The added value of systematic biopsy in men with suspicion of prostate cancer undergoing multiparametric MRI-targeted biopsy

Purpose

Incorporation of multiparametric magnetic resonance imaging (mpMRI) and targeted biopsy (TBx) in the diagnostic pathway for prostate cancer (CaP) is rapidly becoming common practice. In men with a prebiopsy positive mpMRI a TBx only approach, thereby omitting transrectal ultrasound-guided systematic biopsy (SBx), has been postulated. In this study we evaluated the additional clinical relevance of SBx in men with a positive prebiopsy mpMRI (Prostate Imaging Reporting and Data System [PI-RADS] ≥ 3) undergoing TBx for CaP detection, Gleason grading and CaP localization.

Fusion prostate biopsy outperforms 12-core systematic prostate biopsy in patients with prior negative systematic biopsy: A multi-institutional analysis

Introduction and objectives

Patients with persistently elevated prostate specific antigen (PSA) and prior negative 12-core TRUS prostate biopsy (or biopsies) (systematic biopsy—SBx) are a diagnostic challenge. Repeat SBx or saturation biopsy in this cohort has been shown to have an even lower yield. The aim of our study is to compare the prostate cancer yield of magnetic resonance imaging (MRI) fusion biopsy (FBx) to SBx in a multi-institutional cohort comprised of patients with prior negative biopsies.

前列腺特异性抗原持续异常患者前列腺重复穿刺活检的临床分析

目的 探讨PSA持续异常患者前列腺重复穿刺活检的诊断价值及适应证. 方法选取2004年1月至2011年9月首次穿刺活检诊断为前列腺良性病变但PSA持续异常的患者90例,其中BPH、正常前列腺组织及前列腺炎症患者组(BPH组)66例,前列腺上皮内瘤变(prostatic intraepithelial neoplasia,PIN)组10例,前列腺不典型小腺泡增生(atypical small acinar proliferation,ASAP)组14例.年龄43～86岁,平均71岁.PSA 3.1～168.0μg/L,平均17.6 μg/L.直肠指检(digital rectal examination,DRE)触及结节26例.采用模板定位经会阴重复穿刺活检. 结果 本组90例根据重复穿刺活检病理结果分为良性组57例,PIN或ASAP组5例,前列腺癌(prostate cancer,PCa)组28例.其中BPH组发现PCa为14例(21.2％),PIN组发现PCa为6例(60.0％),ASAP组发现PCa为8例(57.1％),BPH组与PIN组、ASAP组比较差异均有统计学意义(P＜0.05).BPH组重复穿刺活检诊断为良性组的平均前列腺体积为(65.9±22.6)ml,DRE阳性7例,PCa组为(50.4±20.8) ml,DRE阳性5例,两组间比较差异有统计学意义(P＜0.05).PIN组和ASAP组的患者重复穿刺活检结果显示年龄、PSA值、PSAD值、前列腺体积、DRE阳性例数在重复穿刺后诊断为良性组、PIN或ASAP组和PCa组间差异均无统计学意义(P＞0.05). 结论 对PSA持续异常患者行前列腺重复穿刺活检可以提高PCa的诊断率.首次穿刺诊断为BPH的患者,前列腺体积越小及DRE结果阳性者,若PSA持续升高,应强烈建议重复穿刺活检.首次穿刺诊断为PIN或ASAP的患者,不论年龄、PSA、PSAD、前列腺体积和DRE结果如何,均应建议重复穿刺活检.     

Prostate cancer management choices in patients undergoing multiparametric magnetic resonance imaging/ultrasound fusion biopsy compared to systematic biopsy

Objectives

To assess management choices in patients who undergo magnetic resonance imaging (MRI)/ultrasound (MRI/US) fusion-guided prostate biopsy compared to patients who undergo systematic biopsy.

