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1.
Curr Opin Pulm Med ; 21(4): 314-21, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25978629

RESUMO

PURPOSE OF REVIEW: The aim of this review is to provide an outline of current evidence for the use of F-18-fluoro-deoxy-glucose PET computed tomography (FDG-PET/CT) in nonsmall cell lung cancer (NSCLC) for diagnosis, staging, radiotherapy planning, response assessment and response monitoring. RECENT FINDINGS: Management of patients with NSCLC requires a multimodality approach to accurately diagnose and stage patients. In this approach, FDG-PET/CT has become a standard staging instrument in lung cancer. FDG-PET/CT is, in addition to staging, also valuable for the characterization of the solitary pulmonary nodule. An increased uptake in the nodule as compared with mediastinal blood pool is suspected for malignancy. In radiotherapy planning, FDG-PET/CT can assist the radiation oncologist for optimal dose delivery to the tumour, while sparing healthy tissues. Evidence of the prognostic and predictive implications of FDG-PET/CT is accumulating. Volumetric parameters of PET, such as metabolic active tumour volume and total lesion glycolysis, are promising predictive and prognostic biomarkers. However, for implementation of metabolic response parameters in clinical practice, more randomized, PET-based, multicentre trials are necessary. The introduction of integrated PET and MRI scanners did not change the pivotal role of standard FDG-PET/CT yet, as with current technology, PET/MRI did not show superior performance in thoracic staging. SUMMARY: The role of PET is described for diagnosis, staging and response assessment.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Fluordesoxiglucose F18 , Humanos , Neoplasias Pulmonares/patologia , Tomografia por Emissão de Pósitrons , Prognóstico , Nódulo Pulmonar Solitário/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos
2.
Int J Gynecol Cancer ; 24(9): 1628-35, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25244605

RESUMO

OBJECTIVE: Chemoradiation is the standard therapy for advanced stages of cervical cancer. In developing countries, where 80% of cervical cancers occur, this is not always available. Carbogen breathing and oral nicotinamide (CON) therapy, aimed at overcoming tumor hypoxia, has shown to improve treatment efficacy in some epithelial tumors. This study investigates the effect of CON during (chemo)radiation of advanced stages of cervical cancer on overall survival, local and regional control, and toxicity. METHODS: From December 2006 to February 2010, 139 patients with stage IB2 to IVA cervical cancer were nonrandomly assigned to receive radiotherapy (RT) or chemoradiation (CRT) with or without CON. Differences in overall survival, local and regional control after 1 year, and toxicity were assessed in 113 evaluable patients. Thirty-two patients received RT, 16 received CRT, 45 received CON-RT, and 20 received CON-CRT. RESULTS: The CON-RT and RT groups contained significantly more patients with a poor performance status and IIIB and IVA tumors. Despite these differences in baseline characteristics, overall survival and local and regional control at 1 year were not significantly different (P = 0.10 and P = 0.19, respectively). Toxicity scores also did not differ (P = 0.60 and P = 0.73 for acute and late toxicity). CONCLUSIONS: Addition of CON to standard (chemo)radiation gives comparable survival and control rates. The effect of CON might be underestimated due to differences in baseline characteristics. Because chemotherapy cannot always be (completely) administered in low-resource settings, CON could be a worthy substitute. The CON treatment is feasible and safe.


Assuntos
Dióxido de Carbono/administração & dosagem , Quimiorradioterapia , Niacinamida/administração & dosagem , Oxigênio/administração & dosagem , Terapia Respiratória , Neoplasias do Colo do Útero/terapia , Administração Oral , Adulto , Idoso , Antineoplásicos/uso terapêutico , Cisplatino/uso terapêutico , Feminino , Seguimentos , Humanos , Indonésia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Radiossensibilizantes/administração & dosagem , Taxa de Sobrevida , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/patologia , Complexo Vitamínico B/administração & dosagem
3.
Radiother Oncol ; : 110601, 2024 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-39481607

