bluuebunny/crossref_metadata_2025 huggingface dataset:
Creation of a low-risk reference group and referenceinterval of fasting venous plasma glucose
Authors: Jørgensen Lone G. M. , Brandslund Ivan , Petersen Per Hyltoft , Stahl Marta , Olivarius Niels de Fine
Published: August 2004

Reference intervals are recommended for naturally occurring quantities and required in the evaluation of new components in order to provide clinically useful information.

The aim of the present study is to present a method for selecting reference individuals for the determination of fasting venous plasma glucose (f-vPG) reference intervals and ways to determine if disease groups can share reference intervals with an ideal reference population.

Reference subjects were randomly selected, eligibility was judged according to predetermined inclusion and exclusion criteria. Using the literature we selected risk indicators for diabetes mellitus (DM) and used these indicators to rule out high-risk individuals in order to obtain a reference distribution of f-vPG determined using individuals with low risk of DM. The distributions of f-vPG in the high-risk individuals was compared with that determined for the low-risk group. We then estimated the ability of the high-risk individuals to share the reference interval of the low risk individuals, and calculated the fraction that was outside this interval. Distributions were also investigated for linearity in the cumulated frequency rankit distribution of ln-values. The allowable difference between two reference limits could not exceed 0.375 times the population biological variation.

Most risk indicators were powerful predictors of high f-vPG values. Subgroups with these risk indicators should not be included in the homogeneous ln-normally distributed reference distribution. Distributions of f-vPG concentrations in individuals with risk factors were not homogeneous and varying percentages of individuals were outside the reference distribution, having f-vPG greater than 7.0 mmol/l.

We conclude that randomisation is only useful to recruit candidate reference subjects. To rule out subjects according to clinical risk factors for diabetes, it is necessary to identify a reference population with low risk of exhibiting increased f-vPG concentrations. This method may be used to validate a reference interval for a particular analyte with respect to an investigated disease, and to stratify risk factors of importance.
Metrological traceability of calibration in the estimation and use of common medical decision-making criteria
Authors: Thienpont Linda M. , Uytfanghe Katleen Van , Cabaleiro Diego Rodríguez
Published: August 2004

This manuscript explains the establishment andvalidation of metrological traceability of calibration for routine measurement procedures using common medical decision-making criteria. Metrological traceability is considered the basis for achieving comparability of measurement results in laboratory medicine. This concept is supported by European legislation, which demands that manufacturers provide assurance andd emonstrate metrological traceability of in vitro Diagnostic Medical Devices. The guidance to comply with these legislative requirements is available in different CEN/ISO standards and is used as a basis of this manuscript. The goals andaccomplishments in metrological traceability of SI- and non-SI analytes is considered. Specific problems, such as non-availability of primary reference materials and measurement procedures, lack of official endorsement, andnon-commutability of certain reference materials are discussed. With respect to non-commutability, the use of split-sample measurements is advocated. Also, the expression of measurement uncertainty associatedwith the application of the metrological traceability chain is discussed. In addition, the needfor post-market vigilance assessment of traceable performance is considered. Finally, laboratory medicine scientific and professional societies, diagnostics manufacturers, and clinicians are urged to share responsibilities for understanding the implications of metrological traceability of routine measurements.
Repetitive Behaviors in Monkeys Are Linked to Specific Striatal Activation Patterns
Authors: Saka Esen , Goodrich Claudia , Harlan Patricia , Madras Bertha K. , Graybiel Ann M.
Published: August 2004

The spontaneous behavior of humans can be altered dramatically by repeated exposure to psychomotor stimulants. We have developed a primate model for analyzing the neurobiology underlying such drug-induced behavioral changes. We performed ethogram-based behavioral assays on squirrel monkeys given single or multiple cocaine treatments, and in the same monkeys made anatomical plots of striatal neurons that were activated to express early-gene proteins. A final cocaine challenge after chronic intermittent exposure to cocaine induced highly patterned behavioral changes in the monkeys, affecting individual behavioral motifs in distinct ways. In the striatum, the challenge dose induced striosome-predominant expression combined with intense dorsal early-gene expression, especially in the putamen. These patterns of gene expression were highly predictive of the levels of stereotypy exhibited by the monkeys in response to cocaine challenge. The total levels of expression, on the other hand, appeared to reflect increased spontaneous behavioral activation during the drug-free period after the cocaine exposure. We suggest that in the primate, compartmentally and regionally specific striatal activation patterns contribute to the striatal modulation of psychostimulant-induced behaviors. These observations in nonhuman primates raise the possibility that monitoring such basal ganglia activity patterns could help to delineate the neural mechanisms underlying drug-induced repetitive behaviors and related syndromes in which stereotypies are manifest.
Acute and Chronic Cocaine-Induced Potentiation of Synaptic Strength in the Ventral Tegmental Area: Electrophysiological and Behavioral Correlates in Individual Rats
Authors: Borgland Stephanie L. , Malenka Robert C. , Bonci Antonello
Published: August 2004

