RESUMEN
PURPOSE: Chemotherapy with or without radiotherapy is the standard in patients with initially nonmetastatic unresectable pancreatic cancer. Additional surgery is in discussion. The CONKO-007 multicenter randomized trial examines the value of radiotherapy. Our interim analysis showed a significant effect of surgery, which may be relevant to clinical practice. METHODS: One hundred eighty patients received induction chemotherapy (gemcitabine or FOLFIRINOX). Patients without tumor progression were randomized to either chemotherapy alone or to concurrent chemoradiotherapy. At the end of therapy, a panel of five independent pancreatic surgeons judged the resectability of the tumor. RESULTS: Following induction chemotherapy, 126/180 patients (70.0%) were randomized to further treatment. Following study treatment, 36/126 patients (28.5%) underwent surgery; (R0: 25/126 [19.8%]; R1/R2/Rx [nâ¯= 11/126; 6.1%]). Disease-free survival (DFS) and overall survival (OS) were significantly better for patients with R0 resected tumors (median DFS and OS: 16.6 months and 26.5 months, respectively) than for nonoperated patients (median DFS and OS: 11.9 months and 16.5 months, respectively; pâ¯= 0.003). In the 25 patients with R0 resected tumors before treatment, only 6/113 (5.3%) of the recommendations of the panel surgeons recommended R0 resectability, compared with 17/48 (35.4%) after treatment (pâ¯< 0.001). CONCLUSION: Tumor resectability of pancreatic cancer staged as unresectable at primary diagnosis should be reassessed after neoadjuvant treatment. The patient should undergo surgery if a resectability is reached, as this significantly improves their prognosis.
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Carcinoma Ductal Pancreático/cirugía , Quimioradioterapia , Pancreatectomía/métodos , Neoplasias Pancreáticas/cirugía , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/terapia , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Fluorouracilo/administración & dosificación , Humanos , Irinotecán/administración & dosificación , Leucovorina/administración & dosificación , Terapia Neoadyuvante , Oxaliplatino/administración & dosificación , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/terapia , Complicaciones Posoperatorias , Radioterapia Conformacional , Radioterapia de Intensidad Modulada , Análisis de Supervivencia , GemcitabinaRESUMEN
PURPOSE: In order to evaluate resource requirements, the German Society of Radiation Oncology (DEGRO) recorded the times needed for core procedures in the radio-oncological treatment of various cancer types within the scope of its QUIRO trial. The present study investigated the personnel and infrastructural resources required in radiotherapy of prostate cancer. METHODS: The investigation was carried out in the setting of definitive radiotherapy of prostate cancer patients between July and October 2008 at two radiotherapy centers, both with well-trained staff and modern technical facilities at their disposal. Personnel attendance times and room occupancy times required for core procedures (modules) were each measured prospectively by two independently trained observers using time measurements differentiated on the basis of professional group (physician, physicist, and technician), 3D conformal (3D-cRT), and intensity-modulated radiotherapy (IMRT). RESULTS: Total time requirements of 983 min for 3D-cRT and 1485 min for step-and-shoot IMRT were measured for the technician (in terms of professional group) in all modules recorded and over the entire course of radiotherapy for prostate cancer (72-76 Gy). Times needed for the medical specialist/physician were 255 min (3D-cRT) and 271 min (IMRT), times of the physicist were 181 min (3D-cRT) and 213 min (IMRT). The difference in time was significant, although variations in time spans occurred primarily as a result of various problems during patient treatment. CONCLUSION: This investigation has permitted, for the first time, a realistic estimation of average personnel and infrastructural requirements for core procedures in quality-assured definitive radiotherapy of prostate cancer. The increased time needed for IMRT applies to the step-and-shoot procedure with verification measurements for each irradiation planning.
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Cuerpo Médico/estadística & datos numéricos , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/radioterapia , Oncología por Radiación , Radioterapia Conformacional/estadística & datos numéricos , Administración del Tiempo , Carga de Trabajo/estadística & datos numéricos , Alemania/epidemiología , Humanos , Masculino , Prevalencia , Oncología por Radiación/estadística & datos numéricos , Radioterapia Guiada por Imagen/estadística & datos numéricos , Estudios de Tiempo y Movimiento , Revisión de Utilización de Recursos , Recursos HumanosRESUMEN
During the last decade, a multitude of experimental evidence has accumulated showing that low-dose radiation therapy (single dose 0.5-1 Gy) functionally modulates a variety of inflammatory processes and cellular compounds including endothelial (EC), mononuclear (PBMC) and polymorphonuclear (PMN) cells, respectively. These modulations comprise a hampered leukocyte adhesion to EC, induction of apoptosis, a reduced activity of the inducible nitric oxide synthase, and a lowered oxidative burst in macrophages. Moreover, irradiation with a single dose between 0.5-0.7 Gy has been shown to induce the expression of X-chromosome linked inhibitor of apoptosis and transforming growth factor beta 1, to reduce the expression of E-selectin and L-selectin from EC and PBMC, and to hamper secretion of Interleukin-1, or chemokine CCL20 from macrophages and PMN. Notably, a common feature of most of these responses is that they display discontinuous or biphasic dose dependencies, shared with "non-targeted" effects of low-dose irradiation exposure like the bystander response and hyper-radiosensitivity. Thus, the purpose of the present review is to discuss recent developments in the understanding of low-dose irradiation immune modulating properties with special emphasis on discontinuous dose response relationships.
