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Sample records for microbeams tumor therapy

  1. Synchrotron microbeam radiation therapy for rat brain tumor palliation—influence of the microbeam width at constant valley dose

    NASA Astrophysics Data System (ADS)

    Serduc, Raphaël; Bouchet, Audrey; Bräuer-Krisch, Elke; Laissue, Jean A.; Spiga, Jenny; Sarun, Sukhéna; Bravin, Alberto; Fonta, Caroline; Renaud, Luc; Boutonnat, Jean; Siegbahn, Erik Albert; Estève, François; Le Duc, Géraldine

    2009-11-01

    To analyze the effects of the microbeam width (25, 50 and 75 µm) on the survival of 9L gliosarcoma tumor-bearing rats and on toxicity in normal tissues in normal rats after microbeam radiation therapy (MRT), 9L gliosarcomas implanted in rat brains, as well as in normal rat brains, were irradiated in the MRT mode. Three configurations (MRT25, MRT50, MRT75), each using two orthogonally intersecting arrays of either 25, 50 or 75 µm wide microbeams, all spaced 211 µm on center, were tested. For each configuration, peak entrance doses of 860, 480 and 320 Gy, respectively, were calculated to produce an identical valley dose of 18 Gy per individual array at the center of the tumor. Two, 7 and 14 days after radiation treatment, 42 rats were killed to evaluate histopathologically the extent of tumor necrosis, and the presence of proliferating tumors cells and tumor vessels. The median survival times of the normal rats were 4.5, 68 and 48 days for MRT25, 50 and 75, respectively. The combination of the highest entrance doses (860 Gy per array) with 25 µm wide beams (MRT25) resulted in a cumulative valley dose of 36 Gy and was excessively toxic, as it led to early death of all normal rats and of ~50% of tumor-bearing rats. The short survival times, particularly of rats in the MRT25 group, restricted adequate observance of the therapeutic effect of the method on tumor-bearing rats. However, microbeams of 50 µm width led to the best median survival time after 9L gliosarcoma MRT treatment and appeared as the better compromise between tumor control and normal brain toxicity compared with 75 µm or 25 µm widths when used with a 211 µm on-center distance. Despite very high radiation doses, the tumors were not sterilized; viable proliferating tumor cells remained present at the tumor margin. This study shows that microbeam width and peak entrance doses strongly influence tumor responses and normal brain toxicity, even if valley doses are kept constant in all groups. The use of

  2. Synchrotron microbeam radiation therapy for rat brain tumor palliation-influence of the microbeam width at constant valley dose.

    PubMed

    Serduc, Raphaël; Bouchet, Audrey; Bräuer-Krisch, Elke; Laissue, Jean A; Spiga, Jenny; Sarun, Sukhéna; Bravin, Alberto; Fonta, Caroline; Renaud, Luc; Boutonnat, Jean; Siegbahn, Erik Albert; Estève, François; Le Duc, Géraldine

    2009-11-07

    To analyze the effects of the microbeam width (25, 50 and 75 microm) on the survival of 9L gliosarcoma tumor-bearing rats and on toxicity in normal tissues in normal rats after microbeam radiation therapy (MRT), 9L gliosarcomas implanted in rat brains, as well as in normal rat brains, were irradiated in the MRT mode. Three configurations (MRT25, MRT50, MRT75), each using two orthogonally intersecting arrays of either 25, 50 or 75 microm wide microbeams, all spaced 211 microm on center, were tested. For each configuration, peak entrance doses of 860, 480 and 320 Gy, respectively, were calculated to produce an identical valley dose of 18 Gy per individual array at the center of the tumor. Two, 7 and 14 days after radiation treatment, 42 rats were killed to evaluate histopathologically the extent of tumor necrosis, and the presence of proliferating tumors cells and tumor vessels. The median survival times of the normal rats were 4.5, 68 and 48 days for MRT25, 50 and 75, respectively. The combination of the highest entrance doses (860 Gy per array) with 25 microm wide beams (MRT25) resulted in a cumulative valley dose of 36 Gy and was excessively toxic, as it led to early death of all normal rats and of approximately 50% of tumor-bearing rats. The short survival times, particularly of rats in the MRT25 group, restricted adequate observance of the therapeutic effect of the method on tumor-bearing rats. However, microbeams of 50 microm width led to the best median survival time after 9L gliosarcoma MRT treatment and appeared as the better compromise between tumor control and normal brain toxicity compared with 75 microm or 25 microm widths when used with a 211 microm on-center distance. Despite very high radiation doses, the tumors were not sterilized; viable proliferating tumor cells remained present at the tumor margin. This study shows that microbeam width and peak entrance doses strongly influence tumor responses and normal brain toxicity, even if valley doses are

  3. Effects of microbeam radiation therapy on normal and tumoral blood vessels.

    PubMed

    Bouchet, Audrey; Serduc, Raphäel; Laissue, Jean Albert; Djonov, Valentin

    2015-09-01

    Microbeam radiation therapy (MRT) is a new form of preclinical radiotherapy using quasi-parallel arrays of synchrotron X-ray microbeams. While the deposition of several hundred Grays in the microbeam paths, the normal brain tissues presents a high tolerance which is accompanied by the permanence of apparently normal vessels. Conversely, the efficiency of MRT on tumor growth control is thought to be related to a preferential damaging of tumor blood vessels. The high resistance of the healthy vascular network was demonstrated in different animal models by in vivo biphoton microscopy, magnetic resonance imaging, and histological studies. While a transient increase in permeability was shown, the structure of the vessels remained intact. The use of a chick chorioallantoic membrane at different stages of development showed that the damages induced by microbeams depend on vessel maturation. In vivo and ultrastructural observations showed negligible effects of microbeams on the mature vasculature at late stages of development; nevertheless a complete destruction of the immature capillary plexus was found in the microbeam paths. The use of MRT in rodent models revealed a preferential effect on tumor vessels. Although no major modification was observed in the vasculature of normal brain tissue, tumors showed a denudation of capillaries accompanied by transient increased permeability followed by reduced tumor perfusion and finally, a decrease in number of tumor vessels. Thus, MRT is a very promising treatment strategy with pronounced tumor control effects most likely based on the anti-vascular effects of MRT. Copyright © 2015. Published by Elsevier Ltd.

  4. 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

  5. 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.

  6. 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.

  7. 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.

  8. Brain tumor vessel response to synchrotron microbeam radiation therapy: a short-term in vivo study

    NASA Astrophysics Data System (ADS)

    Serduc, Raphaël; Christen, Thomas; Laissue, Jean; Farion, Régine; Bouchet, Audrey; van der Sanden, Boudewijn; Segebarth, Christoph; Bräuer-Krisch, Elke; LeDuc, Géraldine; Bravin, Alberto; Rémy, Chantal; Barbier, Emmanuel L.

    2008-07-01

    The aim of this work focuses on the description of the short-term response of a 9L brain tumor model and its vasculature to microbeam radiation therapy (MRT) using magnetic resonance imaging (MRI). Rat 9L gliosarcomas implanted in nude mice brains were irradiated by MRT 13 days after tumor inoculation using two orthogonal arrays of equally spaced 28 planar microbeams (25 µm width, 211 µm spacing and dose 500 Gy). At 1, 7 and 14 days after MRT, apparent diffusion coefficient, blood volume and vessel size index were mapped by MRI. Mean survival time after tumor inoculation increased significantly between MRT-treated and untreated groups (23 and 28 days respectively, log-rank test, p < 0.0001). A significant increase of apparent diffusion coefficient was observed 24 h after MRT in irradiated tumors versus non-irradiated ones. In the untreated group, both tumor size and vessel size index increased significantly (from 7.6 ± 2.2 to 19.2 ± 4.0 mm2 and +23%, respectively) between the 14th and the 21st day after tumor cell inoculation. During the same period, in the MRT-treated group, no difference in tumor size was observed. The vessel size index measured in the MRT-treated group increased significantly (+26%) between 14 and 28 days of tumor growth. We did not observe the significant difference in blood volume between the MRT-treated and untreated groups. MRT slows 9L tumor growth in a mouse brain but MRI results suggest that the increase in survival time after our MRT approach may be rather due to a cytoreduction than to early direct effects of ionizing radiation on tumor vessels. These results suggest that MRT parameters need to be optimized to further damage tumor vessels.

  9. X-ray microbeams: Tumor therapy and central nervous system research

    NASA Astrophysics Data System (ADS)

    Dilmanian, F. A.; Qu, Y.; Liu, S.; Cool, C. D.; Gilbert, J.; Hainfeld, J. F.; Kruse, C. A.; Laterra, J.; Lenihan, D.; Nawrocky, M. M.; Pappas, G.; Sze, C.-I.; Yuasa, T.; Zhong, N.; Zhong, Z.; McDonald, J. W.

    2005-08-01

    Irradiation with parallel arrays of thin, planar slices of X-ray beams (microplanar beams, or microbeams) spares normal tissue, including the central nervous system (CNS), and preferentially damages tumors. The effects are mediated, at least in part, by the tissue's microvasculature that seems to effectively repair itself in normal tissue but fails to do so in tumors. Consequently, the therapeutic index of single-fraction unidirectional microbeam irradiations has been shown to be larger than that of single-fraction unidirectional unsegmented beams in treating the intracranial rat 9L gliosarcoma tumor model (9LGS) and the subcutaneous murine mammary carcinoma EMT-6. This paper presents results demonstrating that individual microbeams, or arrays of parallel ones, can also be used for targeted, selective cell ablation in the CNS, and also to induce demyelination. The results highlight the value of the method as a powerful tool for studying the CNS through selective cell ablation, besides its potential as a treatment modality in clinical oncology.

  10. 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.

  11. WE-EF-BRA-09: Microbeam Radiation Therapy Enhances Tumor Drug Uptake of PEGylated Liposomal Doxorubicin (PLD) in a Triple Negative Breast Cancer GEM Model

    SciTech Connect

    Chang, SX; Madden, AJ; Rivera, JN; Santos, CM; Hunter, LM; Darr, DB; Zamboni, WC

    2015-06-15

    Purpose: Overcoming low anti-cancer drug uptake in tumors is a key challenge limiting its clinical use. We propose to enhance the drug delivery using upfront Microbeam Radiation Therapy (MRT). MRT is a preclinical cancer therapy that utilizes microplanar beams to deliver spatially oscillating planes of high and low doses. Animal studies have demonstrated that ultrahigh dose (100s Gy) MRT eradicates tumors without damaging the function of normal tissue exposed to the same radiation. Our previous study indicated that MRT induces intense angiogenesis in tumor rim and surrounding normal tissue 1–2 days post radiation. We hypothesize that the tumor microenvironment modulation induced by MRT may enhance carrier-mediated agent drug delivery to tumors with inherent poor drug uptake. We thus investigated MRT-induced pharmacokinetics (PK) of PEGylated liposomal doxorubicin (PLD), a nano-scale doxorubicin, in T11 genetically engineered mouse model of triple negative breast cancer. Methods: A research irradiator (160kVp, RadSource Technologies) with a customized collimator was used to produce the MRT microbeam of in average 390µm width and 1190µm peak-to-peak distance. The peak dose rate of 1–2Gy/min. Dosimetry is by EBT3 film cross-calibrated with ion chamber at large fields. All mice were administered PLD at 6mg/kg IV x1 at 16h post MRT and sacrificed at 5min, 6h, 24h, and 96h post PLD administration (n=3 or 4 per group). Results: The MRT(28Gy)+PLD group mice had a total doxorubicin tumor concentration (area-under-the concentration-curve, AUC) of 206,040ng/mL•h, 3.71 times the concentration of the PLD-alone group. The MRT(34Gy)+PLD group had a higher mean total doxorubicin concentration in tumor (20,779ng/ml) than the MRT(28Gy)+PLD group (10,665ng/ml). Conclusion: Our preliminary results indicate that microbeam radiation therapy (MRT) can enhance nano-scale anti-cancer drug delivery to tumors approximately 4-fold. The exact working mechanism, the comparison with

  12. Early gene expression analysis in 9L orthotopic tumor-bearing rats identifies immune modulation in molecular response to synchrotron microbeam radiation therapy.

    PubMed

    Bouchet, Audrey; Sakakini, Nathalie; El Atifi, Michèle; Le Clec'h, Céline; Brauer, Elke; Moisan, Anaïck; Deman, Pierre; Rihet, Pascal; Le Duc, Géraldine; Pelletier, Laurent

    2013-01-01

    Synchrotron Microbeam Radiation Therapy (MRT) relies on the spatial fractionation of the synchrotron photon beam into parallel micro-beams applying several hundred of grays in their paths. Several works have reported the therapeutic interest of the radiotherapy modality at preclinical level, but biological mechanisms responsible for the described efficacy are not fully understood to date. The aim of this study was to identify the early transcriptomic responses of normal brain and glioma tissue in rats after MRT irradiation (400Gy). The transcriptomic analysis of similarly irradiated normal brain and tumor tissues was performed 6 hours after irradiation of 9 L orthotopically tumor-bearing rats. Pangenomic analysis revealed 1012 overexpressed and 497 repressed genes in the irradiated contralateral normal tissue and 344 induced and 210 repressed genes in tumor tissue. These genes were grouped in a total of 135 canonical pathways. More than half were common to both tissues with a predominance for immunity or inflammation (64 and 67% of genes for normal and tumor tissues, respectively). Several pathways involving HMGB1, toll-like receptors, C-type lectins and CD36 may serve as a link between biochemical changes triggered by irradiation and inflammation and immunological challenge. Most immune cell populations were involved: macrophages, dendritic cells, natural killer, T and B lymphocytes. Among them, our results highlighted the involvement of Th17 cell population, recently described in tumor. The immune response was regulated by a large network of mediators comprising growth factors, cytokines, lymphokines. In conclusion, early response to MRT is mainly based on inflammation and immunity which appear therefore as major contributors to MRT efficacy.

  13. Early Gene Expression Analysis in 9L Orthotopic Tumor-Bearing Rats Identifies Immune Modulation in Molecular Response to Synchrotron Microbeam Radiation Therapy

    PubMed Central

    Bouchet, Audrey; Sakakini, Nathalie; El Atifi, Michèle; Le Clec'h, Céline; Brauer, Elke; Moisan, Anaïck; Deman, Pierre; Rihet, Pascal; Le Duc, Géraldine; Pelletier, Laurent

    2013-01-01

    Synchrotron Microbeam Radiation Therapy (MRT) relies on the spatial fractionation of the synchrotron photon beam into parallel micro-beams applying several hundred of grays in their paths. Several works have reported the therapeutic interest of the radiotherapy modality at preclinical level, but biological mechanisms responsible for the described efficacy are not fully understood to date. The aim of this study was to identify the early transcriptomic responses of normal brain and glioma tissue in rats after MRT irradiation (400Gy). The transcriptomic analysis of similarly irradiated normal brain and tumor tissues was performed 6 hours after irradiation of 9 L orthotopically tumor-bearing rats. Pangenomic analysis revealed 1012 overexpressed and 497 repressed genes in the irradiated contralateral normal tissue and 344 induced and 210 repressed genes in tumor tissue. These genes were grouped in a total of 135 canonical pathways. More than half were common to both tissues with a predominance for immunity or inflammation (64 and 67% of genes for normal and tumor tissues, respectively). Several pathways involving HMGB1, toll-like receptors, C-type lectins and CD36 may serve as a link between biochemical changes triggered by irradiation and inflammation and immunological challenge. Most immune cell populations were involved: macrophages, dendritic cells, natural killer, T and B lymphocytes. Among them, our results highlighted the involvement of Th17 cell population, recently described in tumor. The immune response was regulated by a large network of mediators comprising growth factors, cytokines, lymphokines. In conclusion, early response to MRT is mainly based on inflammation and immunity which appear therefore as major contributors to MRT efficacy. PMID:24391709

  14. Scatter factors assessment in microbeam radiation therapy

    SciTech Connect

    Prezado, Y.; Martinez-Rovira, I.; Sanchez, M.

    2012-03-15

    Purpose: The success of the preclinical studies in Microbeam Radiation Therapy (MRT) paved the way to the clinical trials under preparation at the Biomedical Beamline of the European Synchrotron Radiation Facility. Within this framework, an accurate determination of the deposited dose is crucial. With that aim, the scatter factors, which translate the absolute dose measured in reference conditions (2 x 2 cm{sup 2} field size at 2 cm-depth in water) to peak doses, were assessed. Methods: Monte Carlo (MC) simulations were performed with two different widely used codes, PENELOPE and GEANT4, for the sake of safety. The scatter factors were obtained as the ratio of the doses that are deposited by a microbeam and by a field of reference size, at the reference depth. The calculated values were compared with the experimental data obtained by radiochromic (ISP HD-810) films and a PTW 34070 large area chamber. Results: The scatter factors for different microbeam field sizes assessed by the two MC codes were in agreement and reproduced the experimental data within uncertainty bars. Those correction factors were shown to be non-negligible for the future MRT clinical settings: an average 30% lower dose was deposited by a 50 {mu}m microbeam with respect to the reference conditions. Conclusions: For the first time, the scatter factors in MRT were systematically studied. They constitute an essential key to deposit accurate doses in the forthcoming clinical trials in MRT. The good agreement between the different calculations and the experimental data confirms the reliability of this challenging micrometric dose estimation.

  15. Multi-strip silicon sensors for beam array monitoring in micro-beam radiation therapy.

    PubMed

    Alagoz, E; Brauer-Krisch, E; Bravin, A; Cornelius, I; Fournier, P; Hansen, T E; Kok, A; Lerch, M; Monakhov, E; Morse, J; Pacifico, N; Petasecca, M; Povoli, M; Requard, H; Rozenfeld, A D; Salome, M; Sandaker, H; Stugu, B

    2016-12-01

    We present here the latest results from tests performed at the ESRF ID17 and ID21 beamlines for the characterization of novel beam monitors for Microbeam Radiation Therapy (MRT), which is currently being implemented at ID17. MRT aims at treating solid tumors by exploiting an array of evenly spaced microbeams, having an energy spectrum distributed between 27 and 600keV and peaking at 100keV. Given the high instantaneous dose delivered (up to 20kGy/s), the position and the intensity of the microbeams has to be precisely and instantly monitored. For this purpose, we developed dedicated silicon microstrip beam monitors. We have successfully characterized them, both with a microbeam array at ID17, and a submicron scanning beam at ID21. We present here the latest results obtained in recent tests along with an outlook on future developments.

  16. 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

  17. 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

  18. 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.

  19. 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.

  20. 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

  1. 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.

  2. 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.

  3. Characterization and quantification of cerebral edema induced by synchrotron x-ray microbeam radiation therapy

    NASA Astrophysics Data System (ADS)

    Serduc, Raphaël; van de Looij, Yohan; Francony, Gilles; Verdonck, Olivier; van der Sanden, Boudewijn; Laissue, Jean; Farion, Régine; Bräuer-Krisch, Elke; Siegbahn, Erik Albert; Bravin, Alberto; Prezado, Yolanda; Segebarth, Christoph; Rémy, Chantal; Lahrech, Hana

    2008-03-01

    Cerebral edema is one of the main acute complications arising after irradiation of brain tumors. Microbeam radiation therapy (MRT), an innovative experimental radiotherapy technique using spatially fractionated synchrotron x-rays, has been shown to spare radiosensitive tissues such as mammal brains. The aim of this study was to determine if cerebral edema occurs after MRT using diffusion-weighted MRI and microgravimetry. Prone Swiss nude mice's heads were positioned horizontally in the synchrotron x-ray beam and the upper part of the left hemisphere was irradiated in the antero-posterior direction by an array of 18 planar microbeams (25 mm wide, on-center spacing 211 mm, height 4 mm, entrance dose 312 Gy or 1000 Gy). An apparent diffusion coefficient (ADC) was measured at 7 T 1, 7, 14, 21 and 28 days after irradiation. Eventually, the cerebral water content (CWC) was determined by microgravimetry. The ADC and CWC in the irradiated (312 Gy or 1000 Gy) and in the contralateral non-irradiated hemispheres were not significantly different at all measurement times, with two exceptions: (1) a 9% ADC decrease (p < 0.05) was observed in the irradiated cortex 1 day after exposure to 312 Gy, (2) a 0.7% increase (p < 0.05) in the CWC was measured in the irradiated hemispheres 1 day after exposure to 1000 Gy. The results demonstrate the presence of a minor and transient cellular edema (ADC decrease) at 1 day after a 312 Gy exposure, without a significant CWC increase. One day after a 1000 Gy exposure, the CWC increased, while the ADC remained unchanged and may reflect the simultaneous presence of cellular and vasogenic edema. Both types of edema disappear within a week after microbeam exposure which may confirm the normal tissue sparing effect of MRT. For more information on this article, see medicalphysicsweb.org

  4. 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.

  5. 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

  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. Optimizing dose enhancement with Ta2O5 nanoparticles for synchrotron microbeam activated radiation therapy.

    PubMed

    Engels, Elette; Corde, Stéphanie; McKinnon, Sally; Incerti, Sébastien; Konstantinov, Konstantin; Rosenfeld, Anatoly; Tehei, Moeava; Lerch, Michael; Guatelli, Susanna

    2016-12-01

    Microbeam Radiation Therapy (MRT) exploits tumour selectivity and normal tissue sparing with spatially fractionated kilovoltage X-ray microbeams through the dose volume effect. Experimental measurements with Ta2O5 nanoparticles (NPs) in 9L gliosarcoma treated with MRT at the Australian Synchrotron, increased the treatment efficiency. Ta2O5 NPs were observed to form shells around cell nuclei which may be the reason for their efficiency in MRT. In this article, our experimental observation of NP shell formation is the basis of a Geant4 radiation transport study to characterise dose enhancement by Ta2O5 NPs in MRT. Our study showed that NP shells enhance the physical dose depending microbeam energy and their location relative to a single microbeam. For monochromatic microbeam energies below ∼70keV, NP shells show highly localised dose enhancement due to the short range of associated secondary electrons. Low microbeam energies indicate better targeted treatment by allowing higher microbeam doses to be administered to tumours and better exploit the spatial fractionation related selectivity observed with MRT. For microbeam energies above ∼100keV, NP shells extend the physical dose enhancement due to longer-range secondary electrons. Again, with NPs selectively internalised, the local effectiveness of MRT is expected to increase in the tumour. Dose enhancement produced by the shell aggregate varied more significantly in the cell population, depending on its location, when compared to a homogeneous NP distribution. These combined simulation and experimental data provide first evidence for optimising MRT through the incorporation of newly observed Ta2O5 NP distributions within 9L cancer cells.

  8. 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. Copyright © 2015. Published by Elsevier Ltd.

  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. WE-AB-BRB-12: Nanoscintillator Fiber-Optic Detector System for Microbeam Radiation Therapy Dosimetry

    SciTech Connect

    Rivera, J; Dooley, J; Chang, S; Belley, M; Yoshizumi, T; Stanton, I; Langloss, B; Therien, M

    2015-06-15

    Purpose: Microbeam Radiation Therapy (MRT) is an experimental radiation therapy that has demonstrated a higher therapeutic ratio than conventional radiation therapy in animal studies. There are several roadblocks in translating the promising treatment technology to clinical application, one of which is the lack of a real-time, high-resolution dosimeter. Current clinical radiation detectors have poor spatial resolution and, as such, are unsuitable for measuring microbeams with submillimeter-scale widths. Although GafChromic film has high spatial resolution, it lacks the real-time dosimetry capability necessary for MRT preclinical research and potential clinical use. In this work we have demonstrated the feasibility of using a nanoscintillator fiber-optic detector (nanoFOD) system for real-time MRT dosimetry. Methods: A microplanar beam array is generated using a x-ray research irradiator and a custom-made, microbeam-forming collimator. The newest generation nanoFOD has an effective size of 70 µm in the measurement direction and was calibrated against a kV ion chamber (RadCal Accu-Pro) in open field geometry. We have written a computer script that performs automatic data collection with immediate background subtraction. A computer-controlled detector positioning stage is used to precisely measure the microbeam peak dose and beam profile by translating the stage during data collection. We test the new generation nanoFOD system, with increased active scintillation volume, against the previous generation system. Both raw and processed data are time-stamped and recorded to enable future post-processing. Results: The real-time microbeam dosimetry system worked as expected. The new generation dosimeter has approximately double the active volume compared to the previous generation resulting in over 900% increase in signal. The active volume of the dosimeter still provided the spatial resolution that meets the Nyquist criterion for our microbeam widths. Conclusion: We have

  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. 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.

  13. High resolution 3D dosimetry for microbeam radiation therapy using optical CT

    NASA Astrophysics Data System (ADS)

    McErlean, C.; Bräuer-Krisch, E.; Adamovics, J.; Leach, M. O.; Doran, S. J.

    2015-01-01

    Optical Computed Tomography (CT) is a promising technique for dosimetry of Microbeam Radiation Therapy (MRT), providing high resolution 3D dose maps. Here different MRT irradiation geometries are visualised showing the potential of Optical CT as a tool for future MRT trials. The Peak-to-Valley dose ratio (PVDR) is calculated to be 7 at a depth of 3mm in the radiochromic dosimeter PRESAGE®. This is significantly lower than predicted values and possible reasons for this are discussed.

  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. New 3D Silicon detectors for dosimetry in Microbeam Radiation Therapy

    NASA Astrophysics Data System (ADS)

    Lerch, M. L. F.; Dipuglia, A.; Cameron, M.; Fournier, P.; Davis, J.; Petasecca, M.; Cornelius, I.; Perevertaylo, V.; Rosenfeld, A. B.

    2017-01-01

    Microbeam Radiation Therapy (MRT) involves the use of a spatially fractionated beam of synchrotron generated X-rays to treat tumours. MRT treatment is delivered via an array of high dose ‘peaks’ separated by low dose ‘valleys’. A good Peak to Valley Dose Ratio (PVDR) is an important indicator of successful treatment outcomes. MRT dosimetry requires a radiation hard detector with high spatial resolution, large dynamic range, which is ideally real-time and tissue equivalent. We have developed a Silicon Strip Detector (SSD) and very recently, a new 3D MESA SSD to meet the very stringent requirements of MRT dosimetry. We have compared these detectors through the characterisation of the MRT radiation field at the Australian Synchrotron Imaging and Medical Beamline. The EPI SSD was able to measure the microbeam profiles and PVDRs, however the effective spatial resolution was limited by the detector alignment options available at the time. The geometry of the new 3D MESA SSD is less sensitive to this alignment restriction was able to measure the microbeam profiles within 2 μm of that expected. The 3D MESA SSD measured PVDRs were possibly affected by undesired and slow charge collection outside the sensitive volume and additional scattering from the device substrate.

  16. 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.

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

    PubMed

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

    2014-06-01

    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. 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. 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. The first prototype CNT

  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. 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.

  20. Ultra-high resolution optical CT dosimetry for the visualisation of synchrotron microbeam therapy doses

    NASA Astrophysics Data System (ADS)

    Doran, S. J.; Rahman, A. T. Abdul; Bräuer-Krisch, E.; Brochard, T.; Adamovics, J.

    2013-06-01

    Optical CT is a method that can potentially provide both accurate dosimetry at high spatial resolution and 3-D visualisation over a large field-of-view in a single dataset. The major factors limiting spatial resolution in previous studies are analysed here and it is shown that improvements in equipment specification can overcome many of these. The need for ultra-high spatial resolution in the verification of microbeam radiation therapy verification is demonstrated and example images of a PRESAGE® sample are presented.

  1. 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

  2. The development and characterization of a first generation carbon nanotube x-ray based microbeam radiation therapy system

    NASA Astrophysics Data System (ADS)

    Hadsell, Michael John, Jr.

    Microbeam radiation therapy (MRT) is a new type of cancer treatment currently being studied at scattered synchrotron sites throughout the world. It has been shown to be capable of ablating aggressive brain tumors in rats while almost completely sparing the surrounding normal tissue. This promising technique has yet to find its way to the clinic, however, because the radiobiological mechanisms behind its efficacy are still largely unknown. This is partly due to the lack of a compact device that could facilitate more large scale research. The challenges inherent to creating a compact device lie within the structure of MRT, which uses parallel arrays of ultra high-dose, orthovoltage, microplanar beams on the order of 100mum thick and separated by four to ten times their width. Because of focal spot limitations, current commercial orthovoltage devices are simply not capable of creating such arrays at dose rates high enough for effective treatment while maintaining the microbeam pattern necessary to retain the high therapeutic ratio of the technique. Therefore, the development of a compact MRT device using carbon nanotube (CNT) cathode based X-ray technology is presented here. CNT cathodes have been shown to be capable of creating novel focal spot arrays on a single anode while being robust enough for long-term use in X-ray tubes. Using these cathodes, an X-ray tube with a single focal line has been created for the delivery of MRT dose distributions in radiobiological studies on small animals. In this work, the development process and final design of this specialized device will be detailed, along with the optimization and stabilization of its use for small animal studies. In addition, a detailed characterization of its final capabilities will be given; including a comprehensive measurement of its X-ray focal line dimensions, a description and evaluation of its collimator alignment and microbeam dimensions, and a full-scale phantom-based quantification of its dosimetric

  3. The use of optical trap and microbeam to investigate the mechanical and transport characteristics of tunneling nanotubes in tumor spheroids.

    PubMed

    Patheja, Pooja; Dasgupta, Raktim; Dube, Alok; Ahlawat, Sunita; Verma, Ravi Shanker; Gupta, Pradeep Kumar

    2015-09-01

    The use of optical trap and microbeam for investigating mechanical and transport properties of inter cellular tunneling nanotubes (TnTs) in tumor spheroids has been demonstrated. TnTs in tumor spheroids have been visualized by manipulating TnT connected cells using optical tweezers. Functionality of the TnTs for transferring cytoplasmic vesicles and injected dye molecules by optoporation method has been studied. Further, the TnTs could be longitudinally stretched by manipulating the connected cells and their elastic response was studied. Manipulation of cells at the surface of tumor spheroid using optical tweezers and injection of fluorescent dye into a trapped cell using optoporation technique.

  4. 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.

  5. 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).

  6. Monte Carlo Simulations Of The Dose Distributions From Carbon Microbeams Used In An Experimental Radiation Therapy Method

    NASA Astrophysics Data System (ADS)

    Dioszegi, I.; Rusek, A.; Dane, B. R.; Chiang, I. H.; Meek, A. G.; Dilmanian, F. A.

    2011-06-01

    Recent upgrades of the MCNPX Monte Carlo code include transport of heavy ions. We employed the new code to simulate the energy and dose distributions produced by carbon beams in rabbit's head in and around a brain tumor. The work was within our experimental technique of interlaced carbon microbeams, which uses two 90° arrays of parallel, thin planes of carbon beams (microbeams) interlacing to produce a solid beam at the target. A similar version of the method was earlier developed with synchrotron-generated x-ray microbeams. We first simulated the Bragg peak in high density polyethylene and other materials, where we could compare the calculated carbon energy deposition to the measured data produced at the NASA Space Radiation Laboratory (NSRL) at Brookhaven National Laboratory (BNL). The results showed that new MCNPX code gives a reasonable account of the carbon beam's dose up to ˜200 MeV/nucleon beam energy. At higher energies, which were not relevant to our project, the model failed to reproduce the Bragg-peak's extent of increasing nuclear breakup tail. In our model calculations we determined the dose distribution along the beam path, including the angular straggling of the microbeams, and used the data for determining the optimal values of beam spacing in the array for producing adequate beam interlacing at the target. We also determined, for the purpose of Bragg-peak spreading at the target, the relative beam intensities of the consecutive exposures with stepwise lower beam energies, and simulated the resulting dose distribution in the spread out Bragg-peak. The details of the simulation methods used and the results obtained are presented.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. Synchrotron microbeam irradiation induces neutrophil infiltration, thrombocyte attachment and selective vascular damage in vivo

    PubMed Central

    Brönnimann, Daniel; Bouchet, Audrey; Schneider, Christoph; Potez, Marine; Serduc, Raphaël; Bräuer-Krisch, Elke; Graber, Werner; von Gunten, Stephan; Laissue, Jean Albert; Djonov, Valentin

    2016-01-01

    Our goal was the visualizing the vascular damage and acute inflammatory response to micro- and minibeam irradiation in vivo. Microbeam (MRT) and minibeam radiation therapies (MBRT) are tumor treatment approaches of potential clinical relevance, both consisting of parallel X-ray beams and allowing the delivery of thousands of Grays within tumors. We compared the effects of microbeams (25–100 μm wide) and minibeams (200–800 μm wide) on vasculature, inflammation and surrounding tissue changes during zebrafish caudal fin regeneration in vivo. Microbeam irradiation triggered an acute inflammatory response restricted to the regenerating tissue. Six hours post irradiation (6 hpi), it was infiltrated by neutrophils and fli1a+ thrombocytes adhered to the cell wall locally in the beam path. The mature tissue was not affected by microbeam irradiation. In contrast, minibeam irradiation efficiently damaged the immature tissue at 6 hpi and damaged both the mature and immature tissue at 48 hpi. We demonstrate that vascular damage, inflammatory processes and cellular toxicity depend on the beam width and the stage of tissue maturation. Minibeam irradiation did not differentiate between mature and immature tissue. In contrast, all irradiation-induced effects of the microbeams were restricted to the rapidly growing immature tissue, indicating that microbeam irradiation could be a promising tumor treatment tool. PMID:27640676

  13. In vivo pink-beam imaging and fast alignment procedure for rat brain lesion microbeam radiation therapy

    PubMed Central

    Serduc, Raphaël; Berruyer, Gilles; Brochard, Thierry; Renier, Michel; Nemoz, Christian

    2010-01-01

    A fast 50 µm-accuracy alignment procedure has been developed for the radiosurgery of brain lesions in rats, using microbeam radiation therapy. In vivo imaging was performed using the pink beam (35–60 keV) produced by the ID17 wiggler at the ESRF opened at 120 mm and filtered. A graphical user interface has been developed in order to define the irradiation field size and to position the target with respect to the skull structures observed in X-ray images. The method proposed here allows tremendous time saving by skipping the swap from white beam to monochromatic beam and vice versa. To validate the concept, the somatosensory cortex or thalamus of GAERS rats were irradiated under several ports using this alignment procedure. The magnetic resonance images acquired after contrast agent injection showed that the irradiations were selectively performed in these two expected brain regions. Image-guided microbeam irradiations have therefore been realised for the first time ever, and, thanks to this new development, the ID17 biomedical beamline provides a major tool allowing brain radiosurgery trials on animal patients. PMID:20400830

  14. [Immunological tumor therapy].

    PubMed

    Dietrich, K; Theobald, M

    2015-08-01

    Tumor cells could fundamentally be recognized and eliminated by the immune system but malignant cells are able to escape the immune surveillance system. The idea of immunotherapy of cancer is to activate, modulate and amplify the host immune response or to genetically equip the immune repertoire of patients with anti-tumor specificities and effectors. In recent years, a variety of promising immunotherapy strategies have been developed, such as bispecific, multispecific and immunoregulatory antibodies, gene-modified T lymphocytes and tumor vaccines. Some drugs have already been approved and others are available for patients in clinical trials. This article presents the current anti-tumor immune strategies and their molecular basis. Even though further research is needed in some areas, such as the establishment of biomarkers for targeted therapy, duration of therapeutic activity and compatibility of combined strategies, cancer immunotherapy is likely to be a key component in oncological treatment concepts in the very near future.

  15. An Evaluation of Dose Equivalence between Synchrotron Microbeam Radiation Therapy and Conventional Broadbeam Radiation Using Clonogenic and Cell Impedance Assays

    PubMed Central

    Ibahim, Mohammad Johari; Crosbie, Jeffrey C.; Yang, Yuqing; Zaitseva, Marina; Stevenson, Andrew W.; Rogers, Peter A. W.; Paiva, Premila

    2014-01-01

    Background High-dose synchrotron microbeam radiation therapy (MRT) has shown the potential to deliver improved outcomes over conventional broadbeam (BB) radiation therapy. To implement synchrotron MRT clinically for cancer treatment, it is necessary to undertake dose equivalence studies to identify MRT doses that give similar outcomes to BB treatments. Aim To develop an in vitro approach to determine biological dose equivalence between MRT and BB using two different cell-based assays. Methods The acute response of tumour and normal cell lines (EMT6.5, 4T1.2, NMuMG, EMT6.5ch, 4T1ch5, SaOS-2) to MRT (50–560 Gy) and BB (1.5–10 Gy) irradiation was investigated using clonogenic and real time cell impedance sensing (RT-CIS)/xCELLigence assays. MRT was performed using a lattice of 25 or 50 µm-wide planar, polychromatic kilovoltage X-ray microbeams with 200 µm peak separation. BB irradiations were performed using a Co60 teletherapy unit or a synchrotron radiation source. BB doses that would generate biological responses similar to MRT were calculated by data interpolation and verified by clonogenic and RT-CIS assays. Results For a given cell line, MRT equivalent BB doses identified by RT-CIS/xCELLigence were similar to those identified by clonogenic assays. Dose equivalence between MRT and BB were verified in vitro in two cell lines; EMT6.5ch and SaOS-2 by clonogenic assays and RT-CIS/xCELLigence. We found for example, that BB doses of 3.4±0.1 Gy and 4.40±0.04 Gy were radiobiologically equivalent to a peak, microbeam dose of 112 Gy using clonogenic and RT-CIS assays respectively on EMT6.5ch cells. Conclusion Our data provides the first determination of biological dose equivalence between BB and MRT modalities for different cell lines and identifies RT-CIS/xCELLigence assays as a suitable substitute for clonogenic assays. These results will be useful for the safe selection of MRT doses for future veterinary and clinical trials. PMID:24945301

  16. A preclinical microbeam facility with a conventional x-ray tube.

    PubMed

    Bartzsch, Stefan; Cummings, Craig; Eismann, Stephan; Oelfke, Uwe

    2016-12-01

    Microbeam radiation therapy is an innovative treatment approach in radiation therapy that uses arrays of a few tens of micrometer wide and a few hundreds of micrometer spaced planar x-ray beams as treatment fields. In preclinical studies these fields efficiently eradicated tumors while normal tissue could effectively be spared. However, development and clinical application of microbeam radiation therapy is impeded by a lack of suitable small scale sources. Until now, only large synchrotrons provide appropriate beam properties for the production of microbeams. In this work, a conventional x-ray tube with a small focal spot and a specially designed collimator are used to produce microbeams for preclinical research. The applicability of the developed source is demonstrated in a pilot in vitro experiment. The properties of the produced radiation field are characterized by radiochromic film dosimetry. 50 μm wide and 400 μm spaced microbeams were produced in a 20 × 20 mm(2) sized microbeam field. The peak to valley dose ratio ranged from 15.5 to 30, which is comparable to values obtained at synchrotrons. A dose rate of up to 300 mGy/s was achieved in the microbeam peaks. Analysis of DNA double strand repair and cell cycle distribution after in vitro exposures of pancreatic cancer cells (Panc1) at the x-ray tube and the European Synchrotron leads to similar results. In particular, a reduced G2 cell cycle arrest is observed in cells in the microbeam peak region. At its current stage, the source is restricted to in vitro applications. However, moderate modifications of the setup may soon allow in vivo research in mice and rats.

  17. Gene Therapy for Pituitary Tumors

    PubMed Central

    Seilicovich, Adriana; Pisera, Daniel; Sciascia, Sandra A.; Candolfi, Marianela; Puntel, Mariana; Xiong, Weidong; Jaita, Gabriela; Castro, Maria G.

    2009-01-01

    Pituitary tumors are the most common primary intracranial neoplasms. Although most pituitary tumors are considered typically benign, others can cause severe and progressive disease. The principal aims of pituitary tumor treatment are the elimination or reduction of the tumor mass, normalization of hormone secretion and preservation of remaining pituitary function. In spite of major advances in the therapy of pituitary tumors, for some of the most difficult tumors, current therapies that include medical, surgical and radiotherapeutic methods are often unsatisfactory and there is a need to develop new treatment strategies. Gene therapy, which uses nucleic acids as drugs, has emerged as an attractive therapeutic option for the treatment of pituitary tumors that do not respond to classical treatment strategies if the patients become intolerant to the therapy. The development of animal models for pituitary tumors and hormone hypersecretion has proven to be critical for the implementation of novel treatment strategies and gene therapy approaches. Preclinical trials using several gene therapy approaches for the treatment of anterior pituitary diseases have been successfully implemented. Several issues need to be addressed before clinical implementation becomes a reality, including the development of more effective and safer viral vectors, uncovering novel therapeutic targets and development of targeted expression of therapeutic transgenes. With the development of efficient gene delivery vectors allowing long-term transgene expression with minimal toxicity, gene therapy will become one of the most promising approaches for treating pituitary adenomas. PMID:16457646

  18. 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.

  19. 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.

  20. Monte Carlo simulation of stereotactic microbeam radiation therapy: evaluation of the usage of a linear accelerator as the x-ray source.

    PubMed

    Gokeri, Gurdal; Kocar, Cemil; Tombakoglu, Mehmet; Cecen, Yigit

    2013-07-07

    The usage of linear accelerator-generated x-rays for the stereotactic microbeam radiation therapy technique was evaluated in this study. Dose distributions were calculated with the Monte Carlo code MCNPX. Unidirectional single beams and beam arrays were simulated in a cylindrical water phantom to observe the effects of x-ray energies and irradiation geometry on dose distributions. Beam arrays were formed with square pencil beams. Two orthogonally interlaced beam arrays were simulated in a detailed head phantom and dose distributions were compared with ones which had been calculated for a bidirectional interlaced microbeam therapy (BIMRT) technique that uses synchrotron-generated x-rays. A parallel pattern of the beams was preserved through the phantom; however an unsegmented dose region could not be formed at the target. Five orthogonally interlaced beam array pairs (ten beam arrays) were simulated in a mathematical head phantom and the unsegmented dose region was formed. However, the dose fall-off distance is longer than the one that had been calculated for the BIMRT technique. Besides, the peak-to-dose ratios between the phantom's outer surface and the target region are lower. Therefore, the advantages of the MRT technique may not be preserved with the usage of a linac as the x-ray source.

  1. 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.

  2. Smithsonian Microbeam Standards.

    PubMed

    Jarosewich, Eugene

    2002-01-01

    This is a short history of the Smithsonian Microbeam Standards; their sources, selection, preparation, and analyses. Fifty-eight minerals, natural glasses, and synthetic samples have been characterized in the past 25 years. During that time, over 750 requests were received for approximately 11 000 individual samples. These reference samples are referred to as the Smithsonian Microbeam Standards.

  3. Smithsonian Microbeam Standards

    PubMed Central

    Jarosewich, Eugene

    2002-01-01

    This is a short history of the Smithsonian Microbeam Standards; their sources, selection, preparation, and analyses. Fifty-eight minerals, natural glasses, and synthetic samples have been characterized in the past 25 years. During that time, over 750 requests were received for approximately 11 000 individual samples. These reference samples are referred to as the Smithsonian Microbeam Standards. PMID:27446760

  4. Genome-wide transcription responses to synchrotron microbeam radiotherapy.

    PubMed

    Sprung, Carl N; Yang, Yuqing; Forrester, Helen B; Li, Jason; Zaitseva, Marina; Cann, Leonie; Restall, Tina; Anderson, Robin L; Crosbie, Jeffrey C; Rogers, Peter A W

    2012-10-01

    The majority of cancer patients achieve benefit from radiotherapy. A significant limitation of radiotherapy is its relatively low therapeutic index, defined as the maximum radiation dose that causes acceptable normal tissue damage to the minimum dose required to achieve tumor control. Recently, a new radiotherapy modality using synchrotron-generated X-ray microbeam radiotherapy has been demonstrated in animal models to ablate tumors with concurrent sparing of normal tissue. Very little work has been undertaken into the cellular and molecular mechanisms that differentiate microbeam radiotherapy from broad beam. The purpose of this study was to investigate and compare the whole genome transcriptional response of in vivo microbeam radiotherapy versus broad beam irradiated tumors. We hypothesized that gene expression changes after microbeam radiotherapy are different from those seen after broad beam. We found that in EMT6.5 tumors at 4-48 h postirradiation, microbeam radiotherapy differentially regulates a number of genes, including major histocompatibility complex (MHC) class II antigen gene family members, and other immunity-related genes including Ciita, Ifng, Cxcl1, Cxcl9, Indo and Ubd when compared to broad beam. Our findings demonstrate molecular differences in the tumor response to microbeam versus broad beam irradiation and these differences provide insight into the underlying mechanisms of microbeam radiotherapy and broad beam.

  5. 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. Copyright © 2012 Wiley Periodicals, Inc.

  6. Techniques of interventional tumor therapy.

    PubMed

    Mahnken, Andreas H; Bruners, Philipp; Günther, Rolf W

    2008-09-01

    The last few years have seen the rapid development of new image-guided interventions for the local treatment of malignant tumors. The goal of this article is to provide an overview of the techniques that are most commonly used today in interventional oncology. Selective literature review on the current state of image-guided interventional techniques for local tumor therapy. While surgery, radiation oncology, and systemic chemotherapy are still the three main pillars of tumor therapy, a broad range of minimally invasive, image-guided techniques for local tumor treatment is now available. These may be categorized as percutaneous injection of a toxic substance, transarterial embolization, thermal ablation, and internal radiotherapy. The choice of treatment depends on the type, location, and size of tumor. The greatest amount of clinical experience to date has been gathered in the treatment of primary and secondary hepatic malignancy, but there are interventional treatment options for virtually all regions of the body. At present, the utility of this form of treatment is limited for very large or multiple tumors; novel therapeutic options for these situations are now being studied. The outcome of treatment depends on a judicious determination of the indication for it. The indication should be established by interdisciplinary consensus after all treatment options have been considered.

  7. 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

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

    PubMed

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

    2014-08-01

    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. 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 portion of the mouse

  9. Radionuclide Therapy for Neuroendocrine Tumors.

    PubMed

    Cives, Mauro; Strosberg, Jonathan

    2017-02-01

    Peptide receptor radionuclide therapy (PRRT) is a form of systemic radiotherapy that allows targeted delivery of radionuclides to tumor cells expressing high levels of somatostatin receptors. The two radiopeptides most commonly used for PRRT, (90)Y-DOTATOC and (177)Lu-DOTATATE, have been successfully employed for more than a decade for the treatment of advanced neuroendocrine tumors (NETs). Recently, the phase III, randomized NETTER-1 trial has compared (177)Lu-DOTATATE versus high-dose octreotide LAR in patients with progressive, metastatic midgut NETs, demonstrating exceptional tolerability and efficacy. This review summarizes recent developments in the field of radionuclide therapy for gastroenteropancreatic and lung NETs and considers possible strategies to further enhance its clinical efficacy.

  10. 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

  11. 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

  12. 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

  13. Photodynamic therapy for esophageal tumors.

    PubMed

    McCaughan, J S; Nims, T A; Guy, J T; Hicks, W J; Williams, T E; Laufman, L R

    1989-01-01

    Between 1982 and 1987, 40 patients with esophageal tumors (19 adenocarcinomas, 19 squamous carcinomas, and two melanomas) in whom conventional treatments were unsuccessful were treated with photodynamic therapy (PDT) after injection with either hematoporphyrin derivative or dihematoporphyrin ether. Patients underwent endoscopy again two to three days and one month after PDT and as needed when symptoms recurred. At one month, the average minimal diameter opening of 28 assessable tumors increased from 6 to 9 mm. Of the 35 patients who could be evaluated one month after PDT, the average improvement in food intake was from a liquid to a soft diet. Average survival time (from time of first treatment) was 7.7 months (n = 17) for adenocarcinoma, 5.8 months (n = 12) for squamous cell carcinoma, and 25 months (n = 2) for melanoma. Two patients with stage I adenocarcinoma were alive with no evidence of disease at 11 and 23 months. One patient with stage I squamous cell cancer died 18 months after PDT, with recurrence of tumor above the treated area noted eight months after treatment. One patient with stage I melanoma died of a synchronous colon cancer 31 months after PDT, with no evidence of residual melanoma.

  14. Therapy of melanocytic conjunctival tumors.

    PubMed

    Halas, Jr M; Svetlosakova, Z; Babal, P

    2013-01-01

    Clinical experience of our single center in dealing with pigmented epibulbar lesions - melanocytic conjunctival tumors is presented. Since 2008 we use the topical treatment with mitomycin C (MMC) as an alternative or adjunctive method for excision in the treatment of melanocytic neoplasia of the conjunctiva. The retrospective case series of 85 patients with pigmented lesions of the conjunctiva - melanocytic conjunctival tumors, histopathologically examined in the period 2001-2010 is presented. Since 2008 we started to apply MMC in the treatment of primary acquired melanosis (PAM) and dysplastic nevi. We apply MMC topically directly after an excision as 2-times five minutes application. In 85 patients with pigmented lesions of the conjunctiva histopathological findings after excision of the lesion showed in 68 (80 %) cases melanocytic nevocelullar nevus, out of which 55 cases were combined and 13 cases were junctional nevi. In 60 (80 %) cases of melanocytic nevi atypia was found in 25 patients (42 %), nevus without atypia was present in 35 cases (58 %). PAM with atypia was found in 16 patients (classified since 2000). During the period of application of MMC we diagnosed only one patient with primary conjunctival melanoma. There was no presence of relapse of the pigmented lesion either after primary excision or after excision with MMC. Resection of more than one quadrant of bulbar conjunctiva in patients with pigmented lesions of the conjunctiva in cases of conjunctival nevus with atypia and PAM with atypia combined with topical MMC chemotherapy is an alternative therapy for residual pigmented lesions. There was no presence of relapse of pigmentation in area of excision with or without using MMC during the surgery in patients with PAM. The number of our patients is not sufficient yet to draw a conclusion (Fig. 6, Ref. 21).

  15. Systemic Therapies for Advanced Pancreatic Neuroendocrine Tumors

    PubMed Central

    Raj, Nitya; Reidy-Lagunes, Diane

    2016-01-01

    SYNOPSIS Pancreatic neuroendocrine tumors are a rare tumor type, and comprise 1-2% of all pancreatic neoplasms. When nonfunctional (i.e. nonhormone secreting), these tumors generally cause few symptoms and often go unnoticed for several years; for this reason, they are rarely localized at presentation, and are typically diagnosed in the presence of metastatic disease, most commonly to the liver. Although pancreatic neuroendocrine tumors can be less aggressive than other tumor types, the management poses a significant challenge because of the heterogeneous clinical presentations and varying degrees of aggressiveness. The therapy of pancreatic neuroendocrine tumors includes a multimodality approach and can often include surgery, liver-directed therapies (i.e. embolization), as well as targeted and cytotoxic systemic treatments. A variety of systemic therapies have been developed for the management of pancreatic neuroendocrine tumors. These therapies include somatostatin analogs (octreotide or lanreotide), a select group of cytotoxic chemotherapy agents (alkylating, fluorouracil and platinum drugs), as well as targeted or biologic agents (everolimus and sunitinib). This chapter will review the available systemic therapy options for advanced pancreatic neuroendocrine tumors. PMID:26614372

  16. Targeting Therapy Resistant Tumor Vessels

    DTIC Science & Technology

    2008-08-01

    implanted Lewis lung carcinomas. Strikingly, within 24 hours, endothelial fenestrations in RIP-Tag2 tumors disap- peared, vascular sprouting was...reduced in sur- viving endothelial cells. Vessels in Lewis lung tumors, which lacked endothelial fenestrations, showed less regression. In both tumors...express unique proteins7 and have bi- Supported in part by the National Institutes of Health (grants HL-24136 and HL-59157 from the National, Heart, Lung

  17. 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.

  18. 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.

  19. A therapy inactivating the tumor angiogenic factors.

    PubMed

    Morales-Rodrigo, Cristian

    2013-02-01

    This paper is devoted to a nonlinear system of partial differential equations modeling the effect of an anti-angiogenic therapy based on an agent that binds to the tumor angiogenic factors. The main feature of the model under consideration is a nonlinear flux production of tumor angiogenic factors at the boundary of the tumor. It is proved the global existence for the nonlinear system and the effect in the large time behavior of the system for high doses of the therapeutic agent.

  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. Advancement and prospects of tumor gene therapy.

    PubMed

    Zhang, Chao; Wang, Qing-Tao; Liu, He; Zhang, Zhen-Zhu; Huang, Wen-Lin

    2011-03-01

    Gene therapy is one of the most attractive fields in tumor therapy. In past decades, significant progress has been achieved. Various approaches, such as viral and non-viral vectors and physical methods, have been developed to make gene delivery safer and more efficient. Several therapeutic strategies have evolved, including gene-based (tumor suppressor genes, suicide genes, antiangiogenic genes, cytokine and oxidative stress-based genes) and RNA-based (antisense oligonucleotides and RNA interference) approaches. In addition, immune response-based strategies (dendritic cell- and T cell-based therapy) are also under investigation in tumor gene therapy. This review highlights the progress and recent developments in gene delivery systems, therapeutic strategies, and possible clinical directions for gene therapy.

