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Biomedical subjects

O Gimm

Publications and source records attributed to O Gimm.

At least 55 records · Page 3Linked to original sources
PubMed2000

Differential nuclear and cytoplasmic expression of PTEN in normal thyroid tissue, and benign and malignant epithelial thyroid tumors.

Germline mutations in PTEN (MMAC1/TEP1) are found in patients with Cowden syndrome, a familial cancer syndrome which is characterized by a high risk of breast and thyroid neoplasia. Although somatic intragenic PTEN mutations have rarely been found in benign and malignant sporadic thyroid tumors, loss of heterozygosity (LOH) has been reported in up to one fourth of follicular thyroid adenomas (FAs) and carcinomas. In this study, we examined PTEN expression in 139 sporadic nonmedullary thyroid tumors (55 FA, 27 follicular thyroid carcinomas, 35 papillary thyroid carcinomas, and 22 undifferentiated thyroid carcinomas) using immunohistochemistry and correlated this to the results of LOH studies. Normal follicular thyroid cells showed a strong to moderate nuclear or nuclear membrane signal although the cytoplasmic staining was less strong. In FAs the neoplastic nuclei had less intense PTEN staining, although the cytoplasmic PTEN-staining intensity did not differ significantly from that observed in normal follicular cells. In thyroid carcinomas as a group, nuclear PTEN immunostaining was mostly weak in comparison with normal thyroid follicular cells and FAs. The cytoplasmic staining was more intense than the nuclear staining in 35 to 49% of carcinomas, depending on the histological type. Among 81 informative tumors assessed for LOH, there seemed to be an associative trend between decreased nuclear and cytoplasmic staining and 10q23 LOH (P = 0.003, P = 0.008, respectively). These data support a role for PTEN in the pathogenesis of follicular thyroid tumors.

Cell Nucleus↗
PubMed2000

Over-representation of PPARgamma sequence variants in sporadic cases of glioblastoma multiforme: preliminary evidence for common low penetrance modifiers for brain tumour risk in the general population.

PPARgamma, the gamma isoform of a family of peroxisome proliferator activated receptors, plays a key role in adipocyte differentiation. Recently, its broad expression in multiple tissues and several epithelial cancers has been shown. Further, somatic loss of function mutations in PPARgamma have been found in primary colorectal carcinomas. We sought to determine if somatic high penetrance mutations in this gene might also play a role in glioblastoma multiforme (GBM). We also examined this gene to determine if common low penetrance polymorphic alleles might lend low level susceptibility to GBM in the general population. No somatic high penetrance mutations were detected in 96 sporadic GBMs. However, polymorphic alleles at codons 12 and 449 were significantly over-represented among the 27 unrelated American patients with sporadic GBM compared to 80 race matched controls. While nine (33%) were heterozygous for the P12A variant, c.34C/G (cytosine to guanine change at nucleotide 34), 12 (15%) controls were heterozygous for P12A (p<0.05). Similarly, 13 of 26 (50%) glioblastoma patients compared to 10 of 80 (12%) normal controls were found to have the heterozygous H449H polymorphism (p<0.001). The over-representation of H449H in glioblastoma patients was confirmed with a second validation set of American patients. When both American series were combined, polymorphic H449H was over-represented among cases versus controls (p<0.001) and there was a similar trend (p=0.07) for P12A. The precise mechanism for this association is unknown but these PPARgamma polymorphisms may be acting in a low penetrance predisposing manner. However, these associations were not found in a German population, possibly arguing that if these variants are in linkage disequilibrium with a third locus, then this effect is relatively new, after the settlement of the American colonies.

Alleles↗
PubMed2000

RET genotypes comprising specific haplotypes of polymorphic variants predispose to isolated Hirschsprung disease.

