Dr. Electron Kebebew is an internationally recognized expert in Endocrine Oncology and Surgery. He has performed more than four thousand operations on the adrenal, parathyroid, and thyroid glands, and for neuroendocrine tumors of the gastrointestinal tract and pancreas. He has given over 200 invited lectures and visiting professorships. His clinical and translational studies on endocrine and neuroendocrine tumors have been awarded more than $30 million in research funding. Dr. Kebebew has authored and coauthored over 400 scientific articles, 40 book chapters, and edited or co-edited four textbooks. His scientific contributions include the use of molecular markers in thyroid nodule to refine diagnosis and prognostication, identification of novel target for endocrine cancer therapy, implementation of genetic testing and advanced imaging modality to optimize the management of patients with endocrine neoplasm and to allow the practice of precision surgery, and the identification and characterization of inherited endocrine and neuroendocrine syndromes, and their susceptibility genes.

Clinical Focus

  • Thyroid Cancer/Nodules
  • Hyperthyroidism
  • Goiter
  • Thyroid Surgery
  • Hyperparathyroidism
  • Parathyroid Surgery
  • Endocrine Surgery
  • Endocrine Tumors
  • Neuroendocrine tumors of the gastrointestinal tract and pancreas
  • Adrenalectomy/Adrenal Surgery
  • Adrenal Tumors
  • Primary hyperaldosteronism
  • Adrenal Cushing's syndrome
  • Pheochromocytoma/Paraganglioma
  • General Surgery

Academic Appointments

Professional Education

  • Board Certification: American Board of Surgery, General Surgery (2003)
  • Residency: UCSF General Surgery Residency (2002) CA
  • Postdoctoral training, NCI T32 fellowship, Cancer Biology (1998)
  • Medical Education: University of California at San Francisco School of Medicine (1995) CA

Current Research and Scholarly Interests

Dr. Kebebew’s translational and clinical investigations have three main scientific goals: 1) to develop effective therapies for fatal, rare and neglected endocrine cancers, 2) to identify new methods, strategies and technologies for improving the diagnosis and treatment of endocrine neoplasms and the prognostication of endocrine cancers, and 3) to develop methods for precision treatment of endocrine tumors.

Clinical Trials

  • Study of Relacorilant in Combination With Pembrolizumab for Patients With Adrenocortical Carcinoma Which Produces Too Much Stress Hormone (Cortisol) Not Recruiting

    This study will investigate the safety and efficacy of Relacorilant in combination with Pembrolizumab for Patients with Adrenocortical Carcinoma which Produces Too Much Stress Hormone (Cortisol).

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

    View full details

Stanford Advisees

All Publications

  • Evaluation of Adrenal Incidentaloma. The Surgical clinics of North America Hu, J., Kassu, R., Titanji, B., Kebebew, E. 2024; 104 (4): 837-849


    Adrenal incidentalomas have increased due to advanced and more sensitive imaging modalities, their increased utilization, and the aging population. Most adrenal incidentalomas are nonfunctional and benign, but a subset of patients has functional and/or malignant tumors. The evaluation of patients with an adrenal incidentaloma involves addressing 2 clinical questions: (1) Is the tumor functional? (2) Is the tumor malignant? A careful history and physical examination focused on signs and symptoms of adrenal functional tumors, biochemical testing, and imaging features are the cornerstone in the evaluation of patients with an adrenal incidentaloma.

    View details for DOI 10.1016/j.suc.2024.02.012

    View details for PubMedID 38944503

  • Beta Probe for Radioguided Surgery in Gastrointestinal Neuroendocrine Tumors: A Move in the Right Direction. Annals of surgical oncology Kebebew, E. 2024

    View details for DOI 10.1245/s10434-024-15439-x

    View details for PubMedID 38743279

  • Anaplastic thyroid cancer spheroids as preclinical models to test therapeutics. Journal of experimental & clinical cancer research : CR Hu, J., Liu, K., Ghosh, C., Khaket, T. P., Shih, H., Kebebew, E. 2024; 43 (1): 85


    Anaplastic thyroid cancer (ATC) is the most aggressive thyroid cancer. Despite advances in tissue culture techniques, a robust model for ATC spheroid culture is yet to be developed. In this study, we created an efficient and cost-effective 3D tumor spheroids culture system from human ATC cells and existing cell lines that better mimic patient tumors and that can enhance our understanding of in vivo treatment response. We found that patient-derived ATC cells and cell lines can readily form spheroids in culture with a unique morphology, size, and cytoskeletal organization. We observed both cohesive (dense and solid structures) and discohesive (irregularly shaped structures) spheroids within the same culture condition across different cell lines. BRAFWT ATC spheroids grew in a cohesive pattern, while BRAFV600E-mutant ATC spheroids had a discohesive organization. In the patient-derived BRAFV600E-mutant ATC spheroids, we observed both growth patterns, but mostly the discohesive type. Histologically, ATC spheroids had a similar morphology to the patient's tumor through H&E staining and proliferation marker staining. Moreover, RNA sequencing analysis revealed that the gene expression profile of tumor cells derived from the spheroids closely matched parental patient tumor-derived cells in comparison to monolayer cultures. In addition, treatment response to combined BRAF and MEK inhibition in BRAFV600E-mutant ATC spheroids exhibited a similar sensitivity to the patient clinical response. Our study provides a robust and novel ex vivo spheroid model system that can be used in both established ATC cell lines and patient-derived tumor samples to better understand the biology of ATC and to test therapeutics.

    View details for DOI 10.1186/s13046-024-03009-8

    View details for PubMedID 38500204

  • Festschrift for Dr. Jeffrey A. Norton, 12-13 October 2023, Stanford, CA, USA. Annals of surgical oncology Poultsides, G. A., Kebebew, E., Hawn, M. T. 2024

    View details for DOI 10.1245/s10434-024-15160-9

    View details for PubMedID 38488895

    View details for PubMedCentralID 1876967

  • Evidence of the Role of Inflammation and the Hormonal Environment in the Pathogenesis of Adrenal Myelolipomas in Congenital Adrenal Hyperplasia. International journal of molecular sciences Kolli, V., Frucci, E., da Cunha, I. W., Iben, J. R., Kim, S. A., Mallappa, A., Li, T., Faucz, F. R., Kebebew, E., Nilubol, N., Quezado, M. M., Merke, D. P. 2024; 25 (5)


    Adrenal myelolipomas (AML) are composed of mature adipose and hematopoietic components. They represent approximately 3 percent of adrenal tumors and are commonly found in patients with congenital adrenal hyperplasia (CAH). CAH provides a unique environment to explore AML pathogenesis. We aimed to evaluate the role of the immune system and hormones that accumulate in poorly controlled CAH in the development of AML. When compared to normal adrenal tissue, CAH-affected adrenal tissue and myelolipomas showed an increased expression of inflammatory cells (CD68, IL2Rbeta), stem cells (CD117) B cells (IRF4), and adipogenic markers (aP2/FABP4, AdipoQ, PPARγ, Leptin, CideA), and immunostaining showed nodular lymphocytic accumulation. Immunohistochemistry staining revealed a higher density of inflammatory cells (CD20, CD3, CD68) in CAH compared to non-CAH myelolipomas. In vitro RNA-sequencing studies using NCI-H295R adrenocortical cells with exogenous exposure to ACTH, testosterone, and 17-hydroxyprogesterone hormones, showed the differential expression of genes involved in cell cycle progression, phosphorylation, and tumorigenesis. Migration of B-lymphocytes was initiated after the hormonal treatment of adrenocortical cells using the Boyden chamber chemotaxis assay, indicating a possible hormonal influence on triggering inflammation and the development of myelolipomas. These findings demonstrate the important role of inflammation and the hormonal milieu in the development of AML in CAH.

    View details for DOI 10.3390/ijms25052543

    View details for PubMedID 38473790

  • Disparities in access to high-volume parathyroid surgeons in the United States: A call to action. Surgery Wright, K., Squires, S., Cisco, R., Trickey, A., Kebebew, E., Suh, I., Seib, C. D. 2023


    Parathyroidectomy by a high-volume surgeon is associated with a reduced risk of perioperative complications and of failure to cure primary and secondary hyperparathyroidism. There are limited data on disparities in access to high-volume parathyroid surgeons in the United States.We used publicly available 2019 Medicare Provider Utilization and Payment data to identify all surgeons who performed >10 parathyroidectomies for Medicare fee-for-service beneficiaries, anticipating that fee-for-service beneficiaries likely represent only a subset of their high-volume practices. High-volume parathyroid surgeon characteristics and geographic distribution were evaluated. Inequality in the distribution of surgeons was measured by the Gini coefficient. The association between neighborhood disadvantage, based on the Area Deprivation Index, and proximity to high-volume parathyroid surgeons was evaluated using a one-way analysis of variance with Bonferroni-corrected pairwise comparisons. A sensitivity analysis was performed restricting to high-volume parathyroid surgeons within each hospital referral region, evidence-based regional markets for tertiary medical care.We identified 445 high-volume parathyroid surgeons who met inclusion criteria with >10 parathyroidectomies for Medicare fee-for-service beneficiaries. High-volume parathyroid surgeons were 71% male sex, and 59.8% were general surgeons. High-volume parathyroid surgeons were more likely to practice in a Metropolitan Statistical Area with a population >1 million than in less populous metropolitan or rural areas. The number of high-volume parathyroid surgeons per 100,000 fee-for-service Medicare beneficiaries in the 53 most populous Metropolitan Statistical Areas ranged from 0 to 4.94, with the highest density identified in Salt Lake City, Utah. In 2019, 50% of parathyroidectomies performed by high-volume parathyroid surgeons were performed by 20% of surgeons in this group, suggesting unequal distribution of surgical care (Gini coefficient 0.41). Patients in disadvantaged neighborhoods were farther from high-volume parathyroid surgeons than those in advantaged neighborhoods (median distance: disadvantaged 27.8 miles, partially disadvantaged 20.7 miles, partially advantaged 12.1 miles, advantaged 8.4 miles; P < .001). This association was also shown in the analysis of distance to high-volume parathyroid surgeons within the hospital referral region (P < .001).Older adults living in disadvantaged neighborhoods have less access to high-volume parathyroid surgeons, which may adversely affect treatment and outcomes for patients with primary and secondary hyperparathyroidism. This disparity highlights the need for actionable strategies to provide equitable access to care, including improved regionalization of high-volume parathyroid surgeon services and easing travel-related burdens for underserved patients.

    View details for DOI 10.1016/j.surg.2023.03.028

    View details for PubMedID 37940435

  • Advances in translational research of the rare cancer type adrenocortical carcinoma. Nature reviews. Cancer Ghosh, C., Hu, J., Kebebew, E. 2023


    Adrenocortical carcinoma is a rare malignancy with an annual worldwide incidence of 1-2 cases per 1 million and a 5-year survival rate of <60%. Although adrenocortical carcinoma is rare, such rare cancers account for approximately one third of patients diagnosed with cancer annually. In the past decade, there have been considerable advances in understanding the molecular basis of adrenocortical carcinoma. The genetic events associated with adrenocortical carcinoma in adults are distinct from those of paediatric cases, which are often associated with germline or somatic TP53 mutations and have a better prognosis. In adult primary adrenocortical carcinoma, the main somatic genetic alterations occur in genes that encode proteins involved in the WNT-β-catenin pathway, cell cycle and p53 apoptosis pathway, chromatin remodelling and telomere maintenance pathway, cAMP-protein kinase A (PKA) pathway or DNA transcription and RNA translation pathways. Recently, integrated molecular studies of adrenocortical carcinomas, which have characterized somatic mutations and the methylome as well as gene and microRNA expression profiles, have led to a molecular classification of these tumours that can predict prognosis and have helped to identify new therapeutic targets. In this Review, we summarize these recent translational research advances in adrenocortical carcinoma, which it is hoped could lead to improved patient diagnosis, treatment and outcome.

    View details for DOI 10.1038/s41568-023-00623-0

    View details for PubMedID 37857840

    View details for PubMedCentralID 8679848

  • Combination BRAFV600E inhibition with the multitargeting tyrosine kinase inhibitor axitinib shows additive anticancer activity in BRAFV600E-mutant anaplastic thyroid cancer. Thyroid : official journal of the American Thyroid Association Gunda, V., Ghosh, C., Hu, J., Zhang, L., Zhang, Y. Q., Shen, M., Kebebew, E. 2023


    Anaplastic thyroid cancer (ATC) is uniformly lethal. BRAFV600E mutation is present in up to 45% of patients with ATC. Targeted therapy with combined BRAF and MEK inhibition in BRAFV600E-mutant ATC can be effective, but acquired resistance is common because this combination targets the same pathway. Drug matrix screening, in BRAFV600E ATC cells, of highly active compounds in combination with BRAF inhibition showed multitargeting tyrosine kinase inhibitors (MTKIs) had the highest synergistic/additive activity. Thus, we hypothesized that the combination of BRAFV600E inhibition and an MTKI is more effective than a single drug or combined BRAF and MEK inhibition in BRAFV600E-mutant ATC. We evaluated the effect of BRAFV600E inhibitors in combination with the MTKI axitinib and its mechanism(s) of action.We evaluated the effects of BRAFV600E inhibitors and axitinib alone and in combination in in vitro and in vivo models of BRAFV600E-mutant and wildtype ATC.The combination of axitinib and BRAFV600E inhibitors (dabrafenib and PLX4720) showed an additive effect on inhibiting cell proliferation based on the Chou-Talalay algorithm in BRAFV600E-mutant ATC cell lines. This combination also significantly inhibited cell invasion and migration (P < 0.001) compared with the control. Dabrafenib and PLX4720 arrested ATC cells in the G0/G1 phase. Axitinib arrested ATC cells in the G2/M phase by decreasing phosphorylation of aurora kinase B (Thr232) and histone H3 (Ser10) proteins and by upregulating the c-JUN signaling pathway. The combination of BRAF inhibition and axitinib significantly inhibited tumor growth and was associated with improved survival in an orthotopic ATC model.The novel combination of axitinib and BRAFV600E inhibition enhanced anticancer activity in in vitro and in vivo models of BRAFV600E-mutant ATC. This combination may have clinical utility in BRAFV600E-mutant ATC that is refractory to current standard therapy, namely combined BRAF and MEK inhibition.

    View details for DOI 10.1089/thy.2023.0201

    View details for PubMedID 37675898

  • Estimated Effect of Parathyroidectomy on Long-Term Kidney Function in Adults With Primary Hyperparathyroidism. Annals of internal medicine Seib, C. D., Ganesan, C., Furst, A., Pao, A. C., Chertow, G. M., Leppert, J. T., Suh, I., Montez-Rath, M. E., Harris, A. H., Trickey, A. W., Kebebew, E., Tamura, M. K. 2023


    BACKGROUND: Multidisciplinary guidelines recommend parathyroidectomy to slow the progression of chronic kidney disease in patients with primary hyperparathyroidism (PHPT) and an estimated glomerular filtration rate (eGFR) less than 60mL/min/1.73 m2. Limited data address the effect of parathyroidectomy on long-term kidney function.OBJECTIVE: To compare the incidence of a sustained decline in eGFR of at least 50% among patients with PHPT treated with parathyroidectomy versus nonoperative management.DESIGN: Target trial emulation was done using observational data from adults with PHPT, using an extended Cox model with time-varying inverse probability weighting.SETTING: Veterans Health Administration.PATIENTS: Patients with a new biochemical diagnosis of PHPT in 2000 to 2019.MEASUREMENTS: Sustained decline of at least 50% from pretreatment eGFR.RESULTS: Among 43697 patients with PHPT (mean age, 66.8years), 2928 (6.7%) had a decline of at least 50% in eGFR over a median follow-up of 4.9years. The weighted cumulative incidence of eGFR decline was 5.1% at 5years and 10.8% at 10 years in patients managed with parathyroidectomy, compared with 5.1% and 12.0%, respectively, in those managed nonoperatively. The adjusted hazard of eGFR decline did not differ between parathyroidectomy and nonoperative management (hazard ratio [HR], 0.98 [95% CI, 0.82 to 1.16]). Subgroup analyses found no heterogeneity of treatment effect based on pretreatment kidney function. Parathyroidectomy was associated with a reduced hazard of the primary outcome among patients younger than 60years (HR, 0.75 [CI, 0.59 to 0.93]) that was not evident among those aged 60years or older (HR, 1.08 [CI, 0.87 to 1.34]).LIMITATION: Analyses were done in a predominantly male cohort using observational data.CONCLUSION: Parathyroidectomy had no effect on long-term kidney function in older adults with PHPT. Potential benefits related to kidney function should not be the primary consideration for PHPT treatment decisions.PRIMARY FUNDING SOURCE: National Institute on Aging.

    View details for DOI 10.7326/M22-2222

    View details for PubMedID 37037034

  • Increased Risk of Complications Associated With Concurrent Parathyroidectomy in Patients Undergoing Total Thyroidectomy. The Journal of surgical research Cisco, R., Arnow, K., Barreto, N., Lin, D., Kebebew, E., Seib, C. 2023; 288: 275-281


    We sought to investigate the association of concurrent parathyroidectomy (PTX) with risks of total thyroidectomy (TTX) through analysis of Collaborative Endocrine Surgery Quality Improvement Program data. TTXis a common operation with complications including recurrent laryngeal nerve injury, neck hematoma, and hypoparathyroidism. A subset of patients undergoing thyroidectomy undergoes planned concurrent PTX for treatment of primary hyperparathyroidism. There are limited data on the risk profile of TTX with concurrent PTX (TTX + PTX).We queried the Collaborative Endocrine Surgery Quality Improvement Program database for patients who underwent TTX or TTX + PTX from January 2014 through April 2020. Multivariable logistic regression was performed to predict hypoparathyroidism, vocal cord dysfunction, neck hematoma, and postoperative emergency department visit. Covariates included patient demographics, patient body mass index, indication for surgery, central neck dissection, anticoagulation use, and surgeon volume.Thirteen thousand six hundred forty seven patients underwent TTX and 654 patients underwent TTX + PTX. Unadjusted rates of hypoparathyroidism were higher in TTX + PTX patients at 30 d (9.6% versus 7.4%, P = 0.04) and 6 mo (7.9% versus 3.1%, P < 0.001). On multivariable regression, TTX + PTX was associated with an increased risk of hypoparathyroidism at 30 d (odds ratio [OR] 2.09, 95% confidence interval [CI] 1.57-2.79) and 6 mo (OR 4.63, 95% CI 3.06-7.00) and an increased risk of postoperative emergency department visit (OR 1.66, 95% CI 1.20-2.31). TTX + PTX was not associated with recurrent laryngeal nerve injury or neck hematoma.Concurrent PTX in patients undergoing TTX is associated with increased risk of immediate and long-term hypoparathyroidism, which should be considered in informed consent discussions and operative decision-making.

    View details for DOI 10.1016/j.jss.2023.02.036

    View details for PubMedID 37043874

  • A Contemporary Review of the Treatment of Medullary Thyroid Carcinoma in the Era of New Drug Therapies. Surgical oncology clinics of North America Seib, C. D., Beck, T. C., Kebebew, E. 2023; 32 (2): 233-250


    Medullary thyroid cancer (MTC) is a rare neuroendocrine tumor that can be sporadic or inherited and is often associated with mutations in the RET (Rearranged during Transfection) oncogene. The primary treatment for MTC is surgical resection of all suspected disease, but recent advances in targeted therapies for MTC, including the selective RET inhibitors selpercatinib and pralsetinib, have led to changes in the management of patients with locally advanced, metastatic, or recurrent MTC. In this article, we review updates on the evaluation and management of patients with MTC, focusing on new and emerging therapies that are likely to improve patient outcomes.

