The Exploration Of MR DWI Combined With Biomarkers To Predict The Efficacy And Toxicity Of Concurrent Chemoradiotherapy In Locally Advanced Non-small Cell Lung Cancer

In China,the incidence and mortality of lung cancer ranks first among malignant tumors.Non-small cell lung cancer(NSCLC)is the most common type of lung cancer.and concurrent chemoradiotherapy(CCRT)is the standard treatment for unresectable locally advanced non-small cell lung cancer.At present.the main method for evaluating the efficacy of radiotherapy and chemotherapy for lung cancer is still CT and other conventional anatomical imaging examinations,which have limitations,and functional imaging examinations are increasingly used in clinics.such as functional magnetic resonance and PET-CT.Diffusion weighted imaging(DWI)is a kind of magnetic resonance functional imaging.The imaging principle is Brownian motion of water molecules,which can reflect the cell density of the tissue,the integrity of the cell membrane and vascular permeability.Observe the changes of tumor tissue early The apparent diffusion coefficient(ADC value)is used to realize the quantitative analysis of DW1.The changes in tumor cell density.cell membrane integrity and vascular permeability during treatment can lead to changes in DWI signaling and ADC values.so that changes in ADC values can be used to predict and evaluate the efficacy and prognosis of concurrent chemoradiotherapyThe response of patients with lung cancer to radiotherapy and chemotherapy varies among individuals,which may be related to some molecular biological characteristics of the body.In the NSCLC study,there have been many studies exploring biomarkers to predict and evaluate prognosis,tumor response to treatment,and toxic reactions.These biomarkers mainly include immune cells,cytokines,genomics,tumor metabolites,proteomics and microRNA.Survivin is a new member of the inhibitor of apoptosis protein(IAP)family.It is highly expressed in tumor tissues,has the function of preventing apoptosis and regulating the cell cycle,and is closely related to tumor cell proliferation and metastasis.Survivin has been identified as an independent predictor of prognosis in patients with cancer.Radiation pneumonitis is a common complication of radiotherapy for lung cancer,especially in patients with concurrent chemoradiotherapy.If radiation pneumonitis occurs during treatment,it may affect the smooth progress of treatment.Based on the above research background,in this study,We will use the ADC value of magnetic resonance DWI to predict the efficacy of concurrent chemoradiotherapy for locally advanced non-small cell lung cancer,and combine it with Survivin to predict the efficacy in order to find the best combined prediction model.If the occurrence of radiation pneumonitis can be predicted and avoided in radiotherapy,it will provide safety guarantee for the smooth progress of concurrent radiotherapy and chemotherapy.Part I The exploration of MR DWI in predicting the efficacy of concurrent chemoradiotherapy in locally advanced NSCLCObjectiveTo explore the value of MR DWI in predicting the efficacy of concurrent chemoradiotherapy in locally advanced non-small cell lung cancer.MethodsIn this study,81 patients with locally advanced NSCLC were treated with concurrent chemoradiotherapy based on the inclusion and exclusion criteria.All patients received MRI examinations,conventional MRI and DWI sequence scans before treatment and the middle of concurrent chemoradiotherapy(radiotherapy dose 40Gy).Combined with the conventional MRI sequence,the lesion location is clarified in the DWI image,and then the ADC value is measured on the corresponding ADC map.According to the evaluation of the efficacy of CT at the end of radiotherapy,ADC values were analyzed to predict the short-term efficacy of locally advanced NSCLC patients.The patients were followed up after treatment,and the effect of ADC value on the survival was further analyzed.Note:ADCpre is the average ADC value before treatment,ADCmid is the average ADC value in the middle of radiotherapy,and ?ADC is the rate of change in ADC value before and after treatment.?ADC=(ADCmid-ADCpre)/ADCprex100%.Results1.A total of 81 patients with non-small cell lung cancer were enrolled.The data of 72 patients can be used for analysis.Based on the evaluation of CT,50 patients in the sensitive group(CR+PR)and 22 patients in the non-sensitive group(SD+PD)The tumor regression rate in the sensitive group was(54.31±21.56)%,and the tumor regression rate in the non-sensitive group was(23.11±12.66)%.The difference between the two groups was statistically significant(P<0.05).2.The ADCpre,ADCmid and AADC of the sensitive group were(1.33±0.22)x 10-3mm2/s,(1.85±0.39)×10-3mm2/s,(40.01±32.33)%,and the ADCpre,ADCmid and AADC of the non-sensitive group were(1.52±0.26)×10-3mm2/s,(1.64±0.25)×10-3mm2/s,and(9.63±16.86)%,the differences were statistically significant(P<0.05).After the concurrent chemoradiotherapy,the tumor regression rate was negatively correlated with ADCpre,positively correlated with AADC.ROC curve analysis showed that ADCpre,ADCmid,and AADC were significant in predicting the curative effect of CCRT,and the areas under the curve were 0.7532,0.6655 and 0.7991 respectively3.According to CT efficacy evaluation(RECIST standard),the average progression-free survival time of the radiochemotherapy-sensitive group was(18.3±11.8)months,which was higher than that of the insensitive group(6.8±4.9)months;22.5±12.6)months,which was higher than that of the insensitive group(9.1±1.3)months,and the differences were statistically significant(P<0.05).4.According to the ROC curve,the critical value of the ADC value is the best in predicting efficiency.Using ADC threshold,divide ADCpre.ADCmid and AADC values into two groups,divide ADCpre into ADCpre?1.41×10-3mm2/s group and ADCpre<1.41×10-3mm2/s group,the average progression-free survival time of the two groups was(10.49±6.20)vs(18.35±10.71)months,and the average total survival time was(13.62±7.57)vs(22.56±11.54)months.Divided ADCmid into ADCmid?1.66×10-3mm2/s group and ADCmid<1.66×10-3mm2/s group,the average progression-free survival time of the two groups was(1 8.75±10.90)vs(9.14±4.73)months,and the average total survival time was(22.66±12.10)vs.(12.59±4.96)months.Divided ?ADC into ?ADC>18.18%group and ?ADC<18.18%group,the average progression-free survival time of the two groups was(19.60±9.65)vs(6.65±4.79)months,and the average total survival time was(23.91±10.48)vs(9.37±5.96)Months.There was a statistical difference in each of the above comparisons(P<0.05).ConclusionADC value can predict the effect of concurrent chemoradiotherapy for locally advanced non-small cell lung cancer at an early stage.Survival analysis results obtained by ADC threshold grouping are consistent with RECIST standard grouping.Therefore,MR DWI can predict the efficacy and survival of locally advanced non-small cell lung cancer with concurrent chemoradiotherapy.Part II The exploration of MR DWI combined with Survivin in predicting the efficacy of concurrent chemoradiotherapy in locally advanced NSCLCObjectiveTo explore the value of MR DWI combined with Survivin in predicting the efficacy of concurrent chemoradiotherapy for locally advanced non-small cell lung cancer.MethodsTissue samples(obtained by percutaneous lung puncture or bronchoscopy biopsy)were taken from 72 patients who could be analyzed before treatment.2ml of peripheral venous blood was collected 1 week before treatment and at the middle stage of radiotherapy(40Gy).The expression of Survivin in tissues was detected by immunohistochemical S-P method,and the expression of Survivin in peripheral blood was detected by RT-PCR method.According to the evaluation of the efficacy of CT at the end of radiotherapy,the predictive value of Survivin expression in tissues and peripheral blood on the short-term effect of locally advanced NSCLC patients was analyzed,and then the ADC value was combined to further analyze the predictive value of combined factors on the short-term effect of patients.The patients were followed up after treatment,and the ADC value and Survivin multiple