A Review of Parathyroid Surgery for Primary Hyperparathyroidism from the United Kingdom Registry of Endocrine and Thyroid Surgery (UKRETS).

BACKGROUND: The United Kingdom Registry of Endocrine and Thyroid Surgeons is a national database holding details on > 28,000 parathyroidectomies. METHODS: An extract (2004-2017) of the database was analysed to investigate the reported efficacy, safety and use of intra-operative surgical adjuncts in targeted parathyroidectomy (tPTx) and bilateral neck exploration (BNE) for adult, first-time primary hyperparathyroidism (PHPT). RESULTS: 50.9% of 21,738 cases underwent tPTx. Excellent short-term (median follow-up 35 days) post-operative normocalcaemia rates were reported overall (tPTx 96.6%, BNE 94.5%, p < 0.05) and in image-positive cases (tPTx 96.7%, BNE 96%, p < 0.05). Intra-operative PTH improved overall normocalcaemia rates (tPTx 97.8% vs 96.3%, BNE 95% vs 94.4%: both p < 0.05). Intra-operative nerve monitoring reduced vocal cord (VC) dysfunction in image-positive tPTx, but not in BNE (97.8% vs 93.2%, p < 0.05). Complications were higher following BNE (7.4% vs 3.8%, p < 0.05), especially hypocalcaemia (5.3% vs 2%, p < 0.05). There was no difference in rates of subjective dysphonia following tPTx or BNE (2.4% vs 2.3%, p > 0.05), nor any difference in VC dysfunction when formally examined (4.9% vs 4.1%, p > 0.05). CONCLUSIONS: In image-positive, first time, adult PHPT cases, tPTx is as safe and effective as BNE, with both achieving excellent short-term results with minimal complications.

Re-operative thyroid surgery: a 20-year prospective cohort study at a tertiary referral centre.

Re-operative thyroid surgery is a relatively uncommon procedure complicated by distorted anatomy and post-operative tissue changes. Surgery may follow initial benign or malignant pathology. Published outcomes vary widely in the literature. This study aims to report our outcomes from re-operative thyroid surgery. Patient demographics and complication rates for consecutive thyroidectomies performed by a single surgeon at a tertiary centre were collected between 1993 and 2013. Outcomes in re-operative surgery are analysed and compared with local and national data. Cases of re-operative surgery following benign disease are further analysed for histology, re-presenting symptoms and time between procedures. Our cohort comprised 1,657 cases including 164 re-operative procedures (101 malignant, 63 benign). Within our cohort re-operative cases were on average 4 years older (mean 49.9 vs 45.9 years, p = 0.001) and had a higher incidence of haematoma formation (4.3 vs 1.7 %, p = 0.033) and transient recurrent laryngeal nerve palsy (5.5 vs 2.5 %, p = 0.044) compared to primary surgery. Rates of permanent hypocalcaemia (2.4 vs 1.8 %, p = 0.540) and permanent RLN palsy (1.8 vs 0.4 %, p = 0.051) were higher in the re-operative group but did not reach significance. Comparison of complications following re-operation for benign and malignant disease revealed no significant differences. Mean interval to re-operation for benign cases was 17.4 years with 74.6 % found to have multinodular goitre at repeat procedure. Re-operative procedures comprised around 10 % of thyroid surgery at our centre. Re-operative cases experienced more complications than primary surgery but permanent rates were low. Re-operative surgery may therefore be safely considered in experienced hands.

'From Felix to the helix, and from the cradle to the grave - Semon's contribution to thyroid surgery', Royal Society of Medicine, 1 November 2019, London, UK.

Mr President, Mr President Elect, Fellows and Members, Ladies and Gentleman, it is a pleasure to address the Section of Laryngology this morning and deliver the 94th Semon Lecture. I would like to thank the Semon Committee for their kind invitation. My lecture will discuss Sir Felix Semon (the man himself), highlight the history of head and neck surgery, and then discuss the requirements of a modern-day thyroid surgeon. I have no conflict of interest and nothing to declare.

PTTG and PBF repress the human sodium iodide symporter.

