Richard Laforest

Gold Nanocages as Photothermal Transducers for Cancer Treatment

Gold nanocages represent a new class of nanomaterials with compact size and tunable optical properties for biomedical applications. They exhibit strong light absorption in the near-infrared region in which light can penetrate deeply into soft tissue. After PEGylation, the Au nanocages can be passively delivered to tumors in animals. Analysis of tissue distribution for the PEGylated Au nanocages showed that the tumor uptake was 5.7 %ID/g at 96 h post injection. The Au nanocages were found not only on the surface, but also in the core of the tumor. By exposing tumors to a near-infrared diode laser (0.7 W/cm2, CW, λ=808 nm) for 10 min, the photothermal effect of the Au nanocages could selectively destroy tumor tissue with minimum damage to the surrounding healthy tissue. Data from functional [18F]fluorodexoyglucose positron emission tomography revealed a decrease in tumor metabolic activity upon the photothermal treatment. Histological examination identified extensive damage to the nuclei of tumor cells and tumor interstitium.

In vivo assessment of tumor hypoxia in lung cancer with 60Cu-ATSM

Tumor hypoxia is recognized as an important determinant of response to therapy. In this study we investigated the feasibility of clinical imaging with copper-60 diacetyl-bis(N4-methylthiosemicarbazone) (60Cu-ATSM) in patients with non-small-cell lung cancer (NSCLC) and also assessed whether pretreatment tumor uptake of 60Cu-ATSM predicts tumor responsiveness to therapy. Nineteen patients with biopsy-proved NSCLC were studied by positron emission tomography (PET) with 60Cu-ATSM before initiation of therapy. 60Cu-ATSM uptake was evaluated semiquantitatively by determining the tumor-to-muscle activity ratio (T/M). All patients also underwent PET with fluorine-18 fluorodeoxyglucose (FDG) prior to institution of therapy. The PET results were correlated with follow-up evaluation (2–46 months). It was demonstrated that PET imaging with 60Cu-ATSM in patients with NCSLC is feasible. The tumor of one patient had no discernible 60Cu-ATSM uptake, whereas the tumor uptake in the remaining patients was variable, as expected. Response was evaluated in 14 patients; the mean T/M for 60Cu-ATSM was significantly lower in responders (1.5±0.4) than in nonresponders (3.4±0.8) (P=0.002). However, the mean SUV for 60Cu-ATSM was not significantly different in responders (2.8±1.1) and nonresponders (3.5±1.0) (P=0.2). An arbitrarily selected T/M threshold of 3.0 discriminated those likely to respond to therapy: all eight responders had a T/M <3.0 and all six nonresponders had a T/M ≥3.0. Tumor SUV for FDG was not significantly different in responders and nonresponders (P=0.7) and did not correlate with 60Cu-ATSM uptake (r=0.04; P=0.9). 60Cu-ATSM-PET can be readily performed in patients with NSCLC and the tumor uptake of 60Cu-ATSM reveals clinically unique information about tumor oxygenation that is predictive of tumor response to therapy.

Exploring feature-based approaches in PET images for predicting cancer treatment outcomes

Accumulating evidence suggests that characteristics of pre-treatment FDG-PET could be used as prognostic factors to predict outcomes in different cancer sites. Current risk analyses are limited to visual assessment or direct uptake value measurements. We are investigating intensity-volume histogram metrics and shape and texture features extracted from PET images to predict patients response to treatment. These approaches were demonstrated using datasets from cervix and head and neck cancers, where AUC of 0.76 and 1.0 were achieved, respectively. The preliminary results suggest that the proposed approaches could potentially provide better tools and discriminant power for utilizing functional imaging in clinical prognosis.

