Michael Kreissl

Estimation of the 18F-FDG Input Function in Mice by Use of Dynamic Small-Animal PET and Minimal Blood Sample Data

Derivation of the plasma time–activity curve in murine small-animal PET studies is a challenging task when tracers that are sequestered by the myocardium are used, because plasma time–activity curve estimation usually involves drawing a region of interest within the area of the reconstructed image that corresponds to the left ventricle (LV) of the heart. The small size of the LV relative to the resolution of the small-animal PET system, coupled with spillover effects from adjacent myocardial pixels, makes this method reliable only for the earliest frames of the scan. We sought to develop a method for plasma time–activity curve estimation based on a model of tracer kinetics in blood, muscle, and liver. Methods: Sixteen C57BL/6 mice were injected with 18F-FDG, and approximately 15 serial blood samples were taken from the femoral artery via a surgically inserted catheter during 60-min small-animal PET scans. Image data were reconstructed by use of filtered backprojection with CT-based attenuation correction. We constructed a 5-compartment model designed to predict the plasma time–activity curve of 18F-FDG by use of data from a minimum of 2 blood samples and the dynamic small-animal PET scan. The plasma time–activity curve (TACp) was assumed to have 4 exponential components \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \((TAC_{P}{=}A_{1}e^{\mathrm{{\lambda}}_{1}t}{+}A_{2}e^{\mathrm{{\lambda}}_{2}t}{+}A_{3}e^{\mathrm{{\lambda}}_{3}t}{-}(A_{1}{+}A_{2}{+}A_{3})e^{\mathrm{{\lambda}}_{4}t})\) \end{document} based on the serial blood samples. Using Bayesian constraints, we fitted 2-compartment submodels of muscle and liver to small-animal PET data for these organs and simultaneously fitted the input (forcing) function to early small-animal PET LV data and 2 blood samples (∼10 min and ∼1 h). Results: The area under the estimated plasma time–activity curve had an overall Spearman correlation of 0.99 when compared with the area under the gold standard plasma time–activity curve calculated from multiple blood samples. Calculated organ uptake rates (Patlak Ki) based on the predicted plasma time–activity curve had a correlation of approximately 0.99 for liver, muscle, myocardium, and brain when compared with those based on the gold standard plasma time–activity curve. The model was also able to accurately predict the plasma time–activity curve under experimental conditions that resulted in different rates of clearance of the tracer from blood. Conclusion: We have developed a robust method for accurately estimating the plasma time–activity curve of 18F-FDG by use of dynamic small-animal PET data and 2 blood samples.

[131I]Iodometomidate for Targeted Radionuclide Therapy of Advanced Adrenocortical Carcinoma

CONTEXT In advanced adrenocortical carcinoma (ACC), many patients have progressive disease despite standard treatment, indicating a need for new treatment options. We have shown high and specific retention of [123I]metomidate ([123I]IMTO) in ACC lesions, suggesting that labeling of metomidate with 131I offers targeted radionuclide therapy for advanced ACC. OBJECTIVE Safety and efficacy of radionuclide therapy with [131I]IMTO in advanced ACC. DESIGN/SETTING This monocentric case series comprised 19 treatments in 11 patients with nonresectable ACC. PATIENTS AND INTERVENTION Between 2007 and 2010, patients with advanced ACC not amenable to radical surgery and exhibiting high uptake of [123I]IMTO in their tumor lesions were offered treatment with [131I]IMTO (1.6-20 GBq in one to three cycles of [131I]IMTO). MAIN OUTCOME MEASURE Tumor response was assessed according to response evaluation criteria in solid tumors (RECIST version 1.1) criteria, and side effects were assessed by Common Toxicity Criteria (version 4.0). RESULTS Best response was classified as partial response in one case with a change in target lesions of -51% from baseline, as stable disease in five patients, and as progressive disease in four patients. One patient died 11 d after treatment with [131I]IMTO unrelated to radionuclide therapy. In patients responding to treatment, median progression-free survival was 14 months (range, 5-33) with ongoing disease stabilization in three patients at last follow-up. Treatment was well tolerated, but transient bone marrow depression was observed. Adrenal insufficiency developed in two patients. CONCLUSIONS Radionuclide therapy with [131I]IMTO is a promising treatment option for selected patients with ACC, deserving evaluation in prospective clinical trials.

