Ronald A Ghossein

Memorial Sloan-Kettering Cancer Center, New York City, New York, United States

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Publications (116)659.69 Total impact

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    ABSTRACT: The prognosis of the encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) and its relationship to encapsulated follicular carcinoma (EFC) and follicular adenoma (FA) is subject to controversy. All EFVPTCs, EFCs, and FAs identified at a single institution between 1981 and 2003 were analyzed microscopically. A cohort of FAs from a different hospital was also examined. EFVPTCs were subdivided into noninvasive EFVPTC (NIEFVPTC) and invasive EFVPTC (IEFVPTC) displaying capsular/vascular invasion. There were 83 EFVPTCs (57 noninvasive, 26 invasive), 14 EFCs, and 52 FAs. Similar to FA, over a median follow-up of 9.5 years, none of the NIEFVPTCs manifested lymph node metastasis (LNM) or recurred. Furthermore, with a median follow-up of 10.5 years, none of 39 NIEFVPTCs without radioactive iodine therapy recurred. Four (15%) of 26 IEFVPTCs and none of 14 EFCs harbored distant metastasis (P = .29). There was no difference in LNM rate and degree of vascular or capsular invasion between IEFVPTC and EFC (P > .1). All 4 IEFVPTCs with adverse behavior presented with distant metastasis and no LNM. Sixteen percent of IEFVPTCs had poor outcome, whereas there was none in the NIEFVPTCs (P = .007). In conclusion, NIEFVPTC seems to behave similarly to FA, whereas IEFVPTC can metastasize and spread like EFC. Thus, invasion rather than nuclear features drives outcome in encapsulated follicular tumors. Non-IEFVPTC could be treated in a conservative manner sparing patients unnecessary total thyroidectomy and radioactive iodine therapy. The position of the EFVPTC in the classification of thyroid neoplasia should be reconsidered. Copyright © 2015 Elsevier Inc. All rights reserved.
    Human Pathlogy 02/2015; · 2.81 Impact Factor
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    ABSTRACT: Carcinoma ex-pleomorphic adenoma (CA ex-PA) is a malignant salivary gland tumor that arises in association with pleomorphic adenoma (PA). Both PA and CA ex-PA have a broad spectrum of histology and distinction from their histologic mimics may be difficult based on morphology alone. PLAG1 and HMGA2 abnormalities are the most common genetic events in both PA and CA ex-PA; however, the utility of PLAG1 and HMGA2 as adjunct molecular tests has not been well established. FISH for PLAG1 and HMGA2 was performed on 22 CA ex-PA (10 myoepithelial carcinomas (MECA), 10 salivary duct carcinomas (SDC), 1 carcinoma with squamo-glandular features, and 1 mixed MECA-adenocarcinoma not otherwise specified (NOS), 20 de novo carcinomas (11 MECA and 9 SDC), 16 PAs and 11 PA-histologic mimics. All except 3 CAs ex-PA (86%) were positive for PLAG1 or HMGA2 rearrangements/amplifications. In contrast, 18/20 (90%) de novo carcinomas lacked abnormalities in PLAG1 or HMGA2 (p < 0.01). PLAG1 or HMGA2 rearrangements were identified in 6/9 (67%) hypocellular myxoid PAs and in 2/7 (29%) cellular PAs. Furthermore, all morphologic mimics of PA were negative for PLAG1 or HMGA2. PLAG1 and HMGA2 rearrangements are the most common genetic events in CA ex-PA regardless of the histologic subtype. Unlike CA ex-PA, de novo carcinomas were negative for PLAG1 and HMGA2. Interestingly, rearrangements of PLAG1/HMGA2 were identified in the majority of hypocellular PAs but only in a small subset of cellular PAs. FISH for PLAG1 or HMGA2 can be used to distinguish between PA and CA ex-PA and their morphologic mimics.
