Showing papers by "Hebron University published in 2004"

Combined Epidermal Growth Factor Receptor Targeting with the Tyrosine Kinase Inhibitor Gefitinib (ZD1839) and the Monoclonal Antibody Cetuximab (IMC-C225) Superiority Over Single-Agent Receptor Targeting

Abstract: Purpose: The epidermal growth factor receptor (EGFR) is abnormally activated in cancer and two classes of anti-EGFR agents, monoclonal antibodies and low-molecular-weight tyrosine kinase inhibitors, have shown antitumor activity in patients. Because these two classes of antireceptor agents target the EGFR at different sites, we decided to explore whether the combined administration of gefitinib, a tyrosine kinase inhibitor, and cetuximab, a monoclonal antibody, had superior antitumor activity than either agent given alone. Experimental Design: We studied the effects of the combination of gefitinib and cetuximab in a panel of human cancer cell lines and in an EGFR-dependent human tumor xenograft model (A431). The effects of these two agents on EGFR signaling, proliferation, apoptosis, and vascularization were evaluated. In addition, we analyzed, with cDNA arrays, changes in gene expression profiles induced by both agents. Results: The combined treatment with gefitinib and cetuximab resulted in a synergistic effect on cell proliferation and in superior inhibition of EGFR-dependent signaling and induction of apoptosis. In a series of in vivo experiments, single-agent gefitinib or cetuximab resulted in transient complete tumor remission only at the highest doses. In contrast, suboptimal doses of gefitinib and cetuximab given together resulted in a complete and permanent regression of large tumors. In the combination-treated tumors, there was a superior inhibition of EGFR, mitogen-activated protein kinase, and Akt phosphorylation, as well as greater inhibition of cell proliferation and vascularization and enhanced apoptosis. Using cDNA arrays, we found 59 genes that were coregulated and 45 genes differentially regulated, including genes related to cell proliferation and differentiation, transcription, DNA synthesis and repair, angiogenesis, signaling molecules, cytoskeleton organization, and tumor invasion and metastasis. Conclusions: Our findings suggest both shared and complementary mechanisms of action with gefitinib and cetuximab and support combined EGFR targeting as a clinically exploitable strategy.

Consensus meeting on microdialysis in neurointensive care

Abstract: Background Microdialysis is used in many European neurointensive care units to monitor brain chemistry in patients suffering subarachnoid hemorrhage (SAH) or traumatic brain injury (TBI).

Reliability of clinical guidelines in the detection of patients at risk following mild head injury: results of a prospective study

Abstract: Object. The aims of this study were to analyze the relevance of risk factors in mild head injury (MHI) by studying the possibility of establishing prediction models based on these factors and to evaluate the reliability of the clinical guidelines proposed for the management of MHI. Methods. A series of 1101 patients with MHI were prospectively enrolled in this study. In all cases clinical data were collected and a computerized tomography (CT) scan was obtained. The relationship between clinical findings and the presence of intracranial lesions was studied to establish prediction models based on logistic regression and recursive partitioning analysis. Recently proposed guidelines and recommendations for the treatment of MHI were selected, calculating their diagnostic efficiency when applying each of them to our series. The incidence of acute intracranial lesions was 7.5% (83 patients). A Glasgow Coma Scale score of 14, loss of consciousness, vomiting, headache, signs of basilar skull fracture, neurological...

The benefits of early combination treatment of carvedilol and an ACE-inhibitor in mild heart failure and left ventricular systolic dysfunction. The carvedilol and ACE-inhibitor remodelling mild heart failure evaluation trial (CARMEN).

Abstract: Aims: Heart failure (HF) treatment guidelines of the ESC recommend ACE-inhibitors (ACE-I) as first-line treatment and β-blockers added if patients remain symptomatic. CARMEN explored the need for combined treatment for remodelling and order of introduction by comparing the ACE-I enalapril against carvedilol and their combination.

Is the placement of shunts in patients with idiopathic normal-pressure hydrocephalus worth the risk? Results of a study based on continuous monitoring of intracranial pressure.

