Safety and feasibility of an in situ vaccination and immunomodulatory targeted radionuclide combination immuno-radiotherapy approach in a comparative (companion dog) setting.

RATIONALE: Murine syngeneic tumor models have revealed efficacious systemic antitumor responses following primary tumor in situ vaccination combined with targeted radionuclide therapy to secondary or metastatic tumors. Here we present studies on the safety and feasibility of this approach in a relevant translational companion dog model (n = 17 dogs) with advanced cancer. METHODS: The three component of the combination immuno-radiotherapy approach were employed either separately or in combination in companion dogs with advanced stage cancer. In situ vaccination was achieved through the administration of hypofractionated external beam radiotherapy and intratumoral hu14.18-IL2 fusion immunocytokine injections to the index tumor. In situ vaccination was subsequently combined with targeted radionuclide therapy using a theranostic pairing of IV 86Y-NM600 (for PET imaging and subject-specific dosimetry) and IV 90Y-NM600 (therapeutic radionuclide) prescribed to deliver an immunomodulatory 2 Gy dose to all metastatic sites in companion dogs with metastatic melanoma or osteosarcoma. In a subset of dogs, immunologic parameters preliminarily assessed. RESULTS: The components of the immuno-radiotherapy combination were well tolerated either alone or in combination, resulting in only transient low grade (1 or 2) adverse events with no dose-limiting events observed. In subject-specific dosimetry analyses, we observed 86Y-NM600 tumor:bone marrow absorbed-dose differential uptakes ≥2 in 4 of 5 dogs receiving the combination, which allowed subsequent safe delivery of at least 2 Gy 90Y-NM600 TRT to tumors. NanoString gene expression profiling and immunohistochemistry from pre- and post-treatment biopsy specimens provide evidence of tumor microenvironment immunomodulation by 90Y-NM600 TRT. CONCLUSIONS: The combination of external beam radiotherapy, intratumoral immunocytokine, and targeted radionuclide immuno-radiotherapy known to have activity against syngeneic melanoma in murine models is feasible and well tolerated in companion dogs with advanced stage, spontaneously arising melanoma or osteosarcoma and has immunomodulatory potential. Further studies evaluating the dose-dependent immunomodulatory effects of this immuno-radiotherapy combination are currently ongoing.

Thalamic and basal ganglia metabolism on interictal 18F-FDG PET in temporal lobe epilepsy: an SUV-based analysis.

The aim of this study was to investigate thalamic and basal ganglia (BG) metabolism in temporal lobe epilepsy (TLE) on interictal 18F-FDG PET using standardized uptake value (SUV). Retrospective review of data was undertaken for patients who were surgically treated for medically intractable TLE. All patients underwent 18F-FDG PET, MRI brain and EEG as preoperative workup, and subsequently underwent temporal lobe resection. Postoperative outcomes were analyzed as without or with residual disabling seizures. SUVmax and SUVpeak values were calculated for thalamus and BG. Subgroup comparisons were performed with non-parametric tests. Study sample consisted of 33 patients (58% female; mean age 44.7 years) and 33 age- and sex-matched controls. Mean SUVpeak for both right and left thalamus was significantly lower in TLE than controls (8.1 ± 1.9 vs. 9.7 ± 2.9 and 8.1 ± 1.9 vs. 9.8 ± 2.9, respectively, both p=0.035). Mean SUVpeak for thalamus on the epileptogenic side was overall significantly lower than the contralateral side (8.0 ± 2.0 vs. 8.3 ± 2.0, p=0.040). One (3%) patient with MRI- and EEG-congruent left TLE showed marked left thalamic hypometabolism as the only finding on PET. There was no evidence of basal ganglia hypometabolism. No correlation was noted between thalamic metabolic asymmetry and postoperative outcomes. Thalamic metabolism was significantly reduced in patients with TLE compared to controls, and on the epileptogenic compared to the contralateral side among patients. Thalamic hypometabolism can have value in seizure focus localization in patients without interictal temporal hypometabolism.

Differentiation of metastatic vs degenerative joint disease using semi-quantitative analysis with (18)F-NaF PET/CT in castrate resistant prostate cancer patients.

