Clinical Characteristics and Management of Hypercalcemic Crisis in 155 Patients: A Single Center Retrospective Study.

Objective: This study aimed to analyse the etiology and clinical characteristics of hypercalcemic crisis in a large cohort of Chinese patients and summarised our clinical experience in the management of this serious endocrinological emergency. Methods: This was a retrospective analysis of a cohort of patients with hypercalcemic crisis hospitalized in the First Medical Center of Chinese PLA General Hospital between January 2009 and March 2024. The general data, clinical manifestations, etiology, photographic examination, emergency treatment, etiological treatment, and prognosis were analysed. Results: A total of 155 patients with hypercalcemic crisis (91 males and 64 females) with a mean age of 54.60 ± 16.99 years old were enrolled. The most frequent disease-causing hypercalcemic crisis was hyperparathyroidism (41.94%), followed by solid malignancy (41.29%) and multiple myeloma (9.03%), et al. Patients mainly presented with symptoms of the digestive system (78.10%), nervous system (63.30%), skeletal system (59.60%), urinary system (59.50%), and cardiovascular system (34.90%). These 155 patients with hypercalcemic crisis got effective therapies that included simultaneous administration of intravenous injection (IV) isotonic saline, subcutaneous calcitonin, bisphosphonate, or hemodialysis in serious cases. After emergency treatment, all the symptoms in the patients were relieved obviously. The cure rate of hypercalcemic with etiological treatments was 84.50% (131/155). Conclusion: Hypercalcemic crisis is a serious endocrinological emergency with a variety of etiologies and a high risk of mortality. A prompt diagnosis and the implementation of a comprehensive and effective treatment can efficiently alleviate this endocrinological emergency. Etiological treatment targeting different causes can improve prognosis significantly.

Clinical characteristics and complication risks in data-driven clusters among Chinese community diabetes populations.

BACKGROUND: Novel diabetes phenotypes were proposed by the Europeans through cluster analysis, but Chinese community diabetes populations might exhibit different characteristics. This study aims to explore the clinical characteristics of novel diabetes subgroups under data-driven analysis in Chinese community diabetes populations. METHODS: We used K-means cluster analysis in 6369 newly diagnosed diabetic patients from eight centers of the REACTION (Risk Evaluation of cAncers in Chinese diabeTic Individuals) study. The cluster analysis was performed based on age, body mass index, glycosylated hemoglobin, homeostatic modeled insulin resistance index, and homeostatic modeled pancreatic ß-cell functionality index. The clinical features were evaluated with the analysis of variance (ANOVA) and chi-square test. Logistic regression analysis was done to compare chronic kidney disease and cardiovascular disease risks between subgroups. RESULTS: Overall, 2063 (32.39%), 658 (10.33%), 1769 (27.78%), and 1879 (29.50%) populations were assigned to severe obesity-related and insulin-resistant diabetes (SOIRD), severe insulin-deficient diabetes (SIDD), mild age-associated diabetes mellitus (MARD), and mild insulin-deficient diabetes (MIDD) subgroups, respectively. Individuals in the MIDD subgroup had a low risk burden equivalent to prediabetes, but with reduced insulin secretion. Individuals in the SOIRD subgroup were obese, had insulin resistance, and a high prevalence of fatty liver, tumors, family history of diabetes, and tumors. Individuals in the SIDD subgroup had severe insulin deficiency, the poorest glycemic control, and the highest prevalence of dyslipidemia and diabetic nephropathy. Individuals in MARD subgroup were the oldest, had moderate metabolic dysregulation and the highest risk of cardiovascular disease. CONCLUSION: The data-driven approach to differentiating the status of new-onset diabetes in the Chinese community was feasible. Patients in different clusters presented different characteristics and risks of complications.

M2 macrophage infusion ameliorates diabetic glomerulopathy via the JAK2/STAT3 pathway in db/db mice.

Objectives: To explore the therapeutic effects of M2 macrophages in diabetic nephropathy (DN) and their mechanism.Methods: We infused M2 macrophages stimulated with IL-4 into 10-week-old db/db mice once a week for 4 weeks through the tail vein as M2 group. Then we investigated the role of M2 macrophages in alleviating the infammation of DN and explored the mechanism.Results: M2 macrophages hindered the progression of DN, reduced the levels of IL-1ß (DN group was 34%, M2 group was 13%, p < 0.01) and MCP-1 (DN group was 49%, M2 group was 16%, p < 0.01) in the glomeruli. It was also proven that M2 macrophages alleviate mesangial cell injury caused by a high glucose environment. M2 macrophage tracking showed that the infused M2 macrophages migrated to the kidney, and the number of M2 macrophages in the kidney reached a maximum on day 3. Moreover, the ratio of M2 to M1 macrophages was 2.3 in the M2 infusion group, while 0.4 in the DN group (p < 0.01). Mechanistically, M2 macrophages downregulated Janus kinase (JAK) 2 and signal transducer and activator of transcription (STAT) 3 in mesangial cells.Conclusions: Multiple infusions of M2 macrophages significantly alleviated inflammation in the kidney and hindered the progression of DN at least partially by abrogating the M1/M2 homeostasis disturbances and suppressing the JAK2/STAT3 pathway in glomerular mesangial cells. M2 macrophage infusion may be a new therapeutic strategy for DN treatment.