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 60Cu-labeled diacetyl-bis(N4-methylthiosemicarbazone) (60Cu-ATSM) is a biomarker of poor prognosis in patients with cervical cancer. Thirty-eight women with biopsy-proved cervical cancer underwent 60Cu-ATSM PET before the initiation of radiotherapy and chemotherapy. 60Cu-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 18F-FDG before the institution of therapy. The PET results were correlated with clinical follow-up. Tumor 60Cu-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 ≤3.5) was 71%, and that of patients with hypoxic tumors (T/M of >3.5) was 28% (P = 0.01). Tumor 18F-FDG uptake did not correlate with 60Cu-ATSM uptake, and there was no significant difference in tumor 18F-FDG uptake between patients with hypoxic tumors and those with normoxic tumors (P = 0.9). Pretherapy 60Cu-ATSM PET provides clinically relevant information about tumor oxygenation that is predictive of outcome in patients with cervical cancer.

Small animal imaging: current technology and perspectives for oncological imaging

Advances in the biomedical sciences have been accelerated by the introduction of many new imaging technologies in recent years. With animal models widely used in the basic and pre-clinical sciences, finding ways to conduct animal experiments more accurately and efficiently becomes a key factor in the success and timeliness of research. Non-invasive imaging technologies prove to be extremely valuable tools in performing such studies and have created the recent surge in small animal imaging. This review is focused on three modalities, PET, MR and optical imaging which are available to the scientist for oncological investigations in animals.

An Imaging Comparison of 64Cu-ATSM and 60Cu-ATSM in Cancer of the Uterine Cervix

Tumor uptake of copper(II)-diacetyl-bis(N4-methylthiosemicarbazone) (copper-ATSM), a hypoxia-targeting radiopharmaceutical, assessed by PET has been found to correlate with prognosis in several human cancers. Wide clinical utility of this tracer will require its labeling with a copper radionuclide having a longer half-life than the 60Cu used in studies to date. The purpose of this work was to obtain the requisite preclinical data for copper-ATSM to file an investigational new drug application, followed by a crossover comparison of PET image quality and tumor uptake with 60Cu-ATSM and 64Cu-ATSM in women with cancer of the uterine cervix. Methods: The preclinical toxicology and pharmacology of a copper-ATSM formulation was examined using standard in vitro and in vivo assays, as well as 14-d toxicity studies in both rats and rabbits. For the clinical test–retest imaging study, 10 patients with cervical carcinoma underwent PET on separate days with 60Cu-ATSM and 64Cu-ATSM. Image quality was assessed qualitatively, and the tumor-to-muscle activity ratio was measured for each tracer. Results: The toxicology and pharmacology data demonstrated that the formulation has an appropriate margin of safety for clinical use. In the patient study, we found that the image quality with 64Cu-ATSM was better than that with 60Cu-ATSM because of lower noise. In addition, we found that the pattern and magnitude of tumor uptake of 60Cu-ATSM and 64Cu-ATSM on studies separated by 1–9 d were similar. Conclusion: 64Cu-ATSM appears to be a safe radiopharmaceutical that can be used to obtain high-quality images of tumor hypoxia in human cancers.

Preparation of 66Ga- and 68Ga-labeled Ga(III)-deferoxamine-folate as potential folate-receptor-targeted PET radiopharmaceuticals

A folate-receptor-targeting radiopharmaceutical, Ga(III)-deferoxamine-folate (Ga-DF-Folate), was radiolabeled with two positron-emitting isotopes of gallium, cyclotron-produced (66)Ga (9.5 hour half-life) and generator-produced (68)Ga (68 minute half-life). The [(66)Ga]Ga-DF-Folate was administered to athymic mice with folate-receptor-positive human KB cell tumor xenografts to demonstrate that microPET mouse tumor imaging is feasible with (66)Ga, despite the relatively high positron energy of this radionuclide. Using the athymic mouse KB tumor xenograft model, dual-isotope autoradiography was also performed following i.v. co-administration of [(18)F]-FDG, a marker of regional metabolic activity, and folate-receptor-targeted [(111)In]In-DTPA-Folate. The autoradiographic images of 1 mm tumor sections demonstrate the gross heterogeneity of the KB cell tumor xenograft, as well as subtle disparity in the regional accumulation of the two radiotracers.

