Therapy-naive Patients Research Articles

B-Cell Activating Factor Belonging to the Tumor Necrosis Factor Family and Interferon-γ-Inducible Protein-10 in Autoimmune Hepatitis.

The aims of the present study were to examine the relationship between serum B-cell activating factor belonging to the tumor necrosis factor family (BAFF) levels and serum interferon-γ-inducible protein-10 (IP-10) levels in patients with autoimmune hepatitis (AIH).A total of 80 corticosteroid therapy naive AIH patients were analyzed in this analysis. First, we examined the relationship between pretreatment serum BAFF and IP-10 levels and liver histological findings. Next, we investigated the relationship of pretreatment serum BAFF and IP-10 levels and aspartate aminotransferase value (AST), alanine aminotransferase value, and serum Immunoglobulin G (IgG) level as serum liver inflammation markers.Our study included 14 men and 66 women with the median (range) age of 64 (21–83) years. The serum BAFF levels ranged from 122.5 to 7696.0 pg/mL (median value, 1417.8 pg/mL), whereas the serum IP-10 levels ranged from 142.0 to 4198.7 pg/mL (median value, 640.1 pg/mL). The serum BAFF levels were significantly stratified in each 2 liver inflammation stage. Similarly, the serum IP-10 levels were significantly stratified in each 2 liver inflammation stage. Among 3 serum inflammation markers, AST value had the highest rs value in terms of the relationship with BAFF level (rs = 0.511, P < 0.001) and IP-10 level (rs = 0.626, P < 0.001). In addition, the serum BAFF level significantly correlated with serum IP-10 level (rs = 0.561, P < 0.001). In patients without advanced fibrosis (F3 or more), the serum BAFF level significantly correlated with serum IP-10 level (rs = 0.658, P < 0.001), whereas in patients with advanced fibrosis, the serum BAFF level significantly correlated with serum IP-10 level (rs = 0.542, P < 0.001).In conclusion, both BAFF and IP-10 are useful for predicting the degree of liver inflammation activity in AIH. BAFF and IP-10 may have the common clinical implication for liver inflammation activity for AIH patients.

Association between statin treatment and LDL-cholesterol levels on the rate of ST-elevation myocardial infarction among patients with acute coronary syndromes: ACS Israeli Survey (ACSIS) 2002–2010

BackgroundSTEMI is thought to occur as a result of a vulnerable coronary plaque rupture. Statins possess hypolipidemic and pleotropic effects that stabilize coronary plaque. We sought to determine the association between LDL-C levels, statin use prior to the index event on the type of acute coronary syndrome (ACS) presentation: STEMI vs. non-STEMI/unstable angina. MethodsData was drawn from the ACS Israeli Survey (ACSIS), a biennial prospective survey of ACS patients hospitalized in all CCU/Cardiology departments during 2002–2010. ResultsAmong 6790 patients, 2760 (41%) reported statin use prior to the index ACS event. The proportion of STEMI was significantly lower among statin treated vs. statin naive patients (36% vs. 57%, p<0.0001). At each LDL-C level, the proportion of STEMI was significantly lower only among statin treated patients (p<0.0001). LDL-C<70mg/dL was associated with a lower proportion of STEMI only among statin treated but not among statin naive patients (33% vs. 57%, p<0.0001). Multivariate analysis revealed that statin use was independently associated with a lower probability of presenting with STEMI (ORadj=0.73, p=0.007), but not LDL-C<70mg/dL (ORadj=1.13, p=0.32). Patients on high-intensity statin therapy (HIST) were less likely to present with STEMI as compared with low-intensity statin therapy (LIST) or statin naive patients (27%, 38%, 56%, respectively, p for trend <0.0001; HIST ORadj=0.28, p=0.01; LIST ORadj=0.48, p=0.026). ConclusionsAmong patients admitted with ACS, statin use but not LDL-C level, was associated with a lower probability of presenting with STEMI. Patients on HIST had the lowest likelihood of presenting with STEMI.