The efficacy and safety of iGlarLixi versus IDegAsp in Chinese people with type 2 diabetes suboptimally controlled with oral antidiabetic drugs: The Soli-D randomized controlled trial.

AIM: To compare the efficacy and safety of a fixed-ratio combination of insulin glargine 100 U/mL plus lixisenatide (iGlarLixi) with premixed insulin, insulin degludec plus insulin aspart (IDegAsp), in Chinese people with type 2 diabetes (T2D) suboptimally controlled with oral antidiabetic drug(s) (OADs). METHODS: In Soli-D, a 24-week, multicentre, open-label, study, insulin-naïve adults were randomized 1:1 to once-daily injections of iGlarLixi (n = 291) or IDegAsp (n = 291), with continued metformin ± sodium-glucose co-transporter-2 inhibitors. The primary endpoint was non-inferiority in HbA1c change from baseline to week 24. Key secondary endpoints included superiority in HbA1c change and body weight (BW) change at week 24. Hypoglycaemia rates were also assessed. RESULTS: At week 24, iGlarLixi showed non-inferiority and superiority over IDegAsp in HbA1c reduction (least squares [LS] mean difference: -0.20 [95% confidence interval {CI}: -0.33, -0.07]; P < .001 for non-inferiority; [97.5% CI: -0.35, -0.05]; P = .003 for superiority). iGlarLixi decreased BW and IDegAsp increased BW from baseline to week 24, with a statistically significant LS mean difference of -1.49 kg in favour of iGlarLixi (97.5% CI: -2.32, -0.66; P < .001). Event rates (per person-year) for American Diabetes Association (ADA) Level 1, 2 or 3 hypoglycaemia were lower for iGlarLixi (1.90) versus IDegAsp (2.72) (relative risk: 0.71; 95% CI: 0.52, 0.98). No ADA Level 3 hypoglycaemia or unexpected safety findings were reported. CONCLUSIONS: In Chinese people with T2D suboptimally controlled with OADs, once-daily iGlarLixi provided better glycaemic control with BW benefit and lower hypoglycaemia event rates versus IDegAsp.

Predictive factors that influence the clinical efficacy of umbilical cord-derived mesenchymal stromal cells in the treatment of type 2 diabetes mellitus.

BACKGROUND: Our previous single-center, randomized, double-blinded, placebo-controlled phase 2 study evaluated the safety and effectiveness of human umbilical cord mesenchymal stromal cell (UC-MSC) transfusion for treating patients with type 2 diabetes mellitus (T2DM). Indeed, this potential treatment strategy was able to reduce insulin use by half in a considerable number of patients. However, many other patients' responses to UC-MSC transfusion were insignificant. The selection of patients who might benefit from UC-MSC treatment is crucial from a clinical standpoint. METHODS: In this post hoc analysis, 37 patients who received UC-MSC transfusions were divided into two groups based on whether their glycated hemoglobin (hemoglobin A1c, or HbA1c) level was less than 7% after receiving UC-MSC treatment. The baseline differences between the two groups were summarized, and potential factors influencing efficacy of UC-MSCs for T2DM were analyzed by univariate and multivariate logistic regression. The correlations between the relevant hormone levels and the treatment effect were further analyzed. RESULTS: At the 9-week follow-up, 59.5% of patients achieved their targeted HbA1c level. Male patients with lower baseline HbA1c and greater C-peptide area under the curve (AUCC-pep) values responded favorably to UC-MSC transfusion, according to multivariate analysis. The effectiveness of UC-MSCs transfusion was predicted by AUCC-pep (cutoff value: 14.22 ng/h/mL). Further investigation revealed that AUCC-pep was increased in male patients with greater baseline testosterone levels. CONCLUSIONS: Male patients with T2DM with greater AUCC-pep may be more likely to respond clinically to UC-MSC therapy, and further large-scale multi-ethnic clinical studies should be performed to confirm the conclusion.

Efficacy of Umbilical Cord-Derived Mesenchymal Stem Cells in the Treatment of Type 2 Diabetes Assessed by Retrospective Continuous Glucose Monitoring.

