Biomedical subjects

A Frilling

Publications and source records attributed to A Frilling.

At least 73 records · Page 4Linked to original sources

PubMed1997

[Surgical therapy of primary and secondary liver tumors].

Advances in operative, diagnostic and post-operative care technique have rendered liver resections safe. Consecutively, indications for operative interventions in primary and secondary liver tumors have changed. A current state of the art is presented. Focal nodular hyperplasia, if found incidentally during laparotomy, should be removed en-passant. Large or central lesions should be biopsied and can be observed if they remain asymptomatic and stable in size. Symptomatic or growing FNH should be removed. If the diagnosis is evasive resection should be favored. Most patients with hepatocellular adenoma are symptomatic and the lesion should therefore be removed. Hemangiomas are rarely causing symptoms. In case they truly are, or if they cause complications they should be excised. Anatomical resections for hepatocellular carcinoma are only feasible in non-cirrhotic livers or in patients with cirrhosis and compensated liver function. Other patients are candidates for liver transplantation if the cancer is stage I or II. Stage III and IVa lesions are subject of current studies. Surgical resection remains the only potentially curative treatment for intrahepatic cholangiocellular carcinoma. Because of their dismal prognosis these patients are not candidates for transplantation. Resection continues to be the most effective therapy for colorectal metastases to the liver. Patients with non-colorectal, non-neuroendocrine metastases are usually only candidates for surgical palliation. Cure can be achieved in patients with renal cell carcinoma or Wilms' tumor. Additionally, neuroendocrine metastases to the liver can be resected in curative intent if extrahepatic disease was excluded. In the few symptomatic patients in whom extrahepatic disease was excluded, symptomatic treatment has failed, and the lesions are not resectable, liver transplantation can provide a reasonable therapeutic choice.

Carcinoma, Hepatocellular↗

PubMed1997

[Somatic ret proto-oncogene mutations in sporadic C-cell carcinoma of the thyroid gland].

Germline mutations of the RET proto-oncogene localized on chromosome 10q11.2 are the underlying cause of hereditary medullary thyroid carcinoma. In MEN 2A and FMTC, mutations can be found in exons 10, 11, 13 or 14. MEN 2B is characterized by a specific mutation in exon 16. In a significant number of sporadic MTC somatic mutations in codon 918 (exon 16) are detectable. Some rare sporadic MTC present somatic mutations in codons 611, 634, 768 and 883. Recently, deletion-insertion of the RET proto-oncogene in exon 11 and a deletion in exon 10 has been found. RET proto-oncogene mutations are not only responsible for the development of the familial MTC, but may also play an important role in the pathogenesis of sporadic MTC. However, the prognostic relevance of these somatic events is still unclear.

Carcinoma, Medullary↗

PubMed1997

Detection of RET proto-oncogene codon 634 mutations using mass spectrometry.

Mutations located in the RET proto-oncogene at codon 634 associated with multiple endocrine neoplasia type 2A and medullary thyroid carcinoma are detected by low-resolution and high-resolution mass spectrometry schemes not requiring labeling or electrophoretic separation of diagnostic products. The former requires measurement by matrix-assisted laser desorption ionization time-of-flight mass spectrometry of 21- to 27-mer oligonucleotides generated by a primer oligo base extension reaction. The latter is based upon direct measurement of artificial products which include the mutation site using matrix-assisted laser desorption ionization Fourier transform mass spectrometry. In this feasibility study a synthetic 25-mer representing the wildtype allele (7660.3 Da) was easily distinguished from G to A (7644.3 Da) and G to T (7635.3 Da) mutant alleles; the mutant alleles, which differed in mass by only 9.0 Da, were easily resolved when analyzed as a mixture. The results of both detection schemes were highly accurate and reliable, indicating mass spectrometry to be a high-quality alternative for future DNA diagnostics performed in clinical laboratories and genetic profiling studies.

Base Sequence↗

PubMed1997

Germline dinucleotide mutation in codon 883 of the RET proto-oncogene in multiple endocrine neoplasia type 2B without codon 918 mutation.

