Managing hemolysis in serum neuron-specific enolase measurements - an automated algorithm for routine practice.

Neuron-specific enolase (NSE) derived from neurons and peripheral neuroendocrine cells is a biomarker for neuroendocrine tumors and for prognostication in comatose cardiac arrest survivors. However, as platelets and erythrocytes contain NSE, hemolysis causes falsely elevated NSE. We used native serum and hemolysate derived from the same patients to make serial dilutions, and subsequently measured NSE (mNSE) and hemolytic index (HI) in each dilution. An algorithm suitable for the laboratory information system was developed based on the mNSE, HI and the estimated gradient of hemolytic interference from 30 patients. We estimated the associated uncertainty of the corrected NSE (cNSE) results based on the observed range of the gradient and derived an equation for cNSE for samples with limited hemolysis (i.e. 5 < HI ≤ 30): cNSE = mNSE - HI × (0.34 ± 0.23) µg/L. By semi-quantitatively grading the contribution from limited hemolysis, a texted result noting the hemolysis-associated degree of uncertainty can accompany the cNSE result. The major challenge of hemolysis when using serum NSE as a biomarker can be managed using an automated algorithm for correction of NSE results based on degree of hemolysis. However, laboratorians and clinicians should be aware of the limitations associated with in vivo hemolysis.

Thyroid hypofunction in aging testicular cancer survivors.

PURPOSE: Thyroid hypofunction is a late effect observed in several groups of cancer survivors, but has to date not been evaluated in-depth in testicular cancer survivors (TCSs). We investigated the prevalence of thyroid hypofunction in long-term TCSs and compared the findings with those of a comparison group from the general population. PATIENTS AND METHODS: Norwegian TCSs diagnosed with unilateral testicular cancer in the period 1980-1994 (N = 1,436) were grouped according to their cancer treatment (Surgery only; Radiotherapy only; Cisplatin-based chemotherapy, eventually combined with radiotherapy). They were invited to participate in three surveys covering up to three decades post-diagnosis. Serum thyrotropin (s-TSH) from samples collected from the last survey were analyzed. S-TSH results were also available from a health survey of the general population performed in a county in mid-Norway (the HUNT3 Survey [comparison group]). Data on the prescription of thyroid hormone replacement therapy (levothyroxine) from the Norwegian Prescription Database were obtained for the TCSs and the comparison group's participants. Thyroid hypofunction was defined as 'untreated' (overt or subclinical) hypothyroidism (with s-TSH ≥3.5 mIU/L and no regular prescription of levothyroxine) or 'treated' hypothyroidism with regular prescription of levothyroxine. RESULTS: Three decades after diagnosis the prevalence of thyroid hypofunction (i.e., both treated and untreated) was 11% in the TCSs and the prevalence ratio was 1.9 indicating an almost doubled prevalence in the TCSs compared to the comparison group (prevalence ratio 1.91, 95% CI [1.54; 2.38]). However, there were no significant differences in the risk of thyroid hypofunction related to the TCSs' treatment modality. CONCLUSION: TCSs may have an increased prevalence of thyroid hypofunction compared to the general population. Hypothyroidism has negative consequences related both to primary hypogonadism and to cardiovascular disease. As both conditions are overrepresented in TCSs, regular monitoring of thyroid hormones may be advisable.

Rheumatoid factor and falsely elevated results in commercial immunoassays: data from an early arthritis cohort.

