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The aim of this study is to examine the epidemiologic and economic burden in surgically resected localized gastrointestinal stromal tumor (GIST) patients versus age- and gender-matched controls. Two data sources were used to conduct a series of complementary analyses. First, the Surveillance, Epidemiology, and End Results (SEER) cancer registry was used to identify diagnosed GIST patients from 1993 to 2002 and determine incidence, prevalence, and 3-year survival. Second, using the SEER-Medicare linked database, a matched case-control analysis was conducted to determine resource utilization, GIST recurrence, and costs. Because GIST recurrence is not explicitly defined in the database, patterns in resource use were used to identify probable recurrence. Kaplan-Meier Sample Average (KMSA) Estimator technique was used to estimate costs of GIST and recurrence. SEER registry results show over the 10-year time horizon average annual GIST incidence was 0.32 per 100,000 persons in the United States, 15-year limited-duration prevalence was 1.62 per 100,000 persons, and 3-year survival was 73%. A total of 292 GIST patients were included in the SEER-Medicare analyses; 35 were identified with probable recurrence. GIST patients had increased risk of mortality (hazard ratio: 1.23; 95% confidence intervals: 0.94-1.61) compared to controls. Median recurrence-free and postrecurrence survival was 45 and 46 months, respectively. GIST patients incurred significantly higher medical care costs in the first year after initial resection, with $23,221 attributable to GIST. GIST recurrence costs totaled $101,700 over 5 years after initial resection. GIST is associated with substantial medical care costs, estimated recurrence costs more than $100,000; treatments that delay or reduce recurrence could substantially reduce the burden of GIST.

Background : Mathematical models are commonly used to predict future benefits of new therapies or interventions in the healthcare setting. The reliability of model results is greatly dependent on accuracy of model inputs but on occasion, data sources may not provide all the required inputs. Therefore, calibration of model inputs to epidemiological endpoints informed by existing data can be a useful tool to ensure credibility of the results. Objective : To compare different computational methods of calibrating a Markov model to US data. Methods : We developed a Markov model that simulates the natural history of human papillomavirus (HPV) infection and subsequent cervical disease in the US. Because the model consists of numerous transition probabilities that cannot be directly estimated from data, calibration to multiple disease endpoints was required to ensure its predictive validity. Goodness of fit was measured as the mean percentage deviation of model-predicted endpoints from target estimates. During the calibration process we used the manual, random and Nelder-Mead calibration methods. Results : The Nelder-Mead and manual calibration methods achieved the best fit, with mean deviations of 7% and 10%, respectively. Nelder-Mead accomplished this result with substantially less analyst time than the manual method, but required more intensive computing capability. The random search method achieved a mean deviation of 39%, which we considered unacceptable despite the ease of implementation of that method. Conclusions : The Nelder-Mead and manual techniques may be preferable calibration methods based on both performance and efficiency, provided that sufficient resources are available.

Background : A recent study found fewer hospitalizations for congestive heart failure (CHF) patients receiving high-dose versus low-dose statin therapy. Objective : To examine the cost effectiveness of high-dose versus low-dose statin therapy in CHF patients. Methods : Two scenarios (literature-based [base-case scenario] vs trial-based post-event mortality [alternative scenario]) assessed the cost effectiveness of atorvastatin 80mg/day (A80) versus atorvastatin 10 mg/day (A10) in patients with both CHF and coronary heart disease (CHD) [CHF/CHD], using a lifetime Markov model. The model predicts treatment-specific probabilities of major and minor cardiovascular events and death, based on clinical trial data. The quality of life and costs were literature based. Measures included costs per life-year saved (LYS) and QALY gained. Health consequences and costs were discounted at 3.0% annually. Analyses were conducted from the payer perspective and valued in $US, year 2006–7 values. Results : Literature-based mortality estimates (base case) increased life-years and QALYs for A80 compared with A10 (incremental cost-effectiveness ratios [ICERs]: $US9600 per LYS; $US13 600 per QALY). At a willingness to pay of $US100 000 per QALY, A80 was cost effective in 80% of simulations. A10 dominated A80 when using trial-based mortality estimates (alternative scenario). At a willingness to pay of $US100 000 per QALY, A80 was cost effective in 48% of simulations. Conclusions : Intensive A80 treatment may be cost effective versus A10 in cardiovascular prevention in CHF/CHD patients in the US, due to projected gains in life expectancy and health-related quality of life. However, the results are highly sensitive to assumptions about the mortality rate in the model. When using the mortality rate observed in the trial, A10 dominates A80.