The ability of the thyroid to accumulate iodide provides the basis for radioiodine ablation of differentiated thyroid cancers and their metastases. Most thyroid tumours exhibit reduced iodide uptake, although the mechanisms accounting for this remain poorly understood. Pituitary tumour transforming gene (PTTG) is a proto-oncogene implicated in the pathogenesis of thyroid tumours. We now show that PTTG and its binding factor PBF repress expression of sodium iodide symporter (NIS) messenger RNA (mRNA), and inhibit iodide uptake. This process is mediated at least in part through fibroblast growth factor-2. In detailed studies of the NIS promoter in rat FRTL-5 cells, PTTG and PBF demonstrated specific inhibition of promoter activity via the human upstream enhancer element (hNUE). Within this approximately 1 kb element, a complex PAX8-upstream stimulating factor 1 (USF1) response element proved critical both to basal promoter activity and to PTTG and PBF repression of NIS. In particular, repression by PTTG was contingent upon the USF1, but not the PAX8, site. Finally, in human primary thyroid cells, PTTG and PBF similarly repressed the NIS promoter via hNUE. Taken together, our data suggest that the reported overexpression of PTTG and PBF in differentiated thyroid cancer has profound implications for activity of the NIS gene, and hence significantly impacts upon the efficacy of radioiodine treatment.

Systematic review of cure and recurrence rates following minimally invasive parathyroidectomy.

BACKGROUND: The majority of patients with primary hyperparathyroidism (PHPT) have a single overactive adenoma. Advances in preoperative imaging and surgical adjuncts have given rise to minimally invasive parathyroidectomy (MIP), with lower complication rates in comparison with bilateral neck exploration. Misdiagnosis and undertreatment of multiglandular disease, leading to potentially higher recurrence rates, remains a concern. This study evaluated risks of long-term (1 year or more) recurrence following 'targeted' MIP in PHPT. METHODS: Multiple databases were searched for studies published between January 2004 and March 2017, looking at long-term outcomes (1 year or more) following targeted MIP for PHPT. English-language studies, with at least 50 patients and a mean follow-up of 1 year, were included. RESULTS: A total of 5282 patients from 14 studies were included. Overall mean recurrence and cure rates were 1·6 (range 0-3·5) and 96·9 (95·5-100) per cent respectively. Mean follow-up was 33·5 (1-145) months. When intraoperative parathyroid hormone (PTH) measurements were not done, cure rates were higher (99·3 per cent versus 98·1 per cent with use of intraoperative PTH measurement; P < 0·001) and recurrence rates lower (0·2 versus 1·5 per cent respectively; P < 0·001). CONCLUSION: Targeted MIP for a presumed single overactive adenoma was associated with very low recurrence rates, without the need for intraoperative PTH measurement when preoperative imaging studies were concordant. Targeted MIP should be encouraged.

Elevated PTTG and PBF predicts poor patient outcome and modulates DNA damage response genes in thyroid cancer.

The proto-oncogene PTTG and its binding partner PBF have been widely studied in multiple cancer types, particularly thyroid and colorectal, but their combined role in tumourigenesis is uncharacterised. Here, we show for the first time that together PTTG and PBF significantly modulate DNA damage response (DDR) genes, including p53 target genes, required to maintain genomic integrity in thyroid cells. Critically, DDR genes were extensively repressed in primary thyrocytes from a bitransgenic murine model (Bi-Tg) of thyroid-specific PBF and PTTG overexpression. Irradiation exposure to amplify p53 levels further induced significant repression of DDR genes in Bi-Tg thyrocytes (P=2.4 × 10-4) compared with either PBF- (P=1.5 × 10-3) or PTTG-expressing thyrocytes (P=NS). Consistent with this, genetic instability was greatest in Bi-Tg thyrocytes with a mean genetic instability (GI) index of 35.8±2.6%, as well as significant induction of gross chromosomal aberrations in thyroidal TPC-1 cells following overexpression of PBF and PTTG. We extended our findings to human thyroid cancer using TCGA data sets (n=322) and found striking correlations with PBF and PTTG expression in well-characterised DDR gene panel RNA-seq data. In addition, genetic associations and transient transfection identified PBF as a downstream target of the receptor tyrosine kinase-BRAF signalling pathway, emphasising a role for PBF as a novel component in a pathway well described to drive neoplastic growth. We also showed that overall survival (P=1.91 × 10-5) and disease-free survival (P=4.9 × 10-5) was poorer for TCGA patients with elevated tumoural PBF/PTTG expression and mutationally activated BRAF. Together our findings indicate that PBF and PTTG have a critical role in promoting thyroid cancer that is predictive of poorer patient outcome.

