Biopsy tissue microarray study of Ki-67 expression in untreated, localized prostate cancer managed by active surveillance

Active surveillance provides a unique opportunity to study biomarkers of prostate cancer behaviour, although only small volumes of tumor tissue are typically available. We have evaluated a technique for constructing tissue microarrays (TMAs) from needle biopsies for assessing immunohistochemical markers in localized prostate cancer managed by active surveillance. TMAs were constructed from diagnostic prostate biopsies for 60 patients with localized prostatic adenocarcinoma in a prospective cohort study of active surveillance. Radical treatment was recommended for a prostate-specific antigen (PSA) velocity greater than 1 ng ml(-1) per year or adverse histology in repeat biopsies, defined as Gleason score > or =4+3 or >50% of cores involved. Sections from the TMAs were stained with H&E, P63/AMACR and Ki-67. Time to radical treatment was analysed with respect to clinical characteristics and Ki-67 LI. At a median follow up of 36 months, 25/60 (42%) patients had received radical treatment. On univariate analysis, PSA density (P=0.001), Gleason score (P=0.001), clinical T stage (P=0.01), Ki-67 LI (P=0.02) and initial PSA (P=0.04) were associated with time to radical treatment. On multivariate analysis, PSA density (P=0.01), Ki-67 LI (P=0.03) and Gleason score (P=0.04) were independent determinants of progression to radical treatment. TMAs constructed from prostate needle biopsies can be used to assess immunohistochemical markers in localized prostate cancer managed by active surveillance. Ki-67 LI merits further study as a possible biomarker of early prostate cancer behaviour.     

Predictability of PSA failure in prostate cancer by computerized cytometric assessment of tumoral cell proliferation

OBJECTIVES: To evaluate the relationship of DNA ploidy and cell proliferation (CP) with Gleason score (GS) and clinical outcome in prostate cancer. METHODS: Sixteen patients with benign prostatic hyperplasia (BPH) and 65 patients with prostate cancer classified by GS (four groups: 2 to 4, 5 to 6, 7, and 8 to 10) were studied. All patients with carcinoma underwent prostatectomy and were separated into prostate-specific antigen (PSA) failure and nonfailure groups (failure if PSA 0.1 ng/mL or more three times after surgery). Tumoral CP (Ki-67 inmunostaining and SG2M phase) and DNA ploidy were evaluated by computerized cytometry. RESULTS: BPH were diploid with low CP (8% SG2M cells or less). Carcinomas were either diploid with high CP (greater than 8% SG2M cells) or aneuploid. CP was significantly higher (P <0.001) in tumors with GS 7 or greater than in tumors with GS less than 7 (mean percent Ki-67 cells 18.3% versus 7.8%, respectively). PSA failure increased with GS (7.1% in GS 2 to 4, 21% in GS 5 to 6, 28.6% in GS 7, and 50% in GS 8 to 10), as well as with aneuploidy (18.5% in diploid tumors versus 72.7% in aneuploid tumors). Those experiencing PSA failure had significantly higher (P <0.001) CP than those not failing (mean percent Ki-67 cells 24% and mean percent SG2M 30.4% versus 8.7% and 13.5%, respectively). Cox regression analysis showed GS, DNA ploidy, Ki-67, and SG2M to each be univariately prognostic for time to PSA failure; however, Ki-67 and SG2M were more highly significant (P <0.0001 for both) than GS (P = 0.007) or DNA ploidy (P = 0.002). After adjusting for either SG2M or Ki-67 measures of CP, neither ploidy nor GS contained additional prognostic value. CONCLUSIONS: Tumor CP and DNA ploidy can be reliably determined in prostate cancer by computerized cytometry. On the basis of our preliminary results, CP correlates well with GS and predicts PSA failure better than DNA ploidy or GS.     

