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Multifocal growth is characteristic of hereditary medullary thyroid cancer (MTC), whereas origin and impact of multifocal growth is enigmatic for sporadic MTC. To address this, 460 RET-negative patients with sporadic MTC, stratified by 1 (93.3 %), 2 (5.7 %) and 3 (1.1 %) thyroid tumor foci, were compared with 219 RET-positive patients with hereditary MTC, stratified by 1 (38.4 %), 2 (45.7 %), 3 (6.4 %), 4 (6.8 %) and ≥5 (2.7 %) thyroid tumor foci. For sporadic MTC, significant associations were identified with bilateral thyroid lobe involvement, microscopic lymphatic invasion, extrathyroid extension, node and distant metastases, number of node metastases, preoperative basal calcitonin level, and decreasing biochemical cure. For hereditary MTC, significant associations were limited to bilateral thyroid lobe involvement, largest thyroid tumor diameter, and preoperative basal calcitonin level. In sporadic MTC, multifocal growth is due to lymphatic invasion with frequent node metastases, whereas in hereditary MTC, it reflects malignant progression from C-cell hyperplasia to cancer., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported., (Copyright © 2024 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Detectable, and especially rising postthyroidectomy serum calcitonin and carcinoembryonic antigen levels, as per American Thyroid Association guidelines, indicate potential disease presence, requiring frequent calcitonin measurement or imaging for early detection of persistent or recurrent medullary thyroid carcinoma. Thus, defining the clinical cutoff value of detection of calcitonin assays relative to imaging and clinical status is crucial for patient care. This study aimed to evaluate postoperative calcitonin levels using the new Siemens Atellica assay system to determine the most appropriate levels for clinical decision-making., Methods: A retrospective analysis was conducted using Siemens Atellica for calcitonin testing on 56 samples from 40 patients between September 27, 2022 and August 11, 2023. Only calcitonin results performed at least 3 months post-total thyroidectomy were included. Imaging studies, within 6 months of the calcitonin report, were assessed. Carcinoembryonic antigen results were also reviewed., Results: Precision analysis at 2.94 and 5.24 pg/mL revealed coefficients of variation at 16.49% and 8.87%, respectively. For the evidence of post-total thyroidectomy persistent or recurrent medullary thyroid carcinoma confirmed by imaging, using a 1.89 pg/mL cutoff for calcitonin yielded 43% sensitivity and 67% specificity. Using a 5.00 pg/mL cutoff resulted in 0% sensitivity and 100% specificity., Conclusions: Our findings indicate the potential suitability of a 5 pg/mL calcitonin cutoff on the Siemens Atellica platform for evaluating tumor persistence or recurrence in post-thyroidectomy patients in our institution. However, individual laboratories should establish their own clinical cutoff value when evaluating calcitonin levels for monitoring tumor recurrence post-thyroidectomy., Competing Interests: Disclosure The authors declare that the article does not contain previously published material, and is not under consideration for publication elsewhere. Each author has made an important scientific contribution to the study and is thoroughly familiar with the primary data. All the authors listed have read the complete manuscript and have approved submission of the paper. The manuscript is a truthful original work without fabrication, fraud or plagiarism. The authors have no conflicts of interest to disclose., (Copyright © 2024 AACE. Published by Elsevier Inc. All rights reserved.)

Background: Conceptually, thyroid tumor desmoplasia may be better suited for excluding node metastases in sporadic MTC than preoperative serum calcitonin levels., Methods: This analysis included 181 patients with unilateral sporadic MTC graded on the 7-grade desmoplasia scale after thyroidectomy and neck dissection., Results: When thyroid tumor desmoplasia reached 1% and ≥50%, node metastases increased from 0% to 7% (median of 0 metastases) and 83% (median of 7.5 metastases), microscopic lymphatic invasion from 0% to 3% and 35%, extrathyroid extension from 0% to 5% and 22%, and extranodal growth from 0% to 0% and 44%, whereas biochemical cure declined from 100% to 95% and 25%. Thyroid tumor diameters and basal calcitonin overlapped widely among the seven desmoplasia groups, precluding differentiation by thyroid tumor size or serum calcitonin levels., Conclusions: Thyroid tumor desmoplasia, unlike serum calcitonin levels, discriminates extremely well between node-negative and node-positive sporadic MTC, opening new avenues for precision surgery., (© 2024 Wiley Periodicals LLC.)

MANAGING MEDULLARY THYROID CARCINOMA IN 2024: Medullary thyroid carcinoma is a rare neuroendocrine thyroid cancer with a heterogeneous prognosis which has the particularity of being associated with a RET gene mutation, germline in 20-25% of cases in the context of multiple endocrine neoplasia type 2 (NEM2), and somatic in 70% of sporadic cases. It is often diagnosed on a thyroid nodule or in the context of genetic screening. Calcitonin is a biological marker, used for diagnosis, monitoring of therapeutic response and prognostic evaluation. The only curative treatment is surgery for localized disease. The extent must be carefully assessed, particularly in terms of calcitonin levels and imaging, and carried out by an expert surgeon. The prognosis of locally advanced or metastatic disease is highly heterogeneous. Histological factors, such as high grade, or biological factors, such as calcitonin doubling time, can help assess prognosis. The development of multi-kinase inhibitors cabonzantinib and vandetanib, and RET-targeted inhibitors selpercatinib, has completely changed the therapeutic arsenal for advanced disease, but their prescription is reserved to progressive disease with high tumor volume or to symptomatic disease inaccessible to local treatment in expert centers from the ENDOCAN-TUTHYREF network. Active surveillance is the alternative of choice for slowly progressing disease., Competing Interests: Liens d’intérêts H. Lasolle, F. Borson-Chazot, T. Gauduchon, M. Haissaguerre, F. Illouz, J.-C. Lifante, C. Lussey-Lepoutre, D. Prunier, C. Sajous et R. Varnier déclarent ne pas avoir de liens d’intérêts. J. Hadoux déclare avoir des liens d’intérêts pour grants/research support de la part du laboratoire Lilly; pour des honoraires versés par les laboratoires Lilly, Ipsen, Bayer, PharmaMAr, Roche, HRA pharma, AAA et Eisai. Cet article fait partie du supplément Prise en charge des cancers thyroïdiens en 2024 : avancées diagnostiques et thérapeutiques réalisé avec le soutien institutionnel de Lilly., (Copyright © 2024 Elsevier Masson SAS. Tous droits réservés. Published by Elsevier Masson SAS. All rights reserved.)

Calcitonin (CT), a hormone secreted by thyroid parafollicular C cells, plays a role in calcium homeostasis and bone health. Understanding the relationship between CT levels and dietary, sociodemographic, and lifestyle factors is essential for public health and hormonal balance studies. This study encompassed 3323 healthy participants from the Croatian biobank. We utilized principal component analysis (PCA) to reduce food items into dietary patterns. Regression analysis was used to investigate the relationship between CT levels and data collected through questionnaires, accounting for age and sex. CT levels exhibited sex-specific differences, with higher values observed in males. Positive associations were found between CT levels and age, body mass index (BMI), as well as weekly consumption of white and red wine mixed with water. While height and sternal notch-finger length initially correlated positively with CT levels, this relationship reversed upon adjusting for age and sex. Regarding sport activities, CT levels were significantly increased in non-participants compared to occasional sport participants (p = 0.043). Dietary factors yielded intriguing findings, with frequent consumption of butter, animal fat and veal associated with lower CT levels, while higher CT levels were associated with the frequent consumption of white fish, blue fish, pasta, and rice. However, no significant correlation was found between CT levels and bone mineral density (BMD), weight, or body surface area (BSA). This study highlights the complex interplay of dietary, lifestyle, and sociodemographic factors influencing CT levels. These findings suggest that a broad range of factors should be considered in hormonal balance studies, underlining their potential implications for public health., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: The survival rate of patients with medullary thyroid carcinoma (MTC) who fail to achieve a biochemical cure after surgery is reduced. This study aimed to investigate the prognostic factors affecting the survival of MTC patients who do not achieve a biochemical cure after surgery., Methods: Cox univariate and multivariate proportional hazard models were used to determine the influence of different variables on overall survival (OS). Pearson's chi-square test was used for categorical variables, and paired t-test was used for continuous variables., Results: In our study of 277 MTC patients treated between 2012 and 2022, there were 96 with raised postoperative 1-month calcitonin (Ct) levels (0-9.52 pg/ml). The overall survival (OS) rates of patients with high postoperative 1-month Ct values at 1, 3, and 5 years were 97.9%, 94.6%, and 86.8%, respectively. The univariate analysis revealed that patients with a postoperative 1-month Ct > 441.9 pg/ml had a greater risk of mortality than patients with postoperative 1-month Ct values ranging from 9.52 to 73.4 pg/ml (p = 0.043). Subsequent analyses revealed that receiving targeted therapy did not improve the OS of patients with distant metastasis among those with high postoperative 1-month Ct values (p = 0.527)., Conclusion: This study confirmed that MTC patients who did not achieve biochemical remission after surgery had an increased risk of death when the Ct level was > 441.9 pg/ml 1 month after surgery. Additionally, for MTC patients who have not achieved biochemical remission and have experienced disease progression or distant metastasis after surgery, the use of targeted therapy does not prolong survival., (© 2024. The Author(s).)