Decision analysis model comparing cost of multiparametric magnetic resonance imaging vs. repeat biopsy for detection of prostate cancer in men with prior negative findings on biopsy

PurposeWe compared cost of multiparametric magnetic resonance imaging (MP-MRI) vs. repeat biopsy in detection of prostate cancer (PCa) in men with prior negative findings on biopsy.MethodsA decision tree model compared the strategy of office-based transrectal ultrasound–guided biopsy (TRUS) for men with prior negative findings on biopsy with a strategy of initial MP-MRI with TRUS performed only in cases of abnormal results on imaging. Study end points were cost, number of biopsies, and cancers detected. Cost was based on Medicare reimbursement. Cost of sepsis and minor complications were incorporated into analysis. Sensitivity analyses were performed by varying model assumptions.ResultsThe baseline model with 24% PCa found that the overall cost for 100 men was $90,400 and $87,700 for TRUS and MP-MRI arms, respectively. The MP-MRI arm resulted in 73 fewer biopsies per 100 men but detected 4 fewer cancers (16 vs. 20.4) than the TRUS arm did. A lower risk of PCa resulted in lower costs for the MP-MRI arm and a small difference in detected cancers. At lower cancer rates, MP-MRI is superior to TRUS over a wide range of sensitivity and specificity of MRI. A lower sensitivity of MP-MRI decreases the cost of the MP-MRI, as fewer biopsies are performed, but this also reduces the number of cancers detected.ConclusionsThe use of MP-MRI to select patients for repeat biopsy reduced the number of biopsies needed by 73% but resulted in a few cancers being missed at lower cost when compared with the TRUS arm. Further studies are required to determine whether cancers missed represent clinically significant tumors.     

Performance of multiparametric magnetic resonance imaging in the evaluation and management of clinically low-risk prostate cancer

ObjectiveThe purpose of this article is to review the multiparametric magnetic resonance imaging (mMRI) of the prostate and MR-guided prostate biopsy, and their role in the evaluation and management of men with low-risk prostate cancer.MethodsWe performed a literature review based on the MEDLINE database search for publications on the role of mMRI (a) in detection and localization of prostate cancer, prediction of tumor aggressiveness and progression and (b) in guiding targeted prostate biopsy.ResultsThe mMRI, particularly diffusion-weighted imaging with T2-weighted imaging, is a useful tool for tumor localization in low-risk prostate cancer as it can detect lesions that are more likely missed on extended biopsy schemes and can identify clinically significant disease requiring definitive treatment. The MR-guided biopsy of the most suspicious lesions enables more accurate and safer approach to guide enrollment into the active surveillance program. However, the MR-guided biopsy is complex. The fusion of MRI data with transrectal ultrasound for the purpose of biopsy provides a more feasible technique with documented accurate sampling.ConclusionAlthough the mMRI is not routinely used for risk stratification and prognostic assessment in prostate cancer, it can provide valuable information to guide management of men with low-risk disease. Incorporation of mMRI into the workup and monitoring of patients with low-risk prostate cancer can help discriminate clinically significant disease from indolent disease. Targeted biopsy of MR-suspicious lesions enables accurate sampling of potentially aggressive tumors that may affect outcomes.     

PI-RADS评分1~2分患者诊断前列腺癌的危险因素分析

目的探讨多参数MRI PI-RADS评分1~2分患者前列腺癌及有临床意义前列腺癌(CsPCa)的检出率,分析该类患者诊断前列腺癌的危险因素。方法回顾性分析2011年7月至2018年6月行多参数MRI检查并行经直肠12针前列腺系统穿刺的196例患者的临床资料。患者年龄(66.6±9.0)岁,中位前列腺特异性抗原(PSA)7.44(4.93,10.98)ng/ml,中位前列腺体积63(43,78)ml。196例PI-RADS评分1~2分;28例PSA<4 ng/ml,前列腺指检异常;168例PSA>4 ng/ml。前列腺癌如满足以下任一条:PSA密度>0.15 ng/ml²,Gleason评分>6分,≥3针阳性,肿瘤≥50%穿刺长度,则诊断为CsPCa。分析前列腺癌及CsPCa的危险因素,单因素分析采用χ2检验或Fisher’s确切概率法,多因素分析采用logistic回归。结果196例中42例(21.4%)病理证实为前列腺癌,其中30例(15.3%)为CsPCa。多参数MRI诊断前列腺癌的阴性预测值为78.6%(154/196),诊断CsPCa的阴性预测值为84.7%(166/196)。单因素分析结果显示,患者年龄、PSA密度越高,前列腺癌阳性率越高;年龄、PSA、PSA密度越高,f/tPSA越低,则CsPCa的比例越高,差异均有统计学意义(P<0.05)。多因素logistic回归分析结果显示,PSA密度>0.15 ng/ml²(OR=2.94,95%CI 1.45~5.95,P<0.05)是前列腺癌的独立危险因素;年龄>70岁(OR=2.49,95%CI 1.22~5.07)、f/tPSA<0.2(OR=3.70,95%CI 1.25~11.23)、PSA密度>0.15 ng/ml²(OR=5.77,95%CI 1.96~16.96)是CsPCa的独立危险因素(均P<0.05)。结论对于PSA升高或前列腺指检异常的PI-RADS评分1~2分患者,前列腺癌检出率为21.4%,PSA密度>0.15 ng/ml²是前列腺癌的独立危险因素;CsPCa检出率为15.3%,年龄>70岁、f/tPSA<0.2、PSA密度>0.15 ng/ml²是其独立危险因素。     

