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PubMed2006

Heat shock treatment of tumor lysate-pulsed dendritic cells enhances their capacity to elicit antitumor T cell responses against medullary thyroid carcinoma.

BACKGROUND: In vitro and in vivo studies have shown that dendritic cells (DCs) can stimulate antitumor T cell responses against medullary thyroid carcinoma (MTC). However, despite promising results in selected cases, the clinical efficacy of DC immunotherapy in patients with MTC has been limited. Recently, it has been demonstrated in mice that heat shock enhances the capacity of bone-marrow-derived DCs to stimulate antigen-specific T cells. The aim of our investigations was to evaluate whether heat shock also increases the capacity of human monocyte-derived DCs to stimulate antitumor T cell responses against MTC tumor cells. METHODS: DCs from six patients with metastatic MTC were pulsed with tumor lysate derived from allogeneic MTC tumor cells and were heat shocked for 12 h at 40 C or kept at 37 C. Thereafter, the DCs were matured and cocultured with T cells. Finally, the cytotoxic activity of T cells against MTC tumor cells was measured in vitro. RESULTS: In all patient samples, cytotoxic T cell responses against MTC tumor cells could be induced. Notably, heat-shocked DCs were more potent stimulators of cytotoxic T cell responses than control DCs, with T cells stimulated with heat-shocked DCs displaying a significantly increased cytotoxic activity against MTC tumor cells as compared with T cells stimulated with control DCs. In none of the experiments was a cytotoxic T cell response against unrelated pancreatic tumor cells (PANC-1) observed, using both control and heat-shocked DCs. CONCLUSIONS: Our study shows that heat-shocking DCs may be a valuable strategy to increase the immunostimulatory capacity of DCs used for immunotherapy of MTC.

Adult↗
PubMed1984

Human medullary thyroid carcinoma in culture provides a model relating growth dynamics, endocrine cell differentiation, and tumor progression.

We used an unique model, human medullary thyroid carcinoma (MTC) in culture (the TT line), to study features of neuroendocrine-related biochemistry in relationship to growth, differentiation, and tumor progression. Tumor tissues from patients with virulent MTC contain a very heterogeneous distribution of cells staining for calcitonin (CT) and have a high ratio of intracellular L-dopa decarboxylase activity (DDC) to CT. We found, in a culture line of MTC derived from a patient with virulent disease, that the degree of the inverse relationship between DDC and CT and the heterogeneous cellular distribution of CT probably relate to the rate of cellular growth and the biochemical set of individual cell clones. During exponential growth of the parent TT cell line, intracellular DDC and CT varied. DDC increased by 70% and CT decreased by 40%. Single time-point measurements in 54 cell clones or highly enriched cell populations revealed a more dramatic variability for CT (15-fold) than for DDC (5-fold). During growth of the clones having the highest and lowest CT measurements, respectively, inverse dynamics between DDC and CT were again found. However, each clone maintained a distinct range of CT during the entire growth curve, with a 2- to 4-fold difference in CT between the two clones throughout. In the low producing CT clone, ratios between DDC and CT rose to greater than 1.0 during growth, a very high value found before this study only in MTC tissues from patients with virulent disease. Immunohistochemical staining for CT of parent cells and clones grown on embryonic chick skin revealed increased cellular heterogeneity for CT distribution during growth. The TT line provides a powerful tool to study neuroendocrine related biochemical events in relationship to growth, differentiation, and tumor progression in MTC. Our in vitro findings in the TT line well explain observations made previously in patients. We conclude that: (1) DDC, a neural property of MTC, is an early differentiation marker as compared to CT and that the differentiation status of MTC cells varies inversely with cell growth rate; and (2) in patients with MTC, the virulence of the tumor probably varies inversely with differentiation status. The inverse ratio of DDC to CT is probably determined in MTC by the proportion of rapidly growing cells and numbers of cell clones which have a poor ability for maturation.

Calcitonin↗
PubMed1994

Pentagastrin stimulation test and early diagnosis of medullary thyroid carcinoma using an immunoradiometric assay of calcitonin: comparison with genetic screening in hereditary medullary thyroid carcinoma.

