RESUMO
Microbeam radiation therapy (MRT), a preclinical form of radiosurgery, uses spatially fractionated micrometre-wide synchrotron-generated X-ray beams. As MRT alone is predominantly palliative for animal tumors, the effects of the combination of MRT and a newly synthesized chemotherapeutic agent JAI-51 on 9L gliosarcomas have been evaluated. Fourteen days (D14) after implantation (D0), intracerebral 9LGS-bearing rats received either MRT, JAI-51 or both treatments. JAI-51, alone or immediately after MRT, was administered three times per week. Animals were kept up to â¼20 weeks after irradiation or sacrificed at D16 or D28 after treatment for cell cycle analysis. MRT plus JAI-51 increased significantly the lifespan compared with MRT alone (p = 0.0367). JAI-51 treatment alone had no effect on rat survival. MRT alone or associated with JAI-51 induced a cell cycle blockade in G2/M (p < 0.01) while the combined treatment also reduced the proportion of G0/G1 cells. At D28 after irradiation, MRT and MRT/JAI-51 had a smaller cell blockade effect in the G2/M phase owing to a significant increase in tumor cell death rate (<2c) and a proportional increase of endoreplicative cells (>8c). The combination of MRT and JAI-51 increases the survival of 9LGS-bearing rats by inducing endoreduplication of DNA and tumor cell death; further, it slowed the onset of tumor growth resumption two weeks after treatment.
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Neoplasias Encefálicas/cirurgia , Chalconas/uso terapêutico , Gliossarcoma/cirurgia , Radiocirurgia , Animais , Neoplasias Encefálicas/tratamento farmacológico , Gliossarcoma/tratamento farmacológico , Masculino , Ratos , Ratos Endogâmicos F344 , Síncrotrons , Tubulina (Proteína)/efeitos dos fármacosRESUMO
PURPOSE: This extraordinary woman worked her professional way from a radiation protection engineer to become the successful principal investigator of a prestigious international European project for a new radiation therapy (ERC Synergy grant, HORIZON 2020). The evaluation of the submitted proposal was very positive. The panel proposed that it be funded. Elke tragically passed away a few days before this conclusion of the panel. The present account describes her gradual career development; it includes many episodes that Elke personally chronicled in her curriculum of 2017. METHODS: An internet literature search was performed using Google Scholar and other sources to assist in the writing of this narrative review and account. CONCLUSIONS: In parallel to the development of the new Biomedical Beamline ID17 at the European Synchrotron Radiation Facility in Grenoble in the late nineties, Elke focused her interest and her personal and professional priorities on MRT, particularly on its clinical goals. She outlined her main objectives in several documents: (1) develop a new paradigm of cancer care by broadening the foundation for MRT. (2) Filling the gaps in basic biological knowledge about the mechanisms of MRT effects on normal and neoplastic tissues. (3) Broaden the preclinical level of evidence for the low normal organ toxicity of MRT versus standard X-ray irradiations; preclinical experiments involved the application of MRT to animal tumor patients, to animals of larger size than laboratory rodents, using larger radiation field sizes, and irradiating in a real-time scenario comparable to the one planned for human patients. (4) To foster the specific purpose of radiosurgical MRT of tumor patients at the ESRF that required development of new, specific state of the art modalities and tools for treatment planning, dosimetry, dose calculation, patient positioning and, of particular importance, redundant levels of patient safety. Just as she was about to take responsibility as principal investigator for a prestigious international European project on a new radiation therapy, death called Elke in.
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Neoplasias , Radiocirurgia , Animais , Humanos , Radiometria , Síncrotrons , Raios XRESUMO
Ultra-high-dose rate "FLASH" radiotherapy (FLASH-RT) has been shown to drastically reduce normal tissue toxicities while being as efficacious as conventional dose rate radiotherapy to treat tumors. A large number of preclinical studies describing this so-called FLASH effect have led to the clinical translation of FLASH-RT using ultra-high-dose rate electron and proton beams. Although the vast majority of radiation therapy treatments are delivered using X-rays, few preclinical data using ultra-high-dose rate X-ray irradiation have been published. This review focuses on different methods that can be used to generate ultra-high-dose rate X-rays and their beam characteristics along with their effect on the biological tissues and the perspectives for the development of FLASH-RT with X-rays.
