Thomas Levin Klausen

PET/CT with intravenous contrast can be used for PET attenuation correction in cancer patients

PurposeIf the CT scan of a combined PET/CT study is performed as a full diagnostic quality CT scan including intravenous (IV) contrast agent, the quality of the joint PET/CT procedure is improved and a separate diagnostic CT scan can be avoided. CT with IV contrast can be used for PET attenuation correction, but this may result in a bias in the attenuation factors. The clinical significance of this bias has not been established. Our aim was to perform a prospective clinical study where each patient had CT performed with and without IV contrast agent to establish whether PET/CT with IV contrast can be used for PET attenuation without reducing the clinical value of the PET scan.MethodsA uniform phantom study was used to document that the PET acquisition itself is not significantly influenced by the presence of IV contrast medium. Then, 19 patients referred to PET/CT with IV contrast underwent CT scans without, and then with contrast agent, followed by an 18F-fluorodeoxyglucose whole-body PET scan. The CT examinations were performed with identical parameters on a GE Discovery LS scanner. The PET data were reconstructed with attenuation correction based on the two CT data sets. A global comparison of standard uptake value (SUV) was performed, and SUVs in tumour, in non-tumour tissue and in the subclavian vein were calculated. Clinical evaluation of the number and location of lesions on all PET/CT scans was performed twice, blinded and in a different random order, by two independent nuclear medicine specialists.ResultsIn all patients, the measured global SUV of PET images based on CT with IV contrast agent was higher than the global activity using non-contrast correction. The overall increase in the mean SUV (for two different conversion tables tested) was 4.5±2.3% and 1.6±0.5%, respectively. In 11/19 patients, focal uptake was identified corresponding to malignant tumours. Eight out of 11 tumours showed an increased SUVmax (2.9±3.1%) on the PET images reconstructed using IV contrast. The clinical evaluation performed by the two specialists comparing contrast and non-contrast CT attenuated PET images showed weighted kappa values of 0.92 (doctor A) and 0.82 (doctor B). No contrast-introduced artefacts were found.ConclusionThis study demonstrates that CT scans with IV contrast agent can be used for attenuation correction of the PET data in combined modality PET/CT scanning, without changing the clinical diagnostic interpretation.

Clinical PET of Neuroendocrine Tumors Using 64Cu-DOTATATE: First-in-Humans Study

UNLABELLED The use of positron emitter-labeled compounds for somatostatin receptor imaging (SRI) has become attractive because of the prospect of improved spatial resolution, accelerated imaging procedures, and the ability to quantify tissue radioactivity concentrations. This paper provides results from first-in-humans use of (64)Cu-DOTATATE, an avidly binding somatostatin receptor ligand linked to a radioisotope with intermediate half-life and favorable positron energy (half-life, 12.7 h; maximum positron energy, 0.653 MeV). METHODS In a prospective setup, 14 patients with a history of neuroendocrine tumors underwent both PET/CT with (64)Cu-DOTATATE and SPECT/CT with our current routine imaging agent (111)In-diethylenetriaminepentaacetic acid-octreotide. After intravenous injection of 193-232 MBq of (64)Cu-DOTATATE, whole-body PET scans were acquired at 1 h (n = 14), 3 h (n = 12), and 24 h (n = 5) after administration. Tissue radioactivity concentrations for normal organs and lesions were quantified, and standardized uptake values were calculated for the early (1 h) and delayed (3 h) scans. Using the data for 5 patients, we assessed the radiation dose with OLINDA/EXM software. Furthermore, the clinical performance of (64)Cu-DOTATATE with respect to lesion detection was compared with conventional SRI. RESULTS SRI with (64)Cu-DOTATATE produced images of excellent quality and high spatial resolution. Images were characterized by high and stable tumor-to-background ratios over an imaging time window of at least 3 h. Compared with conventional scintigraphy, (64)Cu-DOTATATE PET identified additional lesions in 6 of 14 patients (43%). In 5 patients, lesions were localized in organs and organ systems not previously known as metastatic sites, including the early-stage detection of a secondary neuroendocrine tumor in a patient with a known mutation in the multiple endocrine neoplasia type I gene. All major additional findings seen only on PET could be confirmed on the basis of a clinical follow-up interval of 18 mo. Calculated radiation dose estimates yielded an effective dose of 6.3 mSv for an injected activity of 200 MBq of (64)Cu-DOTATATE, with the liver being the organ with the highest absorbed radiation dose (0.16 mGy/MBq). CONCLUSION This first-in-humans study supports the clinical use of (64)Cu-DOTATATE for SRI with excellent imaging quality, reduced radiation burden, and increased lesion detection rate when compared with (111)In-diethylenetriaminepentaacetic acid-octreotide.