    Human pathology 09/2014; · 2.81 Impact Factor
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    ABSTRACT: Poorly differentiated tumors of the thyroid gland (PDTC) are generally characterized by a poor prognosis due to their resistance to available therapeutic approaches. The relative rarity of these tumors is a major obstacle to our understanding of the molecular mechanisms leading to tumor aggressiveness and drug resistance, and consequently to the development of novel therapies. By simultaneously activating Kras and deleting p53 in thyroid follicular cells, we have developed a novel mouse model that develops papillary thyroid cancer invariably progressing to PDTC. In several cases, tumors further progress to anaplastic carcinomas. The poorly differentiated tumors are morphologically and functionally similar to their human counterparts and depend on MEK/ERK signaling for proliferation. Using primary carcinomas as well as carcinoma-derived cell lines, we also demonstrate that these tumors are intrinsically resistant to apoptosis due to high levels of expression of the Bcl2 family members Bcl2a1 and Mcl1, and can be effectively targeted by Obatoclax, a small molecule pan-inhibitor of the Bcl2 family. Furthermore, we show that Bcl2 family inhibition synergizes with MEK inhibition as well as with doxorubicin in inducing cell death. Thus, our studies in a novel, relevant mouse model, uncover a promising druggable feature of aggressive thyroid cancers.
    Endocrine Related Cancer 07/2014; · 4.91 Impact Factor
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    ABSTRACT: Background: While radioactive iodine (RAI) adjuvant therapy is commonly recommended for most papillary thyroid cancer patients presenting with large volume nodal involvement, it remains unclear if such therapy impacts the disease specific recurrence rate and overall survival (1). In this study, we compared the risk of achieving a structural persistent response after low administered activity (100 mCi), intermediate administered activity (150 mCi) and high administered activity (>200 mCi) RAI adjuvant therapy in patients presenting with pathologic N1b disease. Methods: This was a retrospective review of 181 papillary thyroid cancer patients with N1b disease treated with total thyroidectomy, neck dissection, and RAI remnant ablation. Dose response relationships were determined between the administered activity of 131I and the best response to initial therapy. Results: Out of the 181 patients, only 39% achieved no clinical evidence of disease (NED) after initial therapy. Young patients (stage I) had a non-statistically significant trend toward higher rates of NED with increasing dose (34% low activity, 36% intermediate activity, 46% high activity), but there was no evidence of dose response effect with regard to the likelihood of having a structural persistent response to initial therapy or the likelihood of having persistent biochemical evidence of disease. However, analysis of the older patients (Stage IVa) did reveal a trend toward statistically significant dose response relationships with increasing administered activities being associated with lower rates of structural persistent response (46% low activity, 23% intermediate activity, 17% high dose). Unfortunately, the lower rate of structural persistent response only modestly increased the likelihood that patients would be NED but was instead associated with a higher proportion of patients being classified as having biochemical persistent disease. Conclusions: It appears that administering more than 100 mCi of RAI as adjuvant therapy in N1b disease is unlikely to improve the initial response to therapy. This is especially true for the younger (stage I) patients. It is plausible that administered activities of 150-260 mCi may be associated with an improved response to initial therapy in older patients (stage IVa) that are probably at highest risk of having poor outcomes, but the potential benefit from RAI should be balanced against potential adverse effects in those patients.
    Thyroid: official journal of the American Thyroid Association 02/2014; · 2.60 Impact Factor
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    ABSTRACT: Although obesity increases risk and negatively affects survival for many malignancies, the prognostic implications in squamous cell carcinoma (SCC) of the oral tongue, a disease often associated with prediagnosis weight loss, are unknown. Patients with T1-T2 oral tongue SCC underwent curative-intent resection in this single-institution study. All patients underwent nutritional assessment prior to surgery. Body mass index (BMI) was calculated from measured height and weight and categorized as obese (≥ 30 kg/m(2) ), overweight (25-29.9 kg/m(2) ), or normal (18.5-24.9 kg/m(2) ). Clinical outcomes, including disease-specific survival, recurrence-free survival, and overall survival, were compared by BMI group using Cox regression. From 2000 to 2009, 155 patients (90 men, 65 women) of median age 57 years (range, 18-86 years) were included. Baseline characteristics were similar by BMI group. Obesity was significantly associated with adverse disease-specific survival compared with normal weight in univariable (hazard ratio [HR] = 2.65, 95% confidence interval [CI] = 1.07-6.59; P = .04) and multivariable analyses (HR = 5.01; 95% CI = 1.69-14.81; P = .004). A consistent association was seen between obesity and worse recurrence-free survival (HR = 1.87; 95% CI = 0.90-3.88) and between obesity and worse overall survival (HR = 2.03; 95% CI = 0.88-4.65) though without reaching statistical significance (P = .09 and P = .10, respectively) in multivariable analyses. In this retrospective study, obesity was an adverse independent prognostic variable. This association may not have been previously appreciated due to confounding by multiple factors including prediagnosis weight loss. Cancer 2013. © 2013 American Cancer Society.
