Case Report: Medullary Thyroid Cancer Workup Initiated by Unexpectedly High Procalcitonin Level-Endocrine Training Saves Life in the COVID-19 Unit.

Background: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a novel coronavirus that has caused a worldwide pandemic. The majority of medullary thyroid cancers present as a thyroid nodule. At the time of diagnosis, cervical lymph nodes and distant metastases are frequently detected. Case Report: Here, we present a case of a 46-year-old man with coronavirus disease (COVID) pneumonia, who had persistently high serum procalcitonin levels despite normal C-reactive protein levels. The attending infectologist happened to be a colleague who spent some time, as part of her internal medicine rotation, in the Endocrine Ward and recalled that medullary thyroid cancer might be the cause. This led to the timely workup and treatment of the medullary cancer.

Irisin Stimulates the Release of CXCL1 From Differentiating Human Subcutaneous and Deep-Neck Derived Adipocytes via Upregulation of NFκB Pathway.

Thermogenic brown and beige adipocytes might open up new strategies in combating obesity. Recent studies in rodents and humans have indicated that these adipocytes release cytokines, termed "batokines". Irisin was discovered as a polypeptide regulator of beige adipocytes released by myocytes, primarily during exercise. We performed global RNA sequencing on adipocytes derived from human subcutaneous and deep-neck precursors, which were differentiated in the presence or absence of irisin. Irisin did not exert an effect on the expression of characteristic thermogenic genes, while upregulated genes belonging to various cytokine signaling pathways. Out of the several upregulated cytokines, CXCL1, the highest upregulated, was released throughout the entire differentiation period, and predominantly by differentiated adipocytes. Deep-neck area tissue biopsies also showed a significant release of CXCL1 during 24 h irisin treatment. Gene expression data indicated upregulation of the NFκB pathway upon irisin treatment, which was validated by an increase of p50 and decrease of IκBα protein level, respectively. Continuous blocking of the NFκB pathway, using a cell permeable inhibitor of NFκB nuclear translocation, significantly reduced CXCL1 release. The released CXCL1 exerted a positive effect on the adhesion of endothelial cells. Together, our findings demonstrate that irisin stimulates the release of a novel adipokine, CXCL1, via upregulation of NFκB pathway in neck area derived adipocytes, which might play an important role in improving tissue vascularization.

ASC-1 transporter-dependent amino acid uptake is required for the efficient thermogenic response of human adipocytes to adrenergic stimulation.

Brown and beige adipocytes dissipate energy by uncoupling protein 1 (UCP1)-dependent and UCP1-independent thermogenesis, which may be utilized to develop treatments against obesity. We have found that mRNA and protein expression of the alanine/serine/cysteine transporter-1 (ASC-1) was induced during adipocyte differentiation of human brown-prone deep neck and beige-competent subcutaneous neck progenitors, and SGBS preadipocytes. cAMP stimulation of differentiated adipocytes led to elevated uptake of serine, cysteine, and glycine, in parallel with increased oxygen consumption, augmented UCP1-dependent proton leak, increased creatine-driven substrate cycle-coupled respiration, and upregulation of thermogenesis marker genes and several respiratory complex subunits; these outcomes were impeded in the presence of the specific ASC-1 inhibitor, BMS-466442. Our data suggest that ASC-1-dependent consumption of serine, cysteine, and glycine is required for efficient thermogenic stimulation of human adipocytes.

Role of 3D echocardiography-determined atrial volumes in distinguishing between pre-capillary and post-capillary pulmonary hypertension.

