PURPOSE Prostate needle biopsy (PNB) is the definitive method for the diagnosis of prostate cancer. Our objective was to evaluate prebiopsy parameters, including lower urinary tract symptoms, that may be predictive of positive biopsy. PATIENTS AND METHODS We performed a prospective review of 569 consecutive men who underwent transrectal ultrasound (TRUS)-guided PNB. The prebiopsy variables recorded included age, prostate-specific antigen (PSA) levels, prostate volume (PV), percent free PSA levels, suspicious digital rectal examination (DRE) findings, TRUS-detected lesions, race, and American Urologic Association Symptom Score (AUASS). RESULTS Low AUASS, PV, patient age, and abnormal TRUS findings were independent predictors of positive PNB results (P < 0.05). In patients with PSA levels between 4 and 10 ng/mL, the positive predictive value of a low AUASS (< 8) in predicting a positive PNB result is 68.7%. When race was considered (black vs. white), univariate analysis (UVA) indicated that race was a significant predictor (P = 0.034) of positive PNB. A subgroup analysis was performed for black men undergoing PNB (n = 256). Multivariate analysis (MVA) indicates that abnormal TRUS findings; low AUASS, PV, and PSA levels; and absence of prior biopsy are all independent predictors of PNB in the black patient group. A final subgroup analysis (UVA and MVA) was performed for white men (n = 310). Only patient age and PV demonstrated significance as independent predictors of PNBs in this group. CONCLUSION This prospective analysis of 569 men demonstrates that traditional indicators for PNB (abnormal DRE findings and PSA levels) are not significant predictors of prostate cancer. Independent predictors for prostate included age, low AUASS, low PV, and abnormal TRUS findings. A low AUASS (indicative of the absence of benign disease) is an important predictor of prostate cancer.
BACKGROUNDAntigen-presenting cells 8015 (APC8015; Provenge) is an immunotherapeutic product designed to initiate a T-cell-mediated immune response against prostatic acid phosphatase, an antigen overexpressed in 95% of prostate cancer cells. In phase I/II trials, APC8015 has shown immunologic and clinical responses in patients with androgen-independent prostate cancer. This phase II trial was conducted to assess the prostate-specific antigen (PSA)-modulating effects of APC8015 in patients with androgen-dependent prostate cancer (ADPC) with biochemical progression.PATIENTS AND METHODSPatients with nonmetastatic recurrent disease as manifested by increasing PSA levels (0.4-6.0 ng/mL) and who had undergone previous definitive surgical or radiation therapy were enrolled. Therapy consisted of APC8015 infusion on weeks 0, 2, and 4 (ie, 3 infusions). Prostate-specific antigen was measured at baseline and monthly until disease progression, defined as a doubling of the baseline or nadir PSA value (whichever was lower) to > or = 4 ng/mL or development of distant metastases.RESULTSThirteen of 18 patients demonstrated an increase in PSA doubling time (PSADT), with a median increase of 62% (4.9 months before treatment vs. 7.9 months after treatment; P = 0.09; signed-rank test).CONCLUSIONTherapy was well tolerated. APC8015 as single-agent immunotherapy for patients with ADPC and biochemical progression did not result in > or = 50% decrease in PSA from baseline levels but did appear to modulate PSADT in some patients. Further manipulations of host immunity may be required to achieve a significant antitumor effect.
