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J Zedenius

Publications and source records attributed to J Zedenius.

At least 19 recordsLinked to original sources
PubMed2006

Predictors of outcome in patients with papillary thyroid carcinoma.

AIM OF THE STUDY: To evaluate prognostic factors with respect to the outcome in a consecutive series of patients with papillary thyroid carcinoma (PTC) treated at the same institution during a 20-year-period, and to evaluate further the predictive ability of outcome of the pTNM, AMES and MACIS prognostic systems in these patients. MATERIALS AND METHODS: Two hundred and twenty consecutive patients operated on for primary PTC at the Karolinska Hospital between 1980 and 1999 were examined retrospectively. Patient and tumour characteristics at the time of surgery were compared to the patients' outcomes. Univariate and multiple logistic regression analyses were used to identify independently significant prognostic factors with respect to the outcome. In addition, the classification of the patients according to the pTNM, AMES and MACIS prognostic systems were compared to the outcomes. RESULTS: At the end of the follow-up period 201 patients were still alive without disease, 6.5% had died from PTC and 2.5% were alive with persisting disease. In 16 patients, radical surgery could not be performed due to extensive tumour growth and/or distant metastases. Recurrences were detected in 14% of the patients considered as radically operated. The strongest independent predictors for local or distant recurrences and poor clinical outcome were the lack of radical surgery and increasing tumour size. In this investigation MACIS appeared to be the better system, regarding efficacy in predicting the outcome of PTC. CONCLUSION: Removal of all tumour tissue appears most important to a favorable outcome and in our patients MACIS appears the most useful prognostic system taking completeness of resection into account.

Adolescent↗
PubMed2005

Lack of mutations in the TSHr and Gsalpha genes in TSHr antibody negative Graves' disease.

The aim of this study was to investigate whether TSHr antibody negative Graves' disease is associated with somatic mutations in the TSHr or Gsalpha genes and whether histopathologically defined thyroid lesions, i.e., hyperfunctioning adenoma, non-functioning follicular adenomas, or nodules in toxic and non-toxic multinodular goiters are associated with such mutations. No mutations but three germ-line polymorphisms were found in patients with TSHr antibody negative Graves' disease. The three polymorphisms are expected to have no or only minor effects on the signaling properties, and is not associated with altered antigenecity imposed by such mutations. Two heterozygous somatic TSHr mutations were found in two hyperfunctioning adenomas and in two toxic multinodular goiters. The lack of TSHr and Gsalpha mutations in TSHr antibody negative Graves' disease patients indicates that such mutations are neither primary nor secondary events in this disease. The results also confirm that somatic gain-of-function TSHr mutations are present in hyperfunctioning follicular adenomas and goiters, but not in non-functioning thyroid lesions.

Adenoma↗
PubMed2001

[Hereditary thyroid cancer can be cured by prophylactic surgery].

Multiple endocrine neoplasia type 2 (MEN 2) is a rare syndrome in which the consequences for the patient and family members are considerable. Mutation analysis of the RET proto-oncogene is crucial for decision-making regarding each patient. Today, carriers of MEN 2 mutations should be offered prophylactic thyroidectomy with the potential to eliminate the risk for potentially lethal medullary thyroid carcinoma (MTC). Here, we present the first Swedish experience of such operations performed mainly on the basis of genetic analysis. Twenty patients underwent total thyroidectomy at a mean age of 13.5 (6-43) years. In all cases, either manifest MTC (n = 11) or C-cell hyperplasia was found. So far, no patient has any sign of recurrence or developmental insufficiency at 1-5 years follow-up. As the medical and ethical problems in this group of patients are substantial, and as the operations are performed in otherwise healthy children, they should be treated at centers with adequate multidisciplinary expertise and competence.

Adolescent↗
PubMed2001

Gain of 1q and loss of 9q21.3-q32 are associated with a less favorable prognosis in papillary thyroid carcinoma.

