Prostatic Neoplasms: Richie JP

Montie JE, Clark PE, Eisenberger MA, El-Galley R, Greenberg RE, Herr HW, Hudes GR, Kuban DA, Kuzel TM, Lange PH, Lele SM, Michalski J, Patterson A, Pohar KS, Richie JP, Sexton WJ, Shipley WU, Small EJ, Trump DL, Walther PJ, Wilson TG, Anonymous00046. · University of Michigan Comprehensive Cancer Center. · J Natl Compr Canc Netw. · Pubmed #19176203 No free full text.

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Montie JE, Abrahams NA, Bahnson RR, Eisenberger MA, El-Galley R, Herr HW, Hudes GR, Kuzel TM, Lange PH, Patterson A, Pollack A, Richie JP, Sexton WJ, Shipley WU, Small EJ, Trump DL, Walther PJ, Wilson TG, Anonymous00097. · No affiliation provided · J Natl Compr Canc Netw. · Pubmed #17112448 No free full text.

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Richie JP. · Division of Urology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. · Urology. · Pubmed #10606279 No free full text.

Abstract: Many men who show evidence of a progression of prostate cancer by rising prostate-specific antigen (PSA) or other symptoms are treated with anti-androgens. Anti-androgen withdrawal represents the first line of treatment after failure of hormonal manipulation. Flutamide is an approved anti-androgen that has been incorporated in many of the combined androgen blockade studies. Bicalutamide is also a nonsteroidal anti-androgen that offers the advantages of reduced dosage amounts and reduction in side effects. Additionally, there are a variety of therapeutic agents that can suppress adrenal secretion of androgens. The most promising of these agents include aminoglutethamide, ketoconazole, and corticosteroids, with an expected response rate of 10% to 15%. Studies have shown that some patients may respond to an anti-estrogen such as tamoxifen. There are a variety of therapeutic treatment options available for patients with hormone refractory prostate cancer. However, quality-of-life issues are becoming increasingly important and should be incorporated into clinical trial endpoints.

Hegarty NJ, Fitzpatrick JM, Richie JP, Scardino PT, deVere White RW, Schröder FH, Coffey DS. · Department of Surgery/Urology, Mater Misericordiae Hospital and University College Dublin, Dublin, Ireland. · Prostate. · Pubmed #10420155 No free full text.

Abstract: BACKGROUND: Prostate cancer has displayed an increase in incidence unparalleled by any other tumor in the last two decades, with a steady, more gradual increase in mortality rate. Current curative strategies are focused on the detection and treatment of early-stage (T1-2 N0 M0), clinically significant tumors. METHODS: To this aim, refinement of surgical approaches, with appropriate adjuvant therapies, will ensure more complete cancer control, while minimizing associated morbidity. New delivery systems for radiotherapy, as well as other energy sources, are evolving, while a number of promising pharmacological agents, including angiogenesis inhibitors and drugs which alter signal transduction pathways, are currently under investigation. Early detection is also being facilitated by a more widespread implementation of screening programs. Advances in tumor markers, and imaging and biopsy techniques, will allow more accurate preoperative staging. These, coupled with improvements in prognostic markers, aid the physician and patient alike in deciding on the suitability of treatment options with better estimation of outcome. Perhaps the most exciting developments in prostate cancer will come from knowledge of the molecular mechanisms underlying carcinogenesis. The potential for the development of diagnostic and therapeutic tools is immense. The efficacy of treatment can be studied at a molecular level, and strategies for preventing or slowing the development of malignancy can be formulated. RESULTS AND CONCLUSIONS Application of this knowledge in the form of gene and cellular therapy and in the development of novel systemic agents is beginning to enter the realm of clinical practice, and it may be in this field that means for cure and prevention of prostate cancer will eventually be found.

Richie JP. · Brigham and Women's Hospital, Boston, MA 02115, USA. · J Am Coll Surg. · Pubmed #10024165 No free full text.

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Febbo PG, Richie JP, George DJ, Loda M, Manola J, Shankar S, Barnes AS, Tempany C, Catalona W, Kantoff PW, Oh WK. · Lank Center for Genitourinary Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston Massachusetts 02115, USA. · Clin Cancer Res. · Pubmed #16033841 links to  free full text

