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Context: Limited population-based study focused on relationship between eosinophil and type 2 diabetes (T2D). Objectives: We aimed to evaluate the relationship between peripheral eosinophil percentage and glucose metabolism and insulin resistance in a large sample size of Chinese population aged 40 and older. Design and Methods: A cross-sectional study was performed among 9,111 Chinese adults including 3,561 men and 5,550 women. The glucose metabolism status was confirmed by 75-g oral glucose tolerance test. Homeostasis model assessment of insulin resistance index and serum insulin levels were used to evaluate insulin resistance. Homeostasis model assessment-B was used to evaluate β cell function. Results: The average age of participants was 58.5 years. The prevalence of T2D decreased across the tertiles of eosinophil percentage (21.3%, 18.2% and 16.9%, P<0.0001). Each one tertile increase of eosinophil percentage inversely associated with risk of T2D when referred not only to normal glucose tolerance (NGT) (odds ratio (OR) 0.81, 95% CI 0.76–0.87, P< 0.0001), but also to impaired glucose regulation (OR 0.89, 95% CI 0.83–0.97, P = 0.006), respectively, after adjustment for the confounding factors. Compared with the first tertile, the third tertile of eosinophil percentage associated with a 23% decrease of insulin resistance in NGT participants after full adjustments (P = 0.005). Each 1-standard deviation of increment of eosinophil percentage associated with a 37% decrease of insulin resistance (P = 0.005). Conclusions: Higher peripheral eosinophil percentage was associated with decreased risk of T2D. The inverse relation to insulin resistance was detected in NGT participants. [ABSTRACT FROM AUTHOR]

Objective Phaeochromocytomas ( PHEO) and functional paragangliomas ( PGLs) are catecholamine-secreting neuroendocrine tumours. Although most PHEO/ PGLs are benign, 10-35% present as (or develop into) malignant tumours with a poor prognosis. Overexpression of ERBB2 (v-erb-b2 erythroblastic leukaemia viral oncogene homologue 2) has been reported to be associated with malignant PHEO. We used gene expression profiling of PHEO/ PGLs to gain a better understanding of the tumourigenic pathways associated with ERBB2. Methods We used the Affymetrix Gene Chip U133 Plus 2·0 genome-wide gene expression cDNA microarray of 18 PHEO/ PGLs (12 benign and six malignant, divided into two groups depending on ERBB2 expression levels) to analyse the gene expression patterns. Results Unsupervised hierarchical cluster analysis of transcription profiles of 18 samples identified two dominant expression clusters corresponding to samples belonging to the ERBB2+ and ERBB2− groups. According to the gene ontology ( GO) and Kyoto encyclopedia of genes and genomes ( KEGG) databases, the differentially expressed genes were classified into diverse functional categories and signalling pathways. In particular, the focal adhesion signalling pathway showed significant differences between the groups; specifically, the FAK- Src- MAPK pathway was prominently activated in the ERBB2+ group. Conclusions In summary, ERBB2+ PHEO/ PGLs have a distinct expression pattern compared with the ERBB2− group. The focal adhesion signalling pathway may participate in ERBB2-induced tumourigenesis in PHEO/ PGLs. [ABSTRACT FROM AUTHOR]

Objective No single histological or molecular marker is diagnostic for malignant phaeochromocytomas and paragangliomas ( PPGLs). This study aimed to establish and evaluate a prognostic nomogram to improve the prediction of metastatic probability in individual PPGL patients. Methods Three hundred and 47 consecutive PPGL patients from January 2002 through December 2014 were randomly divided into a training set (n=208) and a validation set (n=139). A multivariate logistic regression analysis of selected prognostic features was performed, and a nomogram to predict metastasis was constructed. Discrimination and calibration were employed to evaluate the performance of the nomogram. Clinical usefulness was calculated using decision curve analysis. Results The overall metastatic rate was 10.6%. Primary tumour size, primary tumour location, vascular invasion, ERBB-2 overexpression, SDHB mutation and catecholamine type were associated with malignancy in the logistic analysis and were included in the nomogram. The nomogram showed an area under the receiver operating characteristic curve ( AUC) of 0.872 (95% confidence interval [ CI], 0.819-0.914) in the training set. The validation set showed good discrimination, with an AUC of 0.870 (95% CI, 0.803-0.921). The nomogram was well calibrated, with no significant difference between the predicted and the observed probabilities (Hosmer-Lemeshow test: P=.510 for the training set; .314 for the validation set). Decision curve analysis revealed that molecular markers ( ERBB-2 overexpression and SDHB mutation) could increase the clinical benefit of the nomogram. Conclusion Our results support the use of the present biomarker-based nomogram, which has good discriminative ability, to predict the metastatic probability of PPGLs. [ABSTRACT FROM AUTHOR]

