Citations

Background and Purpose— Mortality after cerebral infarction (CI) has remained unchanged during the past 20 years, despite advances in neurologic care. Key factors affecting survival may be underrecognized. The purpose of this study was to determine the rate and cause of mortality after first CI. Methods— In this case-control, population-based study, all available medical records were reviewed for Rochester (Minnesota) residents with a first CI between 1985 and 1989 to identify morbidities and cause of death. Predictors for mortality were analyzed. Results— First CI was recorded for 444 patients. Survival was 83% at 1 month, 71% at 1 year, and 46% at 5 years. The most frequent causes of death were cardiovascular events (22%), respiratory infection (21%), and initial stroke complications (14%). Recurrent stroke and cancer accounted for 9% and 7.5% of deaths, respectively. In the first month after CI, 51% of deaths were attributed to the initial CI, 22% to respiratory infections, and 12% to cardiovascular events. During the first year, 26% of deaths resulted from respiratory infections and 28% from cardiovascular disease. Mortality was higher among patients than controls for at least 2 years after CI. Age, cardiac comorbid conditions, CI severity, stroke recurrence, seizures, and respiratory and cardiovascular morbidities were independent predictors of death. Conclusions— In the first month after CI, mortality resulted predominantly from neurologic complications. Later mortality remained high because of respiratory and cardiovascular causes. To improve long-term survival after CI, aggressive management of pulmonary and cardiac disease is as important as secondary stroke prevention.

Purpose: To determine if increasing the dose of paclitaxel increases the probability of clinical response, progression-free survival, or overall survival in women who have persistent or recurrent ovarian cancer, and whether doubling the dose of prophylactic filgrastim accompanying the higher paclitaxel dose decreases the frequency of neutropenic fever. Patients and Methods: Consenting patients with persistent, recurrent, or progressing ovarian cancer, despite first-line platinum therapy (but no prior taxane), were randomly assigned to paclitaxel 135 mg/m2, 175 mg/m2, or 250 mg/m2 over 24 hours every 3 weeks. Patients receiving paclitaxel 250 mg/m2 were also randomly assigned to 5 or 10 μg/kg of filgrastim per day subcutaneously. Results: Accession to the paclitaxel 135-mg/m2 arm was closed early. Among the 271 patients on the other regimens with measurable disease, partial and complete response on paclitaxel 250 mg/m2 (36%) was significantly higher than on 175 mg/m2 (27%, P = .027). This difference was more evident among patients who never responded to prior platinum. However, progression-free and overall survival results were similar. The median durations of overall survival were 13.1 and 12.3 months for paclitaxel 175 mg/m2 and 250 mg/m2, respectively. Thrombocytopenia, neuropathy, and myalgia were greater with paclitaxel 250 mg/m2 (P < .05). The incidence of neutropenic fever after the first cycle of paclitaxel 250 mg/m2 was 19% and 18% on the 5-μg/kg and 10-μg/kg filgrastim dose, respectively (22% for paclitaxel 175 mg/m2 without filgrastim). Conclusion: Paclitaxel exhibits a dose effect with regard to response rate, but there is more toxicity and no survival benefit to justify paclitaxel 250 mg/m2 plus filgrastim. Doubling the filgrastim dose from 5 to 10 μg/kg did not reduce the probability of neutropenic fever after high-dose paclitaxel.

Background and Purpose— Association of mitral valve prolapse (MVP) with ischemic neurological events (INEs) is uncertain. Methods— In the community of Olmsted County (Minn), we identified all MVP diagnosed (1989 to 1998) in patients in sinus rhythm with no prior history of INE. We measured INE rates and compared them with expected rates in our community to define the excess risk of INE. Results— Among 777 eligible subjects (age, 49±20 years; 66% female; follow-up, 5.5±3.0 years), 30 patients had at least 1 INE during follow-up (at 10 years, 7±1%). Compared with expected INEs in the same community, subjects with MVP showed excess risk of lifetime INE (relative risk [RR], 2.2; 95% CI, 1.5 to 3.2; P <0.001) and during follow-up under purely medical management (RR, 1.8; 95% CI, 1.1 to 2.8; P =0.009). Independent determinants of INE were older age (RR, 1.08 per year; 95% CI, 1.04 to 1.11; P <0.001), mitral thickening (RR, 3.2; 95% CI, 1.4 to 7.4; P =0.008), atrial fibrillation (AFib) during follow-up (RR, 4.3; 95% CI, 1.9 to 10.0; P <0.001), and need for cardiac surgery (RR, 2.5; 95% CI, 1.1 to 5.8; P =0.03). INE 10-year rates were low in patients <50 years of age (0.4±0.4%, P =0.60 versus expected) but were excessive in patients >50 years of age (16±3%, P <0.001 versus expected) or with thickened leaflets (7±2%, P <0.001 versus expected). Predictors of follow-up AFib were age, mitral regurgitation, and left atrium diameter (all P <0.01). Conclusions— In the community, subjects with MVP display a lifetime excess rate of INE compared with expected. Clinical (older age) and echocardiographic (leaflets thickening) characteristics define patients with MVP at high risk for INE, and subsequent AFib or need for cardiac surgery, both related to the degree of mitral regurgitation, increase the risk of INE.

