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Background: Parathyroid cancer is rare. Differentiating parathyroid carcinoma from degenerative changes at histopathology can be difficult and studies investigating the value of single immunohistochemical markers have had variable results. In this study we aimed to investigate whether a panel of immunohistochemistry markers could aid the diagnosis of parathyroid cancer., Methods: All cases of parathyroid cancer at our institution from 1998 to 2012 were identified retrospectively. Cases were classified as definite cancers (those with evidence of metastatic spread) or histological cancers (those with features of carcinoma without evidence of metastasis). Controls with benign parathyroid disease were included for comparison. Immunohistochemistry for parafibromin, galectin-3, PGP9.5, Ki67, and cyclin D1 was analysed by an experienced endocrine pathologist., Results: There were 24 cases and 14 benign adenomas. Four cases had evidence of metastatic spread and 20 were diagnosed on histological criteria alone. Sixteen of the 24 cases had further surgery with ipsilateral thyroid lobectomy and 15 also had a prophylactic level VI lymph node dissection. Apart from one patient with distant metastases at presentation, none developed recurrence at follow-up (median = 38 months). Immunohistochemistry results associated with parathyroid cancer were seen in 11/24 parafibromin, 13/24 galectin-3, 8/24 PGP9.5, 5/24 Ki67, and 2/24 cyclin D1. None of the controls had immunohistochemical staining suggestive of cancer. Nineteen of the 24 patients had at least one immunohistochemical result associated with parathyroid cancer (sensitivity 79 %, specificity 100 %). Cyclin D1 did not suggest malignancy in any case that did not already have another abnormal marker, and so did not add value to the panel in this study., Conclusion: A panel of immunohistochemistry (PGP9.5, galectin-3, parafibromin, and Ki67) is better than any single marker and can be used to supplement classical histopathology in diagnosing parathyroid cancer.

The majority of deaths in ovarian cancer are caused by recurrent metastatic disease which is usually multidrug resistant. This progression has been hypothesised to be due in part to the presence of cancer stem cells, a subset of cells which are capable of self-renewal and are able to survive chemotherapy and migrate to distant sites. Side population (SP) cells, identified by the efflux of the DNA-binding dye Hoechst 33342 through ATP-binding cassette (ABC) transporters, are a known adult stem cell group and have been suggested as a cancer stem cell in various cancers. Despite the identification of SP cells in cancer cell lines and patient samples, little attention has been paid to the identification of specific ABC transporters within this cell fraction which efflux Hoechst dye and thus may facilitate drug resistance. In this study, we demonstrate that SP cells can be detected in both ovarian cancer cell lines and ascitic fluid samples, and these SP cells possess stem cell and drug resistance properties. We show that ABCB1 is the functioning ABC transporter in ovarian cancer cell lines, and expression of ABCB1 is associated with a paclitaxel-resistant phenotype. Moreover, silencing of ABCB1 using a specific morpholino oligonucleotide results in an inhibition of the SP phenotype and a sensitising of ovarian cancer cell lines to paclitaxel. ABCB1 should therefore be considered as a therapeutic target in ovarian cancer.

The X-linked transcription factor FOXP3 is expressed by epithelial cells of organs including the breast, where it is considered a tumour suppressor. The chemokine receptor CXCR4 also regulates the development of breast cancer by stimulating cell migration towards CXCL12-expressing sites of metastatic spread. During activation, human T cells show reciprocal regulation of FOXP3 and CXCR4. This study was designed to examine the role FOXP3 plays in metastatic breast cancer, with a particular focus on its potential to regulate CXCR4. Human breast cancer samples showed significantly decreased FOXP3 protein expression but an increased number of CXCR4 transcripts. In comparison with normal primary breast epithelial cells, FOXP3 was down-regulated at both transcript and protein levels in the breast cancer cell lines MCF-7 and MDA-MB-231. In the invasive MDA-MB-231 cells, the remaining FOXP3 was located predominately within the cytoplasm. Following stable FOXP3 overexpression in MDA-MB-231 cells, significant decreases were observed in the expression of ErbB2/HER2, SKP2, c-MYC, and CXCR4. In contrast, an increase in p21 expression led to inhibition of cell proliferation, with a greater proportion in the G1 phase of the cell cycle suggesting the induction of senescence. Specific knockdown of FOXP3 in normal human breast epithelial cells with siRNA significantly increased ErbB2/HER2, SKP2, c-MYC, and CXCR4, and decreased p21 expression. These cells also showed a significantly increased chemotactic response towards CXCL12, consistent with a role for FOXP3 in the regulation of cell migration. Results from this study are consistent with FOXP3 functioning as an important tumour suppressor in breast cancer. Indeed, the potential functions of FOXP3 in breast epithelium can now be extended to include regulation of CXCR4 expression and response to the pro-metastatic chemokine CXCL12., (Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Background: There remains still no clear answer as to whether or not prophylactic central compartment neck dissection (pCCND) is indicated for the treatment of patients with papillary thyroid cancer., Methods: The published studies, including single cohort, comparative studies and meta-analysis, were critically appraised. Aspects beyond postoperative complications and loco-regional recurrence rates in the analysis, as the impact of pre- and post-ablation thyroglobuline levels, multifocality, bilaterality and additional risk factors for recurrence, were also considered., Results: Thirty studies and five meta-analyses were assessed. The lack of randomized clinical trials on the subject and the heterogeneity of study populations are the main limiting factors to draw clear conclusions, and a comprehensive list of bias sources has been identified. Recent comparative studies and systematic reviews all associate the pCCND with higher proportions of temporary postoperative hypocalcemia but not with significantly higher permanent hypoparathyroidism, recurrent laryngeal nerve injury or permanent vocal cord paralysis. The risk of recurrence appears to be reduced after pCCND, and the number of patients needed to treat to avoid a recurrence is between 20 and 31., Conclusions: It is suggested that routine level 6 prophylactic dissections should be risk-stratified. Larger tumours (T3, T4), patients aged 45 years and older or 15 years and younger, male patients, patients with bilateral or multifocal tumours, and patients with known involved lateral lymph nodes could all be candidates for routine unilateral level 6 dissection. The operation should be limited to surgeons who have the available expertise and experience.

