Showing papers by "Bruce E. Johnson published in 2004"
TL;DR: Results suggest that EGFR mutations may predict sensitivity to gefitinib, and treatment with the EGFR kinase inhibitor gefitsinib causes tumor regression in some patients with NSCLC, more frequently in Japan.
Abstract: Receptor tyrosine kinase genes were sequenced in nonsmall cell lung cancer (NSCLC) and matched normal tissue. Somatic mutations of the epidermal growth factor receptor gene EGFR were found in 15 of 58 unselected tumors from Japan and 1 of 61 from the United States. Treatment with the EGFR kinase inhibitor gefitinib (Iressa) causes tumor regression in some patients with NSCLC, more frequently in Japan. EGFR mutations were found in additional lung cancer samples from U.S. patients who responded to gefitinib therapy and in a lung adenocarcinoma cell line that was hypersensitive to growth inhibition by gefitinib, but not in gefitinibinsensitive tumors or cell lines. These results suggest that EGFR mutations may predict sensitivity to gefitinib. Protein kinase activation by somatic mutation or
9,265 citations
TL;DR: A mechanism by which gefitinib treatment of NSCLC harboring EGFRL858R leads to a dramatic response to gef itinib is characterized.
Abstract: Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) have recently been described in patients with non-small-cell lung cancer (NSCLC) who achieve radiographic regressions to the EGFR inhibitor gefitinib. One of these mutations, L858R (Leu-->Arg), is also found in NSCLC cell line H3255, which is very sensitive to gefitinib treatment. We characterized nine NSCLC cell lines (three isolated from patients with bronchioloalveolar carcinoma and six isolated from patients with adenocarcinoma) for their in vitro sensitivity to gefitinib. Of these, only H3255 (EGFR(L858R)) and H1666 (EGFR(WT)) are sensitive to gefitinib with IC(50) values of 40 nmol/L and 2 micromol/L, respectively. We examined the effects of gefitinib on H3255 and cell lines containing wild-type EGFR that are either sensitive (H1666) or resistant (A549 and H441) to gefitinib exposure in vitro. Gefitinib treatment (1 micromol/L) leads to significant apoptosis accompanied by increased poly(ADP-ribose) polymerase cleavage only in the H3255 cell line, leads to G(1)-S arrest in H1666, and has no effects in the A549 and H441 cell lines. Although EGFR and AKT are constitutively phosphorylated in H3255, H1666, and H441 cell lines, AKT is completely inhibited by gefitinib treatment only in the H3255 cell line. These findings further characterize a mechanism by which gefitinib treatment of NSCLC harboring EGFR(L858R) leads to a dramatic response to gefitinib.
358 citations
TL;DR: Treatment with gefitinib in this population of NSCLC patients treated on the EAP study is associated with a longer survival in women, those with good performance status and in patients with adenocarcinomas.
196 citations
TL;DR: Eerlotinib combined with carboplatin and paclitaxel chemotherapy did not confer a survival advantage over carboplarin and pac litaxel alone in pts with previously untreated advanced NSCLC and TTSP results to be presented.
Abstract: 7011 Background: Tarceva™ (erlotinib) is a potent reversible HER1/EGFR tyrosine kinase inhibitor with single-agent antitumor activity. TRIBUTE was a prospective, placebo-controlled study randomizing patients (pts) with previously untreated advanced (Stage IIIB / IV) NSCLC to receive erlotinib at 150 mg/d or placebo (PBO) with a course of 6 cycles of CP followed by maintenance monotherapy. Methods: Pts with performance status (PS) of 0 or 1 were eligible. Randomization was stratified by stage, >5% weight loss prior 6 months, measurable disease, and study site. The primary endpoint was overall survival (OS). Secondary endpoints included time to progression (TTP), objective response (OR), duration of response and time to symptomatic progression (TTSP; as determined by the Lung Cancer Symptom Scale). Sample size of 1050 was based on 80% power to detect a 25% benefit in OS, α=0.05. Results: 1059 pts were randomized / treated (526 erlotinib; 533 PBO). As shown in the table below, there was no difference in medi...
