calca-protein--human and Thyroid-Neoplasms

An increased calcitonin serum level is suggestive of a medullary thyroid cancer (MTC), but is not pathognomonic. The possibility of false positives or other calcitonin-secreting neuroendocrine neoplasms (NENs) should be considered. Serum calcitonin levels are generally assessed by immunoradiometric and chemiluminescent assays with high sensitivity and specificity; however, slightly moderately elevated levels could be attributable to various confounding factors. Calcitonin values >100 pg/mL are strongly suspicious of malignancy, whereas in patients with moderately elevated values (10-100 pg/mL) a stimulation test may be applied to improve diagnostic accuracy. Although the standard protocol and the best gender-specific cut-offs for calcium-stimulated calcitonin are still controversial, the fold of the calcitonin increase after stimulation seems to be more reliable. Patients with MTC show stimulated calcitonin values at least three to four times higher than the basal values, whereas calcitonin-secreting NENs can be distinguished from a C-cell disease by the absence of or

Topics: Biomarkers, Tumor; Calcitonin; Calcitonin Gene-Related Peptide; Carcinoma, Neuroendocrine; Diagnosis, Differential; Endocrine Gland Neoplasms; False Positive Reactions; Female; Humans; Janus Kinases; Male; Middle Aged; Reference Values; Sensitivity and Specificity; Thyroid Neoplasms

The aim of the present study was to perform a systematic review of published studies to provide a robust estimation of the use of procalcitonin (ProCT) as a diagnostic marker of medullary thyroid carcinoma (MTC), with particular focus on its specificity and negative predictive value in excluding MTC. A comprehensive computer literature search was conducted to find relevant published articles on the topic. We used a search algorithm based on a combination of the terms 'medullary,' 'thyroid,' and 'ProCT.' The search was updated until February 2015. To expand our search, references of the retrieved articles were also screened. A total of 39 articles were retrieved, of which nine original papers published from 2003 to 2014 were selected for the review. Some of these studies used ProCT in the preoperative diagnosis of MTC, whereas others measured ProCT during the follow-up of patients who had been previously treated for MTC. Other laboratory measurements were performed in some of the included studies. The results of the majority of the studies indicate that ProCT measurement appears to be a very promising and reliable serum marker for the diagnosis of MTC, and it is not inferior to calcitonin (CT). The sample handling is less laborious, and in the few CT-negative cases reviewed, the assay had even greater sensitivity. It would be worthwhile to establish cutoff levels using larger patient series, because we speculate that this assay could potentially replace CT measurement in the future.

Topics: Biomarkers, Tumor; Calcitonin; Calcitonin Gene-Related Peptide; Carcinoma, Neuroendocrine; Humans; Protein Precursors; Thyroid Neoplasms; Thyroid Nodule

Topics: Biomarkers; Calcitonin; Calcitonin Gene-Related Peptide; Carcinoma, Medullary; Humans; Hypercalcemia; Hypocalcemia; Immunoradiometric Assay; Inflammation; Kidney Failure, Chronic; Luminescent Measurements; Osteoporosis; Protein Precursors; Radioimmunoassay; Reference Values; Sepsis; Thyroid Neoplasms

