Highlights of the 78th Annual Meeting American Thyroid ... - Thyrolink

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8 Thyroid International 2 2008Clinical SymposiaCurrent Thyroid Nodule EvaluationErik Alexander, Boston, MA, described the apparentlyincreasing prevalence of thyroid nodules, whether itwas found in older people or even in postmortemstudies. The ‘more we look the more we find’. He posedthe question “What proportion are cancerous?” Whileimproved detection would account for a major part ofthe increase, 8–15 % had nodules > 1.0 cm. He pointedout that persons aged < 30 years carried a higher riskof malignancy (15–30 %), while those aged 30–60years had a lower risk (8–15 %). The risk in subjectsaged >60 years was uncertain. He concurred with theuse of a nodule size < 1.0 cm being used as a cutoffindicating minimum risk. Susan Mandel, Philadelphia,PA, addressed the question “When to biopsy a nodule?When not?” The criteria might be nodule size, sonographiccharacteristics, and clinical history. She repeatedthe 1.0 cm nodule size cutoff described by Alexanderbut noted the interobserver variability of 20 % perultrasound measurement and 50 % by volume reportedand its implications for reporting a 1 cm nodule versusa true 1 cm nodule. There is frequently a disconnectionbetween pathology and clinical significance. She outlinedthe sonographic feature of thyroid malignancybut cautioned that ultrasound is not adequately sensitivebut can be highly predictive.Bryan Haugen, Aurora, CO, discussed molecular profilingof thyroid carcinomas. He categorized molecularmarkers as those involved in diagnosis, tumor progression,therapeutic targets and pathogenesis. One of themajor diagnostic problems remains the separation offollicular adenoma from follicular carcinoma. This andother important distinctions will require the identificationof the differential expression of a protein betweentumor and normal tissue. To date, no single marker wasadequately sensitive and specific using immunochemicaltechniques. Finally, he outlined various techniquesof genomics and proteomics which will assist in identifyingsuitable tumor markers.Abbott State of the Art LectureCraig Thompson, Philadelphia, PA, talking about“Programmed Cell Death as a Means to Enhance CancerTreatment” described the regulation of angiogenesisand how the cell has the ability to maintain itself independentlyof nutrients and growth factors. In a normalcell, significant loss of nutrient transporters results inbioenergetic decline. Oncogenic stress with decreasedATP:ADP ratio is a major factor in apoptosis. Signalingpathways instruct cells to take up glucose, which,in turn, must be converted to lactate and excreted.Both mutations and local environmental conditionspromote increased glucose uptake by thyroid cancercells. Other factors, such as inflammation and loss ofP53 suppressor, have been implicated particularly inapoptosis. These features have stimulated efforts tofind targeted drugs to replace 131 I in the treatment ofthyroid cancer.Genetics of Thyroid CancerActivation of MAP kinase pathways occurs in manycancers. Mingzhao Xing, Baltimore, MD, described howactivating BRAF mutations constitutively phosphorylateMEK1 and 2, which, in turn, phosphorylate andactivate ERK1 and 2, which then alter the activity ofmany nuclear proteins involved in proliferation. TheT1799A point mutation is by far the most common ofthe many BRAF mutations found in papillary thyroidcancer, but BRAF mutations are not found in follicularcancer. Although some regional and ethnic differencesexist, papillary cancers containing BRAF mutations aregenerally associated with a higher risk of extrathyroidalspread, metastases, and tumor recurrence. Papillarycancers with BRAF mutations are also associated withoverexpression of VEGF, metalloproteases, NF-κB andc-Met.Antonio Di Cristofano, Philadelphia, PA, discussed therole of PTEN, which dephosphorylates phosphatidylinositol-3-phosphates, thus deactivating phosphatidylinositol3OH-kinase (PI3K) and preventing it fromphosphorylating and activating AKT. Loss of PTEN
