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PubMed2001

[Phenotypic expression of a mutation in MEN 2A documented in a family in the western part of Sweden].

A missense mutation at codon 618 of the RET proto-oncogene is a rather unusual cause of multiple endocrine neoplasia 2A. We report the phenotypic expression of this specific RET mutation in a large Swedish family. The family was mapped back to the 18th century. Since 1971 the family has been included in a biochemical screening program, and since 1994 has undergone genetic screening. Twenty-seven individuals were found to have medullary thyroid carcinoma (MTC). Eighteen were detected by screening. The incidence of pheochromocytoma (4%) and hyperparathyroidism (7%) was low. Five individuals died of MTC, but of these none had been included in the screening program. One patient underwent prophylactic thyroidectomy after positive genetic screening. MTC tumor aggressivity differed markedly between gene carriers. The screening program shows that the clinical aggressivity of MTC can be mitigated by early and adequate surgical intervention.

Female↗
PubMed2001

Two cases of medullary thyroid carcinoma.

INTRODUCTION: Medullary thyroid carcinoma (MTC) is a rare thyroid malignancy but accounts for a significant mortality. We present 2 cases of MTC and review the literature regarding its management and genetic screening. CLINICAL PICTURE: Patient 1 presented after a routine health screening and subsequently was found to have a germline mutation for MEN 2A. Patient 2 presented with sweating irritability and a thyroid mass which illustrates the progressive relentless nature of the disease and highlights current imaging practice. TREATMENT: Both patients underwent extensive surgery and received postoperatively ablative dose of radioactive iodine. Patient 2 also had a large dose I-131 MIBG therapy and further surgery. OUTCOME: In Patient 1, postoperative calcitonins remained elevated indicating residual disease. Patient 2 underwent further radioguided surgery; however, his postoperative calcitonins remained elevated. CONCLUSION: MTC can be relentless. Routine genetic screening of all patients with MTC, Tc-99m pentavalent (V) DMSA imaging, near total thyroidectomy with routine central neck dissections and removal of all lymph nodes in the central neck compartment should be performed.

Adult↗
PubMed2002

[Difficulties in diagnosis and localization of recurrent medullary thyroid carcinoma].

Recurrent and residual medullary thyroid carcinoma (MTC) are common in patients following primary surgical resection. Difficulty arises in performing precise localization of the tumor because of anatomical distortion of the neck structures following surgery. To date, no modality has been shown superior to others in the diagnosis of recurrent or residual MTC, and the issue is currently under debate in the literature. We report a case in which secondary recurrence of MTC was detected and localized using a novel combination of preoperative and intraoperative radionuclide imaging, and a method of preventing intraoperative damage to the recurrent laryngeal nerve in the anatomically disrupted neck. To our knowledge, this is the first report of a combination of these three modalities in detection and localization of recurrent MTC, while minimizing the possibility for nerve injury during the operative procedure. Such a therapeutic strategy may prove useful in the management of patients who have previously undergone neck surgery and suffer from anatomical distortion of normal neck structures.

Carcinoma, Medullary↗
PubMedDate not supplied

Gas chromatographic detection of Mycobacterium tuberculosis complex in pure cultures from respiratory specimens.

It is important to identify mycobacteria to the species level in order to establish their clinical significance and to take the appropriate therapeutical decision. Biochemical tests on primary cultures take time (3-6 weeks) until the report of results; that's why more rapid techniques are needed. We have used gas chromatography with flame-ionisation detection (GC-FID) as an alternative identification method for 53 mycobacterial strains isolated from respiratory specimens. We have extracted fatty acids from whole mycobacterial cells, then derivatized them into methylesters, detectable by GC-FID. All the strains were identified as M. tuberculosis complex (MTC), using the Microbial Identification System (MIS) software. The specificity of the identification by GC-FID of MTC is 100%. In conclusion, pulmonary mycobacteriosis are dominated by MTC; GC-FID is a rapid and accurate method for the identification of MTC.

Chromatography, Gas↗
PubMed2002

[Usefulness of serum calcitonin, CEA and AFP assays in the early detection of medullary thyroid carcinoma relapse].

