Capurso, Gabriele

Abstract Monoclonal gammopathy of undetermined significance (MGUS) is a necessary precursor condition to multiple myeloma (MM). Given the role of autophagy in modulating MM risk, we investigated whether genetic variation in autophagy‐related genes influences susceptibility to MGUS. We analyzed the association of 34,042 common autophagy‐related single nucleotide polymorphisms (SNPs) with MGUS across six independent cohorts, five from Europe and one from North America, comprising 2317 MGUS cases and 282,358 controls. We also assessed their impact on immune parameters, including absolute counts of 91 blood‐derived immune cell subsets and 103 circulating immunological proteins. Meta‐analysis revealed a genome‐wide significant association between the ULK4 rs6599175C allele and increased MGUS risk ( p = 3.35 × 10 −8 ). Carriers of this allele showed reduced counts of memory B cell subsets (IgM+CD38+CD27+ and IgD+IgM+CD27+; p = .0038 and p = .0056, respectively) and natural effector B cells (CD24+CD38+IgD+IgM+ cells; p = .0060). Although these associations were not statistically significant after multiple testing correction, they suggest a role of ULK4 in early B‐cell differentiation. Additionally, the CDKN2A rs2811710 variant showed a suggestive association with MGUS risk ( p = 2.17 × 10 −4 ), affecting transcription factor binding involved in B‐cell proliferation and differentiation, although it lacked association with immune markers. In conclusion, we confirm a genome‐wide significant association of the ULK4 locus and MGUS risk, supporting its role in early B‐cell differentiation, and identify CDKN2A as a candidate susceptibility locus warranting further investigation.

ABSTRACT This international, multidisciplinary consensus report represents the first effort to systematically define and characterize fatty pancreas. A key outcome of this endeavor was the recommendation to adopt “fatty pancreas” as the standardized and inclusive term to describe all forms of fat accumulation in the pancreas. This terminological consensus provides a critical foundation for unified reporting and clinical communication. Another major contribution of the report is the consensus on diagnostic imaging findings, which was based on radiological and endoscopic modalities. The proposed criteria aim to enhance consistency in clinical assessment and support the development of standardized research protocols. In addition to establishing terminology and diagnostic frameworks, the report also synthesizes current knowledge across a wide range of relevant domains. These include the etiology and epidemiology of fatty pancreas, as well as its associations with alcohol consumption, smoking, acute and chronic pancreatitis, pancreatic exocrine insufficiency, type 2 diabetes mellitus, and surgical outcomes. The potential links between fatty pancreas and neoplastic conditions such as intraductal papillary mucinous neoplasms and pancreatic cancer are also addressed, alongside the current understanding of its metabolic implications (beta‐cell function and glucose homeostasis) and treatment strategies. Throughout the consensus process, a consistent theme emerged: the limited availability of high‐quality, prospective clinical data. Therefore, many of the recommendations in this report are based on expert consensus rather than strong empirical evidence. As such, the statements require rigorous prospective validation before they can be adopted into routine clinical practice. This underscores a critical need for further research, particularly studies aimed at clarifying causal relationships, validating diagnostic tools, and determining the clinical relevance of fatty pancreas across diverse patient populations. This report serves as both a summary of our current understanding and a roadmap for future investigations, aiming to close existing knowledge gaps and guide evidence‐based clinical practice in this emerging field.

