Dec; 74(4):409-11.
We present 2 cases of HIV-related cryptococcal meningitis, persisting after 3 and 9 months, respectively, of standard treatment. Both patients were treated successfully with a salvage regimen consisting of the combination of liposomal amphotericin B (3 mg/kg), intravenous voriconazole, and subcutaneous recombinant interferon γ-1b (200 μg thrice weekly). Voriconazole was administered at an increased dose (5 mg/kg, twice daily) to overcome interactions with co-administered ritonavir. In both patients, resolution of clinical signs and symptoms, as well as sterilization of cerebrospinal fluid cultures occurred after 10 weeks of salvage therapy. No major side effects were encountered. At the end of treatment, both patients were placed on maintenance therapy with oral fluconazole; no recurrence has been observed after 4 years of follow-up.
- Quantitative and qualitative QuantiFERON(®)-TB gold in-tube results among groups with varying risks of exposure to tuberculosis. [Comparative Study, Journal Article]
- Heart Lung 2012 Nov-Dec; 41(6):553-61.
We sought to describe qualitative and borderline quantitative QuantiFERON(®)-TB Gold In-Tube (QFT-IT; Cellestis, Valencia, CA) results among persons screened in the context of routine reasons, employment, contact investigation, high-risk foreign-born arrivals in the United States ≤ 5 years, and high-risk United States residents >5 years.We performed a retrospective review of 3288 QFT-IT results from a clinical laboratory in the Pacific Northwest from January 2, 2008 to June 5, 2009. Interferon-γ (IFN-γ) responses were quantified as low, borderline, or high for tuberculosis (TB) antigens (IFN-γ [TB]) and a positive mitogen control (IFN-γ [mitogen]), after subtracting a background control (IFN-γ [nil]). Qualitative results were categorized as negative, positive, or indeterminate.Quantitative values categorized as borderline, well above, or well below the cut-point were associated with qualitative results for IFN-γ (TB-nil) (χ(2) = 2913.178, degrees of freedom [df] = 4, P < .001) and IFN-γ (mitogen-nil) values (χ(2) = 2559.758, df = 4, P < .001).Quantitative data enhance the interpretation of qualitative QFT-IT results for persons with varying risks of exposure.
- Assessing the treatment effect from multiple trials in idiopathic pulmonary fibrosis. [Journal Article, Review]
- Eur Respir Rev 2012 Jun 1; 21(124):147-51.
The magnitude of treatment effect can be assessed by a number of methods. One method of collectively analysing data is that used by the Cochrane Collaboration. Their systematic reviews identify, analyse and present research-based evidence in an accessible format. These reviews may contain meta-analyses combining data from multiple studies to provide robust evaluations of overall treatment effects. In 2003, Cochrane reviews of data for treatment with corticosteroids in idiopathic pulmonary fibrosis (IPF) found no evidence supporting their use; similarly, reviews of immunomodulatory agents found very little evidence to support their use. A recent update of these Cochrane reviews failed to identify any evidence supporting the use of corticosteroids in IPF; however, a review of non-steroid agents in the treatment of IPF identified 15 clinical trials suitable for analysis. Two trials of interferon-γ-1b were combined, and no treatment effect was observed in terms of survival. Two Japanese trials of treatment with pirfenidone were combined, and a positive effect of pirfenidone on pulmonary function decline was observed. Meta-analysis of three phase III studies suggested that pirfenidone significantly increased progression-free survival by 30%. The findings of this systematic review, although not presenting new original data, together with an acceptable safety profile, suggest that pirfenidone may have a role in IPF treatment.