An approach to the validation of biomarkers of harm for use in a tobacco context.

There is both a call and a need for biomarkers of harm that are validated for use in a tobacco context. Currently, there are no validated biomarkers and there is no consensus about which ones may be suitable for this purpose. To advance the science in this area a working definition of biomarkers of harm and a shortlist of candidate biomarkers are proposed. A framework for the validation of biomarkers of harm using of a series of epidemiological studies culminating in a targeted prospective study is outlined. The candidate biomarkers have advanced to preliminary testing although this does not imply that any on the shortlist will become validated. This framework could also be used for the evaluation of proteomic, genomic, transcriptosomic or metabonomic profiles, which may turn out to be the preferred biomarkers for use in harm prediction. Biomarker studies would complement data that are generated from specific in vitro tests and from animal studies to evaluate tobacco products.

Integrating risk profiles for disease progression in the treatment choice for patients with lower urinary tract symptoms/benign prostatic hyperplasia: a combined analysis of external evidence and clinical expertise.

The RAND appropriateness method was used to explore the relevance of risk factors for disease progression in the treatment choice for patients with lower urinary tract symptoms/benign prostatic hyperplasia (LUTS/BPH). A total of, 12 international experts assessed the appropriateness of various treatments for 243 risk profiles. Highest appropriateness rates were found for alpha1-adrenoceptor antagonists (68% of profiles) and combination therapy (46%). A large prostate volume was the dominant argument in favour of 5alpha-reductase inhibitors and combination therapy, but was irrelevant for the choice of surgery. Considerable postvoid residual, severe symptoms and poor maximum flow rate were the most important factors in favour of surgery.

Risk factors for disease progression in patients with lower urinary tract symptoms/benign prostatic hyperplasia (LUTS/BPH): a systematic analysis of expert opinion.

Disease progression has become an important issue for the management of lower urinary tract symptoms/benign prostatic hyperplasia (LUTS/BPH). Although several risk factors have been identified, no specific patient risk profiles have been established that can be useful in the day-to-day management of LUTS/BPH. In this study, an international panel of urologists developed a risk classification based on the attribution of a risk score to 243 unique patient profiles. From the perspective of clinical decision making, it was concluded that postvoid residual, symptom severity and maximum flow rate are the most relevant determinants of the risk of disease progression.

High incidence of HER-2 positivity in inflammatory breast cancer.

HER-2 is over-expressed in around 25% of human breast cancers, and is associated with poor outcome. We examined the incidence of HER-2 status in inflammatory breast cancer (IBC). Forty-nine newly diagnosed IBCs were studied. Formalin-fixed paraffin-embedded pre-treatment tissue biopsies were examined immunohistochemically for the over-expression of the HER-2 protein and gene using the HercepTest and FISH assay. Clinical outcome was compared between the HER-2 positive (HercepTest score 3 + and FISH positive) and negative groups. Fifty-two per cent of the IBCs examined were HER-2 positive. The HER-2 positive group were demographically comparable to the HER-2 negative group. Ninety-six per cent of the HER-2 positive patients responded to primary chemotherapy compared to 76% of the HER-2 negative (P = 0.09). No significant differences in outcome emerged between the two groups. In conclusion, this study found the incidence of HER-2 protein over-expression in IBC is higher than previously reported in non-IBC. Early HER-2 directed therapy (such as the monoclonal antibody trastuzumab) as a part of multimodal treatment may improve outcome in this poor prognosis cancer.

Updated meta-analysis of clinical trials of Serenoa repens extract in the treatment of symptomatic benign prostatic hyperplasia.

OBJECTIVES: To determine, by analysing all available clinical trial data, the clinical efficacy against placebo of an extract from the fruit of the American dwarf palm tree, Serenoa repens (Permixon, Pierre Fabre Médicament, Castres, France), as there is controversy about the use of phytotherapeutic agents in men with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH). METHODS: All clinical trial data published on Permixon, comprising 14 randomized clinical trials and three open-label trials, involving 4280 patients, were analysed. These trials were of different size (22-1100 patients) and duration (21-720 days). The peak urinary flow rate and nocturia were the two common endpoints. The statistical analysis was based on a random-effects meta-analysis. RESULTS: Permixon was associated with a mean (sem) reduction in the International Prostate Symptom Score (IPSS) of 4.78 (0.41). The mean placebo effect on peak urinary flow rate was an increase of 1.20 (0.49) mL/s. The estimated effect of Permixon was a further increase of 1.02 (0.50) mL/s (P = 0.042). Placebo was associated with a reduction in the mean number of nocturnal voids of 0.63 (0.14); there was a further reduction attributable to Permixon of 0.38 (0.07) (P < 0.001). There was some heterogeneity among the studies for nocturia; one over 2 years involving 396 patients and showing no difference between placebo and Permixon had a large effect on the results. CONCLUSIONS: This meta-analysis of all available published trials of Permixon for treating men with BPH showed a significant improvement in peak flow rate and reduction in nocturia above placebo, and a 5-point reduction in the IPSS.

