Cu-ATSM PET Research Articles

Precise Evaluation of Striatal Oxidative Stress Corrected for Severity of Dopaminergic Neuronal Degeneration in Patients with Parkinson’s Disease: A Study with 62Cu-ATSM PET and 123I-FP-CIT SPECT

Background: This study sought to precisely evaluate striatal oxidative stress and its relationship with the disease severity in Parkinson’s disease (PD) using double brain imaging, ⁶²Cu-diacetyl-bis (N⁴-methylthiosemicarbazone) (⁶²Cu-ATSM) PET and ¹²³I-FP-CIT SPECT. Methods: Nine PD patients were studied with brain ⁶²Cu-ATSM PET for oxidative stress and ¹²³I-FP-CIT SPECT for the density of striatal dopamine transporter. Standardized uptake values (SUVs) were obtained from the delayed phase of dynamic ⁶²Cu-ATSM PET, and striatum-to-cerebellum SUV ratio (SUVR) was calculated. To correct the effect of neuronal loss in the striatum, ⁶²Cu-ATSM SUVR was corrected for striatal specific binding ratio (SBR) values of ¹²³I-FP-CIT (SUVR/SBR). Results: ⁶²Cu-ATSM SUVR without correction was not significantly correlated with disease severity estimated by the Unified Parkinson’s Disease Rating Scale (UPDRS) scores or ¹²³I-FP-CIT SBR. In contrast, the SUVR/SBR showed significant correlations with the UPDRS total and motor scores, and ¹²³I-FP-CIT SBR. Conclusion: Oxidative stress in the remaining striatal dopaminergic neurons estimated by SUVR/SBR was increased with disease severity in PD patients, suggesting that oxidative stress based on mitochondrial dysfunction contributes to promoting dopaminergic neuronal degeneration in PD. ⁶²Cu-ATSM PET with ¹²³I-FP-CIT SPECT correction would be a promising tool to evaluate dopaminergic neuronal oxidative stress in PD.

An imaging-based computational model for simulating angiogenesis and tumour oxygenation dynamics

Tumour growth, angiogenesis and oxygenation vary substantially among tumours and significantly impact their treatment outcome. Imaging provides a unique means of investigating these tumour-specific characteristics. Here we propose a computational model to simulate tumour-specific oxygenation changes based on the molecular imaging data. Tumour oxygenation in the model is reflected by the perfused vessel density. Tumour growth depends on its doubling time (Td) and the imaged proliferation. Perfused vessel density recruitment rate depends on the perfused vessel density around the tumour (sMVDtissue) and the maximum VEGF concentration for complete vessel dysfunctionality (VEGFmax). The model parameters were benchmarked to reproduce the dynamics of tumour oxygenation over its entire lifecycle, which is the most challenging test. Tumour oxygenation dynamics were quantified using the peak pO2 (pO2peak) and the time to peak pO2 (tpeak). Sensitivity of tumour oxygenation to model parameters was assessed by changing each parameter by 20%. tpeak was found to be more sensitive to tumour cell line related doubling time (~30%) as compared to tissue vasculature density (~10%). On the other hand, pO2peak was found to be similarly influenced by the above tumour- and vasculature-associated parameters (~30–40%). Interestingly, both pO2peak and tpeak were only marginally affected by VEGFmax (~5%). The development of a poorly oxygenated (hypoxic) core with tumour growth increased VEGF accumulation, thus disrupting the vessel perfusion as well as further increasing hypoxia with time. The model with its benchmarked parameters, is applied to hypoxia imaging data obtained using a [64Cu]Cu-ATSM PET scan of a mouse tumour and the temporal development of the vasculature and hypoxia maps are shown. The work underscores the importance of using tumour-specific input for analysing tumour evolution. An extended model incorporating therapeutic effects can serve as a powerful tool for analysing tumour response to anti-angiogenic therapies.

