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Sample records for microbeams tumor therapy

  1. Method for microbeam radiation therapy

    DOEpatents

    Slatkin, D.N.; Dilmanian, F.A.; Spanne, P.O.

    1994-08-16

    A method is disclosed of performing radiation therapy on a patient, involving exposing a target, usually a tumor, to a therapeutic dose of high energy electromagnetic radiation, preferably X-ray radiation. The dose is in the form of at least two non-overlapping microbeams of radiation, each microbeam having a width of less than about 1 millimeter. Target tissue exposed to the microbeams receives a radiation dose during the exposure that exceeds the maximum dose that such tissue can survive. Non-target tissue between the microbeams receives a dose of radiation below the threshold amount of radiation that can be survived by the tissue, and thereby permits the non-target tissue to regenerate. The microbeams may be directed at the target from one direction, or from more than one direction in which case the microbeams overlap within the target tissue enhancing the lethal effect of the irradiation while sparing the surrounding healthy tissue. No Drawings

  2. Method for microbeam radiation therapy

    DOEpatents

    Slatkin, Daniel N.; Dilmanian, F. Avraham; Spanne, Per O.

    1994-01-01

    A method of performing radiation therapy on a patient, involving exposing a target, usually a tumor, to a therapeutic dose of high energy electromagnetic radiation, preferably X-ray radiation, in the form of at least two non-overlapping microbeams of radiation, each microbeam having a width of less than about 1 millimeter. Target tissue exposed to the microbeams receives a radiation dose during the exposure that exceeds the maximum dose that such tissue can survive. Non-target tissue between the microbeams receives a dose of radiation below the threshold amount of radiation that can be survived by the tissue, and thereby permits the non-target tissue to regenerate. The microbeams may be directed at the target from one direction, or from more than one direction in which case the microbeams overlap within the target tissue enhancing the lethal effect of the irradiation while sparing the surrounding healthy tissue.

  3. Microbeam radiation therapy

    NASA Astrophysics Data System (ADS)

    Laissue, Jean A.; Lyubimova, Nadia; Wagner, Hans-Peter; Archer, David W.; Slatkin, Daniel N.; Di Michiel, Marco; Nemoz, Christian; Renier, Michel; Brauer, Elke; Spanne, Per O.; Gebbers, Jan-Olef; Dixon, Keith; Blattmann, Hans

    1999-10-01

    The central nervous system of vertebrates, even when immature, displays extraordinary resistance to damage by microscopically narrow, multiple, parallel, planar beams of x rays. Imminently lethal gliosarcomas in the brains of mature rats can be inhibited and ablated by such microbeams with little or no harm to mature brain tissues and neurological function. Potentially palliative, conventional wide-beam radiotherapy of malignant brain tumors in human infants under three years of age is so fraught with the danger of disrupting the functional maturation of immature brain tissues around the targeted tumor that it is implemented infrequently. Other kinds of therapy for such tumors are often inadequate. We suggest that microbeam radiation therapy (MRT) might help to alleviate the situation. Wiggler-generated synchrotron x-rays were first used for experimental microplanar beam (microbeam) radiation therapy (MRT) at Brookhaven National Laboratory's National Synchrotron Light Source in the early 1990s. We now describe the progress achieved in MRT research to date using immature and adult rats irradiated at the European Synchrotron Radiation Facility in Grenoble, France, and investigated thereafter at the Institute of Pathology of the University of Bern.

  4. Nanotube x-ray for cancer therapy: a compact microbeam radiation therapy system for brain tumor treatment.

    PubMed

    Zhang, Lei; Yuan, Hong; Inscoe, Christina; Chtcheprov, Pavel; Hadsell, Michael; Lee, Yueh; Lu, Jianping; Chang, Sha; Zhou, Otto

    2014-12-01

    Microbeam radiation therapy (MRT) is a promising preclinical modality for cancer treatment, with remarkable preferential tumoricidal effects, that is, tumor eradication without damaging normal tissue functions. Significant lifespan extension has been demonstrated in brain tumor-bearing small animals treated with MRT. So far, MRT experiments can only be performed in a few synchrotron facilities around the world. Limited access to MRT facilities prevents this enormously promising radiotherapy technology from reaching the broader biomedical research community and hinders its potential clinical translation. We recently demonstrated, for the first time, the feasibility of generating microbeam radiation in a laboratory environment using a carbon nanotube x-ray source array and performed initial small animal studies with various brain tumor models. This new nanotechnology-enabled microbeam delivery method, although still in its infancy, has shown promise for achieving comparable therapeutic effects to synchrotron MRT and has offered a potential pathway for clinical translation. PMID:25417729

  5. Nanotube x-ray for cancer therapy: a compact microbeam radiation therapy system for brain tumor treatment

    PubMed Central

    Zhang, Lei; Yuan, Hong; Inscoe, Christina; Chtcheprov, Pavel; Hadsell, Michael; Lee, Yueh; Lu, Jianping; Chang, Sha; Zhou, Otto

    2014-01-01

    Microbeam radiation therapy (MRT) is a promising preclinical modality for cancer treatment, with remarkable preferential tumoricidal effects, that is, tumor eradication without damaging normal tissue functions. Significant lifespan extension has been demonstrated in brain tumor-bearing small animals treated with MRT. So far, MRT experiments can only be performed in a few synchrotron facilities around the world. Limited access to MRT facilities prevents this enormously promising radiotherapy technology from reaching the broader biomedical research community and hinders its potential clinical translation. We recently demonstrated, for the first time, the feasibility of generating microbeam radiation in a laboratory environment using a carbon nanotube x-ray source array and performed initial small animal studies with various brain tumor models. This new nanotechnology-enabled microbeam delivery method, although still in its infancy, has shown promise for achieving comparable therapeutic effects to synchrotron MRT and has offered a potential pathway for clinical translation. PMID:25417729

  6. Tumor Cell Response to Synchrotron Microbeam Radiation Therapy Differs Markedly From Cells in Normal Tissues

    SciTech Connect

    Crosbie, Jeffrey C.; Anderson, Robin L.; Rothkamm, Kai; Restall, Christina M.; Cann, Leonie; Ruwanpura, Saleela; Meachem, Sarah; Yagi, Naoto; Svalbe, Imants; Lewis, Robert A.; Williams, Bryan R.G.; Rogers, Peter A.W.

    2010-07-01

    Purpose: High-dose synchrotron microbeam radiation therapy (MRT) can be effective at destroying tumors in animal models while causing very little damage to normal tissues. The aim of this study was to investigate the cellular processes behind this observation of potential clinical importance. Methods and Materials: MRT was performed using a lattice of 25 {mu}m-wide, planar, polychromatic, kilovoltage X-ray microbeams, with 200-{mu}m peak separation. Inoculated EMT-6.5 tumor and normal mouse skin tissues were harvested at defined intervals post-MRT. Immunohistochemical detection of {gamma}-H2AX allowed precise localization of irradiated cells, which were also assessed for proliferation and apoptosis. Results: MRT significantly reduced tumor cell proliferation by 24 h post-irradiation (p = 0.002). An unexpected finding was that within 24 h of MRT, peak and valley irradiated zones were indistinguishable in tumors because of extensive cell migration between the zones. This was not seen in MRT-treated normal skin, which appeared to undergo a coordinated repair response. MRT elicited an increase in median survival times of EMT-6.5 and 67NR tumor-inoculated mice similar to that achieved with conventional radiotherapy, while causing markedly less normal tissue damage. Conclusions: This study provides evidence of a differential response at a cellular level between normal and tumor tissues after synchrotron MRT.

  7. Methods for implementing microbeam radiation therapy

    DOEpatents

    Dilmanian, F. Avraham; Morris, Gerard M.; Hainfeld, James F.

    2007-03-20

    A method of performing radiation therapy includes delivering a therapeutic dose such as X-ray only to a target (e.g., tumor) with continuous broad beam (or in-effect continuous) using arrays of parallel planes of radiation (microbeams/microplanar beams). Microbeams spare normal tissues, and when interlaced at a tumor, form a broad-beam for tumor ablation. Bidirectional interlaced microbeam radiation therapy (BIMRT) uses two orthogonal arrays with inter-beam spacing equal to beam thickness. Multidirectional interlaced MRT (MIMRT) includes irradiations of arrays from several angles, which interleave at the target. Contrast agents, such as tungsten and gold, are administered to preferentially increase the target dose relative to the dose in normal tissue. Lighter elements, such as iodine and gadolinium, are used as scattering agents in conjunction with non-interleaving geometries of array(s) (e.g., unidirectional or cross-fired (intersecting) to generate a broad beam effect only within the target by preferentially increasing the valley dose within the tumor.

  8. Identification of AREG and PLK1 pathway modulation as a potential key of the response of intracranial 9L tumor to microbeam radiation therapy.

    PubMed

    Bouchet, Audrey; Sakakini, Nathalie; Atifi, Michèle El; Le Clec'h, Céline; Bräuer-Krisch, Elke; Rogalev, Léonid; Laissue, Jean Albert; Rihet, Pascal; Le Duc, Géraldine; Pelletier, Laurent

    2015-06-01

    Synchrotron microbeam radiation therapy (MRT) relies on the spatial fractionation of a synchrotron beam into parallel micron-wide beams allowing deposition of hectogray doses. MRT controls the intracranial tumor growth in rodent models while sparing normal brain tissues. Our aim was to identify the early biological processes underlying the differential effect of MRT on tumor and normal brain tissues. The expression of 28,000 transcripts was tested by microarray 6 hr after unidirectional MRT (400 Gy, 50 µm-wide microbeams, 200 µm spacing). The specific response of tumor tissues to MRT consisted in the significant transcriptomic modulation of 431 probesets (316 genes). Among them, 30 were not detected in normal brain tissues, neither before nor after MRT. Areg, Trib3 and Nppb were down-regulated, whereas all others were up-regulated. Twenty-two had similar expression profiles during the 2 weeks observed after MRT, including Ccnb1, Cdc20, Pttg1 and Plk1 related to the mitotic role of the Polo-like kinase (Plk) pathway. The up-regulation of Areg expression may indicate the emergence of survival processes in tumor cells triggered by the irradiation; while the modulation of the "mitotic role of Plk1" pathway, which relates to cytokinetic features of the tumor observed histologically after MRT, may partially explain the control of tumor growth by MRT. The identification of these tumor-specific responses permit to consider new strategies that might potentiate the antitumoral effect of MRT. PMID:25382544

  9. New irradiation geometry for microbeam radiation therapy

    NASA Astrophysics Data System (ADS)

    Bräuer-Krisch, E.; Requardt, H.; Régnard, P.; Corde, S.; Siegbahn, E.; LeDuc, G.; Brochard, T.; Blattmann, H.; Laissue, J.; Bravin, A.

    2005-07-01

    Microbeam radiation therapy (MRT) has the potential to treat infantile brain tumours when other kinds of radiotherapy would be excessively toxic to the developing normal brain. MRT uses extraordinarily high doses of x-rays but provides unusual resistance to radioneurotoxicity, presumably from the migration of endothelial cells from 'valleys' into 'peaks', i.e., into directly irradiated microslices of tissues. We present a novel irradiation geometry which results in a tolerable valley dose for the normal tissue and a decreased peak-to-valley dose ratio (PVDR) in the tumour area by applying an innovative cross-firing technique. We propose an MRT technique to orthogonally crossfire two arrays of parallel, nonintersecting, mutually interspersed microbeams that produces tumouricidal doses with small PVDRs where the arrays meet and tolerable radiation doses to normal tissues between the microbeams proximal and distal to the tumour in the paths of the arrays.

  10. Microbeam radiation therapy: A Monte Carlo study of the influence of the source, multislit collimator, and beam divergence on microbeams

    SciTech Connect

    Nettelbeck, H.; Takacs, G. J.; Lerch, M. L. F.; Rosenfeld, A. B.

    2009-02-15

    Microbeam radiation therapy (MRT) is a new oncology method currently under development for the treatment of inoperable pediatric brain tumors. Monte Carlo simulation, or the computational study of radiation transport in matter, is often used in radiotherapy to theoretically estimate the dose required for treatment. However, its potential use in MRT dose planning systems is currently hindered by the significant discrepancies that have been observed between measured and theoretical dose and the PVDR (peak to valley dose ratio). The need to resolve these discrepancies is driven by the desirability of making MRT available to humans in the next few years. This article aims to resolve some of the discrepancies by examining the simplifications adopted in previous MRT Monte Carlo studies, such as the common practice of commencing microbeam transport on the surface of the target which neglects the influence of the distributed synchrotron source, multislit collimator, and the beam divergence between them. This article uses PENELOPE Monte Carlo simulation to investigate the influence of these beamline components upstream of the target on the lateral dose profiles and PVDRs of an array of 25 microbeams. It also compares the dose profiles and PVDRs of a microbeam array produced from a single simulation (full array) to those produced from the superposition of a single microbeam profile (sup array). The effect of modeling the distributed source and the beam divergence was an increase in the absorbed dose in the penumbral and valley regions of the microbeam profiles. Inclusion of the multislit collimator resulted in differences of up to 5 {mu}m in the FWHM of microbeam profiles across the array, which led to minor variations in the corresponding PVDR yields.

  11. Monte Carlo dose enhancement studies in microbeam radiation therapy

    SciTech Connect

    Martinez-Rovira, I.; Prezado, Y.

    2011-07-15

    Purpose: A radical radiation therapy treatment for gliomas requires extremely high absorbed doses resulting in subsequent deleterious side effects in healthy tissue. Microbeam radiation therapy (MRT) is an innovative technique based on the fact that normal tissue can withstand high radiation doses in small volumes without any significant damage. The synchrotron-generated x-ray beam is collimated and delivered to an array of narrow micrometer-sized planar rectangular fields. Several preclinical experiments performed at the Brookhaven National Laboratory (BNL) and at the European Synchrotron Radiation Facility (ESRF) confirmed that MRT yields a higher therapeutic index than nonsegmented beams of the same characteristics. This index can be greatly improved by loading the tumor with high atomic number (Z) contrast agents. The aim of this work is to find the high-Z element that provides optimum dose enhancement. Methods: Monte Carlo simulations (PENELOPE/penEasy) were performed to assess the peak and valley doses as well as their ratio (PVDR) in healthy tissue and in the tumor, loaded with different contrast agents. The optimization criteria used were maximization of the ratio between the PVDR values in healthy tissue respect to the PVDR in the tumor and minimization of bone and brain valley doses. Results: Dose enhancement factors, PVDR, and valley doses were calculated for different high-Z elements. A significant decrease of PVDR values in the tumor, accompanied by a gain in the valley doses, was found in the presence of high-Z elements. This enables the deposited dose in the healthy tissue to be reduced. The optimum high-Z element depends on the irradiation configuration. As a general trend, the best outcome is provided by the highest Z contrast agents considered, i.e., gold and thallium. However, lanthanides (especially Lu) and hafnium also offer a satisfactory performance. Conclusions: The remarkable therapeutic index in microbeam radiation therapy can be further

  12. WE-E-BRE-06: High-Dose Microbeam Radiation Induces Different Responses in Tumor Microenvironment Compared to Conventional Seamless Radiation in Window Chamber Tumor Models

    SciTech Connect

    Chang, S; Zhang, J; Hadsell, M; Fontanella, A; Schroeder, T; Palmer, G; Dewhirst, M; Boss, M; Berman, K

    2014-06-15

    Purpose: Microbeam radiation therapy and GRID therapy are different forms of Spatially-Fractioned Radiation Therapy (SFRT) that is fundamentally different from the conventional seamless and temporally fractionated radiation therapy. SFRT is characterized by a ultra-high dose (10s –100s Gy) dose single treatment with drastic inhomogeneity pattern of given spatial frequencies. Preclinical and limited clinical studies have shown that the SFRT treatments may offer significant improvements in reducing treatment toxicity, especially for those patients who have not benefited from the state-of-the-art radiation therapy approaches. This preliminary study aims to elucidate the underlying working mechanisms of SFRT, which currently remains poorly understood. Methods: A genetically engineered 4T1 murine mammary carcinoma cell line and nude mice skin fold window chamber were used. A nanotechnology-based 160kV x-ray irradiator delivered 50Gy (entrance dose) single treatments of microbeam or seamless radiation. Animals were in 3 groups: mock, seamless radiation, and 300μm microbeam radiation. The windows were imaged using a hyperspectral system to capture total hemoglobin/saturation, GFP fluorescence emission, RFP fluorescence emission, and vessel density at 9 time points up to 7 days post radiation. Results: We found unique physiologic changes in different tumor/normal tissue regions and differential effects between seamless and microbeam treatments. They include 1) compared to microbeam and mock radiation seamless radiation damaged more microvasculature in tumor-surrounding normal tissue, 2) a pronounced angiogenic effect was observed with vascular proliferation in the microbeam irradiated portion of the tumor days post treatment (no such effect observed in seamless and mock groups), and 3) a notable change in tumor vascular orientation was observed where vessels initially oriented parallel to the beam length were replaced by vessels running perpendicular to the irradiation

  13. Effects of High-Dose Microbeam Irradiation on Tumor Microvascular Function and Angiogenesis

    PubMed Central

    Fontanella, Andrew N.; Boss, Mary-Keara; Hadsell, Michael; Zhang, Jian; Schroeder, Thies; Berman, Katherine G.; Dewhirst, Mark W.; Chang, Sha; Palmer, Gregory M.

    2015-01-01

    Microbeam radiation therapy (MRT) is a form of cancer treatment in which a single large dose of radiation is spatially fractionated in-line or grid-like patterns. Preclinical studies have demonstrated that MRT is capable of eliciting high levels of tumor response while sparing normal tissue that is exposed to the same radiation field. Since a large fraction of the MRT-treated tumor is in the dose valley region that is not directly irradiated, tumor response may be driven by radiation bystander effects, which in turn elicit a microvascular response. Differential alterations in hemodynamics between the tumor and normal tissue may explain the therapeutic advantages of MRT. Direct observation of these dynamic responses presents a challenge for conventional ex vivo analysis. Furthermore, knowledge gleaned from in vitro studies of radiation bystander response has not been widely incorporated into in vivo models of tumor radiotherapy, and the biological contribution of the bystander effect within the tumor microenvironment is unknown. In this study, we employed noninvasive, serial observations of the tumor microenvironment to address the question of how tumor vasculature and HIF-1 expression are affected by microbeam radiotherapy. Tumors (approximately 4 mm in diameter) grown in a dorsal window chamber were irradiated in a single fraction using either a single, microplanar beam (300 micron wide swath) or a wide-field setup (whole-window chamber) to a total dose of 50 Gy. The tumors were optically observed daily for seven days postirradiation. Microvascular changes in the tumor and surrounding normal tissue differed greatly between the wide-field and microbeam treatments. We present evidence that these changes may be due to dissimilar spatial and temporal patterns of HIF-1 expression induced through radiation bystander effects. PMID:25574586

  14. Effects of high-dose microbeam irradiation on tumor microvascular function and angiogenesis.

    PubMed

    Fontanella, Andrew N; Boss, Mary-Keara; Hadsell, Michael; Zhang, Jian; Schroeder, Thies; Berman, Katherine G; Dewhirst, Mark W; Chang, Sha; Palmer, Gregory M

    2015-02-01

    Microbeam radiation therapy (MRT) is a form of cancer treatment in which a single large dose of radiation is spatially fractionated in-line or grid-like patterns. Preclinical studies have demonstrated that MRT is capable of eliciting high levels of tumor response while sparing normal tissue that is exposed to the same radiation field. Since a large fraction of the MRT-treated tumor is in the dose valley region that is not directly irradiated, tumor response may be driven by radiation bystander effects, which in turn elicit a microvascular response. Differential alterations in hemodynamics between the tumor and normal tissue may explain the therapeutic advantages of MRT. Direct observation of these dynamic responses presents a challenge for conventional ex vivo analysis. Furthermore, knowledge gleaned from in vitro studies of radiation bystander response has not been widely incorporated into in vivo models of tumor radiotherapy, and the biological contribution of the bystander effect within the tumor microenvironment is unknown. In this study, we employed noninvasive, serial observations of the tumor microenvironment to address the question of how tumor vasculature and HIF-1 expression are affected by microbeam radiotherapy. Tumors (approximately 4 mm in diameter) grown in a dorsal window chamber were irradiated in a single fraction using either a single, microplanar beam (300 micron wide swath) or a wide-field setup (whole-window chamber) to a total dose of 50 Gy. The tumors were optically observed daily for seven days postirradiation. Microvascular changes in the tumor and surrounding normal tissue differed greatly between the wide-field and microbeam treatments. We present evidence that these changes may be due to dissimilar spatial and temporal patterns of HIF-1 expression induced through radiation bystander effects. PMID:25574586

  15. Phase contrast portal imaging for image-guided microbeam radiation therapy

    NASA Astrophysics Data System (ADS)

    Umetani, Keiji; Kondoh, Takeshi

    2014-03-01

    High-dose synchrotron microbeam radiation therapy is a unique treatment technique used to destroy tumors without severely affecting circumjacent healthy tissue. We applied a phase contrast technique to portal imaging in preclinical microbeam radiation therapy experiments. Phase contrast portal imaging is expected to enable us to obtain higherresolution X-ray images at therapeutic X-ray energies compared to conventional portal imaging. Frontal view images of a mouse head sample were acquired in propagation-based phase contrast imaging. The phase contrast images depicted edge-enhanced fine structures of the parietal bones surrounding the cerebrum. The phase contrast technique is expected to be effective in bony-landmark-based verification for image-guided radiation therapy.

  16. SYRA3 COST Action--Microbeam radiation therapy: Roots and prospects.

    PubMed

    Bravin, Alberto; Olko, Pawel; Schültke, Elisabeth; Wilkens, Jan J

    2015-09-01

    Microbeam radiation therapy (MRT) is an irradiation modality for therapeutic purposes which uses arrays of collimated quasi parallel microbeams, each up to 100 μm wide, to deliver high radiation doses. Several studies have reported the extraordinary tolerance of normal tissues to MRT irradiation; conversely, MRT has been shown to be highly efficient on tumor growth control. The original and most widely developed application of MRT, yet in the preclinical phase, consists in using spatially fractionated X-ray beams issued from a synchrotron radiation source in the treatment of brain tumors. More recently, MRT has been tested in successful pioneering assays to reduce or interrupt seizures in preclinical models of epilepsy. The MRT concept has also been extended to proton therapy. The development of MRT towards its clinical implementation is presently driven by an EU-supported consortium of laboratories from 16 countries within the COST Action TD1205 (SYRA3). The results of the first SYRA3 workshop on "Radiation Therapy with Synchrotron Radiation: Achievements and Challenges" held in Krakow (Poland) during March 25-26 2014 are summarized in this issue with an overview presented in this paper. The papers reflect the multidisciplinary international activities of SYRA3. The topics covered in this focus issue include medical physics aspects, pre-clinical studies, clinical applications, and an industrial perspective; finally an outlook towards future prospects of compact sources and proton microbeams. PMID:26123367

  17. Method and devices for performing stereotactic microbeam radiation therapy

    DOEpatents

    Dilmanian, F. Avraham

    2010-01-05

    A radiation delivery system generally includes either a synchrotron source or a support frame and a plurality of microbeam delivery devices supported on the support frame, both to deliver a beam in a hemispherical arrangement. Each of the microbeam delivery devices or synchrotron irradiation ports is adapted to deliver at least one microbeam of radiation along a microbeam delivery axis, wherein the microbeam delivery axes of the plurality of microbeam delivery devices cross within a common target volume.

  18. The GEANT4 toolkit for microdosimetry calculations: application to microbeam radiation therapy (MRT).

    PubMed

    Spiga, J; Siegbahn, E A; Bräuer-Krisch, E; Randaccio, P; Bravin, A

    2007-11-01

    Theoretical dose distributions for microbeam radiation therapy (MRT) are computed in this paper using the GEANT4 Monte Carlo (MC) simulation toolkit. MRT is an innovative experimental radiotherapy technique carried out using an array of parallel microbeams of synchrotron-wiggler-generated x rays. Although the biological mechanisms underlying the effects of microbeams are still largely unknown, the effectiveness of MRT can be traced back to the natural ability of normal tissues to rapidly repair small damages to the vasculature, and on the lack of a similar healing process in tumoral tissues. Contrary to conventional therapy, in which each beam is at least several millimeters wide, the narrowness of the microbeams allows a rapid regeneration of the blood vessels along the beams' trajectories. For this reason the calculation of the "valley" dose is of crucial importance and the correct use of MC codes for such purposes must be understood. GEANT4 offers, in addition to the standard libraries, a specialized package specifically designed to deal with electromagnetic interactions of particles with matter for energies down to 250 eV. This package implements two different approaches for electron and photon transport, one based on evaluated data libraries, the other adopting analytical models. These features are exploited to cross-check theoretical computations for MRT. The lateral and depth dose profiles are studied for the irradiation of a 20 cm diameter, 20 cm long cylindrical phantom, with cylindrical sources of different size and energy. Microbeam arrays are simulated with the aid of superposition algorithms, and the ratios of peak-to-valley doses are computed for typical cases used in preclinical assays. Dose profiles obtained using the GEANT4 evaluated data libraries and analytical models are compared with simulation results previously obtained using the PENELOPE code. The results show that dose profiles computed with GEANT4's analytical model are almost

  19. The GEANT4 toolkit for microdosimetry calculations: Application to microbeam radiation therapy (MRT)

    SciTech Connect

    Spiga, J.; Siegbahn, E. A.; Braeuer-Krisch, E.; Randaccio, P.; Bravin, A.

    2007-11-15

    Theoretical dose distributions for microbeam radiation therapy (MRT) are computed in this paper using the GEANT4 Monte Carlo (MC) simulation toolkit. MRT is an innovative experimental radiotherapy technique carried out using an array of parallel microbeams of synchrotron-wiggler-generated x rays. Although the biological mechanisms underlying the effects of microbeams are still largely unknown, the effectiveness of MRT can be traced back to the natural ability of normal tissues to rapidly repair small damages to the vasculature, and on the lack of a similar healing process in tumoral tissues. Contrary to conventional therapy, in which each beam is at least several millimeters wide, the narrowness of the microbeams allows a rapid regeneration of the blood vessels along the beams' trajectories. For this reason the calculation of the 'valley' dose is of crucial importance and the correct use of MC codes for such purposes must be understood. GEANT4 offers, in addition to the standard libraries, a specialized package specifically designed to deal with electromagnetic interactions of particles with matter for energies down to 250 eV. This package implements two different approaches for electron and photon transport, one based on evaluated data libraries, the other adopting analytical models. These features are exploited to cross-check theoretical computations for MRT. The lateral and depth dose profiles are studied for the irradiation of a 20 cm diameter, 20 cm long cylindrical phantom, with cylindrical sources of different size and energy. Microbeam arrays are simulated with the aid of superposition algorithms, and the ratios of peak-to-valley doses are computed for typical cases used in preclinical assays. Dose profiles obtained using the GEANT4 evaluated data libraries and analytical models are compared with simulation results previously obtained using the PENELOPE code. The results show that dose profiles computed with GEANT4's analytical model are almost

  20. High resolution X-ray fluorescence imaging for a microbeam radiation therapy treatment planning system

    NASA Astrophysics Data System (ADS)

    Chtcheprov, Pavel; Inscoe, Christina; Burk, Laurel; Ger, Rachel; Yuan, Hong; Lu, Jianping; Chang, Sha; Zhou, Otto

    2014-03-01

    Microbeam radiation therapy (MRT) uses an array of high-dose, narrow (~100 μm) beams separated by a fraction of a millimeter to treat various radio-resistant, deep-seated tumors. MRT has been shown to spare normal tissue up to 1000 Gy of entrance dose while still being highly tumoricidal. Current methods of tumor localization for our MRT treatments require MRI and X-ray imaging with subject motion and image registration that contribute to the measurement error. The purpose of this study is to develop a novel form of imaging to quickly and accurately assist in high resolution target positioning for MRT treatments using X-ray fluorescence (XRF). The key to this method is using the microbeam to both treat and image. High Z contrast media is injected into the phantom or blood pool of the subject prior to imaging. Using a collimated spectrum analyzer, the region of interest is scanned through the MRT beam and the fluorescence signal is recorded for each slice. The signal can be processed to show vascular differences in the tissue and isolate tumor regions. Using the radiation therapy source as the imaging source, repositioning and registration errors are eliminated. A phantom study showed that a spatial resolution of a fraction of microbeam width can be achieved by precision translation of the mouse stage. Preliminary results from an animal study showed accurate iodine profusion, confirmed by CT. The proposed image guidance method, using XRF to locate and ablate tumors, can be used as a fast and accurate MRT treatment planning system.

  1. High resolution optical calorimetry for synchrotron microbeam radiation therapy

    NASA Astrophysics Data System (ADS)

    Ackerly, T.; Crosbie, J. C.; Fouras, A.; Sheard, G. J.; Higgins, S.; Lewis, R. A.

    2011-03-01

    We propose the application of optical calorimetry to measure the peak to valley ratio for synchrotron microbeam radiation therapy (MRT). We use a modified Schlieren approach known as reference image topography (RIT) which enables one to obtain a map of the rate of change of the refractive index in a water bath from which the absorbed dose can be determined with sufficient spatial accuracy to determine the peak to valley ratio. We modelled the calorimetric properties of X-rays using a heated wire in a water bath. Our RIT system comprised a light source, a textured reference object and a camera and lens combination. We measured temperature contours and showed a plume rising from the heated wire. The total temperature change in water was 12 degrees C, 500 times greater than the calculated change from a 1 ms exposure on a synchrotron. At 1.0 ms, thermal diffusion will be the major cause of uncertainty in determining the peak to valley ratio, and we calculate thermal diffusion will reduce the measured peak to valley ratio to 76% of its initial value, but the individual microbeams will still resolve. We demonstrate proof of concept for measuring X-ray dose using a modified RIT method.

  2. A white-beam fast-shutter for microbeam radiation therapy at the ESRF

    NASA Astrophysics Data System (ADS)

    Renier, M.; Brochard, T.; Nemoz, C.; Thomlinson, W.

    2002-03-01

    The ID17 Medical Beamline port at the European Synchrotron Radiation Facility (ESRF) delivers white beam generated by a 1.4 T wiggler. It is devoted to medical applications of synchrotron radiation. One major program of the beamline is called Microbeam Radiation Therapy (MRT). In this radiotherapy technique, still under development, the white beam fan is divided into several microbeams before reaching the target which is a tumoral brain. The maximum skin-entrance absorbed dose can reach extremely high values (over 1000 Gy) before causing tissue necrosis, while causing tumor necrosis. One of the key parameters for the success of the MRT is the accurate control of the radiation dose delivered to the target, as well as its location with respect to the tumor, to prevent unnecessary damage to normal tissues. Therefore, the opening and closing positions of the shutter while the target is moving vertically at a constant speed reaching 150 mm/s must be carefully controlled. Shutter opening times as short as 5±0.5 ms must be achieved. The total power of the white beam generated by the wiggler may reach 14.5 kW. It is essential to maintain vacuum continuity in the entire beamline and therefore the shutter had to be built to be vacuum compatible to a level of 10 -8 mbar. This paper describes the fast shutter mechanics and its associated electronics.

  3. Weanling piglet cerebellum: a surrogate for tolerance to MRT (microbeam radiation therapy) in pediatric neuro-oncology

    NASA Astrophysics Data System (ADS)

    Laissue, Jean A.; Blattmann, Hans; Di Michiel, Marco; Slatkin, Daniel N.; Lyubimova, Nadia; Guzman, Raphael; Zimmermann, Werner; Birrer, Stephan; Bley, Tim; Kircher, Patrick; Stettler, Regina; Fatzer, Rosmarie; Jaggy, Andre; Smilowitz, Henry; Brauer, Elke; Bravin, Alberto; Le Duc, Geraldine; Nemoz, Christian; Renier, Michel; Thomlinson, William C.; Stepanek, Jiri; Wagner, Hans-Peter

    2001-12-01

    The cerebellum of the weanling piglet (Yorkshire) was used as a surrogate for the radiosensitive human infant cerebellum in a Swiss-led program of experimental microbeam radiation therapy (MRT) at the ESRF. Five weanlings in a 47 day old litter of seven, and eight weanlings in a 40 day old litter of eleven were irradiated in November, 1999 and June, 2000, respectively. A 1.5 cm-wide x 1.5 xm-high array of equally space approximately equals 20-30 micrometers wide, upright microbeams spaced at 210 micrometers intervals was propagated horizontally, left to right, through the cerebella of the prone, anesthetized piglets. Skin-entrance intra-microbeam peak adsorbed doses were uniform, either 150, 300, 425, or 600 gray (Gy). Peak and inter-microbeam (valley) absorbed doses in the cerebellum were computed with the PSI version of the Monte Carlo code GEANT and benchmarked using Gafchromic and radiochromic film microdosimetry. For approximately equals 66 weeks [first litter; until euthanasia], or approximately equals 57 weeks [second litter; until July 30, 2001] after irradiation, the littermates were developmentally, behaviorally, neurologically and radiologically normal as observed and tested by experienced farmers and veterinary scientists unaware of which piglets were irradiated or sham-irradiated. Morever, MRT implemented at the ESRF with a similar array of microbeams and a uniform skin-entrance peak dose of 625 Gy, followed by immunoprophylaxis, was shown to be palliative or curative in young adult rats bearing intracerebral gliosarcomas. These observations give further credence to MRT's potential as an adjunct therapy for brain tumors in infancy, when seamless therapeutic irradiation of the brain is hazardous.

  4. WE-G-BRE-01: A High Power Nanotube X-Ray Microbeam Irradiator for Preclinical Brain Tumor Treatment

    SciTech Connect

    Chtcheprov, P; Inscoe, C; Zhang, L; Lu, J; Zhou, O; Chang, S; Sprenger, F; Laganis, P

    2014-06-15

    Purpose: Microbeam radiation therapy (MRT) is a new type of cancer treatment undergoing studies at various synchrotron facilities. The principle of MRT is using arrays of microscopically small, low-energy X-radiation for the treatment of various radio-resistant, deep-seated tumors. Our motivation is to develop a compact and inexpensive image guided MRT irradiator to use in the research lab setting. After a successful initial demonstration, here we report a second generation carbon nanotube (CNT) cathode based MRT tube, capable of producing multiple microbeam lines with an anticipated dose rate of 11 Gy/min per line. Methods: The system uses multiple line CNT source arrays to generate multiple focal lines on the anode. The increase in dose-rate, compared to our first generation system, is achieved by increasing the operating voltage from 160 kVp to 225kVp, adding multiple simultaneous focal lines on the anode, and a more efficient cooling mechanism using a 6kW oil-cooled anode. Results: This work will present the design and development process, challenges and solutions to meeting operating specifications, and the final design of the tube and collimator, along with optimization and stabilization of its use. A detailed characterization of its capabilities will be included with a comprehensive measurement of its X-ray focal line dimensions, an evaluation of its collimator alignment and microbeam dimensions, and phantom-based quantification of its dosimetric output. Conclusion: The development of a second generation, compact, multiple line MRT device using carbon nanotube (CNT) cathode based X-ray technology and a novel oil cooled anode design is presented here. With this new source, we are capable of delivering a total microbeam radiation dose comparable to the low end of the synchrotron based MRT systems for small animal brain tumor models.

  5. Medical physics aspects of the synchrotron radiation therapies: Microbeam radiation therapy (MRT) and synchrotron stereotactic radiotherapy (SSRT).

    PubMed

    Bräuer-Krisch, Elke; Adam, Jean-Francois; Alagoz, Enver; Bartzsch, Stefan; Crosbie, Jeff; DeWagter, Carlos; Dipuglia, Andrew; Donzelli, Mattia; Doran, Simon; Fournier, Pauline; Kalef-Ezra, John; Kock, Angela; Lerch, Michael; McErlean, Ciara; Oelfke, Uwe; Olko, Pawel; Petasecca, Marco; Povoli, Marco; Rosenfeld, Anatoly; Siegbahn, Erik A; Sporea, Dan; Stugu, Bjarne

    2015-09-01

    Stereotactic Synchrotron Radiotherapy (SSRT) and Microbeam Radiation Therapy (MRT) are both novel approaches to treat brain tumor and potentially other tumors using synchrotron radiation. Although the techniques differ by their principles, SSRT and MRT share certain common aspects with the possibility of combining their advantages in the future. For MRT, the technique uses highly collimated, quasi-parallel arrays of X-ray microbeams between 50 and 600 keV. Important features of highly brilliant Synchrotron sources are a very small beam divergence and an extremely high dose rate. The minimal beam divergence allows the insertion of so called Multi Slit Collimators (MSC) to produce spatially fractionated beams of typically ∼25-75 micron-wide microplanar beams separated by wider (100-400 microns center-to-center(ctc)) spaces with a very sharp penumbra. Peak entrance doses of several hundreds of Gy are extremely well tolerated by normal tissues and at the same time provide a higher therapeutic index for various tumor models in rodents. The hypothesis of a selective radio-vulnerability of the tumor vasculature versus normal blood vessels by MRT was recently more solidified. SSRT (Synchrotron Stereotactic Radiotherapy) is based on a local drug uptake of high-Z elements in tumors followed by stereotactic irradiation with 80 keV photons to enhance the dose deposition only within the tumor. With SSRT already in its clinical trial stage at the ESRF, most medical physics problems are already solved and the implemented solutions are briefly described, while the medical physics aspects in MRT will be discussed in more detail in this paper. PMID:26043881

  6. A first generation compact microbeam radiation therapy system based on carbon nanotube X-ray technology

    SciTech Connect

    Hadsell, M.; Shan, J.; Burk, L.; Zhang, J.; Chang, S.; Laganis, P.; Sprenger, F.; Zhang, L.; Yuan, H.; Lu, J.; Zhou, O.

    2013-10-28

    We have developed a compact microbeam radiation therapy device using carbon nanotube cathodes to create a linear array of narrow focal line segments on a tungsten anode and a custom collimator assembly to select a slice of the resulting wedge-shaped radiation pattern. Effective focal line width was measured to be 131 μm, resulting in a microbeam width of ∼300 μm. The instantaneous dose rate was projected to be 2 Gy/s at full-power. Peak to valley dose ratio was measured to be >17 when a 1.4 mm microbeam separation was employed. Finally, multiple microbeams were delivered to a mouse with beam paths verified through histology.

  7. A first generation compact microbeam radiation therapy system based on carbon nanotube X-ray technology

    PubMed Central

    Hadsell, M.; Zhang, J.; Laganis, P.; Sprenger, F.; Shan, J.; Zhang, L.; Burk, L.; Yuan, H.; Chang, S.; Lu, J.; Zhou, O.

    2013-01-01

    We have developed a compact microbeam radiation therapy device using carbon nanotube cathodes to create a linear array of narrow focal line segments on a tungsten anode and a custom collimator assembly to select a slice of the resulting wedge-shaped radiation pattern. Effective focal line width was measured to be 131 μm, resulting in a microbeam width of ∼300 μm. The instantaneous dose rate was projected to be 2 Gy/s at full-power. Peak to valley dose ratio was measured to be >17 when a 1.4 mm microbeam separation was employed. Finally, multiple microbeams were delivered to a mouse with beam paths verified through histology. PMID:24273330

  8. X-Tream quality assurance in synchrotron X-ray microbeam radiation therapy.

    PubMed

    Fournier, Pauline; Cornelius, Iwan; Donzelli, Mattia; Requardt, Herwig; Nemoz, Christian; Petasecca, Marco; Bräuer-Krisch, Elke; Rosenfeld, Anatoly; Lerch, Michael

    2016-09-01

    Microbeam radiation therapy (MRT) is a novel irradiation technique for brain tumours treatment currently under development at the European Synchrotron Radiation Facility in Grenoble, France. The technique is based on the spatial fractionation of a highly brilliant synchrotron X-ray beam into an array of microbeams using a multi-slit collimator (MSC). After promising pre-clinical results, veterinary trials have recently commenced requiring the need for dedicated quality assurance (QA) procedures. The quality of MRT treatment demands reproducible and precise spatial fractionation of the incoming synchrotron beam. The intensity profile of the microbeams must also be quickly and quantitatively characterized prior to each treatment for comparison with that used for input to the dose-planning calculations. The Centre for Medical Radiation Physics (University of Wollongong, Australia) has developed an X-ray treatment monitoring system (X-Tream) which incorporates a high-spatial-resolution silicon strip detector (SSD) specifically designed for MRT. In-air measurements of the horizontal profile of the intrinsic microbeam X-ray field in order to determine the relative intensity of each microbeam are presented, and the alignment of the MSC is also assessed. The results show that the SSD is able to resolve individual microbeams which therefore provides invaluable QA of the horizontal field size and microbeam number and shape. They also demonstrate that the SSD used in the X-Tream system is very sensitive to any small misalignment of the MSC. In order to allow as rapid QA as possible, a fast alignment procedure of the SSD based on X-ray imaging with a low-intensity low-energy beam has been developed and is presented in this publication. PMID:27577773

  9. Preferential Effect of Synchrotron Microbeam Radiation Therapy on Intracerebral 9L Gliosarcoma Vascular Networks

    SciTech Connect

    Bouchet, Audrey; Lemasson, Benjamin; Le Duc, Geraldine; Maisin, Cecile; Braeuer-Krisch, Elke; Siegbahn, Erik Albert; Renaud, Luc; Khalil, Enam; Remy, Chantal; Poillot, Cathy; Bravin, Alberto; Laissue, Jean A.; Barbier, Emmanuel L.; Serduc, Raphael

    2010-12-01

    Purpose: Synchrotron microbeam radiation therapy (MRT) relies on spatial fractionation of the incident photon beam into parallel micron-wide beams. Our aim was to analyze the effects of MRT on normal brain and 9L gliosarcoma tissues, particularly on blood vessels. Methods and Materials: Responses to MRT (two arrays, one lateral, one anteroposterior (2 x 400 Gy), intersecting orthogonally in the tumor region) were studied during 6 weeks using MRI, immunohistochemistry, and vascular endothelial growth factor Western blot. Results: MRT increased the median survival time of irradiated rats (x3.25), significantly increased blood vessel permeability, and inhibited tumor growth; a cytotoxic effect on 9L cells was detected 5 days after irradiation. Significant decreases in tumoral blood volume fraction and vessel diameter were measured from 8 days after irradiation, due to loss of endothelial cells in tumors as detected by immunochemistry. Edema was observed in the normal brain exposed to both crossfired arrays about 6 weeks after irradiation. This edema was associated with changes in blood vessel morphology and an overexpression of vascular endothelial growth factor. Conversely, vascular parameters and vessel morphology in brain regions exposed to one of the two arrays were not damaged, and there was no loss of vascular endothelia. Conclusions: We show for the first time that preferential damage of MRT to tumor vessels versus preservation of radioresistant normal brain vessels contributes to the efficient palliation of 9L gliosarcomas in rats. Molecular pathways of repair mechanisms in normal and tumoral vascular networks after MRT may be essential for the improvement of such differential effects on the vasculature.

