bluuebunny/crossref_metadata_2025 huggingface dataset:
A Clinical Interactive Technique for MR-CT Image Registration for Target Delineation of Intracranial Tumors
Authors: Luu Q. T. , Levy R. P. , Miller D. W. , Shahnazi K. , Yonemoto L. T. , Slater J. M. , Slater J. D.
Published: October 2014

Replacement of current CT-based, three-dimensional (3D) treatment planning systems by newer versions capable of automated multi-modality image registration may be economically prohibitive for most radiation oncology clinics. We present a low-cost technique for MR-CT image registration on a “first generation” CT-based, 3D treatment planning system for intracranial tumors. The technique begins with fabrication of a standard treatment mask. A second truncated mask, the “minimask,” is then made, using the standard mask as a mold. Two orthogonal leveling vials glued onto the minimask detect angular deviations in pitch and roll. Preservation of yaw is verified by referencing a line marked according to the CT laser on the craniocaudal axis. The treatment mask immobilizes the patient's head for CT. The minimask reproduces this CT-based angular treatment position, which is then maintained by taping the appropriately positioned head to the MR head coil for MR scanning. All CT and MR images, in DICOM 3.0 format, are entered into the treatment planning system via a computer network. Interactive registration of MR to CT images is controlled by real-time visual feedback on the computer monitor. Translational misalignments at the target are eliminated or minimized by iterative use of qualitative visual inspection. In this study, rotational errors were measured in a retrospective series of 20 consecutive patients who had undergone CT-MR image registration using this technique. Anatomic structures defined the three CT orthogonal axes from which angular errors on MR image were measured. Translational errors at the target isocenter were within pixel size, as judged by visual inspection. Clinical setup using the minimask resulted in overall average angular deviation of 3°±2° (mean ± SD) and translational deviation within the edges of the target volume of typically less than 2 mm. The accuracy of this registration technique for target delineation of intracranial tumors is compatible with practice guidelines. This method, then, provides a cost-effective means to register MR and CT images for target delineation of intracranial tumors.
Cancer Gene Therapy
Authors: Yamamoto Masato , Curiel David T.
Published: October 2014

The prognosis of patients with some kinds of cancers whose patients are often found unresectable upon diagnosis is still dismal. In these fields, development of a new therapeutic modality is needed and gene therapy represents one promising strategy. So far, numerous cancer gene therapy clinical trials based on these principles have been carried out and have shown the safety of such modalities, but have fallen short of the initial expectations to cure cancers. In this review, we would like to make a problem-oriented discussion of current status of cancer gene therapy research by using mainly gastrointestinal cancers as an example. In order to overcome obstacles for full realization of cancer gene therapy, numerous researches have been conducted by many researchers. Various cancer-selective and non-selective genes, as well as lytic viruses themselves have been employed for gene therapy. In the context of gene delivery method, different kinds of viral and non-viral strategies have been utilized. In addition, surrogate assays, such as soluble markers and imaging, have been developed for safer and more informative clinical trials. Many experiments and clinical trials to date have figured out current obstacles for the realization of an effective cancer gene therapy modality. Tireless efforts to overcome such hurdles and continuous infusion of novel concepts into this field should lead to break through technologies and the cure of the patients.
Cancer Therapy with Radiolabeled and Drug/Toxin-conjugated Antibodies
Authors: Govindan Serengulam V. , Griffiths Gary L. , Hansen Hans J. , Horak Ivan D. , Goldenberg David M.
Published: October 2014

Radioimmunotherapy and antibody-directed chemotherapy have emerged as cancer treatment modalities with the regulatory approval of products for non-Hodgkin's lymphoma and acute myeloid leukemia. Antibody-toxin therapy is likewise on the verge of clinical fruition. Accumulating evidence suggests that radioimmunotherapy may have the best impact in minimal-disease and adjuvant settings, especially with radioresistant solid tumors. For the latter, ongoing efforts in ‘pretargeting’ to increase deliverable tumor radiation dose, combination therapies, and locoregional applications are also of importance. Antibody-drug conjugates have the potential to increase the therapeutic index of chemotherapy by minimizing systemic toxicity and improving tumor targeting. The design of optimal drug conjugates in this regard is predicated upon the proper choice of the target antigen, the cleavable-linker, and the drug. In respect of antibody-toxin conjugates, considerable progress has been made in chemical and recombinant immunotoxin designs, and in the advancement of many products to clinical trials. Continued development of antibody-directed therapies should expand the options available for the management of cancer.
Novel Advances in Drug Delivery to Brain Cancer
Authors: Lesniak Maciej S.
Published: October 2014

