Kent Friedman

Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours: a proof-of-principle trial

BACKGROUND An abscopal response describes radiotherapy-induced immune-mediated tumour regression at sites distant to the irradiated field. Granulocyte-macrophage colony-stimulating factor is a potent stimulator of dendritic cell maturation. We postulated that the exploitation of the pro-immunogenic effects of radiotherapy with granulocyte-macrophage colony-stimulating factor might result in abscopal responses among patients with metastatic cancer. METHODS Patients with stable or progressing metastatic solid tumours, on single-agent chemotherapy or hormonal therapy, with at least three distinct measurable sites of disease, were treated with concurrent radiotherapy (35 Gy in ten fractions, over 2 weeks) to one metastatic site and granulocyte-macrophage colony-stimulating factor (125 μg/m(2) subcutaneously injected daily for 2 weeks, starting during the second week of radiotherapy). This course was repeated, targeting a second metastatic site. A Simons optimal two-stage design was chosen for this trial: an additional 19 patients could be enrolled in stage 2 only if at least one patient among the first ten had an abscopal response. If no abscopal responses were seen among the first ten patients, the study would be deemed futile and terminated. The primary endpoint was the proportion of patients with an abscopal response (defined as at least a 30% decrease in the longest diameter of the best responding abscopal lesion). Secondary endpoints were safety and survival. Analyses were done based on intention to treat. The trial has concluded accrual, and is registered with ClinicalTrials.gov, number NCT02474186. FINDINGS From April 7, 2003, to April 3, 2012, 41 patients with metastatic cancer were enrolled. In stage 1 of the Simons two-stage design, ten patients were enrolled: four of the first ten patients had abscopal responses. Thus, the trial proceeded to stage 2, as planned, and an additional 19 patients were enrolled. Due to protocol amendments 12 further patients were enrolled. Abscopal responses occurred in eight (27·6%, 95% CI 12·7-47·2) of the first 29 patients, and 11 (26·8%, 95% CI 14·2-42·9) of 41 accrued patients (specifically in four patients with non-small-cell lung cancer, five with breast cancer, and two with thymic cancer). The most common grade 3-4 adverse events were fatigue (six patients) and haematological (ten patients). Additionally, a serious adverse event of grade 4 pulmonary embolism occurred in one patient. INTERPRETATION The combination of radiotherapy with granulocyte-macrophage colony-stimulating factor produced objective abscopal responses in some patients with metastatic solid tumours. This finding represents a promising approach to establish an in-situ anti-tumour vaccine. Further research is warranted in this area. FUNDING New York University School of Medicines Department of Radiation Oncology and Cancer Institute.

Pulmonary Nodules in Patients with Primary Malignancy: Comparison of Hybrid PET/MR and PET/CT Imaging

PURPOSE To assess diagnostic sensitivity of radial T1-weighted gradient-echo (radial volumetric interpolated breath-hold examination [VIBE]) magnetic resonance (MR) imaging, positron emission tomography (PET), and combined simultaneous PET and MR imaging with an integrated PET/MR system in the detection of lung nodules, with combined PET and computed tomography (CT) as a reference. MATERIALS AND METHODS In this institutional review board-approved HIPAA-compliant prospective study, 32 patients with tumors who underwent clinically warranted fluorine 18 ((18)F) fluorodeoxyglucose (FDG) PET/CT followed by PET/MR imaging were included. In all patients, the thorax station was examined with free-breathing radial VIBE MR imaging and simultaneously acquired PET data. Presence and size of nodules and FDG avidity were assessed on PET/CT, radial VIBE, PET, and PET/MR images. Percentage of nodules detected on radial VIBE and PET images was compared with that on PET/MR images by using generalized estimating equations. Maximum standardized uptake value (SUVmax) in pulmonary nodules with a diameter of at least 1 cm was compared between PET/CT and PET/MR imaging with Pearson rank correlation. RESULTS A total of 69 nodules, including 45 FDG-avid nodules, were detected with PET/CT. The sensitivity of PET/MR imaging was 70.3% for all nodules, 95.6% for FDG-avid nodules, and 88.6% for nodules 0.5 cm in diameter or larger. PET/MR imaging had higher sensitivity than PET for all nodules (70.3% vs 61.6%, P = .002) and higher sensitivity than MR imaging for FDG-avid nodules (95.6% vs 80.0%, P = .008). There was a significantly strong correlation between SUVmax of pulmonary nodules obtained with PET/CT and that obtained with PET/MR imaging (r = 0.96, P < .001). CONCLUSION Radial VIBE and PET data acquired simultaneously with PET/MR imaging have high sensitivity in the detection of FDG-avid nodules and nodules 0.5 cm in diameter or larger, with low sensitivity for small non-FDG-avid nodules.

