| OBJECTIVEWith the progress of science and technology,nasopharyngeal carcino ma radiotherapy from traditional two-dimensional radiotherapy to intensitymodulated radiotherapy(IMRT),now many domestic large sample survey showed strong efficacy of adjustable radiotherapy in the treatment of naso pharyngeal carcinoma,5 year survival rate is more than 80%,5 year loca l control rate in 88% ~ 95%.The improvement of the treatment method significantly increased the survival time of patients with nasopharyngeal ca rcinoma,and the quality of life of patients became more and more concer ned.Modern oncology also reached a consensus: the quality of life better rate of treatment response in cancer patients and rehabilitation status than the survival rate,mortality,radiation damage will become one of the top ics to explore and study of nasopharyngeal carcinoma.Radiation therapy has toxic effects on tumor cells and normal tissue cells.Therefore,the normal tissues of the human body are bound to cause certain radiation reactions and damage while killing the tumor tissues.Because of the submandibular gland and the carotid artery during nasopharyngeal carcinoma radiotherapy often in the radiation field,the radiation injury risk.Xerostomia is one of the most common postoperative complications after radiotherapy.It is mainly caused by radiation damage of salivary glands after radiation.The submandibular gland is one of the major salivary glands of the human body,the resting salivary secretion accounted for total saliva secretion of 65%-70% in submandibular gland secretion of saliva is the main source of mucin,and mucin is the main substance of human subjective perception of dry mouth symptoms,so the radiation injury of submandibular gland is one of the factors of xerostomia after radiotherapy.The clinical thought radiation tolerance dose high large blood vessels,not easy to cause radiation damage,but now more and more research found that the function of patients with cerebral perfusion decreased1-2 years after radiotherapy,research shows that lead to injury of carotid artery after carotid artery stenosis and atherosclerosis is the main influencing factor.The carotid arteries supply the blood of the 2/3 before the cerebral hemisphere,and the radiation damage of the carotid artery can have a serious impact on the quality of life.The literature we found that the majority of patients with nasopharyngeal carcinoma after radiotherapy have risk of submandibular gland and carotid artery injury analysis,thus affecting the quality of life of patients after radiotherapy,after radiotherapy of patients with carotid artery of submandibular gland and radiation injury and follow-up phase shutdown is very valuable.The main purpose of this study is to understand the submandibular gland of patients with nasopharyngeal carcinoma after radiotherapy and carotid artery injury of the short term after radiotherapy;improve the clinical for the submandibular gland and carotid artery injury attention;determination method of submandibular gland and carotid artery injury diagnosis and follow-up,the main purpose of this study is the evaluation of two kinds of diagnostic value of ultrasound elastography acoustic palpation method quantification of VTQ and ultrasonic echo tracking Echo-tracking ET,to further improve the clinical radiotherapy plan.METHODThe study was approved by the ethics committee of the Affiliated Cancer Hospital of Guangxi Medical University(Guangxi Medical University Medical College)and registered by the international clinical trial center.The registration number is Chi CTR-OOC-16008853.This study is divided into four parts.The first part is the basic research of submandibular gland injury.We choose 30 New Zealand rabbits were used as the research object,randomly divided into control group,A group and B group,the control group was not given irradiation,A,B x two group were given 15 Gy and 30 Gy dose of irradiation,irradiation for cervical and abdominal X-ray irradiation,using 6MV X-ray source skin distance 100 cm.The prescription dose points located in the carotid artery,posterior cervical gland plane,abdominal irradiation with regional celiac artery plane,dose depth were 2.5-3cm and 4.5-5.5cm,3Gy/min.After irradiation,group B died of 4,and finally included in the study 26,of which 2 were in the control group,12 in the A and B groups.A,B the same time in two groups before irradiation and after irradiation of 1W,2W,4W,8W,12 W,16W 2were selected for body weight,saliva flow and determination of submandibular gland of VTQ ultrasound examination were sacrificed left submandibular gland tissue for pathological examination,the control group at the same time the weight and saliva flow VTQ ultrasound