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1.
Radiat Oncol ; 15(1): 171, 2020 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-32653003

RESUMEN

BACKGROUND: To date, only limited magnetic resonance imaging (MRI) data are available concerning tumor regression during neoadjuvant radiochemotherapy (RCT) of rectal cancer patients, which is a prerequisite for adaptive radiotherapy (RT) concepts. This exploratory study prospectively evaluated daily fractional MRI during neoadjuvant treatment to analyze the predictive value of MR biomarkers for treatment response. METHODS: Locally advanced rectal cancer patients were examined with daily MRI during neoadjuvant RCT. Contouring of the tumor volume was performed for each MRI scan by using T2- and diffusion-weighted-imaging (DWI)-sequences. The daily apparent-diffusion coefficient (ADC) was calculated. Volumetric and functional tumor changes during RCT were analyzed and correlated with the pathological response after surgical resection. RESULTS: In total, 171 MRI scans of eight patients were analyzed regarding anatomical and functional dynamics during RCT. Pathological complete response (pCR) could be achieved in four patients, and four patients had a pathological partial response (pPR) following neoadjuvant treatment. T2- and DWI-based volumetry proved to be statistically significant in terms of therapeutic response, and volumetric thresholds at week two and week four during RCT were defined for the prediction of pCR. In contrast, the average tumor ADC values widely overlapped between both response groups during RCT and appeared inadequate to predict treatment response in our patient cohort. CONCLUSION: This prospective exploratory study supports the hypothesis that MRI may be able to predict pCR of rectal cancers early during neoadjuvant RCT. Our data therefore provide a useful template to tailor future MR-guided adaptive treatment concepts.


Asunto(s)
Quimioradioterapia , Imagen de Difusión por Resonancia Magnética/métodos , Imagen por Resonancia Magnética/métodos , Neoplasias del Recto/terapia , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Estudios Prospectivos , Planificación de la Radioterapia Asistida por Computador , Neoplasias del Recto/diagnóstico por imagen , Neoplasias del Recto/patología
2.
Cancer Manag Res ; 11: 8327-8335, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31686914

RESUMEN

BACKGROUND: Considering the increasing simultaneous application of magnetic resonance imaging (MRI) for more precise photon radiotherapy, it will be likely for particle radiotherapy to adopt MRI for future image guiding. It will then be imperative to evaluate the potential biological effects of a magnetic field (MF) on particle irradiation. This study explores such effects on the highly radiosensitive TK6 lymphoblastoid human cell line. METHODS: The following three parameters were measured after irradiation with either carbon ion or proton beams using spread out Bragg peaks and applying different doses within a perpendicular 1.0 T MF: (1) cell survival fraction (14 days postirradiation), (2) treatment-specific apoptosis, which was determined through the measurement of population in the sub-G1 phase, and (3) cell cycle progression by means of flow cytometry. These were compared to the same parameters measured without an MF. RESULTS: The clonogenic assay in both treatment groups showed almost identical survival curves with overlapping error bars. The calculated α values with and without an MF were 2.18 (σ=0.245) and 2.17 (σ=0.234) for carbon ions and 1.08 (σ=0.138) and 1.13 (σ=0.0679) for protons, respectively. Similarly, the treatment-specific apoptosis and cell cycle progression showed almost identical curves with overlapping error bars. A two-sample, unpooled t-test analysis was implemented for comparison of all mean values and showed p-values >0.05. CONCLUSION: No statistically significant difference in biological response of the TK6 cells was observed when they were irradiated using spreadout Bragg peaks within a perpendicular 1.0 T MF as compared to those, which received the same dose without the MF. This should serve as another supporting piece of evidence toward the implementation of MRI in particle radiotherapy, though further research is necessary.

3.
Radiat Oncol ; 14(1): 11, 2019 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-30654822

RESUMEN

BACKGROUND: The implementation of magnetic resonance imaging (MRI) guided radiotherapy (RT) continues to increase. Very limited in-vitro data on the interaction of ionizing radiation and magnetic fields (MF) have been published. In these experiments we focused on the radiation response in a MF of the TK6 human lymphoblastoid cells which are known to be highly radiosensitive due to efficient radiation-induced apoptosis. METHODS: Clonogenicity was determined 12-14 days after irradiation with 1-4 Gy 6 MV photons with or without a 1.0 Tesla MF. Furthermore, alterations in cell cycle distribution and rates of radiation induced apoptosis (FACS analysis of cells with sub-G1 DNA content) were analyzed. RESULTS: Clonogenic survival showed an exponential dose-dependence, and the radiation sensitivity parameter (α = 1.57/Gy) was in accordance with earlier reports. Upon comparing the clonogenic survival between the two groups, identical results within error bars were obtained. The survival fractions at 2 Gy were 9% (without MF) and 8.5% (with MF), respectively. CONCLUSION: A 1.0 Tesla MF does not affect the clonogenicity of TK6 cells irradiated with 1-4 Gy 6MV photons. This supports the use of MRI guided RT, however ongoing research on the interaction of MF and radiotherapy is warranted.