Whole-Body PET/MR Imaging: Quantitative Evaluation of a Novel Model-Based MR Attenuation Correction Method Including Bone

In routine whole-body PET/MR hybrid imaging, attenuation correction (AC) is usually performed by segmentation methods based on a Dixon MR sequence providing up to 4 different tissue classes. Because of the lack of bone information with the Dixon-based MR sequence, bone is currently considered as soft tissue. Thus, the aim of this study was to evaluate a novel model-based AC method that considers bone in whole-body PET/MR imaging. Methods: The new method (“Model”) is based on a regular 4-compartment segmentation from a Dixon sequence (“Dixon”). Bone information is added using a model-based bone segmentation algorithm, which includes a set of prealigned MR image and bone mask pairs for each major body bone individually. Model was quantitatively evaluated on 20 patients who underwent whole-body PET/MR imaging. As a standard of reference, CT-based μ-maps were generated for each patient individually by nonrigid registration to the MR images based on PET/CT data. This step allowed for a quantitative comparison of all μ-maps based on a single PET emission raw dataset of the PET/MR system. Volumes of interest were drawn on normal tissue, soft-tissue lesions, and bone lesions; standardized uptake values were quantitatively compared. Results: In soft-tissue regions with background uptake, the average bias of SUVs in background volumes of interest was 2.4% ± 2.5% and 2.7% ± 2.7% for Dixon and Model, respectively, compared with CT-based AC. For bony tissue, the −25.5% ± 7.9% underestimation observed with Dixon was reduced to −4.9% ± 6.7% with Model. In bone lesions, the average underestimation was −7.4% ± 5.3% and −2.9% ± 5.8% for Dixon and Model, respectively. For soft-tissue lesions, the biases were 5.1% ± 5.1% for Dixon and 5.2% ± 5.2% for Model. Conclusion: The novel MR-based AC method for whole-body PET/MR imaging, combining Dixon-based soft-tissue segmentation and model-based bone estimation, improves PET quantification in whole-body hybrid PET/MR imaging, especially in bony tissue and nearby soft tissue.

Kidney Function: Glomerular Filtration Rate Measurement with MR Renography in Patients with Cirrhosis

PURPOSE To assess the accuracy of glomerular filtration rate (GFR) measurements obtained with low-contrast agent dose dynamic contrast material-enhanced magnetic resonance (MR) renography in patients with liver cirrhosis who underwent routine liver MR imaging, with urinary clearance of technetium 99m ((99m)Tc) pentetic acid (DTPA) as the reference standard. MATERIALS AND METHODS This HIPAA-compliant study was institutional review board approved. Written informed patient consent was obtained. Twenty patients with cirrhosis (14 men, six women; age range, 41-70 years; mean age, 54.6 years) who were scheduled for routine 1.5-T liver MR examinations to screen for hepatocellular carcinoma during a 6-month period were prospectively included. Five-minute MR renography with a 3-mL dose of gadoteridol was performed instead of a routine test-dose timing examination. The GFR was estimated at MR imaging with use of two kinetic models. In one model, only the signal intensities in the aorta and kidney parenchyma were considered, and in the other, renal cortical and medullary signal intensities were treated separately. The GFR was also calculated by using serum creatinine levels according to the Cockcroft-Gault and modification of diet in renal disease (MDRD) formulas. All patients underwent a (99m)Tc-DTPA urinary clearance examination on the same day to obtain a reference GFR measurement. The accuracies of all MR- and creatinine-based GFR estimations were compared by using Wilcoxon signed rank tests. RESULTS The mean reference GFR, based on (99m)Tc-DTPA clearance, was 74.9 mL/min/1.73 m(2) ± 27.7 (standard deviation) (range, 10.3-120.7 mL/min/1.73 m(2)). With both kinetic models, 95% of MR-based GFRs were within 30% of the reference values, whereas only 40% and 60% of Cockcroft-Gault- and MDRD-based GFRs, respectively, were within this range. MR-based GFR estimates were significantly more accurate than creatinine level-based estimates (P < .001). CONCLUSION GFR assessment with MR imaging, which outperformed the Cockcroft-Gault and MDRD formulas, adds less than 10 minutes of table time to a clinically indicated liver MR examination without ionizing radiation. SUPPLEMENTAL MATERIAL http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.11101338/-/DC1.