Abstract: PURPOSE: To determine the clinical, pathologic, and molecular effects of neoadjuvant docetaxel chemotherapy in high-risk localized prostate cancer. EXPERIMENTAL DESIGN: Patients with biopsy Gleason scores of 8 to 10, serum prostate-specific antigen levels >20 ng/mL, and/or clinical stage T3 disease received weekly docetaxel (36 mg/m2) for 6 months, followed by radical prostatectomy, and were monitored with weekly visits, serum prostate-specific antigen measurements, and endorectal magnetic resonance imaging (MRI). Frozen tumor specimens were collected for microarray analysis. RESULTS: The 19 patients enrolled received 82% of the planned chemotherapy. Toxicity was mild to moderate; fatigue and taste disturbance were common. Prostate-specific antigen declines of >50% were seen in 11 of 19 patients (58%; 95% confidence interval, 33-80%) and endorectal MRI showed maximum tumor volume reduction of at least 25% in 13 of 19 patients (68%; 95% confidence interval, 47-85%) and at least 50% in 4 patients (21%; 95% confidence interval, 6-46%). Sixteen patients completed chemotherapy and had radical prostatectomy; none achieved pathologic complete response. Microarray analysis identified coordinate up-regulation of genes involved in androgen metabolism associated with docetaxel therapy. Specifically, RNA expression for genes that decrease cellular levels of bioactive androgens was coordinately increased in response to chemotherapy. CONCLUSIONS: Neoadjuvant docetaxel administered for 6 months before radical prostatectomy is feasible, well tolerated, and often results in prostate-specific antigen declines of >50% and decreased tumor volume on endorectal MRI. No pathologic complete responses were observed. Altered androgen metabolism may partially account for the noted declines in prostate-specific antigen and be a mechanism for chemotherapy resistance.

Oh WK, George DJ, Kaufman DS, Moss K, Smith MR, Richie JP, Kantoff PW. · Lank Center for Genitourinary Oncology, Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. · Semin Oncol. · Pubmed #11685727 No free full text.

Abstract: Effective treatment options for high-risk localized prostate cancer are limited. Patients at high risk for recurrence include those with biopsy Gleason scores of 8 to 10, prostate specific antigen (PSA) levels > 20 ng/mL, and clinical stage T3 disease. Docetaxel chemotherapy is active in hormone-refractory prostate cancer, either combined with estramustine or used as a single agent. To determine if systemic therapy can improve the outcome of radical prostatectomy in men with high-risk localized prostate cancer, we are undertaking a pilot phase II clinical trial of weekly docetaxel at 36 mg/m(2) for up to 6 months, followed by surgery. Patients are monitored with weekly visits, monthly digital rectal examinations, PSA measurement, and testosterone tests, and endorectal magnetic resonance imaging done at baseline, after two cycles, and again after six cycles. To date, 15 patients have been enrolled, and 70 cycles of chemotherapy have been administered. Toxicity has been mostly grade 1 in intensity, and fatigue has been the most common grade 2 toxicity reported. The primary endpoint of the trial is measurement of pathologic complete response rate, for which data are not yet available. Recruitment to the trial is ongoing.

Catalona WJ, Southwick PC, Slawin KM, Partin AW, Brawer MK, Flanigan RC, Patel A, Richie JP, Walsh PC, Scardino PT, Lange PH, Gasior GH, Loveland KG, Bray KR. · Division of Urologic Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA. · Urology. · Pubmed #10925089 No free full text.

Abstract: OBJECTIVES: Various methods have been proposed to increase the specificity of prostate-specific antigen (PSA), including age-specific PSA reference ranges, PSA density (PSAD), and percent free PSA (%fPSA). In this multicenter study, we compared these methods for their utility in cancer detection and their ability to predict pathologic stage after radical prostatectomy in patients with clinically localized, Stage T1c cancer. METHODS: Seven hundred seventy-three men (379 with prostate cancer, 394 with benign prostatic disease), 50 to 75 years old, from seven medical centers were enrolled in this prospective blinded study. All subjects had a palpably benign prostate, PSA 4.0 to 10.0 ng/mL, and a histologically confirmed diagnosis. Hybritech's Tandem PSA and free PSA assays were used. RESULTS: %fPSA and age-specific PSA cutoffs enhanced PSA specificity for cancer detection, but %fPSA maintained significantly higher sensitivities. Age-specific PSA cutoffs missed 20% to 60% of cancers in men older than 60 years of age. %fPSA and PSAD performed equally well for detection (95% sensitivity) if cutoffs of 25% fPSA or 0.078 PSAD were used. The commonly used PSAD cutoff of 0.15 detected only 59% of cancers. %fPSA and PSAD also produced similar results for prediction of the post-radical prostatectomy pathologic stage. Patients with cancer with higher %fPSA values (greater than 15%) or lower PSAD values (0.15 or less) tended to have less aggressive disease. CONCLUSIONS: The results of this study demonstrated that cancer detection (sensitivity) is significantly higher with %fPSA than with age-specific PSA reference ranges. %fPSA and PSAD provide comparable results, suggesting that %fPSA may be used in place of PSAD for biopsy decisions and in algorithms for prediction of less aggressive tumors since the determination of %fPSA does not require ultrasound.

D'Amico AV, Weinstein M, Li X, Richie JP, Fujimoto J. · Department of Radiation Oncology, Brigham and Women's Hospital and Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA. · Urology. · Pubmed #10792101 No free full text.

