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1.  NOVEL ALKYLPHOSPHOCHOLINE ANALOGS FOR BROAD SPECTRUM CANCER IMAGING AND THERAPY 
Neuro-Oncology  2014;16(Suppl 3):iii10-iii11.
BACKGROUND: We present in vitro and in vivo imaging and therapeutic studies using a novel alkylphosphocholine (APC)-based molecular scaffold (CLR1404) that combines selective targeting of cancer (including cancer stem cells) with broad-spectrum activity against many different cancer types. CLR1404 APC analogs were created to exploit the finding that phospholipid ethers selectively accumulate in many cancers versus normal cells. METHODS: Depending on the iodine isotope used, radioiodinated CLR1404 is either a PET imaging (124I) or molecular radiotherapeutic agent (131I), with fluorescence analogs created by replacing iodide with various fluorophores. Standard tissue culture, xenograft and molecular biology protocols were used for these studies. RESULTS: CLR1404 displayed preferential uptake and retention in cancer and cancer stem cells compared to normal cells in vitro and in vivo. After 24 hours, selective uptake of fluorescent or radioiodinated CLR1404 analogs by multiple human cancer cell lines in vitro compared to patient-matched normal human fibroblasts was observed (2.3-2.8x). CLR1404 showed highly specific labeling of both human patient-matched glioblastoma stem cells and serum-cultured glioblastoma cells (3x over minimal labeling of control normal human astrocytes and neural stem cells). Lipid raft disruption reduced in vitro CLR1404 analog uptake.In vivo, CLR1404 analogs displayed prolonged tumor-selective retention in 55 different rodent and human cancer models (including triple-negative breast, lung, pancreatic, colorectal, prostate, renal, melanoma, GBM). Tumor accumulation was seen by 24 hours with continued normal tissue clearance between 48-120 hours. In vivo cancer stem cell labeling was also demonstrated. CLR1404 analogs do not visualize inflammatory or premalignant lesions (unlike currently used 18F-fluorodeoxy glucose (FDG)-PET tumor imaging).131I-CLR1404 also displayed therapeutic efficacy (tumor growth suppression, survival extension) especially in renal, colorectal, ovarian, prostate and triple-negative breast cancer, GBM models. CONCLUSIONS: The novel APC CLR1404 analogs potentially offer a powerful multi- modality strategy to detect, treat and follow primary and metastatic cancers in humans. Initial clinical trials strongly suggest CLR1404 has similar broad tumor targeting and retention properties in animals and humans. The pathological correlation between CLR1404 imaging and GBM is being tested in an ongoing multi-institutional Phase II clinical trial. SECONDARY CATEGORY: Preclinical Experimental Therapeutics.
doi:10.1093/neuonc/nou206.37
PMCID: PMC4144503
2.  Amyloid burden and neural function in people at risk for Alzheimer's Disease 
Neurobiology of aging  2013;35(3):576-584.
To determine the relationship between amyloid burden and neural function in healthy adults at risk for Alzheimer's Disease (AD), we used multimodal imaging with [C-11]Pittsburgh compound B positron emission tomography, [F-18]fluorodeoxyglucose, positron emission tomography, and magnetic resonance imaging, together with cognitive measurement in 201 subjects (mean age, 60.1 years; range, 46–73 years) from the Wisconsin Registry for Alzheimer's Prevention. Using a qualitative rating, 18% of the samples were strongly positive Beta-amyloid (Ab+), 41% indeterminate (Aβi), and 41% negative (Aβ–). Aβ+ was associated with older age, female sex, and showed trends for maternal family history of AD and APOE4. Relative to the Aβ– group, Aβ+ and Aβi participants had increased glucose metabolism in the bilateral thalamus; Aβ+ participants also had increased metabolism in the bilateral superior temporal gyrus. Aβ+ participants exhibited increased gray matter in the lateral parietal lobe bilaterally relative to the Aβ– group, and no areas of significant atrophy. Cognitive performance and self report cognitive and affective symptoms did not differ between groups. Amyloid burden can be identified in adults at a mean age of 60 years and is accompanied by glucometabolic increases in specific areas, but not atrophy or cognitive loss. This asymptomatic stage may be an opportune window for intervention to prevent progression to symptomatic AD.
doi:10.1016/j.neurobiolaging.2013.09.028
PMCID: PMC4018215  PMID: 24269021
Alzheimer's disease; Amyloid imaging; Cognitive function; Glucose metabolism; AD risk
3.  Alkylphosphocholine Analogs for Broad-Spectrum Cancer Imaging and Therapy 
Science translational medicine  2014;6(240):240ra75.
Many solid tumors contain an overabundance of phospholipid ethers relative to normal cells. Capitalizing on this difference, we created cancer-targeted alkylphosphocholine (APC) analogs through structure-activity analyses. Depending on the iodine isotope used, radioiodinated APC analog CLR1404 was used as either a positron emission tomography (PET) imaging (124I) or molecular radiotherapeutic (131I) agent. CLR1404 analogs displayed prolonged tumor-selective retention in 55 in vivo rodent and human cancer and cancer stem cell models. 131I-CLR1404 also displayed efficacy (tumor growth suppression and survival extension) in a wide range of human tumor xenograft models. Human PET/CT (computed tomography) and SPECT (single-photon emission computed tomography)/CT imaging in advanced-cancer patients with 124I-CLR1404 or 131I-CLR1404, respectively, demonstrated selective uptake and prolonged retention in both primary and metastatic malignant tumors. Combined application of these chemically identical APC-based radioisosteres will enable personalized dual modality cancer therapy of using molecular 124I-CLR1404 tumor imaging for planning 131I-CLR1404 therapy.