Combination of peptide receptor radionuclide therapy with fractionated external beam radiotherapy for treatment of advanced symptomatic meningioma

BackgroundExternal beam radiotherapy (EBRT) is the treatment of choice for irresectable meningioma. Due to the strong expression of somatostatin receptors, peptide receptor radionuclide therapy (PRRT) has been used in advanced cases. We assessed the feasibility and tolerability of a combination of both treatment modalities in advanced symptomatic meningioma.Methods10 patients with irresectable meningioma were treated with PRRT (177Lu-DOTA0,Tyr3 octreotate or - DOTA0,Tyr3 octreotide) followed by external beam radiotherapy (EBRT). EBRT performed after PRRT was continued over 5–6 weeks in IMRT technique (median dose: 53.0 Gy). All patients were assessed morphologically and by positron emission tomography (PET) before therapy and were restaged after 3–6 months. Side effects were evaluated according to CTCAE 4.0.ResultsMedian tumor dose achieved by PRRT was 7.2 Gy. During PRRT and EBRT, no side effects > CTCAE grade 2 were noted. All patients reported stabilization or improvement of tumor-associated symptoms, no morphologic tumor progression was observed in MR-imaging (median follow-up: 13.4 months). The median pre-therapeutic SUVmax in the meningiomas was 14.2 (range: 4.3–68.7). All patients with a second PET after combined PRRT + EBRT showed an increase in SUVmax (median: 37%; range: 15%–46%) to a median value of 23.7 (range: 8.0–119.0; 7 patients) while PET-estimated volume generally decreased to 81 ± 21% of the initial volume.ConclusionsThe combination of PRRT and EBRT is feasible and well tolerated. This approach represents an attractive strategy for the treatment of recurring or progressive symptomatic meningioma, which should be further evaluated.

Functional characterization of adrenal lesions using [123I]IMTO-SPECT/CT.

CONTEXT Adrenal tumors are highly prevalent and represent a wide range of different pathological entities. Conventional imaging often provides only limited information on the origin of these lesions. Novel specific imaging methods are, therefore, of great clinical interest. OBJECTIVE We evaluated [(123)I]iodometomidate ([(123)I]IMTO) imaging for noninvasive characterization of adrenal masses. DESIGN/SETTING This was a prospective monocentric diagnostic study in a tertiary care center. PATIENTS AND INTERVENTION A total of 51 patients with an adrenal lesion underwent [(123)I]IMTO imaging after injection of 185 MBq of [(123)I]IMTO. Sequential planar whole-body scans until 24 hours postinjection and single photon emission computed tomography (SPECT)/computed tomography imaging 4 to 6 hours postinjection were performed. MAIN OUTCOME MEASURE Sensitivity and specificity of [(123)I]IMTO imaging for the noninvasive characterization of adrenal lesions were measured. RESULTS Adrenocortical tissue showed high and specific tracer uptake with a short investigation time and low radiation exposure. Qualitative analysis of SPECT/computed tomography data resulted in a sensitivity of 89% and a specificity of 85% for differentiating adrenocortical tumors from lesions of nonadrenocortical origin. Receiver-operating characteristic analysis of semiquantitative data revealed a sensitivity of 83% and a specificity of 86% for identification of adrenocortical lesions at a cutoff value of tumor to liver ratio of 1.3. CONCLUSIONS [(123)I]IMTO is a highly specific radiotracer for imaging of adrenocortical tissue with a short investigation time and low radiation exposure. Because of the general availability of SPECT technology, [(123)I]IMTO scintigraphy has the potential to become a widely used tool to noninvasively characterize the biology of adrenal lesions.

[123I]Iodometomidate Imaging in Adrenocortical Carcinoma

CONTEXT Imaging with [¹²³I]iodometomidate ([¹²³I]IMTO) has been shown to diagnose adrenocortical lesions with high sensitivity and specificity. OBJECTIVE Our objective was to evaluate the clinical utility of [¹²³I]IMTO imaging in adrenocortical carcinoma (ACC). DESIGN We conducted a prospective monocentric diagnostic study and a prospective case series at a single tertiary referral center. PATIENTS AND INTERVENTIONS Fifty-eight patients with histologically confirmed ACC, all European Network for the Study of Adrenal Tumors stage IV (with distant metastases), received 185 MBq [¹²³I]IMTO. Sequential planar whole-body scans until 24 hours post injection and single photon emission computed tomography/computed tomography (SPECT/CT) hybrid imaging 4 to 6 hours post injection were performed. MAIN OUTCOME MEASURES Outcome measures included uptake of [¹²³I]IMTO in ACC lesions, sensitivity and specificity of [¹²³I]IMTO imaging compared with conventional imaging, and number of patients eligible for [¹³¹I]IMTO therapy. RESULTS Of 430 lesions detected by conventional imaging, 30% showed strong, 8% moderate, and 62% no tracer accumulation. [¹²³I]IMTO detected both primary and metastatic lesions of ACC. However, a substantial percentage of lesions failed to show [¹²³I]IMTO uptake. The overall sensitivity and specificity values were 38% and 100%, respectively. Thirty-four patients (59%) had at least 1 [¹²³I]IMTO-positive lesion. Cortisol and aldosterone secretion by ACC was positively correlated to [¹²³I]IMTO uptake (P = .01); cytotoxic chemotherapy and mitotane treatment presumably did not influence tracer uptake. Twenty-one patients (36.2%) had radiotracer uptake in all lesions ≥ 2 cm and therefore were potential candidates for targeted systemic radiotherapy with [¹³¹I]IMTO. CONCLUSION About one-third of patients with ACC show specific retention of [¹²³I]IMTO in metastatic lesions. This study provides support for the conduct of a prospective trial to determine whether the first molecular informed therapy using [¹³¹I]IMTO will be of value to patients with metastatic ACC.

