bluuebunny/crossref_metadata_2025_split huggingface dataset:
Measuring VEGF-Flk-1 Activity and Consequences of VEGF-Flk-1 Targeting In Vivo Using Intravital Microscopy: Clinical Applications
Authors: Vajkoczy Peter , Thurnher Andreas , Hirth K. Peter , Schilling Lothar , Schmiedek Peter , Ullrich Axel , Menger Michael D. 
Published: August 2004

Abstract
Vascular endothelial growth factor (VEGF)-Flk-1/KDR tyrosine kinase signaling pathway plays a pivotal role in tumor angiogenesis. Targeting this angiogenic signaling pathway presents a promising alternative for the treatment of neoplasms. However, recent experimental and clinical studies have suggested that VEGF-Flk-1/KDR activity is unevenly distributed throughout the tumor microvasculature. To further evaluate this phenomenon, the regional differences in VEGF-Flk-1/KDR signaling activities in vivo were studied using intravital fluorescence videomicroscopy in an experimental murine brain tumor model. Regional VEGF-Flk-1/KDR was assessed using the small molecule inhibitor SU5416, which selectively inhibits the tyrosine kinase receptor Flk-1. C6 glioblastoma cells were implanted into the dorsal skinfold chamber preparation of nude mice. The process of tumor vascularization was repeatedly assessed over 22 days. SU5416 treatment resulted in a significant reduction in tumor vascular density (p &lt; 0.05). Regional microvascular evaluation indicated that the magnitude of this antiangiogenic effect was pronounced in the more angiogenic and better vascularized peritumoral areas than in the intratumoral areas of the tumor microvasculature. These results demonstrate regional differences in Flk-1 activity in vivo that may have significant impact on the susceptibility of tumors to compounds that target VEGF-Flk-1/KDR. This finding should be considered in upcoming clinical trials targeting individual signal transduction systems in cancer patients.
VEGF Receptor Signaling in Tumor Angiogenesis
Authors: McMahon Gerald 
Published: August 2004

Abstract
The growth of human tumors and development of metastases depend on the de novo formation of blood vessels. The formation of new blood vessels is tightly regulated by specific growth factors that target receptor tyrosine kinases (RTKs). Vascular endothelial growth factor (VEGF) and the Flk-1/KDR RTK have been implicated as the key endothelial cell-specific factor signaling pathway required for pathological angiogenesis, including tumor neovascularization. Inhibition of the VEGF tyrosine kinase signaling pathway blocks new blood vessel formation in growing tumors, leading to stasis or regression of tumor growth. Advances in understanding the biology of angiogenesis have led to the development of several therapeutic modalities for the inhibition of the VEGF tyrosine kinase signaling pathway. A number of these modalities are under investigation in clinical studies to evaluate their potential to treat human cancers.
von Hippel-Lindau Syndrome: Target for Anti-Vascular Endothelial Growth Factor (VEGF) Receptor Therapy
Authors: Harris Adrian L. 
Published: August 2004

Abstract
von Hippel-Lindau (VHL) syndrome is a familial cancer syndrome caused by germline mutations in the VHL tumor suppressor gene. Mutations in the VHL gene result in the constitutive stabilization of transcription factors hypoxia-inducible factors 1α and 2α, which bind to specific enhancer elements in the vascular endothelial growth factor (VEGF) gene and stimulate angiogenesis. This increase in angiogenesis under normoxic conditions in key target organs such as the brain, kidney, and eye leads to high morbidity and reduced life expectancy. Drugs designed to block the VEGF signaling pathway may prevent the long-term complications of the disease. To test this hypothesis, a clinical study was initiated to evaluate the effect of the VEGF tyrosine kinase receptor inhibitor SU5416 in patients with VHL syndrome. Preliminary data on SU5416 indicate that it is well tolerated when administered chronically in such patients. However, since little is known about the long-term use of such inhibitors, patients will need careful monitoring. Data obtained from monitoring these patients will provide valuable information for adjuvant treatment trials in cancer patients.
Prognostic Value of Vascular Endothelial Growth Factor in Breast Cancer
Authors: Gasparini Giampietro 
Published: August 2004