177 citations
TL;DR: A novel informatics platform, dChipSNP, was used to perform hierarchical tumor clustering based on genome-wide LOH patterns and it is demonstrated that this method can separate non-small-cell and small-cell lung cancer samples based on their shared LOH.
Abstract: Chromosomal loss of heterozygosity (LOH) is a common mechanism for the inactivation of tumor suppressor genes in human epithelial cancers. Hybridization to single-nucleotide polymorphism (SNP) arrays is an efficient method to detect genome-wide cancer LOH. Here, we survey LOH patterns in a panel of 33 human lung cancer cell lines using SNP array hybridization containing 1500 SNPs. We compared the LOH patterns generated by SNP array hybridization to those previously obtained by 399 microsatellite markers and find a high degree of concordance between the two methods. A novel informatics platform, dChipSNP, was used to perform hierarchical tumor clustering based on genome-wide LOH patterns. We demonstrate that this method can separate non-small-cell and small-cell lung cancer samples based on their shared LOH. Furthermore, we analysed seven human lung cancer cell lines using a novel 10 000 SNP array and demonstrate that this is an efficient and reliable method of high-density allelotyping. Using this array, we identified small regions of LOH that were not detected by lower density SNP arrays or by standard microsatellite marker panels.
118 citations
Patent•
09 Jul 2004TL;DR: In this article, the authors present a fiber-channel Arbitrated Loop System (ARB, OPN, and CLS) for switching between a plurality of Fiber Channel Loop devices, which switches based at least in part on arbitrated loop primitives.
Abstract: The method and apparatus for switching Fiber Channel Arbitrated Loop Systems (figure 1) is provided between a plurality of Fiber Channel Loop devices (10-16). The system switches based at least in part on arbitrated loop primitives. An exemplary interconnect system (20-26) include a first port and a second port, both including port logic to monitor certain arbitrary loop primitives, a connectivity apparatus, a route determination apparatus including a routing table consisting of ALPA addresses and their associated ports, the route determination apparatus coupled to each port and the connectivity apparatus, where the connectivity apparatus creates paths between the ports based on arbitrated loop primitives (ARB, OPN and CLS).
100 citations
TL;DR: Patients with typical and atypical pulmonary carcinoid tumors can respond to chemotherapy with or without chest radiotherapy, though with response rates that appear less than those of small cell lung cancers.
92 citations
TL;DR: R115777 showed no significant antitumor activity as a single agent in sensitive-relapse SCLC and was terminated because no objective responses were observed in 20 patients evaluable for response.
87 citations
TL;DR: Although erlotinib with CP did not confer an advantage in OS over CP alone in all enrolled NSCLC pts, the addition of erlot inib to CP markedly prolonged survival in pts who reported never smoking, consistent with results of prior studies of EGFR-TKIs and warrants confirmation in a randomized trial.
Abstract: 7061 Background: Erlotinib (Tarceva) is a potent HER1/EGFR tyrosine kinase inhibitor (TKI). Monotherapy trials of EGFR-TKIs have suggested never smokers and pts with bronchioloalveolar cell carcinoma (Shah, Proc ASCO 2003 #2524; Miller, Proc ASCO 2003 #2491) are more likely to benefit from these agents. TRIBUTE was a placebo-controlled study randomizing pts with previously untreated advanced NSCLC to receive erlotinib, 150 mg/d, or placebo (PBO) with 6 cycles of carboplatin/paclitaxel (CP) followed by maintenance monotherapy. Methods: Pts with performance status (PS) of 0 or 1 were eligible. Randomization was stratified by stage, >5% weight loss (WL) prior 6 mos., measurable disease (MD), and study site. The primary endpoint was overall survival (OS). Other endpoints included time to progression (TTP), objective response (OR) and duration of response. Results: 1059 pts randomized/treated (526 erlotinib; 533 PBO). No difference was observed in OS (p=0.95), OR (p=0.36) or TTP (p=0.36) with erlotinib and CP ...
