Faculty Bibliography

Imiquimod is a topical toll-like-receptor-7 agonist currently used for treating basal cell carcinoma. Recently, imiquimod has demonstrated tumor regression in melanoma and breast cancer skin metastases. However, the molecular perturbations induced by imiquimod in breast cancer metastases have not been previously characterized. Here, we describe transcriptomic profiles associated with responsiveness to imiquimod in breast cancer skin metastases. Baseline and post-treatment tumor samples from patients treated with imiquimod in a clinical trial were profiled using Nanostring technology. Through an integrative analytic pipeline, we showed that tumors from patients who achieved a durable clinical response displayed a permissive microenvironment, substantiated by the upregulation of transcripts encoding for molecules involved in leukocyte adhesion and migration, cytotoxic functions, and antigen presentation. In responding patients, Imiquimod triggered a strong T-helper-1 (Th-1)/cytotoxic immune response, characterized by the coordinated upregulation of Th-1 chemokines, migration of Th-1 and cytotoxic T cells into the tumor, and activation of immune-effector functions, ultimately mediating tumor destruction. In conclusion, we have shown that topical imiquimod can induce a robust immune response in breast cancer metastases, and this response is more likely to occur in tumors with a pre-activated microenvironment. In this setting, imiquimod could be utilized in combination with other targeted immunotherapies to increase therapeutic efficacy.

IMPORTANCE:There is new emphasis on clinician trust in health care organizations but little empirical data about the association of trust with clinician satisfaction and retention. OBJECTIVE:To examine organizational characteristics associated with trust. DESIGN, SETTING, AND PARTICIPANTS:This prospective cohort study uses data collected from 2012 to 2014 from 34 primary care practices employing physicians (family medicine and general internal medicine) and advanced practice clinicians (nurse practitioners and physician assistants) in the upper Midwest and East Coast of the United States as part of the Healthy Work Place randomized clinical trial. Analyses were performed from 2015 to 2016. MAIN OUTCOMES AND MEASURES:Clinician trust was measured using a 5-item scale, including belonging, loyalty, safety focus, sense of trust, and responsibility to clinicians in need (range, 1-4, with 1 indicating low and 4 indicating high; Cronbach α = 0.77). Other metrics included work control, work atmosphere (calm to chaotic), organizational culture (cohesiveness, emphases on quality and communication, and values alignment; range, 1-4, with 1 indicating low and 4 indicating high), and clinician stress (range, 1-5, with 1 indicating low and 5 indicating high), satisfaction (range, 1-5, with 1 indicating low and 4 indicating high), burnout (range, 1-5, with 1 indicating no burnout and 5 indicating very high feeling of burnout), and intention to leave (range, 1-5, with 1 indicating no intention to leave and 5 indicating definite intention to leave). Analyses included 2-level hierarchical modeling controlling for age, sex, specialty, and clinician type. Cohen d effect sizes (ESs) were considered small at 0.20, moderate at 0.50, and large at 0.80 or more. RESULTS:The study included 165 clinicians (mean [SD] age, 47.3 [9.2] years; 86 [52.1%] women). Of these, 143 (87.7%) were physicians and 22 (13.3%) were advanced practice clinicians; 105 clinicians (63.6%) worked in family medicine, and 60 clinicians (36.4%) worked in internal medicine. Compared with clinicians with low levels of trust, clinicians who reported high levels of trust had higher mean (SD) scores for work control (2.49 [0.52] vs 2.18 [0.45]; P < .001), cohesiveness (3.11 [0.46] vs 2.51 [0.51]; P < .001), emphasis on quality vs productivity (3.12 [0.48] vs 2.58 [0.41]; P < .001), emphasis on communication (3.39 [0.41] vs 3.01 [0.44]; P < .001), and values alignment (2.61 [0.59] vs 2.12 [0.52]; P < .001). Men were more likely than women to express loyalty (ES, 0.35; 95% CI, 0.05-0.66; P = .02) and high trust (ES, 0.31; 95% CI, 0.01-0.62; P = .04). Compared with clinicians with low trust at baseline, clinicians with high trust at baseline had a higher mean (SD) satisfaction score (3.99 [0.08] vs 3.51 [0.07]; P < .001; ES, 0.70; 95% CI, 0.39-1.02). Compared with clinicians in whom trust declined or remained low, clinicians with improved or stable high trust reported higher mean (SD) satisfaction (4.01 [0.07] vs 3.43 [0.06]; P < .001; ES, 0.98; 95% CI, 0.66-1.31) and lower stress (3.21 [0.09] vs 3.53 [0.09]; P = .02; ES, -0.39; 95% CI, -0.70 to -0.08) scores and had approximately half the odds of intending to leave (odds ratio, 0.481; 95% CI, 0.241-0.957; P = .04). CONCLUSIONS AND RELEVANCE:Addressing low levels of trust by improving work control and emphasizing quality, cohesion, communication, and values may improve clinician satisfaction, stress, and retention.