Umbilical cord-derived mesenchymal stem cells (UC-MSCs) have been proved a promising clinical strategy for the treatment of diabetes, and time in range (TIR) has been demonstrated a new metric of glycemic control links to diabetes complications. To further assess the therapeutic effect of UC-MSCs on TIR, a phase II study investigating the efficacy of UC-MSCs in Chinese adults with type 2 diabetes (T2D) assessed by retrospective continuous glucose monitoring (CGM) was conducted. In this randomized and placebo-controlled trial, a total of 73 patients were randomly assigned to receive intravenous infusion of UC-MSCs (n = 37) or placebo (n = 36) 3 times at 4-week intervals and followed up for 48 weeks. The primary endpoint was the changes in TIR and glycosylated hemoglobin (HbA1c). TIR and HbA1c were both significantly improved in UC-MSCs and placebo groups after 48 weeks of therapy compared with baseline. Compared with placebo group, UC-MSCs group exhibited more pronounced changes at 9 and 48 weeks from baseline in TIR (26.54 vs. 15.84 and 21.36 vs. 6.32) and HbA1c (-1.79 vs. -0.96 and -1.36 vs. -0.51). More patients in UC-MSCs group achieved the glycemic control target of TIR ≥ 70% and HbA1c < 7% at 9 and 48 weeks than in placebo group (59.5% vs. 27.8% and 43.2% vs. 11.1%). The C-peptide area under the curve (AUCC-pep) was an independent risk factor associated with efficacy in T2D undergoing UC-MSCs intervention. These results illustrate that UC-MSCs administration via intravenous infusion is an effective approach for ameliorating TIR.

Association between hemoglobin glycation index and 5-year major adverse cardiovascular events: the REACTION cohort study.

BACKGROUND: The hemoglobin glycation index (HGI) was developed to quantify glucose metabolism and individual differences and proved to be a robust measure of individual glycosylated hemoglobin (HbA1c) bias. Here, we aimed to explore the relationship between different HGIs and the risk of 5-year major adverse cardiovascular events (MACEs) by performing a large multicenter cohort study in China. METHODS: A total of 9791 subjects from the Risk Evaluation of Cancers in Chinese Diabetic Individuals: a Longitudinal Study (the REACTION study) were divided into five subgroups (Q1-Q5) with the HGI quantiles (≤5th, >5th and ≤33.3th, >33.3th and ≤66.7th, >66.7th and ≤95th, and >95th percentile). A multivariate logistic regression model constructed by the restricted cubic spline method was used to evaluate the relationship between the HGI and the 5-year MACE risk. Subgroup analysis between the HGI and covariates were explored to detect differences among the five subgroups. RESULTS: The total 5-year MACE rate in the nationwide cohort was 6.87% (673/9791). Restricted cubic spline analysis suggested a U-shaped correlation between the HGI values and MACE risk after adjustment for cardiovascular risk factors ( χ2 = 29.5, P <0.001). After adjustment for potential confounders, subjects with HGIs ≤-0.75 or >0.82 showed odds ratios (ORs) for MACE of 1.471 (95% confidence interval [CI], 1.027-2.069) and 2.222 (95% CI, 1.641-3.026) compared to subjects with HGIs of >-0.75 and ≤-0.20. In the subgroup with non-coronary heart disease, the risk of MACE was significantly higher in subjects with HGIs ≤-0.75 (OR, 1.540 [1.039-2.234]; P = 0.027) and >0.82 (OR, 2.022 [1.392-2.890]; P <0.001) compared to those with HGIs of ≤-0.75 or >0.82 after adjustment for potential confounders. CONCLUSIONS: We found a U-shaped correlation between the HGI values and the risk of 5-year MACE. Both low and high HGIs were associated with an increased risk of MACE. Therefore, the HGI may predict the 5-year MACE risk.

Analysis of characteristics of four patients with adrenal unicentric Castleman disease.

Background: Castleman Disease (CD) is a group of diseases with characteristic lymph node histopathology, characterized by marked enlargement of deep or superficial lymph nodes. Adrenal CD is rarely reported, and an accurate preoperative diagnosis of adrenal CD is difficult. Method: We report four cases of CD in the adrenal gland confirmed by pathology and review the characteristics of this rare disease, highlighting the necessity of diagnostic evaluation and follow-up of the patients. Results: All of the patients sought medical advice because of adrenal incidentalomas. No significant abnormalities were presented in the biochemistry or endocrine systems. The imaging suggested a moderate-to-large mass with uneven moderate contrast enhancement of the adrenal region, similar to a pheochromocytoma. All cases were misdiagnosed as pheochromocytomas before operation and finally confirmed by histopathology. Three cases were pathologically diagnosed as hyaline vascular CD, and one case was diagnosed as plasma cell CD. All the patients are alive without recurrence after a median follow-up of 8 years. Conclusion: The adrenal CD should be considered after excluding pheochromocytoma and malignancy in the adrenal region. The long-term prognosis of patients with complete resection of the mass is excellent.

