Showing papers by "Bruce E. Johnson published in 2003"

c-MET Mutational Analysis in Small Cell Lung Cancer Novel Juxtamembrane Domain Mutations Regulating Cytoskeletal Functions

Abstract: Small cell lung cancer (SCLC) is an aggressive cancer, and most patients present with cancer already spread beyond the lung. The receptor tyrosine kinase (RTK) c-MET has been implicated in various solid tumors, including SCLC, and is involved in mediating tumorigenesis, cell motility, scattering, invasion and metastasis. Mutations of c-Met have been described in renal papillary carcinoma and gastrointestinal cancers including hepatocellular carcinoma. The sequence of c-MET was examined for possible mutations in the 10 SCLC cell lines and 32 paired-SCLC/normal tissues. Novel c-MET alterations were identified among 3 of 10 separate SCLC cell lines and in 4 of 32 SCLC tumor tissue samples. These include two different c-MET missense mutations in the juxtamembrane (JM) domain (R988C found in NCI-H69 and H249 cell lines; and T1010I in SCLC tumor sample T31). Also, there are one Sema domain missense mutation (E168D in SCLC tumor sample T5), two-base-pair insertional mutations (IVS13- (52–53)insCT in both SCLC tumor samples T26 and T27) within the pre-JM intron 13, as well as an alternative transcript involving exon 10 (H128 cell line). c-MET receptors are expressed at various levels among the 10 SCLC cell lines studied (high expression: H69, H345, H510, and H526; medium-expression: H128 and H146; and low/no-expression: H82, H209, H249, and H446). The level of c-MET expression does not have any apparent correlation with presence or absence of mutations of c-MET in the cell lines. We show that the two identified JM mutations (R988C and T1010I), when introduced into the interleukin-3 (IL-3)-dependent BaF3 cell line, regulated cell proliferation resulting in a small but significant growth factor independence. When introduced into a SCLC cell line (H446, with minimal endogenous wild-type c-MET expression), the JM mutations also regulated cell morphology and adhesion, as well as causing enhanced tumorigenicity by both increases in focus-formation and soft-agar colony-formation assays. Both of the JM mutations also increased cell motility and migration evident in wound healing assay and time-lapse video-microscopy speed analysis. The JM mutations also altered the c-MET RTK signaling, resulting in preferentially increased constitutive tyrosine phosphorylation of various cellular proteins, including the key focal adhesion protein paxillin on tyrosine residue Y31 (first CRKL-binding site), correlating with increased motility. These results suggest a novel and unique role of the JM domain in c-MET signaling in SCLC with significant implications in cytoskeletal functions and metastatic potential. The novel JM gain-of-function somatic mutations described are the first to be reported in SCLC, and may be associated with a more aggressive phenotype. It would now be useful to study the inhibition of c-MET as a therapeutic target against SCLC.

Phase II study of imatinib in patients with small cell lung cancer.

Abstract: Purpose: The purpose of our study was to assess the objective response to imatinib administered to patients with small cell lung cancer (SCLC). Experimental Design: Eligible patients were those with SCLC who either had chemotherapy-naive extensive-stage or had SCLC in a sensitive relapse. Patients enrolled on the trial were treated with 600 mg of imatinib daily. The response was assessed using Southwest Oncology Group (SWOG) criteria after 3 and 6 weeks. Tumor specimens were examined by immunohistochemistry for the KIT receptor. Results: Nineteen patients with SCLC entered on the study, including 16 men and 3 women. Nine patients had previously untreated extensive-stage disease and 10 patients had sensitive relapse. A central pathology review confirmed SCLC in only 14 of the 19 patients. There were no objective responses; however, one patient with sensitive-relapse disease had prolonged stabilization of disease (>3 months) while on imatinib therapy. The median time to progression was 0.8 months (range, 0.6–1.3 months) and 1.2 months (range, 0.2–4.1 months) in the previously untreated and sensitive-relapse groups, respectively. Tumor tissue samples from 4 (21%) of the 19 patients had the KIT receptor (CD117). Conclusions: There was no observed antitumor activity in this limited Phase II trial of patients with SCLC, of which only a few tumors showed expression of the imatinib target. The results of this trial are, thus, inconclusive about the antitumor activity of imatinib against SCLC with the targeted KIT receptor (CD117). Further testing of imatinib in patients with SCLC will focus on demonstration of KIT expression in the setting of confirmed SCLC histology.

Methods and apparatus for switching Fibre Channel Arbitrated Loop devices

Abstract: Methods and apparatus for switching Fiber Channel Arbitrated Loop Systems is provided between a plurality of Fiber 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. In yet other aspects, the system ensures device access fairness through one or more techniques, including a rotating priority system, a counter to count the number of OPNs, especially sequential OPNs, and/or priority based on port type. Device zoning may be implemented. In one implementation, the system includes trunking such that frames may be transferred on multiple ports.

