Publications by authors named "Electron Kebebew"

338 Publications

Adrenal Incidentaloma.

Authors:
Electron Kebebew

N Engl J Med 2021 Apr;384(16):1542-1551

From the Division of General Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA.

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http://dx.doi.org/10.1056/NEJMcp2031112DOI Listing
April 2021

2021 American Thyroid Association Guidelines for Management of Patients with Anaplastic Thyroid Cancer.

Thyroid 2021 03;31(3):337-386

Mayo Clinic, Jacksonville, Florida, USA.

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. 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. 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. 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.
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http://dx.doi.org/10.1089/thy.2020.0944DOI Listing
March 2021

Patient Factors Associated With Parathyroidectomy in Older Adults With Primary Hyperparathyroidism.

JAMA Surg 2021 Apr;156(4):334-342

Department of Surgery, Stanford University School of Medicine, Stanford, California.

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.
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http://dx.doi.org/10.1001/jamasurg.2020.6175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788507PMC
April 2021

2020 to 2021.

Authors:
Electron Kebebew

Thyroid 2021 01;31(1)

Stanford University, Stanford, California, USA.

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http://dx.doi.org/10.1089/thy.2020.0933DOI Listing
January 2021

Comprehensive guidance on the diagnosis and management of primary mesenchymal tumours of the thyroid gland.

Lancet Oncol 2020 11;21(11):e528-e537

National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/S1470-2045(20)30332-6DOI Listing
November 2020

Probability of positive genetic testing in patients diagnosed with pheochromocytoma and paraganglioma: Criteria beyond a family history.

Surgery 2021 02 3;169(2):298-301. Epub 2020 Oct 3.

Department of Surgery and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.surg.2020.08.027DOI Listing
February 2021

GATA3 and APOBEC3B are prognostic markers in adrenocortical carcinoma and APOBEC3B is directly transcriptionally regulated by GATA3.

Oncotarget 2020 Sep 8;11(36):3354-3370. Epub 2020 Sep 8.

The Department of Surgery and Stanford Cancer Institute, Stanford University, Stanford, CA, USA.

Recent evidence has implicated (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 expression is associated with a higher copy number gain/loss at chromosome 4 and 8 and mutation rate in ACC. GATA3 was identified as a positive regulator of 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.
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http://dx.doi.org/10.18632/oncotarget.27703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486697PMC
September 2020

Contemporary Management of Anaplastic Thyroid Cancer.

Curr Treat Options Oncol 2020 Aug 7;21(10):78. Epub 2020 Aug 7.

Division of General Surgery, Department of Surgery, Stanford University School of Medicine, 300 Pasteur Drive, H3591, Stanford, CA, 94305, USA.

Opinion Statement: 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.
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http://dx.doi.org/10.1007/s11864-020-00776-2DOI Listing
August 2020

Distinct DNA Methylation Signatures in Neuroendocrine Tumors Specific for Primary Site and Inherited Predisposition.

J Clin Endocrinol Metab 2020 10;105(10)

Department of Surgery and Stanford Cancer Institute, Stanford University, Stanford, California.

Purpose: To compare the deoxyribonucleic acid (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. Principal components analysis (PCA) and unsupervised hierarchical clustering analyses were used to determine DNA methylome signatures.

Results: Hypomethylated CpGs were significantly more common in VHL-related versus sporadic and MEN1-related NETs (P < .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 < .001 for all comparisons). There was complete separation of SINETs on PCA, and 3 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 (adenomatous polyposis coli) gene, with higher methylation levels in MEN1-related NETs versus VHL-related and sporadic NETs (P < .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 noninvasive molecular characterization of NETs, through DNA methylation profiling of biopsy samples or even circulating tumor DNA in the near future.
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http://dx.doi.org/10.1210/clinem/dgaa477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456345PMC
October 2020

Epidural anesthesia and hypotension in pheochromocytoma and paraganglioma.