  2. Behavior of tumors under nonstationary therapy

    NASA Astrophysics Data System (ADS)

    Sotolongo-Costa, O.; Morales Molina, L.; Rodríguez Perez, D.; Antoranz, J. C.; Chacón Reyes, M.

    2003-04-01

    We present a model for the interaction dynamics of lymphocytes-tumor cells population. This model reproduces all known states for the tumor. Further, we develop it taking into account periodical immunotherapy treatment with cytokines alone. A detailed analysis for the evolution of tumor cells as a function of frequency and therapy burden applied for the periodical treatment is carried out. Certain threshold values for the frequency and applied doses are derived from this analysis. So it seems possible to control and reduce the growth of the tumor. Also, constant values for cytokines doses seems to be a successful treatment.

  3. 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

  4. Targeting Therapy Resistant Tumor Vessels

    DTIC Science & Technology

    2007-05-01

    other recognition sequences for integrins. Annu Rev Cell Dev Biol 1996;12:697–715. 34. Parsons-Wingerter P, Kasman IM, Norberg S, et al. Uniform...overexpression and rapid accessibility of a5h1 integrin on blood vessels in tumors. Am J Pathol 2005;167:193–211. 35. Magnussen A, Kasman IM, Norberg S

  5. Microbeam formation system

    NASA Astrophysics Data System (ADS)

    Kazarinov, N. Yu.; Kazacha, V. I.; Kalagin, I. V.

    2017-01-01

    Equations for calculating the microbeam formation channel are derived. The channel consists of two coaxial diaphragms with radii r 1,2 and a target with a radius r T . With the given ion beam parameters, distance between the diaphragms L, beam radius on the target r T , and desired efficiency of beam passage through the diaphragms η0, the system of equations allows calculating the distance from the second diaphragm to the target L 1 and the radii of both diaphragms. Dependences of the diaphragm radii and the distance L 1on the efficiency η0 at a fixed target radius r T and of the efficiency η0 and the diaphragm radii r 1,2 on the distance L at a fixed distance L 1 are found. The effect of the deviations of the main channel and beam parameters from the optimum values on the microbeam formation efficiency is estimated. Tolerable values are determined for the diaphragm displacement and background magnetic field.

  6. Photodynamic therapy of solid tumors

    NASA Astrophysics Data System (ADS)

    Jori, Giulio

    Some porphyrin compounds, which are characterized by a relatively large degree of hydrophobicity (n-octanol/water partition coefficient above 8), are accumulated in greater amounts and retained for longer periods of time by neoplastic as compared with normal tissues. The affinity of these dyes for tumors is partially a consequence of their in vivo transport by low-density lipoproteins, which are preferentially endocytosized by hyperproliferating tissues in a receptor-mediated process. In general, at 24-48 h after the systematic administration of porphyrin doses in the range of 2.5 mg/kg body weight, the ratio of drug concentration between the neoplastic and the surrounding tissues is sufficiently large to guarantee a selective photoexcitation of the porphyrin. Toward this aim, the porphyrin-containing tumor tissues are irradiated with light wavelengths longer than 600 nm, since the transmittance of biological tissues is maximal in this spectral region. The electronically excited porphyrin transfers its excitation energy to oxygen, thus generating activated oxygen species (mainly, singlet oxygen): as a consequence, the photooxidative modification of subcellular targets (e.g. the plasma membrane and mitochondria) is readily obtained leading to an irreversible necrosis of the cell. With the most frequently used porphyrins for clinical phototherapy (including hematoporphyrin and its derivatives HpD and Photofrin II), one observes the preferential photosensitized destruction of endothelial cells, hence the vascular damage is a major process involved in the necrosis of tumors. The optimization of the phototherapy of tumors is presently pursued by the definition of clinical protocols tailored to the optical properties of specific neoplastic tissues as well as by the use of porphyrin analogs, such as chlorins and phthalocyanines, having an extinction coefficient in the red spectral region larger than that typical of hematoporphyrin and HpD.

  7. 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.

  8. 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.

  9. 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.

  10. Personalized Therapy: Tumor Antigen Discovery for Adoptive Cellular Therapy.

    PubMed

    Yee, Cassian; Lizee, Gregory A

    Adoptive cell therapy using endogenous T cells involves the ex vivo isolation and expansion of antigen-specific T cells from the peripheral blood and is uniquely suited for validating and translating antigen discovery. Endogenous T-cell therapy does not require accessible tumor as a source of infiltrating T cells and is free of regulatory and logistical constraints associated with engineering T cells. Candidate epitope peptides identified through antigen discovery may be rapidly implemented as targets in clinical trials of endogenous T-cell therapy and even incorporated as an "ad hoc" approach to personalized treatment when autologous tumor is available. Several first-in-human studies using a uniform population of antigen-specific T cells defined by phenotype and specificity have provided a means to confirm candidate antigens as potential tumor rejection antigens and to evaluate the reasons for success or failure using as a "transferrable cellular biomarker" the adoptively transferred T cells.

  11. 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.

  12. Tumor Static Concentration Curves in Combination Therapy.

    PubMed

    Cardilin, Tim; Almquist, Joachim; Jirstrand, Mats; Sostelly, Alexandre; Amendt, Christiane; El Bawab, Samer; Gabrielsson, Johan

    2017-03-01

    Combination therapies are widely accepted as a cornerstone for treatment of different cancer types. A tumor growth inhibition (TGI) model is developed for combinations of cetuximab and cisplatin obtained from xenograft mice. Unlike traditional TGI models, both natural cell growth and cell death are considered explicitly. The growth rate was estimated to 0.006 h(-1) and the natural cell death to 0.0039 h(-1) resulting in a tumor doubling time of 14 days. The tumor static concentrations (TSC) are predicted for each individual compound. When the compounds are given as single-agents, the required concentrations were computed to be 506 μg · mL(-1) and 56 ng · mL(-1) for cetuximab and cisplatin, respectively. A TSC curve is constructed for different combinations of the two drugs, which separates concentration combinations into regions of tumor shrinkage and tumor growth. The more concave the TSC curve is, the lower is the total exposure to test compounds necessary to achieve tumor regression. The TSC curve for cetuximab and cisplatin showed weak concavity. TSC values and TSC curves were estimated that predict tumor regression for 95% of the population by taking between-subject variability into account. The TSC concept is further discussed for different concentration-effect relationships and for combinations of three or more compounds.

  13. Non-Invasive Monitoring of Breast Tumor Oxygenation: A Key to Tumor Therapy Planning and Tumor Prognosis

    DTIC Science & Technology

    2004-09-01

    AD_ Award Number: DAMD17-00-1-0459 TITLE: Non-Invasive Monitoring of Breast Tumor Oxygenation: A Key to Tumor Therapy Planning and Tumor Prognosis...SUBTITLE 5. FUNDING NUMBERS Non-Invasive Monitoring of Breast Tumor Oxygenation: A Key DAMD17-00-1-0459 to Tumor Therapy Planning and Tumor Prognosis 6...research project is to develop and evaluate a new approach to monitoring of oxygenated hemoglobin concentration (HbO 2) of breast tumors under

  14. 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.

  15. Oxygenation-Enhanced Radiation Therapy of Breast Tumors

    DTIC Science & Technology

    2011-11-01

    10-1-0751 TITLE: Oxygenation-Enhanced Radiation Therapy of Breast Tumors PRINCIPAL INVESTIGATOR: Dr. Mikhail Skliar...locoregional breast cancer has evolved from radical mastectomy to targeted local therapy with breast conservation. The efficacy of conserving treatments...of breast cancers is impeded by tumor hypoxia, which affects 50% of locally advanced breast tumors. Poor oxygenation of hypoxic tumors reduces

  16. Targeting tumor suppressor genes for cancer therapy.

    PubMed

    Liu, Yunhua; Hu, Xiaoxiao; Han, Cecil; Wang, Liana; Zhang, Xinna; He, Xiaoming; Lu, Xiongbin

    2015-12-01

    Cancer drugs are broadly classified into two categories: cytotoxic chemotherapies and targeted therapies that specifically modulate the activity of one or more proteins involved in cancer. Major advances have been achieved in targeted cancer therapies in the past few decades, which is ascribed to the increasing understanding of molecular mechanisms for cancer initiation and progression. Consequently, monoclonal antibodies and small molecules have been developed to interfere with a specific molecular oncogenic target. Targeting gain-of-function mutations, in general, has been productive. However, it has been a major challenge to use standard pharmacologic approaches to target loss-of-function mutations of tumor suppressor genes. Novel approaches, including synthetic lethality and collateral vulnerability screens, are now being developed to target gene defects in p53, PTEN, and BRCA1/2. Here, we review and summarize the recent findings in cancer genomics, drug development, and molecular cancer biology, which show promise in targeting tumor suppressors in cancer therapeutics.

  17. Pulsed laser radiation therapy of skin tumors

    SciTech Connect

    Kozlov, A.P.; Moskalik, K.G.

    1980-11-15

    Radiation from a neodymium laser was used to treat 846 patients with 687 precancerous lesions or benign tumors of the skin, 516 cutaneous carcinomas, 33 recurrences of cancer, 51 melanomas, and 508 metastatic melanomas in the skin. The patients have been followed for three months to 6.5 years. No relapses have been observed during this period. Metastases to regional lymph nodes were found in five patients with skin melanoma. Pulsed laser radiation may be successfully used in the treatment of precancerous lesions and benign tumors as well as for skin carcinoma and its recurrences, and for skin melanoma. Laser radiation is more effective in the treatment of tumors inaccessible to radiation therapy and better in those cases in which surgery may have a bad cosmetic or even mutilating effect. Laser beams can be employed in conjunction with chemo- or immunotherapy.

  18. Tumor-Infiltrating Lymphocyte Therapy and Neoantigens.

    PubMed

    Robbins, Paul F

    The adoptive cell transfer (ACT) of autologous tumor-infiltrating lymphocytes has been shown to be effective at mediating tumor regression in more than half of patients with metastatic melanoma and in mediating long-term complete regression in approximately one fourth of all patients with this cancer. The success of this approach in patients with cholangiocarcinoma and colon cancer supports efforts to expand ACT therapies to treatment of patients bearing a wide array of cancer types. Recent improvements in deep sequencing of the patient cancers, combined with extensive immunological testing of autologous tumor-infiltrating lymphocytes, indicate that T cells targeting epitopes arising from nonsynonymous somatic mutations, termed neoantigens, play important roles in mediating many of the effective cancer immunotherapies seen in response to ACT.

  19. CAR T Cell Therapy for Solid Tumors.

    PubMed

    Newick, Kheng; O'Brien, Shaun; Moon, Edmund; Albelda, Steven M

    2017-01-14

    The field of cancer immunotherapy has been re-energized by the application of chimeric antigen receptor (CAR) T cell therapy in cancers. These CAR T cells are engineered to express synthetic receptors that redirect polyclonal T cells to surface antigens for subsequent tumor elimination. Many CARs are designed with elements that augment T cell persistence and activity. To date, CAR T cells have demonstrated tremendous success in eradicating hematologic malignancies (e.g., CD19 CARs in leukemias). However, this success has yet to be extrapolated to solid tumors, and the reasons for this are being actively investigated. We characterize some of the challenges that CAR T cells have to surmount in the solid tumor microenvironment and new approaches that are being considered to overcome these hurdles.

  20. 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.

  1. 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.

  2. 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).

  3. Photodynamic Therapy for Malignant Brain Tumors.

    PubMed

    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.

  4. New Pharmacologic Therapies for Gastroenteropancreatic Neuroendocrine Tumors

    PubMed Central

    Lawrence, Ben; Gustafsson, Bjorn I.; Kidd, Mark

    2011-01-01

    Synopsis Successful treatment of unresectable and metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) requires the thoughtful choice of systemic therapy as a component of a multidisciplinary therapeutic approach. The role of somatostatin analogs is established in symptom relief, but there is less clarity in respect of the efficacy of interferon and radiopeptide targeted therapy. The utility of a variety of tyrosine kinase and anti-angiogenic agents is very variable and under investigation, while a role for cytotoxic chemotherapy in poorly differentiated GEP-NETs is accepted. Overall, the ideal treatment of more indolent tumors is less certain. Reassessments of the GEP-NET pathology classification has provided improved logic for the role of a variety of agents, while the precise positioning of many new agents that target molecular pathways of angiogenesis and proliferation are under examination. This paper describes the current options for systemic therapy for GEP-NETs within the framework of the current (World Health Organization) WHO classification system PMID:20951920

  5. Mertk on tumor macrophages is a therapeutic target to prevent tumor recurrence following radiation therapy

    PubMed Central

    Crittenden, Marka R.; Baird, Jason; Friedman, David; Savage, Talicia; Uhde, Lauren; Alice, Alejandro; Cottam, Benjamin; Young, Kristina; Newell, Pippa; Nguyen, Cynthia; Bambina, Shelly; Kramer, Gwen; Akporiaye, Emmanuel; Malecka, Anna; Jackson, Andrew; Gough, Michael J.

    2016-01-01

    Radiation therapy provides a means to kill large numbers of cancer cells in a controlled location resulting in the release of tumor-specific antigens and endogenous adjuvants. However, by activating pathways involved in apoptotic cell recognition and phagocytosis, irradiated cancer cells engender suppressive phenotypes in macrophages. We demonstrate that the macrophage-specific phagocytic receptor, Mertk is upregulated in macrophages in the tumor following radiation therapy. Ligation of Mertk on macrophages results in anti-inflammatory cytokine responses via NF-kB p50 upregulation, which in turn limits tumor control following radiation therapy. We demonstrate that in immunogenic tumors, loss of Mertk is sufficient to permit tumor cure following radiation therapy. However, in poorly immunogenic tumors, TGFb inhibition is also required to result in tumor cure following radiation therapy. These data demonstrate that Mertk is a highly specific target whose absence permits tumor control in combination with radiation therapy. PMID:27602953

  6. Microbeam radiosurgery: An industrial perspective.

    PubMed

    Wright, Michael D

    2015-09-01

    In spite of its long demonstrated potential, microbeam radiosurgery (MBRS) has yet to be developed into a clinical tool. This article examines the problems associated with MBRS, and potential solutions. It is shown that a path to a clinically useful device is emerging.

  7. Microbeam MOMeNT: non-contact laser microdissection of membrane-mounted native tissue.

    PubMed Central

    Böhm, M.; Wieland, I.; Schütze, K.; Rübben, H.

    1997-01-01

    The analysis of tissue-specific genetic alterations depends on the selective procurement of homogeneous cell populations. Microbeam microdissection of membrane-mounted native tissue (MOMeNT) permits the rapid, selective, and low-contamination procurement of tumor or other cells from histological sections by non-thermic non-contact laser microdissection. Tissue sections are mounted on a specifically designed ultrathin transparent supporter membrane. Tissue together with the membrane are then dissected with an ultraviolet (337-nm) pulsed laser microbeam coupled into a robot-stage microscope. The ultraviolet laser causes dissection by cold photolysis due to the high photon density of the microbeam rather than by local heating. The track of the laser microbeam can be preselected freely on a video screen, and the size and form of the dissectates can thus be adapted to the histological features of the section with a delineation accuracy in the micron range. Polymerase chain reaction amplification of DNA from the dissectates is not impaired, and tumor-specific loss of heterozygosity of the APC gene as well as homozygous deletion of the MTS1 gene are demonstrated in bladder carcinomas. Taken together, microbeam MOMeNT is a novel technique that utilizes membrane-based microdissection by an ultraviolet laser microbeam, thus providing a flexible, easy-to-use high-performance tool for the molecular pathologist. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:9212732

  8. 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

  9. Current applications and future prospects of nanomaterials in tumor therapy

    PubMed Central

    Huang, Yu; Fan, Chao-Qiang; Dong, Hui; Wang, Su-Min; Yang, Xiao-Chao; Yang, Shi-Ming

    2017-01-01

    Tumors are one of the most serious human diseases and cause numerous global deaths per year. In spite of many strategies applied in tumor therapy, such as radiation therapy, chemotherapy, surgery, and a combination of these treatments, tumors are still the foremost killer worldwide among human diseases, due to their specific limitations, such as multidrug resistance and side effects. Therefore, it is urgent and necessary to develop new strategies for tumor therapy. Recently, the fast development of nanoscience has paved the way for designing new strategies to treat tumors. Nanomaterials have shown great potential in tumor therapy, due to their unique properties, including passive targeting, hyperthermia effects, and tumor-specific inhibition. This review summarizes the recent progress using the innate antitumor properties of metallic and nonmetallic nanomaterials to treat tumors, and related challenges and prospects are discussed. PMID:28331307

  10. Targeting Quiescent Cancer Cells to Eliminate Tumor Recurrence After Therapy

    DTIC Science & Technology

    2016-12-01

    AD_________________ Award Number: W81XWH-14-1-0350 TITLE: Targeting Quiescent Cancer Cells to Eliminate Tumor Recurrence After Therapy PRINCIPAL...30 Sep 2014 - 29 Sep 2016 4. TITLE AND SUBTILE Targeting Quiescent Cancer Cells to Eliminate Tumor Recurrence After Therapy 5a. CONTRACT NUMBER...cancer. To eradicate chemoresistant tumor cells , it is important to identify the subset of tumor cells that can survive from chemotherapy and

  11. 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

  12. Musculoskeletal tumor imaging, biopsy, and therapies: self-assessment module.

    PubMed

    Roberts, Catherine C; Liu, Patrick T; Wenger, Doris E

    2009-12-01

    The educational objectives for this self-assessment module are for the participant to exercise, self-assess, and improve his or her understanding of musculoskeletal tumor imaging, biopsy, and therapies. The solutions in this activity review the imaging characteristics of musculoskeletal tumors, biopsy approaches, and therapies.

  13. Clinical use of photodynamic therapy in ocular tumors.

    PubMed

    Cerman, Eren; Çekiç, Osman

    2015-01-01

    Although the introduction of intravitreal anti-vascular endothelial growth factor drugs reduced the indications for photodynamic therapy in ophthalmology, it may still be used in various ocular tumors. Although many studies have shown that photodynamic therapy is effective in ocular tumors, the literature consists of case reports and series. In this review, we systematically performed a meta-analysis for the use of photodynamic therapy in circumscribed choroidal hemangioma, diffuse choroidal hemangioma, retinal capillary hemangioma, von Hippel-Lindau angiomatosis, choroidal melanoma, retinal astrocytoma, retinoblastoma, eyelid tumors, conjunctival tumors, and choroidal metastasis. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. 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+}.

  15. Addressing intra-tumoral heterogeneity and therapy resistance

    PubMed Central

    Rybinski, Brad; Yun, Kyuson

    2016-01-01

    In the last several years, our appreciation of intra-tumoral heterogeneity has greatly increased due to accumulating evidence for the co-existence of genetically and epigenetically divergent cancer cells residing in different microenvironments within a tumor. Herein, we review recent literature discussing intra-tumoral heterogeneity in the context of therapy resistance mechanisms at the genetic, epigenetic and microenvironmental levels. We illustrate the influence of tumor microenvironment on therapy resistance and epigenetic states of cancer cells by highlighting the role of cancer stem cells in therapy resistance. We also summarize different strategies that have been employed to address various resistance mechanisms at genetic, epigenetic, and microenvironmental levels in preclinical and clinical studies. We propose that future personalized cancer therapy design needs to incorporate dynamic and comprehensive analyses of tumor heterogeneity landscape and multi-dimensional mechanisms of therapy resistance. PMID:27608848

  16. Neural stem cell-based gene therapy for brain tumors.

    PubMed

    Kim, Seung U

    2011-03-01

    Advances in gene-based medicine since 1990s have ushered in new therapeutic strategy of gene therapy for inborn error genetic diseases and cancer. Malignant brain tumors such as glioblastoma multiforme and medulloblastoma remain virtually untreatable and lethal. Currently available treatment for brain tumors including radical surgical resection followed by radiation and chemotherapy, have substantially improved the survival rate in patients suffering from these brain tumors; however, it remains incurable in large proportion of patients. Therefore, there is substantial need for effective, low-toxicity therapies for patients with malignant brain tumors, and gene therapy targeting brain tumors should fulfill this requirement. Gene therapy for brain tumors includes many therapeutic strategies and these strategies can be grouped in two major categories: molecular and immunologic. The widely used molecular gene therapy approach is suicide gene therapy based on the conversion of non-toxic prodrugs into active anticancer agents via introduction of enzymes and genetic immunotherapy involves the gene transfer of immune-stimulating cytokines including IL-4, IL-12 and TRAIL. For both molecular and immune gene therapy, neural stem cells (NSCs) can be used as delivery vehicle of therapeutic genes. NSCs possess an inherent tumor tropism that supports their use as a reliable delivery vehicle to target therapeutic gene products to primary brain tumors and metastatic cancers throughout the brain. Significance of the NSC-based gene therapy for brain tumor is that it is possible to exploit the tumor-tropic property of NSCs to mediate effective, tumor-selective therapy for primary and metastatic cancers in the brain and outside, for which no tolerated curative treatments are currently available.

  17. Microbeam Studies of the Bystander Response

    PubMed Central

    PRISE, Kevin M.; SCHETTINO, Giuseppe; VOJNOVIC, Boris; BELYAKOV, Oleg; SHAO, Chunlin

    2010-01-01

    Microbeams have undergone a renaissance since their introduction and early use in the mid 60s. Recent advances in imaging, software and beam delivery have allowed rapid technological developments in microbeams for use in a range of experimental studies. The resurgence in the use of microbeams since the mid 90s has coincided with major changes in our understanding of how radiation interacts with cells. In particular, the evidence that bystander responses occur, where cells not directly irradiated can respond to irradiated neighbours, has brought about the evolution of new models of radiation response. Although these processes have been studied using a range of experimental approaches, microbeams offer a unique route by which bystander responses can be elucidated. Without exception, all of the microbeams currently active internationally have studied bystander responses in a range of cell and tissue models. Together these studies have considerably advanced our knowledge of bystander responses and the underpinning mechanisms. Much of this has come from charged particle microbeam studies, but increasingly, X-ray and electron microbeams are starting to contribute quantitative and mechanistic information on bystander effects. A recent development has been the move from studies with 2-D cell culture models to more complex 3-D systems where the possibilities of utilizing the unique characteristics of microbeams in terms of their spatial and temporal delivery will make a major impact. PMID:19346680

  18. Laser effect in photodynamic therapy of tumors

    NASA Astrophysics Data System (ADS)

    Ion, Rodica-Mariana; Brezoi, Dragos-Viorel; Neagu, Monica; Manda, Gina; Constantin, Carolina

    2007-03-01

    Photodynamic therapy is a method that provides a reasonable alternative to other treatment modalities for patients with certain cancers, and in some cases may be the preferred treatment. The therapy implies the intravenous administration of a light-sensitive substance, the photosensitizer. The used sensitizer must absorb at long wavelength. For these purposes, the carbon dioxide laser, He-Ne and the argon laser are particularly suitable. In this study we evaluate in vitro the cytotoxic activity of three synthesized metallo-phthalocyanines with absorption bands in the red part of the spectrum: zinc-di-sulphonated phthalocyanine (ZnS IIPc), zinc-tri-sulphonated phthalocyanine (ZnS 3Pc) and zinc-tetrasulphonated phthalocyanine (ZnS 4Pc). Some cellular models have been used in this paper, in order to optimize the conditions of this method, as we are presenting in this paper (LSR-SF(SR) - transplantable sarcoma in rat induced by Rous sarcoma virus strain Schmidt-Ruppin; LSCC-SF(Mc29) - transplantable chicken hepatoma induced by the myelocytomatosis virus Mc29, MCF-7 cell line (human breast adenocarcinoma) derived from a patient with metastatic breast cancer, 8-MG-BA - glioblastoma multiforme 8-MG-BA, K562 - lymphoblastic human cell line, LLC-WRC 256 - Walker epithelial carcinoma. Activation of these photosensitizers retained in the cancerous cells, by red light emitted from a He-Ne laser at λ= 632.8 nm laser system, or by a diode laser emitting at 672 nm, produces a photochemical reaction that results in the selective destruction of tumor cells.

  19. X-ray microbeam measurements with a high resolution scintillator fibre-optic dosimeter.

    PubMed

    Archer, James; Li, Enbang; Petasecca, Marco; Dipuglia, Andrew; Cameron, Matthew; Stevenson, Andrew; Hall, Chris; Hausermann, Daniel; Rosenfeld, Anatoly; Lerch, Michael

    2017-09-29

    Synchrotron microbeam radiation therapy is a novel external beam therapy under investigation, that uses highly brilliant synchrotron x-rays in microbeams 50 μm width, with separation of 400 μm, as implemented here. Due to the fine spatial fractionation dosimetry of these beams is a challenging and complicated problem. In this proof-of-concept work, we present a fibre optic dosimeter that uses plastic scintillator as the radiation conversion material. We claim an ideal one-dimensional resolution of 50 μm. Using plastic scintillator and fibre optic makes this dosimeter water-equivalent, a very desirable dosimetric property. The dosimeter was tested at the Australian Synchrotron, on the Imaging and Medical Beam-Line. The individual microbeams were able to be resolved and the peak-to-valley dose ratio and the full width at half maximum of the microbeams was measured. These results are compared to a semiconductor strip detector of the same spatial resolution. A percent depth dose was measured and compared to data acquired by an ionisation chamber. The results presented demonstrate significant steps towards the development of an optical dosimeter with the potential to be applied in quality assurance of microbeam radiation therapy, which is vital if clinical trials are to be performed on human patients.

  20. Bio and nanotechnological strategies for tumor-targeted gene therapy.

    PubMed

    Kang, Jeong-Hun; Toita, Riki; Katayama, Yoshiki

    2010-01-01

    Gene therapy is a new medical approach for the treatment of tumors. For safe and efficient gene therapy, therapeutic genes need to be delivered efficiently into the target tumor cells. Development of gene delivery systems to specifically recognize and target tumor cells and to distinguish them from normal cells, especially in the same tissue or organ, is one of the most important issues regarding the present gene delivery methodologies. The enhanced permeability and retention (EPR) effect using the characteristics of angiogenic tumor blood vessels, as well as gene delivery systems recognizing hyperactivated receptors or intracellular signals, is broadly applied to tumor-targeted gene therapy. In addition, bacterial vectors can be a useful means for targeting hypoxic or anoxic regions of a tumor.

  1. 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

  2. Ozone Therapy for Tumor Oxygenation: a Pilot Study.

    PubMed

    Clavo, Bernardino; Pérez, Juan L.; López, Laura; Suárez, Gerardo; Lloret, Marta; Rodríguez, Victor; Macías, David; Santana, Maite; Hernández, María A.; Martín-Oliva, Roberto; Robaina, Francisco

    2004-06-01

    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 tumor pO(2) 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.

  3. 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

  4. Applications of nanotechnology to imaging and therapy of brain tumors.

    PubMed

    Mohs, Aaron M; Provenzale, James M

    2010-08-01

    In the past decade, numerous advances in the understanding of brain tumor physiology, tumor imaging, and tumor therapy have been attained. In some cases, these advances have resulted from refinements of pre-existing technologies (eg, improvements of contrast-enhanced magnetic resonance imaging). In other instances, advances have resulted from development of novel technologies. The development of nanomedicine (ie, applications of nanotechnology to the field of medicine) is an example of the latter. In this review, the authors explain the principles that underlay nanoparticle design and function as well as the means by which nanoparticles can be used for imaging and therapy of brain tumors.

  5. Patients With Brain Tumors: Who Receives Postacute Occupational Therapy Services?

    PubMed

    Chan, Vincy; Xiong, Chen; Colantonio, Angela

    2015-01-01

    Data on the utilization of occupational therapy among patients with brain tumors have been limited to those with malignant tumors and small samples of patients outside North America in specialized palliative care settings. We built on this research by examining the characteristics of patients with brain tumors who received postacute occupational therapy services in Ontario, Canada, using health care administrative data. Between fiscal years 2004-2005 and 2008-2009, 3,199 patients with brain tumors received occupational therapy services in the home care setting after hospital discharge; 12.4% had benign brain tumors, 78.2% had malignant brain tumors, and 9.4% had unspecified brain tumors. However, patients with benign brain tumors were older (mean age=63.3 yr), and a higher percentage were female (65.2%). More than 90% of patients received in-home occupational therapy services. Additional research is needed to examine the significance of these differences and to identify factors that influence access to occupational therapy services in the home care setting.

  6. A history of laser scissors (microbeams).

    PubMed

    Berns, Michael W

    2007-01-01

    This introductory chapter reviews the history of microbeams starting with the original UV microbeam work of Tchakhotine in 1912 and covers the progress and application of microbeams through 2006. The main focus of the chapter is on laser "scissors" starting with Marcel Bessis' and colleagues work with the ruby laser microbeam in Paris in 1962. Following this introduction, a section is devoted to describing the different laser microbeam systems and then the rest of the chapter is devoted to applications in cell and developmental biology. The approach is to focus on the organelle/structure and describe how the laser microbeam has been applied to studying its structure and/or function. Since considerable work has been done on chromosomes and the mitotic spindle (Section V.A and C), these topics have been divided in distinct subsections. Other topics discussed are injection of foreign DNA through the cell membrane (optoporation/optoinjection), cell migration, the nucleolus, mitochondria, cytoplasmic filaments, and embryos fate-mapping. A final technology section is devoted to discussing the pros and cons of building/buying your own laser microbeam system and the option of using the Internet-based RoboLase system. Throughout the chapter, reference is made to other chapters in the book that go into more detail on the subjects briefly mentioned.

  7. 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.

  8. The new Sandia light ion microbeam

    NASA Astrophysics Data System (ADS)

    Vizkelethy, G.; Doyle, B. L.; McDaniel, F. L.

    2012-02-01

    The Ion Beam Laboratory of Sandia National Laboratories (SNL) was recently relocated into a brand new building. The 6 MV High Voltage Engineering (HVE) tandem accelerator (hosting the heavy ion microbeam and several analytical beam lines) and the 350 kV HVE implanter with a nanobeam were moved to the new building. There were several new pieces of equipment acquired associated with the move, among them a new high brightness 3 MV Pelletron accelerator, a high resolution light ion microbeam, a nanoimplanter, and a transmission electron microscope (TEM) connected to the tandem accelerator. In this paper this new facility will be described, and initial results of the new microbeam will be presented.

  9. 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

  10. 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.

  11. 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

  12. Current status of gene therapy for brain tumors.

    PubMed

    Murphy, Andrea M; Rabkin, Samuel D

    2013-04-01

    Glioblastoma (GBM) is the most common and deadliest primary brain tumor in adults, with current treatments having limited impact on disease progression. Therefore the development of alternative treatment options is greatly needed. Gene therapy is a treatment strategy that relies on the delivery of genetic material, usually transgenes or viruses, into cells for therapeutic purposes, and has been applied to GBM with increasing promise. We have included selectively replication-competent oncolytic viruses within this strategy, although the virus acts directly as a complex biologic anti-tumor agent rather than as a classic gene delivery vehicle. GBM is a good candidate for gene therapy because tumors remain locally within the brain and only rarely metastasize to other tissues; the majority of cells in the brain are post-mitotic, which allows for specific targeting of dividing tumor cells; and tumors can often be accessed neurosurgically for administration of therapy. Delivery vehicles used for brain tumors include nonreplicating viral vectors, normal adult stem/progenitor cells, and oncolytic viruses. The therapeutic transgenes or viruses are typically cytotoxic or express prodrug activating suicide genes to kill glioma cells, immunostimulatory to induce or amplify anti-tumor immune responses, and/or modify the tumor microenvironment such as blocking angiogenesis. This review describes current preclinical and clinical gene therapy strategies for the treatment of glioma.

  13. Drug delivery systems for brain tumor therapy.

    PubMed

    Rautioa, Jarkko; Chikhale, Prashant J

    2004-01-01

    Brain tumors are one of the most lethal forms of cancer. They are extremely difficult to treat. Although, the rate of brain tumor incidence is relatively low, the field clearly lacks therapeutic strategies capable of overcoming barriers for effective delivery of drugs to brain tumors. Clinical failure of many potentially effective therapeutics for the treatment of brain tumors is usually not due to a lack of drug potency, but rather can be attributed to shortcomings in the methods by which a drug is delivered to the brain and into brain tumors. In response to the lack of efficacy of conventional drug delivery methods, extensive efforts have been made to develop novel strategies to overcome the obstacles for brain tumor drug delivery. The challenge is to design therapeutic strategies that deliver drugs to brain tumors in a safe and effective manner. This review provides some insight into several potential techniques that have been developed to improve drug delivery to brain tumors, and it should be helpful to clinicians and research scientists as well.

  14. 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

  15. 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

  16. Polyamine-Blocking Therapy Reverses Immunosuppression in the Tumor Microenvironment

    PubMed Central

    Hayes, Candace S.; Shicora, Allyson C.; Keough, Martin P.; Snook, Adam E.; Burns, Mark R.; Gilmour, Susan K.

    2014-01-01

    Correcting T cell immunosuppression may unleash powerful antitumor responses, however, knowledge about the mechanisms and modifiers that may be targeted to improve therapy remains incomplete. Here we report that polyamine elevation in cancer, a common metabolic aberration in aggressive lesions, contributes significantly to tumor immunosuppression and that a polyamine depletion strategy can exert antitumor effects that may also promote immunity. A polyamine-blocking therapy (PBT) that combines the well-characterized ornithine decarboxylase (ODC) inhibitor difluoromethylornithine (DFMO) with AMXT1501, a novel inhibitor of the polyamine transport system, blocked tumor growth in immunocompetent mice but not in athymic nude mice lacking T cells. PBT had little effect on the proliferation of epithelial tumor cells but it increased the number of apoptotic cells. Analysis of CD45+ tumor immune infiltrates revealed that PBT decreased levels of Gr-1+CD11b+ myeloid suppressor cells and increased CD3+ T cells. Strikingly, in a model of neoadjuvant therapy, mice administered PBT one week before surgical resection of engrafted mammary tumors exhibited resistance to subsequent tumor re-challenge. Collectively, our results indicate that therapies targeting polyamine metabolism do not act exclusively as anti-proliferative agents, but also act strongly to prevent immune escape by the tumor. PBT may offer a general approach to heighten immune responses in cancer. PMID:24778323

  17. Improvement of tumor localization of photosensitizers for photodynamic therapy and its application for tumor diagnosis.

    PubMed

    Ogura, Shun-Ichiro; Hagiya, Yuichiro; Tabata, Kenji; Kamachi, Toshiaki; Okura, Ichiro

    2012-01-01

    Photodynamic therapy (PDT) and photodynamic diagnosis of cancer are widely used in clinical fields. These are performed using photosensitizers. Many metalloporphyrin-related compounds have been developed as photosensitizers for use in PDT, and these tumor localization ability have been improved in recent research. Moreover, the precursor of porphyrin 5-aminolevulinic acid is used in fluorescence diagnosis using its tumor localization ability. In this review, these applications of photosensitizers in cancer therapy and diagnosis are summarized.

  18. Photodynamic therapy for implanted VX2 tumor in rabbit brains

    NASA Astrophysics Data System (ADS)

    Li, Fei; Feng, Hua; Lin, Jiangkai; Zhu, Gang; Chen, Zhi; Li, Cong-yan

    2005-07-01

    To evaluate the therapeutic effect and the safety of single photodynamic therapy (PDT) with hematoporphyrin derivative produced in China, 60 New Zealand adult rabbits with VX2 tumor implanted into the brain were divided randomly into non-PDT-group and PDT-group. 36 rabbits of the PDT-group were performed photodynamic therapy. The survival time, neurological deteriorations, intracranial pressure (ICP), histology, pathology, tumor volume and brain water content were measured. Other 12 rabbits were received hematoporphyrin derivative and light irradiation of the normal brain. The ICP, histology, pathology, and brain water content were measured. The result indicated that Simple PDT may elongate the average survival time of the rabbits with VX2 tumors significantly; kill tumor cells; cause transient brain edema and increase ICP, but it is safe to be used in treating brain tumor.

  19. Hypoxic Tumor Microenvironment: Opportunities to Develop Targeted Therapies

    PubMed Central

    Patel, Akhil; Sant, Shilpa

    2016-01-01

    Recent few years have seen great progress in understanding tumor biology and 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 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

  20. 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. Published by Elsevier Inc.

  1. Contrast-enhanced Ultrasound Imaging of Antiangiogenic Tumor Therapy.

    PubMed

    Klotz, Laura V; Clevert, Dirk-Andre; Scheckinger, Siiri; Strieth, Sebastian; Eichhorn, Martin E

    2015-05-01

    Anti-angiogenic treatment is a promising strategy for cancer therapy and is currently evaluated in clinical trials. The aim of the present study was to further investigate the effects of an anti-angiogenic therapy, inhibiting vascular endothelial growth factor (VEGF) and endothelial growth factor (EGF) using a tyrosine kinase inhibitor for blocking tumor angiogenesis and tumor progression in vivo. Experiments were performed using C57/Bl6 mice (25 ± 5 g of body weight (b.w.)) implanted with subcutaneous Lewis lung carcinoma (LLC-1). From day 7 till 21 after tumor cell implantation, animals (n=7 per group) were treated by monotherapy using ZD6474 (50 mg/kg b.w. per os (p.o.)) daily. A control group received only the solvent polysorbate 80. Using contrast enhanced ultrasound (CE-US) parameters of intra-tumoral microcirculation animals were examined 24 h after the last application of ZD6474. Moreover, subcutaneous tumor growth was measured over the whole therapy period. Finally, histological analyses were performed to analyze the functional vessel density in the tumor tissue. ZD6474 reduced tumor growth of LLC-1 in C57/Bl6 mice significantly. A significant difference of maximal signal intensity (ΔSImax) and area below the intensity time curve (AUC) after antiangiogenic therapy was recorded in the tumor center by CE-US. Vessel density after hematoxyline and eosin, as well as CD31, staining showed no significant difference in both groups. Anti-angiogenic effects can be quantitatively demonstrated using CE-US imaging, which represents the spreading of efficient vessels in the tumor tissue, especially in the tumor center. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  2. Tumor-associated B-cells induce tumor heterogeneity and therapy resistance.

    PubMed

    Somasundaram, Rajasekharan; Zhang, Gao; Fukunaga-Kalabis, Mizuho; Perego, Michela; Krepler, Clemens; Xu, Xiaowei; Wagner, Christine; Hristova, Denitsa; Zhang, Jie; Tian, Tian; Wei, Zhi; Liu, Qin; Garg, Kanika; Griss, Johannes; Hards, Rufus; Maurer, Margarita; Hafner, Christine; Mayerhöfer, Marius; Karanikas, Georgios; Jalili, Ahmad; Bauer-Pohl, Verena; Weihsengruber, Felix; Rappersberger, Klemens; Koller, Josef; Lang, Roland; Hudgens, Courtney; Chen, Guo; Tetzlaff, Michael; Wu, Lawrence; Frederick, Dennie Tompers; Scolyer, Richard A; Long, Georgina V; Damle, Manashree; Ellingsworth, Courtney; Grinman, Leon; Choi, Harry; Gavin, Brian J; Dunagin, Margaret; Raj, Arjun; Scholler, Nathalie; Gross, Laura; Beqiri, Marilda; Bennett, Keiryn; Watson, Ian; Schaider, Helmut; Davies, Michael A; Wargo, Jennifer; Czerniecki, Brian J; Schuchter, Lynn; Herlyn, Dorothee; Flaherty, Keith; Herlyn, Meenhard; Wagner, Stephan N

    2017-09-19

    In melanoma, therapies with inhibitors to oncogenic BRAF(V600E) are highly effective but responses are often short-lived due to the emergence of drug-resistant tumor subpopulations. We describe here a mechanism of acquired drug resistance through the tumor microenvironment, which is mediated by human tumor-associated B cells. Human melanoma cells constitutively produce the growth factor FGF-2, which activates tumor-infiltrating B cells to produce the growth factor IGF-1. B-cell-derived IGF-1 is critical for resistance of melanomas to BRAF and MEK inhibitors due to emergence of heterogeneous subpopulations and activation of FGFR-3. Consistently, resistance of melanomas to BRAF and/or MEK inhibitors is associated with increased CD20 and IGF-1 transcript levels in tumors and IGF-1 expression in tumor-associated B cells. Furthermore, first clinical data from a pilot trial in therapy-resistant metastatic melanoma patients show anti-tumor activity through B-cell depletion by anti-CD20 antibody. Our findings establish a mechanism of acquired therapy resistance through tumor-associated B cells with important clinical implications.Resistance to BRAFV600E inhibitors often occurs in melanoma patients. Here, the authors describe a potential mechanism of acquired drug resistance mediated by tumor-associated B cells-derived IGF-1.

  3. Amorphous liquid metal electrodes enabled conformable electrochemical therapy of tumors.

    PubMed

    Sun, Xuyang; Yuan, Bo; Rao, Wei; Liu, Jing

    2017-11-01

    Electrochemical treatment of tumors (EChT) has recently been identified as a very effective way for local tumor therapy. However, hindered by the limited effective area of a single rigid electrode, multiple electrodes are often recruited when tackling large tumors, where too many electrodes not only complicate the clinical procedures but also aggravate patients' pain. Here we present a new conceptual electric stimulation tumor therapy through introducing the injectable liquid metal electrodes, which can adapt to complex tumor shapes so as to achieve desired therapeutic performance. This approach can offer evident merits for dealing with the complex physiological situations, especially for those irregular body cavities like stomach, colon, rectum or even blood vessel etc., which are hard to tackle otherwise. As it was disclosed from the conceptual experiments that, Unlike traditional rigid and uncomfortable electrodes, liquid metal possesses high flexibility to attach to any crooked biological position to deliver and adjust targeted electric field to fulfill anticipated tumor destruction. And such amorphous electrodes exhibit rather enhanced treatment effect of tumors. Further, we also demonstrate that EChT with liquid metal electrodes produced more electrochemical products during electrolysis. Transformations with the shapes of liquid metal provided an easily regulatable strategy to improve EChT efficiency, which can conveniently aid to achieve better output compared to multiple electrodes. In vivo EChT of tumors further clarified the effect of liquid metal electrodes in retarding tumor growth and increasing life spans. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. 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

  5. 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.

  6. Targeted toxins in brain tumor therapy.

    PubMed

    Li, Yan Michael; Hall, Walter A

    2010-11-01

    Targeted toxins, also known as immunotoxins or cytotoxins, are recombinant molecules that specifically bind to cell surface receptors that are overexpressed in cancer and the toxin component kills the cell. These recombinant proteins consist of a specific antibody or ligand coupled to a protein toxin. The targeted toxins bind to a surface antigen or receptor overexpressed in tumors, such as the epidermal growth factor receptor or interleukin-13 receptor. The toxin part of the molecule in all clinically used toxins is modified from bacterial or plant toxins, fused to an antibody or carrier ligand. Targeted toxins are very effective against cancer cells resistant to radiation and chemotherapy. They are far more potent than any known chemotherapy drug. Targeted toxins have shown an acceptable profile of toxicity and safety in early clinical studies and have demonstrated evidence of a tumor response. Currently, clinical trials with some targeted toxins are complete and the final results are pending. This review summarizes the characteristics of targeted toxins and the key findings of the important clinical studies with targeted toxins in malignant brain tumor patients. Obstacles to successful treatment of malignant brain tumors include poor penetration into tumor masses, the immune response to the toxin component and cancer heterogeneity. Strategies to overcome these limitations are being pursued in the current generation of targeted toxins.

  7. Stem and progenitor cell-mediated tumor selective gene therapy.

    PubMed

    Aboody, K S; Najbauer, J; Danks, M K

    2008-05-01

    The poor prognosis for patients with aggressive or metastatic tumors and the toxic side effects of currently available treatments necessitate the development of more effective tumor-selective therapies. Stem/progenitor cells display inherent tumor-tropic properties that can be exploited for targeted delivery of anticancer genes to invasive and metastatic tumors. Therapeutic genes that have been inserted into stem cells and delivered to tumors with high selectivity include prodrug-activating enzymes (cytosine deaminase, carboxylesterase, thymidine kinase), interleukins (IL-2, IL-4, IL-12, IL-23), interferon-beta, apoptosis-promoting genes (tumor necrosis factor-related apoptosis-inducing ligand) and metalloproteinases (PEX). We and others have demonstrated that neural and mesenchymal stem cells can deliver therapeutic genes to elicit a significant antitumor response in animal models of intracranial glioma, medulloblastoma, melanoma brain metastasis, disseminated neuroblastoma and breast cancer lung metastasis. Most studies reported reduction in tumor volume (up to 90%) and increased survival of tumor-bearing animals. Complete cures have also been achieved (90% disease-free survival for >1 year of mice bearing disseminated neuroblastoma tumors). As we learn more about the biology of stem cells and the molecular mechanisms that mediate their tumor-tropism and we identify efficacious gene products for specific tumor types, the clinical utility of cell-based delivery strategies becomes increasingly evident.

  8. Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy

    PubMed Central

    Pfirschke, Christina; Engblom, Camilla; Rickelt, Steffen; Cortez-Retamozo, Virna; Garris, Christopher; Pucci, Ferdinando; Yamazaki, Takahiro; Colame, Vichnou Poirier; Newton, Andita; Redouane, Younes; Lin, Yi-Jang; Wojtkiewicz, Gregory; Iwamoto, Yoshiko; Mino-Kenudson, Mari; Huynh, Tiffany G.; Hynes, Richard O.; Freeman, Gordon J.; Kroemer, Guido; Zitvogel, Laurence; Weissleder, Ralph; Pittet, Mikael J.

    2016-01-01

    SUMMARY Checkpoint blockade immunotherapies can be extraordinarily effective, but may benefit only the minority of patients whose tumors are pre-infiltrated by T cells. Here, using lung adenocarcinoma mouse models, including genetic models, we show that autochthonous tumors that lacked T cell infiltration and resisted current treatment options could be successfully sensitized to host antitumor T cell immunity when using appropriately selected immunogenic drugs (e.g. oxaliplatin combined with cyclophosphamide for treatment against tumors expressing oncogenic Kras and lacking Trp53). The antitumor response was triggered by direct drug actions on tumor cells, relied on innate immune sensing through toll-like receptor 4 signaling, and ultimately depended on CD8+ T cell antitumor immunity. Furthermore, instigating tumor infiltration by T cells sensitized tumors to checkpoint inhibition and controlled cancer durably. These findings indicate that the proportion of cancers responding to checkpoint therapy can be feasibly and substantially expanded by combining checkpoint blockade with immunogenic drugs. PMID:26872698

  9. Tumor vasculature targeted photodynamic therapy for enhanced delivery of nanoparticles.

    PubMed

    Zhen, Zipeng; Tang, Wei; Chuang, Yen-Jun; Todd, Trever; Zhang, Weizhong; Lin, Xin; Niu, Gang; Liu, Gang; Wang, Lianchun; Pan, Zhengwei; Chen, Xiaoyuan; Xie, Jin

    2014-06-24

    Delivery of nanoparticle drugs to tumors relies heavily on the enhanced permeability and retention (EPR) effect. While many consider the effect to be equally effective on all tumors, it varies drastically among the tumors' origins, stages, and organs, owing much to differences in vessel leakiness. Suboptimal EPR effect represents a major problem in the translation of nanomedicine to the clinic. In the present study, we introduce a photodynamic therapy (PDT)-based EPR enhancement technology. The method uses RGD-modified ferritin (RFRT) as "smart" carriers that site-specifically deliver (1)O2 to the tumor endothelium. The photodynamic stimulus can cause permeabilized tumor vessels that facilitate extravasation of nanoparticles at the sites. The method has proven to be safe, selective, and effective. Increased tumor uptake was observed with a wide range of nanoparticles by as much as 20.08-fold. It is expected that the methodology can find wide applications in the area of nanomedicine.

  10. Dosimetric aspects of radiolabeled antibodies for tumor therapy

    SciTech Connect

    Humm, J.L.

    1986-09-01

    Radioimmunotherapy (RIT) is rapidly attracting interest as a potential new weapon in the arsenal for cancer therapy. This article concentrates on some of the dosimetric aspects affecting the potential success of RIT, and examines factors which influence the choice of a radiolabel for RIT. No radionuclide is likely to give an optimum tumor/nontumor insult for all tumor types; therefore, the concept of matching the source to tumor morphology is introduced. Lists of candidate radionuclides are given, classified according to the type of decay, range, and energy of the emission. The article examines how the choice of radionuclide for radiolabeling the antibody affects the local energy deposition in the tumor. Both the effect of tumor size on the energy absorbed fraction and the problem of antibody binding heterogeneity are discussed. The approach to RIT is to relate the choice of radionuclide to the physical properties of the tumor. 26 references.

  11. 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.

  12. Brain tumors in children--current therapies and newer directions.

    PubMed

    Khatua, Soumen; Sadighi, Zsila Sousan; Pearlman, Michael L; Bochare, Sunil; Vats, Tribhawan S

    2012-07-01

    Brain tumors are the second most common malignancy and the major cause of cancer related mortality in children. Though significant advances in neuroimaging, neurosurgery, radiation therapy and chemotherapy have evolved over the years, overall survival rate remains less than 75%. Malignant gliomas, high risk medulloblastoma with recurrence and infant brain tumors continue to be a major cause of therapeutic frustration. Even today diffuse pontine gliomas are universally fatal. Though tumors like low grade glioma have an overall excellent survival, recurrences and progression in eloquent areas pose therapeutic challenges. As research continues to unravel the biology including key molecules and signaling pathways responsible for the oncogenesis of different childhood brain tumors, novel targeted therapies are profiled. Identification of major targets like the Epidermal Growth factor Receptor (EGFR), Platelet Derived Growth Factor Receptor (PDGFR), Vascular Endothelial Growth factor (VEGF) and key signaling pathways like the MAPK and PI3K/Akt/mTOR has enabled us over the recent years to better understand tumor behavior and design tailored therapy. These efforts have improved overall survival of children with brain tumors. This review article discusses the current status of common brain tumors in children and the newer therapeutic approaches.

  13. Circulating biomarker panels for targeted therapy in brain tumors.

    PubMed

    Tanase, Cristiana; Albulescu, Radu; Codrici, Elena; Popescu, Ionela Daniela; Mihai, Simona; Enciu, Ana Maria; Cruceru, Maria Linda; Popa, Adrian Claudiu; Neagu, Ana Iulia; Necula, Laura Georgiana; Mambet, Cristina; Neagu, Monica

    2015-01-01

    An important goal of oncology is the development of cancer risk-identifier biomarkers that aid early detection and target therapy. High-throughput profiling represents a major concern for cancer research, including brain tumors. A promising approach for efficacious monitoring of disease progression and therapy could be circulating biomarker panels using molecular proteomic patterns. Tailoring treatment by targeting specific protein-protein interactions and signaling networks, microRNA and cancer stem cell signaling in accordance with tumor phenotype or patient clustering based on biomarker panels represents the future of personalized medicine for brain tumors. Gathering current data regarding biomarker candidates, we address the major challenges surrounding the biomarker field of this devastating tumor type, exploring potential perspectives for the development of more effective predictive biomarker panels.

  14. Tumor exosomes: cellular postmen of cancer diagnosis and personalized therapy.

    PubMed

    Sharma, Aman; Khatun, Zamila; Shiras, Anjali

    2016-02-01

    Nanosized (30-150 nm) extracellular vesicles 'exosomes' are secreted by cells for intercellular communication during normal and pathological conditions. Exosomes carry biomacromolecules from cell-of-origin and, therefore, represent molecular bioprint of the cell. Tumor-derived exosomes or TDEx modulate tumor microenvironment by transfer of macromolecules locally as well as at distant metastatic sites. Due to their biological stability, TDEx are rich source of biomarkers in cancer patients. TDEx focused cancer diagnosis allows liquid biopsy-based tumor typing and may facilitate therapy response monitoring by developing novel exosomes diagnostics. Therefore, efficient and specific capturing of exosomes for subsequent amplification of the biomessages; for example, DNA, RNA, miRNA can reinvent cancer diagnosis. Here, in this review, we discuss advancements in exosomes isolation strategies, presence of exosomes biomarkers and importance of TDEx in gauging tumor heterogeneity for their potential use in cancer diagnosis, therapy.

  15. 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.