In order to approach the genetic mechanisms behind initiation and progression of papillary thyroid carcinoma (PTC) tumorigenesis, we characterized numerical chromosomal imbalances in a panel of 25 PTCs with varying histopathological and clinical features using comparative genomic hybridization (CGH). The most frequently detected imbalance was gain of 9q33-qter, which was seen in close to 30% of the cases. The commonly occurring regions of loss were assigned to 22q (12%) and 9q21.3-q32 (12%), while gains preferentially involved the entire X chromosome (20%), 1q (16%), 17q (16%), and 22q (12%). The distribution of CGH alterations supports the idea of a progression of genetic events in the development of PTC, where gain of 9q33-qter would represent a relatively early event that is followed by loss of 22q and gain of X, 1q, 17q, and 22q. When the detected CGH alterations were compared with the clinical outcome and the histopathological features of the 25 PTC cases, several statistically significant correlations were revealed. The total number of genetic alterations was higher in tumors from patients with aggressive disease as compared to those without signs of aggressiveness. Gain of 1q and loss of 9q21.3-q32 were exclusively seen in tumors from patients with aggressive disease, and the presence of distant metastases was associated with gain of 1q. A sex-dependent distribution was also evident for one of the common alterations, with gain of X exclusively seen in male cases. Taken together, the findings identify several candidate locations for tumor suppressor genes and oncogenes that are potentially involved in the establishment and progression of papillary thyroid carcinogenesis.

Adult↗
PubMed2001

Expression of the RET proto-oncogene in papillary thyroid carcinoma and its correlation with clinical outcome.

BACKGROUND: In papillary thyroid carcinoma (PTC), presence of the oncogenes RET/PTC has been described, but their correlation with prognosis is debated. The aim of this study was to investigate the expression of the RET proto-oncogene (RET) and correlate it with clinical outcome. METHODS: Sixty-one PTCs were analysed for expression of RET and the oncogenes RET/PTC1-4 by polymerase chain reaction of complementary DNA. RESULTS: Twenty-nine PTCs (48 per cent) expressed the RET tyrosine kinase domain (RET-TK). Twelve expressed wild-type RET (WT-RET). One tumour expressed RET/PTC3, one a variant of RET/PTC3, and one RET/PTC1 and WT-RET simultaneously. The remaining 14 expressed RET-TK only. WT-RET expression was detected more frequently in poorly differentiated PTCs (P < 0.05) and in PTCs from patients with aggressive disease (P < 0.01). WT-RET expression remained an independently significant risk factor for aggressive disease when analysed together with other recognized risk factors using a stepwise multiple logistic regression model. CONCLUSION: Almost half of the PTCs showed RET-TK expression; in only three was this explained by expression of a RET/PTC rearrangement. Instead, expression of WT-RET was detected in 45 per cent of the RET-TK-positive tumours and this expression was an independently significant risk factor for aggressive PTC. Presented in abstract form to the Millennium Meeting of Endocrine Surgeons held by the American Association of Endocrine Surgeons, British Association of Endocrine Surgeons and Swedish Association of Endocrine Surgeons, London, UK, May 2000

Carcinoma, Papillary↗
PubMed2001

Surgical treatment of hyperthyroidism: a ten-year experience.

Hyperthyroidism is treated either by antithyroid drugs, radioiodine (I131) or surgery. In Sweden, surgery is often performed in patients with large goiter or severe hyperthyroidism with infiltrative endocrine ophthalmopathy. To evaluate indications and results of surgical treatment, data from 380 patients operated on for hyperthyroidism at our department during 1986-1995 were analyzed. Twenty-six percent were referred for surgery because of failure of treatment with antithyroid drugs or I131. Ninety-one percent were subjected to subtotal thyroidectomy with a median remnant weight of less than 2 g. In the remaining patients, total thyroidectomy was performed. Transient vocal cord affection occurred in 2.6%, none of which was permanent. Prolonged postoperative hypocalcemia occurred in 3.1%, and permanent hypoparathyroidism in 1%. There was no difference in complication rate between subtotal or total thyroidectomy. In patients with Graves' disease, 5% worsened with regard to ophthalmopathy initially after surgery but later improved. Recurrent disease occurred in 2% of the patients, all of whom had undergone subtotal thyroidectomy. Surgery is not first-line therapy in all patients with hyperthyroidism. However, in experienced hands, surgery is a good therapeutic alternative that can be carried out with no mortality, few complications, and, provided that a minimal remnant is left, very few recurrences.