Abstract
Angiogenesis, the process leading to the formation of new blood vessels from a preexisting vascular network, is necessary for tumor growth, invasion, and metastasis. Data from experimental and clinical studies indicate that breast carcinoma is an angiogenesis-dependent tumor.
Most retrospective studies evaluating the prognostic value of determination of intratumoral microvessel density (IMD) at the vascular “hot spot” (a surrogate marker of angiogenesis) found that IMD is a significant and independent prognostic indicator in patients with both node-negative and node-positive breast cancers. More recently, the expression of certain endothelial growth factors has been tested. Among these, vascular endothelial growth factor (VEGF), the most potent endothelial cell mitogen and also a regulator of vascular permeability, is emerging as a powerful new prognostic tool. Eight of the nine published retrospective studies reported that VEGF is significantly associated with relapse-free survival, overall survival, or both. Patients with early stage breast cancer who have tumors with elevated levels of VEGF have a higher likelihood of recurrence or death than patients with low-angiogenic tumors, even if treated with conventional adjuvant therapy.
High levels of VEGF can differentiate the subgroups of patients with breast cancer with poor prognosis who benefit minimally from conventional adjuvant therapy but who may benefit from validated anti-VEGF treatments.
Targeting Vascular Endothelial Growth Factor Blockade: Ascites and Pleural Effusion Formation
Authors: Verheul H.M.W. , Hoekman K. , Jorna A.S. , Smit E.F. , Pinedo H.M. 
Published: August 2004

AbstractPrimary Purpose. Formation of ascites and pleural effusion (PE) is a common problem for patients with advanced-stage cancer. These fluid accumulations cause severe symptoms such as abdominal distention, shortness of breath, cachexia, anorexia, and fatigue. Preclinical models have demonstrated that vascular endothelial growth factor (VEGF) plays a pivotal role in the accumulation of malignant PE or ascites. This study investigated whether blockade of VEGF activity would reduce biological activity of PE and ascites on endothelial cells of cancer patients.Patients and Methods. The activity of VEGF in PE and ascites of 58 patients (39 with PE and 19 with ascites) was measured. An endothelial cell proliferation assay with human umbilical vein endothelial cells was used to determine the biological activity of ascites and PE.Results. VEGF concentrations ranged from 67-6,245 pg/ml. A significantly higher concentration of VEGF was detected in the ascites and PE of patients with cancer (median, 1,290 pg/ml) than in patients with nonmalignant disease (median, 250 pg/ml; p = 0.02). Of the 58 PE and ascites samples, 41 were biologically active, based on a two- to fourfold stimulation of endothelial cell proliferation in 72 hours. VEGF concentrations were significantly higher in the biologically active samples compared with the 17 nonactive samples (2,056 pg/ml versus 771 pg/ml; p = 0.02). Coincubation of the samples with either a neutralizing polyclonal antibody against VEGF or SU5416, a small molecule inhibitor of the VEGF receptor Flk-1/KDR, inhibited endothelial cell proliferation by 66% and 100%, respectively. The inhibition caused by the antibody and that caused by SU5416 correlated significantly (r = 0.8, p &lt; 0.001).Conclusion. We conclude that malignant ascites and PE contain high levels of biologically active VEGF. This study strongly supports the hypothesis that blockade of VEGF, such as that afforded by SU5416, may benefit cancer patients with recurrent ascites or PE formation.
Clinical Strategy for the Development of Angiogenesis Inhibitors
Authors: Carter Stephen K. 
Published: August 2004