    View details for DOI 10.1016/j.soc.2022.10.002

    View details for PubMedID 36925182

  • In Memoriam: Orlo H. Clark, MD (1941-2022). Thyroid : official journal of the American Thyroid Association Shen, W. T., Kebebew, E., Shoback, D., Liu, C., Gosnell, J. E., Caron, N. R. 2023



    View details for DOI 10.1089/thy.2023.0019

    View details for PubMedID 36719769

  • A multicenter evaluation of near-infrared autofluorescence imaging of parathyroid glands in thyroid and parathyroid surgery. Surgery Sehnem, L. J., Noureldine, S. I., Avci, S., Isiktas, G., Elshamy, M., Saito, Y., Ahmed, A. H., Tierney, H. T., Trinh, L. N., Karcioglu, A. S., Cheung, A. Y., Otremba, M., Krishnamurthy, V., Heiden, K., Jin, J., Shin, J., Siperstein, A., Zafereo, M., Tufano, R. P., Randolph, G. W., Kebebew, E., Milas, M., Duh, Q., Berber, E. 2023; 173 (1): 132-137


    BACKGROUND: The usefulness of incorporating near-infrared autofluorescence into the surgical workflow of endocrine surgeons is unclear. Our aim was to develop a prospective registry and gather expert opinion on appropriate use of this technology.METHODS: This was a prospective multicenter collaborative study of patients undergoing thyroidectomy and parathyroidectomy at 7 academic centers. A questionnaire was disseminated among 24 participating surgeons.RESULTS: Overall, 827 thyroidectomy and parathyroidectomy procedures were entered into registry: 42% of surgeons found near-infrared autofluorescence useful in identifying parathyroid glands before they became apparent; 67% correlated near-infrared autofluorescence pattern to normal and abnormal glands; 38% of surgeons used near-infrared autofluorescence, rather than frozen section, to confirm parathyroid tissue; and 87% and 78% of surgeons reported near-infrared autofluorescence did not improve the success rate after parathyroidectomy or the ability to find ectopic glands, respectively. During thyroidectomy, 66% of surgeons routinely used near-infrared autofluorescence to rule out inadvertent parathyroidectomy. However, only 36% and 45% felt near-infrared autofluorescence decreased inadvertent parathyroidectomy rates and improved ability to preserve parathyroid glands during central neck dissections, respectively.CONCLUSION: This survey study identified areas of greatest potential use for near-infrared autofluorescence, which can form the basis of future objective trials to document the usefulness of this technology.

    View details for DOI 10.1016/j.surg.2022.07.057

    View details for PubMedID 36511281

  • Risk of permanent hypoparathyroidism requiring calcitriol therapy in a population-based cohort of adults older than 65 undergoing total thyroidectomy for Graves' disease. Thyroid : official journal of the American Thyroid Association Seib, C. D., Meng, T., Cisco, R. M., Lin, D. T., McAninch, E. A., Chen, J., Tamura, M. K., Trickey, A. W., Kebebew, E. 2022


    Total thyroidectomy for Graves' disease (GD) is associated with rapid treatment of hyperthyroidism and low recurrence rates. However, it carries the risk of surgical complications including permanent hypoparathyroidism, which contribute to long-term impaired quality of life. The objective of this study was to determine the incidence of permanent hypoparathyroidism requiring calcitriol therapy among a population-based cohort of older adults undergoing total thyroidectomy for GD in the U.S.We performed a population-based cohort study using 100% Medicare claims from beneficiaries older than 65 with GD who underwent total thyroidectomy from 2007 to 2017. We required continuous enrollment in Medicare Parts A, B, and D for 12 months before and after surgery to ensure access to comprehensive claims data. Patients were excluded if they had a preoperative diagnosis of thyroid cancer or were on long-term preoperative calcitriol. Our primary outcome was permanent hypoparathyroidism, which was identified based on persistent use of calcitriol between 6-12 months following thyroidectomy. We used multivariable logistic regression to identify characteristics associated with permanent hypoparathyroidism, including patient age, sex, race/ethnicity, neighborhood disadvantage, Charlson-Deyo Comorbidity Index, urban or rural residence, and frailty.We identified 4,650 patients who underwent total thyroidectomy for GD during the study period and met inclusion criteria (mean age 72.8 years [SD 5.5], 86% female, and 79% white). Among this surgical cohort, 104 (2.2%, 95% CI: 1.8-2.7%) patients developed permanent hypoparathyroidism requiring calcitriol therapy. Patients who developed permanent hypoparathyroidism were on average older (mean age 74.1 vs. 72.8 years) than those who did not develop permanent hypoparathyroidism (p=0.04). On multivariable regression, older age was the only patient characteristic associated with permanent hypoparathyroidism (odds ratio [OR] age ≥ 76 years 1.68 [95% CI 1.13-2.51] compared to age 66-75 years).The risk of permanent hypoparathyroidism requiring calcitriol therapy among this national, U.S. population-based cohort of older adults with GD treated with total thyroidectomy was low, even when considering operations performed by a heterogeneous group of surgeons. These findings suggest the risk of hypoparathyroidism should not be a deterrent to operative management for GD in older adults who are appropriate surgical candidates.

    View details for DOI 10.1089/thy.2022.0140

    View details for PubMedID 36416252

  • Just a Little Bit of Anaplastic Thyroid Cancer? Annals of surgical oncology Kebebew, E. 2022

    View details for DOI 10.1245/s10434-022-12703-w

    View details for PubMedID 36271305

  • Adverse Cardiovascular Outcomes Among Older Adults with Primary Hyperparathyroidism Treated with Parathyroidectomy vs. non-operative Management. Annals of surgery Seib, C. D., Meng, T., Cisco, R. M., Suh, I., Lin, D. T., Harris, A. H., Trickey, A. W., Tamura, M. K., Kebebew, E. 2022


    We sought to compare the incidence of adverse cardiovascular events in older adults with primary hyperparathyroidism (PHPT) treated with parathyroidectomy versus non-operative management.PHPT is a common endocrine disorder that is associated with increased cardiovascular mortality, but it is not known whether parathyroidectomy reduces the incidence of adverse cardiovascular events.We conducted a population-based, longitudinal cohort study of Medicare beneficiaries diagnosed with PHPT (2006-2017). Multivariable, inverse probability weighted Cox proportional hazards regression was used to determine the associations of parathyroidectomy with major adverse cardiovascular events (MACE), cardiovascular disease-related hospitalization, and cardiovascular hospitalization-associated mortality.We identified 210,206 beneficiaries diagnosed with PHPT from 2006-2017. Among 63,136 (30.0%) treated with parathyroidectomy and 147,070 (70.0%) managed non-operatively within one year of diagnosis, the unadjusted incidence of MACE was 10.0% (mean follow-up 59.1 [SD 35.6] months) and 11.5% (mean follow-up 54.1 [SD 34.0] months), respectively. In multivariable analysis, parathyroidectomy was associated with a lower incidence of MACE (HR 0.92 [95%CI 0.90-0.94]), cardiovascular disease-related hospitalization (HR 0.89 [95%CI 0.87-0.91]), and cardiovascular hospitalization-associated mortality (HR 0.76 [95%CI 0.71-0.81]) compared to non-operative management. At 10 years, parathyroidectomy was associated with adjusted absolute risk reduction for MACE of 1.7% (95%CI 1.3%-2.1%), for cardiovascular disease-related hospitalization of 2.5% (95%CI 2.1%-2.9%), and for cardiovascular hospitalization-associated mortality of 1.4% (95%CI 1.2%-1.6%).In this large, population-based cohort study, parathyroidectomy was associated with a lower long-term incidence of adverse cardiovascular outcomes when compared with non-operative management for older adults with PHPT, which is relevant to surgical decision-making for patients with a long life expectancy.

    View details for DOI 10.1097/SLA.0000000000005691

    View details for PubMedID 36005546

  • Integrated single-cell and plasma proteomic modeling to predict surgical site complications, a prospective cohort study Tsai, A. S., Hedou, J., Einhaus, J., Rumer, K., Verdonk, F., Stanley, N., Choisy, B., Ganio, E. A., Bonham, A., Jacobsen, D., Warrington, B., Gao, X., Tingle, M., McAllister, T., Fallahzadeh, R., Feyaerts, D., Stelzer, I., Gaudilliere, D., Ando, K., Shelton, A., Morris, A., Kebebew, E., Aghaeepour, N., Kin, C., Angst, M. S., Gaudilliere, B. LIPPINCOTT WILLIAMS & WILKINS. 2022: 1204-1205
  • Kidney stone events following parathyroidectomy vs. non-operative management for primary hyperparathyroidism. The Journal of clinical endocrinology and metabolism Seib, C. D., Ganesan, C., Arnow, K. D., Pao, A. C., Leppert, J. T., Barreto, N. B., Kebebew, E., Tamura, M. K. 2022


    CONTEXT: Primary hyperparathyroidism (PHPT) is associated with an increased risk of kidney stones. Few studies account for PHPT severity or stone risk when comparing stone events after parathyroidectomy vs. non-operative management.OBJECTIVE: Compare the incidence of kidney stone events in PHPT patients treated with parathyroidectomy vs. non-operative management.DESIGN: Longitudinal cohort study with propensity score inverse probability weighting and multivariable Cox proportional hazards regression.SETTING: Veterans Health Administration integrated health care system.PATIENTS: 44,978 patients with >2 years follow-up after PHPT diagnosis (2000-2018). 5,244 patients (11.7%) were treated with parathyroidectomy.MAIN OUTCOMES MEASURE: Clinically significant kidney stone event.RESULTS: The cohort had a mean age of 66.0 years, was 87.8% male, 66.4% White. Patients treated with parathyroidectomy had higher mean serum calcium (11.2 vs. 10.8mg/dL) and were more likely to have a history of kidney stone events. Among patients with baseline history of kidney stones, the unadjusted incidence of ≥1 kidney stone event was 30.5% in patients managed with parathyroidectomy (mean follow-up 5.6 years) compared to 18.0% in those managed non-operatively (mean follow-up 5.0 years). Patients treated with parathyroidectomy had a higher adjusted hazard of recurrent kidney stone events (hazard ratio[HR] 1.98, 95%CI 1.56-2.51); however, this association declined over time (parathyroidectomy*time HR 0.80, 95%CI 0.73-0.87).CONCLUSION: In this predominantly male cohort with PHPT, patients treated with parathyroidectomy continued to be at higher risk of kidney stone events in the immediate years after treatment than patients managed non-operatively, although the adjusted risk of stone events declined with time, suggesting a benefit to surgical treatment.

    View details for DOI 10.1210/clinem/dgac193

    View details for PubMedID 35363858

  • Succinate Accumulation Is Not Sufficient for Tumorigenesis in Mouse Chromaffin Cells But Dual Loss of SDHB and NF1 Yields SDHx-Like Pheochromocytomas Armstrong, N., Storey, C. M., Noll, S. E., Margulis, K., Soe, M. H., Xu, H., Yeh, B., Fishbein, L., Kebebew, E., Howitt, B. E., Zare, R. N., Sage, J., Annes, J. P. LIPPINCOTT WILLIAMS & WILKINS. 2022: E32-E33
  • SDHB knockout and succinate accumulation are insufficient for tumorigenesis but dual SDHB/NF1 loss yields SDHx-like pheochromocytomas. Cell reports Armstrong, N., Storey, C. M., Noll, S. E., Margulis, K., Soe, M. H., Xu, H., Yeh, B., Fishbein, L., Kebebew, E., Howitt, B. E., Zare, R. N., Sage, J., Annes, J. P. 2022; 38 (9): 110453


    Inherited pathogenic succinate dehydrogenase (SDHx) gene mutations cause the hereditary pheochromocytoma and paraganglioma tumor syndrome. Syndromic tumors exhibit elevated succinate, an oncometabolite that is proposed to drive tumorigenesis via DNA and histone hypermethylation, mitochondrial expansion, and pseudohypoxia-related gene expression. To interrogate this prevailing model, we disrupt mouse adrenal medulla SDHB expression, which recapitulates several key molecular features of human SDHx tumors, including succinate accumulation but not 5hmC loss, HIF accumulation, or tumorigenesis. By contrast, concomitant SDHB and the neurofibromin 1 tumor suppressor disruption yields SDHx-like pheochromocytomas. Unexpectedly, invivo depletion of the 2-oxoglutarate (2-OG) dioxygenase cofactor ascorbate reduces SDHB-deficient cell survival, indicating that SDHx loss may be better tolerated by tissues with high antioxidant capacity. Contrary to the prevailing oncometabolite model, succinate accumulation and 2-OG-dependent dioxygenase inhibition are insufficient for mouse pheochromocytoma tumorigenesis, which requires additional growth-regulatory pathway activation.

    View details for DOI 10.1016/j.celrep.2022.110453

    View details for PubMedID 35235785

  • Integrated Single-Cell and Plasma Proteomic Modeling to Predict Surgical Site Complications: A Prospective Cohort Study. Annals of surgery Rumer, K. K., Hedou, J., Tsai, A., Einhaus, J., Verdonk, F., Stanley, N., Choisy, B., Ganio, E., Bonham, A., Jacobsen, D., Warrington, B., Gao, X., Tingle, M., McAllister, T. N., Fallahzadeh, R., Feyaerts, D., Stelzer, I., Gaudilliere, D., Ando, K., Shelton, A., Morris, A., Kebebew, E., Aghaeepour, N., Kin, C., Angst, M. S., Gaudilliere, B. 1800


    OBJECTIVE: The aim of this study was to determine whether single-cell and plasma proteomic elements of the host's immune response to surgery accurately identify patients who develop a surgical site complication (SSC) after major abdominal surgery.SUMMARY BACKGROUND DATA: SSCs may occur in up to 25% of patients undergoing bowel resection, resulting in significant morbidity and economic burden. However, the accurate prediction of SSCs remains clinically challenging. Leveraging high-content proteomic technologies to comprehensively profile patients' immune response to surgery is a promising approach to identify predictive biological factors of SSCs.METHODS: Forty-one patients undergoing non-cancer bowel resection were prospectively enrolled. Blood samples collected before surgery and on postoperative day one (POD1) were analyzed using a combination of single-cell mass cytometry and plasma proteomics. The primary outcome was the occurrence of an SSC, including surgical site infection, anastomotic leak, or wound dehiscence within 30 days of surgery.RESULTS: A multiomic model integrating the single-cell and plasma proteomic data collected on POD1 accurately differentiated patients with (n = 11) and without (n = 30) an SSC [area under the curve (AUC) = 0.86]. Model features included coregulated proinflammatory (eg, IL-6- and MyD88- signaling responses in myeloid cells) and immunosuppressive (eg, JAK/STAT signaling responses in M-MDSCs and Tregs) events preceding an SSC. Importantly, analysis of the immunological data obtained before surgery also yielded a model accurately predicting SSCs (AUC = 0.82).CONCLUSIONS: The multiomic analysis of patients' immune response after surgery and immune state before surgery revealed systemic immune signatures preceding the development of SSCs. Our results suggest that integrating immunological data in perioperative risk assessment paradigms is a plausible strategy to guide individualized clinical care.

    View details for DOI 10.1097/SLA.0000000000005348

    View details for PubMedID 34954754

  • Treatment for Advanced and Metastatic Thyroid Cancer Refractory to Standard Treatment-We Need to Know the When, What, and Who. JAMA oncology Kebebew, E. 1800

    View details for DOI 10.1001/jamaoncol.2021.6247

    View details for PubMedID 34913944

  • Factors associated with postoperative complications and costs for adrenalectomy in benign adrenal disorders. Surgery Sung, T., Tennakoon, L., Alobuia, W. M., Seib, C., Cisco, R., Lin, D., Kebebew, E. 2021


    BACKGROUND: The incidence of adrenal incidentaloma has been increasing, and indications of and approaches to adrenalectomy are diverse. Drivers of complications and costs are not well identified.METHODS: The 2016 National Inpatient Sample data were used to identify patients who underwent adrenalectomy for benign adrenal disorders, such as Cushing syndrome, primary hyperaldosteronism, pheochromocytoma, and other benign neoplasms defined using the 10th Revision of the International Classification of Diseases. The primary outcome was determining the factors associated with clinical outcomes, perioperative complications, and hospitalization costs.RESULTS: Using weighted estimates of the national sample data, 5,140 patients were identified. The mean age was 55 years. The majority of adrenalectomies were performed laparoscopically (48.5%) followed by a robotic approach (32.7%). The postoperative complication rate was 7.6%. In adjusted multivariable analyses, independent risk factors for perioperative complications included Hispanic race (odds ratio, 2.5; P = .01), and perioperative comorbid heart failure (odds ratio, 6.3; P < .001) and respiratory failure (odds ratio, 9.9; P < .001). The mean cost was $18,122. Independent risk factors associated with decrease of cost were female sex and primary hyperaldosteronism; factors associated with increased cost were pheochromocytoma, intraoperative complications, perioperative underlying comorbid respiratory failure and heart failure, and postoperative complications (P < .001).CONCLUSION: Among patients undergoing adrenalectomy for benign adrenal disorders, underlying comorbidities, including heart and respiratory failure, should be considered when recommending adrenalectomy, as these may increase the postoperative complication rates and hospitalization costs.

    View details for DOI 10.1016/j.surg.2021.10.065

    View details for PubMedID 34857386

  • Risk of Fracture Among Older Adults With Primary Hyperparathyroidism Receiving Parathyroidectomy vs Nonoperative Management. JAMA internal medicine Seib, C. D., Meng, T., Suh, I., Harris, A. H., Covinsky, K. E., Shoback, D. M., Trickey, A. W., Kebebew, E., Tamura, M. K. 2021


    Importance: Primary hyperparathyroidism (PHPT) contributes to the development and progression of osteoporosis in older adults. The effectiveness of parathyroidectomy for reducing fracture risk in older adults is unknown.Objective: To compare the incidence of clinical fracture among older adults with PHPT treated with parathyroidectomy vs nonoperative management.Design, Setting, and Participants: This was a population-based, longitudinal cohort study of all Medicare beneficiaries with PHPT from 2006 to 2017. Multivariable, inverse probability weighted Cox proportional hazards and Fine-Gray competing risk regression models were constructed to determine the association of parathyroidectomy vs nonoperative management with incident fracture. Data analysis was conducted from February 17, 2021, to September 14, 2021.Main Outcomes and Measures: The primary outcome was clinical fracture at any anatomic site not associated with major trauma during the follow-up period.Results: Among the 210 206 Medicare beneficiaries with PHPT (mean [SD] age, 75 [6.8] years; 165 637 [78.8%] women; 183 433 [87.3%] White individuals), 63 136 (30.0%) underwent parathyroidectomy within 1 year of diagnosis, and 147 070 (70.0%) were managed nonoperatively. During a mean (SD) follow-up period of 58.5 (35.5) months, the unadjusted incidence of fracture was 10.2% in patients treated with parathyroidectomy. During a mean (SD) follow-up of 52.5 (33.8) months, the unadjusted incidence of fracture was 13.7% in patients observed nonoperatively. On multivariable analysis, parathyroidectomy was associated with lower adjusted rates of any fracture (hazard ratio [HR], 0.78; 95% CI, 0.76-0.80]) and hip fracture (HR, 0.76; 95% CI, 0.72-0.79). At 2, 5, and 10 years, parathyroidectomy was associated with adjusted absolute fracture risk reduction of 1.2% (95% CI, 1.0-1.4), 2.8% (95% CI, 2.5-3.1), and 5.1% (95% CI, 4.6-5.5), respectively, compared with nonoperative management. On subgroup analysis, there were no significant differences in the association of parathyroidectomy with fracture risk by age group, sex, frailty, history of osteoporosis, or meeting operative guidelines. Fine-Gray competing risk regression confirmed parathyroidectomy was associated with a lower probability of any fracture and hip fracture when accounting for the competing risk of death (HR, 0.84; 95% CI, 0.82-0.85; and HR, 0.83; 95% CI, 0.80-0.85, respectively).Conclusions and Relevance: This longitudinal cohort study found that parathyroidectomy was associated with a lower risk of any fracture and hip fracture among older adults with PHPT, suggesting a clinically meaningful benefit of operative management in this population.

    View details for DOI 10.1001/jamainternmed.2021.6437

    View details for PubMedID 34842909

  • This Year in Thyroid and Farewell. Thyroid : official journal of the American Thyroid Association Kebebew, E. 2021



    View details for DOI 10.1089/thy.2021.0620

    View details for PubMedID 34806431

  • Adrenal Incidentaloma REPLY NEW ENGLAND JOURNAL OF MEDICINE Kebebew, E. 2021; 385 (8): 768
  • Racial disparities in the utilization of parathyroidectomy among patients with primary hyperparathyroidism: Evidence from a nationwide analysis of Medicare claims. Surgery Alobuia, W. M., Meng, T., Cisco, R. M., Lin, D. T., Suh, I., Tamura, M. K., Trickey, A. W., Kebebew, E., Seib, C. D. 2021


    BACKGROUND: Among patients with primary hyperparathyroidism, parathyroidectomy offers a chance of cure and mitigation of disease-related complications. The impact of race/ethnicity on referral and utilization of parathyroidectomy has not been fully explored.METHODS: Population-based, retrospective cohort study using 100% Medicare claims from beneficiaries with primary hyperparathyroidism from 2006 to 2016. Associations of race/ethnicity with disease severity, surgeon evaluation, and subsequent parathyroidectomy were analyzed using adjusted multivariable logistic regression models.RESULTS: Among 210,206 beneficiaries with primary hyperparathyroidism, 63,136 (30.0%) underwent parathyroidectomy within 1 year of diagnosis. Black patients were more likely than other races/ethnicities to have stage 3 chronic kidney disease (10.8%) but had lower prevalence of osteoporosis and nephrolithiasis compared to White patients, Black and Hispanic patients were more likely to have been hospitalized for primaryhyperparathyroidism-associated conditions (White 4.8%, Black 8.1%, Hispanic 5.8%; P < .001). Patients who were White and met operative criteria were more likely to undergo parathyroidectomy than Black, Hispanic, or Asian patients (White 30.5%, Black 23.0%, Hispanic 21.4%, Asian 18.7%; P < .001). Black and Hispanicpatients had lower adjusted odds of being evaluated by a surgeon (odds ratios 0.71 [95% confidenceinterval 0.69-0.74], 0.68 [95% confidence interval 0.61-0.74], respectively) and undergoing parathyroidectomy if evaluated by a surgeon (odds ratios 0.72 [95% confidence interval 0.68-0.77], 0.82 [95%confidence interval 0.67-0.99]). Asian race was associated with lower adjusted odds of being evaluated by a surgeon (odds ratio 0.64 [95% confidence interval 0.57-0.71]), but no difference in odds of parathyroidectomy.CONCLUSION: Racial/ethnic disparities exist in the management of primary hyperparathyroidism among older adults. Determining the factors that account for this disparity require urgent attention to achieve parity in the management of primary hyperparathyroidism.