Correlation Between Standardized Uptake Value and Apparent Diffusion Coefficient of Neoplastic Lesions Evaluated With Whole-Body Simultaneous Hybrid PET/MRI

OBJECTIVE The purpose of this study was to assess the correlation between standardized uptake value (SUV) and apparent diffusion coefficient (ADC) of neoplastic lesions in the use of a simultaneous PET/MRI hybrid system. SUBJECTS AND METHODS Twenty-four patients with known primary malignancies underwent FDG PET/CT. They then underwent whole-body PET/MRI. Diffusion-weighted imaging was performed with free breathing and a single-shot spin-echo echo-planar imaging sequence with b values of 0, 350, and 750 s/mm(2). Regions of interest were manually drawn along the contours of neoplastic lesions larger than 1 cm, which were clearly identified on PET and diffusion-weighted images. Maximum SUV (SUVmax) on PET/MRI and PET/CT images, mean SUV (SUVmean), minimum ADC (ADCmin), and mean ADC (ADCmean) were recorded on PET/MR images for each FDG-avid neoplastic soft-tissue lesion with a maximum of three lesions per patient. Pearson correlation coefficient was used to asses the following relations: SUVmax versus ADCmin on PET/MR and PET/CT images, SUVmean versus ADCmean, and ratio of SUVmax to mean liver SUV (SUV ratio) versus ADCmin. A subanalysis of patients with progressive disease versus partial treatment response was performed with the ratio of SUVmax to ADCmin for the most metabolically active lesion. RESULTS Sixty-nine neoplastic lesions (52 nonosseous lesions, 17 bone metastatic lesions) were evaluated. The mean SUVmax from PET/MRI was 7.0 ± 6.0; SUVmean, 5.6 ± 4.6; mean ADCmin, 1.10 ± 0.58; and mean ADCmean, 1.48 ± 0.72. A significant inverse Pearson correlation coefficient was found between PET/MRI SUVmax and ADCmin (r = -0.21, p = 0.04), between SUVmean and ADCmean (r = -0.18, p = 0.07), and between SUV ratio and ADCmin (r = -0.27, p = 0.01). A similar inverse Pearson correlation coefficient was found between the PET/CT SUVmax and ADCmin. Twenty of 24 patients had previously undergone PET/CT; five patients had a partial treatment response, and six had progressive disease according to Response Evaluation Criteria in Solid Tumors 1.1. The ratio between SUVmax and ADCmin was higher among patients with progressive disease than those with a partial treatment response. CONCLUSION Simultaneous PET/MRI is a promising technology for the detection of neoplastic disease. There are inverse correlations between SUVmax and ADCmin and between SUV ratio and ADCmin. Correlation coefficients between SUVmax and ADCmin from PET/MRI were similar to values obtained with SUVmax from the same-day PET/CT. Given that both SUV and ADC are related to malignancy and that the correlation between the two biomarkers is relatively weak, SUV and ADC values may offer complementary information to aid in determination of prognosis and treatment response. The combined tumoral biomarker, ratio between SUVmax and ADCmin, may be useful for assessing progressive disease versus partial treatment response.

Comparison of the accuracy of PET/CT and PET/MRI spatial registration of multiple metastatic lesions.