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Inflamación/radioterapia , Radiación Ionizante , Apoptosis/genética , Apoptosis/inmunología , Apoptosis/efectos de la radiación , Relación Dosis-Respuesta en la Radiación , Selectina E/genética , Selectina E/inmunología , Regulación de la Expresión Génica/efectos de la radiación , Humanos , Inflamación/genética , Inflamación/inmunología , Modelos Genéticos , Modelos Inmunológicos , Proteína Inhibidora de la Apoptosis Ligada a X/genética , Proteína Inhibidora de la Apoptosis Ligada a X/inmunologíaRESUMEN
The anti-inflammatory efficiency of low-dose radiotherapy (LD-RT) for degenerative joint disorders was demonstrated over decades but had no explanation on a cellular or molecular level. As inflammatory diseases are the results of complex and pathologically unbalanced cellular and molecular interactions more recent in-vivo and in-vitro data will be discussed for possible explanation of the mechanism underlying ant-inflammatory LD-RT.2.
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Sistema Inmunológico/efectos de la radiación , Inflamación/radioterapia , Radioterapia/tendencias , Animales , HumanosRESUMEN
Rheumatoid arthritis (RA) displays a chronic inflammatory joint disease, accompanied by symmetric polyarthritis (PA) which evokes synovial inflammation, cartilage damage, and bone erosion. Patients with RA are routinely treated by immunosuppressive drugs. The therapy of inflammatory diseases and degenerative disorders with Low-dose radiotherapy (LD-RT) (single doses from 0.3 to 1.0 Gy) represents a low cost therapy with low toxicity, and is able to substitute at least in part treatment with drugs. The efficiency of LD-RT has already been proven in several animal models of inducible arthritis. In the present study we used a human TNF transgenic mouse model to examine the effects of LD-RT on PA. We observed a significant temporal improvement of the clinical progression of disease when mice were irradiated at the beginning of the disease. These data emphasize the role of LD-RT in clinical settings to treat patients with chronic and degenerative disorders and diseases.
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Artritis/radioterapia , Irradiación Corporal Total , Animales , Artritis/genética , Artritis Experimental/genética , Artritis Experimental/radioterapia , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Transgénicos , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
PURPOSE: Whereas X-irradiation with high doses is established to exert pro-inflammatory effects, low-dose radiotherapy (LD-RT) with single fractions below 1.0 Gy and a total dose below 12 Gy is clinically well known to exert anti-inflammatory and analgesic effects on several inflammatory diseases and painful degenerative disorders. Experimental studies to confirm the effectiveness, the empirical dose and fractionation schemes, and the underlying radiobiological mechanisms are still fragmentary. METHOD: The anti-inflammatory efficiency of LD-RT was confirmed in several experimental in vitro and in vivo models. RESULTS: In vitro studies revealed a variety of mechanisms related to the anti-inflammatory effect, in particular the modulation of cytokine and adhesion molecule expression on activated endothelial cells and leukocytes, and of nitric oxide (NO) production and oxidative burst in activated macrophages and native granulocytes. CONCLUSION: Inflammatory diseases are the result of complex and pathologically unbalanced multicellular interactions. It is, therefore, reasonable to assume that further molecular pathways and cellular components contribute to the anti-inflammatory effect of LD-RT. This review discusses data and models revealing aspects of the mechanisms underlying the anti-inflammation induced by low doses of X-irradiation and may serve as a basis for systematic analyses, necessary to optimize LD-RT in clinical practice.
