We aimed to determine the long-term yield of pancreatic cancer surveillance in hereditary predisposed high-risk individuals.
From 2006 to 2019, we prospectively enrolled asymptomatic individuals with ...an estimated 10% or greater lifetime risk of pancreatic ductal adenocarcinoma (PDAC) after obligatory evaluation by a clinical geneticist and genetic testing, and subjected them to annual surveillance with both endoscopic ultrasonography (EUS) and MRI/cholangiopancreatography (MRI/MRCP) at each visit.
366 individuals (201 mutation-negative familial pancreatic cancer (FPC) kindreds and 165 PDAC susceptibility gene mutation carriers; mean age 54 years, SD 9.9) were followed for 63 months on average (SD 43.2). Ten individuals developed PDAC, of which four presented with a symptomatic interval carcinoma and six underwent resection. The cumulative PDAC incidence was 9.3% in the mutation carriers and 0% in the FPC kindreds (p<0.001). Median PDAC survival was 18 months (range 1-32). Surgery was performed in 17 individuals (4.6%), whose pathology revealed 6 PDACs (3 T1N0M0), 7 low-grade precursor lesions, 2 neuroendocrine tumours <2 cm, 1 autoimmune pancreatitis and in 1 individual no abnormality. There was no surgery-related mortality. EUS detected more solid lesions than MRI/MRCP (100% vs 22%, p<0.001), but less cystic lesions (42% vs 83%, p<0.001).
The diagnostic yield of PDAC was substantial in established high-risk mutation carriers, but non-existent in the mutation-negative proven FPC kindreds. Nevertheless, timely identification of resectable lesions proved challenging despite the concurrent use of two imaging modalities, with EUS outperforming MRI/MRCP. Overall, surveillance by imaging yields suboptimal results with a clear need for more sensitive diagnostic markers, including biomarkers.
Imaging-based surveillance programs fail to detect pancreatic ductal adenocarcinoma at a curable stage, creating an urgent need for diagnostic biomarkers.
Secretin-stimulated pancreatic juice (PJ) ...was collected from the duodenal lumen during endoscopic ultrasound. The yield of biomarkers and organoids was compared for 2 collection techniques (endoscope suction channel vs catheter-based) and 3 periods (0-4 vs 4-8 vs 8-15 minutes).
Collection through the endoscope suction channel was superior to collection with a catheter. Collection beyond 8 minutes reduced biomarker yield. PJ-derived organoid culture was feasible.
The optimal protocol for secretin-stimulated PJ collection is through the endoscope suction channel for 8 minutes allowing biomarker detection and organoid culture.
Molecular profiling may enable earlier detection of pancreatic cancer (PC) in high-risk individuals undergoing surveillance and allow for personalization of treatment. We hypothesized that the ...detection rate of DNA mutations is higher in pancreatic juice (PJ) than in plasma due to its closer contact with the pancreatic ductal system, from which pancreatic cancer cells originate, and higher overall cell-free DNA (cfDNA) concentrations. In this study, we included patients with pathology-proven PC or intraductal papillary mucinous neoplasm (IPMN) with high-grade dysplasia (HGD) from two prospective clinical trials (KRASPanc and PACYFIC) for whom both PJ and plasma were available. We performed next-generation sequencing on PJ, plasma, and tissue samples and described the presence (and concordance) of mutations in these biomaterials. This study included 26 patients (25 PC and 1 IPMN with HGD), of which 7 were women (27%), with a median age of 71 years (IQR 12) and a median BMI of 23 kg/m
(IQR 4). Ten patients with PC (40%) were (borderline) resectable at baseline. Tissue was available from six patients (resection
= 5, biopsy
= 1). A median volume of 2.9 mL plasma (IQR 1.0 mL) and 0.7 mL PJ (IQR 0.1 mL,
< 0.001) was used for DNA isolation. PJ had a higher median cfDNA concentration (2.6 ng/μL (IQR 4.2)) than plasma (0.29 ng/μL (IQR 0.40)). A total of 41 unique somatic mutations were detected: 24 mutations in plasma (2
, 15
, 2
, 3
1
, and 1
), 19 in PJ (3
, 15
, and 1
), and 8 in tissue (2
, 2
, and 4
). The mutation detection rate (and the concordance with tissue) did not differ between plasma and PJ. In conclusion, while the concentration of cfDNA was indeed higher in PJ than in plasma, the mutation detection rate was not different. A few cancer-associated genetic variants were detected in both biomaterials. Further research is needed to increase the detection rate and assess the performance and suitability of plasma and PJ for PC (early) detection.
