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PubMed2006

Prognostic significance of disseminated tumor cells in the connective tissue of patients with medullary thyroid carcinoma.

INTRODUCTION: Disseminated tumor cells in the connective tissue (CT-DTCs) do not have any connection to a primary tumor or the lymph nodes. They are identified quite often in patients with medullary thyroid carcinoma (MTC), but nothing is known regarding their prognostic significance. METHODS: Among 450 patients with MTC, 69 (15%) were identified as having CT-DTCs. A case-control group of patients without CT-DTCs was selected. The two groups were matched concerning TNM classification, age, heredity, and sex. Because many patients with CT-DTCs had extrathyroidal tumor extension (pT4 category), distant metastases (M1 category), or both, only 35 matched pairs could be identified. The TNM classification in both groups was as follows: pT1, n = 8; pT2, n = 15; pT3, n = 4; pT4, n = 8; pN0, n = 4; pN1, n = 31; M0, n = 30; M1, n = 5. The mean age was 46.8 +/- 17.0 years in the CT-DTC group and 44.4 +/- 15.0 years in the case-control group (NS). RESULTS: In both groups, 23 patients had sporadic MTC, and 12 patients had hereditary MTC. Neither mean basal preoperative nor postoperative calcitonin levels differed significantly between the two groups. In contrast, none of the patients with CT-DTCs was biochemically cured (normal calcitonin level after pentagastrin stimulation) compared to eight patients without CT-DTCs (P < 0.005). The two groups did not differ concerning other parameters (basal calcitonin level > 3000 pg/ml, more than 10 lymph node metastases, more than two involved locoregional lymph node compartments, mediastinal lymph node metastases) that have been reported to correlate with the lack of or almost (< 10%) lack of biochemical cure. CONCLUSIONS: In patients with MTC, disseminated tumor cells in the connective tissue correlate with advanced tumor stages and appear to be of prognostic significance.

Adolescent↗
PubMed2000

Temporal bone findings in multiple endocrine neoplasia type 2B.

To our knowledge, present case is the first published report of temporal bone findings in multiple endocrine neoplasia type 2B (MEN-2B). We describe a 43-year-old Japanese man with medullary thyroid carcinoma (MTC), pheochromocytoma, mucosal neuroma and a Marfanoid body habitus. The collateral adrenal tumors and MTC were removed surgically. However, 14 years after surgery, the MTC and pheochromocytoma recurred and the patient died of intracranial hemorrhage due to hypertension. During the autopsy, metastatic MTC was detected in the liver, lungs, kidneys, pancreas and cervical lymph nodes. Recurrent pheochromocytoma was present in the right kidney. Mucosal neuromas were found in the tongue, gastrointestinal tract and vesical nerve plexus. The following histopathological findings were seen in both temporal bones: metastatic MTC was found as well as neuromas and the cochlear aqueduct was widely patent.

Adult↗
PubMed2006

Genotype-phenotype correlations in Hungarian patients with hereditary medullary thyroid cancer.

The genotype and phenotype characteristics of Hungarian patients with RET proto-oncogene mutations operated on for hereditary medullary thyroid cancer (MTC) were studied. The genetic screening was performed in two centers and 40 patients with hereditary MTC or C-cell hyperplasia (CCH) from 18 unrelated families were analyzed. One patient having a mutation in exon 16 (Met918Thr) presented with the MEN2B phenotype, six patients from two families had hereditary MTC without pheochromocytoma (pheo) and primary hyperparathyroidism (PHPT), whereas 33 patients from 15 families showed the MEN2A phenotype. Two different mutations were identified in exon 10 (Cys609Tyr and Cys609Ser), five different mutations were present in exon 11 (Cys634Phe, Cys634Arg, Cys634Tyr, Cys634Trp and Cys634Ser), and two different mutations were localized in exon 14 (Val804Met and Val804Leu). Mutations in exon 10 were associated with hereditary MTC (Cys609Tyr) or with MEN2A syndrome (Cys609Ser). Mutations in exon 11 were always associated with the MEN2A phenotype. PHPT was present in one patient with mutation in exon 14 (Val804Met), whereas all other patients affected with mutations in exon 14 had hereditary MTC without PHPT and/or pheos.

