Development and validation of a cell cycle progression signature for decentralized testing of men with prostate cancer.

Aim: The 46-gene Prolaris® cell cycle progression test provides information on the risk of prostate cancer progression. Here we developed and validated a 16-gene kit-based version. Methods: RNA was extracted from prostate cancer biopsy tissue. Amplification efficiency, minimum tumor content, repeatability, reproducibility and equivalence with the 46-gene test were evaluated. Results: Amplification efficiencies for all genes were within the acceptable range (90-110%), and samples with ≥50% tumor content were appropriate for the 16-gene test. Results were repeatable (standard deviation: 0.085) and reproducible (standard deviation: 0.115). Instrument, operator and kit lot had minimal impact on results. Cell cycle progression scores from the 46- and 16-gene tests were highly correlated (r = 0.969; bias = 0.217). Conclusion: The 16-gene test performs consistently and similarly to the 46-gene test.

Prostate cancer does not always require aggressive treatment, and some men with low risk of disease progression may chose active surveillance. One way to measure the risk of disease progression is the Prolaris^® cell cycle progression test, which is performed at a commercial testing facility and measures the expression of 46 genes. However, certain European countries would prefer to run this test at a centralized testing facility. To this end we developed a streamlined kit measuring 16 genes to be used in these testing facilities, and showed that the cell cycle progression scores derived from the kit test are robust and equivalent to those obtained with the larger 46-gene test.

Comparison of EndoPredict and EPclin With Oncotype DX Recurrence Score for Prediction of Risk of Distant Recurrence After Endocrine Therapy.

BACKGROUND: Estimating distant recurrence (DR) risk among women with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2 (HER2)-negative early breast cancer helps decisions on using adjuvant chemotherapy. The 21-gene Oncotype DX recurrence score (RS) is widely used for this. EndoPredict (EPclin) is an alternative test combining prognostic information from an eight-gene signature (EP score) with tumor size and nodal status. We compared the prognostic information provided by RS and EPclin for 10-year DR risk. METHODS: We used likelihood ratio χ² and Kaplan-Meier survival analyses to compare prognostic information provided by EP, EPclin, RS, and the clinical treatment score (CTS) of clinicopathologic parameters in 928 patients with ER+ disease treated with five years' anastrozole or tamoxifen. Comparisons were made for early (0-5 years) and late (5-10 years) DR according to nodal status. All statistical tests were two-sided. RESULTS: In the overall population, EP and EPclin provided substantially more prognostic information than RS (LRχ(2): EP = 49.3; LRχ(2): EPclin = 139.3; LRχ(2): RS = 29.1), with greater differences in late DR and in node-positive patients. EP and EPclin remained statistically significantly prognostic when adjusted for RS (ΔLRχ(2): EP+RS vs RS = 20.2; ΔLRχ(2): EPclin+RS vs RS = 113.8). Using predefined cut-offs, EPclin and RS identified 58.8% and 61.7% patients as low risk, with hazard ratios for non-low vs low risk of 5.99 (95% confidence interval [CI] = 3.94 to 9.11) and 2.73 (95% CI = 1.91 to 3.89), respectively. CONCLUSIONS: EP and EPclin were highly prognostic for DR in endocrine-treated patients with ER+, HER2-negative disease. EPclin provided more prognostic information than RS. This was partly but not entirely because of EPclin integrating molecular data with nodal status and tumor size.

Specific Metabolic Profiles and Their Relationship to Insulin Resistance in Recent-Onset Type 1 and Type 2 Diabetes.

