| Part I.Preliminary feasibility study of intranipple tracer injection foraxillary sentinel lymph node biopsy in rats Objective:To investigate the feasibility of using intranipple injection of tracer to detect rat axillary sentinel lymph node(SLN),to provide different injection sites and methods of tracer injection for SLN,as well as to compare the effects of different tracers and combinations of tracer for SLN under intranipple injection conditions,and to provide experimental basis for specific localization of SLN.Methods:Fifty Sprague-Dawley adult female rats,were randomly divided into 5 groups of10 rats each,and the third pair of breast was selected as the tracer injection site,and each rat was injected with the tracer by intradermal injection in the areola area of the left side and by intranipple injection in the right side(Group 1: Methylene blue(MB)0.05 m L(concentration 1%)combined with Indocyanine Green(ICG)0.1m L(concentration 0.125mg/m L),Group 2: ICG 0.1m L(concentration 0.125mg/m L),Group 3: MB 0.05 m L(concentration 1%),Group 4: 99 m Tc sulfur colloid 0.01ml(specific activity 2.5m Ci/ m L-5.0 m Ci/ m L)combined with MB 0.05 m L(concentration 1%),group 5: 99 m Tc sulfur colloid 0.01ml(specific activity 2.5m Ci/m L-5.0 m Ci/ m L)).Group 1 and group 2 applied Femur Far Infrared Vascular System Detection Imager immediately after the tracer injection,group 4 and group 5 appliedγ-ray detector before the rats were sacrificed to detect tracer accumulation SLN body surface localization and labeling,Group 1,group 2,group 3 and group 4 dissected the rats’ bilateral axillary fossa 10 minutes after the end of the last injection of tracer,and group 5 dissected the rats’ bilateral axillary fossa after the end of body surface positioning,according to the body surface localization markers to find the target lymph nodes and record the number,the number of SLN detections and the success rate of sentinel lymph node biopsy(SLNB)detections were used as evaluation indicators,compare and analyze the tracer or combination of each group to take the areola area intradermal injection and intranipple injection of the two differences.The99 mTc sulfur colloid combined with MB dual tracer method was used as a reference to compare the differences in the number of SLN detections and the success rate of SLNB detection by ICG combined with MB dual tracer method,MB,ICG,and 99 m Tc sulfur colloid single tracer method under the intranipple injection method.Data were stored and analyzed using Microsoft Excel and SPSS 25.0 statistical software.non-normally distributed measures were expressed as M(Q1,Q3)and compared using the rank sum test,and count data were expressed as cases or percentages and compared using the c 2 test.p < 0.05 was considered a statistically significant difference.Results:Comparison of the number of SLNs detection by intranipple injection versus intradermal injection in the areola area: ICG combined with MB dual tracer method:intranipple injection(3.0pieces)vs.intradermal injection in the areola area(2.0 pieces)(Z=-2.584,P=0.01);ICG single tracer method: intranipple injection(3.0 pieces)vs.intradermal injection in the areola area(2.0 pieces)(Z=-1.770,P=0.077);MB single tracer method: intranipple injection(2.0 pieces)vs.intradermal injection in the areola area(1.5 pieces)(Z=-0.438,P=0.661);99m Tc sulfur colloid combined with MB dual tracer method: intranipple injection(2.0 pieces)vs.intradermal injection in the areola area(2.0 pieces)(Z=-0.448,P=0.654);99m Tc sulfur colloid single tracer method:intranipple injection(3.0 pieces)vs.intradermal injection in the areola area(3.0pieces)(Z=-0.642,P=0.521).Comparison of the success rate of SLNB detection by intranipple injection versus intradermal injection in the areola area: ICG combined with MB dual tracer method: intranipple injection(100%)vs.intradermal injection(100%);ICG single tracer method: intranipple injection(100%)vs.intradermal injection(100%);MB single tracer method: intranipple injection(100%)vs.intradermal injection(100%);99m Tc sulfur colloid combined with MB dual tracer method: intranipple injection(90%)vs.intradermal injection(100%)(c2=6.906,P=0.05);99m Tc sulfur colloid single tracer method: intranipple injection(100%)vs.intradermal injection(100%).Comparison of the number of SLNs detection with different tracers and combinations under intranipple injection methods: ICG combined with MB dual tracer method(3.0pieces)vs.99 m Tc sulfur colloid combined with MB dual tracer method(2.0 pieces)(Z=-2.640,P=0.083);ICG single tracer method(3.0pieces)vs.99 m Tc sulfur colloid combined with MB dual tracer method(2.0 pieces)(Z=1.457,P=1.000);MB single tracer method(2.0 pieces)vs.99 m Tc sulfur colloid combined with MB dual tracer method(2.0 pieces)(Z=-0.863,P=1.000);99m Tc sulfur colloid single tracer method(3.0 pieces)vs.99 m Tc sulfur colloid combined with MB dual tracer method(2.0 pieces)(Z=-1.835,P=0.665).Comparison of SLNB detection success rates by intranipple injection: SLNB detection success rate of ICG combined with MB dual tracer