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PRISMA 2020 flow diagram for new systematic reviews which included searches of databases and registers only. From: Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. doi: 10.1136/bmj.n71 For more information, visit: http://www.prisma-statement.org/
Forest plot of outcomes
Forest plot of hyperkalemia
Purpose Assess the effect of intensive vs conventional blood pressure goals on patient-important outcomes in older adults with type 2 diabetes. Methods A comprehensive search was performed using electronic databases. Randomized controlled trials comparing intensive vs conventional blood pressure goals in adults over 60 years of age with type 2 diabetes were included. Events were evaluated using a modified Mantel-Haenszel meta-analysis with Peto’s method. Study selection and data extraction were performed independently and in duplicate. Results Seven trials were included. A 19% risk reduction (OR 0.81; 95% CI 0.69–0.95; I² = 8%; p = 0.35) in the occurrence of major adverse cardiovascular events (MACE) and 37% risk reduction (OR 0.63; 95% CI 0.51–0.79; I² = 0%; p = 0.56) in the occurrence of fatal or non-fatal stroke was documented in the intensive treatment group. There were no differences in the occurrence of all-cause mortality, cardiovascular mortality, non-fatal myocardial infarction, and peripheral vascular disease. Data regarding treatment adverse effects and microvascular outcomes was scarce. Conclusions Intensive blood pressure goals in older patients with diabetes were associated with a lower risk of stroke and MACE, but not with all-cause mortality, cardiovascular mortality, non-fatal myocardial infarction, and peripheral vascular disease.
Surgical outcomes in 226 pituitary tumors according to tumor consistency (*p < 0.05; **p < 0.01)
Surgical outcomes according to tumor consistency in the group of 146 pituitary tumors with a maximum diameter 10–40 mm (*p < 0.05; **p < 0.01)
Surgical complications in 226 pituitary tumors according to tumor consistency (*p < 0.05; **p < 0.01)
Background Most pituitary adenomas (PAs) are considered to have a soft tumor consistency. However, there is a non-negligible percentage (5–13%) of tumors presenting or exhibiting a fibrous consistency that would entail a more difficult and complicated surgical excision with higher surgical morbidity and mortality rates. Purpose To analyze the clinical consequences of PA tumor consistency on the surgical outcomes in patients undergoing endonasal endoscopic transsphenoidal (EET) pituitary surgery. Methods An ambispective study of patients with PAs operated on through an EET approach in two Spanish tertiary hospitals over the last 12 years. A total of 226 consecutive interventions were carried out in the Neurosurgery Departments of the Hospital Universitario Ramón y Cajal (HURC) and the Hospital Universitario Puerta del Sur by the same neurosurgeon. PAs were grouped into soft (n = 150) and fibrous (n = 76). All patients underwent hormonal and magnetic resonance imaging (MRI) studies before and after surgery. In addition, neurosurgical complications were recorded in each patient. Results Fibrous adenomas were independently associated with lower resection rates compared to soft adenomas (fibrous gross total resection [GTR] rate 48.7% vs. 76.3%, p < 0.001), even in those adenomas without invasion of the cavernous sinus (Knosp grades 0, I, and II). There were more intraoperative cerebrospinal fluid (CSF) leaks in patients with fibrous PAs. Moreover, fibrous PAs showed higher rates of postoperative hypopituitarism, permanent diabetes insipidus (DI) and postoperative treatments (hormonal treatment and radiotherapy). The excision of a fibrous PA required a longer surgical time (22.5 min more than soft PAs, p = 0.014), regardless of other factors. Conclusion The consistency of the PAs significantly conditions both the results of surgery (lower resections rates), complications (higher incidence of postoperative hypopituitarism, permanent DI), and the prognosis (higher incidence of postoperative treatments) of the patient undergoing EET.
Background Graves’ disease (GD) is an autoimmune disease, the incidence of which is increasing yearly. GD requires long-life therapy. Therefore, the potential immune-related biomarkers of GD need to be studied. Method In our study, differentially expressed genes (DEGs) were derived from the online Gene Expression Omnibus (GEO) microarray expression dataset GSE71956. Protein‒protein interaction (PPI) network analyses were used to identify hub genes, which were validated by qPCR. GSEA was used to screen potential pathways and related immune cells. Next, CIBERSORT analysis was used to further explore the immune subtype distribution pattern among hub genes. ROC curves were used to analyze the specificity and sensitivity of hub genes. Result 44 DEGs were screened from the GEO dataset. Two hub genes, EEF1A1 and EIF4B, were obtained from the PPI network and validated by qPCR (p < 0.05). GSEA was conducted to identify potential pathways and immune cells related to these the two hub genes. Immune cell subtype analysis revealed that hub genes had extensive associations with many different types of immune cells, particularly resting memory CD4⁺ T cells. AUCs of ROC analysis were 0.687 and 0.733 for EEF1A1 and EIF4B, respectively. Conclusion Our study revealed two hub genes, EEF1A1 and EIF4B, that are associated with resting memory CD4⁺ T cells and potential immune-related molecular biomarkers and therapeutic targets of GD.
The effects of TMB on PTC recurrence
A Effects of different TMB cut-off values on PTC recurrence. B–D Effects of the median TMB (B), the upper tertile TMB (C) and the upper quartile TMB (D) on tumor recurrence-free survival in PTC
Kaplan-Meier survival curves of interaction of TMB-H with clinicopathologic risk factors in affecting recurrence-free probability
A Patients age ≥55 years, B patients age ≥55 years and TMB-H, C EXT, D EXT and TMB-H, E LNM, F LNM and TMB-H. In each panel, P values were from log-rank tests. (B) (D) and (F) were adjusted for multiple comparisons, comparing each stratum with patients negative for both TMB-H and indicated clinicopathologic factor. G The PPVs of PTC recurrence
Kaplan-Meier analyses of impacts of TMB-H or BRAF/TERT mutations or their coexistence on recurrence-free survival
A Effects of TMB-H on tumor recurrence-free survival in the wild type BRAF/TERT patients. B BRAF V600E mutation only patients. C TERT C228/250 T mutations only patients. D The coexisting of BRAF V600E and TERT C228/250 T patients. E, F Effects of different mutations on tumor recurrence-free survival in the TMB-L (E) and TMB-H patients (F). G Effects of the interaction of different mutations with TMB-H on tumor recurrence-free survival in the overall patients. In each panel, P-values were from log-rank tests and P-values in (E) and (F) were adjusted for multiple comparisons, comparing each stratum with patients negative for mutations
Purpose Although papillary thyroid cancer (PTC) has a low mortality rate, the rate of recurrence remains relatively high. This study aims to develop a molecular signature to predict the recurrence of PTC. Methods A total of 333 PTC patients’ data from The Cancer Genome Atlas (TCGA) were included. We calculated tumor mutation burden (TMB) and analyzed the mutation status of BRAF and TERT promoter. Results Tumor recurrence occurred in 17 of 263 cases in TMB-L patients versus 14 of 70 cases in TMB-H patients (hazard ratio [HR], 3.55; 95% confidence interval [CI], 1.75–7.21; P < 0.001). The HR for recurrence in TMB-H patients remained significant after adjustment for classical clinicopathologic factors (patient age, gender, extrathyroidal extension and lymph node metastasis). These clinical factors had no effect on recurrence rate in TMB-L patients, but had a strong adverse effect on the prognosis of TMB-H patients. Compared with TMB-L patients lacking mutation, the HR (95% CI) of recurrence for TMB-H patients with coexisting BRAF V600E and/or TERT C228/250 T mutations was 6.68 (2.41–18.57), which remained significant after adjustment for clinicopathological factors. The mutation status of BRAF V600E and TERT C228/250 T had little effect on PTC recurrence in TMB-L patients. Either of the mutation was associated with high recurrence rate in TMB-H patients. Conclusions The presence of BRAF V600E and/or TERT promoter mutations denotes a high risk of recurrence in TMB-H patients. This represents a powerful molecular prognostic genotype that can help predict patients with the highest risk of recurrence.
The characteristics of mRNA expression in GHPA. A Volcano plot shows the transcript levels differentially expressed genes (DEGs) between the para-adenoma normal pituitary tissues and pituitary tumors. 725 significantly up-regulated genes are shown as red dots, whereas 803 down-regulated genes are shown as blue dots. Filtered by q value < 0.05, |log2(FC) | ≥ 2 and average FPKM ≥ 10, 64 significantly differentially expressed key genes are labeled and shown in different colors according to log2(FC). B Heatmap of 64 key genes labeled in volcano plot (A), listed in a descending order based on log2(FC). The numeric values are log2(FPKM + 1). C Bubble plot showing GO enrichment analysis of upregulated genes. Top 20 GO terms of biological processes (BP) significantly enriched by up-regulated genes are depicted. D Bubble plot showing GO enrichment analysis of down-regulated genes. Top 20 GO terms of biological processes (BP) significantly enriched by down-regulated genes are depicted. E Bar plot showing top 20 KEGG pathways significantly enriched by upregulated genes. The polygonal chain in black shows the gene count related to each GO term. F Bar plot showing top 20 KEGG pathways significantly enriched by downregulated genes. The polygonal chain in black shows the gene count related to each GO term
The accessible chromatin landscape of GHPA. A Distribution of ATAC-seq fragment size in each sample. B Annotation of ATAC-seq peaks to genomic features: exon, intergenic regions, introns, 3′ UTR, 5′ UTR, promoters-TSS, TES and no-coding regions. Peak summit located up to 1 Kb upstream and 100 bp downstream of the TSS are determined as promoter-TSS regions. C Average read density (top panel) and heatmaps (bottom panel) indicating ATAC-seq signal across a genomic window of 5 Kb upstream of the TSS and 5 Kb downstream of the TES. D Distribution of hyper- (red) and hypo-accessible (blue) regions over chromosomes in pituitary tumors compared with normal pituitary tissues. E Distance to closest transcription start site (TSS) of all accessible regions and differentially open and closed regions. F Heatmap representation of normalized ATAC-seq signal in the para-adenoma normal tissues and tumors tissues over DARs. The top set of panels show read signal over the 3916 hyper-accessible regions in pituitary tumors, while the bottom set of panels show read signal over the 2895 hypo-accessible regions. Signals within 1.5 Kb surrounding the center of DARs are displayed in a descending order. G Profiles of normalized tag density across a genomic window of ±1.5 Kb surrounding the center of hyper-accessible regions. Pie chart showing the proportion of these sites within the indicated genomic regions. H Profiles of normalized tag density across a genomic window of ±1.5 Kb surrounding the center of hypo-accessible regions. Pie chart showing the proportion of these sites within the indicated genomic regions
Filtration of key DEGs related to differentially accessible regions. A Venn diagram illustrating the overlap among all DEGs and nearest genes associated with the differentially accessible regions. B Box plots for mRNA expression levels of DEGs relative to hyper- (left panel) and (right panel) hypo-accessible regions. Notches of the boxes indicate medians. The p values are calculated by Wilcoxon’s signed-rank test. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001; ns, no significance. C Bar plot showing average expression levels (FPKM) of 31 key DEGs related to hyper- (red shade area) and hypo-accessible (blue shade area) regions. DEGs are listed in a descending order based on log2(FC)
KEGG pathway associated key DEGs related to differentially accessible regions. A Top 20 KEGG pathway-associated DEGs related to hyper-accessible regions. The polygonal chain in black shows the gene count enriched in each KEGG pathway. B Top 20 KEGG pathway-associated DEGs related to hypo-accessible regions. The polygonal chain in black shows the gene count enriched in each KEGG pathway. C KEGG pathway associated key DEGs related to hyper- (left panel) and hypo-accessible (right panel) regions. Inner hexagons represent key DEGs and outside rectangles represent relative KEGG pathways. D Genomic snapshots of ATAC-seq (red) and mRNA-seq (blue) signal of representative (left panel) up-regulated and (right panel) down-regulated genes associated with key signal pathways and positively correlated to hyper- (red shade area) and hypo-accessible (blue shade area) regions, respectively
Prediction of transcription factors involved in chromatin accessibility changes between the para-adenoma normal tissues and GHPA. A Top 20 enriched known TF motifs of hyper- (left panel) and hypo-accessible (right panel) sites, with p values estimated from HOMER v4.9. The polygonal chain in black shows the percentages of target sequences with TF motif. B Putative TF occupancy of representative up- (left panel) and down-regulated (right panel) genes positively correlated to chromatin accessibility changes
Purpose Growth hormone-secreting pituitary adenoma (GHPA) is an insidious disease with persistent hypersecretion of growth hormone and insulin-like growth factor 1, causing increased morbidity and mortality. Previous studies have investigated the transcription of GHPA. However, the gene regulatory landscape has not been fully characterized. The objective of our study was to unravel the changes in chromatin accessibility and transcription in GHPA. Methods Six patients diagnosed with GHPA in the Department of Neurosurgery at Huashan Hospital were enrolled in our study. Primary pituitary adenoma tissues and adjacent normal pituitary specimens with no morphologic abnormalities from these six patients were obtained at surgery. RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) were applied to investigate the underlying relationship between gene expression and chromatin accessibility changes in GHPA. Results Totally, 1528 differential expression genes (DEGs) were identified by transcriptomics analyses, including 725 up-regulated and 803 down-regulated. Further, we obtained 64 significantly DEGs including 10 DEGs were elevated and 54 DEGs were negligibly expressed in tumors tissues. The up-regulated DEGs were mainly involved in terms related to synapse formation, nervous system development and secretory pathway. In parallel, 3916 increased and 2895 decreased chromatin-accessible regions were mapped by ATAC-seq. Additionally, the chromatin accessible changes were frequently located adjacent to transcription factor CTCF and Rfx2 binding site. Conclusions Our results are the first to demonstrate the landscape of chromatin accessibility in GHPA, which may contribute to illustrate the underlying transcriptional regulation mechanism of this disease.