Predicting location of recurrence using FDG, FLT, and Cu-ATSM PET in canine sinonasal tumors treated with radiotherapy

Dose painting relies on the ability of functional imaging to identify resistant tumor subvolumes to be targeted for additional boosting. This work assessed the ability of FDG, FLT, and Cu-ATSM PET imaging to predict the locations of residual FDG PET in canine tumors following radiotherapy. Nineteen canines with spontaneous sinonasal tumors underwent PET/CT imaging with radiotracers FDG, FLT, and Cu-ATSM prior to hypofractionated radiotherapy. Therapy consisted of 10 fractions of 4.2 Gy to the sinonasal cavity with or without an integrated boost of 0.8 Gy to the GTV. Patients had an additional FLT PET/CT scan after fraction 2, a Cu-ATSM PET/CT scan after fraction 3, and follow-up FDG PET/CT scans after radiotherapy. Following image registration, simple and multiple linear and logistic voxel regressions were performed to assess how well pre- and mid-treatment PET imaging predicted post-treatment FDG uptake. R2 and pseudo R2 were used to assess the goodness of fits. For simple linear regression models, regression coefficients for all pre- and mid-treatment PET images were significantly positive across the population (P < 0.05). However, there was large variability among patients in goodness of fits: R2 ranged from 0.00 to 0.85, with a median of 0.12. Results for logistic regression models were similar. Multiple linear regression models resulted in better fits (median R2 = 0.31), but there was still large variability between patients in R2. The R2 from regression models for different predictor variables were highly correlated across patients (R ≈ 0.8), indicating tumors that were poorly predicted with one tracer were also poorly predicted by other tracers. In conclusion, the high inter-patient variability in goodness of fits indicates that PET was able to predict locations of residual tumor in some patients, but not others. This suggests not all patients would be good candidates for dose painting based on a single biological target.

Comment: Cu-ATSM to treat and image amyotrophic lateral sclerosis.

Diagnostic imaging for amyotrophic lateral sclerosis (ALS) has the potential to alleviate elements of uncertainty associated with the current diagnostic process and to improve probability of successful outcomes from therapeutic clinical trials via earlier enrollment and treatment of participants. Ikawa et al.1 describe outcomes from an assessment of 62Cu-ATSM in patients with ALS using PET. Selective accumulation of the radiotracer in the motor cortex of patients with ALS and its correlation with disease severity supports the use of this compound to image ALS via PET. Although the study involved a limited number of participants (12 ALS and 9 healthy controls), the outcomes are nonetheless encouraging. Increasing radioactive half-life of the tracer by using 64Cu-ATSM (12 hours) instead of 62Cu-ATSM (10 minutes) together with a longer postinjection imaging interval could afford greater sensitivity and thereby better insight to whether Cu-ATSM PET may be used for diagnostic purposes.

Increased oxidative stress is related to disease severity in the ALS motor cortex: A PET study.

To investigate cerebral oxidative stress based on an over-reductive state caused by mitochondrial dysfunction and its relationship to disease severity in patients with amyotrophic lateral sclerosis (ALS) using PET with [(62)Cu]diacetyl-bis(N(4)-methylthiosemicarbazone) ((62)Cu-ATSM). Twelve patients with ALS and 9 age-matched healthy controls underwent a 20-minute dynamic brain PET scan after (62)Cu-ATSM injection. The standardized uptake value (SUV) images obtained from the last 10 minutes of frames were normalized by the global mean (nSUV). Regional (62)Cu-ATSM retention in the nSUV images was compared between groups using statistical parametric mapping (SPM) and region of interest (ROI) analysis. Secondary analyses evaluated the correlations between regional nSUVs and the clinical characteristics of the participants. In SPM mapping, patients with ALS showed a significantly greater accumulation of (62)Cu-ATSM compared to controls in the bilateral cortices around the central sulcus, including the motor cortex, and the right superior parietal lobule. ROI analysis also revealed significantly greater nSUVs in patients than controls in these regions. Increases in nSUV for these regions were associated with decreases in the revised ALS Functional Rating Scale score, suggesting a good correlation with the severity of ALS. In controls, age was correlated with nSUV for the bilateral cortices around the central sulcus, although this correlation was not observed in patients with ALS. (62)Cu-ATSM PET imaging demonstrated increased oxidative stress based on an over-reductive state, primarily in the motor cortex, in patients with ALS. The magnitude of oxidative stress correlated well with clinical severity, indicating that it may be associated with neurodegenerative changes in ALS.