Abstract: Object. Data from many studies have demonstrated that shunt insertion in patients with idiopathic normal-pressure hydrocephalus (NPH) is associated with high morbidity and a lack of significant improvement; however, the use of strict diagnostic and treatment protocols can improve the results of surgery in these patients. The primary aim in this prospective study was to analyze the results of shunt placement in 43 patients with idiopathic NPH. A secondary aim was to determine the relationship between several clinical and neuroimaging factors, and patient outcome after surgery. Methods. Thirty men and 13 women with a mean age of 71.1 ± 6.9 years participated in this study. All patients underwent clinical, neuropsychological, and radiological assessment before and 6 months after surgery. In all patients continuous monitoring of intracranial pressure was performed using a fiberoptic extradural sensor. In 31 patients cerebrospinal fluid dynamics were also determined. Eighty-six percent of patients showed clini...

Tolerability of carvedilol and ACE‐Inhibition in mild heart failure. Results of CARMEN (Carvedilol ACE‐Inhibitor Remodelling Mild CHF EvaluatioN)

Abstract: Background: Management guidelines for heart failure recommend ACE-I and β-blockers. The perception of difficult up-titration might have added to the slow uptake of β-blockers despite their mortality and morbidity benefits. Aims: CARMEN offered a possibility to study safety and tolerability of enalapril against carvedilol and their combination. Methods: Five hundred and seventy-two patients were blindly up-titrated on carvedilol (target 25 mg bid) and/or enalapril (target 10 mg bid), and continued for 18 months. In the combination arm, carvedilol was up-titrated before enalapril. Results: There was no group related difference in adverse events during up-titration. Withdrawal rates were 31, 30 and 30%, and serious adverse events 28, 29 and 34% in the combination, carvedilol and enalapril arms. Mortality was similar in all groups (all-cause N=14, 14 and 14; cardiovascular N=9, 13 and 14). All-cause and cardiovascular hospitalizations occurred in 26, 27 and 32%, and in 12, 16 and 22% in the combination, carvedilol and enalapril arms, respectively. Conclusion: The safety profile was similar in all treatment arms. In contrast to common perception, there was no difference in tolerability between the ACE-I and carvedilol. This result is even more remarkable as the high prestudy use of ACE-I (65%) might have introduced a bias by selecting ACE-I tolerant patients, who were only switched from their former ACE-I to enalapril.

Combining the Anti-EGFR Agent Gefitinib With Chemotherapy in Non–Small-Cell Lung Cancer: How Do We Go From INTACT to Impact?

Abstract: In this issue of the Journal of Clinical Oncology are the final results of two large phase III randomized controlled trials of the anti– epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib in combination with chemotherapy in untreated patients with advanced non–smallcell lung cancer (NSCLC) [1,2]. In these two trials, with more than 2,000 patients combined, the addition of gefitinib to chemotherapy failed to meet either the primary end point of survival or the secondary end points of time to disease progression or response rates. There was not even a suggestion of a nonsignificant trend in any of these end points in favor of gefitinib. In addition, a similar absence of benefit of two comparable phase III studies in NSCLC with erlonitib, another EGFR tyrosine kinase inhibitor, has been recently reported. The two gefitinib trials, INTACT 1 and 2, were well designed, adequately powered, and well conducted. The conclusion that concomitant gefitinib administration does not add clinical benefit to conventional chemotherapy in NSCLC seems, therefore, irrefutable. These results would not have been readily anticipated a priori for a series of reasons: first, gefitinib has demonstrated well-documented activity as a single agent in the initial phase I studies that included a large number of patients with NSCLC, and the antitumor activity of gefitinib has been confirmed in two large phase II studies in the secondand third-line setting, with response rates ranging from 9% to 18%, depending on the study and the dose [3,4]. Second, unlike with triplet chemotherapy combinations, full doses of chemotherapy could be given in combination with gefitinib, because no overlapping toxicities between gefitinib and chemotherapy have been observed in the phase I studies with these combinations. Third, available preclinical data for gefitinib combined with chemotherapy were impressively additive [5,6]. Given the outcome of the INTACT trials, it is obvious that some of these observations were incorrect or that some additional key determinants had not been taken into account. The first criticism of these trials is the lack of selection of the subset of patients likely to respond to gefitinib. Unlike trastuzumab, there are not available predictive markers of sensitivity to anti-EGFR agents; in fact, there is evidence of a lack of correlation between EGFR expression levels in the tumor and response to anti-EGFR agents, and a retrospective analysis of tumor samples from the gefitinib phase II single agent studies in NSCLC has confirmed this lack of correlation with gefitinib as well [7,8]. It is, therefore, possible that in a situation in which the responding phenotype to gefitinib has not been yet characterized, the molecular heterogeneity of lung cancer could have resulted in a false-negative result in the overall study population [9]. Although there was no evidence of patient enrichment in the phase II studies in favor of treatment sensitive subtypes or a suggestion of a negative effect in nonresponders, it would have been extremely important to have collected tumor samples to allow for post hoc clinical correlations, assuming a molecular signature of receptor sensitivity is identified. However, let us go back to the trastuzumab comparison. The initial pivotal studies with trastuzumab showed single-agent activity and improvement in survival when combined with chemotherapy in a suboptimal population because, in addition to patients with 3 HER2 overexpressing tumors, patients with 2 HER2 ovexpressing tumors were also included [10,11]; it is now known that 2 HER2 overexpressing, fluorescence in situ hybridization–negative tumors do not respond to trastuzumab [12]. The consequence was that the combined response rate in 2 and 3 HER2 overexpressing breast tumors to single agent trastuJOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 5 MARCH 1 2004