Endocr Relat Cancer 2020 09;27(9):519-527

National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Postoperative hypotension frequently occurs 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 to 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 beta-blockade. A prospective evaluation with standardized protocols for the use of EA and management of hemodynamic variability is necessary.
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http://dx.doi.org/10.1530/ERC-20-0139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482424PMC
September 2020

Genetic and epigenetic alterations in pancreatic neuroendocrine tumors.

J Gastrointest Oncol 2020 Jun;11(3):567-577

Department of Surgery and Stanford Cancer Institute, Stanford University, Stanford, CA, USA.

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 , and genes involved in the mTOR pathway, and/or 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.
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http://dx.doi.org/10.21037/jgo.2020.03.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340809PMC
June 2020

Undertreatment of primary hyperparathyroidism in a privately insured US population: Decreasing utilization of parathyroidectomy despite expanding surgical guidelines.

Surgery 2021 01 9;169(1):87-93. Epub 2020 Jul 9.

Department of Surgery, Stanford University School of Medicine, CA.

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.
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http://dx.doi.org/10.1016/j.surg.2020.04.066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736152PMC
January 2021

Racial disparities in knowledge, attitudes and practices related to COVID-19 in the USA.

J Public Health (Oxf) 2020 Aug;42(3):470-478

Department of Health Research & Policy, Stanford University, Stanford, CA 94305, USA.

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1093/pubmed/fdaa069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313911PMC
August 2020

Adrenal Vein Sampling to Distinguish Between Unilateral and Bilateral Primary Hyperaldosteronism: To ACTH Stimulate or Not?

J Clin Med 2020 May 13;9(5). Epub 2020 May 13.

Department of Surgery and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.

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.
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http://dx.doi.org/10.3390/jcm9051447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291054PMC
May 2020

Genetic testing in endocrine surgery: Opportunities for precision surgery.

Surgery 2020 Aug 4;168(2):328-334. Epub 2020 May 4.

Department of Surgery and Stanford Cancer Institute, Stanford University School of Medicine, CA. Electronic address:

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 endocrine surgical 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.
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http://dx.doi.org/10.1016/j.surg.2020.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724998PMC
August 2020

Editorial: Translational Research in Thyroid Cancer.

Front Endocrinol (Lausanne) 2020 15;11:224. Epub 2020 Apr 15.

Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD, United States.

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http://dx.doi.org/10.3389/fendo.2020.00224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174598PMC
April 2020

Surgery for adrenocortical carcinoma: When and how?

Best Pract Res Clin Endocrinol Metab 2020 05 3;34(3):101408. Epub 2020 Mar 3.

Division of General Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.beem.2020.101408DOI Listing
May 2020

An update on familial nonmedullary thyroid cancer.

Endocrine 2020 06 11;68(3):502-507. Epub 2020 Mar 11.

Department of Surgery and Stanford Cancer Institute, Stanford University, Stanford, CA, 94305, USA.

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.
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http://dx.doi.org/10.1007/s12020-020-02250-3DOI Listing
June 2020

The American Association of Endocrine Surgeons Guidelines for the Definitive Surgical Management of Thyroid Disease in Adults.

Ann Surg 2020 03;271(3):e21-e93

Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA.

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.
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http://dx.doi.org/10.1097/SLA.0000000000003580DOI Listing
March 2020

Executive Summary of the American Association of Endocrine Surgeons Guidelines for the Definitive Surgical Management of Thyroid Disease in Adults.

Ann Surg 2020 03;271(3):399-410

Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA.

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.
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http://dx.doi.org/10.1097/SLA.0000000000003735DOI Listing
March 2020

A phase 1 study of nevanimibe HCl, a novel adrenal-specific sterol O-acyltransferase 1 (SOAT1) inhibitor, in adrenocortical carcinoma.

Invest New Drugs 2020 10 27;38(5):1421-1429. Epub 2020 Jan 27.

