Validation of metastasis-free survival as a surrogate endpoint for overall survival in localized prostate cancer in the era of docetaxel for castration-resistant prostate cancer.

BACKGROUND: Prior work from the Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) consortium (ICECaP-1) demonstrated that metastasis-free survival (MFS) is a valid surrogate for overall survival (OS) in localized prostate cancer (PCa). This was based on data from patients treated predominantly before 2004, prior to docetaxel being available for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). We sought to validate surrogacy in a more contemporary era (ICECaP-2) with greater availability of docetaxel and other systemic therapies for mCRPC. PATIENTS AND METHODS: Eligible trials for ICECaP-2 were those providing individual patient data (IPD) after publication of ICECaP-1 and evaluating adjuvant/salvage therapy for localized PCa, and which collected MFS and OS data. MFS was defined as distant metastases or death from any cause, and OS was defined as death from any cause. Surrogacy was evaluated using a meta-analytic two-stage validation model, with an R2 ≥ 0.7 defined a priori as clinically relevant. RESULTS: A total of 15 164 IPD from 14 trials were included in ICECaP-2, with 70% of patients treated after 2004. The median follow-up was 8.3 years and the median postmetastasis survival was 3.1 years in ICECaP-2, compared with 1.9 years in ICECaP-1. For surrogacy condition 1, Kendall's tau was 0.92 for MFS with OS at the patient level, and R2 from weighted linear regression (WLR) of 8-year OS on 5-year MFS was 0.73 (95% confidence interval 0.53-0.82) at the trial level. For condition 2, R2 was 0.83 (95% confidence interval 0.64-0.89) from WLR of log[hazard ratio (HR)]-OS on log(HR)-MFS. The surrogate threshold effect on OS was an HR(MFS) of 0.81. CONCLUSIONS: MFS remained a valid surrogate for OS in a more contemporary era, where patients had greater access to docetaxel and other systemic therapies for mCRPC. This supports the use of MFS as the primary outcome measure for ongoing adjuvant trials in localized PCa.

Next generation radiotheranostics promoting precision medicine.

Radiotheranostics is a field of rapid growth with some approved treatments including 131I for thyroid cancer, 223Ra for osseous metastases, 177Lu-DOTATATE for neuroendocrine tumors, and 177Lu-PSMA (prostate-specific membrane antigen) for prostate cancer, and several more under investigation. In this review, we will cover the fundamentals of radiotheranostics, the key clinical studies that have led to current success, future developments with new targets, radionuclides and platforms, challenges with logistics and reimbursement and, lastly, forthcoming considerations regarding dosimetry, identifying the right line of therapy, artificial intelligence and more.

Advances in targeted alpha therapy for prostate cancer.

Amongst therapeutic radiopharmaceuticals, targeted alpha therapy (TαT) can deliver potent and local radiation selectively to cancer cells as well as the tumor microenvironment and thereby control cancer while minimizing toxicity. In this review, we discuss the history, progress, and future potential of TαT in the treatment of prostate cancer, including dosimetry-individualized treatment planning, combinations with small-molecule therapies, and conjugation to molecules directed against antigens expressed by prostate cancer cells, such as prostate-specific membrane antigen (PSMA) or components of the tumor microenvironment. A clinical proof of concept that TαT is efficacious in treating bone-metastatic castration-resistant prostate cancer has been demonstrated by radium-223 via improved overall survival and long-term safety/tolerability in the phase III ALSYMPCA trial. Dosimetry calculation and pharmacokinetic measurements of TαT provide the potential for optimization and individualized treatment planning for a precision medicine-based cancer management paradigm. The ability to combine TαTs with other agents, including chemotherapy, androgen receptor-targeting agents, DNA repair inhibitors, and immuno-oncology agents, is under investigation. Currently, TαTs that specifically target prostate cancer cells expressing PSMA represents a promising therapeutic approach. Both PSMA-targeted actinium-225 and thorium-227 conjugates are under investigation. The described clinical benefit, safety and tolerability of radium-223 and the recent progress in TαT trial development suggest that TαT occupies an important new role in prostate cancer treatment. Ongoing studies with newer dosimetry methods, PSMA targeting, and novel approaches to combination therapies should expand the utility of TαT in prostate cancer treatment.