Recurrence-free survival curve according to pregnancy occurrence. PS pituitary surgery
Purpose Pregnancy is associated with the activation of the hypothalamus–pituitary–adrenal axis, which can cause a misdiagnosis of Cushing’s syndrome. The aim of this study is to evaluate the impact of pregnancy after pituitary surgery on the recurrence rate in Cushing’s disease (CD) patients. Methods This was a retrospective study in a tertiary center. Between 1990 and 2020, 355 CD patients underwent pituitary surgery. Of those, we included 113 female patients who were ≤ 45 years old (median age of 32 years, 14–45), PS remission, a follow-up of ≥6 months (median of 122 months, 6–402) and an available obstetric history. Recurrence was defined as the diagnosis of Cushing’s syndrome via at least two altered first-line methods. The patients were divided into two subgroups according to pregnancy: no pregnancy or pregnancy prior to CD diagnosis (NP/PP) and pregnancy after CD pituitary surgery (PA). Results Overall, recurrence occurred in 43 out of 113 patients (38%). A higher recurrence rate was seen in the PA subgroup (11/22, 50%), but there was no significant difference between the NP/PP subgroup (32/91, 35%). No difference in survival-free recurrence (SFR) was found between NP/PP and PA subgroups. The lower SFR was related to a higher PS plasma ACTH and normal pituitary at pathological analyses. Conclusions There was no difference in the recurrence rate in patients according to pregnancy history. Other studies with higher numbers of patients are needed to confirm these data.
Flow-chart of the study protocol
Bootstrap-validated calibration curve of the multivariate logistic prediction model (B = 100 repetitions, boot, mean absolute error = 0.016, n = 311)
Predicted probability of CD in ACTH-dependent CS patients using our noninvasive scoring system
ROC curves of Noninvasive Scoring Model, BIPSS baseline, BIPSS after stimulation, HDDST
Objectives The differential diagnosis of ACTH-dependent Cushing’s disease (CS) is challenging. The gold standard approach bilateral inferior petrosal sinus sampling (BIPSS) is expensive and invasive, while other noninvasive tests, like the high-dose dexamethasone suppression test (HDDST), provide unsatisfactory diagnostic accuracy. This study aimed to find a new noninvasive practical approach with higher diagnostic accuracy to differently diagnose ACTH-dependent CS, which can be used in centers where BIPSS cannot be applied. Methods 264 Cushing’s disease (CD) patients and 47 ectopic ACTH secretion syndrome (EAS) patients were analyzed in this single-center retrospective study (2011–2021). The multivariate logistic model was used to construct the scoring model. Results Female (adjusted OR 3.030, 95%CI 1.229–7.471), hypokalemia (0.209, 0.076–0.576), ACTH (0.988, 0.982–0.994), MRI pituitary lesion positive (8.671, 3.521–21.352), and HDDST positive (2.768, 1.139–6.726) have a strong association with the differential diagnosis of ACTH-dependent CS and were included in the final multivariable logistic regression model. A -14-to-14-point noninvasive scoring model was built on the model. The AUC of the noninvasive scoring model was 0.915 (95% CI 0.869–0.960), significantly higher than the AUC of HDDST (0.756, 95% CI 0.685–0.825, P = 0.004). The optimal cutoff of the model was ≥0 to diagnose CD. The sensitivity of the noninvasive scoring model was 91.3% (95% CI 87.3%–94.1%), and the specificity was 80.9% (95% CI 67.5%–89.6%). When the model’s sensitivity was 100.0%, the cutoff was ≥ −10 with a specificity of 19.2%; when the model’s specificity was 100.0%, the cutoff was ≥ 13 with a sensitivity of 22.7%. Conclusions We developed a noninvasive scoring model to distinguish CD and EAS in ACTH-dependent CS patients with higher diagnostic utility than HDDST in the same cohort. The noninvasive scoring model might be applied in areas where BIPSS is unavailable, the CRH is hard to obtain, or the desmopressin stimulation is not widely applied. It also provided a triage tool for selecting patients that might benefit the most from a further BIPSS test.
The most frequent endocrine Carney complex manifestation is a bilateral primary pigmented nodular adrenocortical disease and bilateral adrenalectomy (BA) is therefore its main treatment. In this study, a 40 years follow-up of six members of the same family with heterozygous PRKAR1A germline mutation, is reported over two generations. The first cases, two sisters with severe hyperandrogenism and Cushing syndrome (CS) diagnosed in 1972 at age 14 and 25, were successfully treated with unilateral adrenalectomy (UA). Their two brothers were then diagnosed, one with a CS-related severe osteoporosis treated with BA and the other with CS treated with UA. The second generation was diagnosed with CS signs at 7 and 21 years of age and were treated with BA and UA respectively. Out of the four patients treated with UA, the only event possibly related to CS was spontaneous episode of pulmonary embolism, 30 years after surgery. Hormonal evaluation revealed either eucortisolism in one patient or partial adrenal deficiency in two and mild hypercortisolism in one patient. For the two patients with BA, one of them accidentally died. The second one, surprisingly, recovered progressively normal cortisol secretion and circadian variation. Steroid substitution was stopped 6 years after her surgery and we demonstrated by iodocholesterol scintigraphy the presence of bilateral adrenal remnants. In conclusion, our results of long term evolution of PPNAD patients show that UA in this subset of patients could be considered to treat CS.
Flow chart of the study. T2D, type 2 diabetes; eDia3, early-onset diabetes involving three consecutive generations; eDia0, early-onset type 2 diabetes without a family history of diabetes; MODY, maturity-onset diabetes of the young
Family hierarchical diagram of the genetic confirmed MODY. Squares denote male family members and circles denote female family members. Solid symbols represent subjects with diabetes and open symbols represent nondiabetic individuals. The genotype is shown underneath each symbol. N/M denotes mutation, while N/N denotes no mutation. Below the genotype are age in years at observation, age in years at diabetes diagnosis, then the BMI and the specific anti-hyperglycemic treatment. Arrow indicates the proband of the family. Ins, insulin treatment; OADs, oral anti-diabetes drugs
Purpose Early-onset, multigenerational diabetes is a heterogeneous disease, which is often simplistically classified as type 1 diabetes (T1D) or type 2 diabetes(T2D). However, its clinical and genetic characteristics have not been clearly elucidated. The aim of our study is to investigate the clinical features of early-onset diabetes involving three consecutive generations (eDia3) in a Chinese diabetes cohort. Methods Of 6470 type 2 diabetic patients, 105 were identified as eDia3 (1.6%). After a case–control match on age, we compared the clinical characteristics of 89 eDia3 patients with 89 early-onset T2D patients without a family history of diabetes (eDia0). WES was carried out in 89 patients with eDia3. We primarily focused on 14 known maturity-onset diabetes of the young (MODY) genes. Variants were predicted by ten tools (SIFT, PolyPhen2_HDIV, PolyPhen2_HVAR, LRT, Mutation Assessor, Mutation Taster, FATHMM, GERP++, PhyloP, and PhastCons). All suspected variants were then validated by Sanger sequencing and further investigated in the proband families. Results Compared to age-matched eDia0, eDia3 patients had a younger age at diagnosis (26.5 ± 5.8 vs. 29.4 ± 5.3 years, P = 0.001), lower body mass index (25.5 ± 3.9 vs. 27.4 ± 4.6 kg/m ² , P = 0.003), lower systolic blood pressure (120 ± 15 vs. 128 ± 18 mmHg, P = 0.003), and better metabolic profiles (including glucose and lipids). Of the 89 eDia3 patients, 10 (11.2%) carried likely pathogenic variants in genes ( KLF11 , GCK , ABCC8 , PAX4 , BLK and HNF1A ) of MODY. Conclusions eDia3 patients had unique clinical features. Known MODY genes were not common causes in these patients.
Kaplan–Meier survival curves for overall survival and cancer-specific survival between patients <55 years and patients ≥55 years. A Data from the SEER database. B Data from our two centers
Kaplan–Meier survival curves for overall survival and cancer-specific survival using 5-year increments in DTC patients aged from 40 to 70 years. A Data from the SEER database. B Data from our two centers
Kaplan–Meier survival curves for overall survival and cancer-specific survival using 1-year increments in DTC patients aged from 50 to 60 years and the C-index to assess the statistical model. A Data from the SEER database. B Data from our two centers. C Distribution of p values in the SEER database and our two centers. The left side of the dotted line indicates p > 0.05, and the right side indicates p < 0.05. D Statistical model performance of the 6th edition TNM staging system with several age cutoffs and without an age cutoff (age as a continuous variable). E The age cutoffs for PTC and FTC in OS. F The age cutoffs for PTC and FTC in CSS
Nomogram using age as a continuous variable along with TNM for predicting survival. A Nomogram to estimate the 5 and 10-year survival of DTC patients. To use the nomogram, find the position of each variable on the corresponding axis, draw a vertical line to the points axis for the number of points, add the points from all of the variables, and draw a line from the total points axis to determine the survival probabilities at the lower line of the nomogram. B, C AUC and calibration curve of the nomogram for the prediction of 5 and 10-year survival in the training set. D AUC and calibration curve of the nomogram for the prediction of 5-year survival in the validation set
Purpose The current tumor, node, metastasis (TNM) system uses an age of 55 years as a threshold for differentiated thyroid cancer (DTC). The aim of our study was to explore the concept of using age as a continuous variable. Methods A total of 36,559 patients with DTC in the Surveillance, Epidemiology, and End Results (SEER) database and 7491 patients in our centers were enrolled. Overall survival (OS) and cancer-specific survival (CSS) were compared. Furthermore, the different statistical model performance of the 6th edition TNM system and age cutoffs for papillary (PTC) and follicular thyroid cancer (FTC) were assessed. Then, a nomogram was built and validated to evaluate the efficacy of age as a continuous variable for predicting survival. Results The OS and CSS of patients with DTC were significantly increased in patients <55 years compared with those aged ≥55 years. However, no significant differences in prognosis were observed in certain groups as patients between 50 and 60 years were stratified by 1-year increments. Furthermore, the highest concordance index (C-index) was observed in the TNM staging without an age cutoff in SEER database (0.895), our two centers (0.877) and receiver operating characteristic (ROC) curves showed different age cutoffs for PTC and FTC. More importantly, the nomogram incorporating age as a continuous variable showed a favorable area under the ROC curve and calibration for training and validation groups. Conclusions The utilization of age as a continuous variable is a rational approach for predicting outcome in DTC patients.
