The surgical scientist.
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Education, Medical, Continuing↗
Biomedical subjects
S A Wells
Publications and source records attributed to S A Wells.
Parathyroid adenomas in the aortopulmonary window.
PURPOSE: To describe localization studies in nine patients with ectopic parathyroid adenomas in the aortopulmonary window. MATERIALS AND METHODS: Nine patients with ectopic parathyroid tissue (eight adenomas, one hyperplastic gland) in the aortopulmonary window were examined with ultrasound (US), computed tomography (CT), magnetic resonance (MR) imaging, and scintigraphy. Diagnostic arteriography (n = 4) and venous sampling (n = 3) were performed in the first four patients; arteriography for the purpose of staining was attempted in the last five patients. RESULTS: The results of CT and MR imaging studies were positive in eight of nine patients (89%) and five of eight patients (63%), respectively. The results of thallium/technetium scintigraphy were negative in three patients scanned (0%), but the results of a repeat study in one patient were positive (33%). Sestamibi scans were positive in six of six patients (100%). Single photon emission CT was performed in all six patients and enabled distinction between adenomas in the aortopulmonary window and those in the thymus. CONCLUSION: Ectopic parathyroid glands in the aortopulmonary window are usually detected at sestamibi scintigraphy, and SPECT is helpful in distinguishing these adenomas from more common adenomas in the anterior mediastinum. CT and MR imaging studies can also enable this distinction, but imaging must extend below the aortic arch.
Adenoma↗
Genetic testing and early thyroidectomy for inherited medullary thyroid carcinoma.
The recent identification of mutations in the RET proto-oncogene that are associated with multiple endocrine neoplasia type 2 (MEN 2) syndromes has allowed therapeutic intervention in affected individuals on the basis of direct genetic testing. The principal endocrine neoplasm that occurs in patients with the MEN 2 syndromes is medullary thyroid carcinoma. This thyroid neoplasm is the only consistently malignant feature of the MEN 2 syndromes and it is the most common cause of death in affected patients. Kindred members at risk for one of the MEN 2 syndromes can be studied by direct DNA analysis to determine whether they have inherited a RET mutation. Those with a positive test can be treated by early thyroidectomy and cured when the disease is microscopic and localized to the thyroid gland. Total thyroidectomy is performed as early as 5 years of age and is associated with minimal morbidity and virtually no mortality. Residual or persistent medullary thyroid carcinoma following thyroidectomy can best be determined by detecting increased levels of calcitonin following the administration of intravenous calcium gluconate and pentagastrin.
Adolescent↗
RET gene and its implications for cancer.
The RET proto-oncogene encodes a protein receptor tyrosine kinase. RET mutations are associated with the dominantly inherited cancer syndromes multiple endocrine neoplasia (MEN) types 2A and 2B and familial medullary thyroid carcinoma (FMTC). In MEN 2A, MEN 2B, and FMTC, direct detection of RET mutations can be used to identify disease allele carriers prior to the development of clinically evident neoplasms. RET mutations are also associated with sporadic thyroid carcinomas. The effects of RET mutation on protein function have been investigated both in vivo and in vitro, and the study of RET has served to provide insights into the mechanisms of tumorigenesis in general.
Alleles↗
Colors of the spectrum. Advanced practitioners in gerontology.
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Aged↗
The surgical journal in the year 2000.
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Forecasting↗
Research support under various federal proposals.
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Government↗
Frequent mutations of CDKN2 in primary pancreatic adenocarcinomas.
