Assessing biases of information contained in pedigrees for the classification of BRCA-genetic variants: a study arising from the ENIGMA analytical working group.

PURPOSE: One way of evaluating family history (FH) for classifying BRCA1/2 variants of uncertain clinical significance (VUS) is to assess the "BRCA-ness" of a pedigree by comparing it to reference populations. The aim of this study was to assess if prediction of BRCA pathogenic variant (mutation) status based on pedigree information differed due to changes in FH since intake, both in families with a pathogenic variant (BRCAm) and in families with wild-type (BRCAwt). PATIENTS AND METHODS: We compared the BRCA1/2 pathogenic variant detection probabilities between intake and most recent pedigree for BRCAm families (n = 64) and BRCAwt (n = 118) using the BRCAPRO software program. RESULTS: Follow-up time between intake and most recent pedigree was significantly longer (p < 0.001) in the BRCAm compared to the BRCAwt families. Among BRCAwt families, the probability to detect a pathogenic variant did not change over time. Conversely, among the BRCAm, this probability was significantly higher for most recent vs. intake pedigree (p = 0.006). CONCLUSION: Clinical scores change significantly over time for BRCAm families. This may be due to differences in follow-up, but also to differences in cancer risks from carrying a pathogenic variant in a highly penetrant gene. To reduce bias, models for VUS classification should incorporate FH collected at intake.

Proton pump inhibitors do not increase the risk of acute rejection.

BACKGROUND: Mycophenolate mofetil (MMF) is the prodrug of mycophenolic acid (MPA). Proton pump inhibitors impair exposure to MPA due to incomplete conversion from MMF. Lower exposure to MPA could result in an increased risk of acute rejection. We investigated whether MMF-treated renal transplant patients who concomitantly used pantoprazole as ulcer prophylaxis had a higher risk of acute rejection within the first three months after transplantation than those who used ranitidine. METHODS: We performed a retrospective study in adult patients who underwent kidney transplantation between January 2007 and December 2011. Their immunosuppressive therapy consisted of steroids, tacrolimus and MMF and they used either pantoprazole or ranitidine as ulcer prophylaxis. RESULTS: 202 patients were included: 125 using pantoprazole and 77 using ranitidine. There was no difference in the number of patients with biopsy-proven acute rejection (BPAR): 13 (10.4%) in the pantoprazole group versus 7 (9.1%) in the ranitidine group (NS). Also after correction for inequalities between the two groups, there was no significant relationship between the risk of BPAR and the type of anti-ulcer agent. CONCLUSION: There was no evidence for an increased incidence of BPAR in renal transplant patients who use pantoprazole in combination with MMF.

Identification of peripartum near-miss for perinatal audit.

INTRODUCTION: Today, perinatal audit focuses basically on cases of perinatal mortality. In most centres in Western Europe, perinatal mortality is low. Identification of metabolic acidosis at birth may increase index cases eligible for evaluation of perinatal care, and this might improve quality of perinatal audit. The aim of this study is to assess the incidence of metabolic acidosis at birth in order to estimate its impact on perinatal audit. PATIENTS AND METHODS: Cord blood was analysed for every neonate born between January 1, 2010 and December 31, 2012 in Ziekenhuis Oost-Limburg, Genk. Acidosis was defined as an umbilical arterial pH ≤ 7.05 with or without a venous pH ≤ 7.17. Respiratory acidosis (RA) was defined as acidosis with normal base excess, and metabolic acidosis (MA) was defined as acidosis with an arterial or venous base excess ≤ -10 mmol/L. In case of failed cord blood sampling, 5 minute Apgar score ≤ 6 was considered as the clinical equivalent of MA. Retrospective chart review of obstetric and paediatric files was performed for all cases of MA, together with review of paediatric follow-up charts from at least 6 months after birth. Perinatal asphyxia was defined as biochemical evidence for MA at birth, associated with early onset neonatal encephalopathy and long-term symptoms of cerebral palsy. RESULTS: In a total of 6614 babies, perinatal death up to 7 days of life occurred in 40 babies (6.0‰). Acidosis was present in 183 neonates (2.8%), of which 130 (2.0%) had RA and 53 (0.8%) had MA. Of the 173 neonates with unknown pH values, 6 had Apgar scores ≤ 6. Of 59 babies born with MA or its clinical equivalent, 52 (88.1%) showed no neurologic symptoms at birth. Two (3.4%) died in the early neonatal period, one after abruptio placentae and one due to chorioamnionitis and severe prematurity. Five (8.5%) MA babies had symptoms of early onset neonatal encephalopathy, which recovered in three (5.1%), and persisted long-term in two others (3.4%). The two babies with cerebral palsy (prevalence 1/3300) were both born after instrumental vaginal delivery for foetal distress. CONCLUSION: In our study cohort, the incidence of perinatal mortality is 6‰. The incidence of metabolic acidosis is 9‰. Addition of cases of metabolic acidosis to those of mortality doubles index cases eligible for perinatal audit. The incidence of babies surviving with cerebral palsy after metabolic acidosis at birth is very low (0.3‰). Our results suggest that instrumental delivery for foetal distress might be a risk factor for metabolic acidosis with persisting neurologic dysfunction. Our study illustrates that identification of peripartum near-miss is useful for perinatal audit.