and submandibular gland.The second part is the basic research of the carotid artery injury,and the first part uses the same group of New Zealand white rabbits to group,illuminate and check the time point,which is the same as in the first part.Detection of carotid artery injury is mainly of A,B group of rabbit celiac artery ET examination,arterial serum vascular endothelin-1 and serum NO,the rabbits were sacrificed after the left carotid artery and celiac artery tissue for pathological examination.The above two parts of all data using IBM SPSS Statistics 22 software package for statistical analysis,the value of X±s representation.Related graphs and tables are made by Graph Pad Prism 6.Paired samples t test was used to compare the numerical changes of submandibular gland at different time after radiotherapy.P<0.05 has statistical significance.The third part is the clinical study of submandibular gland injury,we choose between July 2015 and Mar 2016 pathologically diagnosed as nasopharyngeal carcinoma and in Affiliated Tumor Hospital of Guangxi Medical University(Guangxi Medical University Medical College)in the Department of radiotherapy received full IMRT treatment and volunteered to join the study patients as the research object,the follow-up time of 6 months,61 patients completed the final were included in the study,male 44 cases,female 17 cases,age 44.475 ± 12.477 years old,the median age was 46 years.Bilateral submandibular glands were located in the clinical target area(CTV)in 61 patients,and unilateral in CTV in 33 cases,in 28 cases.The 122 submandibular glands were divided into two groups according to whether they were located in the clinical target.The submandibular gland tissue in A group CTV was 89,B group CTV,and the outer submandibular gland tissue 33.The patient underwent a radical IMRT,using the Varian Corporation(USA)6MV-X linear accelerator.The radiation dose was based on the specific amount of radiation taken into the patient.TPS system was used to analyze the radiation dose and DVH diagram of submandibular gland in the doctors’ workstation,and Dmax,Dmean,D50 and D30 were used for dosimetric analysis.The ultrasonic instrument uses TOSHIBA Aplio500 machine,high frequency probe,frequency is 4-9MHz,carries on the CDFI and the VTQ examination.After radiotherapy xerostomia,we refer to the European cancer patient life quality scale(EORTC QLQ-C30V3.0)related projects,using the improved 5 level evaluation criteria.Using IBM SPSS Statistics 22 software package for statistical analysis,the value of X±s representation.Comparison of the volume and SWV at different time and before radiotherapy was performed by paired sample t test.The independent t test was used to compare the results between the two groups.The two factor Logistic regression was used in the multiple factor analysis.P<0.05 has statisticalThe fourth part is the clinical study of carotid artery injury.The patients were the same as those in the third study,and we enrolled 10 healthy adults as controls.The irradiation group received radical IMRT,and at least one side of the carotid artery was located in the clinical target area(CTV).The irradiation group started to 2W,4W,6W,after the end of radiotherapy in March and June respectively by carotid ultrasound examination in the beginning to accept before radiotherapy and treatment,the control group only in irradiation group before and after treatment,after treatment in March June during the same period of 3times of ultrasound.One side of the carotid artery in the target area was examined by the radiation group,and the mean value of bilateral examination was taken in the target area,while the control group received the mean value of bilateral examination.The examination was performed with the Aloka all digital pure beam color Doppler ultrasound diagnostic system,Prosound alpha 6(Hitachi),electronic linear probe,and frequency 5-13.3MHz.They were divided into routine ultrasonography and ET examination.All data are analyzed by IBM SPSS Statistics 22 software package.the value of X±s representation.The paired sample t test was used between the results of different time periods and before radiotherapy,and the independent sample t test was used between the two groups,and P<0.05 was statistically significant.RESULTThe first part Experimental Study of submandibular gland injury in rabbits:1.Changes in body weight and saliva flow.The weight of the sham irradiation group increased continuously,the initial average weight was 2.45 kg,and the average weight of 3.42 kg was 16 weeks.There was no significant difference in weight change between the two groups of A and B.After 1 weeks,the saliva flow rate of A and B irradiation group was significantly lower than