前列腺癌组织中蛋白表达与内分泌治疗后进展的相关性研究

目的 探讨前列腺癌内分泌治疗前癌组织中多种蛋白标记表达与内分泌治疗后发生进展的相关性,筛选内分泌治疗后进展的预测因子.方法 收集116例接受内分泌治疗的前列腺癌患者的临床病理资料,检测患者内分泌治疗前癌组织中雄激素受体(AR)、上皮型钙黏附索(E-cad-herin)、嗜铬粒蛋白A(CgA)、核增殖抗原(Ki67)、凋亡抑制蛋白(Survivin)、EZH2、hepsin蛋白表达,应用Cox比例风险模型进行多因素分析.结果 Ki67、EZH2、Survivin 3种蛋白表达与传统临床病理学因素存在Spearman等级相关.单因素分析中发现临床分期(P<0.001)、Gleason评分(P=0.005)、治疗前血清PSA值(P<0.001)以及Ki67(P=0.032)、Survivin蛋白(P=0.002)表达与内分泌治疗后的进展相关,多因素分析结果 显示临床分期(T_x N_+/M_+)(P<0.001)、高病理分级(Gleason评分≥8分)(P-0.038)和Survivin蛋白高表达(p＝0.031)是内分泌治疗后进展的重要危险因素.其中T_x N_+/M_+者67例(57.8%),Gleason评分≥8分者56例(48.3%),Survivin蛋白高表达者91例(78.4%). 结论 临床分期、病理分级、Survivin蛋白表达对于预测前列腺癌内分泌治疗后进展有重要意义.     

Percentage of positive biopsy cores as predictor of clinical outcome in prostate cancer treated with radiotherapy

PURPOSE: The clinical significance of pretreatment biopsy characteristics is not well understood relative to known prognostic factors. We performed a complete pathology analysis of pretreatment biopsy specimens in an attempt to clarify their impact on clinical outcome following radiotherapy. MATERIALS AND METHODS: From 1991 to 1999, 160 patients with locally advanced prostate cancer were prospectively treated with external beam radiotherapy in combination with high dose rate brachytherapy at our hospital and had pretreatment biopsy material available for complete pathological review. Patients with pretreatment prostate specific antigen (PSA) 10.0 ng./ml. or greater, Gleason 7 or greater or clinical stage T2b-T3c N0 M0 disease were eligible for study entry. Pelvic external beam radiotherapy (46.0 Gy.) was supplemented with 3 (1991 to 1995) or 2 (1995 to 1999) ultrasound guided transperineal interstitial iridium high dose rate implants. The brachytherapy dose was escalated from 5.50 to 10.50 Gy. per implant. All pretreatment biopsy specimen slides from each case were reviewed by a single pathologist (N. S. G.). Median followup was 4.2 years. Biochemical failure was defined as 3 consecutive PSA increases. RESULTS: On univariate analysis pretreatment PSA, Gleason score, clinical T classification, percentage of positive biopsy cores, dose per implant and total radiotherapy dose (equivalent in 2 Gy. fractions) were significantly associated with biochemical failure. Perineural invasion was of borderline significance (p = 0.07). On univariate analysis for clinical failure only Gleason score and percent positive cores were significant. Percent positive cores was associated with biochemical and clinical failure whether analyzed in subgroups or as a continuous variable. Patients with less than 33% positive cores had a 5-year biochemical control rate of 83% and 5-year clinical failure rate of only 7%. Conversely, patients with more than 67% positive cores had a 5-year biochemical control rate of only 57% and 25% had clinical failure at 5 years. Since percent positive cores correlated with biochemical and clinical failure, an analysis was performed to determine which other prognostic factors were associated with percent positive cores. Pretreatment PSA level, Gleason score, clinical T classification and perineural invasion were significantly associated with a higher percent positive cores. Nevertheless, on Cox multiple regression analysis higher percent positive cores, pretreatment PSA and Gleason score remained independently associated with biochemical failure but not T classification. On Cox multiple regression analysis for clinical failure only Gleason score remained independently significant with percent positive cores maintaining borderline significance (p = 0.07). CONCLUSIONS: Percent positive pretreatment biopsy cores is a powerful predictor of biochemical and clinical outcome for prostate cancer treated with radiotherapy, independent of other known prognostic factors. Percent positive cores should be seriously considered as a primary factor in risk group stratification for prostate cancer.     

Prognostic significance of proliferation activity and neuroendocrine differentiation to predict treatment failure after radical prostatectomy

