A phase I/II study of weekly high-dose erlotinib in previously treated patients with nonsmall cell lung cancer

BACKGROUND: Preclinical studies have suggested that erlotinib at high doses may inhibit additional sites downstream of the epidermal growth factor receptor (EGFR), resulting in greater antitumor efficacy. The objective of this study was to determine the tolerability and efficacy of high-dose erlotinib administered on a weekly schedule to patients with advanced nonsmall cell lung cancer (NSCLC). METHODS: The authors conducted a Phase I/II trial of weekly erlotinib in patients with progressive NSCLC who had received previous chemotherapy. In the Phase I portion, patients were enrolled in 3-patient cohorts at erlotinib dose levels of 1200 mg, 1600 mg, and 2000 mg once weekly. The Phase II portion was designed to determine the major objective response rate of the dose identified in the Phase I portion of the trial. RESULTS: Twenty-seven patients were enrolled. No dose-limiting toxicity was observed. Grade 1 and 2 rash and diarrhea were the principle toxicities, and each occurred in 92% of patients. Among 21 patients who were treated at the Phase II dose of 2000 mg weekly, a single objective response was identified, yielding a response rate of 5% (95% confidence interval, 0.2-22%). For this cohort, the median survival was 9.5 months. The sole radiographic response occurred in a patient whose pretreatment tumor specimen harbored an EGFR exon 19 deletion. CONCLUSIONS: Erlotinib at a dose of 2000 mg administered weekly was tolerated well by these patients with advanced NSCLC. The 5% objective response rate did not reach the stated objective at the interim efficacy analysis, prompting the closure of the study.     

An enteric-coated high-buffered pancrelipase reduces steatorrhea in patients with cystic fibrosis: a prospective, randomized study

OBJECTIVE: Enteric-coated (EC) high-buffered (2.5 mEq [2.5 mmol] bicarbonate per capsule) pancrelipase microsphere enzymes were compared to EC-nonbuffered pancreatic enzymes for efficacy in reducing steatorrhea in patients with cystic fibrosis. DESIGN: Prospective, randomized, controlled trial using a crossover design with each subject as his/her own control. SUBJECTS/SETTING: Eighteen subjects with cystic fibrosis, who had pancreatic insufficiency and required large enzyme doses, were studied over two consecutive 7-day treatment periods. INTERVENTION: Each 7-day period consisted of 3 days at home followed by 4 days in a general clinical research center for careful control of diets, enzyme lipase doses (given at approximately 50% of the subject's usual lipase dose), and carmine red-labeled stool collections for 72-hour fecal fat balance studies. MAIN OUTCOME MEASURE: Fecal fat excretion. STATISTICAL ANALYSES PERFORMED: Differences in fat excretion, when each subject received EC-high-buffered pancrelipase vs EC-nonbuffered enzymes, were compared using linear modeling. RESULTS: Mean fat excretion decreased significantly in each subject during periods when given EC-high-buffered pancrelipase compared with periods when given EC-nonbuffered enzymes (fat excretion 18.2% vs 24.9% or fat absorption 81.8% vs 75.1%, respectively; P=0.01). Thirteen of 18 subjects (72%) excreted less fat when receiving EC-high-buffered pancrelipase whereas 10 (56%) decreased fat excretion by more than 5%, and five subjects did not respond. CONCLUSIONS: EC-high-buffered pancrelipase decreased fat excretion, symbolizing improved fat absorption, when compared with EC-nonbuffered pancreatic enzymes given at equivalent, reduced (approximately 50% of usual) lipase doses in nourished subjects with cystic fibrosis and mild pulmonary disease.     

Spondyloarthropathy: an independent risk factor for kidney stones

PURPOSE: To better stratify risk and to verify previous prevalence reports, we conducted a retrospective cohort study comparing the lifetime incidence of nephrolithiasis in patients with spondyloarthropathies (SpA) and rheumatoid arthritis (RA). PATIENTS AND METHODS: Patients with SpA or rheumatoid factor-positive RA were identified from the rheumatology clinics of two Veterans Affairs hospitals and the University of Minnesota. Among them, 168 were confirmed to meet the American College of Rheumatology criteria and gave informed consent to participation. They were sent a survey regarding their rheumatologic diagnosis, coexistent conditions, medications, and history of kidney stones. Of the total, 143 patients responded and met the criteria for analysis. Rheumatoid arthritis patients were age and sex matched with SpA patients as controls. RESULTS: Populations were similar in all categories except that RA patients were more likely to have used prednisone (P < 0.001), bisphosphonates (P < 0.001), and calcium supplementation (P = 0.03). Kidney stones were reported by 23 (29.11%) of the 79 SpA patients compared with 8 (12.5%) of the 64 RA patients (chi (2) = 5.75; P = 0.025). Subgroup analysis of self-reporting stone history in 85 patients was found to be reliable on imaging review (sensitivity 82%; specificity 100%). CONCLUSIONS: Self-reporting of kidney stones by patients is a reliable measure. Despite adjusting for medication use and matching two similar arthritic populations, patients with SpA had a higher incidence of kidney stones than those with RA. This finding suggests that SpA is an independent risk factor for nephrolithiasis. Future studies will evaluate urinary risk factors and polymorphisms in the ANKH gene that may predispose to stone formation in this high-risk group.     

