Liver-directed therapies for liver metastases from neuroendocrine neoplasms:Can laser ablation play any role?

Aggressive cytoreduction can prolong survival in patients with unresectable liver metastases(LM)from neuroendocrine neoplasms(NEN),and minimally invasive,liver-directed therapies are gaining increasing interest.Catheter-based treatments are used in disseminated disease,whereas ablation techniques are usually indicated when the number of LM is limited.Although radiofrequency ablation(RFA)is by far the most used ablative technique,the goal of this opinion review is to explore the potential role of laser ablation(LA)in the treatment of LM from NEN.LA uses thinner needles than RFA,and this is an advantage when the tumors are in at-risk locations.Moreover,the multi-fiber technique enables the use of one to four laser fibers at once,and each fiber provides an almost spherical thermal lesion of 12-15 mm in diameter.Such a characteristic enables to tailor the size of each thermal lesion to the size of each tumor,sparing the liver parenchyma more than any other liver-directed therapy,and allowing for repeated treatments with low risk of liver failure.A recent retrospective study reporting the largest series of LM treated with LA documents both safety and effectiveness of LA,that can play a useful role in the multimodality approach to LM from NEN.

Hepatectomy vs radiofrequency ablation for colorectal liver metastasis:A propensity score analysis

AIM:To compare outcomes from radiofrequency ablation(RFA) and hepatectomy for treatment of colorectal liver metastasis(CRLM).METHODS:From January 2000 to December 2009,408 patients underwent curative intent treatment for CRLM.We excluded patients using the criteria:size of CRLM > 3 cm,number of CRLM ≥ 5,percutaneous RFA,follow-up period < 12 mo,double primary cancer,or treatment with both RFA and hepatectomy.We matched 51 patients who underwent RFA with 102 patients who underwent hepatectomy by propensity scores.RESULTS:The median follow-up period was 45 mo(range,12 mo to 158 mo).Hepatic recurrence was more frequent in the RFA than the hepatectomy group(P = 0.021) although extrahepatic recurrence curves were similar(P = 0.716).Survival curves of hepatectomy group were better than that of RFA for multiple,large(> 2 cm) CRLM(P = 0.034).However,survival curves were similar for single or small(≤ 2 cm) CRLM(P = 0.714,P = 0.740).CONCLUSION:Hepatectomy is better than RFA for the treatment of CRLM.However,RFA might be suitable for selected patients with single,small(≤ 2 cm) CRLM.

CT assessment of liver hemodynamics in patients with hepatocellular carcinoma after argon-helium cryoablation

BACKGROUND:Assessment of tumor response after argonhelium cryoablation is critical in guiding future therapy for unresectable hepatocellular carcinoma.This study aimed to evaluate liver hemodynamics in hepatocellular carcinoma after argon-helium cryoablation with computed tomography perfusion.METHODS:The control group comprised 40 volunteers without liver disease.The experimental group was composed of 15 patients with hepatocellular carcinoma treated with argon-helium cryoablation.Computed tomography perfusion parameters were measured:hepatic blood flow,hepatic blood volume,mean transit time,permeability of capillary vessel surface,hepatic arterial fraction,hepatic arterial perfusion,and hepatic portal perfusion.RESULTS:After treatment,in the tumor foci,permeability of capillary vessel surface was higher,and hepatic blood flow,hepatic blood volume,hepatic arterial fraction,and hepatic arterial perfusion values were lower(P【0.05).In the liver parenchyma surrounding the tumor,hepatic arterial perfusion was significantly lower(P【0.05);however,there was no significant difference in hepatic blood flow,hepatic blood volume,mean transit time,permeability of capillary vessel surface,hepatic arterial fraction,or hepatic portal perfusion(P】0.05).CONCLUSION:Computed tomography perfusion can evaluate tumor response after argon-helium cryoablation.

