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PubMed1998

Mutation of the RET proto-oncogene is correlated with RET immunostaining in subpopulations of cells in sporadic medullary thyroid carcinoma.

Mutations in the RET proto-oncogene, which encodes a receptor tyrosine kinase, are associated with the pathogenesis of medullary thyroid carcinoma (MTC). Somatic mutations in RET, predominantly at codon 918, and very rarely at codon 883, have been found in a proportion of sporadic MTC. We have previously shown that approximately 80% of sporadic MTCs had at least one subpopulation with a somatic RET mutation. Uneven distribution of somatic mutation within a single tumor or among metastases from a single individual was notable. In the present study, we sought to correlate RET expression, as demonstrated by RET immunohistochemistry, with mutation status in sporadic MTC for each tumor. Seventy evaluable subpopulations, belonging to 28 unrelated sporadic cases, comprising primary MTC and metastases, were immunostained with two different polyclonal antibodies raised against the C-terminus of RET. The regional presence of codon 918 or 883 seemed to coincide with increased RET immunopositivity in at least 62 of 70 (89%, P < 0.000001) tumor subpopulations. The reasons for this concordance are not entirely clear but could be related to either RNA or protein stability. Preliminary studies have suggested that the presence of somatic codon 918 mutation in MTC has a prognostic significance. If these preliminary results prove true, then given our data, we can further explore the feasibility of RET immunocytochemistry as a rapid assessment for the presence of somatic codon 918 for molecular diagnostic and prognostic purposes.

Carcinoma, Medullary↗
PubMed1999

Mutation analysis reveals novel sequence variants in NTRK1 in sporadic human medullary thyroid carcinoma.

Tyrosine kinase NTRK1 is expressed in neural and nonneuronal tissues. Like RET, NTRK1 is often activated by rearrangements that involve one of at least five other genes in papillary thyroid carcinoma (PTC). Because of similarities in involvement of the two tyrosine kinases RET (rearranged during transfection) and NTRK1 in the pathogenesis of PTC, the obvious parallels between RET and NTRK1 and between PTC and medullary thyroid carcinoma (MTC), NTRK1 seemed to be an excellent candidate gene to play a role in the genesis of MTC. Single-strand conformational polymorphism analysis of 16 exons of NTRK1, from 31 sporadic MTC, revealed variants in five exons (exons 4 and 14-17). Sequence analysis demonstrated one sequence variant each in exons 4, 14, 16, and 17, and four different variants in exon 15. Differential restriction enzyme digestion specific for each variant confirmed the sequencing results. All variants were also present in the corresponding germline DNA. Interestingly, the sequence variants at codon 604 (c1810C>T) and codon 613 (c1838G>T) ofexon 15 always occurred together and might represent linkage disequilibrium. The frequencies of the sequence variants in germline DNA from patients with sporadic MTC did not differ significantly from those in a race-matched control group. Although we did not find any somatic mutations of NTRK1 in sporadic MTC, the single-strand conformational polymorphism conditions reported here, together with the knowledge of the frequency of various sequence variants, may help in future mutation analyses of DNA from other neural and nonneural tissues.

Carcinoma, Medullary↗
PubMed2000

Preoperative calcitonin levels are predictive of tumor size and postoperative calcitonin normalization in medullary thyroid carcinoma. Groupe d'Etudes des Tumeurs a Calcitonine (GETC).

