Search

BACKGROUND: Fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) imaging is recommended in patients with metastatic pheochromocytoma (PC) and paraganglioma (PGL). There are no data on whether routine preoperative (18)F-FDG PET/CT in all patients with PC/PGL impacts surgical management. OBJECTIVE: The aim of this study was to determine whether routine preoperative (18)F-FDG PET/CT imaging affects the surgical management of patients with PC/PGLs. METHODS: We analyzed clinical, biochemical, genetic, and anatomic imaging data in 93 consecutive patients with PC/PGL who collectively underwent a total of 100 operations and who had preoperative (18)F-FDG PET/CT imaging. RESULTS: Of 100 operations, preoperative (18)F-FDG PET/CT showed additional lesions compared to anatomic imaging in 15 cases. These patients were more likely to undergo an open surgical approach (P < 0.05). Presence of genetic mutation, redo operations, sex, age, or tumor size had no significant association with finding additional lesions on (18)F-FDG PET/CT. CONCLUSIONS: Additional lesions detected on preoperative (18)F-FDG-PET/CT imaging have an impact on the surgical approach in patients with PC/PGLs. Therefore, surgeons should routinely obtain (18)F-FDG-PET/CT imaging in patients with PC/PGL to allow for a more precise surgical intervention.

Background Approximately 10% of patients with primary hyperparathyroidism (PHPT) have hereditary disease. Hereditary PHPT may be syndromic (MEN1, 2, and 4 and hyperparathyroidism-jaw tumor syndrome) or non-syndromic (familial isolated PHPT). There are limited data on the probability of testing positive for genetic mutation based on clinical presentation. The aim of this study was to determine potential associations between clinical and biochemical features and mutation in susceptibility genes for PHPT in patients with a family history of PHPT. Study Design A retrospective analysis of 657 patients who had an initial parathyroidectomy for PHPT at a tertiary referral center. Logistic regression analyses were performed in 205 patients with a family history of PHPT to identify factors associated with a positive genetic test. Results Of 657 patients, 205 (31.2%) had a family history of PHPT. Of those 205 patients, 123 (60%) had a germline mutation detected (91 MEN1 , 14 CDC73 , and 18 GCM2 ). In univariate analysis, younger age (45 years and younger), male sex, multigland disease, and parathyroid carcinoma were associated with positive germline mutation; biochemical cure after an initial parathyroidectomy was less frequent in patients with familial PHPT (96.2% vs 89.2%; p = 0.005). In multivariable analysis, age 45 years and younger, male sex, and multigland disease were independent factors associated with positive genetic testing. Conclusions In addition to a family history of PHPT, male sex, age 45 years and younger, and presence of multigland disease, should prompt physicians to offer the opportunity for genetic counseling and testing, as it could influence the management of patients with PHPT.

Background Our knowledge of the susceptibility genes for pheochromocytomas/paragangliomas has increased; however, data on its impact on surgical decision-making has not been described. The aim of this study was to determine the effect of routine preoperative genetic testing on the operative intervention in patients with pheochromocytomas/paragangliomas. Methods One-hundred-eight patients diagnosed with pheochromocytomas/paragangliomas who underwent 118 operations had preoperative genetic testing for 9 known pheochromocytoma/paraganglioma susceptibility genes. A retrospective analysis of a prospective database was performed to evaluate clinical factors associated with the surgical approach selected and the outcome of the surgical intervention. Results In 51 patients (47%), a germline mutation was detected and one-third had no family history of pheochromocytoma/paraganglioma. In 77 operations (65%), it was the first operative intervention for the disease site (60 laparoscopic, 17 open), and 41 (35%) were reoperative interventions (36 open, 5 laparoscopic). For initial operations, variables associated with whether an open or laparoscopic approach was used were tumor size (P = .009) and presence of germline mutation (P = .042). Sixty-eight adrenal operations were performed (54 total, 14 cortical-sparing). Variables significantly associated with a cortical-sparing adrenalectomy being performed were the presence of germline mutation (P = .006) and tumor size (P = .013). Conclusion Preoperative knowledge of the germline mutation status affects the surgical approach and extent of adrenalectomy.