  10. Revealing the underlying mechanism of microbeam radiation therapy with low energy Monte Carlo simulations

    NASA Astrophysics Data System (ADS)

    McNamara, A. L.; Oelfke, U.; Kuncic, Z.

    2014-03-01

    Microbeam radiation therapy (MRT) is a new experimental oncological modality, intended for the treatment of inoperable brain tumours, particularly in difficult cases where conventional radiation therapy can cause irreversible damage. MRT consists of an array of highly collimated, quasi-parallel x-ray microbeams aimed at the tumour tissue, delivering high dose within the beam path and low doses in regions between the beams. For reasons still not fully understood, healthy tissue exposed to the microbeam array is able to regenerate while tumour volumes are significantly reduced. Low energy Monte Carlo radiative transport simulations provide new insight into understanding the underlying mechanisms of MRT. In particular, predicting the ionisation cluster distribution, which is a significant cause of lethal damage to cells, would provide insight into the biological responses. Geant4-DNA was used to model an x-ray microbeam of width 20 μm in liquid water. Secondary electrons, predominately responsible for ionisation clustering, were tracked to predict damage to cells within and adjacent to the beams. We find that higher energy beams (100 keV) produce less secondary electrons in the regions outside the beam than low energy beams (30-50 keV).

  11. X-Tream: a novel dosimetry system for Synchrotron Microbeam Radiation Therapy

    NASA Astrophysics Data System (ADS)

    Petasecca, M.; Cullen, A.; Fuduli, I.; Espinoza, A.; Porumb, C.; Stanton, C.; Aldosari, A. H.; Bräuer-Krisch, E.; Requardt, H.; Bravin, A.; Perevertaylo, V.; Rosenfeld, A. B.; Lerch, M. L. F.

    2012-07-01

    Microbeam Radiation Therapy (MRT) is a radiation treatment technique under development for inoperable brain tumors. MRT is based on the use of a synchrotron generated X-ray beam with an extremely high dose rate ( ~ 20 kGy/sec), striated into an array of X-ray micro-blades. In order to advance to clinical trials, a real-time dosimeter with excellent spatial resolution must be developed for absolute dosimetry. The design of a real-time dosimeter for such a radiation scenario represents a significant challenge due to the high photon flux and vertically striated radiation field, leading to very steep lateral dose gradients. This article analyses the striated radiation field in the context of the requirements for temporal dosimetric measurements and presents the architecture of a new dosimetry system based on the use of silicon detectors and fast data acquisition electronic interface. The combined system demonstrates micrometer spatial resolution and microsecond real time readout with accurate sensitivity and linearity over five orders of magnitude of input signal. The system will therefore be suitable patient treatment plan verification and may also be expanded for in-vivo beam monitoring for patient safety during the treatment.

  12. New technology enables high precision multislit collimators for microbeam radiation therapy

    NASA Astrophysics Data System (ADS)

    Bräuer-Krisch, E.; Requardt, H.; Brochard, T.; Berruyer, G.; Renier, M.; Laissue, J. A.; Bravin, A.

    2009-07-01

    During the past decade microbeam radiation therapy has evolved from preclinical studies to a stage in which clinical trials can be planned, using spatially fractionated, highly collimated and high intensity beams like those generated at the x-ray ID17 beamline of the European Synchrotron Radiation Facility. The production of such microbeams typically between 25 and 100 μm full width at half maximum (FWHM) values and 100-400 μm center-to-center (c-t-c) spacings requires a multislit collimator either with fixed or adjustable microbeam width. The mechanical regularity of such devices is the most important property required to produce an array of identical microbeams. That ensures treatment reproducibility and reliable use of Monte Carlo-based treatment planning systems. New high precision wire cutting techniques allow the fabrication of these collimators made of tungsten carbide. We present a variable slit width collimator as well as a single slit device with a fixed setting of 50 μm FWHM and 400 μm c-t-c, both able to cover irradiation fields of 50 mm width, deemed to meet clinical requirements. Important improvements have reduced the standard deviation of 5.5 μm to less than 1 μm for a nominal FWHM value of 25 μm. The specifications of both devices, the methods used to measure these characteristics, and the results are presented.

  13. Spatially resolved measurement of high doses in microbeam radiation therapy using samarium doped fluorophosphate glasses

    SciTech Connect

    Okada, Go; Morrell, Brian; Koughia, Cyril; Kasap, Safa; Edgar, Andy; Varoy, Chris; Belev, George; Wysokinski, Tomasz; Chapman, Dean

    2011-09-19

    The measurement of spatially resolved high doses in microbeam radiation therapy has always been a challenging task, where a combination of high dose response and high spatial resolution (microns) is required for synchrotron radiation peaked around 50 keV. The x-ray induced Sm{sup 3+}{yields} Sm{sup 2+} valence conversion in Sm{sup 3+} doped fluorophosphates glasses has been tested for use in x-ray dosimetry for microbeam radiation therapy. The conversion efficiency depends almost linearly on the dose of irradiation up to {approx}5 Gy and saturates at doses exceeding {approx}80 Gy. The conversion shows strong correlation with x-ray induced absorbance of the glass which is related to the formation of phosphorus-oxygen hole centers. When irradiated through a microslit collimator, a good spatial resolution and high ''peak-to-valley'' contrast have been observed by means of confocal photoluminescence microscopy.

  14. Monte Carlo-based treatment planning system calculation engine for microbeam radiation therapy

    SciTech Connect

    Martinez-Rovira, I.; Sempau, J.; Prezado, Y.

    2012-05-15

    Purpose: Microbeam radiation therapy (MRT) is a synchrotron radiotherapy technique that explores the limits of the dose-volume effect. Preclinical studies have shown that MRT irradiations (arrays of 25-75-{mu}m-wide microbeams spaced by 200-400 {mu}m) are able to eradicate highly aggressive animal tumor models while healthy tissue is preserved. These promising results have provided the basis for the forthcoming clinical trials at the ID17 Biomedical Beamline of the European Synchrotron Radiation Facility (ESRF). The first step includes irradiation of pets (cats and dogs) as a milestone before treatment of human patients. Within this context, accurate dose calculations are required. The distinct features of both beam generation and irradiation geometry in MRT with respect to conventional techniques require the development of a specific MRT treatment planning system (TPS). In particular, a Monte Carlo (MC)-based calculation engine for the MRT TPS has been developed in this work. Experimental verification in heterogeneous phantoms and optimization of the computation time have also been performed. Methods: The penelope/penEasy MC code was used to compute dose distributions from a realistic beam source model. Experimental verification was carried out by means of radiochromic films placed within heterogeneous slab-phantoms. Once validation was completed, dose computations in a virtual model of a patient, reconstructed from computed tomography (CT) images, were performed. To this end, decoupling of the CT image voxel grid (a few cubic millimeter volume) to the dose bin grid, which has micrometer dimensions in the transversal direction of the microbeams, was performed. Optimization of the simulation parameters, the use of variance-reduction (VR) techniques, and other methods, such as the parallelization of the simulations, were applied in order to speed up the dose computation. Results: Good agreement between MC simulations and experimental results was achieved, even at

  15. Physiologically gated micro-beam radiation therapy using electronically controlled field emission x-ray source array

    NASA Astrophysics Data System (ADS)

    Chtcheprov, Pavel; Hadsell, Michael; Burk, Laurel; Ger, Rachel; Zhang, Lei; Yuan, Hong; Lee, Yueh Z.; Chang, Sha; Lu, Jianping; Zhou, Otto

    2013-03-01

    Micro-beam radiation therapy (MRT) uses parallel planes of high dose narrow (10-100 um in width) radiation beams separated by a fraction of a millimeter to treat cancerous tumors. This experimental therapy method based on synchrotron radiation has been shown to spare normal tissue at up to 1000Gy of entrance dose while still being effective in tumor eradication and extending the lifetime of tumor-bearing small animal models. Motion during the treatment can result in significant movement of micro beam positions resulting in broader beam width and lower peak to valley dose ratio (PVDR), and thus can reduce the effectiveness of the MRT. Recently we have developed the first bench-top image guided MRT system for small animal treatment using a high powered carbon nanotube (CNT) x-ray source array. The CNT field emission x-ray source can be electronically synchronized to an external triggering signal to enable physiologically gated firing of x-ray radiation to minimize motion blurring. Here we report the results of phantom study of respiratory gated MRT. A simulation of mouse breathing was performed using a servo motor. Preliminary results show that without gating the micro beam full width at tenth maximum (FWTM) can increase by 70% and PVDR can decrease up to 50%. But with proper gating, both the beam width and PVDR changes can be negligible. Future experiments will involve irradiation of mouse models and comparing histology stains between the controls and the gated irradiation.

  16. Micrometer-resolved film dosimetry using a microscope in microbeam radiation therapy

    SciTech Connect

    Bartzsch, Stefan Oelfke, Uwe; Lott, Johanna; Welsch, Katrin; Bräuer-Krisch, Elke

    2015-07-15

    Purpose: Microbeam radiation therapy (MRT) is a still preclinical tumor therapy approach that uses arrays of a few tens of micrometer wide parallel beams separated by a few 100 μm. The production, measurement, and planning of such radiation fields are a challenge up to now. Here, the authors investigate the feasibility of radiochromic film dosimetry in combination with a microscopic readout as a tool to validate peak and valley doses in MRT, which is an important requirement for a future clinical application of the therapy. Methods: Gafchromic{sup ®} HD-810 and HD-V2 films are exposed to MRT fields at the biomedical beamline ID17 of the European Synchrotron Radiation Facility (ESRF) and are afterward scanned with a microscope. The measured dose is compared with Monte Carlo calculations. Image analysis tools and film handling protocols are developed that allow accurate and reproducible dosimetry. The performance of HD-810 and HD-V2 films is compared and a detailed analysis of the resolution, noise, and energy dependence is carried out. Measurement uncertainties are identified and analyzed. Results: The dose was measured with a resolution of 5 × 1000 μm{sup 2} and an accuracy of 5% in the peak and between 10% and 15% in the valley region. As main causes for dosimetry uncertainties, statistical noise, film inhomogeneities, and calibration errors were identified. Calibration errors strongly increase at low doses and exceeded 3% for doses below 50 and 70 Gy for HD-V2 and HD-810 films, respectively. While the grain size of both film types is approximately 2 μm, the statistical noise in HD-V2 is much higher than in HD-810 films. However, HD-810 films show a higher energy dependence at low photon energies. Conclusions: Both film types are appropriate for dosimetry in MRT and the microscope is superior to the microdensitometer used before at the ESRF with respect to resolution and reproducibility. However, a very careful analysis of the image data is required

  17. Microbeam Radiation Therapy: Tissue Dose Penetration and BANG-Gel Dosimetry of Thick-Beams' Array Intelacing

    SciTech Connect

    Dilmanian, F.; Romanelli, P; Zhong, Z; Wang, R; Wagshul, M; Kalef-Ezra, J; Maryanski, M; Rosen, E; Anschel, D

    2008-01-01

    The tissue-sparing effect of parallel, thin (narrower than 100em) synchrotron-generated X-ray planar beams (microbeams) in healthy tissues including the central nervous system (CNS) is known since early 1990s. This, together with a remarkable preferential tumoricidal effect of such beam arrays observed at high doses, has been the basis for labeling the method microbeam radiation therapy (MRT). Recent studies showed that beams as thick as 0.68mm ('thick microbeams') retain part of their sparing effect in the rat's CNS, and that two such orthogonal microbeams arrays can be interlaced to produce an unsegmented field at the target, thus producing focal targeting. We measured the half-value layer (HVL) of our 120-keV median-energy beam in water phantoms, and we irradiated stereotactically bis acrylamide nitrogen gelatin (BANG)-gel-filled phantoms, including one containing a human skull, with interlaced microbeams and imaged them with MRI. A 43-mm water HVL resulted, together with an adequately large peak-to-valley ratio of the microbeams' three-dimensional dose distribution in the vicinity of the 20mmx20mmx20mm target deep into the skull. Furthermore, the 80-20% dose falloff was a fraction of a millimeter as predicted by Monte Carlo simulations. We conclude that clinical MRT will benefit from the use of higher beam energies than those used here, although the current energy could serve certain neurosurgical applications. Furthermore, thick microbeams particularly when interlaced present some advantages over thin microbeams in that they allow the use of higher beam energies and they could conceivably be implemented with high power orthovoltage X-ray tubes.

  18. Pilot study for compact microbeam radiation therapy using a carbon nanotube field emission micro-CT scanner

    SciTech Connect

    Hadsell, Mike Cao, Guohua; Zhang, Jian; Burk, Laurel; Schreiber, Torsten; Lu, Jianping; Zhou, Otto; Schreiber, Eric; Chang, Sha

    2014-06-15

    Purpose: Microbeam radiation therapy (MRT) is defined as the use of parallel, microplanar x-ray beams with an energy spectrum between 50 and 300 keV for cancer treatment and brain radiosurgery. Up until now, the possibilities of MRT have mainly been studied using synchrotron sources due to their high flux (100s Gy/s) and approximately parallel x-ray paths. The authors have proposed a compact x-ray based MRT system capable of delivering MRT dose distributions at a high dose rate. This system would employ carbon nanotube (CNT) field emission technology to create an x-ray source array that surrounds the target of irradiation. Using such a geometry, multiple collimators would shape the irradiation from this array into multiple microbeams that would then overlap or interlace in the target region. This pilot study demonstrates the feasibility of attaining a high dose rate and parallel microbeam beams using such a system. Methods: The microbeam dose distribution was generated by our CNT micro-CT scanner (100μm focal spot) and a custom-made microbeam collimator. An alignment assembly was fabricated and attached to the scanner in order to collimate and superimpose beams coming from different gantry positions. The MRT dose distribution was measured using two orthogonal radiochromic films embedded inside a cylindrical phantom. This target was irradiated with microbeams incident from 44 different gantry angles to simulate an array of x-ray sources as in the proposed compact CNT-based MRT system. Finally, phantom translation in a direction perpendicular to the microplanar beams was used to simulate the use of multiple parallel microbeams. Results: Microbeams delivered from 44 gantry angles were superimposed to form a single microbeam dose distribution in the phantom with a FWHM of 300μm (calculated value was 290 μm). Also, during the multiple beam simulation, a peak to valley dose ratio of ∼10 was found when the phantom translation distance was roughly 4x the beam width

  19. Pilot study for compact microbeam radiation therapy using a carbon nanotube field emission micro-CT scanner

    PubMed Central

    Hadsell, Mike; Cao, Guohua; Zhang, Jian; Burk, Laurel; Schreiber, Torsten; Schreiber, Eric; Chang, Sha; Lu, Jianping; Zhou, Otto

    2014-01-01

    Purpose: Microbeam radiation therapy (MRT) is defined as the use of parallel, microplanar x-ray beams with an energy spectrum between 50 and 300 keV for cancer treatment and brain radiosurgery. Up until now, the possibilities of MRT have mainly been studied using synchrotron sources due to their high flux (100s Gy/s) and approximately parallel x-ray paths. The authors have proposed a compact x-ray based MRT system capable of delivering MRT dose distributions at a high dose rate. This system would employ carbon nanotube (CNT) field emission technology to create an x-ray source array that surrounds the target of irradiation. Using such a geometry, multiple collimators would shape the irradiation from this array into multiple microbeams that would then overlap or interlace in the target region. This pilot study demonstrates the feasibility of attaining a high dose rate and parallel microbeam beams using such a system. Methods: The microbeam dose distribution was generated by our CNT micro-CT scanner (100 μm focal spot) and a custom-made microbeam collimator. An alignment assembly was fabricated and attached to the scanner in order to collimate and superimpose beams coming from different gantry positions. The MRT dose distribution was measured using two orthogonal radiochromic films embedded inside a cylindrical phantom. This target was irradiated with microbeams incident from 44 different gantry angles to simulate an array of x-ray sources as in the proposed compact CNT-based MRT system. Finally, phantom translation in a direction perpendicular to the microplanar beams was used to simulate the use of multiple parallel microbeams. Results: Microbeams delivered from 44 gantry angles were superimposed to form a single microbeam dose distribution in the phantom with a FWHM of 300 μm (calculated value was 290 μm). Also, during the multiple beam simulation, a peak to valley dose ratio of ∼10 was found when the phantom translation distance was roughly 4x the beam width

  20. Treating Brain Tumor with Microbeam Radiation Generated by a Compact Carbon-Nanotube-Based Irradiator: Initial Radiation Efficacy Study.

    PubMed

    Yuan, Hong; Zhang, Lei; Frank, Jonathan E; Inscoe, Christina R; Burk, Laurel M; Hadsell, Mike; Lee, Yueh Z; Lu, Jianping; Chang, Sha; Zhou, Otto

    2015-09-01

    Microbeam radiation treatment (MRT) using synchrotron radiation has shown great promise in the treatment of brain tumors, with a demonstrated ability to eradicate the tumor while sparing normal tissue in small animal models. With the goal of expediting the advancement of MRT research beyond the limited number of synchrotron facilities in the world, we recently developed a compact laboratory-scale microbeam irradiator using carbon nanotube (CNT) field emission-based X-ray source array technology. The focus of this study is to evaluate the effects of the microbeam radiation generated by this compact irradiator in terms of tumor control and normal tissue damage in a mouse brain tumor model. Mice with U87MG human glioblastoma were treated with sham irradiation, low-dose MRT, high-dose MRT or 10 Gy broad-beam radiation treatment (BRT). The microbeams were 280 μm wide and spaced at 900 μm center-to-center with peak dose at either 48 Gy (low-dose MRT) or 72 Gy (high-dose MRT). Survival studies showed that the mice treated with both MRT protocols had a significantly extended life span compared to the untreated control group (31.4 and 48.5% of life extension for low- and high-dose MRT, respectively) and had similar survival to the BRT group. Immunostaining on MRT mice demonstrated much higher DNA damage and apoptosis level in tumor tissue compared to the normal brain tissue. Apoptosis in normal tissue was significantly lower in the low-dose MRT group compared to that in the BRT group at 48 h postirradiation. Interestingly, there was a significantly higher level of cell proliferation in the MRT-treated normal tissue compared to that in the BRT-treated mice, indicating rapid normal tissue repairing process after MRT. Microbeam radiation exposure on normal brain tissue causes little apoptosis and no macrophage infiltration at 30 days after exposure. This study is the first biological assessment on MRT effects using the compact CNT-based irradiator. It provides an alternative

  1. Dose distribution from x-ray microbeam arrays applied to radiation therapy: an EGS4 Monte Carlo study.

    PubMed

    De Felici, M; Felici, R; Sanchez del Rio, M; Ferrero, C; Bacarian, T; Dilmanian, F A

    2005-08-01

    We present EGS4 Monte Carlo calculations of the spatial distribution of the dose deposited by a single x-ray pencil beam, a planar microbeam, and an array of parallel planar microbeams as used in radiation therapy research. The profiles of the absorbed dose distribution in a phantom, including the peak-to-valley ratio of the dose distribution from microbeam arrays, were calculated at micrometer resolution. We determined the dependence of the findings on the main parameters of photon and electron transport. The results illustrate the dependence of the electron range and the deposited in-beam dose on the cut-off energy, of the electron transport, as well as the effects on the dose profiles of the beam energy, the array size, and the beam spacing. The effect of beam polarization also was studied for a single pencil beam and for an array of parallel planar microbeams. The results show that although the polarization effect on the dose distribution from a 3 cm x 3 cm microbeam array inside a water phantom is large enough to be measured at the outer side of the array (16% difference of the deposited dose for x-ray beams of 200 keV), it is not detectable at the array's center, thus being irrelevant for the radiation therapy purposes. Finally we show that to properly compare the dose profiles determined with a metal oxide semiconductor field emission transistor detector with the computational method predictions, it is important to simulate adequately the size and the material of the device's Si active element. PMID:16193774

  2. Assessment of optical CT as a future QA tool for synchrotron x-ray microbeam therapy.

    PubMed

    McErlean, Ciara M; Bräuer-Krisch, Elke; Adamovics, John; Doran, Simon J

    2016-01-01

    Synchrotron microbeam radiation therapy (MRT) is an advanced form of radiotherapy for which it is extremely difficult to provide adequate quality assurance. This may delay or limit its clinical uptake, particularly in the paediatric patient populations for whom it could be especially suitable. This study investigates the extent to which new developments in 3D dosimetry using optical computed tomography (CT) can visualise MRT dose distributions, and assesses what further developments are necessary before fully quantitative 3D measurements can be achieved. Two experiments are reported. In the first cylindrical samples of the radiochromic polymer PRESAGE(®) were irradiated with different complex MRT geometries including multiport treatments of collimated 'pencil' beams, interlaced microplanar arrays and a multiport treatment using an anthropomorphic head phantom. Samples were scanned using transmission optical CT. In the second experiment, optical CT measurements of the biologically important peak-to-valley dose ratio (PVDR) were compared with expected values from Monte Carlo simulations. The depth-of-field (DOF) of the optical CT system was characterised using a knife-edge method and the possibility of spatial resolution improvement through deconvolution of a measured point spread function (PSF) was investigated. 3D datasets from the first experiment revealed excellent visualisation of the 50 μm beams and various discrepancies from the planned delivery dose were found. The optical CT PVDR measurements were found to be consistently 30% of the expected Monte Carlo values and deconvolution of the microbeam profiles was found to lead to increased noise. The reason for the underestimation of the PVDR by optical CT was attributed to lack of spatial resolution, supported by the results of the DOF characterisation. Solutions are suggested for the outstanding challenges and the data are shown already to be useful in identifying potential treatment anomalies. PMID:26657052

  3. Assessment of optical CT as a future QA tool for synchrotron x-ray microbeam therapy

    NASA Astrophysics Data System (ADS)

    McErlean, Ciara M.; Bräuer-Krisch, Elke; Adamovics, John; Doran, Simon J.

    2016-01-01

    Synchrotron microbeam radiation therapy (MRT) is an advanced form of radiotherapy for which it is extremely difficult to provide adequate quality assurance. This may delay or limit its clinical uptake, particularly in the paediatric patient populations for whom it could be especially suitable. This study investigates the extent to which new developments in 3D dosimetry using optical computed tomography (CT) can visualise MRT dose distributions, and assesses what further developments are necessary before fully quantitative 3D measurements can be achieved. Two experiments are reported. In the first cylindrical samples of the radiochromic polymer PRESAGE® were irradiated with different complex MRT geometries including multiport treatments of collimated ‘pencil’ beams, interlaced microplanar arrays and a multiport treatment using an anthropomorphic head phantom. Samples were scanned using transmission optical CT. In the second experiment, optical CT measurements of the biologically important peak-to-valley dose ratio (PVDR) were compared with expected values from Monte Carlo simulations. The depth-of-field (DOF) of the optical CT system was characterised using a knife-edge method and the possibility of spatial resolution improvement through deconvolution of a measured point spread function (PSF) was investigated. 3D datasets from the first experiment revealed excellent visualisation of the 50 μm beams and various discrepancies from the planned delivery dose were found. The optical CT PVDR measurements were found to be consistently 30% of the expected Monte Carlo values and deconvolution of the microbeam profiles was found to lead to increased noise. The reason for the underestimation of the PVDR by optical CT was attributed to lack of spatial resolution, supported by the results of the DOF characterisation. Solutions are suggested for the outstanding challenges and the data are shown already to be useful in identifying potential treatment anomalies.

  4. In vivo pink-beam imaging and fast alignment procedure for rat brain tumor radiation therapy.

    PubMed

    Nemoz, Christian; Kibleur, Astrid; Hyacinthe, Jean Noël; Berruyer, Gilles; Brochard, Thierry; Bräuer-Krisch, Elke; Le Duc, Géraldine; Brun, Emmanuel; Elleaume, Hélène; Serduc, Raphaël

    2016-01-01

    A fast positioning method for brain tumor microbeam irradiations for preclinical studies at third-generation X-ray sources is described. The three-dimensional alignment of the animals relative to the X-ray beam was based on the X-ray tomography multi-slices after iodine infusion. This method used pink-beam imaging produced by the ID17 wiggler. A graphical user interface has been developed in order to define the irradiation parameters: field width, height, number of angles and X-ray dose. This study is the first reporting an image guided method for soft tissue synchrotron radiotherapy. It allowed microbeam radiation therapy irradiation fields to be reduced by a factor of ∼20 compared with previous studies. It permitted more targeted, more efficient brain tumor microbeam treatments and reduces normal brain toxicity of the radiation treatment. PMID:26698083

  5. Thin silicon strip detectors for beam monitoring in Micro-beam Radiation Therapy

    NASA Astrophysics Data System (ADS)

    Povoli, M.; Alagoz, E.; Bravin, A.; Cornelius, I.; Bräuer-Krisch, E.; Fournier, P.; Hansen, T. E.; Kok, A.; Lerch, M.; Monakhov, E.; Morse, J.; Petasecca, M.; Requardt, H.; Rosenfeld, A. B.; Röhrich, D.; Sandaker, H.; Salomé, M.; Stugu, B.

    2015-11-01

    Microbeam Radiation Therapy (MRT) is an emerging cancer treatment that is currently being developed at the European Synchrotron Radiation Facility (ESRF) in Grenoble, France. This technique uses a highly collimated and fractionated X-ray beam array with extremely high dose rate and very small divergence, to benefit from the dose-volume effect, thus sparing healthy tissue. In case of any beam anomalies and system malfunctions, special safety measures must be installed, such as an emergency safety shutter that requires continuous monitoring of the beam intensity profile. Within the 3DMiMic project, a novel silicon strip detector that can tackle the special features of MRT, such as the extremely high spatial resolution and dose rate, has been developed to be part of the safety shutter system. The first prototypes have been successfully fabricated, and experiments aimed to demonstrate their suitability for this unique application have been performed. Design, fabrication and the experimental results as well as any identified inadequacies for future optimisation are reported and discussed in this paper.

  6. Monte Carlo dosimetry for forthcoming clinical trials in x-ray microbeam radiation therapy

    NASA Astrophysics Data System (ADS)

    Martínez-Rovira, I.; Sempau, J.; Fernández-Varea, J. M.; Bravin, A.; Prezado, Y.

    2010-08-01

    The purpose of this work is to define safe irradiation protocols in microbeam radiation therapy. The intense synchrotron-generated x-ray beam used for the treatment is collimated and delivered in an array of 50 μm-sized rectangular fields with a centre-to-centre distance between microplanes of 400 μm. The absorbed doses received by the tumour and the healthy tissues in a human head phantom have been assessed by means of Monte Carlo simulations. The identification of safe dose limits is carried out by evaluating the maximum peak and valley doses achievable in the tumour while keeping the valley doses in the healthy tissues under tolerances. As the skull receives a significant fraction of the dose, the dose limits are referred to this tissue. Dose distributions with high spatial resolution are presented for various tumour positions, skull thicknesses and interbeam separations. Considering a unidirectional irradiation (field size of 2×2 cm2) and a centrally located tumour, the largest peak and valley doses achievable in the tumour are 55 Gy and 2.6 Gy, respectively. The corresponding maximum valley doses received by the skin, bone and healthy brain are 4 Gy, 14 Gy and 7 Gy (doses in one fraction), respectively, i.e. within tolerances (5% probability of complication within 5 years).

  7. Optically erasable samarium-doped fluorophosphate glasses for high-dose measurements in microbeam radiation therapy

    NASA Astrophysics Data System (ADS)

    Morrell, B.; Okada, G.; Vahedi, S.; Koughia, C.; Edgar, A.; Varoy, C.; Belev, G.; Wysokinski, T.; Chapman, D.; Sammynaiken, R.; Kasap, S. O.

    2014-02-01

    Previous work has demonstrated that fluorophosphate (FP) glasses doped with trivalent samarium (Sm3+) can be used as a dosimetric detector in microbeam radiation therapy (MRT) to measure high radiation doses and large dose variations with a resolution in the micrometer range. The present work addresses the use of intense optical radiation at 405 nm to erase the recorded dose information in Sm3+-doped FP glass plates and examines the underlying physics. We have evaluated both the conversion and optical erasure of Sm3+-doped FP glasses using synchrotron-generated high-dose x-rays at the Canadian Light Source. The Sm-ion valency conversion is accompanied by the appearance of x-ray induced optical absorbance due to the trapping of holes and electrons into phosphorus-oxygen hole (POHC) and electron (POEC) capture centers. Nearly complete Sm2+ to Sm3+ reconversion (erasure) may be achieved by intense optical illumination. Combined analysis of absorbance and electron spin resonance measurements indicates that the optical illumination causes partial disappearance of the POHC and the appearance of new POEC. The suggested model for the observed phenomena is based on the release of electrons during the Sm2+ to Sm3+ reconversion process, the capture of these electrons by POHC (and hence their disappearance), or by PO groups, with the appearance of new and/or additional POEC. Optical erasure may be used as a practical means to erase the recorded data and permits the reuse of these Sm-doped FP glasses in monitoring dose in MRT.

  8. Optically erasable samarium-doped fluorophosphate glasses for high-dose measurements in microbeam radiation therapy

    SciTech Connect

    Morrell, B.; Okada, G.; Vahedi, S.; Koughia, C. Kasap, S. O.; Edgar, A.; Varoy, C.; Belev, G.; Wysokinski, T.; Chapman, D.; Sammynaiken, R.

    2014-02-14

    Previous work has demonstrated that fluorophosphate (FP) glasses doped with trivalent samarium (Sm{sup 3+}) can be used as a dosimetric detector in microbeam radiation therapy (MRT) to measure high radiation doses and large dose variations with a resolution in the micrometer range. The present work addresses the use of intense optical radiation at 405 nm to erase the recorded dose information in Sm{sup 3+}-doped FP glass plates and examines the underlying physics. We have evaluated both the conversion and optical erasure of Sm{sup 3+}-doped FP glasses using synchrotron-generated high-dose x-rays at the Canadian Light Source. The Sm-ion valency conversion is accompanied by the appearance of x-ray induced optical absorbance due to the trapping of holes and electrons into phosphorus-oxygen hole (POHC) and electron (POEC) capture centers. Nearly complete Sm{sup 2+} to Sm{sup 3+} reconversion (erasure) may be achieved by intense optical illumination. Combined analysis of absorbance and electron spin resonance measurements indicates that the optical illumination causes partial disappearance of the POHC and the appearance of new POEC. The suggested model for the observed phenomena is based on the release of electrons during the Sm{sup 2+} to Sm{sup 3+} reconversion process, the capture of these electrons by POHC (and hence their disappearance), or by PO groups, with the appearance of new and/or additional POEC. Optical erasure may be used as a practical means to erase the recorded data and permits the reuse of these Sm-doped FP glasses in monitoring dose in MRT.

  9. Comparison of two methods for measuring γ-H2AX nuclear fluorescence as a marker of DNA damage in cultured human cells: applications for microbeam radiation therapy

    NASA Astrophysics Data System (ADS)

    Anderson, D.; Andrais, B.; Mirzayans, R.; Siegbahn, E. A.; Fallone, B. G.; Warkentin, B.

    2013-06-01

    Microbeam radiation therapy (MRT) delivers single fractions of very high doses of synchrotron x-rays using arrays of microbeams. In animal experiments, MRT has achieved higher tumour control and less normal tissue toxicity compared to single-fraction broad beam irradiations of much lower dose. The mechanism behind the normal tissue sparing of MRT has yet to be fully explained. An accurate method for evaluating DNA damage, such as the γ-H2AX immunofluorescence assay, will be important for understanding the role of cellular communication in the radiobiological response of normal and cancerous cell types to MRT. We compare two methods of quantifying γ-H2AX nuclear fluorescence for uniformly irradiated cell cultures: manual counting of γ-H2AX foci by eye, and an automated, MATLAB-based fluorescence intensity measurement. We also demonstrate the automated analysis of cell cultures irradiated with an array of microbeams. In addition to offering a relatively high dynamic range of γ-H2AX signal versus irradiation dose ( > 10 Gy), our automated method provides speed, robustness, and objectivity when examining a series of images. Our in-house analysis facilitates the automated extraction of the spatial distribution of the γ-H2AX intensity with respect to the microbeam array — for example, the intensities in the peak (high dose area) and valley (area between two microbeams) regions. The automated analysis is particularly beneficial when processing a large number of samples, as is needed to systematically study the relationship between the numerous dosimetric and geometric parameters involved with MRT (e.g., microbeam width, microbeam spacing, microbeam array dimensions, peak dose, valley dose, and geometric arrangement of multiple arrays) and the resulting DNA damage.

  10. Benchmarking and validation of a Geant4-SHADOW Monte Carlo simulation for dose calculations in microbeam radiation therapy.

    PubMed

    Cornelius, Iwan; Guatelli, Susanna; Fournier, Pauline; Crosbie, Jeffrey C; Sanchez Del Rio, Manuel; Bräuer-Krisch, Elke; Rosenfeld, Anatoly; Lerch, Michael

    2014-05-01

    Microbeam radiation therapy (MRT) is a synchrotron-based radiotherapy modality that uses high-intensity beams of spatially fractionated radiation to treat tumours. The rapid evolution of MRT towards clinical trials demands accurate treatment planning systems (TPS), as well as independent tools for the verification of TPS calculated dose distributions in order to ensure patient safety and treatment efficacy. Monte Carlo computer simulation represents the most accurate method of dose calculation in patient geometries and is best suited for the purpose of TPS verification. A Monte Carlo model of the ID17 biomedical beamline at the European Synchrotron Radiation Facility has been developed, including recent modifications, using the Geant4 Monte Carlo toolkit interfaced with the SHADOW X-ray optics and ray-tracing libraries. The code was benchmarked by simulating dose profiles in water-equivalent phantoms subject to irradiation by broad-beam (without spatial fractionation) and microbeam (with spatial fractionation) fields, and comparing against those calculated with a previous model of the beamline developed using the PENELOPE code. Validation against additional experimental dose profiles in water-equivalent phantoms subject to broad-beam irradiation was also performed. Good agreement between codes was observed, with the exception of out-of-field doses and toward the field edge for larger field sizes. Microbeam results showed good agreement between both codes and experimental results within uncertainties. Results of the experimental validation showed agreement for different beamline configurations. The asymmetry in the out-of-field dose profiles due to polarization effects was also investigated, yielding important information for the treatment planning process in MRT. This work represents an important step in the development of a Monte Carlo-based independent verification tool for treatment planning in MRT. PMID:24763641

  11. Proton Therapy for Thoracoabdominal Tumors

    NASA Astrophysics Data System (ADS)

    Sakurai, Hideyuki; Okumura, Toshiyuki; Sugahara, Shinji; Nakayama, Hidetsugu; Tokuuye, Koichi

    In advanced-stage disease of certain thoracoabdominal tumors, proton therapy (PT) with concurrent chemotherapy may be an option to reduce side effects. Several technological developments, including a respiratory gating system and implantation of fiducial markers for image guided radiation therapy (IGRT), are necessary for the treatment in thoracoabdominal tumors. In this chapter, the role of PT for tumors of the lung, the esophagus, and liver are discussed.

  12. Monte Carlo simulation of microbeam radiation therapy with an interlaced irradiation geometry and an Au contrast agent in a realistic head phantom

    NASA Astrophysics Data System (ADS)

    Gokeri, Gurdal; Kocar, Cemil; Tombakoglu, Mehmet

    2010-12-01

    In this study, dose distribution calculations for bidirectional interlaced microbeam radiation therapy (BIMRT) were performed with a detailed head phantom model and the Monte Carlo code MCNPX. Doses were calculated in intracranial targets of dimensions 20 × 6.8 × 20 mm3 and 20 × 20 × 20 mm3 and surrounding tissue for which interlacing arrays are composed of 5 and 15 microbeams, respectively. Simulations were performed with a realistic head phantom and a homogenized head phantom of the same outer shape to study the effects of the structure of the realistic phantom on dose distribution and to show how important it is to use realistic phantoms. Depth-dose profiles and dose falloffs at the edges of the targets were calculated for cases with and without an Au contrast agent deposited in the target region and surrounding tissue. The parallel pattern of the microbeam arrays was preserved through the head phantom which makes it possible to interlace microbeam arrays even at deep seated targets. As the dimensions of the target volume were increased, the valley dose values increased with the number of microbeams. This sets limits on the size and position of the target. The usage of gold as a contrast agent provided a substantial increase in target dose and decreased the skin entrance, maximum skull bone and maximum brain doses inevitable to produce the desired target dose. Short dose falloffs at the edges of the targets were preserved for all cases.

  13. Laser therapy in intraocular tumors

    NASA Astrophysics Data System (ADS)

    Carstocea, Benone D.; Gafencu, Otilia L.; Apostol, Silvia

    1995-01-01

    Intraocular tumors present special problems of diagnosis and treatment. Diagnostic methods include, in addition to systemic and ophthalmological examinations, ancillary examinations such as transillumination, fluorescein angiography, ultrasonography, radioactive phosphorus uptake test, radiology, computerized tomography, and fine-needle aspiration biopsy with cytological analyses. Previously, enucleation of the involved eye was generally accepted as management of malignant tumors. Improved therapeutic methods such as photocoagulation and better surgical techniques now provide a variety of therapeutical alternatives. This study consists of 21 cases of intraocular tumors that were managed by Argon laser photocoagulation. Four cases were intraocular metastasis and 17 cases were primitive intraocular tumors. Argon laser therapy proved to be totally ineffective for the intraocular metastasis and a very adequate therapy for the primitive tumors. Tumor extirpations (choroidal, cillary body, or iris tumors) using laser lancet proved to be more suitable than classic surgery.

  14. Radionuclide therapy of adrenal tumors.

    PubMed

    Carrasquillo, Jorge A; Pandit-Taskar, Neeta; Chen, Clara C

    2012-10-01

    Adrenal tumors arising from chromaffin cells will often accumulate radiolabeled metaiodobenzylguanidine (MIBG) and thus are amenable to therapy with I-131 MIBG. More recently, therapy studies have targeted the somatostatin receptors using Lu-177 or Y-90 radiolabeled somatostatin analogs. Because pheochromocytoma (PHEO)/paraganglioma (PGL) and neuroblastoma (NB), which often arise from the adrenals, express these receptors, clinical trials have been performed with these reagents. We will review the experience using radionuclide therapy for targeting PHEO/PGL and NBs. PMID:22718415

  15. Laser therapy in ocular tumors

    NASA Astrophysics Data System (ADS)

    Carstocea, Benone D.; Gafencu, Otilia L.; Apostol, Silvia; Ionita, Marcel A.; Moroseanu, A.; Dascalu, Traian; Lupei, Voicu; Ionita-Manzatu, V.

    1998-07-01

    The medical laser equipments made at NILPRP have been exploited intensively for more than 10 years at CMH. The availability and reliability of the first like-on equipment have increased, following improvements in optical delivery system and cooling circuit. This paper shows the impact of technical advances on the development of ophthalmologic laser therapy. Intraocular tumors pose special problems of diagnosis and treatment. Diagnostic methods include addition to systemic and ophthalmologic examinations, ancillary examinations, such as transillumination, fluorescence angiography, ultrasonography, radioactive phosphorus uptake tests, radiology, computerized tomography and fine-needle aspiration biopsy with cytological analyses. The enucleation of the involved eye used to be a generally accepted management of malignant tumors. Improved therapeutic methods such as photocoagulation and better surgical techniques now provide a variety of therapeutic alternatives. This study covers 31 cases of intraocular tumors that were managed either by Argon Laser photocoagulation and/or by Nd:YAG laser surgical treatment. Four cases were intraocular metastasse and 17 cases were primitive intraocular tumors. Argon laser therapy proved to be totally ineffective for intraocular metastasse but very adequate therapy for primitive tumors. Tumor extirpations (choroidal, cillary body or iris tumors) using Nd:YAG laser lancet proved to be more suitable than classic surgery.

  16. Expanding Therapy for Neuroendocrine Tumors.

    PubMed

    2016-03-01

    Results from two phase III studies suggest that everolimus, an mTOR inhibitor, and (177)Lutetium-DOTATATE, a radiopharmaceutical, may be effective new options for patients with advanced neuroendocrine tumors of the gastrointestinal tract. Both therapies were well tolerated and significantly prolonged progression-free survival. PMID:26826165

  17. Ablative therapies for renal tumors

    PubMed Central

    Ramanathan, Rajan; Leveillee, Raymond J.

    2010-01-01

    Owing to an increased use of diagnostic imaging for evaluating patients with other abdominal conditions, incidentally discovered kidney masses now account for a majority of renal tumors. Renal ablative therapy is assuming a more important role in patients with borderline renal impairment. Renal ablation uses heat or cold to bring about cell death. Radiofrequency ablation and cryoablation are two such procedures, and 5-year results are now emerging from both modalities. Renal biopsy at the time of ablation is extremely important in order to establish tissue diagnosis. Real-time temperature monitoring at the time of radiofrequency ablation is very useful to ensure adequacy of ablation. PMID:21789083

  18. The preclinical set-up at the ID17 biomedical beamline to achieve high local dose deposition using interlaced microbeams

    NASA Astrophysics Data System (ADS)

    Bräuer-Krisch, E.; Nemoz, C.; Brochard, Th; Berruyer, G.; Renier, M.; Pouyatos, B.; Serduc, R.

    2013-03-01

    Microbeam Radiation Therapy (MRT) uses spatially a fractionated "white beam" (energies 50-350 keV) irradiation from a Synchrotron Source. The typical microbeams used at ID17 are 25-100μm-thick, spaced by 200-400μm, and carry extremely high dose rates (up to about 16 kGy/s). These microbeams are well tolerated by biological tissue, i.e. up to several hundred of Gy in the peaks. When valley doses, caused by Compton scattering in between two microbeams, remain within a dose regime similar to conventional RT, a superior tumour control can be achieved with MRT than with conventional RT. The normal tissue tolerance of these microscopically small beams is outstanding and well documented in the literature. The hypothesis of a differential effect in particular on the vasculature of normal versus tumoral tissue might best be proven by using large animal models with spontaneous tumors instead of small laboratory animals with transplantable tumors, an ongoing project on ID17. An alternative approach to deposit a high dose, while preserving the feature of the spatial separation of these microbeams outside the target has opened up new applications in preclinical research. The instrumentation of this method to produce such interlaced beams is presented with an outlook on the challenges to build a treatment platform for human patients. Dose measurements using Gafchromic films exposed in interlaced geometries with their steep profiles highlight the potential to deposit radiotoxic doses in the vicinity of radiosensitive tissues.

