Incidence of thyroid cancer in England by ethnic group, 2001-2007.

BACKGROUND: Thyroid cancer incidence is increasing worldwide, but with large variations in incidence that may reflect either diagnostic bias or true ethnic differences. We sought to determine the effect of ethnicity on the incidence of thyroid cancer in England, a multiethnic population with a single health-care system. METHODS: We analysed 11,263 thyroid cancer registrations with ethnicity obtained by linkage to the Hospital Episodes Statistics database. Incidence rate ratios (RRs) adjusted for age, sex and income were calculated for the six main non-White ethnic groups in England compared with Whites and to each other. RESULTS: Thyroid cancer incidence was higher in all ethnic groups, except Indians, compared with Whites: in Pakistanis (RR 1.79, 99% floating confidence interval (FCI) 1.47-2.19); Bangladeshis (RR 1.99, 99% FCI 1.46-2.71); Black Africans (RR 1.69, 99% FCI 1.34-2.13); Black Caribbeans (RR 1.56, 99% FCI 1.25-1.93); and Chinese (RR 2.14, 99% FCI 1.63-2.80). CONCLUSION: The risk of thyroid cancer in England varies significantly by ethnicity. The elevated incidence in most ethnic minorities is unlikely to be due to diagnostic bias and warrants further investigation.

Prostate-specific antigen (PSA) promoter-driven androgen-inducible expression of sodium iodide symporter in prostate cancer cell lines.

Currently, no curative therapy for metastatic prostate cancer exists. Causing prostate cancer cells to express functionally active sodium iodide symporter (NIS) would enable those cells to concentrate iodide from plasma and might offer the ability to treat prostate cancer with radioiodine. Therefore, the aim of our study was to achieve tissue-specific expression of full-length human NIS (hNIS) cDNA in the androgen-sensitive human prostatic adenocarcinoma cell line LNCaP and in subcell lines C4, C4-2, and C4-2b in vitro. For this purpose, an expression vector was generated in which full-length hNIS cDNA coupled to the prostate-specific antigen (PSA) promoter has been ligated into the pEGFP-1 vector (NIS/PSA-pEGFP-1). The PSA promoter is responsible for androgen-dependent expression of PSA in benign and malignant prostate cells and was therefore used to mediate androgen-dependent prostate-specific expression of NIS. In addition, two control vectors were designed, which consist of the pEGFP-1 vector containing the PSA promoter without NIS cDNA (PSA-pEGFP-1) and NIS cDNA without the PSA promoter (NIS-pEGFP-1). Prostate cancer cells were transiently transfected with each of the above-described expression vectors, incubated with or without androgen (mibolerone) for 48 h, and monitored for iodide uptake activity. In addition, stably transfected LNCaP cell lines were established for each vector. Prostate cells transfected with NIS/PSA-pEGFP-1 showed perchlorate-sensitive, androgen-dependent iodide uptake in a range comparable to that observed in control cell lines transfected with hNIS cDNA. Perchlorate-sensitive iodide uptake was not observed in cells transfected with NIS/PSA-pEGFP-1 and treated without androgen or in cells transfected with the control vectors. In addition, prostate cancer cell lines without PSA expression (PC-3 and DU-145) did not show iodide uptake activity when transfected with NIS/PSA-pEGFP-1. Western blotting of LNCaP and C4-2b cell membranes transfected with NIS/PSA-pEGFP-1 using a monoclonal antibody that recognizes the COOH-terminus of hNIS revealed a band with a molecular weight of 90,000 that was not detected in androgen-deprived cells or in cells transfected with the control vectors, as well as a minor band at Mr 150,000 in transiently transfected LNCaP cell membranes. In conclusion, tissue-specific androgen-dependent iodide uptake activity has been induced in prostate cancer cells by PSA promoter-directed NIS expression. This study represents an initial step toward therapy of prostate cancer with radioiodine.

