Longitudinal Copy-Number Alteration Analysis in Plasma Cell-Free DNA of Neuroendocrine Neoplasms is a Novel Specific Biomarker for Diagnosis, Prognosis, and Follow-up.

PURPOSE: As noninvasive biomarkers are an important unmet need for neuroendocrine neoplasms (NEN), biomarker potential of genome-wide molecular profiling of plasma cell-free DNA (cfDNA) was prospectively studied in patients with NEN. EXPERIMENTAL DESIGN: Longitudinal plasma samples were collected from patients with well-differentiated, metastatic gastroenteropancreatic and lung NEN. cfDNA was subjected to shallow whole-genome sequencing to detect genome-wide copy-number alterations (CNA) and estimate circulating tumor DNA (ctDNA) fraction, and correlated to clinicopathologic and survival data. To differentiate pancreatic NENs (PNEN) from pancreatic adenocarcinomas (PAAD) using liquid biopsies, a classification model was trained using tissue-based CNAs and validated in cfDNA. RESULTS: One hundred and ninety-five cfDNA samples from 43 patients with NEN were compared with healthy control cfDNA (N = 100). Plasma samples from patients with PNEN (N = 21) were used for comparison with publicly available PNEN tissue (N = 98), PAAD tissue (N = 109), and PAAD cfDNA (N = 96). Thirty percent of the NEN cfDNA samples contained ctDNA and 44% of the patients had at least one ctDNA-positive (ctDNA+) sample. CNAs detected in cfDNA were highly specific for NENs and the classification model could distinguish PAAD and PNEN cfDNA samples with a sensitivity, specificity, and AUC of 62%, 86%, and 79%, respectively. ctDNA-positivity was associated with higher World Health Organization (WHO) grade, primary tumor location, and higher chromogranin A and neuron-specific enolase values. Overall survival was significantly worse for ctDNA+ patients and increased ctDNA fractions were associated with poorer progression-free survival. CONCLUSIONS: Sequential genome-wide profiling of plasma cfDNA is a novel, noninvasive biomarker with high specificity for diagnosis, prognosis, and follow-up in metastatic NENs.

Health Literacy and Quality of Life in Young Adults From The Belgian Crohn's Disease Registry Compared to Type 1 Diabetes Mellitus.

Background and Aims: The management of chronic inflammatory bowel diseases in youth is challenging. We aimed to determine health literacy (HL), quality of life (QoL) and clinical outcomes in young adults from the BELgian CROhn's disease registry (BELCRO) in comparison to type 1 diabetes mellitus (DM) as a control. Methods: In this prospective and observational study, young adults with Crohn's disease (CD) diagnosed < 18 years and with > 5 years disease duration and a comparable group of patients with DM completed validated HL, QoL and work productivity and activity impairment questionnaires (HLS-EU-Q16, EQ-5D-5L and WPAI). HL was scored as sufficient (13-16), problematic (9-12) or inadequate (0-8). QoL was dichotomized into "no problems" (EQ-5D level 1) or "problems" (EQ-5D levels 2 to 5). Non-parametric (Mann-Whitney U) analyses and Spearman correlations were performed. Results: A total of 52 CD (median [IQR] age of 25.0 [23.8-27.0], 64% male) and 50 DM (age 20.0 [19.0-22.0], 50% male) patients were included. HL was 14.0 [11.0-16.0] for CD and 14.0 [11.3-14.8] for DM (p = 0.6) with similar proportions of sufficient (60 vs. 68%, p = 0.4), problematic (34 vs. 26%, p = 0.3) and inadequate HL (both 6%, p = 1). Although QoL was comparable for CD and DM (77.0 [68.8-82.0] vs. 75.0 [65.0-80.0] %, p =0.4), CD had a trend for higher pain/discomfort (50 vs. 32%, p = 0.06). HL and QoL correlated in CD (r = 0.6, p < 0.001) and DM patients (r = 0.6, p < 0.001). Fewer CD patients with recent hospitalization/surgery had sufficient HL (31 vs. 69%, p = 0.01) and had lower QoL (70.0 [60.0-77.0] vs. 80.0 [70.0-85.0], p = 0.04) compared to those without. Conclusions: Selected young Belgian adults suffering from CD for >5 years have similar and sufficient HL compared to DM patients. However, CD patients requiring hospitalization/surgery have lower HL, which indicates the need for targeted educational programs.