RESUMO

INTRODUCTION: Healthcare systems contribute significantly to CO2 emissions, accounting for 7 % of emissions in the Netherlands. Understanding the environmental footprint of medical treatments can help identify opportunities for reducing climate impact. We evaluated the climate impact of stereotactic body radiotherapy (SBRT) and Video-Assisted Thoracic Surgery VATS) when treating T1-2N0M0 Non-Small Cell Lung Cancer (NSCLC). MATERIALS AND METHODS: We used life cycle assessment(LCA) to evaluate climate impact in emissions of kilograms of CO2 equivalent. Care trajectories were inventoried for both VATS and SBRT with the same entry and end point of the paths. We analyzed a range of factors contributing to climate impact, such as patient and staff travel, energy consumption, disposables and medication using direct measurements: questionnaires and waste audits, or retrospective record analysis. As is common in LCA, existing infrastructure was excluded from the analysis. Reductions that can be influenced by individual departments were also modeled. RESULTS: Using LCA we calculated the impact of all categorized contributions for two treatments for NSCLC. In total, VATS generates approximately 547 kg CO2 equivalent (CO2e), whereas SBRT generates 172 kg CO2e per treatment. For SBRT, the largest contributors were energy use in the hospital (52 % of total), of which 22 % is from the linac, and patient travel (23 %). For VATS, major contributions were hospital energy use (52 %) and disposables (23 %). Climate impact could be reduced by 20 % (SBRT) by hypofractionation, reduced linac idle time and patient travel impact, and 13 % (VATS) with fast track recovery and a reduction of disposables. CONCLUSION: When treating T1-2N0M0 NSCLC, surgery has a larger climate impact than SBRT. For both modalities reductions are possible.

4.
Int J Clin Oncol ; 18(6): 988-96, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23011101

RESUMO

BACKGROUND: Improving survival in non-small cell lung cancer (NSCLC) will require new strategies or new drugs. Sequential administration of conventional non-cross-resistant cytotoxic drugs offers an opportunity to increase drug diversity while maintaining dose intensity. This Phase II trial was designed to assess the efficacy and feasibility of such a regimen in advanced NSCLC. METHODS: Patients with NSCLC stage IIIB or IV received as first-line treatment four cycles of carboplatin (AUC 5) (day 1) plus gemcitabine 1000 mg/m(2) (days 1 and 8) every 3 weeks. Thereafter, treatment continued with 12 weekly cycles of paclitaxel 80 mg/m(2). RESULTS: In total, 46 patients were included. Median age was 59.6 years (range 41.3-74.3 years) and 93.5 % (n = 43) had Eastern Cooperative Oncology Group performance score of 0 or 1. All but 6 had stage IV disease, and 13 (28.3 %) had squamous cell carcinomas. Thirty-six (78 %) patients completed 4 cycles of carboplatin-gemcitabine and 35 patients received at least 1 cycle of paclitaxel, of whom 16 (46 % of total) patients completed 12 cycles of paclitaxel. The overall objective response rate was 49 %. Sixteen (37 %) patients had a response to carboplatin-gemcitabine, increasing to 21 (49 %) patients after administration of paclitaxel. Of the 13 assessable patients who showed a partial response (PR) on carboplatin-gemcitabine, 12 (92 %) patients showed also a PR on paclitaxel. Of 19 assessable patients with stable disease (SD) on carboplatin-gemcitabine, 4 (21 %) had a PR and 13 (68 %) SD on paclitaxel. Toxicity was moderate: 24 % stopped because of toxicity. CONCLUSION: Sequential chemotherapy with carboplatin-gemcitabine and weekly paclitaxel is active and feasible in advanced NSCLC patients.


