Animal Experiment And Clinical Study Of Ultrasound-guided Percutaneous Thermal Ablation For Prostate Diseases

BackgroundWith the advent of an aging society and changes in people's diet,the incidence of prostate cancer(PCa)and benign prostatic hyperplasia(BPH)has been increasing year by year.The patients with advanced age and basic diseases cannot tolerate traditional surgical treatment,so minimally invasive treatment is urgently needed to solve this problem.The European Urological Association and the National Comprehensive Cancer Network(NCCN)guidelines recommend that minimally invasive focal therapy can be used as an alternative treatment for PCa who cannot tolerate surgery.Focal ablation therapy aims to provide the effective oncological benefit of active treatment options while reducing the risk of side effects through preserving noncancerous tissues.The advantages of focal therapy including minimal invasiveness,less side effects,less cost and shorter hospital stay.At present,the researches on focal therapy of prostate diseases mainly focus on high-intensity focused ultrasound and cryoablation.However,there are few reports about percutaneous laser ablation(PLA),radiofrequency ablation(RFA)and microwave ablation(MWA)on prostate diseases,and there was no comparative study about thermal ablation on prostate diseases.PLA,RFA and MWA are all thermal ablation which used different methods to increase the local tissue temperature(> 60°C),resulting in irreversible damage and coagulation necrosis in target tissue.The prostate is located in the center of the pelvis,surrounding the front urethra,and adjacent to important organs such as the rectum,bladder,and seminal vesicle glands,so the ablation for prostate requires precision and conformal.Interventional operation guided by imaging equipment provides feasibility for precision treatment.Ultrasound,as one of the imaging guidance equipment,that has the advantages of high resolution,no radiation,portability,real-time and inexpensive,is widely used in clinical practice.Transrectal ultrasound(TRUS)has high-frequency probe and could be close to the prostate,so it can clearly show the prostate and surrounding organs,which has more advantages in the diagnosis and treatment of prostate disease.In this study,PLA,RFA and MWA were applied in the beagle prostate under the guidance of TRUS.The dynamic changes of volume in prostate and ablation lesions were observed and the mechanism of changes was explored through inflammatory response,which provides reference and information for choosing right ablation techniques for prostate diseases.These three thermal ablation technologies were safe and feasible in prostate through this animal experiment.We chose the RFA which has stability and controllable ablation lesion shape to treat the PCa patients under guidance TRUS.The information of tumor control and the relief of Bladder outlet obstruction(BOO)symptoms were explored.Part I The animal experiment of percutaneous laser,radiofrequency and microwave ablation under guided TRUS in the beagle prostate PurposeTo explore the shape and volume of the ablation lesions in beagle prostate underwent percutaneous laser ablation(PLA),radiofrequency ablation(RFA),and microwave ablation(MWA),and compare the change of prostate and ablation lesion volume,to explore the mechanism of this change through inflammatory response.MethodsFifteen adult beagles with a history of mating were randomly divided into three groups(PLA,RFA and MWA group).The therapeutic doses of three ablation techniques are selected through the literatures,which set high energy group(PLA:3W/1200 J,RFA and MWA:30W/120s)and low energy group(PLA:3W/600 J,RFA and MWA:30W/60s).The ablations were conducted for one region in the left and right lobes of the prostate,which totally resulted in thirty ablation lesions.To observe the pathological tissues,two beagles from each group were randomly selected and sacrificed one day and one week after ablation,respectively.The remaining three beagles in each group were sacrificed after finishing blood test,transrectal contrast-enhanced ultrasound(TR-CEUS),multi-parameter MRI at four time periods.The four time periods include before ablation,the day of ablation,one week and one month after ablation.Specimen of prostate gland and surrounding organs were acquired and underwent the pathological