Pub Date : 2001-04-01DOI: 10.1046/J.1525-1411.2001.32005.X
J. Chun, R. Pruthi
{"title":"Is Neoadjuvant Hormonal Therapy Before Radical Prostatectomy Indicated","authors":"J. Chun, R. Pruthi","doi":"10.1046/J.1525-1411.2001.32005.X","DOIUrl":"https://doi.org/10.1046/J.1525-1411.2001.32005.X","url":null,"abstract":"","PeriodicalId":22947,"journal":{"name":"The open prostate cancer journal","volume":"134 25","pages":"59-64"},"PeriodicalIF":0.0,"publicationDate":"2001-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91403235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2001-04-01DOI: 10.1046/J.1525-1411.2001.32001.X
P. Clark, H. Levin, P. Kupelian, C. Reddy, C. Zippe, E. Klein
Purpose: We examined the results after radical prostatectomy (RP) for clinically localized prostate cancer to determine the 5- and 8-year disease-specific and biochemical relapse-free survival (bRFS), and the clinical and pathologic variables that predict biochemical failure. Materials and Methods: Nine hundred six patients underwent RP for clinically localized prostate cancer between 1990 and 1999. No patient received neoadjuvant or adjuvant therapy. The mean age was 61.9 years (range 40–77 years). The mean preoperative prostate specific antigen (PSA) level was 8.7 ng/ml (range 0.3–54.0). Seventy-six percent of patients had a biopsy Gleason score ≤6, and 49% had disease at clinical Stage T1c. Eighteen percent of patients reported a family history of prostate cancer. Actuarial bRFS rates were calculated using Kaplan-Meier analysis. Results: Pathologic analysis showed that 43% of patients had extracapsular extension, 44% had pathologic Gleason scores ≤6, 23% had positive margins, 8.9% had seminal vesicle invasion, and 1.9% had lymph node metastases. At a mean follow-up of 44 months (range 1–114), the 5- and 8-year cancer-specific survival rates were 97% and 95%, respectively. The actuarial 5- and 8-year bRFS rates were 81% and 76%, respectively. Patients with organ-confined disease had a 100% cancer-specific survival rate and a 92% bRFS rate at both 5 and 8 years. On multivariate analysis, a positive family history (p = 0.019), clinical stage (p = 0.014), preoperative PSA level (p < 0.001), pathologic Gleason score (p < 0.001), extracapsular extension (p = 0.03), positive margins (p < 0.0001), and seminal vesicle invasion (p = 0.0003) were all independent predictors of bRFS. Conclusion: Radical prostatectomy for patients with localized prostate cancer has a high rate of cure for appropriately selected patients.
{"title":"Intermediate‐Term Outcome with Radical Prostatectomy for Localized Prostate Cancer: The Cleveland Clinic Experience","authors":"P. Clark, H. Levin, P. Kupelian, C. Reddy, C. Zippe, E. Klein","doi":"10.1046/J.1525-1411.2001.32001.X","DOIUrl":"https://doi.org/10.1046/J.1525-1411.2001.32001.X","url":null,"abstract":"Purpose: We examined the results after radical prostatectomy (RP) for clinically localized prostate cancer to determine the 5- and 8-year disease-specific and biochemical relapse-free survival (bRFS), and the clinical and pathologic variables that predict biochemical failure. \u0000 \u0000 \u0000 \u0000Materials and Methods: Nine hundred six patients underwent RP for clinically localized prostate cancer between 1990 and 1999. No patient received neoadjuvant or adjuvant therapy. The mean age was 61.9 years (range 40–77 years). The mean preoperative prostate specific antigen (PSA) level was 8.7 ng/ml (range 0.3–54.0). Seventy-six percent of patients had a biopsy Gleason score ≤6, and 49% had disease at clinical Stage T1c. Eighteen percent of patients reported a family history of prostate cancer. Actuarial bRFS rates were calculated using Kaplan-Meier analysis. \u0000 \u0000 \u0000 \u0000Results: Pathologic analysis showed that 43% of patients had extracapsular extension, 44% had pathologic Gleason scores ≤6, 23% had positive margins, 8.9% had seminal vesicle invasion, and 1.9% had lymph node metastases. At a mean follow-up of 44 months (range 1–114), the 5- and 8-year cancer-specific survival rates were 97% and 95%, respectively. The actuarial 5- and 8-year bRFS rates were 81% and 76%, respectively. Patients with organ-confined disease had a 100% cancer-specific survival rate and a 92% bRFS rate at both 5 and 8 years. On multivariate analysis, a positive family history (p = 0.019), clinical stage (p = 0.014), preoperative PSA level (p < 0.001), pathologic Gleason score (p < 0.001), extracapsular extension (p = 0.03), positive margins (p < 0.0001), and seminal vesicle invasion (p = 0.0003) were all independent predictors of bRFS. \u0000 \u0000 \u0000 \u0000Conclusion: Radical prostatectomy for patients with localized prostate cancer has a high rate of cure for appropriately selected patients.","PeriodicalId":22947,"journal":{"name":"The open prostate cancer journal","volume":"16 1","pages":"118-125"},"PeriodicalIF":0.0,"publicationDate":"2001-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81964429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2001-04-01DOI: 10.1046/J.1525-1411.2001.32002.X
