bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlating the Ground Truth of Mammographic Histology with the Success or Failure of Imaging
Authors: Tot Tibor
Published: October 2014

Detailed and systematic mammographic-pathologic correlation is essential for evaluation of the advantages and disadvantages of mammography as an imaging method as well as for establishing the role of additional methods or alternatives. Two- and three-dimensional large section histopathology represents an ideal tool for this correlation. This kind of interdisciplinary approach (“mammographic histology”) is slowly but irrevocably becoming accepted as the new golden standard in diagnosing breast abnormalities. In this review, upon summarizing the theoretical background and our practical experience in routine diagnostic use of these advantageous techniques, we report on the accuracy of the preoperative radiological diagnosis. As compared to the final diagnostic outcome, stellate lesions on the mammogram and microcalcifications of casting type indicate malignancy with very high accuracy while predicting malignancy in cases of powdery and crushed stone type microcalcifications is problematic. The extent of the disease is regularly underestimated on the mammogram by the radiologist. Combining different radiological signs, and comparing repeated static images taken in regular intervals in screening or postoperative follow-up, the mammographer may type and grade the lesions properly in a considerable number of cases. Regular mammographic-pathologic correlation may increase the specificity and sensitivity of mammographic diagnosis. This correlation is essential for establishing the proper pre- and postoperative histological diagnosis, too.
3D Breast Image Registration — A Review
Authors: Sivaramakrishna Radhika
Published: October 2014

Image registration is an important problem in breast imaging. It is used in a wide variety of applications that include better visualization of lesions on pre- and post-contrast breast MRI images, speckle tracking and image compounding in breast ultrasound images, alignment of positron emission, and standard mammography images on hybrid machines et cetera. It is a prerequisite to align images taken at different times to isolate small interval lesions. Image registration also has useful applications in monitoring cancer therapy. The field of breast image registration has gained considerable interest in recent years. While the primary focus of interest continues to be the registration of pre- and post-contrast breast MRI images, other areas like breast ultrasound registration have gained more attention in recent years. The focus of registration algorithms has also shifted from control point based semiautomated techniques, to more sophisticated voxel based automated techniques that use mutual information as a similarity measure. This paper visits the problem of breast image registration and provides an overview of the current state-of-the-art in this area.
Review of Monoisocentric Split-Field Technique for Conventional and IMRT Treatment in Head and Neck Cancers: Technical Limitations and Approaches for Optimization
Authors: Abdel-Hakim Khaled , Nishimura Tetsuo , Takai Michikatsu , Sakahara Harumi
Published: October 2014

The importance of treatment planning of head and neck malignancies arises from the necessity to achieve homogenous doses to localized target volume surrounded by normal structures, which can produce acute and long-term morbidity. In many radiotherapy departments, a commonly employed strategy is a 3-field technique. Bilateral parallel-opposed fields are matched to anterior lower neck field. In recent years, Intensity Modulated Radiotherapy (IMRT) is used to radiate head and neck tumors. When the target extends to the lower neck regions, abutment of upper IMRT and lower neck fields is required. Field matching represents a technical challenge for the medical physicist, medical engineer, and radiation oncologist to treat multiple fields while avoiding their overlap on the spinal cord. The monoisocentric split field technique has recently become a common technique to achieve matchline homogenous dose while respecting normal tissue tolerance. The aim of this work is to review merits, limitations, and recent approaches to optimize matchline dose in monoisocentric technique in conventional and intensity modulated radiotherapy for head and neck cancers. Although the technique has many advantages, it is subjected to some systematic and random errors due to equipment and patient setup inaccuracies. To decrease the magnitude of matchline inhomogeneities, customized penumbra generator or multileaf collimator have been used. Both methods are viable and represent alternative approaches to the problem of field matching using the asymmetric jaws.
Reconstruction of 3D Regions-of-Interest from Data in Reduced Helical Cone-beam Scans
Authors: Pan Xiaochuan , Zou Yu , Xia Dan , Sidky Emil Y.
Published: October 2014

The suffciency conditions are derived for exact image reconstruction of a 3D ROI from projections acquired with a reduced helical scan over an angular range considerably smaller than that required by image reconstruction in, e.g., the conventional long object problem, for which the scanned angular range is often more than 2π. ROI reconstruction is investigated by a recently developed filtered-backprojection algorithm that can make use of data acquired with a reduced helical scan. Preliminary numerical studies demonstrate and validate the ROI reconstruction. This work may have significant practical implications because a reduced scan in CT often translates to reduced motion artifacts and reduced radiation dose delivered to the subject.
Enhancement of Drug Delivery in Tumors by Using Interaction of Nanoparticles with Ultrasound Radiation
Authors: Larina Irina V. , Evers B. Mark , Ashitkov Taras V. , Bartels Christian , Larin Kirill V. , Esenaliev Rinat O.
Published: October 2014