Molecular Imaging Biomarkers of Resistance to Radiation Therapy for Spontaneous Nasal Tumors in Canines

Imaging biomarkers of resistance to radiation therapy can inform and guide treatment management. Most studies have so far focused on assessing a single imaging biomarker. The goal of this study was to explore a number of different molecular imaging biomarkers as surrogates of resistance to radiation therapy. Twenty-two canine patients with spontaneous sinonasal tumors were treated with accelerated hypofractionated radiation therapy, receiving either 10 fractions of 4.2 Gy each or 10 fractions of 5.0 Gy each to the gross tumor volume. Patients underwent fluorodeoxyglucose (FDG)-, fluorothymidine (FLT)-, and Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM)-labeled positron emission tomography/computed tomography (PET/CT) imaging before therapy and FLT and Cu-ATSM PET/CT imaging during therapy. In addition to conventional maximum and mean standardized uptake values (SUV(max); SUV(mean)) measurements, imaging metrics providing response and spatiotemporal information were extracted for each patient. Progression-free survival was assessed according to response evaluation criteria in solid tumor. The prognostic value of each imaging biomarker was evaluated using univariable Cox proportional hazards regression. Multivariable analysis was also performed but was restricted to 2 predictor variables due to the limited number of patients. The best bivariable model was selected according to pseudo-R(2). The following variables were significantly associated with poor clinical outcome following radiation therapy according to univariable analysis: tumor volume (P=.011), midtreatment FLT SUV(mean) (P=.018), and midtreatment FLT SUV(max) (P=.006). Large decreases in FLT SUV(mean) from pretreatment to midtreatment were associated with worse clinical outcome (P=.013). In the bivariable model, the best 2-variable combination for predicting poor outcome was high midtreatment FLT SUV(max) (P=.022) in combination with large FLT response from pretreatment to midtreatment (P=.041). In addition to tumor volume, pronounced tumor proliferative response quantified using FLT PET, especially when associated with high residual FLT PET at midtreatment, is a negative prognostic biomarker of outcome in canine tumors following radiation therapy. Neither FDG PET nor Cu-ATSM PET were predictive of outcome.

Predicting Location of Recurrence Using FDG, FLT, and Cu-ATSM PET in Canine Sinonasal Tumors Treated With Radiation Therapy

Biologically-conformal radiation therapy relies on the ability of functional imaging to identify resistant tumor subvolumes to be targeted for additional boosting. The goal of this work was to assess the ability of FDG, FLT, and Cu-ATSM PET imaging to predict the locations of recurrent tumor following radiation therapy, as assessed by follow-up FDG PET, in canine sinonasal tumors.

PET With 62Cu-ATSM and 62Cu-PTSM Is a Useful Imaging Tool for Hypoxia and Perfusion in Pulmonary Lesions

Hypoxia is a characteristic of many tumors and portends a worse prognosis in lung, cervical, prostate, and rectal cancers. Unlike the others, lung cancers present a unique challenge in measuring hypoxia, with invasive biopsies and higher rates of complications. Noninvasive imaging studies detecting hypoxia using isotopes of copper-diacetyl-bis(N4-methylthiosemicarbazone) ((62)Cu-ATSM) have predicted prognosis and treatment outcomes in some small feasibility trials. These images, however, may not identify all areas of hypoxia. Hence, we hypothesize that the addition of another PET imaging agent, copper-pyruvaldehyde-bis(N4-methylthiosemicarbazone) ((62)Cu-PTSM), which can detect areas of perfusion, can augment the information obtained in (62)Cu-ATSM PET scans. To characterize tumors on the basis of both perfusion and hypoxia, 10 patients were studied using both (62)Cu-ATSM and (62)Cu-PTSM PET scans. In addition, proteomic arrays looking at specific proangiogenic, survival, and proinflammatory targets were assessed. Six of 10 patients had evaluable PET scans. Our initial experience of characterizing lung tumor hypoxia using (62)Cu-ATSM and (62)Cu-PTSM PET scans showed that visualization of areas with hypoxia normalized for perfusion is feasible. All studied tumors exhibited some hypoxia. Despite the small sample size, a positive relationship was noted between epidermal growth factor levels and (62)Cu-ATSM-detected hypoxia. This initial series of (62)Cu-ATSM and (62)Cu-PTSM PET scans shows that evaluating lung masses by visualizing hypoxia and perfusion is a feasible and novel technique to provide more information. Further investigation is warranted to assess the potential role of (62)Cu-ATSM and (62)Cu-PTSM PET techniques combined with proteomics as alternatives to invasive biopsy techniques in clinical care.

