A platform-independent AI tumor lineage and site (ATLAS) classifier.

Histopathologic diagnosis and classification of cancer plays a critical role in guiding treatment. Advances in next-generation sequencing have ushered in new complementary molecular frameworks. However, existing approaches do not independently assess both site-of-origin (e.g. prostate) and lineage (e.g. adenocarcinoma) and have minimal validation in metastatic disease, where classification is more difficult. Utilizing gradient-boosted machine learning, we developed ATLAS, a pair of separate AI Tumor Lineage and Site-of-origin models from RNA expression data on 8249 tumor samples. We assessed performance independently in 10,376 total tumor samples, including 1490 metastatic samples, achieving an accuracy of 91.4% for cancer site-of-origin and 97.1% for cancer lineage. High confidence predictions (encompassing the majority of cases) were accurate 98-99% of the time in both localized and remarkably even in metastatic samples. We also identified emergent properties of our lineage scores for tumor types on which the model was never trained (zero-shot learning). Adenocarcinoma/sarcoma lineage scores differentiated epithelioid from biphasic/sarcomatoid mesothelioma. Also, predicted lineage de-differentiation identified neuroendocrine/small cell tumors and was associated with poor outcomes across tumor types. Our platform-independent single-sample approach can be easily translated to existing RNA-seq platforms. ATLAS can complement and guide traditional histopathologic assessment in challenging situations and tumors of unknown primary.

Using 18F-DCFPyL Prostate-Specific Membrane Antigen-Directed Positron Emission Tomography/Magnetic Resonance Imaging to Define Intraprostatic Boosts for Prostate Stereotactic Body Radiation Therapy.

Purpose: The recently reported FLAME trial demonstrated a biochemical disease-free survival benefit to using a focal intraprostatic boost to multiparametric magnetic resonance imaging (mpMRI)-identified lesions in men with localized prostate cancer treated with definitive radiation therapy. Prostate-specific membrane antigen (PSMA)-directed positron emission tomography (PET) may identify additional areas of disease. In this work, we investigated using both PSMA PET and mpMRI in planning focal intraprostatic boosts using stereotactic body radiation therapy (SBRT). Methods and Materials: We evaluated a cohort of patients (n = 13) with localized prostate cancer who were imaged with 2-(3-(1-carboxy-5-[(6-[18F]fluoro-pyridine-2-carbonyl)-amino]-pentyl)-ureido)-pentanedioic acid (18F-DCFPyL) PET/MRI on a prospective imaging trial before undergoing definitive therapy. The number of lesions concordant (overlapping) and discordant (no overlap) on PET and MRI was assessed. Overlap between concordant lesions was evaluated using the Dice and Jaccard similarity coefficients. Prostate SBRT plans were created fusing the PET/MRI imaging to computed tomography scans acquired the same day. Plans were created using only MRI-identified lesions, only PET-identified lesions, and the combined PET/MRI lesions. Coverage of the intraprostatic lesions and doses to the rectum and urethra were assessed for each of these plans. Results: The majority of lesions (21/39, 53.8%) were discordant between MRI and PET, with more lesions seen by PET alone (12) than MRI alone (9). Of lesions that were concordant between PET and MRI, there were still areas that did not overlap between scans (average Dice coefficient, 0.34). Prostate SBRT planning using all lesions to define a focal intraprostatic boost provided the best coverage of all lesions without compromising constraints on the rectum and urethra. Conclusions: Using both mpMRI and PSMA-directed PET may better identify all areas of gross disease within the prostate. Using both imaging modalities could improve the planning of focal intraprostatic boosts.

Toxicity and Patient-Reported Quality-of-Life Outcomes After Prostate Stereotactic Body Radiation Therapy With Focal Boost to Magnetic Resonance Imaging-Identified Prostate Cancer Lesions: Results of a Phase 2 Trial.

