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DOES SMOKING AFFECT ORAL MUCOSITIS DURING RADIOTHERAPY FOR HEAD-AND-NECK TUMOURS?
S 20
EFFECTS OF BIOLOGICAL MODIFIERS ON NORMAL TISSUE TOLERANCE (AMELIORATION /
EXACERBATION) Conclusions: Comparable to rats, lung histology of C57BI/6 mice showed radiation-induced pulmonary vascular damage. Therefore, this mouse-strain seems to be a suitable model to study the mechanism of- and intervention strategies for early radiation-induced pulmonary vascular damage. These studies might lead to opportunities to optimize radiotherapeutic treatment of thoracic tumors. 35 poster MECHANISMS OF LATE MICRO-VASCULAR DAMAGE IN IRRADIATED BREAST CANCER PATIENTS M. Scharptenecker", B. Ftcot", F. Stewart 1 , N. Russell 2 1 THE NETHERLANDS CANCER INSTITUTE, Department of Experimental Therapy, Amsterdam, Netherlands 2 THE NETHERLANDS CANCER INSTITUTE, Department of Radiotherapy, Amsterdam, Netherlands
Purpose: A major cause of late radiation morbidity is vascular injury, which develops progressively over many years. Vascular lesions manifest in microvessels as telangiectasia, which are characterised as dilated, tortuous and thin-walled blood vessels. In skin, telangiectasia appear after radiotherapy for breast cancer in 80% of the patients, with a mean latency of 4.7 years. Skin telangiectasia may be dismissed as only having cosmetic consequences, but they have a negative impact on quality of life. Further, radiation-induced damage in the skin can be a cause of graft failure after free flap reconstructive surgery. A further problem in irradiated skin is lymphoedema, caused by perturbations in the lymphatic network. This causes discomfort and functional impairment in a significant proportion of patients. Microvascular damage in the skin can be considered a model for microvascular damage in other tissues and organs to study the aetiology and therapeutic interventions. The mechanism how these aberrations develop is not clear, but the phenotype implies that an imbalance between repair and homeostasis pathways causes vessel injury and dilation.This study was aimed at determining mRNA and protein expression levels of blood and lymph vessel markers after irradiation and at correlating them to vessel damage. Materials: Skin biopsies from the irradiated and non-irradiated contralateral breast were collected from 30 patients undergoing breast reconstruction and were analysed by immunohistochemistry. For gene expression analysis, skin punch biopsies were taken from ten breast cancer patients after radiotherapy. Biopsies were collected from the irradiated breast from areas with and without macroscopic telangiectasia formation. Biopsies from the non-irradiated contralateral breast served as control. Gene expression was analysed by quantitative PCR. Results: The number of lymphatic vessels was increased in 67% of the irradiated biopsies. Irradiated biopsies also contained significantly more macrophages than the respective non-irradiated controls. 75% of the patients with increased lymphatic score also displayed an increase in macrophage numbers. Interestingly, except for endoglin, RNA expression of markers for blood and lymphatic growth and repair (TGF-,B, VEGF-A, VEGFR2, VEGFR3, and VEGF-D) was decreased in most irradiated telangiectatic biopsies. Ongoing studies include the analysis of protein levels of these molecules and whether there is a correlation of endoglin expression with blood/lymphatic vessel phenotypes and macrophage infiltration. Conclusions: We suggest that irradiation induces an inflammatory infiltrate that contributes to late vessel damage. Changes in the expression levels of vessel repair molecules in macrophages, but also in the irradiated tissues may contribute to the development of the lymphatic and vascular phenotypes observed.
