In 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) studies, maximum standardized uptake value (SUVmax) is the parameter commonly used to provide a measurement of the metabolic activity of a tumor. SUV normalized by body mass is affected by the proportions of body fat and lean tissue, which present high variability in patients with cancer. SUV corrected by lean body mass (LBM), denoted as SUL, is recommended to provide more accurate, consistent, and reproducible SUV results; however, LBM is frequently estimated rather than measured. Given the increasing importance of a quantitative PET parameter, especially when comparing PET studies over time to evaluate disease response clinically, and its use in oncological clinical trials, we set out to evaluate the commonly used equations originally derived by James (1976) and Janmahasatian et al. (2005) against computerized tomography (CT)-derived measures of LBM.MethodsWhole-body 18F-FDG PET images of 195 adult patients with cancer were analyzed retrospectively. Representative liver SUVmean was normalized by total body mass. SUL was calculated using a quantitative determination of LBM based on the CT component of the PET/CT study (LBMCT) and compared against the equation-estimated SUL. Bland and Altman plots were generated for SUV-SUL differences.ResultsThis consecutive sample of patients undergoing usual care (men, n = 96; women, n = 99) varied in body mass (38–127 kg) and in Body Mass Index (BMI) (14.7–47.2 kg/m2). LBMCT weakly correlated with body mass (men, r2 = 0.32; women, r2 = 0.22), and thus SUV and SULCT were also weakly correlated (men, r2 = 0.24; women, r2 = 0.11). Equations proved inadequate for the assessment of LBM. LBM estimated by James’ equation showed a mean bias (overestimation of LBM compared with LBMCT) in men (+6.13 kg; 95% CI 4.61–7.65) and in women (+6.32 kg; 95% CI 5.26–7.39). Janmahasatian’s equation provided similarly poor performance.ConclusionsCT-based LBM determinations incorporate the patient’s current body composition at the time of a PET/CT study, and the information garnered can provide care teams with information with which to more accurately determine FDG uptake values, allowing comparability over multiple scans and treatment courses and will provide a robust basis for the use of PET Response Criteria in Solid Tumors (PERCIST) in clinical trials.

Theragnostic pairs of isotopes are used to infer radiation dosimetry for a therapeutic radiopharmaceutical from a diagnostic imaging study with the same tracer molecule labelled with an isotope better suited for the imaging task. We describe the transfer of radiation dosimetry from the diagnostic radioiodine isotope 123I, labelled for the hypoxia tracer molecule iodoazomycin arabinoside ([123I]IAZA), to isotopes 131I (therapeutic) and 124I (PET imaging). Uncertainties introduced by the dissimilar isotope half-lives are discussed in detail. Radioisotope dosimetries for [123I]IAZA were obtained previously. These data are used here to calculate residence times for 131I and 124I and their uncertainties. We distinguish two cases when extrapolating to infinity: purely physical decay (case A) and physical decay plus biological washout (case B). Organ doses were calculated using the MIRD schema with the OLIDNA/EXM code. Significant increases in some organ doses (in mSv per injected activity) were found for 131I and 124I. The most affected organs were the intestinal walls, thyroid, and urinary bladder wall. Uncertainty remained similar to 123I for case A but considerably greater for case B, especially for long biological half-lives (GI tract). Normal tissue dosimetries for IAZA must be considered carefully when substituting isotope species. A long biological half-life can significantly increase dosimetric uncertainties. These findings are relevant when considering PET imaging studies with [124I]IAZA or therapeutic administration of [131I]IAZA.

