Samira M. Sadowski

Prospective Study of 68Ga-DOTATATE Positron Emission Tomography/Computed Tomography for Detecting Gastro-Entero-Pancreatic Neuroendocrine Tumors and Unknown Primary Sites

PURPOSE Gastro-entero-pancreatic neuroendocrine tumors (GEPNETs) are increasing in incidence, and accurate staging is important for selecting the appropriate treatment. (68)Ga-DOTATATE imaging is a promising approach for detecting GEPNETs and could help in selecting optimal therapeutic strategies. The aim of this study was to prospectively determine the clinical utility of (68)Ga-DOTATATE positron emission tomography (PET)/computed tomography (CT) in detecting unknown primary and metastatic GEPNETs. PATIENTS AND METHODS One hundred thirty-one patients were enrolled in a prospective study of patients undergoing (68)Ga-DOTATATE PET/CT, (111)In-pentetreotide single-photon emission computed tomography (SPECT)/CT and multiphasic CT scan, and/or magnetic resonance imaging in a blinded fashion with comprehensive biochemical testing. The primary outcome measure was the detection of lesions by each imaging study. RESULTS (68)Ga-DOTATATE PET/CT imaging detected 95.1% of lesions (95% CI, 92.4% to 96.8%) with an average maximum standardized uptake value of 65.4 ± 47 (range, 6.9 to 244), anatomic imaging detected 45.3% of lesions (95% CI, 37.9% to 52.9%), and (111)In-pentetreotide SPECT/CT detected 30.9% of lesions (95% CI, 25.0% to 37.5%), with a significant difference between imaging modalities (P < .001). In four of 14 patients (28.6%), (68)Ga-DOTATATE PET/CT found a previously unknown primary tumor, and detected primary GEPNET, lymph node, and distant metastases correctly in 72 of 113 lesions (63.7%) when compared with histopathology, with 22.1% and 38.9% detected by using (111)In-pentetreotide SPECT/CT and anatomic imaging, respectively. On the basis of findings with (68)Ga-DOTATATE PET/CT, 43 of 131 patients (32.8%) had a change in management recommendation. In patients with carcinoid symptoms but negative biochemical testing, (68)Ga-DOTATATE PET/CT detected lesions in 65.2% of patients, 40% of which were detected neither by anatomic imaging nor by (111)In-pentetreotide SPECT/CT. CONCLUSION (68)Ga-DOTATATE PET/CT imaging provides important information for accurate staging of GEPNETs and selection of appropriate treatment interventions even in the absence of biochemical evidence of disease in symptomatic patients.

Systematic Use of Recurrent Laryngeal Nerve Neuromonitoring Changes the Operative Strategy in Planned Bilateral Thyroidectomy

BACKGROUND One of the worst complications in thyroid surgery is bilateral recurrent laryngeal nerve paralysis, which can lead to transient or definitive tracheotomy. METHODS We implemented a strict standard operative procedure beginning in January 2010 and modified our operative procedure. In all patients undergoing bilateral operation, we begin with the largest side or with the cancerous/suspicious side without dissecting the contralateral side. If the intraoperative neuromonitoring (IONM) signal is lost after stimulation of the vagus nerve at the end of the first side, we stop the procedure after the unilateral lobectomy, even if the recurrent nerve is anatomically intact and regardless of malignancy. If the IONM signal is lost, serial laryngoscopies are performed until recovery or definitive recurrent laryngeal nerve palsy is demonstrated. We report here our results in patients with loss of the IONM signal after lobectomy and discuss the medical implications for benign and malignant thyroid conditions. RESULTS Since January 2010, the operation has been stopped at the first side in 9 out of 220 planned bilateral thyroidectomies. There were five benign thyroid conditions and four thyroid cancers, including three papillary thyroid cancers and one bilateral medullary thyroid cancer in a patient with multiple endocrine neoplasia 2a. In two patients, it was a false-positive IONM loss. One of these two patients had the other lobe removed at day 3. In seven patients the laryngoscopy demonstrated total or partial laryngeal nerve palsy at day 1, but the recurrent nerve function recovered fully in all patients between 1 and 4 months postoperatively. All cancer patients were operated on the other side within 3 days to 3 months; one patient with a benign condition is being followed conservatively. One of the eight re-operated patients had transient recurrent nerve palsy postoperatively. CONCLUSION In our opinion, the systematic use of IONM and the change in operative strategy will lead to an almost 0% rate of bilateral laryngeal nerve palsy, at least in benign thyroid conditions. A loss of signal after the first side should prompt a halt in the procedure, even in cases of malignancies.