BACKGROUND: Hirschsprung disease (HSCR), which may be sporadic or familial, occurs in 1:5000 live births and presents with functional intestinal obstruction secondary to aganglionosis of the hindgut. Germline mutations of the RET proto-oncogene are believed to account for up to 50% of familial cases and up to 30% of isolated cases in most series. However, these series are highly selected for the most obvious and severe cases and large familial aggregations. Population based studies indicate that germline RET mutations account for no more than 3% of isolated HSCR cases. Recently, we and others have noted that specific polymorphic sequence variants, notably A45A (exon 2), are over-represented in isolated HSCR. PURPOSE: In order to determine if it is the variant per se, a combination thereof, or another locus in linkage disequilibrium which predisposes to HSCR, we looked for association of RET haplotype(s) and disease in HSCR cases compared to region matched controls. METHODS: Seven loci across RET were typed and haplotypes formed for HSCR cases, their unaffected parents, and region matched controls. Haplotype and genotype frequencies and distributions were compared among these groups using the transmission disequilibrium test and standard case-control statistic. RESULTS: Twelve unique haplotypes, labelled A-L, were obtained. The distributions of haplotypes between cases and controls (chi(11)(2) =81.4, p<<0.0001) and between cases and non-transmitted parental haplotypes were significantly different (chi(2)(11)=53.1, p<0.0001). Genotypes comprising pairs of haplotypes were formed for cases and controls. There were 38 different genotypes among cases and controls combined. Inspection of the genotypes in these two groups showed that the genotype distribution between cases and controls was distinct (chi(37)(2)=93. 8, p<<0.0001). For example, BB, BC, BD, and CD, all of which contain at least one allele with the polymorphic A45A, are prominently represented among HSCR cases, together accounting for >35% of the case genotypes, yet these four genotypes were not represented among the population matched normal controls. Conversely, AA, AG, DD, GG, and GJ, none of which contains A45A, are commonly represented in the controls, together accounting for 43% of the control genotypes, and yet they are never seen among the HSCR cases. CONCLUSIONS: Our data suggest that genotypes comprising specific pairs of RET haplotypes are associated with predisposition to HSCR either in a simple autosomal recessive manner or in an additive, dose dependent fashion.

Alleles↗
PubMed1999

Over-representation of a germline RET sequence variant in patients with sporadic medullary thyroid carcinoma and somatic RET codon 918 mutation.

The aetiology of sporadic medullary thyroid carcinoma is unknown. About 50% harbour a somatic mutation at codon 918 of RET (M918T). To investigate whether other RET sequence variants may be associated with or predispose to the development of sporadic medullary thyroid carcinoma, we analysed genomic DNA from the germline and corresponding tumour from 50 patients to identify RET sequence variants. In one patient, tumour DNA showed a novel somatic 12 bp in-frame deletion in exon 15. More interestingly, we found that the rare polymorphism at codon 836 (c.2439C > T; S836S) occurred at a significantly higher frequency than that in control individuals without sporadic medullary thyroid carcinoma (Fisher's exact test, P = 0.03). Further, among the nine evaluable cases with germline c.2439C/T, eight also had the somatic M918T mutation in MTC DNA which was more frequent than in patients with the more common c.2439C/C (89% vs 40%, respectively; Fisher's exact test, P = 0.01). These findings suggest that the rare sequence variant at codon 836 may somehow play a role in the genesis of sporadic medullary thyroid carcinoma.

Carcinoma, Medullary↗
PubMed1999

C-cell cancer--prevention and treatment.

INTRODUCTION: C-cell cancer of the thyroid or medullary thyroid carcinoma (MTC) exists in a sporadic and a hereditary form, the latter of which is part of the multiple endocrine neoplasia type-2 (MEN-2) syndromes. DISCUSSION: MTC metastasises early to local (lymph nodes) and distant sites (liver, lung, bone). Therefore, early detection is mandatory to enable a chance of cure. In sporadic MTC, the sensitive tumour marker calcitonin enables detection of the disease at an early stage. In hereditary MTC, more than 95% of the patients have germline RET mutations. Thus, MEN-2 has become the paradigm for the practice of molecular medicine, and gene carriers can be identified before MTC even occurs. Surgery is the only chance of cure and recently developed surgical techniques provide the therapeutic prerequisite to achieve calcitonin normalisation in both sporadic and hereditary MTC.

Carcinoma, Medullary↗
PubMed1999

Repeat mediastinal lymph-node dissection for palliation in advanced medullary thyroid carcinoma.

BACKGROUND: In medullary thyroid carcinoma (MTC), the effectiveness of repeat mediastinal lymph-node dissection for palliation of specific symptoms caused by discrete mediastinal lesions is unclear in non-bulky tumor disease. METHODS: Between November 1994 and August 1998, five symptomatic MTC patients with radiologic evidence of mediastinal tumor and elevated calcitonin levels were subjected to repeat mediastinal lymph-node dissection. RESULTS: At reoperation, an average of 7 of 25 (28%) removed cervical and 5 of 9 (56%) dissected mediastinal lymph-nodes were positive on histopathology. A substantial fraction of these were excised from anatomical regions inaccessible through a purely cervical or partial sternotomy approach. Clinical symptoms were effectively palliated in all five patients. Basal serum calcitonin levels fell only moderately, suggesting distant micrometastases. Mortality was nil. Morbidity encompassed two cases of hypoparathyroidism and a lymphatic fistula that closed spontaneously on total parenteral nutrition. One patient later required cervical reoperation deferred at secondary surgery. All five patients have since remained free of cervical and mediastinal tumor at a mean follow-up of 15 months. CONCLUSIONS: In mediastinal lymph-node metastases, repeat lymph-node dissection is warranted for palliation of discrete anatomic lesions inaccessible through a cervical approach.