The initiation of the psychostimulant sensitization process depends on the mesolimbic system, which projects from the ventral tegmental area (VTA) to the nucleus accumbens. Although such initiation is primarily dependent on glutamatergic activity in VTA neurons, the exact role VTA excitatory synapses play in this process is poorly understood. Here, we examine the effects of repeatedin vivoinjections of cocaine on the magnitude and duration of the increase in strength at VTA excitatory synapses reported previously to be elicited by a singlein vivoexposure to cocaine (Ungless et al., 2001; Saal et al., 2003). We also compare the synaptic modifications induced by cocaine with its effects on locomotor activity. Surprisingly, repeated cocaine exposure potentiated the ratio of AMPA receptor-mediated to NMDA receptor-mediated EPSCs to a similar extent and duration as a singlein vivococaine exposure. In naive animals, the magnitude of the cocaine-induced locomotor activity after a single injection of cocaine correlated with the magnitude of the accompanying synaptic enhancement. This correlation was lost on the seventh day of repeated cocaine administration, as well as when a challenge injection was given 10 d after the cessation of repeated cocaine administration. These results suggest that the cocaine-induced synaptic plasticity at VTA excitatory synapses is transient, and its duration depends on the last exposure to cocaine. Furthermore, chronic cocaine exposure disrupts the normal, presumably adaptive relationship between synaptic enhancement in the VTA and behavior.
Memory of Learning Facilitates Saccadic Adaptation in the Monkey
Authors: Kojima Yoshiko , Iwamoto Yoshiki , Yoshida Kaoru
Published: August 2004

A motor learning mechanism called saccadic adaptation ensures accuracy of saccades throughout life despite growth, aging, and some pathologies of the oculomotor plant or nervous system. The present study investigates effects of preceding adaptation on the speed of subsequent adaptation during single experiments. Adaptive changes in gain (movement size divided by target eccentricity) were induced by intrasaccadic step (ISS) of the target. After the gain was altered (control block), we reversed the direction of ISS to bring the gain back to ∼1.0 (recovery). We then reversed ISS direction again to induce another adaptation (test block). Analyses revealed that the gain changed at a higher rate in the early part of test adaptation than in the corresponding part of control. After ∼100-300 saccades in the test block, adaptation slowed down. The gain value at which adaptation slowed was correlated with the gain achieved in the control. We further examined effects of a 30 min intervention inserted between recovery and test blocks. When zero-visual-error trials (∼700 saccades) were repeated during this period, the rate of test adaptation was similar to that of control. In contrast, when the animal was deprived of visual inputs during this period, test adaptation was still influenced by preceding learning. We conclude that a memory of previous learning remains during recovery to facilitate subsequent adaptation and that such a memory does not disappear merely with time but is erased actively by repeated zero-error movements. Our results, which cannot be explained by a single mechanism, suggest that the saccadic system is equipped with more than one plasticity process.
Intercircuit Control via Rhythmic Regulation of Projection Neuron Activity
Authors: Wood Debra E. , Manor Yair , Nadim Farzan , Nusbaum Michael P.
Published: August 2004

Synaptic feedback from rhythmically active neuronal circuits commonly causes their descending inputs to exhibit the rhythmic activity pattern generated by that circuit. In most cases, however, the function of this rhythmic feedback is unknown. In fact, generally these inputs can still activate the target circuit when driven in a tonic activity pattern. We are using the crab stomatogastric nervous system (STNS) to test the hypothesis that the neuronal circuit-mediated rhythmic activity pattern in projection neurons contributes to intercircuit regulation. The crab STNS contains an identified projection neuron, modulatory commissural neuron 1 (MCN1), whose tonic stimulation activates and modulates the gastric mill (chewing) and pyloric (filtering of chewed food) motor circuits in the stomatogastric ganglion (STG). During tonic stimulation of MCN1, the pyloric circuit regulates both gastric mill cycle frequency and gastropyloric coordination via a direct synapse onto a gastric mill neuron in the STG. However, when MCN1 is spontaneously active, it has a pyloric-timed activity pattern attributable to synaptic input from the pyloric circuit. This pyloric-timed activity in MCN1 provides the pyloric circuit with a second pathway for regulating the gastric mill rhythm. At these times, the direct STG synapse from the pyloric circuit to the gastric mill circuit is not necessary for pyloric regulation of the gastric mill rhythm. However, in the intact system, these two pathways play complementary roles in this intercircuit regulation. Thus, one role for rhythmicity in modulatory projection neurons is to enable them to mediate the interactions between distinct but related neuronal circuits.
Bilateral Orbital Prefrontal Cortex Lesions in Rhesus Monkeys Disrupt Choices Guided by Both Reward Value and Reward Contingency
Authors: Izquierdo Alicia , Suda Robin K. , Murray Elisabeth A.
Published: August 2004

