Jens Hiller

ABO Blood Group IgM Isoagglutinins Interact with Tumor-Associated O-Glycan Structures in Pancreatic Cancer

Purpose: The ABO gene locus is associated with the risk of developing pancreatic ductal adenocarcinoma (PDAC) resulting in an increased incidence in individuals with non-O blood groups. Up to 90% of PDAC specimens display alterations in mucin type O-GalNAc glycosylation. Because aberrant O-GalNAc glycans (Tn and T antigen) are structurally related to blood group A and B glycans, we investigated the role of IgM isoagglutinins in PDAC. Experimental Design: Binding studies of IgM isoagglutinins toward blood group A, B, Tn antigen, and T antigen glycoconjugates from patients with PDAC and healthy individuals were conducted. Isoagglutinin titers and total IgM were compared between patients with PDAC and control group. An anti-A antibody was used for immunoprecipitation of aberrant O-glycosylated tumor proteins and subsequent mass spectromic analysis. Results: We found that IgM isoagglutinins bind blood group antigens, Tn and T glycoconjugates as well as tumor-derived glycoproteins. Blood group A isoagglutinins exhibited a strong binding toward blood group B antigen and T antigen, whereas blood group B showed binding to blood group A antigen and Tn antigen. Furthermore, we confirmed a decreased frequency in individuals with blood group O and observed a significant decrease of IgM isoagglutinin titers in PDAC sera compared with control sera, whereas total IgM levels were unaltered. We identified new PDAC-derived O-GalNAc glycoproteins by mass spectrometry using a blood group A-specific antibody. Conclusion: Our data elucidated a novel interaction of blood group IgM isoagglutinins and PDAC O-GalNAc glycoproteins that may contribute to the pathogenesis and progression of pancreatic cancer. Clin Cancer Res; 20(23); 6117–26. ©2014 AACR.

HEV-positive blood donations represent a relevant infection risk for immunosuppressed recipients

BACKGROUND & AIMS Routine HEV testing of blood products has recently been implemented in Great Britain and the Netherlands. The relevance of transfusion-transmitted HEV infections is still controversially discussed in Europe. METHODS All blood donations at the University Medical Center Hamburg-Eppendorf were prospectively tested for HEV RNA by pooled PCR from October 2016 to May 2017. Reactive samples were individually retested. Additionally, stored samples from previous donations of positive donors were tested to determine the duration of HEV viraemia. HEV RNA-positive donors and a control cohort were asked to answer a questionnaire. RESULTS Twenty-three out of 18,737 HEV RNA-positive donors were identified (0.12%). Only two of the positive donors (8.7%) presented with elevated aminotransferases at time of donation (alanine aminotransferase: 192 and 101 U/L). The retrospective analysis of all positive donors revealed that four asymptomatic donors had been HEV viraemic for up to three months with the longest duration of HEV viraemia exceeding four months. Despite the HEV-testing efforts, 14 HEV RNA-positive blood products were transfused into 12 immunocompromised and two immunocompetent patients. One recipient of these products developed fatal acute-on-chronic liver failure complicated by Pseudomonas septicemia. The questionnaire revealed that HEV RNA-positive donors significantly more often consumed raw pork meat (12 out of 18; 67%) than controls (89 out of 256; 35%; p = 0.01). In two donors, undercooked pork liver dishes were identified as the source of infection. HEV genotyping was possible in 7 out of 23 of HEV viraemic donors and six out of seven isolates belonged to HEV Genotype 3, Group 2. CONCLUSIONS Prolonged HEV viraemia can be detected at a relatively high rate in Northern German blood donors, leading to transfusion-transmitted HEV infections in several patients with the risk of severe and fatal complications. Eating raw pork tartare represented a relevant risk for the acquisition of HEV infection. LAY SUMMARY The relevance of transfusion-transmitted hepatitis E virus infections has been discussed controversially. Herein, we present the first report on routine hepatitis E virus screening of blood donations at a tertiary care centre in Germany. Hepatitis E viraemia was found at a relatively high rate of 0.12% among blood donors, which represents a relevant transfusion-related risk for vulnerable patient populations.

Course of HEV viremia and anti-HEV IgM/IgG response in asymptomatic blood donors

BACKGROUND Globally, an estimated 20 million Hepatitis E infections occur every year. The course of viremia and antibody response has been investigated in patients with symptomatic hepatitis E. However, the majority of HEV infections in industrialized countries take a subclinical course. OBJECTIVES To investigate the course of HEV viremia and epitope specific anti-HEV IgM/IgG response in asymptomatic blood donors in order to understand the immune response and viral clearance in asymptomatic blood donors with HEV infections. METHODS In this study 27 HEV viremic donors were identified by HEV-PCR during routine screening of blood donors and the course of anti-HEV IgM/IgG and HEV-RNA was retrospectively studied using RT-PCR and a commercial immunoblot (Mikrogen®) allowing classification of the antibody response according to HEV epitopes. RESULTS At time of donation, serological testing failed to identify viremic donors as 70.4% had no detectable antibody response. Anti-HEV IgM could be detected in 22.2% of viremic donors while anti-HEV IgG could be found in 7.4%. At least three donors experienced prolonged viremia beyond 100 days. Spontaneous HEV-RNA clearance within a median time span of 57 days was observed in all 27 donors. In all donors anti-HEV IgG specific for the immunogenic viral epitope O2C could be detected in close temporal association with viral clearance. CONCLUSION Serological testing is inappropriate for identifying HEV-viremic blood donors. Acute HEV infection in asymptomatic blood donors can persist for more than 100 days. HEV-RNA clearance coincided with the appearance of anti-HEV IgM/IgG confirming the importance of a B-cell mediated response in clearing acute infections. Anti-HEV IgM and IgG specific for the epitope O2C are associated with the clearance of HEV-viremia.

AB0/Rhesus Blood Group Does Not Influence Clinicopathological Tumor Characteristics or Oncological Outcome in Patients Undergoing Radical Prostatectomy

Objectives AB0 blood group is an inherited characteristic that has been associated with the incidence as well as the prognosis of several malignancies. The aim of the current study was to clarify the role of the blood group in cancer epidemiology and clinical outcome of patients with prostate cancer (PCa). Methods Data from 3,574 patients undergoing radical prostatectomy between 2009 and 2010 at a single European institution were retrospectively analyzed. The correlation of AB0 and Rhesus blood group with PCa-related characteristics and oncological outcome were evaluated using univariable and multivariable Cox proportional hazard models. Results Median follow-up was 36.9 months. The overall distributions of AB0, as well as Rhesus blood groups among patients with PCa, did not differ from the distribution observed in the normal population. There was no significant association between AB0/Rhesus blood groups and Gleason score, prostate volume, surgical margin, pT-stage, pN-status, or preoperative prostate-specific antigen level. In multivariable Cox regression analysis, no statistically significant correlation between AB0/Rhesus group and biochemical recurrence was observed (all p > 0.05). Conclusion Our data suggest no relevant association of AB0/Rhesus blood group with adverse clinicopathological tumor characteristics or oncological outcome after surgery in contrast to several other malignancies.