Abstract: OBJECTIVES: Optical coherence tomography (OCT) is a new optical imaging technique capable of providing cross-sectional imaging of tissue microstructure in vivo and in real time. OCT was used in the setting of the human prostate ex vivo, and the images acquired were compared with those obtained using standard histopathologic methods. METHODS: Multiple samples (3 to 6) were obtained from the radical prostatectomy specimens of 7 men with clinically localized (T1c-2, N0, M0) adenocarcinoma of the prostate. These specimens were 1 cm in length and 1 mm x 1 mm in rectangular cross section. Specimens were first imaged using OCT and then embedded and stained in preparation for histopathologic evaluation. Co-registration of the images obtained using OCT and standard histopathologic evaluation provided the basis for comparison. RESULTS: Structural architecture on the order of 50 to 150 microm within benign glandular epithelium, fibroadipose tissue, and malignant glandular epithelium could be resolved to a depth of approximately 0.5 mm using OCT. CONCLUSIONS: Microscopic resolution is possible in human prostatic tissue using OCT. Further studies using this technique to improve the detection and staging of adenocarcinoma of the prostate are ongoing.

Catalona WJ, Partin AW, Slawin KM, Naughton CK, Brawer MK, Flanigan RC, Richie JP, Patel A, Walsh PC, Scardino PT, Lange PH, deKernion JB, Southwick PC, Loveland KG, Parson RE, Gasior GH. · Division of Urologic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA. · Urology. · Pubmed #10699613 No free full text.

Abstract: OBJECTIVES: In predominately white populations, measurement of the percentage of free prostate-specific antigen (%fPSA) has been shown to enhance the specificity of total PSA testing for prostate cancer while maintaining high sensitivity and to aid in prostate cancer staging. This study evaluated whether the %fPSA cutoff that maintained a 95% sensitivity in a white population yielded the same sensitivity and specificity in a black population and whether %fPSA was useful in predicting postoperative pathologic features in blacks. METHODS: We evaluated 647 white and 79 black men, prospectively enrolled at prostate cancer screening and surgical referral centers. Subjects were 50 to 75 years old with digital rectal examination findings that were not suspicious for prostate cancer and total PSA values between 4.0 and 10.0 ng/mL. All had undergone needle biopsy of the prostate. Hybritech's Tandem total and free PSA assays were used. RESULTS: Ninety-five percent sensitivity was attained with a %fPSA cutoff of 25% in both races. Use of this cutoff could have avoided unnecessary biopsies in 20% of white and 17% of black subjects (P = 0.69). In receiver operating characteristic (ROC) curve analysis, the area under the curve (AUC) for %fPSA was significantly higher than for total PSA in both blacks (0.76 versus 0.56, P <0.01) and whites (0.70 versus 0.54, P <0.001). In both races, higher %fPSA values indicated a lower risk of cancer and also predicted favorable pathologic features in radical prostatectomy specimens. CONCLUSIONS: A 25% fPSA cutoff detected 95% of cancers and reduced unnecessary biopsies in both races. Higher %fPSA values were associated with favorable postoperative histopathologic findings in both races.

Southwick PC, Catalona WJ, Partin AW, Slawin KM, Brawer MK, Flanigan RC, Patel A, Richie JP, Walsh PC, Scardino PT, Lange PH, Gasior GH, Parson RE, Loveland KG. · Division of Urologic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA. · J Urol. · Pubmed #10492194 No free full text.

Abstract: PURPOSE: Prostate specific antigen (PSA) exists in bound (complexed) and unbound (free) forms in serum. The percentage of free PSA enhances the specificity of PSA testing for prostate cancer detection. We evaluated the use of percent free PSA preoperatively to predict pathological stage. MATERIALS AND METHODS: A total of 379 men with prostate cancer and 394 with benign prostatic disease 50 to 75 years old were enrolled in this prospective study at 7 medical centers. All subjects had a palpably benign prostate gland, serum PSA 4.0 to 10.0 ng./ml. and a histologically confirmed diagnosis. The Hybritech Tandem PSA and free PSA assays were used. Of the 379 cancer patients 268 (71%) underwent radical prostatectomy. RESULTS: Higher percent free PSA levels were associated with more favorable histopathological findings in prostatectomy specimens. A value of 15% free PSA provided the greatest discrimination in predicting favorable pathological outcome. Organ confined cancer, Gleason sum less than 7 and small tumors (10% or less involvement of the prostate) were noted in 75% of patients with greater than 15% and only 34% with 15% or less free PSA (p<0.001). Multivariate logistic regression analysis revealed percent free PSA to be the strongest predictor of postoperative pathological outcome (odds ratio 2.25), followed by biopsy Gleason sum (2.06) and patient age (1.35). Total PSA was not predictive in this cohort but has been shown in prior studies to be predictive of outcome when a broader range of PSA values is evaluated. CONCLUSIONS: Percent free PSA may be used for risk assessment of the presence (diagnosis) and stage of prostate cancer in men with PSA between 4 and 10 ng./ml. Percent free PSA may be combined with PSA, digital rectal examination and biopsy findings to help predict postoperative pathological stage and grade, and may assist the patient and physician in making more informed treatment decisions.