Asunto(s)
Apoptosis/efectos de la radiación , Ciclo Celular , Linfocitos/citología , Linfocitos/efectos de la radiación , Campos Magnéticos , Fotones , Supervivencia Celular , Células Cultivadas , Ensayo de Unidades Formadoras de Colonias , Humanos
4.
Radiologe ; 58(8): 746-753, 2018 08.
Artículo en Alemán | MEDLINE | ID: mdl-29992402

RESUMEN

Along with chemotherapy, surgery and immunotherapy, radiotherapy is a mainstay of cancer treatment. Considering the improving survival rates for various malignancies during the past decades, the importance of radiation-induced late normal tissue response is increasing. Quality of life is becoming an important issue in modern cancer treatment and is correlated with acute and late normal tissue response after radiotherapy. A profound understanding of radiation-induced normal tissue response is necessary to sufficiently diagnose and treat radiation-induced side effects and thereby increase the patients' quality of life. Here, the various normal tissue responses in consideration of the radiation biology are specified and prospective options to attenuate radiation-induced side effects are discussed.


Asunto(s)
Neoplasias , Traumatismos por Radiación , Tolerancia a Radiación , Humanos , Neoplasias/radioterapia , Estudios Prospectivos , Calidad de Vida
5.
Radiat Oncol ; 10: 251, 2015 Dec 04.
Artículo en Inglés | MEDLINE | ID: mdl-26637471

RESUMEN

BACKGROUND: To report our long-term results with postoperative intensity-modulated radiation therapy (IMRT) in patients suffering from squamous-cell carcinoma (SCC) of the oral cavity or oropharynx. METHODS: Seventy five patients were retrospectively analyzed. Median age was 58 years and 84 % were male. 76 % of the primaries were located in the oropharynx. Surgery resulted in negative margins (R0) in 64 % of the patients while 36 % suffered from positive margins (R1). Postoperative stages were as follows: stage 1:4 %, stage 2:9 %, stage 3:17 %, stage 4a:69 % with positive nodes in 84 %. Perineural invasion (Pn+) and extracapsular extension (ECE) were present in 7 % and 29 %, respectively. All patients received IMRT using the step-and-shoot approach with a simultaneously integrated boost (SIB) in 84 %. Concurrent systemic therapy was applied to 53 patients, mainly cisplatin weekly. RESULTS: Median follow-up was 55 months (5-150). 13 patients showed locoregional failures (4 isolated local, 4 isolated neck, 5 combined) transferring into 5-year-LRC rates of 85 %. Number of positive lymph nodes (n > 2) and presence of ECE were significantly associated with decreased LRC in univariate analysis, but only the number of nodes remained significant in multivariate analysis. Overall treatment failures occurred in 20 patients (9 locoregional only, 7 distant only, 4 combined), transferring into 3-and 5-year-FFTF rates of 77 % and 75 %, respectively. The 3-and 5-year-OS rates were 80 % and 72 %, respectively. High clinical stage, high N stage, number of positive nodes (n > 2), ECE and Pn1 were significantly associated with worse FFTF and OS in univariate analysis, but only number of nodes remained significant for FFTF in multivariate analysis. Maximum acute toxicity was grade 3 in 64 % and grade 4 in 1 %, mainly hematological or mucositis/dysphagia. Maximum late toxicity was grade 3 in 23 % of the patients, mainly long-term tube feeding dependency. CONCLUSION: Postoperative IMRT achieved excellent LRC and good OS with acceptable acute and low late toxicity rates. The number of positive nodes (n > 2) was a strong prognostic factor for all endpoints in univariate and the only significant factor for LRC and FFTF in multivariate analysis. Patients with feeding tubes due to postoperative complications had an increased risk for long-term feeding tube dependency.


Asunto(s)
Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeza y Cuello/radioterapia , Neoplasias Orofaríngeas/radioterapia , Radioterapia de Intensidad Modulada/métodos , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Carcinoma de Células Escamosas/mortalidad , Quimioterapia Adyuvante , Cisplatino/administración & dosificación , Terapia Combinada , Femenino , Neoplasias de Cabeza y Cuello/mortalidad , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Procedimientos Quirúrgicos Orales , Neoplasias Orofaríngeas/mortalidad , Modelos de Riesgos Proporcionales , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por Computador , Radioterapia Adyuvante/efectos adversos , Radioterapia Adyuvante/métodos , Radioterapia de Intensidad Modulada/efectos adversos , Estudios Retrospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello
6.
Strahlenther Onkol ; 189(8): 684-92, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23793865

