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Targeted inhibition of BRAF V600E achieves tumor control in a subset of advanced thyroid tumors. Nearly all tumors develop resistance, and some have been observed to subsequently undergo dedifferentiation. The molecular alterations associated with thyroid cancer dedifferentiation in the setting of BRAF inhibition are unknown. We analyzed targeted next-generation sequencing data from 639 advanced, recurrent and/or metastatic thyroid carcinomas, including 15 tumors that were treated with BRAF inhibitor drugs and had tissue sampled during or posttreatment, 8 of which had matched pretherapy samples. Pre- and posttherapy tissues from one additional patient were profiled with whole-exome sequencing and RNA expression profiling. Mutations in genes comprising the SWI/SNF chromatin remodeling complex and the PI3K–AKT–mTOR, MAPK, and JAK–STAT pathways all increased in prevalence across more dedifferentiated thyroid cancer histologies. Of 7 thyroid cancers that dedifferentiated after BRAF inhibition, 6 had mutations in these pathways. These mutations were mostly absent from matched pretreatment samples and were rarely detected in tumors that did not dedifferentiate. Additional analyses in one of the vemurafenib-treated tumors before and after anaplastic transformation revealed the emergence of an oncogenic PIK3CA mutation, activation of ERK signaling, dedifferentiation, and development of an immunosuppressive tumor microenvironment. These findings validate earlier preclinical data implicating these genetic pathways in resistance to BRAF inhibitors, and suggest that genetic alterations mediating acquired drug resistance may also promote thyroid tumor dedifferentiation. Implications: The possibility that thyroid cancer dedifferentiation may be attributed to selective pressure applied by BRAF inhibitor–targeted therapy should be investigated further.

BACKGROUND AND OBJECTIVES 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (18 F-FDG-PET/CT) parameters may help distinguish malignant from benign adrenal tumors, but few have been externally validated or determined based on definitive pathological confirmation. We determined and validated a threshold for 18 F-FDG-PET/CT maximum standard uptake value (SUVmax) in patients who underwent adrenalectomy for a nonfunctional tumor. METHODS Database review identified patients with 18 F-FDG-PET/CT images available (training cohort), or only SUVmax values (validation cohort). Discriminative accuracy was assessed by area under the curve (AUC), and the optimal cutoff value estimated by maximally selected Wilcoxon rank statistics. RESULTS Of identified patients (n = 171), 86 had adrenal metastases, 20 adrenal cortical carcinoma, and 27 adrenal cortical adenoma. In the training cohort (n = 96), SUVmax was significantly higher in malignant versus benign tumors (median 8.3 vs. 3.0, p

The genetic, biologic, and clinical heterogeneity of sarcomas poses a challenge for the identification of therapeutic targets, clinical research, and advancing patient care. Because there are > 100 sarcoma subtypes, in-depth genetic studies have focused on one or a few subtypes. Herein, we report a comparative genetic analyses analysis of 2,138 sarcomas representing 45 pathological entities. This cohort was prospectively analyzed using targeted sequencing to characterize subtype-specific somatic alterations in targetable pathways, rates of whole genome doubling, mutational signatures, and subtype-agnostic genomic clusters. The most common alterations were in cell cycle control andTP53, receptor tyrosine kinases/PI3K/RAS, and epigenetic regulators. Subtype-specific associations includedTERTamplification in intimal sarcoma and SWI/SNF alterations in uterine adenosarcoma. Tumor mutational burden, while low compared to other cancers, varied between and within subtypes. This resource will improve sarcoma models, motivate studies of subtype-specific alterations, and inform investigations of genetic factors and their correlations with treatment response.

OBJECTIVE To determine if there are differences in overall survival (OS) or event-free survival (EFS) in patients with and without concomitant extra-adrenal metastases undergoing adrenal metastasectomy. BACKGROUND There is growing interest in the use of local therapies in patients with oligometastatic disease. Previously published series have indicated that long-term survival is possible with resection. Adrenalectomy has been used to treat adrenal metastases in select patients. METHODS Patients who underwent adrenal metastasectomy from 1994 to 2015 were identified from a prospectively maintained institutional database of adrenalectomy patients, excluding adrenalectomies due to tumor extension or for palliation. Sites of disease, treatment history, and survival data were extracted from chart review. RESULTS One hundred seventy-four patients were included. Tumor histology included 68 nonsmall cell lung cancer, 34 renal cancer, 18 colorectal cancer, 11 melanoma cancer, 10 hepatocellular cancer, 8 sarcoma cancer, and 25 other cancers. The median follow-up among survivors was 5.2 (1-21) years. OS at 3 and 5 years was 50% and 40%, respectively. Patients with (n = 83) and without (n = 91) extra-adrenal metastases did not differ with respect to age, adrenal tumor size, or margin status. Median OS (3.3 years for patients with concomitant extra-adrenal metastases and 3.0 years for patients with isolated adrenal metastases; P = 0.816) and EFS (9.39 vs 9.59 months; P = 0.87) were similar. Factors negatively associated with OS included adrenal tumor size (P < 0.01), renal primary versus other (P < 0.01), and adrenal margin status (P < 0.01). CONCLUSIONS In selected patients undergoing adrenal metastasectomy, there were no significant differences in OS or EFS between patients with and without concomitant extra-adrenal metastases.

BackgroundThe ThyroSeq v2 next-generation sequencing assay (ThyroSeq) estimates the probability of malignancy in indeterminate thyroid nodules (ITN). Its diagnostic accuracy in different practice settings and patient populations is not well understood.MethodsWe analyzed 273 Bethesda III/IV ITN evaluated with ThyroSeq at 4 institutions: 2 comprehensive cancer centers (n=98 and 102), a multicenter healthcare system (n=60), and an academic medical center (n=13). The positive (PPV) and negative predictive values (NPV) of ThyroSeq, and distribution of final pathology were analyzed and compared to values predicted by Bayes Theorem.ResultsAcross 4 institutions, the PPV was 35% (22-43%), and NPV was 93% (88-100%). Predictive values correlated closely with Bayes Theorem estimates (r2=.84), although PPVs were lower than expected. RAS mutations were the most frequent molecular alteration. Among 84 RAS-mutated nodules, malignancy risk was variable (25%, range 10-37%), and distribution of benign diagnoses differed across institutions (adenoma/hyperplasia 12-85%, NIFTP 5-46%).ConclusionsIn a multi-institutional analysis, ThyroSeq PPVs were variable and lower than expected. This is attributable to differences in the prevalence of malignancy, and variability in pathologist interpretations of non-invasive tumors. It is important that clinicians understand ThyroSeq performance in their practice setting when evaluating these results.

PURPOSE Adrenocortical carcinomas (ACC) are rare and aggressive malignancies with limited treatment options. This study was undertaken to evaluate the immunogenicity of ACC. PATIENTS AND METHODS Patients with advanced ACC were enrolled in a phase II study to evaluate the clinical activity of pembrolizumab 200 mg every 3 weeks, without restriction on prior therapy. The primary end point was objective response rate. Efficacy was correlated with tumor programmed death-ligand 1 expression, microsatellite-high and/or mismatch repair deficient (MSI-H/MMR-D) status, and somatic and germline genomic correlates. RESULTS We enrolled 39 patients with advanced ACC and herein report after a median follow-up of 17.8 months (range, 5.4 months to 34.7 months). The objective response rate to pembrolizumab was 23% (nine patients; 95% CI, 11% to 39%), and the disease control rate was 52% (16 patients; 95% CI, 33% to 69%). The median duration of response was not reached (lower 95% CI, 4.1 months). Two of six patients with MSI-H/MMR-D tumors responded. The other seven patients with objective responses had microsatellite stable tumors. The median progression-free survival was 2.1 months (95% CI, 2.0 months to 10.7 months), and the median overall survival was 24.9 months (95% CI, 4.2 months to not reached). Thirteen percent of patients (n = 5) had treatment-related grade 3 or 4 adverse events. Tumor programmed death-ligand 1 expression and MSI-H/MMR-D status were not associated with objective response. CONCLUSION MSI-H/MMR-D tumors, for which pembrolizumab is a standard therapy, are more common in ACC than has been recognized. In advanced ACC that is microsatellite stable, pembrolizumab provided clinically meaningful and durable antitumor activity with a manageable safety profile.