OBJECTIVES: Neuroendocrine (NE) cells in prostate cancer may influence tumor cell proliferation in a paracrine fashion. The aims of this study were to clarify the prognostic value of tumor cell proliferation and NE tumor cell differentiation in prostate cancer after radical prostatectomy, and to compare these parameters with each other. MATERIAL AND METHODS: Specimens were pooled from a total of 528 patients treated with radical prostatectomy without neoadjuvant hormonal therapy between 1996 and 2003. NE differentiation (NED) was determined by immunohistochemistry using antibodies directed against chromogranin A (CgA), and was scored as either NE-negative (0-1+) or -positive (2-3+). Tumor cell proliferation was assessed by means of the Ki-67 labeling index (Ki-67 LI). The mean post-surgical follow-up period was 49 months (range 10-116 months). Any subsequent rise in prostate-specific antigen (PSA) level was regarded as reflecting disease progression. The prognostic values of Ki-67 and CgA were comparatively analyzed using multivariate Cox regression. RESULTS: NED was present in 6.1% of tumors. The mean Ki-67 LI was significantly higher in the CgA-positive group in comparison with CgA-negative specimens (6.6% vs 5.0%; p=0.029). The Ki-67 LI showed the highest correlations with Gleason score and pathological tumor stage (r=0.31 and r=0.3, respectively). NED was found to have the strongest association with pathological tumor stage (r=0.2). Multivariate analysis determined Gleason score > or =7 (4+3) [hazard ratio (HR) 3.04], NED (HR 1.89), lymph node metastases (HR 1.84), preoperative PSA level>20 ng/ml (HR 1.66), and Ki-67 LI > or = 5% (HR 1.62) to be significant predictors of biochemical progression. CONCLUSION: Our results identify Ki-67 LI and NED as additional prognostic markers after radical prostatectomy.     

Mammographic Density in Women on Postmenopausal Hormone Replacement Therapy

Background . Fine-needle aspiration (FNA) biopsy has been used increasingly in the diagnosis and biologic characterization of breast carcinomas in patients who receive preoperative chemotherapy. Because proliferative activity of breast carcinoma has been shown to be of prognostic significance, the authors compared immunocytochemical Ki-67 growth fraction and flow cytometric S-phase fraction (SPF), both evaluated on FNA samples. Methods . The proliferative activity of 134 FNA samples from primary breast carcinoma patients was studied using both immunocytochemistry with the monoclonal antibody Ki-67 and SPF determined by DNA flow cytometry. Results . Ki-67 and SPF were evaluable in 114 and 107 cases, respectively, and both were evaluable in 95 cases. Of the 134 FNA samples studied, 37% were diploid and 63% were aneuploid. The distribution of both Ki-67 and SPF was different in diploid and aneuploid tumors. The median Ki-67 value as well as the median SPF were significantly higher in aneuploid versus diploid tumors (p < 0.001). Median Ki-67 and SPF values were used to discriminate between low versus high proliferating tumors. The overall concordance between Ki-67 and SPF was 75% (p < 0.001). A good correlation was found between Ki-67 and SPF (correlation coefficient = 0.72; p < 0.001). Conclusions . The results of the current study suggest the Ki-67 growth fraction and SPF determined by FNA may be used as measurements of the proliferative activity of breast carcinoma. The authors recommend these determinations be used as preoperative procedures in patients with a cytologic diagnosis of breast carcinoma who are candidates for neoadjuvant chemotherapy and/or endocrine therapy.     

Increased Akt and phosphorylated Akt expression are associated with malignant biological features of prostate cancer in Japanese men

OBJECTIVE: To investigate the relationship between the expression of Akt (a serine/threonine kinase that plays a central role in tumorigenesis), phosphorylated Akt (p-Akt), prostate cancer tumour grade, androgen receptor (AR)-staining score, and Ki67 labelling index (LI) in Japanese men. PATIENTS, MATERIALS AND METHODS: The expression and activation of the cell survival protein Akt was analysed by immunohistochemical staining of paraffin-embedded tissue microarray sections of prostate carcinoma taken from 52 Japanese men who under radical prostatectomy. The correlation between the expression of Akt and p-Akt, and their relationship to primary Gleason grade, AR expression and Ki-67 LI was investigated. RESULTS: The expression of Akt and p-Akt were positively related to primary Gleason grade (Fisher's exact test, P = 0.002 and P = 0.032, respectively). Both AR-staining score and Ki67 LI were were positively related to the expression of Akt (both P < 0.001) and p-Akt (P < 0.001 and P = 0.008, respectively). There was a significant positive correlation between the expression of Akt and p-Akt (Spearman's correlation, r = 0.644, P < 0.001). CONCLUSIONS: Increased expression of both Akt and p-Akt were associated with higher tumour grade as well as a higher AR-staining score and Ki67 LI. These data indicate that Akt and p-Akt might be molecular markers for detecting malignant biological features of prostate cancer in the Japanese population.     