Effects of biological modifiers on normal tissue tolerance (amelioration / exacerbation)
the treatment days, according to the RTOG/EORTC scoring system; confluent mucositis (grade 3) was stringently defined as any pseudomembranousulcerative lesion with a diameter> 1 cm. Endpoints of the analysis were incidence and time-to-onset of mucositis grade 3. Patients were categorized as active smokers, never-smokers or non-smokers for less or more than one year before the onset of radiotherapy. The mean age of the patients was 59 years (range 20-94); 22 % were female. Radiotherapy was administered in a conventional (n=202), hyperfractionated (n=22) or a combined conventionalhyperfractionated protocol (n=56). Of all patients, 101 (36 %) were active smokers, 49 (17 %) were never-smokers, 67 (24 %) non-smokers since more and 63 (23 %) for less than one year. Results: A total of 66 % of all patients developed confluent mucositis with a mean latent time of 24 days after onset of radiotherapy; both parameters were significantly dependent on the treatment protocol. Within the individual radiotherapy protocols, a univariate analysis of nicotine consumption - yes vs. no - did not yield a significant difference. Multivariate analysis (independent variables: smoking habit, age, gender, treatment protocol, chemotherapy), however, indicated a clear disadvantage of active smoking for both the incidence (61 % vs. 75 %, p=0.0329) and the latent time (25 ± 1 days vs. 23 ± 1 days, p=0.0347) of oral mucositis. The univariate comparison of active vs. never-/non-smokers > 1 Ydid not yield significant differences, while the multivariate analysis showed a trend for the incidence (65 % vs. 75 %, p=0.0899) and a significant difference (25 ± 1 days vs. 23 ± 1 days, p=0.0030) for the latent time. Conclusions: In summary, a significant impact of active smoking on the clinical manifestation of confluent oral mucositis can be demonstrated based on large patient numbers. However the effect is only minor and clinically negligible, particularly for the time-to-onset of the mucosal response with a difference of only 2 days. Hence, other parameters appear to dominate the inter-individual differences in the development of the radiation response of the oral mucosa. 37 poster PROTECTIVE ROLE OF CARNITINE AGAINST RADIATIONINDUCED KIDNEY DAMAGE IN INFANT RATS: SCINTIGRAPHIC AND HISTOPATHOLOGIC EVALUATION R. Cesar", G. Durmus Atturr'. F. Oz Puyan", M. Saynak", K. lbls", A. Ozen", G. Baylr-Anqin", F. ustun", B. Denizli 1 , S. Parlar", M. Caloqlu", V. Yurut-Caloglu 1 , M. C. Uzal", Z. Ko<;ak1 1 TRAKYA UNIVERSITY MEDICAL FACULTY, Radiation Oncology, Edirne, Turkey 2 TRAKYA UNIVERSITY MEDICAL FACULTY, Nuclear Medicine, Edirne, Turkey 3 TRAKYA UNIVERSITY MEDICAL FACULTY, Pathology, Edirne, Turkey 4 CANAKKALE UNIVERSITY FACULTY OF MEDICINE, Nuclear Medicine, Canakkale, Turkey
Purpose: The aim of this paper is to clarify, whether L-carnitine has a protective effect in prevention of radiation induced nefrotoxicity (RIN) during late phase following radiation therapy in an infant rat model. Materials: Thirty-one two-week-old male Wistar albino rats divided into four groups. Group 1 (n=10): Control, Group 2 (n=10): L-Carnitine alone, Group 3 (n=10): Irradiation alone (RT), Group 4 (n=10): L-Carnitine before irradiation (L-Carnitine + RT), injected with L-Carnitine (LC) (300 mg/kg) i.p., 30 minutes before the irradiation. The rats in the RT and L-Carnitine + RT groups were irradiated individually with a single dose of 8 Gy. 2,2,4 and 1 deaths were occurred in groups, respectively. Animals underwent both Tc99m DTPA (Diethylene triamine pentaacetic acid) dynamic renal imaging and Tc99m DMSA (Dimercaptosuccinic acid) static renal imaging at the end of three months follow-up period. Proximal tubular degeneration, tubular atrophy, interstitial fibrosis and glomerular degeneration were assessesed histopathologically. Results: The mean Tmax and T1/2 values in the RT group were 4.2 ± 0.8 and 14.5 ± 4.1, respectively. In the L-Carnitine + RT group, those values were 2.8 ± 0.4 and 12.8 ± 1.7 and significantly lower than those in the RT group (p=0.03, p=0.04). In L-Carnitine + RT group, the glomerular structures were well protected compared to RT group (0.78 ± 0.22 vs. 1.88 ± 0.58, p=0.04) (Table 1).
