bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of Coagulation Cascade and Endothelial Cell Activation During Inhibition of Vascular Endothelial Growth Factor/Vascular Endothelial Growth Factor Receptor Pathway in Cancer Patients
Authors: Kuenen B.C. , Levi M. , Meijers J.C.M. , Kakkar A.K. , van Hinsbergh V.W.M. , Kostense P.J. , Pinedo H.M. , Hoekman K.
Published: September 2002

Objective—

The angiogenesis inhibitor SU5416 is a potent inhibitor of vascular endothelial growth factor (VEGF) receptor-1 and -2. VEGF may be involved in hemostasis by altering the hemostatic properties of endothelial cells. We analyzed the effects of SU5416 on the coagulation cascade and the vessel wall in patients with advanced cancer.

Methods and Results—

Markers for thrombin generation, activation of the protein C pathway, fibrinolysis, and endothelial cell activation were measured in patients with renal cell carcinoma, soft tissue sarcoma, or melanoma on days 0, 14, and 28 of treatment with SU5416. Three of 17 sampled patients developed a thromboembolic event in the fifth week of treatment. Markers for thrombin generation and fibrinolysis did not show significant changes. We observed a significant increase in endogenous thrombin potential and of parameters reflecting endothelial cell activation (von Willebrand antigen, soluble tissue factor, and soluble E-selectin) in all patients (
P
≤0.001). In patients experiencing a thromboembolic event, endogenous thrombin potential, soluble tissue factor, and soluble E-selectin increased to a significantly greater extent (
P
=0.029,
P
=0.021, and
P
=0.007, respectively).

Conclusions—

VEGF is not only a permeability, proliferation, and migration factor, but it is also a maintenance and protection factor for endothelial cells.
Microsomal Triglyceride Transfer Protein Gene Expression and Triglyceride Accumulation in Hypoxic Human Hearts
Authors: Nielsen Lars B. , Perko Mario , Arendrup Henrik , Andersen Claus B.
Published: September 2002

Objectives—

Cardiac myocytes secrete apolipoprotein (apo)B-containing lipoproteins. Their function may be the removal of triglycerides when β-oxidation of fatty acids is decreased, eg, during hypoxia. To test this hypothesis, we examined heart biopsies from patients undergoing coronary artery bypass graft (CABG, n=13) or valve replacement (n=6) surgery.

Methods and Results—

Ventricular microsomal triglyceride transfer protein (
P
=0.02) and apoB (
P
=0.04) mRNA levels were both ≈2-fold higher in CABG compared with valve replacement patients. In CABG patients, ventricular microsomal triglyceride transfer protein mRNA levels were negatively associated with the triglyceride content in ventricular myocytes (
r
=−0.70;
P
=0.02) and with mRNA levels of sterol regulatory element binding protein-1 (
r
=−0.74;
P
=0.004).

Conclusions—

The results are compatible with the notion that cardiac lipoprotein production is increased in hypoxic human ventricle, possibly as a result of decreased sterol regulatory element binding protein-1 expression. This might attenuate accumulation of triglycerides in cardiac myocytes.
Plasmin Induces
Cyr61
Gene Expression in Fibroblasts Via Protease-Activated Receptor-1 and p44/42 Mitogen-Activated Protein Kinase–Dependent Signaling Pathway
Authors: Pendurthi Usha R. , Ngyuen Mylinh , Andrade-Gordon Patricia , Petersen Lars C. , Rao L. Vijaya Mohan
Published: September 2002

Objective—

The plasminogen system has been proposed to participate in vascular remodeling and angiogenesis. Although plasmin-mediated proteolysis could contribute these processes, proteolytic targets for plasmin and their downstream effector molecules are yet to be fully defined. The aim of the present study was to elucidate potential mechanisms by which plasmin affects various cellular processes.

Methods and Results—

Plasmin upregulated the expression of
Cyr61
, a growth factor–like gene that has been implicated in cell proliferation, adhesion, and migration. Plasmin-induced gene expression is dependent on its proteolytic activity and requires its binding to cells. Studies that used wild-type fibroblasts and fibroblasts derived from PAR-1– and PAR-2–deficient mice showed that plasmin induced
Cyr61
gene expression in wild-type fibroblasts and PAR-2–deficient cells but not in PAR-1–deficient cells. Consistent with this, plasmin induced the activation of p44/42 mitogen-activated protein kinase in wild-type, PAR-2 −/− cells but not in PAR-1 −/− cells. In contrast with thrombin, plasmin failed to induce Ca
2+
signaling in fibroblasts.

Conclusions—

Plasmin induced an angiogenic and wound-healing promoter, Cyr61, in fibroblasts through activation of PAR-1. Plasmin-induced
Cyr61
expression is mediated via the p44/42 mitogen-activated protein kinase pathway independent of Ca
2+
signaling.
Quantitative Trait Loci and Candidate Genes Regulating HDL Cholesterol
Authors: Wang Xiaosong , Paigen Beverly
Published: September 2002

Objective—Summarizing the many discovered mouse and human quantitative trait loci (QTL) for high density lipoprotein (HDL) cholesterol (HDL-C) levels is important for guiding future research on the genetic regulation of HDL concentrations and for finding gene targets for upregulating HDL levels in mice and humans.

Methods and Results—We summarized the 27 QTL and candidate genes associated with HDL-C concentrations in mice and plotted them on a mouse chromosome map. We also summarized the 22 human QTL for HDL-C levels and compared them with those of the mouse by comparative genomics. At least part of the mouse homologies for 18 of the 22 human HDL-C QTL were within the murine HDL-C QTL.