Men with prostate cancer are at high risk of developing bone metastases that can lead to clinically significant skeletal morbidity. Recently, a randomized, placebo-controlled, phase III trial in 422 men with hormone-refractory prostate cancer and bone metastases demonstrated that zoledronic acid (4 mg every 3 weeks) significantly reduced the incidence and onset of skeletal complications and provided significant long-term reductions in bone pain compared with placebo. Patients received zoledronic acid for a 15-month core phase, with the option to continue therapy for 9 more months on the extension phase. To evaluate the continuing benefit of long-term zoledronic acid therapy, retrospective exploratory analyses were conducted based on the incidence of skeletal-related events (SREs; defined as pathologic bone fracture, spinal cord compression, surgery or radiation therapy to bone, or change in antineoplastic therapy for bone pain) occurring only during the extension phase of this trial. Quality of life parameters included assessment with the Brief Pain Inventory. Similar to results reported for the 15-month core phase and the entire 24-month study, the 9-month extension phase demonstrated that zoledronic acid significantly reduced the percentage of patients with an SRE (P = 0.017), prolonged the median time to first SRE (P = 0.036), reduced the annual incidence of SREs by 52% (P = 0.016), and reduced the risk of SREs by 53% (P = 0.022) compared with placebo. Furthermore, zoledronic acid was safe and well tolerated. Therefore, zoledronic acid provides long-term continuing clinical benefit for men with prostate cancer and bone metastases and represents a new therapeutic option for this population.
Patients diagnosed with clinically localized prostate cancer face a daunting variety of management choices, including conservative management, brachytherapy, external-beam irradiation therapy with or without neoadjuvant hormonal therapy, as well as surgery. As we have learned to characterize the nature of each cancer, we can now "risk-adjust" treatment decisions. Physicians have long sought to guide patients through these choices based on their best judgment about the threat posed by the cancer, the effectiveness of treatment, the side effects of therapy, and the life expectancy of the patient. Today, many patients wish to participate more actively in decisions about their care, weighing the risks of treatment-related complications and the anxiety of living with an untreated or uncontrolled cancer. Patient utilities measure the value patients place on a health state, such as living with cancer or becoming incontinent, allowing quantitative assessments of risks and benefits of different therapeutic options specific for each patient's own preferences and the nature of his cancer and life expectancy. As early detection programs for prostate cancer expand, men are being diagnosed with prostate cancer earlier in its natural history. Some of these cancers may not require immediate treatment but rather a period of active surveillance with definitive curative therapy being administered only if there are signs of cancer progression. This review summarizes our current understanding of active surveillance with selective delayed definitive therapy.
We report a case of orbital metastasis from a neuroendocrine dedifferentiated prostate cancer during progression from hormone-sensitive to hormone refractory stage. A patient receiving androgen deprivation for hormone-sensitive prostate cancer presented with sudden-onset rightsided ptosis and an increasing serum prostate-specific antigen level. Imaging studies revealed a mixed blastic and lytic lesion involving the right orbital wall and the right cavernous sinus. Comparison of the metastatic histology with the original pathology confirmed a histologic change to poorly differentiated prostate adenocarcinoma with neuroendocrine features. Local radiation of the lesion and palliative systemic chemotherapy resulted in marked short-term improvement of all presenting symptoms. Because prostate cancer metastasis involves hematogenous and lymphatic routes, we also evaluated expression of the vascular endothelial growth factor (VEGF) and receptors (VEGFR-1, VEGFR-2, and VEGFR-3) in the metastatic deposit by immunohistochemistry. Strong expression of VEGFR-2 and VEGFR-3 restricted to the malignant epithelium was noted. We recommend a second biopsy of atypical prostate metastasis associated with sudden change to aggressive clinical behavior in order to evaluate for dedifferentiation features before planning appropriate treatment interventions especially in patients who are candidates for systemic chemotherapy.
There is a growing need to understand how nutritional and lifestyle practices may optimize quality of life (QOL) and health after diagnosis for the 1.5 million men living with prostate cancer in the United States. We are establishing a clinical cohort of men with prostate cancer at the University of California San Francisco. Men completed detailed dietary and lifestyle questionnaires annually and provided consent for blood and tissue specimens to be stored for research if they underwent radical prostatectomy. We examined the feasibility of establishing this cohort and analyzed preliminary baseline data on participant demographics, lifestyle habits, and QOL using χ2 and t-tests and logistic regression models. Between February 2002 and July 2004, we enrolled 343 men with prostate cancer into the survey portion of this cohort. The response rate was approximately 85% via in-clinic enrollment and 30% via mail enrollment. Based on analysis of the first 193 men enrolled, there was a high level of treatment satisfaction in this population (88% of men were satisfied or extremely satisfied with treatment) and positive reports of general health perception (73% of men perceived themselves to be in excellent [34%] or very good [39%] health). Whether treatment interfered with diet was an independent predictor of health perception and treatment satisfaction. Use of dietary supplements was high (90%) in this well-educated population. In conclusion, we demonstrated good feasibility for conducting this longitudinal study and observed initial indications that diet and other lifestyle practices were important predictors of patient QOL.