Thyroid incidentalomas are commonly found on cross-sectional imaging of the neck and they are equally likely to be malignant as palpable thyroid nodules. Guidelines on their management are conflicting. Ultrasonography cannot accurately differentiate benign from malignant thyroid nodules and fine needle aspiration biopsy should be used selectively to avoid over-diagnosis and over-treatment. If the clinician follows current guidelines for the investigation of thyroid incidentalomas a proportion of malignant incidentalomas will inevitably be missed. Whether this is clinically important is controversial as it is generally agreed that the natural history of small incidental thyroid cancers is indolent. However a subset may have a more aggressive behaviour and it is not currently possible to predict whether a malignant incidentaloma will progress to clinical disease or remain latent. In this article we review the evidence-base around the current guidelines for investigating thyroid incidentalomas and suggest a practical approach to their management., (Copyright © 2012 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.)

Background: Phaeochromocytoma in pregnancy is a rare and potentially dangerous situation for mother and fetus. This review aimed to assess current mortality rates and how medical and surgical management affect these., Methods: Articles in English published between 2000 and 2011 were obtained from a MEDLINE search. Eligible publications presented women diagnosed with phaeochromocytoma in the antenatal or immediate postnatal period, and reported management and outcomes., Results: A total of 135 reports were identified. After applying inclusion criteria, 77 pregnancies involving 78 fetuses were analysed. Fetal and maternal mortality rates were 17 per cent (13 of 78) and 8 per cent (6 of 77) respectively. Better outcomes were achieved when the diagnosis of phaeochromocytoma was made in the antenatal period than when it was made during labour or immediately postpartum (survival of both mother and fetus(es) in 48 of 56 versus 12 of 21 respectively; P = 0·012). When the diagnosis was made before 23 weeks' gestation, there was no difference in outcomes when phaeochromocytoma surgery was carried out in the second trimester, compared with when it was postponed to the third trimester or after delivery (fetal death 2 of 18 versus 2 of 8 respectively; P = 0·563)., Conclusion: This review, although limited by the rarity of the condition and level of available evidence, demonstrated that survival rates are improved if the diagnosis of phaeochromocytoma can be established antenatally. With diagnosis before 23 weeks' gestation, no definite advantage of proceeding with tumour removal during the second trimester could be demonstrated., (Copyright © 2012 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

Progesterone receptor (PR) expression is measured in breast cancer by immunohistochemistry using N-terminally targeted antibodies and serves as a biomarker for endocrine therapeutic decisions. Extensive PR alternative splicing has been reported which may generate truncated PR variant proteins which are not detected by current breast cancer screening or may alter the function of proteins detected in screening. However, the existence of such truncated PR variants remains controversial. We have characterised PR protein expression in breast cancer cell lines using commercial PR antibodies targeting different epitopes. Truncated PR proteins are detected in reportedly PR negative MDA-MB-231 cells using a C-terminally targeted antibody. Antibody specificity was confirmed by immunoblotting following siRNA knockdown of PR expression. We have further demonstrated that alternatively spliced PR mRNA is present in MDA-MB-231 cells and in reportedly PR-negative breast tumour tissue which could encode the truncated PR proteins detected by the C-terminal antibody. The potential function of PR variant proteins present in MDA-MB-231 cells was also assessed, indicating the ability of these PR variants to bind progesterone, interact with a nuclear PR co-factor and bind DNA. These findings suggest that alternative splicing may generate functional truncated PR variant proteins which are not detected by breast cancer screening using N-terminally targeted antibodies leading to misclassification as PR negative.

Introduction: Surgeon-based ultrasonography (SUS) for parathyroid disease has not been widely adopted by British endocrine surgeons despite reports worldwide of accuracy in parathyroid localisation equivalent or superior to radiology-based ultrasonography (RUS). The aim of this study was to determine whether SUS might benefit parathyroid surgical practice in a British endocrine unit., Methods: Following an audit to establish the accuracy of RUS and technetium sestamibi (MIBI) in 54 patients, the accuracy of parathyroid localisation by SUS and RUS was compared prospectively with operative findings in 65 patients undergoing surgery for primary hyperparathyroidism (pHPT)., Results: The sensitivity of RUS (40%) was below and MIBI (57%) was within the range of published results in the audit phase. The sensitivity (64%), negative predictive value (86%) and accuracy (86%) of SUS were significantly greater than RUS (37%, 77% and 78% respectively). SUS significantly increased the concordance of parathyroid localisation with MIBI (58% versus 32% with RUS)., Conclusions: SUS improves parathyroid localisation in a British endocrine surgical practice. It is a useful adjunct to parathyroid practice, particularly in centres without a dedicated parathyroid radiologist, and enables more patients with pHPT to benefit from minimally invasive surgery.

The induction of an effective immune response requires the activation of CD4+ T lymphocytes by APCs. While DCs have been shown to be pivotal in this process, it is now apparent that optimal CD4+ T-cell activation also requires B-lymphocyte APC function. Along with the acquisition of soluble antigens, it is known that B cells also acquire membrane-tethered antigens. Recent reports have described the relocation of intracellular antigens to the cell surface following immunogenic apoptosis. This study was designed to determine whether B cells can acquire and present such antigens to CD4+ T cells. By targeting the model antigen tetanus toxin C fragment to various cellular locations, we show that antigen-specific B cells acquire intracellular antigens that have relocated to the surface of cells undergoing immunogenic apoptosis. Crucially, we also demonstrate that antigen-specific B cells acquiring relocated antigen from apoptotic targets are capable of efficiently inducing CD4+ T-cell activation. We propose that the acquisition and presentation of intracellular antigens that have relocated to the cell surface during immunogenic apoptosis represents a novel means by which antigen-specific B cells contribute to the generation of immunity., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In breast cancer it is never the primary tumour that is fatal; instead it is the development of metastatic disease which is the major cause of cancer related mortality. There is accumulating evidence that suggests that Cancer Stem Cells (CSC) may play a role in breast cancer development and progression. Breast cancer stem cell populations, including side population cells (SP), have been shown to be primitive stem cell-like populations, being long-lived, self-renewing and highly proliferative. SP cells are identified using dual wavelength flow cytometry combined with Hoechst 33342 dye efflux, this ability is due to expression of one or more members of the ABC transporter family. They have increased resistance to chemotherapeutic agents and apoptotic stimuli and have increased migratory potential above that of the bulk tumour cells making them strong candidates for the metastatic spread of breast cancer. Treatment of nearly all cancers usually involves one first-line agent known to be a substrate of an ABC transporter thereby increasing the risk of developing drug resistant tumours. At present there is no marker available to identify SP cells using immunohistochemistry on breast cancer patient samples. If SP cells do play a role in breast cancer progression/Metastatic Breast Cancer (MBC), combining chemotherapy with ABC inhibitors may be able to destroy both the cells making up the bulk tumour and the cancer stem cell population thus preventing the risk of drug resistant disease, recurrence or metastasis.

