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Macrosomia risk remains high in type 1 diabetes (T1DM) complicated pregnancies. A linear relationship between macrosomia risk and glycated hemoglobin A1c (HbA1c) was described; however, low range of HbA1c has not been studied. We aimed to identify risk factors and examine the impact of HbA1c on the occurrence of macrosomia in newborns of T1DM women from a cohort with good glycemic control. In this observational retrospective one-center study we analyzed records of 510 consecutive T1DM pregnancies (1998–2012). The analyzed group consisted of 375 term singleton pregnancies. We used multiple regression models to examine the impact of HbA1c and self-monitored glucose in each trimester on the risk of macrosomia and birth weight. The median age of T1DM women was 28 years, median T1DM duration—11 years, median pregestational BMI—23.3 kg/m2. Median birth weight reached 3520 g (1st and 3rd quartiles 3150 and 3960, respectively) at median 39 weeks of gestation. There were 85 (22.7 %) macrosomic (>4000 g) newborns. Median HbA1c levels in the 1st, 2nd, and 3rd trimester were 6.4, 5.7, and 5.6 %. Third trimester HbA1c, mean fasting self-monitored glucose and maternal age were independent predictors of birth weight and macrosomia. There was a linear relationship between 3rd trimester HbA1c and macrosomia risk in HbA1c range from 4.5 to 7.0 %. Macrosomia in children of T1DM mothers was common despite excellent metabolic control. Glycemia during the 3rd trimester was predominantly responsible for this condition.

ObjectiveCorticotroph macroadenomas are a rare cause of Cushing's disease (CD), but their properties are not well-recognised. The aim of this study was to evaluate the clinical and pathological aspects of corticotroph macroadenomas with particular emphasis on proliferation markers and their associations with the efficacy of surgical treatment.DesignA prospective cohort study was conducted in a tertiary referral centre in Poland.MethodsIn total, 59 patients with CD (20 macroadenomas and 39 microadenomas) were included in this study. Hormonal and imaging parameters, histopathological and ultrastructural features of the corticotroph tumours and the early surgical outcomes were evaluated.ResultsACTH and ACTH/cortisol ratios were higher in macroadenomas (P<0.001 and P=0.002 respectively). Greater tumour volumes were associated with higher Ki-67 and p53 expression (Ptrend=0.009 and Ptrend=0.024 respectively) and the rates of sparsely granulated adenomas (Ptrend=0.036). Immediate postoperative remission and early biochemical remission rates were lower in macroadenomas compared to microadenomas (P<0.001). A logistic regression model showed that the immediate postoperative remission or early biochemical remission depended on tumour volume (P=0.005 and P=0.006 respectively) and invasiveness based on Knosp grades 3 and 4 for macroadenomas and a lack of surgical pseudocapsule for microadenomas (P=0.004 and P=0.007 respectively).ConclusionCorticotroph macroadenomas differ from the more common microadenomas not only in terms of hormonal and imaging characteristics but also in terms of immunohistochemical and ultrastructural features and proliferation markers. The early effectiveness of surgery depends primarily on tumour volume and invasiveness.

Purpose The efficacy of levoketoconazole in treating hypercortisolism was demonstrated in an open-label phase 3 study (SONICS) of adults with endogenous Cushing’s syndrome (CS) and baseline mean urinary free cortisol (mUFC) ≥  1.5× ULN. Clinical signs and symptoms and patient-reported outcomes from the SONICS trial were evaluated in the current manuscript. Methods Patients titrated to an individualized therapeutic dose entered a 6-month maintenance phase. Secondary endpoints included investigator-graded clinical signs and symptoms of CS during the maintenance phase, and patient-reported quality of life (CushingQoL questionnaire) and depression symptoms (Beck Depression Inventory II [BDI-II]). Results Of 94 enrolled patients, 77 entered the maintenance phase following individualized dose titration. Significant mean improvements from baseline were noted at end of maintenance (Month 6) for acne, hirsutism (females only), and peripheral edema. These improvements were observed as early as Day 1 of maintenance for hirsutism (mean baseline score, 7.8; ∆ − 1.9; P < 0.0001), end of Month 1 for acne (mean baseline score, 2.8; ∆ − 1.2; P = 0.0481), and Month 4 for peripheral edema (mean baseline score, 1.0; ∆ − 0.5; P = 0.0052). Significant mean improvements from baseline were observed by Month 3 of maintenance for CushingQoL (mean baseline score, 44.3; ∆ + 6.9; P = 0.0018) and at Month 6 for BDI-II (mean baseline score, 17.1; ∆ − 4.3; P = 0.0043) scores. No significant mean improvement was identified in a composite score of 7 other clinical signs and symptoms. Conclusions Treatment with levoketoconazole was associated with sustained, meaningful improvements in QoL, depression, and certain clinical signs and symptoms characteristic of CS. ClinialTrials.gov identifier: NCT01838551.