factors were used to evaluate the prognosis.Note:SurvivinP,e is the average Survivin level before peripheral blood treatment,Survivinmid is the average Survivin level during peripheral blood treatment,and ?Survivin is the change rate of Survivin before and after treatment.?Survivin=(Survivinpre-Survivinmid)/Survivinprex100%.Results1.For the 72 patients enrolled,the Survivin expression in the tissues was determined by semi-quantitative results.There were 31 patients with positive Survivin expression,with a positive expression rate of 43%.Survivin positive expression rate in the sensitive group was 34%;The positive expression ratein the non-sensitive group was 63.6%,and the difference between the two groups was statistically significant(P<0.05).2.There was no statistically significant difference in Survivinpre expression level between peripheral blood in sensitive group and insensitive group before and after treatment(P>0.05).Survivinmid in the sensitive group was(2.86±1.29)lower than that in the insensitive group(4.41±1.78),and the differences were statistically significant(P<0.05).The change rate of Survivin before and after treatment in the sensitive group was(39.51±26.66)higher than that in the insensitive group(19.72±22.32),the difference was statistically significant(P<0.05).Tumor regression rate was negatively correlated with Survivinmid.ROC curve analysis showed that Survivinmid and ?Survivin were meaningful in predicting the efficacy of CCRT.The areas under the curve were 0.7514 and 0.6900 respectively.3.Compare the correlation between tissue and peripheral blood Survivin expression.It was found that the level of Survivinpre in peripheral blood was higher in the tissue Survivin positive expression group,but it was relatively meaningless(P>0.05).Survivinmid in peripheral blood decreased and ?Survivin changed significantly in tissue Survivin negative expression group,which was statistically significant compared with Survivin positive expression group(P<0.05).4.Comparing the ADCpre,ADCmid and ?ADC of Survivin positive expression group and Survivin negative expression group in the tissues,the differences were statistically significant(P<0.05).5.The best specificity,sensitivity and accuracy of predicting the efficacy of CCRT using ADCpre,AADC,and peripheral blood Survivinmid factors were 76.00%,77.27%and 76.39%,and the area under the curve was 0.8727.6.The mean survival-free survival time and mean overall survival time of Survivin positive expression group in tissues were lower than Survivin negative expression group,the difference was statistically significant(P<0.05).The peripheral blood Survivinmid and ?Survivin thresholds were grouped,and the average progression-free survival time and the average total survival time were compared,and the difference was statistically significant(P<0.05).7.We performed a Cox proportional hazard regression analysis on clinical features,including gender,age,stage,and ADCpre,ADCmid,AADC,Survivinmid,ASurvivin,and Survivin in the tissue.Multi-factor prognostic analysis showed that clinical stage,AADC,and Survivin expression in the tissues are the main factor affecting prognosis.ConclusionSurvivin is highly expressed in locally advanced NSCLC tissues.Survivin can predict the effect of concurrent chemoradiotherapy.ADC value combined with Survivin can better predict the effect of concurrent chemoradiotherapy than alone.Cox regression was used to analyze the prognosis of multiple factors,suggesting that the patient's prognosis is related to the clinical stage of the tumor,the rate of change in ADC value before and after treatment,and the expression of Survivin in the tissue.Part ? The predictive value of MR DWI and biomarkers for radiation pneumonia ObjectiveTo investigate the predictive value of DWI combined with biomarkers for radiation pneumonitis and to evaluate the safety of patients undergoing concurrent chemoradiotherapy.MethodsA total of 72 patients who could be analyzed were collected 2ml of peripheral venous blood 1 week before treatment and at the middle stage of