Phytotherapy in the management of benign prostatic hyperplasia.

Phytotherapeutic agents have gained widespread usage in the treatment of benign prostatic hyperplasia/lower urinary tract symptoms. They are marketed as over-the-counter medications in the United States and by prescription in many European countries. Although numerous mechanisms of action have been postulated, it is uncertain which of these are responsible for their clinical response. The efficacy of these agents has not been conclusively proven. Almost all the studies with these products have not been placebo-controlled, double-blind trials of at least 6 months' duration. Thus, the magnitude of the clinical effect is uncertain. It is impossible to compare the phytotherapeutic agents-either the single or multiple extract products-because manufacturers use different extraction processes. So each agent/product must be studied individually. Until more appropriately conducted trials are undertaken, the efficacy of phytotherapeutic agents will remain unproven.

Saw Palmetto Berry as a Treatment for BPH.

Phytotherapeutic agents are often prescribed in Europe for the treatment of benign prostatic hyperplasia with lower urinary tract symptoms and are commonly used in the United States in over-the-counter preparations. Saw palmetto berry is the most popular of these agents, and in vitro some studies suggest that liposterolic extract of the plant has antiandrogenic effects that inhibit the type 1 and type 2 isoenzymes of 5alpha-reductase; however there are no clinical studies that show any decrease in serum dihydrotestosterone or prostate-specific antigen. Its efficacy in the treatment of lower urinary tract symptoms has not been conclusively proven. Clinical efficacy was suggested by a meta-analysis of Permixon, a formulation of saw palmetto, but the meta-analysis was done on suboptimal studies. One trial supports the equivalency of Permixon to finasteride in treating moderate to severe symptoms of benign prostatic hyperplasia, with less decrease in sexual function. However, without a control/placebo arm, the actual efficacy of the agents cannot be determined. Other than occasional gastrointestinal upset, no other side effects have been reported.

Meta-analysis of clinical trials of permixon in the treatment of symptomatic benign prostatic hyperplasia.

OBJECTIVES: Permixon is a compound extracted from the fruit of the American dwarf palm tree, Serenoa repens. Controversy regarding the use of phytotherapeutic agents in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia is significant. We analyzed all available clinical trial data of the Permixon preparation to determine its clinical efficacy compared with placebo. METHODS: All published clinical trial data on Permixon (11 randomized clinical trials and 2 open label trials), involving 2859 patients, were used. These trials were disparate in size (from 22 to 592 patients) and duration (from 21 to 180 days). Peak urinary flow rate and nocturia were the two common end points. The statistical analysis was based on a random effects meta-analysis. RESULTS: The average +/- SE placebo effect on the peak urinary flow rate was an increase of 0.51 +/- 0.51 mL/s. The estimated effect of Permixon was a further increase of 2.20 +/- 0.51 mL/s (P <0.001). Placebo was associated with a reduction in the mean number +/- SE of nocturnal urinations of 0.69 +/- 0.15. A further reduction of 0.50 +/- 0.01 episodes of urination (P <0.001) occurred that was attributable to Permixon. Some heterogeneity was found among the studies. Treatment duration did not appear to impact either of these effects. CONCLUSIONS: This meta-analysis of all available published trials of Permixon in the treatment of men with benign prostatic hyperplasia revealed a significant improvement in peak flow rate and reduction in nocturia greater than with placebo.

Phytotherapy for chronic prostatitis.

Chronic prostatitis is a poorly defined condition that is difficult to treat; there are therefore multiple therapies. Although there is a paucity of trials using phytotherapeutic agents, plant extracts have been postulated to have anti-inflammatory effects that might be useful in the treatment of chronic prostatitis. More placebo-controlled trials of longer duration in this condition are needed to ascertain whether there is a significant benefit to the use of phytotherapeutic agents for chronic prostatitis.

Economic analysis of finasteride: a model-based approach using data from the Proscar Long-Term Efficacy and Safety Study.

