Significant Role of Procalcitonin and Proinflammatory Markers in Diabetic Foot Ulcer Infections

Background: Procalcitonin (PCT), an amino acid protein precursor of calcitonin hormone released by thyroid C cells or other body cells, can be used as a marker for diagnosing infection. PCT has a suggestive role in diagnosing diabetic foot infection alone or in combination with other markers of infection. Aim: We aimed to evaluate the roles of interleukin-6 (IL-6), CRP, and PCT levels in the differential diagnosis of the patients with infected diabetic foot ulcer (IDFU) and non-infected diabetic foot ulcer (NIDFU) and to compare those with C-reactive protein (CRP), white blood cell (WBC), and erythrocyte sedimentation rate (ESR). Methods: A total of 95 subjects with DFU and NIDFU were enrolled. WBC count, ESR, CRP, and PCT were done for all subjects at admission after obtaining informed consent. Patients over 18 years with a diagnosis of type 2 diabetes mellitus and DFU who were followed up in our hospital were included in the study. In addition to this patient group, patients with diabetes but without DFU were determined as the control group. Results: Twenty nine patients with IDFU, 29 patients with NIDFU, and 43 patients as the control group were included in the study. Fifty-six point three percent of the patients who participated in the study were males, and the mean age was 62.87 ± 10.99 years. WBC, ESR, CRP, and IL-6 levels of the cases with IDFU were determined to be significantly higher compared to the cases in NIDFU (p <0.001). The area under the ROC curve (AUROC) value was highest for CRP (p <0.001), and the best cut-off value for CRP was 36 m/L. The best cut-off values for IL-6, ESR, and WBC were 109.4 pg/mL, 53 mm/h, and 13.7 (103 μ/L), respectively. Conclusion: Serum PCT levels were not found to be effective in the discrimination of IDFU and NIDFU. Serum IL-6 level seems to be one promising inflammatory markers in the discrimination of IDFU. Based on our results, we conclude that PCT has a valuable role in diagnosing infection in DFUs.

Oncocytic Change in Thyroid Pathology

Oncocytes are cells that have abundant eosinophilic cytoplasm due to the accumulation of mitochondria; they are also known as oxyphils. In the thyroid they have been called Hürthle cells but this is a misnomer, since Hürthle described C cells; for this reason, we propose the use of “oncocyte” as a scientific term rather than an incorrect eponym. Oncocytic change occurs in nontumorous thyroid disorders, in benign and malignant tumors of thyroid follicular cells, in tumors composed of thyroid C cells, and intrathyroidal parathyroid proliferations as well as in metastatic lesions. The morphology of primary oncocytic thyroid tumors is similar to that of their non-oncocytic counterparts but also is complicated by the cytologic features of these cells that include both abundant eosinophilic cytoplasm and large cherry red nucleoli. The molecular alterations in oncocytic thyroid tumors echo those of their non-oncocytic counterparts but in addition feature mitochondrial DNA mutations as well as chromosomal gains and losses. In this review we emphasize the importance of recognition of the spectrum of oncocytic thyroid pathology. The cell of origin, morphologic features including architecture, nuclear atypia and invasive growth, as well as high grade features such as mitoses and necrosis, enable accurate classification of these lesions. The molecular alterations underlying the pathological entity are associated with genetic alterations associated with oncocytic change. The arbitrary cut-off of 75% oncocytic change to classify a lesion as an oncocytic variant brings another complexity to the classification scheme of tumors that frequently have mixed oncocytic and non-oncocytic components. This controversial and often confusing area of thyroid pathology requires thoughtful and cautious investigation to clarify accurate diagnosis, prognosis and prediction for patients with oncocytic thyroid lesions.