Adenoma↗
PubMed2001

CGH alterations in medullary thyroid carcinomas in relation to the RET M918T mutation and clinical outcome.

Apart from the RET proto-oncogene (RET) no other genes have been found to be involved in medullary thyroid carcinoma (MTC) tumorigenesis. Germline RET mutations are seen virtually in all familial forms of MTC and somatic RET mutations are often detected in sporadic MTC. In sporadic MTCs the RET gene is mutated in codon 918, where a methionine is substituted to a threonine (M918T). In this study 24 MTCs were analyzed by comparative genomic hybridization (CGH) for chromosomal imbalances. Overall, alterations were detected in approximately 60% of the samples. The most common aberrations were gains on chromosome 19q (29%), 19p (21%), 11c-q12 (12.5%), and 22q (12.5%) and losses on 13q21 (21%) and 3q23-qter (12.5%). Gain of chromosome 11c-q12 was only detected in samples from patients whom died of MTC (p=0.001). These MTCs also harbored the somatic RET M918T mutation and also showed the highest numbers of CGH alterations in the series (p<0.003). Although there was a tendency towards a higher number of CGH imbalances in the tumors with RET M918T mutation, this difference was not significant. The results indicate that MTC is a comparatively genetically stable tumor, and that chromosomal regions 19q, 19p, 13q and 11q may be involved in MTC carcinogenesis.

Adolescent↗
PubMed2000

Molecular genetics of thyroid tumors and surgical decision-making.

The study of thyroid tumor genetics has great relevance to surgeons and facilitates understanding tumor pathogenesis, prediction of tumor behavior, and management decisions. The genes implicated can be broadly categorized as oncogenes or tumor-suppressor genes. The RET oncogene has well established roles in the development of both papillary (PTC) and medullary (MTC) thyroid carcinoma. Genetic screening for germline RET mutations in members of multiple endocrine neoplasia type II (MEN-II) families is now widely performed, and prophylactic thyroidectomy in gene carriers is advisable at an early age. Patients with apparently sporadic MTC can also be screened to rule out familial disease. The demonstration of a RET rearrangement in a patient's PTC may have prognostic significance, but as yet there are no management implications. The thyrotropin receptor (TSH-R) and Gsalpha become oncogenic through point mutation and are associated with the development of toxic thyroid adenomas. The ras oncogene is implicated in the early stages of development of several thyroid tumor types. Tumor-suppressor genes also have a role in thyroid tumor formation. The p53 gene appears to be involved in the process of transformation to the anaplastic phenotype and the PTEN gene in the development of follicular adenomas but not carcinomas. There is still limited evidence for the so called adenoma-carcinoma sequence of the thyroid follicular cell. Loss of heterozygosity studies have enabled identification of tumor-suppressor genes, and their findings suggests differences in the pathogenesis of PTCs compared with follicular cancers. Surgical decision-making will benefit from these basic molecular advances, which rapidly translates into improved patient management.

DNA, Neoplasm↗
PubMed2000

Loss of heterozygosity in sporadic parathyroid tumours: involvement of chromosome 1 and the MEN1 gene locus in 11q13.

