Correlation of surgeon-performed parathyroid ultrasound with the Perrier classification and gland weight.

BACKGROUND: Ultrasound localisation of parathyroid glands correlates with gland weight. We hypothesise that gland identification is also dependent on anatomical location. Perrier et al. have described a uniform and reliable nomenclature for parathyroid locations. We aimed to correlate surgeon-performed ultrasound (SUS) with intra-operative Perrier classification and gland weight. METHODS: Review of a prospectively maintained single operator SUS database of 194 patients referred with non-familial primary hyperparathyroidism (PHPT) at a tertiary centre between 2010 and 2015. Patients underwent MIBI localisation as well as on table SUS. Intra-operative pathological gland locations were classified according to the Perrier nomenclature. RESULTS: Mean weight of pathological glands found and missed by SUS was 1.07 ± 0.1 g and 0.48 ± 0.08 g respectively (p = 0.0001, unpaired t test). The weight of glands identified was greater than that of missed glands for each of the Perrier locations (p < 0.001, Mann-Whitney). The proportion of pathological glands found at each Perrier location varied significantly (p < 0.0001, Chi Square); so we find proportionally more B-, D-, E- and F-type glands and miss more A- and C-type glands. The median weight of glands missed on SUS varied significantly across the Perrier groups (Kruskal-Wallis, p = 0.0034) and suggests that SUS can miss quite large glands (> 0.5 g) in locations B, C and F; whereas missed glands in locations A, D and E were all small (< 0.5 g). CONCLUSION: Whilst gland identification correlates well with gland weight, anatomical location has a significant impact on failure of localisation irrespective of gland weight. For the surgeon operating on PHPT patients with negative US localisation, particular attention should be paid to locations C, D and A as these are the sites where pathological glands are most often missed on pre-operative US.

Systematic review of phaeochromocytoma in pregnancy.

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.

Primary squamous cell carcinoma of the thyroid gland: a case report and role of radiotherapy.

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.

Ultrasound scan-guided core sampling for diagnosis versus freehand FNAC of the thyroid gland.

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.

Chemokines and breast cancer: a gateway to revolutionary targeted cancer treatments?

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.

The proliferative effects of 5-androstene-3 beta,17 beta-diol and 5 alpha-dihydrotestosterone on cell cycle analysis and cell proliferation in MCF7, T47D and MDAMB231 breast cancer cell lines.

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.

Serum adrenal androgens in women with primary operable breast cancer and their relationship with age and body mass index.

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.

The impact of surgeon-based ultrasonography for parathyroid disease on a British endocrine surgical practice.

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.

Breast cancer, side population cells and ABCG2 expression.

Recurrent metastatic breast cancer may arise in part due to the presence of drug resistant adult stem cells such as Side Population (SP) cells, whose phenotype has been demonstrated to be due to the expression of ABCG2. We hypothesised that SP may be identified in Fine Needle Aspirates (FNAs) and their presence may be determined by expression of ABCG2 in breast tumours. SP and non-side population cells (NSP) were isolated using dual wavelength flow cytometry combined with Hoechst 33342 dye efflux and analysed for expression of ABCG2 and chemoresistance. FNA samples used in SP analysis were matched with paraffin-embedded tissue which was used in immunohistochemical analysis to assess ABCG2 expression. Results were correlated to the pathobiology of the tumour. MCF7 and MDA-MB-231 cell lines contain SP cells. MCF7 SP have increased expression of ABCG2 and increased resistance to mitoxantrone compared to NSP cells. The presence of SP in FNAs were significantly associated with ER-negative (p=0.008) and with triple negative breast cancers (p=0.011) which were also found to have a significant increase in ABCG2 protein expression. ABCG2 transcript was detected in some but not all SP cell populations isolated from FNA samples.

Breast cancer: role of neoadjuvant therapy.

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.

The use of the harmonic scalpel in thyroidectomy: 'beyond the learning curve'.

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.

Voice change following thyroid and parathyroid surgery.

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.

Impact of standardised reporting in adrenocortical carcinoma: a single centre clinicopathological review.

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.

Ectopic pheochromocytoma: does the rule of tens apply?

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.

Modulatory effects of heparin and short-length oligosaccharides of heparin on the metastasis and growth of LMD MDA-MB 231 breast cancer cells in vivo.

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.

Ultrasound guidance improves the adequacy of our preoperative thyroid cytology but not its accuracy.

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.

Phaeochromocytomas presenting as acute crises after beta blockade therapy.

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.

Vascular endothelial growth factor receptors in osteoclast differentiation and function.

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.