Differential loss of heterozygosity at 7q31.2 in follicular and papillary thyroid tumors.

We analysed 42 differentiated thyroid tumors including 15 follicular adenomas (FA), 13 papillary thyroid cancers (PTC) and 14 follicular thyroid carcinomas (FTC) with 13 microsatellite markers specific for the long arm of human chromosome 7 within 7q31; this region is deleted frequently in several other tumor types. Overall, 20 of the 42 samples analysed (48%) displayed LOH with one or more of the markers tested. LOH was detected most frequently (78%) in FTC, the most malignant of the thyroid tumors. A smallest common deleted region (SCDR) was defined in this tumor type flanked by markers D7S480 and D7S490. This SCDR is distinct from D7S522, the most commonly deleted locus in many other tumors, which was deleted in only one FTC. D7S522 did show LOH in two of six informative PTCs. None of the PTC and only two of the FAs showed LOH in the FTC SCDR. Since FA is considered a premalignant stage of FTC, our results suggest that inactivation of a putative tumor suppressor at 7q31.2 may be acquired during adenoma to carcinoma progression. The absence of LOH at this locus amongst PTC suggests that inactivation of this tumor suppressor is specific for FTC. In conclusion, LOH at 7q31 is a frequent event in differentiated thyroid cancer, and we have defined a 2 cM SCDR specific for FTC.

Development of monoclonal antibodies against the human sodium iodide symporter: immunohistochemical characterization of this protein in thyroid cells.

The thyroid sodium-iodide symporter (NIS) is responsible for iodide concentrating ability within thyroid follicular cells. We sought to develop monoclonal antibodies against human NIS (hNIS) for use as reagents in structure-function studies of the protein, as well as potential tools in the assessment of NIS expression in benign and malignant thyroid tissues. Synthetic peptides corresponding to the second ExMD and to the carboxy-terminal ExMD of hNIS were produced and utilized as antigens to develop monoclonal antibodies, which were tested by Western blotting using membranes prepared from COS-7 cells transiently transfected with a pcDNA3 plasmid containing the gene for the full-length hNIS, or a control vector. Western blotting showed a major band with molecular weight (MW) of approximately 97 kDa and several minor bands with MW of approximately 160 kDa, 68 kDa, 30 kDa, and 15 kDa, all specific for hNIS-transfected cells. Immunohistochemistry was performed in various types of thyroid tissues and nonthyroidal tissues, using the monoclonal antibodies. Strong immunostaining was observed in Graves' tissue, intermediate staining in papillary and follicular thyroid cancer, and no staining in Hürthle cell cancer or in nonthyroidal tissue. The staining was specific for the follicular epithelium in each of the tissues and was most intense in the basolateral portion of the cell membrane. Overall, our observations indicate that the monoclonal antibodies are specific for hNIS and will be invaluable reagents for investigating the role of NIS in thyroid disease.

Frequent loss of heterozygosity on chromosomes 3p and 17p without VHL or p53 mutations suggests involvement of unidentified tumor suppressor genes in follicular thyroid carcinoma.

Follicular thyroid carcinoma (FTC) exhibits frequent loss of heterozygosity (LOH) on chromosomes 10q and 3p, suggesting involvement of tumor suppressor genes. We screened 14 FTC (10 Hurthle cell carcinomas and 4 nonoxyphilic FTC), 14 papillary thyroid carcinomas, and 7 follicular adenomas for LOH on chromosome arms 1p, 3p, 3q, 10p, 10q, 11p, 11q, 13q, 17p, and 17q. LOH was more frequent in FTC than in follicular adenoma or papillary thyroid carcinoma. In FTC, rates of LOH on 3p (86%), 17p (72%), and 10q (57%) were higher than the average rate of LOH (33%; P < 0.05). Most frequently involved were 3p21-25 and 17p13.1-13.3, the sites for the VHL (3p25-26) and p53 (17p13.1) tumor suppressors. We, therefore, characterized these genes by dideoxy fingerprinting and DNA sequencing. Two FTC had mutations in p53, but only 1 of these exhibited LOH at 17p. No VHL gene mutations were found. Thus, neither p53 nor VHL genes play a significant role in the pathogenesis of differentiated thyroid cancer. LOH on 17p, but not on 3p or 10q, was correlated with mortality. Accordingly, 3p and 10q LOH may represent early, and 17p LOH late, events in FTC development. The data suggest the presence of novel tumor suppressor genes on chromosomes 3p and 17p that may be important in the pathogenesis of FTC.