BACKGROUND:News stories represent an important source of information. We aimed to evaluate the impact of "spin" (i.e., misrepresentation of study results) in health news stories reporting studies of pharmacologic treatments on patients'/caregivers' interpretation of treatment benefit. METHODS:We conducted three two-arm, parallel-group, Internet-based randomized trials (RCTs) comparing the interpretation of news stories reported with or without spin. Each RCT considered news stories reporting a different type of study: (1) pre-clinical study, (2) phase I/II non-RCT, and (3) phase III/IV RCT. For each type of study, we identified news stories reported with spin that had earned mention in the press. Two versions of the news stories were used: the version with spin and a version rewritten without spin. Participants were patients/caregivers involved in Inspire, a large online community of more than one million patients/caregivers. The primary outcome was participants' interpretation assessed by one specific question "What do you think is the probability that 'treatment X' would be beneficial to patients?" (scale, 0 [very unlikely] to 10 [very likely]). RESULTS:For each RCT, 300 participants were randomly assigned to assess a news story with spin (n = 150) or without spin (n = 150), and 900 participants assessed a news story. Participants were more likely to consider that the treatment would be beneficial to patients when the news story was reported with spin. The mean (SD) score for the primary outcome for abstracts reported with and without spin for pre-clinical studies was 7.5 (2.2) versus 5.8 (2.8) (mean difference [95% CI] 1.7 [1.0-2.3], p < 0.001); for phase I/II non-randomized trials, 7.6 (2.2) versus 5.8 (2.7) (mean difference 1.8 [1.0-2.5], p < 0.001); and for phase III/IV RCTs, 7.2 (2.3) versus 4.9 (2.8) (mean difference 2.3 [1.4-3.2], p < 0.001). CONCLUSIONS:Spin in health news stories reporting studies of pharmacologic treatments affects patients'/caregivers' interpretation. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov, NCT03094078 , NCT03094104 , NCT03095586.

A colonic perineurioma is often considered a benign cousin to a colonic polyp. However, in the submucosal type of perineurioma, it is important to rule out the malignant gastrointestinal stromal tumor (GIST). Alternatively, in the BRAF-positive serrated types of perineuriomas, surveillance is equivalent to intervals designated to serrated polyps due to a similar malignant potential. These versions serve as reminders that colonic perineuriomas are not to be disregarded.

Glioblastoma (GBM), representing WHO grade IV astrocytoma, is a relatively common primary brain tumor in adults with an exceptionally dismal prognosis. With an incidence rate of over 10 000 cases in the United States annually, the median survival rate ranges from 10-15 months in IDH1/2-wildtype tumors and 24-31 months in IDH1/2-mutant tumors, with further variation depending on factors such as age, MGMT methylation status, and treatment regimen. We present a cohort of 4 patients, aged 37-60 at initial diagnosis, with IDH1-mutant GBMs that were associated with unusually long survival intervals after the initial diagnosis, currently ranging from 90 to 154 months (all still alive). We applied genome-wide profiling with a methylation array (Illumina EPIC Array 850k) and a next-generation sequencing panel to screen for genetic and epigenetic alterations in these tumors. All 4 tumors demonstrated methylation patterns and genomic alterations consistent with GBM. Three out of four cases showed focal amplification of the CCND2 gene or gain of the region on 12p that included CCND2, suggesting that this may be a favorable prognostic factor in GBM. As this study has a limited sample size, further evaluation of patients with similar favorable outcome is warranted to validate these findings.