  19. Radiofrequency Ablation Therapy for Solid Tumors

    SciTech Connect

    Kam, Anthony

    2002-12-04

    Surgical resection, systemic chemotherapy, and local radiation have been the conventional treatments for localized solid cancer. Because certain patients are not candidates for tumor resection and because many tumors are poorly responsive to chemotherapy and radiation, there has been an impetus to develop alternative therapies. Radiofrequency ablation (RFA) is a minimally invasive therapy for localized solid cancers that has gained considerable attention in the last 12 years. Advantages of minimally invasive therapies over surgery include less recovery time, lower morbidity and mortality, eligibility of more patients, and lower cost. RFA has been applied most extensively to inoperable hepatic tumors. It is investigational for tumors in the kidney, lung, bone, breast, and adrenal gland. This colloquium will review the mechanism, techniques, limitations, and clinical applications of RFA. The ultimate role that RFA will play in cancer therapy will depend on the results of long-term follow-up and prospective randomized trials.

  20. Targeted Radionuclide Therapy of Human Tumors

    PubMed Central

    Gudkov, Sergey V.; Shilyagina, Natalya Yu.; Vodeneev, Vladimir A.; Zvyagin, Andrei V.

    2015-01-01

    Targeted radionuclide therapy is one of the most intensively developing directions of nuclear medicine. Unlike conventional external beam therapy, the targeted radionuclide therapy causes less collateral damage to normal tissues and allows targeted drug delivery to a clinically diagnosed neoplastic malformations, as well as metastasized cells and cellular clusters, thus providing systemic therapy of cancer. The methods of targeted radionuclide therapy are based on the use of molecular carriers of radionuclides with high affinity to antigens on the surface of tumor cells. The potential of targeted radionuclide therapy has markedly grown nowadays due to the expanded knowledge base in cancer biology, bioengineering, and radiochemistry. In this review, progress in the radionuclide therapy of hematological malignancies and approaches for treatment of solid tumors is addressed. PMID:26729091

  1. Physiologically gated microbeam radiation using a field emission x-ray source array

    SciTech Connect

    Chtcheprov, Pavel E-mail: zhou@email.unc.edu; Burk, Laurel; Inscoe, Christina; Ger, Rachel; Hadsell, Michael; Lu, Jianping; Yuan, Hong; Zhang, Lei; Chang, Sha; Zhou, Otto E-mail: zhou@email.unc.edu

    2014-08-15

    Purpose: Microbeam radiation therapy (MRT) uses narrow planes of high dose radiation beams to treat cancerous tumors. This experimental therapy method based on synchrotron radiation has been shown to spare normal tissue at up to 1000 Gy of peak entrance dose while still being effective in tumor eradication and extending the lifetime of tumor-bearing small animal models. Motion during treatment can lead to significant movement of microbeam positions resulting in broader beam width and lower peak to valley dose ratio (PVDR), which reduces the effectiveness of MRT. Recently, the authors have demonstrated the feasibility of generating microbeam radiation for small animal treatment using a carbon nanotube (CNT) x-ray source array. The purpose of this study is to incorporate physiological gating to the CNT microbeam irradiator to minimize motion-induced microbeam blurring. Methods: The CNT field emission x-ray source array with a narrow line focal track was operated at 160 kVp. The x-ray radiation was collimated to a single 280 μm wide microbeam at entrance. The microbeam beam pattern was recorded using EBT2 Gafchromic{sup ©} films. For the feasibility study, a strip of EBT2 film was attached to an oscillating mechanical phantom mimicking mouse chest respiratory motion. The servo arm was put against a pressure sensor to monitor the motion. The film was irradiated with three microbeams under gated and nongated conditions and the full width at half maximums and PVDRs were compared. An in vivo study was also performed with adult male athymic mice. The liver was chosen as the target organ for proof of concept due to its large motion during respiration compared to other organs. The mouse was immobilized in a specialized mouse bed and anesthetized using isoflurane. A pressure sensor was attached to a mouse's chest to monitor its respiration. The output signal triggered the electron extraction voltage of the field emission source such that x-ray was generated only during a

  2. Physiologically gated microbeam radiation using a field emission x-ray source array

    PubMed Central

    Chtcheprov, Pavel; Burk, Laurel; Yuan, Hong; Inscoe, Christina; Ger, Rachel; Hadsell, Michael; Lu, Jianping; Zhang, Lei; Chang, Sha; Zhou, Otto

    2014-01-01

    Purpose: Microbeam radiation therapy (MRT) uses narrow planes of high dose radiation beams to treat cancerous tumors. This experimental therapy method based on synchrotron radiation has been shown to spare normal tissue at up to 1000 Gy of peak entrance dose while still being effective in tumor eradication and extending the lifetime of tumor-bearing small animal models. Motion during treatment can lead to significant movement of microbeam positions resulting in broader beam width and lower peak to valley dose ratio (PVDR), which reduces the effectiveness of MRT. Recently, the authors have demonstrated the feasibility of generating microbeam radiation for small animal treatment using a carbon nanotube (CNT) x-ray source array. The purpose of this study is to incorporate physiological gating to the CNT microbeam irradiator to minimize motion-induced microbeam blurring. Methods: The CNT field emission x-ray source array with a narrow line focal track was operated at 160 kVp. The x-ray radiation was collimated to a single 280 μm wide microbeam at entrance. The microbeam beam pattern was recorded using EBT2 Gafchromic© films. For the feasibility study, a strip of EBT2 film was attached to an oscillating mechanical phantom mimicking mouse chest respiratory motion. The servo arm was put against a pressure sensor to monitor the motion. The film was irradiated with three microbeams under gated and nongated conditions and the full width at half maximums and PVDRs were compared. An in vivo study was also performed with adult male athymic mice. The liver was chosen as the target organ for proof of concept due to its large motion during respiration compared to other organs. The mouse was immobilized in a specialized mouse bed and anesthetized using isoflurane. A pressure sensor was attached to a mouse's chest to monitor its respiration. The output signal triggered the electron extraction voltage of the field emission source such that x-ray was generated only during a

  3. Evaluation of dose-volume metrics for microbeam radiation therapy dose distributions in head phantoms of various sizes using Monte Carlo simulations

    NASA Astrophysics Data System (ADS)

    Anderson, Danielle; Siegbahn, E. Albert; Fallone, B. Gino; Serduc, Raphael; Warkentin, Brad

    2012-05-01

    This work evaluates four dose-volume metrics applied to microbeam radiation therapy (MRT) using simulated dosimetric data as input. We seek to improve upon the most frequently used MRT metric, the peak-to-valley dose ratio (PVDR), by analyzing MRT dose distributions from a more volumetric perspective. Monte Carlo simulations were used to calculate dose distributions in three cubic head phantoms: a 2 cm mouse head, an 8 cm cat head and a 16 cm dog head. The dose distribution was calculated for a 4 × 4 mm2 microbeam array in each phantom, as well as a 16 × 16 mm2 array in the 8 cm cat head, and a 32 × 32 mm2 array in the 16 cm dog head. Microbeam widths of 25, 50 and 75 µm and center-to-center spacings of 100, 200 and 400 µm were considered. The metrics calculated for each simulation were the conventional PVDR, the peak-to-mean valley dose ratio (PMVDR), the mean dose and the percentage volume below a threshold dose. The PVDR ranged between 3 and 230 for the 2 cm mouse phantom, and between 2 and 186 for the 16 cm dog phantom depending on geometry. The corresponding ranges for the PMVDR were much smaller, being 2-49 (mouse) and 2-46 (dog), and showed a slightly weaker dependence on phantom size and array size. The ratio of the PMVDR to the PVDR varied from 0.21 to 0.79 for the different collimation configurations, indicating a difference between the geometric dependence on outcome that would be predicted by these two metrics. For unidirectional irradiation, the mean lesion dose was 102%, 79% and 42% of the mean skin dose for the 2 cm mouse, 8 cm cat and 16 cm dog head phantoms, respectively. However, the mean lesion dose recovered to 83% of the mean skin dose in the 16 cm dog phantom in intersecting cross-firing regions. The percentage volume below a 10% dose threshold was highly dependent on geometry, with ranges for the different collimation configurations of 2-87% and 33-96% for the 2 cm mouse and 16 cm dog heads, respectively. The results of this study

  4. Establishing the suitability of quantitative optical CT microscopy of PRESAGE® radiochromic dosimeters for the verification of synchrotron microbeam therapy

    NASA Astrophysics Data System (ADS)

    Doran, Simon J.; Rahman, A. T. Abdul; Bräuer-Krisch, Elke; Brochard, Thierry; Adamovics, John; Nisbet, Andrew; Bradley, David

    2013-09-01

    Previous research on optical computed tomography (CT) microscopy in the context of the synchrotron microbeam has shown the potential of the technique and demonstrated high quality images, but has left two questions unanswered: (i) are the images suitably quantitative for 3D dosimetry? and (ii) what is the impact on the spatial resolution of the system of the limited depth-of-field of the microscope optics? Cuvette and imaging studies are reported here that address these issues. Two sets of cuvettes containing the radiochromic plastic PRESAGE® were irradiated at the ID17 biomedical beamline of the European Synchrotron Radiation facility over the ranges 0-20 and 0-35 Gy and a third set of cuvettes was irradiated over the range 0-20 Gy using a standard medical linac. In parallel, three cylindrical PRESAGE® samples of diameter 9.7 mm were irradiated with test patterns that allowed the quantitative capabilities of the optical CT microscope to be verified, and independent measurements of the imaging modulation transfer function (MTF) to be made via two different methods. Both spectrophotometric analysis and imaging gave a linear dose response, with gradients ranging from 0.036-0.041 cm-1 Gy-1 in the three sets of cuvettes and 0.037 (optical CT units) Gy-1 for the imaging. High-quality, quantitative imaging results were obtained throughout the 3D volume, as illustrated by depth-dose profiles. These profiles are shown to be monoexponential, and the linear attention coefficient of PRESAGE® for the synchrotron-generated x-ray beam is measured to be (0.185 ± 0.02) cm-1 in excellent agreement with expectations. Low-level (<5%) residual image artefacts are discussed in detail. It was possible to resolve easily slit patterns of width 37 µm (which are smaller than many of the microbeams used on ID-17), but some uncertainty remains as to whether the low values of MTF for the higher spatial frequencies are scanner related or a result of genuine (but non-ideal) dose

  5. Mutant Sodium Channel for Tumor Therapy

    PubMed Central

    Tannous, Bakhos A; Christensen, Adam P; Pike, Lisa; Wurdinger, Thomas; Perry, Katherine F; Saydam, Okay; Jacobs, Andreas H; García-Añoveros, Jaime; Weissleder, Ralph; Sena-Esteves, Miguel; Corey, David P; Breakefield, Xandra O

    2009-01-01

    Viral vectors have been used to deliver a wide range of therapeutic genes to tumors. In this study, a novel tumor therapy was achieved by the delivery of a mammalian brain sodium channel, ASIC2a, carrying a mutation that renders it constitutively open. This channel was delivered to tumor cells using a herpes simplex virus-1/Epstein–Barr virus (HSV/EBV) hybrid amplicon vector in which gene expression was controlled by a tetracycline regulatory system (tet-on) with silencer elements. Upon infection and doxycycline induction of mutant channel expression in tumor cells, the open channel led to amiloride-sensitive sodium influx as assessed by patch clamp recording and sodium imaging in culture. Within hours, tumor cells swelled and died. In addition to cells expressing the mutant channel, adjacent, noninfected cells connected by gap junctions also died. Intratumoral injection of HSV/EBV amplicon vector encoding the mutant sodium channel and systemic administration of doxycycline led to regression of subcutaneous tumors in nude mice as assessed by in vivo bioluminescence imaging. The advantage of this direct mode of tumor therapy is that all types of tumor cells become susceptible and death is rapid with no time for the tumor cells to become resistant. PMID:19259066

  6. Microwave Therapy for Bone Tumors

    NASA Astrophysics Data System (ADS)

    Takakuda, Kazuo; Inaoka, Shuken; Saito, Hirokazu; Hassan, Moinuddin; Koyama, Yoshikazu; Kuroda, Hiroshi; Kanaya, Tomohiro; Kosaka, Toshifumi; Tanaka, Shigeo; Miyairi, Hiroo; Shinomiya, Kenichi

    In vivo microwave treatments for bone tumor are designed, which enable us to conserve the activity and functionality of the matrix of living tissues. This treatment is composed of two steps. In the first step, the tumor was coagulated by the application of microwaves emitted from the antenna inserted into the tumor tissue, and then removed. In the second step, the surrounding tissue suspected to be invaded with transformed cells was covered with hydro gels and heated similarly. The tissue itself was heated by the conduction from the gels. The tissue temperature should be kept at 60°C for 30 minutes. This treatment should kill the whole cells within the tissues, but the mechanical strength and the biochemical activity of the matrix should be left intact. The matrix preserves the mechanical functions and ensures the maximum regeneration ability of the tissue. In this study, various hydro gels were examined and the most promising one was selected. Animal experiments were carried out and successful heating verified the applicability of the treatment.

  7. Antiangiogenic therapy in brain tumors

    PubMed Central

    Lakka, Sajani S; Rao, Jasti S

    2008-01-01

    Angiogenesis, the recruitment of new blood vessels, is an essential component of tumor progression. Malignant brain tumors are highly vascularized and their growth is angiogenesis-dependent. As such, inhibition of the sprouting of new capillaries from pre-existing blood vessels is one of the most promising antiglioma therapeutic approaches. Numerous classes of molecules have been implicated in regulating angiogenesis and, thus, novel agents that target and counteract angiogenesis are now being developed. The therapeutic trials of a number of angiogenesis inhibitors as antiglioma drugs are currently under intense investigation. Preliminary studies of angiogenic blockade in glioblastoma have been promising and several clinical trials are now underway to develop optimum treatment strategies for antiangiogenic agents. This review will cover state-of-the-art antiangiogenic targets for brain tumor treatment and discuss future challenges. An increased understanding of the angiogenic process, the diversity of its inducers and mediators, appropriate drug schedules and the use of these agents with other modalities may lead to radically new treatment regimens to achieve maximal efficacy. PMID:18928341

  8. Noncirrhotic portal fibrosis after Wilms' tumor therapy

    SciTech Connect

    Barnard, J.A.; Marshall, G.S.; Neblett, W.W.; Gray, G.; Ghishan, F.K.

    1986-04-01

    A 9-yr-old girl developed massive hemorrhage from esophageal varices 2 yr after combined modality therapy for Wilms' tumor. Evaluation showed a patent extrahepatic portal venous system and an elevated splenic pulp pressure. In contrast to previous reports of hepatopathy after irradiation injury, histologic sections of the liver did not demonstrate occlusion of the central veins, but rather a diffuse obliteration of intrahepatic portal venous radicles. This pattern of noncirrhotic portal fibrosis has not been described following antitumor therapy.

  9. Tumor Stroma, Tumor Blood Vessels, and Antiangiogenesis Therapy.

    PubMed

    Dvorak, Harold F

    2015-01-01

    Solid tumors generally require a vascularized connective tissue stroma if they are to grow beyond minimal size. They generate that stroma in part by secreting vascular endothelial growth factor (VEGF), a potent vascular permeability and angiogenic factor. Increased vascular permeability leads to deposition of a provisional fibrin stroma, which supports tumor, connective tissue, and inflammatory cell migration and plays an active role in the formation of mature vascularized stroma. Vascular endothelial growth factor-induced tumor blood vessels are heterogeneous, of at least 6 distinct types, and develop linearly over time. They include both angiogenic (mother vessels, glomeruloid microvascular proliferations, vascular malformations, capillaries) and arteriovenogenic (feeding arteries, draining veins) blood vessels. Attacking the tumor vasculature with drugs that target VEGF or its receptors (VEGFR) has come into vogue but has been less effective than had been hope for. One reason for this is that anti-VEGF/VEGFR therapy attacks only a subset of tumor blood vessels, the earliest to form. New targets on late-forming blood vessels such as feeding arteries would be useful in helping antivascular cancer therapy fulfill its promise. PMID:26222073

  10. Therapy for metastatic pancreatic neuroendocrine tumors

    PubMed Central

    Massironi, Sara; Conte, Dario; Peracchi, Maddalena

    2014-01-01

    Background Pancreatic neuroendocrine tumors (pNETs) are frequently malignant (50-80%, except for insulinoma) and may show an aggressive course with metastases to the liver as well as more distant sites. These heterogeneous neoplasms include functioning tumors, which secrete a variety of peptide hormones, and non-functioning tumors (up to 90% of pNETs), which often show metastases at the time of diagnosis. Methods A PubMed search was performed for English-language publications from 1995 through December 2012. Reference lists from studies selected were manually searched to identify further relevant reports. Manuscripts comparing different therapeutic options and advances for metastatic pNETs were selected. Results The therapeutic options for metastatic pNETs are expanding and include surgery, which remains the only curative approach, liver-directed therapies, and medical therapy. In selected cases also liver transplantation (OLT) may be considered. The option of OLT for metastatic disease is unique to neuroendocrine tumors. Recently, novel promising targeted therapies have been proposed for progressive well-differentiated pNETs. Conclusions The best therapeutic approach for pNETs is still matter of debating. However, since pNETs often show a more indolent behavior compared to other malignancies, the preservation of the quality of life of the patient and the personalization of the therapy according to tumor’s and patient’s features are mandatory. PMID:25332984

  11. X-ray induced Sm3+ to Sm2+ conversion in fluorophosphate and fluoroaluminate glasses for the monitoring of high-doses in microbeam radiation therapy

    NASA Astrophysics Data System (ADS)

    Vahedi, Shahrzad; Okada, Go; Morrell, Brian; Muzar, Edward; Koughia, Cyril; Edgar, Andy; Varoy, Chris; Belev, George; Wysokinski, Tomasz; Chapman, Dean; Kasap, Safa

    2012-10-01

    Fluorophosphate and fluoroaluminate glasses doped with trivalent samarium were evaluated as sensors of x-ray radiation for microbeam radiation therapy at the Canadian Light Source using the conversion of trivalent Sm3+ to the divalent form Sm2+. Both types of glasses show similar conversion rates and may be used as a linear sensor up to ˜150 Gy and as a nonlinear sensor up to ˜2400 Gy, where saturation is reached. Experiments with a multi-slit collimator show high spatial resolution of the conversion pattern; the pattern was acquired by a confocal fluorescence microscopy technique. The effects of previous x-ray exposure may be erased by annealing at temperatures exceeding the glass transition temperature Tg while annealing at TA < Tg enhances the Sm conversion. This enhancement is explained by a thermally stimulated relaxation of host glass ionic matrix surrounding x-ray induced Sm2+ ions. In addition, some of the Sm3+-doped glasses were codoped with Eu2+-ions but the results show that there is no marked improvement in the conversion efficiency by the introduction of Eu2+.

  12. Hormonal component of tumor photodynamic therapy response

    NASA Astrophysics Data System (ADS)

    Korbelik, Mladen; Merchant, Soroush

    2008-02-01

    The involvement of adrenal glucocorticoid hormones in the response of the treatment of solid tumors by photodynamic therapy (PDT) comes from the induction of acute phase response by this modality. This adrenal gland activity is orchestrated through the engagement of the hypothalamic-pituitary-adrenal hormonal axis incited by stress signals emanating from the PDT-treated tumor. Glucocorticoid hormone activity engendered within the context of PDT-induced acute phase response performs multiple important functions; among other involvements they beget acute phase reactant production, systemic neutrophil mobilization, and control the production of inflammation-modulating and immunoregulatory proteins.

  13. Tumor therapy with heavy charged particles

    NASA Astrophysics Data System (ADS)

    Blattmann, Hans

    1999-11-01

    Nuclear science has contributed significantly to the development of tumor therapy with heavy charged particles. Interest evolved for neutron therapies in the forties because of the increased radiobiological effectiveness (RBE) compared to photon irradiation. The development of more powerful proton and heavy ion accelerators with higher energies or higher intensities, made new particles for radiation therapy available. Pions, protons, light ions, from helium up to silicon were studied in view of precision dose delivery and increased RBE. Without the parallel development of new diagnostic techniques such as computer tomography (CT) and positron emission tomography (PET) the rapid development would not have been possible. Heavy-charged particle therapy has now come into a consolidation phase. Hospital-based facilities are built by industry, and research institutes focus on refinements in dose delivery and treatment planning, as well as systems for monitoring dose delivery and for dose distribution verification.

  14. Combined Therapy of Gastrointestinal Stromal Tumors.

    PubMed

    Rutkowski, Piotr; Hompes, Daphne

    2016-10-01

    Radical surgery is the mainstay of therapy for primary resectable, localized gastrointestinal stromal tumors (GIST). Nevertheless, approximately 40% to 50% of patients with potentially curative resections develop recurrent or metastatic disease. The introduction of imatinib mesylate has revolutionized the therapy of advanced (inoperable and/or metastatic) GIST and has become the standard of care in treatment of patients with advanced GIST. This article discusses the proper selection of candidates for adjuvant and neoadjuvant treatment in locally advanced GIST, exploring the available evidence behind the combination of preoperative imatinib and surgery. PMID:27591496

  15. Scanned Carbon Pencil Beams for Tumor Therapy

    NASA Astrophysics Data System (ADS)

    Gemmel, A.; Saito, N.; Chaudhri, N.; Lü; chtenborg, R.; Schardt, D.; Rietzel, E.; Bert, Ch.

    2009-03-01

    At GSI a fully active beam application has been developed for tumor therapy with carbon ions. In this so-called rasterscan system the tumor volume is typically split into ˜60 slices of iso-energies taken from a list of 252 energies ranging from ˜90-430 MeV/u (range: 1.8-30.7 cm). The energies can be combined with variable beam diameters and intensities. For each iso-energy slice beam is requested from the synchrotron and delivered as a narrow pencil beam (beam's full width at half maximum 3-10 mm). For lateral target coverage this pencil beam is deflected to several hundreds of grid positions per iso-energy slice by orthogonal dipole magnets. At each grid position an optimized number of particles is deposited intensity-controlled, i.e. ionization chambers monitor the dose deposition and trigger deflection to the next grid position once the required dose level is achieved. This method allows intensity-modulated treatment fields necessary to deposit a uniform biological effective dose. Additionally, it allows for simultaneous optimization of multiple fields that allow better sparing of organs at risk partially or fully surrounded by the tumor. Scanned beam delivery facilitates target conformal and homogeneous dose delivery for stationary targets. For tumors located in the head & neck as well as tumors in the pelvic region very promising results were achieved in the carbon therapy pilot project started at GSI in 1993. A comparable project is conducted at Paul-Scherrer-Institut (PSI) in Switzerland with a scanned proton beam. One of the current research topics is the treatment of moving targets such as lung tumors. Scanned beam delivery requires but also offers possibilities to conformably irradiate moving target sites.

  16. [Photodynamic therapy of superficial bladder tumors].

    PubMed

    Misaki, T; Hisazumi, H; Hirata, A; Kunimi, K; Yamamoto, H; Amano, T; Kumaki, O; Koshida, K; Nishino, A; Nakazima, K

    1986-12-01

    Photodynamic therapy (PDT), using hematoporphyrin derivative (HPD) and the red light (wavelength 630 nm) of an argon-dye laser as the source of excitation energy was performed on 46 patients with superficial bladder tumors. Two methods of laser irradiation, (1) focal PDT using a 400 micron quartz fiber through a cystourethroscope in 22 patients with superficial bladder tumors and (2) whole bladder wall total PDT using a motor-driven laser light scattering device in 24 patients with multifocal carcinoma in situ and/or dysplasia of bladder mucosa associated with multicentric concurrent superficial tumors, were used. The patients in (2) had been referred for total cystectomy, and 19 of these 24 patients had a history of several transurethral resections, hyperthermia and/or instillation therapy. HPD 2-4 mg/kg was i.v. injected 48 to 72 hours before PDT. Judging from the results of 60 protrusions treated by focal PDT, the light power should be 200 mW/cm2 for 5-10 minutes or more and the total light energy should be 100 J/cm2 or more in tumors up to 2 cm in size. With focal PDT, 4 of the 22 patients had no recurrence with the mean tumor free time of 20.8 months. In 6 of the 24 patients treated with total PDT using 10, 20 or 30 J/cm2 of light energy, there was no recurrence with a mean tumor-free time of 7.5 months and there was no significant relationship between the recurrence rate and total light energy used. PMID:3825831

  17. Proton therapy for tumors of the base of the skull.

    PubMed

    Noel, Georges; Gondi, Vinai

    2016-08-01

    Relative to conventional photon irradiation, proton therapy has distinct advantages in its ability to more precisely target tumor while shielding adjacent normal tissues. In the setting of skull base tumors, proton therapy plays a critical role in the dose-escalation required for optimal tumor control of chordomas, chondrosarcomas, and malignancies of the paranasal sinuses and nasal cavity. For benign tumors such as craniopharyngiomas, pituitary adenomas and meningiomas, proton therapy can limit long-term adverse effects, such as secondary malignancies. This review summarizes published literature to date regarding the role of proton therapy in skull base tumors and introduces emerging proton therapy approaches such as pencil-beam scanning (PBS). PMID:27558252

  18. [Neuroendocrine tumors: Peptide receptors radionuclide therapy (PRRT)].

    PubMed

    Papamichail, Dimitris G; Exadaktylou, Paraskevi E; Chatzipavlidou, Vasiliki D

    2016-01-01

    Neuroendocrine tumors (neuroendocrine tumors-NET) are a heterogeneous group of neoplasms with a common embryological origin and diverse biological behavior, derived from cells of the neuroendocrine system, the system APUD (amine precursor uptake and decarboxylation). They are characterized by overexpression of all five somatostatin receptors (SSTR1-SSTR5), particularly type 2 (SST2). Surgical resection of the tumor is the treatment option, with a possibility of complete remission in patients with limited disease. Somatostatin analogs (octreotide and lanreotide) are the treatment of choice in patients with residual disease, particularly when it comes to NET non-pancreatic origin. Systemic chemotherapy is administered primarily to patients with poorly differentiated carcinomas. PRRT treatment is recommended in case of non-responsiveness of the disease. The ideal candidates for PRRT are patients with unresectable disease of high and intermediate differentiation. Somatostatine analogs radiolabelled with Indium-111 ((111)In), Yttrium-90 ((90)Y), Lutetium-177 ((177)Lu) and Bismuth-213 ((213)Bi), are selectively concentrated in the tumor cells, causing maximum tissue damage to tumors and with fewer effects on healthy tissue and the immune system. In the current review, it was demonstrated that patients with unresectable grade 1 or 2 disease showed increased PFS (progression free survival) and OS (overall survival), while quality of life was improved after PRRT treatment as compared to somatostatin analogs, chemotherapy and other targeted therapies. PMID:27035909

  19. Photodynamic therapy of advanced malignant tumors

    NASA Astrophysics Data System (ADS)

    Wang, Lian-xing; Dai, Lu-pin; Lu, Wen-qin

    1993-03-01

    Forty patients with advanced tumors were treated by photodynamic therapy (PDT) from May 1991 to August 1991 in our hospital with age ranges from 30 to 81 years old. The pathological diagnosis shows that 13 had tumors in the colon, 3 in the stomach, 2 in the oesophageal, 2 in the palatum, 1 in the cervix, and 19 others with malignant cancers of the skin. The histology was as follows: squamous cell in 20, adenocarcinoma in 19, melanocarcinoma in 1. By TNM classification there were no cases of T1, 5 cases of T2, and 35 cases of T2 - T3. All patients were stage IV. The overall effective rate was 85%, our experience is that the PDT is suitable for the patients with advanced tumor, especially those whose tumor recurrences are hard to treat after conventional treatment (surgery, radiotherapy, chemotherapy). The PDT appears to be a new and promising possibility to treat advanced tumors and to improve the patients' survival rates.

  20. Surgical Therapy of Glomus Vagale Tumors

    PubMed Central

    Browne, J. Dale; Fisch, Ugo; Valavanis, Anton

    1993-01-01

    Lying between the carotid bifurcation and the jugular foramen, glomus vagale tumors share characteristics with paragangliomas of those two structures, such as invasion of the carotid artery, destruction of the skull base, and cranial neuropathies. This capability for local invasion provides a therapeutic challenge with regard to the proper assessment of tumor extent and the selection of appropriate treatment. In order to clarify an approach to the management of glomus vagale tumors, we reviewed a 10-year experience with 15 patients treated for this tumor at the University of Zürich Department of Otolaryngology, using a new system of classification. This system highlights the relative position of a vagal paraganglioma to the jugular foramen and is helpful in designing the proper therapy. Pitfalis in surgical technique, recommended preoperative evaluation, and the roles of balloon occlusion and irradiation in the treatment of these tumors, are discussed. ImagesFigure 2Figure 3Figure 4Figure 4p188-bFigure 5 PMID:17170910

  1. Photodynamic Therapy for Malignant Brain Tumors.

    PubMed

    Akimoto, Jiro

    2016-04-15

    Photodynamic therapy (PDT) using talaporfin sodium together with a semiconductor laser was approved in Japan in October 2003 as a less invasive therapy for early-stage lung cancer. The author believes that the principle of PDT would be applicable for controlling the invading front of malignant brain tumors and verified its efficacy through experiments using glioma cell lines and glioma xenograft models. An investigator-initiated clinical study was jointly conducted with Tokyo Women's Medical University with the support of the Japan Medical Association. Patient enrollment was started in May 2009 and a total of 27 patients were enrolled by March 2012. Of 22 patients included in efficacy analysis, 13 patients with newly diagnosed glioblastoma showed progression-free survival of 12 months, progression-free survival at the site of laser irradiation of 20 months, 1-year survival of 100%, and overall survival of 24.8 months. In addition, the safety analysis of the 27 patients showed that adverse events directly related to PDT were mild. PDT was approved in Japan for health insurance coverage as a new intraoperative therapy with the indication for malignant brain tumors in September 2013. Currently, the post-marketing investigation in the accumulated patients has been conducted, and the preparation of guidelines, holding training courses, and dissemination of information on the safe implementation of PDT using web sites and videos, have been promoted. PDT is expected to be a breakthrough for the treatment of malignant glioma as a tumor cell-selective less invasive therapy for the infiltrated functional brain area. PMID:26888042

  2. Photodynamic Therapy for Malignant Brain Tumors

    PubMed Central

    AKIMOTO, Jiro

    2016-01-01

    Photodynamic therapy (PDT) using talaporfin sodium together with a semiconductor laser was approved in Japan in October 2003 as a less invasive therapy for early-stage lung cancer. The author believes that the principle of PDT would be applicable for controlling the invading front of malignant brain tumors and verified its efficacy through experiments using glioma cell lines and glioma xenograft models. An investigator-initiated clinical study was jointly conducted with Tokyo Women’s Medical University with the support of the Japan Medical Association. Patient enrollment was started in May 2009 and a total of 27 patients were enrolled by March 2012. Of 22 patients included in efficacy analysis, 13 patients with newly diagnosed glioblastoma showed progression-free survival of 12 months, progression-free survival at the site of laser irradiation of 20 months, 1-year survival of 100%, and overall survival of 24.8 months. In addition, the safety analysis of the 27 patients showed that adverse events directly related to PDT were mild. PDT was approved in Japan for health insurance coverage as a new intraoperative therapy with the indication for malignant brain tumors in September 2013. Currently, the post-marketing investigation in the accumulated patients has been conducted, and the preparation of guidelines, holding training courses, and dissemination of information on the safe implementation of PDT using web sites and videos, have been promoted. PDT is expected to be a breakthrough for the treatment of malignant glioma as a tumor cell-selective less invasive therapy for the infiltrated functional brain area. PMID:26888042

  3. [Klatskin tumors--diagnostic and interventional therapy].

    PubMed

    Ortner, M A

    2006-10-18

    Klatskin tumors are defined as malignant tumors of the bile duct involving the bifurcation and intrahepatic bile ducts. The most common presenting clinical feature, obstructive jaundice, usually occurs with advanced disease. Diagnostic tools currently available are therefore either performed too late or are not able to detect early disease stage. Imaging procedures for diagnosis and staging are ultrasonography, magnetic resonance imaging with cholangiopancreaticography, intravenous bolus-enhanced spiral computed tomography and endoscopic retrograde cholangiopancreaticography. Before initiating any palliative measure, a proper staging and a surgical consultation at a hepatobiliary center is necessary. To assess resectability, additional diagnostic methods like angiography, positron emission tomography, cholangioscopy, endoscopic or intraluminal ultrasonography and finally even explorative laparoscopy may be required. At time of diagnosis only a small percentage of Klatskin tumors is curative resectable. Therefore, palliative treatment options play an important role. Endoprostheses insertion is the method of choice to relieve jaundice. Although it improves quality of life, it does not seem to improve survival time. Definitive evidence for a benefit of additional radio and/or chemotherapy is still missing. Photodynamic therapy, a light therapy, is the first approach leading to an improvement of cholestasis and quality of life as well as to a prolongation of survival time. PDT should therefore be offered to all patients with nonresectable cholangiocarcinoma. PMID:17111849

  4. Therapy of leptomeningeal metastasis in solid tumors.

    PubMed

    Mack, F; Baumert, B G; Schäfer, N; Hattingen, E; Scheffler, B; Herrlinger, U; Glas, M

    2016-02-01

    Leptomeningeal metastasis (LM), i.e. the seeding of tumor cells to the cerebrospinal fluid (CSF) and the leptomeninges, is a devastating and mostly late-stage complication of various solid tumors. Clinical signs and symptoms may include cranial nerve palsies, radicular symptoms, signs of increased intracranial pressure such as headache, nausea and vomiting, and cognitive dysfunction. In cases of suspected LM, the highest diagnostic sensitivity is provided by the combination of CSF cytology and contrast-enhanced MRI (cranial as well as complete spine). The therapeutic spectrum includes radiotherapy of the clinically involved region as well as systemic and intrathecal chemotherapy. The choice of treatment modalities depends on the type of LM (non-adherent tumor cells in the CSF vs. nodular contrast-enhancing tumor growth), additional systemic involvement (uncontrolled vs. controlled systemic disease) and additional involvement of the CNS parenchyma (LM as the only CNS involvement vs. LM+parenchymal CNS metastases). Larger contrast-enhancing nodular LM or symptomatic lesions of the spine may be treated with radiotherapy. In case of uncontrolled systemic disease, the treatment regimen should include systemic chemotherapy. The choice of systemic treatment should take into account the histology of the primary tumor. Intrathecal chemotherapy is most important in cases of LM of the non-adherent type. There are three substances for routine use for intrathecal chemotherapy: methotrexate, cytarabine, and thiotepa. Liposomal cytarabine shows advantages in terms of longer injection intervals, a sufficient distribution in the entire subarachnoid space after lumbar administration and improved quality-of-life. The role of new agents (e.g. rituximab and trastuzumab) for intrathecal therapy is still unclear. PMID:26827696

  5. Tumor-associated macrophages: from mechanisms to therapy

    PubMed Central

    Noy, Roy; Pollard, Jeffrey W.

    2014-01-01

    The tumor microenvironment is a complex ecology of cells that evolves with and provides support to tumor cells during the transition to malignancy. Among the innate and adaptive immune cells recruited to the tumor site, macrophages are particularly abundant and are present at all stages of tumor progression. Clinical studies and experimental mouse models indicate these macrophages generally play a pro-tumoral role. In the primary tumor, macrophage can stimulate angiogenesis and enhance tumor cell invasion, motility and intravasation. During metastasis, macrophages prime the pre-metastatic site and promote tumor cell extravasation, survival and persistent growth. Macrophages are also immunosuppressive preventing tumor cell attack by natural killer and T cells during tumor progression and after recovery from chemo- or immuno-therapy. Therapeutic success in targeting these pro-tumoral roles in pre-clinical models and in early clinical trials suggests that macrophages are attractive targets as part of combination therapy in cancer treatment. PMID:25035953

  6. High resolution 3D imaging of synchrotron generated microbeams

    SciTech Connect

    Gagliardi, Frank M.; Cornelius, Iwan; Blencowe, Anton; Franich, Rick D.; Geso, Moshi

    2015-12-15

    Purpose: Microbeam radiation therapy (MRT) techniques are under investigation at synchrotrons worldwide. Favourable outcomes from animal and cell culture studies have proven the efficacy of MRT. The aim of MRT researchers currently is to progress to human clinical trials in the near future. The purpose of this study was to demonstrate the high resolution and 3D imaging of synchrotron generated microbeams in PRESAGE® dosimeters using laser fluorescence confocal microscopy. Methods: Water equivalent PRESAGE® dosimeters were fabricated and irradiated with microbeams on the Imaging and Medical Beamline at the Australian Synchrotron. Microbeam arrays comprised of microbeams 25–50 μm wide with 200 or 400 μm peak-to-peak spacing were delivered as single, cross-fire, multidirectional, and interspersed arrays. Imaging of the dosimeters was performed using a NIKON A1 laser fluorescence confocal microscope. Results: The spatial fractionation of the MRT beams was clearly visible in 2D and up to 9 mm in depth. Individual microbeams were easily resolved with the full width at half maximum of microbeams measured on images with resolutions of as low as 0.09 μm/pixel. Profiles obtained demonstrated the change of the peak-to-valley dose ratio for interspersed MRT microbeam arrays and subtle variations in the sample positioning by the sample stage goniometer were measured. Conclusions: Laser fluorescence confocal microscopy of MRT irradiated PRESAGE® dosimeters has been validated in this study as a high resolution imaging tool for the independent spatial and geometrical verification of MRT beam delivery.

  7. Solid Tumor Therapy Using a Cannon and Pawn Combination Strategy.

    PubMed

    Song, Wantong; Tang, Zhaohui; Zhang, Dawei; Wen, Xue; Lv, Shixian; Liu, Zhilin; Deng, Mingxiao; Chen, Xuesi

    2016-01-01

    Nanocarrier-based anti-tumor drugs hold great promise for reducing side effects and improving tumor-site drug retention in the treatment of solid tumors. However, therapeutic outcomes are still limited, primarily due to a lack of drug penetration within most tumor tissues. Herein, we propose a strategy using a nanocarrier-based combination of vascular disrupting agents (VDAs) and cytotoxic drugs for solid tumor therapy. Specifically, combretastatin A-4 (CA4) serves as a "cannon" by eradicating tumor cells at a distance from blood vessels; concomitantly, doxorubicin (DOX) serves as a "pawn" by killing tumor cells in close proximity to blood vessels. This "cannon and pawn" combination strategy acts without a need to penetrate every tumor cell and is expected to eliminate all tumor cells in a solid tumor. In a murine C26 colon tumor model, this strategy proved effective in eradicating greater than 94% of tumor cells and efficiently inhibited tumor growth with a weekly injection. In large solid tumor models (C26 and 4T1 tumors with volumes of approximately 250 mm(3)), this strategy also proved effective for inhibiting tumor growth. These results showing remarkable inhibition of tumor growth provide a valuable therapeutic choice for solid tumor therapy. PMID:27217835

  8. Solid Tumor Therapy Using a Cannon and Pawn Combination Strategy

    PubMed Central

    Song, Wantong; Tang, Zhaohui; Zhang, Dawei; Wen, Xue; Lv, Shixian; Liu, Zhilin; Deng, Mingxiao; Chen, Xuesi

    2016-01-01

    Nanocarrier-based anti-tumor drugs hold great promise for reducing side effects and improving tumor-site drug retention in the treatment of solid tumors. However, therapeutic outcomes are still limited, primarily due to a lack of drug penetration within most tumor tissues. Herein, we propose a strategy using a nanocarrier-based combination of vascular disrupting agents (VDAs) and cytotoxic drugs for solid tumor therapy. Specifically, combretastatin A-4 (CA4) serves as a “cannon” by eradicating tumor cells at a distance from blood vessels; concomitantly, doxorubicin (DOX) serves as a “pawn” by killing tumor cells in close proximity to blood vessels. This “cannon and pawn” combination strategy acts without a need to penetrate every tumor cell and is expected to eliminate all tumor cells in a solid tumor. In a murine C26 colon tumor model, this strategy proved effective in eradicating greater than 94% of tumor cells and efficiently inhibited tumor growth with a weekly injection. In large solid tumor models (C26 and 4T1 tumors with volumes of approximately 250 mm3), this strategy also proved effective for inhibiting tumor growth. These results showing remarkable inhibition of tumor growth provide a valuable therapeutic choice for solid tumor therapy. PMID:27217835

  9. Remodeling Components of the Tumor Microenvironment to Enhance Cancer Therapy

    PubMed Central

    Gkretsi, Vasiliki; Stylianou, Andreas; Papageorgis, Panagiotis; Polydorou, Christiana; Stylianopoulos, Triantafyllos

    2015-01-01

    Solid tumor pathophysiology is characterized by an abnormal microenvironment that guides tumor progression and poses barriers to the efficacy of cancer therapies. Most common among tumor types are abnormalities in the structure of the tumor vasculature and stroma. Remodeling the tumor microenvironment with the aim to normalize any aberrant properties has the potential to improve therapy. In this review, we discuss structural abnormalities of the tumor microenvironment and summarize the therapeutic strategies that have been developed to normalize tumors as well as their potential to enhance therapy. Finally, we present different in vitro models that have been developed to analyze and better understand the effects of the tumor microenvironment on cancer cell behavior. PMID:26528429

  10. Novel harmine derivatives for tumor targeted therapy

    PubMed Central

    Gu, Fan; Wang, Zhaohui; Tian, Caiping; Qian, Zhiyu; Tang, Liping; Gu, Yueqing

    2015-01-01

    Harmine is a beta-carboline alkaloid found in medicinal plant PeganumHarmala, which has served as a folk anticancer medicine. However, clinical applications of harmine were limited by its low pharmacological effects and noticeable neurotoxicity. In this study, we modified harmine to increase the therapeutic efficacy and to decrease the systemic toxicity. Specifically, two tumor targeting harmine derivatives 2DG-Har-01 and MET-Har-02 were synthesized by modifying substituent in position-2, -7 and -9 of harmine ring with two different targeting group2-amino-2-deoxy-D-glucose (2DG) and Methionine (Met), respectively. Their therapeutic efficacy and toxicity were investigated both in vitro and in vivo. Results suggested that the two newharmine derivatives displayed much higher therapeutic effects than non-modified harmine. In particular, MET-Har-02 was more potent than 2DG-Har-01 with promising potential for targeted cancer therapy. PMID:25940702

  11. Progress in photodynamic therapy on tumors

    NASA Astrophysics Data System (ADS)

    Tian, Y. Y.; Wang, L. L.; Wang, W.