PURPOSE: In this prospective phase 2 trial, we investigated the toxicity and patient-reported quality-of-life outcomes in patients treated with stereotactic body radiation therapy (SBRT) to the prostate gland and a simultaneous focal boost to magnetic resonance imaging (MRI)-identified intraprostatic lesions while also de-escalating dose to the adjacent organs at risk. METHODS AND MATERIALS: Eligible patients included low- or intermediate-risk prostate cancer (Gleason score ≤7, prostate specific antigen ≤20, T stage ≤2b). SBRT was prescribed to 40 Gy in 5 fractions delivered every other day to the prostate, with any areas of high disease burden (MRI-identified prostate imaging reporting and data system 4 or 5 lesions) simultaneously escalated to 42.5 to 45 Gy and areas overlapping organs at risk (within 2 mm of urethra, rectum, and bladder) constrained to 36.25 Gy (n = 100). Patients without a pretreatment MRI or without MRI-identified lesions were treated to dose of 37.5 Gy with no focal boost (n = 14). RESULTS: From 2015 to 2022, a total of 114 patients were enrolled with a median follow-up of 42 months. No acute or late grade 3+ gastrointestinal (GI) toxicity was observed. One patient developed late grade 3 genitourinary (GU) toxicity at 16 months. In patients treated with focal boost (n = 100), acute grade 2 GU and GI toxicity was seen in 38% and 4% of patients, respectively. Cumulative late grade 2+ GU and GI toxicities at 24 months were 13% and 5% respectively. Patient-reported outcomes showed no significant long-term change from baseline in urinary, bowel, hormonal, or sexual quality-of-life scores after treatment. CONCLUSIONS: SBRT to a dose of 40 Gy to the prostate gland with a simultaneous focal boost up to 45 Gy is well tolerated with similar rates of acute and late grade 2+ GI and GU toxicity as seen in other SBRT regimens without intraprostatic boost. Moreover, no significant long-term changes were seen in patient-reported urinary, bowel, or sexual outcomes from pretreatment baseline.

A clinical-grade liquid biomarker detects neuroendocrine differentiation in prostate cancer.

BackgroundNeuroendocrine prostate cancer (NEPC) is an aggressive subtype, the presence of which changes the prognosis and management of metastatic prostate cancer.MethodsWe performed analytical validation of a Circulating Tumor Cell (CTC) multiplex RNA qPCR assay to identify the limit of quantification (LOQ) in cell lines, synthetic cDNA, and patient samples. We next profiled 116 longitudinal samples from a prospectively collected institutional cohort of 17 patients with metastatic prostate cancer (7 NEPC, 10 adenocarcinoma) as well as 265 samples from 139 patients enrolled in 3 adenocarcinoma phase II trials of androgen receptor signaling inhibitors (ARSIs). We assessed a NEPC liquid biomarker via the presence of neuroendocrine markers and the absence of androgen receptor (AR) target genes.ResultsUsing the analytical validation LOQ, liquid biomarker NEPC detection in the longitudinal cohort had a per-sample sensitivity of 51.35% and a specificity of 91.14%. However, when we incorporated the serial information from multiple liquid biopsies per patient, a unique aspect of this study, the per-patient predictions were 100% accurate, with a receiver-operating-curve (ROC) AUC of 1. In the adenocarcinoma ARSI trials, the presence of neuroendocrine markers, even while AR target gene expression was retained, was a strong negative prognostic factor.ConclusionOur analytically validated CTC biomarker can detect NEPC with high diagnostic accuracy when leveraging serial samples that are only feasible using liquid biopsies. Patients with expression of NE genes while retaining AR-target gene expression may indicate the transition to neuroendocrine differentiation, with clinical characteristics consistent with this phenotype.FundingNIH (DP2 OD030734, 1UH2CA260389, R01CA247479, and P30 CA014520), Department of Defense (PC190039 and PC200334), and Prostate Cancer Foundation (Movember Foundation - PCF Challenge Award).

Longitudinal Molecular Profiling of Circulating Tumor Cells in Metastatic Renal Cell Carcinoma.