The medullary thyroid carcinoma (MTC) occurs in the two major forms, the sporadic medullary carcinoma (SMTC) and hereditary medullary carcinoma, to which belong familial form (FMTC) and the element of Multiple Endocrine Neoplasia Syndrome MEN 2A and 2B. The method-of-choice of treatment is total thyroidectomy with following radiotherapy in selected cases. Among the follow-up methods, there are two used the most frequently: the pentagastrin and omeprazole stimulation test of calcitonin (CT), and CEA antigen assay. The aim of this study is to evaluate usefulness of plasma CT, CEA and AFP assay in the early detection of relapse or metastasis of MTC. 18 patients (14 females and 4 males) were investigated. The following procedures were performed in all the patients: plasma CT assays in the basal conditions and after stimulation tests, CEA and AFP. The results were analysed according to TNM staging and neck USG results. Our conclusion is that calcitonin stimulation tests, and CEA assays are useful methods to estimate the presence of relapse or metastases in the patients after surgical treatment due to MTC. Assays of plasma AFP concentration are not useful in a follow-up of patients operated on MTC.

Adult↗
PubMed2003

[Analysis of mutations in the RET proto-oncogene in patients with medullary thyroid tumor].

The spectrum of mutations of the RET protooncogene was analyzed in Russian patients with inherited or sporadic medullary thyroid carcinoma (MTC). Four RET exons (11, 13, 15, and 16) were subjected to molecular analysis, and mutations were revealed and identified in 47.4% (9/19) patients with sporadic MTC. In total, six mutations (including three new ones) were observed. The most common mutation affected codon 918 to cause substitution of methionine with threonine and accounted for 31.6% alleles. Analysis of exons 11 and 16 revealed four mutations in patients with inherited multiple endocrine neoplasia type 2 (MEN 2). Mutations were found in each patient. Thyroidectomy was performed in four asymptomatic carriers of RET mutations from three MET 2A families (in two families, affected relatives had bilateral pheochromocytoma). In two patients, analysis of the surgery material revealed MTC microfoci in both lobes of the thyroid gland. The results provide the ground for constructing a bank of genetic information on Russian MTC patients with the clinically verified diagnosis.

Adolescent↗
PubMed1992

Peritoneal function tests: usefulness of simplified methods.

The Peritoneal Equilibration Test (PET) as standardized by Twardowski (T) and simplified Mass Transfer Coefficients (MTC) as per Garred (G) and Krediet (K) have been employed in our patients to assess: 1) the reproducibility of results, 2) correlation between methods, and 3) usefulness of patient categorization by simplified methods in contrast to PET patterns. We have performed 29 standardized PET (Dianeal 2.5%) in 24 stable CAPD patients. We have collected dialysate samples at 0, 30, 60, 120, 180 and 240 minutes. With this data we were able to calculate the dialysate/plasma ratio for PET, MTC as per Garred and MTC as per Krediet. Our results were not significantly different from data reported by the original authors, except for PET D/P urea at 240': 0.91 +/- 0.07(T) vs. 0.87 +/- 0.08 (our), p < 0.05. In our patients, good correlation was found between PET and MTC for urea, creatinine, and glucose, using both formulae (G and K). Patient categorization as High, High Average, Low Average, and Low by MTCs can well predict PET categorization with acceptable sensitivity and good specificity. We conclude there is good reproducibility of the methods. There is also a close correlation between PET, K and G methods for solute transport evaluation and patient categorization. Simplified methods can be substituted for the more complex ones.

Adolescent↗
PubMed1992

High-sensitivity serum calcitonin assays applied to screening for thyroid C-cell disease in multiple endocrine neoplasia type 2A.

UNLABELLED: Two serum calcitonin assays with sensitivities < or = 10 pg/mL were compared to our standard radioimmunoassay (sensitivity 100 pg/mL) in multiple endocrine neoplasia type 2A (MEN 2A) screening. Values from the Nichols displacement radioimmunoassay averaged 38% higher than values from the CIS immunoradiometric assay; values from both were highly correlated, r = 0.845. In three individuals, both of the newer assays revealed abnormalities in pentagastrin tests three to four years before abnormalities were detected by the standard assay. Pentagastrin tests after total thyroidectomy were assayed by the newer methods in patients with medullary thyroid carcinoma (MTC) diagnosed at initial testing (group I); in patients with early MTC diagnosed by prospective screening (group II); and in patients with pure C-cell hyperplasia detected by prospective screening (group III). At least 64% of group I, at least 25% of group II, but none of group III had detectable postoperative C-cell function. CONCLUSIONS: 1) The previous estimate of 12 years as median age of onset of C-cell disease in MEN 2A is probably three to four years too old. 2) Patients diagnosed with early MTC by screening had not necessarily skipped a preneoplastic phase of C-cell hyperplasias. At least some early disease was not detected by the standard assay. Higher sensitivity assay should improve screening for C-cell disease by earlier disease detection. 3) Biochemical cure by thyroidectomy after the development of MTC is not as frequent as previously thought, but the apparent cure rate of pure C-cell hyperplasia remains 100%.

