Radioiodine ablation and therapy in differentiated thyroid cancer under stimulation with recombinant human thyroid-stimulating hormone.

We investigated whether recombinant human TSH (rhTSH) safely and effectively induces uptake of high-dose 131-iodine (131I) to ablate thyroid remnant or treat disease, in patients with well-differentiated thyroid carcinoma. Eleven consecutive patients unable to tolerate thyroid hormone withdrawal received one im injection of 0.9 mg rhTSH on 2 consecutive days before receiving 4000 MBq (approximately 108 mCi) radioiodine orally. Eight patients received one, and 3 patients 2 courses. Our series comprised 7 women and 4 men (mean age, 78 yr, range: 56-87 yr). Ten patients had undergone total or near-total thyroidectomy up to 19 yr earlier. rhTSH-stimulated single course radioiodine with the intention to ablate thyroid remnant was performed in 3 patients, with following estimation of radioiodine uptake and TG measurements. Of another 8 patients given this treatment palliatively, 5 had radiological, clinical and/or laboratory response, including: 80% decreased pathological uptake between treatment courses; pronounced decrease in bone pain; diminished symptoms; improved physical condition and quality of life; lower serum TG concentration; and/or normalization of TG recovery test. Two patients with small lung metastases on computed tomography had no detectable radioiodine uptake or other response; they also lacked uptake after withdrawal-stimulated radioiodine treatment. Despite being elderly and frail, patients generally tolerated treatment well; rhTSH caused nausea in one patient and transiently increased pain in bone and soft tissue lesions in another. We conclude that rhTSH-stimulated high-dose radioiodine for remnant ablation or tumor treatment is safe, feasible and seemingly effective, enhancing quality of life and offering reasonable palliation in patients with advanced disease.

A founder mutation of the BRCA1 gene in Western Sweden associated with a high incidence of breast and ovarian cancer.

The aim of this study was to describe and characterise a founder mutation of the BRCA1 gene in western Sweden. Of 62 families screened for BRCA mutations, 24 had BRCA1 mutations and two had BRCA2 mutations. Tumours that occurred in family members were histologically reviewed and mutational status was analysed using archival paraffin-embedded tissues. The same BRCA1 mutation, 3171ins5, was found in 16 families who were clustered along the western coast of Sweden. Mutation analysis revealed a maternal linkage in 13 families and a paternal linkage in 3. There was complete agreement between mutation analysis results obtained from blood and archival tissues. The penetrance of breast or ovarian cancer by age 70 years was estimated to be between 59 and 93%. There were no differences in survivals between breast or ovarian cancer patients with the mutation and age-matched controls. Thus, a predominant BRCA1 gene founder mutation associated with a high risk of breast and ovarian cancer has been identified and found to occur in a restricted geographical area, thereby allowing timely and cost-effective mutation screening using blood samples or archival histological material.

Prediction of prognosis by echocardiography in patients with midgut carcinoid syndrome.

BACKGROUND: The association between malignant midgut carcinoid tumours and right-sided cardiac lesions is well known, but the pathogenetic link between tumour secretion and valvular disease is still obscure. The purpose of this investigation was to describe the morphological and functional changes of valvular heart disease in a large patient series and to correlate these findings with hormonal secretion and prognosis. METHODS: Of 64 consecutive patients with the midgut carcinoid syndrome followed between 1985 and 1998, valvular heart disease was evaluated in 52 patients by two-dimensional echocardiography, Doppler estimation of valvular regurgitation and flow profiles. A majority was also evaluated with exercise electrocardiography and spirometry. RESULTS: Structural and functional abnormalities of the tricuspid valve were found in 65 per cent of patients, while only 19 per cent had pulmonary valve regurgitation. Long-term survival was related to excessive urinary excretion of 5-hydroxyindole acetic acid of over 500 micromol in 24 h, but the main predictor of prognosis was the presence of severe structural and functional abnormalities of the tricuspid valve. Although advanced tricuspid abnormalities were prevalent in this series, only one patient died from right ventricular heart failure. CONCLUSION: Tricuspid valvular disease is a common manifestation of the midgut carcinoid syndrome and advanced changes are associated with poor long-term survival. Active surgical and medical therapy of the tumour disease reduced the hormonal secretion and, combined with cardiological surveillance, made right ventricular heart failure a rare cause of death in these patients.

