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ABSTRACT: In addition to its acute effects on hormone secretion, epithelial transport and shape change, the calcium-sensing receptor (CaSR) modulates the expression of genes that control cell survival, proliferation and differentiation, as well as the synthesis of peptide hormones and enzymes. In the present study, we investigated the impacts of a CaSR agonist and several CaSR modulators on phosphorylation of transcription factor CREB residue S133 in CaSR-expressing HEK-293 cells (HEK-CaSR) cells and human adenomatous parathyroid cells. Elevated Ca(2+)o concentration had no effect on CREB phosphorylation (p-CREB) in control HEK-293 cells but stimulated p-CREB in both HEK-CaSR cells and human parathyroid cells. In addition, p-CREB was stimulated by the positive modulator cinacalcet and inhibited by the negative modulator NPS 2143 in both CaSR-expressing cell types. Two positive modulators that bind in the receptor's Venus FlyTrap (VFT) domain, L-phenylalanine (L-Phe) and S-methylglutathione (SMG) had no effect on p-CREB in HEK-CaSR cells demonstrating the existence of pronounced signalling bias. Analysis of the signaling pathways using specific inhibitors demonstrated that PI-PLC and conventional protein kinase C (PKC) isoforms make major contributions to Ca(2+)o-induced p-CREB in both cell-types, suggesting key roles for Gq/11. In addition, in parathyroid cells but not HEK-CaSR cells, activation of p-CREB was dependent on Gi/o, demonstrating the existence of cell-type specific signalling.
AJP Endocrinology and Metabolism 03/2013; · 4.75 Impact Factor
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ABSTRACT: INTRODUCTION: Lymph node metastases represent a diagnostic and management challenge in patients with disseminated medullary thyroid carcinoma (MTC). Our understanding of microRNA (miRNA) profiles of metastatic disease also remains limited and may unveil novel therapeutic strategies for these patients. METHODS: MTC patients with a history of total thyroidectomy and lymph node dissection were identified from within the prospective Sydney University Endocrine Surgical Unit database. Patients with available formalin-fixed paraffin-embedded tumour tissue were included and clinicopathological data were collated. Total RNA was extracted and quantitave polymerase chain reaction (qPCR) analysis performed on the primary tumour and a corresponding lymph node metastasis for expression of miRNAs of proven significance in MTC (miR-9*, miR-183 and miR-375). RESULTS: Tissue was available for analysis in seven patients. The median age at diagnosis was 55 years (range: 22-67). Median tumour size was 18 mm (range: 6-55) and over a median follow-up period of 34 months (range: 1-210), five further operations were undertaken for residual disease. One patient died of metastatic disease. Pairwise correlations of qPCR expression levels between primary tumours and corresponding lymph node metastases revealed significant correlations for miR-9* (P < 0.001), miR-183 (P = 0.001) and miR-375 (P = 0.004). CONCLUSION: miRNA expression patterns in nodal metastases significantly reflect those of the primary tumour in MTC. This further validates previously reported miRNA profile analyses and reiterates the potential significance of miR-9*, -183 and -375 in the pathophysiology of MTC. The possibility of lymph node biopsy miRNA analysis driven clinical decision making may now also be a possibility where conventional techniques are unhelpful.
