Journal of Hainan Medical University.

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1 132 Journl of Hinn Medicl University 2017; 23(11): Journl of Hinn Medicl University Assessment of the efficcy nd sfety of bronchil rtery perfusion chemotherpy combined with high-frequency hyperthermi for dvnced non-smll cell lung cncer Ji-Cheng Zhng, Wei Lu Deprtment of Interventionl Medicine, Nvy Generl Hospitl, Beijing, ARTICLE INFO Article history: Received 18 My 2017 Received in revised form 23 My 2017 Accepted 5 Jun 2017 Avilble online 14 Jun 2017 Keywords: Non-smll cell lung cncer Bronchil rtery perfusion chemotherpy High-frequency hyperthermi Prolifertion Invsion ABSTRACT Objective: To study the efficcy nd sfety of bronchil rtery perfusion chemotherpy combined with high-frequency hyperthermi for dvnced non-smll cell lung cncer. Methods: Ptients with dvnced non-smll cell lung cncer who were treted in Nvy Generl Hospitl between My 2014 nd October 2016 were selected nd rndomly divided into two groups, the observtion group received bronchil rteril infusion chemotherpy combined with high-frequency hyperthermi, nd the control group received bronchil rteril infusion chemotherpy. Before nd fter tretment, the expression of tumor ctivity indexes nd liver nd kidney function indexes in serum s well s nd prolifertion nd invsion genes in tumor lesions were detected respectively. Results: 5 d nd 7 d fter tretment, serum CEA, MIF, CYFRA21-1 nd HE4 levels of both groups of ptients were significntly lower thn those before tretment nd serum CEA, MIF, CYFRA21-1 nd HE4 levels of observtion group were significntly lower thn those of control group; 7 d fter tretment, MEF2D, c-myc, Survivin, Bcl-2, Vimentin, N-cdherin nd Slug expression in tumor lesions of both groups of ptients were significntly lower thn those before tretment nd MEF2D, c-myc, Survivin, Bcl-2, Vimentin, N-cdherin nd Slug expression in tumor lesions of observtion group were significntly lower thn those of control group; serum Scr, BUN, ALT nd AST levels were not significntly different between two groups of ptients before nd fter tretment. Conclusion: Bronchil rtery perfusion chemotherpy combined with high-frequency hyperthermi for dvnced non-smll cell lung cncer cn significntly inhibit the tumor prolifertion nd invsion nd is with idel sfety. 1. Introduction Non-smll cell lung cncer (NSCLC) is the most common pthologic type of lung cncer nd lso one of the most common mlignnt tumors in Chin. Chemordiotherpy is the min method for current tretment of non-smll cell lung cncer. Bronchil rtery perfusion chemotherpy is the mens for dvnced lung cncer chemotherpy developed in recent yers, which cn on the one hnd, mke chemotherpeutic drugs form high concentrtion Corresponding uthor: Wei Lu, Deprtment of Interventionl Medicine, Nvy Generl Hospitl, Beijing, Tel: Fund Project: Nturl Science Foundtion of Chin ( ); Chin Interntionl Medicl Foundtion (Z ); Nvy Logistics Deprtment (HJHQ ). within the locl lesion nd enhnce the killing effect of the drugs on cncer cells, nd on the other hnd, cn embolize supplying vessels of tumor nd cuse ischemic hypoxi injury to cncer cells[1,2]. The bronchil rtery perfusion chemotherpy is with idel security nd smll systemic toxic nd side effects, but some ptients my develop resistnce to chemotherpeutic drugs, which will ffect the curtive effect. High-frequency hyperthermi is newly developed locl therpy for dvnced mlignnt tumor, which kills cncer cells through therml effect, nd lso increses the sensitivity of cncer cells to chemotherpeutic drugs[3]. In the following study, bronchil rtery perfusion chemotherpy combined with high-frequency hyperthermi for dvnced non-smll cell lung cncer ws nlyzed from the spects of the efficcy nd sfety.