    View details for DOI 10.1016/j.surg.2021.05.037

    View details for PubMedID 34229901

  • Association of parathyroidectomy with 5-year clinically significant kidney stone events in patients with primary hyperparathyroidism. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists Seib, C. D., Ganesan, C., Arnow, K. D., Suh, I., Pao, A. C., Leppert, J. T., Tamura, M. K., Trickey, A. W., Kebebew, E. 2021


    OBJECTIVE: Patients with primary hyperparathyroidism (PHPT) are at increased risk of kidney stones. Guidelines recommend parathyroidectomy in PHPT patients with a history of stone disease. This study aimed to compare the 5-year incidence of clinically significant kidney stone events in patients with PHPT treated with parathyroidectomy vs. non-operative management.METHODS: We performed a longitudinal cohort study of patients with PHPT in a national commercial insurance claims database (2006-2019). Propensity score inverse probability weighting-adjusted multivariable regression models were calculated.RESULTS: We identified 7,623 patients ≥35 years-old with continuous enrollment >1 year before and >5 years after PHPT diagnosis. 2,933 patients (38.5%) were treated with parathyroidectomy. The cohort had a mean age of 66.5 years, 78.1% were female, 72.4% were White. Over 5 years, the unadjusted incidence of ≥1 kidney stone event was higher in patients managed with parathyroidectomy compared to those managed non-operatively overall (5.4% vs. 4.1%) and among those with a history of kidney stones at PHPT diagnosis (17.9% vs. 16.4%). On multivariable analysis, parathyroidectomy was associated with no statistically significant difference in the odds of 5-year kidney stone event among patients with a history of kidney stones (OR 1.03, 95%CI 0.71-1.50) or those without history of kidney stones (OR 1.16, 95%CI 0.84-1.60).CONCLUSION: Based on this claims analysis, there was no difference in the odds of 5-year kidney stone events in PHPT patients treated with parathyroidectomy vs. non-operative management. Time-horizon for benefit should be considered when making treatment decisions for PHPT based on risk of kidney stone events.

    View details for DOI 10.1016/j.eprac.2021.06.004

    View details for PubMedID 34126246

  • Adrenal Incidentaloma. The New England journal of medicine Kebebew, E. 2021; 384 (16): 1542–51

    View details for DOI 10.1056/NEJMcp2031112

    View details for PubMedID 33882207

  • 2021 American Thyroid Association Guidelines for Management of Patients with Anaplastic Thyroid Cancer. Thyroid : official journal of the American Thyroid Association Bible, K. C., Kebebew, E., Brierley, J., Brito, J. P., Cabanillas, M. E., Clark, T. J., Di Cristofano, A., Foote, R., Giordano, T., Kasperbauer, J., Newbold, K., Nikiforov, Y. E., Randolph, G., Rosenthal, M. S., Sawka, A. M., Shah, M., Shaha, A., Smallridge, R., Wong-Clark, C. K. 2021; 31 (3): 337–86


    Background: Anaplastic thyroid cancer (ATC) is a rare but highly lethal form of thyroid cancer. Since the guidelines for the management of ATC by the American Thyroid Association were first published in 2012, significant clinical and scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, and researchers on published evidence relating to the diagnosis and management of ATC. Methods: The specific clinical questions and topics addressed in these guidelines were based on prior versions of the guidelines, stakeholder input, and input of the Task Force members (authors of the guideline). Relevant literature was reviewed, including serial PubMed searches supplemented with additional articles. The American College of Physicians Guideline Grading System was used for critical appraisal of evidence and grading strength of recommendations. Results: The guidelines include the diagnosis, initial evaluation, establishment of treatment goals, approaches to locoregional disease (surgery, radiotherapy, targeted/systemic therapy, supportive care during active therapy), approaches to advanced/metastatic disease, palliative care options, surveillance and long-term monitoring, and ethical issues, including end of life. The guidelines include 31 recommendations and 16 good practice statements. Conclusions: We have developed evidence-based recommendations to inform clinical decision-making in the management of ATC. While all care must be individualized, such recommendations provide, in our opinion, optimal care paradigms for patients with ATC.

    View details for DOI 10.1089/thy.2020.0944

    View details for PubMedID 33728999

  • Patient Factors Associated With Parathyroidectomy in Older Adults With Primary Hyperparathyroidism. JAMA surgery Seib, C. D., Suh, I., Meng, T., Trickey, A., Smith, A. K., Finlayson, E., Covinsky, K. E., Kurella Tamura, M., Kebebew, E. 2021


    Importance: Parathyroidectomy provides definitive management for primary hyperparathyroidism (PHPT), reducing the risk of subsequent fracture, nephrolithiasis, and chronic kidney disease (CKD), but its use among older adults in the US is unknown.Objective: To identify patient characteristics associated with the use of parathyroidectomy for the management of PHPT in older adults.Design, Setting, and Participants: This population-based, retrospective cohort study used 100% Medicare claims from beneficiaries with an initial diagnosis of PHPT from January 1, 2006, to December 31, 2016. Patients were considered to meet consensus guideline criteria for parathyroidectomy based on diagnosis codes indicating osteoporosis, nephrolithiasis, or stage 3 CKD. Multivariable logistic regression was used to identify patient characteristics associated with parathyroidectomy. Data were analyzed from February 11, 2020, to October 8, 2020.Main Outcomes and Measures: The primary outcome was parathyroidectomy within 1 year of diagnosis.Results: Among 210 206 beneficiaries with an incident diagnosis of PHPT (78.8% women; mean [SD] age, 75.3 [6.8] years), 63 136 (30.0%) underwent parathyroidectomy within 1 year of diagnosis. Among the subset of patients who met consensus guideline criteria for operative management (n=131 723), 38 983 (29.6%) were treated with parathyroidectomy. Patients treated operatively were younger (mean [SD] age, 73.5 [5.7] vs 76.0 [7.1] years) and more likely to be White (90.1% vs 86.0%), to be robust or prefrail (92.1% vs 85.7%), and to have fewer comorbidities (Charlson Comorbidity Index score of 0 or 1, 54.6% vs 44.1%), in addition to being more likely to live in socioeconomically disadvantaged (46.9% vs 40.3%) and rural (18.1% vs 13.6%) areas (all P<.001). On multivariable analysis, increasing age had a strong inverse association with parathyroidectomy among patients aged 76 to 85 years (unadjusted rate, 25.9%; odds ratio [OR], 0.68 [95% CI, 0.67-0.70]) and older than 85 years (unadjusted rate, 11.2%; OR, 0.27 [95% CI, 0.26-0.29]) compared with those aged 66 to 75 years (unadjusted rate, 35.6%), as did patients with moderate to severe frailty (unadjusted rate, 18.9%; OR, 0.60 [95% CI, 0.56-0.64]) compared with robust patients (unadjusted rate, 36.1%) and those with a Charlson Comorbidity Index score of 2 or greater (unadjusted rate, 25.9%; OR, 0.77 [95% CI, 0.75-0.79]) compared with a Charlson Comorbidity Index score of 0 (unadjusted rate, 37.0%). With regard to operative guidelines, a history of nephrolithiasis increased the odds of parathyroidectomy (OR, 1.43 [95% CI, 1.39-1.47]); stage 3 CKD decreased the odds of parathyroidectomy (OR, 0.71 [95% CI, 0.68-0.74]); and osteoporosis showed no association (OR, 1.01 [95% CI, 0.99-1.03]).Conclusions and Relevance: In this cohort study, most older adults with PHPT did not receive definitive treatment with parathyroidectomy. Older age, frailty, and multimorbidity were associated with nonoperative management, and guideline recommendations had minimal effect on treatment decisions. Further research is needed to identify barriers to surgical care and develop tools to target parathyroidectomy to older adults most likely to benefit.

    View details for DOI 10.1001/jamasurg.2020.6175

    View details for PubMedID 33404646

  • Co-Occurrence of Familial Non-Medullary Thyroid Cancer (FNMTC) and Hereditary Non-Polyposis Colorectal Cancer (HNPCC) Associated Tumors-A Cohort Study. Frontiers in endocrinology Aswath, K., Welch, J., Gubbi, S., Veeraraghavan, P., Avadhanula, S., Gara, S. K., Dikoglu, E., Merino, M., Raffeld, M., Xi, L., Kebebew, E., Klubo-Gwiezdzinska, J. 2021; 12: 653401


    Familial non-medullary thyroid cancer (FNMTC) is a form of endocrine malignancy exhibiting an autosomal dominant mode of inheritance with largely unknown germline molecular mechanism. Hereditary nonpolyposis colorectal cancer syndrome (HNPCC) is another hereditary autosomal dominant cancer syndrome which, if proven to be caused by germline mutations in mismatch repair genes (MMR)-MLHL,MSH2,MSH6,PMS2, andEPCAM-is called Lynch syndrome (LS). LS results in hereditary predisposition to a number of cancers, especially colorectal and endometrial cancers. Tumors in LS are characterized by microsatellite instability (MSI) and/or loss of MMR protein expression in immunohistochemistry (IHC). MSI is a rare event in thyroid cancer (TC), although it is known to occur in up to 2.5% of sporadic follicular TC cases. There are limited data on the role of germline MMR variants FNMTC. The goal of this study was to analyze the potential clinical and molecular association between HNPCC and FNMTC. We performed a cohort study analyzing the demographic, clinical, and pathologic data of 43 kindreds encompassing 383 participants (104 affected, 279 unaffected), aged 43.5 [7-99] years with FNMTC, and performed high-throughput whole-exome sequencing (WES) of peripheral blood DNA samples of selected 168 participants (54 affected by FNMTC and 114 unaffected). Total affected by thyroid cancer members per family ranged between 2 and 9 patients. FNMTC was more prevalent in women (68.3%) and characterized by a median tumor size of 1.0 [0.2-5.0] cm, multifocal growth in 44%, and gross extrathyroidal extension in 11.3%. Central neck lymph node metastases were found in 40.3% of patients at presentation, 12.9% presented with lateral neck lymph node metastases, and none had distant metastases. Family history screening revealed one Caucasian family meeting the clinical criteria for FNMTC and HNPCC, with five members affected by FNMTC and at least eight individuals reportedly unaffected by HNPCC-associated tumors. In addition, two family members were affected by melanoma. Genome Analysis Tool Kit (GATK) pipeline was used in variant analysis. Among 168 sequenced participants, a heterozygous missense variant in the MSH2 gene (rs373226409; c.2120G>A; p.Cys707Tyr) was detected exclusively in FNMTC- HNPCC- kindred. In this family, the sequencing was performed in one member affected by FNMTC, HPNCC-associated tumors and melanoma, one member affected solely by HNPCC-associated tumor, and one member with FNMTC only, as well as seven unaffected family members. The variant was present in all three affected adults, and in two unaffected children of the affected member, under the age of 18 years, and was absent in non-affected adults. This variant ispredicted to be damaging/pathogenic in 17/20 in-silico models. However, immunostaining performed on the thyroid tumor tissue of two affected by FNMTC family members revealed intact nuclear expression of MSH2, and microsatellite stable status in both tumors that were tested. Although the MSH2 p.Cys707Tyr variant is rare with a minor allele frequency (MAF) of 0.00006 in Caucasians; it is more common in the South Asian population at 0.003 MAF. Therefore, the MSH2 variant observed in this family is unlikely to be an etiologic factor of thyroid cancer and a common genetic association between FNMTC and HNPCC has not yet been identified. This is the first report known to us on the co-occurrence of FNMTC and HNPCC. The co-occurrence of FNMTC and HNPCC-associated tumors is a rare event and although presented in a single family in our large FNMTC cohort, a common genetic background between the two comorbidities could not be established.

    View details for DOI 10.3389/fendo.2021.653401

    View details for PubMedID 34326811

  • Adrenal Incidentaloma. Reply. The New England journal of medicine Kebebew, E. 2021; 385 (8): 768

    View details for DOI 10.1056/NEJMc2108550

    View details for PubMedID 34407359

  • Thyroid 2020 to 2021. Thyroid : official journal of the American Thyroid Association Kebebew, E. 2020



    View details for DOI 10.1089/thy.2020.0933

    View details for PubMedID 33327860

  • Comprehensive guidance on the diagnosis and management of primary mesenchymal tumours of the thyroid gland. The Lancet. Oncology Gubbi, S., Thakur, S., Avadhanula, S., Araque, K. A., Filie, A. C., Raffeld, M., Welch, J., Del Rivero, J., Kebebew, E., Burman, K. D., Wartofsky, L., Klubo-Gwiezdzinska, J. 2020; 21 (11): e528–e537


    Most primary thyroid tumours are of epithelial origin. Primary thyroid mesenchymal tumours are rare but are being increasingly detected. A vast majority of thyroid mesenchymal tumours occur between the fourth and seventh decades of life, presenting as progressively enlarging thyroid nodules that often yield non-diagnostic results or spindle cells on fine needle aspiration biopsy. Surgery is the preferred mode of treatment, with adjuvant chemoradiotherapy used for malignant thyroid mesenchymal tumours. Benign thyroid mesenchymal tumours have excellent prognosis, whereas the outcome of malignant thyroid mesenchymal tumours is variable. Each thyroid mesenchymal tumour is characterised by its unique histopathology and immunohistochemistry. Because of the rarity and aggressive nature of malignant thyroid mesenchymal tumours, a multidisciplinary team-based approach should ideally be used in the management of these tumours. Comprehensive guidelines on the management of thyroid mesenchymal tumours are currently lacking. In this Review, we provide a detailed description of thyroid mesenchymal tumours, their clinical characteristics and tumour behaviour, and provide recommendations for the optimal management of these tumours.

    View details for DOI 10.1016/S1470-2045(20)30332-6

    View details for PubMedID 33152312

  • Comprehensive guidance on the diagnosis and managemen of primary mesenchymal tumours of the thyroid gland LANCET ONCOLOGY Gubbi, S., Thakur, S., Avadhanula, S., Araque, K. A., Filie, A. C., Raffeld, M., Welch, J., Del Rivero, J., Kebebew, E., Burman, K. D., Wartofsky, L., Klubo-Gwiezdzinska, J. 2020; 21 (11): E528–E537
  • Probability of positive genetic testing in patients diagnosed with pheochromocytoma and paraganglioma: Criteria beyond a family history. Surgery Alobuia, W. M., Ammar, S., Tyagi, M., Ghosh, C., Gunda, V., Annes, J. P., Kebebew, E. 2020


    BACKGROUND: Genetic testing for germline pheochromocytoma and paraganglioma susceptibility genes is associated with improved patient management. However, data are currently sparse on the probability of a positive testing result based on an individual's clinical presentation. This study evaluates clinical characteristics for association with testing positive for known pheochromocytoma and paraganglioma susceptibility genes.METHODS: This retrospective analysis examined 111 patients with a diagnosis of pheochromocytoma and paraganglioma who underwent genetic testing. Logistic regression and receiver operating characteristic analyses were performed to identify factors associated with a positive genetic testing result. Probabilities were then calculated for combinations of significant factors to determine the likelihood of a positive test result in each group.RESULTS: Of 32 patients with a family history of pheochromocytoma and paraganglioma, 31 (97%) had a germline mutation detected. Of 79 patients without a family history, 24 (30%) had a pathogenic germline mutation detected. In multivariate analysis, a positive family history, aged ≤47 years, and tumor size ≤2.9 cm were independent factors associated with a positive genetic testing result. Patients meeting all 3 criteria had a 100% probability compared with 13% in those without any of the criteria. In addition to a positive family history, having either aged ≤47 years or tumor size ≤2.9 cm resulted in a 90% and 100% probability of a positive result, respectively. In the absence of a family history, the probability in patients who were aged ≤47 years and had a tumor size ≤2.9 cm was 60%.CONCLUSION: In addition to a family history of pheochromocytoma and paraganglioma, aged ≤47 years, and tumor size ≤2.9 cm are associated with a higher probability of testing positive for a pheochromocytoma and paraganglioma susceptibility gene mutation. Patients meeting all 3 criteria have a 100% probability of a positive genetic testing result.

    View details for DOI 10.1016/j.surg.2020.08.027

    View details for PubMedID 33023754

  • Distinct DNA methylation signatures in neuroendocrine tumors specific for primary site and inherited predisposition. The Journal of clinical endocrinology and metabolism Tirosh, A., Killian, J. K., Petersen, D., Zhu, Y. J., Walker, R. L., Blau, J. E., Nilubol, N., Patel, D., Agarwal, S. K., Weinstein, L. S., Meltzer, P., Kebebew, E. 2020


    PURPOSE: To compare the DNA methylation signature of neuroendocrine tumors (NETs) by primary tumor site and inherited predisposition syndromes von Hippel-Lindau disease (VHL) and multiple endocrine neoplasia type 1 (MEN1).METHODS: Genome-wide DNA methylation (835,424 CpGs) of 96 NET samples. Primary component (PCA) and unsupervised hierarchical clustering analyses were used to determine DNA methylome signatures.RESULTS: Hypomethylated CpGs were significantly more common in VHL-related vs. sporadic and MEN1-related NETs (p < 0.001 for both comparisons). Small-intestinal NETs (SINETs) had the most differentially methylated CpGs, either hyper- or hypomethylated, followed by duodenal NETs (DNETs) and pancreatic NETs (PNETs, p < 0.001 for all comparisons). There was complete separation of SINETs on PCA, and three NETs of unknown origin clustered with the SINET samples. Sporadic, VHL-related and MEN1-related PNETs formed distinct groups on PCA, and VHL clustered separately, showing pronounced DNA hypomethylation, while sporadic and MEN1-related NETs clustered together. MEN1-related PNETs, DNETs and gastric NETs each had a distinct DNA methylome signature, with complete separation by PCA and unsupervised clustering. Finally, we identified 12 hypermethylated CpGs in the 1A promoter of the APC gene, with higher methylation levels in MEN1-related NETs vs. VHL-related and sporadic NETs (p < 0.001 for both comparisons).CONCLUSIONS: DNA CpG methylation profiles are unique in different primary NET types even when occurring in MEN1-related NETs. This tumor DNA methylome signature may be utilized for non-invasive molecular characterization of NETs, through DNA methylation profiling of biopsy samples or even circulating tumor DNA in the near future.

    View details for DOI 10.1210/clinem/dgaa477

    View details for PubMedID 32706863

  • Undertreatment of primary hyperparathyroidism in a privately insured US population: Decreasing utilization of parathyroidectomy despite expanding surgical guidelines. Surgery Seib, C. D., Meng, T., Suh, I., Cisco, R. M., Lin, D. T., Morris, A. M., Trickey, A. W., Kebebew, E. 2020


    BACKGROUND: Primary hyperparathyroidism is associated with substantial morbidity, including osteoporosis, nephrolithiasis, and chronic kidney disease. Parathyroidectomy can prevent these sequelae but is poorly utilized in many practice settings.METHODS: We performed a retrospective cohort study using the national Optum de-identified Clinformatics Data Mart Database. We identified patients aged ≥35 with a first observed primary hyperparathyroidism diagnosis from 2004 to 2016. Multivariable logistic regression was used to determine patient/provider characteristics associated with parathyroidectomy.RESULTS: Of 26,522 patients with primary hyperparathyroidism, 10,101 (38.1%) underwent parathyroidectomy. Of the 14,896 patients with any operative indication, 5,791 (38.9%) underwent parathyroidectomy. Over time, there was a decreasing trend in the rate of parathyroidectomy overall (2004: 54.4% to 2016: 32.4%, P < .001) and among groups with and without an operative indication. On multivariable analysis, increasing age and comorbidities were strongly, inversely associated with parathyroidectomy (age 75-84, odds ratio 0.50 [95% confidence interval 0.45-0.55]; age ≥85, odds ratio 0.21 [95% confidence interval 0.17-0.26] vs age 35-49; Charlson Comorbidity Index ≥2 vs 0 odds ratio 0.62 [95% confidence interval 0.58-0.66]).CONCLUSION: The majority of US privately insured patients with primary hyperparathyroidism are not treated with parathyroidectomy. Having an operative indication only modestly increases the likelihood of parathyroidectomy. Further research is needed to address barriers to treatment and the gap between guidelines and clinical care in primary hyperparathyroidism.

