Showing papers by "Hebron University published in 2002"

Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types.

Abstract: PURPOSE: To establish the safety and tolerability of ZD1839 (Iressa), a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, and to explore its pharmacokinetic and pharmacodynamic effects in patients with selected solid tumor types. PATIENTS AND METHODS: This was a phase I dose-escalating trial of oral ZD1839 150 mg/d to a maximum of 1,000 mg/d given once daily for at least 28 days. Patients with either advanced non-small-cell lung, ovarian, head and neck, prostate, or colorectal cancer were recruited. RESULTS: Eighty-eight patients received ZD1839 (150 to 1,000 mg/d). At 1,000 mg/d, five of 12 patients experienced dose-limiting toxicity (grade 3 diarrhea [four patients] and grade 3 somnolence [one patient]). The most frequent drug-related adverse events (AEs) were acne-like rash (64%) and diarrhea (47%), which were generally mild (grade 1/2) and reversible on cessation of treatment. No change in ZD1839 safety profile was observed with prolonged administration. Pharmacokinetic analysis showed steady-state exposure to ZD1839 in 98% of patients by day 7. Nineteen patients had stable disease and received ZD1839 for >or= 3 months; seven of these patients remained on study drug for >or= 6 months. Serial skin biopsies taken before treatment and at approximately day 28 revealed changes indicative of inhibition of the EGFR signaling pathway. CONCLUSION: ZD1839 was generally well tolerated, with manageable and reversible AEs at doses up to 600 mg/d and dose-limiting toxicity observed at 1,000 mg/d. ZD1839 treatment resulted in clinically meaningful disease stabilization across a range of tumor types and doses. Pharmacodynamic changes in skin confirmed inhibition of EGFR signaling, which was predicted from the mode of action of ZD1839.

PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization.

Abstract: We have shown a novel mechanism of Akt-mediated regulation of the CDK inhibitor p27kip1. Blockade of HER2/neu in tumor cells inhibits Akt kinase activity and upregulates nuclear levels of the CDK inhibitor p27Kip1. Recombinant Akt and Akt precipitated from tumor cells phosphorylated wild-type p27 in vitro. p27 contains an Akt consensus RXRXXT157D within its nuclear localization motif. Active (myristoylated) Akt phosphorylated wild-type p27 in vivo but was unable to phosphorylate a T157A-p27 mutant. Wild-type p27 localized in the cytosol and nucleus, whereas T157A-p27 localized exclusively in the nucleus and was resistant to nuclear exclusion by Akt. T157A-p27 was more effective than wild-type p27 in inhibiting cyclin E/CDK2 activity and cell proliferation; these effects were not rescued by active Akt. Expression of Ser473 phospho Akt in primary human breast cancers statistically correlated with expression of p27 in tumor cytosol. These data indicate that Akt may contribute to tumor-cell proliferation by phosphorylation and cytosolic retention of p27, thus relieving CDK2 from p27-induced inhibition.

Pharmacodynamic Studies of the Epidermal Growth Factor Receptor Inhibitor ZD1839 in Skin From Cancer Patients: Histopathologic and Molecular Consequences of Receptor Inhibition