RESUMEN

BACKGROUND: Inhibition of pyruvate dehydrogenase kinase (PDK) by dichloroacetate (DCA) can shift tumor cell metabolism from anaerobic glycolysis to glucose oxidation, with activation of mitochondrial activity and chemotherapy-dependent apoptosis. In radiotherapy, DCA could thus potentially enhance the frequently moderate apoptotic response of cancer cells that results from their mitochondrial dysfunction. The aim of this study was to investigate tumor-specific radiosensitization by DCA in vitro and in a human tumor xenograft mouse model in vivo. MATERIALS AND METHODS: The interaction of DCA with photon beam radiation was investigated in the human tumor cell lines WIDR (colorectal) and LN18 (glioma), as well as in the human normal tissue cell lines HUVEC (endothelial), MRC5 (lung fibroblasts) and TK6 (lymphoblastoid). Apoptosis induction in vitro was assessed by DAPI staining and sub-G1 flow cytometry; cell survival was quantified by clonogenic assay. The effect of DCA in vivo was investigated in WIDR xenograft tumors growing subcutaneously on BALB/c-nu/nu mice, with and without fractionated irradiation. Histological examination included TUNEL and Ki67 staining for apoptosis and proliferation, respectively, as well as pinomidazole labeling for hypoxia. RESULTS: DCA treatment led to decreased clonogenic survival and increased specific apoptosis rates in tumor cell lines (LN18, WIDR) but not in normal tissue cells (HUVEC, MRC5, TK6). However, this significant tumor-specific radiosensitization by DCA in vitro was not reflected by the situation in vivo: The growth suppression of WIDR xenograft tumors after irradiation was reduced upon additional DCA treatment (reflected by Ki67 expression levels), although early tumor cell apoptosis rates were significantly increased by DCA. This apparently paradoxical effect was accompanied by a marked DCA-dependent induction of hypoxia in tumor-tissue. CONCLUSION: DCA induced tumor-specific radiosensitization in vitro but not in vivo. DCA also induced development of hypoxia in tumor tissue in vivo. Further investigations relating to the interplay between tumor cell metabolism and tumor microenvironment are necessary to explain the limited success of metabolic targeting in radiotherapy.


Asunto(s)
Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Ácido Dicloroacético/administración & dosificación , Neoplasias Experimentales/fisiopatología , Neoplasias Experimentales/radioterapia , Tolerancia a Radiación/efectos de los fármacos , Animales , Línea Celular Tumoral , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Ratas , Resultado del Tratamiento
7.
Strahlenther Onkol ; 189(11): 957-66, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23801068

RESUMEN

BACKGROUND: Osteosarcomas (OS) are highly malignant and radioresistant tumors. Histone deacetylase inhibitors (HDACi) constitute a novel class of anticancer agents. We sought to investigate the effect of combined treatment with suberoylanilide hydroxamic acid (SAHA) and radiotherapy in OS in vivo. METHODS: Clonogenic survival of human OS cell lines as well as tumor growth delay of OS xenografts were tested after treatment with either vehicle, radiotherapy (XRT), SAHA, or XRT and SAHA. Tumor proliferation, necrosis, microvascular density, apoptosis, and p53/p21 were monitored by immunohistochemistry. The CD95 pathway was performed by flow cytometry, caspase (3/7/8) activity measurements, and functional inhibition of CD95 death signaling. RESULTS: Combined treatment with SAHA and XRT markedly reduced the surviving fraction of OS cells as compared to XRT alone. Likewise, dual therapy significantly inhibited OS tumor growth in vivo as compared to XRT alone, reflected by reduced tumor proliferation, impaired angiogenesis, and increased apoptosis. Addition of HDACi to XRT led to elevated p53, p21, CD95, and CD95L expression. Inhibition of CD95 signaling reduced HDACi- and XRT-induced apoptosis. CONCLUSION: Our data show that HDACi increases the radiosensitivity of osteosarcoma cells at least in part via ligand-induced apoptosis. HDACi thus emerge as potentially useful treatment components of OS.


Asunto(s)
Neoplasias Óseas/fisiopatología , Neoplasias Óseas/terapia , Quimioradioterapia/métodos , Inhibidores de Histona Desacetilasas/uso terapéutico , Osteosarcoma/fisiopatología , Osteosarcoma/terapia , Tolerancia a Radiación/efectos de los fármacos , Animales , Neoplasias Óseas/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Relación Dosis-Respuesta en la Radiación , Humanos , Ratones , Ratones SCID , Osteosarcoma/patología , Dosificación Radioterapéutica , Radioterapia Conformacional/métodos , Resultado del Tratamiento
8.
Phys Med ; 27(4): 194-202, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21215671