Abstract
Angiogenesis inhibitors differ from conventional cytotoxic chemotherapy agents by targeting normal cells rather than tumor cells, which may contain multiple mutations. Because of this, the traditional strategy used in clinical development of cytotoxic agents may not be appropriate for these novel agents. Many clinical studies are now evaluating these agents with a new approach, referred to as the cytostatic paradigm. The cornerstone of the cytostatic paradigm is the use of time to progression (TTP) of disease as the decision-making criterion for “go/no go” in the early phases of clinical development. However, the use of TTP as the main criterion for clinical trials is complicated for a variety of reasons, including: A) the lack of standardized criteria accepted by regulatory authorities; B) the heterogeneity of the historical database, and C) the larger number of patients needed for the “go/no go” decision-making process. In addition, clinical trials of cytotoxic agents have traditionally used objective response (despite the controversy regarding objective response as a surrogate for clinical activity) as the main criterion for determining whether the results of phase II studies justify the pivotal phase III studies.
Another aspect of the clinical development strategy is combining angiogenesis inhibitors with cytotoxic chemotherapy. The rationale for combination of angiogenesis inhibitors with cytotoxic agents is based on: A) different targets for these agents; B) lack of cross-resistance patterns; C) lack of myelosuppression with angiogenesis inhibitors allows administration of full doses of all agents, and D) the assumption that combining these agents will result in additive antitumor activity. Combination therapy with angiogenesis inhibitors may be attractive to both clinicians and their patients because it allows cytostatic agents to be used upfront in treatment while contributing to drug registration strategy (cytostatic/cytotoxic combination therapy versus cytotoxic therapy).
The clinical development of the angiogenesis inhibitor SU5416, a small molecule inhibitor of vascular endothelial growth factor, is currently ongoing. In phase I trials, SU5416 demonstrated activity in both colorectal and non-small-cell lung cancer patients. Based on these encouraging results, phase III studies to evaluate combination of SU5416 with established cytotoxic therapy are planned. These studies will include an interim analysis, the equivalent of a phase II evaluation of clinical activity. If successful, this strategic approach will save significant time in the clinical development process.
Radiotherapy-Associated Anemia: The Scope of the Problem
Authors: Harrison Louis B. , Shasha Daniel , White Carol , Ramdeen Beverly 
Published: August 2004

Abstract
The impact of anemia on cancer patients undergoing chemotherapy is well established, but only recently has the prevalence of anemia in patients receiving radiotherapy received much attention. Many cancer patients present with anemia prior to radiotherapy, and even more experience anemia or a worsening of anemia at some point during treatment. However, the problem of anemia is often ignored because patients may experience only functional anemia, defined as a hemoglobin level less than 12 g/dl. Unless physiologic anemia (hemoglobin = 8 g/dl) is discovered, efforts to correct anemia are often not made. Because hemoglobin levels &lt;12 g/dl seem to be associated with tumor hypoxia and poorer outcomes of radiotherapy in a number of patient populations, ignoring even modest anemia can result in decreased locoregional control, overall survival, and quality of life (QOL). Because increasing hemoglobin levels 1-2 g/dl is usually easily accomplished, there exists the potential for improving outcomes by paying greater attention to this problem. This article focuses on the prevalence of anemia, particularly functional anemia, and discusses the impact of anemia on locoregional control, overall survival, and QOL.
The Relationship between Anemia and Quality of Life in Cancer Patients
Authors: Sabbatini Paul 
Published: August 2004

Abstract
Anemia is a common occurrence in patients with cancer, and especially in those who undergo chemotherapy. Traditionally, significantly decreased hemoglobin levels have been considered to be ≤ 8 g/dl and have been associated with physiologic manifestations. More recent data have shown that milder anemia (hemoglobin levels 10-12 g/dl) has functional consequences as well. This article reviews several communitybased studies that have analyzed changes in hemoglobin concentrations, transfusion requirements, and QOL parameters in anemic patients with cancer before and after treatment with epoetin alfa. The results of these studies have been consistent and show an increase in hemoglobin and a reduction in transfusion requirements when compared with baseline. Furthermore, a relationship between increasing hemoglobin levels and an improvement in QOL is suggested that is independent of tumor response. Additional studies are evaluating the optimal hemoglobin levels for the greatest incremental improvement in QOL.
The Impact of Fatigue on Patients with Cancer: Overview of FATIGUE 1 and 2
Authors: Curt Gregory A. 
Published: August 2004

Abstract
Fatigue is a complex, multifactorial disorder with physical, mental, and psychological dimensions that has been associated with diminished quality of life (QOL) in patients with cancer. The prevalence and severity of fatigue, however, has only recently been studied systematically. Two national surveys commissioned by The Fatigue Coalition, a multidisciplinary group of medical practitioners, researchers, and patient advocates, whose mission is to study the importance of fatigue for patients with cancer and their caregivers, have assessed the prevalence, severity, and QOL consequences of fatigue in patients with cancer. The most recent survey, initiated in 1998, sought to confirm and extend observations on the prevalence and impact of fatigue in patients with cancer as part of an initiative to develop guidelines for the differential diagnosis and treatment of fatigue. The FATIGUE 2 study probed the emotional, social, physical, and economic impact of fatigue on patients with cancer and their caregivers. Patient perceptions of the professional response to cancer-related fatigue were also assessed. The key findings of these surveys are reviewed.
New Directions in the Treatment of Non-Small Cell Lung Cancer: An Overview
Authors: Edelman Martin J. 
Published: August 2004