Medullary thyroid carcinoma (MTC) comprises less than 5% of thyroid cancers but is responsible for over 10% of deaths related to thyroid cancer. Regional lymph node metastasis is common and associated with mortality, thus total thyroidectomy with central compartment lymph node dissection is the standard surgical treatment for MTC. In this best practice submission, we aim to review the existing literature and determine whether calcitonin levels can serve as a reliable method for risk-stratifying MTC without overt lymph node involvement., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: To explore individualized treatment and management methods for medullary thyroid microcarcinoma (MTMC)., Methods: Clinical data of patients with medullary thyroid carcinoma with a diameter ≤1 cm admitted to the First Affiliated Hospital of Kunming Medical University from June 2013 to June 20× were collected. Combined with different treatment guidelines for medullary thyroid carcinoma, factors affecting lymph node metastasis and postoperative disease status were analyzed., Results: Twenty-nine patients with MTMC were included in the analysis, including 24 patients who underwent total thyroidectomy, 5 who underwent thyroid gland lobectomy, and 13 who experienced postoperative lymph node metastasis. Multifocal tumor and calcitonin (Ctn) were the influencing factors, while multifocal tumor, Ctn, lymph node metastasis, and AJCC stage affected the dynamic risk stratification of postoperative disease., Conclusion: Calcitonin detection is an important method for detecting MTMC. A tumor diameter ≤1 cm does not indicate that the tumor is in the early stage. The presence of multifocal tumors and Ctn should be used as important indicators for preoperative evaluation. Dynamic stratified risk assessment is critical in postoperative follow-up., Competing Interests: Compliance with ethical standards Conflict of interest The authors declare no competing interests. Ethics approval Approval of the research protocol by an Institutional Review Board: This research met all the guidelines outlined in the Declaration of Helsinki and was approved by Kunming Medical University First Affiliated Hospital’s Ethical Committee (2020) L no. 2)., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Calcitonin is a sensitive marker for medullary thyroid carcinoma (MTC) diagnosis and postsurgical follow-up. This study aimed to define the gender and tumor size-specific calcitonin cutoff values for diagnosing MTC., Methods: This retrospective study recruited 95 MTC patients and 10,523 non-MTC patients who underwent thyroid nodule surgery at Zhongshan Hospital between January 2015 and June 2023. Receiver operating characteristic (ROC) curves were used to assess calcitonin cutoff values for diagnosing MTC., Results: Calcitonin levels in non-MTC patients were influenced by gender, CKD stage and age, with gender being the highest ranked predictor. In MTC patients, calcitonin levels were associated with tumor diameter, lymph node metastasis, and TNM stage. In the entire study population, calcitonin cutoff values to diagnose MTC were 17.75 pg/mL for males (sensitivity: 97.60%, specificity: 99.40%) and 7.15 pg/mL for females (sensitivity: 94.34%, specificity: 99.22%). In patients with a thyroid nodule diameter ≤10 mm, the calcitonin cutoff values to diagnose MTC were 17.50 pg/mL for males (sensitivity: 95.00%, specificity: 99.27%) and 7.15 pg/mL for females (sensitivity: 90.91%, specificity: 99.04%). In patients with a thyroid nodule diameter >10 mm, the calcitonin cutoff values to diagnose MTC were 104.80 pg/mL for males (sensitivity: 100.00%, specificity: 100.00%) and 32.60 pg/mL for females (sensitivity: 96.77%, specificity: 100.00%)., Conclusion: We have identified the gender and tumor size-specific cutoff values for the diagnosis of MTC. Cutoff values based on gender and tumor diameter may help to improve the accuracy of preoperative diagnosis of MTC, which is worth to be verified by future studies., Competing Interests: Compliance with ethical standards Conflict of interest The authors declare no competing interests. Ethical approval This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Zhongshan Hospital affiliated to Fudan University. Consent to participate Written informed consent was obtained from the parents., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: This work aim to evaluate the association of procalcitonin (PCT) levels with disease severity and prognosis in severe fever with thrombocytopenia syndrome (SFTS) patients., Methodology: The medical records of 158 confirmed SFTS patients at two hospitals were reviewed. The patients were divided into survival group and nonsurvival group according to outcomes. Additionally, to assess mortality rates at different PCT levels, patients were divided into two groups, PCT < 0.25 ng/mL and PCT ≥ 0.25 ng/mL., Results: Among the 158 confirmed SFTS patients, 26 died; the case fatality rate was 16.46%. PCT data were available for 132 of these patients; 66 were in the PCT < 0.25 ng/mL group, and 66 were in the PCT ≥ 0.25 ng/mL group. The SFTS patients had abnormal results on routine blood tests, indicating varying degrees of thrombocytopenia and leukopenia, and most patients presented with multiple organ dysfunction. The PCT level of the nonsurvival group was significantly higher than that of the survival group (p < 0.01). Additionally, the mortality of the PCT ≥ 0.25 ng/mL group was significantly higher than that of the PCT < 0.25 ng/mL group (p < 0.01); mortality increased sharply ( ≥ 25%) when the PCT level exceeded 0.1 ng/mL., Conclusions: PCT levels in SFTS patients are closely related to the severity and prognosis of their illness. The serum PCT level is a promising predictor of mortality and severity in SFTS patients when considered in combination with clinical data and other laboratory tests., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2024 Wenjie Wang, Yang Yang, Manman Liang, Aiping Zhang, Zhaoru Zhang, Jianghua Yang.)

Purpose: There is still controversy in different guidelines regarding the necessity of routine preoperative calcitonin (Ctn) testing in medullary thyroid cancer (MTC). The level of preoperative Ctn may influence the extent of surgery., Methods: This retrospective multicenter cohort study involved 149 MTC patients from 6 centers between 2013 to 2023. Clinical characteristics, surgical procedure and clinical outcomes were compared between Ctn-screened and Non-screened group. Kaplan-Meier method was used to estimate recurrence-free survival (RFS) and overall survival (OS)., Results: In total, 127 MTC patients with preoperative Ctn screening and 22 MTC patients without screening were analyzed. MTC patients with preoperative Ctn screening underwent more radical surgical procedures including total thyroidectomy and lymph node dissection, compared to those without screening (84.3% vs. 68.2% and 91.3% vs. 72.7%, respectively). The rate of recurrence and death were lower in the Ctn-screened group (16.1% vs. 36.4%, 0.8% vs. 18.2%, respectively). The survival curve showed a significantly better overall survival in Ctn-screened group than Non-screened group (HR:17.932, 95% CI 1.888-170.294, p-value = 0.001), while no significant difference was observed of RFS between two groups (HR:1.6, 95% CI 0.645-3.966, p-value = 0.307)., Conclusion: Preoperative Ctn screening can prompt surgeons choosing more radical initial surgical treatment for MTC patients, potentially leading to better long-term outcomes. Further evaluation of the cost-effectiveness of routine Ctn screening in thyroid nodule patients is warranted., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Increased exposure to fluoride, which notably affects bone metabolism, is a global concern. However, the correlations and sensitivity of bone metabolism to fluoride remain controversial. In this cross-sectional study, 549 children (aged 7-12 years) and 504 adults (≥ 18 years old) were recruited in the high-fluoride areas of the Henan Province. Urinary fluoride (UF) level was determined using a fluoride electrode. Fasting venous blood serum was collected to measure bone metabolism biomarkers. The selected bone metabolism biomarkers for children included bone alkaline phosphatase (BALP), serum alkaline phosphatase (ALP), osteocalcin (OCN), calcitonin (CT), parathyroid hormone (PTH), phosphorus (P 5+ ), and calcium (Ca 2+ ). For adults, the biomarkers included ALP, CT, PTH, β-CrossLaps (β-CTX), P 5+ , and Ca 2+ . The correlations between UF and bone metabolism biomarkers were analyzed using binary logistic regression, a trend test, a generalized additive model, and threshold effect analysis. Regression analysis indicated a significant correlation between serum OCN, PTH, and UF levels in children aged 7-9 years. Serum OCN, PTH, and BALP contents were significantly correlated with UF in boys (P < 0.05). Furthermore, the interaction between age and UF affected serum P 5+ and PTH (P < 0.05). The generalized additive model revealed nonlinear dose-response relationships between P 5+ , BALP, and UF contents in children (P < 0.05). Serum OCN level was linearly correlated with the UF concentration (P < 0.05). Similarly, a significant correlation was observed between β-CTX and UF levels in adults. In addition, significant correlations were observed between UF-age and serum Ca 2+ , β-CTX, and PTH contents. There was a non-linear correlation between serum Ca 2+ , P 5+ , and β- CTX and UF levels (P < 0.05). Overall, serum OCN, BALP, and P 5+ levels can serve as sensitive bone metabolism biomarkers in children, while β-CTX, P 5+ , and Ca 2+ can be considered fluoride-sensitive bone metabolism biomarkers in adults., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Objective: To evaluate the prevalence of euthyroid sick syndrome (ESS) in sepsis patients and to explore its influencing factors., Methods: In the study, 365 patients diagnosed with sepsis in the emergency critical care department of Shanghai First People's Hospital from January 2017 to January 2023 were retrospectively enrolled. The patients were divided into ESS and non-ESS groups based on whether the patients were complicated with ESS.Baseline variables and relevant clinical data of the enrolled patients were collected. The prevalence of ESS in sepsis patients and its influencing factors were evaluated by multivariate Logistic regression analysis, and the 30-day survival rates were compared between the two groups. The optimal cutoff value for free triiodothyronine (FT3) was explored to predict death in the patients with sepsis., Results: There were 103 sepsis patients with ESS, accounting for 28.2% of the total cases. The severity of sepsis in ESS group was significantly higher than that in non-ESS group ( P < 0.05). The acute physiology and chronic health evaluationⅡ(APACHEⅡ)score and sequential organ failure assessment (SOFA) score of ESS group were significantly higher than those of non-ESS group ( P < 0.05). C-reactive protein (CRP), procalcitonin (PCT), serum amyloid A (SAA) and interleukin-6 (IL-6) in ESS group were higher than those in non-ESS group. total cholesterol(TC)and high-density liptein cholesterol(HDL-C)in ESS group were lower than those in non-ESS group, and the differences were statistically significant ( P < 0.05).Multivariate Logistic regression analysis showed that PCT, IL-6, CRP, SAA and activated partial thromboplatin time (APTT) were independent risk factors for ESS in the sepsis patients ( OR values were 1.105, 1.006, 1.005, 1.009 and 1.033, respectively; 95% CI were 1.044-1.170, 1.001-1.012, 1.001-1.009, 1.005-1.014, 1.004-1.062, respectively, P < 0.05).The 30-day survival rate in ESS group was significantly lower than that in non-ESS group, the Long-rank chi-square test value was 16.611, and the difference was statistically significant ( P < 0.05).The receiver operation characteristic area under the curve (AUCROC)of FT3 predicted death in the patients with sepsis was 0.924 (95% CI 0.894-0.954). The serum FT3 cutoff point was 3.705 pmol/L, the specificity was 0.868, and the sensitivity was 0.950., Conclusion: In this study, the incidence of ESS in sepsis patients was determined to be 28.2% with poor prognosis. The results showed that PCT, IL-6, CRP, SAA and APTT were independent risk factors for ESS in sepsis patients, while HDL-C was a protective factor ( P < 0.05). FT3 is a novel potential biomarker for predicting death in patients with sepsis.

Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor originating from the parafollicular cells (C cells) of the thyroid gland, classified as sporadic and hereditary. Calcitonin (Ctn) secreted by the C cells is a specific serological marker for MTC, which is of great value in diagnosis, treatment and postoperative management of MTC. The effect of chemoradiotherapy and 131 I therapy on MTC is limited, with surgery being the primary therapy. Given the aggressive nature and relatively poor prognosis of MTC, the reasonable surgical extent is crucial for improving cure rate and prognosis of patients. However, there are still some controversies regarding the extent of surgery for MTC. This article elaborates on the research progress and controversies of serum Ctn levels in assisting the evaluation of the extent of surgery for MTC.

Neuroendocrine neoplasms can produce multiple hormones that are released into the bloodstream, causing symptoms that vary depending on the type and quantity of hormones involved. We herein report a 63-year-old asymptomatic patient with pancreatic insulinoma who showed marked elevations in circulating calcitonin and procalcitonin levels that returned to normal following surgery. Immunohistochemical analyses confirmed the co-staining of calcitonin and insulin immunoreactivity in the tumor cells, suggesting a calcitonin-producing insulinoma. This insulinoma released calcitonin and a considerable amount of its precursor peptide, procalcitonin, resulting in both hyperprocalcitoninemia and hypercalcitoninemia.

Background: Medullary thyroid carcinoma (MTC) is a malignant tumor with low incidence. Currently, most studies have focused on the prognostic risk factors of MTC, whatever, time kinetic and risk factors related to calcitonin normalization (CN) and biochemical persistence/recurrence (BP) are yet to be elucidated., Methods: A retrospective study was conducted for 190 MTC patients. Risk factors related to calcitonin normalization (CN) and biochemical persistence/recurrence (BP) were analyzed. The predictors of calcitonin normalization time (CNT) and biochemical persistent/recurrent time (BPT) were identified. Further, the prognostic roles of CNT and BPT were also demonstrated., Results: The 5- and 10-year DFS were 86.7% and 70.2%, respectively. The 5- and 10-year OS were 97.6% and 78.8%, respectively. CN was achieved in 120 (63.2%) patients, whereas BP was presented in 76 (40.0%) patients at the last follow up. After curative surgery, 39 (32.5%) and 106 (88.3%) patients achieved CN within 1 week and 1 month. All patients who failed to achieve CN turned to BP over time and 32/70 of them developed structural recurrence. The median time of CNT and BPT was 1 month (1 day to 84 months) and 6 month (3 day to 63months), respectively. LNR > 0.23 and male gender were independent predictors for CN and BP. LNR > 0.23 (Hazard ratio (HR), 0.24; 95% CI,0.13-0.46; P < 0.01) and male gender (HR, 0.65; 95% CI, 0.42-0.99; P = 0.045) were independent predictors for longer CNT. LNR > 0.23 (HR,5.10; 95% CI,2.15-12.11; P < 0.01) was still the strongest independent predictor followed by preoperative serum Ctn > 1400ng/L (HR,2.34; 95% CI,1.29-4.25; P = 0.005) for shorter BPT. In survival analysis, primary tumor size > 2 cm (HR, 5.81; 95% CI,2.20-15.38; P < 0.01), CNT > 1 month (HR, 5.69; 95% CI, 1.17-27.61; P = 0.031) and multifocality (HR, 3.10; 95% CI, 1.45-6.65; P = 0.004) were independent predictor of DFS., Conclusion: Early changes of Ctn after curative surgery can predict the long-term risks of biochemical and structural recurrence, which provide a useful real-time prognostic information. LNR significantly affect the time kinetic of biochemical prognosis. Tumor burden and CNT play a crucial role in MTC survival, the intensity of follow-up must be tailored accordingly., (© 2024. The Author(s).)

Purpose: Medullary thyroid carcinoma (MTC) in MEN2B syndrome is associated with germline RET mutation. Patients harboring de novo mutations are usually diagnosed at more advanced disease stages. We present a young woman with Met918Th mutation diagnosed with stage IV MTC at age 10 years., Methods: The disease progressed despite total thyroidectomy and multiple surgical interventions for cervical lymph node recurrences, leading to distant metastases in the fifth year after the initial diagnosis. Subsequently, she underwent five different types of tyrosine kinase inhibitor (TKI) treatments. The 17-year disease course was divided into periods defined by four surgical interventions and sequential treatment intervals with four multikinase (sunitinib, vandetanib, cabozantinib, and lenvatinib) and one RET-selective TKI (selpercatinib). Tumor growth for different phases of spontaneous development and drug treatment intervals was characterized by changes in serial log-transformed calcitonin measurements (n = 114)., Results: Three operations (one for calcitonin-producing adrenal pheochromocytoma) were associated with drops in calcitonin levels. All of the nonselective TKIs were stopped due to adverse effects. As reflected by the negative calcitonin doubling rate, the best treatment response was observed with selpercatinib, which was associated with an initial large drop followed by a decreasing calcitonin trajectory over 514 days without any major side effects., Conclusion: This case of MEN2B medullary thyroid cancer with long-term survival presents how the effectiveness of different treatment modalities can be estimated using log-transformed calcitonin levels. Furthermore, our experience supports the view that serial calcitonin measurements may be more sensitive than radiological follow-up in advanced MTC. Our patient also represents a new case of rarely reported calcitonin-producing pheochromocytomas.

Objective: To analyze the early diagnostic value of plasma soluble cluster of differentiation 14 subtype (sCD14-ST, Presepsin) in sepsis in a population with suspected sepsis in fever clinic., Methods: A prospective observational study was conducted. The patients admitted to the fever clinic of Beijing Chaoyang Hospital from April to December 2022 were enrolled as the study objects. According to sequential organ failure assessment (SOFA) score, the patients were divided into low SOFA score group (SOFA score ≤3) and high SOFA score group (SOFA score > 3). Venous blood was collected at the time of admission. The level of plasma Presepsin was detected by chemiluminescence enzyme-linked immunoassay. The level of plasma procalcitonin (PCT) was detected by enzyme-linked immunofluorescence method. The level of C-reactive protein (CRP) was detected by scattering turbidimetry. White blood cell count (WBC) and neutrophil count (NEUT) were measured by automatic blood cell analyzer. For patients with fear of cold or chills, venous blood of upper limbs was taken for blood culture at the time of admission. The differences in inflammatory biomarkers were compared between the two groups. Binary multivariate Logistic regression analysis was used to screen the early risk factors of sepsis in fever outpatients with suspected sepsis. Receiver operator characteristic curve (ROC curve) was drawn to investigate the early diagnostic value of Presepsin and other inflammatory markers in sepsis, and to analyze the optimal cut-off value., Results: A total of 149 fever outpatients with suspected sepsis were enrolled, including 92 patients with low SOFA score and 57 patients with high SOFA score. Plasma PCT and Presepsin levels in the high SOFA score group were significantly higher than those in the low SOFA score group [PCT (μg/L): 0.77 (0.18, 2.02) vs. 0.22 (0.09, 0.71), Presepsin (ng/L): 1 129.00 (785.50, 1 766.50) vs. 563.00 (460.50, 772.25), both P < 0.01]. There was no significant difference in WBC, NEUT, CRP or positive rate of blood culture between the high and low SOFA score groups [WBC (×10 9 /L): 11.32±5.47 vs. 11.14±5.29, NEUT (×10 9 /L): 9.88±4.89 vs. 9.60±5.10, CRP (mg/L): 54.05 (15.95, 128.90) vs. 46.11 (19.60, 104.60), blood culture positivity rate: 42.3% (11/26) vs. 29.4% (10/34), all P > 0.05]. Multivariate Logistic regression analysis showed that Presepsin was an early risk factor for sepsis in suspected sepsis patients in fever clinics [odds ratio (OR) = 16.96, 95% confidence interval (95%CI) was 6.35-45.29, P = 0.000]. ROC curve analysis showed that the early diagnostic value of Presepsin in sepsis was significantly better than WBC, NEUT, CRP, PCT, and blood culture [the area under the ROC curve (AUC) and 95%CI: 0.832 (0.771-0.899) vs. 0.522 (0.424-0.619), 0.532 (0.435-0.629), 0.533 (0.435-0.632), 0.664 (0.574-0.753), 0.554 (0.458-0.650)]. When the optimal cut-off value of Presepsin was 646.50 ng/L, its sensitivity and positive predictive value were higher than those of WBC, NEUT, CRP, and PCT (sensitivity: 89.5% vs. 38.6%, 68.4%, 38.6%, 57.9%; positive predictive value: 64.6% vs. 44.9%, 44.3%, 47.8%, 55.9%)., Conclusions: Plasma PCT and Presepsin have early diagnostic value for sepsis in suspected sepsis patients in fever clinics, and Presepsin is more sensitive than PCT and can be used as an early marker of sepsis.