Comparing prostate specific antigen outcomes after different types of radiotherapy management of clinically localized prostate cancer highlights the importance of controlling for established prognostic factors

PURPOSE: We evaluated the impact that the composition of prognostic factors in a patient cohort may have on prostate specific antigen (PSA) outcome following external beam radiation therapy for clinically localized prostate cancer. MATERIALS AND METHODS: The distribution of PSA, biopsy Gleason score and American Joint Committee on Cancer (AJCC) T stage in men with prostate cancer treated with interstitial plus external beam radiation therapy was used to select a matched cohort who underwent 3-dimensional (D) conformal external beam radiation therapy. We compared PSA outcomes after 3-D conformal external beam radiation therapy in the overall and matched cohorts of 766 and 570 patients, respectively. RESULTS: Men treated with interstitial plus external beam radiation therapy had a significantly lower rate of PSA greater than 10 to 20 (p = 0. 02) and greater than 20 ng./ml. (p <0.0001), biopsy Gleason score 7 (p = 0.02) and 8 to 10 (p <0.0001), and AJCC stage T2c disease (p <0. 0001). Likewise, these men also had a significantly higher rate of PSA greater than 4 to 10 ng./ml. (p <0.0001), biopsy Gleason score 5 to 6 (p = 0.0001) and AJCC stage T1 disease (p <0.0001) than those who underwent 3-D conformal external beam radiation therapy. The 5-year estimate of PSA failure-free survival after 3-D conformal external beam radiation therapy was 45% versus 67% (p = 0.0007) for all 766 consecutively treated patients and the matched cohort of 570, respectively. CONCLUSIONS: The composition of prognostic factors in a patient cohort may impact PSA outcome. Therefore, controlling for established prognostic factors is essential when comparing PSA outcome after different forms of radiotherapy for adenocarcinoma of the prostate.     

前列腺癌血清PSA、f/tPSA与Gleason评分、临床分期的相关性研究

目的 探讨前列腺癌病人血清PSA、f/tPSA（血清游离PSA与总PSA的比值）与前列腺癌Gleason评分、临床分期的相关性.方法 查阅我院1998年1月～2005年6月归档的前列腺癌病历资料,建立临床资料数据库,对归档病理切片进行Gleason评分.采用Spearman等级相关分析,分析血清PSA、f/tPSA与前列腺癌Gleason评分、临床分期的关系.结果 269例前列腺癌中,前列腺癌PSA值与Gleason评分呈正相关（r=0.361,P＜0.01）,与前列腺癌临床分期呈正相关（r=0.586,P＜0.01）;f/tPSA与Gleason评分有弱负相关（r=-0.128,P=0.035）,与前列腺癌临床分期呈负相关（r=-0.226,P＜0.01）.结论 血清PSA、f/tPSA与前列腺癌预后密切相关的指标临床分期和Gleason评分有关.     

Flap endonuclease 1 is overexpressed in prostate cancer and is associated with a high Gleason score

OBJECTIVE: To investigate the expression and potential clinical usefulness of structure-specific flap endonuclease 1 (FEN-1) in human primary prostate cancer using tissue microarray technology, as FEN-1 was recently identified to be overexpressed in CL1.1, the most aggressive clone generated from the hormone-refractory prostate cancer cell line CL1. MATERIALS AND METHODS: Immunohistochemistry was performed on tissue microarrays constructed from paraffin-embedded specimens of primary prostate cancer from 246 patients who had had a radical prostatectomy. Prostatic intraepithelial neoplasia (PIN), benign prostatic hyperplasia (BPH) and normal prostate epithelium were represented on the array. FEN-1 nuclear expression was scored based on the percentage of target cells staining positively, and correlated with Gleason score, preoperative prostate-specific antigen (PSA) level and pathological stage. The time to PSA recurrence was also analysed. RESULTS: The mean expression of FEN-1 was significantly higher in cancer (36.7%) than in normal (13.2%), BPH (4.5%) and PIN (15.4%) specimens (P < 0.001). FEN-1 expression was significantly correlated with Gleason score (ó = 0.23, P = 0.002). A higher preoperative serum PSA level (P = 0.015), Gleason score > or = 7 (P < 0.001), seminal vesicle invasion (P < 0.001) and capsular involvement (P = 0.004) were associated with PSA recurrence, whereas FEN-1 expression was not. In a multivariate analysis, only Gleason score > or = 7 (P < 0.001), seminal vesicle invasion (P = 0.005) and capsular involvement (P = 0.009) were retained as independent predictors for PSA recurrence. CONCLUSIONS: FEN-1 is overexpressed in prostate cancer compared with matched normal prostate, and its expression increases with tumour dedifferentiation, as shown by increasing Gleason score. These results suggest that FEN-1 might be a potential marker for selecting patients at high risk, and a potential target for prostate cancer diagnosis and therapy.     