Randomized Study of Systematic Biopsy Versus Magnetic Resonance Imaging and Targeted and Systematic Biopsy in Men on Active Surveillance (ASIST): 2-year Postbiopsy Follow-up

BackgroundThe initial report from the ASIST trial showed little benefit from targeted biopsy for men on active surveillance (AS) for prostate cancer. Data after 2-yr follow-up are now available for analysis.ObjectiveTo determine if there was a difference in the AS failure rate in a 2-yr follow-up period among men undergoing magnetic resonance imaging (MRI) before initial confirmatory biopsy (CBx) compared to those who did not.Design, setting, and participantsThis is the 2-yr post-CBx follow-up for the ASIST trial, a prospective, randomized, multicenter, open-label study for men with Gleason grade group (GG) 1 cancer eligible for AS. Patients were randomized to CBx with 12-core systematic sampling or MRI with systematic and targeted sampling.Outcome measurements and statistical analysisPatients with GG ≤ 1 on CBx were followed for 2 yr and had MRI and biopsy at that time point. Patients failed AS if they were no longer under AS because of grade progression, clinical progression, subject choice, clinical judgment, treatment, or lost to follow-up. Clinically significant cancer (CSC) was defined as GG ≥ 2.Results and limitationsIn total, 259 men underwent CBx, 132 in the non-MRI and 127 in the MRI arm. After biopsy, 101 men in the non-MRI arm (76%) and 98 in the MRI arm (77%) continued AS. There were fewer men with AS failures in the MRI (19/98, 19%) compared to the non-MRI group (35/101, 35%; p = 0.017). At 2-yr biopsy there were fewer men with CSC in the MRI arm (9.9%, 8/81) than in the non-MRI arm (23%, 17/75; p = 0.048). Significant differences in AS failure rates were detected across the three centers in the MRI arm only (4.2% [2/48] vs 17% [4/24] vs 27% [7/26]; p = 0.019).ConclusionsBaseline MRI before CBx during AS results in 50% fewer AS failures and less grade progression over 2 yr. The center where MRI and targeted biopsy is performed may influence AS failure rates.Patient summaryThe ASIST trial randomized 273 men on active surveillance with low-grade prostate cancer diagnosed within the last year to systematic biopsy or magnetic resonance imaging (MRI) with systematic and targeted biopsy. The initial report showed little benefit from targeted biopsy. However, after 2 yr of follow-up we found that baseline MRI before confirmatory biopsy resulted in 50% fewer failures of surveillance and less progression to higher-grade cancer. This confirms the value of MRI in men on surveillance.This study is registered at ClinicalTrials.gov (NCT01354171).     

Physical after-effects in men undergoing prostate biopsy in routine clinical practice: Results from the PiCTure study

Background

As the incidence of prostate cancer has, until recently, increased in most developed countries, the rates of prostate biopsies, required for histological diagnosis, will also have increased. Little is known about the physical after-effects of prostate biopsy outside randomised control trials. We investigate reports on the physical effect of prostate biopsy undertaken in men in routine practice.