The orbital prefrontal cortex (PFo) operates as part of a network involved in reward-based learning and goal-directed behavior. To test whether the PFo is necessary for guiding behavior based on the value of expected reward outcomes, we compared four rhesus monkeys with two-stage bilateral PFo removals and six unoperated controls for their responses to reinforcer devaluation, a task that assesses the monkeys' abilities to alter choices of objects when the value of the underlying food has changed. For comparison, the same monkeys were tested on a standard test of flexible stimulus-reward learning, namely object reversal learning. Relative to controls, monkeys with bilateral PFo removals showed a significant attenuation of reinforcer devaluation effects on each of two separate assessments, one performed shortly after surgery and the other ∼19 months after surgery; the operated monkeys were also impaired on object reversal learning. The same monkeys, however, were unimpaired in acquisition of object discrimination learning problems and responded like controls when allowed to choose foods alone, either on a food preference test among six different foods or after selective satiation. Thus, satiety mechanisms and the ability to assign value to familiar foods appear to be intact in monkeys with PFo lesions. The pattern of results suggests that the PFo is critical for response selection based on predicted reward outcomes, regardless of whether the value of the outcome is predicted by affective signals (reinforcer devaluation) or by visual signals conveying reward contingency (object reversal learning).
High Doses of Corticosteroid Suppress Resistance to Ichthyophonus in Starry Flounder
Authors: Perry J. A. , Kocan R. M. , Winton J. R. , Hershberger P. K.
Published: August 2004

Application of pharmacological doses of the corticosteroid dexamethasone phosphate to starry flounder Platichthys stellatus resulted in a predisposition to clinical ichthyophoniasis and a progression from latent Ichthyophonus infections to patent, histologically identifiable infections. Among Ichthyophonus-challenged starry flounder, the prevalences of clinical infections and histologically identifiable infections were significantly greater in two groups that received dexamethasone (100% and 31%, respectively) than in the respective control groups (8% and 0%). Proliferation of Ichthyophonus infections in corticosteroid-treated groups may have resulted from suppression of the cellular immune response that typically follows corticosteroid application; however, further studies are needed to determine whether these effects occur at lower, physiological concentrations of corticosteroids.
Gastric Polyp in a Wild-Caught Blue Shark
Authors: Borucinska Joanna D. , Bogicevic Tanja
Published: August 2004

An adult male blue shark Prionace glauca was caught in June 2002 by recreational fisherman off Long Island, New York. The shark was necropsied dockside and all major tissues were collected into elasmobranch formalin and processed for light microscopy. Macroscopic lesions included a polyp arising from the mucosa of the gastric body and numerous larval cestodes Hepatoxylon trichiuri attached to the hepatic capsule. The gastric polyp was a slender, pedunculated growth with a mucosa similar to the remaining gastric lining except for a few pinpoint areas of erosion and hemorrhage. Microscopically, the growth was classified as a well-differentiated adenomatous polyp. Histological evidence suggested minimal chronic gastritis, but special stains failed to reveal intralesional microorganisms, and no histological evidence of viral infection was detected. No other significant microscopic lesions were detected. This is the first literature report of a gastric polyp in a shark and in fishes in the class Chondrichthyes.
Antiangiogenic Strategies and Agents in Clinical Trials
Authors: Rosen Lee
Published: August 2004

The understanding that the growth of tumors depends on the acquisition of a blood supply has led to the development of new therapies for cancer and other angiogenic diseases based on inhibition of neovascularization. This review examines the role of angiogenesis in cancer progression and describes various strategies for interfering with this process. The developmental status of angiogenesis inhibitors in human clinical trials is presented, including their proposed mechanisms of action. Standard chemotherapeutic agents and angiogenesis inhibitors are compared, noting that different end points might need to be considered in clinical trials and that drug resistance may be less of a problem with antiangiogenic therapy than with conventional chemotherapy regimens. The suggestion is made that cytotoxic chemotherapy and angiogenesis inhibitors used in combination may produce complementary therapeutic benefits in the treatment of cancer.
The Role of Vascular Endothelial Growth Factor (VEGF) in AIDS-Related Kaposi's Sarcoma
Authors: Arastéh Keikawus , Hannah Alison
Published: August 2004

Kaposi's sarcoma (KS) is the most common neoplasm associated with human immunodeficiency virus-1 (HIV-1) infection. KS involves the skin and mucous membranes as well as other organs and can lead to tumor-associated edema and ulcerations. Despite therapy with highly active antiviral agents, most patients with HIV-1-related KS eventually develop disseminated disease. In the treatment of KS, a strong rationale exists for the use of agents that inhibit vascular endothelial growth factor (VEGF). Angiogenesis appears to be an important feature of this disease, and recent experimental studies have demonstrated the role of VEGF and its receptors in the pathogenesis of KS. Thus, therapeutic agents that target the VEGF pathway may be an effective strategy in reducing the tumor growth and edema associated with KS. Phase I study results with SU5416, a synthetic low molecular-weight inhibitor of the VEGF-Flk-1/KDR receptor tyrosine kinase, demonstrate that this agent is well tolerated.