Elevated absolute monocyte count predicts unfavorable outcomes in patients with angioimmunoblastic T-cell lymphoma

This study was aimed at investigating the prognostic significance of the absolute monocyte count (AMC) in peripheral blood in patients with newly diagnosed angioimmunoblastic T cell lymphoma (AITL). AMC was performed in 73 therapy-naive patients with AITL in 2 institutions during 2008–2015, and higher AMC was observed in those with extranodal sites >1, bone marrow involvement, high lactate dehydrogenase level, the EBV infection, no response to treatment and high IPI, PIT, PIAI score group. The best AMC cut-off level at diagnosis was 0.8×109/L and the 3-year overall survival (OS) was 64% for patients with low AMC group (≤0.8×109/L) compared to 10% in high AMC group (>0.8×109/L) (P<0.001). Multivariate analysis showed that elevated AMC remained an adverse prognostic parameter. Our results suggest that AMC is an independent prognostic parameter for OS in patients with AITL, and AMC >0.8×109/L can routinely be used to identify high-risk patients with unfavorable survival.

Prediction of Recurrence and Survival for Triple-Negative Breast Cancer (TNBC) by a Protein Signature in Tissue Samples

To date, there is no available targeted therapy for patients who are diagnosed with triple-negative breast cancers (TNBC). The aim of this study was to identify a new specific target for specific treatments. Frozen primary tumors were collected from 83 adjuvant therapy-naive TNBC patients. These samples were used for global proteome profiling by iTRAQ-OFFGEL-LC-MS/MS approach in two series: a training cohort (n = 42) and a test set (n = 41). Patients who remains free of local or distant metastasis for a minimum of 5 years after surgery were classified in the no-relapse group; the others were in the relapse group. OPLS and Kaplan-Meier analyses were performed to select candidate markers, which were validated by immunohistochemistry. Three proteins were identified in the training set and validated in the test set by Kaplan-Meier method and immunohistochemistry (IHC): TrpRS as a good prognostic markers and DP and TSP1 as bad prognostic markers. We propose the establishment of an IHC test to calculate the score of TrpRS, DP, and TSP1 in TNBC tumors to evaluate the degree of aggressiveness of the tumors. Finally, we propose that DP and TSP1 could provide therapeutic targets for specific treatments.

The use of readily available biomarkers to predict CD4 cell counts in HIV-infected individuals

Background: The use of readily available biochemical investigations to predict the CD4 cell count in HIV-infected patients may provide clinicians with insight regarding disease severity at first contact. The aims of the study were to determine the relationship of calculated globulin and white cell count (WCC) with CD4 cell count.Methods: Data were collected prospectively from ambulatory HIV-infected, anti-retro viral therapy (ART) naive patients at the HIV clinic of King Edward Hospital, Durban, between 2010 and 2012.Results: The mean age of the participants was 39 ± 9.53 years and 70% were female. Median calculated globulin and WCC was 49 g/l and 4.74 × 109 cells/l respectively, whilst the CD4 cell count was 244 cells/mm3. A significant positive correlation was demonstrated between CD4 cell count and WCC (r = 0.25, p 0.001). WCC and albumin were identified as potential surrogate markers for CD4 count ≤ 200 cells/mm3. Combination of WCC with either albumin or globulin predicts a CD4 count of less than 200 cells/ mm3 with moderate accuracy.Conclusion: The use of combined biomarkers may influence initiation of Pneumocystis jiroveci pneumonia prophylaxis in resource-limited settings. Further evaluation is warranted to assess the role of these markers in disease progression and ART.