Conclusions—Murine QTL for HDL-C levels may predict their homologous location in humans, and their underlying genes may be appropriate genes to test in humans.
Inhibition of Accelerated Atherosclerosis in Vein Grafts by Placement of External Stent in ApoE*3-Leiden Transgenic Mice
Authors: Lardenoye J.H.P. , de Vries M.R. , Grimbergen J.M. , Havekes L.M. , Knaapen M.W.M. , Kockx M.M. , van Hinsbergh V.W.M. , van Bockel J.H. , Quax P.H.A.
Published: September 2002

Objective—

Vein grafts fail because of the development of intimal hyperplasia and accelerated atherosclerosis. Placement of an external stent around vein grafts resulted in an inhibition of intimal hyperplasia in several animal studies. Here, we assess the effects of external stenting on accelerated atherosclerosis in early vein grafts in carotid arteries in hypercholesterolemic apolipoprotein E*3-Leiden transgenic mice.

Methods and Results—

Venous interposition grafting was performed in apolipoprotein E*3-Leiden mice fed standard chow or a highly cholesterol-rich diet for 4 weeks. After engraftment, external stents with different inner diameters (0.4 or 0.8 mm) were placed. In unstented vein grafts in hypercholesterolemic mice, thickening up to 50 times the original thickness, with foam cell–rich lesions, calcification, and necrosis, was observed within 28 days. The atherosclerotic lesions observed show high morphological resemblance to atherosclerotic lesions observed in human vein grafts. In stented vein grafts in hypercholesterolemic mice, no foam cell accumulation or accelerated atherosclerosis was observed. Compared with unstented vein grafts, stenting of vein grafts in a hypercholesterolemic environment resulted in a 94% reduction of vessel wall thickening. These effects were independent of stent size.

Conclusions—

Extravascular stent placement results in strong inhibition of accelerated vein graft atherosclerosis in hypercholesterolemic transgenic mice and thereby provides a perspective for therapeutic intervention in vein graft diseases.
Statins Reduce Inflammation in Atheroma of Nonhuman Primates Independent of Effects on Serum Cholesterol
Authors: Sukhova Galina K. , Williams J. Koudy , Libby Peter
Published: September 2002

Objective—

Some of the statin-induced reduction in cardiac events in patients with atherosclerosis may be derived from mechanisms independent of lipid lowering. This study tested in nonhuman primates whether statins can influence inflammation (indicated by vascular cell adhesion molecule-1, interleukin-1β, tissue factor, and macrophages) and features of plaque stability (indicated by collagen and smooth muscle cells) independent of their effect on plasma cholesterol level.

Methods and Results—

Adult male cynomolgus monkeys (n=12 per group) consumed an atherogenic diet for 12 months while receiving (1) no treatment (control), (2) pravastatin (Prava, 40 mg/kg per day), or (3) simvastatin (Simva, 20 mg/kg per day). Dietary cholesterol was adjusted to equalize plasma cholesterol levels among groups. Although the intima/media ratio in the abdominal aorta did not differ among groups, drug treatment reduced inflammation and features of plaque vulnerability. Macrophage content in the lesions of statin-treated animals was lowered (2.4-fold with Prava and 1.3-fold with Simva; both P<0.001 versus control). Furthermore, lesions had ≈2-fold less vascular cell adhesion molecule-1, interleukin-1β, and tissue factor expression in statin-treated versus control animals (
P
<0.005). Lesional smooth muscle cell and collagen content was 2.1-fold greater in the Prava-treated group (
P
<0.001) and 1.5-fold greater in the Simva-treated group (
P
<0.005) than in the control group.

Conclusions—

In primates, these results provide further support for the beneficial effect of statins on plaque inflammation and stability in addition to cholesterol lowering.
Platelets and Thrombin Generation
Authors: Monroe Dougald M. , Hoffman Maureane , Roberts Harold R.
Published: September 2002

This review examines the evidence that platelets play a major role in localizing and controlling the burst of thrombin generation leading to fibrin clot formation. From the first functional description of platelets, it has been recognized that platelets supply factors that support the activation of prothrombin. Studies have demonstrated that on activation, the amount of one specific lipid, phosphatidylserine, is significantly increased on the outer leaflet of platelet membranes. When it was found that phosphatidylserine containing lipid extracts could be substituted for platelets in clotting assays, this suggested the possibility that changes in platelet lipid composition were necessary and sufficient to account for platelet surface thrombin generation. Because a growing body of data suggest that platelet-binding proteins provide much of the specificity for platelet thrombin generation, we review in this report data suggesting that changes in lipid composition are necessary but not sufficient to account for platelet surface regulation of thrombin generation. Also, we review data suggesting that platelets from different individuals differ in their capacity to generate thrombin, whereas platelets from a single subject support thrombin generation in a reproducible manner. Individual differences in platelet thrombin generation might be accounted for by differences in platelet-binding proteins.
Progression of Atheroma
Authors: Geng Yong-Jian , Libby Peter
Published: September 2002

