Therapeutic controversy: The role of laparoscopic surgery in adrenal disease.
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Adrenal Gland Diseases↗
Biomedical subjects
S A Wells
Publications and source records attributed to S A Wells.
The American College of Surgeons Oncology Group: its genesis and future directions.
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Group Structure↗
Novel germline RET proto-oncogene mutations associated with medullary thyroid carcinoma (MTC): mutation analysis in Japanese patients with MTC.
Germ-like and somatic mutations in the RET proto-oncogene are associated with inherited and sporadic medullary thyroid carcinoma (MTC). The majority of patients with multiple endocrine neoplasia type 2A (MEN2A) and familial medullary thyroid carcinoma (FMTC) carry germ-line point mutations that result in the substitution of one of five cysteine residues. We investigated exons 10, 11, 13, 14 and 16 of the RET proto-oncogene in 33 unrelated Japanese patients with MTC. Eleven of the 33 cases (33%) were found to have germ-line mutations. Three previously unreported mutations in exon 10 and 11 were identified: one in codon 620, (TGC-->GGC), resulting in a cysteine to glycine substitution, and two in codon 630, (TGC-->TCC) and (TGC-->TAC), resulting in cysteine to serine and cysteine to tyrosine changes, respectively. The new mutations were present in the germ-line DNA of four unrelated patients for whom a family history of MTC had not been documented. Because the new RET alleles described here involve cysteine residues in a region of protein previously associated with FMTC and MEN2A, it is very likely that they represent mutations that predispose to the development of MTC.
Adolescent↗
Mutations in MLH1 are more frequent than in MSH2 in sporadic colorectal cancers with microsatellite instability.
The microsatellite instability that is a feature of tumors in patients with hereditary nonpolyposis colorectal cancer (HNPCC) is a consequence of defective DNA mismatch repair. Mutations in the DNA mismatch repair genes MSH2 and MLH1 may account for up to 90% of HNPCC kindreds. Microsatellite instability is also seen in 10-16% of sporadic colorectal cancers. A limited number of MSH2 and MLH1 mutations have been described for sporadic colorectal cancers. In this study, we screened 12 primary sporadic colorectal cancers with microsatellite instability for mutations in MSH2 and MLH1 by using reverse transcription-polymerase chain reaction (RT-PCR) and single-strand-conformation-variant (SSCV) analysis. Eight mutations were identified in six tumors. One mutation in MLH1 was found to be present in the patient's germline DNA. Four tumors had somatic mutations in MLH1, and, in two of these tumors, two different mutations were identified. A single tumor had a somatic MSH2 mutation. Our observations suggest that MLH1 is mutated more frequently than MSH2 in sporadic colorectal cancers with microsatellite instability.
Adaptor Proteins, Signal Transducing↗
Differential display in primary and metastatic medullary thyroid carcinoma.
Despite recent advances in the understanding of the role of the RET proto-oncogene in the development of familial and approximately 30% of sporadic medullary thyroid carcinomas (MTC), little is known about other genetic events that modify the course and outcome of the disease. We compared the expression of genes in intrathyroidal MTCs to autologous local lymph node metastases by means of mRNA differential display (DDRT-PCR). This is the first report of differential display using surgical specimens of a primary cancer and its metastases. Total RNA was extracted from tumor tissue of two patients with MTC associated with multiple endocrine neoplasia (MEN 2B) and sporadic MTC, respectively. Following reverse transcription (RT), the products were PCR-amplified and separated on a denaturating polyacrylamide gel. RT-PCR products demonstrating differential expression were reamplified and used as probes for Northern blot analysis. Six fragments for which differential expression was confirmed were cloned and sequenced. Resultant sequences were tested for homology to sequences in public data bases, and two novel MTC-derived fragments (MDF-1, MDF-2) were identified. Sensitivity of the method was confirmed by identification of a sequence encoding the calcitonin precursor flanking peptide which is expressed almost exclusively in MTC and normal thyroid C cells. Overexpression of the ribosomal genes S3a and P0 was found in the metastases. Recent reports suggest that components of the translational apparatus act as regulatory mediators of growth, proliferation, and neoplastic change. The altered expression of ribosomal proteins and gene products encoded by MDF-1 or MDF-2 may play an important role in the progression and metastatic spread of MTC.
Blotting, Northern↗
Heterotopic autotransplantation of parathyroid tissue in children undergoing total thyroidectomy.