Adolescent↗
PubMed2004

Multiple endocrine neoplasia type 2.

Multiple endocrine neoplasia type 2 (MEN-2) is a hereditary syndrome that is transmitted in an autosomal dominant pattern. MEN-2A, MEN-2B, and familial medullary thyroid cancer (MTC) comprise the MEN-2 syndrome. A germline mutation in the RET proto-oncogene is responsible for the MEN-2 syndrome. Recent data indicate that in 99% of MEN-2 cases, a germline RET mutation can be identified by genetic testing. The phenotypic variation of MEN-2 is diverse and partly related to the codon and specific point mutation in the RET proto-oncogene. There are increasing data on the genotype-phenotype correlations in patients with MEN-2 and this information should be used for screening at-risk patients and treatment of RET mutation carriers. All patients (especially if young) with MTC or bilateral pheochromocytoma should have a careful family history taken and genetic screening for RET germline mutations. Patients who are RET germline mutation carriers but without clinical or biochemical evidence of MTC should have a prophylactic total thyroidectomy. The optimal age of thyroidectomy should be based on the RET genotype (eg, high-risk mutations within the first year of life, intermediate-risk mutations by 5 years of age, and low-risk mutations by 10 years of age). Patients who are diagnosed with clinical or biochemical evidence of MTC should have a total or a near total thyroidectomy and at least a central neck lymph node dissection. Patients who have pheochromocytoma and a unilateral adrenal tumor on a localizing study should have a unilateral laparoscopic adrenalectomy after preoperative alpha-blockade. However, patients with bilateral adrenal tumors on localizing studies should have bilateral laparoscopic adrenalectomy. A cortical-sparing (subtotal) adrenalectomy may be considered, if technically feasible, to avoid long-term steroid dependence and to reduce the risk of Addisonian crisis. Patients with biochemical evidence of primary hyperparathyroidism should have a bilateral neck exploration and total parathyroidectomy and autotransplantation (30-60 mg of the most normal parathyroid tissue) to the nondominant forearm if asymmetric parathyroid hyperplasia is present. Rarely, patients may have only single-gland disease and excision may be performed if the other parathyroid glands are not found with biopsy to be hyperplastic. All unresected parathyroid glands should be marked with a clip because patients with MEN-2A have a high risk of persistent and recurrent primary hyperparathyroidism. Patients with familial MTC may have not manifested the other features of MEN-2A, thus these patients should have continued follow-up for pheochromocytoma and primary hyperparathyroidism.

Adrenal Gland Neoplasms↗
PubMed2005

Medullary thyroid carcinoma: management of lymph node metastases.

Medullary thyroid carcinoma (MTC) is a neuroendocrine malignancy of the thyroid C cells. Spread of MTC commonly occurs to cervical and mediastinal lymph nodes. MTC cells do not concentrate radioactive iodine, and are not sensitive to hormonal manipulation. Because of these features, the treatment of metastatic or recurrent MTC is different from the treatment of differentiated thyroid cancer. Surgery is the only effective therapy at present that can result in cure, or reduction in tumor burden, or effective palliation. Systematic surgical removal of at-risk or involved lymph node basins should be done in patients with palpable primary tumors and recurrence. A "berry-picking" approach is discouraged. Although data are limited, standard chemotherapy and radiation therapy have not been effective in the treatment of MTC. Newer targeted drug therapies are being examined in therapeutic clinical trials.

Calcitonin↗
PubMed1989

Uptake of 131I-metaiodobenzylguanidine by 6-23 rat medullary thyroid carcinoma.

