The metabolic and endocrinological effects in patients with adult growth hormone deficiency (AGHD) who switched from daily growth hormone (GH) replacement therapy to weekly GH replacement therapy with somapacitan were evaluated and observed over a long follow-up period. Patients were included only if their medical treatments, aside from GH replacement therapy, remained unchanged. Metabolic and endocrinological parameters were assessed at the time of switching, and at 1- and 2-year follow-up after switching from daily GH replacement therapy to weekly GH replacement therapy with somapacitan. The results showed that the body mass index (BMI), fasting plasma glucose (FPG), aspartate transaminase (AST), and triglyceride (TG) levels at 1 year after switching significantly improved compared with those at the time of switching (each P < 0.025). At 2 years, the homeostasis model assessment of insulin resistance (HOMA-IR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and alanine aminotransferase (ALT), as well as BMI, FPG, TG, and AST significantly improved compared with those observed at the time of switching (each P < 0.025). In addition, improvement in HOMA-IR at 2 years after switching was significantly associated with improvement in AST. Switching to GH replacement therapy did not affect endocrinological parameters. These findings, which were revealed by the present real-world exploratory cohort study, indicate that weekly GH replacement therapy with somapacitan may confer more beneficial effects than daily GH replacement therapy.

CONTEXT:Acromegaly poses clinical challenges in terms of early diagnosis and intervention. Therefore, the development of novel diagnostic tools is essential. Although artificial intelligence (AI) models based on external appearance have been proposed, privacy concerns have limited their use. OBJECTIVE:To develop a privacy-conscious deep learning model for detecting acromegaly using hand images. METHODS:This nationwide multicenter study enrolled 716 patients (317 with acromegaly and 399 controls) and 11 480 images from 15 Japanese pituitary centers. The inclusion criteria were age ≥18 years and care received at the participating facilities. Hand images focusing on the dorsal and fist sign, excluding the palm/fingerprint regions, were used to develop the model. The data were split into training/validation (12 centers) and test (3 centers) datasets. A ResNet-50-based model was trained using PyTorch with data augmentation and 5-fold cross-validation. For each patient, the predictions were averaged over 4 images. The performance of the model was compared with that of endocrinologists. RESULTS:The model achieved a sensitivity of 0.89, specificity of 0.91, positive predictive value of 0.88, negative predictive value of 0.93, F1-score of 0.89, and an area under the receiver operating characteristic curve of 0.96, outperforming specialists (F1-score range: 0.43-0.63). CONCLUSION:This study highlights the utility of dorsal hand and fist sign as diagnostic clues for acromegaly, which the AI model captured more accurately than endocrinologists. Using this privacy-conscious feature, this model can be deployed in public settings like health checkups. Further validation using larger datasets, including healthy individuals and diverse diseases, is necessary.

Subclinical Cushing’s syndrome (SCS) is frequently encountered during the clinical evaluation of adrenal incidentalomas and is typically associated with reduced levels of serum dehydroepiandrosterone sulfate (DHEA-S). Cytochrome b5 is a component of the electron transfer system that enhances the activity of 17, 20-lyase relative to that of 17a-hydroxylase. Therefore, tumors harboring cytochrome b5 might be associated with dehydroepiandrosterone sulfotransferase (DHEA-ST) expression, resulting in unsuppressed serum DHEA-S levels. Here, we reported the first case of SCS with elevated serum DHEA-S levels in an incidentally detected adrenocortical adenoma showing immunohistochemical positivity for both cytochrome b5 and DHEA-ST.

Several sodium-glucose cotransporter 2 (SGLT2) inhibitors are known to have beneficial effects on renal function in patients with type 2 diabetes. However, the long-term effects of luseogliflozin, an SGLT2 inhibitor, remain uncertain in real-world settings. This multicenter, open-label, prospective observational study evaluated the long-term effects of luseogliflozin on renal function in Japanese patients with type 2 diabetes. Fifty-four outpatients initiated on luseogliflozin at Fukuoka University Chikushi Hospital or associated clinics were enrolled from April 2018 to December 2019, with 46 patients included in the final analysis set. The primary outcome was the change in estimated glomerular filtration rate (eGFR) from baseline to 104 weeks, and secondary outcomes included the change in eGFR at week 52 and changes in body weight and blood and urinary parameters at 52 and 104 weeks. The mean duration of diabetes was 8.1 years. Baseline eGFR was 75.8 +/- 17.4 mL/ min/1.73m(2), and no decline in eGFR was observed from baseline to 104 weeks. Decline in eGFR was suppressed in the two groups stratified by baseline eGFR (< 60 and >= 60 mL/min/1.73m(2)). No changes were noted in urinary albumin excretion rate. Blood glucose, body weight, blood pressure, liver function, and uric acid levels showed significant improvements. There were four adverse events, but no serious adverse events closely related to luseogliflozin treatment. In type 2 diabetes patients, 2-year treatment with luseogliflozin provided beneficial metabolic effects and improved the rate of decline in eGFR, suggesting a renal protective effect.