Prostate cancer radiotherapy dose response: an update of the fox chase experience

PURPOSE: The effectiveness of increasing radiotherapy dose for men with prostate cancer was evaluated with reference to prognostic groups as defined by pretreatment serum prostate specific antigen (PSA), Gleason score, T stage and perineural invasion. MATERIALS AND METHODS: There were 839 men treated between April 1989 and December 1997 with conformal radiotherapy alone. Cox multivariate analysis was used to establish important predictors of biochemical failure (BF) separately for patients with an initial pretreatment PSA (iPSA) of less than 10, 10 to 19.9, or 20 or greater ng/ml. Radiotherapy (RT) dose was evaluated as a continuous and categorical (dose groups of less than 72, 72 to 75.9 and 76 Gy or greater) variable. RESULTS: At a median 63-month followup multivariate analysis demonstrated that iPSA and radiotherapy (RP) dose were the most significant predictors of BF, followed by Gleason score and T stage. Perineural invasion was not an independent correlate of outcome. RT dose was significant in all iPSA groups (less than 10, 10 to 19.9 and 20 or greater ng/ml). Gleason score was significant when iPSA was less than 10 ng/ml. T stage was significant when iPSA was 20 ng/ml or greater and it was borderline when iPSA was 10 to 19.9 ng/ml (p = 0.08). Prognostic subgroups were derived from these results and tested for an effect of RT dose on univariate analysis. Radiation dose was not a correlate of BF in the most favorable (PSA less than 10 ng/ml and Gleason score 2 to 6) and the most unfavorable (PSA 20 ng/ml or greater and stage T3-T4) prognostic groups but it was otherwise an influential determinant of outcome. CONCLUSIONS: RT dose escalation to 76 Gy or greater improved patient outcome for all prognostic groups except those at the favorable and unfavorable extremes.     

Proliferating-cell nuclear antigen (PCNA) as an independent prognostic marker in patients after prostatectomy: a comparison of PCNA and Ki-67

OBJECTIVE: To investigate the prognostic value of prostatic tumour cell proliferation, as measured by Ki-67 and proliferating cell nuclear antigen (PCNA), and to compare these measures in men at low and high risk for progression of tumour. PATIENTS AND METHODS: Two groups of patients with prostate cancer, i.e. 'metastatic' (M, 22) who had pT3b-4aN0M0 and pTanyN1M0, and 'nonmetastatic' (NM, 18), who had < or =pT3aN0M0 disease, were selected from a well-examined and mapped group of 114 treated by radical prostatectomy. Patients in the NM group were selected by the criteria of having a Gleason score of < or = 7. To assess proliferation, 1000 cells were counted at x 400 magnification by two observers and the percentage of tumour cells positively stained with Ki-67 and PCNA defined as the Ki-67 and PCNA labelling index (LI), respectively. The two LI were compared in the NM and M groups, and the correlation of the LIs with pathological stage, progression and prostate-specific antigen (PSA)-free survival evaluated. Prognostic values of the LI were analysed using multivariate analysis. RESULTS: The mean (range) follow-up was 33 (4-78) months. The mean LIs were higher in the M than the NM group for both PCNA and Ki-67 (P = 0.02 and 0.019, respectively). Both LIs were markedly different between the groups when stratified by progression, with both significantly higher in men with progression in the NM group. Both LIs had a significant association with Gleason score, pathological stage, progression and PSA-free survival. In multivariate analysis the PCNA LI, surgical margin status and pathological stage were independent factors for progression. CONCLUSION: Tumour cell proliferation as assessed by Ki-67 or PCNA correlate significantly with progression. The PCNA LI was an independent predictor of progression, especially in patients with a low risk of progression according to predefined criteria.     

Prognostic value of circulating prostate cells in patients with a rising PSA after radical prostatectomy