Association of skin autofluorescence with depressive symptoms and the severity of depressive symptoms: The prospective REACTION study.

AIM: Millions of people are afflicted by depression, a highly prevalent mental illness with increased morbidity and mortality. Advanced glycation end-products (AGEs) are potential risk factors for depression. We aimed to investigate the correlation of AGEs with depressive symptoms and the severity of depressive symptoms. METHODS: This study was nested in the prospective REACTION (Risk Evaluation of cAncers in Chinese diabeTic Individuals) study and included 4420 eligible participants. skin autofluorescence (SAF) was used to measure skin AGEs. Depressive symptoms were evaluated by the Self-Rating Depression Scale (SDS). Multiple logistic regression analysis was used to assess the association of AGEs with depressive symptoms and the severity of depressive symptoms. RESULTS: Logistic analysis showed a significantly positive relationship between quartiles of SAF-AGEs and the risk of depressive symptoms with the OR [95% confidence interval (CI), p value] of 1.24 (95% CI: 1.03-1.50, p = 0.022), 1.39 (95% CI: 1.15-1.68, p = 0.001) and 1.57 (95% CI: 1.28-1.91, p < 0.001) for multivariable-adjusted model respectively. And SAF-AGEs were associated with the severity of depressive symptoms with the multivariable-adjusted OR (95% CI, p value) of 1.06 (95% CI:0.79-1.43, p = 0.681), 1.47 (95% CI: 1.08-1.99, p = 0.014), and 1.54 (95% CI: 1.12-2.11, p = 0.008) respectively. Stratified analyses showed that SAF-AGEs were significantly associated with the severity of depressive symptoms only in females, overweight people, individuals with hypertension, and those without diabetes and insomnia. CONCLUSIONS: The present study showed that a higher SAF-AGEs level was associated with depressive symptoms and the severity of depressive symptoms.

Nomogram for Predicting Intraoperative Hemodynamic Instability in Patients With Normotensive Pheochromocytoma.

CONTEXT: Intraoperative hemodynamic instability (HI) deteriorates surgical outcomes of patients with normotensive pheochromocytoma (NP). OBJECTIVE: To characterize the hemodynamics of NP and develop and externally validate a prediction model for intraoperative HI. METHODS: Data on 117 patients with NP (derivation cohort) and 40 patients with normotensive adrenal myelolipoma (NAM) who underwent laparoscopic adrenalectomy from January 2011 to November 2021 were retrospectively collected. Data on 22 patients with NP (independent validation cohort) were collected from another hospital during the same period. The hemodynamic characteristics of patients with NP and NAM were compared. Machine learning models were used to identify risk factors associated with HI. The final model was visualized via a nomogram. RESULTS: Forty-eight (41%) out of 117 patients experienced HI, which was significantly more than that for NAM. A multivariate logistic regression including age, tumor size, fasting plasma glucose, and preoperative systolic blood pressure showed good discrimination measured by area under curve (0.8286; 95% CI 0.6875-0.9696 and 0.7667; 95% CI 0.5386-0.9947) for predicting HI in internal and independent validation cohorts, respectively. The sensitivities and positive predictive values were 0.6667 and 0.7692 for the internal and 0.9167 and 0.6111 for the independent validations, respectively. The final model was visualized via a nomogram and yielded net benefits across a wide range of risk thresholds in decision curve analysis. CONCLUSION: Patients with NP experienced HI during laparoscopic adrenalectomy. The nomogram can be used for individualized prediction of intraoperative HI in patients with NP.

Parathyroid carcinoma: Report of 10 patients and literature review.

OBJECTIVE: Parathyroid carcinoma (PC) is a rare disease with high rates of misdiagnosis and recurrence. This report summarized the clinical and pathological characteristics of 10 patients with PC at our hospital, to improve the early recognition and prognosis of PC. METHODS: The clinical manifestations, imaging findings, pathological features, treatments, and prognostic data of 10 patients diagnosed with PC at the First Medical Center, Chinese PLA General Hospital from 2003 to 2021 were analyzed. RESULTS: There were 7 male and 3 female patients with PC whose average age was 41.4 ± 9.4 years. All patients had bone involvement (bone pain and/or osteoporosis), meanwhile 6 patients had kidney stones and 7 patients had palpable neck masses. Five patients presented with tumor metastasis, invading lymph nodes, lung, liver, or bone. Laboratory examinations revealed elevated serum total calcium (4.15 ± 0.81 mmol/L), parathyroid hormone (PTH, 1236.1 ± 519.9 pg/mL) and alkaline phosphatase (405.8 ± 219.0 IU/L) levels. Especially, hypercalcemic crisis occurred in 9 patients. The diagnosis of PC depended on histopathological features of the parathyroid tumor, including capsular and/or vascular invasion. All patients underwent at least en bloc resection. In the follow-up, six patients with relatively high preoperative PTH levels (1519.5 ± 436.8 pg/mL) relapsed postoperatively. Two patients with the Ki-67 index ≥ 10% in parathyroid tumor tissue and distant metastasis died within 2 years after the operation. CONCLUSION: Severe bone pain, kidney stones, hypercalcemic crisis, and markedly elevated PTH usually indicate PC. A markedly elevated PTH level, tumor metastasis, and the Ki-67 index ≥ 10% may be indicators of poor prognosis.