Uptake of 131iodine-metaiodobenzylguanidine (131I-MIBG) by 6-23 rat medullary thyroid carcinoma (MTC), was studied in vitro and in vivo. In vitro, there was an 8-fold increase in 131I uptake by 6-23 cells when labeled with 131I-MIBG (131I 24 +/- 15 cpm/10(6) cells, 131I-MIBG 196 +/- 9 cpm/10(6) cells). MIBG uptake in vitro was the same at 4 degrees C and 37 degrees C. In contrast, 131I-MIBG uptake by PC-12 rat pheochromocytoma cells were 200 times greater (131I-MIBG 42,412 +/- 6,755 cpm/10(6) cells). 131I-MIBG uptake by rat MTC cells in vitro were of a comparable magnitude to the uptake of 131I-MIBG by rat ileal enterochromaffin cells (RIE-1) and mouse colon cancer cells (MC-26). In vivo, uptake of 131I-MIBG by 6-23 MTC tumor was considerably less than in the normal tissues (muscle, liver, spleen, kidney, adrenal and thyroid). Gamma camera studies of 131I-MIBG uptake by 6-23 MTC tumors growing in Wag-Rij rats were only transiently positive in 1 out of 4 rats studied. We conclude that 131I-MIBG is poorly taken up by rat medullary thyroid carcinoma and is an unpredictable marker for localization of rat MTC.

3-Iodobenzylguanidine↗
PubMed1991

Familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2B map to the same region of chromosome 10 as multiple endocrine neoplasia type 2A.

Medullary thyroid carcinoma (MTC) occurs as a component of three well-described autosomal dominant familial cancer syndromes. Multiple endocrine neoplasia type 2A (MEN 2A) is characterized by MTC, pheochromocytomas, and parathyroid hyperplasia. Patients with the rarer multiple endocrine neoplasia type 2B (MEN 2B) syndrome develop MTC and pheochromocytomas, as well as mucosal neuromas, ganglioneuromatosis of the gastrointestinal tract, and a characteristic "marfanoid" habitus. Finally, MTC is transmitted in an autosomal dominant pattern in some families without associated pheochromocytomas or parathyroid hyperplasia (familial medullary thyroid carcinoma, MTC1(2). Sixty-one members of two well-characterized kindreds segregating MTC1 and 34 [corrected] members of six families segregating MEN2B were genotyped using a panel of RFLP probes from the pericentromeric region of chromosome 10 near a locus for MEN 2A. Statistically significant linkage was observed between the chromosome 10 centromere-specific marker D10Z1 and MTC1 (maximum pairwise lod score 5.88 with 0% recombination) and D10Z1 and MEN2B (maximum pairwise lod score 3.58 with 0% recombination). A maximum multipoint lod score of 4.08 was obtained for MEN2B at the position of D10Z1. In addition, 92 members of a previously unreported large MEN2A kindred were genotyped, and linkage to the pericentromeric region of chromosome 10 is reported (maximum pairwise lod score of 11.33 with 0% recombination between MEN2A and RBP3). These results demonstrate that both a locus for familial MTC and a locus for MEN 2B map to the pericentromeric region of chromosome 10, in the same region as a locus for MEN 2A. The finding that each of these three clinically distinct familial cancer syndromes maps to the same chromosomal region suggests that all are allelic mutations at the same locus or represent a cluster of genes involved in the regulation of neuroendocrine tissue development.

Adrenal Gland Neoplasms↗
PubMed2005

Extent of disease and practice patterns for medullary thyroid cancer.

BACKGROUND: There have been significant improvements in the management of medullary thyroid cancer (MTC), and consensus treatment guidelines have been established by numerous international and national societies. It is unclear if the advances in diagnosis and treatment of MTC have led to earlier diagnosis and more complete initial treatment of patients with MTC. STUDY DESIGN: Patients with MTC (n=1,070) were identified in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database from 12 population-based cancer registries between 1973 and 2000. Four equal-time quartiles (group I=1973 to 1979, group II=1980 to 1986, group III=1987 to 1993, and group IV=1994 to 2000) were compared for changes in demographics, extent of disease, and treatment. RESULTS: Mean tumor size was significantly larger in 1988 than in 1989 through 2000 (p=0.044), but there was no significant trend toward smaller tumor size. The number of patients having total or near total thyroidectomy increased significantly in the latter two quartiles (p < 0.001) but not the number of patients having cervical lymph node dissection. Unfortunately, 15% of patients in group IV still had less than total or near total thyroidectomy, and 41% had no cervical lymph node dissection. There were no significant differences in age, gender, rate of lymph node or distant metastasis, SEER stage, TNM stage, and cause-specific mortality among the four time groups and annually. CONCLUSIONS: There was no significant trend toward earlier stage of disease at diagnosis and treatment and no significant increase in the survival of patients with MTC during a 28-year period. A high proportion of patients continue to receive less than optimal initial surgical treatment.

