Prostatic Neoplasms: Lange PH

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.

This publication has no abstract.

Kawachi MH, Bahnson RR, Barry M, Carroll PR, Carter HB, Catalona WJ, Epstein JI, Etzioni RB, Hemstreet GP, Howe RJ, Kopin JD, Lange PH, Lilja H, Mohler J, Moul J, Nadler RB, Patterson S, Pollack A, Presti JC, Stroup AM, Urban DA, Wake R, Wei JT, Anonymous00333. · No affiliation provided · J Natl Compr Canc Netw. · Pubmed #17692177 No free full text.

This publication has no abstract.

Mohler J, Babaian RJ, Bahnson RR, Boston B, D'Amico A, Eastham JA, Hauke RJ, Huben RP, Kantoff P, Kawachi M, Kuettel M, Lange PH, Logothetis C, MacVicar G, Pollack A, Pow-Sang JM, Roach M, Sandler H, Shrieve D, Srinivas S, Twardowski P, Urban DA, Walsh PC, Anonymous00332. · No affiliation provided · J Natl Compr Canc Netw. · Pubmed #17692170 No free full text.

This publication has no abstract.

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.

This publication has no abstract.

Scher HI, Eisenberger M, D'Amico AV, Halabi S, Small EJ, Morris M, Kattan MW, Roach M, Kantoff P, Pienta KJ, Carducci MA, Agus D, Slovin SF, Heller G, Kelly WK, Lange PH, Petrylak D, Berg W, Higano C, Wilding G, Moul JW, Partin AN, Logothetis C, Soule HR. · Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA. · J Clin Oncol. · Pubmed #14752077 No free full text.

Abstract: PURPOSE: To define methodology to show clinical benefit for patients in the state of a rising prostate-specific antigen (PSA). RESULTS: Hypothesis: A clinical states framework was used to address the hypothesis that definitive phase III trials could not be conducted in this patient population. Patient Population: The Group focused on men with systemic (nonlocalized) recurrence and a defined risk of developing clinically detectable metastases. Models to define systemic versus local recurrence, and risk of metastatic progression were discussed. Intervention: Therapies that have shown favorable effects in more advanced clinical states; meaningful biologic surrogates of activity linked with efficacy in other tumor types; and/or effects on a target or pathway known to contribute to prostate cancer progression in this state can be considered for evaluation. Outcomes: An intervention-specific posttherapy PSA-based outcome definition that would justify further testing should be described at the outset. Reporting: Trial reports should include a table showing the number of patients who achieve a specific PSA-based outcome, the number who remain enrolled onto the trial, and the number who came off study at different time points. The term PSA response should be abandoned. Trial Design: The phases of drug development for this state are optimizing dose and schedule, demonstration of a treatment effect, and clinical benefit. To move a drug forward should require a high bar that includes no rise in PSA in a defined proportion of patients for a specified period of time at a minimum. Agents that do not produce this effect can only be tested in combination. The preferred end point of clinical benefit is prostate cancer-specific survival; the time to development of metastatic disease is an alternative. CONCLUSION: Methodology to show that an intervention alters the natural history of prostate cancer is described. At each stage of development, only agents with sufficient activity should be moved forward.

Bahnson RR, Hanks GE, Huben RP, Kantoff P, Kozlowski JM, Kuettel M, Lange PH, Logothetis C, Pow-Sang JM, Roach M, Sandler H, Scardino PT, Taylor RJ, Urban DA, Walsh PC, Wilson TG, Anonymous00207. · James Cancer Hospital and Solove Research Institute at Ohio State University, Columbus, Ohio, USA. · Oncology (Williston Park). · Pubmed #11195405 No free full text.

Abstract: Systemic therapies for prostate cancer are likely to improve, and as they do, they will have enormous impact on the treatment of high-risk and locally advanced cancers. Further technical improvements in radiotherapy and alternative local modalities, such as cryoablation, are also likely, and will bring even more options for local control. It is certain these guidelines will continue to evolve.

Lange PH. · No affiliation provided · Eur Urol. · Pubmed #17070648 No free full text.

This publication has no abstract.

Lange PH. · No affiliation provided · J Urol. · Pubmed #12686823 No free full text.

This publication has no abstract.

Lange PH. · No affiliation provided · Urology. · Pubmed #11248606 No free full text.

This publication has no abstract.

Ellis WJ, Lange PH. · Department of Urology, Washington University, Seattle, WA 98195, USA. · J Natl Compr Canc Netw. · Pubmed #17692171 No free full text.