Department of Investigational Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

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.
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http://dx.doi.org/10.1007/s10637-020-00899-1DOI Listing
October 2020

A Combinatorial Strategy for Targeting -Mutant Cancers with BRAF Inhibitor (PLX4720) and Tyrosine Kinase Inhibitor (Ponatinib).

Clin Cancer Res 2020 04 14;26(8):2022-2036. Epub 2020 Jan 14.

Department of Surgery, Stanford University, Stanford, California.

Purpose: Most aggressive thyroid cancers are commonly associated with a mutation. Preclinical and clinical data in cancers suggest that combined BRAF and MEK inhibitor treatment results 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 thyroid cancer than in 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 and 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 thyroid cancer cell lines and downregulated pERK/MEK and c-JUN signaling pathways, and increased apoptosis. PLX4720-resistant cells became sensitized to the combination treatment, with decreased proliferation at lower PLX4720 concentrations. In an orthotopic thyroid cancer mouse model, combination therapy significantly reduced tumor growth ( < 0.05), decreased the number of metastases ( < 0.05), and increased survival ( < 0.05) compared with monotherapy and vehicle control.

Conclusions: Combination treatment with ponatinib and PLX4720 exhibited significant synergistic anticancer activity in preclinical models of thyroid cancer, in addition to overcoming PLX4720 resistance. Our results suggest this combination should be tested in clinical trials.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1606DOI Listing
April 2020

30th Anniversary and The Future of .

Authors:
Electron Kebebew

Thyroid 2020 01;30(1)

Surgery and Stanford Cancer Center, National Cancer Institute, Stanford, California.

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http://dx.doi.org/10.1089/thy.2019.0794DOI Listing
January 2020

Preoperative systemic inflammatory markers are prognostic indicators in recurrent adrenocortical carcinoma.

J Surg Oncol 2019 Dec 16;120(8):1450-1455. Epub 2019 Nov 16.

Surgical Oncology Program, National Cancer Institute, Bethesda, Maryland.

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1002/jso.25760DOI Listing
December 2019

as A Candidate Modifier Locus for Familial Non-Medullary Thyroid Cancer.

Genes (Basel) 2019 11 7;10(11). Epub 2019 Nov 7.

Faculty of Medicine, University of Barcelona, 08007 Barcelona, Spain.

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 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 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, is likely a low-penetrant gene implicated in FNMTC, possibly a modifier.
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http://dx.doi.org/10.3390/genes10110899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896177PMC
November 2019

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).

Front Oncol 2019 18;9:905. Epub 2019 Sep 18.

Metabolic Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States.

Analysis of plasma circulating cell-free DNA integrity (cfDI) has emerged as a promising tool in the diagnosis of malignant vs. benign tumors. There is limited data on the role of cfDI in thyroid cancer. The goal of this study was to analyze cfDI as a biomarker of malignancy in patients with cytologically indeterminate thyroid nodules. The cfDI was measured in the plasma of patients with cytologically indeterminate thyroid nodules. All patients underwent plasma collection within 24-72 h before surgical treatment for thyroid nodules. Additionally, samples were collected from seven patients via the vein draining the thyroid and peripheral vein during surgery. Quantitative real-time PCR was performed on the isolated cell-free DNA using two different primer sets (115 and 247 bp) to amplify consensus ALU sequences. The cfDI was calculated as the ratio of ALU247 to ALU115. All data are given as median [25th-75th percentile]. The study group consisted of 67 patients with 100 nodules, 80.6% (54/67) women, aged 43 [33-60] years. There was no difference in cfDI between 29 patients with benign nodules (0.49 [0.41-0.59]) and 38 patients with malignant lesions (0.45 [0.36-0.57], = 0.19). There was no difference in cfDI in the vein draining the thyroid (0.47 [0.24-1.05]) and peripheral vein (0.48 [0.36-0.56], = 0.44). In comparison to thyroid cancer patients, patients with benign nodules were characterized by significantly higher concentrations of ALU115 (1,064 [529-2,960] vs. 411 [27-1,049] ng/ml; = 0.002) and ALU247 (548 [276-1,894] vs. 170 [17-540] ng/ml; = 0.0005), most likely because benign tumors were larger (3, [1.8-4.1 cm]) than malignant lesions (0.7 [0.23-1.45], < 0.0001). Women had significantly lower cfDI (0.45 [0.27-0.54]) than men (0.56 [0.44-0.8], = 0.011). The cfDI measured in the vein draining the thyroid is similar to the cfDI measured in the antecubital vein, validating cfDI measurements by peripheral liquid biopsy. Analysis of cfDI needs to be stratified by patients gender. In contrast to its diagnostic utility in aggressive cancers, cfDI has limited utility as a biomarker of malignancy in cytologically indeterminate thyroid nodules.
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http://dx.doi.org/10.3389/fonc.2019.00905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759775PMC
September 2019