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Inflamación/inmunología , Inflamación/radioterapia , Modelos Inmunológicos , Animales , Carga Corporal (Radioterapia) , Relación Dosis-Respuesta en la Radiación , Humanos , Inmunidad Innata/efectos de la radiación , Dosis de Radiación , Radiobiología/métodos , Radioterapia/métodos , Radioterapia/tendencias , Resultado del TratamientoRESUMEN
PURPOSE: Low-dose radiotherapy (LD-RT) is known to exert an anti-inflammatory effect, but the underlying radiobiological and immunological mechanisms remain elusive. In recent studies, we observed a reduced adhesion of peripheral blood mononuclear cells (PBMC) to endothelial cells (EC) after LD-RT (0.3-0.7 Gy). This shows that this treatment affects the initial steps of the inflammatory response. To explore the role of inflammatory mediators in this process, we investigated the expression of Transforming growth factor beta(1) (TGF-beta(1)) and Interleukin 6 (IL-6) after LD-RT. MATERIALS AND METHODS: EC were grown to subconfluence and irradiated with single-dose LD-RT. Twenty-hours after irradiation, EC were treated with IL-1beta for 4 h and then incubated with peripheral blood mononuclear cells (PBMC). Adherent PBMC were counted when using light microscopy. Expression of the cytokines TGF-beta(1) and IL-6 was measured by ELISA, and mRNA levels were analysed by the RNAse-protection assay (RPA). Surface expression of E-selectin was quantified by flow cytometry. RESULTS: A relative minimum of adhesion was observed after LD-RT between 0.3 and 0.7 Gy. This was paralleled by an expression maximum of TGF-beta(1) and IL-6, as shown by protein and mRNA levels, respectively. Neutralization of TGF-beta(1) by monoclonal antibodies, but not of IL-6, increased PBMC adhesion to EC nearly to control levels. In addition, fluorescence activated cell sorter (FACS) analysis of irradiated EC demonstrated a down-regulation of E-selectin in the same dose range. CONCLUSION: Low-dose X-irradiation between 0.3 and 0.7 Gy induced a relative maximum of TGF-beta(1) production by stimulated EC. This results in a down-regulation of leukocyte/PBMC adhesion and may contribute to the anti-inflammatory effect of LD-RT.
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Regulación hacia Abajo , Inflamación/radioterapia , Factor de Crecimiento Transformador beta/metabolismo , Rayos X , Animales , Adhesión Celular , Supervivencia Celular , Relación Dosis-Respuesta en la Radiación , Selectina E/metabolismo , Endotelio/citología , Endotelio/metabolismo , Ensayo de Inmunoadsorción Enzimática , Interleucina-6/metabolismo , Leucocitos/metabolismo , Leucocitos Mononucleares/metabolismo , Ratones , ARN/metabolismo , ARN Mensajero/metabolismo , Ribonucleasas/metabolismo , Factores de Tiempo , Factor de Crecimiento Transformador beta1 , Células Tumorales CultivadasRESUMEN
Adhesion between circulating lymphocytes and endothelial cells of the vessel wall depends on the expression of selectins and is the first step of tissue invasion which characterises inflammation. UV-B is well known to induce apoptosis in lymphocytes. We show that induction of apoptosis by any procedure leads to a metalloprotease mediated shedding of L-selectin from the surface of T-lymphocytes. Together with the previously published immunosuppressive action of apoptotic cells, this may contribute to the clinical effect of UV-B application, especially in photopheresis.
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Apoptosis/fisiología , Selectina L/metabolismo , Linfocitos/efectos de la radiación , Metaloendopeptidasas/farmacología , Rayos Ultravioleta , Humanos , Selectina L/efectos de los fármacos , Linfocitos/metabolismo , Linfocitos/fisiología , Metaloendopeptidasas/metabolismoRESUMEN
In 102 Wistar rats (male, weight 300-500 g), a modified free myocutaneous gracilis flap was obtained from the groin and transplanted to the neck. To create a pre-irradiated transplant bed, a local area of the neck was irradiated preoperatively with 30 Gy (fractionation: 3 x 10 Gy) in 30 animals, and with 50 Gy (fractionation: 5 x 10 Gy) in a further 30 animals. The interval between preoperative irradiation and transplantation was 4 weeks. Forty-two animals received no such preoperative radiation. The evaluation of healing and the success of the transplanted flap was based on a clinical assessment, carried out on postoperative days 1 7. Testing for significant differences was done nonparametrically using the Kruskal-Wallis test. The survival rate in the nonirradiated animals was 86%. In contrast, the healing of the free flaps in the pre-irradiated transplant bed was significantly lower (P=0.003) 76%, after irradiation with 30 Gy and 50% after 50 Gy. The significant difference (P=0.020) in survival rates after irradiation with 30 and 50 Gy was evidence for the dependence of successful healing on the preoperative radiation dose. Transplantation of the free myocutaneous gracilis flap to a previously irradiated transplant bed in the region of the neck is a suitable model for investigating the healing of free transplants to irradiated tissue. The success rate observed in non-irradiated transplant beds is comparable to that seen with other flap models in rats.
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Músculo Esquelético/trasplante , Cuello/cirugía , Trasplante de Piel/métodos , Colgajos Quirúrgicos , Anastomosis Quirúrgica , Animales , Fraccionamiento de la Dosis de Radiación , Supervivencia de Injerto , Masculino , Microcirugia , Modelos Animales , Cuello/efectos de la radiación , Ratas , Ratas Wistar , Estadísticas no Paramétricas , Factores de Tiempo , Resultado del Tratamiento , Grado de Desobstrucción Vascular , Cicatrización de HeridasRESUMEN
PURPOSE: In early stage Dupuytren's contracture radiotherapy was applied to prevent disease progression. Long-term results and late toxicity of this treatment were evaluated in a retrospective analysis. PATIENTS AND METHODS: Between 1982 and 1994, 99 patients (176 hands) received orthovoltage radiotherapy, which consisted of two courses with 5 x 3 Gy (total dose: 30 Gy, daily fractionated; 120 kV, 4 mm Al), separated by a 6 to 8-week pause. The Dupuytren's contracture was staged according to the classification of Tubiana et al. The long-term outcome was analyzed at last follow-up between July and November 1999. The median follow-up was 10 years (range 7-18 years). Late toxicity was assessed using the LENT-SOMA criteria. RESULTS: In Stage N 84% and Stage N/I 67% of cases remained stable. 65% of the cases in Stage I and 83% in Stage II showed progressive nodules and cords. In case of progression we saw no complications after a second radiotherapy or salvage operation. CONCLUSION: Radiotherapy effectively prevents disease progression for early stage Dupuytren's contracture (Stage N, N/I). Moreover, in case of disease progression despite radiotherapy salvage surgery is still feasible.