Secretin-stimulated pancreatic juice (PJ), collected from the duodenum, presents a valuable biomarker source for the (earlier) detection of pancreatic cancer (PC). Here, we evaluate the feasibility ...and performance of shallow sequencing to detect copy number variations (CNVs) in cell-free DNA (cfDNA) from PJ for PC detection. First, we confirmed the feasibility of shallow sequencing in PJ (n = 4), matched plasma (n = 3) and tissue samples (n = 4, microarray). Subsequently, shallow sequencing was performed on cfDNA from PJ of 26 cases (25 sporadic PC, 1 high-grade dysplasia) and 19 controls with a hereditary or familial increased risk of PC. 40 of the 45 PJ samples met the quality criteria for cfDNA analysis. Nine individuals had an 8q24 gain (oncogene MYC; 23%; eight cases (33%) and one control (6%),
= 0.04); six had both a 2q gain (STAT1) and 5p loss (CDH10; 15%; four cases (7%) and two controls (13%),
= 0.72). The presence of an 8q24 gain differentiated the cases and controls, with a sensitivity of 33% (95% CI 16-55%) and specificity of 94% (95% CI 70-100%). The presence of either an 8q24 or 2q gain with a 5p loss was related to a sensitivity of 50% (95% CI 29-71%) and specificity of 81% (95% CI 54-96%). Shallow sequencing of PJ is feasible. The presence of an 8q24 gain in PJ shows promise as a biomarker for the detection of PC. Further research is required with a larger sample size and consecutively collected samples in high-risk individuals prior to implementation in a surveillance cohort.
To successfully implement imaging-based pancreatic cancer (PC) surveillance, understanding the timeline and morphologic features of neoplastic progression is key. We aimed to investigate the ...progression to neoplasia from serial prediagnostic pancreatic imaging tests in high-risk individuals and identify factors associated with successful early detection.
We retrospectively examined the development of pancreatic abnormalities in high-risk individuals who were diagnosed with PC or underwent pancreatic surgery, or both, in 16 international surveillance programs.
Of 2552 high-risk individuals under surveillance, 28 (1%) developed neoplastic progression to PC or high-grade dysplasia during a median follow-up of 29 months after baseline (interquartile range IQR, 40 months). Of these, 13 of 28 (46%) presented with a new lesion (median size, 15 mm; range 7–57 mm), a median of 11 months (IQR, 8; range 3–17 months) after a prior examination, by which time 10 of 13 (77%) had progressed beyond the pancreas. The remaining 15 of 28 (54%) had neoplastic progression in a previously detected lesion (12 originally cystic, 2 indeterminate, 1 solid), and 11 (73%) had PC progressed beyond the pancreas. The 12 patients with cysts had been monitored for 21 months (IQR, 15 months) and had a median growth of 5 mm/y (IQR, 8 mm/y). Successful early detection (as high-grade dysplasia or PC confined to the pancreas) was associated with resection of cystic lesions (vs solid or indeterminate lesions (odds ratio, 5.388; 95% confidence interval, 1.525–19.029) and small lesions (odds ratio, 0.890/mm; 95% confidence interval 0.812–0.976/mm).
In nearly half of high-risk individuals developing high-grade dysplasia or PC, no prior lesions are detected by imaging, yet they present at an advanced stage. Progression can occur before the next scheduled annual examination. More sensitive diagnostic tools or a different management strategy for rapidly growing cysts are needed.
Almost half of pancreatic cancers develop rapidly and without warning signs on scans or endoscopy. The other half grow from earlier visible pancreatic cysts, which are difficult to discern from innocent cysts.
Pancreatic ductal adenocarcinoma (PDAC) is usually diagnosed in an advanced stage, with minimal likelihood of long-term survival. Only a small subset of patients are diagnosed with early (T1) ...disease. Early detection is challenging due to the late onset of symptoms and limited visibility of sub-centimeter cancers on imaging. A novel approach is to support the clinical diagnosis with molecular markers. MicroRNA derived from extracellular vehicles (EVs) in blood has shown promise as a potential biomarker for pancreatic neoplasia, but microRNA derived from pancreatic juice (PJ) may be a more sensitive biomarker, given that is in close contact with ductal cells from which PDAC arises. This study aims to evaluate and compare the performance of PJ- and serum-derived EV-miRNA for the detection of PDAC.
PJ was collected from the duodenum during EUS after secretin stimulation from 54 patients with PDAC and 118 non-malignant controls. Serum was available for a subset of these individuals. MiR-16, miR-21, miR-25, miR-155 and miR-210 derived from EVs isolated from PJ and serum were analyzed by qPCR, and serum CA19-9 levels were determined by electrochemiluminescence immunoassay. For statistical analysis, either a Mann-Whitney U test or a Wilcoxon Signed Rank test was performed. ROC curves and AUC were used to assess the sensitivity and specificity of miR expression for PDAC detection.