The study aimed at analyzing the therapeutic effect of salmon calcitonin on patients with lumbar spine fracture after operation. Eighty-eight cases with lumbar spine fracture who underwent percutaneous vertebroplasty (PVP) in The Huichang People's Hospital from February 2020 to February 2023 were separated into two groups. The 44 cases in the control group were treated with calcium carbonate and Vitamin D3 tablets, on the basis, the salmon calcitonin was applied to treat the 44 cases in study group. The pain degree, bone metabolism index and matrix metalloproteinase levels were determined and compared between two groups. Lumbar function and daily living activity ability in two groups were evaluated, and adverse reactions during treatment were observed. The pain degree in study group was alleviated after treatment for 3 mo compared with the control group (p<0.05). The bone specific alkaline phosphatase (BALP) and osteocalcin (OC) levels were increased, while beta C-terminal cross-linked telopeptides of type I collagen (β-CTX) levels were decreased in study group after treatment for 3 mo compared with control group (p<0.05). After treatment for 3 mo, the serum matrix metalloproteinase-3 (MMP-3) and matrix metalloproteinase-9 (MMP-9) levels in study group were lower than those in control group (p<0.05). Three months after treatment, the Oswestry Disability Index (ODI) score was lower and Barthel Index (BI) score was higher in study group than those of control group (p<0.05). No severe adverse reactions were observed in both groups during treatment (p>0.05). Salmon calcitonin can relieve the pain degree, improve the levels of bone metabolism and matrix metalloproteinase, and improve the lumbar spine function and ability of daily living activity in patients with lumbar spine fracture.

Purpose: To summarize the more robust evidence about the performance of tools useful for diagnosis of medullary thyroid carcinoma (MTC) such as calcitonin (Ctn) and other circulating markers, ultrasound (US), fine-needle aspiration (FNA), and other imaging procedures., Methods: This systematic review of systematic reviews was carried out according to a predefined protocol. A search string was created. An electronical comprehensive search of literature was performed on December 2022. Quality assessment of eligible systematic reviews was performed and main findings were described., Results: Twenty-three systematic reviews were included and several findings were achieved. Ctn is the most reliable diagnostic marker of MTC with no evidence of improvement with stimulation test. CEA doubling time is more reliable than Ctn in identifying MTC with poorer prognosis. US sensitivity is suboptimal in MTC and only just over half of cases are at high risk according to Thyroid Imaging And Reporting Data Systems. Cytology can correctly detect MTC in just over half of cases and measuring Ctn in washout fluid from FNA is necessary. PET/CT is useful for detecting recurrent MTC., Conclusions: Future guidelines of both thyroid nodule management and MTC diagnosis should consider these evidence-based data., (© 2023. The Author(s).)

Medullary thyroid cancer (MTC) is a rare disease from parafollicular C cells. Calcitonin has been suggested as a screening; its levels are proportional to the tumor size and predictive of metastatic disease. We present a case where an early action was taken with lower cut-off points. Male patient, 49 years old. Thyroid ultrasound (US) with a suspicious nodule. Fine Needle Aspiration Biopsy (FNAB) suggests MTC, with pre-operative serum calcitonin (CTN) of 591 pg/mL. Total thyroidectomy with central and bilateral dissection was performed. Biopsy: MTC in left nodule of 26 mm without lymph nodes (LN) metastases. Follow-up with undetectable CTN for six years. After that, CT was 4.7 pg/mL, and carcinoembryonic antigen (CEA) was 1.2 ng/mL. Neck US showed bilateral LN. FNAB of LN does not show recurrence. A progressive rise of markers with doubling time of CTN and CEA was 16 and 51.3 months, respectively. CTN raised until 112 pg/mL. Given the lack of cervical compromise, a neck and lung CT, liver MRI, and bone scintigraphy were ordered despite CTN levels < 150 pg/mL. MRI showed hypervascular hepatic lesions, contrasted with gadoxetic acid. PET Ga68-DOTATATE showed lesions with overexpression of somatostatin receptors in the liver. Surgery was done, and a biopsy confirmed metastases. Conclusions: The clinical guidelines may allow the management of cases; however, they should be used considering each case context. In our patient, if the guidelines had been strictly followed, it would not have been possible to detect liver metastases to achieve a surgical resection with curative intent.

Objective: To explore the diagnostic value of combined detection of serum amyloid A (SAA), C-reactive protein (CRP) and procalcitonin (PCT) in children with bacteria or non-bacterial respiratory tract infection., Methods: 200 children with respiratory tract infections diagnosed in our hospital were included in the study. According to the results of the aetiological examination, they were divided into bacterial infection group and non-bacterial infection group. At the same time, 100 healthy children admitted to the hospital for physical examination during the same period were selected as the healthy subjects control group. Changes in serum SAA, PCT and CRP in three groups were compared. Comparison of a positive rate of the single index and combined detection were performed. Children with bacterial infections were treated with conventional antibiotics. The changes in serum SAA, PCT and CRP in the infection group before and after treatment were compared. The efficacy of SAA, PCT and CRP alone and in combination was compared., Results: The serum SAA, PCT and CRP levels in the bacterial infection group were higher than those in the non-bacterial infection group and healthy children, and the differences were statistically significant. The positive detection rates and combined detection rates of serum SAA, PCT and CRP in the bacterial infection group were higher than those in the non-bacterial infection group and the healthy subject's control group. After conventional antibiotic treatment, serum SAA, PCT and CR levels in children with bacterial infection were significantly decreased., Conclusion: The combined detection based on SAA, CRP and PCT can effectively identify and diagnose respiratory tract infection in children, providing a certain reference for the promotion of the diagnostic scheme. Key messagesSerum SAA, PCT and CRP were highly expressed in children with respiratory tract infection, and the expression level was the highest in children with bacterial pneumonia.The combined detection of serum SAA, CRP and PCT indicators have higher diagnostic efficiency and can effectively make a differential diagnosis of respiratory tract infection in children.

Purpose: The influence of Hashimoto's thyroiditis (HT) on calcitonin (Ct) production is unresolved question. The aim of this study was to explore if basal Ct levels are influenced by the presence/severity of HT or correlated with clinical phenotypes of HT patients., Methods: We included 467 HT patients and 184 control participants, from Croatian Biobank of HT patients (CROHT), in this retrospective study. Calcitonin levels between HT patients and controls were compared using Mann-Whitney test. Ct levels between two subgroups of HT patients, divided by intake of levothyroxine (LT4) therapy, were additionally tested to take into account the illness severity. Spearman rank correlation test was used to analyze correlations between Ct levels and 14 relevant phenotypes., Results: We have not detected significant differences in median Ct levels between HT patients and controls (2.2 vs 2.35 pg/mL, respectively, P = 0.717) nor in-between two subgroups of HT patients (P = 0.347). We have not detected statistically significant correlations between Ct levels and clinical phenotypes, although we identified three weak nominal correlations: negative correlation of Ct with TgAb in all HT patients (r = - 0.1, P = 0.04); negative correlation of Ct with age in subgroup of HT patients without LT4 therapy (r = - 0.13, P = 0.04); positive correlation of Ct with BSA in subgroup of HT patients on LT4 therapy (r = 0.16, P = 0.042)., Conclusion: Our results suggest that HT patients of all disease stages preserve Ct production as healthy individuals and there is no need for Ct measurements in the absence of a nodule. Additional confirmation and clarification of observed nominal correlations are needed due to potential clinical relevance of TgAb and age-dependent Ct decrease in HT women., (© 2021. Italian Society of Endocrinology (SIE).)

Medullary thyroid carcinoma (MTC) is relatively rare, and has the main feature of calcitonin (Ct) secretion. However, a few cases of MTC with negative serum calcitonin have been reported in the literature, so the diagnosis and follow up of Ct-negative MTCs are still a challenge. Here we present three cases of Ct-negative MTCs, illustrating the rarity of the disease and challenges in managing it, together with a review of the literature of 39 MTCs with negative serum Ct.