Breast cancer is now considered to be a systemic disease from the outset, with no correlation seen between the intensity of local treatment and survival or recurrence. Adjuvant therapy has clearly demonstrated a reduction in local and distant relapse; neoadjuvant therapy is similarly being assessed. It aims to treat occult metastases and decrease tumour bulk. Its use has demonstrated down-staging of the tumour with increased rates of breast-conserving surgery. Though neoadjuvant therapy seems to be associated with an increase in loco-regional recurrence compared to adjuvant therapy, no overall difference in survival has been demonstrated. This paper reviews several trials that compare neoadjuvant to adjuvant therapy, and the controversies around managing the axilla in the neoadjuvant setting.

Introduction: Adrenocortical carcinomas are rare. This case series is reported to give an overview of how adrenocortical carcinoma is currently managed in the UK., Patients and Methods: A retrospective review was made of case notes from patients with adrenocortical carcinomas presenting to the authors (TWJL, RDB, BJH, and DS-C) over the past 10 years in Newcastle, Sheffield and Cardiff., Results: Newcastle treated twelve, Sheffield eleven and Cardiff seven cases. The median follow-up was 25.5 months (range, 1-102 months). All tumours were greater than 5 cm in diameter. The majority presented with symptoms of hormone excess. Adrenalectomy was performed in 83% - this was radical in 30% and followed by excision of recurrence in 13%. Adjuvant mitotane was given in 64% of patients, in combination with cytotoxic chemotherapy in 20%. One-third of patients did not receive any adjuvant therapy. There was no significant difference in survival between the three centres. The majority of patients (57%) died during the period of follow-up of this study. The median survival was 37 months (range, 2-102 months)., Conclusions: The size of tumour, stage and mode of presentation, age and overall survival of patients in this study are comparable to published series of adrenocortical carcinomas from major endocrine surgical centres world-wide. Despite controversies about benefits, adjuvant mitotane was used in the majority of cases, whereas cytotoxic chemotherapy was only used in the minority. The exact role of adjuvant therapy in the management of adrenocortical carcinoma is not as well established as for other more common malignancies. Establishing a database for adrenocortical carcinomas in the UK would contribute to our understanding of the management of this disease.

Introduction: Safe and effective haemostasis in surgery is clearly essential, and in the neck where risks of airway compromise are also present any new technology that purports to offer advantages must be rigorously evaluated. We describe our experience with the use of the Harmonic Scalpel [Ethicon UK] in thyroidectomy., Patients and Methods: A retrospective clinical review of 183 patients undergoing hemi or total thyroidectomies from 12 months prior to using the harmonic scalpel (2003; n = 77) and 12 months 'beyond the learning curve' (2006; n = 106)., Results: The results demonstrate that, once past the learning curve, the use of the harmonic scalpel during thyroidectomy significantly reduces operative time and postoperative hypocalcaemia, and is as safe as conventional surgery with regard to voice change and bleeding., Conclusions: The harmonic scalpel is as safe as conventional methods of haemostasis and operations using this technique are quicker once the need to have repetitive 'clip, cut and tie' routines is avoided.

Estrogens are critical mediators of breast tumorigenesis. This occurs via the action of estrogens on the estrogen receptor (ER), which regulates the transcriptome of breast cancer cells. Despite the long history of the search for estrogen-regulated genes in breast cancer, knowledge of the E2-regulated transcriptome and its effects is incomplete. We used Affymetrix GeneChips to profile the effects of estradiol on the expression of genes in EFF-3, EFM-19 and MCF-7 cells. In addition to many well-characterized estrogen-regulated genes, this identified a novel group of genes that have roles in vesicle trafficking, including exocytosis. Recent evidence in the literature supports a role for vesicle trafficking in tumorigenesis. We focused on five genes (SYTL5, RAB27B, SNX24, GALNT4 and SLC12A2/NKCC1/BSC2) and confirmed their estrogen-regulation using quantitative real-time PCR (qPCR). qPCR also demonstrated that these five genes were expressed in invasive breast carcinoma tissue. Immunohistochemistry showed expression of SYTL5 in cells of normal breast ductal epithelium, ductal carcinoma in-situ (DCIS) and invasive breast carcinoma. The results suggest that a significant effect of estrogens is to regulate the expression of genes that affect diverse aspects of vesicle trafficking including exocytosis.

Voice complications following thyroid and parathyroid procedures have long been recognized in the literature. However, there is little clear data on the nature, severity, and duration of any changes. No single previous study has comprehensively addressed the multiple issues involved. Most studies have been retrospective, preventing control over extraneous variables, or are small prospective studies using limited assessment measures. Emphasis has been on damage (paralysis) to the recurrent laryngeal nerve (RLN). The effects of surgery on the more subtle (but equally important) aspects of voice disorders have received little attention. This prospective study of 67 participants used multidimensional voice outcomes measures to assess changes in voice following thyroid and parathyroid surgery. Strict exclusion criteria minimized the effects of extraneous variables. Participants were assessed preoperatively to establish a baseline and at least twice more postoperatively. Generally speaking, the patient vocal performance and expert perceptual rating data suggest an incidence of 0% for all operation types. Mild changes at the early postoperative stages had settled in all cases by the 3-month postoperative assessment. Videostroboscopic evaluation revealed an interesting picture of six patients who appeared to have improved vocal function postsurgery, 15 patients who showed signs of neurological damage at their first postoperative examination, and only five "permanent" RLN paralyses at 12 months postsurgery. The potential for improvement in voice quality postsurgery has not previously been reported in the literature as far as we are aware. Symptoms consistent with RLN and superior laryngeal nerve palsy were present both pre- and postoperatively. Apparent nerve damage did not necessarily result in dysphonia. The potential for undiagnosed nerve damage preoperatively has rarely been reported in the literature. These results may have medico-legal implications, in addition to influencing surgical risk management and informed patient consent.

