Faculty Bibliography

Non-small cell lung cancer (NSCLC) patients with loss of the tumor suppressor gene STK11 are resistant to immune checkpoint therapies like anti-PD-1. Here, we conducted an in vivo CRISPR screen that identified HDAC1 as a target to reverse anti-PD-1 resistance driven by loss of STK11 and developed TNG260, a potent small-molecule inhibitor of the CoREST complex with selectivity exceeding previously generated inhibitors in this class in preclinical studies. Treatment with TNG260 led to increased expression of immunomodulatory genes in STK11-deficient cancer cells. When combined with anti-PD-1, TNG260 induced immune-mediated stasis and/or regression in STK11-deficient syngeneic tumor models and autochthonous NSCLC models. In the tumors of patients with STK11-deficient cancers on a clinical trial (NCT05887492), treatment with a combination of TNG260 and pembrolizumab increased intratumoral histone acetylation, PD-L1 tumor proportion scores, and T cell infiltration into the tumor microenvironment. This study illustrates a promising treatment strategy for addressing immune evasion in STK11-mutant NSCLC patients.

IMPORTANCE/UNASSIGNED:Hospital course (HC) summarization represents an increasingly onerous discharge summary component for physicians. Literature supports large language models (LLMs) for HC summarization, but whether physicians can effectively partner with electronic health record-embedded LLMs to draft HCs is unknown. OBJECTIVES/UNASSIGNED:To compare the editing effort required by time-constrained resident physicians to improve LLM- vs physician-generated HCs toward a novel 4Cs (complete, concise, cohesive, and confabulation-free) HC. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:Quality improvement study using a convenience sample of 10 internal medicine resident editors, 8 hospitalist evaluators, and randomly selected general medicine admissions in December 2023 lasting 4 to 8 days at New York University Langone Health. EXPOSURES/UNASSIGNED:Residents and hospitalists reviewed randomly assigned patient medical records for 10 minutes. Residents blinded to author type who edited each HC pair (physician and LLM) for quality in 3 minutes, followed by comparative ratings by attending hospitalists. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Editing effort was quantified by analyzing the edits that occurred on the HC pairs after controlling for length (percentage edited) and the degree to which the original HCs' meaning was altered (semantic change). Hospitalists compared edited HC pairs with A/B testing on the 4Cs (5-point Likert scales converted to 10-point bidirectional scales). RESULTS/UNASSIGNED:Among 100 admissions, compared with physician HCs, residents edited a smaller percentage of LLM HCs (LLM mean [SD], 31.5% [16.6%] vs physicians, 44.8% [20.0%]; P < .001). Additionally, LLM HCs required less semantic change (LLM mean [SD], 2.4% [1.6%] vs physicians, 4.9% [3.5%]; P < .001). Attending physicians deemed LLM HCs to be more complete (mean [SD] difference LLM vs physicians on 10-point bidirectional scale, 3.00 [5.28]; P < .001), similarly concise (mean [SD], -1.02 [6.08]; P = .20), and cohesive (mean [SD], 0.70 [6.14]; P = .60), but with more confabulations (mean [SD], -0.98 [3.53]; P = .002). The composite scores were similar (mean [SD] difference LLM vs physician on 40-point bidirectional scale, 1.70 [14.24]; P = .46). CONCLUSIONS AND RELEVANCE/UNASSIGNED:Electronic health record-embedded LLM HCs required less editing than physician-generated HCs to approach a quality standard, resulting in HCs that were comparably or more complete, concise, and cohesive, but contained more confabulations. Despite the potential influence of artificial time constraints, this study supports the feasibility of a physician-LLM partnership for writing HCs and provides a basis for monitoring LLM HCs in clinical practice.

