高强度聚焦超声治疗小鼠前列腺癌的肿瘤亚致死损伤区的观察

目的探讨高强度聚焦超声（HIFU）治疗小鼠前列腺癌引起的肿瘤凝固性坏死区中存在的肿瘤亚致死损伤，以及HIFU联合放疗对其的影响。方法建立小鼠前列腺癌皮下移植瘤模型，设对照组、HIFU组、低剂量放疗组、放疗组和HIFU联合低剂量放疗组，各组测定肿瘤坏死面积百分比（NAP），并通过TUNEL法和抗CD34微血管染色分别检测残留存活肿瘤组织的凋亡细胞密度（AD）和微血管密度（MVD）。结果与对照组比较，HIFU组NAP（41．18±6．44）％显著增加，肿瘤凝固性坏死区的周边虽残留存活肿瘤组织，但存活肿瘤组织的AD（61．78±20．95）个／视野显著增加，MVD显著降低（P〈0．05）。放疗组和低剂量放疗组各项指标差异元统计学意义（P〈0．05）。HIFU联合低剂量放疗组与HIFU组和2个放疗组比较，NAP（77．95±6．19）％显著增加，残留存活肿瘤组织的AD（183．33±33．62）个／视野显著增加（P〈0．05）。析因方差分析示HIFU和放疗间存在显著的协同增效效应（P〈0．01）。结论HIFU治疗小鼠前列腺癌时，凝固性坏死区周边残留的存活肿瘤组织存在亚致死损伤。HIFU联合低剂量放疗存在协同增效效应，能减少肿瘤的亚致死性损伤，促进肿瘤组织凝固性坏死和肿瘤细胞凋亡，疗效优于单独的放疗或HIFU治疗。     

经直肠高强度聚焦超声联合内分泌疗法治疗前列腺癌

目的探讨经直肠高强度聚焦超声联合内分泌疗法与单纯内分泌疗法治疗前列腺癌的疗效。方法将40例前列腺癌患者分为A、B两组，其中A组采用HIFU联合内分泌治疗，B组采用单纯内分泌治疗。HIFU治疗采用Sonablate 500型经直肠HIFU治疗系统，内分泌治疗采用去势加用抗雄激素药物治疗。随访时间8—24个月，平均16个月。结果A、B两组患者在治疗后，均出现了前列腺体积缩小，血清PSA均有不同程度下降，IPSS评分降低，Qmax明显提高，治疗前后差异有统计学意义（P〈0．05）。其中A组较B组改变更为明显，两者之间差异有统计学意义（P〈0．05）。结论高强度聚焦超声联合内分泌疗法及单纯内分泌疗法对前列腺癌的近期疗效均较好，前者疗效更为明显。     

辅助内分泌治疗和放疗的结合可延长pT2-4pN＋前列腺癌患者的生存期：配对分析结果

既往的回顾性随机调查已证实辅助放疗（RT）对局部进展性前列腺癌患者有积极意义。但这些研究未包括有淋巴结侵犯（LNI）的患者。此次研究目的旨在评价辅助内分泌治疗（HT）联合RT对组织学证实有淋巴结转移（pN＋）的前列腺癌患者生存期的影响。     

载阿霉素的液-固相变型原位凝胶注射治疗兔VX2肝癌HIFU消融后残癌

目的观察载阿霉素液一固相变型原位注射凝胶（DOX-ISFI）治疗高强度聚焦超声（HIFU）消融兔、,x2肝癌后残癌的疗效。方法以24只兔建立VX2肝癌模型,对肿瘤行HIFU不全消融,随机分为HIFU消融与DOX—ISFI联合治疗组（HIFU＋DOX—ISFI组）、HIFU消融与空白液一固相变原位注射凝胶联合治疗组（HIFU＋N—ISFI组）,每组12只,比较两组肿瘤生长率、PCNA表达情况,并以冰冻切片荧光显像观测药物瘤内分布。结果处理后HIFU＋DOX—ISFI组肿瘤生长明显减慢,其生长率明显低于HIFU＋N—ISFI组（P〈O．05）;HIFU十D0X-ISFI组肿瘤增殖指数明显低于HIFU＋N—ISFI组（P〈0．05）;荧光显像姓示药物从注射中心向剧围呈阶梯状分布。结论DOXISFI能钉效治疗HIFUiVX2肝癌后的残癌。     