AIM: The purpose of this study was to examine the efficacy of parathyroid autotransplantation in children undergoing total thyroidectomy. METHODS: We have prospectively evaluated 32 cases of total thyroidectomy in children. The ages ranged from 1 year to 15.7 years, and the mean was 8.9 years. In 31 cases, the indication for surgery was a diagnosis of MEN2A or 2B based on direct DNA testing. One child had suspected sporadic medullary thyroid carcinoma. All of the patients underwent heterotopic autotransplantation of parathyroid gland tissue. In 26 cases, the parathyroid tissue was placed in the nondominant forearm, while in 6 children it was autotransplanted into the sternocleidomastoid muscle. RESULTS: In 31 of 32 children (97%), the serum calcium level transiently decreased in the immediate postoperative period. All of the patients were placed on oral calcium carbonate and vitamin D supplementation, and the serum calcium levels became normal within several days. The supplemental medications were then weaned as tolerated. Within 3 months of their procedure, 30 patients (94%) had adequate parathyroid tissue engraftment, and the calcium and vitamin D medications were discontinued. One child required 9 months of calcium and vitamin D medications before she could be weaned from the medications. One child has been treated more recently, and is currently being weaned from supplemental calcium and vitamin D. Serum PTH levels in 22 patients who had placement of the tissue into their forearms were measured, and in each there was increased PTH in the grafted arm compared with the nongrafted arm. In five children who had parathyroid tissue grafted into the sternocleidomastoid muscle, the peripheral serum PTH levels were in the normal range. CONCLUSION: The heterotopic autotransplantation of resected parathyroid tissue is safe and effective in preventing permanent hypoparathyroidism.
Adolescent↗
"Cold" single-strand conformational variants for mutation analysis of the RET protooncogene.
BACKGROUND: RET protooncogene mutation analysis is a routinely performed predictive DNA test in kindreds affected by multiple endocrine neoplasia (MEN) types 2A and 2B and familial medullary thyroid carcinoma (FMTC), and is a valuable diagnostic tool in newly diagnosed cases of medullary thyroid carcinoma (MTC). METHODS: We tested the suitability of the recently introduced "cold" single-strand conformational variant (SSCV) technique, which promises rapid, simple, nonradioactive detection of sequence variants in the identification of germline and somatic RET mutations. A total of 11 different mutations in exon 10 (codons 609, 611, 618, and 620) and 6 mutations in exon 11 (codon 634) were studied. RESULTS: Conditions were optimized so that conformational variants were demonstrated for all mutations examined in a single setting for exons 10 and 11. A novel six base pair (bp) inframe deletion between cysteines 630 and 634 was detected in a sporadic MTC. This adds to the evidence that not only cysteine deletions and substitutions but also changes in the spacing between cysteine residues have a pathogenic effect. CONCLUSIONS: Our results indicate that the cold SSCV method offers the advantages of simplicity, time savings, and nonradioactive detection for screening for RET sequence variants in hereditary and sporadic MTCs.
Amino Acid Sequence↗
Pancreatic polypeptide is a useful plasma marker for radiographically evident pancreatic islet cell tumors in patients with multiple endocrine neoplasia type 1.
BACKGROUND: The usefulness of human pancreatic polypeptide (hPP) as a plasma marker for islet cell neoplasms is controversial. We sought to determine the relation between fasting plasma hPP levels and radiographically detectable pancreatic islet cell tumors in patients with multiple endocrine neoplasia type 1 (MEN 1). METHODS: Fasting plasma hPP levels were measured prospectively in 202 individuals from 31 independent kindreds with MEN 1. Plasma levels greater than 3.0 times the normal age-specific values were defined as elevated. Patients with elevated plasma hPP levels were evaluated with computed tomographic scanning and magnetic resonance imaging, octreotide scanning, or selective angiography. RESULTS: Twenty-two patients had elevated fasting plasma hPP levels, and 20 of these patients were evaluated radiographically. Pancreatic lesions were detected in 19 patients. A group of eight patients with normal basal fasting plasma hPP levels were evaluated with computed tomography, magnetic resonance imaging, octreotide scanning, or selective angiography based on clinical presentation. One patient in this group had an imaging study that was positive for a pancreatic lesion. CONCLUSIONS: The presence of a markedly elevated fasting plasma hPP level in patients with MEN 1 is 95% sensitive and 88% specific for the presence of radiographically detectable pancreatic islet cell tumors.
Adenoma, Islet Cell↗
Surgical versus medical management of multiple endocrine neoplasia (MEN) type I.
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Humans↗
Allelotype of follicular thyroid carcinomas reveals genetic instability consistent with frequent nondisjunctional chromosomal loss.