How few cancer cells can be detected by positron emission tomography? A frequent question addressed by an in vitro study

PurposePositron emission tomography (PET) has gained widespread use in cancer diagnosis and treatment, but how many malignant cells are required for a tumour to be detected by PET?MethodsThree human cancer cell lines [glioblastoma and two subtypes of small cell lung cancer (SCLC)] in concentrations from 104 to 107 were seeded on six-well plates or plastic tubes and treated with [18F]fluorodeoxy-glucose (FDG) in vitro. FDG retention was measured in a PET/CT scanner and in a calibrated well counter. The clinical situation was simulated using a cylinder phantom with a background concentration of FDG.ResultsThe theoretical detection limit was found to be around 105 malignant cells. In a cylinder phantom the detection limit was increased by a factor of 10. The FDG retention by the glioblastoma cell line was significantly higher than the activity of the SCLC cell line. FDG retention measured by PET and a gamma counter was closely correlated to the number of cells and a linear relationship was found.DiscussionThe detection limit of PET is in the magnitude of 105 to 106 malignant cells. The experimental set-up was robust and well suited as a platform for further investigations of factors influencing the detection limit of PET.

Radiation doses to staff involved in sentinel node operations for breast cancer.

Background:  The use of radioactive compounds for sentinel node biopsy is now a generally accepted part of the surgical treatment of breast cancer and melanoma, with the risk of radiation exposure to the operating team. The aim of this investigation was to study the levels of this exposure in relation to the permissible radiation dose limits.

Prospective phase II trial of image-guided radiotherapy in Hodgkin lymphoma: benefit of deep inspiration breath-hold.

Abstract Background. Long-term Hodgkin lymphoma (HL) survivors have an increased risk of late cardiac morbidity and secondary lung cancer after chemotherapy and mediastinal radiotherapy. In this prospective study we investigate whether radiotherapy with deep inspiration breath-hold (DIBH) can reduce radiation doses to the lungs, heart, and cardiac structures without compromising the target dose. Patients and methods. Twenty-two patients (14 female, 8 male), median age 30 years (18–65 years), with supra-diaphragmatic HL were enrolled and had a thoracic PET/CT with DIBH in addition to staging FDG-PET/CT in free breathing (FB) and a planning CT in both FB and DIBH. For each patient an involved-node radiotherapy plan was done for both DIBH and FB, and the doses to the lungs, heart, and female breasts were recorded prospectively. Mean doses to the heart valves and coronary arteries were recorded retrospectively. Patients were treated with the technique yielding the lowest doses to normal structures. Results. Nineteen patients were treated with DIBH and three with FB. DIBH reduced the mean estimated lung dose by 2.0 Gy (median: 8.5 Gy vs. 7.2 Gy) (p < 0.01) and the mean heart dose by 1.4 Gy (6.0 Gy vs. 3.9 Gy) (p < 0.01) compared to FB. The lung and heart V20Gy were reduced with a median of 5.3% and 6.3%. Mean doses to the female breasts were equal with FB and DIBH. Conclusion. DIBH can significantly decrease the estimated mean doses to the heart and lungs without lowering the dose to the target in radiotherapy for patients with mediastinal HL.

Clinical evaluation of PET image reconstruction using a spatial resolution model

PURPOSE PET image resolution is variable across the measured field-of-view and described by the point spread function (PSF). When accounting for the PSF during PET image reconstruction image resolution is improved and partial volume effects are reduced. Here, we evaluate the effect of PSF-based reconstruction on lesion quantification in routine clinical whole-body (WB) PET/CT imaging. MATERIALS AND METHODS 41 oncology patients were referred for a WB-PET/CT examination (Biograph 40 TruePoint). Emission data were acquired at 2.5 min/bed at 1 hpi of 400 MBq [18F]-FDG. Attenuation-corrected PET images were reconstructed on 336 × 336-matrices using: (R1) standard AW-OSEM (4 iter, 8 subsets, 4 mm Gaussian) and (R2) AW-OSEM with PSF (3 iter, 21 subsets, 2 mm). Blinded and randomised reading of R1- and R2-PET images was performed. Individual lesions were located and counted independently on both sets of images. The relative change in PET quantification (SUVmax, SUVmean, volume) of lesions seen on R1 and R2 is reported as (R2-R1)/R1. Furthermore, SUVmax and SUVmean was measured for a 3 cm spherical norm region in the right lobe of the healthy liver for R1 and R2. RESULTS Clinical reading revealed 91 and 103 positive lesions for R1 and R2, respectively. For all lesions SUVmax (R2) was higher than SUVmax (R1). Regression analysis indicated that the relative increase in SUVmax (and SUVmean) decreased with lesion size, whilst it increased with increasing radial distance from the centre of the field of view (FOV). There was no significant difference in SUVmean in homogenous liver tissue between R1 and R2. CONCLUSION In whole-body FDG-PET/CT using routine clinical protocols, PSF-based PET reconstruction increases lesion detection and affects SUVmax measurements compared to standard AW-OSEM PET reconstruction.