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Contractura de Dupuytren/radioterapia , Adolescente , Adulto , Anciano , Progresión de la Enfermedad , Fraccionamiento de la Dosis de Radiación , Contractura de Dupuytren/diagnóstico , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
PURPOSE: L-selectin (CD62L) is a prerequisite for leucocyte adhesion to endothelial cells of blood vessels and consequently for transmigration. Its expression on the cell surface therefore regulates the ability of lymphocytes to enter lymph nodes, to re-enter blood vessels or to invade tissues at sites of inflammation. The aim of this study was to determine the expression of CD62L on apoptotic lymphocytes after UVB irradiation. MATERIALS AND METHODS: Peripheral blood mononuclear cells (PBMC) were isolated from peripheral blood of normal healthy volunteers. Cells were stimulated with phorbol myristate acetate (PMA) and ionomycin for activation. Apoptosis in peripheral T-cells and Jurkat cells was induced by irradiation with UVB (120 mJ/cm2). In addition, T-cells or Jurkat cells were cultured for the indicated time with anti-Fas antibody CH11. The CH11-induced apoptosis was inhibited by the pan-caspase inhibitor zVAD-fmk. For detection of apoptosis, cells were analysed by cytofluorometry for morphological changes typical for apoptosis. The reliability of the apoptotic cell gate was confirmed by staining with FITC-labelled annexin-V in the presence ofpropidium iodide (PI). For FACS analysis of CD62L expression on the cell-surface immunofluorescence was performed using FITC-conjugated anti-CD62L and PE-conjugated anti-CD3 antibodies. Soluble CD62L (sCD62L) in the cell supernatants was measured by standard ELISA technique. Assays were performed in the presence and absence of metalloprotease inhibitor KB8301. RESULTS: PBMC from healthy volunteers undergoing apoptosis following UVB irradiation selectively shed CD62L, whereas the expression of the lineage-specific marker CD3 showed only minor changes. Shedding was blocked by the hydroxamic acid-based metalloprotease inhibitor KB8301. When Jurkat cells were treated with the caspase inhibitor zVAD-fmk, anti-CD95 antibodies did not induce apoptosis, and the expression of CD62L remained unaltered. CONCLUSION: UVB or ionizing radiation induce apoptosis in lymphocytes. The loss of CD62L is associated with apoptosis and will influence lymphocyte trafficking and, by excluding them from CD62L-mediated adhesion and tissue invasion, might contribute to the regulation of inflammation.
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Apoptosis/efectos de la radiación , Selectina L/metabolismo , Metaloendopeptidasas/metabolismo , Linfocitos T/efectos de la radiación , Rayos Ultravioleta , Clorometilcetonas de Aminoácidos/farmacología , Anexina A5/metabolismo , Complejo CD3/metabolismo , Adhesión Celular , Separación Celular , Células Cultivadas , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Humanos , Células Jurkat , Cinética , Selectina L/biosíntesis , Leucocitos Mononucleares/patología , Leucocitos Mononucleares/efectos de la radiación , Fenotipo , Linfocitos T/patología , Factores de Tiempo , Receptor fas/inmunologíaRESUMEN
The aim of the study was to investigate, histomorphometrically, quantitative and qualitative changes in irradiated neck recipient vessels and transplant vessels used for microsurgical anastomoses in free flaps in patients undergoing preoperative radiotherapy and chemotherapy. In 55 patients receiving 42 radial forearm flaps, 6 latissimus dorsi flaps, 6 osteomyocutaneous fibula grafts and 1 lateral arm flap, a total of 220 vessels were obtained from neck recipient vessels and transplant vessels during anastomosis. Three groups were formed: Group 1 (16 patients) treated with no radiotherapy or chemotherapy; Group 2 (20 patients) treated with preoperative irradiation (40-50 Gy) and chemotherapy (800 mg/m2 5-FU and 20 mg/m2 cisplatin) 1.5 months prior to surgery; Group 3 (19 patients) treated with radiotherapy (60-70 Gy) (median interval 78.7 months; IQR 31.3 months) prior to surgery. From each of the 220 vessel specimens, 3 sections each were histomorphometrically investigated, both qualitatively and quantitatively. To evaluate these changes as a function of age, radiation dose and chemotherapy, a statistical analysis was performed using analysis of covariance and chi-square tests. In Group 3, qualitative changes (intima dehiscence, hyalinosis) were found in recipient arteries significantly more frequently (25%, P=0.009) than in Groups 1 and 2. For Group 3 recipient arteries, histomorphometry revealed a significant decrease in the ratio of media area/total vessel area (median 0.53, IQR 0.10) in comparison with Group 1 (P= 0.02) (median 0.60, IQR 0.29) and Group 2 (P=0.046) (median 0.59, IQR 0.10). No significant differences were found between the vessels of Groups 1 and 2 (P= 0.48). Age and chemotherapy did not appear to have a significant influence on vessel changes in this study.