经尿道前列腺电切术治疗晚期前列腺癌伴膀胱出口梗阻的疗效观察

目的：探讨经尿道前列腺电切术（TURP）联合内分泌治疗晚期前列腺癌伴膀胱出口梗阻的疗效及安全性。方法：回顾性分析2007年5月～2012年5月采用TURP联合内分泌治疗拟或单纯内分泌治疗晚期前列腺癌伴膀胱出口梗阻患者32例,其中13例行单纯行内分泌治疗,19例行TURP联合内分泌治疗。观察两组患者治疗前后血清前列腺特异抗原（PsA）、剩余尿量、最大尿流率、国际前列腺症状评分（IPSS）及5年生存率。结果：术后3个月,TURP＋内分泌治疗组血PSA、剩余尿量及IPSS分别由术前的（35．7±12．1）ng／ml、（145．0±65．8）ml、（21．4±5．1）分降至（4．9±1．9）ng／ml、（27．0±15．2）ml、（8．7±2．6）分（P〈0．05）,最大尿流率由（4．3±1．6）ml／S增至（11．7±3．7）ml／s（P〈0．05）;治疗12个月后差异仍有显著性（P〈0．05）。单纯内分泌组术后3个月血PSA由（31．4±10．7）ng／ml降至（5．6±2．2）ng／ml,两组比较,血PSA差异无统计学意义;剩余尿量、最大尿流率及IPSS差异均有统计学意义（P〈0．05）。内分泌组5年生存率为50％,TURP＋内分泌组为51．5％,总体生存率差异两组无统计学意义（P=0．919）。结论：TURP＋内分泌治疗能够显著缓解晚期前列腺癌患者膀胱出口梗阻症状,提高患者生活质量,且不影响生存率,是一种安全有效的治疗方式。     

去势联合高强度聚焦超声治疗晚期前列腺癌对患者生存及免疫状态的影响

目的:探索晚期前列腺癌(prostate cancer,PCa)去势后,联合高强度聚焦超声(HIFU)局部治疗原发灶对患者生存和免疫状态的影响。方法:我院于2000年3月～2010年12月对64例晚期PCa去势手术后的患者进行前瞻性对照非随机研究,对照组30例接受单纯内分泌治疗,HIFU组34例去势后联合HIFU治疗。绘制两组患者的Kaplan-Meier生存曲线和并计算生存率,进行生存分析。部分患者(对照组11例,HIFU组12例)于治疗前、后采取外周血检测免疫指标,包括IL-2、IFN-γ、VEGF、TGF-β1和CD4+CD25+Foxp3+细胞水平。结果:对照组3年和5年生存率为45.19%和25.83%,HIFU组3年和5年生存率为76.92%和51.26%,两组的生存曲线差异有统计学意义(P=0.0404)。与对照组比较,HIFU组患者治疗后的外周血IL-2(P=0.042)、IFN-γ(P=0.019)水平显著提高,VEGF(P=0.032)、TGF-β1(P=0.042)水平和CD4+CD25+Foxp3+细胞(%)(P=0.001)显著降低。结论:晚期PCa去势后联合HIFU局部治疗原发灶能提高患者对内分泌治疗的反应,并能改善机体的免疫状态,显著延长了患者的生存时间。     

高能聚焦超声治疗激素非依赖性前列腺癌

目的探讨高能聚焦超声（HIFU）治疗激素非依赖性前列腺癌的临床效果。方法对本组12例激素非依赖性前列腺癌行HIFU治疗，术后随访3—20个月，平均14个月。结果治疗前后血清前列腺特异性抗原（PSA）值分别为（42．5±20．2）ng／mL、（10．4±6．6）ng／mL；前列腺体积为（45．2±12．5）mL、（3．5±1．1）mL；国际前列腺症状评分为19．5±5．5、8．5±4．5，治疗前后比较具有显著差异（P〈0．05）；治疗并发症：轻度血尿2例。结论HIFU治疗激素非依赖性前列腺癌近期疗效确切、并发症少。     