Adolescent↗
PubMed2003

Interaction of a putative transcriptional regulatory protein and the thermo-inducible cts-52 mutant repressor in the Bacillus subtilis phage phi105 genome.

A 144 amino acid residue cts-52 mutant repressor (mtc phi 105) located in the EcoRI-F immunity region (immF) of Bacillus subtilis phage phi 105 is involved in the control mechanism of a thermo-inducible expression system. Adjacent to the repressor gene, an open-reading frame, designated ORF4, encodes a polypeptide of 90 amino acid residues, which shares a 37% homology with the amino acid sequence of the repressor. On the basis of the protein sequence alignment, a DNA-binding alpha helix-beta turn-alpha helix (HTH) motif was identified in the N-terminal region (residues 18-37) of the repressor as well as in the polypeptide of ORF4 (residues 22-41). In vivo expression of the mutant repressor and ORF4 were confirmed by real-time reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot analysis. To study their DNA binding properties, the wild-type repressor (wtc phi 105) and the mutant repressor mtc phi 105, which has a Thr17 to Ile substitution, were overexpressed in Escherichia coli and purified for affinity assays. Their affinities towards six operator sites at various temperatures were elucidated by surface plasmon resonance (SPR). Our data showed that a temperature shift does not influence the wtc phi 105-operators' binding affinity, while the binding of mtc phi 105 to the operators was temperature sensitive. This explains how thermo-induction triggers the release of the mutant repressor and renders heterologous gene expression. Interestingly, mtc phi 105 and ORF4 demonstrated a large affinity discrepancy towards individual operators at different temperatures. mRNA levels monitored by real-time RT-PCR indicated a suppression of mtc phi 105 expression, but a stimulation of ORF4 transcription after thermo-induction. Our data suggested that ORF4 might be a counter protein to the phage repressor in the modulation of the two divergent-oriented promoters P(M) and P(R) within the immF region.

Amino Acid Sequence↗
PubMed2006

Identifying Mycobacterium tuberculosis complex strain families using spoligotypes.

We present a novel approach for analysis of Mycobacterium tuberculosis complex (MTC) strain genotyping data. Our work presents a first step in an ongoing project dedicated to the development of decision support tools for tuberculosis (TB) epidemiologists exploiting both genotyping and epidemiological data. We focus on spacer oligonucleotide typing (spoligotyping), a genotyping method based on analysis of a direct repeat (DR) locus. We use mixture models to identify strain families of MTC based on their spoligotyping patterns. Our algorithm, SPOTCLUST, incorporates biological information on spoligotype evolution, without attempting to derive the full phylogeny of MTC. We applied our algorithm to 535 different spoligotype patterns identified among 7166 MTC strains isolated between 1996 and 2004 from New York State TB patients. Two models were employed and validated: a 36-component model based on global spoligotype database SpolDB3, and a randomly initialized model (RIM) containing 48 components. Our analysis both confirmed previously expert-defined families of MTC strains and suggested certain new families. SPOTCLUST, which is available online, can be further improved by incorporating data obtained using additional strain genetic markers and epidemiological information. We demonstrate on New York City (NYC) patient data how the resulting models can potentially form the basis of TB control tools using genotyping.

Adolescent↗
PubMed2005

A unique Vgamma5-T-cell population in the murine mammary gland.

