Evaluation of Intratumoral Response Heterogeneity in Metastatic Colorectal Cancer and Its Impact on Patient Overall Survival: Findings from 10,551 Patients in the ARCAD Database

Metastatic colorectal cancer (mCRC) is a heterogeneous disease that can evoke discordant responses to therapy among different lesions in individual patients. The Response Evaluation Criteria in Solid Tumors (RECIST) criteria do not take into consideration response heterogeneity. We explored and developed lesion-based measurement response criteria to evaluate their prognostic effect on overall survival (OS). Patients and Methods: Patients enrolled in 17 first-line clinical trials, who had mCRC with ≥ 2 lesions at baseline, and a restaging scan by 12 weeks were included. For each patient, lesions were categorized as a progressing lesion (PL: > 20% increase in the longest diameter (LD)), responding lesion (RL: > 30% decrease in LD), or stable lesion (SL: neither PL nor RL) based on the 12-week scan. Lesion-based response criteria were defined for each patient as follows: PL only, SL only, RL only, and varied responses (mixture of RL, SL, and PL). Lesion-based response criteria and OS were correlated using stratified multivariable Cox models. The concordance between OS and classifications was measured using the C statistic. Results: Among 10,551 patients with mCRC from 17 first-line studies, varied responses were noted in 51.6% of patients, among whom, 3.3% had RL/PL at 12 weeks. Among patients with RL/SL, 52% had stable disease (SD) by RECIST 1.1, and they had a longer OS (median OS (mOS) = 19.9 months) than those with SL only (mOS = 16.8 months, HR (95% CI) = 0.81 (0.76, 0.85), p < 0.001), although a shorter OS than those with RL only (mOS = 25.8 months, HR (95% CI) = 1.42 (1.32, 1.53), p < 0.001). Among patients with SL/PL, 74% had SD by RECIST 1.1, and they had a longer OS (mOS = 9.0 months) than those with PL only (mOS = 8.0 months, HR (95% CI) = 0.75 (0.57, 0.98), p = 0.040), yet a shorter OS than those with SL only (mOS = 16.8 months, HR (95% CI) = 1.98 (1.80, 2.18), p < 0.001). These associations were consistent across treatment regimen subgroups. The lesion-based response criteria showed slightly higher concordance than RECIST 1.1, although it was not statistically significant. Conclusion: Varied responses at first restaging are common among patients receiving first-line therapy for mCRC. Our lesion-based measurement criteria allowed for better mortality discrimination, which could potentially be informative for treatment decision-making and influence patient outcomes

Evaluation of intratumoral response heterogeneity in metastatic colorectal cancer and Its impact on patient overall survival: findings from 10,551 patients in the ARCAD database

Metastatic colorectal cancer (mCRC) is a heterogeneous disease that can evoke discordant responses to therapy among different lesions in individual patients. The Response Evaluation Criteria in Solid Tumors (RECIST) criteria do not take into consideration response heterogeneity. We explored and developed lesion-based measurement response criteria to evaluate their prognostic effect on overall survival (OS). Patients and Methods: Patients enrolled in 17 first-line clinical trials, who had mCRC with ≥ 2 lesions at baseline, and a restaging scan by 12 weeks were included. For each patient, lesions were categorized as a progressing lesion (PL: > 20% increase in the longest diameter (LD)), responding lesion (RL: > 30% decrease in LD), or stable lesion (SL: neither PL nor RL) based on the 12-week scan. Lesion-based response criteria were defined for each patient as follows: PL only, SL only, RL only, and varied responses (mixture of RL, SL, and PL). Lesion-based response criteria and OS were correlated using stratified multivariable Cox models. The concordance between OS and classifications was measured using the C statistic. Results: Among 10,551 patients with mCRC from 17 first-line studies, varied responses were noted in 51.6% of patients, among whom, 3.3% had RL/PL at 12 weeks. Among patients with RL/SL, 52% had stable disease (SD) by RECIST 1.1, and they had a longer OS (median OS (mOS) = 19.9 months) than those with SL only (mOS = 16.8 months, HR (95% CI) = 0.81 (0.76, 0.85), p < 0.001), although a shorter OS than those with RL only (mOS = 25.8 months, HR (95% CI) = 1.42 (1.32, 1.53), p < 0.001). Among patients with SL/PL, 74% had SD by RECIST 1.1, and they had a longer OS (mOS = 9.0 months) than those with PL only (mOS = 8.0 months, HR (95% CI) = 0.75 (0.57, 0.98), p = 0.040), yet a shorter OS than those with SL only (mOS = 16.8 months, HR (95% CI) = 1.98 (1.80, 2.18), p < 0.001). These associations were consistent across treatment regimen subgroups. The lesion-based response criteria showed slightly higher concordance than RECIST 1.1, although it was not statistically significant. Conclusion: Varied responses at first restaging are common among patients receiving first-line therapy for mCRC. Our lesion-based measurement criteria allowed for better mortality discrimination, which could potentially be informative for treatment decision-making and influence patient outcomes