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Neoplasias , Radioterapia (Especialidade) , Elétrons , Humanos , Neoplasias/radioterapia , Radioterapia/métodos , Dosagem Radioterapêutica , Raios XRESUMO
PURPOSE: Synchrotron-generated microbeam radiation therapy (MRT) represents an innovative preclinical type of cancer radiation therapy with an excellent therapeutic ratio. Beyond local control, metastatic spread is another important endpoint to assess the effectiveness of radiation therapy treatment. Currently, no data exist on an association between MRT and metastasis. Here, we evaluated the ability of MRT to delay B16F10 murine melanoma progression and locoregional metastatic spread. METHODS AND MATERIALS: We assessed the primary tumor response and the extent of metastasis in sentinel lymph nodes in 2 cohorts of C57BL/6J mice, one receiving a single MRT and another receiving 2 MRT treatments delivered with a 10-day interval. We compared these 2 cohorts with synchrotron broad beam-irradiated and nonirradiated mice. In addition, using multiplex quantitative platforms, we measured plasma concentrations of 34 pro- and anti-inflammatory cytokines and frequencies of immune cell subsets infiltrating primary tumors that received either 1 or 2 MRT treatments. RESULTS: Two MRT treatments were significantly more effective for local control than a single MRT. Remarkably, the second MRT also triggered a pronounced regression of out-of-radiation field locoregional metastasis. Augmentation of CXCL5, CXCL12, and CCL22 levels after the second MRT indicated that inhibition of melanoma progression could be associated with increased activity of antitumor neutrophils and T-cells. Indeed, we demonstrated elevated infiltration of neutrophils and activated T-cells in the tumors after the second MRT. CONCLUSIONS: Our study highlights the importance of monitoring metastasis after MRT and provides the first MRT fractionation schedule that promotes local and locoregional control with the potential to manage distant metastasis.
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Melanoma , Síncrotrons , Animais , Citocinas , Melanoma/radioterapia , Camundongos , Camundongos Endogâmicos C57BL , Síndrome , Linfócitos TRESUMO
BACKGROUND: Microbeam Radiation Therapy (MRT) induces a transient vascular permeability window, which offers a novel drug-delivery system for the preferential accumulation of therapeutic compounds in tumors. MRT is a preclinical cancer treatment modality that spatially fractionates synchrotron X-rays into micrometer-wide planar microbeams which can induce transient vascular permeability, especially in the immature tumor vessels, without compromising vascular perfusion. Here, we characterized this phenomenon using Chicken Chorioallantoic Membrane (CAM) and demonstrated its therapeutic potential in human glioblastoma xenografts in mice. METHODS: the developing CAM was exposed to planar-microbeams of 75 Gy peak dose with Synchrotron X-rays. Similarly, mice harboring human glioblastoma xenografts were exposed to peak microbeam doses of 150 Gy, followed by treatment with Cisplatin. Tumor progression was documented by Magnetic Resonance Imaging (MRI) and caliper measurements. RESULTS: CAM exposed to MRT exhibited vascular permeability, beginning 15 min post-irradiation, reaching its peak from 45 min to 2 h, and ending by 4 h. We have deemed this period the "permeability window". Morphological analysis showed partially fragmented endothelial walls as the cause of the increased transport of FITC-Dextran into the surrounding tissue and the extravasation of 100 nm microspheres (representing the upper range of nanoparticles). In the human glioblastoma xenografts, MRI measurements showed that the combined treatment dramatically reduced the tumor size by 2.75-fold and 5.25-fold, respectively, compared to MRT or Cisplatin alone. CONCLUSIONS: MRT provides a novel mechanism for drug delivery by increasing vascular transpermeability while preserving vessel integrity. This permeability window increases the therapeutic index of currently available chemotherapeutics and could be combined with other therapeutic agents such as Nanoparticles/Antibodies/etc.
