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J E Varhaug

Publications and source records attributed to J E Varhaug.

At least 19 recordsLinked to original sources
PubMed2002

Thymectomy and anti-muscle autoantibodies in late-onset myasthenia gravis.

Thymectomy is still widely carried out in myasthenia gravis (MG) patients, but its role, especially in late-onset MG patients, is not established. These patients are immunologically heterogeneous, some with thymoma-like and others with early onset-like features. We evaluated whether any therapeutic effects of thymectomy correlate with the presence of non-acetylcholine receptor (AChR) muscle antibodies. The severity of MG, and titin and ryanodine receptor (RyR) antibodies, were assessed yearly starting from MG onset in 21 thymectomized and 22 non-thymectomized AChR antibody positive late-onset MG patients, who were followed for 2, 3 and 5 years. Clinical or pharmacological remission were seen in six of 11 titin antibody negative but none of the 10 titin antibody positive thymectomized patients, however, the non-thymectomized cases showed an opposite trend. The three MG-related deaths were all in patients with titin antibodies. There was no significant difference in MG severity between thymectomized and non-thymectomized patients; 2 years after MG onset, both groups were significantly improved. This study showed no dramatic benefit from thymectomy in late-onset MG in general. Any limited improvement appeared less likely in cases with titin and/or RyR antibodies.

Age of Onset↗
PubMed2002

Adjuvant endocrine treatment (goserelin vs tamoxifen) in pre-menopausal patients with operable node positive stage II breast cancer. A prospective randomized national multicenter study.

AIMS: To evaluate possible differences in effect on time to recurrence and overall survival in node positive pre-menopausal breast cancer patients (age < or = 50 years) receiving LHRH analogue or tamoxifen as adjuvant endocrine treatment. METHODS: Between January 1989 and July 1994, 320 patients with node positive (pN(+)) and hormone receptor positive or receptor status unknown tumors were included and randomized in a national multicenter study to receive either tamoxifen or goserelin as adjuvant treatment for two years. Primary surgical treatment was employed according to current standards. Final follow-up was completed as of December 2000. Time to events were estimated by the Kaplan-Meier method, and compared by the log rank test. Relative risks were estimated by the Cox's proportional hazards model. RESULTS: No differences in time to first recurrence or overall survival were observed between treatment groups. Proportions of patients in each group having a second breast cancer were also similar. CONCLUSIONS: Standard adjuvant treatment with tamoxifen as compared to adjuvant LHRH analogue therapy employed in this group of breast cancer patients gave similar outcomes, but the number of patients was too small to formally exclude a potentially clinically relevant difference in survival.

Adult↗
PubMed2002

Endoscopic ultrasonography for preoperative diagnosis and localization of insulinomas.

BACKGROUND: Endoscopic ultrasonography (EUS) is generally accepted as a sensitive method for the detection of small pancreatic tumors. We report our experience with EUS for preoperative imaging of insulinomas. METHODS: Nine patients with clinical and biochemical signs of insulinoma were examined by EUS using a 7.5/12 MHz radial-scanning ultrasound endoscope prior to surgery. EUS outcome was evaluated on the basis of surgery (open or laparoscopic) and examination of the resected specimens. RESULTS: Two EUS-negative patients appeared, by reassessment of clinical and biochemical data, not to have an insulinoma and were not operated on. EUS correctly imaged and localized five of seven insulinomas that were surgically removed. One isoechoic tumor in the pancreatic head and one pedunculated tumor connected to the caudal side of the pancreatic body were missed by EUS. EUS could demonstrate the size and shape of the imaged tumors, as well as their relationship to adjacent structures, such as the pancreatic duct, bile duct, and large vessels. CONCLUSIONS: Our experience with seven insulinomas accords with previous reports claiming EUS to be the method of choice for preoperative imaging and localization of pancreatic islet cell tumors.

Adult↗
PubMed2001

Expression and alternative splicing of c-ret RNA in papillary thyroid carcinomas.

Somatic rearrangements of the ret receptor tyrosine kinase have been consistently reported in papillary thyroid carcinomas (PTC). It is unclear whether the expression of wild-type c-ret may also be implicated in thyroid tumorigenesis. We studied ret mRNA expression in PTC from Norwegian patients. Using RT-PCR, wild-type ret mRNA was detected in all of 22 PTC and in a PTC cell line. c-ret mRNA was clearly overexpressed in PTC as compared to non-neoplastic thyroid tissue. Hybridization using ret exon DNA dot blot arrays and complex cDNA probes confirmed expression of ret RNA in thyroid biopsies. In accordance with the RNA data, Western immunoblotting showed evidence of wild-type Ret protein in PTC. Rearrangements generating the ret/PTC oncogenes co-existed with c-ret mRNA in PTC. Multiple alternative ret splicing variants were detected in PTC. Four novel ret splicing events were found in the region encoding the extracellular domain. The open reading frames of these transcripts were all in-frame with the Ret tyrosine kinase domain. In the central ret mRNA region encoding the cysteine-rich, transmembrane, and main tyrosine kinase domains, no evidence of alternative splicing was detected. Two alternative splice events were detected in the ret mRNA encoding the C-terminal part of Ret protein harboring tyrosine residues important for Ret signaling, excluding exon 19, or retaining intron 19, respectively. Ribonuclease protection assays confirmed the presence of ret alternative splicing events in thyroid biopsies. We conclude that in addition to ret/PTC rearrangements, wild-type c-ret mRNA and alternatively spliced ret transcripts are present in PTC. Transcriptional up-regulation and post-transcriptional mechanisms of c-ret RNA processing may contribute to differences in expression of Ret protein observed in PTC compared to non-neoplastic thyroid tissue.