RESUMEN

INTRODUCTION: Despite enormous efforts to improve therapeutic strategies for patients with advanced ovarian carcinoma, outcome remains poor even with the advent cisplatinum-based chemotherapy regimen or taxanes with over 70% of patients developing local failure. Several trials were able to establish the potential benefit of adjuvant whole abdominal RT (WAI) though at the cost of sometimes marked side-effects. New technologies like IMRT have the potential of sparing normal tissues thus also potentially limiting treatment-related toxicity, hence a phase I trial was initiated to evaluate potential clinical benefit of WAI with IMRT. We intended to demonstrate that whole-abdominal IMRT is feasible and can be used in a routine clinical setting. METHODS: A water-equivalent phantom containing OARs was created simulating organ shape of the upper abdomen to investigate the necessary number of beams for the upper abdominal target irrespective of the number of segments and hence treatment times. We prescribed a total dose of 30 Gy in 1.5 Gy fractions to the median of the target. IMRT treatment plans for three patients with advanced ovarian cancer were created using 2 isocentres and between 12 and 14 beams while restricting the number of segments so as to restrict treatment times to less than 45 min. Dose to OARs such as kidneys and liver was strictly limited even below established maxima. RESULTS: In the phantom plans, no clear indication as to the optimum number of beams could be shown though there seems to be a slight trend toward a higher number of beams yielding better results. Examples demonstrating clinically inacceptable dose distributions for plans using only 9 beams. Acceptable treatment plans for real patients could be achieved using 12-14 beams and 2 isocentres. Treatment plans consisted of 264-286 segments resulting in an overall treatment time of approximately 37-45 min. Mean doses to the kidneys could be limited to 29.3% [23.1-33.2%] (right), and 26.8% [21-30.4%] (left). 50% of the liver received less than 72.4% [61-83%]. CONCLUSION: IMRT for whole abdominal irradiation in patients with advanced ovarian carcinoma is applicable and feasible though treatment planning is complex and time-consuming. There is a significant reduction of dose to critical organs by using IMRT while maintaining target volume coverage.


Asunto(s)
Abdomen/efectos de la radiación , Neoplasias Ováricas/radioterapia , Planificación de la Radioterapia Asistida por Computador/métodos , Radioterapia de Intensidad Modulada/métodos , Estudios de Factibilidad , Femenino , Humanos , Tratamientos Conservadores del Órgano , Fantasmas de Imagen , Radioterapia de Intensidad Modulada/efectos adversos
9.
Oncogene ; 29(10): 1519-30, 2010 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-20023695

RESUMEN

The Ras oncogene is known to activate three major MAPK pathways, ERK, JNK, p38 and exert distinct cellular phenotypes, that is, apoptosis and invasion through the Ras-MKK3-p38-signaling cascade. We attempted to identify the molecular targets of this pathway that selectively govern the invasive phenotype. Stable transfection of NIH3T3 fibroblasts with MKK3(act) cDNA construct revealed similar p38-dependent in vitro characteristics observed in Ha-Ras(EJ)-transformed NIH3T3 cells, including enhanced invasiveness and anchorage-independent growth correlating with p38 phosphorylation status. To identify the consensus downstream targets of the Ras-MKK3-p38 cascade involved in invasion, in vitro invasion assays were used to isolate highly invasive cells from both, MKK3 and Ha-Ras(EJ) transgenic cell lines. Subsequently a genome-wide transcriptome analysis was employed to investigate differentially regulated genes in invasive Ha-Ras(EJ)- and MKK3(act)-transfected NIH3T3 fibroblasts. Using this phenotype-assisted approach combined with system level protein-interaction network analysis, we identified FOXM1, PLK1 and CDK1 to be differentially regulated in invasive Ha-Ras(EJ)-NIH3T3 and MKK3(act)-NIH3T3 cells. Finally, a FOXM1 RNA-knockdown approach revealed its requirement for both invasion and anchorage-independent growth of Ha-Ras(EJ)- and MKK3(act)-NIH3T3 cells. Together, we identified FOXM1 as a key downstream target of Ras and MKK3-induced cellular in vitro invasion and anchorage-independent growth signaling.


Asunto(s)
Factores de Transcripción Forkhead/genética , Perfilación de la Expresión Génica , MAP Quinasa Quinasa 3/genética , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas ras/genética , Animales , Western Blotting , Adhesión Celular , Movimiento Celular , Flavonoides/farmacología , Proteína Forkhead Box M1 , Factores de Transcripción Forkhead/metabolismo , Imidazoles/farmacología , MAP Quinasa Quinasa 3/antagonistas & inhibidores , MAP Quinasa Quinasa 3/metabolismo , Ratones , Células 3T3 NIH , Análisis de Secuencia por Matrices de Oligonucleótidos , Piridinas/farmacología , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Proteínas ras/metabolismo
10.
Br J Cancer ; 99(6): 900-10, 2008 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-19238631

RESUMEN

Drug targeting systems are nanometer-sized carrier materials designed for improving the biodistribution of systemically applied (chemo-) therapeutics. Reasoning that (I) the temporal and spatial interaction between systemically applied chemotherapy and clinically relevant fractionated radiotherapy is suboptimal, and that (II) drug targeting systems are able to improve the temporal and spatial parameters of this interaction, we have here set out to evaluate the potential of 'carrier-based radiochemotherapy'. N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers were used as a model drug targeting system, doxorubicin and gemcitabine as model drugs, and the syngeneic and radio- and chemoresistant Dunning AT1 rat prostate carcinoma as a model tumour model. Using magnetic resonance imaging and gamma-scintigraphy, the polymeric drug carriers were first shown to circulate for prolonged periods of time, to localise to tumours both effectively and selectively, and to improve the tumour-directed delivery of low molecular weight agents. Subsequently, they were then shown to interact synergistically with radiotherapy, with radiotherapy increasing the tumour accumulation of the copolymers, and with the copolymers increasing the therapeutic index of radiochemotherapy (both for doxorubicin and for gemcitabine). Based on these findings, and on the fact that its principles are likely broadly applicable, we propose carrier-based radiochemotherapy as a novel concept for treating advanced solid malignancies.