Preliminary results show that in a majority of patients with autoimmune deficiency syndrome (AIDS)-related disease, SU5416 clearly has biological activity (it flattens, shrinks, or dissolves lesions and reduces or resolves edema) or stabilizes the disease. Angiogenesis inhibition with SU5416 is a promising therapeutic approach in treating patients with KS, and further clinical evaluation is currently under way.
Options in Advanced Non-Small Cell Lung Cancer: A Review and Report on a Phase II Study of Vinorelbine Plus Gemcitabine
Authors: Lilenbaum Rogerio
Published: August 2004

Although platinum-containing regimens prolong survival in advanced non-small cell lung cancer (NSCLC), toxicity remains substantial. There is a clear need for a nonplatinum-based regimen which is active, well tolerated, and suitable for outpatient administration. Vinorelbine and gemcitabine have different mechanisms of action and are both active in NSCLC. A phase II trial was undertaken to evaluate activity and tolerability when the two drugs were administered as a first-line combination regimen in 32 patients with stage IIIB/IV disease. Gemcitabine was administered at a dose of 1,000-1,250 mg/m2 together with vinorelbine 25 mg/m2 on days 1 and 8 of a 21-day cycle. The overall response rate was 25%, median survival 8.3 months and one-year survival rate 38% (48% in patients of performance status 0-1). Grade 3/4 neutropenia was observed in 38% of 148 treatment cycles, however, thrombocytopenia was infrequent and there was no grade 3/4 anemia. Nonhematological toxicity was minimal. The response and survival rates experienced were comparable with standard platinum-based combinations. Ongoing randomized trials will further define the role of the vinorelbine/gemcitabine combination in advanced NSCLC.
Carboplatin/Paclitaxel or Carboplatin/Vinorelbine Followed by Accelerated Hyperfractionated Conformal Radiation Therapy: A Preliminary Report of a Phase I Dose Escalation Trial from the Carolina Conformal Therapy Consortium
Authors: Socinski M. A. , Marks L.B. , Garst J. , Sibley G.S. , Blackstock W. , Turrisi A. , Herndon J. , Zhou S. , Anscher M. , Crawford J. , Shafman T. , Rosenman J.
Published: August 2004

The maximum tolerated dose of conformal radiation therapy delivered at 1.6 Gy bid is being assessed in patients with unresectable stage IIB-IIIB non-small cell lung cancer who have been treated with induction regimens consisting of carboplatin plus paclitaxel or carboplatin plus vinorelbine. Data from the early stages of this parallel phase I study show that the two induction regimens are similar in toxicity and that both induce partial responses in 45% of patients. Both regimens can be followed by conformal radiotherapy using an accelerated hyperfractionated schedule to a dose of at least 80 Gy without experiencing unacceptable toxicity. Key morbidity observed thus far has involved the esophagus. Further cohorts of patients will receive higher doses of conformal radiotherapy (in 6.4 Gy increments) until the maximum tolerated dose is reached.
Long Term Analysis of Survival in the European Randomized Trial Comparing Vinorelbine/Cisplatin to Vindesine/Cisplatin and Vinorelbine Alone in Advanced Non-Small Cell Lung Cancer
Authors: Le Chevalier T. , Brisgand D. , Soria J.C. , Douillard J.Y. , Pujol J.L. , Ruffie P. , Aberola V. , Cigolari S.
Published: August 2004

In the period 1989-1991, 612 patients with inoperable stage IIIA/B and IV non-small cell lung cancer (NSCLC) were randomized in a phase III trial comparing three chemotherapy regimens. Survival data at five and six years of follow-up confirm the overall benefit of treatment with a combination of vinorelbine and cisplatin compared to vindesine plus cisplatin or vinorelbine alone. Of the 612 patients randomized at the start of the study, 17 have survived beyond five years. Of these patients, eight had entered the trial with metastatic disease. Multivariate analysis to detect prognostic factors suggested a possible interaction between the effect of having cisplatin in the chemotherapy received and baseline performance status. Subgroup analysis subsequently confirmed that the survival benefit of the vinorelbine plus chemotherapy regimen is evident only in patients with initial World Health Organization performance status (PS) of 0-1. Among these patients, the one-year survival rate is 38% for the vinorelbine/cisplatin arm, 29% for vindesine/cisplatin and 34% for vinorelbine alone. The corresponding figures for median survival are 43, 33 and 36 weeks. Among inoperable NSCLC patients with a PS of 2, who appear from this trial not to have benefited from the presence of cisplatin in their chemotherapy, use of single agent vinorelbine is an appropriate treatment option.
Clinical Experience of Arsenic Trioxide in Relapsed Acute Promyelocytic Leukemia
Authors: Soignet Steven L.
Published: August 2004

