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Abstract Background and Aims Primary sclerosing cholangitis (PSC) increases the risk of developing cholangiocarcinoma (CCA), which is the leading cause of premature death in these patients. Current diagnostic methods for early detection of either condition remain largely suboptimal. This study investigates serum metabolites as potential non-invasive diagnostic biomarkers. Methods This multicenter international study analyzed 459 serum samples from 13 international centers, including patients with PSC (n = 216), PSC who developed CCA during follow-up (PSC to CCA; n = 24), PSC with concomitant CCA (PSC-CCA; n = 88), ulcerative colitis (UC; n = 14), and healthy individuals (n = 79). Serum metabolomics was evaluated by ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS) and the accuracy of the single candidate metabolite biomarkers was further assessed. Machine learning was used to generate the best diagnostic and predictive algorithms. Results Fifty-two serum metabolites were identified as markers of PSC, independent of age, biological sex, cirrhosis, UC, or ursodeoxycholic acid (UDCA) treatment. A diagnostic model based on only six lipids distinguished PSC patients from healthy controls with high accuracy (AUC 0.952 discovery, 0.918 validation), independently of the levels of transaminases or cholestasis markers (i.e., GGT, AP, bilirubin) in blood. Subgroup analyses were performed in PSC patients with and without inflammatory bowel disease (IBD), confirming the model’s consistent performance across both subgroups when compared with their respective control groups – UC and healthy controls (AUC 0.959 and 0.939, respectively). The PSC model also confirmed its diagnostic performance in patients with established PSC-CCA or progression to CCA within 2 years, when compared to UC and healthy controls, showing AUC values ranging from 0.911 to 0.976. Additionally, 20 metabolites were significantly altered in PSC patients with CCA (PSC-CCA), regardless of demographics, cirrhosis, UDCA treatment, IBD status, or CCA subtype, and independently of serum transaminases and cholestatic markers levels. A model incorporating six lipids accurately identified PSC-CCA cases compared to PSC patients (AUC = 0.912 discovery; 0.896 validation), showing excellent performance in early-stage tumor detection (AUC 0.921) and outperforming CA19-9 (AUC 0.708). Importantly, the model retained high accuracy even in CCA patients with low CA19-9 levels (AUC 0.905) and in PSC patients who developed CCA within a year of clinical diagnosis (AUC 0.792). Conclusion The PSC and PSC-CCA blood tests provide a non-invasive approach for diagnosing PSC and PSC-CCA, addressing an important need in this population. Their integration into clinical practice could enhance risk stratification, early detection, personalized surveillance, and treatment decision-making in PSC patients.

Abstract Rationale Postoperative pulmonary complications (PPCs) importantly contribute to postoperative morbidity and mortality, particularly for American Society of Anesthesiologists (ASA) physical status III patients. It remains unclear whether risk factors for PPCs depend on sex. We hypothesised that sex modifies the relationship between perioperative risk factors and PPCs in ASA III patients undergoing noncardiothoracic surgery with general anesthesia. Methods We performed a secondary analysis of prospective data from 1,202 ASA III patients undergoing non-cardiothoracic surgery. Data consisted of preoperative demographics, comorbidities, intraoperative physiology, medications, and procedure information. The primary outcome was a composite of PPCs by postoperative day 7. Mixed-effects linear models incorporated sex as main effect and interaction with covariates. Results Age, chronic obstructive pulmonary disease, upper abdominal surgery, surgical duration, and emergency surgery significantly increased the odds of ≥ 1 PPC by postoperative day 7. Male patients presented a higher rate of ≥ 3 PPCs, and mechanical ventilation was less protective in female patients. Yet, sex did not significantly modify the relationship between perioperative factors and the primary outcome (no p<0.05 for the interaction effect with sex). In the secondary analysis, gastroesophageal reflux disease affected atelectasis more strongly in male than female patients (relative odds-ratios for female versus male =0.27; 95% CI 0.13 to 0.57). Conclusions In ASA III patients undergoing non-cardiothoracic surgery with general anesthesia, perioperative factors are predominantly not significantly modified by sex in their relationship to PPCs. GERD’s association with atelectasis in male patients could be explored in future prospective studies as a target for reducing pulmonary complications. This abstract is funded by: NHLBI - UH3 HL140177