Medullary Carcinoma of Thyroid Due to GLP-1 Receptor Agonist

Introduction: The first GLP-1 receptor agonist (GLP-1 RA) was approved for the treatment of type 2 Diabetes mellitus in 2005. This class has gained popularity due to its anti-glycemic effect, weight loss and reduction in Cardiovascular disease outcomes1. The effects of this drug class on human thyroid cells are not well known. We hereby report a case of a woman who developed medullary carcinoma of thyroid (MTC) after using Dulaglutide. CaseA 63-year-old female with T2DM for 3 years, taking dulaglutide for 2 years, who presented with a lump in the neck. She had no personal or family history of MEN 2 syndrome, radiation exposure or cancer. Examination showed a 2cm firm nodule in the left lower neck. Thyroid ultrasound revealed a large nodule in the left upper lobe of thyroid. Lab work showed TSH of 1.55mIU/L (0.27-4.2 mIU/L) and serum calcitonin level of 1903 pg/ml (0.0-5.1 pg/mL). FNA biopsy of the nodule showed MTC. She tested negative for RET MEN 2 gene mutation. She underwent total thyroidectomy and neck dissection. Pathological examination confirmed MTC. Post-op calcitonin improved to 2.1 pg/ml. Discussion: GLP-1 RAs provide glycemic control by many mechanisms, including increase in insulin secretion, reduction in postprandial glucagon secretion, delaying gastric emptying, increasing satiety and weight loss. Although they have proved effective in T2DM management, the potential effects on thyroid C-cells should not be ignored. Several in-vitro studies have shown GLP-1 receptors on the rat thyroid tissue C-cells. Stimulation of these receptors resulted in increased production of calcitonin in a dose dependent manner and increased risk of C-cell tumor formation at 104 weeks. Studies initially done by Knudsen et al2 showed that this effect was not seen in humans due to lower expression of GLP-1 receptors in human thyroid tissue C cells. However, a study conducted by Gier et al showed the expression of GLP-1 receptor in some patients with C-cell hyperplasia as well as papillary and medullary carcinoma3. FDA adverse event reporting system database suggested an increased risk of thyroid cancer associated with GLP-1 RAs. It is unclear whether dulaglutide contributed to the development of MTC in this patient. She had not had a baseline calcitonin level prior to the initiation of dulaglutide. The consequence of long-term use of GLP-1 RAs in the thyroid gland in humans still remains unknown and further studies to determine if they increase the risk of MTC are warranted. References: 1. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375(4):311. Epub 2016 Jun 13. 2. Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Endocrinology. 2010;151(4):1473. Epub 2010 Mar 3. Glucagon Like Peptide-1 Receptor Expression in the Human Thyroid Gland

Comprehensive Assessment of Copy Number Alterations Uncovers Recurrent AIFM3 and DLK1 Copy Gain in Medullary Thyroid Carcinoma

Medullary thyroid carcinoma (MTC) is a malignant tumor originating from thyroid C-cells that can occur either in sporadic (70–80%) or hereditary (20–30%) form. In this study we aimed to identify recurrent copy number alterations (CNA) that might be related to the pathogenesis or progression of MTC. We used Affymetrix SNP array 6.0 on MTC and paired-blood samples to identify CNA using PennCNV and Genotyping Console software. The algorithms identified recurrent copy number gains in chromosomes 15q, 10q, 14q and 22q in MTC, whereas 4q cumulated losses. Coding genes were identified within CNA regions. The quantitative PCR analysis performed in an independent series of MTCs (n = 51) confirmed focal recurrent copy number gains encompassing the DLK1 (14q32.2) and AIFM3 (22q11.21) genes. Immunohistochemistry confirmed AIFM3 and DLK1 expression in MTC cases, while no expression was found in normal thyroid tissues and few MTC samples were found with normal copy numbers. The functional relevance of CNA was also assessed by in silico analysis. CNA status correlated with protein expression (DLK1, p = 0.01), tumor size (DLK1, p = 0.04) and AJCC staging (AIFM3p = 0.01 and DLK1p = 0.05). These data provide a novel insight into MTC biology, and suggest a common CNA landscape, regardless of if it is sporadic or hereditary MTC.

Procalcitonin versus C-reactive protein as indicator of acute rejection during orthotropic liver transplanation

Background Procalcitonin is the precursor for the hormone calcitonin (CT), which is found in the thyroid C cells and the pulmonary endocrine cells, it has a metabolic role in calcium homeostasis. In normal subjects, PCT is found in the blood at a very low concentration but during bacterial infection, there is more than 1,000 fold increase in its blood concentration as it is released by many other tissues as Liver, Spleen and Lungs. Aim of the Work to compare between procalcitonin and CRP as a markers of infection versus rejection in orthotropic liver transplantation; this comparison with their plasma level and the clinical difference during postoperative period. Patients and Methods This study was conducted on 25 patients aged 2-60 years old of both sexes scheduled for elective liver transplantation from living donors; after ethical committee approval and informed consent from patients and/or their first degree relatives, Ain Shams Specialized Hospitals. Results The study revealed that the normal course after liver transplantation for postoperative 28 days was (48%), rejection (16%), sepsis (24%) and rejection and sepsis (12%). Conclusion Procalcitonin is a good early diagnostic marker and is superior to CRP and WBCs in early detection of postoperative sepsis after orthotropic liver transplantation.