Barrisford GW, Sartor O, Richie JP. · Department of Urology, National Naval Medical Center, Bethesda, MD 20889, USA. · Clin Genitourin Cancer. · Pubmed #19213672 No free full text.

Abstract: Prostate cancer is the most commonly diagnosed malignancy among American men. Although prostate cancer-related death approximates only 3%, advanced disease can become widely disseminated. Metastatic disease is often found in a number of common sites. We report the uncommon presentation of a solitary adrenal lesion treated with surgical resection.

Sommers BD, Beard CJ, D'Amico AV, Kaplan I, Richie JP, Zeckhauser RJ. · Division of General Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. · Cancer. · Pubmed #18704993 No free full text.

Abstract: BACKGROUND: Little is known regarding how patients select treatment for localized prostate cancer. This study examined determinants of patients' preferences for health states related to prostate cancer, and assessed whether preferences and/or other factors predict treatment choices. METHODS: A survey of 167 patients with newly diagnosed localized prostate cancer was conducted in 4 academic medical practices from 2004 to 2007. The authors assessed demographic and health factors, and used a time-tradeoff method to elicit preferences in the form of quality-adjusted life years (QALYs) regarding health states related to prostate cancer. Linear regressions identified predictors of preferences (in QALYs) for erectile dysfunction (ED), urinary incontinence, rectal/bowel symptoms, and metastatic prostate cancer. Linear probability models identified predictors of treatment choice. RESULTS: Patient preferences were affected by a range of behavioral, demographic, and health factors. For example, sexually active men reported significantly lower QALYs for living with ED, and men with family members who died of cancer reported lower QALYs for metastatic disease. The strongest predictor of treatment was the type of physician seen (radiation oncology vs urology) at the time of the survey. Age and tumor grade also were found to be strongly predictive of treatment. In general, QALYs were not found to predict treatment choice. CONCLUSIONS: Patient preferences, as reported in QALYs, are shaped by reasonable behavioral and demographic influences. However, actual treatment choices appear to bear little relation to these patient preferences, and instead demonstrate a strong association with clinician specialty. More attention to variation in preferences among patients, as well as the use of decision-support technologies, may enable physicians to facilitate more optimal individualized treatment choices for patients with prostate cancer.

Prasad SM, Keating NL, Wang Q, Pashos CL, Lipsitz S, Richie JP, Hu JC. · Division of Urologic Surgery, Brigham and Women's Hospital, Boston, Massachusetts 02478, USA. · Urology. · Pubmed #18649928 No free full text.

Abstract: OBJECTIVES: Although pelvic lymph node dissection (PLND) during radical prostatectomy (RP) improves staging, controversy remains concerning its indications and benefits on cancer control. We examined the factors associated with PLND use among men undergoing open RP (ORP) and minimally invasive RP (MIRP). METHODS: Using a 5% national sample of Medicare beneficiaries from 2003 to 2005, we identified 2702 men who had undergone RP. Multivariate logistic regression analysis was used to assess whether the surgical approach, surgeon volume, patient demographics, comorbidity, and geographic region were associated with the likelihood of performing PLND. RESULTS: Overall, 68% of men underwent PLND, although the rates varied by surgical approach (17% vs 83% for MIRP vs ORP, respectively, P <.001). In adjusted analyses, men undergoing MIRP vs ORP (odds ratio [OR] 0.02, 95% confidence interval [CI], 0.02-0.03), men > or = 75 vs 65-69 years old (OR 0.23, 95% CI 0.17-0.31), and men with multiple vs no comorbidities (OR 0.48, 95% CI 0.35-0.66 for Charlson score > or = 3 vs 0) were less likely to undergo PLND. High-volume minimally invasive surgeons were more likely to perform PLND (OR 1.19, 95% CI 1.14-1.25). Finally, men in the Western vs Southern United States (OR 1.61, 95% CI 1.19-2.17) were more likely to undergo PLND. CONCLUSIONS: Men undergoing MIRP vs ORP were less likely to undergo PLND, although rates of the procedure increased with surgical volume. Additional studies are needed to determine the indications and benefits of this procedure for men with prostate cancer.

Sommers BD, Beard CJ, D'Amico AV, Dahl D, Kaplan I, Richie JP, Zeckhauser RJ. · Division of General Medicine, Brigham & Women's Hospital, Boston, Massachusetts 02115, USA. · Cancer. · Pubmed #17893907 links to  free full text