Efficacy and safety of cancer chemo- and biotherapy are limited by poor penetration of anti-cancer drugs from blood into tumor cells. Tumor blood vessel wall, slow diffusion in the interstitium, and cancer cell membrane create physiological barriers for anti-cancer drugs, in particular promising macromolecular agents. Recently, we proposed to use selective accumulation of exogenous nano- and microparticles in tumors followed by ultrasound-induced cavitation for safe and efficient drug and gene delivery. In this paper, we first investigated the influence of polystyrene nanoparticles (100 and 280 nm in diameter and concentration up to 0.2% w/w) on cavitation threshold in water at the frequency of 20 kHz. Then, using optimal irradiation parameters found in the first part of this work, we studied efficacy of cancer chemotherapy with this technique. The experiments were performed in athymic nude mice bearing human colon KM20 tumors, which are highly resistant to chemotherapy. Ultrasound with the frequency of 20 kHz in combination with i.v. injected polystyrene nanoparticles was applied to enhance delivery of chemotherapeutic agent 5-fluorouracil. Our studies demonstrated that ultrasound irradiation in combination with the nanoparticle and drug injections significantly decreased tumor volume and resulted in complete tumor regression at optimal irradiation conditions, while the volume of control (non-irradiated) tumors increased despite drug injections. These data suggest that ultrasound-induced drug delivery may improve efficacy of current cancer treatment regimens.
Optical Detection of Tumors In Vivo by Visible Light Tissue Oximetry
Authors: Maxim Peter G. , Carson Jeffrey J. L. , Benaron David A. , Loo Billy W. , Xing Lei , Boyer Arthur L. , Friedland Shai
Published: October 2014

Endoscopy is a standard procedure for identifying tumors in patients suspected of having gastrointestinal (G.I.) cancer. The early detection of G.I. neoplasms during endoscopy is currently made by a subjective visual inspection that relies to a high degree on the experience of the examiner. This process can be difficult and unreliable, as tumor lesions may be visually indistinguishable from benign inflammatory conditions and the surrounding mucosa. In this study, we evaluated the ability of local ischemia detection using visible light spectroscopy (VLS) to differentiate neoplastic from normal tissue based on capillary tissue oxygenation during endoscopy. Real-time data were collected (i) from human subjects (N=34) monitored at various sites during endoscopy (enteric mucosa, malignant, and abnormal tissue such as polyps) and (ii) murine animal subjects with human tumor xenografts. Tissue oximetry in human subjects during endoscopy revealed a tissue oxygenation (StO2%, mean ± SD) of 46 ± 22% in tumors, which was significantly lower than for normal mucosal oxygenation (72 ± 4%; P ≤ 0.0001). No difference in tissue oxygenation was observed between normal and non-tumor abnormal tissues ( P = N.S.). Similarly, VLS tissue oximetry for murine tumors revealed a mean local tumor oxygenation of 45% in LNCaP, 50% in M21, and 24% in SCCVII tumors, all significantly lower than normal muscle tissue (74%, P < 0.001). These results were further substantiated by positive controls, where a rapid real-time drop in tumor oxygenation was measured during local ischemia induced by clamping or epinephrine. We conclude that VLS tissue oximetry can distinguish neoplastic tissue from normal tissue with a high specificity (though a low sensitivity), potentially aiding the endoscopic detection of gastrointestinal tumors.
Dexamethasone Normalizes Brain Tumor Hemodynamics as Indicated by Dynamic Susceptibility Contrast MRI Perfusion Parameters
Authors: Quarles Christopher C. , Krouwer Hendrikus G. J. , Rand Scott D. , Schmainda Kathleen M.
Published: October 2014

The purpose of this study is to demonstrate the utility of dynamic susceptibility contrast (DSC) MRI-derived perfusion parameters to characterize the hemodynamic effects of dexamethasone in a 9L gliosarcoma tumor model. Twenty-four rats underwent intracerebral inoculation with 9L tumor cells. Fifteen were treated with a total of 3mg/kg of dexamethasone on days 10–14 post-inoculation, while the remaining 9 rats served as controls. Fourteen days post-inoculation, MRI images, sensitive to total and micro-vascular cerebral blood flow (CBF), mean transit time (MTT), and intravoxel transit time distributions (TTD)s were obtained using a simultaneous gradient-echo(GE)/spin-echo(SE) DSC-MRI method. Dexamethasone-treated animals had a microvascular (SE) tumor CBF that was 45.9% higher ( p = 0.0008) and a MTT that was 47.8% lower ( p = 0.0005) than untreated animals. With treatment, there was a non-significant 91.3% increase in total (GE) vascular CBF ( p = 0.35), and a significant decrease in MTT (49.1%, p = 0.02). The total vascular and microvascular TTDs from the treated tumors were similar to normal brain, unlike the TTDs in the untreated tumors. These findings demonstrate that DSC-MRI perfusion methods can be used to non-invasively detect the morphological and functional changes in tumor vasculature that occur in response to dexamethasone treatment.
A Review of Progress in Clinical Photodynamic Therapy
Authors: Huang Zheng
Published: October 2014

Photodynamic therapy (PDT) has received increased attention since the regulatory approvals have been granted to several photosensitizing drugs and light applicators worldwide. Much progress has been seen in basic sciences and clinical photodynamics in recent years. This review will focus on new developments of clinical investigation and discuss the usefulness of various forms of PDT techniques for curative or palliative treatment of malignant and non-malignant diseases.
Pancreatic Cancer Epidemiology
Authors: Verma Mukesh
Published: October 2014

