Clogged Arteries, Safety Net Holes: Treating an Underinsured Patient for Homozygous Familial Hypercholesterolemia With Plasmapheresis.

This case report explores the difficulties with rapid lipid-lowering therapies in a resource-limited setting. We present a case of an individual with previously diagnosed homozygous familial hypercholesterolemia presenting with anginal chest pain concerning for non-ST elevation myocardial infarction (NSTEMI), with a low-density lipoprotein (LDL) of 984 mg/dL (reference range: 100-129 mg/dL) and a reversible perfusion defect on his nuclear medicine stress test. In addition to the standard treatment for NSTEMI, including cardiac catheterization, the patient was initiated on a proprotein convertase subtilisin/kexin type 9 inhibitor and underwent two rounds of plasmapheresis, which effectively and rapidly lowered his LDL levels.

Advanced Achalasia Mimicking Delayed Gastric Emptying During Standard Gastric Emptying Scintigraphy.

ABSTRACT: An 82-year-old man underwent outpatient nuclear medicine gastric-emptying scintigraphy (GES) for dysphagia and regurgitation. Standard solid-meal GES showed significant elongated tracer retention with calculated 96% retention rate at 3 hours, with a presumed diagnosis of delayed gastric emptying. Subsequent CT of the chest and abdomen and upper gastrointestinal fluoroscopy instead showed normal size and function of the stomach but an enormously dilated esophagus with food debris, compatible with achalasia. Attention should be made on the location and shape of the visualized "stomach" and recognize that significantly dilated esophagus can mimic an elongated stomach during GES.

[124I]CLR1404 PET/CT in High-Grade Primary and Metastatic Brain Tumors.

PURPOSE: There is a continuous search for imaging techniques with high sensitivity and specificity for brain tumors. Positron emission tomography (PET) imaging has shown promise, though many PET agents either have a low tumor specificity or impractical physical half-lives. [124I]CLR1404 is a small molecule alkylphosphocholine analogue that is thought to bind to plasma membrane lipid rafts and has shown high tumor-to-background ratios (TBR) in a previous pilot study in brain tumor patients. This study attempts to define the clinical value of [124I]CLR1404 PET/CT (aka CLR124). PROCEDURES: Adult patients with new or suspected recurrence of high-grade primary or metastatic brain tumors (N = 27) were injected with [124I]CLR1404 followed by PET/CT at 6, 24, and 48 h. Standard uptake values (SUV) and TBR values were calculated for all time points. Uptake of [124I]CLR1404 was qualitatively assessed, compared with magnetic resonance imaging (MRI), and correlated with clinical outcome. Final diagnosis (N = 25) was established based on surgically resected tissue or long-term follow-up. RESULTS: Positive uptake with high TBR was detected in all but one patient with a final diagnosis of primary/recurrent brain tumor (12/13) and in less than half of patients with treatment-related changes (5/12). Concordance between [124I]CLR1404 uptake and contrast enhancement on MRI was seen in < 40 %, with no concordance between T2-hyperintensities and uptake. No significant difference in overall outcome was found between patients with and without [124I]CLR1404 uptake. CONCLUSIONS: The uptake pattern in these patients suggests a very high sensitivity of [124I]CLR1404 PET/CT for diagnosing tumor tissue; however, tumor specificity needs to be further defined. Relative lack of concordance with standard MRI characteristics suggests that [124I]CLR1404 PET/CT provides additional information about brain tumors compared to MRI alone, potentially improving clinical decision-making.

Lateralized periodic discharges frequency correlates with glucose metabolism.

OBJECTIVE: To investigate the correlation between characteristics of lateralized periodic discharges (LPDs) and glucose metabolism measured by 18F-fluorodeoxyglucose (FDG)-PET. METHODS: We retrospectively reviewed medical records to identify patients who underwent FDG-PET during EEG monitoring with LPDs present during the FDG uptake period. Two blinded board-certified neurophysiologists independently interpreted EEGs. FDG uptake was measured using standardized uptake value (SUV). Structural images were fused with PET images to aid with localization of SUV. Two PET readers independently measured maximum SUV. Relative SUV values were obtained by normalization of the maximum SUV to the SUV of pons (SUVRpons). LPD frequency was analyzed both as a categorical variable and as a continuous measure. Other secondary variables included duration, amplitude, presence of structural lesion, and "plus" EEG features such as rhythmic or fast sharp activity. RESULTS: Nine patients were identified and 7 had a structural etiology for LPDs. Analysis using frequency as a categorical variable and continuous variable showed an association between increased LPD frequency and increased ipsilateral SUVRpons (p = 0.02). Metabolism associated with LPDs (0.5 Hz as a baseline) increased by a median of 100% at 1 Hz and for frequencies >1 Hz increased by a median of 309%. There were no statistically significant differences in SUVRpons for other factors including duration (p = 0.10), amplitude (p = 0.80), structural etiology (p = 0.55), or "plus" features such as rhythmic or fast sharp activity (p = 0.84). CONCLUSIONS: Metabolic activity increases monotonically with LPD frequency. LPD frequency should be a measure of interest when developing neuroprotection strategies in critical neurologic illness.