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Vasos Sanguíneos/efectos de la radiación , Carcinoma de Células Escamosas/cirugía , Irradiación Craneana/efectos adversos , Neoplasias de Cabeza y Cuello/cirugía , Colgajos Quirúrgicos/irrigación sanguínea , Adulto , Factores de Edad , Anciano , Análisis de Varianza , Anastomosis Quirúrgica , Antineoplásicos/efectos adversos , Vasos Sanguíneos/efectos de los fármacos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Distribución de Chi-Cuadrado , Relación Dosis-Respuesta en la Radiación , Femenino , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , Humanos , Masculino , Persona de Mediana Edad , Estadísticas no Paramétricas , Resultado del TratamientoRESUMEN
BACKGROUND AND PURPOSE: The anti-inflammatory effect of low-dose radiotherapy (LD-RT) still is not understood. The adhesion of leukocytes to endothelial cells (EC) of the vessel wall is the initial event of tissue invasion, and thus, crucially contributes to the regulation of inflammation. We investigated the influence of LD-RT on the adhesion process in vitro. MATERIALS AND METHODS: Isolated peripheral-blood-mononuclear-cells (PBMC) were incubated with an activated murine endothelioma cell-line under shear conditions at 4 degrees C after irradiation with single doses between 0.1 and 10.0 Gy. Adherent cells were counted microscopically and compared to a non-irradiated control. In parallel, viability and expression of adhesion molecules, especially of L-selectin, and lineage-specific markers on the cell surface were determined by dye exclusion and cytofluorometry, respectively. Modulation of adhesion by soluble L-selectin was tested in the adhesion assay. RESULTS: Radiation doses of 0.1-0.5 Gy reduced the adhesion of viable PBMC to EC in vitro by 70% of the control level 4 h after irradiation. Leukocytes showed a marked reduction of L-selectin expression after LD-RT. Soluble L-selectin can inhibit the adhesion of PBMC to EC. CONCLUSION: The anti-inflammatory effect of LD-RT might, in part, be due to the reduction in the adhesion of PBMC to EC. This reduction in adhesion might be a consequence of the reduced expression of L-selectin on the surface of PBMC, and the inhibition of adherence by soluble L-selectin shed by PBMC in vitro.
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Endotelio Vascular/efectos de la radiación , Leucocitos Mononucleares/efectos de la radiación , Adulto , Adhesión Celular/efectos de la radiación , Línea Celular , Supervivencia Celular/efectos de la radiación , Endotelio Vascular/fisiología , Femenino , Humanos , Selectina L/análisis , Selectina L/farmacología , Leucocitos Mononucleares/química , Leucocitos Mononucleares/fisiología , Masculino , Dosificación RadioterapéuticaRESUMEN
BACKGROUND: Following preoperative radiotherapy prior to ablative surgery of squamous epithelial carcinomas of the head and neck region, inflammatory changes to the connective tissue and vascular endothelium are observed. These processes may lead to a delay in healing of free flaps in the irradiated transplant bed. The aim of the study was to investigate qualitative and quantitative changes in vascularization in irradiated and regular transplant beds. MATERIAL AND METHODS: In Wistar rats (male, weight 300 to 500 g) undergoing preoperative irradiation of the neck region with 3 times 10 Gy (30 animals) and 5 times 10 Gy (30 animals) and non-irradiated rats (42 animals), a free myocutaneous gracilis flap taken from the groin was transplanted to the irradiated region of the neck. The time interval between irradiation and transplantation was 4 weeks. On day 3, 4, 5, 7, 14 and 28 post operation, the capillary sprouting, structural changes and the distribution patterns were analyzed by H & E and immunohistochemical staining (goat-F[ab]-2-anti-von Willebrand factor antibody). Three histological sections (2 to 4 microns) per sample were investigated histomorphometrically, qualitatively and quantitatively (ratio capillary area/total area, and capillary lumen) by NH-image-digitized measurement. A statistical analysis was performed using the Mann-Whitney test. RESULTS: In contrast to non-irradiated rats, irradiated animals showed a qualitatively reduced and a more irregular capillary distribution with more marked pericapillary fibrosis in the irradiated transplant bed. Quantitatively, the ratio capillary area/total area, as a marker of improved capillarization was significantly reduced in the transition area transplant/irradiated transplant bed and in irradiated transplant bed tissues in contrast to the non-irradiated control group (p = 0.004). Also, from day 14 to 28 a significant decrease was found in the transition area between transplanted tissues and irradiated transplant bed tissues in irradiated animals (p = 0.005). The median capillary lumen size also decreased significantly in the transition area and transplant bed in 30 Gy and 50 Gy irradiated animals (p < 0.001 and p = 0.003). CONCLUSIONS: Following irradiation, vascularization of the soft tissue flaps is both reduced and delayed. This is evidence of delayed healing of soft tissue transplants in transplant beds irradiated prior to surgical interventions. Further optimization of the time interval between radiotherapy and surgery and the total radiation dose are therefore needed.