Minimum and maximum prevalence of persistent hypoparathyroidism after total thyroidectomy
According to the present definition of persistent hypoparathyroidism, there were 484 patients with persistent hypoparathyroidism (20.3%) according to the maximum estimation. Of these, 121 patients who were assigned osteoporosis/renal failure-related ICD-10 codes postoperatively were excluded, resulting in 358 patients (15.0%) in the minimum estimation. ICD-10, International Classification of Diseases 10th revision
Purpose Persistent hypoparathyroidism (hypoPT) is a major complication of total thyroidectomy. Nonetheless, previous reports may have underestimated the prevalence of hypoPT due to patient selection bias. We aimed to estimate the actual prevalence of persistent hypoPT after total thyroidectomy and to find predictive factors for postoperative hypoPT. Methods This study retrospectively reviewed data from a health insurance claims-based database provided by the Japan Medical Data Center Co., Ltd. From 2009 to 2019, 2388 patients who underwent total thyroidectomy were identified using the medical procedure codes. Persistent hypoPT was defined as the prescription of active vitamin D supplements for >1 year postoperatively and the assignment of hypoPT codes. The prevalence of persistent hypoPT was estimated at two different levels: minimum and maximum estimations with or without postoperative osteoporosis and/or renal failure codes. Correlates for persistent hypoPT were investigated among several demographic and clinical variables. Results Of the 2388 patients, 1752 (73.4%) were women with a mean age of 45 years. The types of diseases were: benign thyroid disease (n = 235), malignant thyroid tumors (n = 1570), Graves ‘ disease (n = 558), and malignancy combined with Graves’ disease (n = 25). The minimum and the maximum estimation of the prevalence of persistent hypoPT were 15.0 and 20.3%, respectively. Multivariate logistic regression analysis showed that the malignant tumor (odds ratio, 1.8) independently correlated with persistent hypoPT. Conclusions The prevalence of persistent hypoPT after total thyroidectomy estimated by the claims-based database was higher than previously recognized. Comprehensive attempts to preserve parathyroid function, especially in malignant diseases, are essential.
Study flow chart of patient selection. DM diabetes mellitus
Kaplan–Meier curves for overall survival of patients. a–c Kaplan–Meier curves for overall survival of patients with and without preexisting diabetes mellitus for all patients (a), patients who received a curative operation (b), and patients who did not receive a curative operation (c). d–f Kaplan–Meier curves for overall survival of patients with and without hyperglycemia for all patients (d), patients who received a curative operation (e), and patients who did not receive a curative operation (f). P value derived from log-rank tests
Multivariate analysis of overall survival using the Cox proportional hazards regression model. DM diabetes mellitus
Background Although glucose has a well-recognized protumoral role and the pancreas is a critical organ in adjusting glucose metabolism, the clinical value of hyperglycemia in pancreatic neuroendocrine neoplasms (pNENs) remains largely unidentified. Methods A retrospective study including 335 patients with pathologically confirmed pNENs was conducted. A baseline fasting blood glucose concentration ≥5.6 mmol/L was defined as hyperglycemia (otherwise, normal). Survival and regression analyses were performed. Results Compared with patients with normal glucose, patients with hyperglycemia (47.8%) had a higher proportion of preexisting diabetes mellitus (DM) (36.9% vs. 4.6%, p < 0.001), lymph node involvement (31.0% vs. 14.6%, p = 0.002), distant metastasis (34.4% vs. 22.9%, p = 0.019), and carbohydrate antigen 19-9 (CA19-9) ≥ 37 U/mL (16.6% vs. 7.2%, p = 0.009). Hyperglycemia was associated with CA19-9 ≥ 37 U/mL (Odds Ratio (OR) = 3.19, 95% CI: 1.11–9.17, p = 0.031), lymph node involvement (OR = 2.32, 95% CI: 1.02–5.28, p = 0.045), nonfunctional tumors (OR = 9.90, 95% CI: 2.11–46.34, p = 0.004), and preexisting diabetes (OR = 18.24, 95% CI: 4.06–81.95, p < 0.001). Hyperglycemia was an independent determinant for overall survival in the multivariate analysis (hazard ratio (HR) = 2.65, 95% CI: 1.31–5.34, p = 0.006). Conclusion Hyperglycemia is an independent predictor of overall survival and is associated with preexisting DM or lymphatic metastasis in patients with pNENs. Patients with hyperglycemia and resectable pNENs may benefit from radical resection with dissection of regional lymph nodes.
Effects of blood pressure on the risk of CKD (BP blood pressure; ID incidence density; adjusted for gender, age, education level, work type, marital status, family per capital income, BMI, smoking status, drinking status, course of hypertension, course of diabetes, TC, TG, HDL-C, LDL-C, BUN, UA at baseline)
Dose-response relationship between SBP/DBP level and incidence of CKD in different blood glucose groups (The adjustment factors are the same as Cox proportional hazards model, the solid line present HR and the dashed line is 95percent confidence interval)
Effects of FPG on the risk of CKD(ID incidence density; adjusted for gender, age, education level, work type, marital status, family per capital income, BMI, smoking status, drinking status, course of hypertension, course of diabetes, TC, TG, HDL-C, LDL-C, BUN, UA at baseline)
Dose-response relationship between FPG level and incidence of CKD in different blood pressure groups (The adjustment factors are the same as Cox proportional hazards model, the solid line present HR and the dashed line is 95percent confidence interval)
Objective To evaluate the interaction effect of blood glucose and blood pressure on the risk of chronic kidney disease (CKD). Methods 31,165 subjects were selected without CKD at baseline and had completed the first follow-up from “Jinchang cohort”. Cox regression model and restricted cubic splines functions were used to evaluate the effects of blood glucose or pressure on the incidence of CKD and dose-response relationship after adjusting for confounding covariates. Synergic effect was assessed by the multiplicative or additive interaction scale. Results Among 31,165 subjects, 1307 new-onset CKD were observed during 68905.78 person-years follow-up, and the incidence density was 18.97 per 1000 person-years. The risk of CKD gradually increased with the increase of blood pressure in diabetes, pre-diabetes and normal groups (Ptrend < 0.05). And, the risk was greatest when SBP/DBP reached ≥150/≥110 mmHg in three groups, and HRs (95% CI) were 1.610 (1.070–2.422), 2.142 (1.396–3.288) and 2.455 (1.941–3.106), respectively. Additionally, among hypertension, pre-hypertension and normal groups, the risk of CKD increased by 16.0%, 14.3% and 25.2% for each 1 mmol/L of FPG. When FPG level was more than 9.0 mmol/L, the risk was greatest and adjusted HRs (95% CI) were 2.856 (2.176–3.748), 2.979 (1.828–4.854) and 7.520 (4.517–12.519). Furthermore, the risk was highest when hypertension was accompanied by diabetes (HR = 4.915, 95% CI: 3.923–6.157). This analysis supported a less than multiplicative effect (HR = 0.634, 95% CI: 0.417–0.964) for the interaction term of diabetes and hypertension, while there was no additive interaction towards CKD in all interaction term. Conclusions Blood glucose and pressure were independent risk factors in incidence of CKD, but there was only a negative multiplicative interaction between hypertension and diabetes, but no additive interaction effect between them.
Flow-diagram of enrollment, randomization and follow-up. *PPI Proton pump inhibitors
Boxplot of AUC0–3 FT4 values at Baseline and 1 month among RAI and NO RAI groups. The box is delimited by the first and the third quartile in which, the bold horizontal line represents the median value. The slight conjunction lines between couple of points on the boxplot represents the change in FT4 values of a specific patient from baseline to 1 month
Trajectories of AUC0–3 FT4 values determined by the linear conjunction of mean values calculated at Baseline, 1, 3, and 6 months into the 2 groups (RAI and NO RAI)
Trajectories of AUC0–3 FT4 values determined by the linear conjunction of mean values calculated at Baseline, 1, 3, and 6 months into the 2 formulations of LT4 (SOLID and LIQUID) into the RAI group
Purpose Patients undergoing thyroidectomy for differentiated thyroid cancer (DTC) may require 131-radioactive iodine (RAI) administration for remnant ablation or disease treatment. After ingestion, RAI resides within the gastrointestinal tract potentially leading to mucosal damage and abnormalities in the absorption of levothyroxine (LT4). The aim of this study was to evaluate whether serum FT4 peak, induced by a LT4 challenge, changes according to the LT4 formulation (solid or liquid) in both RAI and non-RAI-treated DTC patients. Methods This was a monocentric controlled clinical trial, with a parallel two-groups (1:1) randomization of sequence of LT4 formulation. Patients received 200 mcg LT4 orally administered at 08:00 h, in both solid and liquid formulation, at one-week interval, at baseline and after 1, 3, and 6 months from RAI administration. At each time-point, circulating FT4 was evaluated both before LT4 assumption as well as after 1 and 3 h. FT4 increments were evaluated as area under the curve response (AUC). Analogous protocol with the same time-intervals was followed for non-RAI patients. Results The trial included 29 consecutive DTC patients, nineteen of whom were submitted to RAI. In RAI subjects, we observed an overall significant reduction in serum FT4 increments with the most relevant decrease at the 1-month time-point, (FT4 AUC: 4.46 ± 0.72 (M ± SD) vs 4.07 ± 0.63 in baseline vs 1-month, P = 0.001) without any difference between the two LT4 formulations. No difference in serum FT4 AUC was found in non-RAI subjects. Conclusion LT4-induced serum FT4 responses are reduced following RAI administration in thyroidectomized DTC patients.
Correlation between plasma adiponectin levels with body mass index (BMI) and plasma leptin levels (● male patients; ○ female patients). The regression lines are presented separately for male patients (—) and female patients (----). p < 0.05
Correlation between plasma adiponectin levels with serum HDL cholesterol and serum triglycerides (● male patients; ○ female patients). The regression lines are presented separately for male patients (—) and female patients (----). p < 0.05
Kaplan Meier Survival Curve stratified by adipokine tertiles
Association of adipokines with mortality
Purpose Adipokines have been associated with increased risk of cardiovascular disease. Our aim was to determine if adipokine levels are associated with coronary artery calcification (CAC) as well as all-cause mortality in incident dialysis patients. Methods In patients new to dialysis, we prospectively investigated the association of adiponectin, leptin and resistin with coronary artery calcification measured by ECG-gated computer tomography. Participants were recruited a median of two months after starting dialysis. Results The mean age was 50.0 (12.6) years and 31.1% were women. About 42% percent had BMI > 30. Higher adiponectin levels were inversely associated with CAC progression as change in Agatston score [−155.1 (−267.9, −42.2), p = 0.008] or change in CAC volumes between scans [−2.8 (−4.9, −0.6), p = 0.01]. Higher leptin levels were associated with CAC progression [110.4 (34.3–186.6), p = 0.005]. Decreased leptin [HR 0.5 (0.3–0.9), p = 0.05] was associated with all-cause mortality in adjusted models. There was no significant association between all-cause mortality and adiponectin [1.4 (0.6–3.4), p = 0.4] or resistin [HR 1.7 (0.5–5.0), p = 0.4]. Conclusion High adiponectin protects against CAC progression, but is not associated with increased all-cause mortality. Higher leptin, as well as higher leptin to adiponectin ratio, is associated with CAC progression. Lower leptin levels were associated with all-cause mortality. The association of adipokines and cardiovascular disease in individuals on dialysis is complex and requires further study.