ANZ Journal of Surgery 10/2012; · 1.25 Impact Factor
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Martyn Bullock,
Christine O'Neill,
Angela Chou,
Adele Clarkson,
Tristian Dodds,
Christopher Toon,
Mark Sywak, Leigh Delbridge,
Bruce G Robinson,
Diana Learoyd,
David Capper,
Andreas von Deimling,
Roderick Clifton-Bligh,
Anthony Gill
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ABSTRACT: Identification of BRAFV600E in thyroid neoplasia may be useful because it is specific for malignancy, connotes a worse prognosis and is the target of novel therapies currently under investigation. Sanger sequencing is the 'gold-standard' for mutation detection but is subject to sampling error and requires resources beyond many diagnostic pathology laboratories. In this study, we compared immunohistochemistry using a BRAFV600E mutation-specific monoclonal antibody to Sanger sequencing on DNA from formalin fixed paraffin embedded tissue, in a well characterised cohort of 101 PTC patients. For all cases an IHC result was available, however five cases failed Sanger sequencing. Of the 96 cases with molecular data, 68 (71%) were BRAFV600E positive by IHC and 59 (61%) were BRAFV600E positive by sequencing. Eleven cases were discordant. One case was negative by IHC and initially positive by sequencing. Repeat sequencing of that sample and sequencing of a macrodissected sample were negative for BRAFV600E. Of 10 cases positive by IHC but negative by sequencing on whole sections, repeat sequencing on macrodissected tissue confirmed the IHC result in 7 cases (suggesting these were false negatives of sequencing on whole sections). In 3 cases repeat sequencing on recut tissue remained negative (including using massive parallel sequencing), but these cases demonstrated relatively low neoplastic cellularity. We conclude that immunohistochemistry for BRAFV600E is more sensitive and specific than Sanger sequencing in the routine diagnostic setting and may represent the new gold standard for detection of BRAFV600E mutation in PTC.
Endocrine Related Cancer 09/2012; · 4.36 Impact Factor
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Martyn Bullock,
Emma L Duncan,
Christine O'Neill,
Lyndal Tacon,
Mark Sywak,
Stan Sidhu, Leigh Delbridge,
Diana Learoyd,
Bruce G Robinson,
Marian Ludgate,
Roderick J Clifton-Bligh
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ABSTRACT: Context: Polyalanine tract variations in transcription factors have been identified for a wide spectrum of developmental disorders. The thyroid transcription factor forkhead factor E1 (FOXE1) contains a polymorphic polyalanine tract with 12-22 alanines. Single-nucleotide polymorphisms (SNP) close to this locus are associated with papillary thyroid cancer (PTC), and a strong linkage disequilibrium block extends across this region. Objective: The objective of the study was to assess whether the FOXE1 polyalanine repeat region was associated with PTC and to assess the effect of polyalanine repeat region variants on protein expression, DNA binding, and transcriptional function on FOXE1-responsive promoters. Design: This was a case-control study. Setting: The study was conducted at a tertiary referral hospital. Patients and Methods: The FOXE1 polyalanine repeat region and tag SNP were genotyped in 70 PTC, with a replication in a further 92 PTC, and compared with genotypes in 5767 healthy controls (including 5667 samples from the Wellcome Trust Case Control Consortium). In vitro studies were performed to examine the protein expression, DNA binding, and transcriptional function for FOXE1 variants of different polyalanine tract lengths. Results: All the genotyped SNP were in tight linkage disequilibrium, including the FOXE1 polyalanine repeat region. We confirmed the strong association of rs1867277 with PTC (overall P = 1 × 10(-7), odds ratio 1.84, confidence interval 1.31-2.57). rs1867277 was in tight linkage disequilibrium with the FOXE1 polyalanine repeat region (r(2) = 0.95). FOXE1(16Ala) was associated with PTC with an odds ratio of 2.23 (confidence interval 1.42-3.50; P = 0.0005). Functional studies in vitro showed that FOXE1(16Ala) was transcriptionally impaired compared with FOXE1(14Ala), which was not due to differences in protein expression or DNA binding. Conclusions: We have confirmed the previous association of FOXE1 with PTC. Our data suggest that the coding polyalanine expansion in FOXE1 may be responsible for the observed association between FOXE1 and PTC.
The Journal of clinical endocrinology and metabolism 06/2012; 97(9):E1814-9. · 6.50 Impact Factor
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Aleksandra Popadich,
Olga Levin,
James C Lee,
Stephanie Smooke-Praw,
Kevin Ro,
Maisam Fazel,
Asit Arora,
Neil S Tolley,
Fausto Palazzo,
Diana L Learoyd,
Stan Sidhu, Leigh Delbridge,
Mark Sywak,
Michael W Yeh
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ABSTRACT: The role of routine central lymph node dissection (CLND) for papillary thyroid cancer (PTC) remains controversial. The aim of this study was to evaluate the impact of routine CLND after total thyroidectomy (TTx) in the management of patients with PTC who were clinically node negative at presentation with emphasis on stimulated thyroglobulin (Tg) levels and reoperation rates.