A prospective study of palliative hypofractionated radiation Therapy (8.5Gy × 2) for patients with symptomatic non-small cell lung cancer

Abstract: Purpose Hypofractionated chest radiotherapy regimens have provided excellent palliation of pulmonary symptoms in patients with inoperable non–small-cell lung cancer (NSCLC) and poor performance status in studies from Asia and Europe. We conducted a prospective study of this approach in patients from the United States. Methods and materials Twenty-three patients with symptomatic NSCLC and an Eastern Cooperative Oncology Group performance status of ≥2 were enrolled between December 1994 and October 2001. Two “involved-field” fractions of 8.5 Gy were delivered 1 week apart. Patients were assessed for efficacy, toxicity, and tumor response at baseline, treatment completion, and 1 week, 1 month, and 4 months after completing radiotherapy. Results The median follow-up after treatment began was 4.3 months (range, 0.3–38). The median forced expiratory volume in 1 s and Eastern Cooperative Oncology Group performance status as measured at baseline was 1.05 L and 3, respectively. The most common presenting pulmonary symptoms were dyspnea (100%), cough (96%), anorexia/nausea (65%), and chest pain (52%). Between treatment completion and up to 4 months after treatment, dyspnea, cough, anorexia/nausea, chest pain, hoarseness, hemoptysis, and dysphagia had improved in 30%, 60%, 67%, 75%, 25%, 100%, and 100% of patients, respectively. No cases of treatment-related esophagitis, pneumonitis, or radiation myelopathy occurred. Progressive local disease was seen in only 1 (6%) of 18 assessable patients 4 months after treatment. Conclusion For patients with poor performance status and inoperable NSCLC causing pulmonary symptoms, hypofractionated, involved-field radiotherapy, 8.5 Gy in two fractions, offers acceptable palliation with minimal toxicity. A clear advantage of the very short hypofractionated regimen is that it enables patients with a short expected survival time to spend more of their remaining time away from the hospital.

Sensitivity of Non-Small-Cell Lung Cancer Cell Lines Established from Patients Treated with Prolonged Infusions of Paclitaxel

Abstract: Objective: Regimens with prolonged infusions of taxanes have been developed for patients with cancer to overcome drug resistance. Our objective of the present study was to examine t

A Model to Select Regimens for Phase III Trials for Patients with Advanced-Stage Non-Small Cell Lung Cancer

Abstract: Purpose: Historical data from pilot, Phase II, and Phase III studies for patients with advanced-stage non-small cell lung cancer (NSCLC) were used to evaluate a statistical model developed to provide assistance in selecting regimens from pilot studies for subsequent use in larger Phase III randomized studies. Experimental Design: Information from 33 Phase III trials for patients with advanced-stage NSCLC performed from 1973 and 1994 in the United States and Canada was collected. The data from antecedent pilot or Phase II and subsequent Phase III trials were analyzed using a predictive statistical model. This model uses the number of patients in the pilot/Phase II study, the median survival of patients in the pilot, and the number of deaths observed, to estimate the statistical likelihood that the pilot regimen will be shown superior to standard therapy in a subsequent Phase III trial. Results: Ten pilot/Phase II studies were identified that preceded eleven subsequent Phase III studies. The three pilot regimens associated with Phase III trials, revealing statistically significant longer survival, had an expected power of 0.69, 0.85, and 0.94 respectively. The regimens from the seven other pilot studies for which the median power expected was 0.38 (range, 0.07–0.80) showed no difference when compared with standard treatment in a Phase III trial. Conclusion: The use of the expected power model provides an important enhancement to the screening of new therapies. Regimens with an expected power of >0.55 may be good candidates for testing in Phase III trials.

Expression of bcl-2 protein is associated with shorter survival in nonsmall cell lung carcinoma.

Abstract: BACKGROUND The aim of this study was to assess the relationship between the expression of the 27-kilodalton (kD) bcl-2 protein and survival among nonsmall cell lung carcinoma (NSCLC) patients. METHODS Paired tissue samples of histologically confirmed tumor and uninvolved lung of 91 randomly selected NSCLC patients were used in this study. The expression of 27-kD bcl-2 proteins in uninvolved lung and tumor tissue specimens was analyzed using Western blot analysis. Overall survival was estimated using the Kaplan–Meier method. The relation between patient survival and expression of the 27-kD bcl-2 protein in uninvolved lung, tumor, and in uninvolved lung and/or tumor tissue specimens was assessed using log-rank tests and Cox proportional hazards multiple regression. RESULTS The 27-kD bcl-2 protein was expressed in 54% of the uninvolved lung tissue specimens, in 53% of the tumor tissue specimens, and in 70% of the uninvolved lung and/or tumor tissue specimens. When NSCLC patient survival was considered with respect to the expression of the 27-kD bcl-2 protein, a statistically significant shorter survival was observed for patients whose tissue samples expressed the 27-kD bcl-2 protein in the uninvolved lung and in the uninvolved lung and/or tumor (log-rank test, P = 0.008 and P = 0.001, respectively). Cox proportional hazards multiple regression models also showed statistically significant associations between shorter survival and positive 27-kD protein expression in the uninvolved lung (hazard ratio of 2.27; P = 0.05) and in the uninvolved lung and/or tumor (hazard ratio of 5.58, P = 0.008) after controlling for tumor size, stage, the type of surgery received, smoking status, age, and cell type. CONCLUSIONS In the current study, patients with nonsmall cell lung carcinoma with positive expression of the 27-kD protein bcl-2, either in the uninvolved lung or in uninvolved lung and/or tumor, were found to have significantly poorer postresection survival. Cancer 2003;98:135–43. © 2003 American Cancer Society. DOI 10.1002/cncr.11461