Long-term outcomes after curative resection in patients with germline RET mutations and medullary thyroid cancer (MTC) are highly variable and mutation-specific oncologic outcomes are not well-described. Sixty-six patients identified from 1986 to 2017 from a single-institution cancer database were assessed for recurrence and survival using Kaplan–Meier estimates, and correlated with clinicopathologic features using log-rank or Cox proportional hazards. Median follow-up was 9.3 years (range 0.3–31.5), median tumor diameter was 1.5 cm (range 0.1–7.5), and preoperative calcitonin was known in 41 patients [median 636 (range 0–9600)]. Overall survival (OS) of the cohort was 94% at 10 years, the cumulative incidence of locoregional recurrence was 38% at 10 years, and 19/24 (79%) patients underwent repeat neck operation. The cumulative incidence of distant recurrence was 27% at 10 years. Predictors of distant recurrence were tumor size, positive lymph nodes, and pre- and postoperative carcinoembryonic antigen, but not calcitonin. M918T mutation-bearing patients had 10-year distant recurrence-free survival of 0%, compared with 83% in all other patients (p

Context Most papillary microcarcinomas (PMCs) are indolent and subclinical. However, as many as 10% can present with clinically significant nodal metastases. Objective and Design Characterization of the genomic and transcriptomic landscape of PMCs presenting with or without clinically important lymph node metastases. Subjects and Samples Formalin-fixed paraffin-embedded PMC samples from 40 patients with lateral neck nodal metastases (pN1b) and 71 patients with PMC with documented absence of nodal disease (pN0). Outcome Measures To interrogate DNA alterations in 410 genes commonly mutated in cancer and test for differential gene expression using a custom NanoString panel of 248 genes selected primarily based on their association with tumor size and nodal disease in the papillary thyroid cancer TCGA project. Results The genomic landscapes of PMC with or without pN1b were similar. Mutations in TERT promoter (3%) and TP53 (1%) were exclusive to N1b cases. Transcriptomic analysis revealed differential expression of 43 genes in PMCs with pN1b compared with pN0. A random forest machine learning–based molecular classifier developed to predict regional lymph node metastasis demonstrated a negative predictive value of 0.98 and a positive predictive value of 0.72 at a prevalence of 10% pN1b disease. Conclusions The genomic landscape of tumors with pN1b and pN0 disease was similar, whereas 43 genes selected primarily by mining the TCGA RNAseq data were differentially expressed. This bioinformatics-driven approach to the development of a custom transcriptomic assay provides a basis for a molecular classifier for pN1b risk stratification in PMC.

Purpose We assessed the usefulness of real-time molecular profiling through next-generation sequencing (NGS) in predicting the tumor biology of advanced pancreatic neuroendocrine tumors (panNETs) and in characterizing genomic evolution. Methods Patients with metastatic panNETs were recruited in the routine clinical practice setting (between May 2014 and March 2017) for prospective NGS of their tumors as well as for germline analysis using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) sequencing platform. When possible, NGS was performed at multiple time points. Results NGS was performed in 96 tumor samples from 80 patients. Somatic alterations were identified in 76 of 80 patients (95%). The most commonly altered genes were MEN1 (56%), DAXX (40%), ATRX (25%), and TSC2 (25%). Alterations could be defined in pathways that included chromatin remodeling factors, histone methyltransferases, and mammalian target of rapamycin pathway genes. Somatic loss of heterozygosity was particularly prevalent (55 of 95 tested samples [58%]), and the presence of loss of heterozygosity resulted in improved overall survival (P = .06). Sequencing of pre- and post-treatment samples revealed tumor-grade progression; clonal evolution patterns were also seen (molecular resistance mechanisms and chemotherapy-associated mutagenesis). Germline genetic analysis identified clinically actionable pathogenic or likely pathogenic variants in 14 of 88 patients (16%), including mutations in high-penetrance cancer susceptibility genes ( MEN1, TSC2, and VHL). Conclusion A clinical NGS platform reveals pertubations of biologic pathways in metastatic panNETs that may inform prognosis and direct therapies. Repeat sequencing at disease progression reveals increasing tumor grade and genetic evolution, demonstrating that panNETs adopt a more aggressive behavior through time and therapies. In addition to frequent somatic mutations in MEN1 and TSC2, germline mutations in these same genes underlie susceptibility to panNETs and highlight the need to re-evaluate whether germline genetic analysis should be performed for all patients with panNETs.

Surgery remains the most important treatment modality for most types of thyroid cancer. Thyroid cancers have a remarkable spectrum of clinical behavior; well-differentiated subtypes have excellent 10-year survival rates after surgery in contrast to anaplastic thyroid cancer, which is highly lethal even with aggressive treatment. The extent of thyroidectomy and lymph node dissection should be guided by cancer subtype, preoperative workup including imaging, and disease extent. Thyroidectomy should be carried out in a stepwise fashion with the goal of removing the gland and the cancer while limiting the risk of injury to the recurrent laryngeal nerve (RLN) and parathyroid glands. The surgeon should be vigilant in identifying RLN anatomy variability, and using intraoperative nerve monitor (IONM) can be a helpful adjunct to the surgeon, particularly in complex dissections. Critical to postoperative management is the recognition and treatment of complications from thyroidectomy and lymph node dissection. Surgery for recurrent thyroid cancer can be challenging, but good surgical and oncologic outcomes can be achieved with optimal surgical planning.

Background and Objectives Patients with metastatic RCC can undergo metastasectomy to improve survival time. Our goal was to provide and compare characteristics and oncological outcomes of RCC patients who underwent complete metastasectomy at a single organ site. Methods A total of 138 RCC patients were identified as undergoing complete metastasectomy at a single organ site including adrenal, lung, liver, pancreas, or thyroid. Competing risk regression analysis was used to assess RFS and CSS adjusting for several covariates. Results In this highly selected cohort, RFS and CSS was 27% and 84% at 5 years following metastasectomy, respectively. Univariate analysis revealed that removal of multiple tumors, younger age, and a shorter interval between nephrectomy and metastasis was associated with worse RFS. Larger tumors and sarcomatoid histology at nephrectomy was associated with worse CSS. We found no evidence that metastases at the time of RCC diagnosis influenced recurrence or survival. Tumor size, number of metastases resected, and time from nephrectomy to first recurrence was significantly different, but recurrence rates were not found to be significantly different, when compared across all organ sites. Conclusions These findings inform clinical and surgical management of select RCC patients with isolated metastasis to one of several organ sites. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

To analyze the natural history of small asymptomatic pancreatic neuroendocrine tumors (PanNET) and to present a matched comparison between groups who underwent either initial observation or resection. Management approach for small PanNET is uncertain. Incidentally discovered, sporadic, small (