PURPOSE:17-Allylamino-17-demethoxygeldanamycin (17-AAG) is a benzoquinone ansamycin antibiotic with antiproliferative activity in several mouse xenograft models, including prostate cancer models. A two-stage phase II study was conducted to assess the activity and toxicity profile of 17-AAG administered to patients with metastatic, hormone-refractory prostate cancer.EXPERIMENTAL DESIGN:Patients with at least one prior systemic therapy and a rising prostate-specific antigen (PSA) were eligible. Patients received 17-AAG at a dose of 300 mg/m2 i.v. weekly for 3 of 4 weeks. The primary objective was to assess the PSA response. Secondary objectives were to determine overall survival, to assess toxicity, and to measure interleukin-6, interleukin-8, and maspin levels and quality of life.RESULTS:Fifteen eligible patients were enrolled. The median age was 68 years and the median PSA was 261 ng/mL. Patients received 17-AAG for a median number of two cycles. Severe adverse events included grade 3 fatigue (four patients), grade 3 lymphopenia (two patients), and grade 3 back pain (two patients). The median PSA progression-free survival was 1.8 months (95% confidence interval, 1.3-3.4 months). The 6-month overall survival was 71% (95% confidence interval, 52-100%).CONCLUSIONS:17-AAG did not show any activity with regard to PSA response. Due to insufficient PSA response, enrollment was stopped at the end of first stage per study design. The most significant severe toxicity was grade 3 fatigue. Further evaluation of 17-AAG at a dose of 300 mg/m2 i.v. weekly as a single agent in patients with metastatic, hormone-refractory prostate cancer who received at least one prior systemic therapy is not warranted.
BACKGROUND:We revised our prostate cancer-specific measure to better address the physiologic complications of the 3 major therapies for clinically localized prostate cancer and to assess the impact of symptoms on broader aspects of patient functioning. The study used a cross-sectional design, and participants completed the measure in a clinical setting.PATIENTS AND METHODS:Participants underwent radical prostatectomy (n = 130), external beam radiation therapy (n = 120), or brachytherapy (n = 129). Their mean age was 66 years (standard deviation [SD], 8.2 years), and the median time since treatment was 12.36 months (mean, 21.7; SD, 25.4). Items were derived from previously validated instruments or developed based on the clinical experience of a multidisciplinary group of health professionals.RESULTS:The revised instrument included 46 items that formed 8 physiologic scales (2 urinary, 3 sexual, and 3 bowel function); 3 associated bother scales; and cancer worry, treatment regret, and treatment satisfaction scales. Correlations among scales provided evidence of convergent/divergent validity. Significant group differences were found using analysis of covariance (with time since treatment and age as covariates) on 6 of the 8 physiologic scales and on bowel bother and treatment satisfaction.CONCLUSION:The instrument provides a sensitive measure of physiologic differences across the 3 primary treatment groups and indicates that there are few differences across treatment groups on broader aspects of health-related quality of life. Further development of the measure is recommended.
Combination therapy consists of castration plus an antiandrogen. Following medical or surgical castration, the androgen receptor can be activated by adrenal androgens, low levels of residual testosterone, and ligand-independent activators. The survival benefit of combination therapy compared with castration alone is one of the most studied questions in urology. Results from trials comparing combination therapy to castration alone are variable. A metaanalysis of 26 randomized trials indicated that the type of antiandrogen used is relevant. Combination therapy using nonsteroidal antiandrogens was associated with a statistically significant overall survival benefit. In contrast, combination therapy using steroidal antiandrogens was associated with reduced survival compared with castration alone. Bicalutamide 50 mg has a number of advantages compared with nilutamide and flutamide when used in combination with castration. These include an improved side-effect profile, once-daily dosing, more potent inhibition of androgen-independent activation of the androgen receptor through favorable interactions with nuclear coactivators and corepressors, and evidence for improved survival in one randomized trial. An analysis combining historic trial data suggests that bicalutamide 50 mg in addition to androgen deprivation may reduce the hazard ratio (HR) for prostate cancer mortality by 20% (HR, 0.80; 95% CI, 0.66-0.98).