    2008-10-01

    Photodynamic therapy (PDT) is a promising treatment on neoplastic pathologic tissues, which involves the administration of a photosensitizing agent followed by the exposure of the tissue to visible nonthermal light. Light energy is captured and transferred to other molecules resulting in the formation of short-lived energetic species, which interact with biological systems and then produce tissue damage. Photosensitizer can be taken up selectively by tumor cells because of the upregulation of low-density lipoprotein receptor-mediated endocytosis and the acidic tumor environments. In recent years, the application of PDT in the treatment of malignant lesions has increased dramatically. The first health agency approval for PDT was granted for Photofrin in Canada in 1993, and, now, it is licensed in many countries for the treatment of cancers. Although Photofrin is the most commonly used photosensitizer, it has significant side effects. Therefore, major effort has been invested in the development of new sensitizers and, to this end, many photosensitizers have been described and some are now in clinical trials.

  12. Ozone Therapy for Tumor Oxygenation: a Pilot Study

    PubMed Central

    2004-01-01

    Tumor hypoxia is an adverse factor for chemotherapy and radiotherapy. Ozone therapy is a non-conventional form of medicine that has been used successfully in the treatment of ischemic disorders. This prospective study was designed to assess the effect of ozone therapy on tumor oxygenation. Eighteen subjects were recruited for the study. Systemic ozone therapy was administered by autohemotransfusion on three alternate days over one week. Tumor oxygenation levels were measured using polarographic needle probes before and after the first and the third ozone therapy session. Overall, no statistically significant change was observed in the tumor oxygenation in the 18 patients. However, a significant decrease was observed in hypoxic values ≤10 and ≤5 mmHg of pO2. When individually assessed, a significant and inverse non-linear correlation was observed between increase in oxygenation and the initial tumor pO2 values at each measuring time-point, thus indicating that the more poorly-oxygenated tumors benefited most (rho = −0.725; P = 0.001). Additionally, the effect of ozone therapy was found to be lower in patients with higher hemoglobin concentrations (rho = −0.531; P < 0.034). Despite being administered over a very short period, ozone therapy improved oxygenation in the most hypoxic tumors. Ozone therapy as adjuvant in chemo-radiotherapy warrants further research. PMID:15257330

  13. Tumor microenvironment and cancer therapy resistance.

    PubMed

    Sun, Yu

    2016-09-28

    Innate resistance to various therapeutic interventions is a hallmark of cancer. In recent years, however, acquired resistance has emerged as a daunting challenge to anticancer treatments including chemotherapy, radiation and targeted therapy, which abolishes the efficacy of otherwise successful regimens. Cancer cells gain resistance through a variety of mechanisms in both primary and metastatic sites, involving cell intrinsic and extrinsic factors, but the latter often remains overlooked. Mounting evidence suggests critical roles played by the tumor microenvironment (TME) in multiple aspects of cancer progression particularly therapeutic resistance. The TME decreases drug penetration, confers proliferative and antiapoptotic advantages to surviving cells, facilitates resistance without causing genetic mutations and epigenetic changes, collectively modifying disease modality and distorting clinical indices. Recent studies have set the baseline for future investigation on the intricate relationship between cancer resistance and the TME in pathological backgrounds. This review provides an updated outline of research advances in TME biology and highlights the prospect of targeting the TME as an essential strategy to overcome cancer resistance and improve therapeutic outcomes through precise intervention. In the long run, continued inputs into translational medicine remain highly desired to achieve durable responses in the current era of personalized clinical oncology. PMID:26272180

  14. Impact of tumor microenvironment on oncolytic viral therapy

    PubMed Central

    Wojton, Jeffrey; Kaur, Balveen

    2010-01-01

    Interactions between tumor cells and their microenvironment have been shown to play a very significant role in the initiation, progression, and invasiveness of cancer. These tumor-stromal interactions are capable of altering the delivery and effectiveness of therapeutics into the tumor and are also known to influence future resistance and re-growth after treatment. Here we review recent advances in the understanding of the tumor microenvironment and its response to oncolytic viral therapy. The multifaceted environmental response to viral therapy can influence viral infection, replication, and propagation within the tumor. Recent studies have unveiled the complicated temporal changes in the tumor vasculature post OV treatment, and their impact on tumor biology. Similarly, the secreted extracellular matrix in solid tumors can affect both infection and spread of the therapeutic virus. Together, these complex changes in the tumor microenvironment also modulate the activation of the innate antiviral host immune response, leading to quick and efficient viral clearance. In order to combat these detrimental responses, viruses have been combined with pharmacological adjuvants and “armed” with therapeutic genes in order to suppress the pernicious environmental conditions following therapy. In this review we will discuss the impact of the tumor environment on viral therapy and examine some of the recent literature investigating methods of modulating this environment to enhance oncolysis. PMID:20399700

  15. 6th International Microbeam Workshop

    SciTech Connect

    Dr Kevin M. Prise

    2004-01-01

    The extended abstracts which are submitted here present a summary of the proceedings of the 6th International Workshop/12th LH Gray Workshop: Microbeam Probes of Cellular Radiation Response, held at St. Catherine's College, University of Oxford, UK on March, 29th-31st, 2003. In 1993 the 4th LH Gray Workshop entitled ''Microbeam Probes of Cellular Radiation Response'' was held at the Gray Cancer Institute in Northwood. This was organized by Prof BD Michael, Dr M. Folkard and Dr KM Prise and brought together 40 participants interested in developing and applying new microbeam technology to problems in radiation biology (1). The workshop was an undoubted success and has spawned a series of subsequent workshops every two years. In the past, these workshops have been highly successful in bringing together groups interested in developing and applying micro-irradiation techniques to the study of cell and tissue damage by ionizing radiations. Following the first microbeam workshop, there has been a rapid growth in the number of centres developing radiobiology microbeams, or planning to do so and there are currently 15-20 worldwide. Much of the recent research using microbeams has used them to study low-dose effects and ''non-targeted'' responses such bystander effects, genomic instability and adaptive responses. The goal of the 6th workshop was to build on our knowledge of the development of microbeam approaches and the application to radiation biology in the future with the meeting stretching over a 3 day period. Over 80 participants reviewed the current state of radiobiology microbeam research worldwide and reported on new technological developments both in the fields of physics and biology.

  16. Intra-Arterial Radionuclide Therapies for Liver Tumors.

    PubMed

    Bozkurt, Murat Fani; Salanci, Bilge Volkan; Uğur, Ömer

    2016-07-01

    Intra-arterial radionuclide therapies serve essentially as internal radiation treatment options for both primary and metastatic liver tumors, which imply delivering implantable radioactive microspheres into branches of hepatic arteries that feed liver tumors to provide a high dose of targeted radiation to tumor tissue, while sparing the healthy liver tissue from hazardous effects of radiation. The principle of this therapeutic option depends on the unique preferential arterial supply of malignant liver tumors in contrast with mostly portal venous supply of normal hepatocytes as well as excess amount of arterial neovascularization in the tumor bed. Therefore, intra-arterial radionuclide therapy can provide very high radiation exposure to tumor tissue, which is impossible to reach with external radiation therapy due to serious side effects and moreover, radiation can be targeted to tumor tissue selectively with less side effects. Yttrium-90 (Y-90), a high-energetic beta emitter is the most preferred radionuclide, which is used to label microspheres. Two types of Y-90 microspheres are commercially available that are made of resin and glass. Many studies in the literature have demonstrated that Y-90 microsphere therapy is an efficient and safe locoregional therapeutic option for unresectable primary and metastatic liver tumors such as hepatocellular carcinoma and liver metastases from colorectal cancer and breast cancer as well as neuroendocrine tumors. Furthermore, limited number of studies has reported its use in some relatively uncommon metastatic liver tumors from melanoma, pancreatic, renal, and lung cancer. Besides Y-90 microspheres, Iodine-131 lipiodol, Rhenium-188 lipiodol, Rhenium-188 microspheres, Holmium-166 chitosan, and Holmium-166 microspheres have been introduced as alternative radiopharmaceuticals for intra-arterial therapy for liver tumors. PMID:27237442

  17. Transcriptional targeting of tumor endothelial cells for gene therapy

    PubMed Central

    Dong, Zhihong; Nör, Jacques E.

    2009-01-01

    It is well known that angiogenesis plays a critical role in the pathobiology of tumors. Recent clinical trials have shown that inhibition of angiogenesis can be an effective therapeutic strategy for patients with cancer. However, one of the outstanding issues in anti-angiogenic treatment for cancer is the development of toxicities related to off-target effects of drugs. Transcriptional targeting of tumor endothelial cells involves the use of specific promoters for selective expression of therapeutic genes in the endothelial cells lining the blood vessels of tumors. Recently, several genes that are expressed specifically in tumor-associated endothelial cells have been identified and characterized. These discoveries have enhanced the prospectus of transcriptionaly targeting tumor endothelial cells for cancer gene therapy. In this manuscript, we review the promoters, vectors, and therapeutic genes that have been used for transcriptional targeting of tumor endothelial cells, and discuss the prospects of such approaches for cancer gene therapy. PMID:19393703

  18. Temperature uniformity in hyperthermal tumor therapy

    NASA Technical Reports Server (NTRS)

    Harrison, G. H.; Robinson, J. E.; Samaras, G. M.

    1978-01-01

    Mouse mammary tumors heated by water bath or by microwave-induced hyperthermia exhibit a response that varies sharply with treatment temperature; therefore, uniform heating of the tumor is essential to quantitate the biological response as a function of temperature. C3H tumors implanted on the mouse flank were easily heated to uniformities within 0.1 C by using water baths. Cold spots up to 1 C below the desired treatment temperature were observed in the same tumors implanted on the hind leg. These cold spots were attributed to cooling by major blood vessels near the tumor. In this case temperature uniformity was achieved by the deposition of 2450 MHz microwave energy into the tumor volume by using parallel-opposed applicators.

  19. Multiscale tumor spatiokinetic model for intraperitoneal therapy.

    PubMed

    Au, Jessie L-S; Guo, Peng; Gao, Yue; Lu, Ze; Wientjes, Michael G; Tsai, Max; Wientjes, M Guillaume

    2014-05-01

    This study established a multiscale computational model for intraperitoneal (IP) chemotherapy, to depict the time-dependent and spatial-dependent drug concentrations in peritoneal tumors as functions of drug properties (size, binding, diffusivity, permeability), transport mechanisms (diffusion, convection), spatial-dependent tumor heterogeneities (vessel density, cell density, pressure gradient), and physiological properties (peritoneal pressure, peritoneal fluid volume). Equations linked drug transport and clearance on three scales (tumor, IP cavity, whole organism). Paclitaxel was the test compound. The required model parameters (tumor diffusivity, tumor hydraulic conductivity, vessel permeability and surface area, microvascular hydrostatic pressure, drug association with cells) were obtained from literature reports, calculation, and/or experimental measurements. Drug concentration-time profiles in peritoneal fluid and plasma were the boundary conditions for tumor domain and blood vessels, respectively. The finite element method was used to numerically solve the nonlinear partial differential equations for fluid and solute transport. The resulting multiscale model accounted for intratumoral spatial heterogeneity, depicted diffusive and convective drug transport in tumor interstitium and across blood vessels, and provided drug flux and concentration as a function of time and spatial position in the tumor. Comparison of model-predicted tumor spatiokinetics with experimental results (autoradiographic data of 3H-paclitaxel in IP ovarian tumors in mice, 6 h posttreatment) showed good agreement (1% deviation for area under curve and 23% deviations for individual data points, which were several-fold lower compared to the experimental intertumor variations). The computational multiscale model provides a tool to quantify the effects of drug-, tumor-, and host-dependent variables on the concentrations and residence time of IP therapeutics in tumors. PMID:24570339

  20. Tumor-associated hyaluronan limits efficacy of monoclonal antibody therapy.

    PubMed

    Singha, Netai C; Nekoroski, Tara; Zhao, Chunmei; Symons, Rebecca; Jiang, Ping; Frost, Gregory I; Huang, Zhongdong; Shepard, H Michael

    2015-02-01

    Despite tremendous progress in cancer immunotherapy for solid tumors, clinical success of monoclonal antibody (mAb) therapy is often limited by poorly understood mechanisms associated with the tumor microenvironment (TME). Accumulation of hyaluronan (HA), a major component of the TME, occurs in many solid tumor types, and is associated with poor prognosis and treatment resistance in multiple malignancies. In this study, we describe that a physical barrier associated with high levels of HA (HA(high)) in the TME restricts antibody and immune cell access to tumors, suggesting a novel mechanism of in vivo resistance to mAb therapy. We determined that approximately 60% of HER2(3+) primary breast tumors and approximately 40% of EGFR(+) head and neck squamous cell carcinomas are HA(high), and hypothesized that HA(high) tumors may be refractory to mAb therapy. We found that the pericellular matrix produced by HA(high) tumor cells inhibited both natural killer (NK) immune cell access to tumor cells and antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. Depletion of HA by PEGPH20, a pegylated recombinant human PH20 hyaluronidase, resulted in increased NK cell access to HA(high) tumor cells, and greatly enhanced trastuzumab- or cetuximab-dependent ADCC in vitro. Furthermore, PEGPH20 treatment enhanced trastuzumab and NK cell access to HA(high) tumors, resulting in enhanced trastuzumab- and NK cell-mediated tumor growth inhibition in vivo. These results suggest that HA(high) matrix in vivo may form a barrier inhibiting access of both mAb and NK cells, and that PEGPH20 treatment in combination with anticancer mAbs may be an effective adjunctive therapy for HA(high) tumors. PMID:25512619

  1. Drug therapy in metastatic neuroendocrine tumors of the gastroenteropancreatic system.

    PubMed

    Faiss, S; Scherübl, H; Riecken, E O; Wiedenmann, B

    1996-01-01

    Successful treatment of neuroendocrine tumor disease of the gastroenteropancreatic system requires a multimodal approach. Radical tumor surgery is required before other therapies are initiated. So far, only surgery has proven to be curative. If surgical intervention is not possible or a tumor-free state cannot be achieved, biotherapy with the somatostatin analogues octreotide or lanreotide should then be preferably carried out in patients with functional tumors. Interferon-alpha can alternatively be given. In patients with gastrinoma, therapy with proton pump inhibitors (e.g., omeprazol) is the initial treatment of choice. In patients with nonfunctional tumors, indication for treatment is only given in cases of documented tumor progress. In case of progressive tumor disease or functionality under the above-mentioned therapies, treatment with somatostatin analogues can be intensified by dose escalation or alternatively by a combination therapy with interferon-alpha and a somatostatin analogue. On the basis of the less favorable response of neuroendocrine foregut tumors to biotherapy, chemotherapy should be initiated after failure of biotherapy in documented tumor progression. A combination of streptozotocin and 5-fluorouracil, possibly combined with D,L-folinic acid, is the treatment of choice, considering the response and side effect rates. In case of predominantly anaplastic neuroendocrine tumors in advanced stages, good tumor response rates with a chemotherapeutic scheme consisting of cisplatin and etoposide can be achieved. Since the chemotherapy scheme is less effective in patients with midgut or hindgut tumors, chemoembolization of liver metastases should follow biotherapy. The response to chemoembolization may be increased by simultaneous systemic chemotherapy. Attention should always be paid to an adequate analgesic drug administration. PMID:8893342

  2. Selected anti-tumor vaccines merit a place in multimodal tumor therapies

    PubMed Central

    Weiss, Eva-Maria; Wunderlich, Roland; Ebel, Nina; Rubner, Yvonne; Schlücker, Eberhard; Meyer-Pittroff, Roland; Ott, Oliver J.; Fietkau, Rainer; Gaipl, Udo S.; Frey, Benjamin

    2012-01-01

    Multimodal approaches are nowadays successfully applied in cancer therapy. Primary locally acting therapies such as radiotherapy (RT) and surgery are combined with systemic administration of chemotherapeutics. Nevertheless, the therapy of cancer is still a big challenge in medicine. The treatments often fail to induce long-lasting anti-tumor responses. Tumor recurrences and metastases result. Immunotherapies are therefore ideal adjuncts to standard tumor therapies since they aim to activate the patient's immune system against malignant cells even outside the primary treatment areas (abscopal effects). Especially cancer vaccines may have the potential both to train the immune system against cancer cells and to generate an immunological memory, resulting in long-lasting anti-tumor effects. However, despite promising results in phase I and II studies, most of the concepts finally failed. There are some critical aspects in development and application of cancer vaccines that may decide on their efficiency. The time point and frequency of medication, usage of an adequate immune adjuvant, the vaccine's immunogenic potential, and the tumor burden of the patient are crucial. Whole tumor cell vaccines have advantages compared to peptide-based ones since a variety of tumor antigens (TAs) are present. The master requirements of cell-based, therapeutic tumor vaccines are the complete inactivation of the tumor cells and the increase of their immunogenicity. Since the latter is highly connected with the cell death modality, the inactivation procedure of the tumor cell material may significantly influence the vaccine's efficiency. We therefore also introduce high hydrostatic pressure (HHP) as an innovative inactivation technology for tumor cell-based vaccines and outline that HHP efficiently inactivates tumor cells by enhancing their immunogenicity. Finally studies are presented proving that anti-tumor immune responses can be triggered by combining RT with selected immune

  3. Tumor cells as cellular vehicles to deliver gene therapies to metastatic tumors.

    PubMed

    García-Castro, Javier; Martínez-Palacio, Jesús; Lillo, Rosa; García-Sánchez, Félix; Alemany, Ramón; Madero, Luis; Bueren, Juan A; Ramírez, Manuel

    2005-04-01

    A long-pursued goal in cancer treatment is to deliver a therapy specifically to metastases. As a result of the disseminated nature of the metastatic disease, carrying the therapeutic agent to the sites of tumor growth represents a major step for success. We hypothesized that tumor cells injected intravenously (i.v.) into an animal with metastases would respond to many of the factors driving the metastatic process, and would target metastases. Using a model of spontaneous metastases, we report here that i.v. injected tumor cells localized on metastatic lesions. Based on this fact, we used genetically transduced tumor cells for tumor targeting of anticancer agents such as a suicide gene or an oncolytic virus, with evident antitumoral effect and negligible systemic toxicity. Therefore, autologous tumor cells may be used as cellular vehicles for systemic delivery of anticancer therapies to metastatic tumors. PMID:15650763

  4. Review of Tumor Dormancy Therapy Using Traditional Oriental Herbal Medicine

    PubMed Central

    Lee, Jong-Ho; Koung, Fan-Pei; Cho, Chong-Kwan; Lee, Yeon-Weol; Yoo, Hwa-Seung

    2013-01-01

    Objective: Standard cancer therapy prolongs survival, but can be detrimental to the quality of life, compromise the immune system, and leave residual disease that can cause recurrence years or decades in the future. Tumor dormancy therapy is a novel therapeutic approach that may improve these shortcomings, promote quality of life, and prolong survival. The aim of this study was to analyze studies on dormancy therapy, especially studies using traditional Oriental herbal medicine, so as to evaluate the efficacy of dormancy therapy with traditional oriental herbal medicine. Methods: We conducted a systematic literature review using Scientific and Technical Information Integration Services (NDSL), PubMed, and RISS. We searched for clinical reports, papers, and books related to tumor metastasis, recurrence, immunotherapy, tumor dormancy, and traditional oriental herbal medicine with anticancer effects. Seventy-nine (79) experimental and clinical articles in both Korean and English were reviewed. This study was conducted from March 1, 2012 to May 31, 2012. Results: This approach, Tumor dormancy therapy, rather than seeking to remove the tumor, includes combination of low-dose chemotherapy, immunotherapy, immunosurveillance, and other methods to stabilize tumor growth and to enhance the host is immunity against disseminated tumor cells and thus to manage cancer as a chronic disease while maintaining quality of life. In particular, integrative use of Oriental herbal medicine has been shown to induce or maintain tumor dormancy, increase the effectiveness of conventional chemotherapy, improve quality of life, and prolong survival. Conclusion: Tumor dormancy therapy is a promising novel therapeutic approach that may be especially effective with Oriental herbal medicine. Further research is needed to determine its potential mechanisms and therapeutic applications. PMID:25780657

  5. Galactose as Broad Ligand for Multiple Tumor Imaging and Therapy

    PubMed Central

    Ma, Yuxiang; Chen, Haiyan; Su, Shanyuhan; Wang, Tong; Zhang, Congying; Fida, Guissi; Cui, Sisi; Zhao, Juan; Gu, Yueqing

    2015-01-01

    Galactose residues could be specifically recognized by the asialoglycoprotein receptor (ASGPR) which is highly exhibited on liver tissues. However, ASGPR has not been widely investigated on different tumor cell lines except for hepatoma carcinoma cells, which motivates us to investigate the possibility of galactose serving as a board tumor ligand. In this study, a galactose (Gal)-based probe conjugated with fluorescence dye MPA (Gal-MPA) was constructed for the evaluation of tumor affinities/targeted ability on different tumor cell lines. In the vitro cell study, it was indicated that the fluorescence probe Gal-MPA displayed higher cell affinity to tumor cells (HepG2, MCF-7 and A549) than that of the normal liver cells l02. In the vivo dynamic study of Gal-MPA in tumor-bearing mice (HepG2, MCF-7, A549, HCT116, U87, MDA-MB-231 and S180), it was shown that its high tumor targeted ability with the maximal tumor/normal tissue ratio reached up to 6.8. Meanwhile, the fast tumor-targeted ability within 2 hours and long retention on tumor site up to 120 hours were observed. Our results demonstrated that galactose should be a promising broad ligand for multiple tumor imaging and targeted therapy. Subsequently, Gal was covalently conjugated to doxorubicin (DOX) to form prodrug Gal-DOX for tumor targeted therapy. The therapeutic results of Gal-DOX than DOX being better suggested that galactosylated prodrugs might have the prospective potential in tumor targeted therapy. PMID:26078797

  6. Tumor stroma as targets for cancer therapy

    PubMed Central

    Zhang, Jing; Liu, Jinsong

    2012-01-01

    Cancer is not only composed malignant epithelial component but also stromal components such as fibroblasts, endothelial cells, and inflammatory cells, by which an appropriate tumor microenvironment (TME) is formed to promote tumorigenesis, progression, and metastasis. As the most abundant component in the TME, cancer-associated fibroblasts (CAFs) are involved in multifaceted mechanistic details including remodeling the extracellular matrix, suppressing immune responses, and secreting growth factors and cytokines that mediate signaling pathways to extensively affect tumor cell growth and invasiveness, differentiation, angiogenesis, and chronic inflammatory milieu. Today, more and more therapeutic strategies are purposefully designed to target the TME as well as tumor cells. This review will focus on the role of CAFs in tumor development and the novel strategies to target this component to inhibit the tumor growth. PMID:23064233

  7. Tumor imaging and therapy using radiolabeled somatostatin analogues.

    PubMed

    de Jong, Marion; Breeman, Wout A P; Kwekkeboom, Dik J; Valkema, Roelf; Krenning, Eric P

    2009-07-21

    Molecular imaging plays an essential role in balancing the clinical benefits and risks of radionuclide-based cancer therapy. To effectively treat individual patients, careful assessment of biodistribution, dosimetry, and toxicity is essential. In this Account, we describe advances that combine features of molecular imaging and radionuclide therapy to provide new avenues toward individualized cancer treatment. Selective receptor-targeting radiopeptides have emerged as an important class of radiopharmaceuticals for molecular imaging and therapy of tumors that overexpress peptide receptors on the cell membrane. After such peptides labeled with gamma-emitting radionuclides bind to their receptors, they allow clinicians to visualize receptor-expressing tumors non-invasively. Peptides labeled with beta-particle emitters could also eradicate receptor-expressing tumors. The somatostatin receptors, which are overexpressed in a majority of neuroendocrine tumors, represent the first and best example of targets for radiopeptide-based imaging and radionuclide therapy. The somatostatin analogue (111)In-octreotide permits the localization and staging of neuroendocrine tumors that express the appropriate somatostatin receptors. Newer modified somatostatin analogues, including Tyr(3)-octreotide and Tyr(3)-octreotate, are successfully being used for tumor imaging and radionuclide therapy. Because there are few effective therapies for patients with inoperable or metastasized neuroendocrine tumors, this therapy is a promising novel treatment option for these patients. Peptide receptor imaging and radionuclide therapy can be combined in a single probe, called a "theranostic". To select patients who are likely to benefit from this type of intervention, we first use a peptide analogue labeled with a diagnostic radionuclide to obtain a scan. Selected patients will be treated using the same or a similar peptide analogue labeled with a therapeutic radionuclide. The development of such

  8. Assessment of tumor response on MR imaging after locoregional therapy.

    PubMed

    Vossen, Josephina A; Buijs, Manon; Kamel, Ihab R

    2006-09-01

    Assessment of tumor response after locoregional therapies is important in determining treatment success and in guiding future therapy. Magnetic resonance imaging plays an important role in evaluating treatment response to new therapies directed toward hepatic lesion treatment. The traditional and accepted criteria to determine tumor response in oncology, namely the Response Evaluation Criteria in Solid Tumors (RECIST) and the European Association for the Study of the Liver (EASL) criteria, use decrease in tumor size and lesion enhancement as an indicator of successful therapy. A more recent evaluation method is the Apparent Diffusion Coefficient (ADC) measured by diffusion-weighted MR imaging. Diffusion-weighted MR imaging and ADC values map the thermally induced motion of water molecules in tissues and thereby are able to provide insight into tumor microstructure. In this article we discuss the role of MR imaging in assessing treatment response after various locoregional therapies. We describe the role of tumor size and lesion enhancement as well as ADC mapping. We also discuss the magnetic resonance imaging findings after radiofrequency ablation (RFA), transarterial chemoembolization (TACE) and radioembolization. PMID:17561215

  9. [Endoscopic Ultrasound-guided Local Therapy of Pancreatic Tumors].

    PubMed

    Yoon, Won Jae; Seo, Dong Wan

    2015-09-01

    The development of curvilinear EUS has enabled EUS-guided fine-needle aspiration of intra-abdominal mass lesions. With the introduction of interventional EUS, this technology has undergone several modifications in order to be applied to clinical medicine. One of the potential uses of interventional EUS is the EUS-guided local therapy of pancreatic tumors. Various treatment modalities such as fine-needle injection, radiofrequency ablation, photodynamic therapy, laser ablation, and brachytherapy have been tried under EUS guidance. Some of these modalities are being applied clinically. These methods for EUS-guided local therapy of pancreatic tumors will be reviewed in this article. PMID:26387698

  10. Verification of micro-beam irradiation

    NASA Astrophysics Data System (ADS)

    Li, Qiongge; Juang, Titania; Beth, Rachel; Chang, Sha; Oldham, Mark

    2015-01-01

    Micro-beam Radiation Therapy (MRT) is an experimental radiation therapy with provocative experimental data indicating potential for improved efficacy in some diseases. Here we demonstrated a comprehensive micro-beam verification method utilizing high resolution (50pm) PRESAGE/Micro-Optical-CT 3D Dosimetry. A small PRESAGE cylindrical dosimeter was irradiated by a novel compact Carbon-Nano-Tube (CNT) field emission based MRT system. The Percentage Depth Dose (PDD), Peak-to-Valley Dose Ratio (PVDR) and beam width (FWHM) data were obtained and analyzed from a three strips radiation experiment. A fast dose drop-off with depth, a preserved beam width with depth (an averaged FWHM across three beams remains constant (405.3um, sigma=13.2um) between depth of 3.0~14.0mm), and a high PVDR value (increases with depth from 6.3 at 3.0mm depth to 8.6 at 14.0mm depth) were discovered during this verification process. Some operating procedures such as precise dosimeter mounting, robust mechanical motions (especially rotation) and stray-light artifact management were optimized and developed to achieve a more accurate and dosimetric verification method.

  11. Immune microenvironments in solid tumors: new targets for therapy

    PubMed Central

    Shiao, Stephen L.; Ganesan, A. Preethi; Rugo, Hope S.; Coussens, Lisa M.

    2011-01-01

    Leukocytes and their soluble mediators play important regulatory roles in all aspects of solid tumor development. While immunotherapeutic strategies have conceptually held clinical promise, with the exception of a small percentage of patients, they have failed to demonstrate effective, consistent, and durable anti-cancer responses. Several subtypes of leukocytes that commonly infiltrate solid tumors harbor immunosuppressive activity and undoubtedly restrict the effectiveness of these strategies. Several of these same immune cells also foster tumor development by expression of potent protumor mediators. Given recent evidence revealing that immune-based mechanisms regulate the response to conventional cytotoxic therapy, it seems reasonable to speculate that tumor progression could be effectively diminished by combining cytotoxic strategies with therapies that blunt protumor immune-based effectors and/or neutralize those that instead impede development of desired anti-tumor immunity, thus providing synergistic effects between traditional cytotoxic and immune-modulatory approaches. PMID:22190457

  12. Hypoxic tumor microenvironment: Opportunities to develop targeted therapies.

    PubMed

    Patel, Akhil; Sant, Shilpa

    2016-01-01

    In recent years, there has been great progress in the understanding of tumor biology and its surrounding microenvironment. Solid tumors create regions with low oxygen levels, generally termed as hypoxic regions. These hypoxic areas offer a tremendous opportunity to develop targeted therapies. Hypoxia is not a random by-product of the cellular milieu due to uncontrolled tumor growth; rather it is a constantly evolving participant in overall tumor growth and fate. This article reviews current trends and recent advances in drug therapies and delivery systems targeting hypoxia in the tumor microenvironment. In the first part, we give an account of important physicochemical changes and signaling pathways activated in the hypoxic microenvironment. This is then followed by various treatment strategies including hypoxia-sensitive signaling pathways and approaches to develop hypoxia-targeted drug delivery systems. PMID:27143654

  13. TUMOR PENETRATING MICROPARTICLES FOR INTRAPERITONEAL THERAPY OF OVARIAN CANCER

    PubMed Central

    Lu, Ze; Tsai, Max; Lu, Dan; Wang, Jie; Wientjes, M. Guillaume; Au, Jessie L.-S.

    2009-01-01

    Intraperitoneal (IP) chemotherapy prolongs survival of ovarian cancer patients, but its utility is limited by treatment-related complications and inadequate drug penetration in larger tumors. Previous IP therapy used the paclitaxel/Cremophor formulation designed for intravenous use. The present report describes the development of paclitaxel-loaded microparticles designed for IP treatment (referred to as tumor penetrating microparticles or TPM). Evaluation of TPM was performed using IP metastatic, human ovarian SKOV3 xenograft tumor models in mice. TPM were retained in the peritoneal cavity and adhered to tumor surface. TPM consisted of two biocompatible and biodegradable polymeric components with different drug release rates; one component released the drug load rapidly to induce tumor priming while the second component provided sustained drug release. Tumor priming, by expanding interstitial space, promoted transport and penetration of particulates in tumors. These combined features resulted in the following advantages over paclitaxel/Cremophor: greater tumor targeting (16-times higher and more sustained concentration in omental tumors), lower toxicity to intestinal crypts and less body weight loss, greater therapeutic efficacy (longer survival and higher cure rate), and greater convenience (less frequent dosing). TPM may overcome the toxicities and compliance-related problems that have limited the utility of IP therapy. PMID:18780831

  14. Effect of photodynamic therapy with verteporfin on tumor blood flow

    NASA Astrophysics Data System (ADS)

    Chen, Bin; Pogue, Brian W.; Goodwin, Isak A.; O'Hara, Julia A.; Wilmot, Carmen M.; Hutchins, John E.; Hoopes, P. J.; Hasan, Tayyaba

    2003-06-01

    The success of photodynamic therapy with verteporfin is partially determined by the pharmacokinetic distribution of the sensitizer at the time of treatment. In this study tumor blood flow changes in the RIF-1 murine tumor model and tumor resopnse using the regrowth assay were measured, comparing two different intervals between drug and light administration. Blood flow measurements were taken with a laser Doppler system monitoring continuously over 1 hour and periodically up to 6 hours after treatment. Treatment after the longer interval caused significantly less flow decrease, to only 50% of the initial flow in 6 h. Hoechst staining of functional tumor vasculature confirmed the primary vascular damage and the decrease in tumor perfusion. The regrowth rate of tumors after the longer time interval, the regrowth rate was not signifincalty different from that of the control, indicating that only the 15-min interval group caused serious damage to the vascular bed of the tumor. These studies support the hypothesis that temporal pharmacokinetic changes in the photosensitizer distribution between the tumor parenchyma and blood vessels can significantly alter the mechanism of tumor targeting during therapy.

  15. Solid Tumor Differentiation Therapy – Is It Possible?

    PubMed Central

    Dela Cruz, Filemon; Matushansky, Igor

    2012-01-01

    Genetic and epigenetic events within a cell which promote a block in normal development or differentiation coupled with unregulated proliferation are hallmarks of neoplastic transformation. Differentiation therapy involves the use of agents with the ability to induce differentiation in cells that have lost this ability, i.e. cancer cells. The promise of differentiation-based therapy as a viable treatment modality is perhaps best characterized by the addition of retinoids in the treatment of acute promyelocytic leukemia (APML) revolutionizing the management of APML and dramatically improving survival. However, interest and application of differentiation-based therapy for the treatment of solid malignancies have lagged due to deficiencies in our understanding of differentiation pathways in solid malignancies. Over the past decade, a differentiation-based developmental model for solid tumors has emerged providing insights into the biology of various solid tumors as well as identification of targetable pathways capable of re-activating blocked terminal differentiation programs. Furthermore, a variety of agents including retinoids, histone deacetylase inhibitors (HDACI), PPARγ agonists, and others, currently in use for a variety of malignancies, have been shown to induce differentiation in solid tumors. Herein we discuss the relevancy of differentiation-based therapies in solid tumors, using soft tissue sarcomas (STS) as a biologic and clinical model, and review the preclinical data to support its role as a promising modality of therapy for the treatment of solid tumors. PMID:22643847

  16. Renal and adrenal tumors: Pathology, radiology, ultrasonography, therapy, immunology

    SciTech Connect

    Lohr, E.; Leder, L.D.

    1987-01-01

    Aspects as diverse as radiology, pathology, urology, pediatrics and immunology have been brought together in one book. The most up-do-date methods of tumor diagnosis by CT, NMR, and ultrasound are covered, as are methods of catheter embolization and radiation techniques in case of primarily inoperable tumors. Contents: Pathology of Renal and Adrenal Neoplasms; Ultrasound Diagnosis of Renal and Pararenal Tumors; Computed-Body-Tomography of Renal Carcinoma and Perirenal Masses; Magnetic Resonance Imaging of Renal Mass Lesions; I-125 Embolotherapy of Renal Tumors; Adrenal Mass Lesions in Infants and Children; Computed Tomography of the Adrenal Glands; Scintigraphic Studies of Renal and Adrenal Function; Surgical Management of Renal Cell Carcinoma; Operative Therapy of Nephroblastoma; Nonoperative Treatment of Renal Cell Carcinoma; Prenatal Wilms' Tumor; Congenital Neuroblastoma; Nonsurgical Management of Wilms' Tumor; Immunologic Aspects of Malignant Renal Disease.

  17. Klatskin tumor--results of surgical therapy.

    PubMed

    Zovak, Mario; Doko, Marko; Glavan, Elizabet; Hochstädter, Hrvoje; Roić, Goran; Ljubicić, Neven

    2004-06-01

    Between January 1st 1990 and December 31st 1999, 24 patients affected by Klatskin tumor underwent operation in our department of surgery. According to Bismuth's classification, there were 0 (0%) type I, 5 (21%) type II, 6 (25%) type IIIa, 4 (17%) type IIIb and 9 (37%) type IV tumors. Five patients (21%) were treated by curative resection (group I) while in 14 patients (58%) palliative surgical procedure was performed (group II). In 5 cases (21%) the extension of malignancy did not allowed any procedure (group III). Curative resection for malignant tumors of the hepatic duct bifurcation included wide tumor excision and bile duct resection at the liver hilum (with wedge hepatic resection in one patient) and creation of biliary-enteric anastomosis. Palliative surgical procedure included stent insertion. Jaundice was completely relieved in all patients undergoing resection, since 3 patients (21%) after stenting hadn't satisfactory biliary drainage. There was 1 (20%) perioperative death in the group 1, while in group 2, 5 patients (36%) died postoperatively. In this series, the mean postoperative survival of all patients was 16 months. The mean postoperative survival of patients undergoing localized tumor resection with curative intent was 38 months, in contrast to 10 months for those undergoing operative stent insertion. in addition, only 1 patient from group III, in whom only exploratory surgery were performed survived 7 months, while other 4 patients died in the hospital. This retrospective review suggests that aggressive surgical treatment could improve survival and quality of life in patients suffering from Klatskin tumor. PMID:15636089

  18. Advancements in Tumor Targeting Strategies for Boron Neutron Capture Therapy.

    PubMed

    Luderer, Micah John; de la Puente, Pilar; Azab, Abdel Kareem

    2015-09-01

    Boron neutron capture therapy (BNCT) is a promising cancer therapy modality that utilizes the nuclear capture reaction of epithermal neutrons by boron-10 resulting in a localized nuclear fission reaction and subsequent cell death. Since cellular destruction is limited to approximately the diameter of a single cell, primarily only cells in the neutron field with significant boron accumulation will be damaged. However, the emergence of BNCT as a prominent therapy has in large part been hindered by a paucity of tumor selective boron containing agents. While L-boronophenylalanine and sodium borocaptate are the most commonly investigated clinical agents, new agents are desperately needed due to their suboptimal tumor selectivity. This review will highlight the various strategies to improve tumor boron delivery including: nucleoside and carbohydrate analogs, unnatural amino acids, porphyrins, antibody-dendrimer conjugates, cationic polymers, cell-membrane penetrating peptides, liposomes and nanoparticles. PMID:26033767

  19. Tumor cell response to bevacizumab single agent therapy in vitro

    PubMed Central

    2013-01-01

    Background Angiogenesis represents a highly multi-factorial and multi-cellular complex (patho-) physiologic event involving endothelial cells, tumor cells in malignant conditions, as well as bone marrow derived cells and stromal cells. One main driver is vascular endothelial growth factor (VEGFA), which is known to interact with endothelial cells as a survival and mitogenic signal. The role of VEGFA on tumor cells and /or tumor stromal cell interaction is less clear. Condition specific (e.g. hypoxia) or tumor specific expression of VEGFA, VEGF receptors and co-receptors on tumor cells has been reported, in addition to the expression on the endothelium. This suggests a potential paracrine/autocrine loop that could affect changes specific to tumor cells. Methods We used the monoclonal antibody against VEGFA, bevacizumab, in various in vitro experiments using cell lines derived from different tumor entities (non small cell lung cancer (NSCLC), colorectal cancer (CRC), breast cancer (BC) and renal cell carcinoma (RCC)) in order to determine if potential VEGFA signaling could be blocked in tumor cells. The experiments were done under hypoxia, a major inducer of VEGFA and angiogenesis, in an attempt to mimic the physiological tumor condition. Known VEGFA induced endothelial biological responses such as proliferation, migration, survival and gene expression changes were evaluated. Results Our study was able to demonstrate expression of VEGF receptors on tumor cells as well as hypoxia regulated angiogenic gene expression. In addition, there was a cell line specific effect in tumor cells by VEGFA blockade with bevacizumab in terms of proliferation; however overall, there was a limited measurable consequence of bevacizumab therapy detected by migration and survival. Conclusion The present study showed in a variety of in vitro experiments with several tumor cell lines from different tumor origins, that by blocking VEGFA with bevacizumab, there was a limited autocrine or cell

  20. [Hormonal therapy of advanced or relapsed ovarian granulosa cell tumor].

