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Abstract Disclosure: S. Fansa: None. W. Ghusn: None. B. Nicolalde: None. D. Anazco: None. E. Tama: None. A. Acosta: None. M.D. Hurtado: None. Introduction: The increasing prevalences of obesity and type 2 diabetes (T2D), the “twin epidemics”, have led to the development of drugs targeting both diseases simultaneously. Liraglutide and semaglutide, GLP-1 receptor agonists used for T2DM, are also FDA-approved for weight loss. Tirzepatide, a novel dual GIP/GLP-1 receptor agonist approved for T2D, has shown promising weight loss outcomes in clinical trials. To date, no study has assessed weight loss outcomes of tirzepatide in a real-world setting. Our aim is to assess its efficacy and safety in patients with overweight or obesity. Methods: This is a retrospective cohort study of adults with overweight or obesity taking weekly subcutaneous tirzepatide for T2D or off-label for weight loss. We excluded patients taking tirzepatide for less than one month, prior bariatric procedure, use of any anti-obesity medications, and active malignancy or pregnancy. The primary outcome was total body weight loss percentage (TBWL%) at 3 months. Secondary outcomes included TBWL% at 1 and 2 months; TBWL% difference by T2D status (with and without) and by sex at 3 months; proportion of patients achieving ≥5%, ≥10%, and ≥15% of TBWL% at 3 months; predictors of TBWL% at 3 months; and reported side effects during follow up. We used paired t-test to assess TBWL% compared to baseline, non-paired t-test to compare TBWL% by T2D status and sex, and univariate analyses to estimate the contribution of other variables to TBWL%. Results are presented as mean ± standard deviation. Results: We included 175 participants (81% female, age 49.8±12.2, 91% white, BMI 38.8±7.3 kg/m2). One third of patients had T2D (n=59, 34%). Most patients were on 5mg (39%) or 7.5mg (22%) of tirzepatide weekly. TBWL% at 1, 2, and 3 months was 3.6±2.5% (n=87), 5.8±3.5% (n=100), and 8.4± 4.3% (n=60), respectively (p <0.0001 compared to baseline at all timepoints). Patients with T2D lost less weight at 3 months compared to patients without T2D: 6.9±4.0% vs. 9.1±4.4% (p= 0.03). At 3 months, TBWL% was greater in females, 9.2±4.3% vs. 5.0±2.5% for males, p<0.0001. Greater baseline weight was associated with greater TBWL% (R=0.32, p<0.0001). At 3 months, 60 patients had documented weights with 81.6% achieving ≥ 5%, 30% achieving ≥10%, and 10% achieving ≥15% TBWL. Forty participants (23%) reported side effects. The most frequent were nausea/vomiting (n=27, 15%), constipation (n=6, 3%), and abdominal pain (n=5, 3%). Eight patients (5%) had to either decrease dosage or discontinue the drug due to side effects. Conclusion: In this retrospective cohort study, tirzepatide led to substantial weight loss at 3 months. Patients with T2DM lost less weight than patients without. Further real-world studies with longer follow-up duration and higher tirzepatide doses are needed to establish the long-term efficacy, safety, and tolerability of this drug in this setting. Presentation: Friday, June 16, 2023

AbstractIntegration and mining of bioimaging data remains a challenge and lags behind the rapidly expanding digital pathology field. We introduce Hourglass, an open‐access analytical framework that streamlines biology‐driven visualization, interrogation, and statistical assessment of multiparametric datasets. Cognizant of tissue and clinical heterogeneity, Hourglass systematically organizes observations across spatial and global levels and within patient subgroups. Applied to an extensive bioimaging dataset, Hourglass promptly consolidated a breadth of known interleukin‐6 (IL‐6) functions via its downstream effector STAT3 and uncovered a so‐far unknown sexual dimorphism in the IL‐6/STAT3‐linked intratumoral T‐cell response in human pancreatic cancer. As an R package and cross‐platform application, Hourglass facilitates knowledge extraction from multi‐layered bioimaging datasets for users with or without computational proficiency and provides unique and widely accessible analytical means to harness insights hidden within heterogeneous tissues at the sample and patient level. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Abstract Background The impact of ongoing efforts to decrease opioid use on patients with cancer remains undefined. Our objective was to determine trends in new and additional opioid use in patients with and without cancer. Methods This retrospective cohort study used data from Surveillance, Epidemiology, and End Results program–Medicare for opioid-naive patients with solid tumor malignancies diagnosed from 2012 through 2017 and a random sample of patients without cancer. We identified 238 470 eligible patients with cancer and further focused on 4 clinical strata: patients without cancer, patients with metastatic cancer, patients with nonmetastatic cancer treated with surgery alone (“surgery alone”), and patients with nonmetastatic cancer treated with surgery plus chemotherapy or radiation therapy (“surgery+”). We identified new, early additional, and long-term additional opioid use and calculated the change in predicted probability of these outcomes from 2012 to 2017. Results New opioid use was higher in patients with cancer (46.4%) than in those without (6.9%) (P < .001). From 2012 to 2017, the predicted probability of new opioid use was more stable in the cancer strata (relative declines: 0.1% surgery alone; 2.4% surgery+; 8.8% metastatic cancer), than in the noncancer stratum (20.0%) (P < .001 for each cancer to noncancer comparison). Early additional use declined among surgery patients (‒14.9% and ‒17.5% for surgery alone and surgery+, respectively) but was stable among patients with metastatic disease (‒2.8%, P = .50). Conclusions Opioid prescribing declined over time at a slower rate in patients with cancer than in patients without cancer. Our study suggests important but tempered effects of the changing opioid climate on patients with cancer.