RESUMO
Delivery of high-radiation doses to brain tumors via multiple arrays of synchrotron X-ray microbeams permits huge therapeutic advantages. Brain tumor (9LGS)-bearing and normal rats were irradiated using a conventional, homogeneous Broad Beam (BB), or Microbeam Radiation Therapy (MRT), then studied by behavioral tests, MRI, and histopathology. A valley dose of 10 Gy deposited between microbeams, delivered by a single port, improved tumor control and median survival time of tumor-bearing rats better than a BB isodose. An increased number of ports and an accumulated valley dose maintained at 10 Gy delayed tumor growth and improved survival. Histopathologically, cell death, vascular damage, and inflammatory response increased in tumors. At identical valley isodose, each additional MRT port extended survival, resulting in an exponential correlation between port numbers and animal lifespan (r2 = 0.9928). A 10 Gy valley dose, in MRT mode, delivered through 5 ports, achieved the same survival as a 25 Gy BB irradiation because of tumor dose hot spots created by intersecting microbeams. Conversely, normal tissue damage remained minimal in all the single converging extratumoral arrays. Multiport MRT reached exceptional ~2.5-fold biological equivalent tumor doses. The unique normal tissue sparing and therapeutic index are eminent prerequisites for clinical translation.
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PURPOSE: In the past 3 decades, synchrotron microbeam radiation therapy (S-MRT) has been shown to achieve both good tumor control and normal tissue sparing in a range of preclinical animal models. However, the use of S-MRT for the treatment of lung tumors has not yet been investigated. This study is the first to evaluate the therapeutic efficacy of S-MRT for the treatment of lung carcinoma, using a new syngeneic and orthotopic mouse model. METHODS AND MATERIALS: Lewis Lung carcinoma-bearing mice were irradiated with 2 cross-fired arrays of S-MRT or synchrotron broad-beam (S-BB) radiation therapy. S-MRT consisted of 17 microbeams with a width of 50 µm and center-to-center spacing of 400 µm. Each microbeam delivered a peak entrance dose of 400 Gy whereas S-BB delivered a homogeneous entrance dose of 5.16 Gy (corresponding to the S-MRT valley dose). RESULTS: Both treatments prolonged the survival of mice relative to the untreated controls. However, mice in the S-MRT group developed severe pulmonary edema around the irradiated carcinomas and did not have improved survival relative to the S-BB group. Subsequent postmortem examination of tumor size revealed that the mice in the S-MRT group had notably smaller tumor volume compared with the S-BB group, despite the presence of edema. Mice that were sham-implanted did not display any decline in health after S-MRT, experiencing only mild and transient edema between 4 days and 3 months postirradiation which disappeared after 4 months. Finally, a parallel study investigating the lungs of healthy mice showed the complete absence of radiation-induced pulmonary fibrosis 6 months after S-MRT. CONCLUSIONS: S-MRT is a promising tool for the treatment of lung carcinoma, reducing tumor size compared with mice treated with S-BB and sparing healthy lungs from pulmonary fibrosis. Future experiments should focus on optimizing S-MRT parameters to minimize pulmonary edema and maximize the therapeutic ratio.
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Neoplasias Pulmonares , Edema Pulmonar , Fibrose Pulmonar , Animais , Pulmão , Neoplasias Pulmonares/radioterapia , Camundongos , SíncrotronsRESUMO
PURPOSE: Synchrotron microbeam radiation therapy (MRT) is based on the spatial fractionation of the incident, highly collimated synchrotron beam into arrays of parallel microbeams depositing several hundred grays. It appears relevant to combine MRT with a conventional treatment course, preparing a treatment scheme for future patients in clinical trials. The efficiency of MRT delivered after several broad-beam (BB) fractions to palliate F98 brain tumors in rats in comparison with BB fractions alone was evaluated in this study. METHODS AND MATERIALS: Rats bearing 106 F98 cells implanted in the caudate nucleus were irradiated by 5 fractions in BB mode (3 × 6 Gy + 2 × 8 Gy BB) or by 2 boost fractions in MRT mode to a total of 5 fractions (3 × 6 Gy BB + MRT 2 × 8 Gy valley dose; peak dose 181 Gy [50/200 µm]). Tumor growth was evaluated in vivo by magnetic resonance imaging follow-up at T-1, T7, T12, T15, T20, and T25 days after radiation therapy and by histology and flow cytometry. RESULTS: MRT-boosted tumors displayed lower cell density and cell proliferation compared with BB-irradiated tumors. The MRT boost completely stopped tumor growth during â¼4 weeks and led to a significant increase in median survival time, whereas tumors treated with BB alone recurred within a few days after the last radiation fraction. CONCLUSIONS: The first evidence is presented that MRT, delivered as a boost of conventionally fractionated irradiation by orthovoltage broad x-ray beams, is feasible and more efficient than conventional radiation therapy alone.