AIMS: The current guidelines on pulmonary hypertension (PH) recommend the use of invasive examination for differentiating between left-sided heart disease-related (post-capillary) and pre-capillary PH. However, atrial sizes are considered markers of ventricular filling pressures. Therefore, we aimed to test the clinical applicability of atrial volumes measured by transthoracic three-dimensional echocardiography (3DE) in differentiating between pre-capillary and post-capillary PH. METHODS AND RESULTS: Seventy-five consecutive patients with PH were prospectively examined with transthoracic 3DE. After less than 24 h, the patients underwent right heart catheterization and 3DE and were classified as pre-capillary or post-capillary PH according to the recommendations of the ESC guidelines. The atrial volumes were measured offline with dedicated commercial software. Thirty-eight patients (13 men, age 65 ± 18 year) had pre-capillary PH, and 37 (23 men, age 62 ± year) had post-capillary PH. The mean pulmonary artery pressures were similar in patients with pre-capillary and post-capillary PH (38 [IQR 26, 54] mmHg vs. 41 [IQR 33, 48] mmHg, respectively, P = 0.49). The left atrial indexed maximum (LAVi max) and minimum (LAVi min) volumes were significantly larger in the post-capillary PH patient group than in the pre-capillary PH patient group (LAVi max: 64 ± 32 mL/m2 vs. 41 ± 25 mL/m2 , P = 0.001; LAVi min: 50 ± 22 mL/m2 vs. 26 ± 24 mL/m2 , P < 0.0001). The indexed right atrial minimum volume (RAVi min) was also higher in patients with post-capillary PH (51 ± 27 mL/m2 vs. 38 ± 26 mL/m2 ; P = 0.02). Both the left atrial (LA) and right atrial (RA) volumes, especially the LA minimum volume, correlated with the pulmonary artery wedge pressure (PAWP) (r = 0.62 (P < 0.0001) for LAV min vs. r = 0.49 (P < 0.0001) for LAV max; r = 0.32 (P = 0.005) for RAV min vs. r = 0.24 (P = 0.04) for RAV max). Multivariate logistic regression analysis showed that LAVi min was an independent predictor of post-capillary PH. In the receiver operating characteristic (ROC) curves of parameters predicting the post-capillary PH, the areas under the curve (AUC) for LAVi min, LAVi max, and RAVi min were 0.86 (95% CI, 0.76-0.95), 0.78 (95% CI, 0.67-0.89), and 0.66 (0.53-0.78), respectively. Concerning the performance of the atrial volume ratio for differentiating post-capillary PH, the AUC of the atrial volume ratio was significantly lower [AUC: 0.66 (95% CI, 0.53-0.78)]. The ROC analysis indicated a possible cutoff value of 27.7 mL/m2 for LAVi min to predict post-capillary PH (AUC = 0.86; sensitivity = 86%, specificity = 76%). CONCLUSIONS: The BSA-indexed left atrial minimum volume measured by transthoracic 3DE is a useful parameter for differentiating pre-capillary from post-capillary pulmonary hypertension.

Thermogenic Activation Downregulates High Mitophagy Rate in Human Masked and Mature Beige Adipocytes.

Thermogenic brown and beige adipocytes oxidize metabolic substrates producing heat, mainly by the mitochondrial uncoupling protein UCP1, and can thus counteract obesity. Masked beige adipocytes possess white adipocyte-like morphology, but can be made thermogenic by adrenergic stimuli. We investigated the regulation of mitophagy upon thermogenic activation of human masked and mature beige adipocytes. Human primary abdominal subcutaneous adipose-derived stromal cells (hASCs) and Simpson-Golabi-Behmel syndrome (SGBS) preadipocytes were differentiated to white and beige adipocytes, then their cAMP-induced thermogenic potential was assessed by detecting increased expressions of UCP1, mitochondrial DNA content and respiratory chain complex subunits. cAMP increased the thermogenic potential of white adipocytes similarly to beige ones, indicating the presence of a masked beige population. In unstimulated conditions, a high autophagic flux and mitophagy rates (demonstrated by LC3 punctae and TOM20 co-immunostaining) were observed in white adipocytes, while these were lower in beige adipocytes. Silencing and gene expression experiments showed that the ongoing mitophagy was Parkin-independent. cAMP treatment led to the downregulation of mitophagy through PKA in both types of adipocytes, resulting in more fragmented mitochondria and increased UCP1 levels. Our data indicates that mitophagy is repressed upon encountering a short-term adrenergic stimulus, as a fast regulatory mechanism to provide high mitochondrial content for thermogenesis.

[Multiple endocrine neoplasia type 2A in a family]. / A multiplex endokrin neoplasia-2A szindrómáról egy család kapcsán.