Adult↗
PubMed1999

Mutation and deletion analysis of GFR alpha-1, encoding the co-receptor for the GDNF/RET complex, in human brain tumours.

Glial cell line-derived neurotrophic factor (GDNF) plays a key role in the control of vertebrate neuron survival and differentiation in both the central and peripheral nervous systems. GDNF preferentially binds to GFRalpha-1 which then interacts with the receptor tyrosine kinase RET. We investigated a panel of 36 independent cases of mainly advanced sporadic brain tumours for the presence of mutations in GDNF and GFRalpha-1. No mutations were found in the coding region of GDNF. We identified six previously described GFRalpha-1 polymorphisms, two of which lead to an amino acid change. In 15 of 36 brain tumours, all polymorphic variants appeared to be homozygous. Of these 15 tumours, one also had a rare, apparently homozygous, sequence variant at codon 361. Because of the rarity of the combination of homozygous sequence variants, analysis for hemizygous deletion was pursued in the 15 samples and loss of heterozygosity was found in 11 tumours. Our data suggest that intragenic point mutations of GDNF or GFRalpha-1 are not a common aetiologic event in brain tumours. However, either deletion of GFRalpha-1 and/or nearby genes may contribute to the pathogenesis of these tumours.

Brain Neoplasms↗
PubMed1999

Specific polymorphisms in the RET proto-oncogene are over-represented in patients with Hirschsprung disease and may represent loci modifying phenotypic expression.

Hirschsprung disease (HSCR) is a common genetic disorder presenting with functional intestinal obstruction secondary to enteric aganglionosis. HSCR can be familial or sporadic. Although five putative susceptibility genes have been identified, only germline mutations in the RET proto-oncogene account for a significant minority (up to 50%) of familial HSCR; 3% of sporadic HSCR in a population based series carry RET mutations. From 1998 to February 1999, we prospectively ascertained 64 cases of sporadic HSCR from the western Andalusia region. To determine if polymorphic sequence variants within RET could act as low penetrance predisposing alleles, we examined allelic frequencies at seven polymorphic loci in this population based series. Whether allele frequencies differed from those in the control population were determined by either chi-squared analysis or Fisher's exact test. For two sequence variants, A45A (c 135G-->A) (exon 2) and L769L (c 2307T-->G) (exon 13), the rarer polymorphic allele was over-represented among HSCR cases versus controls (p<0.0006). In contrast, two other polymorphisms, G691S (c 2071C-->A) (exon 11) and S904S (c 2712C-->G) (exon 15), were under-represented in the HSCR patients compared to controls (p=0.02). Polymorphisms in the RET proto-oncogene appear to predispose to HSCR in a complex, low penetrance fashion and may also modify phenotypic expression.

Case-Control Studies↗
PubMed1999

Mutation analysis reveals novel sequence variants in NTRK1 in sporadic human medullary thyroid carcinoma.

Tyrosine kinase NTRK1 is expressed in neural and nonneuronal tissues. Like RET, NTRK1 is often activated by rearrangements that involve one of at least five other genes in papillary thyroid carcinoma (PTC). Because of similarities in involvement of the two tyrosine kinases RET (rearranged during transfection) and NTRK1 in the pathogenesis of PTC, the obvious parallels between RET and NTRK1 and between PTC and medullary thyroid carcinoma (MTC), NTRK1 seemed to be an excellent candidate gene to play a role in the genesis of MTC. Single-strand conformational polymorphism analysis of 16 exons of NTRK1, from 31 sporadic MTC, revealed variants in five exons (exons 4 and 14-17). Sequence analysis demonstrated one sequence variant each in exons 4, 14, 16, and 17, and four different variants in exon 15. Differential restriction enzyme digestion specific for each variant confirmed the sequencing results. All variants were also present in the corresponding germline DNA. Interestingly, the sequence variants at codon 604 (c1810C>T) and codon 613 (c1838G>T) ofexon 15 always occurred together and might represent linkage disequilibrium. The frequencies of the sequence variants in germline DNA from patients with sporadic MTC did not differ significantly from those in a race-matched control group. Although we did not find any somatic mutations of NTRK1 in sporadic MTC, the single-strand conformational polymorphism conditions reported here, together with the knowledge of the frequency of various sequence variants, may help in future mutation analyses of DNA from other neural and nonneural tissues.