Abstract: BACKGROUND: Selecting treatment for clinically localized prostate cancer remains an ongoing challenge. Previous decision analyses focused on a hypothetical patient with average preferences, but preferences differ for clinically similar patients, implying that their optimal therapies may also differ. METHODS: A decision model was constructed comparing 4 treatments for localized prostate cancer: 1) radical prostatectomy (RP); 2) external beam radiation (EB); 3) brachytherapy (BT); and 4) watchful waiting (WW). Published data were used regarding treatment success, side effects, and noncancer survival, and 156 men with prostate cancer were surveyed to elicit preferences in quality-adjusted life years (QALYs). The clinical scenarios were determined (age, tumor grade, and prostate-specific antigen [PSA]) for which variations in patient preferences led to different optimal treatments and those for which the optimal treatment was unaffected by preferences. RESULTS: Patient preferences were critical in determining treatment for low-risk cancers (Gleason score <or=6, PSA <or=10 ng/mL) and for patients aged 75 years and older. In younger patients with more aggressive tumors, RP and EB were always superior to WW or BT, regardless of preferences (average gain in quality-adjusted life expectancy vs WW for a 60-year-old with a medium-risk tumor = +1.4 years for RP and +1.7 for EB; for a high-risk tumor = +2.1 years for RP and +2.4 for EB). BT was a reasonable option for low-risk tumors at any age. WW was only reasonable for patients aged 70 and older with low-risk tumors or those aged 80 years and older with medium-risk tumors. Selecting treatment based on average preferences leads to suboptimal choices for 30% of patients. CONCLUSIONS: The optimal treatment for prostate cancer depends on both the clinical scenario (patient age and tumor aggressiveness) and the patient's preferences. Decision analyses taking individualized preferences into account may be a useful adjunct in clinical decision-making.

Mukhopadhyay NK, Cinar B, Mukhopadhyay L, Lutchman M, Ferdinand AS, Kim J, Chung LW, Adam RM, Ray SK, Leiter AB, Richie JP, Liu BC, Freeman MR. · Department of Urology/Surgery, Children's Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA. · Mol Endocrinol. · Pubmed #17550981 links to  free full text

Abstract: Androgen receptor (AR) plays an important role in normal prostate function as well as in the etiology of prostate cancer. Activation of AR is dictated by hormone binding and by interactions with coregulators. Several of these coregulators are known targets of Ras-related signals. Recent evidence suggests that Ras activation may play a causal role in the progression of prostate cancer toward a more malignant and hormone-insensitive phenotype. In the present study, we used a transcription factor-transcription factor interaction array method to identify the zinc finger protein Ras-responsive element binding protein (RREB-1) as a partner and coregulator of AR. In LNCaP prostate cancer cells, RREB-1 was found to be present in a complex with endogenous AR as determined by coimmunoprecipitation, glutathione S-transferase pull down, and immunofluorescence analyses. RREB-1 bound to the prostate-specific antigen (PSA) promoter as assessed by chromatin immunoprecipitation. Transient expression of RREB-1 down-regulated AR-mediated promoter activity and suppressed expression of PSA protein. The repressor activity of RREB-1 was significantly attenuated by cotransfection of activated Ras. Moreover, expression of the dominant-negative N-17-Ras or, alternatively, use of the MAPK kinase inhibitor PD98059 [2-(2-amino-3-methyoxyphenyl)-4H-1-benzopyran-4-one] abolished the effect of Ras in attenuating RREB-1-mediated repression. Furthermore, inhibition of RREB-1 expression by RNA interference enhanced the effect of Ras on PSA promoter activity and PSA expression. In addition, activation of the Ras pathway depleted AR from the RREB-1/AR complex. Collectively, our data for the first time identify RREB-1 as a repressor of AR and further implicate the Ras/MAPK kinase pathway as a likely antagonist of the inhibitory effects of RREB-1 on androgenic signaling.

Tsai HK, Chen MH, McLeod DG, Carroll PR, Richie JP, D'Amico AV. · Harvard Radiation Oncology Program, Harvard Medical School, Boston, Massachusetts, USA. · Cancer. · Pubmed #17039498 links to  free full text

Abstract: BACKGROUND: The presence of multiple determinants of aggressive cancer biology may impact prostate cancer-specific mortality (PCSM) rates compared with fewer factors. The authors estimated PCSM after radiation therapy with short-course androgen suppression therapy (RT+AST) or radical prostatectomy (RP) in men with clinically localized, intermediate-risk to high-risk prostate cancer. METHODS: The study cohort included 3240 men treated from 1981 to 2002 with RT with 6 months of AST (n = 550) or RP (n = 2690) for localized prostate cancer with at least 1 risk factor (prostate-specific antigen [PSA] >10 ng/mL, biopsy Gleason score 7-10, or clinical tumor category T2b or T2c). Competing risks regression analyses were used to determine whether the number of risk factors present was associated with time to PCSM. RESULTS: Men with all 3 risk factors had significantly shorter time to PCSM after RT+AST (adjusted hazards ratio [HR] of 9.3; 95% confidence interval [95% CI], 1.9-44.5 [P(Gray) = .005]) or RP (adjusted HR of 6.3; 95% CI, 3.2-12.2 [P(Gray) < .001]) when compared with men with any 1 or 2 risk factors. The 7-year estimates of PCSM for men having 1, 2, or 3 risk factors were 0.83% (95% CI, 0.27-1.4%), 2.6% (95% CI, 1.0-4.2%), and 12.6% (95% CI, 7.1-18.1%), respectively. CONCLUSIONS: Men with multiple determinants of intermediate-risk to high-risk prostate cancer have significantly increased estimates of PCSM despite aggressive therapy compared with men with only 1 or 2 determinants. These men are appropriate candidates for enrollment onto randomized controlled trials evaluating the benefit of adding systemic therapies such as docetaxel to RT+AST or RP.

