Optimal Designs for the Hill Model with Three Parameters

Optimal designs specify design points to use and how to distribute subjects over these design points in the most efficient manner. The Hill model with three parameters is often used to describe sigmoid dose response functions. In our paper, we study optimal designs under the Hill model. The first is D-optimal design, which works best to study the model to fit the data. Next is c-optimal design, which works best to study a target dose level, such as ED50 - the dose level with 50% maximum treatment effect. The third is a two-stage optimal design, which considers both D-optimality and c-optimality. In order to compare the optimal designs, their design efficiencies are compared

Breast Cancer Clinical Trial of Chemotherapy and Trastuzumab: Potential Tool to Identify Cardiac Modifying Variants of Dilated Cardiomyopathy

Doxorubicin and the ERBB2 targeted therapy, trastuzumab, are routinely used in the treatment of HER2+ breast cancer. In mouse models, doxorubicin is known to cause cardiomyopathy and conditional cardiac knock out of Erbb2 results in dilated cardiomyopathy and increased sensitivity to doxorubicin-induced cell death. In humans, these drugs also result in cardiac phenotypes, but severity and reversibility is highly variable. We examined the association of decline in left ventricular ejection fraction (LVEF) at 15,204 single nucleotide polymorphisms (SNPs) spanning 72 cardiomyopathy genes, in 800 breast cancer patients who received doxorubicin and trastuzumab. For 7033 common SNPs (minor allele frequency (MAF) > 0.01) we performed single marker linear regression. For all SNPs, we performed gene-based testing with SNP-set (Sequence) Kernel Association Tests: SKAT, SKAT-O and SKAT-common/rare under rare variant non-burden; rare variant optimized burden and non-burden tests; and a combination of rare and common variants respectively. Single marker analyses identified seven missense variants in OBSCN (p = 0.0045–0.0009, MAF = 0.18–0.50) and two in TTN (both p = 0.04, MAF = 0.22). Gene-based rare variant analyses, SKAT and SKAT-O, performed very similarly (ILK, TCAP, DSC2, VCL, FXN, DSP and KCNQ1, p = 0.042–0.006). Gene-based tests of rare/common variants were significant at the nominal 5% level for OBSCN as well as TCAP, DSC2, VCL, NEXN, KCNJ2 and DMD (p = 0.044–0.008). Our results suggest that rare and common variants in OBSCN, as well as in other genes, could have modifying effects in cardiomyopathy

Pilot study of fractional CO2 laser therapy for genitourinary syndrome of menopause in gynecologic cancer survivors

PurposeThe objectives of this study were to evaluate the feasibility and efficacy of fractional CO2 laser therapy in gynecologic cancer survivors.MethodsThis was a pilot, multi-institutional randomized sham-controlled trial of women with gynecologic cancers with dyspareunia and/or vaginal dryness. Participants were randomized to fractional CO2 laser treatment or sham laser treatment. The primary aim was to estimate the proportion of patients who had improvement in symptoms based on the Vaginal Assessment Scale (VAS). Secondary aims included changes in sexual function assessed using the Female Sexual Functioning Index (FSFI) and urinary symptoms assessed using the the Urinary Distress Inventory (UDI-6).ResultsEighteen women participated in the study, ten in the treatment arm and eight in the sham arm. The majority of participants had stage I (n = 11, 61.1 %) or II (n = 3, 16.7 %) endometrial cancer with adenocarcinoma histology (n = 9, 50 %). In total, 15 (83.3 %) of the participants completed all treatments and follow-up visit. There was no difference in the change in the median VAS score from baseline to follow-up. However, there was an improvement in change in the median total FSFI score with treatment compared with sham (Δ 6.5 vs -0.3, p = 0.02). The change in the median UDI-6 score was lower in the treatment arm (Δ -14.6 vs -2.1, p = 0.17), but this was not statistically significant. There were no reported serious adverse events.ConclusionsFractional CO2 laser therapy is feasible in gynecologic cancer survivors, with preliminary evidence of safety. In addition, there was preliminary evidence of improvement in sexual function compared with sham treatment. Clinicaltrial.gov Identifier: NCT03372720 (OSU-17261; NCI-2017-02051)