Combination strategies of KRAS inhibition with immunotherapy in treating advanced or recurrent colorectal carcinoma (CRC) may need to be assessed in circulating tumour cells (CTCs) to achieve better clinical outcomes. This study aimed to investigate the genomic variations of KRAS in CTCs and matched CRC tissues and compared mRNA expression of KRAS and CTLA-4 between wild-type and KRAS-mutated CTCs and CRC tissues. Clinicopathological correlations were also compared. Six known mutations of KRAS were identified at both codon 12 and codon 13 (c.35G>T/G12V, c.35G>A7/G12D, c.35G>C/G12A, c.34G>A/G12S, c.38G>C/G13A, and c.38G>A/G13D). Three CTC samples harboured the identified mutations (16.7%; 3/18), while fifteen matched primary tumour tissues (65.2%, 15/23) showed the mutations. CTCs harbouring the KRAS variant were different from matched CRC tissue. All the mutations were heterozygous. Though insignificant, CTLA-4 mRNA expression was higher in patients carrying KRAS mutations. Patients harbouring KRAS mutations in CTCs were more likely to have poorly differentiated tumours (p = 0.039) and with lymph node metastasis (p = 0.027) and perineural invasion (p = 0.014). KRAS mutations in CTCs were also significantly correlated with overall pathological stages (p = 0.027). These findings imply the genetic basis of KRAS with immunotherapeutic target molecules based on a real-time platform. This study also suggests the highly heterogeneous nature of cancer cells, which may facilitate the assessment of clonal dynamics across a single patient's disease.

In this real-world pilot study, we evaluated the metabolic and endocrinological effects in patients with adult growth hormone deficiency (AGHD) who switched from daily growth hormone (GH) replacement therapy to weekly GH replacement therapy using somapacitan. Eleven patients with AGHD, whose medical treatment aside from GH replacement therapy did not change, were enrolled. We investigated the metabolic and endocrinological parameters between at switching and 6 months after switching from daily GH formulation to somapacitan. The results showed that body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR), fasting plasma glucose (FPG), and liver functions were significantly improved 6 months after switching compared to those at switching (each P < .05). Besides, the improvement in HOMA-IR was significantly associated with the period of daily GH replacement therapy before switching (P = .048), while age, sex, improvement in BMI or liver functions, presence of any hormonal deficiency, and the existence of any hormonal replacement therapy significantly associated (P > .05). In addition, switching to GH replacement therapy did not affect endocrinological parameters. In conclusion, this study might indicate that weekly GH replacement therapy with somapacitan could have more beneficial points than daily GH replacement therapy. Considering the cohort of this study was small, future studies with larger cohorts should be necessary to confirm the results of this study.

Fine-needle aspiration biopsy is the most common method for preoperative diagnosis of thyroid carcinomas including papillary carcinoma. The procedure is best performed with ultrasound by operator with professional skill and knowledge. Several guidelines recommend the indication of fine-needle aspiration concerning the pattern of ultrasound and size of nodules. Besides, fine-needle aspiration biopsy of lymph nodes should be performed if malignancies are suspected. Fine-needle aspiration biopsy of thyroid gland is mostly safe, but complications such as blood extravasation-related complications, acute thyroid enlargement, infection in thyroid gland, and pneumothorax could occur. The most frequent complications are blood extravasation-related complications, which could be fatal. Similarly, acute thyroid enlargement could also be severe. To conclude, fine-needle aspiration biopsy is useful and should be performed under the precise indication and the updated knowledge of complications including the way of handling if they occur.