Active surveillance of low-risk papillary thyroid cancer (PTC) is now an accepted alternative to immediate surgery, but experience with this approach outside of Japan is limited. The kinetics (probability, rate, and magnitude) of PTC tumor growth under active surveillance have not been well defined.To describe the kinetics of PTC tumor growth during active surveillance.Cohort study of 291 patients undergoing active surveillance for low-risk PTC (intrathyroidal tumors ≤1.5 cm) with serial tumor measurements via ultrasonography at a tertiary referral center in the United States.Active surveillance.The cumulative incidence, rate, and magnitude of the change in tumor diameter or volume, as well as associations with patient and tumor characteristics.Of the 291 patients, 219 (75.3%) were women; mean (SD) age was 52 (15) years. During a median (range) active surveillance of 25 (6-166) months, growth in tumor diameter of 3 mm or more was observed in 11 of 291 (3.8%) patients, with a cumulative incidence of 2.5% (2 years) and 12.1% (5 years). No regional or distant metastases developed during active surveillance. In all cases, 3-dimensional measurements of tumor volume allowed for earlier identification of growth (median, 8.2 months; range, 3-46 months before increase in tumor diameter). In multivariable analysis, both younger age at diagnosis (hazard ratio per year, 0.92; 95% CI, 0.87-0.98; P = .006) and risk category at presentation (hazard ratio for inappropriate, 55.17; 95% CI, 9.4-323.19; P .001) were independently associated with the likelihood of tumor growth. Of the tumors experiencing volume growth, kinetics demonstrated a classic exponential growth pattern, with a median doubling time of 2.2 years (range, 0.5-4.8 years; median r2 = 0.75; range, 0.42-0.99).The rates of tumor growth during active surveillance in a US cohort with PTCs measuring 1.5 cm or less were low. Serial measurement of tumor volumes may facilitate early identification of tumors that will continue to grow and thereby inform the timing of surveillance imaging and therapeutic interventions.

Purpose: Patients with anaplastic thyroid cancer (ATC) have a very high death rate. In contrast, deaths from non-anaplastic thyroid (NAT) cancer are much less common. The genetic alterations in fatal NAT cancers have not been reported. Experimental Design: We performed next-generation sequencing of 410 cancer genes from 57 fatal NAT primary cancers. Results were compared with The Cancer Genome Atlas study (TCGA study) of papillary thyroid cancers (PTCs) and to the genomic changes reported in ATC. Results: There was a very high prevalence of TERT promoter mutations, comparable with that of ATC, and these co-occurred with BRAF and RAS mutations. A high incidence of chromosome 1q gain was seen highlighting its importance in tumor aggressiveness. Two novel fusion genes DLG5–RET and OSBPL1A–BRAF were identified. There was a high frequency of mutations in MED12 and these were mutually exclusive to TERT promoter mutations and also to BRAF and RAS mutations. In addition, a high frequency of mutations in RBM10 was identified and these co-occurred with RAS mutations and PIK3CA mutations. Compared with the PTCs in TCGA, there were higher frequencies of mutations in TP53, POLE, PI3K/AKT/mTOR pathway effectors, SWI/SNF subunits, and histone methyltransferases. Conclusions: These data support a model, whereby fatal NAT cancers arise from well-differentiated tumors through the accumulation of key additional genetic abnormalities. The high rate of TERT promoter mutations, MED12 mutations, RBM10 mutations, and chromosome 1q gain highlight their likely association with tumor virulence. Clin Cancer Res; 23(19); 5970–80. ©2017 AACR.

4112 Background: Adrenocortical carcinomas (ACC) are rare and aggressive. Treatment options are limited and marked by poor efficacy and substantial toxicity. In this phase II single-center study, the efficacy and safety of pembrolizumab was assessed in patients (pts) with advanced ACC. Methods: Enrolled pts were aged ≥18 y with advanced ACC, ECOG ≤ 1, available tumor samples for biomarker analysis. Pts received pembrolizumab 200 mg Q3W for 2 y or until disease progression, intolerable toxicity, physician/patient decision to stop treatment. Imaging was performed every 9 wks. Tumor PD-L1 positivity (modified proportion score ≥ 1% or presence of stromal interface) was evaluated. Primary endpoint was ORR (by RECIST v1.1). Secondary endpoints included DOR, PFS, OS, safety. Somatic and germline next-generation sequencing was performed. Results: 39 pts were treated. Median age 62 (range, 19-87), 28% ECOG 0, 72% received ≥ 1 therapy. In available samples to date, 7/31 (23%) PD-L1+. At time of analysis, median follow-up among survivors was 17.8 mo (range, 5.4-34.7). ORR was 23.1% (95% CI, 11.1-39.3); 0 CR, 9PR. Seven pts (17.9%) had SD as best response. Among the 9 PRs, median time to PR was 4.1 mo (range, 1.7-10.5) and median DOR was not reached (95% CI, 4.1-not reached). Three pts achieving PR have completed 2 y of treatment with ongoing response noted. Tumor PD-L1 status is currently available in 6 pts with PR, 2/6 (33%) PD-L1+. Median PFS was 2.1 mo (95% CI, 2.0-10.7). Median OS was 24.9 mo (95% CI, 4.2-not reached); 2-year OS rate was 50% (95% CI, 36-69%). In the 34 tested tumors, germline testing identified 2 PR pts with Lynch syndrome; the remaining 7 PRs were MSS. Median tumor mutation burden for all PRs was 4.1 mutations/megabase (range, 0-31.5). There was no significant relationship between somatic alterations and response to treatment. Grade 3/4 treatment-related AEs occurred in 7/39 (17.9%) pts. Two pts discontinued therapy due to AEs; both pts achieved PRs and continue to respond. All pts with PRs had LFT elevation ≥ grade 2. Conclusions: Pembrolizumab demonstrated antitumor activity and was well tolerated in advanced ACC. Durable responses were noted. Complete evaluation of tumor PD-L1 and microsatellite status will be reported at the meeting. Clinical trial information: NCT02673333.

Bilateral (or four gland) exploration remains an important component of parathyroid surgery.

Purpose Based largely on reports that predate modern reporting standards, mitotane has been considered a systemic treatment option for both hormone control and antitumor control of metastatic adrenocortical cancer (ACC), although the therapeutic window is narrow. Methods We searched electronic medical records to identify patients with metastatic ACC treated and prescribed single-agent mitotane at Memorial Sloan Kettering Cancer Center from March 15, 1989–September 18, 2015. Reference radiologists reviewed all imaging and determined efficacy according to Response Evaluation Criteria in Solid Tumors 1.1. Patient demographics, toxicities, and treatment outcomes were reviewed. Next-generation sequencing was performed in selected cases. Results Thirty-six patients were identified. The mean age was 54 and 50% had functional tumors. Grade 3 or greater toxicities were documented in 16 out of 36 patients (44%) and 17% had documented long term adrenal insufficiency. Progression of the disease as the best response occurred in 30 out of 36 patients (83%) and one patient (3%) experienced clinical progression. Three patients achieved a complete response (CR) (8%), one patient achieved a partial response (3%), and one patient (3%) had stable disease after slow disease progression prior to initiation of therapy (durable for 6 months). All responders had nonfunctional tumors. Next-generation sequencing in two of the three CR patients was performed and failed to identify any novel alterations. Conclusion In this retrospective series, mitotane had a low response rate and low tumor control rate; however, a disproportionately high complete response rate suggested it should be used in selected individuals. Adrenal insufficiency is common with mitotane use and aggressive treatment with steroid supplementation should be considered when appropriate to avoid excess toxicities. Biomarkers are desperately needed to further define this disease.