Aims: Structured multicentre efforts are needed if the prognosis of adrenocortical carcinoma (ACC) is to be improved. Data collection may be enhanced through standardised histopathological reporting using criteria such as the recently published Royal College of Pathologists' (UK) minimum dataset (MDS). This study aimed to perform a clinicopathological review of the adult patients treated at the Royal Victoria Infirmary, Newcastle upon Tyne, in the 10 years preceding the MDS., Methods: Case records were examined for all patients diagnosed with ACC between 1996 and 2006. Pathology was reviewed and compared with the Royal College of Pathologists' MDS along with the original reports. A systematic evaluation of Ki-67 immunolabelling was also performed., Results: Eleven patients with ACC were diagnosed and treated. Histopathological reporting according to the MDS identified more features of malignancy than in the original reports (8.5+/-1.2 versus 5.1+/-0.8, p<0.02). The median number of microscopic criteria of malignancy was 7 (range 5-10), with > or =5 features occurring in all cases. The most commonly observed features of malignancy were diffuse architecture, <25% clear cells, confluent necrosis, abnormal mitoses and mitotic count > or =6 per 50 high-power fields. Capsular invasion and > or =8 MDS criteria of malignancy were associated with a worse outcome (each p<0.01). Median Ki-67 index was 19.0% (range 3.7-44.1%) and was not apparently related to survival., Conclusions: Standardised criteria for histopathological reporting of ACC will improve the accuracy of data for cancer registration and may also assist in individual patient stratification. An elevated Ki-67 index is a feature of ACC, although it does not appear to predict individual patient survival.

Progesterone receptor status is a marker for hormone responsiveness and disease prognosis in breast cancer. Progesterone receptor negative tumours have generally been shown to have a poorer prognosis than progesterone receptor positive tumours. The observed loss of progesterone receptor could be through a range of mechanisms, including the generation of alternatively spliced progesterone receptor variants that are not detectable by current screening methods. Many progesterone receptor mRNA variants have been described with deletions of various whole, multiple or partial exons that encode differing protein functional domains. These variants may alter the progestin responsiveness of a tissue and contribute to the abnormal growth associated with breast cancer. Absence of specific functional domains from these spliced variants may also make them undetectable or indistinguishable from full length progesterone receptor by conventional antibodies. A comprehensive investigation into the expression profile and activity of progesterone receptor spliced variants in breast cancer is required to advance our understanding of tumour hormone receptor status. This, in turn, may aid the development of new biomarkers of disease prognosis and improve adjuvant treatment decisions.

Expression of the chemokine receptor CXCR4 allows breast cancer cells to migrate towards specific metastatic target sites which constitutively express CXCL12. In this study, we determined whether this interaction could be disrupted using short-chain length heparin oligosaccharides. Radioligand competition binding assays were performed using a range of heparin oligosaccharides to compete with polymeric heparin or heparan sulphate binding to I(125) CXCL12. Heparin dodecasaccharides were found to be the minimal chain length required to efficiently bind CXCL12 (71% inhibition; P<0.001). These oligosaccharides also significantly inhibited CXCL12-induced migration of CXCR4-expressing LMD MDA-MB 231 breast cancer cells. In addition, heparin dodecasaccharides were found to have less anticoagulant activity than either a smaller quantity of polymeric heparin or a similar amount of the low molecular weight heparin pharmaceutical product, Tinzaparin. When given subcutaneously in a SCID mouse model of human breast cancer, heparin dodecasaccharides had no effect on the number of lung metastases, but did however inhibit (P<0.05) tumour growth (lesion area) compared to control groups. In contrast, polymeric heparin significantly inhibited both the number (P<0.001) and area of metastases, suggesting a differing mechanism for the action of polymeric and heparin-derived oligosaccharides in the inhibition of tumour growth and metastases.

Primary squamous cell carcinoma is an extremely rare tumour of the thyroid gland. A case of an elderly lady who was diagnosed to have primary squamous cell carcinoma of the thyroid gland is presented and the role of radiotherapy is discussed.

Introduction: The rule of "tens" is often stated to reflect the distribution and histology of pheochromocytomas, with 10% being bilateral, 10%; ectopic in origin, and 10%; malignant. The objective of this study was to review the ectopic pheochromocytomas in a tertiary endocrine center and to establish whether the rule of tens holds true., Methods: Retrospective data were collected on all adrenalectomies and ectopic pheochromocytoma resections performed between 1993 and 2005 at our institution., Results: In total, 77 patients had pheochromocytomas: 75%; (58/77) adrenal and 25%; (19/77) ectopic. Of the adrenal pheochromocytomas, 10%; (6/58) were bilateral. The anatomic locations of the ectopic pheochromocytomas were as follows: 26%; (5/19) adjacent to the adrenals, 53%; (10/19) in the organ of Zuckerkandl, 11%; (2/19) in the bladder, 5%; (1/19) in the mediastinum, and 5%;(1/19) in the neck., Conclusions: Our series demonstrates an incidence of 10%; for bilateral pheochromocytoma, which is similar to that in the published reports. However, 25%; of the pheochromocytomas were ectopic. Zuckerkandl pheochromocytomas were the most common among the ectopic lesions. Rarely, these tumors present outside the abdominal cavity.