First-in-human uPAR PET: Imaging of Cancer Aggressiveness

A first-in-human clinical trial with Positron Emission Tomography (PET) imaging of the urokinase-type plasminogen activator receptor (uPAR) in patients with breast, prostate and bladder cancer, is described. uPAR is expressed in many types of human cancers and the expression is predictive of invasion, metastasis and indicates poor prognosis. uPAR PET imaging therefore holds promise to be a new and innovative method for improved cancer diagnosis, staging and individual risk stratification. The uPAR specific peptide AE105 was conjugated to the macrocyclic chelator DOTA and labeled with 64Cu for targeted molecular imaging with PET. The safety, pharmacokinetic, biodistribution profile and radiation dosimetry after a single intravenous dose of 64Cu-DOTA-AE105 were assessed by serial PET and computed tomography (CT) in 4 prostate, 3 breast and 3 bladder cancer patients. Safety assessment with laboratory blood screening tests was performed before and after PET ligand injection. In a subgroup of the patients, the in vivo stability of our targeted PET ligand was determined in collected blood and urine. No adverse or clinically detectable side effects in any of the 10 patients were found. The ligand exhibited good in vivo stability and fast clearance from plasma and tissue compartments by renal excretion. In addition, high uptake in both primary tumor lesions and lymph node metastases was seen and paralleled high uPAR expression in excised tumor tissue. Overall, this first-in-human study therefore provides promising evidence for safe use of 64Cu-DOTA-AE105 for uPAR PET imaging in cancer patients.

Improving quantitative dosimetry in (177)Lu-DOTATATE SPECT by energy window-based scatter corrections.

PurposePatient-specific dosimetry of lutetium-177 (177Lu)-DOTATATE treatment in neuroendocrine tumours is important, because uptake differs across patients. Single photon emission computer tomography (SPECT)-based dosimetry requires a conversion factor between the obtained counts and the activity, which depends on the collimator type, the utilized energy windows and the applied scatter correction techniques. In this study, energy window subtraction-based scatter correction methods are compared experimentally and quantitatively. Materials and methods177Lu SPECT images of a phantom with known activity concentration ratio between the uniform background and filled hollow spheres were acquired for three different collimators: low-energy high resolution (LEHR), low-energy general purpose (LEGP) and medium-energy general purpose (MEGP). Counts were collected in several energy windows, and scatter correction was performed by applying different methods such as effective scatter source estimation (ESSE), triple-energy and dual-energy window, double-photopeak window and downscatter correction. The intensity ratio between the spheres and the background was measured and corrected for the partial volume effect and used to compare the performance of the methods. ResultsLow-energy collimators combined with 208 keV energy windows give rise to artefacts. For the 113 keV energy window, large differences were observed in the ratios for the spheres. For MEGP collimators with the ESSE correction technique, the measured ratio was close to the real ratio, and the differences between spheres were small. ConclusionFor quantitative 177Lu imaging MEGP collimators are advised. Both energy peaks can be utilized when the ESSE correction technique is applied. The difference between the calculated and the real ratio is less than 10% for both energy windows.

Radioactive Seed Localization or Wire-guided Localization of Nonpalpable Invasive and In Situ Breast Cancer: A Randomized, Multicenter, Open-label Trial

Objective: To compare the rate of positive resection margins between radioactive seed localization (RSL) and wire-guided localization (WGL) after breast conserving surgery (BCS). Background: WGL is the current standard for localization of nonpalpable breast lesions in BCS, but there are several difficulties related to the method. Methods: From January 1, 2014 to February 4, 2016, patients with nonpalpable invasive breast cancer or DCIS visible on ultrasound were enrolled in this randomized, multicenter, open-label clinical trial, and randomly assigned to RSL or WGL. The primary outcome was margin status after BCS. Secondary outcomes were duration of the surgical procedure, weight of surgical specimen, and patients’ pain perception. Analyses were performed by intention-to-treat (ITT) and per protocol. Results: Out of 444 eligible patients, 413 lesions representing 409 patients were randomized; 207 to RSL and 206 to WGL. Twenty-three did not meet inclusion criteria, chose to withdraw, or had a change in surgical management and were excluded. The remaining 390 lesions constituted the ITT population. Here, resection margins were positive in 23 cases (11.8%) in the RSL group compared with 26 cases (13.3%) in the WGL group (P = 0.65). The per-protocol analysis revealed no difference in margin status (P = 0.62). There were no significant differences in the duration of the surgical procedure (P = 0.12), weight of the surgical specimen (P = 0.54) or the patients’ pain perception (P = 0.28). Conclusion: RSL offers a major logistic advantage, as localization can be done several days before surgery without any increase in positive resection margins compared with WGL.

Variability and reproducibility of hepatic FDG uptake measured as SUV as well as tissue-to-blood background ratio using positron emission tomography in healthy humans

Introduction:  To investigate variability and reproducibility of hepatic [18F]‐2‐fluoro‐2‐deoxy‐d‐glucose (FDG) uptake in healthy individuals.