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Capilares/fisiología , Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/cirugía , Neoplasias de Cabeza y Cuello/radioterapia , Neoplasias de Cabeza y Cuello/cirugía , Neovascularización Fisiológica , Colgajos Quirúrgicos , Animales , Capilares/citología , Inmunohistoquímica , Masculino , Ratas , Ratas Wistar , Factor de von WillebrandRESUMEN
PURPOSE: Radiotherapy (RT) is used as last resort for patients with advanced cutaneous malignant melanoma (MM). Herein our 20-year clinical experience is presented analyzing different endpoints and prognostic factors in patients with locally advanced, recurrent or metastatic MM. PATIENTS AND METHODS: From 1977 to 1995, 2,917 consecutive patients were entered in the MM registry of our university hospital. RT was indicated in 121 patients (56 females, 65 males) for palliation in locally advanced recurrent and metastatic MM stages UICC IIB to IV. At the time of RT initiation, 11 patients had primary or recurrent lesions which were either not eligible for surgery or had residual disease (R2) after resection of a primary or recurrent MM lesion (UICC IIB); 57 patients had lymph node (n = 33) or in-transit metastases (n = 24) (UICC III), and 53 had distant organ metastases (7 M1a, 46 M1b) (UICC IV). The time from first diagnosis to on-study RT averaged overall 19 months (median: 18; range: 3 to 186 months). In 77 patients conventional RT and in 44 patients hypofractionted RT was applied with 2 to 6 Gy fractions up to a mean total RT dose of 45 (median: 48; range: 20 to 66) Gy. RESULTS: At 3 months follow-up, complete response (CR) was achieved in 7 (64%), overall response (CR + PR) in all (100%) UICC IIB patients, in 25 (44%) and 44 (77%) of 57 UICC III patients, and in 9 (17%) and 26 (49%) of 53 UICC IV patients. Tumor progression during RT occurred in 25 (21%) patients. Patients with CR survived longer (median: 40 months) than those without CR (median 10 months) (p < 0.01). At the time of evaluation and last FU (December 31, 1996), 26 patients were still alive: 6 (55%) stage UICC IIB, 17 (30%) stage UICC III, and 3 (6%) stage UICC IV patients (p < 0.01). Univariate analysis revealed following prognostic factors for CR and long-term survival: UICC stage (p < 0.001), primary location in the head and neck, total RT dose > 40 Gy (all p < 0.05), while age, gender and primary histological subtype had no impact. In multivariate analysis, UICC stage was the only independent favorable prognostic factor for achievement of CR and long-term survival (p < 0.001). CONCLUSION: External RT provides effective palliation in advanced UICC stages. The UICC staging system is a good predictor of initial and long-term tumor response in metastatic MM. Prospective randomized trials using RT with or without adjuvant therapy for advanced MM are justified.
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Melanoma/radioterapia , Recurrencia Local de Neoplasia/radioterapia , Neoplasia Residual/radioterapia , Cuidados Paliativos , Neoplasias Cutáneas/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Fraccionamiento de la Dosis de Radiación , Femenino , Humanos , Metástasis Linfática , Masculino , Melanoma/mortalidad , Melanoma/patología , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Neoplasia Residual/mortalidad , Neoplasia Residual/patología , Pronóstico , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Tasa de SupervivenciaRESUMEN
The 20-year radiotherapy (RT) experience in patients with locally advanced, recurrent or metastatic malignant melanoma (MM) is analyzed with respect to different endpoints and prognostic factors. From 1977 to 1995, 2917 consecutive patients were entered in our MM registry. RT was indicated in 121 patients (56 females, 65 males) for palliation in advanced MM stages. The histology of the primary lesion was nodular in 51, superficial spreading in 35, acral-lentiginous in 8 and lentigo maligna in 4 patients); 22 were missing or could not be reclassified. Eleven patients had primary or recurrent lesions which were ineligible for surgery or had residual disease (R2) after resection of a primary or recurrent lesion (UICC IIB); 57 patients had lymph node (33) or in-transit metastases (24) (UICC III), 53 had distant organ metastases (7 M1a; 46 M1b) (UICC IV). Time from first diagnosis to on-study RT averaged 19 (median: 18; range: 3-186) months. In most cases conventional RT was applied (2-6 Gy single fractions) up to a mean total RT dose of 45 (median: 48; range: 20-66) Gy. At 3 months follow-up (FU), complete response (CR) was achieved in 7 (64%) and overall response (CR+PR) in all (100%) UICC IIB patients, in 25 (44%)/44 (77%) of 57 UICC III patients, and in 9 (17%)/26 (49%) of 53 UICC IV patients. Progression during RT occurred in 25 (21%) patients. Patients with CR survived longer (median: 40 months) than those without CR (median: 10 months) (p<0. 01). At last FU, 26 patients were alive: 6 (55%) UICC IIB, 17 (30%) UICC III, and 3 (6%) UICC IV patients (p<0.01). In univariate analysis following favorable prognostic factors for CR and long-term survival were identified: low UICC stage (p<0.001), primary site head and neck and total dose >40 Gy (all p<0).