A pentagastrin stimulation test using a calcitonin (CT) immunoradiometric assay was performed in 38 healthy subjects and in the following 50 patients: 25 subjects from families with at least 2 known cases of medullary thyroid carcinoma (MTC), 11 subjects from families with apparently sporadic MTC, 2 pheochromocytoma carriers, 1 primary hyperparathyroidism, 8 patients with thyroid nodules, and 3 others with various diseases. In healthy volunteers, basal CT values were always less than 10 ng/L; the response to pentagastrin was below 30 ng/L for 36, and for the remaining 2, the peaks reached 30 for 1 subject and 48 ng/L for the other. The pentagastrin-stimulated CT peak was above 30 ng/L in each of the patients presented here, and all were thyroidectomized. In screening the 25 relatives of patients with familial MTC, a CT peak level over 30 ng/L was constantly associated with C-cell disease (23 cases of MTC and 2 of C-cell hyperplasia). A response to pentagastrin above 100 ng/L was observed in 15 patients among the 23 with MTC. In 8 of the 10 patients with a peak CT level between 30-100 ng/L, pathological examination showed a MTC; the other 2 had C-cell hyperplasia and a negative linkage study analysis. In the 25 other patients in the study without familial MTC, the pentagastrin-stimulated CT level was over 100 ng/L in 11 of the 14 subjects with MTC. The abnormal CT response to pentagastrin, which has been used as a criterion for surgical treatment, is currently determined by an immunoradiometric assay. Our study confirms that subjects with a peak CT level above 100 ng/L should undergo surgery whatever the reason for the test. In the context of inherited MTC, our results suggest that for patients with a CT peak level between 30-100 ng/L, surgery may actually be postponed when their probability of being gene carriers is low. Recent progress with the characterization of specific mutations in affected individuals will make familial screening much easier in the next few months.

Adolescent↗
PubMed2000

Improved diagnostic methods in the follow-up of medullary thyroid carcinoma by highly specific calcitonin measurements.

Calcitonin (CT) is an important tumor marker for medullary thyroid carcinoma (MTC). Recent CT assays chiefly recognize the monomeric form of CT (mCT). It was the objective of this study to examine the consequences of the higher specificity of the assay for interpretation of the postoperative CT values in MTC patients. The postoperative mCT concentration was measured in 214 patients with differentiated thyroid carcinoma (MTC excepted; non-MTC patients) to determine a reference range of mCT in totally thyroidectomized patients. Monomeric CT was also determined with a two-site chemiluminescence immunoassay (Nichols) in 94 healthy subjects and in 68 MTC patients. The mCT concentrations were below the detection limit in all examined completely thyroidectomized non-MTC patients. Basal and stimulated mCT values were also below the detection limit in 32 of the 68 MTC patients. The biochemical and imaging diagnosis of the latter patients did not give any indication of tumor recurrence. We conclude that completely thyroidectomized patients with non-MTC do not show any measurable mCT concentrations. In comparison with an unspecific CT-RIA, the more specific mCT determination by immunoluminometric assay permits a more precise differentiation between postoperative normal and pathological values and an earlier diagnosis of recurrent MTC.

Adult↗
PubMed1997

Genetic testing in medullary thyroid carcinoma syndromes: mutation types and clinical significance.

OBJECTIVE: To determine the types of mutations and the clinical significance of a specific genotype in familial medullary thyroid carcinoma (MTC) syndromes. DESIGN: We retrospectively and prospectively studied patients with MTC at a tertiary referral center. MATERIAL AND METHODS: The study cohort consisted of 348 affected patients and at-risk family members of MTC kindreds, including 33 multiple endocrine neoplasia type IIA (MEN IIA) kindreds with 165 members, 13 familial MTC alone (FMTC) kindreds (at least 4 affected members with MTC per kindred, without evidence of pheochromocytoma and hyperparathyroidism) with 108 members, 15 "other hereditary MTC" kindreds (2 or 3 affected members) with 42 members, and 33 individuals with sporadic MTC. An additional 53 subjects from the aforementioned MEN IIA kindreds who were clinically affected but not genetically tested were also included in an analysis of the relationship between genotype and phenotype. The presence of germline mutations in the RET proto-oncogene was studied by DNA sequence analysis of exons 10, 11, and 13. RESULTS: Germline RET mutations in exons 10 and 11 were identified in 32 of 33 MEN IIA kindreds (97%), 10 of 13 FMTC kindreds (77%), and 10 of 15 "other hereditary MTC" kindreds (67%). No mutations were identified in exon 13. No patient with sporadic MTC had a germline mutation. In MEN IIA, codon 634 was affected in 73% of the kindreds, whereas in FMTC, the main affected codon was codon 618 (54%). In MEN IIA, patients with codon 634 mutations had a higher risk of having C-cell disease, pheochromocytoma, and hyperparathyroidism than did those with other mutations (P < 0.05, P < 0.001, and P < 0.01, respectively). CONCLUSION: RET analysis is a reliable, practical, and cost-effective test in the screening of at-risk family members of MEN IIA and FMTC kindreds. In addition, RET analysis may be helpful in the follow-up of gene carriers and for the early detection of pheochromocytoma and hyperparathyroidism in patients with codon 634 mutations.