    PubMed

    Sun, H; Bai, P

    2016-07-01

    Ovarian granulosa cell tumor is a rare gynecologic malignancy with hormonal activity. Surgical excision is the standard treatment for this disease. Most patients present excellent short term prognosis, however, late relapse often occurs, even after many years. Viable treatments of advanced or relapsed granulosa cell tumor are still limited, and the optimal therapy method has not been established. Compared with chemotherapy and radiotherapy, hormonal therapy is a well-tolerated treatment which can be administrated over a long period of time without serious side effects, and the combined application of hormones may achieve a better outcome. Therefore, hormonal therapy has been suggested as a potential treatment option for patients with advanced or relapsed granulosa cell tumor, and to extend the tumor-free interval and attenuate the disease progression. Future researches should be focused on the identification of the hormonal therapy which may provide the greatest clinical benefit, comparing and analyzing the effects of different combined therapeutic regimens of hormone drugs, and on the synthesis of drugs highly activating estrogen receptor β expressed in the granulosa cell tumor cells. PMID:27531259

  1. Transarterial therapies for primary liver tumors.

    PubMed

    Talenfeld, Adam D; Sista, Akhilesh K; Madoff, David C

    2014-04-01

    Over the last decade, transarterial therapies have gained worldwide acceptance as standard of care for inoperable primary liver cancer. Survival times after transarterial chemoembolization (TACE) continue to improve as the technique and selection criteria are refined. Transarterial treatments, frequently provided in an outpatient setting, are now safely and effectively being applied to patients with even advanced malignancy or partially decompensated cirrhosis. In the coming years, newer transarterial therapies such as radiation segmentectomy, boosted-transarterial radioembolzation, combined TACE-ablation, TACE-portal vein embolization, and transarterial infusion of cancer-specific metabolic inhibitors promise to continue improving survival and quality of life. PMID:24560113

  2. Hepatic-directed Therapies in Patients with Neuroendocrine Tumors.

    PubMed

    Kennedy, Andrew S

    2016-02-01

    Neuroendocrine tumors (NETs) of the gastrointestinal (GI) tract have a propensity for producing hepatic metastases. Most GI NETs arise from the foregut or midgut, are malignant, and can cause severe debilitating symptoms adversely affecting quality of life. Aggressive treatments to reduce symptoms have an important role in therapy. Patients with GI NETs usually present with inoperable metastatic disease and severe symptoms from a variety of hormones and biogenic amines. This article describes intra-arterial hepatic-directed therapies for metastases from NETs, a group of treatments in which the therapeutic and/or embolic agents are released intra-arterially in specific hepatic vessels to target tumors. PMID:26614377

  3. The interaction of anticancer therapies with tumor-associated macrophages

    PubMed Central

    2015-01-01

    Macrophages are essential components of the inflammatory microenvironment of tumors. Conventional treatment modalities (chemotherapy and radiotherapy), targeted drugs, antiangiogenic agents, and immunotherapy, including checkpoint blockade, all profoundly influence or depend on the function of tumor-associated macrophages (TAMs). Chemotherapy and radiotherapy can have dual influences on TAMs in that a misdirected macrophage-orchestrated tissue repair response can result in chemoresistance, but in other circumstances, TAMs are essential for effective therapy. A better understanding of the interaction of anticancer therapies with innate immunity, and TAMs in particular, may pave the way to better patient selection and innovative combinations of conventional approaches with immunotherapy. PMID:25753580

  4. Knowns and Known Unknowns of Gastrointestinal Stromal Tumor Adjuvant Therapy.

    PubMed

    Martínez-Marín, Virginia; Maki, Robert G

    2016-09-01

    The first 15 years of management of gastrointestinal stromal tumor (GIST) have led to 3 lines of therapy for metastatic disease: imatinib, sunitinib, and regorafenib. In the adjuvant setting, imatinib is usually given for 3 years postoperatively to patients with higher-risk primary tumors that are completely resected. In this review, issues regarding GIST adjuvant therapy are discussed. It is hoped this review will help the reader understand the present standard of care to improve upon it in years to come. PMID:27546844

  5. Radiation therapy of carotid body tumors

    SciTech Connect

    Valdagni, R.; Amichetti, M. )

    1990-02-01

    Chemodectomas of carotid artery bifurcation are generally managed with surgery, irradiation being reserved for inoperable, bulky, and recurrent tumors. Probably due to this pretreatment selection of patients, chemodectomas are anedoctally considered radioresistant tumors, although this concept is not supported by the recent literature. From 1968 to 1987, 13 carotid body tumors in seven patients were treated with irradiation as sole treatment (10 lesions) or as postoperative modality (three lesions). Familial occurrence and bilateral presentation were observed in 3 of 7 and in 6 of 7 patients, respectively. Total dose of irradiation was of 46-60 Gy (median 50 Gy, mean 52.25 Gy) with dose per fraction of 1.8-2.5 Gy. Local control (subjective or objective) was obtained in all the patients. Clinical results following World Health Organization (WHO) criteria were: 3 of 13 complete response, 7 of 13 partial response and 3 of 13 no change. Follow-up range is 1-19 years. Acute side effects were minimal and mid- or long-term toxicity was absent.32 references.

  6. Photodynamic therapy with laser scanning mode of tumor irradiation

    NASA Astrophysics Data System (ADS)

    Chepurna, Oksana; Shton, Irina; Kholin, Vladimir; Voytsehovich, Valerii; Popov, Viacheslav; Pavlov, Sergii; Gamaleia, Nikolai; Wójcik, Waldemar; Zhassandykyzy, Maral

    2015-12-01

    In this study we propose a new version of photodynamic therapy performed by laser scanning. The method consists in tumor treatment by a light beam of a small cross section which incrementally moves through the chosen area with a defined delay at each point and repetitively re-scans a zone starting from the initial position. Experimental evaluation of the method in vitro on murine tumor model showed that despite the dose, applied by scanning irradiation mode, was 400 times lower, the tumor inhibition rate conceded to attained with continuous irradiation mode by only 20%.

  7. Myeloid Cells as Targets for Therapy in Solid Tumors.

    PubMed

    Cotechini, Tiziana; Medler, Terry R; Coussens, Lisa M

    2015-01-01

    It is well established that cancer development ensues based on reciprocal interactions between genomically altered neoplastic cells and diverse populations of recruited "host" cells co-opted to support malignant progression. Among the host cells recruited into tumor microenvironments, several subtypes of myeloid cells, including macrophages, monocytes, dendritic cells, and granulocytes contribute to tumor development by providing tumor-promoting factors as well as a spectrum of molecules that suppress cytotoxic activities of T lymphocytes. Based on compelling preclinical data revealing that inhibition of critical myeloid-based programs leads to tumor suppression, novel immune-based therapies and approaches are now entering the clinic for evaluation. This review discusses mechanisms underlying protumorigenic programming of myeloid cells and discusses how targeting of these has potential to attenuate solid tumor progression via the induction and of mobilization CD8 cytotoxic T cell immunity. PMID:26222088

  8. Myeloid Cells as Targets for Therapy in Solid Tumors

    PubMed Central

    Cotechini, Tiziana; Medler, Terry R.; Coussens, Lisa M.

    2016-01-01

    It is well established that cancer development ensues based on reciprocal interactions between genomically altered neoplastic cells and diverse populations of recruited “host” cells co-opted to support malignant progression. Among the host cells recruited into tumor microenvironments, several subtypes of myeloid cells, including macrophages, monocytes, dendritic cells, and granulocytes contribute to tumor development by providing tumor-promoting factors as well as a spectrum of molecules that suppress cytotoxic activities of T lymphocytes. Based on compelling preclinical data revealing that inhibition of critical myeloid-based programs leads to tumor suppression, novel immune-based therapies and approaches are now entering the clinic for evaluation. This review discusses mechanisms underlying protumorigenic programming of myeloid cells and discusses how targeting of these has potential to attenuate solid tumor progression via the induction and of mobilization CD8+ cytotoxic T cell immunity. PMID:26222088

  9. Stimulation of anti-tumor immunity by photodynamic therapy

    PubMed Central

    Mroz, Pawel; Hashmi, Javad T; Huang, Ying-Ying; Lange, Norbert; Hamblin, Michael R

    2011-01-01

    Photodynamic therapy (PDT) is a rapidly developing cancer treatment that utilizes the combination of nontoxic dyes and harmless visible light to destroy tumors by generating reactive oxygen species. PDT produces tumor-cell destruction in the context of acute inflammation that acts as a ‘danger signal’ to the innate immune system. Activation of the innate immune system increases the priming of tumor-specific T lymphocytes that have the ability to recognize and destroy distant tumor cells and, in addition, lead to the development of an immune memory that can combat recurrence of the cancer at a later point in time. PDT may be also successfully combined with immunomodulating strategies that are capable of overcoming or bypassing the escape mechanisms employed by the progressing tumor to evade immune attack. This article will cover the role of the immune response in PDT anti-tumor effectiveness. It will highlight the milestones in the development of PDT-mediated anti-tumor immunity and emphasize the combination strategies that may improve this therapy. PMID:21162652

  10. Modulation of the Tumor Vasculature and Oxygenation to Improve Therapy

    PubMed Central

    Siemann, Dietmar W.; Horsman, Michael R.

    2015-01-01

    The tumor microenvironment is increasingly recognized as a major factor influencing the success of therapeutic treatments and has become a key focus for cancer research. The progressive growth of a tumor results in an inability of normal tissue blood vessels to oxygenate and provide sufficient nutritional support to tumor cells. As a consequence the expanding neoplastic cell population initiates its own vascular network which is both structurally and functionally abnormal. This aberrant vasculature impacts all aspects of the tumor microenvironment including the cells, extracellular matrix, and extracellular molecules which together are essential for the initiation, progression and spread of tumor cells. The physical conditions that arise are imposing and manifold, and include elevated interstitial pressure, localized extracellular acidity, and regions of oxygen and nutrient deprivation. No less important are the functional consequences experienced by the tumor cells residing in such environments: adaptation to hypoxia, cell quiescence, modulation of transporters and critical signaling molecules, immune escape, and enhanced metastatic potential. Together these factors lead to therapeutic barriers that create a significant hindrance to the control of cancers by conventional anticancer therapies. However, the aberrant nature of the tumor microenvironments also offers unique therapeutic opportunities. Particularly interventions that seek to improve tumor physiology and alleviate tumor hypoxia will selectively impair the neoplastic cell populations residing in these environments. Ultimately, by combining such therapeutic strategies with conventional anticancer treatments it may be possible to bring cancer growth, invasion, and metastasis to a halt. PMID:26073310

  11. Tumor Therapy with Targeted Atomic Nanogenerators

    NASA Astrophysics Data System (ADS)

    McDevitt, Michael R.; Ma, Dangshe; Lai, Lawrence T.; Simon, Jim; Borchardt, Paul; Frank, R. Keith; Wu, Karen; Pellegrini, Virginia; Curcio, Michael J.; Miederer, Matthias; Bander, Neil H.; Scheinberg, David A.

    2001-11-01

    A single, high linear energy transfer alpha particle can kill a target cell. We have developed methods to target molecular-sized generators of alpha-emitting isotope cascades to the inside of cancer cells using actinium-225 coupled to internalizing monoclonal antibodies. In vitro, these constructs specifically killed leukemia, lymphoma, breast, ovarian, neuroblastoma, and prostate cancer cells at becquerel (picocurie) levels. Injection of single doses of the constructs at kilobecquerel (nanocurie) levels into mice bearing solid prostate carcinoma or disseminated human lymphoma induced tumor regression and prolonged survival, without toxicity, in a substantial fraction of animals. Nanogenerators targeting a wide variety of cancers may be possible.

  12. X-ray induced Sm{sup 3+} to Sm{sup 2+} conversion in fluorophosphate and fluoroaluminate glasses for the monitoring of high-doses in microbeam radiation therapy

    SciTech Connect

    Vahedi, Shahrzad; Okada, Go; Morrell, Brian; Muzar, Edward; Koughia, Cyril; Kasap, Safa; Edgar, Andy; Varoy, Chris; Belev, George; Wysokinski, Tomasz; Chapman, Dean

    2012-10-01

    Fluorophosphate and fluoroaluminate glasses doped with trivalent samarium were evaluated as sensors of x-ray radiation for microbeam radiation therapy at the Canadian Light Source using the conversion of trivalent Sm{sup 3+} to the divalent form Sm{sup 2+}. Both types of glasses show similar conversion rates and may be used as a linear sensor up to {approx}150 Gy and as a nonlinear sensor up to {approx}2400 Gy, where saturation is reached. Experiments with a multi-slit collimator show high spatial resolution of the conversion pattern; the pattern was acquired by a confocal fluorescence microscopy technique. The effects of previous x-ray exposure may be erased by annealing at temperatures exceeding the glass transition temperature T{sub g} while annealing at T{sub A} < T{sub g} enhances the Sm conversion. This enhancement is explained by a thermally stimulated relaxation of host glass ionic matrix surrounding x-ray induced Sm{sup 2+} ions. In addition, some of the Sm{sup 3+}-doped glasses were codoped with Eu{sup 2+}-ions but the results show that there is no marked improvement in the conversion efficiency by the introduction of Eu{sup 2+}.

  13. Epigenetic Therapy for Solid Tumors: Highlighting the Impact of Tumor Hypoxia

    PubMed Central

    Ramachandran, Shaliny; Ient, Jonathan; Göttgens, Eva-Leonne; Krieg, Adam J.; Hammond, Ester M.

    2015-01-01

    In the last few decades, epigenetics has emerged as an exciting new field in development and disease, with a more recent focus towards cancer. Epigenetics has classically referred to heritable patterns of gene expression, primarily mediated through DNA methylation patterns. More recently, it has come to include the reversible chemical modification of histones and DNA that dictate gene expression patterns. Both the epigenetic up-regulation of oncogenes and downregulation of tumor suppressors have been shown to drive tumor development. Current clinical trials for cancer therapy include pharmacological inhibition of DNA methylation and histone deacetylation, with the aim of reversing these cancer-promoting epigenetic changes. However, the DNA methyltransferase and histone deacetylase inhibitors have met with less than promising results in the treatment of solid tumors. Regions of hypoxia are a common occurrence in solid tumors. Tumor hypoxia is associated with increased aggressiveness and therapy resistance, and importantly, hypoxic tumor cells have a distinct epigenetic profile. In this review, we provide a summary of the recent clinical trials using epigenetic drugs in solid tumors, discuss the hypoxia-induced epigenetic changes and highlight the importance of testing the epigenetic drugs for efficacy against the most aggressive hypoxic fraction of the tumor in future preclinical testing. PMID:26426056

  14. Saponins as tool for improved targeted tumor therapies.

    PubMed

    Fuchs, H; Bachran, D; Panjideh, H; Schellmann, N; Weng, A; Melzig, M F; Sutherland, M; Bachran, C

    2009-02-01

    Saponins are plant glycosides that consist of a steroid, steroid alkaloid or triterpenoid aglycone and one or more sugar chains that are covalently linked by glycosidic binding to the aglycone. Glucose, galactose, glucuronic acid, xylose and rhamnose are commonly bound monosaccharides. Saponins are found in all organs of a variety of higher plants. Due to the great variability of their structures, diverse functions have been described for distinct saponins; including foaming and pore forming properties as well as selective removal of protozoa from the rumen. The most interesting properties are, however, favorable anti-tumorigenic effects. Several saponins inhibit tumor cell growth by cell cycle arrest and apoptosis with half maximal inhibitory concentrations of down to 0.2 microM. A drawback of saponins in tumor therapy is the non-targeted spreading throughout the whole body. Surprisingly, certain saponins were identified that drastically enhance the efficacy of targeted chimeric toxins bearing the ribosome-inactivating protein saporin as cell-killing moiety. It was demonstrated that this effect is substantially more pronounced on target cells than on non-target cells, thus not only preserving the target specificity of the chimeric toxin but also broadening the therapeutic window with simultaneous dose lowering. This review describes the role of saponins as drug in general, their use as single drug treatment in tumor therapy, their combination with conventional tumor treatment strategies and the synergistic effects with particular targeted tumor therapies that are based on recombinant proteins. PMID:19199910

  15. [Application of dendritic cells in clinical tumor therapy].

    PubMed

    Li, Yan; Xian, Li-jian

    2002-04-01

    The active immunotherapy of dendritic cells is hot in tumor therapy research area. This article is a review of the source of dendritic cells, loading antigen, immunotherapy pathway, clinical application, choice of patients, and so on. It makes preparation for further research of dendritic cells. PMID:12452029

  16. Nd:YAG laser therapy in bronchogenic tumors

    NASA Astrophysics Data System (ADS)

    Benov, Emil; Kostadinov, D.; Mitchev, K.; Vlasov, V.

    1993-03-01

    In 2 years 53 patients with tumors of the tracheobronchial tree have been treated by photocoagulation therapy. Forty cases of them were with different types of cancer and 13 cases with benign lesions of the trachea or bronchi. As a laser source we used an Nd:YAG laser, MBB, Germany. At first the tumor was irradiated with a power of 25 - 30 W, following power up to 90 W. The median energy dose was 3,500 J/sq cm for each patient. The treatment was executed under local anesthesia with a rigid or flexible bronchoscope. In all of the cases with benign tumors we obtained a stable positive effect. In 15 cases of carcinoma we attained a recanalization and restoration of the ventilation to the treated area -- 37.5%. The only complication due to the procedure was the death of one patient with a tracheal cancer and myasthenia gravis. Photocoagulation therapy is an effective method for benign tumors. In cases with carcinoma this therapy is used with palliative purpose -- recanalization of the bronchus. Laser endobronchial therapy shows an immediate positive effect in the treatment of airway obstruction.

  17. The role of mechanical forces in tumor growth and therapy

    PubMed Central

    Jain, Rakesh K.; Martin, John D.; Stylianopoulos, Triantafyllos

    2014-01-01

    Tumors generate physical forces during growth and progression. These physical forces are able to compress blood and lymphatic vessels, reducing perfusion rates and creating hypoxia. When exerted directly on cancer cells, they can increase their invasive and metastatic potential. Tumor vessels - while nourishing the tumor - are usually leaky and tortuous, which further decreases perfusion. Hypo-perfusion and hypoxia contribute to immune-evasion, promote malignant progression and metastasis, and reduce the efficacy of a number of therapies, including radiation. In parallel, vessel leakiness together with vessel compression cause a uniformly elevated interstitial fluid pressure that hinders delivery of blood-borne therapeutic agents, lowering the efficacy of chemo- and nano-therapies. In addition, shear stresses exerted by flowing blood and interstitial fluid modulate the behavior of cancer and a variety of host cells. Taming these physical forces can improve therapeutic outcomes in many cancers. PMID:25014786

  18. New effects in photodynamic therapy of tumors

    NASA Astrophysics Data System (ADS)

    Akimov, A. A.; Barchuk, A. S.; Gel'fond, M. L.; Maslow, V. G.; Mihailova, N. B.; Ogurtsov, Robert P.; Prokof'eva, T. P.; Ryl'kov, Vladimir V.; Samsonova, I. E.; Stukov, Alexsander N.; Filov, V. A.

    1994-08-01

    In this report there are the experimental results, which has been received with cell cultures and animals. We have found the photosensitized stimulation of the protective reactions of an organism, which has no direct connection with the photosensitization of the tumor cell destruction. It has been supposed that this photobiological process started from the photomodification of malignant cell membranes, its making strange cells for organism, and/or from the photomodification of the immunocompetent cells of the peripheral blood, increasing its cell killer activity. It has been shown that there are at least two competitive photoprocesses at use of monochromatic light. The first realizes the sensitized photodestruction of the malignant cells, and the second stimulates their reproduction. The latter decreases efficiency of PDT. It has found that the polychromatic (white) light suppressed processes of the malignant cell reproduction.

  19. Local iontophoretic administration of cytotoxic therapies to solid tumors.

    PubMed

    Byrne, James D; Jajja, Mohammad R N; O'Neill, Adrian T; Bickford, Lissett R; Keeler, Amanda W; Hyder, Nabeel; Wagner, Kyle; Deal, Allison; Little, Ryan E; Moffitt, Richard A; Stack, Colleen; Nelson, Meredith; Brooks, Christopher R; Lee, William; Luft, J Chris; Napier, Mary E; Darr, David; Anders, Carey K; Stack, Richard; Tepper, Joel E; Wang, Andrew Z; Zamboni, William C; Yeh, Jen Jen; DeSimone, Joseph M

    2015-02-01

    Parenteral and oral routes have been the traditional methods of administering cytotoxic agents to cancer patients. Unfortunately, the maximum potential effect of these cytotoxic agents has been limited because of systemic toxicity and poor tumor perfusion. In an attempt to improve the efficacy of cytotoxic agents while mitigating their side effects, we have developed modalities for the localized iontophoretic delivery of cytotoxic agents. These iontophoretic devices were designed to be implanted proximal to the tumor with external control of power and drug flow. Three distinct orthotopic mouse models of cancer and a canine model were evaluated for device efficacy and toxicity. Orthotopic patient-derived pancreatic cancer xenografts treated biweekly with gemcitabine via the device for 7 weeks experienced a mean log2 fold change in tumor volume of -0.8 compared to a mean log2 fold change in tumor volume of 1.1 for intravenous (IV) gemcitabine, 3.0 for IV saline, and 2.6 for device saline groups. The weekly coadministration of systemic cisplatin therapy and transdermal device cisplatin therapy significantly increased tumor growth inhibition and doubled the survival in two aggressive orthotopic models of breast cancer. The addition of radiotherapy to this treatment further extended survival. Device delivery of gemcitabine in dogs resulted in more than 7-fold difference in local drug concentrations and 25-fold lower systemic drug levels than the IV treatment. Overall, these devices have potential paradigm shifting implications for the treatment of pancreatic, breast, and other solid tumors. PMID:25653220

  20. Effective Rat Lung Tumor Model for Stereotactic Body Radiation Therapy.

    PubMed

    Zhang, Zhang; Wodzak, Michelle; Belzile, Olivier; Zhou, Heling; Sishc, Brock; Yan, Hao; Stojadinovic, Strahinja; Mason, Ralph P; Brekken, Rolf A; Chopra, Rajiv; Story, Michael D; Timmerman, Robert; Saha, Debabrata

    2016-06-01

    Stereotactic body radiation therapy (SBRT) has found an important role in the treatment of patients with non-small cell lung cancer, demonstrating improvements in dose distribution and even tumor cure rates, particularly for early-stage disease. Despite its emerging clinical efficacy, SBRT has primarily evolved due to advances in medical imaging and more accurate dose delivery, leaving a void in knowledge of the fundamental biological mechanisms underlying its activity. Thus, there is a critical need for the development of orthotropic animal models to further probe the biology associated with high-dose-per-fraction treatment typical of SBRT. We report here on an improved surgically based methodology for generating solitary intrapulmonary nodule tumors, which can be treated with simulated SBRT using the X-RAD 225Cx small animal irradiator and Small Animal RadioTherapy (SmART) Plan treatment system. Over 90% of rats developed solitary tumors in the right lung. Furthermore, the tumor response to radiation was monitored noninvasively via bioluminescence imaging (BLI), and complete ablation of tumor growth was achieved with 36 Gy (3 fractions of 12 Gy each). We report a reproducible, orthotopic, clinically relevant lung tumor model, which better mimics patient treatment regimens. This system can be utilized to further explore the underlying biological mechanisms relevant to SBRT and high-dose-per-fraction radiation exposure and to provide a useful model to explore the efficacy of radiation modifiers in the treatment of non-small cell lung cancer. PMID:27223828

  1. Local iontophoretic administration of cytotoxic therapies to solid tumors

    PubMed Central

    Byrne, James D.; Jajja, Mohammad R. N.; O’Neill, Adrian T.; Bickford, Lissett R.; Keeler, Amanda W.; Hyder, Nabeel; Wagner, Kyle; Deal, Allison; Little, Ryan E.; Moffitt, Richard A.; Stack, Colleen; Nelson, Meredith; Brooks, Christopher R.; Lee, William; Luft, J. Chris; Napier, Mary E.; Darr, David; Anders, Carey K.; Stack, Richard; Tepper, Joel E.; Wang, Andrew Z.; Zamboni, William C.; Yeh, Jen Jen; DeSimone, Joseph M.

    2015-01-01

    Parenteral and oral routes have been the traditional methods of administering cytotoxic agents to cancer patients. Unfortunately, the maximum potential effect of these cytotoxic agents has been limited because of systemic toxicity and poor tumor perfusion. In an attempt to improve the efficacy of cytotoxic agents while mitigating their side effects, we have developed modalities for the localized iontophoretic delivery of cytotoxic agents. These iontophoretic devices were designed to be implanted proximal to the tumor with external control of power and drug flow. Three distinct orthotopic mouse models of cancer and a canine model were evaluated for device efficacy and toxicity. Orthotopic patient-derived pancreatic cancer xenografts treated biweekly with gemcitabine via the device for 7 weeks experienced a mean log2 fold change in tumor volume of −0.8 compared to a mean log2 fold change in tumor volume of 1.1 for intravenous (IV) gemcitabine, 3.0 for IV saline, and 2.6 for device saline groups. The weekly coadministration of systemic cisplatin therapy and transdermal device cisplatin therapy significantly increased tumor growth inhibition and doubled the survival in two aggressive orthotopic models of breast cancer. The addition of radiotherapy to this treatment further extended survival. Device delivery of gemcitabine in dogs resulted in more than 7-fold difference in local drug concentrations and 25-fold lower systemic drug levels than the IV treatment. Overall, these devices have potential paradigm shifting implications for the treatment of pancreatic, breast, and other solid tumors. PMID:25653220

  2. High Intensity Focused Ultrasound Tumor Therapy System and Its Application

    NASA Astrophysics Data System (ADS)

    Sun, Fucheng; He, Ye; Li, Rui

    2007-05-01

    At the end of last century, a High Intensity Focused Ultrasound (HIFU) tumor therapy system was successfully developed and manufactured in China, which has been already applied to clinical therapy. This article aims to discuss the HIFU therapy system and its application. Detailed research includes the following: power amplifiers for high-power ultrasound, ultrasound transducers with large apertures, accurate 3-D mechanical drives, a software control system (both high-voltage control and low-voltage control), and the B-mode ultrasonic diagnostic equipment used for treatment monitoring. Research on the dosage of ultrasound required for tumour therapy in multiple human cases has made it possible to relate a dosage formula, presented in this paper, to other significant parameters such as the volume of thermal tumor solidification, the acoustic intensity (I), and the ultrasound emission time (tn). Moreover, the HIFU therapy system can be applied to the clinical treatment of both benign and malignant tumors in the pelvic and abdominal cavity, such as uterine fibroids, liver cancer and pancreatic carcinoma.

  3. Hyaluronidase To Enhance Nanoparticle-Based Photodynamic Tumor Therapy.

    PubMed

    Gong, Hua; Chao, Yu; Xiang, Jian; Han, Xiao; Song, Guosheng; Feng, Liangzhu; Liu, Jingjing; Yang, Guangbao; Chen, Qian; Liu, Zhuang

    2016-04-13

    Photodynamic therapy (PDT) is considered as a safe and selective way to treat a wide range of cancers as well as nononcological disorders. However, as oxygen is required in the process of PDT, the hypoxic tumor microenvironment has largely limited the efficacy of PDT to treat tumors especially those with relatively large sizes. To this end, we uncover that hyaluronidase (HAase), which breaks down hyaluronan, a major component of extracellular matrix (ECM) in tumors, would be able to enhance the efficacy of nanoparticle-based PDT for in vivo cancer treatment. It is found that the administration of HAase would lead to the increase of tumor vessel densities and effective vascular areas, resulting in increased perfusion inside the tumor. As a result, the tumor uptake of nanomicelles covalently linked with chlorine e6 (NM-Ce6) would be increased by ∼2 folds due to the improved "enhanced permeability and retention" (EPR) effect, while the tumor oxygenation level also shows a remarkable increase, effectively relieving the hypoxia state inside the tumor. Those effects taken together offer significant benefits in greatly improving the efficacy of PDT delivered by nanoparticles. Taking advantage of the effective migration of HAase from the primary tumor to its drainage sentinel lymph nodes (SLNs), we further demonstrate that this strategy would be helpful to the treatment of metastatic lymph nodes by nanoparticle-based PDT. Lastly, both enhanced EPR effect of NM-Ce6 and relieved hypoxia state of tumor are also observed after systemic injection of modified HAase, proving its potential for clinical translation. Therefore, our work presents a new concept to improve the efficacy of nanomedicine by modulating the tumor microenvironment. PMID:27022664

  4. Nimotuzumab increases the anti-tumor effect of photodynamic therapy in an oral tumor model

    PubMed Central

    Bhuvaneswari, Ramaswamy; Ng, Qin Feng; Thong, Patricia S.P.; Soo, Khee-Chee

    2015-01-01

    Oral squamous cell carcinoma (OSCC) represents 90% of all oral cancers and is characterized with poor prognosis and low survival rate. Epidermal growth factor receptor (EGFR) is highly expressed in oral cancer and is a target for cancer therapy and prevention. In this present work, we evaluate the efficacy of photodynamic therapy (PDT) in combination with an EGFR inhibitor, nimotuzumab in oral cancer cell lines and OSCC xenograft tumor model. PDT is a promising and minimally invasive treatment modality that involves the interaction of a photosensitizer, molecular oxygen and light to destroy tumors. We demonstrated that EGFR inhibitors nimotuzumab and cetuximab exhibits anti-angiogenic properties by inhibiting the migration and invasion of oral cancer cell lines and human endothelial cells. The EGFR inhibitors also significantly reduced tube formation of endothelial cells. Chlorin e6-PDT in combination with nimotuzumab and cetuximab reduced cell proliferation in different oral cancer and endothelial cells. Furthermore, our in vivo studies showed that the combination therapy of PDT and nimotuzumab synergistically delayed tumor growth when compared with control and PDT treated tumors. Downregulation of EGFR, Ki-67 and CD31 was observed in the tumors treated with combination therapy. Analysis of the liver and kidney function markers showed no treatment related toxicity. In conclusion, PDT outcome of oral cancer can be improved when combined with EGFR inhibitor nimotuzumab. PMID:25918252

  5. Nimotuzumab increases the anti-tumor effect of photodynamic therapy in an oral tumor model.

    PubMed

    Bhuvaneswari, Ramaswamy; Ng, Qin Feng; Thong, Patricia S P; Soo, Khee-Chee

    2015-05-30

    Oral squamous cell carcinoma (OSCC) represents 90% of all oral cancers and is characterized with poor prognosis and low survival rate. Epidermal growth factor receptor (EGFR) is highly expressed in oral cancer and is a target for cancer therapy and prevention. In this present work, we evaluate the efficacy of photodynamic therapy (PDT) in combination with an EGFR inhibitor, nimotuzumab in oral cancer cell lines and OSCC xenograft tumor model. PDT is a promising and minimally invasive treatment modality that involves the interaction of a photosensitizer, molecular oxygen and light to destroy tumors. We demonstrated that EGFR inhibitors nimotuzumab and cetuximab exhibits anti-angiogenic properties by inhibiting the migration and invasion of oral cancer cell lines and human endothelial cells. The EGFR inhibitors also significantly reduced tube formation of endothelial cells. Chlorin e6-PDT in combination with nimotuzumab and cetuximab reduced cell proliferation in different oral cancer and endothelial cells. Furthermore, our in vivo studies showed that the combination therapy of PDT and nimotuzumab synergistically delayed tumor growth when compared with control and PDT treated tumors. Downregulation of EGFR, Ki-67 and CD31 was observed in the tumors treated with combination therapy. Analysis of the liver and kidney function markers showed no treatment related toxicity. In conclusion, PDT outcome of oral cancer can be improved when combined with EGFR inhibitor nimotuzumab. PMID:25918252

  6. Anti-tumor immune response after photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Mroz, Pawel; Castano, Ana P.; Wu, Mei X.; Kung, Andrew L.; Hamblin, Michael R.

    2009-06-01

    Anti-tumor immunity is stimulated after PDT due a number of factors including: the acute inflammatory response caused by PDT, release of antigens from PDT-damaged tumor cells, priming of the adaptive immune system to recognize tumor-associated antigens (TAA), and induction of heat-shock proteins. The induction of specific CD8+ T-lymphocyte cells that recognize major histocompatibility complex class I (MHC-I) restricted epitopes of TAAs is a highly desirable goal in cancer therapy as it would allow the treatment of tumors that may have already metastasized. The PDT killed tumor cells may be phagocytosed by dendritic cells (DC) that then migrate to draining lymph nodes and prime naÃve T-cells that recognize TAA epitopes. We have carried out in vivo PDT with a BPD-mediated vascular regimen using a pair of BALB/c mouse colon carcinomas: CT26 wild type expressing the naturally occurring retroviral antigen gp70 and CT26.CL25 additionally expressing beta-galactosidase (b-gal) as a model tumor rejection antigen. PDT of CT26.CL25 cured 100% of tumors but none of the CT26WT tumors (all recurred). Cured CT26.CL25 mice were resistant to rechallenge. Moreover mice with two bilateral CT26.CL25 tumors that had only one treated with PDT demonstrated spontaneous regression of 70% of untreated contralateral tumors. T-lymphocytes were isolated from lymph nodes of PDT cured mice that recognized a particular peptide specific to b-gal antigen. T-lymphocytes from LN were able to kill CT26.CL25 target cells in vitro but not CT26WT cells as shown by a chromium release assay. CT26.CL25 tumors treated with PDT and removed five days later had higher levels of Th1 cytokines than CT26 WT tumors showing a higher level of immune response. When mice bearing CT26WT tumors were treated with a regimen of low dose cyclophosphamide (CY) 2 days before, PDT led to 100% of cures (versus 0% without CY) and resistance to rechallenge. Low dose CY is thought to deplete regulatory T-cells (Treg, CD4+CD25+foxp

  7. Evading anti-angiogenic therapy: resistance to anti-angiogenic therapy in solid tumors

    PubMed Central

    Dey, Nandini; De, Pradip; Brian, Leyland-Jones

    2015-01-01

    Vascular endothelial growth factor (VEGF) dependent tumor angiogenesis is an essential step for the initiation and promotion of tumor progression. The hypothesis that VEGF-driven tumor angiogenesis is necessary and sufficient for metastatic progression of the tumor, has been the major premise of the use of anti-VEGF therapy for decades. While the success of anti-VEGF therapy in solid tumors has led to the success of knowledge-based-therapies over the past several years, failures of this therapeutic approach due to the development of inherent/acquired resistance has led to the increased understanding of VEGF-independent angiogenesis. Today, tumor-angiogenesis is not a synonymous term to VEGF-dependent function. The extensive study of VEGF-independent angiogenesis has revealed several key factors responsible for this phenomenon including the role of myeloid cells, and the contribution of entirely new phenomenon like vascular mimicry. In this review, we will present the cellular and molecular factors related to the development of anti-angiogenic resistance following anti-VEGF therapy in different solid tumors. PMID:26692917

  8. Evading anti-angiogenic therapy: resistance to anti-angiogenic therapy in solid tumors.

    PubMed

    Dey, Nandini; De, Pradip; Brian, Leyland-Jones

    2015-01-01

    Vascular endothelial growth factor (VEGF) dependent tumor angiogenesis is an essential step for the initiation and promotion of tumor progression. The hypothesis that VEGF-driven tumor angiogenesis is necessary and sufficient for metastatic progression of the tumor, has been the major premise of the use of anti-VEGF therapy for decades. While the success of anti-VEGF therapy in solid tumors has led to the success of knowledge-based-therapies over the past several years, failures of this therapeutic approach due to the development of inherent/acquired resistance has led to the increased understanding of VEGF-independent angiogenesis. Today, tumor-angiogenesis is not a synonymous term to VEGF-dependent function. The extensive study of VEGF-independent angiogenesis has revealed several key factors responsible for this phenomenon including the role of myeloid cells, and the contribution of entirely new phenomenon like vascular mimicry. In this review, we will present the cellular and molecular factors related to the development of anti-angiogenic resistance following anti-VEGF therapy in different solid tumors. PMID:26692917

  9. NEUROFIBROMATOSIS-RELATED TUMORS: EMERGING BIOLOGY AND THERAPIES

    PubMed Central

    Karajannis, Matthias A.; Ferner, Rosalie E.

    2015-01-01

    Purpose of review Over the past decade, substantial insight into the biological function of the tumor suppressors neurofibromin (NF1) and Merlin (NF2) has been gained. The purpose of this review is to highlight some of the major advances in the biology of neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2) as they relate to the development of novel therapies for these disorders. Recent findings The development of increasingly sophisticated preclinical models over the recent years has provided the platform from which to rationally develop molecular targeted therapies for both NF1 and NF2 related tumors, such as within the Department of Defense-sponsored Neurofibromatosis Clinical Trials Consortium (NFCTC). Summary Clinical trials with molecular targeted therapies have become a reality for NF patients, and hold substantial promise for improving the morbidity and mortality of individuals affected with these disorders. PMID:25490687

  10. Molecular regulation of vasculogenic mimicry in tumors and potential tumor-target therapy

    PubMed Central

    Fan, Yue-Zu; Sun, Wei

    2010-01-01

    “Vasculogenic mimicry (VM)”, is a term that describes the unique ability of highly aggressive tumor cells to express a multipotent, stem cell-like phenotype, and form a pattern of vasculogenic-like networks in three-dimensional culture. As an angiogenesis-independent pathway, VM and/or periodic acid-schiff-positive patterns are associated with poor prognosis in tumor patients. Moreover, VM is resistant to angiogenesis inhibitors. Here, we will review the advances in research on biochemical and molecular signaling pathways of VM in tumors and on potential anti-VM therapy strategy. PMID:21160860

  11. Percutaneous radiofrequency ablation: minimally invasive therapy for renal tumors.

    PubMed

    Ahrar, Kamran; Wallace, Michael J; Matin, Surena F

    2006-12-01

    Currently, up to 60% of renal tumors are detected incidentally by abdominal imaging. Most of these tumors are small and localized to the kidney. Owing to the shift to lower stage at diagnosis, radical nephrectomy has fallen out of favor and has been replaced by nephron-sparing surgery. Currently, partial nephrectomy is the treatment of choice for patients with small renal tumors. As the trend towards less invasive therapy continues, laparoscopic and percutaneous ablation techniques have gained popularity for the treatment of renal tumors in patients who are high-risk surgical candidates, or have a solitary kidney, limited renal function or multifocal disease. Percutaneous radiofrequency ablation is a safe, minimally invasive treatment option for those patients. PMID:17181487

  12. [Neuroendocrine pancreatic tumors and helpfulness of targeted therapies].

    PubMed

    Vaysse, Thibaut; Coriat, Romain; Perkins, Géraldine; Dhooge, Marion; Brezault, Catherine; Chaussade, Stanislas

    2013-06-01

    The neuroendocrine pancreatic tumors are rare tumors, but their incidence is constantly rising. Even if the management of these tumors has to be surgical as soon as possible, the disease is most often metastatic at the stage of the diagnostic. The prognostic and the therapeutic options differ from pancreatic adenocarcinoma. Available treatments have evolved over the last years with recent publications of studies that bring to light the benefits of targeted therapies in this pathology. This has resulted in modifications of both practices and either French and international guidelines. Therefore, we focus on the management of the grade 1 and grade 2 well-differentiated neuroendocrine pancreatic tumors as classified in new WHO classification of neuroendocrine neoplasms published in 2010. PMID:23009947

  13. Enhancing T cell therapy by overcoming the immunosuppressive tumor microenvironment.

    PubMed

    Arina, Ainhoa; Corrales, Leticia; Bronte, Vincenzo

    2016-02-01

    Immune response to tumors can be successfully oriented for therapeutic purposes, as shown by the clinical efficacy of checkpoint blockade in extending the survival of patients with certain solid and hematologic neoplasms. Nonetheless, numerous patients do not benefit from these new treatments. Tumor-specific CD8(+) T lymphocytes, either endogenously revived by checkpoint interference or adoptively transferred after in vitro expansion and retargeting, can be extremely efficient in controlling metastatic disease but have to overcome a number of restraints imposed by growing tumors. This immune escape relies on a profound modification of the tumor environment, which is rendered less permissive to lymphocyte arrival, persistence, and functional activity. We review here emerging findings on the main negative circuits limiting the efficacy of cancer immunotherapy, as well as novel and conventional approaches that can translate into rational combination therapies. PMID:26872631

  14. Tumor

    MedlinePlus

    ... be removed because of their location or harmful effect on the surrounding normal brain tissue. If a tumor is cancer , possible treatments may include: Chemotherapy Radiation Surgery Targeted cancer therapy Biologic therapy Other treatment options

  15. Adjuvant photodynamic therapy in surgical management of cerebral tumors

    NASA Astrophysics Data System (ADS)

    Chen, Zong-Qian; Wu, Si-En; Zhu, Shu-Gan

    1993-03-01

    We have performed high dose photoradiation therapy in patients with cerebral tumors. Twenty-seven patients had gliomas, two had metastatic cancer of the brain, one had malignant meningioma. Hematoporphyrin derivative was administered intravenously. All patients underwent a craniotomy with a radical or partial excision of the tumor. There was no evidence of increased cerebral edema and other toxicity from the therapy, and all patients were discharged from the hospital within 15 days after surgery. On the basis of animal experiments our institute started using photodynamic therapy (PDT) as an adjuvant measure to the operative therapy in 30 cases of cerebral tumors. Ten of these patients were excluded from this group because of the short postoperative following time. Here, the details of our experiences are presented as follows: 106 of C6 type glioma cell strain were implanted into the frontal lobe of a Chinese hamster. Fourteen days later intracranial gliomas developed, which were larger than 4 mm in diameter, HpD in a dosage of 4 mg/kg was injected into the tail vein of the animals. The fluorescence was seen 5 minutes later. The diagnostic laser used was He-Ca (Hc-type 15A, made at Shanghai Laser Institute) with a wavelength of 441.6 nm, power of 30 mw. The fluorescence reached its peak point 24 hours later, and the normal tissue can be identified by the lack of fluorescence. Then, the tumor tissue was further radiated with an Ar laser (made in Nanjing Electronic Factory, type 360), pumped dye-laser (made in Changchun Optic Machinery Institute, type 901) with a wavelength of 630 nm, and an energy density of more than 200 Joules/cm2, which might get the tumor cells destroyed selectively. The effect of photoradiation may reach as deep as 4 - 7 mm into the brain tissue without cerebral edema or necrosis.

