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At least 739 records · Page 41Linked to original sources
PubMed2002

Expression of the cholecystokinin 2-receptor in normal human thyroid gland and medullary thyroid carcinoma.

OBJECTIVE: The cholecystokinin(2)-receptor (CCK(2)R) promotes secretion and cell growth induced by its ligands cholecystokinin (CCK) and gastrin. The receptor has recently been shown to be expressed in human medullary thyroid carcinomas (MTCs). The objective of this study was to analyze CCK(2)R expression in MTC samples of different tumor stages as well as in non-malignant thyroid tissues. DESIGN AND METHODS: Using RT-PCR we investigated 19 MTC samples and TT-cells (a human MTC cell line), as well as samples of normal thyroid. In addition, we performed immunohistochemistry using calcitonin- and CCK(2)R-specific antibodies on MTCs and samples of C-cell hyperplasia. RESULTS: We demonstrate for the first time that CCK(2)R is expressed not only in MTCs but in all samples of normal thyroid tissue. Using immunohistochemistry the receptor could be localized on calcitonin-secreting C-cells. The highest incidence of CCK(2)R expression in MTCs was observed in early-tumor stages, whereas CCK(2)R could not be detected in advanced or metastasized tumors. CONCLUSIONS: The expression of CCK(2)R in C-cells suggests a physiological function for gastrin and/or CCK in the regulation of calcitonin release, presumably related to bone and calcium metabolism. Moreover, these ligands might act as growth factors in MTCs. Efforts in the development of CCK(2)R scintigraphy for the detection of MTC lesions might have to consider a lower incidence of the receptor in advanced tumor stages.

Adolescent↗
PubMed2003

Review of multiple endocrine neoplasia type 2A in children: therapeutic results of early thyroidectomy and prognostic value of codon analysis.

OBJECTIVES: The aim of this study was first to investigate whether early total thyroidectomy (ETT; 1-5 years of age) can prevent medullary thyroid carcinoma with persistent or recurrent disease (PRD) in pediatric patients with multiple endocrine neoplasia type 2A (MEN-2A) and second, to evaluate the strength of codon analysis in children with MEN-2A as prognostic parameter. METHODS: Case reports and review of the literature for pediatric patients with MEN-2A were conducted. Inclusion criteria were age (0-20 years) and histologic degree of C-cell disease (normal = N, C-cell hyperplasia = CCH, medullary thyroid carcinoma = MTC, metastatic MTC = MMTC). To evaluate therapeutic results of ETT (1-5 years) versus late total thyroidectomy (LTT; 6-20 years), age-dependent histologic stages of C-cell disease and postoperative occurrence of PRD were compared. Prognostic value of specific codons, age-dependent histologic distribution, and long-term outcome were analyzed. RESULTS: In a total of 260 cases, 42 (16%) underwent ETT, and 218 (84%) underwent LTT. Histologic analysis showed significant difference between ETT versus LTT (57% vs 76%) regarding malignant stage of C-cell disease (of combined rate of MTC and MMTC). Long-term outcome was documented in 74 patients (28%). During a median follow-up period of 2 years (range: 0-15 years), 21 of 65 of the LTT group versus 0 of 9 of the ETT group suffered PRD. Information about codon analysis was available in 150 patients (58%). Mutated codons were c634 (63%), c618 (19%), c620 (9%), and c804 (6%). Codon-related histologic analysis resulted in prognostic differences: 81% of patients with c634-mutation had MCT or MMTC in contrast to c804 (44%), c618 (34%), and c620 (7%). Fifteen of 17 MMTC and 7 of 9 PRD occurred in patients with c634-mutation. CONCLUSIONS: 1) ETT until 5 years of age in MEN-2A gene carriers results in significant reduction of MTC and MMTC in favor of CCH and improved disease-free long-term outcome. 2) Codon analysis is an important prognostic factor. Timing of TT could be individualized based on codon-specific prognosis. Until more detailed knowledge is available, consequent genetic and biochemical screening is mandatory for appropriate individual timing of ETT before age of 5 years.