68Ga-DOTATATE PET/CT in the Localization of Head and Neck Paragangliomas Compared with Other Functional Imaging Modalities and CT/MRI

Pheochromocytomas/paragangliomas overexpress somatostatin receptors, and recent studies have already shown excellent results in the localization of sympathetic succinate dehydrogenase complex, subunit B, mutation-related metastatic pheochromocytomas/paragangliomas using 68Ga-DOTATATE PET/CT. Therefore, the goal of our study was to assess the clinical utility of this functional imaging modality in parasympathetic head and neck paragangliomas (HNPGLs) compared with anatomic imaging with CT/MRI and other functional imaging modalities, including 18F-fluorohydroyphenylalanine (18F-FDOPA) PET/CT, currently the gold standard in the functional imaging of HNPGLs. Methods: 68Ga-DOTATATE PET/CT was prospectively performed in 20 patients with HNPGLs. All patients also underwent 18F-FDOPA PET/CT, 18F-FDG PET/CT, and CT/MRI, with 18 patients also undergoing 18F-fluorodopamine (18F-FDA) PET/CT. 18F-FDOPA PET/CT and CT/MRI served as the imaging comparators. Results: Thirty-eight lesions in 20 patients were detected, with 18F-FDOPA PET/CT identifying 37 of 38 and CT/MRI identifying 23 of 38 lesions (P < 0.01). All 38 and an additional 7 lesions (P = 0.016) were detected on 68Ga-DOTATATE PET/CT. Significantly fewer lesions were identified by 18F-FDG PET/CT (24/38, P < 0.01) and 18F-FDA PET/CT (10/34, P < 0.01). Conclusion: 68Ga-DOTATATE PET/CT identified more lesions than other imaging modalities. With the results of the present study, and the increasing availability and use of DOTA analogs in the therapy of neuroendocrine tumors, we expect that 68Ga-DOTATATE PET/CT will become the preferred functional imaging modality for HNPGLs in the near future.

Results of 68Gallium-DOTATATE PET/CT Scanning in Patients with Multiple Endocrine Neoplasia Type 1

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.

Resection of primary tumor site is associated with prolonged survival in metastatic nonfunctioning pancreatic neuroendocrine tumors

BACKGROUND Nonfunctioning pancreatic neuroendocrine tumors (NFpNET) present with distant metastases in up to 50% of patients. It is unknown whether removal of the primary tumor in patients with NFpNET and metastases is beneficial. METHODS We used the Surveillance, Epidemiology, and End Results database to identify patients with NFpNET and distant metastases. The primary outcome measure in this study was overall survival. RESULTS We identified 882 patients with metastatic NFpNET who had survival data; 303 (34%) patients had operative removal of their primary tumor of which 243 (80%) were grade I or II. Median survival of patients undergoing resection of the primary site was 65 (95% confidence interval 60-86) versus 10 (8-12) months for those without resection (P < .0001). Patients diagnosed after 2003 (n = 625, 71%) were more likely to undergo an operation than those diagnosed earlier (P = .001). Multivariable analysis showed that a lesser tumor grade (P < .0001), younger age (P < .0001), diagnosis during or after 2003 (P = .0003), tumor site in the body/tail (P = .009), and operative resection of the primary tumor site (P < .0001) were associated with prolonged survival of patients with NFpNET and distant metastases. CONCLUSION This study suggests that resection of the site of the primary NFpNET is associated with greater survival in patients with distant metastases and could therefore be considered as a additional treatment option in this patient population.

