Study On The Value Of Serum Thymidine Kinase 1 On Diagnosis And Efficacy Evaluation In Primary Nasopharyngeal Carcinoma Based On Magnetic Resonance Imaging

Background and ObjectiveThe most ideal tumor markers are expected to have high sensitivity and specificity,and can be used as a useful tool in the diagnosis,monitoring and prognosis of tumor.At present,there were lots of studies on EB virus Capsid Antigen Immunoglobulin A Antibody?EBV-VCA-IgA antibody?and EB Virus DNA?EBV-DNA??Epstein-Barr Virus Early Antigen Immunoglobulin A Antibody?EBV-EA-IgA Antibody?and Epstein-Barr Virus Early Antigen Immunoglobulin G Antibody?EBV-EA-IgG antibody?within the serological markers used for diagnosis,therapeutic ecaluation and prognosis prediction innasopharyngeal carcinoma.There were differences of sensitivities and specificities among them when detected them singly and jointly.There is no stipulation refer to which one or which joints are more useful.In our hospital,we always detect the first two indicators above.EBV-VCA-IgA antibody and EBV-DNA are considered to be the most sensitive markers in human blood and normally used for diagnosis and evaluating the curative effect and the dynamic changes of nasopharyngeal carcinoma.But they cannot reflect the real-time changes for some objective factors.Thymidine kinase 1?TK1?is the key kinase in S phase of cell cycle.It is the only cell cycle markerwho provide messages about cell proliferation can be detected in serum.There are more and more studies about the use of it in the clinic application of malignant tumor.As a marker for cell proliferation,serum thymidine kinase 1?STK1?has been proved to be useful in the auxiliary diagnosis and monitoring prognosis.But there were only a few studies on if it could be predict the sensitivity of therapies.Apparent diffusion coefficient?ADC?has been proved to be useful in predicting the chemoradiotherapy sensitivity of the nasopharyngeal carcinoma.At present,there was no systematic study on STK1 in nasopharyngeal carcinoma,and there was no reports about the value of the combined application of STK1 and other serological markers or imaging technology.According the current situations at home and abroad and in our hospital,we did research from three parts:Part 1:Part 1:To evaluate the diagnostic efficacy of STK1 separately and jointly detected with EBV-VCA-IgA antibody and EBV-DNA.Part 2:To investigate the relationship between STK1and clinical key indicators?T stage,N stage,ect?and the role STK1 playing in the short-term response prediction and risk of recurrence and metastasis evaluation.Part 3:To investigate the potential value of STK1 and ADC value of primary nasopharyngeal tumor in radiotherapy and chemotherapy sensitivity prediction of nasopharyngeal carcinoma.MethodsPart 1:A total of 82 patients with newly diagnosed nasopharyngeal carcinoma from July 2014 to March 2015 were enrolled in this study.84 healthy subjects were collected and 40 patients with pharynx and paranasal sinuses non-cancerous lesions were selected as controls.?1?To compare the differences of STK1 concentration among the three groups.?2?To compare the sensitivity,specificity,positive predictive value,negative predictive value and accuracy of the detection of STK1,EBV-VCA-IgA antibody and EBV-DNA separately and jointly.Part 2:We collected 237 cases of newly diagnosed nasopharyngeal carcinoma from July 2014 to September 2016,All patients were received examination such as nasopharyngoscope,magnetic resonance imaging?MRI?scan of the head and neck region,and whole body bone scanning.219 patients received chest/abdominal computed tomography?CT?examination and 18 patients received chest radiography and abdominal ultrasound examination.Patients were staged according to 7^thh edition American Joint Committee on Cancer/Union for International Cancer Control?AJCC/UICC?staging system.?1?To investigate the relationship between concentration of STK1 and the clinical characteristics of nasopharyngeal carcinoma?sex,age,T stage,N stage,clinic stage,EBV-VCA-IgA antibody,EBV-DNA,pre-treatment hemoglobin content,CD3+,CD3-CD16+CD56+,CD3+CD8+,CD3+CD4+/CD3+CD8+,CD3+CD4+and pathologic types?.?2?188 patients came back 3 months after the treatment and received nasopharyngeal and cervical MRI and other imaging examinations.We evaluated the short-term response refering to the RECIST?Response Evaluation Criteria In Solid Tumours??version 1.1?.Patients were divided into 2 groups:remission group?CR+PR?and non-remission group?SD+PD?.Concentrations of STK1 before and after treatment were compared between and in the two groups.Conditional Logistic regression model was used for univaritate and multivariate