AbstractBackgroundIdentifying branch‐duct intraductal papillary mucinous neoplasms (BD‐IPMNs) at lowest risk of progression may allow for a reduced intensity of surveillance.ObjectiveWe aimed to externally validate the previously developed Dutch‐American Risk stratification Tool (DART‐1; https://rtools.mayo.edu/DART/), which identifies cysts at low risk of developing worrisome features (WFs) or high‐risk stigmata (HRS).MethodsThree prospective cohorts of individuals under surveillance for BD‐IPMNs were combined, independent from the original development cohort. We assessed the performance (discrimination and calibration) of DART‐1, a multivariable Cox‐proportional logistic regression model with five predictors for the development of WFs or HRS.ResultsOf 832 individuals (mean age 77 years, SD 11.5) under surveillance for a median of 40 months (IQR 44), 163 (20%) developed WFs or HRS. DART‐1's discriminative ability (C‐statistic 0.68) was similar to that in the development cohort (0.64–0.72) and showed moderate calibration. DART‐1 adequately estimated the risk for patients in the middle risk quintile, and slightly underestimated it in the lowest quintiles. Their range of predicted versus observed 3‐year risk was 0%–0% versus 0%–3.7% for Q1; 0.3%–0.4% versus 3%–11% for Q2; and 2.6%–3% versus 2.4%–9.8% for Q3. The development of WFs or HRS was associated with pancreatic cancer (p < 0.001). Vice versa, in absence of WFs or HRS, the risk of malignancy was low (0.3%).ConclusionsThe performance of DART‐1 to predict the development of WFs or HRS in BD‐IPMN was validated in an external international cohort, with a discriminative ability equal as in the development cohort. Risk estimations were most accurate for patients with BD‐IPMNs in the middle risk quintile and slightly underestimated in the lowest quintiles.

Abstract Background Persistent organ failure (POF) is the strongest determinant of mortality in acute pancreatitis (AP). There is a paucity of data regarding the impact of different POF attributes on mortality and the role of different characteristics of systemic inflammatory response syndrome (SIRS) in the risk of developing POF. Objective We aimed to assess the association of POF dynamic features with mortality and SIRS characteristics with POF. Methods We studied 1544 AP subjects prospectively enrolled at 22 international centers (APPRENTICE consortium). First, we estimated the association of onset, duration, and maximal score of SIRS with POF. Then, we evaluated the risk of mortality based on POF onset, duration, number, type, and sequence of organs affected. Analyses were adjusted for potential confounders. Results 58% had SIRS, 11% developed POF, and 2.5% died. Early SIRS, persistent SIRS, and maximal SIRS score ≥ 3 were independently associated with higher risk of POF ( p < 0.05). Mortality risk in POF was higher with two (33%, odds ratio [OR] = 10.8, 3.3–34.9) and three (48%, OR = 20.2, 5.9–68.6) organs failing, in comparison to single POF (4%). In subjects with multiple POF, mortality was higher when the cardiovascular and respiratory systems failed first or concurrently as compared to when the renal system failed first or concurrently with other organ ( p < 0.05). In multivariate regression model, the number and sequence of organs affected in POF were associated with mortality ( p < 0.05). Onset and duration of POF had no impact mortality. Conclusion In AP patients with POF, the risk of mortality is influenced by the number, type, and sequence of organs affected. These results are useful for future revisions of AP severity classification systems.

A small number of common susceptibility loci have been identified for pancreatic cancer, one of which is marked by rs401681 in the TERT–CLPTM1L gene region on chromosome 5p15.33. Because this region is characterized by low linkage disequilibrium, we sought to identify whether additional single nucleotide polymorphisms (SNPs) could be related to pancreatic cancer risk, independently of rs401681. We performed an in‐depth analysis of genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) genes, in 5,550 subjects with pancreatic cancer and 7,585 controls from the PANcreatic Disease ReseArch (PANDoRA) and the PanScan consortia. We identified a significant association between a variant in TERT and pancreatic cancer risk (rs2853677, odds ratio = 0.85; 95% confidence interval = 0.80–0.90, p = 8.3 × 10−8). Additional analysis adjusting rs2853677 for rs401681 indicated that the two SNPs are independently associated with pancreatic cancer risk, as suggested by the low linkage disequilibrium between them (r2 = 0.07, D′ = 0.28). Three additional SNPs in TERT reached statistical significance after correction for multiple testing: rs2736100 (p = 3.0 × 10−5), rs4583925 (p = 4.0 × 10−5) and rs2735948 (p = 5.0 × 10−5). In conclusion, we confirmed that the TERT locus is associated with pancreatic cancer risk, possibly through several independent variants.