Citations

SummaryObjectiveThymic neuroendocrine tumour (TH‐NET) accounts for almost 20% of multiple endocrine neoplasia type 1 (MEN1)‐associated mortality. Identifying risk factors for the development of these rare tumours and prognostic factors for clinical outcomes will be helpful in clinical practice.Design and PatientsWe performed a retrospective analysis of patients treated for TH‐NET associated with MEN1 in a single institution and meta‐analysis of literature reports. We used a fixed effect model to pool results across studies to evaluate the prevalence, clinical features and prognosis.ResultsTH‐NET was detected in 9 (7.4%) of 121 patients with MEN1 seen in our institution, and 5 (55.6%) were women. Seven additional studies were identified through a systematic review of the literature. The pool estimate of TH‐NET prevalence was 3.7% (n = 99) in MEN1 (n = 2710), sex ratio was 79:20 (male vs female), and the median age at diagnosis was 43.0 years (range, 16.0‐72.0 years). Forty‐three patients died with a median survival time of 8.4 years. Older age at diagnosis (HR = 1.4, 95% CI = 1.0‐1.8, P = .03), maximum tumour diameter (HR = 1.5, 95% CI = 1.0‐2.3, P = .04) and presence of metastasis (HR = 1.6, 95% CI = 1.0‐2.5, P = .04) were associated with worse outcome. A male predominance (91.9% vs 59.5%, P < .001) and history of smoking (59.0% vs 23.5%, P = .015) were more common in American/European series compared to Asian reports.ConclusionTH‐NET is a rare but fatal component of MEN1. Earlier detection of TH‐NET in patients with MEN1 may be recommended which should theoretically result in better outcomes. Different genetic backgrounds (race) appear to result in clinical difference.

Bone atrophy and its related fragility fractures are frequent, late side effects of radiotherapy in cancer survivors and have a detrimental impact on their quality of life. In another study, we showed that parathyroid hormone 1‐34 and anti‐sclerostin antibody attenuates radiation‐induced bone damage by accelerating DNA repair in osteoblasts. DNA damage responses are partially regulated by the ubiquitin proteasome pathway. In the current study, we examined whether proteasome inhibitors have similar bone‐protective effects against radiation damage. MG132 treatment greatly reduced radiation‐induced apoptosis in cultured osteoblastic cells. This survival effect was owing to accelerated DNA repair as revealed by γH2AX foci and comet assays and to the up‐regulation of Ku70 and DNA‐dependent protein kinase, catalytic subunit, essential DNA repair proteins in the nonhomologous end‐ joining pathway. Administration of bortezomib (Bzb) reversed the loss of trabecular bone structure and strength in mice at 4 wk after focal radiation. Histomorphometry revealed that Bzb significantly increased the number of osteoblasts and activity in the irradiated area and suppressed the number and activity of osteoclasts, regardless of irradiation. Two weeks of Bzb treatment accelerated DNA repair in bone‐lining osteoblasts and thus promoted their survival. Meanwhile, it also inhibited bone marrow adiposity. Taken together, we demonstrate a novel role of proteasome inhibitors in treating radiation‐induced osteoporosis.—Chandra, A., Wang, L., Young, T., Zhong, L., Tseng, W.‐J., Levine, M. A., Cengel, K., Liu, X. S., Zhang, Y., Pignolo, R. J., Qin, L. Proteasome inhibitor bortezomib is a novel therapeutic agent for focal radiation‐induced osteoporosis. FASEB J. 32, 52‐62 (2018). www.fasebj.org

Purpose: Abnormal ocular biomechanical properties may be important for understanding the risk of glaucoma. However, there are no clinical methods for measuring standard material properties in patients. In this feasibility study we demonstrated proof-of-principle for a novel method, ultrasound surface wave elastography (USWE), to determine the in vivo Young’s modulus of elasticity of corneas in normal human eyes. Methods: In total, 20 eyes of 10 healthy subjects (mean age, 51.4±7.2; ±SD; range, 43 to 64 y) were studied. A spherical-tipped probe (3-mm diameter) was placed on closed eyelids and generated a gentle harmonic vibration at 100 Hz for 0.1 second. Wave speed propagation in the cornea was measured by USWE, and Young’s modulus was calculated from the wave speed. Associations between Young’s modulus and intraocular pressure (IOP), age, central corneal thickness, and axial length were explored by the Pearson correlation. Statistical significance was determined by using generalized estimating equation models to account for possible correlation between fellow eyes. Results: Mean IOP was 12.8±2.7 mm Hg. Mean wave speed in the cornea was 1.82±0.10 m/s. Young’s modulus of elasticity was 696±113 kPa and was correlated with IOP (r=0.57; P=0.004), but none of the other variables (P>0.1). Conclusions: USWE is a novel noninvasive technique for measuring ocular biomechanical properties. Corneal Young’s modulus in normal eyes is associated with IOP, consistent with measurements in cadaver eyes. Further work is needed to determine elasticity in other ocular tissues, particularly the sclera, and if elasticity is altered in glaucoma patients.