Mammary epithelia and the epidermis share a common embryologic origin. Like resident epidermal T cells (ETC), a significant number of murine mammary gland T cells (MTC) express Vgamma5-T-cell receptors (TCR). MTC were assessed to see if they express the same invariant Vgamma5/Vdelta1-TCRs as those of ETC. MTC-derived hybridomas, positive for Vgamma5-TCRs, expressed Vdelta5 instead of Vdelta1. Additionally, they showed non-germline additions in the gamma-TCR and delta-TCR junctions, sharing among them an identical 19-nucleotide N-region in the delta-TCR junctions. Vgamma5-TCR and Vdelta5-TCR gene sequences from fresh peripartum MTC also contained variable N-regions, including a 7-nucleotide N-region similar to one found in the hybridomas. Thus, Vgamma5-TCR+ MTC are distinct from Vgamma5-TCR+ ETC by expressing variable non-canonical TCRs, predicting differences in the two T-cell populations in ligand specificity and in function.

Animals↗
PubMed2004

The cholecystokinin2-receptor mediates calcitonin secretion, gene expression, and proliferation in the human medullary thyroid carcinoma cell line, TT.

Gastrin-induced release of calcitonin from medullary thyroid carcinomas (MTC) is based on the expression of the cholecystokinin(2)-receptor (CCK(2)R) in these tumors. Recently, we have shown that the CCK(2)R is expressed not only in MTC but also in C-cells within the normal thyroid gland. The functions of the CCK(2)R in MTC and C-cells are largely unknown. We therefore explored the effects of gastrin-induced CCK(2)R stimulation in the highly differentiated MTC cell line, TT. CCK(2)R expression in TT-cells is detectable by RT-PCR as well as immunocytochemistry. Stimulation of the CCK(2)R by gastrin induces immediate release of calcitonin from TT-cells. Moreover, quantitative (LightCycler) RT-PCR demonstrates that gastrin stimulates transcription of the calcitonin and chromogranin A genes in TT-cells. TT-cell proliferation, assessed by counting of viable cells and (3)H-thymidine uptake, is markedly increased by gastrin. This effect is inhibited by the CCK(2)R-specific antagonist L-365,260. Our findings suggest physiological functions for the CCK(2)R in calcitonin-secretion and gene expression as well as a pathophysiological role in MTC proliferation. CCK(2)R antagonists might have therapeutic potential in these tumors.

Calcitonin↗
PubMed2004

Hereditary medullary thyroid carcinoma in patients greater than 50 years old.

BACKGROUND: Despite near complete penetrance and frequent early evaluation of medullary thyroid carcinoma (MTC) in multiple endocrine neoplasia 2 (MEN 2) variants, a significant minority of patients are evaluated later in life. METHODS: With the aim of characterizing the expression of hereditary MTC in an older cohort, MEN 2 patients from our institutional database who were evaluated after age 50 years were identified, and clinical data were reviewed. RESULTS: Thirty-nine patients (36 MEN 2A, 3 FMTC, and no MEN 2B) who were evaluated after age 50 years were identified; they represented 9% of all MEN 2 patients who were enrolled in our program. Most of the patients (79%) had abnormal screening examinations, and the AJCC staging was significantly higher in this cohort compared with younger patients. Overall, 43% of the patients had normal calcitonin levels after operation. There were 3 observed MTC-related deaths, all from distant metastases; the overall survival rate was 86% at 5 years and 74% at 10 years. The distribution of RET mutations in this cohort was similar to younger patients. CONCLUSIONS: These results suggest the presence of modifiers of MTC expression. Despite the tendency of older patients with hereditary MTC to have advanced stage disease at evaluation, they have high rates of biochemical cure, and the overall survival is excellent.

Age Factors↗
PubMed2006

Cellular effects of imatinib on medullary thyroid cancer cells harboring multiple endocrine neoplasia Type 2A and 2B associated RET mutations.