Insulin-Mediated Oxidative Stress and DNA Damage in LLC-PK1 Pig Kidney Cell Line, Female Rat Primary Kidney Cells, and Male ZDF Rat Kidneys In Vivo

Hyperinsulinemia, a condition with excessively high insulin blood levels, is related to an increased cancer incidence. Diabetes mellitus is the most common of several diseases accompanied by hyperinsulinemia. Because an elevated kidney cancer risk was reported for diabetic patients, we investigated the induction of genomic damage by insulin in LLC-PK1 pig kidney cells, rat primary kidney cells, and ZDF rat kidneys. Insulin at a concentration of 5nM caused a significant increase in DNA damage in vitro. This was associated with the formation of reactive oxygen species (ROS). In the presence of antioxidants, blockers of the insulin, and IGF-I receptors, and a phosphatidylinositol 3-kinase inhibitor, the insulin-mediated DNA damage was reduced. Phosphorylation of protein kinase B (PKB or AKT) was increased and p53 accumulated. Inhibition of the mitochondrial and nicotinamide adenine dinucleotide phosphatase oxidase-related ROS production reduced the insulin-mediated damage. In primary rat cells, insulin also induced genomic damage. In kidneys from healthy, lean ZDF rats, which were infused with insulin to yield normal or high blood insulin levels, while keeping blood glucose levels constant, the amounts of ROS and the tumor protein (p53) were elevated in the high-insulin group compared with the control level group. ROS and p53 were also elevated in diabetic obese ZDF rats. Overall, insulin-induced oxidative stress resulted in genomic damage. If the same mechanisms are active in patients, hyperinsulinemia might cause genomic damage through the induction of ROS contributing to the increased cancer risk, against which the use of antioxidants and/or ROS production inhibitors might exert protective effects.

The Estrogen Receptor-α Is Required and Sufficient to Maintain Physiological Glucose Uptake in the Mouse Heart

Estrogens attenuate cardiac hypertrophy and increase cardiac contractility via their cognate estrogen receptors (ERs) ER&agr; and ER&bgr;. Because female sex hormones enhance global glucose use and because myocardial function and mass are tightly linked to cardiac glucose metabolism, we tested the hypothesis that expression and activation of the ER&agr; might be required and sufficient to maintain physiological cardiac glucose uptake in the murine heart. Cardiac glucose uptake quantified in vivo by 18F-fluorodeoxyglucose positron emission tomography was strongly impaired in ovariectomized compared with gonadal intact female C57BL/6JO mice. The selective ER&agr; agonist 16&agr;-LE2 and the nonselective ER&agr; and ER&bgr; agonist 17&bgr;-estradiol completely restored cardiac glucose uptake in ovariectomized mice. Cardiac 18F-fluorodeoxyglucose uptake was strongly decreased in female ER&agr; knockout mice compared with wild-type littermates. Analysis of cardiac mRNA accumulation by quantitative RT-PCR revealed an upregulation of genes involved in glycolisis and tricarboxylic acid cycle by ER&agr; treatment. In conclusion, systemic activation of ER&agr; is sufficient, and its expression is required to maintain physiological glucose uptake in the murine heart, which is likely to contribute to known cardioprotective estrogen effects.

Adipose Tissue Lipolysis Promotes Exercise-induced Cardiac Hypertrophy Involving the Lipokine C16:1n7-Palmitoleate

