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Biomedical subjects

B E Johnson

Publications and source records attributed to B E Johnson.

At least 37 records · Page 2Linked to original sources
PubMed1999

Clinical features of patients with stage IIIB and IV bronchioloalveolar carcinoma of the lung.

BACKGROUND: The incidence of bronchioloalveolar carcinoma of the lung (BAC), a pathologically distinct type of nonsmall cell lung carcinoma (NSCLC), appears to be rising. In this study, the authors compared data on the clinical presentation and clinical courses of patients with Stage IIIB and IV BAC with data on other types of NSCLC. METHODS: The authors collected clinical, radiographic, and pathology information about 28 patients with Stage IIIB and IV BAC and 124 patients with other histologic types of NSCLC. RESULTS: Twelve of 28 BAC patients (43%) were women, compared with 40 of 124 control patients (32%). Nine (32%) of the patients with BAC had never smoked cigarettes, versus 20 controls (16%) (P = 0.02). Eighteen patients (64%) with BAC had bilateral multilobar or multicentric pulmonary involvement, compared with 13 controls (15%) (P < 0.001). Patients with advanced stage (IIIB and IV) BAC had a median survival of 15 months from the time of diagnosis; for patients with other types of Stage IIIB and IV NSCLC, had a median survival of 10 months (P = 0.01). CONCLUSIONS: Patients with BAC of the lung have clinical, radiographic, and pathologic characteristics that distinguish them from patients with other types of NSCLC. A greater proportion of women and nonsmokers present with BAC than with other types of NSCLC. Patients with advanced stage BAC are more likely to have bilateral diffuse pulmonary involvement, are less likely to develop brain metastases, and have longer survival than patients with other types of Stage IIIB and IV NSCLC. Further research is warranted to define etiology, molecular abnormalities, and more effective therapeutic interventions.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed1999

Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group.

BACKGROUND: Prophylactic cranial irradiation reduces the incidence of brain metastasis in patients with small-cell lung cancer. Whether this treatment, when given to patients in complete remission, improves survival is not known. We performed a meta-analysis to determine whether prophylactic cranial irradiation prolongs survival. METHODS: We analyzed individual data on 987 patients with small-cell lung cancer in complete remission who took part in seven trials that compared prophylactic cranial irradiation with no prophylactic cranial irradiation. The main end point was survival. RESULTS: The relative risk of death in the treatment group as compared with the control group was 0.84 (95 percent confidence interval, 0.73 to 0.97; P= 0.01), which corresponds to a 5.4 percent increase in the rate of survival at three years (15.3 percent in the control group vs. 20.7 percent in the treatment group). Prophylactic cranial irradiation also increased the rate of disease-free survival (relative risk of recurrence or death, 0.75; 95 percent confidence interval, 0.65 to 0.86; P<0.001) and decreased the cumulative incidence of brain metastasis (relative risk, 0.46; 95 percent confidence interval, 0.38 to 0.57; P<0.001). Larger doses of radiation led to greater decreases in the risk of brain metastasis, according to an analysis of four total doses (8 Gy, 24 to 25 Gy, 30 Gy, and 36 to 40 Gy) (P for trend=0.02), but the effect on survival did not differ significantly according to the dose. We also identified a trend (P=0.01) toward a decrease in the risk of brain metastasis with earlier administration of cranial irradiation after the initiation of induction chemotherapy. CONCLUSIONS: Prophylactic cranial irradiation improves both overall survival and disease-free survival among patients with small-cell lung cancer in complete remission.

Adult↗
PubMed1999

Human small cell lung cancer cells produce brain natriuretic peptide.

The tumoral production of brain natriuretic peptide (BNP) was studied using 9 small cell lung cancer (SCLC) cell lines which were established from patients with small cell lung cancer. BNP cDNA fragment was generated from 20 microg total RNA which was prepared from the human right cardiac atrium by reverse transcription-based polymerase chain reaction. Expression of BNP mRNA was detected in 30 microg total cellular RNA from these cell lines by RNase protection assays in 5 of 9 SCLC cell lines. Radioimmunoassays using 125I-radiolabeled human BNP(1-32) and antihuman BNP(1-32) antibody detected immunoreactivity in cell pellets from SCLC cell lines which had detectable BNP mRNA. BNP immunoreactivity in the cell pellets corresponds with the data from BNP mRNA analyses. We conclude that SCLC cells have detectable BNP mRNA by RNase protection assay and BNP immunoreactivity in the cells.

Carcinoma, Small Cell↗
PubMed1999

Review of the efficacy of individualized chemotherapy selected by in vitro drug sensitivity testing for patients with cancer.