Praise for the previous edition: "At once a textbook, a surgical atlas, and a source of current practice guidelines...This is a high-quality, thorough and insightful resource that provides accessible and essential information...recommend[ed]." -- Doody's Review Thyroid and Parathyroid Diseases, Second Edition, has been revised and updated to reflect recent advances in the medical and surgical management of thyroid and parathyroid diseases. This new edition serves as both a comprehensive guide to patient evaluation as well as an atlas of advanced surgical techniques for managing patients needing operative intervention. Separate chapters are devoted to minimally invasive techniques and remote access/robotic thyroidectomy techniques, both of which have enjoyed increased application throughout the world. New in the second edition: * A section on state-of-the-art, evidence-based management of challenging parathyroid conditions such as multiple endocrine neoplasia and renal hyperparathyroidism * A more detailed discussion of thyroid cancer evaluation and staging * A new chapter dedicated to parathyroid cancer * Nearly 200 additional full-color illustrations This new edition is a valuable resource for all surgeons, endocrinologists, and residents seeking to expand their knowledge of thyroid and parathyroid diseases, as well as seasoned clinicians who want to improve patient care and incorporate the latest surgical advancements into their practice.

This chapter will focus on anaplastic thyroid carcinoma (ATC), thyroid lymphoma, and metastases to the thyroid gland from non-thyroid cancers. Although these entities represent three uncommon clinical scenarios, thyroid physicians should be knowledgeable on how to manage each. ATC is a highly lethal disease with survival usually measured in months. Management should be focused on diagnosis, appropriate counseling, and supportive care, and when possible, clinical trial enrollment. Thyroid lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL), is not typically treated with thyroidectomy, but patients often present to the surgeon for initial management and biopsy. Lastly, metastatic disease that has spread to the thyroid gland has a number of important considerations, most notably that patients undergoing thyroid metastasectomy should be highly selected and offered resection only after multidisciplinary evaluation.

The molecular mechanisms responsible for aberrant calcium signaling in parathyroid disease are poorly understood. The loss of appropriate calcium-responsive modulation of PTH secretion observed in parathyroid disease is commonly attributed to decreased expression of the calcium-sensing receptor (CaSR), a G protein-coupled receptor. However, CaSR expression is highly variable in parathyroid adenomas, and the lack of correlation between CaSR abundance and calcium-responsive PTH kinetics indicates that mechanisms independent of CaSR expression may contribute to aberrant calcium sensing in parathyroid disease. To gain a better understanding of parathyroid tumors and the molecular determinants that drive parathyroid adenoma development, we performed gene expression profiling on a panel of 64 normal and neoplastic parathyroid tissues. The microarray data revealed high-level expression of genes known to be involved in parathyroid biology (PTH, VDR, CGA, CaSR, and GCM2). Moreover, our screen identified regulator of G protein signaling 5 (RGS5) as a candidate inhibitor of CaSR signaling. We confirmed RGS5 to be highly expressed in parathyroid adenomas relative to matched-pair normal glands. Transient expression of RGS5 in cells stably expressing CaSR resulted in dose-dependent abrogation of calcium-stimulated inositol trisphosphate production and ERK1/2 phosphorylation. Furthermore, we found that RGS5-nullizygous mice display reduced plasma PTH levels, an outcome consistent with attenuated opposition to CaSR activity. Collectively, these data suggest that RGS5 can act as a physiological regulator of calcium sensing by CaSR in the parathyroid gland. The abnormally elevated expression of RGS5 observed in parathyroid adenomas could thus represent a novel mechanism of CaSR desensitization in patients with primary hyperparathyroidism.

Pancreatic neuroendocrine tumors (PanNETs) or islet cell tumors are a rare neuroendocrine malignancy with an annual incidence of less than 1 per 100,000 per year. Current classification scheme for PanNETs include grade and stage. While well-differentiated PanNETs can be successfully treated with surgery, there are few treatments for metastatic PanNETs. A greater understanding of the cells of origin of PanNETs, tumor progression and pathway pathogenesis may guide the development of novel therapeutic options. The most commonly mutated genes in PanNETs are ATRX, DAXX, and MEN1. Little is known about the cells-of-origin for non-functional neuroendocrine tumors. Here, we genotyped 64 PanNETs for mutations in ATRX, DAXX, and MEN1 and found 37 tumors (58%) carry mutations in these three genes (A-D-M mutant PanNETs) and this correlates with a worse clinical outcome than tumors carrying the wild-type alleles of all three genes (A-D-M WT PanNETs). We performed RNA sequencing (n=33) and Illumina 450K DNA methylation (n=32) analysis on randomly selected PanNETs to reveal two distinct subgroups with one group consisting exclusively of A-D-M mutant PanNETs. Pair-wise correlation of gene expression between all PanNETs, showed A-D-M mutant PanNETs are more homogeneous as a group than A-D-M WT PanNETs. Among A-D-M mutant PanNETs, mutants with the same genotype (mutations in ATRX/DAXX/MEN1) did not show greater gene expression correlation. Two biomarkers differentiating A-D-M mutant from A-D-M WT PanNETs were high ARX gene expression and low PDX1 gene expression with PDX1 promoter hyper-methylation in the A-D-M mutant PanNETs. Moreover, A-D-M mutant PanNETs had a gene expression signature similar to that of alpha cells (pval < 0.009) of pancreatic islets including increased expression of HNF1A and its transcriptional target genes. We validated our subtype classification and A-D-M mutant panNET alpha signature using two independent PanNETs expression dataset. This gene expression profile suggests that A-D-M mutant PanNETs originate from or transdifferentiate into a distinct cell type similar to alpha cells. Citation Format: Saurabh V. Laddha, Chang S. Chan, Peter Lewis, Matthew Koletsky, Kenneth Robzyk, Edaise Da Silva, Paula J. Torres, Brian Untch, Promita Bose, Timothy Chan, David S. Klimstra, David C. Allis, Laura H. Tang. ATRX, DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct “alpha-cell signature” subgroup [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1799.

Background: Somatostatin receptor ligands are used for the detection and treatment of neuroendocrine tumors. Mutations of MEN1 are frequently observed in human pancreatic neuroendocrine tumors (PanNETs). We utilized a previously described murine model of PanNET that harbors a floxed Men1 allele to study the feasibility of somatostatin receptor type 2 (SSTR2) imaging and therapy in mice. Methods: Mice with pancreatic-specific expression of Cre recombinase and floxed Men1 (Pdx1-cre, Men1f/f) were aged to 9-12 months to allow for the development of PanNETs. Mice were injected with either the SSTR2 agonist 68Ga-DOTA-TATE or antagonist 177Lu-DOTA-JR11 via tail vein. Imaging with 68Ga-DOTA-TATE was performed using PET/CT. Percent uptake of injected activity was calculated for visualized tumors. 177Lu-DOTA-JR11 binding was visualized with autoradiography. Immunofluorescence (IF) detected SSTR2 expression and a marker of DNA damage (γ-H2AX). Results: IF staining for SSTR2 showed membranous localization of the receptor limited to areas of neoplasia with high and low levels of SSTR2 expression variable by individual animal and tumor. Tumors were successfully detected in mice injected with 68Ga-DOTA-TATE using PET/CT. The mean maximum percent uptake of injected activity for visualized tumors was 2.8% +/- 0.34. Injection of 177Lu-DOTA-JR11 and subsequent autoradiography confirmed localization of radionuclide to areas of histology-confirmed neoplasia. Treatment effect (DNA damage) was observed with co-localization of γ-H2AX and SSTR2 staining in neoplastic areas as compared to hyperplastic islets and normal pancreatic parenchyma that were both SSTR2 and γ-H2AX negative. Conclusion: PanNETs from Pdx1-cre, Men1f/f mice can be successfully imaged and treated using somatostatin-based radionuclides. This genetically accurate model can be employed to study peptide receptor radionuclide therapy efficacy and toxicity either alone or in combination with other treatment strategies. Citation Format: Janet W. Li, Hanwen Zhang, Sean D. Carlin, Nitya Raj, David S. Klimstra, Steven K. Libutti, Wolfgang A. Weber, Diane Reidy-Lagunes, Brian R. Untch. Somatostatin receptor-based imaging and treatment of murine pancreatic neuroendocrine tumors induced by MEN1-loss [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3735.