Adolescent↗
PubMed2004

[Medullary thyroid carcinoma: clinical and oncological features and treatment].

Medullary carcinoma of the thyroid (MTC) may be sporadic or may occur on a hereditary basis. Hereditary MTC can occur either alone -- familial MTC (FMTC) -- or as the thyroid manifestation of multiple endocrine neoplasia type 2 (MEN 2) syndromes (MEN 2A and MEN 2B) or other forms. Germ-line mutations in RET cause MEN 2. Genetic testing, now available, forms the basis for MTC screening procedures. In the past few years, several genotype-phenotype correlations have focused on the relationship between specific mutations and different MEN 2 syndrome variants. Differences in dimerization induction intensities are a reasonable explanation for the phenotypes resulting from mutations of the different cysteines. Here we described the molecular mechanisms, diagnose and treatment as well as our experience on the management of this rare form of thyroid cancer.

Carcinoma, Medullary↗
PubMed2006

[Multiple endocrine neoplasia type 2].

The term multiple endocrine neoplasia (MEN) was introduced by Steiner et al. in 1968 to describe disorders that include a combination of endocrine tumors. The Wermer syndrome was designed as MEN 1 and the Sipple syndrome as MEN 2. Sizemore et al. (1974) completed that the MEN 2 category included 2 subgroups: patients with medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid disease and a normal appearance (MEN 2A) and other without parathyroid disease but with mucosal neuromas and mesodermal abnormalities (MEN 2B). MTC is usually the first tumor diagnosed. The diagnosis of MTC has several implications: disease extent should be evaluated, pheochromocytoma and hyperparathyroidism should be screened and whether the MTC is sporadic or hereditary should be determined by a direct analysis of the RET proto-oncogene. Here, the pathological characteristics, genetic abnormalities, and clinical features of MEN 2 are discussed. The diagnostic and therapeutic approaches used to patients with clinical disease and carriers identified through familiar screening are also described. Progresses related especially to genetic screening and earlier intervention have permitted an improvement in the long-term outcome. However, treatment for disseminated disease is still ineffective.

Carcinoma, Medullary↗
PubMed2001

Treatment of medullary thyroid carcinoma: an update.

Prognosis and treatment effectiveness of medullary thyroid carcinoma (MTC) are largely related to the tumour stage, so that early diagnosis represents an important goal for the management of patients. Recent advances in genetic testing have improved the clinical approach to the familial MTC syndromes. There is general agreement that the primary operation for MTC should obtain the complete removal of the neoplastic tissue in the neck, because any adjuvant treatment has never been proven to be effective. The management of residual/recurrent or metastatic MTC still remains controversial, although a multimodal approach to advanced disease may be of value in palliation or local control of tumour progression. The role of surgery, external radiotherapy, radionuclide therapy and medical treatment, including biological response modifiers and cytotoxic drugs, are reviewed and discussed.

Adult↗
PubMed2005

Medullary and papillary carcinoma of the thyroid gland occurring as a collision tumour: report of three cases with molecular analysis and review of the literature.

We report the simultaneous occurrence of medullary thyroid carcinoma (MTC) and papillary thyroid carcinoma (PTC), presenting as spatially distinct and well-defined tumour components, in three cases. In the first patient, histology, immunohistochemistry and electron microscopy demonstrated an MTC in the one nodule and PTC in two additional lesions. Non-neoplastic thyroid parenchyma separated the three nodules. Metastasis from PTC was diagnosed in a regional lymph node. Genetic analysis of both tumour components showed a distinctive mutational pattern: in the MTC a Cys634Arg substitution in exon 11 of the RET gene and in the two PTC foci a Val600Glu substitution in exon 15 of the BRAF gene. The other two patients are members of a large multigenerational family affected with familial MTC due to a germline mutation of the RET gene (Ala891Ser). Both patients harboured, besides medullary cancer and C-cell hyperplasia, distinct foci of papillary thyroid cancer, which was positive for Val600Glu BRAF mutation. Review of the literature disclosed 18 similar lesions reported and allowed the identification of different patterns of clinical presentation and biological behaviour. So far, the pathogenesis of these peculiar cases of thyroid malignancy has been completely unknown, but an underlying common genetic drive has been hypothesised. This is the first report in which two mutations, in the RET and BRAF genes, have been identified in three cases of MTC/PTC collision tumour, thus documenting the different genetic origin of these two coexisting carcinomas.