PURPOSE: Liquid biopsies in metastatic renal cell carcinoma (mRCC) provide a unique approach to understand the molecular basis of treatment response and resistance. This is particularly important in the context of immunotherapies, which target key immune-tumor interactions. Unlike metastatic tissue biopsies, serial real-time profiling of mRCC is feasible with our noninvasive circulating tumor cell (CTC) approach. METHODS: We collected 457 longitudinal liquid biopsies from 104 patients with mRCC enrolled in one of two studies, either a prospective cohort or a phase II multicenter adaptive immunotherapy trial. Using a novel CTC capture and automated microscopy platform, we profiled CTC enumeration and expression of HLA I and programmed cell death-ligand 1 (PD-L1). Given their diametric immunological roles, we focused on the HLA I to PD-L1 ratio (HP ratio). RESULTS: Patients with radiographic responses showed significantly lower CTC abundances throughout treatment. Furthermore, patients whose CTC enumeration trajectory was in the highest quartile (> 0.12 CTCs/mL annually) had shorter overall survival (median 17.0 months v 21.1 months, P < .001). Throughout treatment, the HP ratio decreased in patients receiving immunotherapy but not in patients receiving tyrosine kinase inhibitors. Patients with an HP ratio trajectory in the highest quartile (≥ 0.0012 annually) displayed significantly shorter overall survival (median 18.4 months v 21.2 months, P = .003). CONCLUSION: In the first large longitudinal CTC study in mRCC to date to our knowledge, we identified the prognostic importance of CTC enumeration and the change over time of both CTC enumeration and the HP ratio. These insights into changes in both tumor burden and the molecular profile of tumor cells in response to different treatments provide potential biomarkers to predict and monitor response to immunotherapy in mRCC.

Combining Stereotactic Body Radiotherapy and Microwave Ablation Appears Safe and Feasible for Renal Cell Carcinoma in an Early Series.

Microwave (MW) ablation and stereotactic body radiation therapy (SBRT) are both used in treating inoperable renal cell carcinoma (RCC). MW ablation and SBRT have potentially complementary advantages and limitations. Combining SBRT and MW ablation may optimize tumor control and toxicity for patients with larger (> 5 cm) RCCs or those with vascular involvement. Seven patients with RCC were treated at our institution with combination of SBRT and MW ablation, median tumor size of 6.4 cm. Local control was 100% with a median follow-up of 15 months. Four patients experienced grade 2 nausea during SBRT. Three patients experienced toxicities after MW ablation, 2 with grade 1 hematuria and 1 with grade 3 retroperitoneal bleed/collecting system injury. Median eGFR (estimated glomerular filtration rate) preceding and following SBRT and MW ablation was 69 mL/min/1.73 m2 and 68 mL/min/1.73 m2 (P = .19), respectively. In patients who are not surgical candidates, larger RCCs or those with vascular invasion are challenging to treat. Combination treatment with SBRT and MW ablation may balance the risks and benefits of both therapies and demonstrates high local control in our series. MW ablation and SBRT have potentially complementary advantages and limitations.

Standardized Uptake Value for 18F-Fluorodeoxyglucose Is a Marker of Inflammatory State and Immune Infiltrate in Cervical Cancer.

PURPOSE: Chemoradiotherapy for locally advanced cervical cancer fails in over a third of patients. Biomarkers with therapeutic implications are therefore needed. We investigated the relationship between an established prognostic marker, maximum standardized uptake value (SUVmax) on 18F-fluorodeoxyglucose positron emission tomography, and the inflammatory and immune state of cervical cancers. EXPERIMENTAL DESIGN: An SUVmax most prognostic for freedom from progression (FFP) was identified and compared with known prognostic clinical variables in a cohort of 318 patients treated with definitive radiation with prospectively collected clinical data. Gene set enrichment analysis (GSEA) and CIBERSORT of whole-transcriptome data from 68 patients were used to identify biological pathways and immune cell subpopulations associated with high SUVmax. IHC using a tissue microarray (TMA, N = 82) was used to validate the CIBERSORT findings. The impact of macrophages on cervical cancer glucose metabolism was investigated in coculture experiments. RESULTS: SUVmax <11.4 was most prognostic for FFP (P = 0.001). The GSEA showed that high SUVmax is associated with increased gene expression of inflammatory pathways, including JAK/STAT3 signaling. CIBERSORT and CD68 staining of the TMA showed high SUVmax tumors are characterized by a monocyte-predominant immune infiltrate. Coculture of cervical cancer cells with macrophages or macrophage-conditioned media altered glucose uptake, and IL6 and JAK/STAT3 signaling contribute to this effect. CONCLUSIONS: SUVmax is a prognostic marker in cervical cancer that is associated with activation of inflammatory pathways and tumor infiltration of myeloid-derived immune cells, particularly macrophages. Macrophages contribute to changes in cervical cancer glucose metabolism.See related commentary by Williamson et al., p. 4136.