Adolescent↗
PubMedDate not supplied

RET tyrosine kinase and medullary thyroid cells are unaffected by clinical doses of STI571.

BACKGROUND: Activating mutations in the RET receptor tyrosine kinase are responsible for the development of medullary thyroid cancer (MTC) in persons with Multiple Endocrine Neoplasia type 2. We hypothesized that STI571 (Gleevec) would inhibit RET kinase and be a useful agent in the treatment of MTC. MATERIALS AND METHODS: We determined the IC50 of STI571 for RET using an in vitro kinase assay and also examined the effects of STI571 on cellular proliferation and viability in TT cells, a human MTC cell line. RESULTS: The average in vitro IC50 of STI571 for RET is 37 microM +/- 4 microM. Additionally, TT cells incubated with 10 microM STI571 for up to 8 days showed no apparent reduction in cell proliferation or viability. Higher concentrations of STI571, from 25 to 100 microM, induced necrosis of TT cells. CONCLUSION: The concentrations of STI571 required to significantly inhibit RET and to inhibit TT cell proliferation are not clinically achievable. We conclude that STI571 is not likely to be an effective treatment for MTC.

Antineoplastic Agents↗
PubMed2003

Efficacy of procalcitonin measurement in patients after total thyroidectomy due to medullary thyroid carcinoma.

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.

Adolescent↗
PubMed2003

[Application of multiplex polymerase chain reaction in rapid identification of Mycobacterium bovis BCG].

OBJECTIVE: To establish a method for the rapid identification of Mycobacterium bovis BCG. METHODS: A genomic region designated RD1 was found to be deleted from BCG strains, but present in other strains of Mycobacterium bovis and other members of the Mycobacterium tuberculosis complex (MTC) including Mycobacterium tuberculosis, Mycobacterium africanum, and Mycobacterium microti. With this information, a multiplex PCR method, developed to detect the deletion of RD1, was used to differentiate BCG strains from other strains of Mycobacterium bovis and other members of MTC. RESULTS: RD1 was shown to be absent in 5 BCG vaccine strains and 2 BCG strains isolated from an infant who died of systemic disseminated infection induced by BCG vaccination, but it was present in 3 Mycobacterium bovis standard strains, 6 Mycobacterium bovis strains isolated from diseased cows, deer or patients with pulmonary tuberculosis and other MTC strains including Mycobacterium tuberculosis H(37)Rv and H(37)Ra strains, 48 Mycobacterium tuberculosis strains isolated from patients with pulmonary tuberculosis, and 3 Mycobacterium africanum standard strains. CONCLUSION: The multiplex PCR method is simple, rapid, and specific for the identification of BCG among strains of MTC, and is applicable in clinical laboratories.

Mycobacterium bovis↗
PubMed2004

Expression of CD97 and CD55 in human medullary thyroid carcinomas.

The heterodimeric CD97 protein is a member of the EGF-TM7 family of class II seven-transmembrane (7TM) receptors of 75-90 kDa and structurally related to the secretin receptor family. CD97 is expressed on leucocytes, lymphocytes and in cells of the hematopoietic system. The precise role for CD97 is still unknown. The ubiquitously expressed CD55 (also known as decay accelerating factor, DAF) protects host cells from complement attack. In addition, CD55 is a bacterial/viral receptor and was identified as a ligand for CD97. Employing computer aided UV-laser microdissection CD97 and CD55 were investigated in C-cells of non-neoplastic thyroid specimens (n=3) and in medullary thyroid carcinomas (n=54) by multiplex RT-PCR. Frozen sections of all tissues were investigated by immunohistochemistry. All non-malignant thyroid specimens expressed CD97 mRNA weakly and were devoid of immunoreactive CD97 protein. Transcripts for CD97 were detected in all 54 MTC tissue specimens and CD97 gene activity directly correlated with the histopathological stage of the MTC. CD97 transcriptional activity was high in advanced stages of MTC such as pT3/4. pT1/2 tumors with exclusive intrathyroidal growth revealed weak CD97 expression. CD55 gene expression was significantly lower in normal C-cells than in tumor tissues and all MTC displayed strong and specific CD55 immunostaining. We did not observe a correlation between the expression of CD55 mRNA or protein, respectively, and pTNM classification. In summary, in the present study we have identified CD97 as a novel marker expressed in dedifferentiated neoplastic human thyroid C-cells. CD97 and CD55 may facilitate adhesion of C-cell carcinoma to surrounding surfaces which would result in rapid tumor cell spread.

Adolescent↗
PubMedDate not supplied

[MEN 1 and 2: the role of diagnostic imaging].