The pathogenesis of Graves' disease.

Graves' disease, one of the autoimmune thyroid diseases, is caused by the production of IgG autoantibodies directed against the thyrotropin receptor. These antibodies bind to and activate the receptor, causing the autonomous production of thyroid hormones. Despite recent improvements in our understanding of the cellular and molecular basis of autoimmunity, our currently available treatments for Graves' disease have remained largely unchanged over the last 50 years. Nevertheless, new concepts in immune system regulation hold out the prospect in the future for intervention designed to modify, and possibly cure, the underlying disease process.

Evaluation and management of amenorrhea.

All women who enter menopause experience amenorrhea unless they receive hormone replacement therapy. In younger women, amenorrhea unrelated to pregnancy and lactation can be a distressing symptom. In addition to its psychologic morbidity, amenorrhea may be the manifesting feature of a wide array of anatomic and endocrine abnormalities. Amenorrhea results in impaired fertility. When estrogen levels are low, changes in mineral, glucose, and fat metabolism accompany amenorrhea. These metabolic changes affect bone and cardiovascular health, increasing the risk of osteoporosis and coronary heart disease in later life. Amenorrhea with hyperandrogenism, most commonly caused by the polycystic ovarian syndrome, may cause endometrial hyperplasia and increases the risk of endometrial adenocarcinoma. Because of the broad differential diagnosis of amenorrhea, establishing an accurate diagnosis can prove challenging. In this article, we outline one approach to the assessment of patients with amenorrhea and to the management of its common causes and consequences.

Anaplastic thyroid carcinoma: a 50-year experience at a single institution.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is among the most aggressive of human malignancies. However, there have been few large studies of histologically well-defined ATC. We report the results of a 50-year experience of this lethal malignancy. METHODS: We reviewed all cases of ATC managed in this institution between 1949 and 1999. One pathologist (J.R.G.) reviewed all pathologic material. Clinical details were obtained from medical records, and current status of all patients was determined. RESULTS: There were 134 cases, with a female-to-male ratio of 1.5:1 and a mean age of 67 years. Benign thyroid disease was present in 27 cases (20%) and well-differentiated thyroid carcinoma in 31 (23%). Sixty-two patients (46%) had distant metastases at diagnosis, and 98% of the tumors were locally invasive. Primary treatment was surgical for 96 patients (72%). Complete resection was achieved in 29 cases (30%), with "minimal residual disease" in 25. Neither extent of operation nor completeness of resection affected survival (P > .4). Postoperative radiotherapy gave slightly longer median survival (5 vs 3 months), which was not significant (P < .08). Multimodal therapy, including operation, chemotherapy, and radiotherapy, did not improve survival. CONCLUSIONS: The outlook for patients with ATC remains grim. Novel treatments for ATC are desperately needed.

Impact of primary surgery on outcome in 300 patients with pathologic tumor-node-metastasis stage III papillary thyroid carcinoma treated at one institution from 1940 through 1989.