Alternative Splicing↗
PubMed2001

Difference in patterns of Met expression in papillary thyroid carcinomas and nonneoplastic thyroid tissue.

Met protein is a tyrosine kinase receptor for hepatocyte growth factor (HGF). c-Met has morphogenic, mitogenic, and motogenic properties and is overexpressed in many solid tumors. We studied c-met mRNA and protein expression in papillary thyroid carcinomas and nonneoplastic thyroid tissue. The c-met mRNA was detected in all biopsies by reverse transcriptase-polymerase chain reaction and by hybridization of complex cDNA probes to a c-met-specific DNA fragment in a dot blot array. Immunohistochemistry on fresh frozen biopsies showed Met protein localized along the basal cell membrane of normal thyrocytes in 32 of 35 nonneoplastic thyroid tissue specimens, sometimes associated with weak cytoplasmic reactivity but without apical cell membrane staining. In papillary carcinomas an increased Met protein expression was seen, comprising a cytoplasmic (33 of 49) and apical cell membrane (24 of 49) immunoreactivity, whereas only 1 of 49 biopsies showed basal cell membrane staining. A 145-kDa Met-specific band was detected by Western immunoblotting on protein extracts from papillary carcinomas. The tight junction protein zona occludens-1 (ZO-1), studied by immunohistochemistry, was weakly expressed along the apical cell membrane in 10 nonneoplastic biopsies. In contrast, increased and cytoplasmic/apical membranous ZO-1 immunostaining was seen in 11 of 15 papillary carcinomas. Nuclear ZO-1 staining was present in a few papillary carcinomas with partial dedifferentiation. The concomitant overexpression and subcellular redistribution of Met and ZO-1 proteins indicate a change in cell polarity in papillary carcinomas compared to nonneoplastic thyroid tissue. These observations may reflect an important feature of the tumorigenesis of papillary thyroid carcinomas. No significant association was found between semiquantitative immunohistochemical assessment of Met protein and clinical parameters in papillary carcinoma patients.

Adenoma↗
PubMed2000

Expression of heregulins and associations with the ErbB family of tyrosine kinase receptors in papillary thyroid carcinomas.

Heregulin (Hrg) growth factors are natural ligands for ErbB3 and ErbB4. Because these receptors are involved in papillary thyroid carcinomas, we studied expression of Hrgs in fresh-frozen thyroid tissue and analyzed for possible coexpressions among the 4 members of the ErbB family of growth factor receptors and Hrgs in papillary carcinomas. Immunohistochemistry for the Hrg precursor isoform (134 biopsies from 101 patients) showed nuclear immunostaining in 83% of papillary carcinomas but not in normal thyroid tissue. Cytoplasmic immunopositivity for the Hrg precursor isoform was moderate or strong in 78% of papillary carcinoma specimens and weak in 13% of normal thyroid tissue samples. Western blot for the Hrg precursor isoform showed the expected protein band of approximately 70 kDa in papillary carcinomas, but not in non-neoplastic thyroid biopsies. Whereas weak cytoplasmic immunostaining for the mature Hrg alpha, beta1, and beta3, was present in 48, 38, and 51% of papillary carcinomas, respectively, normal thyroid tissue samples were negative. Hrg mRNA was present in both tumor and nontumor tissue, with evidence of increased mRNA expression in 5 of 12 papillary carcinomas. RT-PCR of hrg mRNA, with subsequent DNA sequencing, confirmed the presence of hrg alpha, beta1, beta2, and beta3 mRNA in papillary carcinomas. In 55 papillary carcinomas, increased cytoplasmic immunostaining of the ErbB2 and ErbB3 receptors was significantly associated with each other and with cytoplasmic epidermal growth factor receptor (EGFR) immunoreactivity, indicating a common regulatory mechanism. Cytoplasmic staining for Hrg beta3 was significantly associated with ErbB3 immunostaining, indicating this receptor as the cognate one. The overexpression and nuclear localization of the Hrg precursor isoform were not associated with the expression of ErbB-receptors. This may reflect an unknown mechanism of action, possibly independent of the ErbB receptor system.