Acute promyelocytic leukemia (APL) has unique clinical, cytogenetic, and molecular features and is one of the most potentially curable human malignancies. The current standard treatment given to patients with newly diagnosed APL con-sists of all-trans retinoic acid and anthracycline-based cytotoxic chemotherapy, which is highly effective for remission induction. However, despite the potential for cure with existing treatments, approximately 20%-30% of patients relapse and require salvage therapy. Reports of the safety and efficacy of arsenic trioxide from centers in China led to a pivotal trial of this agent in the United States for patients with relapsed APL. In an initial pilot study, 11 of 12 patients experienced a complete response, and a subsequent multicenter trial confirmed the efficacy and safety of arsenic trioxide for remission induction in this patient population. Additional trials are under way to evaluate the use of this agent alone or as part of a chemotherapy regimen for consolidation and maintenance of patients with APL.
Nonanthracycline Containing Docetaxel-Based Combinations in Metastatic Breast Cancer
Authors: Crown John
Published: August 2004

Many active nonanthracycline-containing regimens are emerging from clinical trials and may offer the option of treating metastatic breast cancer without resorting to doxorubicin or analogues. When used first-line in metastatic breast cancer, both cisplatin and carboplatin are active agents and hence candidates for combination therapy. In a dose-finding study in patients with no prior chemotherapy for metastatic disease, docetaxel administered together with cisplatin produced a promising response rate (RR) of 60% (73% in patients without prior adjuvant chemotherapy). The combination is feasible, although adequate hydration and antiemetic medication must be given. There is also an early indication that it may be possible to dramatically cytoreduce disease in patients with locally advanced breast cancer who are treated with docetaxel plus cisplatin. Given its lower toxicity, carboplatin may also have a role in combination with the taxanes. Of the nonplatinum agents, vinorelbine appears to hold promise; its combination with docetaxel produced an RR of 59% in a group of anthracycline-pretreated patients with progressive disease. Forty-two percent of the patients studied also had prior exposure to a taxane. Weekly gemcitabine plus monthly docetaxel is feasible and active, as is the combination of docetaxel q 3 weeks with daily oral capecitabine.
Neoadjuvant Therapy in Breast Cancer: Can We Define Its Role?
Authors: Aapro Matti S.
Published: August 2004

It remains unclear whether neoadjuvant therapy increases disease-free survival when compared with an approach in which chemotherapy is delayed until after surgery. However, the current rationale for neoadjuvant therapy is based on its usefulness in quickly evaluating the likely benefit of new approaches to treatment and tailoring therapy to the biological characteristics of the individual tumor. In the primary therapy of breast cancer, the Aberdeen study shows that patients unresponsive to an anthracycline-based neoadjuvant regimen may achieve a response when switched to docetaxel. Further, patients with an initial clinical response to CVAP were more likely to show a pathological complete response (pCR) at final assessment when four cycles of CVAP were followed by four of docetaxel than when CVAP was maintained for eight cycles (pCR rate 34% versus 16%). Early data suggest that this difference translates into significantly lengthened progression-free survival. As in other disease settings, it may be possible to devise nonanthracycline-containing neoadjuvant regimens which are at least as effective as those in current use.
Integrating Oxaliplatin into the Management of Colorectal Cancer
Authors: Schmoll Hans-Joachim , Cassidy Jim
Published: August 2004

Oxaliplatin, a third-generation platinum analogue, is a novel compound with proven anti-tumor activity in colorectal cancer that has demonstrated synergy with 5-fluorouracil (5-FU) in human tumor xenograft models. A series of phase II trials demonstrated that, as second-line therapy, oxaliplatin in combination with 5-FU/leucovorin (LV) is active and can overcome clinical resistance to 5-FU. Subsequently, two large, randomized, phase III trials demonstrated that the addition of oxaliplatin to 5-FU/LV significantly improved response rates and time to disease progression in the first-line setting, but had no statistically significant impact on survival. Oxaliplatin in combination with 5-FU/LV represents an important treatment option for patients in whom 5-FU-based therapy has failed and as first-line therapy. Oxaliplatin has also been investigated in combination with the oral fluoropyrimidine, capecitabine. As an oral agent that exploits the high intratumoral activity of thymidine phosphorylase to generate 5-FU preferentially within tumor tissue, capecitabine may improve the efficacy and tolerability of fluoropyrimidine/oxaliplatin combination therapy. A phase I dose-escalation study has been performed in patients with advanced/metastatic solid tumors to establish the most appropriate regimen. The study indicated that the combination is feasible and has substantial antitumor activity in patients with colorectal cancer. This article provides an overview of the clinical trial data for oxaliplatin and discusses how oxaliplatin may best be used in the future.
Improving Chemoradiotherapy in Rectal Cancer
Authors: Glynne-Jones Robert , Debus Jürgen
Published: August 2004

The optimal management of rectal cancer remains a major challenge for oncologists. The treatment of stage II/III rectal cancer has historically been associated with a high risk of local recurrence and poor survival, which led to the development of adjuvant treatments in the hope of improving outcomes. The approach to adjuvant therapy for rectal cancer currently varies widely between Europe and the U.S. Postoperative adjuvant chemoradiation is the standard of care in the U.S. In contrast, in Europe, because there is a greater emphasis placed on preoperative imaging, meticulous surgical technique, and accurate pathologic reporting of the circumferential or radial margin, preoperative treatment (radiotherapy and chemoradiation) is used widely. The aims of preoperative radiotherapy and chemoradiation are to facilitate a curative resection (R0) and to increase the chance of performing sphincter-sparing procedures, and, therefore, to improve both survival and quality of life.

