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1.  Randomized Phase 3 Trial of Abiraterone Acetate in Men with Metastatic Castration-Resistant Prostate Cancer and No Prior Chemotherapy 
The New England journal of medicine  2012;368(2):138-148.
Background
Abiraterone acetate, an androgen biosynthesis inhibitor, improves overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) post-chemotherapy. Many mCRPC patients never receive chemotherapy and thus cannot benefit from abiraterone acetate; we evaluated this agent in mCRPC patients who had not received chemotherapy.
Methods
In this double-blind study, 1088 patients were randomized 1:1 to abiraterone acetate (1000 mg) plus prednisone (5 mg twice daily) or placebo plus prednisone. Co-primary end points were radiographic progression-free survival (rPFS) and OS. Secondary end points measured clinically relevant landmarks of mCRPC progression. Patient-reported outcomes included pain progression and quality of life.
Results
The study was unblinded after a planned interim analysis (IA) at 43% of OS events. Treatment with abiraterone acetate-prednisone resulted in a 57% reduction in the risk of radiographic progression or death (hazard ratio [HR], 0.43; 95% confidence interval [CI]: 0.35 to 0.52; P<0.001; 13% OS events IA) and an estimated 25% decrease in the risk of death (HR, 0.75; 95% CI: 0.61 to 0.93; P=0.009; 43% OS events IA). Secondary end points supported superiority of abiraterone acetate-prednisone: time to cytotoxic chemotherapy initiation, opiate use for cancer-related pain, prostate-specific antigen progression (all P<0.001) and performance status deterioration (P=0.005). Self-reported time to pain progression and patient functional status degradation favored abiraterone acetate-prednisone (P=0.05 and P=0.003). Grade 3/4 mineralocorticoid-related adverse events and liver function test abnormalities were more common with abiraterone acetate-prednisone.
Conclusions
Abiraterone acetate produces OS and rPFS benefits, as well as significant delays in clinical deterioration and initiation of chemotherapy, in mCRPC.
doi:10.1056/NEJMoa1209096
PMCID: PMC3683570  PMID: 23228172
Abiraterone acetate; prednisone; metastatic castration-resistant prostate cancer; androgen; CYP17
2.  A non-comparative randomized phase II study of two doses of ATN-224, a copper/zinc superoxide dismutase inhibitor, in patients with biochemically recurrent hormone-naïve prostate cancer 
Urologic oncology  2011;31(5):581-588.
Objective
ATN-224 (choline tetrathiomolybdate) is an oral Cu2+/Zn2+-superoxide dismutase 1 (SOD1) inhibitor with preclinical antitumor activity. We hypothesized that ATN-224 may induce antitumor effects as an antiangiogenic agent at low dose-levels while possessing direct antitumor activity at higher dose-levels. The objective of this study was to screen its clinical activity in patients with biochemically recurrent hormone-naïve prostate cancer.
Methods
Biochemically-recurrent prostate cancer patients with prostate specific antigen doubling times (PSADT) <12 months, no radiographic evidence of metastasis, and no hormonal therapy within 6 months (with serum testosterone levels >150 ng/dL) were eligible. ATN-224 was administered at two dose-levels, 300 mg (n=23) or 30 mg (n=24) daily, by way of randomization. PSA progression was defined as a ≥50% increase (and >5 ng/mL) in PSA from baseline or post-treatment nadir. Endpoints included the proportion of patients who were free of PSA progression at 24 weeks, changes in PSA slope/PSADT, and safety. The study was not powered to detect differences between the two treatment groups.
Results
At 24 weeks, 59% (95% CI 33–82%) of men in the low-dose arm and 45% (95% CI 17–77%) in the high-dose arm were PSA progression-free. Median PSA progression-free survival was 30 weeks (95% CI 21–40+) and 26 weeks (95% CI 24–39+) in the low-dose and high-dose groups, respectively. Pre- and on-treatment PSA kinetics analyses showed a significant mean PSA slope decrease (p=0.006) and a significant mean PSADT increase (p=0.032) in the low-dose arm only. Serum ceruloplasmin levels, a biomarker for ATN-224 activity, were lowered in the high-dose group, but did not correlate with PSA changes.