Adolescent↗
PubMed1992

Familial nonmultiple endocrine neoplasia medullary thyroid carcinoma: an evolving clinical entity.

BACKGROUND: A rare kindred of familial nonmultiple endocrine neoplasia medullary thyroid carcinoma arising from a 73-year-old proband case is reported to further define this distinct entity. METHODS: Twenty-four family members across four generations, four with medullary thyroid carcinoma (MTC) and two with C-cell hyperplasia (CCH), were studied. RESULTS: Basal calcitonin levels were elevated in three patients with MTC and were normal in one patient with microscopic MTC and two patients with CCH who had persistent subtle elevation in calcium and/or pentagastrin-stimulated calcitonin levels. One patient had unilateral MTC without CCH. Associated abnormalities included papillary carcinoma (2), thyroiditis (4), adenoma (2), and colloid nodule (1). Minimum treatment was total thyroidectomy. Two patients with MTC and marked hypercalcitonemia have recurrent disease at 2.5-year and 11-year follow-up. Two patients with MTC and normal or minor elevations in basal calcitonin and two with CCH had normal provocative calcitonin testing at 6 to 18 months follow-up. CONCLUSIONS: Unilateral MTC without CCH and MTC in the elderly do not preclude a familial cause. Microscopic MTC or CCH may be seen with subtle elevations in stimulated calcitonin levels, and recognition allows for curative thyroidectomy. Other apparent dominant thyroid pathologic conditions may occur concomitantly with familial medullary thyroid carcinoma and thus routine calcitonin, and immunohistochemical testing should be performed in patients with an appropriate family history.

Adult↗
PubMedDate not supplied

[Clinical and genetic profile of patients with medullary thyroid cancer treated in the Cancer Centre--Institute of Oncology in Warsaw].

INTRODUCTION: The aim of this study was to analyse the distribution and frequency of mutations and their correlations with clinical phenotypes of patients with MTC, to reveal the differences between sporadic and familial type of MTC, and to describe the phenotypes of patients. MATERIALS AND METHODS: 212 patients with medullary thyroid cancer (MTC) were treated in Cancer Centre in Warsaw between 1997 and 2005. In most patients, DNA isolated from peripheral blood leukocytes was tested for RET gene mutations by sequencing and accordingly MTC form was assessed. Genetic testing was performed in the relatives of patients with familial MTC in order to distinguish asymptomatic mutation carriers from noncarriers. RESULTS: RET gene mutations were identified in 46 patients (22%). The others were found noncarriers and sporadic MTC was diagnosed. MEN 2A/FMTC syndrome (multiple endocrine neoplasia type 2A/ familial type of MTC) was diagnosed in 44 patients, MEN 2B syndrome (multiple endocrine neoplasia type 2B) in 2 patients. In patients with sporadic and familial MTC, age at diagnosis and multifocal occurrence was analysed, and the results were found to be in accordance with those of other research centres. However, the distribution and frequency of mutations, as well as some clinical data, such as the frequency of pheochromocytoma occurrence as the first manifestation of MEN syndrome, differed from the published data, and further studies are necessary to reveal the reasons of these differences. CONCLUSIONS: DNA testing for RET gene mutations is reliable as a diagnostic tool and therefore it should be performed for screening of all patients with MTC or other diseases of MEN syndrome.

Adolescent↗
PubMedDate not supplied

[Gene expression profile of medullary thyroid carcinoma--preliminary results].