OBJECTIVE The purpose of this study was to compare the accuracy of the spatial registration of conventional PET/CT with that of hybrid PET/MRI of patients with FDG-avid metastatic lesions. SUBJECTS AND METHODS Thirteen patients with known metastatic lesions underwent FDG PET/CT followed by PET/MRI with a hybrid whole-body system. The inclusion criterion for tumor analysis was spherical or oval FDG-avid tumor clearly identified with both CT and MRI. The spatial coordinates (x, y, z) of the visually estimated centers of the lesions were determined for PET/CT (PET and CT independently) and PET/MRI (PET, T1-weighted gradient-echo sequence with radial stack-of-stars trajectory, T2-weighted sequence), and the b0 images of an echo-planar imaging (EPI) diffusion-weighted imaging (DWI) acquisition. All MRI sequences were performed in the axial plane with free breathing. The spatial coordinates of the estimated centers of the lesions were determined for PET and CT and PET and MRI sequences. Distance between the isocenter of the lesion on PET images and on the images obtained with the anatomic modalities was measured, and misregistration (in millimeters) was calculated. The degree of misregistration was compared between PET/CT and PET/MRI with a paired Student t test. RESULTS Nineteen lesions were evaluated. On PET/CT images, the average of the total misregistration in all planes of CT compared with PET was 4.13 ± 4.24 mm. On PET/MR images, lesion misregistration between PET and T1-weighted gradient-echo images had a shift of 2.41 ± 1.38 mm and between PET and b0 DW images was 5.97 ± 2.83 mm. Similar results were calculated for 11 lesions on T2-weighted images. The shift on T2-weighted images compared with PET images was 2.24 ± 1.12 mm. Paired Student t test calculations for PET/CT compared with PET/MRI T1-weighted gradient-echo images with a radial stack-of-stars trajectory, b0 DW images, and T2-weighted images showed significant differences (p < 0.05). Similar results were seen in the analysis of six lung lesions. CONCLUSION PET/MRI T1-weighted gradient-echo images with a radial stack-of-stars trajectory and T2-weighted images had more accurate spatial registration than PET/CT images. This may be because that the whole-body PET/MRI system used can perform simultaneous acquisition, whereas the PET/CT system acquires data sequentially. However, the EPI-based b0 DWI datasets were significantly misregistered compared with the PET/CT datasets, especially in the thorax. Radiologists reading PET/MR images should be aware of the potential for misregistration on images obtained with EPI-based DWI sequences because of inherent spatial distortion associated with this type of MRI acquisition.

I-131 SPECT/CT Elucidates Cryptic Findings on Planar Whole-Body Scans and Can Reduce Needless Therapy with I-131 in Post-Thyroidectomy Thyroid Cancer Patients

BACKGROUND Interpreting I-131 whole-body scans (WBSs) after thyroidectomy for thyroid cancer is not simple. There are scans in which interpretation is speculative because of cryptic findings (CF). Complexity is added in scans that are done a week after an ablative or therapeutic dose of I-131 because not only is I-131-labeled thyroxine (T4) distributed throughout the body, but inorganic I-131 that is derived from the de-iodination of T4 may be also detected. We present our observations regarding the analysis of CF on WBS using I-131 single-photon emission computed tomography (SPECT) in fusion with noncontrast computed tomography (CT), referred to here and elsewhere as I-131 SPECT/CT. METHODS Forty of 184 WBSs in 38 thyroidectomized thyroid cancer patients were followed up with I-131 SPECT/CTs. The SPECT/CT images were acquired after a tracer dose of I-131 (n=82) or a week after an ablative or therapeutic dose of I-131 (n=102). RESULTS Among 184 WBSs, 40 (22%) had CF. In 35 patients the WBS was negative for metastatic disease except for the CF and 5 patients had evidence of thyroid cancer in addition to the CF. There were 49 CF in the planar scans that were localized by SPECT/CT. These were characterized as physiological uptake in gingiva, thymus, gall bladder, menstrual blood, uterine fibroid, recto-sigmoid, colon, and bladder. Also observed was uptake in sites that represented nonthyroidal pathology including dental abscess, hiatal hernia, renal cyst, and struma ovarii. SPECT/CT suggested that 10 of the CF were actually of thyroid origin. In 40 SPECT/CT scans, the images contributed to interpreting the scan. In 15 of 40 patients the SPECT/CT analysis of WBS was performed with tracer doses of I-131 and was important for determining whether to administer ablative I-131 treatment. In another 25 patients, in whom SPECT/CT was performed after ablative or therapeutic doses of 131-I, information regarding the characterization of CF by SPECT/CT was useful in determining if thyroid cancer metastases or thyroid remnants were present. CONCLUSIONS I-131 SPECT/CT is a useful tool to characterize atypical or CF on WBS by differentiating thyroid remnant or cancer from physiologic activity or nonthyroid pathology. In the past, uptake on a WBS that was not explicable as physiologic activity was identified as putative or possible thyroid cancer and generally was treated with I-131. Now, by identifying activity in some possible cancer sites as not thyroid cancer, SPECT/CT can reduce inappropriate treatment with I-131. SPECT/CT of WBS performed after ablative doses of 131-I is useful in determining the nature of CF and therefore likely providing prognostic information.

