ABSTRACT
Therapeutic intervention for atherosclerosis has predominantly concentrated on regulating cholesterol levels; however, these therapeutics are not efficacious for all patients, suggesting that other factors are involved. This study was initiated to identify mechanisms that regulate atherosclerosis predisposition in mice other than cholesterol level regulation. To do so we performed quantitative trait locus analysis using two inbred strains that each carry the atherosclerosis phenotype-sensitizing Apoe deficiency and that have been shown to have widely disparate predilection to atherosclerotic lesion formation. One highly significant locus on chromosome 10 (LOD = 7.8) accounted for 19% of the variance in lesion area independent of cholesterol. Two additional suggestive loci were identified on chromosomes 14 (LOD = 3.2) and 19 (LOD = 3.2), each accounting for 7-8% of the lesion variance. In all, five statistically significant and suggestive loci affecting lesion size but not lipoprotein levels were identified. Many of these were recapitulated in an independent confirmatory cross. In summary, two independently performed crosses between C57BL/6 and FVB/N Apoe-deficient mice have revealed several previously unreported atherosclerosis susceptibility loci that are distinct from loci linked to lipoprotein levels.
Subject(s)
Apolipoproteins E/deficiency , Arteriosclerosis/genetics , Genetic Predisposition to Disease , Animals , Apolipoproteins E/genetics , Cholesterol/blood , Female , Gene Frequency , Lipids/blood , Male , Mice , Mice, Inbred C57BL , Phenotype , Quantitative Trait, HeritableSubject(s)
Cancer Care Facilities/trends , Hospitals, Special/trends , Neoplasms/therapy , Clinical Trials as Topic , Humans , Research , VermontABSTRACT
Two hundred and eighty-four patients with inoperable non-small cell lung carcinoma were randomized by the Eastern Cooperative Oncology Group to receive one of seven primary chemotherapy regimens: cyclophosphamide and methotrexate; Baker's antifol; vincristine, bleomycin, and methotrexate; melphalan; cyclophosphamide and CCNU (control arm); 5-FU procarbazine; and hexamethylmelamine, doxorubicin, and methotrexate (HAM). Patients with disease progression were eligible for treatment with VM-26 or ascorbic acid. HAM resulted in higher response rates than cyclophosphamide and CCNU in patients with adenocarcinoma (32%) and large cell carcinoma (23%). It was not tested in patients with squamous cell carcinoma. In terms of survival, HAM was significantly better than cyclophosphamide and CCNU in patients with limited disease. Its toxicity was predominantly hematologic and gastrointestinal. This regimen is being further evaluated by the Eastern Cooperative Oncology Group in patients with inoperable non-small cell lung carcinoma. Crossover therapy with VM-26 or ascorbic acid had no therapeutic benefit.
Subject(s)
Antineoplastic Agents/administration & dosage , Lung Neoplasms/drug therapy , Adenocarcinoma/drug therapy , Antineoplastic Agents/adverse effects , Carcinoma, Small Cell/drug therapy , Carcinoma, Squamous Cell/drug therapy , Drug Evaluation , Drug Therapy, Combination , Humans , PrognosisSubject(s)
Altretamine/therapeutic use , Methotrexate/therapeutic use , Neoplasms/drug therapy , Triazines/therapeutic use , Vincristine/therapeutic use , Adult , Aged , Altretamine/administration & dosage , Altretamine/adverse effects , Clinical Trials as Topic , Drug Therapy, Combination , Female , Humans , Methotrexate/administration & dosage , Methotrexate/adverse effects , Middle Aged , Time Factors , Vincristine/administration & dosage , Vincristine/adverse effectsABSTRACT
Instilled bleomycin and thoracostomy were utilized in 38 patients with malignant pleural effusions; the therapy produced a complete or partial response rate of 63%. Toxicity was minimal. In patients with intraperitoneal effusions, bleomycin instillation after drainage produced a complete or partial response in 36%. One patient had severe hypotension and fever. Patients with ovarian and breast carcinoma responded best, among them, effusions were controlled in greater that 70%. Because of its low systemic toxicity, absence of marrow toxicity, and virtual absence of discomfort, we think that the local instillation of bleomycin is indicated in the management of malignant effusions.
Subject(s)
Ascites/drug therapy , Bleomycin/administration & dosage , Pleural Effusion/drug therapy , Thorax , Bleomycin/adverse effects , Bleomycin/therapeutic use , Drainage , Humans , Injections , Neoplasms/pathologyABSTRACT
Twenty-six patients with small cell carcinoma of the lung were treated with a combination of methyl-CCNU (75 mg/m2 orally), cyclophosphamide (750 mg/m2iv), and vincristine (1.4 mg/m2iv) once every 3 weeks and followed for 2-56 weeks (mean, 24 weeks). An average of seven treatments were given per patient. Myelotoxicity was mild to moderate with no white blood cell count (wbc) less than 1000 cells/mm3 and no platelet count less than 25,000 cells/mm3. Six patients (23%) had a wbc of 1000-2000 cells/mm3 and two (8%) had a platelet count of 25,000-75,000 cells/mm3. Sixty-eight persons of the projected dose of methyl-CCNU was given. Fourteen of 22 patients with measurable disease (54%) responded. Of 14 patients who had received no prior treatment 64% responded with a median survival duration of 40 weeks. Complete responses occurred only in patients without prior radiation therapy or chemotherapy. We conclude that methyl-CCNU may be given with an acceptable level of toxicity in an every 3-week schedule and that the combination of cyclophosphamide, methyl-CCNU, and vincristine warrants further evaluation in the treatment of small cell carcinoma of the lung.