PURPOSE: The purpose of this study is to review the potential efficacy of individualized chemotherapy selected by in vitro drug sensitivity testing (DST) compared with empiric regimens for patients with cancer. METHODS: MEDLINE and CANCERLIT were searched for articles published (in English) about prospective clinical trials in which patients were treated with chemotherapy that was selected with the use of in vitro DST. RESULTS: We identified 12 prospective studies that examined the benefit of chemotherapy selected by DST. Five hundred six patients (33%) were treated with chemotherapy that was selected with the use of in vitro DST. The mean response rate for patients treated with in vitro-selected therapy was 27% (range, 10% to 100%; n = 12 studies) compared with 18% (range, 0% to 100%; n = 7 studies) for patients treated with empiric therapy. Five studies (only one randomized) evaluated the impact of chemotherapy selected by in vitro DST on patient survival. Three studies showed that survival was 1 to 4 months longer for the 238 patients treated with empiric chemotherapy compared with that of the 65 patients treated with chemotherapy that was selected by in vitro testing. Two nonrandomized studies showed that survival was 4 or 19 months longer for 27 patients treated with chemotherapy selected by in vitro testing compared with that of 80 patients who were treated with empiric chemotherapy. CONCLUSION: Only one third of patients entered in prospective trials of in vitro DST were actually treated with an in vitro best regimen. The response rates seem to be better with in vitro selected chemotherapy regimens than with empiric regimens, but the impact on survival has not been adequately addressed.

Carcinoma, Small Cell↗
PubMed1999

Twenty years of phase III trials for patients with extensive-stage small-cell lung cancer: perceptible progress.

PURPOSE: All cooperative group studies performed in North America for patients with extensive-stage small-cell lung cancer (SCLC) were evaluated to determine the pattern of the clinical trials and the outcome of patients over the past 20 years. PATIENTS AND METHODS: Phase III trials for patients with extensive-stage SCLC were identified through a search of the National Cancer Institute Cancer Therapy Evaluation Program database from 1972 to 1993. Patients with extensive-stage SCLC treated during a similar time interval listed in the Surveillance, Epidemiology, and End Results (SEER) database were also examined. Trends were tested in the number of trials over time, the number and sex of patients entered onto the trials, and the survival time of patients treated over time. RESULTS: Twenty-one phase III trials for patients with extensive-stage SCLC were initiated between 1972 and 1990. The median of the median survival times of patients treated on the control arms of the phase III trials initiated between 1972 and 1981 was 7.0 months; for those patients enrolled onto control arms between 1982 and 1990, the median survival time was 8.9 months (P =.001). Analysis of the SEER database of patients with extensive-stage SCLC over the same time period shows a similar 2-month prolongation in median survival time. CONCLUSION: Analysis of 21 phase III trials initiated in North America and the SEER database from 1972 to 1994 demonstrates that there has been a modest improvement in the survival time of patients with extensive-stage SCLC.

Carcinoma, Small Cell↗
PubMed1999

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.

Animals↗
PubMed1999

The p16 status of tumor cell lines identifies small molecule inhibitors specific for cyclin-dependent kinase 4.

Loss of p16 functional activity leading to disruption of the p16/cyclin-dependent kinase (CDK) 4:cyclin D/retinoblastoma pathway is the most common event in human tumorigenesis, suggesting that compounds with CDK4 kinase inhibitory activity may be useful to regulate cancer cell growth. To identify such inhibitors, the 60 cancer cell lines of the National Cancer Institute drug screen panel were examined for p16 alterations (biallelic deletion, intragenic mutations, or absent p16 protein), and the growth-inhibitory activity of more than 50,000 compounds against these 60 cell lines was compared with their p16 status. One compound, 3-amino thioacridone (3-ATA; NSC 680434), whose growth-inhibitory activity correlated with the p16 status of the cell lines had an IC50 of 3.1 microM in a CDK4 kinase assay. In addition, four compounds structurally related to 3-ATA inhibited CDK4 kinase with IC50s ranging from 0.2-2.0 microM. All five of these compounds were less potent inhibitors of cell division cycle 2 and CDK2 kinases, with IC50s 30- to 500-fold higher than that for CDK4. ATP competition experiments demonstrated a noncompetitive mode of inhibition for 3-ATA (K(i) = 5.5 microM) and a linear mixed mode for benzothiadiazine (NSC 645787; K(i) = 0.73 microM). We have successfully demonstrated a novel approach to identify specific CDK4 kinase inhibitors that may selectively induce growth inhibition of p16-altered tumors.

Antineoplastic Agents↗
PubMed1998

Down-regulation of transmembrane carbonic anhydrases in renal cell carcinoma cell lines by wild-type von Hippel-Lindau transgenes.