Conclusions
Low-dose ATN-224 (30 mg daily) may have biologic activity in men with biochemically-recurrent prostate cancer, as suggested by an improvement in PSA kinetics. However, the clinical significance of PSA kinetics changes in this patient population remains uncertain. The absence of a dose-response effect also reduces enthusiasm, and there are currently no plans to further develop this agent in prostate cancer.
doi:10.1016/j.urolonc.2011.04.009
PMCID: PMC3227793  PMID: 21816640
3.  Platinum-Based Chemotherapy for Variant Castrate-Resistant Prostate Cancer 
Purpose
Clinical features characteristic of small-cell prostate carcinoma (SCPC), (““anaplastic””) often emerge during the progression of prostate cancer. We sought to determine the efficacy of platinum-based chemotherapy in patients meeting at least one of seven prospectively defined “anaplastic” clinical criteria, including exclusive visceral or predominantly lytic bone metastases, bulky tumor masses, low PSA levels relative to tumor burden or short response to androgen deprivation therapy.
Experimental Design
A 120-patient phase II trial of frontline carboplatin and docetaxel (CD) and second-line etoposide and cisplatin (EP) was designed to provide reliable clinical response estimates under a Bayesian probability model with early stopping rules in place for futility and toxicity.
Results
Seventy-four of 113 (65.4%) and 24 of 71 (33.8%) were progression free after 4 cycles of CD and EP, respectively. Median overall survival (OS) was 16 months (95% CI, 13.6-19.0 months). Of the 7 “anaplastic” criteria, bulky tumor mass was significantly associated with poor outcome. Lactic acid dehydrogenase (LDH) strongly predicted for OS and rapid progression. Serum carcinoembryonic antigen (CEA) concentration strongly predicted OS but not rapid progression. Neuroendocrine markers did not predict outcome or response to therapy.
Conclusion
Our findings support the hypothesis that patients with “anaplastic” prostate cancer are a recognizable subset characterized by a high response rate of short duration to platinum-containing chemotherapies, similar to SCPC. Our results suggest that CEA is useful for selecting therapy in men with CRPC and consolidative therapies to bulky high-grade tumor masses should be considered in this patient population.
doi:10.1158/1078-0432.CCR-12-3791
PMCID: PMC3699964  PMID: 23649003
Small-cell; neuroendocrine; castration-resistant; prostate carcinoma; platinum chemotherapy
4.  Phase II Study of Abiraterone Acetate Plus Prednisone in Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer Demonstrating Radiographic Flare Discordant With Serologic Measures of Response 
Purpose
Abiraterone is an oral inhibitor of CYP17, essential for androgen biosynthesis. This multicenter study assessed its efficacy in patients with CRPC without prior exposure to chemotherapy or CYP17 targeted therapy, and assessed the frequency of interpretation of bone scans discordant with PSA and clinical response.
Patients and Methods
33 patients received abiraterone acetate 1000 mg daily with prednisone 5 mg twice daily in continuous 28-day cycles. Patients were evaluated monthly for efficacy and safety. Bone scan flare was defined as the combination, after 3 months of therapy, of an interpreting radiologist's report indicating “disease progression” in the context of a ≥50% decline in PSA, with scan improvement 3 months later.
Results
A ≥ 50% PSA decline at week 12 was confirmed in 22/33 (67%) patients. PSA declines of ≥ 50% were seen in 26 (79%) patients. Undetectable PSA levels (≤ 0.1 ng/mL) occurred in 2 patients. Median time on therapy and time to PSA progression are 63 and 71 weeks, respectively. Twenty three patients were evaluable for bone scan flare. Progression was indicated in the radiologist's report in 12/23 (52 %), and 10/12 subsequently showed improvement. As prospectively defined, bone scan flare was observed in 10/23 (43.5%) evaluable patients or 10/33 (30%) enrolled patients. Adverse events were typically grade 1/2 and consistent with prior published abiraterone reports.