The gene encoding the cell-cycle regulatory protein p16, CDKN2, is localized on chromosome band 9p21. CDKN2 is frequently deleted or mutated in a variety of tumor cell lines, including pancreatic cancer cell lines and xenografts, as well as in some primary tumors. We examined 32 primary pancreatic adenocarcinomas for CDKN2 mutations and for loss of heterozygosity of 9p21 sequences to assess the role of CDKN2 in pancreatic carcinogenesis. Single-strand conformation variant analysis (SSCV) and direct sequencing of the variants revealed somatic CDKN2 mutations in 11 of 32 tumors (five frame-shift mutations, five nonsense mutations, and one missense mutation). One tumor appeared to be characterized by homozygous deletion of CDKN2. These results suggest that CDKN2 plays an important role during tumorigenesis or tumor progression in a significant proportion of pancreatic adenocarcinomas.
Adenocarcinoma↗
Mapping eight new polymorphisms in 11q13 in the vicinity of multiple endocrine neoplasia type 1: identification of a new distal recombinant.
Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant disorder that predisposes affected individuals to neoplasms of the parathyroid glands, endocrine pancreas, anterior pituitary, and carcinoids. The MEN1 locus has been localized by family studies to 11q13, flanked by markers PGA and D11S97. Eight new polymorphisms located in three separate radiation-reduced somatic cell hybrid segregation groups were developed. The order of the new markers, within the context of previously described loci, was determined by linkage analysis on the Venezuelan reference pedigree. Four independent MEN1 families, consisting of 57 affected individuals, and 70 individuals at-risk for the disease were genotyped. Sixteen people inherited a chromosome that shows recombination between a linked marker and the disease. The nearest proximal and distal markers that show recombination with the disease are D11S822 and GSTP1, respectively, thereby narrowing the candidate region for MEN1 by 50% on the distal side. Using these loci in haplotype analysis, an accurate presymptomatic molecular diagnostic test has been developed. These new markers in 11q13 linked to MEN1 also facilitate the genetic and physical characterization of this very gene-rich region.
Adolescent↗
Two maternally derived missense mutations in the tyrosine kinase domain of the RET protooncogene in a patient with de novo MEN 2B.
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Adult↗
Creating a culturally competent workforce.
Culturally sensitive health care professionals will have a distinct advantage in the 21st century. As the United States continues to grow as a multicultural society, practitioners will require access to cultural diversity training tailored to the needs of health care providers. The American Occupational Therapy Association offers an array of such educational resources through its Multicultural Affairs Program.
Allied Health Personnel↗
Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B.
Multiple endocrine neoplasia type 2B (MEN 2B) is a human cancer syndrome characterized by medullary thyroid carcinoma (MTC), pheochromocytomas, mucosal neuromas, ganglioneuromas of the intestinal tract, and skeletal and ophthalmic abnormalities. It appears both as an inherited disorder and as de novo disease. Sequence analysis of germ-line DNA from MEN 2B patients revealed the existence of the same point mutation in the RET protooncogene in 34 unrelated individuals. This sequence difference was not observed in 93 unaffected individuals, including the normal parents of 14 de novo MEN 2B patients. The mutation (ATG-->ACG) results in the replacement of methionine with threonine within the catalytic core region of the tyrosine kinase domain. We propose that this amino acid replacement effects substrate interactions and results in dominant oncogenic activity by the RET protein. Missense mutations in the extracellular ligand-binding domain of the RET protooncogene previously have been associated with two other disorders [MEN 2A and familial MTC (FMTC)] in which MTC is observed. MEN 2B represents the third form of heritable MTC known to be an allele of RET. Alterations in two different functional domains of the putative receptor protein tyrosine kinase are implicated in development of MTC.
Alleles↗
Surgical treatment of primary hyperaldosteronism.
