Comparing of Modified Wet Suction Technique and Dry Suction Technique for EUS-FNA of Solid Occupying Lesions

Comparing of Modified Wet Suction Technique and Dry Suction Technique for Endoscopic Ultrasound -Guided Fine Needle Aspiration (EUS-FNA) of Solid Occupying Lesions: a Prospective Multi-center,Randomized,and Controlled Trial

The purpose of this study is to compare the diagnosis accuracy of modified wet suction technique and 5ml dry suction technique on solid occupying lesions.

Patients will be divided into two groups, arm A and arm B according to two different methods adopted in their first needle, which refers to the modified wet suction technique or 5ml dry suction technique.Take the solid occupying lesion diagnosis accuracy as the research major indicator to compare the the modified wet suction technique or 5ml dry suction technique as optimal efficiency test. Take classⅠerror, a=0.05, class II error, β=0.2, power=0.8, suppose that the diagnostic accuracy of dry suction technique to the solid occupying lesions is 75%, the diagnostic accuracy of modified wet suction technique to the solid occupying lesions is 85%, the minimum sample size are 248 patients with 5ml dry suction technique and 248 patients with modified wet suction technique, the 2x2 cross-over design is adopted, namely, each arm has 124 patients respectively. Considering factors including defluxion, 20% cases will be added to two arms, therefore, each arm has 148 patients respectively, the total number of patients is 296.

The statistics experts generated randomized serial numbers（001-296）according to same-size allocation ratio between arm A and arm B with Statistical Analysis System 9.2(SAS 9.2), a statistical software in the randomized block method. The serial numbers are the randomized grouping numbers for the trial patients, block capacity is 8, totally 37 randomized block. One copy send to trial centers for patient allocating, and the another copy be saved by the trial applicant unit. Every trail centers will be responsible for the screening of qualified patients, rank them in visit time to get the randomized grouping number so as to determine them goes to arm A or arm B .The research people and patients in all trial centers should not know the randomized grouping number and relevant arms. The arm name will be sealed under scratch card. Every trial patients will get a unique randomized number, and it will not change through out the whole trial.

Use the inclusion and exclusion criteria to observe the patients and do relative inspections, and confirm if the patients qualified or not to the trial. Record the result of last time test before the treatment. Although it is better to get the informed consent before doing all kinds of observation and tests, if for some reason, the medical imaging examination has completed,as long as the imaging examination was done within 3 weeks before the needle biopsy, it can still be collect as baseline data (imaging examination can be done at other hospitals, but the trial center should issue a new evaluation report 1 week before the patient join the trial group); other lab test items done at 2 weeks before the needle biopsy can still be collect as baseline data for pre-research use, but these tests should be done at the trail center hospital so as to guarantee the data trace ability.

The investigator will puncture the lesion for four needle passes for all of them:For Arm A,5ml dry suction technique is adopted in their first needle, then modified wet suction technique/5ml dry suction technique/modified wet suction technique is operated successively;For Arm B, modified wet suction technique is adopted in their first needle, then 5ml dry suction technique/ modified wet suction technique /5ml dry suction technique is operated successively.Well,the 5ml dry suction technique is conducted as follow:after the needle puncturing into the lesion under ultrasound scanning, remove the stylet and connect the needle to syringe with 5ml negative pressure aspiration, then the needle will be moved to-and-fro within the lesion 20 times. Suction will be released before the needle is withdrawn from the lesion.And the modified wet suction technique is conducted as follow:the needle whose stylet is pulled out will be flushed with 2ml saline solution before puncturing when the lesion has been found, then puncture into the lesions and replace syringe with 5ml negative pressure aspiration, then the needle will be moved to-and-fro within the lesion 20 times. Suction will be released before the needle is withdrawn from the lesion.If no core tissues obtained or the operator determine insufficient specimen according to Macroscopic rapid on-site(MOSE) after the operations above, then remedy procedures will be done, and the punctuation process should be continued with the appropriate punctuation methods until the satisfactory specimens are obtained.Experts in cytology and pathology evaluate the specimen quality and make a diagnosis under the condition that they do not know punctuation methods. The evaluation and diagnosis of each specimen are made by two experts independently. If the two experts hold different opinions, they will make a conclusion after full discussion. If there are two or more cytological smears with same punctuation method, the highest-rate smear should be taken as the standard smear.Follow up (outpatient follow up or telephone follow up) the patients at 1 week, 12 weeks and 36 weeks after the needle biopsy and collect the patients clinical data and confirm their final diagnosis.

