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ABSTRACT: Context:Reports of the coexistence of pituitary adenomas and pheochromocytoma/paraganglioma are uncommon. Recently germline mutations in 2 of the genes encoding succinate dehydrogenase, SDHC and SDHD, were associated with pituitary tumors.Objective:Our aim was to determine whether the development of a pituitary adenoma was associated with SDHA mutation.Patients:A 46-year-old female presented with carotid body paraganglioma (proband). Subsequently the proband's son was diagnosed with a nonfunctioning pituitary macroadenoma at age 30 years.Results:An immunohistochemical analysis of the resected paraganglioma and pituitary adenoma revealed the loss of succinate dehydrogenase subunit B and succinate dehydrogenase subunit A (SDHA) expression in both tumors, with the preservation of staining in nonneoplastic tissue. Mutation analysis showed a novel SDHA mutation (c.1873C>T, p.His625Tyr) in the germline of the proband as well as in the proband's son. In the paraganglioma of the proband, in addition to the germline mutation, a somatic mutation was observed (c.1865G>A, p.Trp622*). In the pituitary adenoma of the proband's son, loss of SDHA immunoreactivity was paradoxically accompanied by loss of the mutant allele.Conclusions:This is the first report of a pituitary adenoma arising in the setting of germline SDHA mutation. The loss of SDHA protein expression in both the paraganglioma (proband) and pituitary adenoma (proband's son) argues strongly for a causative role of SDHA mutation. This report further strengthens the link between pituitary neoplasia and germline SDH mutation. Although pituitary adenomas appear rare among patients carrying SDH subunit mutations, they may have been underrecognized due to the low penetrance of disease and lack of systematic surveillance.
The Journal of clinical endocrinology and metabolism 04/2013; · 6.50 Impact Factor
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ABSTRACT: Autophagy is an increasingly well characterised process of cell component auto-digestion and recycling thought necessary for cellular subsistence. As we gain a more thorough understanding of the mechanisms underlying autophagy, its relevance to human disease and therapeutic potential are being clarified. This review summarises the evidence implicating autophagy in the pathogenesis and potential treatment of malignant disease. In addition, we explore the molecular role of microRNAs as key regulators in what we propose should now become known as 'oncophagy'.
Endocrine Related Cancer 10/2012; · 4.36 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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ABSTRACT: Succinate dehydrogenase-deficient gastrointestinal stromal tumors (SDH-deficient GISTs) are a unique class of GIST defined by negative immunohistochemical staining for succinate dehydrogenase B (SDHB). SDH-deficient GISTs show distinctive clinical and pathologic features including absence of KIT and PDGFRA mutations, exclusive gastric location, common lymph node metastasis, a prognosis not predicted by size and mitotic rate, and indolent behavior of metastases. They may be syndromal with some being associated with the Carney Triad or germline SDHA, SDHB, SDHC, or SDHD mutations (Carney-Stratakis syndrome). It is normally recommended that genetic testing for SDHA, SDHB, SDHC, and SDHD be offered whenever an SDH-deficient GIST is encountered. However, testing for all 4 genes is burdensome and beyond the means of most centers. In this study we performed SDHA mutation and immunohistochemical analyses for SDHA on 10 SDH-deficient GISTs. Three showed negative staining for SDHA, and all of these were associated with germline SDHA mutations. In 2 tumors, 3 novel mutations were identified (p.Gln54X, p.Thr267Met, and c.1663+3G>C), none of which have previously been reported in GISTs or other SDH-associated tumors. Seven showed positive staining for SDHA and were not associated with SDHA mutation. In conclusion, 30% of SDH-deficient GISTs in this study were associated with germline SDHA mutation. Negative staining for SDHA can be used to triage formal genetic testing for SDHA when an SDH-deficient GIST is encountered.