    Cancer 01/2014; · 5.20 Impact Factor
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    ABSTRACT: Background: The Bethesda System for thyroid cytopathology is the standard for interpreting fine needle aspiration (FNA) specimens. The Atypia of Undetermined Significance/Follicular Lesion of Undetermined Significance (AUS/FLUS) category, known as Bethesda Category III, has been ascribed a malignancy risk of 5-15%, but the probability of malignancy in AUS/FLUS specimens remains unclear. Our objective was to determine the risk of malignancy in thyroid FNAs categorized as AUS/FLUS. Methods: The management of 541 AUS/FLUS thyroid nodule patients between 2008-2011 was analyzed. Clinical and radiologic features were examined as predictors for surgery. Target AUS/FLUS nodules were correlated with surgical pathology. Results: Of patients with an FNA initially categorized as AUS/FLUS, 64.7% (350/541) underwent immediate surgery, 17.7% (96/541) had repeat FNA, and 17.6% (95/541) were observed. Repeat FNA cytology was unsatisfactory in 5.2% (5/96), benign in 42.7% (41/96), AUS/FLUS in 38.5% (37/96), suspicious for follicular neoplasm in 5.2% (5/96), suspicious for malignancy in 4.2% (4/96), and malignant in 4.2% (4/96). Of nodules with two consecutive AUS/FLUS diagnoses that were resected, 26.3% (5/19) were malignant. Among all index AUS/FLUS nodules (triaged to surgery, repeat FNA, or observation), malignancy was confirmed on surgical pathology in 26.6% (95% CI, 22.4-31.3). Among AUS/FLUS nodules triaged to surgery, the malignancy rate was 37.8% (95% CI, 33.1-42.8). Incidental cancers were found in 22.3% of patients. On univariate logistic regression analysis, factors associated with triage to surgery were younger patient age (p < 0.0001), increasing nodule size (p < 0.0001), and nodule hypervascularity (p = 0.032). Conclusions: Malignancy rates in nodules with AUS/FLUS cytology are higher than previously estimated, with 26.6-37.8% of AUS/FLUS nodules harboring cancer. These data imply that Bethesda Category III nodules may have a higher risk of malignancy than traditionally believed, and that guidelines recommending repeat FNA or observation merit reconsideration.
    Thyroid: official journal of the American Thyroid Association 12/2013; · 2.60 Impact Factor
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    ABSTRACT: Background: The prognostic implications of the diagnosis of a papillary thyroid carcinoma (PTC) with tall cell features (TCF) are unknown. Methods: All PTC patients identified between 1985 and 2005 were analyzed histologically. Classical PTC (cPTC) were defined as having <30% tall cells, PTC TCF (30-49% tall cells), tall cell variant (TCV) (>50% tall cells). All cPTC, PTC TCF and TCV > 1 cm in size were included. Results: 453 patients satisfied the inclusion criteria (288 cPTC, 31 PTC TCF and 134 TCV). cPTC patients were younger than their PTC TCF and TCV counterparts (p<0.0002). There was an increase in tumor size from cPTC to PTC TCF and TCV (p=0.05). Extensive extra-thyroid extension and positive margins were more often present in TCV and PTC TCF than in cPTC . (p=0.0001, 0.03 respectively). Overall pathologic tumor (pT) stage was more advanced in TCV and PTC TCF than in cPTC (p<0.0001). Total thyroidectomy and radioactive iodine therapy were more often performed and administered on TCV patients than on their PTC TCF and cPTC counterparts (p=0.001, p=0.0001 respectively). Median follow up was 9.3 years. 10 year disease specific survival (DSS) was lower in TCV (96%) and PTC TCF (91%) than in cPTC (100%) (p<0.001). 10 year distant recurrence free (RFS) survival was higher in cPTC (98%) than in PTC TCF (89%) and TCV (96%) (p=0.03). In multivariate analysis, the presence of >5 positive nodes and extra-nodal extension were the only independent prognostic factors of neck and distant RFS respectively. Four (2.4%) of 165 PTC with TCF and PTC TCV developed poorly differentiated or anaplastic carcinoma in their recurrence while none of 288 classical PTC transformed into higher grades (p=0.017). Conclusions: 1) PTC TCF and TCV have similar clinico-pathologic features that are more aggressive than cPTC 2) PTC TCF and TCV have similar DSS and distant RFS but poorer than cPTC 3) PTC TCF are currently being treated like cPTC less aggressively than TCV 4) PTC TCF and PTC TCV have a higher rate of high grade transformation than cPTC. 5) Consideration should be given to use a 30% tall cells threshold to diagnose TCV.