Background: Endurance training induces physiological cardiac hypertrophy and elevates adipose tissue lipolysis. Results: Adipose-specific adipose triglyceride lipase (Atgl)-knock-out mice exhibit attenuated exercise-induced cardiac hypertrophy likely mediated by the lack of C16:1n7 palmitoleate actions on the heart. Conclusion: Atgl-mediated adipose lipolysis regulates physiological cardiac hypertrophy. Significance: Adipose-derived lipokines may serve as important molecular mediators of cardiac physiology and pathology. Endurance exercise training induces substantial adaptive cardiac modifications such as left ventricular hypertrophy (LVH). Simultaneously to the development of LVH, adipose tissue (AT) lipolysis becomes elevated upon endurance training to cope with enhanced energy demands. In this study, we investigated the impact of adipose tissue lipolysis on the development of exercise-induced cardiac hypertrophy. Mice deficient for adipose triglyceride lipase (Atgl) in AT (atATGL-KO) were challenged with chronic treadmill running. Exercise-induced AT lipolytic activity was significantly reduced in atATGL-KO mice accompanied by the absence of a plasma fatty acid (FA) increase. These processes were directly associated with a prominent attenuation of myocardial FA uptake in atATGL-KO and a significant reduction of the cardiac hypertrophic response to exercise. FA serum profiling revealed palmitoleic acid (C16:1n7) as a new molecular co-mediator of exercise-induced cardiac hypertrophy by inducing nonproliferative cardiomyocyte growth. In parallel, serum FA analysis and echocardiography were performed in 25 endurance athletes. In consonance, the serum C16:1n7 palmitoleate level exhibited a significantly positive correlation with diastolic interventricular septum thickness in those athletes. No correlation existed between linoleic acid (18:2n6) and diastolic interventricular septum thickness. Collectively, our data provide the first evidence that adipose tissue lipolysis directly promotes the development of exercise-induced cardiac hypertrophy involving the lipokine C16:1n7 palmitoleate as a molecular co-mediator. The identification of a lipokine involved in physiological cardiac growth may help to develop future lipid-based therapies for pathological LVH or heart failure.

The Treatment of Well-Differentiated Thyroid Carcinoma.

BACKGROUND Recent decades have seen a rise in the incidence of well-differentiated (mainly papillary) thyroid carcinoma around the world. In Germany, the age-adjusted incidence of well-differentiated thyroid carcinoma in 2010 was 3.5 per 100 000 men and 8.7 per 100 000 women per year. METHODS This review is based on randomized, controlled trials and multicenter trials on the treatment of well-differentiated thyroid carcinoma that were retrieved by a selective literature search, as well as on three updated guidelines issued in the past two years. RESULTS The recommended extent of surgical resection depends on whether the tumor is classified as low-risk or high-risk, so that papillary microcarcinomas, which carry a highly favorable prognosis, will not be overtreated. More than 90% of localized, well-differentiated thyroid carcinomas can be cured with a combination of surgery and radioactive iodine therapy. Radioactive iodine therapy is also effective in the treatment of well-differentiated thyroid carcinomas with distant metastases, yielding a 10-year survival rate of 90%, as long as there is good iodine uptake and the tumor goes into remission after treatment; otherwise, the 10-year survival rate is only 10%. In the past two years, better treatment options have become available for radioactive-iodine-resistant thyroid carcinoma. Phase 3 studies of two different tyrosine kinase inhibitors have shown that either one can markedly prolong progression-free survival, but not overall survival. Their more common clinically significant side effects are hand-foot syndrome, hypertension, diarrhea, proteinuria, and weight loss. CONCLUSION Slow tumor growth, good resectability, and susceptibility to radioactive iodine therapy lend a favorable prognosis to most cases of well-differentiated thyroid carcinoma. The treatment should be risk-adjusted and interdisciplinary, in accordance with the current treatment guidelines. Even metastatic thyroid carcinoma has a favorable prognosis as long as there is good iodine uptake. The newly available medical treatment options for radioactive-iodine-resistant disease need to be further studied.

Left ventricular blood TAC quantitation with microPET imaging in mice using MAP, FBP and blood sampling

Improved resolution with iterative maximum a posteriori (MAP) image reconstruction is promising; however in the past, image values varied based on the detected total counts, therefore filtered backprojection (FBP) has remained the first choice for quantitation using microPET. To determine if MAP can be utilized to generate accurate noninvasive blood and organ time activity curves (TACs) in mice using FDG, we compared ordinary Poisson MAP (OP-MAP) and MAP to FBP and arterial blood samples. C57BL/6 mice (n=13) were imaged for up to 90 min using a Focus 220 microPET. Blood samples (n=9 to 25, 5-15 muL) from a femoral artery catheter were drawn after injection of 30-50 muL FDG (17-37 MBq) and converted to PET counts. Data was binned into 32 frames and reconstructed using FBP (all 32 frames), MAP and OP-MAP (6 or more frames). Frame durations ranged from 0.3 sec to 15 min. Volumes of interest (VOI) were assigned to the left ventricular blood pool (LV, ~1.2 mm), whole body (WB), liver, whole heart and myocardium (average of the 4 walls). No correction was made for partial volume or myocardium spillover of activity. WB VOI values from the older version of MAP were not well matched to the FBP WB values and were variable depending on frame duration. OP-MAP VOI values were not substantially different from FBP values in WB and liver (no partial volume effect; PVE). LV values were higher during the first passage of the tracer bolus with OP-MAP, due to less PVE, and lower at later times due to less spillover of activity from the myocardium. Initial results indicate that OP-MAP image values are well matched to FBP values where PVE is not a factor, and that OP-MAP data are not count rate or time duration dependant. Further work is underway to verify that OP-MAP data can be useful for quantitative kinetic modeling