Treating cancer's kinase 'addiction'.

Abstract: When the tyrosine kinase inhibitor imatinib (Gleevec) was found to induce high remission rates in patients with chronic myeloid leukemia, this was hailed as a success for targeted tumor therapy. Since then, the repertoire of cancer types that respond to such inhibitors has expanded and researchers are beginning to grapple with the problem of acquired drug resistance. The activating kinase mutations targeted by these drugs can be viewed as the Achilles heel of cancer—they promote malignant progression, yet can turn cancer into a therapeutically exploitable disease.

Systemic sclerosis developing in association with the use of interferon alpha therapy for chronic viral hepatitis.

Abstract: In 1992 interferon alpha (IFNalpha) was approved by the FDA for the treatment of chronic viral hepatitis B and C. Since then IFNalpha has been implicated in the development of several autoantibodies as well as in the development or exacerbation of various autoimmune disorders. Herein, we describe a 47-year-old female who developed a limited form of systemic sclerosis (SSc) with lung involvement 6 months after the institution of IFNalpha therapy for chronic active hepatitis C. There was no family or personal history of autoimmune diseases. We speculate that the immunomodulatory effects of IFNalpha triggered the clinical manifestations of SSc in this patient. To our knowledge, this is the second case of SSc developing after therapy with IFNalpha and the first in a patient treated for chronic viral hepatitis C.

R3-survey of traumatic brain injury management in European Brain IT centres year 2001.

Abstract: To obtain knowledge about the conditions and management of traumatic brain injury (TBI) in a collaborative network of Brain Information Technology centres. The Brain IT (Brain monitoring with Information Technology) survey comprised two parts: local conditions and policies (part A), and a case study part (part B). The information was gathered by written questionnaires followed by telephone interviews. Twenty-four Brain IT centres participated (two respondents from 18 sites). The average proportion of agreement between duplicate respondents was 0.79 (range 0.44–1.00). All Brain IT centres monitored ICP. The reported order of treatment for intracranial hypertension was: evacuation of mass-lesions and head elevation (1), increase of sedation and Mannitol scheme (2), hyperventilation (3), ventricular drainage (4), craniectomy and pentothal coma (5), and decompressive lobectomy (6). The respondents were less prone to evacuate expansive contusions in relation to extra cerebral hematomas. The most common suggested interventions (alone or in combination) for treatment of intracranial hypertension without mass lesions was the Mannitol scheme (included in 71% of the suggestions), CSF drainage (included in 56%), hyperventilation (included in 32%), and pentothal coma (included in 22%). The suggested management of TBI was mainly in accordance with published guidelines, although a minor proportion of the answers deviated to some extent. The suggested order and combinations of different treatment interventions varied. Variation of treatment within the range of prescribed standards provides optimal conditions for an interesting future analysis of treatment and monitoring data as collected prospectively in a Brain IT database.