The use of readily available biomarkers to predict CD4 cell counts in HIV-infected individuals

Background: The use of readily available biochemical investigations to predict the CD4 cell count in HIV-infected patients may provide clinicians with insight regarding disease severity at first contact. The aims of the study were to determine the relationship of calculated globulin and white cell count (WCC) with CD4 cell count.Methods: Data were collected prospectively from ambulatory HIV-infected, anti-retro viral therapy (ART) naive patients at the HIV clinic of King Edward Hospital, Durban, between 2010 and 2012.Results: The mean age of the participants was 39 ± 9.53 years and 70% were female. Median calculated globulin and WCC was 49 g/l and 4.74 × 109 cells/l respectively, whilst the CD4 cell count was 244 cells/mm3. A significant positive correlation was demonstrated between CD4 cell count and WCC (r = 0.25, p < 0.001). WCC and albumin were identified as potential surrogate markers for CD4 count ≤ 200 cells/mm3. Combination of WCC with either albumin or globulin predicts a CD4 count of less than 2...

Impact of glatiramer acetate on paraclinical markers of neuroprotection in multiple sclerosis: A prospective observational clinical trial

Data from in vitro and animal studies support a neuroprotective role of glatiramer acetate (GA) in multiple sclerosis (MS). We investigated prospectively whether treatment with GA leads to clinical and paraclinical changes associated with neuroprotection in patients with relapsing-remitting (RR) MS. Primary aim of this clinical study was to determine serum BDNF levels in RR-MS patients who were started on GA as compared to patients who remained therapy-naive throughout 24months. Secondary outcomes included relapses and EDSS, cognition, quality of life, fatigue and depression, BDNF expression levels on peripheral immune cells (FACS, RT-PCR), serum anti-myelin basic peptide (MBP) antibody status, evoked potential and cerebral MRI studies. While GA treatment did not alter serum levels or expression levels on peripheral immune cells of BDNF over time it resulted in a transient increase of serum IgG antibody response to MBP, mainly due to subtype IgG1 (p<0.05), after 3months. However, no significant differences were found between GA treated and therapy-naive patients with regard to serum BDNF and intracellular BDNF expression levels, nerve conduction (including median and tibial nerve somatosensory, pattern-shift visual and upper and lower limb motor evoked potentials) or MRI (including volume of hyperintense lesions, volume of hypointense lesions after CE, mean diffusivity and fractional anisotropy) outcome parameters. In conclusion, our findings do not support a major impact of GA treatment on paraclinical markers of neuroprotection in human RR-MS.

Molecular epidemiology of HIV-1 strains in the south-east and east of Turkey

ObjectiveTo detect the subtype characterization and drug-resistant mutations in HIV-1 strains after the refugee movement from Syria to Turkey between 2011 and 2014 in south east border lines. MethodsA total of 65 patients were included in this study, of which 57 (88%) patients were antiretroviral therapy-naive patients. HIV-1 RNA was detected and quantified by real-time PCR assay. HIV-1 subtypes and circulating recombinant forms (CRFs) were identified by phylogenetic analysis (neighbor-joining method), and drug-resistant mutations were analyzed. ResultsThree major HIV groups were indicated. Two of these groups were located in subtype B. The other group showed heterogeneity. Subtype B (48/65, 73.8%), followed by CRFs (12/65, 18.5%) was the most common strain. Subtype of CRFs consisted of CRF01_AE (9/65, 13.8%) and CRF02_AG (3/65, 4.6%). Subtype C (1/65, 1.5%), sub-subtypes A1 (2/65, 3.1%) and F1 (2/65, 3.1%) were also detected with low prevalence. The rate of overall primary antiretroviral resistance was 4.9% (3/61). Drug-resistant rate for non-nucleoside reverse transcriptase inhibitors was 4.9%. The thymidine analogue mutation rate was 13.1% (8/61). ConclusionsHIV molecular epidemiology studies are necessary to determine transmission patterns and spread. Subtype B and CRF01_AE, CRF02_AG are the most prevalent strains in the south-east of Turkey. However, subtype C, sub-subtypes A1 and F1 are of low prevalence but persist in the south-east of Turkey. In the near future, changing of HIV epidemiology will be possible in Turkey due to migration movement in border lines and resistance testing will play an important role in HIV management.

Interferon-Beta Therapy of Multiple Sclerosis Patients Improves the Responsiveness of T Cells for Immune Suppression by Regulatory T Cells.

