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PurposeTo observe the late toxicities in nasopharyngeal carcinoma (NPC) patients who achieved long-term survival after intensity modulated radiation therapy (IMRT).Methods208 untreated NPC patients who received IMRT and survived more than five years with locoregional disease control and no metastasis were evaluated in this study. The prescription dose to the gross target volume of nasopharynx (GTVnx), positive neck lymph nodes (GTVnd), clinical target volume 1 (CTV1) and 2 (CTV2) was 68Gy/30f, 60-66Gy/30f, 60 Gy/30f and 54Gy/30f, respectively. The nasopharynx and upper neck targets were irradiated using IMRT, and the lower neck and supraclavicular fossae targets were irradiated using the half-beam technique with conventional irradiation. The late toxicities were evaluated according to the LENT/SOMA criteria of 1995.ResultsThe median follow-up time was 78 months (60–96 months). The occurrence rates of cervical subcutaneous fibrosis, hearing loss, skin dystrophy, xerostomia, trismus, temporal lobe injury, cranial nerve damage, cataract, and brain stem injury induced by radiotherapy were 89.9%, 67.8%, 47.6%, 40.9%, 7.21%, 4.33%, 2.88%, 1.44%, and 0.48%, respectively. No spinal cord injury and mandible damage were found. Grade 3–4 late injuries were observed as follows: 1 (0.48%) skin dystrophy, 4 (1.92%) cervical subcutaneous fibrosis, 2 (0.96%) hearing loss, 2 (0.96%) cranial nerve palsy, and 1 (0.48%) temporal lobe necrosis. No grade 3–4 late injuries occurred in parotid, temporomandibular joints and eyes. Xerostomia decreased gradually over time and then showed only slight changes after 4 years. The change in the incisor distance stabilised by 1 year after RT, however, the incidence of hearing loss, skin dystrophy, subcutaneous fibrosis and nervous system injuries increased over time after RT.ConclusionThe late injuries in most NPC patients who had long-term survivals after IMRT are alleviated. Within the 5 years of follow-up, we found xerostomia decreased gradually; The change in the incisor distance stabilised by 1 year after RT; while hearing loss, nervous system injuries increased over time after RT.

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AimIn the EMPA‐REG OUTCOME trial, empagliflozin therapy reduced cardiovascular death by 38% compared with placebo when added to standard of care. Using the trial results, we created a discrete‐event simulation model to assess lifetime health economic outcomes in people with Type 2 diabetes and established cardiovascular disease.MethodsTime‐dependent survival regression analysis was performed on data from EMPA‐REG OUTCOME for 10 cardiovascular and renal events (e.g. stroke, heart failure hospitalization, macroalbuminuria, cardiovascular mortality) to capture event rates over time, and interaction between events. Model performance was assessed by comparing predicted and observed outcomes at 3 years. Costs in the United Kingdom (UK) and health utilities were obtained from published literature. Outcomes included cumulative event rates, life‐years, costs and quality‐adjusted life‐years (QALYs).ResultsThe model predicted an 18% relative increase (by 2.1 life‐years) in survival for empagliflozin (14.0 life‐years) vs. standard of care (11.9 life‐years), attributable to direct treatment effect on cardiovascular mortality, and to indirect effect via reductions in other events. Participants treated with empagliflozin may experience improved quality of life (1.0 QALY) and higher costs (£3737/participant), yielding an incremental cost‐effectiveness ratio (ICER) of £4083/QALY. Sensitivity analyses confirmed the robustness of these results to changes in input parameters.ConclusionsBased on extrapolation of EMPA‐REG OUTCOME trial data using a participant‐level simulation model, empagliflozin in addition to standard of care is projected to be highly cost‐effective using UK healthcare costs. The impact in other countries will vary due to differences in drug pricing and accrual of other costs. (Clinical Trial Registry No: NCT01131676)

BackgroundIvabradine is a heart rate–lowering agent approved to reduce the risk of hospitalization for worsening heart failure. This study assessed the cost‐effectiveness of adding ivabradine to background therapy in the United States from the perspective of a commercial or Medicare Advantage payer.Methods and ResultsA cost‐effectiveness, cohort‐based Markov model using a state transition approach tracked a cohort of heart failure patients with heart rate ≥70 beats per minute in sinus rhythm who were treated with ivabradine+background therapy or background therapy alone. Model inputs, including adjusted hazard ratios, rates of hospitalization and mortality, adverse events, and utility‐regression equations, were derived from a large US claims database and SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial). In the commercial population, ivabradine+background therapy was associated with a cost savings of $8594 versus the cost of background therapy alone over a 10‐year time horizon, primarily because of reduced hospitalization. Ivabradine was associated with an incremental benefit of 0.24 quality‐adjusted life years over a 10‐year time horizon. In the Medicare Advantage population, the incremental cost‐effectiveness ratio for ivabradine was estimated to be $24 920/quality‐adjusted life years.ConclusionsThe cost‐effectiveness model suggests that for a commercial population, the addition of ivabradine to background therapy was associated with cost savings and improved clinical outcomes. For a Medicare Advantage population, the analysis indicates that the clinical benefit of ivabradine can be achieved at a reasonable cost.

BackgroundSeveral studies on the association of TNF-alpha (−308 G/A), IL-6 (−174 G/C) and IL-1beta (−511 C/T) polymorphisms with polycystic ovary syndrome (PCOS) risk have reported conflicting results. The aim of the present study was to assess these associations by meta-analysis.ResultsA total of 14 eligible articles (1665 cases/1687 controls) were included in this meta-analysis. The results suggested that there was no obvious association between the TNF-alpha (−308 G/A) polymorphism and PCOS in the overall population or subgroup analysis by ethnicity, Hardy–Weinberg equilibrium (HWE) in controls, genotyping method, PCOS diagnosis criteria, and study sample size. Also, no obvious association was found between the TNF-alpha (−308 G/A) polymorphism and obesity in patients with PCOS (body mass index [BMI] ≥ 25 kg/m2 vs. BMI < 25 kg/m2). Regarding the IL-6 (−174 G/C) polymorphism, also no association was found in the overall population in heterozygote comparison, dominant model, and recessive model. Even though an allelic model (odds ratio [OR] = 0.63, 95% confidence interval [CI] = 0.41–0.96) and a homozygote comparison (OR = 0.52, 95% CI = 0.30–0.93) showed that the IL-6 (−174 G/C) polymorphism was marginally associated with PCOS. Further subgroup analysis suggested that the effect size was not significant among HWE in controls (sample size ≤ 200) and genotyping method of pyrosequencing under all genetic models. Similarly, there was no association between the IL-1beta (−511 C/T) polymorphism and PCOS in the overall population or subgroup analysis under all genetic models. Furthermore, no significant association was found between the IL-1beta (−511 C/T) polymorphism and several clinical and biochemical parameters in patients with PCOS.ConclusionsThe results of this meta-analysis suggest that the TNF-alpha (−308 G/A), IL-6 (−174 G/C), and IL-1beta (−511 C/T) polymorphisms may not be associated with PCOS risk. However, further case–control studies with larger sample sizes are needed to confirm our results.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-015-0165-4) contains supplementary material, which is available to authorized users.