The therapy of brain tumors has been limited by a lack of effective methods of drug delivery to the brain. Systemic administration is often associated with toxic side effects and ultimately fails to achieve therapeutic concentrations within a tumor. An attractive strategy that has gained importance in brain tumor therapy has relied on local and controlled delivery of chemotherapeutic agents by biodegradable polymers. This technique allows direct exposure of tumor cells to a therapeutic agent for a prolonged period of time and has been shown to prolong the survival of patients with malignant brain tumors. The use of polymers for local drug delivery greatly expands the spectrum of drugs available for the treatment of malignant brain tumors. This review discusses the rationale for local drug delivery, describes the development of currently available polymer-based therapeutic agents, and highlights examples of promising non-polymer based drug delivery methods for use in the treatment of malignant brain tumors.
Spectral Polarization Imaging of Human Prostate Cancer Tissue Using a Near-infrared Receptor-targeted Contrast Agent
Authors: Pu Y. , Wang W. B. , Tang G. C. , Zeng F. , Achilefu S. , Vitenson J. H. , Sawczuk I. , Peters S. , Lombardo J. M. , Alfano R. R.
Published: October 2014

The Cypate-Bombesin Peptide Analogue Conjugate (Cybesin) was used as a prostate tumor receptor-targeted contrast agent. The absorption and fluorescence spectra of Cybesin were measured and shown to exist in the NIR tissue “optical window”. The spectral polarization imaging of Cybesin-stained prostate cancerous and normal tissues shows that prostate cancerous tissue takes-up more Cybesin than that of prostate normal tissue, making Cybesin a potential marker of prostate cancer.
Spatial and Spectral Information in Optical Mammography
Authors: Fantini Sergio , Heffer Erica L. , Pera Vivian E. , Sassaroli Angelo , Liu Ning
Published: October 2014

This article reviews our research activities in the area of optical mammography and relates them to the historical developments and the current state and trends in the field. The guiding threads for this article are the roles played in optical mammography by spatial and spectral information. The first feature, spatial information, is limited by the diffusive nature of light propagation but can take advantage of the exceptionally high optical contrast featured by blood vessels and blood-rich areas in the breast. We describe a method to correct for edge effects, a spatial second-derivative algorithm, and a two-dimensional phased-array approach that enhance the image contrast, the spatial resolution, and the depth discrimination in optical mammograms. The second feature, spectral information, is the most powerful and unique capability of optical mammography, and allows for functional measurements associated with hemoglobin concentration and oxygenation, water concentration, lipids content, and the wavelength dependence of tissue scattering. We present oxygenation-index images obtained from multi-wavelength optical data that point to the diagnostic potential of oxygenation information in optical mammography. The optimization of the spatial and spectral information in optical mammography has the potential to create a role for this imaging modality in the detection and monitoring of breast cancer.
NIR Spectroscopic Detection of Breast Cancer
Authors: Nioka S. , Chance B.
Published: October 2014

Near infrared spectroscopy (NIRS) utilizes intrinsic optical absorption signals of blood, water, and lipid concentration available in the NIR window (600–1000 nm) as well as a developing array of extrinsic organic compounds to detect and localize cancer. This paper reviews optical cancer detection made possible through high tumor-tissue signal-to-noise ratio (SNR) and providing biochemical and physiological data in addition to those obtained via other methods.

NIRS detects cancers in vivo through a combination of blood volume and oxygenation from measurements of oxy- and deoxy-hemoglobin giving signals of tumor angiogenesis and hypermetabolism. The Chance lab tends towards CW breast cancer systems using manually scannable detectors with calibrated low pressure tissue contact. These systems calculate angiogenesis and hypermetabolism by using a pair of wavelengths and referencing the mirror image position of the contralateral breast to achieve high ROC/AUC. Time domain and frequency domain spectroscopy were also used to study similar intrinsic breast tumor characteristics such as high blood volume. Other NIRS metrics are water-fat ratio and the optical scattering coefficient. An extrinsic FDA approved dye, ICG, has been used to measure blood pooling with extravasation, similar to Gadolinium in MRI.

A key future development in NIRS will be new Molecular Beacons targeting cancers and fluorescing in the NIR window to enhance in vivo tumor-tissue ratios and to afford biochemical specificity with the potential for effective photodynamic anti-cancer therapies.
Near-Infrared Characterization of Breast Tumors In Vivo using Spectrally-Constrained Reconstruction
Authors: Srinivasan Subhadra , Pogue Brian W. , Brooksby Ben , Jiang Shudong , Dehghani Hamid , Kogel Christine , Wells Wendy A. , Poplack Steven P. , Paulsen Keith D.
Published: October 2014

Multi-wavelength Near-Infrared (NIR) Tomography was utilized in this study to non-invasively quantify physiological parameters of breast tumors using direct spectral reconstruction. Frequency domain NIR measurements were incorporated with a new spectrally constrained direct chromophore and scattering image reconstruction algorithm, which was validated in simulations and experimental phantoms. Images of total hemoglobin, oxygen saturation, water, and scatter parameters were obtained with higher accuracy than previously reported. Using this spectral approach, in vivo NIR images are presented and interpreted through a series of case studies (n=6 subjects) having differing abnormalities. The corresponding mammograms and ultrasound images are also evaluated. Three of six cases were malignant (infiltrating ductal carcinomas) and showed higher hemoglobin (34–86% increase), a reduction in oxygen saturation, an increase in water content as well as scatter changes relative to surrounding normal tissue. Three of six cases were benign, two of which were diagnosed with fibrocystic disease and showed a dominant contrast in water, consistent with fluid filled cysts. Scatter amplitude was the main source of contrast in the volunteer with the benign condition fibrosis, which typically contains denser collagen tissue. The changes monitored correspond to physiological changes associated with angiogenesis, hypoxia and cell proliferation anticipated in cancers. These changes represent potential diagnostic indicators, which can be assessed to characterize breast tumors.
Multi-wavelength Time Domain Optical Mammography
Authors: Taroni P. , Spinelli L. , Torricelli A. , Pifferi A. , Danesini G.M. , Cubeddu R.
Published: October 2014