Adult↗
PubMed2006

An in-frame complex germline mutation in the juxtamembrane intracellular domain causing RET activation in familial medullary thyroid carcinoma.

Activating mutations of the RET proto-oncogene are associated with inherited syndromes, multiple endocrine neoplasia (MEN2A/2B) and with familial and sporadic medullary thyroid cancer (MTC). Single base pair missense mutations in the extracellular Cys-rich domain are responsible for most MEN2A and familial MTC (FMTC) cases. Rarely, somatic deletions and germline duplications have been described in sporadic MTC and in FMTC. We report the detection and functional studies of a deletion/insertion in exon 11 (c.2646delGinsTTCT) associated with FMTC. This in-frame complex rearrangement leads to an Asn to Lys change (Lys666Asn) and to a Ser insertion. The mutation was found in the proband, who was diagnosed with metastatic MTC at 41 years, and in her son, who presented diffuse C-cells hyperplasia at 4 years of age. The mutation displayed a transforming activity stronger than Ret wild type (Ret-WT) at the focus formation assay and functional analyses after transient and stable transfection revealed an increased autophosphorylation, indicating the constitutive activation of the receptor. The transforming activity may be favoured by an increased stabilization of the fully mature form of the mutant receptor. Dimerization assay demonstrated that the activation mechanism of the complex mutation is not mediated by stable dimer formation. Computational analysis predicted nonconservative alterations in the mutant protein consistent with a possible modification of the conformation of the receptor. In conclusion, the first molecular studies on a complex germline RET mutation lying in the juxtamembrane region of the receptor are reported. Functional analyses showed that alterations at this level too can lead to a ligand independent Ret activation.

Adult↗
PubMed2001

Molecular genetic diagnostic program of multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma syndromes in Hungary.

Medullary thyroid carcinoma (MTC) occurs usually in sporadic form, but about a quarter of the cases are hereditary and appear as part of one of the multiple endocrine neoplasia type 2 (MEN2) syndromes. Mutations in the RET protooncogene are known to be the cause of the MEN2A and familial medullary thyroid carcinoma (FMTC) syndromes in the majority of the families. Direct DNA testing allows prophylactic thyroidectomy to be offered to individuals carrying a mutation in the above codons, and in mutation-negative cases it reduces the yearly screening-related burden on family members at risk of the disease. By DNA sequencing and PCR-restriction fragment length polymorphisms, 65 MTC probands were examined for mutations in residues 609, 611, 618, 620 of exon 10, and in residues 634, 768, 804 of exons 11, 13, and 14 respectively of the RET protooncogene. In our study, mutations in the above codons were detected in all of the 14 clinically MEN2A and FMTC families. One of these mutations, TGC609 TCC has not been reported previously. Of the 14 probands with the mutation, 25 relatives also had the identified mutation and 18 relatives proved to be non-carriers. Among the 51 probands with clinically sporadic MTC, none was found to carry a mutation in the above positions even if indirect signs of MTC, pheochromocytoma or hyperparathyroidism could be detected in some families. The frequency of the TGC634AGC mutation is unexpectedly high in our samples, which can probably be attributed to a founder effect. We conclude that screening for mutations in these codons is effective in families fulfilling the strict clinical criteria of MEN2A or FMTC.

Adult↗
PubMed2001

Increasing peritoneal contact area during dialysis improves mass transfer.