Medullary thyroid carcinoma (MTC) is a calcitonin (CT)-secreting endocrine tumor. Although plasma CT level is a specific and sensitive marker of MTC, its preoperative usefulness in predicting tumor size and postoperative CT normalization has not been documented. From a nationwide database set up by the French CT Tumor Study Group, 226 MTC patients were selected according to the following criteria: preoperative CT level determination by an immunoradiometric assay (normal value, < 10 pg/mL) within the 6 months prior to surgery, total thyroidectomy and diagnosis of MTC ascertained by histological report including tumor size. Patients were 129 females and 97 males (female/male ratio, 1.3). One hundred and twelve patients (49.6%) had the sporadic variety of the disease, 74 (32.7%) had multiple endocrine neoplasia 2A, three (1.3%) had multiple endocrine neoplasia 2B, and 37 (16.4%) had familial MTC. Median age at diagnosis was 44.8 yr (range, 4.9-80.1 yr). Complete neck dissection was performed in 159 patients (70.4%). Postoperative CT normalization was ascertained by negative response of CT to pentagastrin stimulation (< 10 pg/mL) in 94 patients. Seventy-one patients were considered as not cured because of residual tumor tissue and/or elevated CT levels. Median tumor size was 11.0 mm (range, 0.2-80.0 mm), significantly larger in females (15.0 vs. 8.0 mm, P < 0.05), and in sporadic forms (15.0 vs. 7.0 mm, P < 0.05). Tumor size was significantly correlated (r2 = 0.52, P < 0.01) with preoperative CT levels, the relationship being more straight in familial (r2 = 0.71) than in sporadic (r2 = 0.36) forms. Furthermore, preoperative CT levels under 50 pg/mL appeared to be predictive of postoperative CT normalization (44 of 45 patients). However, higher CT levels did not mean absence of postoperative CT normalization (50 of 120 patients). We conclude that low preoperative CT levels are predictive of tumor size and postoperative CT normalization.

Adolescent↗
PubMed2002

Stimulation of autologous antitumor T-cell responses against medullary thyroid carcinoma using tumor lysate-pulsed dendritic cells.

Dendritic cells (DCs) have attracted wide interest because of their unique capacity to elicit primary and secondary antitumor responses. We have generated autologous tumor lysate-pulsed DCs from three patients with medullary thyroid carcinoma (MTC) and tested them for their ability to stimulate cytotoxic T-cell responses against autologous MTC tumor cells in vitro. The aim of our investigations was to evaluate the potential efficacy of DC-based immunotherapy in patients with MTC. DCs were generated from peripheral blood monocytes using GM-CSF and IL-4 (immature DCs) or GM-CSF, IL-4, and TNFalpha (mature DCs). Our results indicate that mature tumor lysate-pulsed DCs are able to elicit a human leukocyte antigen class I-restricted cytotoxic T-cell response against autologous MTC tumor cells, whereas immature tumor lysate-pulsed DCs do not stimulate significant antitumor activity. We feel that our data may be relevant for future clinical trials of active immunotherapy using tumor lysate-pulsed DCs in patients with MTC who have residual or distant disease after surgical treatment. The fact that mature DCs displayed a substantially higher capacity to stimulate autologous antitumor T-cell responses than immature DCs underlines the importance of a maturation step in immunotherapy protocols based on DCs.

Adult↗
PubMed1996

Low body weight in Alzheimer's disease is associated with mesial temporal cortex atrophy.

There are reports of weight loss and low body mass index (BMI) in patients with AD. The mesial temporal cortex (MTC) is involved in feeding behavior and memory and is preferentially involved in AD. We studied 74 subjects, including 58 AD patients and 16 control subjects, to determine whether BMI is associated with atrophy of the MTC or other brain regions. We used MRI morphometric analysis to provide measures of regional brain atrophy. AD patients had significant brain atrophy in all measured brain regions, except the white matter, compared with normal control subjects. The MTC was the only brain region significantly associated with BMI in AD patients (r = 0.39, p = 0.003). Multiple-regression analysis indicated that addition of brain regions other than the MTC to the model did not significantly add to the prediction of BMI. We conclude that low BMI correlates best and specifically with MTC atrophy. This finding supports a connection between limbic system damage and low body weight in AD.

Aged↗
PubMed1984

Elevated serum calcitonin levels in patients with thyroid disorders.