    Thyroid: official journal of the American Thyroid Association 11/2013; · 2.60 Impact Factor
  • Ronald A Ghossein, Nora Katabi, Snjezana Dogan
    The American journal of surgical pathology 10/2013; · 4.59 Impact Factor
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    ABSTRACT: Background:TERT encodes the reverse transcriptase component of telomerase, which adds telomere repeats to chromosome ends, thus enabling cell replication. Telomerase activity is required for cell immortalization. Somatic TERT promoter mutations modifying key transcriptional response elements were recently reported in several cancers, such as melanomas and gliomas.Objectives:The objectives of the study were: 1) to determine the prevalence of TERT promoter mutations C228T and C250T in different thyroid cancer histological types and cell lines; and 2) to establish the possible association of TERT mutations with mutations of BRAF, RAS, or RET/PTC.Methods:TERT promoter was PCR-amplified and sequenced in 42 thyroid cancer cell lines and 183 tumors: 80 papillary thyroid cancers (PTCs), 58 poorly differentiated thyroid cancers (PDTCs), 20 anaplastic thyroid cancers (ATCs), and 25 Hurthle cell cancers (HCCs).Results:TERT promoter mutations were found in 98 of 225 (44%) specimens. TERT promoters C228T and C250T were mutually exclusive. Mutations were present in 18 of 80 PTCs (22.5%), in 40 of 78 (51%) advanced thyroid cancers (ATC + PDTC) (P < 3 × 10(-4) vs PTC), and in widely invasive HCCs (4 of 17), but not in minimally invasive HCCs (0 of 8). TERT promoter mutations were seen more frequently in advanced cancers with BRAF/RAS mutations compared to those that were BRAF/RAS wild-type (ATC + PDTC, 67.3 vs 24.1%; P < 10(-4)), whereas BRAF-mutant PTCs were less likely to have TERT promoter mutations than BRAF wild-type tumors (11.8 vs 50.0%; P = .04).Conclusions:TERT promoter mutations are highly prevalent in advanced thyroid cancers, particularly those harboring BRAF or RAS mutations, whereas PTCs with BRAF or RAS mutations are most often TERT promoter wild type. Acquisition of a TERT promoter mutation could extend survival of BRAF- or RAS-driven clones and enable accumulation of additional genetic defects leading to disease progression.
    The Journal of Clinical Endocrinology and Metabolism 07/2013; · 6.31 Impact Factor
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    ABSTRACT: Inhibitors of RET, a tyrosine kinase receptor encoded by a gene that is frequently mutated in medullary thyroid cancer, have emerged as promising novel therapies for the disease. Rapalogs and other mTOR inhibitors are effective agents in patients with gastro-entero-pancreatic neuroendocrine tumors, which share lineage properties with MTCs. The objective of this study was to investigate the contribution of mTOR activity to RET-induced signaling and cell growth, and to establish whether growth suppression is enhanced by co-targeting RET and mTOR kinase activities. Treatment of the RET mutant cell lines TT, TPC-1 and MZ-CRC-1 with AST487, a RET kinase inhibitor, suppressed growth and showed profound and sustained inhibition of mTOR signaling, which was recapitulated by siRNA-mediated RET knockdown. Inhibition of mTOR with INK128, a dual mTORC1 and mTORC-2 kinase inhibitor, also resulted in marked growth suppression, to levels comparable to those seen with RET blockade. Moreover, combined treatment with AST487 and INK128 at low concentrations suppressed growth and induced apoptosis. These data establish mTOR as a key mediator of RET-mediated cell growth in thyroid cancer cells, and provide rationale for combinatorial treatments in thyroid cancers with oncogenic RET mutations.