The American journal of surgical pathology 10/2012; · 4.06 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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ABSTRACT: BACKGROUND: There are conflicting reports in the literature regarding the prognostic influence of pregnancy on patients with papillary thyroid carcinoma (PTC), and there is no literature on specific microRNA (miRNA) profiles of PTC in the context of pregnancy. We aim to examine clinically if pregnancy is an adverse factor in PTC, and if pregnancy-associated PTC are biologically different from those in nonpregnant women in terms of their miRNA profiles. METHODS: Women diagnosed with PTC during or soon after pregnancy were recruited into the pregnancy group. Age-matched nonpregnant females were recruited into the nonpregnancy group. MiRNA microarray was performed on PTC tissue of pregnant patients (10), nonpregnant patients (10), and normal thyroids (5). There were 6 differentially expressed miRNAs from the microarray comparisons validated with RT-PCR. RESULTS: There were 24 patients in the clinical pregnancy group and 30 in the nonpregnancy group. Tumors from the pregnancy group were significantly larger and showed more regional lymph node metastases. The microarray data showed a total of 27 miRNAs that were potential differentiators of PTC tissue samples from pregnant and nonpregnant patients. Of the 6 selected for validation, no significant difference in expression was found. CONCLUSIONS: Our clinical data suggests that PTC during pregnancy may be more locoregionally aggressive. However, no difference in survival or recurrence is demonstrated. The miRNA profiles of the pregnancy-associated PTC have not been shown to be different to the nonpregnancy counterparts. This likely suggests that the differences seen clinically are related to patient factors rather than the disease itself.
Annals of Surgical Oncology 08/2012; · 4.17 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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ABSTRACT: BACKGROUND: Primary mucoepidermoid carcinoma (MEC) of the thyroid is a rare clinical and pathological entity that accounts for <0.5% of all thyroid malignancies. Although the histogenesis has been controversial, most investigators now favor it as arising from either metaplasia of thyroid follicular epithelium or heterologous de-differentiation from papillary thyroid carcinoma (PTC). We report three cases of thyroid MEC found in continuity with, and clearly arising from de-differentiation of, well-differentiated thyroid carcinomas (WDTCs). PATIENT FINDINGS AND SUMMARY: The cases presented here included two women (aged 22 and 52) and one man (aged 58). One of these cases arose in conjunction with PTC, one with follicular thyroid carcinoma (FTC), and one with Hurthle cell carcinoma (HCC). In all three cases, there was a gradual transition in morphology between the areas of typical WDTC and the areas showing MEC differentiation. In addition, immunohistochemistry demonstrated a gradual loss of thyroid specific markers (thyroid transcription factor-1, thyroglobulin) mirroring the change in morphology. CONCLUSION: We conclude that thyroid MEC can arise from metaplastic de-differentiation of WDTC, including FTC or HCC in addition to PTC. Currently, we recommend that after excision, each of the WDTC and MEC components of these tumors be treated with targeted adjuvant therapies, which may involve radioactive-iodine ablation, thyrotropin suppression, and external beam radiotherapy.
Thyroid: official journal of the American Thyroid Association 02/2012; 22(2):205-9. · 2.60 Impact Factor
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ABSTRACT: MicroRNAs (miRs) are increasingly important diagnostic and prognostic markers in cancer but have not been defined in medullary thyroid carcinoma (MTC). MiR microarray profiling was performed on 19 primary MTC tumors, validated with qPCR in 45 cases and correlated with clinical outcomes. MiRs-183 and 375 were overexpressed and miR-9* underexpressed in sporadic vs. hereditary MTC (SMTC; HMTC). MiR-183 and 375 overexpression predicted lateral nodal metastases, residual disease, distant metastases and mortality. MiR-183 knockdown in an MTC cell line (TT cells) reduced cellular proliferation in association with elevated LC3B expression. This is suggestive of increased autophagic flux and potential cell death via autophagy induction. MiRs may subsequently be shown to serve as efficacious therapeutic strategies in MTC with a mechanism based upon autophagy.