BACKGROUND: Activating mutations in the RET gene, which encodes a tyrosine kinase receptor, often cause medullary thyroid carcinoma (MTC). Surgical resection is the only curative treatment; no effective systemic treatment is available. We evaluated imatinib, a tyrosine kinase inhibitor currently used to treat chronic myelogenous leukemia and gastrointestinal stromal tumors, as a potential drug for systemic treatment of MTC, in 2 MTC-derived cell lines expressing multiple endocrine neoplasia-associated mutant RET receptors. METHODS: We determined RET expression and Y1062 phosphorylation using Western blot analysis and quantitative polymerase chain reaction. We determined the effects on cell proliferation by a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay, and we used fluorescence-activated cell sorter analysis with annexin V/propidium iodide staining to study imatinib-induced cell-cycle arrest, apoptosis, and cell death. RESULTS: Imatinib inhibited RET Y1062 phosphorylation in a dose-dependent manner after 1.5 hours of exposure. After 16 hours both RET Y1062 phosphorylation and protein expression levels were affected. Dose-dependent decreases in cell proliferation of both cell lines after exposure to imatinib with inhibitory concentration of 50% levels of 23 +/- 2 micromol/L and 25 +/- 4 micromol/L were seen. These values are high, compared with those for chronic myelogenous leukemia and gastrointestinal stromal tumors. We further could show that imatinib induced cell-cycle arrest, and apoptotic and nonapoptotic cell death. CONCLUSIONS: Imatinib inhibits RET-mediated MTC cell growth affecting RET protein levels in vitro in a dose-dependent manner. The concentration of imatinib necessary to inhibit RET in vitro, however, makes it impossible to conclude that imatinib monotherapy will be a good option for systemic therapy of MTC.

Apoptosis↗
PubMed2006

Apoptosis-mediated medullary thyroid cancer growth suppression by the PI3K inhibitor LY294002.

BACKGROUND: Medullary thyroid cancer (MTC) cells exhibit frequent activation of the PI3K pathway as evidenced by the presence of hyperactivation of Akt kinases and overexpression of neuroendocrine (NE) markers. We hypothesized that the inhibition of the PI3K pathway in MTC may lead to a reduction in cell growth and NE tumor marker production. METHODS: Human MTC-TT cells were treated with the PI3K inhibitor LY294002 (0-60 micromol/L) for 8 days, and cellular growth was measured. Further, TT cells were treated with nontoxic concentrations of LY294002 for 2 days, and Western blot analyses were performed for phospho-Akt, total Akt, and the NE tumor markers CgA and human achaete-scute homolog1 (ASCL1). RESULTS: Treatment of TT cells with LY294002 significantly suppressed levels of phospho-Akt. Notably, a dose-dependent reduction in cellular proliferation was also observed. Importantly, NE marker production was also reduced. Mechanistically, we show that cell growth inhibition by PI3K inactivation is mediated by apoptosis attributable to an increase in the levels of cleaved poly(ADP-ribose) polymerase and caspase-3. CONCLUSIONS: MTC cell growth and NE marker production appear to depend on activation of the PI3K-signaling cascade. Inhibition of this important signal transduction pathway may lead to a possible therapeutic strategy to treat patients with MTC.

Apoptosis↗
PubMed1996

Familial medullary thyroid carcinoma: not a distinct entity? Genotype-phenotype correlation in a large family.

BACKGROUND: Multiple endocrine neoplasia type 2A (MEN 2A) is a hereditary syndrome characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism. Familial MTC (FMTC) is characterized by MTC only. Both MEN 2A and FMTC are caused by germline mutations of the RET proto-oncogene. PURPOSE: To assess genotype/phenotype correlations, large families have to be examined periodically over a long period using an extensive screening program. PATIENTS AND METHODS: Since 1973, we screened a large family with hereditary C cell carcinoma for MTC, pheochromocytoma, and parathyroid disease by clinical tests and imaging methods. A germline codon Cys618 to Ser mutation in the RET proto-oncogene was recently identified in this family. The disease phenotype associated with this mutation was compared with that of Cys634 mutations in some other large MEN 2A families. RESULTS: The distinct course of disease in the family described here is similar to that in other FMTC families and MEN 2A families with a Cys618 mutation of the RET gene, but clearly different from that in families with a Cys634 mutation. The frequency of pheochromocytomas and parathyroid disease is clearly lower, whereas cure rates and life expectancy are higher. However, in families with a Cys618 mutation, pheochromocytoma and parathyroid disease do occur. CONCLUSION: In FMTC families with cysteine codon mutations of the RET proto-oncogene, screening for other endocrinopathies is mandatory, since these may not be MTC-only families. Therefore, we suggest that MEN 2A families should not be subclassified into MEN 2A and FMTC, but rather according to their specific mutation in the RET protein (i.e., for this family MEN 2A RET C618S).