that of sham irradiation group,the difference between the two groups was statistically significant(P < 0.05).2.The change of SWV value.A group of submandibular gland SWV before radiotherapy was 1.81 + 0.29 m/s,after eighth weeks the SWV value began to increase to 2.11 ± 0.23 m/s,compared with before radiotherapy group difference was statistically significant(P < 0.05),second week SWV increased slowly,fourth weeks began to increase.The change of SWV value in B group was more obvious,compared with SWV before radiotherapy,the difference between first groups was statistically significant(P=0.015),and the SWV value increased slowly at second weeks.The difference between group A and group B was statistically significant at the beginning of the fourth week(P < 0.05).3.The morphological changes: after irradiation,HE staining showed that the rabbit submandibular gland acinar cells swelling,interstitial increased in A group at 2 week to acinar cells arranged disorderly,cell swelling,4 weeks earlier and the emergence of catheter dilatation,vacuolar degeneration,8 and 16 weeks of vacuolar degeneration.B group in 2 weeks after irradiation changed significantly compared with A group,there were serous cell edema,cell swelling,cytoplasm components increased,8 and 16 weeks of vacuolar degeneration and neutrophil infiltration than in the A group were more obvious at 12 weeks,karyopycnosis.The second part: the experimental results of rabbit carotid artery injury:1.Endothelin-1(ET-1)results: there was no significant difference between two groups of ET-1 before irradiation.After the experiment,from the beginning of the first week,B group compared with before irradiation,ET-1 increased significantly,there were significant differences(P<0.05);A group 2 weeks after irradiation,there was no statistical difference,fourth weeks began to have statistical difference(P<0.05).The difference between the two groups was statistically significant at the beginning of the first week(P<0.05).2.Serum nitric oxide(NO)test results: before the experiment,there was no significant difference between the two groups of NO.At the beginning of the first week after the experiment,the B group had statistical difference(P<0.05)compared with before irradiation().There was statistical difference between the A group and the pre irradiation group(P<0.05).Between groups,NO levels were statistically significant at first weeks(P<0.05).The biggest difference appeared on the second weekend.3.Echo tracking(ET)examination results: ET index changes: in group A,Ep,PWV-beta and beta irradiation in second weeks after the start of increased compared with before irradiation,the difference was statistically significant(P<0.05),the peak appeared in the 12 week,second weeks before the change is not obvious.In group B,Ep,beta and PWV-were also increased at the beginning of the second week after irradiation,compared with the basal state before irradiation.The difference was statistically significant(P<0.01),and the peak values appeared on the 12 weekend.Between the two groups,the value of Ep,beta and PWV-beta increased at the end of the second week,and the change of B in the A group was statistically significant(P<0.05).At 16 weeks,the Ep,beta,B and PWV-of the two groups decreased compared with the 12 week,but there was no statistical difference in the PWV-and P>0.05 levels in the A group,but the difference was not statistically significant(P >0.05).The AC of the two groups at the beginning of the 4 weekend was significantly lower than the basal state(P<0.05),the lowest value group A appeared in the twelfth week,and the B group appeared in eighth weeks.The difference of AI was not statistically significant.4.Carotid artery and celiac artery morphology results: under the light microscope(left)of carotid artery and celiac artery intimal smooth,visible monolayer endothelial cells,internal elastic membrane integrity,uniform thickness,neat,no lipid deposition.First weeks after irradiation,group A arterial intima arranged in neat,internal elastic membrane integrity,no lipid deposition,B group abdominal artery intima visible local micro uplift;second week A group did not change significantly in B group,carotid artery and celiac artery inner cortical cells arranged in disorder;fourth weeks in the A group of celiac artery showed a small foam cell carotid artery,and celiac artery were mild thickening,B group changed significantly compared with A group,especially the celiac artery thickening.The eighth week A,B two groups of carotid artery and celiac artery intimal thickening appeared in B group,carotid artery and celiac artery were intimal lipid deposition;12 weeks in the B group of celiac artery foam cells increased significantly,at the