The autosomal dominant multiple endocrine neoplasia type 2 syndromes (MEN 2) comprise three clinically distinct entities, MEN 2A, familial medullary thyroid carcinoma and MEN 2B, which share a common clinical feature: medullary thyroid carcinoma (MTC). MEN 2B is considered to have the most aggressive form of MTC. Therefore, early detection of MEN 2B in order to prevent potentially lethal MTC is important. More than 95% of all MEN 2B cases are caused by germline mutation at codon 918 (M918T) in exon 16 of the RET proto-oncogene. In this study, we demonstrate the presence of germline codon 883 mutation (A883F) in 2 of 3 unrelated MEN 2B cases without codon 918 mutation. Our data demonstrate a novel etiologic event which may have roles in predisposition to MEN 2B when present in the germline and in the pathogenesis of sporadic MTC when somatic.

Alanine↗

PubMed1997

Mutation analysis of glial cell line-derived neurotrophic factor, a ligand for an RET/coreceptor complex, in multiple endocrine neoplasia type 2 and sporadic neuroendocrine tumors.

Causative germline missense mutations in the RET proto-oncogene have been associated with over 92% of families with the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN 2). MEN 2A is characterized primarily by medullary thyroid carcinoma (MTC) and pheochromocytoma, both tumors of neural crest origin. Parathyroid hyperplasia or adenoma is also seen in MEN 2A, but rarely in MEN 2B, which has additional stigmata, including a marfanoid habitus, mucosal neuromas, and ganglioneuromatosis of the gastrointestinal tract. In familial MTC, MTC is the only lesion present. Somatic RET mutations have also been identified in a subset of sporadic MTCs, pheochromocytomas, and rarely, small cell lung cancer, but not in sporadic parathyroid hyperplasias/adenomas or other neuroendocrine tumors. Glial cell line-derived neurotrophic factor (GDNF) and its receptor molecule GDNFR-alpha, have recently been identified as members of the RET ligand binding complex. Therefore, the genes encoding both GDNF and GDNFR-alpha are excellent candidates for a role in the pathogenesis of those MEN 2 families and sporadic neuroendocrine tumors without RET mutations. No mutations were found in the coding region of GDNF in DNA samples from 9 RET mutation negative MEN 2 individuals (comprising 6 distinct families), 12 sporadic MTCs, 17 sporadic cases of parathyroid adenoma, and 10 small cell lung cancer cell lines. Therefore, we find no evidence that mutation within the coding regions of GDNF plays a role in the genesis of MEN 2 and sporadic neuroendocrine tumors.

DNA Mutational Analysis↗

PubMed1996

Heterogeneous mutation of the RET proto-oncogene in subpopulations of medullary thyroid carcinoma.

Mutations in the RET proto-oncogene are associated with the pathogenesis of medullary thyroid carcinoma (MTC). In an attempt to understand this process, we examined microdissected subpopulations from MTC and multiple metastases from these tumors. Approximately 80% of sporadic MTC's had at least one subpopulation with the RET codon 918 mutation, which is a mutation previously detected in sporadic MTC as a somatic mutation and in multiple endocrine neoplasia type 2B as a germline mutation. However, the distribution of this mutation was nonhomogeneous, occurring only in subpopulations in most tumors and among subsets of multiple metastases, thus implying that although the codon 918 mutation could be an early event, it is not necessarily an early or essential event in tumorigenesis. This heterogeneity suggests either that the codon 918 mutation can arise as an event in progression within a metastatic clone or within a single tumor, or that MTC can be of polyclonal origin. Of significance, one of two multiple endocrine neoplasia type 2A MTCs carried a somatic mutation at codon 918, in addition to the RET mutation present in the germline. We found no correlation between the presence of other somatic genetic events, such as loss of heterozygosity on chromosome arms 1p and 22q, and RET mutation status in the various subpopulations of MTC.

Carcinoma, Medullary↗

PubMed1996

Isolated familial pheochromocytoma as a variant of von Hippel-Lindau disease.