Positron emission tomography (PET) using 2‐deoxy‐2‐[18F]fluoro‐d‐glucose ([18F]FDG), a marker of energy metabolism and cell proliferation, is routinely used in the clinic to assess patient response to chemotherapy and to monitor tumor growth. Treatment with some tyrosine kinase inhibitors (TKIs) causes changes in blood glucose levels in both nondiabetic and diabetic patients. We evaluated the interaction of several classes of TKIs with human glucose transporter‐1 (hGLUT‐1) in FaDu and GIST‐1 cells by measuring [3H]2‐deoxy‐d‐glucose ([3H]2‐DG) and [3H]FDG uptake. Uptake of both was inhibited to varying extents by the TKIs, and representative TKIs from each class showed competitive inhibition of [3H]2‐DG uptake. In GIST‐1 cells, [3H]FDG uptake inhibition by temsirolimus and nilotinib was irreversible, whereas inhibition by imatinib, gefitinib, and pazopanib was reversible. Molecular modeling studies showed that TKIs form multiple hydrogen bonds with polar residues of the sugar binding site (i.e., Q161, Q282, Q283, N288, N317, and W388), and van der Waals interactions with the H‐pocket site. Our results showed interaction of TKIs with amino acid residues at the glucose binding site to inhibit glucose uptake by hGLUT‐1. We hypothesize that inhibition of hGLUT‐1 by TKIs could alter glucose levels in patients treated with TKIs, leading to hypoglycemia and fatigue, although further studies are required to evaluate roles of other SLC2 and SLC5 members. In addition, TKIs could affect tumor [18F]FDG uptake, increasingly used as a marker of tumor response. The hGLUT‐1 inhibition by TKIs may have implications for routine [18F]FDG‐PET monitoring of tumor response in patients.

Thyroid cancer is the most common type of endocrine malignancy. Cornerstones of thyroid cancer treatment include surgery, radioactive iodine ablation, and thyroid stimulating hormone suppression. The National Comprehensive Cancer Network guidelines recommend two tyrosine kinase inhibitors for thyroid cancer patients who are non-responsive to iodine: sorafenib and lenvatinib. Another oral kinase inhibitor, regorafenib, is not considered standard of care treatment for differentiated thyroid cancer. The chemical structures of regorafenib and sorafenib differ by a single fluorine atom. Given the significant improvement in progression-free survival (PFS) of sorafenib compared to placebo demonstrated in the phase 3 DECISION trial, we report on a patient with iodine-refractory follicular thyroid cancer treated with regorafenib as part of a phase 1 clinical trial. A 75 year old woman was diagnosed with follicular thyroid carcinoma in 2006 and initiated on treatment with regorafenib in 2011. She has completed 76 cycles with stable disease and pulmonary metastases 34% smaller than baseline.

OBJECTIVE:The purpose of this study was to assess the efficacy of Lu-labeled peptide receptor radionuclide therapy (PRRT) induction treatments for patients with unresectable metastatic neuroendocrine tumors.METHODS:MEDLINE, EMBASE, and Ovid were systematically searched with keywords "lutetium," "Lu-177," "PRRT," "neuroendocrine," and "prognosis." Studies evaluating treatment with Lu-labeled PRRT were assessed for disease response and/or disease control rate by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 or 1.1, modified RECIST, Southwest Oncology Group (SWOG), or modified SWOG criteria. Pooled proportions of disease response and control rates were calculated for both fixed- and random-effects models.RESULTS:Eighteen studies with 1920 patients were included (11 with 1268 patients using RECIST and 6 with 804 patients using SWOG). By RECIST criteria, the pooled disease response rate by random-effects model was 29.1% (95% confidence interval [CI], 20.2%-38.9%), and disease control rate was 74.1% (95% CI, 67.8%-80.0%). By SWOG criteria, the pooled disease response rate by random-effects model was 30.6% (95% CI, 20.7%-41.5%), and disease control rate was 81.1% (95% CI, 76.4%-85.4%).CONCLUSIONS:Induction therapy, typically 4 treatments, with Lu PRRT is an effective method of treating unresectable metastatic neuroendocrine tumors with significant disease response and control rates.