Fluorine 18 Sodium Fluoride ((18)F-NaF) (sodium fluoride) PET/CT is a highly sensitive but is a non-specific method for identifying bone metastases. Qualitative scan interpretation using low dose CT for lesion localization is often complicated by the presence of co-existing degenerative joint disease (DJD). A semi-quantitative analysis might help in accurately differentiating benign from metastatic osseous lesions. The aim of the study was to evaluate the clinical utility of (18)F-NaF PET/CT in differentiating DJD from metastatic disease in the skeleton using a qualitative analysis as well as a semi-quantitative approach using the SUVmax and to determine if there is an upper limit of SUVmax value that can reliably differentiate metastases from DJD. Baseline (18)F-NaF PET/CT scans were performed for 17 castrate resistant prostate cancer patients (CRPC). A qualitative as well as semi-quantitative analysis using maximum standardized uptake value (SUVmax) based on body weight was performed for 65 metastatic and 56 DJD sites identified on the low dose CT scan acquired as a part of whole body PET/CT scan. The SUVmax range in DJD was 2.6-49.9 (mean: 6.2). The SUVmax range for metastatic lesions was 11.2-188 (mean: 160). The SUVmax value for metastatic as well as areas of DJD showed significant variation during treatment. Bone metastases showed statistically significantly higher SUVmax than DJD using a mixed effect regression model. ROC/AUC analysis was performed based on averaging the SUVs over all lesions in each subject. The AUC was found to be fairly high at 0.964 (95% CI: 0.75-0.996). The SUVmax over 50 always represented a bone metastasis and below 12 always represented a site of DJD. The results of our preliminary data show that semi-quantitative analysis is complementary to the qualitative analysis in accurately identifying DJD from metastatic disease. The cut-off SUVmax of 50 can help in differentiating DJD from bone metastases.

Impact of expectation-maximization reconstruction iterations on the diagnosis of temporal lobe epilepsy with PET.

There is a well known tradeoff between image noise and image sharpness that is dependent on the number of iterations performed in ordered subset expectation maximization (OSEM) reconstruction of PET data. We aim to evaluate the impact of this tradeoff on the sensitivity and specificity of (18)F-FDG PET for the diagnosis of temporal lobe epilepsy. A retrospective blinded reader study was performed on two OSEM reconstructions, using either 2 or 5 iterations, of 32 (18)F-FDG PET studies acquired at our institution for the diagnosis of temporal lobe epilepsy. The sensitivity and specificity of each reconstruction for identifying patients who were ultimately determined to be surgical candidates was assessed using an ROC analysis. The sensitivity of each reconstruction for identifying patients who showed clinical improvement following surgery was also assessed. Our results showed no significant difference between the two reconstructions studied for either the sensitivity and specificity of (18)F-FDG PET for predicting surgical candidacy, or its sensitivity for predicting positive surgical outcomes. This implies that the number of iterations performed during OSEM reconstruction will have little impact on a reader based interpretation of (18)F-FDG PET scans acquired for the diagnosis of temporal lobe epilepsy, and can be determined by physician and institutional preference.

(18)F-DOPA PET with and without MRI fusion, a receiver operator characteristics comparison.

This study is a retrospective analysis of the diagnostic accuracy of FDOPA PET with MRI fusion to FDOPA PET without MRI fusion. Clinical FDOPA PET scans obtained between 2000 and 2008 at the University of Wisconsin Hospital and Clinics were assessed using measures derived from regions of interest (ROI) generated with fused MRI (fused group) and again with ROIs derived solely from PET data (non-fused groups). The ROIs were used to calculate ratios (Striatum/Occipital cortex, Striatum/Cerebellum) pertinent to Parkinson's disease (PD) pathology. The clinical records were assessed for demographic data, follow-up length, and diagnosis. Receiver Operator Characteristics with area under the curve (AUC) measures were calculated and compared using confidence intervals and hypothesis testing. 27 patients had FDOPA PET with median clinical follow-up of 4 years. Of these, 17 patients had FDOPA PET with a fusible MR image. Seven of the 27 had a non-PD movement disorder. AUCs for the ratio measures ranged from 0.97-1.0 (fused), 0.73-0.83 (non-fused), and 0.63-0.82 (matched non-fused). The fused images had improved accuracy compared to the matched non-fused and all non-fused groups for the striatum to occipital group (p=0.04, p=0.03), while the striatum to cerebellum ratio had improvement over the non-fused all group (p=0.041). MR fusion to FDOPA PET improves the accuracy of at least some measures (Striatum/Occiput, Striatum/Cerebellum) in the diagnosis of PD.