Re-treatment with radium-223: first experience from an international, open-label, phase I/II study in patients with castration-resistant prostate cancer and bone metastases.

BACKGROUND: Six radium-223 injections at 4-week intervals is indicated for patients with castration-resistant prostate cancer and symptomatic bone metastases. However, patients usually develop disease progression after initial treatment. This prospective phase I/II study assessed re-treatment safety and efficacy of up to six additional radium-223 injections. PATIENTS AND METHODS: Patients had castration-resistant prostate cancer and bone metastases and six initial radium-223 injections with no on-treatment bone progression; all had subsequent radiologic or clinical progression. Concomitant agents were allowed at investigator discretion, excluding chemotherapy and initiation of new abiraterone or enzalutamide. The primary endpoint was safety; additional exploratory endpoints included time to radiographic bone progression, time to total alkaline phosphatase and prostate-specific antigen progression, radiographic progression-free survival, overall survival, time to first symptomatic skeletal event (SSE), SSE-free survival, and time to pain progression. RESULTS: Among 44 patients, 29 (66%) received all six re-treatment injections. Median time from end of initial radium-223 treatment was 6 months. Forty-one (93%) reported ≥1 treatment-emergent adverse event. No grade 4-5 hematologic treatment-emergent adverse events occurred. Only one (2%) patient had radiographic bone progression; eight (18%) had radiographic soft tissue tumor progression (three lymph node and five visceral metastases). Median times to total alkaline phosphatase and prostate-specific antigen progression were not reached and 2.2 months, respectively. Median radiographic progression-free survival was 9.9 months (12.8-month maximum follow-up). Five (11%) patients died and eight (18%) experienced first SSEs. Median overall survival, time to first SSE, and SSE-free survival were not reached. Five (14%) of 36 evaluable patients (baseline worst pain score ≤7) had pain progression. After 2 years of follow-up, 28 (64%) patients died, and the median overall survival was 24.4 months. CONCLUSIONS: Re-treatment with a second course of six radium-223 injections after disease progression is well tolerated, with minimal hematologic toxicity and low radiographic bone progression rates in this small study with limited follow-up. Favorable safety and early effects on disease progression indicate that radium-223 re-treatment is feasible and warrants further evaluation in larger prospective trials.

An exploratory analysis of alkaline phosphatase, lactate dehydrogenase, and prostate-specific antigen dynamics in the phase 3 ALSYMPCA trial with radium-223.

Background: Baseline clinical variables are prognostic for overall survival (OS) in patients with castration-resistant prostate cancer (CRPC). Their prognostic and predictive value with agents targeting bone metastases, such as radium-223, is not established. Patients and methods: The radium-223 ALSYMPCA trial enrolled patients with CRPC and symptomatic bone metastases. Prognostic potential of baseline variables was assessed using Cox models. Percentage changes in biomarker levels from baseline were evaluated during the trial period; changes from baseline to week 12 were evaluated for association with OS and surrogacy. Results: Eastern Cooperative Oncology Group performance status, total alkaline phosphatase (tALP), lactate dehydrogenase (LDH), and prostate-specific antigen (PSA) at baseline were associated with OS (P ≤ 0.0003) in the intent-to-treat population (radium-223, N = 614; placebo, N = 307). tALP declined from baseline within 4 weeks after beginning radium-223, by week 12 declining in 87% of radium-223 and 23% of placebo patients (P < 0.001). LDH declined in 51% and 34% (P = 0.003), whereas PSA declined in 27% and 14% (P = 0.160). Mean tALP change from baseline was 32.2% decrease with radium-223 and 37.2% increase with placebo. Radium-223 patients with tALP decline from baseline to week 12 (confirmed ≥3 weeks from week 12) had 55% lower risk of death (hazard ratio = 0.45; 95% CI 0.34-0.61) versus those with no confirmed tALP decline. Proportional treatment effect (PTE) values for tALP, LDH, and PSA changes from baseline at week 12 as OS surrogate markers were 0.34 (95% CI: 0-0.746), 0.07 (95% CI: 0-0.211), and 0 (95% CI: 0-0.082), respectively. Conclusions: Significant tALP declines (versus placebo) occurred as early as 4 weeks after beginning radium-223 therapy. tALP or LDH declines at 12 weeks correlated with longer OS, but did not meet statistical surrogacy requirements. Dynamic changes in tALP and LDH during radium-223 treatments may be useful to monitor, but do not serve as surrogates for survival.