C. Zeoli, M. Maitland, Herbert Rose, B. Bloom, A. Mittelman, J. Geliebter
Objective: The objective is to develop an immunotherapeutic vaccine for the treatment of metastatic prostate cancer. Results: Bacille Calmette Guerin (BCG) were engineered to express prostate specific antigen (PSA) or prostate specific membrane antigen (PSMA). Western blotting techniques indicate that recombinant BCG (rBCG) express approximately 25 ng PSA or 112 pg PSMA per 1 μg microgram of protein in rBCG bacterial lysates. Discussion: BCG, the vaccine for tuberculosis, is a potent immunologic adjuvant stimulating both the humoral and cell-mediated immune systems. Prostate cancer patients can generate cytotoxic lymphocytes against specific peptides from normal, self-molecules such as PSA and PSMA. Therefore, a rBCG vaccine that expresses prostate specific proteins may stimulate an immune response to recognize and destroy prostate cancer cells. Conclusion: BCG can be engineered to express prostate specific molecules and may be useful as an immunotherapeutic vaccine against prostate cancer.
目的:目的是开发一种用于治疗转移性前列腺癌的免疫治疗疫苗。结果:卡介苗(Bacille Calmette Guerin, BCG)表达前列腺特异性抗原(PSA)或前列腺特异性膜抗原(PSMA)。Western blotting技术表明重组卡介苗(rBCG)在rBCG细菌裂解物中每1 μg微克蛋白表达约25 ng PSA或112 pg PSMA。讨论:结核疫苗卡介苗是一种有效的免疫佐剂，可刺激体液免疫系统和细胞免疫系统。前列腺癌患者可以产生细胞毒性淋巴细胞，对抗来自正常、自我分子(如PSA和PSMA)的特定肽。因此，表达前列腺特异性蛋白的rBCG疫苗可能会刺激免疫反应来识别和摧毁前列腺癌细胞。结论:卡介苗可表达前列腺特异性分子，可作为前列腺癌免疫治疗疫苗。
{"title":"Expression of Prostate Specific Molecules in Bacille Calmette‐Guerin: An Immunotherapeutic Approach to Prostate Cancer","authors":"C. Zeoli, M. Maitland, Herbert Rose, B. Bloom, A. Mittelman, J. Geliebter","doi":"10.1046/J.1525-1411.2001.32002.X","DOIUrl":"https://doi.org/10.1046/J.1525-1411.2001.32002.X","url":null,"abstract":"Objective: The objective is to develop an immunotherapeutic vaccine for the treatment of metastatic prostate cancer. \u0000 \u0000 \u0000 \u0000Results: Bacille Calmette Guerin (BCG) were engineered to express prostate specific antigen (PSA) or prostate specific membrane antigen (PSMA). Western blotting techniques indicate that recombinant BCG (rBCG) express approximately 25 ng PSA or 112 pg PSMA per 1 μg microgram of protein in rBCG bacterial lysates. \u0000 \u0000 \u0000 \u0000Discussion: BCG, the vaccine for tuberculosis, is a potent immunologic adjuvant stimulating both the humoral and cell-mediated immune systems. Prostate cancer patients can generate cytotoxic lymphocytes against specific peptides from normal, self-molecules such as PSA and PSMA. Therefore, a rBCG vaccine that expresses prostate specific proteins may stimulate an immune response to recognize and destroy prostate cancer cells. \u0000 \u0000 \u0000 \u0000Conclusion: BCG can be engineered to express prostate specific molecules and may be useful as an immunotherapeutic vaccine against prostate cancer.","PeriodicalId":22947,"journal":{"name":"The open prostate cancer journal","volume":"24 1","pages":"92-97"},"PeriodicalIF":0.0,"publicationDate":"2001-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84925994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2001-04-01DOI: 10.1046/J.1525-1411.2001.32007.X
D. Reese, Paige Fratesi, Michelle Corry, W. Novotny, E. Holmgren, E. Small
Objective: Vascular endothelial growth factor (VEGF) is a glycoprotein that is important in promoting tumor angiogenesis. Recombinant humanized anti (rhuMAb)-VEGF is a humanized murine monoclonal antibody that neutralizes VEGF activity and has shown promise in animal tumor models. Methods: To evaluate the efficacy and safety of single-agent rhuMAb VEGF in metastatic androgen-independent prostate cancer (AIPC), we treated 15 patients with 10 mg/kg rhuMAb VEGF every 14 days for six infusions (one cycle), followed by additional treatment for selected patients who had a response or were stable. Results: After one cycle, none of the 15 patients who were evaluable for tumor response had an objective complete or partial response. Three possible mixed responses were observed. No patient achieved a >50% decrease in serum prostate specific antigen (PSA) level after one cycle. Four patients (27%) had a PSA decline of 50%. The median time to objective progression was 118 days, and the median time to PSA progression was 57 days. Toxicity was generally mild, with asthenia present in 6 (40%) of 15 patients. Severe hyponatremia developed in two patients, although the association with rhuMAb VEGF was unclear. Conclusions: We concluded that single-agent rhuMAb VEGF in this dose and with this schedule did not produce significant objective responses in patients with AIPC. Further development of this agent in patients with prostate cancer should focus on earlier stage disease or should evaluate it in combination with other therapies.