p21WAF1/Cip1 at the Switch Between the Anti-Oncogenic and Oncogenic Faces of TGF-beta

Abstract: Commentary to: p21 (WAF1/CIP1) Mediates the Growth Response to TGF-b in Human Epithelial Cells Kurtis E. Bachman, Brian G. Blair, Keith Brenner, Alberto Bardelli, Sabrina Arena, Shibin Zhou, Jessica Hicks, Angelo De Marzo, Pedram Argani and Ben Ho Park

Prospective study of methodological issues in intracranial pressure monitoring in patients with hydrocephalus.

Abstract: Object Continuous intracranial pressure (ICP) monitoring is performed in selected patients with hydrocephalus to determine whether shunt placement is required. The mean ICP is usually calculated from end-hour readings manually recorded by nurses. The aim of this study was to evaluate the accuracy of manual recordings by comparing nurses' end-hour ICP readings with those of an online computerized ICP monitoring system that records one ICP value per second. Methods Continuous ICP monitoring was performed using a fiberoptic extradural sensor in 115 patients with hydrocephalus of different origins. A notebook computer was connected to an ICP monitor and was programmed to register one ICP value per second. In all patients, mean ICP values were calculated from data recorded manually by nurses at the end of every hour and from data recorded by the computer within the preselected time period. The two methods were compared using correlation analysis and the Bland and Altman method. The median number of ICP values ...

Moderate hypothermia in the management of severe traumatic brain injury: a good idea proved ineffective?

Abstract: Many drugs with proven efficacy in the preclinical stage have failed to show any benefit in improving the outcome of severe traumatic brain injury (TBI) when tested in controlled clinical trials. Hypothermia is still the most powerful neuroprotective method in experimental models of TBI. Its ability to influence the multiple biochemical cascades that are set in motion after TBI is quite unique. In experimental models hypothermia protects against mechanical neuronal and axonal injury and improves behavioral outcome. Encouraging results from phase II and III clinical trials of hypothermia in TBI reported in the 1990s generated great enthusiasm. However, enthusiasm faded in 2001 after the final report of the multicenter phase III trial in which the neuroprotective effects of moderate hypothermia in TBI were formally tested. This study found no significant effect on outcome in the hypothermia group, leading many clinicians to lose interest in this therapy. The present article reviews the historical background of the use of hypothermia, presents the rationale for using both immediate and deferred hypothermia, and summarizes both experimental and clinical evidence supporting its potential benefits in the management of severe TBI. New technologies using intravascular methods to induce fast hypothermia have recently become available. Cooling either through the intravenous or intra-arterial route is an exciting alternative with great potential. We argue that moderate hypothermia is still the most powerful neuroprotective candidate for severe TBI and that it merits further research and discussion. We also defend the need for further clinical trials to prove or refute its potential for treating high intracranial pressure refractory to first level therapeutic measures. The premature abandonment of hypothermia could close new avenues for improving the devastating effects of TBI.

A Mutant Impaired in SNARE Complex Dissociation Identifies the Plasma Membrane as First Target of Synaptobrevin 2

Abstract: Membrane fusion depends on the formation of a complex of four SNARE motifs, three that bear a central glutamine and are localized in the target membrane (t-SNARE) and one that bears an arginine and is localized in the donor vesicle (v-SNARE). We have characterized the arginine 56 to proline mutant (R56P) of synaptobrevin-2 (Sb). SbR56P was blocked at the plasma membrane in association with the endogenous plasma membrane t-SNARE due to an inhibition of SNARE complex dissociation, suggesting that the plasma membrane is its first target. Cell surface blockade of SbR56P could be rescued by coexpression of synaptophysin, a partner of Sb. Sb was blocked at the plasma membrane but SNARE complexes were unaffected in cells expressing defective dynamin, indicating that the phenotype of SbR56P was not due to an internalization defect. When expressed in neurons, SbR56P localized both to axonal and dendritic plasma membranes, showing that both domains are initial targets of Sb. The R56P mutation affects a highly conserved position in v-SNAREs, and might thus provide a general tool for identifying their first target membranes.