Abstract Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) are two rare diseases typically separated by clinical, radiologic, and histologic criteria. However, coexistence of both entities is rare, with fewer than 50 cases reported. Although there are reports of patients with LCH and ECD in the same organ, there have been no reported cases of the two diseases involving the lung. We report two cases of ECD-LCH “overlap syndrome” occurring in the lung. In both cases, the diagnoses were supported by typical immunohistochemical patterns, and in both cases, the BRAF V600E mutation was identified by next-generation sequencing and confirmed by droplet digital polymerase chain reaction. In neither case was either diagnosis suspected. The recognition of overlap histiocytoses is important. Although LCH and ECD may differ in treatment and prognosis, in some cases, such as the two patients reported here, they may have the same activating mutations and may be able to be treated with the same targeted therapy.

Abstract Background Carbapenem-resistant Acinetobacter baumannii (CRAb) is 1 of the most problematic antimicrobial-resistant bacteria. We sought to elucidate the international epidemiology and clinical impact of CRAb. Methods In a prospective observational cohort study, 842 hospitalized patients with a clinical CRAb culture were enrolled at 46 hospitals in five global regions between 2017 and 2019. The primary outcome was all-cause mortality at 30 days from the index culture. The strains underwent whole-genome analysis. Results Of 842 cases, 536 (64%) represented infection. By 30 days, 128 (24%) of the infected patients died, ranging from 1 (6%) of 18 in Australia-Singapore to 54 (25%) of 216 in the United States and 24 (49%) of 49 in South-Central America, whereas 42 (14%) of non-infected patients died. Bacteremia was associated with a higher risk of death compared with other types of infection (40 [42%] of 96 vs 88 [20%] of 440). In a multivariable logistic regression analysis, bloodstream infection and higher age-adjusted Charlson comorbidity index were independently associated with 30-day mortality. Clonal group 2 (CG2) strains predominated except in South-Central America, ranging from 216 (59%) of 369 in the United States to 282 (97%) of 291 in China. Acquired carbapenemase genes were carried by 769 (91%) of the 842 isolates. CG2 strains were significantly associated with higher levels of meropenem resistance, yet non-CG2 cases were over-represented among the deaths compared with CG2 cases. Conclusions CRAb infection types and clinical outcomes differed significantly across regions. Although CG2 strains remained predominant, non-CG2 strains were associated with higher mortality. Clinical Trials Registration. NCT03646227.