Abstract: Robotic-assisted laparoscopic radical prostatectomy is now one of the most common ways to treat prostate cancer. Although it is undoubtedly an outstanding procedure, in many contexts the advantages of the laparoscopic approach are overstated. The authors believe that open radical prostatectomy will continue to have an important role. For example, an extensive lymphadenectomy is more easily accomplished with the open technique and may be important in staging and possibly curing patients at high risk for prostate cancer. Also, tactile sensation is a valuable asset in assessing the extent of local tumor, and this cannot yet be replicated with a robotic approach. Furthermore, obese patients, those with a history of extensive prior surgical procedures, and men with extremely large prostates may experience advantages with the open technique. Finally, the open approach has a significant advantage in terms of hospital costs.

Morgan TM, Lange PH, Vessella RL. · Department of Urology, University of Washington School of Medicine, Seattle, WA 98195, USA. · Front Biosci. · Pubmed #17485277 No free full text.

Abstract: The dissemination of prostate cancer cells to secondary sites appears to be an intermediate step in the formation of tumor metastases. However, the significance of tumor cell dissemination into the blood and bone marrow as well as the characteristics of these cells remains largely unknown. In attempts to correlate the presence of disseminated tumor cells with disease prognosis, studies have utilized a range of molecular and histologic techniques. The results of this research have been largely inconclusive in terms of clinical utility. Nevertheless, they have demonstrated that these cells are detectable and present much more often than would be expected based on the rate of prostate cancer recurrence. Further research has thus begun to focus on the isolation of individual disseminated tumor cells which can then be analyzed with techniques such as gene expression microarrays and comparative genomic hybridization in order to better characterize the cells. This review paper will examine the various methods of detecting disseminated tumor cells in patients with prostate cancer and the results of studies correlating these cells with clinical variables. Additionally, we discuss the isolation and analysis of disseminated cells and examine their potential value in helping to understand the relationship between these cells and tumor metastasis.

Crawford ED, Rosenblum M, Ziada AM, Lange PH. · Division of Urology, University of Colorado Health Sciences Center, Denver 80262, USA. · Urology. · Pubmed #10606277 No free full text.

This publication has no abstract.

Huang CY, Beer TM, Higano CS, True LD, Vessella R, Lange PH, Garzotto M, Nelson PS. · Division of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington 98105-1024, USA. · Clin Cancer Res. · Pubmed #17908975 links to  free full text

Abstract: PURPOSE: To identify molecular alterations associating with in vivo exposure of prostate carcinoma to chemotherapy and assess functional roles modulating tumor response and resistance. EXPERIMENTAL DESIGN: Patients with high-risk localized prostate cancer (tumor-node-metastasis >or= T(2b) or prostate-specific antigen >or= 15 ng/mL or Gleason glade >or= 4+3) were enrolled into a phase II clinical trial of neoadjuvant chemotherapy with docetaxel and mitoxantrone followed by prostatectomy. Pretreatment prostate tissue was acquired by needle biopsy and posttreatment tissue was acquired by prostatectomy. Prostate epithelium was captured by microdissection, and transcript levels were quantitated by cDNA microarray hybridization. Gene expression changes associated with chemotherapy were determined by a random variance t test. Several were verified by quantitative reverse transcription PCR. In vitro analyses determining the influence of growth differentiation factor 15 (GDF15) on chemotherapy resistance were done. RESULTS: Gene expression changes after chemotherapy were measured in 31 patients who completed four cycles of neoadjuvant chemotherapy. After excluding genes shown previously to be influenced by the radical prostatectomy procedure, we identified 51 genes with significant transcript level alterations following chemotherapy. This group included several cytokines, including GDF15, chemokine (C-X-C motif) ligand 10, and interleukin receptor 1beta. Overexpression of GDF15 or exposure of prostate cancer cell lines to exogenous recombinant GDF15 conferred resistance to docetaxel and mitoxantrone. CONCLUSIONS: Consistent molecular alterations were identified in prostate cancer cells exposed to docetaxel and mitoxantrone chemotherapy. These alterations include transcripts encoding cytokines known to be regulated through the nuclear factor-kappaB pathway. Chemotherapy-induced cytokines and growth factors, such as GDF15, contribute to tumor cell therapy resistance and may serve as targets to improve responses.