Alpha emitter radium-223 and survival in metastatic prostate cancer.

BACKGROUND: Radium-223 dichloride (radium-223), an alpha emitter, selectively targets bone metastases with alpha particles. We assessed the efficacy and safety of radium-223 as compared with placebo, in addition to the best standard of care, in men with castration-resistant prostate cancer and bone metastases. METHODS: In our phase 3, randomized, double-blind, placebo-controlled study, we randomly assigned 921 patients who had received, were not eligible to receive, or declined docetaxel, in a 2:1 ratio, to receive six injections of radium-223 (at a dose of 50 kBq per kilogram of body weight intravenously) or matching placebo; one injection was administered every 4 weeks. In addition, all patients received the best standard of care. The primary end point was overall survival. The main secondary efficacy end points included time to the first symptomatic skeletal event and various biochemical end points. A prespecified interim analysis, conducted when 314 deaths had occurred, assessed the effect of radium-223 versus placebo on survival. An updated analysis, when 528 deaths had occurred, was performed before crossover from placebo to radium-223. RESULTS: At the interim analysis, which involved 809 patients, radium-223, as compared with placebo, significantly improved overall survival (median, 14.0 months vs. 11.2 months; hazard ratio, 0.70; 95% confidence interval [CI], 0.55 to 0.88; two-sided P=0.002). The updated analysis involving 921 patients confirmed the radium-223 survival benefit (median, 14.9 months vs. 11.3 months; hazard ratio, 0.70; 95% CI, 0.58 to 0.83; P<0.001). Assessments of all main secondary efficacy end points also showed a benefit of radium-233 as compared with placebo. Radium-223 was associated with low myelosuppression rates and fewer adverse events. CONCLUSIONS: In this study, which was terminated for efficacy at the prespecified interim analysis, radium-223 improved overall survival. (Funded by Algeta and Bayer HealthCare Pharmaceuticals; ALSYMPCA ClinicalTrials.gov number, NCT00699751.).

Patient-reported quality-of-life analysis of radium-223 dichloride from the phase III ALSYMPCA study.

BACKGROUND: Radium-223 dichloride (radium-223), a first-in-class α-emitting radiopharmaceutical, is recommended in both pre- and post-docetaxel settings in patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases based on overall survival benefit demonstrated in the phase III ALSYMPCA study. ALSYMPCA included prospective measurements of health-related quality of life (QOL) using two validated instruments: the general EuroQoL 5D (EQ-5D) and the disease-specific Functional Assessment of Cancer Therapy-Prostate (FACT-P). PATIENTS AND METHODS: Analyses were conducted to determine treatment effects of radium-223 plus standard of care (SOC) versus placebo plus SOC on QOL using FACT-P and EQ-5D. Outcomes assessed were percentage of patients experiencing improvement, percentage of patients experiencing worsening, and mean QOL scores during the study. RESULTS: Analyses were carried out on the intent-to-treat population of patients randomized to receive radium-223 (n = 614) or placebo (n = 307). The mean baseline EQ-5D utility and FACT-P total scores were similar between treatment groups. A significantly higher percentage of patients receiving radium-223 experienced meaningful improvement in EQ-5D utility score on treatment versus placebo {29.2% versus 18.5%, respectively; P = 0.004; odds ratio (OR) = 1.82 [95% confidence interval (CI) 1.21-2.74]}. Findings were similar for FACT-P total score [24.6% versus 16.1%, respectively; P = 0.020; OR = 1.70 (95% CI 1.08-2.65)]. A lower percentage of patients receiving radium-223 experienced meaningful worsening versus placebo measured by EQ-5D utility score and FACT-P total score. Prior docetaxel use and current bisphosphonate use did not affect these findings. Treatment was a significant predictor of EQ-5D utility score, with radium-223 associated with higher scores versus placebo (0.56 versus 0.50, respectively; P = 0.002). Findings were similar for FACT-P total score (99.08 versus 95.22, respectively; P = 0.004). CONCLUSIONS: QOL data from ALSYMPCA demonstrated that improved survival with radium-223 is accompanied by significant QOL benefits, including a higher percentage of patients with meaningful QOL improvement and a slower decline in QOL over time in patients with CRPC.