Percutaneous ultrasound-guided thermal ablation for liver tumor with artificial pleural effusion or ascites

Background and Objective:Percutaneous ultrasound-guided thermal ablation is one of the major treatment methods for liver cancer.Tumor location close to the diaphragm or gastrointestinal tract was regarded as the treatment contraindication before due to poor visibility of the tumor or increased risk of thermal injury to the adjacent organs.This study used artificial pleural effusion or ascites to extend the indications of thermal ablation for liver cancer.Methods:Artificial pleural effusion (20 cases) or ascites (36 cases) was performed in 56 difficult cases of percutaneous thermal ablation for liver tumors.The technical success rates, the rate of approaching the procedure goal, complications, and local treatment response were assessed.Results:The technical success rates were 95%(19/20) for artificial pleural effusion and 100% (36/36) for artificial ascites, the achieve purpose rates were 100%(19/19) and 91.7% (33/36), the complete ablation rates were 84.2% (16/19) and 93.9% (31/33), respectively.Coughing, transient hematuria, and subcutaneous effusion were observed in 3 patients after the procedure of artificial pleural effusion, and hydrothorax in the right chest occurred in 1 patient during the artificial ascites process.Conclusions:Thermal ablation with the use of artificial pleural effusion or ascites is a safe and effective treatment for liver tumors, and the technique can widen the indications of thermal ablation for liver tumors.

Needle track seeding:A real hazard after percutaneous radiofrequency ablation for colorectal liver metastasis

Neoplastic needle track seeding following percutaneous radiofrequency ablation(RFA)of secondary liver tumors is exceedingly rare.Reports on cutaneous tumor seeding after percutaneous RFA for colorectal liver metastasis are even rarer in the literature.Here we report a case of a 46-year-old female who developed an ulcerating skin lesion along the needle track of a previous percutaneous RFA site around 6 mo after the procedure.The previous RFA was performed by the LeVeen needle for a secondary liver tumor from a primary rectal cancer.The diagnosis of secondary skin metastasis was confirmed by fine needle aspiration cytology.The lesion was successfully treated with wide local excision.We believe that tumor seeding after percutaneous RFA in our patient was possibly related to its unfavorable subcapsular location and the use of an expansion-type needle.Hence,prophylactic ablation of the needle track should be performed whenever possible.Otherwise,alternative routes of tumor ablation such as laparoscopic or open RFA should be considered.

Laser ablation of liver tumors:An ancillary technique,or an alternative to radiofrequency and microwave?

Radiofrequency ablation(RFA) is currently the most popular and used ablation modality for the treatment ofnon surgical patients with primary and secondary liver tumors, but in the last years microwave ablation(MWA) is being technically improved and widely rediscovered for clinical use. Laser thermal ablation(LTA) is by far less investigated and used than RFA and MWA, but the available data on its effectiveness and safety are quite good and comparable to those of RFA and MWA. All the three hyperthermia-based ablative techniques, when performed by skilled operators, can successfully treat all liver tumors eligible for thermal ablation, and to date in most centers of interventional oncology or interventional radiology the choice of the technique usually depends on the physician's preference and experience, or technical availability. However, RFA, MWA, and LTA have peculiar advantages and limitations that can make each of them more suitable than the other ones to treat patients and tumors with different characteristics. When all the three thermal ablation techniques are available, the choice among RFA, MWA, and LTA should be guided by their advantages and disadvantages, number, size, and location of the liver nodules, and cost-saving considerations, in order to give patients the best treatment option.

Practice guidelines for ultrasound-guided percutaneous microwave ablation for hepatic malignancy

Primary liver cancer and liver metastases are among the most frequent malignancies worldwide,with an increasing number of new cases and deaths every year.Traditional surgery is only suitable for a limited proportion of patients and imaging-guided percutaneous thermal ablation has achieved optimistic results for management of hepatic malignancy.This synopsis outlines the first clinical practice guidelines for ultrasoundguided percutaneous microwave ablation therapy for hepatic malignancy,which was created by a joint task force of the Society of Chinese Interventional Ultrasound.The guidelines aim at standardizing the microwave ablation procedure and therapeutic efficacy assessment,as well as proposing the criteria for the treatment candidates.