Beer TM, Garzotto M, Lowe BA, Ellis WJ, Montalto MA, Lange PH, Higano CS. · Divisions of Hematology and Medical Oncology, Oregon Health Sciences University and Portland Veterans Affairs Medical Center, Portland, Oregon 97239, USA. · Clin Cancer Res. · Pubmed #14977829 links to  free full text

Abstract: PURPOSE: The purpose is to determine the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of mitoxantrone and docetaxel administered weekly before prostatectomy in men with localized prostate cancer at high risk for recurrence. EXPERIMENTAL DESIGN: Twenty-two patients were treated with four cycles of docetaxel 35 mg/m(2) and increasing doses of mitoxantrone starting at 2 mg/m(2) repeated weekly for 3 weeks of a 4-week cycle before prostatectomy. The MTD was defined as that dose at which fewer than one-third of patients experienced a DLT (>or=grade 4 hematological or >or=>grade 3 nonhematological toxicity). Changes in serum prostate-specific antigen and serum testosterone, and pathological outcome with surgery were secondary endpoints. RESULTS: The MTD for mitoxantrone in combination with this dose of docetaxel was 4 mg/m(2). Neutropenia was the DLT for the combination. Ten of 12 patients treated at the MTD completed the planned 16 weeks of chemotherapy, whereas 2 discontinued therapy early because of toxicity. The median reduction in PSA was 41% (range, 4-88%). Serum testosterone levels remained constant postchemotherapy. CONCLUSIONS: In this patient population, the planned Phase II regimen is 4 mg/m(2) mitoxantrone and 35 mg/m(2) docetaxel weekly for 3 of every 4 weeks. Delivery of this regimen before prostatectomy is feasible with acceptable toxicity. Additional studies are needed to determine whether this combined modality approach will reduce cancer recurrence rates in this high-risk population. Because extent of disease and exposure to prior therapy may impact treatment tolerance these safety data may not be applicable to patients with advanced prostate cancer.

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.

Vessella RL, Lange PH, Partin AW, Chan DW, Sokoll LJ, Sasse EA, Crawford ED. · University of Washington Medical School, Seattle, Washington 98195, USA. · Urology. · Pubmed #10840107 No free full text.

Abstract: OBJECTIVES: The determination of the percentage of free prostate-specific antigen (%fPSA) enhances the specificity of prostate cancer (CaP) detection. This study was undertaken to assess the performance of %fPSA in differentiating benign prostate disease from CaP and to determine the CaP probability estimates using the AxSYM Free PSA and AxSYM Total PSA assays. METHODS: In this prospective study, 297 men, 50 years old or older, with a total PSA level between 4 and 10 ng/mL and a nonsuspicious digital rectal examination were enrolled at 10 clinical sites. All subjects underwent at least sextant prostate biopsies to establish the diagnosis. fPSA and total PSA (tPSA) levels were determined using the AxSYM Free PSA and AxSYM Total PSA assays. Percent fPSA values were compared with tPSA values to determine the appropriate cutoffs for prostate biopsy and to calculate the CaP probability estimates. RESULTS: The strongest predictor of CaP in a logistic regression model was %fPSA (odds ratio 2.29), which contributed significantly more than age or tPSA to the predictive model. In this study population, a %fPSA cutoff of 26.4% would have detected 96% of subjects with CaP (sensitivity) and would have eliminated 27.4% of unnecessary biopsies (specificity). CaP probability estimates ranged from 9% to 69% and increased as the %fPSA value decreased. Men with a %fPSA level of 10% or lower had a 69% probability of CaP, and men with a %fPSA level of greater than 26% had a 9% probability of CaP. CONCLUSIONS: Percent fPSA values can help differentiate CaP from benign prostate disease and reduce unnecessary biopsies in 27% of men 50 years old or older whose digital rectal examination was normal and whose tPSA level was between 4 and 10 ng/mL. A %fPSA result can assist the physician and patient in determining the probability of CaP and assessing the need for prostate biopsy.

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.

Qian DZ, Huang CY, O'Brien CA, Coleman IM, Garzotto M, True LD, Higano CS, Vessella R, Lange PH, Nelson PS, Beer TM. · Division of Hematology and Medical Oncology, Oregon Health and Science University, OR, USA. · Clin Cancer Res. · Pubmed #19366833 No free full text.

