Marizomib, a proteasome inhibitor for all seasons: preclinical profile and a framework for clinical trials.

The proteasome has emerged as an important clinically relevant target for the treatment of hematologic malignancies. Since the Food and Drug Administration approved the first-in-class proteasome inhibitor bortezomib (Velcade) for the treatment of relapsed/refractory multiple myeloma (MM) and mantle cell lymphoma, it has become clear that new inhibitors are needed that have a better therapeutic ratio, can overcome inherent and acquired bortezomib resistance and exhibit broader anti-cancer activities. Marizomib (NPI-0052; salinosporamide A) is a structurally and pharmacologically unique ß-lactone-γ-lactam proteasome inhibitor that may fulfill these unmet needs. The potent and sustained inhibition of all three proteolytic activities of the proteasome by marizomib has inspired extensive preclinical evaluation in a variety of hematologic and solid tumor models, where it is efficacious as a single agent and in combination with biologics, chemotherapeutics and targeted therapeutic agents. Specifically, marizomib has been evaluated in models for multiple myeloma, mantle cell lymphoma, Waldenstrom's macroglobulinemia, chronic and acute lymphocytic leukemia, as well as glioma, colorectal and pancreatic cancer models, and has exhibited synergistic activities in tumor models in combination with bortezomib, the immunomodulatory agent lenalidomide (Revlimid), and various histone deacetylase inhibitors. These and other studies provided the framework for ongoing clinical trials in patients with MM, lymphomas, leukemias and solid tumors, including those who have failed bortezomib treatment, as well as in patients with diagnoses where other proteasome inhibitors have not demonstrated significant efficacy. This review captures the remarkable translational studies and contributions from many collaborators that have advanced marizomib from seabed to bench to bedside.

Combination of ballistic lithotripsy and transurethral prostatectomy in bladder stones with benign prostatic hyperplasia: report of 120 cases.

PURPOSE: We report our experience with the combination of ballistic lithotripsy (BL) and transurethral resection of the prostate (TURP) in 120 patients with benign prostatic hyperplasia (BPH) and bladder stone(s). PATIENTS AND METHODS: The mean stone size, appreciated by measuring the greatest diameter, was 18.5 mm (range 10-80 mm). The mean prostate volume was 35.4 cc (26-62 cc). All procedures were monitored under direct endoscopic control with a videocamera. RESULTS: Lithotripsy and evacuation of fragments was performed in an average time of 27.5 minutes (10-80 minutes). The only intraoperative complication was mild hematuria in 38 patients (32%), which did not affect vision for TURP. The mean resection time was 42 minutes (range 15-65 minutes). Four patients experienced mild postoperative bleeding, and one patient had clot retention. The mean hospital stay was 1.2 days (range 1-4 days). CONCLUSIONS: Combined BL and TURP is effective, safe, and economical.

Effect of aggressive therapy on laryngeal symptoms and voice characteristics in patients with gastroesophageal reflux.

Gastroesophageal reflux (GER) is associated with a variety of laryngopharyngeal signs and symptoms. Injury of the laryngopharynx as a result of GER can be refractory to conventional antireflux therapy. This prospective study was undertaken to evaluate the prevalence of laryngopharyngeal signs and symptoms in patients with documented GER and to assess the response to a high-dose combination antireflux therapy consisting of cisapride and pantoprazole. Twenty-two patients with symptoms of GER were enrolled. After baseline evaluation using a history questionnaire for symptoms, laryngeal endoscopy and vocal acoustic analysis, patients were started on treatment consisting of pantoprazole 40 mg b.d. and cisapride 20 mg twice daily. Repeat history and otolaryngologic evaluation was performed at 4 weeks. Laryngopharyngeal symptoms were frequent in most patients, with throat clearing and globus being the most prevalent symptoms followed by vocal fatigue and excess mucus production. Almost 90% of the patients had abnormal endoscopic laryngeal findings but the acoustic parameters did not show any abnormal results except for mild elevation in the shimmer. After treatment, all symptoms and endoscopic abnormalities improved significantly except for intermittent dysphonia and laryngeal mucosal redness. Acoustic abnormalities did not change significantly following therapy. Laryngeal symptoms and voice abnormalities are highly prevalent in patients with GER. Combination antireflux therapy with a proton pump inhibitor and a prokinetic agent results in rapid symptomatic and endoscopic response in the majority of patients.