Mukhopadhyay NK, Ferdinand AS, Mukhopadhyay L, Cinar B, Lutchman M, Richie JP, Freeman MR, Liu BC. · Molecular Urology Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. <> · Exp Cell Res. · Pubmed #17011549 No free full text.

Abstract: The androgen receptor (AR) plays a key role in the development and function of male reproductive organs. Using a high-throughput transcription factor-transcription factor (TF-TF) interaction array method, we captured the AR interactomes in androgen-responsive LNCaP cells. Several known and unknown partners of AR, including AP-2, Pax 3/5 (BSAP), c-Rel, RREB-1, LIII BP, and NPAS2 were identified. We investigated one unreported AR-associated transcription factor, the proto-oncoprotein c-Rel, in detail. C-Rel belongs to the NF-kB/Rel families and is persistently active in a number of diseases, including cancer. The presence of c-Rel transcript, protein, and its in vitro and in vivo association with AR was determined. Co-localization of c-Rel with AR both in cytoplasm and nucleus was confirmed by indirect immunofluorescence analysis. Chromatin immunoprecipitation data indicated that c-Rel, like AR, is a part of the nucleoprotein complex regulating the androgen-responsive prostate-specific antigen (PSA) promoter. Overexpression of c-Rel downregulated the promoter activity of both PSA and GRE4-TATA-Luc plasmids in LNCaP and COS cells. Analysis of AR and c-Rel protein levels indicated that the promoter downregulation was not due to reciprocal decrease in the amounts of AR or c-Rel. In summary, we have identified several new partners of AR by using the TF-TF array method and have provided the first evidence of a functional role for c-Rel in androgen-responsive human prostate cancer cells.

Hurwitz MD, Schultz D, Richie JP, Wein AJ, Whittington R, Malkowicz SB, D'Amico AV. · Harvard Medical School, and Department of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts 02115, USA. · Urology. · Pubmed #16904454 No free full text.

Abstract: OBJECTIVES: Patients with high-grade clinically localized disease often have disease beyond the prostate and, if so, are unlikely to benefit from radical prostatectomy in the long-term. The objective of this study was to assess whether use of other known prognostic factors could be helpful in defining which men with Gleason 8 to 10 prostate cancer are most likely to benefit from surgical management. METHODS: A retrospective analysis was performed on men with biopsy Gleason 8 to 10 prostate cancer who underwent radical prostatectomy at two major university centers. No patients received hormonal therapy as part of initial treatment or adjuvant radiation therapy. Surgery was performed using a retropubic approach, and lymph node dissection was performed in all patients. Risk groups were defined based on prostate-specific antigen (PSA) value and percent positive biopsy cores (%PBC). A Cox proportional hazards analysis was performed to assess for differences in pretreatment prognostic factors. Kaplan-Meier curves were generated for each group, and then comparisons between groups were performed using log-rank analysis to assess for differences in 5-year actuarial freedom from biochemical failure. RESULTS: Radical prostatectomy was performed on 196 patients between 1987 and 2002, of whom 168 had sufficient data for analysis. Median follow-up was 18 months (range, 1 to 130 months), with 31 patients at risk for more than 5 years. Patients with a PSA value of less than 10 ng/mL and %PBC of less than 50% had a 5-year actuarial biochemical control rate of 67% versus 23% for all other patients (P = 0.0001). CONCLUSIONS: PSA value and %PBC are useful in selecting patients with high-grade prostate cancer most likely to benefit by radical prostatectomy.

Oh WK, Hayes J, Evan C, Manola J, George DJ, Waldron H, Donovan M, Varner J, Orechia J, Katcher B, Lu D, Nevins A, Wright RL, Tormey L, Talcott J, Rubin MA, Loda M, Sellers WR, Richie JP, Kantoff PW, Weeks J. · Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. · Clin Genitourin Cancer. · Pubmed #16859581 No free full text.