Pretreatment CLR 124 Positron Emission Tomography Accurately Predicts CLR 131 Three-Dimensional Dosimetry in a Triple-Negative Breast Cancer Patient.

INTRODUCTION: CLR1404 is a theranostic molecular agent that can be radiolabeled with 124I (CLR 124) for positron emission tomography (PET) imaging, or 131I (CLR 131) for single-photon emission computed tomography (SPECT) imaging and targeted radionuclide therapy. This pilot study evaluated a pretreatment dosimetry methodology in a triple-negative breast cancer patient who was uniquely enrolled in both a CLR 124 PET imaging clinical trial and a CLR 131 therapeutic dose escalation clinical trial. MATERIALS AND METHODS: Three-dimensional PET/CT images were acquired at 1, 3, 24, 48, and 120 h postinjection of 178 MBq CLR 124. One month later, pretherapy 2D whole-body planar images were acquired at 0.25, 5, 24, 48, and 144 h postinjection of 370 MBq CLR 131. Following the therapeutic administration of 1990 MBq CLR 131, 3D SPECT/CT images were acquired at 74, 147, 334, and 505 h postinjection. The therapeutic CLR 131 voxel-level absorbed dose was estimated from PET (RAPID PET) and SPECT (RAPID SPECT) images using a Geant4-based Monte Carlo dosimetry platform called RAPID (Radiopharmaceutical Assessment Platform for Internal Dosimetry), and region of interest (ROI) mean doses were also estimated using the OLINDA/EXM software based on PET (OLINDA PET), SPECT (OLINDA SPECT), and planar (OLINDA planar) images. RESULTS: The RAPID PET and OLINDA PET tracer-predicted ROI mean doses correlated well (m ≥ 0.631, R2 ≥ 0.694, p ≤ 0.01) with both the RAPID SPECT and OLINDA SPECT therapeutic mean doses. The 2D planar images did not have any significant correlations. The ROI mean doses differed by -4% to -43% between RAPID and OLINDA/EXM, and by -19% to 29% between PET and SPECT. The 3D dose distributions and dose volume histograms calculated with RAPID were similar for the PET/CT and SPECT/CT. CONCLUSIONS: This pilot study demonstrated that CLR 124 pretreatment PET images can be used to predict CLR 131 3D therapeutic dosimetry better than CLR 131 2D planar images. In addition, unlike OLINDA/EXM, Monte Carlo dosimetry methods were capable of accurately predicting dose heterogeneity, which is important for predicting dose-response relationships and clinical outcomes.

Enhanced Radiosensitivity in Solid Tumors using a Tumor-selective Alkyl Phospholipid Ether Analog.

Antitumor alkyl phospholipid (APL) analogs comprise a group of structurally related molecules with remarkable tumor selectivity. Some of these compounds have shown radiosensitizing capabilities. CLR127 is a novel, clinical-grade antitumor APL ether analog, a subtype of synthetic APL broadly targeting cancer cells with limited uptake in normal tissues. The purpose of this study was to investigate the effect of CLR127 to modulate radiation response across several adult and pediatric cancer types in vitro as well as in murine xenograft models of human prostate adenocarcinoma, neuroblastoma, Ewing sarcoma, and rhabdomyosarcoma. In vitro, CLR127 demonstrated selective uptake in cancer cells compared to normal cells. In cancer cells, CLR127 treatment prior to radiation significantly decreased clonogenic survival in vitro, and led to increased radiation-induced double-stranded DNA (dsDNA) breakage compared with radiation alone, which was not observed in normal controls. In animal models, CLR127 effectively increased the antitumor response to fractionated radiotherapy and led to delayed tumor regrowth at potentially clinically achievable doses. In conclusion, our study highlights the ability of CLR127 to increase radiation response in several cancer types. Given almost universal uptake of CLR127 in malignant cells, future research should test whether the observed effects can be extended to other tumor types. Our data provide a strong rationale for clinical testing of CLR127 as a tumor-targeted radiosensitizing agent. Mol Cancer Ther; 17(11); 2320-8. ©2018 AACR.