INTRODUCTION: Medullary thyroid carcinoma occurs both as a sporadic and a familial disease. Inherited MTC (iMTC) patients usually exhibit better prognosis than patients with sporadic form of MTC (sMTC), however, in both subtypes the outcome is unpredictable. No molecular markers contributing to the prognosis or predicting the type of therapy have been introduced to clinical practice until now. The aim of this study was to analyze gene expression pattern of MTC by high density oligonucleotide microarray. MATERIAL AND METHODS: 24 samples were studied: 12 MTC and 12 corresponding normal tissues, (Affymetrix HG-U 133A). Among MTC patients there were half inherited cases and half sporadic ones. RESULTS: First, the differences between MTC and thyroid tissue were analyzed by Singular Value Decomposition (SVD) which indicated three main modes determining the variability of gene expression profile: the first two were related to the tumor/normal tissue difference and the third one was related to the immune response. The characteristic expression pattern, beside of numerous changes within cancer- related genes, included many up-regulated genes specific for thyroid C cells. Further analysis of the second component revealed two subgroups of MTC, but the subdivision was not related to the iMTC/sMTC difference. Recursive Feature Replacement (RFR) confirmed the very similar expression profile in both forms of MTC. With subsequent ANOVA analysis some genes with differential expression could be specified, among them monoamine oxidase B (MAOB) and gamma-aminobutyric acid receptor (GABRR1) which were consistently up-regulated in sMTC. In contrary, some genes involved in regulation of cell proliferation: opioid growth factor receptor(OGFR) and synaptotagmin V (SYT 5) were up-regulated in iMTC. CONCLUSIONS: The obtained data indicate a very similar gene expression pattern in inherited and sporadic MTC. Minor differences in their molecular profile require further analysis.

Biomarkers, Tumor↗
PubMed1998

Visuotopic organisation and neuronal response selectivity for direction of motion in visual areas of the caudal temporal lobe of the marmoset monkey (Callithrix jacchus): middle temporal area, middle temporal crescent, and surrounding cortex.

On the basis of extracellular recordings in marmoset monkeys, we report on the organisation of the middle temporal area (MT) and the surrounding middle temporal crescent (MTc). Area MT is approximately 5-mm long and 2-mm wide, whereas the MTc forms a crescent-shaped band of cortex 1-mm wide. Neurones in area MT form a first-order representation of the contralateral hemifield, whereas those in the MTc form a second-order representation with a field discontinuity near the horizontal meridian. The representation of the vertical meridian forms the border between area MT and the MTc. In both areas, the fovea is represented ventrocaudally, and the visual field periphery is represented dorsorostrally. Analysis of single units revealed that 86% of cells in area MT show a strong selectivity for the direction of motion of visual stimuli. The proportion of direction-selective cells in the MTc (53%), whereas lower than that in area MT, is much higher than that observed in most other visual areas. Neurones in the cortex immediately rostral to area MT and the MTc are direction selective, with receptive fields predominantly located in the visual field periphery. In contrast, only a minority of the cells in the cortex ventral to the MTc are direction selective, and their receptive fields emphasise central vision. The results suggest that the MTc is functionally closely related to area MT, and distinct from the areas forming the dorsolateral complex. The MTc may have a role in combining information about motion in the visual field, processed by area MT, with information about stimulus shape, processed by the dorsolateral complex.

Animals↗
PubMed2003

Multiple endocrine neoplasia type 2: evaluation of the genotype-phenotype relationship.