Numerous studies aimed at the identification of chromosomal regions that are frequently deleted in specific tumor types have pointed to the location and involvement of specific tumor suppressor genes. Previous studies of loss of heterozygosity (LOH) among thyroid tumors have revealed frequent allelic deletions at a few chromosomal regions. A systematic genome-wide examination of LOH in a substantial number of follicular carcinomas, however, has not been performed previously. We assessed LOH at polymorphic markers from each nonacrocentric autosomal arm in a panel of 28 follicular thyroid carcinoma tumor and normal pairs. In contrast to the results of previous allelotype studies, we found high rates of LOH at multiple chromosomal regions. The highest rate of loss in our study was at 2p (50.0%), and 2q (50.0%), and the mean rate of LOH was 20.4%. Marked genetic instability in a subset of tumors was demonstrated by high fractional allelic loss, which accounted for more than 80% of observed LOH in this study. High fractional allelic loss was significantly associated with oxyphilic features and poor differentiation of these tumors. Our data provide evidence of a prevalent phenotype of nondisjunctional whole chromosomal loss in follicular thyroid carcinomas.
Adenocarcinoma, Follicular↗
Medullary carcinoma of the thyroid gland and the MEN 2 syndromes.
Medullary thyroid carcinoma (MTC) is an uncommon neoplasm in children that usually is associated with the multiple endocrine neoplasia (MEN) syndrome types 2A and 2B and with familial medullary thyroid carcinoma (FMTC). Recently, germline mutations in the RET proto-oncogene have been found in patients with these syndromes. Thus, with direct DNA testing, kindred members with MEN 2A, MEN 2B, or FMTC can be identified before clinical of biochemical evidence of MTC develops. It has been hypothesized that prophylactic thyroidectomy early in childhood, based on a positive genetic test, produces a better clinical outcome than thyroidectomy at the time MTC is diagnosed either clinically or biochemically. In the present report, the Washington University experience with MTC in children with MEN 2A and 2B is reviewed. Sixteen patients with MEN 2A who had thyroidectomy based on the biochemical diagnosis of MTC are compared with 14 children with MEN 2A who underwent prophylactic thyroidectomy based on direct genetic testing. In addition, the clinical results of 11 patients with MEN 2B treated for MTC are reviewed. After 3 years of follow-up there has been no biochemical or clinical evidence of MTC among the 14 children who had prophylactic thyroidectomy. Among the 16 children with MEN 2A who had thyroidectomy because of elevated basal of stimulated calcitonin levels, four (25%) have persistent of recurrent MTC after a mean follow-up period of 7.6 years. Of the 11 patients with MEN 2B who underwent thyroidectomy during childhood, one has died and seven (70%) of the remaining patients have recurrent MTC after a mean follow-up period of 11 years. The authors conclude that a significant number of children with MEN 2A or MEN 2B, who have clinical of biochemical evidence of MTC before thyroidectomy, have persistent or recurrent disease after long-term clinical follow-up. The diagnosis by direct DNA testing in patients with these syndromes allows prophylactic thyroidectomy before the development of extensive local or metastatic MTC.
Carcinoma, Medullary↗
Reduced survival in patients with ductal pancreatic adenocarcinoma associated with CDKN2 mutation.
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Actuarial Analysis↗
Mxi1 tumor suppressor gene is not mutated in primary pancreatic adenocarcinoma.
Amplification of the c-myc oncogene occurs in a variety of solid tumors, including pancreatic adenocarcinomas. The MXI1 gene, located at 10q24-q25, may serve to negatively regulate c-myc oncogene activity, and potentially has tumor suppressor function. As such, altered MXI1 function might contribute to tumorigenesis. We examined 40 primary human pancreatic adenocarcinomas for MXI1 mutations. Single-strand conformation variant analysis and direct sequencing of the variants revealed a MXI1 polymorphism in 1 of 40 tumors. No MXI1 mutations were identified. Southern blot analyses did not reveal any gross rearrangements of MXI1. These results suggest that MXI1 is unlikely to play a role in human pancreatic adenocarcinoma tumorigenesis.
Adenocarcinoma↗
Infrequent CDKN2 mutation in human differentiated thyroid cancers.