Carcinoma of the exocrine pancreas remains a challenging disease mainly due to advanced stage diagnosis, the early systemic dissemination, aggressive local tumor progression, and subsequent short patient survival. Thus, assessment of incidence markers instead of prevalence indicators is recommended because the time between diagnosis and death is usually very short. Investigations to date have led to the discovery of many rare genes and environmental factors that contribute to pancreatic cancer. However, common genes involved in genetic polymorphisms, and specific risk factors have not been identified. Furthermore, the role of gene-environment interactions on the tumorogenesis and progression of pancreatic cancer need to be further investigated. Given current therapeutic modalities, only early detection of cancer of the pancreas, followed by surgical resection, offers the possibility of lengthening survival time.
Targeted Drug Delivery for Cancer
Authors: Jain K. K.
Published: October 2014

Cancer drug delivery is no longer simply wrapping the drug in new formulations for different routes of delivery. Knowledge and experience from other technologies such as nanotechnology, advanced polymer chemistry, and electronic engineering, are being brought together in developing novel methods of drug delivery. Advances in our knowledge of molecular biology of cancer and pathways involved in malignant transformation of cells are revolutionizing the approach to cancer treatment with a focus is on targeted cancer therapy. The newer approaches to cancer treatment not only supplement the conventional chemotherapy and radiotherapy but also aim to prevent damage to the normal tissues and overcome drug resistance. Innovative methods of cancer treatment require new concepts of drug delivery in cancer.
Delivery of Antiangiogenic Agents for Cancer Gene Therapy
Authors: Dickson Paxton V. , Nathwani Amit C. , Davidoff Andrew M.
Published: October 2014

The understanding that tumor growth and metastasis are angiogenesis dependent processes has led to interest in targeting tumor vasculature in anticancer therapy. Furthermore, recent insights into the molecular interactions that orchestrate physiologic and pathologic angiogenesis have resulted in a variety of antiangiogenic strategies. A gene therapy-mediated approach for the delivery of antiangiogenic agents has several advantages, including the potential for sustained expression. However, the choice of angiogenesis inhibitor, method of gene delivery, and target/site for transgene expression are important variables to be considered when designing this approach. Here we review the major alternatives within each of these categories and provide illustrative examples of their use in preclinical models.
Targeted Cancer Therapy Using Radiolabeled Monoclonal Antibodies
Authors: Bethge Wolfgang A. , Sandmaier Brenda M.
Published: October 2014

Radioimmunotherapy (RIT) combines the advantages of targeted radiation therapy and specific immunotherapy using monoclonal antibodies. RIT can be used either to target tumor cells or to specifically suppress immunocompetent host cells in the setting of allogeneic transplantation. The choice of radionuclide used for RIT depends on its distinct radiation characteristics and the type of malignancy or cells targeted. Beta-emitters with their lower energy and longer path length are more suitable to target bulky, solid tumors whereas α-emitters with their high linear energy transfer and short path length are better suited to target hematopoietic cells (normal or malignant). Different approaches of RIT such as the use of stable radioimmunoconjugates or of pretargeting strategies are available. Encouraging results have been obtained with RIT in patients with hematologic malignancies. The results in solid tumors are somewhat less favorable but new strategies for patients with minimal residual disease using adjuvant and locoregional treatment are evolving. This report outlines basic principles of RIT, gives an overview of available radionuclides and radioimmunoconjugates, and discusses clinical results with special emphasis on their use in hematologic malignancies including use in conditioning regimens for bone marrow transplantation.
Nanotechnology-based Drug Delivery for Cancer
Authors: Jain K. K.
Published: October 2014

Nanobiotechnologies have been applied to improve drug delivery and to overcome some of the problems of drug delivery in cancer. These can be classified into many categories that include use of various nanoparticles, nanoencapsulation, targeted delivery to tumors of various organs, and combination with other methods of treatment of cancer such as radiotherapy. Nanoparticles are also used for gene therapy for cancer. Some of the technologies enable combination of diagnostics with therapeutics which will be important for the personalized management of cancer. Some of the limitations of these technologies and prospects for future development are discussed.
Protein Fingerprints of Anti-cancer Effects of Cyclin-dependent Kinase Inhibition: Identification of Candidate Biomarkers Using 2-D Liquid Phase Separation Coupled to Mass Spectrometry
Authors: Skalnikova Helena , Halada Petr , Dzubak Petr , Hajduch Marian , Kovarova Hana
Published: October 2014