  16. Tumor Microenvironment Targeting and Responsive Peptide-Based Nanoformulations for Improved Tumor Therapy.

    PubMed

    Qin, Hao; Ding, Yanping; Mujeeb, Ayeesha; Zhao, Ying; Nie, Guangjun

    2017-09-01

    The tumor microenvironment participates in all stages of tumor progression and has emerged as a promising therapeutic target for cancer therapy. Rapid progress in the field of molecular self-assembly using various biologic molecules has resulted in the fabrication of nanoformulations that specifically target and regulate microenvironment components to inhibit tumor growth. This inhibition process is based on differentiating between biophysicochemical cues guiding tumor and normal tissue microenvironments. Peptides and peptide derivatives, owing to their biocompatibility, chemical versatility, bioactivity, environmental sensitivity, and biologic recognition abilities, have been widely used as building blocks to construct multifunctional nanostructures for targeted drug delivery and controlled release. Several groups of peptides have been identified as having the ability to penetrate plasma membranes, regulate the essential signaling pathways of angiogenesis and immune reactions, and recognize key components in the tumor microenvironment (such as vascular systems, stromal cells, and abnormal tumor biophysicochemical features). Thus, using different modules, various functional peptides, and their derivatives can be integrated into nanoformulations specifically targeting the tumor microenvironment with increased selectivity, on-demand response, elevated cellular uptake, and improved tumor therapy. In this review, we introduce several groups of functional peptides and highlight peptide-based nanoformulations that specifically target the tumor microenvironment. We also provide our perspective on the development of smart drug-delivery systems with enhanced therapeutic efficacy. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  17. Solid-tumor radionuclide therapy dosimetry: New paradigms in view of tumor microenvironment and angiogenesis

    PubMed Central

    Zhu, Xuping; Palmer, Matthew R.; Makrigiorgos, G. Mike; Kassis, Amin I.

    2010-01-01

    Purpose: The objective of this study is to evaluate requirements for radionuclide-based solid tumor therapy by assessing the radial dose distribution of beta-particle-emitting and alpha-particle-emitting molecules localized either solely within endothelial cells of tumor vasculature or diffusing from the vasculature throughout the adjacent viable tumor cells. Methods: Tumor blood vessels were modeled as a group of microcylindrical layers comprising endothelial cells (one-cell thick, 10 μm diameter), viable tumor cells (25-cell thick, 250 μm radius), and necrotic tumor region (>250 μm from any blood vessel). Sources of radioactivity were assumed to distribute uniformly in either endothelial cells or in concentric cylindrical 10 μm shells within the viable tumor-cell region. The EGSnrc Monte Carlo simulation code system was used for beta particle dosimetry and a dose-point kernel method for alpha particle dosimetry. The radioactive decays required to deposit cytocidal doses (≥100 Gy) in the vascular endothelial cells (endothelial cell mean dose) or, alternatively, at the tumor edge [tumor-edge mean dose (TEMD)] of adjacent viable tumor cells were then determined for six beta (32P, 33P, 67Cu, 90Y, 131I, and 188Re) and two alpha (211At and 213Bi) particle emitters. Results: Contrary to previous modeling in targeted radionuclide therapy dosimetry of solid tumors, the present work restricts the region of tumor viability to 250 μm around tumor blood vessels for consistency with biological observations. For delivering ≥100 Gy at the viable tumor edge (TEMD) rather than throughout a solid tumor, energetic beta emitters 90Y, 32P, and 188Re can be effective even when the radionuclide is confined to the blood vessel (i.e., no diffusion into the tumor). Furthermore, the increase in tumor-edge dose consequent to beta emitter diffusion is dependent on the energy of the emitted beta particles, being much greater for lower-energy emitters 131I, 67Cu, and 33P relative to

  18. 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.

  19. 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

    2014-03-07

    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.

  20. 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

  1. Gene Therapy for Brain Tumors: Basic Developments and Clinical Implementation

    PubMed Central

    Assi, Hikmat; Candolfi, Marianela; Baker, Gregory; Mineharu, Yohei; Lowenstein, Pedro R; Castro, Maria G

    2012-01-01

    Glioblastoma multiforme (GBM) is the most common and deadliest of adult primary brain tumors. Due to its invasive nature and sensitive location, complete resection remains virtually impossible. The resistance of GBM against chemotherapy and radiotherapy necessitate the development of novel therapies. Gene therapy is proposed for the treatment of brain tumors and has demonstrated pre-clinical efficacy in animal models. Here we review the various experimental therapies that have been developed for GBM including both cytotoxic and immune stimulatory approaches. We also review the combined conditional cytotoxic immune stimulatory therapy that our lab has developed which is dependent on the adenovirus mediated expression of the conditional cytotoxic gene, Herpes Simplex Type 1 Thymidine Kinase (TK) and the powerful DC growth factor Fms-like tyrosine kinase 3 ligand (Flt3L). Combined delivery of these vectors elicits tumor cell death and an anti-tumor adaptive immune response that requires TLR2 activation. The implications of our studies indicate that the combined cytotoxic and immunotherapeutic strategies are effective strategies to combat deadly brain tumors and warrant their implementation in human Phase I clinical trials for GBM. PMID:22906921

  2. Gene therapy for brain tumors: basic developments and clinical implementation.

    PubMed

    Assi, Hikmat; Candolfi, Marianela; Baker, Gregory; Mineharu, Yohei; Lowenstein, Pedro R; Castro, Maria G

    2012-10-11

    Glioblastoma multiforme (GBM) is the most common and deadliest of adult primary brain tumors. Due to its invasive nature and sensitive location, complete resection remains virtually impossible. The resistance of GBM against chemotherapy and radiotherapy necessitate the development of novel therapies. Gene therapy is proposed for the treatment of brain tumors and has demonstrated pre-clinical efficacy in animal models. Here we review the various experimental therapies that have been developed for GBM including both cytotoxic and immune stimulatory approaches. We also review the combined conditional cytotoxic immune stimulatory therapy that our lab has developed which is dependent on the adenovirus mediated expression of the conditional cytotoxic gene, Herpes Simplex Type 1 Thymidine Kinase (TK) and the powerful DC growth factor Fms-like tyrosine kinase 3 ligand (Flt3L). Combined delivery of these vectors elicits tumor cell death and an anti-tumor adaptive immune response that requires TLR2 activation. The implications of our studies indicate that the combined cytotoxic and immunotherapeutic strategies are effective strategies to combat deadly brain tumors and warrant their implementation in human Phase I clinical trials for GBM.

  3. Engineering of magnetic DNA nanoparticles for tumor-targeted therapy

    NASA Astrophysics Data System (ADS)

    Hosseinkhani, Hossein; Chen, Yi-Ru; He, Wenjie; Hong, Po-Da; Yu, Dah-Shyong; Domb, Abraham J.

    2013-01-01

    This study aims to engineer novel targeted delivery system composed of magnetic DNA nanoparticles to be effective as an efficient targeted gene therapy vehicle for tumor therapy. A polysaccharide, dextran, was chosen as the vector of plasmid DNA-encoded NK4 that acts as an HGF-antagonist and anti-angiogenic regulator for inhibitions of tumor growth, invasion, and metastasis. Spermine (Sm) was chemically introduced to the hydroxyl groups of dextran to obtain dextran-Sm. When Fe2+ solution was added to the mixture of dextran-Sm and a plasmid DNA, homogenous DNA nanoparticles were formed via chemical metal coordination bonding with average size of 230 nm. Characterization of DNA nanoparticles was performed via dynamic light scattering measurement, electrophoretic light scattering measurement, as well as transmission electron microscope. DNA nanoparticles effectively condensed plasmid DNA into nanoparticles and enhanced the stability of DNA, while significantly improved transfection efficiency in vitro and tumor accumulation in vivo. In addition, magnetic DNA nanoparticles exhibited high efficiency in antitumor therapy with regards to tumor growth as well as survival of animals evaluated in the presence of external magnetic field. We conclude that the magnetic properties of these DNA nanoparticles would enhance the tracking of non-viral gene delivery systems when administrated in vivo in a test model. These findings suggest that DNA nanoparticles effectively deliver DNA to tumor and thereby inhibiting tumor growth.

  4. 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

  5. Genetic tumor profiling and genetically targeted cancer therapy.

    PubMed

    Goetsch, Cathleen M

    2011-02-01

    To discuss how understanding and manipulation of tumor genetics information and technology shapes cancer care today and what changes might be expected in the near future. Published articles, web resources, clinical practice. Advances in our understanding of genes and their regulation provide a promise of more personalized cancer care, allowing selection of the most safe and effective therapy in an individual situation. Rapid progress in the technology of tumor profiling and targeted cancer therapies challenges nurses to keep up-to-date to provide quality patient education and care. Copyright © 2011 Elsevier Inc. All rights reserved.

  6. Atypical Teratoid Rhabdoid Tumor: Current Therapy and Future Directions

    PubMed Central

    Ginn, Kevin F.; Gajjar, Amar

    2012-01-01

    Atypical teratoid rhabdoid tumors (ATRTs) are rare central nervous system tumors that comprise approximately 1–2% of all pediatric brain tumors; however, in patients less than 3 years of age this tumor accounts for up to 20% of cases. ATRT is characterized by loss of the long arm of chromosome 22 which results in loss of the hSNF5/INI-1 gene. INI1, a member of the SWI/SNF chromatin remodeling complex, is important in maintenance of the mitotic spindle and cell cycle control. Overall survival in ATRT is poor with median survival around 17 months. Radiation is an effective component of therapy but is avoided in patients younger than 3 years of age due to long term neurocognitive sequelae. Most long term survivors undergo radiation therapy as a part of their upfront or salvage therapy, and there is a suggestion that sequencing the radiation earlier in therapy may improve outcome. There is no standard curative chemotherapeutic regimen, but anecdotal reports advocate the use of intensive therapy with alkylating agents, high-dose methotrexate, or therapy that includes high-dose chemotherapy with stem cell rescue. Due to the rarity of this tumor and the lack of randomized controlled trials it has been challenging to define optimal therapy and advance treatment. Recent laboratory investigations have identified aberrant function and/or regulation of cyclin D1, aurora kinase, and insulin-like growth factor pathways in ATRT. There has been significant interest in identifying and testing therapeutic agents that target these pathways. PMID:22988546

  7. 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%.

  8. Gene therapeutics: the future of brain tumor therapy?

    PubMed

    Cutter, Jennifer L; Kurozumi, Kazuhiko; Chiocca, E Antonio; Kaur, Balveen

    2006-07-01

    Primary glioblastoma multiforme is an aggressive brain tumor that has no cure. Current treatments include gross resection of the tumor, radiation and chemotherapy. Despite valiant efforts, prognosis remains dismal. A promising new technique involves the use of oncolytic viruses that can specifically replicate and lyse in cancers, without spreading to normal tissues. Currently, these are being tested in relevant preclinical models and clinical trials as a therapeutic modality for many types of cancer. Results from recent clinical trials with oncolytic viruses have revealed the safety of this approach, although evidence for efficacy remains elusive. Oncolytic viral strategies are summarized in this review, with a focus on therapies used in brain tumors.

  9. 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

  10. Combination bacteriolytic therapy for the treatment of experimental tumors

    PubMed Central

    Dang, Long H.; Bettegowda, Chetan; Huso, David L.; Kinzler, Kenneth W.; Vogelstein, Bert

    2001-01-01

    Current chemotherapeutic approaches for cancer are in part limited by the inability of drugs to destroy neoplastic cells within poorly vascularized compartments of tumors. We have here systematically assessed anaerobic bacteria for their capacity to grow expansively within avascular compartments of transplanted tumors. Among 26 different strains tested, one (Clostridium novyi) appeared particularly promising. We created a strain of C. novyi devoid of its lethal toxin (C. novyi-NT) and showed that intravenously injected C. novyi-NT spores germinated within the avascular regions of tumors in mice and destroyed surrounding viable tumor cells. When C. novyi-NT spores were administered together with conventional chemotherapeutic drugs, extensive hemorrhagic necrosis of tumors often developed within 24 h, resulting in significant and prolonged antitumor effects. This strategy, called combination bacteriolytic therapy (COBALT), has the potential to add a new dimension to the treatment of cancer. PMID:11724950

  11. 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

  12. 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

  13. 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.

  14. Tumor therapy with targeted atomic nanogenerators.

    PubMed

    McDevitt, M R; Ma, D; Lai, L T; Simon, J; Borchardt, P; Frank, R K; Wu, K; Pellegrini, V; Curcio, M J; Miederer, M; Bander, N H; Scheinberg, D A

    2001-11-16

    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.

  15. [Gastroenteropancreatic neuroendocrine tumors : targeted diagnostics and therapy].

    PubMed

    Holzer, K

    2014-08-01

    Gastroenteropancreatic neuroendocrine tumors (GEP-NET) are rare but an increase in incidence has been recognized worldwide. Approximately 70 % of NETs are localized in the gastrointestinal tract and in the pancreas, other locations are in the lungs (25 %) and rarely in the skin, urogenital tract and ovaries. Depending on the size, localization, grading (G1-G3) and production of hormones, the symptoms of patients can greatly vary. Outcome and survival of patients depend on the biological behavior and grading of the NET. Patients with a well differentiated G1 grade NET have a slow, sometimes also benign course over decades even with metastases in contrast to patients with G3 grade NETs. These tumors exhibit an aggressive behavior and patient survival is short. Liver and lymph node metastases are common (about 50 %) in GEP-NETs even at the initial diagnosis. The 5-year and 10-year survival of patients with GEP-NETs is increasing (currently approximately 80 % and 60 %, respectively), especially when a multidisciplinary team (e.g. surgery, endocrinology, oncology, nuclear medicine and gastroenterology) manages GEP-NET patients.

  16. Choline PET for Monitoring Early Tumor Response to Photodynamic Therapy

    PubMed Central

    Fei, Baowei; Wang, Hesheng; Wu, Chunying; Chiu, Song-mao

    2010-01-01

    Photodynamic therapy (PDT) is a relatively new therapy that has shown promise for treating various cancers in both preclinical and clinical studies. The present study evaluated the potential use of PET with radiolabeled choline to monitor early tumor response to PDT in animal models. Methods Two human prostate cancer models (PC-3 and CWR22) were studied in athymic nude mice. A second-generation photosensitizer, phthalocyanine 4 (Pc 4), was delivered to each animal by a tail vein injection 48 h before laser illumination. Small-animal PET images with 11C-choline were acquired before PDT and at 1, 24, and 48 h after PDT. Time–activity curves of 11C-choline uptake were analyzed before and after PDT. The percentage of the injected dose per gram of tissue was quantified for both treated and control tumors at each time point. In addition, Pc 4-PDT was performed in cell cultures. Cell viability and 11C-choline uptake in PDT-treated and control cells were measured. Results For treated tumors, normalized 11C-choline uptake decreased significantly 24 and 48 h after PDT, compared with the same tumors before PDT (P < 0.001). For the control tumors, normalized 11C-choline uptake increased significantly. For mice with CWR22 tumors, the prostate-specific antigen level decreased 24 and 48 h after PDT. Pc 4-PDT in cell culture showed that the treated tumor cells, compared with the control cells, had less than 50% 11C-choline activity at 5, 30, and 45 min after PDT, whereas the cell viability test showed that the treated cells were viable longer than 7 h after PDT. Conclusion PET with 11C-choline is sensitive for detecting early changes associated with Pc 4-PDT in mouse models of human prostate cancer. Choline PET has the potential to determine whether a PDT-treated tumor responds to treatment within 48 h after therapy. PMID:20008981

  17. Potential of Gene Therapy for the Treatment of Pituitary Tumors

    PubMed Central

    Goya, R G.; Sarkar, D.K.; Brown, O.A.; Hereñú, C.B.

    2010-01-01

    Pituitary adenomas constitute the most frequent neuroendocrine pathology, comprising up to 15% of primary intracranial tumors. Current therapies for pituitary tumors include surgery and radiotherapy, as well as pharmacological approaches for some types. Although all of these approaches have shown a significant degree of success, they are not devoid of unwanted side effects, and in most cases do not offer a permanent cure. Gene therapy—the transfer of genetic material for therapeutic purposes—has undergone an explosive development in the last few years. Within this context, the development of gene therapy approaches for the treatment of pituitary tumors emerges as a promising area of research. We begin by presenting a brief account of the genesis of prolactinomas, with particular emphasis on how estradiol induces prolactinomas in animals. In so doing, we discuss the role of each of the recently discovered growth inhibitory and growth stimulatory substances and their interactions in estrogen action. We also evaluate the cell-cell communication that may govern these growth factor interactions and subsequently promote the growth and survival of prolactinomas. Current research efforts to implement gene therapy in pituitary tumors include the treatment of experimental prolactinomas or somatomammotropic tumors with adenoviral vector-mediated transfer of the suicide gene for the herpes simplex type 1 (HSV1) thymidine kinase, which converts the prodrug ganciclovir into a toxic metabolite. In some cases, the suicide transgene has been placed under the control of pituitary cell-type specific promoters, like the human prolactin or human growth hormone promoters. Also, regulatable adenoviral vector systems are being assessed in gene therapy approaches for experimental pituitary tumors. In a different type of approach, an adenoviral vector, encoding the human retinoblastoma suppressor oncogene, has been successfully used to rescue the phenotype of spontaneous pituitary

  18. Targeted radionuclide therapy for solid tumors: An overview

    SciTech Connect

    De Nardo, Sally J.

    2006-10-01

    Although radioimmunotherapy (RIT) has been effective in non-Hodgkin's lymphoma (NHL) as a single agent, solid tumors have shown less clinically significant therapeutic response to RIT alone. The clinical impact of RIT or other forms of targeted radionuclide therapy for solid tumors depends on the development of a high therapeutic index (TI) for the tumor vs. normal tissue effect, and the implementation of RIT as part of synergistic combined modality therapy (CMRIT). Preclinical and clinical studies have provided a wealth of information, and new prototypes or paradigms have shed light on future possibilities in many instances. Evidence suggests that combination and sequencing of RIT in CMRIT appropriately can provide effective treatment for many solid tumors. Vascular targets provide RIT enhancement opportunities and nanoparticles may prove to be effective carriers for RIT combined with intracellular drug delivery or alternating magnetic frequency (AMF) induced thermal tumor necrosis. The sequence and timing of combined modality treatments will be of critical importance to achieve synergy for therapy while minimizing toxicity. Fortunately, the radionuclide used for RIT also provides a signal useful for nondestructive quantitation of the influence of sequence and timing of CMRIT on events in animals and patients. This can be readily accomplished clinically using quantitative high-resolution imaging (e.g., positron emission tomography [PET])

  19. Spondylectomy for Giant Cell Tumor After Denosumab Therapy

    PubMed Central

    de Carvalho Cavalcante, Rodrigo Alves; Silva Marques, Rômulo Alberto; dos Santos, Vinicius Gonçalves; Sabino, Eduardo; Fraga, Ailton Cabral; Zaccariotti, Vladimir Arruda; Arruda, Joao Batista; Fernandes, Yvens Barbosa

    2016-01-01

    Study Design. A case report. Objective. To report a case of the lumbar giant cell tumor (GCT) utilizing a new clinical treatment modality (denosumab therapy), which showed a massive tumor reduction combined with the L4 spondylectomy. Summary of Background Data. There are some controversies about spinal GCT treatments. Denosumab has provided good clinical results in terms of tumor shrinkage, and local control in a short-time follow-up clinical study phase 2, although for spinal lesions, it has not been described. Nonetheless, “en bloc” spondylectomy has been accepted as being the best treatments modalities in terms of oncological control. Methods. A case study with follow-up examination and series radiological assessments 6 months after therapy started, followed by a complex spine surgery. Results. The denosumab therapy showed on the lumbar computed tomography scans follow-up 6 months later, a marked tumor regression around 90% associated to vertebral body calcification, facilitating a successful L4 spondylectomy with an anterior and posterior reconstruction. The patient recovered without neurological deficits. Conclusion. A new therapeutic modality for spinal GCT is available and showing striking clinical results; however, it is necessary for well-designed studies to answer the real role of denosumab therapy avoiding or facilitating complex spine surgeries as spondylectomies for spinal GCT. Level of Evidence: 5 PMID:26579960

  20. 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.

  1. Use of bispecific antibodies in the therapy of tumors.

    PubMed

    Fanger, M W; Morganelli, P M; Guyre, P M

    1993-01-01

    Progress toward an understanding of the construction and use of BsAb in therapy has been considerable. The importance of accessory (adhesion) molecules as well as the requirements for killing and the mechanisms by which cytotoxicity is mediated are being clarified. New approaches to simultaneous activation and targeting of effector cells have been developed. Most important, limited clinical trials have demonstrated little toxicity and in several instances promising responses and long-term survivals, if not cures. It seems likely, therefore, that BsAb will be very useful tools for therapy of tumors that may be most efficacious as an adjunct tumor therapy after surgery, chemotherapy, and/or irradiation in order to further reduce, and to potentially eliminate, tumor cells in the patient. Clearly, much remains to be done before BsAb are used routinely for therapy, but the results thus far demonstrate the considerable potential of BsAb to redirect and focus natural immune mechanisms in the treatment of tumors.

  2. 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.

  3. 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

  4. Feasibility of boron neutron capture therapy for malignant spinal tumors.

    PubMed

    Nakai, Kei; Kumada, Hiroaki; Yamamoto, Tetsuya; Tsurubuchi, Takao; Zaboronok, Alexander; Matsumura, Akira

    2009-07-01

    Treatment of malignant spinal cord tumors is currently ineffective. The characteristics of the spine are its seriality, small volume, and vulnerability: severe QOL impairment can be brought about by small neuronal damage. The present study aimed to investigate the feasibility of BNCT as a tumor-selective charged particle therapy for spinal cord tumors from the viewpoint of protecting the normal spine. A previous report suggested the tolerance dose of the spinal cord was 13.8 Gy-Eq for radiation myelopathy; a dose as high as 11 Gy-Eq demonstrated no spinal cord damage in an experimental animal model. We calculated the tumor dose and the normal spinal cord dose on a virtual model of a spinal cord tumor patient with a JAEA computational dosimetry system (JCDS) treatment planning system. The present study made use of boronophenylalanine (BPA). In these calculations, conditions were set as follows: tumor/normal (T/N) ratio of 3.5, blood boron concentration of 12 ppm, tumor boron concentration of 42 ppm, and relative biological effectiveness (RBE) values for tumor and normal spinal cord of 3.8 and 1.35, respectively. We examined how to optimize neutron irradiation by changing the beam direction and number. In our theoretical example, simple opposed two-field irradiation achieved 28.0 Gy-Eq as a minimum tumor dose and 7.3 Gy-Eq as a maximum normal spinal dose. The BNCT for the spinal cord tumor was therefore feasible when a sufficient T/N ratio could be achieved. The use of F-BPA PET imaging for spinal tumor patients is supported by this study.

  5. 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

  6. 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

  7. Harnessing the potential of epigenetic therapy to target solid tumors

    PubMed Central

    Ahuja, Nita; Easwaran, Hariharan; Baylin, Stephen B.

    2014-01-01

    Epigenetic therapies may play a prominent role in the future management of solid tumors. This possibility is based on the clinical efficacy of existing drugs in treating defined hematopoietic neoplasms, paired with promising new data from preclinical and clinical studies that examined these agents in solid tumors. We suggest that current drugs may represent a targeted therapeutic approach for reprogramming solid tumor cells, a strategy that must be pursued in concert with the explosion in knowledge about the molecular underpinnings of normal and cancer epigenomes. We hypothesize that understanding targeted proteins in the context of their enzymatic and scaffolding functions and in terms of their interactions in complexes with proteins that are targets of new drugs under development defines the future of epigenetic therapies for cancer. PMID:24382390

  8. Stereotactic body radiation therapy for liver tumors.

    PubMed

    Maingon, P; Nouhaud, É; Mornex, F; Créhange, G

    2014-01-01

    Recent improvements in radiation therapy delivery techniques provide new tools to treat patients with liver-confined disease, either with hepatocellular carcinoma or liver metastases. An appropriate selection of the patients made during a multidisciplinary specialized tumour board is mandatory. It should be based on the disease extension, an accurate evaluation of the comorbidities and the liver functions. The added value of this approach has to be evaluated in well-designed trials, alone or in combination with other treatments such as surgery, local treatments, chemoembolization and/or chemotherapy with or without targeted agents. Stereotactic body radiation therapy should be applied under strict conditions of expertise of the radiation oncology departments, including equipment and educational training programmes. However under these conditions, preliminary results seems highly encouraging in terms of local control and tolerance but should be confirmed in large controlled prospective trials. Copyright © 2014 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

  9. Exploiting tumor cell senescence in anticancer therapy

    PubMed Central

    Lee, Minyoung; Lee, Jae-Seon

    2014-01-01

    Cellular senescence is a physiological process of irreversible cell-cycle arrest that contributes to various physiological and pathological processes of aging. Whereas replicative senescence is associated with telomere attrition after repeated cell division, stress-induced premature senescence occurs in response to aberrant oncogenic signaling, oxidative stress, and DNA damage which is independent of telomere dysfunction. Recent evidence indicates that cellular senescence provides a barrier to tumorigenesis and is a determinant of the outcome of cancer treatment. However, the senescence-associated secretory phenotype, which contributes to multiple facets of senescent cancer cells, may influence both cancer-inhibitory and cancer-promoting mechanisms of neighboring cells. Conventional treatments, such as chemo- and radiotherapies, preferentially induce premature senescence instead of apoptosis in the appropriate cellular context. In addition, treatment-induced premature senescence could compensate for resistance to apoptosis via alternative signaling pathways. Therefore, we believe that an intensive effort to understand cancer cell senescence could facilitate the development of novel therapeutic strategies for improving the efficacy of anticancer therapies. This review summarizes the current understanding of molecular mechanisms, functions, and clinical applications of cellular senescence for anticancer therapy. [BMB Reports 2014; 47(2): 51-59] PMID:24411464

  10. 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

  11. Electrogene therapy with interleukin-12 in canine mast cell tumors

    PubMed Central

    Pavlin, Darja; Cemazar, Maja; Cör, Andrej; Sersa, Gregor; Pogacnik, Azra; Tozon, Natasa

    2011-01-01

    Background Mast cell tumors (MCT) are the most common malignant cutaneous tumors in dogs with extremely variable biological behaviour. Different treatment approaches can be used in canine cutaneous MCT, with surgical excision being the treatment of choice. In this study, electrogene therapy (EGT) as a new therapeutic approach to canine MCTs, was established. Materials and methods. Eight dogs with a total of eleven cutaneous MCTs were treated with intratumoral EGT using DNA plasmid encoding human interleukin-12 (IL-12). The local response to the therapy was evaluated by repeated measurements of tumor size and histological examination of treated tumors. A possible systemic response was assessed by determination of IL-12 and interferon- γ (IFN-γ) in patients’ sera. The occurence of side effects was monitored with weekly clinical examinations of treated animals and by performing basic bloodwork, consisting of the complete bloodcount and determination of selected biochemistry parameters. Results Intratumoral EGT with IL-12 elicits significant reduction of treated tumors’ size, ranging from 13% to 83% (median 50%) of the initial tumor volume. Additionally, a change in the histological structure of treated nodules was seen. There was a reduction in number of malignant mast cells and inflammatory cell infiltration of treated tumors. Systemic release of IL-12 in four patients was detected, without any noticeable local or systemic side effects. Conclusions These data suggest that intratumoral EGT with plasmid encoding IL-12 may be useful in the treatment of canine MCTs, exerting a local antitumor effect. PMID:22933932

  12. Herpes virus oncolytic therapy reverses tumor immune dysfunction and facilitates tumor antigen presentation.

    PubMed

    Benencia, Fabian; Courrèges, Maria C; Fraser, Nigel W; Coukos, George

    2008-08-01

    We have previously shown that intratumor administration of HSV-1716 (an ICP34.5 null mutant) resulted in significant reduction of tumor growth and a significant survival advantage in a murine model of ovarian cancer. Herewith we report that oncolytic HSV-1716 generates vaccination effects in the same model. Upon HSV-1716 infection, mouse ovarian tumor cells showed high levels of expression viral glycoproteins B and D and were highly phagocyted by dendritic cells (DCs). Interestingly, increased phagocytosis of tumor-infected cells by DCs was impaired by heparin, and anti-HSV glycoproteins B and D, indicating that viral infection enhances adhesive interactions between DCs and tumor apoptotic bodies. Moreover, HSV-1716 infected cells expressed high levels of heat shock proteins 70 and GRP94, molecules that have been reported to induce maturation of DCs, increase cross-presentation of antigens and promote antitumor immune response. After phagocytosis of tumor-infected cells, DCs acquired a mature status in vitro and in vivo, upregulated the expression of costimulatory molecule and increased migration towards MIP-3beta. Furthermore, HSV-1716 oncolytic treatment markedly reduced vascular endothelial growth factor (VEGF) levels in tumor-bearing animals thus abrogating tumor immunosuppressive milieu. These mechanisms may account for the highly enhanced antitumoral immune responses observed in HSV-1716 treated animals. Oncolytic treatment induced a significantly higher frequency of tumor-reactive IFNgamma producing cells, and induced a robust tumor infiltration by T cells. These results indicate that oncolytic therapy with HSV-1716 facilitates antitumor immune responses.

  13. 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.

  14. Neurofibromatosis-related tumors: emerging biology and therapies.

    PubMed

    Karajannis, Matthias A; Ferner, Rosalie E

    2015-02-01

    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 our understanding of the biology of neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2) as they relate to the development of novel therapies for these disorders. 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. Clinical trials with molecular-targeted therapies have become a reality for neurofibromatosis patients, and hold substantial promise for improving the morbidity and mortality of individuals affected with these disorders.

  15. GENE THERAPY FOR THE TREATMENT OF PITUITARY TUMORS

    PubMed Central

    Rodriguez, Silvia S.; Castro, Maria G.; Brown, Oscar A.; Goya, Rodolfo G.; Console, Gloria M.

    2010-01-01

    Pituitary adenomas constitute the most frequent neuroendocrine pathology in humans. Current therapies include surgery, radiotherapy and pharmacological approaches. Although useful, none of them offers a permanent cure. Current research efforts to implement gene therapy in pituitary tumors include the treatment of experimental adenomas with adenoviral vector-mediated transfer of the suicide gene for thymidine kinase, which converts the prodrug ganciclovir into a toxic metabolite. In some cases, the suicide transgene has been placed under the control of pituitary cell-type specific promoters. Also, regulatable adenoviral vector systems are being assessed in gene therapy approaches for experimental pituitary tumors. Although the efficiency and safety of current viral vectors must be optimized before clinical use, they remain as highly promising therapeutic tools. PMID:20186255

  16. 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.

  17. [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.

  18. Intraoperative photodynamic therapy on spontaneous canine nasal tumors

    NASA Astrophysics Data System (ADS)

    Fonda, Diego; Mortellaro, Carlo M.; Romussi, Stefano; Taroni, Paola; Cubeddu, Rinaldo

    1994-09-01

    Promising results obtained by photodynamic therapy (PDT) with porphyrins on superficial spontaneous canine tumors suggested the experiment of this technique on intracavitary tumors, specifically at the endonasal site. The supposed neoplastic residual bed was irradiated directly during surgery at the end of the debulking. Five dogs referred to the surgical department of the veterinary school, University of Milan and affected by endonasal neoplasias were submitted to PDT after radiologic and cyto-histologic diagnosis and TNM stadiation. All the selected tumors were included in the clinical stage 1 (T1NOMO). Mean and median survival time (from the day of treatment) were 11.6 - 5.4 and 12 months, respectively. Different staging of the treated tumors limits the possibility of an objective comparison with other alternative therapeutic procedures.

  19. 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

  20. Photodynamic therapy and immune response in tumor-bearing mice

    NASA Astrophysics Data System (ADS)

    Canti, Gianfranco L.; Cubeddu, Rinaldo; Taroni, Paola; Valentini, Gianluca

    1999-06-01

    Since immune response of the host is important in the control of tumor growth and spreading, and the Photodynamic therapy (PDT) is able to increase the antitumor immunity, in our laboratory we examine the effect of PDT on immune compartment of tumor bearing mice. Lymphocytes and macrophages collected from tumor bearing mice pretreated with PDT are cytotoxic in vitro and in vivo against the parental tumor lines, in contrast the same immune cells population collected from tumor bearing mice pretreated only with laser light are unable to lyse the parental tumor cells. In adoptive immunotherapy experiments, treatment of mice bearing MS-2 tumor with adoptive transfer of immune lymphocytes collected from mice pretreated with PDT is able to significantly increase the survival time; in contrast the lymphocytes collected from mice pretreated only with laser light were not able to modify the survival time suggesting that the laser treatment alone did not increase the immune response of the host. In conclusion these results demonstrate that the PDT induce a strong immune response on the host and the stimulated lymphocytes generated could be used for an adoptive immunotherapy approach; moreover laser treatment alone (thermal effect) is unable to modulate the immune response of the host.

  1. Nanomedicine engulfed by macrophages for targeted tumor therapy.

    PubMed

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

    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.

  2. Neutron-Activatable Needles for Radionuclide Therapy of Solid Tumors.

    PubMed

    Kim, Junghyun; Narayan, Roger J; Lu, Xiuling; Jay, Michael

    2017-08-14

    Various approaches have been undertaken to enhance the delivery of therapeutic agents, including tissue-killing radionuclides, into solid tumors. Here we describe the preparation of conical needles composed of Ti and Mo coated by pulsed laser deposition or chemical vapor deposition with elements (Ho and Re) that can readily yield radioactive isotopes following irradiation in a neutron flux. The radioactive needles, whose design were based on solid microneedle arrays used in transdermal drug delivery, can be produced with minimal handling of radioactivity and subsequently inserted into tumors as a means of internal radiation therapy. Ho and Re, were specifically chosen because of their large neutron capture cross-sections as well as the desirable radiotherapeutic properties of the resultant radionuclides. Neutron-absorbing shields were also developed to prevent the production of unwanted radionuclides after neutron irradiation of the needle base materials. Neutron activation calculations showed that therapeutically significant amounts of radionuclides can be produced for treating solid tumors. Stability studies demonstrated that Re did not leach off the Mo needles. These coated neutron-activatable needles offer a new approach to internal radiation therapy of tumors that allows precise tailoring of the absorbed radiation dose delivered to the tumor by controlling the coating thickness and the irradiation time. This article is protected by copyright. All rights reserved. © 2017 Wiley Periodicals, Inc.

  3. 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

  4. 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.

  5. 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.

  6. 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

  7. Tumor necrosis factor (TNF) inhibitor therapy for rheumatoid arthritis.

    PubMed

    Segal, Barbara; Rhodus, Nelson L; Patel, Ketan

    2008-12-01

    Rheumatoid arthritis (RA) is a systemic autoimmune disorder characterized by inflammation involving large and small joints. Systemic manifestations as well as involvement of paraoral tissues contribute to morbidity. Tumor necrosis factor (TNF) plays a central role in RA by amplifying inflammation in multiple pathways that lead to joint destruction. Tumor necrosis factor inhibitors were first licensed for clinical use in 1998; 3 have been approved for the treatment of RA: Iinfliximab, etanercept, and adalimumab. The purpose of this paper is to review the pathogenesis of RA, the state of the art of therapy, and the most current information on the safety and efficacy of TNF inhibitors for treatment of RA.

  8. Mreg Activity in Tumor Response to Photodynamic Therapy and Photodynamic Therapy-Generated Cancer Vaccines

    PubMed Central

    Korbelik, Mladen; Banáth, Judith; Zhang, Wei

    2016-01-01

    Myeloid regulatory cells (Mregs) are, together with regulatory T cells (Tregs), a dominant effector population responsible for restriction of the duration and strength of antitumor immune response. Photodynamic therapy (PDT) and cancer vaccines generated by PDT are modalities whose effectiveness in tumor destruction is closely dependent on the associated antitumor immune response. The present study investigated whether the immunodepletion of granulocytic Mregs in host mice by anti-GR1 antibody would improve the response of tumors to PDT or PDT vaccines in these animals. Anti-GR1 administration immediately after Temoporfin-PDT of mouse SCCVII tumors abrogated curative effect of PDT. The opposite effect, increasing PDT-mediated tumor cure-rates was attained by delaying anti-GR1 treatment to 1 h post PDT. With PDT vaccines, multiple anti-GR1 administrations (days 0, 4, and 8 post vaccination) improved the therapy response with SCCVII tumors. The results with PDT suggest that neutrophils (boosting antitumor effect of this therapy) that are engaged immediately after photodynamic light treatment are within one hour replaced with a different myeloid population, presumably Mregs that hampers the therapy-mediated antitumor effect. Anti-GR1 antibody, when used with optimal timing, can improve the efficacy of both PDT of tumors in situ and PDT-generated cancer vaccines. PMID:27754452

  9. Addressing genetic tumor heterogeneity through computationally predictive combination therapy.

    PubMed

    Zhao, Boyang; Pritchard, Justin R; Lauffenburger, Douglas A; Hemann, Michael T

    2014-02-01

    Recent tumor sequencing data suggest an urgent need to develop a methodology to directly address intratumoral heterogeneity in the design of anticancer treatment regimens. We use RNA interference to model heterogeneous tumors, and demonstrate successful validation of computational predictions for how optimized drug combinations can yield superior effects on these tumors both in vitro and in vivo. Importantly, we discover here that for many such tumors knowledge of the predominant subpopulation is insufficient for determining the best drug combination. Surprisingly, in some cases, the optimal drug combination does not include drugs that would treat any particular subpopulation most effectively, challenging straightforward intuition. We confirm examples of such a case with survival studies in a murine preclinical lymphoma model. Altogether, our approach provides new insights about design principles for combination therapy in the context of intratumoral diversity, data that should inform the development of drug regimens superior for complex tumors. This study provides the first example of how combination drug regimens, using existing chemotherapies, can be rationally designed to maximize tumor cell death, while minimizing the outgrowth of clonal subpopulations. 2013 AACR

  10. Tumor Metabolism, the Ketogenic Diet and β-Hydroxybutyrate: Novel Approaches to Adjuvant Brain Tumor Therapy

    PubMed Central

    Woolf, Eric C.; Syed, Nelofer; Scheck, Adrienne C.

    2016-01-01

    Malignant brain tumors are devastating despite aggressive treatments such as surgical resection, chemotherapy and radiation therapy. The average life expectancy of patients with newly diagnosed glioblastoma is approximately ~18 months. It is clear that increased survival of brain tumor patients requires the design of new therapeutic modalities, especially those that enhance currently available treatments and/or limit tumor growth. One novel therapeutic arena is the metabolic dysregulation that results in an increased need for glucose in tumor cells. This phenomenon suggests that a reduction in tumor growth could be achieved by decreasing glucose availability, which can be accomplished through pharmacological means or through the use of a high-fat, low-carbohydrate ketogenic diet (KD). The KD, as the name implies, also provides increased blood ketones to support the energy needs of normal tissues. Preclinical work from a number of laboratories has shown that the KD does indeed reduce tumor growth in vivo. In addition, the KD has been shown to reduce angiogenesis, inflammation, peri-tumoral edema, migration and invasion. Furthermore, this diet can enhance the activity of radiation and chemotherapy in a mouse model of glioma, thus increasing survival. Additional studies in vitro have indicated that increasing ketones such as β-hydroxybutyrate (βHB) in the absence of glucose reduction can also inhibit cell growth and potentiate the effects of chemotherapy and radiation. Thus, while we are only beginning to understand the pluripotent mechanisms through which the KD affects tumor growth and response to conventional therapies, the emerging data provide strong support for the use of a KD in the treatment of malignant gliomas. This has led to a limited number of clinical trials investigating the use of a KD in patients with primary and recurrent glioma. PMID:27899882

  11. Tumor Metabolism, the Ketogenic Diet and β-Hydroxybutyrate: Novel Approaches to Adjuvant Brain Tumor Therapy.

    PubMed

    Woolf, Eric C; Syed, Nelofer; Scheck, Adrienne C

    2016-01-01

    Malignant brain tumors are devastating despite aggressive treatments such as surgical resection, chemotherapy and radiation therapy. The average life expectancy of patients with newly diagnosed glioblastoma is approximately ~18 months. It is clear that increased survival of brain tumor patients requires the design of new therapeutic modalities, especially those that enhance currently available treatments and/or limit tumor growth. One novel therapeutic arena is the metabolic dysregulation that results in an increased need for glucose in tumor cells. This phenomenon suggests that a reduction in tumor growth could be achieved by decreasing glucose availability, which can be accomplished through pharmacological means or through the use of a high-fat, low-carbohydrate ketogenic diet (KD). The KD, as the name implies, also provides increased blood ketones to support the energy needs of normal tissues. Preclinical work from a number of laboratories has shown that the KD does indeed reduce tumor growth in vivo. In addition, the KD has been shown to reduce angiogenesis, inflammation, peri-tumoral edema, migration and invasion. Furthermore, this diet can enhance the activity of radiation and chemotherapy in a mouse model of glioma, thus increasing survival. Additional studies in vitro have indicated that increasing ketones such as β-hydroxybutyrate (βHB) in the absence of glucose reduction can also inhibit cell growth and potentiate the effects of chemotherapy and radiation. Thus, while we are only beginning to understand the pluripotent mechanisms through which the KD affects tumor growth and response to conventional therapies, the emerging data provide strong support for the use of a KD in the treatment of malignant gliomas. This has led to a limited number of clinical trials investigating the use of a KD in patients with primary and recurrent glioma.

  12. The therapy of infantile malignant brain tumors: current status?

    PubMed

    Kalifa, Chantal; Grill, Jacques

    2005-12-01

    Malignant brain tumors are not uncommon in infants as their occurrence before the age of three represents 20-25% of all malignant brain tumors in childhood [1]. Genetic predisposition to infantile malignant brain tumors are known in Gorlin syndrome for example who present with desmoplastic medulloblastoma in about 5% of the affected patients. In addition, sequelae from tumor and its treatment are more severe at this age [2]. Thus, malignant brain tumors represent a true therapeutic challenge in neuro-oncology. Before the era of modern imaging and modern neurosurgery these malignant brain tumors were misdiagnosed or could not benefit of the surgical procedures as well as older children because of increased risks in this age group. Since the end of the 80s, noninvasive imaging procedures produce accurate diagnosis of brain tumors and improvement in neurosurgery, neuroanesthesia and perioperative intensive care permit safe tumor resections or at least biopsies. Consequently, the pediatric oncologists are more often confronted with very young children who need a complementary treatment. Before the development of specific approaches for this age group, these children received the same kind of treatment than the older children did, but their survival and quality of life were significantly worse. The reasons of these poor results were probably due in part to the fear of late effects induced by radiation therapy, leading to decrease the necessary doses of irradiation which increased treatment failures without avoiding treatment related complications [3]. At the end of the 80s, pilot studies were performed using postoperative chemotherapy in young medulloblastoma patients. Van Eys treated 12 selected children with medulloblastoma with MOPP regimen and without irradiation; 8 of them were reported to be long term survivors [4]. Subsequently, the pediatric oncology cooperative groups studies have designed therapeutic trials for very young children with malignant brain tumors

  13. Temperature rise during photoradiation therapy of malignant tumors

    SciTech Connect

    Svaasand, L.O.; Doiron, D.R.; Dougherty, T.J.

    1983-01-01

    This report discusses the optical and thermal distribution during photoradiation therapy of malignant tumors. Emphasis is put on the therapeutic procedure with the light dose delivered through an inserted optical fiber. Theoretical predictions and experimental results indicate that the temperature rise during the procedure may give rise to hyperthermal cell kill. The report discusses the extent of the regions with hyperthermal bioeffects in terms of tissue parameters as optical absorption and scattering, thermal conductivity, specific heat, blood flow, and optical dose parameters as optical power and exposure time. Key words: photoradiation therapy, hematoporphyrin derivative, hyperthermia

  14. Gastrointestinal Stromal Tumors: Management of metastatic disease and emerging therapies

    PubMed Central

    Vadakara, Joseph

    2013-01-01

    Synopsis Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Prior to the advent of tyrosine kinase inhibitors like imatinib, there were few treatment options available to patients with metastatic GIST. Surgery was the mainstay of treatment and the prognosis for patients with metastatic GIST was dismal. With the advent of imatinib the prognosis of metastatic GIST has improved dramatically. Second line tyrosine kinase inhibitors (TKI) such as sunitinib and regorafenib have further bettered prognosis, however there is still a need for therapies for patients with disease refractory to TKI therapy. Newer agents such as the Hsp90 inhibitors, PI3K-AKT-mTOR inhibitors and IGF1-R inhibitors are currently under investigation and may have promise. This review discusses the current standard of care in terms of pharmacotherapy, both standard and investigational (summarized in Box 1), in the management of metastatic GIST. PMID:24093167

  15. 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

  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. Eclipse photodynamic therapy for a presumed peripapillary metastatic tumor.

    PubMed

    Tsai, Shawn; Yeh, Shu-I; Chan, Wei-Chun; Chen, Lee-Jen

    2012-01-01

    We report a successful use of a modified photodynamic therapy (PDT) termed Eclipse PDT in treating a patient with peripapillary metastatic choroidal tumor. Optic disk protection effect was measured with different colored paper disk attached to the reflecting mirror of the laser machine. Black paper disk was chosen to perform Eclipse PDT because of its maximal blocking effect. A patient with peripapillary metastatic choroidal tumor was treated using this method, and the postoperative outcome was favorable, with improvement in visual acuity and resolution of subretinal fluid. With the new technique, treatment can be modified according to the lesion's shape and location without damaging the optic disk. Eclipse PDT can further extend the indication of PDT treatment to peripapillary choroidal neovascularization as well as choroidal tumors close to the optic disk.

  18. 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.

  19. 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.

  20. Targeting tumors with nanobodies for cancer imaging and therapy.

    PubMed

    Oliveira, Sabrina; Heukers, Raimond; Sornkom, Jirawas; Kok, Robbert J; van Bergen En Henegouwen, Paul M P

    2013-12-28

    The use of monoclonal antibodies has revolutionized both cancer therapy and cancer imaging. Antibodies have been used to directly inhibit tumor cell proliferation or to target drugs to tumors. Also in molecular imaging, monoclonal antibodies have found their way to the clinic. Nevertheless, distribution within tumors is hampered by their size, leading to insufficient efficacy of cancer treatment and irregular imaging. An attractive alternative for monoclonal antibodies are nanobodies or VHHs. These are the variable domain of heavy-chain antibodies from animals from the Camelidae family that were first discovered in 1993. Stimulated by the ease of nanobody selection, production, and low immunogenicity potential, a number of nanobodies specific to different disease-related targets have been developed. For cancer therapy, nanobodies have been employed as antagonistic drugs, and more recently, as targeting moieties of effector-domaINS and of drug delivery systems. In parallel, nanobodies have also been employed for molecular imaging with modalities such as nuclear and optical imaging. In this review, we discuss recent developments in the application of nanobodies as targeting moieties in cancer therapy and cancer imaging. With such a wide range of successful applications, nanobodies have become much more than simple antagonists.

  1. 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.

  2. [Safety evaluation of Chinese medicine on tumor therapy].

    PubMed

    Liu, Rui; Hua, Bao-Jin; Li, Jie

    2013-12-01

    As a characteristic tumor therapy in China, Chinese medicine (CM) plays an important position in comprehensive treatment of tumor. It's a critical issue of objective realization, analysis and evaluation of CM safety for scientific decision-making in tumor safe medication and it also is a pivotal issue which affects the international communication. The safety evaluation of CM includes three phases: pre-clinical safety evaluation, clinical trials (micro-dose studies and traditional clinical trials) and post-marketing CM safety assessment. The key point of evaluation should be distinguished among different stages and various types of CM (such as classic formulas, Chinese herbal extracts, etc). Emphasis should be given to chronic toxicity when evaluating oral Chinese herbal , microdose studies and quality control must be underlined while injection is evaluated and more attention should be pay to the dose-effect relationship and time-effect relationship when turned to toxic Chinese medicine , and so as for the toxicity grading study. Moreover, we should constantly improve CM safety assessment method in various stages of tumor treatment, such as introducing the concept of syndrome classification theory, bringing in metabonomics and real-world research method which are similar to the CM therapeutic concept. Most importantly, we must keep its own feature of CM theory when we learn the concept of safety evaluation from abroad. Actively exploring the anti-tumor medicine safety evaluation methods and strategies is of great significance for clinical and experimental research, and it can provide supportability platform to CM's international communication.

  3. Radiation therapy for older patients with brain tumors.

    PubMed

    Minniti, Giuseppe; Filippi, Andrea Riccardo; Osti, Mattia Falchetto; Ricardi, Umberto

    2017-06-19

    The incidence of brain tumors in the elderly population has increased over the last few decades. Current treatment includes surgery, radiotherapy and chemotherapy, but the optimal management of older patients with brain tumors remains a matter of debate, since aggressive radiation treatments in this population may be associated with high risks of neurological toxicity and deterioration of quality of life. For such patients, a careful clinical status assessment is mandatory both for clinical decision making and for designing randomized trials to adequately evaluate the optimal combination of radiotherapy and chemotherapy.Several randomized studies have demonstrated the efficacy and safety of chemotherapy for patients with glioblastoma or lymphoma; however, the use of radiotherapy given in association with chemotherapy or as salvage therapy remains an effective treatment option associated with survival benefit. Stereotactic techniques are increasingly used for the treatment of patients with brain metastases and benign tumors, including pituitary adenomas, meningiomas and acoustic neuromas. Although no randomized trials have proven the superiority of SRS over other radiation techniques in older patients with brain metastases or benign brain tumors, data extracted from recent randomized studies and large retrospective series suggest that SRS is an effective approach in such patients associated with survival advantages and toxicity profile similar to those observed in young adults. Future trials need to investigate the optimal radiation techniques and dose/fractionation schedules in older patients with brain tumors with regard to clinical outcomes, neurocognitive function, and quality of life.

  4. Peptide-based radiopharmaceuticals for targeted tumor therapy.

    PubMed

    Dong, C; Liu, Z; Wang, F

    2014-01-01

    A series of radiolabeled peptides have been designed and optimized for tumor-targeted peptide receptor radionuclide therapy (PRRT). Pre-clinical and clinical applications of PRRT have shown promising results on tumor response, overall survival, and quality of life in patients with several kinds of tumors. (90)Y-DOTA-TOC and (177)Lu-DOTA-TATE are two of the most common radiopharmaceuticals with symptomatic improvements and complete clinical data. In addition to somatostatin analogs, radiolabeled peptides have been developed to target the relative receptors overexpressed in the tumors, such as integrin αvβ3, gastrin-releasing peptide receptor (GRPR), melanocortin-1 receptor (MC1-R), cholecystokinin (CCK) receptor, and glucagon-like peptide-1 receptor (GLP-1R). Several strategies have been designed to improve the therapeutic efficacy of PRRT. For instance, radiolabeled peptides could be optimized by the amino acid modification and radionuclide selection. Healthy tissue protective agents and multi-cycle procedures could effectively decrease the side effects of PRRT. Furthermore, combination treatments, including PRRT combined with surgery, chemotherapeutic agents, or radiosensitizing agents could be applied to increase the effectiveness of PRRT. In this review, the current progress of peptide-based radiopharmaceuticals for tumor-targeted PRRT was summarized. Radiopharmaceuticals currently under clinical investigation were also described.

  5. IL-6 Potentiates Tumor Resistance to Photodynamic Therapy (PDT)

    PubMed Central

    Brackett, Craig M.; Owczarczak, Barbara; Ramsey, Kimberley; Maier, Patricia G.; Gollnick, Sandra O.