A time-resolved optical mammograph operating at 7 wavelengths (637, 683, 785, 832, 905, 916, and 975 nm) in compressed breast geometry was developed. Its clinical application was started on patients bearing malignant and benign lesions. Late gated intensity images are used to obtain information on the spatial distribution of the absorption properties of breast. Scattering images derived from the diffusion theory are also applied for lesion detection and characterization. Cancers are identified in intensity images at short wavelengths, due to the high blood content, while cysts are typically characterized by low scattering at all wavelengths. The increase (from 4 to 7) in the number of wavelengths as compared to the previous versions of the instrument aims at improving the robustness of the fitting procedures for a better estimate of tissue composition and structure and of physiological parameters. Moreover, the new wavelengths contribute to the qualitatively identify tissue composition from intensity images, and could assist lesion detection.
CyberKnife Frameless Radiosurgery for the Treatment of Extracranial Benign Tumors
Authors: Bhatnagar Ajay K. , Gerszten Peter C. , Ozhasaglu Cihat , Vogel William J. , Kalnicki Shalom , Welch William C. , Burton Steven A.
Published: October 2014

Limited data exists for the use of radiosurgery for benign extracranial tumors. The purpose of this study was to evaluate the feasibility, toxicity, and local control of patients with benign extracranial lesions treated with the CyberKnife Frameless Radiosurgery System. From September 2001 thru January 2004, 59 benign tumors in 44 patients were treated using the CyberKnife a frameless image-guided radiosurgery system. Of these tumors, there were 21 neurofibromas, ten schwannomas, eight meningiomas, eight hemangioblastomas, seven paragangliomas, two hemangiopericytomas, one pseudotumor, one ependymoma, and one arteriovenous malformation (AVM). The anatomic locations of these tumors were spinal (25 cervical, four thoracic, 14 lumbar, and two sacral), neck (eight), orbital (three), brainstem (one), and foramen magnum (one). All patients were treated in a single fraction except three lesions were treated in a fractionated manner. The median treatment delivery time per fraction was 59 minutes (range 11–194). Twenty three lesions initially underwent surgical resection. Ten lesions received prior external beam radiation with a median dose 48 Gy (range 40–54 Gy), and one lesion received two prior CyberKnife treatments for a total dose of 32 Gy to the 80% isodose line. The median follow-up was eight months (range 1–25 months). Acute and late toxicity was graded using the National Cancer Institute Common Toxicity Criteria (CTC) scale. Symptomatic response was documented as “improved,” “stable,” or “progression”. The median tumor dose delivered was 16.0 Gy to the 80% isodose line (range 10–31 Gy). The median tumor volume was 4.3 cc (range 0.14–98.6 cc). The median spinal cord volume receiving more than 8 Gy was 0.035 cc (range 0–2.5 cc) and the median maximum spinal cord dose 11.5 Gy (range 0–19.8 Gy). There were no patients that suffered a significant (Grade 3, 4, or 5) acute toxicity. There was no observed late toxicity. 78% of patients experienced an improvement of their pre-treatment symptoms while only one patient experienced symptom progression. Of the 26 patients who underwent follow-up imaging, the local control rate was 96%. This study suggests that CyberKnife Radiosurgery is a safe and efficacious treatment modality for benign tumors, even for those patients with recurrent previously irradiated lesions.
Whole-Body PET/MRI: The Future in Oncological Imaging
Authors: Seemann Marcus D.
Published: October 2014

Positron emission tomography (PET) facilitates the evaluation of molecular aspects and metabolic alterations that are fundamental in detecting of malignancies, characterization of tumor stage and assessment of therapeutical response, and tumor recurrence. The main advantage of PET is its high sensitivity in identifying of areas of cancerous involvement at an early stage. In general, the accelerated radiotracer activity occurs before anatomical structure changes. The main difficulty with PET is the lack of an anatomical reference frame. Magnetic resonance imaging (MRI) is an excellent morphological imaging modality with a high anatomical resolution. Whole-body MRI produce large amounts of image data, resulting in the possibility of overlooking subtle pathological findings. The fusion of PET with MRI can compensate for their disadvantages and therefore offers several advantages in comparison to PET or MRI alone. The combination of these two excellent diagnostic imaging modalities into a single scanner improves the diagnostic accuracy by facilitating the accurate registration of molecular aspects and metabolic alterations of the diseases with exact correlation to anatomical findings and morphological information. Whole-body PET/MRI is a very promising diagnostic modality for oncological imaging and for use in cancer screening in the decades to come due to the considerably lower radiation exposure in contrast to PET/CT and the high soft tissue resolution of MRI.
Mitochondrial Correlation Microscopy and Nanolaser Spectroscopy — New Tools for Biophotonic Detection of Cancer in Single Cells
Authors: Gourley Paul L. , Hendricks Judy K. , McDonald Anthony E. , Copeland R. Guild , Barrett Keith E. , Gourley Cheryl R. , Singh Keshav K , Naviaux Robert K.
Published: October 2014