Serum thyrotropin concentration as a novel predictor of malignancy in thyroid nodules investigated by fine-needle aspiration.

CONTEXT: Thyroid nodules and goiter are common, and fine-needle aspiration biopsy (FNAB) is the first investigation of choice in distinguishing benign from malignant disease. OBJECTIVE: The objective of the study was to assess whether simple clinical and biochemical parameters can predict the likelihood of thyroid malignancy in subjects undergoing FNAB. DESIGN: The design was a prospective cohort. SETTING: The study was conducted at a single secondary/tertiary care clinic. PARTICIPANTS: One thousand five hundred consecutive patients without overt thyroid dysfunction (1304 females and 196 males, mean age 47.8 yr) presenting with palpable thyroid enlargement between 1984 and 2002 were evaluated by FNAB of the thyroid. INTERVENTION(S): There were no interventions. MAIN OUTCOME MEASURES: Goiter type was assessed clinically and classified as diffuse in 183, multinodular in 456, or solitary nodule in 861 cases. Serum TSH concentration at presentation was measured in a sensitive assay in patients presenting after 1988 (n = 1183). The final cytological or histological diagnosis was determined after surgery (n = 553) or a minimum 2-yr clinical follow-up period (mean 9.5 yr, range 2-18 yr). RESULTS: The overall sensitivity and specificity of FNAB in predicting malignancy were 88 and 84%, respectively. The risk of diagnosis of malignancy rose in parallel with the serum TSH at presentation, with significant increases evident in patients with serum TSH greater than 0.9 mU/liter, compared with those with lower TSH. Binary logistic regression analysis revealed significantly increased adjusted odds ratios (AORs) for the diagnosis of malignancy in subjects with serum TSH 1.0-1.7 mU/liter, compared with TSH less than 0.4 mU/liter [AOR 2.72, 95% confidence interval (CI) 1.02-7.27, P = 0.046], with further increases evident in those with TSH 1.8-5.5 mU/liter (AOR 3.88, 95% CI 1.48-10.19, P = 0.006, compared with TSH < 0.4 mU/liter) and greater than 5.5 mU/liter (AOR 11.18, 95% CI 3.23-8.63, P < 0.001, compared with TSH < 0.4 mU/liter). Males (AOR 1.8, 95% CI 1.04-3.1, P = 0.04), younger patients (AOR 1.1, 95% CI 1.01-1.15, P = 0.025), and those with clinically solitary nodules (AOR 2.53, 95% CI 1.5-4.28, P = 0.001) were also at increased risk. Based on these findings, a formula to predict the risk of the diagnosis of thyroid malignancy in individual patients, taking into account their gender, age, goiter type determined clinically, and serum TSH, was calculated. CONCLUSIONS: The risk of malignancy in a thyroid nodule increases with serum TSH concentrations within the normal range. In addition to patient's gender, age, and goiter type, the serum TSH concentration at presentation is an independent predictor of the presence of thyroid malignancy. We propose that these simple clinical and biochemical factors can serve as an adjunct to FNAB in predicting risk of malignancy.

Pituitary tumor transforming gene (PTTG) stimulates thyroid cell proliferation via a vascular endothelial growth factor/kinase insert domain receptor/inhibitor of DNA binding-3 autocrine pathway.