Background: Further characterization of insulinomas from MEN1 patients versus sporadic cases may help elucidate pathophysiological differences and improve future diagnostic algorithms. Methods A retrospective analysis of all patients with insulinoma were included (MEN1 between 1971-2019; sporadic between 1997-2019). Demographic, clinical, laboratory results including a supervised fast, imaging and intra-arterial calcium stimulation (CaStim) data were retrieved when available. Categorical and continuous variables were compared using Fisher’s exact test and Mann-Whitney U-test, respectively. Results One hundred and thirteen patients were identified with insulinoma (69 women, median 44 years, range 13-78 years); of these, 27 patients had MEN1 (11 women, median 37 years, range 18-64 years). Patients with MEN1-related insulinomas sustained a significantly longer duration of the fast and had larger surgically resected tumors (29.73±15.32 vs 15.4±10.8 hours, p

Patients with the multiple endocrine neoplasia 1 (MEN1) syndrome develop various tumors during their lifetime. One of the rare manifestations observed in MEN1 patients is thymic neuroendocrine tumor (Th-NET) or thymic carcinoid, which is a major cause of death due to its aggressive nature, frequent recurrence, and lack of effective treatment. The goal of this study was to analyze the clinical presentation and outcome of Th-NETs in MEN1 patients at our institution and to investigate the correlation between genotype and phenotype. We evaluated the clinical characteristics of MEN1 patients with Th-NETs from a cohort of 350 patients with a MEN1 germline mutation and identified 13 patients (3.7%) with Th-NETs: 11 with thymic carcinoid, 1 with a thymoma demonstrating a neuroendocrine phenotype, and 1 with a non-neuroendocrine thymoma. Thymic carcinoid occurred exclusively in men and was the first tumor identified in 2 of the patients, while the 2 patients with thymoma were both females. Median age of diagnosis for Th-NETs was 43 years (range: 29-65 years). Mean tumor largest diameter was 7.18 cm (range: 2.5-15 cm). ACTH production was not detected in any of the thymic carcinoid cases. Seven patients died, 4 of them are still followed, and 2 of them were lost to follow-up. Th-NETs recurred following surgical resection in 7 patients. Family history of thymic carcinoid was identified in 6 patients. Smoking history was found in 6 patients. MEN1-associated tumors in our cohort included parathyroid adenoma (n=13), pancreatic NET (n=11), pituitary adenoma (n=8), Zollinger-Ellison syndrome (n=7), and lung carcinoid (n=1). In archived tumor samples obtained from 11 patients, chromogranin-A and synaptophysin immunohistochemistry confirmed the neuroendocrine phenotype in thymic carcinoids and showed neuroendocrine differentiation in one of the thymomas. Tumor grade analysis was performed using Ki-67 staining. Genomic DNA was isolated from peripheral blood leukocytes and the following MEN1 germline heterozygous mutations were identified: 8 frameshift, 3 nonsense, 1 in-frame deletion, and 1 missense mutation (found in a thymoma sample). The mutations were scattered throughout the entire MEN1 coding region without specific clustering. Moreover, the only genotype-phenotype correlation observed was a preponderance of protein truncating mutations (frameshift and nonsense) in the Th-NET cohort. Th-NETs are uncommon in MEN1 syndrome. Our Th-NET cohort showed a male predominance. MEN1 mutations in the Th-NET patients did not show any specific clustering, but a preponderance of protein truncating mutations was observed in the MEN1 gene. Further analysis of Th-NET samples for genetic alterations and gene expression profiles will help to uncover the yet to be determined modifying factors in the pathophysiology of Th-NETs.