HYPOTHESIS: Multiple endocrine neoplasia type 2 (MEN 2) is caused by RET proto-oncogene mutations and has a strong penetrance for medullary thyroid carcinoma (MTC). Subtypes are defined by the presence or absence of pheochromocytomas, hyperparathyroidism, and characteristic clinical stigmas. We hypothesize that specific RET mutations correlate with the MEN 2 phenotype and aggressiveness of MTC. DESIGN: Review of endocrine surgery database from 1951 through 2002. SETTING: Tertiary referral center. PATIENTS: Eighty-six patients from 47 kindreds were identified with MEN 2A, MEN 2B, or familial MTC. Patients were classified into 3 RET mutation risk groups: level 1, low risk for MTC (codons 609, 768, 790, 791, 804, and 891); level 2, intermediate risk (codons 611, 618, 620, and 634); and level 3, highest risk (codons 883 and 918). MAIN OUTCOME MEASURES: Stage of MTC at diagnosis and at last follow-up and frequency of pheochromocytomas and hyperparathyroidism. RESULTS: RET analysis was complete for 71 patients from 39 kindreds. Multivariate analysis identified an increased likelihood of stage III or IV MTC at diagnosis with increasing age (odds ratio, 1.12 per year of age at thyroidectomy; 95% confidence interval, 1.07-1.17; P<.001) and increasing risk group (odds ratio, 14.23 per incremental increase in MTC risk group from 1 to 3; 95% confidence interval, 3.05-66.55; P<.001). Pheochromocytomas were found in 21 patients from 12 kindreds; 20 of 21 patients had codon 634 or 918 mutations. Hyperparathyroidism was found in 10 patients from 7 kindreds; 7 of 10 patients had codon 634 mutations. CONCLUSION: Specific RET mutations predict the phenotypic expression of disease and the MTC aggressiveness in patients with MEN 2, guiding the timing of thyroidectomy and screening for pheochromocytoma.

Adolescent↗
PubMed1996

Medullary thyroid carcinoma experienced at Kanazawa University Hospital.

Eleven cases of medullary thyroid carcinoma (MTC), which were experienced at Kanazawa University Hospital between 1975 and 1993, were examined to correlate the clinical, histologic, and immunohistochemical findings. Seven patients were women and four men, and the mean age was 46.6 years. The mean follow-up was 88.3 months. Three patients had familial non-multiple endocrine neoplasia (MEN) MTC (familial MTC unassociated with other endocrinopathies) and the remaining eight had sporadic disease. At the end of the observation period, six patients were alive without disease and four were alive with metastatic disease. One patient died of MTC 8.3 years after surgery. Thus, the 10-year survival and disease-free survival rates were 67% and 53%, respectively. Histologically MTCs from the 10 surviving patients showed a classic type, while the one patient who died had a tubular variant MTC. Immunohistochemically, there were no significant correlations between the outcome of the patients and the expression of calcitonin (CT), carcinoembryonic antigen (CEA), calcitonin gene-related peptide (CGRP), or chromogranin A (CgA) in the primary tumors, and there were no differences in expression of these antigens between the primary and the recurrent tumors. Although only a small number of patients with MTC were studied here, it was suggested that the prognosis of MTC is worse than that of papillary and follicular thyroid carcinoma. The patients with lymph node involvement at the time of primary surgery showed a high risk of persistent or recurrent disease. The expressional level for the antigens did not influence the prognosis of MTC.

Adult↗
PubMed1997

Anti-carcinoembryonic antigen antibodies versus somatostatin analogs in the detection of metastatic medullary thyroid carcinoma: are carcinoembryonic antigen and somatostatin receptor expression prognostic factors?