Comparison of bone turnover markers in T2DM patients. a Comparison of bone turnover markers between low-eGDR group and high-eGDR group. b Comparison of bone turnover markers between male group and postmenopausal female group
The correlation between eGDR and bone turnover markers levels. a The correlation between eGDR and bone turnover markers levels in all participants. b The correlation between eGDR and bone turnover markers levels in male participants. c The correlation between eGDR and bone turnover markers levels in postmenopausal female participants
Purpose To investigate the relationship between estimated glucose disposal rate (eGDR) and bone turnover markers in patients with type 2 diabetes mellitus (T2DM). Materials and methods This is a cross-sectional study, which recruited 549 patients with T2DM. The eGDRs of patients were calculated based on the presence of hypertension, glycated hemoglobin, and body mass index. All patients were divided into high-eGDR group and low-eGDR group using the median of eGDR as the boundary. The patients were further divided into two subgroups: males and postmenopausal females. Results The lower the eGDR, the more severe was insulin resistance. The levels of osteocalcin (OC), type I collagen carboxyl-terminal peptide (β-CTX), and type I procollagen amino-terminal peptide (PINP) were significantly lower in the low-eGDR group than those in the high-eGDR group. The eGDR was positively correlated with OC, β-CTX, and PINP in all patients, and in the male subgroups. In the postmenopausal female subgroup, there was no correlation between eGDR and OC, β-CTX, or PINP. In addition, this positive correlation remained after adjusting for other factors in multilinear regression analysis. Conclusion Our study was the first to demonstrate that eGDR is positively correlated with bone turnover markers in patients with T2DM. This correlation was observed among the male patients with T2DM but not among postmenopausal female patients with T2DM.
FT4 measurements in all samples (n = 15,213) and euthyroid patients (n = 5111). FT4 free thyroxine. Vertical dotted lines at 12 and 22 pmol/L FT4 show the normal range provided by the manufacturer. Only one sample per patient was included for euthyroid patients
Determination of RIs for FT4 using the direct and indirect methods. FT4 free thyroxine, RI reference interval. Vertical dotted lines at 12 and 22 pmol/L FT4 show the normal range provided by the manufacturer. Plots show estimated lower (2.5% quantile) and upper (97.5% quantile) RI limits with 95% confidence intervals
Purpose Measurement of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) is important for assessing thyroid dysfunction. After changing assay manufacturer, high FT4 versus TSH levels were reported at Ente Ospedaliero Cantonale (EOC; Bellinzona, Switzerland). Methods Exploratory analysis used existing TSH and FT4 measurements taken at EOC during routine clinical practice (February 2018–April 2020) using Elecsys® TSH and Elecsys FT4 III immunoassays on cobas® 6000 and cobas 8000 analyzers (Roche Diagnostics). Reference intervals (RIs) were estimated using both direct and indirect (refineR algorithm) methods. Results In samples with normal TSH levels, 90.9% of FT4 measurements were within the normal range provided by Roche (12–22 pmol/L). For FT4 measurements, confidence intervals (CIs) for the lower end of the RI obtained using direct and indirect methods were lower than estimated values in the method sheet; the estimated value of the upper end of the RI (UEoRI) in the method sheet was within the CI for the UEoRI using the direct method but not the indirect method. CIs for the direct and indirect methods overlapped at both ends of the RI. The most common cause of increased FT4 with normal TSH was identified in a subset of patients as use of thyroxine therapy (72.6%). Conclusions It is important to verify RIs for FT4 in the laboratory population when changing testing platforms; indirect methods may constitute a convenient tool for this. Applying specific RIs for selected subpopulations should be considered to avoid misinterpretations and inappropriate clinical actions.
Spirometry pulmonary function tests and spine deformity index correlations. SDI spine deformity index, FVC forced vital capacity, FEV1 forced expiratory volume 1st s. Empy dots represent each single patient data
Purpose Morphometric vertebral fractures (VFs) have been recently reported as an important component of the endocrine phenotype of COVID-19 and emerging data show negative respiratory sequelae at long-term follow-up in COVID-19 survivors. The aim of this study was to evaluate the impact of VFs on respiratory function in COVID-19 survivors. Methods We included patients referred to our Hospital Emergency Department and re-evaluated during follow-up. VFs were detected on lateral chest X-rays on admission using a qualitative and semiquantitative assessment and pulmonary function tests were obtained by Jaeger-MasterScreen-Analyzer Unit 6 months after discharge. Results Fifty patients were included. Median age was 66 years and 66% were males. No respiratory function data were available at COVID-19 diagnosis. VFs were detected in 16 (32%) patients. No differences between fractured and non-fractured patients regarding age and sex were observed. Although no difference was observed between VF and non-VF patient groups in the severity of pneumonia as assessed by Radiological-Assessment-of-Lung-Edema score at admission, (5 vs. 6, p = 0.69), patients with VFs were characterized as compared to those without VFs by lower Forced Vital Capacity (FVC, 2.9 vs. 3.6 L, p = 0.006; 85% vs. 110% of predicted, respectively, p = 0.001), Forced Expiratory Volume 1st s (FEV1, 2.2 vs. 2.8 L, p = 0.005; 92% vs. 110% of predicted, respectively, p = 0.001) and Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO 5.83 vs. 6.98 mmol/min/kPa, p = 0.036, 59% vs. 86.3% of predicted, respectively, p = 0.043) at 6-month follow up. Conclusions VFs, expression of the endocrine phenotype of the disease, appear to influence medium-term impaired respiratory function of COVID-19 survivors which may significantly influence their recovery. Therefore, our findings suggest that a VFs assessment at baseline may help in identifying patients needing a more intensive respiratory follow-up and patients showing persistent respiratory impairment without evidence of pulmonary disease may benefit from VFs assessment to preventing the vicious circle of further fractures and respiratory deterioration.
Study design, selection, and categorization of patients. Flow chart showing the study design, inclusion, and exclusion criteria for controls (CTL), NCAME (12.6%), PA (11.2%), NCAME&PA (6.8%) subjects, and essential hypertensives (EH). Seventy-four subjects (35.9%) did not fit to any group
Characterization of urinary extracellular vesicles from subjects. a A representative image of human urinary EVs obtained by Transmission Electron Microscopy (TEM) (indicated with white arrows). b Western blot of characteristic exosomal proteins, TSG101 (44 kDa), CD9 (25 kDa), and CD63 (25 kDa)
Urinary EV-miRNAs expression by Taqman qRT-PCR. Plots shows the expression of 4 miRNAs, normalized by SNRNA-U6 and by urinary creatinine: (a) hsa-miR-192-5p, (b) hsa-miR-133a, (c) hsa-miR-21-5p, (d) hsa-let-7i-5p in urinary EVs from controls (CTL), NCAME, PA, NCAME&PA subjects, and essential hypertensives (EH). Mean and standard deviation are shown. Significant differences between groups we observed with p < 0.05. Comparison were performed by Kruskal–Wallis and Dunn´s post-hoc test. Mir-192-5p: ap = 0.003; bp < 0.0001; cp < 0.0001; dp = 0.0004; ep = 0.008. Mir-133ª: ap = 0.01; bp = 0.0005; cp = 0.04. Mir-21-5p: ap = 0,002; bp = 0.0004; cp = 0.006; dp = 0.01; ep = 0.002; fp = 0.03. Let-7i-5p: ap = 0.01
Receiver operating characteristic (ROC) curve. Plots shows the ROC curve of 3 miRNAs: (a) miR-192-5p, (b) miR-133a, (c) miR-21-5p, and their potential ability to discriminate NCAME&PA from EH, PA, NCAME and CTL subjects. Confidence interval (CI) were calculated by Brown Wilson method with a 95%, p < 0.05
Primary aldosteronism (PA) and nonclassic apparent mineralocorticoid excess (NCAME) have been recognized as endocrine-related conditions having a broad clinical-biochemical spectrum, spanning from normotension to severe arterial hypertension (AHT). However, the coexistence of both phenotypes have not been reported to date. Aim To identify and characterize clinical and biochemical parameters of subjects with both PA and NCAME conditions (NCAME&PA) and study the miRNA cargo in their urinary extracellular vesicles as potential biomarkers for this novel condition. Methods We performed a cross-sectional study of 206 Chilean adult subjects from a primary care cohort. We measured blood pressure (BP), cortisol (F), cortisone (E), aldosterone, plasma renin activity (PRA), microalbuminuria (MAC), plasma NGAL, MMP9, fractional-potassium-excretion (FEK). Subjects were classified as NCAME&PA, PA, NCAME, essential hypertensives (EH), or healthy controls (CTL). EV-miRNAs were quantified by Taqman-qPCR. Results We found that 30.6% subjects had an abnormal endocrine phenotype: NCAME&PA (6.8%), PA (11.2%) or NCAME (12.6%), and the prevalence of AHT was 92.9%, 82.6%, and 65%, respectively. NCAME&PA subjects had both lower cortisone (p < 0.05) and lower PRA (p < 0.0001), higher FEK (p = 0.02) and higher MAC (p = 0.01) than EH or CTL. NCAME&PA subjects had also higher NGAL levels than CTL and PA (p < 0.05). Exosome miR-192, miR-133a and miR-21 expression decreased with phenotype severity and correlated with BP and PRA (p < 0.05). Conclusion We identified adult subjects with a combined condition of NCAME and PA associated with higher BP, increased renal and endothelial damage markers than control and EH. Additionally, we observed a differential expression of a specific miRNAs, suggesting a potential role of these miRNAs associated to this novel combined phenotype.
Bar charts showed the difference between the percent of at risk subjects by comparing the different indirect cardiometabolic indexes
Purpose The aim of the study was to evaluate indexes of insulin resistance and cardiometabolic risk in a large population of workers with overweight or obesity, in order to identify a possible efficient, cheap and simple strategy to apply in workers’ health surveillance. Methods The evaluation of IR and cardiometabolic risk indexes (HOMA, QUICKI, Ty/HDLC, TyG, insuTAG, Castelli risk indexes 1 and 2, non-HDLC, TRL-C, AIP, and VAI) was performed in a population of 1195 working-age subjects with overweight or obesity (322 males, mean age 49 ± 11 years). Results The prevalence of IR and cardiometabolic risk was higher among males for all indexes. Aging, waist circumference, BMI, blood pressure, glucose, CRP, fibrinogen and uric acid were correlated more frequently with IR/cardiometabolic indexes in women, homocysteine in men. The percentage of the workers identified as insulin resistant (IR+) or at higher cardiometabolic risk greatly vary according to the different index used. Conclusion With a small group of biomarkers and anthropometric measures (fasting glucose and insulin, lipid profile, BMI and waist circumference) is possible to calculate a number of IR/cardiometabolic indexes, which, likely reflecting different pathophysiological aspects also related to gender, might help in a personalized evaluation of IR and cardiometabolic risk. Graphical abstract
Correlation of fT3 levels and thyroid volume with CD4+/CD8+ ratio
Correlation among TRAB levels and CD4+/CD8+ ratio
Correlation among ATD dose and CD4+/CD8+ ratio
Purpose To date, few data are available on the prognostic role of lymphocyte subsets in pediatric Graves’ Disease (GD). The aim of this retrospective study is to analyze the role of lymphocyte subtypes in predicting the severity of GD. Methods Data of 10 pediatric subjects aged <18 years with GD onset in the period November 2017–April 2021 were collected. The lymphocyte population was assessed at the onset of GD as well as hormonal and clinical data. The follow-up period was 2.4 ± 0.8 years. Results Pearson correlation coefficient between CD4+ /CD8+ ratio and fT3 levels and thyroid volume at diagnosis was 0.72 (p = 0.04) and 0.81 (p = 0.004) respectively; that between CD4+ /CD8+ ratio and the TRAb titer at diagnosis and after 6, 12 and 24 months was 0.89, 0.89, 0.73 and 0.77 respectively ( p = 0.02 , p = 0.01 , p = 0.03 and 0.04 ). The correlation coefficient of anti-thyroid drug (ATD) dose after 6 and 12 months with CD4+ /CD8 ratio was 0.88 and 0.78 ( p = 0.001 and p = 0.02 respectively). Patients with a higher CD4+ /CD8+ ratio at diagnosis displayed higher fT3 levels (28.73 ± 2.18 vs 13.48 ± 2.19 pmol/L, p = 0.03 ) and higher TRAb titers (28.9 ± 11.2 vs 4.88 ± 0.97, p = 0.01 ). Conclusion CD4+/CD8+ ratio appears as a promising predictive tool to be considered together with other prognostic factors to better manage pediatric GD. These preliminary data need to be confirmed over a longer follow-up period and in larger cohorts.