    Endocrine Related Cancer 07/2013; · 5.26 Impact Factor
  • Ronald A Ghossein, Nora Katabi, James A Fagin
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    ABSTRACT: Background:The mutated BRAFV600E protein has been specifically detected in papillary thyroid carcinomas (PTC) using immunohistochemistry (IHC). The clonal origin of PTC harboring BRAF mutations has recently been called into question.Objectives:1) Compare BRAF V600E IHC expression in PTC, poorly differentiated (PDTC) and anaplastic thyroid carcinoma (ATC) with DNA mutation analysis. 2) Study the distribution of BRAF V600E IHC staining within thyroid cancer tissues.Methods:Whole sections and tissue microarrays from 31 PTC, 38 PDTC and 22 ATC were subjected to both mass spectrometry genotyping for the BRAF(T1799A) mutation as well as IHC for V600E BRAF protein.Results:16 of 31 (52%) PTC showed strong (3+) IHC staining and harbored BRAF(T1799A), whereas the remaining 15 (48%) showed absent/faint (0/1+) staining, and were wild type for BRAF (BRAF-wt). Only 5/38 (13%) PDTC harbored mutant BRAF, and these were the only ones with moderate (2+) or 3+ IHC staining. All 14 ATC with a staining intensity of 3+ harbored BRAF(T1799A), whereas the 2 ATC with 0/1+ staining were BRAF-wt. Six ATC showed a staining of 2+, 5 of which had a high background staining. Of those 6 cases, BRAF(T1799A) was present only in the tumor without background. Homogeneous staining was found in 13 of 14 (93%) PTC, 3 of 3 (100%) PDTC and 12 of 14 ATC (86%).Conclusions:1) Absent/faint staining for V600E BRAF correlates perfectly with lack of BRAF(T1799A) mutation while strong staining is highly specific for BRAF(T1799A) mutation in PTC, PDTC and ATC. Moderate staining intensity cannot be relied upon and should lead to genotypic analysis. 2) Homogenous staining occurs in the vast majority of cases, demonstrating that the BRAF(T1799A) mutation is a clonal event in thyroid cancer.
    The Journal of Clinical Endocrinology and Metabolism 06/2013; · 6.31 Impact Factor
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    ABSTRACT: Background: There continues to be controversy regarding what clinico-pathological features confer a higher risk of adverse outcome in papillary microcarcinomas (PMC). The aim of this study is to assess the prognostic values of a meticulous histologic examination in PMC. Methods: All papillary thyroid carcinoma (PTC) <1 cm in size without associated larger thyroid carcinomas (TC), identified between 1977 and 2002, were categorized as PMC and subjected to a meticulous histopathologic examination by 2 thyroid pathologists. Results: 148 PMC fulfilled the inclusion criteria. Within PMC, young age, male sex, tumor multicentricity, extrathyroidal extension, infiltrative and larger tumor (> 0.5 cm) correlated with the presence of >1 cm metastatic node (MN) or >3 MN at presentation (p<0.05). With a median follow up (FU) of 9.9 years. only one (0.7%) of 134 PMC patients died of TC and 3 (2.2%) had recurrences in the neck. The patient who died harbored a poorly differentiated carcinoma (PDC) in his MN. The presence of MN and especially a large size MN (>1 cm) correlated with worse Recurrence free survival (RFS) (p=0.005, p<0.0001 respectively). Except for one, all individuals with clinically adverse outcomes had >1 cm MN. Patients whose MN were predominantly composed of PDC or tall cell variant PTC had a significant shorter RFS (p<0.0001). Only 1 of 80 radioactive iodine (RAI) naïve PMC patients with absent or small MN (<=1 cm) recurred with a median FU of 9.2 years. Conclusions: 1) The size and histotype of the MN are predictors of outcome in PMC and should be recorded. 2) The very rare PMC who recur or even die of disease have usually aggressive histopathologic features at presentation. 3) PMC with nodal disease that is small or absent at presentation are at very low risk of recurrence and may be spared RAI therapy.
    Thyroid: official journal of the American Thyroid Association 06/2013; · 2.60 Impact Factor
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    ABSTRACT: Context:Hurthle cell cancer (HCC) is an understudied cancer with poor prognosis.Objective:Our objective was to elucidate the genomic foundations of HCC.Design and Setting:We conducted a large-scale integrated analysis of mutations, gene expression profiles, and copy number alterations in HCC at a single tertiary-care cancer institution.Methods:Mass spectrometry-based genotyping was used to interrogate hot spot point mutations in the most common thyroid oncogenes: BRAF, RET, NRAS, HRAS, KRAS, PIK3CA, MAP2K1, and AKT1. In addition, common oncogenic fusions of RET and NTRK1 as well as PAX8/PPARγ and AKAP9-BRAF were also assessed by RT-PCR. Global copy number changes and gene expression profiles were determined in the same tumor set as the mutational analyses.Results:We report that the mutational, transcriptional, and copy number profiles of HCC were distinct from those of papillary thyroid cancer and follicular thyroid cancer, indicating HCC to be a unique type of thyroid malignancy. Unsupervised hierarchical clustering of gene expression showed the 3 groups of Hurthle tumors (Hurthle cell adenoma [HA], minimally invasive Hurthle cell carcinoma [HMIN], and widely invasive Hurthle cell carcinoma [HWIDE] clustered separately with a marked difference between HWIDE and HA. Global copy number analysis also indicated distinct subgroups of tumors that may arise as HWIDE and HMIN. Molecular pathways that differentiate HA from HWIDE included the PIK3CA-Akt-mTOR and Wnt/β-catenin pathways, potentially providing a rationale for new targets for this type of malignancy.Conclusions:Our data provide evidence that HCC may be a unique thyroid cancer distinct from papillary and follicular thyroid cancer.
