间歇性雄激素抑制：晚期前列腺癌治疗及改善生活质量的又一选择

背景：持续性雄激素抑制(continuous androgen suppression，CAS)是目前晚期前列腺癌内分泌治疗的金标准。CAS不仅可能导致前列腺癌的雄激素依赖状态迅速丧失，使预后更差，而且可能导致生活质量下降，以及与治疗相关的副作用及费用明显增加。近年来的一些实验研究及临床观察性试验显示，间歇性雄激素抑制(intermittent androgen suppression．LAS)可能避免或至少能够减少以上缺点。但是目前仍有争议。目的：回顾关于LAS的实验及临床研究结果，明确LAS是否为晚期前列腺癌的较为理想的治疗方式。研究选择：选择关于LAS的献，不排除其是否为随机、盲法等论证推荐的章。数据来源：进行全面的检索，检索手段包括电子检索、手工检索及个人通信等。数据提取：对检索到的LAS及CAS研究章中相关信息进行综述。主要观察指标：LAS与CAS比较，可能延缓前列腺癌进展为雄激素非依赖状态，延长生存期，提高生活质量，减少副作用和治疗费用。结果：实验研究提示，周期性地进行LAS可能恢复肿瘤细胞的凋亡能力，从而延缓雄激素非依赖状态的产生；临床观察也提示LAS可能能够延缓前列腺癌进展为雄激素非依赖状态，延长生存期，提高生活质量(恢复性欲、性功能等)以及减少治疗相关的费用和副作用。2个正在进行的随机临床试验的中期分析也证实LAS较之于CAS3年进展率要低，而生活质量尤其是性功能明显改善。结论：越来越多的证据表明LAS治疗晚期前列腺癌是可行的，可能是比CAS更为理想的治疗方式。在推荐其作为晚期前列腺癌的常规甚至标准治疗方式之前，有必要获取来自随机临床试验乃至系统综述的证据进一步证实其可行性及优越性。     

雄激素撤除治疗影响前列腺癌患者健康相关生活质量的因素及护理对策

雄激素撤除治疗(androgen deprivation therapy, ADT)是晚期前列腺癌的主要治疗手段,撤除雄激素后,由于内分泌的改变,使得前列腺癌患者产生严重的雄激素缺乏症状,如潮热、抑郁症、性功能障碍、贫血、肌张力下降,骨质疏松等,甚至发生自发性骨折,严重影响患者的健康相关生活质量(health-related quality of life, Hr-QOL).     

前列腺癌研究新进展:SOX7、SOX9、SOX10在预测前列腺癌生化复发中的重要作用

在西方国家,前列腺癌是老年男性发病率最高的肿瘤之一,致死率排在第二位,仅次于肺癌[1].前列腺特异抗原(PSA)筛选能早期发现前列腺癌并使大量早期前列腺癌得到根治.然而,PSA虽然有很好的敏感性,但其特异性差,前列腺炎、前列腺增生症、急性尿潴留等均可导致PSA升高,加上前列腺癌发病缓慢而且隐匿,所以不能单凭PSA判断前列腺癌的预后.虽然手术去势或者药物去势治疗能极大地降低血清PSA水平、延缓前列腺癌进展,但几乎所有患者在经过14~30个月的雄激素阻断治疗(androgen deprivation therapy,ADT)后产生雄激素抵抗,使其从雄激素依赖型前列腺癌(androgen dependent prostate cancer,ADPC)发展成为雄激素非依赖型前列腺癌(androgen independent prostate cancer,AIPC)或激素抵抗型前列腺癌(hormone-resistant prostate cancer,HRPC),导致前列腺癌复发.一旦发展成为AIPC或HRPC,大多数患者在18个月后死亡[2].所以,很有必要在确诊前列腺癌后找到能判断前列腺癌进展为AIPC或HRPC的生物学指标.     

去势抵抗性前列腺癌药物治疗的新进展

前列腺癌是一种雄激素依赖性恶性肿瘤,雄激素去除是晚期前列腺癌的一线治疗方法,虽然初期疗效肯定,但经过18～20个月,疾病即进展为去势抵抗性前列腺癌（castration—resistantprostatecancer,CRPC）,中位生存期只有1～2年。     