This article reviews the clinical trials that led to these diverging standards of care. An interesting new approach in chemoradiation is the use of the oral fluoropyrimidine capecitabine as a combination partner for radiotherapy. Preclinical studies have demonstrated that the combination of capecitabine and radiotherapy has highly enhanced antitumor activity. This is most likely attributable to the upregulation of thymidine phosphorylase (the rate-limiting enzyme needed to convert capecitabine to 5-fluorouracil [5-FU]) in tumor cells following radiotherapy. A phase I study has consequently been performed to establish a feasible chemoradiotherapy combination. Capecitabine has the potential to replace bolus or continuous infusion 5-FU as the standard treatment for rectal cancer and offers a potentially enhanced therapeutic ratio. Oral chemotherapy has the additional advantage of simplifying chemoradiation and providing a treatment that is more appealing to patients.
The Evolution of Fluoropyrimidine Therapy: From Intravenous to Oral
Authors: Hoff Paulo M. , Cassidy Jim , Schmoll Hans-Joachim
Published: August 2004

Chemotherapy for advanced colorectal cancer is based on i.v. 5-fluorouracil (5-FU). Numerous attempts have been made to increase the therapeutic benefit of 5-FU through schedule modification and biomodulation, but only modest improvements have been achieved. Capecitabine is an oral fluoropyrimidine that was developed in response to the clinical need for new therapeutic options offering improved efficacy, tolerability, and convenience for patients. Capecitabine was rationally designed to mimic continuous infusion 5-FU. It is rapidly and almost completely absorbed through the gastrointestinal wall and is converted to 5-FU via a three-step enzymatic cascade. 5-FU is generated preferentially in tumor by exploiting the higher activity of thymidine phosphorylase in tumor tissue compared with normal tissue. Results of a randomized, phase II trial led to the selection of a regimen of capecitabine for further clinical development (1,250 mg/m2 twice daily for 14 days followed by a 7-day rest period). Subsequently, two large, randomized, phase III trials were conducted to compare capecitabine with i.v. bolus 5-FU/leucovorin ([LV]; Mayo Clinic regimen) in patients with metastatic colorectal cancer. A prospective, integrated analysis of data from the studies showed that capecitabine offers superior activity and an improved safety profile compared with 5-FU/LV. This article summarizes these developments in the treatment of colorectal cancer and assesses the feasibility of replacing i.v. 5-FU-based therapy with oral capecitabine. In addition, retrospective analyses assessing the impact of the dose modification scheme on the efficacy and tolerability of capecitabine are presented, and dose recommendations in special populations are reviewed.
Angiogenic Growth Factors: Autocrine and Paracrine Regulation of Survival in Hematologic Malignancies
Authors: Gabrilove Janice L.
Published: August 2004

Recent research has focused on the role of angiogenic growth factors and their ability to mediate tumor growth and metastases, both in solid tumors and in hematologic malignancies. The bone marrow microenvironment is the setting for a wealth of complex interactions that include cell-to-cell contacts as well as secretion of and response to soluble factors. Abundant evidence supports the role of basic fibroblast growth factor (bFGF) in contributing to the dysregulation of apoptosis that is the hallmark of chronic lymphocytic leukemia (CLL). In fact, CLL cells themselves express bFGF; intracellular levels of this cytokine correlate with clinical CLL stage. Other stromal factors mediate the inhibition of apoptosis in CLL as well, suggesting that strategies to block the responses of CLL cells to these factors may represent effective therapies. More broadly, the class of agents known as angiogenesis inhibitors may offer important advantages with respect to the treatment of numerous types of malignancies. Currently, a number of clinical trials are under way to evaluate the clinical potential of several different angiogenesis inhibitors in several hematologic neoplasms.
Advances in the Management of Acute Promyelocytic Leukemia and Other Hematologic Malignancies with Arsenic Trioxide
Authors: Slack James L. , Waxman Samuel , Tricot Guido , Tallman Martin S. , Bloomfield Clara D.
Published: August 2004

Learning Objectives

After taking all of the CME courses in this supplement the reader will be able to:

Describe the basic biology of various leukemias, multiple myeloma, and myelodysplastic syndrome (MDS). Discuss new targeted treatment strategies for hematologic malignancies. Understand the rationale for the use of nontraditional cytotoxic agents such as arsenic trioxide in the treatment of hematologic malignancies. Examine the role of arsenic trioxide and other novel agents in early- versus accelerated-stage hematologic disease. Discuss the preclinical and clinical efficacy of arsenic trioxide and various agents in treating acute promyelocytic leukemia, MDS, and multiple myeloma.