征文通知

各位医师：阿斯利康前列腺癌诊治研究栏目征文的有关事项如下：一、征文内容：1．前列腺癌早期诊断（PSA筛查、穿刺活检等）2．前列腺癌治疗（手术、放疗、内分泌治疗经验及综述）     

乌司他丁对肝癌患者高强度聚焦超声治疗后细胞免疫功能的影响

目的 探讨乌司他丁对肝癌患者高强度聚焦超声（HIFU）治疗后细胞免疫功能的影响。方法 择期行HIFU治疗的肝癌患者20例，ASAⅡ或Ⅲ级，随机分为2组（n=10）：对照组（C组）和乌司他丁组（U组）。U组于麻醉诱导后缓慢静脉注射乌司他丁20万U，C组输注等量生理盐水。于HIFU治疗前即刻（T1）、治疗结束即刻（T2）及治疗结束后24h（T3）采取肘静脉血样2ml，使用流式细胞仪检测CD3^＋、CD4^＋、CD8^＋T淋巴细胞和NK细胞百分率。结果 与T1比较，C组T2、T3时CD3^＋、CD4^＋、CD8^＋T淋巴细胞百分率差异无统计学意义（P〉0．05），T2时CD4^＋，CD8^＋比值增高，T2、T3时NK细胞百分率增高（P〈0．05），U组T2、T3时CD3^＋T淋巴细胞百分率差异无统计学意义（P〉0．05），T2时CD4^＋、CD8^＋T淋巴细胞百分率增高（P〈0．05），T2、T3时CD4^＋／CD8^＋比值、NK细胞百分率增高（P〈0．01）；与C组比较，T2、T3时U组NK细胞百分率增高（P〈0．05）。结论 乌司他丁可有效提高HIFU治疗肝癌患者的细胞免疫功能。     

间歇内分泌治疗联合调强适形放射治疗局限性前列腺癌的临床研究

目的：探讨间歇性内分泌治疗联合调强适形放射治疗局限性前列腺癌的临床价值。方法：选择局限性前列腺癌患者72例,分为两组,联合治疗组37例,采用间歇内分泌治疗联合调强适形放射治疗;单纯治疗组35例,采用单纯调强适形放射治疗。分析比较两组患者的临床症状缓解率、前列腺体积变化情况、血清前列腺特异抗原（PSA）值改变、肿瘤控制率、放疗不良反应发生率及生存率等方面。结果：随访5～118个月,平均56个月。联合治疗组与单纯治疗组比较,临床症状缓解率差异有统计学意义（x^2=3．280,P=0．036）;前列腺体积差值的差异有统计学意义（t=5．1353,P=0．000）;血清PsA〈0．2μg／L者所占比例差异有统计学意义（x^2=20．182,P=0．000）;1年、3年、5年和8年PSA无进展生存率差异均有统计学意义（P〈0．05）;1年、3年均无死亡病例,差异均无统计学意义;5年生存率差异有统计学意义（x^2=5．168,P=0．023）;8年生存率差异有统计学意义（x^2=5．061,P=0．024）;早期放疗不良反应发生率差异有统计学意义（P〈0．05）。结论：间歇内分泌治疗联合调强适形放射治疗局限性前列腺癌可明显改善患者的临床症状,降低血清PSA水平,提高疾病控制率及患者生存率,降低放疗早期不良反应发生率,疗效优于单纯调强适形放射治疗,是一种安全、有效的治疗措施。     

Outcomes of locally advanced prostate cancer： a single institution study of 209 patients in Japan