High PSA anxiety and low health literacy skills: drivers of early use of salvage ADT among men with biochemically recurrent prostate cancer after radiotherapy?

BACKGROUND: Although commonly used, early initiation of salvage androgen deprivation therapy (ADT) has not been proven to enhance survival. We evaluated whether prostate-specific antigen (PSA) anxiety or health literacy are associated with use of early salvage ADT among men with recurrent prostate cancer after radiotherapy. PATIENTS AND METHODS: The prospective Comprehensive, Observational, Multicenter, Prostate Adenocarcinoma Registry was used to study 375 men with biochemically recurrent prostate cancer after external beam radiation or brachytherapy. Multivariable logistic regression was used to determine whether PSA anxiety and health literacy are associated with salvage ADT as initial management after biochemical recurrence. RESULTS: Sixty-eight men (18.1%) received salvage ADT as initial management for PSA recurrence. Men with high PSA anxiety were twice as likely to receive salvage ADT compared with men who did not have high PSA anxiety on both univariable [28.8% versus 13.1%; odds ratio (OR) 2.15; 95% confidence interval (CI) 1.16-4.00; P = 0.015] and multivariable analysis [adjusted OR (AOR) 2.36; 95% CI 1.21-4.62; P = 0.012]. Furthermore, men who had higher levels of health literacy were nearly half as likely to undergo salvage ADT compared with men who had lower levels of health literacy on univariable analysis (15.2% versus 26.3%; OR 0.50; 95% CI 0.29-0.88; P = 0.016), with a trend toward this association on multivariable analysis (AOR 0.58; 95% CI 0.32-1.05; P = 0.07). CONCLUSIONS: Among men with PSA recurrence after radiotherapy, odds of use of salvage ADT were nearly twice as great among men with high PSA anxiety or low health literacy, suggesting that these men are receiving higher rates of unproven treatment. Given that early salvage ADT is costly, worsens quality of life, and has not been shown to improve survival, quality improvement strategies are needed for these individuals.

Baseline neutrophil-lymphocyte ratio (NLR) is associated with survival and response to treatment with second-line chemotherapy for advanced prostate cancer independent of baseline steroid use.

BACKGROUND: The neutrophil-lymphocyte ratio (NLR), proposed as an indicator of cancer-related inflammation, has known prognostic value in prostate cancer. We examine its association with survival (OS) and response in patients treated with second-line chemotherapy. METHODS: We analysed patients with metastatic castration-resistant prostate cancer (mCRPC) treated in the TROPIC trial, evaluating cabazitaxel versus mitoxantrone. Cox regression models were used to investigate the association of baseline NLR (BLNLR) with OS and the significance of a change in NLR count with treatment. Logistic regression models were used to determine the association of BLNLR counts with prostate specific antigen (PSA) and RECIST responses. The optimal NLR cut-off was established based on the concordance index of different values. RESULTS: Data from 755, 654 and 405 patients was available for OS, PSA and RECIST response analysis respectively. Median OS was 14.0 months [95% confidence interval (CI) 13.2-14.8]. Median NLR was 2.9 (IQR: 1.9-5.1). BLNLR was associated with survival (HR 1.5, 95% CI 1.1-2.1, P = 0.011) in multivariable analysis (MVA) independently of variables included in the Halabi nomogram, treatment arm and corticosteroid use. The optimal cut-off for a dichotomous NLR was selected at 3.0 based on its higher c-index related to survival. BLNLR ≥3.0 was associated with lower PSA response (40.1% versus 59.9%; P < 0.001) and RECIST response (7.7% versus 15.6%, P = 0.022) in MVA. Conversion from high (≥3) to low (<3) NLR was associated with improved survival (HR 0.66; 95% CI 0.51-0.85; P = 0.001) and higher PSA response rates (66.4% versus 33.6%; P = 0.000). Use of corticosteroids at baseline did not modify the association between NLR and survival. CONCLUSIONS: NLR is a valid prognostic biomarker in CRPC and is associated with survival, PSA and RECIST responses in patients treated with second-line chemotherapy. Changes in NLR counts with treatment may indicate benefit. NLR prognostic value is independent of prior use of corticosteroids. CLINICALTRIALSGOV: NCT00417079.