18F-FDOPA PET/CT accurately identifies pheochromocytoma in 70-year-old male with MEN1 Background: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant inherited disorder that causes tumors most often in the parathyroid, pancreas, and pituitary. Pheochromocytoma in MEN1 is extremely rare (< 2% of cases). Identifying tumor functionality by imaging is challenging given the multiplicity of tumors in MEN1. Case Report: We are reporting a case of a 75-year old male first diagnosed at age 60 with MEN1. Sequencing of MEN1 revealed the pathogenic variant c.249_252delGTCT causing a frameshift mutation. At the time of diagnosis, he was found to have mild hyperparathyroidism status post 2-gland resection, non-functional pituitary microadenoma and bilateral adrenal masses (2.6 cm left; 2.4 cm right). The patient was normotensive and asymptomatic, with elevated plasma normetanephrine 114 pg/mL (upper limit of normal 112) and metanephrine 148 pg/mL (upper limit of normal 61). The remainder of his biochemical workup at that time was normal. The patient remained normotensive and asymptomatic, and routine yearly CT evaluation demonstrated growth of the left adrenal mass to 3.9 cm (9 Hounsfield unit (HU) pre-contrast, and post-contrast HU of 15), and right adrenal mass to 2.6 cm. Follow-up biochemical evaluation revealed an adrenergic biochemical phenotype with elevated plasma metanephrine 432 (12-61 pg/ml) and normetanephrine 291 (18-112 pg/ml) levels, with normal norepinephrine 198 (84-794 pg/ml), dopamine

BACKGROUND: Gastric neuroendocrine tumors (carcinoid) associated with Zollinger Ellison Syndrome (ZES) induced hypergastrinemia in Multiple Endocrine Neoplasia type 1 (MEN1) occur in 15-50% of patients and are generally thought to be benign. Here we present a case of metastatic grade 3 gastric neuroendocrine tumor in MEN1. CASE: A 41-year male with history of MEN1 syndrome manifested by hyperparathyroidism, pancreatic neuroendocrine tumors, and Zollinger-Ellison Syndrome had been followed for 10 years. The patient had undergone yearly surveillance including CT, MRI, upper GI endoscopy (EGD) and 68Ga-DOTATATE, which had identified multiple small foci in the pancreas and duodenum. However, only MRI revealed a T2 hypointense 2.6 cm mildly enhancing mass along the lesser curvature of the stomach that was not visible on CT, MRI, EGD or 68Ga-DOTATATE within the 2 years prior. Gastrin levels remained 20% and mitotic count >20 per 10 high powered fields. At the time of diagnosis, this lesion was histologically classified as well to moderately differentiated, high grade neuroendocrine carcinoma (Grade 3), large cell type. Loss of heterozygosity for the MEN1 gene at 11q13 was confirmed in the tumor. Monitoring with serial scans demonstrated right hepatic lobe metastasis by 1-year post-surgery. CONCLUSION: Previous reports of MEN1/ZES gastric carcinoid are associated with high gastrin levels, long disease duration, and are typically grade 1 or 2[i]. Special attention to identification of gastric mucosal nodules with well-controlled ZES is required as these lesions may rarely become malignant. Endnotes i Berna MJ, et al. A prospective study of gastric carcinoids and enterochromaffin-like cell changes in multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome: identification of risk factors. JCEM. 2008; 93(5):1582-91.