Multiple sclerosis (MS) is an inflammatory autoimmune disease characterized by imbalanced immune regulatory networks, and MS patient-derived T effector cells are inefficiently suppressed through regulatory T cells (Treg), a phenomenon known as Treg resistance. In the current study we investigated T cell function in MS patients before and after interferon-beta therapy. We compared cytokine profile, responsiveness for Treg-mediated suppression ex vivo and evaluated reactivity of T cells in vivo using a humanized mouse model. We found that CD4+ and CD8+ T cells of therapy-naive MS patients were resistant to Treg-mediated suppression. Treg resistance is associated with an augmented IL-6 production, enhanced IL-6 receptor expression, and increased PKB/c-Akt phosphorylation. These parameters as well as responsiveness of T cells to Treg-mediated suppression were restored after interferon-beta therapy of MS patients. Following transfer into immunodeficient mice, MS T cells induced a lethal graft versus host disease (GvHD) and in contrast to T cells of healthy volunteers, this aggressive T cell response could not be controlled by Treg, but was abolished by anti-IL-6 receptor antibodies. However, magnitude and lethality of GvHD induced by MS T cells was significantly decreased after interferon-beta therapy and the reaction was prevented by Treg activation in vivo. Our data reveals that interferon-beta therapy improves the immunoregulation of autoaggressive T effector cells in MS patients by changing the IL-6 signal transduction pathway, thus restoring their sensitivity to Treg-mediated suppression.

Reduced Bone Mineral Density Among ART-Naive Male Patients with HIV in China

Aims: To evaluate the prevalence and associated factors of reduced bone mineral density (BMD) among antiretroviral therapy (ART) naive HIV-infected male patients in China. Methods: We compared BMD between HIV-infected male patients and healthy controls. Risk factors of reduced BMD were studied using multivariable linear regression. Results: Reduced BMD rate of chronic HIV infection patients was higher. HIV infection was independently associated with decreased BMD after adjusting for demographic factors. Older age, lower BMI and men who have sex with men (MSM) were revealed as the risk factors of lower BMD in HIV-infected male patients. Conclusion: Reduced BMD rate of HIV-infected patients was high. Policies are needed for prevention and treatment.

Sarcoidosis in Melanoma Patients: Case Report and Literature Review.

Sarcoidosis is a systemic inflammatory disease characterized by the development of noncaseating granulomas in multiple organ systems. Many hematologic malignancies and solid tumors, including melanoma, have been associated with sarcoidosis. We describe the clinical and pathologic findings of a 54-year-old man with melanoma-associated sarcoidosis. In addition, we not only review the literature describing characteristics of other melanoma patients with sarcoidosis, but also the features of melanoma patients with antineoplastic therapy-associated sarcoidosis. Sarcoidosis has been described in 80 melanoma patients; sufficient information for analysis was provided in 39 of these individuals. In 43.6% of individuals (17 out of 39), sarcoidosis was directly associated with melanoma; in 56.4% of oncologic patients (22 out of 39), sarcoidosis was induced by antineoplastic therapy that had been administered for the treatment of their metastatic melanoma. The discovery of melanoma preceded the development of sarcoidosis in 12 of the 17 (70.5%) individuals who did not receive systemic treatment. Pulmonary and/or cutaneous manifestations of sarcoidosis were common among both groups of patients. Most patients did not require treatment for sarcoidosis. Melanoma patients—either following antineoplastic therapy or without systemic treatment—may be at an increased risk to develop sarcoidosis. In antineoplastic therapy naive melanoma patients, a common etiologic factor—such as exposure to ultraviolet light—may play a role in their developing melanoma and sarcoidosis.