The aim of the study was to  assess RF cross-reactivity to animal antibodies used in immunoassays, and to test if selected commercial immunoassays are vulnerable to interference from RF, causing false test results. Our study included samples from patients with RF-positive rheumatoid arthritis (RA) and controls (patients with RF-negative RA and psoriatic arthritis), included in an early arthritis-cohort. Reactivity to mouse IgG1, mouse IgG2a, rabbit IgG, bovine IgG, sheep/goat IgG and human IgG was analysed using in-house interference assays. RF-positive sera with strong reactivity to mouse IgG1 were analysed in three commercial immunoassays. To reveal interference, results before and after addition of blocking aggregated murine IgG1 were compared. Samples from 124 RF-positive RA patients and 66 controls were tested. We found considerably stronger reactivity toward animal antibodies, particularly mouse IgG1 (73% vs. 12%) and rabbit IgG (81% vs. 6%), in sera from RF-positive RA-patients compared to controls (p < 0.001). After selecting samples for testing in commercial assays, interference was revealed in 6/30 sera in the Architect ß-hCG assay, 7/10 sera in the 27-plex cytokine assays, and in 2/33 samples in the Elecsys Soluble Transferrin Receptor assay. Our study revealed considerable RF reactivity to animal antibodies used in immunoassays and RF was associated with falsely elevated results in immunoassays used in clinical care and research. Clinicians, laboratorians, researchers and assay manufacturers must be alert to the risk of falsely elevated test results in RF-positive RA patients.

Longitudinal kidney function outcome in aging testicular cancer survivors.

Purpose: Testicular cancer survivors (TCSs) have increased risk of reduced kidney function related to treatment burden, but longitudinal studies of renal outcome in aging TCSs have been lacking. This longitudinal study describes age- and treatment-related kidney function changes in TCSs compared to a comparison group from the general population.Patients and methods: Estimated glomerular filtration rate (eGFR) was determined in blood samples from Norwegian TCSs (diagnosed 1980-1994) and surveyed median 11, 19 and 26 years since diagnosis (Survey1 [N = 1273], 2 [N = 849] and 3 [N = 670]) defining four treatment groups; Surgery only, Radiotherapy (RT) only, Cisplatin-based chemotherapy (CBCT) ≤850 mg and High CBCT/RT >850 mg cisplatin or any combination of CBCT with RT. A comparison group was constructed from similarly aged men who participated in a population-based health survey. By multiple linear regressions and generalized mixed models for repeated measurements, we studied difference in eGFR between TCSs and the comparison group for all TCSs combined and stratified by treatment modality.Results: At Survey 1, the kidney function for the youngest TCSs combined versus the comparison group was significantly reduced by mean six units (mL/min/1.73 m2) with further decline to mean 12 units at Survey 3. The kidney function was significantly reduced in all treatment groups with the largest differences emerging for TCSs from the High CBCT/RT Group, thus indicating a deteriorating impact of high cumulative doses of cisplatin.Conclusion: Collated to the comparison group, the kidney function in TCSs became increasingly impaired during nearly three post-treatment decades, related to the treatment modality. Early detection and intervention of kidney dysfunction is important to reduce the risk of TCSs' long-term morbidity and mortality related to nephrotoxicity, such as cardio-vascular diseases.

Low thyroid function is not associated with an accelerated deterioration in renal function.

BACKGROUND: Chronic kidney disease (CKD) is frequently accompanied by thyroid hormone dysfunction. It is currently unclear whether these alterations are the cause or consequence of CKD. This study aimed at studying the effect of thyroid hormone alterations on renal function in cross-sectional and longitudinal analyses in individuals from all adult age groups. METHODS: Individual participant data (IPD) from 16 independent cohorts having measured thyroid stimulating hormone, free thyroxine levels and creatinine levels were included. Thyroid hormone status was defined using clinical cut-off values. Estimated glomerular filtration rates (eGFR) were calculated by means of the four-variable Modification of Diet in Renal Disease (MDRD) formula. For this IPD meta-analysis, eGFR at baseline and eGFR change during follow-up were computed by fitting linear regression models and linear mixed models in each cohort separately. Effect estimates were pooled using random effects models. RESULTS: A total of 72 856 individuals from 16 different cohorts were included. At baseline, individuals with overt hypothyroidism (n = 704) and subclinical hypothyroidism (n = 3356) had a average (95% confidence interval) -4.07 (-6.37 to -1.78) and -2.40 (-3.78 to -1.02) mL/min/1.73 m2 lower eGFR as compared with euthyroid subjects (n = 66 542). In (subclinical) hyperthyroid subjects (n = 2254), average eGFR was 3.01 (1.50-4.52) mL/min/1.73 m2 higher. During 329 713 patient years of follow-up, eGFR did not decline more rapidly in individuals with low thyroid function compared with individuals with normal thyroid function. CONCLUSIONS: Low thyroid function is not associated with a deterioration of renal function. The cross-sectional association may be explained by renal dysfunction causing thyroid hormone alterations.