Medullary thyroid carcinoma beyond surgery: advances, challenges, and perspectives

Medullary thyroid carcinoma (MTC) is a rare type of tumor that originates from thyroid C cells and accounts for 2–4% of all malignant thyroid neoplasms. MTC may occur sporadically or be inherited, as part of the MEN 2 syndrome. Germline mutations of the RET (REarranged during Transfection) proto-oncogene cause hereditary cancer, whereas somatic RET mutations and, less frequently, RAS mutations have been described in sporadic MTC samples. Since early surgery with complete resection of tumor mostly determines the likelihood of attaining cure for MTC, the broader use of RET genetic screening has dramatically changed the prognostic of gene carriers in hereditary MTC. Nevertheless, despite recent advances, the management of advanced, progressive MTC remains challenging. The multikinase inhibitors (MKI), vandetanib and cabozantinib, were approved for the treatment of progressive or symptomatic MTC, and several other compounds have exhibited variable efficacy. Although these drugs have been shown to improve progression-free survival, no MKI has been shown to increase the overall survival. As these drugs are nonselective, significant off-target toxicities may occur, limiting achievement of the required TK-specific inhibition. Recently, next-generation small-molecule TKI has been developed. These TKI are specifically designed for highly potent and selective targeting of oncogenic RET alterations, making them promising drugs for the treatment of advanced MTC. Here, we summarize the current understanding of the intracellular signaling pathways involved in MTC pathogenesis as well as the therapeutic approaches and challenges for the management of advanced MTC, focusing on targeted molecular therapies.

The Role of Serum Procalcitonin in Predicting Bacterial Sepsis in Patients With Hypothyroidism

Context Serum levels of procalcitonin (PCT), a protein produced by the thyroid C cells under physiologic conditions, are high during sepsis. Objective To assess the test performance of serum PCT in predicting bacterial sepsis and septic shock in patients with hypothyroidism compared with those who have euthyroidism. Design and Methods This retrospective study evaluated patients with no history of thyroid dysfunction (euthyroid), primary hypothyroidism [medical hypothyroidism (MH)], and postsurgical hypothyroidism from total thyroidectomy (TT) identified from a prospectively maintained database who had PCT testing from 2005 to 2018. Quick Sequential Organ Failure Assessment score ≥ 2 or positive bacterial cultures identified bacterial sepsis, and a mean arterial pressure less than 65 mm Hg or a vasopressor requirement defined septic shock. Sensitivity and specificity of PCT for evaluation of bacterial sepsis and septic shock were measured. Results We identified 217 euthyroid patients, 197 patients with MH, and 84 patients with TT. Bacterial sepsis was found in 98 (45.2%), 92 (46.7%), and 36 (42.9%) of these patients, respectively (P > 0.05). Septic shock was identified in 13 (6.0%), 13 (6.6%), and 5 (6.0%) patients (P > 0.05), respectively. With use of a PCT cutoff of 0.5 µg/L for bacterial sepsis, the sensitivity was 59%, 61%, and 53% (P > 0.05) and specificity was 81%, 77%, and 81% (P > 0.05) for the diagnosis of bacterial sepsis in euthyroid, MH, and TT patients, respectively. With use of a PCT cutoff of 2.0 µg/L for septic shock, the sensitivity was 46%, 62%, and 63% (P > 0.05) and specificity was 86%, 82%, and 91% (P > 0.05) for the diagnosis of septic shock in these patients, respectively. Conclusions Despite the thyroidal origin of PCT, hypothyroidism did not affect the diagnostic performance of serum PCT levels in predicting bacterial sepsis or septic shock.

Medullary Thyroid Cancer

Medullary thyroid cancer (MTC) arises from the thyroid C-cells and accounts for 1 to 2% of thyroid cancers in the United States. Most tumors are sporadic but may occur as a part of the familial syndromes multiple endocrine neoplasia (MEN) 2A, MEN2B, and familial MTC. Surgery is the mainstay of treatment of these tumors, although recent advances in molecular genetics have enabled the development and use of targeted therapies such as tyrosine kinase inhibitors to treat patients with symptomatic metastatic disease. This review contains 2 figures, 3 tables and 34 references Key Words: genetics, management, medullary thyroid cancer, MEN2A, MEN2B, targeted therapies

Medullary Thyroid Cancer

Medullary thyroid cancer (MTC) arises from the thyroid C-cells and accounts for 1 to 2% of thyroid cancers in the United States. Most tumors are sporadic but may occur as a part of the familial syndromes multiple endocrine neoplasia (MEN) 2A, MEN2B, and familial MTC. Surgery is the mainstay of treatment of these tumors, although recent advances in molecular genetics have enabled the development and use of targeted therapies such as tyrosine kinase inhibitors to treat patients with symptomatic metastatic disease. This review contains 2 figures, 3 tables and 34 references Key Words: genetics, management, medullary thyroid cancer, MEN2A, MEN2B, targeted therapies