2 Reserch subjects nd reserch methods 2.1 Reserch subjects Ptients with dvnced non-smll cell lung cncer who were treted in Nvy Generl Hospitl between My 2014 nd October 2016 were selected s the reserch subjects, ll NSCLC ptients were dignosed with dvnced non-smll cell lung cncer by pthologicl biopsy, they were not in conformity with the indictions for surgicl resection nd never treted with chemordiotherpy or trgeted drug therpy, nd they were expected to survive longer thn 3 months. A totl of 98 cses were included nd divided into two groups by rndom number tble, 49 cses in ech group. The observtion group received bronchil rtery perfusion chemotherpy combined with high-frequency hyperthermi, including 33 mle cses nd 16 femle cses tht were yers old; the control group received bronchil rtery perfusion chemotherpy lone, including 35 mle cses nd 14 femle cses tht were yers old. There ws no significnt difference between the two groups of ptients (P>0.05). 2.2 Therpy 2.3 Serum index detection methods Before tretment s well s 5 nd 7 d fter tretment, 5 ml of cubitl venous blood ws collected from two groups of ptients nd centrifuged to get serum, then enzyme-linked immunosorbent ssy kits were used to determine the contents of CEA, MIF, CYFRA21-1 nd HE4, nd utomtic biochemicl nlyzer ws used to detect the contents of Scr, BUN, ALT nd AST. 2.4 Tumor prolifertion nd invsion gene expression detection methods The tumor lesions for pthologicl biopsy were collected before tretment, biopsy ws conducted gin 7 d fter tretment to get tumor lesions, the lesions were dded in protein lysis buffer to extrct the totl protein, nd the enzyme-linked immunosorbent ssy kits were used to determine the contents of MEF2D, c-myc, Survivin, Bcl-2, Vimentin, N-cdherin nd Slug. 2.5 Sttisticl methods SPSS 19.0 softwre ws used to nlyze dt serum indexes nd gene expression indexes, nlysis of bove indexes between two groups ws by T test nd P<0.05 indicted sttisticl significnce in differences. Both groups of ptients received bronchil rtery perfusion chemotherpy, nd the method ws s follows: Cobr ctheter ws imbedded fter femorl rtery puncture, bronchil rteriogrphy ws conducted, the rteriogrphy results nd tumor loction were referred to super select 2.4 F microtubule into the supplying rtery of tumor, 75 mg/m 2 of cispltin nd mg/m 2 of gemcitbine were injected, nd then the geltin sponge ws filled into the supplying rtery of tumor in order to chieve the embolism effect. Observtion group received high-frequency hyperthermi 3, 5 nd 7 d fter bronchil rtery perfusion chemotherpy respectively, s follows: HG-2000Ⅲ high-frequency het therpy instrument ws used for deep hyperthermi of lung cncer lesions, temperture ws set to 41-42, nd the time ws set to 60 min. 3. Results 3.1 Serum tumor ctivity mrker levels before nd fter tretment serum tumor ctivity mrkers CEA (ng/ml), MIF (μg/ml), CA125 (U/mL), Cyfr21-1 (ng/ml) nd HE4 (pg/ml) ws s follows: differences in serum CEA, MIF, CYFRA21-1 nd HE4 levels were significnt within group before nd fter tretment (P<0.05); serum CEA, MIF, CYFRA21-1 nd HE4 levels were not significntly different between two groups of ptients before tretment (P>0.05), nd serum CEA, MIF, CYFRA21-1 nd HE4 levels were significntly different between two groups of ptients fter tretment (P<0.05). Tble 1. Serum tumor ctivity mrker levels in two groups of ptients. Groups n Time point CEA MIF CYFRA21-1 HE4 Before tretment 30.25± ± ± ±33.56 Observtion group 49 5 d fter tretment 13.21±1.93 b 0.68±0.09 b 10.24±1.68 b ±22.16 b 7 d fter tretment 8.58±1.14 b 0.42±0.06 b 6.78±0.93 b ±19.25 b Before tretment 31.18± ± ± ± d fter tretment 18.95± ± ± ± d fter tretment 12.03± ± ± ±26.83 : comprison within group before tretment nd fter tretment, P<0.05; b : comprison between observtion group nd control group fter tretment, P<