Purpose: A phase III, randomized, double-blind study was conducted by the North Central Cancer Treatment Group to determine the efficacy and toxicity of oral glutamine for the prevention of acute diarrhea in patients receiving pelvic radiation therapy (RT). Patients and Methods: All 129 patients enrolled from 14 institutions between February 1998 and October 1999 were eligible. Patients received 4 g of glutamine or placebo orally, twice a day, beginning with the first or second day of RT and continuing for 2 weeks after RT. During treatment, patients were assessed weekly for toxicity, and a bowel function questionnaire was administered. The primary measures of treatment efficacy were diarrhea levels measured by maximum grade of diarrhea, incidence of diarrhea, and average diarrhea score. After completion of RT, the bowel function questionnaire was administered weekly for 4 weeks and at 12 and 24 months. Toxicity was measured by National Cancer Institute common toxicity criteria. Results: The median age of patients was 69 years (range, 34 to 86 years). The two treatment arms were balanced with respect to all baseline factors. There were no significant differences in toxicity by treatment. Quality-of-life scores and the mean number of problems reported on the bowel function questionnaire were virtually identical for both treatment groups. The incidence of grade 3 or higher diarrhea was 20% for the glutamine arm and 19% for the placebo arm (P = .99). The maximum number of stools per day was 5.1 for the glutamine arm and 5.2 for the placebo arm (P = .99). Conclusion: There is no evidence of a beneficial effect of glutamine during pelvic RT.

Abstract Glucocorticoids (GCs) are commonly used to treat inflammatory disease; unfortunately, the long-term use of these steroids leads to a large number of debilitating side effects. The antiinflammatory effects of GCs are a result of GC receptor (GR)-mediated inhibition of expression of proinflammatory genes as well as GR-mediated activation of antiinflammatory genes. Similarly, side effects are most likely due to both activated and repressed GR target genes in affected tissues. An as yet unachieved pharmaceutical goal is the development of a compound capable of separating detrimental side effects from antiinflammatory activity. We describe the discovery and characterization of AL-438, a GR ligand that exhibits an altered gene regulation profile, able to repress and activate only a subset of the genes normally regulated by GCs. When tested in vivo, AL-438 retains full antiinflammatory efficacy and potency comparable to steroids but its negative effects on bone metabolism and glucose control are reduced at equivalently antiinflammatory doses. The mechanism underlying this selective in vitro and in vivo activity may be the result of differential cofactor recruitment in response to ligand. AL-438 reduces the interaction between GR and peroxisomal proliferator-activated receptor γ coactivator-1, a cofactor critical for steroid-mediated glucose up-regulation, while maintaining normal interactions with GR-interacting protein 1. This compound serves as a prototype for a unique, nonsteroidal alternative to conventional GCs in treating inflammatory disease.

Purpose: To evaluate the role of adjuvant interferon alfa after complete resection of locally extensive renal cell carcinoma. Patients and Methods: A total of 283 eligible patients with pT3–4a and/or node-positive disease were randomly assigned after radical nephrectomy and lymphadenectomy to observation or to interferon alfa-NL (Wellferon, Burroughs-Wellcome, Research Park, NC) given daily for 5 days every 3 weeks for up to 12 cycles. Patients were stratified on the basis of pathologic stage. Patients remained on treatment until documented recurrence, excessive toxicity, or patient/physician preference deemed removal appropriate. Results: At median follow-up of 10.4 years, median survival was 7.4 years in the observation arm and 5.1 year in the treatment arm (log-rank P = .09). Median recurrence-free survival was 3.0 years in the observation arm and 2.2 years in the interferon arm (P = .33). Performance status (P = .003), nodal status (N2 v N0, P < .0001), and tumor stage (P = .0002) were significant prognostic factors in multivariate analysis. A proportional hazards model examining the effects of treatment arm and time to recurrence on survival after recurrence among patients who recurred found that random assignment to interferon treatment (P = .009) and shorter time to recurrence (P < .0001) were independent predictors of shorter survival after recurrence. Although no lethal toxicities were observed, severe (grade 4) toxicities including neutropenia, myalgia, fatigue, depression, and other neurologic toxicities occurred in 11.4% of those randomly assigned to interferon treatment. Conclusion: Adjuvant treatment with interferon did not contribute to survival or relapse-free survival in this group of patients.

Abstract We examined the accuracy of preoperative assessment in predicting postoperative pulmonary risk in a prospective cohort of 272 consecutive patients referred for evaluation before nonthoracic surgery. Outcomes were assessed by an independent investigator who was blinded to the preoperative data. There were 22 (8%) postoperative pulmonary complications. Statistically significant predictors of pulmonary complications (all p ≤ 0.005) were as follows: hypercapnea of 45 mm Hg or more (odds ratio, 61.0), a FVC of less than 1.5 L/minute (odds ratio, 11.1), a maximal laryngeal height of 4 cm or less (odds ratio, 6.9), a forced expiratory time of 9 seconds or more (odds ratio, 5.7), smoking of 40 pack-years or more (odds ratio, 5.7), and a body mass index of 30 or more (odds ratio, 4.1). Multiple regression analyses revealed three preoperative clinical factors that are independently associated with pulmonary complications: an age of 65 years or more (odds ratio, 1.8; p = 0.02), smoking of 40 pack-years or more (odds ratio, 1.9; p = 0.02), and maximum laryngeal height of 4 cm or less (odds ratio, 2.0; p = 0.007). Thus, preoperative factors can identify those patients referred to pulmonologists or internists who are at increased risk for pulmonary complications after nonthoracic surgery.