P112: Hepatitis C virus NS3 polymorphism Q80K in genotype 1 therapy‐naive Brazilian patients

Journal of Viral HepatitisVolume 22, Issue S2 p. 77-77 Poster PresentationFree Access P112: Hepatitis C virus NS3 polymorphism Q80K in genotype 1 therapy-naive Brazilian patients First published: 25 June 2015 https://doi.org/10.1111/jvh.106_12425AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume22, IssueS2Special Issue: 15th International Symposium on Viral Hepatitis and Liver Diseases (ISVHLD) held from June 26th to 28th, 2015, in Berlin, GermanyJune 2015Pages 77-77 RelatedInformation

Transmitted Drug Resistance Among Recently Diagnosed Adults and Children in São Paulo, Brazil

Transmitted drug resistance mutations (TDRM) have been a constant threat to treatment efficacy. We evaluated TDRM in plasma RNA of 217 antiretroviral therapy-naive patients from sites in the São Paulo metropolitan area, collected from 2012 to 2014. The partial HIV-1 polymerase region was sequenced using Big Dye terminators at an ABI 3130 Genetic Analyzer. TDRM was defined according to the Stanford database calibrated population resistance (CPR v.6.0), but other drug resistance mutations (DRM) considered at the IAS list (IAS, 2014) and at the Stanford HIV Database Genotyping Resistance Interpretation (GRI-HIVdb) were also described. Out of 78% (170/217) of patients with information on the time of diagnosis, most (83%, 141/170) had been recently diagnosed, with the first positive HIV serology at a median of 58 days (IQR 18-184). Subtype B predominated (70%), followed by subtype F (10%), BF (7.5%), C (7.5%), and BC (5%). TDRMs were observed in 9.2% (20/217, CI 95% 5.9% to 13.6%), mostly (5.2%) to nonnucleoside reverse transcriptase inhibitor (NNRTI) antiretroviral class. Among children and adolescents, only a single patient showed TDRMs. Additional non-CPR mutations were observed: 11.5% (25/217) according to IAS or 4.6% (10/217) according to GRI-HIVdb. Overall, 23.5% (51/217) of the cases had one or more DRM identified. TDRM prevalence differed significantly among some sites. These trends deserve continuous and systematic surveillance, especially with the new policies of treatment as prevention being implemented in the country.

C-Reactive Protein in Idiopathic Inflammatory Myopathies

AbstractObjectives: To characterize C-reactive protein [CRP] in polymyositis [PM], dermatomyositis [DM], Jo-1 syndrome [Jo-1] and sporadic inclusion body myositis [sIBM].Methods: C-reactive protein obtained before the start of immunosuppressive therapy was analyzed retrospectively in 61 therapy naive patients [PM n = 27, DM n = 15, Jo-1 n = 5, sIBM n = 14]. All patients had a diagnosis of idiopathic inflammatory myopathy confirmed by muscle biopsy.Results: C-reactive protein was significantly higher in DM and Jo-1 compared to PM and sIBM [ANOVA p < 0.001]. The CRP levels less than twice the upper limit were found in 79% of sIBM patients, 85% of PM patients, 20% Jo-1 of patients, 53% of DM patients. C-reactive protein showed no correlation with creatine kinase and erythrocyte sedimentation rate.Conclusions: The CRP is elevated in a minority of patients with myositis, mostly associated with interstitial lung disease and malignancies.

CCAAT/Enhancer binding protein β controls androgen-deprivation-induced senescence in prostate cancer cells.