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Neoplasias Encefálicas/radioterapia , Fracionamento da Dose de Radiação , Glioblastoma/radioterapia , Glioma/radioterapia , Síncrotrons , Terapia por Raios X/instrumentação , Animais , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Ciclo Celular/efeitos da radiação , Proliferação de Células/efeitos da radiação , Glioblastoma/diagnóstico por imagem , Glioblastoma/patologia , Imageamento por Ressonância Magnética , Masculino , Ratos , Ratos Wistar , Carga Tumoral/efeitos da radiaçãoRESUMO
The purpose of this work was the understanding of microbeam radiation therapy at the ESRF in order to find the best compromise between curing of tumors and sparing of normal tissues, to obtain a better understanding of survival curves and to report its efficiency. This method uses synchrotron-generated x-ray microbeams. Rats were implanted with 9L gliosarcomas and the tumors were diagnosed by MRI. They were irradiated 14 days after implantation by arrays of 25 microm wide microbeams in unidirectional mode, with a skin entrance dose of 625 Gy. The effect of using 200 or 100 microm center-to-center spacing between the microbeams was compared. The median survival time (post-implantation) was 40 and 67 days at 200 and 100 microm spacing, respectively. However, 72% of rats irradiated at 100 microm spacing showed abnormal clinical signs and weight patterns, whereas only 12% of rats were affected at 200 microm spacing. In parallel, histological lesions of the normal brain were found in the 100 microm series only. Although the increase in lifespan was equal to 273% and 102% for the 100 and 200 microm series, respectively, the 200 microm spacing protocol provides a better sparing of healthy tissue and may prove useful in combination with other radiation modalities or additional drugs.
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Cérebro/patologia , Irradiação Craniana/métodos , Gliossarcoma/radioterapia , Síncrotrons , Animais , Peso Corporal , Linhagem Celular Tumoral , Gliossarcoma/diagnóstico , Gliossarcoma/patologia , Imageamento por Ressonância Magnética , Masculino , Transplante de Neoplasias , Ratos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
OBJECT: The aim of this study was to develop and characterize a new orthotopic, syngeneic, transplantable mouse brain tumor model by using the cell lines Tu-9648 and Tu-2449, which were previously isolated from tumors that arose spontaneously in glial fibrillary acidic protein (GFAP)-v-src transgenic mice. METHODS: Striatal implantation of a 1-microl suspension of 5000 to 10,000 cells from either clone into syngeneic B6C3F1 mice resulted in tumors that were histologically identified as malignant gliomas. Prior subcutaneous inoculations with irradiated autologous cells inhibited the otherwise robust development of a microscopically infiltrating malignant glioma. Untreated mice with implanted tumor cells were killed 12 days later, when the resultant gliomas were several millimeters in diameter. Immunohistochemically, the gliomas displayed both the astroglial marker GFAP and the oncogenic form of signal transducer and activator of transcription-3 (Stat3). This form is called tyrosine-705 phosphorylated Stat3, and is found in many malignant entities, including human gliomas. Phosphorylated Stat3 was particularly prominent, not only in the nucleus but also in the plasma membrane of peripherally infiltrating glioma cells, reflecting persistent overactivation of the Janus kinase/Stat3 signal transduction pathway. The Tu-2449 cells exhibited three non-random structural chromosomal aberrations, including a deletion of the long arm of chromosome 2 and an apparently balanced translocation between chromosomes 1 and 3. The GFAP-v-src transgene was mapped to the pericentromeric region of chromosome 18. CONCLUSIONS: The high rate of engraftment, the similarity to the high-grade malignant glioma of origin, and the rapid, locally invasive growth of these tumors should make this murine model useful in testing novel therapies for human malignant gliomas.