PURPOSE: To report the results of a retrospective study on the use of the different imaging methods in the diagnosis of type 1 and type 2 multiple endocrine neoplasias, and to provide an overall evaluation of the diagnostic yield of the various examinations performed correlating the results with the surgical findings. MATERIALS AND METHODS: The study was conducted by reviewing the data of 12 patients, of whom four with MEN1 and eight with MEN2, assessed with different imaging modalities. In the patients with MEN1 the examinations revealed 4 parathyroid hyperplasias, 4 gastro-pancreatic endocrine-secreting lesions, one hypophyseal adenoma, one bronchial carcinoid and two bilateral adrenal hyperplasias. In the patients with MEN2 the examinations revealed 6 medullary thyroid carcinomas (MTC), 4 pheochromocytomas and 3 parathyroid hyperplasias. RESULTS: In MEN1 the parathyroid hyperplasias were diagnosed by scintigraphy in all four cases, whereas neck ultrasound was positive in only two cases. The gastro-pancreatic endocrine-secreting lesions were demonstrated in all four patients with CT and endoscopic ultrasound (two patients also underwent scintigraphy with octreotide, which was positive). In only one patient with MEN1 did the chest X-ray detect a bronchial carcinoma, confirmed by CT. CT also enabled identification of a single hypophyseal adenoma. The patients with MEN2 were divided into two groups: one consisting of asymptomatic patients undergoing screening following positive genetic testing and one of symptomatic patients. In the first group the imaging examinations diagnosed one MTC and three pheochromocytomas; all patients in the second group had MTC (detected by positive ultrasound and scintigraphy examinations). DISCUSSION AND CONCLUSIONS: Given the rarity of this condition we believe that the only statistically important finding in our series concerns the sensitivity of the imaging examinations performed in that, with adequate clinical and laboratory data, the possible problem of false positive results is exceptional. The role of diagnostic imaging in the management of patients with MEN1 and 2 is twofold: identification of the target organs of lesions suspected on the basis of clinical and laboratory findings to enable adequate medical and/or surgical treatment; staging of malignant lesions to enable correct surgical planning. In particular, our study once again highlights the diagnostic efficacy of CT for the diagnosis of pheochromocytomas and of the combination of biopsy plus ultrasound and ultrasound plus scintigraphy for the diagnosis of MTC in MEN 2. As for MEN1 spiral CT was found to have good sensitivity (66%) in localising endocrine neoplasias of the gastrointestinal tract; endoscopic ultrasound on the other hand revealed good diagnostic efficacy, showing constantly positive findings. Finally, in both pathologies we believe that the assessment of parathyroid conditions to be mainly a matter for nuclear medicine.

Adrenal Gland Neoplasms↗
PubMed2004

A humanized monoclonal antibody to carcinoembryonic antigen, labetuzumab, inhibits tumor growth and sensitizes human medullary thyroid cancer xenografts to dacarbazine chemotherapy.

A variety of observations have shown that carcinoembryonic antigen (CEA) is associated with growth and metastasis of cancers, including correlation of CEA serum levels with poor clinical outcome, mediation of cell-cell adhesion by CEA, and involvement of CEA in the immune recognition of tumors and apoptotic pathways. The purpose of this study was to investigate the effect that an anti-CEA monoclonal antibody (MAb) may have on the growth of medullary thyroid cancer (MTC), a CEA-expressing tumor, alone and in combination with chemotherapy. Antitumor effects were evaluated in a nude mouse-human MTC xenograft model. Using the TT MTC cell line grown s.c., we compared tumor growth in untreated mice with that of mice given the humanized anti-CEA MAb labetuzumab or an isotype-matched control MAb. The effects of time of administration post-tumor injection, MAb dose response, specificity of response, and combination with dacarbazine (DTIC) chemotherapy were studied. The humanized anti-CEA MAb, labetuzumab, has direct, specific, antitumor effects in this model, without conjugation to a cytotoxic agent. In addition, labetuzumab sensitizes these tumor cells to chemotherapy with an effective drug in this model, DTIC, without increased toxicity. Significant delays in tumor growth were caused by the MAb therapy or chemotherapy alone; however, the combination of these agents was significantly more effective than either agent given as a monotherapy or use of an irrelevant MAb in this model. The superiority of the combined modality treatment argues for the integration of CEA MAb therapy into chemotherapeutic regimens for MTC management and possibly other CEA-expressing neoplasms.

Animals↗
PubMed2006

Functional hyperprolactinemia and hypophyseal microadenoma in systemic sclerosis.