Purpose: The pattern of breast cancer metastasis may be determined by interactions between CXCR4 on breast cancer cells and CXCL12 within normal tissues. Glycosaminoglycans bind chemokines for presentation to responsive cells. This study was designed to test the hypothesis that soluble heparinoid glycosaminoglycan molecules can disrupt the normal response to CXCL12, thereby reducing the metastasis of CXCR4-expressing cancer cells., Experimental Design: Inhibition of the response of CXCR4-expressing Chinese hamster ovary cells to CXCL12 was assessed by measurement of calcium flux and chemotaxis. Radioligand binding was also assessed to quantify the potential of soluble heparinoids to prevent specific receptor ligation. The human breast cancer cell line MDA-MB-231 and a range of sublines were assessed for their sensitivity to heparinoid-mediated inhibition of chemotaxis. A model of hematogenous breast cancer metastasis was established, and the potential of clinically relevant doses of heparinoids to inhibit CXCL12 presentation and metastatic disease was assessed., Results: Unfractionated heparin and the low-molecular-weight heparin tinzaparin inhibited receptor ligation and the response of CXCR4-expressing Chinese hamster ovary cells and human breast cancer cell lines to CXCL12. Heparin also removed CXCL12 from its normal site of expression on the surface of parenchymal cells in the murine lung. Both heparin and two clinically relevant dose regimens of tinzaparin reduced hematogenous metastatic spread of human breast cancer cells to the lung in a murine model., Conclusions: Clinically relevant concentrations of tinzaparin inhibit the interaction between CXCL12 and CXCR4 and may be useful to prevent chemokine-driven breast cancer metastasis.

Objectives: Minichromosome maintenance protein 2 (Mcm-2) is essential for DNA replication and serves as a useful biomarker of cell-cycle state in human tissue samples. Ki-67 is an established proliferation marker. Because Mcm-2 expression has not previously been assessed in thyroid tissue, the aim of this study was to assess the expression of both proteins in a range of thyroid lesions to determine their potential value as preoperative markers of thyroid malignancy., Methods: Mcm-2 and Ki-67 protein expression were assessed by immunohistochemistry in formalin-fixed, paraffin-embedded thyroid tissues from 128 patients with histologic diagnoses of papillary carcinoma (n = 38), follicular carcinoma (n = 22), follicular adenoma (n = 33), and dominant nodules of multinodular goitre (n = 35)., Results: Mcm-2 and Ki-67-labeling indices (LIs) were both higher in follicular and papillary carcinomas than in follicular adenomas or dominant nodules. The Ki-67 LI discriminated better between follicular carcinomas and follicular adenomas (P < .0001) than Mcm-2 (P = .0273). However, the Mcm-2 and Ki-67 LIs overlapped widely between the four histologic groups, and the expression of these proteins was also noted to be heterogenous within these lesions., Conclusion: Neither Mcm-2 or Ki-67 can currently be reliably applied as preoperative markers to distinguish benign from malignant thyroid lesions.

Objective: Phaeochromocytoma crisis is a life-threatening emergency that may be undiagnosed because of its numerous, nonspecific manifestations. We analysed, retrospectively, the presentation, management and outcome of patients who were admitted to our institution with phaeochromocytoma crises over a 5-year period., Results: Five patients (two males, three females; mean age 34.6 years, range 19-51 years) who presented as emergencies requiring intensive care, with multiple non-specific manifestations and previously undiagnosed pheochromocytoma, were identified. The initial presentation included features of cardiomyopathy (n = 3), atypical pneumonia with myocarditis (n = 1) and acute abdomen (n = 1). Only one of the five cases had a raised blood pressure at the time of the acute presentation. Initiation of beta blockers in four patients was associated with further deterioration in haemodynamic status, labile blood pressure and cardiac arrhythmias, which led to the diagnosis of the underlying phaeochromocytoma. Following intensive supportive therapy and alpha blockade, all five patients recovered and underwent elective surgical removal of phaeochromocytoma, uneventfully., Conclusion: Unexplained cardiopulmonary dysfunction, particularly after the institution of beta blockers, should alert clinicians to the possibility of phaeochromocytoma. A high index of suspicion is essential to reduce morbidity and mortality in these patients through early diagnosis and aggressive management.

Aims: Our thyroid cytology audit results of 1990-1995 showed an unsatisfactory rate of 43.1% and prediction of neoplasia with a sensitivity of 86.8%. Increasingly, ultrasound scan (USS)-guided core sampling for cytology is proving a valuable tool instead of freehand fine needle aspiration (FNA) or following unsatisfactory freehand FNA. We present the results of freehand FNA and USS-guided core samples for cytology in two separate patient groups in our centre., Methods: Patients who had a thyroid resection and preoperative thyroid cytology in our institution between 1996 and 2002 were included. The histological diagnoses were correlated with the preceding cytology results., Results: A total of 450 FNAs were performed on 394 patients. Freehand FNAs were performed for 348 (77.3%) samples and USS-guided core for 102 (22.7%) samples; 121 (26.8%) were repeat aspirates performed on 45 patients. Using aspiration cytology (AC) grading, freehand FNA was cytologically inadequate (AC0 or AC1) in 34.8% cases whereas USS-guided core was inadequate in 17.6% cases (P = 0.001). Freehand FNA (AC3, AC4, AC5) predicted neoplasia with a sensitivity of 83.2%, specificity of 46.6%, accuracy of 63.0%, positive predictive value of 56.0% and negative predictive value of 77.1%. USS-guided core sample for cytology (AC3, AC4, AC5) predicted neoplasia with a sensitivity of 93.5%, specificity of 26.0%, accuracy of 51.9%, positive predictive value of 43.9% and negative predictive value of 86.7%., Conclusions: Although USS-guided core provides more satisfactory specimens than freehand FNA, in our centre it does not provide increased accuracy.

Osteoclasts are derived from haematopoietic stem cell precursors of the monocyte/macrophage cell lineage, through interaction with factors that are believed to include M-CSF and RANKL. VEGF is a proangiogenic cytokine that has been shown to promote osteoclast differentiation and survival. In this study, we assessed the role of VEGF and its receptors in osteoclastogenesis, in vitro, by culturing osteoclast precursors in the presence of VEGF, VEGF receptor-specific ligands, and blocking antibodies to VEGF receptors. Activation of VEGFR1 in the presence of RANKL induces osteoclast differentiation. Stimulating the receptors individually induced increased resorption by osteoclasts compared to controls but not to the level observed when stimulating both receptors simultaneously. We have shown that VEGF induces osteoclast differentiation through its action on VEGFR1. The way in which VEGF mediates its effect on mature osteoclast activity, however, may be through its interaction with both receptor subtypes.