Medullary carcinoma of the thyroid (MCT) develops from the thyroid C-cells. Thyroid C-cells and MCTs secrete calcitonin (CT), a 32 amino acid polypeptide hormone. The author has described a sensitive direct sequential radioimmunoassay of CT in human serum. The vast majority of healthy subjects had detectable values of serum immunoreactive calcitonin (iCT) and elevated levels were found in patients with MCT. Besides CT, several higher molecular weight substances contribute to CT-immunoreactivity. These substances may represent metabolic products in the processing of a glycosylated procalcitonin to CT. Calcium, several gastrointestinal hormones and ethanol increases CT secretion from normal and neoplastic C-cells, but the physiological regulation of CT secretion has not been firmly established. The author has shown that the levels of serum iCT vary little during day and nighttime. CT acutely reduces bone resorption and, in pharmacological doses, increases urinary electrolyte excretions. A lowering in serum calcium, magnesium and phosphorus levels result but the effect is pronounced only in disease states with a high bone turnover. The physiological role for CT may be preservation of the skeleton at times of increased need for calcium. A causal relationship between postmenopausal osteoporosis and CT deficiency has been proposed. The author has described increased serum 1,25-dihydroxyvitamin D levels and increased trabecular bone remodeling in patients with MCT and normalization of these parameters following surgical cure for MCT. These results were interpreted to indicate that chronic endogenous CT excess directly enhances the renal production of 1,25-dihydroxyvitamin D which, acting synergistically with parathyroid hormone, increases trabecular bone remodeling. Elevated serum iCT is almost invariably found in patients with clinically manifest MCT as well as in several patients with clinically occult MCT. An exaggerated increase in serum iCT levels after provocative testing with pentagastrin and/or calcium can disclose early C-cell neoplasia. Elevated serum iCT may be encountered in non-C-cell neoplasias and in renal insufficiency. Compared to MCT, circulating iCT may show a different immunochemical profile and the response to provocative testing is blunted in these conditions. MCT occurs in a sporadic variety, and in a familial variety as part of two related multiple endocrine neoplasia (MEN) syndromes. MEN IIa consists of MCT and often phaeochromocytomas a

Topics: Animals; APUD Cells; Bone and Bones; Bone Resorption; Calcitonin; Calcitonin Gene-Related Peptide; Carcinoma; Diagnosis, Differential; Humans; Hyperparathyroidism; Kidney; Mucous Membrane; Multiple Endocrine Neoplasia; Neuroma; Paraneoplastic Syndromes; Pheochromocytoma; Prognosis; Protein Precursors; Radioimmunoassay; Rats; Thyroid Gland; Thyroid Neoplasms; Thyroidectomy; Vitamin D

Early cervical lymph node (LN) metastasis is an important cause of poor survival in patients with medullary thyroid cancer (MTC). This study evaluated whether the preoperative serum calcitonin level in combination with ultrasonographic features of MTC can be used to assess the LN status as well as predict the risk of metastasis in patients with MTC.. We retrospectively analyzed the clinical data of 95 patients with MTC, and a nomogram model was constructed and validated. Using integrated database analysis of The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx), we mined pathways wherein. Correlation analysis revealed a significant association between the infiltrating range, diameter, calcification, blood flow, the preoperative serum calcitonin level, and metastasis. The metastasis risk-prediction model showed great accuracy in determining the risk of metastasis in MTC (area under the curve of the receiver operating characteristic [ROC] curve: 0.979 [95% confidence interval 0.946-1.000]). Decision curve analysis (DCA) showed that the model has excellent clinical utilization potential. Significantly,. The preoperative serum calcitonin level, in combination with ultrasonographic features, can be used to predict the risk of metastasis in patients with MTC and constitute a noninvasive accurate method for preoperative diagnosis of MTC.

Topics: Aged; Calcitonin Gene-Related Peptide; Carcinoma, Neuroendocrine; Female; Humans; Male; Middle Aged; Predictive Value of Tests; Preoperative Period; Retrospective Studies; Risk Assessment; Thyroid Neoplasms; Ultrasonography

Topics: Amyloidosis; Calcitonin; Calcitonin Gene-Related Peptide; Carcinoma; Carcinoma, Neuroendocrine; Female; Humans; Kidney; Middle Aged; Thyroid Neoplasms

Topics: Calcitonin; Calcitonin Gene-Related Peptide; Carcinoma, Medullary; Humans; Male; Middle Aged; Protein Precursors; Thyroid Neoplasms; Thyroidectomy

