Faculty Bibliography

PURPOSE/OBJECTIVE:Pancreatic cystic lesions (PCL) commonly undergo surveillance using MRI with MR cholangiopancreatography (MRCP). Our objective is to compare the performance of a single-shot fat-saturated T2-weighted technique with deep-learning reconstruction (DL HASTE-FS) to a conventional T2-weighted Half fourier Single-shot Turbo spin-Echo (HASTE) sequence and to MRCP for the purpose of PCL detection, characterization, and surveillance. METHODS:In this retrospective study, 91 consecutive patients underwent 3T abdominal MRI with MRCP protocol including DL HASTE-FS and conventional HASTE between 8/2/2023 and 10/3/2023. Three abdominal radiologists rated overall and lesion-specific image quality on a 5-point Likert scale, including pancreatic margin and duct sharpness, and PCL conspicuity. A subset of 70 preselected index PCLs were evaluated for cyst features, confidence of diagnosing side-branch IPMN, and suitability of DL HASTE-FS in replacing MRCP for PCL surveillance. RESULTS:DL HASTE-FS received higher scores for pancreatic duct border sharpness (4.1 vs. 3.9; p = .004), pancreatic duct visibility compared to MRCP (2.0 vs. 1.9; p = .04), cyst conspicuity (4.4 vs. 3.9; p < .001), and sharpness of cyst wall and internal septations (4.3 vs. 3.7; p < .001) compared to conventional HASTE. In contrast, conventional HASTE received higher scores for pancreatic margin sharpness (4.2 vs. 3.8; p < .001) and peripancreatic vessel clarity (4.2 vs. 3.4; p < .001). For the 70 preselected index PCLs, readers visualized more PCLs and had higher confidence in diagnosing SB-IPMN on DL HASTE-FS than on conventional HASTE (3.6 vs. 3.4; p < .001). Finally, DL HASTE-FS was deemed a suitable replacement to MRCP for more cases than conventional HASTE (83% vs. 48%; p < .001). CONCLUSION/CONCLUSIONS:DL HASTE-FS outperforms conventional HASTE for PCL detection and characterization, and is a suitable alternative to 3D MRCP in the context of PCL surveillance, potentially reducing exam time and cost.

BACKGROUND AND AIMS/OBJECTIVE:There are currently no brief quantitative assessments that capture the drug patterns of people who engage in use of more than one drug on the same day or simultaneously. The current study examined the retest reliability, acceptability and feasibility of a new quantitative assessment to measure polysubstance use. DESIGN/METHODS:A tool for assessing simultaneous and same-day polysubstance behaviors, the polysubstance assessment tool (PAT) was developed in interviewer-administered and electronic self-administered formats. Participants were allocated 1:1 to receive either version of the PAT and returned one to three days later to repeat the assessment. SETTING/METHODS:New York City, New York, USA. PARTICIPANTS/METHODS:Adults (18 + years, n = 115) who reported use of more than one drug per day in the last 30 days. MEASUREMENTS/METHODS:Test-retest reliability estimates for dichotomous items were assessed using Cohen's kappa, Gwet's Agreement Coefficient 1 (AC1) and percent agreement. Continuous items were assessed with two-way mixed effects intraclass correlations. Bivariate analyses examined acceptability using nine Likert-type survey questions. Feasibility was examined via time to completion. FINDINGS/RESULTS:Overall reliability was moderate to excellent [Gwet's AC1 range 0.70-0.96; intraclass correlation (ICC) range 0.62-0.88]. Reliability was higher for simultaneous polysubstance use (Gwet's AC1 = 0.90) as compared with same-day (Gwet's AC1 = 0.70). Acceptability was high, with no statistically significant difference between the self- and interviewer-administered versions of the tool. Median time to completion was 7 minutes, and was statistically significantly lower for the self-administered tool (median = 5 minutes) compared with the interviewer-administered version (median = 8 minutes) (P < 0.001). CONCLUSIONS:A new polysubstance assessment tool appears to have good reliability and can be considered by researchers seeking a quantitative measure of polysubstance use behaviors given its simplicity, high acceptability and quick completion time.

BACKGROUND/UNASSIGNED:Effective management of alcohol withdrawal syndrome during hospitalization is paramount to patient safety and quality care. NYC Health + Hospitals initiated a quality improvement project to pilot an electronic health record (EHR) integrated, nurse-driven CIWA-Ar symptom-triggered protocol, including recommendations for medications for alcohol use disorder (MAUD), in medical and surgical units at 3 public hospitals. OBJECTIVE/UNASSIGNED:To describe implementation processes and to report related implementation outcomes (appropriateness, feasibility, and adoption) of the updated CIWA-Ar protocol in a safety net hospital setting. METHODS/UNASSIGNED:NYC Health + Hospitals implemented a standardized CIWA-Ar symptom-triggered, nurse-driven EHR protocol on March 15, 2022. The protocol included order sets, practice advisories, task lists, and reminders for assessments and orders. We measured nursing perspectives on feasibility and appropriateness at 6 months via a survey. We measured provider adoption as the proportion of admissions with a CIWA-Ar protocol ordered among admissions that triggered a recommendation, and MAUD use as the proportion of admissions with a MAUD order during hospitalization among all patients with a protocol ordered. RESULTS/UNASSIGNED:= .249). CONCLUSIONS/UNASSIGNED:The CIWA-Ar protocol was appropriate, feasible, and adopted at NYC public hospitals. Quality improvements to ensure protocol fidelity with benzodiazepine dosing and MAUD prescribing are needed.