Importance/UNASSIGNED:There is clinical equipoise for COVID-19 convalescent plasma (CCP) use in patients hospitalized with COVID-19. Objective/UNASSIGNED:To determine the safety and efficacy of CCP compared with placebo in hospitalized patients with COVID-19 receiving noninvasive supplemental oxygen. Design, Setting, and Participants/UNASSIGNED:CONTAIN COVID-19, a randomized, double-blind, placebo-controlled trial of CCP in hospitalized adults with COVID-19, was conducted at 21 US hospitals from April 17, 2020, to March 15, 2021. The trial enrolled 941 participants who were hospitalized for 3 or less days or presented 7 or less days after symptom onset and required noninvasive oxygen supplementation. Interventions/UNASSIGNED:A unit of approximately 250 mL of CCP or equivalent volume of placebo (normal saline). Main Outcomes and Measures/UNASSIGNED:The primary outcome was participant scores on the 11-point World Health Organization (WHO) Ordinal Scale for Clinical Improvement on day 14 after randomization; the secondary outcome was WHO scores determined on day 28. Subgroups were analyzed with respect to age, baseline WHO score, concomitant medications, symptom duration, CCP SARS-CoV-2 titer, baseline SARS-CoV-2 serostatus, and enrollment quarter. Outcomes were analyzed using a bayesian proportional cumulative odds model. Efficacy of CCP was defined as a cumulative adjusted odds ratio (cOR) less than 1 and a clinically meaningful effect as cOR less than 0.8. Results/UNASSIGNED:Of 941 participants randomized (473 to placebo and 468 to CCP), 556 were men (59.1%); median age was 63 years (IQR, 52-73); 373 (39.6%) were Hispanic and 132 (14.0%) were non-Hispanic Black. The cOR for the primary outcome adjusted for site, baseline risk, WHO score, age, sex, and symptom duration was 0.94 (95% credible interval [CrI], 0.75-1.18) with posterior probability (P[cOR<1] = 72%); the cOR for the secondary adjusted outcome was 0.92 (95% CrI, 0.74-1.16; P[cOR<1] = 76%). Exploratory subgroup analyses suggested heterogeneity of treatment effect: at day 28, cORs were 0.72 (95% CrI, 0.46-1.13; P[cOR<1] = 93%) for participants enrolled in April-June 2020 and 0.65 (95% CrI, 0.41 to 1.02; P[cOR<1] = 97%) for those not receiving remdesivir and not receiving corticosteroids at randomization. Median CCP SARS-CoV-2 neutralizing titer used in April to June 2020 was 1:175 (IQR, 76-379). Any adverse events (excluding transfusion reactions) were reported for 39 (8.2%) placebo recipients and 44 (9.4%) CCP recipients (P = .57). Transfusion reactions occurred in 2 (0.4) placebo recipients and 8 (1.7) CCP recipients (P = .06). Conclusions and Relevance/UNASSIGNED:In this trial, CCP did not meet the prespecified primary and secondary outcomes for CCP efficacy. However, high-titer CCP may have benefited participants early in the pandemic when remdesivir and corticosteroids were not in use. Trial Registration/UNASSIGNED:ClinicalTrials.gov Identifier: NCT04364737.

IMPORTANCE/OBJECTIVE:Patient-driven mobile teledermoscopy may be applicable for monitoring of skin lesions. OBJECTIVE:To assess the feasibility, efficacy, and patient receptivity of teledermoscopy for short-term monitoring of clinically atypical nevi. DESIGN, SETTING, AND PARTICIPANTS/METHODS:This was a prospective cohort study performed at an institutional referral center in New York. Consecutive patients 18 years or older, with 1 or more clinically atypical nevi that required short-term monitoring and were accessible by a mobile imaging device were recruited for the study. All 34 patients consented to the study, and 29 completed follow-up. Dermoscopic images were obtained in the office-based setting by a dermatologist and with an iPhone by the patient at baseline and follow-up (3-4 months). Patients completed surveys that included questions about skincare awareness and attitudes toward teledermoscopy. Standard dermoscopic images were evaluated by the office-based dermatologist, and mobile dermoscopic images were sent via the Internet to a teledermatologist to evaluate image quality and presence of significant clinical lesion change. The decisions of the teledermatologist and office-based dermatologist were compared. MAIN OUTCOMES AND MEASURES/METHODS:(1) Feasibility of using mobile dermatoscope by patients, (2) diagnostic concordance of teledermoscopy vs conventional office-based visit, and (3) patient receptivity to teledermoscopy for short-term monitoring of nevi. RESULTS:Of the 29 patients who completed the study, 28 (97%) were able to acquire baseline and follow-up images that were subsequently deemed evaluable by the teledermatologist. The diagnostic concordance between conventional office-based visits and teledermoscopy encounters was 0.87 (SE, 0.13) (κ statistic). In addition, patients reported high receptivity to teledermoscopy for short-term monitoring of nevi. CONCLUSIONS AND RELEVANCE/CONCLUSIONS:Results from this pilot study suggest that teledermoscopy is feasible and effective as a method for short-term monitoring of clinically atypical nevi. The implementation of teledermoscopy can potentially enhance patient convenience, optimize physician scheduling, and promote efficiency.