To discover genes involved in von Hippel-Lindau (VHL)-mediated carcinogenesis, we used renal cell carcinoma cell lines stably transfected with wild-type VHL-expressing transgenes. Large-scale RNA differential display technology applied to these cell lines identified several differentially expressed genes, including an alpha carbonic anhydrase gene, termed CA12. The deduced protein sequence was classified as a one-pass transmembrane CA possessing an apparently intact catalytic domain in the extracellular CA module. Reintroduced wild-type VHL strongly inhibited the overexpression of the CA12 gene in the parental renal cell carcinoma cell lines. Similar results were obtained with CA9, encoding another transmembrane CA with an intact catalytic domain. Although both domains of the VHL protein contribute to regulation of CA12 expression, the elongin binding domain alone could effectively regulate CA9 expression. We mapped CA12 and CA9 loci to chromosome bands 15q22 and 17q21.2 respectively, regions prone to amplification in some human cancers. Additional experiments are needed to define the role of CA IX and CA XII enzymes in the regulation of pH in the extracellular microenvironment and its potential impact on cancer cell growth.

Amino Acid Sequence↗
PubMed1998

Second lung cancers in patients after treatment for an initial lung cancer.

BACKGROUND: Prospectively and retrospectively identified patient cohorts that were successfully treated for primary lung cancer have been followed to document the rate of development of and the effectiveness of treatment of second lung cancers. This review was performed to assess rates of second lung cancer development, factors associated with the development of these cancers, and the success of their treatment. METHODS: The MEDLINE database was searched to identify articles published in English concerning lung cancers, second primary cancers, treatment of these cancers, and patient survival. RESULTS: The risk of developing a second lung cancer in patients who survived resection of a non-small-cell lung cancer is approximately 1%-2% per patient per year. Approximately one half of the patients who develop second non-small-cell lung cancers can have these tumors resected. The median survival from diagnosis of a second lung cancer in these patients is between 1 and 2 years, with a 5-year survival of approximately 20% (range, 4%-32%). The average risk of developing a second lung cancer in patients who survived small-cell lung cancer is approximately 6% per patient per year. For patients who survived small-cell cancer, the risk increases from approximately 2% to greater than 10% per patient per year 10 years after initial treatment. Only 7% (range, 6%-12%) of patients treated for small-cell lung cancer survive 2 years or more. Survivors who continue to smoke cigarettes have an increased risk of developing a second lung cancer. CONCLUSIONS: In patients surviving an initial lung cancer, the cumulative risk for the development of a second primary lung cancer makes this cancer a common cause of death. The high risk of developing a second lung cancer makes patients with these cancers an important population for study of surveillance strategies and chemoprevention agents.

Carcinoma, Non-Small-Cell Lung↗
PubMed1998

Co-amplification of a novel cyclophilin-like gene (PPIE) with L-myc in small cell lung cancer cell lines.

Specific genetic alterations affecting proto-oncogenes of the myc gene family are frequently detected in human lung cancer. Among 11 SCLC cell lines with L-myc gene amplification, four were found to have alteration of the RLF gene by Southern blot and RT-PCR analyses. One cell line, NCI-H378, contained aberrantly-sized L-myc-hybridizing bands by Southern and Northern blot hybridization but had no alteration of RLF. Some L-myc-hybridizing cDNAs from NCI-H378 contained a novel sequence with close homology to the cyclophilins joined to antisense L-myc exon 2 sequence. Full length cDNAs isolated from human skeletal muscle containing only the novel sequence identify open reading frames of 301 and 296 amino acids and differ in the C-terminal region by 22 and 17 amino acids. This gene, tentatively named PPIE (peptidyl-prolyl cis-trans isomerase E), has 83% amino acid identity with the central conserved region of cyclophilin A, is evolutionarily conserved by Southern blot, and exhibits differential tissue expression with highest levels found in muscle and brain. Co-amplification of PPIE was observed in seven of eleven L-myc amplified cell lines. Analysis of radiation hybrids suggests that the gene order is RLF-PPIE-L-myc on chromosome 1p and pulse-field gel electrophoresis localizes all three genes to an 800 megabase Mlu I fragment. The prognostic and functional consequences of PPIE gene amplification in SCLC can now be determined.

Amino Acid Sequence↗
PubMed1998

Tobacco and lung cancer.

Cigarette smoking is responsible for enormous health consequences. Lung cancer is fatal in over 80% of cases, and effective treatment is limited. The medical impact of cigarette smoking will diminish with effective measures to prevent smoking and nicotine addiction and to promote smoking cessation. Efforts should focus on the teenage population, with a combination of social, economic, and legislative interventions.

Health Policy↗
PubMed1998

Correlation of expression of bombesin-like peptides and receptors with growth inhibition by an anti-bombesin antibody in small-cell lung cancer cell lines.

