Cardiovascular disease (CVD) is the leading cause of death worldwide and new approaches for both diagnosis and treatment are required. Autoantibodies directed against apolipoprotein A-I (ApoA-I) represent promising biomarkers for use in risk stratification of CVD and may also play a direct role in pathogenesis.
To characterize the anti-ApoA-I autoantibody response, we measured the immunoreactivity to engineered peptides corresponding to the different alpha-helical regions of ApoA-I, using plasma from acute chest pain cohort patients known to be positive for anti-ApoA-I autoantibodies.
Our results indicate that the anti-ApoA-I autoantibody response is strongly biased towards the C-terminal alpha-helix of the protein, with an optimized mimetic peptide corresponding to this part of the protein recapitulating the diagnostic accuracy for an acute ischemic coronary etiology (non-ST segment elevation myocardial infarction and unstable angina) obtainable using intact endogenous ApoA-I in immunoassay. Furthermore, the optimized mimetic peptide strongly inhibits the pathology-associated capacity of anti-ApoA-I antibodies to elicit proinflammatory cytokine release from cultured human macrophages.
In addition to providing a rationale for the development of new approaches for the diagnosis and therapy of CVD, our observations may contribute to the elucidation of how anti-ApoA-I autoantibodies are elicited in individuals without autoimmune disease.

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Patients with previously untreated BRAF V600E mutation-positive melanoma in BREAK-3 showed a median overall survival (OS) of 18.2 months for dabrafenib versus 15.6 months for dacarbazine (hazard ratio [HR], 0.76; 95% confidence interval, 0.48-1.21). Because patients receiving dacarbazine were allowed to switch to dabrafenib at disease progression, we attempted to adjust for the confounding effects on OS.
Rank preserving structural failure time models (RPSFTMs) and the iterative parameter estimation (IPE) algorithm were used. Two analyses, "treatment group" (assumes treatment effect could continue until death) and "on-treatment observed" (assumes treatment effect disappears with discontinuation), were used to test the assumptions around the durability of the treatment effect.
A total of 36 of 63 patients (57%) receiving dacarbazine switched to dabrafenib. The adjusted OS HRs ranged from 0.50 to 0.55, depending on the analysis. The RPSFTM and IPE "treatment group" and "on-treatment observed" analyses performed similarly well.
RPSFTM and IPE analyses resulted in point estimates for the OS HR that indicate a substantial increase in the treatment effect compared with the unadjusted OS HR of 0.76. The results are uncertain because of the assumptions associated with the adjustment methods. The confidence intervals continued to cross 1.00; thus, the adjusted estimates did not provide statistically significant evidence of a treatment benefit on survival. However, it is clear that a standard intention-to-treat analysis will be confounded in the presence of treatment switching-a reliance on unadjusted analyses could lead to inappropriate practice. Adjustment analyses provide useful additional information on the estimated treatment effects to inform decision making.
Treatment switching is common in oncology trials, and the implications of this for the interpretation of the clinical effectiveness and cost-effectiveness of the novel treatment are important to consider. If patients who switch treatments benefit from the experimental treatment and a standard intention-to-treat analysis is conducted, the overall survival advantage associated with the new treatment could be underestimated. The present study applied established statistical methods to adjust for treatment switching in a trial that compared dabrafenib and dacarbazine for metastatic melanoma. The results showed that this led to a substantially increased estimate of the overall survival treatment effect associated with dabrafenib.
©AlphaMed Press.