    2013-01-01

    Background and Objective Photodynamic therapy (PDT) is an anticancer modality approved for the treatment of early disease and palliation of late stage disease. PDT of tumors results in the generation of an acute inflammatory response. The extent and duration of the inflammatory response is dependent upon the PDT regimen employed and is characterized by rapid induction of proinflammatory cytokines, such as IL-6, and activation and mobilization of innate immune cells. The importance of innate immune cells in long-term PDT control of tumor growth has been well defined. In contrast the role of IL-6 in long-term tumor control by PDT is unclear. Previous studies have shown that IL-6 can diminish or have no effect on PDT antitumor efficacy. Study Design/Materials and Methods In the current study we used mice deficient for IL-6, Il6−/−, to examine the role of IL-6 in activation of antitumor immunity and PDT efficacy by PDT regimens known to enhance antitumor immunity. Results Our studies have shown that elimination of IL-6 had no effect on innate cell mobilization into the treated tumor bed or tumor draining lymph node (TDLN) and did not affect primary antitumor T-cell activation by PDT. However, IL-6 does appear to negatively regulate the generation of antitumor immune memory and PDT efficacy against murine colon and mammary carcinoma models. The inhibition of PDT efficacy by IL-6 appears also to be related to regulation of Bax protein expression. Increased apoptosis was observed following treatment of tumors in Il6−/− mice 24 hours following PDT. Conclusions The development of PDT regimens that enhance antitumor immunity has led to proposals for the use of PDT as an adjuvant treatment. However, our results show that the potential for PDT induced expression of IL-6 to enhance tumor survival following PDT must be considered. PMID:22057495

  6. Proton microbeam radiotherapy with scanned pencil-beams--Monte Carlo simulations.

    PubMed

    Kłodowska, M; Olko, P; Waligórski, M P R

    2015-09-01

    Irradiation, delivered by a synchrotron facility, using a set of highly collimated, narrow and parallel photon beams spaced by 1 mm or less, has been termed Microbeam Radiation Therapy (MRT). The tolerance of healthy tissue after MRT was found to be better than after standard broad X-ray beams, together with a more pronounced response of malignant tissue. The microbeam spacing and transverse peak-to-valley dose ratio (PVDR) are considered to be relevant biological MRT parameters. We investigated the MRT concept for proton microbeams, where we expected different depth-dose profiles and PVDR dependences, resulting in skin sparing and homogeneous dose distributions at larger beam depths, due to differences between interactions of proton and photon beams in tissue. Using the FLUKA Monte Carlo code we simulated PVDR distributions for differently spaced 0.1 mm (sigma) pencil-beams of entrance energies 60, 80, 100 and 120 MeV irradiating a cylindrical water phantom with and without a bone layer, representing human head. We calculated PVDR distributions and evaluated uniformity of target irradiation at distal beam ranges of 60-120 MeV microbeams. We also calculated PVDR distributions for a 60 MeV spread-out Bragg peak microbeam configuration. Application of optimised proton MRT in terms of spot size, pencil-beam distribution, entrance beam energy, multiport irradiation, combined with relevant radiobiological investigations, could pave the way for hypofractionation scenarios where tissue sparing at the entrance, better malignant tissue response and better dose conformity of target volume irradiation could be achieved, compared with present proton beam radiotherapy configurations.

  7. Roscovitine confers tumor suppressive effect on therapy-resistant breast tumor cells

    PubMed Central

    2011-01-01

    Introduction Current clinical strategies for treating hormonal breast cancer involve the use of anti-estrogens that block estrogen receptor (ER)α functions and aromatase inhibitors that decrease local and systemic estrogen production. Both of these strategies improve outcomes for ERα-positive breast cancer patients, however, development of therapy resistance remains a major clinical problem. Divergent molecular pathways have been described for this resistant phenotype and interestingly, the majority of downstream events in these resistance pathways converge upon the modulation of cell cycle regulatory proteins including aberrant activation of cyclin dependent kinase 2 (CDK2). In this study, we examined whether the CDK inhibitor roscovitine confers a tumor suppressive effect on therapy-resistant breast epithelial cells. Methods Using various in vitro and in vivo assays, we tested the effect of roscovitine on three hormonal therapy-resistant model cells: (a) MCF-7-TamR (acquired tamoxifen resistance model); (b) MCF-7-LTLTca (acquired letrozole resistance model); and (c) MCF-7-HER2 that exhibit tamoxifen resistance (ER-growth factor signaling cross talk model). Results Hormonal therapy-resistant cells exhibited aberrant activation of the CDK2 pathway. Roscovitine at a dose of 20 μM significantly inhibited the cell proliferation rate and foci formation potential of all three therapy-resistant cells. The drug treatment substantially increased the proportion of cells in G2/M cell cycle phase with decreased CDK2 activity and promoted low cyclin D1 levels. Interestingly, roscovitine also preferentially down regulated the ERα isoform and ER-coregulators including AIB1 and PELP1. Results from xenograft studies further showed that roscovitine can attenuate growth of therapy-resistant tumors in vivo. Conclusions Roscovitine can reduce cell proliferation and survival of hormone therapy-resistant breast cancer cells. Our results support the emerging concept that inhibition

  8. Roscovitine confers tumor suppressive effect on therapy-resistant breast tumor cells.

    PubMed

    Nair, Binoj C; Vallabhaneni, Sreeram; Tekmal, Rajeshwar R; Vadlamudi, Ratna K

    2011-08-11

    Current clinical strategies for treating hormonal breast cancer involve the use of anti-estrogens that block estrogen receptor (ER)α functions and aromatase inhibitors that decrease local and systemic estrogen production. Both of these strategies improve outcomes for ERα-positive breast cancer patients, however, development of therapy resistance remains a major clinical problem. Divergent molecular pathways have been described for this resistant phenotype and interestingly, the majority of downstream events in these resistance pathways converge upon the modulation of cell cycle regulatory proteins including aberrant activation of cyclin dependent kinase 2 (CDK2). In this study, we examined whether the CDK inhibitor roscovitine confers a tumor suppressive effect on therapy-resistant breast epithelial cells. Using various in vitro and in vivo assays, we tested the effect of roscovitine on three hormonal therapy-resistant model cells: (a) MCF-7-TamR (acquired tamoxifen resistance model); (b) MCF-7-LTLTca (acquired letrozole resistance model); and (c) MCF-7-HER2 that exhibit tamoxifen resistance (ER-growth factor signaling cross talk model). Hormonal therapy-resistant cells exhibited aberrant activation of the CDK2 pathway. Roscovitine at a dose of 20 μM significantly inhibited the cell proliferation rate and foci formation potential of all three therapy-resistant cells. The drug treatment substantially increased the proportion of cells in G2/M cell cycle phase with decreased CDK2 activity and promoted low cyclin D1 levels. Interestingly, roscovitine also preferentially down regulated the ERα isoform and ER-coregulators including AIB1 and PELP1. Results from xenograft studies further showed that roscovitine can attenuate growth of therapy-resistant tumors in vivo. Roscovitine can reduce cell proliferation and survival of hormone therapy-resistant breast cancer cells. Our results support the emerging concept that inhibition of CDK2 activity has the potential to

  9. Focus small to find big - the microbeam story.

    PubMed

    Wu, Jinhua; Hei, Tom K

    2017-08-29

    Even though the first ultraviolet microbeam was described by S. Tschachotin back in 1912, the development of sophisticated micro-irradiation facilities only began to flourish in the late 1980s. In this article, we highlight significant microbeam experiments, describe the latest microbeam irradiator configurations and critical discoveries made by using the microbeam apparatus. Modern radiological microbeams facilities are capable of producing a beam size of a few micrometers, or even tens of nanometers in size, and can deposit radiation with high precision within a cellular target. In the past three decades, a variety of microbeams has been developed to deliver a range of radiations including charged particles, X-rays, and electrons. Despite the original intention for their development to measure the effects of a single radiation track, the ability to target radiation with microbeams at sub-cellular targets has been extensively used to investigate radiation-induced biological responses within cells. Studies conducted using microbeams to target specific cells in a tissue have elucidated bystander responses, and further studies have shown reactive oxygen species (ROS) and reactive nitrogen species (RNS) play critical roles in the process. The radiation-induced abscopal effect, which has a profound impact on cancer radiotherapy, further reaffirmed the importance of bystander effects. Finally, by targeting sub-cellular compartments with a microbeam, we have reported cytoplasmic-specific biological responses. Despite the common dogma that nuclear DNA is the primary target for radiation-induced cell death and carcinogenesis, studies conducted using microbeam suggested that targeted cytoplasmic irradiation induces mitochondrial dysfunction, cellular stress, and genomic instability. A more recent development in microbeam technology includes application of mouse models to visualize in vivo DNA double-strand breaks. Microbeams are making important contributions towards our

  10. EUS-Guided Antitumor Therapy for Pancreatic Tumors.

    PubMed

    Seo, Dong Wan

    2010-09-01

    Endoscopic ultrasound (EUS) is a very useful modality for the diagnosis and staging of pancreatic masses. With the advent of EUS-guided fine-needle aspiration technology, this modality has made a tremendous leap from imaging modality to histologic diagnosis and therapeutic intervention. EUS offers high-resolution images of and unparalleled access to the pancreas. After locating the tip of the echoendoscope in the duodenum or stomach, several drugs or local treatment modalities can be delivered directly into the pancreas. EUS-guided ethanol lavage with/without paclitaxel injection has been tested for the treatment of cystic tumors of the pancreas, with complete resolution of cystic tumor being observed in up to 70-80% of patients. Ethanol injection is also performed for the management of solid neuroendocrine tumors of the pancreas. Various type of EUS-guided injection have also been investigated for the treatment of pancreatic cancer. An activated allogenic mixed lymphocyte culture (Cytoimplant) was injected in patients with advanced pancreatic cancer. A replication-deficient adenovirus vector carrying the tumor necrosis factor-alpha gene was also delivered intratumorally by EUS. ONYX-015 is an oncolytic attenuated adenovirus that exhibits replication preferentially in malignant cells, causing cell death, and this has also been injected into pancreatic cancers under EUS guidance. EUS-guided local ablation therapies such as radiofrequency ablation, photodynamic therapy, and brachytherapy are also under investigation. EUS-guided fine-needle injection for various solid or cystic lesions is a rapidly expanding field. This article reviews the various applications of EUS for the treatment of pancreatic tumors.

  11. EUS-Guided Antitumor Therapy for Pancreatic Tumors

    PubMed Central

    2010-01-01

    Endoscopic ultrasound (EUS) is a very useful modality for the diagnosis and staging of pancreatic masses. With the advent of EUS-guided fine-needle aspiration technology, this modality has made a tremendous leap from imaging modality to histologic diagnosis and therapeutic intervention. EUS offers high-resolution images of and unparalleled access to the pancreas. After locating the tip of the echoendoscope in the duodenum or stomach, several drugs or local treatment modalities can be delivered directly into the pancreas. EUS-guided ethanol lavage with/without paclitaxel injection has been tested for the treatment of cystic tumors of the pancreas, with complete resolution of cystic tumor being observed in up to 70-80% of patients. Ethanol injection is also performed for the management of solid neuroendocrine tumors of the pancreas. Various type of EUS-guided injection have also been investigated for the treatment of pancreatic cancer. An activated allogenic mixed lymphocyte culture (Cytoimplant) was injected in patients with advanced pancreatic cancer. A replication-deficient adenovirus vector carrying the tumor necrosis factor-alpha gene was also delivered intratumorally by EUS. ONYX-015 is an oncolytic attenuated adenovirus that exhibits replication preferentially in malignant cells, causing cell death, and this has also been injected into pancreatic cancers under EUS guidance. EUS-guided local ablation therapies such as radiofrequency ablation, photodynamic therapy, and brachytherapy are also under investigation. EUS-guided fine-needle injection for various solid or cystic lesions is a rapidly expanding field. This article reviews the various applications of EUS for the treatment of pancreatic tumors. PMID:21103299

  12. 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.

  13. 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

  14. Responsiveness of human prostate carcinoma bone tumors to interleukin-2 therapy in a mouse xenograft tumor model.

    PubMed

    Kocheril, S V; Grignon, D J; Wang, C Y; Maughan, R L; Montecillo, E J; Talati, B; Tekyi-Mensah, S; Pontes, J e; Hillman, G G

    1999-01-01

    We have tested an immunotherapy approach for the treatment of metastatic prostate carcinoma using a bone tumor model. Human PC-3 prostate carcinoma tumor cells were heterotransplanted into the femur cavity of athymic Balb/c nude mice. Tumor cells replaced marrow cells in the bone cavity, invaded adjacent bone and muscle tissues, and formed a palpable tumor at the hip joint. PC-3/IF cell lines, generated from bone tumors by serial in vivo passages, grew with faster kinetics in the femur and metastasized to inguinal lymph nodes. Established tumors were treated with systemic interleukin-2 (IL-2) injections. IL-2 significantly inhibited the formation of palpable tumors and prolonged mouse survival at nontoxic low doses. Histologically IL-2 caused vascular damage and infiltration of polymorphonuclear cells and lymphocytes in the tumor as well as necrotic areas with apoptotic cells. These findings suggest destruction of tumor cells by systemic IL-2 therapy and IL-2 responsiveness of prostate carcinoma bone tumors.

  15. 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

  16. 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

  17. 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.

  18. 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

  19. Peptide receptor radionuclide therapy: focus on bronchial neuroendocrine tumors.

    PubMed

    Lo Russo, Giuseppe; Pusceddu, Sara; Prinzi, Natalie; Imbimbo, Martina; Proto, Claudia; Signorelli, Diego; Vitali, Milena; Ganzinelli, Monica; Maccauro, Marco; Buzzoni, Roberto; Seregni, Ettore; de Braud, Filippo; Garassino, Marina Chiara

    2016-10-01

    Well-differentiated bronchial neuroendocrine tumors (B-NETs) are rare. They represent 1-5 % of all lung cancers. The incidence of these neoplasms has risen over the past 30 years and, especially for advanced or metastatic disease, management is complex and requires a multidisciplinary approach. Treatment with somatostatin analogs (SSAs) is the most important first-line therapy, in particular in well-differentiated NETs with high somatostatin type receptor (SSTR) expression. In these tumors, the role of mammalian target of rapamycin (m-TOR) inhibitors and the potential utility of other target therapies remain unclear while chemotherapy represents the gold standard treatment only for aggressive forms with low SSTR expression. Peptide receptor radionuclide therapy (PRRT) is an emerging treatment modality for advanced NETs. There are many cumulative evidences about the effectiveness and tolerability of this therapeutic approach, especially in gastro-entero-pancreatic (GEP)-NETs. For B-NETs, scientific research is moving more slowly. Here, we performed a review in order to evaluate the efficacy and toxicity of PRRT with a focus on patients with inoperable or metastatic well-differentiated B-NETs.

  20. 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.

  1. Optofluidic cell manipulation for a biological microbeam

    PubMed Central

    Grad, Michael; Bigelow, Alan W.; Garty, Guy; Attinger, Daniel; Brenner, David J.

    2013-01-01

    This paper describes the fabrication and integration of light-induced dielectrophoresis for cellular manipulation in biological microbeams. An optoelectronic tweezers (OET) cellular manipulation platform was designed, fabricated, and tested at Columbia University's Radiological Research Accelerator Facility (RARAF). The platform involves a light induced dielectrophoretic surface and a microfluidic chamber with channels for easy input and output of cells. The electrical conductivity of the particle-laden medium was optimized to maximize the dielectrophoretic force. To experimentally validate the operation of the OET device, we demonstrate UV-microspot irradiation of cells containing green fluorescent protein (GFP) tagged DNA single-strand break repair protein, targeted in suspension. We demonstrate the optofluidic control of single cells and groups of cells before, during, and after irradiation. The integration of optofluidic cellular manipulation into a biological microbeam enhances the facility's ability to handle non-adherent cells such as lymphocytes. To the best of our knowledge, this is the first time that OET cell handling is successfully implemented in a biological microbeam. PMID:23387672

  2. Optofluidic cell manipulation for a biological microbeam

    NASA Astrophysics Data System (ADS)

    Grad, Michael; Bigelow, Alan W.; Garty, Guy; Attinger, Daniel; Brenner, David J.

    2013-01-01

    This paper describes the fabrication and integration of light-induced dielectrophoresis for cellular manipulation in biological microbeams. An optoelectronic tweezers (OET) cellular manipulation platform was designed, fabricated, and tested at Columbia University's Radiological Research Accelerator Facility (RARAF). The platform involves a light induced dielectrophoretic surface and a microfluidic chamber with channels for easy input and output of cells. The electrical conductivity of the particle-laden medium was optimized to maximize the dielectrophoretic force. To experimentally validate the operation of the OET device, we demonstrate UV-microspot irradiation of cells containing green fluorescent protein (GFP) tagged DNA single-strand break repair protein, targeted in suspension. We demonstrate the optofluidic control of single cells and groups of cells before, during, and after irradiation. The integration of optofluidic cellular manipulation into a biological microbeam enhances the facility's ability to handle non-adherent cells such as lymphocytes. To the best of our knowledge, this is the first time that OET cell handling is successfully implemented in a biological microbeam.

  3. Induction of abscopal anti-tumor immunity and immunogenic tumor cell death by ionizing irradiation - implications for cancer therapies.

    PubMed

    Frey, B; Rubner, Y; Wunderlich, R; Weiss, E-M; Pockley, A G; Fietkau, R; Gaipl, U S

    2012-01-01

    Although cancer progression is primarily driven by the expansion of tumor cells, the tumor microenvironment and anti-tumor immunity also play important roles. Herein, we consider how tumors can become established by escaping immune surveillance and also how cancer cells can be rendered visible to the immune system by standard therapies such as radiotherapy or chemotherapy, either alone or in combination with additional immune stimulators. Although local radiotherapy results in DNA damage (targeted effects), it is also capable of inducing immunogenic forms of tumor cell death which are associated with a release of immune activating danger signals (non-targeted effects), such as necrosis. Necrotic tumor cells may result from continued exposure to death stimuli and/or an impaired phosphatidylserine (PS) dependent clearance of the dying tumor cells. In such circumstances, mature dendritic cells take up tumor antigen and mediate the induction of adaptive and innate anti-tumor immunity. Locally-triggered, systemic immune activation can also lead to a spontaneous regression of tumors or metastases that are outside the radiation field - an effect which is termed abscopal. Preclinical studies have demonstrated that combining radiotherapy with immune stimulation can induce anti-tumor immunity. Given that it takes time for immunity to develop following exposure to immunogenic tumor cells, we propose practical combination therapies that should be considered as a basis for future research and clinical practice. It is essential that radiation oncologists become more aware of the importance of the immune system to the success of cancer therapy.

  4. Antitumor activity of an enzyme prodrug therapy targeted to the breast tumor vasculature.

    PubMed

    Van Rite, Brent D; Krais, John J; Cherry, Mohamad; Sikavitsas, Vassilios I; Kurkjian, Carla; Harrison, Roger G

    2013-10-01

    The L-methioninase-annexin V/selenomethionine enzyme prodrug system, designed to target the tumor vasculature and release the methylselenol anticancer drug in the tumor, was tested in mice with implanted MBA-MB-231 breast tumors. This therapy was able to cause a reduction in the size of the tumors during the treatment period. It was shown that L-methioninase-annexin V was uniformly bound at the blood vessel surface in the tumor and also that there was a substantial cutoff of blood flowing through the treated tumor, consistent with the therapy's design. This new approach for enzyme prodrug therapy of breast cancer appears promising.

  5. 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

  6. The radionuclide molecular imaging and therapy of neuroendocrine tumors.

    PubMed

    Li, Shuren; Beheshti, Mohsen

    2005-03-01

    Neuroendocrine tumors (NETs) represent a large group of neoplasms deriving from pluripotent stem cells or from differentiated neuroendocrine cells that are characterized by the expression of different peptides and biogenic amines. These rare tumors tend to grow slowly and are notoriously difficult to localize, at least in the early stages. Diagnostics involve blood, urine and biochemical examination as well as imaging modalities. Imaging is achieved by a variety of techniques such as radiological morphological imaging methods, for example, sonography, computerized tomography (CT)/magnetic resonance imaging (MRI), angiography and finally, nuclear functional imaging methods such as metaiodobenzylguanidine (MIBG), somatostatin receptor scintigraphy (SRS), vasoactive intestinal peptide receptor scintigraphy (VIPRS) and positron emission tomography (PET) using (18)F labeled deoxyglucose (FDG) and fluorinated dihydroxyphenylalanine ((18)F-DOPA) as a radioisotopic marker. (131)I-labeled MIBG is a well-established radiopharmaceutical for localization and therapy of phechromocytoma and paraganglioma. The majority of neuroendocrine tumors possess a high density of somatostatin receptors. This observation provided the basis for the development of various radiolabeled somatostatin peptide analogs as imaging agents and therapeutics in nuclear medicine. FDG-PET is now performed in a wide variety of tumors and indications, including diagnosis, staging, re-staging and evaluation of the response to treatment. (18)F-DOPA-PET may be useful if (18)F-FDG-PET scan result is negative. (99m)Tc-pentavalent dimercaptosuccinic acid ((99m)Tc-DMSA-V) or (99m)Tc sestamibi ((99m)Tc-MIBI) or (99m)Tc-tetrofosmin is used only for diagnosis of certain NETs such as medullary thyroid cancer. The expiences with other nuclear medicinie imaging and therapy modalities such as cholecystokinin (CCK)-B/gastrin-receptors, bombesin/gastrin-releasing peptide receptor scintigraphy are still limited, and further

  7. Sequence dependence of administration of human recombinant tumor necrosis factor and interleukin-2 in murine tumor therapy.

    PubMed

    Zimmerman, R J; Gauny, S; Chan, A; Landre, P; Winkelhake, J L

    1989-02-01

    Simultaneous administration of recombinant human tumor necrosis factor (rhTNF) and interleukin-2 (rhIL-2) has been shown to block tumor take in murine models. We investigated the effects of sequence and schedule of administration as a function of tumor burden with two tumor models (B16 and Meth A). rhTNF followed by rhIL-2 had extraordinary antitumor efficacy, but rhIL-2 followed by rhTNF was much less effective. Sequential rhTNF/rhIL-2 therapy resulted in complete tumor regression, whereas simultaneous therapy resulted in complete tumor regression, whereas simultaneous therapy resulted in only reduced growth rate. Experiments with genetically immunodeficient mice suggested that T cell factors may be required for synergistic antitumor activity.

  8. 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.

  9. Functionalized Gold Nanorods for Tumor Imaging and Targeted Therapy

    PubMed Central

    Gui, Chen; Cui, Da-xiang

    2012-01-01

    Gold nanorods, as an emerging noble metal nanomaterial with unique properties, have become the new exciting focus of theoretical and experimental studies in the past few years. The structure and function of gold nanorods, especially their biocompatibility, optical property, and photothermal effects, have been attracting more and more attention. Gold nanorods exhibit great potential in applications such as tumor molecular imaging and photothermal therapy. In this article, we review some of the main advances made over the past few years in the application of gold nanorods in surface functionalization, molecular imaging, and photothermal therapy. We also explore other prospective applications and discuss the corresponding concepts, issues, approaches, and challenges, with the aim of stimulating broader interest in gold nanorod-based nanotechnology and improving its practical application. PMID:23691482

  10. Laser-driven ion accelerators for tumor therapy revisited

    NASA Astrophysics Data System (ADS)

    Linz, Ute; Alonso, Jose

    2016-12-01

    Ten years ago, the authors of this report published a first paper on the technical challenges that laser accelerators need to overcome before they could be applied to tumor therapy. Among the major issues were the maximum energy of the accelerated ions and their intensity, control and reproducibility of the laser-pulse output, quality assurance and patient safety. These issues remain today. While theoretical progress has been made for designing transport systems, for tailoring the plumes of laser-generated protons, and for suitable dose delivery, today's best lasers are far from reaching performance levels, in both proton energy and intensity to seriously consider clinical ion beam therapy (IBT) application. This report details these points and substantiates that laser-based IBT is neither superior to IBT with conventional particle accelerators nor ready to replace it.

  11. Tumor-Triggered Geometrical Shape Switch of Chimeric Peptide for Enhanced in Vivo Tumor Internalization and Photodynamic Therapy.

    PubMed

    Han, Kai; Zhang, Jin; Zhang, Weiyun; Wang, Shibo; Xu, Luming; Zhang, Chi; Zhang, Xianzheng; Han, Heyou

    2017-03-28

    Geometrical shape of nanoparticles plays an important role in cellular internalization. However, the applicability in tumor selective therapeutics is still scarcely reported. In this article, we designed a tumor extracellular acidity-responsive chimeric peptide with geometrical shape switch for enhanced tumor internalization and photodynamic therapy. This chimeric peptide could self-assemble into spherical nanoparticles at physiological condition. While at tumor extracellular acidic microenvironment, chimeric peptide underwent detachment of acidity-sensitive 2,3-dimethylmaleic anhydride groups. The subsequent recovery of ionic complementarity between chimeric peptides resulted in formation of rod-like nanoparticles. Both in vitro and in vivo studies demonstrated that this acidity-triggered geometrical shape switch endowed chimeric peptide with accelerated internalization in tumor cells, prolonged accumulation in tumor tissue, enhanced photodynamic therapy, and minimal side effects. Our results suggested that fusing tumor microenvironment with geometrical shape switch should be a promising strategy for targeted drug delivery.

  12. The Role of Hypoxia in the Tumor Microenvironment: Implications for Ovarian Cancer Therapy

    DTIC Science & Technology

    2016-07-01

    dynamic process that involves critical interactions between tumor cells and the microenvironment . Hypoxia is a potent microenvironmental factor...AWARD NUMBER: W81XWH-15-1-0097 TITLE: The Role of Hypoxia in the Tumor Microenvironment : Implications for Ovarian Cancer Therapy PRINCIPAL... Microenvironment : Implications for Ovarian Cancer Therapy Ovarian Cancer Therapy 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6

  13. 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.

  14. Constraint-Induced Movement Therapy for Children With Brain Tumors.

    PubMed

    Sparrow, Jessica; Zhu, Liang; Gajjar, Amar; Mandrell, Belinda N; Ness, Kirsten K

    2017-01-01

    The purpose of this pilot study was to investigate the feasibility of a 3-week constraint-induced movement therapy program in children with brain tumors and upper extremity hemiplegia and to describe resultant change in extremity use. Affected arm use, health-related quality of life, and parent-reported feasibility of program participation were measured before and after the intervention and at a 3-month follow-up visit. All 9 participants completed the entire study. The quality and amount of affected arm use improved significantly; gains were maintained at the 3-month follow-up evaluation. Some parents (44%) reported that program participation was difficult; however, all reported satisfaction with the program. Participants did not experience negative changes in health-related quality of life during the intervention, indicating that they tolerated the program well. Findings suggest that a child with hemiplegia as a result of a brain tumor can adhere to and benefit from a constraint-induced movement therapy program.

  15. 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

  16. Standard of care therapy for malignant glioma and its effect on tumor and stromal cells.

    PubMed

    Jones, T S; Holland, E C

    2012-04-19

    Glioblastoma is the most common and deadly of the primary central nervous system tumors. Recent advances in molecular characterization have subdivided these tumors into at least three main groups. In addition, these tumors are cellularly complex with multiple stromal cell types contributing to the biology of the tumor and treatment response. Because essentially all glioma patients are treated with radiation, various chemotherapies and steroids, the tumor that finally kills them has been modified by these treatments. Most of the investigation of the effects of therapy on these tumors has focused on the glioma cells per se. However, despite the importance of the stromal cells in these tumors, little has been done to understand the effects of treatment on stromal cells and their contribution to disease. Understanding how current standard therapy affects the biology of the tumor and the tumor stroma may provide insight into the mechanisms that are important to the inhibition of tumor growth as well as the biology of recurrent tumors.

  17. 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.

  18. 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

  19. Trial Watch: Tumor-targeting monoclonal antibodies in cancer therapy.

    PubMed

    Vacchelli, Erika; Aranda, Fernando; Eggermont, Alexander; Galon, Jérôme; Sautès-Fridman, Catherine; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

    2014-01-01

    In 1997, for the first time in history, a monoclonal antibody (mAb), i.e., the chimeric anti-CD20 molecule rituximab, was approved by the US Food and Drug Administration for use in cancer patients. Since then, the panel of mAbs that are approved by international regulatory agencies for the treatment of hematopoietic and solid malignancies has not stopped to expand, nowadays encompassing a stunning amount of 15 distinct molecules. This therapeutic armamentarium includes mAbs that target tumor-associated antigens, as well as molecules that interfere with tumor-stroma interactions or exert direct immunostimulatory effects. These three classes of mAbs exert antineoplastic activity via distinct mechanisms, which may or may not involve immune effectors other than the mAbs themselves. In previous issues of OncoImmunology, we provided a brief scientific background to the use of mAbs, all types confounded, in cancer therapy, and discussed the results of recent clinical trials investigating the safety and efficacy of this approach. Here, we focus on mAbs that primarily target malignant cells or their interactions with stromal components, as opposed to mAbs that mediate antineoplastic effects by activating the immune system. In particular, we discuss relevant clinical findings that have been published during the last 13 months as well as clinical trials that have been launched in the same period to investigate the therapeutic profile of hitherto investigational tumor-targeting mAbs.

  20. 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.

  1. 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.

  2. Photothermal therapy of melanoma tumor using multiwalled carbon nanotubes.

    PubMed

    Sobhani, Zahra; Behnam, Mohammad Ali; Emami, Farzin; Dehghanian, Amirreza; Jamhiri, Iman

    2017-01-01

    Photothermal therapy (PTT) is a therapeutic method in which photon energy is transformed into heat rapidly via different operations to extirpate cancer. Nanoparticles, such as carbon nanotubes (CNTs) have exceptional optical absorbance in visible and near infrared spectra. Therefore, they could be a good converter to induce hyperthermia in PTT technique. In our study, for improving the dispersibility of multiwalled CNTs in water, the CNTs were oxidized (O-CNTs) and then polyethylene glycol (PEG) was used for wrapping the surface of nanotubes. The formation of a thin layer of PEG around the nanotubes was confirmed through Fourier transform infrared, thermogravimetric analysis, and field emission scanning electron microscopy techniques. Results of thermogravimetric analysis showed that the amount of PEG component in the O-CNT-PEG was approximately 80% (w/w). Cell cytotoxicity study showed that O-CNT was less cytotoxic than pristine multiwalled nanotubes, and O-CNT-PEG had the lowest toxicity against HeLa and HepG2 cell lines. The effect of O-CNT-PEG in reduction of melanoma tumor size after PTT was evaluated. Cancerous mice were exposed to a continuous-wave near infrared laser diode (λ=808 nm, P=2 W and I=8 W/cm(2)) for 10 minutes once in the period of the treatment. The average size of tumor in mice receiving O-CNT-PEG decreased sharply in comparison with those that received laser therapy alone. Results of animal studies indicate that O-CNT-PEG is a powerful candidate for eradicating solid tumors in PTT technique.

  3. Submucosal tumors: comprehensive guide for the diagnosis and therapy of gastrointestinal submucosal tumors.

    PubMed

    Nishida, Toshirou; Kawai, Naoki; Yamaguchi, Shinjiro; Nishida, Yoshiki

    2013-09-01

    Small submucosal tumors (SMT) without symptoms are frequently found by endoscopic and radiological examinations. To find proper diagnostic measures and therapeutic indications for histologically undiagnosed SMT, we reviewed published articles in PubMed between 1990 and March 2013 using the key words 'submucosal tumor' and the name of a specific disease. SMT is observed in a wide range of gastrointestinal (GI) diseases and conditions, including compression by extra-GI organs and lesions, congenital tumors, inflammation, and benign as well as malignant neoplastic lesions. In the diagnosis of diseases and decision-making for therapy, endoscopic ultrasonography (EUS) and endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) may play a key role. Symptomatic SMT and SMT histologically diagnosed as malignant or potentially malignant tumors such as gastrointestinal stromal tumor (GIST) should be treated by surgery. SMT >5 cm, SMT increasing in size and those with'high-risk features' including irregular border, heterogeneous internal echo such as anechoic area, and heterogeneous enhancement by contrast media may also be removed by surgery. Laparoscopic approach is feasible for gastric GIST <5 cm and this is considered less invasive than the open approach. Emerging techniques using flexible endoscopes appear less invasive, but require further evidence and are still under clinical study. Correct diagnosis of SMT is challenging; however, EUS and EUS-FNA are useful in the histological diagnosis and clinical decision-making. In the future, minimally invasive approaches may be a mainstream of surgical treatment for small SMT. © 2013 The Authors. Digestive Endoscopy © 2013 Japan Gastroenterological Endoscopy Society.

  4. PULMONARY COMPLICATIONS OF TUMOR NECROSIS FACTOR-TARGETED THERAPY

    PubMed Central

    Thavarajah, Krishna; Wu, Peggy; Rhew, Elisa J.; Yeldandi, Anjana K; Kamp, David W.

    2009-01-01

    Tumor necrosis factor (TNF)-targeted therapies are increasingly being prescribed in the management of a variety of inflammatory and autoimmune diseases. The use of this class of medications also pose risks of developing an assortment of pulmonary side effects including infections (TB, bacterial, and fungal infections), pulmonary nodules, chronic pneumonitis/fibrosis, SLE-like reactions, vasculitis, and exacerbations of underlying lung disease. In addition to surveillance for tuberculosis prior to initiation of TNF-targeted therapy, a high level of vigilance should be maintained during administration for infectious and non-infectious complications, even years into a patient’s course. The available evidence argues for caution in using these agents in patients with pre-existing lung disease and heightened suspicion of accelerated nodule formation in those with preexisting rheumatoid nodules. Management centers on excluding infection, identifying confounders (especially methotrexate or pre-existing lung disease), and promptly discontinuing TNF-targeted therapy. In some instances, invasive procedures (e.g. bronchoscopy or VATS lung biopsy) will be necessary to establish the proper diagnosis, and the administration of steroids may be beneficial. PMID:19201589

  5. Tumor-specific allogeneic cells for cancer therapy.

    PubMed

    Marcus, Assaf; Eshhar, Zelig

    2011-12-01

    Adoptive cell transfer (ACT) therapy involves transfer of therapeutic lymphocytes to patients mostly for the treatment of cancer and viral infections. One modality to generate therapeutic lymphocytes is to genetically engineer them to express a chimeric antigen receptor (CAR) capable of recognizing the desired target. Current ACT approaches employ the patient's own (syngeneic) lymphocytes, which is both economically and technically challenging. Using foreign (allogeneic) lymphocytes in ACT is problematic because of the severe immunological reaction that occurs between genetically mismatched individuals. However, recently our group has developed a protocol, which allows for safe and effective ACT therapy in a murine model of metastatic disease using allogeneic T cells redirected with a human EGFR2/neuregulin (Her2/neu)-specific CAR. Mild preconditioning of the recipient delayed the rejection of the allogeneic donor T cells such that they had enough time to destroy the tumor, but not enough to cause significant damage to the host. By modulating lymphocyte migration using FTY720, we were actually able to exploit the allogeneic anti-host reaction in order to augment therapeutic benefit while concurrently improving the safety of the treatment. Therefore, we suggest that CAR-based allogeneic ACT therapy could be universally used as a safe and potent 'off-the-shelf' treatment for cancer.

  6. 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

  7. Inhibition of tumor energy pathways for targeted esophagus cancer therapy.

    PubMed

    Shafaee, Abbas; Dastyar, Davood Zarei; Islamian, Jalil Pirayesh; Hatamian, Milad

    2015-10-01

    Interest in targeting cancer metabolism has been renewed in recent years with the discovery that many cancer related pathways have a profound effect on metabolism and that many tumors become dependent on specific metabolic processes. Accelerated glucose uptake during anaerobic glycolysis and loss of regulation between glycolytic metabolism and respiration, are the major metabolic changes found in malignant cells. The non-metabolizable glucose analog, 2-deoxy-D-glucose inhibits glucose synthesis and adenosine triphosphate production. The adenosine monophosphate-activated protein kinase (AMPK) is a key sensor of cellular energy and AMPK is a potential target for cancer prevention and/or treatment. Metformin is an activator of AMPK which inhibits protein synthesis and gluconeogenesis during cellular stress. This article reviews the status of clinical and laboratory researches exploring targeted therapies via metabolic pathways for treatment of esophageal cancer.

  8. [Current therapy of endocrine organ tumors (adrenal and parathyroid glands)].

    PubMed

    Nakano, M; Tajima, A; Aso, Y

    1988-02-01

    Since the adrenal or parathyroid cancer is a clinically rare entity. We often have difficulty in its diagnosis and treatment. The adrenocortical cancer is usually classified into two categories--endocrinologically functioning or non-functioning. The incidence is not different between them. It is often found in an advanced stage as it does not show clinical manifestation before it has grown up to a large tumor. Only an effective agent for the adrenal cancer is op'-DDD so far. Recently, cisplatin, VP-16 (etoposide) and others are administered as trial use. Most of malignant pheochromocytomas are endocrinologically active and they often cause hypertension leading to death. Therefore it is important to control hypertension in malignant pheochromocytoma. Chemotherapy and irradiation are not effective for it. Recently, 131I-MIBG (metaiodobenzylguanidine) is found to be useful not only for diagnosis but also treatment of malignant pheochromocytoma. 131I-MIBG is accumulated specifically in the chromaffin cells and with helpful to find out metastatic foci. It is also used in a large amount as a specific irradiation therapy for this malignancy. Parathyroid cancer is found in approximately 3 percent of primary hyperparathyroidism. Clinically it usually reveal serum calcium level higher than 14 mg/dl, bone lesions and renal dysfunction in addition to palpable cervical tumors adhering with skin. Sometimes it is difficult to differentiate malignancy from adenoma in histology. Most cases develop local recurrences and distant metastases in due course and dies of hypercalcemia. It is very important to control hypercalcemia in inoperable cases. As both chemotherapy and radiation therapy render no effect on this malignancy. Surgery is a sole strategy for it.

  9. Molecular Pathways: Mitochondrial Reprogramming in Tumor Progression and Therapy

    PubMed Central

    Caino, M. Cecilia; Altieri, Dario C.

    2015-01-01

    Small molecule inhibitors of the phosphatidylinositol 3-kinase (PI3K), Akt and mTOR pathway currently in the clinic produce a paradoxical reactivation of the pathway they are intended to suppress. Furthermore, fresh experimental evidence with PI3K antagonists in melanoma, glioblastoma and prostate cancer shows that mitochondrial metabolism drives an elaborate process of tumor adaptation culminating with drug resistance and metastatic competency. This is centered on reprogramming of mitochondrial functions to promote improved cell survival and to fuel the machinery of cell motility and invasion. Key players in these responses are molecular chaperones of the Heat Shock Protein 90 (Hsp90) family compartmentalized in mitochondria, which suppress apoptosis via phosphorylation of the pore component, Cyclophilin D, and enable the subcellular repositioning of active mitochondria to membrane protrusions implicated in cell motility. An inhibitor of mitochondrial Hsp90s in preclinical development (Gamitrinib) prevents adaptive mitochondrial reprogramming and shows potent anti-tumor activity in vitro and in vivo. Other therapeutic strategies to target mitochondria for cancer therapy include small molecule inhibitors of mutant isocitrate dehydrogenase (IDH) IDH1 (AG-120) and IDH2 (AG-221) which opened new therapeutic prospects for high-risk AML patients. A second approach of mitochondrial therapeutics focuses on agents that elevate toxic ROS levels from a leaky electron transport chain, nevertheless the clinical experience with these compounds, including a quinone derivative, ARQ 501, and a copper chelator, elesclomol (STA-4783) is limited. In light of these evidences, we discuss how best to target a resurgence of mitochondrial bioenergetics for cancer therapy. PMID:26660517

  10. 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.

  11. Drug delivery and release systems for targeted tumor therapy.

    PubMed

    Böhme, David; Beck-Sickinger, Annette G

    2015-03-01

    Most toxic agents currently used for chemotherapy show a narrow therapeutic window, because of their inability to distinguish between healthy and cancer cells. Targeted drug delivery offers the possibility to overcome this issue by selectively addressing structures on the surface of cancer cells, therefore reducing undesired side effects. In this broad field, peptide-drug conjugates linked by intracellular cleavable structures have evolved as highly promising agents. They can specifically deliver toxophores to tumor cells by targeting distinct receptors overexpressed in cancer. In this review, we focus on these compounds and describe important factors to develop a highly efficient peptide-drug conjugate. The necessary properties of tumor-targeting peptides are described, and the different options for cleavable linkers used to connect toxic agents and peptides are discussed, and synthetic considerations for the introduction of these structures are reported. Furthermore, recent examples and current developments of peptide-drug conjugates are critically evaluated with a special focus on the applied linker structures and their future use in cancer therapy. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.

  12. Cognitive Remediation Therapy for Brain Tumor Survivors with Cognitive Deficits

    PubMed Central

    Sacks-Zimmerman, Amanda; Liberta, Taylor

    2015-01-01

    Cognitive deficits have been widely observed in patients with primary brain tumors consequent to diagnosis and treatment. Given the early onset and the relatively long survival rate of patients, it seems pertinent to study and refine the techniques used to treat these deficits. The purpose of this article is to discuss cognitive deficits that follow neurosurgical treatment for low-grade gliomas as well as to outline a neuropsychological intervention to treat these deficits, specifically working memory and attention. Cognitive remediation therapy is a neuropsychological intervention that aims to enhance attention, working memory, and executive functioning, thereby diminishing the impact of these deficits on daily functioning. Computerized cognitive remediation training programs facilitate access to treatment through providing online participation. The authors include preliminary results of three participants who have completed the computerized training program as part of an ongoing study that is investigating the efficacy of this program in patients who have undergone treatment for low-grade gliomas. The results so far suggest some improvement in working memory and attention from baseline scores. It is the hope of the present authors to highlight the importance of this treatment in the continuity of care of brain tumor survivors. PMID:26623205

  13. "Armed" oncolytic herpes simplex viruses for brain tumor therapy.

    PubMed

    Todo, Tomoki

    2008-01-01

    Genetically engineered, conditionally replicating herpes simplex viruses type 1 (HSV-1) are promising therapeutic agents for brain tumors and other solid cancers. They can replicate in situ, spread and exhibit oncolytic activity via a direct cytocidal effect. One of the advantages of HSV-1 is the capacity to incorporate large and/or multiple transgenes within the viral genome. Oncolytic HSV-1 can therefore be "armed" to add certain functions. Recently, the field of armed oncolytic HSV-1 has drastically advanced, due to development of recombinant HSV-1 generation systems that utilize bacterial artificial chromosome and multiple DNA recombinases. Because antitumor immunity is induced in the course of oncolytic activities of HSV-1, transgenes encoding immunomodulatory molecules have been most frequently used for arming. Other armed oncolytic HSV-1 include those that express antiangiogenic factors, fusogenic membrane glycoproteins, suicide gene products, and proapoptotic proteins. Provided that the transgene product does not interfere with viral replication, such arming of oncolytic HSV-1 results in augmentation of antitumor efficacy. Immediate-early viral promoters are often used to control the arming transgenes, but strict-late viral promoters have been shown useful to restrict the expression in the late stage of viral replication when desirable. Some armed oncolytic HSV-1 have been created for the purpose of noninvasive in vivo imaging of viral infection and replication. Development of a wide variety of armed oncolytic HSV-1 will lead to an establishment of a new genre of therapy for brain tumors as well as other cancers.

  14. Attogram mass sensing based on silicon microbeam resonators

    NASA Astrophysics Data System (ADS)

    Baek, In-Bok; Byun, Sangwon; Lee, Bong Kuk; Ryu, Jin-Hwa; Kim, Yarkyeon; Yoon, Yong Sun; Jang, Won Ik; Lee, Seongjae; Yu, Han Young

    2017-04-01

    Using doubly-clamped silicon (Si) microbeam resonators, we demonstrate sub-attogram per Hertz (ag/Hz) mass sensitivity, which is extremely high sensitivity achieved by micro-scale MEMS mass sensors. We also characterize unusual buckling phenomena of the resonators. The thin-film based resonator is composed of a Si microbeam surrounded by silicon nitride (SiN) anchors, which significantly improve performance by providing fixation on the microbeam and stabilizing oscillating motion. Here, we introduce two fabrication techniques to further improve the mass sensitivity. First, we minimize surface stress by depositing a sacrificial SiN layer, which prevents damage on the Si microbeam. Second, we modify anchor structure to find optimal design that allows the microbeam to oscillate in quasi-one dimensional mode while achieving high quality factor. Mass loading is conducted by depositing Au/Ti thin films on the local area of the microbeam surface. Using sequential mass loading, we test effects of changing beam dimensions, position of mass loading, and distribution of a metal film on the mass sensitivity. In addition, we demonstrate that microbeams suffer local micro-buckling and global buckling by excessive mass loading, which are induced by two different mechanisms. We also find that the critical buckling length is increased by additional support from the anchors.

  15. Targeting distinct tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor: combating tumor evasion of antiangiogenic therapy.

    PubMed

    Priceman, Saul J; Sung, James L; Shaposhnik, Zory; Burton, Jeremy B; Torres-Collado, Antoni X; Moughon, Diana L; Johnson, Mai; Lusis, Aldons J; Cohen, Donald A; Iruela-Arispe, M Luisa; Wu, Lily

    2010-02-18

    Tumor-infiltrating myeloid cells (TIMs) support tumor growth by promoting angiogenesis and suppressing antitumor immune responses. CSF-1 receptor (CSF1R) signaling is important for the recruitment of CD11b(+)F4/80(+) tumor-associated macrophages (TAMs) and contributes to myeloid cell-mediated angiogenesis. However, the impact of the CSF1R signaling pathway on other TIM subsets, including CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs), is unknown. Tumor-infiltrating MDSCs have also been shown to contribute to tumor angiogenesis and have recently been implicated in tumor resistance to antiangiogenic therapy, yet their precise involvement in these processes is not well understood. Here, we use the selective pharmacologic inhibitor of CSF1R signaling, GW2580, to demonstrate that CSF-1 regulates the tumor recruitment of CD11b(+)Gr-1(lo)Ly6C(hi) mononuclear MDSCs. Targeting these TIM subsets inhibits tumor angiogenesis associated with reduced expression of proangiogenic and immunosuppressive genes. Combination therapy using GW2580 with an anti-VEGFR-2 antibody synergistically suppresses tumor growth and severely impairs tumor angiogenesis along with reverting at least one TIM-mediated antiangiogenic compensatory mechanism involving MMP-9. These data highlight the importance of CSF1R signaling in the recruitment and function of distinct TIM subsets, including MDSCs, and validate the benefits of targeting CSF1R signaling in combination with antiangiogenic drugs for the treatment of solid cancers.

  16. 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.

  17. A Brain Tumor/Organotypic Slice Co-culture System for Studying Tumor Microenvironment and Targeted Drug Therapies

    PubMed Central

    Chadwick, Emily J.; Yang, David P.; Filbin, Mariella G.; Mazzola, Emanuele; Sun, Yu; Behar, Oded; Pazyra-Murphy, Maria F.; Goumnerova, Liliana; Ligon, Keith L.; Stiles, Charles D.; Segal, Rosalind A.

    2015-01-01

    Brain tumors are a major cause of cancer-related morbidity and mortality. Developing new therapeutics for these cancers is difficult, as many of these tumors are not easily grown in standard culture conditions. Neurosphere cultures under serum-free conditions and orthotopic xenografts have expanded the range of tumors that can be maintained. However, many types of brain tumors remain difficult to propagate or study. This is particularly true for pediatric brain tumors such as pilocytic astrocytomas and medulloblastomas. This protocol describes a system that allows primary human brain tumors to be grown in culture. This quantitative assay can be used to investigate the effect of microenvironment on tumor growth, and to test new drug therapies. This protocol describes a system where fluorescently labeled brain tumor cells are grown on an organotypic brain slice from a juvenile mouse. The response of tumor cells to drug treatments can be studied in this assay, by analyzing changes in the number of cells on the slice over time. In addition, this system can address the nature of the microenvironment that normally fosters growth of brain tumors. This brain tumor organotypic slice co-culture assay provides a propitious system for testing new drugs on human tumor cells within a brain microenvironment. PMID:26575352

  18. A Brain Tumor/Organotypic Slice Co-culture System for Studying Tumor Microenvironment and Targeted Drug Therapies.

    PubMed

    Chadwick, Emily J; Yang, David P; Filbin, Mariella G; Mazzola, Emanuele; Sun, Yu; Behar, Oded; Pazyra-Murphy, Maria F; Goumnerova, Liliana; Ligon, Keith L; Stiles, Charles D; Segal, Rosalind A

    2015-11-07

    Brain tumors are a major cause of cancer-related morbidity and mortality. Developing new therapeutics for these cancers is difficult, as many of these tumors are not easily grown in standard culture conditions. Neurosphere cultures under serum-free conditions and orthotopic xenografts have expanded the range of tumors that can be maintained. However, many types of brain tumors remain difficult to propagate or study. This is particularly true for pediatric brain tumors such as pilocytic astrocytomas and medulloblastomas. This protocol describes a system that allows primary human brain tumors to be grown in culture. This quantitative assay can be used to investigate the effect of microenvironment on tumor growth, and to test new drug therapies. This protocol describes a system where fluorescently labeled brain tumor cells are grown on an organotypic brain slice from a juvenile mouse. The response of tumor cells to drug treatments can be studied in this assay, by analyzing changes in the number of cells on the slice over time. In addition, this system can address the nature of the microenvironment that normally fosters growth of brain tumors. This brain tumor organotypic slice co-culture assay provides a propitious system for testing new drugs on human tumor cells within a brain microenvironment.

  19. 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.

  20. Tumor bioenergetics: An emerging avenue for cancer metabolism targeted therapy

    PubMed Central

    Kee, Hyun Jung; Cheong, Jae-Ho

    2014-01-01

    Cell proliferation is a delicately regulated process that couples growth signals and metabolic demands to produce daughter cells. Interestingly, the proliferation of tumor cells immensely depends on glycolysis, the Warburg effect, to ensure a sufficient amount of metabolic flux and bioenergetics for macromolecule synthesis and cell division. This unique metabolic derangement ould provide an opportunity for developing cancer therapeutic strategy, particularly when other diverse anti-cancer treatments have been proved ineffective in achieving durable response, largely due to the emergence of resistance. Recent advances in deeper understanding of cancer metabolism usher in new horizons of the next generation strategy for cancer therapy. Here, we discuss the focused review of cancer energy metabolism, and the therapeutic exploitation of glycolysis and OXPHOS as a novel anti-cancer strategy, with particular emphasis on the promise of this approach, among other cancer metabolism targeted therapies that reveal unexpected complexity and context-dependent metabolic adaptability, complicating the development of effective strategies. [BMB Reports 2014; 47(3): 158-166] PMID:24499670

  1. [Interdisciplinary neuro-oncology: part 2: systemic therapy of primary brain tumors].

    PubMed

    Tabatabai, G; Hattingen, E; Schlegel, J; Stummer, W; Schlegel, U

    2014-08-01

    By combining the expertise of clinical neuroscience, the aim of neuro-oncology is to optimize diagnostic planning and therapy of primary brain tumors in an interdisciplinary setting together with radio-oncology and medical oncology. High-end imaging frequently allows brain tumors to be diagnosed preoperatively with respect to tumor entity and even tumor malignancy grade. Moreover, neuroimaging is indispensable for guidance of biopsy resection and monitoring of therapy. Surgical resection of intracranial lesions with preservation of neurological function has become dramatically more extensive. Tools to achieve this goal are, for example neuronavigation, functional magnetic resonance imaging (fMRI), tractography, intraoperative cortical stimulation and precise intraoperative definition of tumor margins by virtue of various techniques. In addition to classical histopathological diagnosis and tumor classification, modern neuropathology is supplemented by molecular characterization of brain tumors in order to provide clinicians with prognostic and predictive (of therapy) markers, such as codeletion of chromosomes 1p and 19q in anaplastic gliomas and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation in glioblastomas. Although this is not yet individualized tumor therapy, the increasingly more detailed analysis of the molecular pathogenesis of an individual glioma will eventually lead to specific pharmacological blockade of disturbed intracellular pathways in individual patients. This article gives an overview of the state of the art of interdisciplinary neuro-oncology whereby part 1 deals with the diagnostics and surgical therapy of primary brain tumors and part 2 describes the medical therapy of primary brain tumors.

  2. [Interdisciplinary neuro-oncology: part 1: diagnostics and operative therapy of primary brain tumors].

    PubMed

    Tabatabai, G; Hattingen, E; Schlegel, J; Stummer, W; Schlegel, U

    2014-08-01

    By combining the expertise of clinical neuroscience, the aim of neuro-oncology is to optimize diagnostic planning and therapy of primary brain tumors in an interdisciplinary setting together with radio-oncology and medical oncology. High-end imaging frequently allows brain tumors to be diagnosed preoperatively with respect to tumor entity and even tumor malignancy grade. Moreover, neuroimaging is indispensable for guidance of biopsy resection and monitoring of therapy. Surgical resection of intracranial lesions with preservation of neurological function is increasingly feasible. Tools to achieve this goal are, for example neuronavigation, functional magnetic resonance imaging (fMRI), tractography, intraoperative cortical stimulation and precise intraoperative definition of tumor margins by virtue of various techniques. In addition to classical histopathological diagnosis and tumor classification, modern neuropathology is supplemented by molecular characterization of brain tumors in order to provide clinicians with prognostic and predictive (of therapy) markers, such as codeletion of chromosomes 1p and 19q in anaplastic gliomas and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation in glioblastomas. Although this is not yet individualized tumor therapy, the increasingly more detailed analysis of the molecular pathogenesis of an individual glioma will eventually lead to specific pharmacological blockade of disturbed intracellular pathways in individual patients. This article gives an overview of the state of the art of interdisciplinary neuro-oncology whereby part 1 deals with the diagnostics and surgical therapy of primary brain tumors and part 2 describes the medical therapy of primary brain tumors.

