| Background and Purpose:Lung adenocarcinoma(LUAD)is the most widespread histological subtype of lung cancer.Its incidence has been increasing over the past few decades,and it has overtaken other subtypes to become the dominant category of pathological findings.In2011,A subtype of histological classification of invasive LUAD has been proposed by the International Association for the Study of Lung Cancer(IASLC),the American Thoracic Society(ATS)and the European Respiratory Society(ERS).This classification is based on six histological types(acinoid,papillary,micropapillary,adherent,and solid).Surgical resection is the most curable treatment for stage I invasive lung adenocarcinoma,but the prognosis of some patients is not very optimistic.At present,preoperative screening and postoperative monitoring of stage I lung cancer mainly rely on imaging and histopathological examination,but there is a certain lag and one-sidedness,which makes it difficult to monitor tumor recurrence early and timely.Therefore,it is critical to seek more effective surveillance programs for tumor recurrence.With the rapid development of biotechnology,circulating tumor cell(CTCS),a new liquid biopsy technique,has been gradually attracting the attention of clinical workers due to its advantages of non-invasive,real-time and high sensitivity,which plays an important role in the early diagnosis and prognostic monitoring of various cancers.In this study,CTCS were isolated based on the technology of combining the 2.5D microporous arrangement filtration membrane developed by the Institute of Micro and Nano Electronics of Peking University and the construction of a negative magnetic field sorting microfluidic device,to confirm the existence of blood micrometastases in some patients with stage I invasive lung adenocarcinoma(qualitative detection),and to clarify the correlation between different pathological subtypes and the detection of CTCS and their quantitative correlation(quantitative detection).For the current diagnosis and treatment status of lung adenocarcinoma,this project will explore the deficiencies of existing TNM staging of lung cancer and determine whether there is an "M0+" stage.If the project achieves the expected goal,it may play an important role in the revision of existing TNM staging,which can further break the constraints of guidelines,and again explore the treatment strategy of stage I invasive lung adenocarcinoma,so as to change the current diagnosis and treatment status.Method:A total of 150 patients with stage I invasive lung adenocarcinoma diagnosed in the Department of Thoracic Surgery,XX Hospital of Dalian Medical University from April 2019 to December 2020 were included in this study.Meanwhile,CTC-positive rates of stage I invasive lung adenocarcinoma and different pathological subtypes were calculated.Patients were grouped according to different age,gender,lesion status,serum markers and pathological subtypes,and 15 healthy control group(1)and 15 benign lung lesion group(2)were added respectively.10 ml of venous peripheral blood was collected 12 hours before surgery and 3 days and 3 years after surgery,respectively.CTCS were detected by filtering and screening through a 2.5-day highthroughput liquid biopsy platform with filter membrane as the main body.Using SPSS24 statistical analysis software,the correlation between CTC and analysis of the above factors,the present form of measurement value is a mean ± standard deviation(namely x±s),two independent sample measurement value t test;The statistical value was P<0.05 by χ2 test..Kaplan-Meier survival analysis was performed and log-rank test was used to compare survival analysis groups.Results:1.A total of 150 untreated stage I patients with invasive lung adenocarcinoma were collected in this study,and 15 healthy and 15 benign lung lesions were added as the control group,respectively.The overall CTC-positive rate of lung cancer group was35.33%,while the CTC-positive rate of healthy control group and benign lesion group was 0% and 6.67% respectively.Lung cancer patients were significantly higher than those in the other two control groups(P<0.05).Moreover,statistical comparison showed that the lung cancer group was significantly different from the benign tumor control group,P < 0.05,indicating that although the patients with invasive LUAD were in stage I,the detection rate was still obvious compared with the benign tumor.Compared with the healthy control group,P > 0.05 indicated that it was difficult to distinguish the two by means of CTC detection.2.Relationship between positive proportion