Carcinoma, Medullary↗
PubMed1999

Differences in allelic distribution of two polymorphisms in the VHL-associated gene CUL2 in pheochromocytoma patients without somatic CUL2 mutations.

Although the two major familial forms of pheochromocytomas, multiple endocrine neoplasia type 2 and von-Hippel-Lindau disease (VHL), have been associated with mutations of the RET and VHL genes, respectively, the molecular pathogenesis of sporadic pheochromocytomas is largely unknown. Recently, a putative tumor suppressor gene has been identified, CUL2, whose product has been shown to interact with the VHL tumor suppressor. To examine whether CUL2 plays a role in pheochromocytoma pathogenesis, we analyzed a series of 26 distinct tumor samples for mutations in the whole coding region of this gene. There were no somatic pathogenic mutations in CUL2, except for 1 sporadic tumor that had a hemizygous gene deletion. We also found 3 novel polymorphisms in the gene. One of these variants, IVS5-6C/T, as well as another previously described one, c.2057G/A, were overrepresented among the pheochromocytoma patients compared to that in a control population (P < 0.005 and P < 0.01, respectively). Although our findings suggest that CUL2 does not play a major role in the pathogenesis of pheochromocytomas, it is still unknown whether epigenetic mechanisms are involved in its inactivation in VHL-associated tumors. Furthermore, the potential role for the overrepresented alleles in the pheochromocytoma group requires further investigation.

Adolescent↗
PubMed1998

Determinative factors of biochemical cure after primary and reoperative surgery for sporadic medullary thyroid carcinoma.

Normalization of calcitonin levels after surgery has been regarded as the most powerful prognostic factor for medullary thyroid carcinoma (MTC). Although the prognosis of patients with persistent hypercalcitoninemia may be acceptable, the biochemical cure rate can be improved by new microdissection techniques. This raises certain questions: Can extension of locoregional lymphadenectomy (LA) further improve biochemical cure and survival after primary or reoperative MTC surgery? Which factors concerning TNM categories are associated with the possibility of postoperative normalization of calcitonin levels? This study included 64 patients with sporadic MTC operated on from 1986 to 1997. Altogether 27 patients underwent primary surgery, and 37 patients were reoperated, performing a microdissection of all four locoregional compartments (four-compartment lymphadenectomy, or 4CLA). For primary MTC the biochemical cure rate was 100% in node-negative patients and 33% in node-positive patients; the latter could be improved to 45% after 4CLA. In contrast to reoperative MTC, the rate of lymph node metastases (LNMs) with primary MTC correlated with the pT category (pT1 33%, pT2 53%, pT3 100%, pT4 100%) but not with age or sex. Again in contrast to reoperative MTC, mediastinal LNMs in primary MTC were present only in patients with a pT4 tumor. At reoperation, 4CLA was able to cure 22% of node-positive patients, 28% without proved distant metastases. No patient with extrathyroidal tumor involvement or distant metastases was biochemically cured after either primary or reoperative surgery. For all node-positive MTC patients, in addition to cervicocentral LA at least a bilateral cervicolateral LA is recommended. Transsternal mediastinal lymph node dissection is indicated in patients with LNMs in the cervicomediastinal transition, facilitating biochemical cure in up to 45% after the first operation and 22% after reoperative surgery of sporadic MTC.

Adult↗
PubMed1998

Prophylactic thyroidectomy in 75 children and adolescents with hereditary medullary thyroid carcinoma: German and Austrian experience.

When mutations of the RETproto-oncogene were found in 1993 to account for hereditary medullary thyroid carcinoma (MTC), surgeons obtained the opportunity to operate on patients prophylactically (i. e., at a clinically asymptomatic stage). Whether this approach is justified, and, if so, when and to which extent surgery should be performed remained to be clarified. A questionnaire was sent to all surgical departments in Germany and Austria. All of the patients who fulfilled the following criteria were enrolled: (1) preoperatively proved RET mutation; (2) age </= 20 years, (3) clinically asymptomatic thyroid C cell disease; and (4) TNM classification pT0-1/pNX/pN0-1/M0. Seventy-five patients were identified, and fifteen mutations were detected in six codons. Two adolescents had unilateral pheochromocytomas as part of the multiple endocrine neoplasia II (MEN-II) syndrome. No hyperparathyroidism was noted. All patients underwent total thyroidectomy, and 57 patients went on to have lymph node dissection. Parathyroid glands were removed in 34 patients and autografted in 11. Histopathology revealed MTC in 46 patients (61%, youngest 4 years); C cell hyperplasia (CCH) only was detected in the other 29 patients. Three patients had lymph node metastases (LNMs) the youngest being age 14 years. Calcitonin levels were not useful for differentiating between CCH and MTC, but in all patients with LNMs at least the stimulated calcitonin levels were assayed. After surgery, five patients (6.7%) sustained permanent hypoparathyroidism, and one patient (1.3%) had a permanent unilateral recurrent nerve palsy. All but three patients (96%) were biochemically cured. In conclusion, prophylactic total thyroidectomy can be performed safely in experienced centers. We recommend prophylactic total thyroidectomy at age 6. Cervicocentral lymph node dissection should be included when calcitonin levels are elevated or if patients are older than 10 years. Bilateral lymph node dissection should be performed if LNMs are suspected or when patients with elevated calcitonin are older than 15 years.