Objective: The accurate classification of mass lesions in the adrenal glands ('adrenal masses'), detected with computed tomography (CT), is important for diagnosis and patient management. Adrenal masses can be benign or malignant and benign masses have varying prevalence. Classification methods based on convolutional neural networks (CNNs) are the state-of-the-art in maximizing inter-class differences in large medical imaging training datasets. The application of CNNs, to adrenal masses is challenging due to large intra-class variations, large inter-class similarities and imbalanced training data due to the size of the mass lesions.Methods: We developed a deep multi-scale resemblance network (DMRN) to overcome these limitations and leveraged paired CNNs to evaluate the intra-class similarities. We used multi-scale feature embedding to improve the inter-class separability by iteratively combining complementary information produced at different scales of the input to create structured feature descriptors. We augmented the training data with randomly sampled paired adrenal masses to reduce the influence of imbalanced training data.Results: We used 229 CT scans of patients with adrenal masses for evaluation. In a five-fold cross-validation, our method had the best results (89.52 % in accuracy) when compared to the state-of-the-art methods (p < 0.05). We conducted a generalizability analysis of our method on the ImageCLEF 2016 competition dataset for medical subfigure classification, which consists of a training set of 6776 images and a test set of 4166 images across 30 classes. Our method achieved better classification performance (85.90 % in accuracy) when compared to the existing methods and was competitive when compared with methods that require additional training data (1.47 % lower in accuracy).Conclusion: Our DMRN sub-classified adrenal masses on CT and was superior to state-of-the-art approaches. [ABSTRACT FROM AUTHOR]

Purpose: Transsphenoidal surgery is the first-line treatment for Cushing's disease (CD), even with negative preoperative magnetic resonance imaging (MRI) results. Some patients with persistent or recurring hypercortisolism have negative MRI findings after the initial surgery. We aimed to analyze the efficacy of repeat surgery in two groups of patients and determine if there is an association between positive MRI findings and early remission. Patients and Methods: Clinical, imaging, and biochemical information of 42 patients who underwent repeat surgery by a single neurosurgeon between 2002 and 2021 was retrospectively analyzed. We compared the endocrinological, histopathological, and surgical outcomes before and after repeat surgery among 14 CD patients with negative MRI findings and 28 patients with positive MRI findings. Results: Immediate remission was achieved in 29 patients (69.0%) who underwent repeat surgery. Among all patients, 28 (66.7%) had MRI findings consistent with solid lesions. There was no significant difference in remission rates between the recurrence and persistence groups (77.8% vs. 57.1%, odds ratio = 2.625, 95% confidence interval = 0.651 to 10.586). Patients in remission after repeat surgery were not associated with positive MRI findings (odds ratio = 3.667, 95% confidence interval = 0.920 to 14.622). Conclusions: In terms of recurrence, repeat surgery in patients with either positive or negative MRI findings showed reasonable remission rates. For persistent disease with positive MRI findings, repeat surgery is still an option; however, more solid evidence is needed to determine if negative MRI findings are predictors for failed reoperations for persistent hypercortisolism. [ABSTRACT FROM AUTHOR]

Objective Previous studies have investigated the genetic and molecular basis of primary aldosteronism ( PA), a common cause of human hypertension, but the effects of micro RNAs (mi RNAs) on the adrenocortical cell proliferation and aldosterone production are largely obscure. Here, we characterized mi RNA expression patterns in the subtypes of PA to gain a better understanding of its pathogenesis. Methods mi RNA expression was assessed by microarray profiling analysis in aldosterone-producing adenoma ( APA), unilateral adrenal hyperplasia ( UAH) and normal adrenal cortex tissues. Selected differentially expressed mi RNAs were further validated in a validation cohort by qRT- PCR. A gain-of-function approach was used to explore the functional role of the specific mi RNA in vitro. Results Of 31 mi RNAs including miR-375, miR-7 and miR-29b were found to be significantly differentially expressed among these three groups. miR-375 was the most downregulated one in adrenal cortex tissues from PA patients, and its expression level was inversely correlated with the tumour size in APA. Overexpression of miR-375 in a human adrenocortical cell line (H295R) reduced cell proliferation and suppressed the expression of MTDH (metadherin, also known as astrocyte elevated gene-1). Moreover, MTDH was verified as a direct target of miR-375 through luciferase reporter assays. Knock-down of MTDH in H295R cells attenuated Akt-Ser473 phosphorylation and inhibited cell viability. Conclusion Our findings suggest that miR-375 exerts its tumour-suppressive function via targeting MTDH/Akt pathway and implicate a potential therapeutic target in PA. [ABSTRACT FROM AUTHOR]