The purpose of this study was to apply a recently introduced proteomic based approach to identify candidate biomarkers of the response to anticancer activity of cyclin-dependent kinase inhibitor, bohemine. Mapping of the total protein expression of CEM lymphoblastic leukemia cells following bohemine treatment was performed by 2-D liquid phase separation. Proteins were fractionated by isoelectric points in pH gradient in the first dimension and each of these pI protein fractions was further separated by hydrophobicity using non-porous silica reverse phase chromatography in the second dimension. 2-D protein expression maps of control untreated and bohemine treated cells were generated and inter-sample comparison was performed. Most of the differentially expressed proteins were present at a decreased level after bohemine treatment while there were four proteins, which were up regulated. These proteins representing candidate biomarkers of cancer cell response to the treatment were selected for identification by mass spectrometry. Our results demonstrating down regulation of three histone variants, different in their pI and hydrophobicity, in response to bohemine indicated that anti-mitotic and anti-cancer activities of this compound may be associated with epigenetic regulation at the level of chromatin structure. Furthermore, crk-like adaptor scaffolding protein represents a new important protein family affected by bohemine. This strategy is valuable for comprehensive proteomic analysis of cellular protein targets and pathways that are relevant to anticancer activity of cyclin-dependent kinase inhibition.
Optical Biopsy of Lymph Node Morphology using Optical Coherence Tomography
Authors: Luo Wei , Nguyen Freddy T. , Zysk Adam M. , Ralston Tyler S. , Brockenbrough John , Marks Daniel L. , Oldenburg Amy L. , Boppart Stephen A.
Published: October 2014

Optical diagnostic imaging techniques are increasingly being used in the clinical environment, allowing for improved screening and diagnosis while minimizing the number of invasive procedures. Diffuse optical tomography, for example, is capable of whole-breast imaging and is being developed as an alternative to traditional X-ray mammography. While this may eventually be a very effective screening method, other optical techniques are better suited for imaging on the cellular and molecular scale. Optical Coherence Tomography (OCT), for instance, is capable of high-resolution cross-sectional imaging of tissue morphology. In a manner analogous to ultrasound imaging except using optics, pulses of near-infrared light are sent into the tissue while coherence-gated reflections are measured interferometrically to form a cross-sectional image of tissue. In this paper we apply OCT techniques for the high-resolution three-dimensional visualization of lymph node morphology. We present the first reported OCT images showing detailed morphological structure and corresponding histological features of lymph nodes from a carcinogen-induced rat mammary tumor model, as well as from a human lymph node containing late stage metastatic disease. The results illustrate the potential for OCT to visualize detailed lymph node structures on the scale of micrometastases and the potential for the detection of metastatic nodal disease intraoperatively.
Coregistration of Dynamic Contrast Enhanced MRI and Broadband Diffuse Optical Spectroscopy for Characterizing Breast Cancer
Authors: Hsiang David , Shah Natasha , Yu Natasha , Su Min-Ying , Cerussi Albert , Butler John , Baick Choong , Mehta Rita , Nalcioglu Orhan , Tromberg Bruce
Published: October 2014

A handheld scanning probe based on broadband Diffuse Optical Spectroscopy (DOS) was used in combination with dynamic contrast enhanced MRI (DCE-MRI) to quantitatively characterize locally-advanced breast cancers in six patients. Measurements were performed sequentially using external fiducial markers for co-registration. Tumor patterns were categorized according to MRI morphological data, and 3D DCE-MRI slices were converted into a volumetric matrix with isotropic voxels to generate views that coincided with the DOS scanning plane. Tumor volume and depth at each DOS measurement site were determined, and a tissue optical index (TOI) that reflects both angiogenic and stromal characteristics was derived from broadband DOS data.

In all six cases, optical scans showed significant TOI contrast corresponding to MRI morphological information. Sharp TOI peaks were recovered for well-circumscribed masses. A reduction in TOI was found inside a tumor with a necrotic center. A broadened peak was observed for a diffuse tumor pattern, and an inflammatory septal case provided two TOI peaks that correlated qualitatively with MRI enhancement. These results provide qualitative confirmation of the common signal origin and complementary information content that can be achieved by combining optical and MR imaging for breast cancer detection and clinical management.
Long-Circulating Polymeric Nanovectors for Tumor-Selective Gene Delivery
Authors: Kommareddy Sushma , Tiwari Sandip B. , Amiji Mansoor M.
Published: October 2014

Significant advances in the understanding of the genetic abnormalities that lead to the development, progression, and metastasis of neoplastic diseases has raised the promise of gene therapy as an approach to medical intervention. Most of the clinical protocols that have been approved in the United States for gene therapy have used the viral vectors because of the high efficiency of gene transfer. Conventional means of gene delivery using viral vectors, however, has undesirable side effects such as insertion of mutational viral gene into the host genome and development of replication competent viruses. Among non-viral gene delivery methods, polymeric nanoparticles are increasingly becoming popular as vectors of choice. The major limitation of these nanoparticles is poor transfection efficiency at the target site after systemic administration due to uptake by the cells of reticuloendothelial system (RES). In order to reduce the uptake by the cells of the RES and improve blood circulation time, these nanoparticles are coated with hydrophilic polymers such as poly(ethylene glycol) (PEG). This article reviews the use of such hydrophilic polymers employed for improving the circulation time of the nanocarriers. The mechanism of polymer coating and factors affecting the circulation time of these nanocarriers will be discussed. In addition to the long circulating property, modifications to improve the target specificity of the particles and the limitations of steric protection will be analyzed.
Targeted Gene Delivery to Cancer Cells with Nanometric DNA Particles Enveloped with Folic Acid Using a Polymerisable Anchor
Authors: Zuber Guy , Muller Christian D. , Behr Jean-Paul
Published: October 2014