OBJECTIVE: Hyperparathyroidism (HPT) is a common endocrine disorder. Several loci of genetic interest have been identified in parathyroid tumours, including the MEN1 gene locus at 11q13; the HPT-JT region at 1q21-q32; and a putative tumour suppressor gene on 1p. We analysed these intervals, which harbour known genes or putative loci associated with familial hyperparathyroidism, in order to clarify the involvement of the respective regions in parathyroid tumourigenesis. DESIGN: We performed loss of heterozygosity (LOH) studies on 33 sporadic parathyroid tumours using a PCR based technique. A total of 22 microsatellite markers were used to analyse loci at 11q13, 1q21-q32 and 1p. Ten markers located distal on 1p, eight markers encompassed the HPT-JT region at 1q21-q32 and four markers surrounded the MEN1 gene locus at 11q13. MEN1 mutations were screened for using Single Strand Conformation Polymorphism analysis (SSCP) and automated sequencing of SSCP variants. PATIENTS: Thirty-three parathyroid glands and the corresponding blood samples were obtained from 33 patients (26 females and seven males) who underwent parathyroidectomy for primary hyperparathyroidism. RESULTS: Loss of heterozygosity was detected in 13 of 33 (39%) cases at 11q13, 6 of 33 (18%) cases at 1p, and in three of 33 (9%) cases at 1q (in conjunction with 1p loss). Only one of the 18 tumours in which LOH was detected, showed LOH at both chromosome 1 and chromosome 11. Additionally, those tumours found to exhibit LOH at 11q13 were screened for MEN1 mutations using single strand conformation polymorphism analysis (SSCP) and automated sequencing. Nine novel somatic mutations were found on the remaining allele in 13 (69%) tumours. CONCLUSIONS: This study consolidates the role of multiple loci in the pathogenesis of sporadic parathyroid tumours. The results indicate that there are at least two genetic loci involved in sporadic parathyroid tumourigenesis on chromosome 1, one of which has been linked to the distinct familial parathyroid condition, hyperparathyroidism-jaw tumour (HPT-JT) syndrome. The high frequency of loss of heterozygosity at 1p suggests the presence of a tumour suppressor at this locus.

Adenoma↗
PubMed2000

Expression of RET and its ligand complexes, GDNF/GFRalpha-1 and NTN/GFRalpha-2, in medullary thyroid carcinomas.

OBJECTIVE: Mutations in the RET proto-oncogene are found in about one third of sporadic medullary thyroid carcinomas (MTCs), mostly affecting codon 918. Glial cell line derived neurotropic factor (GDNF) and its membrane-bound GDNF family receptor alpha (GFRalpha-1), as well as neurturin (NTN) and its membrane-bound receptor GFRalpha-2 form a complex with the RET product, a receptor tyrosine kinase, resulting in downstream signaling to the nucleus. DESIGN: To elucidate the role of these RET ligands in MTC tumorigenesis, their expression was determined in 15 MTC samples, one papillary thyroid carcinoma (PTC) and three normal thyroid tissue specimens. METHODS: The mRNA expression of RET, GDNF, GFRalpha-1, NTN and GFRalpha-2 was investigated by mRNA in situ hybridization, and confirmed by reverse transcription-PCR analysis. RESULTS: None of the five genes was expressed in the normal thyroids or in the PTC. All MTCs showed expression of RET, 13 expressed GDNF, 12 expressed GFRalpha-1 and 9 expressed NTN and GFRalpha-2. In 7 of the tumors RET, GDNF and GFRalpha-1 were expressed at high levels, and in five of these seven tumors NTN and GFRalpha-2 genes were also expressed at high levels. The high level of expression was preferentially seen in tumor cells adjacent to stroma and connective tissue. All MTCs without expression of the RET ligands harbored the RET codon 918 mutation. CONCLUSIONS: The results suggest that this signaling pathway is important for MTC development, and that it may be activated by expression of the RET ligand complexes by the tumor cells themselves.

Adult↗
PubMed1999

Sporadic follicular thyroid tumors show loss of a 200-kb region in 11q13 without evidence for mutations in the MEN1 gene.

Loss of heterozygosity (LOH) in 11q13 where the tumor suppressor gene for multiple endocrine neoplasia type 1 (MEN 1) is located has been demonstrated in several tumor types, including follicular thyroid tumors, but whether the MEN1 gene is actually involved in their tumorigenesis is not known. In the present study, the involvement of the MEN1 gene in follicular thyroid tumors was investigated. By using 14 MEN1-linked microsatellite markers, LOH was demonstrated in 12 out of 60 follicular thyroid tumors: 2/18 adenomas, 4/15 atypical adenomas, 1/6 Hürthle cell adenomas, 1/9 carcinomas, 3/6 Hürthle cell carcinomas, and 1/6 anaplastic carcinomas. In the tumors with LOH, a single minimal region of overlapping deletions was mapped to the 200-kb interval between D11S4946 and D11S4939. Tumors that showed 11q13 LOH were screened for mutations of the MEN1 gene using single-strand conformation analysis. Abnormal shifts detected in seven tumors in two exons were sequenced, which revealed two different polymorphisms present in both tumor and constitutional DNA, but without somatic mutation. Taken together, these results suggest that in this region, a tumor suppressor gene other than MEN1 might be involved in the tumorigenesis of follicular thyroid tumors. Genes Chromosomes Cancer 26:35-39, 1999.