275 Background: To assess the utility of molecular profiling to predict tumor biology, we performed next-generation sequencing (NGS) of metastatic well differentiated (WD) pancreatic neuroendocrine tumors (panNETs) in the routine practice setting. Our institutional NGS platform allows for evaluation of genetic alterations that contribute to tumorigenesis (sequence variants, copy number alterations, insertions/deletions, select rearrangements) as well as somatic loss of heterozygosity (LOH). Methods: NGS was performed using MSK-IMPACT, a matched tumor-normal sequencing platform that interrogates 468 cancer-related genes. LOH for all cases was determined by analysis of total, allele-specific, and integer DNA copy number genome-wide using the FACETS algorithm. Results: Since 2014, NGS has been performed in 96 tumor samples from 80 patients. The most commonly altered genes were MEN1 (56%), DAXX (40%), ATRX (25%), and TSC2 (25%). LOH was highly prevalent, identified in 51/96 samples (53%). A significant association (q-value < 0.05) was noted between LOH and the presence of altered MEN1, DAXX, PTEN, or TSC2. LOH was recurrently observed in chromosomes 1, 2, 3, 6, 8, 10, 11, 15, 16, 21, and 22. Since MEN1 alterations predict improved outcome, comparison was made between patients with LOH present/MEN1 wild type (WT) tumors (n = 16) and LOH absent/MEN1 altered tumors (n = 21); inferior overall survival (OS) was noted with LOH present/MEN1 WT status (p < 0.01). High grade pathology was observed in 6/16 (38%) LOH present/MEN1 WT tumors and in 1/21 (5%) LOH absent/MEN1 altered tumors (p < 0.0001). The mean Ki-67 index of LOH present/MEN1 WT tumors was 22% and that of LOH absent/MEN1 altered tumors was 9%. Conclusions: This is the first study to report widespread somatic LOH in metastatic WD panNETs. PanNETs appear to exhibit more LOH overall than virtually any tumor type studied. In this cohort, LOH was a prognostic marker of inferior OS and was associated with more aggressive pathologic features. LOH warrants further investigation as it may help better characterize these clinically heterogeneous tumors.

Background Successful parathyroidectomy for sporadic primary hyperparathyroidism (pHPT) is predicted by a 50% drop in PTH intra-operatively. Vitamin D is a known inhibitor of PTH secretion and is associated with secondary HPT following adenoma resection. This study examined the impact of 25-hydroxyvitamin D (25OHD) deficiency on perioperative PTH kinetics and outcomes following parathyroidectomy. Methods Patients undergoing adenoma resection for pHPT (n=93) had PTH levels recorded at six perioperative time points. Preoperative 25OHD levels were examined retrospectively. Patients were considered 25OHD deficient if the level was

Purpose: Most well-differentiated neuroendocrine tumors (WD-NET) of the enteropancreatic system are low-intermediate grade (G1, G2). Elevated proliferation demonstrated by either a brisk mitotic rate (>20/10 high power fields) or high Ki-67 index (>20%) defines a group of aggressive neoplasms designated as high-grade (G3) neuroendocrine carcinoma (NEC). High-grade NEC is equated with poorly differentiated NEC (PD-NEC) and is associated with a dismal outcome. Progression of WD-NETs to a high-grade neuroendocrine neoplasm very rarely occurs and their clinicopathologic and molecular features need to be characterized. Experimental Design: We investigated 31 cases of WD-NETs with evidence of a component of a high-grade neoplasm. The primary sites included pancreas, small bowel, bile duct, and rectum. Histopathology of the cases was retrospectively reviewed and selected IHC and gene mutation analyses performed. Results: The high-grade component occurred either within the primary tumor (48%) or at metastatic sites (52%). The clinical presentation, radiographic features, biomarkers, and the genotype of these WD-NETs with high-grade component remained akin to those of G1–G2 WD-NETs. The median disease-specific survival (DSS) was 55 months (16–119 months), and 2-year and 5-year DSS was 88% and 49%, respectively—significantly better than that of a comparison group of true PD-NEC (DSS 11 months). Conclusions: Mixed grades can occur in WD-NETs, which are distinguished from PD-NECs by their unique phenotype, proliferative indices, and the genotype. This phenomenon of mixed grade in WD-NET provides additional evidence to the growing recognition that the current WHO G3 category contains both WD-NETs as well as PD-NECs. Clin Cancer Res; 22(4); 1011–7. ©2015 AACR.

Anaplastic thyroid carcinoma, thyroid lymphoma, and secondary metastasis to the thyroid gland are uncommon thyroid malignancies. They represent significant challenges for the surgeon owing to difficulties in diagnosis, aggressive biology, and the infrequency of their presentation. An awareness and appreciation of multimodality treatment strategies is essential for their management.

Isolated pancreatic metastases may occur in patients with many types of cancer. Several retrospective case series have been published demonstrating the feasibility of resection in selected patients. Here we report our experience with pancreatic metastasectomy in 70 patients and review the published literature. Our findings suggest that long-term survival is associated with resection in selected patients but these outcomes must be weighed against the significant morbidity that is associated with pancreatic resection.

The purpose of this study was to characterize the responses of human and non-human primate (Macaca mulatta) platelets to anti-heparin-platelet factor 4 (AHPF4) antibodies. Due to the variations observed in the functionality and immunoglobulin isotypes in patients with heparin-induced thrombocytopenia (HIT), we used highly characterized human AHPF4 antibodies to study platelet activation responses. Using ELISA and 14C-serotonin release assay (SRA) systems, three patients' plasmapheresis fluid with similar responses to these assays were pooled. This pool was then used to study the platelet activation responses of human and primate platelets in the HIT platelet aggregation assay, a flow cytometry assay, and a variation of the aggregation assay in which glycoprotein IIb/IIIa inhibitors were supplemented. In the plasmapheresis fluid from three patients, the most significant AHPF4 immunoglobulin isotype present (based on optical density readings) was IgG, with less IgM (p0.001) and IgA (p0.001). The SRA yielded equivalent platelet activation results in all three patients. Using this pool in the platelet aggregation assay, without any heparin present, there was less percent aggregation (p0.001) with human platelets (11.8 +/- 2.35, n = 5) compared to the primate platelets (54.3 +/- 10.2, n = 9). In presence of 0.4 U/ml heparin, both platelet types had similar percent aggregations (p0.05). Three glycoprotein IIb/IIIa receptor inhibitors were used to evaluate the similarities in platelet activation. Eptifibatide was found to be a strong inhibitor of both species' platelet types at concentrations greater than 0.01 microg/ml. This was not the case with tirofiban which inhibited both human and monkey platelets at concentrations greater than 0.025 microg/ml. Abciximab inhibited aggregation at concentrations greater than 6.25 microg/ml. These data indicate that phylogenetic similarities in platelets of humans and primates may be used to further characterize the pathophysiology of HIT syndrome.