Vascular endothelial growth factor (VEGF) is a proangiogenic cytokine that is expressed highly in many solid tumours often correlating with a poor prognosis. In this study, we investigated the expression of VEGF and its receptors in bone metastases from primary human breast tumours and further characterised its effects on osteoclasts in vitro. Breast cancer metastases to bone were immunohistochemically stained for VEGF, its receptors VEGFR1 and 2 (vascular endothelial growth factor receptor 1 and 2), demonstrating that breast cancer metastases express VEGF strongly and that surrounding osteoclasts express both VEGFR1 and VEGFR2. RAW 264.7 cells (mouse monocyte cell line) and human peripheral blood mononuclear cells (PBMCs) were cultured with VEGF, RANKL and M-CSF. VEGF and RANKL together induced differentiation of multinucleated, tartrate-resistant acid phophatase (TRAP)-positive cells in similar numbers to M-CSF and RANKL. The PBMCs were also able to significantly stimulate resorption of mineralised matrix after treatment with M-CSF with RANKL and VEGF with RANKL. We have shown that VEGF in the presence of RANKL supports PBMC differentiation into osteoclast-like cells, able to resorb substrate. Vascular endothelial growth factor may therefore play a role in physiological bone resorption and in pathological situations. Consequently, VEGF signalling may be a therapeutic target for osteoclast inhibition in conditions such as tumour osteolysis.

Background and Aim: Freehand fine needle aspiration cytology (FNAC) is an obligatory investigation of the thyroid nodule. Between 5.0-43.1% of FNAC samples are reported as being initially unsatisfactory. In our unit, thyroid freehand FNAs are performed with a small needle (21 or 23G). Non-dominant nodules as part of multinodular goitres, difficult to palpate nodules or nodules with previously unsatisfactory freehand FNACs are sampled under ultrasound scan (USS) guidance with the larger 20G cutting core sampling technique. We aimed to compare the satisfactory sampling rate and safety of the two different methods., Patients and Methods: Cytology forms were reviewed for 262 freehand FNACs and USS-guided core samples, performed in our unit over a two-year interval (1 July 1999 to 30 June 2001)., Results: Ultrasound-guided core samples for cytology were unsatisfactory (AC0-1) in 19/121 (15.6%) of the cases, compared with 66/141 (46.8%) of freehand FNACs (p value = < 0.0001). Ten out of eleven patients (91%) had a satisfactory USS-guided core after an unsatisfactory freehand FNA; 7/15 patients (46.7%) had satisfactory repeat freehand FNACs following an initial unsatisfactory freehand FNAC (p value = 0.0191). There were no complications as a result of either freehand FNAC or USS-guided core sampling., Conclusion: USS-guided cores provided more satisfactory samples for assessment than freehand FNACs. The USS-guided technique is safe despite the use of the larger cuffing needle. The USS-guided core sampling was also a useful tool for repeat thyroid nodule sampling after an unsatisfactory freehand FNAC.

Metastasis is the major cause of mortality and morbidity for patients with cancer. The high-mobility group protein 1(Y) [HMG-1(Y)] has a role in the transcription of many genes involved at different steps in the metastatic cascade and has been linked with cancer in human and animal models. This may represent a potential therapeutic target for patients. The following review summarizes and critically appraises the evidence for the role of HMG-1(Y) in metastasis., ((c) 2004 Wiley-Liss, Inc.)

Aims: To determine whether galectin-3 is a sensitive indicator of thyroid malignancy. It has been suggested as a potential marker for differentiating thyroid carcinoma from benign or non-neoplastic lesions in preoperative fine-needle aspirates (FNAs)., Methods: Galectin-3 protein expression was assessed by immunohistochemistry in formalin-fixed thyroid tissues from 124 patients with histological diagnoses of papillary carcinoma (n = 38), follicular carcinoma (n = 19), follicular adenoma (n = 32) and dominant nodules of multinodular goitre (n = 35). Expression of galectin-3 was also assessed by Western blotting in 24 fresh thyroid tissues., Results: Galectin-3 expression was observed in the majority of carcinomas (papillary 92%; follicular 74%). However, a large proportion of follicular adenomas (72%) and multinodular goitres (57%) also expressed galectin-3. In addition, galectin-3 expression was observed in epithelial cells of normal thyroid tissue and Hashimoto's thyroiditis. Galectin-3 immunopositivity was significantly greater in papillary carcinomas than in dominant nodules or follicular adenomas (P < 0.0001, P = 0.0005, respectively). However, galectin-3 expression was no greater in follicular carcinomas than in follicular adenomas (P = 0.8735). Western blotting analysis confirmed both the specificity of the antiserum and expression of galectin-3 in multinodular goitres, follicular adenomas/carcinomas and papillary carcinomas., Conclusion: The data demonstrate that galectin-3 is not a reliable immunohistochemical marker to distinguish benign from malignant thyroid follicular lesions.

Epidemiological studies suggest that precursor steroids are implicated in the aetiology of breast cancer. However, our understanding of the role of precursor steroids in breast cancer is complicated by fact that there are many precursor steroids, which are metabolically inter-related and have divergent proliferative activities on the growth of breast cancer cell lines. In this study the proliferative affects of 5 alpha-dihydrotestosterone and 5-androstene-3 beta,17 beta-diol, which may be considered true metabolites acting at a tissue level, on MCF7, T47D and MDAMB231 breast cancer cell lines have been examined by a flow cytometric technique. DNA cell cycle analysis demonstrates that 5-androstene-3 beta,17 beta-diol stimulates the proliferation of hormone-dependent cell lines at physiological levels by an oestrogen receptor mediated mechanism whereas 5 alpha-dihydrotestosterone does not affect the proliferation of MCF7 and T47D cell lines at physiological levels over short (48 h) incubations. Both 5 alpha-dihydrotestosterone and 5-androstene-3 beta,17 beta-diol stimulate proliferation of hormone-dependent cell lines at pharmacological levels via and interaction with the oestrogen receptor. In long (6-9 days) incubations both 5 alpha-dihydrotestosterone and 5-androstene-3 beta,17 beta-diol inhibit the 17 beta-oestradiol induced proliferation of MCF7 and T47D cell lines, however, 5 alpha-dihydrotestosterone inhibits while 5-androstene-3 beta,17 beta-diol stimulates basal proliferation. These cell line studies suggest a model for the role of precursor steroids in pre- and postmenopausal breast cancer.