Estimation of causal effects in clinical endpoint bioequivalence studies in the presence of intercurrent events: noncompliance and missing data

<p>In clinical endpoint bioequivalence (BE) studies, the primary analysis for assessing equivalence between a generic and an innovator product is based on the observed per-protocol (PP) population (usually completers and compliers). However, missing data and noncompliance are post-randomization intercurrent events and may introduce selection bias. Therefore, PP analysis is generally not causal. The FDA Missing Data Working Group recommended using “causal estimands of primary interest.” In this paper, we propose a principal stratification causal framework and co-primary causal estimands to test equivalence, which was also recommended by the recently published ICH E9 (R1) addendum to address intercurrent events. We identify three conditions under which the current PP estimator is unbiased for one of the proposed co-primary causal estimands – the “Survivor Average Causal Effect” (SACE) estimand. Simulation shows that when these three conditions are not met, the PP estimator is biased and may inflate Type 1 error and/or change power. We also propose a tipping point sensitivity analysis to evaluate the robustness of the current PP estimator in testing equivalence when the sensitivity parameters deviate from the three identified conditions, but stay within a clinically meaningful range. Our work is the first causal equivalence assessment in equivalence studies with intercurrent events.</p

Characteristics of older adults using patient web portals to view their DXA results

Abstract Background Sharing test results with patients via patient web portals is a new trend in healthcare. No research has been done examining patient web portal use with bone density test results. The objective of our study was to identify patient characteristics associated with the use of patient web portals to view their bone density test results. Methods A secondary analysis of data from a pragmatic randomized controlled trial of 7749 participants ≥50 years old that had presented for a dual energy X-ray absorptiometry (DXA) bone density test. Patients were interviewed at enrollment and 12 weeks later. Multivariable logistic regression identified patient characteristics that differentiated those who used the web portal from those who did not. Results Our sample included 4669 patients at the two (University of Iowa [UI], and Kaiser Permanente of Georgia [KPGA]) clinical sites that had patient web portals. Of these patients, 3399 (72.8%) reported knowing their test results 12 weeks post-DXA, with 649 (13.9%) reporting that they viewed their DXA results using the web portal. Web portal users were more likely to be from UI than KPGA, and were younger, more educated, had higher health literacy, had osteopenia, and had the same sex as their referring physician (all p < 0.05). Conclusion Only 19.1% of the 3399 patients who knew their DXA results used the available patient web portals to find out about them. Web portal users differed from non-users on several characteristics. This suggests that simply making patient web portals available for use may not be sufficient to appreciably enhance patient awareness of their test results. Based on these findings, a better understanding of the reasons why older, less educated, and less activated patients do not access their test results through patient web portals is needed

Effects of a DXA result letter on satisfaction, quality of life, and osteoporosis knowledge: a randomized controlled trial