Alteration of Cellular Reduction Potential Will Change 64Cu-ATSM Signal With or Without Hypoxia.

Therapies targeting reductive/oxidative (redox) metabolism hold potential in cancers resistant to chemotherapy and radiation. A redox imaging marker would help identify cancers susceptible to redox-directed therapies. Copper(II)-diacetyl-bis(4-methylthiosemicarbazonato) (Cu-ATSM) is a PET tracer developed for hypoxia imaging that could potentially be used for this purpose. We aimed to demonstrate that Cu-ATSM signal is dependent on cellular redox state, irrespective of hypoxia. Methods: We investigated the relationship between 64Cu-ATSM signal and redox state in human cervical and colon cancer cells. We altered redox state using drug strategies and single-gene mutations in isocitrate dehydrogenases (IDH1/2). Concentrations of reducing molecules were determined by spectrophotometry and liquid chromatography-mass spectrometry and compared with 64Cu-ATSM signal in vitro. Mouse models of cervical cancer were used to evaluate the relationship between 64Cu-ATSM signal and levels of reducing molecules in vivo, as well as to evaluate the change in 64Cu-ATSM signal after redox-active drug treatment. Results: A correlation exists between baseline 64Cu-ATSM signal and cellular concentration of glutathione, nicotinamide adenine dinucleotide phosphate (NADPH), and nicotinamide adenine dinucleotide (NADH). Altering NADH and NADPH metabolism using drug strategies and IDH1 mutations resulted in significant changes in 64Cu-ATSM signal under normoxic conditions. Hypoxia likewise changed 64Cu-ATSM signal, but treatment of hypoxic cells with redox-active drugs resulted in a more dramatic change than hypoxia alone. A significant difference in NADPH was seen between cervical tumor orthotopic implants in vivo, without a corresponding difference in 64Cu-ATSM signal. After treatment with ß-lapachone, there was a change in 64Cu-ATSM signal in xenograft tumors smaller than 50 mg but not in larger tumors. Conclusion:64Cu-ATSM signal reflects redox state, and altering redox state impacts 64Cu-ATSM metabolism. Our animal data suggest there are other modulating factors in vivo. These findings have implications for the use of 64Cu-ATSM as a predictive marker for redox therapies, though further in vivo work is needed.

Manipulation of Glucose and Hydroperoxide Metabolism to Improve Radiation Response.

Dysregulated glucose and redox metabolism are near universal features of cancers. They therefore represent potential selectively toxic metabolic targets. This review outlines the preclinical and clinical data for targeting glucose and hydroperoxide metabolism in cancer, with a focus on drug strategies that have the most available evidence. In particular, inhibition of glycolysis using 2-deoxyglucose, and inhibition of redox metabolism using the glutathione pathway inhibitor buthionine sulfoximine and the thioredoxin pathway inhibitor auranofin, have shown promise in preclinical studies to increase sensitivity to chemotherapy and radiation by increasing intracellular oxidative stress. Combined inhibition of glycolysis, glutathione, and thioredoxin pathways sensitizes highly glycolytic, radioresistant cancer models in vitro and in vivo. Although the preclinical data support this approach, clinical data are limited to exploratory trials using a single drug in combination with either chemotherapy or radiation. Open research questions include optimizing drug strategies for targeting glycolysis and redox metabolism, determining the appropriate timing for administering this therapy with concurrent chemotherapy and radiation, and identifying biomarkers to determine the cancers that would benefit most from this approach. Given the quality of preclinical evidence, dual targeting of glycolysis and redox metabolism in combination with chemotherapy and radiation should be further evaluated in clinical trials.

Pretreatment metabolic tumor volume as a prognostic factor in HPV-associated oropharyngeal cancer in the context of AJCC 8th edition staging.