Breast cancer is an example of a solid tumour which is well treated in the early stages of disease by surgical excision, but once metastatic spread has occurred, medical therapies (chemotherapy and radiotherapy) are highly toxic, expensive and palliative. It is known that certain tumours exhibit specific patterns of metastasis, chemokines may provide a molecular answer to this mystery. Chemokines and their receptors play important roles in the various stages of tumour development and metastasis. Chemokines interact with their specific receptors as well as interacting with the glycosaminoglycan (GAG) component of proteoglycan. We discuss the basic metastatic process and the involvement of chemokines in breast cancer biology. Finally, we summarize potential therapeutic applications of chemokines and chemokine/glycosaminoglycan interactions including chemokine agonists, antagonists, anti-sense therapy, immunotherapy and soluble GAGs, as well as future perspectives in this field.

Several studies have found elevated levels of adrenal androgens in postmenopausal women and depressed levels in premenopausal women with breast cancer, suggesting a role for adrenal androgens in the aetiology of breast cancer. We have measured serum dehydroepiandrosterone sulphate and androstenedione in 81 women with primary operable breast cancer and 62 age-matched controls. Results showed that serum levels of both adrenal androgens fell significantly with age in women with breast cancer (P=0.003). However, no relationship was observed between serum adrenal androgen levels and body mass index in either women with breast cancer or controls. Dehydroepiandrosterone sulphate levels were elevated in postmenopausal women with breast cancer compared to controls, and this was not due to preoperative stress. No differences were observed in androstenedione levels between premenopausal or postmenopausal women with breast cancer and controls, nor were dehydroepiandrostenedione sulphate levels significantly different between premenopausal women with breast cancer and controls. These results suggest that dehydroepiandrosterone sulphate has a role in the aetiology of postmenopausal breast cancer.

We have evaluated tumour characteristics, local recurrence rates and prognostic markers in 40 women with symptomatic palpable breast cancer proven by cytology, but in whom routine two-view mammography failed to detect a radiological abnormality. False negative mammograms were identified by cross-referencing all negative mammograms performed at the Royal Victoria Infirmary during the period 1995-1999, with pathological records at the same institution. The average age was 48 years. The majority of the tumours were invasive ductal carcinomas, 35 with an average size of 24 mm. There were 16 Grade II and 15 Grade III tumours. Lymphovascular invasion was seen in 18 on histology and six patients had distant metastases. Of those patients treated by conservation therapy there has been only one local recurrence, with a median follow-up of 18 months. We conclude that mammographically invisible tumours are of common histological type, are frequently high grade and node positive and occur mainly in the younger age group. However, BCT remains a viable option in the treatment of these tumours.

Aims: To review our institution's practice of treatment of a mammographically detected population of ductal carcinoma in situ (DCIS) patients and to determine the outcome., Methods: Between April 1989 and March 1994, 304 women with median age 59 years (range 51-65) with DCIS detected on screening mammogram, were treated in the Newcastle General and Royal Victoria Infirmary Hospitals, Newcastle-upon-Tyne, UK. More than half of the women (n=176, 57.8%) decided to have mastectomy. Other treatment options were wide local excision (WLE) with radiotherapy (n=97, 32%) and WLE alone (n=31, 10.2%). All except five received adjuvant hormone treatment., Results: Predominant DCIS was comedo in 122 (42%), followed by cribriform in 87 (30%) and micropapillary in 44 (15%) cases. Grade I was found to be commonest grade (54%) followed by grade II (27%) and grade III (11%). With a median follow-up of 88 months, there were six (2%) recurrences, all of which were in women who were given breast conservation treatment, WLE with radiotherapy (n=1, 1%) and without radiotherapy (n=5, 16.6%). Mastectomy in this series was not associated with any recurrence at all. In three cases the recurrence was invasive, one of who also had distant metastasis., Conclusions: The findings of this study suggest that in women with DCIS suitable for breast conservation, WLE when combined with radiotherapy is associated with a very low recurrence rate., (Copyright Harcourt Publishers Limited.)

Most general surgeons will face at sometime in their career an 'incidentaloma' of the adrenal gland. How should a surgeon approach an incidentaloma found during routine investigation for other unrelated disease processes? This paper discusses the investigation and management of adrenal incidentalomas and includes guidelines for the non-specialist.

Plants are of relevance to dermatology for both their adverse and beneficial effects on skin and skin disorders respectively. Virtually all cultures worldwide have relied historically, or continue to rely on medicinal plants for primary health care. Approximately one-third of all traditional medicines are for treatment of wounds or skin disorders, compared to only 1-3% of modern drugs. The use of such medicinal plant extracts for the treatment of skin disorders arguably has been based largely on historical/anecdotal evidence, since there has been relatively little data available in the scientific literature, particularly with regard to the efficacy of plant extracts in controlled clinical trials. In this article therefore, adverse and beneficial aspects of medicinal plants relating to skin and skin disorders have been reviewed, based on recently available information from the peer-reviewed scientific literature. Beneficial aspects of medicinal plants on skin include: healing of wounds and burn injuries (especially Aloe vera); antifungal, antiviral, antibacterial and acaricidal activity against skin infections such as acne, herpes and scabies (especially tea tree (Melaleuca alternifolia) oil); activity against inflammatory/immune disorders affecting skin (e.g. psoriasis); and anti-tumour promoting activity against skin cancer (identified using chemically-induced two-stage carcinogenesis in mice). Adverse effects of plants on skin reviewed include: irritant contact dermatitis caused mechanically (spines, irritant hairs) or by irritant chemicals in plant sap (especially members of the Ranunculaceae, Euphorbiaceae and Compositae plant families); phytophotodermatitis resulting from skin contamination by plants containing furocoumarins, and subsequent exposure to UV light (notably members of the Umbelliferae and Rutaceae plant families); and immediate (type I) or delayed hypersensitivity contact reactions mediated by the immune system in individuals sensitized to plants or plant products (e.g. peanut allergy, poison ivy (Toxicodendron) poisoning).