Conclusion
Clinical response to abiraterone acetate plus prednisone was frequent and durable in men with metastatic CRPC progressing on hormonal therapy with over half of patients on therapy > 1 year. Further investigation is needed to clarify the potential confounding effect of the frequently occurring bone scan flare phenomena on patient management and interpretation of clinical trial results.
doi:10.1158/1078-0432.CCR-11-0815
PMCID: PMC3657705  PMID: 21632851
abiraterone acetate; castration-resistant prostate cancer; CRPC; hormone-resistant prostate cancer; therapy; efficacy
5.  Castration-Resistant Prostate Cancer: Targeted Therapies and Individualized Treatment 
The Oncologist  2011;16(3):264-275.
Several novel therapies for castration-resistant prostate cancer targeted to androgen receptor–mediated and non–androgen receptor–mediated pathways that have recently entered clinical trials are highlighted, including the molecular rationale and available clinical data, and emerging evidence on the potential of individualized therapy for castration-resistant prostate cancer is summarized.
Various molecular mechanisms have been implicated in the progression from hormone-sensitive to castration-resistant prostate cancer (CRPC). Novel targeted agents to treat CRPC have been developed that inhibit either androgen receptor (AR)-mediated signaling (AR antagonists and inhibitors of androgen synthesis) or non–AR-mediated signaling (inhibitors of Src, mammalian target of rapamycin, chaperone proteins, insulin-like growth factor-1 receptor, vascular endothelial growth factor, and endothelin-A receptor) pathways. However, variable efficacy has been observed in clinical trials, most likely because of the biologic heterogeneity of CRPC. To account for potential differences in disease biology, a more individualized approach to treatment, based on genomic and/or proteomic analyses of individual tumors, is being investigated. By identifying tumors with a characteristic molecular subtype and assigning treatment accordingly, it is hoped that a higher proportion of patients will benefit from targeted therapy. Additionally, lessons learned through the application of these technologies to prostate cancer may subsequently influence therapeutic development in other solid tumors.
doi:10.1634/theoncologist.2010-0216
PMCID: PMC3228103  PMID: 21339259
Prostatic neoplasms; Androgen receptor; Signal transduction; Investigational treatments
6.  Phase I Clinical Trial of the CYP17 Inhibitor Abiraterone Acetate Demonstrating Clinical Activity in Patients With Castration-Resistant Prostate Cancer Who Received Prior Ketoconazole Therapy 
Journal of Clinical Oncology  2010;28(9):1481-1488.
Purpose
Abiraterone acetate is a prodrug of abiraterone, a selective inhibitor of CYP17, the enzyme catalyst for two essential steps in androgen biosynthesis. In castration-resistant prostate cancers (CRPCs), extragonadal androgen sources may sustain tumor growth despite a castrate environment. This phase I dose-escalation study of abiraterone acetate evaluated safety, pharmacokinetics, and effects on steroidogenesis and prostate-specific antigen (PSA) levels in men with CPRC with or without prior ketoconazole therapy.
Patients and Methods
Thirty-three men with chemotherapy-naïve progressive CRPC were enrolled. Nineteen patients (58%) had previously received ketoconazole for CRPC. Bone metastases were present in 70% of patients, and visceral involvement was present in 18%. Three patients (9%) had locally advanced disease without distant metastases. Fasted or fed cohorts received abiraterone acetate doses of 250, 500, 750, or 1,000 mg daily. Single-dose pharmacokinetic analyses were performed before continuous daily dosing.
Results
Adverse events were predominantly grade 1 or 2. No dose-limiting toxicities were observed. Hypertension (grade 3, 12%) and hypokalemia (grade 3, 6%; grade 4, 3%) were the most frequent serious toxicities and responded to medical management. Confirmed ≥ 50% PSA declines at week 12 were seen in 18 (55%) of 33 patients, including nine (47%) of 19 patients with prior ketoconazole therapy and nine (64%) of 14 patients without prior ketoconazole therapy. Substantial declines in circulating androgens and increases in mineralocorticoids were seen with all doses.
Conclusion
Abiraterone acetate was well tolerated and demonstrated activity in CRPC, including in patients previously treated with ketoconazole. Continued clinical study is warranted.
doi:10.1200/JCO.2009.24.1281
PMCID: PMC2849769  PMID: 20159824
7.  Cilengitide (EMD 121974, NSC 707544) in asymptomatic metastatic castration resistant prostate cancer patients: A randomized phase II trial by the Prostate Cancer Clinical Trials Consortium 
Investigational new drugs  2010;29(6):1432-1440.