Gender differences in patients with severe aortic stenosis: impact on preoperative left ventricular geometry and function, as well as early postoperative morbidity and mortality.

OBJECTIVE: In patients with severe aortic stenosis, we studied the impact of gender on preoperative left ventricular geometry and function, as well as on early postoperative mortality and morbidity. METHODS: Prospective Doppler echocardiographic evaluation was performed in 99 female patients and 96 males. RESULTS: The patients had severe aortic stenosis and the mean pressure gradients were similar in females and males. Left ventricular diastolic volume adjusted for body surface area (BSA) was larger in males, 55+/-17.4 ml/m2 versus 43+/-13.1 mL/m2 (mean+/-standard deviation; P = 0.0001). The ejection fraction was similar in females (55+/-14%) and males (55+/-13%), and patients of both sexes had significantly lower stroke volume and cardiac index than healthy controls. The relative wall thickness (wall thickness/diastolic diameter ratio) was higher (P = 0.03) in females (0.47+/-0.10) than in males (0.43+/-0.10) Consequently, the diastolic diameter/wall thickness ratio (a substitute for wall tension) was higher (P = 0.02) in males (4.2+/-0.99) than in females (3.9+/-0.80). Compared with survivors, patients who died within 30 days of the operation (n = 17, 11 females) had a smaller body surface area (1.70+/-0.19 vs. 1.82+/-0.19 m2, P = 0.012), smaller left ventricular outflow tract (20.8+/-0.21 vs. 22.0+/-0.22 mm, P = 0.023), higher incidence of abnormal intraventricular flow velocity (33 vs. 8%, P = 0.018) and increased relative wall thickness (0.52+/-0.17 vs. 0.45+/-0.09 P = 0.039). Gender was of no independent importance for early mortality when age and left ventricular outflow tract diameter were accounted for. CONCLUSIONS: Cardiac adaptation to aortic stenosis seems to be influenced by gender, males presenting larger left ventricular volumes and higher wall tension. The echocardiographic findings of a narrow left ventricular outflow tract, abnormally increased intraventricular velocity and increased relative wall thickness identified patients with increased risk of early postoperative mortality. However gender had no independent impact on early postoperative outcome.

The red cell mass, plasma erythropoietin and spleen size in apparent polycythaemia.

It has been shown previously that measurement of the spleen size and plasma erythropoietin (EPO) concentration are valuable adjuncts in the diagnostic work-up of patients with polycythaemia vera. The aim of the present work was to evaluate their value in the assessment of apparent polycythaemia (AP). Therefore, over a 24-month period we routinely performed bone marrow biopsies, measurement of red cell mass (RCM) and plasma volume (PV), spleen size determination by gamma camera scintigraphy and determination of the plasma EPO concentration in consecutive patients referred to us because of elevated values for packed cell volume (>0.48 in females and >0.51 in males). After having excluded patients with clonal and secondary polycythaemias we were left with 38 patients (27 males and 11 females) with AP. In all of them the measured RCM was within normal range, i.e. <36 ml/kg for males and <32 ml/kg for females. The subjects were characterized by moderate increase in RCM and a concomitant moderate decrease in PV. Thus, as an average the measured RCM exceeded the predicted values by 14% in males and by 12% in females; conversely, as compared to the predicted values the average measured value for PV was reduced by 17% in males and by 8% in females. The average RCM for males was 29+/-3 ml/kg; the corresponding figure for females was 23+/-4 ml/kg. It was shown that 86% of the subjects had plasma EPO concentrations within the control range; the remaining had values slightly above or below the control range. The mean posterior spleen scan area was 57+/-16 cm2 and mean left lateral area 57+/-17 cm2; the reference value for spleen scan area (for both projections) is 57+/-12 cm2. Of the patients 35/38 (92%) had a spleen scan area within the mean+2SD for controls and 38 subjects (100%) had values within the mean+3SD. It is concluded that measurement of plasma EPO and a careful assessment of the spleen size should always be considered in the evaluation of patients with elevated values for venous packed cell volume.