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Neoplasias Encefálicas/genética , Modelos Animais de Doenças , Genes src/fisiologia , Glioma/genética , Transplante de Neoplasias/métodos , Neoplasias Cutâneas/genética , Animais , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral/transplante , Glioma/patologia , Camundongos , Camundongos Transgênicos , Neoplasias Cutâneas/patologiaRESUMO
Among patients with differentiated thyroid carcinoma (diffTCa), the rare hyperfunctioning or toxic TCa (ToxTCa) was diagnosed when scintigraphic hot thyroid areas were attributable only to diffTCa (diameter >1 cm by pathological examination) and/or total thyroidectomy failed to induce hypothyroidism. Of 924 cases of all TCa (papillary diffTCa 47.3%, follicular diffTCa 44.2%, others 8.5%), 19 had ToxTCa (2.1%, 15 of 19 follicular, 4 of 19 papillary, P = 0.008). These received a more intensive radioiodine therapy (average cumulated (131)I activities 21.8 vs. 15.2 GBq, P < 0.01). Five-year survival rates for ToxTCa (n = 19, 56%) and diffTCa (n = 545, 94.5%) differed [hazard ratio 4.8, 95% confidence interval (CI) 2.8-8.1, P = 0.001]. However, the differences were attenuated by matching ToxTCa and diffTCa (n = 57, 5-yr survival rate 74%) for age, sex, and histopathologic type (hazard ratio 2.1, 95% CI 1.13-3.9, P = 0.02). Correcting statistically for M(1) against M(0) stage distribution resulted in a further reduction of the hazard ratio (hazard ratio 1.8, 95% CI 0.93-3.48, P = 0.08). An M(1) stage is an important prognostic factor in ToxTCa patients. Thus, ToxTCa, treated with higher activities of (131)I, has a survival prognosis close to that of matched diffTCa cases, both groups consisting mainly (79%) of follicular subtypes.
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Neoplasias da Glândula Tireoide/mortalidade , Tireotoxicose/mortalidade , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Cintilografia , Estudos Retrospectivos , Análise de Sobrevida , Neoplasias da Glândula Tireoide/complicações , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/patologia , Tireotoxicose/complicações , Fatores de TempoRESUMO
The histopathologic features of acute radiation-induced colitis in humans have been described in occasional, >20-year-old studies, but they have not been analyzed in detail. We characterize such findings in 34 patients with rectal cancer who underwent surgery a few days after preoperative irradiation with 25 Gy given over 5-7 days, and we compare the results to the histopathologic features detected in 18 patients treated by a conventional preoperative irradiation protocol consisting of 45 Gy during 5 weeks followed by surgery after a time interval of at least 3 weeks. Short-term preoperative irradiation therapy generally induced severe mucosal inflammation characterized by increased cellularity of the lamina propria, prominent eosinophilic infiltrates, crypt disarray, surface and crypt epithelial damage, nuclear abnormalities, and presence of apoptotic bodies in the crypt epithelium. These histopathologic features were absent or detected only occasionally in the patient group treated according to the long-term preoperative irradiation protocol. Despite acute severe inflammation, none of the patients treated by short-term irradiation developed perioperative complications. These observations indicate that acute radiation colitis may remain clinically silent and resolve spontaneously within a few weeks after irradiation. Given the widening acceptance of short-term preoperative irradiation protocols for rectal cancer, pathologists should be aware of the rather characteristic histologic findings of acute radiation colitis and avoid unnecessary concern of clinicians. The differential diagnosis includes infectious colitis, collagenous and ischemic colitis, nonsteroidal anti-inflammatory drug-associated colitis, and chronic idiopathic inflammatory bowel disease.