The clinical utility of procalcitonin has not been demonstrated across the whole spectrum of medullary thyroid cancer (MTC).. This serum biomarker validation study aimed at defining the diagnostic accuracy of procalcitonin for screening and risk stratification of MTC and delineating biochemical thresholds predictive of lymph node involvement in the neck and mediastinum.. This was a retrospective analysis at a tertiary referral center.. Included in this study were 457 consecutive patients with previously untreated MTC, 112 of whom had procalcitonin and calcitonin serum levels determined before the initial operation.. The intervention was compartment-oriented surgery.. Main outcome measures included primary tumor diameter, extrathyroidal extension, lymph node metastases, distant metastases, and biochemical cure.. Receiver operating characteristics analyses revealed similar diagnostic accuracy for procalcitonin vs the current calcitonin standard, yielding comparable areas under the curve for primary tumors at thresholds of 10 (0.94 vs 0.93) and 40 (0.92 vs 0.84) mm; extrathyroidal extension (0.84 vs 0.83), lymph node metastasis (0.88 vs 0.86), and distant metastasis (0.93 vs 0.91). Lymph node metastases were present in the ipsilateral lateral neck with procalcitonin levels ≤1.0 ng/mL and the ipsilateral central neck with procalcitonin levels ≤0.25 ng/mL. Above a threshold of 1.0 ng/mL, lymph node metastases emerged in the contralateral central and lateral neck and above 5.0 ng/mL also in the upper mediastinum. When procalcitonin levels exceeded 1, 5, 10, and 50 ng/mL, biochemical cure rates declined to no more than 71%, 36%, 23%, and 10%, respectively.. Serum procalcitonin, having comparable diagnostic accuracy, has great potential to replace serum calcitonin as a new standard of care in the management of MTC because it does not need to be kept cool on ice or frozen and is easier to manage at the community level.

Topics: Adult; Biomarkers, Tumor; Calcitonin; Calcitonin Gene-Related Peptide; Carcinoma, Neuroendocrine; Early Detection of Cancer; Female; Humans; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Predictive Value of Tests; Prognosis; Protein Precursors; Retrospective Studies; Risk Factors; Sensitivity and Specificity; Thyroid Neoplasms

Serum calcitonin (sCT) is the main tumor marker for medullary thyroid cancer (MTC), but it has certain limitations. Various sCT assays may have important intra-assay or interassay variation and may yield different and sometimes conflicting results. A pentagastrin- or calcium-stimulation calcitonin (CT) test may be desirable in some situations. Alternatively, or in the absence of the stimulation test, mRNA detection offers the advantages of being more comfortable and less invasive; it only requires blood collection and has no side effects. The objective of this study was to investigate the applicability of measuring calcitonin-related polypeptide alpha (CALCA) gene transcripts (CT-CALCA and calcitonin gene-related peptide [CGRP]-CALCA) in patients with MTC and in relatives diagnosed with a RET mutation and to test mRNA as an alternative diagnostic tool for the calcitonin-stimulation test.. Twenty-three healthy controls and 26 individuals evaluated for MTC were selected, including patients with sporadic or hereditary MTC and RET mutation-carrying relatives. For molecular analysis, RNA was extracted from peripheral blood, followed by cDNA synthesis using 3.5 μg of total RNA. Quantitative real-time polymerase chain reaction (RT-qPCR) was performed with SYBR Green and 200 nM of each primer for the two specific mRNA targets (CT-CALCA or CGRP-CALCA) and normalized with the ribosomal protein S8 as the reference gene.. We detected CALCA transcripts in the blood samples and observed a positive correlation between them (r=0.946, p<0.0001). Both mRNAs also correlated with sCT (CT-CALCA, r=0.713, p<0.0001; CGRP-CALCA, r=0.714, p<0.0001). The relative expression of CT-CALCA and CGRP-CALCA presented higher clinical sensitivity (86.67 and 100, respectively), specificity (97.06 and 97.06), positive predictive value (92.86 and 93.75), and negative predictive value (94.29 and 100), than did sCT (73.33, 82.35, 64.71, and 87.50, respectively). In addition, the CALCA transcript measurement mirrored the response to the pentagastrin test.. We demonstrate that the measurement of CALCA gene transcripts in the bloodstream is feasible and may refine the management of patients with MTC and RET mutation-carrying relatives. We propose considering the application of this diagnostic tool as an alternative to the calcitonin-stimulation test.

