Gamal Akabani

Intracerebral infusion of an EGFR-targeted toxin in recurrent malignant brain tumors

The purpose of this study is to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and intracerebral distribution of a recombinant toxin (TP-38) targeting the epidermal growth factor receptor in patients with recurrent malignant brain tumors using the intracerebral infusion technique of convection-enhanced delivery (CED). Twenty patients were enrolled and stratified for dose escalation by the presence of residual tumor from 25 to 100 ng/ml in a 40-ml infusion volume. In the last eight patients, coinfusion of (123)I-albumin was performed to monitor distribution within the brain. The MTD was not reached in this study. Dose escalation was stopped at 100 ng/ml due to inconsistent drug delivery as evidenced by imaging the coinfused (123)I-albumin. Two DLTs were seen, and both were neurologic. Median survival after TP-38 was 28 weeks (95% confidence interval, 26.5-102.8). Of 15 patients treated with residual disease, two (13.3%) demonstrated radiographic responses, including one patient with glioblastoma multiforme who had a nearly complete response and remains alive >260 weeks after therapy. Coinfusion of (123)I-albumin demonstrated that high concentrations of the infusate could be delivered >4 cm from the catheter tip. However, only 3 of 16 (19%) catheters produced intraparenchymal infusate distribution, while the majority leaked infusate into the cerebrospinal fluid spaces. Intracerebral CED of TP-38 was well tolerated and produced some durable radiographic responses at doses <or=100 ng/ml. CED has significant potential for enhancing delivery of therapeutic macromolecules throughout the human brain. However, the potential efficacy of drugs delivered by this technique may be severely constrained by ineffective infusion in many patients.

Molecular imaging of small animals with a triple-head SPECT system using pinhole collimation

Pinhole collimation yields high sensitivity when the distance from the object to the aperture is small, as in the case of imaging small animals. Fine-resolution images may be obtained when the magnification is large since this mitigates the effect of detector resolution. Large magnifications in pinhole single-photon emission computed tomography (SPECT) may be obtained by using a collimator whose focal length is many times the radius of rotation. This may be achieved without truncation if the gamma camera is large. We describe a commercially available clinical scanner mated with pinhole collimation and an external linear stage. The pinhole collimation gives high magnification. The linear stage allows for helical pinhole SPECT. We have used the system to image radiolabeled molecules in phantoms and small animals.

Microbial influences on hormesis, oncogenesis, and therapy: A review of the literature.

Utilization of environmental stimuli for growth is the main factor contributing to the evolution of prokaryotes and eukaryotes, independently and mutualistically. Epigenetics describes an organisms ability to vary expression of certain genes based on their environmental stimuli. The diverse degree of dose-dependent responses based on their variances in expressed genetic profiles makes it difficult to ascertain whether hormesis or oncogenesis has or is occurring. In the medical field this is shown where survival curves used in determining radiotherapeutic doses have substantial uncertainties, some as large as 50% (Barendsen, 1990). Many in-vitro radiobiological studies have been limited by not taking into consideration the innate presence of microbes in biological systems, which have either grown symbiotically or pathogenically. Present in-vitro studies neglect to take into consideration the varied responses that commensal and opportunistic pathogens will have when exposed to the same stimuli and how such responses could act as stimuli for their macro/microenvironment. As a result many theories such as radiation carcinogenesis explain microscopic events but fail to describe macroscopic events (Cohen, 1995). As such, this review shows how microorganisms have the ability to perturb risks of cancer and enhance hormesis after irradiation. It will also look at bacterial significance in the microenvironment of the tumor before and during treatment. In addition, bacterial systemic communication after irradiation and the hosts immune responses to infection could explain many of the phenomena associated with bystander effects. Therefore, the present literature review considers the paradigms of hormesis and oncogenesis in order to find a rationale that ties them all together. This relationship was thus characterized to be the microbiome.

Rapid synthesis of 125 I integrated gold nanoparticles for use in combined neoplasm imaging and targeted radionuclide therapy

The selective delivery of radionuclides to tissues of interest remains a problematic task during treatment. The lack of tissue specificity for many therapeutics limit their efficacy by putting healthy organs and tissues at risk (e.g., side effects). Therefore, high specificity therapeutic strategies are needed to overcome these risks. The objective of this study was to use a modified citrate reduction technique to synthesize gold nanoparticles (AuNPs) containing 125I in order to combine their unique therapeutic and diagnostic properties. This task was accomplished by varying the insertion time of 125I, which will cause complete aggregation if added too early in the AuNP synthesis process. Even though 125I was utilized in this experiment, studies are underway to see if this approach can be extrapolated to shorter-lived isotopes (e.g., 211At). Characterization of the 125I-AuNPs was carried out using UV-Vis spectrometry and Transmission Electron Microscopy (TEM). The appropriate addition time of 125I was determined to be approximately 50s after the addition of sodium citrate. TEMxa0measured the nanoparticles diameters to be in the 10-20nm range. The AuNPs were found to be extremely stable, with no observable leaching of radioactivity into the solution. 125I-AuNPs could be beneficial as a contrast agent in CT imaging and therapy since AuNPs enhance the bio-delivery of 125I to neoplasms.