Aim:To investigate the outcomes for Asian populations with locally advanced/clinical stage Ⅲ prostate cancer(PCa)treated with currently prevailing modalities.Methods:We reviewed the record of 209 patients with clinical stage ⅢPCa,who were treated at Niigata Cancer Center Hospital between 1992 and 2003.Treatment options included hor-mone therapy-combined radical prostatectomy(RP HT),hormone therapy-combined external beam irradiation(EBRT HT)and primary hormone therapy(PHT).Results:The 5-and 10-year overall survival rates were 80.3%and 46.1% in all cohorts,respectively.The survival rates were 87.3% and 66.5% in the RP HT group,94.9% and70.0% in the EBRT HT group and 66.1% and 17.2% in the PHT group,respectively.A significant survival advantagewas found in the EBRT HT group compared with that in the PHT group(P<0.0001).Also,the RP HT group hadbetter survival than the PHT group(P=0.0107).The 5-and 10-year disease-specific survival rates for all cases were92.5% and 80.0%,respectively.They were 93.8% and 71.4% in the RP HT group,96.6% and 93.6% in theEBRT HT group and 88.6% and 62.3% in the PHT group,respectively.A survival advantage was found in theEBRT HT group compared with the PHT group(P=0.029).No significant difference was found in disease-specificsurvival between the EBRT HT and RP HT groups or between the RP HT and PHT groups.Conclusion:Althoughour findings indicate that radiotherapy plus HT has a survival advantage in this stage of PCa,we recommend therapiesthat take into account the patients'social and medical conditions for Asian men with clinical stage Ⅲ PCa.(Asian JAndrol 2006 Sep;8:555-561)     

老年前列腺癌伴骨转移患者的临床特征及治疗策略

为确定老年前列腺癌伴骨转移患者的临床特征及预后的独立预测因子。本研究回顾性分析了205例老年性前列腺癌伴骨转移患者的临床资料,运用生存曲线分析生存率,运行Cox回归模型进行多因素分析。同时,我们对比了197例年轻的前列腺癌伴骨转移的患者,运用卡方检验比较了上述得到的预测因子。结果显示,所有患者均得到完整随访,其1、2、3和5年生存率分别为95．5％,77．5％,68．5％和33．7％。Gleason评分,原发肿瘤放疗、骨转移数目、ALP、器官和区域淋巴结转移数目均与生存率密切相关。多因素回归分析表明Gleason评分是独立预测因子。相较于年轻患者,老年患者生存率更好,但是接受放疗的老年患者生存率却显著低于年轻患者。以上结果为今后前列腺癌伴骨转移生存预测模型的建立提供了数据支持。     

Evaluating the use of early hormonal therapy in patients with localised or locally advanced prostate cancer

This article evaluates the use of early hormonal therapy in patients with localised or locally advanced prostate cancer. In patients receiving radiotherapy, an overall survival benefit is proven for adjuvant goserelin ('Zoladex') in locally advanced disease. Adjuvant to radical prostatectomy, castration (goserelin or orchiectomy) has demonstrated an overall survival benefit in patients with lymph node metastases. Survival advantages have not yet been proven with nonsteroidal antiandrogens, but immediate or adjuvant bicalutamide ('Casodex') improves objective progression-free survival in patients with locally advanced disease, with certain quality-of-life advantages over castration.     

Clinical features and prognostic factors for patients with bone metastases from prostate cancer

To identify the clinical features and independent predictors of survival in patients with bone metastases from prostate cancer (PCa). We retrospectively analysed 115 PCa patients with bone metastases between 1997 and 2009. The overall survival rate after bone metastases was calculated using the Kaplan–Meier method. The prognostic factors were identified by univariate analysis using a log-rank test and by multivariate analysis using Cox proportional hazards regression models. The follow-up rate was 100%, the follow-up cases during 1, 3 and 5 years were 103, 79 and 55, respectively. The 1-, 3- and 5-year survival rates were 89.1%, 60.9% and 49.8%, respectively, with a median survival time of 48.5 months for patients with bone metastases from PCa. In univariate analysis, age, Gleason score, clinical stage, the number of bone lesions, alkaline phosphatase (ALP) level, invasion of neighbouring organs and non-regional lymph node metastases were correlated with prognosis. By multivariate analysis using Cox regression, ALP level, Gleason score and non-regional lymph node metastases were independent prognostic factors. These prognostic factors will help us to determine the appropriate dose and fraction of radiotherapy for these patients.     