Benign prostatic hyperplasia (BPH) is one of the most common medical conditions in older men in the United States. BPH is often associated with a reduction in quality of life and may progress to acute urinary retention (AUR), the inability to pass any urine. Recently, a 4-year placebo-controlled clinical trial known as the Proscar Long-Term Efficacy and Safety Study (PLESS) demonstrated that finasteride use reduces the risk of developing AUR by 57% and the need for BPH-related surgery by 55%. The economic implications of these findings were investigated using a model-based decision-analytic approach to compare finasteride with both watchful waiting and alpha-blocker therapy. The modeling used the longest-term published controlled data concerning alpha-blockers, which were for the alpha-blocker terazosin. The base case considered a 64-year-old man (the mean age of a PLESS patient) with prostatic enlargement on digital rectal examination and moderate-to-severe symptoms of BPH. The model suggested savings in surgical and AUR costs with finasteride versus watchful waiting, with an estimated 25% of total finasteride costs recouped in savings on surgical events avoided in the first year. Over 2 years, the expected cost per patient starting finasteride therapy was $2304, whereas the expected cost per patient starting terazosin was $2334. Analyses also explored the variation in economic results by baseline levels of prostate-specific antigen (PSA), a proxy for prostate volume. For patients with PSA levels > or =1.4 ng/mL, expected 2-year costs with finasteride and terazosin were $2342 and $2479, respectively. For patients with PSA levels > or =3.3 ng/mL, expected 2-year costs with finasteride were $373 less than with terazosin ($2347 vs $2720). Results were robust over a range of model assumptions and cost estimates. The analyses illustrate that all medical interventions, including watchful waiting, have associated costs. Finasteride shows cost offsets compared with watchful waiting and cost savings compared with terazosin over 2 years. Finasteride appears to be more economical in men with higher PSA levels.

Effects of terazosin therapy on blood pressure in men with benign prostatic hyperplasia concurrently treated with other antihypertensive medications.

OBJECTIVES: To review and assess the cardiovascular safety of the alpha1-blocker terazosin when used to treat symptomatic benign prostatic hyperplasia (BPH) in patients taking concurrent antihypertensive medications. METHODS: This retrospective analysis focused on blood pressure changes and blood pressure-related side effects in 555 of 2084 patients randomized to either terazosin or placebo in the Hytrin Community Assessment Trial (HYCAT) study who were following either single or combination antihypertensive regimens (treated patients). We also compared results in normotensive and hypertensive patients, whether treated or not. RESULTS: The addition of terazosin lowered mean systolic blood pressure by 5.3 mm Hg for untreated patients and 6.7 mm Hg for treated patients. For patients hypertensive on entry, mean reductions in systolic blood pressure in those untreated and treated were 12.1 and 11.1 mm Hg, respectively. The addition of terazosin to an existing antihypertensive regimen had its greatest impact (a mean reduction of 12.3 mm Hg) in those receiving diuretic therapy alone. Diastolic pressure changes followed a similar pattern. The incidences of blood pressure-related side effects in patients on terazosin were comparable between untreated (13.5%) and treated patients (14.3%), as were premature withdrawal rates, with 4.2% of untreated patients and 4.5% of treated patients withdrawing due to blood pressure-related side effects. CONCLUSIONS: Terazosin can be safely used to treat patients with symptomatic BPH regardless of their blood pressure status and antihypertensive regimen. Terazosin may be safely added to ongoing antihypertensive therapy.

Alpha-1-adrenoceptor blockade in the treatment of benign prostatic hyperplasia.

In light of the growing interest in the concept of 'uroselectivity' and in the increased worldwide use of alpha-blockers for benign prostatic hyperplasia (BPH), this review evaluates the relative benefits of various alpha-blocking agents in the treatment of BPH. The pharmacological and physiological selectivity as well as the clinical efficacy and safety of alfuzosin, doxazosin (Cardura(R)), tamsulosin (Flomax(R)), and terazosin (Hytrin(R)) are compared. In reviewing efficacy and safety, emphasis is given to 17 placebo-controlled, double-blind trials of these alpha-blockers published in peer-reviewed journals. This review also considers long-term data, effects on blood pressure, costs, and dose ranges.

Use of magnetic resonance urography.

OBJECTIVES: Magnetic resonance urography (MRU) is a new technique that uses heavily weighted T2 coronal images with fat suppression pulse. Urine appears white on MRU, resembling an intravenous urogram (IVU). Contrast agents are not necessary. This study describes the use of MRU in the diagnosis and treatment of patients with hematuria. METHODS: One hundred six patients with microscopic or gross hematuria and 6 normal volunteers underwent MRU between 1992 and 1995. A modified, heavily weighted T2 technique with intravenous administration of furosemide and ureteral compression was used. Thirty-two patients had other imaging techniques as well for comparison. RESULTS: MRU provided high-resolution images in almost all cases; 73 (69%) had a normal MRU. Significant findings in the 33 patients with abnormalities included renal cysts in 17 (51%), renal cell carcinoma in 6 (18%), transitional cell carcinoma in 5 (15%), ureteropelvic junction obstruction in 3 (9%), and stones causing obstruction in 6 (18%). Five patients with renal failure also had good visualization of the entire urinary tract. MRU was comparable to other imaging modalities except in identifying nonobstructing calculi. CONCLUSIONS: MRU provides an alternative to conventional imaging of the urinary tract, especially in those patients who have contraindications to ionizing radiation and contrast agents. Improvements in resolution, technique, and cost have to be addressed before it can be used regularly in urologic practice.