    View details for DOI 10.1016/j.surg.2020.04.066

    View details for PubMedID 32654861

  • Epidural anesthesia and hypotension in pheochromocytoma and paraganglioma. Endocrine-related cancer Wiseman, D., McDonald, J. D., Patel, D., Kebebew, E., Pacak, K., Nilubol, N. 2020


    Postoperative hypotension occurs frequently after resection of pheochromocytoma and/or paraganglioma (PPGLs). Epidural anesthesia (EA) is often used for pain control in open resection of these tumors; one of its side effects is hypotension. Our aim is to determine if EA is associated with an increased risk of postoperative hypotension after open resection of PPGLs. We conducted a retrospective review of patients who underwent open resection of PPGLs at the National Institutes of Health from 2004-2019. Clinical and perioperative parameters were analyzed by the use of EA. The primary endpoint was postoperative hypotension. Ninety-seven patients (46 female and 51 male; mean age, 38.5 years) underwent open resection of PPGLs, and 69 (71.1%) received EA. Patients with EA had a higher rate beta-blocker use (79.7% vs. 57.1%, P=0.041), metastasis (69.6% vs. 39.3%, P=0.011), and were more frequently hypotensive after surgery (58.8% vs. 25.0%, P=0.003) compared to those without EA. Patients with postoperative hypotension had higher plasma normetanephrines than those without (7.3-fold vs. 4.1-fold above the upper limit of normal, P=0.018). Independent factors associated with postoperative hypotension include the use of beta-blockers (HR = 3.35 [95% CI: 1.16-9.67], P=0.026) and EA (HR = 3.49 [95% CI: 1.25-9.76], P=0.017). Data from this retrospective study suggest that in patients with open resection of PPGLs, EA is an independent risk factor for early postoperative hypotension. Special caution is required in patients on betablockade. A prospective evaluation with standardized protocols for the use of EA and management of hemodynamic variability is necessary.

    View details for DOI 10.1530/ERC-20-0139

    View details for PubMedID 32698142

  • IMMUNE PROFILING TO PREDICT RECOVERY OUTCOMES AFTER SURGERY Tsai, E. S., Rumer, K., Wong, K., Warrington, B., Shelton, E., Ganio, E., Verdonk, F., Ando, K., Tingle, M., Folk-Tolbert, M., Shankar, K., Shelton, A., Morris, A., Kirilcuk, N., Gurland, B., Kebebew, E., Kin, C., Angst, M. S., Aghaeepour, N., Gaudilliere, B. LIPPINCOTT WILLIAMS & WILKINS. 2020: 66–67
  • Genetic and epigenetic alterations in pancreatic neuroendocrine tumors JOURNAL OF GASTROINTESTINAL ONCOLOGY Tirosh, A., Kebebew, E. 2020; 11 (3): 567–77


    Neuroendocrine tumors (NETs) are a heterogenous group of tumors that originate from neuroendocrine cells, mainly in the pancreas and the gastrointestinal and bronchopulmonary tracts. There has been considerable progress in our understanding of the genetic and epigenetic changes associated with pancreatic NETs (PNETs). The main genetic alterations that drive PNETs include genetic alterations in MEN1, VHL and genes involved in the mTOR pathway, DAXX and/or ATRX mutations and their association with alternative telomere lengthening, and genes involved in DNA damage repair and chromatin modification. The epigenetic alterations in PNETs are also common based on genome-wide DNA methylation profiling studies, with a high rate of CpG hypermethylation in MEN1-associated PNETs compared to sporadic and VHL-associated PNETs. Moreover, the dysregulated DNA methylation status is associated with distinct gene expression profiles. This article reviews the commonly and recently discovered genetic and epigenetic changes that are associated with PNETs, inherited PNETs, and genotype-phenotype associations, and it discusses their clinical relevance.

    View details for DOI 10.21037/jgo.2020.03.11

    View details for Web of Science ID 000544513800014

    View details for PubMedID 32655936

    View details for PubMedCentralID PMC7340809

  • Genetic testing in endocrine surgery: Opportunities for precision surgery. Surgery Alobuia, W., Annes, J., Kebebew, E. 2020


    Recent innovations in molecular and genetic diagnostic techniques have led to rapid advances in genomic medicine and their application to the clinic. The identification and classification of various genetic associations, syndromes, and susceptibility genes in endocrine surgical disorders are increasingly relevant to patient care. Hereditary endocrine disorders represent a significant proportion of disease encountered by endocrine surgeons. Hence, genetic testing has emerged as an important adjunct for the diagnosis and management of patients with endocrinesurgical disorders. This article summarizes commonly encountered inherited endocrine disorders and their tumor susceptibility genes, with a focus on the clinical utility of genetic testing and its impact on the surgical management of endocrine disorders.

    View details for DOI 10.1016/j.surg.2020.03.009

    View details for PubMedID 32376047

  • Executive Summary of the American Association of Endocrine Surgeons Guidelines for the Definitive Surgical Management of Thyroid Disease in Adults. Annals of surgery Patel, K. N., Yip, L., Lubitz, C. C., Grubbs, E. G., Miller, B. S., Shen, W., Angelos, P., Chen, H., Doherty, G. M., Fahey, T. J., Kebebew, E., Livolsi, V. A., Perrier, N. D., Sipos, J. A., Sosa, J. A., Steward, D., Tufano, R. P., McHenry, C. R., Carty, S. E. 2020; 271 (3): 399–410


    OBJECTIVE: The aim of this study was to develop evidence-based recommendations for safe, effective and appropriate thyroidectomy.BACKGROUND: Surgical management of thyroid disease has evolved considerably over several decades leading to variability in rendered care. Over 100,000 thyroid operations are performed annually in the United States.METHODS: The medical literature from January 1, 1985 to November 9, 2018 was reviewed by a panel of 19 experts in thyroid disorders representing multiple disciplines. The authors used the best available evidence to construct surgical management recommendations. Levels of evidence were determined using the American College of Physicians grading system, and management recommendations were discussed to consensus. Members of the American Association of Endocrine Surgeons reviewed and commented on preliminary drafts of the content.RESULTS: These clinical guidelines analyze the indications for thyroidectomy as well as its definitions, technique, morbidity, and outcomes. Specific topics include Pathogenesis and Epidemiology, Initial Evaluation, Imaging, Fine Needle Aspiration Biopsy Diagnosis, Molecular Testing, Indications, Extent and Outcomes of Surgery, Preoperative Care, Initial Thyroidectomy, Perioperative Tissue Diagnosis, Nodal Dissection, Concurrent Parathyroidectomy, Hyperthyroid Conditions, Goiter, Adjuncts and Approaches Laryngology Familial Thyroid Cancer, Postoperative Care and Complications, Cancer Management, and Reoperation.CONCLUSION: Evidence-based guidelines were created to assist clinicians in the optimal surgical management of thyroid disease.

    View details for DOI 10.1097/SLA.0000000000003735

    View details for PubMedID 32079828

  • The American Association of Endocrine Surgeons Guidelines for the Definitive Surgical Management of Thyroid Disease in Adults. Annals of surgery Patel, K. N., Yip, L., Lubitz, C. C., Grubbs, E. G., Miller, B. S., Shen, W., Angelos, P., Chen, H., Doherty, G. M., Fahey, T. J., Kebebew, E., Livolsi, V. A., Perrier, N. D., Sipos, J. A., Sosa, J. A., Steward, D., Tufano, R. P., McHenry, C. R., Carty, S. E. 2020; 271 (3): e21–e93


    OBJECTIVE: To develop evidence-based recommendations for safe, effective, and appropriate thyroidectomy.BACKGROUND: Surgical management of thyroid disease has evolved considerably over several decades leading to variability in rendered care. Over 100,000 thyroid operations are performed annually in the US.METHODS: The medical literature from 1/1/1985 to 11/9/2018 was reviewed by a panel of 19 experts in thyroid disorders representing multiple disciplines. The authors used the best available evidence to construct surgical management recommendations. Levels of evidence were determined using the American College of Physicians grading system, and management recommendations were discussed to consensus. Members of the American Association of Endocrine Surgeons reviewed and commented on preliminary drafts of the content.RESULTS: These clinical guidelines analyze the indications for thyroidectomy as well as its definitions, technique, morbidity, and outcomes. Specific topics include Pathogenesis and Epidemiology, Initial Evaluation, Imaging, Fine Needle Aspiration Biopsy Diagnosis, Molecular Testing, Indications, Extent and Outcomes of Surgery, Preoperative Care, Initial Thyroidectomy, Perioperative Tissue Diagnosis, Nodal Dissection, Concurrent Parathyroidectomy, Hyperthyroid Conditions, Goiter, Adjuncts and Approaches to Thyroidectomy, Laryngology, Familial Thyroid Cancer, Postoperative Care and Complications, Cancer Management, and Reoperation.CONCLUSIONS: Evidence-based guidelines were created to assist clinicians in the optimal surgical management of thyroid disease.

    View details for DOI 10.1097/SLA.0000000000003580

    View details for PubMedID 32079830

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A., Kim, H., Kim, J., Koscher, M., Koures, A., Kovacevic, M., Lawerenz, C., Liu, J., Mijalkovic, S., Mijalkovic-Lazic, A., Miyano, S., Nastic, M., Nicholson, J., Ocana, D., Ohi, K., Ohno-Machado, L., Pihl, T. D., Prinz, M., Radovic, P., Short, C., Sofia, H. J., Spring, J., Struck, A. J., Tijanic, N., Vicente, D., Wang, Z., Williams, A., Woo, Y., Wright, A. J., Yang, L., Hamilton, M. P., Johnson, T. A., Kahraman, A., Kellis, M., Polak, P., Sallari, R., Sinnott-Armstrong, N., von Mering, C., Beltran, S., Gerhard, D. S., Gut, M., Trotta, J., Whalley, J. P., Niu, B., Espiritu, S. G., Gao, S., Huang, Y., Lalansingh, C. M., Teague, J. W., Wendl, M. C., Abascal, F., Bader, G. D., Bandopadhayay, P., Barenboim, J., Brunak, S., Fita, J., Chakravarty, D., Chan, C., Choi, J., Diamanti, K., Fink, J., Frigola, J., Gambacorti-Passerini, C., Garsed, D. W., Haradhvala, N. J., Harmanci, A. O., Helmy, M., Herrmann, C., Hobolth, A., Hodzic, E., Hong, C., Isaev, K., Izarzugaza, J. 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A., Kakavand, H., Kefford, R. F., Lau, L. S., Long, G., Pickett, H. A., Pritchard, A. L., Pupo, G. M., Saw, R. M., Schramm, S., Shang, C. A., Shang, P., Spillane, A. J., Stretch, J. R., Tembe, V., Thompson, J. F., Vilain, R. E., Wilmott, J. S., Yang, J. Y., Hayward, N. K., Mann, G. J., Scolyer, R. A., Bartlett, J., Bavi, P., Chadwick, D. E., Chan-Seng-Yue, M., Cleary, S., Connor, A. A., Czajka, K., Denroche, R. E., Dhani, N. C., Eagles, J., Gallinger, S., Grant, R. C., Hedley, D., Hollingsworth, M. A., Jang, G., Johns, J., Kalimuthu, S., Liang, S., Lungu, I., Luo, X., Mbabaali, F., McPherson, T. A., Miller, J. K., Moore, M. J., Notta, F., Pasternack, D., Petersen, G. M., Roehrl, M. A., Sam, M., Selander, I., Serra, S., Shahabi, S., Thayer, S. P., Timms, L. E., Wilson, G. W., Wilson, J. M., Wouters, B. G., McPherson, J. D., Beck, T. A., Bhandari, V., Collins, C. C., Fleshner, N. E., Fox, N. S., Fraser, M., Heisler, L. E., Lalonde, E., Livingstone, J., Meng, A., Sabelnykova, V. Y., Shiah, Y., Van Der Kwast, T., Bristow, R. G., Ding, S., Fan, D., Li, L., Nie, Y., Xiao, X., Xing, R., Yang, S., Yu, Y., Zhou, Y., Banks, R. E., Bourque, G., Brennan, P., Letourneau, L., Riazalhosseini, Y., Scelo, G., Vasudev, N., Viksna, J., Lathrop, M., Tost, J., Ahn, S., Aparicio, S., Arnould, L., Aure, M. R., Bhosle, S. G., Birney, E., Borg, A., Boyault, S., Brinkman, A. B., Brock, J. E., Broeks, A., Borresen-Dale, A., Caldas, C., Chin, S., Davies, H., Desmedt, C., Dirix, L., Dronov, S., Ehinger, A., Eyfjord, J. E., Fatima, A., Foekens, J. A., Futreal, P., Garred, O., Giri, D. D., Glodzik, D., Grabau, D., Hilmarsdottir, H., Hooijer, G. K., Jacquemier, J., Jang, S., Jonasson, J. G., Jonkers, J., Kim, H., King, T. A., Knappskog, S., Kong, G., Krishnamurthy, S., Lakhani, S. R., Langerod, A., Larsimont, D., Lee, H., Lee, J., Lee, M., Lingjaerde, O., MacGrogan, G., Martens, J. M., O'Meara, S., Pauporte, I., Pinder, S., Pivot, X., Provenzano, E., Purdie, C. A., Ramakrishna, M., Ramakrishnan, K., Reis-Filho, J., Richardson, A. L., Ringner, M., Rodriguez, J., Rodriguez-Gonzalez, F., Romieu, G., Salgado, R., Sauer, T., Shepherd, R., Sieuwerts, A. M., Simpson, P. T., Smid, M., Sotiriou, C., Span, P. N., Stefansson, O., Stenhouse, A., Stunnenberg, H. G., Sweep, F., Tan, B., Thomas, G., Thompson, A. M., Tommasi, S., Treilleux, I., Tutt, A., Ueno, N. T., Van Laere, S., Van den Eynden, G. G., Vermeulen, P., Viari, A., Vincent-Salomon, A., Wong, B. H., Yates, L., Zou, X., van Deurzen, C. M., van de Vijver, M. J., van't Veer, L., Ammerpohl, O., Aukema, S., Bergmann, A. K., Bernhart, S. H., Borkhardt, A., Borst, C., Burkhardt, B., Claviez, A., Goebler, M., Haake, A., Haas, S., Hansmann, M., Hoell, J., Hummel, M., Karsch, D., Klapper, W., Kneba, M., Kreuz, M., Kube, D., Kueppers, R., Lenze, D., Loeffler, M., Lopez, C., Mantovani-Loeffler, L., Moeller, P., Ott, G., Radlwimmer, B., Richter, J., Rohde, M., Rosenstiel, P. C., Rosenwald, A., Schilhabel, M. B., Schreiber, S., Stadler, P. F., Staib, P., Stilgenbauer, S., Sungalee, S., Szczepanowski, M., Toprak, U. H., Truemper, L. P., Wagener, R., Zenz, T., Hovestadt, V., von Kalle, C., Kool, M., Korshunov, A., Landgraf, P., Lehrach, H., Northcott, P. A., Pfister, S. M., Reifenberger, G., Warnatz, H., Wolf, S., Yaspo, M., Assenov, Y., Gerhauser, C., Minner, S., Schlomm, T., Simon, R., Sauter, G., Sueltmann, H., Biswas, N. K., Maitra, A., Majumder, P. P., Sarin, R., Barbi, S., Bonizzato, G., Cantu, C., Dei Tos, A. P., Fassan, M., Grimaldi, S., Luchini, C., Malleo, G., Marchegiani, G., Milella, M., Paiella, S., Pea, A., Pederzoli, P., Ruzzenente, A., Salvia, R., Sperandio, N., Arai, Y., Hama, N., Hiraoka, N., Hosoda, F., Nakamura, H., Ojima, H., Okusaka, T., Totoki, Y., Urushidate, T., Fukayama, M., Ishikawa, S., Katai, H., Katoh, H., Komura, D., Rokutan, H., Saito-Adachi, M., Suzuki, A., Taniguchi, H., Tatsuno, K., Ushiku, T., Yachida, S., Yamamoto, S., Aikata, H., Arihiro, K., Ariizumi, S., Chayama, K., Furuta, M., Gotoh, K., Hayami, S., Hirano, S., Kawakami, Y., Maejima, K., Nakamura, T., Nakano, K., Ohdan, H., Sasaki-Oku, A., Tanaka, H., Ueno, M., Yamamoto, M., Yamaue, H., Choo, S., Cutcutache, I., Khuntikeo, N., Ong, C., Pairojkul, C., Popescu, I., Ahn, K., Aymerich, M., Lopez-Guillermo, A., Lopez-Otin, C., Puente, X. S., Campo, E., Amary, F., Baumhoer, D., Behjati, S., Bjerkehagen, B., Futreal, P. A., Myklebost, O., Pillay, N., Tarpey, P., Tirabosco, R., Zaikova, O., Flanagan, A. M., Boultwood, J., Bowen, D. T., Cazzola, M., Green, A. R., Hellstrom-Lindberg, E., Malcovati, L., Nangalia, J., Papaemmanuil, E., Vyas, P., Ang, Y., Barr, H., Beardsmore, D., Eldridge, M., Gossage, J., Grehan, N., Hanna, G. B., Hayes, S. J., Hupp, T. R., Khoo, D., Lagergren, J., Lovat, L. B., MacRae, S., O'Donovan, M., O'Neill, J., Parsons, S. L., Preston, S. R., Puig, S., Roques, T., Sanders, G., Sothi, S., Tavare, S., Tucker, O., Turkington, R., Underwood, T. J., Welch, I., Fitzgerald, R. C., Berney, D. M., De Bono, J. S., Cahill, D., Camacho, N., Dennis, N. M., Dudderidge, T., Edwards, S. E., Fisher, C., Foster, C. S., Ghori, M., Gill, P., Gnanapragasam, V. J., Gundem, G., Hamdy, F. C., Hawkins, S., Hazell, S., Howat, W., Isaacs, W. B., Karaszi, K., Kay, J. D., Khoo, V., Kote-Jarai, Z., Kremeyer, B., Kumar, P., Lambert, A., Leongamornlert, D. A., Livni, N., Lu, Y., Luxton, H. J., Marsden, L., Massie, C. E., Matthews, L., Mayer, E., McDermott, U., Merson, S., Neal, D. E., Ng, A., Nicol, D., Ogden, C., Rowe, E. W., Shah, N. C., Thomas, S., Thompson, A., Verrill, C., Visakorpi, T., Warren, A. Y., Whitaker, H. C., Zhang, H., van As, N., Eeles, R. A., Abeshouse, A., Agrawal, N., Akbani, R., Al Ahmadie, H., Albert, M., Aldape, K., Ally, A., Appelbaum, E. L., Armenia, J., Asa, S., Auman, J., Balasundaram, M., Balu, S., Barnholtz-Sloan, J., Bathe, O. F., Baylin, S. B., Benz, C., Berchuck, A., Berrios, M., Bigner, D., Birrer, M., Bodenheimer, T., Boice, L., Bootwalla, M. S., Bosenberg, M., Bowlby, R., Boyd, J., Broaddus, R. R., Brock, M., Brooks, D., Bullman, S., Caesar-Johnson, S. J., Carey, T. E., Carlsen, R., Cerfolio, R., Chandan, V. S., Chen, H., Cherniack, A. D., Chien, J., Cho, J., Chuah, E., Cibulskis, C., Cope, L., Cordes, M. G., Curley, E., Czerniak, B., Danilova, L., Davis, I. J., Defreitas, T., Demchok, J. A., Dhalla, N., Dhir, R., Doddapaneni, H., El-Naggar, A., Felau, I., Ferguson, M. L., Finocchiaro, G., Fong, K. M., Frazer, S., Friedman, W., Fronick, C. C., Fulton, L. A., Gabriel, S. B., Gao, J., Gehlenborg, N., Gershenwald, J. E., Ghossein, R., Giama, N. H., Gibbs, R. A., Gomez, C., Govindan, R., Hayes, D., Hegde, A. M., Heiman, D., Heins, Z., Hepperla, A. J., Holbrook, A., Holt, R. A., Hoyle, A. P., Hruban, R. H., Hu, J., Huang, M., Huntsman, D., Huse, J., Donahue, C., Ittmann, M., Jayaseelan, J. C., Jefferys, S. R., Jones, C. D., Jones, S. M., Juhl, H., Kang, K., Karlan, B., Kasaian, K., Kebebew, E., Kim, H., Korchina, V., Kundra, R., Lai, P. H., Lander, E., Le, X., Lee, D., Levine, D. A., Lewis, L., Ley, T., Li, H., Lin, P., Linehan, W. M., Liu, F., Lu, Y., Lype, L., Ma, Y., Maglinte, D. T., Mardis, E. R., Marks, J., Marra, M. A., Matthew, T. J., Mayo, M., McCune, K., Meier, S. R., Meng, S., Mieczkowski, P. A., Mikkelsen, T., Miller, C. A., Mills, G. B., Moore, R. A., Morrison, C., Mose, L. E., Moser, C. D., Mungall, A. J., Mungall, K., Mutch, D., Muzny, D. M., Myers, J., Newton, Y., Noble, M. S., O'Donnell, P., O'Neill, B., Ochoa, A., Park, J., Parker, J. S., Pass, H., Pastore, A., Pennell, N. A., Perou, C. M., Petrelli, N., Potapova, O., Rader, J. S., Ramalingam, S., Rathmell, W., Reuter, V., Reynolds, S. M., Ringel, M., Roach, J., Roberts, L. R., Robertson, A., Sadeghi, S., Saller, C., Sanchez-Vega, F., Schadendorf, D., Schein, J. E., Schmidt, H. K., Schultz, N., Seethala, R., Senbabaoglu, Y., Shelton, T., Shi, Y., Shih, J., Shmulevich, I., Shriver, C., Signoretti, S., Simons, J., Singer, S., Sipahimalani, P., Skelly, T. J., McCune, K., Socci, N. D., Soloway, M. G., Sood, A. K., Tam, A., Tan, D., Tarnuzzer, R., Thiessen, N., Thompson, R., Thorne, L. B., Tsao, M., Umbricht, C., Van Den Berg, D. J., Van Meir, E. G., Veluvolu, U., Voet, D., Wang, L., Weinberger, P., Weisenberger, D. J., Wigle, D., Wilkerson, M. D., Wilson, R. K., Winterhoff, B., Wiznerowicz, M., Wong, T., Wong, W., Xi, L., Yau, C., Zhang, H., Zhang, H., Zhang, J. 2020; 578 (7793): 82-+


    Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1-3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10-18.