Association of skin autofluorescence with low bone density/osteoporosis and osteoporotic fractures in type 2 diabetes mellitus.

BACKGROUND: Advanced glycation end products (AGEs) that abnormally accumulate in diabetic patients have been reported to damage bone health. We aimed to investigate the association between skin autofluorescence (SAF)-AGEage (SAF - AGEs × age/100) and low bone density (LBD)/osteoporosis or major osteoporotic fractures (MOFs) in patients with type 2 diabetes mellitus (T2DM). METHODS: This study was nested in the prospective REACTION (Risk Evaluation of Cancers in Chinese Diabetic Individuals) study and included 1214 eligible participants. SAF was used to measure skin AGEs (SAF-AGEs). Fracture events were determined by an in-person clinical follow-up. Binary logistic regression analysis, linear regression analysis, and a restricted cubic spline nested in logistic models were used to test outcomes. RESULTS: The overall prevalence of LBD/osteoporosis in middle-aged or elderly T2DM patients was 35.7% (n = 434), and the overall incidence of MOFs was 10.5% (n = 116). Logistic analysis showed a significantly positive relationship between quartiles of SAF-AGEage and the risk of LBD/osteoporosis (odds ratio [OR] 2.02, 95% CI 1.34-3.03; OR 3.63, CI 2.44-5.39; and OR 6.51, CI 4.34-9.78) for the multivariate-adjusted models, respectively. SAF-AGEage was associated with MOFs with a multivariate-adjusted OR of 1.02 (CI 0.52-2.02), 2.42 (CI 1.32-4.46), and 2.70 (CI 1.48-4.91), respectively. Stratified analyses showed that SAF-AGEage was significantly associated with MOFs only in females, nonsmokers, nondrinkers, individuals with lower body mass index, and those without LBD/osteoporosis. Linear regression analyses showed that higher SAF-AGEs were associated with a higher level of serum N-terminal propeptide of type I procollagen (s-PINP) and serum carboxy-terminal cross-linking peptide of type I collagen (s-CTX), with a multivariate-adjusted OR of 1.02 (CI 0.24-1.80) and 6.30 (CI 1.77-10.83), respectively. CONCLUSIONS: In conclusion, SAF-AGEage was positively associated with the prevalence of LBD/osteoporosis or MOFs in patients with T2DM. A positive association between SAF-AGEs and the level of s-PINP and s-CTX was found.

Expression and clinical significance of Cathepsin K and MMPs in invasive non-functioning pituitary adenomas.

Background: Cathepsin K (CTSK) is a protease that degrades type I collagen and extracellular matrix, thereby contributing to bone resorption and tumor invasion. Some pituitary adenomas (PAs) could invade the sphenoid sinus (SS) and cavernous sinus (CS). Purpose: This retrospective cohort study aimed to study the expression of tumoral biomarkers (CTSK, MMP9, MMP2, TIMP2, and PTTG1) and evaluate their clinical significance in non-functioning pituitary adenomas (NFPAs) with different invasion patterns. Methods: We assessed the expression levels of candidate invasion-specific protein biomarkers CTSK, MMP9, MMP2, TIMP2, and PTTG1 by immunohistochemical staining in paraffin-embedded NFPA tumor tissues. Variations in staining intensity were analyzed in cases with SS and CS invasion and non-invasive NFPAs. Results: We found that the levels of CTSK were higher in PA cases with SS invasion than that in PA cases with CS invasion (95.57 ± 31.57 vs. 65.29 ± 29.64, P < 0.001), and the expression of MMP9 and MMP2 was higher in CS-invasive cases than that in SS-invasive cases (145.02 ± 49.25 vs. 111.80 ± 51.37, P = 0.002, and 138.67 ± 52.06 vs. 108.30 ± 41.70, P = 0.002). Multiple Cox regression demonstrated that higher CTSK expression (P=0.011), subtotal resection (P<0.001), invasion (P=0.037), and larger tumor diameter (P=0.001) were independent risk factors for recurrence. A positive correlation was observed between CTSK expression and tumor size (r=0.671, p<0.001). There was no significant difference in TIMP2 and PTTG1 levels between CS-and SS-invasive cases (97.42± 39.80 vs. 102.10± 43.22, P = 0.58 and 13.89 ± 4.59 vs. 12.56 ± 3.96, P = 0.14). Conclusion: Our data indicated that CTSK has the potential as a marker for SS invasion of PAs, whereas MMP9 and MMP2 may be markers for CS invasion. And CTSK may play an important role in tumor relapse.