Development and Validation of RAPID: A Patient-Specific Monte Carlo Three-Dimensional Internal Dosimetry Platform.

This work describes the development and validation of a patient-specific Monte Carlo internal dosimetry platform called RAPID (Radiopharmaceutical Assessment Platform for Internal Dosimetry). RAPID utilizes serial PET/CT or SPECT/CT images to calculate voxelized three-dimensional (3D) internal dose distributions with the Monte Carlo code Geant4. RAPID's dosimetry calculations were benchmarked against previously published S-values and specific absorbed fractions (SAFs) calculated for monoenergetic photon and electron sources within the Zubal phantom and for S-values calculated for a variety of radionuclides within spherical tumor phantoms with sizes ranging from 1 to 1000 g. The majority of the S-values and SAFs calculated in the Zubal Phantom were within 5% of the previously published values with the exception of a few 10 keV photon SAFs that agreed within 10%, and one value within 16%. The S-values calculated in the spherical tumor phantoms agreed within 2% for 177Lu, 131I, 125I, 18F, and 64Cu, within 3.5% for 211At and 213Bi, within 6.5% for 153Sm, 111In, 89Zr, and 223Ra, and within 9% for 90Y, 68Ga, and 124I. In conclusion, RAPID is capable of calculating accurate internal dosimetry at the voxel-level for a wide variety of radionuclides and could be a useful tool for calculating patient-specific 3D dose distributions.

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.

Targeted Molecular Radiotherapy of Pediatric Solid Tumors Using a Radioiodinated Alkyl-Phospholipid Ether Analog.

External-beam radiotherapy plays a critical role in the treatment of most pediatric solid tumors. Particularly in children, achieving an optimal therapeutic index to avoid damage to normal tissue is extremely important. Consequently, in metastatic disease, the utility of external-beam radiotherapy is limited. Molecular radiotherapy with tumor-targeted radionuclides may overcome some of these challenges, but to date there exists no single cancer-selective agent capable of treating various pediatric malignancies independently of their histopathologic origin. We tested the therapeutic potential of the clinical-grade alkyl-phospholipid ether analog CLR1404, 18-(p-iodophenyl)octadecyl phosphocholine, as a scaffold for tumor-targeted radiotherapy of pediatric malignancies. Methods: Uptake of CLR1404 by pediatric solid tumor cells was tested in vitro by flow cytometry and in vivo by PET/CT imaging and dosimetry. The therapeutic potential of 131I-CLR1404 was evaluated in xenograft models. Results: In vitro, fluorescent CLR1404-BODIPY showed significant selective uptake in a variety of pediatric cancer lines compared with normal controls. In vivo tumor-targeted uptake in mouse xenograft models using 124I-CLR1404 was confirmed by imaging. Single-dose intravenous injection of 131I-CLR1404 significantly delayed tumor growth in all rodent pediatric xenograft models and extended animal survival while demonstrating a favorable side effect profile. Conclusion:131I-CLR1404 has the potential to become a tumor-targeted radiotherapeutic drug with broad applicability in pediatric oncology. Because 131I-CLR1404 has entered clinical trials in adults, our data warrant the development of pediatric clinical trials for this particularly vulnerable patient population.

PET/CT imaging of the diapeutic alkylphosphocholine analog 124I-CLR1404 in high and low-grade brain tumors.