    The Journal of Clinical Endocrinology and Metabolism 03/2013; · 6.31 Impact Factor
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    ABSTRACT: BACKGROUND: Metastatic thyroid cancers that are refractory to radioiodine (iodine-131) are associated with a poor prognosis. In mouse models of thyroid cancer, selective mitogen-activated protein kinase (MAPK) pathway antagonists increase the expression of the sodium-iodide symporter and uptake of iodine. Their effects in humans are not known. METHODS: We conducted a study to determine whether the MAPK kinase (MEK) 1 and MEK2 inhibitor selumetinib (AZD6244, ARRY-142886) could reverse refractoriness to radioiodine in patients with metastatic thyroid cancer. After stimulation with thyrotropin alfa, dosimetry with iodine-124 positron-emission tomography (PET) was performed before and 4 weeks after treatment with selumetinib (75 mg twice daily). If the second iodine-124 PET study indicated that a dose of iodine-131 of 2000 cGy or more could be delivered to the metastatic lesion or lesions, therapeutic radioiodine was administered while the patient was receiving selumetinib. RESULTS: Of 24 patients screened for the study, 20 could be evaluated. The median age was 61 years (range, 44 to 77), and 11 patients were men. Nine patients had tumors with BRAF mutations, and 5 patients had tumors with mutations of NRAS. Selumetinib increased the uptake of iodine-124 in 12 of the 20 patients (4 of 9 patients with BRAF mutations and 5 of 5 patients with NRAS mutations). Eight of these 12 patients reached the dosimetry threshold for radioiodine therapy, including all 5 patients with NRAS mutations. Of the 8 patients treated with radioiodine, 5 had confirmed partial responses and 3 had stable disease; all patients had decreases in serum thyroglobulin levels (mean reduction, 89%). No toxic effects of grade 3 or higher attributable by the investigators to selumetinib were observed. One patient received a diagnosis of myelodysplastic syndrome more than 51 weeks after radioiodine treatment, with progression to acute leukemia. CONCLUSIONS: Selumetinib produces clinically meaningful increases in iodine uptake and retention in a subgroup of patients with thyroid cancer that is refractory to radioiodine; the effectiveness may be greater in patients with RAS-mutant disease. (Funded by the American Thyroid Association and others; number, NCT00970359.)
    New England Journal of Medicine 02/2013; 368(7):623. · 54.42 Impact Factor
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    ABSTRACT: The RAF inhibitor vemurafenib (PLX4032) increases survival in patients with BRAF-mutant metastatic melanoma, but has limited efficacy in patients with colorectal cancers. Thyroid cancer cells are also comparatively refractory to RAF inhibitors. By contrast to melanomas, inhibition of MAPK signaling by vemurafenib is transient in thyroid and colorectal cancer cells. The rebound in ERK in thyroid cells is accompanied by increased HER3 signaling caused by induction of HER3 transcription through decreased promoter occupancy by the transcriptional repressors CtBP1 and 2, and by autocrine secretion of neuregulin-1. The HER kinase inhibitor lapatinib prevents MAPK rebound and sensitizes BRAF-mutant thyroid cancer cells to RAF or MEK inhibitors. This provides a rationale for combining ERK pathway antagonists with inhibitors of feedback-reactivated HER signaling in this disease. The determinants of primary resistance to MAPK inhibitors vary between cancer types, due to preferential upregulation of specific RTKs, and the abundance of their respective ligands.