Currently, pathologists rely on labor-intensive microscopic examination of tumor cells using century-old staining methods that can give false readings. Emerging BioMicroNano-technologies have the potential to provide accurate, realtime, high-throughput screening of tumor cells without the need for time-consuming sample preparation. These rapid, nanooptical techniques may play an important role in advancing early detection, diagnosis, and treatment of disease. In this report, we show that laser scanning confocal microscopy can be used to identify a previously unknown property of certain cancer cells that distinguishes them, with single-cell resolution, from closely related normal cells. This property is the correlation of light scattering and the spatial organization of mitochondria. In normal liver cells, mitochondria are highly organized within the cytoplasm and highly scattering, yielding a highly correlated signal. In cancer cells, mitochondria are more chaotically organized and poorly scattering. These differences correlate with important bioenergetic disturbances that are hallmarks of many types of cancer. In addition, we review recent work that exploits the new technology of nanolaser spectroscopy using the biocavity laser to characterize the unique spectral signatures of normal and transformed cells. These optical methods represent powerful new tools that hold promise for detecting cancer at an early stage and may help to limit delays in diagnosis and treatment.
Fluorescent Nanoparticle Probes for Cancer Imaging
Authors: Santra Swadeshmukul , Dutta Debamitra , Walter Glenn A. , Moudgil Brij M.
Published: October 2014

Optical imaging technique has strong potential for sensitive cancer diagnosis, particularly at the early stage of cancer development. This is a sensitive, non-invasive, non-ionizing (clinically safe) and relatively inexpensive technique. Cancer imaging with optical technique however greatly relies upon the use of sensitive and stable optical probes. Unlike the traditional organic fluorescent probes, fluorescent nanoparticle probes such as dye-doped nanoparticles and quantum dots (Qdots) are bright and photostable. Fluorescent nanoparticle probes are shown to be very effective for sensitive cancer imaging with greater success in the cellular level. However, cancer imaging in an in vivo setup has been recently realized. There are several challenges in developing fluorescent nanoparticle probes for in vivo cancer imaging applications. In this review, we will discuss various aspects of nanoparticle design, synthesis, surface functionalization for bioconjugation and cancer cell targeting. A brief overview of in vivo cancer imaging with Qdots will also be presented.
Lasers in Cancer Detection and Diagnosis Research: Enabling Characteristics with Illustrative Examples
Authors: Alfano Scott , Wang W. B. , Gayen S. K.
Published: October 2014

The salient properties of laser light and the way light interacts with biological tissues and molecular constituents of tissues offer possibilities for detection and diagnosis of cancer. In particular, the wavelength selectivity of tunable lasers, narrow bandwidth around the selected wavelength, and spectral brightness enable probing of key molecular constituents of tissues, and endow laser-based techniques with much desired diagnostic potential. This article presents an overview of some recent developments in optical imaging and optical biopsy of different types of cancers, and illustrates the diagnostic role of the color of light.
Cancer Cells Ablation with Irreversible Electroporation
Authors: Miller Liron , Leor Jonathan , Rubinsky Boris
Published: October 2014

In this study we perform in vitro irreversible electroporation (IRE) experiments with human hepatocarcinoma cells (HepG2) to investigate IRE as a new technique for undesirable tissue ablation. Irreversible electroporation (IRE) is the irreversible permeabilization of the cell membrane through the application of microsecond through millisecond electrical pulses. Until now IRE was studied only as an undesirable condition during the use of reversible electroporation in gene therapy and electrochemotherapy. There was a possibility that the IRE ablation domain is mostly superimposed on the electrical pulses induced Joule heating thermal ablation domain. This study demonstrates that there is a real and substantial domain of electrical parameters for IRE ablation of cancer that is distinct from the thermal domain and which results in complete cancer cell ablation. Experiments show that the application of 1500 V/cm in three sets of ten pulses of 300 microseconds each can produce complete cancer cell ablation. We also find that the use of multiple pulses appears to be more effective for cancer cell ablation than the application of the same energy in one single pulse.
Technical Note: Gold Marker Implants and High-Frequency Jet Ventilation for Stereotactic, Single-Dose Irradiation of Liver Tumors
Authors: Fritz Peter , Kraus Hans-Jörg , Dölken Wolfram , Mühlnickel Werner , Müller-Nolte Franz , Hering Werner
Published: October 2014