Progress in the design of gene delivery system is vital for cancer gene therapy since many physiological and intracellular barriers remain. We have developed a technology for condensing genes into nanometric delivery systems. In this paper, we present a novel strategy for decorating 30 nm DNA particles with folic acid for cancer cell recognition. Physicochemical and biological experiments show that these DNA complexes selectively bind to cells expressing the corresponding folic acid receptor.
Evaluation of Integral Dose in Cranio-spinal Axis (CSA) Irradiation with Conventional and Helical Delivery
Authors: Peñagarícano José A. , Shi Chengyu , Ratanatharathorn Vaneerat
Published: October 2014

In cranio-spinal axis (CSA) irradiation, patients are usually treated in the prone position with junctions between cranial and spinal fields. Collimator angle and pedestal rotations are introduced to obtain coplanar alignment of the matched junction. Furthermore, daily moving junctions are commonly used to feather out the junctional dose as additional safe-guards to avoid radiation myelopathy.

Helical tomotherapy integrates linear accelerator and CT technology capable of delivering CSA treatment without geometric matches or feathering of junctions. The patient is treated with helical beams in the supine position. Since CSA is used mainly in the pediatric population, the potential increase in integral dose to structures or the whole body from linac- or tomotherapy-based IMRT raises concerns of increased rates of secondary malignancies.

In this study, we will present an integral dose comparison between conventional CSA (3D) and helical delivery to the CSA (TOMO) utilizing the Tomotherapy Hi-ART system for three pediatric patients. Integral dose was calculated for organ at risk (OAR), two targets (PTV-BRAIN and PTV-SPINE), entire planning CT data set and to the healthy tissue (entire CT-DATA SET minus the PTV).

Overall integral dose was 8% higher in the TOMO plans for Patients #1 and #3, but 2% lower in Patient #2. DVH analysis shows that TOMO plans give lower doses to larger volumes and higher doses to smaller volumes of tissue in all three cases. The advantages of the TOMO plans are minimization of matched junctions and better sparing of most OARs. With increased computational and memory power in the tomotherapy planning station, the excess integral dose to the healthy tissue can be re-distributed within the patient and in turn the total integral dose can be same or lower than in conventional delivery. The impact of a small increase in overall integral dose and the associated risks of secondary malignancies are unknown. Long-term follow-up is needed to answer this question.
Innovative Strategies for Image-Guided Proton Treatment of Prostate Cancer
Authors: Schulte Reinhard W. , Li Tianfang
Published: October 2014

Proton beam therapy has a proven track record of treating non-metastatic prostate cancer with excellent disease-free survival results when using homogeneous doses between 75 and 82 CGE (Cobalt Gray Equivalent) to the prostate target volume. In clinically organ-confined prostate cancer, it may be possible, in principle, to further improve outcomes by reducing the margins of the high-dose planning target volume to the gross tumor volume and by covering the clinical target volume with a dose sufficient to control microscopic extensions of the tumor. This would allow further dose escalation without increasing the risk of acute and late effects. In this paper, we undertake a careful review of existing histopathological data that support this view and discuss technical possibilities to this approach utilizing the highly conformal characteristics of proton beams and combining them with modern 4D imaging and treatment techniques.
PET-CT: Evolving Role in 3-D Radiation Therapy
Authors: Levy Richard P.
Published: October 2014

Traditional imaging techniques, such as computed tomography (CT), have high spatial resolution for changes in the anatomy or structure of organs, but are not very useful for detecting early biochemical changes. Conversely, positron emission tomography (PET) relies on changes in molecular biology to identify the earliest stages of disease but, if used alone, has sub-optimal spatial delineation. However, computer-assisted fused-image and/or single-machine integrated PET-CT can show early biochemical changes with improved anatomic resolution, often before there is any structural change. This approach enables the clinician to view and assess the patient's body from a biochemical perspective. In an era of rapidly evolving 3D conformal radiation treatment, accurate target delineation is a crucial factor in optimization of clinical results. This paper reviews some of the basic-science underpinnings of PET-CT, and highlights some important findings in the early clinical work thus far performed.
Assessing Neurocognitive Dysfunction in Cranial Radiotherapy: Can Cognitive Event-related Potentials Help?
Authors: Pearlstein Robert D. , Whitten Crystal , Haerich Paul
Published: October 2014

Cognitive changes are common sequelae of cancer and cancer treatment, particularly in patients receiving cranial radiotherapy (RT). These effects are typically assessed by subjective clinical examination or using objective neuropsychological tests. Biologically based neurophysiological methods have been increasingly applied to the study of cognitive processing in neuropsychiatric and neurological disorders and as objective measures of cognitive status for patients with dementia. These methods detect the activation of neural circuits that directly mediate cognitive function in the human brain and include metabolic and electrophysiology based techniques. Neuroimaging procedures such as 18FDG PET and more recently fMRI, which detect metabolic activation associated with cognitive processing, provide excellent spatial resolution and can be directly correlated with neuroradiological findings associated with cranial RT neurotoxicity. Clinical electrophysiology procedures such as cognitive event-related potentials (ERP), which detect the neuronal electrical activity associated with cognitive processing, offer excellent temporal resolution at low cost. Cognitive ERP techniques are already being used to assess severity and progression of cognitive dysfunction in patients with vascular and degenerative dementias, but have been largely overlooked in studies of radiation-related cognitive impairments. We review these various electrophysiological methods in the context of their relevance to assessing cranial RT effects on cognitive function, and provide recommendations for a neurophysiological approach to supplement current neuropsychological tests for RT cognitive impairments. This technology is well suited for clinical assessment of neurocognitive sequelae of cancer and should provide new insights into the mechanism of RT-related cognitive dysfunction.
Radiation and Endostatin Gene Therapy in a Lung Carcinoma Model: Pilot Data on Cells and Cytokines that Affect Angiogenesis and Immune Status
Authors: Luo Xian , Slater James M. , Gridley Daila S.
Published: October 2014