Previous studies in mice demonstrated that relatively large volumes in the peritoneal cavity made contact with only 40% of the anatomic peritoneum and that this contact area (A(contact)) could be increased with use of a surfactant, dioctyl sodium sulfosuccinate (DSS). To investigate the hypothesis that mass transfer rates during peritoneal dialysis are dependent on the area of peritoneum in contact with the dialysis solution, rats were dialyzed for 2 h with a solution that contained (14)C-mannitol, with or without 0.02% DSS. The mass transfer-area coefficients (MTAC) were determined to be (mean +/- SEM, ml/min): no DSS, 0.163 +/- 0.008; with DSS, 0.247 +/- 0.006 (P < 0.002). DSS also caused an increase in total protein loss over 2 h (mean +/- SEM, mg): no DSS, 83.8 +/- 15.8; DSS, 159.5 +/- 6.3 (P < 0.001). In a separate set of animals, the ratio (R) of A(contact) to anatomic area in each plane was measured as in the previous study R(mean) (mean +/- SEM) and equaled 0.466 +/- 0.075, no DSS; 0.837 +/- 0.074, with DSS. The ratio of MTAC (1.52) and protein loss (1.90) approximate the ratio of R(mean(S)) (1.78). Because MTAC = mass transfer coefficient (MTC) x A(contact), small peritoneal transport chambers were used to determine MTC for (14)C-mannitol and fluorescein isothiocyanate-albumin. MTC(mannitol) did not change significantly with the addition of DSS. MTC(albumin) (cm/min x 10(4), mean +/- SEM) equaled 1.47 +/- 0.45 without DSS and 1.78 +/- 0.52 with DSS (P < 0.04). It was concluded that DSS increases the mass transfer rates of mannitol and protein by increasing A(contact), whereas protein transport is further augmented by an apparent increase in the barrier permeability to protein.

Animals↗
PubMed1990

Incidence of sporadic and familial medullary thyroid carcinoma in Sweden 1959 through 1981. A nationwide study in 126 patients. Swedish MCT Study Group.

Medullary thyroid carcinoma (MTC) was identified in 276 patients (in 27 diagnosed at autopsy) by a review of virtually all 6,513 notifications of primary thyroid cancer ot the National Cancer Registry in Sweden 1959 through 1981. The diagnosis was confirmed in 268 of the 276 cases by histopathological and histochemical reexamination. Anamnestic data and morphological characteristics indicated that 208 (75%) patients had sporadic and 68 (25%) familial MTC. The mean ages at diagnosis of these two groups were 57.0 and 42.6 years respectively. The age-standardized incidence rate per 10(5) inhabitants was 0.18 for males and 0.23 for females. The age-specific incidence of sporadic MTC increased markedly with age, whereas no unequivocal rise was found after the age of 20 for familial disease. Standardized morbidity ratios (SMR), calculated separately for each of the six Swedish health care regions, revealed a roughly two-fold and mostly non-significant geographical variation in the occurrence of sporadic MTC. SMR for familial disease varied, however, between 0 and 306 and deviated highly significantly from the national average in four of the six regions. Regional differences in diagnostic intensity were considered unlikely as the sole explanation of this finding.

Adult↗
PubMedDate not supplied

Combretastatin A-4 and doxorubicin combination treatment is effective in a preclinical model of human medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC), both in patients and in preclinical models, is resistant to chemotherapy. In this study, we show that the anti-neovascular agent combretastatin A-4 phosphate prodrug (CA4P) in combination with doxorubicin was effective in curtailing tumor growth in a preclinical model of human MTC. This combination of combretastatin and doxorubicin extended the doubling time of established MTC tumors in nude mice to 29 days, compared to 12 days in untreated controls. This suggests that a combination of combretastatin and a cytotoxic chemotherapeutic agent may be an effective treatment for MTC.

Angiogenesis Inhibitors↗
PubMedDate not supplied

Increased serum carcinoembryonic antigen levels as an early sign of medullary thyroid carcinoma.