Asunto(s)
Acrilamidas/uso terapéutico , Diagnóstico por Imagen , Doxorrubicina/uso terapéutico , Radioisótopos de Yodo/uso terapéutico , Nanomedicina , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/radioterapia , Acrilamidas/farmacocinética , Animales , Antimetabolitos Antineoplásicos/farmacocinética , Antimetabolitos Antineoplásicos/uso terapéutico , Terapia Combinada , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Desoxicitidina/uso terapéutico , Doxorrubicina/farmacocinética , Sistemas de Liberación de Medicamentos , Resistencia a Antineoplásicos , Gadolinio , Imagen por Resonancia Magnética , Masculino , Dosis Máxima Tolerada , Neoplasias de la Próstata/diagnóstico , Tolerancia a Radiación , Ratas , Ribonucleótido Reductasas/antagonistas & inhibidores , Distribución Tisular , Gemcitabina
11.
Phys Med Biol ; 51(19): 4789-806, 2006 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-16985271

RESUMEN

Image registration has many medical applications in diagnosis, therapy planning and therapy. Especially for time-adaptive radiotherapy, an efficient and accurate elastic registration of images acquired for treatment planning, and at the time of the actual treatment, is highly desirable. Therefore, we developed a fully automatic and fast block matching algorithm which identifies a set of anatomical landmarks in a 3D CT dataset and relocates them in another CT dataset by maximization of local correlation coefficients in the frequency domain. To transform the complete dataset, a smooth interpolation between the landmarks is calculated by modified thin-plate splines with local impact. The concept of the algorithm allows separate processing of image discontinuities like temporally changing air cavities in the intestinal track or rectum. The result is a fully transformed 3D planning dataset (planning CT as well as delineations of tumour and organs at risk) to a verification CT, allowing evaluation and, if necessary, changes of the treatment plan based on the current patient anatomy without time-consuming manual re-contouring. Typically the total calculation time is less than 5 min, which allows the use of the registration tool between acquiring the verification images and delivering the dose fraction for online corrections. We present verifications of the algorithm for five different patient datasets with different tumour locations (prostate, paraspinal and head-and-neck) by comparing the results with manually selected landmarks, visual assessment and consistency testing. It turns out that the mean error of the registration is better than the voxel resolution (2 x 2 x 3 mm(3)). In conclusion, we present an algorithm for fully automatic elastic image registration that is precise and fast enough for online corrections in an adaptive fractionated radiation treatment course.


Asunto(s)
Planificación de la Radioterapia Asistida por Computador/métodos , Radioterapia/métodos , Técnica de Sustracción , Algoritmos , Análisis de Fourier , Neoplasias de Cabeza y Cuello/diagnóstico , Neoplasias de Cabeza y Cuello/patología , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Modelos Estadísticos , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/patología , Radiometría , Tomografía Computarizada por Rayos X
12.
BMC Cancer ; 6: 122, 2006 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-16681848

RESUMEN

BACKGROUND: Even today, treatment of Stage III NSCLC still poses a serious challenge. So far, surgical resection is the treatment of choice. Patients whose tumour is not resectable or who are unfit to undergo surgery are usually referred to a combined radio-chemotherapy. However, combined radio-chemotherapeutic treatment is also associated with sometimes marked side effects but has been shown to be more efficient than radiation therapy alone. Nevertheless, there is a significant subset of patients whose overall condition does not permit administration of chemotherapy in a combined-modality treatment. It could be demonstrated though, that NSCLCs often exhibit over-expression of EGF-receptors hence providing an excellent target for the monoclonal EGFR-antagonist cetuximab (Erbitux) which has already been shown to be effective in colorectal as well as head-and-neck tumours with comparatively mild side-effects. METHODS/DESIGN: The NEAR trial is a prospective phase II feasibility study combining a monoclonal EGF-receptor antibody with loco-regional irradiation in patients with stage III NSCLC. This trial aims at testing the combination's efficacy and rate of development of distant metastases with an accrual of 30 patients. Patients receive weekly infusions of cetuximab (Erbitux) plus loco-regional radiation therapy as intensity-modulated radiation therapy. After conclusion of radiation treatment patients continue to receive weekly cetuximab for 13 more cycles. DISCUSSION: The primary objective of the NEAR trial is to evaluate toxicities and feasibility of the combined treatment with cetuximab (Erbitux) and IMRT loco-regional irradiation. Secondary objectives are remission rates, 3-year-survival and local/systemic progression-free survival.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Radioterapia de Intensidad Modulada , Adulto , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Antineoplásicos/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Cetuximab , Terapia Combinada/métodos , Receptores ErbB/antagonistas & inhibidores , Estudios de Factibilidad , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/radioterapia , Masculino , Estudios Prospectivos
13.
BMC Cancer ; 5: 131, 2005 Oct 11.
Artículo en Inglés | MEDLINE | ID: mdl-16219105