The dose of radiation that can be safely delivered to cancers residing in sensitive areas such as the lungs is limited by concern for normal tissue damage. Therapies that target tumor vasculature have potential to enhance the efficacy of radiotherapy, with minimal risk for toxicity. We constructed a unique plasmid, pXLG-mEndo, containing the mouse endostatin gene. A significantly greater anti-tumor effect was obtained against Lewis lung carcinoma (LLC) in mice when pXLG-mEndo was combined with radiation compared to radiation alone. Here we report results of cellular and cytokine assessments performed one day after treatment. These analyses were done to obtain baseline data on leukocytes that affect angiogenesis, as well as anti-tumor immunity, and to detect possible treatment-related toxicities. White blood cell counts were dramatically elevated in blood and spleens of untreated tumor-bearing mice, primarily due to granulocytosis. Overall, the effect of radiation was more evident than that of the plasmids (pXLG-mEndo and parental pWS4); radiosensitivity of specific lymphocyte subsets was variable (B > T > NK; CD8+ Tc > CD4+ Th). Tumor presence resulted in dramatically elevated interleukin-2 (IL-2) and decreased tumor necrosis factor-α (TNF-α) in supernatants of activated splenocytes, but had no significant effect on interferon-γ (IFN-γ). Administration of pXLG-mEndo, radiation, or both modified the tumor-induced aberrations in IL-2 and TNF-α; IFN-γ production was decreased by radiation. Red blood cell counts, hemoglobin, and hematocrit were low in tumor-bearing mice, but there were no treatment-related differences among groups. Platelet counts were reduced, whereas their volumes were increased in tumor-bearing mice; both parameters were only slightly affected by either pXLG-mEndo or control plasmid injection, however. The data demonstrate in the Lewis lung carcinoma model that tumor-localized endostatin gene therapy and radiation had significant effects on cells and cytokines that can influence angiogenesis, tumor growth, and immune status.
Bioinformatics for Cancer Management in the Post-Genome Era
Authors: Katoh Masuko , Katoh Masaru
Published: October 2014

Human cancer is caused by multiple factors, such as genetic predisposition, chronic persistent inflammation, environmental factors, life style, and aging. Dysregulated proliferation, dysregulated adhesion, resistance to apoptosis, resistance to senescence, and resistance to anti-cancer drugs are features of cancer cells. Accumulation of multiple epigenetic changes and genetic alterations of cancer-associated genes during multi-stage carcinogenesis results in more malignant phenotypes. Post-genome science is characterized by omics data related to genome, transcriptome, proteome, metabolome, interactome, and epigenome as well as by high-throughput technology, such as whole-genome tiling oligonucleotide array, array CGH with 32,433 overlapping BAC clones, transcriptome microarray, mass spectrometry, tissue-based expression array, and cell-based transfection array. Benchtop oncology supplies Desktop oncology with large amounts of omics data produced by high-throughput technology. Desktop oncology establishes knowledge on cancer-related biomarkers, such as predisposition markers, diagnostic markers, prognostic markers, and therapeutic markers, by using bioinformatics and human intelligence of experts for data mining and text mining. Bedside oncology applies the knowledge established by Desktop oncology to determine therapeutics for cancer patients. Antibody drugs (Trastuzumab/Herceptin, Cetuximab/Erbitux, Bevacizumab/Avastin, et cetera), small molecule inhibitors for tyrosine kinases (Gefitinib/Iressa, Erlotinib/Tarceva, Imatinib/Gleevec, et cetera), conventional cytotoxic drugs, and anti-hormonal drugs are used for cancer chemotherapy. Biomarker monitoring contributes to therapeutic optional choice and drug dosage determination for cancer patients. Knowledge on biomarkers is feedforwarded from desktop to bedside in the translational research, and then biomarker monitoring is feedbacked from bedside to desktop in the reverse translational research. Desktop oncology is indispensable for cancer research in the post-genome era. Combination of genetic screening for cancer predisposition in the general population and precise selection of therapeutic options during cancer management could contribute to the realization of personalized prevention and to dramatically improve the prognosis of cancer patients in the future.
Overexpression of IGFBP5, but not IGFBP3, Correlates with the Histologic Grade of Human Diffuse Glioma: A Tissue Microarray and Immunohistochemical Study
Authors: Wang Huamin , Wang Hua , Zhang Wei , Fuller Gregory N.
Published: October 2014