Adrenal pheochromocytoma (PCC) is a very rare tumor that stems from chromaffin cells, which can develop into malignant tumor. During the operation, abundant blood vessels were often observed in PCC than other adrenal tumors, which increases the difficulty and risk of the surgery. Therefore, it is important to investigate the mechanism of PCC angiogenesis. Twelve surgical specimens of PCC from Ruijin Hospital, Shanghai Jiaotong University were grouped into high and low microvessel density (MVD) group. They were also divided into rich blood supply and nonenriched blood supply group, according to computed tomography (CT) manifestation. Comparative proteomic analysis based on liquid chromatography–tandem mass spectrometry (LC–MS/MS) and bioinformatics analysis revealed that 206 proteins differentially regulated in the high MVD group compared with low MVD group (p < 0.05). Besides, 61 proteins were discovered to be significantly changed when the 12 samples were grouped according to CT manifestation. By intersecting the differentially changed protein from MVD and CT grouping, 25 proteins were filtered out, with pathological function. COX4I2 was verified to be increased gradually with angiogenesis with increasing severity, and PLAT was shown to be decreased with angiogenesis in PCC, by quantitative reverse‐transcription polymerase chain reaction and immunohistochemistry. The quantitative proteomics result indicated that the tumor angiogenesis in PCC is associated with hypoxia. COX4I2 and PLAT were highly correlated with blood supply in PCC which contribute to angiogenesis in PCC, which could be used as biomarkers to better indicate tumor angiogenesis, or targets to regress tumor angiogenesis as treatment. [ABSTRACT FROM AUTHOR]

Summary: Context: Adrenal venous sampling (AVS) is recommended as the gold standard for subtype classification in primary aldosteronism (PA); however, this approach has limited availability. Objective: We aimed to develop a novel clinical nomogram to predict PA subtype based on routine variables, thereby reducing the number of candidates for AVS. Patients and method: Patients were randomly divided into a training set (n = 185) and a validation set (n = 79). Risk factors for idiopathic hyperaldosteronism (IHA) differentiating from aldosterone‐producing adenoma (APA) were identified using logistic regression analysis. A nomogram was constructed to predict the probability of IHA. A receiver operating characteristic (ROC) curve and a calibration plot were applied to assess the predictive value. Then, 115 patients were prospectively enrolled, and a nomogram was used to predict the subtypes before AVS. Results: Body mass index (BMI), serum potassium and computed tomography (CT) finding were adopted in the nomogram. The nomogram presented an area under the ROC (AUC) of 0.924 (95% CI: 0.875‐0.957), sensitivity of 86.59% and specificity of 87.38% in the training set and an AUC of 0.894 (95% CI: 0.804‐0.952), sensitivity of 82.86% and specificity of 84.09% in the validation set. Predicted probability and actual probability matched well in the nomogram (Hosmer‐Lemeshow test: P > 0.05). Using the nomogram as a surrogate to predict IHA in the prospective set before AVS, the specificity reached 100% when we increased the threshold to a probability of 90%. Conclusion: We have developed a tool that is able to predict IHA in patients with PA and potentially avoid AVS. [ABSTRACT FROM AUTHOR]

The association of pathological features of cortisol-producing adrenocortical adenomas (ACAs) with somatic driver mutations and their molecular classification remain unclear. In this study, we explored the association between steroidogenic acute regulatory protein (StAR) expression and the driver mutations activating cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling to identify the pathological markers of ACAs. Immunohistochemical staining for StAR and mutations in the protein kinase cAMP-activated catalytic subunit alpha (PRKACA), protein kinase cAMP-dependent type I regulatory subunit alpha (PRKAR1A) and guanine nucleotide binding protein, alpha stimulating (GNAS) genes were examined in 97 ACAs. The association of StAR expression with the clinical and mutational features of the ACAs was analyzed. ACAs with mutations in PRKACA, GNAS, and PRKAR1A showed strong immunopositive staining for StAR. The concordance between high StAR expression and mutations activating cAMP/PKA signaling in the ACAs was 99.0%. ACAs with high expression of StAR had significantly smaller tumor volume (P < 0.001) and higher urinary cortisol per tumor volume (P = 0.032) than those with low expression of StAR. Our findings suggest that immunohistochemical staining for StAR is a reliable pathological approach for the diagnosis and classification of ACAs with cAMP/PKA signaling-activating mutations. [ABSTRACT FROM AUTHOR]