Serum calcitonin was measured by radioimmunoassay (RIA) in 63 patients with hyperthyroidism, 37 with hypothyroidism, 9 with surgically proven medullary thyroid carcinoma (MTC) and 81 normal subjects. Provocative tests of calcitonin by calcium infusion were performed in 11 with hyperthyroidism, 10 with hypothyroidism, 6 with MTC and 14 normal subjects. Changes of calcitonin were also studied before and after treatment in 17 patients with hyperthyroidism and 12 with hypothyroidism. The basal calcitonin levels were increased in both hyperthyroidism (117 +/- 60.1 pg/ml (mean +/- SD): n = 63, P less than 0.001) and hypothyroidism (137 +/- 107 pg/ml, n = 37, P less than 0.001), and significantly increased in MTC 14 765 +/- 25 039 pg/ml, range 390 to 70 400 pg/ml, n = 9, P less than 0.001) compared with those in normal subjects (45.8 +/- 22.3 pg/ml, n = 81). Increases of calcitonin during calcium load (iv 4.5 mg calcium/kg for 10 min) were significantly lower in both hyperthyroidism and hypothyroidism patients than in those in MTC. The calcitonin levels were not correlated with the serum T3, T4, TSH concentrations or titres of serum antithyroid antibodies in hyperthyroidism and hypothyroidism. We found some tendency toward decreasing calcitonin levels with the euthyroid state after treatment in both groups, but the changes were not significant. Although exact mechanisms of increased calcitonin in hyperthyroidism and hypothyroidism were not clear, our findings suggest that a 2- to 3-fold elevation of calcitonin levels in these patients did not indicate malignancy; MTC could be readily differentiated by a calcium infusion test.

Adolescent↗
PubMed2002

Circulating procalcitonin and cleavage products in septicaemia compared with medullary thyroid carcinoma.

OBJECTIVE: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Aged↗
PubMed2005

No mutations but an increased frequency of SDHx polymorphisms in patients with sporadic and familial medullary thyroid carcinoma.

Germline mutations of the three succinate dehydrogenase subunits SDHB, SDHC and SDHD have recently been associated with familial pheochromocytoma and paraganglioma. Several reasons make these genes candidate tumor suppressor genes for medullary thyroid carcinoma (MTC): (1) SDHB lies on chromosome 1p, the region known to be deleted most frequently in MTC, (2) MTCs develop from neural crest-derived cells, as do pheochromocytomas and paragangliomas and (3) patients with germline mutations of the Ret-protooncogene develop MTCs as well as pheochromocytomas, indicating a relationship of these tumors on a genetic level. Therefore, we attempted to determine whether the tumor suppressor genes SDHB, SDHC and SDHD are involved in sporadic and familial MTC. Somatic mutations of the SDH subunits were absent in all 35 investigated MTCs. Loss of heterozygosity was found in 27% (SDHB) and 4% (SDHD) respectively. While the frequency of non-coding, intronic polymorphisms did not differ in MTC patients compared with a control population, an accumulation of amino-acid coding polymorphisms (S163P in SDHB as well as G12S and H50R in SDHD) was found among MTC patients especially patients with familial tumors, suggesting a functional connection of coding SDH polymorphisms to activating Ret mutations.

Adult↗
PubMed2004

Screening of six risk exons of the RET proto-oncogene in families with medullary thyroid carcinoma in the Czech Republic.

Medullary thyroid carcinoma (MTC) occurs as a sporadic form (75%) or as an autosomal dominant inherited familial disorder (25%) called familial MTC (FMTC) or as multiple endocrine neoplasia type 2 (MEN2) syndromes. Germ-line mutations in the rearranged during transfection (RET) proto-oncogene in exons 10, 11, 13, 14, 15 and 16 are known to be a cause of most of the familial forms. In this paper we report molecular genetic testing of 106 families with MTC (358 tested persons) from the Czech Republic in which we directly sequenced these six exons of the RET proto-oncogene. We detected germ-line mutations in 100% of MEN2B families (4/4 families), 90% of MEN2A families (9/10), 40% of FMTC families (4/10) and 7% of apparently sporadic MTC (6/82). Eleven different germ-line mutations were revealed. MEN2B was associated with mutation Met918 Thr in exon 16. In one MEN2B family beside this mutation the Tyr791 Phe was also found, which has not yet been reported. MEN2A was restricted to different mutations in exon 11 (codon 634). In FMTC and 'sporadic' MTC families the mutations in exons 10, 11, 13 and 14 were detected. The genotype/phenotype correlations are given. Genetic testing revealed germ-line mutations in 23 index patients, 24 family members and excluded them in 53 relatives.

Adolescent↗
PubMed1996

Small-solute transport across specific peritoneal tissue surfaces in the rat.