Abstract Castleman disease (CD) describes a group of rare lymphoproliferative disorders that exhibit a wide range of symptomatology and degree of lymphadenopathy, particularly across the 2 forms of CD with unknown etiology, unicentric CD (UCD), and human herpesvirus-8–negative/idiopathic multicentric CD (iMCD). Whereas UCD cases typically present with localized lymphadenopathy and mild symptoms, iMCD involves multicentric lymphadenopathy and cytokine storm–driven symptoms with 3 recognized clinical phenotypes. Increasingly, there are anecdotal reports of cases that do not fit into this framework, but these cases have not been systematically described. Herein, we use the ACCELERATE natural history registry to characterize the spectrum of CD based on disease features, symptomatology, and severity. Our results characterize a cohort of 179 CD cases, which were reviewed and confirmed by an expert panel of clinicians and hematopathologists. We show that patients with CD present on a continuous spectrum of clinical phenotypes, and we describe oligocentric CD (OligoCD), an intermediate phenotype that does not fit the criteria for UCD or iMCD. These cases tend to have “oligocentric” lymphadenopathy (median [interquartile range] regions of lymphadenopathy, 3.0 [2.0-4.0]) in a regional pattern and exhibit a mild clinical phenotype that is more similar to UCD than iMCD. We also show that patients with OligoCD are inconsistently categorized as UCD vs iMCD, highlighting the need for this characterization. Future data collected through ACCELERATE may further elucidate the natural history and risk profile of these patients.

9069 Background: With the emergence of effective targeted-therapies for KRAS G12C, and the development of promising agents for KRAS G12V and G12D among others, the identity of unique KRAS mutations in non-small cell lung cancer (NSCLC) has become increasingly relevant. Acquired KRAS mutations are a known mechanism of resistance observed across driver mutation-positive (DM+) NSCLC. The incidence and diversity of these acquired alterations, and whether they differ from those observed in de novo KRAS-mutated NSCLC, is unknown. Methods: NSCLC molecular profiles were obtained using next-generation sequencing (Caris Life Sciences) with paired whole-transcriptomic sequencing (Illumina NovaSeq) and immunohistochemistry (Caris Life Sciences). Demographic data were abstracted from medical records. KRAS mutation diversity was defined for de novo KRAS-mutated ( KRASmt) NSCLC ( KRAS as only identified driver – KRASmt_dn) and DM+ NSCLC with acquired KRAS mutations (concurrent KRASmt with other known driver – KRASmt_acq). Fisher’s exact test was used to compare the distribution of unique KRAS mutations between the groups. Due to the unique biology of NSCLC with class II/III BRAF mutations, this subset was removed from the KRASmt_acq subgroup for the final analysis. Results: A total of 5932 KRASmt NSCLC samples were identified, among which 5879 were KRASmt_dn and 53 were KRASmt_acq (see table). The distribution of unique KRAS mutations was not significantly different between groups (p = 0.14). Within the KRASmt_dn group, KRAS G12C was most common (40%), followed by G12V (19%), G12D (14%), G12A (7%) and Q61H/G13C (4% each). In the KRASmt_acq group, KRAS G12C was most common (30%), followed by G12D (19%), G12V (17%), Q61H (11%), G12A (7%), and G13C (6%). The most common observed driver mutations in the KRASmt_acq group were EGFR (38%) and MET (30%). In the EGFR group, KRAS G12D (25%), Q61H/G12C (20% each), G12V/G13C (10% each), and G12F/A/R (5% each) were observed. In the MET group, KRAS G12C (25%), G12D/V/A (19% each), Q61H (12%) and G12S (6%) were seen. Among 7 patients with a documented history of smoking in the KRASmt_acq group, KRAS G12D and Q61H were most common (29% each), followed by G12V/F and G13C (14% each). Conclusions: While the distribution of unique KRAS mutations did not differ significantly between KRASmt_dn and KRASmt_acq groups, acquired KRAS mutations were seen across DM+ NSCLC subsets, among which the frequency of observed mutations appeared to vary. The functional and immunological significance of these mutations, and their impact on clinical outcomes, warrants further investigation. [Table: see text]