With reference to radiosurgery of the liver, we describe techniques designed to solve the methodological problem of striking targets subject to respiratory motion with the necessary precision. Implanting a gold marker in the vicinity of the liver tumor was the first step in ensuring the reproducibility of the isocenter's position. An 18-karat gold rod measuring 1.9 × 3 mm was implanted approximately 2 cm from the edge of the tumor as this was displayed in the spiral, thin-slice CT with contrast media. Both the implantation of the marker and the required, CT-controlled biopsy of the liver tumor can be achieved simultaneously with the same puncture needle. The efficiency of high-frequency jet ventilation (HFJV) in neutralizing the targeted organ's respiratory motion during stereotactic single-dose irradiation was evaluated. The procedure was carried out on ten patients without any complications. In the time between treatment planning and irradiation (3 days), no significant marker migration was observable. In all cases, the gold marker (volume: 7.5 mm3) was readily observable in the treatment beam using portal imaging. HFJV provided reliable immobilization. The liver motion in each anesthetized patient was limited to under 3.0 mm in all directions. Thus, the correct field settings and target reproducibility were able to be analyzed and documented during the irradiation. The combination of marker and HFJV enables the determination of stereotactic coordinates directly related to the liver itself and, in this way, stereotactic radiation treatment of liver tumors is freed from the uncertainties involved in orientation to bony landmarks, in respiratory motion, and in changes of position in the stereotactic body frame. The method is feasible and can improve the accuracy of stereotactic body radiation therapy.
Serum Proteomic Pattern Analysis for Early Cancer Detection
Authors: Liu Ying
Published: October 2014

The ability of physicians to effectively treat and cure cancer is directly dependent on their ability to detect cancers at their early stages. The early detection of cancer has the potential to dramatically reduce mortality. Recently, the use of mass spectrometry to develop profiles of patient serum proteins has been reported as a promising method to achieve this goal. In this paper, we analyzed the ovarian cancer and prostate cancer data sets using support vector machine (SVM) to detect cancer at the early stages based on serum proteomic pattern. The results showed that SVM, in general, performed well on these two data sets, as measured by sensitivity, specificity, positive predictive value, negative predictive value, and accuracy. Linear kernel worked the best on ovarian cancer data with a sensitivity of 0.99 and an accuracy of 0.97, while polynomial kernel worked the best on prostate cancer data with a sensitivity of 0.79 and an accuracy of 0.82. When redial kernel was applied to either of the two data sets, all the samples were predicted as cancer samples, with a sensitivity of 1 and a specificity of 0. Furthermore, feature selection did not improve SVM performance.
Protein Profiling of Bladder Cancer Using the 2D-PAGE and SELDI-TOF-MS Technique
Authors: Langbein S. , Lehmann J. , Harder A. , Steidler A. , Michel M. S. , Alken P. , Badawi J. K.
Published: October 2014

Protein profiling is a promising tool for tumor characterization and the detection of tumor markers in bladder cancer. Techniques for 2-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and surface-enhanced laser desorption/ionization with time-of-flight mass spectrometry (SELDI-TOF-MS) have improved; both were evaluated using bladder tumor tissue. Normal urothelium and pTa G2, pT1 G3, and ≥pT3 G3 tissues were obtained from the operating room and, after macrodissection, subjected to 2D-PAGE and to SELDI-TOF-MS ProteinChip®. 2D-PAGE gels expressed significantly different protein patterns for pTa G2 and pT3 G3 tumors. pT1 G3 tumors showed expression profiles similar to those of the invasive tumors, with upregulation of galectin 3, gelsolin, villin 2, moesin, and annexin 6. Similarly, distinct protein peaks were detected for superficial and muscle-invasive urothelial cancers by SELDI-TOF-MS. Six of seven superficial pTa G2 tumors showed an intense peak at 6.7 and 10.1 kD, while invasive carcinomas showed an intense peak near 9.5 kD. No disturbing influence of surrounding tissue on the results was detected. It was shown that both techniques (2D-PAGE and ProteinChip) work well, and especially ProteinChip analysis seems promising for clinical application.
Considerations in Identifying Optimal Particles for Radiation Medicine
Authors: Slater James M.
Published: October 2014

Of the many ionizing particles discovered so far, only a few are reasonable to consider for radiation therapy. These include photons, protons, neutrons, electrons, mesons, antiprotons, and ions heavier than hydrogen. Most of these particles are used therapeutically to destroy or inactivate malignant and sometimes benign cells. Since the late 1930s, accelerators have been developed that have expanded radiation oncologists' abilities to produce various ionizing particle beams. Over the past decade, radiation oncologists have become increasingly interested in pursuing particles other than the conventional photons that have been used almost exclusively since X-rays were discovered in 1895. Physicians recognize that normal-tissue morbidity from all forms of anti-cancer treatment is the primary factor limiting the success of those treatments. In radiation therapy, all particles mentioned above can destroy any cancer cell; controlling the beam in three dimensions, thus providing the physician with the capability of avoiding normal-tissue injury, is the fundamental deficiency in the use of X-rays (photons). Heavy charged particles possess near-ideal characteristics for exercising control in three dimensions; their primary differences are due to the number of protons contained within their nuclei. As their number of protons increase (atomic number) their ionization density (LET) increases. In selecting the optimal particle for therapy from among the heavy charged particles, one must carefully consider the ionization density created by each specific particle. Ionization density creates both advantages and disadvantages for patient treatment; these factors must be matched with the patients' precise clinical needs. The current state of the art involves studying the clinical advantages and disadvantages of the lightest ion, the proton, as compared to other particles used or contemplated for use. Full analysis must await adequate data developed from long-term studies to determine the precise role of each potential particle for human use. It is expected that one particle beam will emerge as the mainstream for treating human disease, and a small number of particles may emerge in an adjunctive role.
A Quantitative Study of the Effects of Ionizing Radiation on Endothelial Cells and Capillary-like Network Formation
Authors: Mao Xiao Wen
Published: October 2014