CONTEXT: Vascular endothelial growth factor (VEGF) exerts its biological effects by binding to the tyrosine kinase receptors VEGF receptor type 1 (VEGFR1/Flt-1) and VEGFR2 (Flk-1/KDR). Kinase insert domain receptor (KDR) is the critical receptor controlling proliferation and migration of endothelial cells and has been shown to be expressed in some nonendothelial cells. We recently reported that the proangiogenic pituitary tumor transforming gene (PTTG) stimulates VEGF and up-regulates inhibitor of DNA binding-3 (ID3), an important gene in VEGF-dependent angiogenesis. OBJECTIVE: Our objective was to test whether VEGF, ID3, and KDR confer a PTTG-mediated effect on thyroid cell growth. DESIGN: Gene expression, MAPK stimulation, and cell proliferation were assessed in follicular thyroid cancer FTC133 cells. Gene expression and clinical associations were determined in 21 normal and 38 tumorous thyroid specimens (nine follicular and 29 papillary). RESULTS: ID3 correlated with VEGF mRNA expression in our series of thyroid cancers, which also showed up-regulated KDR mRNA. Stimulation of FTC133 cells with exogenous VEGF enhanced ID3 expression, which could be abrogated by the KDR-specific inhibitor ZM323881, suggesting that VEGF regulation of ID3 is KDR dependent. PTTG significantly correlated with KDR mRNA expression in our thyroid cancer cohort and up-regulated KDR and VEGF expression in FTC133 cells. Finally, cells transfected with PTTG demonstrated increased cell proliferation and phosphorylation of MAPK, which was abrogated by ZM323881. CONCLUSIONS: We report the presence of a VEGF/KDR/ID3-dependent autocrine pathway in FTC133 thyroid cells. By up-regulating both VEGF and KDR expression, we propose a novel PTTG-mediated proliferative pathway that may be critical to thyroid cancer growth and progression.

Pituitary tumor-transforming gene regulates multiple downstream angiogenic genes in thyroid cancer.

CONTEXT: Pituitary tumor-transforming gene (PTTG) is a multifunctional protein involved in several tumorigenic mechanisms, including angiogenesis. PTTG has been shown to promote angiogenesis, a key rate-limiting step in tumor progression, by up-regulation of fibroblast growth factor-2 and vascular endothelial growth factor. OBJECTIVE: To investigate whether PTTG regulates other angiogenic genes in thyroid cells, we performed angiogenesis-specific cDNA arrays after PTTG transfection. Two of the genes [inhibitor of DNA binding-3 (ID3) and thrombospondin-1 (TSP-1)] which showed differential expression in primary thyroid cells were validated in vitro and in vivo. RESULTS: TSP-1 showed a 2.5-fold reduction and ID3 showed a 3.5-fold induction in expression in response to PTTG overexpression in vitro. Conversely, suppression of PTTG with small interfering RNA was associated with a 2-fold induction of TSP-1 and a 2.2-fold reduction in ID3 expression. When we examined TSP-1 and ID3 expression in 34 differentiated thyroid cancers, ID3 was significantly increased in tumors compared with normal thyroid tissue. Furthermore, ID3 expression was significantly higher in follicular thyroid tumors than in papillary tumors. Although mean TSP-1 expression was not altered in cancers compared with normal thyroids, we observed a significant independent association between TSP-1 expression and early tumor recurrence, with recurrent tumors demonstrating 4.2-fold lower TSP-1 expression than normal thyroid tissues. CONCLUSION: We have identified ID3 and TSP-1 as two new downstream targets of PTTG in thyroid cancer. We propose that PTTG may promote angiogenesis by regulating the expression of multiple genes with both pro- and antiangiogenic properties and may thus be a key gene in triggering the angiogenic switch in thyroid tumorigenesis.

Carboplatin and hypofractionated accelerated radiotherapy: a dose escalation study of an outpatient chemoradiation schedule for squamous cell carcinoma of the head and neck.

AIM: To examine the feasibility and determine the maximum tolerated dose of outpatient carboplatin given with synchronous hypofractionated accelerated radiotherapy for squamous cell carcinoma of the head and neck (SCCHN). MATERIALS AND METHODS: Patients with stages II-IV SCCHN and unresected primary tumour were treated with synchronous carboplatin given in an outpatient setting on day 1 and day 21 in cohorts of three to six patients with incremental area under curve (AUC) factors commencing at 3.5. Grade 3 mucositis persisting for 4 weeks in two patients in a cohort was considered dose limiting. RESULTS: A total of 19 patients were enrolled and assessable for toxicity. All 19 patients completed 55 Gy of radiotherapy and were assessable for response. Grade 3 mucositis lasting 4 weeks or more was seen in three patients, two of them received AUC 5 carboplatin. A complete response was seen in 16 patients, with a further patient having a partial response, giving a response rate of 89%. With a median follow-up of 24 months (range 11-30 months), 13 patients were alive with no evidence of recurrent disease. Local recurrence had occurred in four patients with distant spread in three patients. CONCLUSION: Carboplatin with concurrent hypofractionated accelerated radiotherapy is feasible for patients with advanced SCCHN and good performance status. The recommended phase II dose of carboplatin given in week 1 and week 4 with 55 Gy in 20 fractions is AUC 4.5.