BACKGROUND:Reducing costs while increasing or maintaining quality is crucial to delivering high value care. OBJECTIVE:To assess the impact of a hospital value-based management programme on cost and quality. DESIGN/METHODS:Time series analysis of non-psychiatric, non-rehabilitation, non-newborn patients discharged between 1 September 2011 and 31 December 2017 from a US urban, academic medical centre. INTERVENTION/METHODS:NYU Langone Health instituted an institution-wide programme in April 2014 to increase value of healthcare, defined as health outcomes achieved per dollar spent. Key features included joint clinical and operational leadership; granular and transparent cost accounting; dedicated project support staff; information technology support; and a departmental shared savings programme. MEASUREMENTS/METHODS:Change in variable direct costs; secondary outcomes included changes in length of stay, readmission and in-hospital mortality. RESULTS:The programme chartered 74 projects targeting opportunities in supply chain management (eg, surgical trays), operational efficiency (eg, discharge optimisation), care of outlier patients (eg, those at end of life) and resource utilisation (eg, blood management). The study cohort included 160 434 hospitalisations. Adjusted variable costs decreased 7.7% over the study period. Admissions with medical diagnosis related groups (DRG) declined an average 0.20% per month relative to baseline. Admissions with surgical DRGs had an early increase in costs of 2.7% followed by 0.37% decrease in costs per month. Mean expense per hospitalisation improved from 13% above median for teaching hospitals to 2% above median. Length of stay decreased by 0.25% per month relative to prior trends (95% CI -0.34 to 0.17): approximately half a day by the end of the study period. There were no significant changes in 30-day same-hospital readmission or in-hospital mortality. Estimated institutional savings after intervention costs were approximately $53.9 million. LIMITATIONS/CONCLUSIONS:Observational analysis. CONCLUSION/CONCLUSIONS:A systematic programme to increase healthcare value by lowering the cost of care without compromising quality is achievable and sustainable over several years.

BACKGROUND:Patients with chronic conditions routinely see multiple outpatient providers, who may or may not communicate with each other. Gaps in information across providers caring for the same patient can lead to harm for patients. However, the exact causes and consequences of healthcare fragmentation are not understood well enough to design interventions to address them. OBJECTIVE:We sought to elicit patients' and providers' views on the causes and consequences of healthcare fragmentation. DESIGN AND PARTICIPANTS:We conducted a qualitative study with focus groups of patients and, separately, of providers (attending physicians and nurse practitioners) at an academic hospital-based primary care practice in New York City in June-August 2017. Patient participants were English-speaking adults with ≥ 2 chronic conditions. APPROACH:Each focus group lasted 1 h and asked the same two questions: "Why do you think some patients receive care from many different providers and others do not?" and "What do you think happens as a result of patients receiving care from many different providers?" Data collection continued until a point of data saturation was reached. Thematic analysis was used to identify themes and subthemes. KEY RESULTS:We conducted 6 focus groups with a total of 46 participants (25 patients and 21 providers). Study participants identified 41 unique causes of fragmentation, which originate from 4 different levels of the healthcare system (patient, provider, healthcare organization, and healthcare environment); most causes were not related to medical need. Participants also identified 24 unique consequences of fragmentation, of which 3 were desirable and 21 were undesirable. CONCLUSIONS:The results of this study offer a granular roadmap for how to decrease healthcare fragmentation. The large number and severity of negative consequences (including medical errors, misdiagnosis, increased cost, and provider burnout) underscore the urgent need for interventions to address this problem directly.

In the original paper, we used the variable "URBRUR08," from the 2008 survey wave as a measure of childhood urbanicity. Upon further investigation we realized that this variable actually measured Beale urban-rural code during the respondent's adulthood.  Thus, we reran our analysis of the pseudo-heritability of childhood urbanicity using the variable. The original results hold such that even with the first 20 principal components held constant, childhood urban-rural status appears to be ~20% "heritable" in GREML models-a figure that is actually higher than the original estimate reported in the paper (14% controlling for 25 PCs, 15% controlling for 10 PCs, and 29% controlling for two PCs). Meanwhile, the heritabilities of the other phenotypes-height, BMI and education-still do not change when they are residualized on childhood urbanicity. In other words, the original results of the paper do not change.