Autophagy 12/2011; 7(12):1553-4. · 7.45 Impact Factor
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Anthony J Gill,
Nicholas S Pachter,
Angela Chou,
Barbara Young,
Adele Clarkson,
Katherine M Tucker,
Ingrid M Winship,
Peter Earls,
Diana E Benn, Bruce G Robinson,
Stewart Fleming,
Roderick J Clifton-Bligh
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ABSTRACT: Germline succinate dehydrogenase B (SDHB) mutation causes pheochromocytoma/paraganglioma syndrome type 4 (PGL4). PGL4 is characterized by pheochromocytoma and paraganglioma, type 2 (SDHB negative) gastrointestinal stromal tumors and renal tumors, which are usually classified as carcinoma. We report 4 kindreds with 5 PGL4-associated renal tumors. Four of the tumors occurred before the age of 30 years, 4 were in the left kidney, 3 were in female patients, and 4 demonstrated consistent but previously unrecognized morphology. The tumors were composed of cuboidal cells with bubbly eosinophilic cytoplasm and indistinct cell borders. Many of the cells displayed distinctive cytoplasmic inclusions, which were vacuolated or contained eosinophilic fluid-like material. The cells were arranged in solid nests or in tubules surrounding central spaces. The tumors were well circumscribed or lobulated and frequently showed cystic change. Benign tubules or glomeruli were often entrapped at the edges of the tumors. The fifth tumor lacked these features but displayed sarcomatoid dedifferentiation. Immunohistochemistry for SDHB was completely negative in all 4 available tumors. Death from metastatic disease occurred in the patient with dedifferentiated tumor 1 year after diagnosis, whereas the other 4 tumors were cured by local excision alone (mean follow-up, 11 y; range, 2 to 30 y). We conclude that morphology supported by negative immunohistochemistry for SDHB can be used to identify kindreds with germline SDHB mutations (PGL4 syndrome) presenting with this unique type of renal tumor. These renal tumors appear to have a good prognosis after complete excision unless there is sarcomatoid dedifferentiation.
The American journal of surgical pathology 09/2011; 35(10):1578-85. · 4.06 Impact Factor
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ABSTRACT: Thyroid cancer typically has a good outcome following standard treatments, which include surgery, radioactive iodine ablation and treatment with TSH-suppressive levothyroxine. Thyroid cancers that persist or recur following these therapies have a poorer prognosis. Activation of mitogenic and angiogenic signaling pathways occurs in these cancers, and preclinical models have shown that inhibition of key kinase steps in these pathways can have antitumoral effects. Several of these kinase inhibitors have now been tested in phase II and phase III trials, with modestly encouraging results. Some promising data exist for the use of vandetanib (also known as ZD6474), motesanib, axitinib, cabozantinib (also known as XL184), sorafenib, sunitinib, pazopanib and lenvatinib (also known as E7080) in progressive thyroid cancer of medullary, papillary and follicular subtypes. These drugs are generally well-tolerated, although dose-limiting toxicities are common, and a few (probable) treatment-related deaths have been reported. Additional phase III trials will be needed to conclusively show that treatment benefit exceeds risk. Drug resistance can occur via activation of alternate mitogenic signals (pathway switching), as has been reported for the use of kinase inhibitors in other malignancies, such as melanoma. The hypothesis that combinations of kinase inhibitors targeting different pathways might produce better results is currently being tested in several clinical trials.
Nature Reviews Endocrinology 08/2011; 7(10):617-24. · 9.97 Impact Factor
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New England Journal of Medicine 03/2011; 364(9):885-6. · 53.30 Impact Factor
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ABSTRACT: Adrenocortical carcinoma (ACC) is a rare but aggressive malignancy with a poor prognosis. Complete surgical resection offers the only potential for cure; however, even after apparently successful excision, local or metastatic recurrence is frequent. Treatment options for advanced ACC are severely limited. Mitotane is the only recognized adrenolytic therapy available; however, response rates are modest and unpredictable whereas systemic toxicities are significant. Reported responses to conventional cytotoxic chemotherapy have also been disappointing, and the rarity of ACC had hampered the ability to undertake randomized clinical studies until the establishment of the First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma. This yet-to-be reported study seeks to identify the most effective first- and second-line cytotoxic regimens. The past decade has also seen increasing research into the molecular pathogenesis of ACCs, with particular interest in the insulin-like growth factor signaling pathway. The widespread development of small molecule tyrosine kinase inhibitors in broader oncological practice is now allowing for the rational selection of targeted therapies to study in ACC. In this review, we discuss the currently available therapeutic options for patients with advanced ACC and detail the molecular rationale behind, and clinical evidence for, novel and emerging therapies.