Original scientific articleResults of 68Gallium-DOTATATE PET/CT Scanning in Patients with Multiple Endocrine Neoplasia Type 1

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.

Management of anaplastic thyroid cancer.

Anaplastic thyroid cancer (ATC) is a deadly disease with a dismal prognosis. Molecular analyses of ATC tumors have yielded interesting results, which could help in understanding the underlying mechanisms of this aggressive disease process. Managing ATC can be challenging and includes rapid diagnosis, adequate staging, and interdisciplinary, multimodal treatments to optimize patient outcome. Treatments include surgical resection to gross negative margins when possible, as well as neo- or adjuvant treatment with chemotherapy or external beam radiation (XRT) for locoregional disease. New treatment strategies include evaluating the benefits of vascular disrupting agents and tyrosine kinase inhibitors for advanced ATC with driver mutations, which can be targeted. This review summarizes key concepts in managing ATC.

miR30a Inhibits LOX Expression and Anaplastic Thyroid Cancer Progression

Anaplastic thyroid cancer (ATC) is one of the most lethal human malignancies, but its genetic drivers remain little understood. In this study, we report losses in expression of the miRNA miR30a, which is downregulated in ATC compared with differentiated thyroid cancer and normal tissue. miR30a downregulation was associated with advanced differentiated thyroid cancer and higher mortality. Mechanistically, we found miR30a decreased cellular invasion and migration, epithelial-mesenchymal transition marker levels, lysyl oxidase (LOX) expression, and metastatic capacity. LOX was identified as a direct target of miR30a that was overexpressed in ATC and associated with advanced differentiated thyroid cancer and higher mortality rate. Consistent with its role in other cancers, we found that LOX inhibited cell proliferation, cellular invasion, and migration and metastasis in vitro and in vivo. Together, our findings establish a critical functional role for miR30a downregulation in mediating LOX upregulation and thyroid cancer progression, with implications for LOX targeting as a rational therapeutic strategy in ATC.

Patient Specific Tumor Growth Prediction Using Multimodal Images

Personalized tumor growth model is valuable in tumor staging and therapy planning. In this paper, we present a patient specific tumor growth model based on longitudinal multimodal imaging data including dual-phase CT and FDG-PET. The proposed Reaction-Advection-Diffusion model is capable of integrating cancerous cell proliferation, infiltration, metabolic rate and extracellular matrix biomechanical response. To bridge the model with multimodal imaging data, we introduce Intracellular Volume Fraction (ICVF) measured from dual-phase CT and Standardized Uptake Value (SUV) measured from FDG-PET into the model. The patient specific model parameters are estimated by fitting the model to the observation, which leads to an inverse problem formalized as a coupled Partial Differential Equations (PDE)-constrained optimization problem. The optimality system is derived and solved by the Finite Difference Method. The model was evaluated by comparing the predicted tumors with the observed tumors in terms of average surface distance (ASD), root mean square difference (RMSD) of the ICVF map, average ICVF difference (AICVFD) of tumor surface and tumor relative volume difference (RVD) on six patients with pathologically confirmed pancreatic neuroendocrine tumors. The ASD between the predicted tumor and the reference tumor was 2.4±0.5mm, the RMSD was 4.3±0.4%, the AICVFD was 2.6±0.6%, and the RVD was 7.7±1.3%.

Parathyroid gland angiography with indocyanine green fluorescence to predict parathyroid function after thyroid surgery

Postoperative hypoparathyroidism remains the most common complication following thyroidectomy. The aim of this pilot study was to evaluate the use of intraoperative parathyroid gland angiography in predicting normal parathyroid gland function after thyroid surgery.