BACKGROUND: Surgery is currently the only potentially curative approach in the treatment of medullary thyroid carcinoma (MTC). In many instances however, postsurgically elevated or rising plasma calcitonin and/or carcinoembryonic antigen (CEA) levels indicate persistent metastatic disease, although conventional diagnostic procedures (computed tomography (CT), magnetic resonance imaging (MRI), and invasive venous catheterization) fail to localize the responsible lesions. Recently, anti-CEA antibodies and somatostatin analogs have shown promising results in the staging of MTC. The aim of this study was to compare the sensitivity of both methodologies, especially for the detection of occult MTC, and to assess whether there may be correlations between the scintigraphic behavior and the patients' prognosis. METHODS: A total of 26 patients with medullary thyroid carcinoma were examined at our institution between 1977 and 1996. Ten of them had known disease, 14 had occult metastatic MTC, and 2 were free of disease at the time of presentation. Fourteen patients were investigated with anti-CEA monoclonal antibodies (MAbs) (receiving a total of 35 injections: clones BW431/26, BW431/31, IMACIS, or F023C5, labeled with 99mTc, (111)In or (131)I), and 8 patients were studied with (111)In-labeled octreotide. Two patients received potentially therapeutic doses of (131)I-labeled anti-CEA antibodies. All patients underwent conventional radiologic evaluation (ultrasonography, CT, and MRI) and/or biopsy within 4 weeks. Additional imaging was performed with 99mTc-(V)-DMSA, (131)I-metaiodobenzylguanidine, 201thallium chloride, 99mTc-methylene diphosphate, and/or 18F-fluorodeoxyglucose-positron emission tomography. Clinical follow-up was obtained. RESULTS: All patients with established disease had elevated plasma CEA (range, 6.8-345 ng/mL; calcitonin levels between 92 and 11,497 pg/mL), whereas in 9 of 14 occult cases, levels were < or = 5 ng/mL (range, 0.6-829 ng/mL; calcitonin, 72-2920 pg/mL). In patients with known disease, the overall lesion-based sensitivity was 86% for the anti-CEA MAbs, whereas octreotide was unable to target any tumor in patients with rapidly progressing disease or distant metastases (overall sensitivity, 47%). In all patients with occult MTC, anti-CEA MAbs and octreotide were able to localize at least one lesion (patient-based sensitivity, virtually 100%). In patients with postsurgically persistent hypercalcitoninemia, cervical lymph nodes were identified as the most frequent site of metastases, whereas in patients with occult and slowly progressing disease several years after primary surgery, anti-CEA MAbs and octreotide showed bilateral involvement of mediastinal lymph nodes; however, tumor to nontumor ratios were usually higher with octreotide in these cases. With anti-CEA Mabs, the highest tumor to nontumor ratios were observed in clinically aggressive, rapidly progressing disease. The sensitivity of all other diagnostic modalities was, at < or = 50%, significantly lower. Indication for antitumor effects was observed in a patient receiving 65 mCi of (111)I-labeled F(ab')2 fragments of the clone F023C5. CONCLUSIONS: For the detection of occult MTC, anti-CEA MAbs and octreotide seem to have a sensitivity that is superior to conventional diagnostic modalities, especially also when used in combination. Better detectability with anti-CEA antibodies (which may result in higher CEA expression) seems to be associated with more aggressively growing forms of MTC, whereas somatostatin receptor expression at normal CEA plasma levels and weaker MAb targeting may be associated with a more benign clinical course. This is in accordance with the study of Busnardo et al. (Cancer 1984; 53:278-85), who showed higher CEA serum levels to be associated with a worse prognosis, as well as with the in vitro findings of Reubi et al. (Lab Invest 1991;64:567-73), who demonstrated lower somatostatin receptor expression in less differentiated MTC. Fu

Adult↗
PubMed1995

Intraoperative microwave tissue coagulation as treatment for patients with nonresectable hepatocellular carcinoma.

BACKGROUND: The microwave tissue coagulator (2450 MHz) has been used clinically in the treatment of hepatocellular carcinoma (HCC) to transection of the liver parenchyma and has proven an excellent method for hemostasis. There are, however, few reports on the application of this coagulator to the induction of tumor necrosis. METHODS: Microwave tissue coagulation (MTC) was applied at laparotomy in eight patients with nonresectable multiple HCCs. All patients were treated with a combination of resection or intrahepato-arterial chemotherapy and MTC. A total of 222 bouts of MTC were applied to 21 tumors, the largest of which was 65 mm in largest dimension. The monopolar needle electrode was inserted directly into the tumor and the procedure was repeated at approximately 5 mm intervals. RESULTS: Levels of alpha-fetoprotein in serum were found to have decreased in all patients one month after surgery with MTC. Contrast-enhanced computerized tomography (CT) showed the complete absence of blood flow in all tumors subjected to MTC. Needle biopsy one month after MTC confirmed tumor necrosis in all cases. All patients are alive at the time of this report, with the longest survival period being 24 months. In three of eight patients, new tumors were confirmed by angiographic CT at sites separate from the treated tumors. MTC resulted in fewer adverse effects on liver function and less extensive inflammatory reactions than liver resection. CONCLUSION: Intraoperative MTC appears to be an effective method for inducing local tumor necrosis, and may be of use in combination with palliative surgery for multiple HCC when radical liver resection is not feasible.

Aged↗
PubMed2001

Current approaches and perspectives in the therapy of medullary thyroid carcinoma.

