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PubMed1997

Sporadic medullary thyroid carcinoma associated with toxic multinodular goitre.

First described in 1959, medullary thyroid carcinoma (MTC) arises from parafollicular C cells distributed throughout the thyroid, and may occur in one of two clinical forms, sporadic (80%) or familial. Familial MTC may present as a palpable thyroid nodule, but may also be diagnosed by screening relatives of an index case for a raised basal serum calcitonin or a rise in calcitonin following a stimulated pentagastric test. Both tests are highly sensitive for C-cell hyperplasia and MTC. Sporadic cases of MTC most commonly present as asymptomatic thyroid nodules with normal thyroid function tests. In this note, the history of a patient is presented in which a sporadic MTC was associated with goitre and both symptoms and biochemical evidence of thyrotoxicosis.

Adult↗
PubMed1997

Single-dose gadolinium with magnetization transfer versus triple-dose gadolinium in the MR detection of multiple sclerosis lesions.

PURPOSE: To compare the efficacy of single-dose gadolinium with magnetization transfer contrast (MTC) with that of triple-dose gadolinium in detecting enhancing multiple sclerosis lesions. METHODS: Twenty-one patients with multiple sclerosis were examined with MR imaging first with 0.1 mmol/kg gadolinium (single dose) and then, after 24 to 72 hours, with 0.3 mmol/kg gadolinium (triple dose). T2-weighted fast spin-echo and T1-weighted spin-echo MR images with and without MTC were obtained before contrast administration followed by either T1-weighted spin-echo images with MTC (single dose) or conventional T1-weighted spin-echo images (triple dose), starting 5, 17, and 29 minutes after contrast administration. All images were evaluated in a blinded fashion and scored in random order by two readers. Outcome parameters included number of enhancing lesions, number of active MR examinations (those containing at least one enhancing lesion), contrast ratio (signal intensity of enhancing lesion divided by signal intensity of normal-appearing white matter), and size of enhancing lesions. RESULTS: Eighty-one percent more enhancing lesions and 49% more active MR examinations were detected when a triple dose of gadolinium was used as compared with a single dose. The level of agreement between readers as to the number of enhancing lesions was significantly higher for triple-dose than for single-dose gadolinium. With triple-dose gadolinium, contrast ratios and areas of enhancement increased by 10% and 33%, respectively. Delayed imaging increased the size of the lesion by 11% on single-dose MTC images and by 18% on triple-dose images. CONCLUSION: Triple-dose gadolinium is more effective (higher sensitivity and interobserver agreement) than single-dose gadolinium in combination with MTC in detecting enhancing multiple sclerosis lesions.

Adult↗
PubMed1997

[Intraoperative interstitial microwave therapy for recurrent hepatocellular carcinoma of the caudate lobe: a case report].

Microwave tissue coagulation (MTC) therapy was given patients with recurrent hepatocellular carcinoma (HCC) of the caudate lobe of the liver, in which radical surgery for deteriorated liver function was impossible. A total of 40 MTC sessions was applied to two tumors under laparotomy. MTC was administered for 20 seconds in each session. Microwave energy output was 70 watts for 15 mm needle-electrodes and 100 watts for 30 mm electrodes. Alpha-fetoprotein levels in serum had decreased after surgery. Abdominal computed tomography showed no blood flow whatsoever in tumors undergoing MTC. There are fewer limits to the sites and angles for insertion of electrodes under laparotomy. Thus, the surgical approach provides access to all parts of the liver for treatment. We conclude that intraoperative MTC is highly effective in tumor necrosis, and can be a useful local treatment for nonresectable HCC.

Carcinoma, Hepatocellular↗
PubMedDate not supplied

Induction of nitric oxide production by ganglioside GM3 in murine peritoneal macrophages activated for tumor cytotoxicity.