This retrospective, multicenter, cohort study used pooled data from 3 international Endocrine Surgery units in Australia, the United States, and England. All study participants had PTC >1 cm without preoperative evidence of lymph node disease (cN0). Group A patients had TTx alone and group B had TTx with the addition of CLND.
There were 606 patients included in the study. Group A had 347 patients and group B 259 patients. Stimulated Tg values were lower in group B before initial radioiodine ablation (15.0 vs 6.6 ng/mL; P = .025). There was a trend toward a lower Tg at final follow-up in group B (1.9 vs 7.2 ng/mL; P = .11). The rate of reoperation in the central compartment was lower in group B (1.5 vs 6.1%; P = .004). The number of CLND procedures required to prevent 1 central compartment reoperation was calculated at 20.
The addition of routine CLND in cN0 papillary thyroid carcinoma is associated with lower postoperative Tg levels and reduces the need for reoperation in the central compartment.
Surgery 12/2011; 150(6):1048-57. · 3.10 Impact Factor
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ABSTRACT: While the molecular basis of hereditary medullary thyroid cancer (HMTC) has been well defined, little is known about the molecular pathogenesis of sporadic medullary thyroid cancer (SMTC). In addition, microRNAs (miRNAs) have been shown to be important diagnostic and prognostic markers in cancer but have not been defined in MTC. Our aim was to study the miRNA profile of MTC to identify prognostic biomarkers and potential therapeutic targets.
MiRNA microarray profiling was carried out in fresh frozen tissues from patients with SMTC (n = 12) and HMTC (n = 7). Differential expression of three miRNAs was confirmed in a validation cohort of SMTC and HMTC samples (n = 45) using quantitative reverse transcriptase-PCR and correlated with clinical outcomes. The functional role of a selected miRNA was investigated in vitro in the human medullary thyroid carcinoma cell line (TT cells) using cell proliferation assays and Western blotting analysis.
MiRs-183 and 375 were overexpressed (P = 0.001; 0.031) and miR-9* was under-expressed (P = 0.011) in SMTC versus HMTC. Overexpression of miRs-183 and 375 in MTC predicted lateral lymph node metastases (P < 0.001; P = 0.001) and was associated with residual disease (P = 0.001; 0.003), distant metastases (P = 0.003; 0.001), and mortality (P = 0.01; 0.011). Knock down of miR-183 expression in the TT cell line induced a significant decrease in the viable cell count and upregulation of the protein LC3B, which is associated with autophagy.
Our data indicate that miRNAs play a pivotal role in the biology of MTC and represent an important class of prognostic biomarkers and therapeutic targets warranting further investigation.
Clinical Cancer Research 05/2011; 17(14):4772-81. · 7.74 Impact Factor
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ABSTRACT: Papillary thyroid cancer (PTC) has an impressive propensity for lymphatic spread. Signal transducers and activators of transcription 3 (STAT3), constitutively activated in many different cancers, may play a role in PTC lymphatic metastases. We examined 49 patients with PTC, 22 with and 27 without lymphatic metastases. All patients had a total thyroidectomy with lymph node dissection to document true node negative cases. The level of STAT3 expression in benign, non-neoplastic thyroid tissue is barely detectable by immunohistochemistry. Only 11 of the 35 (31%) specimens exhibited weak immunostainingfor STAT3 and pSTAT3 was found weakly positive in 3 of 35 (9%) benign specimens. Expression of STAT3 in all PTC primary tumors was 98% (40/41) and thus significantly higher than corresponding benign thyroid tissue (p=0.0001). pSTAT3 was found in 37% of primary tumors (15/41) and this was significantly higher than pSTAT3 expression in benign tissue (p=0.006). Comparing node-positive and node-negative primary tumors, there was no difference in staining intensity for STAT3 where strong (2+) staining was seen 12/19 node-positive tumors and 13/22 node-negative tumors (p=1). Regarding pSTAT3 expression in primary PTC tumors, node negative cases (n=22) exhibited significantly less staining compared to node positive cases (n=19). Only 4 of 22 (18%) cases in the node-negative group were weakly (1+) positive for pSTAT3 while 12 of 19 (58%) cases in the node-positive group were positive (p=0.011) with 45% of these specimens exhibiting strong (2+) staining. Lymphatic metastases were highly positive (>93%) for both STAT3 and pSTAT3. The STAT3 pathway is ubiquitous in PTC and activated pSTAT3 is significantly upregulated in PTC tumors with metastatic disease. This study is the first to suggest a potential role for activated pSTAT3 in lymphatic metastases in thyroid cancer.