The processes associated with transition to castration independent prostate cancer growth are not well understood. Cellular senescence is a stable cell cycle arrest that occurs in response to sublethal stress. It is often overcome in malignant transformation to confer a survival advantage. CCAAT/Enhancer Binding Protein (C/EBP) β function is frequently deregulated in human malignancies and interestingly, androgen dependent prostate cancer cells express primarily the LIP isoform. We found that C/EBPβ expression is negatively regulated by androgen receptor activity and that treatment of androgen dependent cell lines with anti-androgens increases C/EBPβ mRNA and protein levels. Accordingly, we also find that C/EBPβ levels are significantly elevated in primary prostate cancer samples from castration resistant compared with therapy naive patients. Chromatin immunoprecipitation demonstrated enhanced binding of the androgen receptor to the proximal promoter of the CEBPB gene in the presence of dihydroxytestosterone. Upon androgen deprivation, induction of C/EBPβ is facilitated by active transcription as evident by increased histone 3 acetylation at the C/EBPβ promoter. Also, the androgen agonist R1881 suppresses the activity of a CEBPB promoter reporter. Loss of C/EBPβ expression prevents growth arrest following androgen deprivation or anti-androgen challenge. Accordingly, suppression of C/EBPβ under low androgen conditions results in reduced expression of senescence-associated secretory genes, significantly decreased number of cells displaying heterochromatin foci, and increased numbers of Ki67 positive cells. Ectopic expression of C/EBPβ caused pronounced morphological changes, reduced PC cell growth, and increased the number of senescent LNCaP cells. Lastly, we found that senescence contributes to prostate cancer cell survival under androgen deprivation, and C/EBPβ deficient cells were significantly more susceptible to killing by cytotoxic chemotherapy following androgen deprivation. Our data demonstrate that up-regulation of C/EBPβ is critical for complete maintenance of androgen deprivation induced senescence and that targeting C/EBPβ expression may synergize with anti-androgen or chemotherapy in eradicating prostate cancer.

Increased Lysyl oxidase-like 2 (LOXL2) gene expression accurately designates advanced liver fibrosis induced by the Hepatitis C Virus (HCV) regardless race, blood specimen or co-infection with the Human Immunodeficiency Virus (HIV)

Background: The LOX gene encodes a member of the lysyl-oxidase (LOX) gene family, which is involved in biogenesis of connective tissue, and 4 LOX-like proteins (LOXL1 – 4) have been identified so far. This study was aimed to investigate gene expression of LOXL1 – 4 in association with fibrogenesis in Hepatitis C Virus (HCV) infected patients with and without co-infection with the Human Immundeficiency Virus (HIV) in peripheral blood mononuclear cells (PBMC), peripheral whole blood (PwB) and liver tissue (LT) samples. Materials and Methods: PwB samples from 34 therapy-naive patients (34/34 Caucasians, 18/34 males, 28/34 with HCV-genotype-1) with chronic HCV infection treated at the University Hospital Essen (Germany) and PBMC samples from 23 HIV/HCV co-infected subjects (11/23 African Americans and none Caucasian, 20/23 males, 23/23 with HCV-genotype-1) recruited at the NIAID/NIH (MD/U.S.A.) were enrolled in this study. Liver biopsies obtained at baseline were evaluated using the Batts-Ludwig staging (BL-S) system for HCV mono-infected patients and the Ishak score (IS) for HIV/HCV co-infected donors. 34 PwB and 23 PBMC samples (and 7 LT samples from HIV/HCV co-infected participants) were subjected to microarray analysis. For all statistical analyses (i.e. pair-wise group comparison) 1-way-ANOVA was performed. Overall, a P< 0.05 was considered significant. Results: PwB samples from 34 HCV mono-infected patients were grouped according to BL-S as early fibrosis (BL-S: 0 – 1, “EF”, N= 20,) and late fibrosis (BL-S: 2 – 4, “LF”, N= 14) and PBMC samples from 23 HIV/HCV co-infected patients were grouped based on IS as early fibrosis (IS: 0 – 2, “EF”, N= 20) and late fibrosis (IS: 3 – 6, “LF”, N= 14). We consistently detected significantly increased LOXL-2 gene expression levels in association with “LF” in HCV mono-infected patients (PwB, P< 0.041) and HIV/HCV co-infected subjects (PBMC, P< 0.038). In addition, linear regression analysis was performed between fibrosis grades (IS: 0 – 6) and LOXL1 – 4 gene expression levels measured in LT samples of 7 HIV/HCV co-infected subjects; here, a significant correlation was found only for LOXL1 (r= 0.8, P> 0.031). These results are currently being validated by quantitative real-time polymerase chain reaction (qRT-PCR). Conclusions: This study suggests significant involvement of LOX-like proteins, especially LOXL2, in the fibrogenic liver transformation process during chronic HCV infection. Previous research reported: 1. Association between increased mRNA levels of LOXL2 and type-III-procollagen in liver fibrosis in mice. 2. Abnormal deposition of collagen in hepatocytes obtained from humans with Wilson's disease. 3. LOXL2 involvement in fibroblast activation. These findings (1.-3.) along with the present data demonstrating consistent significance in two demographically very heterogeneous cohorts further highlight the pathogenic role suggested for LOXL in fibrogenesis and the importance of generating LOXL2-targeted therapies for the prevention/treatment of liver fibrosis.