BACKGROUND: The pathologic tumor-node-metastasis (pTNM) system is universally used to define the extent of disease in human malignancies. This study evaluated the impact of initial therapy on cause-specific mortality (CSM) rates and recurrence rates in pTNM stage III papillary thyroid carcinoma. METHODS: Three hundred patients (median age, 58 years) were followed on average for 14 postoperative years. Of these, 246 patients (82%) had complete primary tumor resection; 208 patients (69%) had nodal metastases; 161 (54%) had locally invasive primary tumors; 45 patients (15%) underwent initial unilateral lobectomy (UL). Bilateral lobar resection (BLR) accounted for 242 patients (near-total, 54%; total thyroidectomy, 23%). RESULTS: The 30-year rates for CSM, distant metastases, nodal metastases, and local recurrence (LR) were 29%, 22%, 19%, and 16%, respectively. The 20-year rates for CSM were significantly higher (50% vs 14%) when primary tumor was incompletely resected (P = .0001). After complete resection, 20-year rates for CSM and LR after BLR were 12% and 10%, respectively, which were significantly lower (P < .05) than the 23% and 26% rates seen after UL. There were no significant differences in nodal metastases or distant metastases rates between UL and BLR (P > .4). The 20-year LR rate after total thyroidectomy (13%) was not different (P = .5) from the 11% seen after near-total thyroidectomy. CONCLUSIONS: In this nonrandomized evaluation of patients with pTNM stage III papillary thyroid carcinoma, the extent of primary thyroid resection appeared to significantly impact CSM and LR but did not apparently influence regional or distant metastasis.

Papillary thyroid cancer with pulmonary metastases in children: long-term prognosis.

BACKGROUND: Papillary thyroid cancer (PTC) in young patients may rarely be encountered with pulmonary metastases. Previous studies have suggested that, in the pediatric population, this may not portend a lethal outcome. Our present study, children with pulmonary metastases, was designed to clarify this issue. METHODS: Fourteen children and young adolescents (mean age, 13.5 years; range, 9.8-17 years) with PTC and pulmonary metastases were treated at our institution between 1937 and 1998. Surgical treatment consisted of total thyroidectomy (n = 10 patients), subtotal thyroidectomy (n = 3 patients), and a biopsy only procedure (n = 1 patient). All patients who underwent thyroidectomy also underwent a variety of cervical lymph node dissections, and all patients proved to have regional nodal disease. After the operation, 12 patients were treated with ablative doses of (131)I, 1 patient was treated with external beam irradiation, and all patients were placed on suppressive thyroid hormone therapy. The mean length of follow-up was 19.3 years (range, 1-45 years). RESULTS: Regional recurrent disease developed in 2 patients (15%). No patient experienced the development of worsening pulmonary disease or extra-pulmonary metastases. All patients with recurrent disease underwent selective nodal resections. No patient died of metastatic PTC. Seven patients (50%) remain completely free of disease and are probably cured; 7 patients (50%) are asymptomatic with residual pulmonary disease. CONCLUSIONS: A stepwise treatment approach allows long-term survival and frequent cure for young patients with PTC and concomitant pulmonary metastases.

Holmium:yttrium-aluminum-garnet laser cystolithotripsy of large bladder calculi.

OBJECTIVES: Patients with large bladder calculi (4 cm or larger) have traditionally been managed with open cystolithotomy. Endoscopic management with cystolitholapaxy or electrohydraulic lithotripsy risks complications. In an effort to spare patients the morbidity of open cystolithotomy, the results of holmium:yttrium-aluminum-garnet (YAG) laser cystolithotripsy for bladder calculi 4 cm or larger were reviewed. METHODS: Consecutive patients with bladder calculi of 4 cm or larger were managed with holmium:YAG laser cystolithotripsy. Laser energy was delivered using either the 365-micron end-firing fiber or the 550-micron side-firing fiber. RESULTS: Fourteen consecutive patients were managed with holmium:YAG cystolithotripsy. All patients were rendered stone free, regardless of stone composition or size. Median anesthesia time was 57 minutes. Twelve of 14 patients were discharged by the first postoperative day. The procedure times normalized for stone size (mean +/- standard deviation) for the end-firing versus the side-firing fibers were 13 +/- 6 min/cm versus 6 +/- 1 min/cm, respectively; P = 0.04. CONCLUSIONS: Holmium:YAG laser cystolithotripsy of large bladder calculi is effective, technically facile, and safe. The 550-micron side-firing fiber may be better suited for large bladder calculi compared with the 365-micron end-firing fiber. Holmium:YAG cystolithotripsy may obviate open cystolithotomy in selected patients.