36 poster DOES SMOKING AFFECT ORAL MUCOSITIS DURING RADIOTHERAPY FOR HEAD-AND-NECK TUMOURS? E. Dorr 1 , W. Dorr 1 1 UNIVERSITY HOSPITAL DRESDEN, Department of Radiotherapy and Radiation Oncology, Dresden, Germany
Purpose: Oral mucositis is a severe, dose-limiting side-effect of radio(chemo)therapy of head-and-neck tumours. It is frequently postulated that smoking aggravates the mucosal radiation response. The present analysis was initiated to test this hypothesis. Materials: In the present analysis, 280 patients were included, who received a dose of at least 40 Gy in the oral cavity. Oral mucositis was scored daily at
R.....l ..f.:.wniline
COl'llroi
l ..C ",niline
RT
99PtTc--
IF''
4]~3
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~~'3
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AFX
5:l.t2
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65.t9
LTmax
1.5tQ5
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4."<.t0.S
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LF": The tM tM41 fur">~M percentagt t~ f~t I,R: Right L L&I'l. T m.u. The time 'N pellI.)hait tlXXlt
Conclusions: The use of radioprotective drug is more important for children where there is probability of long-term survival. L-Carnitine is a natural
EFFECTS OF BIOLOGICAL MODIFIERS ON NORMAL TISSUE TOLERANCE (AMELIORATION /
EXACERBATION) Conclusions: Comparable to rats, lung histology of C57BI/6 mice showed radiation-induced pulmonary vascular damage. Therefore, this mouse-strain seems to be a suitable model to study the mechanism of- and intervention strategies for early radiation-induced pulmonary vascular damage. These studies might lead to opportunities to optimize radiotherapeutic treatment of thoracic tumors. 35 poster MECHANISMS OF LATE MICRO-VASCULAR DAMAGE IN IRRADIATED BREAST CANCER PATIENTS M. Scharptenecker", B. Ftcot", F. Stewart 1 , N. Russell 2 1 THE NETHERLANDS CANCER INSTITUTE, Department of Experimental Therapy, Amsterdam, Netherlands 2 THE NETHERLANDS CANCER INSTITUTE, Department of Radiotherapy, Amsterdam, Netherlands
Purpose: A major cause of late radiation morbidity is vascular injury, which develops progressively over many years. Vascular lesions manifest in microvessels as telangiectasia, which are characterised as dilated, tortuous and thin-walled blood vessels. In skin, telangiectasia appear after radiotherapy for breast cancer in 80% of the patients, with a mean latency of 4.7 years. Skin telangiectasia may be dismissed as only having cosmetic consequences, but they have a negative impact on quality of life. Further, radiation-induced damage in the skin can be a cause of graft failure after free flap reconstructive surgery. A further problem in irradiated skin is lymphoedema, caused by perturbations in the lymphatic network. This causes discomfort and functional impairment in a significant proportion of patients. Microvascular damage in the skin can be considered a model for microvascular damage in other tissues and organs to study the aetiology and therapeutic interventions. The mechanism how these aberrations develop is not clear, but the phenotype implies that an imbalance between repair and homeostasis pathways causes vessel injury and dilation.This study was aimed at determining mRNA and protein expression levels of blood and lymph vessel markers after irradiation and at correlating them to vessel damage. Materials: Skin biopsies from the irradiated and non-irradiated contralateral breast were collected from 30 patients undergoing breast reconstruction and were analysed by immunohistochemistry. For gene expression analysis, skin punch biopsies were taken from ten breast cancer patients after radiotherapy. Biopsies were collected from the irradiated breast from areas with and without macroscopic telangiectasia formation. Biopsies from the non-irradiated contralateral breast served as control. Gene expression was analysed by quantitative PCR. Results: The number of lymphatic vessels was increased in 67% of the irradiated biopsies. Irradiated biopsies also contained significantly more macrophages than the respective non-irradiated controls. 75% of the patients with increased lymphatic score also displayed an increase in macrophage numbers. Interestingly, except for endoglin, RNA expression of markers for blood and lymphatic growth and repair (TGF-,B, VEGF-A, VEGFR2, VEGFR3, and VEGF-D) was decreased in most irradiated telangiectatic biopsies. Ongoing studies include the analysis of protein levels of these molecules and whether there is a correlation of endoglin expression with blood/lymphatic vessel phenotypes and macrophage infiltration. Conclusions: We suggest that irradiation induces an inflammatory infiltrate that contributes to late vessel damage. Changes in the expression levels of vessel repair molecules in macrophages, but also in the irradiated tissues may contribute to the development of the lymphatic and vascular phenotypes observed.
Effects of biological modifiers on normal tissue tolerance (amelioration / exacerbation)