Carcinoma, Papillary↗
PubMed2000

The value of ultrasonography in predicting autoimmune thyroid disease.

Ultrasonography (US) may demonstrate a diffuse reduction in thyroid echogenicity (low-amplitude echoes) in autoimmune thyroid disease (AITD), which includes chronic lymphocytic thyroiditis and Graves' disease, as well as in subacute thyroiditis. The reported occurrence of this finding in AITD varies from 19% to 95%. To assess the validity of diffuse reduction in thyroid echogenicity as a predictor of AITD, 3,077 patients referred for US of the thyroid were examined prospectively with regard to reduced versus normal thyroid echogenicity. The most frequent reasons for referral were goiter, thyroid dysfunction, neck discomfort, and/or difficulty in swallowing. Ultrasonography demonstrated diffuse reduction in thyroid echogenicity in 485 patients. Of these, 452 patients had available records of fine-needle aspiration biopsy (FNAB), and were included in the study. From the remaining patients, with normal thyroid echogenicity, 100 consecutive patients were selected as controls. In 411 of the 452 study patients (90.9%) there was at least one laboratory finding consistent with possible AITD: cytology indicating lymphocytic thyroiditis, 287 of 363 patients (79.1%) with diagnostic specimens; elevated levels of peroxidase antibodies (TPOAb), 225 of 337 (66.8%); elevated thyrotropin (TSH) levels, 290 of 450 (64.4%); or low TSH levels, 79 of 450 (17.6%). The final diagnosis was: chronic autoimmune (Hashimoto's) thyroiditis in 352 patients; Graves' disease in 47 patients; subacute (granulomatous) thyroiditis in 7 patients; toxic nodular goiter in 3 patients; and toxic adenoma in 2 patients. In the remaining 41 patients, those without laboratory results consistent with AITD, the final diagnosis was colloid goiter in 37 and thyroid cancer in 4 patients. In the 100 controls, laboratory results were consistent with possible AITD in 14 patients: elevated TPOAb levels in 5 of 49 patients with retrieved antibody results; lymphocytic thyroiditis in 2 patients; elevated TSH levels in 2 patients; and low TSH levels in 2 patients. In these controls, the final diagnosis was: chronic autoimmune thyroiditis in 7; toxic nodular goiter in 6 patients, and toxic adenoma in 1 patient. The corresponding positive and negative predictive values of reduced thyroid echogenicity as an indicator of AITD were 399 of 452 (88.3% [95% CI, 85% to 91%]), and 93 of 100 (93.0% [95% CI, 88% to 98%]), respectively. Thus, diffuse reduction in thyroid echogenicity was a valid predictor of AITD.

Adolescent↗
PubMed2000

Plasma total homocysteine levels during short-term iatrogenic hypothyroidism.

Hypothyroidism is associated with increased cardiovascular morbidity, which cannot be fully explained by the atherogenic lipid profile observed in these patients. We have previously found elevated levels of the cardiovascular risk factor, plasma total homocysteine (tHcy), in hypothyroidism. We conducted a longitudinal study on 17 patients who had undergone total thyroidectomy for thyroid cancer. During 6 weeks of discontinued T4 substitution before radioscintigraphy (phase I), they attained a hypothyroid state, which was reversed by resupplementation (phase II). Plasma tHcy, serum creatinine, serum and red blood cell folate, serum cobalamin, and serum cholesterol were determined at 2-week intervals throughout phases I and II. There was a progressive and parallel increase in tHcy (mean, 27%), serum creatinine (37%), and serum cholesterol (100%) during phase I, and these values returned to the original level within 4-6 weeks after reinitiating T4 therapy. Serum and red blood cell folate levels showed only minor, but statistically significant, changes. In a bivariate model, serum creatinine and serum cholesterol were strongly associated with the changes observed in tHcy during short term hypothyroidism. In conclusion, we found a transient increase in both plasma tHcy and serum cholesterol during short term iatrogenic hypothyroidism, and the tHcy response is probably mainly explained by concurrent changes in renal function. The increase in both plasma tHcy and serum cholesterol may confer increased cardiovascular risk in hypothyroid patients.

Adult↗
PubMed1999

[Borderline primary hyperparathyroidism].