BACKGROUND: Recently, it was found that ganglioside GM3, known as a potent monocytic cell differentiation inducer, mimicked bacterial lipopolysaccharide (LPS) in the activation of macrophage-mediated tumor cytotoxicity (MTC). Since GM3 and LPS share partial structural and functional similarity, we postulate that the GM3-induced MTC was due to the induction of nitric oxide(NO) production in murine peritoneal macrophages (M phi s). MATERIALS RESULTS, CONCLUSIONS: Ganglioside GM3 was highly purified from canine erythrocytes by the authors. Murine peritoneal M phi s were used as the effector cells, and mouse ascites hepatoma cell line HCa-F25/16A3-F as the target cells. We found that: GM3 induced NO production by macrophages in a time- and dose-dependent manner; GM3 and IFN-gamma synergistically increased NO production; GM3 markedly enhanced MTC; both NO production and MTC were significantly inhibited by aminoguanidine. These results demonstrated for the first time that ganglioside GM3 in vitro induces the production of nitric oxide by macrophages, and the GM3-induced MTC is NO-dependent.

Animals↗
PubMed1998

[Microwave hepatic tumor coagulation therapy during stoppage of hepatic blood flow using balloon catheters].

The usefulness of microwave hepatic tumor coagulation therapy (MTC) with stoppage of hepatic blood flow using a balloon catheter was assessed. By placing a 5-French balloon catheter in a hepatic artery and 6-French balloon catheter in a hepatic vein, hepatic arterial and portal venous flow of the liver segment including the tumor was interrupted. The effects of balloon occlusion were evaluated by CT during arterial portography. MTC with stoppage of hepatic flow was performed for two patients with metastatic liver tumor 2 cm in diameter. Enhanced CT obtained after MTC showed no enhancement of the tumor, indicating complete necrosis. There were no complications and the two patients were discharged within 4 days after MTC. MTC with stoppage of hepatic blood flow is effective for treatment of hepatic metastatic tumor.

Catheterization↗
PubMed1998

RET protooncogene mutations in patients with apparently sporadic medullary thyroid carcinoma.

We examined RET protooncogene mutations in sporadic medullary thyroid carcinoma (MTC), using polymerase chain reaction (PCR)-based sequencing. DNA was extracted from tumor tissue and peripheral blood leukocytes of seven unrelated individuals with apparently sporadic MTC. Oligonucleotide primers were selected to amplify exons 10, 11, 13, 15, and 16 of the RET protooncogene, to examine the sequences of codons 609, 611, 618, and 620 of exon 10, codon 634 of exon 11, codon 768 of exon 13, codon 883 of exon 15, and codon 918 of exon 16. Direct DNA sequencing from PCR products was then performed. The results showed that one patient had a somatic mutation at codon 918 (ATG-->ACG), causing a Met-->Thr substitution. One patient had a de novo germline mutation at codon 634 (TGC-->CGC), causing a Cys-->Arg substitution. Another patient had a germline mutation at codon 634 (TGC-->TTC), causing a Cys-->Phe substitution. In the remaining four cases, no RET mutations were found. Unexpectedly, two offspring of the patient (a female) with a germline mutation at codon 634 (TGC-->TTC) harbored homozygous alleles for the mutation; because the father did not carry this mutation, the other affected allele was suspected to have resulted from a de novo germline mutation of paternal origin. One of these offspring was subsequently diagnosed as having MTC. Our findings suggest that all patients with apparently sporadic MTC should be screened for the RET protooncogene by molecular analysis to detect occult or de novo multiple endocrine neoplasia 2 (MEN 2) or familial MTC. This would allow early treatment of affected family members.

Adult↗
PubMed1998

[The RET gene in thyroid pathology].

The RET proto-oncogene encodes a receptor tyrosine kinase which plays a crucial role during the embryonic development of the enteric nervous system and of the kidney. Cytogenetic analyses of papillary thyroid carcinoma (PTC), a neoplasm which originates from thyrocytes, have revealed that somatic rearrangements of the RET gene are involved in the etiology of a significant proportion of this tumour. Medullary thyroid carcinoma (MTC) which arises from neural-crest derived C-cells is the cardinal disease feature of multiple endocrine neoplasia type 2 (MEN 2), a dominantly inherited cancer syndrome. Recent studies have provided evidence that germline mutations of the RET gene are the underlying genetic events responsible for MEN 2. This review focuses on the role of RET mutations in the pathogenesis of PTC and MTC and summarizes our present knowledge on the consequences of these alterations on the RET tyrosine kinase function. We further describe a transgenic mouse model for hereditary MTC. Mice carrying a MEN 2A allele of RET under the control of the CGRP/calcitonin promoter develop bilateral and multifocal MTC, morphologically and biologically similar to human MTC.