International journal of clinical and experimental pathology 04/2011; 4(4):356-62. · 1.89 Impact Factor
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ABSTRACT: Parathyroid carcinoma has been regarded as an exceedingly rare disease worldwide, responsible for less than 1% of cases of primary hyperparathyroidism. However, there have been anecdotal reports recently of an increasing number of patients presenting with parathyroid carcinoma. The aim of this study was to examine the changing incidence and presentation of parathyroid cancer within a single centre.
This is a retrospective case series. Data were obtained from the University of Sydney Endocrine Surgical Unit database, as well as a review of hospital records. All pathology was independently reviewed.
Over the 52-year period of the study from 1958 to 2010, there were 21 cases of confirmed parathyroid cancer. Only three cases were reported in the first 30 years of the study with the majority of cases (n = 11) presenting in the last 5 years. Despite the exponential increase in presentations, no significant differences in demographics or mode of presentation were found.
Possible reasons for the dramatic increase in parathyroid cancer include increased screening, an increase in referrals for parathyroid surgery overall associated with the availability of minimally invasive techniques, changes in diagnostic techniques with immunohistochemistry for parafibromin and protein gene product 9.5 (PGP9.5) or possibly a true increase in the incidence of the disease.
ANZ Journal of Surgery 12/2010; 81(7-8):528-32. · 1.25 Impact Factor
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ABSTRACT: γ-Glutamyl peptides were identified previously as novel positive allosteric modulators of Ca(2+)(o)-dependent intracellular Ca(2+) mobilization in HEK-293 cells that bind in the calcium-sensing receptor VFT domain. In the current study, we investigated whether γ-glutamyl-tripeptides including γ-Glu-Cys-Gly (glutathione) and its analogs S-methylglutathione and S-propylglutathione, or dipeptides including γ-Glu-Ala and γ-Glu-Cys are positive allosteric modulators of Ca(2+)(o)-dependent Ca(2+)(i) mobilization and PTH secretion from normal human parathyroid cells as well as Ca(2+)(o)-dependent suppression of intracellular cAMP levels in calcium-sensing receptor (CaR)-expressing HEK-293 cells. In addition, we compared the effects of the potent γ-glutamyl peptide S-methylglutathione, and the amino acid L-Phe on HEK-293 cells that stably expressed either the wild-type CaR or the double mutant T145A/S170T, which exhibits selectively impaired responses to L-amino acids. We find that γ-glutamyl peptides are potent positive allosteric modulators of the CaR that promote Ca(2+)(o)-dependent Ca(2+)(i) mobilization, suppress intracellular cAMP levels and inhibit PTH secretion from normal human parathyroid cells. Furthermore, we find that the double mutant T145A/S170T exhibits markedly impaired Ca(2+)(i) mobilization and cAMP suppression responses to S-methylglutathione as well as L-Phe indicating that γ-glutamyl peptides and L-amino acids activate the CaR via a common mechanism.
Journal of Biological Chemistry 12/2010; 286(11):8786-97. · 4.77 Impact Factor
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ABSTRACT: Carcinoembryonic antigen (CEA) is a tumour marker commonly associated with gastrointestinal malignancy. Patients presenting with an elevated CEA will therefore often undergo extensive investigations in order to elucidate an underlying gastrointestinal malignancy that may not be clinically apparent. However the GI tract is not the only source of CEA elevation.
We present a series of patients presenting with raised CEA levels that were initially investigated for a gastrointestinal cause, but after work up were detected to have medullary thyroid cancer.
Four patients with raised CEA were evaluated for a gastrointestinal cause for the elevation. We discuss the non gastrointestinal causes for an elevated CEA.