Clinical utility of positron emission tomography/computed tomography in inflammatory bowel disease.

PURPOSE: The clinical utility of positron emission tomography/computed tomography (PET/CT) in comparison to standard workup in patients with known or suspected inflammatory bowel disease (IBD) is unknown. PROCEDURES: Clinical data were collected on seven patients with known or suspected IBD undergoing PET/CT. Standard workup included history, physical exam, laboratory tests, colonoscopy and/or cross-sectional imaging. We divided the intestine into five regions [small bowel and four colon (ascending, transverse, descending and rectosigmoid)] and graded relative standard uptake values 0, 1, 2 or 3 by comparison to the liver, using a region-of-interest analysis (0 = no activity, 1 = liver, 2 and 3 = significant inflammation). RESULTS: In patients 1 and 2, PET/CT demonstrated more activity than we thought clinically present. The other patients avoided unnecessary escalation or initiation of IBD therapy based on PET/CT results. Compared with standard workup, all seven patients had superior results when therapeutic decisions were based on PET/CT. CONCLUSIONS: We found PET/CT to be very useful in diagnosis and management in patients with known or suspected IBD.

PET/CT in the evaluation of inflammatory bowel disease: studies in patients before and after treatment.

PURPOSE: The purpose of this study was to evaluate the appropriate 2-deoxy-2-[(18)F]fluoro-D-glucose-positron emission tomography (FDG-PET) determination in patients with inflammatory bowel disease (IBD) before and after clinical improvement to see if this determination correlates with clinical activity. PROCEDURES: We performed PET-computed tomography (PET/CT) on five patients before and after successful medical therapy in patients with moderately active IBD. Each patient had five bowel segments scored (0-3) for the appropriate FDG-PET determination. RESULTS: There were five patients [Crohn's disease (CD) = 3, ulcerative colitis = 2] who were studied an average of 437 days (range, 77-807) after initial PET/CT scan. All patients showed significant improvement in physician global assessment scores (p = 0.004) and underwent repeat PET/CT. The total score of all segments was 32 pretreatment and 14 posttreatment (p < 0.01). Of 11 pretreatment active segments, nine (82%) segments either became inactive or displayed decreased activity, while two showed no change (p < 0.001). CONCLUSION: Appropriate FDG-PET determination decreases with successful treatment of inflammation in active IBD and correlates with symptom improvement.

Pilot study using PET/CT as a novel, noninvasive assessment of disease activity in inflammatory bowel disease.

BACKGROUND: A pilot study was performed investigating the possibility that positron emission tomography (PET) activity using 18-fluorodeoxyglucose (FDG) with nearly simultaneous computerized tomography (CT) for anatomic accuracy would identify regions of active inflammation in both ulcerative colitis (UC) and Crohn's disease (CD). METHODS: Prospective clinical data was collected in 12 patients experiencing an exacerbation of their inflammatory bowel disease; 7 with CD and 5 with UC. A PET/CT scan (GE Discovery LS PET/CT scanner) was performed in all patients. Twenty patients undergoing PET/CT because of solitary pulmonary nodules served as controls. We graded the small bowel and 4 colon regions (ascending, transverse, descending, and rectosigmoid) with PET activity scores assigned to each region based on the amount of FDG uptake using the liver as the reference organ. RESULTS: In UC patients, PET activity was seen in 13 of 24 (52%) regions. There was high (23 of 24; 95.8%) correlation between PET activity and disease activity as determined by colonoscopy, disease activity indices, and radiology. In patients with CD, PET activity was seen in 19 of 32 (59.4%) regions. Again, there was a high (26 of 32; 81.3%) correlation between PET activity and clinical disease activity. Of the 20 controls, significant PET activity (Grades 2 and 3) was seen in only 2 of 100 regions (2%). CONCLUSIONS: We found that PET activity correlated well with active inflammation in both UC and CD, suggesting that this may be a noninvasive method of identifying disease activity in patients with inflammatory bowel disease.