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Jerome P Richie

Publications and source records attributed to Jerome P Richie.

At least 19 recordsLinked to original sources
PubMed2006

Cancer-specific mortality after radiation therapy with short-course hormonal therapy or radical prostatectomy in men with localized, intermediate-risk to high-risk prostate cancer.

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.

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PubMed2006

Predictors of mortality after androgen-deprivation therapy in patients with rapidly rising prostate-specific antigen levels after local therapy for prostate cancer.

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.

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PubMed2006

Unraveling androgen receptor interactomes by an array-based method: discovery of proto-oncoprotein c-Rel as a negative regulator of androgen receptor.

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.

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PubMed2006

Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo.

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.

Animals↗
PubMed2006

Development of a "reverse capture" autoantibody microarray for studies of antigen-autoantibody profiling.

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.

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PubMed2006

Radical prostatectomy for high-grade prostate cancer.

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.

Follow-Up Studies↗
PubMed2006

Evidence to support a continued stage migration and decrease in prostate cancer specific mortality.

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.

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PubMed2006

Development of an integrated prostate cancer research information system.

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.

Adult↗
PubMed2005

Neoadjuvant docetaxel before radical prostatectomy in patients with high-risk localized prostate cancer.

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.

Adult↗
PubMed2005

Chromatofocusing fractionation and two-dimensional difference gel electrophoresis for low abundance serum proteins.

The technical challenge to analysis of the serum proteome is that the serum proteins are present at unequal concentrations. A few are so dominant, such as serum albumin and immunoglobulins, that they mask detection of other proteins. Because of these high abundance proteins, current technologies, while theoretically capable of analyzing protein amounts spanning four orders of magnitude, are only able to analyze proteins ranging over two orders of magnitude and cannot analyze the lower abundance proteins that may be the next biomarkers and drug targets. To facilitate the identification of low abundance proteins, we fractionated serum samples from patients with prostate cancer and patients with benign prostate hyperplasia using anion displacement liquid chromatofocusing chromatography, which separates proteins by a pH gradient and a positively charged column. Differential expression of proteins from fractions was then determined and identified by IEF gels and 2-D DIGE. Results demonstrate improved resolution of proteins within the chosen pH gradient when compared to the unfractionated samples. Several proteins that were differentially expressed in serum from patients with prostate cancer were identified in the fractionated serum. Three of these proteins, squamous cell carcinoma antigen 1 (SCCA1), calgranulin B, and haptoglobin-related protein, are present in the serum at levels below the classical protein level of mg/mL. SCCA1 is normally expressed in serum at ng/mL levels, and calgranulin B is an intracellular protein. Our results demonstrate that the use of anion displacement liquid chromatofocusing chromatography may reduce the complexity of the serum proteome by separating proteins into distinct pH ranges, and facilitate the identification of low abundance proteins.

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PubMed2005

Intertubular growth in pure seminomas: associations with poor prognostic parameters.

Clinical stage I seminomas are effectively treated with surgery raising concerns as to when to give adjuvant radiation therapy given the risk of secondary malignancies. A recent randomized trial found tumor size and rete testis invasion to be the strongest predictors of relapse in clinical stage I seminomas. These 2 parameters may be surrogate measures of tumor volume. Intertubular seminoma (ITS) of the testis describes the presence of neoplastic germ cells within the interstitium of the testis. These cells are detected away from the main macroscopic mass. Because ITS can infiltrate in a 3-dimensional fashion, it may also represent a measure of tumor volume not usually noted in standard pathology reporting. The goal of this study was to determine the incidence of ITS in pure seminomas and its association with other prognostic parameters. One hundred twenty consecutive pure seminomas surgically removed between 1998 and 2003 were evaluated. ITS was defined as the presence of an interstitial or intertubular growth pattern of tumor cells, which was noncontiguous with the main tumor and present at least 3 high-power fields away from the tumor mass. The average tumor size was 3.4 cm. Of the entire cohort of patients, which included pathological stages T1 through T3, 11% had invasion through the tunica albuginea, 51% had rete testis invasion, 51% had lymphovascular invasion, 93% had associated intratubular germ-cell neoplasia, and 36% had ITS. ITS was significantly associated with rete testis invasion ( P = .001). Logistic regression analysis looking at ITS, tumor size, patient age, and lymphovascular invasion revealed that only ITS was associated with rete testis invasion (RR, 4.1, P < .0001). ITS is present in a significant proportion of pure seminomas and has a significant association with rete testis invasion. The presence of ITS may therefore be an important prognostic factor, not only because it alters the calculated size of the tumor but also because it has an association with rete testis invasion.

Adult↗
PubMed2005

Predictors of short postoperative prostate-specific antigen doubling time for patients diagnosed during PSA era.

OBJECTIVES: To determine the preoperative and postoperative predictors of a short prostate-specific antigen (PSA) doubling time (PSADT) after radical prostatectomy for patients diagnosed during the PSA era. METHODS: Between 1989 and 2003, 1785 men underwent radical prostatectomy for 2002 American Joint Committee on Cancer (AJCC) Stage T1c or T2 prostate cancer. Of these men, 205 had documented PSA failure. The PSADT was calculated by assuming first-order kinetics and using a minimum of two detectable postoperative PSA measurements after a previous undetectable level. Multivariable logistic regression analyses were performed to determine the significant preoperative and postoperative predictors of a PSADT of less than 6 months. RESULTS: Patients with a greater biopsy Gleason score (P = 0.006), greater preoperative risk group (P = 0.002), greater prostatectomy Gleason score (P = 0.0006), greater 2002 AJCC pathologic stage (P = 0.01), or shorter time to postoperative PSA failure (P = 0.04) were more likely to have a shorter PSADT. Using multivariable analysis, high-risk disease (P = 0.0001) was the only preoperative factor that remained an independent significant predictor of a PSADT of less than 6 months. Of the postoperative factors, a prostatectomy Gleason score of 8 to 10 (P = 0.002), 2002 AJCC pathologic Stage T3b (P = 0.03), and time to PSA failure of less than 2 years (P = 0.05) remained significant independent predictors of a PSADT of less than 6 months. CONCLUSIONS: High-risk disease preoperatively and a prostatectomy Gleason score of 8 to 10, seminal vesicle invasion, or a time to PSA failure of less than 2 years postoperatively were significant independent indicators of developing a postoperative PSADT of less than 6 months. For these men, trials studying systemic therapy in addition to radical prostatectomy are needed.

Adult↗
PubMed2005

Maximal tumor diameter and the risk of PSA failure in men with specimen-confined prostate cancer.

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.

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