The clinical presentation of primary hyperparathyroidism has changed considerably after the application of biochemical autoanalysers. The condition was previously found with characteristic symptoms in bone, kidneys and the gastrointestinal tract; less than 1% of patients were assumed to be asymptomatic. Today, most patients have mild and uncharacteristic symptoms. Primary hyperparathyroidism has been detected with increasing frequency in the western world, but there are large variations within demographically otherwise comparable areas. There are also regional differences regarding the incidence of surgical treatment of the disease. Demographic studies have shown increased morbidity and mortality primarily from cardiovascular and possibly malign diseases related to hypercalcemia. Follow-up studies based on surgical series have shown increased mortality related to preoperative serum calcium level. In view of the altered clinical picture of primary hyperparathyroidism, treatment of moderate and possibly "benign" primary hyperparathyroidism has been actualised. At an international consensus conference in 1990, this patient group was defined by an arbitrary serum calcium limit of 3.0 mmol/l, but this limit has been found to be unacceptably high. Regardless of where the upper limit is set, there are so far well accepted indications for surgery, but only one in two patients fulfil these criteria. A working group of endocrinologists and endocrine surgeons from nine university clinics in Scandinavia have recently initiated a prospective, randomised study evaluating surgical treatment and a systematic follow-up of patients with borderline primary hyperparathyroidism.

Bone Density↗
PubMed1998

[Diagnostic molecular biology in solid tumors--thyroid gland].

Thyroid cancer is not a common disease. It includes tumour types of great diversity in clinical course and molecular basis. Mutations of TSH-receptor, rearrangements of ret proto-oncogene, and altered expression of other tyrosine kinase growth factor receptors are characteristics of the follicular neoplasias and papillary carcinomas, while undifferentiated tumours harbour p53 mutations. Knowledge acquired to date has led to an increased understanding of thyroid growth and tumour development, but it has had no significant impact on diagnostic and treatment measures. On the other hand, the C-cell derived medullary carcinomas include familial cases where identification of germ-line ret mutations provides the basis for prophylactic thyroidectomy in affected individuals.

Carcinoma↗
PubMed1997

[Diagnosis of thymoma and thymic atrophy in patients with myasthenia gravis].

We have compared clinical, immunological and radiological data in 20 patients with myasthenia gravis and thymoma and in 21 patients with myasthenia gravis and thymic atrophy. The median age at onset was 54 years in the thymoma group and 63 years in the thymic atrophy group (p = 0.04). The severity of the disease was similar in the two groups, and there was no significant difference in the concentration of acetylcholine receptor antibodies. CA antibodies were demonstrated in 17/20 thymoma patients and in 6/21 with thymic atrophy, while 19/20 thymoma patients had antibodies to titin, compared with 9/21 among those with thymic atrophy. The diagnosis and treatment of patients with myasthenia gravis is based upon an evaluation of clinical, immunological and radiological data.

Adult↗
PubMed1996

Expression of c-erbB-3 and c-erbB-4 proteins in papillary thyroid carcinomas.

c-erbB-3 and c-erbB-4 protein expression was analyzed using immunohistochemistry in 138 fresh-frozen thyroid tissue samples from 106 patients, including 56 cases of papillary thyroid carcinoma. Increased expression of c-erbB-3 and c-erbB-4 proteins was observed in papillary carcinomas compared to nonneoplastic thyroid tissue. No amplifications of the c-erbB-3 and c-erbB-4 genes were detected. Coexisting overexpression of epidermal growth factor receptor, c-erbB-2, c-erbB-3, and c-erbB-4 was demonstrated in 36 (64%) of 56 papillary thyroid carcinomas. These findings suggest a common regulatory mechanism for the type I (epidermal growth factor receptor-related) receptors in papillary thyroid carcinomas and provide numerous possibilities for functional receptor interactions.

Biomarkers, Tumor↗
PubMed1996

[Breast cancer].

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Breast Neoplasms↗
PubMed1996

Cytoplasmic localization of EGF receptor in papillary thyroid carcinomas: association with the 150-kDa receptor form.

We have previously reported that papillary thyroid carcinomas show an increased expression of EGFR mRNA and protein, compared to non-tumorous thyroid tissue. EGFR immunoreactivity was localized to the cytoplasm as well as to the membrane in papillary carcinomas. To further study EGFR protein expression in human thyroid tissue, we performed immunohistochemistry and Western blots of 64 different thyroid tissue samples from 36 patients, including 23 patients with papillary carcinomas. Two receptor forms were identified in human thyroid tissue, a 170-kDa and a 150-kDa form. The 150-kDa receptor form was more pronounced in papillary carcinomas, while the 170-kDa receptor was the dominant form in non-malignant thyroid tissues. Predominance of the 150-kDa EGFR in the tumour samples was associated with strong cytoplasmic EGFR staining. EGFR gene structure, protein synthesis and maturation were found to be normal. Immunoprecipitation and Western-blot analysis of EGFR from the human thyroid SGHTL-34 cells after increased ligand concentration showed a decreased amount of the mature 170-kDa receptor and a relative increase in the 150-kDa receptor. We have previously demonstrated the presence of a TGF-alpha-EGFR autocrine loop in papillary thyroid carcinomas, and this may explain increased receptor turnover and accumulation of a cytoplasmic degradation product.

Blotting, Western↗