The management of squamous cell carcinoma of the neck. The Birmingham UK experience.

AIMS: To review our treatment strategy and outcomes for metastatic squamous cell carcinoma of the neck. METHODS: One hundred and six consecutive patients treated between 1992 and 1998 were analysed retrospectively. The following data were obtained. Demographic details, tumour site, clinical and pathological TMN staging, tumour grade and presence of extracapsular spread, treatment modality (surgery, radiotherapy and chemotherapy), type of neck dissection and complications, 2-year loco-regional control and 5-year overall survival. RESULTS: Ninety-two patients had advanced disease (stages 3 and 4) and of these, 57% had palpable neck metastases. One hundred and six patients underwent a total of 132 neck dissections. Seventy-three patients had post-operative radiotherapy to both sides of the neck and a total of 31 patients took part in the UKHAN 1 trial. Seventy percent of patients achieved 2-year loco-regional control and 63% survived 5-years. CONCLUSION: Metastatic squamous cell carcinoma of the neck can successfully be treated with an aggressive surgical approach and post-operative radiotherapy when indicated. Excellent 2-year loco-regional control and 5-year survival rates are possible.

Tie-2 is expressed on thyroid follicular cells, is increased in goiter, and is regulated by thyrotropin through cyclic adenosine 3',5'-monophosphate.

Angiogenesis is coordinated with follicular cell growth in goitrogenesis. The angiopoietins, Ang-1 and Ang-2, are angiogenic growth factors acting through Tie-2, a tyrosine kinase receptor. We have examined the expression and regulation of the angiopoietins and Tie-2 in human and rat thyroids. In human goiters there was increased Tie-2 immunostaining, compared with that in normal thyroids, on both follicular and endothelial cells. In an induced goiter in rats, in situ hybridization showed increased expression of messenger ribonucleic acids (mRNAs) for Tie-2 and Ang-1 in follicular cells. As Tie-2 has previously been believed to be restricted to cells of endothelial lineage in adults, we examined its expression further in isolated follicular cells. Tie-2 and Ang-1 mRNA expression in human thyrocytes was confirmed by ribonuclease protection assay. Ang-2 mRNA was not detected in human cultures or rat thyroids. In both human follicular cell cultures and FRTL-5 cells, immunoblotting showed that Tie-2 expression was increased by TSH and agents that increased intracellular cAMP. In conclusion, we have demonstrated the expression of Tie-2 and Ang-1 in thyroid epithelial and endothelial cells, and have shown the regulation of Tie-2 by TSH and cAMP in follicular cells. Tie-2 expression is increased in goiter in both humans and rats, consistent with a role in goitrogenesis.

Fibroblast growth factors 1 and 2 and fibroblast growth factor receptor 1 are elevated in thyroid hyperplasia.

We have previously reported increased expression of fibroblast growth factor (FGF-1 and FGF-2) in benign and malignant human thyroid neoplasia. To determine the role of these factors in thyroid hyperplasia we have examined their expression in multinodular goiter and compared findings with those in normal thyroid tissue. Because the effects of FGF-1 and FGF-2 are predominantly mediated through the FGF receptor-1 (FGFR-1), its expression has also been examined. Immunocytochemistry was performed on sections from multinodular goiters (n = 18) and normal thyroid (n = 7). Cytoplasmic staining for FGF-1, FGF-2, and FGFR-1 was scored on a scale of 0 (no staining) to 3 (heavy staining) and expressed as a percentage of total cells stained. Confocal microscopy of immunofluorescent staining for FGF-1, FGF-2, and FGFR-1 in sections of multinodular goiter (n = 3) and normal thyroid (n = 3) provided quantitation of immunostaining. FGF-1 expression was significantly increased in multinodular goiter when compared with normal. A mean of 74% of follicular cells in multinodular goiter compared with 9% of follicular cells in normal thyroid expressed FGF-1 (P < 0.0001). When expression of FGF-2 was examined, 77% of the follicular cells in multinodular goiter compared with 5% in normal thyroids were immunopositive (P < 0.0001). Confocal microscopy revealed that the intensity was 160 times greater in follicular cells in sections of multinodular goiters when compared with normal. When expression of FGFR-1 was analyzed, 89% of the follicular cells in multinodular goiter stained positively, compared with 15% of follicular cells in sections of normal thyroid. Confocal microscopy revealed a 6-fold increase in intensity of FGFR-1 expression in follicular cells of multinodular goiter (P < 0.05). In addition, there was significant nuclear expression of FGFR-1 in multinodular goiter contrasting with negligible expression in normal thyroid. These data show that enhanced expression of FGF-1, FGF-2, and FGFR-1 accompany thyroid hyperplasia and are not exclusively associated with the neoplastic state. These factors may be involved in the pathogenesis of uncontrolled thyroid growth observed in these conditions.

