Faculty Bibliography

Sezary syndrome (SS), a leukemic variant of cutaneous T-cell lymphoma (CTCL), is associated with a significantly shorter life expectancy compared to skin-restricted mycosis fungoides. Early diagnosis of SS is, therefore, key to achieving enhanced therapeutic responses. However, the lack of a biomarker(s) highly specific for malignant CD4+ T cells in SS patients has been a serious obstacle in making an early diagnosis. We recently demonstrated the high expression of CD164 on CD4+ T cells from Sezary syndrome patients with a wide range of circulating tumor burdens. To further characterize CD164 as a potential biomarker for malignant CD4+ T cells, CD164+ and CD164-CD4+ T cells isolated from patients with high-circulating tumor burden, B2 stage, and medium/low tumor burden, B1-B0 stage, were assessed for the expression of genes reported to differentiate SS from normal controls, and associated with malignancy and poor prognosis. The expression of Sezary signature genes: T plastin, GATA-3, along with FCRL3, Tox, and miR-214, was significantly higher, whereas STAT-4 was lower, in CD164+ compared with CD164-CD4+ T cells. While Tox was highly expressed in both B2 and B1-B0 patients, the expression of Sezary signature genes, FCRL3, and miR-214 was associated predominantly with advanced B2 disease. High expression of CD164 mRNA and protein was also detected in skin from CTCL patients. CD164 was co-expressed with KIR3DL2 on circulating CD4+ T cells from high tumor burden SS patients, further providing strong support for CD164 as a disease relevant surface biomarker.

PURPOSE: The expanding number of targeted therapeutics for non-small cell lung cancer (NSCLC) necessitates real-time tumor genotyping, yet tissue biopsies are difficult to perform serially and often yield inadequate DNA for next-generation sequencing (NGS). We evaluated the feasibility of using cell-free circulating tumor DNA (ctDNA) NGS as a complement or alternative to tissue NGS. EXPERIMENTAL DESIGN: A total of 112 plasma samples obtained from a consecutive study of 102 prospectively enrolled patients with advanced NSCLC were subjected to ultra-deep sequencing of up to 70 genes and matched with tissue samples, when possible. RESULTS: We detected 275 alterations in 45 genes, and at least one alteration in the ctDNA for 86 of 102 patients (84%), with EGFR variants being most common. ctDNA NGS detected 50 driver and 12 resistance mutations, and mutations in 22 additional genes for which experimental therapies, including clinical trials, are available. Although ctDNA NGS was completed for 102 consecutive patients, tissue sequencing was only successful for 50 patients (49%). Actionable EGFR mutations were detected in 24 tissue and 19 ctDNA samples, yielding concordance of 79%, with a shorter time interval between tissue and blood collection associated with increased concordance (P = 0.038). ctDNA sequencing identified eight patients harboring a resistance mutation who developed progressive disease while on targeted therapy, and for whom tissue sequencing was not possible. CONCLUSIONS: Therapeutically targetable driver and resistance mutations can be detected by ctDNA NGS, even when tissue is unavailable, thus allowing more accurate diagnosis, improved patient management, and serial sampling to monitor disease progression and clonal evolution. Clin Cancer Res; 22(23); 5772-82. (c)2016 AACR.