模板定位下经会阴前列腺穿刺活检在经直肠途径初次活检阴性患者检查中的应用

目的 探讨模板定位下经会阴前列腺穿刺活检术在对经直肠前列腺穿刺活检阴性患者检查中的有效性及安全性.方法 收集2010年1月至2012年1月经直肠前列腺穿刺活检阴性患者42例.年龄50 ～81岁,平均67岁.PSA 0.9 ～27.3 μg/L,平均13.1 μg/L.入组条件:曾行前列腺穿刺活检≥1次,结果为阴性或前列腺上皮内瘤(PIN)或非典型小细胞腺泡样增生(AAH),但术后tPSA仍＞10 μg/L和(或)PSA速率仍＞0.75 μg/L.取膀胱截石位,会阴部皮下及前列腺尖部包膜浸润麻醉下,行经直肠超声引导下模板定位经会阴前列腺穿刺活检术.分析模板定位下经会阴前列腺穿刺活检术的阳性率、影响因素及并发症.结果 本组行前列腺穿刺16 ～ 44针,平均18.7针.穿刺阳性率为44％ (19/42),Gleason评分4～9分,平均6分.穿刺阳性者前列腺体积27～67 ml,平均44 ml;阴性者37 ～104 ml,平均71 ml,两组比较差异有统计学意义(P＜0.05).穿刺阳性率与患者是否为PIN和AHH、前列腺穿刺针数、PSA值无相关性(P＞0.05).穿刺阳性者前列腺癌在移行区的发生率为74％(14/19),其中36％(5/14)只发生在移行区.穿刺后1周内血尿发生率为29％(12/42),尿潴留发生率为9％ (4/42),无严重感染等并发症发生.结论 模板定位下经会阴前列腺穿刺活检术诊断经直肠途径初次活检阴性患者安全、有效.     

Preoperative prostate biopsy and multiparametric magnetic resonance imaging: reliability in detecting prostate cancer

Purpose

The aim of the study was to analyse and compare the ability of multiparametric magnetic resonance imaging (mp–MRI) and prostate biopsy (PB) to correctly identify tumor foci in patients undergoing radical prostatectomy (RP) for prostate cancer (PCa).

Materials and Methods

157 patients with clinically localised PCa with a PSA <10 ng/mL and a negative DRE diagnosed on the first (12 samples, Group A) or second (18 samples, Group B) PB were enrolled at our institution. All patients underwent mp-MRI with T2-weighted images, diffusion-weighted imaging, dynamic contrast enhanced-MRI prior to RP. A map of comparison describing each positive biopsy sample was created for each patient, with each tumor focus shown on the MRI and each lesion present on the definitive histological examination in order to compare tumor detection and location. The sensitivity of mp-MRI and PB for diagnosis was compared using Student’s t-test. The ability of the two exams to detect the prevalence of Gleason pattern 4 in the identified lesions was compared using a chi-square test.

Results

Overall sensitivity of PB and mp-MRI to identify tumor lesion was 59.4% and 78.9%, respectively (p<0.0001). PB missed 144/355 lesions, 59 of which (16.6%) were significant. mp-MRI missed 75/355 lesions, 12 of which (3.4%) were significant. No lesions with a GS≥8 were missed. Sensitivity of PB and mp-MRI to detect the prevalence of Gleason pattern 4 was 88.2% and 97.4%, respectively.

Conclusions

mp-MRI seems to identify more tumor lesions than PB and to provide more information concerning tumor characteristics.     

Pretreatment multiparametric MRI is independently associated with biochemical outcome in men treated with radiation therapy for prostate cancer

Purpose

The purpose of this study was to investigate the utility of pre-treatment multiparametric magnetic resonance imaging (mpMRI) in a modern cohort of intermediate and high-risk prostate cancer patients treated with primary radiotherapy.

Comparing 3-T multiparametric MRI and the Partin tables to predict organ-confined prostate cancer after radical prostatectomy