    Cancer Discovery 01/2013; 3(5). · 15.93 Impact Factor
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    ABSTRACT: Advanced human thyroid cancers are densely infiltrated with tumor-associated macrophages (TAMs) and this correlates with a poor prognosis. We used BRAF-induced papillary thyroid cancer (PTC) mouse models to examine the role of TAMs in PTC progression. Following conditional activation of BRAF(V600E) in murine thyroids there is an increased expression of the TAM chemoattractants Csf-1 and Ccl-2. This is followed by the development of PTCs that are densely infiltrated with TAMs that express Csf-1r and Ccr2. Targeting CCR2-expressing cells during BRAF-induction reduced TAM density and impaired PTC development. This strategy also induced smaller tumors, decreased proliferation and restored a thyroid follicular architecture in established PTCs. In PTCs from mice that lacked CSF-1 or that received a c-FMS/CSF-1R kinase inhibitor, TAM recruitment and PTC progression was impaired, recapitulating the effects of targeting CCR2-expressing cells. Our data demonstrate that TAMs are pro-tumorigenic in advanced PTCs and that they can be targeted pharmacologically, which may be potentially useful for patients with advanced thyroid cancers.
    PLoS ONE 01/2013; 8(1):e54302. · 3.53 Impact Factor
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    ABSTRACT: To describe the outcome of patients with poorly differentiated thyroid cancer (PDTC) presenting with gross extrathyroidal extension (ETE). After IRB approval we performed retrospective review of consecutive series of thyroid cancer patients treated by primary surgical resection with or without adjuvant therapy at MSKCC from 1986-2009. Out of 91 PDTC patients, 27 (30%) had gross ETE (T4a) and they formed the basis of our study. Of 27 patients, 52% were female. The median age was 70 (range 27-87). Ten patients (37%) presented with distant metastases; four to the bone, three to lung and three had both bone and lung metastases. All patients had extended total thyroidectomy except two who had subtotal thyroidectomy. 20 patients (74%) had central compartment neck dissection and 11 also had lateral neck dissection. Four patients had pN0, 6 (30%) pN1a and 10 (50%) pN1b neck disease. 21 patients (77%) had adjuvant therapy: 15 (55%) RAI only, 3 (11%) postoperative external beam radiation (PORT) only and 3 (11%) had both RAI and PORT. Overall survival (OS), disease specific survival (DSS), local recurrence free survival (LRFS) and regional recurrence free survival (RRFS) were calculated by the Kaplan Meier method. Median follow-up time was 57 months (range 1-197 months). The 5 year OS and DSS were 47% and 49% respectively. This poor outcome was due to distant metastatic disease; 10 patients had distant metastases at presentation and a further 6 developed distant metastases during follow up. Locoregional control was good with 5 year LRFS and RRFS of 70% and 62% respectively. Overall, 8 patients (30%) had recurrences: 2 had distant alone, 2 regional, 2 regional and distant, 1 local and distant, and 1 had local, regional and distant recurrence. Aggressive surgery in patients with PDTC showing gross ETE resulted in satisfactory locoregional control. Due to the small proportion of patients who received PORT (22%), it is not possible to analyze its benefit on locoregional control. Of significance is the observation that the majority of patients (60%) who presented with or subsequently developed distant metastases eventually died of distant disease. New systemic therapies to target distant metastatic disease are required for improvements in outcome.
    Thyroid: official journal of the American Thyroid Association 01/2013; · 2.60 Impact Factor
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    ABSTRACT: Context:Medullary thyroid cancer (MTC) is a rare thyroid cancer that can occur sporadically or as part of a hereditary syndrome.Objective:To explore the genetic origin of MTC, we sequenced the protein coding exons of approximately 21,000 genes in 17 sporadic MTCs.Patients and Design:We sequenced the exomes of 17 sporadic MTCs and validated the frequency of all recurrently mutated genes and other genes of interest in an independent cohort of 40 MTCs comprised of both sporadic and hereditary MTC.Results:We discovered 305 high-confidence mutations in the 17 sporadic MTCs in the discovery phase, or approximately 17.9 somatic mutations per tumor. Mutations in RET, HRAS, and KRAS genes were identified as the principal driver mutations in MTC. All of the other additional somatic mutations, including mutations in spliceosome and DNA repair pathways, were not recurrent in additional tumors. Tumors without RET, HRAS, or KRAS mutations appeared to have significantly fewer mutations overall in protein coding exons.Conclusions:Approximately 90% of MTCs had mutually exclusive mutations in RET, HRAS, and KRAS, suggesting that RET and RAS are the predominant driver pathways in MTC. Relatively few mutations overall and no commonly recurrent driver mutations other than RET, HRAS, and KRAS were seen in the MTC exome.