  16. Nanomedicine engulfed by macrophages for targeted tumor therapy.

    PubMed

    Li, Siwen; Feng, Song; Ding, Li; Liu, Yuxi; Zhu, Qiuyun; Qian, Zhiyu; Gu, Yueqing

    2016-01-01

    Macrophages, exhibiting high intrinsic accumulation and infiltration into tumor tissues, are a novel drug vehicle for directional drug delivery. However, the low drug-loading (DL) capacity and the drug cytotoxicity to the cell vehicle have limited the application of macrophages in tumor therapy. In this study, different drugs involving small molecular and nanoparticle drugs were loaded into intrinsic macrophages to find a better way to overcome these limitations. Their DL capacity and cytotoxicity to the macrophages were first compared. Furthermore, their phagocytic ratio, dynamic distributions, and tumoricidal effects were also investigated. Results indicated that more lipid-soluble molecules and DL particles can be phagocytized by macrophages than hydrophilic ones. In addition, the N-succinyl-N'-octyl chitosan (SOC) DL particles showed low cytotoxicity to the macrophage itself, while the dynamic biodistribution of macrophages engulfed with different particles/small molecules showed similar profiles, mainly excreted from liver to intestine pathway. Furthermore, macrophages loaded with SOC-paclitaxel (PTX) particles exhibited greater therapeutic efficacies than those of macrophages directly carrying small molecular drugs such as doxorubicin and PTX. Interestingly, macrophages displayed stronger targeting ability to the tumor site hypersecreting chemokine in immunocompetent mice in comparison to the tumor site secreting low levels of chemokine in immunodeficiency mice. Finally, results demonstrated that macrophages carrying SOC-PTX are a promising pharmaceutical preparation for tumor-targeted therapy. PMID:27601898

  17. Bioreductive drugs for cancer therapy: the search for tumor specificity.

    PubMed

    Adams, G E; Stratford, I J

    1994-05-15

    The activity of three different classes of bioreductive drug, i.e., heterocyclic nitro compounds, N-oxides and quinones are compared. The major characteristics of RB-6145, tirapazamine and E09 are summarized and future directions for development of new bioreductive drugs are outlined. The concept of potentiating bioreductive drug activity by increasing tumor hypoxia is described and illustrated in particular by the use of photodynamic therapy (PDT) in combination with RSU-1069. Examples of how the therapeutic effectiveness of this approach can be studied by the use of 31P magnetic resonance spectroscopy is described. The effects of manipulation of nitric oxide (NO) levels in tumors by the use of modifiers of NO-synthase activity is illustrated by studies with the inhibitor nitro-L-arginine in experimental tumors. Associated changes in tumor physiology indicate promise for potential applications in therapy. Finally, changes in expression of reductase enzyme levels are considered in the context of the heterogenous nature of the tumor microenvironment. PMID:8195012

  18. Nanomedicine engulfed by macrophages for targeted tumor therapy

    PubMed Central

    Li, Siwen; Feng, Song; Ding, Li; Liu, Yuxi; Zhu, Qiuyun; Qian, Zhiyu; Gu, Yueqing

    2016-01-01

    Macrophages, exhibiting high intrinsic accumulation and infiltration into tumor tissues, are a novel drug vehicle for directional drug delivery. However, the low drug-loading (DL) capacity and the drug cytotoxicity to the cell vehicle have limited the application of macrophages in tumor therapy. In this study, different drugs involving small molecular and nanoparticle drugs were loaded into intrinsic macrophages to find a better way to overcome these limitations. Their DL capacity and cytotoxicity to the macrophages were first compared. Furthermore, their phagocytic ratio, dynamic distributions, and tumoricidal effects were also investigated. Results indicated that more lipid-soluble molecules and DL particles can be phagocytized by macrophages than hydrophilic ones. In addition, the N-succinyl-N′-octyl chitosan (SOC) DL particles showed low cytotoxicity to the macrophage itself, while the dynamic biodistribution of macrophages engulfed with different particles/small molecules showed similar profiles, mainly excreted from liver to intestine pathway. Furthermore, macrophages loaded with SOC–paclitaxel (PTX) particles exhibited greater therapeutic efficacies than those of macrophages directly carrying small molecular drugs such as doxorubicin and PTX. Interestingly, macrophages displayed stronger targeting ability to the tumor site hypersecreting chemokine in immunocompetent mice in comparison to the tumor site secreting low levels of chemokine in immunodeficiency mice. Finally, results demonstrated that macrophages carrying SOC–PTX are a promising pharmaceutical preparation for tumor-targeted therapy. PMID:27601898

  19. The Use of Anthracyclines for Therapy of CNS Tumors

    PubMed Central

    da Ros, Martina; Iorio, Anna Lisa; Lucchesi, Maurizio; Stival, Alessia; de Martino, Maurizio; Sardi, Iacopo

    2015-01-01

    Despite being long lived, anthracyclines remain the “evergreen” drugs in clinical practice of oncology, showing a potent effect in inhibiting cell growth in many types of tumors, including brain neoplasms. Unfortunately, they suffer from a poor penetration into the brain when intravenously administered due to multidrug resistance mechanism, which hampers their delivery across the blood brain barrier. In this paper, we summarize the current literature on the role of anthracyclines in cancer therapy and highlight recent efforts on 1) development of tumor cell resistance to anthracyclines and 2) the new approaches to brain drug delivery across the blood brain barrier. PMID:25846760

  20. Onivyde for the therapy of multiple solid tumors.

    PubMed

    Zhang, Haijun

    2016-01-01

    Drug delivery system based on nanobiotechnology can improve the pharmacokinetics and therapeutic index of chemotherapeutic agents, which has revolutionized tumor therapy. Onivyde, also known as MM-398 or PEP02, is a nanoliposomal formulation of irinotecan which has demonstrated encouraging anticancer activity across a broad range of malignancies, including pancreatic cancer, esophago-gastric cancer, and colorectal cancer. This up-to-date review not only focuses on the structure, pharmacokinetics, and pharmacogenetics of Onivyde but also summarizes clinical trials and recommends Onivyde for patients with advanced solid tumors. PMID:27284250

  1. [Principles of adoptive cell therapy based on "Tumor Infiltrating Lymphocytes"].

    PubMed

    Martins, Filipe; Orcurto, Angela; Michielin, Olivier; Coukos, George

    2016-05-18

    Adoptive cell therapy consists in the use of T lymphocytes for therapeutic purposes. Up to now, of limited use in clinical practice for logistical reasons, technical progress and substantial level of evidence obtained in the last decade allow its arrival in universitary hospitals. We will principally discuss the administration of expanded tumor infiltrating T cells in the treatment of metastatic melanoma. This treatment modality exploits the natural specificity of these cells and aims to potentiate their effectiveness. This personalized immunotherapy detains a potential for expansion to many other advanced tumor types. PMID:27424426

  2. Biomodulatory Approaches to Photodynamic Therapy for Solid Tumors

    PubMed Central

    Anand, Sanjay; Ortel, Bernhard J.; Pereira, Stephen P.; Hasan, Tayyaba; Maytin, Edward V.

    2012-01-01

    Photodynamic Therapy (PDT) uses a photosensitizing drug in combination with visible light to kill cancer cells. PDT has an advantage over surgery or ionizing radiation because PDT can eliminate tumors without causing fibrosis or scarring. Disadvantages include the dual need for drug and light, and a generally lower efficacy for PDT versus surgery. This minireview describes basic principles of PDT, photosensitizers available, and aspects of tumor biology that may provide further opportunities for treatment optimization. An emerging biomodulatory approach, using methotrexate or Vitamin D in combination with aminolevulinate-based PDT, is described. Finally, current clinical uses of PDT for solid malignancies are reviewed. PMID:22842096

  3. Onivyde for the therapy of multiple solid tumors

    PubMed Central

    Zhang, Haijun

    2016-01-01

    Drug delivery system based on nanobiotechnology can improve the pharmacokinetics and therapeutic index of chemotherapeutic agents, which has revolutionized tumor therapy. Onivyde, also known as MM-398 or PEP02, is a nanoliposomal formulation of irinotecan which has demonstrated encouraging anticancer activity across a broad range of malignancies, including pancreatic cancer, esophago-gastric cancer, and colorectal cancer. This up-to-date review not only focuses on the structure, pharmacokinetics, and pharmacogenetics of Onivyde but also summarizes clinical trials and recommends Onivyde for patients with advanced solid tumors. PMID:27284250

  4. Medical therapy of maxillary sinus inflammatory myofibroblastic tumors.

    PubMed

    Kim, Jong Seung; Hong, Ki Hwan; Kim, June Sun; Song, Jong Hoon

    2016-01-01

    Inflammatory myofibroblastic tumor (IMT) in the maxillary sinus is a diagnostic challenge. As IMT has various names, it has various findings in magnetic resonance image. Although destructive pattern in computed tomography and hypermetabolism in PET CT suggest malignancy, it is debatable whether it is a tumor or inflammatory lesion. Treatment of IMT usually includes surgery. However, IMT can be dealt with medical treatment according to histologic type and localization. We report a rare case of IMT in the maxillary sinus which is controlled by medical therapy. PMID:27038822

  5. Reduction of setup uncertainties and tumor motion in the radiation therapy of lung tumors

    NASA Astrophysics Data System (ADS)

    Nelson, Christopher Lee

    Because the goal of radiation therapy is to deliver a lethal dose to the tumor, accurate information on the location of the tumor needs to be known. Margins are placed around the tumor to account for variations in the daily position of the tumor. If tumor motion and patient setup uncertainties can be reduced, margins that account for such uncertainties in tumor location in can be reduced allowing dose escalation, which in turn could potentially improve survival rates. In the first part of this study, we monitor the location of fiducials implanted in the periphery of lung tumors to determine the extent of non-gated and gated fiducial motion, and to quantify patient setup uncertainties. In the second part we determine where the tumor is when different methods of image-guided patient setup and respiratory gating are employed. In the final part we develop, validate, and implement a technique in which patient setup uncertainties are reduced by aligning patients based upon fiducial locations in projection images. Results from the first part indicate that respiratory gating reduces fiducial motion relative to motion during normal respiration and setup uncertainties when the patients were aligned each day using externally placed skin marks are large. The results from the second part indicate that current margins that account for setup uncertainty and tumor motion result in less than 2% of the tumor outside of the planning target volume (PTV) when the patient is aligned using skin marks. In addition, we found that if respiratory gating is going to be used, it is most effective if used in conjunction with image-guided patient setup. From the third part, we successfully developed, validated, and implemented on a patient a technique for aligning a moving target prior to treatment to reduce the uncertainties in tumor location. In conclusion, setup uncertainties and tumor motion are a significant problem when treating tumors located within the thoracic region. Image

  6. Tumors and new endoscopic ultrasound-guided therapies

    PubMed Central

    Carrara, Silvia; Petrone, Maria Chiara; Testoni, Pier Alberto; Arcidiacono, Paolo Giorgio

    2013-01-01

    With the advent of linear echoendoscopes, endoscopic ultrasound (EUS) has become more operative and a new field of oncological application has been opened up. From tumor staging to tissue acquisition under EUS-guided fine-needle aspiration, new operative procedures have been developed on the principle of the EUS-guided puncture. A hybrid probe combining radiofrequency with cryotechnology is now available, to be passed through the operative channel of the echoendoscope into the tumor to create an area of ablation. EUS-guided fine-needle injection is emerging as a method to deliver anti-tumoral agents inside the tumor. Ethanol lavage, with or without paclitaxel, has been proposed for the treatment of cystic tumors in non-resectable cases and complete resolution has been recorded in up to 70%-80%. Many other chemical or biological agents have been investigated for the treatment of pancreatic adenocarcinoma: activated allogenic lymphocyte culture (Cytoimplant), a replication-deficient adenovirus vector carrying the tumor necrosis factor-α gene, or an oncolytic attenuated adenovirus (ONYX-015). The potential advantage of treatment under EUS control is the real-time imaging guidance into a deep target like the pancreas which is extremely difficult to reach by a percutaneous approach. To date there are no randomized controlled trials to confirm the real clinical benefits of these treatments compared to standard therapy so it seems wise to reserve them only for experimental protocols approved by ethics committees. PMID:23596535

  7. Tumors and new endoscopic ultrasound-guided therapies.

    PubMed

    Carrara, Silvia; Petrone, Maria Chiara; Testoni, Pier Alberto; Arcidiacono, Paolo Giorgio

    2013-04-16

    With the advent of linear echoendoscopes, endoscopic ultrasound (EUS) has become more operative and a new field of oncological application has been opened up. From tumor staging to tissue acquisition under EUS-guided fine-needle aspiration, new operative procedures have been developed on the principle of the EUS-guided puncture. A hybrid probe combining radiofrequency with cryotechnology is now available, to be passed through the operative channel of the echoendoscope into the tumor to create an area of ablation. EUS-guided fine-needle injection is emerging as a method to deliver anti-tumoral agents inside the tumor. Ethanol lavage, with or without paclitaxel, has been proposed for the treatment of cystic tumors in non-resectable cases and complete resolution has been recorded in up to 70%-80%. Many other chemical or biological agents have been investigated for the treatment of pancreatic adenocarcinoma: activated allogenic lymphocyte culture (Cytoimplant), a replication-deficient adenovirus vector carrying the tumor necrosis factor-α gene, or an oncolytic attenuated adenovirus (ONYX-015). The potential advantage of treatment under EUS control is the real-time imaging guidance into a deep target like the pancreas which is extremely difficult to reach by a percutaneous approach. To date there are no randomized controlled trials to confirm the real clinical benefits of these treatments compared to standard therapy so it seems wise to reserve them only for experimental protocols approved by ethics committees. PMID:23596535

  8. Overcoming tumor resistance by heterologous adeno-poxvirus combination therapy

    PubMed Central

    Vähä-Koskela, Markus; Tähtinen, Siri; Grönberg-Vähä-Koskela, Susanna; Taipale, Kristian; Saha, Dipongkor; Merisalo-Soikkeli, Maiju; Ahonen, Marko; Rouvinen-Lagerström, Noora; Hirvinen, Mari; Veckman, Ville; Matikainen, Sampsa; Zhao, Fang; Pakarinen, Päivi; Salo, Jarmo; Kanerva, Anna; Cerullo, Vincenzo; Hemminki, Akseli

    2015-01-01

    Successful cancer control relies on overcoming resistance to cell death and on activation of host antitumor immunity. Oncolytic viruses are particularly attractive in this regard, as they lyse infected tumor cells and trigger robust immune responses during the infection. However, repeated injections of the same virus promote antiviral rather than antitumor immunity and tumors may mount innate antiviral defenses to restrict oncolytic virus replication. In this article, we have explored if alternating the therapy virus could circumvent these problems. We demonstrate in two virus-resistant animal models a substantial delay in antiviral immune- and innate cellular response induction by alternating injections of two immunologically distinct oncolytic viruses, adenovirus, and vaccinia virus. Our results are in support of clinical development of heterologous adeno-/vaccinia virus therapy of cancer. PMID:27119097

  9. MOSFET dosimetry with high spatial resolution in intense synchrotron-generated x-ray microbeams

    SciTech Connect

    Siegbahn, E. A.; Braeuer-Krisch, E.; Bravin, A.; Nettelbeck, H.; Lerch, M. L. F.; Rosenfeld, A. B.

    2009-04-15

    Various dosimeters have been tested for assessing absorbed doses with microscopic spatial resolution in targets irradiated by high-flux, synchrotron-generated, low-energy ({approx}30-300 keV) x-ray microbeams. A MOSFET detector has been used for this study since its radio sensitive element, which is extraordinarily narrow ({approx}1 {mu}m), suits the main applications of interest, microbeam radiation biology and microbeam radiation therapy (MRT). In MRT, micrometer-wide, centimeter-high, and vertically oriented swaths of tissue are irradiated by arrays of rectangular x-ray microbeams produced by a multislit collimator (MSC). We used MOSFETs to measure the dose distribution, produced by arrays of x-ray microbeams shaped by two different MSCs, in a tissue-equivalent phantom. Doses were measured near the center of the arrays and maximum/minimum (peak/valley) dose ratios (PVDRs) were calculated to determine how variations in heights and in widths of the microbeams influenced this for the therapy, potentially important parameter. Monte Carlo (MC) simulations of the absorbed dose distribution in the phantom were also performed. The results show that when the heights of the irradiated swaths were below those applicable to clinical therapy (<1 mm) the MC simulations produce estimates of PVDRs that are up to a factor of 3 higher than the measured values. For arrays of higher microbeams (i.e., 25 {mu}mx1 cm instead of 25x500 {mu}m{sup 2}), this difference between measured and simulated PVDRs becomes less than 50%. Closer agreement was observed between the measured and simulated PVDRs for the Tecomet MSC (current collimator design) than for the Archer MSC. Sources of discrepancies between measured and simulated doses are discussed, of which the energy dependent response of the MOSFET was shown to be among the most important.

  10. MOSFET dosimetry with high spatial resolution in intense synchrotron-generated x-ray microbeams.

    PubMed

    Siegbahn, E A; Bräuer-Krisch, E; Bravin, A; Nettelbeck, H; Lerch, M L F; Rosenfeld, A B

    2009-04-01

    Various dosimeters have been tested for assessing absorbed doses with microscopic spatial resolution in targets irradiated by high-flux, synchrotron-generated, low-energy (approximately 30-300 keV) x-ray microbeams. A MOSFET detector has been used for this study since its radio sensitive element, which is extraordinarily narrow (approximately 1 microm), suits the main applications of interest, microbeam radiation biology and microbeam radiation therapy (MRT). In MRT, micrometer-wide, centimeter-high, and vertically oriented swaths of tissue are irradiated by arrays of rectangular x-ray microbeams produced by a multislit collimator (MSC). We used MOSFETs to measure the dose distribution, produced by arrays of x-ray microbeams shaped by two different MSCs, in a tissue-equivalent phantom. Doses were measured near the center of the arrays and maximum/minimum (peak/valley) dose ratios (PVDRs) were calculated to determine how variations in heights and in widths of the microbeams influenced this for the therapy, potentially important parameter. Monte Carlo (MC) simulations of the absorbed dose distribution in the phantom were also performed. The results show that when the heights of the irradiated swaths were below those applicable to clinical therapy (< 1 mm) the MC simulations produce estimates of PVDRs that are up to a factor of 3 higher than the measured values. For arrays of higher microbeams (i.e., 25 microm x 1 cm instead of 25 x 500 microm2), this difference between measured and simulated PVDRs becomes less than 50%. Closer agreement was observed between the measured and simulated PVDRs for the Tecomet MSC (current collimator design) than for the Archer MSC. Sources of discrepancies between measured and simulated doses are discussed, of which the energy dependent response of the MOSFET was shown to be among the most important. PMID:19472618

  11. Potential of epigenetic therapies in the management of solid tumors

    PubMed Central

    Valdespino, Victor; Valdespino, Patricia M

    2015-01-01

    Cancer is a complex disease with both genetic and epigenetic origins. The growing field of epigenetics has contributed to our understanding of oncogenesis and tumor progression, and has allowed the development of novel therapeutic drugs. First-generation epigenetic inhibitor drugs have obtained modest clinical results in two types of hematological malignancy. Second-generation epigenetic inhibitors are in development, and have intrinsically greater selectivity for their molecular targets. Solid tumors are more genetic and epigenetically complex than hematological malignancies, but the transcriptome and epigenome biomarkers have been identified for many of these malignancies. This solid tumor molecular aberration profile may be modified using specific or quasi-specific epidrugs together with conventional and innovative anticancer treatments. In this critical review, we briefly analyze the strategies to select the targeted epigenetic changes, enumerate the second-generation epigenetic inhibitors, and describe the main signs indicating the potential of epigenetic therapies in the management of solid tumors. We also highlight the work of consortia or academic organizations that support the undertaking of human epigenetic therapeutic projects as well as some examples of transcriptome/epigenome profile determination in clinical assessment of cancer patients treated with epidrugs. There is a good chance that epigenetic therapies will be able to be used in patients with solid tumors in the future. This may happen soon through collaboration of diverse scientific groups, making the selection of targeted epigenetic aberration(s) more rapid, the design and probe of drug candidates, accelerating in vitro and in vivo assays, and undertaking new cancer epigenetic-therapy clinical trails. PMID:26346546

  12. Heavy-ion tumor therapy: Physical and radiobiological benefits

    NASA Astrophysics Data System (ADS)

    Schardt, Dieter; Elsässer, Thilo; Schulz-Ertner, Daniela

    2010-01-01

    High-energy beams of charged nuclear particles (protons and heavier ions) offer significant advantages for the treatment of deep-seated local tumors in comparison to conventional megavolt photon therapy. Their physical depth-dose distribution in tissue is characterized by a small entrance dose and a distinct maximum (Bragg peak) near the end of range with a sharp fall-off at the distal edge. Taking full advantage of the well-defined range and the small lateral beam spread, modern scanning beam systems allow delivery of the dose with millimeter precision. In addition, projectiles heavier than protons such as carbon ions exhibit an enhanced biological effectiveness in the Bragg peak region caused by the dense ionization of individual particle tracks resulting in reduced cellular repair. This makes them particularly attractive for the treatment of radio-resistant tumors localized near organs at risk. While tumor therapy with protons is a well-established treatment modality with more than 60 000 patients treated worldwide, the application of heavy ions is so far restricted to a few facilities only. Nevertheless, results of clinical phase I-II trials provide evidence that carbon-ion radiotherapy might be beneficial in several tumor entities. This article reviews the progress in heavy-ion therapy, including physical and technical developments, radiobiological studies and models, as well as radiooncological studies. As a result of the promising clinical results obtained with carbon-ion beams in the past ten years at the Heavy Ion Medical Accelerator facility (Japan) and in a pilot project at GSI Darmstadt (Germany), the plans for new clinical centers for heavy-ion or combined proton and heavy-ion therapy have recently received a substantial boost.

  13. Heavy-ion tumor therapy: Physical and radiobiological benefits

    SciTech Connect

    Schardt, Dieter; Elsaesser, Thilo; Schulz-Ertner, Daniela

    2010-01-15

    High-energy beams of charged nuclear particles (protons and heavier ions) offer significant advantages for the treatment of deep-seated local tumors in comparison to conventional megavolt photon therapy. Their physical depth-dose distribution in tissue is characterized by a small entrance dose and a distinct maximum (Bragg peak) near the end of range with a sharp fall-off at the distal edge. Taking full advantage of the well-defined range and the small lateral beam spread, modern scanning beam systems allow delivery of the dose with millimeter precision. In addition, projectiles heavier than protons such as carbon ions exhibit an enhanced biological effectiveness in the Bragg peak region caused by the dense ionization of individual particle tracks resulting in reduced cellular repair. This makes them particularly attractive for the treatment of radio-resistant tumors localized near organs at risk. While tumor therapy with protons is a well-established treatment modality with more than 60 000 patients treated worldwide, the application of heavy ions is so far restricted to a few facilities only. Nevertheless, results of clinical phase I-II trials provide evidence that carbon-ion radiotherapy might be beneficial in several tumor entities. This article reviews the progress in heavy-ion therapy, including physical and technical developments, radiobiological studies and models, as well as radiooncological studies. As a result of the promising clinical results obtained with carbon-ion beams in the past ten years at the Heavy Ion Medical Accelerator facility (Japan) and in a pilot project at GSI Darmstadt (Germany), the plans for new clinical centers for heavy-ion or combined proton and heavy-ion therapy have recently received a substantial boost.

  14. Diphtheria toxin-based targeted toxin therapy for brain tumors.

    PubMed

    Li, Yan Michael; Vallera, Daniel A; Hall, Walter A

    2013-09-01

    Targeted toxins (TT) are molecules that bind cell surface antigens or receptors such as the transferrin or interleukin-13 receptor that are overexpressed in cancer. After internalization, the toxin component kills the cell. These recombinant proteins consist of an antibody or carrier ligand coupled to a modified plant or bacterial toxin such as diphtheria toxin (DT). These fusion proteins are very effective against brain cancer cells that are resistant to radiation therapy and chemotherapy. TT have shown an acceptable profile for toxicity and safety in animal studies and early clinical trials have demonstrated a therapeutic response. This review summarizes the characteristics of DT-based TT, the animal studies in malignant brain tumors and early clinical trial results. Obstacles to the successful treatment of brain tumors include poor penetration into tumor, the immune response to DT and cancer heterogeneity. PMID:23695514

  15. Breast Tumor Heterogeneity: Source of Fitness, Hurdle for Therapy.

    PubMed

    Koren, Shany; Bentires-Alj, Mohamed

    2015-11-19

    Tumor heterogeneity impinges on prognosis, response to therapy, and metastasis. As such, heterogeneity is one of the most important and clinically relevant areas of cancer research. Breast cancer displays frequent intra- and inter-tumor heterogeneity as the result of genetic and non-genetic alterations that often enhance the vigor of cancer cells. In-depth characterization and understanding of the origin of this phenotypic and molecular diversity is paramount to improving diagnosis, the definition of prognostic and predictive biomarkers, and the design of therapeutic strategies. Here, we summarize current knowledge about sources of breast cancer heterogeneity, its consequences, and possible counter-measures. We discuss especially the impact on tumor heterogeneity of the differentiation state of the cell-of-origin, cancer cell plasticity, the microenvironment, and genetic evolution. Factors that enhance cancer cell vigor are clearly detrimental for patients. PMID:26590713

  16. Endoscopic photodynamic therapy of tumors using gold vapor laser

    NASA Astrophysics Data System (ADS)

    Kuvshinov, Yury P.; Poddubny, Boris K.; Mironov, Andrei F.; Ponomarev, Igor V.; Shental, V. V.; Vaganov, Yu. E.; Kondratjeva, T. T.; Trofimova, E. V.

    1996-01-01

    Compact sealed-off gold vapor laser (GVL) with 2 W average power and 628 nm wavelength was used for endoscopic photodynamic therapy in 20 patients with different tumors in respiratory system and upper gastrointestinal tract. Russian-made hematoporphyrin derivative (Hpd) `Photohem' was used as a photosensitizer. It was given intravenously at a dose of 2 - 2.5 mg/kg body weight 48 hours prior to tumor illumination with 628 nm light from GVL. Intermittent irradiation with GVL was done through flexible endoscope always under local anaesthesia at a power of 200 - 400 mW/sm2 and a dose of 150 - 400 J/sm2. 80% patients showed complete or partial response depending on stage of tumor. In cases of early gastric cancer all patients had complete remission with repeated negative biopsies. No major complication occurred.

  17. Dysregulated pH in Tumor Microenvironment Checkmates Cancer Therapy

    PubMed Central

    Barar, Jaleh; Omidi, Yadollah

    2013-01-01

    Introduction: The dysregulation of pH by cancerous cells of solid tumors is able to create a unique milieu that is in favor of progression, invasion and metastasis as well as chemo-/immuno-resistance traits of solid tumors. Bioelements involved in pH dysregulation provide new set of oncotargets, inhibition of which may result in better clinical outcome. Methods: To study the impacts of pH dysregulation, we investigated the tumor development and progression in relation with Warburg effect, glycolysis and formation of aberrant tumor microenvironment. Results: The upregulation of glucose transporter GLUT-1 and several enzymes involve in glycolysis exacerbates this phenomenon. The accumulation of lactic acids in cancer cells provokes upregulation of several transport machineries (MCT-1, NHE-1, CA IX and H+ pump V-ATPase) resulting in reinforced efflux of proton into extracellular fluid. This deviant event makes pH to be settled at 7.4 and 6.6 respectively in cancer cells cytoplasm and extracellular fluid within the tumor microenvironment, which in return triggers secretion of lysosomal components (various enzymes in acidic milieu with pH 5) into cytoplasm. All these anomalous phenomena make tumor microenvironment (TME) to be exposed to cocktail of various enzymes with acidic pH, upon which extracellular matrix (ECM) can be remodeled and even deformed, resulting in emergence of a complex viscose TME with high interstitial fluid pressure. Conclusion: It seems that pH dysregulation is able to remodel various physiologic functions and make solid tumors to become much more invasive and metastatic. It also can cause undesired resistance to chemotherapy and immunotherapy. Hence, cancer therapy needs to be reinforced using specific inhibitors of bioelements involved in pH dysregulation of TME in solid tumors. PMID:24455478

  18. Biomarkers in Tumor Angiogenesis and Anti-Angiogenic Therapy

    PubMed Central

    Pircher, Andreas; Hilbe, Wolfgang; Heidegger, Isabel; Drevs, Joachim; Tichelli, André; Medinger, Michael

    2011-01-01

    Tumor angiogenesis has been identified to play a critical role in tumor growth and tumor progression, and is regulated by a balance of angiogenic and anti-angiogenic cytokines. Among them VEGF (vascular endothelial growth factor) and its signaling through its receptors are of crucial relevance. Inhibition of VEGF signaling by monoclonal antibodies or small molecules (kinase inhibitors) has already been successfully established for the treatment of different cancer entities and multiple new drugs are being tested in clinical trials. However not all patients are likely to respond to these therapies, but to date there are no reliable biomarkers available to predict therapy response. Many studies integrated biomarker programs in their study protocols, thus several potential biomarkers have been identified which are currently under clinical investigation in prospective randomized studies. This review intends to give an overview of the described potential biomarkers as well as different imaging techniques such as ultrasound and magnetic resonance imaging that can indicate benefit, resistance and toxicity to anti-angiogenic therapies. PMID:22072937

  19. Intensity-Modulated Arc Therapy for Pediatric Posterior Fossa Tumors

    SciTech Connect

    Beltran, Chris; Gray, Jonathan; Merchant, Thomas E.

    2012-02-01

    Purpose: To compare intensity-modulated arc therapy (IMAT) to noncoplanar intensity-modulated radiation therapy (IMRT) in the treatment of pediatric posterior fossa tumors. Methods and Materials: Nine pediatric patients with posterior fossa tumors, mean age 9 years (range, 6-15 years), treated using IMRT were chosen for this comparative planning study because of their tumor location. Each patient's treatment was replanned to receive 54 Gy to the planning target volume (PTV) using five different methods: eight-field noncoplanar IMRT, single coplanar IMAT, double coplanar IMAT, single noncoplanar IMAT, and double noncoplanar IMAT. For each method, the dose to 95% of the PTV was held constant, and the doses to surrounding critical structures were minimized. The different plans were compared based on conformity, total linear accelerator dose monitor units, and dose to surrounding normal tissues, including the entire body, whole brain, temporal lobes, brainstem, and cochleae. Results: The doses to the target and critical structures for the various IMAT methods were not statistically different in comparison with the noncoplanar IMRT plan, with the following exceptions: the cochlear doses were higher and whole brain dose was lower for coplanar IMAT plans; the cochleae and temporal lobe doses were lower and conformity increased for noncoplanar IMAT plans. The advantage of the noncoplanar IMAT plan was enhanced by doubling the treatment arc. Conclusion: Noncoplanar IMAT results in superior treatment plans when compared to noncoplanar IMRT for the treatment of posterior fossa tumors. IMAT should be considered alongside IMRT when treatment of this site is indicated.

  20. Optical imaging predicts tumor response to anti-EGFR therapy

    PubMed Central

    Helman, Emily E; Newman, J Robert; Dean, Nichole R; Zhang, Wenyue; Zinn, Kurt R

    2010-01-01

    To evaluate cetuximab treatment in head and neck squamous cell carcinoma xenografts and cell lines, we investigated a preclinical model of head and neck squamous cell carcinoma. Head and neck squamous cell carcinoma cell lines SCC-1, FaDu, CAL27, UM-SCC-5 and UM-SCC-22A were used to generate subcutaneous flank xenografts in SCID mice. Mice were divided into control and cetuximab treatment groups, mice in the latter group received 250 µg cetuximab once weekly for four weeks. After completion of therapy, SCC-1 (p < 0.001), UM-SCC-5 (p < 0.001), UM-SCC-22A (p = 0.016) and FaDu (p = 0.007) tumors were significantly smaller than control, while CAL27 tumors were not different from controls (p = 0.90). Mice were systemically injected with 50 µg of the Cy5.5-cetuximab bioconjugate and imaged by stereomicroscopy to determine if tumor fluorescence predicted tumor response. Intact tumor fluorescence did not predict response. Tissue was harvested from untreated xenografts to evaluate ex vivo imaging. Cell lines were then evaluated in vitro for fluorescence imaging after Cy5.5-cetuximab bioconjugate labeling. The location of fluorescence observed in labeled cells was significantly different for cell lines that responded to treatment, relative to unresponsive cells. Tumors from cell lines that showed low internalized signal in vitro responded best to treatment with cetuximab. This preclinical model may aid in determining which cancer patients are best suited for cetuximab therapy. PMID:20505368

  1. Advanced multimodal nanoparticles delay tumor progression with clinical radiation therapy.

    PubMed

    Detappe, Alexandre; Kunjachan, Sijumon; Sancey, Lucie; Motto-Ros, Vincent; Biancur, Douglas; Drane, Pascal; Guieze, Romain; Makrigiorgos, G Mike; Tillement, Olivier; Langer, Robert; Berbeco, Ross

    2016-09-28

    Radiation therapy is a major treatment regimen for more than 50% of cancer patients. The collateral damage induced on healthy tissues during radiation and the minimal therapeutic effect on the organ-of-interest (target) is a major clinical concern. Ultra-small, renal clearable, silica based gadolinium chelated nanoparticles (SiGdNP) provide simultaneous MR contrast and radiation dose enhancement. The high atomic number of gadolinium provides a large photoelectric cross-section for increased photon interaction, even for high-energy clinical radiation beams. Imaging and therapy functionality of SiGdNP were tested in cynomolgus monkeys and pancreatic tumor-bearing mice models, respectively. A significant improvement in tumor cell damage (double strand DNA breaks), growth suppression, and overall survival under clinical radiation therapy conditions were observed in a human pancreatic xenograft model. For the first time, safe systemic administration and systematic renal clearance was demonstrated in both tested species. These findings strongly support the translational potential of SiGdNP for MR-guided radiation therapy in cancer treatment. PMID:27423325

  2. Effects of vascular targeting photodynamic therapy on lymphatic tumor metastasis

    NASA Astrophysics Data System (ADS)

    Fateye, B.; He, C.; Chen, B.

    2009-06-01

    Vascular targeting photodynamic therapy (vPDT) is currently in clinical trial for prostate cancer (PCa) treatment. In order to study the effect of vPDT on tumor metastasis, GFP-PC3 or PC-3 xenografts were treated with verteporfin (BPD) PDT. Vascular function was assessed by ultrasound imaging; lymph node and lung metastasis were assessed by fluorescence imaging. vPDT significantly reduced tumor blood flow within 30minutes to 2 hours of treatment. Sub-curative treatment resulted in re-perfusion within 2 weeks of treatment and increased lymph node metastasis. With curative doses, no metastasis was observed. In order to identify cellular or matrix factors and cytokines implicated, conditioned medium from BPD PDTtreated endothelial cells was incubated with PC3 cells in vitro. Tumor cell proliferation and migration was assessed. By immunoblotting, we evaluated the change in mediators of intracellular signaling or that may determine changes in tumor phenotype. Low sub-curative dose (200ng/ml BPD) of endothelial cells was associated with ~15% greater migration in PC3 cells when compared with control. This dose was also associated with sustained activation of Akt at Ser 473, an upstream effector in the Akt/ mTOR pathway that has been correlated with Gleason scores in PCa and with survival and metastasis in vitro and in vivo. In conclusion, the study implicates efficacy of PDT of endothelial cells as an important determinant of its consequences on adjacent tumor proliferation and metastasis.

  3. Localized electric field of plasmonic nanoplatform enhanced photodynamic tumor therapy.

    PubMed

    Li, Yiye; Wen, Tao; Zhao, Ruifang; Liu, Xixi; Ji, Tianjiao; Wang, Hai; Shi, Xiaowei; Shi, Jian; Wei, Jingyan; Zhao, Yuliang; Wu, Xiaochun; Nie, Guangjun

    2014-11-25

    Near-infrared plasmonic nanoparticles demonstrate great potential in disease theranostic applications. Herein a nanoplatform, composed of mesoporous silica-coated gold nanorods (AuNRs), is tailor-designed to optimize the photodynamic therapy (PDT) for tumor based on the plasmonic effect. The surface plasmon resonance of AuNRs was fine-tuned to overlap with the exciton absorption of indocyanine green (ICG), a near-infrared photodynamic dye with poor photostability and low quantum yield. Such overlap greatly increases the singlet oxygen yield of incorporated ICG by maximizing the local field enhancement, and protecting the ICG molecules against photodegradation by virtue of the high absorption cross section of the AuNRs. The silica shell strongly increased ICG payload with the additional benefit of enhancing ICG photostability by facilitating the formation of ICG aggregates. As-fabricated AuNR@SiO2-ICG nanoplatform enables trimodal imaging, near-infrared fluorescence from ICG, and two-photon luminescence/photoacoustic tomography from the AuNRs. The integrated strategy significantly improved photodynamic destruction of breast tumor cells and inhibited the growth of orthotopic breast tumors in mice, with mild laser irradiation, through a synergistic effect of PDT and photothermal therapy. Our study highlights the effect of local field enhancement in PDT and demonstrates the importance of systematic design of nanoplatform to greatly enhancing the antitumor efficacy. PMID:25375193

  4. Microbeam-coupled capillary electrophoresis.

    PubMed

    Garty, G; Ehsan, M U; Buonanno, M; Yang, Z; Sweedler, J V; Brenner, D J

    2015-09-01

    Within the first few microseconds following a charged particle traversal of a cell, numerous oxygen and nitrogen radicals are formed along the track. Presented here is a method, using capillary electrophoresis, for simultaneous measurement, within an individual cell, of specific reactive oxygen species, such as the superoxide radical ([Formula: see text]) as well as the native and oxidised forms of glutathione, an ubiquitous anti-oxidant that assists the cell in coping with these species. Preliminary data are presented as well as plans for integrating this system into the charged particle microbeam at Columbia University. PMID:25870435

  5. Anti-tumor immunity generated by photodynamic therapy in a metastatic murine tumor model

    NASA Astrophysics Data System (ADS)

    Castano, Ana P.; Hamblin, Michael R.

    2005-04-01

    Photodynamic therapy (PDT) is a modality for the treatment of cancer involving excitation of photosensitizers with harmless visible light producing reactive oxygen species. The major biological effects of PDT are apoptosis of tumor cells, destruction of the blood supply and activation of the immune system. The objective of this study is to compare in an animal model of metastatic cancer, PDT alone and PDT combined with low-dose cyclophosphamide (CY). Since the tumor we used is highly metastatic, it is necessary to generate anti-tumor immunity using PDT to both cure the primary tumor and prevent death from metastasis. This immunity may be potentiated by low dose CY. In our model we used J774 cells (a Balb/c reticulum cell sarcoma line with the characteristics of macrophages) and the following PDT regimen: benzoporphyrin derivative monoacid ring A (BPD, 2mg/kg injected IV followed after 15 min by 150 J/cm2 of 690-nm light). CY (50 mg/kg i.p.) was injected 48 hours before light delivery. BPD-PDT led to complete regression of the primary tumor in more than half the mice but no permanent cures were obtained. BPD-PDT in combination with CY led to 60% permanent cures. CY alone gave no permanent cures but did provide a survival advantage. To probe permanent immunity cured animals were rechallenged with the same tumor cell line and the tumors were rejected in 71% of mice cured with BPD-PDT plus CY. We conclude that BPD-PDT in combination with CY gives best overall results and that this is attributable to immunological response activation in addition to PDT-mediated destruction of the tumor.

  6. Anti-tumor effect of Radix Paeoniae Rubra extract on mice bladder tumors using intravesical therapy

    PubMed Central

    Lin, Mei-Yi; Chiang, Su-Yin; Li, Yi-Zhen; Chen, Mei-Fang; Chen, Yueh-Sheng; Wu, Jin-Yi; Liu, Yi-Wen

    2016-01-01

    Radix Paeoniae Rubra (RPR) is the dried root of Paeonia lactiflora Pallas and Paeonia veitchii Lynch, and is a herbal medicine that is widely used in traditional Chinese medicine for the treatment of blood-heat and blood-stasis syndrome, similarly to Cortex Moutan. The present study identified the same three components in RPR and Cortex Moutan extracts. In addition, it has been reported that RPR has an anti-cancer effect. Bladder cancer is the seventh most common type of cancer worldwide. Due to the high recurrence rate, identifying novel drugs for bladder cancer therapy is essential. In the present study, RPR extract was evaluated as a bladder cancer therapy in vitro and in vivo. The present results revealed that RPR extract reduced the cell viability of bladder cancer cells with a half maximal inhibitory concentration of 1–3 mg/ml, and had an extremely low cytotoxic effect on normal urothelial cells. Additionally, RPR decreased certain cell cycle populations, predominantly cells in the G1 phase, and caused a clear sub-G increase. In a mouse orthotopic bladder tumor model, intravesical application of RPR extract decreased the bladder tumor size without altering the blood biochemical parameters of the mice. In summary, the present results demonstrate the anti-proliferative properties of RPR extract on bladder cancer cells, and its anti-bladder tumor effect in vivo. Compared to Cortex Moutan extract, RPR extract may provide a more effective alternative therapeutic strategy for the intravesical therapy of superficial bladder cancer. PMID:27446367

  7. Targeted Cancer Therapy with Tumor Necrosis Factor-Alpha

    PubMed Central

    Cai, Weibo; Kerner, Zachary J.; Hong, Hao; Sun, Jiangtao

    2013-01-01

    Tumor necrosis factor-alpha (TNF-α), a member of the TNF superfamily, was the first cytokine to be evaluated for cancer biotherapy. However, the clinical use of TNF-α is severely limited by its toxicity. Currently, TNF-α is administered only through locoregional drug delivery systems such as isolated limb perfusion and isolated hepatic perfusion. To reduce the systemic toxicity of TNF-α, various strategies have been explored over the last several decades. This review summarizes current state-of-the-art targeted cancer therapy using TNF-α. Passive targeting, cell-based therapy, gene therapy with inducible or tissue-specific promoters, targeted polymer-DNA complexes, tumor pre-targeting, antibody-TNF-α conjugate, scFv/TNF-α fusion proteins, and peptide/TNF-α fusion proteins have all been investigated to combat cancer. Many of these agents are already in advanced clinical trials. Molecular imaging, which can significantly speed up the drug development process, and nanomedicine, which can integrate both imaging and therapeutic components, has the potential to revolutionize future cancer patient management. Cooperative efforts from scientists within multiple disciplines, as well as close partnerships among many organizations/entities, are needed to quickly translate novel TNF-α-based therapeutics into clinical investigation. PMID:24115841

  8. Dynamic Lung Tumor Tracking for Stereotactic Ablative Body Radiation Therapy

    PubMed Central

    Kunos, Charles A.; Fabien, Jeffrey M.; Shanahan, John P.; Collen, Christine; Gevaert, Thierry; Poels, Kenneth; Van den Begin, Robbe; Engels, Benedikt; De Ridder, Mark

    2015-01-01

    Physicians considering stereotactic ablative body radiation therapy (SBRT) for the treatment of extracranial cancer targets must be aware of the sizeable risks for normal tissue injury and the hazards of physical tumor miss. A first-of-its-kind SBRT platform achieves high-precision ablative radiation treatment through a combination of versatile real-time imaging solutions and sophisticated tumor tracking capabilities. It uses dual-diagnostic kV x-ray units for stereoscopic open-loop feedback of cancer target intrafraction movement occurring as a consequence of respiratory motions and heartbeat. Image-guided feedback drives a gimbaled radiation accelerator (maximum 15 x 15 cm field size) capable of real-time ±4 cm pan-and-tilt action. Robot-driven ±60° pivots of an integrated ±185° rotational gantry allow for coplanar and non-coplanar accelerator beam set-up angles, ultimately permitting unique treatment degrees of freedom. State-of-the-art software aids real-time six dimensional positioning, ensuring irradiation of cancer targets with sub-millimeter accuracy (0.4 mm at isocenter). Use of these features enables treating physicians to steer radiation dose to cancer tumor targets while simultaneously reducing radiation dose to normal tissues. By adding respiration correlated computed tomography (CT) and 2-[18F] fluoro-2-deoxy-ᴅ-glucose (18F-FDG) positron emission tomography (PET) images into the planning system for enhanced tumor target contouring, the likelihood of physical tumor miss becomes substantially less1. In this article, we describe new radiation plans for the treatment of moving lung tumors. PMID:26131774

  9. Development of multifunctional nanoparticles for brain tumor diagnosis and therapy

    NASA Astrophysics Data System (ADS)

    Veiseh, Omid

    Magnetic nanoparticles (MNPs) represent a class of non-invasive imaging agents developed for magnetic resonance (MR) imaging and drug delivery. MNPs have traditionally been developed for disease imaging via passive targeting, but recent advances in nanotechnology have enabled cellular-specific targeting, drug delivery and multi-modal imaging using these nanoparticles. Opportunities now exist to engineer MNP with designated features (e.g., size, coatings, and molecular functionalizations) for specific biomedical applications. The goal of this interdisciplinary research project is to develop targeting multifunctional nanoparticles, serving as both contrast agents and drug carriers that can effectively pass biological barriers, for diagnosis, staging and treatment of brain tumors. The developed nanoparticle system consists of a superparamagnetic iron oxide nanoparticle core (NP) and a shell comprised of biodegradable polymers such as polyethylene glycol (PEG) and chitosan. Additionally, near-infrared fluorescing (NIRF) molecules were integrated onto the NP shell to enable optical detection. Tumor targeting was achieved by the addition of chlorotoxin, a peptide with that has high affinity to 74 out of the 79 classifications of primary brain tumors and ability to illicit a therapeutic effect. This novel NP system was tested both in vitro and in vivo and was shown to specifically target gliomas in tissue culture and medulloblastomas in transgenic mice with an intact blood brain barriers (BBB), and delineate tumor boundaries in both MR and optical imaging. Additionally, the therapeutic potential of this NP system was explored in vitro, which revealed a unique nanoparticle-enabled pathway that enhances the therapeutic potential of bound peptides by promoting the internalization of membrane bound cell surface receptors. This NP system was further modified with siRNA and evaluated as a carrier for brain tumor targeted gene therapy. Most significantly, the evaluation of

  10. Phthalocyanine-labeled LDL for tumor imaging and photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Li, Hui; Marotta, Diane; Kim, Soungkyoo; Chance, Britton; Glickson, Jerry D.; Busch, Theresa M.; Zheng, Gang

    2005-01-01

    Current limitation of both near-infrared (NIR) tumor imaging and photodynamic therapy (PDT) is their lack of sufficient tumor-to-tissue contrast due to the relatively non-specific nature of delivering dye to the tumor, which has led to false negatives for NIR imaging and inadequate therapeutic ratio for PDT. Hence, agents targeting "cancer signatures", i.e. molecules that accumulate selectively in cancer cells, are particular attractive. One of these signatures is low-density-lipoprotein receptor (LDLR), which is overexpressed in many tumors. We have developed pyropheophorbide cholesterol oleate reconstituted LDL as a LDLR-targeting photosensitizer (PS) and demonstrated its LDLR-mediated uptake in vitro and in vivo. To improve the labeling efficiency for achieving high probe/protein ratio, tetra-t-butyl silicon phthalocyanine bearing two oleate moieties at its axial positions, (tBu)4SiPcBOA, was designed and synthesized. This compound was designed to 1) prevent the PS aggregation; 2) improve the PS solubility in non-polar solvent; and 3) maximize the PS binding to LDL phospholipid monolayer. Using this novel strategy, (tBu)4SiPcBOA was reconstituted into LDL (r-SiPcBOA-LDL) with a very high payload (500:1 molar ratio). In addition, (tBu)4SiPcBOA reconstituted acetylated LDL (r-SiPcBOA)-AcLDL with similar payload was also prepared. Since Ac-LDL cannot bind to LDLR, (r-SiPcBOA)-AcLDL can serve as the negative control to evaluate LDLR targeting specificity. For biological evaluation of these new agents, confocal microscopy and in vitro PDT protocols were performed using LDLR-overexpressing human hepatoblastoma G2 (HepG2) tumor model. These studies suggest that LDL serves as a delivery vehicle to bring large amount of the NIR/PDT agents selectively to tumor cells overexpressing LDLR.