The paper highlights that in patients presenting with an elevated CEA, in whom a gastrointestinal cause has been ruled out, a tumour of neuroendocrine origin needs to be considered as a cause for the elevated CEA.
ANZ Journal of Surgery 11/2010; 80(11):831-3. · 1.25 Impact Factor
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ABSTRACT: Thyroid nodules occupy a unique position in relation to clinical diagnosis since most patients with a thyroid nodule do not present with overt symptoms. There are, however, no good published data demonstrating the way in which clinically solitary thyroid nodules come to medical attention, with most of the literature being anecdotal. This study aims to evaluate the mode of presentation of solitary thyroid nodules, and to assess whether the presence of a malignancy influences that presentation.
In this retrospective cohort study, data were obtained from the University of Sydney Endocrine Surgery Database and through a review of the patient records. The study cohort comprised 419 consecutive patients who presented with a clinically solitary thyroid nodule and who subsequently underwent surgery. Patient files lacking data on mode of presentation and patients in whom thyroid nodules were incidentally discovered during parathyroid surgery were excluded, leaving a total of 299 patients. Data were analyzed using a computer-based statistical software package. Continuous variables were compared using Student's t-test. Categorical variables were analyzed using Fishers exact test. Statistical significance was set at p < 0.05.
Solitary thyroid nodules are most commonly detected by the patients themselves (40%), followed by the incidental discovery of nodules on imaging studies performed for unrelated reasons (30%), and lastly due to third-party diagnosis by family, friends, acquaintances, or medical practitioners (30%). Nodules detected by medical practitioners were statistically more likely to be malignant (p = 0.02). No other differences between the clinical presentation of benign and malignant nodules were found.
Patients themselves are the ones who most commonly first become aware of the thyroid nodules that are eventually seen by thyroid surgeons. Incidental discovery on image studies is also important. Thyroid nodules detected by medical practitioners should be dealt with most urgently because they are most likely to be malignant.
Thyroid: official journal of the American Thyroid Association 10/2010; 21(1):55-9. · 2.60 Impact Factor
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ABSTRACT: Advanced vessel sealing devices provide an alternative to conventional ligation techniques for thyroidectomy. To date, most studies have been inadequately powered to explore differences in the infrequent post-operative complications following thyroidectomy. This study is designed to compare the outcomes of sutureless thyroidectomy and conventional thyroidectomy for recurrent laryngeal nerve (RLN) injury, permanent hypoparathyroidism, and haematoma formation.
A cohort study of consecutive patients undergoing total thyroidectomy using conventional versus sutureless techniques was performed. Sutureless thyroidectomy was performed using either Ligasure Precise (Covidien) or Harmonic Focus (Johnson and Johnson) devices. The primary outcome measures were post-operative haemorrhage, permanent RLN injury and hypoparathyroidism. Secondary outcome measures were operative time, temporary hypoparathyroidism and vocal cord dysfunction. A cost minimization analysis comparing the two techniques was performed.
From January 2006 to July 2009, 1935 consecutive patients underwent total thyroidectomy. Of these, 772 underwent conventional thyroidectomy and 1163 were performed using a sutureless technique. The mean operative time was significantly lower in the sutureless group (71 versus 86 min, P = 0.02). There was no difference in the post-operative complications of haematoma (0.78% conventional versus 1.12% sutureless, P = 0.46), permanent hypoparathyroidism (1.30% conventional versus 0.52% sutureless, P = 0.06) or permanent RLN injury (0.26% conventional versus 0.52% sutureless, P = 0.39). There was an overall cost saving of AUD$14,300 per 100 total thyroidectomy cases performed using the sutureless technique.
Sutureless thyroidectomy is a safe and efficient way of performing total thyroidectomy and has the potential to reduce operating room costs.
ANZ Journal of Surgery 09/2010; 81(7-8):510-4. · 1.25 Impact Factor
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Deepak T Abraham,
Tsu-Hui Low,
Marinella Messina,
Nicole Jackson,
Anthony Gill,
Angela S Chou, Leigh Delbridge,
Diana Learoyd,
Bruce G Robinson,
Stan Sidhu,
Mark Sywak
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ABSTRACT: Medullary thyroid carcinoma (MTC) accounts for 5 to 10% of all thyroid cancers but is responsible for a disproportionate number of deaths.