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Colite/patologia , Lesões por Radiação/patologia , Neoplasias Retais/radioterapia , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Colite/etiologia , Seguimentos , Humanos , Inflamação/patologia , Pessoa de Meia-Idade , Lesões por Radiação/etiologia , Neoplasias Retais/cirurgiaRESUMO
Since approximately two thirds of epileptic patients are non-eligible for surgery, local axonal fiber transections might be of particular interest for them. Micrometer to millimeter wide synchrotron-generated X-ray beamlets produced by spatial fractionation of the main beam could generate such fiber disruptions non-invasively. The aim of this work was to optimize irradiation parameters for the induction of fiber transections in the rat brain white matter by exposure to such beamlets. For this purpose, we irradiated cortex and external capsule of normal rats in the antero-posterior direction with a 4 mm×4 mm array of 25 to 1000 µm wide beamlets and entrance doses of 150 Gy to 500 Gy. Axonal fiber responses were assessed with diffusion tensor imaging and fiber tractography; myelin fibers were examined histopathologically. Our study suggests that high radiation doses (500 Gy) are required to interrupt axons and myelin sheaths. However, a radiation dose of 500 Gy delivered by wide minibeams (1000 µm) induced macroscopic brain damage, depicted by a massive loss of matter in fiber tractography maps. With the same radiation dose, the damage induced by thinner microbeams (50 to 100 µm) was limited to their paths. No macroscopic necrosis was observed in the irradiated target while overt transections of myelin were detected histopathologically. Diffusivity values were found to be significantly reduced. A radiation dose ≤ 500 Gy associated with a beamlet size of < 50 µm did not cause visible transections, neither on diffusion maps nor on sections stained for myelin. We conclude that a peak dose of 500 Gy combined with a microbeam width of 100 µm optimally induced axonal transections in the white matter of the brain.
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Axônios/patologia , Encéfalo/patologia , Imagem de Tensor de Difusão/métodos , Animais , Axônios/efeitos da radiação , Encéfalo/efeitos da radiação , Bainha de Mielina/patologia , Bainha de Mielina/efeitos da radiação , Fibras Nervosas Mielinizadas/patologia , Fibras Nervosas Mielinizadas/efeitos da radiação , Doses de Radiação , Ratos , Síncrotrons , Raios XRESUMO
PURPOSE: To further evaluate the use of microbeam irradiation (MBI) as a potential means of non-invasive brain tumor treatment by investigating the induction of a bystander effect in non-irradiated tissue. METHODS: Adult rats were irradiated with 35 or 350 Gy at the European Synchotron Research Facility (ESRF), using homogenous (broad beam) irradiation (HI) or a high energy microbeam delivered to the right brain hemisphere only. The proteome of the frontal lobes were then analyzed using two-dimensional electrophoresis (2-DE) and mass spectrometry. RESULTS: HI resulted in proteomic responses indicative of tumourigenesis; increased albumin, aconitase and triosphosphate isomerase (TPI), and decreased dihydrolipoyldehydrogenase (DLD). The MBI bystander effect proteomic changes were indicative of reactive oxygen species mediated apoptosis; reduced TPI, prohibitin and tubulin and increased glial fibrillary acidic protein (GFAP). These potentially anti-tumourigenic apoptotic proteomic changes are also associated with neurodegeneration. However the bystander effect also increased heat shock protein (HSP) 71 turnover. HSP 71 is known to protect against all of the neurological disorders characterized by the bystander effect proteome changes. CONCLUSIONS: These results indicate that the collective interaction of these MBI-induced bystander effect proteins and their mediation by HSP 71, may confer a protective effect which now warrants additional experimental attention.