Adenocarcinoma, Follicular↗
PubMed1999

Fine-structure deletion mapping of 10q22-24 identifies regions of loss of heterozygosity and suggests that sporadic follicular thyroid adenomas and follicular thyroid carcinomas develop along distinct neoplastic pathways.

Previous studies have demonstrated frequent loss of heterozygosity (LOH) of markers on chromosome arm 10q in both follicular thyroid carcinomas (FTCs) and follicular thyroid adenomas (FAs). A novel tumor suppressor gene, PTEN, has been mapped to 10q23.3 and is the susceptibility gene for Cowden syndrome, an autosomal dominant disorder characterized by multiple hamartomas and a risk of benign and malignant tumors of the breast and thyroid. Studies examining the relationship of somatic PTEN status and follicular thyroid neoplasms have only demonstrated a variable subset of tumors that have somatic monoallelic deletions of PTEN, suggesting that other tumor suppressor genes may be present in this region. We therefore sought to conduct a detailed examination of LOH of 20 polymorphic markers in a 19-cM region spanning 10q22-24, including PTEN, in 44 FAs and 17 FTCs. Using this fine-structure somatic mapping approach, we defined at least two novel regions of LOH in follicular adenomas and follicular carcinomas, suggesting the presence of at least two distinct tumor suppressor genes that may play a role in thyroid neoplasia. Furthermore, the difference in patterns of LOH in adenomas versus carcinomas lends additional support to the hypothesis that adenomas and carcinomas can develop along two separate, nonserial pathways. Genes Chromosomes Cancer 26:322-328, 1999.

Adenocarcinoma, Follicular↗
PubMed1999

Multinodular goitre presenting as a clinical single nodule: how effective is hemithyroidectomy?

BACKGROUND: Patients who present with a single thyroid nodule that requires surgery will generally undergo hemithyroidectomy. If, however, the subsequent histological examination shows unsuspected multinodular change, there is a risk of recurrence in the remain ing lobe. The aim of this study was to determine the clinical outcome in patients who have had a hemithyroidectomy for a single thyroid nodule that was shown on subsequent histopathological examination to be part of a multinodular goitre. METHODS: A survey was undertaken of patients who were identified from a thyroid surgery database with the following criteria: (i) hemithyroidectomy for clinical single nodule; and (ii) multinodular change on histopathology. Main outcome measures were clinical recurrence rate, the frequency of further thyroid surgery, and the efficacy of thyroxine treatment on recurrence. RESULTS: In the 229 patients studied, the clinical recurrence rate was 12%. Fourteen of the 28 patients with recurrence required further surgery. Thyroxine therapy did not influence the recurrence rate. CONCLUSION: When surgery for a clinically benign single thyroid nodule is indicated, hemithyroidectomy is an adequate surgical procedure in cases where the single nodule is subsequently found to be part of a multinodular goitre. Such patients can be reassured that the chance of clinical recurrence is low. Thyroxine replacement therapy appears not to prevent recurrence.

Adolescent↗
PubMed1999

Routine autotransplantation of at least one parathyroid gland during total thyroidectomy may reduce permanent hypoparathyroidism to zero.

