Citations

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.

There is a current need for a small diameter vascular graft due to the limited supply of autogenous grafts and the failure of synthetic grafts due to thrombosis and/or intimal hyperplasia. The use of living cells and tissues to fabricate a small diameter graft (i.e., tissue engineered blood vessel, TEBV) could be useful given the endothelialization potential and biocompatibility benefits of such a graft. However, while sufficient strength has been attained in a TEBV, coordinate compliance has yet to be fine-tuned. In this study we investigate the effects of biological response modifiers, retinoic acid (RA) and ascorbic acid (AA) on TEBV biomechanics as a function of time and subsequently correlate observed RA/AA induced changes in TEBV mechanics with alterations in smooth muscle cell (SMC) biochemistry. TEBVs were constructed using a fibrillar type I collagen network populated by human aortic smooth muscle cells (AoSMC). Following construction this TEBV was treated with 0.3 mM AA and 0.1 mM RA (concentrations found to induce changes in VSMC phenotype). Ultimate tensile stress (UTS), rate of relaxation (RR) and elastic efficiency (EE) of RA/AA treated and untreated TEBVs were measured following 1, 7, 15, 30, 45, and 60 days of treatment. At corresponding time points, the effect of these treatments on collagen and elastin protein synthesis and mRNA expression was examined. RA/AA treated TEBV strength increased and stiffness decreased compared to controls as a function of time. Relative collagen synthesis in treated TEBVs exceeded control levels by nearly two-fold at 15 and 30 days of incubation. RA/AA treated collagen gene expression followed a similar trend. Relative elastin synthesis was also greater in treated TEBVs as compared to untreated TEBVs at 15 and 30 days of incubation and correspondingly elastin mRNA expression was significantly elevated at 15 days of incubation. These data provide evidence that RA/AA treated TEBVs exhibit mechanical properties which more closely mimic those of a native vessel than their untreated counterparts and that changes in extracellular matrix composition and matrix gene expression in the presence of RA/AA treatment may play an important role in the development of said mechanical properties.

PURPOSE: To evaluate quality of life (QOL) and tumor response after administration of an oral chemotherapy regimen in patients with previously untreated metastatic colorectal cancer. PATIENTS AND METHODS: Seventy-eight patients received a mean number of 5.8 cycles of therapy. QOL data were analyzed at baseline, after every two cycles of therapy, and at the time of treatment discontinuation. The Uniscale and the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire C30 were both utilized. RESULTS: The confirmed response rate was 26% (95% confidence interval [CI], 17% to 37%). Median survival was 11.3 months (95% CI, 9.6 to 15.1 months). Global QOL scores were unchanged over the course of therapy by either tool. Only the physical function subscale score had worsened at the end of therapy. In an analysis of responding patients, significant and durable improvements in both global QOL measures as well as select subscale scores were observed. Diarrhea and physical function QOL scores had declined at the time of treatment discontinuation. Patients who did not respond to therapy had preserved QOL scores when they were evaluated after two cycles of therapy. CONCLUSION: This oral treatment strategy preserved QOL in treated patients. Global QOL measures as well as several QOL subscale scores significantly improved in patients with a documented response to therapy. The profile of improved QOL components indicated that patient well-being was related to tumor response in specific and perceivable ways. Nonresponding patients reported preserved QOL during the first two cycles of therapy. QOL analysis was feasible and informative in this moderately sized multicenter phase II trial.

ABSTRACT: Prospective clinical trials are the gold standard for evidence-based methodology used to support changes in the practice of medicine. Clinical researchers, regulatory agencies, payers, and the public embrace the conduct of phase I, II, and III clinical trials as integral to improving patient care. The National Cancer Institute (NCI) funds a number of cooperative oncology groups to conduct such clinical trials in the United States. In order to protect enrolling patients, the NCI requires expedited reporting to allow rapid identification of severe side effects on NCI-sponsored clinical trials. However, chemotherapy drugs frequently cause predictable side effects, the rapid reporting of which would potentially overwhelm the system. This article describes the development and documents the performance of a real-time toxicity reporting system implemented by the North Central Cancer Treatment Group. The goal of this system is to supplement the currently required NCI adverse event monitoring procedures and to permit study teams to identify the need to modify ongoing clinical trials. The system has proven its value in the monitoring of phase II and III trials, including trial N9741, a three-arm, phase III, advanced colorectal cancer chemotherapy study exploring combinations of irinotecan, oxaliplatin, and fluorouracil. We believe the methods described present opportunities for improving patient safety in clinical research.

PURPOSE: To evaluate the value of thymidylate synthase (TS), Ki-67, and p53 as prognostic markers in patients with Dukes’ B2 and C colon carcinoma. METHODS: We conducted a retrospective analysis to evaluate the prognostic value of TS, Ki-67, and p53 in 465 patients with Dukes’ B2 (220 patients) or Dukes’ C (245 patients) colon carcinoma. Patients represent a nonrandom subset obtained from five randomized phase III trials and were treated with either surgery alone (151 patients) or surgery plus fluorouracil-based chemotherapy (314 patients). All three markers were assayed using immunohistochemical techniques. RESULTS: With a minimum follow-up of 5 years, our retrospective analysis failed to demonstrate a consistent and significant association between TS, Ki-67, or p53 and either disease-free survival or overall survival. Exploratory analyses did not reveal a convincing explanation for these results that are in conflict with the published literature. Notable interactions were observed. In particular, high Ki-67 levels were associated with increased (decreased) survival in patients with low (high) TS intensity. Patients whose tumors stained positively for p53 seemed to benefit substantially from the use of adjuvant chemotherapy compared with those who were not treated (P = .05). CONCLUSION: This retrospective investigation failed to demonstrate a significant association between TS, Ki-67, or p53 staining and clinical outcome.

The Rac1 guanine nucleotide exchange factor, Vav, is activated in hematopoietic cells in response to a large variety of stimuli. The downstream signaling events derived from Vav have been primarily characterized as leading to transcription or transformation. However, we report here that Vav and Rac1 in natural killer (NK) cells regulate the development of cell-mediated killing. There is a rapid increase in Vav tyrosine phosphorylation during the development of antibody-dependent cellular cytotoxicity and natural killing. In addition, overexpression of Vav, but not of a mutant lacking exchange factor activity, enhances both forms of killing by NK cells. Furthermore, dominant-negative Rac1 inhibits the development of NK cell–mediated cytotoxicity by two mechanisms: (a) conjugate formation between NK cells and target cells is decreased; and (b) those NK cells that do form conjugates have decreased ability to polarize their granules toward the target cell. Therefore, our results suggest that in addition to participating in the regulation of transcription, Vav and Rac1 are pivotal regulators of adhesion, granule exocytosis, and cellular cytotoxicity.