CONTEXT: Insulin resistance reflects the inadequate insulin-mediated use of metabolites and predicts type 2 diabetes (T2D) but is also frequently seen in long-standing type 1 diabetes (T1D) and represents a major cardiovascular risk factor. OBJECTIVE: We hypothesized that plasma metabolome profiles allow the identification of unique and common early biomarkers of insulin resistance in both diabetes types. DESIGN, SETTING, AND PATIENTS: Two hundred ninety-five plasma metabolites were analyzed by mass spectrometry from patients of the prospective observational German Diabetes Study with T2D (n = 244) or T1D (n = 127) and known diabetes duration of less than 1 year and glucose-tolerant persons (CON; n = 129). Abundance of metabolites was tested for association with insulin sensitivity as assessed by hyperinsulinemic-euglycemic clamps and related metabolic phenotypes. MAIN OUTCOMES MEASURES: Sixty-two metabolites with phenotype-specific patterns were identified using age, sex, and body mass index as covariates. RESULTS: Compared with CON, the metabolome of T2D and T1D showed similar alterations in various phosphatidylcholine species and amino acids. Only T2D exhibited differences in free fatty acids compared with CON. Pairwise comparison of metabolites revealed alterations of 28 and 49 metabolites in T1D and T2D, respectively, when compared with CON. Eleven metabolites allowed differentiation between both diabetes types and alanine, α-amino-adipic acid, isoleucin, and stearic acid showed an inverse association with insulin sensitivity in both T2D and T1D combined. CONCLUSION: Metabolome analyses from recent-onset T2D and T1D patients enables identification of defined diabetes type-specific differences and detection of biomarkers of insulin sensitivity. These analyses may help to identify novel clinical subphenotypes diabetes.

Economic evaluation of brief psychodynamic interpersonal therapy in patients with multisomatoform disorder.

BACKGROUND: A brief psychodynamic interpersonal therapy (PIT) in patients with multisomatoform disorder has been recently shown to improve health-related quality of life. AIMS: To assess cost-effectiveness of PIT compared to enhanced medical care in patients with multisomatoform disorder. METHOD: An economic evaluation alongside a randomised controlled trial (International Standard Randomised Controlled Trial Number ISRCTN23215121) conducted in 6 German academic outpatient centres was performed. Incremental cost-effectiveness ratio (ICER) was calculated from the statutory health insurance perspective on the basis of quality adjusted life years (QALYs) gained at 12 months. Uncertainty surrounding the cost-effectiveness of PIT was presented by means of a cost-effectiveness acceptability curve. RESULTS: Based on the complete-case analysis ICER was 41840 Euro per QALY. The results did not change greatly with the use of multiple imputation (ICER = 44222) and last observation carried forward (LOCF) approach to missing data (ICER = 46663). The probability of PIT being cost-effective exceeded 50% for thresholds of willingness to pay over 35 thousand Euros per QALY. CONCLUSIONS: Cost-effectiveness of PIT is highly uncertain for thresholds of willingness to pay under 35 thousand Euros per QALY.

Time-dependent impact of diabetes on mortality in patients after major lower extremity amputation: survival in a population-based 5-year cohort in Germany.

OBJECTIVE: To estimate the impact of diabetes on mortality in patients after first major lower extremity amputation (LEA). RESEARCH DESIGN AND METHODS: Using claims data of a nationwide statutory health insurance, we assessed all deaths in a cohort of all 444 patients with a first major LEA since 2005 (71.8% male; mean age 69.1 years; 58.3% diabetic; 43% with amputation above the knee) up to 2009. Using Cox regression, we estimated the time-dependent hazard ratios to compare patients with and without diabetes. RESULTS: The cumulative 5-year mortality was 68% in diabetic and 59% in nondiabetic individuals. In the first course, mortality was lower in diabetic compared with nondiabetic patients. Later, the diabetes risk increased yielding crossed survival curves after 2 to 3 years (time dependency of diabetes; P = 0.003). Age- and sex-adjusted hazard ratios for diabetes were as follows: 0-30 days: 0.50 [95% CI 0.31-0.84]; 31-60 days: 0.60 [0.25-1.41]; 61 days to 6 months: 0.75 [0.38-1.48]; >6-12 months: 1.27 [0.63-2.53]; >12-24 months: 1.65 [0.88-3.08]; >24-36 months: 2.02 [0.80-5.09]; and >36-60 months: 1.91 [0.70-5.21]. The pattern was similar in both sexes. In the full model, significant risk factors for mortality were age (1.05; 1.03-1.06), amputation above the knee (1.50; 1.16-1.94), and quartile category 3 or 4 of the number of prescribed medications (1.64; 1.12-2.40 and 1.76; 1.20-2.59). Further adjustment for comorbidity did not alter the results. CONCLUSIONS: In this population-based study, we found a time-dependent mortality risk of diabetes following first major LEA, which may be in part a result of a healthier lifestyle in diabetic patients or the access to specific treatment structures in diabetic individuals.