OBJECTIVE: To emphasize the potential association between increased levels of carcinoembryonic antigen (CEA) and the presence of medullary thyroid carcinoma (MTC). METHODS: We present two case reports of this association, including long-term serial measurements of CEA in one patient. RESULTS: CEA is a tumor marker often associated with colon cancer. In recent years, increased CEA in plasma has been reported in patients with other cancers. Diagnoses of MTC in two patients were preceded by increased CEA levels (for 6 years in one patient). Because CEA levels returned to normal after thyroidectomy, MTC may have been the cause of the increases. CONCLUSION: In patients with increased plasma CEA levels, MTC should be considered in the differential diagnosis even if thyroid palpation is nonrevealing and thyroid function is normal.

Journal Article↗
PubMed2006

Immunoexpression of multidrug-resistance protein 2 and cyclooxygenase 2 in medullary thyroid carcinomas.

CONTEXT: Chemoresistance is due to the expression of multidrug-resistance proteins (MRPs). Cyclooxygenase 2 (COX2), a key enzyme in prostaglandins synthesis, upregulates MRP1. MRP1 is overexpressed in medullary thyroid carcinomas (MTCs), but it is not involved in resistance to doxorubicin and cisplatin, which are commonly used in MTC treatment. MRP2 is specifically involved in resistance to both chemotherapeutic agents, but no data exist on the expression of MRP2 and COX2 in MTC. OBJECTIVE: To evaluate MRP2 and COX2 expressions in MTC. DESIGN: We analyzed immunohistochemical expression of MRP2 and COX2 in 12 MTCs and in 6 lymph node metastases. Results were correlated with pTNM and clinical stage. RESULTS: MRP2 and COX2 expressions were observed only in tumor samples and metastases. Nine MTCs, all pTNM stage T4, were positive for MRP2, whereas 3 MTCs, pTNM stages T2 and T3, were unreactive for MRP2. Six metastatic MTCs at stage T4 showed higher proportion of MRP2+ cells, compared with primary tumors. All 12 MTCs were positive for COX2. Three MTCs, pTNM stage T2 and T3, showed COX2 positivity in all cells. The proportion of COX2+ cells decreased with increased pTNM stage. Four out of 6 metastatic MTCs, stage T4, showed a lower proportion of COX2+ cells, compared with primary tumors. The proportion of MRP2+ cells was inversely related to the proportion of COX2+ cells. CONCLUSIONS: MRP2 and COX2 expression correlated with pTNM stage. High MRP2 and low COX2 expression may explain resistance to doxorubicin and cisplatin, which is observed in advanced stage MTC. Evaluation of the expression pattern of these 2 proteins may be useful to predict chemosensitivity of these types of tumors.

Adult↗
PubMed1999

[Molecular genetic study of medullary thyroid cancer].

Around 25% of medullary thyroid carcinoma (MTC) cases are familial and follow an autosomal dominant mode of inheritance. In these cases, MTC is part of an inherited cancer syndrome that has three distinct forms: MEN2A, MEN2B and familial MTC (FMTC). MEN2A is the most frequent syndrome, followed by FMTC and MEN2B. In 95% of MEN2A families and 85% of FMTC families, the germ-line missense mutations underlying the disease affect one of the five cysteine codons of the extracellular domain of the RET proto-oncogene. The mutated codons are 609, 611, 618 and 620 in exon 10, and 634 in exon 11. The most frequent mutations (80% in MEN2A, and 50% in FMTC) occur in codon 634. In our laboratory, the mutations of the codon 634 was detected by two independent methods: DNA sequencing and restriction fragment length polymorphism with polymerase chain reaction (PCR-RFLP). We have so far examined 105 persons at risk and found 19 positive cases. A positive genetic diagnosis allows preventive thyroidectomy, with a resultant cause-specific survival similar to that for the general population. In the event of a negative result, the family members of the affected proband are relieved of the physical and emotional consequences of the disease and the follow-up procedures. We plan to screen all 240 known Hungarian MTC patients and their relatives.

Base Sequence↗
PubMedDate not supplied

[Medullary carcinoma of the thyroid: diagnosis and therapy].

