Statistical analysis of comparative tumor growth repeated measures experiments in the ovarian cancer patient derived xenograft (PDX) setting.

Repeated measures studies are frequently performed in patient-derived xenograft (PDX) models to evaluate drug activity or compare effectiveness of cancer treatment regimens. Linear mixed effects regression models were used to perform statistical modeling of tumor growth data. Biologically plausible structures for the covariation between repeated tumor burden measurements are explained. Graphical, tabular, and information criteria tools useful for choosing the mean model functional form and covariation structure are demonstrated in a Case Study of five PDX models comparing cancer treatments. Power calculations were performed via simulation. Linear mixed effects regression models applied to the natural log scale were shown to describe the observed data well. A straight growth function fit well for two PDX models. Three PDX models required quadratic or cubic polynomial (time squared or cubed) terms to describe delayed tumor regression or initial tumor growth followed by regression. Spatial(power), spatial(power) + RE, and RE covariance structures were found to be reasonable. Statistical power is shown as a function of sample size for different levels of variation. Linear mixed effects regression models provide a unified and flexible framework for analysis of PDX repeated measures data, use all available data, and allow estimation of tumor doubling time.

The effect of diabetes and metformin on clinical outcomes is negligible in risk-adjusted endometrial cancer cohorts.

OBJECTIVE: To examine the influence of diabetes and metformin therapy on overall survival (OS) and progression-free survival (PFS) in patients with endometrial cancer (EC) by using propensity score (PS) matching to account for confounding factors. METHODS: We retrospectively identified consecutive patients with stage I-IV EC managed surgically from 1999 through 2008 and stratified patients by diabetes status. PS matching was used to adjust for confounding covariates. OS and PFS were compared between diabetic and nondiabetic matched pairs and between matched pairs of diabetic patients with or without metformin therapy. Cox proportional hazards models were fit to estimate the effects on outcomes. RESULTS: Among 1303 eligible patients (79% stage I, 28% grade 3), 277 (21.3%) had a history of diabetes. Among diabetic patients, treatment consisted of metformin in 116 (41.9%); 57 (20.6%) had other oral agents, 51 (18.4%) insulin with or without other oral agents, and 53 (19.1%) diet modification only. For PS-matched diabetic and nondiabetic patients with EC, OS (hazard ratio [HR], 1.01; 95% CI, 0.72-1.42) and PFS (HR, 1.01; 95% CI, 0.60-1.69) were similar between matched subsets. No differences in OS and PFS were observed when comparing PS-matched metformin users with nondiabetic patients (OS HR, 1.03; 95% CI, 0.57-1.85; PFS HR, 1.14; 95% CI, 0.49-2.62) or with other diabetic patients (OS HR, 0.61; 95% CI, 0.30-1.23; PFS HR, 1.06; 95% CI, 0.34-3.30). CONCLUSIONS: When adjusted for confounding covariates, OS and PFS are similar between diabetic and nondiabetic patients with EC and between metformin users and nonusers or nondiabetic patients.

Lymphedema after surgery for endometrial cancer: prevalence, risk factors, and quality of life.

OBJECTIVE: To estimate lower extremity lymphedema prevalence in patients surgically treated for endometrial cancer, identify predictors of lymphedema, and evaluate the effects of lymphedema on quality of life. METHODS: One thousand forty-eight consecutive patients who were operated on between 1999 and 2008 at the Mayo Clinic were mailed a survey, which included our validated 13-item lymphedema screening questionnaire and two validated quality-of-life measures. Logistic regression models were fit to identify factors associated with prevalent lymphedema; a multivariable model was obtained using stepwise and backward variable selection methods. The relationship between lymphedema and obesity with each quality-of-life score was evaluated separate multivariable linear models. RESULTS: There were 591 responders (56%) after exclusions. Our questionnaire revealed a previous self-reported lymphedema diagnosis in 103 (17%) patients and identified undiagnosed lymphedema in 175 (30%) (overall prevalence 47.0%, median 6.2 years follow-up). Lymphedema prevalence in patients treated with hysterectomy alone compared with lymphadenectomy was 36.1% and 52.3%, respectively (attributable risk 23%). Lymphedema risk was not associated with the number of nodes removed or the extent of lymphadenectomy after adjusting for other factors. On multivariable analysis, higher body mass index, congestive heart failure, performance of lymphadenectomy, and radiation therapy were associated with prevalent lymphedema. Multiple quality-of-life scores were worse in women with lymphedema. CONCLUSION: The attributable risk of developing lower extremity lymphedema was 23% for patients with endometrial cancer who underwent lymphadenectomy compared with hysterectomy alone with an overall prevalence of 47%. Lymphedema was associated with reductions in multiple quality-of-life domains. LEVEL OF EVIDENCE: II.

Magnetic resonance-guided focused ultrasound surgery.

Magnetic resonance guided focused ultrasound surgery (MRgFUS) is a noninvasive thermoablative therapy that was approved by the Food and Drug Administration in 2004 for the treatment of uterine fibroids (leiomyomas). Data on safety and long-term efficacy are accumulating to establish the unique usefulness of this therapy in targeting and treating leiomyomas through the integration of MR imaging. This article describes the established thermoablative therapies in the treatment of uterine fibroids, emphasizing their role in the genesis of MRgFUS. Treatment specifications are highlighted, and an overview of the procedure is given. Data from both clinical trials and commercial treatments are detailed for multiple efficacy outcomes, including symptom improvement, leiomyoma shrinkage, and use of alternative procedures. The concept of nonperfused volume as a surrogate marker for treatment success is discussed. Importantly, favorable pregnancy outcomes following MRgFUS have been reported. Applications of MRgFUS have recently expanded into the realm of adenomyosis treatment. MRgFUS has been deemed a safe and effective method of fibroid treatment and offers the advantages of no incisions or blood loss, speedy recovery, and a cost-effective means of treatment.