{"title":"A Phase II Trial of Humanized Anti‐Vascular Endothelial Growth Factor Antibody for the Treatment of Androgen‐Independent Prostate Cancer","authors":"D. Reese, Paige Fratesi, Michelle Corry, W. Novotny, E. Holmgren, E. Small","doi":"10.1046/J.1525-1411.2001.32007.X","DOIUrl":"https://doi.org/10.1046/J.1525-1411.2001.32007.X","url":null,"abstract":"Objective: Vascular endothelial growth factor (VEGF) is a glycoprotein that is important in promoting tumor angiogenesis. Recombinant humanized anti (rhuMAb)-VEGF is a humanized murine monoclonal antibody that neutralizes VEGF activity and has shown promise in animal tumor models. Methods: To evaluate the efficacy and safety of single-agent rhuMAb VEGF in metastatic androgen-independent prostate cancer (AIPC), we treated 15 patients with 10 mg/kg rhuMAb VEGF every 14 days for six infusions (one cycle), followed by additional treatment for selected patients who had a response or were stable. Results: After one cycle, none of the 15 patients who were evaluable for tumor response had an objective complete or partial response. Three possible mixed responses were observed. No patient achieved a >50% decrease in serum prostate specific antigen (PSA) level after one cycle. Four patients (27%) had a PSA decline of 50%. The median time to objective progression was 118 days, and the median time to PSA progression was 57 days. Toxicity was generally mild, with asthenia present in 6 (40%) of 15 patients. Severe hyponatremia developed in two patients, although the association with rhuMAb VEGF was unclear. Conclusions: We concluded that single-agent rhuMAb VEGF in this dose and with this schedule did not produce significant objective responses in patients with AIPC. Further development of this agent in patients with prostate cancer should focus on earlier stage disease or should evaluate it in combination with other therapies.","PeriodicalId":22947,"journal":{"name":"The open prostate cancer journal","volume":"15 1","pages":"65-70"},"PeriodicalIF":0.0,"publicationDate":"2001-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85367254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2001-04-01DOI: 10.1046/J.1525-1411.2001.32009.X
A. Pecora, F. Richter, A. Pavlick, V. Lanteri, John Scheuch, S. Levy, G. Rosenberg, J. Vitenson
Objective: Patients with metastatic hormone-refractory prostate cancer have a poor overall survival rate. Newer agents have shown promise in slowing disease progression but are mostly ineffective in improving the overall survival rate, are toxic, and require intravenous administration. In an attempt to maintain treatment efficacy, but to minimize toxicity and improve ease of use, we conducted a pilot trial of an oral regimen consisting of ketoconazole, hydrocortisone, and cyclophosphamide combination therapy. Materials and Methods: Twenty-seven patients with metastatic hormone-refractory prostate cancer were treated with an oral regimen of ketoconazole, 400 mg tid, and hydrocortisone, 20 mg qam and 10 mg qpm, on Days 1–28. Cyclophosphamide, 100 mg/m2, was added on Days 1–14. Treatment was recycled every 28 days. Progression of disease was defined by a progressively rising prostate specific antigen (PSA) level, new lesions as seen on bone scans, or progression of soft-tissue disease. Patient age ranged from 57 to 87 years. Performance status (PS; Eastern Cooperative Oncology Group scale) was 0–2. Pretreatment PSA values ranged from 5.8 ng/mL to 3400 ng/mL (median 68). Results: Twenty-one (78%) of 27 patients with elevated PSA levels demonstrated a ≥50% decline in PSA level for 3 consecutive months. Of the remaining six patients (22%), two progressed within 3 months, two withdrew from the study due to toxicity, and two responded with 96 months, with a median response duration of 9 months. Twenty-two (81%) of 27 patients experienced no significant toxicity, 4 of 27 patients experienced Grade I–III gastrointestinal toxicity, and 1 of 27 patients experienced Grade III hematologic toxicity. Conclusions: The combination of ketoconazole, hydrocortisone, and cyclophosphamide is a well-tolerated oral regimen for the treatment of patients with metastatic hormone-refractory prostate cancer with significant disease activity, and it warrants further investigation.