ObjectivesThe purpose of our study was to test our hypothesis that multiparametric magnetic resonance imaging (mpMRI) may have a higher prognostic accuracy than the Partin tables in predicting organ-confined (OC) prostate cancer and extracapsular extension (ECE) after radical prostatectomy (RP).Methods and materialsAfter institutional review board approval, we retrospectively reviewed 60 patients who underwent 3-T mpMRI before RP. mpMRI was used to assess clinical stage and the updated version of the Partin tables was used to calculate the probability of each patient to harbor OC disease. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of mpMRI in detecting OC and ECE were calculated. Logistic regression models predicting OC pathology were created using either clinical stage at mpMRI or Partin tables probability. The area under the curve was used to calculate the predictive accuracy of each model.ResultsMedian prostate-specific antigen level at diagnosis was 5 ng/ml (range: 4.1–6.7 ng/ml). Overall, 52 (86.7%) men had cT1 disease, 7 (11.7%) had cT2a/b, and 1 (1.6%) had cT3b at digital rectal examination. Biopsy Gleason score was 6, 3+4 = 7, 4+3 = 7, 8, and 9 to 10 in 28 (46.7%), 15 (25%), 3 (5%), 10 (16.7%), and 4 (6.6%) patients, respectively. At mpMRI, clinical stage was defined as cT2a/b, cT2c, cT3a, and cT3b in 11 (18.3%), 23 (38.3%), 21 (35%), and 5 (8.4%) patients, respectively. At final pathology, 38 men (63.3%) had OC disease, whereas 18 (30%) had ECE and 4 (6.7%) had seminal vesicle invasion.The sensitivity, specificity, PPV, and NPV of mpMRI in detecting OC disease were 81.6%, 86.4%, 91.2%, and 73.1%, respectively, whereas in detecting ECE were 77.8%, 83.4%, 66.7%, and 89.7%, respectively. At logistic regression, both the Partin tables–derived probability and the mpMRI clinical staging were significantly associated with OC disease (all P<0.01). The area under the curves of the model built using the Partin tables and that of the mpMRI model were 0.62 and 0.82, respectively (P = 0.04).ConclusionsThe predictive accuracy of mpMRI in predicting OC disease on pathological analysis is significantly greater than that of the Partin tables. mpMRI had a high PPV (91.2%) when predicting OC disease and a high NPV (89.7%) with regard to ECE. mpMRI should be considered when planning prostate cancer treatment in addition to readily available clinical parameters.     

A comparison of prostate cancer detection rates by 12 or 6 core biopsy at different prostate-specific antigen densities in Korean men

OBJECTIVES: To evaluate the diagnostic value of 12 core biopsy versus sextant biopsy at different prostatic-specific antigen densities (PSAD). METHODS: We retrospectively analyzed the records of 1,463 patients who underwent transrectal ultrasound-guided prostate biopsies at our institution. 995 patients underwent 12 core biopsy and 468 sextant biopsy of the prostate. The cancer detection rates achieved by these two methods were analyzed at different PSAD levels. RESULTS: All patients were stratified into 5 groups according to PSAD level; group A: PSAD < 0.1 (n = 290), group B: 0.1 /= 0.4 (n = 231). In group B, 12 core biopsy had a higher detection rate than 6 core biopsy (P = 0.017). CONCLUSIONS: These results demonstrate 12 core biopsy is better able to detect cancer than 6 core biopsy in patients with a PSAD in the range 0.1-0.2, which suggests that PSAD be considered when deciding on the number of prostate biopsy cores required.     

Three-tesla magnetic resonance-guided prostate biopsy in men with increased prostate-specific antigen and repeated, negative, random, systematic, transrectal ultrasound biopsies: detection of clinically significant prostate cancers

Background

Patients with elevated prostate-specific antigen (PSA) and one or more previous negative transrectal ultrasound (TRUS) biopsy sessions are subject to diagnostic uncertainty due to TRUS-biopsy undersampling. Magnetic resonance (MR)–guided biopsy (MRGB) has shown high prostate cancer (PCa)–detection rates in studies with limited patient numbers.

Objective

Determine the detection rate of (clinically significant) PCa for MRGB of cancer-suspicious regions (CSRs) on 3-T multiparametric MR imaging (MP-MRI) in patients with elevated PSA and one or more negative TRUS-biopsy sessions.

Design, setting, and participants

Of 844 patients who underwent 3-T MP-MRI in our referral centre between March 2008 and February 2011, 438 consecutive patients with a PSA >4.0 ng/ml and one negative TRUS-biopsy session or more were included. MRGB was performed in 265 patients. Exclusion criteria were existent PCa, endorectal coil use, and MP-MRI for indications other than cancer detection.

Intervention

Patients underwent MRGB of MP-MRI CSRs.

Measurements

(Clinically significant) MRGB cancer-detection rates were determined. Clinically significant cancer was defined by accepted (i.a. Epstein and d’Amico) criteria based on PSA, Gleason score, stage, and tumour volume. Follow-up PSA and histopathology were collected. Sensitivity analysis was performed for patients with MP-MRI CSRs without MRGB.