Inherited pheochromocytomas are often part of familial syndromes, especially multiple endocrine neoplasia type 2 (MEN 2), retinal cerebellar hemangioblastomatosis [von Hippel-Lindau (vHL) disease] or neurofibromatosis type 1. It is not clear whether isolated familial pheochromocytoma exists as a separate clinical entity. In a family with pheochromocytomas in three generations and with at least seven affected members, we investigated by clinical and genetic analyses the presence or absence of associated conditions. The clinical investigations included ophthalmological and radiological studies for von Hippel-Lindau disease (magnetic resonance imaging of the brain, computed tomography of the abdomen, and direct ophthalmoscopy after mydriasis) and annual calcitonin stimulation tests for C cell disease in five members who agreed to regular follow-up. Besides the pheochromocytomas (so far, these have been multiple in five of seven individuals) no definite second associated condition was found. Genetic analysis did not identify any MEN 2-specific RET protooncogene point mutations (which are present in 97% of MEN 2a families). However, despite the complete absence of other clinical manifestations of the vHL disease (besides pheochromocytomas), a previously undescribed germline missense mutation in the vHL tumor suppressor gene was found (C775G transversion with a predicted substitution of a leucine by a valine at codon 259 in the putative vHL protein). We conclude that in this family the sole occurrence of pheochromocytoma is a variant of vHL disease.

Adrenal Gland Neoplasms↗

PubMed1996

Mutations of the ret protooncogene in German multiple endocrine neoplasia families: relation between genotype and phenotype. German Medullary Thyroid Carcinoma Study Group.

It has been suggested that not only the position but also the nature of the mutations of the ret protooncogene strongly correlate with the clinical manifestation of the multiple endocrine neoplasm type 2 (MEN 2) syndrome. In particular, individuals with a Cys634-Arg substitution should have a greater risk of developing parathyroid disease. We, therefore, analyzed 94 unrelated families from Germany with inherited medullary thyroid carcinoma (MTC) for mutation of the ret protooncogene. In all but 1 of 59 families with MEN 2A, germline mutations in the extracellular domain of the ret protein were found. Some 81% of the MEN 2A mutations affected codon 634. Phenotype-genotype correlations suggested that the prevalence of pheochromocytoma and hyperparathyroidism is significantly higher in families with codon 634 mutations, but there was no correlation with the nature of the mutation. In all but 1 of 27 familial MTC (FMTC) families, mutations were detected in 1 of 4 cysteines in the extracellular domain of the ret protooncogene. Half of the FMTC mutations affected codon 634. Mutations outside of codon 634 occurred more often in FMTC families than in MEN 2A families. In all but 1 of 8 MEN 2B patients, de novo mutations in codon 918 were found. These data confirm the preferential localization of MEN 2-associated mutations and the correlation between disease phenotype and the position of the ret mutation, but there was no correlation between the occurrence of hyperparathyroidism or pheochromocytoma and the nature of the mutation.

Amino Acid Sequence↗

PubMed1996

[Sporadic unilateral adrenal medullary hyperplasia--a rare cause of hypertension].

Sporadic adrenomedullary hyperplasia (AMH) is characterized by a clinical history of hypertension, increased plasma and/or urinary catecholamine levels and histomorphometric evidence of increased adrenal medullary mass in the absence of MEN 2 syndrome. The case of a 42-year-old female patient is reported who presented with typical clinical and laboratory findings of episodic hypertension and elevated plasma and urinary catecholamines. Sonography and computed tomography revealed no abnormality, but 131I-metaiodobenzylguanidine (131I-MIBG) scintigraphy showed increased uptake in the right adrenal. Transabdominal unilateral adrenalectomy was performed. The right adrenal gland was macroscopically inconspicuous. Upon histomorphometry, however, an increased adrenal medullary cell mass was shown, thus confirming AMH. Two years following surgery the patient is asymptomatic and normotensive.