OBJECTIVE: A retrospective review of patients with primary hyperaldosteronism treated at the Duke University Medical Center was performed. SUMMARY BACKGROUND DATA: The management of patients with primary hyperaldosteronism has changed dramatically in the past 20 years. The outcome of surgical treatment was examined to optimize the management of these patients. METHODS: All patients who were evaluated for primary hyperaldosteronism before operation and who had adrenal surgery at Duke University Medical Center from 1970 to 1993 were included in the study. RESULTS: A ratio of plasma aldosterone concentration to plasma renin activity greater than 250 was predictive of hyperaldosteronism in 94% of patients. This ratio also predicted the size of the adenoma. Surgical treatment cured hypokalemia in 90% of the patients. Hypertension was cured or greatly improved, with an average decrease of 50.4 mmHg and 25.2 mmHg for systolic and diastolic pressures, respectively. Patients who had hypertension for less than 5 years achieved a satisfactory blood pressure response more often (13 of 14 patients) than did patients who had hypertension for 5 or more years (15 of 20 patients). CONCLUSIONS: Preoperative evaluation of patients with primary hyperaldosteronism using current modes allows a posterior approach to be used in most patients. Adrenalectomy cures hypokalemia and hypertension; however, patients with a history of hypertension for less than 5 years may be more likely to be cured by adrenal resection.
Adenoma↗
Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A.
BACKGROUND: Missense germ-line mutations in the RET protooncogene are associated with multiple endocrine neoplasia type 2A (MEN 2A). Detection of these mutant alleles in kindred members predicts disease inheritance and provides the basis for preventative thyroidectomy. METHODS: A polymerase chain reaction (PCR)-based genetic test for the 19 known RET mutations was designed to study 132 members of 7 kindreds with MEN 2A. Haplotypes also were constructed using genetic markers flanking the MEN 2A locus. Plasma calcitonin (CT) concentrations were determined before and after provocative testing. RESULTS: Direct DNA testing and haplotype analysis showed that 21 of 58 kindred members at risk for disease had inherited a mutation in the RET protooncogene associated with MEN 2A. Plasma CT concentrations were elevated in 9 of the 21 family members, but were normal in 12. After genetic counseling, 13 of the 21 kindred members (6 with normal and seven with elevated plasma CT levels), consented to immediate thyroidectomy. In each patient, the resected thyroid gland showed C-cell hyperplasia with or without medullary thyroid carcinoma. There were no metastases to regional lymph nodes, and postoperative stimulated plasma CT levels were normal. CONCLUSION: The PCR-based direct DNA test for RET mutations is accurate, rapid, and reproducible. For all 132 individuals evaluated, the results of direct DNA analysis were consistent with haplotype studies. The direct test for mutations in the RET protooncogene is the preferred method for screening MEN 2A kindreds. In family members who have inherited a RET mutation, total thyroidectomy is indicated, regardless of the plasma CT values.
Adolescent↗
Current perspectives on the diagnosis and management of patients with multiple endocrine neoplasia type 2 syndromes.
Patients with MEN 2A, MEN 2B, and familial non-MEN medullary thyroid carcinoma (MTC) inherit MTC in an autosomal dominant fashion. This malignancy has been diagnosed previously by detecting elevated plasma calcitonin levels, a tumor marker for MTC, following the intravenous administration of secretagogues. Although the study of large pedigrees with MEN 2A, using highly informative flanking markers and linkage analysis, are highly accurate in predicting the inheritance of the disease, the method is indirect and somewhat cumbersome. Mutations in the RET proto-oncogene have been identified independently in patients with MEN 2A and familial medullary thyroid carcinoma. Even though the RET mutations are inherited with disease, there is no direct evidence that the mutations cause the MEN 2 syndromes. The usefulness of molecular methods in the diagnosis and treatment of patients with these syndromes is discussed, and a strategy for deciding operative intervention is presented.
DNA, Neoplasm↗
Predictive testing for multiple endocrine neoplasia type 2A (MEN 2A) based on the detection of mutations in the RET protooncogene.