Hypothalamic adrenal insufficiency (AI) is a rare but distinct type of AI. The leading cause of hypothalamic AI is a secondary side-effect of exogenous steroid intake, particularly in large amounts and/or long-term periods. The next cause would be the effect of the tumor in the hypothalamic lesions. We show here 9 cases of hypothalamic AI without any disorder on imagings and a history of steroid administration. All patients had general fatigue; 7 patients (77.8%) had a history of hypoglycemia; 5 patients (55.6%) had a history of hypotension. None of the patients had hyponatremia, hyperkalemia, or eosinophilia. Their morning plasma adrenocorticotropic hormone (ACTH) value was low at 8.5 ± 4.2 pg/mL, and serum cortisol value was low at 4.5 ± 1.3 µg/dL. All patients demonstrated normal responses during the corticotropin-releasing hormone loading (CRH) test but inadequate responses during the insulin tolerance test (ITT). After hydrocortisone replacement therapy, their morning plasma ACTH and serum cortisol values were significantly recovered (P < .05). Moreover, more than half of the patients were fine after discontinuing hydrocortisone replacement therapy. These results indicate that this unique type of hypothalamic AI has a curable clinical course making hydrocortisone replacement therapy a novel therapeutic option.

Pituitary apoplexy is an uncommon syndrome that often results in spontaneous hemorrhage or infarction of pituitary tumors or glands. We previously reported pituitary apoplexy occurred most frequently in nonfunctional pituitary adenomas among all types of pituitary incidentalomas. In the present study, we aimed to investigate the characteristics of pituitary apoplexy in patients with incidental nonfunctional pituitary adenomas. 65 patients with pituitary incidentaloma were enrolled. All patients underwent clinical/endocrinological/pathological investigations. As a result, 33 patients were diagnosed with nonfunctional pituitary adenomas. Of these, 12.1% of patients had pituitary apoplexy. There was no difference in tumor diameter, age, or sex between the apoplexy and the non-apoplexy groups. However, the liver enzymes aspartate transaminase and alanine aminotransferase were significantly higher, and plasma sodium and chloride levels were significantly lower in the apoplexy group than in the non-apoplexy group (each P < .05). In addition, low-density lipoprotein-cholesterol was significantly higher in the apoplexy group than in the non-apoplexy group (P < .05). Besides, thyroid-stimulating hormone, luteinizing hormone, follicle-stimulating hormone, and prolactin deficiencies were significantly more frequent in the apoplexy group than in the non-apoplexy group (each P < .05), and growth hormone and adrenocorticotropic hormone deficiencies were more frequent in the apoplexy group than in the non-apoplexy group (P = .09 and.08, respectively). Furthermore, tumor diameter was not associated with pituitary apoplexy, whereas thyroid-stimulating hormone, luteinizing hormone, and follicle-stimulating hormone deficiencies were significantly associated with the apoplexy group (each P < .05). Hence, the present study indicated that pituitary apoplexy could not be related to tumor diameter. Moreover, hormonal deficiencies, hepatic dysfunction, hyponatremia or hypochloremia, and dyslipidemia might be indicators of pituitary apoplexy. There could be the possibility the treatment for dyslipidemia prevents pituitary apoplexy.

Ultrasound examination of the thyroid is useful for preoperative assessment of thyroid nodules including papillary thyroid carcinoma. The examination mainly is to determine the malignant potential of thyroid nodule(s). There are different systems to predict malignant potential in the thyroid nodules and cervical lymph nodes by ultrasound. Ultrasound is used in conjunction with fine-needle aspiration to diagnosis papillary thyroid carcinoma. It is used as guidance to locate the sites to obtain the samples for diagnosis and research in papillary thyroid carcinoma.

Context: Mutations in the NR0B1 gene, also well-known as the DAX1 gene, are known to cause congenital adrenal hypoplasia associated with hypogonadotropic hypogonadism. The abnormal NR0B1 protein fails to suppress the transcription of promoters of steroidogenic enzymes, which are also targets of NR5A1 protein, also well-known as Ad4BP/SF-1 protein. Since NR5A1 and NR0B1 have antagonistic effects on steroidogenesis, the loss of function due to NR0B1 mutations may be compensated by inducing loss of function of NR5A1 protein. Patient: A middle-aged man was diagnosed with congenital adrenal hypoplasia associated with hypogonadotropic hypogonadism and genetic analysis revealed him to have a novel NR0B1 mutation, c.1222C>T(p.Gln408Ter). Methods: NR0B1 activity was evaluated in CLK1/4 inhibitor-treated 293T cells via immunoblotting and luciferase assays of the STAR promoter. Results: TG003 treatment suppressed NR5A1 protein function to compensate for the mutant NR0B1 showing inhibited suppression of transcription. Immunoblotting analyses showed that the phosphorylation status of NR5A1 at Ser203 was attenuated by the CLK1/4 inhibitor. Conclusion: The specific reduction of NR5A1 phosphorylation by a CLK1/4 inhibitor may alleviate developmental defects in patients with NR0B1 mutations.