  3. 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.

  4. Computational modelling of the cerebral cortical microvasculature: effect of x-ray microbeams versus broad beam irradiation

    NASA Astrophysics Data System (ADS)

    Merrem, A.; Bartzsch, S.; Laissue, J.; Oelfke, U.

    2017-05-01

    Microbeam Radiation Therapy is an innovative pre-clinical strategy which uses arrays of parallel, tens of micrometres wide kilo-voltage photon beams to treat tumours. These x-ray beams are typically generated on a synchrotron source. It was shown that these beam geometries allow exceptional normal tissue sparing from radiation damage while still being effective in tumour ablation. A final biological explanation for this enhanced therapeutic ratio has still not been found, some experimental data support an important role of the vasculature. In this work, the effect of microbeams on a normal microvascular network of the cerebral cortex was assessed in computer simulations and compared to the effect of homogeneous, seamless exposures at equal energy absorption. The anatomy of a cerebral microvascular network and the inflicted radiation damage were simulated to closely mimic experimental data using a novel probabilistic model of radiation damage to blood vessels. It was found that the spatial dose fractionation by microbeam arrays significantly decreased the vascular damage. The higher the peak-to-valley dose ratio, the more pronounced the sparing effect. Simulations of the radiation damage as a function of morphological parameters of the vascular network demonstrated that the distribution of blood vessel radii is a key parameter determining both the overall radiation damage of the vasculature and the dose-dependent differential effect of microbeam irradiation.

  5. 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.

  6. 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.

  7. 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.

  8. Photodynamic therapy and imaging based on tumor-targeted nanoprobe, polymer-conjugated zinc protoporphyrin

    PubMed Central

    Fang, Jun; Liao, Long; Yin, Hongzhuan; Nakamura, Hideaki; Subr, Vladimir; Ulbrich, Karel; Maeda, Hiroshi

    2015-01-01

    Aim: To evaluate the potential of tumor-targeted nanoprobe, N-(2-hydroxypropyl)methacrylamide copolymer-conjugated zinc protoporphyrin (PZP) for photodynamic therapy (PDT) and tumor imaging. Materials & Methods: Different tumor models including carcinogen-induced cancer were used, PZP was intravenously injected followed by irradiation with xenon or blue fluorescent light on tumor. Results: One PZP 20 mg/kg (ZnPP equivalent) dose with two or three treatments of light at an intensity of ≥20 J/cm2 caused necrosis and disappearance of most tumors (>70%) in different tumor models. We also confirmed PZP-based tumor imaging in carcinogen-induced breast tumor and colon cancer models. Conclusion: These findings support the potential application of PZP as a tumor-selective nanoprobe for PDT as well as tumor imaging, by virtue of the enhanced permeability and retention effect. PMID:28031879

  9. Micro-beam friction liner and method of transferring energy

    DOEpatents

    Mentesana, Charles

    2007-07-17

    A micro-beam friction liner adapted to increase performance and efficiency and reduce wear in a piezoelectric motor or actuator or other device using a traveling or standing wave to transfer energy in the form of torque and momentum. The micro-beam friction liner comprises a dense array of micro-beam projections having first ends fixed relative to a rotor and second ends projecting substantially toward a plurality of teeth of a stator, wherein the micro-beam projections are compressed and bent during piezoelectric movement of the stator teeth, thereby storing the energy, and then react against the stator teeth to convert the stored energy stored to rotational energy in the rotor.

  10. Development of microbeam technology to expand applications at TIARA

    NASA Astrophysics Data System (ADS)

    Kamiya, T.; Satoh, T.; Koka, M.; Kada, W.

    2015-04-01

    Herein, we review the last half decade of progress in ion-microbeam technology and applications at the Takasaki Ion Accelerators for Advanced Radiation Applications facility. Materials were microanalysed with the light-ion-microbeam system by combining micro-particle-induced X-ray and γ-ray emission, nuclear-reaction analysis and micro-ion-beam-induced luminescence to analyse elements, including light elements such as lithium, boron or fluoride, and also their chemical states. For microfabrication, we used particle-beam writing and techniques of maskless patterning to processes materials without etching. The goal was to develop optical, magnetic or other new types of microdevices with both light-ion and the heavy-ion microbeam systems. In addition, techniques were developed to monitor in real time every individual ion injection by using an efficient scintillator or a thin diamond particle detector in both heavy-ion and high-energy heavy-ion microbeam systems.

  11. Induction of CD4(+) and CD8(+) anti-tumor effector T cell responses by bacteria mediated tumor therapy.

    PubMed

    Stern, Christian; Kasnitz, Nadine; Kocijancic, Dino; Trittel, Stephanie; Riese, Peggy; Guzman, Carlos A; Leschner, Sara; Weiss, Siegfried

    2015-10-15

    Facultative anaerobic bacteria like E. coli can colonize solid tumors often resulting in tumor growth retardation or even clearance. Little mechanistic knowledge is available for this phenomenon which is however crucial for optimization and further implementation in the clinic. Here, we show that intravenous injections with E. coli TOP10 can induce clearance of CT26 tumors in BALB/c mice. Importantly, re-challenging mice which had cleared tumors showed that clearance was due to a specific immune reaction. Accordingly, lymphopenic mice never showed tumor clearance after infection. Depletion experiments revealed that during induction phase, CD8(+) T cells are the sole effectors responsible for tumor clearance while in the memory phase CD8(+) and CD4(+) T cells were involved. This was confirmed by adoptive transfer. CD4(+) and CD8(+) T cells could reject newly set tumors while CD8(+) T cells could even reject established tumors. Detailed analysis of adoptively transferred CD4(+) T cells during tumor challenge revealed expression of granzyme B, FasL, TNF-α and IFN-γ in such T cells that might be involved in the anti-tumor activity. Our findings should pave the way for further optimization steps of this promising therapy.

  12. Photodynamic therapy for the treatment of induced mammary tumor in rats.

    PubMed

    Ferreira, Isabelle; Ferreira, Juliana; Vollet-Filho, José Dirceu; Moriyama, Lilian T; Bagnato, Vanderlei S; Salvadori, Daisy Maria Favero; Rocha, Noeme S

    2013-02-01

    The objective of this work was to evaluate photodynamic therapy (PDT) by using a hematoporphyrin derivative as a photosensitizer and light-emitting diodes (LEDs) as light source in induced mammary tumors of Sprague-Dawley (SD) rats. Twenty SD rats with mammary tumors induced by DMBA were used. Animals were divided into four groups: control (G1), PDT only (G2), surgical removal of tumor (G3), and submitted to PDT immediately after surgical removal of tumor (G4). Tumors were measured over 6 weeks. Lesions and surgical were LEDs lighted up (200 J/cm(2) dose). The light distribution in vivo study used two additional animals without mammary tumors. In the control group, the average growth of tumor diameter was approximately 0.40 cm/week. While for PDT group, a growth of less than 0.15 cm/week was observed, suggesting significant delay in tumor growth. Therefore, only partial irradiation of the tumors occurred with a reduction in development, but without elimination. Animals in G4 had no tumor recurrence during the 12 weeks, after chemical induction, when compared with G3 animals that showed 60 % recurrence rate after 12 weeks of chemical induction. PDT used in the experimental model of mammary tumor as a single therapy was effective in reducing tumor development, so the surgery associated with PDT is a safe and efficient destruction of residual tumor, preventing recurrence of the tumor.

  13. In situ macromolecular crystallography using microbeams

    PubMed Central

    Axford, Danny; Owen, Robin L.; Aishima, Jun; Foadi, James; Morgan, Ann W.; Robinson, James I.; Nettleship, Joanne E.; Owens, Raymond J.; Moraes, Isabel; Fry, Elizabeth E.; Grimes, Jonathan M.; Harlos, Karl; Kotecha, Abhay; Ren, Jingshan; Sutton, Geoff; Walter, Thomas S.; Stuart, David I.; Evans, Gwyndaf

    2012-01-01

    Despite significant progress in high-throughput methods in macromolecular crystallography, the production of diffraction-quality crystals remains a major bottleneck. By recording diffraction in situ from crystals in their crystallization plates at room temperature, a number of problems associated with crystal handling and cryoprotection can be side-stepped. Using a dedicated goniometer installed on the microfocus macromolecular crystallography beamline I24 at Diamond Light Source, crystals have been studied in situ with an intense and flexible microfocus beam, allowing weakly diffracting samples to be assessed without a manual crystal-handling step but with good signal to noise, despite the background scatter from the plate. A number of case studies are reported: the structure solution of bovine enterovirus 2, crystallization screening of membrane proteins and complexes, and structure solution from crystallization hits produced via a high-throughput pipeline. These demonstrate the potential for in situ data collection and structure solution with microbeams. PMID:22525757

  14. Microbeam-integrated multiphoton imaging system

    PubMed Central

    Bigelow, Alan W.; Geard, Charles R.; Randers-Pehrson, Gerhard; Brenner, David J.

    2008-01-01

    Multiphoton microscopy has been added to the array of imaging techniques at the endstation for the Microbeam II cell irradiator at Columbia University’s Radiological Research Accelerator Facility (RARAF). This three-dimensional (3D), laser-scanning microscope functions through multiphoton excitation, providing an enhanced imaging routine during radiation experiments with tissuelike samples, such as small living animals and organisms. Studies at RARAF focus on radiation effects; hence, this multiphoton microscope was designed to observe postirradiation cellular dynamics. This multiphoton microscope was custom designed into an existing Nikon Eclipse E600-FN research fluorescence microscope on the irradiation platform. Design details and biology applications using this enhanced 3D-imaging technique at RARAF are reviewed. PMID:19123569

  15. In situ macromolecular crystallography using microbeams.

    PubMed

    Axford, Danny; Owen, Robin L; Aishima, Jun; Foadi, James; Morgan, Ann W; Robinson, James I; Nettleship, Joanne E; Owens, Raymond J; Moraes, Isabel; Fry, Elizabeth E; Grimes, Jonathan M; Harlos, Karl; Kotecha, Abhay; Ren, Jingshan; Sutton, Geoff; Walter, Thomas S; Stuart, David I; Evans, Gwyndaf

    2012-05-01

    Despite significant progress in high-throughput methods in macromolecular crystallography, the production of diffraction-quality crystals remains a major bottleneck. By recording diffraction in situ from crystals in their crystallization plates at room temperature, a number of problems associated with crystal handling and cryoprotection can be side-stepped. Using a dedicated goniometer installed on the microfocus macromolecular crystallography beamline I24 at Diamond Light Source, crystals have been studied in situ with an intense and flexible microfocus beam, allowing weakly diffracting samples to be assessed without a manual crystal-handling step but with good signal to noise, despite the background scatter from the plate. A number of case studies are reported: the structure solution of bovine enterovirus 2, crystallization screening of membrane proteins and complexes, and structure solution from crystallization hits produced via a high-throughput pipeline. These demonstrate the potential for in situ data collection and structure solution with microbeams.

  16. 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.

  17. Wide area scanning system and carbon microbeams at the external microbeam facility of the INFN LABEC laboratory in Florence

    NASA Astrophysics Data System (ADS)

    Giuntini, L.; Massi, M.; Calusi, S.; Castelli, L.; Carraresi, L.; Fedi, M. E.; Gelli, N.; Liccioli, L.; Mandò, P. A.; Mazzinghi, A.; Palla, L.; Romano, F. P.; Ruberto, C.; Taccetti, F.

    2015-04-01

    Recently, developments have been made to the external scanning microbeam of INFN-LABEC laboratory in Florence. A new system for mechanical sample scanning was implemented. This system allows us to acquire large maps (up to 20 × 20 cm2), of great interest in the Cultural Heritage field. In parallel, the possibility of using carbon microbeams for experiments, such as, for example, ion beam modification of materials and MeV Secondary Ion Mass Spectrometry, has been investigated. As a test application, Particle Induced X-ray Emission with carbon microbeams has been performed on a lapis lazuli stone. First results for both wide area imaging and external carbon microbeams are briefly reported.

  18. New generations of targeted therapies fighting the resistance in solid tumors.

    PubMed

    Barthélémy, Philippe; Aftimos, Philippe; Awada, Ahmad

    2015-05-01

    The identification of molecular alterations that drive tumor growth and spread of solid tumors has led to the development of multiple targeted therapies considered as first-generation agents that have improved clinical benefit. However, tumor cells are able to rapidly develop resistance to these agents. The growing understanding of the biology of the resistance mechanisms has spurred ongoing development of second-generation and third-generation targeted therapies aiming at new strategies to overcome resistance. Several generations of targeted therapies have been developed in order to prevent, delay or overcome tumor resistance. Some agents have already been approved, and others are currently under active clinical investigation in several cancer subtypes, including breast cancer, nonsmall cell lung cancer, head and neck squamous cell cancer and colorectal cancer. In the present review, we will discuss in solid tumors, the recent development of next generation anticancer-targeted therapies and new strategies including combination agents currently under active clinical investigation.

  19. Tumor-targeting bacterial therapy: A potential treatment for oral cancer (Review)

    PubMed Central

    LIU, SAI; XU, XIAOPING; ZENG, XIN; LI, LONGJIANG; CHEN, QIANMING; LI, JING

    2014-01-01

    Certain obligate or facultative anaerobic bacteria, which exhibit an inherent ability to colonize solid tumors in vivo, may be used in tumor targeting. As genetically manipulated bacteria may actively and specifically penetrate into the tumor tissue, bacterial therapy is becoming a promising approach in the treatment of tumors. However, to the best of our knowledge, no reports have been published thus far regarding the bacterial treatment of oral cancer, one of the most common types of cancer worldwide. In this review, the progress in the understanding of bacterial strategies used in tumor-targeted therapy is discussed and particular bacterial strains that may have great therapeutic potential in oral squamous cell carcinoma (OSCC) tumor-targeted therapy are predicted as determined by previous studies. PMID:25364397

  20. 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.

  1. 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.

  2. Optimization of the tumor microenvironment and nanomedicine properties simultaneously to improve tumor therapy

    PubMed Central

    Jiang, Ting; Wang, Lanting; Mei, Heng; Lu, Heng; Hu, Yu; Pang, Zhiqing

    2016-01-01

    Effective delivery of nanomedicines to tumor tissues depends on both the tumor microenvironment and nanomedicine properties. Accordingly, tumor microenvironment modification or advanced design of nanomedicine was emerging to improve nanomedicine delivery to tumors. However, few studies have emphasized the necessity to optimize the tumor microenvironment and nanomedicine properties simultaneously to improve tumor treatment. In the present study, imatinib mesylate (IMA) was used to normalize the tumor microenvironment including platelet-derived growth factor receptor-β expression inhibition, tumor vessel normalization, and tumor perfusion improvement as demonstrated by immunofluorescence staining. In addition, the effect of tumor microenvironment normalization on tumor delivery of nanomedicines with different sizes was carefully investigated. It was shown that IMA treatment significantly reduced the accumulation of nanoparticles (NPs) around 110 nm but enhanced the accumulation of micelles around 23 nm by in vivo fluorescence imaging experiment. Furthermore, IMA treatment limited the distribution of NPs inside tumors but increased that of micelles with a more homogeneous pattern. Finally, the anti-tumor efficacy study displayed that IMA pretreatment could significantly increase the therapeutic effects of paclitaxel-loaded micelles. All-together, a new strategy to improve nanomedicine delivery to tumor was provided by optimizing both nanomedicine size and the tumor microenvironment simultaneously, and it will have great potential in clinics for tumor treatment. PMID:27566585

  3. Optimization of the tumor microenvironment and nanomedicine properties simultaneously to improve tumor therapy.

    PubMed

    Zhang, Bo; Shi, Wei; Jiang, Ting; Wang, Lanting; Mei, Heng; Lu, Heng; Hu, Yu; Pang, Zhiqing

    2016-09-20

    Effective delivery of nanomedicines to tumor tissues depends on both the tumor microenvironment and nanomedicine properties. Accordingly, tumor microenvironment modification or advanced design of nanomedicine was emerging to improve nanomedicine delivery to tumors. However, few studies have emphasized the necessity to optimize the tumor microenvironment and nanomedicine properties simultaneously to improve tumor treatment. In the present study, imatinib mesylate (IMA) was used to normalize the tumor microenvironment including platelet-derived growth factor receptor-β expression inhibition, tumor vessel normalization, and tumor perfusion improvement as demonstrated by immunofluorescence staining. In addition, the effect of tumor microenvironment normalization on tumor delivery of nanomedicines with different sizes was carefully investigated. It was shown that IMA treatment significantly reduced the accumulation of nanoparticles (NPs) around 110 nm but enhanced the accumulation of micelles around 23 nm by in vivo fluorescence imaging experiment. Furthermore, IMA treatment limited the distribution of NPs inside tumors but increased that of micelles with a more homogeneous pattern. Finally, the anti-tumor efficacy study displayed that IMA pretreatment could significantly increase the therapeutic effects of paclitaxel-loaded micelles. All-together, a new strategy to improve nanomedicine delivery to tumor was provided by optimizing both nanomedicine size and the tumor microenvironment simultaneously, and it will have great potential in clinics for tumor treatment.

  4. Efficacy of CAR T-cell therapy in large tumors relies upon stromal targeting by IFNγ.

    PubMed

    Textor, Ana; Listopad, Joanna J; Wührmann, Lara Le; Perez, Cynthia; Kruschinski, Anna; Chmielewski, Markus; Abken, Hinrich; Blankenstein, Thomas; Charo, Jehad

    2014-12-01

    Adoptive T-cell therapy using chimeric antigen receptor-modified T cells (CAR-T therapy) has shown dramatic efficacy in patients with circulating lymphoma. However, eradication of solid tumors with CAR-T therapy has not been reported yet to be efficacious. In solid tumors, stroma destruction, due to MHC-restricted cross-presentation of tumor antigens to T cells, may be essential. However, CAR-Ts recognize antigens in an MHC-independent manner on cancer cells but not stroma cells. In this report, we show how CAR-Ts can be engineered to eradicate large established tumors with provision of a suitable CD28 costimulatory signal. In an HER2-dependent tumor model, tumor rejection by HER2-specific CAR-Ts was associated with sustained influx and proliferation of the adoptively transferred T cells. Interestingly, tumor rejection did not involve natural killer cells but was associated instead with a marked increase in the level of M1 macrophages and a requirement for IFNγ receptor expression on tumor stroma cells. Our results argue that CAR-T therapy is capable of eradicating solid tumors through a combination of antigen-independent stroma destruction and antigen-specific tumor cell targeting. ©2014 American Association for Cancer Research.

  5. 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

  6. Favorable alteration of tumor microenvironment by immunomodulatory cytokines for efficient T-cell therapy in solid tumors.

    PubMed

    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.

  7. Hypoxia in Astrocytic Tumors and Implications for Therapy

    PubMed Central

    Cavazos, David A.; Brenner, Andrew J.

    2015-01-01

    Glioblastoma (GBM, Grade IV astrocytoma) is the most common and most aggressive of the primary malignant brain tumors in adults. Hypoxia is a distinct feature in GBM and plays a significant role in tumor progression, resistance to treatment and poor outcomes. This review considers the effects of hypoxia on astrocytic tumors and the mechanisms that contribute to tumor progression and therapeutic resistance, with a focus on the vascular changes, chemotaxic signaling pathways and metabolic alterations involved. PMID:26094595

  8. Development of Biologically Based Therapies for Basal-Like Tumors

    DTIC Science & Technology

    2006-04-01

    across a breast tumor data set of 150 samples. Squalene epoxidase (SQLE) was expressed in most Basal-like tumors, as well as in the Basal-like tumor...1500 drug targets was examined across a breast tumor data set of 150 samples. HER1 and squalene epoxidase (SQLE) were identified as being highly...pathway, which is necessary for dividing cells. A specific squalene epoxidase inhibitor is available (NB-598), and we also have examined an HMG-CoA

  9. 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

  10. 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.

  11. 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

  12. T-Cell Receptor Gene Therapy of Established Tumors in a Murine Melanoma Model

    PubMed Central

    Abad, John D.; Wrzensinski, Claudia; Overwijk, Willem; De Witte, Moniek A.; Jorritsma, Annelies; Hsu, Gary; Gattinoni, Luca; Cohen, Cyrille J.; Paulos, Chrystal M.; Palmer, Douglas C.; Haanen, John B. A. G.; Schumacher, Ton N. M.; Rosenberg, Steven A.; Restifo, Nicholas P.; Morgan, Richard A.

    2008-01-01

    Summary Adoptive cell transfer therapy using tumor-infiltrating lymphocytes for patients with metastatic melanoma has demonstrated significant objective response rates. One major limitation of these current therapies is the frequent inability to isolate tumor-reactive lymphocytes for treatment. Genetic engineering of peripheral blood lymphocytes with retroviral vectors encoding tumor antigen-specific T-cell receptors (TCRs) bypasses this restriction. To evaluate the efficacy of TCR gene therapy, a murine treatment model was developed. A retroviral vector was constructed encoding the pmel-1 TCR genes targeting the B16 melanoma antigen, gp100. Transduction of C57BL/6 lymphocytes resulted in efficient pmel-1 TCR expression. Lymphocytes transduced with this retrovirus specifically recognized gp100-pulsed target cells as measured by interferon-γ secretion assays. Upon transfer into B16 tumor-bearing mice, the genetically engineered lymphocytes significantly slowed tumor development. The effectiveness of tumor treatment was directly correlated with the number of TCR-engineered T cells administered. These results demonstrated that TCR gene therapy targeting a native tumor antigen significantly delayed the growth of established tumors. When C57BL/6 lymphocytes were added to antigen-reactive pmel-1 T cells, a reduction in the ability of pmel-1 T cell to treat B16 melanomas was seen, suggesting that untransduced cells may be deleterious to TCR gene therapy. This model may be a powerful tool for evaluating future TCR gene transfer-based strategies. PMID:18157006

  13. T-cell receptor gene therapy of established tumors in a murine melanoma model.

    PubMed

    Abad, John D; Wrzensinski, Claudia; Overwijk, Willem; De Witte, Moniek A; Jorritsma, Annelies; Hsu, Cary; Gattinoni, Luca; Cohen, Cyrille J; Paulos, Chrystal M; Palmer, Douglas C; Haanen, John B A G; Schumacher, Ton N M; Rosenberg, Steven A; Restifo, Nicholas P; Morgan, Richard A

    2008-01-01

    Adoptive cell transfer therapy using tumor-infiltrating lymphocytes for patients with metastatic melanoma has demonstrated significant objective response rates. One major limitation of these current therapies is the frequent inability to isolate tumor-reactive lymphocytes for treatment. Genetic engineering of peripheral blood lymphocytes with retroviral vectors encoding tumor antigen-specific T-cell receptors (TCRs) bypasses this restriction. To evaluate the efficacy of TCR gene therapy, a murine treatment model was developed. A retroviral vector was constructed encoding the pmel-1 TCR genes targeting the B16 melanoma antigen, gp100. Transduction of C57BL/6 lymphocytes resulted in efficient pmel-1 TCR expression. Lymphocytes transduced with this retrovirus specifically recognized gp100-pulsed target cells as measured by interferon-gamma secretion assays. Upon transfer into B16 tumor-bearing mice, the genetically engineered lymphocytes significantly slowed tumor development. The effectiveness of tumor treatment was directly correlated with the number of TCR-engineered T cells administered. These results demonstrated that TCR gene therapy targeting a native tumor antigen significantly delayed the growth of established tumors. When C57BL/6 lymphocytes were added to antigen-reactive pmel-1 T cells, a reduction in the ability of pmel-1 T cell to treat B16 melanomas was seen, suggesting that untransduced cells may be deleterious to TCR gene therapy. This model may be a powerful tool for evaluating future TCR gene transfer-based strategies.

  14. Efficient carboplatin single therapy in a mouse model of human testicular nonseminomatous germ cell tumor.

    PubMed

    Aharinejad, Seyedhossein; Fink, Melanie; Abri, Hojatollah; Nedwed, Stephan; Schlag, Michael G; Macfelda, Karin; Abraham, Dietmar; Miksovsky, Aurelia; Höltl, Eva; Höltl, Wolfgang

    2002-01-01

    Cisplatin based combination therapy has shown excellent clinical results in patients with testicular nonseminomatous germ cell tumor but chemotherapy induced morbidity and reduced patient compliance are limiting factors in this regimen. To decrease cisplatin based combination therapy induced morbidity we examined carboplatin versus etoposide single therapy in an animal model. A total of 180 SCID mice bearing testicular nonseminomatous germ cell tumor xenografts received 120 mg./kg. carboplatin as a single cycle, 60 or 30 mg./kg. carboplatin cycled twice, 80, 50 or 30 mg./kg. etoposide cycled twice, or Ringer solution as the control. An additional 20 sham treated and 20 untreated mice also served as controls. Histological and immunocytochemical testing, in vivo microscopy, vascular corrosion casting, serum tumor markers, complete blood count and real-time polymerase chain reaction were used to monitor therapy efficacy. Carboplatin at 60 mg./kg. cycled twice eradicated the tumor and significantly reduced vascular density and vascular endothelial growth factor-A messenger RNA (p <0.05). Elevated tumor markers returned to baseline after carboplatin administration. Therapy was well tolerated, resulting thrombocytopenia disappeared 6 weeks after therapy and the animals were tumor-free 6 months after treatment. Although 120 mg./kg. carboplatin eradicated the tumor, it resulted in extensive mortality and morbidity. Single treatment 30, 50 and 80 mg./kg. etoposide failed. Carboplatin single therapy was highly effective in our nonseminomatous germ cell tumor model and it may be examined in future clinical trials in patients with high risk stage I nonseminomatous germ cell cancer for reducing cisplatin based combination therapy induced morbidity. Vascular density and vascular endothelial growth factor messenger RNA were elevated in our animal model and deserve further study in nonseminomatous germ cell tumor cases as potential risk factors.

  15. Adoptive T cell therapy promotes the emergence of genomically altered tumor escape variants

    PubMed Central

    Kaluza, Karen M.; Thompson, Jill M.; Kottke, Timothy J.; Flynn Gilmer, Heather C.; Knutson, Darlene L.; Vile, Richard G.

    2014-01-01

    Adoptive T cell therapy has proven effective against melanoma in mice and humans. However, because most responses are incomplete or transient, cures remain rare. To maximize the efficacy of this therapy, it will be essential to gain a better understanding of the processes which result in tumor relapse. We studied these processes using B16ova murine melanoma and adoptive transfer of OT-I T cells. Transfer of T cells as a single therapy provided a significant survival benefit for mice with established subcutaneous tumors. However, tumors which initially regressed often recurred. By analyzing tumors which emerged in the presence of a potent OT-I response, we identified a novel tumor escape mechanism in which tumor cells evaded T cell pressure by undergoing major genomic changes involving loss of the gene encoding the target tumor antigen. Furthermore, we show that these in vivo processes can be recapitulated in vitro using T cell/tumor cell co-cultures. A single round of in vitro co-culture led to significant loss of the ova gene and a tumor cell population with rapidly induced and diverse karyotypic changes. Although these current studies focus on the model OVA antigen, the finding that T cells can directly promote genomic instability has important implications for the development of adoptive T cell therapies. PMID:21935923

  16. Photodynamic therapy stimulates anti-tumor immunity in a murine mastocytoma model

    NASA Astrophysics Data System (ADS)

    Mroz, Pawel; Hamblin, Michael R.

    2008-02-01

    Photodynamic therapy (PDT) involves the IV administration of photosensitizers followed by illumination of the tumor with red light producing reactive oxygen species that eventually cause vascular shutdown and tumor cell apoptosis. Anti-tumor immunity is stimulated after PDT due to the acute inflammatory response, recognition of tumor-specific antigens, and induction of heat-shock proteins, while the three commonest cancer therapies (surgery, chemotherapy and radiotherapy) all tend to suppress the immune system. Like many other immunotherapies, the extent of the immune response after PDT tends to depend on the antigenicity of the particular tumor, or in other words, whether the tumor contains proteins with the correct characteristics to provide peptides that can bind to MHC class I molecules and provide a target for cytolytic T lymphocytes. We have described certain mouse tumors containing defined or naturally occurring tumor associated antigens that respond particularly well to PDT, and potent immune responses capable of destroying distant untreated tumors can be induced. In this report we address the induction of immunity after PDT of the DBA2 mastocytoma known as P815. This tumor was the first mouse tumor to be shown to possess a tumor-rejection antigen capable of being recognized by cytotoxic T-cells.

  17. DNA Alkylating Therapy Induces Tumor Regression through an HMGB1-Mediated Activation of Innate Immunity

    PubMed Central

    Guerriero, Jennifer L.; Ditsworth, Dara; Catanzaro, Joseph M.; Sabino, Gregory; Furie, Martha B.; Kew, Richard R.; Crawford, Howard C.; Zong, Wei-Xing

    2011-01-01

    Dysregulation of apoptosis is associated with the development of human cancer and resistance to anticancer therapy. We have previously shown in tumor xenografts that DNA alkylating agents induce sporadic cell necrosis and regression of apoptosis-deficient tumors. Sporadic tumor cell necrosis is associated with extracellular release of cellular content such as the high mobility group box 1 (HMGB1) protein and subsequent recruitment of innate immune cells into the tumor tissue. It remained unclear whether HMGB1 and the activation of innate immunity played a role in tumor response to chemotherapy. In this study, we show that whereas DNA alkylating therapy leads to a complete tumor regression in an athymic mouse tumor xenograft model, it fails to do so in tumors deficient in HMGB1. The HMGB1-deficient tumors have an impaired ability to recruit innate immune cells including macrophages, neutrophils, and NK cells into the treated tumor tissue. Cytokine array analysis reveals that whereas DNA alkylating treatment leads to suppression of protumor cytokines such as IL-4, IL-10, and IL-13, loss of HMGB1 leads to elevated levels of these cytokines upon treatment. Suppression of innate immunity and HMGB1 using depleting Abs leads to a failure in tumor regression. Taken together, these results indicate that HMGB1 plays an essential role in activation of innate immunity and tumor clearance in response to DNA alkylating agents. PMID:21300822

  18. Solid tumor therapy by selectively targeting stromal endothelial cells

    PubMed Central

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

    2016-01-01

    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

  19. 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.

  20. Integrated patient and tumor genetic testing for individualized cancer therapy.

    PubMed

    Hertz, D L; McLeod, H L

    2016-02-01

    Tumor genome analysis is transforming cancer treatment by enabling identification of specific oncogenic drivers and selection of effective targeted agents. Meanwhile, patient genome analysis is being employed across therapeutic areas to inform selection of appropriate drugs and doses for treatment safety. Integration of patient genome analysis concurrent with preemptive tumor genetic testing will enable oncologists to make informed treatment decisions to select the right dose of the right drug for each patient and their tumor.

  1. Therapy of Experimental Nerve Sheath Tumors Using Oncolytic Viruses

    DTIC Science & Technology

    2005-06-01

    SUPPLEMENTARY NOTES 14. ABSTRACT Abstract follows. 15. SUBJECT TERMS Oncolytic HSV, angiogenesis, MPNST , mouse model 16. SECURITY CLASSIFICATION OF: 17...reliable tumor models for malignant peripheral nerve sheath tumors ( MPNST ). Several existing and novel oncolytic HSV vectors will then be tested on these...from G47A increases cytotoxicity in vitro to human endothelial cells and murine Nfl" MPNST cell lines. Inhibition of MPNST M2 tumor growth in vivo was

  2. Yoga Therapy in Treating Patients With Malignant Brain Tumors

    ClinicalTrials.gov

    2017-01-17

    Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Meningioma; Adult Anaplastic Oligodendroglioma; Adult Brain Stem Glioma; Adult Choroid Plexus Tumor; Adult Diffuse Astrocytoma; Adult Ependymoblastoma; Adult Ependymoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Grade II Meningioma; Adult Medulloblastoma; Adult Meningeal Hemangiopericytoma; Adult Mixed Glioma; Adult Oligodendroglioma; Adult Papillary Meningioma; Adult Pineal Gland Astrocytoma; Adult Pineoblastoma; Adult Pineocytoma; Adult Supratentorial Primitive Neuroectodermal Tumor (PNET); Recurrent Adult Brain Tumor

  3. Modeling Tumor-Associated Edema in Gliomas during Anti-Angiogenic Therapy and Its Impact on Imageable Tumor

    PubMed Central

    Hawkins-Daarud, Andrea; Rockne, Russell C.; Anderson, Alexander R. A.; Swanson, Kristin R.

    2013-01-01

    Glioblastoma, the most aggressive form of primary brain tumor, is predominantly assessed with gadolinium-enhanced T1-weighted (T1Gd) and T2-weighted magnetic resonance imaging (MRI). Pixel intensity enhancement on the T1Gd image is understood to correspond to the gadolinium contrast agent leaking from the tumor-induced neovasculature, while hyperintensity on the T2/FLAIR images corresponds with edema and infiltrated tumor cells. None of these modalities directly show tumor cells; rather, they capture abnormalities in the microenvironment caused by the presence of tumor cells. Thus, assessing disease response after treatments impacting the microenvironment remains challenging through the obscuring lens of MR imaging. Anti-angiogenic therapies have been used in the treatment of gliomas with spurious results ranging from no apparent response to significant imaging improvement with the potential for extremely diffuse patterns of tumor recurrence on imaging and autopsy. Anti-angiogenic treatment normalizes the vasculature, effectively decreasing vessel permeability and thus reducing tumor-induced edema, drastically altering T2-weighted MRI. We extend a previously developed mathematical model of glioma growth to explicitly incorporate edema formation allowing us to directly characterize and potentially predict the effects of anti-angiogenics on imageable tumor growth. A comparison of simulated glioma growth and imaging enhancement with and without bevacizumab supports the current understanding that anti-angiogenic treatment can serve as a surrogate for steroids and the clinically driven hypothesis that anti-angiogenic treatment may not have any significant effect on the growth dynamics of the overall tumor cell populations. However, the simulations do illustrate a potentially large impact on the level of edematous extracellular fluid, and thus on what would be imageable on T2/FLAIR MR. Additionally, by evaluating virtual tumors with varying growth kinetics, we see tumors

  4. Modeling Tumor-Associated Edema in Gliomas during Anti-Angiogenic Therapy and Its Impact on Imageable Tumor.

    PubMed

    Hawkins-Daarud, Andrea; Rockne, Russell C; Anderson, Alexander R A; Swanson, Kristin R

    2013-01-01

    Glioblastoma, the most aggressive form of primary brain tumor, is predominantly assessed with gadolinium-enhanced T1-weighted (T1Gd) and T2-weighted magnetic resonance imaging (MRI). Pixel intensity enhancement on the T1Gd image is understood to correspond to the gadolinium contrast agent leaking from the tumor-induced neovasculature, while hyperintensity on the T2/FLAIR images corresponds with edema and infiltrated tumor cells. None of these modalities directly show tumor cells; rather, they capture abnormalities in the microenvironment caused by the presence of tumor cells. Thus, assessing disease response after treatments impacting the microenvironment remains challenging through the obscuring lens of MR imaging. Anti-angiogenic therapies have been used in the treatment of gliomas with spurious results ranging from no apparent response to significant imaging improvement with the potential for extremely diffuse patterns of tumor recurrence on imaging and autopsy. Anti-angiogenic treatment normalizes the vasculature, effectively decreasing vessel permeability and thus reducing tumor-induced edema, drastically altering T2-weighted MRI. We extend a previously developed mathematical model of glioma growth to explicitly incorporate edema formation allowing us to directly characterize and potentially predict the effects of anti-angiogenics on imageable tumor growth. A comparison of simulated glioma growth and imaging enhancement with and without bevacizumab supports the current understanding that anti-angiogenic treatment can serve as a surrogate for steroids and the clinically driven hypothesis that anti-angiogenic treatment may not have any significant effect on the growth dynamics of the overall tumor cell populations. However, the simulations do illustrate a potentially large impact on the level of edematous extracellular fluid, and thus on what would be imageable on T2/FLAIR MR. Additionally, by evaluating virtual tumors with varying growth kinetics, we see tumors

  5. Tumor Stiffening, a Key Determinant of Tumor Progression, is Reversed by Nanomaterial-Induced Photothermal Therapy

    PubMed Central

    Marangon, Iris; Silva, Amanda A. K.; Guilbert, Thomas; Kolosnjaj-Tabi, Jelena; Marchiol, Carmen; Natkhunarajah, Sharuja; Chamming's, Foucault; Ménard-Moyon, Cécilia; Bianco, Alberto; Gennisson, Jean-Luc; Renault, Gilles; Gazeau, Florence

    2017-01-01

    Tumor stiffening, stemming from aberrant production and organization of extracellular matrix (ECM), has been considered a predictive marker of tumor malignancy, non-invasively assessed by ultrasound shear wave elastography (SWE). Being more than a passive marker, tumor stiffening restricts the delivery of diagnostic and therapeutic agents to the tumor and per se could modulate cellular mechano-signaling, tissue inflammation and tumor progression. Current strategies to modify the tumor extracellular matrix are based on ECM-targeting chemical agents but also showed deleterious systemic effects. On-demand excitable nanomaterials have shown their ability to perturb the tumor microenvironment in a spatiotemporal-controlled manner and synergistically with chemotherapy. Here, we investigated the evolution of tumor stiffness as well as tumor integrity and progression, under the effect of mild hyperthermia and thermal ablation generated by light-exposed multi-walled carbon nanotubes (MWCNTs) in an epidermoid carcinoma mouse xenograft. SWE was used for real-time mapping of the tumor stiffness, both during the two near infrared irradiation sessions and over the days after the treatment. We observed a transient and reversible stiffening of the tumor tissue during laser irradiation, which was lowered at the second session of mild hyperthermia or photoablation. In contrast, over the days following photothermal treatment, the treated tumors exhibited a significant softening together with volume reduction, whereas non-treated growing tumors showed an increase of tumor rigidity. The organization of the collagen matrix and the distribution of CNTs revealed a spatio-temporal correlation between the presence of nanoheaters and the damages on collagen and cells. This study highlights nanohyperthermia as a promising adjuvant strategy to reverse tumor stiffening and normalize the mechanical tumor environment. PMID:28042338

  6. Induction of anti-tumor immunity by photodynamic therapy (PDT)

    NASA Astrophysics Data System (ADS)

    Gollnick, Sandra O.; Owczarczak, Barbara; Maier, Patricia

    2006-02-01

    Tumor directed PDT has been shown by a number of pre-clinical studies to enhance a specific anti-tumor immune response, which appears to be critical to long-term tumor growth control by PDT. The PDT enhanced immune response is T cell dependent, however the mechanism behind the potentiation of the immune response by PDT is unknown. Induction of T cell dependent immunity depends upon the presence of activated antigen presenting cells. Therefore we have examined the ability of PDT to stimulate maturation and activation of antigen presenting cells in the PDT-treated tumor bed and tumor draining lymph node. Our studies demonstrate and increase in the number of activated antigen presenting cells in the tumor bed 24h following treatment of EMT6 murine tumors with Photofrin-PDT. Tumor draining lymph nodes also showed increased levels of activated antigen presenting cells within 4h of treatment. The levels peaked at 24h and declined by 48h after PDT. These results demonstrate that PDT-enhanced anti-tumor immunity is accompanied by an increase in antigen presenting cell activity. Therefore it is possible that T cell dependent immunity is enhanced following PDT through enhanced antigen presenting cell activity.

  7. Combined Therapy Conquers Resistant Tumors: Bortezomib and TRAIL | Center for Cancer Research

    Cancer.gov

    The principal strategy in the battle against cancer is simple: kill as many tumor cells as possible while sparing healthy cells. Unfortunately, traditional treatments, such as chemotherapy and radiation, have substantial side effects, and many cancers develop resistance to therapy.

  8. Laser interstitial thermal therapy in treatment of brain tumors--the NeuroBlate System.

    PubMed

    Mohammadi, Alireza M; Schroeder, Jason L

    2014-03-01

    Treatment of brain tumors remains challenging. Cytoreductive surgery is used as the first line treatment for most brain tumors. However complete, curative, resection is not achievable in many tumors leading to the need for adjuvant chemotherapy and radiation therapy. Laser interstitial thermal therapy (LITT) is a minimally invasive cytoreductive treatment. A low voltage laser is used to induce hyperthermia and to kill tumor cells. The extent of thermal damage is controlled through use of real-time MR-thermography guidance. Initial results have shown the feasibility of LITT for a variety of brain pathologies. LITT can be considered as an alternative type of surgery for difficult to access brain tumors and also for tumors in patients who are deemed high risk for more traditional surgery. Randomized trials are currently planned to continue assessing the efficacy of LITT and long-term follow-up data are awaited.

  9. Mathematical modeling of tumor therapy with oncolytic viruses: effects of parametric heterogeneity on cell dynamics

    PubMed Central

    Karev, Georgy P; Novozhilov, Artem S; Koonin, Eugene V

    2006-01-01

    Background: One of the mechanisms that ensure cancer robustness is tumor heterogeneity, and its effects on tumor cells dynamics have to be taken into account when studying cancer progression. There is no unifying theoretical framework in mathematical modeling of carcinogenesis that would account for parametric heterogeneity. Results: Here we formulate a modeling approach that naturally takes stock of inherent cancer cell heterogeneity and illustrate it with a model of interaction between a tumor and an oncolytic virus. We show that several phenomena that are absent in homogeneous models, such as cancer recurrence, tumor dormancy, and others, appear in heterogeneous setting. We also demonstrate that, within the applied modeling framework, to overcome the adverse effect of tumor cell heterogeneity on the outcome of cancer treatment, a heterogeneous population of an oncolytic virus must be used. Heterogeneity in parameters of the model, such as tumor cell susceptibility to virus infection and the ability of an oncolytic virus to infect tumor cells, can lead to complex, irregular evolution of the tumor. Thus, quasi-chaotic behavior of the tumor-virus system can be caused not only by random perturbations but also by the heterogeneity of the tumor and the virus. Conclusion: The modeling approach described here reveals the importance of tumor cell and virus heterogeneity for the outcome of cancer therapy. It should be straightforward to apply these techniques to mathematical modeling of other types of anticancer therapy. Reviewers: Leonid Hanin (nominated by Arcady Mushegian), Natalia Komarova (nominated by Orly Alter), and David Krakauer. PMID:17018145

  10. NaK alloy-induced in vivo tumor ablation therapy.

    PubMed

    Wang, Wei; Liu, Ying; Liu, Huan; An, Yonghui; Wang, Qian; Liu, Jing

    2017-06-12

    Alkali metal ablation is newly emerging as an effective, economic and minimally invasive ablation therapy. This study is dedicated to demonstrate the high efficiency of NaK alloy ablation on in vivo tumors with different stages in mice. Panc02 tumor cells were injected into 21 female C57B/L mice, which were divided into three groups. Two experimental groups of mice received the same percutaneous NaK alloy injection for a week apart. The inner temperature response and surface temperature distribution were measured using a thermal couple and an infrared camera. After each ablation experiment, two mice in each group were chosen randomly to make pathological sections. The tumor volumes were measured once every two days. At the end, all tumors were cut off to calculate the tumor inhibition rates. The NaK alloy-induced ablation therapy produced an obvious temperature increase (85 °C) in the ablation region and the high temperature distribution was relatively concentrated. The histopathology sections showed that developing stage tumors received incomplete destruction of the malignant cells compared with early stage tumors. The tumor inhibition rate in the early and developing tumor treatment groups were 88.5% and 67.6%, respectively. This technology provides a nearly thorough ablation treatment for early stage tumors and also a palliative treatment for developing tumors.

  11. Increasing oxygenation and radiation sensitivity following photodynamic therapy with verteporfin in the RIF-1 tumor

    NASA Astrophysics Data System (ADS)

    Pogue, Brian W.; O'Hara, Julia A.; Demidenko, Eugene; Wilmot, Carmen M.; Chen, Bin; Swartz, Harold M.; Hasan, Tayyaba

    2003-06-01

    The combination of verteporfin-based photodynamic therapy (PDT) wiht radiaiton therapy from an orthovoltage device has been examiend in the radiation induced fibrosarcoma tumor model. PDT with verteporfin using a 3 hour delay between injection and the time of optical irradiation has been shown to cause a significant rise in overlal tumor oxygenation. It was huypothesized that this mechanism arises from the reduced oxygen consumption from cells where the PDT has targeted the mitochondria and shut down cellular respiration. Tumor blood flow was measured and found to be still be patent immediately following therapy. This increasing oxygenation was thought to provide an opportunity to increase the radiation sensitivity of the tumor immediately following PDT. When this type of treatment was combined with radiation therapy, a delay in the tumor regrowth time demonstrated that the combined effect was greater than additive. Further study of this phenomenon will provide a more complete mechanistic understanding of the effect and possibly provide a viable pre-treatment for radiation therapy of tumore that increases the therapeutic ratio. This effect could be used to either increase the radiaton dose without increasing the side effects or decrease the dose needed for the same effect on the tumor.

  12. Comparing immune-tumor growth models with drug therapy using optimal control

    NASA Astrophysics Data System (ADS)

    Martins, Marisa C.; Rocha, Ana Maria A. C.; Costa, M. Fernanda P.; Fernandes, Edite M. G. P.

    2016-06-01

    In this paper we compare the dynamics of three tumor growth models that include an immune system and a drug administration therapy using optimal control. The objective is to minimize a combined function of the total of tumor cells over time and a chemotherapeutic drug administration.

  13. Monitoring liver tumor therapy with ( sup 18 F)FDG positron emission tomography

    SciTech Connect

    Nagata, Y.; Yamamoto, K.; Hiraoka, M.; Abe, M.; Takahashi, M.; Akuta, K.; Nishimura, Y.; Jo, S.; Masunaga, S.; Kubo, S. )

    1990-05-01

    Positron emission tomography (PET) with (18F)-2-flurodeoxy-glucose (FDG) can be utilized as a functional imaging modality for monitoring liver tumor therapy. We report three cases in which PET-FDG was more useful for this purpose than other imaging methods and tumor markers.

  14. Drug-Resistant Brain Metastases: A Role for Pharmacology, Tumor Evolution, and Too-Late Therapy.

    PubMed

    Stricker, Thomas; Arteaga, Carlos L

    2015-11-01

    Two recent studies report deep molecular profiling of matched brain metastases and primary tumors. In both studies, somatic alterations in the brain metastases were frequently discordant with those in the primary tumor, suggesting divergent evolution at metastatic sites and raising questions about the use of biomarkers in patients in clinical trials with targeted therapies. ©2015 American Association for Cancer Research.

  15. Endoscopic ultrasound-guided ethanol ablation therapy for tumors

    PubMed Central

    Zhang, Wen-Ying; Li, Zhao-Shen; Jin, Zhen-Dong

    2013-01-01

    Endoscopic ultrasonography (EUS) has evolved into a useful therapeutic tool for treating a broad range of tumors since being introduced into clinical practice as a diagnostic modality nearly three decades ago. In particular, EUS-guided fine-needle injection has proven a successful minimally invasive approach for treating benign lesions such as pancreatic cysts, relieving pancreatic pain through celiac plexus neurolysis, and controlling local tumor growth of unresectable malignancies by direct delivery of anti-tumor agents. One such ablative agent, ethanol, is capable of safely ablating solid or cystic lesions in hepatic tissues via percutaneous injection. Recent research and clinical interest has focused on the promise of EUS-guided ethanol ablation as a safe and effective method for treating pancreatic tumor patients with small lesions or who are poor operative candidates. Although it is not likely to replace radical resection of localized lesions or systemic treatment of metastatic tumors in all patients, EUS-guided ablation is an ideal method for patients who refuse or are not eligible for surgery. Moreover, this treatment modality may play an active role in the development of future pancreatic tumor treatments. This article reviews the most recent clinical applications of EUS-guided ethanol ablation in humans for treating pancreatic cystic tumors, pancreatic neuroendocrine tumors, and metastatic lesions. PMID:23801831

  16. Tumor response parameters for head and neck cancer derived from tumor-volume variation during radiation therapy

    SciTech Connect

    Chvetsov, Alexei V.

    2013-03-15

    Purpose: The main goal of this paper is to reconstruct a distribution of cell survival fractions from tumor-volume variation for a heterogeneous group of head and neck cancer patients and compare this distribution to the data from predictive assays. Methods: To characterize the tumor-volume variation during radiation therapy treatment, the authors use a two-level tumor-volume model of cell population that separates the entire tumor cell population into two subpopulations of viable cells and lethally damaged cells. This parameterized radiobiological model is integrated with a least squares objective function and a simulated annealing optimization algorithm to describe time-dependent tumor-volume variation rates in individual patients. Several constraints have been used in the optimization problem because tumor-volume variation during radiotherapy is described by a sum of exponentials; therefore, the problem of accurately fitting a model to measured data is ill-posed. The model was applied to measured tumor-volume variation curves from a clinical study on tumor-volume variation during radiotherapy for 14 head and neck cancer patients in which an integrated CT/linear particle accelerator (LINAC) system was used for tumor-volume measurements. Results: The two-level cell population tumor-volume modeling is capable of describing tumor-volume variation throughout the entire treatment for 11 of the 14 patients. For three patients, the tumor-volume variation was described only during the initial part of treatment, a fact that may be related to the neglected hypoxia in the two-level approximation. The predicted probability density distribution for the survival fractions agrees with the data obtained using in vitro studies with predictive assays. The mean value 0.35 of survival fraction obtained in this study is larger than the value 0.32 from in vitro studies, which could be expected because of greater repair in vivo. The mean half-life obtained in this study for the head

  17. Prevention of Distant Lung Metastasis After Photodynamic Therapy Application in a Breast Cancer Tumor Model.

    PubMed

    Longo, João Paulo Figueiró; Muehlmann, Luis Alexandre; Miranda-Vilela, Ana Luisa; Portilho, Flávia Arruda; de Souza, Ludmilla Regina; Silva, Jaqueline Rodrigues; Lacava, Zulmira Guerrero Marques; Bocca, Anamelia Lorenzetti; Chaves, Sacha Braun; Azevedo, Ricardo Bentes

    2016-04-01

    The objective of this study was to investigate the activity of photodynamic therapy mediated by aluminum-chlorophthalocyanine contained in a polymeric nanostructured carrier composed by methyl vinyl ether-co-maleic anhydride (PVM/MA) against local subcutaneous breast cancer tumors and its effects against distant metastasis in a mouse tumor model. In our results, we observed a decrease in breast cancer tumor growth, prevention of distant lung metastases, and a significant increased survival in mice treated with photodynamic therapy. In addition to these results, we observed that tumor-bearing mice without treatment developed a significant extension of liver hematopoiesis that was significantly reduced in mice treated with photodynamic therapy. We hypothesized and showed that this reduction in (1) metastasis and (2) liver hematopoiesis may be related to the systemic activity of immature hematopoietic cells, specifically the myeloid-derived suppressor cells, which were suppressed in mice treated with photodynamic therapy. These cells produce a tolerogenic tumor environment that protects tumor tissues from immunological surveillance. Therefore, we suggest that photodynamic therapy could be employed in combination with other conventional therapies; such as surgery and radiotherapy, to improve the overall survival of patients diagnosed with breast cancer, as observed in our experimental resuIts.

  18. ABCB5 identifies a therapy-refractory tumor cell population in colorectal cancer patients

    PubMed Central

    Wilson, Brian J.; Schatton, Tobias; Zhan, Qian; Gasser, Martin; Ma, Jie; Saab, Karim R.; Schanche, Robin; Waaga-Gasser, Ana-Maria; Gold, Jason S.; Huang, Qin; Murphy, George F.; Frank, Markus H.; Frank, Natasha Y.