The use of chlorpromazine for symptom control in dying cancer patients.

Terminal restlessness is a significant problem in deaths from advanced cancer, it is difficult not only for patients, but for family and health-care providers also. Chlorpromazine is an antipsychotic phenothiazine, safe at high doses and by many routes. It has also been used as an adjunct to morphine in advanced cancer. We have conducted a study using chlorpromazine in 20 patients, in which the drug was administered intravenously (i.v.) or rectally (PR) in inpatients and outpatients for terminal restlessness and dyspnea. The median PR dose was 25 mg every 4-12 hr. The median IV dose was 12.5 mg every 4-12 hr. Eighteen patients had complete relief and two had partial relief before death. We find chlorpromazine safe and effective for the relief of terminal restlessness and dyspnea in advanced cancer.

Euthyroid sick syndrome: an overview.

Abnormalities of thyroid hormone concentrations are seen commonly in a wide variety of nonthyroidal illnesses, resulting in low triiodothyronine, total thyroxine, and thyroid stimulating hormone concentrations. These thyroid hormone changes may be mediated in part by cytokines or other inflammatory mediators, acting at the level of the hypothalamus and pituitary, the thyroid gland, and the hepatic deiodinase system, as well as on binding of thyroxine to thyroid binding globulin. The degree of thyroid function disturbance correlates with disease severity and low levels of thyroid hormones predict a poor prognosis in several illnesses. It remains unresolved whether the hormone responses in the euthyroid sick syndrome represent part of an adaptive response, which lowers tissue energy requirements in the face of systemic illness, or a maladaptive response, which induces damaging tissue hypothyroidism. Consequently, the use of thyroid hormone therapy in the euthyroid sick syndrome is controversial. The small number of controlled trials performed to date have shown conflicting results on the cardiovascular effects of triiodothyronine, and none has had the statistical power to address the question of altered mortality. Future trials of therapy should concentrate on patients with severe nonthyroidal illness and a high mortality rate. Meanwhile, better understanding is needed of the impact of the altered thyroid hormone status on tissue function.

Comparison of anticoagulant control among patients attending general practice and a hospital anticoagulant clinic.

Management of patients receiving oral anticoagulant therapy was assessed in general practice and a dedicated hospital anticoagulant clinic. The demographic characteristics of patients in both groups were similar, as were the indications for anticoagulation therapy and the duration of treatment. General practice patients were reviewed significantly more frequently, with a median interval of 16 days compared with 42 days for hospital patients (P < 0.001). Twenty four per cent of general practice visits and 26% of hospital attendances resulted in an alteration to the warfarin dosage. Overall, 52% of general practice thrombotest results lay within the ranges recommended by the British Society for Haematology, compared with 45% of hospital results (P < 0.001). There was no difference in the rate of complications in general practice and the hospital clinic. In this study, the anticoagulant control achieved in a general practice setting was superior to that in a dedicated hospital outpatient clinic, although control was far from ideal in either setting.

Redifferentiation and induction of tumor suppressors miR-122 and miR-375 by the PAX8/PPARγ fusion protein inhibits anaplastic thyroid cancer: a novel therapeutic strategy.