BACKGROUND: Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor derived from parafollicular cells. At present, surgery is the most important treatment for MTC. METHODS: We describe the current approaches of MTC treatment (surgery, chemotherapy, radiation therapy, and biologic therapy). RESULTS: MTC is currently approached surgically in the main part through total thyroidectomy and compartment-oriented microdissection of cervicomediastinal lymph nodes. Substitutive l-thyroxine administration together with close clinical monitoring and the measurement of basal and stimulated serum calcitonin are subsequently performed. Radiotherapy and chemotherapy play a marginal role in advanced MTC. Recently, it has been found that somatostatin analogs and type I interferon are able to control the neuroendocrine symptoms induced by advanced MTC and that they provide clinical benefit by improving the lifestyle of these patients. CONCLUSION: Although these agents are poorly active in inducing a shrinkage in tumor mass, the combined use of different biologic agents and cytotoxic drugs needs to be explored in advanced MTC. However, at present, surgery is the only curative treatment for MTC.

Antineoplastic Agents↗
PubMed2002

Cholecystokinin-B (CCK-B)/gastrin receptor targeting peptides for staging and therapy of medullary thyroid cancer and other CCK-B receptor expressing malignancies.

Nuclear medicine is engaged with the detection of pathological processes with the help of radionuclides. An interesting approach is to target antigens, symporters, or receptors with diagnostic and therapeutic radionuclides. Different peptide receptors like somatostatin, bombesin/GRP or VIP are (over)expressed on cancer cells, and are therefore an ideal target for the diagnosis and therapy in nuclear medicine with radiolabeled peptides. The somatostatin analogue OctreoScan [octreotide coupled with diethylene-triamine-pentaacetate (DTPA)] can be labeled with In-111 and is widely used in nuclear oncology for the staging of different tumors (e.g., carcinoids). Other peptides like neurotensin, bombesin/GRP, and VIP are under (pre)clinical investigations. The staging of metastatic medullary thyroid cancer (MTC) with the conventional radiological procedures is sometimes difficult. The high sensitivity of the pentagastrin stimulation test in detecting primary or metastatic MTC indicates the presence of tumor, but its localization is often not possible. This reaction of the tumor cells to the pentagastrin stimulation test suggests a widespread expression of the corresponding receptor type on human MTC. Indeed, autoradiographic studies demonstrated cholecystokinin (CCK)-B/gastrin receptors not only in over 90% of MTCs, but in a high percentage of small cell lung cancers, stromal ovarian, and potentially a variety of other tumors, including gastrointestinal adenocarcinomas, neuroendocrine tumors, and malignant glioma. The aim of our recent work was to develop and systematically optimize suitable radioligands for targeting CCK-B receptors in vivo and to investigate their role in the staging and therapy of MTC and other CCK-B receptor expressing malignancies. For this purpose, a variety of CCK/gastrin-related peptides, all having in common the C-terminal CCK receptor binding tetrapeptide sequence -Trp-Met-Asp-PheNH(2) or derivatives thereof, were investigated. They were members of the gastrin- or cholecystokinin families, or possessed characteristics of both, which differ by the intramolecular position of a tyrosyl moiety. Their stability and affinity were studied and optimized in vitro and in vivo; their biodistribution and therapeutic efficacy were tested in preclinical models. Best tumor uptake and tumor-to-nontumor ratios were obtained with members of the gastrin family, due to their superior selectivity and affinity for the CCK-B receptor subtype. Radiometal-labeled derivatives of minigastrin showed excellent targeting of CCK-B receptor expressing tissues in animals and healthy human volunteers. Preclinical therapy experiments in MTC-bearing animals showed significant antitumor efficacy. In a subsequent clinical study, 75 MTC patients with metastatic MTC were investigated; 43 suffered of known, 32 of occult disease. CCK-B receptor scintigraphy was performed with (111)In-DTPA-D-Glu(1)-minigastrin. The normal organ uptake was essentially confined to the stomach (and to a lower extent, to the gallbladder and, in premenopausal women, to normal breast tissue) as a result of CCK-B receptor specific binding, and to the kidneys as excretory organs. All tumor manifestations known from conventional imaging were visualized as early as 1 h p.i., with increasing tumor-to-background ratios over time; at least one lesion was detected in 29/32 patients with occult disease (patient-based sensitivity 91%). Among them were local recurrences, lymph node, pulmonary, hepatic, splenic, and bone (marrow) metastases. Eight patients with advanced metastatic disease were injected in a dose-escalation study with potentially therapeutic activities of a (90)Y-labeled minigastrin derivative at 4-6-weekly intervals (30-50 mCi/m(2) per injection for a maximum of four injections). Hematologic and renal were identified as the dose-limiting toxicities at the 40 and 50 mCi/m(2) levels. Two patients experienced partial remissions, 4 stabilization of their previously rapidly progressing disease. These data suggest that CCK-B receptor ligands may be a useful new class of receptor binding peptides for diagnosis and therapy of a variety of (CCK-B receptor expressing) tumor types. They allow for a sensitive and reliable staging of patients with metastatic MTC. Initial therapeutic results are promising, but nephrotoxicity is a major concern to be solved.

