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J C Watkinson

Publications and source records attributed to J C Watkinson.

At least 19 recordsLinked to original sources
PubMed2006

Securin induces genetic instability in colorectal cancer by inhibiting double-stranded DNA repair activity.

Genetic instability (GI) is a hallmark feature of tumor development. Securin, also known as pituitary tumor transforming gene (PTTG), is a mitotic checkpoint protein which is highly expressed in numerous cancers, is associated with tumor invasiveness, and induces GI in thyroid cells. We used fluorescence inter-simple sequence repeat PCR to assess GI caused primarily by DNA breakage events in 19 colorectal tumors. GI values ranged significantly, with Dukes' stage C&D colorectal tumors exhibiting greater GI and higher securin expression than Dukes' stage A&B tumors. Consistent with these findings, we observed a dose-dependent increase in GI in HCT116 cells in response to securin overexpression, as well as in non-transformed human fibroblasts. As securin has been implicated in a novel DNA repair pathway in fission yeast, we investigated its potential role in chemotoxic DNA damage response pathways in mammalian cells, using host cell reactivation assays. Securin overexpression in HCT116 cells inhibited etoposide-induced double-stranded DNA damage repair activity, and repressed Ku heterodimer function. Additionally, we observed that securin and Ku70 showed a reciprocal cytosol-nuclear translocation in response to etoposide-induced dsDNA damage. Our data suggest that, by repressing Ku70 activity and inhibiting the non-homologous end-joining dsDNA repair pathway, securin may be a critical gene in the development of GI in colorectal cancer.

Animals↗
PubMed2006

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.

Adenocarcinoma, Follicular↗
PubMed2006

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.

Adolescent↗
PubMed2006

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.

Cell Line, Tumor↗
PubMed2006

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.

Adult↗
PubMed2005

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.

Adult↗
PubMed2003

External beam radiotherapy in the management of differentiated thyroid cancer.

AIMS: No randomised trials have addressed the use of external beam radiotherapy (EBRT) in the treatment of differentiated thyroid cancer. The indications for EBRT, the technique and recommended dose all remain controversial. MATERIALS AND METHODS: We included patients treated with EBRT with curative intent from two cancer centres between 1988 and 2001. Data were collected from hospital notes, radiotherapy prescriptions and local cancer registry. RESULTS: The indications for treatment in the 41 identified patients were macroscopic residual disease 23 (56%), microscopic residual disease 10 (25%), Hurthle cell variants 3 (7%), multiple lymph-node involvement 3 (7%) and other 2 (5%). Delivered doses ranged from 37.5-66 Gy over 3-6.5 weeks. Rate of local recurrence and overall survival at 5 years were as follows: papillary 26% and 67%; follicular 43% and 48%; well differentiated 21% and 67%; focus of poor differentiation/Hurthle cell variants 69% and 32%; complete excision 25% and 61%; residual disease 37% and 59%; EBRT total dose < 50 Gy 63% and 42%; 50-54 Gy 15% and 72%; > 54 Gy 18%, and 68%. CONCLUSIONS: The results in this study are consistent with previous retrospective studies of EBRT. The wide range of indications and doses used with radical intent highlights the lack of clinical and radiobiological data on the response of differentiated thyroid cancer to EBRT. Despite the small study size, the 5-year local recurrence results indicate a possible dose response within the dose range used.

Carcinoma, Papillary, Follicular↗
PubMed2003

Oncogenes in thyroid cancer.

There have been significant advances in our understanding of carcinogenesis at the molecular level over the last 25 years. Oncogenes are of major interest as part of our search for knowledge surrounding the aetiology of cancer. There are several oncogenes associated with thyroid cancer. Detailed investigation of the nature and function of these tumour genes has provided important insights into both the tumour biology and the complex biochemical pathways of normal cellular functioning. Our knowledge of oncogene biology offers the hope of better diagnostic, therapeutic and prognostic modalities in our fight against this and other common cancers. Development of specific thyroid tumour markers and gene therapy is now a realistic prospect to supplement our present armamentarium of surgery and radiotherapy. This review aims to outline the pertinent information gained so far from studies of these oncogenes and provides both clinical relevance and fuel for further interest amongst the ENT thyroid community in this exciting area of research.

Carcinoma, Medullary↗
PubMed2003

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.

Adult↗
PubMed2002

Who performs thyroid surgery: a review of current otolaryngological practice.