    2012-01-01

    Identification and reversal of treatment resistance mechanisms of clinically refractory tumor cells is critical for successful cancer therapy. Here we show that ATP-binding cassette member B5 (ABCB5) identifies therapy-refractory tumor cells in colorectal cancer patients following fluorouracil (5-FU)-based chemoradiation therapy and provide evidence for a functional role of ABCB5 in colorectal cancer 5-FU resistance. Examination of human colon and colorectal cancer specimens revealed ABCB5 to be expressed only on rare cells within healthy intestinal tissue, whereas clinical colorectal cancers exhibited substantially increased levels of ABCB5 expression. Analysis of successive, patient-matched biopsy specimens obtained prior to and following neoadjuvant 5-FU-based chemoradiation therapy in a series of colorectal cancer patients revealed markedly enhanced abundance of ABCB5-positive tumor cells when residual disease was detected. Consistent with this finding, the ABCB5-expressing tumor cell population was also treatment-refractory and exhibited resistance to 5-FU-induced apoptosis in a colorectal cancer xenograft model of 5-FU monotherapy. Mechanistically, shRNA-mediated ABCB5 knockdown significantly inhibited tumorigenic xenograft growth and sensitized colorectal cancer cells to 5-FU-induced cell killing. Our results identify ABCB5 as a novel molecular marker of therapy-refractory tumor cells in colorectal cancer patients and point to a need for consistent eradication of ABCB5-positive resistant tumor cell populations for more effective colorectal cancer therapy. PMID:21652540

  19. Pharmacokinetics, tissue distribution and photodynamic therapy efficacy of liposomal-delivered hypocrellin A, a potential photosensitizer for tumor therapy.

    PubMed

    Wang, Z J; He, Y Y; Huang, C G; Huang, J S; Huang, Y C; An, J Y; Gu, Y; Jiang, L J

    1999-11-01

    Hypocrellin A, from Hypocrella bambusae, is a novel photosensitizer of high singlet oxygen quantum yield for photodynamic therapy (PDT). Tissue distributions were studied in tumor-bearing mice as a function of time following administration. The tumor model was S-180 sarcoma transplanted into one hind leg of male Kunming mice; hypocrellin A (HA) was delivered to the mice by intravenous injection of 5 mg/kg of body weight as a suspension either as a unilamellar liposome or in dimethyl sulfoxide (DMSO)-solubilized saline. The HA was isolated from several tissues and organs, as well as tumors and peritumoral muscles and skin. Quantitation was performed by a high-performance liquid chromatographic technique with detection that utilizes the native fluorescence of HA. Independent of the delivery system, the dye was retained in tumors at higher concentrations than in normal tissues, except for kidney, liver, lung and spleen. The dye retention in tumors was high and was vehicle dependent. For the liposomal system, the maximal accumulation in tumor and maximal ratios of dye in tumor versus peritumoral muscle and skin occurred 12 h postinjection; for the DMSO saline system, the maximal ratio occurred earlier, 6 h postadministration. Liposomal delivery improved the selective accumulation of the dye in tumor with higher maximal levels in tumor and higher ratios of tumor-to-muscle and tumor-to-skin. Levels of dye were very low or not detectable in the brain. The PDT efficacy of HA in the liposome and DMSO saline systems was determined by evaluating the tumor volume regression percent. The PDT efficacy of HA in liposomes was highest when light treatment was performed at 12 h postinjection, consistent with the highest retention of HA in tumors. Similarly, the maximal PDT efficacy in DMSO saline was attained at 6 h postinjection, the highest HA retention point in tumor. Moreover, the peak PDT efficacy of HA in liposomes was much higher than that of HA in DMSO saline and even

  20. Enhancing Nanoparticle Accumulation and Retention in Desmoplastic Tumors via Vascular Disruption for Internal Radiation Therapy.

    PubMed

    Satterlee, Andrew B; Rojas, Juan D; Dayton, Paul A; Huang, Leaf

    2017-01-01

    Aggressive, desmoplastic tumors are notoriously difficult to treat because of their extensive stroma, high interstitial pressure, and resistant tumor microenvironment. We have developed a combination therapy that can significantly slow the growth of large, stroma-rich tumors by causing massive apoptosis in the tumor center while simultaneously increasing nanoparticle uptake through a treatment-induced increase in the accumulation and retention of nanoparticles in the tumor. The vascular disrupting agent Combretastatin A-4 Phosphate (CA4P) is able to increase the accumulation of radiation-containing nanoparticles for internal radiation therapy, and the retention of these delivered radioisotopes is maintained over several days. We use ultrasound to measure the effect of CA4P in live tumor-bearing mice, and we encapsulate the radio-theranostic isotope (177)Lutetium as a therapeutic agent as well as a means to measure nanoparticle accumulation and retention in the tumor. This combination therapy induces prolonged apoptosis in the tumor, decreasing both the fibroblast and total cell density and allowing further tumor growth inhibition using a cisplatin-containing nanoparticle.

  1. The pharmacological point of view of resistance to therapy in tumors.

    PubMed

    Damia, Giovanna; Garattini, Silvio

    2014-09-01

    Resistance to therapy is a challenging clinical problem, whose solution is far from being reached. Gains in current knowledge have identified key elements at the basis of drug resistance and have suggested possible ways to overcome it. However, some points have always to be kept in mind whatever the type of tumor or drug (cytotoxic or targeted agent) when considering treatment resistance in tumors. In this review we discuss these points and their impact in resistance to cancer therapy: the importance of reaching active tumor drug concentration, reviewing the various micro- and macro-components of the host that can influence their concentrations and activity, the evolving complex heterogeneity of tumors, the intrinsic tumor cell susceptibility to the drug, and the emerging role of the tumor microenvironment. Both the data from the molecular and biological characterization of human tumors allow a better rational and timing use of the available arsenal of anticancer therapy and new strategies to improve the penetration of antitumor drugs in tumors are the new chances to delay and possibly eliminate the emergence of resistance in tumors.

  2. Enhancing Nanoparticle Accumulation and Retention in Desmoplastic Tumors via Vascular Disruption for Internal Radiation Therapy

    PubMed Central

    Satterlee, Andrew B.; Rojas, Juan D.; Dayton, Paul A.; Huang, Leaf

    2017-01-01

    Aggressive, desmoplastic tumors are notoriously difficult to treat because of their extensive stroma, high interstitial pressure, and resistant tumor microenvironment. We have developed a combination therapy that can significantly slow the growth of large, stroma-rich tumors by causing massive apoptosis in the tumor center while simultaneously increasing nanoparticle uptake through a treatment-induced increase in the accumulation and retention of nanoparticles in the tumor. The vascular disrupting agent Combretastatin A-4 Phosphate (CA4P) is able to increase the accumulation of radiation-containing nanoparticles for internal radiation therapy, and the retention of these delivered radioisotopes is maintained over several days. We use ultrasound to measure the effect of CA4P in live tumor-bearing mice, and we encapsulate the radio-theranostic isotope 177Lutetium as a therapeutic agent as well as a means to measure nanoparticle accumulation and retention in the tumor. This combination therapy induces prolonged apoptosis in the tumor, decreasing both the fibroblast and total cell density and allowing further tumor growth inhibition using a cisplatin-containing nanoparticle. PMID:28042332

  3. Tumor-Unrelated CD4 T Cell Help Augments CD134 plus CD137 Dual Costimulation Tumor Therapy

    PubMed Central

    Mittal, Payal; St Rose, Marie-Clare; Wang, Xi; Ryan, Joseph M.; Wasser, Jeffrey S.; Vella, Anthony T.; Adler, Adam J.

    2015-01-01

    The ability of immune-based cancer therapies to elicit beneficial CD8+ CTL is limited by tolerance pathways that inactivate tumor-specific CD4 helper T cells. A strategy to bypass this problem is to engage tumor-unrelated CD4 helper T cells. Thus, CD4 T cells, regardless of their specificity per se, can boost CD8+ CTL priming so long as the cognate epitopes are linked via presentation on the same dendritic cell. Here, we assessed the therapeutic impact of engaging tumor-unrelated CD4 T cells during dual costimulation with CD134 plus CD137 that not only provide help via the above-mentioned classical linked pathway, but also provide non-linked help that facilitates CTL function in T cells not directly responding to cognate antigen. We found that engagement of tumor-unrelated CD4 helper T cells dramatically boosted the ability of dual costimulation to control the growth of established B16 melanomas. Surprisingly, this effect depended upon a CD134-dependent component that was extrinsic to the tumor-unrelated CD4 T cells, suggesting that the dual-costimulated helper cells are themselves helped by a CD134+ cell(s). Nevertheless, the delivery of therapeutic help tracked with an increased frequency of tumor-infiltrating granzyme B+ effector CD8 T cells and a reciprocal decrease in Foxp3+CD4+ cell frequency. Notably, the tumor-unrelated CD4 helper T cells also infiltrated the tumors, and their deletion several days following initial T cell priming negated their therapeutic impact. Taken together, dual costimulation programs tumor-unrelated CD4 T cells to deliver therapeutic help during both the priming and effector stages of the anti-tumor response. PMID:26561553

  4. Combining Cytotoxic and Immune-Mediated Gene Therapy to Treat Brain Tumors

    PubMed Central

    Curtin, James F.; King, Gwendalyn D.; Candolfi, Marianela; Greeno, Remy B.; Kroeger, Kurt M.; Lowenstein, Pedro R.; Castro, Maria G.

    2006-01-01

    Glioblastoma (GBM) is a type of intracranial brain tumor, for which there is no cure. In spite of advances in surgery, chemotherapy and radiotherapy, patients die within a year of diagnosis. Therefore, there is a critical need to develop novel therapeutic approaches for this disease. Gene therapy, which is the use of genes or other nucleic acids as drugs, is a powerful new treatment strategy which can be developed to treat GBM. Several treatment modalities are amenable for gene therapy implementation, e.g. conditional cytotoxic approaches, targeted delivery of toxins into the tumor mass, immune stimulatory strategies, and these will all be the focus of this review. Both conditional cytotoxicity and targeted toxin mediated tumor death, are aimed at eliminating an established tumor mass and preventing further growth. Tumors employ several defensive strategies that suppress and inhibit anti-tumor immune responses. A better understanding of the mechanisms involved in eliciting anti-tumor immune responses has identified promising targets for immunotherapy. Immunotherapy is designed to aid the immune system to recognize and destroy tumor cells in order to eliminate the tumor burden. Also, immune-therapeutic strategies have the added advantage that an activated immune system has the capability of recognizing tumor cells at distant sites from the primary tumor, therefore targeting metastasis distant from the primary tumor locale. Pre-clinical models and clinical trials have demonstrated that in spite of their location within the central nervous system (CNS), a tissue described as ‘immune privileged’, brain tumors can be effectively targeted by the activated immune system following various immunotherapeutic strategies. This review will highlight recent advances in brain tumor immunotherapy, with particular emphasis on advances made using gene therapy strategies, as well as reviewing other novel therapies that can be used in combination with immunotherapy. Another

  5. Combining cytotoxic and immune-mediated gene therapy to treat brain tumors.

    PubMed

    Curtin, James F; King, Gwendalyn D; Candolfi, Marianela; Greeno, Remy B; Kroeger, Kurt M; Lowenstein, Pedro R; Castro, Maria G

    2005-01-01

    Glioblastoma (GBM) is a type of intracranial brain tumor, for which there is no cure. In spite of advances in surgery, chemotherapy and radiotherapy, patients die within a year of diagnosis. Therefore, there is a critical need to develop novel therapeutic approaches for this disease. Gene therapy, which is the use of genes or other nucleic acids as drugs, is a powerful new treatment strategy which can be developed to treat GBM. Several treatment modalities are amenable for gene therapy implementation, e.g. conditional cytotoxic approaches, targeted delivery of toxins into the tumor mass, immune stimulatory strategies, and these will all be the focus of this review. Both conditional cytotoxicity and targeted toxin mediated tumor death, are aimed at eliminating an established tumor mass and preventing further growth. Tumors employ several defensive strategies that suppress and inhibit anti-tumor immune responses. A better understanding of the mechanisms involved in eliciting anti-tumor immune responses has identified promising targets for immunotherapy. Immunotherapy is designed to aid the immune system to recognize and destroy tumor cells in order to eliminate the tumor burden. Also, immune-therapeutic strategies have the added advantage that an activated immune system has the capability of recognizing tumor cells at distant sites from the primary tumor, therefore targeting metastasis distant from the primary tumor locale. Pre-clinical models and clinical trials have demonstrated that in spite of their location within the central nervous system (CNS), a tissue described as 'immune privileged', brain tumors can be effectively targeted by the activated immune system following various immunotherapeutic strategies. This review will highlight recent advances in brain tumor immunotherapy, with particular emphasis on advances made using gene therapy strategies, as well as reviewing other novel therapies that can be used in combination with immunotherapy. Another important

  6. [A case of a nonseminomatous germ cell tumor responding to MEA therapy].

    PubMed

    Nagai, Yasuharu; Minami, Takafumi; Itami, Yoshitaka; Kobayashi, Yasuyuki; Shimizu, Nobutaka; Yamamoto, Yutaka; Hayashi, Taiji; Nozawa, Masahiro; Yoshimura, Kazuhiro; Ishii, Tokumi; Uemura, Hirotugu

    2013-10-01

    We experienced a case of testicular cancer that was successfully treated by salvage chemotherapy comprised of methotrexate, actinomycin D and etoposide (MEA). A 25-year-old man was admitted to our hospital with a diagnosis of stage III B2 (JUA classification) testicular cancer. The patient had multiple lung metastases, and underwent a left orchiectomy. A histopathological examination revealed a choriocarcinoma, embryonal carcinoma, mature teratoma, and a yolk sac tumor. Tumor marker levels were elevated ; human chorionic gonadotropin β was 46 mIU/ml and alpha fetoprotein was 437 ng/ml. Although he was treated post-operatively with two courses of bleomycin, etoposide and cisplatin therapy, four courses of high-dose carboplatin, etoposide and iphosphamide (VIP) therapy, and two courses of CPT-11+ cisplatin therapy, tumor maker levels remained elevated and lung metastases were stable. Accordingly, he received three courses of MEA therapy. MEA therapy is regimen used to treat gestational trophoblastic neoplasia. After MEA therapy, levels of the tumor markers normalized. He then underwent a partial resection of lung and enucleation of lung metastasis by the video assisted thoracoscopic surgery method. Histopathological examination of the lung metastasis revealed only necrotic tissue. Tumor recurrence has not been observed in the 14 months since the MEA therapy.

  7. Histone Deacetylase Inhibitors Delivery using Nanoparticles with Intrinsic Passive Tumor Targeting Properties for Tumor Therapy

    PubMed Central

    el Bahhaj, Fatima; Denis, Iza; Pichavant, Loic; Delatouche, Régis; Collette, Floraine; Linot, Camille; Pouliquen, Daniel; Grégoire, Marc; Héroguez, Valérie; Blanquart, Christophe; Bertrand, Philippe

    2016-01-01

    Fast clearance, metabolism and systemic toxicity are major limits for the clinical use of anti-cancer drugs. Histone deacetylase inhibitors (HDACi) present these defects despite displaying promising anti-tumor properties on tumor cells in vitro and in in vivo model of cancers. Specific delivery of anti-cancer drugs into the tumor should improve their clinical benefit by limiting systemic toxicity and by increasing the anti-tumor effect. In this work, we describe a simple and flexible polymeric nanoparticle platform highly targeting the tumor in vivo and triggering impressive tumor weight reduction when functionalized with HDACi. Our nanoparticles were produced by Ring-Opening Metathesis Polymerization of azido-polyethylene oxide-norbornene macromonomers and functionalized using click chemistry. Using an orthotopic model of peritoneal invasive cancer, a highly selective accumulation of the particles in the tumor was obtained. A combination of epigenetic drugs involving a pH-responsive histone deacetylase inhibitor (HDACi) polymer conjugated to these particles gave 80% reduction of tumor weight without toxicity whereas the free HDACi has no effect. Our work demonstrates that the use of a nanovector with theranostic properties leads to an optimized delivery of potent HDACi in tumor and then, to an improvement of their anti-tumor properties in vivo. PMID:27162550

  8. Vaccine Therapy Plus Biological Therapy in Treating Adults With Metastatic Solid Tumors

    ClinicalTrials.gov

    2013-06-19

    Colorectal Cancer; Endometrial Cancer; Head and Neck Cancer; Liver Cancer; Lung Cancer; Melanoma (Skin); Pancreatic Cancer; Testicular Germ Cell Tumor; Unspecified Adult Solid Tumor, Protocol Specific

  9. Dextran-doxorubicin/chitosan nanoparticles for solid tumor therapy.

    PubMed

    Bisht, Savita; Maitra, Amarnath

    2009-01-01

    Chemotherapy is a major therapeutic approach for the treatment of localized and metastasized cancers. Whereas potent chemotherapeutic agents seem promising in the test tube, clinical trials often fail due to unfavorable pharmacokinetics, poor delivery, low local concentrations, and limited accumulation in the target cell. The pathophysiology of the tumor vasculature and stromal compartment presents a major obstacle to effective delivery of agents to solid tumors. Poor perfusion of the tumor, arterio-venous shunting, necrotic and hypoxic areas, as well as a high interstitial fluid pressure work against favorable drug uptake. Thus, targeted drug delivery using long-circulating particulate drug carriers such as hydrogels of controlled size (<100 nm diameter) holds immense potential to improve the treatment of cancer by selectively providing therapeutically effective drug concentrations at the tumor site [through enhanced permeability and retention (EPR) effect] while reducing undesirable side effects. This review focuses on the progress of targeted delivery of nanoparticulated anticancer drug such as doxorubicin chemically conjugated with dextran and encapsulated in chitosan nanoparticles to solid tumor with reduced side effect of drug. Regulated particle size and long circulation of these hydrogel nanoparticles in blood help them accumulate in tumor tissue through EPR effect as evident from the significant regression of the tumor volume. The cardiotoxicity of doxorubicin can be minimized by coupling the drug with dextran and encapsulating it in chitosan nanoparticles. (c) 2009 John Wiley & Sons, Inc.

  10. [Possibilities of boron neutron capture therapy in the treatment of malignant brain tumors].

    PubMed

    Kanygin, V V; Kichigin, A I; Gubanova, N V; Taskaev, S Yu

    2015-01-01

    Boron neutron capture therapy (BNCT) that is of the highest attractiveness due to its selective action directly on malignant tumor cells is a promising approach to treating cancers. Clinical interest in BNCT focuses in neuro-oncology on therapy for gliomas, glioblastoma in particular, and BNCT may be used in brain metastatic involvement. This needs an epithermal neutron source that complies with the requirements for BNCT, as well as a 10B-containing agent that will selectively accumulate in tumor tissue. The introduction of BNCT into clinical practice to treat patients with glial tumors will be able to enhance therapeutic efficiency.

  11. Enhancing the Efficacy of Drug-loaded Nanocarriers against Brain Tumors by Targeted Radiation Therapy

    PubMed Central

    Baumann, Brian C.; Kao, Gary D.; Mahmud, Abdullah; Harada, Takamasa; Swift, Joe; Chapman, Christina; Xu, Xiangsheng; Discher, Dennis E.; Dorsey, Jay F.

    2013-01-01

    Glioblastoma multiforme (GBM) is a common, usually lethal disease with a median survival of only ~15 months. It has proven resistant in clinical trials to chemotherapeutic agents such as paclitaxel that are highly effective in vitro, presumably because of impaired drug delivery across the tumor's blood-brain barrier (BBB). In an effort to increase paclitaxel delivery across the tumor BBB, we linked the drug to a novel filomicelle nanocarrier made with biodegradable poly(ethylene-glycol)-block-poly(ε-caprolactone-r-D,L-lactide) and used precisely collimated radiation therapy (RT) to disrupt the tumor BBB's permeability in an orthotopic mouse model of GBM. Using a non-invasive bioluminescent imaging technique to assess tumor burden and response to therapy in our model, we demonstrated that the drug-loaded nanocarrier (DLN) alone was ineffective against stereotactically implanted intracranial tumors yet was highly effective against GBM cells in culture and in tumors implanted into the flanks of mice. When targeted cranial RT was used to modulate the tumor BBB, the paclitaxel-loaded nanocarriers became effective against the intracranial tumors. Focused cranial RT improved DLN delivery into the intracranial tumors, significantly improving therapeutic outcomes. Tumor growth was delayed or halted, and survival was extended by >50% (p<0.05) compared to the results obtained with either RT or the DLN alone. Combinations of RT and chemotherapeutic agents linked to nanocarriers would appear to be an area for future investigations that could enhance outcomes in the treatment of human GBM. PMID:23296073

  12. Design of a proton microbeam of the PEFP

    SciTech Connect

    Kim, Kye Ryung; Kim, Yong Hwan; Chang, Ji Ho; Kim, Kui Young

    2008-02-15

    The PEFP has been developing a 100 MeV proton linear accelerator and user facilities for 20 and 100 MeV proton beams. At one end of the five 20 MeV proton beam lines, a proton microbeam construction was considered for an application in the fields of material, biological, and medical sciences. To develop the proton microbeam, realization of a few MeV proton beam with a few tens of microamperes in diameter of a beam spot was essentially required. In this report, the basic descriptions of the proton microbeam which is composed of an energy degrader, slits, magnetic lens, a target chamber, and detectors are presented including a consideration of unfavorable aspects concerning some specific characteristics of a linear accelerator, such as pulse mode operation and fixed energy. Some calculation results from a Monte Carlo simulation by using the SRIM2006 and the TURTLE codes are also included.

  13. Applications of particle microbeams in space radiation research.

    PubMed

    Durante, Marco

    2009-03-01

    Galactic cosmic radiation is acknowledged as one of the major barriers to human space exploration. In space, astronauts are exposed to charged particles from Z = 1 (H) up to Z = 28 (Ni), but the probability of a hit to a specific single cell in the human body is low. Particle microbeams can deliver single charged particles of different charge and energy to single cells from different tissues, and microbeam studies are therefore very useful for improving current risk estimates for long-term space travel. 2D in vitro cell cultures can be very useful for establishing basic molecular mechanisms, but they are not sufficient to extrapolate risk, given the substantial evidence proving tissue effects are key in determining the response to radiation insult. 3D tissue or animal systems represent a more promising target for space radiobiology using microbeams.

  14. Design of a proton microbeam of the PEFPa)

    NASA Astrophysics Data System (ADS)

    Kim, Kye Ryung; Kim, Yong Hwan; Chang, Ji Ho; Kim, Kui Young

    2008-02-01

    The PEFP has been developing a 100MeV proton linear accelerator and user facilities for 20 and 100MeV proton beams. At one end of the five 20MeV proton beam lines, a proton microbeam construction was considered for an application in the fields of material, biological, and medical sciences. To develop the proton microbeam, realization of a few MeV proton beam with a few tens of microamperes in diameter of a beam spot was essentially required. In this report, the basic descriptions of the proton microbeam which is composed of an energy degrader, slits, magnetic lens, a target chamber, and detectors are presented including a consideration of unfavorable aspects concerning some specific characteristics of a linear accelerator, such as pulse mode operation and fixed energy. Some calculation results from a Monte Carlo simulation by using the SRIM2006 and the TURTLE codes are also included.

  15. Status of Charged Particle Microbeams for Radiation Biology

    NASA Astrophysics Data System (ADS)

    Folkard, M.; Prise, K. M.; Vojnovic, B.

    2007-03-01

    The Gray Cancer Institute is one of a small number of laboratories worldwide routinely using particle microbeam techniques for radiobiological applications. Cellular micro-irradiation methods have been used to provide experimental opportunities not possible with typical 'broad-field' irradiation methods. Using microbeams, it is possible to deliver precise doses of radiation to selected individual cells, or sub-cellular targets in vitro. This technique continues to be applied to the investigation of a number of phenomena currently of great interest to the radiobiological community. In particular, it is the study of so-called 'non-targeted' effects (where cells are seen to respond indirectly to ionizing radiation) that are benefiting most from the use of microbeam approaches. One important non-targeted effect is the 'bystander-effect' where it is observed that unirradiated cells exhibit damage in response to signals transmitted by irradiated neighbours.

  16. Neutron micro-beam design simulation by Monte Carlo

    NASA Astrophysics Data System (ADS)

    Pazirandeh, Ali; Taheri, Ali

    2007-09-01

    Over the last two decades neutron micro-beam has increasingly been developing in view of various applications in molecular activation analysis, micro-radiography in space and aviation and in radiation induced bystander effects in bio-cells. In this paper the structure and simulation of a neutron micro-beam is presented. The collimator for micro-beam is made of a polyethylene cylinder with a small hole along the centerline of the cylinder. The hole is filled with very thin needles in triangular or rectangular arrangement. The neutron source was reactor neutrons or a spontaneous Cf-252 neutron source falling on the top side of the collimator. The outgoing thermal and epithermal neutron fluxes were calculated.

  17. Targeted Therapies Improve Survival for Patients with Pancreatic Neuroendocrine Tumors

    Cancer.gov

    In 2011, based on initial findings from two clinical trials, the Food and Drug Administration approved sunitinib and everolimus for patients with pancreatic neuroendocrine tumors. Updated results from the everolimus trial were published in September 2016.

  18. Tumor Initiation in Human Malignant Melanoma and Potential Cancer Therapies

    PubMed Central

    Ma, Jie; Frank, Markus H.

    2010-01-01

    Cancer stem cells (CSCs), also known as tumor-initiating cells, have been identified in several human malignancies, including human malignant melanoma. The frequency of malignant melanoma-initiating cells (MMICs), which are identified by their expression of ATP-binding cassette (ABC) family member ABCB5, correlates with disease progression in human patients. Furthermore, targeted MMIC ablation through ABCB5 inhibits tumor initiation and growth in preclinical xenotransplantation models, pointing to potential therapeutic promise of the CSC concept. Recent advances also show that CSCs can exert pro-angiogenic roles in tumor growth and serve immunomodulatory functions related to the evasion of host anti-tumor immunity. Thus, MMICs might initiate and sustain tumorigenic growth not only as a result of CSC-intrinsic self-renewal, differentiation and proliferative capacity, but also based on pro-tumorigenic interactions with the host environment. PMID:20184545

  19. Tumor initiation in human malignant melanoma and potential cancer therapies.

    PubMed

    Ma, Jie; Frank, Markus H

    2010-02-01

    Cancer stem cells (CSCs), also known as tumor-initiating cells, have been identified in several human malignancies, including human malignant melanoma. The frequency of malignant melanoma-initiating cells (MMICs), which are identified by their expression of ATP-binding cassette (ABC) family member ABCB5, correlates with disease progression in human patients. Furthermore, targeted MMIC ablation through ABCB5 inhibits tumor initiation and growth in preclinical xenotransplantation models, pointing to potential therapeutic promise of the CSC concept. Recent advances also show that CSCs can exert pro-angiogenic roles in tumor growth and serve immunomodulatory functions related to the evasion of host anti-tumor immunity. Thus, MMICs might initiate and sustain tumorigenic growth not only as a result of CSC-intrinsic self-renewal, differentiation and proliferative capacity, but also based on pro-tumorigenic interactions with the host environment.

  20. A novel anticancer therapy that simultaneously targets aberrant p53 and Notch activities in tumors.

    PubMed

    Yao, Yuting; Wang, Li; Zhang, He; Wang, Haibo; Zhao, Xiaoping; Zhang, Yidan; Zhang, Leilei; Fan, Xianqun; Qian, Guanxiang; Hu, Ji-Fan; Ge, Shengfang

    2012-01-01

    Notch signaling pathway plays an important role in tumorigenesis by maintaining the activity of self-renewal of cancer stem cells, and therefore, it is hypothesized that interference of Notch signaling may inhibit tumor formation and progression. H101 is a recombinant oncolytic adenovirus that is cytolytic in cells lacking intact p53, but it is unable to eradicate caner stem cells. In this study, we tested a new strategy of tumor gene therapy by combining a Notch1-siRNA with H101 oncolytic adenovirus. In HeLa-S3 tumor cells, the combined therapy blocked the Notch pathway and induced apoptosis in tumors that are p53-inactive. In nude mice bearing xenograft tumors derived from HeLa-S3 cells, the combination of H101/Notch1-siRNA therapies inhibited tumor growth. Moreover, Notch1-siRNA increased Hexon gene expression at both the transcriptional and the translational levels, and promoted H101 replication in tumors, thereby enhancing the oncolytic activity of H101. These data demonstrate the feasibility to combine H101 p53-targted oncolysis and anti-Notch siRNA activities as a novel anti-cancer therapy.

  1. Targeted Therapy in Sarcomas Other than GIST Tumors

    PubMed Central

    Sborov, Douglas; Chen, James L

    2015-01-01

    Non-GIST soft tissue sarcomas are a heterogeneous grouping of mesenchymal tumors that comprise less than 1% of adult malignancies. Treatment continues to be based on cytotoxic chemotherapy regimens. However, characterization of the molecular pathway deregulations that drive these tumors has led to the emergence of more customized treatment options. In this review, we focus on the multitude of molecular inhibitors targeting angiogenesis and cell cycle pathways being tested in clinical trials. PMID:25330750

  2. Low-dose dacarbazine-doxorubicin therapy against intra-abdominal desmoid tumors.

    PubMed

    Yamamoto, Hirofumi; Oshiro, Ryota; Nishimura, Junichi; Uemura, Mamoru; Haraguchi, Naotsugu; Hata, Taishi; Takemasa, Ichiro; Mizushima, Tsunekazu; Sekimoto, Mitsugu; Doki, Yuichiro; Mori, Masaki

    2013-05-01

    Intra-abdominal desmoid tumor is a life-threatening disease. Studies have shown that dacarbazine (DTIC)-doxorubicin (DOX) (D-D) therapy is the most effective treatment. However, myelosuppression is a major problem, and cardiac muscle disorders due to DOX limit the number of administration cycles, whereas it usually requires a long time to achieve tumor shrinkage. To resolve these issues, we introduced low-dose D-D therapy to 3 patients employing 50 mg/m² DOX and 600-700 mg/m² DTIC per cycle, which permits repeated administration cycles up to 10-11 times. Case 1 was a 23-year-old female with a sporadic recurrent mesenterium desmoid tumor located in the pelvis (maximum diameter, 8 cm). Cases 2 and 3 were a 33-year-old female and a 36-year-old male. Both patients had intra-abdominal mesenterium desmoid tumors (maximum diameter 9.6 and 9.0 cm, respectively) that were generated after proctocolectomy due to familial adenomatous polyposis. No severe adverse events occurred during the therapy. With the aid of sulindac and tamoxifen after low-dose D-D therapy, the first two patients achieved a complete response, and the third patient achieved a partial response and awaits further tumor shrinkage. Our experience indicates that low-dose DT-D therapy is a safe and effective regimen for patients with intra-abdominal desmoid tumors.

  3. Photosensitizer-Conjugated Hyaluronic Acid-Shielded Polydopamine Nanoparticles for Targeted Photomediated Tumor Therapy.

    PubMed

    Han, Jieun; Park, Wooram; Park, Sin-Jung; Na, Kun

    2016-03-01

    Photodynamic therapy (PDT) is a widely used clinical option for tumor therapy. However, the clinical utilization of conventional small-molecule photosensitizers (PSs) for PDT has been limited by their low selectivity for disease sites, and undesirable photoactivation. To overcome these limitations, we demonstrated a tumor-specific and photoactivity-controllable nanoparticle photomedicine based on a combination of PS-biomacromolecule conjugates and polydopamine nanoparticles (PD-NP) for an effective tumor therapy. This novel photomedicine consisted of a PD-NP core and a PS-conjugated hyaluronic acid (PS-HA) shell. The PD-NP and the PS-HA play roles as a quencher for PSs and a cancer targeting moiety, respectively. The synthesized PS-HA-shielded PD-NPs (PHPD-NPs) had a relatively narrow size distribution (approximately 130 nm) with uniform spherical shapes. In response to cancer-specific intracellular enzymes (e.g., hyaluronidase), the PHPD-NPs exhibited an excellent singlet oxygen generation capacity for PDT. Furthermore, an efficient photothermal conversion ability for photothermal therapy (PTT) was also shown in the PHPD-NPs system. These properties provide superior therapeutic efficacy against cancer cells. In mice tumor model, the photoactive restorative effects of the PHPD-NPs were much higher in cancer microenvironments compared to that in the normal tissue. As a result, the PHPD-NPs showed a significant antitumor activity in in vivo mice tumor model. The nanoparticle photomedicine design is a novel strategy for effective tumor therapy.

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

    PubMed

    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. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. Tumor-targeting hyaluronic acid nanoparticles for photodynamic imaging and therapy.

    PubMed

    Yoon, Hong Yeol; Koo, Heebeom; Choi, Ki Young; Lee, So Jin; Kim, Kwangmeyung; Kwon, Ick Chan; Leary, James F; Park, Kinam; Yuk, Soon Hong; Park, Jae Hyung; Choi, Kuiwon

    2012-05-01

    Tumor-targeted imaging and therapy have been the challenging issue in the clinical field. Herein, we report tumor-targeting hyaluronic acid nanoparticles (HANPs) as the carrier of the hydrophobic photosensitizer, chlorin e6 (Ce6) for simultaneous photodynamic imaging and therapy. First, self-assembled HANPs were synthesized by chemical conjugation of aminated 5β-cholanic acid, polyethylene glycol (PEG), and black hole quencher3 (BHQ3) to the HA polymers. Second, Ce6 was readily loaded into the HANPs by a simple dialysis method resulting in Ce6-loaded hyaluronic acid nanoparticles (Ce6-HANPs), wherein in the loading efficiency of Ce6 was higher than 80%. The resulting Ce6-HANPs showed stable nano-structure in aqueous condition and rapid uptake into tumor cells. In particular Ce6-HANPs were rapidly degraded by hyaluronidases abundant in cytosol of tumor cells, which may enable intracellular release of Ce6 at the tumor tissue. After an intravenous injection into the tumor-bearing mice, Ce6-HANPs could efficiently reach the tumor tissue via the passive targeting mechanism and specifically enter tumor cells through the receptor-mediated endocytosis based on the interactions between HA of nanoparticles and CD44, the HA receptor on the surface of tumor cells. Upon laser irradiation, Ce6 which was released from the nanoparticles could generate fluorescence and singlet oxygen inside tumor cells, resulting in effective suppression of tumor growth. Overall, it was demonstrated that Ce6-HANPs could be successfully applied to in vivo photodynamic tumor imaging and therapy simultaneously.

  6. A Drug-Free Tumor Therapy Strategy: Cancer-Cell-Targeting Calcification.

    PubMed

    Zhao, Ruibo; Wang, Ben; Yang, Xinyan; Xiao, Yun; Wang, Xiaoyu; Shao, Changyu; Tang, Ruikang

    2016-04-18

    Herein, we propose a drug-free approach to cancer therapy that involves cancer cell targeting calcification (CCTC). Several types of cancer cells, such as HeLa cells, characterized by folate receptor (FR) overexpression, can selectively adsorb folate (FA) molecules and then concentrate Ca(2+) locally to induce specific cell calcification. The resultant calcium mineral encapsulates the cancer cells, inducing their death, and in vivo assessments confirm that CCTC treatment can efficiently inhibit tumor growth and metastasis without damaging normal cells compared with conventional chemotherapy. Accordingly, CCTC remarkably improve the survival rate of tumor mice. Notably, both FA and calcium ions are essential ingredients in human metabolism, which means that CCTC is a successful drug-free method for tumor therapy. This achievement may further represent an alternative cancer therapy characterized by selective calcification-based substitution of sclerosis for tumor disease. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Tumor treating fields therapy device for glioblastoma: physics and clinical practice considerations.

    PubMed

    Lok, Edwin; Swanson, Kenneth D; Wong, Eric T

    2015-01-01

    Alternating electric fields therapy, as delivered by the tumor treating fields device, is a new modality of cancer treatment that has been approved by the US FDA for recurrent glioblastoma. At a frequency of 200 kHz, these fields emanate from transducer arrays on the surface of the patient's scalp into the brain and perturb processes necessary for cytokinesis during tumor cell mitosis. In the registration Phase III trial for recurrent glioblastoma patients, the efficacy of the tumor treating fields as monotherapy was equivalent to chemotherapy, while scalp irritation was its major adverse event compared with systemic toxicities that were associated with cytotoxic chemotherapies. Alternating electric fields therapy is, therefore, an essential option for the treatment of recurrent glioblastoma. Here, we summarize our current knowledge of the physics, cell biology and clinical data supporting the use of the tumor treating fields therapy.

  8. Synchrotron Radiation Therapy from a Medical Physics point of view

    SciTech Connect

    Prezado, Y.; Berkvens, P.; Braeuer-Krisch, E.; Renier, M.; Bravin, A.; Adam, J. F.; Martinez-Rovira, I.; Fois, G.; Thengumpallil, S.; Edouard, M.; Deman, P.; Vautrin, M.

    2010-07-23

    Synchrotron radiation (SR) therapy is a promising alternative to treat brain tumors, whose management is limited due to the high morbidity of the surrounding healthy tissues. Several approaches are being explored by using SR at the European Synchrotron Radiation Facility (ESRF), where three techniques are under development Synchrotron Stereotactic Radiation Therapy (SSRT), Microbeam Radiation Therapy (MRT) and Minibeam Radiation Therapy (MBRT).The sucess of the preclinical studies on SSRT and MRT has paved the way to clinical trials currently in preparation at the ESRF. With this aim, different dosimetric aspects from both theoretical and experimental points of view have been assessed. In particular, the definition of safe irradiation protocols, the beam energy providing the best balance between tumor treatment and healthy tissue sparing in MRT and MBRT, the special dosimetric considerations for small field dosimetry, etc will be described. In addition, for the clinical trials, the definition of appropiate dosimetry protocols for patients according to the well established European Medical Physics recommendations will be discussed. Finally, the state of the art of the MBRT technical developments at the ESRF will be presented. In 2006 A. Dilmanian and collaborators proposed the use of thicker microbeams (0.36-0.68 mm). This new type of radiotherapy is the most recently implemented technique at the ESRF and it has been called MBRT. The main advantage of MBRT with respect to MRT is that it does not require high dose rates. Therefore it can be more easily applied and extended outside synchrotron sources in the future.

  9. The mechanism of local tumor irradiation combined with interleukin 2 therapy in murine renal carcinoma: histological evaluation of pulmonary metastases.

    PubMed

    Dezso, B; Haas, G P; Hamzavi, F; Kim, S; Montecillo, E J; Benson, P D; Pontes, J E; Maughan, R L; Hillman, G G

    1996-09-01

    We have demonstrated that tumor irradiation enhanced the therapeutic effect of interleukin 2 (IL-2) on pulmonary metastases from a murine renal adenocarcinoma, Renca. To investigate the mechanism of interaction between tumor irradiation and IL-2 therapy, we have histologically evaluated the effects of each therapy alone or in combination on Renca pulmonary metastases. Following treatment of established lung metastases with irradiation and IL-2 therapy, lung sections were processed for H&E or immunohistochemical staining. We found that tumor irradiation or IL-2 therapy locally induced vascular damage, resulting in multifocal hemorrhages and mononuclear cell mobilization in the lung tissue. This effect was amplified in lungs treated with the combined therapy. Immunohistochemistry showed that irradiation produced a macrophage influx into irradiated tumor nodules, and systemic IL-2 therapy induced T-cell infiltration in tumor nodules. Lungs treated with the combined therapy exhibited massive macrophage, T-cell, and natural killer cell mobilization in disintegrating tumor nodules and in the lung tissue. This combined therapy caused a decrease in the number of proliferating tumor cells and an increase in the number of apoptotic cells, which were more marked than with either therapy alone. We suggest that the macrophages mobilized by radiation-induced tissue injury could play a role in phagocytosis of apoptotic tumor cells, processing and presenting of tumor antigens for a systemic immune response activated by IL-2. Tumor destruction may result from the concomitant action of activated T cells, natural killer cells, and macrophages infiltrating the tumor nodules.

  10. A Mathematical Model of Prostate Tumor Growth Under Hormone Therapy with Mutation Inhibitor

    NASA Astrophysics Data System (ADS)

    Tao, Youshan; Guo, Qian; Aihara, Kazuyuki

    2010-04-01

    This paper extends Jackson’s model describing the growth of a prostate tumor with hormone therapy to a new one with hypothetical mutation inhibitors. The new model not only considers the mutation by which androgen-dependent (AD) tumor cells mutate into androgen-independent (AI) ones but also introduces inhibition which is assumed to change the mutation rate. The tumor consists of two types of cells (AD and AI) whose proliferation and apoptosis rates are functions of androgen concentration. The mathematical model represents a free-boundary problem for a nonlinear system of parabolic equations, which describe the evolution of the populations of the above two types of tumor cells. The tumor surface is a free boundary, whose velocity is equal to the cell’s velocity there. Global existence and uniqueness of solutions of this model is proved. Furthermore, explicit formulae of tumor volume at any time t are found in androgen-deprived environment under the assumption of radial symmetry, and therefore the dynamics of tumor growth under androgen-deprived therapy could be predicted by these formulae. Qualitative analysis and numerical simulation show that controlling the mutation may improve the effect of hormone therapy or delay a tumor relapse.

  11. Tumor Microenvironment Modulation by Cyclopamine Improved Photothermal Therapy of Biomimetic Gold Nanorods for Pancreatic Ductal Adenocarcinomas.

    PubMed

    Jiang, Ting; Zhang, Bo; Shen, Shun; Tuo, Yanyan; Luo, Zimiao; Hu, Yu; Pang, Zhiqing; Jiang, Xinguo

    2017-09-20

    Due to the rich stroma content and poor blood perfusion, pancreatic ductal adenocarcinoma (PDA) is a tough cancer that can hardly be effectively treated by chemotherapeutic drugs. Tumor microenvironment modulation or advanced design of nanomedicine to achieve better therapeutic benefits for PDA treatment was widely advocated by many reviews. In the present study, a new photothermal therapy strategy of PDA was developed by combination of tumor microenvironment modulation and advanced design of biomimetic gold nanorods. On one hand, biomimetic gold nanorods were developed by coating gold nanorods (GNRs) with erythrocyte membrane (MGNRs). It was shown that MGNRs exhibited significantly higher colloidal stability in vitro, stronger photothermal therapeutic efficacy in vitro, and longer circulation in vivo than GNRs. On the other hand, tumor microenvironment modulation by cyclopamine treatment successfully disrupted the extracellular matrix of PDA and improved tumor blood perfusion. Moreover, cyclopamine treatment significantly increased the accumulation of MGNRs in tumors by 1.8-fold and therefore produced higher photothermal efficiency in vivo than the control group. Finally, cyclopamine treatment combined with photothermal MGNRs achieved the most significant shrinkage of Capan-2 tumor xenografts among all the treatment groups. Therefore, with the integrated advantages of tumor microenvironment regulation and long-circulation biomimetic MGNRs, effective photothermal therapy of PDA was achieved. In general, this new strategy of combining tumor microenvironment modulation and advanced design of biomimetic nanoparticles might have great potential in PDA therapy.

  12. Maturation of pulmonary metastases of Wilms' tumor after therapy: A case report

    SciTech Connect

    Shimmoto, K.; Ushigome, S.; Nikaido, T.; Kikuchi, Y.; Kobayashi, N.; Yamazaki, Y. )

    1991-04-01

    A case is reported of Wilms' tumor associated with multiple pulmonary metastases histologically showing maturation of the tumor cells at 9 years after the resection of the primary tumor and intensive therapy. A huge tumor of a 22-month-old patient's right kidney was resected. The tumor was diagnosed as Wilms' tumor of mesenchymal type (stage 1), which consisted of predominantly immature mesenchymal tissue including rhabdomyoblasts, smooth muscle and fibrous tissue, and few blastemal and epithelial components. Intensive preoperative and postoperative chemotherapy with actinomycin D and vincristine and postoperative irradiation therapy totaling 16 Gy were carried out. The patient was regularly followed up uneventfully until 9 years after the surgery. On routine chest x ray at the age of 10 years 11 months, multiple pulmonary nodules were found. The excised nodules from the bilateral lungs disclosed similar histology, exclusively composed of dense collagen bundles and fibrocytes intermingled with mature striated muscle bundles. No immature tumor components were detected. The possible effect of intensive therapy in this maturation was stressed, although spontaneous benign differentiation of tumor cells cannot be excluded.

  13. Tumor relapse prevented by combining adoptive T cell therapy with Salmonella typhimurium

    PubMed Central

    Binder, David C.; Arina, Ainhoa; Wen, Frank; Tu, Tony; Zhao, Ming; Hoffman, Robert M.; Wainwright, Derek A.; Schreiber, Hans

    2016-01-01

    ABSTRACT We recently reported that therapeutic vaccination with live tumor antigen-producing Salmonella typhimurium rescues dysfunctional endogenous T cell responses and eradicates long-established tumors refractory to αCTLA-4 and αPD-L1 checkpoint inhibitor blockade. Here, we show that live intravenously injected or heat-killed (HK) intratumorally injected Salmonella typhimurium, even when not producing tumor antigen, synergize with adoptive T cell therapy to eradicate tumors. These data demonstrate that the combination of adoptive T cell transfer with the injection of live or dead Salmonella typhimurium is a promising approach for cancer treatment. PMID:27471609

  14. Photodynamic therapy cures green fluorescent protein expressing RIF1 tumors in mice

    NASA Astrophysics Data System (ADS)

    Castano, Ana P.; Liu, Qingde; Hamblin, Michael R.

    2004-07-01

    Cancer is a leading cause of death among modern people, largely due to metastatic disease. The ideal cancer treatment should destroy both the primary tumor and distant metastases with minimal toxicity to normal tissue. This is best accomplished by educating the body's immune system to recognize the tumor as foreign so that after the primary tumor is destroyed, distant metastases will also be eradicated. Photodynamic therapy (PDT) involves the IV administration of photosensitizers followed by illumination of the tumor with red light producing reactive oxygen species that eventually cause vascular shutdown and tumor cell apoptosis. Anti-tumor immunity is stimulated after PDT due to the acute inflammatory response, generation of tumor-specific antigens, and induction of heat-shock proteins. Combination regimens are likely to emerge in the future to even further enhance immunity. Green fluorescent protein is used as an optical reporter to non-invasively image the progression of mouse tumors, and in addition, may act as a foreign (jellyfish) antigen. We asked whether the response of tumor bearing mice to PDT differed when a non-immunogenic tumor cell line was transfected with GFP? We injected RIF-1 or RIF1-EGFP cells in the leg of C3H/HeN mice and both the cells and tumors grew equally well. We used two PDT protocols (benzoporphyrin derivative (BPD) with 15-minute interval or Photofrin with 24-hour interval). The results showed significant differences between the responses of RIF1 or RIF1-EGFP tumors after BPD or Photofrin PDT and complete cures and mouse survival when RIF-1 EGFP tumors were treated with BPD. This increased tumor response may be due to antibody-mediated cytotoxicity and the presence of an artificial tumor antigen (GFP) that can produce a CD8 T-cell response against the whole tumor. The presence of antibodies against EGFP in mouse serum correlates with the hypothesis.

  15. Radio-Photothermal Therapy Mediated by a Single Compartment Nanoplatform Depletes Tumor Initiating Cells and Reduces Lung Metastasis in Orthotopic 4T1 Breast Tumor Model

    PubMed Central

    Zhou, Min; Zhao, Jun; Tian, Mei; Song, Shaoli; Zhang, Rui; Gupta, Sanjay; Tan, Dongfeng; Shen, Haifa; Ferrari, Mauro; Li, Chun

    2016-01-01

    Tumor Initiating Cells (TICs) are resistant to radiotherapy and chemotherapy, and are believed to be responsible for tumor recurrence and metastasis. Combination therapies can overcome the limitation of conventional cancer treatments, and has demonstrated promising application in clinic. Here, we show that dual modality radiotherapy (RT) and photothermal therapy (PTT) mediated by a single compartment nanosystem copper-64-labeled copper sulfide nanoparticles ([64Cu]CuS NPs) could suppress breast tumor metastasis through eradication of TICs. Positron electron tomography (PET) imaging and biodistribution studies showed that more than 90% of [64Cu]CuS NPs was retained in subcutaneously grown BT474 breast tumor 24 h after intratumoral (i.t.) injection, indicating the NPs is suitable for the combination therapy. Combined RT/PTT therapy resulted in significant tumor growth delay in subcutaneous BT474 breast cancer model. Moreover, RT/PTT treatment significantly prolonged the survival of mice bearing orthotopic 4T1 breast tumors compared to no treatment, RT alone, or PTT alone. The RT/PTT combination therapy significantly reduced the number of tumor nodules in the lung and the formation of tumor mammospheres from treated 4T1 tumors. No obvious side effects of the CuS NPs were noted in the treated mice in a pilot toxicity study. Taken together, our data support the feasibility of a therapeutic approach for suppression of tumor metastasis through localized RT/PTT therapy. PMID:26376843

  16. Radio-photothermal therapy mediated by a single compartment nanoplatform depletes tumor initiating cells and reduces lung metastasis in the orthotopic 4T1 breast tumor model.

    PubMed

    Zhou, Min; Zhao, Jun; Tian, Mei; Song, Shaoli; Zhang, Rui; Gupta, Sanjay; Tan, Dongfeng; Shen, Haifa; Ferrari, Mauro; Li, Chun

    2015-12-14

    Tumor Initiating Cells (TICs) are resistant to radiotherapy and chemotherapy, and are believed to be responsible for tumor recurrence and metastasis. Combination therapies can overcome the limitation of conventional cancer treatments, and have demonstrated promising application in the clinic. Here, we show that dual modality radiotherapy (RT) and photothermal therapy (PTT) mediated by a single compartment nanosystem copper-64-labeled copper sulfide nanoparticles ([(64)Cu]CuS NPs) could suppress breast tumor metastasis through eradication of TICs. Positron electron tomography (PET) imaging and biodistribution studies showed that more than 90% of [(64)Cu]CuS NPs was retained in subcutaneously grown BT474 breast tumor 24 h after intratumoral (i.t.) injection, indicating the NPs are suitable for the combination therapy. Combined RT/PTT therapy resulted in significant tumor growth delay in the subcutaneous BT474 breast cancer model. Moreover, RT/PTT treatment significantly prolonged the survival of mice bearing orthotopic 4T1 breast tumors compared to no treatment, RT alone, or PTT alone. The RT/PTT combination therapy significantly reduced the number of tumor nodules in the lung and the formation of tumor mammospheres from treated 4T1 tumors. No obvious side effects of the CuS NPs were noted in the treated mice in a pilot toxicity study. Taken together, our data support the feasibility of a therapeutic approach for the suppression of tumor metastasis through localized RT/PTT therapy.

  17. Use of novel metalloporphyrins as imageable tumor-targeting agents for radiation therapy

    DOEpatents

    Miura, Michiko; Slatkin, Daniel N.

    2005-10-04

    The present invention covers halogenated derivatives of boronated phorphyrins containing multiple carborane cages having the formula ##STR1## which selectively accumulate in neoplastic tissue within the irradiation volume and thus can be used in cancer therapies including, but not limited to, boron neutron-capture therapy and photodynamic therapy. The present invention also covers methods for using these halogenated derivatives of boronated porphyrins in tumor imaging and cancer treatment.

  18. Metalloporphyrins and their uses as imageable tumor-targeting agents for radiation therapy

    DOEpatents

    Miura, Michiko; Slatkin, Daniel N.

    2003-05-20

    The present invention covers halogenated derivatives of boronated porphyrins containing multiple carborane cages having the formula ##STR1## which selectively accumulate in neoplastic tissue within the irradiation volume and thus can be used in cancer therapies including, but not limited to, boron neutron- capture therapy and photodynamic therapy. The present invention also covers methods for using these halogenated derivatives of boronated porphyrins in tumor imaging and cancer treatment.

  19. Confocal Microscopy for Modeling Electron Microbeam Irradiation of Skin

    SciTech Connect

    Miller, John H.; Chrisler, William B.; Wang, Xihai; Sowa, Marianne B.

    2011-08-01

    For radiation exposures employing targeted sources such as particle microbeams, the deposition of energy and dose will depend on the spatial heterogeneity of the spample. Although cell structural variations are relatively minor for two-dimensional cell cultures, they can vary significantly for fully differential tissues. Employing high-resolution confocal microscopy, we have determined the spatial distribution, size, and shape of epidermal kerantinocyte nuclei for the full-thickness EpiDerm skin model (MatTek, Ashland, VA). Application of these data to claculate the microdosimetry and microdistribution of energy deposition by an electron microbeam is discussed.