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The treatment of autoimmune disorders has been revolutionised by the introduction of biologics such as anti-tumour necrosis factor (anti-TNF). Although in rheumatoid arthritis patients a bone sparing effect of anti-TNF has been shown, the mechanism is not fully understood. Anti-TNF molecules block tumour necrosis factor (TNF) and prevent signalling via both TNF receptor 1 (TNFR1; p55) and TNF receptor 2 (TNFR2; p75). However, signalling via TNFR2 is reported to have protective effects in a number of cell and organ systems. Hence we set out to investigate if pharmacological inhibition of TNFR1 had differential effects compared to pan-TNF inhibition in both an in vitro cell-based model of human osteoclast activity and an in vivo mouse model of lipopolysaccharide (LPS)-induced osteolysis. For the in vitro experiments the anti-human TNFR1 domain antibody (dAb) DMS5541 was used, whereas for the in vivo mouse experiments the anti-mouse TNFR1 dAb DMS5540 was used. We show that selective blocking of TNFR1 signalling reduced osteoclast formation in the presence of TNF. Subcutaneous LPS injection over the calvaria leads to the development of osteolytic lesions within days due to inflammation driven osteoclast formation. In this model, murine TNFR2 genetically fused with mouse IgG1 Fc domain (mTNFR2.Fc), an anti-TNF, did not protect from bone loss in contrast to anti-TNFR1, which significantly reduced lesion development, inflammatory infiltrate, and osteoclast number and size. These results support further exploring the use of TNFR1-selective inhibition in inflammatory bone loss disorders such as osteomyelitis and peri-prosthetic aseptic loosening.
Copyright © 2015 Elsevier Inc. All rights reserved.

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We had previously developed an algorithm for Medicare claims data to detect bone metastases associated with breast, prostate, or lung cancer. This study was conducted to examine whether this algorithm accurately documents bone metastases on the basis of diagnosis codes in Medicare claims data.
We obtained data from Medicare claims and electronic medical records of patients 65 years or older with a breast, prostate, or lung cancer diagnosis at a teaching hospital and/or affiliated clinics during 2005 or 2006. We calculated the sensitivity and positive predictive value (PPV) of our algorithm using medical records as the "gold standard." The κ statistic was used to measure agreement between claims and medical record data.
The agreement between claims and medical record data for bone metastases among breast, prostate, and lung cancer patients was 0.93, 0.90, and 0.69, respectively. The sensitivities of our algorithm for bone metastasis in patients with breast, prostate, and lung were 96.8% [95% confidence interval (CI)=83.8% to 99.4%], 91.7% (95% CI=78.2% to 97.1%), and 74.1% (95% CI=55.3% to 86.8%), respectively; and the PPVs were 90.9% (95% CI=76.4% to 96.9%), 91.7% (95% CI=78.2% to 97.1%), and 71.4% (95% CI=52.9% to 84.8%), respectively.
The algorithm for detecting bone metastases in claims data had high sensitivity and PPV for breast and prostate cancer patients. Sensitivity and PPV were lower but still moderate for lung cancer patients.

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To describe treatment patterns, outcomes and healthcare resource use in patients with metastatic and/or locally recurrent, unresectable gastric cancer (MGC) in Taiwan.
Patients who had received first-line therapy (platinum and/or fluoropyrimidine) followed by second-line therapy or best supportive care (BSC) only were eligible. Participating physicians provided de-identified information from patient charts. Data were summarized descriptively and Kaplan-Meier analysis was used to describe time to events.
Overall, 37 physicians contributed 122 patient charts. Of the 122 patients (median age, 61 years; 62% male), 43 (35%) received BSC only following first-line therapy, whereas 79 (65%) received second-line therapy. There was heterogeneity in second-line treatment, although fluoropyrimidine with or without a platinum agent was most frequently used. Median survival was 12.5 (interquartile range [IQR], 8.2-20.8) months from MGC diagnosis for patients receiving second-line therapy and 8.0 (IQR, 5.6-not reached) months for patients receiving BSC only. The most common treatment-related symptoms were nausea/vomiting (58%); the most common cancer-related symptoms were pain (61%), ascites (35%) and nausea/vomiting (33%). Inpatient and outpatient hospitalizations were numerically more common for patients receiving second-line therapy than for those receiving BSC only; the prevalence of hospice and skilled nursing facility stays were numerically more common for patients receiving BSC only.
In this Taiwanese MGC population, 65% received active second-line therapy with heterogeneity seen in the regimen used. Clinical outcomes suggest an unmet medical need in this population. This study may help inform clinical practice and future research to ultimately improve patient outcomes in Taiwan.
© 2016 John Wiley & Sons Australia, Ltd.

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