D-Glucosamine-induced increase of the glycerol-containing lipids in growing cultures of human malignant epithelial cells

D-Glucosamine was found to inhibit the growth of human malignant epithelial cells SW-839, HT-29, RT-4, and SK-OV-3 in culture in a process that was associated with significant increments in glycerol-containing lipids. Each cell line had a different sensitivity to the drug, but all four cell lines shared the same features in their response, i.e., dose-dependent (at concentrations of 1, 5, and 10 mM), noncytotoxic reductions in growth (minimum 30%, maximum 70%), and simultaneous 1.5-fold to sevenfold increases in lipid contents. Cells regained their normal growth and lipid patterns when glucosamine was removed. Glucosamine did not modify the lipid contents of cells in the late phase of culture when growth was minimal.     

Practical application of logistic function to the growth of experimental tumors

The properties of the logistic law of growth (Verhulst-Pearl) and a simple method for computing of statistical approximation are described. Two parameters are estimated: the generation rate c and the mortality rate c0, although the real biological processes are of greater complexity. The logistic law is modified by an additional term concerning the prefinal decline in the last life span. To prove the curve fitting to tumour growth by the modified logistic function the total number of Ehrlich ascites tumour cells was measured in 144 mice at 12 different times after inoculation. The accuracy of the curve fitting proved to be very good. Therefore the logistic function modified by an additional term for the final stages, is particularly suited for the characterization of Ehrlich ascites tumour growth and its changes.     

Hemithoracic radiation therapy after pleurectomy/decortication for malignant pleural mesothelioma

PURPOSE: To evaluate pleurectomy/decortication (P/D) and adjuvant radiotherapy (RT) in the treatment of malignant pleural mesothelioma (MPM). METHODS AND MATERIALS: In a retrospective review, we included MPM patients treated with P/D and adjuvant RT at Memorial Sloan-Kettering Cancer Center from 1974 to 2003. When indicated, patients received intraoperative brachytherapy to residual tumor. RESULTS: All 123 patients received external beam RT (median dose, 42.5 Gy; range, 7.2-67.8 Gy) to the ipsilateral hemithorax postoperatively. Fifty-four patients underwent brachytherapy (matched peripheral dose, 160 Gy). The median and 2-year overall survival for all patients was 13.5 months (range, 1-199 months) and 23%, respectively. One-year actuarial local control for all patients was 42%. Multivariate analysis for overall survival revealed radiation dose <40 Gy (p = 0.001), nonepithelioid histology (p = 0.002), left-sided disease (p = 0.01), and the use of an implant (p = 0.02) to be unfavorable. Two patients (1.6%) died from Grade 5 toxicity within 1 month of treatment. CONCLUSIONS: Pleurectomy/decortication with adjuvant radiotherapy is not an effective treatment option for patients with MPM. Our results imply that residual disease cannot be eradicated with external RT with or without brachytherapy and that a more extensive surgery followed by external RT might be required to improve local control and overall survival.     

Sinusoidal Obstruction Syndrome of the Liver after Hematopoietic Stem Cell Transplantation: Decision Making for Orthotopic Liver Transplantation

Sinusoidal obstruction syndrome (SOS) is a specific complication of hematopoietic stem cell transplantation (HSCT) that can lead to substantial morbidity and treatment-related mortality. Heparin is frequently used as prophylaxis of and defibrotide as therapy for mild to moderate SOS. In severe cases of SOS these therapies are often ineffective, and orthotopic liver trans-plantation (OLT) may be the only option. Reports in the literature about the outcome of liver transplantation for SOS are contradictory. We describe our second case of OLT after HSCT. The patient died of intracranial hemorrhage 2 weeks after liver transplantation with good initial organ function. In the first case at our center, however, the patient survived more then 8 years. The reported short- to medium-range survival rate for OLT following HSCT is approximately 50%. On the basis of the experience at our center and the findings in a review of the literature, we developed a rational approach to the selection for liver transplantation of patients with life-threatening liver dysfunction after marrow transplantation.