Topics: Biomarkers, Tumor; Calcitonin; Calcitonin Gene-Related Peptide; Carcinoma, Neuroendocrine; Case-Control Studies; DNA, Complementary; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Male; Mutation; Pentagastrin; Predictive Value of Tests; Protein Precursors; Proto-Oncogene Proteins c-ret; RNA, Messenger; Sensitivity and Specificity; Thyroid Neoplasms

To prospectively evaluate the role of procalcitonin (PCT) in detecting or excluding medullary thyroid carcinoma (MTC) among patients with thyroid nodules and increased calcitonin (CT) levels.. Fourteen of 1236 patients referred for thyroid nodules had increased serum CT >10 pg/mL. A stimulation test with pentagastrin was done and both CT and PCT were measured after stimulation. All patients underwent thyroid ultrasound, fine-needle cytology and, if indicated, surgery with histological and immunohistochemical examination of the surgical specimens.. After follow-up, two MTCs were found. These two patients had basal CT >100 pg/mL and detectable (>0.1 ng/mL) PCT, with 100% sensitivity. Pentagastrin stimulated CT achieved values above 100 pg/mL in two MTCs and in other two cases with no MTC outcome (50% PPV and 83% NPV). On the contrary, all patients with no MTC had both basal and stimulated undetectable PCT (100% PPV and 100% NPV).. The addition of basal PCT measurement in patients with thyroid nodule(s) and increased CT may significantly improve accuracy of CT measurement without needing a PG stimulation test.

Topics: Adult; Aged; Biomarkers, Tumor; Biopsy, Fine-Needle; Calcitonin; Calcitonin Gene-Related Peptide; Carcinoma, Neuroendocrine; Female; Humans; Male; Middle Aged; Pentagastrin; Predictive Value of Tests; Protein Precursors; Thyroid Gland; Thyroid Neoplasms; Thyroid Nodule; Ultrasonography

Calcitonin (CT) is a sensitive marker for evaluation of medullary thyroid cancer (MTC). However, CT measurement can vary with assay- and nonassay-dependent factors, and procalcitonin (PCT) measurement has been proposed for evaluating questionable increases in CT.. We tested 2 fully automated CT assays (Immulite [IL] and Liaison [LIA]) and 1 nonautomated CT assay (IRMA, Medipan) and compared these results with PCT (Brahms Kryptor). We evaluated preanalytical conditions and PCT cross-reactivity in sera of 437 patients with clinical conditions associated with hypercalcitoninemia. Additionally, we determined the true "nil" CT concentration in 60 thyroidectomized patients and defined CT cutoff concentrations for pentagastrin stimulation testing in 13 chronic kidney disease (CKD) patients and 10 MTC patients.. Markedly decreased CT concentrations were found after storage of sera for >2 h at room temperature and >6 h at 4 °C. Cutoff concentrations for basal and stimulated CT were disease and assay dependent. Proton pump inhibitor therapy was the most frequent reason for increased CT. PCT concentrations were higher in patients with MTC than in patients with CKD without infections (P<0.001). Whereas IL and LIA demonstrated comparable analytical quality, the IRMA gave increased CT concentrations in nil sera and showed cross-reactivity with PCT in patients with concomitant bacterial infection.. IL, LIA, and IRMA detected increased CT concentrations in non-MTC patients and discriminated MTC from CKD patients in pentagastrin tests. PCT assessment may be helpful in the diagnostic work-up of increased CT concentrations in questionable clinical circumstances.

Topics: Automation; Biomarkers, Tumor; Calcitonin; Calcitonin Gene-Related Peptide; Calibration; Carcinoma, Medullary; Case-Control Studies; Cohort Studies; Female; Humans; Immunoassay; Luminescent Measurements; Male; Pentagastrin; Protein Precursors; Protein Stability; Reference Standards; Sensitivity and Specificity; Sex Characteristics; Thyroid Neoplasms; Thyroidectomy

Topics: Adult; Calcitonin; Calcitonin Gene-Related Peptide; Carcinoma; Case-Control Studies; Female; Humans; Male; Middle Aged; Prognosis; Protein Precursors; Sensitivity and Specificity; Thyroid Neoplasms; Thyroid Nodule; Thyroidectomy; Up-Regulation; Young Adult