Assuntos
Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Desoxicitidina/análogos & derivados , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/administração & dosagem , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Paclitaxel/efeitos adversos , Resultado do Tratamento , Gencitabina
5.
Phys Imaging Radiat Oncol ; 20: 69-75, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34816024

RESUMO

PURPOSE: Although quantitative image biomarkers (radiomics) show promising value for cancer diagnosis, prognosis, and treatment assessment, these biomarkers still lack reproducibility. In this systematic review, we aimed to assess the progress in radiomics reproducibility and repeatability in the recent years. METHODS AND MATERIALS: Four hundred fifty-one abstracts were retrieved according to the original PubMed search pattern with the publication dates ranging from 2017/05/01 to 2020/12/01. Each abstract including the keywords was independently screened by four observers. Forty-two full-text articles were selected for further analysis. Patient population data, radiomic feature classes, feature extraction software, image preprocessing, and reproducibility results were extracted from each article. To support the community with a standardized reporting strategy, we propose a specific reporting checklist to evaluate the feasibility to reproduce each study. RESULTS: Many studies continue to under-report essential reproducibility information: all but one clinical and all but two phantom studies missed to report at least one important item reporting image acquisition. The studies included in this review indicate that all radiomic features are sensitive to image acquisition, reconstruction, tumor segmentation, and interpolation. However, the amount of sensitivity is feature dependent, for instance, textural features were, in general, less robust than statistical features. CONCLUSIONS: Radiomics repeatability, reproducibility, and reporting quality can substantially be improved regarding feature extraction software and settings, image preprocessing and acquisition, cutoff values for stable feature selection. Our proposed radiomics reporting checklist can serve to simplify and improve the reporting and, eventually, guarantee the possibility to fully replicate and validate radiomic studies.

6.
Cancers (Basel) ; 11(10)2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31615071

RESUMO

Radiotherapy is given to a majority of patients with cancer, and remains one of the most (cost)effective treatment options available [...].

7.
Br J Radiol ; 92(1093): 20180047, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29493265

RESUMO

Over the last decades, the incidence of human papilloma virus (HPV) positive head and neck squamous-cell carcinoma (HNSCC) has significantly increased. Infection with high-risk HPV types drives tumourigenesis through expression of the oncoproteins E6 and E7. Currently, the primary treatment of HNSCC consists of radiotherapy, often combined with platinum-based chemotherapeutics. One of the common features of HNSCC is the occurrence of tumour hypoxia, which impairs the efficacy of radiotherapy and is a negative prognostic factor. Therefore, it is important to detect and quantify the severity of hypoxia, as well as develop strategies to specifically target hypoxic tumours. HPV-positive tumours are remarkably radiosensitive compared to HPV-negative tumours and consequently the HPV-positive patients have a better prognosis. This provides an opportunity to elucidate mechanisms of radiation sensitivity, which may reveal targets for improved therapy for HPV-negative head and neck cancers. In this review, we will discuss the differences between HPV-positive and HPV-negative head and neck tumours and methods of hypoxia detection and targeting in these disease types. Particular emphasis will be placed on the mechanisms by which HPV infection impacts radiosensitivity.


Assuntos
Neoplasias de Cabeça e Pescoço/radioterapia , Infecções por Papillomavirus/complicações , Tolerância a Radiação , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Hipóxia Tumoral/efeitos da radiação , Quimiorradioterapia/métodos , Relação Dose-Resposta à Radiação , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Masculino , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/radioterapia , Prognóstico , Radioterapia/métodos , Dosagem Radioterapêutica , Medição de Risco , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Análise de Sobrevida , Resultado do Tratamento
8.
Lung Cancer ; 101: 68-75, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27794410