CRABP1, C1QL1 and LCN2 are biomarkers of differentiated thyroid carcinoma, and predict extrathyroidal extension.

BACKGROUND: The prognostic variability of thyroid carcinomas has led to the search for accurate biomarkers at the molecular level. Follicular thyroid carcinoma (FTC) is a typical example of differentiated thyroid carcinomas (DTC) in which challenges are faced in the differential diagnosis. METHODS: We used high-throughput paired-end RNA sequencing technology to study four cases of FTC with different degree of capsular invasion: two minimally invasive (mFTC) and two widely invasive FTC (wFTC). We searched by genes differentially expressed between mFTC and wFTC, in an attempt to find biomarkers of thyroid cancer diagnosis and/or progression. Selected biomarkers were validated by real-time quantitative PCR in 137 frozen thyroid samples and in an independent dataset (TCGA), evaluating the diagnostic and the prognostic performance of the candidate biomarkers. RESULTS: We identified 17 genes significantly differentially expressed between mFTC and wFTC. C1QL1, LCN2, CRABP1 and CILP were differentially expressed in DTC in comparison with normal thyroid tissues. LCN2 and CRABP1 were also differentially expressed in DTC when compared with follicular thyroid adenoma. Additionally, overexpression of LCN2 and C1QL1 were found to be independent predictors of extrathyroidal extension in DTC. CONCLUSIONS: We conclude that the underexpression of CRABP1 and the overexpression of LCN2 may be useful diagnostic biomarkers in thyroid tumours with questionable malignity, and the overexpression of LCN2 and C1QL1 may be useful for prognostic purposes.

Specific antibodies and sensitive immunoassays for the human epidermal growth factor receptors (HER2, HER3, and HER4).

The use of trastuzumab in patients with breast cancer that overexpresses human epidermal growth factor receptor 2 has significantly improved treatment outcomes. However, a substantial proportion of this patient group still experiences progression of the disease after receiving the drug. Evaluation of the changes in expression of the human epidermal growth factor receptors could be of interest. Monoclonal antibodies against the extracellular domain of the human growth factor receptors, 2, 3, and 4, have been raised, and specific and sensitive immunoassays have been established. Sera from healthy individuals (Nordic Reference Interval Project and Database) were analyzed in the human epidermal growth factor receptor 2 assay (N = 805) and the human epidermal growth factor receptor 3 and 4 assays (N = 114), and reference limits were calculated. In addition, sera from 208 individual patients with breast cancer were tested in all three assays. Finally, the human epidermal growth factor receptor 2 assay was compared with a chemiluminescent immunoassay for serum human epidermal growth factor receptor 2/neu. Reference values were as follows: human epidermal growth factor receptor 2, <2.5 µg/L; human epidermal growth factor receptor 3, <2.8 µg/L; and human epidermal growth factor receptor 4, <1.8 µg/L. There were significant differences in human epidermal growth factor receptor 2 and human epidermal growth factor receptor 3 serum levels between the patients with tissue human epidermal growth factor receptor 2-positive and tissue human epidermal growth factor receptor 2-negative ( p = 0.0026, p = 0.000011) tumors, but not in the serum levels of human epidermal growth factor receptor 4 ( p = 0.054). There was good agreement between the in-house human epidermal growth factor receptor 2 assay and the chemiluminescent immunoassay. Our new specific antibodies for all the three human epidermal growth factor receptors may prove valuable in the development of novel anti-human epidermal growth factor receptor targeted therapies with sensitive immunoassays for measuring serum levels of the respective targets and in monitoring established treatment.

Bone mineral density is close to normal for age in long-term lymphoma survivors treated with high-dose therapy with autologous stem cell transplantation.