{"title":"Treatment of Metastatic Hormone Refractory Prostate Cancer with Ketoconazole, Hydrocortisone, and Cyclophosphamide","authors":"A. Pecora, F. Richter, A. Pavlick, V. Lanteri, John Scheuch, S. Levy, G. Rosenberg, J. Vitenson","doi":"10.1046/J.1525-1411.2001.32009.X","DOIUrl":"https://doi.org/10.1046/J.1525-1411.2001.32009.X","url":null,"abstract":"Objective: Patients with metastatic hormone-refractory prostate cancer have a poor overall survival rate. Newer agents have shown promise in slowing disease progression but are mostly ineffective in improving the overall survival rate, are toxic, and require intravenous administration. In an attempt to maintain treatment efficacy, but to minimize toxicity and improve ease of use, we conducted a pilot trial of an oral regimen consisting of ketoconazole, hydrocortisone, and cyclophosphamide combination therapy. \u0000 \u0000 \u0000 \u0000Materials and Methods: Twenty-seven patients with metastatic hormone-refractory prostate cancer were treated with an oral regimen of ketoconazole, 400 mg tid, and hydrocortisone, 20 mg qam and 10 mg qpm, on Days 1–28. Cyclophosphamide, 100 mg/m2, was added on Days 1–14. Treatment was recycled every 28 days. Progression of disease was defined by a progressively rising prostate specific antigen (PSA) level, new lesions as seen on bone scans, or progression of soft-tissue disease. Patient age ranged from 57 to 87 years. Performance status (PS; Eastern Cooperative Oncology Group scale) was 0–2. Pretreatment PSA values ranged from 5.8 ng/mL to 3400 ng/mL (median 68). \u0000 \u0000 \u0000 \u0000Results: Twenty-one (78%) of 27 patients with elevated PSA levels demonstrated a ≥50% decline in PSA level for 3 consecutive months. Of the remaining six patients (22%), two progressed within 3 months, two withdrew from the study due to toxicity, and two responded with 96 months, with a median response duration of 9 months. Twenty-two (81%) of 27 patients experienced no significant toxicity, 4 of 27 patients experienced Grade I–III gastrointestinal toxicity, and 1 of 27 patients experienced Grade III hematologic toxicity. \u0000 \u0000 \u0000 \u0000Conclusions: The combination of ketoconazole, hydrocortisone, and cyclophosphamide is a well-tolerated oral regimen for the treatment of patients with metastatic hormone-refractory prostate cancer with significant disease activity, and it warrants further investigation.","PeriodicalId":22947,"journal":{"name":"The open prostate cancer journal","volume":"45 1","pages":"71-75"},"PeriodicalIF":0.0,"publicationDate":"2001-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79897213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2001-04-01DOI: 10.1046/J.1525-1411.2001.32003.X
L. Drew, R. Fine, A. Raffo, D. Petrylak
Objectives: The mitogen-activated protein kinase (MAPK) cascade is involved in the control of cell growth and differentiation. In this study, we have investigated the effect of androgen withdrawal on this pathway and its potential role in the induction of neuroendocrine (NE) differentiation. For this purpose, we used the androgen-sensitive human prostate cancer LNCaP cells as an in vitro model. Methods and Results: The incubation of LNCaP cells for 6 days in medium, either free of serum or supplemented with serum depleted of steroids (i.e., charcoal-stripped serum), resulted in NE differentiation as determined by growth arrest, the formation of neurites, and an increase in neuron-specific enolase protein expression. Sustained extracellular-regulated kinase (ERK) phosphorylation/activity and enhanced ERK/MAPK kinase (MEK) activity also were observed on serum or steroid withdrawal. A synthetic androgen, mibolerone, blocked both NE differentiation and ERK phosphorylation induced by the incubation of the cells in steroid-depleted medium, thus confirming androgen specificity. Furthermore, a culture of LNCaP cells in complete medium supplemented with a 5-α-reductase inhibitor, finasteride, also induced NE differentiation and ERK phosphorylation. This implicates depletion of the principal prostatic androgen, dihydrotestosterone, as the specific mediator of these effects. In contrast to ERK, the phosphorylation status of the stress-activated MAPK members c-Jun N-terminal kinase and p38 was not altered by steroid withdrawal. The MEK inhibitor U0126 was used to study the potential role of ERK in regulating NE differentiation. However, U0126 did not reverse NE differentiation associated with steroid depletion, even though ERK phosphorylation was suppressed. The role of erb B tyrosine kinase receptors in mediating ERK phosphorylation during steroid depletion also was investigated. erb B1 protein levels decreased, erb B3 protein levels and phosphorylation remained unaltered, and erb B2 phosphoprotein levels increased after steroid depletion. Stable expression of an intracellular antibody to erb B2, however, did not prevent the up-regulation of ERK phosphorylation that is associated with steroid depletion. Conclusions: Androgen depletion induces sustained erb B-independent ERK signaling in LNCaP cells, however, this pathway is not essential for the associated NE differentiation.