3 Prolifertion gene expression in tumor lesions before nd fter tretment Before tretment s well s 7 d fter tretment, nlysis of prolifertion genes MEF2D, c-myc, Survivin nd Bcl-2 expression in tumor lesions ws s follows: differences in MEF2D, c-myc, Survivin nd Bcl-2 expression in tumor lesions were significnt within group before nd fter tretment (P<0.05); MEF2D, c-myc, Survivin nd Bcl-2 expression in tumor lesions were not significntly different between two groups of ptients before tretment (P>0.05), nd MEF2D, c-myc, Survivin nd Bcl-2 expression in tumor lesions were significntly different between two groups of ptients fter tretment (P<0.05). 3.4 Serum liver nd kidney function index levels before nd fter tretment serum liver nd kidney function indexes Scr (μmol/l), BUN (mmol/ L), ALT (U/L) nd AST (U/L) ws s follows: differences in serum Scr, BUN, ALT nd AST levels were not significnt within group before nd fter tretment (P>0.05); serum Scr, BUN, ALT nd AST levels were not significntly different between two groups of ptients before tretment (P>0.05), nd serum Scr, BUN, ALT nd AST levels were not significntly different between two groups of ptients fter tretment (P>0.05). 3.3 Invsion gene expression in tumor lesions before nd fter tretment invsion genes Vimentin, N-cdherin nd Slug expression in tumor lesions ws s follows: differences in Vimentin, N-cdherin nd Slug expression in tumor lesions were significnt within group before nd fter tretment (P<0.05); Vimentin, N-cdherin nd Slug expression in tumor lesions were not significntly different between two groups of ptients before tretment (P>0.05), nd Vimentin, N-cdherin nd Slug expression in tumor lesions were significntly different between two groups of ptients fter tretment (P<0.05). 4. Discussion Bronchil rtery perfusion chemotherpy is common therpy for dvnced lung cncer, but some ptients will develop resistnce to chemotherpeutic drugs. High-frequency hyperthermi cn cuse tumor lesion temperture increse, protein denturtion nd cell poptosis through het effect, which not only hs killing effect on cncer cells, but cn lso increse the cncer cell sensitivity to chemotherpeutic drugs[4]. In order to define the vlue of bronchil rtery perfusion chemotherpy combined with high-frequency Tble 2. Prolifertion gene expression in tumor lesions of two groups of ptients (ng/ml). Groups n Time points MEF2D C-myc Survivin Bcl-2 Before tretment 6.92± ± ± ±1.17 Observtion group 49 7 d fter tretment 2.77±0.35 b 0.92±0.11 b 3.68±0.51 b 2.69±0.36 b Before tretment 6.98± ± ± ± d fter tretment 4.02± ± ± ±0.68 : comprison within group before tretment nd fter tretment, P<0.05; b : comprison between observtion group nd control group fter tretment, P< Tble 3. Invsion gene expression in tumor lesions of two groups of ptients (ng/ml). Groups n Time points Vimentin N-cdherin Slug Before tretment 8.39± ± ±0.22 Observtion group 49 7 d fter tretment 2.57±0.36 b 1.02±0.16 b 0.48±0.07 b Before tretment 8.68± ± ± d fter tretment 4.72± ± ±0.11 : comprison within group before tretment nd fter tretment, P<0.05; b : comprison between observtion group nd control group fter tretment, P< Tble 4. Serum liver nd kidney function index levels in two groups of ptients. Groups n Time point Scr BUN ALT AST Before tretment 93.51± ± ± ±3.85 Observtion group 49 5 d fter tretment 96.21± ± ± ± d fter tretment 93.21± ± ± ±3.22 Before tretment 94.52± ± ± ± d fter tretment 95.46± ± ± ± d fter tretment 92.39± ± ± ±4.10

4 135 hyperthermi for dvnced non-smll cell lung cncer, serum mrkers tht reflected the tumor growth ctivity were nlyzed t first in the study before nd fter tretment. CEA is nonspecific mrker closely ssocited with the growth ctivity of vriety of mlignnt tumors[5]; MIF belongs to trnsforming growth fctor superfmily, nd the MIF secretion increses significntly in cncer cells[6]; CYFRA21-1 is the product fter kertin 19 sheds into cells, nd the CYFRA21-1 genertion increses significntly in cncer cells[7]; HE4 is type of protein tht is expressed significntly during the mlignnt trnsformtion of squmous epithelil cells in respirtory trct[8]. Comprison of the tumor ctivity mrker levels between the two groups in the study showed tht serum CEA, MIF, CYFRA21-1 nd HE4 levels of both groups of ptients significntly decresed fter tretment nd serum CEA, MIF, CYFRA21-1 nd HE4 levels of observtion group fter tretment were significntly lower thn those of control group. It mens tht both bronchil rtery perfusion chemotherpy monotherpy nd its combintion with highfrequency hyperthermi cn effectively reduce the tumor growth ctivity, nd bronchil rtery perfusion chemotherpy combined with high-frequency hyperthermi cn more effectively inhibit tumor growth ctivity. Bronchil rtery