BACKGROUND: This study evaluates the prognostic significance of 18 F-fluorodeoxyglucose-positron emission tomography ([F-18]FDG-PET)-derived metabolic tumor volume (MTV) in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinomas (OPSCCs) in the context of AJCC 8th edition staging. METHODS: We performed a retrospective study of HPV-associated OPSCCs treated with postoperative or definitive radiation. The prognostic significance of pretreatment MTV for freedom from recurrence (FFR), freedom from distant metastasis (FFDM), and overall survival (OS) was determined using Kaplan-Meier analysis. Multivariate analysis (MVA) was performed using Cox regression. RESULTS: In this 153-patient cohort, stratifying by the optimum MTV (24 cm3 ) was prognostic for FFR (P = .0002), FFDM (P = .001), and OS (P < .0001). Metabolic tumor volume (MTV) was prognostic of FFR in AJCC 8th edition stage I/II (P = .03), and stage III patients (P = .04). On multivariate analysis only MTV was a significant factor for OS. CONCLUSION: Metabolic tumor volume (MTV) is a significant prognostic factor in HPV-associated OPSCCs, independent of AJCC 8th edition stage.

Spatial relationship of 2-deoxy-2-[18F]-fluoro-D-glucose positron emission tomography and magnetic resonance diffusion imaging metrics in cervical cancer.

BACKGROUND: This study investigated the spatial relationship of 2-deoxy-2-[18F]-fluoro-D-glucose positron emission tomography ([18F]FDG-PET) standardized uptake values (SUVs) and apparent diffusion coefficients (ADCs) derived from magnetic resonance (MR) diffusion imaging on a voxel level using simultaneously acquired PET/MR data. We performed an institutional retrospective analysis of patients with newly diagnosed cervical cancer who received a pre-treatment simultaneously acquired [18F]FDG-PET/MR. Voxel SUV and ADC values, and global tumor metrics including maximum SUV (SUVmax), mean ADC (ADCmean), and mean tumor-to-muscle ADC ratio (ADCT/M) were compared. The impacts of histology, grade, and tumor volume on the voxel SUV to ADC relationship were also evaluated. The potential prognostic value of the voxel SUV/ADC relationship was evaluated in an exploratory analysis using Kaplan-Meier/log-rank and univariate Cox analysis. RESULTS: Seventeen patients with PET/MR scans were identified. There was a significant inverse correlation between SUVmax and ADCmean, and SUVmax and ADCT/M. In the voxelwise analysis, squamous cell carcinomas (SCCAs) and poorly differentiated tumors showed a consistent significant inverse correlation between voxel SUV and ADC values; adenocarcinomas (AdenoCAs) and well/moderately differentiated tumors did not. The strength of the voxel SUV/ADC correlation varied with metabolic tumor volume (MTV). On log-rank analysis, the correlation between voxel SUV/ADC values was prognostic of disease-free survival (DFS). CONCLUSIONS: In this hypothesis-generating study, a consistent inverse correlation between voxel SUV and ADC values was seen in SCCAs and poorly differentiated tumors. On univariate statistical analysis, correlation between voxel SUV and ADC values was prognostic for DFS.

Radioresistant Cervical Cancers Are Sensitive to Inhibition of Glycolysis and Redox Metabolism.

Highly glycolytic cervical cancers largely resist treatment by cisplatin and coadministered pelvic irradiation as the present standard of care. In this study, we investigated the effects of inhibiting glycolysis and thiol redox metabolism to evaluate them as alternate treatment strategies in these cancers. In a panel of multiple cervical cancer cell lines, we evaluated sensitivity to inhibition of glycolysis (2-deoxyglucose, 2-DG) with or without simultaneous inhibition of glutathione and thioredoxin metabolism (BSO/AUR). Intracellular levels of total and oxidized glutathione, thioredoxin reductase activity, and indirect measures of intracellular reactive oxygen species were compared before and after treatment. Highly radioresistant cells were the most sensitive to 2-DG, whereas intermediate radioresistant cells were sensitive to 2-DG plus BSO/AUR. In response to 2-DG/BSO/AUR treatment, we observed increased levels of intracellular oxidized glutathione, redox-sensitive dye oxidation, and decreased glucose utilization via multiple metabolic pathways including the tricarboxylic acid cycle. 2-DG/BSO/AUR treatment delayed the growth of tumors composed of intermediate radioresistant cells and effectively radiosensitized these tumors at clinically relevant radiation doses both in vitro and in vivo Overall, our results support inhibition of glycolysis and intracellular redox metabolism as an effective alternative drug strategy for the treatment of highly glycolytic and radioresistant cervical cancers.Significance: This study suggests a simple metabolic approach to strike at an apparent Achilles' heel in highly glycolytic, radioresistant forms of cervical cancers, possibly with broader applications in cancer therapy. Cancer Res; 78(6); 1392-403. ©2018 AACR.