Adrenal Hyperplasia, Congenital↗

PubMed1995

Mutation of the RET protooncogene in sporadic medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) occurs sporadically or as part of the inherited cancer syndrome multiple endocrine neoplasia (MEN) type 2. In MEN 2A, germline missense mutations are found in one of five cysteine codons within exons 10 and 11 in the extracellular domain of the RET protooncogene. In MEN 2B, germline mutations occur in codon 918 (exon 16) within the catalytic core of the tyrosine kinase domain. To determine if RET mutations similar to those in MEN 2A and 2B play a role in the pathogenesis of sporadic MTC, we analysed 71 sporadic tumours comprising 68 primary tumours and three cell lines, for mutations in RET exons 10, 11, and 16. We found that 23% of sporadic MTC had RET codon 918 mutations, while only 3% had exon 10 mutations, and none had mutations in exon 11. We found no exon 16 mutations in MTC from 14 MEN 2A cases. Thus, exon 10 and 11 mutations, commonly found in familial MTC and MEN 2A, rarely occur in sporadic MTC; somatic mutation of RET codon 918 appears to play a role in the tumourigenesis of a significant minority of sporadic MTC but not MEN 2A tumours. In addition to their biological interest, these findings may have some clinical application in determining whether a patient presenting with isolated MTC is truly sporadic or is part of an inherited cancer syndrome.

Carcinoma, Medullary↗

PubMed1995

Presymptomatic genetic screening in families with multiple endocrine neoplasia type 2.

Medullary thyroid carcinoma occurs sporadically or as a part of the inherited cancer syndrome multiple endocrine neoplasia (MEN) type 2. The MEN 2 gene has been identified as the RET proto-oncogene on chromosome 10. In MEN 2A, RET mutations are detectable in one of five cysteine codons within exons 10 and 11 and in MEN 2B in codon 918 (exon 16). Direct DNA testing for RET proto-oncogene mutations is the method of first choice in presymptomatic screening of MEN 2 families. Gene carriers should be offered prophylactic thyroidectomy. The process of DNA analysis for RET proto-oncogene mutations is demonstrated in one family with hereditary medullary thyroid carcinoma. RET mutations were detectable in five of the nine family members at risk.

Adult↗

PubMed1995

Multiple endocrine neoplasia type 1 (MEN 1) revisited.

Multiple endocrine neoplasia type 1 (MEN 1) is an inherited disease of the neuroendocrine cell system affecting primarily the parathyroids, pancreas, duodenum and the anterior pituitary. The pancreatic and duodenal tumours may metastasize, but generally have a low malignant potential. The diagnosis of MEN 1 is usually made in the second decade of life and based on the involvement of at least two organs and a family history. The recent discovery of the MEN 1 locus on the centromeric region of the long arm of chromosome 11 may become a further diagnostic criterion. The use of flanking DNA markers permits presymptomatic testing for MEN 1 in affected families.

Age Factors↗

PubMed1995

Genetic screening to identify the gene carrier in Italian and German kindreds affected by multiple endocrine neoplasia type 1 (MEN 1) syndrome.

Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominantly inherited disorder characterized by parathyroid hyperplasia, anterior pituitary adenomas and neoplasms of the endocrine cells of the gastroenteric tract. It has been established that also other tissues exhibit excessive proliferation associated to the MEN 1 syndrome: carcinoids (bronchial and intestinal), lipomas (visceral and cutaneous), thyroid adenomas and goiter, and adrenal gland cortex adenomas. The men 1 gene has been mapped by genetic studies to the long arm of human chromosome 11, region q12-13. Genetic analysis of families and tumoral deletion mapping made possible to narrow the men 1 region to a 5 cM interval on chromosome 11q12-13. Thirteen marker complexes (17 DNA probes) were found to be linked to the men 1 gene and they span a 14% meiotic recombination with the men 1 locus in the middle. We report a genetic study on 103 subjects from 7 collected MEN 1-kindreds, six Italian and one German, including 30 affected individuals. By linkage analysis to 9 DNA markers (10 DNA probes) of the chromosome region where the men 1 gene maps (11q12-13), we identified 10 mutant gene carriers. The predicted MEN 1 diagnosis was clinically confirmed for 2 of these identified carriers. A predictive accuracy of this genetic test can reach up to 99.5% when it is possible to exclude meiotic crossing-over between the analyzed DNA markers and the disease locus.