Management of patients with advanced prostate cancer: recommendations of the St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) 2015.

The first St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) Expert Panel identified and reviewed the available evidence for the ten most important areas of controversy in advanced prostate cancer (APC) management. The successful registration of several drugs for castration-resistant prostate cancer and the recent studies of chemo-hormonal therapy in men with castration-naïve prostate cancer have led to considerable uncertainty as to the best treatment choices, sequence of treatment options and appropriate patient selection. Management recommendations based on expert opinion, and not based on a critical review of the available evidence, are presented. The various recommendations carried differing degrees of support, as reflected in the wording of the article text and in the detailed voting results recorded in supplementary Material, available at Annals of Oncology online. Detailed decisions on treatment as always will involve consideration of disease extent and location, prior treatments, host factors, patient preferences as well as logistical and economic constraints. Inclusion of men with APC in clinical trials should be encouraged.

An analysis of health-related quality of life in the phase III PROSELICA and FIRSTANA studies assessing cabazitaxel in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: Men with metastatic castration-resistant prostate cancer (mCRPC) are living longer, therefore optimizing health-related quality of life (HRQL), as well as survival outcomes, is important for optimal patient care. The aim of this study was to assess the HRQL in patients with mCRPC receiving docetaxel or cabazitaxel. PATIENTS AND METHODS: PROSELICA (NCT01308580) assessed the non-inferiority of cabazitaxel 20 mg/m2 (C20) versus 25 mg/m2 (C25) in patients with mCRPC after docetaxel. FIRSTANA (NCT01308567) assessed the superiority of C25 or C20 versus docetaxel 75 mg/m2 (D75) in patients with chemotherapy-naive mCRPC. HRQL and pain were analyzed using protocol-defined, prospectively collected, Functional Assessment of Cancer Therapy-Prostate (FACT-P) and McGill-Melzack questionnaires. Analyses included definitive improvements in HRQL, maintained or improved HRQL, and HRQL over time. RESULTS: In total, 2131 patients were evaluable for HRQL across the two studies. In PROSELICA, 38.8% and 40.5% of patients receiving C20 and C25, respectively, had definitive FACT-P total score (TS) improvements. In FIRSTANA, 43.4%, 49.7%, and 44.9% of patients receiving D75, C20, and C25, respectively, had definitive FACT-P TS improvements. In both trials, definitive improvements started after cycle 1 and were maintained for the majority of subsequent treatment cycles. More than two-thirds of patients maintained or improved their FACT-P TS. CONCLUSIONS: In PROSELICA and FIRSTANA, >40% of the 2131 evaluable patients with mCRPC had definitive FACT-P TS improvements; improvements occurred early and were maintained. More than 75% of patients maintained or improved their FACT-P TS.

A randomized phase IIa study of quantified bone scan response in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with radium-223 dichloride alone or in combination with abiraterone acetate/prednisone or enzalutamide.