The mountain building processes in Taiwan are currently among the most rapid in the world. However, the spatial and temporal dynamics of this orogen are still poorly resolved within the <0.5 Ma timescale, reflecting methodological gaps in addressing young and rapid bedrock cooling by erosion. Optically Stimulated Luminescence (OSL) from quartz is an emerging thermochronometer that could potentially provide valuable low-temperature markers on a ∼0.1 Ma timescale. Here we study four meta-sandstone samples from the Hsuehshan Range in central Taiwan. We characterize the OSL from these samples in terms of feldspar contamination, saturation dose, signal components, and thermal stability. We conclude that the OSL is dominated by the fast component, and is therefore amenable to dose measurement using the SAR protocol. Based on the luminescence characteristics and ambient dose rate, we suggest that these samples may be valuable for evaluating recent cooling rates exceeding 360 ± 100 °C/Ma, in places where the alternative thermal scenarios (instantaneous cooling or prolonged isothermal storage) may be ruled out by external geological constraints.
The molecular profile of radiation-induced cancers remains poorly understood. This case report describes a 59-year-old male never smoker with a distant history of Hodgkin's lymphoma treated with mantle radiation who decades later develops primary lung adenocarcinoma within the prior radiation portal. Genomic profiling of the cancer demonstrated a KRAS G12V mutation. We briefly review the clinical entity of radiation-induced second malignancies and KRAS mutant lung adenocarcinoma. Although to date there is no standard molecularly targeted therapy available for KRAS mutant lung cancer, prior reports of activating EGFR mutations in a proportion of radiation-induced lung cancers suggest that a variety of genomic alterations may occur in these secondary malignancies. Given the potential to identify other molecularly defined subsets of lung cancer for which specific therapies exist, routine molecular profiling of these cases seems reasonable.
Prostate cancer and its various forms of treatment remain a source of significant controversy and morbidity despite recent advances. In response, there is an increasing trend toward the development of treatments aimed at cancer prevention and at maximizing the preservation of function without sacrificing cancer control. This article reviews the current prostate cancer literature and reports on improvements in existing surgical treatments and developing technologies aimed toward achieving these goals. Specific therapies addressed include improvements in surgical techniques, laparoscopy, robotics, cryosurgical and thermal ablation, and high-intensity focused ultrasound.
BACKGROUNDHormone-refractory prostate cancer (HRPC) has modest response rates to second-line estrogenic agents such as diethylstilbestrol and the herbal product PC SPES. Estramustine phosphate (EMP) is a microtubule inhibitory agent with estrogenic properties commonly used in patients with metastatic HRPC. To determine whether previous response to second-line estrogen therapy would predict subsequent response to EMP-based chemotherapy, a retrospective study was conducted.PATIENTS AND METHODSPatients with HRPC previously treated with second-line estrogenic therapy who subsequently received EMP-based chemotherapy were enrolled in a retrospective analysis. The progression of disease or response to treatment was determined with use of standard prostate-specific antigen (PSA) criteria and Response Evaluation Criteria in Solid Tumors.RESULTSSeventy-eight patients were included in the analysis. Twenty-five patients with disease progression after receiving estrogen therapy received subsequent EMP-based chemotherapy. Overall, initial PSA response to any estrogen therapy was 54%. The overall PSA response to EMP-based chemotherapy was 60%, and the objective response was 36%. The PSA response to subsequent EMP-based chemotherapy was independent of patients having a previous response to estrogen therapy (70% vs. 53%; P = 0.68). The median overall survival for patients receiving estrogenic therapy and subsequent EMP-based chemotherapy was 12.7 months.CONCLUSIONPrevious response to second-line hormonal maneuvers with estrogen therapy does not predict subsequent response to EMP-based chemotherapy.