We performed a retrospective review to describe clinical outcomes in patients with medullary thyroid carcinoma, screening a subset of patients for somatic mutations in the RET and p18 genes and performing genotype-phenotype correlation in a tertiary-care referral hospital from 1967 to 2009.
We studied a total of 94 patients identified from a prospectively maintained thyroid cancer database. Data gathered included patient demographics, serum calcitonin, clinical outcomes, histopathology, genetic analysis, and status at final follow-up. A subset cohort (n = 50) was screened for somatic mutations in the RET gene and the three exons of the p18 gene. The subset cohort was composed of hereditary medullary thyroid carcinoma (HMTC) (n = 19, index patients = 10, screen detected = 9) and sporadic medullary thyroid carcinoma (SMTC) (n = 31). There were no mutations in the p18 gene in the subset cohort.
A total of 67 SMTC and 27 (28.7%) HMTC cases identified. SMTC were older at initial presentation (52 vs. 34, P = 0.003), had higher preoperative serum calcitonin levels (7968 vs. 1346 ng/L, P = 0.008), and had lymph node recurrence (P = 0.001) compared to HMTC. The tumors were smaller in HMTC (P = 0.038). Overall 10-year survival in SMTC versus HMTC was 69 versus 93% (P = 0.12). On multivariate analysis, vascular invasion (hazard ratio 6.4, P = 0.019) was an adverse predictor for disease-free survival. HMTC in the era of RET analysis presents with a smaller primary tumor, lower preoperative serum calcitonin levels, and lower rates of lymph node metastasis. Mutations in the p18 gene were not a major factor in medullary thyroid carcinoma tumorigenesis.
Annals of Surgical Oncology 09/2010; 18(1):219-25. · 4.17 Impact Factor
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ABSTRACT: Focused parathyroidectomy (FP) is offered to 60% to 70% of patients presenting to our unit with primary hyperparathyroidism (PHPT). A recent report identified bilateral internal jugular venous sampling (BIJVS) as a useful tool for localization of parathyroid adenomas in patients with scan-negative PHPT. The purpose of this study was to evaluate the utility of this approach in a clinical setting.
A prospective case-control trial was undertaken. Bilateral internal jugular venous blood samples were obtained. Patients were stratified into three groups: Group A consisted of patients with a negative sestamibi scan undergoing bilateral exploration; group B consisted of patients undergoing FP following a positive sestamibi scan; and group C patients were a control group undergoing total thyroidectomy.
In group A, 17 of 30 patients (56%) had lateralization of the parathyroid hormone (PTH) levels, with 11 correctly lateralizing to the side of the adenoma, 5 lateralizing despite bilateral disease, and 1 lateralizing to the contralateral side. Of the remaining 13 patients in whom there was no lateralization, 3 had bilateral multigland disease, and 10 had a single parathyroid adenoma. In group B, 17 of 30 patients (56%) also had lateralization of PTH levels, with 15 lateralizing to the side of the adenoma and 2 to the contralateral side. Lateralization failed in the remaining 13 patients, although in all of these patients the calcium and PTH levels normalized postoperatively. The control group of patients without parathyroid disease (group C) demonstrated lateralization of PTH levels in 23 of 30 patients (76%).
In our hands, BIJVS for PTH determination was not a useful adjunctive test facilitating FP. We continue to offer all patients with PHPT and a negative sestamibi scan a standard bilateral neck exploration.
World Journal of Surgery 04/2010; 34(6):1299-303. · 2.36 Impact Factor
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ABSTRACT: Of all thyroid nodules assessed by fine needle aspiration cytology (FNAC), 10-20% are classified as indeterminate/atypical. Traditionally, this group is considered to primarily represent follicular neoplasia. We hypothesize that papillary carcinoma accounts for a significant proportion of lesions classified as "atypical" on FNAC.