56 citations
TL;DR: R115777 and L-778,123 were well tolerated in these studies but showed no significant activity as single-agent therapy in relapsed SCLC or untreated NSLC and no objective responses in patients with stage IIIB/IV NSCLC were seen.
Abstract: The ras family of genes have been identified as potential targets for therapeutic intervention because of somatic mutations in different human cancers. They are mutated in non-small cell lung cancer (NSCLC) ∼20% of the time. The enzyme farnesyl transferase is involved in posttranslational modification of the ras proteins by covalently linking a farnesyl group to the ras protein. This permits the ras protein to be translocated to the surface membrane, allowing the protein to be involved in signaling for increased proliferation and inhibition of apoptosis. The class of farnesyl transferase inhibitors is designed to block farnesylation and prevent the mature ras signaling and thus inhibit cell proliferation and facilitate apoptosis. Multiple agents that inhibit farnesylation have been developed, and two farnesyl transferase inhibitors have been tested in patients with lung cancer in three Phase II trials. R115777 has been studied in patients with NSCLC and in patients with relapsed small cell lung cancer (SCLC) after chemotherapy. There has been a single trial of L-778,123 in patients with untreated NSCLC. No objective tumor responses in patients with stage IIIB/IV NSCLC were seen in these studies. There were also no objective responses among the 22 patients with relapsed SCLC treated with R115777. The median survival for the 44 patients with NSCLC treated with R115777 was ∼8 months, whereas it was 11 months for the 23 patients treated with L-778,123. R115777 and L-778,123 were well tolerated in these studies but showed no significant activity as single-agent therapy in relapsed SCLC or untreated NSLC.
52 citations
Patent•
09 Jul 2004
TL;DR: In this article, a Fibre Channel Arbitrated Loop System (FCLS) is described, which switches based at least in part on arbitrated loop primitives, such as ARB, OPN and CLS.
Abstract: Methods and apparatus for switching Fibre Channel Arbitrated Loop Systems is provided between a plurality of Fibre Channel Loop devices. In one aspect of the invention, the system switches based at least in part on arbitrated loop primitives. An exemplary interconnect system may include a first port and a second port, both including port logic to monitor certain arbitrated loop primitives, a connectivity apparatus, a route determination apparatus including a routing table consisting of ALPA addresses and their associated ports, the route determination apparatus coupled to each port and the connectivity apparatus, where the connectivity apparatus creates paths between the ports based on arbitrated loop primitives. In one embodiment, the connectivity apparatus is a crossbar switch. Examples of the arbitrated loop primitives that cause the switch to create paths between ports includes one or more of the following: ARB, OPN and CLS.
TL;DR: Basic treatment considerations of chemotherapy include applications in different clinical settings and different times during the treatment course, which should be incorporated into ongoing preclinical and clinical research to develop more effective therapies for patients.
Abstract: Despite the initial high response rates and some cures with combination chemotherapy, small cell lung cancer (SCLC) remains fatal in 95% of the patients treated for this disease in the United States. Extensive laboratory and clinical research has been ongoing to attempt to improve the outcome of patients with SCLC. The basic treatment considerations of chemotherapy include applications in different clinical settings and different times during the treatment course. Most of the clinical research information in this article describes considerations regarding the initial induction chemotherapy. Other considerations include induction chemotherapy combined with chest irradiation, maintenance chemotherapy administered after completing an initial course of induction chemotherapy or induction chemotherapy combined with chest radiotherapy, and adjuvant chemotherapy administered after surgical resection of SCLC. This article reviews these basic treatment considerations that should be incorporated into ongoing preclinical and clinical research to develop more effective therapies for patients.