Thyroid surgery has been traditionally a general surgical practice, but recently more otolaryngologists have been offering a thyroid service. We have quantified thyroid surgery performed by the different specialties, and looked more closely at the practice of otolaryngologists. Data was obtained from the Department of Health for UK thyroid surgery in all specialties for the year 1998-99 and validated against a survey of members of the British Association of Otolaryngologists-Head & Neck Surgeons (BAO-HNS). The use of investigations of a simple clinical case (solitary thyroid nodule) was compared with best practice. General surgeons still perform the majority of thyroid surgery (83%) but ENT surgeons now perform significant numbers (15.4% of all cases), which translates to 1499 cases per annum. A total of 102 BAO-HNS members were performing thyroid surgery with an average case-load of 19.1 per year. In total, 35% of ENT surgeons see thyroid patients in multidisciplinary clinics. The choice of investigation is consistent with European guidelines. ENT surgeons are doing significant amounts of thyroid surgery and the numbers appear to be increasing. The formation of multidisciplinary teams including general surgeons and otolaryngologists who are committed to subspecialization can only improve both training and treatment outcomes.

General Surgery↗
PubMed2002

Conservation surgery in the management of T1 and T2 oropharyngeal squamous cell carcinoma: the Birmingham UK experience.

The aim of this paper was to evaluate our experience using conservation surgery in the management of T1 and T2 oropharyngeal squamous cell carcinoma. Eighteen patients underwent conservation surgery between 1993 and 2000 and were analysed retrospectively. The mean age was 54 years and the male to female ratio was 8:1. There were 14 tonsil and 4 tongue base tumours and 83% of cases presented with neck nodes, thereby classifying them as having advanced disease (stages 2-4). All patients received postoperative radiotherapy. All patients were followed up to December 2001. The median follow-up time was 3.8 years (minimum was 1.5 years). The 2-year and 5-year survival rates were 100% and 92% respectively. Approximately 66% of patients returned the EORTC and GHQ/12 quality-of-life questionnaires. Of these, seventy-five percent had a high healthy level of general functioning in accordance with the EORTC general health section. These results show that conservation surgery techniques are effective in the treatment of T1 and T2 oropharyngeal squamous carcinoma associated with significant metastatic neck disease. The techniques are well tolerated, produce minimal functional deficit and do not have a negative impact on the patients quality of life in either the immediate postoperative period or up to 4 years post-treatment.

Adult↗
PubMed2002

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.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2001

An audit of management of differentiated thyroid cancer in specialist and non-specialist clinic settings.

OBJECTIVE: Thyroid cancer is the most common endocrine malignancy but is none the less rare. Some aspects of its management remain controversial. Previous audits of patient management in the United Kingdom have revealed deficiencies, especially in communication between specialists. We have audited patient management in a large university-associated teaching hospital, assessing points of good practice identified from published guidelines and reviews, and have compared findings in groups of patients managed jointly by specialists with an interest in thyroid cancer (including surgeon, endocrinologist and oncologist) with a group managed by other clinicians outside that setting. DESIGN AND PATIENTS: Retrospective case-note review of 205 patients with differentiated (papillary or follicular) cancer including group A (n = 134; managed in a specialist multi-disciplinary clinic setting) and group B (n = 71; managed in other clinic settings). Points of good practice investigated were adequacy of surgery, surgical complications, prescription and adequacy of T4 treatment, adequacy of monitoring by measurement of serum thyroglobulin and action taken and appropriate administration of ablative radioiodine. RESULTS: Deficiencies in management of the cohort as a whole were identified, including inadequate surgery and inadequate TSH suppression in approximately one-fifth of the cases. Monitoring with thyroglobulin measurements and action when serum thyroglobulin was high were also inadequate in some cases and ablative radioiodine was not given, despite being indicated in 11.7% of the cohort. Inadequate surgery and failure to administer radioiodine were less common in those managed in a specialist clinic setting than in those managed in other clinic settings. CONCLUSIONS: The findings highlight the need for locally agreed protocols in managing relatively rare endocrine disorders such as thyroid cancer and argue in favour of centralization of expertise and patient management in multi-disciplinary specialist clinic settings.

Adolescent↗
PubMed2001

The aetiology of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma is a disease with a remarkable racial and geographical distribution. In most parts of the world it is a rare condition and in only a handful of places does this low risk profile alter. These include the Southern Chinese, Eskimos and other Arctic natives, inhabitants of South-East Asia and also the populations of North Africa and Kuwait.

Adolescent↗
PubMed2001

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.

Angiopoietin-1↗