Chronic Pb exposure associated systemic illness are partly posited to involve calcium homeostasis. Present systematic review aims to comprehensively evaluate the association between chronic lead exposure and markers of calcium homeostasis. Observational studies documenting the changes in calcium homeostasis markers (i.e. serum calcium, parathyroid hormone, vitamin D & calcitonin) between occupationally Pb exposed group and control group were systematically searched from pubmed-Medline, Scopus, and Embase digital databases since inception to September 24, 2021. The protocol was earlier registered at PROSPERO (ID: CRD42020199503) and executed adhering to PRISMA 2020 guidelines. Mean differences of calcium homeostasis markers between the groups were analysed using random-effects model. Conventional I 2 statistics was employed to assess heterogeneity, while the risk for various biases were assessed using Newcastle Ottawa Scale. Sub-group, sensitivity and meta-regression analyses were performed where data permitted. Eleven studies including 837 Pb exposed and 739 controls were part of the present study. Pb exposed group exhibited higher mean blood lead level [i.e. 36.13 (with 95% CI 25.88-46.38) µg/dl] significantly lower serum calcium (i.e. - 0.72 mg/dl with 95% CI - 0.36 to - 1.07) and trend of higher parathyroid levels and lower vitamin D levels than controls. Heterogeneity was high (I 2  > 90%) among the studies. Considering the cardinal role of calcium in multiple biological functions, present observations emphasis the need for periodic evaluation of calcium levels and its markers among those with known cumulative Pb exposure., (© 2022. The Author(s).)

Aim: Calcitonin (Ctn) measurement in patients with thyroid disease could potentially increase the detection rates of medullary thyroid carcinoma (MTC) but remains a controversial issue. The aim of this study was to evaluate routine preoperative Ctn measurements., Methods: All patients with thyroid surgery documented in the prospective StuDoQ|Thyroid registry between March 2017 and September 2020 were included. Cutoff levels for Ctn were determined with receiver-operating characteristic analyses to assess the preoperative diagnosis of MTC in subgroups for females and males., Findings: In 29 590 of 39 679 patients (75%) participating in the registry, routine preoperative Ctn testing was performed. In 357 patients (227 females and 130 males), histopathology confirmed MTC with a mean tumor size of 14.7 mm (±12.43). Biochemical cure was achieved in 71.4% of the patients. Ctn levels between 11 and 20 pg/mL were seen in 2.6% of the patients, and only 0.7% of the patients had Ctn levels above 21 pg/mL. Cutoff levels for the diagnosis of MTC were 7.9 pg/mL for females and 15 pg/mL for males (P < 0.001). The sensitivity and specificity for females were 95 and 98%, and 96 and 97% for males, respectively., Conclusion: Routine Ctn testing is a reliable predictor for MTC and provides the opportunity for earlier thyroidectomy before lymph node metastases occur, resulting in a better prognosis. Females with Ctn levels >7.9 pg/mL and males >15 pg/mL without any other extrathyroidal sources for an elevated Ctn should be monitored. Thyroid surgery should be considered if Ctn levels are increasing or ultrasound detects suspicious thyroid lesions.

Background: Early diagnosis, precise antimicrobial treatment and subsequent patient stratification can improve sepsis outcomes. Circulating biomarkers such as plasma microRNAs (miRNAs) have proven to be surrogates for diagnosis, severity and case management of infections. The expression of four selected miRNAs (miR-146-3p, miR-147b, miR-155 and miR-223) was validated for their prognostic and diagnostic potential in a clinically defined cohort of patients with sepsis and septic shock., Methods: The expression of plasma miRNAs was quantified by quantitative PCR (qPCR) in patients with bacterial sepsis (n = 78), in patients with septic shock (n = 52) and in patients with dengue haemorrhagic fever (DHF; n = 69) and in healthy controls (n = 82)., Results: The expression of studied miRNA was significantly increased in patients with bacterial sepsis and septic shock. The plasma miR-147b was able to differentiate bacterial sepsis from non-sepsis and septic shock (AUC = 0.77 and 0.8, respectively, p≤ 0.05), while the combination of plasma miR-147b and procalcitonin (PCT) predicted septic shock (AUC = 0.86, p≤ 0.05)., Conclusions: The plasma miR-147b may be an useful biomarker independently or in combination with PCT to support clinical diagnosis of sepsis and equally prognosis of patients with septic shock., Competing Interests: All authors declare no conflict of interests in this study.

Background/aim: Calcitonin level in fine-needle aspirate washout fluid (Ct-FNA) was extensively studied for thyroid nodules and lymph nodes (LN). However, the data was scarce for neck recurrences/metastases of medullary thyroid cancer (MTC). Thus, the diagnostic accuracy of Ct-FNA and cytology in the detection of neck LN metastases of recurrent MTC cases were assessed., Materials and Methods: The database of MTC patients between 2010 and 2021 was retrospectively reviewed. A total of 32 patients with recurrent MTC and suspicious LN who underwent FNA and Ct measurement from washout samples were included in this study. Preoperative serum Ct (sCt), Ct-FNA, Ct-FNA/sCt ratio, cytology data were recorded for all participants., Results: Median sCt of 32 patients and Ct-FNA washout fluid levels of operated suspicious 44 LNs were 723 (54–9000) pg/mL and 1800 (151–9500) pg/mL, respectively. The diagnostic accuracy of Ct-FNA washout fluid was greater than cytology (95.4% vs. 86%, respectively). Using a cut-off level of >638.5 pg/mL, the Ct-FNA predicted the diagnosis of LN metastasis of recurrent MTC with a sensitivity of 80% and specificity of 94.9%. Furthermore, using a cut-off level of >1.16, the Ct-FNA/sCt ratio well predicted the diagnosis of LN metastasis of recurrent MTC with a sensitivity of 92.3% and specificity of 100%., Conclusion: As Ct-FNA has greater diagnostic accuracy in our study, it would be complementary to cytology results to localize metastatic LNs in recurrent MTC. Furthermore, for the first time, we demonstrated that the Ct-FNA/sCt ratio was a better predictor of metastatic LNs in recurrent MTC than a particular cut-off for Ct-FNA alone., Competing Interests: There is no conflict of interest related to our manuscript, and the authors have nothing to disclose. There is no funding., (This work is licensed under a Creative Commons Attribution 4.0 International License.)

Several reports highlighted the central role of inflammation in the pathogenesis of corona virus disease-19 (COVID-19) disease. Also, the hyper-inflammatory response that is triggered by severe acute respiratory syndrom-Covid-2 (SARS-CoV-2) infection was believed to play an essential role in disease severity and adverse clinical course. For that reason, the classical inflammatory markers were proposed as a possible indicator for COVID-19 severity. However, an extensive analysis of the predictive value of inflammatory biomarkers in large patients' cohorts is still limited and critically needed. In this study we investigated the predictive value of the classical inflammatory biomarkers in a patient cohort consists of 541 COVID-19 patients admitted to Al Kuwait Hospital, Dubai, UAE. A detailed analysis of the association between the essential inflammatory markers and clinical characteristics as well as clinical outcome of the patients were made. In addition, the correlation between those markers and a wide range of laboratory biomarkers and incidence of acute organs injury were investigated. Our results showed a significant elevation of many inflammatory markers including white cell count (WBC) count, neutrophils count, C-reactive protein (CRP), D-Dimer, ferritin, procalcitonin (PCT), and lactate dehydrogenase (LDH) levels in patients with more severe illness. Also, our results highlighted that higher levels of those markers can predict worse patient outcome including the need of ventilation, intensive care unit (ICU) admission, multiple organs dysfunction as well as death. In addition, Our results showed that the presence of lymphopenia and lower absolute lymphocyte count (ALC) at the time of admission were associated with severe to critical COVID-19 illness (P<0.0001), presence of acute respiratory distress syndrome (ARDS) (P<0.0001) and the need for ventilation and ICU admission., Moreover, our results showed a strong association between lower ALC count and multiple organs dysfunction and patient's death (P<0.0001). In conclusion, our results highlighted the possible use of classical inflammatory biomarkers at time of admission as a potential predictive marker for more severe clinical course in COVID-19 patients that might need more aggressive therapeutic approach including the need of ventilators and ICU admission. The presence of such predictive markers might improve patient's stratification and help in the direction of the available resources to patients in need, which in turn help in improving our response to the disease pandemic., Competing Interests: The authors have declared that no competing interests exist.