The authors present the case of a multiplex endocrine neoplasia type 2A (MEN2A). The 55-year-old woman underwent detailed examinations for abdominal complaints. Bilateral adrenal masses and thyroid nodular goiter were found. Based on metanephrine excretion and MIBG imaging, bilateral phaeochromocytomas were diagnosed. The thyroid nodules were confirmed by thyroidectomy as bilateral medullary thyroid carcinoma. Asymptomatic primary hyperparathyroidism was also detected. Laparoscopic adrenalectomy and parathyroid adenoma removal were performed. Based on family history and the characteristic clinical presentation, MEN2A syndrome was confirmed by genetic testing. During genetic screening of first-degree relatives, the patient's 25-year-old daughter was shown to be a gene carrier. Preventive thyroidectomy was performed and histology proved multifocal medullary thyroid cancer. In addition to the importance of genetic testing, the authors emphasize the guideline-based, but individualized approach to patients with suspected MEN2A syndrome. Orv Hetil. 2020; 161(2): 75-79.

High Genetic Diversity and No Evidence of Clonal Relation in Synchronous Thyroid Carcinomas Associated with Hashimoto's Thyroiditis: A Next-Generation Sequencing Analysis.

The close association between pre-existing Hashimoto's thyroiditis and thyroid cancer is well established. The simultaneous occurrence of multiple neoplastic foci within the same organ suggests a common genotoxic effect potentially contributing to carcinogenesis, the nature of which is still not clear. Next-generation sequencing (NGS) provides a potent tool to demonstrate and compare the mutational profile of the independent neoplastic foci. Our collection of 47 cases with thyroid carcinoma and Hashimoto's thyroiditis included 14 with at least two tumorous foci. Detailed histological analysis highlighted differences in histomorphology, immunoprofile, and biological characteristics. Further, a 67-gene NGS panel was applied to demonstrate the mutational diversity of the synchronic tumors. Significant differences could be detected with a wide spectrum of pathogenic gene variants involved (ranging between 5 and 18, cutoff >5.0 variant allele frequencies (VAF)). Identical gene variants represented in both synchronous tumors of the same thyroid gland were found in only two cases (BRAF and JAK3 genes). An additional set of major driver mutations was identified at variable allele frequencies in a highly individual setup suggesting a clear clonal independence. The different BRAF statuses in coincident thyroid carcinoma foci within the same organ outline a special challenge for molecular follow-up and therapeutic decision-making.

Interleukin-6 released from differentiating human beige adipocytes improves browning.

Brown and beige adipocytes contribute significantly to the regulation of whole body energy expenditure and systemic metabolic homeostasis not exclusively by thermogenesis through mitochondrial uncoupling. Several studies have provided evidence in rodents that brown and beige adipocytes produce a set of adipokines ("batokines") which regulate local tissue homeostasis and have beneficial effects on physiological functions of the entire body. We observed elevated secretion of Interleukin (IL)-6, IL-8 and monocyte chemoattractant protein (MCP)-1, but not tumor necrosis factor alpha (TNFα) or IL-1ß pro-inflammatory cytokines, by ex vivo differentiating human beige adipocytes (induced by either PPARγ agonist or irisin) compared to white. Higher levels of IL-6, IL-8 and MCP-1 were released from human deep neck adipose tissue biopsies (enriched in browning cells) than from subcutaneous ones. IL-6 was produced in a sustained manner and mostly by the adipocytes and not by the undifferentiated progenitors. Continuous blocking of IL-6 receptor by specific antibody during beige differentiation resulted in downregulation of brown marker genes and increased morphological changes that are characteristic of white adipocytes. The data suggest that beige adipocytes adjust their production of IL-6 to reach an optimal level for differentiation in the medium enhancing browning in an autocrine manner.

Thyroid Carcinoma Coexisting with Hashimoto's Thyreoiditis: Clinicopathological and Molecular Characteristics Clue up Pathogenesis.

Thyroid cancer (TC) coexisting with Hashimoto's thyroiditis (HT) presents with several characteristic features including multifocality and lower clinical stages compared to de novo carcinomas but its exact biology is still not understood. We reexamined clinico-pathological and molecular correlations between Hashimoto's thyroditis and papillary thyroid cancer. A total of 262 patients with TC was evaluated who underwent thyroidectomy at the Surgical Department of the University of Debrecen. Clinical data, histology and molecular data were evaluated. Our cohort included 43 patients (16.4%) with (5 male, 38 female) and 219 (83.6%) patients without coexisting HT (48 male, 171 female). Hashimoto's thyroiditis related thyroid cancer presented predominantly (93.0% of the cases) with the papillary histological type. Multifocality was observed more frequently with coexisting HT (16/40; 40.0%) compared to cases uninvolved (45/190; 23.7%)(p = 0.034). In contrast, lymphatic metastasis (pN1) with a significantly reduced frequency in patients with HT (4/11; 36.4%) then without HT (34/41 pN1; 82.9%)(p = 0.002). BRAF V600E mutation could be demonstrated at significantly lower rates in cases of PTC + HT (32.1 vs 60.7%, p < 0.005). High incidence, multifocality and papillary morphology strongly support a causal relation between TC and preexisting Hashimoto's thyroiditis, the latter to be considered as a preneoplastic condition promoting thyroid carcinogenesis.