Abstract Highly conserved transport protein particle (TRAPP) complexes regulate subcellular trafficking pathways. Accurate protein trafficking has been increasingly recognized to be critically important for normal development, particularly in the nervous system. Variants in most TRAPP complex subunits have been found to lead to neurodevelopmental disorders with diverse but overlapping phenotypes. We expand on limited prior reports on TRAPPC6B with detailed clinical and neuroradiologic assessments, and studies on mechanisms of disease, and new types of variants. We describe 29 additional patients from 18 independent families with biallelic variants in TRAPPC6B. We identified seven homozygous nonsense (n = 12 patients) and eight canonical splice-site variants (n = 17 patients). In addition, we identified one patient with compound heterozygous splice-site/missense variants with a milder phenotype and one patient with homozygous missense variants. Patients displayed non-progressive microcephaly, global developmental delay/intellectual disability, epilepsy and absent expressive language. Movement disorders including stereotypies, spasticity and dystonia were also observed. Brain imaging revealed reductions in cortex, cerebellum and corpus callosum size with frequent white matter hyperintensity. Volumetric measurements indicated globally diminished volume rather than specific regional losses. We identified a reduced rate of trafficking into the Golgi apparatus and Golgi fragmentation in patient-derived fibroblasts that was rescued by wild-type TRAPPC6B. Molecular studies revealed a weakened interaction between mutant TRAPPC6B (c.454C>T, p.Q152*) and its TRAPP binding partner TRAPPC3. Patient-derived fibroblasts from the TRAPPC6B (c.454C>T, p.Q152*) variant displayed reduced levels of TRAPPC6B as well as other TRAPP II complex-specific members (TRAPPC9 and TRAPPC10). Interestingly, the levels of the TRAPPC6B homologue TRAPPC6A were found to be elevated. Moreover, co-immunoprecipitation experiments showed that TRAPPC6A co-precipitates equally with TRAPP II and TRAPP III, while TRAPPC6B co-precipitates significantly more with TRAPP II, suggesting enrichment of the protein in the TRAPP II complex. This implies that variants in TRAPPC6B may preferentially affect TRAPP II functions compared to TRAPP III functions. Finally, we assessed phenotypes in a Drosophila TRAPPC6B-deficiency model. Neuronal TRAPPC6B knockdown impaired locomotion and led to wing posture defects, supporting a role for TRAPPC6B in neuromotor function. Our findings confirm the association of damaging biallelic TRAPPC6B variants with microcephaly, intellectual disability, language impairments, and epilepsy. A subset of patients also exhibited dystonia and/or spasticity with impaired ambulation. These features overlap with disorders arising from pathogenic variants in other TRAPP subunits, particularly components of the TRAPP II complex. These findings suggest that TRAPPC6B is essential for brain development and function, and TRAPP II complex activity may be particularly relevant for mediating this function.

INTRODUCTION: The American Gastroenterological Association (AGA) has compiled risk factors that may be predictive of disease complications in Crohn's disease (CD) and ulcerative colitis (UC). The aim of this study was to evaluate the performance of the AGA risk factors for risk stratification in UC and CD. METHODS: We included participants of 2 cohorts: the Ocean State Crohn's and Colitis Area Registry cohort and the Mayo Clinic cohort. Baseline clinical risk factors were extracted according to the AGA pathway. Our primary end point was defined as follows: (i) any inflammatory bowel disease related–hospitalization, (ii) any inflammatory bowel disease–related bowel surgery, or (iii) any progression of disease. We analyzed the association of the number of AGA risk factors with our end point. Statistical multivariable modeling was performed with Cox proportional hazards model. RESULTS: A total of 412 patients with CD were included. Comparing ≥3 risk factors with 0–1 risk factor, we found a significantly increased risk of complications in both the Ocean State Crohn's and Colitis Area Registry cohort (hazard ratio [HR] 2.75, 95% confidence interval 1.71–4.41) and Mayo Clinic cohort (HR 2.07, 95% confidence interval 1.11–3.84). Diagnosis at younger age (HR 2.07), perianal disease (HR 1.99), and B2/B3 behavior (HR 1.92) were significantly associated with disease complications. We did not observe a consistent association between number of risk factors nor any specific individual risk factors and risk of disease complications in the 265 patients with UC included. DISCUSSION: We found a significant association between the number of AGA risk factors and the risk of disease complication in CD; this association was not significant in UC. The presence of ≥ 3 risk factors in CD leads to the highest risk of complications. The AGA care pathway is a useful tool to stratify patients who are at higher risk of disease complications in patients with CD.