On the basis of a theoretical analysis of peritoneal transport, the tissue-specific mass transfer coefficients (MTC) for sucrose were calculated, and the MTCliver was found to be five times the magnitude of other tissue MTC. It was hypothesized that the liver was potentially the most significant single transport organ for small solutes during peritoneal dialysis. To test this hypothesis, diffusion chambers were affixed to the peritoneal surface of the rat cecum, liver, stomach, or abdominal wall to measure the in vivo bidirectional mass transfer rates of 14C-mannitol between the plasma and the fluid contained in the diffusion chambers. It was determined that the rate of mannitol transport in either direction of transport was similar for all four tissues. The MTC for plasma-to-chamber transport varied between 1.59 x 10(-3) and 2.36 x 10(-3) cm/min with MTCliver = 1.87 +/- 0.24 x 10(-3) cm/min. MTC in the opposite direction ranged between 1.73 x 10(-3) and 2.68 x 10(-3) cm/min with the MTCliver = 2.34 +/- 0.06 x 10(-3) cm/min. The authors' hypothesis concerning the MTCliver was therefore disproved. Peritoneal dialysis was also carried out in a separate series of rats, in which the area of the dissected peritoneal tissues was measured and the mass transfer-area coefficient (MTAC) for 14C-mannitol was determined to be 0.364 +/- 0.068 cm3/min (cavity to plasma) and 0.240 +/- 0.039 cm3/min (plasma to cavity). The tissue-specific MTC were then multiplied by the corresponding tissue areas and summed to estimate an MTAC of 1.0 cm3/min, which is 3 to 4 times the measured MTAC. It was concluded that the importance of a particular tissue to plasma-peritoneal transport is primarily dependent on the surface area exposed to the dialysis solution. However, only 25 to 30% of the dissected-organ tissue area may be in contact with the dialysate fluid.

Animals↗
PubMed2003

[Medullary carcinoma of the thyroid gland (sporadic, familial)].

Medullary thyroid cancer (MTC) is uncommon thyroid tumor with specific characteristics which undoubtedly divide this tumor from other thyroid malignancies. Patients with sporadic or hereditary form of MTC differ in clinical presentation, recurrence of the disease and outcome. The aim of study was to establish surgical characteristics of MTC as well as clinical factors that influence surgical treatment. The study group consisted of 68 patients with MTC managed at the Center for Endocrine Surgery between 1987 and 1999. Retrospective analysis included clinical form of the disease, general data, histological and other tumor characteristics. Mean age of the patients were 47.3 years (female/male ratio: 1.5:1). Mean size of tumor was 80.5 cm3, 72.1% patients had tumor greater than 4 cm. in diameter or extrathyroid spread. The majority of patients were in II and III stadium of the disease. Primary operation (at least total thyroidectomy) was performed in 57 (84%) patients. 2(3%) had postoperatively temporally nerve palsy and 7(10.29%) temporally hypoparathyroidism. The overall survival was 46.8 +/- 9.9% after 9 years and 63.6 +/- 7.2% at 5 years. Postoperative calcitonin value is significant predictor of survival/Spearman's coefficient (R = 0.7048)/, worse prognosis is in correlation with high postoperative calcitonin values. The treatment of choice is at least total thyroidectomy and central lymph nodes resection if enlarged lymph nodes are found. Precise operative technique lowers the risk of postoperative complications. Complex approach to the patient with MTC includes all available methods in pre and postoperative evaluation as well as surgeon's knowledge and skill.

Adolescent↗
PubMed2003

Medullary thyroid carcinoma. Genetic screening and prophylactic thyroidectomies.

Medullary thyroid cancer is a rare, neuroendocrine, tumor. It arises from parafollicular or C-cells with the ability to produce and secrete different bioactive substances like calcitonin (TC) and CEA (1-5) TC is ideal tumor marker in early diagnosis, in patents' follow up and in evaluation of their treatment. TC determinations after ca/pentagastrine stimulation test give us even more accurate results and the procedure is used for biochemical family screening. MTC occurs as a sporadic tumor or in hereditary settings MEN 2A, MEN 2B and FMCT. Germ/line point mutations in RET proto/onkogene are responsible for tumor arise and inheritance of settings. Genetic screening provides information of these RET mutations in family members even before pathologic changes occur. These individuals with MEN 2A, 2B and FMCT characteristic RET mutations are almost certain to acquire MTC (95% penetrance) in their lives and are candidates for preventive total thyroidectomy (TT), with or without central neck dissection (CND). Surgery is still the treatment of choice for MTC and only C-cell hyperplasia and early stage of MTC can be cured. Prophylactic thyroid surgery eliminates the possibility of MTC but doesn't influence appearance of other diseases (PHEO, HPTH) of MEN 2 syndromes.