Sex Differences in Hypercortisolism and Glucose-Metabolism Disturbances in Patients with Mild Autonomous Cortisol Secretion: Findings From a Single Center in China.

Background and objective: Mild autonomous cortisol secretion (MACS) presents with a marked female preponderance, but whether the sex difference in its distribution has any relevance to the presentation and outcome of the disease is unknown. The aim of this study was therefore to compare biochemical indices of hypercortisolism and impaired glucose metabolism between male and female patients with MACS. Method: We enrolled a total of 98 patients with autonomous/possible autonomous cortisol secretion in our study, and indices of hypercortisolism and glucose metabolism were collected and compared between the male and female patients. Logistic regression models were used to evaluate the association between sex and cortisol-secretory ability, as well as between the latter and glucose metabolism. In addition, we conducted further stratified analyses according to the degree of autonomous cortisol secretion and menopausal status. Results: Cortisol levels at 00:00 and 08:00 h after a 1-mg dexamethasone suppression test (DST) and low-dose DST were significantly higher in female than in male MACS patients, and the inhibition rate of 1-mg DST was lower in the women than in the men. This significant difference still remained after adjusting for age, BMI, and the course of the disease. Logistic regression analysis revealed a significant association between autonomous cortisol secretion and fasting C-peptide, as well as with the C-peptide-to-glucose ratio in females relative to male patients. In addition, stratified analyses indicated that this association was observed only among women with autonomous cortisol secretion and who were premenopausal. Conclusion: The level of autonomic cortisol secretion in female patients with MACS was higher than in male patients, and the association between autonomous cortisol secretory ability and glucose homeostasis was only noted in patients with autonomous cortisol secretion and in premenopausal women. This phenomenon will, however, require closer follow-up.

Clinical analysis of the etiological spectrum of bilateral adrenal lesions: A large retrospective, single-center study.

PURPOSE: To investigate the clinical characteristics, endocrinological function, and etiology of bilateral adrenal lesions in hospitalized patients. METHODS: A retrospective study of 777 patients with bilateral adrenal lesions was conducted at the Chinese People's Liberation Army General Hospital between January 2013 and January 2018. Patients' demographic features, hormonal profiles, imaging findings, and histopathological findings were reviewed from database records. RESULTS: Of the 777 patients with bilateral adrenal lesions, 495 were men. The mean age at diagnosis was 52.0 ± 13.0 years. Overall, 511 (65.8%) cases were benign, followed by adrenal metastases (n = 224, 28.8%), pheochromocytoma (n = 26, 3.3%), adrenal lymphoma (n = 9, 1.2%), and adrenal corticocarcinoma (ACC; n = 7, 0.9%). Hormonal evaluation revealed that 34.3% of bilateral adrenal lesions were functional. The primary etiologies of functional lesions were primary aldosteronism (16.6%, 129/777), and primary bilateral macronodular adrenocortical hyperplasia (PBMAH; 8.8%, 68/777). Patients with lymphoma and metastases were significantly older than those with benign nonfunctional lesions (60.4 ± 11.0 years vs. 54.5 ± 10.4 years and 57.9 ± 10.8 years vs. 54.5 ± 10.4 years, respectively; both P < 0.001). Lesions in patients with adrenal lymphoma, ACC, pheochromocytoma, metastases, congenital adrenal hyperplasia, tuberculosis, and Cushing's syndrome were significantly larger than benign nonfunctional lesions (all P < 0.001). CONCLUSION: Benign adrenal lesions and metastases from the lungs are the most common causes of bilateral adrenal lesions. Primary aldosteronism and PBMAH are the most prevalent functional lesions. Moreover, patients with lymphoma or metastases are older and their masses are larger.

Efficacy and safety of umbilical cord-derived mesenchymal stem cells in Chinese adults with type 2 diabetes: a single-center, double-blinded, randomized, placebo-controlled phase II trial.