Adrenal Gland Neoplasms↗
PubMed1998

Prophylactic thyroidectomy for medullary thyroid carcinoma in gene carriers of MEN2 syndrome.

BACKGROUND/PURPOSE: Although medullary thyroid carcinoma (MTC) can occur sporadically, in the pediatric population it is most often associated with the multiple endocrine neoplasia syndrome (MEN type 2). Traditional screening was based on evaluation of basal and stimulated serum calcitonin levels. The recent cloning of the MEN2 gene on the RET proto-oncogene of chromosome 10 now allows for testing of gene carrier status in individuals at risk who could benefit from prophylactic treatment. The current study was undertaken to determine the appropriate age for safe total prophylactic thyroidectomy. METHODS: Over a 16-year period, 12 patients with a family history of MEN2A and one with a MEN2B underwent total thyroidectomy and central neck dissection without parathyroid autotransplantation. Four patients (31%) were treated previously for Hirschsprung's disease. RESULTS: In seven patients (mean age, 11.8 years) undergoing biochemical screening for diagnosis, multifocal MTC and C cell hyperplasia (CCH) were found in all the resected specimens. Of six patients identified with genetic screening (mean age, 9.1 years), two had elevated stimulated calcitonin levels, one (age 14) had evidence of MTC, and one (age 6) had CCH. Four patients with normal calcitonin levels had no evidence of MTC (ages 6, 8, 10) but there was one occurrence of CCH (age 11). No permanent postoperative hypoparathyroidism or recurrent laryngeal nerve damage occurred in this series. With a mean follow-up of 4 years (range, 1 to 14 years), the overall disease-free survival is 100%. CONCLUSIONS: From this study the authors conclude that total thyroidectomy can be performed safely in children and should be the treatment of choice in patients with a family history of MEN2A carrying a germinal RET mutation even if the serum basal or stimulated serum calcitonin level is normal. Total thyroidectomy should be performed as early as 5 years of age before the occurrence of CCH or MTC.

Adolescent↗
PubMed1998

Sensitivity and cost minimization analysis of radiology versus olive palpation for the diagnosis of hypertrophic pyloric stenosis.

BACKGROUND/PURPOSE: Two strategies are commonly used for the initial diagnosis of hypertrophic pyloric stenosis (HPS): (1) physical examination and (2) radiologic evaluation using upper gastrointestinal series (UGI) or sonography. The authors wished to determine the sensitivity and relative cost of each strategy. METHODS: The charts of 234 patients presenting over 3 years with a history suggestive of HPS were reviewed retrospectively. Cost, expressed as mean diagnostic charges (MDC) and mean total charges (MTC), was calculated according to two theoretical models. In model A, all patients first are examined by a surgeon. If an olive is palpable, they proceed to surgery. If not, they are sent to radiology. In model B, all patients have radiologic investigation first, and then surgical evaluation if the study result is positive. RESULTS: Of the 234 patients, 150 had HPS (64%). Olives were appreciated in 111 of these (palpation sensitivity of 74%). There was one false-positive olive (0.7%) and no false-negatives. Sonography and UGI were equally accurate (sensitivity of 100%, 0.5% false-positive). Equations were generated to estimate MDC and MTC for our patient population under each model. In model A, MDC = $507 - ($221 x palpation sensitivity) and MTC = $2,543 ($240 x palpation sensitivity). In model B, MDC = $449 and MTC = $2,454, and costs were independent of ability to feel an olive. When cost was plotted against palpation sensitivity, model A yielded a lower MDC than model B if palpation sensitivity was at least 26%, and a lower MTC if palpation sensitivity was at least 37%. Because our palpation sensitivity was 74%, approximately $100 per patient would be saved by sending all infants suspected of having HPS to a surgeon for examination as an initial step. CONCLUSIONS: Although highly sensitive, imaging is superfluous if an olive is palpable. Children suspected of having HPS should have a surgical consultation before a radiology study as long as the surgeon's palpation sensitivity for an olive is at least 37%. Improved palpation skills will result in maximum financial savings.

Costs and Cost Analysis↗