Animals↗
PubMed1995

Mutation of the RET protooncogene in sporadic medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) occurs sporadically or as part of the inherited cancer syndrome multiple endocrine neoplasia (MEN) type 2. In MEN 2A, germline missense mutations are found in one of five cysteine codons within exons 10 and 11 in the extracellular domain of the RET protooncogene. In MEN 2B, germline mutations occur in codon 918 (exon 16) within the catalytic core of the tyrosine kinase domain. To determine if RET mutations similar to those in MEN 2A and 2B play a role in the pathogenesis of sporadic MTC, we analysed 71 sporadic tumours comprising 68 primary tumours and three cell lines, for mutations in RET exons 10, 11, and 16. We found that 23% of sporadic MTC had RET codon 918 mutations, while only 3% had exon 10 mutations, and none had mutations in exon 11. We found no exon 16 mutations in MTC from 14 MEN 2A cases. Thus, exon 10 and 11 mutations, commonly found in familial MTC and MEN 2A, rarely occur in sporadic MTC; somatic mutation of RET codon 918 appears to play a role in the tumourigenesis of a significant minority of sporadic MTC but not MEN 2A tumours. In addition to their biological interest, these findings may have some clinical application in determining whether a patient presenting with isolated MTC is truly sporadic or is part of an inherited cancer syndrome.

Carcinoma, Medullary↗
PubMedDate not supplied

Gadolinium-enhanced magnetization transfer contrast imaging of intracranial tumors.

The magnetization transfer contrast (MTC) technique was used in low-field-strength (0.1 T) magnetic resonance (MR) imaging of 28 patients with intracranial tumors. MTC images were generated with an off-resonance, low-power radio-frequency pulse applied during the interpulse delay period of a gradient-echo partial-saturation sequence (TR msec/TE msec = 200/20). Images in the presence and absence of the MTC pulse were concurrently acquired before and after injection of gadopentetate dimeglumine at a dose of 0.1 mmol/kg. The contrast agent enhanced 27 of 28 tumors. Application of the MTC pulse improved the contrast-to-noise ratio (C/N) between tumor and normal white matter in 26 of 28 cases on the preinjection images and in 25 of 28 cases on the postinjection images. On the gadolinium-enhanced images, the mean C/N was 2.6 +/- 1.7 without the MTC pulse and 3.2 +/- 1.9 with the MTC pulse. The greatest contrast improvement with the MTC technique was obtained in tumors showing the strongest paramagnetic enhancement. The results indicate that MTC can improve contrast between normal brain and some intracranial neoplasms. The use of gadopentetate dimeglumine generally intensified this effect.

Adenoma↗
PubMed1986

Purification and characterization of metallothionein from liver of cadmium exposed rhesus monkeys (Macaca mulatta).

Metallothionein (MT) a low molecular weight, Cd-binding, cysteine rich, cytosolic protein has been isolated, purified and characterized from cadmium exposed Rhesus monkeys maintained on protein calorie malnourished (PCM) diet. Metallothionein was resolved into three isoforms i.e. MTa, MTb and MTc. The ratio of Cd, Zn and Cu varied in these isometallothioneins. MTc was the major isometallothionein. U.V. Spectra of MTc revealed the presence of mercaptide bonds and absence of aromatic amino acids. These observations were further confirmed by amino acid analysis of MTc which demonstrated high cysteine content (22.6) followed by serine, glycine and lysine. The molecular weight of MTc as determined by gel filtration and amino acid analysis was 13,000 and 6398 daltons respectively. This demonstrates that MTc is a nonglobular ellipsoid polypeptide. MTc showed a unique property of binding selenium. Monkey liver metallothionein was immunologically identical with human metallothionein. All the characteristics of MTc obtained in the present study reveal a similarity between monkey and human metallothionein probably due to closer phylogenetic relationship between the two species.

Amino Acids↗