Assessment of the treatment approach and survival outcomes in a modern cohort of patients with atypical teratoid rhabdoid tumors using the National Cancer Database.

BACKGROUND: Atypical teratoid rhabdoid tumors (ATRTs) are rare brain tumors that occur primarily in children under the age of 3 years. This report evaluates the treatment approach and survival outcomes in a large cohort of patients treated in the United States. METHODS: Using the National Cancer Database, the analysis included all ATRT patients aged 0 to 18 years who were diagnosed between 2004 and 2012 and had complete treatment data. RESULTS: Three hundred sixty-one ATRT patients were evaluated. The 5-year overall survival (OS) rate was 29.9%, and it was significantly lower for children who were less than 3 years old (5-year OS, 27.7%) versus those who were 3 years old or older (5-year OS, 37.5%; P < .001). The best outcome was seen for patients with localized disease who received trimodality therapy (surgery, chemotherapy, and radiation therapy [RT]) with a 5-year OS rate of 46.8%. The utilization of trimodality therapy significantly increased during the study period (27.7% in 2004-2008 vs 45.1% in 2009-2012; P < .01), largely because of the increased use of RT. In a multivariate analysis, treatment that did not utilize trimodality therapy was associated with significantly worse OS (hazard ratio, 2.52; 95% confidence interval (1.82-3.51). Children aged 0 to 2 years were significantly less likely to receive trimodality therapy because of decreased utilization of RT in this age group. CONCLUSIONS: The use of trimodality therapy significantly increased during the study period and was associated with improved outcomes. For patients with localized disease who received trimodality therapy, the OS rate at 5 years approached 50%. However, further research into the optimal management of children less than 3 years old is needed because of their significantly worse OS in comparison with older children. Cancer 2017;123:682-687. © 2016 American Cancer Society.

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%).

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.

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.

Improved kinetic analysis of dynamic PET data with optimized HYPR-LR.

PURPOSE: Highly constrained backprojection-local reconstruction (HYPR-LR) has made a dramatic impact on magnetic resonance angiography (MRA) and shows promise for positron emission tomography (PET) because of the improvements in the signal-to-noise ratio (SNR) it provides dynamic images. For PET in particular, HYPR-LR could improve kinetic analysis methods that are sensitive to noise. In this work, the authors closely examine the performance of HYPR-LR in the context of kinetic analysis, they develop an implementation of the algorithm that can be tailored to specific PET imaging tasks to minimize bias and maximize improvement in variance, and they provide a framework for validating the use of HYPR-LR processing for a particular imaging task. METHODS: HYPR-LR can introduce errors into non sparse PET studies that might bias kinetic parameter estimates. An implementation of HYPR-LR is proposed that uses multiple temporally summed composite images that are formed based on the kinetics of the tracer being studied (HYPR-LR-MC). The effects of HYPR-LR-MC and of HYPR-LR using a full composite formed with all the frames in the study (HYPR-LR-FC) on the kinetic analysis of Pittsburgh compound-B ([11C]-PIB) are studied. HYPR-LR processing is compared to spatial smoothing. HYPR-LR processing was evaluated using both simulated and human studies. Nondisplaceable binding potential (BP(ND)) parametric images were generated from fifty noise realizations of the same numerical phantom and eight [(11)C]-PIB positive human scans before and after HYPR-LR processing or smoothing using the reference region Logan graphical method and receptor parametric mapping (RPM2). The bias and coefficient of variation in the frontal and parietal cortex in the simulated parametric images were calculated to evaluate the absolute performance of HYPR-LR processing. Bias in the human data was evaluated by comparing parametric image BP(ND) values averaged over large regions of interest (ROIs) to Logan estimates of the BP(ND) from TACs averaged over the same ROIs. Variance was assessed qualitatively in the parametric images and semiquantitatively by studying the correlation between voxel BP(ND) estimates from Logan analysis and RPM2. RESULTS: Both the simulated and human data show that HYPR-LR-FC overestimates BP(ND) values in regions of high [(11)C]-PIB uptake. HYPR-LR-MC virtually eliminates this bias. Both implementations of HYPR-LR reduce variance in the parametric images generated with both Logan analysis and RPM2, and HYPR-LR-FC provides a greater reduction in variance. This reduction in variance nearly eliminates the noise-dependent Logan bias. The variance reduction is greater for the Logan method, particularly for HYPR-LR-MC, and the variance in the resulting Logan images is comparable to that in the RPM2 images. HYPR-LR processing compares favorably with spatial smoothing, particularly when the data are analyzed with the Logan method, as it provides a reduction in variance with no loss of spatial resolution. CONCLUSIONS: HYPR-LR processing shows significant potential for reducing variance in parametric images, and can eliminate the noise-dependent Logan bias. HYPR-LR-FC processing provides the greatest reduction in variance but introduces a positive bias into the BP(ND) of high-uptake border regions. The proposed method for forming HYPR composite images, HYPR-LR-MC, eliminates this bias at the cost of less variance reduction.