Traditional thinking accorded a major role to deranged cell proliferation as a determinant of the abnormal cellularity of atheroma. However, studies conducted in several laboratories have documented the occurrence of disordered apoptosis during atherogenesis, leading to the death of lipid-rich foam cells (promoting lipid-core formation) and depletion of vascular smooth muscle cells (fostering fragility of the fibrous cap). A complex interplay of environmental factors and endogenous proteins regulates apoptosis and contributes to the struggle between cell death and procreation in atherosclerosis. In addition to a variety of growth factors, chemically modified lipids, reactive oxygen species, proinflammatory cytokines, and Fas ligand produced by activated immune cells may influence cell viability through a diversity of pathways, including the caspase cascade, the Bcl-2 protein family, and the oncogene/antioncogene system. A clarification of the molecular mechanisms responsible for vascular cell death may aid in the development of novel therapeutic strategies to treat atherosclerosis and its complications, including the acute coronary syndromes.
Relationship Between Cholesteryl Ester Transfer Protein and Atherogenic Lipoprotein Profile in Morbidly Obese Women
Authors: Ebenbichler C.F. , Laimer M. , Kaser S. , Ritsch A. , Sandhofer A. , Weiss H. , Aigner F. , Patsch J.R.
Published: September 2002

Objective—

Obesity is associated with increased morbidity and mortality from atherosclerotic disease. Lipid abnormalities contribute to the increased relative risk in obese subjects. Cholesteryl ester transfer protein (CETP) mass is increased in these patients and might mediate the atherogenic lipoprotein pattern observed in obesity.

Methods and Results—

Twenty-one morbidly obese, middle-aged, female subjects participated in this prospective study. Subjects were examined before and 1 year after surgical treatment. Fat mass was determined by body impedance analysis; CETP mass, by ELISA; CETP activity, by exogenous substrate assay; and LDL particle diameter, by gradient gel electrophoresis. Mean weight loss after 1 year was 28.7 kg; mean fat mass loss was 22.6 kg. Mean CETP mass decreased from 1.81 to 1.32 μg/mL (
P
=0.008); mean CETP activity decreased from 244 to 184 nmol · mL
−1
· h
−1
(
P
=0.004); and in parallel, the mean diameter of LDL particles increased (256.8 to 258.4 Å,
P
=0.04).

Conclusions—

We conclude that weight loss is associated with a pronounced decrease in CETP mass and activity and a consistent increase in LDL particle diameter. After 1 year of this prospective study in morbidly obese subjects undergoing weight loss by surgical treatment, it has been determined that some features of the atherogenic lipoprotein profile can be reversed.
A Species Conserving Genetic Algorithm for Multimodal Function Optimization
Authors: Li Jian-Ping , Balazs Marton E. , Parks Geoffrey T. , Clarkson P. John
Published: September 2002

This paper introduces a new technique called species conservation for evolving paral-lel subpopulations. The technique is based on the concept of dividing the population into several species according to their similarity. Each of these species is built around a dominating individual called the species seed. Species seeds found in the current gen-eration are saved (conserved) by moving them into the next generation. Our technique has proved to be very effective in finding multiple solutions of multimodal optimiza-tion problems. We demonstrate this by applying it to a set of test problems, including some problems known to be deceptive to genetic algorithms.
Modeling the Dynamics of Ant Colony Optimization
Authors: Merkle Daniel , Middendorf Martin
Published: September 2002

The dynamics of Ant Colony Optimization (ACO) algorithms is studied using a deterministic model that assumes an average expected behavior of the algorithms. The ACO optimization metaheuristic is an iterative approach, where in every iteration, artificial ants construct solutions randomly but guided by pheromone information stemming from former ants that found good solutions. The behavior of ACO algorithms and the ACO model are analyzed for certain types of permutation problems. It is shown analytically that the decisions of an ant are influenced in an intriguing way by the use of the pheromone information and the properties of the pheromone matrix. This explains why ACO algorithms can show a complex dynamic behavior even when there is only one ant per iteration and no competition occurs. The ACO model is used to describe the algorithm behavior as a combination of situations with different degrees of competition between the ants. This helps to better understand the dynamics of the algorithm when there are several ants per iteration as is always the case when using ACO algorithms for optimization. Simulations are done to compare the behavior of the ACO model with the ACO algorithm. Results show that the deterministic model describes essential features of the dynamics of ACO algorithms quite accurately, while other aspects of the algorithms behavior cannot be found in the model.
Combining Convergence and Diversity in Evolutionary Multiobjective Optimization
Authors: Laumanns Marco , Thiele Lothar , Deb Kalyanmoy , Zitzler Eckart
Published: September 2002

Over the past few years, the research on evolutionary algorithms has demonstrated their niche in solving multiobjective optimization problems, where the goal is to find a number of Pareto-optimal solutions in a single simulation run. Many studies have depicted different ways evolutionary algorithms can progress towards the Pareto-optimal set with a widely spread distribution of solutions. However, none of the multiobjective evolutionary algorithms (MOEAs) has a proof of convergence to the true Pareto-optimal solutions with a wide diversity among the solutions. In this paper, we discuss why a number of earlier MOEAs do not have such properties. Based on the concept of ɛ-dominance, new archiving strategies are proposed that overcome this fundamental problem and provably lead to MOEAs that have both the desired convergence and distribution properties. A number of modifications to the baseline algorithm are also suggested. The concept of ɛ-dominance introduced in this paper is practical and should make the proposed algorithms useful to researchers and practitioners alike.
Improved Sampling of the Pareto-Front in Multiobjective Genetic Optimizations by Steady-State Evolution: A Pareto Converging Genetic Algorithm
Authors: Kumar Rajeev , Rockett Peter
Published: September 2002