of serological tumor markers and CTCS in patients with Stage I invasive lung adenocarcinoma: Values of tumor markers in CTC-positive lung cancer patients: CEA value was 33.18±76.46 ng/ml,CA125 value was 44±149.33 ng/ml,Pro GRP value was 84.29±195.81 ng/ml,NSE value was26.91±155.21 ng/ml.CYFRA21-1 value was 11.76±30.38 ng/ml;Values of various tumor markers(TM)in lung cancer patients with CTC(-): CEA,CA125,Pro GRP,NSE and CYFRA21-1 were 1.26±1.74 ng/ml,37.12±16.72 ng/ml,21±0.56 ng/ml,29.63±9.22 ng/ml,0.31±0.43 ng/ml,respectively.Through statistical comparison,it was found that for all the patients with stage I invasive lung adenocarcinoma included in the test,the positive rate of CTC was correlated with tumor markers CEA(t value14.089,P value <0.001),NSE(t value 3.177,P value 0.002),CYFRA21-1(t value9.237,P<0.001)showed statistically significant difference.There was no statistical significance except for CA125(t =1.766,P =0.079)and Pro GRP(t =1.733,P =0.105).3.Comparison of CTC-positive rates in patients with stage I invasive lung adenocarcinoma with different pathological subtypes 12 hours before surgery and 3days after surgery: First,we collected the results of preoperative and postoperative CTCS of different pathological subtypes.In 150 patients with lung cancer,the positive rates of acinoid type were 35.85% and 11.32%,respectively.The positive detection rates of papillae were 33.33% and 8.33%.The positive detection rates of micropapillae were 46.15% and 17.65%.The positive rates of adherent were 22.58% and 3.23%.The positive detection rates of solid type were 52.94% and 17.65%.Secondly,the results of CTC detection at two stages of each pathological subtype showed an obvious downward trend,but the detection rate of micropapillary and solid subtypes was still higher than that of other subtypes.The results of statistical analysis showed that there were significant differences in the positive rates of CTCS between different pathological subtypes before and after surgery(P<0.05).Surgical treatment is currently the most effective treatment for stage I invasive lung adenocarcinoma.According to the above results,selective surgical methods or active postoperative chemoradiotherapy and related immunotherapy can be considered for some stage I patients with adenocarcinoma,in order to delay the recurrence or metastasis rate.4.Relationship between CTC detection and prognosis 3 years after surgery in patients with Stage I invasive lung adenocarcinoma with different pathological subtypes: 120 patients with lung cancer who were not receiving other treatments 3 years after surgery were followed up.Firstly,the results of survival chart analysis by Kaplan-Meier survival analysis showed that DFS was 0.870 and OS was 0.889 3 years after surgery.Meanwhile,CTC detection was carried out.The DFS and DS of patients with acinoid,papillary,micropapillary,adherent and solid tumors were 0.854 and 0.858 at 3 years after surgery,respectively.0.810,0.942;0.692,0.800;0.932,0.968;0.697,0.779,logrank test indicated that there were significant differences in DFS 3 years after surgery among patients with different pathological types(χ2=8.413,P=0.029),and significant differences in OS(χ2=7.515,P=0.038),which were statistically significant.Finally,the relationship between CTC test results and DFS and OS 3 years after surgery was explored.The DFS of CTC positive and negative patients were 0.467 and 0.898,respectively.The log-rank test indicated that there was a significant difference between CTC positive and negative patients at 3 years after surgery(χ2=32.790,P < 0.001).The OS values were 0.646 and 0.913,respectively.log-rank test indicated that there was a significant difference in OS between CTC-positive and negative patients 3 years after surgery(χ2=14.981,P < 0.001).Conclusion:CTC were detected and statistically analyzed in five pathological subtypes of lung adenocarcinoma patients: acinoid,papillary,micropapillary,adherent and solid.The results showed that the number of CTC was related to the pathological subtype,disease progression and therapeutic effect.As a less invasive but more sensitive tool,CTCS could be dynamically monitored.It can well link clinical biopsy techniques with clinical diagnosis and treatment,and make up for the disadvantage of some traditional tumor markers with low sensitivity to stage I invasive lung adenocarcinoma.In the near future,the mature application of CTCS will precisely guide the individualized treatment of early stage lung adenocarcinoma and reduce the burden on patients. |
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