The impact of post-radioiodine therapy SPECT/CT on early risk stratification in differentiated thyroid cancer; a bi-institutional study.

OBJECTIVE: SPECT/CT has numerous advantages over planar and traditional SPECT images. The aim of this study was to evaluate the role of post-radioiodine therapy SPECT/CT of patients with differentiated thyroid cancer (DTC) in early risk classification and in prediction of late prognosis. PATIENTS AND METHODS: 323 consecutive patients were investigated after their first radioiodine treatment (1100-3700 MBq). Both whole body scan and SPECT/CT images of the head, neck, chest and abdomen regions were taken 4-6 days after radioiodine therapy. Patients were re-evaluated 9-12 months later as well as at the end of follow up (median 37 months). RESULTS: Post-radioiodine therapy SPECT/CT showed metastases in 22% of patients. Lymph node, lung and bone metastases were detected in 61, 13 and 5 patients, respectively, resulting in early reclassification of 115 cases (36%). No evidence of disease was found in 251 cases at 9-12 months after radioiodine treatment and 269 patients at the end of follow-up. To predict residual disease at the end of follow-up, the sensitivities, specificities and diagnostic accuracies of the current risk classification systems and SPECT/CT were: ATA: 77%, 47% and 53%; ETA: 70%, 62% and 64%; SPECT/CT: 61%, 88% and 83%, respectively. There was no difference between cohorts of the two institutions when data were analyzed separately. CONCLUSIONS: Based on our bi-institutional experience, the accuracy of post-radioiodine SPECT/CT outweighs that of the currently used ATA and ETA risk classification systems in the prediction of long-term outcome of DTC.

[Clinico-pathological features of papillary thyroid cancer coexistent with Hashimoto's thyroiditis]. / A Hashimoto-thyreoiditisben kialakuló papillaris pajzsmirigy-carcinoma klinikopatológiai jellegzetességei.

INTRODUCTION AND AIM: Former studies suggest the frequent coexistence of Hashimoto's thyreoditis with papillary thyroid cancer, frequently featured by multifocal carcinogenesis but lower clinical stages compared to thyroid cancers lacking thyroiditis. We examined the clinico-pathological correlations between Hashimoto's thyroditis and papillary thyroid cancer in our region in the North-Eastern part of Hungary. PATIENTS AND METHOD: We included a total of 230 patients with papillary thyroid cancer who underwent thyroid surgery at the Surgical Department of the University of Debrecen. Patients' sex, age, multifocality of thyroid cancer and clinical stage were evaluated. RESULTS: Cases included 40 patients (17.4%) with (4 male, 36 female) and 190 (82.6%) patients without HT (44 male, 146 female). Hashimoto's thyroiditis related thyroid cancer was almost exclusively associated with the papillary histological type. Multifocality of papillary cancer was significantly more frequent with coexisting Hashimoto's thyroiditis (16/40; 40.0%) compared to cases uninvolved (45/190; 23.7%; p = 0.034). In contrast, lymph node metastasis was significantly less frequent among patients with Hashimoto's thyroiditis (4 pN1 [36.4%]; 7 pN0 [63.6%]) then without it (34 pN1 [82.9%]; 7 pN0 [17.1%]; p = 0.002). CONCLUSION: Higher frequency and multifocality of papillary thyroid cancer might be the consequence of preexisting Hashimoto's thyroiditis to be considered as a preneoplastic stimulus supporting carcinogenesis, though the exact pathomechanism of this correlation is not clear yet. Orv. Hetil., 2017, 158(5), 178-182.

[Novel treatment opportunities in Graves' orbitopathy]. / Új lehetoségek az endokrin orbitopathia kezelésében.

Graves' orbitopathy is the most common extrathyroidal manifestation of Graves' disease. Up to now, curative treatment modalities for the most severe sight-threatening cases have not been developed. Here the authors summarize the treatment protocol of Graves' orbitopathy and review novel therapeutic options. They review the literature on this topic and present their own clinical experience. The authors point out that anti-CD20 antibody could positively influence the clinical course of Graves' orbitopathy. Selenium is efficient in mild cases. Further prospective investigations are warranted.