the treatment days, according to the RTOG/EORTC scoring system; confluent mucositis (grade 3) was stringently defined as any pseudomembranousulcerative lesion with a diameter> 1 cm. Endpoints of the analysis were incidence and time-to-onset of mucositis grade 3. Patients were categorized as active smokers, never-smokers or non-smokers for less or more than one year before the onset of radiotherapy. The mean age of the patients was 59 years (range 20-94); 22 % were female. Radiotherapy was administered in a conventional (n=202), hyperfractionated (n=22) or a combined conventionalhyperfractionated protocol (n=56). Of all patients, 101 (36 %) were active smokers, 49 (17 %) were never-smokers, 67 (24 %) non-smokers since more and 63 (23 %) for less than one year. Results: A total of 66 % of all patients developed confluent mucositis with a mean latent time of 24 days after onset of radiotherapy; both parameters were significantly dependent on the treatment protocol. Within the individual radiotherapy protocols, a univariate analysis of nicotine consumption - yes vs. no - did not yield a significant difference. Multivariate analysis (independent variables: smoking habit, age, gender, treatment protocol, chemotherapy), however, indicated a clear disadvantage of active smoking for both the incidence (61 % vs. 75 %, p=0.0329) and the latent time (25 ± 1 days vs. 23 ± 1 days, p=0.0347) of oral mucositis. The univariate comparison of active vs. never-/non-smokers > 1 Ydid not yield significant differences, while the multivariate analysis showed a trend for the incidence (65 % vs. 75 %, p=0.0899) and a significant difference (25 ± 1 days vs. 23 ± 1 days, p=0.0030) for the latent time. Conclusions: In summary, a significant impact of active smoking on the clinical manifestation of confluent oral mucositis can be demonstrated based on large patient numbers. However the effect is only minor and clinically negligible, particularly for the time-to-onset of the mucosal response with a difference of only 2 days. Hence, other parameters appear to dominate the inter-individual differences in the development of the radiation response of the oral mucosa. 37 poster PROTECTIVE ROLE OF CARNITINE AGAINST RADIATIONINDUCED KIDNEY DAMAGE IN INFANT RATS: SCINTIGRAPHIC AND HISTOPATHOLOGIC EVALUATION R. Cesar", G. Durmus Atturr'. F. Oz Puyan", M. Saynak", K. lbls", A. Ozen", G. Baylr-Anqin", F. ustun", B. Denizli 1 , S. Parlar", M. Caloqlu", V. Yurut-Caloglu 1 , M. C. Uzal", Z. Ko<;ak1 1 TRAKYA UNIVERSITY MEDICAL FACULTY, Radiation Oncology, Edirne, Turkey 2 TRAKYA UNIVERSITY MEDICAL FACULTY, Nuclear Medicine, Edirne, Turkey 3 TRAKYA UNIVERSITY MEDICAL FACULTY, Pathology, Edirne, Turkey 4 CANAKKALE UNIVERSITY FACULTY OF MEDICINE, Nuclear Medicine, Canakkale, Turkey
Purpose: The aim of this paper is to clarify, whether L-carnitine has a protective effect in prevention of radiation induced nefrotoxicity (RIN) during late phase following radiation therapy in an infant rat model. Materials: Thirty-one two-week-old male Wistar albino rats divided into four groups. Group 1 (n=10): Control, Group 2 (n=10): L-Carnitine alone, Group 3 (n=10): Irradiation alone (RT), Group 4 (n=10): L-Carnitine before irradiation (L-Carnitine + RT), injected with L-Carnitine (LC) (300 mg/kg) i.p., 30 minutes before the irradiation. The rats in the RT and L-Carnitine + RT groups were irradiated individually with a single dose of 8 Gy. 2,2,4 and 1 deaths were occurred in groups, respectively. Animals underwent both Tc99m DTPA (Diethylene triamine pentaacetic acid) dynamic renal imaging and Tc99m DMSA (Dimercaptosuccinic acid) static renal imaging at the end of three months follow-up period. Proximal tubular degeneration, tubular atrophy, interstitial fibrosis and glomerular degeneration were assessesed histopathologically. Results: The mean Tmax and T1/2 values in the RT group were 4.2 ± 0.8 and 14.5 ± 4.1, respectively. In the L-Carnitine + RT group, those values were 2.8 ± 0.4 and 12.8 ± 1.7 and significantly lower than those in the RT group (p=0.03, p=0.04). In L-Carnitine + RT group, the glomerular structures were well protected compared to RT group (0.78 ± 0.22 vs. 1.88 ± 0.58, p=0.04) (Table 1).
36 poster DOES SMOKING AFFECT ORAL MUCOSITIS DURING RADIOTHERAPY FOR HEAD-AND-NECK TUMOURS? E. Dorr 1 , W. Dorr 1 1 UNIVERSITY HOSPITAL DRESDEN, Department of Radiotherapy and Radiation Oncology, Dresden, Germany
Purpose: Oral mucositis is a severe, dose-limiting side-effect of radio(chemo)therapy of head-and-neck tumours. It is frequently postulated that smoking aggravates the mucosal radiation response. The present analysis was initiated to test this hypothesis. Materials: In the present analysis, 280 patients were included, who received a dose of at least 40 Gy in the oral cavity. Oral mucositis was scored daily at
R.....l ..f.:.wniline
COl'llroi
l ..C ",niline
RT
99PtTc--
IF''
4]~3
ll?~3
34:?
~~'3
DMSA
AFX
5:l.t2
52.t3
SSt?
65.t9
LTmax
1.5tQ5
2.';:'1.;).4
4."<.t0.S
l&Q4
99mTc:-
lT12
79t1.7
lfJ.4%l2
14~41
12.9%1.7
DTPA
RTmou
3.3tO.7
3.4r2.7
3.5ttl
3.3t:18
RTI2
Yl'3t1.6
9.6t1.5
12.4r3.2
12.7r4.2
LF": The tM tM41 fur">~M percentagt t~ f~t I
Conclusions: The use of radioprotective drug is more important for children where there is probability of long-term survival. L-Carnitine is a natural