Macarena Rodriguez-Fraile

Prognostic factors and prevention of radioembolization‐induced liver disease

Radioembolization (RE)‐induced liver disease (REILD) has been defined as jaundice and ascites appearing 1 to 2 months after RE in the absence of tumor progression or bile duct occlusion. Our aims were to study the incidence of REILD in a large cohort of patients and the impact of a series of changes introduced in the processes of treatment design, activity calculation, and the routine use of ursodeoxycholic acid and low‐dose steroids (modified protocol). Between 2003 and 2011, 260 patients with liver tumors treated by RE were studied (standard protocol: 75, modified protocol: 185). REILD appeared only in patients with cirrhosis or in noncirrhosis patients exposed to systemic chemotherapy prior to RE. Globally, the incidence of REILD was reduced in the modified protocol group from 22.7% to 5.4% and the incidence of severe REILD from 13.3% to 2.2% (P < 0.0001). Treatment efficacy was not jeopardized since 3‐month disease control rates were virtually identical in both groups (66.7% and 67.2%, P = 0.93). Exposure to chemotherapy in the 2‐month period following RE and being treated by the standard protocol were independent predictors of REILD among noncirrhosis patients. In cirrhosis, the presence of a small liver (total volume <1.5 L), an abnormal bilirubin (>1.2 mg/dL), and treatment in a selective fashion were independently associated with REILD. Conclusion: REILD is an uncommon but relevant complication that appears when liver tissue primed by cirrhosis or prior and subsequent chemotherapy is exposed to the radiation delivered by radioactive microspheres. We designed a comprehensive treatment protocol that reduces the frequency and the severity of REILD. (HEPATOLOGY 2013)

Promising Prospects for 44Sc-/47Sc-Based Theragnostics: Application of 47Sc for Radionuclide Tumor Therapy in Mice

In recent years, 47Sc has attracted attention because of its favorable decay characteristics (half-life, 3.35 d; average energy, 162 keV; Eγ, 159 keV) for therapeutic application and for SPECT imaging. The aim of the present study was to investigate the suitability of 47Sc for radionuclide therapy in a preclinical setting. For this purpose a novel DOTA-folate conjugate (cm10) with an albumin-binding entity was used. Methods: 47Sc was produced via the 46Ca(n,γ)47Ca→β−47Sc nuclear reaction at the high-flux reactor at the Institut Laue-Langevin. Separation of the 47Sc from the target material was performed by a semi-automated process using extraction chromatography and cation exchange chromatography. 47Sc-labeled cm10 was tested on folate receptor–positive KB tumor cells in vitro. Biodistribution and SPECT imaging experiments were performed in KB tumor–bearing mice. Radionuclide therapy was conducted with two groups of mice, which received either 47Sc-cm10 (10 MBq) or only saline. Tumor growth and survival time were compared between the two groups of mice. Results: Irradiation of 46Ca resulted in approximately 1.8 GBq of 47Ca, which subsequently decayed to 47Sc. Separation of 47Sc from 47Ca was obtained with 80% yield in only 10 min. The 47Sc was then available in a small volume (∼500 μL) of an ammonium acetate/HCl (pH 4.5) solution suitable for direct radiolabeling. 47Sc-cm10 was prepared with a radiochemical yield of more than 96% at a specific activity of up to 13 MBq/nmol. In vitro 47Sc-cm10 showed folate receptor–specific binding and uptake into KB tumor cells. In vivo SPECT/CT images allowed the visualization of accumulated radioactivity in KB tumors and in the kidneys. The therapy study showed a significantly delayed tumor growth in mice, which received 47Sc-cm10 (10 MBq, 10 Gy) resulting in a more than 50% increase in survival time, compared with untreated control mice. Conclusion: With this study, we demonstrated the suitability of using 47Sc for therapeutic purposes. On the basis of our recent results obtained with 44Sc-folate, the present work confirms the applicability of 44Sc/47Sc as an excellent matched pair of nuclides for PET imaging and radionuclide therapy.