    View details for DOI 10.1038/s41586-020-1969-6

    View details for Web of Science ID 000529097800007

    View details for PubMedID 32025007

    View details for PubMedCentralID PMC7025898

  • A combinatorial strategy for targeting BRAF V600E mutant cancers with BRAF V600E inhibitor (PLX4720) and tyrosine kinase inhibitor (ponatinib). Clinical cancer research : an official journal of the American Association for Cancer Research Kebebew, E., Ghosh, C., Kumar, S., Kushchayeva, Y., Gaskins, K., Boufraqech, M., Wei, D., Gara, S. K., Zhang, L., Zhang, Y., Shen, M., Mukherjee, S. 2020


    PURPOSE: Most aggressive thyroid cancers are commonly associated with a BRAF V600E mutation. Preclinical and clinical data in BRAF V600E cancers suggest that combined BRAF and MEK inhibitor treatment result in a response, but resistance is common. One mechanism of acquired resistance is through persistent activation of tyrosine kinase (TK) signaling by alternate pathways. We hypothesized that combination therapy with BRAF and multitargeting TK inhibitors (MTKI) might be more effective in BRAF V600E thyroid cancer than single agent or BRAF and MEK inhibitors.EXPERIMENTAL DESIGN: The combined drug activity was analyzed to predict any synergistic effect using high throughput screening (HTS) of active drugs. We performed follow up in vitro and in vivo studies to validate and determine the mechanism of action of synergistic drugs.RESULTS: The MTKI ponatinib and the BRAF inhibitor PLX4720 showed synergistic activity by HTS. This combination significantly inhibited proliferation, colony formation, invasion and migration in BRAF V600E thyroid cancer cell lines and downregulated pERK/MEK and c-JUN signaling pathways, and increased apoptosis. PLX4720 resistant BRAF V600E cells became sensitized to the combination treatment, with decreased proliferation at lower PLX4720 concentrations. In orthotopic thyroid cancer mouse model, combination therapy significantly reduced tumor growth (p < 0.05), lower number of metastases (p < 0.05) and longer survival (p < 0.05) compared to monotherapy and vehicle control.CONCLUSIONS: Combination treatment with ponatinib and PLX4720 exhibited significant synergistic anticancer activity in preclinical models of BRAF V600E thyroid cancer, in addition to overcoming PLX4720 resistance. Our results suggest this combination should be tested in clinical trials.

    View details for DOI 10.1158/1078-0432.CCR-19-1606

    View details for PubMedID 31937621

  • A phase 1 study of nevanimibe HCl, a novel adrenal-specific sterol O-acyltransferase 1 (SOAT1) inhibitor, in adrenocortical carcinoma. Investigational new drugs Smith, D. C., Kroiss, M. n., Kebebew, E. n., Habra, M. A., Chugh, R. n., Schneider, B. J., Fassnacht, M. n., Jafarinasabian, P. n., Ijzerman, M. M., Lin, V. H., Mohideen, P. n., Naing, A. n. 2020


    Background Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with very limited treatment options. Nevanimibe HCl (formerly ATR-101), a novel adrenal-specific sterol O-acyltransferase 1 (SOAT1) inhibitor, has been shown in nonclinical studies to decrease adrenal steroidogenesis at lower doses and to cause apoptosis of adrenocortical cells at higher doses. Methods This phase 1, multicenter, open-label study assessed the safety and pharmacokinetics (PK) of nevanimibe in adults with metastatic ACC (NCT01898715). A "3 + 3" dose-escalation design was used. Adverse events (AEs), PK, and tumor response based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were evaluated every 2 months. Results 63 patients with metastatic ACC, all of whom had previously failed systemic chemotherapy and only 2 of whom were mitotane-naïve, were dosed with oral nevanimibe at doses ranging from 1.6 mg/kg/day to 158.5 mg/kg/day. Subjects who did not experience tumor progression or a dose-limiting toxicity (DLT) could continue to receive additional cycles. No patients experienced a complete or partial response; however, 13 of the 48 (27%) patients who underwent imaging at 2 months had stable disease (SD), and 4 of these had SD > 4 months. In addition, drug-related adrenal insufficiency, considered a pharmacologic effect of nevanimibe, was observed in two patients. The most common treatment-emergent AEs were gastrointestinal disorders (76%), including diarrhea (44%) and vomiting (35%). A maximum tolerated dose (MTD) could not be defined, as very few dose-limiting toxicities (DLTs) occurred. Because the large number of tablets required at the highest dose (i.e., ~24 tablets/day) resulted in low-grade gastrointestinal adverse effects, a maximum feasible dose of 128.2 mg/kg/day was established as a dose that could be taken on a long-term basis. Conclusions This study demonstrated the safety of nevanimibe at doses of up to ~6000 mg BID. As the total number of tablets required to achieve an MTD exceeded practical administration limits, a maximum feasible dose was defined. Given that the expected exposure levels necessary for an apoptotic effect could not be achieved, the current formulation of nevanimibe had limited efficacy in patients with advanced ACC.

    View details for DOI 10.1007/s10637-020-00899-1

    View details for PubMedID 31984451

  • Surgery for adrenocortical carcinoma: When and how? Best practice & research. Clinical endocrinology & metabolism Sinclair, T. J., Gillis, A. n., Alobuia, W. M., Wild, H. n., Kebebew, E. n. 2020: 101408


    Adrenocortical carcinoma (ACC) is a rare malignancy that is frequently asymptomatic at presentation, yet has a high rate of metastatic disease at the time of diagnosis. Prognosis is overall poor, particularly with cortisol-producing tumors. While the treatment of ACC is guided by stage of disease, complete surgical resection is the most important step in the management of patients with primary, recurrent, or metastatic ACC. Triphasic chest, abdomen, and pelvis computer tomography (CT) scans and 18F flourodeoxyglucose positron emission tomography CT scanning are essential for accurate staging; moreover, MRI may be helpful to identify liver metastasis and evaluate the involvement of adjacent organs for operative planning. Surgical resection with negative margins is the single most important prognostic factor for survival in patients with ACC. To achieve the highest rate of R0 resection, open adrenalectomy is the gold standard surgical approach for confirmed or highly suspected ACC. It is extremely important that the tumor capsule is not ruptured, regardless of the surgical approach used. The best post-operative outcomes (complications and oncologic) are achieved by high-volume surgeons practicing at high-volume centers.

    View details for DOI 10.1016/j.beem.2020.101408

    View details for PubMedID 32265101

  • Contemporary Management of Anaplastic Thyroid Cancer. Current treatment options in oncology Alobuia, W. n., Gillis, A. n., Kebebew, E. n. 2020; 21 (10): 78


    Anaplastic thyroid cancer (ATC) is a rare but very aggressive form of undifferentiated thyroid cancer. Due to its rapid rate of progression and invasive nature, ATC poses significant risks of morbidity and mortality. The cornerstone in the management of ATC remains a prompt diagnosis of the disease and timely management of complications depending on the stage of disease. Surgery continues to offer a higher chance of a cure, although not all patients are candidates for surgical management. Patients with advanced disease may be considered for palliative surgery to reduce morbidity and complications from advanced disease. With the advent of new molecular testing and improved methods of diagnosis, novel therapeutic targets have been identified. Systemic therapy (chemotherapy and radiation therapy) as well as novel immunotherapy have shown some promise in patients with targetable genetic mutations. Patients should therefore have molecular testing of their tumor-if it is unresectable-and be tested for mutations that are targetable. Mutation-targeted therapy may be effective and may result in a significant response to allow surgical intervention for exceptional responders. Overall, patients who receive all three modalities of therapy (surgery, chemotherapy, and radiation therapy) have the highest overall survival.

    View details for DOI 10.1007/s11864-020-00776-2

    View details for PubMedID 32767129

  • An update on familial nonmedullary thyroid cancer. Endocrine Ammar, S. A., Alobuia, W. M., Kebebew, E. n. 2020


    Familial nonmedullary thyroid cancer (FNMTC) constitutes 3-9% of all thyroid cancer cases. FNMTC is divided into two groups: syndromic and nonsyndromic. Nonsyndromic FNMTC is more common as compared with syndromic FNMTC. In syndromic FNMTC, patients are at risk of nonmedullary thyroid cancer (NMTC) and other tumors, and the susceptibility genes are known. In nonsyndromic FNMTC, NMTC is the major feature of the disease and occurs in isolation with an autosomal dominant pattern of inheritance and variable penetrance. New data have emerged on the genetics, clinical characteristics, and outcomes of patients with FNMTC that may have clinical relevance in the management of patients. In this review, we focus on newly characterized syndromic FNMTC entities, criteria for screening and surveillance of nonsyndromic FNMTC, and the classification of nonsyndromic FNMTC as well as the genetic background and heterogeneity of nonsyndromic FNMTC.

    View details for DOI 10.1007/s12020-020-02250-3

    View details for PubMedID 32162184

  • Adrenal Vein Sampling to Distinguish Between Unilateral and Bilateral Primary Hyperaldosteronism: To ACTH Stimulate or Not? Journal of clinical medicine Sung, T. Y., Alobuia, W. M., Tyagi, M. V., Ghosh, C. n., Kebebew, E. n. 2020; 9 (5)


    The aim of this study is to determine the accuracy of adrenal vein sampling (AVS) with and without adrenocorticotropic hormone (ACTH) stimulation to distinguish between unilateral and bilateral primary hyperaldosteronism (PA). Retrospective analysis of a prospective database from a referral center between 1984 and 2009, 76 patients had simultaneous cannulation of bilateral adrenal veins and AVS with and without ACTH stimulation. All patients had adrenalectomies. The selectivity index (SI, cut-off value ≥2) was used for confirmation of successful cannulation of the adrenal vein. The lateralization index (LI, cut-off value >2 and >4) was used for distinguishing between unilateral and bilateral PA. The SI ratio was higher with ACTH stimulation compared to without for the right adrenal vein (p = 0.027). The LI >2 ratio was higher with ACTH stimulation compared to without (p = 0.007). For the LI >4 ratio, there was no difference between with and without ACTH stimulation (p = 0.239). However, for a LI >4, 7 patients (9.2%) were not lateralized with ACTH stimulation, but they did lateralize without ACTH stimulation. AVS with ACTH stimulation is associated with a higher SI ratio compared to AVS without ACTH stimulation. However, when using LI >4 for AVS, samples without ACTH stimulation should also be included to detect a subset of patients with unilateral disease that are not detected with ACTH stimulation.

    View details for DOI 10.3390/jcm9051447

    View details for PubMedID 32413990

  • GATA3 and APOBEC3B are prognostic markers in adrenocortical carcinoma and APOBEC3B is directly transcriptionally regulated by GATA3. Oncotarget Gara, S. K., Tyagi, M. V., Patel, D. T., Gaskins, K. n., Lack, J. n., Liu, Y. n., Kebebew, E. n. 2020; 11 (36): 3354–70


    Recent evidence has implicated APOBEC3B (Apolipoprotein B mRNA editing enzyme catalytic subunit 3B) as a source of mutations in breast, bladder, cervical, lung, head, and neck cancers. However, the role of APOBEC3B in adrenocortical carcinoma (ACC) and the mechanisms through which its expression is regulated in cancer are not fully understood. Here, we report that APOBEC3B is overexpressed in ACC and it regulates cell proliferation by inducing S phase arrest. We show high APOBEC3B expression is associated with a higher copy number gain/loss at chromosome 4 and 8 and TP53 mutation rate in ACC. GATA3 was identified as a positive regulator of APOBEC3B expression and directly binds the APOBEC3B promoter region. Both GATA3 and APOBEC3B expression levels were associated with patient survival. Our study provides novel insights into the function and regulation of APOBEC3B expression in addition to its known mutagenic ability.

    View details for DOI 10.18632/oncotarget.27703

    View details for PubMedID 32934779

    View details for PubMedCentralID PMC7486697

  • Editorial: Translational Research in Thyroid Cancer. Frontiers in endocrinology Vasko, V. n., Kebebew, E. n., Cheng, S. Y., Jensen, K. E. 2020; 11: 224

    View details for DOI 10.3389/fendo.2020.00224

    View details for PubMedID 32351455

    View details for PubMedCentralID PMC7174598

  • Racial disparities in knowledge, attitudes and practices related to COVID-19 in the USA. Journal of public health (Oxford, England) Alobuia, W. M., Dalva-Baird, N. P., Forrester, J. D., Bendavid, E. n., Bhattacharya, J. n., Kebebew, E. n. 2020


    Recent reports indicate racial disparities in the rates of infection and mortality from the 2019 novel coronavirus (coronavirus disease 2019 [COVID-19]). The aim of this study was to determine whether disparities exist in the levels of knowledge, attitudes and practices (KAPs) related to COVID-19.We analyzed data from 1216 adults in the March 2020 Kaiser Family Foundation 'Coronavirus Poll', to determine levels of KAPs across different groups. Univariate and multivariate regression analysis was used to identify predictors of KAPs.In contrast to White respondents, Non-White respondents were more likely to have low knowledge (58% versus 30%; P < 0.001) and low attitude scores (52% versus 27%; P < 0.001), but high practice scores (81% versus 59%; P < 0.001). By multivariate regression, White race (odds ratio [OR] 3.06; 95% confidence interval [CI]: 1.70-5.50), higher level of education (OR 1.80; 95% CI: 1.46-2.23) and higher income (OR 2.06; 95% CI: 1.58-2.70) were associated with high knowledge of COVID-19. Race, sex, education, income, health insurance status and political views were all associated with KAPs.Racial and socioeconomic disparity exists in the levels of KAPs related to COVID-19. More work is needed to identify educational tools that tailor to specific racial and socioeconomic groups.

    View details for DOI 10.1093/pubmed/fdaa069

    View details for PubMedID 32490519

  • 30th Anniversary and The Future of Thyroid. Thyroid : official journal of the American Thyroid Association Kebebew, E. 2019


    30th Anniversary and The Future of Thyroid.

    View details for DOI 10.1089/thy.2019.0794

    View details for PubMedID 31842720

  • NOP53 as A Candidate Modifier Locus for Familial Non-Medullary Thyroid Cancer. Genes Orois, A., Gara, S. K., Mora, M., Halperin, I., Martinez, S., Alfayate, R., Kebebew, E., Oriola, J. 2019; 10 (11)


    Nonsyndromic familial non-medullary thyroid cancer (FNMTC) represents 3-9% of thyroid cancers, but the susceptibility gene(s) remain unknown. We designed this multicenter study to analyze families with nonsyndromic FNMTC and identify candidate susceptibility genes. We performed exome sequencing of DNA from four affected individuals from one kindred, with five cases of nonsyndromic FNMTC. Single Nucleotide Variants, and insertions and deletions that segregated with all the affected members, were analyzed by Sanger sequencing in 44 additional families with FNMTC (37 with two affected members, and seven with three or more affected members), as well as in an independent control group of 100 subjects. We identified the germline variant p. Asp31His in NOP53 gene (rs78530808, MAF 1.8%) present in all affected members in three families with nonsyndromic FNMTC, and not present in unaffected spouses. Our functional studies of NOP53 in thyroid cancer cell lines showed an oncogenic function. Immunohistochemistry exhibited increased NOP53 protein expression in tumor samples from affected family members, compared with normal adjacent thyroid tissue. Given the relatively high frequency of the variant in the general population, these findings suggest that instead of a causative gene, NOP53 is likely a low-penetrant gene implicated in FNMTC, possibly a modifier.

    View details for DOI 10.3390/genes10110899

    View details for PubMedID 31703244

  • Resection of the Primary Tumor in Patients with Distant Thyroid Cancer Metastasis Is Associated with Longer Survival Sedaghati, M., Lin, D. T., Cisco, R. M., Kebebew, E. ELSEVIER SCIENCE INC. 2019: S82
  • Pediatric vs Adult Adrenocortical Carcinoma: Different Rate of Surgical Treatment and Patient Outcome Sedaghati, M., Lin, D. T., Cisco, R. M., Kebebew, E. ELSEVIER SCIENCE INC. 2019: S81–S82
  • Limited Utility of Circulating Cell-Free DNA Integrity as a Diagnostic Tool for Differentiating Between Malignant and Benign Thyroid Nodules With Indeterminate Cytology (Bethesda Category III) FRONTIERS IN ONCOLOGY Thakur, S., Tobey, A., Daley, B., Auh, S., Walter, M., Patel, D., Nilubol, N., Kebebew, E., Patel, A., Jensen, K., Vasko, V., Klubo-Gwiezdzinska, J. 2019; 9
  • Surgical Resection of Pheochromocytomas and Paragangliomas is Associated with Lower Cholesterol Levels. World journal of surgery Good, M. L., Malekzadeh, P., Ruff, S. M., Gupta, S., Copeland, A., Pacak, K., Nilubol, N., Kebebew, E., Patel, D. 2019


    BACKGROUND: Catecholamine excess in patients with pheochromocytomas or paragangliomas (PPGLs) can lead to hypertension, diabetes and hyperlipidemia. The aim was to investigate the prevalence of hyperlipidemia and the effect of surgical resection.METHODS: One hundred and thirty-two patients with PPGLs underwent an operation at the National Institutes of Health from 2009 to 2016, of which 54 patients met the inclusion criteria. Clinical demographics, BMI, genetic mutations, tumor size, perioperative catecholamine levels and perioperative lipid panels were retrospectively reviewed. Spearman correlation between catecholamines and lipid levels was evaluated. Paired Wilcoxon and paired t test were used to analyze differences in pre- and postoperative lipid levels.RESULTS: Preoperatively, 51 patients (94.4%) had elevated catecholamines, thirteen (24.1%) had elevated total cholesterol (TC) (>200mg/dL), nine (16.6%) had elevated LDL (>130mg/dL) and ten (18.5%) had elevated triglycerides (>150mg/dL). Serum and urinary metanephrine levels were positively associated with TC (r=0.2792, p=0.0372 and r=0.4146, p=0.0031, respectively) and LDL levels (r=0.2977, p=0.0259 and r=0.4434, p=0.0014, respectively). Mean TC decreased from 176.4 to 166.3mg/dL (p=0.0064) and mean HDL decreased from 56.7 to 53.2mg/dL (p=0.0253) after PPGL resection (median 3.1months (range 1.3-50.2) between lipid panels). Most patients with elevated TC (76.9%) had improvement with mean TC decreasing from 225 to 200.2mg/dL (p=0.0230). Of patients with elevated LDL, 66.7% had improvement with mean LDL decreasing from 149 to 131.1mg/dL (p=0.0313).CONCLUSIONS: The prevalence of hyperlipidemia in patients with PPGLs is 46%. Future prospective studies are needed to determine whether surgical resection improves TC and/or LDL levels.