We examined the frequency of cyclin-dependent kinase (CDK) N2 alterations in differentiated and anaplastic thyroid cancers to assess the involvement of CDKN2 in the development of these cancers. The CDKN2 gene, which encodes the cell-cycle regulator p16, was recently shown to be mutated or deleted in many tumor cell lines. Its role in the genesis of primary tumors is uncertain, however. Tumor and corresponding normal DNAs were prepared by microdissection of paraffin-embedded tissue blocks or from frozen surgical specimens of 15 papillary, 15 follicular, and five anaplastic thyroid carcinomas. The entire CDKN2 coding region was screened by single-strand conformational variant analysis and direct sequencing of variants. The presence of homozygous deletions was evaluated by multiplex polymerase chain reaction (PCR) analysis. Loss of heterozygosity (LOH) in the CDKN2 region was assessed by using flanking polymorphic markers. Two somatic missense mutations were found among the 35 thyroid cancers, one in a follicular tumor and one in an anaplastic tumor. Multiplex PCR suggested the presence of homozygous deletion in one anaplastic tumor and hemizygous deletions in four tumors. LOH studies revealed loss of 9p sequences in four follicular (27%) and two anaplastic (50%) cancers. Our data suggest that alterations in CDKN2 played a role in a minority of thyroid cancers (three of 35). LOH in the region of CDKN2 is seen in a significant proportion of follicular and anaplastic but not papillary cancers. Loss of 9p sequences suggests a role for a tumor suppressor gene in the development of follicular and anaplastic thyroid cancers.
Adenocarcinoma, Follicular↗
Medullary thyroid carcinoma in children with multiple endocrine neoplasia types 2A and 2B.
Recently it has become possible to identify persons who have multiple endocrine neoplasia (MEN) syndrome types 2A and 2B based on the presence of missense mutations in the RET protooncogene. Kindred members who have inherited these syndromes can be identified before clinical or biochemical evidence of medullary thyroid carcinoma (MTC) develops, the malignancy that occurs in all affected patients. It is not known whether prophylactic removal of the thyroid gland early in childhood, based on a positive genetic test result, has a better clinical outcome than that associated with thyroidectomy after MTC is diagnosed clinically or biochemically. The authors' goal was to determine the long-term outcome for patients with MEN 2A and 2B who had thyroidectomy for MTC during childhood. These results were compared with those of patients who had prophylactic removal of the thyroid gland after the genetic diagnosis of MEN 2A was established. The hospital records of 49 children with MEN 2A or 2B were reviewed. Each patient had thyroidectomy for MTC before 16 years of age. The mean age at the time of operation was 10 years, and the mean follow-up period for those who had surgery before the availability of direct DNA genetic testing was 9.8 years. The indications for surgery included an elevated basal or stimulated plasma calcitonin level, a positive genetic test result, a thyroid mass, family history of MTC, or a phenotype diagnostic of MEN 2B. All children for whom the diagnosis of MEN 2A was established by direct genetic testing had thyroidectomy within the last 2 years. Of the 11 patients with MEN 2B who underwent thyroidectomy during childhood, 10 had MTC, and only 3 (27%) remain free of disease after the mean follow-up period of 11 years. One patient died, and seven are alive with persistent MTC. Among the 24 patients with MEN 2A who had their thyroid glands removed because of a family history of MTC or because of biochemical evidence of the disease, 5 (21%) have persistent or recurrent MTC after the mean follow-up period of 9.3 years. In four of these, the MTC was confined to the thyroid gland at the time of thyroidectomy. Of the 14 children who had thyroidectomy based on direct DNA testing, MTC was present in 11. Only four had elevated levels of stimulated plasma calcitonin before surgery. None had lymph node metastasis or surgical complications. The authors conclude that a significant number of patients with MEN 2A or 2B who undergo thyroidectomy in childhood for MTC have persistent or recurrent disease long-term. The genetic diagnosis of patients with these syndromes may allow for prophylactic surgery before the development of biochemical or clinical evidence of MTC. This approach is safe, but longer clinical follow-up will be necessary to confirm that MTC has been cured.
Adolescent↗
Surgical management of hyperparathyroidism in patients with multiple endocrine neoplasia type 2A.