Adolescent↗
PubMed1998

Primary hereditary medullary thyroid carcinoma--C-cell morphology and correlation with preoperative calcitonin levels.

Early thyroidectomy offers an opportunity of preventing the development of medullary thyroid carcinoma (MTC) in patients at risk for hereditary MTC. We investigated the thyroid glands of 32 patients with hereditary MTC to identify the changes in C-cell morphology and to correlate these with plasma calcitonin (CT) levels and with clinical data. The entire thyroid gland was processed for histological examination including immunostaining for CT. All glands revealed C-cell hyperplasia (CCH), and MTC was found in 21 patients (66% of 32, youngest patient 6 years, youngest with lymph node metastases [LNM] 17 years). The transition from CCH to MTC was characterized by destruction of the follicular basement membrane and by diminished intensity of CT immunostaining. Normal plasma CT levels after provocation with pentagastrin were found only in patients with CCH. Basally elevated plasma CT levels were restricted to MTC. LNM were only found in multifocal tumours at least 4 mm in diameter. It is not yet clear whether or not CCH in patients at risk for hereditary MTC is a neoplastic change, but in these patients the term 'C-cell hyperplasia' is of doubtful value. All MEN gene carriers reveal CCH, and almost all of them will develop multifocal MTC, so that CCH is probably a precursor lesion of an indubitably malignant tumour. Prophylactic thyroidectomy is justified at the age of 6 to anticipate development of a MTC. Lymphadenectomy is necessary in children if they are older than 10 years or have elevated plasma CT levels.

Adolescent↗
PubMed1998

Pattern of lymph node metastases in papillary thyroid carcinoma.

BACKGROUND: Incidence and pattern of lymph node metastasis (LNM) were evaluated in 35 patients who underwent primary surgery for papillary thyroid carcinoma. METHODS: Total thyroidectomy with systematic cervicocentral lymphadenectomy was performed routinely. Additionally, 22 patients underwent lymphadenectomy of the ipsilateral cervicolateral compartment. Sternotomy was performed in four patients. RESULTS: Primary tumour status was: pT1, n = 7; pT2, n = 12; pT3, n = 4; pT4, n = 12. Twenty-four patients had LNM in the ipsilateral cervicocentral compartment (pT1, n = 2; pT2, n = 8; pT3, n = 4; pT4, n = 10). Nineteen had LNM in the ipsilateral cervicolateral compartment (pT1, n = 4; pT2, n = 6; pT3, n = 2; pT4, n = 7). Contralateral cervicocentral LNM was restricted to patients with pT3 tumours (n = 2) or pT4 tumours (n = 3). No patient had LNM in the contralateral cervicolateral compartment. Only one patient (pT3 tumour) had mediastinal LNM. CONCLUSION: The cervicocentral compartment was most commonly involved with metastases, although the ipsilateral cervicolateral compartment was almost as often affected. In some patients ipsilateral cervicolateral LNM was present in the absence of cervicocentral LNM. Contralateral cervicolateral and upper mediastinal LNM, however, were rare. This study helps to plan radical surgery for papillary thyroid carcinoma.

Adolescent↗
PubMed1997

Ectopic intrathyroidal thymus diagnosed as a solid thyroid lesion: case report and review of the literature.

The authors report a case of a 6-year-old boy in whom aberrant thymic tissue was misdiagnosed as an intrathyroidal solid lesion. The patient underwent hemithyroidectomy and did well. Because cervical ectopic thymus rarely produces symptoms, the true incidence in children is unclear. Surgeons need to consider this rare entity, not to mistake it as a thyroid neoplasm, and not to perform extensive thyroid resection.

Child↗