Adolescent↗
PubMed1997

Dopamine infusion enhances the adrenocorticotropic hormone and cortisol response to metoclopramide in hyperprolactinemic patients but not in normal subjects.

Based on the facts that prolactin and adrenocorticotropic hormone (ACTH) each seem to influence the secretion of the other, that dopamine is the established inhibitory factor for prolactin secretion and negatively modulates ACTH release, and finally that alterations of the central dopaminergic tone have been postulated in tumorous hyperprolactinemia, we studied the effects of pharmacological manipulations of the dopaminergic system on ACTH and cortisol secretion in patients bearing a prolactinoma and in normal subjects. Twenty-seven patients with a prolactin-secreting pituitary tumor and 12 healthy controls were submitted to three tests: (a) 4-h saline infusion; (b) 10 mg metoclopramide (MTC) as an intravenous bolus after a 2-h saline infusion; and (c) 4-h dopamine infusion at the dose of 0.01 microgram/kg/min with a 10-mg intravenous bolus of MTC given at the second hour of dopamine infusion. Administration of MTC, compared to saline, caused a moderate (not significant) plasma ACTH increase, and a significant cortisol increase (p < 0.05), both in hyperprolactinemic and normal subjects, without statistically significant differences between the two group. When MTC was administered during dopamine infusion, the ACTH and cortisol elevation was significantly potentiated in prolactinoma patients while it was similar in magnitude to that recorded after MTC alone in control subjects. These findings support the concept of an inhibitory role exerted by dopamine and are compatible with a stimulatory influence exerted by prolactin on corticotropin-releasing hormone and ACTH secretion, and also favor the view of a reduced central dopaminergic tone in patients with tumorous hyperprolactinemia.

Adrenocorticotropic Hormone↗
PubMed2005

[Prophylactic thyroidectomy in children and young people with hereditary medullary thyroid carcinoma: a Chilean experience].

BACKGROUND: With the availability of the RET proto-oncogene genetic testing, it is possible to perform prophylactic total thyroidectomy among carriers of RET mutation. AIM: To evaluate the histological findings and the effects of the prophylactic total thyroidectomy in first-degree relatives of Chilean patients with multiple endocrine neoplasia type 2 (MEN 2) based on the Ret proto-oncogene analysis. SUBJECTS AND METHODS: Nineteen patients belonging to 11 MEN 2 families underwent total thyroidectomy. Of these, 16 either with C cell hyperplasia (CCH) or microscopic medullary thyroid carcinoma (MTC) were selected for the final analysis. RESULTS: The age at the moment of thyroidectomy ranged from 3 to 24 years (median 9.5). The most common mutation was located in codon 634 (69%) followed by codon 620 (25%). Histopathology revealed MTC in 13 patients (81%, youngest 3 years, oldest ones 19 and 24 years) and CCH in 3. A significant correlation was observed between basal preoperative serum calcitonin/tumor size (r = 0.53, P < 0.05) and age/tumor size (r = 0.56, P < 0.03), but not between basal preoperative serum calcitonin and age. Stimulated preoperative calcitonin levels were confounding and not useful for differentiating CCH from MTC. None of patients in whom cervical dissection was done (9/16) presented lymph node metastases, including the oldest ones. All patients but the older ones were biochemically cured after a mean of 5 years of follow-up. CONCLUSION: Prophylactic total thyroidectomy should be done early in life because there is an age-dependent progression from HCC to MTC. MTC often precedes biochemical detection of the disease.

Adolescent↗
PubMed2005

Surgical management of thyroid carcinoma.