RESUMEN

BACKGROUND: Pancreatic cancer is the fourth commonest cause of death from cancer in men and women. Advantages in surgical techniques, radiation therapy techniques, chemotherapeutic regimes, and different combined-modality approaches have yielded only a modest impact on the prognosis of patients with pancreatic cancer. Thus there is clearly a need for additional strategies. One approach involves using the identification of a number of molecular targets that may be responsible for the resistance of cancer cells to radiation or to other cytotoxic agents. As such, these molecular determinants may serve as targets for augmentation of the radiotherapy or chemotherapy response. Of these, the epidermal growth factor receptor (EGFR) has been a molecular target of considerable interest and investigation, and there has been a tremendous surge of interest in pursuing targeted therapy of cancers via inhibition of the EGFR. METHODS/DESIGN: The PARC study is designed as an open, controlled, prospective, randomized phase II trial. Patients in study arm A will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine infusions weekly over 4 weeks. Patients in study arm B will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine weekly over 4 weeks and cetuximab infusions over 12 weeks. A total of 66 patients with locally advanced adenocarcinoma of the pancreas will be enrolled. An interim analysis for patient safety reasons will be done one year after start of recruitment. Evaluation of the primary endpoint will be performed two years after the last patient's enrollment. DISCUSSION: The primary objective of this study is to evaluate the feasibility and the toxicity profile of trimodal therapy in pancreatic adenocarcinoma with chemoradiation therapy with gemcitabine and intensity modulated radiation therapy (IMRT) and EGFR-targeted therapy using cetuximab and to compare between two different methods of cetuximab treatment schedules (concomitant versus concomitant and sequential cetuximab treatment). Secondary objectives are to determine the role and the mechanism of cetuximab in patient's chemoradiation regimen, the response rate, the potential of this combined modality treatment to concert locally advanced lesions to potentially resectable lesions, the time to progression interval and the quality of life.


Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Combinada/métodos , Desoxicitidina/análogos & derivados , Receptores ErbB/metabolismo , Neoplasias Pancreáticas/terapia , Anticuerpos Monoclonales Humanizados , Cetuximab , Ensayos Clínicos como Asunto , Desoxicitidina/administración & dosificación , Femenino , Humanos , Masculino , Estudios Prospectivos , Calidad de Vida , Radioterapia de Intensidad Modulada/métodos , Factores de Tiempo , Resultado del Tratamiento , Gemcitabina
14.
Lab Anim ; 39(4): 377-83, 2005 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-16197704

RESUMEN

Here is reported the development of an experimental model using intravital microscopy as a tool to orthotopically investigate malignant bone tumours. Although up to 85% of the most frequently occurring malignant solid tumours, such as lung and prostate carcinomas, metastasize into the bone, and despite the knowledge that a tumour's course may be altered by its surrounding tissue, there is no adequate experimental model available enabling the investigation of orthotopically grown bone tumours in vivo. Intravital microscopy is an internationally accepted experimental method, used in various acute and chronic animal models, that enables qualitative and quantitative analysis of the angiogenesis, microcirculation, growth behaviour, etc. of various benign and malignant tissues. Non-invasive investigations of up to several weeks are possible. Additionally, tissue samples can be taken after termination of the in vivo experiments for further ex vivo investigation (histology, immunohistochemistry, molecular biology, etc.), elucidating the mechanisms that underlie the in vivo observations. Severe combined immunodeficient mice were fitted with a cranial window preparation where the calvaria served as the site for orthotopic implantation of the solid human tumours Saos-2 osteosarcoma (primary) and A 549 lung carcinoma and PC-3 prostate carcinoma (secondary). In all preparations, the take rate was 100%. Histological assessment confirmed the data obtained in vivo, showing typical tumour growth with infiltration of the surrounding osseous and soft tissues. This novel model serves as a valuable tool in understanding the biology of primary and secondary bone tumours in physiological and pathophysiological situations, with implications for the most areas of tumour therapy such as chemotherapy, radiation and antiangiogenesis.


Asunto(s)
Neoplasias Óseas/patología , Osteosarcoma/patología , Animales , Neoplasias Óseas/irrigación sanguínea , Neoplasias Óseas/secundario , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones SCID , Microscopía Fluorescente , Microscopía por Video , Trasplante de Neoplasias , Neovascularización Patológica/patología , Osteosarcoma/irrigación sanguínea , Osteosarcoma/secundario , Neoplasias de la Próstata/patología
15.
Radiologe ; 43(10): 805-12, 2003 Oct.
Artículo en Alemán | MEDLINE | ID: mdl-14605696

RESUMEN

There is an increasing interest in high intensity focused ultrasound (HIFU) for thermo ablative tumor therapy. The attractiveness of this method is based on its ability to destroy tumor tissue non invasively while sparing surrounding tissue from outside the body. HIFU induced tissue necroses are sharply circumscribed. Therefore this method was termed focused ultrasound surgery (FUS). The therapeutic potential of FUS is under investigation in several clinical studies. Main objects of these studies are prostate carcinomas, breast kidney and liver tumors. The next innovative step will be the non invasive FUS treatment of brain through the intact skull. Combining FUS with magnetic resonance imaging (MRI) or diagnostic ultrasound allows accurate and online therapy guiding and monitoring. This article gives an overview of the basics, the latest developments and actual clinical studies in the field of focused ultrasound surgery.


