Introduction

Pancreatic cancer (PC) screening can improve survival in high-risk patients by detecting preneoplastic lesions or early-stage tumors.
Surveillances is mainly based on annual magnetic resonance imaging (MRI) and endoscopic ultrasound (EUS). However, little has been described regarding the possibility of finding other morphological changes that may be also important.

Aims & Methods

The aim of the study is to evaluate all the findings described in screening test and to analyze the correlation between these two screening techniques.
Descriptive observational single-center study that includes high-risk PC patients either due to family history (familial pancreatic cancer) or because they belong to hereditary syndromes, who have been undergone pancreatic cancer screening at our center from 2015 to 2023. Demographic variables and findings described in the EUS or MRI were collected.

Results

Thirty-five patients were included, with a mean age of 57.3 ± 8.2 years and a predominance of females (65.7%). Four patients (11.4%) were smokers, two were diabetic (5.7%), and one had a history of chronic pancreatitis (2.9%). The median follow-up time was 23 months (interquartile range 8-59 months).
The most frequent hereditary syndrome was hereditary breast and ovarian cancer syndrome (n=19, 54.3%), followed by familial atypical multiple mole melanoma syndrome (n=4; 11.4%). The BRCA2 mutation was the most common identifiable genetic factor (34.8%).
Regarding screening test findings, solid tumors were detected in three patients (8.6%) (Two stage I and IV adenocarcinomas and one stage I neuroendocrine tumor). In two individuals (5.7%) branch-duct intraductal papillary mucinous neoplasm were observed. Other pancreatic abnormalities were detected in 18 patients (51.4%) that include chronic pancreatitis-like parenchymal changes (34.3%), peripancreatic lymph nodes and fatty pancreas (5.7%). Finally, in 12 patients (34.3%) the screening tests were normal.
In relation to the concordance between MRI and EUS, in ten patients (28.6%) there was no agreement between these two techniques. EUS detected more parenchymal changes (n=5), pancreatic steatosis (n=2) and one neuroendocrine tumor that were not described on MRI. In contrast, MRI detected a cystic lesion and a pseudonodular enhancement that were not found on EUS.

Conclusion

Pancreatic cancer screening in high-risk individuals, detects neoplastic and preneoplastic lesions at a high rate.
Other findings, such as chronic pancreatitis-like parenchymal changes, peripancreatic lymph nodes or fatty pancreas, were also common in these patients
MRI and EUS have a good correlation, but EUS detects more parenchymal changes.

References

1. Goggins M, Overbeek KA, Brand R et al. Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. Gut 2020; 69 (1): 7-17
2. Bogdanski AM, van Hooft JE, Boekestijn B, Bonsing BA, Wasser MNJM, Klatte DCF, van Leerdam ME. Aspects and outcomes of surveillance for individuals at high‑risk of pancreatic cancer. Fam Cancer 2024; 23(3):323-339.
3. Blackford AL, Canto MI, Dbouk M, Hruban RH, Katona BW, Chak A et al. Pancreatic Cancer Surveillance and Survival of High-Risk Individuals. JAMA Oncol. 2024;10(8):1087-1096.
4. Maurer E, Lehman B, Matthäi E, Denzer U, Figiel J, Jseinghaus M et al. Pancreatic cancer screening is effective in individuals at risk with predisposing germline gene variants, but not in gene variant‐negative familial pancreatic cancer families. United European Gastroenterol J 2024; 12 (9): 1211-1221

Introduction

The PAN-PROMISE symptom score is the first patient-reported outcome (PROM) in acute pancreatitis (AP), and it was developed and validated in a prospective cohort of patients to be used as an endpoint in research. The aim of this study was to assess the performance of the score in a large randomized controlled trial (RCT) and its association with well-established AP endpoints.

Aims & Methods

This is an ancillary study of the WATERFALL trial, where PAN-PROMISE was evaluated at baseline, 24, 48 and 72 hours. The study examined the association between PAN-PROMISE with stablished endpoints in AP: severity, pancreatic and/or peripancreatic fat necrosis (necrosis), infected necrosis, intensive care unit (ICU) admission, persistent organ failure (POF), prolonged hospital stay and mortality. Areas under the ROC curve (AUC) were calculated and used to compare baseline PAN-PROMISE and baseline Bedside Index for Severity in AP (BISAP) for the prediction of these endpoints.

Results

248 patients from the WATERFALL trial were included. A statistically significant association was found between PAN-PROMISE and severity, necrosis, POF, ICU admission, and prolonged hospital stay at all checkpoints (p<0.05). Higher scores were also significantly associated with infected pancreatic necrosis at 24, 48, and 72h and death at baseline and 24 hours. PAN-PROMISE baseline score had a higher AUC than BISAP for severity and necrosis, but the results were not statistically significant.

Conclusion

In the context of a RCT, the PAN-PROMISE score, a patient-centered measure, has been validated with established AP outcomes and as an endpoint for future clinical trials.