Dynamics of chelation-supercritical fluid extraction from wood fibers.

Abstract: The dynamics of supercritical fluid extraction (SFE) of the metal content of wood fibers chelated with lithium bis(trifluoroethyl) dithiocarbamate (FDDC) by supercritical (SF) CO2 was investigated experimentally by monitoring the spectra of the eluted metal complex as a function of time. The characteristic shape of the dynamic SFE curve was determined mainly by the flow conditions in the extraction vessel, the mass transfer resistance in the SF phase, and the solubility. High extraction yields of metal content were obtained in two-stage extraction including static (batch) and dynamic (semi-batch) stages. Increasing the length of the static stage increased the rate of dynamic elution of metal complex until it approached the dynamics of fluid displacement for a continuous stirred tank reactor (CSTR). In such cases, increasing the flow rate had no effect on the dynamic extraction curve when it was plotted using dimensionless time. Efficient chelation-SFE from wood fibers was obtained at a pressure of 20.3 MPa and with a static time of 30 min.

The anti-epidermal growth factor receptor (EGFR) monoclonal antibody Cetuximab and the EGFR tyrosine kinase inhibitor Gefitinib, alone and in combination, induce a differential gene expression profile by cDNA microarray analysis in A431 cells

Abstract: 5333 Although molecular inhibitors of EGFR signaling carry high promise in cancer therapeutics, clinical trial results to date indicate that only a small subset of patients (10-20%) achieve objective tumor responses. To investigate potential mechanisms of resistance to EGFR inhibitors, acquired resistance has been established across a panel of human tumor cell lines. Specifically, we established in vitro resistance to cetuximab (ErbituxTM, C225), gefitinib (IressaTM, ZD1839) and erlotinib (TarcevaTM, OSI-774) in human head and neck (H&N) and lung cancer cell lines. Over a period of 6 months, tumor cells in culture were continuously exposed to increasing concentrations of either anti-EGFR mAb or receptor tyrosine kinase inhibitors (TKI). Concentrations commenced at the IC50 for a particular cell line and were doubled every 10-14 days up to the maximum tolerated dose level that enabled cell viability. Once fully established, we characterized the proliferative growth profiles for resistant versus parental cells to EGFR inhibitor challenge. Following exposure to high dose gefitinib (1 uM), erlotinib (1 uM) or cetuximab (100 nM) over 16 days, the parental cell populations showed significantly greater growth inhibition than that achieved in the resistant cell populations across all time points. Across the various tumor cell lines and EGFR inhibitors tested, we observed a 10 to 30-fold increase in the resultant IC50 values to EGFR inhibitor challenge for resistant cells. Flow cytometry analysis using propidium iodide staining demonstrated that TKI- resistant H&N cells failed to demonstrate the characteristic G1 cell cycle arrest following exposure to 0.5 uM of gefitinib or erlotinib that was common for parental cells. These results correlate with the higher proliferation rates observed in EGFR-resistant cells over that observed in parental cells. Interestingly, when cetuximab-resistant cells were exposed to gefitinib or erlotinib, a dose-dependent inhibition of cellular proliferation was observed not only in parental cells but also in cetuximab-resistant cells. Conversely, when gefitinib or erlotinib-resistant cells were exposed to varying concentrations of cetuximab, consistent growth inhibition was not observed. These preliminary results suggest that cross-resistance of TKI-resistant cells to mAb-challenge has been achieved, but not cross-resistance of mAb-resistant cells to TKI challenge. Additional studies to more fully characterize differences between the EGFR-resistant versus parental cell lines are in progress, as well as studies to explore the patterns and maintenance of EGFR resistance once the cell lines are established as xenografts in athymic mice. (Cetuximab was kindly provided by ImClone Systems, gefitinib by AstraZeneca, and erlotinib by OSI/Genentech/Roche).