Production of 99 Mo/ 99m Tc via photoneutron reaction using natural molybdenum and enriched 100 Mo: part 1, theoretical analysis

A theoretical analysis was performed for the production of 99Mo via the 100Mo(γ,n)99Mo reaction using natural (natMo) and enriched (100Mo) molybdenum targets in a modified NIRTA® Targetry system. High energy electrons from a linear accelerator were simulated on a tungsten converter to produce bremsstrahlung incident on molybdenum targets using the TALYS computer code. All open channels and decay schemes were used to assess the production rates and final amounts of radioactive and stable components at end-of-bombardment (3-day irradiation), and after 2xa0h of cooling. Computations were performed at an accelerator energy of 40xa0MeV, correlating to a maximized photon fluence at 14xa0MeV. Impurities of Zr and Nb were found when utilizing enriched 100Mo (excluding Mo isotopes). Targets utilizing natMo added substantial stable and radioactive impurities of Mo, Nb, Zr, Y, and Sr; however, all but the Mo impurities can be readily separated. This study confirms the potential of producing 99Mo via 100Mo(γ,n)99Mo using natMo with manageable impurities.

A dose constraint proposal for members of the public taking into account multi-unit nuclear power plants in Korea

In the 2007 recommendations, the International Commission on Radiological Protection (ICRP) changed from a process-based system of practices and intervention to a system based on the characteristics of the radiation exposure situation. In addition, the ICRP now recommends the application of source-related dose constraints under a planned exposure situation as a tool for the optimization of measures to protect the workers and members of the public. In this study, an analysis of radioactive effluents from Korean nuclear power plants and a public dose assessment were conducted using these source-related dose constraints. As a result, this analysis suggests appropriate dose constraints for members of the public taking into account the operation of multi-unit nuclear reactors at a single site in Korea.

THE SPARSITY-PROMOTED SOLUTION TO THE UNDERSAMPLING TOF-PET IMAGING: NUMERICAL SIMULATIONS

Recently, the limited-angle TOF-PET system has become an active research topic due to the considerable reduction of hardware cost and potential applicability for performing needle biopsy on patients while in the scanner. This undersampling measurement conflguration oftentimes sufiers from the deteriorated reconstructed images. However, the established theory of Compressed Sampling (CS) provides a potential framework for undertaking this problem, given that the imaged object can be sparse in some transformed domain. In here, we studied using numerical simulations the application of sparsity-promoted framework to TOF-PET imaging for two undersampling conflgurations. From these simulations, a relationship was obtained between the number of detectors (or the range of angle) and TOF time resolution, which provided an empirical guide of designing a low-cost TOF-PET systems while ensuring good reconstruction quality. Another contribution is the exploration of p- TV regularization, which showed that RMSE (Root of Mean Square Error) and SSIM (Structural Similarity) were optimized when p = 0:5. Several sets of representative numerical experiments were executed to validate the proposed methodology, which demonstrates the promising applicability of undersampling TOF-PET imaging.

A STUDY OF A DOSE CONSTRAINT FOR OCCUPATIONALLY EXPOSED WORKERS IN THE US NUCLEAR POWER PLANTS

One of the most important issues in the nuclear power industry is the implementation of the 2007 Recommendations of the International Commission on Radiological Protection (ICRP) published in ICRP Publication 103. These recommendations include the implementation of the concept of dose constraints for occupationally exposed workers at nuclear power plants (NPPs). When considering these changes from a cost-benefit standpoint, the implementation of dose constraints is still highly controversial. This study analysed annual occupational dose distributions to determine whether a dose constraint is needed for occupationally exposed workers at the US NPPs. Results of the analysis showed that the use of dose constraints had no positive impact on radiation safety of workers at NPPs in the USA. In fact, it appears that the implementation of dose constraints will impose an unnecessary regulatory burden on licensees. Based on these results, implementation of dose constraints is not recommended.

Dosimetry of a 90Y-hydroxide liquid brachytherapy treatment approach to canine osteosarcoma using PET/CT

A new treatment strategy based on direct injections of (90)Y-hydroxide into the tumor bed in dogs with osteosarcoma was studied. Direct injections of the radiopharmaceutical into the tumor bed were made according to a pretreatment plan established using (18)F-FDG images. Using a special drill, cannulas were inserted going through tissue, tumor and bone. Using these cannulas, direct injections of the radiopharmaceutical were made. The in vivo biodistribution of (90)Y-hydroxide and the anatomical tumor bed were imaged using a time-of-flight (TOF) PET/CT scanner. The material properties of the tissues were estimated from corresponding CT numbers using an electron-density calibration. Radiation absorbed dose estimates were calculated using Monte Carlo methods where the biodistribution of the pharmaceutical from PET images was sampled using a collapsing 3-D rejection technique. Dose distributions in the tumor bed and surrounding tissues were calculated, showing significant heterogeneity with multiple hot spots at injection sites. Dose volume histograms showed that approximately 33.9% of bone and tumor and 70.2% of bone marrow and trabecular bone received an absorbed dose over 200Gy; approximately 3.2% of bone and tumor and 31.0% of bone marrow and trabecular bone received a total dose of over 1000Gy.

Applicability test of methods for discrimination between external and internal contamination using an ORTEC whole body counter

Whole-body counters (WBCs) are generally used for monitoring internal radioactive contamination of radiation workers in nuclear power plants. However, it has been found that external contamination is occasionally counted as internal contamination. The previous study was conducted to provide guidance on measuring the exact internal radioactivity using a Canberra WBC. However, there is strong need to verify the application of the previous study to whole-body counting using a different type of WBC, ORTEC StandFAST II. Thus, in this study, several experiments were conducted focusing on the discrimination between external and internal contamination. Finally, it was found that counts from the front and back are still effective to distinguish external contamination from internal contamination for whole-body counting.