BACKGROUND: Few studies have assessed bone health in lymphoma survivors treated with high-dose therapy with autologous stem cell transplantation (HDT-ASCT). Therefore, we aimed to assess bone mineral density (BMD) at six different skeletal sites and to investigate associations between clinical factors and BMD in these survivors. MATERIAL AND METHODS: Eligible lymphoma survivors were aged ≥18 years at diagnosis and at HDT-ASCT given between 1987 and 2008. Participants responded to questionnaires, blood samples were drawn, and a dual energy X-ray absorptiometry (DXA) was performed. Mean Z-score was applied for assessment of BMD in relation to age. Prevalence of Z-scores ≥-1, between -1 and -2, and ≤-2 is reported for each measurement site and for the lumbar spine, femoral neck, and hip in combination. Likewise, T-scores were applied to assess the prevalence of normal BMD (≥-1), osteopenia (between -1 and -2.5), and osteoporosis (≤-2.5). RESULTS: We included 228 lymphoma survivors, of whom 62% were males. The median age at survey was 56 years, and median observation time from HDT-ASCT was eight years. Among males, Z-scores were lower at the left femoral neck and higher at the ultra-distal (UD) radius and whole body compared to the Lunar reference database. In females, Z-scores were lower at UD radius and one-third (33%) radius and higher at the whole body. Using a classification based on Z-scores at the lumbar spine, femoral neck, and hip in combination, 25% of males and 16% of females had Z-scores <-1 and >-2, while 8% and 6% had Z-scores ≤-2. According to T-scores, 35% of males and 41% of females had osteopenia, while 8% and 13% had osteoporosis, respectively. CONCLUSION: BMD was close to normal for age in this population of long-term lymphoma survivors treated with HDT-ASCT.

Characterization of a new highly sensitive immunometric assay for thyroglobulin with reduced interference from autoantibodies.

Measurements of serum thyroglobulin (Tg) with sensitive immunoassays are of great importance for the management of patients with differentiated thyroid carcinomas. However, interference of circulating autoantibodies to Tg (hTgAb) hampers the usefulness of most assays. We have produced a panel of monoclonal antibodies (mAbs) selected to bind Tg in the presence of Tg autoantibodies and developed a sensitive immunoassay for Tg with minor interference by hTgAbs. The antibodies were characterized by cross-inhibition and immunoassay combination studies, as well as affinity estimation. The within-run and total imprecision of the assay were determined with 2664 samples in 60 separate runs. The most sensitive assay combination with superior protection against autoantibodies consisted of two solid phase mAbs and two tracer mAbs with distinct binding sites. The assay was linear and displayed a wide dynamic range up to 1342 µg/l with a functional sensitivity of 0.1 µg/l and a total imprecision of less than 10 %. There was good agreement between the new high sensitive immunofluorometric assay (IFMA) and two well-established Tg assays from Brahms Kryptor and Roche Diagnostics. Mean difference between the new IFMA and the Kryptor assay was 0.059 µg/l with a 95 % confidence interval of -0.032 to 0.151 µg/l, whereas the mean difference between the new IFMA and the Roche assay was -0.80 µg/l with a 95 % confidence interval of -1.24 to -0.35 µg/l.

Fatigue in male lymphoma survivors differs between diagnostic groups and is associated with latent hypothyroidism.

