Kahramangil, Doga

210 Background: ERBB2/HER2 amplification defines a rare but clinically distinct subtype of colorectal cancer (CRC), associated with favorable responses to HER2-targeted therapies. In contrast, ERBB2/HER2 -mutant CRCs show limited therapeutic benefit, and their clinical and molecular features remain poorly defined. This study investigated the molecular and clinical features of ERBB2/HER2 -mutant CRCs to provide insight into the molecular basis of their differential therapeutic vulnerabilities compared to amplified CRC. Methods: CRC cases were identified from cBioPortal studies with available clinical and ERBB2/HER2 genomic data. After quality control and deduplication, the cohort included 4407 unique cases: 97 with driver mutation(s) only (2.2%), 86 with amplification only (2%), and 4224 wild-type (95.9%). Demographic, clinical, and molecular features, including microsatellite instability (MSI), tumor mutational burden (TMB), and alterations in 94 oncogenic pathway genes, were compared across groups. Statistical analyses used chi-square/Fisher’s exact tests for categorical data, Kruskal-Wallis tests for continuous variables, and the Benjamini-Hochberg correction for multiple comparisons. Odds ratios and FDR-adjusted p-values were calculated to assess associations. Results: Across groups, the distributions of gender, race, and primary cancer site (colon or rectal cancer) were comparable. However, significant differences were observed in age (mean 58.7 ± 15.0 years for ERBB2/HER2 -mutant, 55 ± 13.9 for amplified, and 59 ± 14.8 for wild-type; p = 0.035) and tumor sidedness (among ERBB2/HER2 -mutant cases: right-colon 30.8%, left-colon 15.2%; among ERBB2/HER2 -amplified: right-colon 12.1%, left-colon 37.9%, p = 0.011). KRAS alterations were significantly more common in ERBB2/HER2 -mutant CRCs (50.5%) compared with both amplified (19.8%) and wild-type (37.6%). MSI-H was detected in 34.5% of ERBB2/HER2 -mutant cases, whereas no MSI-H was observed among amplified tumors (p < 0.001). Expectedly, ERBB2/HER2 -mutant tumors exhibited a hypermutated phenotype, with significantly higher TMB (30.3 ± 45.5) and total mutation count (232.8 ± 926.0), compared to amplified (6.1 ± 9.7 and 15.3 ± 28.4) and wild-type (10.5 ± 20.3 and 126.3 ± 424.5; both p < 0.001). Conversely, ERBB2/HER2 -amplified tumors had the highest fraction of overall genomic alterations including chromosomal changes (0.24 ± 0.17 in amplified vs 0.14 ± 0.17 in mutants and 0.20 ± 0.16 in wild-type; p < 0.001). Hierarchical clustering demonstrated that ERBB2/HER2 -mutant tumors form a distinct molecular cluster, whereas amplified tumors cluster closely with wild-type CRC. Conclusions: ERBB2/HER2 - mutant and amplified CRCs show highly distinct genomic and clinical features, supporting the need for tailored treatment approaches.