Harvard University1, Mayo Clinic2, University of Colorado Denver3, Vanderbilt University4, University of California, Davis5, VU University Amsterdam6, Washington University in St. Louis7, University of Texas MD Anderson Cancer Center8, Emory University9, Yeshiva University10, Autonomous University of Barcelona11, University of Texas Health Science Center at San Antonio12, University of Turin13, University of Wisconsin-Madison14, University of North Carolina at Chapel Hill15
TL;DR: A small, international, closed-door conference on Novel Agents in the Treatment of Lung Cancer, held in Cambridge, Massachusetts, October 17–18, 2003, was convened to present and discuss findings from recent and ongoing trials of investigational drugs for the treatment of lung cancer.
Abstract: A small, international, closed-door conference on Novel Agents in the Treatment of Lung Cancer, held in Cambridge, Massachusetts, October 17–18, 2003, was convened to present and discuss findings from recent and ongoing trials of investigational drugs for the treatment of lung cancer. Invited
TL;DR: A single center phase II trial of erlotinib in patients ≥ 70 with previously untreated advanced NSCLC with median survival and secondary endpoints: response rate, quality of life, and analysis of EGFR signaling pathway from pre-treatment tumor specimens.
Abstract: 7080 Background: Chemotherapy for patients ≥ 70 years of age with advanced NSCLC can be associated with greater toxicities than in younger patients. The identification of an efficacious therapy with minimal systemic toxicity would be particularly beneficial to elderly subjects. Erlotinib (Tarceva™) has shown promising activity, and a tolerable side effect profile, in the treatment of patients who have failed prior chemotherapy. We thus chose to conduct a single center phase II trial of erlotinib in patients ≥ 70 with previously untreated advanced NSCLC. Methods: Patients: chemotherapy naive, IIIB (w/malignant effusion)/IV, PS 0–2; treated with erlotinib, 150 mg p.o. q.d., until evidence of disease progression or toxicity. Primary endpoint: median survival; secondary endpoints: response rate, quality of life (using LCSS), changes in FDG-PET, and analysis of EGFR signaling pathway from pre-treatment tumor specimens. Results: From 3/03 to 12/03, 36 pts were treated; 30 evaluable for toxicity and response; 1 ...
TL;DR: This phase has confirmed that the combination of ZD6474 and doc is not associated with significant changes in exposure to either drug and the toxicities are manageable, and preliminary PK assessment shows that ZD 6474 did not appear to affect exposure to doc, with any changes observed being similar to the intra-patient variability for doc alone.
Abstract: 3051 Background: ZD6474 is a novel, orally available VEGFR-2 TKI that also has activity against EGFR. Objective tumor responses in NSCLC patients (pts) were observed during Phase I evaluation. In t...
TL;DR: There are an estimated 25,000 patients who develop small cell lung cancer per year in the United States and the currently available therapy is inadequate because >95% of patients die from their small cell Lung cancer.
Abstract: There are an estimated 25,000 patients who develop small cell lung cancer per year in the United States. The currently available therapy is inadequate because >95% of patients die from their small cell lung cancer [(1][1] [, 2)][2] . The work with conventional chemotherapy has not dramatically
TL;DR: Source Citation Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC, et al.
Abstract: Source Citation Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC, et al. Effect of vitamin D on falls: a meta-analysis. JAMA. 2004;291:1999-2006. 15113819
TL;DR: P a t i e n t s 252 women who were 45 to 60 years of age and had ≥ 35 hot flashes per week; a follicle-stimulating hormone (FSH) level ≥ 30 mIU/mL; either bilateral oophorectomy or ≥ 2 consecutive months of amenorrhea in the previous year were studied.
Abstract: P a t i e n t s 252 women who were 45 to 60 years of age (mean age 52 y) and had ≥ 35 hot flashes per week; a follicle-stimulating hormone (FSH) level ≥ 30 mIU/mL; either bilateral oophorectomy or ≥ 2 consecutive months of amenorrhea; and ≥ 6 months of amenorrhea in the previous year. Exclusion criteria were vegetarian diet; regular use of dietary supplements containing isoflavones; allergy to red clover; consumption of soy products more than once per week; use of medications affecting isoflavone absorption or use of hormone preparations in the previous 3 months; consumption of > 2 alcoholic beverages per day; or gastrointestinal disease. 98% of women completed the study.