PURPOSE First-line chemotherapy with docetaxel in patients with progressive castrate metastatic prostate cancer has been shown to improve overall survival compared with mitoxantrone-based therapies. The use and outcomes of chemotherapy after first-line antimicrotubule-based therapy have not been well described. PATIENTS AND METHODS Patients with progressive castrate metastatic prostate cancer enrolled on an antimicrotubule-based protocol for treatment were followed to determine their baseline characteristics and outcomes with second- or third-line systemic therapy. RESULTS Of 108 patients treated with antimicrotubule-based therapy, 81% received second-line therapy, and 40% received third-line therapies. Corresponding prostate-specific antigen (PSA) decreases > or = 50% were observed in 72%, 15%, and 22% of patients. Median survival times from the start of first-, second-, and third-line therapy were 21 months (95% confidence interval [CI], 18-25 months), 13 months (95% CI, 10-15 months) and 12 months (95% CI, 9-19 months). Significant prognostic indicators for survival in the second-line setting include pretreatment PSA level, alkaline phosphatase level, and performance status. Patients not fit to receive second-line therapy were more symptomatic with first-line therapy, as illustrated by a greater need for narcotic therapy (67% vs. 15%) and palliative radiation therapy after first-line therapy (57% vs. 10%) in lieu of second-line systemic therapy. CONCLUSION Eighty percent of patients received second-line chemotherapy, with a median survival of 12 months from the start of second-line treatment. Although only 40% received third-line chemotherapy, median survival was similar to that of patients in the second-line setting. Our data show that patients who initiate chemotherapy with symptoms are more likely to require palliative radiation therapy rather than chemotherapy as second-line therapy. A sequential or continuous administration of therapy may optimize the care of this subset of symptomatic patients.
Structural studies of topoisomerase-fluoroquinolone-DNA ternary complexes revealed a cavity between the quinolone N-1 position and the active site tyrosine. Fluoroquinolone derivatives having positively charged or aromatic moieties extended from the N-1 position were designed to probe for binding contacts with the phosphotyrosine residue in ternary complex. While alkylamine, alkylphthalimide, and alkylphenyl groups introduced at the N-1 position afforded derivatives that maintained modest inhibition of the supercoiling activity of DNA gyrase, none retained ability to poison DNA gyrase. Thus, the addition of a large and/or long moiety at the N-1 position disrupts ternary complex formation, and retained ability to inhibit supercoiling is likely through interference with the strand breakage reaction. Two derivatives were found to possess inhibitory effects on the decatenation activity of human topoisomerase II.
BACKGROUND:The safety, tolerability, and pharmacokinetic and preliminary efficacy of PCK3145 were determined in patients with metastatic hormone-refractory prostate cancer.PATIENTS AND METHODS:PCK3145 was administered in ascending doses of 5, 20, 40, and 80 mg/m2 3 times per week for 4 weeks to cohorts of 4 patients. Dose escalation was based on dose-limiting toxicity (DLT). Pharmacokinetic profiles, tumor burden, and tumor markers (including prostate-specific antigen [PSA] and matrix metalloproteinase-9 [MMP-9] levels) were assessed. Sixteen patients received PCK3145. The median age was 66 years, and the median PSA level was 232.5 microg/L. A total of 32 cycles of therapy were administered.RESULTS:The most common adverse events reported were pain and nausea. The only DLT was a grade 4 cardiac arrhythmia in a patient treated at the 80-mg/m2 dose level. Pharmacokinetic analysis using a 2-compartment model indicated that the mean area under the curve values increased as the dose range increased, and the mean elimination half-life ranged from 0.35 hours to 1.45 hours. The best tumor response was stable disease in 10 patients and progressive disease in 5 patients. No PSA responses were observed, but 1 patient showed a marked reduction in PSA of 41% at cycle 2. A substantial reduction in MMP-9 levels was observed in patients with baseline levels of MMP-9 > 100 microg/L.CONCLUSION:PCK3145 was safe and well tolerated at all doses. Efficacy observations were encouraging, and the biologic activity of PCK3145 in reducing MMP-9 level may suggest a potential role of this peptide in the regulation of metastatic tumor growth.