A novel PET tumor delineation method based on adaptive region-growing and dual-front active contours

To more accurately and precisely delineate a tumor in a 3D PET image, we proposed a novel, semi-automatic, two-stage method by utilizing an adaptive region-growing algorithm and a dual-front active contour model. First, a rough region of interest (ROI) is manually drawn by a radiation oncologist that encloses a tumor. The voxel having the highest intensity in the ROI is chosen as a seed point. An adaptive region growing algorithm successively appends to the seed point all neighboring voxels whose intensities > = T of the mean of the current region. When T varies from 100% to 0%, a sharp volume increase, indicating the transition from the tumor to the background, always occurs at a certain T value. A preliminary tumor boundary is determined just before the sharp volume increase, which is found to be slightly outside of the known tumor in all tested phantoms. A novel dual-front active contour model utilizing region-based information is then applied to refine the preliminary boundary automatically. We tested the two-stage method on six spheres (0.5-20 ml) in a cylindrical container under different source to background ratios. Comparisons between the two-stage method and an iterative threshold method demonstrate its higher detection accuracy for small tumors (less than 6 ml). One patient study was tested and evaluated by two experienced radiation oncologists. The study illustrated that this two-stage method has several advantages. First, it does not require any threshold-volume curves, which are different and must be calibrated for each scanner and image reconstruction method. Second, it does not use any iso-threshold lines as contours. Third, the final result is reproducible and is independent of the manual rough ROIs. Fourth, this method is an adaptive algorithm that can process different images automatically.

NEMA NU 4-2008 Comparison of Preclinical PET Imaging Systems

The National Electrical Manufacturers Association (NEMA) standard NU 4-2008 for performance measurements of small-animal tomographs was recently published. Before this standard, there were no standard testing procedures for preclinical PET systems, and manufacturers could not provide clear specifications similar to those available for clinical systems under NEMA NU 2-1994 and 2-2001. Consequently, performance evaluation papers used methods that were modified ad hoc from the clinical PET NEMA standard, thus making comparisons between systems difficult. Methods: We acquired NEMA NU 4-2008 performance data for a collection of commercial animal PET systems manufactured since 2000: microPET P4, microPET R4, microPET Focus 120, microPET Focus 220, Inveon, ClearPET, Mosaic HP, Argus (formerly eXplore Vista), VrPET, LabPET 8, and LabPET 12. The data included spatial resolution, counting-rate performance, scatter fraction, sensitivity, and image quality and were acquired using settings for routine PET. Results: The data showed a steady improvement in system performance for newer systems as compared with first-generation systems, with notable improvements in spatial resolution and sensitivity. Conclusion: Variation in system design makes direct comparisons between systems from different vendors difficult. When considering the results from NEMA testing, one must also consider the suitability of the PET system for the specific imaging task at hand.

Performance evaluation of the microPET-Focus - F120

microPETreg-Focus-F120 is the latest model of dedicated small animal PET scanners from CTI-Concorde Microsystems LLC, (Knoxville, TN). This scanner, based on the geometry of the microPET-R4, takes advantage of several detector modifications to the coincidence processing electronics that improve the image resolution, sensitivity, and counting rate performance as compared to the predecessor models. This work evaluates the performance of the Focus-F120 system and shows its improvement over the earlier models. In particular, the spatial resolution is shown to improve from 2.32 to 1.69 mm at 5 mm radial distance and the peak absolute sensitivity increases from 4.1% to 7.1% compared to the microPET-R4. The counting rate capability, expressed in noise equivalent counting rate (NEC-1R), was shown to peak at over 800 kcps at 88 MBq for both systems using a mouse phantom. For this small phantom, the NECR counting rate is limited by the data transmission bandwidth between the scanner and the acquisition console. The rat-like phantom showed peak NEC-1R value at 300 kcps at 140 MBq. Evaluation of image quality and quantitation accuracy was also performed using specially designed phantoms and animal experiments