The Rethinking Clinical Trials (REaCT) Program. A Canadian-Led Pragmatic Trials Program: Strategies for Integrating Knowledge Users into Trial Design

We reviewed patient and health care provider (HCP) surveys performed through the REaCT program. The REaCT team has performed 15 patient surveys (2298 respondents) and 13 HCP surveys (1033 respondents) that have addressed a broad range of topics in breast cancer management. Over time, the proportion of surveys distributed by paper/regular mail has fallen, with electronic distribution now the norm. For the patient surveys, the median duration of the surveys was 3 months (IQR 2.5–7 months) and the median response rate was 84% (IQR 80–91.7%). For the HCP surveys, the median survey duration was 3 months (IQR 1.75–4 months), and the median response rate, where available, was 28% (IQR 21.2–49%). The survey data have so far led to: 10 systematic reviews, 6 peer-reviewed grant applications and 19 clinical trials. Knowledge users should be an essential component of clinical research. The REaCT program has integrated surveys as a standard step of their trials process. The COVID-19 pandemic and reduced face-to-face interactions with patients in the clinic as well as the continued importance of social media highlight the need for alternative means of distributing and responding to surveys.

Lymphatic malformations in children: treatment outcomes of sclerotherapy in a large cohort

This retrospective study examines the outcomes of sclerotherapy in children with (veno)lymphatic malformations who received sclerotherapy between 2011 and 2016 (116 children, 234 procedures). Complication severity was classified using the Society of Interventional Radiology classification. Clinical response was rated on a scale of 0 (no change) to 3 (good improvement). The sclerosants used were bleomycin (n = 132; 56%), lauromacrogol (n = 42; 18%), doxycycline (n = 15; 6%), ethanol (n = 12; 5%), or a combination (n = 33; 14%). Four major and 25 minor complications occurred without significant differences between the agents. The median response rate per procedure was 2—some improvement—for all sclerosants. However, in pure LMs (67%), bleomycin and a combination of agents resulted in the best clinical response. On patient level, all had some or good clinical response. Mixed macrocystic and microcystic lesions showed a significantly lower clinical response (median 2 versus 3; p = 0.023 and p = 0.036, respectively) and required significantly more procedures (median 2 versus 1; p = 0.043 and p = 0.044, respectively) compared with lesions with one component. Conclusion: Sclerotherapy for (V)LMs in children is safe and effective. Bleomycin is the most frequently used agent in this clinic and seemed most effective for pure LMs. Mixed macrocystic and microcystic lesions are most difficult to treat effectively. What is Known:• A variety of agents can be used for sclerotherapy of lymphatic malformations in children.• Macrocystic lesions have favorable outcomes compared with microcystic and mixed lesions. What is New:• Bleomycin and a combination of agents seem to be most effective to treat lymphatic malformations in children.• Mixed macrocystic and microcystic lesions are more difficult to treat effectively compared with lesions with either one of these components.

Relationship Between Response and Dose in Published, Contemporary Phase I Oncology Trials

Background: As progress continues in oncology drug development, this study aimed to examine whether the previously established association between drug dose and efficacy in the era of cytotoxic therapies remains true in today’s phase I dose-escalation oncology trials. Methods: A systematic review of early-phase dose-finding trials of single-agent oncology drugs from 2015 to 2018 was conducted to examine the relationship between drug dose and objective responses. Cancer-specific trials were included if they determined maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D). Data related to the study drug, study design, treatment response, cancer type, dose levels, MTD, and RP2D were all collected. Dose level was categorized into 4 categories (≤40%, 41%–80%, 81%–120%, and >120% of the RP2D) and was further analyzed by class of drug. Results: A total of 175 phase I studies were identified, with a total of 7,330 patients showing a median response rate of 5% (range, 0%–83%) across trials. A total of 93 trials with 2,506 participants had response data corresponding to drug dose level. In this subset, the median response rate was 5% (range, 0%–83%) across trials. Across all participants in this subset, the response rate was 12% (57 of 491) among those in the dose range of ≤40% of RP2D, 17% (95 of 562) among those in 41% to 80% of RP2D, 23% (272 of 1,206) among those in 81% to 120% of RP2D, and 29% (71 of 247) among those in >120% of RP2D (P<.001). The response rate at ≤40% of RP2D for targeted antibody was 5%, 4% for cellular therapy, 19% for immunotherapy, and 21% for small-molecule targeted inhibitors. Conclusions: Whereas our study of published phase I trials continued to show a low response rate consistent with earlier studies, the relationship between response and dose does not always peak at 81% to 120% of RP2D anymore, likely due to the use of novel immunotherapy and targeted agents with distinct efficacy and toxicity patterns.

Assessments of Otolaryngology Resident Operative Experiences Using Mobile Technology: A Pilot Study

Objectives Surgical education has shifted from the Halstedian model of “see one, do one, teach one” to a competency-based model of training. Otolaryngology residency programs can benefit from a fast and simple system to assess residents’ surgical skills. In this quality initiative, we hypothesize that a novel smartphone application called System for Improving and Measuring Procedural Learning (SIMPL) could be applied in an otolaryngology residency to facilitate the assessment of resident operative experiences. Methods The Plan Do Study Act method of quality improvement was used. After researching tools of surgical assessment and trialing SIMPL in a resident-attending pair, we piloted SIMPL across an otolaryngology residency program. Faculty and residents were trained to use SIMPL to rate resident operative performance and autonomy with a previously validated Zwisch Scale. Results Residents (n = 23) and faculty (n = 17) were trained to use SIMPL using a standardized curriculum. A total of 833 assessments were completed from December 1, 2017, to June 30, 2018. Attendings completed a median 20 assessments, and residents completed a median 14 self-assessments. All evaluations were resident initiated, and attendings had a 78% median response rate. Evaluations took residents a median 22 seconds to complete; 126 unique procedures were logged, representing all 14 key indicator cases for otolaryngology. Discussion This is the first residency-wide application of a mobile platform to track the operative experiences of otolaryngology residents. Implications for Practice We adapted and implemented a novel assessment tool in a large otolaryngology program. Future multicenter studies will benchmark resident operative experiences nationwide.