RESUMO

OBJECTIVES: Symptomatic brain metastases (BM) occur frequently after chemoradiotherapy (CRT) for stage III NSCLC. Aim of the current study was to determine whether the specific chemotherapy used in a CRT regimen influences BM development. MATERIALS AND METHODS: Retrospective multicenter study including all consecutive stage III NSCLC who completed CRT. Primary endpoints: symptomatic BM development, whether this was the only site of first relapse. Differences between regimens were assessed with a logistic regression model including known BM risk factors and the specific chemotherapy: concurrent versus sequential (cCRT/sCRT), within cCRT: daily low dose cisplatin (LDC)-cyclic dose polychemotherapy; LDC-(non-)taxane cyclic dose; LDC-polychemotherapy subgroups of ≥50 patients. RESULTS: Between January 2006 and June 2014, 838 patients were eligible (737 cCRT, 101 sCRT). 18.2% developed symptomatic BM, 8.0% had BM as only site of first relapse. BM patients were significantly younger, female, had more advanced N-stage and had adenocarcinoma histology. In both cCRT and sCRT BM were found in 18% (p=0.904). In cyclic dose cCRT (N=346) and LDC (N=391) BM were found in 18.8% and 17.9%, respectively (p=0.757). In 7.2% and 8.7%, respectively, BM were the only site of first relapse (p=0.463). The chemotherapy used (cCRT versus sCRT) had no influence on BM development, not for all brain relapses nor as only site of first relapse (OR 0.88 (p=0.669), OR 0.93 (p=0.855), respectively). LDC versus cyclic dose cCRT was not significantly different: neither for all brain relapses nor as only site of first relapse (OR 0.96 (p=0.819), OR 1.21 (p=0.498), respectively). Comparable results were found for LDC versus cyclic dose non-taxane (N=277) and cyclic dose taxane regimens (N=69) and for cCRT regimens with ≥50 patients (LDC versus cisplatin/etoposide (N=188), cisplatin/vinorelbin (N=65), weekly cisplatin/docetaxel (N=60)). CONCLUSION: approximately 18% developed symptomatic BM after stage III diagnosis, not dependent on type of chemotherapy regimen used within a CRT treatment.


Assuntos
Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/patologia , Quimiorradioterapia/métodos , Neoplasias Pulmonares/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/patologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/radioterapia , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Cisplatino , Terapia Combinada , Docetaxel , Etoposídeo , Feminino , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , Taxoides/uso terapêutico , Resultado do Tratamento , Vimblastina/análogos & derivados , Vimblastina/uso terapêutico , Vinorelbina
9.
Int J Radiat Oncol Biol Phys ; 62(4): 1169-75, 2005 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-15990022

RESUMO

PURPOSE: To validate the use of the thymidine analogues as local perfusion markers in human tumors (no labeling indicates no perfusion) by comparison with the well-characterized perfusion marker Hoechst 33342. METHODS AND MATERIALS: Human tumor xenografts from gliomas and head-and-neck cancers were injected with iododeoxyuridine (IdUrd) or bromodeoxyuridine (BrdUrd) and the fluorescent dye Hoechst 33342. In frozen sections, each blood vessel was scored for the presence of IdUrd/BrdUrd labeling and Hoechst in surrounding cells. The percentage of analogue-negative vessels was compared with the fraction of Hoechst-negative vessels. Collocalization of the two markers was also scored. RESULTS: We found considerable intertumor variation in the fraction of perfused vessels, measured by analogue labeling, both in the human tumor xenografts and in a series of tumor biopsies from head-and-neck cancer patients. There was a significant correlation between the Hoechst-negative and IdUrd/BrdUrd-negative vessels in the xenografts (r = 85, p = 0.0004), despite some mismatches on a per-vessel basis. CONCLUSIONS: Thymidine analogues can be successfully used to rank tumors according to their fraction of perfused vessels. Whether this fraction correlates with the extent of acute hypoxia needs further confirmation.