Atherosclerotic disease in the femoral artery in hypertensive patients at high cardiovascular risk. The value of ultrasonographic assessment of intima-media thickness and plaque occurrence. Risk Intervention Study (RIS) Group.

The aim of the present investigation was to examine the occurrence of ultrasound-assessed morphological changes in the right common femoral artery and relate these findings to the ankle-arm index and to symptoms of lower-extremity arterial disease in hypertensive men at high cardiovascular risk (n = 143). Comparisons were made with a healthy reference group consisting of age-matched men at low risk (n = 46). The results showed that it was possible to obtain high-quality measurements of intima-media thickness in about 80% of all men and that the intraobserver variability was satisfactory (14%). A normal mean intima-media thickness was defined, using data from the low-risk group. Plaque occurrence and mean intima-media thickness in the right common femoral artery were significantly associated with ankle-arm index both in the right and left leg. There were more and larger plaques, as well as thicker mean and maximum intima-media complexes, in the high-risk group than in the low-risk group. In the high-risk group, 11% suffered from symptoms of right lower-extremity artery disease, 20% had an ankle-arm index < or= 0.9, 62% had moderate or large plaques (compared with 28% in the low-risk group, P < .001), and 77% had an enlarged intima-media complex. The cumulative frequency of signs of atherosclerosis in the right leg was 81% among the 110 patients in whom complete results from all examinations were available. Our conclusion is that ultrasound measurement of the intima-media thickness of the common femoral artery is a valuable method to evaluate morphological changes related to atherosclerotic disease in the lower extremity.

Multiple risk intervention in high-risk hypertensive patients. A 3-year ultrasound study of intima-media thickness and plaques in the carotid artery. Risk Intervention Study (RIS) Group.

In spite of optimal blood pressure control, available data indicate that the risk of coronary heart disease remains high in many patients with hypertension. Multifactorial risk intervention programs have therefore been advocated. The aim of the present randomized study was to analyze whether a favorable change in risk factors caused by a comprehensive risk factor modification program (focused mainly on nonpharmacological intervention) might beneficially affect ultrasound-assessed far-wall common carotid intima-media thickness or plaques in the carotid artery in high-risk hypertensive patients (n=81) in comparison with those undergoing usual care (n=83). A further aim was to analyze whether risk factors measured at baseline or follow-up were related to the change recorded in intima-media thickness during follow-up. The results showed in the intervention group a favorable change in LDL cholesterol (-9%), in smoking habits (32% of smokers quit smoking), and in HbA1c (-17% in patients with diabetes mellitus) over the 3.5-year observation period. However, no difference between the two randomization groups could be observed for far-wall common carotid intima-media thickness or plaque status during follow-up. Of all tested potential risk factors, only fasting insulin at baseline (available in nondiabetic patients) was significantly related to the change in mean intima-media thickness during follow-up (r=.25, n=92, P<.01). The relationship (negative) between follow-up serum HDL and change in mean intima-media thickness during the preceding follow-up was of borderline significance. Patients with moderate to large plaques in the carotid artery region at baseline had a significantly larger increase in common carotid artery intima-media thickness during follow-up than patients with no or only small plaques. The results are disappointing and may indicate that either the change in risk factors occurred too late in life or a considerably larger change in concomitant risk factors than we observed is needed to favorably affect intima-media thickness during an observation period of around 3 years in high-risk hypertensive patients.

Body weight and fat cell size in young men with mild blood pressure elevation.