BACKGROUND: To determine the efficacy and safety of umbilical cord-derived mesenchymal stem cells (UC-MSCs) in Chinese adults with type 2 diabetes mellitus (T2DM). METHODS: In this single-center, double-blinded, randomized, placebo-controlled phase II trial, 91 patients were randomly assigned to receive intravenous infusion of UC-MSCs (n = 45) or placebo (n = 46) three times with 4-week intervals and followed up for 48 weeks from October 2015 to December 2018. The primary endpoint was the percentage of patients with glycated hemoglobin (HbA1c) levels of < 7.0% and daily insulin reduction of ≥ 50% at 48 weeks. Additional endpoints were changes of metabolic control, islet ß-cell function, insulin resistance, and safety. RESULTS: At 48 weeks, 20% of the patients in the UC-MSCs group and 4.55% in the placebo group reached the primary endpoint (p < 0.05, 95% confidence interval (CI) 2.25-28.66%). The percentage of insulin reduction of the UC-MSCs group was significantly higher than that of the placebo group (27.78% versus 15.62%, p < 0.05). The levels of HbA1c decreased 1.31% (9.02 ± 1.27% to 7.52 ± 1.07%, p < 0.01) in the UC-MSCs group, and only 0.63% in the placebo group (8.89 ± 1.11% to 8.19 ± 1.02%, p˃0.05; p = 0.0081 between both groups). The glucose infusion rate (GIR) increased significantly in the UC-MSCs group (from 3.12 to 4.76 mg/min/kg, p < 0.01), whereas no significant change was observed in the placebo group (from 3.26 to 3.60 mg/min/kg, p ˃ 0.05; p < 0.01 between both groups). There was no improvement in islet ß-cell function in both groups. No major UC-MSCs transplantation-related adverse events occurred. CONCLUSIONS: UC-MSCs transplantation could be a potential therapeutic approach for Chinese adults with T2DM. Trial registration This study was registered on ClinicalTrials.gov (identifier: NCT02302599).

Human umbilical cord-derived mesenchymal stem cells alleviate insulin resistance in diet-induced obese mice via an interaction with splenocytes.

BACKGROUND: Previous research has demonstrated that the spleen plays an important role in mesenchymal stem cell (MSC)-mediated alleviation of acute inflammation, as MSC infusion increases the spleen-derived anti-inflammatory cytokine interleukin 10 (IL-10) levels. However, studies on splenic involvement in MSC-induced protection against chronic inflammatory diseases are limited. Obesity is characterized by chronic low-grade inflammation, a key driver of insulin resistance. This study aims to evaluate the effects of MSCs on obesity-related insulin resistance and explore the underlying mechanism, particularly regarding splenic involvement. METHODS: We induced obesity in mice by feeding them high-fat diets for 20 weeks. Human umbilical cord-derived MSCs (UC-MSCs) were systemically infused into the obese mice once per week for 6 weeks. Systemic glucose metabolic homeostasis and insulin sensitivity in epididymal adipose tissue (EAT) were evaluated. Then, we conducted in vivo blockade of IL-10 during UC-MSC infusion by intraperitoneally administrating an IL-10-neutralizing antibody twice per week. We also investigated the therapeutic effects of UC-MSCs on obese mice after removal of the spleen by splenectomy. RESULTS: UC-MSC infusions improved systemic metabolic homeostasis and alleviated insulin resistance in EAT but elicited no change in weight. Despite rare engraftment of UC-MSCs in EAT, UC-MSC infusions attenuated insulin resistance in EAT by polarizing macrophages into the M2 phenotype, coupled with elevated serum IL-10 levels. In vivo blockade of IL-10 blunted the effects of UC-MSCs on obese mice. Furthermore, UC-MSCs overwhelmingly homed to the spleen, and the ability of UC-MSCs to elevate serum IL-10 levels and alleviate insulin resistance was impaired in the absence of the spleen. Further in vivo and in vitro studies revealed that UC-MSCs promoted the capacity of regulatory T cells (Treg cells) to produce IL-10 in the spleen. CONCLUSIONS: Our results demonstrated that UC-MSCs elevated serum IL-10 levels and subsequently promoted macrophage polarization, leading to alleviation of insulin resistance in EAT. The underlying mechanism was that UC-MSCs improved the capacity of Treg cells to produce IL-10 in the spleen. Our findings indicated that the spleen played a critical role in amplifying MSC-mediated immunomodulatory effects, which may contribute to maximizing MSC efficacy in clinical applications in the future.

Case Report: Three Rare Cases of Ectopic ACTH Syndrome Caused by Adrenal Medullary Hyperplasia.