Abstract Assessing tactile function among children with intellectual, motor, and communication impairments remains a clinical challenge. A case control design was used to test whether children with global developmental delays (GDD; n = 20) would be more/less reactive to a modified quantitative sensory test (mQST) compared to controls (n = 20). Reactivity was indexed by blinded behavioral coding across vocal, facial, and gross motor responses during the mQST. On average the children with GDD were significantly more reactive than controls to most tactile sensory modalities including light touch (p = .034), pin prick (p = .008), cool (p = .039), pressure (p = .037), and repeated von Frey (p = .003). The results suggest the mQST approach was feasible and highlights the GDD sample was more reactive than controls to a range of stimuli.

SummaryObjectiveEvidence on the diagnostic performance of adrenal imaging is limited. We aimed to assess the diagnostic performance of unenhanced computed tomography (CT) and 18F‐fluorodeoxyglucose (18FDG) positron emission tomography (PET)/CT imaging in a high‐risk population for adrenal malignancy using an optimal reference standard.DesignRetrospective cohort study.MethodsImaging studies of patients with adrenal nodules who underwent adrenal biopsy and/or adrenalectomy between 1994 and 2014 were reviewed and compared to the reference standard of histology. Eighty % of patients presented with known or suspected extra‐adrenal malignancy.ResultsUnenhanced abdominal CT was performed in 353 patients with adrenal lesions; median size was 3 (0.7‐15) cm and median radiodensity was 33 (−21‐78) Hounsfield units (HU). Radiodensity of >10 HU diagnosed malignancy with a sensitivity of 100%, specificity of 33%, positive predictive value (PPV) of 72% and negative predictive value (NPV) of 100%. 18FDG‐PET/CT was performed in 89 patients; median tumour size was 2.1 (0.7‐9.2) cm. Maximum standardized uptake (SUV max) was higher in malignant lesions when compared to benign lesions (median=10 [2.3‐29.4] vs 3.7 [1.4‐24.5], respectively, P<.0001). Similarly, median SUV max lesion to SUV max liver ratio (ALR) in malignant lesions was higher than in benign lesions (median=3 [0.74‐13.4] vs 1.2 [0.5‐6.6], respectively, P<.0001). 18FDG‐PET/CT ALR >1.8 diagnosed malignancy with a sensitivity of 87%, specificity of 84%, PPV of 85% and NPV of 86%.ConclusionNoncontract CT radiodensity of ≤10 HU excludes malignancy even in a high‐risk population. For indeterminate adrenal lesions, given a superior specificity, 18FDG‐PET/CT could be considered as a second stage imaging study.

Abstract BACKGROUND Steroid profiling is a promising diagnostic tool with adrenal tumors, Cushing syndrome (CS), and disorders of steroidogenesis. Our objective was to develop a multiple-steroid assay using liquid-chromatography, high-resolution, accurate-mass mass spectrometry (HRAM LC-MS) and to validate the assay in patients with various adrenal disorders. METHODS We collected 24-h urine samples from 114 controls and 71 patients with adrenal diseases. An HRAM LC-MS method was validated for quantitative analysis of 26 steroid metabolites in hydrolyzed urine samples. Differences in steroid excretion between patients were analyzed based on Z-score deviation from control reference intervals. RESULTS Limits of quantification were 20 ng/mL. Dilution linearity ranged from 80% to 120% with means of 93% to 110% for all but 2 analytes. Intraassay and interassay imprecision ranged from 3% to 18% for all but 1 analyte. Control women had lower excretion of androgen and glucocorticoid precursors/metabolites than men (P &lt; 0.001), but no difference in mineralocorticoids was seen (P = 0.06). Androgens decreased with age in both sexes (P &lt; 0.001). Compared with patients with adrenocortical adenoma (ACA), patients with adrenocortical carcinoma (ACC) had 11 steroids with increased Z scores, especially tetrahydro-11-deoxycortisol (14 vs 0.5, P &lt; 0.001), pregnanetriol (7.5 vs −0.4, P = 0.001), and 5-pregnenetriol (5.4 vs −0.4, P = 0.01). Steroid profiling also demonstrated metabolite abnormalities consistent with enzymatic defects in congenital adrenal hyperplasia and differences in pituitary vs adrenal CS. CONCLUSIONS Our HRAM LC-MS assay successfully quantifies 26 steroids in urine. The statistically significant differences in steroid production of ACC vs ACA, adrenal vs pituitary CS, and in congenital adrenal hyperplasia should allow for improved diagnosis of patients with these diseases.

Key Points KMT2C mutations occur in 15% and 25% of patients with cHCL and vHCL, respectively, along with CCND3 and U2AF1 mutations each in 13% of vHCLs. NF1, NF2, N/KRAS, and IRS1 alterations contribute to clinical resistance to vemurafenib treatment in patients with cHCL.