BACKGROUND: Few studies have explored fatigue in different groups of lymphoma survivors and the association with hormonal dysfunctions. The aims were to analyze associations between fatigue and thyroid and gonadal function in male lymphoma survivors. In addition, the impact of chronic fatigue on work situation and daily functioning were explored. PATIENTS AND METHODS: This cross-sectional study included male lymphoma survivors diagnosed in 1980-2002, aged ≤ 50 years at diagnosis and > 18 years at survey in 2007. The participants (n = 233, median age at survey: 48 years, median observation time: 15 years) completed questionnaires assessing levels of fatigue, chronic fatigue (duration ≥ 6 months), mental distress, daily functioning and work situation. Levels of thyroid and gonadal hormones were assessed. The participants were grouped according to diagnosis: Hodgkin lymphoma (HL, n = 131), aggressive/very aggressive non-Hodgkin lymphoma (NHL) (n = 67) and indolent NHL (n = 35). Thyroid hormones were categorized as normal (n = 174) or latent hypothyroidism (elevated thyroid stimulating hormone, n = 59). Gonadal hormones were categorized as normal (n = 111), elevated follicle stimulating hormone only (n = 45), primary (n = 35) or secondary hypogonadism (n = 42). Uni- and multivariate regression analyses were performed. A p value < 0.05 indicated the level of significance. RESULTS: The survivors of HL and aggressive/very aggressive NHL had similar fatigue levels and similar prevalence of chronic fatigue (HL: 31%, aggressive/very aggressive; NHL: 27%). Survivors of indolent NHL had lower fatigue levels and prevalence of chronic fatigue (11%). Latent hypothyroidism was associated with increased fatigue levels (p = 0.042). Gonadal function was not associated with levels of fatigue or chronic fatigue. Mental distress was associated with increasing fatigue levels and chronic fatigue (p < 0.001). We found negative associations between chronic fatigue, daily functioning and work status. CONCLUSIONS: Fatigued lymphoma survivors should be investigated for thyroid function. The negative impact of chronic fatigue on daily functioning and work status emphasizes the importance of maintaining the effort in understanding the mechanisms behind fatigue.

Meta-analysis of two genome-wide association studies identifies four genetic loci associated with thyroid function.

Thyroid hormones play key roles in cellular growth, development and metabolism. Although there is a strong genetic influence on thyroid hormone levels, the genes involved are widely unknown. The levels of circulating thyroid hormones are tightly regulated by thyrotropin (TSH), which also represents the most important diagnostic marker for thyroid function. Therefore, in order to identify genetic loci associated with TSH levels, we performed a discovery meta-analysis of two genome-wide association studies including two cohorts from Germany, KORA (n = 1287) and SHIP (n = 2449), resulting in a total sample size of 3736. Four genetic loci at 5q13.3, 1p36, 16q23 and 4q31 were associated with serum TSH levels. The lead single-nucleotide polymorphisms of these four loci were located within PDE8B encoding phosphodiesterase 8B, upstream of CAPZB that encodes the ß-subunit of the barbed-end F-actin-binding protein, in a former 'gene desert' that was recently demonstrated to encode a functional gene (LOC440389) associated with thyroid volume, and upstream of NR3C2 encoding the mineralocorticoid receptor. The latter association for the first time suggests the modulation of thyroid function by mineral corticoids. All four loci were replicated in three additional cohorts: the HUNT study from Norway (n = 1487) and the two German studies CARLA (CARLA, n = 1357) and SHIP-TREND (n = 883). Together, these four quantitative trait loci accounted for ∼3.3% of the variance in TSH serum levels. These results contribute to our understanding of genetic factors and physiological mechanisms mediating thyroid function.

Surgical curability of medullary thyroid cancer in multiple endocrine neoplasia 2B: a changing perspective.

OBJECTIVE: This investigation aimed at exploring the suitability of nonendocrine manifestations preceding medullary thyroid cancer (MTC) for early diagnosis of multiple endocrine neoplasia type 2B (MEN 2B). BACKGROUND: MEN 2B patients, running a high risk of metastatic MTC, must be diagnosed early for biochemical cure. METHODS: Forty-four MEN 2B patients carrying inherited (3 patients) and de novo (41 patients) M918T RET mutations were examined for signs and symptoms prompting MEN 2B. RESULTS: All 3 patients with inherited mutations were diagnosed before the age of 1 year and cured of their C-cell disease. Among 41 patients with de novo mutations, MEN 2B was diagnosed in 12 patients after recognition of nonendocrine manifestations [intestinal ganglioneuromatosis (6 patients), oral symptoms (5 patients), ocular ("tearless crying") (4 patients), and skeletal stigmata (1 patient) alone or concomitantly]. In the remaining 29 patients with de novo mutations, the diagnosis of MEN 2B was triggered by symptomatic MTC (28 patients) or pheochromocytoma (1 patient). The former patients, being significantly (P < 0.001) younger (means of 5.3 vs 17.6 years) and having lower calcitonin levels (means of 115 vs 25,519 pg/mL), smaller tumors (67% vs 0% were ≤10 mm) and less often extrathyroidal extension (0% vs 81%), lymph node (42% vs 100%), and distant metastases (8% vs 79%), were biochemically cured more often (58% vs 0%). CONCLUSIONS: MTC is curable in patients with de novo mutations when nonendocrine MEN 2B components are quickly appreciated and surgical intervention is performed before patients turn 4 years old.