Feasibility of CT scan-guided Tru-Cut serial liver biopsies to evaluate pharmacodynamic endpoints in patients with liver metastasis treated with experimental drugs

Abstract: We assessed the feasibility of using computed tomographically guided, Tru-Cut serial liver biopsies to perform pharmacodynamic studies in patients with liver metastasis who had been treated with experimental drugs. Twenty-three patients with liver metastasis were enrolled in two protocols for evaluation of the response to two new biologic drugs: a farnesyltransferase inhibitor and a tyrosine kinase inhibitor of the epidermal growth factor receptor. Computed tomographically guided Tru-Cut biopsies with an 18-gauge needle were performed. The procedure was performed at baseline and 2, 6, and 24 h after starting the administration of the drug. The procedures were scheduled on an outpatient basis. We obtained 271 samples (168 from metastatic lesions and 103 from surrounding normal liver tissue) from 23 patients. Biochemical determination of farnesyltransferase activity and different immunohistochemistry stainings (pEGRF, pMAPK, p27, Ki67, and apoptosis) of the signal transduction pathway were determined in each tissue sample, and all scheduled tissue assays were performed with the tissues obtained. Complete serial biopsies were performed in 20 patients. Three patients were excluded due to minor complications after the first biopsy. The morbidity rate in relation to the number of procedures was 1.1% (three of 271 samples). We found serial liver biopsies using Tru-Cut to be a safe and easy procedure. In our series, we could evaluate samples for molecular changes that influence the optimal dose, sequence, and schedule of the new antineoplastic agents.

Bidentate bonding mode of tetrahydroborate and nitrite towards copper(II) in open-faced macrocyclic complexes

Abstract: Novel seven-coordinate complexes formulated as [CuL(BH4)2], [CuL(BH4)(NO2)] and [CuL(NO2)2] (L = 1,4,7-triazacyclononane) have been prepared and structurally characterized by elemental analyses, spectroscopic data (u.v., i.r. and e.p.r.), magnetic susceptibility and conductivity measurements. The results reveal that the complexes are non-electrolytic. The coordination geometry around the copper(II) ion is a seven coordinated square pyramidal structure with three nitrogen atoms of the 1,4,7-triazacyclononane and either four hydrogen atoms of two bidentate tetrahydroborate groups or two hydrogen atoms of the bidentate tetrahydroborate group and two oxygen atoms of the bidentate nitrite group or four oxygen atoms of two bidentate nitrito groups. A cyclic voltammetric study on the complexes indicates an irreversible redox couple (CuII/CuI) in DMF, giving a voltage of ca. −0.37 V versus s.c.e.

Chemotherapy in resectable non-small cell lung cancer

Abstract: Although radical surgery is the primary treatment for early non-small cell lung cancer (NSCLC), the longterm survival of patients who undergo surgery alone is largely disappointing. More than half of those patients who present with stage I-IIIA disease and are resected will experience distant relapse. Postoperative adjuvant chemotherapy has been evaluated in several randomized trials but the results of these trials have been inconclusive with increased survival reported in few trials. However, the largest randomized adjuvant study presented to date, reported a 4.1% improvement in survival at 5 years, a benefit comparable to that observed using adjuvant chemotherapy in breast and colon cancer. A meta-analysis of new generation adjuvant trials is planned, it will include over 4,000 patients and will be of major relevance in this field. In resectable stage IIIA NSCLC the findings of randomized trials have indicated that the survival of these patients is better with neoadjuvant chemotherapy plus surgical resection than with resection alone. Phase II trials using preoperative concurrent chemoradiotherapy have been carried out with encouraging results. The majority of patients with stage IIIA NSCLC require multimodality therapy if they are to achieve a 5-year survival. Combined modality treatment in NSCLC continues to evolve and is a subject of ongoing research. Some data suggest that induction chemotherapy in stage I-II is feasible, does not appear to compromise surgery and yields high response rates. Neoadjuvant chemotherapy is potentially useful not only in locally advanced disease, but also in patients with earlier disease.

Ligation behaviour of tetrahydroborate and azide towards copper(II)

Abstract: A new complex formulated as [Cu(Pn)2(N3)(BH4)](Pn = 1,3-propanediamine) has been prepared and characterized. The results indicate that the tetrahydroborate and azide ions complete the coordination. The complex is octahedral and non-electrolytic. A cyclic voltammetric study shows that the complex exhibits a single one-electron redox couple (Cu2+/Cu+).