Procalcitonin has been well established as an important marker of sepsis and systemic infection. The authors evaluated the diagnostic and predictive value of calcitonin and its prohormone procalcitonin in medullary thyroid cancer.. The authors systematically explored the ability of calcitonin and procalcitonin to identify medullary thyroid cancer and predict the endpoints local recurrence and distant metastases, as well as the progression-free survival. Patients with C-cell hyperplasia; patients after thyroidectomy for differentiated thyroid cancer, goiter, or Graves disease; and healthy subjects served as controls. The study was performed in accordance with the Reporting Recommendations for Tumor Marker Prognostic Studies of the National Cancer Institute.. Sixty-nine medullary thyroid cancer patients and 96 controls were included (median observed interval: 10.9 years [range, 1.4-47.5 years]; 981.8 patient-years). The 1-year, 5-year, 10-year, and 20-year recurrence rates were 9%, 34%, 45%, and 56%, respectively. Calcitonin had a higher diagnostic accuracy for detecting medullary thyroid cancer than procalcitonin (area under the curve [AUC], 0.94; 95% confidence interval [95% CI], 0.90-0.99 vs AUC, 0.89; 95% CI, 0.83-0.95 [P = .038]). The procalcitonin:calcitonin ratio predicted disease progression (AUC, 0.63; 95% CI, 0.51-0.75 [P = .036]) and progression-free survival (hazards ratio, 1.49; 95% CI, 1.09-2.04 [P = .013]).. The results of the current study indicate a superior diagnostic accuracy of calcitonin and an independent predictive value of the procalcitonin:calcitonin ratio. These findings may lead to improved diagnostic and therapeutic strategies for medullary thyroid cancer patients.

Topics: Adult; Aged; Biomarkers, Tumor; Calcitonin; Calcitonin Gene-Related Peptide; Carcinoma, Medullary; Disease Progression; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Protein Precursors; Thyroid Neoplasms; Treatment Outcome

Calcitonin (CT) is the main medullary thyroid carcinoma (MTC) tumor marker. However, it has several limitations, including a concentration-dependent biphasic half-life, sensitivity to rapid in vitro degradation, and the presence of different isoforms/fragments. Procalcitonin (PCT), the prohormone of calcitonin, is free of these limitations but is currently used only as a sepsis marker.. The objective of the study was to determine whether PCT is suited as a MTC tumor marker by comparing the diagnostic performance of PCT with that of CT in MTC.. PCT and CT were measured in a total of 835 subjects, including normal volunteers (n = 197) and patients with active-MTC (n = 91), cured-MTC (n = 42), neuroendocrine tumors (n = 225), mastocytosis (n = 48), follicular cell-derived thyroid carcinoma (cured = 120, persistent/recurrent = 55), and benign thyroid disease (n = 57).. PCT levels were significantly higher in the active-MTC patients (mean 126.4 ng/ml) than the cured-MTC patients (mean <0.1 ng/ml). The overall concordance between the two markers was 95.7% (kappa = 0.81). Receiver-operating characteristic curve analysis showed no significant difference in diagnostic performance between CT and PCT. PCT's diagnostic sensitivity and specificity were 91 and 96%, respectively. The corresponding values for CT were 99 and 98%. Analyte stability studies showed that CT is very unstable in vitro with a decrease of 35-50% from the original value 24 h after the blood draw, whereas PCT levels did not significantly change during this time.. A strong correlation was observed between PCT and CT levels in patients with MCT. Given PCT's greater analytical stability, we conclude that it represents a promising complementary MTC tumor marker.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Calcitonin; Calcitonin Gene-Related Peptide; Carcinoma, Medullary; Female; Follow-Up Studies; Humans; Male; Middle Aged; Protein Precursors; Reference Values; Retrospective Studies; Thyroid Neoplasms

Topics: C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Carcinoma, Medullary; Creatinine; Enzyme-Linked Immunosorbent Assay; Humans; Male; Middle Aged; Protein Precursors; Sepsis; Thyroid Neoplasms