BACKGROUND: To predict poor outcome in patients with a biochemical recurrence (rising PSA) after radical prostatectomy (RP), urologists rely primarily on Gleason score, PSA doubling time, and time from surgery to biochemical (i.e., PSA) recurrence. In the present study, we assess the value of RT-PCR detection circulating prostate cells in blood of patients with a rising PSA. METHODS: RNA from blood samples was obtained from 55 patients with a rising PSA and from 45 patients without evidence of biochemical failure (PSA < 0.1 ng/ml). Both groups were matched for age, Gleason score, pT stage, and interval between radical prostatectomy and PCR testing. RESULTS: PSA positive cells were detected in 1/45 (2%) patients without a PSA recurrence and 19/55 (34%) patients with a PSA recurrence. In the rising PSA group, mean PSA doubling time was significantly shorter in patients with positive RT-PCR (5 months) than in patients with negative RT-PCR (16 months; P = 0.001). An earlier onset of recurrence was also detected in patients with a positive RT-PCR (31 months for positive RT-PCR vs. 50 months for negative RT-PCR) but this result did not achieve statistical significance (P = 0.102). Salvage radiation therapy was administered in 15 patients. Three of the five patients with a positive RT-PCR progressed during radiotherapy whereas 7 of the 10 patients with a negative RT-PCR obtained a complete response and none have progressed. CONCLUSIONS: These preliminary results suggest that RT-PCR detection of prostate cells in blood of patients after RP correlates with rapidly progressing biochemical failure after RP.     

前列腺癌根治术后无瘤生存期的影响因素分析

目的探讨前列腺癌根治术后无瘤生存期的影响因素及Bcl-2、C-erbB-2、Ki-67在前列腺癌中的表达及意义。方法回顾性分析51例前列腺癌患者根治术后无瘤生存期的影响因素，应用Cox比例风险模型进行多因素统计分析。对其中15例术前穿刺标本及手术切除标本行3种癌基因蛋白免疫组化检查，分析其表达与术后无瘤生存期的关系。结果Cox比例风险模型发现有意义的因素为年龄(P=0．011)、术前雄激素全阻断治疗(P=0．017)、阳性切缘(P=0.000)、切除标本Gleason评分(P=0．002)、术前或术后行睾丸切除(P=0．040)。前列腺癌穿刺标本、切除标本中Bcl-2、C-erbB-2、Ki-67蛋白表达与术后无瘤生存期存在相关性。结论标本阳性切缘是影响无瘤生存期的因素，前列腺癌根治术术前雄激素全阻断治疗可提高患者术后无瘤生存期，术中探查未发现肿大淋巴结时未行盆腔淋巴结清扫对术后无瘤生存时间无明显影响，术前或术后睾丸切除患者的无瘤生存期明显好于未行睾丸切除患者。Ki-67、Bcl-2与C—erbB—2可作为术前、术后预测前列腺癌患者根治术后无瘤生存期的指标。     

Does a delay in initiating definitive therapy affect biochemical recurrence rates in men with clinically localized prostate cancer?

PURPOSE: To assess whether a delay in initiating definitive therapy for clinically localized prostate cancer affects outcome. METHODS: We retrospectively reviewed 393 men with localized prostate cancer treated with radiation therapy or surgery without systemic therapy between 1991 and 2004. Data included: time from diagnosis to treatment initiation (more or less than 3 months); biopsy Gleason score grouped by low (2-6), intermediate (7), or high risk (8-10); clinical stage grouped by low (T1/T2a) or high risk (T2b or higher); pretreatment prostate-specific antigen (PSA) grouped by low (<10 ng/ml), intermediate (10-20), or high risk (>20); and biochemical recurrence-free survival. RESULTS: Median patient age was 63.1 years (range 39.7-79.5). Median pretreatment PSA was 6.5 ng/ml (range 0.4-411). Median time from diagnosis to treatment was 57 days (range 8-2927). A total of 310 patients (79%) were treated within 3 months. Median follow-up was 2.3 years (range 0.1-14.0). On univariate analysis using Kaplan-Meier survival curves and the log-rank test, only pretreatment PSA was associated with worse biochemical recurrence-free survival (P = 0.008). Biochemical recurrence-free survival was not associated with time from diagnosis to treatment (P = 0.28), clinical stage (P = 0.50), or biopsy Gleason score (P = 0.19). The results were the same when analyzed in a multivariable analysis using the Cox proportional hazards model. CONCLUSION: A delay in treatment of > or =3 months does not appear to affect adversely biochemical recurrence-free survival in patients who undergo definitive therapy for clinically localized prostate cancer in those with low risk features.     