ABSTRACT Background: Cannabis is widely used among patients with type 1 diabetes (T1D) in Colorado. Despite increasing use of cannabis among patients with T1D, the frequency and characteristics of unhealthy cannabis use are unknown. We investigated the differences in unhealthy cannabis use in recreational and medical cannabis users with T1D. Methods: Adult cannabis users with T1D completed an in-person questionnaire regarding their cannabis use patterns. They further divided into 2 categories; recreational and medical users. Cannabis Use Disorder Identification Test-Revised (CUDIT-R) was used to identify unhealthy cannabis use (CUDIT-R ≥ 8). Characteristics of cannabis users and unhealthy cannabis use between recreational and medical cannabis users were compared using unpaired t test. Results: Out of 117 patients, 85 patients reported recreational and 32 patients reported medical cannabis use. Based on CUDIT-R scores, 37.6% of adults with T1D had unhealthy cannabis use. Frequency of cannabis use ≥4 times a week was higher among medical users compared to recreational users (59.4% vs 28.2%, P < 0.01). There was no difference between the groups in duration of cannabis use. There was no difference in mean overall CUDIT-R score (7.14 vs 7.5, P = 0.76) between recreational and medical cannabis users. There were also no significant differences in mean CUDIT-R score between recreational and medical users within the nonhazardous use category (3.70 vs 4.4, P = 0.15) and unhealthy cannabis use category (12.84 vs 12.67, P = 0.92). Conclusions: Our study showed no difference in unhealthy cannabis use among recreational and medical cannabis users with T1D. Unhealthy cannabis use should be considered among users with T1D regardless of the reason for its use. Contexte: Le cannabis est largement utilisé chez les patients atteints de diabète de type 1 (DT1) au Colorado. Malgré l’augmentation de la consommation de cannabis chez les patients atteints de DT1, la fréquence et les caractéristiques d’une consommation de cannabis malsaine sont inconnues. Nous avons étudié les différences entre la consommation de cannabis malsaine chez les consommateurs de cannabis récréatifs et médicaux atteints de DT1. Méthodes: Les consommateurs de cannabis adultes atteints de DT1 ont rempli un questionnaire personnel sur leurs habitudes de consommation de cannabis. Ils ont été ensuite divisés en deux catégories; utilisateurs récréatifs et médicaux. Le Test d’identification des troubles liés à l’utilisation du cannabis révisé (CUDIT-R) a été utilisé pour identifier une utilisation malsaine du cannabis (CUDIT-R ≥8). Les caractéristiques des consommateurs de cannabis, ainsi que ceux d’une consommation de cannabis malsaine, entre les consommateurs de cannabis récréatifs et médicaux ont été comparées en utilisant un test t non apparié. Résultats: Sur 117 patients, 85 patients ont signalé des activités récréatives et 32 patients ont déclaré avoir utilisé du cannabis à des fins médicales. D’après les scores CUDIT-R, 37,6% des adultes atteints de DT1 avaient une consommation de cannabis malsaine. La fréquence de consommation de cannabis ≥ 4 fois par semaine était plus élevée chez les utilisateurs de médicaments que chez les utilisateurs récréatifs (59,4% contre 28,2%, p < 0,01). Il n’y avait pas de différence entre les groupes quant à la durée de consommation de cannabis. Il n’y avait pas de différence dans le score CUDIT-R global moyen (7,14 vs 7,5, p = 0,76) entre les utilisateurs de cannabis à des fins récréatives et médicales. Il n’existait pas non plus de différence significative entre le score CUDIT-R moyen entre les utilisateurs récréatifs et les utilisateurs à des fins médicales dans la catégorie d’usages non dangereux (3,70 contre 4,4, p = 0,15) et dans la catégorie d’abus de cannabis (12,84 contre 12,67, p = 0,92). Conclusions: Notre étude n’a montré aucune différence dans la consommation de cannabis malsaine chez les consommateurs de cannabis récréatifs et médicaux atteints de DT1. Une consommation de cannabis malsaine doit être envisagée chez les utilisateurs atteints de DT1, quelle que soit la raison de sa consommation.

Aim To conduct a systematic review and meta‐analysis to understand the timing and factors associated with anti‐programmed cell death protein‐1 ( PD ‐1)/anti‐programmed cell death protein‐1 ligand ( PD ‐L1) inhibitor‐induced Type 1 diabetes. Methods We searched MEDLINE , EMBASE , SCOPUS and Cochrane databases (August 2000–2018) for studies of any design on immune checkpoint inhibitors. A total of 71 cases were reviewed from 56 publications. Comparisons were made using Fisher's exact and Student's t ‐tests. Results The mean ± sd age at Type 1 diabetes presentation was 61.7±12.2 years, 55% of cases were in men, and melanoma (53.5%) was the most frequent cancer. The median time to Type 1 diabetes onset was 49 (5–448) days with ketoacidosis in 76% of cases. The average ± sd HbA 1c concentration was 62 ± 0.3 mmol/mol (7.84±1.0%) at presentation. All cases had insulin deficiency and required permanent exogenous insulin treatment. Half of the cases had Type 1 diabetes‐associated antibodies at presentation, and those with antibodies had a more rapid onset ( P =0.005) and higher incidence of diabetic ketoacidosis ( P =0.02) compared to people without antibodies. Conclusions Many people developed Type 1 diabetes within 3 months of initial PD ‐1/ PD ‐L1 inhibitor exposure. People presenting with Type 1 diabetes‐associated antibodies had a more rapid onset and higher incidence of ketoacidosis than those without antibodies. Healthcare providers caring for people receiving these state‐of‐the‐art therapies need to be aware of this potential severe adverse event.