Insulin-like growth factor binding proteins (IGFBPs) comprise a family of proteins that bind and regulate the functions of IGFs. One of the IGFBPs, IGFBP2, has recently been shown to be overexpressed in glioblastoma. Overexpression of IGFBP2 contributes to the invasiveness of glioblastoma and correlates with histologic grade and survival in patients with diffuse gliomas, suggesting that IGFBP2 expression may contribute to the glioma formation and/or progression. The expression of other IGFBP family members in gliomas has, however, not been examined in detail. This study was designed to evaluate the expression of IGFBP3 and IGFBP5 in diffuse gliomas using immunohistochemistry applied to a tissue array constructed from 259 gliomas, including ten gliosarcomas. Expression of IGFBP5 correlated significantly with glioma histologic grade. 83% (58/70) of glioblastomas (WHO Grade IV) were positive for IGFBP5, which was significantly higher than WHO Grade III gliomas (41%, 41/101) or WHO Grade II gliomas (18%, 13/72) (p<0.001). In contrast, IGFBP3 was expressed in 17%, 23%, and 17% of WHO Grade IV, Grade III, and Grade II gliomas, respectively (p>0.05). There was no significant difference in IGFBP3 expression among different grades of glioma. Our study thus demonstrates that the expression of IGFBP5, but not IGFBP3, increases with glioma anaplastic progression. The strong correlation between overexpression of IGFBP5 and histologic grade suggests that, in addition to IGFBP2, IGFBP5 may also play a role in glioma progression.
Molecular Diagnostics as a Tool to Personalize Treatment in Adult Glioma Patients
Authors: Jeuken Judith W. M. , van der Maazen Richard W. M. , Wesseling Pieter
Published: October 2014

Gliomas, the most frequent primary brain tumors in humans, form a heterogeneous group, encompassing many different histological types and malignancy grades. Within this group, the diffuse infiltrative gliomas are by far the most common in adults. The major representatives in this subgroup are the diffuse astrocytic, oligodendroglial, and mixed oligo-astrocytic tumors. Especially in these diffuse gliomas, the role of molecular diagnostics is rapidly increasing. After summarizing the most relevant genetic aberrations and pathways in these tumors detected up till now, this review will discuss the clinical relevance of this information. Several molecular markers have been identified in diffuse gliomas that carry diagnostic and prognostic information. In addition, some of these and other markers predict the response of these gliomas to particular (chemo)therapeutic approaches. The techniques used to obtain this molecular information, as well as the advantages and disadvantages of the different techniques will be discussed. Finally, future perspectives will be presented with regard to the contribution of molecular diagnostics to tailor-made therapy in glioma patients.
Development of a Combined microPET®-MR System
Authors: Lucas A. J. , Hawkes R. C. , Ansorge R. E. , Williams G. B. , Nutt R. E. , Clark J. C. , Fryer T. D. , Carpenter T. A.
Published: October 2014

As evidenced by the success of PET-CT, there are many benefits from combining imaging modalities into a single scanner. The combination of PET and MR offers potential advantages over PET-CT, including improved soft tissue contrast, access to the multiplicity of contrast mechanisms available to MR, simultaneous imaging and fast MR sequences for motion correction. In addition, PET-MR is more suitable than PET-CT for cancer screening due to the elimination of the radiation dose from CT.

A key issue associated with combining PET and MR is the fact that the performance of the photomultiplier tubes (PMTs) used in conventional PET detectors is degraded in the magnetic field required for MR. Two approaches have been adopted to circumvent that issue: retention of conventional, magnetic field-sensitive PMT-based PET detectors by modification of other features of the MR or PET system, or the use of new, magnetic field-insensitive devices in the PET detectors including avalanche photo-diodes (APDs) and silicon photomultipliers (SiPMs).

Taking the former approach, we are assembling a modified microPET® Focus 120 within a gap in a novel, 1T superconducting magnet. The PMTs are located in a low magnetic field (~30mT) through a combination of magnet design and the use of fiber optic ‘bundles’.

Two main features of the modified PET system have been tested, namely the effect of using long fiber optic bundles in the PET detector, and the impact of magnetic field upon the performance of the position sensitive PMTs.

The design of a modified microPET®-MR system for small animal imaging is completed, and assembly and testing is underway.
Retinoblastoma with Cerebrospinal Fluid Metastasis Treated with Orbital and Craniospinal Irradiation Using IMRT
Authors: Malik Monica , Prabhakar R. , Sharma Daya Nand , Rath Goura K.
Published: October 2014

A 4-year-old male child presented with history of leucocoria, photophobia, and progressive visual deterioration in the left eye. Clinical examination and computed tomography revealed a unilateral retinoblastoma involving the left globe. He underwent enucleation of the left eye and was referred for adjuvant radiotherapy in view of optic nerve infiltration up to the line of resection. However, he did not report for treatment and presented six months later with a recurrent mass in the left orbit with intracranial extension. Cerebrospinal fluid (CSF) cytology was positive for malignant retinoblastoma cells. He received multiagent chemotherapy with vincristine, carboplatin, and etoposide along with intrathecal methotrexate. Although the recurrent orbital mass reduced significantly with chemotherapy, malignant cells persisted in the CSF. He was subsequently treated using intensity modulated radiation therapy (IMRT) to treat the left orbital mass along with craniospinal axis irradiation. Computed tomography done at three and nine months after completion of radiotherapy showed complete disappearance of orbital tumor. CSF cytology also showed no evidence of malignant cells.
Pharmacogenomics of the Polyamine Analog 3,8,13,18-tetraaza-10,11-[(E)-1,2-cyclopropyl] eicosane Tetrahydrochloride, CGC-11093, in the Colon Adenocarcinoma Cell Line HCT1161
Authors: Ignatenko Natalia A. , Yerushalmi Hagit F. , Watts George S. , Futscher Bernard W. , Stringer David E. , Marton Laurence J. , Gerner Eugene W.
Published: October 2014