Abstract: PURPOSE: To accurately identify gene expression alterations that differentiate neoplastic from normal prostate epithelium using an approach that avoids contamination by unwanted cellular components and is not compromised by acute gene expression changes associated with tumor devascularization and resulting ischemia. EXPERIMENTAL DESIGN: Approximately 3,000 neoplastic and benign prostate epithelial cells were isolated using laser capture microdissection from snap-frozen prostate biopsy specimens provided by 31 patients who subsequently participated in a clinical trial of preoperative chemotherapy. cDNA synthesized from amplified total RNA was hybridized to custom-made microarrays composed of 6,200 clones derived from the Prostate Expression Database. Expression differences for selected genes were verified using quantitative reverse transcription-PCR. RESULTS: Comparative analyses identified 954 transcript alterations associated with cancer (q < 0.01%), including 149 differentially expressed genes with no known functional roles. Gene expression changes associated with ischemia and surgical removal of the prostate gland were absent. Genes up-regulated in prostate cancer were statistically enriched in categories related to cellular metabolism, energy use, signal transduction, and molecular transport. Genes down-regulated in prostate cancers were enriched in categories related to immune response, cellular responses to pathogens, and apoptosis. A heterogeneous pattern of androgen receptor expression changes was noted. In exploratory analyses, androgen receptor down-regulation was associated with a lower probability of cancer relapse after neoadjuvant chemotherapy followed by radical prostatectomy. CONCLUSIONS: Assessments of tumor phenotypes based on gene expression for treatment stratification and drug targeting of oncogenic alterations may best be ascertained using biopsy-based analyses where the effects of ischemia do not complicate interpretation.

Morgan TM, Lange PH, Porter MP, Lin DW, Ellis WJ, Gallaher IS, Vessella RL. · Department of Urology, University of Washington School of Medicine, 1959 NE Pacific, BB-1115, Box 356510, Seattle, WA 98195, USA. · Clin Cancer Res. · Pubmed #19147774 No free full text.

Abstract: PURPOSE: Men with apparently localized prostate cancer often relapse years after radical prostatectomy. We sought to determine if epithelial-like cells identified from bone marrow in patients after radical prostatectomy, commonly called disseminated tumor cells (DTC), were associated with biochemical recurrence. EXPERIMENTAL DESIGN: We obtained bone marrow aspirates from 569 men prior to radical prostatectomy and from 34 healthy men with prostate-specific antigens <2.5 ng/mL to establish a comparison group. Additionally, an analytic cohort consisting of 98 patients with no evidence of disease (NED) after radical prostatectomy was established to evaluate the relationship between DTC and biochemical recurrence. Epithelial cells in the bone marrow were detected by magnetic bead enrichment with antibodies to CD45 and CD61 (negative selection) followed by antibodies to human epithelial antigen (positive selection) and confirmation with FITC-labeled anti-BerEP4 antibody. RESULTS: DTC were present in 72% (408 of 569) of patients prior to radical prostatectomy. There was no correlation with pathologic stage, Gleason grade, or preoperative prostate-specific antigens. Three of 34 controls (8.8%) had DTC present. In patients with NED after radical prostatectomy, DTC were present in 56 of 98 (57%). DTC were detected in 12 of 14 (86%) NED patients after radical prostatectomy who subsequently suffered biochemical recurrence. The presence of DTC in NED patients was an independent predictor of recurrence (hazard ratio 6.9; 95% confidence interval, 1.03-45.9). CONCLUSIONS: Approximately 70% of men undergoing radical prostatectomy had DTC detected in their bone marrow prior to surgery, suggesting that these cells escape early in the disease. Although preoperative DTC status does not correlate with pathologic risk factors, persistence of DTC after radical prostatectomy in NED patients was an independent predictor of recurrence.

Holcomb IN, Grove DI, Kinnunen M, Friedman CL, Gallaher IS, Morgan TM, Sather CL, Delrow JJ, Nelson PS, Lange PH, Ellis WJ, True LD, Young JM, Hsu L, Trask BJ, Vessella RL. · Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. · Cancer Res. · Pubmed #18632612 links to  free full text