Medullary thyroid carcinoma (MTC) originates in the thyroid C cells, or parafollicular cells, secreting calcitonin. It may be either sporadic or familial. Familial form can be isolated or expression of a multiple endocrine neoplasia type II. Mutations of the RET proto-oncogene have been identified in the germline DNA of patients with familial MTC syndromes. Genetic testing can identify patients affected by multiple endocrine neoplasia and familial MTC, allowing early diagnosis and possible cure. The initial treatment is surgical and the adequate surgery consists of total thyroidectomy. The treatment of occult or minimal disease can be curative. Plasma calcitonin measurements are excellent markers for post-operative follow-up. Imaging study can help to discover recurrent or metastatic disease. Adjunctive therapy includes radiotherapy and chemotherapy. Radiotherapy is reserved for bone metastases or for non resectable neck recurrences. Chemotherapy is reserved for patients with progressive MTC. Many chemotherapeutic regimens have been tried, results are controversial.

Calcitonin↗
PubMed2000

Intraoperative use of gamma-detecting probes to localize neuroendocrine tumors.

Neuroendocrine tumors are characterized by the expression of different peptides and biogenic amines. These rare tumors tend to grow slowly and are notoriously difficult to localize, at least in the early stages. Surgical removal is the only definitive therapeutic option for neuroendocrine tumors and relief from hyperfunctional status. The effectiveness of surgical treatment is invariably dependent upon the complete surgical excision of all tumor tissue, because microscopic and occult disease not readily seen by the surgeon may remain in situ, leading to shortened survival. Therefore, pre- and intraoperative localization of the primary as well as of metastatic tumors is of utmost importance. Radioguided surgery (RGS) is an intraoperative technique that enables the surgeon to localize radiolabelled tissue based on the characteristics of the various tissues. Concerning gastroenteropancreatic tumors (GEP), intraoperative gamma probe examination is able to reveal small tumor sites accumulating (111In-DTPA-D-Phe1)-pentetreotide more efficiently (> 90%) than somatostatin receptor scintigraphy (68%-77%), because lesions with a size smaller than 5 mm in greatest dimension could be identified. Furthermore, RGS identified 57% more lesions when compared to the "palpating finger" of the surgeon. In medullary thyroid cancer (MTC), surgical removal of the tumor is the first and most efficient treatment of the disease. Persistent or increasing serum calcitonin and carcinoembryonic antigen (CEA) levels imply tumor recurrence after thyroid ablation. For imaging recurrent MTC many radiopharmaceuticals have been used to visualize tumor sites, but none of them has shown excellent sensitivity. Preoperative somatostatin receptor scintigraphy and intraoperative RGS in patients with recurrent MTC demonstrate only part of the tumor sites and cannot visualize small tumor sites (less than 10 mm). In comparison, RGS using 99mTc(V)-DMSA detects metastases with a size of 5 mm in diameter, whereas the "palpating finger" of the surgeon localized metastases with a size of more than 1 cm in diameter. In patients with recurrent MTC, intraoperative gamma probe examination is able to localize over 30% more tumor lesions when compared with conventional preoperative imaging modalities and surgical findings. MIBG scintigraphy is the most sensitive technique for the detection and staging of neuroblastoma (sensitivity 92%; specificity nearly 100%). Intraoperative RGS with iodine labelled MIBG has been developed to improve the definition of tumor limits or to localize small, nonpalpable tumors. Comparison of 123I- and 125I-labelled MIBG revealed a sensitivity of 91% and 92%, respectively; the specificity of 125I (85%) was significantly higher than that of 123I (55%). In addition to scintigraphy of the adrenal glands by precusors of adrenal hormones, imaging with a radiolabelled somatostatin analogue is possible; however, (111In-DTPA-D-Phe1)-pentetreotide is not specific for any adrenal disease or function and the relatively high radioligand accumulation in the kidneys limited the use for detection of tumors in the area of the adrenal glands.

Endocrine Gland Neoplasms↗
PubMed2000

Serum level of vascular endothelial growth factor is influenced by erythropoietin treatment in peritoneal dialysis patients. (Grupo de Estudios Peritoneales de Madrid).