  20. Local tumor irradiation augments the response to IL-2 therapy in a murine renal adenocarcinoma.

    PubMed

    Younes, E; Haas, G P; Dezso, B; Ali, E; Maughan, R L; Kukuruga, M A; Montecillo, E; Pontes, J E; Hillman, G G

    1995-10-15

    We have previously demonstrated that local tumor irradiation effectively enhanced the therapeutic effect of IL-2 therapy on pulmonary metastases from a murine renal adenocarcinoma, Renca. Irradiation with 300 rad to the left lung only, followed by systemic IL-2 therapy, results in increased tumor reduction in both lungs, suggesting that radiation enhances the systemic effect of immunotherapy. In this study, we show that irradiation of the tumor-bearing organ is essential for the combined effect of both modalities. This effect is radiation dose-dependent as increases in the radiation dosage result in greater tumor reduction in the irradiated field as well as systemically in nonirradiated fields when combined with immunotherapy. We find that irradiation has a direct inhibitory effect on Renca cell growth in vitro. Irradiation of Renca cells also causes an upregulation in H-2Kd class I MHC antigen detectable at 300 rad and more pronounced with 800 rad. By in vivo selective depletion of lymphocyte subsets, we demonstrate the involvement of Lyt-2+ and L3T4+ T cell subsets and AsGM1+ cells, including NK cells, in the antitumor effect mediated by tumor irradiation and IL-2 therapy. Immunohistochemistry studies, performed on lung sections, showed a significant infiltration of CD3+ T cells and macrophages in the tumor nodules following treatment with tumor irradiation and IL-2 therapy. Our studies indicate that the mechanism of interaction between tumor irradiation and immunotherapy may include radiation-induced alterations in the tumor growth and antigenicity which may enhance or trigger an anti-tumor response elicited by IL-2 and mediated by T cells, AsGM1+ cells, and macrophages.

  1. VEGF-ablation therapy reduces drug delivery and therapeutic response in ECM-dense tumors.

    PubMed

    Röhrig, F; Vorlová, S; Hoffmann, H; Wartenberg, M; Escorcia, F E; Keller, S; Tenspolde, M; Weigand, I; Gätzner, S; Manova, K; Penack, O; Scheinberg, D A; Rosenwald, A; Ergün, S; Granot, Z; Henke, E

    2017-01-05

    The inadequate transport of drugs into the tumor tissue caused by its abnormal vasculature is a major obstacle to the treatment of cancer. Anti-vascular endothelial growth factor (anti-VEGF) drugs can cause phenotypic alteration and maturation of the tumor's vasculature. However, whether this consistently improves delivery and subsequent response to therapy is still controversial. Clinical results indicate that not all patients benefit from antiangiogenic treatment, necessitating the development of criteria to predict the effect of these agents in individual tumors. We demonstrate that, in anti-VEGF-refractory murine tumors, vascular changes after VEGF ablation result in reduced delivery leading to therapeutic failure. In these tumors, the impaired response after anti-VEGF treatment is directly linked to strong deposition of fibrillar extracellular matrix (ECM) components and high expression of lysyl oxidases. The resulting condensed, highly crosslinked ECM impeded drug permeation, protecting tumor cells from exposure to small-molecule drugs. The reduced vascular density after anti-VEGF treatment further decreased delivery in these tumors, an effect not compensated by the improved vessel quality. Pharmacological inhibition of lysyl oxidases improved drug delivery in various tumor models and reversed the negative effect of VEGF ablation on drug delivery and therapeutic response in anti-VEGF-resistant tumors. In conclusion, the vascular changes after anti-VEGF therapy can have a context-dependent negative impact on overall therapeutic efficacy. A determining factor is the tumor ECM, which strongly influences the effect of anti-VEGF therapy. Our results reveal the prospect to revert a possible negative effect and to potentiate responsiveness to antiangiogenic therapy by concomitantly targeting ECM-modifying enzymes.

  2. Liquid biopsies for solid tumors: Understanding tumor heterogeneity and real time monitoring of early resistance to targeted therapies.

    PubMed

    Esposito, Angela; Criscitiello, Carmen; Locatelli, Marzia; Milano, Monica; Curigliano, Giuseppe

    2016-01-01

    In the era of personalized medicine detection of the molecular drivers of tumors and of specific DNA mutations predicting response or resistance to targeted agents has become routine practice in clinical oncology. The tumor biopsy depicts only a single timeframe from a single site, and might be inadequate to characterize a tumor because of intratumoral and intermetastatic heterogeneity. Circulating tumor DNA offers a "real time" tool for serially monitoring tumor genomes in a non-invasive manner providing accessible genetic biomarkers for cancer diagnosis, prognosis, and response to therapy. The liquid biopsy can be used for a variety of clinical and investigational applications. Future development will have to provide a cost effective analysis mainly identifying the genes known to be recurrently mutated in each tumor. Therefore, developing standardized methodologies for DNA analyses and validation in large prospective clinical studies is mandatory to implement the 'liquid biopsy' approach in the clinical management of cancer patients. In our review, we will focus on the clinical applications of liquid biopsies and on the recent findings in this field.

  3. Exercise Therapy in the Management of Solid Tumors

    PubMed Central

    Peppercorn, Jeffrey; Scott, Jessica M.; Battaglini, Claudio

    2013-01-01

    Opinion statement The benefits of exercise in patients with chronic disease have been studied extensively over the last half century. In contrast, investigation of the role of exercise following a diagnosis of cancer has received comparably less attention. In this article, we review the efficacy of exercise training in specific areas across the cancer survivorship continuum [i.e., pre-surgery, post-surgery during adjuvant therapy, following the completion of primary adjuvant therapy (survivorship), and palliation], with a view toward future research. The current evidence base provides strong but preliminary evidence that exercise training is a well-tolerated and safe adjunct therapy that can mitigate several common treatment-related side-effects among cancer patients with early disease both during and following adjuvant therapy although many questions remain unanswered. Preliminary evidence in this area supports that exercise therapy may be an important consideration in multidisciplinary management of patients following a cancer diagnosis. PMID:20645033

  4. Tumor Vascular Targeted Delivery of Polymer-conjugated Adenovirus Vector for Cancer Gene Therapy

    PubMed Central

    Yao, Xinglei; Yoshioka, Yasuo; Morishige, Tomohiro; Eto, Yusuke; Narimatsu, Shogo; Kawai, Yasuaki; Mizuguchi, Hiroyuki; Gao, Jian-Qing; Mukai, Yohei; Okada, Naoki; Nakagawa, Shinsaku

    2011-01-01

    Previously, we generated a cancer-specific gene therapy system using adenovirus vectors (Adv) conjugated to polyethylene glycol (Adv-PEG). Here, we developed a novel Adv that targets both tumor tissues and tumor vasculatures after systemic administration by conjugating CGKRK tumor vasculature homing peptide to the end of a 20-kDa PEG chain (Adv-PEGCGKRK). In a primary tumor model, systemic administration of Adv-PEGCGKRK resulted in ~500- and 100-fold higher transgene expression in tumor than that of unmodified Adv and Adv-PEG, respectively. In contrast, the transgene expression of Adv-PEGCGKRK in liver was about 400-fold lower than that of unmodified Adv, and was almost the same as that of Adv-PEG. We also demonstrated that transgene expression with Adv-PEGCGKRK was enhanced in tumor vessels. Systemic administration of Adv-PEGCGKRK expressing the herpes simplex virus thymidine kinase (HSVtk) gene (Adv-PEGCGKRK-HSVtk) showed superior antitumor effects against primary tumors and metastases with negligible side effects by both direct cytotoxic effects and inhibition of tumor angiogenesis. These results indicate that Adv-PEGCGKRK has potential as a prototype Adv with suitable efficacy and safety for systemic cancer gene therapy against both primary tumors and metastases. PMID:21673661

  5. Relationships between tumor size and curablity for uniformly targeted therapy with beta-emitting radionuclides

    SciTech Connect

    O`Donoghue, J.A.; Bardies, M.; Wheldon, T.E. |

    1995-10-01

    Targeted radionuclide therapy is a new form of radiotherapy that differs in some important respects from external beam irradiation. One of the most important differences is due to the finite range of ionizing beta particles emitted as a result of radionuclide disintegration. The effects of particle range have important implications for the curability of tumors. We used a mathematical model to examine tumor curability and its relationship to tumor size for 22 beta-emitting radionuclides that may have therapeutic potential. The model assumed a uniform distribution of radionuclide throughout. For targeted radionuclide therapy, the relationship between tumor curability and tumor size is different from that for conventional external beam radiotherapy. With targeted radionuclides, there is an optimal tumor size for cure. Tumors smaller than the optimal size are less vulnerable to irradiation from radionuclides because a substantial proportion of the disintegration energy escapes and is deposited outside the tumor volume. We found an optimal tumor size for radiocurability by each of the 22 radionuclides considered. Optimal cure diameters range from less than 1 mm for short-range emitters such as {sup 199}Au and {sup 33}P to several centimeters for long-range emitters such as {sup 90}Y and {sup 188}Re. The energy emitted per disintegration may be used to predict optimal cure size for uniform distributions of radionuclide. 17 refs., 8 figs., 3 tabs.

  6. Hyaluronic acid ion-pairing nanoparticles for targeted tumor therapy.

    PubMed

    Li, Wenhao; Yi, Xiaoli; Liu, Xing; Zhang, Zhirong; Fu, Yao; Gong, Tao

    2016-03-10

    Hyaluronic acid (HA)-based doxorubicin (DOX) nanoparticles (HA-NPs) were fabricated via ion-pairing between positively charged DOX and negatively charged HA, which displayed near-spherical shapes with an average size distribution of 180.2nm (PDI=0.184). Next, HA-NPs were encapsulated in liposomal carriers to afford HA-based DOX liposomes (HA-LPs), which also showed near-spherical morphology with an average size of 130.5nm (PDI=0.201). HA-NPs and HA-LPs displayed desirable sustained-release profiles compared to free DOX, and moreover, HA-LPs were proven to prevent premature release of DOX from HA-NPs. Cell based studies demonstrated HA-NPs and HA-LPs were selectively taken up by CD44(+) tumor cells, and DOX was released intracellularly to target the cell nuclei. Both HA-NPs and HA-LPs showed comparable levels of penetration efficiency in tumor spheroids. In vivo studies revealed that HA-NPs and HA-LPs significantly prolonged the blood circulation time of DOX, decreased accumulation in the normal tissues and enriched drugs into the tumors. Furthermore, HA-NPs and HA-LPs greatly enhanced therapeutic efficacy of DOX in tumor-bearing mice and minimized systemic toxicity against vital organs. In sum, HA-NPs and HA-LPs represent promising nanocarriers for CD44(+) tumor-targeted delivery.

  7. Targeted Cell Immobilization by Ultrasound Microbeam

    PubMed Central

    Lee, Jungwoo; Lee, Changyang; Kim, Hyung Ham; Jakob, Anette; Lemor, Robert; Teh, Shia-Yen; Lee, Abraham; Shung, K. Kirk

    2011-01-01

    Various techniques exerting mechanical stress on cells have been developed to investigate cellular responses to externally controlled stimuli. Fundamental mechanotransduction processes, how applied physical forces are converted into biochemical signals, have often been examined by transmitting such forces through cells and probing its pathway at cellular levels. In fact, many cellular biomechanics studies have been performed by trapping (or immobilizing) individual cells, either attached to solid substrates or suspended in liquid media. In that context, we demonstrated two-dimensional acoustic trapping, where a lipid droplet of 125 μm in diameter was directed transversely towards the focus (or the trap center) similar to that of optical tweezers. Under the influence of restoring forces created by a 30 MHz focused ultrasound beam, the trapped droplet behaved as if tethered to the focus by a linear spring. In order to apply this method to cellular manipulation in the Mie regime (cell diameter > wavelength), the availability of sound beams with its beamwidth approaching cell size is crucial. This can only be achieved at a frequency higher than 100 MHz. We define ultrasound beams in the frequency range from 100 MHz to a few GHz as ultrasound microbeams because the lateral beamwidth at the focus would be in the micron range (reviewer #1). Hence a zinc oxide (ZnO) transducer that was designed and fabricated to transmit a 200 MHz focused sound beam was employed to immobilize a 10 μm human leukemia cell (K-562) within the trap. The cell was laterally displaced with respect to the trap center by mechanically translating the transducer over the focal plane. Both lateral displacement and position trajectory of the trapped cell were probed in a two-dimensional space, indicating that the retracting motion of these cells was similar to that of the lipid droplets at 30 MHz. The potential of this tool for studying cellular adhesion between white blood cells and endothelial cells

  8. Human natural killer cells: news in the therapy of solid tumors and high-risk leukemias.

    PubMed

    Pietra, Gabriella; Vitale, Chiara; Pende, Daniela; Bertaina, Alice; Moretta, Francesca; Falco, Michela; Vacca, Paola; Montaldo, Elisa; Cantoni, Claudia; Mingari, Maria Cristina; Moretta, Alessandro; Locatelli, Franco; Moretta, Lorenzo

    2016-04-01

    It is well established that natural killer (NK) cells play an important role in the immunity against cancer, while the involvement of other recently identified, NK-related innate lymphoid cells is still poorly defined. In the haploidentical hematopoietic stem cell transplantation for the therapy of high-risk leukemias, NK cells have been shown to exert a key role in killing leukemic blasts residual after conditioning. While the clinical results in the cure of leukemias are excellent, the exploitation of NK cells in the therapy of solid tumors is still limited and unsatisfactory. In solid tumors, NK cell function may be inhibited via different mechanisms, occurring primarily at the tumor site. The cellular interactions in the tumor microenvironment involve tumor cells, stromal cells and resident or recruited leukocytes and may favor tumor evasion from the host's defenses. In this context, a number of cytokines, growth factors and enzymes synthesized by tumor cells, stromal cells, suppressive/regulatory myeloid and lymphoid cells may substantially impair the function of different tumor-reactive effector cells, including NK cells. The identification and characterization of such mechanisms may offer clues for the development of new immunotherapeutic strategies to restore effective anti-tumor responses. In order to harness NK cell-based immunotherapies, several approaches have been proposed, including reinforcement of NK cell cytotoxicity by means of specific cytokines, antibodies or drugs. These new tools may improve NK cell function and/or increase tumor susceptibility to NK-mediated killing. Hence, the integration of NK-based immunotherapies with conventional anti-tumor therapies may increase chances of successful cancer treatment.

  9. Improvement of tumor response to photodynamic therapy by manipulation of tumor oxygenation in an in-vivo model system

    NASA Astrophysics Data System (ADS)

    Chen, Qun; Huang, Zheng; Chen, Hua; Shapiro, Howard; Beckers, Jill; Hetzel, Fred W.

    2002-09-01

    Photodynamic therapy (PDT) requires molecular oxygen during light irradiation in order to generate reactive oxygen species. Tumor hypoxia, either pre-existing or induced by PDT, can severely hamper the effectiveness of PDT treatment. Lowering the light irradiation dose rate or fractionating a light dose may improve cell kill of PDT induced hypoxic cells, but will have no effect on pre-existing hypoxic cells. In this study, hyper-oxygenation technique was used during PDT to overcome hypoxia. C3H mice with transplanted mammary carcinoma tumors were injected with 12.5 mg/kg Photofrin and irradiated with 630 nm laser light 24 hours later. Tumor oxygenation was manipulated by subjecting the animals to 3 atp hyperbaric oxygen or normobaric oxygen during PDT light irradiation. The results show a significant improvement in tumor response when PDT was delivered during hyper-oxygenation. With hyper-oxygenation, up to 80% of treated tumors showed no re-growth after 60 days. In comparison, only 20% of tumors treated while animals breathed room air did not re-grow. To explore the effect of hyper-oxygenation on tumor oxygenation, tumor pO2 was measured with microelectrodes positioned in pre-existing hypoxic regions before and during the PDT. The results show that hyper-oxygenation may oxygenate pre-existing hypoxic cells and compensate for oxygen depletion induced by PDT light irradiation. In conclusion, hyper-oxygenation may provide effective ways to improve PDT treatment efficiency by oxygenating both pre-existing and treatment induced cell hypoxia.

  10. Dual antibody therapy to harness the innate anti-tumor immune response to enhance antibody targeting of tumors.

    PubMed

    Chester, Cariad; Marabelle, Aurelien; Houot, Roch; Kohrt, Holbrook E

    2015-04-01

    Cancer immunotherapy is a rapidly evolving field that offers a novel paradigm for cancer treatment: therapies focus on enhancing the immune system's innate and adaptive anti-tumor response. Early immunotherapeutics have achieved impressive clinical outcomes and monoclonal antibodies are now integral to therapeutic strategies in a variety of cancers. However, only recently have antibodies targeting innate immune cells entered clinical development. Innate immune effector cells play important roles in generating and maintaining antitumor immunity. Antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) are important innate immune mechanisms for tumor eradication. These cytolytic processes are initiated by the detection of a tumor-targeting antibody and can be augmented by activating co-stimulatory pathways or blocking inhibitory signals on innate immune cells. The combination of FDA-approved monoclonal antibodies with innate effector-targeting antibodies has demonstrated potent preclinical therapeutic synergy and early-phase combinatorial clinical trials are ongoing.

  11. Monitoring brain tumor response to therapy using MRI segmentation.

    PubMed

    Vaidyanathan, M; Clarke, L P; Hall, L O; Heidtman, C; Velthuizen, R; Gosche, K; Phuphanich, S; Wagner, H; Greenberg, H; Silbiger, M L

    1997-01-01

    The performance evaluation of a semi-supervised fuzzy c-means (SFCM) clustering method for monitoring brain tumor volume changes during the course of routine clinical radiation-therapeutic and chemo-therapeutic regimens is presented. The tumor volume determined using the SFCM method was compared with the volume estimates obtained using three other methods: (a) a k nearest neighbor (kNN) classifier, b) a grey level thresholding and seed growing (ISG-SG) method and c) a manual pixel labeling (GT) method for ground truth estimation. The SFCM and kNN methods are applied to the multispectral, contrast enhanced T1, proton density, and T2 weighted, magnetic resonance images (MRI) whereas the ISG-SG and GT methods are applied only to the contrast enhanced T1 weighted image. Estimations of tumor volume were made on eight patient cases with follow-up MRI scans performed over a 32 week interval during treatment. The tumor cases studied include one meningioma, two brain metastases and five gliomas. Comparisons with manually labeled ground truth estimations showed that there is a limited agreement between the segmentation methods for absolute tumor volume measurements when using images of patients after treatment. The average intraobserver reproducibility for the SFCM, kNN and ISG-SG methods was found to be 5.8%, 6.6% and 8.9%, respectively. The average of the interobserver reproducibility of these methods was found to be 5.5%, 6.5% and 11.4%, respectively. For the measurement of relative change of tumor volume as required for the response assessment, the multi-spectral methods kNN and SFCM are therefore preferred over the seedgrowing method.

  12. Magnetic nanoparticles: an emerging technology for malignant brain tumor imaging and therapy

    PubMed Central

    Wankhede, Mamta; Bouras, Alexandros; Kaluzova, Milota; Hadjipanayis, Costas G

    2012-01-01

    Magnetic nanoparticles (MNPs) represent a promising nanomaterial for the targeted therapy and imaging of malignant brain tumors. Conjugation of peptides or antibodies to the surface of MNPs allows direct targeting of the tumor cell surface and potential disruption of active signaling pathways present in tumor cells. Delivery of nanoparticles to malignant brain tumors represents a formidable challenge due to the presence of the blood–brain barrier and infiltrating cancer cells in the normal brain. Newer strategies permit better delivery of MNPs systemically and by direct convection-enhanced delivery to the brain. Completion of a human clinical trial involving direct injection of MNPs into recurrent malignant brain tumors for thermotherapy has established their feasibility, safety and efficacy in patients. Future translational studies are in progress to understand the promising impact of MNPs in the treatment of malignant brain tumors. PMID:22390560

  13. Magnetic nanoparticles: an emerging technology for malignant brain tumor imaging and therapy.

    PubMed

    Wankhede, Mamta; Bouras, Alexandros; Kaluzova, Milota; Hadjipanayis, Costas G

    2012-03-01

    Magnetic nanoparticles (MNPs) represent a promising nanomaterial for the targeted therapy and imaging of malignant brain tumors. Conjugation of peptides or antibodies to the surface of MNPs allows direct targeting of the tumor cell surface and potential disruption of active signaling pathways present in tumor cells. Delivery of nanoparticles to malignant brain tumors represents a formidable challenge due to the presence of the blood-brain barrier and infiltrating cancer cells in the normal brain. Newer strategies permit better delivery of MNPs systemically and by direct convection-enhanced delivery to the brain. Completion of a human clinical trial involving direct injection of MNPs into recurrent malignant brain tumors for thermotherapy has established their feasibility, safety and efficacy in patients. Future translational studies are in progress to understand the promising impact of MNPs in the treatment of malignant brain tumors.

  14. Targeting Notch, a key pathway for ovarian cancer stem cells, sensitizes tumors to platinum therapy.

    PubMed

    McAuliffe, Shannon M; Morgan, Stefanie L; Wyant, Gregory A; Tran, Lieu T; Muto, Katherine W; Chen, Yu Sarah; Chin, Kenneth T; Partridge, Justin C; Poole, Barish B; Cheng, Kuang-Hung; Daggett, John; Cullen, Kristen; Kantoff, Emily; Hasselbatt, Kathleen; Berkowitz, Julia; Muto, Michael G; Berkowitz, Ross S; Aster, Jon C; Matulonis, Ursula A; Dinulescu, Daniela M

    2012-10-23

    Chemoresistance to platinum therapy is a major obstacle that needs to be overcome in the treatment of ovarian cancer patients. The high rates and patterns of therapeutic failure seen in patients are consistent with a steady accumulation of drug-resistant cancer stem cells (CSCs). This study demonstrates that the Notch signaling pathway and Notch3 in particular are critical for the regulation of CSCs and tumor resistance to platinum. We show that Notch3 overexpression in tumor cells results in expansion of CSCs and increased platinum chemoresistance. In contrast, γ-secretase inhibitor (GSI), a Notch pathway inhibitor, depletes CSCs and increases tumor sensitivity to platinum. Similarly, a Notch3 siRNA knockdown increases the response to platinum therapy, further demonstrating that modulation of tumor chemosensitivity by GSI is Notch specific. Most importantly, the cisplatin/GSI combination is the only treatment that effectively eliminates both CSCs and the bulk of tumor cells, indicating that a dual combination targeting both populations is needed for tumor eradication. In addition, we found that the cisplatin/GSI combination therapy has a synergistic cytotoxic effect in Notch-dependent tumor cells by enhancing the DNA-damage response, G(2)/M cell-cycle arrest, and apoptosis. Based on these results, we conclude that targeting the Notch pathway could significantly increase tumor sensitivity to platinum therapy. Our study suggests important clinical applications for targeting Notch as part of novel treatment strategies upon diagnosis of ovarian cancer and at recurrence. Both platinum-resistant and platinum-sensitive relapses may benefit from such an approach as clinical data suggest that all relapses after platinum therapy are increasingly platinum resistant.

  15. Prediction of Tumor Recurrence and Therapy Monitoring Using Ultrasound-Guided Photoacoustic Imaging

    PubMed Central

    Mallidi, Srivalleesha; Watanabe, Kohei; Timerman, Dmitriy; Schoenfeld, David; Hasan, Tayyaba

    2015-01-01

    Selection and design of individualized treatments remains a key goal in cancer therapeutics; prediction of response and tumor recurrence following a given therapy provides a basis for subsequent personalized treatment design. We demonstrate an approach towards this goal with the example of photodynamic therapy (PDT) as the treatment modality and photoacoustic imaging (PAI) as a non-invasive, response and disease recurrence monitor in a murine model of glioblastoma (GBM). PDT is a photochemistry-based, clinically-used technique that consumes oxygen to generate cytotoxic species, thus causing changes in blood oxygen saturation (StO2). We hypothesize that this change in StO2 can be a surrogate marker for predicting treatment efficacy and tumor recurrence. PAI is a technique that can provide a 3D atlas of tumor StO2 by measuring oxygenated and deoxygenated hemoglobin. We demonstrate that tumors responding to PDT undergo approximately 85% change in StO2 by 24-hrs post-therapy while there is no significant change in StO2 values in the non-responding group. Furthermore, the 3D tumor StO2 maps predicted whether a tumor was likely to regrow at a later time point post-therapy. Information on the likelihood of tumor regrowth that normally would have been available only upon actual regrowth (10-30 days post treatment) in a xenograft tumor model, was available within 24-hrs of treatment using PAI, thus making early intervention a possibility. Given the advances and push towards availability of PAI in the clinical settings, the results of this study encourage applicability of PAI as an important step to guide and monitor therapies (e.g. PDT, radiation, anti-angiogenic) involving a change in StO2. PMID:25553116

  16. Image-Based Monitoring of Magnetic Resonance-Guided Thermoablative Therapies for Liver Tumors

    SciTech Connect

    Rempp, Hansjoerg Clasen, Stephan; Pereira, Philippe L.

    2012-12-15

    Minimally invasive treatment options for liver tumor therapy have been increasingly used during the last decade because their benefit has been proven for primary and inoperable secondary liver tumors. Among these, radiofrequency ablation has gained widespread consideration. Optimal image-guidance offers precise anatomical information, helps to position interventional devices, and allows for differentiation between already-treated and remaining tumor tissue. Patient safety and complete ablation of the entire tumor are the overriding objectives of tumor ablation. These may be achieved most elegantly with magnetic resonance (MR)-guided therapy, where monitoring can be performed based on precise soft-tissue imaging and additional components, such as diffusion-weighted imaging and temperature mapping. New MR scanner types and newly developed sequence techniques have enabled MR-guided intervention to move beyond the experimental phase. This article reviews the current role of MR imaging in guiding radiofrequency ablation. Signal characteristics of primary and secondary liver tumors are identified, and signal alteration during therapy is described. Diffusion-weighted imaging (DWI) and temperature mapping as special components of MR therapy monitoring are introduced. Practical information concerning coils, sequence selection, and parameters, as well as sequence gating, is given. In addition, sources of artifacts are identified and techniques to decrease them are introduced, and the characteristic signs of residual tumor in T1-, T2-, and DWI are described. We hope to enable the reader to choose MR sequences that allow optimal therapy monitoring depending on the initial signal characteristics of the tumor as well as its size and location in the liver.

  17. Desmoid tumors: local control and patterns of relapse following radiation therapy

    SciTech Connect

    Leibel, S.A.; Wara, W.M.; Hill, D.R.; Bovill, E.G. Jr.; De Lorimier, A.A.; Beckstead, J.H.; Phillips, T.L.

    1983-08-01

    Desmoid tumors are benign neoplasms, arising from musculoaponeurotic tissues, which tend to be locally infiltrative, resulting in a high rate of local recurrence following surgical resection. Nineteen patients with desmoid tumors underwent radiation therapy at the University of California, San Francisco, between 1970 and 1980. Fifteen patients were referred with local recurrence following one or more surgical resections. Three patients were referred for initial radiation therapy with unresectable tumors, and one patient received planned postoperative irradiation following subtotal tumor resection. At the time of treatment, 8 patients had nonresectable disease measuring greater than 10 cm. The majority of patients were treated to a tumor dose of 50 to 55 Gy at 1.6 to 1.8 Gy per fraction. With a median follow-up of 8 years, 13 patients remained free of recurrent disease following radiation therapy. Local control was not related to the amount of disease present at the time of treatment. Of the 6 patients who developed recurrent disease, only 1 patient had a true in-field recurrence. Four patients recurred at the margin of the radiation field 1 to 5 years following therapy. Moderate dose radiation therapy to desmoid tumors can result in lasting local control when surgical resection is not possible. Post operative radiation can improve the rate of local control for patients with a high risk of recurrence. As desmoid tumors tend to be locally infiltrative, fields must be very generous to prevent marginal recurrence. Systemic chemotherapy offers an alternative to ablative surgery in the event of local failure following radiation therapy.

  18. CAR-T cell therapy in gastrointestinal tumors and hepatic carcinoma: From bench to bedside.

    PubMed

    Zhang, Qi; Zhang, Zimu; Peng, Meiyu; Fu, Shuyu; Xue, Zhenyi; Zhang, Rongxin

    2016-01-01

    The chimeric antigen receptor (CAR) is a genetically engineered receptor that combines a scFv domain, which specifically recognizes the tumor-specific antigen, with T cell activation domains. CAR-T cell therapies have demonstrated tremendous efficacy against hematologic malignancies in many clinical trials. Recent studies have extended these efforts to the treatment of solid tumors. However, the outcomes of CAR-T cell therapy for solid tumors are not as remarkable as the outcomes have been for hematologic malignancies. A series of hurdles has arisen with respect to CAR-T cell-based immunotherapy, which needs to be overcome to target solid tumors. The major challenge for CAR-T cell therapy in solid tumors is the selection of the appropriate specific antigen to demarcate the tumor from normal tissue. In this review, we discuss the application of CAR-T cells to gastrointestinal and hepatic carcinomas in preclinical and clinical research. Furthermore, we analyze the usefulness of several specific markers in the study of gastrointestinal tumors and hepatic carcinoma.

  19. CAR-T cell therapy in gastrointestinal tumors and hepatic carcinoma: From bench to bedside

    PubMed Central

    Zhang, Qi; Zhang, Zimu; Peng, Meiyu; Fu, Shuyu; Xue, Zhenyi; Zhang, Rongxin

    2016-01-01

    ABSTRACT The chimeric antigen receptor (CAR) is a genetically engineered receptor that combines a scFv domain, which specifically recognizes the tumor-specific antigen, with T cell activation domains. CAR-T cell therapies have demonstrated tremendous efficacy against hematologic malignancies in many clinical trials. Recent studies have extended these efforts to the treatment of solid tumors. However, the outcomes of CAR-T cell therapy for solid tumors are not as remarkable as the outcomes have been for hematologic malignancies. A series of hurdles has arisen with respect to CAR-T cell-based immunotherapy, which needs to be overcome to target solid tumors. The major challenge for CAR-T cell therapy in solid tumors is the selection of the appropriate specific antigen to demarcate the tumor from normal tissue. In this review, we discuss the application of CAR-T cells to gastrointestinal and hepatic carcinomas in preclinical and clinical research. Furthermore, we analyze the usefulness of several specific markers in the study of gastrointestinal tumors and hepatic carcinoma. PMID:28123893

  20. Improving cancer therapies by targeting the physical and chemical hallmarks of the tumor microenvironment.

    PubMed

    Ivey, Jill W; Bonakdar, Mohammad; Kanitkar, Akanksha; Davalos, Rafael V; Verbridge, Scott S

    2016-09-28

    Tumors are highly heterogeneous at the patient, tissue, cellular, and molecular levels. This multi-scale heterogeneity poses significant challenges for effective therapies, which ideally must not only distinguish between tumorous and healthy tissue, but also fully address the wide variety of tumorous sub-clones. Commonly used therapies either leverage a biological phenotype of cancer cells (e.g. high rate of proliferation) or indiscriminately kill all the cells present in a targeted volume. Tumor microenvironment (TME) targeting represents a promising therapeutic direction, because a number of TME hallmarks are conserved across different tumor types, despite the underlying genetic heterogeneity. Historically, TME targeting has largely focused on the cells that support tumor growth (e.g. vascular endothelial cells). However, by viewing the intrinsic physical and chemical alterations in the TME as additional therapeutic opportunities rather than barriers, a new class of TME-inspired treatments has great promise to complement or replace existing therapeutic strategies. In this review we summarize the physical and chemical hallmarks of the TME, and discuss how these tumor characteristics either currently are, or may ultimately be targeted to improve cancer therapies.

  1. Toward Brain Tumor Gene Therapy Using Multipotent Mesenchymal Stromal Cell Vectors

    PubMed Central

    Bexell, Daniel; Scheding, Stefan; Bengzon, Johan

    2010-01-01

    Gene therapy of solid cancers has been severely restricted by the limited distribution of vectors within tumors. However, cellular vectors have emerged as an effective migratory system for gene delivery to invasive cancers. Implanted and injected multipotent mesenchymal stromal cells (MSCs) have shown tropism for several types of primary tumors and metastases. This capacity of MSCs forms the basis for their use as a gene vector system in neoplasms. Here, we review the tumor-directed migratory potential of MSCs, mechanisms of the migration, and the choice of therapeutic transgenes, with a focus on malignant gliomas as a model system for invasive and highly vascularized tumors. We examine recent findings demonstrating that MSCs share many characteristics with pericytes and that implanted MSCs localize primarily to perivascular niches within tumors, which might have therapeutic implications. The use of MSC vectors in cancer gene therapy raises concerns, however, including a possible MSC contribution to tumor stroma and vasculature, MSC-mediated antitumor immune suppression, and the potential malignant transformation of cultured MSCs. Nonetheless, we highlight the novel prospects of MSC-based tumor therapy, which appears to be a promising approach. PMID:20407426

  2. Tumor infiltrating lymphocyte therapy for ovarian cancer and renal cell carcinoma

    PubMed Central

    Andersen, Rikke; Donia, Marco; Westergaard, Marie Christine Wulff; Pedersen, Magnus; Hansen, Morten; Svane, Inge Marie

    2015-01-01

    Personalized cancer immunotherapy based on infusion of T cells holds the promise to specifically target a patient’s individual tumor. Accumulating evidence indicates that the T cells mediating these tumor regressions after cancer immunotherapies may primarily target patient-specific mutations expressed by the patients’ tumors and that the presence of these “neo-antigen” specific T-cells may be related to a high number of mutations in the tumor. In melanoma, treatment with autologous tumor-infiltrating lymphocytes (TILs) can mediate durable complete responses. Previous trials investigating TIL therapy in solid tumors other than melanoma have shown limited success, however none of these early trials used current preparative chemotherapy regimens, and the methods for in vitro lymphocyte expansion have changed considerably. New advances and understandings in T cell based immunotherapies have stimulated the interest in developing this approach for other indications. Here, we summarize the early clinical data in the field of adoptive cell transfer therapy (ACT) using tumor-infiltrating lymphocytes for patients with renal cell carcinoma (RCC) and ovarian cancer (OC). In addition we describe the major advances in the characterization and application of TIL therapy for patients with RCC and OC. PMID:26308285

  3. Microbeam Characterization of Corning Archeological Reference Glasses: New Additions to the Smithsonian Microbeam Standard Collection

    PubMed Central

    Vicenzi, Edward P.; Eggins, Stephen; Logan, Amelia; Wysoczanski, Richard

    2002-01-01

    An initial study of the minor element, trace element, and impurities in Corning archeological references glasses have been performed using three microbeam techniques: electron probe microanalysis (EPMA), laser ablation ICP-mass spectrometry (LA ICP-MS), and secondary ion mass spectrometry (SIMS). The EPMA results suggest a significant level of heterogeneity for a number of metals. Conversely, higher precision and a larger sampling volume analysis by LA ICP-MS indicates a high degree of chemical uniformity within all glasses, typically <2 % relative (1 σ). SIMS data reveal that small but measurable quantities of volatile impurities are present in the glasses, including H at roughly the 0.0001 mass fraction level. These glasses show promise for use as secondary standards for minor and trace element analyses of insulating materials such as synthetic ceramics, minerals, and silicate glasses. PMID:27446764

  4. Microbeam Characterization of Corning Archeological Reference Glasses: New Additions to the Smithsonian Microbeam Standard Collection.

    PubMed

    Vicenzi, Edward P; Eggins, Stephen; Logan, Amelia; Wysoczanski, Richard

    2002-01-01

    An initial study of the minor element, trace element, and impurities in Corning archeological references glasses have been performed using three microbeam techniques: electron probe microanalysis (EPMA), laser ablation ICP-mass spectrometry (LA ICP-MS), and secondary ion mass spectrometry (SIMS). The EPMA results suggest a significant level of heterogeneity for a number of metals. Conversely, higher precision and a larger sampling volume analysis by LA ICP-MS indicates a high degree of chemical uniformity within all glasses, typically <2 % relative (1 σ). SIMS data reveal that small but measurable quantities of volatile impurities are present in the glasses, including H at roughly the 0.0001 mass fraction level. These glasses show promise for use as secondary standards for minor and trace element analyses of insulating materials such as synthetic ceramics, minerals, and silicate glasses.

  5. Giant cell tumor: rapid recurrence after cessation of long-term denosumab therapy.

    PubMed

    Matcuk, George R; Patel, Dakshesh B; Schein, Aaron J; White, Eric A; Menendez, Lawrence R

    2015-07-01

    We report a case of rapid recurrence of a giant cell tumor (GCT) of the distal radius in a 24-year-old woman following the cessation of long-term denosumab therapy. GCT of bone is a histologically benign tumor with multinucleated giant cells on a background of mononuclear giant cells usually presenting as a well-defined epi-metaphyseal lytic lesion without sclerotic margins. Denosumab, a monoclonal antibody to the receptor activator of nuclear factor kappa-B ligand (RANKL), has proven to be an effective neoadjuvant treatment for GCT. The tumor in this case had demonstrated a good response with sustained control for over 2 years while on denosumab therapy. However, within 2 months of cessation of therapy, the tumor demonstrated rapid recurrence and progression with growth, osteolysis, and increased soft tissue component. Despite reinitiating denosumab therapy, there was progressive tumor growth and destruction, ultimately necessitating below-the-elbow amputation. This case illustrates the need for maintenance of denosumab therapy for GCT of bone or definitive surgical treatment prior to its cessation.

  6. Microwave pumped high-efficient thermoacoustic tumor therapy with single wall carbon nanotubes.

    PubMed

    Wen, Liewei; Ding, Wenzheng; Yang, Sihua; Xing, Da

    2016-01-01

    The ultra-short pulse microwave could excite to the strong thermoacoustic (TA) shock wave and deeply penetrate in the biological tissues. Based on this, we developed a novel deep-seated tumor therapy modality with mitochondria-targeting single wall carbon nanotubes (SWNTs) as microwave absorbing agents, which act efficiently to convert ultra-short microwave energy into TA shock wave and selectively destroy the targeted mitochondria, thereby inducing apoptosis in cancer cells. After the treatment of SWNTs (40 μg/mL) and ultra-short microwave (40 Hz, 1 min), 77.5% of cancer cells were killed and the vast majority were caused by apoptosis that initiates from mitochondrial damage. The orthotopic liver cancer mice were established as deep-seated tumor model to investigate the anti-tumor effect of mitochondria-targeting TA therapy. The results suggested that TA therapy could effectively inhibit the tumor growth without any observable side effects, while it was difficult to achieve with photothermal or photoacoustic therapy. These discoveries implied the potential application of TA therapy in deep-seated tumor models and should be further tested for development into a promising therapeutic modality for cancer treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Photodynamic therapy stimulates anti-tumor immunity in a murine model

    NASA Astrophysics Data System (ADS)

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

    2007-02-01

    Cancer is a leading cause of death among modern peoples largely due to metastatic disease. The ideal cancer treatment should target both the primary tumor and the metastases with the minimal toxicity. This is best accomplished by educating the body's immune system to recognize the tumor as foreign so that after the primary tumor is destroyed, distant metastases will also be eradicated. Photodynamic therapy (PDT) involves the IV administration of photosensitizers followed by illumination of the primary tumor with red light producing reactive oxygen species that cause vascular shutdown and tumor cell apoptosis. Anti-tumor immunity is stimulated after PDT due to the acute inflammatory response, priming of the 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. We here report on PDT of mice bearing tumors that either do or do not express an established TAA. We utilized a BALB/c colon adenocarcinoma cell line termed CT26.CL25 retrovirally transduced to stably express β-galactosidase ( β-gal, a bacterial protein), and its non-β-gal expressing wild-type counterpart termed CT26 WT, as well as the control cell line consisting of CT26 transduced with the empty retroviral vector termed CT26-neo. All cells expressed class I MHC restriction element H-2Ld syngenic to BALB/c mice. Vascular PDT with a regimen of 1mg/kg BPD injected IV, and 120 J/cm2 of 690-nm laser light after 15 minutes successfully cured 100% of CT26.CL25 tumors but 0% of CT26-neo tumors and 0% of CT26 WT tumors. After 90 days tumor free interval the CT26.CL25 cured mice were rechallenged with CT26.CL25 tumor cells and 96% rejected the rechallenge while the CT26.CL25 cured mice did not reject a CT26 WT tumor cell challenge. Experiments with mice bearing two CT26.CL25 tumors (one

  8. A hybrid actuated microrobot using an electromagnetic field and flagellated bacteria for tumor-targeting therapy.

    PubMed

    Li, Donghai; Choi, Hyunchul; Cho, Sunghoon; Jeong, Semi; Jin, Zhen; Lee, Cheong; Ko, Seong Young; Park, Jong-Oh; Park, Sukho

    2015-08-01

    In this paper, we propose a new concept for a hybrid actuated microrobot for tumor-targeting therapy. For drug delivery in tumor therapy, various electromagnetic actuated microrobot systems have been studied. In addition, bacteria-based microrobot (so-called bacteriobot), which use tumor targeting and the therapeutic function of the bacteria, has also been proposed for solid tumor therapy. Compared with bacteriobot, electromagnetic actuated microrobot has larger driving force and locomotive controllability due to their position recognition and magnetic field control. However, because electromagnetic actuated microrobot does not have self-tumor targeting, they need to be controlled by an external magnetic field. In contrast, the bacteriobot uses tumor targeting and the bacteria's own motility, and can exhibit self-targeting performance at solid tumors. However, because the propulsion forces of the bacteria are too small, it is very difficult for bacteriobot to track a tumor in a vessel with a large bloodstream. Therefore, we propose a hybrid actuated microrobot combined with electromagnetic actuation in large blood vessels with a macro range and bacterial actuation in small vessels with a micro range. In addition, the proposed microrobot consists of biodegradable and biocompatible microbeads in which the drugs and magnetic particles can be encapsulated; the bacteria can be attached to the surface of the microbeads and propel the microrobot. We carried out macro-manipulation of the hybrid actuated microrobot along a desired path through electromagnetic field control and the micro-manipulation of the hybrid actuated microrobot toward a chemical attractant through the chemotaxis of the bacteria. For the validation of the hybrid actuation of the microrobot, we fabricated a hydrogel microfluidic channel that can generate a chemical gradient. Finally, we evaluated the motility performance of the hybrid actuated microrobot in the hydrogel microfluidic channel. We expect

  9. Tumor Blood Flow Differs between Mouse Strains: Consequences for Vasoresponse to Photodynamic Therapy

    PubMed Central

    Mesquita, Rickson C.; Han, Sung Wan; Miller, Joann; Schenkel, Steven S.; Pole, Andrew; Esipova, Tatiana V.; Vinogradov, Sergei A.; Putt, Mary E.; Yodh, Arjun G.; Busch, Theresa M.

    2012-01-01

    Fluctuations in tumor blood flow are common and attributed to factors such as vasomotion or local vascular structure, yet, because vessel structure and physiology are host-derived, animal strain of tumor propagation may further determine blood flow characteristics. In the present report, baseline and stress-altered tumor hemodynamics as a function of murine strain were studied using radiation-induced fibrosacomas (RIF) grown in C3H or nude mice. Fluctuations in tumor blood flow during one hour of baseline monitoring or during vascular stress induced by photodynamic therapy (PDT) were measured by diffuse correlation spectroscopy. Baseline monitoring revealed fluctuating tumor blood flow highly correlated with heart rate and with similar median periods (i.e., ∼9 and 14 min in C3H and nudes, respectively). However, tumor blood flow in C3H animals was more sensitive to physiologic or stress-induced perturbations. Specifically, PDT-induced vascular insults produced greater decreases in blood flow in the tumors of C3H versus nude mice; similarly, during baseline monitoring, fluctuations in blood flow were more regular and more prevalent within the tumors of C3H mice versus nude mice; finally, the vasoconstrictor L-NNA reduced tumor blood flow in C3H mice but did not affect tumor blood flow in nudes. Underlying differences in vascular structure, such as smaller tumor blood vessels in C3H versus nude animals, may contribute to strain-dependent variation in vascular function. These data thus identify clear effects of mouse strain on tumor hemodynamics with consequences to PDT and potentially other vascular-mediated therapies. PMID:22624014

  10. Tumor blood flow differs between mouse strains: consequences for vasoresponse to photodynamic therapy.

    PubMed

    Mesquita, Rickson C; Han, Sung Wan; Miller, Joann; Schenkel, Steven S; Pole, Andrew; Esipova, Tatiana V; Vinogradov, Sergei A; Putt, Mary E; Yodh, Arjun G; Busch, Theresa M

    2012-01-01

    Fluctuations in tumor blood flow are common and attributed to factors such as vasomotion or local vascular structure, yet, because vessel structure and physiology are host-derived, animal strain of tumor propagation may further determine blood flow characteristics. In the present report, baseline and stress-altered tumor hemodynamics as a function of murine strain were studied using radiation-induced fibrosacomas (RIF) grown in C3H or nude mice. Fluctuations in tumor blood flow during one hour of baseline monitoring or during vascular stress induced by photodynamic therapy (PDT) were measured by diffuse correlation spectroscopy. Baseline monitoring revealed fluctuating tumor blood flow highly correlated with heart rate and with similar median periods (i.e., ∼9 and 14 min in C3H and nudes, respectively). However, tumor blood flow in C3H animals was more sensitive to physiologic or stress-induced perturbations. Specifically, PDT-induced vascular insults produced greater decreases in blood flow in the tumors of C3H versus nude mice; similarly, during baseline monitoring, fluctuations in blood flow were more regular and more prevalent within the tumors of C3H mice versus nude mice; finally, the vasoconstrictor L-NNA reduced tumor blood flow in C3H mice but did not affect tumor blood flow in nudes. Underlying differences in vascular structure, such as smaller tumor blood vessels in C3H versus nude animals, may contribute to strain-dependent variation in vascular function. These data thus identify clear effects of mouse strain on tumor hemodynamics with consequences to PDT and potentially other vascular-mediated therapies.

  11. Legubicin a Tumor-activated Prodrug for Breast Cancer Therapy

    DTIC Science & Technology

    2008-04-01

    labels. For example, when cytotoxic drugs are part of the prodrug, a hydrophilic group is preferably used for R1 to limit cell uptake by non-target... myeloma , non-small cell lung cancer, retinoblastoma, or tumors in the ovaries. The invention also provides a method for inhibiting cancer metastasis and...

  12. Role of somatostatins in gastroenteropancreatic neuroendocrine tumor development and therapy.

    PubMed

    Oberg, Kjell E; Reubi, Jean-Claude; Kwekkeboom, Dik J; Krenning, Eric P

    2010-09-01

    The incidence and prevalence of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have increased in the past 20 years. GEP-NETs are heterogeneous tumors, in terms of clinical and biological features, that originate from the pancreas or the intestinal tract. Some GEP-NETs grow very slowly, some grow rapidly and do not cause symptoms, and others cause hormone hypersecretion and associated symptoms. Most GEP-NETs overexpress receptors for somatostatins. Somatostatins inhibit the release of many hormones and other secretory proteins; their effects are mediated by G protein-coupled receptors that are expressed in a tissue-specific manner. Most GEP-NETs overexpress the somatostatin receptor SSTR2; somatostatin analogues are the best therapeutic option for functional neuroendocrine tumors because they reduce hormone-related symptoms and also have antitumor effects. Long-acting formulations of somatostatin analogues stabilize tumor growth over long periods. The development of radioactive analogues for imaging and peptide receptor radiotherapy has improved the management of GEP-NETs. Peptide receptor radiotherapy has significant antitumor effects, increasing overall survival times of patients with tumors that express a high density of SSTRs, particularly SSTR2 and SSTR5. The multi-receptor somatostatin analogue SOM230 (pasireotide) and chimeric molecules that bind SSTR2 and the dopamine receptor D2 are also being developed to treat patients with GEP-NETs. Combinations of radioactive labeled and unlabeled somatostatin analogues and therapeutics that inhibit other signaling pathways, such as mammalian target of rapamycin (mTOR) and vascular endothelial growth factor, might be the most effective therapeutics for GEP-NETs. Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

  13. Targeting melanoma with front-line therapy does not abrogate Nodal-expressing tumor cells.

    PubMed

    Hendrix, Mary Jc; Kandela, Irawati; Mazar, Andrew P; Seftor, Elisabeth A; Seftor, Richard Eb; Margaryan, Naira V; Strizzi, Luigi; Murphy, George F; Long, Georgina V; Scolyer, Richard A

    2017-02-01

    Metastatic melanoma is a highly aggressive skin cancer with a poor prognosis. It is the leading cause of skin cancer deaths with a median overall survival for advanced-stage metastatic disease of <6 months. Despite advances in the field with conventional and targeted therapies, the heterogeneity of melanoma poses the greatest ongoing challenge, ultimately leading to relapse and progression to a more drug-resistant tumor in most patients. Particularly noteworthy are recent findings, indicating that these therapies exert selective pressure on tumors resulting in the activation of pathways associated with cancer stem cells that are unresponsive to current therapy. Our previous studies have shown how Nodal, an embryonic morphogen of the transforming growth factor-beta superfamily, is one of these critical factors that is reactivated in aggressive melanoma and resistant to conventional chemotherapy, such as dacarbazine. In the current study, we sought to determine whether BRAF inhibitor (BRAFi) therapy targeted Nodal-expressing tumor cells in uniquely matched unresectable stage III and IV melanoma patient samples before and after therapy that preceded their eventual death due to disease. The results demonstrate that BRAFi treatment failed to affect Nodal levels in melanoma tissues. Accompanying experiments in soft agar and in nude mice showed the advantage of using combinatorial treatment with BRAFi plus anti-Nodal monoclonal antibody to suppress tumor growth and metastasis. These data provide a promising new approach using front-line therapy combined with targeting a cancer stem cell-associated molecule-producing a more efficacious response than monotherapy.

  14. [Clinical observation of music therapy combined with anti-tumor drugs in treating 116 cases of tumor patients].

    PubMed

    Cai, G R; Li, P W; Jiao, L P

    2001-12-01

    To observe the clinical effect of music therapy in treating tumor patients. Music therapy combined with anti-tumor drugs, including chemotherapy and Chinese drugs, was given to 162 tumor patients according to syndrome differentiation to observe the change of self-rating depression scale (SDS), self-rating anxiety scale (SAS), minnesota multiphasic personality inventory (MMPI), Hamilton rating scale for depression (HAMD) and T lymphocyte subsets (immuno-histochemical assay), NK cell anti-tumor activity (NAG method), etc. while 46 caces didn't receive music therapy were taken as the control group. The scale marks of SDS and SAS of the treated group after treatment were obviously lower than that of the control group significantly (P < 0.05, P < 0.01). After treatment, the average values of MMPI on falseness (F), hypochondriasis (HS), depression (D) and psychosthenia (Pt) in the treated group were all improved (P < 0.01 or P < 0.05); but in the control group, significant difference only showed in MMPI on HS (P < 0.05). HAMD in the treated group revealed some improvement in insomnia, early awakening, daily work and interest, systemic symptoms and hypochondriasis (P < 0.05), and significant improvement in depression, difficulty in falling asleep, psychiatric anxiety and somatic anxiety (P < 0.01); while in the control group, only work interest and HS had some improvement (P < 0.05). CD8 percent was reduced in both groups after treatment (P < 0.01), but in the treated group CD3, CD4 and CD4/CD8 ratio were not significantly changed after treatment (P > 0.05); while in the control group they lowered obviously (P < 0.05). As for NK cell anti-tumor activity in the treated group before and after treatment, it was not significantly lowered (P > 0.05); while in the control group the lowering after treatment was significant (P < 0.05). Music therapy could regulate the emotion of tumor patient, optimize the emotional effect, improve the somatic symptoms, enhance the immune

  15. Monitoring Tumor Hypoxia Using 18F-FMISO PET and Pharmacokinetics Modeling after Photodynamic Therapy

    PubMed Central

    Tong, Xiao; Srivatsan, Avinash; Jacobson, Orit; Wang, Yu; Wang, Zhantong; Yang, Xiangyu; Niu, Gang; Kiesewetter, Dale O.; Zheng, Hairong; Chen, Xiaoyuan

    2016-01-01

    Photodynamic therapy (PDT) is an efficacious treatment for some types of cancers. However, PDT-induced tumor hypoxia as a result of oxygen consumption and vascular damage can reduce the efficacy of this therapy. Measuring and monitoring intrinsic and PDT-induced tumor hypoxia in vivo during PDT is of high interest for prognostic and treatment evaluation. In the present study, static and dynamic 18F-FMISO PET were performed with mice bearing either U87MG or MDA-MB-435 tumor xenografts immediately before and after PDT at different time points. Significant difference in tumor hypoxia in response to PDT over time was found between the U87MG and MDA-MB-435 tumors in both static and dynamic PET. Dynamic PET with pharmacokinetics modeling further monitored the kinetics of 18F-FMISO retention to hypoxic sites after treatment. The Ki and k3 parametric analysis provided information on tumor hypoxia by distinction of the specific tracer retention in hypoxic sites from its non-specific distribution in tumor. Dynamic 18F-FMISO PET with pharmacokinetics modeling, complementary to static PET analysis, provides a potential imaging tool for more detailed and more accurate quantification of tumor hypoxia during PDT. PMID:27546160

  16. The targeting mechanism of DHA ligand and its conjugate with Gemcitabine for the enhanced tumor therapy

    PubMed Central

    Li, Siwen; Qin, Jingyi; Tian, Caiping; Cao, Jie; Fida, Guissi; Wang, Zhaohui; Chen, Haiyan; Qian, Zhiyu; Chen, Wei R; Gu, Yueqing

    2014-01-01

    Docosahexaenoic acid (DHA), an omega-3 C22 natural fatty acid serving as a precursor for metabolic and biochemical pathways, was reported as a targeting ligand of anticancer drugs. However, its tumor targeting ability and mechanism has not been claimed. Here we hypothesized that the uptake of DHA by tumor cells is related to the phosphatidylethanolamine (PE) contents in cell membranes. Thus, in this manuscript, the tumor-targeting ability of DHA was initially demonstrated in vitro and in vivo on different tumor cell lines by labeling DHA with fluorescence dyes. Subsequently, the tumor targeting ability was then correlated with the contents of PE in cell membranes to study the uptake mechanism. Further, DHA was conjugated with anticancer drug gemcitabine (DHA-GEM) for targeted tumor therapy. Our results demonstrated that DHA exhibited high tumor targeting ability and PE is the main mediator, which confirmed our hypothesis. The DHA-GEM displayed enhanced therapeutic efficacy than that of GEM itself, indicating that DHA is a promising ligand for tumor targeted therapy. PMID:25004114

  17. Activation of mechanosensitive ion channel TRPV4 normalizes tumor vasculature and improves cancer therapy

    PubMed Central

    Adapala, Ravi K.; Thoppil, Roslin J.; Ghosh, Kaustabh; Cappelli, Holly; Dudley, Andrew C.; Paruchuri, Sailaja; Keshamouni, Venkateshwar; Klagsbrun, Michael; Meszaros, J. Gary; Chilian, William M.; Ingber, Donald E.; Thodeti, Charles K.