end of the 16 B 1 cases of celiac artery plaque.The intima thickness of arteries measured by micrometer method showed that the intima of A and B in two groups increased at fourth weeks,and peaked at 12 weeks.The trend test showed that Ep,beta and PWV-beta three indexes had a good correlation with intimal thickness(P<0.05),and there was a linear correlation between the increase of EQ,B and PWV-B with the increase of intima thickness.The third part: the clinical trial result of submaxillary gland injury:1.The volume change of submandibular gland: the volume of submandibular gland decreases during radiotherapy.In group A,the volume of the 89 submandibular gland tissues was 7.863-10.682cm3(mean 9.485cm3),and the volume of the 33 submandibular gland tissues in group B before radiotherapy was 8.473-10.057cm3(mean 9.327cm3).In group A,after radiotherapy,the average reduction was 36.89% in June and 14.61% in the B group,compared with before radiotherapy.The volume of A group began to shrink after radiotherapy,and the difference was statistically significant compared with that before radiotherapy(P < 0.05).At fourth weeks,the frequency of volume reduction was significantly decreased,and the volume change was the most significant at sixth weeks,compared with the second week.Group B volume is also reduced,second weeks with the original volume had no significant difference(P=0.080),data and radiotherapy fourth weeks before the difference was statistically significant(P=0.034),and sixth weeks after radiotherapy,6months after the end of group B compared with group A,volume reduced obviously,the difference was statistically significant(P < 0.05).The volume of B group decreased for second weeks and fourth weeks,and the volume change was most remarkable at sixth weeks2.Ultrasound examination results: A group of 89 submandibular glands before radiotherapy SWV = 1.68 ± 0.21 m/s,after second weeks the SWV value began to increase for 1.81 ± 0.30 m/s,the difference was statistically significant(P <0.05),fourth week SWV value increased slowly and the difference reaches the maximum value sixth weeks after radiotherapy.March,June is still a state of increased.B group second weeks before radiotherapy and SWV value had no significant difference(P=0.088),the fourth week was statistically significant(P=0.006),and sixth weeks after radiotherapy,6 months after the end of group B compared with group A,the SWV value was not obviously increased,the difference was statistically significant(P < 0.05).The B group decreased at 6months after the end of radiotherapy,compared with 3 months after the end.For6 weeks,the best threshold was shear wave velocity =2.37m/s,sensitivity was96.80%,specificity was 86.41%,and the area under curve was 0.924,(P=0.001).For 30 weeks,the best threshold was shear wave velocity =2.52m/s,sensitivity was 100%,specificity was 97.10%,and the area under curve was 0.965,(P=0.000).3.Change of submandibular gland during radiotherapy,61 patients with submandibular glands of Dmax was 70.08 ± 4.08 Gy Gy,Dmean ± 3.66 Gy 30%58.24 Gy,the volume dose of 57.13 Gy ± 2.96 Gy,50% volume dose of 52.87Gy± 2.18 Gy,30% volume dose of 57.13 Gy ± 2.96 Gy,50% volume irradiated the dose of 52.87 Gy ± 2.18 Gy.In the course of radiotherapy,the submandibular gland volume began to shrink after exposure to radiation.The tendency to shrink from the beginning of second weeks slowed down,and after fourth weeks Dmean reached 35.02 Gy,the trend of narrowing began to increase significantly.SWV is worth changing trends,similar in volume,slow increase relative to the first 4 weeks,and rapid increase in SWV after fourth week dose over 35.02.4.Xerostomia after radiotherapy: bilateral submandibular glands were located in the target area in 28 cases.The incidence of xerostomia at the end of radiotherapy was 78.57%,and 3 and 6 months after radiotherapy were 82.14%.Located in the target area of unilateral submandibular gland in 33 cases,the incidence of radiotherapy and after radiotherapy xerostomia were bilateral were located in the target area with a low incidence of xerostomia in the highest point at the end of radiotherapy,radiotherapy(42.42%)after the end of March decreased,after the end of radiotherapy in June the incidence rate dropped to30.30%.In the 61 groups of patients,the parotid gland underwent the necessary protective measures.Both sides of the submandibular gland were located in the target area,28 patients and the unilateral submandibular gland were located in the target area,and there was no statistically significant difference in parotid Dmean between the 33 patients.After radiotherapy,the incidence of xerostomia after radiotherapy in June was analyzed.The submandibular glands Dmean,Dmax,D30 and