Clinical significance of pulmonary metastases in stage D2 prostate cancer patients

Several prognostic factors such as the extent of bone metastases (EOD) in advanced prostate cancer (PCa) have been reported. Metastasis of the lung is rarely a significant clinical factor in the management of prostate cancer. The present study evaluates the clinical significance of lung metastases. We retrospectively reviewed the PCa database to identify patients with pulmonary metastases at initial diagnosis. The medical records of the patients were examined with respect to age, histologic grade, EOD score, marker response to endocrine therapy and clinical outcome. We then compared several potential clinical factors between patients with and without pulmonary metastases. Next, we retrospectively reviewed autopsy records of 60 Japanese patients who died of hormone-refractory metastatic PCa with particular focus upon metastatic profiles. A comparative study of stage D(2) patients with (n=20) and without (n=77) pulmonary metastases found no significant differences in EOD score, performance status, marker response and survival. Only tumor grade was better in the group with, than without pulmonary metastases (P=0.0120, chi-square analysis). In the series of autopsies, we found pulmonary metastases in 38 cases (63%), following metastases of the bone (57 cases, 95%) and lymph nodes (52 cases, 87%). A retrospective analysis of survival showed that patients with bone or lymph node metastases had a positive relative risk. In contrast, lung metastasis could be a positive prognostic indicator, although the findings were not statistically significant. These data suggest that the presence of pulmonary metastasis has no ominous impact on clinical course and disease outcome even in patients with disseminated prostate cancer.     

Current state of high intensity focused ultrasound (HIFU) as treatment of prostatic carcinoma

ObjectiveTo evaluate the current state of high intensity focused ultrasound as therapeutical option of prostatic carcinoma (PCa)MethodsWe completed an extense review of urologic literature on the role of HIFU on the treatment of PCa.ResultsThis technique is nowadays usually being indicated in Europe as treatment of many cases of either primary or relapsed PCa after radiotherapy. Although some reports suggest that HIFU is very effective as treatment for low and medium risk localized PCa patients, no randomized series comparing this technique with conventional therapies have been presented yet. Great disparity in criteria to define free-disease survival is detected, which make difficult the interpretation of results.ConclusionsExperience of some groups in HIFU is highly promising. Local tumour destruction is evident both in primary and relapsed PCa cases. To make conclusions in the long-term, controlled-randomized trials must be designed, with follow-up to measure benefits in global survival and quality of live. Comparisons must be completed with conventional techniques, and a uniform definition of disease free-survival is necessary.     

Neoadjuvant and Adjuvant Hormone Therapy: How and When?

ContextA significant proportion of patients with prostate cancer (PCa) will experience clinical or biochemical failure after local treatment with radical prostatectomy (RP) or radiotherapy (RT). It is still a matter of debate whether hormone therapy (HT) in either a neoadjuvant or adjuvant setting can offer a survival benefit for these patients.ObjectiveThis review paper discusses how and when neoadjuvant and adjuvant HT could be applied for treatment of PCa. Furthermore, the paper outlines the optimal duration of adjuvant HT to RT for treatment of patients with high-grade localised or locally advanced PCa.Evidence acquisitionThis paper is based on a presentation given at a satellite symposium held at the European Association of Urology (EAU) 2008 annual congress in Milan, Italy. Data were retrieved from recent review articles, original articles, and abstracts on neoadjuvant or adjuvant HT in PCa.Evidence synthesisLuteinising hormone-releasing hormone agonists have become the standard of care in HT. Neoadjuvant androgen deprivation therapy (ADT) to RP seems to have potential to downstage PCa disease but does not offer a survival benefit over RP alone in patients with localised PCa. On the other hand, short-term neoadjuvant ADT to RT appears to improve treatment outcomes compared with RT alone in patients with locally advanced PCa but seems to be specifically indicated in patients with Gleason score 2–6. Adjuvant ADT with RT seems to offer a survival benefit over RT alone in high-risk localised and locally advanced PCa. Recent data indicate that 6-mo ADT is inferior in terms of survival to 3-yr adjuvant ADT after RT for patients with locally advanced PCa. The role of immediate ADT for men with node-positive PCa after RP should be further investigated.ConclusionsNeoadjuvant and adjuvant ADT to local treatment may be indicated in carefully selected patients with PCa.     