  11. Mechanisms of tumor destruction caused by photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Zhou, Chuannong

    2005-07-01

    Photodynamic therapy is a relatively new treatment modality and is becoming widely accepted as a standard treatment of a variety of solid tumors. This includes palliative treatments for advanced or obstructive cancers in many organs as well as a curative treatment for some early cancers and pre-cancerous lesions. It has been approved by health authorities in a number of countries in America, Europe and Asia [1]. PDT is a procedure requiring 3 elements: photosensitizer, light and oxygen [2]. The typical technique involves an intravenous administration of a photosensitizing agent, which is preferentially accumulated or retained in tumor tissue, followed by irradiation of the tumor area with light of appropriate wavelength. In the presence of oxygen it generates highly reactive and cytotoxic molecular species, in particular, singlet oxygen (1O2), which may oxidize various bio-molecules and finally leading to cell death and tumor destruction [3]. The most widely used photosensitizer in clinical treatment of cancers is Photofrin (porfimer sodium), and most widely used light sources are lasers of various types, in recent years preferentially, diode laser, which emits a red light of 630 nm wavelength.

  12. Detecting Tumor Metastases: The Road to Therapy Starts Here.

    PubMed

    Menezes, M E; Das, S K; Minn, I; Emdad, L; Wang, X-Y; Sarkar, D; Pomper, M G; Fisher, P B

    2016-01-01

    Metastasis is the complex process by which primary tumor cells migrate and establish secondary tumors in an adjacent or distant location in the body. Early detection of metastatic disease and effective therapeutic options for targeting these detected metastases remain impediments to effectively treating patients with advanced cancers. If metastatic lesions are identified early, patients might maximally benefit from effective early therapeutic interventions. Further, monitoring patients whose primary tumors are effectively treated for potential metastatic disease onset is also highly valuable. Finally, patients with metastatic disease can be monitored for efficacy of specific therapeutic interventions through effective metastatic detection techniques. Thus, being able to detect and visualize metastatic lesions is key and provides potential to greatly improve overall patient outcomes. In order to achieve these objectives, researchers have endeavored to mechanistically define the steps involved in the metastatic process as well as ways to effectively detect metastatic progression. We presently overview various preclinical and clinical in vitro and in vivo assays developed to more efficiently detect tumor metastases, which provides the foundation for developing more effective therapies for this invariably fatal component of the cancerous process. PMID:27613128

  13. Irinotecan and Whole-Brain Radiation Therapy in Treating Patients With Brain Metastases From Solid Tumors

    ClinicalTrials.gov

    2010-03-15

    Brain and Central Nervous System Tumors; Cognitive/Functional Effects; Long-term Effects Secondary to Cancer Therapy in Adults; Long-term Effects Secondary to Cancer Therapy in Children; Poor Performance Status; Unspecified Adult Solid Tumor, Protocol Specific; Unspecified Childhood Solid Tumor, Protocol Specific

  14. Salvage therapy in patients with germ cell tumors.

    PubMed

    Einhorn, Lawrence H

    2015-01-01

    Testicular cancer is the most curable metastatic solid tumor. Initial chemotherapy is evidence based with risk stratification into three prognostic categories: good, intermediate, and advanced disease. Guidelines for disease management following progression after initial cisplatin combination chemotherapy are less clear. Options include salvage surgery for patients with anatomically confined relapse, standard-dose cisplatin combination chemotherapy, or high-dose chemotherapy with carboplatin plus etoposide with peripheral blood stem cell transplantation. Proper interpretation of a presumed relapse can be complicated. Growing masses on imaging studies might reflect a growing teratoma. Persistent elevations of serum human chorionic gonadotropin (hCG) or alpha fetoprotein (AFP) are only an indication for salvage therapy if there is a definitive rise in the tumor marker. Elevated and rising serum hCG as the only evidence of recurrence can be because of cross reactivity with luteinizing hormone or usage of marijuana rather than progressive cancer. Elevated liver function tests can cause rising serum AFP. PMID:25993183

  15. Biocompatible conjugated polymer nanoparticles for efficient photothermal tumor therapy.

    PubMed

    Geng, Junlong; Sun, Chunyang; Liu, Jie; Liao, Lun-De; Yuan, Youyong; Thakor, Nitish; Wang, Jun; Liu, Bin

    2015-04-01

    Conjugated polymers (CPs) with strong near-infrared (NIR) absorption and high heat conversion efficiency have emerged as a new generation of photothermal therapy (PTT) agents for cancer therapy. An efficient strategy to design NIR absorbing CPs with good water dispersibility is essential to achieve excellent therapeutic effect. In this work, poly[9,9-bis(4-(2-ethylhexyl)phenyl)fluorene-alt-co-6,7-bis(4-(hexyloxy)phenyl)-4,9-di(thiophen-2-yl)-thiadiazoloquinoxaline] (PFTTQ) is synthesized through the combination of donor-acceptor moieties by Suzuki polymerization. PFTTQ nanoparticles (NPs) are fabricated through a precipitation approach using 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2000 ) as the encapsulation matrix. Due to the large NIR absorption coefficient (3.6 L g(-1) cm(-1) ), the temperature of PFTTQ NP suspension (0.5 mg/mL) could be rapidly increased to more than 50 °C upon continuous 808 nm laser irradiation (0.75 W/cm(2) ) for 5 min. The PFTTQ NPs show good biocompatibility to both MDA-MB-231 cells and Hela cells at 400 μg/mL of NPs, while upon laser irradiation, effective cancer cell killing is observed at a NP concentration of 50 μg/mL. Moreover, PFTTQ NPs could efficiently ablate tumor in in vivo study using a Hela tumor mouse model. Considering the large amount of NIR absorbing CPs available, the general encapsulation strategy will enable the development of more efficient PTT agents for cancer or tumor therapy. PMID:25367500

  16. On molecular mechanism of the photodynamic therapy of tumors

    NASA Astrophysics Data System (ADS)

    Mostovnikov, Vasili A.; Mostovnikova, Galina R.; Plavski, Vitali Y.; Tretjakov, S. A.

    1995-01-01

    In this work we present the experimental results indicating that the photodestruction (inactivation) of glycolysis enzymes located in mitochondria and responsible for the energy providing of malignant tumors, could serve as a possible molecular mechanism of a photodynamic therapy of cancer. The formation of complexes between the glycolysis enzymes and sensitizer favors can lead to an effective photodestruction of the former [in the experiments lactate dehydrogenase (LDH), pyruvate kinase (PK), glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and water-soluble tetra(carboxiphenyl)porphyrine [T(CP)P] (the analogue of coprorphyrin) were used as photosensitizer.

  17. Targeted photodynamic therapy--a promising strategy of tumor treatment.

    PubMed

    Bugaj, Andrzej M

    2011-07-01

    Targeted therapy is a new promising therapeutic strategy, created to overcome growing problems of contemporary medicine, such as drug toxicity and drug resistance. An emerging modality of this approach is targeted photodynamic therapy (TPDT) with the main aim of improving delivery of photosensitizer to cancer tissue and at the same time enhancing specificity and efficiency of PDT. Depending on the mechanism of targeting, we can divide the strategies of TPDT into "passive", "active" and "activatable", where in the latter case the photosensitizer is activated only in the target tissue. In this review, contemporary strategies of TPDT are described, including new innovative concepts, such as targeting assisted by peptides and aptamers, multifunctional nanoplatforms with navigation by magnetic field or "photodynamic molecular beacons" activatable by enzymes and nucleic acid. The imperative of introducing a new paradigm of PDT, focused on the concepts of heterogeneity and dynamic state of tumor, is also called for. PMID:21547329

  18. Tin Tungstate Nanoparticles: A Photosensitizer for Photodynamic Tumor Therapy.

    PubMed

    Seidl, Carmen; Ungelenk, Jan; Zittel, Eva; Bergfeldt, Thomas; Sleeman, Jonathan P; Schepers, Ute; Feldmann, Claus

    2016-03-22

    The nanoparticulate inorganic photosensitizer β-SnWO4 is suggested for photodynamic therapy (PDT) of near-surface tumors via reiterated 5 min blue-light LED illumination. β-SnWO4 nanoparticles are obtained via water-based synthesis and comprise excellent colloidal stability under physiological conditions and high biocompatibility at low material complexity. Antitumor and antimetastatic effects were investigated with a spontaneously metastasizing (4T1 cells) orthotopic breast cancer BALB/c mouse model. Besides protamine-functionalized β-SnWO4 (23 mg/kg of body weight, in PBS buffer), chemotherapeutic doxorubicin was used as positive control (2.5 mg/kg of body weight, in PBS buffer) and physiological saline (DPBS) as a negative control. After 21 days, treatment with β-SnWO4 resulted in a clearly inhibited growth of the primary tumor (all tumor volumes below 3 cm(3)) as compared to the doxorubicin and DPBS control groups (volumes up to 6 cm(3)). Histological evaluations of lymph nodes and lungs as well as the volume of ipsilateral lymph nodes show a remarkable antimetastatic effect being similar to chemotherapeutic doxorubicin but-according to blood counts-at significantly reduced side effects. On the basis of low material complexity, high cytotoxicity under blue-light LED illumination at low dark and long-term toxicity, β-SnWO4 can be an interesting addition to PDT and the treatment of near-surface tumors, including skin cancer, esophageal/gastric/colon tumors as well as certain types of breast cancer. PMID:26894966

  19. Differential growth and responsiveness to cancer therapy of tumor cells in different environments.

    PubMed

    Alsaggar, Mohammad; Yao, Qian; Cai, Houjian; Liu, Dexi

    2016-02-01

    Tumor metastasis often confers poor prognosis for cancer patients due to lack of comprehensive strategy in dealing with cells growing in different environment. Current anticancer therapies have incomplete effectiveness because they were designed assuming metastatic tumors behave similarly in different organs. We hypothesize that tumors growing in different sites are biologically heterogeneous in growth potential, as well as in tumor response to anti-cancer therapies. To test this hypothesis, we have developed a multi-organ tumor growth model using the hydrodynamic cell delivery method to establish simultaneous and quantifiable tumor growth in the liver, lungs and kidneys of mice. We demonstrated that growth rate of melanoma tumor in the liver is higher than that of the lungs and kidneys. Tumors in the lungs and kidneys grew minimally at the early stage and aggressively thereafter. Tumors in different organs were also heterogeneous in response to chemotherapy and immune gene therapy using dacarbazine and interferon beta gene, respectively. Lung tumors responded to chemotherapy better than tumors in the liver, but showed minimal response to interferon beta gene therapy, compared to tumors in the liver and kidneys. We also confirmed differential tumor growth of the metastatic colon cancer in mice. Our results point out the importance of a better understanding of the differences in tumor growing in diverse environments. The biological heterogeneity of metastatic tumors demonstrated in this study necessitates establishing new drug screening strategies that take into account the environmental difference at the sites of tumor growth. PMID:26476830

  20. Molecular Magnetic Resonance Imaging of Tumor Response to Therapy

    PubMed Central

    Shuhendler, Adam J.; Ye, Deju; Brewer, Kimberly D.; Bazalova-Carter, Magdalena; Lee, Kyung-Hyun; Kempen, Paul; Dane Wittrup, K.; Graves, Edward E.; Rutt, Brian; Rao, Jianghong

    2015-01-01

    Personalized cancer medicine requires measurement of therapeutic efficacy as early as possible, which is optimally achieved by three-dimensional imaging given the heterogeneity of cancer. Magnetic resonance imaging (MRI) can obtain images of both anatomy and cellular responses, if acquired with a molecular imaging contrast agent. The poor sensitivity of MRI has limited the development of activatable molecular MR contrast agents. To overcome this limitation of molecular MRI, a novel implementation of our caspase-3-sensitive nanoaggregation MRI (C-SNAM) contrast agent is reported. C-SNAM is triggered to self-assemble into nanoparticles in apoptotic tumor cells, and effectively amplifies molecular level changes through nanoaggregation, enhancing tissue retention and spin-lattice relaxivity. At one-tenth the current clinical dose of contrast agent, and following a single imaging session, C-SNAM MRI accurately measured the response of tumors to either metronomic chemotherapy or radiation therapy, where the degree of signal enhancement is prognostic of long-term therapeutic efficacy. Importantly, C-SNAM is inert to immune activation, permitting radiation therapy monitoring. PMID:26440059

  1. Subacute brain atrophy after radiation therapy for malignant brain tumor

    SciTech Connect

    Asai, A.; Matsutani, M.; Kohno, T.; Nakamura, O.; Tanaka, H.; Fujimaki, T.; Funada, N.; Matsuda, T.; Nagata, K.; Takakura, K.

    1989-05-15

    Brain atrophy with mental and neurologic deterioration developing a few months after radiation therapy in patients without residual or recurrent brain tumors has been recognized. Two illustrative case reports of this pathologic entity are presented. Six autopsy cases with this entity including the two cases were reviewed neurologically, radiographically, and histopathologically. All patients presented progressive disturbances of mental status and consciousness, akinesia, and tremor-like involuntary movement. Computerized tomography (CT) demonstrated marked enlargement of the ventricles, moderate widening of the cortical sulci, and a moderately attenuated CT number for the white matter in all six patients. Four of the six patients had CSF drainage (ventriculoperitoneal shunt or continuous lumbar drainage), however, none of them improved. Histologic examination demonstrated swelling and loss of the myelin sheath in the white matter in all patients, and reactive astrocytosis in three of the six patients. Neither prominent neuronal loss in the cerebral cortex or basal ganglia, nor axonal loss in the white matter was generally identified. The blood vessels of the cerebral cortex and white matter were normal. Ependymal layer and the surrounding brain tissue were normal in all patients. These findings suggested that this pathologic condition results from demyelination secondary to direct neurotoxic effect of irradiation. The authors' previous report was reviewed and the differential diagnoses, the risk factors for this pathologic entity, and the indication for radiation therapy in aged patients with a malignant brain tumor are discussed.

  2. Boron Neutron Capture Therapy for Malignant Brain Tumors.

    PubMed

    Miyatake, Shin-Ichi; Kawabata, Shinji; Hiramatsu, Ryo; Kuroiwa, Toshihiko; Suzuki, Minoru; Kondo, Natsuko; Ono, Koji

    2016-07-15

    Boron neutron capture therapy (BNCT) is a biochemically targeted radiotherapy based on the nuclear capture and fission reactions that occur when non-radioactive boron-10, which is a constituent of natural elemental boron, is irradiated with low energy thermal neutrons to yield high linear energy transfer alpha particles and recoiling lithium-7 nuclei. Therefore, BNCT enables the application of a high dose of particle radiation selectively to tumor cells in which boron-10 compound has been accumulated. We applied BNCT using nuclear reactors for 167 cases of malignant brain tumors, including recurrent malignant gliomas, newly diagnosed malignant gliomas, and recurrent high-grade meningiomas from January 2002 to May 2014. Here, we review the principle and history of BNCT. In addition, we introduce fluoride-18-labeled boronophenylalanine positron emission tomography and the clinical results of BNCT for the above-mentioned malignant brain tumors. Finally, we discuss the recent development of accelerators producing epithermal neutron beams. This development could provide an alternative to the current use of specially modified nuclear reactors as a neutron source, and could allow BNCT to be performed in a hospital setting. PMID:27250576

  3. Boron Neutron Capture Therapy for Malignant Brain Tumors

    PubMed Central

    MIYATAKE, Shin-Ichi; KAWABATA, Shinji; HIRAMATSU, Ryo; KUROIWA, Toshihiko; SUZUKI, Minoru; KONDO, Natsuko; ONO, Koji

    2016-01-01

    Boron neutron capture therapy (BNCT) is a biochemically targeted radiotherapy based on the nuclear capture and fission reactions that occur when non-radioactive boron-10, which is a constituent of natural elemental boron, is irradiated with low energy thermal neutrons to yield high linear energy transfer alpha particles and recoiling lithium-7 nuclei. Therefore, BNCT enables the application of a high dose of particle radiation selectively to tumor cells in which boron-10 compound has been accumulated. We applied BNCT using nuclear reactors for 167 cases of malignant brain tumors, including recurrent malignant gliomas, newly diagnosed malignant gliomas, and recurrent high-grade meningiomas from January 2002 to May 2014. Here, we review the principle and history of BNCT. In addition, we introduce fluoride-18-labeled boronophenylalanine positron emission tomography and the clinical results of BNCT for the above-mentioned malignant brain tumors. Finally, we discuss the recent development of accelerators producing epithermal neutron beams. This development could provide an alternative to the current use of specially modified nuclear reactors as a neutron source, and could allow BNCT to be performed in a hospital setting. PMID:27250576

  4. Skeletal sequelae of radiation therapy for malignant childhood tumors

    SciTech Connect

    Butler, M.S.; Robertson, W.W. Jr.; Rate, W.; D'Angio, G.J.; Drummond, D.S. )

    1990-02-01

    One hundred forty-three patients who received radiation therapy for childhood tumors, and survived to the age of skeletal maturity, were studied by retrospective review of oncology records and roentgenograms. Diagnoses for the patients were the following: Hodgkin's lymphoma (44), Wilms's tumor (30), acute lymphocytic leukemia (26), non-Hodgkin's lymphoma (18), Ewing's sarcoma (nine), rhabdomyosarcoma (six), neuroblastoma (six), and others (four). Age at the follow-up examination averaged 18 years (range, 14-28 years). Average length of follow-up study was 9.9 years (range, two to 18 years). Asymmetry of the chest and ribs was seen in 51 (36%) of these children. Fifty (35%) had scoliosis; 14 had kyphosis. In two children, the scoliosis was treated with a brace, while one developed significant kyphosing scoliosis after laminectomy and had spinal fusion. Twenty-three (16%) patients complained of significant pain at the radiation sites. Twelve of the patients developed leg-length inequality; eight of those were symptomatic. Three patients developed second primary tumors. Currently, the incidence of significant skeletal sequelae is lower and the manifestations are less severe than reported in the years from 1940 to 1970. The reduction in skeletal complications may be attributed to shielding of growth centers, symmetric field selection, decreased total radiation doses, and sequence changes in chemotherapy.

  5. Molecular targets in Gastrointestinal Stromal Tumors (GIST) therapy.

    PubMed

    Braconi, C; Bracci, R; Cellerino, R

    2008-08-01

    Gastrointestinal Stromal Tumors (GISTs) are the most common mesenchimal tumors of the gastrointestinal tract. Such tumors usually have activating mutations in either KIT (75-80%) or Platelet Derived Growth Factor Receptor alpha (PDGFRa) (5-10%) which lead to ligand-independent signal transduction. Targeting these activated proteins with Imatinib mesylate, a small-molecule kinase inhibitor, has proven useful in the treatment of recurrent or metastatic GISTs. However, more than half of patients develop resistance to Imatinib after about 2 years. Therefore, other targets have been studying in order to implement the therapeutical armamentarium for this disease. Sunitinib malate is an oral multikinase inhibitor that targets several receptor tyrosine kinases and has proved to prolong survival in Imatinib-resistant patients. Other molecules, such as Nilotinib, Sorafenib and Dasatinib were shown to be useful in Imatinib resistant mutant cell lines and the results of their activity in humans are being awaited. Recent evidence suggests that GIST cells acquire the capability to escape from the control of KIT and PDGFRa through the activation of alternative pathways. Therefore, further effort should be invested in the discovery of new signaling pathways, such as AXL, MET, IGF-R, which might be involved in the evolution of the disease. After a description of KIT and PDGFRa as known targets of anti-GIST treatments, we review other mechanisms and mediators that might be potential targets of new therapies, providing a comprehensive revision of the new molecular strategies under investigation. PMID:18690842

  6. Endothelin receptors as novel targets in tumor therapy

    PubMed Central

    Bagnato, Anna; Natali, Pier Giorgio

    2004-01-01

    The endotelin (ET) axis, that includes ET-1, ET-2, ET-3, and the ET receptors, ETA and ETB, plays an important physiological role, as modulator of vasomotor tone, tissue differentiation and development, cell proliferation, and hormone production. Recently, investigations into the role of the ET axis in mitogenesis, apoptosis inhibition, invasiveness, angiogenesis and bone remodeling have provided evidence of the importance of the ET-1 axis in cancer. Data suggest that ET-1 participates in the growth and progression of a variety of tumors such as prostatic, ovarian, renal, pulmonary, colorectal, cervical, breast carcinoma, Kaposi's sarcoma, brain tumors, melanoma, and bone metastases. ET-1 receptor antagonists beside providing ideal tools for dissecting the ET axis at molecular level have demonstrated their potential in developing novel therapeutic opportunity. The major relevance of ETA receptor in tumor development has led to an extensive search of highly selective antagonists. Atrasentan, one of such antagonists, is orally bioavailable, has suitable pharmacokinetic and toxicity profiles for clinical use. Preliminary data from clinical trials investigating atrasentan in patients with prostate cancer are encouraging. This large body of evidence demonstrates the antitumor activity of endothelin receptor antagonists and provides a rationale for the clinical evaluation of these molecules alone and in combination with cytotoxic drugs or molecular inhibitors leading to a new generation of anticancer therapies targeting endothelin receptors. PMID:15165288

  7. New approaches to photodynamic therapy of tumors with Al phthalocyanine

    NASA Astrophysics Data System (ADS)

    Vakoulovskaya, Elena G.; Chental, V. V.; Kuvshinov, Yury P.; Poddubny, Boris K.

    1999-12-01

    The aim of the study was to determine the efficacy of photodynamic therapy (PDT) of tumors of different localization and histology with new photosensitizer aluminum sulfonated phthalocyanine (Photosense, Russia). PDT have been provided in 106 patients with different tumors. The initial dose (2.0 - 2.5 mg/kg) of PHS was significantly reduced till 0.5 - 0.8 mg/kg during clinical trials because of phototoxicity. The results of PDT, side effects and ways of their correction and prevention, as well as possibility to work out less toxic regimes of PDT with photosense, choice of laser and type of irradiation are discussed. Efficacy of PDT depended on tumor size and it's histological type. Using low doses of PHS we've reduced the phototoxicity of sensitizer with the same direct effectiveness of treatment. Undesirable changes in plasma content of antioxidants by means of high pressure liquid chromatography have been found in patients after PHS injection. Influence of short-term and long-term supplementation with beta- carotene and vitamin E on this parameters are discussed.

  8. Circulating tumor cells in breast cancer beyond the genotype of primary tumor for tailored therapy.

    PubMed

    Ren, Chuanli; Han, Chongxu; Fu, Deyuan; Wang, Daxin; Chen, Hui; Chen, Yong; Shen, Ming

    2016-04-01

    Although TNM staging based on tumor, node lymph status and metastasis status-is the most widely used method in the clinic to classify breast cancer (BC) and assess prognosis, it offers limited information for different BC subgroups. Circulating tumor cells (CTCs) are regarded as minimal residual disease and are proven to have a strong relationship with BC. Detection of ≥5 CTCs per 7.5 mL in peripheral blood predicts poor prognosis in metastatic BC irrespective of other clinical parameters, whereas, in early-stage BC, detection of CK19(+) CTCs are also associated with poor prognosis. Increasing data and clinical trials show that CTCs can improve prognostic accuracy and help tailor treatment for patients with BC. However, heterogeneous CTCs in the process of an epithelial-mesenchymal transition (EMT) in BC makes it a challenge to detect these rare cells. Moreover, the genotypic and phenotypic features of CTCs are different from primary BC tumors. Molecular analysis of CTCs in BC may benefit patients by identifying those amenable to tailored therapy. We propose that CTCs should be used alongside the TNM staging system and the genotype of primary tumor to guide tailored BC diagnosis and treatment. PMID:26178386

  9. Cardiac metastases of neuroendocrine tumors treated with 177Lu DOTATATE peptide receptor radionuclide therapy or 131I-MIBG therapy.

    PubMed

    Makis, William; McCann, Karey; Bryanton, Mark; McEwan, Alexander J B

    2015-12-01

    Neuroendocrine tumors have a propensity to metastasize to the heart, although the reason for this remains unknown. A review of 251 neuroendocrine tumor patients treated with Lu DOTATATE peptide receptor radionuclide therapy or I-MIBG therapy at our institution since 2003 revealed 2 patients with cardiac metastases (incidence, 0.8%), one treated with Lu DOTATATE and one with I-MIBG. We present the imaging findings of these 2 patients, as well as their management and responses to therapy. PMID:26359563

  10. Peptide receptor radionuclide therapy with somatostatin analogues in neuroendocrine tumors.

    PubMed

    Giovacchini, Giampiero; Nicolas, Guillaume; Forrer, Flavio

    2012-06-01

    Neuroendocrine tumors (NETs) are rare tumors with variable malignant behavior. The majority of NETs express increased levels of somatostatin (SST) receptors, particularly SST2 receptors. Radiolabeled peptides specific for the SST2 receptors may be used for diagnosis of NETs and for peptide receptor radionuclide therapy (PRRT). [(111)In-DTPA(0)]-octreotide has been the first peptide used for PRRT. This radiolabeled peptide, emitting Auger electrons, often induced symptomatic relief, but objective morphological responses were rarely documented. After the introduction of the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) other peptides, primarily [DOTA(0),Tyr(3)]octreotate (DOTATATE) and [DOTA(0),Tyr(3)]octreotide (DOTATOC) were labeled with (90)Y or (177)Lu and used for therapy applications. The rate of objective response obtained with these radiolabeled peptides ranges between 6% and 46%, owing to differences in inclusion criteria adopted in different studies, length and type of therapy, and criteria of evaluation of the response. The present data in the literature do not allow defining the most suitable peptide and radionuclide for the treatment of NETs. Instead emerging evidence indicates that a combination of nuclides with different physical characteristics might be more effective than the use of a single nuclide. Kidney and bone marrow toxicity are the limiting factors for PRRT. Mild toxicity is often encountered while severe toxicity is rarer. Toxicity could be reduced and therapeutic efficacy enhanced by patient-specific dosimetry. Future directions include different issues of PRRT, such as defining the most suitable treatment scheme, evaluation of new peptides with different affinity profiles to other SST receptor subtypes, and reduction of toxicity. PMID:22292758

  11. Undermining tumor angiogenesis by gene therapy: an emerging field.

    PubMed

    Indraccolo, S

    2004-09-01

    The recent discovery of several molecules that negatively modulate the migration and growth of endothelial cells, collectively referred to as inhibitors of angiogenesis, has made it possible to test the hypothesis that control of angiogenesis might be an effective strategy in controlling tumor growth, as well as ameliorating the course of other life-threatening diseases. Angiogenesis inhibitors are heterogeneous in origin and potency, and their growing list includes products of the proteolysis of larger molecules with a different function, such as angiostatin and endostatin, natural modulators of vascular endothelial growth factor activity, such as sFLT-1, and some cytokines with a marked anti-endothelial activity, such as IL-12 and interferon-alpha. Pre-clinical studies have clearly indicated that most of these factors exert cytostatic rather than cytotoxic effects, thus implying the need for long-term administration in order to obtain a prolonged therapeutic effect. This feature of angiostatic therapy and the difficulty in synthesizing large amounts of recombinant functional proteins have prompted several studies, which have investigated their delivery by a gene therapy approach. This review addresses the several experimental approaches attempted to date, points out the constraints that have delayed clinical application, and envisions possible areas of integration between antiangiogenic gene therapy and other established therapeutic options against cancer. PMID:15384943

  12. Acute phase response induced following tumor treatment by photodynamic therapy: relevance for the therapy outcome

    NASA Astrophysics Data System (ADS)

    Korbelik, Mladen; Merchant, Soroush; Stott, Brandon; Cecic, Ivana; Payne, Peter; Sun, Jinghai

    2006-02-01

    Acute phase response is an effector process orchestrated by the innate immune system for the optimal mobilization of the resources of the organism distant from the local insult site needed in the execution of a host-protecting reaction. Our research has shown that mice bearing tumors treated by photodynamic therapy (PDT) exhibit the three major hallmarks of acute phase response: release of acute phase reactants, neutrophilia, and pituitary/adrenal axis activation. Of particular interest in this study were acute phase proteins that have a pivotal role in the clearance of dead cells, since the occurrence of this process in PDT-treated tumors emerges as a critical event in the course of PDT-associated host response. It is shown that this type of acute phase reactants, including complement proteins (C3, C5, C9, mannose-binding lectin, and ficolin A) and related pentraxins (serum amyloid P component and PTX3), are upregulated following tumor PDT and accumulate in the targeted lesions. Based on the recently accumulated experimental evidence it is definitely established that the acute phase response is manifested in the hosts bearing PDT-treated tumors and it is becoming clear that this effector process is an important element of PDT-associated host response bearing in impact on the eventual outcome of this therapy.

  13. FAK regulates platelet extravasation and tumor growth after antiangiogenic therapy withdrawal.

    PubMed

    Haemmerle, Monika; Bottsford-Miller, Justin; Pradeep, Sunila; Taylor, Morgan L; Choi, Hyun-Jin; Hansen, Jean M; Dalton, Heather J; Stone, Rebecca L; Cho, Min Soon; Nick, Alpa M; Nagaraja, Archana S; Gutschner, Tony; Gharpure, Kshipra M; Mangala, Lingegowda S; Rupaimoole, Rajesha; Han, Hee Dong; Zand, Behrouz; Armaiz-Pena, Guillermo N; Wu, Sherry Y; Pecot, Chad V; Burns, Alan R; Lopez-Berestein, Gabriel; Afshar-Kharghan, Vahid; Sood, Anil K

    2016-05-01

    Recent studies in patients with ovarian cancer suggest that tumor growth may be accelerated following cessation of antiangiogenesis therapy; however, the underlying mechanisms are not well understood. In this study, we aimed to compare the effects of therapy withdrawal to those of continuous treatment with various antiangiogenic agents. Cessation of therapy with pazopanib, bevacizumab, and the human and murine anti-VEGF antibody B20 was associated with substantial tumor growth in mouse models of ovarian cancer. Increased tumor growth was accompanied by tumor hypoxia, increased tumor angiogenesis, and vascular leakage. Moreover, we found hypoxia-induced ADP production and platelet infiltration into tumors after withdrawal of antiangiogenic therapy, and lowering platelet counts markedly inhibited tumor rebound after withdrawal of antiangiogenic therapy. Focal adhesion kinase (FAK) in platelets regulated their migration into the tumor microenvironment, and FAK-deficient platelets completely prevented the rebound tumor growth. Additionally, combined therapy with a FAK inhibitor and the antiangiogenic agents pazopanib and bevacizumab reduced tumor growth and inhibited negative effects following withdrawal of antiangiogenic therapy. In summary, these results suggest that FAK may be a unique target in situations in which antiangiogenic agents are withdrawn, and dual targeting of FAK and VEGF could have therapeutic implications for ovarian cancer management. PMID:27064283

  14. FAK regulates platelet extravasation and tumor growth after antiangiogenic therapy withdrawal

    PubMed Central

    Haemmerle, Monika; Bottsford-Miller, Justin; Pradeep, Sunila; Taylor, Morgan L.; Hansen, Jean M.; Dalton, Heather J.; Stone, Rebecca L.; Cho, Min Soon; Nick, Alpa M.; Nagaraja, Archana S.; Gutschner, Tony; Gharpure, Kshipra M.; Mangala, Lingegowda S.; Han, Hee Dong; Zand, Behrouz; Armaiz-Pena, Guillermo N.; Wu, Sherry Y.; Pecot, Chad V.; Burns, Alan R.; Lopez-Berestein, Gabriel; Afshar-Kharghan, Vahid; Sood, Anil K.

    2016-01-01

    Recent studies in patients with ovarian cancer suggest that tumor growth may be accelerated following cessation of antiangiogenesis therapy; however, the underlying mechanisms are not well understood. In this study, we aimed to compare the effects of therapy withdrawal to those of continuous treatment with various antiangiogenic agents. Cessation of therapy with pazopanib, bevacizumab, and the human and murine anti-VEGF antibody B20 was associated with substantial tumor growth in mouse models of ovarian cancer. Increased tumor growth was accompanied by tumor hypoxia, increased tumor angiogenesis, and vascular leakage. Moreover, we found hypoxia-induced ADP production and platelet infiltration into tumors after withdrawal of antiangiogenic therapy, and lowering platelet counts markedly inhibited tumor rebound after withdrawal of antiangiogenic therapy. Focal adhesion kinase (FAK) in platelets regulated their migration into the tumor microenvironment, and FAK-deficient platelets completely prevented the rebound tumor growth. Additionally, combined therapy with a FAK inhibitor and the antiangiogenic agents pazopanib and bevacizumab reduced tumor growth and inhibited negative effects following withdrawal of antiangiogenic therapy. In summary, these results suggest that FAK may be a unique target in situations in which antiangiogenic agents are withdrawn, and dual targeting of FAK and VEGF could have therapeutic implications for ovarian cancer management. PMID:27064283

  15. In vivo two-photon microscopy study of short-term effects of microbeam irradiation on normal mouse brain microvasculature

    SciTech Connect

    Serduc, Raphael . E-mail: rserduc@ujf-grenoble.fr; Verant, Pascale; Vial, Jean-Claude; Farion, Regine; Rocas, Linda; Remy, Chantal; Fadlallah, Taoufik M.S.; Brauer, Elke M.S.; Bravin, Alberto; Laissue, Jean; Blattmann, Hans; Sanden, Boudewijn van der

    2006-04-01

    Purpose: The purpose of this study was to assess the early effects of microbeam irradiation on the vascular permeability and volume in the parietal cortex of normal nude mice using two-photon microscopy and immunohistochemistry. Methods and Materials: The upper part of the left hemisphere of 55 mice was irradiated anteroposteriorly using 18 vertically oriented beams (width 25 {mu}m, interdistance 211 {mu}m; peak entrance doses: 312 or 1000 Gy). At different times after microbeam exposure, the microvasculature in the cortex was analyzed using intravital two-photon microscopy after intravascular injection of fluorescein isothiocyanate (FITC)-dextrans and sulforhodamine B (SRB). Changes of the vascular volume were observed at the FITC wavelength over a maximum depth of 650 {mu}m from the dura. The vascular permeability was detected as extravasations of SRB. Results: For all times (12 h to 1 month) after microbeam irradiation and for both doses, the FITC-dextran remained in the vessels. No significant change in vascular volume was observed between 12 h and 3 months after irradiation. Diffusion of SRB was observed in microbeam irradiated regions from 12 h until 12 days only after a 1000 Gy exposure. Conclusion: No radiation damage to the microvasculature was detected in normal brain tissue after a 312 Gy microbeam irradiation. This dose would be more appropriate than 1000 Gy for the treatment of brain tumors using crossfired microbeams.

  16. Anti-tumor necrosis factor-α therapy in uveitis.

    PubMed

    Cordero-Coma, Miguel; Sobrin, Lucia

    2015-01-01

    Since the first reported use in 2001 of an anti-tumor necrosis factor-alpha (TNF-α) agent, infliximab, for the treatment of uveitis, several new anti-TNF-α agents have emerged for the treatment of refractory noninfectious uveitides, although their use remains off-label in the US. These agents have demonstrated remarkable clinical antiinflammatory efficacy and a potential immunoregulatory role in selected uveitis patients, but it is currently unclear whether they can modify the natural history of disease. We review the rationale and clinical indications for this therapy, the differences between agents, how to manage dosing and intervals, and how to screen for and identify potential side effects. We also present a summary of the science behind the use of anti-TNF-α agents in ocular inflammation and the evidence for their efficacy. PMID:26164735

  17. Nano-aggregates: emerging delivery tools for tumor therapy.

    PubMed

    Sharma, Vinod Kumar; Jain, Ankit; Soni, Vandana

    2013-01-01

    A plethora of formulation techniques have been reported in the literature for site-specific targeting of water-soluble and -insoluble anticancer drugs. Along with other vesicular and particulate carrier systems, nano-aggregates have recently emerged as a novel supramolecular colloidal carrier with promise for using poorly water-soluble drugs in molecular targeted therapies. Nano-aggregates possess some inherent properties such as size in the nanometers, high loading efficiency, and in vivo stability. Nano-aggregates can provide site-specific drug delivery via either a passive or active targeting mechanism. Nano-aggregates are formed from a polymer-drug conjugated amphiphilic block copolymer. They are suitable for encapsulation of poorly water-soluble drugs by covalent conjugation as well as physical encapsulation. Because of physical encapsulation, a maximum amount of drug can be loaded in nano-aggregates, which helps to achieve a sufficiently high drug concentration at the target site. Active transport can be achieved by conjugating a drug with vectors or ligands that bind specifically to receptors being overexpressed in the tumor cells. In this review, we explore synthesis and tumor targeting potential of nano-aggregates with active and passive mechanisms, and we discuss various characterization parameters, ex vivo studies, biodistribution studies, clinical trials, and patents. PMID:24099399

  18. Radiation therapy of conjunctival and orbital lymphoid tumors

    SciTech Connect

    Jereb, B.; Lee, H.; Jakobiec, F.A.; Kutcher, J.

    1984-07-01

    Lymphoid tumors of the conjuctiva and orbit are rare and remain localized in the majority of cases. Sometimes it is not possible either clinically or histologically to differentiate between a non-Hodgkin's lymphoma (NHL) and benign lymphoid hyperplasia. A series of 24 patients is reported. Nineteen were classified as having malignant NHL and 5 benign hyperplasia; 1 of these 5 later developed metastases, however. All patients had systemic work-up: 18 had Stage I, 1 had Stage II, and 5 had Stage IV disease. All patients received local radiation therapy with doses of 2400 to 2750 rad in 2-3 weeks for lesions of the eyelid and conjunctiva, and between 3000 and 3750 rad in 3-4 weeks for retrobulbar lesions. A method of shielding the lens with a lead block mounted on a low vac lens is described, and the dose distribution within the eye and orbit is presented. Patients who were treated with doses higher than 3000 rad experienced conjunctivitis and skin erythema that resolved completely. No other effects of radiation on normal structures of the ocular adnexa were observed in the 20 patients who are alive and without signs of tumor 10-46 months with a median follow-up time of 22 months.