Expression of p27<Superscript>(Kip1)</Superscript>, cyclin D3 and Ki67 in BPH,prostate cancer and hormone-treated prostate cancer cells

p27^(Kip1), cyclin D3 and Ki67 are the markers of DNA damage and cell proliferation. The goal of the current study was to analyze expression of the markers in benign and malignant prostate cancer tissues. Activity of p27^(Kip1), cyclin D3 and Ki67 was immunohistochemically evaluated in different cells of BPH, prostate cancer (PCa) and hormonally treated prostate cancer (HTPCa) tissues. The tissue samples were derived by means of TURP or radical prostatectomy. Intensity of the expression was compared between the groups, and association was sought with clinical parameters. Total expression of p27^(Kip1) was significantly higher in BPH as compared with PCa. Epithelial marker expression was higher in HTPCa than in PCa. Intensity of the expression in epithelial, vascular and ductal cells was negatively associated with the tumor stage and Gleason grades. Total Ki67 activity was positively correlated with patient age and serum PSA level. There was significantly higher expression in PCa and hormone-escaped PCa (HEPCa) as compared with BPH. Epithelial and vascular marker expression was positively associated with tumor stage and Gleason grades. There was a positive correlation between cyclin D3 and serum PSA level. With the increase of Gleason grades, cyclin D3 expression increased significantly. Expression of p27^(Kip1) negatively correlated with Ki67 and cyclin D3, while the latter two markers correlated positively. p27^(Kip1) is down-regulated, whereas Ki67 and cyclin D3 are up-regulated in PCa. Intensity of the markers’ expression is associated with tumor stage and grades. Hormonotherapy of PCa causes activation of p27^(Kip1). HEPCa is characterized by increased Ki67 expression.     

腹膜外途径腹腔镜下根治性前列腺切除术切缘阳性的影响因素

目的探讨经腹膜外途径腹腔镜下根治性前列腺切除术后切缘阳性的影响因素。方法回顾性分析我院2010年1月至2018年12月99例行腹膜外途径腹腔镜下根治性前列腺切除术患者的临床资料。年龄51~79岁,平均(65.37±6.07)岁;前列腺特异抗原(PSA)2.80~79.50ng/mL,平均(16.84±12.28)ng/mL。分析术后病理切缘阳性的特征。按年龄、体质指数、术前PSA水平、穿刺针数阳性百分率、穿刺至手术时间、穿刺病理Gleason评分、临床T分期、前列腺癌危险分度、术后病理Gleason评分、术后T分期、腹盆腔手术史等进行分组,分析各组切缘阳性率的差异。采用χ^2检验进行单因素分析,有统计学差异的变量进入多因素Logistic回归分析,评价临床及病理相关资料与切缘阳性的关系。结果本组99例患者均在腹腔镜下顺利完成,无1例中转开放,手术时间平均(199.66±66.01)min,术中出血量平均(152.02±140.28)mL。术后病理证实均为前列腺癌,术后病理切缘阳性26例(26.3%)。将各危险因素分组后进行单因素分析,结果显示不同穿刺针数阳性百分率(P=0.047)、穿刺病理Gleason评分(P=0.023)、术后病理Gleason评分(P=0.007)、术后T分期(P=0.004)与切缘阳性存在相关性(P<0.05),而年龄(P=0.134)、体质指数(P=0.838)、术前PSA水平(P=0.299)、穿刺至手术时间(P=1.000)、临床T分期(P=0.821)、前列腺癌危险分度(P=0.903)、腹盆腔手术史(P=0.607)与切缘阳性均无相关性(P>0.05)。将单因素分析差异有统计学意义的指标及术前PSA、临床分期进行多因素分析,结果显示仅术后T分期(P=0.011)是切缘阳性的独立危险因素。结论穿刺针数阳性百分率、穿刺病理Gleason评分、术后病理Gleason评分、术后T分期与切缘阳性存在相关性,其中穿刺针数阳性百分率、穿刺病理Gleason评分及术后T分期越高,切缘阳性率越高。术后T分期是经腹膜外途径腹腔镜下根治性前列腺切除术后切缘阳性的独立危险因素。     

Tertiary Gleason pattern 5 is a powerful predictor of biochemical relapse in patients with Gleason score 7 prostatic adenocarcinoma