analysis.?3?235 patients with nasopharyngeal carcinoma were followed-up after treatment,and were divided into two groups:with and without recurrence and metastasis.We compared the concentrations of STK1 between thetwogroups,andusedconditionalLogistic regression model for univariate and multivariate analysis.Part 3:A total of 30 patients diagnosed as primary nasopharyngeal carcinoma?NPC?without metastasis from May 2016 to September 2016 were enrolled in this study.All patients were received examination such as nasopharyngoscope,magnetic resonance imaging?MRI?scan of the head and neck region,chest radiography/computed tomography?CT?,abdominal ultrasound/CT,and whole body bone scanning.Patients were staged according to 7^thh edition American Joint Committee on Cancer/Union for International Cancer Control?AJCC/UICC?staging system.Among them,6 patients took intensity-modulated radiotherapy,and 24 patients had concurrent chemoradiotherapy.All patients were detected STK1 and underwent nasopharyngeal MRI and DWI before and during treatment?receiving radiotherapy of 10 times?.3 months after treatment,everyone received nasopharyngeal and cervical MRI.We evaluated the local short-term response refering to the RECIST?Response Evaluation Criteria In Solid Tumours??version 1.1?.Patients were divided into 2 groups:sensitivity group?CR+PR?and insensitivity group?SD+PD?.To study the relationship between the expression of STK1 and the ADC value of primary tumor before and during treatment,and compare the differences of STK1 and ADC between the two groups.ResultsPart 1:There were differences of the concentration of STK1between the nasopharyngeal carcinoma group?2.75±2.01 pmol/L?and the healthy control group?0.56 pmol/L?and the non-cancerous control group?0.96±0.43 pmol/L??P<0.001?.The concentration of STK1 in healthy control group was slightly lower than that in non-cancer control group?P=0.001?.The STK1 concentration in nasopharyngeal carcinoma group was higher than that in healthy control group and non-cancerous control group?P<0.001,P<0.001?.The AUC was 0.870,P<0.001,the 95%confidence interval was?0.813,0.927?and the STK1 threshold was 1.24pmol/L.The diagnostic value of STK1?sensitivity0.77,specificity 0.85,positive predictive value 0.77,negative predictive value0.85,accuracy 0.82?was somewhere between EBV-VCA-IgA antibody?sensitivity0.87,specificity 0.95,positive predictive value 0.92,negative predictive value 0.91,accuracy 0.92?and EBV-DNA?sensitivity 0.50,specificity0.97,positive predictive value 0.91,negative predictive value 0.75,accuracy0.78?when they were detected separately.The value of combined detection of STK1and EBV-VCA-IgA are the same as that of STK1,EBV-VCA-IgA and EBV-DNA?sensitivity 0.96,specificity 0.90,positive predictive value 0.86,negative predictive value 0.97,accuracy 0.92?,and the sensitivity and negative predictive value were higher than those of EBV-VCA-IgA and EBV-DNA?sensitivity 0.88,specificity 0.92,positive predictive value 0.88,negative predictive value 0.92,accuracy 0.90?combined detection.Part 2:The STK1 concentration in 237 patients with nasopharyngeal carcinoma were different in different T stage,N stage,clinical stage,EBV-DNA levels?P<0.05?,and had no differences in different genders,ages,pathological types,EBV-VCA-IgA antibodies.There were significant differences on post hoc multiple comparisons of T stage?T3:4.00±2.10pmol/L,T4:5.06±2.41pmol/L?except for T2?1.79±1.05pmol/L?and T1?1.86±1.30pmol/L?.The concentration of STK1 in N0?1.92±1.11 pmol/L?was lower than that of N1?3.31±2.16pmol/L?,N2?3.78±2.47pmol/L?and N3?4.01±3.21pmol/L??all P<0.05?.There were no differences on post hoc multiplecomparisons of N1,N2and N3.The STK1 concentration increased with the progression of the clinical stages??+?:1.77±1.06 pmol/L?,??3.14±2.03 pmol/L?,?a+?b?4.69±2.49pmol/L?.The STK1 concentrations in high expression of EBV-DNA group(?5×10³?Median=2.56pmol/L??P=0.002?was higher than that of the low expression group?<5×10³ copies/mL?.The results of bivariate correlation analysis showed that STK1 concentration was positively correlated with T stage,N stage,clinical stage and EBV-DNA expression level?P<0.05?.?2?There were19 patients with complete remission?CR?,155 patients with partial remission?PR?,14 patients without remission?SD:12 cases,PD:2 cases?.And the patients were divided into two groups:remission group and non-remission group.The STK1 concentrations in the remission group and the non-remission group were significantly lower than those in the untreated group?P<0.05?.The STK1concentration in the remission group was higher than that in the non-remission group before treatment,andwas lower than that in the non-remission