Polyamine analogs are known to inhibit tumorigenesis at least in part by mimicking some of the regulatory roles of natural polyamines. To begin the identification of those signaling pathways that are involved in differential cellular responses to the synthetic conformationally restricted polyamine analog CGC-11093, we conducted gene expression profiling, proteomic, and genome-wide DNA methylation and histone acetylation analyses of the HCT116 colon adenocarcinoma cell line after treatment with this analog. Gene expression analysis was performed using Affymetrix GeneChip human genome U133 Plus 2.0 arrays. Changes in protein expression were evaluated using 2D polyacrylamide gels followed by LCMS/MS. DNA methylation was measured using 6,800 element CpG island microarrays. Treatment of cells with CGC-11093 at concentrations ranging from 0.1 to 10 μM caused inhibition of cell growth and metabolic activity, but only minimally affected cell viability. Gene expression analysis showed concentration-dependent effects of CGC-11093 on the DNA/RNA binding transcription factor, cell cycle, signaling, transport, cytoskeletal/structural, and serine protease genes. Functional gene analysis revealed distinct expression patterns related to inhibition of cell cycle control, TGF beta signaling, proteasome and RNA polymerase pathways, upregulation of the aminoacyl-tRNA synthesis pathway, and perturbations in the MAPK and Wnt signaling pathways. Microarray results were validated for selected genes with real time RT PCR. Proteomics analysis showed correlative changes in the expression of proteins involved in the regulation of proteasome function (proteasome subunit Y) and tRNA synthesis. CGC-11093 treatment did not produce any detectable changes in DNA methylation or histone acetylation in cells. This study validates specific target pathways for a specific conformationally restricted polyamine analog and suggests the utility of combined gene and DNA methylation microarrays along with proteomic analyses as a useful approach to the evaluation of the mechanisms of action of anticancer drugs.
Design and Development of Motorized Multileaf Collimator for Telecobalt Unit
Authors: Singh I. Rabi Raja , Ravindran B. Paul , Ayyangar K. M.
Published: October 2014

A manual multileaf collimator developed for telecobalt unit was motorized to accomplish the easy movement of the leaves. The required field shaping using MLC could be achieved by either using template or display. The beam characteristics were investigated and then compared with those of customized blocks. The maximum interleaf leakage and the percentage of transmission measured at the depth of maximum ionization (0.5cm) were found to be 2.7% and 2.4%, respectively. The field shaping performed by the MLC was verified using film dosimetry. The comparative study of treatment plans of 3DCRT and IMRT between 60 Co beam and 6 MV beams was carried out. This MLC could be used as a substitute for conventional blocks in static fields, there by eliminating the effort and cost of fabricating customized blocks, the need for storage space for blocks and other practical difficulties during the process of the block making. It is also demonstrated that if a provision for IMRT delivery with MLC for 60 Co is made, could be a cost effective alternative to IMRT with 6 MV beam.
Spatially Fractionated GRID Radiation Treatment of Advanced Neck Disease Associated with Head and Neck Cancer
Authors: Huhn Jeniffer L , Regine William F. , Valentino Joseph P. , Meigooni Ali S. , Kudrimoti Mahesh , Mohiuddin Mohammed
Published: October 2014

Advanced nodal disease associated with head and neck cancer warrants aggressive, often multi-modality therapy to maximize local-regional control. The expansion of a novel treatment paradigm developed by our institution includes the addition of a single-fraction of high dose spatially-fractionated radiation (GRID) to a conventional course of treatment.

Between 1995 and 2002 a series of 27 patients (median age 65) with bulky N2-3 disease were treated. Median nodal tumor size was 7 cm. Two groups of patients were evaluated. Group 1 (N=14) patients received a median neck dose 69 Gy (range 54–79 Gy) plus GRID treatment. Group 2 (N=13) patients received a median neck dose of 59 Gy (range 54–72 Gy) plus GRID treatment followed by planned neck dissection. Patients were evaluated for local-regional control, pathological response, survival, and morbidity.

Median time to follow-up for Group 1 was 10 months (range 3–44 months). Neck control was 93%. Disease specific survival was 50%. Morbidity was limited to soft-tissue related damage and was mild. Median time to follow-up for Group 2 was 38 months (range 5–116 months). Pathologic complete response rate was 85%. Overall neck control rate was 92%. Disease specific survival was 85%. Surgical morbidity was limited to three wound healing complications.

GRID treatment may be safely added to conventional treatment management of locally advanced neck disease related to cancer with acceptable morbidity. It may improve pathologic complete response rates in those patients who undergo planned neck dissection, possibly leading to improved survival. In patients with inoperable bulky disease, addition of GRID enhances local-regional control.