手术去势联合间断抗雄激素药物治疗晚期前列腺癌的疗效和安全性

目的探讨手术去势联合间断抗雄激素药物治疗晚期前列腺癌的疗效和安全性。方法依据不同的治疗方法,将100例晚期前列腺癌患者随机分为对照组和观察组,每组50例。观察组使用手术去势和间断抗雄激素结合治疗患者,对照组选择抗雄激素治疗。观察对照组和观察组治疗前后血清前列腺特异性抗原(PSA)水平、生活质量指标和并发症发生率。随访1～6年,对两组患者无进展生存期及总生存期进行统计学分析。结果观察组治疗6个月后PSA水平[(3.18±1.17)ng/ml]明显低于对照组[(17.32±10.32) ng/ml],生活质量指标比较,观察组明显高于对照组(P0.05)。观察组性欲缺乏率明显高于对照组(P0.05)。两组患者骨质疏松、贫血率、潮热比较差异未见统计学意义(P0.05)。结论手术切除和抗雄激素结合治疗晚期前列腺癌效果明显,可延长患者的生存期,使患者的生活质量得到明显的改善。     

晚期前列腺癌治疗的新靶点

前列腺癌是一种雄激素依赖性恶性肿瘤,雄激素去除是晚期前列腺癌的一线治疗方法,虽然初期疗效肯定,但经过18～20个月,疾病即进展为去势抵抗性前列腺癌(castration-resistant prostate cancer,CRPC),剩余的中位生存期只有1～2年。     

不同去势方法对晚期前列腺癌病人心理状态的影响

前列腺癌在欧美国家是男性最常见的恶性肿瘤。在我国近年来由于人口老龄化的进展和人们生活方式的改变,前列腺的发病率呈逐年升高的趋势。前列腺癌发病呈隐蔽性,大约60%病人确诊时已出现邻近器官浸润、骨转移等,属于晚期前列腺癌。前列腺癌是雄激素依赖的肿瘤。以全面阻断雄激素作用为基础的内分泌治疗是晚期前列腺癌治疗的主要手段[1]。睾丸产生男性机体大约90%雄激素(10%由肾上腺产生)。去势是指     

护理干预在前列腺癌撤除雄激素病人中的应用

前列腺癌是老年男性较常见的恶性肿瘤,随着男性平均寿命的延长,前列腺癌发病率呈明显增加的趋势。前列腺癌撤除雄激素的结果使病人产生比一般中老年男子雄激素部分缺乏综合征更加强烈的雄激素缺乏症状,比较明显的有潮热、骨质疏松症、骨折、性功能障碍、贫血、体重和脂类成分的改变、抑郁等,使前列腺癌病人生存期间的生活质量降低。     

1例进展期前列腺癌的循证治疗

针对进展期前列腺癌的治疗问题,运用循证医学的方法 全面检索相关的临床治疗证据并进行质量评价.结果 显示,各种雄激素阻断方法疗效相似,但早期进行雄激素全阻断的疗效更好;对激素不敏感性前列腺癌,采用米托蒽醌、强的松、多西他赛及苏拉明等化疗药物有一定疗效;锶-89内照射的镇痛效果较传统的外照射好,而双磷酸盐无效;抗雄激素撤退可使部分患者前列腺特异性抗原下降,但临床疗效有待进一步评价.     

生物标记物早期诊断前列腺癌的研究进展

1引言 前列腺癌是欧美国家男性发病率最高的恶性肿瘤,病死率仅次于肺癌.我国作为世界人口最多的发展中国家,近年来随着人均寿命延长,生活西化特别是高热量饮食及缺乏运动,前列腺癌发病率日趋上升[1].早期前列腺癌适宜外科根治术[2],且内分泌治疗效果良好,但大多数前列腺癌诊断时已是进展期或晚期,最终转变为雄激素非依赖型前列腺癌,而目前雄激素非依赖型前列腺癌尚缺乏有效的治疗手段,这使得前列腺癌的早期诊断显得特别重要[3].     

Treatment of advanced prostate cancer

OBJECTIVES: To review the management of advanced prostate cancer, including symptom management, hormonal therapy, and the use of chemotherapy. DATA SOURCES: Published articles and book chapters on advanced prostate cancer. CONCLUSIONS: Advanced prostate cancer is a common problem that has a significant impact on the patient's quality of life. Multiple complications may develop during the course of the disease. Treatment may include local and systemic approaches. Advances in disease treatment include hormonal therapies and chemotherapy. Additional research is needed to determine the optimal treatment for these men. IMPLICATIONS FOR NURSING PRACTICE: Patient education is crucial to the management of advanced prostate cancer in all practice settings. Early and prompt recognition of disease complications will enhance the patient's quality of life.     