Survey of 548 oncogenic fusion transcripts in thyroid tumors supports the importance of the already established thyroid fusions genes.

Neoplasms frequently present structural chromosomal aberrations that can alter the level of expression of a protein or to the expression of an aberrant chimeric protein. In the thyroid, the PAX8-PPARG fusion is present in the neoplastic lesions that have a follicular architecture-follicular thyroid carcinoma (FTC) and follicular variant of papillary thyroid carcinoma (FVPTC), and less frequently in follicular thyroid adenoma (FTA), while the presence of RET/PTC fusions are largely restricted to papillary thyroid carcinoma (PTC). The ability to detect fusion genes is relevant for a correct diagnosis and for therapy. We have developed a new fusion gene microarray-based approach for simultaneous analysis of all known and predicted fusion gene variants. We did a comprehensive screen for 548 known and putative fusion genes in 27 samples of thyroid tumors and three positive controls-one thyroid cancer cell line (TPC-1) and two PTCs with known CCDC6-RET (alias RET/PTC1) fusion gene, using this microarray. Within the thyroid tumors tested, only well known, previously reported fusion genes in thyroid oncology were identified. Our results reinforce the pathogenic role played by RET/PTC1, RET/PTC3, and PAX8-PPARG fusion genes in thyroid tumorigenesis.

The new molecular markers DDIT3, STT3A, ARG2 and FAM129A are not useful in diagnosing thyroid follicular tumors.

Preoperative characterization of thyroid follicular lesions is challenging. Fine-needle aspiration specimens cannot differentiate follicular carcinomas from benign follicular neoplasias. Recently, promising markers have been detected using modern molecular techniques. We conducted a retrospective study to confirm the usefulness of immunohistochemical staining for the protein markers, DDIT3, STT3A (ITM1), ARG2 and FAM129A (C1orf24) in separating benign and malignant thyroid follicular lesions. Formalin-fixed, paraffin-embedded thyroid tissue from 30 in-house cases (15 follicular carcinomas and 15 follicular adenomas), as well as 8 follicular carcinomas and 21 follicular adenomas on tissue microarray slides were stained immunohistochemically for DDIT3, STT3A, ARG2 and FAM129A expression. Control tissue consisted of thyroid parenchyma adjacent to the tumors and 11 separate cases of normal thyroid parenchyma. All in-house cases of follicular adenomas, follicular carcinomas and adjacent normal thyroid tissue showed positive immunostaining with anti-DDIT3 and anti-STT3A. Anti-ARG2 and anti-FAM129A polyclonal antibodies showed positive staining in 20 and 60% of in-house follicular adenomas, and 40 and 87% of in-house follicular carcinomas, respectively. Monoclonal anti-FAM129A demonstrated positive staining in 13 and 33% of in-house follicular adenomas and follicular carcinomas, respectively. Polyclonal anti-DDIT3, -STT3A and -FAM129A antibodies showed positive staining in all tissue microarray slides of follicular carcinoma and in 76, 85 and 81% of the follicular adenomas, respectively. Monoclonal anti-STT3A stained 81% of the follicular adenoma cores. Anti-ARG2 stained positive in 13% of follicular carcinomas and 10% of follicular adenomas on the tissue microarray slides. In conclusion, DDIT3, STT3A, ARG2 and FAM129A immunohistochemistry does not appear to be useful in the diagnosis of thyroid follicular neoplasias, as they do not reliably distinguish follicular thyroid carcinoma from follicular thyroid adenoma.

Thyroid function and the risk of coronary heart disease: 12-year follow-up of the HUNT study in Norway.