Due to its rarity, adrenal hemorrhage is difficult to diagnose, and its precise etiology has remained unknown. One of the pivotal mechanisms of adrenal hemorrhage is the thrombosis of the adrenal vein, which could be due to thrombophilia. However, detailed pathological evaluation of resected adrenal glands is usually required for definitive diagnosis. Here, we report a case of a cortisol-secreting adenoma with concomitant foci of hemorrhage due to antiphospholipid syndrome diagnosed both clinically and pathologically. In addition, the tumor in this case was pathologically diagnosed as cortisol-secreting adenoma, although the patient did not necessarily fulfill the clinical diagnostic criteria of full-blown Cushing or sub-clinical Cushing syndrome during the clinical course, which also did highlight the importance of detailed histopathological investigations of resected adrenocortical lesions.

Vascular endothelial growth factor (VEGF) is important in pathogenesis of different cancers. The aim of this study is to investigate the relationships between different VEGFs and clinicopathological factors in patients with phaeochromocytomas. Twenty patients (10 men; 10 women) with non-hereditary, non-metastatic phaeochromocytomas were examined for VEGF mRNA expressions by polymerase chain reaction. The expressions were correlated with the clinical and pathological factors of the patients. In addition, mouse double minute 2 (MDM2) expression in these tumours were studied by immunohistochemistry. High expressions of VEGF-A, VEGF-B, and VEGF-C mRNA were detected in 11 (55%), 9 (45%), and 9 (45%) of the tumours respectively. High expression of VEGF-A in phaeochromocytomas was significantly correlated with the tumour size (p=0.025) but did not correlate with patients' age, gender, and tumour laterality. Besides, there was a trend of VEGF-A expression correlated with MDM2 expression (p=0.064). On the other hand, expressions of VEGF-B and VEGF-C were not significantly correlated with tumour size, patients' age, gender, tumour laterality, and MDM2 expression. In addition, high expressions of VEGF-B and VEGF-A were associated with increase of tumour size (p=0.042). Co-expression of different VEGFs did not correlate with MDM2 expression. To conclude, there is a role for VEGF-A/VEGF-B/VEGF-C in the pathogenesis of non-hereditary, non-metastatic phaeochromocytomas.

EDITORIAL article Front. Endocrinol., 23 August 2021 | https://doi.org/10.3389/fendo.2021.720983

Anaplastic thyroid carcinoma is a type of thyroid carcinoma with the most aggressive biological behaviour amongst thyroid cancer. Here, we review the current genomic and the impacts of advances in therapies to improve the management of patients with the cancer.Common mutations being identified in anaplastic thyroid carcinoma are p53 and TERT promoter mutations. Other common mutated genes included BRAF, RAS, EIF1AX, PIK3CA, PTEN and AKT1, SWI/SNF, ALK and CDKN2A. Changes in expression of different microRNAs are also involved in the pathogenesis of anaplastic thyroid carcinoma. Curative resection combined with radiotherapy and combination chemotherapies (such as anthracyclines, platins and taxanes) has been shown to have effects in the treatment of some patients with anaplastic thyroid carcinoma. Newer molecular targeted therapies in clinical trials target mostly the cell membrane kinase and downstream proteins. These include targeting the EGFR, FGFR, VEGFR, c-kit, PDGFR and RET on the cell membrane as well as VEGF itself and the downstream targets such as BRAF, MEK and mTOR. Immunotherapy is also being tested in the cancer. Updated knowledge of genomic as well as clinical trials on novel therapies is needed to improve the management of the patients with this aggressive cancer.