Treatment efficacy of radiof requency ablation of 338 patients with hepatic malignant tumor and the relevant complications

AIM: To investigate the treatment efficacy of radiofrequency ablation (RFA) of hepatic malignant tumor and the relevant complications.METHODS: A total of 338 patients with 763 hepatic tumors underwent ultrasound-guided RFA (565 procedures).There were 204 cases of hepatic cellular carcinoma (HCC)with 430 tumors, the mean largest diameter was 4.0 cm.Of them, 48 patients (23.5％) were in stages Ⅰ-Ⅱ (UICC Systems) and 156 (76.5％) in stages Ⅲ-Ⅳ There were 134 cases of metastatic liver carcinoma (MLC), with 333metastases in the liver, the mean diameter was 4.1 cm,the liver metastases of 96 patients (71.6％) came from gastrointestinal tract. Ninety-three percent of the 338patients were treated using the relatively standard protocol. Crucial attention must be paid to monitor the abnormal changes in ultrasound images as well as the vital signs of the patients to find the possible hemorrhage and peripheral structures injury in time. The tumors were considered as ablated completely, if no viability was found on enhanced CT within 24 h or at 1 mo after RFA. These patients were followed up for 3-57 mo.RESULTS: The ablation success rate was 93.3％ (401/430tumors) for HCC and was 96.7％ (322/333 tumors) for MLC. The local recurrence rate for HCC and MLC was 7.9％ (34/430 tumors) and 10.5％ (35/333 tumors),respectively. A total of 137 patients (40.5％) underwent 2-11times of repeated ablations because of tumor recurrence or metastasis. The 1st, 2nd, and 3rd year survival rate was84.6％, 66.6％, and 63.1％, respectively;the survival rate from 48 patients of Ⅰ-Ⅱ stage HCC was 93.7％, 80.4％,and 80.4％, respectively. The major complication rate in this study was 2.5％ (14 of 565 procedures), which consisted of 5 hemorrhages, 1 colon perforation, 5 injuries of adjacent structures, 2 bile leakages, and 1 skin burn.CONCLUSION: RFA, as a minimally invasive local treatment,has become an effective and relatively safe alternative for the patients of hepatic malignant tumor, even of advanced liver tumor, tumor recurrence, and liver metastases. Knowledge about possible complications and their control may increase the treatment efficacy and help to promote the use of RFA technique.

Rapid progression of hepatocellular carcinoma after Radiofrequency Ablation

To report the results of radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC)in cirrhotic patients and to describe the treatment related complications (mainly the rapid intrahepatic neoplastic progression).

Long-term outcomes of hepatectomy vs percutaneous ablation for treatment of hepatocellular carcinoma≤4 cm

AIM:To determine which treatment modality-hepatectomy or percutaneous ablation-is more beneficialfor patients with small hepatocellular carcinoma(HCC)(≤4 cm)in terms of long-term outcomes.METHODS:A retrospective analysis of 149 patientswith HCC≤4 cm was conducted.Eighty-five patientsunderwent partial hepatectomy(anatomic in 47 and non-anatomic in 38)and 64 underwent percutaneous ablation(percutaneous ethanol injection in 37,radiofrequencyablation in 21,and microwave coagulation in 6).Themedian follow-up period was 69 mo.RESULTS:Hepatectomy was associated with largertumor size(P<0.001),whereas percutaneous ablationwas significantly associated with impaired hepaticfunctional reserve.Local recurrence was less frequentfollowing hepatectomy(P<0.0001).Survival wasbetter following hepatectomy(median survival time:122 mo)than following percutaneous ablation(mediansurvival time:66 mo;P=0.0123).When tumor size wasdivided into≤2 cm vs>2 cm,the favorable effectsof hepatectomy on long-term survival was seen onlyin patients with tumors>2 cm(P=0.0001).The Coxproportional hazards regression model revealed thathepatectomy(P=0.006)and tumors≤2 cm(P=0.017)were independently associated with better survival.CONCLUSION:Hepatectomy provides both better localcontrol and better long-term survival for patients withHCC≤4 cm compared with percutaneous ablation.Ofthe patients with HCC≤4 cm,those with tumors>2 cm are good candidates for hepatectomy,provided thatthe hepatic functional reserve of the patient permitsresection.