Factors Associated With Frequency of Sugar-Sweetened Beverage Consumption Among US Adults With Diabetes or Prediabetes

Purpose: This study assessed the associations between sociodemographic and behavioral characteristics and sugar-sweetened beverage (SSB) intake among US adults with diabetes or prediabetes. Design: Quantitative, cross-sectional study. Setting: The 2013 Behavioral Risk Factor Surveillance System. Participants: A total of 13 268 adults with diabetes and 9330 adults with prediabetes (median response rate: 46.8%). Measures: The outcome measure was SSB intake (0, >0 to <1, and ≥1 time/day). The exposure measures were sociodemographic and behavioral characteristics. Analysis: Both crude and age-adjusted prevalences were calculated. Multinomial logistic regressions were used to estimate the adjusted prevalence ratio (PR) for SSB intake by participants’ characteristics. Results: In 2013, 22.0% adults with diabetes and 38.2% adults with prediabetes consumed SSBs ≥1 time/day. Among adults with diabetes, adjusted PR for consuming SSBs ≥1 time/day was significantly greater for those who had shorter duration of diabetes (≤5 years: PR = 1.47; 6-10 years: PR = 1.33 vs ≥11 years), less frequently self-checking blood sugar (≥0 to <1 time/day: PR = 1.69; ≥1 to <3 times/day: PR = 1.43 vs ≥3 times/day), and no self-management of diabetes course taken (PR = 1.25 vs yes). Among adults with prediabetes, testing blood sugar ≤3 years was not associated with consuming SSBs ≥1 time/day. Conclusion: Daily SSB intake was associated with various characteristics among adults with diabetes or prediabetes. The findings can inform efforts to decrease SSB intake among high-risk populations.

Prospective phase II trial of GTX in metastatic pancreatic cancer: Laboratory and clinical studies.

209 Background: We found that in pancreatic cancer (PC) cells, when gemcitabine, docetaxel, capecitabine (GTX) are given in a sequence and time specific manner, it 1) increased Bax, Bak, Fas and decreased Bcl-2 and Bcl-XL expression; 2) increased hENT-1 expression >8 fold, which increased intracellular gemcitabine accumulation by 220%; 3) specifically inhibited MEK to ERK phosphorylation (p-MEK) by >70%. Methods: From this pre-clinical data, we developed the GTX regimen utilizing: capecitabine 750 mg/m2/BID capped at 2500mg/day for days 1-14; on days 4 and 11 gemcitabine at 750mg/m2 given over 75mins (FDR), followed by docetaxel at 30mg/m2. Week 3 is off all drugs. Forty four patients with previously untreated metastatic PC were enrolled and followed until death. ECOG PS was: 0(2%), 1(63%), 2(35%), and median age was 60 (33-72). Over 85% of patients had >3 liver metastases. Results: Median response rate (RR) was 38% with 14% CR in metastatic or primary sites and 40% stable disease using RECIST 1.0 indices. Median PFS was 6.9 months and median OS was 14.5 months. After failing GTX, 80% of patients received our second line synergistic regimen called ICM (irinotecan 80mg/m2 and cisplatin 25mg/m2 on days 1 and 8, and mitomycin C 5mg/m2 on day 1 only, out of a 28 day cycle). The 6, 12, 18, 24, 30 and 36 month survival on GTX was 77, 59, 35, 16, 14 and 7%, respectively. Grade3/4 toxicities were: leukopenia (32%), neutropenia (29%), febrile neutropenia (3%), anemia (12%), thrombocytopenia (12%), diarrhea (5%), HFS (3%), fatigue (8%), and mucositis (8%). GTX inhibited MEK to ERK phosphorylation (P-MEK). We performed IHC (0-4+) for P-MEK in 16 patients and found high P-MEK (3-4+) correlated with an 85% RR while low P-MEK (0-1+) correlated with a 90% rate of PD to GTX. Conclusions: GTX is an effective regimen for metastatic PC with durable RR, PFS, OS rates, and acceptable toxicities. IHC for P-MEK seems to be a good biomarker to identify subsets of patients who will respond to GTX. GTX is a rationally designed regimen derived from lab studies. GTX increases pro-apoptotic and decreases anti-apoptotic proteins, inhibiting MEK to ERK in the MAPK pathway. Clinical trial information: NCT00996333.

Image and Imaging an Emergency Department: Expense and Benefit of Different Quality Assessment Methods

Introduction. In this era of high-tech medicine, it is becoming increasingly important to assess patient satisfaction. There are several methods to do so, but these differ greatly in terms of cost, time, and labour and external validity. The aim of this study is to describe and compare the structure and implementation of different methods to assess the satisfaction of patients in an emergency department.Methods. The structure and implementation of the different methods to assess patient satisfaction were evaluated on the basis of a 90-minute standardised interview.Results. We identified a total of six different methods in six different hospitals. The average number of patients assessed was 5012, with a range from 230 (M5) to 20 000 patients (M2). In four methods (M1, M3, M5, and M6), the questionnaire was composed by a specialised external institute. In two methods, the questionnaire was created by the hospital itself (M2, M4).The median response rate was 58.4% (range 9–97.8%). With a reminder, the response rate increased by 60% (M3).Conclusion. The ideal method to assess patient satisfaction in the emergency department setting is to use a patient-based, in-emergency department-based assessment of patient satisfaction, planned and guided by expert personnel.