Background
Integrins are involved in prostate cancer metastasis by regulating cell adhesion, migration, invasion, motility, angiogenesis and bone metabolism. We evaluated the efficacy of two dose levels of cilengitide in patients (pts) with castrate resistant prostate cancer (CRPC).
Methods
Chemotherapy-naïve, asymptomatic metastatic CRPC pts were randomized to cilengitide 500mg or 2000mg IV twice weekly using parallel 2-stage design. The primary endpoint was rate of objective clinical progression at six-months. Secondary endpoints included clinical and PSA response rates, safety and effects of cilengitide treatment on circulating tumor cells (CTCs) and bone remodeling markers.
Results
Forty-four pts were accrued to first stage (22/arm). Median number of cycles was three in both arms (500mg arm: 1–8; 2000 mg arm: 1–15). At six months, two pts (9%) on the 500mg arm and five pts (23%) on the 2000mg arm had not progressed. Best objective response was stable disease (SD) in seven pts for 9.9[8.1,20.9] months. There were three grade 3 and no grade 4 toxicities. At 12 weeks, analysis of bone markers did not reveal significant trends. At progression, bone specific alkaline phosphatase and N-telopeptide increased in all pts, less so in pts on the 2000mg arm and in pts on both arms who obtained SD at 6 months. CTCs increased over time in both arms.
Conclusion
Cilengitide was well tolerated with modest clinical effect in favor of the higher dose. The unique trial design including a shift from response rate to objective progression as the endpoint, and not acting on PSA increases was feasible.
doi:10.1007/s10637-010-9420-8
PMCID: PMC2917503  PMID: 20336348
prostate cancer; metastatic disease; integrins; angiogenesis; cilengitide; bone biomarkers
8.  Abiraterone and Increased Survival in Metastatic Prostate Cancer 
The New England journal of medicine  2011;364(21):1995-2005.
BACKGROUND
Biosynthesis of extragonadal androgen may contribute to the progression of castration-resistant prostate cancer. We evaluated whether abiraterone acetate, an inhibitor of androgen biosynthesis, prolongs overall survival among patients with metastatic castration-resistant prostate cancer who have received chemotherapy.
METHODS
We randomly assigned, in a 2:1 ratio, 1195 patients who had previously received docetaxel to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (797 patients) or placebo (398 patients). The primary end point was overall survival. The secondary end points included time to prostate-specific antigen (PSA) progression (elevation in the PSA level according to prespecified criteria), progression-free survival according to radiologic findings based on prespecified criteria, and the PSA response rate.
RESULTS
After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate–prednisone group than in the placebo–prednisone group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001). Data were unblinded at the interim analysis, since these results exceeded the preplanned criteria for study termination. All secondary end points, including time to PSA progression (10.2 vs. 6.6 months; P<0.001), progression-free survival (5.6 months vs. 3.6 months; P<0.001), and PSA response rate (29% vs. 6%, P<0.001), favored the treatment group. Mineralocorticoid-related adverse events, including fluid retention, hypertension, and hypokalemia, were more frequently reported in the abiraterone acetate–prednisone group than in the placebo–prednisone group.
CONCLUSIONS
The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy. (Funded by Cougar Biotechnology; COU-AA-301 ClinicalTrials.gov number, NCT00638690.)
doi:10.1056/NEJMoa1014618
PMCID: PMC3471149  PMID: 21612468
9.  Isolation and genomic analysis of circulating tumor cells from castration resistant metastatic prostate cancer 
BMC Cancer  2012;12:78.
Background
The number of circulating tumor cells (CTCs) in metastatic prostate cancer patients provides prognostic and predictive information. However, it is the molecular characterization of CTCs that offers insight into the biology of these tumor cells in the context of personalized treatment.