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Encéfalo/metabolismo , Encéfalo/efeitos da radiação , Efeito Espectador/efeitos da radiação , Proteoma/metabolismo , Proteoma/efeitos da radiação , Sequência de Aminoácidos , Animais , Apoptose/efeitos da radiação , Encéfalo/citologia , Neoplasias Encefálicas/etiologia , Eletroforese em Gel Bidimensional , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Proteína Glial Fibrilar Ácida/efeitos da radiação , Proteínas de Choque Térmico/metabolismo , Proteínas de Choque Térmico/efeitos da radiação , Masculino , Dados de Sequência Molecular , Neoplasias Induzidas por Radiação/etiologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/efeitos da radiação , Estresse Oxidativo/efeitos da radiação , Proibitinas , Proteoma/genética , Proteômica , Ratos , Ratos Wistar , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Proteínas Repressoras/efeitos da radiação , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Síncrotrons , Triose-Fosfato Isomerase/genética , Triose-Fosfato Isomerase/metabolismo , Triose-Fosfato Isomerase/efeitos da radiação , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismo , Tubulina (Proteína)/efeitos da radiaçãoRESUMO
PURPOSE: Synchrotron microbeam radiation therapy (MRT) is an innovative irradiation modality based on spatial fractionation of a high-dose X-ray beam into lattices of microbeams. The increase in lifespan of brain tumor-bearing rats is associated with vascular damage but the physiological consequences of MRT on blood vessels have not been described. In this manuscript, we evaluate the oxygenation changes induced by MRT in an intracerebral 9L gliosarcoma model. METHODS: Tissue responses to MRT (two orthogonal arrays (2 × 400Gy)) were studied using magnetic resonance-based measurements of local blood oxygen saturation (MR_SO2) and quantitative immunohistology of RECA-1, Type-IV collagen and GLUT-1, marker of hypoxia. RESULTS: In tumors, MR_SO2 decreased by a factor of 2 in tumor between day 8 and day 45 after MRT. This correlated with tumor vascular remodeling, i.e. decrease in vessel density, increases in half-vessel distances (×5) and GLUT-1 immunoreactivity. Conversely, MRT did not change normal brain MR_SO2, although vessel inter-distances increased slightly. CONCLUSION: We provide new evidence for the differential effect of MRT on tumor vasculature, an effect that leads to tumor hypoxia. As hypothesized formerly, the vasculature of the normal brain exposed to MRT remains sufficiently perfused to prevent any hypoxia.
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Neoplasias Encefálicas/radioterapia , Encéfalo/efeitos da radiação , Gliossarcoma/radioterapia , Oxigênio/sangue , Síncrotrons , Terapia por Raios X/métodos , Animais , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/metabolismo , Gliossarcoma/irrigação sanguínea , Gliossarcoma/metabolismo , Transportador de Glucose Tipo 1/análise , Imageamento por Ressonância Magnética , RatosRESUMO
BACKGROUND AND PURPOSE: To quantify the late dose-related responses of the rat cervical spinal cord to X-ray irradiations by an array of microbeams or by a single millimeter beam. MATERIALS AND METHODS: Necks of anesthetized rats were irradiated transversely by an 11 mm wide array of 52 parallel, 35 µm wide, vertical X-ray microbeams, separated by 210 µm intervals between centers. Comparison was made with rats irradiated with a 1.35 mm wide single beam of similar X-rays. Rats were killed when paresis developed, or up to 383 days post irradiation (dpi). RESULTS: Microbeam peak/valley doses of ≈357/12.7 Gy to 715/25.4 Gy to an 11 mm long segment of the spinal cord, or single beam doses of ≈146-454 Gy to a 1.35 mm long segment caused foreleg paresis and histopathologically verified spinal cord damage; rats exposed to peak/valley doses up to 253/9 Gy were paresis-free at 383 dpi. CONCLUSIONS: Whereas microbeam radiation therapy [MRT] for malignant gliomas implanted in rat brains can be safe, palliative or curative, the high tolerance of normal rat spinal cords to similar microbeam exposures justifies testing MRT for autochthonous malignancies in the central nervous system of larger animals with a view to subsequent clinical applications.