OBJECTIVE: In a mortality follow-up of the HUNT Study, serum TSH within the reference range was positively associated with the risk of coronary death in women. We now aimed to confirm the association of high serum TSH with the risk of coronary heart disease, using hospital-based diagnoses of myocardial infarction. DESIGN: Prospective population-based study with linkage to hospital information on myocardial infarction and to the national Cause of Death Registry. PARTICIPANTS: A total of 26, 707 people without previously known thyroid or cardiovascular disease or diabetes at baseline. MEASUREMENTS: Hazard ratios (HR) of coronary death and HRs of hospitalization with a first-time acute myocardial infarction, by baseline thyroid function. RESULTS: During 12, years of follow-up, 960 (3·6%) participants had been hospitalized with first-time myocardial infarction and 558 (2·1%) had died from coronary heart disease. High TSH within the reference range was associated with increased risk of coronary death in women (P(trend) 0·005), but not in men. The risk of coronary death was also increased among women with subclinical hypothyroidism or subclinical hyperthyroidism, compared to women with TSH of 0·50-1·4 mU/l. However, thyroid function was not associated with the risk of being hospitalized with myocardial infarction. CONCLUSIONS: High serum TSH was associated with increased mortality from coronary heart disease in women, but we found no association of thyroid function with the risk of being hospitalized with myocardial infarction. Thus, the morbidity finding does not confirm the suggestion that low thyroid function within the clinically normal range is associated with increased risk of coronary heart disease.

Long-Term Efficacy of Ethanol Ablation as Treatment of Metastatic Lymph Nodes From Papillary Thyroid Carcinoma.

CONTEXT: Ethanol ablation (EA) is considered an alternative to surgery for metastatic lymph nodes from papillary thyroid carcinoma (PTC) in selected patients. OBJECTIVE: The aim of this study was to evaluate the long-term efficacy and safety of this treatment. DESIGN AND SETTING: Adult patients with PTC who had received EA in lymph node metastasis at a tertiary referral center, and were included in a published study from 2011, were invited to participate in this follow-up study. METHODS: Radiologic and medical history were reviewed. Ultrasound examination of the neck was performed by radiologists, and clinical examination was performed by an endocrine surgeon. Response was reported according to predefined criteria for satisfactory EA treatment. Adverse events associated with EA were evaluated. Cause of death was reported for deceased patients. RESULTS: From the 2011 study, 51 of 63 patients were included. Forty-four patients were reexamined (67/109 lesions) and 7 patients were deceased. Median follow-up time from primary surgery was 14.5 years. Median follow-up from the latest performed EA in the 2011 study was 11.3 years. Local control was permanently achieved in most patients (80%). Recurrence within an ablated node was registered in 13 metastases in 10 patients. Seven of these patients also had recurrent disease elsewhere in the neck. No major side effects were reported. CONCLUSION: EA is a minimally invasive procedure with a low risk of complications. Our data suggest that EA is a safe and efficient treatment, providing excellent results for a large group of patients in the long term.

Serum TSH related to measures of body mass: longitudinal data from the HUNT Study, Norway.

OBJECTIVE: Thyroid function and body mass are related, but the causal relationship remains unclear. Our objective was to investigate the longitudinal relationship between thyroid stimulating hormone (TSH) and body mass measures [body weight, body mass index (BMI), waist circumference (WC) and waist-hip-ratio (WHR)]. DESIGN: We used data from two waves of a population-based study: HUNT 2 (1995-1997) and 3 (2006-2008). Average follow-up time was 10·5 years. Multivariable general linear and logistic regression models were used to assess the relation between TSH and the body mass measures. PARTICIPANTS: In total 9954 women and 5066 men without self-reported thyroid disease and TSH within the reference range (0·5-3·5 mU/l) at baseline and <10 mU/l at follow-up. RESULTS: For each mU/l increase in TSH among women, weight increased 0·9 kg (95% CI 0·8, 1·1), BMI 0·3 kg/m(2) (95% CI 0·3, 0·4) and WC 0·6 cm (95% CI 0·3, 0·8). In men, the corresponding figures were 0·8 kg (95% CI 0·5, 1·0), 0·2 kg/m(2) (95% CI 0·2, 0·3) and 0·5 cm (95% CI 0·2, 0·8). In line with this, a weight gain of more than 5 kg was associated with a TSH increase of 0·08 mU/l (95% CI 0·06, 0·11) in women and 0·15 mU/l (95% CI 0·12, 0·18) in men. Women who lost more than 5 kg decreased their TSH by 0·12 mU/l (95% CI 0·09, 0·16) and men by 0·03 mU/l (95% CI -0.02, 0·09). CONCLUSION: Weight gain is accompanied by increasing TSH, and weight loss in women is related to decreasing TSH.