OBJECTIVE: Hyperprolactinemia (HPRL) has been identified in more than half of patients with systemic sclerosis (SSc). However, the association with pituitary adenoma and the status of hypothalamic dopaminergic tone using metoclopramide (MTC) test has not been studied. We investigated the prevalence of prolactin (PRL)-secreting pituitary adenoma and evaluated production of PRL by dynamic testing with MTC in SSc. METHODS: We studied 30 patients with SSc (mean age 38 +/- 10 yrs) and 20 healthy controls (mean age 37 +/- 11 yrs). Serum PRL concentrations were determined by radioimmunoassay in all subjects, and PRL response was measured 30, 60, 90, and 120 min after injection of 10 mg of MTC. Computed tomography (CT) of the sella turcica was performed. RESULTS: The mean basal serum PRL levels before and after stimulation with MTC in SSc patients versus controls were: basal 18.2 +/- 5.4 versus 8.7 +/- 1.6 ng/ml, p = NS; 30 min: 175.0 +/- 5.4 versus 61.0 +/- 42 ng/ml, p < 0.001; 60 min: 160 +/- 64 versus 52 +/- 30 ng/ml, p < 0.001; 90 min: 125 +/- 57 versus 42 +/- 21.0 ng/ml, p < 0.05; 120 min: 108.0 +/- 57 versus 30.0 +/- 10 ng/ml, p < 0.005. CT scan showed microadenomas in 24/30 SSc patients and 1/20 controls (p = 0.001). CONCLUSION: Our study suggests that a group of patients with SSc have a high prevalence of HPRL with increased central dopaminergic tone, and microadenomas. PRL may have a role in the pathogenesis of SSc. Further studies are necessary to confirm our results.

Adenoma↗
PubMedDate not supplied

Diagnostic and therapeutic aspects in medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) is a rare and particularly aggressive type of thyroid cancer with several distinctive features that distinguish its management from other thyroid cancers. Since MTC was first recognised as a distinct tumour in 1959, it became clear that MTC is more difficult to cure than differentiated thyroid cancer and has higher rates of recurrence and mortality, but it is usually a slow growing tumor compared with other malignancies. In addition, unlike differentiated thyroid cancer, there is no known effective systemic therapy for MTC.

Carcinoma, Medullary↗
PubMed2006

One-tube multiplex PCR method for rapid identification of mycobacterium tuberculosis.

A rapid, inexpensive, simple, and accurate multiplex polymerase chain reaction (PCR) was developed in a single tube for identification of Mycobacterium tuberculosis. Assessment of sensitivity and specificity of simple PCR was performed with 116 strains of M. tuberculosis complex (MTC) and 144 strains of nontuberculous mycobacteria (NTM) compared with the biochemical method. Specific amplification of KS4, MTC-specific DNA fragment, was found in 98% (114/116) of MTC and not detected in 99% (143/144) of NTM. Amplification of the mtp40 gene revealed 95% sensitivity (100/105 strains of M. tuberculosis) and 77% specificity (not found in 119/155 mycobacterial strains). A multiplex PCR method based on the combination of KS4- and mtp40-derived primers was used for identification of M. tuberculosis. Crude DNA from slow growing mycobacteria with cream rough colonies that showed both 768-bp amplified product for KS4 and 396-bp for mtp40 was identified as M. tuberculosis whereas that from MTC gave only the 768-bp product.

Base Sequence↗
PubMed1991

Prognostic significance of calcitonin immunoreactivity, amyloid staining, and flow cytometric DNA measurements in medullary thyroid carcinoma.

The proven power of DNA ploidy to predict mortality risk in medullary thyroid carcinoma (MTC) may be weakened when analyzed in conjunction with calcitonin immunoreactivity (CI) and amyloid staining (AS) of tumors. In this study 12 prognostic variables, including DNA ploidy, CI, and AS, were studied in 65 patients with MTC (57 sporadic; mean age 51 years) treated during 1946 through 1970. Cause-specific mortality rates at 10 and 15 years were 15% and 26%, respectively. By univariate analysis, TNM stages III or IV (p less than 0.0001), tumor unresectability (p less than 0.0001), male sex (p = 0.019), negative AS (p = 0.032), and low CI (p = 0.033) were significant predictors of increased mortality rates. DNA ploidy (p = 0.058) and inheritance pattern (p = 0.25) were nonsignificant. By multivariate analysis, only TNM stage, tumor resectability, and AS were independently significant (p less than 0.005). A prognostic model was created, based on presence or absence of these independent risk factors, and four risk groups were defined, capable of predictably defining mortality rates in MTC (p less than 0.0001). The model requires validation in larger series and independent verification by others. However, we believe that a risk-group scheme for MTC based on AS, disease stage, and completeness of tumor resection may have wide applicability and prove relevant to clinicians treating this disease.

Adolescent↗