Surgical Resection of Pheochromocytomas and Paragangliomas is Associated with Lower Cholesterol Levels.

World J Surg 2020 02;44(2):552-560

Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA.

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) (>200 mg/dL), nine (16.6%) had elevated LDL (>130 mg/dL) and ten (18.5%) had elevated triglycerides (>150 mg/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 166.3 mg/dL (p = 0.0064) and mean HDL decreased from 56.7 to 53.2 mg/dL (p = 0.0253) after PPGL resection (median 3.1 months (range 1.3-50.2) between lipid panels). Most patients with elevated TC (76.9%) had improvement with mean TC decreasing from 225 to 200.2 mg/dL (p = 0.0230). Of patients with elevated LDL, 66.7% had improvement with mean LDL decreasing from 149 to 131.1 mg/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.
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http://dx.doi.org/10.1007/s00268-019-05175-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442156PMC
February 2020

Adrenocortical tumors have a distinct, long, non-coding RNA expression profile and LINC00271 is downregulated in malignancy.

Surgery 2020 01 13;167(1):224-232. Epub 2019 Sep 13.

Center for Cancer Research, National Cancer Institute, Bethesda, MD; Department of Surgery and Stanford Cancer Institute, Stanford University, CA.

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1016/j.surg.2019.04.067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904435PMC
January 2020

Long noncoding RNAs in thyroid cancer.

Curr Opin Endocrinol Diabetes Obes 2019 10;26(5):275-281

Department of Surgery and Stanford Cancer Institute, Stanford University, Stanford, California, USA.

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.
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http://dx.doi.org/10.1097/MED.0000000000000497DOI Listing
October 2019

National Treatment Practice for Adrenocortical Carcinoma: Have They Changed and Have We Made Any Progress?

J Clin Endocrinol Metab 2019 12;104(12):5948-5956

Endocrine Surgery Research Program, Division of General Surgery and Surgical Oncology, Department of Surgery, The University of Chicago, Chicago, Illinois.

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: The National Cancer Database was used to examine treatment patterns and survival in patients diagnosed with ACC from 2006 to 2015. Treatment modalities were compared within that group and with a historical cohort (1985 to 2005). χ2 tests were performed, and Cox proportional hazards models were created.

Results: From 2006 to 2015, 2752 patients were included; 38% of patients (1042) underwent surgery alone, and 31% (859) underwent surgery with adjuvant therapy. Overall 5-year survival rates for all stages after resection were 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 5-year survival with adjuvant chemotherapy improved (41% vs 25%; P = 0.02). However, survival did not improve in patients with unresectable tumors after 2011 compared with 2006 to 2011 (P = 0.79). Older age, tumor size ≥10 cm, distant metastases, and positive margins were associated with lower survival after resection (hazard ratio range: 1.39 to 3.09; P < 0.03).

Conclusions: Since 2007, adjuvant therapy has been used more frequently in patients with resected ACC, and survival for these patients has improved but remains low. More effective systemic therapies for patients with ACC, especially those in advanced stages, are desperately needed.
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http://dx.doi.org/10.1210/jc.2019-00915DOI Listing
December 2019