Abstract
Despite unequivocal evidence of activity and tolerability, the potential contribution of vinorelbine to the management of non-small cell lung cancer (NSCLC) has been relatively unappreciated. A phase III trial of vinorelbine as a single agent in the elderly demonstrated clear benefits in terms of survival and quality of life compared with supportive care. Two other phase III trials demonstrated that vinorelbine plus platinum was superior when compared either with one of the older platinum combinations, platinum as a single agent or vinorelbine alone. New vinorelbine-based regimens appear to be active but with less toxicity than older combinations in stage IV disease. Chemotherapy plays an essential role in the management of locally advanced (i.e., stage III) disease with the weight of evidence supporting improved curability of this stage when drugs are employed either preoperatively or as part of a chemoradiotherapy regimen. It has been reported that induction therapy using carboplatin/vinorelbine or carboplatin/paclitaxel followed by accelerated conformal radiation therapy has promising results without causing undue toxicity.
Clearly, vinorelbine is an active agent which is well tolerated and suitable for use in the management of NSCLC. It is likely to play a greater role in the future.
Carboplatin and Vinorelbine in Advanced Non-Small Cell Lung Cancer: A Phase I/II Study
Authors: Masters Gregory 
Published: August 2004

Abstract
Standard options for advanced non-small cell lung cancer have focused on cisplatin-based regimens, including the combination of cisplatin with vinorelbine shown in randomized trials to be at least as effective as comparator regimens. Given its lower incidence of nonhematological toxicity, carboplatin may be an attractive alternative agent in combination with vinorelbine. To determine the tolerability of this regimen, a phase I/II study was conducted in 21 patients with stage IIIB/IV disease. A fixed dose of carboplatin (area under the concentration time curve = 2.5) was administered on days 1 and 8 q 21 days, together with vinorelbine also on days 1 and 8 at doses increasing from 20 mg/m2 to 25 mg/m2. This regimen was very well tolerated: only one case of grade 4 hematological toxicity and one case of grade 3 nonhematological toxicity occurred. Objective responses were seen. Given its tolerability and activity, the combination of carboplatin with vinorelbine at the doses and schedule studied should be further evaluated.
Induction Chemotherapy Followed by Concomitant Chemoradiotherapy for Non-Small Cell Lung Cancer
Authors: Vokes Everett E. 
Published: August 2004

Abstract
Multiple concepts of combined modality therapy for locoregionally advanced inoperable non-small cell lung cancer have been investigated. These include induction chemotherapy, concomitant chemoradiotherapy, and intensified radiation therapy schedules. To date, induction chemotherapy has been validated in randomized prospective trials versus radiotherapy alone. Concomitant chemoradiotherapy has led to promising results when combination chemotherapy regimens were used in the phase II setting. In addition, concomitant chemoradiotherapy has been shown to be superior to induction chemotherapy in direct comparison. Finally, accelerated radiotherapy has been shown to lead to improved locoregional control and survival in one randomized study. Based on these observations, the Cancer and Leukemia Group B (CALGB study 9431) investigated the addition of either vinorelbine, paclitaxel, or gemcitabine to cisplatin. In this trial, patients with locally advanced and inoperable non-small cell lung cancer received two cycles of induction chemotherapy with an additional two cycles of concomitant chemoradiotherapy utilizing the same agents accompanied by standard radiation to a total dose of 66 Gy. One hundred eighty-seven patients were entered on this study. An early analysis showed the median survival time was 17 months for all patients entered on the trial. In the context of other CALGB studies, the data from this trial are encouraging, and the regimens used warrant further study.
The ELVIS Trial: A Phase III Study of Single-Agent Vinorelbine as First-Line Treatment in Elderly Patients with Advanced Non-Small Cell Lung Cancer
Authors: Gridelli Cesare 
Published: August 2004

