Phase 1 and 2 studies demonstrate the safety and efficacy of intraprostatic injection of PRX302 for the targeted treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia

Background

PRX302 is a prostate specific antigen (PSA)–activated pore-forming protein toxin under development as a targeted approach for improving lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH) without affecting sexual function.

Objective

To evaluate the safety and efficacy of PRX302 in men with moderate to severe BPH.

Design, setting, and participants

Eligible subjects were refractory, intolerant, or unwilling to undergo medical therapies for BPH and had International Prostate Symptom Score (IPSS) ≥12, a quality of life (QoL) score ≥3, and prostate volumes between 30 and 80 g. Fifteen patients were enrolled in phase 1 studies, and 18 patients entered phase 2 studies.

Interventions

Subjects received intraprostatic injection of PRX302 into the right and left transition zone via a transperineal approach in an office-based setting. Phase 1 subjects received increasing concentrations of PRX302 at a fixed volume; phase 2 subjects received increasing volumes per deposit at a fixed concentration.

Measurements

IPSS, QoL, prostate volume, maximum flow rate (Q_max), International Index of Erectile Function, serum PSA levels, pharmacokinetics, and adverse events were recorded at 30, 60, 90, 180, 270, and 360 d after treatment with PRX302.

Results and limitations

Sixty percent of men in the phase 1 study and 64% of men in the phase 2 study treated with PRX302 had ≥30% improvement compared to baseline in IPSS out to day 360. Patients also experienced improvement in QoL and reduction in prostate volume out to day 360. Patients receiving ≥1 ml of PRX302 per deposit had the best response overall. PRX302 had no deleterious effect on erectile function. Adverse events were mild to moderate and transient in nature. The major study limitation was the small sample size.

Conclusions

The promising safety profile and evidence of efficacy in the majority of treated subjects in these phase 1 and 2 studies supports further development of PRX302 as a minimally invasive, targeted treatment for BPH.     

Minimally invasive esophagectomy: the evolution and technique of minimally invasive surgery for esophageal cancer

Beginning with the widespread introduction of laparoscopic cholecystectomy in late 1989, minimally invasive surgical technique has been refined in conjunction with the development of advanced instrumentation and have subsequently been applied to increasingly complicated disease processes. Esophageal surgeons have increasingly incorporated minimally invasive surgery into their practice since the first laparoscopic fundoplication was described by Dallemagne et al. in 1991. Esophagectomy is associated with significant morbidity and mortality even in highly experienced centers. Many esophageal surgeons have had a great deal of interest in minimally invasive esophagectomy (MIE), which has the potential advantages of being a less traumatic procedure with a resultant improvement in postoperative convalescence and fewer wound and cardiopulmonary complications compared to the open approaches. Throughout the 1990s, as confidence with laparoscopic surgery of the esophagogastric junction grew, MIE was initially attempted with hybrid operations combining traditional open surgery with minimally invasive approaches. Subsequently, a totally laparoscopic transhiatal approach was described; however, this approach was perceived to be very challenging and has not gained widespread acceptance. Approaches used at present depend on cancer stage, cancer location, body habitus, and pulmonary function. For localized cancer (T1N0) or HGD, we prefer laparoscopic inversion esophagectomy (retrograde or antigrade). This approach may also be used for patients at high risk for thoracotomy. For locally advanced cancer in the middle third of the esophagus or for proximal third esophageal cancer, we prefer 3-field MIE (abdomen, and chest with neck anastomosis). For locally advanced cancer in the distal esophagus, especially in patients with a short thick neck, we prefer thoracoscopic-laparoscopic (2-field) esophagectomy (TLE).     