Anaplastic thyroid cancer (ATC) is an aggressive, fatal disease unresponsive to traditional therapies, generating a need to develop effective therapies. The PAX8/PPARγ fusion protein (PPFP) has been shown to favorably modulate tumor growth in follicular thyroid cancer, prompting our evaluation of its efficacy to inhibit ATC cell and tumor growth in vitro and in vivo. PPFP was constitutively expressed in five ATC cell lines: BHT-101, FRO, C-643, KTC-2 and KTC-3, and inhibited cell growth in four of five cell lines and xenograft tumor growth in four of four cell lines. PPFP-mediated growth inhibition involved multiple mechanisms, including upregulation of miR-122 and miR-375, associated with decreased angiogenesis and AKT pathway inactivation, respectively. Also, PPFP expression resulted in marked increase of thyroid-specific marker transcripts, including PAX8, thyroid peroxidase (TPO), sodium iodide symporter (NIS) and thyroglobulin, to varying degrees by activating their respective promoters, suggesting that PPFP induced cellular redifferentiation. Functional studies demonstrate that increased NIS messenger RNA is not associated with increased 125I uptake. However, ectopic expression of wild-type NIS-induced perchlorate-sensitive iodine uptake, suggesting that endogenous NIS in ATC cell lines is defective. As current treatment for ATC is only palliative, overexpression of PPFP may offer a novel therapeutic strategy for the treatment of ATC.

Preclinical efficacy of the oncolytic measles virus expressing the sodium iodide symporter in iodine non-avid anaplastic thyroid cancer: a novel therapeutic agent allowing noninvasive imaging and radioiodine therapy.

Anaplastic thyroid cancer is an extremely aggressive disease resistant to radioiodine treatment because of loss of sodium iodide symporter (NIS) expression. To enhance prognosis of this fatal cancer, we validated the preclinical efficacy of measles virus (MV)-NIS, the vaccine strain of the oncolytic MV (MV-Edm), modified to include the NIS gene. Western blotting analysis confirmed that a panel of eight anaplastic thyroid cancer (ATC)-derived cell lines do not express NIS protein, but do express CD46, the MV receptor. In vitro cell death assays and in vivo xenograft studies demonstrate the oncolytic efficacy of MV-NIS in BHT-101 and KTC-3, ATC-derived cell lines. Radioactive iodine uptake along with single-photon emission computed tomography (SPECT)-computed tomography imaging of KTC-3 xenografts after (99)Tc(m) administration confirmed NIS expression in vitro and in vivo, respectively, after virus treatment. Adjuvant administration of RAI, to MV-NIS-treated KTC-3 tumors showed a trend for increased tumor cell killing. As current treatment for ATC is only palliative, and MV-NIS is currently Food and Drug Administration approved for human clinical trials in myeloma, our data indicate that targeting ATC with MV-NIS could prove to be a novel therapeutic strategy for effective treatment of iodine-resistant ATC and will expedite its testing in clinical trials for this aggressive disease.

Expression of the PAX8/PPARγ Fusion Protein Is Associated with Decreased Neovascularization In Vivo: Impact on Tumorigenesis and Disease Prognosis.

The PAX8/PPARγ fusion protein (PPFP) occurs in 36% of human follicular thyroid carcinoma (FTC) and is associated with favorable prognosis. To elucidate the function of PPFP in FTC, we analyzed the consequences of PPFP expression in immortalized thyrocytes in vitro and in vivo via xenograft tumorigenesis. While PPFP-expressing cells exhibited oncogenic hallmarks, including increased growth and decreased apoptosis, in vitro, xenograft tumors were initiated but not sustained in vivo. PPFP xenograft tumors exhibited reduced CD31 staining and VEGF expression, suggesting that PPFP modulates neovascularization. Microarray analysis demonstrated increased expression of tissue inhibitor of metalloproteinase (TIMP-3), an inhibitor of angiogenesis, in PPFP cells and tumors, a finding confirmed by quantitative PCR and immunohistochemistry. Immunohistochemical staining of archival human thyroid tumors demonstrates a significant decrease in CD31 staining in all adenomas and carcinomas containing the PAX8/PPARγ rearrangement. Decreased angiogenesis in PPFP-containing tumors is directly correlated with our observations in the xenograft model and provides evidence for the first time that PPFP may impact FTC tumorigenesis by modulating angiogenesis in vivo.