Paragangliomas and pheochromocytomas (PPGLs) are chromaffin tumors associated with severe catecholamine-induced morbidities. Surgical removal is often curative. However, complete resection may not be an option for patients with succinate dehydrogenase subunit A-D (SDHx) mutations. SDHx mutations are associated with a high risk for multiple recurrent, and metastatic PPGLs. Treatment options in these cases are limited and prognosis is dismal once metastases are present. Identification of new therapeutic targets and candidate drugs is thus urgently needed. Previously, we showed elevated expression of succinate receptor 1 (SUCNR1) in SDHB PPGLs and SDHD head and neck paragangliomas. Its ligand succinate has been reported to accumulate due to SDHx mutations. We thus hypothesize that autocrine stimulation of SUCNR1 plays a role in the pathogenesis of SDHx mutation-derived PPGLs. We confirmed elevated SUCNR1 expression in SDHx PPGLs and after SDHB knockout in progenitor cells derived from a human pheochromocytoma (hPheo1). Succinate significantly increased viability of SUCNR1-transfected PC12 and ERK pathway signaling compared to control cells. Candidate SUCNR1 inhibitors successfully reversed proliferative effects of succinate. Our data reveal an unrecognized oncometabolic function of succinate in SDHx PPGLs, providing a growth advantage via SUCNR1.
Objective Antenatal steroids improve the neonatal outcome if they are
administered within a therapeutic window of seven days before preterm birth.
The aim of this study was to evaluate the timing of antenatal steroids for
imminent preterm birth at a single center in Germany.
Material and Methods A 10-year retrospective analysis of 843 preterm
births between 24/0 and 33/6 weeks was performed from
January 2008 to December 2017 at a German university hospital. We evaluated
the timing of antenatal steroids according to the indication for their
application. Descriptive statistics and binomial regression were performed
to analyze factors influencing the timing of antenatal steroid
administration.
Results Of 843 preterm births below 34 weeks included in our study,
752 pregnant women received antenatal steroids (89.2%). Only
301/843 women (35.7%) gave birth within the optimal window
of 7 days after antenatal steroids. 91/843 women (10.8%) did
not receive steroids. 130/843 women (15.4%) only received
one dose, 76/843 (9.0%) gave birth within 8 to 14 days, and
245/843 (29.1%) more than 14 days later. In a binomial
regression model, preterm premature rupture of membranes (OR 3.40,
95% CI 1.81 to 6.39, p<0.001), fetal growth restriction (OR
3.27, 95% CI 1.63 to 6.58, p=0.001), and preeclampsia (OR
2.83, 95% CI 1.37 to 5.83, p=0.005) were positively
associated with optimal timing.
Conclusion Two thirds of women with preterm birth before 34 weeks
received antenatal steroids outside the optimal therapeutic window. Further
research is needed to achieve an optimal effect of antenatal steroids on
neonatal outcome and to reduce untimely as well as unnecessary
interventions.
We present a case of a 30‐year old patient who devoloped a disseminated abdominal pregnancy after receiving a salpingotomy due to a prior tubal pregnancy.
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