Flowchart for the selection of patients, with inclusion and exclusion criteria. NIFTP non-invasive follicular thyroid neoplasm with papillary-like nuclear features
Total surgeries, cases of papillary thyroid microcarcinoma, and benign histology
Introduction The incidence of thyroid carcinoma has grown significantly over the last few decades. A possible explanation is the increased diagnosis of small thyroid microcarcinoma (TMc). TMc reach a maximum diameter of ≤1 cm, identified during histopathology examination following a thyroidectomy performed for reasons not pertaining to malignancy. This study aims to investigate the prevalence of papillary thyroid microcarcinoma (PTMc) according to the benign pathology that refers patients to surgery and its trend evolution. Methods Retrospective cohort analysis of 1815 patients who underwent total thyroidectomy for non-malignant diseases in the 2005–2020 period. Results The mean age of the subjects was 53.5 years, with a higher proportion of women (1481, 82.1%). A total of 167 PTMc (9.3%) were incidentally discovered. A multivariate logistic regression analysis was performed, showing no differences in prevalence according to sex or age in patients with PTMc compared to final benign histology. Multinodular goiter increases the risk of PTMc with an odds ratio of 2.2 (p = 0.001) compared to Hashimoto’s thyroiditis and Graves’ disease (GD). There is a statistically significant increase in the incidence of PTMc in the group operated in the 2017–2020 vs. 2005–2008 period (p = 0.005). Conclusion The overall prevalence of PTMc in patients who underwent thyroid surgery for the benign disease was 9.3%. Thyroid nodular hyperplasia was the most frequent benign pathology associated with PTMc compared to Hashimoto’s or GD. Gender and age were not correlated with the prevalence of TMc. Over the years, surgical findings of PTMc have grown, particularly in the 2017–2020 period.
Total testosterone was negatively correlated with ACTH and 24-hour UFC
Prevalence of hypogonadism according to tertiles of 8 a.m. ACTH (%)
Prevalence of hypogonadism according to tertiles of 16 p.m. ACTH (%)
Prevalence of hypogonadism according to tertiles of 24 p.m. ACTH (%)
Objective Gonadal and sexual disturbances are commonly encountered in patients with Cushing’s disease. Nevertheless, the prevalence of hypogonadism in male Cushing’s disease, the risk factors as well as the recovery time have been scarcely reported. Therefore, we aimed to explore the prevalence of hypogonadism at baseline and its determinants. In addition, the recovery time of hypogonadism and risk factors for unrecovered gonadal axis in male Cushing’s disease with biochemical remission were investigated. Methods We reviewed medical records of males with Cushing’s disease managed between 2010 and 2020. Fifty-two male patients were enrolled according to the criteria. Each case attained biochemical remission after transsphenoidal surgery. Demographic details, clinical features, 24-hour UFC, hormonal profile [serum PRL, FSH, LH, TT, ACTH, cortisol, TT4/FT4, TT3/ FT3, TSH and IGF-1] were measured at baseline and during follow-up. The maximal tumor diameter on MRI was recorded at diagnosis. Results Hypogonadotropic hypogonadism was observed in thirty-nine patients (75%) at diagnosis. Total testosterone was negatively correlated with ACTH and 24-hour UFC. Midnight serum ACTH level at diagnosis was significantly associated with hypogonadism after adjusting for confounding factors. Thirty-two (80%) patients achieved eugonadism within 12 months after the surgery, of which twenty-eight (87.5%) achieved eugonadism within 3 months. Seven patients were persistently hypogonadal during the follow-up (≥1 year), mainly due to the hypopituitarism as a complication of the therapies such as surgery. Conclusion Hypogonadotropic hypogonadism is frequent in male Cushing’s disease, but it is reversible in most cases within one-year follow-up after remission.
Comparison of AMH levels between type 1 diabetes patients and healthy controls
Comparison of AMH levels between type 1 diabetes patients and healthy controls stratified by the diagnosis of PCOS
Comparison of FSH levels between type 1 diabetes patients and healthy controls
Comparison of serum estradiol levels between type 1 diabetes patients and healthy controls
Purpose Current knowledge about the ovarian reserve in patients with type 1 diabetes is inconsistent and based on studies with small sample size. This meta-analysis aimed to produce a comprehensive evaluation on the ovarian reserve of type 1 diabetes female patients and to analyze the associated factors with the ovarian reserve. Methods Systematic searches were conducted for studies published from the inception to December 2021. Original human observational studies either with case-control, cross-sectional, or longitudinal design evaluating ovarian reserve markers between type 1 diabetes patients and healthy controls were included. Levels of anti-müllerian hormone (AMH), follicle-stimulating hormone (FSH), and estradiol (E2) were extracted. Results It was indicated that women with type 1 diabetes were associated with decreased levels of AMH compared with healthy controls (weighted mean difference [WMD] −0.70 ng/ml, 95% confidence intervals [CI] −1.05 to −0.34 ng/ml, P = 0.0001). Subgroup analyses stratified by age showed that adult patients with type 1 diabetes were associated with decreased levels of AMH (WMD −0.70 ng/ml, 95% CI −1.06 to −0.34 ng/ml, P = 0.0001) and FSH (WMD −1.07 IU/L, 95% CI −1.75 to −0.39 IU/L, P = 0.002) compared with healthy controls. Meta-regression analysis showed no significant correlation between AMH, FSH, and clinical factors, while level of E2 was negatively correlated with daily insulin doses and glycosylated hemoglobin A1c (HbA1c) values. Conclusion According to this meta-analysis, type 1 diabetes might be associated with decreased AMH levels. Further studies using different markers and fertility outcomes focus on the ovarian reserve of women with type 1 diabetes are urgently needed.
Purpose We investigated the autophagic response of rat Müller rMC-1 cells during a short-term high glucose challenge. Methods rMC-1 cells were maintained in 5 mM glucose (LG) or exposed to 25 mM glucose (HG). Western blot analysis was used to evaluate the expression levels of markers of autophagy (LC3-II, p62) and glial activation (AQP4), as well as the activation of TRAF2/JNK, ERK and AKT pathways. Autophagic flux assessment was performed using the autophagy inhibitor chloroquine. ROS levels were measured by flow cytometry using dichlorofluorescein diacetate. ERK involvement in autophagy induction was addressed using the ERK inhibitor FR180204. The effect of autophagy inhibition on cell viability was evaluated by SRB assay. Results Activation of autophagy was observed in the first 2–6 h of HG exposure. This early autophagic response was transient, not accompanied by an increase in AQP4 or in the phospho-activation of JNK, a key mediator of cellular response to oxidative stress, and required ERK activity. Cells exposed to HG had a lower viability upon autophagy inhibition by chloroquine, as compared to those maintained in LG. Conclusion A short-term HG challenge triggers in rMC-1 cells a process improving the ability to cope with stressful conditions, which involves ERK and an early and transient autophagy activation.
Background Thyroid carcinoma is the only cancer that regards age as an important predictor of thyroid cancer-specific survival (CSS). While the 8th American Joint Committee on Cancer (AJCC) staging system raised the age cutoff from 45 to 55 years for differentiated thyroid carcinoma (DTC) to more accurately predict the prognosis, there is no new information regarding the role of age in the prognosis of anaplastic thyroid carcinoma (ATC). The aim of this study was to determine the optimal age cutoff values for mortality risk stratification in ATC patients. Furthermore, a nomogram to predict ATC CSS was developed in each age group. Methods Patients diagnosed with ATC between 2004 and 2015 were identified in the Surveillance, Epidemiology, and End Results (SEER) database. After applying inclusion and exclusion criteria, a total of 1140 patients were enrolled as cohort 1 to describe the characteristics of ATC, while a total of 556 patients were included as cohort 2 to determine age cutoff values for risk stratification by X-tile program. Training set and testing set were randomly generated to develop and validate a predictive nomogram of CSS in each age group. Results The 6-month, 1-year, and 2-year survival was 27.6%, 15.1%, and 6.2%, respectively, in cohort 1. X-tile program results showed that the optimal age cutoff values for mortality risk stratification were 65 and 85 years old (p < 0.001). Distant metastasis was independently associated with CSS in patients younger than 85 years old, and these patients benefited more from complete resection of the tumor and radiotherapy/chemotherapy. However, no predictors of CSS were identified in patients over 85 years old, and interventions (surgery, radiotherapy, and chemotherapy) targeting ATC had little role in disease control in these patients. The nomogram was developed and validated based on the independent CSS predictors in each age group. The C-index values of the training set and testing set were 0.735 [95% CI, 0.696–0.774] and 0.733 [95% CI, 0.663–0.804] for CSS in patients of ≤64 years old, while the values were 0.767 [95% CI, 0.730–0.804] and 0.783 [95% CI, 0.718–0.848] in patients of 65–84 years old. All of the C-index values were larger than 0.7, which showed acceptable prediction performance of the nomograms. Conclusions Age can be used as an auxiliary stratification factor of prognosis in ATC patients. The survival may be improved in patients younger than 85 years old if combination therapy (surgery, radiotherapy, and chemotherapy) was indicated and applicable, while no optimal therapeutic strategy was determined in patients older than 85 years old. The established nomograms can provide good prediction of CSS according to age group.
Purpose To investigate the prevalence of cancer in patients with acromegaly and the variables associated with malignant and premalignant lesions detected by cancer screening. Methods The data of 214 patients diagnosed with acromegaly in our institution were evaluated retrospectively. Prevalence of cancer was compared with national rates to estimate standardized incidence ratios (SIRs). The relationships of malignant and premalignant lesions detected by cancer screening with demographic, clinical, and radiological variables were also analyzed. Results Cancer was detected in 24 (13.4%) of 179 patients enrolled in the study. Compared to the general population, the incidence of all malignancies was increased in both women and men with acromegaly (SIR: 4.78, 95% CI: 2.43–8.53, p = 0.002 and SIR: 8.97, 95% CI: 5.51–14.7, p < 0.001, respectively). The most common cancers were thyroid, colorectal, breast, kidney, gastric, and testicular cancer, respectively. Duration of disease was the only independent risk factor for the development of cancer (OR: 1.007, 95% CI: 1.002–1.011, p = 0.002). Malignant/premalignant lesions were detected in 21.5% of the patients with a colonoscopy scanning procedure and in 20.8% with an esophagogastroduodenoscopy procedure, and current age was found to be higher among the patients with malignant/premalignant lesions (p = 0.023 and p = 0.003, respectively). Breast cancer was detected in 3.7% of screening tests performed with mammography. Conclusion In this study, it was shown that the prevalence of cancer increases with acromegaly and this increase is associated with disease duration. Considering the increase in the number of premalignant lesions, the scope of cancer screening recommendations in the guidelines should be expanded to ensure early diagnosis.
Purpose Prolactin (PRL)-secreting tumors are the most common functional pituitary adenomas. They usually respond to dopamine agonist (DA) treatment, with PRL normalization and adenoma shrinkage. Our aim was to characterize patients with prolactinoma resistant to DA treatment. Methods This retrospective case series included patients diagnosed with DA-resistant prolactinomas between 1993–2017 in three medical centers. Resistance was defined as PRL levels above three times the upper limit of normal (ULN) despite a weekly dose of ≥2 mg cabergoline (CAB). Clinical and biochemical information, and response to treatment, were retrieved from medical records. Results Twenty-six patients were identified; 20 males. Of 25 macroadenomas, three were giant tumors (>40 mm) and 15 (57.7%) were invasive. The mean age at diagnosis was 31.8 ± 14.9 years (range: 13–62). The median maximal CAB dose was 3.5 mg/week (IQR, 2.5–5). Half the patients received only CAB in escalating doses, nine received CAB and underwent transsphenoidal surgery, and four underwent surgery and radiotherapy in addition to CAB treatment. PRL levels at baseline between patients treated only with CAB and those operated were (91.6 [51.1–296.7] vs. 73.1 [22.6–170.9] XULN p = 0.355), and under maximal CAB dose PRL levels between patients treated only with CAB and those operated were similar (5.77 [1.27–11.27] vs 5.27 (2.9–26) XULN p = 0.317). At the last visit patients who received combined therapy achieved lower PRL levels than those treated with DA only (5.22 [1.7–21.6] vs 1.1 [0.44–3.99] XULN p = 0.017) PRL normalization was attained in seven patients and levels below 3 × ULN in fourteen patients; the overall response was 56%. Conclusions Resistant prolactinomas usually require a multi-modal treatment strategy. We were able to control 14/25 (56%) of resistant tumors.