目的:丝裂原活化蛋白激酶(MAPK)级联参与细胞生长和分化的调控。在这项研究中，我们研究了雄激素戒断对这一途径的影响及其在诱导神经内分泌(NE)分化中的潜在作用。为此，我们使用雄激素敏感的人前列腺癌LNCaP细胞作为体外模型。方法和结果:LNCaP细胞在培养基中孵育6天，不含血清或添加去类固醇血清(即木炭剥离血清)，通过生长停滞、神经突形成和神经元特异性烯醇化酶蛋白表达的增加，导致NE分化。持续的细胞外调节激酶(ERK)磷酸化/活性和增强的ERK/MAPK激酶(MEK)活性也在血清或类固醇戒断中观察到。合成雄激素米bolerone阻断了细胞在缺乏类固醇的培养基中孵育引起的NE分化和ERK磷酸化，从而证实了雄激素的特异性。此外，在添加5-α-还原酶抑制剂非那雄胺的完全培养基中培养LNCaP细胞，也能诱导NE分化和ERK磷酸化。这意味着主要的前列腺雄激素，双氢睾酮的消耗，作为这些影响的特定中介。与ERK相反，应激激活的MAPK成员c-Jun n -末端激酶和p38的磷酸化状态不受类固醇停药的影响。我们使用MEK抑制剂U0126来研究ERK在调节NE分化中的潜在作用。然而，U0126并没有逆转与类固醇消耗相关的NE分化，即使ERK磷酸化被抑制。在类固醇耗竭过程中，erbb酪氨酸激酶受体介导ERK磷酸化的作用也被研究。erb B1蛋白水平下降，erb B3蛋白水平和磷酸化保持不变，erb B2磷酸化蛋白水平升高。然而，细胞内erbb B2抗体的稳定表达并不能阻止与类固醇耗竭相关的ERK磷酸化上调。结论:雄激素消耗诱导LNCaP细胞中持续的erbb -独立ERK信号传导，然而，这一途径并不是相关NE分化所必需的。
{"title":"Sustained Activation of Extracellular Signal‐Regulated Kinase (ERK) Signaling in Human Prostate Cancer LNCaP Cells Depleted of Androgen","authors":"L. Drew, R. Fine, A. Raffo, D. Petrylak","doi":"10.1046/J.1525-1411.2001.32003.X","DOIUrl":"https://doi.org/10.1046/J.1525-1411.2001.32003.X","url":null,"abstract":"Objectives: The mitogen-activated protein kinase (MAPK) cascade is involved in the control of cell growth and differentiation. In this study, we have investigated the effect of androgen withdrawal on this pathway and its potential role in the induction of neuroendocrine (NE) differentiation. For this purpose, we used the androgen-sensitive human prostate cancer LNCaP cells as an in vitro model. \u0000 \u0000 \u0000 \u0000Methods and Results: The incubation of LNCaP cells for 6 days in medium, either free of serum or supplemented with serum depleted of steroids (i.e., charcoal-stripped serum), resulted in NE differentiation as determined by growth arrest, the formation of neurites, and an increase in neuron-specific enolase protein expression. Sustained extracellular-regulated kinase (ERK) phosphorylation/activity and enhanced ERK/MAPK kinase (MEK) activity also were observed on serum or steroid withdrawal. A synthetic androgen, mibolerone, blocked both NE differentiation and ERK phosphorylation induced by the incubation of the cells in steroid-depleted medium, thus confirming androgen specificity. Furthermore, a culture of LNCaP cells in complete medium supplemented with a 5-α-reductase inhibitor, finasteride, also induced NE differentiation and ERK phosphorylation. This implicates depletion of the principal prostatic androgen, dihydrotestosterone, as the specific mediator of these effects. In contrast to ERK, the phosphorylation status of the stress-activated MAPK members c-Jun N-terminal kinase and p38 was not altered by steroid withdrawal. The MEK inhibitor U0126 was used to study the potential role of ERK in regulating NE differentiation. However, U0126 did not reverse NE differentiation associated with steroid depletion, even though ERK phosphorylation was suppressed. The role of erb B tyrosine kinase receptors in mediating ERK phosphorylation during steroid depletion also was investigated. erb B1 protein levels decreased, erb B3 protein levels and phosphorylation remained unaltered, and erb B2 phosphoprotein levels increased after steroid depletion. Stable expression of an intracellular antibody to erb B2, however, did not prevent the up-regulation of ERK phosphorylation that is associated with steroid depletion. \u0000 \u0000 \u0000 \u0000Conclusions: Androgen depletion induces sustained erb B-independent ERK signaling in LNCaP cells, however, this pathway is not essential for the associated NE differentiation.","PeriodicalId":22947,"journal":{"name":"The open prostate cancer journal","volume":"5 1","pages":"105-117"},"PeriodicalIF":0.0,"publicationDate":"2001-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86505209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2001-01-01DOI: 10.1046/J.1525-1411.2001.31003.X
S. Halabi, M. Conaway, E. Small, N. Vogelzang, N. Dawson
Objectives: To explore whether serum prostate specific antigen (PSA) decline can be used as a prognostic factor for survival among patients with androgen-independent prostate cancer (AIPC) who are treated with a secondary hormonal therapy, megestrol acetate. Materials and Methods: One hundred forty-nine patients were randomized with equal probability to either low-dose (160 mg/day) or high-dose (640 mg/day) megestrol acetate. Patients were stratified on performance status (0–1, or 2) and on disease measurability (measurable, or evaluable disease). Results: Patients with high pretreatment PSA (≥95 ng/ml) had worse survival times than patients with low PSA (<95), with a hazard