Thyroid carcinoma has a unique biologic behavior characterized by early spread to regional lymph nodes and occasional extrathyroidal soft tissue extension but a low incidence of distant metastasis and infrequent disease-related death. Therefore, controversy exists over the proper extent of thyroidectomy and regional lymph node dissection in patients with differentiated thyroid carcinoma (DTC) and medullary thyroid carcinoma (MTC). The modest disease-specific mortality makes it unlikely that the extent of surgery will ever be the subject of a prospective randomized trial. Although more extensive cervical surgery may have only a limited effect on the duration of survival in patients with DTC, it may significantly improve quality of life by minimizing cervical recurrence. The high rates of cervical recurrence in patients with DTC and MTC have alerted physicians to the importance of fine-needle aspiration biopsy and ultrasonography for the diagnosis, preoperative staging, and follow-up of thyroid cancer. In patients with MTC, death caused by disease is uncommon in the absence of radiographically evident distant metastasis at the time of thyroidectomy. Cervical recurrence is even more common with MTC, and the need for compartment-oriented lymphadenectomy is accepted as standard surgical treatment to minimize disease recurrence. Postoperatively, calcitonin (CT) levels can be used to guide clinical management, but basal CT levels should not be used to direct the timing of prophylactic thyroidectomy in affected high-risk patients with familial MTC.

Biopsy, Fine-Needle↗
PubMed1999

Radiolabeled peptides for targeting cholecystokinin-B/gastrin receptor-expressing tumors.

UNLABELLED: The high sensitivity of pentagastrin stimulation in detecting primary or metastatic medullary thyroid cancer (MTC) suggests widespread expression of the corresponding receptor type on human MTC. Indeed, autoradiographic studies have demonstrated cholecystokinin (CCK)-B/gastrin receptors not only in more than 90% of MTCs but also in a high percentage of small cell lung cancers, some ovarian cancers, astrocytomas and potentially a variety of adenocarcinomas. The aim of this study was to systematically screen and optimize, in a preclinical model and a pilot clinical study, suitable radioligands for targeting CCK-B receptors in vivo. METHODS: A variety of CCK/gastrin-related peptides, all bearing the C-terminal CCK receptor-binding tetrapeptide sequence Trp-Met-Asp-PheNH2 or derivatives thereof, were studied. They were radioiodinated by the lodogen or Bolton-Hunter procedures. The peptides were members of the gastrin or CCK families, which differ by the intramolecular position of a tyrosyl moiety. Their stability and affinity were studied in vitro and in vivo; their biodistribution and therapeutic efficacy were tested in nude mice bearing subcutaneous human MTC xenografts. Diethylenetriamine pentaacetic acid (DTPA) derivatives of suitable peptides were synthesized successfully, and their preclinical and initial clinical evaluations were performed, labeled with 111In. RESULTS: All members of the CCK or gastrin families were stable in serum (with half-lives of several hours at 37 degrees C); nevertheless, the stability of those peptides bearing N-terminal pGlu residues or D-amino acids was significantly higher. In accordance with their comparably low affinity, nonsulfated members of the CCK family showed fairly low uptake in the tumor and other CCK-B receptor-expressing tissues. Sulfated CCK derivatives performed significantly better but also displayed a comparably high uptake in normal CCK-A receptor-expressing tissues. This effect was probably due to their similar affinity for both CCK-A and CCK-B receptors. Best tumor uptake and tumor-to-nontumor ratios were obtained with members of the gastrin family because of their selectivity and affinity for the CCK-B receptor subtype. Pilot therapy experiments in MTC-bearing animals showed significant antitumor efficacy compared with untreated controls. DTPA derivatives of minigastrin were successfully developed. In a pilot clinical study, radioiodinated and 111In-labeled derivatives showed excellent targeting of physiological CCK-B receptor-expressing organs, as well as all known tumor sites. CONCLUSION: CCK/gastrin analogs may be a useful new class of receptor-binding peptides for diagnosis and therapy of CCK-B receptor-expressing tumors, such as MTC or small cell lung cancer. Nonsulfated gastrin derivatives may be preferable because of their CCK-B receptor selectivity, hence lower accretion in normal CCK-A receptor-expressing organs.

Adult↗
PubMed1999

Cholecystokinin-B/gastrin receptor binding peptides: preclinical development and evaluation of their diagnostic and therapeutic potential.