Serum estradiol levels associated with specific gene expression patterns in normal breast tissue and in breast carcinomas.

BACKGROUND: High serum levels of estradiol are associated with increased risk of postmenopausal breast cancer. Little is known about the gene expression in normal breast tissue in relation to levels of circulating serum estradiol. METHODS: We compared whole genome expression data of breast tissue samples with serum hormone levels using data from 79 healthy women and 64 breast cancer patients. Significance analysis of microarrays (SAM) was used to identify differentially expressed genes and multivariate linear regression was used to identify independent associations. RESULTS: Six genes (SCGB3A1, RSPO1, TLN2, SLITRK4, DCLK1, PTGS1) were found differentially expressed according to serum estradiol levels (FDR = 0). Three of these independently predicted estradiol levels in a multivariate model, as SCGB3A1 (HIN1) and TLN2 were up-regulated and PTGS1 (COX1) was down-regulated in breast samples from women with high serum estradiol. Serum estradiol, but none of the differentially expressed genes were significantly associated with mammographic density, another strong breast cancer risk factor. In breast carcinomas, expression of GREB1 and AREG was associated with serum estradiol in all cancers and in the subgroup of estrogen receptor positive cases. CONCLUSIONS: We have identified genes associated with serum estradiol levels in normal breast tissue and in breast carcinomas. SCGB3A1 is a suggested tumor suppressor gene that inhibits cell growth and invasion and is methylated and down-regulated in many epithelial cancers. Our findings indicate this gene as an important inhibitor of breast cell proliferation in healthy women with high estradiol levels. In the breast, this gene is expressed in luminal cells only and is methylated in non-BRCA-related breast cancers. The possibility of a carcinogenic contribution of silencing of this gene for luminal, but not basal-like cancers should be further explored. PTGS1 induces prostaglandin E2 (PGE2) production which in turn stimulates aromatase expression and hence increases the local production of estradiol. This is the first report studying such associations in normal breast tissue in humans.

Thyroid function and cancer risk: a prospective population study.

BACKGROUND: It has been hypothesized that thyroid function may influence cancer risk, but few studies with adequate statistical power have investigated this question, and the results have not been consistent. METHODS: In a prospective study of 29,691 people (19,710 women and 9,981 men) without previously known thyroid disease, thyrotropin was measured at baseline, and cancer incidence was recorded during 9 years of follow-up. Using Cox regression analysis, we studied the associations (hazard ratios) of thyrotropin categories with total cancer risk, and specifically, with risk of lung, colon, prostate, and breast cancer adjusted for age, sex, and smoking status. RESULTS: Low thyrotropin levels (<0.50 mU/L) were associated with increased cancer risk [adjusted hazard ratio (HR), 1.34; 95% confidence interval (CI), 1.06-1.69] compared with the euthyroid reference group. The higher risk was driven by lung cancer (adjusted HR, 2.34; 95% CI, 1.24-4.40) and prostate cancer (adjusted HR, 1.97; 95% CI, 1.04-3.76). After excluding the first 2 years of follow-up, the associations were strengthened to 2.91 (1.49-5.70) for lung cancer and 2.60 (1.36-4.99) for prostate cancer. CONCLUSION: Thyrotropin levels suggestive of hyperthyroid function are associated with increased cancer risk, and specifically, with increased risk of lung and prostate cancer, whereas hypothyroid function does not seem to be associated with cancer risk.