Induction docetaxel and carboplatin followed by weekly docetaxel and carboplatin with concurrent radiotherapy, then surgery in stage III non-small cell lung cancer: a Phase I study.

Abstract: Purpose: To determine the maximum-tolerated dose of docetaxel (DOC) in combination with carboplatin (CAR) and thoracic radiotherapy (RT), in the setting of trimodality treatment of patients with stage III non-small cell lung cancer (NSCLC). Experimental Design: Thirty-two patients with biopsy-proven stage IIIA ( n = 20) or IIIB ( n = 12) NSCLC were given two initial cycles of CAR (area under the curve = 6) and DOC (75 mg/m 2 ), subsequent RT (54 Gy) with concurrent weekly CAR (area under the curve = 2), and DOC at six dose levels from 10 to 40 mg/m 2 , then surgery if the patient’s disease was resectable. Results: Three patients did not complete induction computed tomography (CT). Twenty-nine patients received concurrent CT/RT. Fifteen patients were eligible for surgery. Dose-limiting toxicities occurred in 2 patients, at dose levels two (atrial fibrillation) and three (transaminitis). The maximum-tolerated dose, as defined by the protocol, was not reached, although grade 3 and 4 toxicities were encountered at all dose levels. The most common more than or equal to grades 3 toxicities were neutropenia, nausea, vomiting, and fatigue. Four patients (13.3%) responded to induction CT. Ten patients (38.5%) responded to CT/RT. Eight surgical patients (57.1%) were downstaged, including 3 pathologic complete responses. Median relapse free and overall survivals are 8.5 and 12 months. One-year and estimated 2-year survival rates are 56.3 and 34.3%. Conclusion: This new regimen for stage III NSCLC of induction CAR/DOC, then weekly CAR/DOC with concurrent RT followed by surgery, can be safely administered and offers encouraging results. DOC at 30 mg/m 2 in combination with CAR and RT is recommended for Phase II study.

Prospective study of the airways and pulmonary parenchyma of patients at risk for a second lung cancer.

Abstract: Purpose: We conducted our study to compare the number of preneoplastic lesions in the airways and nodules in the pulmonary parenchyma of patients with resected non-small cell lung cancer with the patients whose treatment included chest radiotherapy. Experimental Design: Patients were eligible if they had successfully resected stage I and II non-small cell lung cancer or advanced stage non-small cell or small cell lung cancer treated with chest radiotherapy with or without chemotherapy and were free of cancer for >2 years. Patients underwent a history and physical examination, white light and fluorescence bronchoscopy, and computerized tomography of the chest. The airway epithelium was examined for preneoplastic histological changes, and the pulmonary parenchyma was examined for the presence of nodules. Results: Twenty-nine patients at risk for lung cancer were studied between 1997 and 1999. Two patients treated with chest radiotherapy had an area of moderate dysplasia ( n = 1) and carcinoma in situ ( n = 1), whereas one patient treated with surgical resection alone had an area of mild dysplasia. Six other patients had metaplasia detected in their airway epithelium. Ten of the 13 patients treated with chest radiotherapy had pulmonary nodules compared with 5 of the 13 patients treated with surgical resection alone. Conclusions: Mild dysplasia, moderate dysplasia, severe dysplasia, and carcinoma in situ are unusual in patients with resected lung cancer who have stopped smoking for an extended period of time. Patients with lung cancer treated with chest irradiation may be at higher risk for preneoplastic lesions and pulmonary nodules than patients treated with surgical resection alone, but additional patients will need to be studied.

A home based intervention reduced disability in physically frail older people

Abstract: Participants 188 people ≥ 75 years of age (mean age 83 y, 80% women) who lived at home and were physically frail (needed > 10 s to walk a 3.0 m course and back and inability to stand from a seated position in a hardback chair with their arms folded). People who met 1 of the frailty criteria were moderately frail; people who met both were severely frail. Exclusion criteria included inability to walk; receipt of physical therapy or exercise programme; dementia; and stroke, hip fracture, myocardial infarction, or hip or knee replacement surgery in the past 6 months. Follow up data were available for 176 people (94%).