doi:10.1126/scitranslmed.3007646
PMCID: PMC4336181  PMID: 24920661
4.  18F-FDG PET/CT and pain in metastatic bone cancer 
This study aims to determine if the pain intensity of patients with oncologic bone metastases (BM) correlates with metabolic activity measured by 18F-FDG PET/CT. Twenty-eight patients, ages: 21-89 years (mean: 58.8) with BM were included in the study between September 2011 to September 2013. All patients completed a detailed questionnaire regarding pain symptoms on the visual analog scale (VAS), analgesic use, and areas of chronic pain, prior to obtaining an 18F-FDG PET/CT. Pain symptoms were queried for 11 body regions including limbs, head, torso, etc. and the corresponding SUVmax of BMs within that region were modeled with the corresponding clinical data using a linear mixed effects model and a linear regression model. Overall 64 areas in the 28 subjects were found to have BM. SUVmax was found to be a significant predictor of pain intensity as measured by the VAS, with a P-value of 0.045, with a modest effect-size on linear regression of R2 of 0.11.
PMCID: PMC4446397  PMID: 26069862
18F-FDG; bone metastasis; SUV pain
5.  Differentiation of metastatic vs degenerative joint disease using semi-quantitative analysis with 18F-NaF PET/CT in castrate resistant prostate cancer patients 
Fluorine 18 Sodium Fluoride (18F-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 18F-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 18F-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.
PMCID: PMC4396008  PMID: 25973337
F-18 NaF; castrate resistant prostate cancer; PET/CT; degenerative joint disease; bone metastases
6.  Phospholipid Ether Analogs for the Detection of Colorectal Tumors 
PLoS ONE  2014;9(10):e109668.
The treatment of localized colorectal cancer (CRC) depends on resection of the primary tumor with adequate margins and sufficient lymph node sampling. A novel imaging agent that accumulates in CRCs and the associated lymph nodes is needed. Cellectar Biosciences has developed a phospholipid ether analog platform that is both diagnostic and therapeutic. CLR1502 is a near-infrared fluorescent molecule, whereas 124/131I-CLR1404 is under clinical investigation as a PET tracer/therapeutic agent imaged by SPECT. We investigated the use of CLR1502 for the detection of intestinal cancers in a murine model and 131I-CLR1404 in a patient with metastatic CRC. Mice that develop multiple intestinal tumors ranging from adenomas to locally advanced adenocarcinomas were utilized. After 96 hours post CLR1502 injection, the intestinal tumors were analyzed using a Spectrum IVIS (Perkin Elmer) and a Fluobeam (Fluoptics). The intensity of the fluorescent signal was correlated with the histological characteristics for each tumor. Colon adenocarcinomas demonstrated increased accumulation of CLR1502 compared to non-invasive lesions (total radiant efficiency: 1.76×1010 vs 3.27×109 respectively, p = 0.006). Metastatic mesenteric tumors and uninvolved lymph nodes were detected with CLR1502. In addition, SPECT imaging with 131I-CLR1404 was performed as part of a clinical trial in patients with advanced solid tumors. 131I-CLR1404 was shown to accumulate in metastatic tumors in a patient with colorectal adenocarcinoma. Together, these compounds might enhance our ability to properly resect CRCs through better localization of the primary tumor and improved lymph node identification as well as detect distant disease.
doi:10.1371/journal.pone.0109668
PMCID: PMC4186834  PMID: 25286226
7.  18F-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.
PMCID: PMC3484423  PMID: 23145363
18F-Fluorodopa; positron emission tomography; image fusion; receiver operator characteristics; Parkinson’s
8.  Surgical decision making in Temporal Lobe Epilepsy (TLE): a comparison of 18Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET), MRI, and EEG 
Epilepsy & behavior : E&B  2011;22(2):293-297.
Purpose
(1) Determine the effect of 18Fluorodeoxyglucose Positron Emission Tomography (FDG-PET), magnetic resonance imaging (MRI), and electroencephalogram (EEG) on the decision for temporal lobe epilepsy (TLE) surgery. (2) Determine if FDG-PET, MRI, or EEG predict surgical outcome.
Procedures
All PET scans ordered (2000–2010) for epilepsy or seizure were tabulated. Medical records were investigated to determine eligibility and collect data. Statistical analysis included odds ratios, kappa statistics, univariate analysis, and logistic regression.
Results
186 patients had an FDG-PET, 124 patients had TLE, 50 were surgical candidates, and 27 had operations with > 6 months follow-up. Median length of follow-up was 24 months. MRI, FDG-PET, and EEG were significant predictors of surgical candidacy (p<0.001) with odds ratio of 42.8, 20.4, and 6.3 respectively. PET was the only significant predictor of post-operative outcome. (p<0.01)
Conclusion
MRI had a trend toward most influence on surgical candidacy, but only FDG-PET predicted the surgical outcome.
doi:10.1016/j.yebeh.2011.06.022
PMCID: PMC3260654  PMID: 21798813
temporal lobe epilepsy; medication refractory epilepsy; epilepsy surgery; fluorodeoxyglucose (FDG); positron emission tomography (PET); magnetic resonance imaging (MRI); Electroencephalogram (EEG)
9.  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 18F-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 18F-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 18F-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 18F-FDG PET scans acquired for the diagnosis of temporal lobe epilepsy, and can be determined by physician and institutional preference.
PMCID: PMC3477742  PMID: 23133820
18F-FDG PET; temporal lobe epilepsy; OSEM reconstruction; ROC analysis

Results 1-9 (9)