Background Thyroid ultrasound (US) and US-guided fine needle aspiration biopsy (FNAB) have been widely used to stratify the risk of malignancy in thyroid nodules (TN). Cytology material characterized as category III and IV by the Bethesda System for Reporting Thyroid Cytopathology is associated with thyroid cancer (TC) risk ranging between 5-30%. The use of molecular markers may help defining the management strategy in these indeterminate nodules. The goal of this study was to create a risk stratification system based on US features and the results of molecular profiling of cytologically indeterminate TN and to assess its diagnostic accuracy. Methods We performed a cohort study including patients with TN who underwent thyroid US and FNAB revealing indeterminate cytology (Bethesda III, IV). Final pathology diagnosis was available for all patients. DNA and RNA were extracted from pathology material and subjected to Ion Torrent™ Oncomine™ Comprehensive Assay v3 (OCAv3) next-generation sequencing, analyzing single nucleotide variants (SNV), small insertions and deletions (INDEL), copy number variants (CNV) and gene fusions (GF) from 161 cancer driver genes. Each genetic alteration was annotated (X) based on its strength of association with TC per TCGA and COSMIC database. US features of TN were similarly categorized (Xus) by two independent clinicians, blinded to pathology report. The total risk score (TRS) was estimated based on the following formula TRS= (XSNV/INDEL)*n + XGF + XCNV + XUS , where X is the annotated score and n is the number of SNVs/INDELs. ROC curve was performed to assess the diagnostic accuracy of US alone, OCAv3 alone and TRS. Results We analyzed 84 TN in 50 patients (39 females and 11 males), age 47.2 ± 14.8 years. Thirty-four patients (68%) were diagnosed with TC: 21 papillary (PTC), 6 follicular variant of PTC (FVPTC), 1 noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), 2 Hürthle cell (HTC), 1 poorly differentiated carcinoma (PD) and 3 medullary TC (MTC). The molecular signature revealed the BRAF V600E mutation as the most common in PTC, while KRAS and NRAS mutations were associated with FVPTC. A NIFTP showed a PAX8-PPARG fusion. HTC had pathogenic variants of SLX4, ATM and NRAS genes, PD was associated with HRAS mutation, and MTC with RET pathogenic variants. Benign lesions were characterized by either no mutations or the presence of GNAS, HRAS, NRAS and ESR1 variants. The diagnostic accuracy of US alone was 68% (sensitivity 41.2%, specificity 93.8%), while for OCAv3 alone it was 79% (sensitivity 65%, specificity 93.8%). TRS was associated with the highest diagnostic accuracy of 83.5% (sensitivity 79.4%, specificity 88%). Conclusions Combining risk stratification based on thyroid US and molecular signature improves diagnostic accuracy of TC in patients with indeterminate TN. Our pilot study requires validation in independent larger cohorts.

SummaryObjective Valproic acid (VA) is a histone deacetylase (HDAC) inhibitor that has antiproliferative effects on several types of cancer, including thyroid cancer. In addition, VA has been reported to upregulate the sodium-iodine symporter in thyroid cancer cells and increases radioiodine uptake in preclinical studies. The aim of this study was to assess the antiproliferative effects of VA and to evaluate if VA can increase the radioiodine uptake in patients with advanced, radioiodine-negative thyroid cancer. Design An open-label Simon two-stage phase II trial. Patients and Measurements Valproic acid was administered orally, and doses were adjusted to maintain serum trough levels between 50 and 100 mg/l for 10 weeks, followed by injections of recombinant human thyroid-stimulating hormone and a radioiodine uptake scan. Anatomical imaging studies were performed at week 16 to assess tumour response and radioiodine therapy in patients with increased radioiodine uptake. Results Thirteen patients with a median age of 66 years (50–78 years) were enrolled and evaluated. Seven patients had papillary thyroid cancer (PTC), two had follicular variant PTC, two had follicular thyroid cancer, and two had Hurthle cell carcinoma. None of the 10 patients who completed the 10-week treatment had increased radioiodine uptake at their tumour sites. Three patients were taken off the study prior to the 10-week radioiodine uptake scan: one with grade-3 hepatic toxicity, one with disease progression and one for noncompliance. Four of 13 patients had decreased stimulated serum thyroglobulin with VA treatment. None of the patients had complete or partial responses based on Response Evaluation Criteria in Solid Tumors (RECIST), and six patients had disease progression. Conclusions Valproic acid does not increase radioiodine uptake and does not have anticancer activity in patients with advanced, radioiodine-negative thyroid cancer of follicular cell origin.

PURPOSE: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: Hyperglycemia is common after insulinoma resection, and a subset of patients require transient treatment with insulin.

