Phase I and imaging trial of a monoclonal antibody directed against gastrin-releasing peptide in patients with lung cancer.

Small cell lung cancer (SCLC) cells express and secrete bombesin-like peptides (BLP) that can activate specific receptors that stimulate the growth of these cells. A murine monoclonal antibody, 2A11, which binds to the BLP, gastrin-releasing peptide with high affinity, has been reported to decrease the growth of SCLC cells in vitro and in athymic nude mice. A Phase I trial in lung cancer patients was performed using multiple doses of 2A11. Thirteen patients with lung cancer received 12 doses of 2A11 antibody three times a week for 4 weeks at one of four dose levels. Serum samples were obtained prior to initiation and before each dose of 2A11 antibody therapy for measurement of 2A11 antibody levels and determination of serum human anti-mouse antibody levels. A pilot imaging evaluation using 111In conjugated 2A11 monoclonal antibody was also performed in the same patients to aid in the study of pharmacokinetics and biodistribution. No toxic reactions were observed, and none of the patients developed detectable human antimouse antibody; however, no objective antitumor responses were observed. The mean trough serum 2A11 levels in patients increased with increasing dose level: 0.26+/-0.2 microg/ml, 6.7+/-6 microg/ml, 71.5+/-60 microg/ml, 248+/-184 microg/ml for dose levels 1 mg/m2, 10 mg/m2, 100 mg/m2, and 250 mg/m2, respectively. At each dose level, sustained detectable serum levels of the monoclonal antibody were achieved. Tumor uptake was noted in 11 of 12 patients who were injected with 111In conjugated 2A11. Because no dose-limiting clinical toxicity was observed, a mathematical model was used to define the recommended Phase II dose of 250 mg/m2. This trial established that repeated doses of monoclonal antibody 2A11 could be given safely to patients, and sustained levels could be achieved for a 4-week schedule. Further evaluation of the antitumor effects of 2A11 is warranted.     

Application of bioluminescent urine screens in a tertiary care facility

Two adenosine triphosphate (ATP)-detection systems for quantitating bacteriuria, the LUMAC (noncentrifugation method) and MONOLIGHT (centrifugation method) urine screens, were separately evaluated for their capacity to detect bacteriuria in specimens from patients at a tertiary care teaching hospital. Results of each study were compared with the findings of conventional culture. Indices of test efficacy, sensitivity/predictive value for a negative test, were as follows: at greater than or equal to 10(4) CFU/ml--LUMAC 88%/93% and MONOLIGHT 82%/88%; and at greater than or equal to 10(5) CFU/ml--LUMAC 99%/99% and MONOLIGHT 97%/99%. Both systems were satisfactory urine screens for catheterized and midstream urine specimens when used at the traditional level of significance (greater than or equal to 10(5) CFU/ml). An assessment of the MONOLIGHT noncentrifugation protocol demonstrated efficacy of the system to detect significant bacteriuria at greater than or equal to 10(5) CFU/ml. Decreased numbers of false-positive results compared to the centrifugation method were obtained with this assay. False-positive and false-negative results were attributable to threshold sensitivity of the instruments. The presence of somatic cells and yeasts were associated with false-positive results. False-positive results might stem from the inability of conventional culture to recover selected microorganisms. Time and cost analyses of the LUMAC system indicated that significant savings over conventional methodology were not effected.     

Epidemiology of all-complaint injuries in youth basketball

This study evaluated the incidence and characteristics of all-complaint injuries, including acute and overuse injuries, in female and male youth basketball players. A total of 518 players (16 ± 1.4 years; 38.6% females), from 63 teams, participated in this prospective cohort study. Players were observed through one competitive high school or club basketball season to record exposure and all-complaint injuries, defined as any complaint resulting from participating in basketball-related activities, including but irrespective of the need for medical attention or time loss. Injury incidence rates and rate ratios were derived from Poisson's regression with 99.4% CI (Bonferroni's correction for multiple comparisons). The overall injury incidence rate was 14.4 (99.4% CI: 12.2-17.0) injuries/1000 h; 13.8 (99.4% CI: 11.2-16.8) in females and 14.8 (99.4% CI: 11.7-18.8) in males. While the incidence of injury was similar across injury classifications for female and male players, a potential lower overuse knee injury rate was noted for females vs males [IRR = 0.61 (99.4% CI: 0.34-1.07)]. The most commonly injured body location was the ankle (45%) in females and the knee (51%) in males. Overuse (vs acute) injuries were about 2x more common in the knee while acute (vs overuse) injuries were about 3x more common in the ankle, overall, and for female and male players. Based on an all-complaint injury definition, injury rates in competitive female and male youth basketball players are much higher than previously reported. This study provides an evidence base to inform more tailored interventions to reduce injuries in youth basketball.     