    The Journal of Clinical Endocrinology and Metabolism 12/2012; · 6.31 Impact Factor
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    ABSTRACT: BACKGROUND: Historically, systemic therapy for radioactive iodine (RAI)-refractory thyroid cancer has been understudied. Available drugs have modest efficacy. Romidepsin is a histone deacetylase inhibitor with potent anti-tumor effects both in vitro and in vivo. In thyroid cancer cell lines, romidepsin increases expression of both thyroglobulin and the sodium iodide symporter (NIS) messenger RNAs, suggesting the possibility of improved iodine concentrating ability of RAI-resistant tumors. METHODS: This was a single institution Simon 2-stage Phase II clinical study. Eligible patients had progressive, RAI-refractory, recurrent/metastatic, non-medullary, non-anaplastic thyroid cancer. RECIST 1.0 measurable disease and adequate organ/marrow function were required. Romidepsin 13 mg/m2 IV was administered on days 1, 8, 15, every 28 days. The primary endpoint was response rate by RECIST (Response Evaluation Criteria In Solid Tumors) criteria; change in RAI avidity was a secondary endpoint. The study closed after the first stage due to the lack of response. RESULTS: 20 patients were enrolled: female-50%; median age-64 years; histology-papillary (8)/follicular (1)/Hürthle (11). Grade 4-5 adverse events possibly related to drug: grade 5 sudden death (1); grade 4 -pulmonary embolus (1). Twelve of 20 subjects had a reported adverse event. No RECIST major responses have been seen. Response per protocol: stable disease (13); disease progression (7). Restoration of RAI avidity was documented in 2 patients. Median overall survival and time on study was 33.2 (1-71+) and 1.7 (0.46-12) months, respectively. CONCLUSIONS: We observed preliminary signs of in vivo reversal of RAI resistance after treatment with romidepsin. However, no major responses were observed and accrual was poor after the grade 5 AE.
    Thyroid: official journal of the American Thyroid Association 11/2012; · 2.60 Impact Factor
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    ABSTRACT: Flavopiridol, a Cdk inhibitor, potentiates irinotecan-induced apoptosis. In a phase I trial of sequential irinotecan and flavopiridol, 2 patients with advanced hepatocellular carcinoma (HCC) had stable disease (SD) for ≥14 months. We thus studied the sequential combination of irinotecan and flavopiridol in patients with HCC. Patients with advanced HCC naïve to systemic therapy, Child-Pugh ≤B8, and Karnofsky performance score (KPS) ≥70% received 100 mg/m(2) irinotecan followed 7 hours later by flavopiridol 60 mg/m(2) weekly for 4 of 6 weeks. The primary end point was an improvement in progression-free survival at 4 months (PFS-4) from 33% to 54%, using a Simon's two-stage design. Tumors were stained for p53. Only 16 patients in the first stage were enrolled: median age, 64 years; median KPS, 80%; Child-Pugh A, 87.5%; and stage III/IV, 25%/75%. The primary end point was not met; PFS-4 was 20%, leading to early termination of the study. Ten patients were evaluable for response: 1 had SD >1 year and 9 had disease progression. Grade 3 fatigue, dehydration, diarrhea, neutropenia with or without fever, lymphopenia, anemia, hyperbilirubinemia, and transaminitis occurred in ≥10% of the patients. Of the 9 patients who progressed, 5 had mutant p53 and 4 had wild-type p53. The patient with stable disease had wild-type p53. Sequential irinotecan and flavopiridol are ineffective and poorly tolerated in patients with advanced HCC. Despite our limited assessments, it is possible that the presence of wild-type p53 is necessary but not sufficient to predict response in HCC.
    Gastrointestinal cancer research: GCR 11/2012; 5(6):185-9.

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  • 1995–2014
    • Memorial Sloan-Kettering Cancer Center
      • • Human Oncology & Pathogenesis Program
      • • Department of Pathology
      • • Head and Neck Service
      New York City, New York, United States
  • 2013
    • Baylor College of Medicine
      Houston, Texas, United States
  • 2008
    • New York University
      • Department of Pathology
      New York City, NY, United States
  • 2007
    • University of Nebraska at Omaha
      • Department of Surgery
      Omaha, NE, United States
  • 2006
    • Columbia University
      New York City, New York, United States
  • 1998
    • Yale-New Haven Hospital
      • Department of Pathology
      New Haven, Connecticut, United States