Stroke in the diabetic and non-diabetic population in Germany: relative and attributable risks, 2005-2007.

BACKGROUND: Reduction of cardiovascular events has been declared to be a main objective in diabetes care. Little is known about incidences of stroke in the diabetic compared to the non-diabetic population and its trend. We evaluated nationwide incidence of stroke in the diabetic compared to the non-diabetic populations as well as relative and attributable stroke risks due to diabetes in Germany. METHODS: Using data of a statutory health insurance (1.6 million members in Germany), we assessed all first strokes in 2005-2007. We estimated sex/age-specific and standardised incidence of strokes in the diabetic and non-diabetic populations and relative and attributable risks due to diabetes. RESULTS: A total of 6160 subjects had a first stroke [66.6% male, mean age (S.D.)=67.0 (13.9) years]; 31.4% had diabetes. Incidence per 100,000 person years (standard: 2004 German population) in the diabetic and non-diabetic populations, respectively, is as follows: men: 476 [95% confidence interval (CI)=438-514] and 255 (95% CI=243-266); women: 342 (95% CI=305-378) and 173 (95% CI=163-182). Age-standardised relative risks are as follows: 1.9 (95% CI=1.7-2.0) in men and 2.0 (95% CI=1.8-2.2) in women. The following are attributable risks among exposed: 0.46 (95% CI=0.41-0.51) in men and 0.49 (95% CI=0.43-0.55) in women; population attributable risks are as follows: 0.14 (95% CI=0.11-0.16) in men and 0.14 (95% CI=0.11-0.17) in women. CONCLUSIONS: In this nationwide study, we found the stroke risk in the diabetic population to be still significantly increased compared to the non-diabetic population. The risk increase seems to be as high as earlier observations in other countries, despite large efforts to improve diabetes care.

Within-trial economic evaluation of diabetes-specific cognitive behaviour therapy in patients with type 2 diabetes and subthreshold depression.

BACKGROUND: Despite the high prevalence of subthreshold depression in patients with type 2 diabetes, evidence on cost-effectiveness of different therapy options for these patients is currently lacking. METHODS/DESIGN: Within-trial economic evaluation of the diabetes-specific cognitive behaviour therapy for subthreshold depression. Patients with diabetes and subthreshold depression are randomly assigned to either 2 weeks of diabetes-specific cognitive behaviour group therapy (n = 104) or to standard diabetes education programme only (n = 104). Patients are followed for 12 months. During this period data on total health sector costs, patient costs and societal productivity costs are collected in addition to clinical data. Health related quality of life (the SF-36 and the EQ-5D) is measured at baseline, immediately after the intervention, at 6 and at 12 months after the intervention. Quality adjusted life years (QALYs), and cumulative costs will be estimated for each arm of the trial. Cost-effectiveness of the diabetes-specific cognitive behaviour group therapy will be analysed from the perspective of the German statutory health insurance and from the societal perspective. To this end, incremental cost-effectiveness ratio (ICER) in terms of cost per QALY gained will be calculated. DISCUSSION: Some methodological issues of the described economic evaluation are discussed. TRIAL REGISTRATION: The trial has been registered at the Clinical Trials Register (NCT01009138).