Abstract: PURPOSE: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 (Iressa; AstraZeneca Pharmaceuticals, Alderley Park, United Kingdom) is under development as an anticancer agent. We studied the pharmacodynamic effects of ZD1839 on EGFR in the skin, an EGFR-dependent tissue, in cancer patients participating in ZD1839 phase I clinical trials. PATIENTS AND METHODS: We studied 104 pre– and/or on–ZD1839 therapy (≈ at day 28 of therapy) skin biopsies from 65 patients receiving escalating doses of daily oral ZD1839. We measured ZD1839 effects on EGFR activation by immunohistochemistry using an antibody specific for the activated (phosphorylated) EGFR. Effects on receptor signaling (activated mitogen-activated protein kinase [MAPK]), proliferation, p27KIP1, and maturation were also assessed. RESULTS: Histopathologically, the stratum corneum of the epidermis was thinner during therapy (P < .001). In hair follicles, prominent keratin plugs and microorganisms were found in dilated infundibula. ZD1839 suppressed EGFR phosphorylation in all EGFR-expressing cells (P < .001). In addition, ZD1839 inhibited MAPK activation (P < .001) and reduced keratinocyte proliferation index (P < .001). Concomitantly, ZD1839 increased the expression of p27KIP1 (P < .001) and maturation markers (P < .001) and increased apoptosis (P < .001). These effects were observed at all dose levels, before reaching dose-limiting toxicities. CONCLUSION: ZD1839 inhibits EGFR activation and affects downstream receptor-dependent processes in vivo. These effects were profound at doses well below the one producing unacceptable toxicity, a finding that strongly supports pharmacodynamic assessments to select optimal doses instead of a maximum-tolerated dose for definitive efficacy and safety trials.

Pretreatment prognostic factors for survival in patients with advanced urothelial tumors treated in a phase I/II trial with paclitaxel, cisplatin, and gemcitabine

Abstract: BACKGROUND New chemotherapeutic agents, including paclitaxel and gemcitabine, are active in advanced bladder carcinoma, and combination regimens with these agents have shown promising results. Unlike conventional chemotherapy regimens, such as methotrexate, vinblastine, doxorubicin, and cisplatin, there are no data available on key predictive factors for response and survival with these novel agents. Since this information is needed for selection of patients for these new combinations and for stratification purposes in ongoing randomized trials, the authors aimed to study the predictive factors for response and survival to the current regimen containing cisplatin, paclitaxel, and gemcitabine. METHODS The authors studied 56 patients with advanced urothelial tumors treated on a Phase I/II trial of paclitaxel, cisplatin, and gemcitabine (TCG) to identify pretreatment characteristics that were prognostic for survival using this novel combination. The pretreatment characteristics analyzed were age, gender, Eastern Cooperative Oncology Group performance status, histopathology (pure transitional versus other), visceral (liver, lung, or bone) metastasis, number of sites of disease, lactate dehydrogenase, and hemoglobin. RESULTS The factors that were associated with a worse survival in univariate analysis were performance status > 0, presence of visceral metastasis, and more than one site of malignant disease. In a multivariate model, performance status (P = 0.044) and visceral disease (P = 0.008) showed independent statistical significance for decreased survival. Patients were then grouped based on these two independent prognostic factors. Median survival times in the groups of patients with zero, one, or two of these risk factors were 32.8 months, 17 months, and 9.6 months, respectively (P = 0.0005). CONCLUSIONS A pretreatment performance status > 0 and the presence of visceral metastasis have a profound impact on survival when using the TCG regimen. These two variables will be used to stratify patients in the upcoming Phase III randomized trial comparing this TGC regimen with a gemcitabine/cisplatin regimen in advanced urothelial tumors. Cancer 2002;95:751–7. © 2002 American Cancer Society. DOI 10.1002/cncr.10762

Fiberoptic intraparenchymal brain pressure monitoring with the Camino V420 monitor: reflections on our experience in 163 severely head-injured patients.

Abstract: To assess the safety and accuracy of the Camino intraparenchymal sensor, we prospectively evaluated hemorrhagic complications, zero-drift, infection, and system malfunction in 163 patients monitored after a severe head injury. Mean duration of intracranial pressure (ICP) monitoring was 5 ± 2.2 days (range: 12 h to 11 days). Of the 141 patients with a control CT scan, four showed a 1-2-cc collection of blood at the catheter's end. When removed, the sensors underread the true ICP value (negative zero-drift) in 80 of the 126 sensors evaluated (63.5%). Fourteen sensors showed no zero-drift, and 32 sensors overread the true ICP value (positive zero-drift) (median: -1 mm Hg; interquartile range: -4 to +1 mm Hg). No significant relationship was found between zero-drift, the surgeon who implanted the sensor, intracranial hypertension, or duration of ICP monitoring. No clinical infections could be attributed to the devices. Sixteen patients (9.8%) required more than one ICP sensor due to malfunctioning of the syst...