The Oncologist 01/2011; 16(1):36-48. · 3.91 Impact Factor
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ABSTRACT: The role of the B-isoform of the Raf kinase (BRAF) mutation BRAF(V600E) as an independent prognostic factor in papillary thyroid cancer (PTC) remains controversial. Some studies suggest that tumors containing BRAF(V600E) have decreased radioiodine avidity and present a greater risk of nodal recurrence and distant metastases.
Paraffin-embedded specimens from consecutive patients who underwent surgery for PTC before 2003 were independently reviewed by an endocrine pathologist. DNA was extracted, amplified by polymerase chain reaction, and the presence of the BRAF(V600E) mutation was determined by restriction digest. Tumor characteristics and long-term disease outcomes were analyzed according to BRAF(V600E) status.
BRAF(V600E) was identified in 60 (59%) of 101 patients. At a median follow-up of 106 months, the overall disease-free survival was 78%. Clinically evident nodal recurrence occurred in 11% of BRAF(V600E)-positive patients, and all patients required lateral neck dissection (P = .02). In contrast, subclinical nodal recurrence occurred in 7% of BRAF(V600E)-negative patients, and all recurrences were successfully ablated with radioactive iodine. There was a trend toward poorer disease-free survival among patients with stage III/IV PTC and BRAF(V600E) mutation (P = .08). All 5 disease-related deaths occurred in patients with BRAF(V600E)-positive primary tumors (P = .06).
The BRAF(V600E) mutation in PTC is associated with an increased risk of palpable nodal recurrence and the need for reoperative surgery.
Surgery 12/2010; 148(6):1139-45; discussion 1145-6. · 3.10 Impact Factor
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ABSTRACT: Recent published data has shown that metastatic involvement of the prelaryngeal or Delphian lymph node (DLN), the highest of the central (level VI) cervical lymph nodes, is highly predictive of advanced nodal disease in papillary thyroid cancer (PTC). The aims of this study were to determine the diagnostic accuracy of all the level VI cervical nodes in PTC and to determine which node group, if any, is the most accurate in predicting lateral node (N1b) disease.
This was a retrospective cohort study. Data were obtained from the University of Sydney Endocrine Surgical Unit Database and through a review of the histopathology records. The study cohort was composed of 177 consecutive patients with a final diagnosis of PTC who underwent total thyroidectomy and lymph node dissection, spanning the period from May 2001 to December 2006.
Of the 177 patients with PTC, 86 had the DLN removed, 51 had a pretracheal node removed and 76 had the paratracheal group removed. DLN, paratracheal and pretracheal node disease was present in 21%, 39% and 46%, respectively. Lateral node (N1b) disease was present in 35%. Paratracheal node involvement was mildly predictive of further disease with patients 1.7 times more likely to have lateral node involvement (sensitivity=55%, specificity=68%). Pretracheal node involvement was moderately predictive of further disease with patients three times more likely to have lateral node involvement (sensitivity=72%, specificity=74%). DLN involvement was highly predictive of further node involvement with patients nine times more likely to have lateral node disease (sensitivity=53%, specificity=94%) and 40 times more likely to have any nodal disease (sensitivity=41%, specificity=100%).
This is the first study to examine the diagnostic accuracy of all level VI lymph nodes in PTC. While, metastatic involvement of all central nodal groups is indicative of further disease, the DLN is the most accurate predictor.