Adult↗

PubMed1995

Presymptomatic DNA screening in families with multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma.

BACKGROUND: Missense mutations of the ret proto-oncogene on chromosome 10q11.2 are the underlying cause of hereditary medullary thyroid carcinoma (MTC), either as familial MTC only (FMTC) or as a part of multiple endocrine neoplasia type 2 syndrome (MEN 2). This study presents our experience with direct presymptomatic DNA screening in MEN 2 and FMTC kindreds. METHODS: Twenty one families with MEN 2 or FMTC were considered in the study. One hundred three individuals had been analyzed; 56 were at risk. The ret mutations were detected by DNA analysis of exons 10, 11, and 16 by using nonradioactive labeling method based on digoxigenin DNA sequencing technique. Serum calcitonin evaluation was carried out in all individuals at risk. Thyroidectomy was performed in those who had to undergo surgery. RESULTS: The ret mutations were identified in all 21 families. In MEN 2A and FMTC families mutations occurred in exons 10 and 11. MEN 2B families had mutations in exon 16. The most frequent mutation in MEN 2A and FMTC affected codon 634. Twenty one gene carriers were identified in unaffected individuals at risk. Ten of 21 gene carriers had elevated calcitonin levels, and 11 had normal levels. MTC or C-cell hyperplasia was found in six gene carriers with pathologic calcitonin values who underwent operation. In a 5-year-old gene carrier with normal calcitonin values C-cell hyperplasia was evident. CONCLUSIONS: Direct predictive DNA analysis allows us to identify MEN 2 or FMTC gene carriers and offer them prophylactic treatment.

Base Sequence↗

PubMed1995

Low frequency of germline mutations in the RET proto-oncogene in patients with apparently sporadic medullary thyroid carcinoma.

BACKGROUND AND OBJECTIVES: Medullary thyroid carcinoma (MTC) occurs both sporadically and in the autosomal dominantly inherited multiple endocrine neoplasia (MEN) type 2 syndromes. The distinction between true sporadic MTC and a new mutation familial case is important for future clinical management of both the patient and family. The susceptibility gene for MEN 2 is the RET proto-oncogene. Systematic analysis for germline mutations of the RET proto-oncogene was performed in a series of 67 patients with apparently sporadic MTC to determine whether they were true sporadic cases or unsuspected de novo MEN 2 cases. DESIGN AND PATIENTS: Sixty-seven unselected patients with sporadic MTC were randomly ascertained from clinic patients from four centres. The diagnosis of MTC was confirmed by histopathology. Germline DNA was extracted from peripheral blood leucocytes or from paraffin-embedded tissue and subsequently used for polymerase chain reaction amplification. MEASUREMENTS: Polymerase chain reaction based RET mutation analysis was performed by direct double-stranded cycle sequencing of exons 10, 11, 13 and 16, within which the majority of MEN2 mutations have been shown to occur. RESULTS: In this series, there was one proven case of germline mutation in RET codon 620, which previously has been shown to be responsible for MEN 2, thus indicating heritable disease. No germline mutation in codon 918, typical of MEN 2B, was found. CONCLUSIONS: A figure of 1.5% germline mutations in 67 apparently sporadic MTC is lower than the incidence of familial disease reported in previous series involving clinical and biochemical screening. The presence of a germline mutation in the RET proto-oncogene in a patient with MTC indicates heritable disease. The absence of germline RET exon 10, 11, 13 or 16 mutation appears to rule out MEN 2A to a high probability, although the presence of a familial form of MTC other than classical MEN 2A cannot be excluded conclusively.

Adolescent↗

PubMed1995

The value of lymph node dissection in hereditary medullary thyroid carcinoma: a retrospective, European, multicentre study.