Correlation of PET images of metabolism, proliferation and hypoxia to characterize tumor phenotype in patients with cancer of the oropharynx

Spatial organization of tumor phenotype is of great interest to radiotherapy target definition and outcome prediction. We characterized tumor phenotype in patients with cancers of the oropharynx through voxel-based correlation of PET images of metabolism, proliferation, and hypoxia. MethodsPatients with oropharyngeal cancer received 18F-fluorodeoxyglucose (FDG) PET/CT, 18F-fluorothymidine (FLT) PET/CT, and 61Cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) PET/CT. Images were co-registered and standardized uptake values (SUV) were calculated for all modalities. Voxel-based correlation was evaluated with Pearson’s correlation coefficient in tumor regions. Additionally, sensitivity studies were performed to quantify the effects of image segmentation, registration, noise, and segmentation on R. ResultsOn average, FDG PET and FLT PET images were most highly correlated (RFDG:FLT=0.76, range 0.53–0.85), while Cu-ATSM PET showed greater heterogeneity in correlation to other tracers (RFDG:Cu-ATSM=0.64, range 0.51–0.79; RFLT:Cu-ATSM=0.61, range 0.21–0.80). Of the tested parameters, correlation was most sensitive to image registration. Misregistration of one voxel lead to ΔRFDG=0.25, ΔRFLT=0.39, and ΔRCu-ATSM=0.27. Image noise and reconstruction also had quantitative effects on correlation. No significant quantitative differences were found between GTV, expanded GTV, or CTV regions. ConclusionsVoxel-based correlation represents a first step into understanding spatial organization of tumor phenotype. These results have implications for radiotherapy target definition and provide a framework to test outcome prediction based on pretherapy distribution of phenotype.

Application of62Cu-Diacetyl-Bis (N4-Methylthiosemicarbazone) PET Imaging to Predict Highly Malignant Tumor Grades and Hypoxia-Inducible Factor-1α Expression in Patients with Glioma

Hypoxic tissue evaluation in glioma is important for predicting treatment response and establishing antihypoxia therapy. In this preliminary study, (62)Cu-ATSM PET was used to determine its validity as a biomarker for distinguishing tumor grade and tissue hypoxia. (62)Cu-ATSM PET was performed in 22 patients with glioma, and the (62)Cu-ATSM SUV(max) and T/B ratio were semiquantitatively evaluated. (62)Cu-ATSM uptake distribution was qualitatively evaluated and compared with MR imaging findings. HIF-1α expression, a hypoxia marker, was compared with (62)Cu-ATSM uptake values. The (62)Cu-ATSM SUV(max) and T/B ratio were significantly higher in grade IV than in grade III gliomas (P = .014 and .018, respectively), whereas no significant differences were found between grade III and grade II gliomas. At a T/B ratio cutoff threshold of 1.8, (62)Cu-ATSM uptake was predictive of HIF-1α expression, with 92.3% sensitivity and 88.9% specificity. The mean T/B ratio was also significantly higher in HIF-1α-positive glioma tissue than in HIF-1α-negative tissue (P = .001). Using this optimal threshold of T/B ratio, (62)Cu-ATSM PET showed regional uptake in 61.9% (13/21) of tumors within the contrast-enhanced region on MR imaging, which was significantly correlated with presence of a necrotic component (P = .002). Our results demonstrated that (62)Cu-ATSM uptake is relatively high in grade IV gliomas and correlates with the MR imaging findings of necrosis. Moreover, the (62)Cu-ATSM T/B ratio showed significant correlation with HIF-1α expression. Thus, (62)Cu-ATSM appears to be a suitable biomarker for predicting highly malignant grades and tissue hypoxia in patients with glioma.

Spatially resolved regression analysis of pre-treatment FDG, FLT and Cu-ATSM PET from post-treatment FDG PET: An exploratory study