BACKGROUND: In metastatic castration-resistant prostate cancer (mCRPC), assessing treatment response and bone lesions with technetium-99m is limited by image resolution and subjectivity. We evaluated bone scan lesion area (BSLA), a quantitative imaging assessment of response in patients with mCRPC receiving radium-223 alone or in combination with androgen receptor pathway inhibitors (abiraterone/prednisone or enzalutamide). PATIENTS AND METHODS: This randomized, non-comparative phase IIa three-arm trial (NCT02034552) evaluated technetium-99m-based BSLA response rate (RR), safety, radiologic progression-free survival (rPFS), and time to first symptomatic skeletal event (SSE) in men with mCRPC and bone metastases receiving radium-223 with/without abiraterone/prednisone or enzalutamide. The primary endpoint was week 24 BSLA RR. RESULTS: Overall, 63 patients received treatment (abiraterone/prednisone combination, n = 22; enzalutamide combination, n = 22; radium-223 monotherapy, n = 19). Median treatment duration (first to last dose of any study treatment) was 12 months (abiraterone/prednisone combination), 10 months (enzalutamide combination), and 3 months (radium-223 monotherapy). Week 24 BSLA RR was 58% [80% confidence interval (CI) 41% to 74%; one-sided P < 0.0001; 11/19 patients] with abiraterone/prednisone combination, 50% (32% to 68%; one-sided P < 0.0001; 8/16 patients) with enzalutamide combination, and 22% (10% to 40%; one-sided P = 0.0109; 4/18 patients) with radium-223 monotherapy. Median rPFS was not evaluable for combination arms and 4 months (80% CI 4 to 12) for monotherapy. SSEs were reported in 32% of patients; median time to first SSE was not estimable. Fatigue and back pain were the most commonly reported treatment-emergent adverse events (TEAEs); more patients receiving combination therapy than monotherapy had TEAEs. Fractures were reported in 18% receiving abiraterone/prednisone, 32% receiving enzalutamide, and 11% receiving radium-223 monotherapy. Fracture rates were lower in patients taking bone health agents versus not taking bone health agents at baseline. CONCLUSIONS: Technetium-99m imaging BSLA may offer objective, quantifiable assessment of isotope uptake changes, and potentially treatment response, in patients with mCRPC and bone metastases treated with radium-223 alone or in combination with abiraterone/prednisone or enzalutamide. In this largely treatment-naive population, BSLA RR was numerically lower with radium-223 monotherapy versus combination therapy, indicating a limited role as first-line treatment. Use of radium-223 should follow evidence-based treatment guidelines and the licensed indication.

cAMP-responsive element-binding protein regulates vascular endothelial growth factor expression: implication in human prostate cancer bone metastasis.

Aberrant expression of vascular endothelial growth factor (VEGF) is associated with human prostate cancer (PCa) metastasis and poor clinical outcome. We found that both phosphorylation of cyclic AMP-responsive element-binding protein (CREB) and VEGF levels were significantly elevated in patient bone metastatic PCa specimens. A PCa ARCaP progression model demonstrating epithelial-to-mesenchymal transition exhibited increased CREB phosphorylation and VEGF expression as ARCaP cells became progressively more mesenchymal and bone-metastatic. Activation of CREB induced, whereas inhibition of CREB blocked, VEGF expression in ARCaP cells. CREB may regulate VEGF transcription via a hypoxia-inducible factor-dependent mechanism in normoxic conditions. Activation of CREB signaling is involved in the coordinated regulation of VEGF and may pre-dispose to PCa bone metastasis.

Suramin, an experimental chemotherapeutic drug, activates the receptor for epidermal growth factor and promotes growth of certain malignant cells.

Previous studies have shown that suramin is capable of disrupting autocrine growth involving coexpression of platelet-derived growth factor and its receptors in a fibroblast model for mesenchymal oncogenesis. Suramin is currently in use as an experimental drug for the treatment of patients with epithelial cell tumors. In the present study, we have investigated the efficacy of suramin in a carcinoma model system. Our findings demonstrate that suramin enhances cell surface signaling in A431 cells by activating an autocrine loop involving the receptor for epidermal growth factor (EGFR). The mechanism of suramin action was shown to be indirect, not affecting the ability of ligand to bind and activate the EGFR. Instead, suramin induced the release of membrane-bound transforming growth factor alpha, thereby increasing its potential to activate cell surface EGFRs. Since suramin potently blocks tyrosine phosphorylation induced by platelet-derived growth factor but can activate the growth pathway regulated by the EGFR, biological responses of tumor cells to suramin treatment may differ dramatically.