The objective of this work is to evaluate the potential effect of cardiac stress exercise on 16 the accumulation of [123I]IAZA, a radiopharmaceutical used to image focal tissue hypoxia, in 17 otherwise normal myocardium in healthy volunteers, and to determine the impact of exercise on 18 [123I]IAZA pharmacokinetics. The underlying goal is to establish a rational basis and a baseline for 19 studies of focal myocardial hypoxia in cardiac patients using [123I]IAZA. Three healthy male 20 volunteers ran the ‘Bruce’ treadmill protocol, a clinically-accepted protocol designed to expose 21 myocardial ischemia in patients. The ‘Bruce’ criterion heart rate is 85% of [220 – age]. 22 Approximately one minute before reaching this level, [123I]IAZA (5.0 mCi/0.85 mg) was 23 administered as a slow (1–3 min) single intravenous (i.v.) injection via an indwelling venous 24 catheter. The volunteer continued running for an additional 1 min before being transferred to a 25 gamma camera. Serum samples were collected from the arm contralateral to the administration site 26 at pre-determined intervals from 1 min to 45 h post injection and were analyzed by radio HPLC. 27 Pharmacokinetic (PK) parameters were derived for [123I]IAZA and total radioactivity (total[123I]) 28 using compartmental and noncompartmental analyses. Whole-body planar scintigraphic images 29 were acquired from 0.75 to 24 h after dosing. PK data and scintigraphic images were compared to 30 previously published [123I]IAZA data from healthy volunteers rest. Following exercise stress, both 31 [123I]IAZA and total[123I] exhibited bi-exponential decline profiles, with rapid distribution phases 32 [half-lives (t1/2α) of 1.2 and 1.4 min, respectively], followed by slower elimination phases [t1/2β of 195 33 and 290 min, respectively]. Total body clearance (CLTB) and the steady state volume of 34 distribution (Vss) were 0.647 L/kg and 185 mL/min, respectively, for [123I]IAZA and 0.785 L/kg and 35 135 mL/min, respectively, for total[123I]. The t1/2β, CLTB and Vss values were comparable to those 36 reported previously for rested volunteers. The t1/2α was approximately 4-fold shorter for [123I]IAZA 37 and approximately 3-fold shorter for total[123I] under exercise relative to rested subjects. The heart 38 region was visualized in early whole body scintigraphic images, but later images showed no 39 accumulated radioactivity in this region, and no differences from images reported for rested 40 volunteers were apparent. Minimal uptake of radiotracer in myocardium and skeletal muscle was 41 consistent with uptake in non-stressed myocardium. Whole-body scintigrams for [123I]IAZA in 42 exercise-stressed healthy volunteers were indistinguishable from images of non-exercised 43 volunteers. There was no evidence of hypoxia-dependent binding in exercised but otherwise 44 Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 24 February 2018 doi:10.20944/preprints201710.0034.v2 © 2018 by the author(s). Distributed under a Creative Commons CC BY license. healthy myocardium, supporting the conclusion that exercise stress at Bruce protocol intensity 45 does not induce measurable myocardial hypoxia. Effects of exercise on PK parameters were 46 minimal; specifically, the t1/2α was shortened, reflecting increased cardiac output associated with 47 exercise. It is concluded that because [123I]IAZA was not metabolically bound in exercise-stressed 48 myocardium, a stress test will not create elevated myocardial background that would mask regions 49 of myocardial perfusion deficiency. [123I]IAZA would therefore be suitable for the detection of 50 viable, hypoxic myocardium in patients undergoing stress-test-based diagnosis. 51

Purpose of the study: To compare efficacy of thyroid remnant ablation using 30 mCi or 50 mCi 131-I in papillary thyroid cancer patients. Materials and methods: Five hundred and fifteen consecutive patients with Tumor-Node-Metastasis (TNM) stages T1-T3 N1/N0/NX receiving either 30 mCi or 50 mCi I-131 were analyzed for the effectiveness of remnant ablation using rhTSH-stimulated serum thyroglobulin. One hundred and five consecutive patients receiving 100 mCi I-131 were analyzed for the incidence of radiation thyroiditis and sialadenitis. Results and conclusions: Doses of 30 mCi and 50 mCi were equally effective for low- and moderate-risk disease but 30 mCi was less effective for T1T2NX disease, and 50 mCi was less effective for T3 compared to T1T2 disease. Low dose radiation hypersensitivity or unknown more extensive disease may have accounted for observed differences. Radiation thyroiditis and sialadenitis were more common in a comparison series of 100 mCi dose compared to 30 mCi, but not more common than in 50 mCi doses.