Since medullary thyroid carcinoma is an aggressive cancer, it is important to have an early detection based on stimulated calcitonin (CT), especially when basal-CT is slightly elevated. The objective of this work was to set specific thresholds for basal-CT- and calcium-stimulated calcitonin for prediction of thyroid malignancy in female population. The study included 2 groups: group A-women with elevated basal-CT (>9.82 pg/ml) and group B-women with normal basal-CT (control group). After calcium stimulation test precise protocol, histopathological reports of those that required surgery were correlated with both basal and stimulated calcitonin. The best basal and stimulated calcitonin cut-offs for distinguishing female patients with medullary thyroid carcinoma or C-Cell-hyperplasia from other pathologies or normal cases were: 12.9 pg/ml, respectively 285.25 pg/ml. For basal-CT above 30 pg/ml, malignancy was diagnosed in 9/9 patients (100%): 9 MTC. For stimulated calcitonin above 300 pg/ml, malignancy was diagnosed in 17/21 patients (80.95%): 12 MTC and 5 papillary thyroid carcinomas. The smallest nodule that proved to be medullary thyroid carcinoma had only 0.56/0.34/0.44 cm on ultrasound, with no other sonographic suspicious criteria. In conclusion, we have identified in Romanian female population basal and stimulated calcitonin thresholds to discriminate medullary thyroid carcinoma or C-Cell-hyperplasia from other cases. We recommend thyroid surgery in all women with stimulated calcitonin above 285 pg/ml. Further studies on larger groups are necessary to establish and confirm male and female cut-offs for early diagnosis of medullary thyroid carcinoma, and interestingly, maybe for macro-papillary thyroid carcinomas alike. The calcium administration has minimum side-effects, but continuous cardiac monitoring is required., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Introduction: Medullary thyroid carcinoma (MTC) is a rare cancer that accounts for 5% of thyroid cancers. Serum calcitonin is a good biomarker for MTC, which is used for diagnosis, prognosis, and monitoring of recurrence. Calcitonin-negative MTC (CNMTC) is rare but confounds diagnostic and prognostic directions. This study introduces 19 cases of CNMTC in a single center., Method: From 2002 March to 2020 July, more than 76,500 patients had undergone thyroid surgery due to thyroid cancer at the Severance Hospital, and a total of 320 patients were diagnosed with MTC (0.4%). Serum calcitonin levels were obtained from every patient who was suspected with MTC. These patients had undergone either bilateral total thyroidectomy or unilateral thyroidectomy with central compartment lymph node dissection, and additional modified radical lymph node dissection if lateral lymph node metastasis was positive. Postoperative monitoring and out-patient clinic follow-up were performed with obtaining the serum calcitonin levels., Result: Nineteen patients tested negative for calcitonin preoperatively (6%). The mean preoperative calcitonin level was 5.1pg/mL if undetectable level is regarded as 0pg/mL. Only two patients were males, and the female bias was significant (p = 0.017). No one except two patients with modified radical neck dissection showed central compartment lymph node metastasis. Every patient's postoperative calcitonin level remained low. The median follow-up period was 71 months. There was no recurrence and only one fatality, and the overall survival rate was 95%., Conclusion: Since incidence of CNMTC is not negligible, MTC should not be ruled out in the diagnostic phase even if serum calcitonin is negative in preoperative examination. We presented 19 cases of CNMTC whose prognosis in general were favorable. Markers of serum and immunohistochemical samples other than calcitonin should be actively examined., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kim, Yun, Shin, Lee and Chang.)

Background: Recently, presepsin has been reported to be a useful biomarker for early diagnosis of sepsis and evaluation of prognosis in septic patients. However, few reports have evaluated its usefulness in patients with urinary tract infections (UTI). This study aimed to evaluate whether presepsin could be a valuable marker for detecting severe sepsis, and whether it could predict the therapeutic course in patients with UTI compared with markers already used: procalcitonin (PCT) and C-reactive protein (CRP)., Methods: From April 2014 to December 2016, a total of 50 patients with urinary tract infections admitted to Gunma university hospital were enrolled in this study. Vital signs, presepsin, PCT, CRP, white blood cell (WBC) count, causative agents of urinary-tract infections, and other data were evaluated on the enrollment, third, and fifth days. The patients were divided into two groups: with (n = 11) or without (n = 39) septic shock on the enrollment day, and with (n = 7) or without (n = 43) sepsis on the fifth day, respectively. Presepsin was evaluated as a biomarker for systemic inflammatory response syndrome (SIRS) or septic shock., Results: Regarding the enrollment day, there was no significant difference of presepsin between the SIRS and non-SIRS groups (p = 0.276). The median value of presepsin (pg/mL) was significantly higher in the septic shock group (p < 0.001). Multivariate logistic regression analysis showed that presepsin (≥ 500 pg/ml) was an independent risk factor for septic shock (p = 0.007). ROC curve for diagnosing septic shock indicated an area under the curve (AUC) of 0.881 for presepsin (vs. 0.690, 0.583, and 0.527 for PCT, CRP and WBC, respectively). Regarding the 5th day after admission, the median presepsin value on the enrollment day was significantly higher in the SIRS groups than in the non-SIRS groups (p = 0.006). On the other hand, PCT (≥ 2 ng/ml) on the enrollment day was an independent risk factor for SIRS. ROC curve for diagnosing sepsis on the fifth day indicated an AUC of 0.837 for PCT (vs. 0.817, 0.811, and 0.802 for presepsin, CRP, and WBC, respectively)., Conclusions: This study showed that presepsin may be a good marker for diagnosing septic shock based on admission data in patients with UTI., (© 2021. The Author(s).)

Background: Serum calcitonin level is a useful biomarker for predicting primary tumor size, the extent of lymph node, and distant metastasis in patients with medullary thyroid carcinoma (MTC). However, the association between preoperative serum calcitonin levels and long-term oncologic outcomes has not yet been established. The aims of this study were to determine the preoperative serum calcitonin cut-off value for predicting disease recurrence and to evaluate its prognostic value., Methods: Patients with MTC ( n = 169) who were treated at a tertiary referral hospital in Korea between 1995 and 2019 were enrolled. To determine the preoperative serum calcitonin cut-off value for predicting structural recurrence, the maximum of the standardized log-rank statistics of all possible cut-off values was used. Multivariable Cox regression analysis was used to determine prognostic factors for disease-free survival., Results: The overall disease-free survival rate was 75.7%. The preoperative serum calcitonin cut-off value that predicted structural recurrence was 309 pg/mL. Preoperative serum calcitonin levels of > 309 pg/mL were the strongest independent predictor of disease recurrence (hazard ratio (HR) 5.33, 95% confidence interval (85% CI) 1.67-16.96; P = 0.005). Lateral lymph node metastasis (HR 3.70, 95% CI 1.61-8.51; P = 0.002) and positive resection margins (HR 3.57, 95% CI 1.44-8.88; P = 0.006) were also significant predictors of disease recurrence., Conclusions: The preoperative serum calcitonin cut-off value is useful in clinical practice. It is also the best predictive factor for disease-free survival. Preoperative serum calcitonin levels may help determine the optimal postoperative follow-up strategy for patients with MTC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Park, Park, Park, Choe, Chung, Woo, Choi, Kim, Chung and Kim.)

Medullary thyroid carcinoma (MTC) is a relatively rare thyroid carcinoma of C-cell deviation and produces and secrete calcitonin (CT) and chromogranin A (CgA) into the blood. Thus, both CT and CgA are immunohistochemical and serum markers for MTCs. MTC occurs in both sporadic and inheritable cases and the hallmark of inheritable cases in multiple endocrine neoplasm 2 (NEN2) is MTC. MEN2 cases represent 30% of MTCs through germline RET protooncogene mutation and occur in younger ages involving bilateral thyroid lobes. Sporadic cases are 70% of cases of solitary tumor and occur in older ages. CgA and synaptophysin (SPY) are the two, most widely used and reliable immunohistochemical markers for neuroendocrine tumors including MTCs. This study aimed to detect different immunohistochemical staining patterns for CgA and SPY between non-symptomatic small, microscopic lesions and invading larger aggressive tumors in both MEA2 cases and sporadic cases. There was different CgA and SPY immunostaining in MEA2 cases where small tumors (≤ 0.3 cm) were lesser immunostained for CgA and SPY, despite strong staining for CT, compared to the larger (≥ 0.5cm) tumors, stronger immunostained for CgA. There was also different CgA and SPY immunohistochemical staining in sporadic cases between small lesion (≤ 0.5 cm) and larger tumors (≥ 1.0cm). One small sporadic tumor (0.5 x 0.3 cm) was strongly and weakly, patchy (about 10% of tumor tissue) stained for CgA and SPY, respectively, while larger sporadic tumors were diffusely, stronger stained for CgA and SPY. Therefore, stronger CgA and SPY immunostaining for larger tumors in both MEA2 and sporadic cases may be used as independent aggressive immunohistochemical markers for MTCs.