RAS proteins control signals required for cell growth and survival and, when constitutively activated by mutation, can drive oncogenesis. RAS proteins are primarily regulated by their GTP or GDP binding state, which is controlled by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). RAS proteins are also substrates for dozens of posttranslational modifications (PTMs) that target them to membranes and serve as a secondary means of regulation. Because the newly developed direct RAS inhibitors do not produce durable responses in RAS-dependent cancer, there is renewed interest in targeting the PTMs of RAS. These modifications are the subject of this review.

Aneuploidy is common in cancer and has been implicated in promoting tumor progression, yet the underlying mechanisms remain poorly understood. By generating models of aneuploidy, we found that aneuploidy confers resistance to reactive oxygen species (ROS)-mediated cell death, independent of the specific chromosomes gained or lost. Mechanistically, poly(ADP-ribose) polymerase 1 (PARP1) is suppressed in aneuploid cells, which inhibits PARP1-mediated cell death (parthanatos). We validated aneuploidy-associated PARP1 suppression across 15 cell models and human tumors, with pronounced effects in metastatic tumors. Importantly, PARP1 downregulation promotes tumor metastasis while PARP1 upregulation suppresses it. Through a genome-wide CRISPR screen and functional validation, we identified the transcription factor CCAAT/enhancer-binding protein beta (CEBPB) as a mediator of PARP1 downregulation and ROS resistance in aneuploid cells. Lysosomal dysfunction serves as the upstream activator of CEBPB in aneuploid cells. We propose that aneuploidy-driven CEBPB activation suppresses PARP1, fostering ROS resistance and cancer progression.

BACKGROUND:Decisions involving the purchase of procedural equipment at the health system level require balancing efficacy, safety, physician preference, and cost. The application of efficient and low-cost pragmatic study designs has the potential to rapidly generate data to inform health system operations. METHODS:The aim of the pragmatic RAISE-EMR study is to determine physician preference between two commercially available radial artery introducer sheaths, one of which has a higher acquisition cost, to guide inventory selection in the hospital system's catheterization laboratories. Patients undergoing coronary angiography using 6-French radial artery access were prospectively identified and randomized through the health system's electronic medical record (EMR). Among 1696 eligible unique patients, 554 patients (32.7%) were randomized over 37 days across three hospitals. Randomization took place through the EMR after the attending interventional cardiologist signed a mandated pre-procedure note. The study was deemed non-human subject research and approved by the NYU Langone Health Quality Improvement Oversight Committee. The primary endpoint, a physician satisfaction score, will be ascertained by a mandated semi-quantitative survey within the electronic procedure note. All data, including co-variables and clinical outcomes, will be ascertained using structured data within the EMR. CONCLUSIONS:The RAISE-EMR study is designed to determine physician preference of two commercially available radial artery introducer sheaths and potentially reduce supply costs using an entirely EMR-based randomized study design. Pragmatic study designs leveraging structured data within an EMR can be used to rapidly provide data to inform operational decision-making and have implications for the future of evidence generation.

The 2022 global outbreak of clade IIb mpox represented a turning point in public health's handling of poxviruses. The primary vaccine available for the prevention of mpox is modified vaccinia Ankara from Bavarian-Nordic (MVA-BN). We previously reported a nondurable and low-avidity antibody response against mpox elicited by MVA-BN. In this study, we expanded upon this knowledge by employing a microneutralization assay to measure monkeypox virus (MPXV) neutralizing titers and a multiplexed immunoassay to assess IgG titers and avidity against eight MPXV antigens and two vaccinia antigens. Through a machine learning analysis, we uncovered that MVA-BN vaccinees without prior smallpox vaccination largely return to a baseline seroprofile within a year of immunization. Notably, we identified a discrete population within this group that mounted a robust neutralizing antibody response associated with a longer dosing interval during the MVA-BN primary series. Furthermore, we found that boosting with a third dose of MVA-BN increases IgG avidity against certain MPXV antigens, as part of a booster-specific seroprofile. These findings provide critical insights into optimizing immune responses through MVA-BN boosters, presenting a potential approach to addressing the limited MPXV-specific immunity observed following the primary series.

BACKGROUND:mutations occur in more than 90% of PDAC tumors. Daraxonrasib (RMC-6236) is an oral RAS(ON) multiselective inhibitor that targets guanosine triphosphate-bound mutant and wild-type RAS. METHODS:-mutated PDAC. RESULTS:G12, G13, or Q61 mutations, 29% (95% CI, 15 to 46) had an objective response. The median duration of response was 8.2 months (95% CI, 3.8 to 8.8), with median values of 8.1 months for progression-free survival and 15.6 months for overall survival. CONCLUSIONS:-mutated PDAC; antitumor activity was also reported. (Funded by Revolution Medicines; RMC-6236-001 ClinicalTrials.gov number, NCT05379985.).

Advanced solid tumors remain largely incurable, with most patients ultimately progressing despite modern therapies, including immune checkpoint blockade. The limited impact of these approaches reflects the biological complexity of solid tumors, including intratumoral heterogeneity, an immunosuppressive microenvironment, and the predominance of "undruggable" oncogenic drivers. Adoptive cellular therapy (ACT) offers a complementary strategy by delivering tumor-specific lymphocytes directly into patients. Among ACT modalities, T-cell receptor (TCR)-engineered T cells stand out for their ability to recognize intracellular neoantigens presented by MHC molecules, thus accessing a broader antigenic landscape. Early successes, such as the FDA approvals of lifileucel and afamitresgene autoleucel, highlight the promise of these approaches, while proof-of-concept clinical studies demonstrate activity of personalized neoantigen-reactive TCRs in advanced solid tumors. Major challenges remain, including safety concerns from off-tumor toxicities and resistance mechanisms such as HLA loss of heterozygosity. Ongoing innovations in target discovery, TCR engineering, and combination strategies aim to overcome these barriers and establish mutant-selective TCR therapy as a viable therapeutic strategy in the treatment of solid tumors.