气管内超声引导纵隔肿瘤激光多点消融操作流程

由于纵隔解剖位置复杂,重要脏器较多,纵隔肿瘤的治疗一直是临床难点。相比传统局部治疗,气道内超声引导纵隔肿瘤激光多点消融具有较多优势,包括消融范围及效果可实时监控、避免损伤正常组织、不良反应少、耐受性好等。该文阐述了气管内超声引导纵隔肿瘤激光多点消融的操作流程。

比较TACE+微波消融+程序性死亡受体-1与TACE+微波消融治疗原发性肝癌

目的比较TACE+微波消融(MWA)+程序性死亡受体-1(PD-1)与TACE+MWA治疗原发性肝癌(PHC)的价值。方法回顾性纳入接受TACE+MWA+PD-1(观察组)或TACE+MWA治疗(对照组)的PHC患者各40例,比较组间基线资料、疗效和并发症。结果2组患者基线资料差异均无统计学意义(P均>0.05)。观察组与对照组客观缓解率(ORR)分别为90.00%和72.50%,疾病控制率(DCR)分别为97.50%和95.00%;组间差异均无统计学意义(P均>0.05)。观察组与对照组中位总生存期(OS)分别为30.80个月和15.70个月,中位无进展生存期(PFS)分别为23.35个月和6.80个月;观察组OS和PFS均长于对照组(P均<0.05)。组间并发症发生率差异均无统计学意义(P均>0.05),且均经相关对症治疗后好转。结论TACE+MWA+PD-1联合治疗PHC效果优于TACE+MWA。

介电特性测量技术在肝癌诊断与治疗中的研究进展

介电特性是生物组织在电磁场作用下表现出的固有物理属性。细胞癌变引起细胞膜的组成和通透性的改变,导致肿瘤组织表现出较高的介电特性。由于常规肝脏筛查指标的敏感性和特异度不高,因此可以利用生物组织介电特性作为一种新的生物标志物用于肝癌快速准确鉴别。本文首先介绍了组织介电特性测量常用方法,在此基础上总结了介电特性测量在肝癌诊断和射频消融中的研究进展,最后对介电特性测量技术的未来发展及其临床实践的改进方向进行了展望。

不可逆电穿孔和射频消融治疗原发性肝癌效果比较

目的评价不可逆电穿孔技术治疗原发性肝癌的初步效果。方法2019年1月—2021年10月,采用前瞻性研究方法选择在河北中石油中心医院诊治的原发性肝癌病人102例为研究对象,按照随机数字表法分为2组,每组51例。观察组采用不可逆电穿孔技术治疗,对照组采用射频消融技术治疗。评估两组临床效果、术后并发症、6和12个月的生存率和复发率,以及甲胎蛋白(AFP)的转阴率。比较两组总胆红素(TBiL)、清蛋白(Alb)、丙氨酸氨基转移酶(ALT)、血清糖类抗原125(CA125)、癌胚抗原(CEA)和AFP等生化指标。结果观察组总体临床效果、6和12个月生存率、AFP转阴率均高于对照组(χ^(2)=7.933、8.254,Log-rankχ^(2)=8.254、8.541,P<0.05),术后并发症发生率、6和12个月复发率低于对照组(χ^(2)=4.317,Log-rankχ^(2)=6.331、7.256,P<0.05)。治疗后,观察组ALT、Alb、TBil、AFP、CEA和CA125等指标均低于对照组(t=8.660~40.741,P<0.05)。结论不可逆电穿孔技术治疗原发性肝癌的效果显著,对病人肝功能影响较小,能够有效降低病人血清ALT、Alb和TBil等指标的水平。

超声引导下微波消融联合小剂量阿帕替尼治疗肝癌的疗效

目的:评价超声引导下微波消融联合小剂量阿帕替尼治疗中晚期肝癌患者的疗效,探讨其应用价值。方法:将46例中晚期原发性肝癌患者分为微波消融组和联合组(微波消融联合阿帕替尼),每组各23例,观察并记录所有患者治疗前及治疗后3个月、6个月、9个月、12个月的甲胎蛋白(AFP)水平、超声造影测量的病灶大小及病灶内血流灌注情况,并对所有患者治疗随访期内的疗效进行评价。结果:消融组和联合组患者的AFP在治疗后3个月及6个月均明显降低,与治疗前比较差异有统计学意义(P<0.05),两组之间比较差异无统计学意义(P>0.05);治疗后9个月与12个月,联合组的AFP明显低于消融组,差异有统计学意义(P<0.05)。治疗后3个月及6个月,两组患者的客观缓解率(ORR)差异无统计学意义(P>0.05),6个月时联合组的疾病控制率(DCR)优于消融组,差异有统计学意义(P<0.05);治疗后9个月与12个月,联合组的ORR、DCR均明显优于消融组,差异有统计学意义(P<0.05);联合组的疾病无进展生存期(PFS)高于消融组,差异有统计学意义(Z=3.224,P<0.05)。两组之间不同时间段的肿瘤大小差异无统计学意义(P>0.05),两组患者瘤体造影增强范围术后不同时间段与治疗前相比差异有统计学意义(P<0.05);治疗前及治疗后3个月、6个月、9个月三个时间段,两组之间相同时间段瘤体造影增强范围差异无统计学意义(P>0.05),12个月时联合组的造影增强范围小于消融组,差异有统计学意义(F=4.99,P=0.31)。结论:超声引导下微波消融联合小剂量阿帕替尼治疗中晚期肝癌患者疗效明显,能有效控制中晚期肝癌的疾病进展,提高患者生存时间,具有重要的临床意义。