American Thyroid Association – Highlights of the 78 th Annual Meeting9heterozygosity or mutations in PTEN do occur in somethyroid cancers, but overexpression of PI3K is morecommon. When PTEN was selectively knocked out inthe mouse thyroid, the animals were born with goitersthat displayed increased levels of PI3K, p-AKT, andthe proliferation marker, Ki67. The TSH level in themice, however, remained normal. With increasing age,the thyroids of female mice developed adenomas orlocally-invasive follicular carcinomas, but the thyroidsof males showed no such pathology. If the animals weretreated with an mTOR inhibitor starting at four weeksof age, their thyroid weights fell, as did Ki67 and cyclinD1/D3 protein levels, although there were no changesin the mRNA levels. The marked increase in proliferationat 12 weeks in the females could be stopped byremoving their ovaries, while, on the other hand, givingestrogen to males increased thyrocyte proliferation.If these PTEN thyroid knock-out mice were crossbredwith a K-ras mutant mouse, the animals developed hugethyroids and died of anaplastic thyroid cancer withina few months.Matthew Ringel, Columbus, OH, reviewed the role ofAKT in thyroid tumorigenesis and progression. TheAKT family of protein kinases transmits signals frommany pathways to a wide variety of proteins, includingmany that regulate cell survival and apoptosis. Thepleckstrin homology domain of AKT lets it bind tophosphatidyl-myo-inositol-3-phosphates (PIP3s) in theplasma membrane. Thus, when growth factor tyrosinekinase receptors activate PI3K, the PIP3s formed inthe membrane bind AKT. Another kinase, PDK1, thenactivates AKT, allowing it to phosphorylate many targetproteins. Normally, the rise in AKT activity is transient:as the signal from a tyrosine kinase receptor decreases,PTEN dephosphorylates PIP3s, thus reducing PI3Kactivity, while protein phosphatases dephosphorylateAKT, inactivating it. However, AKT1 and 2 protein levelsare commonly increased in follicular thyroid cancer,which in some cases could reflect activating mutationsand/or increased gene copy number of PI3K. IncreasedAKT activity is associated with increased tumor size andinvasiveness in many papillary and follicular thyroidcancers. Conversely, inhibitors of PI3K and AKT inhibitthe growth of many thyroid cancer cell lines. Ringelalso reviewed studies showing that the invasive edgeof papillary cancers show higher levels of markersof epithelial–mesenchymal transition than the centralarea of the tumors.Communications: Thyroid CancerJoshua Klopper, Denver, CO, whose group had previouslyshowed that the RXR-selective ligand, bexarotene,inhibits proliferation in human thyroid cancer cell linesthat express the RXR gamma receptor, presented datasuggesting that bexarotene acts indirectly by causingthe cells to secrete the cytokine LIF (leukemia inhibitoryfactor). When these cells were grown in nude mice,the plasma contained substantial levels of human LIFprotein. Tumors that lacked the RXR gamma receptorproduced no human LIF, suggesting that LIF might bea plasma marker for bexarotene-responsive thyroidcancers.Jeffrey Knauf, New York, NY, described how a singlebase mutation in the BRAF gene produces the V600Emutant found in over 40 % of papillary and 20 % ofanaplastic thyroid cancers, which is associated with aworse prognosis. They bred mice that express the V600Emutation selectively in the thyroid. At 5 weeks, theTSH in these mice rose transiently, and then fell as themice developed goiters, then cancers. They microdissectedpoorly- and well-differentiated papillary cancerswithin the same animal, and compared the patternsof gene expression. Poorly-differentiated cancers hadmuch less e-cadherin and desmocollin 2 but increasedexpression of procollagen and vimentin – all hallmarksof epithelial–mesenchymal transition. TGFβ wasincreased in the thyroids of the BRAF mutant mice, andPDGF-B or -D was increased in 8 out of 8 foci of poorlydifferentiated cancer, suggesting that an autocrine loopbetween TGFb and PDGF is involved in the epithelial–mesenchymal transition.Targeted Therapies in Thyroid Cancer:Current Updates and ChallengesModerators:Martin Schlumberger and Manisha ShahManisha Shah, Columbus, OH, reported on currenttrends of targeted molecular therapies in DTC. She
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