method,MB,ICG,99 m Tc sulfur colloid single tracer method and99 mTc sulfur colloid combined with MB dual tracer method were 100%.Conclusion:It is feasible to find SLN by intranipple injection of tracer in rats,Compared with the intradermal tracer injection in the areola area,the intranipple injection is the optimal injection site for finding SLN because of the high number of SLN and the equal success rate of SLNB detection.;the nipple can be used as one of the injection sites for axillary SLNB tracer;Compared with the blue dye combined with radioisotope dual tracer method recommended by current guidelines,ICG combined with MB dual tracer method,ICG,MB,99 m Tc sulfur colloid single tracer method can replace 99 m Tc sulfur colloid combined with MB dual tracer method and obtain equivalent SLNB detection efficacy under the conditions of intranipple injection,and the tracer and combination selection is flexible and has some advantages.Part II.Clinical evaluation of the first domestically produced generic isosulfan blue injection in sentinel lymph node biopsy for early breast cancer in China: A multicenter,single-arm,open validation trial(CSBr S-024)Objective:To evaluate the efficacy and safety of the first domestically produced generic isosulfan blue injection in SLNB for early breast cancer in China.Methods:Five participating institutions screened patients with early-stage breast cancer who met the trial entry criteria,and all patients received informed consent to undergo SLNB surgery,and domestic first imitation isosulfan blue injection(total dose ≤3ml)was injected subcutaneously(1-3 points)in the areola or around the swelling before the start of surgery(within ≤5min).During the operation,a transverse axillary incision was made to reveal the subcutaneous tissues,the SLN was separated along the blue-stained lymphatic vessels to the blue-stained lymph nodes,and the number of SLNs was counted and sent for pathological examination after excision.The number of successful tracer lymphatic vessels was recorded(the success of tracer lymphatic vessels was judged by the clinician based on intraoperative visual inspection,and the result was judged as adequate or inadequate tracing;adequate tracing was considered as successful tracing,and intraoperative photographs were required to indicate adequate tracing),and the number of blue-stained SLNs resected was recorded in the pathology section,and the axillary lymph node operation mode was selected based on the pathology results.Postoperative follow-up was performed for 14±2 days,and the occurrence of adverse events was recorded.The validity was evaluated by the success rate of SLN tracing(number of successful SLN tracing cases/number of cases given tracer × 100%(successful SLN tracing was defined as finding ≥1 SLN under tracer staining)),the accuracy rate(number of SLNs stained with tracer blue and confirmed in pathological sections/(number of SLNs confirmed in pathological sections stained with tracer blue + number of non-SLNs confirmed in pathological sections)× 100%)and the success rate of lymphatic vessel tracing(number of successful lymphatic vessel tracing cases/number of cases given tracer × 100%),and the safety index was evaluated by adverse events,laboratory tests and vital signs.SAS(Version 9.4)statistical software was used for data analysis,and descriptive statistics were used for quantitative and quantitative indicators with a one-sided significance level of 0.025.Results:Analysis of validity results based on the set of conforming scenarios(N=150):The number of SLNs found under tracer staining was 141 out of 150 patients,and the success rate of SLN tracing and its 95% confidence interval(CI)was 94.0%(88.9%-97.2%);The number of successful lymphatic vessel tracing cases was 147,and the success rate of lymphatic vessel tracing and its 95% confidence interval(CI)was98.0%(94.3%-99.6%);The number of excised SLNs detected under tracer blue staining was 362,the number of SLNs sent for examination was 362,the number of pathological sections confirmed as SLNs was 382,and the number of pathological sections confirmed as non-SLNs was 16;SLN tracer accuracy and its 95% confidence interval(CI)was 96.0%(93.6%-97.7%);Analyzing security results based on the security analysis set(N=158):There were 40 cases(25.3%)and 49 instances of adverse events observed during the trial observation period.37 cases(23.4%)and 46 instances of general adverse events,which mostly improved and healed on their own without treatment,and it was determined by the trial expert group that the general adverse events were probably or definitely not related to drug use;The number of serious adverse events was 3 cases(1.9%)and 3 instances,which were determined by the trial panel to be definitely unrelated to drug use and showed good regression with active treatment.Conclusion:The first domestically produced generic isosulfan blue injection is safe and effective for SLNB in Chinese patients with early-stage breast cancer.Part III.Multicenter real-world study of the use of tracers for sentinel