Asunto(s)
Electrocoagulación/instrumentación , Neoplasias/cirugía , Terapia por Ultrasonido/instrumentación , Diseño de Equipo/tendencias , Predicción , Humanos , Necrosis , Neoplasias/patología , Sistemas en Línea/instrumentación , Cirugía Asistida por Computador/instrumentación , Transductores
16.
Gene Ther ; 10(18): 1600-7, 2003 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-12907952

RESUMEN

The development of accurate, safe, and efficient gene delivery remains a major challenge towards the realization of gene therapeutic prevention and treatment of cardiovascular diseases. In this study, we investigated the ability of high-intensity focused ultrasound (HIFU), a form of mechanical wave transmission, to act as a noninvasive tool for the enhancement of in vivo gene transfer into rabbit carotid arteries. Segments of the common carotid arteries of New Zealand white rabbits were isolated and infused with plasmid DNA encoding the reporter beta-galactosidase either with or without the addition of ultrasound contrast agent consisting of small (approximately 2-5 microm) gas-filled human albumin microspheres to augment cavitation. Infused arteries were exposed to pulsed ultrasound for 1 min (frequency 0.85 MHz, burst length 50 ms, repetition frequency 1 Hz, duration 60 s, peak pressure amplitude of 15 MPa). At 6.3 MPa, HIFU enhanced gene expression eight-fold, and 17.5-fold in the presence of contrast. We found increasing amounts of beta-galactosidase expression in the carotid vessel with increasing pressure amplitude. This dose-response relation was present with and without contrast. Without contrast, no vessel damage was detected up to 15 MPa, while the addition of contrast induced side effects above a threshold of 6.3 MPa peak pressure. The entire procedure was feasible and safe for the animals, and the results suggest that HIFU has the potential to assist in the noninvasive spatial regulation of gene transfer into the vascular system.


Asunto(s)
Arterias Carótidas/enzimología , Enfermedades de las Arterias Carótidas/terapia , ADN/administración & dosificación , Terapia Genética/métodos , Transfección/métodos , Terapia por Ultrasonido/métodos , Animales , Expresión Génica , Técnicas In Vitro , Operón Lac , Microesferas , Modelos Animales , Conejos
17.
Radiologe ; 43(6): 489-94, 2003 Jun.
Artículo en Alemán | MEDLINE | ID: mdl-12827264

RESUMEN

AIM: The aim of this study was the noninvasive characterization of prostate carcinoma orthotopically implanted in rats using Gd-DTPA-assisted dynamic MRI (dMRI) and proton magnetic resonance spectroscopy ((1)H-MRS). MATERIAL AND METHODS: After surgical exposure of the prostate, Dunning R3327 orthotopic prostate carcinoma was induced by injecting cells of the MAT-LyLu subline. Six rats were examined 5 and 14 days after tumor induction with dMRI and (1)H-MRS at 1.5 T. Six tumor-free rats served as controls. Using an open two-compartment model, the parameters A (amplitude) and k(ep) (exchange rate constants) were calculated from the signal time curves of the dMRI. The relative signal intensities (Cho/Cr) of the resonances of choline (Cho) and the creatine-phosphocreatine complex (Cr) were computed from the MR spectra. RESULTS: Already after 5 days, the tumors in the prostate could be clearly identified based on the decrease in signal intensity to T2w and increase of A and k(ep). High Cho/Cr levels and resonances of two lipid fractions (Lip(1) at 0.8-1.5 ppm and Lip(2) at 2.0-2.2 ppm) were observed by MRS in the highly necrotic tumors. CONCLUSIONS: The orthotopic rat prostate carcinoma model resembles human prostate carcinoma in regard to MR morphology, dMRI, and (1)H-MRS. The noninvasive characterization of perfusion and metabolism makes a comparative examination of different treatment modalities possible.


Asunto(s)
Imagen por Resonancia Magnética/métodos , Espectroscopía de Resonancia Magnética , Próstata/metabolismo , Neoplasias de la Próstata/diagnóstico , Algoritmos , Animales , Modelos Animales de Enfermedad , Hemodinámica , Humanos , Inmunohistoquímica , Masculino , Trasplante de Neoplasias , Próstata/anatomía & histología , Próstata/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/fisiopatología , Neoplasias de la Próstata/radioterapia , Protones , Ratas , Factores de Tiempo
18.
Cancer Res ; 61(23): 8441-7, 2001 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-11731425