ANZ Journal of Surgery 11/2010; 80(11):834-8. · 1.25 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: Background: Recent published data has shown that metastatic involvement of the prelaryngeal or Delphian lymph node (DLN), the highest of the central (level VI) cervical lymph nodes, is highly predictive of advanced nodal disease in papillary thyroid cancer (PTC). The aims of this study were to determine the diagnostic accuracy of all the level VI cervical nodes in PTC and to determine which node group, if any, is the most accurate in predicting lateral node (N1b) disease.Methods: This was a retrospective cohort study. Data were obtained from the University of Sydney Endocrine Surgical Unit Database and through a review of the histopathology records. The study cohort was composed of 177 consecutive patients with a final diagnosis of PTC who underwent total thyroidectomy and lymph node dissection, spanning the period from May 2001 to December 2006.Results: Of the 177 patients with PTC, 86 had the DLN removed, 51 had a pretracheal node removed and 76 had the paratracheal group removed. DLN, paratracheal and pretracheal node disease was present in 21%, 39% and 46%, respectively. Lateral node (N1b) disease was present in 35%. Paratracheal node involvement was mildly predictive of further disease with patients 1.7 times more likely to have lateral node involvement (sensitivity = 55%, specificity = 68%). Pretracheal node involvement was moderately predictive of further disease with patients three times more likely to have lateral node involvement (sensitivity = 72%, specificity = 74%). DLN involvement was highly predictive of further node involvement with patients nine times more likely to have lateral node disease (sensitivity = 53%, specificity = 94%) and 40 times more likely to have any nodal disease (sensitivity = 41%, specificity = 100%).Conclusion: This is the first study to examine the diagnostic accuracy of all level VI lymph nodes in PTC. While, metastatic involvement of all central nodal groups is indicative of further disease, the DLN is the most accurate predictor.
ANZ Journal of Surgery 10/2010; 80(11):834 - 838. · 1.25 Impact Factor
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Goswin Y Meyer-Rochow,
Nicole E Jackson,
John V Conaglen,
Denis E Whittle,
Muthusamy Kunnimalaiyaan,
Herbert Chen,
Gunnar Westin,
Johanna Sandgren,
Peter Stålberg,
Elham Khanafshar,
Daniel Shibru,
Quan-Yang Duh,
Orlo H Clark,
Electron Kebebew,
Anthony J Gill,
Rory Clifton-Bligh, Bruce G Robinson,
Diana E Benn,
Stan B Sidhu
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ABSTRACT: MicroRNAs (miRNAs) are small RNAs ( approximately 22 bp) that post-transcriptionally regulate protein expression and are found to be differentially expressed in a number of human cancers. There is increasing evidence to suggest that miRNAs could be useful in cancer diagnosis, prognosis, and therapy. We performed miRNA microarray expression profiling on a cohort of 12 benign and 12 malignant pheochromocytomas and identified a number of differentially expressed miRNAs. These results were validated in a separate cohort of ten benign and ten malignant samples using real-time quantitative RT-PCR; benign samples had a minimum follow-up of at least 2 years. It was found that IGF2 as well as its intronic miR-483-5p was over-expressed, while miR-15a and miR-16 were under-expressed in malignant tumours compared with benign tumours. These miRNAs were found to be diagnostic and prognostic markers for malignant pheochromocytoma. The functional role of miR-15a and miR-16 was investigated in vitro in the rat PC12 pheochromocytoma cell line, and these miRNAs were found to regulate cell proliferation via their effect on cyclin D1 and apoptosis. These data indicate that miRNAs play a pivotal role in the biology of malignant pheochromocytoma, and represent an important class of diagnostic and prognostic biomarkers and therapeutic targets warranting further investigation.
Endocrine Related Cancer 09/2010; 17(3):835-46. · 4.36 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: Diagnosis of an anaplastic astrocytoma (World Health Organization grade III) is associated with a highly variable prognosis. The identification of clinical markers that allow a more careful delineation of this prognostic spectrum is urgently needed. In this study, we analysed 48 patients with a histological diagnosis of anaplastic astrocytoma and found peritumoral post-gadolinium contrast enhancement to be a clear prognostic marker of poor prognosis. Multivariate analysis also confirmed surgery type, Karnofsky Performance Status score (<70) and increasing age as independent adverse predictors of survival. The survival differences observed in the enhancing and non-enhancing lesions in patients diagnosed with anaplastic astrocytoma supports the existence of a broad anaplastic spectrum of disease, with enhancement being a clinical marker of tumour progression along this spectrum.
Journal of Clinical Neuroscience 08/2010; 17(8):993-6. · 1.25 Impact Factor