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Melanoma/radioterapia , Recurrencia Local de Neoplasia/radioterapia , Neoplasias Cutáneas/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Melanoma/mortalidad , Melanoma/patología , Persona de Mediana Edad , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Radioterapia Adyuvante , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: Radiotherapy is used as a "last resort" for patients with advanced cutaneous malignant melanoma. We have analyzed our 20-year clinical experience with respect to different endpoints and prognostic factors in patients with locally advanced, recurrent, or metastatic malignant melanoma. METHODS: From 1977 to 1995, 2,917 consecutive patients were entered in the melanoma registry of our hospital. Radiotherapy was indicated in 121 patients (56 females, 65 males) for palliative reasons in advanced malignant melanoma stages UICC IIB/III/IV. The histology of the primary lesion was nodular in 51 patients, superficial spreading in 35, acral-lentiginous in 8, and lentigo maligna melanoma in 4 patients. Eleven patients had primary or recurrent lesions which were either not eligible for surgery or had residual disease (R2) after resection of a primary or recurrent lesion (UICC IIB); 57 patients had lymph node (n = 33) or in-transit metastases (n = 24) (UICC III), and 53 had distant organ metastases (7 M1a; 46 M1b) (UICC IV). Time from first diagnosis to on-study radiotherapy averaged 19 (median: 18; range: 3-186) months. In most cases, conventional RT was applied with 2-6 Gy single fractions up to a median total radiation dose of 48 (mean: 45; range: 20-66) Gy. RESULTS: At 3 months follow-up, complete response (CR) was achieved in 7 (64%) and overall response [complete (CR) and partial response (PR)] in all (100%) UICC IIB patients, in 25 (44%) and 44 (77%) of 57 UICC III patients, and in 9 (17%) and 26 (49%) of 53 UICC IV patients. Tumor progression during radiotherapy occurred in 25 (21%) patients. Patients with CR survived longer (median: 40 months) than those without CR (median 10 months) (p < 0.01). At last follow-up (Dec 31, 1996), 26 patients were still alive: 6 (55%) UICC IIB, 17 (30%) UICC III, and 3 (6%) UICC IV patients (p < 0.01). Univariate analysis revealed the following prognostic factors for complete response and long-term survival: UICC stage (p < 0.001), primary location in the head and neck region, total radiation dose above 40 Gy (all p < 0.05), while age, gender, and histology had no impact. In multivariate analysis, UICC stage was the only independent prognostic factor (p < 0.001). CONCLUSION: External beam radiotherapy can provide long-term local control and effective palliation in malignant melanoma UICC stages IIB-IV. The current UICC staging system is an excellent prognostic factor for initial and long-term tumor response in metastatic melanoma. Therefore, prospective randomized trials using external radiotherapy with or without adjuvant therapy for advanced malignant melanoma are justified.
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Melanoma/radioterapia , Recurrencia Local de Neoplasia/radioterapia , Neoplasias Cutáneas/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Femenino , Estudios de Seguimiento , Humanos , Metástasis Linfática , Masculino , Melanoma/mortalidad , Melanoma/secundario , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Estadificación de Neoplasias , Cuidados Paliativos , Pronóstico , Estudios Retrospectivos , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Tasa de Supervivencia , Insuficiencia del TratamientoRESUMEN
PURPOSE: Cells undergoing apoptosis contribute to the regulation of activated mononuclear cells (Voll et al. 1997). Low-dose radiotherapy (LD-RT) is known to improve inflammatory symptoms, but the mechanism of action is still unclear. The aim of this study was to investigate the rate of apoptosis of peripheral blood mononuclear cells (PBMC) induced by LD-RT within the therapeutic dose range of anti-inflammatory RT. MATERIALS AND METHODS: PBMC were isolated from venous blood of ten healthy volunteers and were irradiated with single doses between 0.1 and 3.0 Gy. Apoptotic nuclei were detected by flow cytometry after propidium iodide (PI) triton staining, and apoptotic cells were detected by annexin V/PI staining and cell scatter analysis. Since apoptotic cells display increased cytoplasmatic granularity and concomitant reduced cell size, they can be distinguished from viable cells in forward/side scatter (FSC/SSC) histograms. Apoptotic PBMC were further subtyped by double staining with annexin V and directly labelled monoclonal antibodies recognizing the lineage-specific surface markers CD4, CD8, and CD19, respectively. The apoptosis rate of irradiated cells was analysed in a time and dose dependent fashion and was compared to a sham-irradiated control. RESULTS: After irradiation, a dose-dependent increase in apoptosis was observed, with a discontinuity (plateau or peak) between 0.3Gy and 0.7Gy in 9/10 donors (90%) and 59/80 samples (74%). 8/10 donors (80%) and 38/80 samples (47%) showed not only a discontinuous increase with a plateau but a relative maximum of apoptosis peaking within the dose range of 0.3 Gy and up to 0.7 Gy. CONCLUSION: LD-RT induces a relative maximum of apoptosis in PBMC in the does range between 0.3 Gy and 0.7 Gy. This may contribute to its anti-inflammatory effect observed clinically.