Previous work on multiobjective genetic algorithms has been focused on preventing genetic drift and the issue of convergence has been given little attention. In this paper, we present a simple steady-state strategy, Pareto Converging Genetic Algorithm (PCGA), which naturally samples the solution space and ensures population advancement towards the Pareto-front. PCGA eliminates the need for sharing/niching and thus minimizes heuristically chosen parameters and procedures. A systematic approach based on histograms of rank is introduced for assessing convergence to the Pareto-front, which, by definition, is unknown in most real search problems. We argue that there is always a certain inheritance of genetic material belonging to a population, and there is unlikely to be any significant gain beyond some point; a stopping criterion where terminating the computation is suggested. For further encouraging diversity and competition, a nonmigrating island model may optionally be used; this approach is particularly suited to many difficult (real-world) problems, which have a tendency to get stuck at (unknown) local minima. Results on three benchmark problems are presented and compared with those of earlier approaches. PCGA is found to produce diverse sampling of the Pareto-front without niching and with significantly less computational effort
Spatial prediction in hydrology: status and implications in the estimation of hydrological processes for applied research
Authors: Mendoza Manuel , Bocco Gerardo , Bravo Miguel
Published: September 2002

Based on a review of research, the linkages between distributed hydrological modelling (DHM) remote sensing (RS) and geographical information system (GIS) techniques, coupled with geomorphological knowledge are discussed. While presenting characteristics of the models, techniques, and supporting analytical tools of geographical hydrology, the emphasis is on the estimation of hydrological variables. The first is limited to the spatialization and integration of low resolution meteorological data with hydrological models in a GIS environment. The second includes research in the calculation of precipitation, evapotranspiration, radiation, etc., from the digital analyses of remote sensing data, to feed either lumped or spatially distributed models. The third links the tools of GIS and RS with hydrological modelling; usually it makes intensive use of the tools of GIS for several scales of spatial modelling. The last group integrates GIS, RS and hydrological modelling supported by the delimitation and characterization of environmental units, generally to detailed and semi-detailed scales.
Landscapes, space and equilibrium: shifting viewpoints
Authors: Perry George L.W.
Published: September 2002

The classical view of ecological systems has been one that assumes a state of equilibrium and stability; this is encapsulated in the ‘balance of nature’ paradigm. Over the last 30 years ecologists and biogeographers have rejected the view that ecological systems are inherently stable or at some sort of equilibrium. Instead a nonequilibrium view, emphasizing the role of chance events such as disturbance in ecological dynamics, has become dominant. Alongside this change, the way in which the roles of space and spatial heterogeneity in ecological dynamics are viewed has shifted. Classical ecological theory tended to ignore spatial dynamics and heterogeneity and focused instead on temporal pattern. Over the last 20 years this view has also changed and the importance of spatial pattern has been emphasized. Through the explicit consideration of space and spatial pattern it has been shown that spatial heterogeneity may act to either stabilize or destabilize ecological systems and processes. This paper reviews these two changes in the way ecological systems are conceptualized and explores how they are inter-related. Advances in our understanding of the role of space and the nature of equilibrium in ecological systems are discussed within the context of both modelling and empirical studies, as are the problems involved with experimentally testing the large body of spatial theory developed.
Emergence and evolution of Himalaya: reconstructing history in the light of recent studies
Authors: Valdiya K. S.
Published: September 2002

India collided with mainland Asia at 65 Ma. The pressure rose to 9-11 kbar in the collision zone. As the Indian lithosphere bent down and its upper crust buckled up as an upwarp in the period 35-45 Ma, the southern margin of Asia became the water-divide of the Himalayan rivers. A variety of Eurasian fauna migrated to the Indian landmass. The southern margin of the Himalayan province synchronously sagged to give rise to the foreland basin that was linked with the Indian sea. In this Paleocene foreland basin 48-49 Ma ago, the whales from one of the species of the immigrant terrestrial mammals evolved. The sea retreated from the Himalayan province by the early Miocene, even as the crust broke up along faults 20-22 million years ago. The basement rocks, which had attained high-grade metamorphism at 600-800°C and 6-10 kbar, were thrust up to give rise to what later became the Himādri or Great Himalaya. Differential melting of the high-grade metamorphic rocks of the Himadri extensively produced 21 ± 1 Maold granites.

Rivers carried detritus generated by the denudation of the fast emerging Himalaya and deposited it in the foreland basin which turned fluvial around 23 Ma. Another fluvial foreland basin, the Siwalik, was formed at ~18 Ma in front of the rapidly rising orogen and was filled by river-borne sediments at the rate of 20-30 cm year-1in the early stage and at 50-55 cm year-1later when the Himadri was uplifted and briskly exhumed in the Late Miocene (9-7.5 Ma). The Himadri then became high enough to cause disruption of wind circulation, culminating in the onset of monsoon. The climate change that followed caused migration of a variety of quadrupeds from Africa and Eurasia, bringing about considerable faunal turnovers in the Siwalik life.

Spasmodic uplift of the outer ranges of the Lesser Himalaya and tectonic convulsion in the Siwalik domain at 1.6 Ma resulted in widespread landslides with debris flows and emplacement of the Upper Siwalik Boulder Conglomerate. Strong tectonic movements at 0.8 Ma caused the partitioning of the foreland basin into the rising Siwalik Hills and the subsiding IndoGangetic Plains, and also the initiation of glaciation in the uplifted domain of the Great Himalaya. After the end of the Pleistocene ice age around 0.2 Ma, there was oscillation of dry-cold and wet-warm climates. This climatic vicissitude is recorded in the sediments of the lakes that had formed because of reactivation of faults crossing rivers and streams. Activeness of faults, continuing uplift and current seismicity imply ongoing strain-buildup in the Himalayan domain.
Mechanisms and Future Directions for Angiogenesis-Based Cancer Therapies
Authors: Scappaticci Frank A.
Published: September 2002