Some patients on long-term peritoneal dialysis (PD) develop a hyperpermeability state, owing to peritoneal neoangiogenesis. Vascular endothelial growth factor (VEGF), a potent mitogen for endothelial cells, has been implicated in most diseases characterized by microvascular neoformation. Erythropoietin (EPO) is able to induce endothelial proliferation in vitro. Our aim was to elucidate whether VEGF serum levels are influenced by EPO treatment, and whether VEGF serum level maintains a relationship with peritoneal transport data. We analyzed serum levels of VEGF in 35 PD patients (18 males, 17 females). Mean age was 58 years, with a mean time on PD of 98 +/- 75 months. Of the 35 patients, 19 were on automated peritoneal dialysis, and 16 were on continuous ambulatory peritoneal dialysis. Seven patients had diabetes. Peritoneal transport parameters were: urea mass transfer coefficient (MTC), 19.5 +/- 6.6 mL/min; creatinine MTC, 9.9 +/- 4.7 mL/min; net ultrafiltration, 491 +/- 166 mL per 4-hour dwell. Twenty seven patients were under therapy with recombinant human erythropoietin (rHuEPO). Mean serum VEGF levels were 347 +/- 203 pg/mL (range 66-857 pg/mL), with most patients in the normal range (60-700 pg/mL). VEGF levels did not correlate with age, sex, primary renal disease, diabetes, type of PD, time on PD, peritonitis, and cumulative glucose load. We found no correlation with urea MTC, creatinine MTC, ultrafiltration rate, or protein effluent levels. However, a significant negative correlation with residual renal function was seen (r = -0.39, p < 0.05). Patients treated with rHuEPO showed significantly higher serum levels of VEGF than non treated patients (375 +/- 220 pg/mL vs 251 +/- 75 pg/mL, p < 0.05), although they had similar residual renal function. We conclude that increased serum VEGF levels are associated with EPO treatment. Consequently, VEGF might have a role in the EPO effects found in PD patients. Whether both agents are related to peritoneal neoangiogenesis requires further research.

Biological Transport↗
PubMed2001

Mutation analysis of NTRK2 and NTRK3, encoding 2 tyrosine kinase receptors, in sporadic human medullary thyroid carcinoma reveals novel sequence variants.

Somatic mutations in the proto-oncogene RET are found in 25% to 80% of sporadic medullary thyroid carcinomas (MTCs). The significance of somatic RET mutation in MTC initiation and progression, however, remains unknown. Like RET, TRK is a neurotrophic receptor tyrosine kinase. Immunostaining has shown that only a subset of normal C cells expresses Trk family receptors, but in C-cell hyperplasia, they consistently express NTRK2, with variable expression of NTRK1 and NTRK3. In later stages of MTC, NTRK2 expression was reduced while NTRK3 expression was increased. In the context of these data, we sought to determine whether sequence variants in NTRK2 and NTRK3 are responsible for these differences in protein expression. We determined the genomic structure of NTRK2 and found that it consists of at least 17 exons varying in size from 36 to 306 bp. Mutation analysis of sporadic MTC did not reveal any sequence variants in NTRK2 but did reveal 3 variants in NTRK3, c.573C >T (N191N, exon 5), c.678T > C (N226N, exon 6) and c.1488C > G (A496A, exon 12) occurring among 19 chromosomes (31%), 1 chromosome (2%) and 24 chromosomes (39%), respectively. Corresponding germline also harbored these variants. There was a trend toward excess association of the NTRK3 variant c.1488C > G (A496A) in cases (24/62 chromosomes, 39%) compared to controls (18/62, 29%), but this difference did not reach significance (p > 0.05). The remaining 2 NTRK3 variants occurred with similar frequencies between MTC cases and population-matched controls (19 vs. 17 and 1 vs. 0, p > 0.05). We conclude that sequence variants in NTRK2 and NTRK3 are not likely to be responsible for large differences in expression at the protein level, but we cannot exclude very low penetrance effects.

Carcinoma, Medullary↗