PurposeTo quantify associations between pre-radiotherapy and post-radiotherapy PET parameters via spatially resolved regression. Materials and methodsTen canine sinonasal cancer patients underwent PET/CT scans of [18F]FDG (FDGpre), [18F]FLT (FLTpre), and [61Cu]Cu-ATSM (Cu-ATSMpre). Following radiotherapy regimens of 50Gy in 10 fractions, veterinary patients underwent FDG PET/CT scans at 3months (FDGpost). Regression of standardized uptake values in baseline FDGpre, FLTpre and Cu-ATSMpre tumour voxels to those in FDGpost images was performed for linear, log-linear, generalized-linear and mixed-fit linear models. Goodness-of-fit in regression coefficients was assessed by R2. Hypothesis testing of coefficients over the patient population was performed. ResultsMultivariate linear model fits of FDGpre to FDGpost were significantly positive over the population (FDGpost∼0.17·FDGpre, p=0.03), and classified slopes of RECIST non-responders and responders to be different (0.37 vs. 0.07, p=0.01). Generalized-linear model fits related FDGpre to FDGpost by a linear power law (FDGpost∼FDGpre0.93,p<0.001). Univariate mixture model fits of FDGpre improved R2 from 0.17 to 0.52. Neither baseline FLT PET nor Cu-ATSM PET uptake contributed statistically significant multivariate regression coefficients. ConclusionsSpatially resolved regression analysis indicates that pre-treatment FDG PET uptake is most strongly associated with three-month post-treatment FDG PET uptake in this patient population, though associations are histopathology-dependent.

Different Distribution of 62Cu ATSM and 18F-FDG in Head and Neck Cancers

[⁶²Cu]-diacetyl-bis(N4-methlythiosemicarbazone) (Cu-ATSM) was used to delineate hypoxic tissue in head-and-neck cancer, and its distribution was compared with that of ¹⁸F-FDG. Thirty patients with head-and-neck cancer underwent Cu-ATSM and FDG PET within a 1 week interval. Accumulation of tracer for each PET image was converted to SUV. After coregisteration of PET images with individual anatomic images, multiple small ROIs were drawn on the tumor mass and applied to both PET images. SUV values were obtained for all ROIs (SUV(roi)), and the SUV(roi) regression lines between Cu-ATSM and FDG of each tumor were determined. The SUV mean of Cu-ATSM was lower than that of FDG for both squamous cell carcinoma (SCC) and adenocarcinoma (P < 0.05). In 27 patients with SCC, Cu-ATSM accumulated higher in the peripheral region than in the center of the tumor, and FDG showed the other tendency. Thus, the relationship of the SUV(roi) for Cu-ATSM and FDG showed a negative correlation in SCC. However, 3 adenocarcinoma cases showed similar and homogenous accumulation in the tumor mass with a positive SUV(roi) correlation for the 2 tracers. The regression slope means were -0.12 ± 0.08 for SCC (n = 27) and 0.28 ± 0.12 (n = 3) for adenocarcinoma. In patients with head-and-neck cancer, intratumoral distribution of Cu-ATSM and FDG showed a negative correlation in SCC and a positive correlation in adenocarcinoma. The 2 tracers represented different pathophysiological microenvironments in different tumors, suggesting that noninvasive hypoxic tissue imaging with Cu-ATSM would be beneficial in the pretreatment evaluation of head-and-neck cancer.

Pathophysiologic Correlation Between 62Cu-ATSM and 18F-FDG in Lung Cancer

The purpose of this study was to delineate the differences in intratumoral uptake and tracer distribution of (62)Cu-diacetyl-bis(N(4)-methylthiosemicarbazone) ((62)Cu-ATSM), a well-known hypoxic imaging tracer, and (18)F-FDG in patients with lung cancer of pathohistologically different types. Eight patients with squamous cell carcinoma (SCC) and 5 with adenocarcinoma underwent (62)Cu-ATSM and (18)F-FDG PET within a 1-wk interval. For (62)Cu-ATSM PET, 10-min static data acquisition was started at 10 min after a 370- to 740-MBq tracer injection. After image reconstruction, (62)Cu-ATSM and (18)F-FDG images were coregistered, and multiple small regions of interest were drawn on tumor lesions of the 2 images to obtain standardized uptake values (SUVs). The regression lines were determined between SUVs for (62)Cu-ATSM and (18)F-FDG in each tumor. The slope values were compared between SCC and adenocarcinoma to observe pathohistologic differences in intratumoral distribution of the tracers. SUVs for (62)Cu-ATSM were lower than those for (18)F-FDG in both SCC and adenocarcinoma. SCC tumors showed high (62)Cu-ATSM and low (18)F-FDG uptakes in the peripheral region of tumors but low (62)Cu-ATSM and high (18)F-FDG uptakes toward the center (spatial mismatching). The relationship of SUVs for the 2 tracers was negatively correlated with a mean regression slope of -0.07 +/- 0.05. On the other hand, adenocarcinoma tumors had a spatially similar distribution of (62)Cu-ATSM and (18)F-FDG, with positive regression slopes averaging 0.24 +/- 0.13. The regression slopes for (62)Cu-ATSM and (18)F-FDG differed significantly between SCC and adenocarcinoma (P < 0.001). The intratumoral distribution patterns of (62)Cu-ATSM and (18)F-FDG were different between SCC and adenocarcinoma in lung cancers, indicating that intratumoral regions of high glucose metabolism and hypoxia could differ with the pathohistologic type of lung cancer. The identification of regional biologic characteristics in tumors such as hypoxia, energy metabolism, and proliferation could play a significant role in the clinical diagnosis and therapy planning for non-small cell lung cancer patients.