The initial events of angiogenesis comprise endothelial cell activation, migration, and proliferation. The characteristics of retinal endothelial cells and capillaries are significantly altered in a number of diseases including cancer. Since radiation has been shown as a useful tool in radiotherapy by altering the proliferative changes, it is important to evaluate the responses of the endothelial cells and the capillary network to radiation. We quantified functional and kinetic responses of endothelial cells and capillaries to radiation in an in vitro model. An in vitro angiogenesis model was introduced in our study with endothelial cells cultured on an extracellular matrix gel in which hollow tube-like structures could be rapidly formed. Vessel formation was quantified using stereological techniques. The cell cycle kinetics of endothelial cells and accumulation of DNA damage after radiation were measured using laser scanning cytometry. To study the response of proliferative capillary-like structures to radiation, the vessel network was irradiated with 2 gray (Gy). To evaluate functional and kinetic responses and differentiation of endothelial cells to radiation, cells were irradiated with 2 and 6 Gy.

Progressive time- and dose-dependent loss of endothelial cells occurred starting 24 hours after radiation. Vessel growth was significantly retarded at the higher dose. A significant percentage of DNA breaks were detected dose-dependently. A large percentage of G1 cells were measured in the irradiated endothelial cell population when compared to the respective sham-treated control population. These results indicate that radiation-induced endothelial cell injuries destroy the integrity of vascular structure. We postulated that apoptosis may represent a biologically relevant mechanism of radiation-induced endothelial cell damage.
Molecular Biology of Human Gliomas
Authors: Bansal Krishan , Liang Muh Lii , Rutka James T.
Published: October 2014

Human gliomas are the most common primary central nervous system neoplasm, and they are a complex, heterogeneous, and difficult disease to treat. In the past two decades, advances in molecular biology have revolutionized our understanding of the mechanism by which these neoplasms are initiated and progress. While surgery, radiation therapy, and chemotherapy have roles to play in the treatment of patients with gliomas; these therapies are self-limited because of the intrinsic resistance of glioma cells to therapy, and the diffusely infiltrating nature of the lesions. It is now known that malignant gliomas arise from a number of well-characterized genetic alterations and activations of oncogenes and inactivation of tumor suppressor genes. These genetic alterations disrupt critical cell cycle, growth factor activation, apoptotic, cell motility, and invasion pathways that lead to phenotypic changes and neoplastic transformation. Research in each of these fields has uncovered potential therapeutic targets that look promising for disease control. Gliomas can now be modeled with fidelity and reproducibility using several transgenic and knockout strategies. Transgenic mouse models are facilitating the testing of various therapeutic strategies in vivo. Finally, the recognition of the putative brain tumor stem cell, the tumor initiating cell in brain cancer, provides an enticing target through which we could eliminate the source of the brain tumor with increased efficacy and less toxicity to normal tissues. In this review, we provide an up-to-date discussion of the many of key technologies and tools that are being used in molecular biology to advance our understanding of the biological behavior of human malignant gliomas.
A Multimodal Contrast Agent for Preoperative MR Imaging and Intraoperative Tumor Margin Delineation
Authors: Uzgiris Egidijus E. , Sood Anup , Bove Kathleen , Grimmond Brian , Lee Deborah , Lomnes Stephen
Published: October 2014

We have constructed a multimodal contrast agent suitable for near-infrared, NIR, fluorescent imaging as well as magnetic resonance imaging, MRI. This class of agents may be useful for preoperative tumor localization and tumor functional evaluation and for intraoperative delineation of tumor margins. We have covalently attached dyes of the cyanine family to a previously described polymeric contrast agent, Gd-DTPA-polylysine, of an extended, uncoiled conformation. The dual modality agent is as effective in imaging tumors by MRI as the parent compound provided that the dye loading on the polymer is such that it does not eliminate all the available free-lysine groups on the parent Gd-DTPA-polylysine polymers. NIR fluorescence from preclinical subcutaneous and orthotopic mammary gland tumors could be detected with a signal to background ratio of as high as 4.5 at 12 hours post agent injection at a dye dose of 125 nmole/kg. For intraoperative delineation of tumor margins, a wide-field illumination camera system was devised giving high signal to background NIR fluorescent images of surgically exposed orthotopic mammary gland tumors. Histologic microscopy confirmed the location of the dual modality agent at the boundary of the tumor with a margin distance of about 0.3 mm from labeled tumor cells.
Dual Energy CT Attenuation Correction Methods for Quantitative Assessment of Response to Cancer Therapy with PET/CT Imaging
Authors: Kinahan Paul E. , Alessio Adam M. , Fessler Jeffrey A.
Published: October 2014