RESUMEN

An ideal vision of modern medicine includes tumor surgery with the human body remaining completely intact. A noninvasive therapy could avoid infections and scar formation; it would require less anesthesia, reduce recovery time, and possibly also reduce costs. This study investigated whether human breast cancer can be effectively treated with a novel combination of image guidance and energy delivery, noninvasive magnetic resonance imaging (MRI)-guided focused ultrasound (FUS). We have developed a FUS therapy unit guided by MRI for the treatment of human breast tumors in a clinical 1.5 T MR scanner. With interactive target segmentation on MRI, defined volumes could be noninvasively treated in a single session with on-line MR temperature control. The ultrasound waves were focused through the intact skin and resulted in the localized thermal tissue ablation at a maximum temperature of 70 degrees C. The therapy principle was first demonstrated in sheep breast in vivo and was then applied in a patient with core biopsy-proven invasive breast cancer 5 days before breast-conserving surgery. MRI proved suitable to delineate the breast cancer, served as stereotactic treatment planning platform, and delineated the FUS-related tissue changes such as interruption of tumor blood flow. Furthermore, MRI localized the hot spot in the tumor and measured temperature elevation during the treatment. This allowed us to monitor the efficacy and safety of FUS therapy. Immunohistochemistry of the resected specimen demonstrated that FUS homogeneously induced lethal and sublethal tumor damage with consecutive up-regulation of p53 and loss of proliferative activity. This effect was realized without anesthesia and damage to the surrounding healthy tissue or systemic effects. Overall, our results show that noninvasive MRI-guided therapy of breast cancer is feasible and effective. Thus, MRI-guided FUS may represent a new strategy for the neoadjuvant, adjuvant, or palliative treatment in selected breast cancer patients and in patients with other soft-tissue tumors.


Asunto(s)
Neoplasias de la Mama/cirugía , Imagen por Resonancia Magnética/métodos , Neoplasias Mamarias Experimentales/cirugía , Animales , Neoplasias de la Mama/irrigación sanguínea , Neoplasias de la Mama/diagnóstico por imagen , Modelos Animales de Enfermedad , Femenino , Humanos , Neoplasias Mamarias Experimentales/irrigación sanguínea , Neoplasias Mamarias Experimentales/diagnóstico por imagen , Persona de Mediana Edad , Ovinos , Ultrasonografía
19.
Radiat Res ; 156(3): 301-9, 2001 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-11500139

RESUMEN

Local tumor therapy using focused ultrasonic waves may become an important treatment option. This technique exploits the ability of mechanical waves to induce thermal and nonthermal effects noninvasively. The cytotoxicity to cultured cells and biological tissues in vivo that results from exposure to ultrasonic shock waves is considered to be a nonthermal effect that is partly a consequence of ultrasound-induced cavitation. Cavitation is defined as the formation of bubbles during the negative wave cycle; their subsequent oscillation and/or violent implosion can affect surrounding structures. To investigate cavitational effects in cells and tissues, defined cavitation doses must be applied while ideally holding all other potential ultrasound parameters constant. The application of independent cavitation doses has been difficult and has yielded little knowledge about quantitative cavitation-tissue interactions. By using a special shock-wave pulse regimen and laser optical calibration in this study, we were able to control the cavitation dose independently of other physical parameters such as the pressure amplitudes, and averaged acoustic intensity. We treated Dunning prostate tumors (subline R3327-AT1) transplanted into Copenhagen rats with shock waves at three cavitation dose levels and then determined the tumor growth delay and the histopathological changes. All of the treated animals exhibited a significant tumor growth delay compared to the controls. Higher cavitation doses were associated with a greater delay in the growth of the tumor and more severe effects on tumor histopathology, such as hemorrhaging, tissue disruption, and necrosis. In vitro, the cavitation dose level correlated with the amount of radical formation. We concluded that the process of acoustic cavitation was responsible; higher cavitation doses caused greater effects in tumors both in vivo and in vitro. These findings may prove important in local tumor therapy and other applications of ultrasound such as ultrasound-mediated drug delivery.


Asunto(s)
Neoplasias de la Próstata/patología , Terapia por Ultrasonido , Animales , División Celular , Radicales Libres , Técnicas In Vitro , Masculino , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/terapia , Ratas
20.
Magn Reson Imaging ; 19(2): 167-75, 2001 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-11358654

RESUMEN

The objective of this study was to investigate MRI methods for monitoring focused ultrasound surgery (FUS) of breast tumors. To this end, the mammary glands of sheep were used as tissue model. The tissue was treated in vivo with numerous single sonications which covered extended target volumes by employing a scanning technique. The ultrasound focus position was controlled by online temperature mapping based on the temperature dependence of the relaxation time T(1). This approach proved to be reliable and offers thus an alternative to proton resonance frequency methods, whose application is hampered in fatty tissues. FUS-induced tissue changes were visible on T(2)- as well as on pre- and post-contrast T(1)-weighted images. According to our initial experience, noninvasive MRI-guided FUS of breast tumors is feasible.


Asunto(s)
Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética/instrumentación , Glándulas Mamarias Animales/cirugía , Monitoreo Intraoperatorio/instrumentación , Terapia por Ultrasonido/instrumentación , Tejido Adiposo/cirugía , Animales , Temperatura Corporal/fisiología , Femenino , Glándulas Mamarias Animales/patología , Ovinos
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