Antibodies to heparin–platelet factor 4 (PF4) complexes have been observed in patient with heparin-induced thrombocytopenia (HIT) syndrome. These antibodies may be of various isotypes and differ with respect to their ability to activate platelets/endothelial cells. This study determined the isotypes and functionality of antiheparin–platelet factor 4 (AHPF4) antibodies in 111 patients treated with heparin and clinically suspected for HIT. In this patient population, 50% had detectable AHPF4 cumulative IgA, IgG, and IgM (determined by enzyme-linked immunosorbent assay, ELISA), but only 35% was positive when tested with the 14 C-serotonin release assay (SRA). Using antihuman Ig specific for different isotypes, we found that 50% of the 111 samples was positive for IgG, 45% for IgM, and 37% for IgA. In 50 normal human serum (NHS) samples, only two were positive for IgG, but 33 were positive for IgM, indicating a potential humoral response to the heparin–PF4 complex prior to heparin administration. Patients that were ELISA + for AHPF4 antibody titer were subdivided into SRA-positive (+) and SRA-negative (−) groups. The SRA + group had a mean ELISA optical density (OD) for AHPF4 IgA/IgG/IgM of 2.1, while the SRA − group had a mean OD of 0.8 ( P + group had greater mean OD values for all three individual isotypes. Using flow cytometry, we determined the ability of different patient samples to activate platelets. Samples that contained IgG and were SRA + activated platelets (as measured by microparticle generation and P-selectin expression) in the presence of therapeutic concentrations of heparin. NHS and samples containing IgA and/or IgM that were SRA − were not able to produce microparticles nor were they able to increase expression of P-selectin. Together, these data indicate that IgG is the principal mediator of platelet activation in patients with HIT, with IgA and IgM playing a less significant role in the pathophysiology of this syndrome.

Of the three RAS oncoproteins, only HRAS is delocalized and functionally inactivated by farnesyltransferase inhibition (FTI), an approach that has yet to be exploited clinically. We treated a murine model of poorly differentiated and anaplastic thyroid cancer (Tpo-cre/HrasG12V/p53flox/flox; Hras;p53) with the FTI tipifarnib, and observed sustained tumor regression and increased survival; however, tumors eventually recurred. Following HRAS delocalization by tipifarnib in vitro, ERK phosphorylation was only inhibited transiently in HRAS-mutant cell lines, which was associated with increased GTP loading of wild-type RAS proteins in the setting of RTK ligand stimulation. This adaptive reactivation of RAS-MAPK signaling was abrogated by selective RTK (i.e. EGFR, FGFR) inhibitors, or by MEK inhibitors. Importantly, tipifarnib combined with the MEK inhibitor AZD6244 led to improved responses in Hras;p53 mouse tumors, whereas combination with the EGFR/FGFR inhibitors erlotinib and ponatinib did not, suggesting heterogeneity of upstream inputs. In order to identify acquired resistance mechanisms, tumor-bearing Hras;p53 mice were treated with tipifarnib until resistance developed (6 months). Whole exome sequencing of resistant tumors identified a truncating NF1 mutation and an activating mutation in GNAS at high allelic frequency. Upon NF1 knockdown in the human HRAS- mutant cell line C643, tipifarnib failed to inhibit pERK in vitro and caused resistance to tipifarnib in xenografts. By contrast, activating GNAS mutations transduced into Hras;p53 mouse tumor cell lines produced tipifarnib-resistant xenografts that activated the GNAS-cAMP-CREB pathway and demonstrated signs of redifferentiation. These data show that pharmacological targeting of RAS in a genetically accurate, mouse model of a RAS-driven virulent cancer leads to objective major responses and improved survival. We identified adaptive and acquired resistance mechanisms, and show that combined treatment with selective MEK inhibitors are beneficial. These data should also inform a currently enrolling clinical trial of tipifarnib for HRAS-mutant malignancies. Citation Format: Brian R. Untch, Vanessa Dos Anjos, Maria ER Garcia-Rendueles, Jeff A. Knauf, Alan L. Ho, James A. Fagin. The farnesyltransferase inhibitor tipifarnib causes dramatic tumor regression and increases survival in murine HrasG12V driven aggressive thyroid cancers: Consequent adaptive and acquired resistance mechanisms inform combination treatments with improved responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2063. doi:10.1158/1538-7445.AM2017-2063

INTRODUCTION AND OBJECTIVES: Carefully selected renal cell carcinoma (RCC) patients with isolated metastases undergoing metastasectomy can have prolonged survival. The goal of this study was to evaluate the oncologic outcomes in patients undergoing metastasectomy from 5 organ sites. METHODS: RCC patients were identified from 5 individual organ-based databases from a single institution and analyzed. Synchronous patients (distant metastases at nephrectomy or within 6 months (mos) of nephrectomy) were compared to metachronous patients (recurrence greater than 6 mos from nephrectomy). Patients with diffuse metastases at the time of nephrectomy or residual disease after metastasectomy were excluded. RESULTS: There were 138 patients undergoing metastasectomy for RCC in this study with a median follow-up of 2.4 years (range: 0-14.2 years) after metastasectomy. The lung was the most commonsite ofmetastasectomy (n1⁄478, 57%) followedby adrenal (n1⁄427, 20%), liver (n1⁄412, 9%), pancreas (n1⁄415, 11%), and thyroid (n1⁄46, 4%). The 5-year overall survival (OS) after nephrectomy was 88% and the 5 year OS after metastasectomy was 73%. Patients undergoing resection of synchronous metastases (n1⁄432) did not differ from those with metachronous metastases (n1⁄4106) with respect to age, gender, KPS, histology, primary tumors size, metatasectomy site or number of metastases. Median recurrence-free survival was similar after metastasectomy between synchronous and metachronous patients (Hazard ratio for metachronous: 0.76, 95% CI: 0.4-1.2). However, univariate analysis for OS identified initial metachronous presentation (p1⁄40.02), time from initial recurrence diagnosis to metastasectomy >12 mos (p1⁄40.02), and disease free interval (DFI) >6 mos after metastasectomy (p

Duodenal neuroendocrine tumors are rare and few studies exist to guide surgical management. This study identifies factors associated with recurrence after resection. A retrospective, single institution review was performed between 1983 and 2011 on patients with a pathologic diagnosis of duodenal neuroendocrine tumor. Tumor grade was assigned based on WHO 2010 criteria (Ki-67 and mitotic rate). Seventy-five patients were identified that underwent curative resection. This included 12 patients with endoscopic mucosal resection, 34 that had local resection, and 29 that underwent pancreaticoduodenectomy. Two-year and 5-year recurrence-free survival was 84 and 81 %, respectively. There were 11 tumor recurrences (either local or distant), and four patients died of their disease (3/4 had high-grade lesions) with an overall median follow-up of 27 months. On univariate analysis, tumor size and tumor grade were identified as being associated with recurrence, but not intervention type, lymph node metastases, ampullary location, or margin status. Tumor grade and size are associated with recurrence-free survival in duodenal neuroendocrine tumors. When feasible, a less aggressive surgical approach to treat low-grade and low-stage duodenal NETs should be considered.