Abstract
In a phase III trial, 191 patients aged over 70 with stage IIIB/IV non-small cell lung cancer were randomized to receive best supportive care (BSC) alone or BSC plus vinorelbine on days 1 and 8, q 21 days for up to six cycles. Increasing difficulties in recruitment meant that the investigators, blinded to the results, stopped the trial early. Data from 161 patients have been analyzed. The vinorelbine regimen was well tolerated. Grade 3/4 neutropenia occurred in 10% of patients and grade 2/3 anemia in 16%. The principle nonhematological toxicities were constipation and fatigue. An objective response rate was recorded in 19.7% of the 76 patients treated with vinorelbine. The survival experience of these patients was significantly superior to that among control patients. The median duration of survival was longer (28 versus 21 weeks) and patients receiving vinorelbine were significantly more likely to survive to one year (32% versus 14%). The relative risk of death in the vinorelbine group was 0.65 (95% confidence interval: 0.45-0.93). Quality of life was extensively investigated using European Organization for Research and Treatment of Cancer scales. While aspects of quality-of-life issues that were directly related to drug toxicity (such as nausea and constipation) were lower in the vinorelbine group, patients who received vinorelbine fared better than controls on measures related to lung cancer symptoms and pain and on social, cognitive, and physical functioning.
Introduction: The History of Arsenic Trioxide in Cancer Therapy
Authors: Antman Karen H. 
Published: August 2004

Abstract
Although arsenic can be poisonous, and chronic arsenic exposure from industrial or natural sources can cause serious toxicity, arsenic has been used therapeutically for more than 2,400 years. Thomas Fowler's potassium bicarbonate-based solution of arsenic trioxide (As2O3) was used empirically to treat a variety of disorders, and in 1878, was reported to reduce white blood cell counts in two normal individuals and one with “leucocythemia.” Salvarsan, an organic arsenical for treating syphilis and trypanosomiasis, was developed in 1910 by Paul Ehrlich. In the 1930s, arsenic was reported to be effective in chronic myelogenous leukemia. After a decline in the use of arsenic during the mid-20th century, reports from China described a high proportion of hematologic responses in patients with acute promyelocytic leukemia (APL) who were treated with arsenic trioxide. Randomized clinical trials in the U.S. led to FDA approval of arsenic trioxide for relapsed or refractory APL in September 2000.
Arsenic Trioxide: An Emerging Therapy for Multiple Myeloma
Authors: Munshi Nikhil C. 
Published: August 2004

Abstract
Arsenic trioxide can inhibit proliferation and induce apoptosis in multiple myeloma (MM) cells in vitro and in vivo. In addition to affecting tumor growth, arsenic trioxide has been shown to inhibit angiogenesis, suggesting that it may have significant potency in the treatment of MM. Based on these observations, the clinical efficacy of arsenic trioxide was evaluated in patients with advanced refractory MM using a fixed-dose intravenous infusion given daily for a maximum of 60 days. Nine patients were evaluable. All nine had extensive prior therapy; seven had two or more high-dose chemotherapy cycles with autologous stem cell support. All nine patients had cytogenetic abnormalities, and six had chromosome 13 deletions. Of the four patients who completed more than 30 days of arsenic trioxide infusion, two had &gt;50% reduction in myeloma paraprotein, one had stable disease, and one progressed. Of the five patients with &lt;30 days infusion, two had stable disease and three progressed. Thus, on an intent-to-treat basis, two of nine (23%) patients responded (&gt;50% paraprotein reduction). The regimen was well tolerated except for development of cytopenia, which responded to G-CSF, and a grade III pulmonary complication in one patient. In summary, arsenic trioxide has activity in end-stage, high-risk myeloma and deserves further evaluation in earlier-stage disease.
Clinical Trials of Arsenic Trioxide in Hematologic and Solid Tumors: Overview of the National Cancer Institute Cooperative Research and Development Studies
Authors: Murgo Anthony J. 
Published: August 2004

Abstract
Arsenic trioxide inhibits growth and promotes apoptosis in many different cancer cell lines. The National Cancer Institute is working cooperatively with research centers across the U.S. to evaluate its clinical activity in hematologic malignancies, such as acute promyelocytic leukemia, acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, chronic lymphocytic leukemia, myelodysplastic syndrome, and multiple myeloma. It is also supporting research in solid tumors, such as advanced hormone-refractory prostate cancer and renal cell cancer and in cervical cancer and refractory transitional cell carcinoma of the bladder. The safety and pharmacokinetics of arsenic trioxide are also being evaluated in pediatric patients with refractory leukemia and lymphoma. The results of these ongoing studies should provide important insights into the clinical utility of arsenic trioxide in these diseases.