BACKGROUND: The identification of inherited mutations in the RET protooncogene (RET) associated with multiple endocrine neoplasia type 2A (MEN 2A) has enabled the development of a genetic test to identify asymptomatic carriers of disease. METHODS: Genomic DNA was extracted from 96 members of an MEN 2A kindred. The polymerase chain reaction was used to amplify the RET exon known to contain the associated mutation. The mutation results in a new restriction endonuclease site and is detected by digestion with the appropriate enzyme. Inheritance of the mutation was verified with a previously developed genetic linkage test. RESULTS: We found that (1) mutations vary among kindreds but are consistently inherited within kindreds, (2) invariable correlation exists between mutation and disease (43 mutations in 43 affected individuals), (3) determination of the genetic status by linkage-based testing was precluded by recombination events and the informativeness of genetic markers, and (4) mutation analysis presymptomatically identified two genetically affected individuals. CONCLUSIONS: Direct genetic analysis for mutations in RET circumvents the limitations of linkage-based genetic testing and current biochemical screening assays. This method will be the diagnostic test of choice for the identification of asymptomatic individuals at risk for MEN 2A.
Amino Acid Sequence↗
Parent-of-origin effects in multiple endocrine neoplasia type 2B.
Multiple endocrine neoplasia type 2B (MEN 2B) is characterized by medullary thyroid carcinoma, pheochromocytomas, mucosal neuromas, ganglioneuromas, and skeletal and ophthalmic abnormalities. It is observed as both inherited and sporadic disease, with an estimated 50% of cases arising de novo. A single point mutation in the catalytic core region of the receptor tyrosine kinase, RET, has been observed in germ-line DNA of MEN 2B patients. We have analyzed 25 cases of de novo disease in order to determine the parental origin of the mutated RET allele. In all cases the new mutation was of paternal origin. We observe a distortion of the sex ratio in both de novo MEN 2B patients and the affected offspring of MEN 2B transmitting males. These results suggests a differential susceptibility of RET to mutation in paternally and maternally derived DNA and a possible role for imprinting of RET during development.
Chromosomes, Human, Pair 10↗
Stimulation of vasoactive intestinal peptide and neurotensin secretion by pentagastrin in a patient with VIPoma syndrome.
BACKGROUND: Pancreatic endocrine tumors (PETs) may secrete a variety of peptide hormones, either alone or in combination, and intravenously administered provocative agents have been used to stimulate hormone release to aid in the diagnosis and localization in suspected cases. These features of PETs led us to perform detailed biochemical investigations and provocative testing in a 26-year-old man with a 5 cm vasoactive intestinal peptide (VIP)-secreting tumor of the head of the pancreas. METHODS: Plasma hormone radioimmunoassays and immunohistochemical studies were performed for a panel of peptide hormones, including VIP, neurotensin, and pancreatic polypeptide (PP). Acid alcohol extracts of tumor specimens were analyzed for these peptide hormones as well. Before operation, four provocative test regimens were administered intravenously after an overnight fast: pentagastrin (0.5 microgram/kg/5 sec); rapid calcium infusion (2 mg/kg/min); a combination of calcium (2 mg/kg/min) followed by pentagastrin (0.5 microgram/kg/min); and secretin (2 clinical units/kg bolus). Blood samples were collected before each test and 1, 2, 3, 5, and 10 minutes after the infusions. RESULTS: Measurement of plasma hormone levels and tumor immunohistochemistry and hormonal extraction studies indicated secretion of VIP, neurotensin, and PP by the tumor. Coexpression of VIP and neurotensin was seen immunohistochemically within some individual tumor cells. Provocative testing resulted in maximal stimulation of VIP and neurotensin secretion with pentagastrin administration, which produced increases in plasma levels of VIP and neurotensin over basal levels of 81% and 87%, respectively. After operation, plasma levels of VIP, neurotensin, and PP were undetectable before and after administration of pentagastrin. CONCLUSIONS: The results emphasize the importance of comprehensive biochemical evaluation in patients with VIPoma syndrome to detect the production of a range of peptide hormones. Administration of intravenous pentagastrin appears to stimulate release of VIP and NT and should be evaluated further as a provocative agent for the diagnosis and follow-up of patients with these tumors.
Adult↗