examination.The inflammatory factor TNF-?,IL-12,TGF-?1 and IL-10 in serum were detected via enzyme-linked immuno sorbent assay(ELISA).The macrophages(CD68),M1 type macrophages(i NOS)and M2 type macrophages(CD163)in beagle prostate tissue were analyzed by immunohistochemistry.All ablation process in beagle prostate was guided and monitored by TRUS.The(Mediolateral dimension,ML),(Anteroposterior diameter,AP)and(Suprainferior diameter,SI)of lesions were measured by TR-CEUS and MRI,and the volume(V)and shape(R)of each ablation lesion were calculated by formula(V = 1/6 × ? ×ML × AP × SI,R =(ML + AP)/ 2SI).The closer R value was to 1,the more spherical the shape of ablation lesion was.The dynamic changes of volume in prostate and thermal ablation lesion in the three groups were observed using the same evaluation method,and the mechanism of volume change was explored through inflammatory response.ResultsThere was no serious complication in all beagles during the process of ablation and the one-month observation.Microscopic inspection of the ablation lesion demonstrated coagulated and necrotic changes and divided into coagulative zone(CZ),marginal transition zone(MZ),and untreated zone(UZ)from the lesion center to normal peripheral prostate tissue in the HE staining images.These three ablation technologies under TRUS guided were safe and effective in prostate.There was no statistically significant difference in the volume of ablation lesions between TR-CEUS and DC-MRI.The TR-CEUS and DC-MRI could evaluate the size of three types of ablation lesions and could be used in the follow up.The volume and shape of the three type ablation lesions were different.Both the high energy group and the low energy group,the volume of MWA lesions were the largest,followed by PLA,and the RFA was the smallest.The difference was statistically significant(P < 0.05).Under the same ablation techology,there was no significant difference in R value of ablation lesion with different ablation parameters.However,the shape of ablation lesion under different technique was different.The R value of RFA ablation lesion was the highest,which of PLA ablation was the smallest,and that of MWA ablation lesion was between the two,and the difference was statistically significant(P < 0.05).The prostatic volume in the three groups increased transiently after ablation.Before ablation,the mean volume of beagle prostate glands in PLA,RFA and MWA group as baseline were 16.3 ± 5.54 ml,17.1 ± 5.66 ml and 17.8 ± 3.22 ml.The volume was the largest one week after ablation: 19.4 ± 5.72 ml,19.8 ± 5.85 ml and22.4 ± 4.14 ml,and it basically recovered to the preoperative level in one month: 18.2± 5.63 ml?17.6 ± 5.90 ml and 16.0 ± 4.32 ml(P > 0.05).There were differences in the dynamic ablation lesion changes of the three groups.The PLA lesions volume gradually increase over time,which increased by320% ± 167% and 110% ± 42% with 3 W/600 J and 3 W/1200 J parameter one month later,respectively.However,the volume of RFA and MWA ablation lesions increased slightly one week after ablation and decrease significantly one month later.The volume decreased by 32 % ± 6 % and 42 % ± 13 % in RFA group with 30 W/60 s and30 W/120 s,respectively.The volume decreased by 88 % ± 10 % and 138% ± 18 %in MWA group with 30 W/60 s and 30 W/120 s,respectively.The mechanism of dynamic volume change was explored through the inflammatory response.Combined with the results of inflammatory factors in the blood and immunohistochemistry in the tissue,the PLA group had the heaviest and longest lasting inflammatory response,while the RFA group and MWA group had less inflammatory response,and anti-inflammatory repair was the main one month after ablation.Conclusions1.All three types of thermal ablation techologies are safe and feasible in the application of beagle prostate.TRUS could accurately guide and monitor the implantation of energy emitter and the process of ablation process.2.Both TR-CEUS and DC-MRI can accurately assess the volume of ablation lesions.The former has real-time and inexpensive advantages and could be popularized and applied.3.There are differences in the volume and shape of the three type ablation lesions.Under similar parameters,the volume of MWA lesion is the largest,followed by PLA,and RFA is the smallest.RFA is more spherical,PLA is more ellipsoidal,and MWA is in between.4.The