Systematic review and meta-analysis: Diagnostic performance of DNA alterations in pancreatic juice for the detection of pancreatic cancer.

BACKGROUND AND AIMS: Pancreatic cancer has a dismal prognosis. So far, imaging has been proven incapable of establishing an early enough diagnosis. Thus, biomarkers are urgently needed for early detection and improved survival. Our aim was to evaluate the pooled diagnostic performance of DNA alterations in pancreatic juice. METHODS: A systematic literature search was performed in EMBASE, MEDLINE Ovid, Cochrane CENTRAL and Web of Science for studies concerning the diagnostic performance of DNA alterations in pancreatic juice to differentiate patients with high-grade dysplasia or pancreatic cancer from controls. Study quality was assessed using QUADAS-2. The pooled prevalence, sensitivity, specificity and diagnostic odds ratio were calculated. RESULTS: Studies mostly concerned cell-free DNA mutations (32 studies: 939 cases, 1678 controls) and methylation patterns (14 studies: 579 cases, 467 controls). KRAS, TP53, CDKN2A, GNAS and SMAD4 mutations were evaluated most. Of these, TP53 had the highest diagnostic performance with a pooled sensitivity of 42% (95% CI: 31-54%), specificity of 98% (95%-CI: 92%-100%) and diagnostic odds ratio of 36 (95% CI: 9-133). Of DNA methylation patterns, hypermethylation of CDKN2A, NPTX2 and ppENK were studied most. Hypermethylation of NPTX2 performed best with a sensitivity of 39-70% and specificity of 94-100% for distinguishing pancreatic cancer from controls. CONCLUSIONS: This meta-analysis shows that, in pancreatic juice, the presence of distinct DNA mutations (TP53, SMAD4 or CDKN2A) and NPTX2 hypermethylation have a high specificity (close to 100%) for the presence of high-grade dysplasia or pancreatic cancer. However, the sensitivity of these DNA alterations is poor to moderate, yet may increase if they are combined in a panel.

Longitudinal changes of serum protein N-Glycan levels for earlier detection of pancreatic cancer in high-risk individuals.

BACKGROUND: Surveillance of individuals at risk of developing pancreatic ductal adenocarcinoma (PDAC) has the potential to improve survival, yet early detection based on solely imaging modalities is challenging. We aimed to identify changes in serum glycosylation levels over time to earlier detect PDAC in high-risk individuals. METHODS: Individuals with a hereditary predisposition to develop PDAC were followed in two surveillance programs. Those, of which at least two consecutive serum samples were available, were included. Mass spectrometry analysis was performed to determine the total N-glycome for each consecutive sample. Potentially discriminating N-glycans were selected based on our previous cross-sectional analysis and relative abundances were calculated for each glycosylation feature. RESULTS: 165 individuals ("FPC-cohort" N = 119; Leiden cohort N = 46) were included. In total, 97 (59%) individuals had a genetic predisposition (77 CDKN2A, 15 BRCA1/2, 5 STK11) and 68 (41%) a family history of PDAC without a known genetic predisposition (>10-fold increased risk of developing PDAC). From each individual, a median number of 3 serum samples (IQR 3) was collected. Ten individuals (6%) developed PDAC during 35 months of follow-up; nine (90%) of these patients carried a CDKN2A germline mutation. In PDAC cases, compared to all controls, glycosylation characteristics were increased (fucosylation, tri- and tetra-antennary structures, specific sialic linkage types), others decreased (complex-type diantennary and bisected glycans). The largest change over time was observed for tri-antennary fucosylated glycans, which were able to differentiate cases from controls with a specificity of 92%, sensitivity of 49% and accuracy of 90%. CONCLUSION: Serum N-glycan monitoring may support early detection in a pancreas surveillance program.

Measuring Barrett's Epithelial Thickness with Volumetric Laser Endomicroscopy as a Biomarker to Guide Treatment.

BACKGROUND: Radiofrequency ablation (RFA) treatment outcomes vary for unknown reasons. One hypothesis is that variations in Barrett's epithelial thickness (BET) are associated with reduced RFA efficacy for thicker BET and strictures for thinner BET. Volumetric laser endomicroscopy (VLE) is an imaging modality that acquires high-resolution, depth-resolved images of BE. However, the attenuation of light by tissue and the lack of layering in Barrett's tissue challenge BET measurements and the study of relationships between thickness and RFA outcomes. We aimed to quantify BET and compared the reliability of standard and contrast-enhanced VLE images. METHODS: Baseline VLE scans from BE patients without prior ablative therapy and a Prague (M) length of > 1 cm were obtained from the US VLE Registry. An algorithm was applied to the VLE images to flatten the mucosal surface and enhance the contrast of different esophageal wall layers. Subsequently, BET was measured by two independent VLE readers using both contrast- and non-contrast-enhanced datasets. In order to validate these adjusted images, intra- and interobserver agreements were calculated. RESULTS: VLE scans from fifty-seven patients were included in this study. BET was measured at eight equidistant locations on the selected cross-sectional images at 0.5 cm intervals from the GEJ to the proximal-most extent of BE. The intra-observer coefficients of the two readers for the contrast-enhanced images were 0.818 (95% CI 0.798-0.836) and 0.890 (95% CI 0.878-0.900). The interobserver agreement for the contrast-enhanced images (0.880; 95% CI 0.867-0.891) was significantly better than for the original images (0.778; 95% CI 0.754-0.799). CONCLUSION: We developed an algorithm that improves VLE visualization of the mucosal layers of the esophageal wall and enables rapid and reliable measurement of BET. Interobserver variability measurements were significantly reduced when using contrast enhancement. Studies are underway to correlate BET with treatment response.