OBJECTIVES: We compared the effectiveness of diabetes-focused messaging strategies at increasing enrolment in a healthy food programme among adults with diabetes. METHODS: Vitality is a multifaceted wellness benefit available to members of Discovery Health, a South Africa-based health insurer. One of the largest Vitality programmes is HealthyFood (HF), an incentive-based programme designed to encourage healthier diets by providing up to 25% cashback on healthy food purchases. We randomised adults with type 2 diabetes to 1 of 5 arms: (1) control, (2) a diabetes-specific message, (3) a message with a recommendation of HF written from the perspective of a HF member with diabetes, (4) a message containing a physician's recommendation of HF, or (5) the diabetes-specific message from arm 2 paired with an 'enhanced active choice'(EAC). In an EAC, readers are asked to make an immediate choice (in this case, to enrol or not enrol); the pros and cons associated with the preferred and non-preferred options are highlighted. HF enrolment was assessed 1 month following the first emailed message. RESULTS: We randomised 3906 members. After excluding those who enrolled in HF or departed from the Vitality programme before the first intervention email, 3665 (94%) were included in a modified intent-to-treat analysis. All 4 experimental arms had significantly higher HF enrolment rates compared with control (p<0.0001 for all comparisons). When comparing experimental arms, the diabetes-specific message with the EAC had a significantly higher enrolment rate (12.6%) than the diabetes-specific message alone (7.6%, p=0.0016). CONCLUSIONS: Messages focused on diabetes were effective at increasing enrolment in a healthy food programme. The addition of a framed active choice to a message significantly raised enrolment rates in this population. These findings suggest that simple, low-cost interventions can enhance enrolment in health promoting programmes and also be pragmatically tested within those programmes. TRIAL REGISTRATION NUMBER: NCT02462057.

BACKGROUND: Previous research has suggested that daily lottery incentives could improve medication adherence. Such daily incentives include implicit reminders. However, the comparative effectiveness of reminders alone versus daily incentives has not been tested. METHODS: A total of 270 patients on warfarin were enrolled in a four-arm, multi-center, randomized controlled trial comparing a daily lottery-based incentive, a daily reminder, and a combination of the two against a control group (usual care). RESULTS: Participants in the reminder group had the lowest percentage of time out of target international normalized ratio (INR) range, the primary outcome, with an adjusted odds of an out-of-range INR 36% lower than among those in the control group, 95%CI [7%, 55%]. No other group had a statistically significant improvement in anticoagulation control relative to the control group or to each other. The only group that had significant improvement in incorrect adherence was the lottery group (incorrect adherence: 12.1% compared with 23.7% in the control group, difference of -7.4% 95%CI [-14%, -0.3%]). However, there was no relationship between changes in adherence and anticoagulation control in the lottery group. CONCLUSIONS: Automated reminders led to the largest improvements in anticoagulation control, although without impacting measured adherence. Lottery-based reminders improved measured adherence but did not lead to improved anticoagulation control

BACKGROUND: Randomized clinical trials provide gold-standard evidence for the efficacy of interventions, but have limitations, including highly selected populations that make inference on effectiveness difficult and a lack of ability to adapt and change midstream. METHODS: We propose two innovations for pragmatic trial design. RESULTS: Evidence-based evolutionary testing, a framework that allows adaptation of interventions and rapid-cycle innovation, preserves the power of randomization while acknowledging the need for adaptation and learning. An opt-out consent framework increases the fraction of the target population who participate in trials, but may lead to dampening of effect sizes. CONCLUSION: Pragmatic trials offer numerous advantages in the evaluation of behavioral interventions in health. Statistical innovations, including evidence-based evolutionary testing and opt-out framing of consent and enrollment processes, can enhance the power of pragmatic trials and lead to more rapid progress.

OBJECTIVES: Diagnostic imaging may be a major source of cancer-related distress, a condition known as "scanxiety". Scant scholarly work has been performed to evaluate scan-associated distress in cancer. We sought to characterize risk factors for scan-associated distress among patients with Non-Small Cell Lung Cancer (NSCLC), and to evaluate the impact of scan-associated distress on quality of life. MATERIALS AND METHODS: We conducted a cross-sectional survey study of patients with recurrent/metastatic NSCLC treated at an academic medical center. Clinical and demographic variables were obtained through chart abstraction and patient self-report. We used a modified version of the Impact of Event Scale 6 (IES-6) to specifically assess distress associated with scans, and quality of life was measured using the Functional Assessment of Cancer Therapy - Lung (FACT-L). RESULTS: Among 103 participants (survey response rate 76.3%), median age was 67, 61.2% were women, and 82.5% were white. At the study visit, 72.8% of subjects discussed a recent scan, and 83% reported some scan-associated distress. Scan-associated distress was not associated with whether the patient had a recent scan, progressive disease or time from diagnosis. Scan-associated distress was associated with impaired quality of life (p=0.004); each unit increase in IES-6 corresponded to an approximately one-unit decrease in FACT-L score. CONCLUSION: Scan-associated distress is a common problem among patients with NSCLC, and is associated with impaired quality of life. Scan-associated distress severity was not associated with time since diagnosis or whether a recent scan was discussed at the study visit, which implies scan-associated distress may be a persistent problem.