Background Recent studies have found that mild secondary hyperparathyroidism might be another clinical feature of patients with primary aldosteronims ( PA), but whether serum parathyroid hormone level ( PTH) is correlated with subtypes of PA and what contributes to the elevated PTH level remains unclear. Objective To illustrate the changes of PTH in PA and to partly explain the mechanism of how the effects of aldosterone regulating the secretion of PTH in PA. Methods We enrolled a total of 120 patients with primary hypertension ( PH) and 242 patients with PA, which included 89 APAs (aldosterone-producing adenoma), 119 IHAs (idiopathic hyperaldosteronism) and 34 UAHs (unilateral adrenal hyperplasia). The plasma levels of aldosterone, renin activity, parathyroid hormone and markers associated with calcium metabolism were measured. Results We found serum PTH level was significantly elevated in patients with PA compared with primary hypertension [9·0 (6·6, 11·7) vs 5·7 (4·4, 7·0)] pmol/l, P < 0·001]. However, no difference was found between the three PA subtypes ( P > 0·05). Stepwise multiple regression analysis showed that in patients with PA, serum levels of K+ and Ca2+ were independently associated with serum PTH level. More importantly, elevated PTH level could be corrected either by unilateral adrenalectomy [9·9 (7·5, 12·8) vs 5·2 (4·4, 7·0) pmol/l, P < 0·001] or mineralocorticoid receptor ( MR) antagonists treatment [11·7 (9·1, 13·4) vs 6·3 (5·1, 7·8) pmol/l, P < 0·001]. Conclusions PTH level is elevated in PA patients and irrelevant with subtypes of PA. Serum K+ and serum Ca2+ level are main factors influence the plasma PTH level in PA patients. After medical or surgical treatment, PTH levels return to normal. [ABSTRACT FROM AUTHOR]

Objective There are currently no good histological or molecular markers to differentiate benign from malignant phaeochromocytomas and paraganglinomas (PPGLs). Our previous cross-sectional study observed that ERBB-2 overexpression was associated with malignant PPGLs. This study aimed to evaluate the predictive value of ERBB-2 overexpression for metastasis in PPGLs in a large population. Methods A total of 262 patients diagnosed as PPGLs in our institution between 2002 and 2012 were included. We analysed ERBB-2 protein expression in the primary PPGL tumours by immunohistochemistry (IHC) and ERBB-2 amplification by fluorescence in situ hybridization (FISH). Direct Sanger sequencing was performed to examine ERBB-2 exon 20 mutations. The occurrence of malignant PPGLs was documented in the follow-up period. Kaplan-Meier analysis and Cox proportional hazard models were used to evaluate the association between ERBB-2 overexpression and metastasis of PPGLs. Results Twenty-six (9·9%) patients had ERBB-2 overexpression in their primary PPGL tumours, which was significantly associated with ERBB-2 amplification (17/25, 68%). No ERBB-2 mutation was found. At a median follow-up of 4·5 years, a total of 23 malignant PPGLs were documented, including eight (30·8%) patients in the ERBB-2 overexpression group and 15 (6·4%) patients in the ERBB-2-negative group. The incidence rate of metastasis was 5·3 per 100 person-years vs 1·4 per 100 person-years in the ERBB-2 overexpression and ERBB-2-negative groups ( P < 0·001), respectively. Kaplan-Meier analysis showed that ERBB-2 overexpression was associated with decreased metastasis-free survival ( P = 0·001, log-rank test). After adjusting for primary tumour size and location, Cox regression analysis revealed that ERBB-2 overexpression was independently associated with risk of malignant PPGLs (HR = 2·78; 95% CI, 1·12-6·90; P = 0·028). Conclusion Patients harbouring tumours with ERBB-2 overexpression have a significantly higher risk of developing malignant PPGLs. [ABSTRACT FROM AUTHOR]