ratio of 1.6 (p = 0.003). The median survival times for patients with a ≥50% reduction in PSA at 8 weeks and those patients without a 50% reduction were 15 and 11 months, respectively (p = 0.763). A landmark analysis at 8 weeks showed that a PSA decline was significantly associated with survival. The survival time for patients whose PSA dropped below the pretreatment levels (median = 15 months) were significantly longer than for patients who did not have a decline in PSA (median = 9 months, p = 0.031). Similar significant results were observed between PSA reduction and survival when landmark analyses were performed at 12 and 16 weeks. PSA changes during the first 45 days after the initiation of therapy were significantly related to survival. The median survival time for patients whose PSA doubled during the first 45 days after treatment and for patients whose PSA did not double during the first 45 days were 10 and 14 months, respectively (p = 0.020). Conclusions: PSA decline is significantly associated with longer survival times in prostate patients treated with secondary hormonal manipulation. Longer survival time is observed among the following AIPC patients: 1) those whose pretreatment PSA were 0% from baseline; and 3) those whose PSA did not double during the first 45 days of therapy. If these observations are generalizeable, PSA decline as a criterion of response could be used to rapidly approve new agents in patients treated with second-line hormonal therapy.
{"title":"Serum Prostate Specific Antigen as a Predictor of Survival in Prostate Cancer Patients Treated with Second‐Line Hormonal Therapy (CALGB 9181)","authors":"S. Halabi, M. Conaway, E. Small, N. Vogelzang, N. Dawson","doi":"10.1046/J.1525-1411.2001.31003.X","DOIUrl":"https://doi.org/10.1046/J.1525-1411.2001.31003.X","url":null,"abstract":"Objectives: To explore whether serum prostate specific antigen (PSA) decline can be used as a prognostic factor for survival among patients with androgen-independent prostate cancer (AIPC) who are treated with a secondary hormonal therapy, megestrol acetate. Materials and Methods: One hundred forty-nine patients were randomized with equal probability to either low-dose (160 mg/day) or high-dose (640 mg/day) megestrol acetate. Patients were stratified on performance status (0–1, or 2) and on disease measurability (measurable, or evaluable disease). Results: Patients with high pretreatment PSA (≥95 ng/ml) had worse survival times than patients with low PSA (<95), with a hazard ratio of 1.6 (p = 0.003). The median survival times for patients with a ≥50% reduction in PSA at 8 weeks and those patients without a 50% reduction were 15 and 11 months, respectively (p = 0.763). A landmark analysis at 8 weeks showed that a PSA decline was significantly associated with survival. The survival time for patients whose PSA dropped below the pretreatment levels (median = 15 months) were significantly longer than for patients who did not have a decline in PSA (median = 9 months, p = 0.031). Similar significant results were observed between PSA reduction and survival when landmark analyses were performed at 12 and 16 weeks. PSA changes during the first 45 days after the initiation of therapy were significantly related to survival. The median survival time for patients whose PSA doubled during the first 45 days after treatment and for patients whose PSA did not double during the first 45 days were 10 and 14 months, respectively (p = 0.020). Conclusions: PSA decline is significantly associated with longer survival times in prostate patients treated with secondary hormonal manipulation. Longer survival time is observed among the following AIPC patients: 1) those whose pretreatment PSA were 0% from baseline; and 3) those whose PSA did not double during the first 45 days of therapy. If these observations are generalizeable, PSA decline as a criterion of response could be used to rapidly approve new agents in patients treated with second-line hormonal therapy.","PeriodicalId":22947,"journal":{"name":"The open prostate cancer journal","volume":"9 1","pages":"18-25"},"PeriodicalIF":0.0,"publicationDate":"2001-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86922281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2001-01-01DOI: 10.1046/J.1525-1411.2001.003001036.X
Joshua D. Hartzell, T. Kao, J. C. Holland, S. Holt, J. Moul