A 31-year-old woman presented with neutropenia due to thionamide drug therapy for Graves' disease. She also reported 8 weeks of amenorrhoea and had a positive pregnancy test. Her drug therapy was discontinued and her neutropenia resolved uneventfully. The hyperthyroidism recurred a week later. After consideration of all treatment options, it was decided to observe until 14 weeks when an elective thyroidectomy was planned. Mother and fetus were monitored closely and both tolerated moderate hyperthyroidism well. At 14 weeks the patient underwent a total thyroidectomy after rendering her euthyroid with a short course of sodium ipodate. Labour was induced at 41 weeks. Delivery was complicated by fetal distress and precipitated a forceps delivery. A 3250 g male infant was born with poor Apgar score and required 2 h of ventilation. At 1 year, the child had reached all developmental milestones at appropriate times. Both mother and fetus may tolerate moderate thyrotoxicosis well in early pregnancy, an alternative that should be considered when thionamide drug therapy is contraindicated.

Various active compounds (or their semi-synthetic derivatives) derived from medicinal plants have been assessed for their efficacy and tolerability in the treatment of breast cancer. Some of these plant species, including Taxus baccata (paclitaxel, docetaxel), Podophyllum peltatum (etoposide), Camptotheca acuminata (camptothecin) and Vinca rosea (vinblastine, vinorelbine) have well recognized antitumour activity in breast cancer, and have been evaluated in clinical trials. For example, results from recent Phase II/III trials have established docetaxel as the most active single agent in the treatment (first or second-line) of advanced metastatic breast cancer. For other plant species such as Panax ginseng and Allium sativum, antitumour activity has been evaluated in experimental studies using cultured cells and animal models, but the therapeutic potential in patients remains to be determined. Antitumour activity derived from medicinal plants may produce results via a number of mechanisms, including effects on cytoskeletal proteins which play a key role in mitosis (paclitaxel), inhibition of activity of topoisomerase enzymes I (camptothecin) or II (etoposide), stimulation of the immune system (Viscum album), or antiprotease-antioxidant activity. Medicinal plant-derived antineoplastic agents may be used in single agent or in combinational therapies, and have been used in first-line or second-line (including anthracycline-refractory patients) treatment of localized or metastatic breast cancer. Adverse effects resulting from the use of these agents include neutropenia and peripheral neuropathies.

Background: Fine needle aspiration cytology (FNAC) is a well-established technique for pre-operative investigation of thyroid nodule(s). Thyroid FNAC was introduced in the teaching hospitals of Newcastle upon Tyne in 1981, initially with a small group of clinicians as aspirators. Audit results for 1981-1986 inclusive showed an unsatisfactory rate of 25.3% and prediction of malignancy with a sensitivity of 93.5%. FNAC has become more popular locally for the investigation of thyroid disease and the number of clinicians performing aspirates has increased. The results for recent years have, therefore, been audited., Methods: Medical records were reviewed for 239 patients with a dominant thyroid nodule who had FNAC carried out in the 6 year period 1990-1995 and subsequent partial or complete thyroidectomy., Results: Histology of thyroid specimens showed 60 follicular adenomas and 34 malignant lesions (including 19 papillary, 10 follicular and 3 medullary carcinomas, one lymphoma and one follicular neoplasm with indeterminate malignant potential). A total of 302 FNAC had been carried out on these 239 patients. On cytological grounds the unsatisfactory sample (AC0 and AC1) rate was 43.1% on initial aspiration which was reduced to 32.2% on repeated aspiration. FNAC predicted neoplasia (AC3, AC4 and AC5) with a sensitivity of 86.8%, a specificity of 67.0%, a negative predictive value of 87.5% and a positive predictive value of 65.5%. Malignancy was predicted by FNAC (AC3, AC4 and AC5) with a sensitivity of 88.9%. A FNAC report of AC5 had a positive predictive value for malignancy of 100%., Conclusions: FNAC is an invaluable and minimally invasive procedure for the pre-operative assessment of patients with a dominant thyroid nodule. It is, however, important that the number of aspirators and cytopathologists be kept small to maintain expertise and also that the results of FNAC be subjected to ongoing audit.

Transforming growth factor-beta (TGF-beta) is secreted by cells in high molecular weight, latent forms and the in vivo mechanisms for the activation remain largely an enigma. Women who have palpable breast cyst with intracystic Na/K < 3 may have a higher risk of developing breast cancer than those with intracystic Na/K > 3. Finding of significantly higher concentrations of TGF-beta 2 in the Na/K > 3 group than Na/K < 3 group may explain the lower risk of breast cancer in the Na/K > 3 group. The aim of the present study was to characterise the latent forms of TGF-beta 2 in breast cyst fluid using HPLC, affinity chromatography, SDS-PAGE and immunostaining techniques. We found that TGF-beta 2 is present in high molecular weight, latent forms in breast cyst fluid: as a complex, probably with alpha 2-macroglobulin and a 56 kD protein which is likely to be a precursor form of TGF-beta 2.

Objective: Mutations at codons 12, 13 or 61 of ras which result in constitutive activation occur frequently in human malignancies. There have been varied reports on their prevalence and hence their likely significance in the pathogenesis of primary thyroid neoplasia. To address this, we have examined a large series of benign and malignant thyroid tumours for ras mutations., Design: Genomic DNA was analysed for the presence of mutations at codons 12, 13 and 61 of H-ras, K-ras and N-ras by allele-specific oligonucleotide hybridization. Direct DNA sequencing was used to confirm the mutations., Patients: A total of 90 samples with benign (66) and malignant (24) thyroid disease were investigated., Results: A total of 14/90 (15.5%) samples had a ras mutation. All mutations were at codon 61 of either N-ras or K-ras. The positive cases were 1/25 (4%) nodular goitre, 7/38 (18%) follicular adenoma, 4/9 (44%) follicular carcinoma, 1/1 anaplastic carcinoma, 1/1 follicular variant of papillary carcinoma, and 1 metastatic follicular carcinoma in which the primary tumour had the same mutation., Conclusions: Our data demonstrate a relatively low overall prevalence of ras mutations in thyroid neoplasia, with a predominance in follicular neoplasms. Their presence in follicular adenomas suggests that they may have an early aetiological role in the development of thyroid neoplasia.