Animals↗
PubMed1998

Indium-111-DTPA-D-Phe-1-octreotide and technetium-99m-(V)-dimercaptosuccinic acid scanning in the preoperative staging of medullary thyroid carcinoma.

UNLABELLED: The early detection of all tumor sites in patients with medullary thyroid carcinoma (MTC) before primary surgery is important, because MTC tends to metastasize to regional lymph nodes of the neck and mediastinum early during the course of the disease. METHODS: In an approach to localize the primary tumor sites and to detect additional tumor involvement, we have performed in 22 patients with MTC either 99mTc(V)-dimercaptosuccinic acid (DMSA) and/or 111In-diethylenetriamine pentaacetic acid-D-Phe-1-octreotide scintigraphy. RESULTS: Indium-111-octreotide (150-200 MBq) identified the primary tumor in 10 of 14 patients (71%), whereas the primary tumor was visualized by 99mTc-DMSA (300-370 MBq) in 10 of 17 patients (58%). In 8 of 22 patients (36%), lymph node metastases were present at the time of diagnosis, as confirmed by histopathology and histochemistry after surgery (all <2 mm). Preoperatively, neither scan was able to detect lymph node involvement in these patients (0/8). CONCLUSION: Both 99mTc-DMSA and 111In-octreotide studies have similar sensitivity to localize primary MTC; however, these scans are not able to detect small lymph node involvement (micrometastases) before initial surgery. Unfortunately, both scans have no clinical implication for preoperative staging in patients with MTC.

Carcinoma, Medullary↗
PubMed1999

Detection of medullary thyroid carcinoma and regional lymph node metastases by magnetic resonance imaging.

OBJECTIVES: To evaluate the usefulness of magnetic resonance imaging in detecting primary medullary thyroid carcinoma (MTC) and regional metastasis to the lymph nodes, and to correlate magnetic resonance signal intensity to pathologic changes. MATERIALS AND METHODS: Magnetic resonance images in 14 patients with MTC (9 with primary disease, 5 with recurrent disease) were reviewed for signal intensities, tumor morphologic characteristics, and tumor invasion with spin-echo T1-weighted images (T1WIs), T2-weighted images (T2WIs), and gadolinium-enhanced T1WIs. Multiple regression analysis was used to examine the correlation between T2-weighted signal intensity and pathologic findings. Lymph nodes were evaluated based on signal and morphologic characteristics. RESULTS: Magnetic resonance imaging detected tumors in 9 (90%) of the 10 patients who had MTC in the thyroid gland. Extrathyroidal spread of the tumors was correctly predicted using this procedure. Most tumors were hyperintense or markedly hyperintense on T2WI. T2-weighted signal intensity of the tumor was associated with increased amyloid deposition and high tumor cellularity and low level of fibrosis (r = 0.91, P = .01). Lymph node metastasis was present in 38 (23%) of 168 surgically dissected nodes. The combined use of 4 criteria (nodule size, a minimum-maximum diameter ratio of 0.80 or greater, marked hyperintensity on T2WI, and necrosis in the node) yielded a high detection accuracy (93%) for nodal metastasis, with 74% sensitivity and 98% specificity. CONCLUSIONS: Magnetic resonance imaging is useful for detecting primary and recurrent MTC, and its signal intensity reflects the underlying pathologic changes.

Adult↗
PubMed1996

Multivariate analysis of patients with medullary thyroid carcinoma. Prognostic significance and impact on treatment of clinical and pathologic variables.