Abstract Background Undiagnosed, or diagnosed and untreated osteoporosis (OP) increases the likelihood that falls result in hip fractures, decreased quality of life (QOL), and significant medical expenditures among older adults. We tested whether a tailored dual energy x-ray absorptiometry (DXA) test result letter and an accompanying educational bone-health brochure affected patient satisfaction, QOL, or OP knowledge. Methods The Patient Activation after DXA Result Notification (PAADRN) study was a double-blinded, pragmatic, randomized trial which enrolled patients from 2012 to 2014. We randomized 7,749 patients presenting for DXA at three health care institutions in the United States who were ≥ 50 years old and able to understand English. Intervention patients received a tailored letter four weeks after DXA containing their results, 10-year fracture risk, and a bone-health educational brochure. Control patients received the results of their DXA per the usual practices of their providers and institutions. Satisfaction with bone health care, QOL, and OP knowledge were assessed at baseline and 12- and 52-weeks after DXA. Intention-to-treat analyses used multiple imputation for missing data and random effects regression models to adjust for clustering within providers and covariates. Results At 12-weeks 6,728 (86.8 %) and at 52-weeks 6,103 participants (78.8 %) completed their follow-up interviews. The intervention group was more satisfied with their bone health care compared to the usual care group at both their 12- and 52-week follow-ups (standardized effect size = 0.28 at 12-weeks and 0.17 at 52-weeks, p < 0.001). There were no differences between the intervention and usual care groups in QOL or OP knowledge at either time point. Conclusions A tailored DXA result letter and bone-health educational brochure sent to patients improved patient satisfaction with bone-related health care. Trial registration Clinical Trials.gov Identifier: NCT01507662 First received: December 8, 2011

Additional file 1 of Psychometric performance of the CFQ-R-8D compared to the EQ-5D-3L and SF-6D in people with cystic fibrosis

Supplementary Material

EFFECT OF ELEXACAFTOR/TEZACAFTOR/IVACAFTOR ON ANNUAL RATE OF LUNG FUNCTION DECLINE IN PEOPLE WITH CYSTIC FIBROSIS

Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in people with cystic fibrosis (CF) with ? 1 F508del-CFTR allele in Phase 3 clinical trials. ELX/TEZ/IVA treatment led to improved lung function, with increases in percent predicted forced expiratory volume in 1 second (ppFEV1) and Cystic Fibrosis Questionnaire-Revised respiratory domain score. Here, we evaluated the impact of ELX/TEZ/IVA on the rate of lung function decline over time by comparing changes in ppFEV1 in participants from the Phase 3 trials with a matched group of people with CF from the US Cystic Fibrosis Foundation Patient Registry not eligible for cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy. Participants treated with ELX/TEZ/IVA had on average no loss of pulmonary function over a 2-year period (mean annualized rate of change in ppFEV1, +0.39 percentage points [95% CI, ?0.06 to 0.85]) compared with a 1.92 percentage point annual decline (95% CI, ?2.16 to ?1.69) in ppFEV1 in untreated controls. ELX/TEZ/IVA is the first CFTR modulator therapy shown to halt lung function decline over an extended time period

Three-dimensional mesostructures as high-temperature growth templates, electronic cellular scaffolds, and self-propelled microrobots

Exploiting advanced 3D designs in micro/nanomanufacturing inspires potential applications in various fields including biomedical engineering, metamaterials, electronics, electromechanical components, and many others. The results presented here provide enabling concepts in an area of broad, current interest to the materials community––strategies for forming sophisticated 3D micro/nanostructures and means for using them in guiding the growth of synthetic materials and biological systems. These ideas offer qualitatively differentiated capabilities compared with those available from more traditional methodologies in 3D printing, multiphoton lithography, and stress-induced bending––the result enables access to both active and passive 3D mesostructures in state-of-the-art materials, as freestanding systems or integrated with nearly any type of supporting substrate