lymph node biopsy after neoadjuvant therapy for breast cancerObjective:Neoadjuvant Therapy(NAT)represented by Neoadjuvant Chemotherapy(NAC)and combination of targeted drug therapy,To understand the real application of tracers for SLNB after NAT in breast cancer in China,to discuss the factors affecting the accuracy and false negatives of SLNB with tracers,and to compare with the recommendations of foreign guidelines,to point out the differences and analyze the reasons,as well as to make suggestions for improvement.Methods:Classify and statistically describe the proportion of breast cancer patients who underwent SLNB and SLNB combined with axillary lymph node dissection(ALND)after NAC and combination of targeted drug therapy after NAC and combined targeted drug therapy from January 1,2010 to December 31,2020 in 20 units of the Breast Group of the Chinese Society of Medical Surgery for tracer or combination use,and the number of SLN detections.The accuracy and false negative rate(FNR)of SLNB with tracers or combinations of tracers were calculated according to the SLNB rubric of Louisville University in the United States,and c2test(Fisher’s exact test was applied when necessary)was used to conduct univariate analysis of clinical and pathological factors that might affect the predictive efficacy(accuracy and false negatives)of SLNB with tracer application.Results:A total of 1251 breast cancer patients who underwent SLNB and SLNB combined with ALND after NAC and combined targeted drug therapy,853(68.2%,853/1251)used single tracer method,predominantly applying MB(60.1%,752/1251);The double tracer method was used in 398 cases(31.8%,398/1251),with the application of MB combined with radioisotope(RI)(18.1%,226/1251)predominantly,There are some differences with the tracing methods recommended bynational and international guidelines,mainly in the low application rate of blue dye combined with RI double tracing method,and the application of blue dye is MB,while isosulfan blue or patent blue,which is better than MB,is not yet available in China.All 5 tracers and combinations detected >50% of cases with >3 SLNs,which is in line with national and international guidelines for the number of SLNBs detected after NAT,ensuring the accuracy of the number of SLNs detected and reducing false negatives in the assessment of axillary conditions.The highest number of cases of 4SLNs(27.1%,204/752)was detected when using the MB single tracer method,with an SLNB accuracy of 93.7% and an FNR of 9.7%.univariate analysis showed that pre-NAT regional lymph node staging and molecular typing were the clinical and pathological factors affecting the predictive efficacy of SLNB using the MB single tracer method.The highest number of cases of 5 SLNs(43.6%,44/101)was detected when using the Nanocarbon single tracer method,with an SLNB accuracy of 84.7%and an FNR of 26.3%.univariate analysis showed that pre-NAT clinical staging of primary breast cancer lesions,pre-NAT regional lymph node staging,histological type,NAT protocol and p CR status of breast cancer lesions were the clinical and pathological factors affecting the predictive efficacy of SLNB using the Nanocarbon single tracer method.The highest number of cases of 4 SLNs(24.8%,56/226)was detected when using the MB combined with RI double tracer method,with an SLNB accuracy of 94.3% and an FNR of 9.3%.univariate analysis showed that histological type was the clinical and pathological factors affecting the predictive efficacy of SLNB using the MB combined with RI double tracer method.The highest number of cases of 2 SLNs(27.4%,20/73)was detected when using the MB combined with ICG double tracer method,with an SLNB accuracy of 79.2% and an FNR of 26.3%,univariate analysis did not identify clinical and pathological factors affecting the efficacy of SLNB prediction using the MB combined with ICG double tracer method.The highest number of cases of 3 SLNs(30.3%,30/99)was detected when using the MB combined with Nanocarbon double tracer method,with an SLNB accuracy of98.1% and an FNR of 8.1%.univariate analysis showed that pre-NAT clinical staging of primary breast cancer lesions was the clinical and pathological factors affecting thepredictive efficacy of SLNB using the MB combined with Nanocarbon double tracer method,histological type failed to perform univariate analysis,Whether histological type affects the predictive efficacy of SLNB using MB combined with nanocarbon dual tracer method failed to perform a univariate analysis.Conclusion:SLNB after NAT for breast cancer in China is dominated by MB single tracer method,which limits the prevalence of SLNB in BC patients after NAT.MB combined with RI is the main double tracer method,MB combined with RI double tracer method detection efficacy is better than a single use of MB.Clinical evidence for the application of Nanocarbon single tracer,MB combined with ICG and MB combined with Nanocarbon double tracer in SLNB after NAT is currently insufficient and needs further study. |
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