Background: DPP4 (dipeptidyl peptidase-4) inhibitors comprise a class of oral diabetes medication that have the potential for off-target cardiovascular effects. We previously showed that DPP4 inhibition attenuates the hypotensive effect of acute ACE (angiotensin-converting enzyme) inhibition and increases norepinephrine. Here, we investigated the effects of DPP4 during sustained ACE inhibition compared with during therapy with an ARB (angiotensin receptor blocker) or calcium channel blocker (neutral comparator) in a randomized, double-blinded crossover study. Methods: We enrolled 106 adults with type 2 diabetes and hypertension and 100 received intervention. Subjects were randomized to one of 3 blood pressure arms: ramipril, valsartan, or amlodipine for a total of 15 weeks and received 3 one-week crossover therapies in random order: placebo + placebo, sitagliptin + placebo, and sitagliptin + aprepitant separated by 4-week washout. Results: We found that DPP4 inhibition increased norepinephrine during ramipril but did not increase blood pressure. Aprepitant, a NK1 (substance P) receptor blocker, lowered standing heart rate during renin-angiotensin-aldosterone system blockade with ramipril or valsartan. Conclusions: Increased catecholamines during concurrent ACE and DPP4 inhibition may contribute to cardiovascular complications in patients predisposed to heart failure.

BRCA2 is essential for homologous recombination DNA repair. BRCA2 mutations lead to genome instability and increased risk of breast and ovarian cancer. Similarly, mutations in BRCA2-interacting proteins are also known to modulate sensitivity to DNA damage agents and are established cancer risk factors. Here we identify the tumor suppressor CDK5RAP3 as a novel BRCA2 helical domain-interacting protein. CDK5RAP3 depletion induced DNA damage resistance, homologous recombination and single-strand annealing upregulation, and reduced spontaneous and DNA damage-induced genomic instability, suggesting that CDK5RAP3 negatively regulates double-strand break repair in the S-phase. Consistent with this cellular phenotype, analysis of transcriptomic data revealed an association between low CDK5RAP3 tumor expression and poor survival of breast cancer patients. Finally, we identified common genetic variations in the CDK5RAP3 locus as potentially associated with breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. Our results uncover CDK5RAP3 as a critical player in DNA repair and breast cancer outcomes.

Abstract Background The European Society of Gastrointestinal Endoscopy (ESGE) has developed a core curriculum for high quality optical diagnosis training for practice across Europe. The development of easy-to-measure competence standards for optical diagnosis can optimize clinical decision-making in endoscopy. This manuscript represents an official Position Statement of the ESGE aiming to define simple, safe, and easy-to-measure competence standards for endoscopists and artificial intelligence systems performing optical diagnosis of diminutive colorectal polyps (1 – 5 mm). Methods A panel of European experts in optical diagnosis participated in a modified Delphi process to reach consensus on Simple Optical Diagnosis Accuracy (SODA) competence standards for implementation of the optical diagnosis strategy for diminutive colorectal polyps. In order to assess the clinical benefits and harms of implementing optical diagnosis with different competence standards, a systematic literature search was performed. This was complemented with the results from a recently performed simulation study that provides guidance for setting alternative competence standards for optical diagnosis. Proposed competence standards were based on literature search and simulation study results. Competence standards were accepted if at least 80 % agreement was reached after a maximum of three voting rounds. Recommendation 1 In order to implement the leave-in-situ strategy for diminutive colorectal lesions (1–5 mm), it is clinically acceptable if, during real-time colonoscopy, at least 90 % sensitivity and 80 % specificity is achieved for high confidence endoscopic characterization of colorectal neoplasia of 1–5 mm in the rectosigmoid. Histopathology is used as the gold standard. Level of agreement 95 %. Recommendation 2 In order to implement the resect-and-discard strategy for diminutive colorectal lesions (1–5 mm), it is clinically acceptable if, during real-time colonoscopy, at least 80 % sensitivity and 80 % specificity is achieved for high confidence endoscopic characterization of colorectal neoplasia of 1–5 mm. Histopathology is used as the gold standard. Level of agreement 100 %. Conclusion The developed SODA competence standards define diagnostic performance thresholds in relation to clinical consequences, for training and for use when auditing the optical diagnosis of diminutive colorectal polyps.