Background Screening for neuroendocrine tumors (NETs) in patients with multiple endocrine neoplasia type 1 (MEN1) is recommended to detect primary and metastatic tumors, which can result in significant morbidity and mortality. The utility of somatostatin receptor imaging 68 Gallium-DOTATATE PET/CT in patients with MEN1 is not known. The aim of this study was to prospectively determine the accuracy of 68 Gallium-DOTATATE PET/CT vs 111 In- pentetreotide single-photon emission CT (SPECT)/CT and anatomic imaging in patients with MEN1. Study Design We performed a prospective study comparing 68 Gallium-DOTATATE PET/CT, 111 In-pentetreotide SPECT/CT, and triphasic CT scan to clinical, biochemical, and pathologic data in 26 patients with MEN1. Results 68 Gallium-DOTATATE PET/CT detected 107 lesions; 111 In-pentetreotide SPECT/CT detected 33 lesions; and CT scan detected 48 lesions. Lesions detected on 68 Gallium-DOTATATE PET/CT had high standard uptake value (SUV) max (median SUV max = 72.8 [range 19 to 191]). In 7 of the 26 patients (27%), 68 Gallium-DOTATATE PET/CT was positive, with a negative 111 In-pentetreotide SPECT/CT, and in 10 patients (38.5%), additional metastases were detected (range 0.3 cm to 1.5 cm). In 8 of the 26 patients (31%), there was a change in management recommendations as a result of the findings on 68 Gallium-DOTATATE PET/CT that were not seen on 111 In-pentetreotide SPECT/CT and CT scan. Conclusions 68 Gallium-DOTATATE PET/CT is more sensitive for detecting NETs than 111 In-pentetreotide SPECT/CT and CT scan in patients with MEN1. This imaging technique should be integrated into radiologic screening and surveillance of patients with MEN1 because it can significantly alter management recommendations.

Aim: The study's aim was to determine the utility of 68-Gallium DOTATATE positron emission tomography (PET)-CT scanning in patients with carcinoid-like symptoms and negative anatomical imaging. Methods: Retrospective analysis of 22 of 196 patients with carcinoid-like symptoms and no evidence of primary neuroendocrine tumor (NET) based on anatomical imaging and endoscopy who underwent 68-Gallium DOTATATE PET-CT as part of a prospective clinical trial. Results: Of the biochemically positive patients (n = 11), 18% (n = 2) had additional evidence of NETs based on 68-Gallium DOTATATE PET-CT. Of the patients identified by 68-Gallium DOTATATE PET-CT, 50% (n = 1) had a treatment change and 100% showed symptom improvement. Of the biochemically negative patients (n = 11), 68-Gallium DOTATATE PET-CT identified NETs in 64% (n = 7). Change in management occurred in 71% patients, and 57% of patients showed symptom improvement. Conclusion: 68-Gallium DOTATATE PET-CT imaging is useful in detecting NETs in symptomatic patients with negative anatomical imaging and changes the treatments in these patients.

Hereditary primary hyperparathyroidism may be syndromic or nonsyndromic (familial isolated hyperparathyroidism). Recently, germline activating mutations in the GCM2 gene were identified in a subset of familial isolated hyperparathyroidism. This study examined the clinical and biochemical characteristics and the treatment outcomes of GCM2 mutation-positive familial isolated hyperparathyroidism as compared to sporadic primary hyperparathyroidism.We performed a retrospective analysis of clinical features, parathyroid pathology, and operative outcomes in 18 patients with GCM2 germline mutations and 457 patients with sporadic primary hyperparathyroidism.Age at diagnosis, sex distribution, race/ethnicity, and preoperative serum calcium concentrations were similar between the 2 groups. The preoperative serum levels of intact parathyroid hormone was greater in patients with GCM2-associated primary hyperparathyroidism (239 ± 394 vs 136 ± 113, P = .005) as were rates of multigland disease and parathyroid carcinoma in the GCM2 group (78% vs 14.3%, P .001 and 5% vs 0%, P = .04, respectively), but the biochemical cure rate was less in the GCM2 group (86% vs 99%, P .001).GCM2-associated primary hyperparathyroidism patients have greater preoperative parathyroid hormone levels, a greater rate of multigland disease, a lesser rate of biochemical cure, and a substantial risk of parathyroid carcinoma. Knowledge of these clinical characteristics could optimize the surgical management of GCM2-associated familial isolated hyperparathyroidism.