Background: Calcitonin (Ct) is a sensitive diagnostic biomarker and one of the most important prognostic factors in medullary thyroid cancer (MTC). This study aimed to evaluate progression-free survival and recurrence rates of MTC associated with undetectable compared with normalized serum Ct levels after surgery., Methods: This retrospective observational study included patients operated for MTC at the Digestive and Endocrine Surgery Department of Lyon Sud Hospital Centre between 2000 and 2019. Clinical and pathological factors were correlated with postoperative Ct concentrations. Undetectable and normalized Ct concentrations were defined as below 2 pg/ml and 2-10 pg/ml respectively., Results: Overall, 176 patients were treated for MTC, and 127 were considered biochemically cured after surgery. Of these, 24 and 103 had normalized and undetectable Ct concentrations respectively. Patients with Ct level normalization had a 25 per cent risk of disease recurrence, compared with 3 per cent in patients with undetectable Ct levels after surgery. The presence of metastasis in two or more compartments was predictive of failure to achieve undetectable Ct concentrations after surgery and an increased risk of recurrence., Conclusion: Among patients with biochemically cured MTC, those with undetectable or normalized Ct concentrations after surgery had different risks of recurrence. Simply assessing postoperative Ct normalization can be falsely reassuring, and long-term follow-up is needed., Lay Summary: Calcitonin (Ct) is a sensitive diagnostic biomarker and one of the most important prognostic factors for medullary thyroid cancer outcomes; however, the significance of postoperative Ct levels remains controversial. This study evaluated the differences between normal and undetectable postoperative Ct levels in patients who had undergone surgical treatment for medullary thyroid cancer. Patients who experienced postoperative Ct level normalization had a higher risk of disease recurrence than those with undetectable Ct levels after surgery., (© The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Abstract: To investigate the association of sleep disturbance with calcium regulatory hormones, disease severity and health index among the patients with ankylosing spondylitis (AS).There were 104 AS patients enrolled in the cross-sectional study, and their sleep quality was recorded. Serum levels of calcium, parathyroid hormone, vitamin D3 and calcitonin were measured. We evaluated patient's disease activity, functional ability, patient's global assessment, physical mobility, radiographic damage and health index. Blood ESR and CRP levels were tested.Sleep quality was positively correlated with serum calcitonin levels (r = 0.260, P = .008). Bad sleep and advanced radiographic damage were found among the AS patients with detectable serum calcitonin levels (P < .05). Sleep quality was significantly correlated with disease duration, CRP, BASDAI, ASDAS-ESR, ASDAS-CRP, BASFI, BAS-G, BASMI and ASAS-HI among the AS patients (all P < .05). Female gender, longer disease duration, higher ASDAS-CRP and serum calcitonin levels (OR [95% CI] = 3.210 [1.012-10.181], P = .048) were independent factors associated with bad sleep. Inflammation, disease activity, functional ability, patient's global assessment and cervical rotation were useful in predicting bad sleep among the AS patients, and ASDAS-CRP was the best predictor (AUC = 0.772, P < .001).Serum calcitonin levels was elevated in the AS patients with bad sleep, and may participate in the pathophysiology of sleep disturbance. Bad sleep was associated with female gender, longer disease duration, higher inflammation, disease activity, functional impairment, mobility restriction, poor patient's global assessment and health index in AS. ASDAS-CRP was best in predicting bad sleep., Competing Interests: The authors have declared no conflicts of interest., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction. Contamination of specimens and overuse of broad spectrum antibiotics contribute to false positives and false negatives, respectively. Therefore, useful and applicable biomarkers of bacteremia are still required. Hypothesis/Gap Statement. IL-6 can be used as a serum biomarker to discriminate among bacterial infections and fungal infections in febrile patients with a bloodstream infection. Aim. We aimed to evaluate the diagnostic efficiency of neutrophil/lymphocyte ratio (NLR), procalcitonin (PCT) and interleukin-6 (IL-6) in discriminating Gram-negative (G - ) bacteria from Gram-positive (G + ) bacteria and fungi in febrile patients. Methodology. A total of 567 patients with fever were evaluated. Serum levels of IL-6, PCT, NLR and CRP were compared among a G - group ( n =188), a G + group ( n =168), a fungal group ( n =38) and a culture negative group ( n =173). Sensitivity, specificity, Yuden's index and area under the Receiver operating characteristic (ROC) curve (AUC) were obtained to analyse the diagnostic abilities of these biomarkers in discriminating bloodstream infection caused by different pathogens. Results. Serum IL-6 and PCT in the G - group increased significantly when compared with both the G + group and fungal group ( P <0.05). AUC of IL-6 (0.767, 95 % CI:0.725-0.805) is higher than AUC of PCT (0.751, 95 % CI:0.708-0.796) in discriminating the G - group from G + group. When discriminating the G - group from fungal group, the AUC of IL-6 (0.695, 95 % CI:0.651-0.747) with a cut-off value of 464.3 pg ml -1 was also higher than the AUC of PCT (0.630, 95 % CI:0.585-0.688) with a cut-off value of 0.68 ng ml -1 . Additionally, AUC of NLR (0.685, 95 % CI:0.646-0.727) in discriminating the fungal group from G + group at the cut-off value of 9.03, was higher than AUC of IL-6, PCT and CRP. Conclusion. This study suggests that IL-6 could be used as a serum biomarker to discriminate among bacterial infections and fungal infections in febrile patients with a bloodstream infection. In addition, NLR is valuable to discriminate fungal infections from Gram-positive infections in febrile patients with a bloodstream infection.

The data from the Indian subcontinent on Medullary thyroid carcinoma (MTC) and associated endocrinopathies in hereditary MTC (HMTC) syndromes are limited. Hence, we analyzed clinical and biochemical characteristics, management, and outcomes of HMTC and other associated endocrinopathies [Pheochromocytoma (PCC) and Primary hyperparathyroidism (PHPT)] and compared with apparently sporadic MTC. The records of 97 (51 sporadic and 46 hereditary) consecutive MTC patients were retrospectively analyzed. RET mutation was available in 38 HMTC patients. HMTC group was subclassified into Multiple endocrine neoplasia (MEN) 2A index (n = 25), MEN2B index (n = 8), and MEN2A detected by familial screening (n = 12). Patients with HMTC and MEN2B index were younger at presentation than sporadic MTC. MEN2A patients detected by familial screening, but not MEN2A index and MEN2B index patients, had significantly lower serum calcitonin, smaller thyroid nodule size, more frequent early stage presentation (AJCC Stage ≤ II), and higher cure rate than sporadic MTC, which emphasizes the need for early diagnosis. RET (REarranged during Transfection) 634 mutations were the most common cause of HMTC and more frequently associated with PCC (overall 54% and 100% in those aged ≥ 35 years). Patients in ATA-Highest (HST) group had a universal presentation in stage IV with no cure. In contrast, the cure rate and postoperative disease progression (calcitonin doubling time) were similar between ATA-High (H) and ATA- Moderate (MOD) groups, suggesting the need for similar follow-up strategies for the latter two groups. Increased awareness of endocrine (PCC/PHPT) and non endocrine components may facilitate early diagnosis and management.

Intravenous magnesium sulfate (MgSO4) is used in equine practice to treat hypomagnesemia, dysrhythmias, neurological disorders, and calcium dysregulation. MgSO4 is also used as a calming agent in equestrian events. Hypercalcemia affects calcium-regulating hormones, as well as plasma and urinary electrolytes; however, the effect of hypermagnesemia on these variables is unknown. The goal of this study was to investigate the effect of hypermagnesemia on blood parathyroid hormone (PTH), calcitonin (CT), ionized calcium (Ca2+), ionized magnesium (Mg2+), sodium (Na+), potassium (K+), chloride (Cl-) and their urinary fractional excretion (F) after intravenous administration of MgSO4 in healthy horses. Twelve healthy female horses of 4-18 years of age and 432-600 kg of body weight received a single intravenous dose of MgSO4 (60 mg/kg) over 5 minutes, and blood and urine samples were collected at different time points over 360 minutes. Plasma Mg2+ concentrations increased 3.7-fold over baseline values at 5 minutes and remained elevated for 120 minutes (P < 0.05), Ca2+ concentrations decreased from 30-60 minutes (P < 0.05), but Na+, K+ and Cl- concentrations did not change. Serum PTH concentrations dropped initially to rebound and remain elevated from 30 to 60 minutes, while CT concentrations increased at 5 minutes to return to baseline by 10 minutes (P < 0.05). The FMg, FCa, FNa, FK, and FCl increased, while urine osmolality decreased from 30-60 minutes compared baseline (P < 0.05). Short-term experimental hypermagnesemia alters calcium-regulating hormones (PTH, CT), reduces plasma Ca2+ concentrations, and increases the urinary excretion of Mg2+, Ca2+, K+, Na+ and Cl- in healthy horses. This information has clinical implications for the short-term effects of hypermagnesemia on calcium-regulation, electrolytes, and neuromuscular activity, in particular with increasing use of Mg salts to treat horses with various acute and chronic conditions as well as a calming agent in equestrian events., Competing Interests: Dr. Stephen Schumacher is employed by the sponsor of the project (USEF). However, this affiliation does not alter our adherence to all PLOS ONE policies on sharing data and materials.

Calcitonin (CT) stimulation tests have great value and could help to: differentiate thyroid causes of elevated CT apart from non-thyroid sources, determine whether the patients with slightly elevated basal CT could/could not be candidates for surgery, and indicate the right moment for prophylactic thyroidectomy in children with MEN syndromes when with normal basal CT. This triggered the requests for development of CT stimulation tests, taking into consideration their safety and aimed us to write a systematic review of literature regarding the rationale, technical issues, and side effects of CT stimulating tests used for diagnosis of MTC. After a thorough review of the literature, we classified the reported side effects by severity, as defined by United States Food and Drug Administration. A statistical analysis was performed using IBM SPSS Statistics version 20. Various side effects were noticed during stimulation tests that differ by intensity, duration and severity, depending on types of substances and protocols used. The side effects after pentagastrin test were significantly more severe than those reported after calcium stimulation test (p=0.0396). There are also significant gender-specific differences in side effects induced by stimulation tests. In conclusion, we recommend performing Ca CT stimulation test when needed, considering preventive evaluation of some clinical, instrumental, and biochemical aspects of each patient. Precise instructions should be followed before a stimulation test and furthermore continuous cardiac monitoring is essential during and after the test to minimize the possibility of a serious event., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background/aim: Medullary thyroid cancer (MTC) originates from parafollicular cells (C cell) and produces calcitonin (CT). Basal serum CT was used in the diagnosis and treatment of MTC. If basal CT level is 100 pg/mL or higher, it is likely to have MTC, but if basal CT level is below 10 pg/mL, the probability of developing thyroid disease is low. In cases with basal CT level between 10–100 pg/mL, pentagastrin-stimulated (PS) CT level is studied to evaluate MTC and C cell hyperplasia (CHH). This study aimed to determine cut-off value for basal and PS peak CT level for diagnosis of MTC., Materials and Methods: We retrospectively reviewed files of patients presented to endocrine outpatient clinic of Ege University, Medicine School, between 2010 and 2019; 176 patients with basal CT level of 10–100 pg/mL and patients with PS test were included to the study., Results: The receiver operating characteristic curve (ROC) analysis was used to determine cut-off value for basal CT that can discriminate cases with MTC and those with nodular goiter. Cut-off value for basal CT was calculated as 46.5 pg/mL (specificity; 100 %, sensitivity; 74 %). In the ROC analysis for peak PS CT, cut-off value was calculated as 285 pg/mL (specificity:100 %; sensitivity:82 %). When peak CT level was > 290 pg/mL in PS test, both specificity and sensitivity for MTC were determined as 100 %. The PS peak CT level > 285 pg/ mL was significant for MTC diagnosis while range of 117–274 pg/mL was significant for CHH., Conclusion: In this study, cut-off value was calculated as 46.5 pg/mL for basal CT, whereas 285 pg/mL for PS peak CT in the diagnosis of preoperative MTC., Competing Interests: The authors do not report any conflict of interest., (This work is licensed under a Creative Commons Attribution 4.0 International License.)