PET Tracers for Clinical Imaging of Breast Cancer.

Molecular imaging of breast cancer has undoubtedly permitted a substantial development of the overall diagnostic accuracy of this malignancy in the last years. Accurate tumour staging, design of individually suited therapies, response evaluation, early detection of recurrence and distant lesions have also evolved in parallel with the development of novel molecular imaging approaches. In this context, positron emission tomography (PET) can be probably seen as the most interesting molecular imaging technology with straightforward clinical application for such purposes. Dozens of radiotracers for PET imaging of breast cancer have been tested in laboratory animals. However, in this review we shall focus mainly in the smaller group of PET radiopharmaceuticals that have lead through into the clinical setting. PET imaging can be used to target general metabolic phenomena related to tumoural transformation, including glucose metabolism and cell proliferation, but can also be directed to specific hormone receptors that are characteristic of the breast cancer cell. Many other receptors and transport molecules present in the tumour cells could also be of interest for imaging. Furthermore, molecules related with the tumour microenvironment, tumour induced angiogenesis or even hypoxia could also be used as molecular biomarkers for breast cancer imaging.

PET optimization for improved assessment and accurate quantification of 90Y-microsphere biodistribution after radioembolization

PURPOSE 90Y-microspheres are widely used for the radioembolization of metastatic liver cancer or hepatocellular carcinoma and there is a growing interest for imaging 90Y-microspheres with PET. The aim of this study is to evaluate the performance of a current generation PET/CT scanner for 90Y imaging and to optimize the PET protocol to improve the assessment and the quantification of 90Y-microsphere biodistribution after radioembolization. METHODS Data were acquired on a Biograph mCT-TrueV scanner with time of flight (TOF) and point spread function (PSF) modeling. Spatial resolution was measured with a 90Y point source. Sensitivity was evaluated using the NEMA 70 cm line source filled with 90Y. To evaluate the count rate performance, 90Y vials with activity ranging from 3.64 to 0.035 GBq were measured in the center of the field of view (CFOV). The energy spectrum was evaluated. Image quality with different reconstructions was studied using the Jaszczak phantom containing six hollow spheres (diameters: 31.3, 28.1, 21.8, 16.1, 13.3, and 10.5 mm), filled with a 207 kBq/ml 90Y concentration and a 5:1 sphere-to-background ratio. Acquisition time was adjusted to simulate the quality of a realistic clinical PET acquisition of a patient treated with SIR-Spheres®. The developed methodology was applied to ten patients after SIR-Spheres® treatment acquiring a 10 min per bed PET. RESULTS The energy spectrum showed the 90Y bremsstrahlung radiation. The 90Y transverse resolution, with filtered backprojection reconstruction, was 4.5 mm in the CFOV and degraded to 5.0 mm at 10 cm off-axis. 90Y absolute sensitivity was 0.40 kcps/MBq in the center of the field of view. Tendency of true and random rates as a function of the 90Y activity could be accurately described using linear and quadratic models, respectively. Phantom studies demonstrated that, due to low count statistics in 90Y PET acquisition, the optimal parameters for the standard OSEM+PSF reconstruction were only one iteration and a postreconstruction filter of 6 mm FWHM, for both TOF and non-TOF reconstructions. Moreover, when TOF is included, the signal to noise ratio increased and visibility achieved 100% by the experienced observers and 93.3% according to the Rose model of statistical detection. In 50% of patients, TOF allowed the visualization of 90Y radioembolized lesions not seen without TOF, confirming phantom results. Liver activity was accurately quantified, with no significant differences between reconstructed and actual delivered activity to the whole-liver [mean relative difference (10.2±14.7)%]. CONCLUSIONS Qualitative and quantitative 90Y PET imaging improved with the introduction of TOF in a PET/CT scanner, thereby allowing the visualization of microsphere deposition in lesions not visible in non-TOF images. This technique accurately quantifies the total activity delivered to the liver during radioembolization with (90)Y-microspheres and allows dose estimation.