A method of quantify confounding in regression analyses applied to data on diet and CHD incidence

We present a method to display the results of linear regression when the independent variables are highly correlated. In this method the sum of squares of regression (SSR) for pairs of variables are partitioned into orthogonal and shared components. A shared component is the reduction in the SSR of one of the variables when the other variable is added to the regression equation. This method shows how the SSR for one variable depends on the other variables present in the regression equation and explains apparent inconsistencies between forward and backward stepwise regression. To demonstrate the potential usefulness of this method we reanalyzed previously reported data on the relationship between coronary heart disease (CHD) and diet. The analysis suggested that carbohydrate and alcohol intake are negatively associated with CHD because they are associated with greater caloric intake. Protein and fat intake are also associated with greater caloric intake, but in addition they are associated with factors that increase the risk of CHD.     

Human leukocyte antigen class I polymorphisms influence the mild clinical manifestation of Plasmodium falciparum infection in Ghanaian children

A prospective study that included 429 children for active detection of mild malaria was conducted in a coastal region of Ghana to reveal whether the incidence of malaria is affected by human leukocyte antigen (HLA) polymorphism. During 12 months of follow-up, 85 episodes of mild clinical malaria in 74 individuals were observed, and 34 episodes among them were accompanied with significant parasitemia at >5000 infected red blood cells per cubic millimeter. Attributable and relative risks conferred by genetic factors in the HLA region were evaluated by comparison of the incidence in children, stratified by carrier status, of a given allele of HLA-A, -B, -DRB1 and TNFA promoter polymorphism. HLA-B*35:01 reduced the incidence by 0.178 events per person per year (0.060 versus 0.239 for B*35:01-positive and -negative subpopulations, respectively), and a relative risk of 0.25, which remained statistically significant after Bonferroni's correction for multiple testing (p(c) = 8.2 × 10(-5)). Further, HLA-B*35:01 and -B*53:01 exhibited opposite effects on the incidence of malaria with significant parasitemia. When parasite densities in different HLA carriers status were compared, HLA-A*01 conferred an increase in parasite load (p = 6.0 × 10(-7)). In addition, we found a novel DRB1 allele that appears to have emerged from DRB1*03:02 by single nucleotide substitution.     

Dietary fish oil and olive oil supplementation in patients with rheumatoid arthritis. Clinical and immunologic effects

Forty-nine patients with active rheumatoid arthritis completed a 24-week, prospective, double-blind, randomized study of dietary supplementation with 2 different dosages of fish oil and 1 dosage of olive oil. Clinical evaluations were performed at baseline and every 6 weeks thereafter, and immunologic variables were measured at baseline and after 24 weeks of study. The 3 groups of patients were matched for age, sex, disease severity, and use of disease-modifying antirheumatic drugs (DMARDs). Subjects continued receiving DMARDs and other background medications without change during the study. Twenty patients consumed daily dietary supplements of n3 fatty acids containing 27 mg/kg eicosapentaenoic acid (EPA) and 18 mg/kg docosahexaenoic acid (DHA) (low dose), 17 patients ingested 54 mg/kg EPA and 36 mg/kg DHA (high dose), and 12 patients ingested olive oil capsules containing 6.8 gm of oleic acid. Significant improvements from baseline in the number of tender joints were noted in the low-dose group at week 24 (P = 0.05) and in the high-dose group at week 18 (P = 0.04) and 24 (P = 0.02). Significant decreases from baseline in the number of swollen joints were noted in the low-dose group at weeks 12 (P = 0.003), 18 (P = 0.002), and 24 (P = 0.001) and in the high-dose group at weeks 12 (P = 0.0001), 18 (P = 0.008), and 24 (P = 0.02). A total of 5 of 45 clinical measures were significantly changed from baseline in the olive oil group, 8 of 45 in the low-dose fish oil group, and 21 of 45 in the high-dose fish oil group during the study (P = 0.0002). Neutrophil leukotriene B4 production decreased by 19% from baseline in the low-dose fish oil group (P = 0.0003) and 20% in the high-dose group (P = 0.03), while macrophage interleukin-1 production decreased by 38.5% in the olive oil group (P not significant), 40.6% in the low-dose group (P = 0.06), and 54.7% in the high-dose group (P = 0.0005). Tritiated thymidine incorporation in peripheral blood mononuclear cells after stimulation with concanavalin A increased significantly in all 3 groups after 24 weeks, compared with baseline values. We conclude that the clinical benefits of dietary supplementation with omega-3 fatty acids are more commonly observed in patients consuming higher dosages of fish oil for time intervals that are longer than those previously studied. Dietary supplementation with olive oil is also associated with certain changes in immune function, which require further investigation.     

FAM chemotherapy +/- aminoglutethimide in the treatment of pancreatic carcinoma

Human pancreas contains receptors for estrogens and androgens as well as aromatase activity. FAM chemotherapy was administered to 14 patients with pancreatic cancer (seven at Stage IV). The median survival of these patients was 24.4 +/- 4.8 weeks. FAM chemotherapy plus aminoglutethimide/hydrocortisone (AG/HC) (250 mg bid AG + 20 mg bid HC) was administered to 14 patients (seven at stage IV). The median survival of this group was 17.3 +/- 2.9 weeks (P = 0.74 vs FAM alone). We conclude that addition of AG/HC does not add to the survival of patients with carcinoma of the pancreas treated with chemotherapy.