Introduction

A male patient in his twenties presented with clinical aspects of primary sclerosing cholangitis (PSC), chronic cholestatic liver disease, and hypothyroidism. PSC is a rare, chronic cholestatic liver disease characterized by biliary strictures and peribiliary fibrosis (1). Susceptible loci were identified in GWAS but the correlation between genetic background and disease pathogenesis needs further investigation (2). In the index patient we identified a heterozygote candidate variant in the ABCC6 gene (c.2279G>A, p.(Arg760Gln)). Dysfunctional ABCC6 was described to cause ABCB11 and ABCG5/G8 genes overexpression, leading to imbalanced bile composition resulting in gallstone formation and cholestasis (3). ABCC6 variants were previously described in cases with low phospholipid-associated cholelithiasis (LPAC) and intrahepatic cholestasis of pregnancy (ICP)(4-6) . Subsequently, we aimed to investigate rare variants in ABCC6 gene in whole exome sequencing (WES) results from patients with suspected cholestatic liver disease.

Aims & Methods

Variant evaluation and annotation analysis was carried out on WES data, with focus on loss of function and missense variants, presenting allele frequency (AF) of ≤1% based on gnomAD database (https://gnomad.broadinstitute.org). Variants were filtered to include only those in genes relevant to the patients’ clinical phenotype. For each rare variant, a comprehensive in silico assessment was performed using tools such as REVEL, AlphaMissense, EVE, SIFT, and MetaLR to evaluate potential pathogenicity. Filtered were prioritized and interpreted using ACMG-AMP guidelines. This systematic approach ensured a clinically meaningful and evidence-based evaluation of the identified variants.

Results

Nine different rare heterozygote variants were identified in fifteen samples of 247 WES results. Among these, the missense variants c.179G>A, p.(Arg60Gln) and c.3139C>T, p.(Arg1047Cys) were found in two LPAC patients. Additionally, the c.1171A>G, p.(Arg391Gly) variant was observed in two related cases: a mother with ICP and her child with elevated gamma-glutamyl transferase (GGT) levels and jaundice. Moreover, this variant was also detected in another patient with elevated transaminases. c.3871G>A, p.(Ala1291Thr) and c.955A>G, p.(Ile319Val) were seen in patients with ICP and cholestasis, respectively. Three other variants were also identified in patients with liver disease of unknown etiology (c.1540G>A, p.(Val514Ile) and c.2707G>C, p.(Glu903Gln) and c.4397G>A, p.CYS1466Tyr). Additionally one splicing variant (c.37-1G>A, p,?) was also detected in a patient with cholangiocarcinoma (CCA). All variants were observed in heterozygote state and classified as variants of uncertain significance (VUS).

Conclusion

An in-depth analysis of WES data led to the identification of several potentially disease-relevant variants in the ABCC6 gene. These variants may play a contributory role in the observed hepatic phenotypes, suggesting a broader functional involvement of ABCC6 beyond its well-established association with pseudoxanthoma elasticum (PXE). Our findings highlight the importance of integrating genetic data with detailed clinical phenotyping to enhance understanding of genotype–phenotype correlations and reveal novel roles for known genes in atypical or organ-specific presentations.

References

1. Reich M, Spomer L, Klindt C, Fuchs K, Stindt J, et al. Downregulation of TGR5 (GPBAR1) in biliary epithelial cells contributes to the pathogenesis of sclerosing cholangitis. J Hepatol. 2021;75(3):634-46.
2. Goode EC, Fachal L, Panousis N, Moutsianas L, McIntyre RE, Bai BYH, et al. Fine-mapping and molecular characterisation of primary sclerosing cholangitis genetic risk loci. Nat Commun. 2024;15(1):9594.
3. Ibold B, Faust I, Tiemann J, Gorgels T, Bergen AAB, Knabbe C, et al. Abcc6 deficiency in mice leads to altered ABC transporter gene expression in metabolic active tissues. Lipids Health Dis. 2019;18(1):2.
4. Liu X, Lai H, Xin S, Li Z, Zeng X, Nie L, et al. Whole-exome sequencing identifies novel mutations in ABC transporter genes associated with intrahepatic cholestasis of pregnancy disease: a case-control study. BMC Pregnancy Childbirth. 2021;21(1):110.
5. Liu X, Zheng J, Xin S, Zeng Y, Wu X, Zeng X, et al. Whole-exome sequencing expands the roles of novel mutations of organic anion transporting polypeptide, ATP-binding cassette transporter, and receptor genes in intrahepatic cholestasis of pregnancy. Front Genet. 2022;13:941027.
6. Romeo M, Dallio M, Federico A. Is it time to reconsider the MRP6 role in bile secretion and LPAC genetic signature? J Hepatol. 2023;79(4):e152-e4.

Disclosure

The authors declare that they have no conflict of interest.