Methods
We developed a novel approach to isolate CTCs away from hematopoietic cells with high purity, enabling genomic analysis of these cells. The isolation protocol involves immunomagnetic enrichment followed by fluorescence activated cell sorting (IE/FACS). To evaluate the feasibility of isolation of CTCs by IE/FACS and downstream genomic profiling, we conducted a pilot study in patients with metastatic castration resistant prostate cancer (CRPC). Twenty (20) sequential CRPC patients were assayed using CellSearch™. Twelve (12) patients positive for CTCs were subjected to immunomagnetic enrichment and fluorescence activated cell sorting (IE/FACS) to isolate CTCs. Genomic DNA of CTCs was subjected to whole genome amplification (WGA) followed by gene copy number analysis via array comparative genomic hybridization (aCGH).
Results
CTCs from nine (9) patients successfully profiled were observed to have multiple copy number aberrations including those previously reported in primary prostate tumors such as gains in 8q and losses in 8p. High-level copy number gains at the androgen receptor (AR) locus were observed in 7 (78%) cases. Comparison of genomic profiles between CTCs and archival primary tumors from the same patients revealed common lineage. However, high-level copy number gains in the AR locus were observed in CTCs, but not in the matched archival primary tumors.
Conclusions
We developed a new approach to isolate prostate CTCs without significant leukocyte admixture, and to subject them to genome-wide copy number analysis. Our assay may be utilized to explore genomic events involved in cancer progression, e.g. development of castration resistance and to monitor therapeutic efficacy of targeted therapies in clinical trials in a relatively non-invasive manner.
doi:10.1186/1471-2407-12-78
PMCID: PMC3395839  PMID: 22373240
Circulating tumor cells; Castration resistant prostate cancer; Copy number analysis; Array comparative genomic hybridization; Androgen receptor
10.  Significant and Sustained Antitumor Activity in Post-Docetaxel, Castration-Resistant Prostate Cancer With the CYP17 Inhibitor Abiraterone Acetate 
Journal of Clinical Oncology  2010;28(9):1489-1495.
Purpose
The principal objective of this trial was to evaluate the antitumor activity of abiraterone acetate, an oral, specific, irreversible inhibitor of CYP17 in docetaxel-treated patients with castration-resistant prostate cancer (CRPC).
Patients and Methods
In this multicenter, two-stage, phase II study, abiraterone acetate 1,000 mg was administered once daily continuously. The primary end point was achievement of a prostate-specific antigen (PSA) decline of ≥ 50% in at least seven of 35 patients. Per an attained phase II design, more than 35 patients could be enrolled if the primary end point was met. Secondary objectives included: PSA declines of ≥ 30% and ≥ 90%; rate of RECIST (Response Evaluation Criteria in Solid Tumors) responses and duration on study; time to PSA progression; safety and tolerability; and circulating tumor cell (CTC) enumeration.
Results
Docetaxel-treated patients with CRPC (N = 47) were enrolled. PSA declines of ≥ 30%, ≥ 50% and ≥ 90% were seen in 68% (32 of 47), 51% (24 of 47), and 15% (seven of 47) of patients, respectively. Partial responses (by RECIST) were reported in eight (27%) of 30 patients with measurable disease. Median time to PSA progression was 169 days (95% CI, 113 to 281 days). The median number of weeks on study was 24, and 12 (25.5%) of 47 patients remained on study ≥ 48 weeks. CTCs were enumerated in 34 patients; 27 (79%) of 34 patients had at least five CTCs at baseline. Eleven (41%) of 27 patients had a decline from at least five to less than 5 CTCs, and 18 (67%) of 27 had a ≥ 30% decline in CTCs after starting treatment with abiraterone acetate. Abiraterone acetate was well tolerated.
Conclusion
Abiraterone acetate has significant antitumor activity in post-docetaxel patients with CRPC. Randomized, phase III trials of abiraterone acetate are underway to define the future role of this agent.
doi:10.1200/JCO.2009.24.6819
PMCID: PMC2849770  PMID: 20159823
11.  Phase II Multicenter Study of Abiraterone Acetate Plus Prednisone Therapy in Patients With Docetaxel-Treated Castration-Resistant Prostate Cancer 
Journal of Clinical Oncology  2010;28(9):1496-1501.
Purpose
Persistence of ligand-mediated androgen receptor signaling has been documented in castration-resistant prostate cancers (CRPCs). Abiraterone acetate (AA) is a potent and selective inhibitor of CYP17, which is required for androgen biosynthesis in the testes, adrenal glands, and prostate tissue. This trial evaluated the efficacy and safety of AA in combination with prednisone to reduce the symptoms of secondary hyperaldosteronism that can occur with AA monotherapy.