The aim of the study was to assess the relationship between body fat distribution and blood pressure. Forty-four men, aged 19-22 years, with mild blood pressure elevation (MBPE) and 29 normotensive controls (NC) were investigated. Body fat distribution was assessed by calculating fat cell size in biopsy samples of adipose tissue from different subcutaneous depots. The subjects in MBPE group were heavier than those in NC group (79.7 +/- 2.7 and 71.5 +/- 1.6 kg, p < 0.05). Total body fat was also significantly higher in the MBPE group (12.5 +/- 1.6 and 8.1 +/- 1.3 kg, p < 0.05) but not the lean body cell mass (36.8 +/- 1.1 and 34.7 +/- 0.9 kg, n.s.). Fat cell size (microgram/cell) in the lower abdominal area were significantly bigger in MBPE than in NC (respectively 40.9 +/- 4.4 and 28.0 +/- 3.1, p < 0.05). The same differences applied for fat cell size in the upper abdominal (respectively 43.1 +/- 3.0 and 26.8 +/- 3.0, p < 0.001) and averaged abdominal areas (respectively 40.1 +/- 3.4 and 26.8 +/- 2.8; p < 0.05). Fat cell size in gluteal, femoral and averaged gluteofemoral areas did not differ between MBPE and NC. Therefore, the abdominal/gluteofemoral ratio was significantly higher in MBPE than in NC (respectively 1.1 +/- 0.1 and 0.7 +/- 0.1; p < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Carotid artery wall morphology, haemostatic factors and cardiovascular disease. An ultrasound study in men at high and low risk for atherosclerotic disease.

The aim of this study was to examine whether there was a relationship between haemostatic factors and ultrasound-assessed morphology of the common carotid artery and cardiovascular disease in 57- to 77-year-old men at high risk for atherosclerotic disease (hypertension and at least one of the following risk factors: hypercholesterolaemia, smoking, diabetes mellitus). They were divided into one group with (n = 59) and one group without (n = 70) manifest cardiovascular disease. An age-matched reference group with no cardiovascular risk factors was used as a comparison (n = 51). Significant associations, independent of smoking, were found between plasma fibrinogen and both the maximal intima-media thickness and the occurrence of plaque in the high-risk group. High-risk patients with clinical signs of cardiovascular disease had higher levels of plasma fibrinogen and prothrombin 1 + 2 fragment compared with both high-risk patients without concomitant cardiovascular disease and low-risk subjects. Plasminogen activator inhibitor, von Willebrand factor and thrombin/antithrombin complex were increased in the high-risk group with signs of cardiovascular disease in comparison with the low-risk group. In conclusion the results indicate that plasma fibrinogen may be operative in the development of atherosclerosis. Clinical signs of cardiovascular disease were associated with increased plasma levels of fibrinogen, von Willebrand factor, plasminogen activator inhibitor, thrombin/antithrombin complex and prothrombin 1 + 2 fragment.

Ultrasound evaluation of atherosclerotic manifestations in the carotid artery in high-risk hypertensive patients. Risk Intervention Study (RIS) Group.

The aim of this study was to evaluate whether high-risk hypertensive patients (n = 137) had larger far-wall common carotid artery intima-media thickness than a control group (n = 37) and to study whether intima-media thickness was related to other signs of atherosclerotic disease. The results showed that intima-media thickness was significantly larger in the hypertension group than in the control group. Lumen diameter and mean cross-sectional area of the intima-media complex were larger both for hypertensive patients with a positive history of manifest clinical cardiovascular disease and for hypertensive patients with no such history than in the control group. There was a significant relationship between far-wall common carotid artery intima-media thickness and plaque status (visual scoring, no, small, moderate/large) in the carotid artery region. In univariate analyses, low diastolic blood pressure and high pulse pressure were both significantly related to plaque status. In multivariate analyses, pulse pressure was significantly and independently related both to common carotid artery intima-media thickness and to plaque status in the carotid artery region. In multivariate analyses, there was also an independent relationship between age and common carotid artery intima-media thickness, between smoking status and plaque status, and between a positive history of manifest clinical cardiovascular disease and plaque status. In conclusion, common carotid artery intima-media thickness and lumen diameter were increased in elderly high-risk hypertensive patients, in whom more than one third of the patients also had a moderate to large plaque in the carotid artery region.(ABSTRACT TRUNCATED AT 250 WORDS)

Chordal tissue in endomyocardial biopsies.