BACKGROUND: The prognostic significance of the histologic and clinical features of medullary thyroid cancer (MTC) and their impact on therapy and outcome have been evaluated infrequently in the same series. METHODS: Fifty-tree patients with MTC (32 females, 21 males; 44 sporadic, 9 familial MTC [4 families]; mean age: 46.11 +/- 14.04 years) who were operated on consecutively between 1970 and 1992 were studied. All pathology slides were reviewed. Patients were followed with clinical examination, serum calcitonin (CT), and carcinoembryonic antigen (CEA) assay, and imaging procedures (median follow-up: 4 years; mean: 5.66 +/- 4.85 years; range: 0-19 years). Impact on survival was evaluated with Kaplan-Meier survival curves compared with the log rank test for these variables: familiarity, sex, age, pT, N, M, stage, histotype, necrosis, calcitonin, gene-related peptide (CGRP), CT, CEA, thyroglobulin, chromogranin A, chromogranin A PHE5, neuron-specific enolase, amyloid, argyrophilia, synaptophysin Y38, external radiotherapy, chemotherapy, 131I therapy, postsurgical serum CT, and postsurgical serum CEA, Multivariate analysis was performed using Cox's proportional hazards model for statistically significant factors (P < 0.05). RESULTS: Ten- and 15-year cause-specific survival were 71% and 54%. Nineteen patients (35.8%) appeared to be cured and 8 (15.1%) were alive with high serum CT levels but no proven metastases. Eight recurrences as distant sites and four at the cervical region were diagnosed. Stage M, N, necrosis, and postsurgical CT and CGRP were significant prognostic factors for survival by univariate analysis, but only the stage was significant by multivariate analysis. CONCLUSIONS: Stage and postsurgical serum CT level are the most powerful and the most useful prognostic factors for MTC, while survival did not correlated significantly with the majority of available immunohistochemical markers.

Adult↗
PubMed1996

Treatment of advanced medullary thyroid carcinoma with a combination of recombinant interferon alpha-2b and octreotide.

BACKGROUND: The medical treatment of advanced medullary thyroid carcinoma (MTC) is still questionable. Results of chemotherapy are disappointing with almost no curative responses, few partial responses, and many side-effects. A recent report has suggested the activity of combination recombinant interferon alpha-2b (rIFN-alpha-2b) and octreotide, a somatostatin analogue, in the treatment of a metastatic carcinoid tumor. This new therapeutic schedule may be used in other neuroendocrine tumors. In this study we evaluated the therapeutic effectiveness of octreotide and rIFN-alpha-2b in patients with advanced MTC. METHODS: Eight patients affected by advanced MTC received octreotide at a daily dose of 150 micrograms for 6 months and subsequently at a daily dose of 300 micrograms for another 6 months, subcutaneously, and rIFN-alpha-2b at a daily dose of 5.000.000 IU intramuscularly 3 times a week for 12 months. Plasma calcitonin, carcinoembryonic antigenic levels, and morphologic staging were evaluated at 0, 1, 3, 6, and 12 months. RESULTS: The therapy was stopped in two patients because of diarrhea and toxicity of drugs used. Pre-existing diarrhea in four patients and flushing in one significantly improved during treatment. A maximum decrease of calcitonin was reached after 1 month in 2 patients and after 3 months in 4. In all of the patients carcinoembryonic antigen levels decreased during treatment. No significant changes of size of metastases were observed. CONCLUSIONS: The combination of octreotide and interferon is well tolerated and can be recommended for the treatment of advanced MTC.

Adult↗
PubMed1999

Co-segregation of MEN2 and Hirschsprung's disease: the same mutation of RET with both gain and loss-of-function?

Multiple endocrine neoplasia type 2 (MEN2) and Hirschsprung's disease (HSCR) are two dominantly inherited neurocristopathies ascribed to mutations in the RET gene [Chakravarti, 1996; Pasini et al., 1996; Eng and Mulligan, 1997]. MEN2 is a cancer syndrome comprising three related clinical subtypes: (1) MEN type 2A (MEN2A; MIM# 171400) characterized by the association of medullary thyroid carcinoma (MTC), pheochromocytoma (Pheo), and hyperparathyroidism; (2) MEN type 2B (MEN2B; MIM# 162300), which includes MTC, Pheo, mucosal neuromas, ganglioneuromatosis of the digestive tract, and skeletal abnormalities; and (3) familial MTC (FMTC; MIM# 155240), defined by the sole occurrence of MTC. HSCR (MIM# 142623) is a congenital malformation caused by the absence of enteric plexuses in the hindgut, leading to bowel obstruction in neonates. The RET gene (MIM# 164761) codes for a transmembrane tyrosine kinase, a component of a multimeric complex that also comprises one of four members of a novel family of glycosylphosphatidylinositol (GPI)-anchored receptor, GFRalpha((1-4) (e.g., GFRA1, MIM# 601496; references are detailed in Baloh et al. [1998]. Four structurally related soluble factors-glial cell line-derived neurotrophic factor (GDNF), neurturin, persephin, and artemin-are the ligands of these multimolecular receptors in which the nature of the GFRalpha determines the ligand specificity of the complex [see Baloh et al., 1998, for references]. It is well documented that RET/GFRalpha-1/GDNF delivers a signal critical for the survival of the early neural crest-derived precursors that colonize the intestine below the rostral foregut and give rise to the enteric nervous plexuses [Gershon, 1997; Cacalano et al., 1998; Enomoto et al., 1998].

