Publications

PURPOSE

CT-2106 is a 20(S)-camptothecin poly-L-glutamate conjugate. This linkage stabilizes the active lactone form of camptothecin and enhances aqueous solubility. In addition, poly-L-glutamate is postulated to increase tumor delivery of the active compound through enhanced permeability and retention effect in tumor. We studied a weekly schedule of CT-2106 in patients with refractory solid tumor malignancies.

EXPERIMENTAL DESIGN

CT-2106 was infused (10 min i.v. infusion) on days 1, 8, and 15 of each 28-day cycle. Plasma and urine were analyzed for total and unconjugated camptothecin by high-performance liquid chromatography equipped with a fluorescence detector. Toxicity and response assessments were done with Common Toxicity Criteria for Adverse Events version 3 and Response Evaluation Criteria in Solid Tumors, respectively.

RESULTS

Twenty-six patients were enrolled. Median age was 58 years (range, 36-83) and median number of doses was 6 (range, 1-9). The most frequent tumor type (50%) was melanoma. Dose limiting toxicities were thrombocytopenia and fatigue. A weekly dose of 25 mg/m2 given every 3 of 4 weeks was the maximum tolerated dose. The majority of grade 3 and 4 toxicities were hematologic. The pharmacokinetic profile of conjugated and unconjugated camptothecin showed a polyexponential decline with similar terminal half life (t1/2 range was 44-63 and 31-48 h for conjugated and unconjugated, respectively). Pharmacokinetics of conjugated and unconjugated camptothecin were dose and time independent in the tested dose range. Urinary excretion of conjugated and unconjugated camptothecin accounted for about 30% and 4% of the administered dose, respectively.

CONCLUSIONS

CT-2106 has a more manageable toxicity profile compared with unconjugated camptothecin. The maximum tolerated dose is 25 mg/m2 weekly given 3 of 4 weeks. This compound results in prolonged release of unconjugated camptothecin.

Enteral nutrition, in many respects more than other medical interventions, has been in the limelight concerning the ethics of withdrawing or withholding nutritional support. This article describes the ethical and legal issues surrounding enteral nutrition, identifies the elements of informed consent for enteral nutrition, provides an overview of the endoscopic gastrostomy procedure, and offers recommendations for addressing ethicolegal issues in enteral nutrition.

BACKGROUND

Current information about outcomes in octogenarians undergoing cancer operations is limited largely to case series from selected centers. Population-based data can provide more realistic estimates of the risks and benefits of operations in this group.

STUDY DESIGN

We performed a retrospective cohort study of patients undergoing major resections for lung, esophageal, and pancreas cancer. Using the Nationwide Inpatient Sample (1994 to 2003), we examined operative mortality and discharge disposition in octogenarians (aged 80+ years), relative to younger patients (aged 65 to 69 years) (n = 272,662). We then used the Surveillance and End Results-Medicare-linked database (1992 to 2001) to measure late survival in the elderly (n = 14,088).

RESULTS

Operative mortality among octogenarians was substantially higher than that of younger patients (aged 65 to 69 years) for all three cancers (esophagectomy, 19.9% versus 8.8%, p < 0.0001; pancreatectomy, 15.5% versus 6.7%, p < 0.0001; lung resection, 6.9% versus 3.7%, p < 0.0001). A large proportion of octogenarians were transferred to extended care facilities after operation, ranging from 24% after lung resection to 44% after esophagectomy. Five-year survival in octogenarians was low for all three cancers: 11% after pancreatectomy, 18% after esophagectomy and 31% after lung cancer resection. Survival among octogenarians with two or more comorbidities was worse than those with fewer comorbid diagnoses--10% versus 14% for pancreatectomy, 15% versus 23% for esophagectomy, and 27% versus 37% for lung resection.

CONCLUSIONS

Population-based outcomes after high-risk cancer operation in octogenarians are considerably worse than typically reported in case series and published survival statistics. Such information might better inform clinical decision making in this high-risk group.

BACKGROUND

Clinical studies have shown that injurious mechanical ventilation is associated with increased airspace and plasma levels of interleukin-1beta (IL-1beta); however, the potential therapeutic value of IL-1 inhibition in acute lung injury has not been thoroughly investigated. A study was undertaken to determine if IL-1 signalling is a necessary early event in the pathogenesis of experimental ventilator-induced lung injury.

METHODS

Mice deficient in IL-1 receptor type 1 (IL1R1) and rats treated with IL-1 receptor antagonist (IL-1Ra) were mechanically ventilated with high tidal volume (30 ml/kg) and the effect of IL-1 signalling blockade on the severity of lung injury was determined.

RESULTS

Permeability, as measured by radiolabelled albumin flux, was significantly lower in IL1R1 null mice than in wild-type mice during injurious ventilation (p<0.05). IL-1Ra significantly decreased protein permeability and pulmonary oedema in rats during injurious ventilation and also decreased airspace and plasma levels of the chemokine CXCL1 and airspace neutrophils. IL-1Ra decreased expression of NOS2 and ICAM-1 mRNA in whole lung. Bronchoalveolar lavage fluid levels of RTI40, a marker of type I cell injury, were 2.5 times lower following IL-1Ra treatment (p<0.05). In isolated type II pneumocytes, IL-1beta reduced electrical resistance and increased transepithelial permeability.

CONCLUSIONS

IL-1 contributes to alveolar barrier dysfunction in VILI by promoting lung neutrophil recruitment and by increasing epithelial injury and permeability. Because preserved alveolar barrier function is associated with better outcomes in patients with acute lung injury, these data support further testing of IL-1Ra for the treatment of acute lung injury.

RATIONALE

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease lacking effective treatment.

OBJECTIVES

To determine the effects of bosentan on exercise capacity and time to disease progression in patients with IPF.

METHODS

In a double-blind, multicenter trial, patients with IPF were randomized to receive oral bosentan 62.5 mg twice daily for 4 weeks, increased to 125 mg twice daily thereafter, or placebo, for 12 months or longer. The primary efficacy endpoint was change from baseline up to Month 12 in exercise capacity, as measured by a modified six-minute-walk test. Secondary endpoints were time to death or disease progression (worsening pulmonary function tests [PFTs] or acute decompensation), change in PFT scores, and quality of life (QOL) assessed using Short-Form 36 and St. George's Respiratory Questionnaire.

MEASUREMENTS AND MAIN RESULTS

A total of 158 patients randomly received bosentan (n = 74) or placebo (n = 84). Bosentan showed no superiority over placebo in six-minute-walk distance (6MWD) up to Month 12, the primary efficacy endpoint. A trend in favor of bosentan was observed in the secondary endpoint of time to death or disease progression (hazard ratio [HR], 0.613; 95% confidence interval [CI], 0.328-1.144; P = 0.119), which was more pronounced in a patient subgroup diagnosed using surgical lung biopsy (post hoc analysis; HR, 0.315; 95% CI, 0.126-0.789; P = 0.009). Changes from baseline up to Month 12 in assessments of dyspnea and QOL favored treatment with bosentan. No unexpected adverse events were reported.

CONCLUSIONS

Bosentan treatment in patients with IPF did not show superiority over placebo on 6MWD. A trend in delayed time to death or disease progression, and improvement in QOL, was observed with bosentan. The more pronounced treatment effect in patients with biopsy-proven IPF warrants further investigation. Clinical trial registered with www.clinicaltrials.gov (NCT 00071461).