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Medula Espinal/efeitos da radiação , Animais , Relação Dose-Resposta à Radiação , Feminino , Masculino , Ratos , Medula Espinal/patologia , Raios XRESUMO
Grid (or sieve) therapy ("Gitter-" oder "Siebtherapie"), spatially fractionated kilo- and megavolt X-ray therapy, was invented in 1909 by Alban Köhler, a radiologist in Wiesbaden, Germany. He tested it on several patients before 1913 using approximately 60-70kV Hittorf-Crookes tubes. Köhler pushed the X-ray tube's lead-shielded housing against a stiff grid of 1 mm-square iron wires woven 3.0-3.5mm on center, taped tightly to the skin over a thin chamois. Numerous islets unshielded by iron in the pressure-blanched skin were irradiated with up to about 6 erythema doses (ED). The skin was then thoroughly cleansed, disinfected, and bandaged; delayed punctate necrosis healed in several weeks. Although grid therapy was disparaged or ignored until the 1930s, it has been used successfully since then to shrink bulky malignancies. Also, advanced cancers in rats and mice have been mitigated or ablated using Köhler's concept since the early 1990s by unidirectional or stereotactic exposure to an array of nearly parallel microplanar (25-75µm-wide) beams of very intense, moderately hard (median energy approximately 100 keV) synchrotron-generated X rays spaced 0.1-0.4mm on center. Such beams maintain sharp edges at high doses well beneath the skin yet confer little toxicity. They could palliate some otherwise intractable malignancies, perhaps in young children too, with tolerable sequelae. There are plans for such studies in larger animals.
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Radioterapia (Especialidade)/história , Radioterapia/história , Alemanha , História do Século XIX , História do Século XXRESUMO
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 × 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 (×3.25), 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.
Assuntos
Neoplasias Encefálicas/irrigação sanguínea , Encéfalo/irrigação sanguínea , Artérias Cerebrais/efeitos da radiação , Veias Cerebrais/efeitos da radiação , Gliossarcoma/irrigação sanguínea , Síncrotrons , Animais , Edema Encefálico/diagnóstico , Edema Encefálico/etiologia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Permeabilidade Capilar/efeitos da radiação , Circulação Cerebrovascular/efeitos da radiação , Gliossarcoma/mortalidade , Gliossarcoma/patologia , Imageamento por Ressonância Magnética , Método de Monte Carlo , Tolerância a Radiação , Dosagem Radioterapêutica , Ratos , Ratos Endogâmicos F344 , Carga Tumoral , Fator A de Crescimento do Endotélio Vascular/análise , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Microbeam Radiation Therapy (MRT) is a preclinical form of radiosurgery dedicated to brain tumor treatment. It uses micrometer-wide synchrotron-generated X-ray beams on the basis of spatial beam fractionation. Due to the radioresistance of normal brain vasculature to MRT, a continuous blood supply can be maintained which would in part explain the surprising tolerance of normal tissues to very high radiation doses (hundreds of Gy). Based on this well described normal tissue sparing effect of microplanar beams, we developed a new irradiation geometry which allows the delivery of a high uniform dose deposition at a given brain target whereas surrounding normal tissues are irradiated by well tolerated parallel microbeams only. Normal rat brains were exposed to 4 focally interlaced arrays of 10 microplanar beams (52 microm wide, spaced 200 microm on-center, 50 to 350 keV in energy range), targeted from 4 different ports, with a peak entrance dose of 200Gy each, to deliver an homogenous dose to a target volume of 7 mm(3) in the caudate nucleus. Magnetic resonance imaging follow-up of rats showed a highly localized increase in blood vessel permeability, starting 1 week after irradiation. Contrast agent diffusion was confined to the target volume and was still observed 1 month after irradiation, along with histopathological changes, including damaged blood vessels. No changes in vessel permeability were detected in the normal brain tissue surrounding the target. The interlacing radiation-induced reduction of spontaneous seizures of epileptic rats illustrated the potential pre-clinical applications of this new irradiation geometry. Finally, Monte Carlo simulations performed on a human-sized head phantom suggested that synchrotron photons can be used for human radiosurgical applications. Our data show that interlaced microbeam irradiation allows a high homogeneous dose deposition in a brain target and leads to a confined tissue necrosis while sparing surrounding tissues. The use of synchrotron-generated X-rays enables delivery of high doses for destruction of small focal regions in human brains, with sharper dose fall-offs than those described in any other conventional radiation therapy.