dynamic changes of the volume of the three type thermal ablation lesions were different.The volume of PLA ablation lesion increases gradually with time,while that of RFA and MWA decreases significantly one month after ablation,which may be related to the inflammatory response.5.The differences in the shape,volume and evolution rule of thermal ablation lesions under PLA,RFA and MWA in the prostate have clinical significances,which is helpful for the selection of indications for ablation technology,indwelling catheter duration and accurate imaging evaluation time after ablation.Part II The clinical study of ultrasound-guided percutaneous RFA localablation for prostate cancerPurposeThe purpose is to investigate the feasibility,safety and clinical effect of TRUS-guided RFA for PCa.MethodsFrom October 2018 to January 2020,the advanced PCa patients with BOO symptoms who were agreed to be enrolled in our hospital were randomly divided into the RFA combined endocrine therapy group(combination group)and the endocrine therapy group(endocrine group),with 10 patients in each group,a total of 20 patients.All patients were confirmed PCa pathologically.Before ablation,the outline of tumor was delineated in dynamic contrast-enhanced magnetic resonance imaging(DC-MRI)and the volume was calculated.The position of radiofrequency electrode placement and ablation parameters were designed according to the tumor conditions.TRUS-guided RFA was performed in PCa patients under general anesthesia through perineum puncture.Patients in the combination group received multi-parameter MRI examination one month after ablation,and the ablation lesion was delineated and its volume was calculated in DC-MRI.The endocrine therapy is total androgen blockade regimen.Patients with bone metastatic received anti-bone metastasis drugs or radiotherapy.The followed up for these patients were done at one month,three months and six months after treatment,which included TRUS,multi-parameter MRI,prostato-specific antigen(PSA),quality of Life Score(QOL),maximun flow rate(Qmax),international prostate symptom score(IPSS),prostate volume(PV)and postvoid residual urine volume(PVR).The PV was measured and calculated by formula in TRUS.ResultsTen PCa patients successfully completed RFA under the guidance of TRUS.The process of puncture and ablation during RFA could clearly show on TRUS image.The average operation time was 60.6 ± 12.7 minutes,the average ablation time was15.0 ± 3.3 minutes,the average number of ablation times was 6.2 ± 1.7 times,and the average indwelling catheter duration after ablation was 9.7 ± 3.2 days.Before ablation,the average volume of prostate tumor was 9.98 ± 2.35 ml.One month after RFA,the ablation lesion was low signal area filled with no contrast agent in DC-MRI,and the average volume of that was 8.37 ± 1.59 ml,so the local ablation rate was85.2% ± 10.9%.There were no serious complications during the operation and follow up.During the follow-up,multi-parameter MRI showed that the local tumor was stable and no new lesions was observed at one,three and six months after treatment,and there was no new metastases appered in the combination group patients.The average PSA values in combination group patients were markedly reduced at the one,three and six months after treatment(215.3 ± 160.9 ng/ml,106.9 ± 134.5 ng/ml,61.8± 113.9 ng/ml VS 689.8 ± 671.4 ng/ml,P < 0.05).The degree of decline in combination group was obviously batter than the endocrine group,and the difference was statistically significant(P < 0.05).After combination treatment,the level of Qmax and IPSS were better than before treatment(12.2 ± 2.7,17.4 ± 2.5,19.4 ± 2.6 VS 4.9 ± 2.2;17.2 ± 4.0,9.7 ± 3.7,5.4 ± 1.6 VS 28.2 ± 3.0;21.4 ± 2.5,14.4 ± 2.2,7.9 ± 1.2 VS 28.1 ± 4.6).The combination group was superior to the endocrine group(P < 0.05).The level of PV and PVR in the combination group were significantly decreased compared with that before treatment(P < 0.05),and the degree of decrease was better than that in the endocrine group(P < 0.05).Conclusion1.TRUS-guided RFA is a safe and feasible technique for PCa patients.2.RFA can eliminate most of local tumor and reduce the tumor burden.RFA combine endocrine therapy was better than endocrine only.3.RFA combined with endocrine therapy can effectively alleviate the symptoms of BOO in PCa patients,which is better than endocrine only.