Ectopic ACTH syndrome (EAS) accounts for 10-20% of endogenous Cushing's syndrome (CS). Hardly any cases of adrenal medullary hyperplasia have been reported to ectopically secrete adrenocorticotropic hormone (ACTH). Here we describe a series of three patients with hypercortisolism secondary to ectopic production of ACTH from adrenal medulla. Cushingoid features were absent in case 1 but evident in the other two cases. Marked hypokalemia was found in all three patients, but hyperglycemia and osteoporosis were present only in case 2. All three patients showed significantly elevated serum cortisol and 24-h urinary cortisol levels. The ACTH levels ranged from 19.8 to 103.0pmol/L, favoring ACTH-dependent Cushing's syndrome. Results of bilateral inferior petrosal sinus sampling (BIPSS) for case 1 and case 3 confirmed ectopic origin of ACTH. The extremely high level of ACTH and failure to suppress cortisol with high dose dexamethasone suppression test (HDDST) suggested EAS for patient 2. However, image studies failed to identify the source of ACTH secretion. Bilateral adrenalectomy was performed for rapid control of hypercortisolism. After surgery, cushingoid features gradually disappeared for case 2 and case 3. Blood pressure, blood glucose and potassium levels returned to normal ranges without medication for case 2. The level of serum potassium also normalized without any supplementation for case 1 and case 3. The ACTH levels of all three patients significantly decreased 3-6 months after surgery. Histopathology revealed bilateral adrenal medullary hyperplasia and immunostaining showed positive ACTH staining located in adrenal medulla cells. In summary, our case series reveals the adrenal medulla to be a site of ectopic ACTH secretion. Adrenal medulla-originated EAS makes the differential diagnosis of ACTH-dependent Cushing's syndrome much more difficult. Control of the hypercortisolism is mandatory for such patients.

The efficacy of pulsatile gonadotropin-releasing hormone therapy in male patients with hypogonadism caused by hypopituitarism.

BACKGROUND: To evaluate the efficacy of pulsatile gonadotropin-releasing hormone (GnRH) therapy in patients with hypogonadism caused by hypopituitarism so as to guide clinical treatment. METHODS: Clinical manifestations, laboratory examinations, and imaging features were collected from 22 patients with hypopituitarism that led to hypogonadism who were treated with pulsatile GnRH. Data were analyzed and the patients were followed up. RESULTS: The average age at which patients began to use pulsatile GnRH was 22.8±3.7 years old. The duration of pulsatile GnRH administration ranged from 3 to 60 months, with an average of 20.5±12.1 months. The dosage of GnRH administered was 10-12 µg/90 minutes. Patients were followed up for 26-81 months, with an average of 50.5±17.3 months. After pulsatile GnRH treatment, the clinical manifestations and hormone levels of these patients improved to varying degrees. The luteinizing hormone (LH) and testosterone (T) levels of 7 patients increased to the normal range, sperm could be detected in seminal fluid samples of 5 patients, and 2 patients successfully reproduced. Within the good-response group, 71.4% of patients achieved spermatogenesis within an average of 13 months of treatment. In patients who had poor response to gonadotropin therapy prior to pulsatile GnRH therapy, 25% achieved spermatogenesis, and 37.5% reached the normal range of LH and T. The levels of LH after pulsatile GnRH treatment was positively correlated with the peak levels of LH and testicular volume prior to treatment (P<0.01). CONCLUSIONS: Pulsatile GnRH therapy can improve gonadal function in most patients with hypogonadism caused by hypopituitarism. Patients were able to achieve spermatogenesis, especially in patients who were poor-responders to gonadotropin treatment. Patients with greater basal testicular volume may respond better to pulsatile GnRH treatment. The GnRH stimulation test not only helps to evaluate the reserve function of pituitary GnRH cells at a certain time but may also serve as a prognostic factor. The results of this study form a basis for guiding clinical therapeutic choices.

Insulinoma misdiagnosed as epilepsy in 44 Chinese patients.

OBJECTIVE: Insulinoma is a rare pancreatic neuroendocrine tumor that can spontaneously produce excess endogenous insulin, resulting in recurrent and serious hypoglycemia. Patients with insulinoma always have intermittent neuroglycopenia, which has been frequently reported as being misdiagnosed as epilepsy. In this report, we analyzed the clinical data of patients with confirmed insulinoma who had ever been misdiagnosed to have epilepsy. METHODS: The retrospective review was performed on 266 patients with confirmed insulinoma at the First Medical Center of Chinese PLA General Hospital between January 2000 and July 2020. RESULTS: 1. The diagnosis of insulinoma was confirmed in 266 patients. Forty-four patients [male/female=1/1.8, aged (41.25±12.30) years old] were misdiagnosed to have epilepsy, with a misdiagnosis rate of 16.5%. 2. Thirty-eight patients presented with consciousness disorder. Eleven patients presented with palpitation, sweating, and anxiety. Five patients presented with convulsion and 6 patients presented with abnormal behavior and delirium. 3. Twenty-two patients underwent EEG examination. EEG showed spike wave or spike-slow complex wave in 5 patients, decreased α wave and increased slow wave in θ and δ band in 7 patients, and was normal in 10 patients. 4. Thirty-five patients were incorrectly prescribed with AEDs and 22 patients were even misdiagnosed to have refractory epilepsy. 5. All these 44 patients underwent successful surgery, and hypoglycemia symptoms were relieved after insulinoma resection. CONCLUSION: Patients with insulinoma sometimes share common clinical characteristics with epilepsy. To patients with epilepsy or suspected epilepsy, especially with poor response to ADEs, hypoglycemia caused by insulinoma should be emphasized in the differential diagnosis.