The distribution of patients according to the departments
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.
Flow chart
Kaplan–Meier estimates of the cumulative probability of (A) Time from admission to discharge in days; (B) Time from admission to death in days; (C) Time from admission to intubation in days
Purpose Coronavirus disease 2019 (COVID-19) clinical outcome and disease severity affected by several factors; deterioration of glycemic control is one of them. Therefore, achieving optimum blood glucose parameters is hypothesized for better consequences of COVID-19. However, varying data supporting this hypothesis is available in literature. The intention of this study was to investigate the role of glycemic management on the prognosis of hospitalized COVID-19 patients with varying degrees of severity. Methods From April 2020 to January 2021, we carried this retrospective cohort in a clinical care facility in Pakistan. Results Mortality was lowest in patients with HbA1c of less than 7% (53 mmol/mol) (p < 0.001). Similarly, mortality was found lowest in patients with fasting blood glucose less than 126 mg/dl and random blood glucose less than 160 mg/dl (p < 0.001 in each). In contrast, need for admission in critical care was found highest in patients with HbA1c between 7 and 10% (53–86 mmol/mol) (p 0.002). However, participants with blood glucose levels during fasting greater than 200 mg/dl and random blood glucose levels greater than 250 mg/dl were found to have a greater need for invasive mechanical ventilation. Cox regression hazard showed no difference in risk of death and invasive mechanical ventilation based on previous glycemic control. Conclusion Effective diabetic management is correlated with a considerably lower risk of mortality and invasive mechanical ventilation in COVID-19 cases.
A case of PTC nodal recurrence/persistence in a 45-year-old man. Preoperative longitudinal gray-scale (A) and color Doppler (B) sonograms showed a primary PTC in the right lobe (largest diameter, 7.5 mm). However, no suspicious lymph node was found during preoperative US. On the 15-month follow-up US after initial surgery, a longitudinal gray-scale (C) sonogram showed a suspicious lymph node with cystic component and loss of echogenic hilum (largest diameter, 14.8 mm) in the ipsilateral lateral region. The suspicious lymph node showed scant vascularity on the color Doppler sonogram (D). After US-guided fine-needle aspiration, nodal metastasis of PTC was diagnosed on cytology. On histopathological examination after nodal dissection in the right neck, nodal metastasis from PTC was confirmed
Recurrence/persistence rates according to time. A high rate was observed within two years with a peak incidence between 1 and 2 years after initial surgery. Recurrence/persistence was noted over 10 years from initial treatment
Recurrence free survival curve based on the results detected by US
According to age, total recurrence/persistence rate showed a modified U-shape, younger (20~30 years old) and older patients (70–80 years old) having a higher recurrence/persistence rate
Objective This study aimed to investigate the predictive factors as well as the time and age course of recurrence/persistence in a large cohort of postoperative patients with papillary thyroid carcinoma (PTC) based on the long-term ultrasonography (US) follow-up data. Methods Between January 2007 and December 2016, 3106 patients underwent surgery for PTC and at least two postoperative US follow-up examination over more than three years. Tumor recurrence/persistence was confirmed based on the follow-up US data and histopathological results. Univariate and multivariate analyses were performed to evaluate the predictive factors of tumor recurrence/persistence. Kaplan–Meier survival analysis was used to evaluate the recurrence-/persistence-free survival curve based on the US results. Results A total of 321(10.3%) patients developed tumor recurrence/persistence during 54.3 months of mean follow-up (range 36–135 months), including 268(83.5%) cases of lymph node recurrence/persistence, 37 (11.5%) cases of non-lymph node recurrence/persistence, and 16(5%) cases of both types. Recurrence/persistence was observed using US examination at a mean interval of 23.6 ± 21.6 months (range 1–135 months) after surgery and peak incidence was observed 1–2 years after initial treatment. Younger (20–30 years old) and older (70–80 years old) patients had a higher proportion of tumor recurrence/persistence. Multifocality, advanced T and advanced N stages were independent risk factors of tumor recurrence/persistence. Conclusion Tumor recurrence/persistence of PTC usually occurs during the early postoperative period. For patients with multifocal cancer, advanced T and N stage, the US surveillance examination should be cautiously performed, especially in younger and older patients.
USP13 variant analysis. A Genealogical tree and USP13 c.1483G > A; p.V495M variant analysis. Open symbols represent individual that are wild type for USP13. Filled symbols indicate individuals that are carriers of the USP13 c.1483G > A variant. Black filled symbols indicate individuals diagnosed with papillary thyroid carcinoma, gray symbols indicate individuals diagnosed with other thyroid problems (Hashimoto Thyroiditis or goiter). Truncated symbols indicate deceased individuals. B Electropherogram of part of USP13 sequence including the position C.1483 of each member represented in the genealogical tree. Diagnosis of papillary thyroid carcinoma or other thyroid complications are indicated above the electropherogram
In silico prediction of the USP13 structure. A Protein sequence alignment evidencing the USP13 p.V495M variant within the USP13 domain and amino acid residue conservation among different species. B I-TASSER predicted ab-initio model of USP13 c.1483G > A; p.V495M variant. Secondary structure of USP domain with a focus on the USP13 c.1483G > A; p.V495M variant
USP13 siRNA in MDA-T32 cells. A USP13 and PTEN expression analysis of MDA-T32 cells transfected with USP13 siRNA performed by western blot. B Band densitometry quantification of USP13 and C PTEN normalized by the non-target siRNA. *p < 0.0001. D Representative images of clonogenic assay to access the capacity of MDA-T32 cells transfected with USP13 siRNA for 48 h to establish colonies. Cells were stained with Crystal Violet after 7 days of transfection. E Absorbance plot of the colony staining. *p < 0.0001. F Cell viability accessed by MTT assay in MDA-T32 cells transfected with USP13 siRNA for 24, 48, and 72 h. *p = 0.013
USP13 c.1483G > A; p.V495M functional assessment. A Electropherogram of part of USP13 sequence including the position c.1483 in the pCMV6 USP13 WT and mutant vector. B Cycloheximide chase assay test performed in MDA-T32 cells transfected with pCMV6 USP13 WT and mutant vector. After 24 h of transfection, cells were treated with cycloheximide for additional 3, 8, and 24 h. Representative blots of USP13 expression analyzed by western blot. C Band densitometry quantification of USP13 expression for all the different times comparing USP13 WT and mutant. *p = 0.01 D Representative images of clonogenic assay to access the capacity of MDA-T32 cells transfected with USP13 WT or USP13c.1483G > A for 48 h to establish colonies. Cells were stained with Crystal Violet after 7 days of transfection. E Absorbance plot of the colony staining. *p < 0.001. WT: wild type
Purpose Papillary thyroid carcinoma (PTC) is the most common type of thyroid carcinoma and its incidence has greatly increased in the last 30 years. Ubiquitin-specific protease 13 (USP13) is a class of deubiquitinating enzymes (DUBs) and plays an important role in cellular functions such as cell cycle regulation, DNA damage repair, and different cell signaling pathways. Studies regarding the role of USP13 in cancer development and progression are divergent and there are no previous data regarding the role of USP13 gene in PTCs. In this study, we investigated the genetic cause of PTC diagnosed in multiple members of a Brazilian family. Methods Whole exome sequencing (WES) was performed to identify the genetic cause of PTC. Cycloheximide chase assay and clonogenic assay were performed to study USP13 stability and function in vitro. Results WES analysis identified a heterozygous missense variant c.1483G > A (p.V495M) in the USP13 gene that fully segregates with the disease. In silico modeling suggests that this variant may cause protein structural perturbations. USP13 overexpression increased the potential of a single cell to form colonies. The USP13 c.1483G > A variant enhanced the effects seen in USP13 overexpression and preserved protein stability for longer hours compared to the non-mutated USP13 protein. Conclusion Our study suggests that USP13 overexpression may play a role in tumorigenesis of PTCs; and that the USP13 p.V495M (c.1483G > A) variant enhances USP13 estability.
The flow chart of patient inclusion
Ultrasonographic images of subacute thyroiditis paranchime and thyroid nodules. a Heterogeneous SAT paranchime with patchy hypoechoic areas and decreased vascularity and a high-risk nodule in EU-TIRADS 5 category with irregular margins, micro, and macrocalcifications and with malignant cytology in the left thyroid lobe; b heterogenous SAT paranchime with avascular hypoechoic areas in different planes and high-risk nodule in EU-TIRADS 5 category with irregular margins, microcalcifications, marked hypoechogenicity, and a taller-than-wide shape and with an FNAB result of suspicious for malignancy, which was visualized after SAT resolution; c heterogenous SAT paranchime involved thyroid lobes bilaterally and a low-risk isoechoic nodule in EU-TIRADS 3 category with an oval shape and with benign cytology which was seen in the remission of SAT. EU-TIRADS European thyroid imaging and reporting data system, FNAB fine-needle aspiration biopsy, SAT subacute thyroiditis
Purpose Nonhomogenous and ill-defined hypoechoic areas are typical ultrasonographic features of subacute thyroiditis (SAT). Evaluating a thyroid nodule accurately in this heterogeneous paranchime may be troublesome. This study aims to compare thyroid nodules, their characteristics, and European Thyroid Imaging and Reporting Data System (EU-TIRADS) categories at the time of the diagnosis and in the remission of SAT. Methods Ultrasonographic features of SAT and characteristics and EU-TIRADS categories of thyroid nodules in the initial and control ultrasonography (US) of 350 patients with SAT have been evaluated in this retrospective observational study. Fine needle aspiration biopsy (FNAB) results and postsurgical data, if performed, have been estimated. Results A hundred patients (28.6%) with SAT had thyroid nodules at the time of the diagnosis, while 152 (43.4%) patients had a nodule in remission US (p < 0.001). The number of thyroid nodules was found to be higher in the control US as against the initial US (p = 0.001). EU-TIRADS scores of the nodules in the remission US were significantly higher than the scores at the time of the diagnosis (p < 0.001). FNAB was performed in 23% of nodules observed in the remission US, and the rate of thyroid carcinoma within them was 3.3%. Conclusion Thyroid nodules, malignancy suspected features, and EU-TIRADS categories of them may not be appropriately evaluated due to heterogenous paranchime of SAT. Performing a control US examination after resolution of hypoechoic areas may be beneficial to avoid missing clinically significant nodules with high EU-TIRADS scores.
LC-MS/MS chromatogram for steroid hormones in mix solution. Numbers indicate the following metabolites. 1: Aldosterone; 2: Cortisol; 3: 21-deoxycortisol, 4: Corticosterone, 5: 11-deoxycortisol, 6: Androstenedione, 7: Estrone, 8: 11-deoxycorticosterone, 9: Testosterone 10: Estradiol, 11: Dehydroepiandrosterone, 12: 17-hydroxyprogesterone, 13: 17-hydroxypPregnenolone, 14: Dihydrotestosterone, 15: Progesterone, 16: Androsterone, 17: Pregnenolone
Distributions of Dehydroepiandrosterone male patients groups a Statistically significant than moderate group b Statistically significant than mild group
Distributions of 11-Deoxycorticosterone levels between groups a Statistically significant than control group b Statistically significant than mild group. c Statistically significant than moderate group
Purpose This study aims to evaluate the correlations between the severity of the disease and serum steroid levels by analyzing the serum steroid levels in COVID-19 patients with different levels of disease progression and the control group. Methods Morning serum Aldosterone, 11-deoxycortisol, Androstenedione, 17-hydroxyprogesterone, Dihydrotestosterone (DHT), Dehydroepiandrosterone (DHEA), Corticosterone, Dehydroepiandrosterone sulfate (DHEAS), Estrone, Estradiol, Progesterone, 11-deoxycorticosterone, Cortisol, Corticosterone, Androsterone, Pregnenolone, 17-hydroxypregnenolone and 21-deoxycortisol levels were measured in 153 consecutive patients were grouped as mild, moderate, and severe based on the WHO COVID-19 disease severity classification and the control group. Steroid hormone levels were analyzed at once with a liquid chromatography-tandem mass spectrometric method (LC-MS/MS). Results In our study, nearly all steroids were statistically significantly higher in the patients’ group than in the control group (p < 0.001). Also, DHEA was an independent indicator of the disease severity with COVID-19 Conclusions Our study reveals that the alteration in steroid hormone levels was correlated with disease severity. Also, steroid hormone levels should be followed up during COVID-19 disease management.