Although a family history of thyroid cancer is one of the main risk factors for thyroid cancer, the benefit of screening individuals with a family history of thyroid cancer is not known.A prospective cohort study was performed with yearly screening using neck ultrasound and fine-needle aspiration biopsy of thyroid nodule(s)0.5 cm in at-risk individuals whose relatives were diagnosed with familial non-medullary thyroid cancer (FNMTC). The eligibility criteria were the presence of thyroid cancer in two or more first-degree relatives and being older than seven years of age. Twenty-five kindred were enrolled in the study (12 families with two members affected, and 13 with three or more members affected at enrollment).Thyroid cancer was detected by screening in 4.6% (2/43) of at-risk individuals from families with two members affected, and in 22.7% (15/66) of at-risk members from families with three or more patients affected (p = 0.01). FNMTC detected by screening was characterized by a smaller tumor size (0.7 ± 0.5 cm vs. 1.5 ± 1.1 cm; p = 0.006), a lower rate of central neck lymph node metastases (17.6% vs. 51.1%; p = 0.02), less extensive surgery (hemithyroidectomy 23.5% vs. 0%; p = 0.002), and a lower rate of radioactive iodine therapy (23.5% vs. 79%; p 0.001) compared to those affected at enrollment.Screening of at-risk family members resulted in earlier detection of low-risk FNMTC and was associated with a less aggressive initial treatment. Screening with thyroid ultrasound should be considered in kindred with three or more family members affected by FNMTC. Since active screening might be associated with the risk of overtreatment, it should be implemented with caution, specifically in elderly individuals.

Context: Phosphaturic mesenchymal tumors (PMTs) are small, typically difficult to localize, and express somatostatin receptors. Recent work suggests imaging studies using 68Gallium (68Ga)-conjugated somatostatin peptide analogues, such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)TATE, which enables somatostatin receptor imaging with positron emission tomography (PET), may be useful at identifying these tumors. Objective: Our objective was to evaluate the use of 68Ga-DOTATATE PET/computed tomography (CT) for tumor localization in tumor-induced osteomalacia (TIO). Design: This was a single-center prospective study of patients with TIO. Setting: The study was conducted at the National Institutes of Health Clinical Center between February 2014 and February 2015. Subjects: Eleven subjects (six females, five males) with TIO were included. Intervention: Subjects underwent 68Ga-DOTATATE PET/CT in addition to 111In-pentetreotide single-photon emission CT (Octreoscan- SPECT/CT) and fluorodeoxy...

Introduction Finding the optimal management strategy for patients with advanced, metastatic neuroendocrine tumours (NETs) of the gastrointestinal tract and pancreas is a work in progress. Sunitinib and everolimus are currently approved for the treatment of progressive, unresectable, locally advanced or metastatic low-grade or intermediate-grade pancreatic NETs. However, mutation-targeted therapy with sunitinib or everolimus has not been studied in this patient population. Methods and analysis This prospective, open-label phase II clinical trial was designed to determine if mutation-targeting therapy with sunitinib or everolimus for patients with advanced low-grade or intermediate-grade NETs is more effective than historically expected results with progression-free survival (PFS) as the primary end point. Patients ≥18 years of age with progressive, low-grade or intermediate-grade locally advanced or metastatic NETs are eligible for this study. Patients will undergo tumour biopsy (if they are not a surgical candidate) for tumour genotyping. Patients will be assigned to sunitininb or everolimus based on somatic/germline mutations profile. Patients who have disease progression on either sunitinib or everolimus will crossover to the other drug. Treatment will continue until disease progression, unacceptable toxicity, or consent to withdrawal. Using the proposed criteria, 44 patients will be accrued within each treatment group during a 48-month period (a total of 88 patients for the 2 treatments), and followed for up to an additional 12 months (a total of 60 months from entry of the first patient) to achieve 80% power in order to test whether there is an improvement in PFS compared to historically expected results, with a 0.10 α level one-sided significance test. Ethics and dissemination The study protocol was approved by the institutional review board of the National Cancer Institute (NCI-IRB Number 15C0040; iRIS Reference Number 339636). The results will be published in a peer-reviewed journal and shared with the worldwide medical community. Trial registration number NCT02315625.