Case Report Form(CRF) will be filled by the researchers, every involved patient must have the CRF filled. This will be audited by clinical monitor and handed over to data administrator to input and manage data, the first copy will be kept by the applicant, the second copy will go to the trial center, and the third copy will be kept by the trail researchers.The data input and management will be taken care by specially assigned person. In order to guarantee the data accuracy, data input will be done twice by two independent data administrators, by computerized and manual verifying, hand over the data to statistical experts to do blind check and statistic analyzing.For the questions and doubts within the case report form, the data administrator make DRQ and via the clinical monitor asking the researchers. The researchers will answer and feed back as soon as possible. According to the researchers answer, data administrator will do the data modifying, confirming or inputting, and when necessary send out DRQ again.After blind audition and confirming that the established data base is correct, major researchers, applicant and the statistic analyzing people lock the data. The locked data will not be changed, and the data base will be handed over to statistical analyzer to do the statistic analyze according to the statistic analyzing plan. Problems found after data locking can be modified during the statistic analyzing procedure.This will be done by specialized statistic analyzing people according to the predetermined statistic analyzing plan. The statistic analyze will be carried out according to intention principle confirmed full analysis set and per-protocol set principle. After completing the statistic analyzing, the statistic analyzer issue the statistic analysis report and send this to major researchers to write the study report.

Statistic analyzing plan:（1）General principle①All statistical tests were two-sided. P<0.05 is regarded that the difference is statistical significance.② Description of quantitative index will calculate the mean and the criteria deviation, description of classification index will describe the number and percentage of each type.（2） Statistical Analysis Method：① For measurement data, compare these data with baseline value during the screening period, adopt the deviation t-test, the variance analysis of cross-over experiment or the rank-sum test of cross-over experiment to make a comparison between these data and baseline value.② For enumeration data, adopt the paired x2-test(including CMH-x2 test) or Fisher's exact test to compare these data of each group.（3）Defluxion Analysis：The total defluxion rate of each group and the defluxion rate caused by adverse events are compared by x2-test or Fisher's exact test.（4）Analysis of baseline value balance：The indexes of some baseline values such as demographic data, vital signs, history of diseases and basic treatment are compared by group t-test and x2 test to measure the balance of each group. Baseline evaluation is made to full analysis set( FAS) and per-protocol set(PPS).（5）Validity Analysis：The primary index of validity analysis is the diagnostic accuracy of the 5ml dry pressure and modified wet pressure to the solid space-occupying lesions. The secondary indexes of validity analysis include the punctuation specimen quality of 5ml dry pressure and modified wet pressure, the diagnostic rate of the first needle of 5ml dry pressure / modified wet pressure and the incidence of complications for modified wet pressure and 5ml dry pressure. The rates of each two arms and Youden indexes are compared by the approximate normal z-test or the central-effect-considered Cochran Mantel Haenszel-x2(CMH-x2 )text.(6)Safety Analysis:The incidences of adverse events/ adverse reactions (including complications from punctuation) of each arm are compared by x2-test or Fisher's exact test and describe the adverse events occurred in this experiment by the list and the normal/abnormal changes of laboratory text results before and after test and the relationship between abnormal changes of laboratory text results and this diagnostic research.(7) All statistical analyses are completed by the professional statistical analysis software, SAS version 9.2.

Inclusion Criteria:

1. Age >18 years old,<80 years old;
2. Gender: Male or Female;
3. The patients who have solid occupying pancreatic lesions and non-pancreatic lesions (the diameter>1cm) within the range of imaging examination(MRI、CT、B-type ultrasonography) and ultrasonic endoscope examination and should conduct the biopsy to identify lesion nature;
4. The patients who receive examinations in the research center;
5. The patients who sign the informed consent.

Exclusion Criteria:

1. Hemoglobin≤8.0 g/dl;
2. Pregnant women;
3. The patients who have coagulation disorders（PLT<50,000/mm3,INR>1.5,roughly calculation, INR>1.5, is equivalent to PT>18 seconds);
4. The patients who took anticoagulants such as aspirin, warfarin in the latest week;
5. The patients who suffered from acute pancreatitis in the past two weeks;
6. The patients who have cardiopulmonary dysfunction, therefore cannot tolerate ultrasonic endoscope examination;
7. The patients who cannot sign the informed consent(such as patients who have mental disease or drug addiction and so on).