PET/MRI for the Evaluation of Patients With Lymphoma: Initial Observations

OBJECTIVE The objective of our study was to assess the role of recently introduced hybrid PET/MRI in the evaluation of lymphoma patients using PET/CT as a reference standard. SUBJECTS AND METHODS In this prospective study 28 consecutive lymphoma patients (18 men, 10 women; mean age, 53.6 years) undergoing clinically indicated PET/ CT were subsequently imaged with PET/MRI using residual FDG activity from the PET/ CT study. Blinded readers evaluated PET/CT (reference standard), PET/MRI, and diffusion-weighted imaging (DWI) studies separately; for each study, they assessed nodal and extranodal involvement. Each FDG-avid nodal station was marked and compared on DWI, PET/MRI, and PET/CT. Modified Ann Arbor staging was performed and compared between PET/MRI and PET/CT. The maximum standardized uptake value (SUVmax) on PET/MRI for FDG-avid nodal lesions was compared with the SUVmax on PET/CT. The apparent diffusion coefficient (ADC) for FDG-avid nodal lesions was compared to SUVmax on PET/MRI. RESULTS Fifty-one FDG-avid nodal groups were identified on PET/CT in 13 patients. PET/MRI identified 51 of these nodal groups with a sensitivity of 100%. DWI identified 32 nodal groups for a sensitivity of 62.7%. PET/MRI staging and PET/CT staging were concordant in 96.4% of patients. For the one patient with discordant staging results, disease was correctly upstaged to stage IV on the basis of the PET/MRI finding of bone marrow involvement, which was missed on PET/CT. DWI staging was concordant with PET/CT staging in 64.3% of the patients. The increased staging accuracy of PET/MRI relative to DWI was significant (p=0.004). SUVmax measured on PET/MRI and PET/CT showed excellent statistically significant correlation (r=0.98, p<0.001). There was a poor negative correlation between ADC and SUVmax (r=-0.036, p=0.847). CONCLUSION PET/MRI can be used to assess disease burden in lymphoma with sensitivity similar to PET/CT and can be a viable alternative for lymphoma staging and follow-up.

Current Status of Hybrid PET/MRI in Oncologic Imaging

OBJECTIVE This review article explores recent advancements in PET/MRI for clinical oncologic imaging. CONCLUSION Radiologists should understand the technical considerations that have made PET/MRI feasible within clinical workflows, the role of PET tracers for imaging various molecular targets in oncology, and advantages of hybrid PET/MRI compared with PET/CT. To facilitate this understanding, we discuss clinical examples (including gliomas, breast cancer, bone metastases, prostate cancer, bladder cancer, gynecologic malignancy, and lymphoma) as well as future directions, challenges, and areas for continued technical optimization for PET/MRI.

Outcome of small lung nodules missed on hybrid PET/MRI in patients with primary malignancy.

To assess outcomes of lung nodules missed on simultaneous positron emission tomography and magnetic resonance imaging (PET/MRI) compared to the reference standard PET and computed tomography (PET/CT) in patients with primary malignancy.