Abstract: Disseminated epithelial cells can be isolated from the bone marrow of a far greater fraction of prostate-cancer patients than the fraction of patients who progress to metastatic disease. To provide a better understanding of these cells, we have characterized their genomic alterations. We first present an array comparative genomic hybridization method capable of detecting genomic changes in the small number of disseminated cells (10-20) that can typically be obtained from bone marrow aspirates of prostate-cancer patients. We show multiple regions of copy-number change, including alterations common in prostate cancer, such as 8p loss, 8q gain, and gain encompassing the androgen-receptor gene on Xq, in the disseminated cell pools from 11 metastatic patients. We found fewer and less striking genomic alterations in the 48 pools of disseminated cells from patients with organ-confined disease. However, we identify changes shared by these samples with their corresponding primary tumors and prostate-cancer alterations reported in the literature, evidence that these cells, like those in advanced disease, are disseminated tumor cells (DTC). We also show that DTCs from patients with advanced and localized disease share several abnormalities, including losses containing cell-adhesion genes and alterations reported to associate with progressive disease. These shared alterations might confer the capability to disseminate or establish secondary disease. Overall, the spectrum of genomic deviations is evidence for metastatic capacity in advanced-disease DTCs and for variation in that capacity in DTCs from localized disease. Our analysis lays the foundation for elucidation of the relationship between DTC genomic alterations and progressive prostate cancer.

Sim HG, Telesca D, Culp SH, Ellis WJ, Lange PH, True LD, Lin DW. · Department of Urology, University of Washington, Seattle, Washington 98195, USA. · J Urol. · Pubmed #18343432 No free full text.

Abstract: PURPOSE: Gleason sum 7 prostate cancers are a heterogeneous group with diverse tumor behaviors and disease outcomes. Tertiary Gleason patterns are reported with increasing frequency, particularly in prostatectomy pathology reports. We studied the pathological and biochemical outcome following radical prostatectomy in men with Gleason sum 7 and tertiary Gleason pattern 5. MATERIALS AND METHODS: We reviewed 1,110 cases of clinically localized prostate cancer treated with primary radical prostatectomy between January 1998 and August 2006 through a prospectively collected prostate cancer database. Patients who underwent neoadjuvant or adjuvant hormonal deprivation, radiation or systemic chemotherapy were excluded. RESULTS: Of the 1,110 patients 509 had Gleason sum 7 cancer. Tertiary Gleason pattern was present in 66 of 509 cases (13%) and it was absent in 443 (87%). On multivariate analysis tertiary Gleason pattern 5 was associated with higher pT stage (OR 2.55, 95% CI 1.40-4.65) and biochemical recurrence (HR 1.78, 95% CI 1.00-3.17). On subgroup analysis when patients with Gleason sum 3 + 4 + 5 and 4 + 3 + 5 were compared to their respective referent groups without the tertiary Gleason pattern, the 2 groups showed a trend toward higher pathological stage and prostate specific antigen progression. Patients with Gleason sum 3 + 4 with no tertiary pattern had higher PSA recurrence-free probability than those with Gleason sum 3 + 4 + 5 or 4 + 3 and patients with Gleason sum 4 + 3 + 5 had the lowest PSA recurrence-free probability. CONCLUSIONS: In patients with Gleason sum 7 prostate cancer tertiary Gleason grade 5 is significantly associated with higher pT stage and biochemical recurrence. Larger studies are needed to assess the predictive value of tertiary grade compared to other established parameters in predicting the long-term oncological outcome after radical prostatectomy.

Lin B, Utleg AG, Gravdal K, White JT, Halvorsen OJ, Lu W, True LD, Vessella R, Lange PH, Nelson PS, Hood L, Kalland KH, Akslen LA. · Zhejiang-California International Nanosystems Institute, Hangzhou, China. · Clin Cancer Res. · Pubmed #18316561 links to  free full text

Abstract: PURPOSE: Prostate cancer is the third leading cause of cancer death in the United States, following lung and colorectal cancer. We previously identified WDR19 as a prostate-specific, androgen-regulated gene. Here, we evaluate its utility as a prostate cancer tissue marker for diagnosis and prognostic evaluation. EXPERIMENTAL DESIGN: Real-time quantitative PCR was done on a panel of prostate tissue isolated by laser capture microdissection. After generating antibodies against WDR19, tissue microarrays (TMA) were employed to compare WDR19 expression between normal, benign prostatic hyperplasia, and prostate cancer tissue. RESULTS: Using microarrays and real-time quantitative PCR, we showed that WDR19 mRNA expression was increased in cancer. We further showed that WDR19 protein is localized to cytoplasmic subcellular granules and is expressed exclusively in prostate epithelia. Large-scale immunohistochemical staining using TMAs reveals a significant percentage of increase in intensely staining tissue cores in cancer tissue when compared with normal or benign prostatic hyperplastic tissue. Based on the analysis of a separate TMA for which clinical follow-up information was available, low-intensity WDR19 staining was significantly associated with decreased time to biochemical failure (P = 0.006) and with decreased time to locoregional recurrence (P = 0.050). CONCLUSIONS: WDR19 should be added to the list of prostate cancer tissue markers. The continued expansion of a multiple-marker panel will conceivably increase the sensitivity and specificity of prostate cancer diagnosis and prognosis.