CLR1404 is a cancer-selective alkyl phosphocholine (APC) analog that can be radiolabeled with 124I for PET imaging, 131I for targeted radiotherapy and/or SPECT imaging, or 125I for targeted radiotherapy. Studies have demonstrated avid CLR1404 uptake and prolonged retention in a broad spectrum of preclinical tumor models. The purpose of this pilot trial was to demonstrate avidity of 124I-CLR1404 in human brain tumors and develop a framework to evaluate this uptake for use in larger studies. 12 patients (8 men and 4 women; mean age of 43.9 ± 15.1 y; range 23-66 y) with 13 tumors were enrolled. Eleven patients had suspected tumor recurrence and 1 patient had a new diagnosis of high grade tumor. Patients were injected with 185 MBq ± 10% of 124I-CLR1404 followed by PET/CT imaging at 6-, 24-, and 48-hour. 124I-CLR1404 PET uptake was assessed qualitatively and compared with MRI. After PET image segmentation SUV values and tumor to background ratios were calculated. There was no significant uptake of 124I-CLR1404 in normal brain. In tumors, uptake tended to increase to 48 hours. Positive uptake was detected in 9 of 13 lesions: 5/5 high grade tumors, 1/2 low grade tumors, 1/1 meningioma, and 2/4 patients with treatment related changes. 124I-CLR1404 uptake was not detected in 1/2 low grade tumors, 2/4 lesions from treatment related changes, and 1/1 indeterminate lesion. For 6 malignant tumors, the average tumor to background ratios (TBR) were 9.32 ± 4.33 (range 3.46 to 15.42) at 24 hours and 10.04 ± 3.15 (range 5.17 to 13.17) at 48 hours. For 2 lesions from treatment related change, the average TBR were 5.05 ± 0.4 (range 4.76 to 5.33) at 24 hours and 4.88 ± 1.19 (range 4.04 to 5.72) at 48 hours. PET uptake had areas of both concordance and discordance compared with MRI. 124I-CLR1404 PET demonstrated avid tumor uptake in a variety of brain tumors with high tumor-to-background ratios. There were regions of concordance and discordance compared with MRI, which has potential clinical relevance. Expansion of these studies is required to determine the clinical significance of the 124I-CLR1404 PET findings.

Impact of PET and MRI threshold-based tumor volume segmentation on patient-specific targeted radionuclide therapy dosimetry using CLR1404.

Variations in tumor volume segmentation methods in targeted radionuclide therapy (TRT) may lead to dosimetric uncertainties. This work investigates the impact of PET and MRI threshold-based tumor segmentation on TRT dosimetry in patients with primary and metastatic brain tumors. In this study, PET/CT images of five brain cancer patients were acquired at 6, 24, and 48 h post-injection of 124I-CLR1404. The tumor volume was segmented using two standardized uptake value (SUV) threshold levels, two tumor-to-background ratio (TBR) threshold levels, and a T1 Gadolinium-enhanced MRI threshold. The dice similarity coefficient (DSC), jaccard similarity coefficient (JSC), and overlap volume (OV) metrics were calculated to compare differences in the MRI and PET contours. The therapeutic 131I-CLR1404 voxel-level dose distribution was calculated from the 124I-CLR1404 activity distribution using RAPID, a Geant4 Monte Carlo internal dosimetry platform. The TBR, SUV, and MRI tumor volumes ranged from 2.3-63.9 cc, 0.1-34.7 cc, and 0.4-11.8 cc, respectively. The average ± standard deviation (range) was 0.19 ± 0.13 (0.01-0.51), 0.30 ± 0.17 (0.03-0.67), and 0.75 ± 0.29 (0.05-1.00) for the JSC, DSC, and OV, respectively. The DSC and JSC values were small and the OV values were large for both the MRI-SUV and MRI-TBR combinations because the regions of PET uptake were generally larger than the MRI enhancement. Notable differences in the tumor dose volume histograms were observed for each patient. The mean (standard deviation) 131I-CLR1404 tumor doses ranged from 0.28-1.75 Gy GBq-1 (0.07-0.37 Gy GBq-1). The ratio of maximum-to-minimum mean doses for each patient ranged from 1.4-2.0. The tumor volume and the interpretation of the tumor dose is highly sensitive to the imaging modality, PET enhancement metric, and threshold level used for tumor volume segmentation. The large variations in tumor doses clearly demonstrate the need for standard protocols for multimodality tumor segmentation in TRT dosimetry.

Diapeutic cancer-targeting alkylphosphocholine analogs may advance management of brain malignancies.

The following is a special report on alkylphosphocholine analogs as targeted imaging and therapy agents for cancer, and their potential role in diagnosis and treatment in glioblastoma and brain metastases. These novel cancer-targeting agents display impressive tumor avidity with low background in the normal brain, and multimodal diagnostic imaging and therapy capabilities. The use of these agents may significantly improve diagnosis, treatment and post-treatment follow-up in patients with brain malignancies.

Metabolic Correlates of the Ictal-Interictal Continuum: FDG-PET During Continuous EEG.