Cinacalcet is a calcimimetic that modulates the functions of calcium-sensing receptor and is currently used to treat patients with primary hyperparathyroidism (PHPT). Although it was reported that cinacalcet treatment reduced the size of hyperplastic parathyroid glands in patients with secondary hyperparathyroidism, whether or not cinacalcet treatment can reduce the size of parathyroid adenomas in patients with PHPT has been unknown. We recruited nine (male: one, female: eight) patients with PHPT due to parathyroid adenomas who did not undergo parathyroidectomy. Cinacalcet was administered at a dose of 50 mg/day, and we evaluated the size of parathyroid adenomas (width × thickness) (mm2) using ultrasonography before and after 6 months of cinacalcet treatment. The mean age of the subjects was 58.1 ± 7.2 years old, and the mean serum intact parathyroid hormone (PTH) concentration was 134.8 ± 8.7 pg/ml. All participants showed hypercalcemia and osteopenia. After 6 months, the mean size of parathyroid adenomas was significantly decreased (baseline: 73.8 ± 33.4 mm2 vs. after 6 months: 52.5 ± 25.0 mm2, p = 0.045). Thus, 6-month cinacalcet treatment induced a 29% size reduction in parathyroid adenomas. Furthermore, the serum intact PTH concentration before cinacalcet treatment was positively correlated with the reduction in the size of parathyroid adenomas. The present study revealed that cinacalcet treatment reduces the size of parathyroid adenomas in patients with PHPT. The accumulation of more PHPT cases with cinacalcet therapy is required to confirm this finding.

Anaplastic thyroid carcinoma is an uncommon carcinoma representing 1 to 4% of all thyroid cancers. The carcinoma is most common in females of the eight decades. It is a locally advanced cancer with frequent infiltration of surrounding organs, blood vessels and skin of neck. Paraneoplastic manifestations could occur. Approximately half of the patients with anaplastic thyroid carcinoma had distant metastasis with lung and brain as the most frequent sites of metastasis. The median survival of patients with anaplastic thyroid carcinoma reported was from 1 to 6 months. The terminology of the cancer in World Health Organization is "anaplastic thyroid carcinoma" rather than "undifferentiated thyroid carcinoma". In the latest American Joint Committee on Cancer (AJCC) TNM staging system for anaplastic thyroid carcinoma, there are updates on T and N categories. To conclude, updated knowledge of clinicopathological features, classification, pathological staging will improve our understanding of the cancer and will help in the management of the patients with this aggressive cancer.

Purpose of Review Anaplastic thyroid carcinoma is a type of thyroid carcinoma with the most aggressive biological behaviour amongst thyroid cancer. Here, we review the current genomic and the impacts of advances in therapies to improve the management of patients with the cancer. Recent Findings Common mutations being identified in anaplastic thyroid carcinoma are p53 and TERT promoter mutations. Other common mutated genes included BRAF , RAS , EIF1AX , PIK3CA , PTEN and AKT1 , SWI/SNF , ALK and CDKN2A . Changes in expression of different microRNAs are also involved in the pathogenesis of anaplastic thyroid carcinoma. Curative resection combined with radiotherapy and combination chemotherapies (such as anthracyclines, platins and taxanes) has been shown to have effects in the treatment of some patients with anaplastic thyroid carcinoma. Newer molecular targeted therapies in clinical trials target mostly the cell membrane kinase and downstream proteins. These include targeting the EGFR, FGFR, VEGFR, c-kit, PDGFR and RET on the cell membrane as well as VEGF itself and the downstream targets such as BRAF, MEK and mTOR. Immunotherapy is also being tested in the cancer. Summary Updated knowledge of genomic as well as clinical trials on novel therapies is needed to improve the management of the patients with this aggressive cancer.

Half of the patients with phaeochromocytoma have glucose intolerance which could be life-threatening as well as causing postoperative hypoglycemia. Glucose intolerance is due to impaired insulin secretion and/or increased insulin resistance. Impaired insulin secretion is caused by stimulating adrenergic α2 receptors of pancreatic β-cells and increased insulin resistance is caused by stimulating adrenergic α1 and β3 receptors in adipocytes, α1 and β2 receptors of pancreatic α-cells and skeletal muscle. Furthermore, different affinities to respective adrenergic receptors exist between epinephrine and norepinephrine. Clinical studies revealed patients with phaeochromocytoma had impaired insulin secretion as well as increased insulin resistance. Furthermore, excess of epinephrine could affect glucose intolerance mainly by impaired insulin secretion and excess of norepinephrine could affect glucose intolerance mainly by increased insulin resistance. Glucose intolerance on paraganglioma could be caused by increased insulin resistance mainly considering paraganglioma produces more norepinephrine than epinephrine. To conclude, the difference of actions between excess of epinephrine and norepinephrine could lead to improve understanding and management of glucose intolerance on phaeochromocytoma.