A phase I-II study of paclitaxel, ifosfamide, and vinorelbine with filgrastim (rhG-CSF) support in advanced non-small-cell lung cancer

PURPOSE: We designed a phase I-II trial of three active agents, paclitaxel, ifosfamide, and vinorelbine, in advanced non-small-cell lung cancer (NSCLC) to: 1) define the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of paclitaxel with filgrastim (G-CSF) support; and 2) determine the overall response rate and median survival of patients treated on this regimen. PATIENTS AND METHODS: We treated cohorts of patients with stage IIIB or IV NSCLC with ifosfamide 1.2-1.6 g/m2/day x 3 and vinorelbine 20-25 mg/m2/day x 3 and escalating doses of paclitaxel at 100-175 mg/m2 on day 2 with G-CSF support on a 21-day cycle. One prior experimental single-agent chemotherapy regimen was allowed. RESULTS: Fifty-six patients, were enrolled on this trial: 27 on the phase I portion of the study and an additional 29 at the recommended phase II dose (RPTD). Thirteen patients had received prior chemotherapy. Paclitaxel doses of 175 mg/m2 and 150 mg/m2 produced dose-limiting myelosuppression, and the RPTD was determined to be paclitaxel 135 mg/m2 with ifosfamide 1.2 g/m2/day on days 1-3 and vinorelbine 20 mg/m2/ day on days 1-3 with G-CSF support. The overall response rate was 18%, with a median survival of 6.1 months. Six of 35 patients (17%) treated at the RPTD achieved a partial response to therapy. Grade IV neutropenia was observed in 19 of 35 patients at this dose, with eight patients suffering febrile neutropenia. CONCLUSIONS: This non-cisplatin-containing three-drug regimen has substantial toxicity and low activity in advanced NSCLC, and does not seem to improve on prior regimens. It is unclear whether the lack of efficacy relates to an antagonistic reaction between the specific drugs, administration schedule, or to subtherapeutic doses of the individual agents.     

Sacrospinous colpopexy in the management of uterovaginal prolapse

The tet(M) genes were characterized from 84 isolates of 10 different bacterial species isolated from the periodontal pockets of 16 patients with periodontal disease. A 740 bp polymerase chain reaction product from the hypervariable region of the tet(M) structural gene was cleaved with the restriction enzymes AluI and HinfI. Three different restriction patterns were identified for each of the two enzymes. By DNA sequencing, using a direct solid-phase automated sequencing method, the isolates could be grouped into 3 different clusters of tet(M) subtypes. The internal DNA homology within each subtype was 98-100%; the homology between clusters was 89-94%. Two different subtypes were identified in 9 of 10 bacterial species, and the remaining species had 3 different subtypes. One of the subtypes (M3) was seen mainly in the anaerobic isolates. This subtype was different from all earlier sequenced structural tet(M) genes present in the Genbank. Most patients had two different subtypes of tet(M), and a third subtype was seen in the 3 patients who exhibited the greatest variety of tetracycline-resistant bacterial species. It appears that the presence of one subtype of the tet(M) gene within a patient or bacterial species does not prevent the acquisition of another subtype of the same gene. This study identified a new subtype of the tet(M) gene and grouped it into 3 distinct yet highly homologous genetic subtypes.     

Predicting postlaryngectomy voice outcome in an era of primary tracheoesophageal fistulization: a retrospective evaluation

The aim of this study was to investigate the effect of the absence of elongate spermatids (ES) from the rat seminiferous epithelium on the quantitative secretion and synthesis of the three major Sertoli cell secretory proteins--SGP-1, SGP-2 and CP-2. Seminiferous tubules (ST) were isolated (a) from normal 28-day-old rats, in which the most mature germ cell type is the round spermatid, (b) from normal adult rats at stages IX-XIV of the spermatogenic cycle, i.e. after spermiation, or at stages I-V and VI-VIII, when ES are still attached to the Sertoli cell, and (c) at stages VI-VIII from normal adult rats and from rats treated with methoxyacetic acid (MAA) in order to specifically deplete ES at these stages. Two-dimensional SDS PAGE combined with computerized image analysis was used to analyse 35S-methionine-labelled intracellular and secreted proteins. In the case of SGP-1 and SGP-2, almost all of the protein synthesized by ST was secreted. The total amount of both SGP-1 and CP-2 secreted by unstaged ST from immature rats was significantly lower than that secreted by unstaged ST from adult rats. The total amount of SGP-1 and CP-2 secreted by adult ST at stages IX-XIV of the spermatogenic cycle also declined dramatically compared to ST at earlier stages. The proportion of the total CP-2 synthesized by ST which was secreted also declined in all situations in which ES were absent from the seminiferous epithelium. The synthesis of only SGP-2 was changed by ES depletion from ST at stages VI-VIII, which was almost doubled compared to synthesis of this protein by ST from control rats. Our results suggest strongly that the secretion of SGP-1 and SGP-2 is via the constitutive pathway, and that regulation of these two proteins by ES is at the level of protein synthesis. In contrast, the regulation of CP-2 by ES is predominantly at the level of secretion, suggesting that this protein is secreted via a regulated pathway. Our findings add to the evidence showing that ES play a major role in the regulation of Sertoli cell function.     