Expression of EV-miR-21, EV-miR-25 and EV-miR-16 were increased in cases vs controls in PJ, while only EV-miR-210 was increased in serum. The potential to detect PC was good for a combination of PJ EV-miR-21, EV-miR-25, EV-miR-16 and serum miR-210, CA-19-9, with an area under the curve of 0.91, a specificity of 84.2% and a sensitivity of 81.5%.
Detection of miRNA from EVs in PJ is feasible. A combined panel of PJ EV-miR-21, EV-miR-25, EV-miR-16, and serum EV-miR-210 and CA19-9 distinguishes cases with PDAC from controls undergoing surveillance with a specificity of 81.5% and sensitivity of 84.2%.
HHLA2 is a recently discovered member of the B7-family of immune checkpoint molecules with limited expression in normal tissues but overexpression in several types of cancer. The aim was to determine ...the expression, prevalence and biological relevance of HHLA2 protein expression in two closely related human cancer types, namely pancreatic cancer and ampullary cancer.
HHLA2 expression levels were retrospectively determined by immunohistochemistry in tissue micro-arrays of surgically resected tumours of 122 pancreatic cancer patients and 72 patients with ampullary cancer of the pancreato-biliary subtype.
HHLA2 was expressed at variable levels by tumour cells in 67% of pancreatic tumours and 93% of ampullary tumours. In the combined cohort high tumoural HHLA2 expression levels were significantly associated with delayed cancer recurrence and improved post-operative cancer-specific survival. The association of HHLA2 expression with cancer-specific survival and recurrence was statistically significant for the pancreatic cancer subgroup while a similar trend was found for the ampullary cancer subgroup. In multivariable analysis together with clinicopathologic characteristics, higher HHLA2 expression was an independent predictor of cancer-specific survival.
The wide expression of HHLA2 in tumour cells and its association with cancer recurrence and patient survival suggest that HHLA2 represents a relevant immune checkpoint molecule in pancreatic and ampullary cancers.
The UEG Journal is committed to values, such as diversity and inclusion, and the composition of this group of Trainee Editors reflects just that. Anna Burelli and Zsa Zsa Weerts will help create ...striking visual abstracts that will enrich our social media platforms, Journal's Website and the understanding of the key points of UEG Journal's articles. ...by (1) expanding the engagement of UEG ambassadors with social media platforms to reach a wider audience; (2) creating a podcast in line with the published content; (3) providing more visual content through visual abstracts.
...Wiley recently launched a Wiley AI Editing Pilot program, which may be a welcome addition for authors with English as their second language, as it provides additional support during the submission ...and reviewing process. ...this program will edit manuscripts with an intelligent, AI-driven tool to ensure that the manuscript is free of any major grammatical or syntactical errors before submission to UEG Journal. The UEG editorial board, in collaboration with the quality-of-care committee, aims to further increase the quality of guidelines by formulating criteria and extensive peer review by reviewers who have undergone training in the guideline formulation.
To date, surveillance of high-risk individuals for pancreatic ductal adenocarcinoma (PDAC) has not lived up to expectations, as identification of curable stages through imaging remains challenging. ...Biomarkers are therefore needed. Pancreatic juice (PJ) may be a promising source, because it is in direct contact with the ductal epithelial lining from which PDAC arises. We aimed to develop a panel of biomarkers from serum and PJ to detect PDAC for future surveillance purposes.
All patients who underwent PJ collection on secretin stimulation at the Erasmus MC were included. Both PJ and serum were evaluated. Protein levels were determined by the Lowry assay. Potential biomarkers (interleukin-8, interferon-γ, neutrophil gelatinase-associated lipocalin NGAL, mucin 5, subtype AC MUC5AC, mucin 2, phospholipase A2 group IB) were selected based on previously reported outcomes and assessed with enzyme-linked immunosorbent assay. Serum carbohydrate antigen 19-9 (CA19-9) values were determined by electrochemiluminescence immunoassay.
This study included 59 cases and 126 surveilled control subjects (who underwent PJ collection), of whom 71 had a hereditary predisposition (35 genetic, 36 familial) and 55 had (suspected neoplastic) pancreatic cysts. CA19-9 values were available for 53 cases and 48 control subjects. Serum CA19-9, as well as PJ interleukin-8, NGAL and MUC5AC, were associated with PDAC independent of age, gender, and presence of diabetes mellitus. Serum CA19-9 had a significantly higher area under the curve (AUC; .86; 95% confidence interval CI, .79-.94) than individual PJ markers (AUC, .62-.70). A combination of PJ markers and serum CA19-9 (panel 2: sensitivity 42% 95% CI, 29-57 and specificity 96% 95% CI, 86-100) did not improve diagnostic performance compared with CA19-9 alone (sensitivity 70% 95% CI, 56-82 and specificity 85% 95% CI, 72-94).
High levels of serum CA19-9 and PJ-derived proteins are associated with PDAC. Prospective surveillance studies including individuals at risk of developing PDAC are required to validate these findings.
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