Long-term follow-up study of gastroduodenal lesions after radioembolization of hepatic tumors

AIM To evaluate the long-term natural history of the gastroduodenal lesions secondary to extrahepatic embolization with Ytrium 90 (⁹⁰Y) spheres. METHODS From September 2003 to January 2012, 379 procedures of liver radioembolization (RE) using resin microspheres loaded with ⁹⁰Y were performed in our center. We have retrospectively compiled the data from 379 RE procedures performed in our center. We report a comprehensive clinical, analytical, endoscopic and histologic long-term follow-up of a series of patients who developed gastroduodenal lesions after the treatment. RESULTS Six patients (1.5%) developed gastrointestinal symptoms and had gastrointestinal lesions as shown by upper endoscopy in the next 12 wk after RE. The mean time between RE and the appearance of symptoms was 5 wk. Only one patient required endoscopic and surgical treatment. The incidence of gastrointestinal ulcerations was 3.75% (3/80) when only planar images were used for the pre-treatment evaluation. It was reduced to 1% (3/299) when single-photon emission computed tomography (SPECT) images were also performed. The symptoms that lasted for a longer time were nausea and vomiting, until 25 mo after the treatment. CONCLUSION All patients were free from severe symptoms at the end of follow-up. The routine use of SPECT has decreased the incidence of gastrointestinal lesions due to unintended deployment of ⁹⁰Y particles.

Index lesion characterization by 11C‐Choline PET/CT and Apparent Diffusion Coefficient parameters at 3 Tesla MRI in primary prostate carcinoma

Index lesion characterization is important in the evaluation of primary prostate carcinoma (PPC). The aim of this study was to analyze the contribution of 11C‐Choline PET/CT and the Apparent Diffusion Coefficient maps (ADC) in detecting the Index Lesion and clinically significant tumors in PPC.

Aportación del tiempo de vuelo y de la modelización de la respuesta a una fuente puntual a las características de funcionamiento del tomógrafo PET/TAC Biograph mCT

OBJECTIVE To characterize the performance of the Biograph mCT PET/CT TrueV scanner with time of flight (TOF) and point spread function (PSF) modeling. MATERIAL AND METHODS The PET/CT scanner combines a 64-slice CT and PET scanner that incorporates in the reconstruction the TOF and PSF information. PET operating characteristics were evaluated according to the standard NEMA NU 2-2007, expanding some tests. In addition, different reconstruction algorithms were included, and the intrinsic radiation and tomographic uniformity were also evaluated. RESULTS The spatial resolution (FWHM) at 1 and 10cm was 4.4 and 5.3mm, improving to 2.6 and 2.5mm when PSF is introduced. Sensitivity was 10.9 and 10.2 Kcps/MBq at 0 and 10cm from the axis. Scatter fraction was less than 34% at low concentrations and the noise equivalent count rate (NECR) was maximal at 27.8 kBq/mL with 182 Kcps, the intrinsic radiation produced a rate of 4.42 true coincidences per second. Coefficient of variation of the volume and system uniformity were 4.7 and 0.8% respectively. The image quality test showed better results when PSF and TOF were included together. PSF improved the hot spheres contrast and background variability, while TOF improved the cold spheres contrast. CONCLUSIONS The Biograph mCT TrueV scanner has good performance characteristics. The image quality improves when the information from the PSF and the TOF is incorporated in the reconstruction.

Whole body 18fluoro-l-dopa PET–CT: a useful tool for location and surgical guidance in primary carcinoid tumours