We hypothesize that improved quantification for PET imaging of high atomic number materials can be achieved by combining low-dose x-ray imaging with dual energy CT for PET attenuation correction. Improved quantification of tracer uptake will lead to improved patient outcomes by providing more accurate information for therapeutic choices. Accurate PET/CT measurements of early response will be critical in determining the best cancer therapy option for each patient in a timely manner and in sparing patients the morbidity and cost of ineffective treatments. We first evaluate the potential errors in PET images arising from CT-based attenuation correction when iodine-based contrast is incorrectly classified as bone when forming the linear attenuation coefficient image. We then investigate two methods of reducing errors in the linear attenuation image: an approximate, but fast, hybrid classification/scaling algorithm and a model-based dual-energy CT method that incorporates the polyenergetic spectrum and a noise model in an iterative reconstruction method. Both methods are shown to reduce errors in the estimated linear attenuation coefficient image, but require further study to determine the effects of noise propagation if low-dose CT scans are used for the estimation of the linear attenuation image.
Progress in SPECT/CT Imaging of Prostate Cancer
Authors: Seo Youngho , Franc Benjamin L. , Hawkins Randall A. , Wong Kenneth H. , Hasegawa Bruce H.
Published: October 2014

Prostate cancer is the most common type of cancer (other than skin cancer) among men in the United States. Although prostate cancer is one of the few cancers that grow so slowly that it may never threaten the lives of some patients, it can be lethal once metastasized. Indium-111 capromab pendetide (ProstaScint®, Cytogen Corporation, Princeton, NJ) imaging is indicated for staging and recurrence detection of the disease, and is particularly useful to determine whether or not the disease has spread to distant metastatic sites. However, the interpretation of 111 In-capromab pendetide is challenging without correlated structural information mostly because the radiopharmaceutical demonstrates nonspecific uptake in the normal vasculature, bowel, bone marrow, and the prostate gland. We developed an improved method of imaging and localizing 111 In-Capromab pendetide using a SPECT/CT imaging system. The specific goals included: i) development and application of a novel iterative SPECT reconstruction algorithm that utilizes a priori information from coregistered CT; and ii) assessment of clinical impact of adding SPECT/CT for prostate cancer imaging with capromab pendetide utilizing the standard and novel reconstruction techniques.

Patient imaging studies with capromab pendetide were performed from 1999 to 2004 using two different SPECT/CT scanners, a prototype SPECT/CT system and a commercial SPECT/CT system (Discovery VH, GE Healthcare, Waukesha, WI). SPECT projection data from both systems were reconstructed using an experimental iterative algorithm that compensates for both photon attenuation and collimator blurring. In addition, the data obtained from the commercial system were reconstructed with attenuation correction using an OSEM reconstruction supplied by the camera manufacturer for routine clinical interpretation. For 12 sets of patient data, SPECT images reconstructed using the experimental algorithm were interpreted separately and compared with interpretation of images obtained using the standard reconstruction technique. The experimental reconstruction algorithm improved spatial resolution, reduced streak artifacts, and yielded a better correlation with anatomic details of CT in comparison to conventional reconstruction methods ( e.g., filtered back-projection or OSEM with attenuation correction only). Images produced with the experimental algorithm produced a subjective improvement in the confidence of interpretation for 11 of 12 studies. There were also changes in interpretations for 4 of 12 studies although the changes were not sufficient to alter prognosis or the patient treatment plan.
Combined Diffuse Optical Tomography (DOT) and MRI System for Cancer Imaging in Small Animals
Authors: Gulsen Gultekin , Birgul Ozlem , Unlu Mehmet Burcin , Shafiiha Roshanak , Nalcioglu Orhan
Published: October 2014

Recently, there has been a great amount of interest in developing multi-modality imaging techniques for oncologic research and clinical studies with the aim of obtaining complementary information and, thus, improving the detection and characterization of tumors. In this present work, the details of a combined MR-diffuse optical imaging system for dual-modality imaging of small animals are given. As a part of this effort, a multi-spectral frequency domain diffuse optical tomography system is integrated with an MRI system. Here, a network analyzer provides the rf modulation signal for the laser diodes and measures the amplitude and the phase of the detected signals. Photomultiplier tubes are utilized to measure low-level signals. The integration of this optical imaging system with the 4T MRI system is realized by incorporating a fiber adaptive interface inside the MR magnet. Coregistration is achieved by a special probe design utilizing fiducial markers. A finite element algorithm is used to solve the diffusion equation and an inverse solver based on this forward solver is implemented to calculate the absorption and scattering maps from the acquired data. The MR a priori information is used to guide the optical reconstruction algorithm. Phantom studies show that the absorption coefficient of a 7 mm inclusion in an irregular object located in 64 mm phantom is recovered with 11% error when MR a priori information is used. ENU induced tumor model is used to test the performance of the system in vivo.
A Computer-Aided Method to Expedite the Evaluation of Prognosis for Childhood Acute Lymphoblastic Leukemia
Authors: Wang Xingwei , Li Shibo , Liu Hong , Mulvihill John J. , Chen Wei , Zheng Bin
Published: October 2014