Assuntos
Bromodesoxiuridina/análise , Corantes Fluorescentes/análise , Idoxuridina/análise , Neoplasias/irrigação sanguínea , Animais , Benzimidazóis/análise , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante Heterólogo
10.
Clin Cancer Res ; 9(17): 6363-70, 2003 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-14695136

RESUMO

PURPOSE: Vascular endothelial growth factor (VEGF) is a mediator of angiogenesis and is up-regulated under hypoxic conditions. Hypoxic tumors are known to exhibit resistance to radiotherapy. We investigated the association between VEGF levels in tumor tissue and the effect of radiotherapy for relapse-free survival (RFS) and overall survival (OS) in node-negative breast cancer. EXPERIMENTAL DESIGN: The study was performed on 489 patients; 221 patients received postoperative radiotherapy as part of the breast-conserving therapy (BCT), and 268 patients were treated by mastectomy only. VEGF levels were measured using a quantitative ELISA. None of the patients received adjuvant systemic therapy. The median follow-up was 64 months (range, 2-149) after BCT and 59 months (range, 2-117) after mastectomy. Correlations with well-known prognostic factors were studied, and univariate and multivariate survival analyses were performed. RESULTS: Only in the BCT group, high VEGF levels (equal or above the median level) predicted a reduced RFS and OS in univariate survival analysis (P = 0.004 and P = 0.028, respectively), implying that patients with high VEGF levels have less benefit from BCT. This was seen as a significant interaction between local treatment and VEGF for the total population for RFS (P = 0.012) and OS (P = 0.004). The interaction between local treatment and tumor size was also significant for both RFS (P = 0.046) and OS (P = 0.019) in the multivariate analysis. CONCLUSIONS: These results show that, in node-negative patients, both tumor size and VEGF content predict for a reduced efficacy of postoperative radiotherapy as part of BCT, indicating that the choice of local treatment of these patients can also be modified based on tumor VEGF content.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/radioterapia , Metástase Linfática , Fator A de Crescimento do Endotélio Vascular/biossíntese , Adulto , Idoso , Neoplasias da Mama/mortalidade , Intervalo Livre de Doença , Ensaio de Imunoadsorção Enzimática , Humanos , Hipóxia , Linfonodos/patologia , Pessoa de Meia-Idade , Análise Multivariada , Metástase Neoplásica , Neovascularização Patológica , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Tempo , Resultado do Tratamento , Regulação para Cima
11.
Expert Rev Anticancer Ther ; 4(4): 561-7, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15270660

RESUMO

Positron emission tomography (PET) using [(18)F]-2-deoxy-2-fluoro-d-glucose (FDG) has emerged as a valuable diagnostic modality in patients with non-small cell lung cancer (NSCLC). Data in the literature show that the addition of FDG-PET definitely alters clinical management in patients with potentially resectable NSCLC by adequately staging the mediastinum and detecting previously unknown distant metastases. Thus, the number of noncurative thoracotomies and unnecessary mediastinoscopies is reduced. Furthermore, there is increasing evidence that FDG-PET will change radiation treatment planning by defining a biologic treatment volume, incorporating unsuspected additional locoregional disease, and avoiding overtreatment by identifying computerized tomography abnormalities as benign. For follow-up during systemic therapy, early FDG-PET appears to be predictive for the response to therapy. However, before FDG-PET-induced changes in patient management can be incorporated into clinical practice both for radiation treatment planning and chemotherapy, technical issues must be resolved, validation studies should be performed and, most importantly, randomized trials are necessary to evaluate the effect of FDG-PET on patient outcome parameters.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Fluordesoxiglucose F18 , Neoplasias Pulmonares/diagnóstico por imagem , Estadiamento de Neoplasias/métodos , Compostos Radiofarmacêuticos , Tomografia Computadorizada de Emissão , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Humanos , Neoplasias Pulmonares/radioterapia , Metástase Linfática/diagnóstico por imagem , Planejamento de Assistência ao Paciente , Tomografia Computadorizada por Raios X
12.
Radiother Oncol ; 108(3): 440-445, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23891097