The incidence of chordal tissue in endomyocardial biopsies from heart transplant recipients and the possibility of an association between this incidence and tricuspid regurgitation or tricuspid valvular abnormalities were prospectively investigated. The biopsies were performed to detect rejection. Postoperative echocardiography and Doppler were done according to routine schedule and always when chordal tissue was found histologically, for specific evaluation of the tricuspid valve function. Chordal tissue was detected in 24 of 1,265 bites at 206 biopsies during the study period. Echocardiographically there was no significant increase in tricuspid regurgitation and no major valvular abnormality in any patient after biopsy showing chordal tissue. The presence of chordal tissue in biopsy specimens implies that the tricuspid valve is potentially at risk in biopsy. Our results, however, also showed that occasional capture of chordal tissue by the bioptome did not necessarily result in tricuspid valve dysfunction.

Regional distribution of melanocytic naevi in relation to sun exposure, and site-specific counts predicting total number of naevi.

The role of exposure to ultraviolet light in the formation of melanocytic naevi was analysed by investigating the regional naevus distribution in 310 subjects (30-50 years) from a Swedish census file. The lateral aspect of the arms and the back had the largest concentration of naevi. The mean naevus count per unit surface area was higher in intermittently exposed than in rarely exposed skin (p less than 0.001), while the lowest mean count was found in chronically exposed skin. These results support the idea that intermittent exposure to ultraviolet light has a "naevogenic" effect while chronic exposure might be protective. Dysplastic naevi had a distribution pattern quite different from common naevi. Considering the distribution pattern solely, dysplastic naevi seem to develop independently of exposure to ultraviolet light. The numbers of naevi in different skin areas were tested for their power in predicting the total body naevus count. The strongest correlations were found between total counts and counts on the anterior surface of the thighs and the lateral aspect of the arms. Counts from any of these areas will provide a practical and satisfactory estimate of the total number of naevi.

Regional distribution of common and dysplastic naevi in relation to melanoma site and sun exposure. A case-control study.

The frequency of melanoma (CMM), and of common and dysplastic naevi (CN and DN) in areas of skin chronically, intermittently and rarely exposed to UV light was investigated in 121 melanoma patients (30-50 years) and 310 controls. Both cases and controls had significantly more CN in intermittently exposed areas than in areas chronically or rarely exposed. The ratio of observed to expected number of CMM was also highest in intermittently exposed skin (1.3 compared to 0.8 in chronically exposed and 0.5 in rarely exposed areas). Thus, intermittent UV exposure seems to have the most potent 'naevogenic' as well as carcinogenic effect on melanocytes. Nineteen per cent of controls and 56% of cases had naevi fulfilling the clinical criteria for DN. The distribution pattern of DN was clearly different from that of CN and does not accord with the idea that UV light is a major aetiological factor for DN. The probability of CMM significantly increased with the degree of relative clustering of CN (p less than 0.05) and of DN (p less than 0.01). This co-variation of naevi and CMM over the body surface might be the result of the local insults to the melanocyte system caused by UV light and/or to the fact that naevi are precursor lesions of CMM.

Prevalence of common and dysplastic naevi in a Swedish population.

The naevus profile was examined in a Swedish population that was randomly selected from a census file. The participation rate was considered high at 82%. The number of common naevi (CN) and the prevalence of dysplastic naevi (DN) were investigated in 379 subjects (aged 30-50 years). The mean total body count of CN greater than or equal to 2 mm was 67 (range 1-300). As many as 22% of the population had 100 naevi or more and only 18% had less than 25. The counts were not influenced by age or sex. DN were diagnosed clinically in 18% (CI 14-22%) of the subjects and histologically in 8% (CI 5-11%). Subjects with dysplastic naevi had a significantly larger number of common naevi and a more sun-sensitive skin type than subjects without DN, P less than 0.001.