Single application of high‐intensity focused ultrasound as a first‐line therapy for clinically localized prostate cancer: 5‐year outcomes

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? High‐intensity focused ultrasound (HIFU) therapy has been proposed for the treatment of localized prostate cancer (PCa) for all risk levels of tumour recurrence. The study adds data on the efficacy of a single HIFU application in the treatment of PCa with different risks of recurrence. Durable cancer control was achieved in 81.7% of patients with low‐risk disease, with rates of efficacy declining in intermediate‐ and high‐risk tumours. The data suggest that the principal domain for minimal invasive HIFU should be low‐risk disease.

OBJECTIVE

• ? To report cancer control results after a single application of high‐intensity focused ultrasonography (HIFU) in patients with localized prostate cancer (PCa), stratified by tumour recurrence risk according to D'Amico risk classification.

PATIENTS AND METHODS

• ? In a retrospective single‐centre study, we analysed the outcomes of patients with localized PCa who were treated with curative intent between December 2002 and October 2006 using an Ablatherm HIFU device (EDAP‐TMS, France).
• ? Transurethral resection of the prostate or adenomectomy were performed before HIFU to downsize large prostate glands.
• ? Oncological failure was determined by the occurrence of biochemical relapse, positive biopsy and/or metastasis. Biochemical relapse was defined as a PSA nadir +1.2 ng/mL (Stuttgart definition), or as a rise in PSA level to ≥0.5 ng/mL if PSA doubling time was ≤6 months. Kaplan–Meier analysis was performed for survival estimates.

RESULTS

• ? A total of 191 consecutive patients were included in the study. The median (range) patient age was 69.7 (51–82) years, and 38, 34 and 28% of these patients were in the low‐, intermediate‐ and high‐risk groups, respectively.
• ? The median (range) follow‐up was 52.8 (0.2–79.8) months.
• ? At 5 years, overall and cancer‐specific survival rates were 86.3% and 98.4%, respectively.
• ? Stratified by risk group, negative biopsy rates were 84.2%, 63.6%, and 67.5% (P = 0.032), 5‐year biochemical‐free survival rates were 84.8%, 64.9% and 54.9% (P < 0.01), and 5‐year disease‐free survival rates were 81.7%, 53.2% and 51.2% (P < 0.01), respectively.

CONCLUSION

• ? Single‐session HIFU is recommended as a curative approach in elderly patients with low‐risk PCa. Patients at higher risk of tumour progression should be counselled regarding the likely need for salvage therapy, including repeat HIFU.

     

Management of High-Risk Localised Prostate Cancer

ContextHigh-risk localised prostate cancer (PCa) is defined as significant likelihood of death from PCa or development of distant metastases. It is important to identify patients at high risk of progression who may benefit from neoadjuvant or adjuvant therapies.ObjectiveTo review definitions for high-risk localised PCa and review outcomes of different treatment modalities.Evidence acquisitionRandomised and nonrandomised clinical trials addressing the characterisation of patients with high-risk PCa and treatment options for this patient population were reviewed, mainly focusing on comparison of monotherapy with multimodality approaches.Evidence synthesisRadical prostatectomy (RP) represents a treatment option for selected high-risk patients and can result in long-term progression-free survival (PFS) in a subset without hormone therapy (HT). HT prior to RP is not considered as a standard treatment in high-risk, clinically localised PC, because survival advantage has never been conclusively demonstrated. Adjuvant “early” androgen-deprivation therapy (ADT) is not recommended for patients with high-risk disease except for pathologically confirmed nodal disease. Adjuvant radiotherapy (RT) after RP in patients with adverse risk factors decreases biochemical recurrence risk with improved local control but without a clear advantage in overall survival (OS). RT with long-term adjuvant HT improves OS. However, the exact period of HT is still controversial, and one must consider the cardiovascular comorbidity status of the patients before initiating ADT. Neoadjuvant chemotherapy can be administered safely in patients with high-risk disease prior to definitive therapy. Although complete responders are very rare, prostate-specific antigen (PSA) responses were present in a substantial number of patients. Early results of adjuvant chemotherapy trials are promising, but ongoing phase 3 trials should be completed to establish any survival advantage.ConclusionsIntegrating local and systemic therapies may be beneficial in the management of high-risk localised or locally advanced PCa.