Results and limitations

In a total of 117 patients, cancer was detected with MRGB (n = 108) or after negative MRGB (n = 9). PCa was detected in 108 of 438 patients (25%) and in 41% (108 of 265) of MRGB patients. The majority of detected cancers (87%) were clinically significant. Clinically significant cancers were detected in seven of nine (78%) negative MRGB patients in whom PCa was detected during follow-up. Sensitivity analysis resulted in increased cancer detection (47–56%). Complications occurred in 0.2% of patients (5 of 265).

Conclusions

In patients with elevated PSA and one or more negative TRUS-biopsy sessions, MRGB of MP-MRI CSRs had a PCa-detection rate of 41%. The majority of detected cancers were clinically significant (87%).     

经直肠超声引导前列腺穿刺活检方案的合理选择

经直肠超声(TRUS)引导前列腺穿刺活检是前列腺癌诊断和制定合理治疗方案的常规手段。制定扩大前列腺系统性穿刺方案时需综合考虑患者的年龄、前列腺体积及健康状况等因素。在系统性穿刺活检的基础上结合靶向性穿刺活检可提高前列腺癌的阳性率。     

Selective transperineal prostate biopsy for fluoroquinolone-resistance patients reduces sepsis and cost

Background:Urosepsis is a recognized complication of transrectal ultrasound-guided prostate biopsy (TRUS-Bx). Pre-biopsy rectal swabs have been used to identify patients with microorganisms in the rectal flora resistant to the conventionally used empirical prophylaxis. The transperineal route of biopsy (TP-Bx) has a lower complication risk but comes at an increased cost.Materials and methods:Retrospective cohort study including patients undergoing prostate biopsies between October/2015 and April/2018. The intervention cohort, a rectal swab was performed, the result of which dictated the biopsy route; TRUS-Bx against TP-Bx. TP-Bx for patients with fluoroquinolone resistance or extended-spectrum β-lactamase. The control cohort underwent TRUS without a rectal swab receiving empirical antibiotics—oral ciprofloxacin and intravenous gentamicin.Results:Total 1000 patients were included in which 500 underwent a swab, 14 (2.8%) developed post-TRUS biopsy infective complications with 3 having positive bacteremia (0.6%); 500 had no swab, 47 (9.4%) developed post-TRUS biopsy infective complications with 22 (4.4%, p < 0.05) having positive bacteremia. Three patients (0.6%) of patients who underwent swab developed urinary tract infection symptoms whilst 12 (2.4%) had urinary tract infection in the control group. In those patients that underwent a swab, 14 required hospitalization with mean length of stay of 2.5 days versus 43 patients of the control with 3.6 days. Cost analysis concluded savings of this strategy was £18,711.Conclusions:We have demonstrated a protocol that reserves template biopsies for higher risk patients and can significantly reduce sepsis and other infectious complication rates whilst also proving to be a cost-efficient strategy. We recommend that units not utilizing rectal swabs to uncover the fluoroquinolone resistance rate by introducing them. We advocate units that already utilize rectal swabs, to introduce transperineal biopsy for their higher risk patients.     

不同穿刺针数经直肠前列腺穿刺活检诊断前列腺癌的研究

目的探讨针对国人的不同体积前列腺理想的前列腺活检穿刺针数。方法临床表现怀疑前列腺癌患者879例,按照前列腺体积分为10～30ml组、30.1～40ml组,40.1～50ml组,以及50.1ml组,记录患者一般临床资料以及活检结果。依穿刺结果,按照不同体积对比分析不同穿刺针数的穿刺结果。结果总的肿瘤检测率为27.3%,随着前列腺体积的增大,肿瘤检测率降低(P0.05)。6、8、10和12针的肿瘤检测率分别为18.0%、28.0%、32.0%和29.0%。与8、10和12针比较,传统的6针穿刺有较低的穿刺阳性率(P0.05)。在不同的前列腺体积之间,8、10和12针穿刺阳性率之间比较,差异无统计学意义(P0.05)。在经直肠超声和经直肠指诊有可疑的患者中,穿刺阳性率分别为71.0%和65.0%。结论 6针穿刺具有较低的穿刺阳性率,按照不同的前列腺体积,8、10和12针有相似的穿刺阳性率,可疑部位活检能够提高穿刺的阳性率。