To construct the expression vectors of procalcitonin (PCT), prepare polyclonal antibodies (pAbs) and monoclonal antibodies (mAbs) against PCT and identify their specific biological activity.. The recombinant expression plasmids of pGEX-4T-1-PCT and PET-32a-PCT were constructed using thyroid carcinoma cell line (TT cell) cDNA as template. The fusion protein of His-PCT was expressed in E.coli and used as immunogen. The specificity of antiserum against human PCT was characterized by ELISA, Western blot and indirect immunofluorescence. The mAbs against human PCT were identified by Western blot and indirect immunofluorescence.. The recombinant expression plasmids of pGEX-4T-1-PCT and PET-32a-PCT were constructed and the fusion protein of His-PCT was expressed and purified. The antiserum against human PCT was prepared and the titer detected by ELISA was 1:256 000. The pAb specifically recognized the recombinant human PCT. Eight hybridoma cell lines secreting specific mAbs against PCT were established. The mAbs recognized the recombinant human PCT and four of them recognized the native PCT of TT cytoplasm in immunofluorescent assay.. The successful preparation of polyclonal and monoclonal antibodies against human PCT is beneficial to further research into the pathological and physiological functions of PCT in severe bacterial infection and sepsis.

Topics: Animals; Antibodies; Antibodies, Monoclonal; Antibody Specificity; Blotting, Western; Calcitonin; Calcitonin Gene-Related Peptide; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique, Indirect; Genetic Vectors; Humans; Protein Precursors; Rabbits; Recombinant Fusion Proteins; Thyroid Neoplasms

The objective of this study was to re-evaluate the adult C(T) reference values determined by five different immunoassays and by introducing criteria for selecting control subjects.. A prospective multicenter study.. Three hundred and seventy-five clinically euthyroid subjects.. We used five different C(T) immunoassays. Sera were assayed for the concentration of TSH, gastrin, procalcitonin, urea, calcium, and anti-thyroperoxidase antibodies.. Screening for the various potential causes of hypercalcitoninemia led to the exclusion of 23% of the sera. Our reference value analysis dealt with 287 subjects (142 men and 145 women). The proportion of samples in which no C(T) was detected varied from 56% (for assay D) to 88% (for assay C). We observed significant correlations (whose magnitude depended on the assay used) between C(T) levels and age or body mass index (BMI) (primarily in men). The distribution of C(T) levels showed that 4.7, 9.8, 2.5, 6.5, and 8.0% of the values were over 10 pg/ml respectively. These values corresponded essentially to samples from 11 male subjects (median age: 55 years), most of whom were smokers. The highest C(T) values were around twice as high in men than women, and were higher in smokers than non-smokers. Conclusion In clinical practice (and after having excluded the usual causes of raised C(T) levels), the interpretation of C(T) assay results must take into account i) the method used; ii) the patient's gender, age, and weight; and iii) the potential influence of cigarette smoking.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Antibodies; Biomarkers, Tumor; Calcitonin; Calcitonin Gene-Related Peptide; Calcium; Carcinoma, Medullary; Female; Gastrins; Humans; Immunoassay; Iodide Peroxidase; Male; Middle Aged; Prospective Studies; Protein Precursors; Reagent Kits, Diagnostic; Reference Values; Smoking; Thyroid Neoplasms; Thyrotropin; Urea

The hormonal serum marker for the presence and course of patients with medullary thyroid cancer (MTC) is the mature calcitonin (CT) peptide. Other CALC-1 gene products such as the 116-amino acid polypeptide prohormone, procalcitonin, as well as its component calcitonin precursors (CTpr) may also be increased in their sera. We performed a study to evaluate the clinical utility of serum levels CTpr in these patients.. Twenty-one patients with MTC (9 males, 12 females; 23-76 years of age) were evaluated. The diagnosis was confirmed by histologic examination, except for 2 (a proven RET mutation plus an abnormal pentagastrin-stimulated CT level). Nine patients had postoperative hypercalcitoninemia and 3 of these died. The specific assay for mature CT was a commercial immunoradiometric assay (hCT-IRMA); the immunoluminometric assay for CTpr (B.R.A.H.M.S Diagnostica, Berlin, Germany) detects intact procalcitonin and the free CT:CT carboxypeptide-1.. All patients had detectable serum CTpr. These levels considerably exceeded those of mature CT, averaging 7.6-fold greater. CTpr levels correlated positively with mature CT (r = 0.61; p < 0.001). After pentagastrin administration, there was a parallelism of response between the two assays. Whenever there were known metastases, CTpr increased markedly.. This study demonstrates the universal presence of CTpr in the blood of patients with MTC. The measurement of these peptides may offer a new dimension to the clinical evaluation of this malignancy.