The prevalence of DM and pre-DM in the cohort patients and the glucose and insulin in the patients in three tertiles according to serum aldosterone level. A 15.0% patients of the total was DM and 31.4% patients of the total was pre-DM; B According to aldosterone level, patients were divided into three tertiles. In Tertile I, the prevalences of DM and pre-DM were 8.6% and 28.4%, repectively. In Tertile II, the prevalences of DM and pre-DM were 16.9% and 32.1%, respectively. In Tertile III, the prevalences of DM and pre-DM were 19.3% and 33.7%, respectively; (C) the plasma glucose in three tertiles at different time points (0 min, 30 min, 60 min, 120 min, 180 min) p for trend at 120 min and 180 min <0.001 and p for trend at 0 min and 60 min <0.05; (D). The serum insulin in three tertiles at different time points (0 min, 30 min, 60 min, 120 min, 180 min) p for trend at 30 min and 60 min <0.001; (E). The AUC of plasma glucose in three tertiles, p for trend = 0.001; (F) the AUC of serum insulin in three tertiles, p trend = 0.003
Effects of selected variables on differences between CCVD–positive PA patients and CCVD-negative PA patients
Objective To explore the prevalence and clinical significance of newly diagnosed diabetes mellitus (DM) in patients with primary aldosteronism (PA). Investigating the risk factors for cardiocerebrovascular disease (CCVD) will guide strategies for reducing CCVD in patients with PA. Methods We retrospectively included 729 PA patients without DM and conducted oral glucose tolerance tests. Results We found that 15.0% of PA patients had newly diagnosed DM. The DM prevalence increased with elevated aldosterone levels [OR = 3.20 (1.77, 5.78), P value < 0.001]. The rate of CCVD in newly diagnosed diabetic PA patients was higher than that in nondiabetic PA patients at diagnosis (11.9% vs. 5.0%, P = 0.005). Furthermore, multivariate logistic analysis revealed that HT duration [1.055 (1.002,1.111), P = 0.041] and newly diagnosed DM [2.600 (1.072,6.303), P = 0.034] were significantly associated with CCVD in PA patients. Conclusion The prevalence of newly diagnosed DM in PA patients was higher than that in the general population. Aldosterone level was an independent risk factor for DM not for CCVD. CCVD was correlated with longer HT duration and newly diagnosed DM. Therefore, it is crucial to screen DM at the diagnosis in PA patients.
Purpose Unlike hyperprolactinemia, clinical significance of prolactin deficiency remains poorly understood. The aim of this study was to assess the cardiometabolic profile of patients with low prolactin levels. Methods The study population consisted of three groups of young women. Two groups were chronically treated with cabergoline but differed in prolactin levels, which were either abnormally low (group A; n = 16) or within the reference range (group B, n = 23). Group C, serving as a control group, included 28 drug-naïve women with normal prolactin levels. The dose of cabergoline in group A was then tapered down. Glucose homeostasis markers, plasma lipids and circulating levels of hormones, uric acid, high-sensitivity C-reactive protein (hsCRP), fibrinogen and homocysteine, as well as the carotid intima-media thickness were assessed at baseline and 6 months later. Results Compared with subjects with normal prolactin levels, women with hypoprolactinemia had higher levels of 2-h postchallenge glucose, glycated hemoglobin, triglycerides, uric acid, hsCRP and fibrinogen, lower values of HDL-cholesterol, total testosterone and free androgen index, as well as reduced insulin sensitivity. No differences in these variables were observed between groups B and C. Apart from prolactin normalization, cabergoline dose reduction reversed all laboratory disturbances reported in group A. Conclusion The obtained results suggest that hypoprolactinemia in women of reproductive age may increase cardiometabolic risk.
IHC staining for Bcl-2 and Noxa. A High and low expression of Bcl-2 protein (200x). B High and low expression of Noxa protein (200x). Second line shows a higher magnification(400x), respectively
Kaplan-Meier analysis showing high Bcl-2 expression is associated with poor DFS (A). When patients were grouped by NET and NEC, this relationship existed only in the NET group (B), but not in the NEC group (C). On the contrary, high Noxa expression is associated with better DFS (D), and this correlation is still existed only in NET group (E) not in NEC group (F)
Kaplan-Meier analysis showing high Bcl-2 expression is associated with poor OS (A). When patients were grouped by NET and NEC, this relationship existed in the NET group (B), and NEC group (C). On the contrary, high Noxa expression is associated with better OS (D), and this correlation is still existed not only in NET group (E) but also in NEC group (F)
Purpose Bcl-2 family proteins are of great significance in the pathogenesis and development of tumors. In this study, the correlations between the expression of Bcl-2 family proteins and clinicopathological features and prognosis of neuroendocrine neoplasms (NENs) were further investigated. Methods 105 Patients diagnosed with gastroenteropancreatic NENs (GEP-NENs) with the paraffin specimen of the tumor available were retrospectively included. Immunohistochemistry (IHC) was performed to detect the expression of Bcl-2 family proteins in paraffin-embedded samples. Student’s t-test and Chi-square test were applied to compare the difference of quantitative and categorical variables, respectively. Survival analysis was conducted according to Kaplan–Meier method. Univariate and multivariate cox regression analysis were used to identify the independent prognostic factors. Results The IHC score of Bcl-2 was significantly higher in neuroendocrine carcinoma (NEC) patients (65.6%), while a higher IHC score of Noxa was more common in neuroendocrine tumor (NET) patients (49.3%). Survival analysis indicated that patients with higher Bcl-2 expression and lower Noxa expression had worse 5-year survival (39.3% vs. 75.6%, p < 0.001; 40.6% vs. 84.9%, p < 0.001). Multivariate cox analysis indicated that high Bcl-2 expression was an independent factor associated with inferior DFS (hazard ratio [HR]: 2.092; 95% confidence interval [CI]: 1.106–3.955; p = 0.023) and OS (HR: 2.784; 95% CI: 1.326–5.846; p = 0.007), while higher Noxa expression was associated with superior DFS (HR:0.398; 95% CI: 0.175–0.907; p = 0.028) and OS (HR: 0.274; 95% CI: 0.110–0.686; p = 0.006). Conclusions Higher expression of Bcl-2 and lower expression of Noxa were associated with unfavorable prognosis of GEP-NENs patients.
Flowchart of Type I g-NEN patient cohort according to management
Effect of type I gastric NEN size on patient prognosis. Kaplan–Meier curve demonstrating probability of a survival depending on size, b Intervention free survival depending on size and c rate of change depending on size
Purpose Type I gastric neuroendocrine neoplasms (g-NENs) have a low risk of metastasis and a generally favourable prognosis. Patients with small type I g-NENs (≤10 mm) frequently require no treatment, whereas those with larger polyps usually undergo resection. We evaluated the safety and outcomes of endoscopic surveillance after no initial treatment in selected patients with type I g-NENs. Methods Retrospective analysis of type I g-NEN patients across two European Neuroendocrine Tumour Society Centers of Excellence 2003–2019. Results Following initial assessment, 87 of 115 patients with type I g-NEN (75 with polyps ≤10 mm) received no initial treatment and underwent endoscopic surveillance. 79/87 (91%) demonstrated no clinically meaningful change in tumour size or grade over a median 62 month follow up. Only two patients developed NEN progression that required a change in management and two other patients developed gastric adenocarcinoma/high grade dysplasia; all four initially had ≥11 mm g-NENs. Conclusions Patients with ≤10 mm type I g-NENs were unlikely to develop clinically significant tumour progression and in most cases, resection was not needed. The endoscopic surveillance interval could therefore potentially be safely increased to every 2–3 years in such patients. However, lifelong surveillance is still advocated due to the additional risk of developing gastric adenocarcinoma.
Potential mechanisms causing thyroid function changes with the severity of COVID-19
The novel coronavirus disease 2019 (COVID-19) produced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious infectious disease. In addition to typical flu-like symptoms, COVID-19 can also cause extrapulmonary spread and systemic inflammation, potentially causing multiorgan dysfunction, including thyroid dysfunction. Thyroid function changes in patients with COVID-19 have been widely reported, but the results are inconsistent. Based on available data, SARS-CoV-2 infection can lead to changes in thyroid function, and the degree of thyroid function changes was positively correlated with the severity of COVID-19, which involved multiple potential mechanisms. In contrast, current evidence was insufficient to prove that thyroid function changes could induce the progression of COVID-19 clinical deterioration.
Relative expression of ADAM10 in PBMC in type 2 diabetes mellitus patients with acute coronary syndrome (cases) compared to type 2 diabetes mellitus patients without acute coronary syndrome (controls). mRNA levels (mean ± standard deviation) were normalised against expression of GAPDH, p < 0.001
ROC curve for serum sRAGE levels (pg/mL) and ADAM10 expression in PBMC discriminatory abilities towards ACS in patients with T2DM
Simple linear regression between study parameters among study participants. a Expression of ADAM10 in PBMC was positively correlated with serum sRAGE levels, p < 0.05. b Serum sRAGE levels were not correlated with serum esRAGE levels, p > 0.05
Purpose Advanced glycation end products (AGEs) are responsible for the complications in type 2 diabetes mellitus (T2DM) patients by acting via its receptor (RAGE). The soluble form of RAGE (sRAGE) prevents the harmful effects of AGE-RAGE signalling. The sRAGE is produced either by alternate splicing (esRAGE) or proteolytic RAGE cleavage by a disintegrin and metalloproteinase 10 (ADAM10). Hence, the study aimed to compare the expression of ADAM10 in peripheral blood mononuclear cell (PBMC), serum sRAGE and esRAGE levels in T2DM patients with and without acute coronary syndrome (ACS). Methods Forty-five T2DM patients with ACS and 45 age, gender and duration of DM-matched T2DM patients without ACS were recruited. Serum sRAGE and esRAGE levels were measured by enzyme-linked immunosorbent assay. The expression of ADAM10 in PBMC was determined by quantitative reverse transcription-polymerase chain reaction. Results The expression of ADAM10 in PBMC and serum sRAGE levels were significantly lower in T2DM patients with ACS than in T2DM patients without ACS (p < 0.001). Serum sRAGE levels and expression of ADAM10 in PBMC were positively correlated with each other and negatively correlated with markers of cardiac injury and glycaemic status (p < 0.05). Simple logistic regression showed that the models containing the expression of ADAM10 and serum sRAGE level could predict the ACS risk among T2DM patients. ROC analysis showed that both might be used for ACS diagnosis in T2DM patients. Conclusion Reduced expression of ADAM10 in PBMC might be responsible for lower serum sRAGE levels, predisposing T2DM patients to high ACS risk.
Purpose Adrenocortical carcinoma (ACC) is a very rare and aggressive malignant disease. Therefore, overall survival (OS) has long been considered as the best endpoint. Yet, a unique endpoint is not optimal to take into account the heterogeneity in tumor profile and the diversification of therapeutic option. The purpose of this mini review was to describe endpoints used in the past, present and future in the field of ACC. Methods Pubmed and Clinicaltrial.gov were used to identify relevant studies. Results Before year 2000 only three endpoints were regularly used: OS, recurrence-free survival (RFS) and response rate. These endpoints were used because ACC was seen as a homogeneous diseases with a high recurrence rate and low rate of long-term survival. Since 2000; along with the apparition of new class of drug, progression-free survival (PFS) has been more and more used. Other endpoints as “time to chemotherapy” or “Progression-free survival 2” were used to evaluate multimodal therapies or treatment with a delayed action. Finally, there is a hope that in the near future, quality of life along with other patient-reported outcomes may be used more frequently. Conclusion While OS and PFS are currently the most used endpoints in ACC, new endpoints are needed to better take into account the challenges offered by different situations and treatment strategies.