Prostate-specific membrane antigen (PSMA) is a relatively omnipresent molecule with a multiplicity of functions and has been shown to be a reasonable target for immunologic approaches such as vaccines or more directed therapy with radioactively labeled monoclonal antibodies against PSMA. Given the abundance of various glycoprotein and carbohydrate antigens expressed on the surface of prostate cancer cells and cell lines, PSMA stands out as another self-antigen that is not only expressed on cancer cells but also on neovasculature. Although vaccines are varied in their design and target goal, recent technology has afforded researchers the opportunity to induce recruitment of multiple effector cell populations, cytokines, and factors that can elicit cellular and humoral responses. This review serves to present unique approaches in vaccine development that can induce immunologic responsiveness to PSMA with potential impact on disease progression.
Hearing impairment is common at an older age and has considerable social, health and economic implications. With an increase in the ageing population, there is a need to identify modifiable risk factors for hearing impairment. A shared aetiology with cardiovascular disease (CVD) has been advanced as CVD risk factors (e.g. obesity, type 2 diabetes) are associated with a greater risk of hearing impairment. Moreover, low-grade inflammation is implicated in the aetiology of CVD. Accordingly, our aim was to investigate the association between several markers of inflammation – C-reactive protein, fibrinogen and white blood cell count – and hearing impairment.Participants of the English Longitudinal Study of Ageing aged 50–93 were included. Inflammatory marker data from both wave 4 (baseline, 2008/09) and wave 6 (2012/13) were averaged to measure systemic inflammation. Hearing acuity was measured with a simple handheld tone-producing device at follow-up (2014/15).Among 4879 participants with a median age of 63 years at baseline, 1878 (38.4%) people presented hearing impairment at follow-up. All three biomarkers were positively and linearly associated with hearing impairment independent of age and sex. After further adjustment for covariates, including cardiovascular risk factors (smoking, physical activity, obesity, diabetes, hypertension, cholesterol), memory and depression, only the association with white blood cell count remained significant: odds ratio per log-unit increase; 95% confidence interval = 1.46; 1.11, 1.93.While white blood cell count was positively associated with hearing impairment in older adults, no relationships were found for two other markers of low-grade inflammation.
PURPOSE Microvessel density within the prostate is associated with presence of cancer, disease stage, and disease-specific survival. We evaluated multidetector computed tomography (CT) to estimate prostate perfusion and localize prostate cancer. PATIENTS AND METHODS Ten subjects were evaluated with contrast enhanced CT before radical prostatectomy with the Mx8000IDT 16-slice scanner. Following baseline pelvic scan, 100 cc of Optiray 300 was administered intravenously (4 cc per second). Repeated dynamic scans through the prostate were obtained at 20, 30, 40, 50, and 60 seconds following initiation of contrast injection. Computed tomography perfusion was compared with pathologic findings of Gleason score and tumor volume on whole-mount prostatectomy specimens. RESULTS Conventional adenocarcinoma (Gleason score, 6-10) was present in all subjects, including one who also demonstrated a mucinous variant of prostate cancer. Visible focal CT enhancement was noted in 1 patient with a high-volume tumor and a Gleason score of 10. A positive correlation between local estimates of CT perfusion and percent of prostate volume occupied by tumor in each sextant was found for half of the subjects (Pearson correlation coefficient, 0.3-0.95; mean, 0.48) but statistically significant correlation (P < 0.05; Pearson coefficient, 0.9-0.95) was present in only the 2 subjects with the highest Gleason scores (8 and 10) and the highest tumor volume (> or = 50% in > or = 1 sextant region). CONCLUSION Visible enhancement of prostate cancer during dynamic CT is present in a minority of subjects. Correlation between quantitative CT perfusion and tumor location is statistically significant only in subjects with localized high-volume, poorly differentiated prostate cancer.