Signal transduction in prostate cancer progression

Prostate cancer is the most frequently diagnosed cancer among men and the second leading cause of male cancer deaths in the United States. When prostate cancer initially presents in the clinic, the tumour is dependent on androgen for growth and, therefore, responsive to the surgical or pharmacological ablation of circulating androgens. However, there is a high rate of treatment failure because the disease often recurs as androgen-independent metastases. Surprisingly, this late-stage androgen-independent prostate cancer almost always retains expression of the AR (androgen receptor), despite the near absence of circulating androgens. Although late-stage prostate cancer is androgen-independent, the AR still seems to play a role in cancer cell growth at this stage of disease. Therefore a key to understanding hormone-independent prostate cancer is to determine the mechanism(s) by which the AR can function even in the absence of physiological levels of circulating androgen. This review will focus on the role of growth factor signalling in prostate cancer progression to androgen independence and thus outline potential molecular areas of intervention to treat prostate cancer progression.     

Quality of life for men with prostate cancer

The aim of this article is to selectively review the current research findings related to quality of life and prostate cancer. English-language journals indexed in MEDLINE, PubMed, and CINAHL published between 1999 and 2005 were searched for relevant articles using the following keywords: "quality of life and prostate cancer," "prostatectomy," "radiation therapy," "brachytherapy," "cryotherapy," or "androgen deprivation therapy." References in selected articles were reviewed for potentially relevant articles not identified through database searches. All treatment modalities have a significant impact on quality of life for men with local or advanced prostate cancer. Alterations in sexual functioning cause the most significant impact on quality of life for men. Quality of life is decreased in both the short and long term for men with prostate cancer. Oncology nurses must be cognizant of the challenges that a diagnosis of prostate cancer presents to the man with prostate cancer and his partner. Patients should be fully informed of the potential for impact on quality of life with all treatment modalities, and the oncology nurse can play an important role in both providing this information and supporting the patient when quality of life is impacted.     

Organ preservation

OBJECTIVES: To review organ preservation in cancer treatment within the context of organ function, treatment-related acute and late toxicities, outcome data, and quality of life. DATA SOURCES: Published review and research articles, proceedings of conferences, and oncology textbooks. CONCLUSIONS: The implementation of surgery, with sequential and/or concurrent chemoradiation, has advanced the success of organ preservation in multiple tumor types and organ systems. Integral to the discussion of organ preservation is consideration of quality of life. IMPLICATIONS FOR NURSING PRACTICE: An understanding of organ preservation in cancer treatment will allow oncology nurses to be more effective patient advocates by providing current information that can be integrated into patient care and education.     

Herbal supplement PC-Spes for prostate cancer

OBJECTIVE: To determine the efficacy and toxicity of the herbal supplement PC-Spes in prostate cancer patients. METHODS: Literature search through MEDLINE (1966-October 2001), PubMed, and abstracts from the Annual Meeting of the American Society of Clinical Oncology (1995-2001). RESULTS: PC-Spes was associated with biochemical and clinical response in some prostate cancer patients. The mechanisms of action of PC-Spes appeared to be related to its estrogenic activity. CONCLUSIONS: PC-Spes is associated with some efficacy in prostate cancer patients. Due to the limited data available, it should not be used to replace standard androgen suppression therapy in androgen-dependent patients. PC-Spes may have a role for patients who have failed standard treatments for androgen-independent disease and have no history of thromboembolism or abnormal bleeding. PC-Spes has a toxicity profile similar to those of androgen suppression and estrogen therapy.     

Modulation of protein phosphatase 2A activity alters androgen-independent growth of prostate cancer cells: therapeutic implications

Earlier we identified PPP2CA, which encodes for the α-isoform of protein phosphatase 2A (PP2A) catalytic subunit, as one of the downregulated genes in androgen-independent prostate cancer. PP2A is a serine/threonine phosphatase and a potent tumor suppressor involved in broad cellular functions; however, its role in prostate cancer has not yet been determined. Here, we have investigated the effect of PP2A activity modulation on the androgen-independent growth of prostate cancer cells. Our data show that the PPP2CA expression and PP2A activity is downregulated in androgen-independent (C4-2) prostate cancer cells as compared with androgen-dependent (LNCaP) cells. Downregulation of PP2A activity by pharmacologic inhibition or short interfering RNA-mediated PPP2CA silencing sustains the growth of LNCaP cells under an androgen-deprived condition by relieving the androgen deprivation-induced cell-cycle arrest and preventing apoptosis. Immunoblot analyses reveal enhanced phosphorylation of Akt, extracellular signal-regulated kinase (ERK), BAD, increased expression of cyclins (A1/D1), and decreased expression of cyclin inhibitor (p27) on PP2A downregulation. Furthermore, our data show that androgen receptor (AR) signaling is partially maintained in PP2A-inhibited cells through increased AR expression and ligand-independent phosphorylation. Pharmacologic inhibition of Akt, ERK, and AR suggest a role of these signaling pathways in facilitating the androgen-independent growth of LNCaP cells. These observations are supported by the effect of ceramide, a PP2A activator, on androgen-independent C4-2 cells. Ceramide inhibited the growth of C4-2 cells on androgen deprivation, an effect that could be abrogated by PP2A downregulation. Altogether, our findings suggest that modulation of PP2A activity may represent an alternative therapeutic approach for the treatment of advanced androgen-independent prostate cancer.     