PURPOSE: In radical prostatectomy specimens Gleason score 7 is among the most commonly assigned scores for prostate carcinoma accounting for 30% to 50% of cases. Gleason score 7 is different from other more differentiated prostate carcinomas (tumors of Gleason scores 5 and 6) with a significantly worse outcome and higher rate of recurrence. Nonetheless, Gleason score 7 tumors are heterogeneous. In this study we examined the differences in clinical outcome between primary Gleason grade 3 and 4 tumors in patients who underwent radical prostatectomy, and determined the influence of tertiary Gleason pattern 5 on patient outcome. MATERIALS AND METHODS: A total of 504 patients underwent radical prostatectomy for prostate cancer and 228 of the patients (45%) had a Gleason score of 7. Cases were analyzed for a variety of clinical and pathological parameters. The influence of primary Gleason pattern and tertiary Gleason pattern 5 on patient outcome was assessed in the Cox regression model. RESULTS: Among 228 patients with Gleason score 7 prostatic adenocarcinoma, 91 (40%) had a primary Gleason pattern 4 and 137 (60%) had primary Gleason pattern 3. Patients of the former group were more likely to have a higher pathological stage (p = 0.003), more likely to have PSA recurrence (p = 0.02) and more likely to have a tertiary Gleason pattern 5 (p <0.0001). A total of 37 (41%) patients with primary Gleason 4 had a tertiary Gleason pattern 5, whereas only 13 (9%) patients with primary Gleason 3 had a tertiary Gleason pattern 5. In the Cox regression model controlling for tumor stage and surgical margin status, the primary Gleason pattern was not an independent predictor of PSA recurrence (p = 0.80), whereas the presence of tertiary Gleason pattern 5 was a significant predictor of PSA recurrence (hazard ratio 2.10, 95% CI 1.24-3.55, p = 0.006). Five-year PSA recurrence-free survival was 70% for patients without a tertiary Gleason pattern 5 compared to 19% for those patients with a tertiary Gleason pattern 5. CONCLUSIONS: Among patients with Gleason score 7, primary Gleason grade 4 indicates a likelihood of higher tumor stage and higher probability of PSA recurrence than does primary pattern 3. However, it does not independently predict a worse outcome after controlling for other known prognostic parameters associated with disease progression. Regardless of whether the primary Gleason pattern is 3 or 4, a tertiary Gleason pattern 5 is the strongest predictor of a worse outcome in patients with Gleason grade 7 prostatic adenocarcinoma. Therefore, tertiary pattern 5 should be reported in radical prostatectomy specimens.     

Prognostic value of p53, proliferating cell nuclear antigen, and Ki-67 expression in undifferentiated nasopharyngeal carcinomas

In this study the prognostic importance of p53, proliferating cell nuclear antigen (PCNA), and Ki-67 expression was analyzed along with the clinical parameters in 35 consecutive patients with undifferentiated nasopharyngeal carcinomas. Immunohistochemistry was used to detect p53, PCNA, and Ki-67 staining. Among the clinical findings, stage IV disease (P = 0.01), cranial nerve paralysis (P = 0.02), and lymph node metastasis (P = 0.06) were associated with shorter survival. The p53 positivity correlated with the presence of lymph nodes, but it was not a significant factor to predict the outcome. PCNA expression was not found to be a prognostic indicator. On the other hand, the proliferative value of Ki-67 staining was suggestive of prognosis. A proliferation index of Ki-67 less than 10% indicated longer survival (P = 0.03). There was no correlation between Ki-67 staining and PCNA index. As a result, the prognostic value of Ki-67 may alert the physician to more aggressive and adjuvant treatment modalities.     

Expression of p21 cell cycle protein is an independent predictor of response to salvage radiotherapy after radical prostatectomy

BACKGROUND: To assess whether the expression of p21, p27, and p53 could predict biochemical failure in prostate cancer patients treated with neoadjuvant androgen deprivation prior to salvage radiotherapy for a rising post-radical prostatectomy (RP) prostate-specific antigen (PSA). METHODS: The expression of p21, p27, and p53 was determined by immunohistochemistry in a cohort of 74 formalin-fixed paraffin-embedded prostate cancer samples obtained from RP. Expression of these markers was then correlated with clinicopathological parameters and biochemical failure-free survival after salvage radiotherapy. RESULTS: Expression of p21, p27, and p53 was observed in 20%, 69%, and 74% of prostate cancer specimens, respectively. Overexpression of p21 correlated with a higher Gleason score (>7) (P = 0.024). Of the three markers, only p21 expression was correlated with PSA failure after radiotherapy (P = 0.034). In multivariate analysis, both positive p21 (P = 0.004) and pre-radiation serum PSA > 1 ng/ml (P < 0.0001) were independent predictors of biochemical failure after salvage radiotherapy. Patients with p21- tumors and a serum PSA level < or = 1 ng/ml before salvage radiotherapy had a biochemical failure-free survival at 5 years of 83%, compared to 16% at 5 years for those patients with either p21+ tumor or a PSA > 1 ng/ml. Patients with both p21+ and a PSA level > 1 ng/ml had a much lower biochemical failure-free survival rate of 25% at only 18 months (P < 0.0001). CONCLUSIONS: The expression of p21 in prostatectomy specimens could help predict the likelihood of response to salvage radiotherapy, particularly in patients treated before PSA reaches 1 ng/ml.