Twenty-four hour 17-hydroxyprogesterone response to adrenocorticotropine in adrenal incidentalomas: augmented response after adrenalectomy in two patients

The current study aimed to investigate the midterm (24 hour) response of 17-hydroxyprogesterone (17-OHP) and dehydroepiandrosterone sulphate (DHEA-S) to synthetic high-dose adrenocorticotropin (ACTH) in adrenal incidentalomas (Al). Seventeen patients with Al and 40 age- and sex-matched controls received synthetic ACTH (tetracosactide, 1000 microg, IM). Plasma, 17-OHP and DHEA-S were collected in basal conditions and after 1, 4, 6, 8 and 24 hours. (HPA) axis was also evaluated using circadian serum cortisol, urinary free cortisol and over-night 2 mg dexamethasone suppression. Basal plasma 17-OHP levels did not differ among the groups. However, the increment in plasma 17-OHP in patients both in terms of peak [13.76 +/- 2.52, 4.77 +/- 0.30ng/ml, mean +/- S.E.M, p < 0.001] and area under the curve [190 +/- 46, 96.75 +/- 32 ng/ml/h, p < 0.001] were significantly higher than that of the controls. Stimulated 17OH-P levels never reached 9.1 ng/ml in controls. Sixty-five (11/17) % of the patients were found to have exaggerated response. Three of the patients were found to have subclinical Cushing's syndrome and interestingly, two augmented their 17-OHP response to ACTH after unilateral adrenalectomy and normalisation of their HPA axis. Basal DHEA-S levels of the patients were significantly lower [99.21 +/- 45, 230.18 +/- 34 microg/dl, p < 0.01] and stayed persistently lower than that of the controls. Evidence of a heterozygous 21 hydroxylase deficiency, as indicated by the exaggerated 17-OHP response to ACTH, has been widely reported in Al patients. However, to our knowledge to date there is no report on augmented 17-OHP response to ACTH after adrenalectomy. Possible reasons for the augmentation were discussed.     

Efficacy,safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I

In the phase III COMFORT-I study, the Janus kinase 1 (JAK1)/JAK2 inhibitor ruxolitinib provided significant improvements in splenomegaly, key symptoms, and quality-of-life measures and was associated with an overall survival benefit relative to placebo in patients with intermediate-2 or high-risk myelofibrosis. This planned analysis assessed the long-term efficacy and safety of ruxolitinib at a median follow-up of 149 weeks. At data cutoff, approximately 50% of patients originally randomized to ruxolitinib remained on treatment whereas all patients originally assigned to placebo had discontinued or crossed over to ruxolitinib. At week 144, mean spleen volume reduction was 34% with ruxolitinib. Previously observed improvements in quality-of-life measures were sustained with longer-term ruxolitinib therapy. Overall survival continued to favor ruxolitinib despite the majority of placebo patients crossing over to ruxolitinib [hazard ratio 0.69 (95% confidence interval: 0.46–1.03); P=0.067]. Exploratory analyses suggest that crossover may have contributed to an underestimation of the true survival difference between the treatment groups. Ruxolitinib continued to be generally well tolerated; there was no pattern of worsening grade ≥3 anemia or thrombocytopenia with longer-term ruxolitinib exposure. These longer-term data continue to support the efficacy and safety of ruxolitinib in patients with myelofibrosis. The study is registered at clinicaltrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT00952289","term_id":"NCT00952289"}}NCT00952289.     

A Homozygous Nonsense Thyroid Peroxidase Mutation (R540X) Consistently Causes Congenital Hypothyroidism in Two Siblings Born to a Consanguineous Family

Objective:

Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder, and mutations in the thyroid peroxidase (TPO) gene have been reported to cause the disease. Our aim in this study was to determine the genetic basis of CH in two affected children coming from a consanguineous family.

Methods:

First, we investigated the potential genetic linkage of the family to any known CH locus using microsatellite markers and then screened for mutations in the linked gene by Sanger sequencing. By using next-generation sequencing, we also checked if any other mutation was present in the remaining 10 causative CH genes.

Results:

The family showed potential linkage to the TPO gene, and we detected a homozygous nonsense mutation (R540X) in both cases. The two patients had total iodide organification defect (TIOD). Both the microsatellite marker haplotypes and the mutation segregated with the disease status in the family, i.e. all healthy subjects were either heterozygous carriers or homozygous wild-type, confirming the pathogenic nature of the mutation. Neither was the mutation present in any of the 400 control chromosomes nor were there any other mutations in the remaining causative CH genes.

Conclusion:

This study proves the pathogenicity of R540X mutation and demonstrates the strong genotype/phenotype correlation associated with this mutation. It also highlights the power of working with familial cases in revealing the molecular basis of CH and in establishing accurate genotype/phenotype relationships associated with disease causing mutations.     

Comparison of acute elastic recoil between the SAPIEN‐XT and SAPIEN valves in transfemoral–transcatheter aortic valve replacement

• Complex arch anatomy (type 2, type 3) and bovine configuration were identified in 34.4% and 20.5% of carotid stent patients, respectively.
• Catheter manipulation time (CMT), rather than arch complexity per se, was the only independent predictor of adverse events after carotid stenting.
• Careful attention to patient selection, preprocedural planning, and stent technique are important to ensure success.