The objective of this work is to evaluate the potential effect of cardiac stress exercise on the accumulation of [123I]IAZA, a radiopharmaceutical used to image focal tissue hypoxia, in otherwise normal myocardium in healthy volunteers, and to determine the impact of exercise on [123I]IAZA pharmacokinetics. The underlying goal is to establish a rational basis and a baseline for studies of focal myocardial hypoxia in cardiac patients using [123I]IAZA. Three healthy male volunteers ran the ‘Bruce’ treadmill protocol, a clinically-accepted protocol designed to expose myocardial ischemia in patients. The ‘Bruce’ criterion heart rate is 85% of [220 – age]. Approximately one minute before reaching this level, [123I]IAZA (5.0 mCi/0.85 mg) was administered as a slow (1–3 min) single intravenous (i.v.) injection via an indwelling venous catheter. The volunteer continued running for an additional 1 min before being transferred to a gamma camera. Serum samples were collected from the arm contralateral to the administration site at pre-determined intervals from 1 min to 45 h post injection and were analyzed by radio HPLC. Pharmacokinetic (PK) parameters were derived for [123I]IAZA and total radioactivity (total[123I]) using compartmental and noncompartmental analyses. Whole-body planar scintigraphic images were acquired from 0.75 to 24 h after dosing. PK data and scintigraphic images were compared to previously published [123I]IAZA data from healthy volunteers rest. Following exercise stress, both [123I]IAZA and total[123I] exhibited bi-exponential decline profiles, with rapid distribution phases [half-lives (t1/2α) of 1.2 and 1.4 min, respectively], followed by slower elimination phases [t1/2β of 195 and 290 min, respectively]. Total body clearance (CLTB) and the steady state volume of distribution (Vss) were 0.647 L/kg and 185 mL/min, respectively, for [123I]IAZA and 0.785 L/kg and 135 mL/min, respectively, for total[123I]. The t1/2β, CLTB and Vss values were comparable to those reported previously for rested volunteers. The t1/2α was approximately 4-fold shorter for [123I]IAZA and approximately 3-fold shorter for total[123I] under exercise relative to rested subjects. The heart region was visualized in early whole body scintigraphic images, but later images showed no accumulated radioactivity in this region, and no differences from images reported for rested volunteers were apparent. Minimal uptake of radiotracer in myocardium and skeletal muscle was consistent with uptake in non-stressed myocardium. Whole-body scintigrams for [123I]IAZA in exercise-stressed healthy volunteers were indistinguishable from images of non-exercised volunteers. There was no evidence of hypoxia-dependent binding in exercised but otherwise healthy myocardium, supporting the conclusion that exercise stress at Bruce protocol intensity does not induce measurable myocardial hypoxia. Effects of exercise on PK parameters were minimal; specifically, the t1/2α was shortened, reflecting increased cardiac output associated with exercise. It is concluded that because [123I]IAZA was not metabolically bound in exercise-stressed myocardium, a stress test will not create elevated myocardial background that would mask regions of myocardial perfusion deficiency. [123I]IAZA would therefore be suitable for the detection of viable, hypoxic myocardium in patients undergoing stress-test-based diagnosis.

Systemic radioisotope therapy with I-metaiodobenzylguanidine (I-MIBG) is an effective form of targeted therapy for neuroendocrine tumors. One of the absolute contraindications to administering I-MIBG therapy listed in the 2008 European Association of Nuclear Medicine guidelines is renal insufficiency requiring dialysis, although this contraindication is not evidence based. We describe a 68-year-old woman with a metastatic small bowel neuroendocrine tumor who developed renal insufficiency requiring hemodialysis. Imaging and dosimetry with I-MIBG were performed and showed that the radiation doses to the whole body and lungs were within safe limits. She was treated with 1820 MBq of I-MIBG with no short-term adverse reactions.

Neuroendocrine tumors have a propensity to metastasize to the orbit, although the reason is unknown. A review of 251 neuroendocrine tumors treated with Lu-DOTATATE or I-MIBG at our institution since 2003 revealed 4 patients with orbital metastases (1.6%), 2 treated with Lu-DOTATATE and 2 with I-MIBG. Of these 4 patients, 1 patient was symptomatic with diplopia and eye pain, and 2 patients had physical signs of orbital involvement. The symptomatic orbital metastasis improved with Lu-DOTATATE therapy, and proptosis improved with I-MIBG therapy in 1 of 2 patients. We present the imaging findings of these 4 patients, as well as their management.