Patients and Methods
Fifty-eight men with progressive metastatic CRPC who experienced treatment failure with docetaxel-based chemotherapy received AA (1,000 mg daily) with prednisone (5 mg twice daily). Twenty-seven (47%) patients had received prior ketoconazole. The primary outcome was ≥ 50% prostate-specific antigen (PSA) decline, with objective response by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and changes in Eastern Cooperative Oncology Group (ECOG) performance status (PS) and circulating tumor cell (CTC) numbers. Safety was also evaluated.
Results
A ≥ 50% decline in PSA was confirmed in 22 (36%) patients, including 14 (45%) of 31 ketoconazole-naïve and seven (26%) of 27 ketoconazole-pretreated patients. Partial responses were seen in four (18%) of 22 patients with RECIST-evaluable target lesions. Improved ECOG PS was seen in 28% of patients. Median time to PSA progression was 169 days (95% CI, 82 to 200 days). CTC conversions with treatment from ≥ 5 to < 5 were noted in 10 (34%) of 29 patients. The majority of AA-related adverse events were grade 1 to 2, and no AA-related grade 4 events were seen.
Conclusion
AA plus prednisone was well tolerated, with encouraging antitumor activity in heavily pretreated CRPC patients. The incidence of mineralocorticoid-related toxicities (hypertension or hypokalemia) was reduced by adding low-dose prednisone. The combination of AA plus prednisone is recommended for phase III investigations.
doi:10.1200/JCO.2009.25.9259
PMCID: PMC3040042  PMID: 20159814
12.  Phase I Study of Ixabepilone, Mitoxantrone, and Prednisone in Patients With Metastatic Castration-Resistant Prostate Cancer Previously Treated With Docetaxel-Based Therapy: A Study of the Department of Defense Prostate Cancer Clinical Trials Consortium 
Journal of Clinical Oncology  2009;27(17):2772-2778.
Purpose
Mitoxantrone plus prednisone and ixabepilone each have modest activity as second-line chemotherapy in docetaxel-refractory castration-resistant prostate cancer (CRPC) patients. Clinical noncrossresistance was previously observed.
Patients and Methods
Metastatic CRPC patients progressing during or after taxane-based chemotherapy enrolled in a phase I multicenter study of ixabepilone and mitoxantrone administered every 21 days along with prednisone. Ixabepilone and mitoxantrone doses were alternately escalated in a standard 3 + 3 design. Patients were evaluated for toxicity and disease response. Dose-limiting toxicities (DLTs) were defined as treatment related, occurring during cycle 1, and included grade 4 prolonged or febrile neutropenia, thrombocytopenia (grade 4 or grade 3 with bleeding), or ≥ grade 3 nonhematologic toxicity.
Results
Thirty-six patients were treated; 59% of patients experienced grade 3/4 neutropenia. DLTs included grade 3 diarrhea (n = 1), prolonged grade 4 neutropenia (n = 4), and grade 5 neutropenic infection (n = 1). Due to prolonged neutropenia, the highest dose levels were repeated with pegfilgrastim on day 2 of each cycle. The maximum tolerated dose in combination with pegfilgrastim was not exceeded. The recommended phase II dose is mitoxantrone 12 mg/m2 and ixabepilone 35 mg/m2 every 21 days, pegfilgrastim 6 mg subcutaneously day 2, and continuous prednisone 5 mg twice per day. Thirty-one percent of patients have experienced ≥ 50% prostate-specific antigen (PSA) declines, and two experienced objective responses. Of 21 patients treated with mitoxantrone 12 mg/m2 plus ixabepilone ≥ 30 mg/m2, nine (43%) experienced ≥ 50% PSA declines (95% CI, 22% to 66%).
Conclusion
These results suggest that the combination of ixabepilone and mitoxantrone is feasible and active in CRPC and requires dosing with pegfilgrastim.
doi:10.1200/JCO.2008.19.8002
PMCID: PMC2698016  PMID: 19349545

Results 1-12 (12)