Objectives: While controversial, the use of prostate specific antigen (PSA) testing is common and may reduce the morbidity and mortality associated with prostate cancer. The use of age-specific reference ranges (ASRRs) has been suggested to increase the sensitivity of the PSA test in younger men. The objective of this study was to determine the normal age-specific reference ranges for a large group of clinically cancer-free men and to compare these findings with similar studies. Materials and Methods: A retrospective chart review of PSA values was conducted on 1199 students from the National Defense University, Fort McNair, Washington, DC, who were matriculating between 1994 and July 1999. The AsXYM system using MEIA technology with monoclonal antibodies from Abbott laboratories was used to determine the PSA values. The mean, median, 95th percentile, 99th percentile, and range were calculated for each decade. Results: A total of 1123 students between the ages of 30 and 59 were included in the study (1105 with PSA levels ≤ 4.0 ng/ml). The largest number of students (67.4%) fell in the 40–49-year-old group. The median PSA level was 0.74 ng/ml. There was a significant correlation between age and PSA level for the 40–59-year-old age group (r = 0.06, p = 0.044). There was no significant correlation between age and PSA for the 40–49-year-old age group (r = 0.048, p = 0.192). The median PSA value and the 95th percentile increased from 0.7 and 2.3, respectively, in the 40–49-year-old age group to 0.8 and 2.7, respectively, in the 50–59-year-old age group. Conclusions: The results of this study indicate that PSA values in young men are quite low. The 95th percentile of PSA levels for men in their 40s and 50s was 2.3 and 2.7 ng/ml, respectively, which is significantly lower than the traditional normal value of 4.0 ng/ml. Although further prospective studies are needed, our data suggest that a lower PSA value threshold of 2.0 to 2.5 ng/ml for younger men is reasonable to dictate further evaluation.
{"title":"Age‐Specific Reference Ranges for Prostate Specific Antigen in Young Men: Retrospective Study from the National Defense University","authors":"Joshua D. Hartzell, T. Kao, J. C. Holland, S. Holt, J. Moul","doi":"10.1046/J.1525-1411.2001.003001036.X","DOIUrl":"https://doi.org/10.1046/J.1525-1411.2001.003001036.X","url":null,"abstract":"Objectives: While controversial, the use of prostate specific antigen (PSA) testing is common and may reduce the morbidity and mortality associated with prostate cancer. The use of age-specific reference ranges (ASRRs) has been suggested to increase the sensitivity of the PSA test in younger men. The objective of this study was to determine the normal age-specific reference ranges for a large group of clinically cancer-free men and to compare these findings with similar studies. Materials and Methods: A retrospective chart review of PSA values was conducted on 1199 students from the National Defense University, Fort McNair, Washington, DC, who were matriculating between 1994 and July 1999. The AsXYM system using MEIA technology with monoclonal antibodies from Abbott laboratories was used to determine the PSA values. The mean, median, 95th percentile, 99th percentile, and range were calculated for each decade. Results: A total of 1123 students between the ages of 30 and 59 were included in the study (1105 with PSA levels ≤ 4.0 ng/ml). The largest number of students (67.4%) fell in the 40–49-year-old group. The median PSA level was 0.74 ng/ml. There was a significant correlation between age and PSA level for the 40–59-year-old age group (r = 0.06, p = 0.044). There was no significant correlation between age and PSA for the 40–49-year-old age group (r = 0.048, p = 0.192). The median PSA value and the 95th percentile increased from 0.7 and 2.3, respectively, in the 40–49-year-old age group to 0.8 and 2.7, respectively, in the 50–59-year-old age group. Conclusions: The results of this study indicate that PSA values in young men are quite low. The 95th percentile of PSA levels for men in their 40s and 50s was 2.3 and 2.7 ng/ml, respectively, which is significantly lower than the traditional normal value of 4.0 ng/ml. Although further prospective studies are needed, our data suggest that a lower PSA value threshold of 2.0 to 2.5 ng/ml for younger men is reasonable to dictate further evaluation.","PeriodicalId":22947,"journal":{"name":"The open prostate cancer journal","volume":"13 1","pages":"36-41"},"PeriodicalIF":0.0,"publicationDate":"2001-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90793764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2001-01-01DOI: 10.1046/J.1525-1411.2001.003001001.X
D. George