Box-whisker plot showing postoperative percentage increase in weight based on preoperative body-mass index. X represents mean value. Horizontal line represents median value. Categories based on body mass index (BMI): obese (BMI ≥ 30 kg/m²), overweight (BMI 25–29.9 kg/m²), and normal weight (BMI < 25 kg/m²). Mean percentage increase in weight based on preoperative BMI: normal weight (20.7 ± 18%) vs. overweight (13.3 ± 18.0 %) vs. obese (6.4 ± 15%), P = 0.012
Body-mass index distribution before surgery and at last follow-up. Categories based on body mass index (BMI): obese (BMI ≥ 30 kg/m²), overweight (BMI 25–29.9 kg/m²), and normal weight (BMI < 25 kg/m²)
Purpose Craniopharyngiomas are nonmalignant sellar and parasellar tumors exhibiting a bimodal age distribution. While the outcomes following treatment in patients with childhood-onset craniopharyngiomas are well characterized, similar information in adult-onset craniopharyngiomas is limited. We aimed to describe the long-term outcomes (weight and metabolic parameters, mortality) in patients with adult-onset craniopharyngioma following treatment. Methods Patients with adult-onset craniopharyngioma with initial treatment (1993–2017) and >6 months of follow-up at our institution were retrospectively identified. Body mass index (BMI) categories included obese (BMI ≥ 30 kg/m²), overweight (BMI 25–29.9 kg/m²), and normal weight (BMI < 25 kg/m²). Results For the 91 patients with adult-onset craniopharyngioma (44% women, mean diagnosis age 48.2 ± 18 years) over a mean follow-up of 100.3 ± 69.5 months, weight at last follow-up was significantly higher than before surgery (mean difference 9.5 ± 14.8 kg, P < 0.001) with a higher percentage increase in weight seen in those with lower preoperative BMI (normal weight (20.7 ± 18%) vs. overweight (13.3 ± 18.0%) vs. obese (6.4 ± 15%), P = 0.012). At last follow-up, the prevalence of obesity (62 vs. 40.5%, P = 0.0042) and impaired glucose metabolism (17.4% vs. 34%, P = 0.017) increased significantly. All-cause mortality was 12%, with the average age of death 71.9 ± 19.7 years (average U.S. life expectancy 77.7 years, CDC 2020). Conclusion Patients with adult-onset craniopharyngioma following treatment may experience weight gain, increased prevalence of obesity, impaired glucose metabolism, and early mortality. Lower preoperative BMI is associated with a greater percentage increase in postoperative weight.
Purpose The incidence of thyroid carcinoma has increased globally in the past years. Papillary thyroid carcinoma (PTC) is the most frequent neoplasm of the thyroid gland comprehending the 90% of the thyroid carcinoma and has an indolent clinical behaviour. However, some variants of follicular cell-derived thyroid carcinoma, including variants of classic of PTC, have been identified that show a more aggressive biological behaviour. An accurate diagnosis of these entities is crucial for planning a more aggressive treatment and improving patients’ prognosis of patients. The aim of this review is to present the main clinical, histological, and molecular features of aggressive variants of follicular cell-derived thyroid carcinoma, and to provide useful histological parameters for determining the most suitable therapeutic strategy for patients affected by these forms. Results Variants of classic PTC such as the diffuse sclerosing variant (DSV), the tall cell variant (TCV), the columnar cell variant (CCV), the solid/trabecular variant (STV) and the hobnail variant (HV), and other variants of follicular cell-derived thyroid carcinoma, such as poorly differentiated thyroid carcinoma (PDTC), and anaplastic thyroid carcinoma (ATC), are associated with aggressive behaviour. Conclusions The correct identification and diagnosis of aggressive variants of follicular cell-derived thyroid carcinoma is important, as they allow the clinician to adopt the most refined therapeutic strategies in order to the survival of the patients.
The proposed pathophysiological mechanisms underlying hypocalcemia in COVID-19. Red solid arrow lines indicate the negative influence of the main pathophysiological mechanisms (Vitamin D deficiency; Impaired compensatory PTH response; viral calcium-dependent mechanisms of actions; cytokines and UFAs hypersecretion; acute malnutrition; coagulopathy; tissue calcium deposit) on hypocalcemia occurrence; red dashed arrow lines indicate the negative influence between each of these mechanisms
Context In the multifaceted COVID-19 clinical scenario characterized by a multi-system disorder with negative implications not only on respiratory function but also on cardiac, hematological, neurological and endocrine-metabolic systems, a distinctive osteo-metabolic phenotype with an independent influence on disease severity and recovery of patients affected was early reported. Aim To summarize and update the main evidences regarding the distinct components of this phenotype in acute and Long COVID-19, reinforcing its clinical relevance and discussing the main pathophysiological and clinical-therapeutic implications of the most recent reported findings. Results This emerging phenotype is characterized by a widespread acute hypocalcemia and hypovitaminosis D with an impaired compensatory parathyroid hormone response, and a high prevalence of skeletal complications such as vertebral fractures. The clinical relevance of this osteo-metabolic phenotype on acute COVID-19 is well characterized, and novel seminal evidences are progressively highlighting its importance also in predicting patient’s long-term outcomes and Long COVID-19 occurrence. Conclusions These findings reinforced the central role of a multidisciplinary team, including endocrinologists, in evaluating these patients for a proactive search of each aspect of the osteo-metabolic phenotype components since they may represent suitable therapeutic targets to prevent SARS-CoV-2 infection, poor COVID-19 outcomes, Long COVID-19 occurrence and even possibly better responses to COVID-19 vaccination.
Purpose: Type-2 diabetes Mellitus (T2DM) is one of the leading causes of death and disability worldwide. This study examines temporal patterns of the global, regional, and national burden of T2DM in the last three decades. Data and methods: The estimates of age, sex and location-wise incident cases, deaths, prevalent cases, and disability-adjusted-life-years (DALYs) and risk factors for 21 regions and 204 countries are retrieved from the Global Burden of Disease 2019 study from 1990 to 2019. Socio-demographic index (SDI) is used as the indicator of the development status of countries, and quadratic regression is employed to examine the relationship between country-level age-standardized rates and SDI. Results: Globally, incident cases of T2DM more than doubled from 8.4 million[95% uncertainty interval, 7.8-9.1 million] in 1990 to 21.7 million[20.0-23.5 million] in 2019, and deaths more than doubled from 606,407[573,069-637,508] to 1.5 million[1.4-1.6 million] between 1990 and 2019. Global T2DM prevalence increased from 148.4 million[135.5-162.6 million] in 1990 to 437.9 million[402.0-477.0 million] in 2019. In 2019, global age-standardized prevalence rate stood at 5282.8/100,000[4853.6-5752.1], varying from 2174.5/100,000[1924.3-2470.5] in Mongolia to 19876.8/100,000[18211.1-21795.3] in American Samoa. SDI exhibited inverted-U shaped relationship with country-level age-standardised rates. Globally, high body-mass-index (51.9%), ambient particulate matter pollution (13.6%), smoking (9.9%) and secondhand smoke (8.7%) were the major contributing risk factors towards T2DM DALYs in 2019. Conclusion: With ubiquitously rising prevalent cases globally, particularly in low and middle-income countries and regions, T2DM requires immediate attention and targeted policy response worldwide centered on lifestyle interventions (e.g., physical activity, smoking, diet, and obesity), air pollution control and cost-effective timely treatment.
Flowchart of the studied sample selection
Purpose: To investigate the effect of restrictive measures the COVID-19 pandemic imposed on glycemic control of patients with type 2 diabetes (T2D) and its associated factors. Methods: Outpatients with T2D who had an appointment scheduled during the social distancing period were eligible for telemonitoring. Clinical and laboratorial data were collected from medical records in the last consultation before and from the first visit after the COVID-19 pandemic lockdown period. Results: From the 1241 eligible patients, 816 (65.7%) could be contacted by phone, 137 (11%) attended the unit for consultation during the social distancing period, and 1040 (83.8%) returned up to 12 months after the end of the lockdown period. We observed a meaningful reduction of glycated hemoglobin (HbA1c) (7.9 [7-9] vs. 7.7 [6.9-8.8] p = 0.004) and no difference in body mass index (29.5 [26-33.7] vs. 29.6 [26.2-34.1], p = 0.17) before and after the social distancing period. According to insulin use at baseline, the HbA1c variation was +0.6 (-0.7 to +2) and -0.6 (-2.1 to +0.7) in patients without and with insulin, respectively (p < 0.001). In the multivariate model, insulin therapy was the only independent significant predictor of HbA1c reduction. Conclusion: This study observed an improvement in glycemic control after the lockdown. The only independent predictor found was previous insulin use. Probably, the longer time available to perform frequent blood glucose self-monitoring at home and adjustments in insulin therapy could explain our findings.
Survival analysis by Kaplan–Meier curves of the entire cohort: a PFS after a median PFS time of 24.6 (min–max: 5–98) months and (b) OS after a median time of 28.5 months (min–max: 0.7–106.3)
Progression-free survival analysis of the entire cohort after at least one cycle of PRRT 177-Lu-DOTATATE by: a a NLR cutoff of 1.8 [estimated medians of 77 months (95% CI: 27.3–127.7) for NLR < 1.8 and 47.7 months (95% CI: 34.7–60.7) for NLR > 1.8 (p = 0.08)] and (b) a PLR cutoff of 123 [estimated medians of 29.9 months (95% CI: 21.6–38.1) for PLR > 123 and 30.8 months (95% CI: 10–51.6) for PLR < 123 (p = 0.98)]
Overall survival analysis of the entire cohort after at least one cycle of PRRT 177-Lu-DOTATATE by: a a NLR cutoff of 1.8 [estimated median of 77.5 months (95% CI: 27.3–127.7) for NLR < 1.8 and 47.7 months (95% CI: 34.7–60.8) for NLR > 1.8 (p = 0.04) and (b) by a PLR cutoff of 123 [estimated median of 77.5 months (95% CI: 38.5–116.5) for PLR < 123 and 45.5 months (95% CI: 33.4–57.5) for PLR > 123 (p = 0.14)
Progression-free survival and overall survival of the entire cohort by embryonic origin and primary tumor site
Purpose: Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-DOTATATE is a palliative therapeutic option for advanced Neuroendocrine Tumors (NETs). Prognostic factors can predict long-term outcomes and determine response to therapy. Among those already explored, biomarkers from full blood count, including neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) has shown value for other solid tumors and for NETs patients submitted to other forms of therapy. However, its relation to PRRT response and patients' prognosis is still to be determined. Methods: Medical records from 96 patients submitted to PRRT between 2010 and 2017 were reviewed, median NLR and PLR were calculated from baseline flood blood count and dichotomized as high or low. Progression-free survival (PFS) and Overall Survival (OS) were calculated. Results: NLR and PLR median values were 1.8 and 123, respectively. Patients with low NLR had a significantly longer OS (estimated median of 77.5 months, 95% CI: 27.3-127.7) when compared to patients with high NLR (estimated median of 47.7 months, 95% CI: 34.7-60.8); p = 0.04. Patients with low NLR had a trend toward a longer median PFS when compared to patients with high NLR [estimated medians of 77 months (95% CI: 27.3-127.7), and 47.7 months, (95% CI: 34.7-60.7)], respectively, p = 0.08. Conclusion: Patients with advanced-stage NET with NLR higher than 1.8 have worse long term clinical outcomes after PPRT. Larger studies are needed to validate the optimal cutoff for this biomarker.
Top-cited authors
Giuseppe Bellastella
  • Università degli Studi della Campania "Luigi Vanvitelli
Maria Ida Maiorino
  • Università degli Studi della Campania "Luigi Vanvitelli
Guang Ning
  • Shanghai Jiao Tong University
Henrik Falhammar
  • Karolinska Institutet
Annamaria Colao
  • University of Naples Federico II