Drosophila Proteins↗
PubMed1988

Metastatic medullary thyroid carcinoma. Complete response to combination chemotherapy with dacarbazine and 5-fluorouracil.

A 20-year-old woman had a sporadic case of medullary thyroid carcinoma (MTC) metastatic to the lungs. After a transient response to streptozotocin and doxorubicin, new subcutaneous lesions appeared on the left chest wall and there was progression of pulmonary disease. Because MTC is one of the amine precursor uptake and decarboxylation (APUD) tumors, treatment was undertaken with agents active in these diseases. Dacarbazine and 5-fluorouracil, given daily for 5 days every 4 weeks, resulted in complete resolution of pulmonary and subcutaneous lesions and a sharp decrease in tumor marker levels that lasted 10 months. Recurrence of the pulmonary disease lead to her death 21 months after presentation. Thus, the chemo-responsiveness of MTC may be akin to that of other APUD carcinomas (APUDomas) and treatment of metastatic MTC and other APUDomas with the combination of dacarbazine and 5-fluorouracil appears to merit further study.

Adult↗
PubMed2001

Prognostic value of codon 918 (ATG-->ACG) RET proto-oncogene mutations in sporadic medullary thyroid carcinoma.

We have determined the frequency of 918 RET proto-oncogene mutations (ATG-->ACG) in primary MTC tumors and metastases and correlated the presence or absence of this mutation with the clinical outcome of patients suffering from sporadic medullary thyroid carcinoma (MTC). A total of 197 samples, consisting of both primary tumors and lymph node metastases from 34 patients with sporadic MTC, were collected for PCR analysis of the RET 918 mutation. In 75 of the samples (38%), codon 918 (ATG-->ACG) mutations could be detected. The mutations showed a heterogeneous distribution: 21/34 patients (62%) had mutations in at least 1 tumor sample, and in 13 patients (38%) the mutation was present in all examined samples. Patients were considered 918mt when at least 1 tumor sample showed the RET 918 mutation. These 918mt and 918 wild-type (918wt) patients did not differ significantly concerning sex, age at diagnosis, TNM stage at diagnosis, number of examined tumor samples or follow-up time. However, 918mt patients showed more aggressive development of distant metastases during follow-up (p = 0.032, Fisher's exact test) with decreased metastases-free survival (p < 0.005, log-rank test). Furthermore, 918mt patients had a significantly lower survival rate than 918wt patients (p = 0.048, log-rank test). These data show that the RET codon 918 mutation has a prognostic impact on patients with sporadic MTC which may influence follow-up treatment.

Adult↗
PubMed2005

Lymph node involvement in macroscopic medullary thyroid carcinoma.

BACKGROUND: Medullary thyroid carcinoma (MTC) is a rare disease, with variable tendency to lymphatic spread. The aim of this retrospective study was to identify distinctive features of large MTC with and without nodal metastases. METHODS: Between 1993 and 2003, 28 consecutive patients underwent total thyroidectomy and neck node dissection for sporadic MTC larger than 10 mm in diameter. RESULTS: All tumours were confirmed to be malignant with a locally invasive pattern of growth. Lymph node metastases were present in 16 patients (N1) and absent in 12 (N0). There were no statistically significant differences between patients with N0 and N1 tumours concerning age (mean 52.1 versus 53.4 years), male:female ratio (0.7 versus 1.0), basal preoperative calcitonin concentration (mean 3238 versus 3076 pg/ml) and tumour size (23.3 versus 23.9 mm). There were differences in the incidence of tumour invasion (P < 0.001), vascular embolism (P = 0.011) and peritumoral thyroiditis (P = 0.039). Measurement of basal and stimulated calcitonin levels after surgery confirmed biochemical cure in all patients with N0 tumours and half of those with N1 disease (P = 0.006). CONCLUSION: There were no preoperative factors that predicted node status for MTC larger than 1 cm in this series. Total thyroidectomy and nodal dissection remains the optimal treatment.