{"title":"An α‐Particle Emitting Antibody ([213Bi] J591) for Radioimmunotherapy of Prostate Cancer","authors":"D. George","doi":"10.1046/J.1525-1411.2001.003001001.X","DOIUrl":"https://doi.org/10.1046/J.1525-1411.2001.003001001.X","url":null,"abstract":"","PeriodicalId":22947,"journal":{"name":"The open prostate cancer journal","volume":"86 1","pages":"1-1"},"PeriodicalIF":0.0,"publicationDate":"2001-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73461433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2001-01-01DOI: 10.1046/J.1525-1411.2001.31004.X
R. Chlebowski, M. Curti
Objectives: To identify recent clinical research trends, all abstracts relevant to prostate and breast cancer reported in the American Society of Clinical Oncology (ASCO) Proceedings from 1994 to 1999 and for 1 year in the American Urological Association Proceedings were reviewed. Methods: Abstracts were identified and prospectively categorized in 31 areas including study design, sample size, and study outcome. Results: In the ASCO Proceedings, abstracts on breast cancer (n = 1718) greatly exceeded those on prostate cancer (n = 340). Randomized clinical trials were also more frequently reported in breast cancer compared to prostate cancer (176 versus 30 reports, respectively [5.7 times greater]; p 12 times as many patients (121,923 women versus 9,761 men, respectively; p < 0.01) in this period. For breast cancer, the number of reported randomized clinical trials increased and nearly doubled over the 6-year period, whereas for prostate cancer no such trend was seen. For prostate cancer, the vast majority (82%) of the 130 clinical trial reports were nonrandomized studies, and most entered very few patients (median patient entry, 26.2). Although randomized clinical trial reports on breast cancer described significant survival benefits in 16 trials in both advanced disease (benefit seen in 7 of 109 studies [6%]) and especially in adjuvant therapy (benefit seen in 9 of 67 studies [12%]), in prostate cancer only a single randomized clinical trial reported a significant survival benefit in this period. Conclusions: Despite comparable annual incidence and mortality, prostate cancer receives only a fraction of the clinical trial activity afforded breast cancer.
{"title":"Trends in Prostate and Breast Cancer Clinical Research as Reported in the American Society of Clinical Oncology Proceedings","authors":"R. Chlebowski, M. Curti","doi":"10.1046/J.1525-1411.2001.31004.X","DOIUrl":"https://doi.org/10.1046/J.1525-1411.2001.31004.X","url":null,"abstract":"Objectives: To identify recent clinical research trends, all abstracts relevant to prostate and breast cancer reported in the American Society of Clinical Oncology (ASCO) Proceedings from 1994 to 1999 and for 1 year in the American Urological Association Proceedings were reviewed. Methods: Abstracts were identified and prospectively categorized in 31 areas including study design, sample size, and study outcome. Results: In the ASCO Proceedings, abstracts on breast cancer (n = 1718) greatly exceeded those on prostate cancer (n = 340). Randomized clinical trials were also more frequently reported in breast cancer compared to prostate cancer (176 versus 30 reports, respectively [5.7 times greater]; p 12 times as many patients (121,923 women versus 9,761 men, respectively; p < 0.01) in this period. For breast cancer, the number of reported randomized clinical trials increased and nearly doubled over the 6-year period, whereas for prostate cancer no such trend was seen. For prostate cancer, the vast majority (82%) of the 130 clinical trial reports were nonrandomized studies, and most entered very few patients (median patient entry, 26.2). Although randomized clinical trial reports on breast cancer described significant survival benefits in 16 trials in both advanced disease (benefit seen in 7 of 109 studies [6%]) and especially in adjuvant therapy (benefit seen in 9 of 67 studies [12%]), in prostate cancer only a single randomized clinical trial reported a significant survival benefit in this period. Conclusions: Despite comparable annual incidence and mortality, prostate cancer receives only a fraction of the clinical trial activity afforded breast cancer.","PeriodicalId":22947,"journal":{"name":"The open prostate cancer journal","volume":"25 1","pages":"26-29"},"PeriodicalIF":0.0,"publicationDate":"2001-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76611352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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