肝动脉化疗栓塞联合微波消融术治疗早中期肝癌疗效分析

目的:探讨早中期肝癌经肝动脉化疗栓塞(TACE)联合经皮微波消融术(MWA)序贯治疗的临床疗效。方法:回顾性分析行TACE(TACE组)及TACE序贯MWA(TACE+MWA组)治疗的病人共108例临床资料,2组病人1∶1进行倾向性匹配,最终各纳入26例。分析2组短期疗效及长期疗效,并按照肿瘤大小及肿瘤数量进行亚组分析。结果:TACE+MWA组和TACE组中位生存时间分别为28个月及13个月,1、2、3年生存率分别为84.6%、59.0%、35.2%及57.7%、30.3%、19.5%,TACE+MWA组生存率优于TACE组(P<0.01)。TACE+MWA组及TACE组的短期疗效客观有效率分别为61.5%、30.8%(P<0.05),疾病控制率分别为80.8%、46.2%,差异均有统计学意义(P<0.05)。TACE+MWA组在肿瘤大小<5 cm及病灶数量2~4枚时获益较TACE组更大(P<0.05)。结论:TACE序贯MWA治疗可有效提高早中期肝癌生存率,延长生存时间。

微波消融治疗原发性肝细胞癌后针道种植转移5例

目的观察微波消融(MWA)治疗原发性肝细胞癌(pHCC)后针道种植转移(NTTS)影像学表现。方法纳入1018例接受MWA治疗的pHCC患者,记录NTTS影像学表现,分析其影响因素。结果1018例中,5例(5/1018,0.49%)分别于MWA治疗后8~75个月发生NTTS,种植部位包括膈肌、胸腹壁、腹腔及大网膜;MRI于5例均见穿刺针道附近混杂信号,动脉期及静脉期呈持续性强化;超声造影(CEUS)显示种植灶于增强早期呈稍高增强、增强晚期呈低增强。MWA治疗过程中是否使用套管穿刺、多针穿刺,以及经肝左叶或肝右叶穿刺对NTTS均无显著影响(P均>0.05)。对种植灶予外科切除,术后病理结果均为HCC;随访中1例出现心膈角淋巴结转移,其余4例均无瘤生存。结论MWA治疗pHCC引发NTTS概率较低,其影像学表现为穿刺针道附近混杂MR信号于动脉期及静脉期增强扫描呈持续性强化,CEUS早期呈稍高增强、晚期呈低增强。

超声引导下经皮穿刺肝脏近心区行微波消融对兔心功能的影响

目的观察超声引导下经皮穿刺近心区肝脏行微波消融(MWA)对兔心功能的影响。方法将60只健康新西兰大白兔随机分为消融组和假手术组,每组30只。对消融组兔行穿刺及MWA,对假手术组兔仅行穿刺;完善心电图、心脏超声及实验室检查,观察不同时间点相关参数的组间差异。结果2组均顺利完成实验。假手术组穿刺前与穿刺即刻、穿刺前与穿刺后心脏超声指标差异均无统计学意义(P均>0.05);穿刺前、后心电图波形及超敏肌钙蛋白T(cTnT)均无明显变化,肌红蛋白(MYO)均为阴性。消融组消融过程中左心室射血分数(LVEF)及短轴缩短率(LVFS)均低于消融前(P均<0.05),消融过程中及其后心率(HR)均低于消融前(P均<0.05),消融后E峰减速时间(DT)高于消融前(P<0.05);消融后cTnT明显高于消融前(P<0.001);消融前MYO均阴性,消融后MYO为38.94(0,95.40)ng/ml;4只兔消融过程中及其后心电图出现变化。结论超声引导下经皮穿刺近心区肝脏行MWA可对兔心功能产生一过性影响。