There is no evidence-based guidance on the extent of prophylactic neck surgery for second-generation multiple endocrine neoplasia type 2B (MEN 2B), a newly emerging entity in the molecular era. In this investigation of MEN 2B children who inherited the M918T RET germline mutation from a phenotypically affected MEN 2B parent, 6 MEN 2B children (4 girls and 2 boys) from 5 MEN 2B parents (4 mothers and 1 father) were identified. None of the 6 second-generation MEN 2B children who had preoperative calcitonin serum levels between 2 and 105 pg/mL and underwent prophylactic total thyroidectomy before the age of 4 years after receiving a positive RET gene test harbored node metastases. There was no recurrent laryngeal nerve palsy or postoperative hypoparathyroidism. Within the limitations of this study, total thyroidectomy alone is adequate therapy for second-generation MEN 2B children aged 1-4 years old with preoperative calcitonin serum levels ≤100 pg/mL., (Copyright © 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

The aim of this study was to investigate the factors that affect cervical lymph node metastasis (CLNM) in individuals with medullary thyroid carcinoma (MTC) in terms of ultrasonic characteristics and other parameters. Single-factor χ 2 analysis showed that the ultrasonic characteristics of tumor size >10 mm, unclear boundary, irregular pattern and capsular invasion, as well as pre-operative calcitonin level >302.50 pg/mL (p < 0.001) and age ≤52.50 y (p = 0.036), were risk factors for CLNM in individuals with MTC. Multivariate logistic regression analysis showed that age ≤52.50 y (odds ratio = 3.796; 95% confidence interval, 1.010-14.259; p = 0.048), irregular pattern (odds ratio = 5.262; 95% confidence interval, 1.200-23.084; p = 0.028) and tumor size >10 mm (odds ratio = 7.789; 95% confidence interval, 1.123-54.005; p = 0.038) were independent risk factors for CLNM in individuals with MTC. Individuals with MTC aged ≤52.50 y with an irregular pattern and tumor size >10 mm were more likely to develop CLNM. In addition, those with a pre-operative calcitonin level >302.50 pg/mL were more likely to have CLNM., Competing Interests: Conflict of interest disclosure The authors declare no competing interests., (Copyright © 2021. Published by Elsevier Inc.)

Background: Medullary thyroid cancer can be subdivided during surgery into tumours with or without a desmoplastic stromal reaction (DSR). DSR positivity is regarded as a sign of disposition to metastasize. The aim of this study was to analyse whether lateral lymph node dissection can be omitted in patients with DSR-negative tumours., Methods: This was a retrospective cohort study of a prospectively maintained database of patients with medullary thyroid cancer treated using a standardized protocol, and subdivided into DSR-negative and -positive groups based on the results of intraoperative frozen-section analysis. Patients in the DSR-negative group did not undergo lateral lymph node dissection. Long-term clinical and biochemical follow-up data were collected, and baseline parameters and histopathological characteristics were compared between groups., Results: The study included 360 patients. In the DSR-negative group (17.8 per cent of all tumours) no patient had lateral lymph node or distant metastases at diagnosis or during follow-up, and all patients were biochemically cured. In the DSR-positive group (82.2 per cent of all tumours), lymph node and distant metastases were present in 31.4 and 6.4 per cent of patients respectively. DSR-negative tumours were more often stage pT1a and were significantly smaller. The median levels of basal calcitonin and carcinoembryonic antigen were significantly lower in the DSR-negative group, although when adjusted for T category both showed widely overlapping ranges., Conclusion: Lymph node surgery may be individualized in medullary thyroid cancer based on intraoperative analysis of the DSR. Patients with DSR-negative tumours do not require lateral lymph node dissection., (© The Author(s) 2020. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Reliable cut-offs for basal (bCT) and calcium stimulated calcitonin (casCT) are needed for an early and accurate diagnosis of medullary thyroid cancer (MTC)., Patients and Methods: Fifty-four new patients with nodular goiter were enrolled and analysed together with those previously published by our group for a total of 135 cases. bCT and casCT were measured by a highly sensitive method and the results compared with histological findings. In a subgroup of patients, cardiac rhythm was recorded before and during the calcium test., Results: In both females (F) and males (M), there was a significant correlation between tumor size and bCT levels (P < 0.001). The receiver operating characteristic plot analyses showed that, for bCT, the new cut-off points able to separate non-MTC from MTC patients were > 30 (F) and > 34 pg/mL (M), whereas the best casCT thresholds were > 79 (F) and > 466 pg/mL (M). bCT was shown to harbour a high accuracy, though some cases were diagnosed only upon stimulation test. Importantly, combining bCT, below or above the cut-offs, with casCT above the cut-offs, all the MTC cases were correctly identified. A reversible sinus bradycardia was observed in 9% of cases during the test., Conclusions: Refined cut-offs for bCT and casCT in patients with nodular goiter are reported. Sensitive bCT was shown to have a high accuracy, but the combination with casCT data was needed to identify all MTC cases. The reliability and safety of calcium test strongly favour the routine use of CT determination in nodular thyroid disease.

Objective: To test the effectiveness of mid-regional pro-adrenomedullin (MR-proADM) in comparison to C-reactive protein (CRP), procalcitonin (PCT), D-dimer, lactate dehydrogenase (LDH) in predicting mortality in COVID-19-ICU-patients., Methods: All consecutive COVID-19 adult patients admitted between March and June 2020 to the ICU of a referral, university hospital in Northern-Italy were enrolled. MR-proADM and routine laboratory test were measured within 48 hours from ICU admission, on day 3, 7 and 14. Survival curves difference with MR-proADM cut-off set to 1.8 nmol/L were tested using log-rank test. Predictive ability was compared using area under the curve and 95% confidence interval of different receiver-operating characteristics curves., Results: 57 patients were enrolled. ICU and overall mortality were 54.4%. At admission, lymphocytopenia was present in 86% of patients; increased D-dimer and CRP levels were found in 84.2% and 87.7% of patients respectively, while PCT values > 0.5 μg/L were observed in 47.4% of patients. MR-proADM, CRP and LDH were significantly different between surviving and non-surviving patients and over time, while PCT, D-dimer and NT-pro-BNP did not show any difference between the groups and over time; lymphocytes were different between surviving and non-surviving patients only. MR-proADM was higher in dying patients (2.65±2.33vs1.18±0.47, p<0.001) and a higher mortality characterized patients with MR-proADM >1.8 nmol/L (p = 0.016). The logistic regression model adjusted for age, gender, cardiovascular disease, diabetes mellitus and PCT values confirmed an odds ratio = 10.3 [95%CI:1.9-53.6] (p = 0.006) for MR-proADM >1.8 nmol/L and = 22.2 [95%CI:1.6-316.9] (p = 0.022) for cardiovascular disease. Overall, MR-proADM had the best predictive ability (AUC = 0.85 [95%CI:0.78-0.90])., Conclusions: In COVID-19 ICU-patients, MR-proADM seems to have constantly higher values in non-survivor patients and predict mortality more precisely than other biomarkers. Repeated MR-proADM measurement may support a rapid and effective decision-making. Further studies are needed to better explain the mechanisms responsible of the increase in MR-proADM in COVID-19 patients., Competing Interests: The authors have declared that no competing interests exist.

Background: Multiple endocrine neoplasia type 2B (MEN 2B) is mainly caused by M918T RET germline mutation, and characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO) and non-endocrine features. However, the diagnosis and treatment are usually delayed., Methods: This study reports 5 Chinese pedigrees with 5 individuals harboring germline RETM918T, and systematically reviewed previous Chinese literature reported., Results: All 5 patients initially presented MTC, but none had biochemically cured postoperatively. 2 also presented bilateral PHEO after adrenal-sparing surgery, 1 needed steroid replacement. Further, a total of 32 MEN 2B patients from literature were clustered with 28 available for analysis. 26 (92.8%) were diagnosed by endocrine-related symptoms; the remaining 2 (7.2%) due to RET testing and oral symptoms, respectively. 25 patients underwent thyroidectomy with/without neck lymph node dissection at the mean age of (23.3 ± 10.4) years. Histopathological examination revealed MTC (100%). Of them, 17 had definite TNM stage, with 1 in stage III and others in IV. Other information of MEN 2B-related symptoms included penetrance of PHEO (60.7%), constipation (32.1%), Hirschsprung disease (25%), alacrima (17.8%), mucosal ganglioneuroma (96.4%) and marfanoid habitus (71.4%). 19 patients were verified harboring RET-M918T (c.2753T>C), of whom 15 (78.9%) were de novo mutation. The other 9 were clinically diagnosed as MEN 2B., Discussion & Conclusion: The initial diagnosis of MEN 2B is relatively later, and diagnosed by non-endocrine components is extremely lower. Recognition of MEN 2B and its non-endocrine-related components is still the utmost requirement for a Chinese physician. Combined RET screening and serum calcitonin detection can facilitate early diagnosis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)