  19. Calcium Channels and Associated Receptors in Malignant Brain Tumor Therapy.

    PubMed

    Morrone, Fernanda B; Gehring, Marina P; Nicoletti, Natália F

    2016-09-01

    Malignant brain tumors are highly lethal and aggressive. Despite recent advances in the current therapies, which include the combination of surgery and radio/chemotherapy, the average survival rate remains poor. Altered regulation of ion channels is part of the neoplastic transformation, which suggests that ion channels are involved in cancer. Distinct classes of calcium-permeable channels are abnormally expressed in cancer and are likely involved in the alterations underlying malignant growth. Specifically, cytosolic Ca(2+) activity plays an important role in the regulation of cell proliferation, and Ca(2+) signaling is altered in proliferating tumor cells. A series of previous studies emphasized the importance of the T-type low-voltage-gated calcium channels (VGCC) in different cancer types, including gliomas, and remarkably, pharmacologic inhibition of T-type VGCC caused antiproliferative effects and triggered apoptosis of human glioma cells. Other calcium permeable channels, such as transient receptor potential (TRP) channels, contribute to changes in Ca(2+) by modulating the driving force for Ca(2+) entry, and some TRP channels are required for proliferation and migration in gliomas. Furthermore, recent evidence shows that TRP channels contribute to the progression and survival of the glioblastoma patients. Likewise, the purinergic P2X7 receptor acts as a direct conduit for Ca(2+)-influx and an indirect activator of voltage-gated Ca(2+)-channel. Evidence also shows that P2X7 receptor activation is linked to elevated expression of inflammation promoting factors, tumor cell migration, an increase in intracellular mobilization of Ca(2+), and membrane depolarization in gliomas. Therefore, this review summarizes the recent findings on calcium channels and associated receptors as potential targets to treat malignant gliomas. PMID:27418672

  20. The host immunological response to cancer therapy: An emerging concept in tumor biology

    SciTech Connect

    Voloshin, Tali; Voest, Emile E.; Shaked, Yuval

    2013-07-01

    Almost any type of anti-cancer treatment including chemotherapy, radiation, surgery and targeted drugs can induce host molecular and cellular immunological effects which, in turn, can lead to tumor outgrowth and relapse despite an initial successful therapy outcome. Tumor relapse due to host immunological effects is attributed to angiogenesis, tumor cell dissemination from the primary tumors and seeding at metastatic sites. This short review will describe the types of host cells that participate in this process, the types of factors secreted from the host following therapy that can promote tumor re-growth, and the possible implications of this unique and yet only partially-known process. It is postulated that blocking these specific immunological effects in the reactive host in response to cancer therapy may aid in identifying new host-dependent targets for cancer, which in combination with conventional treatments can prolong therapy efficacy and extend survival. Additional studies investigating this specific research direction—both in preclinical models and in the clinical setting are essential in order to advance our understanding of how tumors relapse and evade therapy. -- Highlights: • Cancer therapy induces host molecular and cellular pro-tumorigenic effects. • Host effects in response to therapy may promote tumor relapse and metastasis. • The reactive host consists of immunological mediators promoting tumor re-growth. • Blocking therapy-induced host mediators may improve outcome.

  1. Layered bismuth oxyhalide nanomaterials for highly efficient tumor photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Xu, Yu; Shi, Zhenzhi; Zhang, Ling'e.; Brown, Eric Michael Bratsolias; Wu, Aiguo

    2016-06-01

    Layered bismuth oxyhalide nanomaterials have received much more interest as promising photocatalysts because of their unique layered structures and high photocatalytic performance, which can be used as potential inorganic photosensitizers in tumor photodynamic therapy (PDT). In recent years, photocatalytic materials have been widely used in PDT and photothermal therapy (PTT) as inorganic photosensitizers. This investigation focuses on applying layered bismuth oxyhalide nanomaterials toward cancer PDT, an application that has never been reported so far. The results of our study indicate that the efficiency of UV-triggered PDT was highest when using BiOCl nanoplates followed by BiOCl nanosheets, and then TiO2. Of particular interest is the fact that layered BiOCl nanomaterials showed excellent PDT effects under low nanomaterial dose (20 μg mL-1) and low UV dose (2.2 mW cm-2 for 10 min) conditions, while TiO2 showed almost no therapeutic effect under the same parameters. BiOCl nanoplates and nanosheets have shown excellent performance and an extensive range of applications in PDT.

  2. Layered bismuth oxyhalide nanomaterials for highly efficient tumor photodynamic therapy.

    PubMed

    Xu, Yu; Shi, Zhenzhi; Zhang, Ling'e; Brown, Eric Michael Bratsolias; Wu, Aiguo

    2016-07-01

    Layered bismuth oxyhalide nanomaterials have received much more interest as promising photocatalysts because of their unique layered structures and high photocatalytic performance, which can be used as potential inorganic photosensitizers in tumor photodynamic therapy (PDT). In recent years, photocatalytic materials have been widely used in PDT and photothermal therapy (PTT) as inorganic photosensitizers. This investigation focuses on applying layered bismuth oxyhalide nanomaterials toward cancer PDT, an application that has never been reported so far. The results of our study indicate that the efficiency of UV-triggered PDT was highest when using BiOCl nanoplates followed by BiOCl nanosheets, and then TiO2. Of particular interest is the fact that layered BiOCl nanomaterials showed excellent PDT effects under low nanomaterial dose (20 μg mL(-1)) and low UV dose (2.2 mW cm(-2) for 10 min) conditions, while TiO2 showed almost no therapeutic effect under the same parameters. BiOCl nanoplates and nanosheets have shown excellent performance and an extensive range of applications in PDT. PMID:26287933

  3. Development of cell-cycle checkpoint therapy for solid tumors.

    PubMed

    Tamura, Kenji

    2015-12-01

    Cellular proliferation is tightly controlled by several cell-cycle checkpoint proteins. In cancer, the genes encoding these proteins are often disrupted and cause unrestrained cancer growth. The proteins are over-expressed in many malignancies; thus, they are potential targets for anti-cancer therapies. These proteins include cyclin-dependent kinase, checkpoint kinase, WEE1 kinase, aurora kinase and polo-like kinase. Cyclin-dependent kinase inhibitors are the most advanced cell-cycle checkpoint therapeutics available. For instance, palbociclib (PD0332991) is a first-in-class, oral, highly selective inhibitor of CDK4/6 and, in combination with letrozole (Phase II; PALOMA-1) or with fulvestrant (Phase III; PALOMA-3), it has significantly prolonged progression-free survival, in patients with metastatic estrogen receptor-positive, HER2-negative breast cancer, in comparison with that observed in patients using letrozole, or fulvestrant alone, respectively. In this review, we provide an overview of the current compounds available for cell-cycle checkpoint protein-directed therapy for solid tumors. PMID:26486823

  4. Image-guided microbeam irradiation to brain tumour bearing mice using a carbon nanotube X-ray source array

    PubMed Central

    Zhang, Lei; Yuan, Hong; Burk, Laurel M; Inscoe, Christy R; Hadsell, Michael J; Chtcheprov, Pavel; Lee, Yueh Z; Lu, Jianping; Chang, Sha; Zhou, Otto

    2014-01-01

    Microbeam radiation therapy (MRT) is a promising experimental and preclinical radiotherapy method for cancer treatment. Synchrotron based MRT experiments have shown that spatially fractionated microbeam radiation has the unique capability of preferentially eradicating tumour cells while sparing normal tissue in brain tumour bearing animal models. We recently demonstrated the feasibility of generating orthovoltage microbeam radiation with an adjustable microbeam width using a carbon nanotube based X-ray source array. Here we report the preliminary results from our efforts in developing an image guidance procedure for the targeted delivery of the narrow microbeams to the small tumour region in the mouse brain. Magnetic resonance imaging was used for tumour identification, and on-board X-ray radiography was used for imaging of landmarks without contrast agents. The two images were aligned using 2D rigid body image registration to determine the relative position of the tumour with respect to a landmark. The targeting accuracy and consistency were evaluated by first irradiating a group of mice inoculated with U87 human glioma brain tumours using the present protocol and then determining the locations of the microbeam radiation tracks using γ-H2AX immunofluorescence staining. The histology results showed that among 14 mice irradiated, 11 received the prescribed number of microbeams on the targeted tumour, with an average localization accuracy of 454 μm measured directly from the histology (537 μm if measured from the registered histological images). Two mice received one of the three prescribed microbeams on the tumour site. One mouse was excluded from the analysis due to tissue staining errors. PMID:24556798

  5. Image-guided microbeam irradiation to brain tumour bearing mice using a carbon nanotube x-ray source array.

    PubMed

    Zhang, Lei; Yuan, Hong; Burk, Laurel M; Inscoe, Christy R; Hadsell, Michael J; Chtcheprov, Pavel; Lee, Yueh Z; Lu, Jianping; Chang, Sha; Zhou, Otto

    2014-03-01

    Microbeam radiation therapy (MRT) is a promising experimental and preclinical radiotherapy method for cancer treatment. Synchrotron based MRT experiments have shown that spatially fractionated microbeam radiation has the unique capability of preferentially eradicating tumour cells while sparing normal tissue in brain tumour bearing animal models. We recently demonstrated the feasibility of generating orthovoltage microbeam radiation with an adjustable microbeam width using a carbon nanotube based x-ray source array. Here we report the preliminary results from our efforts in developing an image guidance procedure for the targeted delivery of the narrow microbeams to the small tumour region in the mouse brain. Magnetic resonance imaging was used for tumour identification, and on-board x-ray radiography was used for imaging of landmarks without contrast agents. The two images were aligned using 2D rigid body image registration to determine the relative position of the tumour with respect to a landmark. The targeting accuracy and consistency were evaluated by first irradiating a group of mice inoculated with U87 human glioma brain tumours using the present protocol and then determining the locations of the microbeam radiation tracks using γ-H2AX immunofluorescence staining. The histology results showed that among 14 mice irradiated, 11 received the prescribed number of microbeams on the targeted tumour, with an average localization accuracy of 454 µm measured directly from the histology (537 µm if measured from the registered histological images). Two mice received one of the three prescribed microbeams on the tumour site. One mouse was excluded from the analysis due to tissue staining errors. PMID:24556798

  6. Image-guided microbeam irradiation to brain tumour bearing mice using a carbon nanotube x-ray source array

    NASA Astrophysics Data System (ADS)

    Zhang, Lei; Yuan, Hong; Burk, Laurel M.; Inscoe, Christy R.; Hadsell, Michael J.; Chtcheprov, Pavel; Lee, Yueh Z.; Lu, Jianping; Chang, Sha; Zhou, Otto

    2014-03-01

    Microbeam radiation therapy (MRT) is a promising experimental and preclinical radiotherapy method for cancer treatment. Synchrotron based MRT experiments have shown that spatially fractionated microbeam radiation has the unique capability of preferentially eradicating tumour cells while sparing normal tissue in brain tumour bearing animal models. We recently demonstrated the feasibility of generating orthovoltage microbeam radiation with an adjustable microbeam width using a carbon nanotube based x-ray source array. Here we report the preliminary results from our efforts in developing an image guidance procedure for the targeted delivery of the narrow microbeams to the small tumour region in the mouse brain. Magnetic resonance imaging was used for tumour identification, and on-board x-ray radiography was used for imaging of landmarks without contrast agents. The two images were aligned using 2D rigid body image registration to determine the relative position of the tumour with respect to a landmark. The targeting accuracy and consistency were evaluated by first irradiating a group of mice inoculated with U87 human glioma brain tumours using the present protocol and then determining the locations of the microbeam radiation tracks using γ-H2AX immunofluorescence staining. The histology results showed that among 14 mice irradiated, 11 received the prescribed number of microbeams on the targeted tumour, with an average localization accuracy of 454 µm measured directly from the histology (537 µm if measured from the registered histological images). Two mice received one of the three prescribed microbeams on the tumour site. One mouse was excluded from the analysis due to tissue staining errors.

  7. Targeting mutant p53 protein and the tumor vasculature: an effective combination therapy for advanced breast tumors

    PubMed Central

    Liang, Yayun; Besch-Williford, Cynthia; Benakanakere, Indira; Thorpe, Philip E.

    2010-01-01

    Breast cancer progression depends upon the elaboration of a vasculature sufficient for the nourishment of the developing tumor. Breast tumor cells frequently contain a mutant form of p53 (mtp53), a protein which promotes their survival. The aim of this study was to determine whether combination therapy targeting mtp53 and anionic phospholipids (AP) on tumor blood vessels might be an effective therapeutic strategy for suppressing advanced breast cancer. We examined the therapeutic effects, singly, or in combination, of p53 reactivation and induction of massive apoptosis (PRIMA-1), which reactivates mtp53 and induces tumor cell apoptosis, and 2aG4, a monoclonal antibody that disrupts tumor vasculature by targeting AP on the surface of tumor endothelial cells and causes antibody-dependent destruction of tumor blood vessels, leading to ischemia and tumor cell death. Xenografts from two tumor cell lines containing mtp53, BT-474 and HCC-1428, were grown in nude mice to provide models of advanced breast tumors. After treatment with PRIMA-1 and/or 2aG4, regressing tumors were analyzed for vascular endothelial growth factor (VEGF) expression, blood vessel loss, and apoptotic markers. Individual drug treatment led to partial suppression of breast cancer progression. In contrast, combined treatment with PRIMA-1 and 2aG4 was extremely effective in suppressing tumor growth in both models and completely eradicated approximately 30% of tumors in the BT-474 model. Importantly, no toxic effects were observed in any treatment group. Mechanistic studies determined that PRIMA-1 reactivated mtp53 and also exposed AP on the surface of tumor cells as determined by enhanced 2aG4 binding. Combination treatment led to significant induction of tumor cell apoptosis, loss of VEGF expression, as well as destruction of tumor blood vessels. Furthermore, combination treatment severely disrupted tumor blood vessel perfusion in both tumor models. The observed in vitro PRIMA-1-induced exposure of

  8. Combination of angiogenesis inhibitors increases the anti-tumor efficacy of photodynamic therapy in a human bladder tumor xenograft model

    NASA Astrophysics Data System (ADS)

    Bhuvaneswari, Ramaswamy; Gan, Yik Yuen; Thong, Patricia S. P.; Chin, William Wei L.; Soo, Khee Chee; Olivo, Malini

    2009-06-01

    Photodynamic therapy (PDT) is a standard treatment for various malignant and non-malignant conditions. Though therapeutic responses are encouraging, recurrences have been noted, as one of the limitations of PDT is treatment-induced hypoxia that triggers angiogenesis. The present study evaluates the use of angiogenic inhibitors Avastin, that targets vascular endothelial growth factor (VEGF) and Erbitux that targets epidermal growth factor receptor (EGFR) with PDT in an in vivo bladder carcinoma xenograft. Tumor bearing mice were assigned to 6 different categories: control, PDT only, Avastin + Erbitux, PDT + Avastin, PDT + Erbitux and PDT + Avastin and Erbitux. Treated and control tumors were monitored for recurrence for up to 90 days. VEGF and EGFR expression was detected in the tumor tissue. Migratory assay was performed to establish the inhibitory effect of the angiogenesis agents. Using confocal laser endomicroscopy, the tumor microvasculature was assessed. Tumors treated with the combination therapy of PDT + inhibitors showed significantly greater response compared to control and PDT only treated group. Combination therapy treated tumors also showed the most post-treatment damage with reduced tumor vasculature. These results demonstrate that the combination of PDT with inhibitors that target different angiogenesis pathways can improve tumor control.

  9. Modeling subspecies and the tumor-immune system interaction: Steps toward understanding therapy

    NASA Astrophysics Data System (ADS)

    Menchón, S. A.; Ramos, R. A.; Condat, C. A.

    2007-12-01

    A mesoscopic nutrient competition model for cancer growth is generalized to describe the growth of a heterogeneous tumor and the interactions between the tumor and the immune system. Our simulations show that the success of a mutation depends not only on its intrinsic competitive advantages, but also on its location in the tumor mass. It is also shown that the simple killing of tumor cells by immune cells, even when their activity is increased by therapy, is not sufficient to stem tumor growth, but another mechanism (such as pinning) is needed for a successful therapy.

  10. Optical properties of tumor tissues grown on the chorioallantoic membrane of chicken eggs: tumor model to assay of tumor response to photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Honda, Norihiro; Kariyama, Yoichiro; Hazama, Hisanao; Ishii, Takuya; Kitajima, Yuya; Inoue, Katsushi; Ishizuka, Masahiro; Tanaka, Tohru; Awazu, Kunio

    2015-12-01

    Herein, the optical adequacy of a tumor model prepared with tumor cells grown on the chorioallantoic membrane (CAM) of a chicken egg is evaluated as an alternative to the mouse tumor model to assess the optimal irradiation conditions in photodynamic therapy (PDT). The optical properties of CAM and mouse tumor tissues were measured with a double integrating sphere and the inverse Monte Carlo technique in the 350- to 1000-nm wavelength range. The hemoglobin and water absorption bands observed in the CAM tumor tissue (10 eggs and 10 tumors) are equal to that of the mouse tumor tissue (8 animals and 8 tumors). The optical intersubject variability of the CAM tumor tissues meets or exceeds that of the mouse tumor tissues, and the reduced scattering coefficient spectra of CAM tumor tissues can be equated with those of mouse tumor tissues. These results confirm that the CAM tumor model is a viable alternative to the mouse tumor model, especially for deriving optimal irradiation conditions in PDT.

  11. Real-time noninvasive optoacoustic monitoring of nanoparticle-mediated photothermal therapy of tumors

    NASA Astrophysics Data System (ADS)

    Esenaliev, R. O.; Petrov, Y. Y.; Cicenaite, I.; Chumakova, O. V.; Petrova, I. Y.; Patrikeev, I.; Liopo, A.

    2007-02-01

    We proposed and have been developing real-time, noninvasive monitoring of blood oxygenation, total hemoglobin concentration, and thermotherapy including hyperthermia, coagulation, and cryotherapy. In this paper we propose to use the optoacoustic technique for monitoring of nanoparticle-mediated photothermal therapy (NPT) of tumors. NPT is based on heating exogenous strongly-absorbing nanoparticles selectively delivered in tumors. Real-time monitoring of NPT is necessary for precise tumor therapy with minimal damage to normal tissues. In this study we injected PEGylated and non-PEGylated carbon nanoparticles in nude mice bearing human tumors (5-15 mm) and irradiated the tumors for 10 minutes with nanosecond Nd:YAG laser pulses which produced both thermal damage to the tumors and optoacoustic signals for monitoring NPT in real time. Irradiation of tumors was performed during or after (3 or 24 hours) nanoparticle injection. Amplitude and temporal parameters of optoacoustic signals (measured with a custom-made wide-band optoacoustic probe) correlated well with nanoparticle injection, temperature rise in tumors, and tumor coagulation. Substantial thermal damage in large areas of the tumors was produced when optimal irradiation parameters were used. Monte Carlo modeling of light distribution in tumors and optoacoustic theory were applied to study kinetics of nanoparticle concentration in the tumors. Our results demonstrated that the optoacoustic technique can be used for real-time monitoring of NTP and provide precise tumor therapy with minimal damage to normal tissues.

  12. Pronounced antitumor effects and tumor radiosensitization of double suicide gene therapy.

    PubMed

    Rogulski, K R; Zhang, K; Kolozsvary, A; Kim, J H; Freytag, S O

    1997-11-01

    The efficacy of HSV-1 thymidine kinase (TK) and Escherichia coli cytosine deaminase (CD) suicide gene therapies as cancer treatments are currently being examined in humans. We demonstrated previously that compared to single suicide gene therapy, greater levels of targeted cytotoxicity and radiosensitization can be achieved in vitro by genetically modifying tumor cells to express CD and HSV-1 TK concomitantly, as a fusion protein. In the present study, the efficacy of the combined double suicide gene therapy/radiotherapy approach was examined in vivo. Nude mice were injected either s.c. or i.m. with 9L gliosarcoma cells expressing an E. coli CD/HSV-1 TK fusion gene. Double suicide gene therapy using 5-fluorocytosine (500 mg/kg) and ganciclovir (30 mg/kg) proved to be markedly better at delaying tumor growth and achieving a tumor cure than single suicide gene therapy, which used 5-fluorocytosine or ganciclovir administered independently. Importantly, double suicide gene therapy was highly effective against large experimental tumors (>2 cm3), reducing tumor volume an average of 99% and producing a 40% tumor cure. Moreover, double suicide gene therapy profoundly potentiated the antitumor effects of radiation. The results indicate that double suicide gene therapy, particularly when coupled with radiotherapy, may represent a highly effective means of eradicating tumors. PMID:9815600

  13. Structure of solid tumors and their vasculature: Implications for therapy with monoclonal antibodies

    SciTech Connect

    Dvorak, H.F.; Nagy, J.A.; Dvorak, A.M. )

    1991-03-01

    Delivery of monoclonal antibodies to solid tumors is a vexing problem that must be solved if these antibodies are to realize their promise in therapy. Such success as has been achieved with monoclonal antibodies is attributable to the local hyperpermeability of the tumor vasculature, a property that favors antibody extravasation at tumor sites and that is mediated by a tumor-secreted vascular permeability factor. However, leaky tumor blood vessels are generally some distance removed from target tumor cells, separated by stroma and by other tumor cells that together represent significant barriers to penetration by extravasated monoclonal antibodies. For this reason, alternative approaches may be attractive. These include the use of antibody-linked cytotoxins, which are able to kill tumor cells without immediate contact, and direction of antibodies against nontumor cell targets, for example, antigens unique to the tumor vascular endothelium or to tumor stroma. 50 refs.

  14. Mechanisms in photodynamic therapy: Part three—Photosensitizer pharmacokinetics, biodistribution, tumor localization and modes of tumor destruction

    PubMed Central

    Castano, Ana P.; Demidova, Tatiana N.; Hamblin, Michael R.

    2013-01-01

    Summary Photodynamic therapy (PDT) has been known for over a hundred years, but is only now becoming widely used. Originally developed as cancer therapy, some of its most successful applications are for non-malignant disease. The majority of mechanistic research into PDT, however, is still directed towards anti-cancer applications. In the final part of series of three reviews, we will cover the possible reasons for the well-known tumor localizing properties of photosensitizers (PS). When PS are injected into the bloodstream they bind to various serum proteins and this can affect their phamacokinetics and biodistribution. Different PS can have very different pharmacokinetics and this can directly affect the illumination parameters. Intravenously injected PS undergo a transition from being bound to serum proteins, then bound to endothelial cells, then bound to the adventitia of the vessels, then bound either to the extracellular matrix or to the cells within the tumor, and finally to being cleared from the tumor by lymphatics or blood vessels, and excreted either by the kidneys or the liver. The effect of PDT on the tumor largely depends at which stage of this continuous process light is delivered. The anti-tumor effects of PDT are divided into three main mechanisms. Powerful anti-vascular effects can lead to thrombosis and hemorrhage in tumor blood vessels that subsequently lead to tumor death via deprivation of oxygen and nutrients. Direct tumor cell death by apoptosis or necrosis can occur if the PS has been allowed to be taken up by tumor cells. Finally the acute inflammation and release of cytokines and stress response proteins induced in the tumor by PDT can lead to an influx of leukocytes that can both contribute to tumor destruction as well as to stimulate the immune system to recognize and destroy tumor cells even at distant locations. PMID:25048669

  15. Rapid enlargement of an intracranial germ cell tumor after gonadotropin hormone therapy.

    PubMed

    Sasagawa, Yasuo; Tachibana, Osamu; Nakagawa, Athushi; Nakada, Satoko; Nojima, Takayuki; Koya, Daisuke; Iizuka, Hideaki

    2016-09-01

    We report a case of an intracranial germ cell tumor (iGCT) that showed rapid enlargement after human chorionic gonadotropin (hCG) hormone therapy for pituitary hypogonadism. A 16-year-old boy presented with headache and was diagnosed with a suprasellar tumor. He was initially observed without surgery. Intranasal desmopressin therapy was started for central diabetes insipidus, but there was no change in the tumor size on MRI. The diagnosis of the tumor remained unknown for 4years. Levels of serum gonadotropin hormones (follicle-stimulating and luteinizing hormone) and testosterone progressively decreased, and the patient developed pituitary hypogonadism and complained about his undeveloped beard, lack of underarm hair, and erectile dysfunction. Intramuscular gonadotropin injection (hCG 5000U×2/week) was started at age 20. Eight months after the first gonadotropin injection, the MRI showed tumor growth with vivid enhancement. Craniotomy was performed and the tumor was partially resected. The histological diagnosis was immature teratoma. After surgery, the patient was treated with 5 cycles of chemotherapy with carboplatin and etoposide. He also received radiation therapy of 50Gy (20Gy tumor bed and 30Gy whole ventricles) to the residual tumor, after which the tumor decreased in size. We postulate that iGCT may be at risk of progression during hCG hormone therapy. Thus, careful monitoring is required for a patient with iGCT who receives this therapy. PMID:27050912

  16. Molecular strategies targeting the host component of cancer to enhance tumor response to radiation therapy

    SciTech Connect

    Kim, Dong Wook; Huamani, Jessica; Fu, Allie; Hallahan, Dennis E. . E-mail: dennis.hallahan@vanderbilt.edu

    2006-01-01

    The tumor microenvironment, in particular, the tumor vasculature, as an important target for the cytotoxic effects of radiation therapy is an established paradigm for cancer therapy. We review the evidence that the phosphoinositide 3-kinase (PI3K)/Akt pathway is activated in endothelial cells exposed to ionizing radiation (IR) and is a molecular target for the development of novel radiation sensitizing agents. On the basis of this premise, several promising preclinical studies that targeted the inhibition of the PI3K/Akt activation as a potential method of sensitizing the tumor vasculature to the cytotoxic effects of IR have been conducted. An innovative strategy to guide cytotoxic therapy in tumors treated with radiation and PI3K/Akt inhibitors is presented. The evidence supports a need for further investigation of combined-modality therapy that involves radiation therapy and inhibitors of PI3K/Akt pathway as a promising strategy for improving the treatment of patients with cancer.

  17. Nanoparticle-Mediated Photothermal Therapy of Brain Tumors

    NASA Astrophysics Data System (ADS)

    Makkouk, Amani R.; Madsen, Steen J.

    Nanoparticles (10-1,000 nm diameter) have been investigated for use in numerous diagnostic and therapeutic applications. Gold nanoparticles are particularly appealing due to their biological inertness and the ability to conjugate a wide variety of ligands to their surface. Additionally, their optical properties can be tuned through variations of their size, shape, and composition. For example, gold-silica nanoshells, consisting of a spherical dielectric silica core (100-120 nm diameter) surrounded by a 10-20 nm gold shell, have a strong resonant absorption at approximately 800 nm where light has significant penetration in biological tissues. Following light absorption, surface electrons are photoexcited and the resultant heated electron gas is dissipated to the surrounding medium causing thermal damage. The ability of nanoparticles to convert optical energy to thermal energy makes them ideally suited for photothermal therapy (PTT). This review focuses on the utility of gold-silica nanoshells in PTT of brain tumors. PTT has proven effective in a number of in vitro and in vivo studies. Of particular clinical relevance are results demonstrating PTT efficacy in an orthotopic canine model.

  18. Consequences of Cytoplasmic Irradiation: Studies from Microbeam

    PubMed Central

    Zhou, Hongning; Hong, Mei; Chai, Yunfei; Hei, Tom K.

    2013-01-01

    The prevailing dogma for radiation biology is that genotoxic effects of ionizing radiation such as mutations and carcinogenesis are attributed mainly to direct damage to the nucleus. However, with the development of microbeam that can target precise positions inside the cells, accumulating evidences have shown that energy deposit by radiation in nuclear DNA is not required to trigger the damage, extra-nuclear or extra-cellular radiation could induce the similar biological effects as well. This review will summarize the biological responses after cytoplasm irradiated by microbeam, and the possible mechanisms involved in cytoplasmic irradiation. PMID:19346686

  19. The morphological changes in transplanted tumors in rats at plasmonic photothermal therapy

    NASA Astrophysics Data System (ADS)

    Bucharskaya, Alla B.; Maslyakova, Galina N.; Navolokin, Nikita A.; Dikht, Nataliya I.; Terentyuk, Georgy S.; Bashkatov, Alexey N.; Genina, Elina A.; Khlebtsov, Boris N.; Khlebtsov, Nikolai G.; Tuchin, Valery V.

    2016-04-01

    The aim of work was to study the morphological changes in transplanted liver tumors of rats after plasmonic photothermal therapy (PPTT). The gold nanorods functionalized with thiolated polyethylene glycol were injected intravenously to rats with transplanted liver cancer PC-1. A day after injection the tumors were irradiated by the infrared 808-nm diode laser. The withdrawal of the animals from the experiment and sampling of tumor tissue for morphological study were performed 24 hours after the laser exposure. The standard histological and immunohistochemical staining with antibodies to proliferation marker Ki-67 and apoptosis marker BAX were used for morphological study of transplanted tumors. The plasmonic photothermal therapy had pronounced damaging effect in rats with transplanted liver tumors expressed in degenerative and necrotic changes in the tumor cells. The decrease of proliferation marker Ki-67 and increase of expression of apoptosis marker BAX were observed in tumor cells after PPTT.

  20. The dual role of complement in cancer and its implication in anti-tumor therapy

    PubMed Central

    2016-01-01

    Chronic inflammation has been linked to the initiation of carcinogenesis, as well as the advancement of established tumors. The polarization of the tumor inflammatory microenvironment can contribute to either the control, or the progression of the disease. The emerging participation of members of the complement cascade in several hallmarks of cancer, renders it a potential target for anti-tumor treatment. Moreover, the presence of complement regulatory proteins (CRPs) in most types of tumor cells is known to impede anti-tumor therapies. This review focuses on our current knowledge of complement’s potential involvement in shaping the inflammatory tumor microenvironment and its role on the regulation of angiogenesis and hypoxia. Furthermore, we discuss approaches using complement-based therapies as an adjuvant in tumor immunotherapy. PMID:27563652

  1. Blocking lipid synthesis overcomes tumor regrowth and metastasis after antiangiogenic therapy withdrawal.

    PubMed

    Sounni, Nor Eddine; Cimino, Jonathan; Blacher, Silvia; Primac, Irina; Truong, Alice; Mazzucchelli, Gabriel; Paye, Alexandra; Calligaris, David; Debois, Delphine; De Tullio, Pascal; Mari, Bernard; De Pauw, Edwin; Noel, Agnes

    2014-08-01

    The molecular mechanisms responsible for the failure of antiangiogenic therapies and how tumors adapt to these therapies are unclear. Here, we applied transcriptomic, proteomic, and metabolomic approaches to preclinical models and provide evidence for tumor adaptation to vascular endothelial growth factor blockade through a metabolic shift toward carbohydrate and lipid metabolism in tumors. During sunitinib or sorafenib treatment, tumor growth was inhibited and tumors were hypoxic and glycolytic. In sharp contrast, treatment withdrawal led to tumor regrowth, angiogenesis restoration, moderate lactate production, and enhanced lipid synthesis. This metabolic shift was associated with a drastic increase in metastatic dissemination. Interestingly, pharmacological lipogenesis inhibition with orlistat or fatty acid synthase downregulation with shRNA inhibited tumor regrowth and metastases after sunitinib treatment withdrawal. Our data shed light on metabolic alterations that result in cancer adaptation to antiangiogenic treatments and identify key molecules involved in lipid metabolism as putative therapeutic targets. PMID:25017943

  2. Favorable Alteration of Tumor Microenvironment by Immunomodulatory Cytokines for Efficient T-Cell Therapy in Solid Tumors

    PubMed Central

    Tähtinen, Siri; Kaikkonen, Saija; Merisalo-Soikkeli, Maiju; Grönberg-Vähä-Koskela, Susanna; Kanerva, Anna; Parviainen, Suvi; Vähä-Koskela, Markus; Hemminki, Akseli

    2015-01-01

    Unfavorable ratios between the number and activation status of effector and suppressor immune cells infiltrating the tumor contribute to resistance of solid tumors to T-cell based therapies. Here, we studied the capacity of FDA and EMA approved recombinant cytokines to manipulate this balance in favor of efficient anti-tumor responses in B16.OVA melanoma bearing C57BL/6 mice. Intratumoral administration of IFN-α2, IFN-γ, TNF-α, and IL-2 significantly enhanced the anti-tumor effect of ovalbumin-specific CD8+ T-cell (OT-I) therapy, whereas GM-CSF increased tumor growth in association with an increase in immunosuppressive cell populations. None of the cytokines augmented tumor trafficking of OT-I cells significantly, but injections of IFN-α2, IFN-γ and IL-2 increased intratumoral cytokine secretion and recruitment of endogenous immune cells capable of stimulating T-cells, such as natural killer and maturated CD11c+ antigen-presenting cells. Moreover, IFN-α2 and IL-2 increased the levels of activated tumor-infiltrating CD8+ T-cells concomitant with reduction in the CD8+ T-cell expression of anergy markers CTLA-4 and PD-1. In conclusion, intratumoral administration of IFN-α2, IFN-γ and IL-2 can lead to immune sensitization of the established tumor, whereas GM-CSF may contribute to tumor-associated immunosuppression. The results described here provide rationale for including local administration of immunostimulatory cytokines into T-cell therapy regimens. One appealing embodiment of this would be vectored delivery which could be advantageous over direct injection of recombinant molecules with regard to efficacy, cost, persistence and convenience. PMID:26107883

  3. Scavenger receptor-targeted photodynamic therapy of J774 tumors in mice: tumor response and concomitant immunity

    NASA Astrophysics Data System (ADS)

    Hamblin, Michael R.; O'Donnell, David A.; Huzaira, Misbah; Zahra, Touqir

    2002-06-01

    J774 is a cell line derived from Balb/c mice that in vitro behaves as macrophages (including scavenger-receptor expression) and has been widely used to study macrophage cell biology. In vivo it produces histiocytic lymphoma tumors that are invasive and metastatic. We report here on the response of subcutaneous J774 tumors to photodynamic therapy with scavenger-receptor targeted chlorin(e6). Bovine serum albumin was covalently conjugated with chlorin(e6), maleylated and purified by acetone precipitation and both this and free chlorin(e6) were injected IV into mice at 2 mg/kg. When tumors were illuminated with 665 nm laser-light after 24 hours there was a highly significant response (tumor volume and growth rate) for the conjugate, but this led to a relatively small survival increase due to the highly metastatic nature of the tumor. The free chlorin(e6) gave very little tumor response. When light was delivered 3 hours after injection the response from the conjugate disappeared due to insufficient time for the tumor cells to take up the photosensitizer by receptor-mediated endocytosis. Free chlorin(e6) at 3 hours, however, produced a total regression of the tumors due to a primarily vascular effect, but the mice died sooner than control animals. When J774 tumors were surgically removed at different times after implantation the mouse survival was proportional to the length of time they had had the tumor. We interpret this data to show that mice with J774 tumors slowly develop concomitant immunity and a PDT regimen that swiftly ablates the tumor will give worse survival results than a regimen with a slower tumor response.

  4. Radiation microbeams as spatial and temporal probes of subcellular and tissue response

    PubMed Central

    Schettino, Giuseppe; Al-Rashid, Shahnaz T.; Prise, Kevin M.

    2010-01-01

    Understanding the effects of ionising radiations are key to determining their optimal use in therapy and assessing risks from exposure. The development of microbeams where radiations can be delivered in a highly temporal and spatially constrained manner has been a major advance. Several different types of radiation microbeams have been developed using X-rays, charged particles and electrons. For charged particles, beams can be targeted with sub-micron accuracy into biological samples and the lowest possible dose of a single particle track can be delivered with high reproducibility. Microbeams have provided powerful tools for understanding the kinetics of DNA damage and formation under conditions of physiological relevance and have significant advantages over other approaches for producing localised DNA damage, such as variable wavelength laser beam approaches. Recent studies have extended their use to probing for radiosensitive sites outside the cell nucleus, and testing for mechanisms underpinning bystander responses where irradiated and non-irradiated cells communicate with each other. Ongoing developments include the ability to locally target regions of 3-D tissue models and ultimately to target localised regions in vivo. With future advances in radiation delivery and imaging microbeams will continue to be applied in a range of biological studies. PMID:20079877

  5. Barriers Prevent Patient Access to Personalized Therapies Identified by Molecular Tumor Profiling of Gynecologic Malignancies

    PubMed Central

    Hillman, R. Tyler; Ward, Kristy; Saenz, Cheryl; McHale, Michael; Plaxe, Steven

    2015-01-01

    Objective. This study was designed to evaluate the ability of commercial molecular tumor profiling to discover actionable mutations and to identify barriers that might prevent patient access to personalized therapies. Methods. We conducted an IRB-approved retrospective review of 26 patients with gynecologic malignancies who underwent commercial tumor profiling at our institution during the first 18 months of test availability. Tumor profiles reported targeted therapies and clinical trials matched to patient-specific mutations. Data analysis consisted of descriptive statistics. Results. Most patients who underwent tumor profiling had serous epithelial ovarian, primary peritoneal, or fallopian tube carcinoma (46%). Patients underwent profiling after undergoing a median of two systemic therapies (range 0 to 13). A median of one targeted therapy was suggested per patient profile. Tumor profiling identified no clinically actionable mutations for seven patients (27%). Six patients sought insurance approval for a targeted therapy and two were declined (33%). One patient (4%) received a targeted therapy and this was discontinued due to tumor progression. Conclusions. There are formidable barriers to targeted therapy for patients with gynecologic malignancies. These barriers include a dearth of FDA-approved targeted agents for gynecologic malignancies, lack of third party insurance coverage and limited geographic availability of clinical trials. PMID:26011384

  6. Multifunctional nanoparticles for brain tumor imaging and therapy.

    PubMed

    Cheng, Yu; Morshed, Ramin A; Auffinger, Brenda; Tobias, Alex L; Lesniak, Maciej S

    2014-02-01

    Brain tumors are a diverse group of neoplasms that often carry a poor prognosis for patients. Despite tremendous efforts to develop diagnostic tools and therapeutic avenues, the treatment of brain tumors remains a formidable challenge in the field of neuro-oncology. Physiological barriers including the blood-brain barrier result in insufficient accumulation of therapeutic agents at the site of a tumor, preventing adequate destruction of malignant cells. Furthermore, there is a need for improvements in brain tumor imaging to allow for better characterization and delineation of tumors, visualization of malignant tissue during surgery, and tracking of response to chemotherapy and radiotherapy. Multifunctional nanoparticles offer the potential to improve upon many of these issues and may lead to breakthroughs in brain tumor management. In this review, we discuss the diagnostic and therapeutic applications of nanoparticles for brain tumors with an emphasis on innovative approaches in tumor targeting, tumor imaging, and therapeutic agent delivery. Clinically feasible nanoparticle administration strategies for brain tumor patients are also examined. Furthermore, we address the barriers towards clinical implementation of multifunctional nanoparticles in the context of brain tumor management. PMID:24060923

  7. Multifunctional Nanoparticles for Brain Tumor Diagnosis and Therapy

    PubMed Central

    Cheng, Yu; Morshed, Ramin; Auffinger, Brenda; Tobias, Alex L.; Lesniak, Maciej S.

    2013-01-01

    Brain tumors are a diverse group of neoplasms that often carry a poor prognosis for patients. Despite tremendous efforts to develop diagnostic tools and therapeutic avenues, the treatment of brain tumors remains a formidable challenge in the field of neuro-oncology. Physiological barriers including the blood-brain barrier result in insufficient accumulation of therapeutic agents at the site of a tumor, preventing adequate destruction of malignant cells. Furthermore, there is a need for improvements in brain tumor imaging to allow for better characterization and delineation of tumors, visualization of malignant tissue during surgery, and tracking of response to chemotherapy and radiotherapy. Multifunctional nanoparticles offer the potential to improve upon many of these issues and may lead to breakthroughs in brain tumor management. In this review, we discuss the diagnostic and therapeutic applications of nanoparticles for brain tumors with an emphasis on innovative approaches in tumor targeting, tumor imaging, and therapeutic agent delivery. Clinically feasible nanoparticle administration strategies for brain tumor patients are also examined. Furthermore, we address the barriers towards clinical implementation of multifunctional nanoparticles in the context of brain tumor management. PMID:24060923

  8. Mars Mineralogy by Microbeam Raman Spectrometry

    NASA Technical Reports Server (NTRS)

    Haskin, Larry A.; Wang, Alian; Jolliff, Bradley L.; Wdowiak, Thomas J.; Agresti, David G.; Lane, Arthur L.; Squyres, Steven W.

    2001-01-01

    The Mars Microbeam Raman Spectrometer, under development at Washington University and the Jet Propulsion Laboratory, can identify oxide, sulfide, and oxyanion minerals, bound water and OH, and organic and graphitic carbon in Mars rocks and soils in situ. Additional information is contained in the original extended abstract.

  9. Solid tumor therapy by selectively targeting stromal endothelial cells.

    PubMed

    Liu, Shihui; Liu, Jie; Ma, Qian; Cao, Liu; Fattah, Rasem J; Yu, Zuxi; Bugge, Thomas H; Finkel, Toren; Leppla, Stephen H

    2016-07-12

    Engineered tumor-targeted anthrax lethal toxin proteins have been shown to strongly suppress growth of solid tumors in mice. These toxins work through the native toxin receptors tumor endothelium marker-8 and capillary morphogenesis protein-2 (CMG2), which, in other contexts, have been described as markers of tumor endothelium. We found that neither receptor is required for tumor growth. We further demonstrate that tumor cells, which are resistant to the toxin when grown in vitro, become highly sensitive when implanted in mice. Using a range of tissue-specific loss-of-function and gain-of-function genetic models, we determined that this in vivo toxin sensitivity requires CMG2 expression on host-derived tumor endothelial cells. Notably, engineered toxins were shown to suppress the proliferation of isolated tumor endothelial cells. Finally, we demonstrate that administering an immunosuppressive regimen allows animals to receive multiple toxin dosages and thereby produces a strong and durable antitumor effect. The ability to give repeated doses of toxins, coupled with the specific targeting of tumor endothelial cells, suggests that our strategy should be efficacious for a wide range of solid tumors. PMID:27357689

  10. Small Solutions for Big Problems: The Application of Nanoparticles to Brain Tumor Diagnosis and Therapy

    PubMed Central

    Orringer, Daniel A.; Koo, Yong-Eun Lee; Kopelman, Raoul; Sagher, Oren

    2009-01-01

    Synopsis Nanoparticles are likely to play a key role in the future diagnosis and treatment of CNS malignancies. Nanoparticles have the potential to revolutionize both preoperative and intraoperative brain tumor detection. In addition, nanoparticles may also serve as novel, targeted delivery devices for chemotherapy, gene therapy, photodynamic therapy and thermotherapy. The translation of current research in nanotechnology into a clinically relevant component of brain tumor management will rely on solving challenges related to the pharmacology of nanoparticles. PMID:19242401