BACKGROUND: Coronary artery disease is the single leading cause of death in the United States, and medications can significantly reduce the rate of repeat cardiovascular events and treatment procedures. Adherence to these medications, however, is very low. METHODS: HeartStrong is a national randomized trial offering 3 innovations. First, the intervention is built on concepts from behavioral economics that we expect to enhance its effectiveness. Second, the implementation of the trial takes advantage of new technology, including wireless pill bottles and remote feedback, to substantially automate procedures. Third, the trial's design includes an enhancement of the standard randomized clinical trial that allows rapid-cycle innovation and ongoing program enhancement. RESULTS: Using a system involving direct data feeds from 6 insurance partners followed by mail, telephone, and email contact, we enrolled 1,509 patients discharged from the hospital with acute myocardial infarction in a 2:1 ratio of intervention:usual care. The intervention period lasts 1 year; the primary outcome is time to first fatal or nonfatal acute vascular event or revascularization, including acute myocardial infarction, unstable angina, stroke, acute coronary syndrome admission, or death. CONCLUSIONS: Our randomized controlled trial of the HeartStrong program will provide an evaluation of a state-of-the-art behavioral economic intervention with a number of important pragmatic features. These include a tailored intervention responding to patient activity, streamlining of consent and implementation processes using new technologies, outcomes centrally important to patients, and the ability to implement rapid-cycle innovation.

The substantial nationwide investment in inpatient palliative care services stems from their great promise to improve patient-centered outcomes and reduce costs. However, robust experimental evidence of these benefits is lacking. The Randomized Evaluation of Default Access to Palliative Services (REDAPS) study is a pragmatic, stepped-wedge, cluster randomized trial designed to test the efficacy and costs of specialized palliative care consultative services for hospitalized patients with advanced chronic obstructive pulmonary disease, dementia, or end-stage renal disease, as well as the overall effectiveness of ordering such services by default. Additional aims are to identify the types of services that are most beneficial and the types of patients most likely to benefit, including comparisons between ward and ICU patients. We hypothesize that patient-centered outcomes can be improved without raising costs by simply changing the default option for palliative care consultation from opt-in to opt-out for patients with life-limiting illnesses. Patients aged 45 years or older are enrolled at 11 hospitals using an integrated electronic health record (EHR). As a pragmatic trial designed to enroll between 12,000 and 15,000 patients, eligibility is determined using a validated, EHR-based algorithm, and all outcomes are captured via the EHR and billing systems data. The time at which each hospital transitions from control, opt-in palliative care consultation to intervention, opt-out consultation, is randomly assigned. The primary outcome is a composite measure of in-hospital mortality and length of stay. Secondary outcomes include palliative care process measures and clinical and economic outcomes. The REDAPS trial was registered with clinicaltrials.gov, NCT02505035 on July 16, 2015.

Synchronizing medication refills-renewing all medications at the same time from the same pharmacy-is an increasingly popular strategy to improve adherence to medication regimens, but there has been little research regarding its effectiveness. In light of increasing policy interest, we evaluated the impact of a pilot refill synchronization program implemented by a large national insurer. A random sample of Medicare Advantage patients receiving mail-order refills for common maintenance medications (antihypertensive, lipid-lowering, or antidiabetic agents) were invited to join the program and followed for twelve months. On average, the absolute increase in the proportion of patients deemed adherent during follow-up was 3-10 percentage points for the intervention group, compared to 1-5 percentage points for the control group. Patients with poorer baseline adherence showed larger increases in the absolute proportion deemed adherent in intervention (23-26 percentage points) compared to a control group (13-15 percentage points). Synchronizing refills might be a promising intervention to improve adherence to maintenance medications, especially among Medicare patients with low baseline adherence.