Laboratory detection of macro-aspartate aminotransferase: case report and evaluation of the PEG-precipitation method.

BACKGROUND: Chronic elevated AST without other signs of liver disease, cardiac or skeletal abnormalities, is suggestive for macro-AST. Laboratory detection can be performed by gel filtration chromatography, ultrafiltration or precipitation with polyethylene glycol (PEG). PATIENT AND METHODS: A healthy 27 year-old female was referred because of chronic elevated AST (116-704U/L) without other abnormalities. Macro-AST positivity was suspected since AST was no longer measurable in the supernatant of a serum sample (<3U/L) after PEG precipitation. Optimization of this method included analysis of proteins and lipids precipitated, testing the effect of different PEG concentrations and centrifugation times. 25% (m/v) PEG solution gave the most reliable results. No significant difference was seen between 10 and 30 min centrifugation time. A reference range was obtained by analysis of 31 normal patient samples (mean % PEG precipitation activity 35.1% with 95% confidence limits of 14.5-62.5%). Retrospective analysis of 1371 patient samples with elevated AST revealed one other positive patient sample. CONCLUSION: Early recognition of macro-AST, proven by simple PEG precipitation, can avoid time-consuming and invasive investigations.

Contribution of genetic and environmental factors in the pathogenesis of Crohn's disease in a large family with multiple cases.

BACKGROUND: A large family of Moroccan immigrants was investigated. In this family the father developed Crohn's disease (CD) after moving from Morocco to Belgium and successively 4 of his 8 children subsequently developed CD. There was no previous history of familial CD. METHODS: The family was interviewed at their home and an elaborated questionnaire was completed. The food and sanitation characteristics of the family were investigated. Moreover, serological markers were tested in all family members, including ASCA, ASCAg, ALCA, ACCA, Omp, and ANCA, using enzyme-linked immunosorbent assay and indirect immunofluorescence. Genetic variants in CARD15, TLR4, NOD1, CARD8, and DLG5 associated with CD were tested as well. The complete medical history of all patients was reviewed. RESULTS: There were no known genetic variants associated with CD in this family. None of the serological antibodies could discriminate between patients and unaffected family members, although the antibody titers were higher in diseased family members as compared with the healthy family members. CONCLUSION: The occurrence of 5 new cases of CD within 1 Moroccan family after immigration to Belgium cannot be explained by the known genetic susceptibility factors, and thus suggests a major environmental factor probably not related to sanitation in childhood.

A randomized trial comparing injection therapy with hemoclip and with injection combined with hemoclip for bleeding ulcers.

BACKGROUND: A randomized comparative study was conducted of injection therapy with epinephrine-polidocanol (1%) versus hemoclip application, versus injection combined with hemoclip for bleeding peptic ulcers. METHODS: One hundred five patients were randomized and 101 could be evaluated (46 had active spurting or oozing of blood; 55 a visible vessel). Patients were randomized to 1 of the 3 treatment modalities during endoscopy performed within 12 hours of admission. Endoscopy was repeated after 1 day or at recurrence of bleeding and before discharge. In case of recurrent bleeding, patients were retreated with the same modality. RESULTS: Initial failure or the rate of early recurrence of bleeding was highest (but not statistically significant) in the hemoclip group (13/35; 37%), versus the injection (5/34; 15%) and combination (8/32; 25%) groups. Overall failure was significantly (p = 0.01) different among the 3 groups with the highest rate in the hemoclip group (12/35; 34%), versus the injection (2/34; 6%) and combination therapy (8/32; 25%) groups. The use of hemoclips alone appeared to fail because of difficulty with hemoclip placement and incomplete vessel compression. Complications included 1 perforation in the injection group and possibly 1 case of septic arthritis in the combination therapy group. CONCLUSION: In this study, endoscopic treatment of bleeding peptic ulcers with the hemoclip was inferior overall to injection therapy.