This retrospective study includes 228 patients who had an atypical FNAC result and who were subsequently found to have a malignancy on histologic examination of the excised thyroid lesion. Patients with papillary microcarcinomas, defined as lesions less than 10-mm diameter, were excluded. The study period was from 1987 to 2005. The patients were divided chronologically into 3 groups (n = 76) for analysis: group 1, December 1987-March 1997; group 2, July 1997-October 2002; and group 3, October 2002-December 2005.
Age- and sex-distribution of the 3 groups were not significantly different. Median nodule size of group 3 was significantly smaller. The distributions of histopathology of the 3 time periods were significantly different overall (P = .0325). Prevalence of papillary carcinoma was not statistically significant (33/76 vs 34/76 vs 46/76; P = .0636), but showed a statistical significant trend to increase over time (P = .0349). Prevalence of follicular variant papillary carcinoma was also found to be significantly different between the groups (7/76 vs 12/76 vs 19/76; P = .0320; P = .0349).
Papillary carcinoma accounted for most histopathologically confirmed cancers that had an atypical cytology. Papillary cancer in this group of patients trended up, probably due to a significant increase in the diagnosis of follicular variant of papillary cancer.
Surgery 03/2010; 148(3):532-7. · 3.10 Impact Factor
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Michael A Hahn,
Viive M Howell,
Anthony J Gill,
Adele Clarkson,
Graham Weaire-Buchanan,
Bruce G Robinson, Leigh Delbridge,
Oliver Gimm,
Wolfgang D Schmitt,
Bin T Teh,
Deborah J Marsh
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ABSTRACT: The tumor suppressor HRPT2/CDC73 is mutated in constitutive DNA from patients with the familial disorder hyperparathyroidism-jaw tumor syndrome and in approximately 70% of all parathyroid carcinomas. In a number of HRPT2 mutant tumors however, expression of the encoded protein parafibromin is lost in the absence of a clear second event such as HRPT2 allelic loss or the presence of a second mutation in this tumor suppressor gene. We sought to determine whether hypermethylation of a 713 bp CpG island extending 648 nucleotides upstream of the HRPT2 translational start site and 65 nucleotides into exon 1 might be a mechanism contributing to the loss of expression of parafibromin in parathyroid tumors. Furthermore, we asked whether mutations might be present in the 5'-untranslated region (5'-UTR) of HRPT2. We investigated a pool of tissue from 3 normal parathyroid glands, as well as 15 individual parathyroid tumor samples including 6 tumors with known HRPT2 mutations, for hypermethylation of the HRPT2 CpG island. Methylation was not identified in any specimens despite complete loss of parafibromin expression in two parathyroid carcinomas with a single detectable HRPT2 mutation and retention of the wild-type HRPT2 allele. Furthermore, no mutations of a likely pathogenic nature were identified in the 5'-UTR of HRPT2. These data strongly suggest that alternative mechanisms such as mutation in HRPT2 intronic regions, additional epigenetic regulation such as histone modifications, or other regulatory inactivation mechanisms such as targeting by microRNAs may play a role in the loss of parafibromin expression.
Endocrine Related Cancer 12/2009; 17(1):273-82. · 4.36 Impact Factor
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ABSTRACT: The enhancement of metaiodobenzylguanidine single photon emission computed tomography (MIBG SPECT) imaging through the addition of CT images fused with SPECT data (coregistered MIBG SPECT/CT imaging) is new technology that allows direct correlation of anatomical and functional information. We hypothesized that MIBG SPECT/CT imaging would provide additional information and improve diagnostic confidence for the radiological localization of a pheochromocytoma, in particular for patients at high risk of multifocal or recurrent disease.
A retrospective study of all patients investigated by MIBG SPECT/CT at our institution from 2006 to 2008 for a suspected pheochromocytoma was performed. Each case was compared with conventional radiological investigations to determine whether MIBG SPECT/CT was able to improve diagnostic confidence and provide additional diagnostic information compared with conventional imaging alone.
