Inflammatory bowel disease and risk of adenocarcinoma and neuroendocrine tumors in the small bowel.

BACKGROUND: Uncertainty prevails about the magnitude of excess risk of small bowel cancer in patients with inflammatory bowel disease (IBD). PATIENTS AND METHODS: To quantify the risk of small bowel adenocarcinoma and neuroendocrine tumors in patients with ulcerative colitis (UC) and Crohn's disease (CD), we undertook a population-based cohort study of all patients with IBD diagnosed in Norway and Sweden from 1987 to 2016. Patients were followed through linkage to national registers. We calculated standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) of small bowel adenocarcinomas and neuroendocrine tumors for patients with CD and UC. We excluded the first year of follow-up to reduce reverse causality. RESULTS: Among 142 008 patients with a median follow-up of 10.0 years, we identified 66 adenocarcinomas and 57 neuroendocrine tumors in the small bowel. The SIR of small bowel adenocarcinoma was 8.3 (95% CI 5.9-11.3) in CD and 2.0 (95% CI 1.2-3.1) in UC. The incidence rates of adenocarcinomas were highest in CD with stricturing disease and extent limited to the small bowel, at 14.7 (95% CI 8.2-24.2) and 15.8 (95% CI 8.4-27.0) per 100 000 person-years, respectively. The SIR of neuroendocrine tumors was 2.5 (95% CI 1.5-3.9) in CD and 2.0 (95% CI 1.4-2.8) in UC. CONCLUSIONS: Patients with CD experienced an eightfold increased risk of small bowel adenocarcinomas, patients with both UC and CD experienced an about twofold increased risk of neuroendocrine tumors, and patients with UC experienced a twofold increased risk of small bowel adenocarcinoma. The small absolute excess cancer risk suggests that active surveillance to diagnose small intestinal cancer early is unlikely to be cost-effective.

Characterisation of maternal human leukocyte antigen class I antibodies in suspected foetal and neonatal alloimmune thrombocytopenia.

OBJECTIVES: To investigate the specificities and level of HLA class I antibodies in selected cases referred for suspected foetal and neonatal alloimmune thrombocytopenia (FNAIT). BACKGROUND: FNAIT occurs in 1 : 1-2000 live births, whereas maternal immunisation against human leukocyte antigen (HLA) class I is common. Whether HLA class I antibodies alone can cause FNAIT is debatable. MATERIAL AND METHODS: A total of 260 patient samples were referred between 2007 and 2012. Referrals with maternal HLA class I antibodies and no other cause for the neonatal thrombocytopenia were included for analysis (cases, n = 23). HPA-1a negative mothers were excluded. Control groups were screened positive mothers of healthy neonates (controls, n = 33) and female blood donors (blood donors, n = 19). LABScreen single antigen HLA class I beads was used for antibody analysis. Clinical records were reviewed for cases. RESULTS: All groups had broad antibody reactivity. Cases had more antibodies with high SFI levels compared with the controls (SFI>9999; medians 26, 6 and 0; P < 0·05) and higher overall median HLA-ABC and HLA-B SFI (P < 0·05). Many of the antibodies were reactive with rare alleles. When reviewing the clinical records, several of the cases had other contributing factors to the thrombocytopenia. There was no correlation between foetal platelet count and antibody levels. CONCLUSION: Mothers of thrombocytopenic neonates had higher levels of HLA class I antibodies compared with control groups of women with healthy children and female blood donors. However, clinical outcome and antibody response correlated poorly in the heterogeneous case group, indicating a multifactorial cause to the thrombocytopenia in the majority of cases.

Adding to the complexity of fetal and neonatal alloimmune thrombocytopenia: Reduced fibrinogen binding in the presence of anti-HPA-1a antibody and hypo-responsive neonatal platelets.

BACKGROUND: In fetal and neonatal alloimmune thrombocytopenia (FNAIT), maternal alloantibodies directed against paternally-derived platelet antigens are transported across the placenta to the fetus, where they may cause thrombocytopenia. The most serious complication of FNAIT is an intracranial hemorrhage (ICH), which may cause death or life-long disability of the child. Apart from alloantibody-mediated platelet destruction, the clinical outcome in FNAIT may be affected by properties of neonatal platelets and possible functional effects on platelets caused by maternal alloantibodies. METHODS AND RESULTS: The function of umbilical cord blood platelets was compared with adult platelets in two assays, impedance aggregometry (Multiplate) and rotational thromboelastometry (Rotem). Both revealed a decreased in vitro neonatal platelet function compared to adult platelets. Consistent with this finding, activation using TRAP revealed less pronounced changes in the expression of CD62P, PAC-1, CD41 and CD42a in umbilical cord blood platelets compared to adult platelets. Furthermore, a monoclonal anti-HPA-1a antibody, derived from an immunized mother of two children with FNAIT, blocked fibrinogen binding to resting and activated umbilical cord blood and adult HPA-1aa and HPA-1ab platelets, interfered with platelet activation by TRAP, and impaired the function of umbilical cord blood HPA-1aa platelets in rotational thromboelastometry. DISCUSSION AND CONCLUSIONS: Reduced fibrinogen binding in the presence of anti-HPA-1a antibodies may disturb the neonatal hemostatic balance, characterized by poorly responsive platelets. This effect may operate in parallel to platelet destruction and contribute to the clinical outcome in FNAIT.