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Apoptosis , Linfocitos/efectos de la radiación , Dosificación Radioterapéutica , Adulto , Antígenos CD/análisis , Relación Dosis-Respuesta en la Radiación , Femenino , Citometría de Flujo , Humanos , Inflamación/radioterapia , Linfocitos/inmunología , MasculinoRESUMEN
BACKGROUND: Therapeutic results after radiotherapy in thyroid associated orbitopathy (TAO) often are not comparable, because either different therapeutic methods at the same time or different scores were used in the evaluation. This study focuses on radiotherapy alone by means of different evaluation scores. PATIENTS AND METHODS: 60 patients (49 women, 11 men) received standard external beam radiotherapy (20 Gy: 10 fractions of each 2 Gy) as ultima ratio after failing different other therapies of thyroid associated orbitopathy. The mean interval from beginning of the symptoms to the radiotherapy was 17 +/- 36 months (between 6 and 240 months). The follow up was documented--classified by means of 4 different scores--before radiotherapy, 6-12 weeks, 1 year after radiotherapy and at last follow up. The changes of symptom categories or grades of the different scores were analysed. RESULTS: Significant changes of the ophthalmic scores were observed when comparing the endpoints at 6-12 weeks, and at 1-year follow up after radiotherapy. The "classical" Werner score at 12 months follow up did not correlate well with the other TAO scores: American thyroid association (ATA) scoring system, Stanford scoring system, International ophthalmopathy index, while all other TAO scores revealed a high correlation among each other. According to the Orbitopathy Index (OI) of Grussendorf an improvement from 14.2 points to 6.0 points was achieved. Soft tissue involvement and corneal involvement demonstrated the highest response rate (83/87%), extraocular muscle involvement and proptosis a good response rate (69/70%). No long-term complications were observed. CONCLUSION: According to this study there are indications that external beam radiotherapy is a suitable therapy even after pretreatment and a longer course of TAO. The OI, the ATA and the Stanford scoring systems lead to similar results in the assessment of thyroid orbitopathy.
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Enfermedad de Graves/radioterapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Fraccionamiento de la Dosis de Radiación , Femenino , Estudios de Seguimiento , Enfermedad de Graves/clasificación , Humanos , Masculino , Persona de Mediana Edad , Garantía de la Calidad de Atención de Salud , Radioterapia de Alta Energía , Resultado del TratamientoRESUMEN
BACKGROUND: This study compares 4 classifications in patients with progressive refractory Graves orbitopathy (GO) and examines their prognostic value in long-term follow-up. PATIENTS AND METHODS: From 1984 to 1994, 60 consecutive patients (49 female, 11 male) received 20 Gy (10 x 2 Gy) radiotherapy with 6 MV Linac photons. Ocular symptoms and functional impairment was evaluated according to 4 GO-classification systems: Werner-, modified ATA- and Stanford-Score and Ophthalmopathy-Index (OI) according to Grussendorf. In addition, all patients noted their subjective response on a linear scale (0 to 100%). RESULTS: Improvement was achieved within 1 year after radiotherapy according to the Werner-Score in 28 (47%) patients in > or = 1 symptom category, according to the modified ATA-score in 48 (80%), the Stanford-score in 47 (78%) and the OI-Score in 55 (92%) patients (reduction of > 2 points). The Werner-Score correlated less to the other scores (coefficient r < 0.5) than the other scores among themselves (r approximately 0.9). The ATA-Score improved in the different symptom categories between 47% (stage VI) and 87% (stage V). The OI-Score was reduced by a mean of 6 points. The patients reached a mean subjective improvement of +70 +/- 25%. Acute or chronic side effects were not observed. In multivariate analysis the "male gender" (p = 0.08), a "symptom duration prior to radiotherapy > 1 year" (p = 0.14) and a "high symptom category" (p = 0.11) indicated a negative prognostic trend. CONCLUSIONS: External radiotherapy is effective for severe, progressive GO after pretreatment. A minimum follow-up of at least 12 months and standardized classification and success criteria are required.