Context Cushing’s disease, a chronic hypercortisolism disorder, is associated with considerable morbidity and mortality. Normalizing cortisol production is the primary treatment goal. Objective To evaluate the safety and efficacy of osilodrostat, a potent, orally available 11β­hydroxylase inhibitor, compared with placebo in patients with Cushing’s disease. Design, setting, intervention, and participants LINC 4 was a Phase III, multicenter trial comprising an initial 12-week, randomized, double-blind, placebo-controlled (osilodrostat:placebo, 2:1) period followed by a 36-week, open-label treatment period (NCT02697734). Adult patients (aged 18–75 years) with confirmed Cushing’s disease and mean urinary free cortisol (mUFC) excretion ≥1.3 times the upper limit of normal (ULN) were eligible. Main outcome measures The primary endpoint was the proportion of randomized patients with mUFC≤ULN at week 12. The key secondary endpoint was the proportion achieving mUFC≤ULN at week 36 (after 24 weeks’ open-label osilodrostat). Results 73 patients (median age, 39 years [range, 19–67]; mean/median mUFC, 3.1×ULN/2.5×ULN) received randomized treatment with osilodrostat (n=48) or placebo (n=25). At week 12, significantly more osilodrostat (77%) than placebo (8%) patients achieved mUFC≤ULN (odds ratio 43.4; 95% CI 7.1, 343.2; P&lt;0.0001). Response was maintained at week 36, when 81% (95% CI 69.9, 89.1) of all patients achieved mUFC≤ULN. The most common adverse events during the placebo-controlled period (osilodrostat vs placebo) were decreased appetite (37.5% vs 16.0%), arthralgia (35.4% vs 8.0%), and nausea (31.3% vs 12.0%). Conclusions Osilodrostat rapidly normalized mUFC excretion in most patients with Cushing’s disease and maintained this effect throughout the study. The safety profile was favorable.

PurposeNegative pressure wound therapy (NPWT) is an adjunct method used in the treatment of diabetic foot ulceration (DFU). Real world data on its effectiveness and safety is scarce. In this prospective observational study, we assessed the short-term efficacy, safety, and long-term outcomes of NPWT in patients with type 2 diabetes (T2DM) and neuropathic, noninfected DFUs.MethodsBased on wound characteristics, mainly area (>1 vs. ≤1 cm2), 75 patients with DFUs treated in an outpatient clinic were assigned to NPWT (n = 53) or standard therapy (n = 22). Wound area reduction was evaluated after 8 ± 1 days. Long-term outcomes assessed included complete ulceration closure and recurrence rate.ResultsPatients assigned to NPWT were characterized by greater wound area (15.7 vs. 2.9 cm2). Reduction in wound area was found in both the NPWT (−1.1 cm2, −10.2%, p = 0.0001) and comparator group (−0.3 cm2, −18.0%, p = 0.0038). No serious adverse events related to NPWT were noted. Within 1 year, 55.1% (27/49) of DFUs were closed in the NPWT group and 73.7% (14/19) in the comparator group (p = 0.15). In the logistic regression, wound duration and smaller initial area, but not treatment mode, were associated with closure. One-year follow-up after DFU resolution revealed an ~30.0% recurrence rate in both groups (p = 0.88).ConclusionsNPWT is a safe treatment for neuropathic, nonischemic, and noninfected DFU in patients with T2DM, although this observational study did not prove its effectiveness over standard therapy. Additionally, we report a high rate of both closure and recurrence of ulcers, the latter irrespective of initial ulcer area.