Adolescent↗
PubMed2006

Precision study on capillary electrophoresis methods for metacycline.

A CE method for metacycline (MTC) determination was investigated in an inter-laboratory experiment. Many problems were encountered in this study, most of which were related to the transfer of the method to different CE equipment. The reported problems could be classified into different categories: problems related to the precision, to the parameters in the protocol, and to the MTC peak shape. As the peak shape problem was partially responsible for the poor precision, a new CE method was developed in order to obtain a good MTC peak shape on all equipment. The precision of this new method for MTC determination was examined in an intermediate precision study, where the influence of the factors "time" and "equipment" was investigated. Although the new method could be transferred to different instruments, the precision remained poor mainly due to the contributions of the between-replicate and the between-injection variances.

Anti-Bacterial Agents↗
PubMed1993

Genetic events in tumour initiation and progression in multiple endocrine neoplasia type 2.

Multiple endocrine neoplasia type 2 (MEN 2) is a familial cancer syndrome arising from mutation at a locus or loci in chromosome region 10p11.2-q11.2. The disease is characterized by medullary thyroid carcinoma (MTC) and pheochromocytoma (Pheo). To assess the genetic events in tumour initiation and progression in this disease, we have compiled an allelotype for MTC and Pheo tumours using polymorphic marker loci from each chromosome arm. Using a panel of 58 tumours, we found frequent allele losses on chromosome arms 1p (42%), 3p (30%), 3q (38%), 11p (11%), 13q (10%), 17p (8%), and 22q (29%). Loss of heterozygosity (LOH) for loci on chromosome 10 was detected in a single tumour where one whole chromosome copy was lost. We used a panel of polymorphic markers for each of chromosomes 1, 3, 11, and 17 to define a shortest region of overlap for these regions. The most frequent allele losses were on chromosome 1, spanning the entire short arm of the chromosome but not loci on 1q. LOH on chromosome 3 encompassed a minimal common region of 3q12-qter. The regions of allelic deletion on chromosome 11 (11pter-p13), 17 (17pter-p11.2), and 13 (13q) encompass known tumour suppressor loci (WTI, TP53, RBI) which must therefore be candidates for genes contributing to MTC and Pheo development. Our data suggest allele loss on chromosome 11, 13, or 17 occurs predominantly in tumours with losses on chromosome 3, potentially reflecting the accumulation of genetic change in tumour progression. These events may be associated with more advanced disease in MTC. We suggest that at least 7 genes contribute to tumour development in MEN 2, including an initiating locus on chromosome 10 and loci on chromosomes 1, 3, 11, 13, 17, and 22 which have a progressional role in these tumours.

Adrenal Gland Neoplasms↗
PubMed1993

CGRP radioreceptor assay: a new diagnostic tool for medullary thyroid carcinoma.

The quantitative analysis of immunoreactive calcitonin (iCT) is the assay of choice for diagnosis and follow-up of patients with medullary thyroid carcinoma (MTC). However, in a small percentage of patients with MTC or C cell hyperplasia (CCH), basal and stimulated iCT levels may not be significantly elevated. In these patients, calcitonin gene-related peptide (CGRP) radioreceptor assay (RRA) can be used complementary to immunoassay for CT (or katacalcin) for prompt diagnosis of MTC and CCH. CGRP RRA is a robust, rapid, sensitive, and specific determinant of "receptor-recognized" CGRP (RR-CGRP; intact molecule of CGRP) either in plasma or in tissue extracts. Plasma RR-CGRP levels rose > 100% 2-5 minutes after stimulation with intravenous pentagastrin (calcium or oral alcohol) (p < 0.001), whereas iCGRP levels were raised to a lesser degree (p < 0.01). In six patients who had a false positive iCT response after pentagastrin or had raised basal iCT levels measured with a two-site immunoradiometric assay, RR-CGRP showed only a minimal change. On the other hand, in patients with CCH (true positive, n = 8), iCT was increased by only 40% after pentagastrin but RR-CGRP levels rose by 140% (p < 0.001). No change in iCT or RR-CGRP levels in plasma were detected in healthy normal volunteers after administration of pentagastrin. Therefore, in addition to the plasma iCT levels, RR-CGRP would resolve some of the difficult diagnostic problems associated with MTC and likely improve the specificity and sensitivity of identifying CCH.

Adult↗