The Adventitial Angioproliferation in Human Immunodeficiency Virus Associated Large Artery Vasculopathy is Not a Manifestation of Kaposi Sarcoma

Introduction: Human immunodeficiency virus-associated large artery vasculopathy (HIV-vasculopathy) is characterized by distinctive transmural microanatomical alterations, including adventitial angioproliferation, similar to that described in early cutaneous Kaposi sarcoma (KS). Human herpesvirus-8 (HHV8), the etiological agent of KS, is identifiable in tissue sections. The aim of this study was to investigate, based on HHV8-latent nuclear antigen-1 (HHV8-LNA-1) immunohistochemical and HHV8 polymerase chain reaction (PCR) testing, whether KS is the cause of the angioproliferation. Materials and Methods: Sections from 20 large arteries, ten each with HIV-associated occlusive and aneurysmal vasculopathy and ten biopsies with early cutaneous KS from 30 anti-retroviral therapy naive patients were appraised microscopically and subjected to HHV8-LNA-1 immunostaining. Arterial sections were also subjected to HHV8 PCR investigation with appropriate positive and negative controls. Results: The microscopic large arterial adventitial alterations included a dissecting proliferation of capillary-caliber vasculature, surrounded by mixed inflammation, microhemorrhages, hemosiderin and vasa vasorum intimomedial fibrosis, and hypertrophy. Ten vessels also demonstrated adventitial leukocytoclastic and lymphocytic vasculitis. Immunohistochemical and PCR detection of HHV8 was consistently negative. Skin biopsies of KS shared the vascular adventitial alterations, but vasculitis and thrombosis were absent. Endothelial and dermal spindle cells were immunopositive for HHV8. Conclusion: The adventitial angioproliferation in large arteries with HIV-vasculopathy is not a manifestation of KS. The exact roles of HIV, including interaction with co-infective agents and cellular and subcellular responses in the induction of vasculopathic and vasa vasorum abnormalities, including adventitial angioinflammatory alterations, require accelerated investigation for improved disease understanding and patient management.

A cost-effectiveness model to personalize antiviral therapy in naive patients with genotype 1 chronic hepatitis C

Background and aimsRapid virologic response is the best predictor of sustained virologic response with dual therapy in genotype-1 chronic hepatitis C, and its evaluation was proposed to tailor triple therapy in F0–F2 patients. Bio-mathematical modelling of viral dynamics during dual therapy has potentially higher accuracy than rapid virologic in the identification of patients who will eventually achieve sustained response. Study's objective was the cost-effectiveness analysis of a personalized therapy in naïve F0–F2 patients with chronic hepatitis C based on a bio-mathematical model (model-guided strategy) rather than on rapid virologic response (guideline-guided strategy). MethodsA deterministic bio-mathematical model of the infected cell dynamics was validated in a cohort of 135 patients treated with dual therapy. A decision-analytic economic model was then developed to compare model-guided and guideline-guided strategies in the Italian setting. ResultsThe outcomes of the cost-effectiveness analysis with model-guided and guideline-guided strategy were 19.1–19.4 and 18.9–19.3 quality-adjusted-life-years. Total per-patient lifetime costs were €25,200–€26,000 with model-guided strategy and €28,800–€29,900 with guideline-guided strategy. When comparing model-guided with guideline-guided strategy the former resulted more effective and less costly. ConclusionsThe adoption of the bio-mathematical predictive criterion has the potential to improve the cost-effectiveness of a personalized therapy for chronic hepatitis C, reserving triple therapy for those patients who really need it.