Amplification of thymosin beta 10 and AKAP13 genes in metastatic and aggressive papillary thyroid carcinomas.

Papillary thyroid carcinoma (PTC) is the most common well-differentiated thyroid cancer. Although the great majority of the cases exhibit an indolent clinical course, some of them develop local invasion with distant metastasis, and a few cases transform into undifferentiated/anaplastic thyroid carcinoma with a rapidly lethal course. To identify gene copy number alterations predictive of metastatic potential or aggressive transformation, array-based comparative genomic hybridization (CGH-array) was performed in 43 PTC cases. Formalin-fixed and paraffin-embedded samples from primary tumours of 16 cases without metastasis, 14 cases with only regional lymph node metastasis, and 13 cases with distant metastasis, recurrence or extrathyroid extension were analysed. The CGH-array and confirmatory quantitative real-time PCR results identified the deletion of the EIF4EBP3 and TRAK2 gene loci, while amplification of thymosin beta 10 (TB10) and Tre-2 oncogene regions were observed as general markers for PTC. Although there have been several studies implicating TB10 as a specific marker based on gene expression data, our study is the first to report on genomic amplification. Although no significant difference could be detected between the good and bad prognosis cases in the A-kinase anchor protein 13 (AKAP13) gene region, it was discriminative markers for metastasis. Amplification in the AKAP13 region was demonstrated in 42.9% and 15.4% of the cases with local or with distant metastasis, respectively, while no amplification was detected in non-metastatic cases. AKAP13 and TB10 regions may represent potential new genomic markers for PTC and cancer progression.

Well differentiated thyroid carcinoma is associated with human lymphocyte antigen D-related 11 in Eastern Hungarians: a case of changing circumstances.

BACKGROUND: Using serologic human lymphocyte antigen (HLA) typing, the authors previously described a strong association between well differentiated thyroid carcinoma and HLA D-related 1 (HLA-DR1) in a population of unselected patients from Eastern Hungary. METHODS: In the current study, the authors used polymerase chain reaction-single strand conformational polymorphism to determine the HLA-DR type in 75 patients with well differentiated thyroid carcinoma from the same area as their previous population, and they compared the current results with the results from a group of 170 healthy controls. RESULTS: A significant increase in HLA-DR11, rather than HLA-DR1, was observed in patients with well differentiated thyroid carcinoma among a population of patients from the same area that was studied previously. After excluding technical reasons to account for differences in disease association, they postulated that interim environmental factors, possibly radiation fall-out, may have resulted in differences in genetic susceptibility to thyroid carcinoma. Consideration of the potential antigenic peptides that may be restricted by the two HLA-DR alleles may have allowed for the binding of similar peptides to initiate an immune response, likely leading to progressive immunomodulation of the tumor. Discriminat function analysis indicated a significant relation between tumor size and metastases and less lymphocytic infiltration of the tumor, but this was not related to HLA-DR phenotypes. CONCLUSIONS: The authors found that the study of major histocompatability complex alleles holds promise for understanding the events that initiate and maintain tumor immunomodulation.

Oncogene amplification and overexpression of oncoproteins in thyroid papillary cancer.

BACKGROUND: Several oncogene aberrations have been found in papillary thyroid cancer, the incidence of which has increased after the accident in Chernoby. The occurrence and prognostic significance of these aberrations may have importance in therapeutic strategies. MATERIALS AND METHODS: Tumour tissues from 24 patients were investigated by Dot-blot DNA hybridisation for c-myc, Ha-ras amplification and p53 deletion, and by immunohistochemical method for cyclin D1, p53 and p21 overexpression. RESULTS: Overexpression of p53 protein was detected in 66.6%, with p21 expression (25%) without any influence on tumour phenotype. Cyclin D1 overexpression was found in 50% to be associated with p21, in inverse relation to Iymphocytic infiltration. Overexpression of estrogen receptor was shown in 4 cyclin D1-positive samples (17%). CONCLUSION: Our results suggest that cyclin D1 overexpression is associated with poor prognosis. The co-expression of cyclin D1 and p21 causes a CDK-independent, estrogen receptor-mediated effect of the cyclin D1 also described in breast cancer.