Morrissey C, True LD, Roudier MP, Coleman IM, Hawley S, Nelson PS, Coleman R, Wang YC, Corey E, Lange PH, Higano CS, Vessella RL. · Genitourinary Cancer Research Laboratory, Department of Urology, University of Washington, Seattle, WA 98195, USA. · Clin Exp Metastasis. · Pubmed #17972146 No free full text.

Abstract: Our objective was to elucidate phenotypic differences between prostate cancer (PCa) liver, lymph node, and bone metastases. PCa metastases were obtained through a rapid tissue acquisition necropsy protocol. We grossly dissected metastatic foci from frozen samples and performed expression analyses using cDNA microarrays. Immunohistochemical analyses using a tissue microarray from thirty individuals with PCa metastases to lymph nodes, liver, and bone was used to confirm the gene expression changes associated with each metastatic site. Transcript alterations statistically-associated with bone metastases included increased expression of IBSP (Bone sialoprotein), F13A1 (factor XIII), and decreased expression of EFNA1 (ephrin-A1) and ANGPT2 (angiopoietin-2) when compared to liver and lymph node metastases. The metastasis-associated changes in proteins involved in coagulation and angiogenesis prompted further analysis of additional factors known to participate in the clotting cascade and blood vessel formation (angiopoitein-1, PAI-1, uPA, PAI-RBP-1 and hepsin). We also assessed tumor-associated microvessel density and distribution in liver, lymph node, and bone metastasis. Intense fibrin(ogen) and fibulin-1 staining was localized to epithelial cells at the periphery of metastatic tumors possibly to facilitate angiogenesis. The expression of hepsin, uPA, PAI-RBP1, PAI-1, and factor XIII may influence fibrinolysis and are regulated by the tumor microenvironment. The expression of angiopoietin-2 and apparent silencing of angiopoietin-1 in PCa bone, liver, and lymph node metastases may be critical for angiogenesis in this tumor type. In addition, the resulting tumor-associated microvessel density and distribution was significantly different between liver and bone metastasis possibly in response to the protein expression changes detailed above.

Pfitzenmaier J, Ellis WJ, Hawley S, Arfman EW, Klein JR, Lange PH, Vessella RL. · Department of Urology, Medical School, University of Washington, Seattle, WA 98195-6510, USA. · Urol Oncol. · Pubmed #17483018 No free full text.

Abstract: PURPOSE: To isolate prostate epithelial cells from the peripheral blood and bone marrow, and compare prostate-specific antigen (PSA) reverse transcriptase polymerase chain reaction (RT-PCR) performed on unenriched or epithelial enriched peripheral blood and bone marrow samples. PATIENTS AND METHODS: Peripheral blood samples from 371 patients with prostate cancer and 141 controls, and bone marrow samples from 292 patients with prostate cancer and 43 controls were obtained. One aliquot was assessed with PSA RT-PCR. Another was enriched for epithelial cells with paramagnetic immune microbeads and assessed for: (1) PSA immunohistochemistry, (2) PSA RT-PCR, and (3) immunofluorescent detection of epithelial cells. RESULTS: In the bone marrow (P < 0.01), but not the peripheral blood (P = 0.62), we observed significantly higher detection rates of disseminated PSA expressing epithelial cells after enrichment. The presence of epithelial cells with or without evidence of PSA production was uncommon among controls both in peripheral blood (1% and 0%) and bone marrow (11% and 0%). In patients with active prostate cancer, 46% to 74% had epithelial cells in peripheral blood, and 20% to 64% had PSA expressing epithelial cells. In bone marrow, 55% to 92% had epithelial cells, and 43% to 83% had PSA expressing epithelial cells. Particularly in bone marrow, circulating cells were frequently detected in men without evidence of disease after prostatectomy. With limited follow-up, the detection of epithelial cells or PSA expressing epithelial cells in peripheral blood or bone marrow before radical prostatectomy does not define a population of patients that will have biochemical failure. CONCLUSIONS: Immunomagnetic enrichment frequently detects epithelial, presumably malignant, cells in the peripheral blood and, especially, the bone marrow of patients with prostate cancer. Viable cells can be acquired for gene expression and phenotyping studies.