Phase II study of bortezomib in patients with previously treated advanced urothelial tract transitional cell carcinoma: CALGB 90207

Background: There is no standard second-line treatment for advancedurothelial carcinoma (UC). Response rates to second-line chemotherapyfor advanced UC are low and response duration is short. Bortezomibis a proteasome inhibitor with preclinical activity againstUC. Patients and methods: Treatment consisted of bortezomib 1.3mg/m² i.v. twice weekly for two consecutive weeks, followedby a 1-week break. The primary end point was objective responserate (complete response + partial response) by Reponse EvaluationCriteria in Solid Tumors criteria. Secondary end points includedsafety, toxicity, and progression-free and overall survival. Results: In all, 25 patients with advanced UC previously treatedwith combination chemotherapy were enrolled in a multi-institutionalsingle-arm trial from December 2003 through April 2005. Only29% of patients had node-only metastases. Grade 3/4 drug-relatedtoxic effects included thrombocytopenia (4%), anemia (8%), lymphopenia(8%), sensory neuropathy (6%), hyperglycemia (4%), hypernatremia(4%), fatigue (4%), neuropathic pain (6%), dehydration (4%),and vomiting (4%). No objective responses were observed [95%confidence interval (CI) = 0–12]. The median time to progressionwas 1.4 months (95% CI = 1.1–2.0 months), and the mediansurvival time was 5.7 months (95% CI = 3.6–8.4 months).There were no treatment-related deaths. Conclusion: Although bortezomib is well tolerated, it does nothave antitumor activity as second-line therapy in UC. Key words: bladder cancer, bortezomib, proteasome, PS-341, salvage therapy, urothelial carcinoma Received for publication September 27, 2007. Revision received December 4, 2007. Accepted for publication December 17, 2007.     

Septic plasma suppresses superoxide anion synthesis by normal homologous polymorphonuclear leukocytes

In vitro exposure of normal O,Rh- PMN to plasma obtained from patients with septic shock results in inhibition of formyl-methionyl-leucyl-phenylalanine stimulated superoxide anion (O2.-) production by 40%. Although all reaction velocities and extent of reaction at 5 min were suppressed, neither lag time preceding O2.- production nor duration of initial velocity linearity was affected. No such inhibition was noted when plasma from healthy controls or nonseptic critically ill patients was utilized in the reaction. These results demonstrate that neutrophils are not only a cause, but also a target of the septic shock host inflammatory response.     

Laparoscopy in a small community free-standing surgicenter

Two thousand nine hundred twenty-four laparoscopies for both sterilization and diagnosis were performed between 1972 and 1984 in a free-standing surgicenter in a community of 40,000 people. All procedures were performed by seven board-certified obstetrician-gynecologists, and all anesthesia was administered by a partnership of board-certified anesthesiologists. The gynecologic and anesthesia techniques used in these procedures are reviewed, as well as the results and complications that resulted. The excellent outcome and low complication rate suggest that in many small communities gynecologic laparoscopy can be safe and efficient when performed in a free-standing, ambulatory, surgical facility.     

Direct and reflex effects of nitroglycerin on coronary and left ventricular dynamics in conscious dogs

The effects of intravenous and sublingual glyceryl trinitrate (nitroglycerin), 40 mug/kg, were studied on coronary blood flow and resistance, left ventricular (LV) pressures (P) and diameters (D), rate of change of pressure (dP/dt), (dP/dt)/P, and on the velocity (V) of myocardial fiber shortening in conscious dogs. Nitroglycerin i.v. caused substantial coronary vasodilatation prior to any changes in systemic hemodynamics. Mean coronary flow increased by a maximum of 47 ml/min and coronary sinus P(o2) rose from 16 to 26 mm Hg while pressure and diameter began to fall, and heart rate began to rise. After the maximal fall in mean arterial pressure (-26 mm Hg), a secondary peak in coronary flow occurred which was associated with increases in heart rate (100 beats/min), (dP/dt)/P (22%), and isolength V (12%). Beta blockade prevented the reflex increases in contractility but only a part of the reflex tachycardia; the remainder was prevented by cholinergic blockade. Maintaining heart rate constant minimized the decreases in LV D and increases in contractility. When the reflex inotropic and chronotropic effects were prevented by a combination of atrial pacing and beta blockade the early coronary vasodilatation was unaltered, but the later coronary vasodilatation was minimized.Thus i.v. nitroglycerin in the conscious dog exerts a potent direct coronary vasodilating action and also a secondary coronary vasodilation caused by reflex increases in contractility and heart rate. The decreases in diameter are largely the result of tachycardia. Sublingual nitroglycerin produced directionally similar, but quantitatively lesser effects on coronary flow and resistance, LV D, LV P, and contractility.     

Glomerular selective permeability to macromolecular neutral dextrans in experimental diabetes

Summary Rats with streptozotocin-induced chronic diabetes mellitus develop a glomerulopathy functionally manifested by proteinuria. The ability of the glomerular capillary wall to retard filtration of macromolecules was examined in 5 chronically diabetic Munich-Wistar rats exhibiting excessive proteinuria (39±7mg/24h, mean±SEM) and 5 age-matched normal Munich-Wistar rats without increased proteinuria (4.7±0.2 mg/24 h). Urinary albumin excretion was not increased in the diabetic rats (2.0±0.6 mg/24h vs 1.6±0.3 mg/24h) suggesting that the normal net electronegative charge of the glomerular capillary wall was not altered. Fractional clearances of macromolecular neutral dextrans were similar in diabetic and normal rats throughout a wide range of molecular size (18–42 Å). Glomerular filtration rate was the same in the two groups of rats (2.77±0.16ml/min in diabetics and 2.72±0.11ml/ min in normals) suggesting that renal haemodynamic factors did not influence fractional clearances of neutral dextrans in diabetic rats. We conclude that the proteinuria exhibited by these chronically diabetic rats is not attributable to alterations of size-selective properties of the glomerular capillary wall, such as increases in the size or the number of pores.