BACKGROUND: Permanent hypoparathyroidism, although a recognized complication of total thyroidectomy, is an outcome that all endocrine surgeons try to avoid. METHODS: To minimize the risk of postoperative hypoparathyroidism a strategy was developed of routine autotransplantation of at least one parathyroid gland into the ipsilateral sternomastoid muscle during every total thyroidectomy. One hundred consecutive patients undergoing total thyroidectomy were included in the study. Serum calcium and albumin levels were measured pre-operatively, on the first 2 postoperative days, and after 2 weeks, or until return to normal serum calcium levels without calcium supplementation. If patients developed biochemical evidence or symptoms of hypocalcaemia postoperatively, a calcium replacement was administered according to defined protocol. RESULTS: In 74 cases one parathyroid gland was autotransplanted: 44 for inadvertent removal or anatomical reasons, 19 because of devascularization (assessed by a cut through the gland's capsule and evaluation of the capillary bleeding pattern), and 11 by protocol. In 25 cases, two or more glands were autotransplanted. Fourteen patients developed symptoms of hypocalcaemia and received calcium supplementation, as did another 13 asymptomatic patients with only biochemical evidence of hypocalcaemia. At follow-up 3 months postoperatively the incidence of permanent hypoparathyroidism was zero, with all patients being normocalcaemic without calcium supplementation. CONCLUSIONS: This strategy, easily adopted by any experienced surgeon, has the potential to eliminate permanent hypoparathyroidism following total thyroidectomy.

Adolescent↗
PubMed1999

Low frequency of numerical chromosomal aberrations in follicular thyroid tumors detected by comparative genomic hybridization.

Follicular thyroid tumors vary from adenomas to widely invasive carcinomas, and a stepwise progression from normal thyrocyte to malignant tumor has been suggested to be due to an accumulation of genetic alterations. We have used comparative genomic hybridization to screen 21 follicular thyroid tumors (8 adenomas and 13 carcinomas) for gains and losses of DNA sequence copy numbers. In general, the tumors showed few alterations involving several different chromosomal regions. The frequency of alterations was similar in the benign (mean, 1.9) and malignant (mean, 1.5) tumors, as well as in minimally (mean, 1.5) and widely invasive carcinomas (mean, 1.6). However, specific loss of 9q13-q21.3 was detected in three tumors, which were all carcinomas showing oxyphilic changes (Hürthle cell carcinomas; P = 0.003). The fact that DNA copy number alterations were found with a similarly low frequency in both benign and malignant follicular thyroid tumors does not support the hypothesis of a multistep tumor progression in these tumors. Genes Chromosomes Cancer 25:349-353, 1999.

Adenoma↗
PubMed1998

Anaplastic giant cell carcinoma of the thyroid gland: treatment and survival over a 25-year period.

Anaplastic giant cell carcinoma of the thyroid is a rare but highly malignant tumor. At the Karolinska Hospital in Stockholm, surgery, chemotherapy, and radiotherapy have been used separately or in various combinations in 81 patients admitted with this diagnosis during 1971-1997. In this study, we present the various multimodality treatment regimens and their changes over the years and the subsequent differences in survival and local tumor control. Overall, eight patients (10%) survived more than 2 years. All survivors were treated with combinations of chemotherapy, radiotherapy, and surgery. Among the patients who died, local tumor control was achieved by the therapy given in many cases. The results suggest that our current strategy with a combination of preoperative hyperfractionated accelerated radiotherapy, doxorubicin pre- and postoperatively, and debulking surgery whenever possible results in better local tumor control and an increased chance of survival.

Adult↗
PubMed1998

A rapid method for DNA extraction from fine-needle aspiration biopsies of thyroid tumors, and subsequent RET mutation analysis.

The presence of germline and somatic mutations in the RET proto-oncogene (RET) in patients with hereditary and sporadic medullary thyroid carcinoma (MTC) may have important ramifications for patient management. It has been suggested that the presence of the mutation ATG-->ACG at codon 918 in sporadic MTC is associated with a worse prognosis, and hence the need for more aggressive surgical, or other, treatment. Since fine-needle aspiration biopsy (FNAB) is an important component of the preoperative management of patients with thyroid tumors, we developed a rapid (20-min) method that enables extraction of DNA from FNABs for RET mutation analysis. The method allows preoperative genetic analysis to aid in management of patients with MTC, and may be applied to other tumor types where a preoperative mutation analysis based on polymerase chain reaction amplification is desired.

Biopsy, Needle↗