    View details for DOI 10.1007/s00268-019-05175-9

    View details for PubMedID 31531722

  • The Immune Landscape of Cancer. Immunity Thorsson, V., Gibbs, D. L., Brown, S. D., Wolf, D., Bortone, D. S., Ou Yang, T., Porta-Pardo, E., Gao, G. F., Plaisier, C. L., Eddy, J. A., Ziv, E., Culhane, A. C., Paull, E. O., Sivakumar, I. K., Gentles, A. J., Malhotra, R., Farshidfar, F., Colaprico, A., Parker, J. S., Mose, L. E., Vo, N. S., Liu, J., Liu, Y., Rader, J., Dhankani, V., Reynolds, S. M., Bowlby, R., Califano, A., Cherniack, A. D., Anastassiou, D., Bedognetti, D., Mokrab, Y., Newman, A. M., Rao, A., Chen, K., Krasnitz, A., Hu, H., Malta, T. M., Noushmehr, H., Pedamallu, C. S., Bullman, S., Ojesina, A. I., Lamb, A., Zhou, W., Shen, H., Choueiri, T. K., Weinstein, J. N., Guinney, J., Saltz, J., Holt, R. A., Rabkin, C. S., Cancer Genome Atlas Research Network, Lazar, A. J., Serody, J. S., Demicco, E. G., Disis, M. L., Vincent, B. G., Shmulevich, I., Caesar-Johnson, S. J., Demchok, J. A., Felau, I., Kasapi, M., Ferguson, M. L., Hutter, C. M., Sofia, H. J., Tarnuzzer, R., Wang, Z., Yang, L., Zenklusen, J. C., Zhang, J. J., Chudamani, S., Liu, J., Lolla, L., Naresh, R., Pihl, T., Sun, Q., Wan, Y., Wu, Y., Cho, J., DeFreitas, T., Frazer, S., Gehlenborg, N., Getz, G., Heiman, D. I., Kim, J., Lawrence, M. S., Lin, P., Meier, S., Noble, M. S., Saksena, G., Voet, D., Zhang, H., Bernard, B., Chambwe, N., Dhankani, V., Knijnenburg, T., Kramer, R., Leinonen, K., Liu, Y., Miller, M., Reynolds, S., Shmulevich, I., Thorsson, V., Zhang, W., Akbani, R., Broom, B. M., Hegde, A. M., Ju, Z., Kanchi, R. S., Korkut, A., Li, J., Liang, H., Ling, S., Liu, W., Lu, Y., Mills, G. B., Ng, K., Rao, A., Ryan, M., Wang, J., Weinstein, J. N., Zhang, J., Abeshouse, A., Armenia, J., Chakravarty, D., Chatila, W. K., de Bruijn, I., Gao, J., Gross, B. E., Heins, Z. J., Kundra, R., La, K., Ladanyi, M., Luna, A., Nissan, M. G., Ochoa, A., Phillips, S. M., Reznik, E., Sanchez-Vega, F., Sander, C., Schultz, N., Sheridan, R., Sumer, S. O., Sun, Y., Taylor, B. S., Wang, J., Zhang, H., Anur, P., Peto, M., Spellman, P., Benz, C., Stuart, J. M., Wong, C. K., Yau, C., Hayes, D. N., Parker, J. S., Wilkerson, M. D., Ally, A., Balasundaram, M., Bowlby, R., Brooks, D., Carlsen, R., Chuah, E., Dhalla, N., Holt, R., Jones, S. J., Kasaian, K., Lee, D., Ma, Y., Marra, M. A., Mayo, M., Moore, R. A., Mungall, A. J., Mungall, K., Robertson, A. G., Sadeghi, S., Schein, J. E., Sipahimalani, P., Tam, A., Thiessen, N., Tse, K., Wong, T., Berger, A. C., Beroukhim, R., Cherniack, A. D., Cibulskis, C., Gabriel, S. B., Gao, G. F., Ha, G., Meyerson, M., Schumacher, S. E., Shih, J., Kucherlapati, M. H., Kucherlapati, R. S., Baylin, S., Cope, L., Danilova, L., Bootwalla, M. S., Lai, P. H., Maglinte, D. T., Van Den Berg, D. J., Weisenberger, D. J., Auman, J. T., Balu, S., Bodenheimer, T., Fan, C., Hoadley, K. A., Hoyle, A. P., Jefferys, S. R., Jones, C. D., Meng, S., Mieczkowski, P. A., Mose, L. E., Perou, A. H., Perou, C. M., Roach, J., Shi, Y., Simons, J. V., Skelly, T., Soloway, M. G., Tan, D., Veluvolu, U., Fan, H., Hinoue, T., Laird, P. W., Shen, H., Zhou, W., Bellair, M., Chang, K., Covington, K., Creighton, C. J., Dinh, H., Doddapaneni, H., Donehower, L. A., Drummond, J., Gibbs, R. A., Glenn, R., Hale, W., Han, Y., Hu, J., Korchina, V., Lee, S., Lewis, L., Li, W., Liu, X., Morgan, M., Morton, D., Muzny, D., Santibanez, J., Sheth, M., Shinbrot, E., Wang, L., Wang, M., Wheeler, D. A., Xi, L., Zhao, F., Hess, J., Appelbaum, E. L., Bailey, M., Cordes, M. G., Ding, L., Fronick, C. C., Fulton, L. A., Fulton, R. S., Kandoth, C., Mardis, E. R., McLellan, M. D., Miller, C. A., Schmidt, H. K., Wilson, R. K., Crain, D., Curley, E., Gardner, J., Lau, K., Mallery, D., Morris, S., Paulauskis, J., Penny, R., Shelton, C., Shelton, T., Sherman, M., Thompson, E., Yena, P., Bowen, J., Gastier-Foster, J. M., Gerken, M., Leraas, K. M., Lichtenberg, T. M., Ramirez, N. C., Wise, L., Zmuda, E., Corcoran, N., Costello, T., Hovens, C., Carvalho, A. L., de Carvalho, A. C., Fregnani, J. H., Longatto-Filho, A., Reis, R. M., Scapulatempo-Neto, C., Silveira, H. C., Vidal, D. O., Burnette, A., Eschbacher, J., Hermes, B., Noss, A., Singh, R., Anderson, M. L., Castro, P. D., Ittmann, M., Huntsman, D., Kohl, B., Le, X., Thorp, R., Andry, C., Duffy, E. R., Lyadov, V., Paklina, O., Setdikova, G., Shabunin, A., Tavobilov, M., McPherson, C., Warnick, R., Berkowitz, R., Cramer, D., Feltmate, C., Horowitz, N., Kibel, A., Muto, M., Raut, C. P., Malykh, A., Barnholtz-Sloan, J. S., Barrett, W., Devine, K., Fulop, J., Ostrom, Q. T., Shimmel, K., Wolinsky, Y., Sloan, A. E., De Rose, A., Giuliante, F., Goodman, M., Karlan, B. Y., Hagedorn, C. H., Eckman, J., Harr, J., Myers, J., Tucker, K., Zach, L. A., Deyarmin, B., Hu, H., Kvecher, L., Larson, C., Mural, R. J., Somiari, S., Vicha, A., Zelinka, T., Bennett, J., Iacocca, M., Rabeno, B., Swanson, P., Latour, M., Lacombe, L., Tetu, B., Bergeron, A., McGraw, M., Staugaitis, S. M., Chabot, J., Hibshoosh, H., Sepulveda, A., Su, T., Wang, T., Potapova, O., Voronina, O., Desjardins, L., Mariani, O., Roman-Roman, S., Sastre, X., Stern, M., Cheng, F., Signoretti, S., Berchuck, A., Bigner, D., Lipp, E., Marks, J., McCall, S., McLendon, R., Secord, A., Sharp, A., Behera, M., Brat, D. J., Chen, A., Delman, K., Force, S., Khuri, F., Magliocca, K., Maithel, S., Olson, J. J., Owonikoko, T., Pickens, A., Ramalingam, S., Shin, D. M., Sica, G., Van Meir, E. G., Zhang, H., Eijckenboom, W., Gillis, A., Korpershoek, E., Looijenga, L., Oosterhuis, W., Stoop, H., van Kessel, K. E., Zwarthoff, E. C., Calatozzolo, C., Cuppini, L., Cuzzubbo, S., DiMeco, F., Finocchiaro, G., Mattei, L., Perin, A., Pollo, B., Chen, C., Houck, J., Lohavanichbutr, P., Hartmann, A., Stoehr, C., Stoehr, R., Taubert, H., Wach, S., Wullich, B., Kycler, W., Murawa, D., Wiznerowicz, M., Chung, K., Edenfield, W. J., Martin, J., Baudin, E., Bubley, G., Bueno, R., De Rienzo, A., Richards, W. G., Kalkanis, S., Mikkelsen, T., Noushmehr, H., Scarpace, L., Girard, N., Aymerich, M., Campo, E., Gine, E., Guillermo, A. L., Van Bang, N., Hanh, P. T., Phu, B. D., Tang, Y., Colman, H., Evason, K., Dottino, P. R., Martignetti, J. A., Gabra, H., Juhl, H., Akeredolu, T., Stepa, S., Hoon, D., Ahn, K., Kang, K. J., Beuschlein, F., Breggia, A., Birrer, M., Bell, D., Borad, M., Bryce, A. H., Castle, E., Chandan, V., Cheville, J., Copland, J. A., Farnell, M., Flotte, T., Giama, N., Ho, T., Kendrick, M., Kocher, J., Kopp, K., Moser, C., Nagorney, D., O'Brien, D., O'Neill, B. P., Patel, T., Petersen, G., Que, F., Rivera, M., Roberts, L., Smallridge, R., Smyrk, T., Stanton, M., Thompson, R. H., Torbenson, M., Yang, J. D., Zhang, L., Brimo, F., Ajani, J. A., Gonzalez, A. M., Behrens, C., Bondaruk, J., Broaddus, R., Czerniak, B., Esmaeli, B., Fujimoto, J., Gershenwald, J., Guo, C., Lazar, A. J., Logothetis, C., Meric-Bernstam, F., Moran, C., Ramondetta, L., Rice, D., Sood, A., Tamboli, P., Thompson, T., Troncoso, P., Tsao, A., Wistuba, I., Carter, C., Haydu, L., Hersey, P., Jakrot, V., Kakavand, H., Kefford, R., Lee, K., Long, G., Mann, G., Quinn, M., Saw, R., Scolyer, R., Shannon, K., Spillane, A., Stretch, O., Synott, M., Thompson, J., Wilmott, J., Al-Ahmadie, H., Chan, T. A., Ghossein, R., Gopalan, A., Levine, D. A., Reuter, V., Singer, S., Singh, B., Tien, N. V., Broudy, T., Mirsaidi, C., Nair, P., Drwiega, P., Miller, J., Smith, J., Zaren, H., Park, J., Hung, N. P., Kebebew, E., Linehan, W. M., Metwalli, A. R., Pacak, K., Pinto, P. A., Schiffman, M., Schmidt, L. S., Vocke, C. D., Wentzensen, N., Worrell, R., Yang, H., Moncrieff, M., Goparaju, C., Melamed, J., Pass, H., Botnariuc, N., Caraman, I., Cernat, M., Chemencedji, I., Clipca, A., Doruc, S., Gorincioi, G., Mura, S., Pirtac, M., Stancul, I., Tcaciuc, D., Albert, M., Alexopoulou, I., Arnaout, A., Bartlett, J., Engel, J., Gilbert, S., Parfitt, J., Sekhon, H., Thomas, G., Rassl, D. M., Rintoul, R. C., Bifulco, C., Tamakawa, R., Urba, W., Hayward, N., Timmers, H., Antenucci, A., Facciolo, F., Grazi, G., Marino, M., Merola, R., de Krijger, R., Gimenez-Roqueplo, A., Piche, A., Chevalier, S., McKercher, G., Birsoy, K., Barnett, G., Brewer, C., Farver, C., Naska, T., Pennell, N. A., Raymond, D., Schilero, C., Smolenski, K., Williams, F., Morrison, C., Borgia, J. A., Liptay, M. J., Pool, M., Seder, C. W., Junker, K., Omberg, L., Dinkin, M., Manikhas, G., Alvaro, D., Bragazzi, M. C., Cardinale, V., Carpino, G., Gaudio, E., Chesla, D., Cottingham, S., Dubina, M., Moiseenko, F., Dhanasekaran, R., Becker, K., Janssen, K., Slotta-Huspenina, J., Abdel-Rahman, M. H., Aziz, D., Bell, S., Cebulla, C. M., Davis, A., Duell, R., Elder, J. B., Hilty, J., Kumar, B., Lang, J., Lehman, N. L., Mandt, R., Nguyen, P., Pilarski, R., Rai, K., Schoenfield, L., Senecal, K., Wakely, P., Hansen, P., Lechan, R., Powers, J., Tischler, A., Grizzle, W. E., Sexton, K. C., Kastl, A., Henderson, J., Porten, S., Waldmann, J., Fassnacht, M., Asa, S. L., Schadendorf, D., Couce, M., Graefen, M., Huland, H., Sauter, G., Schlomm, T., Simon, R., Tennstedt, P., Olabode, O., Nelson, M., Bathe, O., Carroll, P. R., Chan, J. M., Disaia, P., Glenn, P., Kelley, R. K., Landen, C. N., Phillips, J., Prados, M., Simko, J., Smith-McCune, K., VandenBerg, S., Roggin, K., Fehrenbach, A., Kendler, A., Sifri, S., Steele, R., Jimeno, A., Carey, F., Forgie, I., Mannelli, M., Carney, M., Hernandez, B., Campos, B., Herold-Mende, C., Jungk, C., Unterberg, A., von Deimling, A., Bossler, A., Galbraith, J., Jacobus, L., Knudson, M., Knutson, T., Ma, D., Milhem, M., Sigmund, R., Godwin, A. K., Madan, R., Rosenthal, H. G., Adebamowo, C., Adebamowo, S. N., Boussioutas, A., Beer, D., Giordano, T., Mes-Masson, A., Saad, F., Bocklage, T., Landrum, L., Mannel, R., Moore, K., Moxley, K., Postier, R., Walker, J., Zuna, R., Feldman, M., Valdivieso, F., Dhir, R., Luketich, J., Pinero, E. M., Quintero-Aguilo, M., Carlotti, C. G., Dos Santos, J. S., Kemp, R., Sankarankuty, A., Tirapelli, D., Catto, J., Agnew, K., Swisher, E., Creaney, J., Robinson, B., Shelley, C. S., Godwin, E. M., Kendall, S., Shipman, C., Bradford, C., Carey, T., Haddad, A., Moyer, J., Peterson, L., Prince, M., Rozek, L., Wolf, G., Bowman, R., Fong, K. M., Yang, I., Korst, R., Rathmell, W. K., Fantacone-Campbell, J. L., Hooke, J. A., Kovatich, A. J., Shriver, C. D., DiPersio, J., Drake, B., Govindan, R., Heath, S., Ley, T., Van Tine, B., Westervelt, P., Rubin, M. A., Lee, J. I., Aredes, N. D., Mariamidze, A. 2019; 51 (2): 411–12

    View details for DOI 10.1016/j.immuni.2019.08.004

    View details for PubMedID 31433971

  • Long noncoding RNAs in thyroid cancer. Current opinion in endocrinology, diabetes, and obesity Sedaghati, M., Kebebew, E. 2019


    PURPOSE OF REVIEW: Our understanding of the molecular pathology events involved in thyroid cancer initiation and progression and its subtypes has markedly improved as a result of multiomic studies. Recently, long noncoding RNA (lncRNA) have been shown to have a role in cancer initiation and progression and have also been studied in thyroid cancer.RECENT FINDINGS: lncRNA are dysregulated in thyroid cancer. lncRNA have tumor suppressive and oncogenic function in thyroid cancer cells and play a role in some of the established genetic drivers of thyroid cancer initiation and progression. Lastly, some lncRNA are associated with clinicopathologic features of thyroid cancer and circulating blood lncRNA could potentially detect the presence of thyroid cancer.SUMMARY: We highlight the possible clinical utility of analyzing lncRNAs as biomarkers for thyroid cancer diagnosis and prognosis and their association with common genetic changes associated with thyroid cancer.

    View details for DOI 10.1097/MED.0000000000000497

    View details for PubMedID 31385810

  • National Treatment Practice for Adrenocortical Carcinoma: Have they changed and have we made any progress? The Journal of clinical endocrinology and metabolism Tierney, J. F., Chivukula, S. V., Poirier, J., Pappas, S. G., Schadde, E., Hertl, M., Kebebew, E., Keutgen, X. 2019


    MINI-ABSTRACT: The NCDB was used to examine treatment patterns and survival in patients with adrenocortical carcinoma from 2006-2015. Adjuvant chemotherapy has been used more frequent for patients with resectable ACC since 2007. Survival for patients who undergo surgery with adjuvant chemotherapy has improved but remains low.Accepted for podium presentation at the 2018 Clinical Congress of the American College of Surgeons, Boston, Massachusetts, October 2018.BACKGROUND: Adrenocortical carcinoma (ACC) is a rare malignancy with a dismal prognosis. Two landmark trials, published in 2007 and 2012, showed efficacy for adjuvant mitotane in resectable ACC and Etoposide/Doxorubicin/Cisplatin plus mitotane for unresectable ACC, respectively. In this study, we used the National Cancer Database to examine whether treatment patterns and outcomes changed after these trials.METHODS: Patients diagnosed with ACC from 2006-2015 were identified. Treatment modalities were compared within that group, and with a historical cohort (1985-2005). Chi-square tests were performed and Cox proportional hazards models were created.RESULTS: 2752 patients from 2006-2015 were included. 38% of patients (1042) underwent surgery alone and 31% (859) underwent surgery with adjuvant therapy. Overall five-year survival for all stages after resection was 43% (median 41 months) in the contemporary cohort and 39% (median 32 months) in the historical cohort. After 2007, patients who underwent surgery were more likely to receive adjuvant chemotherapy (p = 0.005), and five-year survival with adjuvant chemotherapy improved (41% vs 25%, p = 0.02). Survival did not improve, however, in patients with unresectable tumors after 2011, compared to 2006-2011 (p = 0.79). Older age, tumor size ≥ 10cm, distant metastases, and positive margins were associated with lower survival after resection (HR range: 1.39-3.09, p < 0.03).CONCLUSIONS: Adjuvant therapy has been used more frequently in patients with resected ACC since 2007, and survival for those patients has improved, but remains low. More effective systemic therapies for patients with ACC and especially those with advanced stages are desperately needed.

    View details for DOI 10.1210/jc.2019-00915

    View details for PubMedID 31361313

  • Solutions to Reduce Unnecessary Imaging-Reply. JAMA Oren, O., Kebebew, E., Ioannidis, J. P. 2019; 321 (22): 2243

    View details for DOI 10.1001/jama.2019.4021

    View details for PubMedID 31184737

  • Reply: Do patients with familial nonmedullary thyroid cancer present with more aggressive disease? Implications for initial surgical treatment SURGERY el Lakis, M., Kebebew, E. 2019; 165 (6): 1246–47
  • ONCOGENE PANEL SEQUENCING ANALYSIS IDENTIFIES CANDIDATE ACTIONABLE GENES IN ADVANCED WELL-DIFFERENTIATED GASTROENTEROPANCREATIC NEUROENDOCRINE TUMORS ENDOCRINE PRACTICE Tirosh, A., Killian, J., Zhu, Y., Petersen, D., Walling, J., Mor-Cohen, R., Neychev, V., Stevenson, H., Keutgen, X. M., Patel, D., Nilubol, N., Meltzer, P., Kebebew, E. 2019; 25 (6): 580–88
  • Distinct genome-wide methylation patterns in sporadic and hereditary nonfunctioning pancreatic neuroendocrine tumors CANCER Tirosh, A., Mukherjee, S., Lack, J., Gara, S., Wang, S., Quezado, M. M., Keutgen, X. M., Wu, X., Cam, M., Kumar, S., Patel, D., Nilubol, N., Tyagi, M., Kebebew, E. 2019; 125 (8): 1247–57

    View details for DOI 10.1002/cncr.31930

    View details for Web of Science ID 000462932300007

  • Reply: Do patients with familial nonmedullary thyroid cancer present with more aggressive disease? Implications for initial surgical treatment. Surgery Lakis, M. E., Kebebew, E. 2019

    View details for PubMedID 30910232

  • ONCOGENE PANEL SEQUENCING ANALYSIS IDENTIFIES CANDIDATE ACTIONABLE GENES IN ADVANCED WELL-DIFFERENTIATED GASTROENTEROPANCREATIC NEUROENDOCRINE TUMORS. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists Tirosh, A., Killian, J. K., Zhu, Y. J., Petersen, D., Walling, J., Mor-Cohen, R., Neychev, V., Stevenson, H., Keutgen, X. M., Patel, D., Nilubol, N., Meltzer, P., Kebebew, E. 2019


    Purpose to report the rate of candidate actionable somatic mutations in patients with locally advanced and metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NET) and of other genetic alterations that may be associated with tumorigenesis Methods A phase II mutation targeted therapy trial was conducted in patients with advanced well differentiated G1/G2 GEP-NETs. Mutations found in mTOR pathway associated genes, led to treatment with the mTOR inhibitor everolimus, and were defined as actionable. Tumor DNA from GEP-NETs were sequenced and compared with germline DNA, using the OncoVar-NET assay, designed for hybrid capture sequencing of 500 tumor suppressor genes and oncogenes. Somatic variants were called, and copy-number (CN) variant analysis was performed. Results Thirty patients (14 small-intestine, 8 pancreatic, 3 unknown primary NETs and 5 of other primary sites), harbored 37 lesions (4 patients had DNA of multiple lesions sequenced). Only 2 patients with sporadic NET (n=26) had an actionable mutation leading to treatment with everolimus. Driver somatic mutations were detected in 18 of 30 patients (21/37 lesions sequenced). In the remaining samples without a driver mutation, CN alterations were found in 11/16 tumors (10/12 patients), including CN loss of chr 18 (p<0.05), and CN gain of chr 5, and loss of chr 13. CN losses in chr 18 were more common in patients without driver mutations detected. Pronounced genetic heterogeneity was detected in patients with multiple lesion sequenced. Conclusions Wide DNA sequencing may identify candidate actionable genes, and lead to the identification of novel target genes for advanced well-differentiated GEP-NETs.