Melanocytic naevi in sun-exposed and protected skin in melanoma patients and controls.

The possible link between exposure to ultraviolet light and naevus development was studied in 121 melanoma patients and 310 controls by comparing the number of naevi in a sun-exposed area on the back with that in a sun-protected area on the buttocks. Both patients and controls had a four-fold increase in the number of naevi in the exposed compared with the protected area, p less than 0.001. The difference in naevus count between the exposed and the protected area was larger in patients than in controls, p less than 0.001. Subjects with dysplastic naevi, melanoma patients as well as controls, had a larger difference in the number of naevi between the two areas than subjects without dysplastic naevi, p less than 0.001. These results support the idea that sunlight plays an important role in naevus development and may explain why a high naevus count is a risk marker for malignant melanoma.

Common and dysplastic naevi as risk factors for cutaneous malignant melanoma in a Swedish population.

Common naevi, dysplastic naevi (DN) and other phenotypic features were evaluated as melanoma risk factors in a Swedish case-control study. One-hundred and twenty-one prevalent melanoma cases and 378 randomly selected controls participated. The mean total body naevus count was 115 in the cases and 67 in the controls. Fifty-six per cent of the cases and 18% of the controls had clinical DN. The corresponding figures for histologically diagnosed DN were 40% and 8% respectively. Clinical DN was as good as histologically diagnosed DN in identifying individuals at risk for melanoma. Subjects with sun-sensitive skin, greater than or equal to 150 naevi and presence of DN have 50 times higher melanoma risk than those without these characteristics.

Ventricular dimensions and wall motion assessed by echocardiography in patients with arrhythmogenic right ventricular dysplasia.

Twenty patients with arrhythmogenic right ventricular dysplasia (ARVD) and 20 healthy volunteers underwent cross-sectional echocardiographic examination for the assessment of ventricular dimensions and wall motion. Right ventricular cavity diameters and wall segments were selected from the inflow and outflow tracts and the right ventricular body. The measurement error for measuring cavity dimensions was low throughout and the reproducibility of wall motion scoring was high in both the normal subjects and the patients. All except one patient had increased dimensions and/or abnormal wall motion in the right ventricle. The right ventricular inflow tract was dilated in nine patients, the outflow tract in 11 patients and the short- or long-axis diameters of the right ventricular body were increased in seven patients. Right ventricular wall motion abnormalities, being the most frequent finding, ranged from mild hypokinesia only to dyskinesia or sacculations, and were fairly evenly distributed among the segments studied. Left ventricular abnormalities, found in eight patients, were generally mild. Cross-sectional echocardiography thus provides highly reproducible measurements of right ventricular size and contraction patterns even in patients with wall shape deformities, and is therefore a feasible non-invasive method for the evaluation of right-sided myocardial abnormalities in patients with ARVD. The diagnostic accuracy of this technique warrants further clarification.

UVB-induced melanocyte proliferation and 5-S-cysteinyldopa excretion in dysplastic nevus syndrome.

This is the first in vivo study of the effects of UV on the epidermal melanocytes in dysplastic nevus syndrome (DNS). Eleven DNS patients and 22 healthy subjects were given total body UVB irradiation 8 times during 17 days and the melanocyte population was estimated in biopsies from shielded and irradiated skin. There was a doubling of the melanocyte counts in irradiated skin and a less pronounced but significant increase in the shielded skin area. The urinary excretion of 5-S-cysteinyldopa (5-S-CD) was measured before, during and after the irradiation period. The 5-S-CD excretion reached a maximum after 2 weeks of irradiation and returned towards the basal value after the irradiation period. We were not able to document any abnormal melanocytic UV response in DNS patients before, during or after the irradiation.