Abstract: BACKGROUND: In this article, we describe the design and implementation of a comprehensive prostate cancer database developed to collect, store, and access clinical, treatment, and outcomes data for research and clinical care. PATIENTS AND METHODS: The Prostate Cancer Clinical Research Information System is a relational database. Data are entered from multiple sources, including medical records, institutional laboratory, patient registration, pharmacy systems, and clinician forms. The history, design, and operational characteristics of the database are described. Issues regarding necessary staffing and funding of databases are reviewed. RESULTS: Four thousand two hundred forty-six patients have information in the Prostate Cancer Clinical Research Information System. Mean age of patients is 62 years, and 89% are white. Seventy-one percent of patients presented at diagnosis with T1 or T2 disease, and 78% had biopsy Gleason scores of <or=7, 8-10 in 18%. Median prostate-specific antigen level at diagnosis was 7 ng/mL, and 77% of patients presented with increased prostate-specific antigen as a trigger symptom. Sixty-four percent of patients presented to our clinic having had no previous treatment for prostate cancer. The majority of approached patients provided consent for collection of clinical data, blood, and tissue. Quality control assessments demonstrate high levels of concordance among data entry personnel. CONCLUSION: Clinical databases are difficult to implement and maintain; however, they represent a valuable resource, particularly when linked to blood and tissue banks. Elements needed for a successful clinical database include engagement of clinicians, utility for research, and the ability to integrate with legacy systems. As cancer centers develop such databases, lessons learned from each experience should be shared in order to optimize the process.

Rodrigues NA, Chen MH, Catalona WJ, Roehl KA, Richie JP, D'Amico AV. · Harvard Radiation Oncology Program, Brigham and Women's Hospital and Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA. · Cancer. · Pubmed #16795068 links to  free full text

Abstract: BACKGROUND: The authors identified biochemical and pathologic factors that were associated significantly with prostate cancer-specific mortality (PCSM) after androgen deprivation therapy (ADT) in men who had rapidly rising prostate-specific antigen (PSA) levels after they received local treatment. METHODS: The study population consisted of 67 patients who had a PSA doubling time (DT) < or =6 months after radical prostatectomy (n = 50 patients) or external beam radiation therapy (n = 17 patients) for localized prostate cancer. Multivariate Cox proportional hazards regression analysis was used to evaluate whether the interval to PSA failure, pre-ADT PSA DT, PSA level at the time of ADT initiation, time to PSA nadir, PSA nadir after 8 months on ADT, and Gleason score were associated significantly with the time to PCSM 8 months after the initiation of ADT. RESULTS.: A PSA nadir >0.2 ng/mL (adjusted hazard ratio [HR], 8.0; 95% confidence interval [95% CI], 1.7-38.7; P = 0.009) and a Gleason score > or =8 (adjusted HR, 5.2; 95% CI, 1.3-20.6; P = 0.02) were associated significantly with a short time to PCSM. The cumulative incidence estimates of 3-year PCSM were 5.8% versus 50.9% for patients with a PSA nadir < or =0.2 ng/mL versus >0.2 ng/mL, respectively, and 10.8% versus 35.8% for patients who had tumors with a Gleason score < or =7 versus > or =8, respectively. CONCLUSIONS.: Among men with a PSA DT < or =6 months, both a PSA nadir >0.2 ng/mL after ADT and a Gleason score > or =8 cancer identified men who were at high risk for PCSM. These men would be ideal candidates for Phase III studies that evaluate the impact on survival of new systemic therapies for prostate cancer.

Farokhzad OC, Cheng J, Teply BA, Sherifi I, Jon S, Kantoff PW, Richie JP, Langer R. · Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA. · Proc Natl Acad Sci U S A. · Pubmed #16606824 links to  free full text

Abstract: Targeted uptake of therapeutic nanoparticles in a cell-, tissue-, or disease-specific manner represents a potentially powerful technology. Using prostate cancer as a model, we report docetaxel (Dtxl)-encapsulated nanoparticles formulated with biocompatible and biodegradable poly(D,L-lactic-co-glycolic acid)-block-poly(ethylene glycol) (PLGA-b-PEG) copolymer and surface functionalized with the A10 2'-fluoropyrimidine RNA aptamers that recognize the extracellular domain of the prostate-specific membrane antigen (PSMA), a well characterized antigen expressed on the surface of prostate cancer cells. These Dtxl-encapsulated nanoparticle-aptamer bioconjugates (Dtxl-NP-Apt) bind to the PSMA protein expressed on the surface of LNCaP prostate epithelial cells and get taken up by these cells resulting in significantly enhanced in vitro cellular toxicity as compared with nontargeted nanoparticles that lack the PSMA aptamer (Dtxl-NP) (P < 0.0004). The Dtxl-NP-Apt bioconjugates also exhibit remarkable efficacy and reduced toxicity as measured by mean body weight loss (BWL) in vivo [body weight loss of 7.7 +/- 4% vs. 18 +/- 5% for Dtxl-NP-Apt vs. Dtxl-NP at nadir, respectively (mean +/- SD); n = 7]. After a single intratumoral injection of Dtxl-NP-Apt bioconjugates, complete tumor reduction was observed in five of seven LNCaP xenograft nude mice (initial tumor volume of approximately 300 mm3), and 100% of these animals survived our 109-day study. In contrast, two of seven mice in the Dtxl-NP group had complete tumor reduction with 109-day survivability of only 57%. Dtxl alone had a survivability of only 14%. Saline and nanoparticles without drug were similarly nonefficacious. This report demonstrates the potential utility of nanoparticle-aptamer bioconjugates for a therapeutic application.