Review of recent placebo-controlled trials utilizing phytotherapeutic agents for treatment of BPH.

BACKGROUND: In order to assess the efficacy of phytotherapeutic agents for the treatment of benign prostatic hyperplasia (BPH), a review of recently published double-blind placebo-controlled trials was undertaken. METHODS: Only those studies reviewed by the Other Medical Therapies Committee of the Fourth International Consultation on BPH were included. RESULTS: These studies suggest a possible benefit for the use of phytotherapeutic preparations in the treatment of BPH. CONCLUSIONS: These studies need to be confirmed in larger long-term placebo-controlled studies in order to ascertain the true efficacy of these agents.

Referral criteria for speech and language therapy assessment of dysphagia caused by idiopathic Parkinson's disease.

OBJECTIVE: To examine the prevalence of dysphagia in idiopathic Parkinson's disease (IPD) in the outpatient setting and to determine what assessment criteria to use to select patients with dysphagia for referral to speech and language therapists. MATERIAL AND METHODS: Sixty-four patients with IPD and 80 age-matched controls were interviewed in clinic about their swallowing history and an objective swallowing test administered. All patients were assessed over the next few weeks by an experienced speech and language therapist and dysphagia rated according to a modified Rehabilitation Institute of Chicago Dysphagia Rating Scale and a novel global rating scale. The ability of various clinic criteria to predict patients with severe dysphagia were examined. RESULTS: Dysphagia for food was found in 30% of patients, significantly more than in controls. Swallowing speed and bolus volume were significantly lower in patients compared with controls and were correlated with declining Hoehn and Yahr score. Swallowing speed fell significantly on withdrawal of medication. The therapist's global rating score and Chicago score declined with Hoehn and Yahr score and duration of disease. However, only 10% of patients required dietary advice and none needed gastrostomy or tracheostomy. Discriminant analysis showed that various combinations of clinic selection criteria were no better than the presence of dysphagia for food at predicting which patients had significant dysphagia requiring advice from a therapist. CONCLUSIONS: Patients with idiopathic Parkinson's disease should be questioned about dysphagia for food on a regular basis and, if present, should be referred to a speech and language therapist for further assessment and treatment. The outcome of this protocol should be tested prospectively.

Phytotherapy in the treatment of benign prostatic hyperplasia.

There are numerous plant extracts that have been used for the treatment of benign prostatic hyperplasia and voiding dysfunction. While some extracts show promise, their efficacy has not been adequately proven in long-term, double-blind, placebo-controlled trials. In addition, the mechanism of action remains poorly defined.

Penile trauma: an etiologic factor in Peyronie's disease and erectile dysfunction.

PURPOSE: It has been postulated that trauma to either the partially or fully erect penis is a potential cause of Peyronie's disease. In addition, it has been proposed that engaging in sexual relations with a partial erection due to mild impotence is a risk factor for the development of Peyronie's disease. This study was performed to determine whether patients with either Peyronie's disease or non-Peyronie's disease impotence had an increased rate of penile trauma compared with potent controls. MATERIALS AND METHODS: We mailed surveys to 207 men who had been seen for management of Peyronie's disease, 250 impotent men without Peyronie's disease, and 275 age-matched urologic patients without a history of either impotence or Peyronie's disease. The survey inquired whether the individual had a history of penile trauma to the flaccid or erect phallus or injury during sexual intercourse. In addition, patients were questioned whether they had been engaging in sexual relations with a partial erection. RESULTS: The mean age of the impotent patients was slightly less than both the Peyronie's disease patients and controls. A similar response rate to the survey was found among the 3 groups. The mean duration of illness was 6 years for Peyronie's disease and 10 years for impotence. The frequency of penile trauma of any kind was significantly greater in both the Peyronie's disease (40%) and impotence (37%) patients than in the controls (11%). There was no significant difference between the Peyronie's disease and impotence groups. However, the Peyronie's disease patients had a lower frequency of attempting sexual relations with a partial erection than the 2 other groups. CONCLUSIONS: The results of this survey demonstrate a significantly higher incidence of penile trauma in both impotent patients and patients with Peyronie's disease compared with controls. This study demonstrates an association between penile trauma and both Peyronie's disease and impotence. The reduced incidence of engaging in sexual relations with a partial erection among the Peyronie's disease patients implies that partial impotence is not a predisposing factor for Peyronie's disease.