The murine anti-bombesin monoclonal antibody, 2A11, has been demonstrated to inhibit growth of some small-cell lung cancer (SCLC) cells in nude mice xenografts and in a clinical trial. To determine if the expression of bombesin-like peptides (BLP) and their receptors (GRP-R and NMB-R) correlate with an in vitro response to 2A11, we measured these parameters in seven SCLC cell lines. Gastrin releasing peptide (GRP) mRNA was detected in three of seven cell lines (NCI-H69, NCI-H345, NCI-H510) and neuromedin B (NMB) mRNA was detected in all seven lines using an RNase protection assay (RPA). Immunoreactive BLP was detected in the cell pellets of all lines (range 0.11-59.90 pmol/mg protein) by a solid phase GRP radioimmunoassay (RIA) using 125I-labeled 2A11. RPA detected GRP-receptor mRNA in two cell lines (NCI-H69 and NCI-H345) and NMB-receptor in three lines (NCI-H345, NCI-H510, and NCI-H660). Reverse transcriptase-PCR confirmed the presence of receptor mRNA in these lines and detected NMB-receptor in an additional three lines (NCI-H69, NCI-H82, and NCI-H187). Calcium mobilization in response to BLP stimulation was detected in the six cell lines expressing either GRP-R or NMB-R mRNA but not in NCI-N417, which had no detectable BLP-receptor. 2A11 (5 microg/ml) inhibited colony formation by 26-61% after 2 weeks in all cell lines except NCI-N417. Thus, growth inhibition by 2A11 requires the presence of at least one BLP-receptor. These findings may be useful in selecting patients with SCLC for treatment with 2A11.

Animals↗
PubMed1998

Lung carcinoma metastasis at the site of central venous access.

Tumor metastases rarely are reported in association with central venous catheters. The case reported herein is that of a solid tumor metastasis at the site of a previous indwelling line ipsilateral to a pleural effusion in a patient with non-small cell lung cancer. A review of the literature reveals a single case of intrathoracic malignancy seeding at the site of a central venous catheter. Other investigators are urged to collect information about the development of tumor implants at the site of catheter insertion in patients with cancer and pleural effusions to further define the extent of the problem.

Carcinoma, Non-Small-Cell Lung↗
PubMed1998

Association of chromosome 11 locus D11S12 with histology, stage, and metastases in lung cancer.

We have reported frequent allele loss for the marker D11S12 on chromosome band 11p15.5 in human lung cancer. The smallest common region of allele loss has been refined to approximately 500 kb and is confined between D11S1758 and D11S860. Here, we investigated the association of D11S12 allele loss with epidemiologic, pathologic, and clinical parameters. Analysis of allele loss was performed by Southern blotting on a cohort of 156 patients with lung cancer, and data were interpreted with the use of a phosphorimager. Results were statistically compared with retrospectively collected variables. D11S12 allele loss was found in 88% of small cell carcinomas, 57% of squamous cell carcinomas, and 40% of adenocarcinomas. Allele loss was associated with tumor stage (p = 0.04) and was more frequent in tumors that had already metastasized. These results suggest that a gene in the D11S12 region may be responsible for the metastatic potential of lung cancer. The functional status of this gene may thus be of future value in guiding clinicians on decisions regarding adjuvant and neoadjuvant therapies for patients with lung cancer.

Aged↗
PubMed1998

Autocrine growth factors and neuroendocrine markers in the development of small-cell lung cancer.

Two different clinical trials using biological agents directed against an autocrine growth factor and a surface marker of neuroendocrine differentiation have been used for patients with relapsed small-cell lung cancer. In a phase II trial, an antibody (2A11) directed against the autocrine growth factor gastrin-releasing peptide has been used to treat patients with relapsed small-cell lung cancer. One of 12 evaluable patients treated with 2A11 250 mg/m2 three times weekly for 4 weeks achieved a complete response. An antibody directed against the neural cell adhesion molecule has been linked to a modified ricin molecule. This immunotoxin, N901-bR, has undergone phase I testing, and a recommended phase II dose of 30 micrograms/kg/day for 7 days by continuous infusion has been determined. In the phase I trial, one of 21 patients with relapsed or refractory small-cell lung cancer had a partial response to this treatment. Therefore, it appears that an antibody directed against an autocrine growth factor and an immunotoxin directed against a surface marker of neuroendocrine differentiation can inhibit the growth of small-cell lung cancer in vitro and in vivo; both produced some evidence of antitumor activity in patients. Further studies with agents directed against autocrine growth factors and surface markers of neuroendocrine differentiation appear warranted.

Antibodies, Monoclonal↗