perfusion chemotherpy cn mke chemotherpeutic drugs form high concentrtion within the lesions, which not only enhnces the killing effect of chemotherpeutic drugs on cncer cells, but lso reduces the chemotherpeutic drug dmge to trget orgns of the whole body. High-frequency het belongs to locl tretment, it uses two groups of microwves with different frequency to mke ions rub ginst ech other in the locl tissue to generte het, nd the het ccumultion cn cuse the temperture in locl tissue rise to destroy the cellulr structure, ffect protein properties, nd finlly cuse poptosis[9,10]. High-frequency hyperthermi cn lso increse the sensitivity of cncer cells to chemotherpeutic drugs, but the effect is limited to locl tumor, nd won't cuse het ccumultion nd dmge in other orgns of the body. In order to define the sfety of bronchil rtery perfusion chemotherpy combined with high-frequency hyperthermi for dvnced non-smll cell lung cncer, liver nd kidney injury before nd fter chemotherpy were nlyzed in the study, nd the results showed tht serum Scr, BUN, ALT nd AST levels were not significntly different between two groups of ptients before nd fter chemotherpy. It mens tht neither bronchil rtery perfusion chemotherpy monotherpy nor its combintion with high-frequency hyperthermi will cuse liver nd kidney injury, nd the sfety for dvnced non-smll cell lung cncer tretment is idel. In the development of dvnced non-smll cell lung cncer, the prolifertion nd invsion of cncer cells re two crucil biologicl behviors. MEF2D, c-myc, Survivin nd Bcl-2 re four genes closely ssocited with the prolifertion of lung cncer cells. The proteins encoded by MEF2D belong to the MEF2 fmily, which cn promote ngiogenesis in tumor lesions nd crete fvorble locl environment for cell prolifertion; the products encoded by c-myc cn prticipte in the positive regultion of the cell cycle nd promote cell prolifertion[11]; Survivin nd Bcl-2 re with ntipoptotic effect, the former cn ntgonize the poptosis cscde mplifiction medited poptosis by vriety of molecules in cspse fmily[12-14], nd the ltter cn inhibit the mitochondril poptosis medited by cytochrome C. Epithelil-mesenchyml trnsition is the process closely ssocited with lung cncer cell invsion, nd the trnsition from epithelil cells to mesenchyml cells cn cuse the reduced intercellulr dhesion nd the enhnced cell movement bility to djcent tissue[15,16]. Slug is the key trnscription fctor to djust epithelil-mesenchyml trnsition process, which inhibits epithelil phenotype mrker E-cdherin expression to mke cells obtin mesenchyml phenotype, nd highly express N-cdherin, Vimentin nd other mesenchyml cell mrkers[17,18]. In the study, nlysis of the prolifertion nd tumor gene expression in tumor lesions before nd fter tretment showed tht MEF2D, c-myc, Survivin, Bcl-2, Vimentin, N-cdherin nd Slug expression in tumor lesions of both groups of ptients significntly decresed fter tretment, nd MEF2D, c-myc, Survivin, Bcl-2, Vimentin, N-cdherin nd Slug expression in tumor lesions of observtion group fter tretment were significntly lower thn those of control group. It mens tht both bronchil rtery perfusion chemotherpy monotherpy nd its combintion with high-frequency hyperthermi cn effectively restrin cncer cell prolifertion nd invsion, nd bronchil rtery perfusion chemotherpy combined with high-frequency hyperthermi hs more significnt inhibiting effect on cncer cell prolifertion nd invsion thn bronchil rtery perfusion chemotherpy lone. Bsed on bove discussion bout serum indexes nd gene expression indexes before nd fter tretment, it is believed tht bronchil rtery perfusion chemotherpy combined with highfrequency hyperthermi for dvnced non-smll cell lung cncer hs good efficcy nd sfety, nd cn significntly inhibit the tumor prolifertion nd invsion without cusing liver nd kidney injury. References [1] Fu YF, Li Y, Wei N, Xu H. Trnsctheter rteril chemicl infusion for dvnced non-smll-cell lung cncer: long-term outcome nd predictor of survivl. Rdiol Med 2016; 121(7): [2] Syh R, Benz T, Hetzel J, Spengler W, Kohlhufl MJ, Gtidis S, et l. Bronchil rtery emboliztion in hemoptysis: 10-yer survivl nd recurrence-free survivl in benign nd mlignnt etiologies - retrospective study. Rofo 2016; 188(11):

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