    View details for PubMedID 30865533

  • Association of Thyrotropin Suppression With Survival Outcomes in Patients With Intermediate- and High-Risk Differentiated Thyroid Cancer. JAMA network open Klubo-Gwiezdzinska, J., Auh, S., Gershengorn, M., Daley, B., Bikas, A., Burman, K., Wartofsky, L., Urken, M., Dewey, E., Smallridge, R., Chindris, A., Kebebew, E. 2019; 2 (2): e187754


    Importance: Suppression of thyrotropin (often referred to as thyroid-stimulating hormone, or TSH) with levothyroxine used in management of intermediate- and high-risk differentiated thyroid cancer (DTC) to reduce the likelihood of progression and death is based on conflicting evidence.Objective: To examine a cohort of patients with intermediate- and high-risk DTC to assess the association of thyrotropin suppression with progression-free survival (PFS) and overall survival.Design, Setting, and Participants: This cohort study used a multicenter database analysis including patients from tertiary referral centers and local clinics followed up for a mean (SD) of 7.2 (5.8) years. Patients with DTC treated uniformly with total thyroidectomy and radioactive iodine between January 1, 1979, and March 1, 2015, were included. Among the 1012 patients, 145 patients were excluded due to the lack of longitudinal thyrotropin measurements.Exposures: Levothyroxine therapy to target thyrotropin suppression with dose adjustments based on changing thyrotropin goal.Main Outcomes and Measures: The primary outcome measures were overall survival and PFS. A Cox proportional hazards model was used to assess the contribution of age, sex, tumor size, histology, and lymph node and distant metastases at landmarks 1.5, 3.0, and 5.0 years. The patients were divided into 3 groups based on mean thyrotropin score before each landmark: (1) suppressed thyrotropin, (2) moderately suppressed or low-normal thyrotropin, and (3) low-normal or elevated thyrotropin.Results: Among 867 patients (557 [64.2%] female; mean [SD] age, 48.5 [16.5] years) treated with a median (range) cumulative dose of 151 (30-1600) mCi radioactive iodine, disease progression was observed in 293 patients (33.8%), and 34 patients (3.9%) died; thus, the study was underpowered in death events. Thyrotropin suppression was not associated with improved PFS at landmarks 1.5 (P=.41), 3.0 (P=.51), and 5.0 (P=.64) years. At 1.5 and 3.0 years, older age (hazard ratio [HR], 1.06; 95% CI, 1.03-1.08 and HR, 1.05; 95% CI, 1.01-1.08, respectively), lateral neck lymph node metastases (HR, 4.64; 95% CI, 2.00-10.70 and HR, 4.02; 95% CI, 1.56-10.40, respectively), and distant metastases (HR, 7.54; 95% CI, 3.46-16.50 and HR, 7.10; 95% CI, 2.77-18.20, respectively) were independently associated with subsequent time to progression, while at 5.0 years, PFS was shorter for patients with lateral neck lymph node metastases (HR, 3.70; 95% CI, 1.16-11.90) and poorly differentiated histology (HR, 71.80; 95% CI, 9.80-526.00).Conclusions and Relevance: Patients with intermediate- and high-risk DTC might not benefit from thyrotropin suppression. This study provides the justification for a randomized trial.

    View details for PubMedID 30707227

  • Association of Thyrotropin Suppression With Survival Outcomes in Patients With Intermediate- and High-Risk Differentiated Thyroid Cancer JAMA NETWORK OPEN Klubo-Gwiezdzinska, J., Auh, S., Gershengorn, M., Daley, B., Bikas, A., Burman, K., Wartofsky, L., Urken, M., Dewey, E., Smallridge, R., Chindris, A., Kebebew, E. 2019; 2 (2)
  • Risk Haplotypes Uniquely Associated with Radioiodine Refractory Thyroid Cancer Patients of High African Ancestry. Thyroid : official journal of the American Thyroid Association Hurst, Z., Liyanarachchi, S., He, H., Brock, P., Sipos, J. A., Nabhan, F., Kebebew, E., Green, P., Cote, G. J., Sherman, S. I., Walker, C. J., Chang, Y. S., Xue, S., Hollingsworth, B., Li, W., Genutis, L., Menq, E., de la Chapelle, A., Jhiang, S. M. 2019


    BACKGROUND: Thyroid cancer patients with radioiodine refractory (RAI-R) disease, resulting from insufficient RAI delivery and/or RAI resistance, have increased mortality and limited treatment options. To date, studies have largely focused on tumor mutations associated with different stages of disease, which could provide prognostic value for RAI-R disease. We hypothesize that germline variants contributing to intrinsic differences in iodine metabolism, tumor microenvironment and/or immune surveillance are associated with RAI-R disease.METHODS: Whole-genome genotyping data analysis was performed on 1,145 Caucasian (CAU) patients, 244 of whom were RAI-R, and 55 African American (AA) patients, 9 of whom were RAI-R. Germline variant association studies were conducted using candidate genes involved in iodine metabolism or DNA-damage repair, as well as genome-wide association analysis. Initial data indicated several notable variants in a small number of patients (N=7), who were later determined to be AA patients of >80% African ancestry (N=37). This prompted us to focus on germline SNPs uniquely associated with RAI-R AA patients. Sanger sequencing was performed to validate risk alleles and identify the incidence of common somatic mutations BRAFV600E, NRASQ61R, and HRASQ61R, in AA patients whose primary tumor samples were available (N=28/55).RESULTS: We identified TG, BRCA1 and NSMCE2 haplotypes uniquely associated with RAI-R AA patients of >80% African ancestry. All patients with the TG haplotype (N=4) had a biochemical incomplete response to RAI therapy. Patients with the NSMCE2 haplotype (N=4) were diagnosed at a young age (13, 17, 17, and 26 years old) with distant metastatic disease at initial diagnosis. The BRCA1 haplotype co-occurred in 3/4 patients with the NSMCE2 haplotype. The incidence of BRAFV600E appears lower in papillary thyroid carcinoma (PTC) from AA patients of >80% African ancestry (N=3/14, 21%) than in AA patients of <80% African ancestry (N=6/9, 67%), albeit only approaching statistical significance (p=0.077). The tumors available from three RAI-R AA patients were negative for BRAFV600E, NRASQ61R, HRASQ61R.CONCLUSIONS: The identification of candidate RAI-R risk haplotypes may allow early stratification of clinical manifestations of RAI-R disease followed by early intervention and personalized treatment strategies. Functional annotation of candidate RAI-R risk haplotypes may provide insight into the mechanisms underlying RAI-R disease.

    View details for PubMedID 30654714

  • Distinct genome-wide methylation patterns in sporadic and hereditary nonfunctioning pancreatic neuroendocrine tumors. Cancer Tirosh, A., Mukherjee, S., Lack, J., Gara, S. K., Wang, S., Quezado, M. M., Keutgen, X. M., Wu, X., Cam, M., Kumar, S., Patel, D., Nilubol, N., Tyagi, M. V., Kebebew, E. 2019


    BACKGROUND: Aberrant methylation is a known cause of cancer initiation and/or progression. There are scant data on the genome-wide methylation pattern of nonfunctioning pancreatic neuroendocrine tumors (NFPanNETs) and sporadic and hereditary NFPanNETs.METHODS: Thirty-three tissue samples were analyzed: they included samples from sporadic (n=9), von Hippel-Lindau (VHL)-related (n=10), and multiple endocrine neoplasia type 1 (MEN1)-related NFPanNETs (n=10) as well as normal islet cells (n=4) for comparison. Genome-wide CpG methylation profiling was performed with the Infinium MethylationEPIC BeadChip assay and was analyzed with R-based tools.RESULTS: In unsupervised hierarchical clustering, sporadic and MEN1-related NFPanNETs clustered together, and the VHL group was in a separate cluster. MEN1-related NFPanNETs had a higher rate of hypermethylated CpG sites in comparison with sporadic and VHL-related tumor groups. Differentially methylated region analysis confirmed the higher rate of hypermethylation in MEN1-related tumors. Moreover, in an integrated analysis of gene expression data for the same tumor samples, downregulated gene expression was found in most genes that were hypermethylated. In a CpG island methylator phenotype analysis, 3 genes were identified and confirmed to have downregulated gene expression: secreted frizzle-related protein 5 (SFRP5) in sporadic NFPanNETs and cell division cycle-associated 7-like (CDCA7L) and RNA binding motif 47 (RBM47) in MEN1-related NFPanNETs.CONCLUSIONS: MEN1 NFPanNETs have a higher rate of geno me-wide hypermethylation than other NFPanNET subtypes. The similarity between the pathways enriched in a methylation analysis of known genes involved in NFPanNET tumorigenesis suggests a key role for aberrant methylation in the pathogenesis of NFPanNETs.

    View details for PubMedID 30620390

  • Curbing Unnecessary and Wasted Diagnostic Imaging. JAMA Oren, O., Kebebew, E., Ioannidis, J. P. 2019

    View details for PubMedID 30615023

  • MicroRNA-210 May Be a Preoperative Biomarker of Malignant Pheochromocytomas and Paragangliomas. The Journal of surgical research Ruff, S. M., Ayabe, R. I., Malekzadeh, P. n., Good, M. L., Wach, M. M., Gonzales, M. K., Tirosh, A. n., Nilubol, N. n., Pacak, K. n., Kebebew, E. n., Patel, D. n. 2019; 243: 1–7


    Currently, no reliable predictive clinical or laboratory tests exist that can accurately distinguish between benign and malignant pheochromocytomas or paragangliomas (PPGLs). The aim of this study was to investigate if serum microRNA-210 (miR-210) levels could be a marker of malignancy in patients with PPGLs.Preoperative serum from patients with PPGLs was collected on the day of surgery. Clinical demographics, germline mutation status, primary tumor size, postoperative biochemical response, and the development of malignant disease were prospectively collected. Total microRNA was extracted from preoperative serum samples, and miR-210 levels were measured by quantitative real-time reverse transcription-polymerase chain reaction and normalized to miR-16. Prognostic variables were compared using univariable and multivariable analyses.Of the 35 patients, 10 (29%) were diagnosed with malignant PPGLs and 25 patients (71%) were diagnosed with benign PPGLs (median follow-up 72.5 mo). Sixty-nine percent of patients had a pheochromocytoma (n = 24/35) compared with 31% of patients with paraganglioma (n = 11/35). The most common germline mutation was succinate dehydrogenase complex subunit B (SDHB) (n = 10). On univariable analysis, lower serum miR-210 expression level (2.3 ± 0.5 versus 3.1 ± 1.2, P = 0.013) and larger primary tumor size (6.7 ± 5.0 cm versus 4.1 ± 2.3 cm, P = 0.043) were significantly associated with malignant disease. No significant prognostic variables were found on multivariable analysis.In this pilot study, low serum miR-210 expression levels and large primary tumors were identified to be markers of PPGL malignancy on univariable analysis. Given the initial encouraging results in a small cohort, further investigation is warranted to determine if serum miR-210 levels are prognostic.

    View details for DOI 10.1016/j.jss.2019.04.086

    View details for PubMedID 31146085

  • Adrenocortical tumors have a distinct, long, non-coding RNA expression profile and LINC00271 is downregulated in malignancy. Surgery Buishand, F. O., Liu-Chittenden, Y. n., Fan, Y. n., Tirosh, A. n., Gara, S. K., Patel, D. n., Meerzaman, D. n., Kebebew, E. n. 2019


    Adrenocortical carcinoma is an aggressive malignancy with a low but variable overall survival rate. The role of in adrenocortical carcinoma is poorly understood. Thus, in this study we performed long noncoding RNA expression profiling in adrenocortical carcinomas, adrenocortical adenomas, and normal adrenal cortex.Long noncoding RNA expression profile using Human LncRNA/mRNA Expression Microarray V3.0 (Arraystar, Inc, Rockville, MD) was analyzed in samples from 11 adrenocortical adenomas, 9 adrenocortical carcinomas, and 5 normal adrenal cortex. Differentially expressed long noncoding RNAs were validated using TaqMan, real-time quantitative polymerase chain reaction with additional samples. The dataset from the adrenocortical carcinoma Cancer Genome Atlas Programproject was used to evaluate the prognostic utility of long noncoding RNAs.Unsupervised hierarchical clustering showed distinct clustering of adrenocortical carcinoma samples compared with normal adrenal cortex and adrenocortical adenoma samples by long noncoding RNA expression profiles. A total of 874 long noncoding RNAs were differentially expressed between adrenocortical carcinoma and normal adrenal cortex. LINC00271 expression level was associated with prognosis, patients with low LINC00271 expression survived a shorter time than patients with high LINC00271 expression. Low LINC00271 expression was positively associated with WNT signaling, cell cycle, and chromosome segregation pathways.Adrenocortical carcinoma has a distinct long noncoding RNA expression profile. LINC00271 is downregulated in adrenocortical carcinoma and appears to be involved in biologic pathways commonly dysregulated in adrenocortical carcinoma.

    View details for DOI 10.1016/j.surg.2019.04.067

    View details for PubMedID 31522749

  • Preoperative systemic inflammatory markers are prognostic indicators in recurrent adrenocortical carcinoma. Journal of surgical oncology Gaitanidis, A. n., Wiseman, D. n., El Lakis, M. n., Nilubol, N. n., Kebebew, E. n., Patel, D. n. 2019


    Recurrent adrenocortical carcinoma (ACC) has a poor prognosis with minimal clinical and biochemical factors to guide management. The aim of this study was to evaluate the prognostic significance of systemic inflammatory response in patients with recurrent ACC.Patients who underwent resection for recurrent ACC were retrospectively analyzed. Preoperative neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio (LMR), and mean platelet volume were calculated.Twenty-five patients (age at operation 52.2 ± 9.5 years) were identified. We observed a statistically significant shorter disease-specific survival (DSS) in patients with LMR less than 4 (41 ± 7.4 months vs 71 ± 12.3, P = .023) and male sex (26.6 ± 4.2 months vs 57.6 ± 9.5 months, P = .079), while time-to-recurrence (TTR) less than 12 months (40 ± 7.7 months vs 70.3 ± 13.1 months, P = .059) had a trend on univariate analysis for worse DSS. On multivariable analysis, LMR < 4 (hazard ratio [HR] 4.18; 95% confidence interval [CI]: 1.18-14.76; P = .027) and TTR less than 12 months (HR 2.77 95% CI: 1-7.62; P = .049) were found to be significantly associated with worse DSS.Preoperative LMR greater than 4 and TTR greater than 12 months are associated with longer DSS. Patients with LMR greater than 4 and TTR greater than 12 months may benefit from a more aggressive therapeutic approach and may require less frequent surveillance.

    View details for DOI 10.1002/jso.25760

    View details for PubMedID 31733070

  • Lysyl Oxidase is a key player in BRAF/MAPK pathway-driven thyroid cancer aggressiveness. Thyroid : official journal of the American Thyroid Association Boufraqech, M., Patel, D., Nilubol, N., Powers, A. S., King, T., Shell, J., Lack, J., Zhang, L., Gara, S. K., Gunda, V., Klubo-Gwiezdzinska, J., Kumar, S., Fagin, J. A., Knauf, J., Parangi, S., Venzon, D. J., Quezado, M., Kebebew, E. 2018


    BACKGROUND: BRAF mutation is the most common somatic mutation in thyroid cancer. The mechanism associated with BRAF mutant tumor aggressiveness remains unclear. Lysyl oxidase (LOX) is highly expressed in aggressive thyroid cancers, and involved in cancer metastasis. The objective is to determine whether LOX mediates the effect of the activated MAPK pathway in thyroid cancer.METHODS: The prognostic value of LOX and its association with BRAF mutation was analyzed in the TCGA and an independent cohort. Inhibition of mutant BRAF and the MAPK pathway, and overexpression of BRAF mutant and mouse models of BRAFV600E were used to test the effect on LOX expression.RESULTS: In the TCGA cohort, LOX expression was higher in BRAF mutant tumors compared to wild-type tumors (P<0.0001).Patients with BRAF mutant tumors with high LOX expression had a shorter disease-free survival (DFS) (P=0.03) compared to patients with BRAF mutation and low LOX group. In the independent cohort, a significant positive correlation between LOX and percentage of BRAF mutated cells was found. The independent cohort confirmed high LOX expression to be associated with a shorter DFS (P=0.01). Inhibition of BRAFV600E and MEK decreased LOX expression. Conversely overexpression of mutant BRAF increased LOX expression. The mice with thyroid-specific expression of BRAFV600E, showed a strong LOX and p-ERK expressions in tumor tissue. Inhibition of BRAFV600E in transgenic and orthotopic mouse models significantly reduced the tumor burden as well as LOX and p-ERK expressions.CONCLUSIONS: Our data suggests that BRAFV600E tumors with high LOX expression are associated with more aggressive disease. The biological underpinnings of the clinical findings were confirmed by showing that BRAF and the MAPK pathway regulate LOX expression.

    View details for PubMedID 30398411

  • ASO Author Reflections: Systemic Inflammatory Markers in Pancreatic Neuroendocrine Tumors. Annals of surgical oncology Gaitanidis, A., Patel, D., Kebebew, E. 2018

    View details for PubMedID 30353397

  • Do patients with familial nonmedullary thyroid cancer present with more aggressive disease? Implications for initial surgical treatment. Surgery El Lakis, M., Giannakou, A., Nockel, P. J., Wiseman, D., Gara, S. K., Patel, D., Sater, Z. A., Kushchayeva, Y. Y., Klubo-Gwiezdzinska, J., Nilubol, N., Merino, M. J., Kebebew, E. 2018


    BACKGROUND: There are conflicting reports on whether familial nonmedullary thyroid cancer is more aggressive than sporadic nonmedullary thyroid cancer. Our aim was to determine if the clinical and pathologic characteristics of familial nonmedullary thyroid cancer are different than nonmedullary thyroid cancer.METHODS: We compared patients with familial nonmedullary thyroid cancer to a cohort of 53,571 nonmedullary thyroid cancer patients from the Surveillance, Epidemiology, and End Results database.RESULTS: A total of 78 patients with familial nonmedullary thyroid cancer from 31 kindreds presented at a younger age (P = .04) and had a greater rate of T1 disease (P = .019), lymph node metastasis (P = .002), and the classic variant of papillary thyroid cancer on histology (P < .001) compared with the Surveillance, Epidemiology, and End Results cohort. Patients with ≥3 affected family members presented at a younger age (P = .04), had a lesser female-to-male ratio (P = .04), and had a greater rate of lymph node metastasis (P = .009). Compared with the Surveillance, Epidemiology, and End Results cohort, we found a higher prevalence of lymph node metastasis in familial nonmedullary thyroid cancer index cases (P = .003) but not in those diagnosed by screening ultrasonography (P = .58).CONCLUSION: Patients with familial nonmedullary thyroid cancer present at a younger age and have a greater rate of lymph node metastasis. The treatment for familial nonmedullary thyroid cancer should be more aggressive in patients who present clinically and in those who have ≥3 first-degree relatives affected.