Qin S, Qiu W, Ehrlich JR, Ferdinand AS, Richie JP, O'leary MP, Lee ML, Liu BC. · Molecular Urology Laboratory, Division of Urology, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, MA 02115, USA. · Proteomics. · Pubmed #16596707 No free full text.

Abstract: Diagnosing cancers based on serum profiling is a particularly attractive concept. However, the technical challenges to analysis of the serum proteome arise from the dynamic range of protein amounts. Cancer sera contain antibodies that react with a unique group of autologous cellular antigens, which affords a dramatic amplification of signal in the form of antibodies relative to the amount of the corresponding antigens. The serum autoantibody repertoire from cancer patients might, therefore, be exploited for antigen-antibody profiling. To date, studies of antigen-antibody reactivity using microarrays have relied on recombinant proteins or synthetic peptides as arrayed features. However, recombinant proteins and/or synthetic peptides may fail to accurately detect autoantibody binding due to the lack of proper PTMs. Here we describe the development and use of a "reverse capture" autoantibody microarray. Our "reverse capture" autoantibody microarray is based on the dual-antibody sandwich immunoassay platform of ELISA, which allows the antigens to be immobilized in their native configuration. As "proof-of-principle", we demonstrate its use for antigen-autoantibody profiling with sera from patients with prostate cancer and benign prostate hyperplasia.

Galper SL, Chen MH, Catalona WJ, Roehl KA, Richie JP, D'Amico AV. · Tufts University School of Medicine, Boston, Massachusetts, USA. · J Urol. · Pubmed #16469577 No free full text.

Abstract: PURPOSE: We evaluated whether the proportion of patients with a postoperative PSA-DT less than 3 months, a surrogate for PCSM, decreased significantly during the PSA era. MATERIALS AND METHODS: Between July 1988 and July 2002, 3,719 men with clinically localized prostate cancer treated with RP comprised the study cohort. A chi-square metric was used to compare the preoperative and postoperative characteristics, 5-year actual PSA failure rates, and PSA-DTs for patients treated during the 2 equally divided eras of the early PSA era, July 1988 to July 1995 and the late PSA era, August 1995 to July 2002. RESULTS: Patients presenting in the more recent PSA era were of younger age (p < 0.0001), with earlier stage (p < 0.0001) and lower grade disease (p = 0.01). Similarly, patients had lower grade (p < 0.001), stage (p < 0.0001), and positive margin (p < 0.0001) and lymph node rates (p = 0.0002) at RP. The 5-year actual PSA failure rates decreased from 14.3% in the early PSA era to 2.5% in the later PSA era (p < 0.0001). There was a 37% reduction in the proportion of patients with a PSA-DT less than 3 months, corresponding to a decrease in absolute magnitude from 9% to 5.7% between the 2 eras. Absolute reductions of 3.1% and 9% were also noted for the proportion of PSA-DTs of 3 to 5.99 months and 6 to 11.99 months, respectively, whereas PSA-DTs of 12 months or greater increased by 15.3%. CONCLUSIONS: During the recent PSA era, postoperative PSA failure has significantly decreased and PSA-DTs have increased, suggesting that PCSM will continue to decrease.

Dvorak T, Chen MH, Renshaw AA, Loffredo M, Richie JP, D'Amico AV. · Department of Radiation Oncology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. · Urology. · Pubmed #16286117 No free full text.

Abstract: OBJECTIVES: To evaluate whether the maximal tumor diameter (MTD) is significantly associated with the time to postoperative prostate-specific antigen (PSA) failure. METHODS: Between 1986 and 2002, 781 men with clinical Stage T1c-T2 prostate cancer underwent radical prostatectomy. The MTD was recorded as the maximal dimension of the largest single focus of cancer from all 3-mm step sections. The median follow-up was 5.4 years (range 0.1 to 14.9); 242 men (31%) experienced PSA failure. A Cox regression analysis was used to determine the predictors of time to postoperative PSA failure. Kaplan-Meier estimates of PSA failure-free survival were made, dichotomized about the median MTD value, and compared using a two-sided log-rank test. RESULTS: The value of the MTD was significantly associated with the time to PSA failure (adjusted hazard ratio 1.04, 95% confidence interval 1.01 to 1.07, P = 0.004), controlling for preoperative PSA level (P < 0.0001), prostatectomy Gleason score (P < 0.0001), and T stage (P < 0.0001). When margin status was added (P = 0.0004), the MTD approached statistical significance (P = 0.07). For patients with a preoperative PSA level of less than 10 ng/mL, prostatectomy Gleason score of 3 + 4 = 7 or less, Stage pT2-T3a, and negative margins, the value of the MTD significantly (P = 0.05) stratified the time to PSA failure, when dichotomized about the median value (13 mm), with 7-year PSA failure estimates of 17% versus 8%. CONCLUSIONS: Whether patients with traditionally low-risk but large MTD prostate cancer fare better when treated with adjuvant radiotherapy compared with salvage radiotherapy remains to be answered in the setting of a randomized trial.