Access CME test online and receive one hour category 1 credit at CME.TheOncologist.com

Acute promyelocytic leukemia (APL), once considered the most devastating subtype of acute myeloid leukemia, is now the most treatable of all subtypes as a result of intensive research into its molecular pathogenesis. This research has led to a rational approach to treatment in which the use of the differentiating agent all-trans-retinoic acid (ATRA) has proven to be effective first-line treatment for inducing complete remission. Arsenic trioxide (ATO) is currently used to treat relapsed disease, further enhancing survival rates in a patient population for which limited salvage options exist. This review discusses the molecular mechanisms responsible for development of APL and the evolution of treatment options over the last three decades, including the major advances using ATRA and ATO in the last 12 years. The mechanism of action of ATO is also described in view of this agent's potential for broader therapeutic application in a variety of hematologic malignancies.
Multifaceted Approach to the Treatment of Bcr-Abl-Positive Leukemias
Authors: O'Dwyer Michael
Published: August 2004

Learning Objectives

After taking all of the CME courses in this supplement the reader will be able to:

Describe the basic biology of various leukemias, multiple myeloma, and myelodysplastic syndrome (MDS). Discuss new targeted treatment strategies for hematologic malignancies. Understand the rationale for the use of nontraditional cytotoxic agents such as arsenic trioxide in the treatment of hematologic malignancies. Examine the role of arsenic trioxide and other novel agents in early-versus accelerated-stage hematologic disease. Discuss the preclinical and clinical efficacy of arsenic trioxide and various agents in treating acute promyelocytic leukemia, MDS, and multiple myeloma.

Access CME test online and receive one hour category 1 credit at CME.TheOncologist.com

Bcr-Abl-positive leukemias include chronic myelogenous leukemia (CML), both myeloid and lymphoid blast-phase CML, and some cases of acute lymphoblastic leukemia. The chimeric bcr-abl gene codes for a tyrosine kinase that is constitutively activated in the leukemic cells and plays the central role in leukemogenesis. Hematologic malignancies, including Bcr-Abl-positive leukemias, also frequently have overactivity of the Ras signaling pathway, leading to abnormal transduction of growth and survival signals. New and investigational therapeutic options that target these specific molecular defects of leukemic cells include the tyrosine kinase inhibitor imatinib mesylate (STI571) and farnesyltransferase inhibitors (R115777, SCH66336), which block localization of Ras proteins to the cell membrane. While single-agent therapy with these new agents may produce hematologic and cytogenetic remissions in patients with Bcr-Abl-positive leukemias, molecular remissions are less common, and resistance may develop. Therefore, the development of a multifaceted therapeutic approach to these leukemias is of great interest. Arsenic trioxide (ATO), which has significant activity in patients with relapsed and refractory acute promyelocytic leukemia, is a potential addition to the therapeutic arsenal. While some of the molecular activities of ATO are specific to acute promyelocytic leukemia, arsenicals also have a broad variety of antineoplastic properties that may be useful in combination therapy with agents that target specific molecular defects of Bcr-Abl-positive leukemias.
A Staff Dialogue on Caring for a Cancer Patient Who Commits Suicide: Psychosocial Issues Faced by Patients, Their Families, and Caregivers
Authors: O'Shea Elizabeth M. , Lintz Kathleen C. , Penson Richard T. , Seiden Michael V. , Chabner Bruce A. , Lynch Thomas J.
Published: August 2004

Shortly before his death in 1995, Kenneth B. Schwartz, a cancer patient at Massachusetts General Hospital (MGH), founded The Kenneth B. Schwartz Center at MGH. The Schwartz Center is a non-profit organization dedicated to supporting and advancing compassionate health care delivery which provides hope to the patient, support to caregivers, and encourages the healing process. The Center sponsors the Schwartz Center Rounds, a monthly multidisciplinary forum during which caregivers discuss a specific cancer patient, reflect on the important psychosocial issues faced by patients, their families, and their caregivers, and gain insight and support from their fellow staff members.

The case presented was of a 31-year-old man who developed adenocarcinoma of the lung with painful bone metastases. His tumor was unresponsive to treatment and he subsequently committed suicide by shooting himself. The verbatim and subsequent discussion raised a number of issues. Staff were devastated by the violent way that he ended his life. They questioned whether more could have been done to prevent this outcome, yet acknowledged that it mirrored the way he had lived, and were able to discuss the values by which we live and die. Some, but not all, felt that the patient had the right to choose how and when to end his life.
The Cell Cycle as a Target for Cancer Therapy: Basic and Clinical Findings with the Small Molecule Inhibitors Flavopiridol and UCN-01
Authors: Senderowicz Adrian M.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to: Describe the basics of cell-cycle regulation.Understand how Rb pathway derangement causes cancer.Relate the clinical findings with flavopiridol and UCN-01 to their mechanisms of action.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com