    2016-01-01

    Tumor vessels are characterized by abnormal morphology and hyper-permeability that together cause inefficient delivery of chemotherapeutic agents. Although VEGF has been established as a critical regulator of tumor angiogenesis, the role of mechanical signaling in the regulation of tumor vasculature or tumor endothelial cell (TEC) function is not known. Here, we show that the mechanosensitive ion channel TRPV4 regulates tumor angiogenesis and tumor vessel maturation via modulation of TEC mechanosensitivity. We found that TEC exhibit reduced TRPV4 expression and function, which is correlated with aberrant mechanosensitivity towards ECM stiffness, increased migration and abnormal angiogenesis by TEC. Further, syngeneic tumor experiments revealed that the absence of TRPV4 induced increased vascular density, vessel diameter and reduced pericyte coverage resulting in enhanced tumor growth in TRPV4 KO mice. Importantly, overexpression or pharmacological activation of TRPV4 restored aberrant TEC mechanosensitivity, migration and normalized abnormal angiogenesis in vitro by modulating Rho activity. Finally, a small molecule activator of TRPV4, GSK1016790A, in combination with anti-cancer drug Cisplatin, significantly reduced tumor growth in WT mice by inducing vessel maturation. Our findings demonstrate TRPV4 channels to be critical regulators of tumor angiogenesis and represent a novel target for anti-angiogenic and vascular normalization therapies. PMID:25867067

  18. Activation of mechanosensitive ion channel TRPV4 normalizes tumor vasculature and improves cancer therapy.

    PubMed

    Adapala, R K; Thoppil, R J; Ghosh, K; Cappelli, H C; Dudley, A C; Paruchuri, S; Keshamouni, V; Klagsbrun, M; Meszaros, J G; Chilian, W M; Ingber, D E; Thodeti, C K

    2016-01-21

    Tumor vessels are characterized by abnormal morphology and hyperpermeability that together cause inefficient delivery of chemotherapeutic agents. Although vascular endothelial growth factor has been established as a critical regulator of tumor angiogenesis, the role of mechanical signaling in the regulation of tumor vasculature or tumor endothelial cell (TEC) function is not known. Here we show that the mechanosensitive ion channel transient receptor potential vanilloid 4 (TRPV4) regulates tumor angiogenesis and tumor vessel maturation via modulation of TEC mechanosensitivity. We found that TECs exhibit reduced TRPV4 expression and function, which is correlated with aberrant mechanosensitivity towards extracellular matrix stiffness, increased migration and abnormal angiogenesis by TEC. Further, syngeneic tumor experiments revealed that the absence of TRPV4 induced increased vascular density, vessel diameter and reduced pericyte coverage resulting in enhanced tumor growth in TRPV4 knockout mice. Importantly, overexpression or pharmacological activation of TRPV4 restored aberrant TEC mechanosensitivity, migration and normalized abnormal angiogenesis in vitro by modulating Rho activity. Finally, a small molecule activator of TRPV4, GSK1016790A, in combination with anticancer drug cisplatin, significantly reduced tumor growth in wild-type mice by inducing vessel maturation. Our findings demonstrate TRPV4 channels to be critical regulators of tumor angiogenesis and represent a novel target for anti-angiogenic and vascular normalization therapies.

  19. DNA vaccination controls Her-2+ tumors that are refractory to targeted therapies

    PubMed Central

    Whittington, Paula J.; Piechocki, Marie P.; Heng, Henry H.; Jacob, Jennifer B.; Jones, Richard F.; Back, Jessica B.; Wei, Wei-Zen

    2008-01-01

    Her-2/neu+ tumor cells refractory to antibody or receptor tyrosine kinase inhibitors (RTKI) are emerging in treated patients. To investigate if drug resistant tumors can be controlled by active vaccination, gefitinib and antibody sensitivity of four neu+ BALB/c mouse mammary tumor (MMT) lines were compared. Significant differences in cell proliferation and Akt phosphorylation were observed. Treatment-induced drug resistance was associated with increased chromosomal aberrations as shown by spectral karyotyping analysis, suggesting changes beyond neu signaling pathways. When mice were immunized with pneuTM encoding the extracellular and transmembrane domains of neu, antibody and T cell responses were induced and both drug sensitive and resistant tumor cells were rejected. In T cell depleted mice, drug sensitive tumors were still rejected by vaccination, but drug- refractory tumors survived in some mice, indicating their resistance to anti-neu antibodies. To further test if T cells alone can mediate tumor rejection, mice were immunized with pcytneu encoding full-length cytoplasmic neu that is rapidly degraded by the proteasome to activate CD8 T cells without inducing antibody response. All test tumors were rejected in pcytneu immunized mice, regardless of their sensitivity to gefitinib or antibody. Therefore, CTL activated by the complete repertoire of neu epitopes were effective against all test tumors. These results warrant Her-2 vaccination whether tumor cells are sensitive or resistant to Her-2 targeted drugs or antibody therapy. PMID:18794138

  20. Differential vascular response and relationship to tumor response with photodynamic therapy using WST-09 (TOOKAD)

    NASA Astrophysics Data System (ADS)

    Garbo, Greta M.; Kik, Peter K.; Harrison, Linda T.; Brun, Pierre H.; Blanc, Dominique; Paulin, Pamela S.; Wieman, Thomas J.; Fingar, Victor H.

    2004-06-01

    Bacteriopheophorbide molecules are second-generation photosensitizers with promise for PHotodynamic Therapy applications due largely to their absorption peaks in the near-Infrared region. Palladium bcteriopheophorbide, also called TOOKAD, has been successfully evaluated in several pre-clinical animal models. In this study the effect on tumor and normal vasculature was evaluated using an intravital vascular model on mouse cremaster muscle implanted with the RIF tumor. For tumor response studies, the same RIF tumor was implanted intradermally on the right flank and regression was evaluated for 42 days or until the tumor reached a 12 mm diameter. A light dose 300 J/cm2 were delivered at 763 nm with power density of 100 mW/cm2. Photosensitizer dose was 4 mg/kg body weight. Mice were treated immediately, 10 minutes, 30 minutes, or 24 hours after injection. Only the higher light dose (300 J/cm2) delivered 10 minutes after injection produced a reproducible and complete vascular and tumor response after PDT in these animals. In the cremaster-tumor model, arterioles and venules partially shutdown as early as 40 minutes after the beginning of treatment, while tumor neovasculature was irreversibly closed within 20 minutes of treatment. Tumor response studies demonstrated that the magnitude of vascular stasis correlates with tumor regression studies. Further studies using this photosensitizer are warranted, given its short clearance time and its near-Infrared activation wavelength.

  1. A longitudinal magnetic resonance elastography study of murine brain tumors following radiation therapy

    NASA Astrophysics Data System (ADS)

    Feng, Y.; Clayton, E. H.; Okamoto, R. J.; Engelbach, J.; Bayly, P. V.; Garbow, J. R.

    2016-08-01

    An accurate and noninvasive method for assessing treatment response following radiotherapy is needed for both treatment monitoring and planning. Measurement of solid tumor volume alone is not sufficient for reliable early detection of therapeutic response, since changes in physiological and/or biomechanical properties can precede tumor volume change following therapy. In this study, we use magnetic resonance elastography to evaluate the treatment effect after radiotherapy in a murine brain tumor model. Shear modulus was calculated and compared between the delineated tumor region of interest (ROI) and its contralateral, mirrored counterpart. We also compared the shear modulus from both the irradiated and non-irradiated tumor and mirror ROIs longitudinally, sampling four time points spanning 9-19 d post tumor implant. Results showed that the tumor ROI had a lower shear modulus than that of the mirror ROI, independent of radiation. The shear modulus of the tumor ROI decreased over time for both the treated and untreated groups. By contrast, the shear modulus of the mirror ROI appeared to be relatively constant for the treated group, while an increasing trend was observed for the untreated group. The results provide insights into the tumor properties after radiation treatment and demonstrate the potential of using the mechanical properties of the tumor as a biomarker. In future studies, more closely spaced time points will be employed for detailed analysis of the radiation effect.

  2. The first interdisciplinary experiments at the IMP high energy microbeam

    NASA Astrophysics Data System (ADS)

    Du, Guanghua; Guo, Jinlong; Wu, Ruqun; Guo, Na; Liu, Wenjing; Ye, Fei; Sheng, Lina; Li, Qiang; Li, Huiyun

    2015-04-01

    The high energy beam of tens to hundred MeV/u ions possesses mm-to-cm penetration depth in materials and can be easily extracted into air without significant energy loss and beam scattering. Combination of high energy ions and microbeam technology facilitates the microprobe application to many practical studies in large scale samples. The IMP heavy ion microbeam facility has recently been integrated with microscopic positioning and targeting irradiation system. This paper introduced the first interdisciplinary experiments performed at the IMP microbeam facility using the beam of 80.5 MeV/u carbon ions. Bystander effect induction via medium transferring was not found in the micro-irradiation study using HeLa cells. The mouse irradiation experiment demonstrated that carbon irradiation of 10 Gy dose to its tuberomammillary nucleus did not impair the sleep nerve system. The fault injection attack on RSA (Rivest-Shamir-Adleman) decryption proved that the commercial field-programmable gate array chip is vulnerable in single event effect to low linear-energy-transfer carbon irradiation, and the attack can cause the leakage of RSA private key. This work demonstrates the potential of high energy microbeam in its application to biology, biomedical, radiation hardness, and information security studies.

  3. Evaluation of lung tumor response to therapy: Current and emerging techniques.

    PubMed

    Coche, E

    2016-10-01

    Lung tumor response to therapy may be evaluated in most instances by morphological criteria such as RECIST 1.1 on computed tomography (CT) or magnetic resonance imaging (MRI). However, those criteria are limited because they are based on tumoral dimensional changes and do not take into account other morphologic criteria such as density evaluation, functional or metabolic changes that may occur following conventional or targeted chemotherapy. New techniques such as dual-energy CT, PET-CT, MRI including diffusion-weighted MRI has to be considered into the new technical armamentarium for tumor response evaluation. Integration of all informations provided by the different imaging modalities has to be integrated and represents probably the future goal of tumor response evaluation. The aim of the present paper is to review the current and emerging imaging criteria used to evaluate the response of therapy in the field of lung cancer.

  4. Insights into a microwave susceptible agent for minimally invasive microwave tumor thermal therapy.

    PubMed

    Shi, Haitang; Liu, Tianlong; Fu, Changhui; Li, Linlin; Tan, Longfei; Wang, Jingzhuo; Ren, Xiangling; Ren, Jun; Wang, Jianxin; Meng, Xianwei

    2015-03-01

    This work develops a kind of sodium alginate (SA) microcapsules as microwave susceptible agents for in vivo tumor microwave thermal therapy for the first time. Due to the excellent microwave susceptible properties and low bio-toxicity, excellent therapy efficiency can be achieved with the tumor inhibiting ratio of 97.85% after one-time microwave thermal therapy with ultralow power (1.8 W, 450 MHz). Meanwhile, the mechanism of high microwave heating efficiency was confirmed via computer-simulated model in theory, demonstrating that the spatial confinement efficiency of microcapsule walls endows the inside ions with high microwave susceptible properties. This strategy offers tremendous potential applications in clinical tumor treatment with the benefits of safety, reliability, effectiveness and minimally invasiveness. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. Targeted therapy in the treatment of solid tumors: practice contradicts theory.

    PubMed

    Zhukov, N V; Tjulandin, S A

    2008-05-01

    The basic principle of targeted therapy formulated about ten years ago consists in the design and application of drugs specifically directed against well-defined targets that are critical for tumor survival and not compromising for normal organs and tissues. The past decade has been marked by the appearance of an immense diversity of novel antitumor agents with claimed targeted action. Unfortunately, despite indisputable progress in clinical settings, some popular drugs against solid tumors (e.g. bevacizumab, trastuzumab, erlotinib, gefitinib) nominally assigned to targeted-action drugs, cannot actually be classified with this group being nonconforming to a priori stated goals of targeted therapy. The state-of-the-art and current problems in targeted therapy of solid tumors are reviewed.

  6. Hyperoxygenation enhances the direct tumor cell killing of photofrin-mediated photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Huang, Zheng; Chen, Qun; Shakil, Abdus; Chen, Hua; Beckers, Jill; Shapiro, Howard; Hetzel, Fred W.

    2003-06-01

    Tumor hypoxia, either pre-existing or as a result of oxygen bleaching during Photodynamic Therapy (PDT) light irradiation, can significantly reduce the effectiveness of PDT induced cell killing. To overcome the effect of tumor hypoxia and improve tumor cell killing, we propose using supplemental hyperoxygenation during Photofrin PDT. Our previous study has demonstrated that, in an in vivo model, tumor control can be improved by normobaric or hyperbaric 100% oxygen supply. The mechanism for the tumor cure enhancement of the hyperoxygenation-PDT combined therapy is investigated in this study by using an in vivo/in vitro technique. A hypoxic tumor model was established by implanting mammary adenocarcinoma (MCA) in hind legs of C3H mice. Light irradiation (200 J/cm2 at either 75 or 150 mW/cm2), under various oxygen supplemental conditions (room air or carbogen or 100% normobaric or hyperbaric 100% oxygen), was delivered through an optical fiber with a microlens to animals who received 12.5 mg/kg Photofrin 24 hours prior to light irradiation. Tumors treated with PDT were harvested and grown in vitro for colony formation analysis. Treated tumors were also analyzed histologically. The results show that, when combined with hyperoxygenation, the cell killing rate immediately after a PDT treatment is significantly improved over that treated without hyperoxygenation, suggesting an enhanced direct cell killing. This study further confirms our earlier observation that when a PDT treatment is combined with hyperoxygenation, it can be more effective in controlling hypoxic tumors. H&E stain revealed that PDT induced tumor necrosis and hemorrhage. In conclusion, by using an in vivo/in vitro assay, we have shown that PDT combined with hyper-oxygenation can enhance direct cell killing and improve tumor cure.

  7. New photosensitizers for the photodynamic therapy of tumors

    NASA Astrophysics Data System (ADS)

    Bonnett, Raymond

    1994-03-01

    This paper reviews the main approaches that have been made worldwide over the past five years (1989 - 1993) in the effort to discover new and more effective sensitizers for tumor phototherapy. Advances in our understanding of haematoporphyrin derivative and its commercial variants are dealt with briefly. New compounds in the porphyrin, chlorin, bacteriochlorin and phthalocyanine series are discussed, and the relationship between spectroscopic and other physical properties and the photoactivity of the drug are explored. The prospects for future developments are considered briefly.

  8. Radiation Therapy for Liver Tumors: Ready for Inclusion in Guidelines?

    PubMed Central

    Tanguturi, Shyam K.; Wo, Jennifer Y.; Zhu, Andrew X.; Dawson, Laura A.

    2014-01-01

    Despite the historically limited role of radiotherapy in the management of primary hepatic malignancies, modern advances in treatment design and delivery have renewed enthusiasm for radiation as a potentially curative treatment modality. Surgical resection and/or liver transplantation are traditionally regarded as the most effective forms of therapy, although the majority of patients with hepatocellular carcinoma and intrahepatic cholangiocarcinoma present with locally advanced or unresectable disease on the basis of local vascular invasion or inadequate baseline hepatobiliary function. In this context, many efforts have focused on nonoperative treatment approaches including novel systemic therapies, transarterial chemoembolization, ethanol ablation, radiofrequency ablation, and stereotactic body radiation therapy (SBRT). This review aims to summarize modern advances in radiotherapy, particularly SBRT, in the treatment of primary hepatic malignancies. PMID:25001265

  9. [Prognostic Impact of Radiation Therapy and Molecular Classification of Infant Atypical Teratoid/Rhabdoid Tumors].

    PubMed

    Otani, Yoshihiro; Ichikawa, Tomotsugu; Kurozumi, Kazuhiko; Yasuhara, Takao; Washio, Kana; Shimada, Akira; Katayama, Norihisa; Katsui, Kuniaki; Yanai, Hiroyuki; Date, Isao

    2017-02-01

    Atypical teratoid/rhabdoid tumor(AT/RT)is a rare and lethal childhood cancer. Although radiation therapy in children less than three years of age is generally deferred because of its neural toxicity, recent studies have shown that multimodal therapies, including radiation therapy, are effective in pediatric patients with AT/RT less than three years of age. We treated four infant AT/RT patients and investigated the impact of radiation therapy and genetic classification on the prognosis. The mean age at the time of the operation was 9.3 months and all patients were female. All patients underwent surgical resection. Of the four patients, two received combined irradiation and chemotherapy. Specifically, one patient received conformal craniospinal radiation therapy and the other received craniospinal irradiation with proton beams. Immunohistochemical analyses of tumor specimens revealed that the two patients were positive for ASCL1, a regulator of Notch signaling. Patients who received radiation therapy and exhibited ASCL1-positive tumors had a better prognosis. We conclude that radiation therapy may prolong survival in AT/RT patients who are less than 3 years of age. However, further study is required to evaluate long-term functional outcomes.

  10. Targeting tumor perfusion and oxygenation to improve the outcome of anticancer therapy.

    PubMed

    Jordan, Bénédicte F; Sonveaux, Pierre

    2012-01-01

    Radiotherapy and chemotherapy are widespread clinical modalities for cancer treatment. Among other biological influences, hypoxia is a main factor limiting the efficacy of radiotherapy, primarily because oxygen is involved in the stabilization of the DNA damage caused by ionizing radiations. Radiobiological hypoxia is found in regions of rodent and human tumors with a tissue oxygenation level below 10 mmHg at which tumor cells become increasingly resistant to radiation damage. Since hypoxic tumor cells remain clonogenic, their resistance to the treatment strongly influences the therapeutic outcome of radiotherapy. There is therefore an urgent need to identify adjuvant treatment modalities aimed to increase tumor pO(2) at the time of radiotherapy. Since tumor hypoxia fundamentally results from an imbalance between oxygen delivery by poorly efficient blood vessels and oxygen consumption by tumor cells with high metabolic activities, two promising approaches are those targeting vascular reactivity and tumor cell respiration. This review summarizes the current knowledge about the development and use of tumor-selective vasodilators, inhibitors of tumor cell respiration, and drugs and treatments combining both activities in the context of tumor sensitization to X-ray radiotherapy. Tumor-selective vasodilation may also be used to improve the delivery of circulating anticancer agents to tumors. Imaging tumor perfusion and oxygenation is of importance not only for the development and validation of such combination treatments, but also to determine which patients could benefit from the therapy. Numerous techniques have been developed in the preclinical setting. Hence, this review also briefly describes both magnetic resonance and non-magnetic resonance in vivo methods and compares them in terms of sensitivity, quantitative or semi-quantitative properties, temporal, and spatial resolutions, as well as translational aspects.

  11. Preferential action of arsenic trioxide in solid-tumor microenvironment enhances radiation therapy

    SciTech Connect

    Griffin, Robert J. . E-mail: griff007@umn.edu; Williams, Brent W.; Park, Heon Joo; Song, Chang W.

    2005-04-01

    Purpose: To investigate the effect of arsenic trioxide, Trisenox (TNX), on primary cultures of endothelial cells and tumor tissue under varying pH and pO{sub 2} environments and the effects of combined TNX and radiation therapy on experimental tumors. Methods and Materials: Human dermal microvascular endothelial cells were cultured in vitro and exposed to TNX under various combinations of aerobic, hypoxic, neutral, or acidic conditions, and levels of activated JNK MAP kinase were assessed by Western blotting. FSaII fibrosarcoma cells grown in the hind limb of female C3H mice were used to study the effect of TNX on tumor blood perfusion and oxygenation. The tumor-growth delay after a single or fractionated irradiation with or without TNX treatment was assessed. Results: A single intraperitoneal injection of 8 mg/kg TNX reduced the blood perfusion in FSaII tumors by 53% at 2 hours after injection. To increase the oxygenation of the tumor vasculature during TNX treatment, some animals were allowed to breathe carbogen (95% O{sub 2}/5% CO{sub 2}). Carbogen breathing alone for 2 hours reduced tumor perfusion by 33%. When carbogen breathing was begun immediately after TNX injection, no further reduction occurred in tumor blood perfusion at 2 hours after injection. In vitro, TNX exposure increased activity JNK MAP kinase preferentially in endothelial cells cultured in an acidic or hypoxic environment. In vivo, the median oxygenation in FSaII tumors measured at 3 or 5 days after TNX injection was found to be significantly elevated compared with control tumors. Subsequently, radiation-induced tumor-growth delay was synergistically increased when radiation and TNX injection were fractionated at 3-day or 5-day intervals. Conclusions: Trisenox has novel vascular-damaging properties, preferentially against endothelium in regions of low pH or pO{sub 2}, which leads to tumor cell death and enhancement of the response of tumors to radiotherapy.

  12. A cellular automata model for avascular solid tumor growth under the effect of therapy

    NASA Astrophysics Data System (ADS)

    Reis, E. A.; Santos, L. B. L.; Pinho, S. T. R.

    2009-04-01

    Tumor growth has long been a target of investigation within the context of mathematical and computer modeling. The objective of this study is to propose and analyze a two-dimensional stochastic cellular automata model to describe avascular solid tumor growth, taking into account both the competition between cancer cells and normal cells for nutrients and/or space and a time-dependent proliferation of cancer cells. Gompertzian growth, characteristic of some tumors, is described and some of the features of the time-spatial pattern of solid tumors, such as compact morphology with irregular borders, are captured. The parameter space is studied in order to analyze the occurrence of necrosis and the response to therapy. Our findings suggest that transitions exist between necrotic and non-necrotic phases (no-therapy cases), and between the states of cure and non-cure (therapy cases). To analyze cure, the control and order parameters are, respectively, the highest probability of cancer cell proliferation and the probability of the therapeutic effect on cancer cells. With respect to patterns, it is possible to observe the inner necrotic core and the effect of the therapy destroying the tumor from its outer borders inwards.

  13. A Mathematical Tumor Model with Immune Resistance and Drug Therapy: An Optimal Control Approach

    DOE PAGES

    De Pillis, L. G.; Radunskaya, A.

    2001-01-01

    We present a competition model of cancer tumor growth that includes both the immune system response and drug therapy. This is a four-population model that includes tumor cells, host cells, immune cells, and drug interaction. We analyze the stability of the drug-free equilibria with respect to the immune response in order to look for target basins of attraction. One of our goals was to simulate qualitatively the asynchronous tumor-drug interaction known as “Jeffs phenomenon.” The model we develop is successful in generating this asynchronous response behavior. Our other goal was to identify treatment protocols that could improve standard pulsed chemotherapymore » regimens. Using optimal control theory with constraints and numerical simulations, we obtain new therapy protocols that we then compare with traditional pulsed periodic treatment. The optimal control generated therapies produce larger oscillations in the tumor population over time. However, by the end of the treatment period, total tumor size is smaller than that achieved through traditional pulsed therapy, and the normal cell population suffers nearly no oscillations.« less

  14. Gene therapy with IL-12 induced enhanced anti-tumor activity in fibrosarcoma mouse model.

    PubMed

    Razi Soofiyani, Saiedeh; Kazemi, Tohid; Lotfipour, Farzaneh; Mohammad Hosseini, Akbar; Shanehbandi, Dariush; Hallaj-Nezhadi, Somayeh; Baradaran, Behzad

    2016-12-01

    Context Immunotherapy is among the most promising modalities for treatment of cancer. Recently, interleukin 12 (IL-12) has been used as an immunotherapeutic agent in cancer gene therapy. IL-12 can activate dendritic cells (DCs) and boost anti-tumor immune responses. Objective In the current study, we have investigated if IL-12 gene therapy can lead to the regression of tumor mass in a mouse model of fibrosarcoma. Material and methods To investigate the therapeutic efficacy of IL-12, WEHI-164 tumor cells were transfected with murine-IL12 plasmids using Lipofectamine. Enzyme linked immunosorbent assay (ELISA) was used to confirm IL-12 expression in transfected cells. The fibrosarcoma mouse model was established by subcutaneous injection of transfected cells to Balb/C mice. Mice were sacrificed and the tumors were extracted. Tumor sizes were measured by caliper. The expression of IL-12 and IFN-γ was studied with real-time PCR and western blotting. The expression of Ki-67(a tumor proliferation marker) in tumor mass was studied by immunohistochemistry staining. Results and discussion The group treated with IL-12 showed a significant decrease in tumor mass volume (P: 0.000). The results of real-time PCR and western blotting showed that IL-12 and IFN-γ expression increased in the group treated with IL-12 (relative expression of IL-12: 1.9 and relative expression of IFN-γ: 1.766). Immunohistochemistry staining showed that Ki-67 expression was reduced in the group treated with IL-12. Conclusion IL-12 gene therapy successfully led to regress of tumor mass in the fibrosarcoma mouse model. This may serve as a candidate therapeutic approach for treatment of cancer.

  15. Epigenetic Modifications and Head and Neck Cancer: Implications for Tumor Progression and Resistance to Therapy

    PubMed Central

    Squarize, Cristiane H.; Almeida, Luciana O.

    2017-01-01

    Head and neck squamous carcinoma (HNSCC) is the sixth most prevalent cancer and one of the most aggressive malignancies worldwide. Despite continuous efforts to identify molecular markers for early detection, and to develop efficient treatments, the overall survival and prognosis of HNSCC patients remain poor. Accumulated scientific evidences suggest that epigenetic alterations, including DNA methylation, histone covalent modifications, chromatin remodeling and non-coding RNAs, are frequently involved in oral carcinogenesis, tumor progression, and resistance to therapy. Epigenetic alterations occur in an unsystematic manner or as part of the aberrant transcriptional machinery, which promotes selective advantage to the tumor cells. Epigenetic modifications also contribute to cellular plasticity during tumor progression and to the formation of cancer stem cells (CSCs), a small subset of tumor cells with self-renewal ability. CSCs are involved in the development of intrinsic or acquired therapy resistance, and tumor recurrences or relapse. Therefore, the understanding and characterization of epigenetic modifications associated with head and neck carcinogenesis, and the prospective identification of epigenetic markers associated with CSCs, hold the promise for novel therapeutic strategies to fight tumors. In this review, we focus on the current knowledge on epigenetic modifications observed in HNSCC and emerging Epi-drugs capable of sensitizing HNSCC to therapy. PMID:28704968

  16. Radiation therapy combined with novel STING-targeting oligonucleotides results in regression of established tumors

    PubMed Central

    Baird, Jason R.; Friedman, David; Cottam, Benjamin; Dubensky, Thomas W.; Kanne, David B.; Bambina, Shelly; Bahjat, Keith; Crittenden, Marka R.; Gough, Michael J.

    2015-01-01

    Cytotoxic therapies prime adaptive immune responses to cancer by stimulating the release of tumor-associated antigens. However, the tumor microenvironment into which these antigens are released is typically immunosuppressed, blunting the ability to initiate immune responses. Recently, activation of the DNA sensor molecule STING by cyclic dinucleotides was shown to stimulate infection-related inflammatory pathways in tumors. In this study, we report that the inflammatory pathways activated by STING ligands generate a powerful adjuvant activity for enhancing adaptive immune responses to tumor antigens released by radiation therapy. In a murine model of pancreatic cancer, we showed that combining CT-guided radiation therapy with a novel ligand of murine and human STING could synergize to control local and distant tumors. Mechanistic investigations revealed T cell-independent and TNFα-dependent hemorrhagic necrosis at early times followed by later CD8 T cell-dependent control of residual disease. Clinically, STING was found to be expressed extensively in human pancreatic tumor and stromal cells. Our findings suggest that this novel STING ligand could offer a potent adjuvant for leveraging radiotherapeutic management of pancreatic cancer. PMID:26567136

  17. Metronomic chemotherapy prevents therapy-induced stromal activation and induction of tumor-initiating cells.

    PubMed

    Chan, Tze-Sian; Hsu, Chung-Chi; Pai, Vincent C; Liao, Wen-Ying; Huang, Shenq-Shyang; Tan, Kok-Tong; Yen, Chia-Jui; Hsu, Shu-Ching; Chen, Wei-Yu; Shan, Yan-Shen; Li, Chi-Rong; Lee, Michael T; Jiang, Kuan-Ying; Chu, Jui-Mei; Lien, Gi-Shih; Weaver, Valerie M; Tsai, Kelvin K

    2016-12-12

    Although traditional chemotherapy kills a fraction of tumor cells, it also activates the stroma and can promote the growth and survival of residual cancer cells to foster tumor recurrence and metastasis. Accordingly, overcoming the host response induced by chemotherapy could substantially improve therapeutic outcome and patient survival. In this study, resistance to treatment and metastasis has been attributed to expansion of stem-like tumor-initiating cells (TICs). Molecular analysis of the tumor stroma in neoadjuvant chemotherapy-treated human desmoplastic cancers and orthotopic tumor xenografts revealed that traditional maximum-tolerated dose chemotherapy, regardless of the agents used, induces persistent STAT-1 and NF-κB activity in carcinoma-associated fibroblasts. This induction results in the expression and secretion of ELR motif-positive (ELR(+)) chemokines, which signal through CXCR-2 on carcinoma cells to trigger their phenotypic conversion into TICs and promote their invasive behaviors, leading to paradoxical tumor aggression after therapy. In contrast, the same overall dose administered as a low-dose metronomic chemotherapy regimen largely prevented therapy-induced stromal ELR(+) chemokine paracrine signaling, thus enhancing treatment response and extending survival of mice carrying desmoplastic cancers. These experiments illustrate the importance of stroma in cancer therapy and how its impact on treatment resistance could be tempered by altering the dosing schedule of systemic chemotherapy. © 2016 Chan et al.

  18. Combination of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and canstatin gene suppression therapy on breast tumor xenograft growth in mice.

    PubMed

    Wang, Wen-Bo; Zhou, Yu-Lin; Heng, De-Feng; Miao, Chuan-Hui; Cao, Ying-Lin

    2008-07-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene therapy and canstatin gene therapy have been investigated extensively in human xenograft tumor models established in immunocompromised nude mice. However, combination antitumor activity of these two agents and the safety of such gene constructs driven by the human telomerase reverse transcriptase (hTERT) promoter in nude mice have not been well documented. We hypothesized that TRAIL and canstatin gene therapy driven by the hTERT promoter might overcome the problem of liver toxicity and still effectively induce apoptosis on tumor cells. In this study, we evaluated the antitumor effects of TRAIL in human breast cancer cell lines and the antiangiogenic effects of canstatin on ECV204 cells. We also analyzed the effects of combined gene therapy using both TRAIL and canstatin in a human breast cancer nude mouse model. Tumor growth, tumor inhibition rate of each group, and toxicity were evaluated after gene therapy. Our results demonstrate that treatment using the canstatin- or TRAIL-expressing vector alone significantly suppresses tumor growth, compared to PBS or a vector control. We also found that combining these two therapies had greater antitumor activity than either treatment alone in the mouse model. Moreover, induction of apoptosis was not detected in normal mouse tissues after intratumoral injection of vectors and liver toxicity did not occur with either treatment. Thus, the combination of TRAIL and canstatin appears to be a promising approach for the gene therapy of breast tumors.

  19. Activation of PI3K/Akt/mTOR signaling in the tumor stroma drives endocrine therapy-dependent breast tumor regression

    PubMed Central

    Polo, María Laura; Riggio, Marina; May, María; Rodríguez, María Jimena; Perrone, María Cecilia; Stallings-Mann, Melody; Kaen, Diego; Frost, Marlene; Goetz, Matthew; Boughey, Judy; Lanari, Claudia; Radisky, Derek; Novaro, Virginia

    2015-01-01

    Improved efficacy of neoadjuvant endocrine-targeting therapies in luminal breast carcinomas could be achieved with optimal use of pathway targeting agents. In a mouse model of ductal breast carcinoma we identify a tumor regressive stromal reaction that is induced by neoadjuvant endocrine therapy. This reparative reaction is characterized by tumor neovascularization accompanied by infiltration of immune cells and carcinoma-associated fibroblasts that stain for phosphorylated ribosomal protein S6 (pS6), downstream the PI3K/Akt/mTOR pathway. While tumor variants with higher PI3K/Akt/mTOR activity respond well to a combination of endocrine and PI3K/Akt/mTOR inhibitors, tumor variants with lower PI3K/Akt/mTOR activity respond more poorly to the combination therapy than to the endocrine therapy alone, associated with inhibition of stromal pS6 and the reparative reaction. In human breast cancer xenografts we confirm that such differential sensitivity to therapy is primarily determined by the level of PI3K/Akt/mTOR in tumor cells. We further show that the clinical response of breast cancer patients undergoing neoadjuvant endocrine therapy is associated with the reparative stromal reaction. We conclude that tumor level and localization of pS6 are associated with therapeutic response in breast cancer and represent biomarkers to distinguish which tumors will benefit from the incorporation of PI3K/Akt/mTOR inhibitors with neoadjuvant endocrine therapy. PMID:26098779

  20. Enhanced Doppler ultrasound imaging of interstitial laser therapy in rat mammary tumors

    NASA Astrophysics Data System (ADS)

    Zasuly, James M.; Fan, Ming; Dowlatshahi, Kambiz

    1997-05-01

    In order to better develop ultrasonography for use in monitoring interstitial laser therapy (ILT), we imaged rat mammary tumors using power Doppler ultrasound in conduction with intravenous contrast agent (Albunex) before and after laser therapy. Small vessel perfusion throughout a variable portion of the tumor could be detected by power Doppler ultrasound. Lesions created with diode laser by delivery of 500 to 3000 J appeared as perfusion defects on post-treatment images. Image topography and lesion size correlated with gross histologic findings. We conclude that ultrasonographic monitoring of local changes in blood flow using contrast enhancing agent can be useful in characterizing lesions created with ILT.

  1. Inhibiting Metastasis and Preventing Tumor Relapse by Triggering Host Immunity with Tumor-Targeted Photodynamic Therapy Using Photosensitizer-Loaded Functional Nanographenes.

    PubMed

    Yu, Xinhe; Gao, Duo; Gao, Liquan; Lai, Jianhao; Zhang, Chenran; Zhao, Yang; Zhong, Lijun; Jia, Bing; Wang, Fan; Chen, Xiaoyuan; Liu, Zhaofei

    2017-09-18

    Effective cancer therapy depends not only on destroying the primary tumor but also on conditioning the host immune system to recognize and eliminate residual tumor cells and prevent metastasis. In this study, a tumor integrin αvβ6-targeting peptide (the HK peptide)-functionalized graphene oxide (GO) was coated with a photosensitizer (HPPH). The resulting GO conjugate, GO(HPPH)-PEG-HK, was investigated whether it could destroy primary tumors and boost host antitumor immunity. We found that GO(HPPH)-PEG-HK exhibited significantly higher tumor uptake than GO(HPPH)-PEG and HPPH. Photodynamic therapy (PDT) using GO(HPPH)-PEG suppressed tumor growth in both subcutaneous and lung metastatic mouse models. Necrotic tumor cells caused by GO(HPPH)-PEG-HK PDT activated dendritic cells and significantly prevented tumor growth and lung metastasis by increasing the infiltration of cytotoxic CD8(+) T lymphocytes within tumors as evidenced by in vivo optical and single-photon emission computed tomography (SPECT)/CT imaging. These results demonstrate that tumor-targeted PDT using GO(HPPH)-PEG-HK could effectively ablate primary tumors and destroy residual tumor cells, thereby preventing distant metastasis by activating host antitumor immunity and suppressing tumor relapse by stimulation of immunological memory.

  2. Quantitative Multi-Parametric Magnetic Resonance Imaging of Tumor Response to Photodynamic Therapy

    PubMed Central

    Schreurs, Tom J. L.; Hectors, Stefanie J.; Jacobs, Igor; Grüll, Holger; Nicolay, Klaas; Strijkers, Gustav J.

    2016-01-01

    Objective The aim of this study was to characterize response to photodynamic therapy (PDT) in a mouse cancer model using a multi-parametric quantitative MRI protocol and to identify MR parameters as potential biomarkers for early assessment of treatment outcome. Methods CT26.WT colon carcinoma tumors were grown subcutaneously in the hind limb of BALB/c mice. Therapy consisted of intravenous injection of the photosensitizer Bremachlorin, followed by 10 min laser illumination (200 mW/cm2) of the tumor 6 h post injection. MRI at 7 T was performed at baseline, directly after PDT, as well as at 24 h, and 72 h. Tumor relaxation time constants (T1 and T2) and apparent diffusion coefficient (ADC) were quantified at each time point. Additionally, Gd-DOTA dynamic contrast-enhanced (DCE) MRI was performed to estimate transfer constants (Ktrans) and volume fractions of the extravascular extracellular space (ve) using standard Tofts-Kermode tracer kinetic modeling. At the end of the experiment, tumor viability was characterized by histology using NADH-diaphorase staining. Results The therapy induced extensive cell death in the tumor and resulted in significant reduction in tumor growth, as compared to untreated controls. Tumor T1 and T2 relaxation times remained unchanged up to 24 h, but decreased at 72 h after treatment. Tumor ADC values significantly increased at 24 h and 72 h. DCE-MRI derived tracer kinetic parameters displayed an early response to the treatment. Directly after PDT complete vascular shutdown was observed in large parts of the tumors and reduced uptake (decreased Ktrans) in remaining tumor tissue. At 24 h, contrast uptake in most tumors was essentially absent. Out of 5 animals that were monitored for 2 weeks after treatment, 3 had tumor recurrence, in locations that showed strong contrast uptake at 72 h. Conclusion DCE-MRI is an effective tool for visualization of vascular effects directly after PDT. Endogenous contrast parameters T1, T2, and ADC, measured at

  3. Perceived social competency in children with brain tumors: comparison between children on and off therapy.

    PubMed

    Hardy, Kristina K; Willard, Victoria W; Watral, Melody Ann; Bonner, Melanie J

    2010-01-01

    Children with brain tumors are at risk for a number of cognitive, academic, and social difficulties as a consequence of their illness and its treatment. Of these, the least is known about social functioning, particularly over the course of the illness. Thirty children with brain tumors were evaluated using neurocognitive and psychological measures, including a measure of perceived competency. Results indicated that off-therapy brain tumor patients reported more concerns about their social competence than both a normative sample and children on treatment. Findings highlight the need for more research aimed at helping survivors cope with long-term stressors associated with their illness.

  4. Potential of boron neutron capture therapy (BNCT) for malignant peripheral nerve sheath tumors (MPNST).

    PubMed

    Fujimoto, Takuya; Andoh, Tooru; Sudo, Tamotsu; Fujita, Ikuo; Fukase, Naomasa; Takeuchi, Tamotsu; Sonobe, Hiroshi; Inoue, Masayoshi; Hirose, Tkanori; Sakuma, Toshiko; Moritake, Hiroshi; Sugimoto, Tohru; Kawamoto, Teruya; Fukumori, Yoshinobu; Yamamoto, Satomi; Atagi, Shinji; Sakurai, Yoshinori; Kurosaka, Masahiro; Ono, Koji; Ichikawa, Hideki; Suzuki, Minoru

    2015-12-01

    Malignant peripheral nerve sheath tumors (MPNST) are relatively rare neoplasms with poor prognosis. At present there is no effective treatment for MPNST other than surgical resection. Nonetheless, the anti-tumor effect of boron neutron capture therapy (BNCT) was recently demonstrated in two patients with MPNST. Subsequently, tumor-bearing nude mice subcutaneously transplanted with a human MPNST cell line were injected with p-borono-L-phenylalanine (L-BPA) and subjected to BNCT. Pathological studies then revealed that the MPNST cells were selectively destroyed by BNCT.

  5. Successful Treatment of Early Detected Trilateral Retinoblastoma Using Standard Infant Brain Tumor Therapy

    PubMed Central

    Wright, Karen D.; Qaddoumi, Ibrahim; Patay, Zoltan; Gajjar, Amar; Wilson, Matthew W.; Rodriguez-Galindo, Carlos

    2011-01-01

    Trilateral retinoblastoma is characterized by the presence of retinoblastoma with an intracranial tumor. The incidence is low and prognosis poor. Due to the paucity of information regarding successful treatment, we report the case of a 6 month old female referred for leukocoria and found to have an associated suprasellar tumor and pineal enhancement. The patient, treated with standard infant brain tumor therapy, remains alive without signs of active disease 35 months after diagnosis; no surgery or irradiation was used. Early diagnosis of trilateral retinoblastoma may facilitate the use of less intensive therapeutic approaches and result in excellent outcomes in these patients. PMID:20658634

  6. A Time-Delayed Mathematical Model for Tumor Growth with the Effect of a Periodic Therapy.

    PubMed

    Xu, Shihe; Wei, Xiangqing; Zhang, Fangwei

    2016-01-01

    A time-delayed mathematical model for tumor growth with the effect of periodic therapy is studied. The establishment of the model is based on the reaction-diffusion dynamics and mass conservation law and is considered with a time delay in cell proliferation process. Sufficient conditions for the global stability of tumor free equilibrium are given. We also prove that if external concentration of nutrients is large the tumor will not disappear and the conditions under which there exist periodic solutions to the model are also determined. Results are illustrated by computer simulations.

  7. Early CT findings after interstitial radiation therapy for primary malignant brain tumors

    SciTech Connect

    Tolly, T.L.; Bruckman, J.E.; Czarnecki, D.J.; Frazin, L.J.; Lewis, H.J.; Richards, M.J.; Adamkiewicz, J.J. Jr.

    1988-11-01

    The CT findings after interstitial radiation therapy for brain tumors have not been extensively described. We evaluated retrospectively the CT scans of 13 patients who were treated with brachytherapy for malignant glioma. We found no typical CT appearance that differentiates recurrent tumor from radiation effect. After undergoing brachytherapy, eight of the 13 patients scanned demonstrated enhancement of brain tissue beyond the margins of the original enhancing tumor mass. In most cases, the pattern of enhancement diminished and extended more peripherally from the central necrotic area with time. We also report a new CT finding of focal calcification developing at the site of the radioactive implant.

  8. Bortezomib-induced enzyme-targeted radiation therapy in herpesvirus-associated tumors.

    PubMed

    Fu, De-Xue; Tanhehco, Yvette; Chen, Jianmeng; Foss, Catherine A; Fox, James J; Chong, Ja-Mun; Hobbs, Robert F; Fukayama, Masashi; Sgouros, George; Kowalski, Jeanne; Pomper, Martin G; Ambinder, Richard F

    2008-10-01

    We investigated the possibility of using a pharmacologic agent to modulate viral gene expression to target radiotherapy to tumor tissue. In a mouse xenograft model, we had previously shown targeting of [(125)I]2'-fluoro-2'-deoxy-beta-D-5-iodouracil-arabinofuranoside ([(125)I]FIAU) to tumors engineered to express the Epstein-Barr virus thymidine kinase (EBV-TK). Here we extend those results to targeting of a therapeutic radiopharmaceutical [(131)I]FIAU to slow or stop tumor growth or to achieve tumor regression. These outcomes were achieved in xenografts with tumors that constitutively expressed the EBV-TK. With naturally infected EBV tumor cell lines (Burkitt's lymphoma and gastric carcinoma), activation of viral gene expression by pretreatment with bortezomib was required. Marked changes in tumor growth could also be achieved in naturally infected Kaposi's sarcoma herpesvirus tumors after pretreatment with bortezomib. Bortezomib-induced enzyme-targeted radiation therapy illustrates the possibility of pharmacologically modulating tumor gene expression to result in targeted radiotherapy.

  9. Multifunctional Gold Nanostar Conjugates for Tumor Imaging and Combined Photothermal and Chemo-therapy

    PubMed Central

    Chen, Haiyan; Zhang, Xin; Dai, Shuhang; Ma, Yuxiang; Cui, Sisi; Achilefu, Samuel; Gu, Yueqing

    2013-01-01

    Uniform gold nanostars (Au NS) were conjugated with cyclic RGD (cRGD) and near infrared (NIR) fluorescence probe (MPA) or anti-cancer drug (DOX) to obtain multi-functional nanoconstructs, Au-cRGD-MPA and Au-cRGD-DOX respectively. The NIR contrast agent Au-cRGD-MPA was shown to have low cytotoxicity. Using tumor cells and tumor bearing mice, these imaging nanoparticles demonstrated favorable tumor-targeting capability mediated by RGD peptide binding to its over-expressed receptor on the tumor cells. The multi-therapeutic analogue, Au-cRGD-DOX, integrates targeting tumor, chemotherapy and photo-thermotherapy into a single system. The synergistic effect of photo-thermal therapy and chemotherapy was demonstrated in different tumor cell lines and in vivo using S180 tumor-bearing mouse models. The viability of MDA-MB-231 cells was only 40 % after incubation with Au-cRGD-DOX and irradiation with NIR light. Both tail vein and intratumoral injections showed Au-cRGD-DOX treated mice exhibiting the slowest tumor increase. These results indicate that the multifunctional nanoconstruct is a promising combined therapeutic agent for tumor-targeting treatment, with the potential to enhance the anti-cancer treatment outcomes. PMID:24019851

  10. TIL therapy broadens the tumor-reactive CD8(+) T cell compartment in melanoma patients.

    PubMed

    Kvistborg, Pia; Shu, Chengyi Jenny; Heemskerk, Bianca; Fankhauser, Manuel; Thrue, Charlotte Albæk; Toebes, Mireille; van Rooij, Nienke; Linnemann, Carsten; van Buuren, Marit M; Urbanus, Jos H M; Beltman, Joost B; Thor Straten, Per; Li, Yong F; Robbins, Paul F; Besser, Michal J; Schachter, Jacob; Kenter, Gemma G; Dudley, Mark E; Rosenberg, Steven A; Haanen, John B A G; Hadrup, Sine Reker; Schumacher, Ton N M

    2012-07-01

    There is strong evidence that both adoptive T cell transfer and T cell checkpoint blockade can lead to regression of human melanoma. However, little data are available on the effect of these cancer therapies on the tumor-reactive T cell compartment. To address this issue we have profiled therapy-induced T cell reactivity against a panel of 145 melanoma-associated CD8(+) T cell epitopes. Using this approach, we demonstrate that individual tumor-infiltrating lymphocyte cell products from melanoma patients contain unique patterns of reactivity against shared melanoma-associated antigens, and that the combined magnitude of these responses is surprisingly low. Importantly, TIL therapy increases the breadth of the tumor-reactive T cell compartment in vivo, and T cell reactivity observed post-therapy can almost in full be explained by the reactivity observed within the matched cell product. These results establish the value of high-throughput monitoring for the analysis of immuno-active therapeutics and suggest that the clinical efficacy of TIL therapy can be enhanced by the preparation of more defined tumor-reactive T cell products.

  11. TIL therapy broadens the tumor-reactive CD8+ T cell compartment in melanoma patients

    PubMed Central

    Kvistborg, Pia; Shu, Chengyi Jenny; Heemskerk, Bianca; Fankhauser, Manuel; Thrue, Charlotte Albæk; Toebes, Mireille; van Rooij, Nienke; Linnemann, Carsten; van Buuren, Marit M.; Urbanus, Jos H.M.; Beltman, Joost B.; thor Straten, Per; Li, Yong F.; Robbins, Paul F.; Besser, Michal J.; Schachter, Jacob; Kenter, Gemma G.; Dudley, Mark E.; Rosenberg, Steven A.; Haanen, John B.A.G.; Hadrup, Sine Reker; Schumacher, Ton N.M.

    2012-01-01

    There is strong evidence that both adoptive T cell transfer and T cell checkpoint blockade can lead to regression of human melanoma. However, little data are available on the effect of these cancer therapies on the tumor-reactive T cell compartment. To address this issue we have profiled therapy-induced T cell reactivity against a panel of 145 melanoma-associated CD8+ T cell epitopes. Using this approach, we demonstrate that individual tumor-infiltrating lymphocyte cell products from melanoma patients contain unique patterns of reactivity against shared melanoma-associated antigens, and that the combined magnitude of these responses is surprisingly low. Importantly, TIL therapy increases the breadth of the tumor-reactive T cell compartment in vivo, and T cell reactivity observed post-therapy can almost in full be explained by the reactivity observed within the matched cell product. These results establish the value of high-throughput monitoring for the analysis of immuno-active therapeutics and suggest that the clinical efficacy of TIL therapy can be enhanced by the preparation of more defined tumor-reactive T cell products. PMID:22754759

  12. Tumor delivery of Photofrin® by PLL-g-PEG for photodynamic therapy.

    PubMed

    Kano, Arihiro; Taniwaki, Yuki; Nakamura, Izumi; Shimada, Naohiko; Moriyama, Kenji; Maruyama, Atsushi

    2013-05-10

    Photofrin® (porfimer sodium) is a photosensitive reagent used for photodynamic therapy (PDT) of tumors and dysplasias. Because only photo-irradiated sites are damaged, PDT is less invasive than systemic treatments. However, a photosensitive reaction is a major side effect of systemically delivered Photofrin. To enhance localization of Photofrin to tumors, we have formulated Photofrin with the tumor-localizing graft copolymer poly(ethylene glycol)-grafted poly(l-lysine), PLL-g-PEG. We demonstrate that Photofrin preferentially interacts with PLL-g-PEG through both ionic and hydrophobic interactions. The serum competitive study showed that the highly PEG-grafted PLL is better for preventing serum binding to the Photofrin/PLL-g-PEG complex. In tumor-bearing mice, formulation of Photofrin with PLL-g-PEG enhanced tumor localization of Photofrin as twice as Photofrin alone and concomitantly suppressed the photosensitivity reaction drastically. Copyright © 2013 Elsevier B.V. All rights reserved.

  13. [Selection of microRNA for providing tumor specificity of transgene expression in cancer gene therapy].

    PubMed

    Shepelev, M V; Kalinichenko, S V; Vikhreva, P N; Korobko, I V

    2016-01-01

    The use of tumor-specific microRNA loss to inhibit transgene expression in normal cells is considered as a way to increase the specificity of gene-therapeutic antitumor drugs. This method assumes the introduction of recognition sites of suppressed in tumor cells microRNAs into transgene transcipt. In the presented work, the efficiency of the strategy for providing the tumor specificity of transgene expression depending on parameters of microRNA expression in normal and tumor cells was studied. It was established that microRNA suppression in tumor cells and the determination of absolute microRNA levels in tumor and normal cells are not sufficient for the adequate estimation of the possibility of specific microRNA usage in the scheme of cancer gene therapy, and particularly do not allow to exclude a significant decrease in the efficiency of the gene-therapeutic drug upon the introduction of microRNA recognition sites. These parameters are only suitable for the preliminary selection of microRNA. The effect of introduction of microRNA recognition sites on transgene expression level in target tumor cells should be validated experimentally. It is suggested that this should be done directly in the cancer gene therapy scheme with monitoring of the therapeutic transgene activity.

  14. Synchrotron X-Ray Synthesized Gold Nanoparticles for Tumor Therapy

    SciTech Connect