ABSTRACT: Targeting angiogenesis represents a new strategy for the development of anticancer therapies. New targets derived from proliferating endothelial cells may be useful in developing anticancer drugs that prolong or stabilize the progression of tumors with minimal systemic toxicities. These drugs may also be used as novel imaging and radiommunotherapeutic agents in cancer therapy. In this review, the mechanisms and control of angiogenesis are discussed. Genetic and proteomic approaches to defining new potential targets on tumor vasculature are then summarized, followed by discussion of possible antiangiogenic treatments that may be derived from these targets and current clinical trials. Such strategies involve the use of endogenous antiangiogenic agents, chemotherapy, gene therapy, antiangiogenic radioligands, immunotherapy, and endothelial cell-based therapies. The potential biologic end points, toxicities, and resistance mechanisms to antiangiogenic agents must be considered as these therapies enter clinical trials.
Lack of Expression of Galectin-3 Is Associated With a Poor Outcome in Node-Negative Patients With Laryngeal Squamous-Cell Carcinoma
Authors: Piantelli Mauro , Iacobelli Stefano , Almadori Giovanni , Iezzi Manuela , Tinari Nicola , Natoli Clara , Cadoni Gabriella , Lauriola Libero , Ranelletti Franco O.
Published: September 2002

PURPOSE: Galectin-3 is a pleiotropic carbohydrate-binding protein participating in a variety of normal and pathologic processes, including cancer progression. This study was aimed at evaluating the prognostic value of galectin-3 expression in node-negative laryngeal squamous-cell carcinoma (SCC).

PATIENTS AND METHODS: Galectin-3 expression was analyzed by immunohistochemistry using M3/38 monoclonal antibody, in a single-institution series of 73 node-negative laryngeal SCC patients (median follow-up, 52 months; range, 2 to 90 months).

RESULTS: Forty-two (57.5%) of 73 patients expressed galectin-3. Galectin-3 expression was positively associated with tumor keratinization and histologic grade. A significant correlation was found between galectin-3 tumor positivity and longer relapse-free and overall survival. In univariate analysis, high-grade (grade 3 or 4) tumors, nonkeratinizing tumors, and galectin-3–negative tumors showed a significantly increased risk of relapse and death. In multivariate analysis, only galectin-3 expression retained an independent prognostic significance for both relapse-free and overall survival.

CONCLUSION: We conclude that the absence of galectin-3 expression is an independent negative prognostic marker in laryngeal SCC patients. Thus, histochemical detection of galectin-3 in these tumors could be useful for the selection of node-negative patients with potentially unfavorable outcomes, to establish adjuvant therapy protocols.
Pegylated Interferon Alfa-2b Treatment for Patients With Solid Tumors: A Phase I/II Study
Authors: Bukowski Ronald , Ernstoff Marc S. , Gore Martin E. , Nemunaitis John J. , Amato Robert , Gupta Samir K. , Tendler Craig L.
Published: September 2002

PURPOSE: The efficacy of interferon alfa has been established in treating advanced melanoma and renal cell carcinoma (RCC) patients. We conducted a phase I/II study to determine the maximum-tolerated dose (MTD), the safety and tolerability, and the preliminary efficacy of once-weekly pegylated interferon alfa-2b (IFNα-2b) in patients with advanced solid tumors (primarily RCC).

PATIENTS AND METHODS: To determine the MTD, 35 patients with a variety of advanced solid tumors received 0.75 to 7.5 μg/kg/wk of pegylated IFNα-2b by subcutaneous injection for 12 weeks. An additional 35 previously untreated RCC patients received 6.0 and 7.5 μg/kg/wk for up to 12 weeks. Patients with a response or stable disease after 12 weeks were eligible for the extension protocol and were treated for up to 1 year or until disease progression.

RESULTS: The MTD for pegylated IFNα-2b at 12 weeks was 6.0 μg/kg/wk. One year of 6.0 μg/kg/wk was well tolerated with appropriate dose modification; no grade 3 or 4 fatigue occurred, and safety was comparable with that with nonpegylated IFNα-2b. The most common nonhematologic adverse events included mild to moderate nausea, anorexia, and fatigue. Six patients had grade 3 or 4 hematologic toxicity. Twenty-nine patients continued on the extension protocol. Four patients had a complete response, and five patients had a partial response. Among 44 previously untreated RCC patients, the objective response rate was 14%. Median survival for all RCC patients was 13.2 months.

CONCLUSION: Pegylated IFNα-2b was active and well tolerated in patients with metastatic solid tumors, including RCC, at doses up to 6.0 μg/kg/wk.
Phase I Clinical Trial of Recombinant Human Endostatin Administered as a Short Intravenous Infusion Repeated Daily
Authors: Eder Joseph P. , Supko Jeffrey G. , Clark Jeffrey W. , Puchalski Thomas A. , Garcia-Carbonero Rocio , Ryan David P. , Shulman Lawrence N. , Proper Joann , Kirvan Moira , Rattner Barbara , Connors Susan , Keogan Mary T. , Janicek Milos J. , Fogler William E. , Schnipper Lowell , Kinchla Nancy , Sidor Carolyn , Phillips Eric , Folkman Judah , Kufe Donald W.
Published: September 2002

PURPOSE: To perform a phase I trial of recombinant human endostatin (rhEndostatin; EntreMed, Rockville, MD) given as a daily 20-minute intravenous (IV) injection in adult patients with refractory solid tumors.