Application of a whole-body pharmacokinetic model for targeted radionuclide therapy to NM404 and FLT.

We have previously developed a model that provides relative dosimetry estimates for targeted radionuclide therapy (TRT) agents. The whole-body and tumor pharmacokinetic (PK) parameters of this model can be noninvasively measured with molecular imaging, providing a means of comparing potential TRT agents. Parameter sensitivities and noise will affect the accuracy and precision of the estimated PK values and hence dosimetry estimates. The aim of this work is to apply a PK model for TRT to two agents with different magnitudes of clearance rates, NM404 and FLT, explore parameter sensitivity with respect to time and investigate the effect of noise on parameter precision and accuracy. Twenty-three tumor bearing mice were injected with a 'slow-clearing' agent, (124)I-NM404 (n = 10), or a 'fast-clearing' agent, (18)F-FLT (3'-deoxy-3'-fluorothymidine) (n = 13) and imaged via micro-PET/CT pseudo-dynamically or dynamically, respectively. Regions of interest were drawn within the heart and tumor to create time-concentration curves for blood pool and tumor. PK analysis was performed to estimate the mean and standard error of the central compartment efflux-to-influx ratio (k(12)/k(21)), central elimination rate constant (k(el)), and tumor influx-to-efflux ratio (k(34)/k(43)), as well as the mean and standard deviation of the dosimetry estimates. NM404 and FLT parameter estimation results were used to analyze model accuracy and parameter sensitivity. The accuracy of the experimental sampling schedule was compared to that of an optimal sampling schedule found using Cramer-Rao lower bounds theory. Accuracy was assessed using correlation coefficient, bias and standard error of the estimate normalized to the mean (SEE/mean). The PK parameter estimation of NM404 yielded a central clearance, k(el) (0.009 ± 0.003 h(-1)), normal body retention, k(12)/k(21) (0.69 ± 0.16), tumor retention, k(34)/k(43) (1.44 ± 0.46) and predicted dosimetry, D(tumor) (3.47 ± 1.24 Gy). The PK parameter estimation of FLT yielded a central elimination rate constant, k(el) (0.050 ± 0.025 min(-1)), normal body retention, k(12)/k(21) (2.21 ± 0.62) and tumor retention, k(34)/k(43) (0.65 ± 0.17), and predicted dosimetry, D(tumor) (0.61 ± 0.20 Gy). Compared to experimental sampling, optimal sampling decreases the dosimetry bias and SEE/mean for NM404; however, it increases bias and decreases SEE/mean for FLT. For both NM404 and FLT, central compartment efflux rate constant, k(12), and central compartment influx rate constant, k(21), possess mirroring sensitivities at relatively early time points. The instantaneous concentration in the blood, C(0), was most sensitive at early time points; central elimination, k(el), and tumor efflux, k(43), are most sensitive at later time points. A PK model for TRT was applied to both a slow-clearing, NM404, and a fast-clearing, FLT, agents in a xenograft murine model. NM404 possesses more favorable PK values according to the PK TRT model. The precise and accurate measurement of k(12), k(21), k(el), k(34) and k(43) will translate into improved and precise dosimetry estimations. This work will guide the future use of this PK model for assessing the relative effectiveness of potential TRT agents.