On the sensitivity of IMRT dose optimization to the mathematical form of a biological imaging-based prescription function

Voxel-based prescriptions of deliberately non-uniform dose distributions based on molecular imaging, so-called dose painting or theragnostic radiation therapy, require specification of a transformation that maps the image data intensities to prescribed doses. However, the functional form of this transformation is currently unknown. An investigation into the sensitivity of optimized dose distributions resulting from several possible prescription functions was conducted. Transformations between the radiotracer activity concentrations from Cu-ATSM PET images, as a surrogate of tumour hypoxia, and dose prescriptions were implemented to yield weighted distributions of prescribed dose boosts in high uptake regions. Dose escalation was constrained to reflect clinically realistic whole tumour doses and constant normal tissue doses. Optimized heterogeneous dose distributions were found by minimizing a voxel-by-voxel quadratic objective function in which all tumour voxels were given equal weight. Prescriptions based on a polynomial mapping function were found to be least constraining on their optimized plans, while prescriptions based on a sigmoid mapping function were the most demanding to deliver. A prescription formalism that fixed integral dose was less sensitive to errors in the choice of the mapping function than one that boosted integral dose. Integral doses to normal tissue and critical structures were insensitive to the shape of the prescription function. Planned target dose conformity improved with smaller beamlet dimensions until the inherent spatial resolution of the functional image was matched. Clinical implementation of dose painting depends on advances in absolute quantification of functional images and improvements in delivery techniques over smaller spatial scales.

Assessing Tumor Hypoxia in Cervical Cancer by PET with 60Cu-Labeled Diacetyl-Bis(N4-Methylthiosemicarbazone)

Tumor hypoxia indicates a poor prognosis. This study was undertaken to confirm our prior pilot results showing that pretreatment tumor hypoxia demonstrated by PET with (60)Cu-labeled diacetyl-bis(N(4)-methylthiosemicarbazone) ((60)Cu-ATSM) is a biomarker of poor prognosis in patients with cervical cancer. Thirty-eight women with biopsy-proved cervical cancer underwent (60)Cu-ATSM PET before the initiation of radiotherapy and chemotherapy. (60)Cu-ATSM uptake was evaluated semiquantitatively as the tumor-to-muscle activity ratio (T/M). A log-rank test was used to determine the cutoff uptake value that was strongly predictive of prognosis. All patients also underwent clinical PET with (18)F-FDG before the institution of therapy. The PET results were correlated with clinical follow-up. Tumor (60)Cu-ATSM uptake was inversely related to progression-free survival and cause-specific survival (P = 0.006 and P = 0.04, respectively, as determined by the log-rank test). We found that a T/M threshold of 3.5 best discriminated patients likely to develop a recurrence from those unlikely to develop a recurrence; the 3-y progression-free survival of patients with normoxic tumors (as defined by T/M of < or = 3.5) was 71%, and that of patients with hypoxic tumors (T/M of > 3.5) was 28% (P = 0.01). Tumor (18)F-FDG uptake did not correlate with (60)Cu-ATSM uptake, and there was no significant difference in tumor (18)F-FDG uptake between patients with hypoxic tumors and those with normoxic tumors (P = 0.9). Pretherapy (60)Cu-ATSM PET provides clinically relevant information about tumor oxygenation that is predictive of outcome in patients with cervical cancer.