PATIENTS AND METHODS: The daily dose was increased from 15 to 240 mg/m2 by a factor of 100% in cohorts of three patients. In the absence of dose-limiting toxicity, uninterrupted treatment was continued until the tumor burden increased by more than 50% from baseline. Correlative studies included dynamic contrast-enhanced magnetic resonance imaging of tumor blood flow, urinary vascular endothelial growth factor and basic fibroblast growth factor levels, rhEndostatin serum pharmacokinetics, and monitoring of circulating antibodies to rhEndostatin.

RESULTS: There were no notable treatment related toxicities among 15 patients receiving a total of 50 monthly cycles of rhEndostatin. One patient with a pancreatic neuroendocrine tumor had a minor response and two patients showed disease stabilization. Linearity in the pharmacokinetics of rhEndostatin was indicated by dose-proportionate increases in the area under the curve for the first dose and the peak serum concentration at steady state. Daily systemic exposure to rhEndostatin in patients receiving 240 mg/m2/d was approximately 50% lower than that provided by the therapeutically optimal dose in preclinical studies.

CONCLUSION: rhEndostatin administered as a 20-minute daily IV injection at doses up to 240 mg/m2 showed no significant toxicities. Evidence of clinical benefit was observed in three patients. Due to high variability between the peak and trough serum concentrations associated with the repeated short IV infusion schedule, daily serum drug levels only briefly exceeded concentrations necessary for in vitro antiangiogenic effects.
Selective Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor ZD1839 Is Generally Well-Tolerated and Has Activity in Non–Small-Cell Lung Cancer and Other Solid Tumors: Results of a Phase I Trial
Authors: Herbst Roy S. , Maddox Anne-Marie , Rothenberg Mace L. , Small Eric J. , Rubin Eric H. , Baselga Jose , Rojo Federico , Hong Waun Ki , Swaisland Helen , Averbuch Steven D. , Ochs Judith , LoRusso Patricia Mucci
Published: September 2002

PURPOSE: To investigate safety, tolerability, dose-related pharmacologic properties, and pharmacodynamics of ZD1839 (gefinitib, Iressa; AstraZeneca Pharmacueticals, Wilmington, DE), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in patients with solid tumor types known to express or highly express EGFR.

METHODS: This was an open-label, phase I, dose escalation safety/tolerability trial of oral ZD1839 (150 to 1,000 mg/d), administered once daily for 28-continuous-day cycles until disease progression or undue toxicity.

RESULTS: Of 71 (69 assessable for safety; 58 for efficacy) patients at seven dose levels, most had non–small-cell lung (n = 39) or head and neck (n = 18) cancer, and 68 of 71 patients received prior cancer therapy (two or more regimens in 54 patients [78%]). Diarrhea and rash, the primary dose-limiting toxicities (DLTs), occurred at 800 mg. Frequent treatment-related grade 1/2 adverse events were diarrhea (55%), asthenia (44%), and acne-like follicular rash (46%). At doses ≥ 800 mg, 45% of patients required dose reductions. No increased or cumulative toxicity was observed over 250 patient-months of exposure. Pharmacokinetic analysis showed that steady-state occurred by day 7, interpatient exposure was more variable than intrapatient exposure, and variability of exposure did not change with dose. One patient experienced a partial response, but antitumor activity manifested mainly as prolonged stable disease (45% of patients ≥ 3 months, 22% ≥ 6 months, and 7.2% ≥ 1 year). No relationship between dose, response, or duration on study was observed.

CONCLUSION: Rash and diarrhea, generally mild and tolerable at doses ≤ 600 mg/d, were DLTs at 800 mg/d (maximum-tolerated dose). Antitumor activity was observed at all doses. Pharmacokinetic analyses confirmed suitability of once-daily oral dosing.
Prognostic Value ofKITMutation Type, Mitotic Activity, and Histologic Subtype in Gastrointestinal Stromal Tumors
Authors: Singer Samuel , Rubin Brian P. , Lux Marcia L. , Chen Chang-Jie , Demetri George D. , Fletcher Christopher D.M. , Fletcher Jonathan A.
Published: September 2002

PURPOSE: Previous studies have reported clinical correlates for KIT mutations in GISTs, but in most of those studies the KIT mutations were found in less than 50% of the GISTs. The aim of this study was to evaluate the prognostic relevance for KIT mutations in a series of GISTs in which the mutations were evaluated intensively by genomic and cDNA sequencing.

PATIENTS AND METHODS: A comprehensive clinical and pathologic analysis of 48 patients with GISTs who had snap-frozen tissue was performed. The median tumor size was 10 cm (range, 2 to 30 cm). Median follow-up for disease-free patients was 48 months. KIT genomic and cDNA was sequenced by using nucleic acid templates isolated from frozen tumors.

RESULTS: The overall 5-year recurrence-free survival was 41% ± 6%. Five-year recurrence-free survival for patients with tumors that had mitotic counts of three mitoses or fewer per 30 high-power fields (HPF), more than three to ≤ 15 mitoses per 30 HPF, and more than 15 mitoses per 30 HPF were 89% ± 7%, 49% ± 12%, and 16% ± 6%, respectively (P = .0001). The 32 patients with spindle-cell histology had a 49% ± 7% 5-year recurrence-free survival; in contrast, the 16 patients with epithelioid or mixed histology had a 23% ± 11% 5-year recurrence-free survival (P = .01). Five-year recurrence-free survival for patients with tumors less than 5 cm, 5 to 10 cm, and more than 10 cm were 82% ± 12%, 45% ± 9%, and 27% ± 8%, respectively (P = .03). Prognostic associations were found with particular KIT mutation types, and patients with missense exon 11 mutations had a 5-year recurrence-free survival of 89% ± 11% compared with 40% ± 8% for GISTs with other mutation types (P = .03). The independent predictors for disease-free survival were the presence of deletion/insertion exon 11 mutations (hazard ratio [HR] = 4; P = .006), more than 15 mitoses per 30 HPF (HR = 18; P = .0001), mixed histology (HR = 21; P = .0001), and male sex (HR = 3; P = .05).