Suramin rapidly alters cellular tyrosine phosphorylation in prostate cancer cell lines.

Suramin, a synthetic polysulfonated anionic compound, is known to abrogate the activity of a variety of growth factors that serve as ligands for receptor-class protein-tyrosine kinases. Based on this information, we initially hypothesized that suramin treatment would be associated with decreased tyrosine phosphorylation. Upon testing this hypothesis in prostate cancer cell lines, we found that the most conspicuous effect of suramin was to increase the tyrosine phosphorylation of several distinct proteins. Further analyses indicate that suramin-induced increases in tyrosine phosphorylation represent a generalized, but not universal, phenomenon found in cell lines derived from a variety of human tissues. These rapid and specific suramin-induced alterations represent a novel finding for a non-polypeptide pharmaceutical agent and question the hypothesis that suramin exerts its antitumor action simply by abrogation of growth factor action.

Selective expression of alternative lck mRNAs in human malignant cell lines.

The lck protein tyrosine kinase is normally expressed in a cell type-specific fashion, with mRNA being confined to cells of lymphoid lineage. Despite this highly specific pattern of expression in normal tissues, lck mRNA has also been detected in selected cell lines derived from human nonlymphoid neoplasms. In this study we explored the mechanisms underlying the expression of lck mRNA within human nonlymphoid neoplastic cell lines. We determined that lck mRNA expression was correlated with transcriptional activation and that there was no evidence for genomic rearrangement or amplification within the lck coding region to account for the expression of lck mRNA in the nonlymphoid neoplastic cell lines. The lck gene has previously been shown to contain two distinct promoter elements. In this study, we demonstrated that lck-producing cell lines derived from human nonlymphoid neoplasms expressed transcripts initiated exclusively from the 3'-most promoter element (3' promoter). In contrast, lymphoid cell lines derived from nonmalignant sources expressed lck transcripts exclusively initiated from the 5'-most promoter element (5' promoter). Most cell lines derived from human lymphoid neoplasms express lck transcripts initiated from both the 5' and 3' promoters in various ratios. Thus, lck expression in a variety of malignant cell lines results from a selective induction of transcription from the 3' promoter.

Clinical characteristics and biopsy specimen features in African-American and white men without prostate cancer.

BACKGROUND: The reported incidence of prostate cancer is higher among African-American men than among white men. We conducted a study of African-American and white men without prostate cancer to determine whether clinical and histologic findings might be associated with racial differences in serum prostate-specific antigen (PSA) levels. METHODS: From January 1990 through March 1997, 493 (59.5%) of 829 African-American men and 736 (74.1%) of 993 white men who had elevated serum PSA levels (> or = 4.0 ng/mL) and/or abnormal digital rectal examinations and who underwent transrectal ultrasound-guided prostate biopsies were found to be without prostate cancer. Also reviewed were patients' age and race, indication for biopsy, histologic features of the prostate biopsy specimen, ultrasound-measured prostate volume, PSA density (i.e., the PSA level divided by the prostate volume), and (in some cases) serum testosterone levels. RESULTS: Among these men without prostate cancer, there were no statistically significant differences by race in the ages of the patients, their prostate volumes, or their serum testosterone levels; however, the mean serum PSA levels and PSA densities were significantly higher in African-American men than in white men (two-sided P values of .00003 and .000009, respectively). A higher proportion of African-American men than white men had inflammation in their prostate biopsy specimen, and men of both races with prostate inflammation had higher PSA values than those without inflammation. African-American men without inflammation had higher PSA values than white men without inflammation. CONCLUSIONS: In this study, African-American men without histologic evidence of prostate cancer had significantly higher PSA levels and PSA densities than similarly aged white men. This finding was not accounted for by racial differences in patients' age, serum testosterone level, or prostate volume.