Denosumab and changes in bone turnover markers during androgen deprivation therapy for prostate cancer

Androgen deprivation therapy (ADT) for prostate cancer increases fracture risk, decreases bone mineral density, and increases bone turnover markers (BTMs) including serum type 1 C‐telopeptide (sCTX), tartrate‐resistant alkaline phosphatase 5b (TRAP‐5b), and procollagen‐1 N‐terminal telopeptide (P1NP). In a prespecified exploratory analysis of a phase 3, multicenter, double‐blind study, we evaluated the effects of denosumab (60 mg subcutaneously every 6 months for 3 years) versus placebo (1468 patients, 734 in each group) on BTM values. BTMs were measured at baseline, month 1, and predose at months 6, 12, 24, and 36 in the overall population. BTMs at month 1 are also reported for subgroups based on age (< 70 years versus ≥ 70 years), prior duration of ADT (≤ 6 months versus >6 months), and baseline BTM (≤ median versus > median BTM values). Treatment with denosumab provided a rapid and sustained decrease of BTM values compared with placebo. The median change in sCTX levels at month 1 was ?90% in the denosumab group and ?3% in the placebo group (p < 0.0001). The median change in TRAP‐5b levels at month 1 was ?55% in the denosumab group and ?3% in the placebo group (p < 0.0001). The maximal median change in P1NP was ?64% in the denosumab group and ?11% in the placebo group, (p < 0.0001). Significantly greater decreases in BTM for denosumab were also seen in subgroup analyses based on age, prior ADT treatment, and baseline BTM values. Suppression of bone turnover markers was consistent with marked increases in bone mineral density reported previously. © 2011 American Society for Bone and Mineral Research     

Diagnosis and management of GERD before and after lung transplantation

The strong association between gastroesophageal reflux disease (GERD) and the development and progression of pulmonary diseases has been suggested, and GERD has been focused on as a potential cause and thus a target for prevention and/or therapy. Because GERD is curable, the proper diagnosis and management of underlying GERD would theoretically improve the outcomes. This article reviews the existing literature and discusses the strategy to manage GERD in patients with end-stage pulmonary diseases before and after lung transplantation.     

Universal access – but when? Treating the right patient at the right time: Access to electrophysiology services in Canada

The Canadian Cardiovascular Society Access to Care Working Group has published a series of commentaries on access to cardiovascular care in Canada. The present article reviews the evidence for timely access to electrophysiology services. Using the best available evidence along with expert consensus by the Canadian Heart Rhythm Society, the panel proposed a series of benchmarks for access to the full scope of electrophysiology services, from initial consultation through to operative procedures. The proposed benchmarks are presented herein.     

Treating the right patient at the right time: Access to cardiac catheterization, percutaneous coronary intervention and cardiac surgery

The Canadian Cardiovascular Society Access to Care Working Group was formed with a mandate to use the best science and information available to establish reasonable triage categories and safe wait times for common cardiovascular services and procedures through a series of commentaries. The present commentary discusses the rationale for access benchmarks for cardiac catheterization and revascularization procedures for patients with stable angina, and access benchmarks for cardiac catheterization and surgery for patients with valvular heart disease. Literature on standards of care, wait times and wait list management was reviewed. A survey of cardiac centres in Canada was performed to develop an inventory of current practices in identifying and triaging patients. The Working Group recommends the following medically acceptable wait times for access to cardiac catheterization: 14 days for symptomatic aortic stenosis and six weeks for patients with stable angina and other valvular disease. For percutaneous coronary intervention in stable patients with high-risk anatomy, immediate revascularization or a wait time of 14 days is recommended; six weeks is recommended for all other patients. The target for bypass surgery in those with high-risk anatomy or valve surgery in patients with symptomatic aortic stenosis is 14 days; for all others, the target is six weeks. All stakeholders must affirm the appropriateness of these standards and work continuously to achieve them. There is an ongoing need to continually reassess current risk stratification methods to limit adverse events in patients on waiting lists and assist clinicians in triaging patients for invasive therapies.     

The cephalosporins

The cephalosporins are a large group of related beta-lactam antimicrobial agents. Favorable attributes of the cephalosporins include low rates of toxicity, relatively broad spectrum of activity, and ease of administration. Various cephalosporins are effective for treatment of many conditions, including pneumonia, skin and soft tissue infections, bacteremia, and meningitis. Differences among the numerous cephalosporin antimicrobial agents are sometimes subtle; however, an understanding of these differences is essential for optimal use of these agents. As a result of widespread use of cephalosporins, bacterial resistance to these drugs is increasingly common. New, fourth-generation agents (such as cefepime) offer an alternative for the treatment of infections caused by some drug-resistant microorganisms.