group after treatment,but there was no significant differences between the two groups.Ages in the remission group was younger than that in the non-remission group.In addition,there are differences in N stage,clinic stage,treatment prescription between the two groups.The results of multivariate Logistic regression equation showed that N stage,clinic stage,treatment prescription were not independent prognostic factors of nasopharyngeal carcinoma?P>0.05?.?3?The risk factors of recurrent and metastatic nasopharyngeal carcinoma in 235 patients was analyzed.The results showed that there were significant differences in STK1concentration,N staging and clinical stage before treatment between recurrence and metastasis group and no recurrence and metastasis group?P<0.05?.The results of multivariate Logistic regression equation showed that the STK1concentration and N staging were the independent prognostic factors of recurrent metastases of nasopharyngeal carcinoma?P<0.05?.The higher the STK1 concentration before treatment,and the later the N staging,the higher the risk of the recurrence and metastasis.Part 3:?1?Compared with STK1?2pmol/L,the overall ADC value before the treatment is slightly higher when STK1?2pmol/L,but the difference was not statistically significant?P=0.261?.Both STK1?2pmol/L and STK1?2pmol/L the ADC value before treatment?ADC₀?had no significant difference between the sensitivity group and non-sensitivity group?P=0.329,P=0.780?.There was no significant difference in the overall ADC value during treatment?ADC₁?with different levels of STK1?P=0.804?.when STK1?2pmol/L,It's hard to take comparison for there is only one patient in insensitivity group.When STK1>2pmol/L,ADC₁ values had no significant difference?P=0.073?between the sensitivity group and insensitivity group.Bivariate correlation analysis showed that the STK1 levels before and during treatment were not significantly correlated with the ADC values of the primary nasopharyngeal tumour?P=0.293,P=0.7?.?2?There was no significant difference in the concentration of STK1before treatment?2.51±1.85 pmol/L?and during treatment?2.51±1.93 pmol/L?in Sensitivity group?P=0.984?.In insensitivity group,the concentration of STK1during treatment?4.14±2.72 pmol/L?is higher than before treatment?3.52±1.91pmol/L?,but the difference was not statistically significant?P=0.516?.There was no significant difference in STK1 concentration between the sensitivity group and the insensitivity group beforeand during treatment?P=0.276,P=0.119?.?3?There was no significant difference of ADC₀ between sensitivity group and insensitivity group?P=0.776?.ADC₁ in sensitivity group was higher that in insensitivity group?P=0.019?.Both ADC₁ values were higher than ADC₀ values both in two groups?P<0.001,P=0.025?,and the changes occurred??ADC?had significant difference?P=0.018?,The changes in sensitivity group(0.38±0.03×10^-3mm/s)is larger than that in insensitivity group(0.18±0.05×10^-3mm/s).ADC₁ had higher predicting efficacy than?ADC.With0.924×10^-3mm/s for the cutoff value,ADC₁ value to predict the sensitivity of radiotherapy and chemotherapy sensitivity in nasopharyngeal carcinoma was0.84,the specificity was 0.8.The positive predictive value was 0.95,and negative predictive value of 0.5,the accuracy rate was 0.83,95%confidence interval was?0,1?.Conclusions1.The concentration of STK1 has a certain reference value in the differential diagnosis of nasopharyngeal carcinoma and benign lesion.Combined detection of STK1 with EBV-VCA-IgA and EBV-DNA in patients with nasopharyngeal carcinoma can improve the sensitivity,negative predictive value,accuracy of nasopharyngeal carcinoma diagnosis,and has a certain value toimprovethediagnosisefficiencyofnasopharyngealcarcinoma in hematological examination.2.The STK1 concentration was positively correlated with T stage,N stage,clinical stage and EBV-DNA expression level.STK1 concentration and N staging are independent prognostic factors of recurrence and metastasis of nasopharyngeal carcinoma.STK1 concentration before treatment has the potential to predict the recurrence and metastasis of nasopharyngeal carcinoma.The STK1 concentration before and after treatment can not yet predict the short-term response of nasopharyngeal carcinoma,and further study is needed.3.Before and during treatment,STK1 levels and the corresponding primary nasopharyngeal ADC values had no significant correlation;the concentration of STK1 before and during treatment still can not predict the Radiochemotherapy sensitivity of nasopharyngeal carcinoma;ADC value after the 10th times of radiotherapy?ADC₁?and the changes occurred??ADC?on nasopharyngeal carcinoma both had certain predictive value.