CONCLUSION: In this series of KIT-expressing GISTs, tumor mitotic activity and histologic subtype were the most important prognostic features. The majority of GISTs contain KIT-activating mutations with the type/location of mutation serving as an independent predictor for disease-free survival. These results suggest that KIT mutation and activation are important in GIST pathogenesis and also may provide important prognostic information.
Study of the Media’s Potential Influence on Prospective Research Participants’ Understanding of and Motivations for Participation in a High-Profile Phase I Trial
Authors: Pentz Rebecca D. , Flamm Anne L. , Sugarman Jeremy , Cohen Marlene Z. , Daniel Ayers G. , Herbst Roy S. , Abbruzzese James L.
Published: September 2002

PURPOSE: To describe prospective participants’ initial source of information about, understanding of, and motivation to participate in a phase I clinical trial of the antiangiogenesis agent human recombinant endostatin.

PATIENTS AND METHODS: We surveyed 100 of 130 persons referred to the endostatin trial between October 1999 and November 2000 and analyzed media coverage of the agent from 1997 to 2000.

RESULTS: Forty-seven percent of survey respondents first heard about the trial from media reports. Fifty-one percent of these subsequently contacted their physicians. Thirty-three percent of respondents correctly understood the purpose of the trial. Seventy-nine respondents were interviewed before they met trial investigators to discuss the trial. Of these, those who first heard about endostatin from the media were five times more likely to understand correctly the trial’s purpose than those who first heard from other sources. Seventy-four percent (70 of 95) of respondents cited hope for personal benefit as the main reason for their willingness to enroll. Those who first heard about endostatin from the media were no more motivated by hope of personal benefit (77%) than those who first heard from other sources (71%) (P = .46). Ninety-nine percent of all respondents cited “joining the study gives me hope” as a contributing factor in their decision making about the trial.

CONCLUSION: Media coverage prompted prospective participants to contact their physicians but did not seem to hinder understanding nor could it be shown to heighten their hope for personal benefit.
Development of Biologic Markers of Response and Assessment of Antiangiogenic Activity in a Clinical Trial of Human Recombinant Endostatin
Authors: Herbst Roy S. , Mullani Nizar A. , Davis Darren W. , Hess Kenneth R. , McConkey David J. , Charnsangavej Chusilp , O’Reilly Michael S. , Kim Hyung-Woo , Baker Cheryl , Roach Jennifer , Ellis Lee M. , Rashid Asif , Pluda James , Bucana Corazon , Madden Timothy L. , Tran Hai T. , Abbruzzese James L.
Published: September 2002

PURPOSE: Angiogenesis is a target for the treatment of cancer and other diseases, and its complex biology suggests that establishing the appropriate dose and schedule for antiangiogenic treatment will require extensive study. We present the initial results of a dose-finding clinical trial of recombinant human endostatin (rh-Endo) that examined potential surrogates for response to antiangiogenic therapy.

PATIENTS AND METHODS: Twenty-five patients were treated with escalating doses of rh-Endo. Positron emission tomography (PET) was used to assess tumor blood flow (with [15O]H2O) and metabolism (with [18F]fluorodeoxyglucose) before the start of therapy and then every 4 weeks. To directly assess the effects of rh-Endo on endothelial cells within the tumors, biopsy specimens of tumor tissue were obtained before therapy and again at 8 weeks and evaluated for endothelial cell and tumor cell apoptosis.

RESULTS: Tumor blood flow and metabolism as measured by PET scans generally decreased with increasing doses of rh-Endo; however, the effects were complex and in some analyses nonlinear. Tumor biopsy analysis revealed a significant increase in tumor cell apoptosis (P = .027) and endothelial cell apoptosis (P = .027) after 8 weeks of therapy. However, there was no statistically significant relationship between rh-Endo dose and induction of tumor cell or endothelial cell apoptosis.

CONCLUSION: These initial data suggest that rh-Endo has measurable effects on tumor blood flow and metabolism and induces endothelial and tumor cell apoptosis even in the absence of demonstrable anticancer effects. Further study and validation of these biomarkers in the context of antiangiogenic therapy will be required.
Treatment of Extranodal Marginal Zone B-Cell Lymphoma of Mucosa-Associated Lymphoid Tissue Type With Cladribine: A Phase II Study
Authors: Jäger Gerald , Neumeister Peter , Brezinschek Ruth , Hinterleitner Thomas , Fiebiger Wolfgang , Penz Melitta , Neumann Hans J. , Mlineritsch Brigitte , DeSantis Maria , Quehenberger Franz , Chott Andreas , Beham-Schmid Christine , Höfler Gerald , Linkesch Werner , Raderer Markus
Published: September 2002

PURPOSE: As chemotherapy has not been extensively studied in patients with lymphoma of the mucosa-associated lymphoid tissue (MALT), we initiated a prospective study to evaluate the activity of the nucleoside analog cladribine (2-chlorodeoxyadenosine [2-CdA]) in this disease.

PATIENTS AND METHODS: Patients with histologically verified MALT-type lymphoma were enrolled. 2-CdA was administered at a dose of 0.12 mg/kg body weight on 5 consecutive days, as a 2-hour infusion. Cycles were repeated every 4 weeks for a maximum of six cycles.