A 52-year-old woman diagnosed with invasive ductal carcinoma of both breasts had a chest x-ray for preoperative assessment. A striking artifact was noted by the x-ray technologist, who, as a result, became very concerned about radiation exposure from the patient. The patient had undergone bilateral sentinel lymph node injections in the nuclear medicine department with Tc-antimony trisulfite colloid just 2 hours before the chest x-ray. Radiation exposure to the x-ray technologist was determined to be similar to 8 hours of naturally occurring background radiation (∼2.96 μSv).

A 70-year-old woman presented with frequent episodes of hypoglycemia. Imaging revealed a 6-cm pancreatic mass with several liver lesions. The pancreatic mass was resected and confirmed to be a well-differentiated insulinoma. Surgery improved but did not resolve her hypoglycemic episodes, and she was referred for peptide receptor radionuclide therapy with 177Lu-DOTATATE to treat her residual disease. A modified protocol with a continuous IV dextrose infusion was used, and the treatments were well tolerated. After 4 induction and 2 maintenance treatments, her hypoglycemic symptoms resolved completely and her disease stabilized. She has been progression free for 24 months.

A single-site prospective open-label clinical study with cyclotron-produced sodium 99mTc-pertechnetate (99mTc-NaTcO4) was performed in patients with indications for a thyroid scan to demonstrate the clinical safety and diagnostic efficacy of the drug and to confirm its equivalence with conventional 99mTc-NaTcO4 eluted from a generator. Methods: 99mTc-NaTcO4 was produced from enriched 100Mo (99.815%) with a cyclotron (24 MeV; 2 h of irradiation) or supplied by a commercial manufacturer (bulk vial eluted from a generator). Eleven patients received 325 ± 29 (mean ± SD) MBq of the cyclotron-produced 99mTc-NaTcO4, whereas the age- and sex-matched controls received a comparable amount of the generator-derived tracer. Whole-body and thyroid planar images were obtained for each participant. In addition to the standard-energy window (140.5 keV ± 7.5%), data were acquired in lower-energy (117 keV ± 10%) and higher-energy (170 keV ± 10%) windows. Vital signs and hematologic and biochemical parameters were monitored before and after tracer administration. Results: Cyclotron-produced 99mTc-NaTcO4 showed organ and whole-body distributions identical to those of conventional 99mTc-NaTcO4 and was well tolerated. All images led to a clear final diagnosis. The fact that the number of counts in the higher-energy window was significantly higher for cyclotron-produced 99mTc-NaTcO4 did not influence image quality in the standard-energy window. Image definition in the standard-energy window with cyclotron-produced 99mTc was equivalent to that with generator-eluted 99mTc and had no particular features allowing discrimination between the 99mTc production methods. Conclusion: The systemic distribution, clinical safety, and imaging efficacy of cyclotron-produced 99mTc-NaTcO4 in humans provide supporting evidence for the use of this tracer as an equivalent for generator-eluted 99mTc-NaTcO4 in routine clinical practice.

A 57-year-old woman diagnosed with ectopic Cushing syndrome was found to have a 111In-octreotide-avid corticotropin-producing pancreatic neuroendocrine tumor with liver metastases. She was treated with 4 induction and 4 maintenance cycles of 177Lu-DOTATATE, which normalized her serum corticotropin levels and dramatically reduced the size of the pancreatic primary and liver metastases.

A 26-year-old woman with a 5-year history of metastatic paraganglioma due to hereditary paraganglioma-pheochromocytoma syndrome with SDHB mutation, who had failed multiple treatment regimens and had transfusion dependent pancytopenia, presented with progressive liver and bone metastases. She was unable to sleep due to painful skull metastases and had severe weakness in her extremities that limited her mobility and daily activities. She was treated with 2 doses of Ra-223-dichloride (Xofigo, Ra-223) and had a dramatic improvement in pain control, mobility, and overall quality of life for 8 weeks, before passing away from pulmonary hemorrhage.