Limited clinical benefit of minority K103N and Y181C-variant detection in addition to routine genotypic resistance testing in antiretroviral therapy-naive patients.

The presence of minority nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV-1 variants prior to antiretroviral therapy (ART) has been linked to virologic failure in treatment-naive patients. We performed a large retrospective study to determine the number of treatment failures that could have been prevented by implementing minority drug-resistant HIV-1 variant analyses in ART-naïve patients in whom no NNRTI resistance mutations were detected by routine resistance testing. Of 1608 patients in the Swiss HIV Cohort Study, who have initiated first-line ART with two nucleoside reverse transcriptase inhibitors (NRTIs) and one NNRTI before July 2008, 519 patients were eligible by means of HIV-1 subtype, viral load and sample availability. Key NNRTI drug resistance mutations K103N and Y181C were measured by allele-specific PCR in 208 of 519 randomly chosen patients. Minority K103N and Y181C drug resistance mutations were detected in five out of 190 (2.6%) and 10 out of 201 (5%) patients, respectively. Focusing on 183 patients for whom virologic success or failure could be examined, virologic failure occurred in seven out of 183 (3.8%) patients; minority K103N and/or Y181C variants were present prior to ART initiation in only two of those patients. The NNRTI-containing, first-line ART was effective in 10 patients with preexisting minority NNRTI-resistant HIV-1 variant. As revealed in settings of case-control studies, minority NNRTI-resistant HIV-1 variants can have an impact on ART. However, the implementation of minority NNRTI-resistant HIV-1 variant analysis in addition to genotypic resistance testing (GRT) cannot be recommended in routine clinical settings. Additional associated risk factors need to be discovered.

Genetic Variability and Clinical Presentation of Patients with Non-Small Cell Lung Cancer (Nsclc) Harboring Met-Amplifications

ABSTRACT Aim: cMET (MNNG HOS Transforming gene) is a proto-oncogene encoding the hepatocyte growth factor receptor (HGFR) with HGF as the only known ligand. Whereas the role of cMET mutations in NSCLC patients remains debated controversively, amplification of cMET is considered as one of the molecular resistance mechanisms in EGFR-mutated NSCLCs treated with 1st or 2nd generation EGFR-TKIs. Further, at least for high-level amplifications, these aberrations might be a possible target for cMET-targeted therapy also in EGFR-wt patients. Nevertheless, much is unknown about the contribution and the impact of cMET amplifications regarding their prognostic or predictive value. Methods: Beside the screening of rebiopsied EGFR-TKI-resistant patients, cMET amplification status as assessed by fluorescence in-situ hybridization (FISH) was also analyzed in therapy-naive patients. A cohort of 588 patients was analyzed using FISH and next-generation sequencing (NGS). The amplifications were categorized as low-level, intermediate, and high-level amplifications. Results: 171 patients with cMET amplification were identified, whereof 11 (6.4%) had a high-level amplification. cMET amplifications cooccured with a large spectrum of other driver mutations (EGFR, KRAS, HER2, STK11, NRAS, BRAF) or amplifications (FGFR1) in both therapy-naive and treated patients, and smoking status represented the known associations (i. e., low smoking association in patients with EGFR mutations, high association in patients with KRAS and NRAS mutations). The amplifications occurred in both adenocarcinoma and squamous cell carcinoma. Preliminary data suggest that low-level amplifications beside EGFR mutations in therapy-naive patients do not alter the predictive value of the EGFR mutation. Conclusions: The preliminary data suggests a higher prevalence of cMET amplifications in a broad spectrum on NSCLC patients. Furthermore, cMET amplifications are not exclusive for EGFR-mutated patients with acquired resistance to EGFR-directed therapy. Preliminary data suggest that low-level amplification does not lead to EGFR-TKI resistance. Disclosure: All authors have declared no conflicts of interest.