Androgen receptor-negative human prostate cancer cells induce osteogenesis in mice through FGF9-mediated mechanisms

In prostate cancer, androgen blockade strategies are commonly used to treat osteoblastic bone metastases. However, responses to these therapies are typically brief, and the mechanism underlying androgen-independent progression is not clear. Here, we established what we believe to be the first human androgen receptor-negative prostate cancer xenografts whose cells induced an osteoblastic reaction in bone and in the subcutis of immunodeficient mice. Accordingly, these cells grew in castrated as well as intact male mice. We identified FGF9 as being overexpressed in the xenografts relative to other bone-derived prostate cancer cells and discovered that FGF9 induced osteoblast proliferation and new bone formation in a bone organ assay. Mice treated with FGF9-neutralizing antibody developed smaller bone tumors and reduced bone formation. Finally, we found positive FGF9 immunostaining in prostate cancer cells in 24 of 56 primary tumors derived from human organ-confined prostate cancer and in 25 of 25 bone metastasis cases studied. Collectively, these results suggest that FGF9 contributes to prostate cancer-induced new bone formation and may participate in the osteoblastic progression of prostate cancer in bone. Androgen receptor-null cells may contribute to the castration-resistant osteoblastic progression of prostate cancer cells in bone and provide a preclinical model for studying therapies that target these cells.     

Gender differences in depression and antidepressant pharmacokinetics and adverse events

OBJECTIVE: To review data generated by studies examining gender differences in the prevalence of depression, as well as in antidepressant pharmacokinetics, pharmacodynamics, and adverse events. DATA SOURCES: Published articles and abstracts were identified through MEDLINE (January 1966-April 1999) using the following search terms: antidepressant, response, gender, pharmacokinetic, pharmacodynamic, female, side effect, and adverse events. All articles that assessed gender differences in antidepressant response, pharmacokinetics, and adverse events, as well as articles that evaluated postulated mechanisms for these differences, were reviewed. Additional articles were identified from bibliographies of retrieved articles. STUDY SELECTION AND DATA EXTRACTION: All relevant abstracts, studies, and review articles were evaluated. DATA SYNTHESIS: Gender differences in the prevalence of depression have been reported and may result from the interaction of several factors. Women have been shown to have a higher incidence of depression, which may be due to artifact, social, or biologic reasons. Studies suggest that the pharmacokinetic disposition of popular antidepressants varies between men and women, and women taking antidepressants may exhibit a different adverse event profile. Only one study specifically evaluated gender differences in antidepressant treatment response. CONCLUSIONS: Further research elucidating gender differences in response to antidepressant treatment and on depression prevalence is needed. Some studies report that the pharmacokinetics of antidepressants may vary between men and women. Therefore, clinicians should be aware that potential differences in antidepressant pharmacokinetics may exist, and a dosage adjustment may be necessary for women to ensure a favorable drug response, compliance, and decreased incidence of adverse events.     

Development of a prostate-specific promoter for gene therapy against androgen-independent prostate cancer

Androgen ablation has been the standard treatment for metastasized prostate cancer. In most cases, however, prostate cancer cells eventually lose androgen dependency and become refractory to the conventional endocrine therapy. Androgen-independent prostate cancer is characterized by a heterogeneous loss of androgen receptor (AR) expression among tumor cells. Prostate-specific promoters such as prostate-specific antigen and rat probasin (rPB) promoters have been examined in the development of gene therapy targeted to prostate cancer. However, those promoters require binding of the androgen–AR complex to the androgen-response element and are active only in the androgen-dependent prostate cancer cell lines and not in the androgen-independent cell lines. To target transgene expression in androgen-independent prostate cancer, we designed a prostate-specific promoter that is activated by the retinoids–retinoid receptor complex instead of the androgen–AR complex. The modified rPB promoters expressed transgenes in response to retinoid in both androgen-dependent and androgen-independent prostate cancer cells and not in other cancer cell lines or in human normal cells, in vitro and in vivo. Furthermore, the combination of retinoid treatment and adenovirus-mediated gene transfer of the modified rPB-driven HSV-tk gene resulted in a significant growth suppression of the androgen-independent prostate cancer cells in the presence of the prodrug ganciclovir. This study suggests that tailoring of the hormone-responsive elements may offer a new therapeutic opportunity against the hormone-refractory stage of prostate cancer.