Panniculitis: A cutaneous manifestation of dermatomyositis

Abstract: Specific and nonspecific panniculitis sometimes occurs during the course of connective tissue diseases However, the association of panniculitis and dermatomyositis (DM) has only rarely been described Previous reports have suggested that panniculitis may be an inherent part of DM but, because the cases reported are few, it is difficult to know the significance of this unusual association We describe 2 patients with DM in whom panniculitis developed during the course of the disease, and discuss its clinical and diagnostic significance

Montelukast and Churg-Strauss syndrome

Abstract: Several cases of eosinophilic conditions including Churg-Strauss syndrome (CSS) have recently been reported in asthmatic patients being treated with antileukotriene receptor antagonists. One patient with CSS who experienced a clinical relapse after treatment with montelukast and two asthmatic patients who developed CSS while receiving montelukast treatment are described. In one case reduction in the dose of oral steroid preceded the onset of CSS. To our knowledge, no case of CSS relapse has previously been reported in association with leukotriene antagonists.

Results of an orthopaedic survey in young patients with severe haemophilia in Spain

Abstract: Summary. This paper outlines the results obtained in a cross-sectional study of a group of young patients with severe haemophilia A and B. The primary aim of the study was to ascertain the level of orthopaedic complications in the group, the effects that these complications have on quality of life, and the medical resources used on these patients. The secondary aim was to relate their current orthopaedic state to the type of treatment received before the study. The study was carried out in 11 hospitals in Spain, where 70 severe haemophilia patients (factor VIII [FVIII] < 2%), with an average age of 21.6 and a median age of 22, and no inhibitors, were monitored. The percentage of patients suffering from articular complaints was 84.3% and 85.7% according to the Gilbert and Petterson scales, respectively. Furthermore, pain was reported in 16.1% of joints, most frequently in ankles. Using the SF-36 Health Survey, patients were observed to have a poorer quality of life relative to healthy controls. Despite high levels of both the coagulant factor given to patients and the financial resources dedicated to their treatment, the type of treatment (on demand and/or as secondary prophylaxis) provided to the young adults was found to be incapable of preventing haemophilic arthropathy and subsequent negative quality of life consequences.

Diffuse axonal injury after head trauma. A review.

Abstract: Traumatic brain injury is a major health problem in all developed countries. Because of the long-term disabilities suffered by head-injured patients, such injuries are a continuous organizational challenge for health systems and a burden for community and families in terms of monetary cost, suffering and disability (Fearnside MR et al. 1997).

Agreement Between CSF Flow Dynamics in MRI and ICP Monitoring in the Diagnosis of Normal Pressure Hydrocephalus. Sensitivity and Specificity of CSF Dynamics to Predict Outcome

Abstract: Objectives The aims of the study were 1) to assess the degree of agreement between CSF flow dynamics determined by MR and ICP monitoring in the diagnosis of NPH, and 2) to determine the sensitivity and specificity of CSF flow dynamics studied by MR in predicting improvement after shunting.

Spinal anaesthesia for inguinal herniotomy in preterm infants sedated with nitrous oxide: a comparison of lumbar puncture in the lateral or sitting position.

Abstract: This study compares spinal anaesthesia for inguinal herniotomy in preterm infants in the lateral or sitting position. Thirty patients were randomly divided into two equal groups. One hour before spinal anaesthesia, a eutetic mixture of local anaesthetic cream was applied to the lower lumbar spine. Sedation with nitrous oxide 50% in oxygen was given to all patients before and during induction of spinal anaesthesia, and throughout surgery. Lumbar punctures were performed at the L4-5 interspace using a 2.5 cm 22 G needle. Isobaric bupivacaine 0.5% with epinephrine 1 : 200 000 at a bupivacaine dose of 1 mg.kg-1 was injected in the lateral or sitting position. Measurements included heart rate, blood pressure, oxygen saturation, maximum sensory block height and duration of motor block and analgesia. There were no statistically significant differences between the groups in any measured parameters. Median [range] maximum block height was T5[T4-T7] in the lateral group and T5[T4-T5] in the sitting group. The median [range] duration of motor blockade was 67 [50-85] min in the lateral group and 63 [50-80] min in the sitting group. Our results indicate that in preterm infants sedated with nitrous oxide, spinal anaesthesia for inguinal herniotomy performed with isobaric bupivacaine 0.5% at a dose 1.0 mg.kg-1 in the lateral or sitting position is equally effective and is associated with minimal side effects.