The high sensitivity of pentagastrin stimulation in detecting primary or metastatic medullary thyroid cancer (MTC) suggests widespread expression of the corresponding receptor type on human MTC. Indeed, autoradiographic studies demonstrated cholecystokinin (CCK)-B/gastrin receptors not only in >90% of MTCs but in a high percentage of small cell lung cancers and potentially a variety of gastrointestinal adenocarcinomas. In a pilot study, we have demonstrated the feasibility of radiolabeled gastrin-I to target CCK-B receptor-expressing tissues in vivo in animals and patients (T. M. Behr et al., Eur. J. Nucl. Med., 25: 424-430, 1998). The aim of the present study was to systematically optimize, in a preclinical model, suitable radioligands for targeting CCK-B receptors in vivo. For this purpose, a variety of CCK/gastrin-related peptides, all having in common the COOH-terminal CCK-receptor binding tetrapeptide sequence Trp-Met-Asp-PheNH2 or derivatives thereof, were studied. They were radioiodinated by the Iodogen or Bolton-Hunter procedures. The peptides tested were members of the gastrin- or cholecystokinin families or possessed characteristics of both, which differ by the intramolecular position of a tyrosyl moiety (occurring in native or sulfated form). Their stability and affinity were studied in vitro and in vivo; their biodistribution and therapeutic efficacy were tested in nude mice bearing s.c. human MTC xenografts. Diethylene-triamine-pentaacetate derivatives of suitable peptides were synthesized, evaluated, and labeled with (111)In. All members of the CCK or gastrin family were stable in serum (with t(1/2)s of several hours at 37 degrees C); nevertheless, the stability of those peptides was highest that bore the NH2-terminal pGlu residues (e.g., big gastrin, gastrin-I, caerulein, and others) or D-amino acids. In accordance to their comparably low affinity, nonsulfated members of the CCK family showed fairly low uptake in the tumor and other CCK-B receptor-expressing tissues (e.g., the stomach). Sulfated CCK derivatives performed significantly better but additionally displayed a high uptake in normal, CCK-A receptor-expressing tissues (such as the liver/gallbladder, pancreas, and bowel). Best tumor uptake and tumor:nontumor ratios were obtained with members of the gastrin family, probably because of their selectivity and affinity for the CCK-B receptor subtype. Pilot therapy experiments in MTC bearing animals showed significant antitumor efficacy as compared with untreated controls. (111)In-Labeled diethylene-triamine-pentaacetate derivatives of minigastrin showed excellent targeting of CCK-B receptor-expressing tissues in animals and a normal human volunteer. These data suggest that CCK/gastrin analogues may be a useful new class of receptor binding peptides for diagnosis and therapy of CCK-B receptor-expressing tumors, such as MTC or small cell lung cancer. Nonsulfated gastrin derivatives may be preferable because of their CCK-B receptor selectivity, and hence, lower accretion in normal CCK-A receptor-expressing organs. Further preclinical as well as clinical studies are ongoing.

Amino Acid Sequence↗
PubMedDate not supplied

Role of nuclear medicine in the diagnosis and therapy of medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) originates in the parafollicular cells (C cells) of the thyroid, secreting both calcitonin and CEA. Genetic and biochemical testing allow early pre-clinical identification of familial forms. Sporadic MTC usually presents as a solitary palpable thyroid nodule and in most cases the definitive diagnosis is established only at the time of surgery. Nuclear medicine procedures, which play a minor role in the preoperative evaluation of MTC, are essential in postoperative follow-up to detect residual and/or recurrent tumor. A number of radiopharmaceuticals are able to visualize MTC lesions with considerable advantages in diagnosis and prognosis, some of them having also a therapeutic role. Among them, 99mTc[V]DMSA shows the highest diagnostic sensitivity and is considered by many authors the radiopharmaceutical of choice in the postoperative work-up of MTC. Radioiodinated MIBG, in spite of its high specificity has a poor sensitivity (30%); however it is useful for the identification of pheochromocytoma and, in patients showing MIBG uptake in tumoral lesions, high activities of 131I-MIBG may be used for therapy. 111In labeled octreotide detects lesions which express somatostatin receptors; a positive scintigraphic result seems to give also prognostic information (higher uptake in slow-growing lesions) and provides the basis for treatment with octreotide or lanreotide and 111In or 90Y-labeled octreotide analogues. Interesting perspectives are offered by 18F-FDG PET and monoclonal anti-CEA labeled antibodies; the latter may be also used for therapy.

Carcinoma↗