RESULTS: Nineteen patients with gastric and seven patients with extragastric MALT lymphoma were enrolled. All patients were chemotherapy-naive, and two had been locally irradiated before systemic relapse of the lymphoma. A total of 102 cycles was administered to our patients (median number of cycles per patient, four). All 25 assessable patients responded to treatment: 21 patients (84%) achieved complete remission (CR) and four patients achieved partial remission. All patients (100%) with gastric presentation, but only three patients (43%) with extragastric presentation, achieved CR. Toxicities were moderate and mainly hematologic and required dose reduction and/or premature discontinuation of therapy in only three cases. Two patients died from vascular events, one shortly after the first cycle because of myocardial infarction and the other from stroke 3 months after the second course. Three patients relapsed after 13, 18, and 22 months and one patient showed progressive disease after 15 months. At present, 24 patients are alive at a median follow-up time of 32 months.

CONCLUSION: Our data demonstrate that 2-CdA is highly effective in inducing CR in 84% of patients with MALT-type lymphoma.
Alemtuzumab in Previously Treated Chronic Lymphocytic Leukemia Patients Who Also Had Received Fludarabine
Authors: Rai K. R. , Freter C. E. , Mercier R. J. , Cooper M. R. , Mitchell B. S. , Stadtmauer E. A. , Santábarbara P. , Wacker B. , Brettman L.
Published: September 2002

PURPOSE: This phase II pilot study determined the efficacy and safety of alemtuzumab (Campath-1H; Burroughs Wellcome, United Kingdom) in patients with chronic lymphocytic leukemia (CLL), all of whom had previously received fludarabine and other chemotherapy regimens.

PATIENTS AND METHODS: Twenty-four patients were treated with intravenous alemtuzumab at six centers in the United States. The target dose of 30 mg over 2 hours, three times weekly, was administered for up to 16 weeks. Responses were evaluated by an independent panel of experts using 1996 National Cancer Institute–sponsored Working Group criteria. Safety assessments included analysis of lymphocyte subpopulations. Antimicrobial prophylaxis was not mandatory.

RESULTS: Eight patients (33%) achieved a major response (all partial remissions), with a median time to response of 3.9 months (range, 1.6 to 5.3 months). The median duration of response was 15.4 months (range, 4.6 to ≥ 38.0 months), the median time to disease progression was 19.6 months (range, 7.7 to ≥ 42.0 months), and the median survival time was 35.8 months (range, 8.8 to ≥ 47.1 months). Acute infusion-related events, mainly grades 1 and 2, were most common and most severe in the first week. Ten patients (eight nonresponders and two responders) experienced major infections on-study. Pneumocystis carinii pneumonia was reported in two patients on-study; neither had received prophylaxis. Median CD4+ and CD8+ counts decreased and then began to increase by the end of the study, with further recovery by 1-month follow-up. One of 53 samples obtained from 10 patients had a low titer of alemtuzumab antibodies.

CONCLUSION: Alemtuzumab has significant activity in poor-prognosis, fludarabine-treated CLL patients. However, because of a relatively high incidence of opportunistic infections accompanying profound lymphopenia, future protocols should include mandatory prophylaxis.
Therapy-Related Myeloid Leukemias Are Observed in Patients With Chronic Lymphocytic Leukemia After Treatment With Fludarabine and Chlorambucil: Results of an Intergroup Study, Cancer and Leukemia Group B 9011
Authors: Morrison Vicki A. , Rai Kanti R. , Peterson Bercedis L. , Kolitz Jonathan E. , Elias Laurence , Appelbaum Frederick R. , Hines John D. , Shepherd Lois , Larson Richard A. , Schiffer Charles A.
Published: September 2002

PURPOSE: Patients with chronic lymphocytic leukemia (CLL) may have disease transformation to non-Hodgkin’s lymphoma or prolymphocytic leukemia; however, development of therapy-related acute myeloid leukemia (t-AML) is unusual. A series of patients enrolled onto an intergroup CLL trial were examined for this complication.

PATIENTS AND METHODS: A total of 544 previously untreated B-cell CLL patients were enrolled onto a randomized intergroup study comparing treatment with chlorambucil, fludarabine, or fludarabine plus chlorambucil. Case report forms from 521 patients were reviewed for t-AML.

RESULTS: With a median follow-up of 4.2 years, six patients (1.2%) to date have developed therapy-related myelodysplastic syndrome (t-MDS; n = 3), t-AML (n = 2), or t-MDS evolving to t-AML (n = 1), from 27 to 53 months (median, 34 months) after study entry. This included five (3.5%) of 142 patients treated with fludarabine plus chlorambucil and one (0.5%) of 188 receiving fludarabine; no chlorambucil-treated patients developed t-MDS or t-AML (P = .007). At study entry, the median age among these six patients was 56 years (range, 44 to 72 years); three were male; the CLL Rai stage was I/II (n = 4) or III/IV (n = 2). Response to CLL therapy was complete (n = 4) or partial remission (n = 1) and stable disease (n = 1). Marrow cytogenetics, obtained in three of six cases at diagnosis of t-MDS or t-AML, were complex, with abnormalities in either or both chromosomes 5 and 7. Other abnormalities involved chromosomes X, 1, 8, 12, 17, and 19. Median survival after diagnosis of t-MDS/AML was 3.5 months (range, 0.5 to 10.1 months).

CONCLUSION: Our findings raise the possibility that alkylator-purine analog combination therapy may increase the risk of therapy-related myeloid malignancies, which is of particular relevance with regard to ongoing trials using these combination therapies.