D50 were included in the multiple factor multiple regression analysis.Dmean and D50 were significant(P=0.000,P=0.002).Dmean and D50 respectively on submandibular gland ROC curve to predict after radiotherapy xerostomia,obtained from ROC curves,the area under the D50 ROC curve of submandibular gland of Dmean were 0.882,0.821,95% confidence interval respectively,0.797-0.967,0.711-0.931.Dmean and D50 have a moderate accuracy in the diagnosis of xerostomia after radiation therapy.We determined the submandibular gland Dmean and D50 for the diagnosis of xerostomia after radiotherapy and the best critical points were: 40.16 Gy,36.38 Gy.The fourth part: clinical results of carotid artery injury:1.The conventional CDFI parameters showed that IMT at the end of radiotherapy and radiotherapy had no significant difference,after radiotherapy,three months and six months before and after radiotherapy was statistically significant(18 weeks after the start of radiotherapy and radiotherapy compared to t=3.532,P=0.01;30 weeks after the start of radiotherapy and radiotherapy compared to t=6.548,P=0.00).The difference of RI between the six months before radiotherapy and before radiotherapy was statistically significant(t=2.548,P=0.01).The other measurements were not statistically significant compared with those before radiotherapy.Compared with the control group at three months and six months after radiotherapy,the irradiation group and the control group increased significantly in the IMT irradiation group compared with the control group for 30 weeks after radiotherapy,with statistical difference(P < 0.05).2.ET detection of Ep(kPa)and beta at the end of radiotherapy,or before radiotherapy,the results were statistically significant.AC(mm2/k Pa)and PWVbeta(m/s)were not statistically different at the end of radiotherapy and before radiotherapy.There were significant differences between three months and six months after radiotherapy.The AI measurements were not statistically significant compared with those before radiotherapy.The difference of Ep(k Pa),beta,AC(mm2/k Pa)and PWV-beta(m/s)between the irradiation group and the control group at the end of three months and six months after radiotherapy was statistically significant(P < 0.05).3.Dosimetric analysis results: selection of carotid artery bifurcation on 1cm,2cm as the research object,in the process of radiotherapy,61 cases of carotid artery in patients with the maximum dose irradiation of 71.08 ± 4.25 Gy,the average dose was 66.38 ± 4.16 Gy,50% volume dose of 57.81 ± 5.88 Gy.In the course of radiotherapy,the carotid arteries were slightly increased after exposure to Ep(k Pa)and beta,and the change was not obvious in the 4 weeks after treatment.The trend began to increase obviously after fourth weeks Dmean reaching45.02 Gy.At the end of the irradiation,Ep(k Pa)and beta were statistically different compared with those before treatment.CONCLUSION:Animal experiments showed that the rabbit submandibular gland secretion of submandibular gland will be seriously damaged in the radiation dose received30 Gy,15Gy doses will be preferred imaging technology on the secretion of submandibular gland function has certain effect when the technology of ultrasound elastography can be used as VTQ for treatment of injury of submandibular gland.After exposure to radiation,the rabbit’s large artery would suffer radiation damage in a relatively short time,and the decrease of vascular elasticity is the earliest damage change.ET technology,especially Ep,β and PWV-β,are indexs to evaluate the early arterial injury,which has a good correlation with pathological findings.In the clinical study,we suggest that the unilateral or bilateral submandibular gland should be shifted to the target area without affecting the therapeutic effect to preserve the salivary secretion function of the submandibular gland.The average dose of the submandibular gland to receive radiation is of significant significance in protecting the function of the submandibular gland.We suggest that the submandibular gland protects the average dose threshold Dmean at 35-40 Gy.The carotid artery in the radiation exposure of more than 45 Gy,self repair function began to be significantly affected in morphological changes before the advent of elasticity has begun to decline,we give the corresponding suggestions for clinical follow-up,give corresponding treatment measures when necessary to prevent premature atherosclerosis.In addition,ET technique can detect the change of carotid elastic function in the early stage of radiotherapy.It is a good assistant examination technique for early diagnosis and follow-up of carotid artery radiation injury. |
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