Longitudinal bone mineral density changes in early rheumatoid arthritis

A prospective longitudinal study of patients with early RA was performed to examine the influence of disease duration, disease activity and physical activity on bone loss. Sixty-seven patients with non-steroid treated RA of less than 5 yr duration, including 16 patients with disease duration less than 6 months, had BMD measurements of the femoral neck and the lumbar spine over a 12-month period using dual energy X-ray absorptiometry. The BMD changes were compared with values from 72 control patients and were also correlated with serial measurements of disease activity (measured by the Stoke Index) and disability [measured by the Health Assessment Questionnaire (HAQ) score], at 3-monthly intervals over the 12-month period. No significant differences in BMD changes were found between RA patients and controls overall. Patients with disease duration of less than 6 months had significantly greater loss of BMD at the femoral neck (-3.9%, S.E.M. 1.5) than the remainder of the cohort (-0.2%, S.E.M. 0.7) (P = 0.02) and controls (-0.8%, S.E.M. 0.6). Lumbar spine BMD changes correlated with the initial Stoke Index (Rs-0.373, P = 0.01) but not mean Stoke Indices. There was no correlation of BMD changes with age or HAQ scores. These findings suggest that significant bone loss occurs within the first few months of disease in patients with RA.     

The use of monoclonal antibodies for detecting the influenza virus

The possibilities of using influenza A (Leningrad) 385/80 (H3N2) virus matrix protein-specific FITC-labeled D8 monoclonal antibodies in immunofluorescence assays were investigated. The virus antigen accumulation was detected in chorioallantoic cells of chick embryos. Exhibiting the type-specific properties, the fluorescent antibodies stain the perinuclear space, cytoplasmic membrane, and granular structures in the cytoplasm of infected cells. The haemagglutination test tires in the corresponding specimens were at least 1:16.     

Concordant but different: Cognitive function, cerebral anatomy, and metabolism in monozygotic twins with Alzheimer's disease.

To illustrate the utility of the twin method in Alzheimer's disease (AD) research, a pair of monozygotic twins, concordant for the disease but markedly different in their clinical presentations, was studied in detail. Neuropsychological evaluation, magnetic resonance imaging (MRI), and cerebral glucose metabolic studies revealed a typical behavioral presentation for AD in Twin A. In contrast, Twin B showed prominent visuospatial impairments. Although there was no identified cause for the disparate presentations, a close correspondence was observed between the neuropsychological findings and the regional brain measures. The results suggest that the trajectory of AD may vary widely even in genetically identical individuals. Factors accounting for the variability include potential intrauterine, early developmental, and environmental differences. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

On-line steam distillation/purge and trap analysis of halogenated, nonpolar, volatile contaminants in foods

An on-line, steam distillation/purge and trap gas chromatographic procedure is described for determination of halogenated analytes in foods and beverages. Recoveries were generally >80% (versus aqueous standards) from vegetable oil, flour, root beer, cream (10% butter fat), and milk spiked at 1-3 micrograms/kg for each of the 32 analytes studied. Analytes ranged in volatility from vinyl chloride to 1,2,3,4-tetrachlorobenzene. Repeatabilities from aqueous standards were <10% for most analytes. For a 1 g food sample, method detection limits ranged from 0.02 to 0.2 micrograms/kg for the 32 analytes. Reduced recoveries for less volatile analytes, however, occurred when steam-distillable, nonpolar food components were carried to the sparger. This effect was observed for citrus beverages containing steam-volatile limonene, roasted and ground coffees, and some salad dressings. The method was applied to a variety of foods.     

Morphology of amorphous layers ballistically deposited on a planar substrate

Identification of a specific biomolecular target appropriately sensitive to a wide array of anesthetics has been elusive. At concentrations close to their respective ED50's for anesthesia in man or other species, 18 compounds, differing in potencies up to 66,000 fold, inhibited cytochrome P450 mediated metabolism of aminopyrine, a synthetic substrate, and arachidonic acid (AA), an endogenous substrate, in isolated liver microsomes. There was a highly significant correlation for both substrates between the absolute concentrations required for anesthesia (EC50) and for inhibition of P450 activity (Ki or IC50). The mean Ki/EC50 ratio was 0.97 for inhibition of aminopyrine demethylase. The mean IC50/EC50 ratios were 0.42 and 0.64 for inhibition of two AA-derived products and 2.8 for a third; a mean ratio of 1.4 for inhibition of overall AA metabolism suggests interaction of general anesthetics with a composite of P450 isozymes. The universal cytochrome P450 monooxygenases, in conjunction with other lipid oxygenases (cyclooxygenases and lipoxygenases) participate in the second messenger AA cascade. In nerve cells the sensitivity of these enzymes to hydrophobic neurodepressant drugs may underlie the state of general anesthesia: reversible disruption of intracellular and intercellular signalling without impairment of enzymes vital to cell respiration.     

Granulation tissue polyposis associated with carcinoid tumours of the small intestine

We report two patients with ileal carcinoid tumours which were associated with polyps due to mucosal granulation tissue proliferation. In both cases the tumours had extensively infiltrated the small bowel wall and mesentery, and one had hepatic metastases. The mucosal surface of each specimen showed numerous, pale brown, sessile polyps which were restricted to the intestinal segment involved by carcinoid tumour, although not always closely related to neoplastic cells. The polyps were formed by the proliferation of capillaries, smooth muscle cells and myofibroblasts as demonstrated by immunohistochemistry and electronmicroscopy.