Radiofrequency ablation combined with transarterial chemoembolization for unresectable primary liver cancer

Background Radiofrequency ablation （RFA） followed by transarterial chemoembolization （TACE） for unresectable primary liver cancer （PLC） has not been widely discussed. In this study, the outcome of the combination of RFA with TACE was retrospectively evaluated. Methods From May 2003 to March 2008, 127 consecutive PLC patients with a median age of 56.4＋8.8 years underwent RFA plus TACE. All patients were deemed to have unresectable PLC based on their tumor characteristics. The maximal diameter of the tumor was between 1.5 cm and 10.0 cm. Twenty-six cases with small （〈3.0 cm）, 33 with medium （3.1-5.0 cm）, and 68 with large （〉5.0 cm） tumors were included in this study. RFA was performed using a RITA Medical Systems expandable electrode device, which was followed by first-time TACE administration one to two months later. Results Technical success of RFA was achieved in all 127 patients with no severe treatment-related complications. RFA was performed percutaneously in 16 （13.5%） cases, by laparoscopic approach in 19 （15.7%）, and through laparotomy in the remaining 92 （72.4%）. RFA response was classified as complete ablation in 48 cases, nearly complete ablation in 28, and partial ablation in 51. The total 1-, 2-, and 3-year survival rates after RFA were 83.1%, 55.7%, and 43.7%, respectively. The survival rates at 3 years were 78.6%, 28.1%, and 0 for complete ablation, nearly complete ablation, or partial ablation groups, respectively. Three-year disease-free survival rates for the complete ablation and nearly complete ablation groups were 50.3% and 21.3%, respectively. RFA response and liver function were significant variables influencing survival time as analyzed using the Cox regression model. Conclusion RFA could be the first-line exterminate treatment for unresectable PLC, and TACE following RFA may assist in eradicatinq the peripheral viable tissue and micro-metastasis.

利伐沙班对心房颤动RFCA术后抗凝效果及肝肾功能影响

目的探究对心房颤动(以下简称房颤)患者经导管射频消融术(radiofrequency catheter ablation,RFCA)后应用不同剂量利伐沙班的抗凝效果及其对肝肾功能的影响。方法选取2020年6月至2022年6月湖州市中心医院收治的150例经RFCA治疗的房颤患者,采用随机数字表法分为低剂量组(n=75)和标准剂量组(n=75)。低剂量组给予15mg利伐沙班,标准剂量组给予国际推荐量20mg利伐沙班。比较两组的抗凝效果[国际标准化比值(international normalized ratio,INR)、纤维蛋白原(fibrinogen,FIB)、D二聚体(D-dimer,D-D)]、肾功能[血尿素氮(blood urea nitrogen,BUN)、血肌酐(creatinine,Scr)、血尿酸(uric acid,UA)]、肝功能[天冬氨酸转氨酶(aspartate aminotransferase,AST)、丙氨酸转氨酶(alanine aminotransferase,ALT)]、心功能[左心室舒张末期内径(left ventricular end diastolic diameter,LVEDD)、左心室收缩末期内径(left ventricular end systolic diameter,LVESD)、左心室射血分数(left ventricular ejection fraction,LVEF)]、血清炎性标志物[同型半胱氨酸(homocysteine,Hcy)、超敏C反应蛋白(high sensitivity C-reactive protein,hs-CRP)]及出血情况。结果与治疗前比较,治疗后两组INR均显著升高(P<0.05),但两组比较差异无统计学意义(P>0.05);血清Hcy、hs-CRP、FIB、D-D水平均显著降低(P<0.05),且与标准剂量组比较,低剂量组降低更显著(P<0.05)。两组治疗前后血清BUN、Scr、UA、AST、ALT水平及LVEDD、LVESD、LVEF比较,差异均无统计学意义(P>0.05)。低剂量组的出血发生率显著低于标准剂量组(P<0.05)。结论术后给予房颤患者RFCA低剂量利伐沙班,其抗凝效果不劣于标准剂量,低剂量利伐沙班有利于术后炎症反应的减轻,降低出血发生率,具有更安全、明显的临床效益。