RESUMO

BACKGROUND AND PURPOSE: Patients with advanced NSCLC have survival rates <15%. The NOTCH pathway plays an important role during lung development and physiology but is often deregulated in lung cancer, making it a potential therapeutic target. We investigated NOTCH signaling in NSCLC and hypothesized that high NOTCH activity contributes to radiation resistance. MATERIALS AND METHODS: NOTCH signaling in NSCLC patient samples was investigated using quantitative RT-PCR. H460 NSCLC cells with either high or blocked NOTCH activity were generated and their radiation sensitivity monitored using clonogenic assays. In vivo, xenograft tumors were irradiated and response assessed using growth delay. Microenvironmental parameters were analyzed by immunohistochemistry. RESULTS: Patients with high NOTCH activity in tumors showed significantly worse disease-free survival. In vitro, NOTCH activity did not affect the proliferation or intrinsic radiosensitivity of NSCLC cells. In contrast, xenografts with blocked NOTCH activity grew slower than wild type tumors. Tumors with high NOTCH activity grew significantly faster, were more hypoxic and showed a radioresistant phenotype. CONCLUSIONS: We demonstrate an important role for NOTCH in tumor growth and correlate high NOTCH activity with poor prognosis and radioresistance. Blocking NOTCH activity in NSCLC might be a promising intervention to improve outcome after radiotherapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/radioterapia , Tolerância a Radiação , Receptores Notch/fisiologia , Animais , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos da radiação , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Transdução de Sinais/fisiologia
14.
Radiother Oncol ; 97(2): 322-9, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20667608

RESUMO

BACKGROUND AND PURPOSE: Previous experiments have shown that application of the anti-EGFR monoclonal antibody C225 (cetuximab) improves local tumour control after irradiation in FaDu human squamous cell carcinoma (hSCC) due to the combined effect of decreased repopulation and improved reoxygenation. The present study investigates early changes of the pimonidazole hypoxic fraction of FaDu tumours and the expression and phosphorylation of the EGFR and its downstream signal transduction molecules after treatment with C225 alone or in combination with irradiation. MATERIAL AND METHODS: FaDu tumour xenografts were irradiated with up to 3×3Gy with or without additional C225 treatment and excised at different time points. Tumour hypoxia was evaluated using pimonidazole. EGFR expression and phosphorylation and intratumoural distribution of C225 were assessed by immunofluorescence analysis. Western blots were performed to evaluate expression and phosphorylation of EGFR, ErbB2, AKT and MAPK (ERK1/2). RESULTS: Hypoxia did not change during the 4days of treatment in the tumours treated with C225 alone or combined with irradiation. C225 treatment led to downregulation of the total EGFR in FaDu tumours, accompanied by a change of the spatial distribution of the receptor favouring the membranous expression. An induction of phosphorylation of the EGFR (tyr992, tyr1173) was observed with C225 alone or combined with irradiation. AKT phosphorylation was decreased, whereas MAPK phosphorylation remained unchanged. C225 membrane staining was homogeneously distributed over the whole tumour with no differences between hypoxic and non-hypoxic tumour cells. CONCLUSION: Pimonidazole-hypoxia of FaDu tumours during the initial part of fractionated irradiation is not influenced by C225, indicating that external hypoxia markers may not be promising as biomarkers for tumour response to combined treatment. The downregulation of the total EGFR, but at the same time higher membrane staining, as well as the changes in downstream signal transduction molecules, warrants further investigation in other tumour models.


Assuntos
Anticorpos Monoclonais/farmacologia , Receptores ErbB/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/terapia , Linhagem Celular Tumoral , Cetuximab , Terapia Combinada , Fracionamento da Dose de Radiação , Feminino , Humanos , Hipóxia , Masculino , Camundongos , Neoplasias/radioterapia , Neoplasias/cirurgia , Neoplasias/terapia , Nitroimidazóis/farmacologia , Nitroimidazóis/uso terapêutico , Radiossensibilizantes/farmacologia , Radiossensibilizantes/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transplante Heterólogo , Ensaios Antitumorais Modelo de Xenoenxerto
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