An area of ongoing controversy in the management of patients with differentiated thyroid cancer is the role of prophylactic central neck dissection (pCND). This review describes the natural history of differentiated thyroid cancer and provides the limited data regarding the role of routine pCND. An evidence-based analysis was performed of the rationale for routine pCND was performed, including reduced rates of central neck recurrence, reduced morbidity with secondary central neck lymphadenectomy, improved rates of postoperative athyroglobulinemia, and improved stratification of radioactive iodine (RAI) dosage. A critical appraisal of the available literature demonstrates insufficient evidence to indicate that this extra procedure performed routinely leads to improvement in clinically meaningful end points.

Recurrent laryngeal nerve (RLN) injury is a rare complication for patients undergoing neck exploration for primary hyperparathyroidism (pHPT). Distances between RLNs and parathyroid adenomas have not been previously published. In this study we used a RLN monitor to identify the RLN and to measure the proximity to parathyroid tumors. Patients with pHPT (n = 136) underwent neck exploration and had the clinical data recorded prospectively. Adenomas were recorded in 1 of 4 locations (right upper, right lower, left upper, left lower). Measurement of RLN to adenoma distances were recorded intraoperatively with the gland in situ. The RLN location was confirmed with a RLN monitor. The average RLN to adenoma distance was 0.52 ± 0.52 cm. Adenomas in the right upper position were significantly closer to the nerve (0.25 ± 0.39 cm) compared with adenomas in the left upper (0.48 ± 0.61 cm, p = .03), left lower (0.70 ± 0.53 cm, p

Surgeon-performed cervical ultrasound (SUS) and 99Tc-sestamibi scanning (MIBI) are both useful in patients with primary hyperparathyroidism (PHPT). We sought to determine the relative contributions of SUS and MIBI to accurately predict adenoma location.We performed a database review of 516 patients undergoing surgery for PHPT between 2001 and 2010. SUS was performed by 1 of 3 endocrine surgeons. MIBI used 2-hour delayed anterior planar and single-photon emission computerized tomography images. Directed parathyroidectomy was performed with extent of surgery governed by intraoperative parathyroid hormone decline of 50%.SUS accurately localized adenomas in 87% of patients (342/392), and MIBI correctly identified their locations in 76%, 383/503 (p0.001). In patients who underwent SUS first, MIBI provided no additional information in 92% (144/156). In patients who underwent MIBI first, 82% of the time (176/214) SUS was unnecessary (p = 0.015). In 32 patients SUS was falsely negative. The reason for these included gland location in either the deep tracheoesophageal groove (n = 9) or the thyrothymic ligament below the clavicle (n = 5), concurrent thyroid goiter (n = 4), or thyroid cancer (n = 1). In 13 cases, the adenoma was located in a normal ultrasound-accessible location but was missed by the preoperative exam. In the 32 ultrasound false-negative cases, MIBI scans were positive in 21 (66%). Of the 516 patients, 7.6% had multigland disease. Persistent disease occurred in 4 patients (1%) and recurrent disease occurred in 6 (1.2%).When performed by experienced surgeons, SUS is more accurate than MIBI for predicting the location of abnormal parathyroids in PHPT patients. For patients facing first-time surgery for PHPT, we now reserve MIBI for patients with unclear or negative SUS.

A relationship between primary hyperparathyroidism (PHPT) and obesity has been observed but is incompletely understood. Furthermore, obesity has been associated with vitamin D deficiency, suggesting that the three conditions may be linked.We hypothesized that PHPT in morbidly obese patients is more severe and that the difference may be explained by vitamin D deficiency. DESIGN AND SETTING, PARTICIPANTS, AND OUTCOME MEASURES: Records of 196 patients with surgically treated PHPT and known body mass index (BMI) were examined. Patients were stratified into three BMI groups: group I (nonobese), BMI25 kg/m(2) (n = 54); group II (non-severely obese), BMI 25-34 kg/m(2) (n = 102); and group III (severely obese), BMI 35 kg/m(2) or greater (n = 40).Preoperative PTH levels were higher in group ΙΙΙ compared with group Ι (181 ± 153 vs. 140 ± 80 pg/ml, p = 0.04). Group III patients had larger tumors on average compared with group I (1.8 ± 1.5 vs. 1.04 ± 1.5 g, P = 0.0002). In group III, BMI positively correlated with parathyroid tumor weight (r = 0.5, P = 0.002). Postoperative PTH was higher in group III compared with group Ι (61 ± 41 vs. 44 ± 28 pg/ml, P = 0.02). There was higher frequency of depression, musculoskeletal symptoms, weakness, and gastroesophageal reflux disease in group III patients.BMI positively correlated with parathyroid tumor weight independent of vitamin D. Severely obese patients have larger parathyroid tumor weight, higher pre- and postoperative PTH, and greater symptoms.

Feasibility and reproducibility of microarray biomarkers in clinical settings are doubted because of reliance on fresh frozen tissue. We sought to develop and validate a paradigm of frozen tissue collection from early breast tumors to enable use of microarray in oncology practice. Frozen core needle biopsies (CNBx) were collected from 150 clinical stage I patients during image-guided diagnostic biopsy and/or surgery. Histology and tumor content from frozen cores were compared to diagnostic specimens. Twenty-eight patients had microarray analysis to examine accuracy and reproducibility of predictive gene signatures developed for estrogen receptor (ER) and HER2. One hundred twenty-seven (85%) of 150 patients had at least one frozen core containing cancer suitable for microarray analysis. Larger tumor size, ex vivo biopsy, and use of a new specimen device increased the likelihood of obtaining adequate specimens. Sufficient quality RNA was obtained from 90% of tumor cores. Microarray signatures predicting ER and HER2 expression were developed in training sets of up to 363 surgical samples and were applied to microarray data obtained from core samples collected in clinical settings. In these samples, prediction of ER and HER2 expression achieved a sensitivity/specificity of 94%/100%, and 82%/72%, respectively. Predictions were reproducible in 83-100% of paired samples. Frozen CNBx can be readily obtained from most breast cancers without interfering with pathologic evaluation in routine clinical settings. Collection of tumor tissue at diagnostic biopsy and/or at surgery from lumpectomy specimens using image guidance resulted in sufficient samples for array analysis from over 90% of patients. Sampling of breast cancer for microarray data is reproducible and feasible in clinical practice and can yield signatures predictive of multiple breast cancer phenotypes.

Minimally invasive parathyroidectomy can reduce operative morbidity and operative time. Radio-guided parathyroidectomy utilizing Tc-99m Sestamibi is one approach to minimally invasive parathyroidectomy. Here, we report a multimedia case study of minimally invasive radio-guided parathyroidectomy.A 60-year-old African American female was found to have total calcium of 11.1 mg/dl, intact parathyroid hormone (iPTH) of 175 pg/ml, and a 24-h urine calcium of 620 mg/24 h. A Tc-99 Sestamibi scan (23.5 mCi of Tc-99 Sestamibi injected i.v.) and ultrasound localized a candidate adenoma to the right upper position. The patient was injected with 5.3 mCi Tc-99m Sestamibi 3 h before incision.A gamma probe (C-Trak Automatic System, Care Wise Medical Products) recorded in vivo counts of the right upper parathyroid (3,465) that were 160% of the background. Background counts were recorded from the resected tumor bed (2,224). A 1.4-g adenoma was identified in this location; ex vivo counts (3,226) were 150% of the background. Intra-operative iPTH baseline values were 176 pg/ml and 148 pg/ml, and 5- and 10-min post-resection levels were 17 pg/ml (90% drop) and 18 pg/ml (90% drop), respectively. The patient's recovery was uncomplicated. At 1 week postoperatively, total calcium was 8.9 mg/dl and iPTH was 16 pg/ml. At 1 year, the calcium and iPTH levels were 8.7 mg/dl and 53 pg/ml, respectively.Radio-guided minimally invasive parathyroidectomy using Tc-99 Sestamibi localization is an effective approach to hyperparathyroidism. For patients without localization, exposure of all four parathyroid glands is preferable. Surgeons should be familiar with both techniques.