Clinical data of 139 patients with hereditary medullary thyroid carcinoma (HMTC) from nine european centres surgically treated from 1980 to 1991 were reviewed retrospectively to analyse the value of systematic versus selective lymphadenectomy (LA). Biochemical cure rate was significantly higher in patients who underwent LA compared to patients who did not. In nodal-positive HMTC, systematic LA compared to selective LA improved biochemical cure in small but not large tumours. In nodal-negative HMTC, systematic LA compared to selective LA could not improve biochemical cure in either small or large primary tumours. To prevent local recurrences with the risk of increased surgical and tumour-related morbidity, systematic LA should be performed in all HMTC patients regardless of the primary tumour stage. However, an improvement of biochemical cure by systematic LA seems to be possible only in nodal-positive small primary tumours without distant metastases.

Adult↗

PubMed1995

Pheochromocytoma in multiple endocrine neoplasia type 2: European study. The Euromen Study Group.

OBJECTIVES: Pheochromocytoma (pheo) is the second component of the multiple endocrine neoplasia type 2 (MEN 2) syndrome. Clinical expression is sometimes poor, and chronology between medullary thyroid carcinoma (MTC) and pheo is not well evaluated. Therefore, a retrospective study was done in eight European countries in order to precise the main characteristics of pheo in MEN 2. SUBJECTS: Data from 300 MEN 2 patients with pheo (274 MEN 2 A and 26 MEN 2 B) were obtained from cases registered by the EuroMen study group, and collected by a medical standardized questionnaire. These cases occurred between 1969 and 1992. RESULTS: Mean age at diagnosis of pheo was 39.5 years (range 14-68 years) in MEN 2A and 32.4 years (range 15-41 years) in MEN 2B patients. Pheo occurred first in 25.1% of the cases (2-15 years before diagnosis of MTC) and after MTC in 40.2% (2-11 years). In other cases (34.7%), MTC and pheo were diagnosed at the same time. Involvement was bilateral in 67.8% of cases. Malignancy was only 4%. Thirty-nine deaths occurred in these 300 patients, 64.1% were linked in pheo, 23.1% to MTC and 12.8% to other causes. Surgery was unilateral in 39.7% of the cases and bilateral adrenalectomy was the first procedure in 48.4%. A bilateral adrenalectomy in two steps had to be done in 11.9% of cases. In conclusion, these results justify systematic and prolonged biochemical screening of pheo during follow-up of MTC and address some questions about the best mode of surgery.

Adolescent↗

PubMed1995

Primary hyperparathyroidism in multiple endocrine neoplasia type 2A.

The rarity of primary hyperparathyroidism (PHPT) in multiple endocrine neoplasia type 2A (MEN 2A) led us to study clinical findings, surgical therapy and outcome in 67 patients in order to evaluate our therapeutic strategy. The retrospective study was based on cases registered by the EUROMEN study group (nine participating centres) from 1972 to 1993. Characteristics of PHPT in 67 patients (41 females, 26 males) with MEN 2A were reviewed. All patients underwent exploratory neck surgery; PHPT was confirmed histologically and/or biochemically. The median age at diagnosis of PHPT was 38 years. In 75% of the patients, PHPT and medullary thyroid carcinoma were diagnosed synchronously, while in 4%. PHT was diagnosed earlier. In 18% of the patients, PHPT was diagnosed after thyroidectomy, and in 3%, after discovery of pheochromocytoma. Primary hyperparathyroidism was asymptomatic in 84% of the patients; 15% suffered from renal stones. Serum calcium was slightly elevated in 69% (2.9 +/- 0.2 mmol-1) and normal in 16% of subjects. A single adenomectomy was performed in 42% of the patients, subtotal parathyroidectomy in 31% and total parathyroidectomy with autotransplantation in 16%. Independent from the extent of resection, cure was achieved in 94% of the patients, including 13% with hypoparathyroidism; hypercalcaemia persisted in 3% and no information was available in 3%. In an 8-year follow-up, hypercalcaemia recurred in 12% of the patients, although half had undergone parathyroidectomy totally or subtotally. CONCLUSION. MEN 2A-related PHPT is characterized by a mild hypercalcemia which is mostly asymptomatic and can be cured by simple resection of an enlarged parathyroid gland in most cases.

Adolescent↗