This study presented a fully-automated computer-aided method (scheme) to detect metaphase chromosomes depicted on microscopic digital images, count the total number of chromosomes in each metaphase cell, compute the DNA index, and correlate the results to the prognosis of childhood acute lymphoblastic leukemia (ALL). The computer scheme first uses image filtering, threshold, and labeling algorithms to segment and count the number of the suspicious “chromosome,” and then computes a feature vector for each “detected chromosome.” Based on these features, a knowledge-based classifier is used to eliminate those “non-chromosome” objects ( i.e., inter-phase cells, stain debris, and other kinds of background noises). Due to the possible overlap of the chromosomes, a classification criterion was used to identify the overlapped chromosomes and adjust the initially counted number of the total chromosomes in each image. In this preliminary study with 60 testing images (depicting metaphase chromosome cells) acquired from three pediatric patients, the computer scheme generated results matched with the diagnostic results provided by the clinical cytogeneticists. The results demonstrated the feasibility or potential of using a computerized method to replace the tedious and the reader-dependent diagnostic methods commonly used in genetic laboratories to date.
Radiation-Guided Gene Therapy of Cancer
Authors: Han Zhaozhong , Wang Hailun , Hallahan Dennis E.
Published: October 2014

Gene therapy has been proposed as a means to combat cancer. However, systemic toxicity observed in preclinical trials suggested the importance of selectively targeted delivery and inducible gene expression in tumor tissues. Discovery of radiation-inducible promoter sequences provides one way to minimize inadvertent toxicity from gene therapy in normal tissues. Radiation is administered to selectively induce cytotoxic gene expression in the targeted tumor tissues. With promising results from phase II clinical trials using TNF-expressing adenovirus, it is possible to have radiation-guided gene therapy regimes once the tumor-targeted delivery has been achieved. Tumor endothelium is an attractive biological target for gene therapy, because it has the advantage of stability, accessibility, and bioavailability for therapeutic agents. Technological development of DNA microarray, proteomic profiling, and phage-displayed libraries accelerates the identification of tumor-specific endothelial biomarkers and discovery of its relevant affinity reagents for targeted delivery. The application of radiation-guided gene delivery, its amplification, as well as expression of gene therapy presents great opportunities to be employed as an alternative cancer treatment.
New Developments in Intensity Modulated Radiation Therapy
Authors: Yu Cedric , Shepard David , Earl Matt , Cao Daliang , Luan Shuang , Wang Chao , Chen Danny Z.
Published: October 2014

As intensity modulated radiation therapy (IMRT) becomes routine clinical practice, its advantages and limitations are better understood. With these new understandings, some new developments have emerged in an effort to alleviate the limitations of the current IMRT practice. This article describes a few of these efforts made at the University of Maryland, including: i) improving IMRT efficiency with direct aperture optimization; ii) broadening the scope of optimization to include the mode of delivery and beam angles; and iii) new planning methods for intensity modulated arc therapy (IMAT).
Clinical Implementation of Adaptive Helical Tomotherapy: A Unique Approach to Image-Guided Intensity Modulated Radiotherapy
Authors: Welsh James S. , Lock Michael , Harari Paul M. , Tomé Wolfgang A. , Fowler Jack , Mackie Thomas Rockwell , Ritter Mark , Kapatoes Jeff , Forrest Lisa , Chappell Richard , Paliwal Bhudatt , Mehta Minesh P.
Published: October 2014

Image-guided IMRT is a revolutionary concept whose clinical implementation is rapidly evolving. Methods of executing beam intensity modulation have included individually designed compensators, static multi-leaf collimators (MLC), dynamic MLC, and sequential (serial) tomotherapy. We have developed helical tomotherapy as an innovative solution to overcome some of the limitations of other IMRT systems. The unique physical design of helical tomotherapy allows the realization of the concepts of adaptive radiotherapy and conformal avoidance. In principle, these advances should improve normal tissue sparing and permit dose reconstruction and verification, thereby allowing significant biologically effective dose escalation.

Recent radiobiological findings can be translated into altered fractionation schemes that aim to improve the local control and long-term survival. This strategy is being tested at the University of Wisconsin using helical tomotherapy with its highly precise delivery and verification system along with meticulous and practical forms of immobilization. Innovative techniques such optical guidance, respiratory gating, and ultrasound assessments are being designed and tailored for helical tomotherapy use. The intrinsic capability of helical tomotherapy for megavoltage CT (MVCT) imaging for IMRT image-guidance is being optimized.

The unique features of helical tomotherapy might allow implementation of image-guided IMRT that was previously impossible or impractical. Here we review the technological, physical, and radiobiological rationale for the ongoing and upcoming clinical trials that will use image-guided IMRT in the form of helical tomotherapy; and we describe our plans for testing our hypotheses in a rigorous prospective fashion.