Pituitary tumor transforming gene and fibroblast growth factor-2 expression: potential prognostic indicators in differentiated thyroid cancer.

Differentiated thyroid cancers are the most common endocrine cancers, but there are no reliable molecular markers of prognosis. Pituitary tumor transforming gene (PTTG) plays several potential roles in tumor initiation and progression, including regulating mitosis and stimulating expression of fibroblast growth factor (FGF)-2. Increased expression of PTTG has been demonstrated in follicular thyroid lesions, and expression of this oncogene has been identified as a potential prognostic marker in pituitary adenomas and colon carcinomas. We assessed the expression of PTTG and FGF-2 and its receptor FGF-R-1 in 27 differentiated thyroid cancers, and we compared this with expression in 11 normal thyroids, 25 multinodular goiters, and 13 Graves' disease specimens. We also examined the relationship between gene expression and clinical markers of tumor behavior. PTTG and FGF-2 were overexpressed in thyroid carcinomas (9.5-fold increase, P = 0.003, and 5.0-fold increase, P < 0.001, respectively) compared with normal thyroid. Increased FGF-2 mRNA expression was independently associated with the findings of lymph node invasion (R(2) = 0.71; P < 0.001) and distant metastasis (R(2) = 0.55; P = 0.009) at tumor presentation, after taking into account known prognostic factors such as age and gender of the patient and size and type of the tumor. High PTTG expression was independently associated with tumor recurrence (R(2) = 0.64; P = 0.003). We conclude that PTTG and FGF-2 expression are potential prognostic markers (and perhaps therapeutic targets) for differentiated thyroid cancer.

The pharmacokinetics and biodistribution of technetium-99m(V)dimercaptosuccinic acid in an animal tumor model.

This study used an established rabbit tumor model with squamous carcinoma to evaluate the pharmacokinetics and biodistribution of technetium-99m-(V)dimercaptosuccinic acid. A total of 54 rabbits were studied (25 with no tumor; 29 with tumor). Technetium-99m(V)dimercaptosuccinic acid had a bi-exponential blood clearance in rabbits with no tumors (28 and 325 min) and in rabbits with tumors (27 and 352 min). There was no significant difference (p greater than 0.05) in mean clearance times between the two groups and clearance appeared unaffected by tumor mass. Technetium-99m(V)dimercaptosuccinic acid had a bi-exponential cumulative urine excretion with no apparent difference in half-times between non-tumor and tumor rabbit groups (200 and 240 min, respectively). Technetium-99m(V)dimercaptosuccinic acid had a major organ biodistribution in rabbits which included bone, kidneys, bladder and the blood pool. The major route of excretion was via the urine. There was no significant difference (p greater than 0.05) in organ biodistribution between rabbits with no tumors and rabbits with tumors and there was no evidence of active uptake of technetium-99m(V)dimercaptosuccinic acid by either squamous carcinoma or inflammatory tissue.

Technetium-99m (v) dimercaptosuccinic acid uptake in patients with head and neck squamous carcinoma: experience in imaging.

A recently developed imaging agent, technetium-99m (v) dimercaptosuccinic acid (99mTc (v) DMSA), has been used to assess head and neck squamous carcinoma (SCC). We have prospectively studied 62 patients of whom 53 had a histologically proven head and neck SCC. The remaining nine had benign lesions. The results of planar imaging in patients with primary disease yielded an 85% sensitivity and 78% specificity. Planar imaging in patients with cervical lymphadenopathy revealed a 59% sensitivity. Nineteen patients also had single photon emission computed tomography imaging which improved the image quality, spatial resolution and sensitivity of the investigation. Twenty-seven patients were scanned before and after radiotherapy and, of these, 96% showed positive uptake in the salivary glands with no evidence of tumor recurrence. This study has shown 99mTc (v) DMSA imaging provides a cheap and rapid method of investigating head and neck SCC and further studies are necessary to evaluate its role in the management of patients with this disease.