Many tumor types are associated with genetic changes in the retinoblastoma pathway, leading to hyperactivation of cyclin-dependent kinases and incorrect progression through the cell cycle. Small-molecule cyclin-dependent kinase inhibitors are being developed as therapeutic agents. Of these, flavopiridol and UCN-01 are being explored in cancer patients in phase I and phase II clinical trials, both as single agents and in combination with conventional chemotherapeutic agents. The present article discusses the mechanisms of action of flavopiridol and UCN-01 as well as the outcome of clinical trials with these novel agents.
Why the Epidermal Growth Factor Receptor? The Rationale for Cancer Therapy
Authors: Baselga José
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:Explain the molecular biology of epidermal growth factor receptor (EGFR) function in malignant cells.Recognize the relationships between and functions of the erbB family of related cell membrane receptors.Describe the current status of clinical strategies to inhibit EGFR function in malignant cells.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com

There is a need for new, selective anticancer agents that differentiate between malignant and nonmalignant cells. The benefits of such agents would include a higher therapeutic index and lower toxicity than conventional therapies. Although expressed in nonmalignant cells, the epidermal growth factor receptor (EGFR) is highly expressed in a variety of tumors, and its expression correlates with poor response to treatment, disease progression, and poor survival. Evidence for a role for the EGFR in the inhibition and pathogenesis of various cancers has led to the rational design and development of agents that selectively target this receptor. Activation of the EGFR signaling pathway in cancer cells has been linked with increased cell proliferation, angiogenesis, and metastasis, and decreased apoptosis. Preclinical data show that anti-EGFR therapies can inhibit these effects in vitro and in vivo. In addition, preclinical data confirm that many such agents have the potential to increase the effectiveness of current cytotoxic agents. Following accelerated drug development programs, phase III trials are now under way for a number of EGFR-targeted therapies, including the monoclonal antibody IMC-C225 and the EGFR-tyrosine kinase inhibitors ZD1839 (IressaTM) and OSI-774. Thus, the rationale for EGFR-targeted approaches to cancer treatment is apparent and now well established, and there is increasing evidence that they may represent a significant contribution to cancer therapy.
Management of Treatment-Related Toxicity in Advanced Ovarian Cancer
Authors: Dunton Charles J.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:Recognize the reversible and irreversible toxicities associated with the management of newly diagnosed ovarian cancer.Better manage recurrent ovarian cancer.Identify the range of chemotherapeutic options in managing recurrent ovarian cancer.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com

Recognition of recurrent ovarian cancer as a disease with significant secondary responses and remissions has led to an increase in the need for oncologists to plan for the long-term therapy of patients. However, many of the currently available front-line and salvage agents used in advanced ovarian cancer are associated with cumulative and/or irreversible toxicities that pose challenges in long-term planning. The irreversible effects associated with some of these therapies may render patients less tolerant to subsequent treatments and lead to a cycle of diminishing treatment options with each remission and disease relapse. Additionally, the potential for patients to experience cumulative toxicity must be carefully weighed against the goals of prolonging the disease-free interval and improving patient quality of life. A number of agents are available in the treatment armamentarium (platinum, paclitaxel, gemcitabine, etoposide, liposomal doxorubicin, and topotecan), many, but not all of which are associated with cumulative toxicity. For instance, cumulative neurotoxicity associated with cisplatin as first-line therapy may diminish the option for retreatment with platinum at first relapse. In contrast, the main toxicity associated with topotecan is noncumulative, manageable myelosuppression. In this review, the major toxicities associated with the predominant chemotherapy agents used in advanced ovarian cancer are discussed along with selected management approaches in the context of long-term treatment planning and sequencing.
Emerging Role of Topotecan in Front-Line Treatment of Carcinoma of the Ovary
Authors: Coleman Robert L.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:Describe the range of different chemotherapy drugs active in newly diagnosed and recurrent ovarian cancer.Explain the mechanism of action and side effects of these drugs.Recognize how topotecan is being incorporated into the treatment of newly diagnosed ovarian cancer.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com

The conventional front-line chemotherapy strategy for advanced epithelial ovarian carcinoma has become adjuvant administration of platinum (carboplatin and cisplatin), either alone or, most often, in combination with a taxane. However, a number of active agents have been identified in phase II/III trials of second-line and salvage ovarian cancer patients that may augment this front-line strategy. One agent, topotecan, has antitumor activity comparable with paclitaxel in patients with recurrent ovarian cancer and is an established treatment in second-line or salvage settings. Additionally, its mechanism of action is different from paclitaxel and is nonoverlapping. These properties, coupled with the in vitro synergy observed in tumor models among topotecan, paclitaxel, and platinum, have provided the rationale for investigators to examine topotecan in front-line ovarian cancer therapy. A number of strategies for incorporating topotecan into front-line therapy are under active investigation, including the replacement of paclitaxel with topotecan, a triplet regimen with cisplatin or carboplatin and paclitaxel, a consolidation regimen consisting of several courses of a platinum agent and paclitaxel followed by several courses of topotecan, and a sequential doublet regimen in which patients receive platinum in every course as part of a doublet with alternating or sequential topotecan and paclitaxel. Preliminary data from ongoing clinical trials of these new regimens show favorable response rates and generally manageable toxicity profiles. This review summarizes the preliminary clinical findings associated with the four strategies and outlines ongoing and future randomized studies of topotecan in front-line ovarian cancer.