Context Pituitary stalk interruption syndrome ( PSIS) is a rare cause of combined pituitary hormone deficiency characterized by a triad shown in pituitary imaging, yet it has never been evaluated due to the visibility of pituitary stalk ( PS) in imaging findings. Objective The major objective of the study was to systematically describe the disease including clinical presentations, imaging findings and to estimate the severity of anterior pituitary hormone deficiency based on the visibility of the PS. Methods This was a retrospective study including 74 adult patients with PSIS in Shanghai Clinical Center for Endocrine and Metabolic Diseases between January 2010 and June 2014. Sixty had invisible PS according to the findings on MRI, while the rest had a thin or intersected PS. Basic characteristics and hormonal status were compared. Results Of the 74 patients with PSIS, age at diagnosis was 25 (22-28) years. Absent pubertal development (97·3%) was the most common presenting symptom, followed by short stature. Insulin tolerance test ( ITT) and gonadotrophin-releasing hormone ( Gn RH) stimulation test were used to evaluate the function of anterior pituitary. The prevalence of isolated deficiency in growth hormone ( GH), gonadotrophins, corticotrophin and thyrotrophin were 100%, 97·2%, 88·2% and 70·3%, respectively. Although the ratio of each deficiency did not vary between patients with invisible PS and with visible PS, panhypopituitarism occurred significantly more frequent in patients with invisible PS. Patients with invisible PS had significantly lower levels of luteinizing hormone ( LH), follicle stimulation hormone ( FSH) and hormones from targeted glands including morning cortisol, 24-h urine free cortisol, free triiodothyronine ( FT3), free thyroxine ( FT4) and testosterone (T) in male than patients with visible PS. Moreover, patients with invisible PS had lower peak LH and FSH in Gn RH stimulation test, and higher peak cortisol in ITT while peak GH remained unchanged between two groups. Conclusions The prevalence of multiple anterior pituitary hormone deficiency was high in adult patients with PSIS. And more importantly, we found the visibility of PS shown on MRI might be an indication of the severity of PSIS. [ABSTRACT FROM AUTHOR]

Objective Most patients with Cushing's disease (CD) will have evidence of an adenoma on high-resolution magnetic resonance imaging (MRI). However, a significant minority of patients with CD and biochemical hypercortisolaemia have no visible adenoma on MRI. The purpose of this study was to evaluate the diagnostic value of preoperative biochemical assessment and accuracy of MRI findings on surgical outcome. Design Retrospective data set analyses. Patients and measurement The clinical, endocrinological, histopathological and surgical outcomes of 24 consecutive CD patients with negative MRI findings were compared with those of 95 consecutive age- and sex-matched CD patients with pituitary adenomas on MRI. Results The total remission rate was 86·6%. Among all patients, 87 had concordant positive endocrine tests and underwent neurosurgery, while bilateral inferior petrosal sinus sampling (BIPSS) was performed in 12 and 50 other patients with negative and positive MRI, respectively. A pituitary adenoma, confirmed by pathological examination, was found in 83·3% and 93·6% of patients with negative and positive MRI, respectively. The remission rate was not different between patients with negative and positive MRI (87·5 % and 86·3%, respectively; P > 0·05) or between patients who did not undergo BIPSS with negative MRI and patients with positive MRI ( P > 0·05). The remission rate of patients who underwent BIPSS with negative MRI was not different from those not undergoing BIPSS ( P > 0·05). The recurrence rate was higher, although not statistically different, in patients with negative MRI compared to positive ones. Conclusions Based on the findings outlined, MRI-negative CD may be a surgically remediable syndrome, with a pathophysiological basis that primarily involves a pituitary cause of the hypercortisolaemia. [ABSTRACT FROM AUTHOR]

Abstract: Thyrotoxic periodic paralysis (TPP), familial periodic paralysis (FPP), and sporadic periodic paralysis (SPP) are the most common causes of hypokalemic periodic paralysis (hypoKPP). The patients present with similar clinical features characterized by episodic attacks of muscle weakness and a decrease in blood potassium. Mutations in the gene encoding the voltage-sensor coding regions of the skeletal muscle sodium channel gene (SCN4A) and the α-1 subunit of the skeletal muscle calcium channel gene were analyzed in 23 Chinese hypoKPP patients, including 1 FPP pedigree, 14 TPP patients, and 8 SPP patients. In addition, R83H mutation of the potassium channel subunit gene which was originally published as periodic paralysis mutation was also analyzed. A heterozygous CGT-TGT mutation at codon 672 in SCN4A gene was identified to segregate with the disease in the FPP family. Mutations in these regions were excluded in those patients with SPP and TPP. The results suggest that a likely genetic basis for FPP does not contribute to TPP and SPP, despite close similarities among FPP, TPP, and SPP. [Copyright &y& Elsevier]