ImportancePatients should have an active role in decisions about pursuing or forgoing specific therapies in treatment de-escalation trials.ObjectiveTo evaluate longitudinal patient-reported outcomes (PROs) encompassing decisional comfort and health-related quality of life (HRQOL) among patients who elected to enroll in a clinical trial evaluating radiotherapy alone, without breast surgery, for invasive breast cancers with exceptional response to neoadjuvant systemic therapy (NST).Design, Setting, and ParticipantsProspective, single-group, phase 2 clinical trial at 7 US medical centers. Women aged 40 years or older with invasive cT1-2 N0-1 M0 triple-negative or human epidermal growth factor receptor 2 (ERBB2)–positive breast cancer with no pathologic evidence of residual disease following standard NST enrolled from March 6, 2017, to November 9, 2021. Validated PRO measures were administered at baseline and 6, 12, and 36 months post-radiotherapy. Data were analyzed from January to February 2023.InterventionsPRO measures included the Decision Regret Scale (DRS), Functional Assessment of Cancer Therapy—Lymphedema (FACT-B+4), and Breast Cancer Treatment Outcomes Scale (BCTOS).Main Outcomes and MeasuresChanges in PRO measure scores and subscores over time.ResultsAmong 31 patients, the median (IQR) age was 61 (56-66) years, 26 (84%) were White, and 26 (84%) were non-Hispanic. A total of 15 (48%) had triple-negative disease and 16 (52%) had ERBB2-positive disease. Decisional comfort was high at baseline (median [IQR] DRS score 10 [0-25] on a 0-100 scale, with higher scores indicating higher decisional regret) and significantly increased over time (median [IQR] DRS score at 36 months, 0 [0-20]; P < .001). HRQOL was relatively high at baseline (median [IQR] FACT-B composite score 121 [111-134] on a 0-148 scale, with higher scores indicating higher HRQOL) and significantly increased over time (median [IQR] FACT-B score at 36 months, 128 [116-137]; P = .04). Perceived differences between the affected breast and contralateral breast were minimal at baseline (median [IQR] BCTOS score 1.05 [1.00-1.23] on a 1-4 scale, with higher scores indicating greater differences) and increased significantly over time (median [IQR] BCTOS score at 36 months, 1.36 [1.18-1.64]; P < .001). At 36 months postradiotherapy, the cosmetic subscore was 0.45 points higher than baseline (95% CI, 0.16-0.74; P = .001), whereas function, pain, and edema subscores were not significantly different than baseline.Conclusions and RelevanceIn this nonrandomized phase 2 clinical trial, analysis of PROs demonstrated an overall positive experience for trial participants, with longitudinal improvements in decisional comfort and overall HRQOL over time and minimal lasting adverse effects of therapy.Trial RegistrationClinicalTrials.gov Identifier: NCT02945579

Bifurcation lesions account for 20% of all percutaneous coronary interventions and represent a complex subset which are associated with lower procedural success and higher rates of restenosis [...]

AbstractBackgroundGastroparesis (GP) is characterized by delayed gastric emptying in the absence of mechanical obstruction.ObjectiveGenetic predisposition may play a role; however, investigation at the genome‐wide level has not been performed.MethodsWe carried out a genome‐wide association study (GWAS) meta‐analysis on (i) 478 GP patients from the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium (GpCRC) compared to 9931 population‐based controls from the University of Michigan Health and Retirement Study; and (ii) 402 GP cases compared to 48,340 non‐gastroparesis controls from the Michigan Genomics Initiative. Associations for 5,811,784 high‐quality SNPs were tested on a total of 880 GP patients and 58,271 controls, using logistic mixed models adjusted for age, sex, and principal components. Gene mapping was obtained based on genomic position and expression quantitative trait loci, and a gene‐set network enrichment analysis was performed. Genetic associations with clinical data were tested in GpCRC patients. Protein expression of selected candidate genes was determined in full thickness gastric biopsies from GpCRC patients and controls.ResultsWhile no SNP associations were detected at strict significance (p ≤ 5 × 10−8), nine independent genomic loci were associated at suggestive significance (p ≤ 1 × 10−5), with the strongest signal (rs9273363, odds ratio = 1.4, p = 1 × 10−7) mapped to the human leukocyte antigen region. Computational annotation of suggestive risk loci identified 14 protein‐coding candidate genes. Gene‐set network enrichment analysis revealed pathways potentially involved in immune and motor dysregulation (pFDR ≤ 0.05). The GP risk allele rs6984536A (Peroxidasin‐Like; PXDNL) was associated with increased abdominal pain severity scores (Beta = 0.13, p = 0.03). Gastric muscularis expression of PXDNL also positively correlated with abdominal pain in GP patients (r = 0.8, p = 0.02). Dickkopf WNT Signaling Pathway Inhibitor 1 showed decreased expression in diabetic GP patients (p = 0.005 vs. controls).ConclusionWe report preliminary GWAS findings for GP, which highlight candidate genes and pathways related to immune and sensory‐motor dysregulation. Larger studies are needed to validate and expand these findings in independent datasets.