BACKGROUND: Ictal-interictal continuum (IIC) continuous EEG (cEEG) patterns including periodic discharges and rhythmic delta activity are associated with poor outcome and in the appropriate clinical context, IIC patterns may represent "electroclinical" status epilepticus (SE). To clarify the significance of IIC patterns and their relationship to "electrographic" SE, we investigated FDG-PET imaging as a complementary metabolic biomarker of SE among patients with IIC patterns. METHODS: A single-center prospective clinical database was ascertained for patients undergoing FDG-PET during cEEG. Following MRI-PET co-registration, the maximum standardized uptake value in cortical and subcortical regions was compared to contralateral homologous and cerebellar regions. Consensus cEEG review and clinical rating of etiology and treatment response were performed retrospectively with blinding. Electrographic SE was classified as discrete seizures without interictal recovery or >3-Hz rhythmic IIC patterns. Electroclinical SE was classified as IIC patterns with electrographic and clinical response to anticonvulsants; clonic activity; or persistent post-ictal encephalopathy. RESULTS: Eighteen hospitalized subjects underwent FDG-PET during contemporaneous IIC patterns attributed to structural lesions (44 %), neuroinflammatory/neuroinfectious disease (39 %), or epilepsy (11 %). FDG-PET hypermetabolism was common (61 %) and predicted electrographic or electroclinical SE (sensitivity 79 % [95 % CI 53-93 %] and specificity 100 % [95 % CI 51-100 %]; p = 0.01). Excluding electrographic SE, hypermetabolism also predicted electroclinical SE (sensitivity 80 % [95 % CI 44-94 %] and specificity 100 % [95 % CI 51-100 %]; p = 0.01). CONCLUSIONS: In hospitalized patients with IIC EEG patterns, FDG-PET hypermetabolism is common and is a candidate metabolic biomarker of electrographic SE or electroclinical SE.

The sensitivity and specificity of F-DOPA PET in a movement disorder clinic.

Idiopathic Parkinson's disease (PD) is the second most common neurodegenerative disorder. Early PD may present a diagnostic challenge with broad differential diagnoses that are not associated with nigral degeneration or striatal dopamine deficiency. Therefore, the early clinical diagnosis alone may not be accurate and this reinforces the importance of functional imaging targeting the pathophysiology of the disease process. (18)F-DOPA L-6-[(18)F] fluoro-3,4-dihydroxyphenylalnine ((18)F-DOPA) is a positron emission tomography (PET) agent that measures the uptake of dopamine precursors for assessment of presynaptic dopaminergic integrity and has been shown to accurately reflect the monoaminergic disturbances in PD. In this study, we aim to illustrate our local experience to determine the accuracy of (18)F-DOPA PET for diagnosis of PD. We studied a total of 27 patients. A retrospective analysis was carried out for all patients that underwent (18)F-DOPA PET brain scan for motor symptoms suspicious for PD between 2001-2008. Both qualitative and semi-quantitative analyses of the scans were performed. The patient's medical records were then assessed for length of follow-up, response to levodopa, clinical course of illness, and laterality of symptoms at time of (18)F-DOPA PET. The eventual diagnosis by the referring neurologist, movement disorder specialist, was used as the reference standard for further analysis. Of the 28 scans, we found that one was a false negative, 20 were true positives, and 7 were true negatives. The resultant values are Sensitivity 95.4% (95% CI: 100%-75.3%), Specificity 100% (95% CI: 100%-59.0%), PPV 100% (95% CI 100%-80.7%), and NPV 87.5% (95% CI: 99.5%-50.5%).

(18)F-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 (18)F-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 (18)F-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 R(2) of 0.11.

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.

Phospholipid ether analogs for the detection of colorectal tumors.

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: 1.76×10(10) vs 3.27×10(9) 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.

Alkylphosphocholine analogs for broad-spectrum cancer imaging and therapy.

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 ((124)I) or molecular radiotherapeutic ((131)I) agent. CLR1404 analogs displayed prolonged tumor-selective retention in 55 in vivo rodent and human cancer and cancer stem cell models. (131)I-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 (124)I-CLR1404 or (131)I-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 (124)I-CLR1404 tumor imaging for planning (131)I-CLR1404 therapy.

Amyloid burden and neural function in people at risk for Alzheimer's Disease.

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 (Aß+), 41% indeterminate (Aßi), and 41% negative (Aß-). Aß+ was associated with older age, female sex, and showed trends for maternal family history of AD and APOE4. Relative to the Aß- group, Aß+ and Aßi participants had increased glucose metabolism in the bilateral thalamus; Aß+ participants also had increased metabolism in the bilateral superior temporal gyrus. Aß+ participants exhibited increased gray matter in the lateral parietal lobe bilaterally relative to the Aß- 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.

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.