    View details for PubMedID 30327187

  • Metastatic neuroendocrine tumors of the gastrointestinal tract and pancreas: A surgeon's plea to centering attention on the liver. Seminars in oncology Keutgen, X. M., Schadde, E., Pommier, R. F., Halfdanarson, T. R., Howe, J. R., Kebebew, E. 2018


    Over 50% of patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have stage IV disease at presentation and the most likely organ to be affected by metastases is the liver. Hepatic involvement and hepatic tumor burden is a key prognostic factor affecting survival of these patients and 80% eventually die of liver failure due to tumor dissemination within the liver. This commentary explores the efficacy and limitations of systemic treatments in patients with GEP-NETs and liver metastases. Landmark randomized trials using systemic therapies including sandostatin (PROMID), lanreotide (CLARINET), everolimus (RADIANT 3 and 4), sunitinib and Peptide Receptor Radionuclide Therapy (NETTER-1) have not shown efficacy in reducing liver tumor burden in patients with stage IV GEP-NETs with liver metastases as outlined in this review. Although often overlooked, surgical debulking has been associated with a significant survival advantage in large retrospective studies and in our opinion should remain an important therapeutic option for patients with stage IV GEP-NETs and liver metastases.

    View details for PubMedID 30318110

  • Metastatic adrenocortical carcinoma displays higher mutation rate and tumor heterogeneity than primary tumors NATURE COMMUNICATIONS Gara, S., Lack, J., Zhang, L., Harris, E., Cam, M., Kebebew, E. 2018; 9: 4172


    Adrenocortical cancer (ACC) is a rare cancer with poor prognosis and high mortality due to metastatic disease. All reported genetic alterations have been in primary ACC, and it is unknown if there is molecular heterogeneity in ACC. Here, we report the genetic changes associated with metastatic ACC compared to primary ACCs and tumor heterogeneity. We performed whole-exome sequencing of 33 metastatic tumors. The overall mutation rate (per megabase) in metastatic tumors was 2.8-fold higher than primary ACC tumor samples. We found tumor heterogeneity among different metastatic sites in ACC and discovered recurrent mutations in several novel genes. We observed 37-57% overlap in genes that are mutated among different metastatic sites within the same patient. We also identified new therapeutic targets in recurrent and metastatic ACC not previously described in primary ACCs.

    View details for PubMedID 30301885

  • Cumulative Radiation Exposures from CT Screening and Surveillance Strategies for von Hippel-Lindau-associated Solid Pancreatic Tumors. Radiology Tirosh, A., Journy, N., Folio, L. R., Lee, C., Leite, C., Yao, J., Kovacs, W., Linehan, W. M., Malayeri, A., Kebebew, E., de Gonzalez, A. B. 2018: 180687


    Purpose To assess the potential ionizing radiation exposure from CT scans for both screening and surveillance of patients with von Hippel-Lindau (VHL) syndrome. Materials and Methods For this retrospective study, abdomen-pelvic (AP) and chest-abdomen-pelvic (CAP) CT scans were performed with either a three-phase (n = 1242) or a dual-energy virtual noncontrast protocol (VNC; n = 149) in 747 patients with VHL syndrome in the National Institutes of Health Clinical Center between 2009 and 2015 (mean age, 47.6 years ± 14.6 [standard deviation]; age range, 12-83 years; 320 women [42.8%]). CT scanning parameters for patients with pancreatic neuroendocrine tumors (PNETs; 124 patients and 381 scans) were compared between a tumor diameter-based surveillance protocol and a VHL genotype and tumor diameter-based algorithm (a tailored algorithm) developed by three VHL clinicians. Organ and lifetime radiation doses were estimated by two radiologists and five radiation scientists. Cumulative radiation doses were compared between the PNET surveillance algorithms by analyses of variance, and a two-tailed P value less than .05 indicated statistical significance. Results Median cumulative colon doses for annual CAP and AP CT scans from age 15 to 40 years ranged from 0.34 Gy (5th-95th percentiles, 0.18-0.75; dual-energy VNC CT) to 0.89 Gy (5th-95th percentiles, 0.42-1.0; three-phase CT). For the current PNET surveillance protocol, the cumulative effective radiation dose from age 40 to 65 years was 682 mSv (tumors < 1.2 cm) and 2125 mSv (tumors > 3 cm). The tailored algorithm could halve these doses for patients with initial tumor diameter less than 1.2 cm (P < .001). Conclusion CT screening of patients with von Hippel-Lindau syndrome can lead to substantial radiation exposures, even with dual-energy virtual noncontrast CT. A genome and tumor diameter-based algorithm for pancreatic neuroendocrine tumor surveillance may potentially reduce lifetime radiation exposure. © RSNA, 2018 Online supplemental material is available for this article.

    View details for PubMedID 30299237

  • Radioguided Surgery With Gallium 68 Dotatate for Patients With Neuroendocrine Tumors. JAMA surgery El Lakis, M., Gianakou, A., Nockel, P., Wiseman, D., Tirosh, A., Quezado, M. A., Patel, D., Nilubol, N., Pacak, K., Sadowski, S. M., Kebebew, E. 2018


    Importance: Neuroendocrine tumors (NETs) express somatostatin receptors, which can be targeted with radiolabeled peptides. In a variety of solid tumors, radioguided surgery (RGS) has been used to guide surgical resection. Gallium 68 (68Ga) dota peptides have been shown to be more accurate than other radioisotopes for detecting NETs. A pilot study previously demonstrated the feasibility and safety of 68Ga-dotatate RGS for patients with NETs.Objective: To evaluate what intraoperative techniques and thresholds define positive lesions that warrant resection during 68Ga-dotatate RGS.Design, Setting, and Participants: This prospective cohort study, conducted between October 23, 2013, and February 14, 2018, included 44 patients with NETs who underwent 68Ga-dotatate RGS.Intervention: Gallium 68-dotatate RGS.Main Outcomes and Measures: The in vivo and ex vivo tumor to background ratio (TBR) was assessed for resected lesions and correlated with the histopathologic findings.Results: Forty-four patients (22 women and 22 men; mean [SD] age, 51.0 [13.7] years) had 133 lesions detected on preoperative imaging scans, with a diagnosis of a pancreatic NET (19 of 44 [43%]), gastrointestinal NET (22 of 44 [50%]), and pheochromocytoma or paraganglioma (3 of 44 [7%]). The TBR was obtained by normalizing to the omentum (106 of 133 [79.7%]) or other solid organs (27 of 133 [20.3%]). The omentum had a significantly lower mean (SD) count than other solid organs for background count activity 3 hours after injection (22.1 [17.0] vs 34.5 [39.0]; P<.001). The lesions containing NETs had a higher TBR than those that did not contain NETs (18.9 vs 4.4; P<.001). On a receiver operating characteristic curve analysis, a TBR of 2.5 had a sensitivity of 90% and a specificity of 25%, and a TBR of 16 had a sensitivity of 54% and a specificity of 81%.Conclusions and Relevance: A TBR of 2.5 or greater is a highly sensitive threshold for indicating a lesion to be consistent with a NET on histologic findings and thus warranting surgical resection. The omentum should be used as the background count activity for 68Ga-dotatate RGS for patients with abdominal NETs.

    View details for PubMedID 30267071

  • Aggressive resection of neuroendocrine tumor (NET) liver metastases: NET neutral or gain? Surgery Cisco, R., Lin, D., Kebebew, E. 2018

    View details for PubMedID 30266442

  • Incidence and management of postoperative hyperglycemia in patients undergoing insulinoma resection ENDOCRINE Nockel, P., Tirosh, A., El Lakis, M., Gaitanidis, A., Merkel, R., Patel, D., Nilubol, N., Sadowski, S. M., Cochran, C., Gorden, P., Kebebew, E. 2018; 61 (3): 422–27


    It has been proposed that rebound hyperglycemia after resection of insulinoma indicates a biochemical cure. However, there is scant objective data in the literature on the rate and need for intervention in hyperglycemia in patients undergoing resection of insulinoma. The goal of our study was to evaluate the rate of postoperative hyperglycemia, any predisposing factors, and the need for intervention in a prospective cohort study of all patients undergoing routine glucose monitoring.A retrospective analysis of 33 patients who had an insulinoma resected and who underwent routine postoperative monitoring of blood glucose (every hour for the first six hours then every four hours for the first 24 h) was performed. Hyperglycemia was defined as glucose greater than 180 mg/dL (10 mmol/l).Twelve patients (36%) developed hyperglycemia within 24 h (range 1-16 h). In patients with hyperglycemia, the mean maximum plasma glucose level was 221.5 mg/dL (range 97-325 mg/dL) (12.3 mmol/l), and four (33%) patients were treated with insulin. There was no significant difference in age, gender, body mass index (BMI), tumor size, biochemical profile, or surgical approach and extent of pancreatectomy between patients who developed hyperglycemia and those who did not. Pre-excision and post-excision intraoperative insulin levels were evaluated in 14 of 33 patients. The percentage decrease of the intraoperative insulin levels was not significantly different between patients who developed hyperglycemia and those who did not. All patients with postoperative hyperglycemia had normalization of their glucose levels, and none were discharged on anti-hyperglycemic agents.Hyperglycemia is common after insulinoma resection, and a subset of patients require transient treatment with insulin.

    View details for PubMedID 29923016

  • Predictors of Survival in Adrenocortical Carcinoma: An Analysis From the National Cancer Database JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Tella, S., Kommalapati, A., Yaturu, S., Kebebew, E. 2018; 103 (9): 3566–73


    Adrenocortical Carcinoma (ACC) is rare and knowledge on the prognostic factors and survival outcomes is limited.To describe predictors of survival and overall survival (OS) outcomes of ACC.Retrospective review of ACC patients from National Cancer Database (NCDB).Nationwide cancer registry based study.Pathologically confirmed 3185 ACC patients identified from NCDB between 2004 and 2015.Baseline description, survival outcomes, and predictors of survival were evaluated in patients with ACC.Median age at diagnosis of ACC was 55 (range:18-90) years and did not differ by sex or stage of disease at diagnosis. On multivariate analysis, increasing age (p < 0.0001), higher Charlson comorbidity index (p < 0.0001), high tumor grade (p < 0.0001), stage IV disease (p=0.002), no surgical therapy (p < 0.0001), and performance of lymphadenectomy during surgery (p=0.02) were associated with poor prognosis. In stage I-III disease, patients treated with surgical resection had significantly better median OS (63 vs 8 months, p <0.001). In stage IV disease, patients treated with surgery (19 vs 6 months, p < 0.001), and post-surgical radiation (29 vs 10 months, p < 0.001) or chemotherapy (22 vs 13 months, p=0.004) had a better median OS.OS of ACC varied with increasing age, higher comorbidity index, grade and stage of the disease at presentation. In addition, we noted improved survival with surgical resection of primary tumor, irrespective of the stage of the disease though, post-surgical chemo or radiation benefitted only in stage IV disease.

    View details for PubMedID 29982685

  • Neural monitoring in endocrine neck surgery GLAND SURGERY El Lakis, M., Kebebew, E. 2018; 7: S86–S88
  • Neural monitoring in endocrine neck surgery. Gland surgery El Lakis, M., Kebebew, E. 2018; 7 (Suppl 1): S86-S88

    View details for DOI 10.21037/gs.2018.03.08

    View details for PubMedID 30178784

    View details for PubMedCentralID PMC6107598

  • Identification of Differential Transcriptional Patterns in Primary and Secondary Hyperparathyroidism JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Sadowski, S., Pusztaszeri, M., Brulhart-Meynet, M., Petrenko, V., De Vito, C., Sobel, J., Delucinge-Vivier, C., Kebebew, E., Regazzi, R., Philippe, J., Triponez, F., Dibner, C. 2018; 103 (6): 2189–98


    Hyperparathyroidism is associated with hypercalcemia and the excess of parathyroid hormone secretion; however, the alterations in molecular pattern of functional genes during parathyroid tumorigenesis have not been unraveled. We aimed at establishing transcriptional patterns of normal and pathological parathyroid glands (PGs) in sporadic primary (HPT1) and secondary hyperparathyroidism (HPT2).To evaluate dynamic alterations in molecular patterns as a function of the type of PG pathology, a comparative transcript analysis was conducted in subgroups of healthy samples, sporadic HPT1 adenoma and hyperplasia, and HPT2.Normal, adenomatous, HPT1, and HPT2 hyperplastic PG formalin-fixed paraffin-embedded samples were subjected to NanoString analysis. In silico microRNA (miRNA) analyses and messenger RNA-miRNA network in PG pathologies were conducted. Individual messenger RNA and miRNA levels were assessed in snap-frozen PG samples.The expression levels of c-MET, MYC, TIMP1, and clock genes NFIL3 and PER1 were significantly altered in HPT1 adenoma compared with normal PG tissue when assessed by NanoString and quantitative reverse transcription polymerase chain reaction. RET was affected in HPT1 hyperplasia, whereas CaSR and VDR transcripts were downregulated in HPT2 hyperplastic PG tissue. CDH1, c-MET, MYC, and CaSR were altered in adenoma compared with hyperplasia. Correlation analyses suggest that c-MET, MYC, and NFIL3 exhibit collective expression level changes associated with HPT1 adenoma development. miRNAs, predicted in silico to target these genes, did not exhibit a clear tendency upon experimental validation.The presented gene expression analysis provides a differential molecular characterization of PG adenoma and hyperplasia pathologies, advancing our understanding of their etiology.

    View details for PubMedID 29659895

  • The Immune Landscape of Cancer IMMUNITY Thorsson, V., Gibbs, D. L., Brown, S. D., Wolf, D., Bortone, D. S., Yang, T., Porta-Pardo, E., Gao, G. F., Plaisier, C. L., Eddy, J. A., Ziv, E., Culhane, A. C., Paull, E. O., Sivakumar, I., Gentles, A. J., Malhotra, R., Farshidfar, F., Colaprico, A., Parker, J. S., Mose, L. E., Nam Sy Vo, Liu, J., Liu, Y., Rader, J., Dhankani, V., Reynolds, S. M., Bowlby, R., Califano, A., Cherniack, A. D., Anastassiou, D., Bedognetti, D., Rao, A., Chen, K., Krasnitz, A., Hu, H., Malta, T. M., Noushmehr, H., Pedamallu, C., Bullman, S., Ojesina, A. I., Lamb, A., Zhou, W., Shen, H., Choueiri, T. K., Weinstein, J. N., Guinney, J., Saltz, J., Holt, R. A., Rabkin, C. E., Lazar, A. J., Serody, J. S., Demicco, E. G., Disis, M. L., Vincent, B. G., Shmulevich, L., Canc Genome Atlas Res Network 2018; 48 (4): 812-+


    We performed an extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types by utilizing data compiled by TCGA. Across cancer types, we identified six immune subtypes-wound healing, IFN-γ dominant, inflammatory, lymphocyte depleted, immunologically quiet, and TGF-β dominant-characterized by differences in macrophage or lymphocyte signatures, Th1:Th2 cell ratio, extent of intratumoral heterogeneity, aneuploidy, extent of neoantigen load, overall cell proliferation, expression of immunomodulatory genes, and prognosis. Specific driver mutations correlated with lower (CTNNB1, NRAS, or IDH1) or higher (BRAF, TP53, or CASP8) leukocyte levels across all cancers. Multiple control modalities of the intracellular and extracellular networks (transcription, microRNAs, copy number, and epigenetic processes) were involved in tumor-immune cell interactions, both across and within immune subtypes. Our immunogenomics pipeline to characterize these heterogeneous tumors and the resulting data are intended to serve as a resource for future targeted studies to further advance the field.

    View details for PubMedID 29628290

  • Comparative Molecular Analysis of Gastrointestinal Adenocarcinomas CANCER CELL Liu, Y., Sethi, N. S., Hinoue, T., Schneider, B. G., Cherniack, A. D., Sanchez-Vega, F., Seoane, J. A., Farshidfar, F., Bowlby, R., Islam, M., Kim, J., Chatila, W., Akbani, R., Kanchi, R. S., Rabkin, C. S., Willis, J. E., Wang, K. K., McCall, S. J., Mishra, L., Ojesina, A. I., Bullman, S., Pedamallu, C., Lazar, A. J., Sakai, R., Thorsson, V., Bass, A. J., Laird, P. W., Canc Genome Atlas Res Network 2018; 33 (4): 721-+


    We analyzed 921 adenocarcinomas of the esophagus, stomach, colon, and rectum to examine shared and distinguishing molecular characteristics of gastrointestinal tract adenocarcinomas (GIACs). Hypermutated tumors were distinct regardless of cancer type and comprised those enriched for insertions/deletions, representing microsatellite instability cases with epigenetic silencing of MLH1 in the context of CpG island methylator phenotype, plus tumors with elevated single-nucleotide variants associated with mutations in POLE. Tumors with chromosomal instability were diverse, with gastroesophageal adenocarcinomas harboring fragmented genomes associated with genomic doubling and distinct mutational signatures. We identified a group of tumors in the colon and rectum lacking hypermutation and aneuploidy termed genome stable and enriched in DNA hypermethylation and mutations in KRAS, SOX9, and PCBP1.

    View details for PubMedID 29622466

  • Machine Learning Identifies Stemness Features Associated with Oncogenic Dedifferentiation CELL Malta, T. M., Sokolov, A., Gentles, A. J., Burzykowski, T., Poisson, L., Weinstein, J. N., Kaminska, B., Huelsken, J., Omberg, L., Gevaert, O., Colaprico, A., Czerwinska, P., Mazurek, S., Mishra, L., Heyn, H., Krasnitz, A., Godwin, A. K., Lazar, A. J., Stuart, J. M., Hoadley, K. A., Laird, P. W., Noushmehr, H., Wiznerowicz, M., Cancer Genome Atlas Res Network 2018; 173 (2): 338-+


    Cancer progression involves the gradual loss of a differentiated phenotype and acquisition of progenitor and stem-cell-like features. Here, we provide novel stemness indices for assessing the degree of oncogenic dedifferentiation. We used an innovative one-class logistic regression (OCLR) machine-learning algorithm to extract transcriptomic and epigenetic feature sets derived from non-transformed pluripotent stem cells and their differentiated progeny. Using OCLR, we were able to identify previously undiscovered biological mechanisms associated with the dedifferentiated oncogenic state. Analyses of the tumor microenvironment revealed unanticipated correlation of cancer stemness with immune checkpoint expression and infiltrating immune cells. We found that the dedifferentiated oncogenic phenotype was generally most prominent in metastatic tumors. Application of our stemness indices to single-cell data revealed patterns of intra-tumor molecular heterogeneity. Finally, the indices allowed for the identification of novel targets and possible targeted therapies aimed at tumor differentiation.

    View details for PubMedID 29625051

  • Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas CELL REPORTS Campbell, J. D., Yau, C., Bowlby, R., Liu, Y., Brennan, K., Fan, H., Taylor, A. M., Wang, C., Walter, V., Akbani, R., Byers, L., Creighton, C. J., Coarfa, C., Shih, J., Cherniack, A. D., Gevaert, O., Prunello, M., Shen, H., Anur, P., Chen, J., Cheng, H., Hayes, D., Bullman, S., Pedamallu, C., Ojesina, A. I., Sadeghi, S., Mungall, K. L., Robertson, A., Benz, C., Schultz, A., Kanchi, R. S., Gay, C. M., Hegde, A., Diao, L., Wang, J., Ma, W., Sumazin, P., Chiu, H., Chen, T., Gunaratne, P., Donehower, L., Rader, J. S., Zuna, R., Al-Ahmadie, H., Lazar, A. J., Flores, E. R., Tsai, K. Y., Zhou, J. H., Rustgi, A. K., Drill, E., Shen, R., Wong, C. K., Stuart, J. M., Laird, P. W., Hoadley, K. A., Weinstein, J. N., Peto, M., Pickering, C. R., Chen, Z., Van Waes, C., Canc Genome Atlas Res Network 2018; 23 (1): 194-+


    This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smoking and/or human papillomavirus (HPV). SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation. Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules. We uncovered hypomethylation of the alternative promoter that drives expression of the ΔNp63 oncogene and embedded miR944. Co-expression of immune checkpoint, T-regulatory, and Myeloid suppressor cells signatures may explain reduced efficacy of immune therapy. These findings support possibilities for molecular classification and therapeutic approaches.

    View details for PubMedID 29617660

  • Four-Gland Exploration Versus Focused Parathyroidectomy for Hyperparathyroidism Jaw Tumor Syndrome DIFFICULT DECISIONS IN ENDOCRINE SURGERY: AN EVIDENCE-BASED APPROACH Patel, D., Kebebew, E., Angelos, P., Grogan, R. H. 2018: 227–37