WE‐D‐L100J‐05: CuATSM and FLT PET Images Stabilization Assessment

Purpose: The level of correlation of a molecular imaging marker to the underlying biological information is critical, and depends on several factors, one of them being pharmacokinetics of the radioisotope uptake. The main aim of this work to assess the level of Cu‐diacetyl‐bis(N4‐methylthiosemicarbazone) ([Cu‐64]‐CuATSM) and 3′‐Deoxy‐3′‐fluorothymidine ([F‐18]‐FLT) uptake stability as a function of imaging time post‐injection to find an acceptable time window for image acquisition. Method and materials: Five canine patients (three nasal carcinomas, two sarcomas) with spontaneous tumors were scanned with CuATSM (hypoxia marker) and FLT (cell proliferation marker). The FLT scans were dynamic up to 70min. The CuATSM scans were dynamic for 3h and followed with a repeat scan at 24h. Correlation coefficients were calculated between individual frames of a dynamic scan and a reference PET image. For the CuATSM scan, the reference PET image was the CuATSM scan at 24h. For the FLT scan, the reference PET image was either the last frame (70min), or the image obtained with a three‐compartment kinetic modeling. The correlation was calculated based on the volume of interest, defined as a CT‐visible tumor with a small margin. Results: Our results indicate relative stability of the CuATSM uptake after approximately 1h, when the correlation coefficient increases over 0.9. Relatively low level of interpatient variability was observed. The FLT uptake analysis shows relatively fast stabilization, typically achieved within first 30min. The stability behavior was tumor‐type dependant. Relatively high correlation between the SUV (60–70 min) and kFLT was observed, warranting further investigation of true benefit of kinetic analysis. Conclusions: This work investigates spatial and temporal stability of CuATSM and FLT uptake in several tumor types. Due to significant variation in observed time required for image stabilization, we have to be aware that spatial distribution in different tumors can last longer than the initial transient indicates.

Monitoring the effect of mild hyperthermia on tumour hypoxia by Cu-ATSM PET scanning

Purpose: Mild hyperthermia can improve tumour oxygenation and enhance radiosensitivity. Imaging the hypoxic fraction of a tumour can guide hyperthermia treatment planning and facilitate treatment optimization. 64Cu-ATSM (Copper-diacetyl-bis(N4-methylthiosemicarbazone)) is a positron emitting compound that has been demonstrated to have rapid uptake and selective retention in hypoxic cells and has been used for imaging human and animal tumours. The purpose of the present report is to establish methodology that will allow one to use Cu-ATSM PET scanning to detect the impact of hyperthermia on tumour physiology in as little time as possible.Materials and methods: EMT6 tumours (mouse mammary carcinoma) were implanted into the subcutaneous tissue of both thighs of 10 BALB/c mice (one heated, one control tumour per animal). The target thermal dose was 41.5°C × 45 min. Without interrupting heating, 64Cu-ATSM (mean activity 1.8 mCi) was then injected and serial PET scans were obtained. In a sub-group of four animals, a low administered activity (∼0.3 mCi) 64Cu-ATSM scan was also conducted before heating to permit a direct comparison of the effects of hyperthermia on the same tumours. In another sub-group of five animals, a low activity (∼0.3 mCi) 64Cu-PTSM (pyruvaldehyde-bis(N*-methylthiosemicarbazone)) scan was conducted before heating, to confirm a posited correlation between perfusion and early 64Cu-ATSM uptake.Results: This study corrected for perfusion differences by dividing tumour uptake by the average early (first minute) uptake (‘self-normalized uptake’). The 10 heated tumours showed a significantly (p = 0.007) lower self-normalized uptake than control tumours by 2 min. For the four mice with low activity Cu-ATSM scans performed before hyperthermia, the tumours to be heated demonstrated self-normalized uptake consistent with the unheated control tumours and which departed significantly (p ≤ 0.02) from their post-hyperthermia scans by 5 min. Comparisons between scans and needle electrode surveys were performed in an additional four animals with eight tumours. For technical reasons electrode surveys were done after the end of hyperthermia—and, therefore, these animals also had comparison scans taken after hyperthermia. Reduced self-normalized uptake on scans was associated with increased pO2 on electrode surveys. These data also suggested a substantial degradation of the effect on tumour hypoxia by ∼15–45 min after the end of mild hyperthermia.Conclusion: Short imaging times of ∼5 min with modest (∼4–10) numbers of mice can discriminate the effects of mild hyperthermia on tumour physiology. The long-term objective is to use this tool to identify as short and mild a hyperthermia session as possible.

Oncologic imaging of tumor hypoxia by Cu-ATSM and correlating findings on Cu-ATSM PET scans to cellular markers that may predict for radiation response

Oncologic imaging of tumor hypoxia by Cu-ATSM and correlating findings on Cu-ATSM PET scans to cellular markers that may predict for radiation response