radiotherapy(40Gy).The levels of cytokines were detected by ELISA.Acute radiation pneumonia was classified according to the classification criteria for radiation pneumonia.Explore the predictive value of ADC value,Survivin and cytokines for radiation pneumonia.ATGF-?1=(TGF-?1,d-TGF-?1pre)/TGF-?1Prex100%,AIL-6=(IL-6mid-IL-6pre)/IL-6prex100%.Results1.Follow-up of 72 patients to 6-8 weeks after the end of radiotherapy,a total of 30 patients(41.6%)developed radiation pneumonitis,including 22 patients with grade 1 reaction(30.5%),5 patients with grade 2 reaction(6.9%),Grade 3 reactions(2.7%),and no patients had grade 4 reactions.2.Comparing the ADCpre,ADCmid and AADC values of patients with radiation pneumonitis and non-radiation pneumonia,there was no statistical difference(P>0.05).According to the incidence of radiation pneumonia,it was divided into a mild group of radiation pneumonia(1 point)and a severe group of radiation pneumonia(2 points and above).There was no difference in ADCpre value between the two groups(P>0.05).The ADCmid(1.67±0.35)×10-3mm2/s in the light radiation pneumonitis group was lower than the heavy group(1.95±0.30)×10-3mm2/s,and the ?ADC(21.70±29.58)%in the light group was lower than the heavy group(51.61±20.79)%,The comparisons are statistically different(P<0.05).3.Comparing the Survivin levels between the radiation pneumonitis group and the non-radiation pneumonia group,and between the radiation pneumonitis light group and the radiation pneumonitis severe group,no Survivin expression was found to have predictive significance for radiation pneumonia(P>0.05).4.The levels of serum TGF-?1pre and IL-6pre before radiotherapy in the radiation pneumonitis group and the non-radiation pneumonia group were not statistically different(P>0.05).The TGF-?1 mid and IL-6mid in the radiation pneumonitis group were(53.72±14.32)pg/ml and(26.2±5.16).pg/ml respectively,and the non-radiation pneumonia group were(47.93±12.38)pg/ml and(20.77±7.04)pg/ml respectively,the level of radiation pneumonitis group was high,and the difference was statistically significant(P<0.05).ATGF-?1 and AIL-6 in the radiation pneumonitis group were(52.59±17.14)%and(54.49±16.48)%respectively,and in the non-radiation pneumonitis group were(27.34±9.68)%and(42.62±26.55)%respectively,the level of radiation pneumonitis group was high,the difference is statistically significant(P<0.05).Comparing the levels of cytokines between the mild group of radiation pneumonitis and the severe group of radiation pneumonia,there was no statistically significant difference in the levels of TGF-?1pre,IL-6pre and AIL-6 between the two groups(P>0.05).The TGF-?1mid,IL-6mid and ATGF-?1 of the radiation pneumonitis light group were(47.31±15.39)pg/ml,(21.29±7.61)pg/ml,(33.41±27.28)%,and the heavy group were(64.17±11.84)pg/ml,(27.55±6.67)pg/ml,(63.94±18.18%,the differences were statistically significant(P<0.05).5.The ROC curve before the classification of radiation pneumonitis showed that the combination of TGF-?1mid,ATGF-?,IL-6 mid and AIL-6 factors had the best predictive efficacy,and the area under the curve could reach 0.8167.The ROC curve after the classification of radiation pneumonitis showed that combining ADCmid,AADC,TGF-?1mid,ATGF-?1,and IL-6 mid factors,the prediction efficiency is the best,and the area under the curve can reach 0.9091.6.Group the critical value of TGF-?1 and IL-6 to predict radiation pneumonitis,analyze the relationship between ADC value and cytokine,and find that ADC value has no correlation-with cytokine level(P>0.05).ConclusionWe found that DWI predicts that radiation pneumonitis is meaningful in subgroup analysis and comparison.Due to the small number of cases enrolled,the results are uncertain and need to be confirmed by expanding the number of cases.Our research shows that the increase of TGF-?1 and IL-6 levels in the middle of radiotherapy is related to the occurrence of radiation pneumonitis.TGF-?1,IL-6 and the rate of change before and after treatment can be used as indicators to predict radiation pneumonia,and the combined prediction is the best.