Twenty-two patients had MIBG SPECT/CT imaging for a suspected pheochromocytoma. Fourteen patients had positive MIBG SPECT/CT imaging results correlating with imaging by CT or magnetic resonance imaging in all cases. In six cases, MIBG SPECT/CT provided additional information that altered the original radiological diagnosis. Five patients with a pheochromocytoma-associated germline mutation had multifocal disease excluded by MIBG SPECT/CT. Patients without a germline mutation that had positive biochemistry and a solitary lesion with conventional imaging had no diagnostic improvement with MIBG SPECT/CT imaging.
MIBG SPECT/CT fusion imaging is a sensitive and specific radiological imaging tool for patients suspected to have pheochromocytoma. The particular strengths of MIBG SPECT/CT are detection of local recurrence, small extra-adrenal pheochromocytomas, multifocal tumors, or the presence of metastatic disease.
Annals of Surgical Oncology 12/2009; 17(2):392-400. · 4.17 Impact Factor
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ABSTRACT: The Internet is increasingly used as a source of health information by patients. Under these circumstances, the opportunity exists for Internet sites ostensibly providing patient information to act to promote surgical referrals based on exaggerated claims. This study aims to assess quantitatively and qualitatively the Internet-based consumer health information for minimally invasive parathyroidectomy (MIP) techniques.
This is a prospective analysis of Internet web sites. Descriptive information about specific published claims on each of the web sites was documented and compared to the published evidence base. Web sites were then rated using a validated composite score (CS) tool and an MIP score tool developed specifically for the study.
The search yielded 308 web sites, which, after assessment by the inclusion criteria left 44 unique web sites suitable for analysis. "Exaggerated," "misleading," or "false" claims were present in 27.3% of the web sites analyzed. The false claims category had a high negative item-total correlation with the overall score, and accuracy was found to have a statistically significant (p < 0.05) negative correlation with quality. However, analysis performed for country of origin and the organization responsible for the web site found no significant difference.
Web sites offering information in relation to MIP have a surprisingly high rate of claims that are not in accord with the evidence. Such claims may be posted to attract surgical referrals. It is difficult for consumers to differentiate quality consumer health web sites from poor ones as there are no hard and fast rules to differentiate them.
World Journal of Surgery 12/2009; 34(6):1304-11. · 2.36 Impact Factor
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ABSTRACT: Routine central lymph node dissection (CLND) for papillary thyroid cancer (PTC) at the time of initial thyroidectomy has been advocated with a demonstrated decrease in post-ablation serum thyroglobulin compared to total thyroidectomy alone. Patients now present with central compartment metastatic disease after initial thyroid cancer surgery, or with a diagnosis of PTC after diagnostic lobectomy requiring completion thyroidectomy, and an undissected central compartment. Our aim was to compare the clinical outcomes in patients with PTC who underwent CLND as a secondary event with those having initial CLND.
A retrospective cohort study of 193 patients who underwent CLND for PTC between June 2002 and November 2007 was undertaken. Data gathered included patient demographics, number of lymph nodes excised, lymph node involvement, and incidence of postoperative complications.
One-hundred and seventy (M/F: 28/142) patients (Grp A) had a CLND as part of their primary surgical procedure while 23 (M/F: 10/13) patients (Grp B) underwent CLND as a secondary procedure (12 therapeutic/11 prophylactic procedures). The mean number of lymph nodes sampled and the % involved in the 2 groups A and B were 9.2 vs 10.2 and 64% vs 61%, respectively. Similarly, the incidence of temporary hypocalcemia (12% vs 9%), permanent hypoparathyroidism (1.8% vs 0%), temporary recurrent laryngeal nerve (RLN) paresis (3% vs 4%), permanent RLN paresis (0.6% vs 0%), and wound infection (0.6% vs 4.3%) was comparable in groups A and B.
This study demonstrates that there is no additional morbidity when CLND is performed as a secondary procedure for patients with PTC. Secondary CLND should be performed in patients with proven central compartment metastatic disease after previous thyroidectomy and can be offered safely as a prophylactic procedure to patients at high risk for central lymph node metastasis when CLND has not been performed at initial primary operation for PTC.
Surgery 06/2009; 145(5):514-8. · 3.10 Impact Factor
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Leigh Delbridge
ANZ Journal of Surgery 06/2009; 79(5):320-2. · 1.25 Impact Factor