BACKGROUND: The surgical management of hyperparathyroidism in patients with multiple endocrine neoplasia type 2A (MEN 2A) is controversial. We report the long-term follow-up, mutational analysis, and surgical outcome in a large group of patients with MEN 2A and hyperparathyroidism. METHODS: Clinical and genetic data for MEN 2A patients with biochemically and pathologically confirmed hyperparathyroidism and a minimum of 5 years of follow-up were analyzed retrospectively, and outcomes after surgical management were compared. RESULTS: Thirty-five (29%) of 119 patients from 14 MEN 2A kindreds had biochemical and pathologic evidence of hyperparathyroidism, with a mean follow-up of 14.7 years. The phenotypic expression of hyperparathyroidism was associated with germline mutations of the RET protooncogene at codons 634 and 618. At initial operation, 21 (62%) patients had a selective resection, eight (24%) had a subtotal resection, five (14%) had total parathyroidectomy with autotransplantation, and one had an inadvertent total parathyroidectomy. Twenty-seven (77%) patients were cured by the first operation. Persistent hyperparathyroidism occurred in three (8.6%) patients, and recurrent hyperparathyroidism occurred in five (14.3%) patients; both occurred only in patients treated with selective or subtotal resection. Permanent postoperative hypoparathyroidism occurred in six (21%) of 29 patients after selective or subtotal resection, in the one patient with inadvertent total parathyroidectomy, and in one (20%) of 5 patients treated with total parathyroidectomy and autotransplantation. CONCLUSIONS: Recurrent or persistent hyperparathyroidism occurs after selective or subtotal parathyroidectomy, as a result of either missed glands or interval development of neoplasia in previously normal parathyroid glands left in situ. Therefore we advocate total parathyroidectomy and heterotopic autotransplantation for patients with hyperparathyroidism and MEN 2A.
Adolescent↗
Progression of postoperative residual medullary thyroid carcinoma as monitored by plasma calcitonin levels.
BACKGROUND: Patients operated on for medullary thyroid carcinoma (MTC) frequently have persistent elevated plasma calcitonin concentrations after operation, indicating remaining tumor. The plasma calcitonin concentration in a patient with MTC roughly reflects the endogenous tumor burden. The only effective treatment for MTC is surgical. The decision about whether a patient with persistent MTC should have a repeat operation would be influenced by knowledge of the natural course of the disease. METHODS: Forty patients with persistently elevated peak plasma calcitonin concentrations after thyroidectomy for MTC were monitored for a mean of 6 years. Serial determinations of plasma calcitonin levels were obtained before and after intravenous injection of calcium and pentagastrin. RESULTS: At the first postoperative test 63% of the patients had undetectable basal calcitonin values, although their stimulated plasma calcitonin concentrations were elevated. The mean annual increase in stimulated plasma calcitonin concentrations was 117%, but plasma calcitonin concentrations were stable in three patients and decreased in one patient. Five patients are known to have experienced distant metastases. CONCLUSIONS: MTC is a progressive disease in most patients with persistent hypercalcitoninemia after thyroidectomy. Stimulated peak plasma calcitonin levels are more meaningful than basal levels in the serial postoperative evaluation of patients with persistent hypercalcitoninemia after thyroidectomy for MTC.
Adolescent↗
Parathyroid autotransplantation during thyroidectomy. Results of long-term follow-up.
SUMMARY BACKGROUND DATA: Permanent hypoparathyroidism is a recognized complication of thyroidectomy. Operative strategies to prevent this complication include preservation of parathyroid glands in situ and autotransplantation of parathyroid glands resected or devascularized during thyroidectomy. METHODS: An analysis of 194 patients having thyroidectomy and simultaneous parathyroid autotransplantation at Barnes Hospital from 1990 to 1994 was performed. Data were collected regarding patient demographics, indication for thyroidectomy, operative procedure, pathologic diagnoses, and postoperative course, including biochemical assessment of parathyroid autograft function. RESULTS: Of 194 patients having either total, subtotal, or completion thyroidectomy, 104 (54%) experienced a [Ca(+2)]nadir less than or equal to 8.0 mg/dL and had symptoms and signs of hypocalcemia. Parathyroid autotransplantation was successful in 103 (99%) of these 104 cases and resulted in a 1.0% incidence of hypoparathyroidism in this series. CONCLUSIONS: Although preservation of parathyroid glands in situ is desirable, routine parathyroid autotransplantation during thyroidectomy virtually eliminates postoperative hypoparathyroidism. Normal parathyroid glands resected or devascularized during thyroidectomy for well-differentiated thyroid carcinoma or benign disease should be transplanted in the sternocleidomastoid muscle. Patients with Multiple Endocrine Neoplasia type 2A should have parathyroid glands resected at the time of thyroidectomy for medullary thyroid carcinoma and transplanted in the nondominant forearm. Postoperative management in most patients after thyroidectomy and parathyroid autotransplantation involves temporary calcium and vitamin D replacement and close biochemical evaluation. This precautionary measure of parathyroid autotransplantation markedly reduces the incidence of permanent postoperative hypoparathyroidism.
Adolescent↗