| Background:Breast cancer is the most common malignant tumor and the second most common cause of cancer-related deaths in women.In China,new diagnosed breast cancer accounts for about12.2% of the world's each year,while deaths account for about 9.6%.Therefore,breast cancer has become a major public health concern.For breast cancer patients from stages I to III,surgery is the standard recommended treatment.Owing to breast asymmetry after surgery,some patients may not be satisfied or may become anxious,and this may lead to poor psychological well-being or the financial burden of breast cosmesis.In addition,with the popularity of screening for breast cancer,more patients can be diagnosed at an early stage or at smaller tumor sizes than before,suggesting that minimally invasive treatment and better esthetic outcomes may come to be expected for early-stage breast cancers.Furthermore,not all patients can tolerate surgery,especially older breast cancer patients with a variety of comorbidities.Therefore,minimally invasive treatment would be a promising approach for early-stage and elder patients with breast cancer.The application of various local ablation techniques including radiofrequency ablation,cryoablation and focused ultrasound ablation have achieved encouraging results in elderly patients with early breast cancer and have improved cosmetic outcomes.These methods are effective for local tumors control in that it had high complete ablation rates,low local recurrence rates and minimal damage to healthy tissues.However,thermal ablation techniques may give rise to the coagulative necrosis whose symptoms are thattumor tissues are replaced by fibrous tissues,and subsequently,there may be an ablation lump that is not life-threatening but may cause discomfort,anxiety and fear in patients.A number of Asian women with the disease were often found with a relatively small breast,which increases the probability of skin damages after ablation.Furthermore,during the follow-up period,it may be difficult to distinguish ablation lumps from local recurrence of a tumor.In contrast to thermal ablation techniques,irreversible electroporation(IRE)is a novelnon-thermal ablation technique.By using the technology,cells are exposed to high-field electrical pulses for several microseconds,giving rise to irreversible,lethal nanoscale pores.In addition to the higher complete ablation rate,IRE may cause limited damages to important vascular and structural tissues,and therefore it is widely used in the treatment of solid tumors around vital blood vessels and other vascular structures.The limited researches indicate that IRE is expected to break through the limitations of thermal ablation,especially skin injury.Despite the fact that IRE has been explored as a treatment for a number of solid tumors,up-to-date studies on IRE therapy for breast cancer animals are limited.The purpose of this study was to evaluate the safety and efficacy of IRE for the treatment of rabbit breast cancer model and its anti-tumor immunological effect.Methods:(1)Thirty female New Zealand white rabbits were randomly divided into 3 groups:normal control group(N = 10),IRE group A(IRE in right breast,N = 10),and IRE group B(IRE in left breast,N = 10).Two mono-electrode needles were inserted into the breast tissue by percutaneous puncture.Electrocardiogram and vital signs were monitored before,during,and after ablation.Histopathology,immunohistochemistry,and transmission electron microscopy were examined at 0 hour,12 hours,24 hours,4 days,7 days,14 days,and 28 days after ablation.(2)Thirty-five female New Zealand white rabbits were inoculated against VX2 breast cancer cells.The rabbits were randomly divided into two groups: a tumor control group of 15 rabbits and an IRE treatment group of 20 rabbits.Treatment and treatment outcome were evaluated by computerized tomography(CT)scan(plain or contrast enhanced),tumor growth curves and pathological examination including H&E,TUNEL,PCNA and CD31 staining.(3)The changes of sIL-2R and TGF-?1 levels in normal control group,tumor control group and IRE treatment group were analyzed with the peripheral blood before IRE,as well as at 7,14 and 21 days after IRE.Results:(1)All the rabbits survived during the procedure with no significant adverse effects.Intra-operative ventricular arrhythmias occurred in 1 rabbit from IRE group B and wasimmediately relieved after ablation.Reversible subcutaneous hemorrhage was observed in 8rabbits from IRE group A and 7 rabbits from IRE group B.No skin was burnt,however,pectoralis major muscle injuries were found in all rabbits.Histopathological and ultrastructural examination revealed the coexistence of cell necrosis and apoptosis.HE,TUNEL,and Masson staining revealed breast tissue injury and the recovery of damage by fibrous tissue and granulation tissue.Notably,the structures of mammary gland lobules and interstitial components of the breasts were well preserved.(2)All rabbits in the IRE treatment group experienced successful IRE without obvious complications except for thoracic major muscle injury.A focused,complete and well-defined ablation zone where tumor cells have been thoroughly eradicated was detected by H&E staining,along with increasing TUNEL staining.The expression of PCNA and CD31 was down-regulated at the periphery of the ablation region.As of the last follow-up,10 rabbits(67%)in IRE group demonstrated disease is under control;2 rabbits(13%)are in stable condition;3 rabbits(20%)suffered from disease progression;the remaining 5 rabbits were sacrificed for pathological examination halfway through the study.(3)The sIL-2R level of the peripheral blood in the IRE treatment group decreased with time and was significantly different from that in the tumor-control group(4.33±0.51ng/ml vs.12.43±1.19ng/ml,P<0.01).Moreover,ablation with IRE significantly decreased the plasma level of TGF-?1(74.17±5.30pg/ml vs.127.0±9.22pg/ml,P<0.01).Conclusions:(1)IRE destroys breast cancer while effectively preserving the skin,the structure of mammary gland lobules,and interstitial components.IRE may be a promising technique to locally control breast cancer and to maintain the esthetic of the breast.(2)The efficacy of IRE was demonstrated by the creation of a complete ablation region,with increasing apoptosis in the ablation zone and decreasing proliferation and microvessel density of tumor tissue at the periphery.IRE is a promising local treatment for breast cancer.(3)IRE enhanced the anti-tumor immune response by reducing the plasma levels ofsIL-2R and TGF-?1 in the tumor bearing rabbits. |
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