Effect of Plant Growth Regulators on White Mould (Sclerotinia sclerotiorum) on Bean and Cucumber

Abstract: The effect of plant growth regulators on the pathogenic fungus Sclerotinia sclerotiorum (white mould) was investigated under in vitro and in vivo conditions. Naphthalene acetic acid inhibits the fungus in vitro and in vivo.It reduced white mould disease severity on bean and cucumber plants at concentrations of 200–400 lg/ml.Gibberellic acid (GA 3) promoted both mycelium and white mould disease severity on plants at concentrations of 50–250 lg/ml.Methyl jasmonate (MeJa), and abscisic acid (ABA) decreased mycelium growth of S. sclerotiorum in vitro.MeJa decreased bean and cucumber white mould disease at concentrations of 75–250 lg/ml.ABA increased disease development on bean and cucumber plants at concentrations of 100–300 lg/ml.

Coexistence of regional cerebral hypoxia with normal or hyperemic brain detected by global monitoring methods. Analysis of apparently contradictory findings based on the Siggaard-Andersen model of tissue hypoxia.

Abstract: The aim of our study was to perform and in—depth analysis of several episodes of regional brain hypoxia detected by monitoring brain partial pressure of oxygen (PtiO2) in which simultaneous measurements of cerebral oxygen extraction fraction (O2EF) suggested a normally perfused or even a hyperemic brain. To gain deeper insight into these episodes, we used the model of tissue hypoxia described by Siggaard—Andersen. In 244 simultaneous measurements, 31 episodes (12.7%) of brain hypoxia (PtiO2 < 15 mmHg) were detected simultaneously with an O2EF within the normal range or below the lowest normal percentile. Using Siggaard—Andersen methodology, we classified 6 episodes (19%) as high—affinity hypoxia and 25 (81%) as shunt hypoxia or dysperfusion hypoxia. Siggaard—Andersen’s comprehensive classification of tissue hypoxia can be used as an integrative model to build coherent algorithms for diag—nosing and managing neurocritical patients that are at risk of brain hypoxia due to either intracranial or extracranial conditions.

Intracranial hypertension after surgery in patients with Chiari I malformation and normal or moderate increase in ventricular size.

Abstract: Objective To determine ICP changes in patients with Chiari type I malformation after posterior fossa reconstruction (PFR).

Monitoring of partial pharyngeal reconstruction.

Abstract: INTRODUCTION The goal in pharyngeal surgery is to achieve surgical margins free of tumor. In some cases it is necessary to perform a wide pharyngectomy that is difficult to close without a reconstructive procedure. In our centers we use the radial forearm free flap when pharyngeal reconstruction is necessary. This is a pliable, thin flap with a large pedicle that makes the reconstruction and the microvascular anastomosis easy to perform. In reconstruction of pharyngeal defects with free flaps, the location of the flap is inconvenient for visual monitoring. Usual monitoring techniques are direct visualization, Doppler ultrasound, laser Doppler, and fluorescein injections. Clinical assessment of the flap is the method of choice, although this is not always possible. For the monitoring of total pharyngectomy, we have been using the design of Urken et al. with a small segment to be monitored connected to the primary skin paddle by a fascial subcutaneous segment of tissue. This monitor segment is exteriorized in the neck to provide clinical monitoring of the flap. Because of the inconvenience of this segment, we tried to find a simpler method for monitoring cases in which we employed the radial forearm flap for pharyngeal reconstruction.