Topics: Biomarkers, Tumor; Calcitonin; Calcitonin Gene-Related Peptide; Humans; Oncogene Proteins; Prognosis; Protein Precursors; Proto-Oncogene Proteins c-ret; Receptor Protein-Tyrosine Kinases; Reference Values; Retrospective Studies; Thyroid Neoplasms

Procalcitonin (PCT) is a protein synthetized by the thyroid C cells, inside which it is cut into calcitonin (CT) and catacalcin. It remains undetectable in serum in normal conditions. Its level increases during inflammation and in small cell lung cancer. There have been studies suggesting that the PCT level increases in medullary thyroid carcinoma (MTC). So far there have been no reports that would assess the usefulness of PCT detection in MTC. Our aim was to evaluate the usefulness of serum PCT assays in patients with MTC. We investigated 24 patients at 17-78 years of age, all after total thyroidectomy due to MTC. All patients had serum CT concentrations measured by radioimmune assay. The upper limit of the CT level was 60 pg/ml. The serum PCT was evaluated with an immunochromatographic kit. The reaction was considered positive when the PCT level exceeded 0.5 ng/ml. In all cases the C-reactive protein (CRP) serum level was measured. The statistical analysis was performed with Statistica 5.1G. The CT levels in all patients varied from 0 to 1410, mean 603.8 pg/ml. In 8 patients the CT level was within normal range, in 6 patients it was marginally, and in 10 patients markedly elevated. The PCT test was considered positive in 16 patients. There was correlation among serum PCT and CT concentrations (Spearman test, p<0.0001). The PCT levels varied considerably among patients with normal, marginally and markedly elevated CT levels (Kruskal-Wallis test, p=0.0013). All patients had normal CRP values. Fisher's exact test revealed a correlation between serum PCT and CT increase (p=0.04). Further studies on a larger group of patients should be considered; thus, the PCT assay can be considered useful in cases of unclear CT concentration.

Topics: Adolescent; Adult; Aged; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Carcinoma, Medullary; Female; Humans; Male; Middle Aged; Protein Precursors; Radioimmunoassay; Statistics as Topic; Thyroid Gland; Thyroid Neoplasms; Thyroidectomy

Raised plasma levels of procalcitonin (proCT) represent an early marker for septicaemia. They are related to disease severity and inversely to outcome and response to treatment. ProCT is presumably synthesised in tIssues other than the thyroid C-cells which are the source of calcitonin (CT) in normal physiology. This study compares proCT and its cleavage products in the serum of patients with septicaemia with those in medullary thyroid carcinoma (MTC).. Immunoreactive proCT and its cleavage products were extracted from the serum of patients with septicaemia or MTC using octadecylsilyl silica columns and characterised by reversed phase HPLC and Western blot analysis. ProCT, CT(1-32) and the flanking peptides PAS-57 and PDN-21 were recognised with antibodies specific for the individual peptides.. ProCT and a 10 kDa polypeptide were recognised with antibodies to PAS-57, CT(1-32) and PDN-21. An 8 kDa proCT fragment was detected with antibodies to CT and PDN-21. However, intact CT(1-32), PAS-57 and PDN-21, found in the serum of MTC patients, were undetectable. The results indicate partial cleavage of proCT in septicaemia different from that in MTC patients.. ProCT and 10 and 8 kDa proCT fragments were recognised in the circulation of septic patients. They were different from the known proCT-processing products PAS-57, CT(1-32) and PDN-21 identified in the serum of normal subjects and of MTC patients. Distinct cleavage of proCT may contribute to the symptoms of septicaemia.