A 64-year-old woman with a 30-year history of recurrent sellar masses presented with severe headache and rapidly progressive visual field loss in the left eye. She was diagnosed with an extraventricular neurocytoma, which was octreotide positive, and was referred for PRRT (peptide receptor radionuclide therapy) with 177Lu [DOTA0,Tyr3]octreotate (DOTATATE). After 4 induction and 4 maintenance treatment cycles, her headaches resolved, her vision improved, and her sellar mass stabilized. The use of 177Lu DOTATATE PRRT in the management of extraventricular neurocytoma warrants further research.

A 56-year-old man presented with a history of 2 prior resections of a recurrent pancreatic glucagonoma in the past 4 years. Workup revealed new liver and abdominal nodal metastases with a rising serum glucagon level. He was started on peptide receptor radionuclide therapy with Lu DOTATATE, and his disease stabilized, while his glucagon levels decreased and also stabilized. After 4 induction and 2 maintenance cycles, he remains progression free for 23 months.

6-Deoxy-6-[F-18] fluoro-D-fructose (6-[F-18] FDF) is a promising PET radiotracer for imaging GLUT5 in breast cancer. The present work describes GMP synthesis of 6-[F-18] FDF in an automated synthesis unit (ASU) and dosimetry calculations to determine radiation doses in humans. GMP synthesis and dosimetry calculations are important prerequisites for first-in-human clinical studies of 6-[F-18] FDF. The radiochemical synthesis of 6-[F-18] FDF was optimized and adapted to an automated synthesis process using a Tracerlab FXFN ASU (GE Healthcare). Starting from 30 GBq of cyclotron-produced n.c.a. [F-18] fluoride, 2.9 +/- 0.1 GBq of 6-[F-18] FDF could be prepared within 50 min including HPLC purification resulting in an overall decay-corrected radiochemical yield of 14 +/- 3% (n = 11). Radiochemical purity exceeded 95%, and the specific activity was greater than 5.1 GBq/mu mol. Sprague-Dawley rats were used for biodistribution experiments, and dynamic and static small animal PET experiments. Biodistribution studies served as basis for allometric extrapolation to the standard man anatomic model and normal organ-absorbed dose calculations using OLINDA/EXM software. The calculated human effective dose for 6-[F-18] FDF was 0.0089 mSv/MBq. Highest organ doses with a dose equivalent of 0.0315 mSv/MBq in a humans were found in bone. Injection of 370 MBq (10 mCi) of 6-[F-18] FDF results in an effective whole body radiation dose of 3.3 mSv in humans, a value comparable to that of other F-18-labeled PET radiopharmaceuticals. The optimized automated synthesis under GMP conditions, the good radiochemical yield and the favorable human radiation dosimetry estimates support application of 6-[F-18] FDF in clinical trials for molecular imaging of GLUT5 in breast cancer patients.

Two patients diagnosed with metastatic medullary thyroid carcinoma (MTC) were referred for peptide receptor radionuclide therapy (PRRT) with 177Lu-[DOTA0,Tyr3]octreotate (DOTATATE). Each patient was treated with 4 doses of 177Lu-DOTATATE given 2 months apart. One patient achieved stable disease for 10 months then chose to pursue surgery, and the other achieved stable disease for 9 months on imaging; however, calcitonin continued to rise. The use of 177Lu-DOTATATE PRRT therapy in the management of MTC warrants further research.

A 54-year-old woman presented with a history of nausea, vomiting, diarrhea, and recurrent episodes of severe hypokalemia requiring hospitalization. Imaging revealed a pancreatic mass with liver metastases, histologically confirmed to be a neuroendocrine tumor. Elevated active renin and aldosterone levels were identified, and the patient was treated with 4 induction cycles of Lu-DOTATATE, which resolved the diarrhea, nausea, and hypokalemia, and normalized the renin and aldosterone levels. After 3 additional maintenance Lu-DOTATATE treatments, the pancreatic tumor had decreased in size, was deemed operable, and was resected. She remains on maintenance Lu-DOTATATE therapy with progression-free survival of 45 months thus far.