Objective: The aim of this study was to examine how calibration uncertainty affects the overall uncertainty of a mathematical model and to evaluate potential drivers of calibration uncertainty. Methods: A lifetime Markov model of the natural history of human papillomavirus (HPV) infection and cervical disease was developed to assess the cost effectiveness of a hypothetical HPV vaccine. Published data on cervical cancer incidence and mortality and prevalence of pre-cursor lesions were used as endpoints to calibrate the age- and HPV-type-specific transition probabilities between health states using the Nelder-Mead simplex method of calibration. A conventional probabilistic sensitivity analysis (PSA) was performed to assess uncertainty in vaccine efficacy, cost and utility estimates. To quantify the uncertainty around calibrated transition probabilities, a second PSA (calibration PSA) was performed using 25 distinct combinations of objective functions and starting simplexes. Results: The initial calibration produced an incremental cost-effectiveness ratio (ICER) of$US4300 per QALY for vaccination compared with no vaccination, and the conventional PSA gave a 95% credible interval of dominant to $ US9800 around this estimate (2005 values). The 95% credible interval for the ICERs in the calibration PSA ranged from$US1000 to $ US37 700. Conclusions: Compared with a conventional PSA, the calibration PSA results reveal a greater level of uncertainty in cost-effectiveness results. Sensitivity analyses around model calibration should be performed to account for uncertainty arising from the calibration process.

This trial revisited research conducted about a decade ago that showed a survival benefit with early neuromuscular blockade in patients with acute respiratory distress syndrome. The new trial did not show a benefit with neuromuscular blockade with respect to overall survival or other clinical outcomes.

Quinquennial overviews (1985–2000) of the randomised trials in early breast cancer have assessed the 5 year and 10-year effects of various systemic adjuvant therapies on breast cancer recurrence and survival. Here, we report the 10-year and 15-year effects. Collaborative meta-analyses were undertaken of 194 unconfounded randomised trials of adjuvant chemotherapy or hormonal therapy that began by 1995. Many trials involved CMF (cyclophosphamide, methotrexate, fluorouracil), anthracycline-based combinations such as FAC (fluorouracil, doxorubicin, cyclophosphamide) or FEC (fluorouracil, epirubicin, cyclophosphamide), tamoxifen, or ovarian suppression: none involved taxanes, trastuzumab, raloxifene, or modern aromatase inhibitors. Allocation to about 6 months of anthracycline-based polychemotherapy (eg, with FAC or FEC) reduces the annual breast cancer death rate by about 38% (SE 5) for women younger than 50 years of age when diagnosed and by about 20% (SE 4) for those of age 50–69 years when diagnosed, largely irrespective of the use of tamoxifen and of oestrogen receptor (ER) status, nodal status, or other tumour characteristics. Such regimens are significantly (2p=0·0001 for recurrence, 2p<0·00001 for breast cancer mortality) more effective than CMF chemotherapy. Few women of age 70 years or older entered these chemotherapy trials. For ER-positive disease only, allocation to about 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31% (SE 3), largely irrespective of the use of chemotherapy and of age (<50, 50–69, ≥70 years), progesterone receptor status, or other tumour characteristics. 5 years is significantly (2p<0·00001 for recurrence, 2p=0·01 for breast cancer mortality) more effective than just 1–2 years of tamoxifen. For ER-positive tumours, the annual breast cancer mortality rates are similar during years 0–4 and 5–14, as are the proportional reductions in them by 5 years of tamoxifen, so the cumulative reduction in mortality is more than twice as big at 15 years as at 5 years after diagnosis. These results combine six meta-analyses: anthracycline-based versus no chemotherapy (8000 women); CMF-based versus no chemotherapy (14 000); anthracycline-based versus CMF-based chemotherapy (14 000); about 5 years of tamoxifen versus none (15 000); about 1–2 years of tamoxifen versus none (33 000); and about 5 years versus 1–2 years of tamoxifen (18 000). Finally, allocation to ovarian ablation or suppression (8000 women) also significantly reduces breast cancer mortality, but appears to do so only in the absence of other systemic treatments. For middle-aged women with ER-positive disease (the commonest type of breast cancer), the breast cancer mortality rate throughout the next 15 years would be approximately halved by 6 months of anthracycline-based chemotherapy (with a combination such as FAC or FEC) followed by 5 years of adjuvant tamoxifen. For, if mortality reductions of 38% (age <50 years) and 20% (age 50–69 years) from such chemotherapy were followed by a further reduction of 31% from tamoxifen in the risks that remain, the final mortality reductions would be 57% and 45%, respectively (and, the trial results could well have been somewhat stronger if there had been full compliance with the allocated treatments). Overall survival would be comparably improved, since these treatments have relatively small effects on mortality from the aggregate of all other causes. Some of the widely practicable adjuvant drug treatments that were being tested in the 1980s, which substantially reduced 5-year recurrence rates (but had somewhat less effect on 5-year mortality rates), also substantially reduce 15-year mortality rates. Further improvements in long-term survival could well be available from newer drugs, or better use of older drugs.