Topics: Aged; Blotting, Western; Calcitonin; Calcitonin Gene-Related Peptide; Carcinoma, Medullary; Chromatography, High Pressure Liquid; Female; Humans; Male; Middle Aged; Peptide Fragments; Protein Precursors; Sepsis; Thyroid Neoplasms

We have identified the amino-terminal cleavage peptide of procalcitonin (PAS-57) in the plasma of normal human subjects and of medullary thyroid carcinoma (MTC) patients together with calcitonin (CT) and CT gene-related peptide (CGRP). Major components on reversed-phase high-pressure liquid chromatography had the retention times of synthetic PAS-57, CT and CGRP as well as of precursor proteins. Plasma levels of PAS-57 (290 +/- 50 pgeq/ml; mean +/- S.E.M.), CT (27 +/- 8 pgeq/ml) and CGRP (8.4 +/- 0.8 pgeq/ml) were respectively 2.3-, 1.6- and 1.5-fold higher in normal men (n = 10) than in women (n = 8). In response to 1 min intravenous calcium infusions (2 mg per kilogram body weight) PAS-57 and CT were increased 3.5- and 2.7-fold (P less than 0.001), respectively, but CGRP remained unchanged. In MTC patients (n = 57) with raised levels of PAS-57 and CT, the molar ratio between PAS-57 and CT was 1.7-times higher than in normal subjects (P less than 0.01). We have found that PAS-57 is a predominant CT/CGRP gene derived product in the circulation of normal subjects and of MTC patients and a potential new MTC tumor marker.

Topics: Adult; Biomarkers, Tumor; Calcitonin; Calcitonin Gene-Related Peptide; Chromatography, High Pressure Liquid; Female; Humans; Male; Protein Precursors; Thyroid Neoplasms

Four peptides derived from procalcitonin were isolated in high yield from an extract of a human medullary thyroid carcinoma. The peptides were identified as procalcitonin-(1-57)-peptide, procalcitonin-(60-91)-peptide (calcitonin), procalcitonin-(60-116)-peptide and procalcitonin-(96-116)-peptide (katacalcin). Determination of the amino acid sequence of procalcitonin-(1-57)-peptide has demonstrated that the Ala25-Ala26 bond in preprocalcitonin is the site of cleavage of the signal peptide. Procalcitonin-(60-116)-peptide represents calcitonin extended from its C-terminus by the sequence Gly-Lys-Lys-Arg-katacalcin, and its formation is indicative of an aberrant pathway of procalcitonin processing in the tumour cells.

Topics: Amino Acids; Calcitonin; Calcitonin Gene-Related Peptide; Humans; Molecular Weight; Neuropeptides; Peptide Fragments; Protein Precursors; Radioimmunoassay; Thyroid Neoplasms

As a first step in studying the biosynthesis of the peptide hormone calcitonin, we have identified procalcitonin species in CA-77 cells, a newly developed rat medullary thyroid carcinoma cell line. mRNA extracted from the cells directed the synthesis of a putative procalcitonin in a reticulocyte lysate translation system containing microsomal membranes. Both this species and a radiolabeled form of immunoreactive calcitonin from intact cells had the same retention time during reverse phase high performance liquid chromatography. The putative cellular procalcitonin was also immunoprecipitated by antiserum to a synthetic peptide whose sequence constitutes the COOH-terminal 16 residues of preprocalcitonin. The polypeptide had a Mr = 13,400, as estimated by gel filtration chromatography under denaturing conditions. Microsequencing of the [35S]methionine-labeled polypeptide indicated that residues 13, 32, and 34 of procalcitonin were methionine. Similar analysis of the peptide labeled with [3H]proline indicated that residues 2 and 11 of the precursor were proline. The positions of methionine and proline could be aligned in a unique manner with the NH2-terminal half of the preprocalcitonin sequence inferred from cDNA analyses. These results indicate that procalcitonin consists of 111 amino acids and suggest that a 25-residue signal sequence is cotranslationally cleaved from preprocalcitonin. From the procalcitonin sequence we can now predict the sequence of likely biosynthetic intermediates and mature secretory products derived from the NH2-terminal as well as COOH-terminal regions of the precursor.

Topics: Amino Acid Sequence; Calcitonin; Calcitonin Gene-Related Peptide; Cell Line; Glycoproteins; Humans; Intracellular Membranes; Microsomes; Poly A; Protein Biosynthesis; Protein Precursors; Reticulocytes; RNA; RNA, Messenger; Thyroid Neoplasms