Neuroendocrine tumours (NETs) represent a diagnostic and therapeutic challenge. Primary tumour is not localised in 20% to 50% of NETs, midgut carcinoids being particularly elusive [1]. 18Fluoro-L-dopa has emerged as a new imaging tool for NETs diagnosis with improved tumour detection and staging compared with conventional imaging (SRS and/or CT) [2, 3]. We present a patient with metastatic carcinoid tumour who underwent PET–CT scan with 18fluoro-L-dopa, which was of key importance to locate the primary tumour and guide its surgical resection. An 18-year-old woman with a 1-year history of progressive facial episodic flushing presented an elevated serotonin serum level and mild elevation of 5-OH-IAA. MRI showed multiple small hypervascular liver lesions, and US-guided liver biopsy revealed a metastatic carcinoid tumour. Imaging tests including thoracic and abdominal CT, SRS with 111-In-octreotide and 18FDG PET–CT, and gastric and colon endoscopies showed no evidence of primary tumour. Because gastroenteropancreatic NETs are known to uptake and decarboxylate L-dopa [4], PET–CT using 18fluoro-L-dopa was carried out. In addition to multiple bilobar liver metastases (SUVmax=15), this study demonstrated three hypermetabolic peritoneal foci: two located at the height of the fifth lumbar vertebra (SUVmax=16.4) (a, b) and a third smaller focus below the others with lower uptake (SUVmax=4) apparently located in the bowel (c).

Significant dose reduction is feasible in FDG PET/CT protocols without compromising diagnostic quality

PURPOSE To reduce the radiation dose to patients by optimizing oncological FDG PET/CT protocols. METHODS The baseline PET/CT protocol in our institution for oncological PET/CT examinations consisted of the administration of 5.18 MBq/kg of FDG and a CT acquisition with a reference current-time product of 120 mAs. In 2016, FDG activity was reduced to 4.44 and 3.70 MBq/kg and reference CT current-time-product was reduced to 100 and 80 mAs. 322 patients scanned with different protocols were retrospectively evaluated. For each patient, effective dose was calculated. The overall image quality was subjectively rated by the referring physician on a 4-point scale (IQ score: 1 excellent, 2 good, 3 poor but interpretable, 4 poor not interpretable). Image quality was quantitatively evaluated measuring noise in the liver. RESULTS CT Results: Effective dose was progressively reduced from 9.5 ± 2.8 to 8.0 ± 2.3 and 6.2 ± 1.5 mSv (p < 0.001). A mean dose reduction of 34.9% was achieved. There was a significant degradation of IQ score (p < 0.05) and noise (p < 0.001). Nevertheless, the number of poor quality studies (IQ score >2) did not increase. PET Results: Effective dose was gradually reduced from 6.5 ± 1.4 to 5.7 ± 1.3 and 5.0 ± 1.0 mSv (p < 0.001). Average dose reduction was 23.4%. IQ score (p < 0.05) and noise (p < 0.001) significantly degraded for lower activity protocols. However, all images with reduced activity were scored as interpretable (IQ score ≤ 3). CONCLUSIONS A significant radiation dose reduction of 28.7% was reached. Despite a slight reduction in image quality, the new regime was successfully implemented with readers reporting unchanged clinical confidence.

Radioembolization: Concepts and Procedures

Radioembolization (RE) is a form of intravascular brachytherapy that consists in delivering implantable radioactive microspheres into the arteries that feed liver tumors in order to provide a high dose of radiation to tumor nodules irrespective of their number, size, and location, while preserving the non-tumoral liver tissue from receiving a harmful level of radiation. The nature of the procedure using Yttrium-90 RE (Y-90 RE) requires the collaboration of a multidisciplinary team including hepatologists or oncologists, interventional radiologists and nuclear medicine specialists working together in close collaboration. To avoid toxicity, a thorough angiographic evaluation is performed to identify every extrahepatic vessel that may feed the tumors (to assure efficiency), accomplished with Tc-99m labeled macroaggregated albumin (Tc-MAA) injection into the vessel of interest, in order to mimic the microsphere application during the treatment. Both procedures combined are essential to plan the radioembolization (RE) therapy and to detect any occult arteriovenous shunt from the hepatic arterial system to the pulmonary or gastrointestinal venous systems and so identify potentially to calculate the degree of hepatopulmonary shunting, and to detect and eventually occlude every collateral vessel that arising from a hepatic artery may carry microspheres to the GI tract or other extrahepatic organs. With all this information, the treatment is designed and activity is calculated in order to maximize the dose of radiation delivered to liver tumors while safely preserving the non-tumoral parenchyma.