Objective We report a case of an adrenal collision tumor composed of a small cell lung carcinoma metastasis and a benign adrenal adenoma identified preoperatively on FDG-PET, CT and MRI and confirmed pathologically. Methods The patient’s history, preoperative imaging characteristics, postoperative course, and histopathology are described. A review of the literature addressing adrenal collision tumors is provided. Results A 47-year-old female was found to have a left upper lobe lung mass and an adrenal lesion on imaging. FDG-PET, CT and MRI of the adrenal suggested a metastatic lesion adjacent to an adrenal adenoma. CT-guided biopsy of the adrenal gland was consistent with a small cell lung cancer metastasis. The patient underwent systemic chemotherapy and had complete resolution of the left upper lobe mass. Post-treatment FDG-PET demonstrated a persistently enlarged adrenal gland with decreased but persistent FDG uptake. The patient underwent adrenalectomy and pathologic examination demonstrated a small cell lung cancer/adenoma collision tumor. Conclusions This case and a review of the literature demonstrate that FDG, CT and MR imaging can all characterize the separate components of collision tumors within the adrenal gland.

e14724 Background: Outcomes are poor in patients with gastric cancer, and recurrence is common. Perioperative chemotherapy and adjuvant chemoradiation therapy (CRT) improve survival in patients with resectable disease. Experience with neoadjuvant CRT for potentially resectable disease is limited, and its role remains undefined. We report our experience using neoadjuvant CRT for potentially resectable gastric cancer. Methods: An IRB-approved, retrospective review from 1994 to 2007 identified 23 patients with biopsy-proven, potentially resectable gastric cancer. Patients had T2/T3 and/or N1 disease and no evidence of metastatic disease by endoscopic ultrasound and cross-sectional imaging. All underwent neoadjuvant external beam radiation with concurrent 5-FU or platinum-based chemotherapy followed by restaging and surgery if appropriate. Results: Of the 23 patients, 20 completed neoadjuvant CRT and surgical exploration. Two patients (n=2) had radiographic disease progression during neoadjuvant CRT and did not undergo resection. One patient (n=1) developed a perforated gastric ulcer during CRT and underwent emergent resection. The median time from diagnosis to surgery and completion of neoadjuvant CRT to surgery was 104 days and 37.5 days, respectively. Gastrectomy was performed in 17 (85%) patients who completed neoadjuvant CRT. Metastatic disease was identified in the remaining 3 (15%) patients. Following gastrectomy, a complete pathologic response was observed in 4 (23.5%) patients, a partial response in 11 (64.7%) patients, and no response was identified in 2 (11.8%) patients. One (6%) patient had microscopic positive margins, and 9 (53%) had positive lymph nodes. There was no perioperative mortality. Two (11.8%) patients had anastomotic leaks, which were managed non-operatively. The median length of stay was 10 days. The median disease-free survival was 10.5 months, and median overall survival was 19.6 months. Conclusions: Gastric cancer carries a poor prognosis. Surgical resection after neoadjuvant CRT has low treatment-associated morbidity and mortality. Survival and complete response rates are comparable to published series. Further evaluation of this treatment strategy is warranted to assess its efficacy.

Background: It is our hypothesis that the extent of thyroid resection for benign nodular thyroid disease (NTD) should be based on the extent of disease. Methods: Patients operated on for benign NTD from 1990-2007 were divided into three groups, those who underwent lobectomy for unilateral NTD (Group 1), near-total or total thyroidectomy for bilateral NTD (Group 2), and reoperation for NTD initially treated at other institutions (Group 3). The incidence of recurrence was determined for Groups 1 and 2 and the timing of diagnosis was compared to Group 3. Potential risk factors for recurrent disease were examined. Results: 511 patients were operated on for benign NTD. Contralateral disease was excluded in Group 1 patients using ultrasound (45%) and/or intraoperative palpation. Five (2%) of 246 patients in Group 1 and one (0.4%) of 230 patients in Group 2 developed recurrent NTD after 8 / 5 and 4 yrs compared to a mean 19 / 11 yrs for the 35 patients in Group 3 following one to three previous thyroidectomies. Recurrent disease was diagnosed by physical exam in 22 (54%) and imaging in 19 (46%) patients. Thyroid hormone was required for post-surgical hypothyroidism in 70 (28%) patients in Group 1. Patients with recurrent disease were younger (38 / 18 yrs vs. 50 / 15 yrs, p 0.05), had a higher body mass index (BMI) (33.3 / 7.3 kg/m vs. 30.6 / 8.0 kg/m, p 0.05) and were more often African American (42.5% versus 34.7%, p 0.05). Conclusion: Thyroid lobectomy is optimal therapy when benign NTD is limited to one lobe, as evidenced by a 2% recurrence rate and maintenance of euthyroidism in 72% of patients. When NTD is bilateral, total thyroidectomy is indicated to eliminate recurrence, underscoring the importance of routine preoperative ultrasound. Young age, African American race and increased BMI are risk factors for recurrent NTD and warrant more aggressive follow up.

Hypothesis Patients receiving neoadjuvant chemoradiotherapy followed by surgery (CRS) undergo downstaging of their tumor and have improved survival when compared with patients undergoing surgery followed by adjuvant chemoradiotherapy (SCR). Design Retrospective study. Setting Tertiary-care university medical center. Patients One hundred twenty-three patients with squamous cell carcinoma and adenocarcinoma of the esophagus underwent Ivor-Lewis esophagectomy from January 1, 1990, through December 31, 2001. Of these, 31 received CRS; 27, SCR; and 65, surgery alone. Interventions Patients were candidates for neoadjuvant or adjuvant therapy if they had locally advanced disease (T3/T4 N0 or any T stage with N1). Neoadjuvant and adjuvant therapies were nonrandomized and based on the preference of the treating oncologist and surgeon. Main Outcome Measurements Pathological downstaging was analyzed in the patients receiving CRS. Operative mortality, postoperative morbidity, median survival, and overall survival were compared between the CRS and SCR groups. Results Pathological downstaging (as characterized by TNM staging) was observed in 20 (64%) of the patients receiving CRS. Complete pathological responses occurred in 5 (16%) of the patients undergoing CRS. No 30-day mortality was observed in either treatment group. No statistical difference in survival was observed between groups, although a trend suggested improved survival with neoadjuvant therapy (3-year survival in CRS and SCR groups was 45% and 22%, respectively; P = .15). Complete pathological responders in the CRS group had a 1-year survival of 80% compared with 29% in nonresponders ( P = .25). No statistical differences were observed between groups in relation to blood loss, length of hospital stay, mortality, or morbidity. Conclusions Neoadjuvant chemoradiotherapy effectively downstages cancer in patients with locally advanced esophageal disease. Morbidity and operative mortality were not significantly different between patients receiving neoadjuvant and adjuvant therapy. The difference in overall survival between the 2 groups did not reach statistical significance, although a trend at 3 years was observed.