Thyroid follicular cells secrete plasminogen activators and can form angiostatin from plasminogen.

Angiostatin, a 38 kDa fragment of plasminogen, potently inhibits the growth of blood vessels. Angiostatin is generated from plasminogen by urokinase-type (uPA) and tissue-type (tPA) plasminogen activators in the presence of free sulphydryl donors. Angiogenesis inhibitors may be important in regulating angiogenesis in developing goitre. We have examined angiostatin formation in human primary thyrocyte cultures and a rat thyrocyte cell line (FRTL-5). We found that human thyroid cells in culture secrete plasminogen activators (both tPA and uPA) as well as matrix metalloproteinase 2 into the medium. When human thyrocyte conditioned medium was incubated with plasminogen (10 microg/ml) and N-acetylcysteine (100 microM) for 24 h, a 38 kDa fragment of plasminogen, which is consistent with angiostatin, was generated. The appearance of the 38 kDa fragment was increased by agents that increase cAMP (forskolin and 8 BrcAMP). FRTL-5 cells, which do not secrete uPA or tPA, did not generate angiostatin. Thyroid cells produce several angiogenic growth factors, and human thyrocyte conditioned medium stimulated growth of endothelial cells. When the conditioned medium was incubated with plasminogen and N-acetylcysteine, this stimulatory effect was lost, consistent with the production of a growth inhibitory factor. We conclude that thyroid cells can produce angiostatin from plasminogen in vitro, and this may play a role in vivo in limiting goitre size.

Gender, clinical findings, and serum thyrotropin measurements in the prediction of thyroid neoplasia in 1005 patients presenting with thyroid enlargement and investigated by fine-needle aspiration cytology.

One thousand five euthyroid patients (870 females and 135 males, mean age 47 years), who presented with thyroid enlargement were evaluated by fine-needle aspiration cytology (FNAC) of the thyroid as the first-line investigation. The final cytological or histological diagnosis was determined after surgery (n = 312) or clinical follow-up for a minimum period of 2 years (range 2-14 years, mean 6.7 years). Goiter type was assessed clinically and was classified as diffuse in 147, multinodular in 247, or solitary nodule in 611. The overall sensitivity and specificity of the procedure in the detection of thyroid neoplasia was 88% and 89%, respectively. Males who presented with thyroid enlargement had significantly higher rates of malignancy (p = 0.007) and neoplasia (benign + malignant) (p = 0.002) than females, as did subjects with solitary nodule compared with diffuse or multinodular goiters (malignancy p = 0.001, neoplasia p < 0.001). Subjects with normal thyrotropin (TSH) (>0.4 mU/L) at presentation had a nonsignificantly increased risk of thyroid neoplasia (p = 0.07) and malignancy, in contrast to those with low TSH (<0.4 mU/L). We confirmed FNAC of the thyroid to be an accurate test in the detection of thyroid neoplasia. Gender and goiter type at presentation both contribute significantly to the prediction of the diagnosis of thyroid neoplasia.

Metastatic squamous carcinoma in the neck: an anatomical and physiological study using CT and SPECT 99Tcm (V) DMSA.

Technetium-99m (99Tcm) (V) dimercaptosuccinic acid (DMSA) is a new tumour imaging agent that has been used to image squamous cell carcinoma (SCC) of the head and neck. This study has been undertaken to compare clinical examination with computed tomography (CT) (anatomical) and SPECT 99Tcm (V) DMSA (physiological) imaging in the evaluation of metastatic SCC of the neck. Twenty-five patients with head and neck cancer were studied. Computed tomography was as sensitive but more accurate than clinical examination in predicting the presence of cancer. SPECT 99Tcm (V) DMSA was inferior to both techniques in identifying metastatic disease. There is no role for SPECT 99Tcm (V) DMSA imaging in the management of patients with SCC metastatic to the neck. Combined imaging with CT offered no advantages over anatomical imaging with CT alone. There is no role for CT in the routine evaluation of the clinically N0 neck and the role of CT of the neck in the management of patients with metastatic SCC is discussed.