bluuebunny/crossref_metadata_2025 huggingface dataset:
SPECIFICATION OF A FUZZY OBJECT INFERENCE: TOWARDS AN ADVANCED KNOWLEDGE-BASED PROGRAMMING
Authors: YANG HYUNG JEONG , YANG JAE DONG
Published: January 2003

This paper provide a formal fuzzy object inference model to solve the following four significant drawbacks identified in extant fuzzy rule-based languages. First, they have difficulty in handling composite objects as a unit of inference. Second, they don't support fuzzy reasoning which is semantically easy to understand and conceptually simple to use. Third, their knowledge representation and reasoning style have a great semantic gap with those of current database models in syntax and semantics. Finally, they do not provide a comprehensive framework in treating uncertainties. In this paper, we demonstrate that the proposed model naturally models a target application environment in terms of composite objects possibly containing uncertain information, and successfully performs a fuzzy inference between them. To practically model the environment, we use the constructs of ICOT (Integrated C-Object Tool) extended for well implementing the structural semantics of the proposed model.
Genetics and Arrhythmias
Authors: Roberts Robert , Brugada Ramon
Published: January 2003

The availability of chromosomal markers that span the human genome and improved high-throughput technology for genotyping and sequencing have led to major advances against genetic diseases. Genes have been identified for several disorders responsible for arrhythmias and sudden death. These genes all encode ion channels and are referred to as channelopathy genes. Congenital long QT syndrome is caused by mutations in genes encoding sodium or potassium channels. Brugada syndrome, only recently described, is due to mutations in a sodium channel and is an important cause of sudden death, particularly in Southeast Asia. Familial polymorphic ventricular tachycardia is due to a defect in the ryanodine receptor. A locus mapped to 10q32 is responsible for familial atrial fibrillation. Treatments based on knowledge of the molecular defect are being implemented for long QT syndrome and will probably provide paradigms for targeted treatment of acquired arrhythmias.
Molecular Genetic Risk Screening
Authors: Grody Wayne W.
Published: January 2003

Under the impetus of the Human Genome Project, new disease-associated genes are being discovered at a rapid pace. Mutations in many of these genes are present in a high enough proportion of the general population, or of particular ethnic groups, that global or targeted population screening can be contemplated. If performed early enough, identification of these mutations by molecular genetic testing can be used not merely to diagnose disease but to predict risk of future disease, either in the individual being tested or in his or her offspring. In some cases this knowledge can be the rationale for heightened surveillance and/or preventive or therapeutic interventions. Mass screening has already commenced for cystic fibrosis mutations and has been discussed for such diverse diseases as hereditary hemochromatosis, thrombophilias, familial cancer predispositions, and pharmacogenetic risk factors. However, implementation of such programs is often impeded by the complexity of the gene mutations, by incomplete penetrance, and by thorny ethical and social issues. This chapter reviews the basic criteria to be considered before embarking on population genetic risk screening, and examines multiple disease-screening examples representing a variety of modes of inheritance and technical challenges.
AIDS-Related Malignancies
Authors: Scadden David T.
Published: January 2003

Immunodeficiency alters the risk of cancer. Specific types of immune dysfunction are associated with different tumor risks, but most tumors are related to oncogenic viruses. In acquired immunodeficiency due to the human immunodeficiency virus (HIV), HIV itself rarely directly causes cancer; rather, it provides the immunologic background against which other viruses can escape immune control and induce tumors. The most common malignancies are Kaposi's sarcoma and non-Hodgkin's lymphoma. This chapter discusses the pathophysiologic background of these tumors, how they have been affected by the use of anti-HIV medications, and their clinical management.
Growth Hormone Therapy in Adults
Authors: Cummings David E. , Merriam George R.
Published: January 2003

Growth hormone (GH) is classically linked with linear growth in childhood but continues to have important metabolic actions throughout life. GH deficiency in adulthood causes a distinct syndrome with significant morbidities. These include increased total and visceral fat, decreased muscle mass and aerobic capacity, affective disturbances, abnormal lipids, and increased vascular mortality, all of which are ameliorated with GH replacement. The possibility of adult GH deficiency (AGHD) should always be considered in individuals with a history of childhood GH deficiency or significant hypothalamic-pituitary damage, and the diagnosis should then be confirmed by biochemical testing. Adult GH dosing is much lower than that in pediatric practice, as appropriate for physiologic reconstitution. Hormonal side effects are minimized by stepwise dose titration. Lingering concerns remain regarding the possibility of increased cancer risk with long-term treatment, but this hazard has not been unequivocally demonstrated. Compared with AGHD, there is much less information about GH replacement in other diseases or in normal aging, or about the use of supraphysiologic GH doses to treat catabolic states. In critical illness, high-dose GH therapy has proven clearly harmful, and the balance of risks and benefits of GH administration in most adult contexts other than AGHD has not been defined.
Molecular Genetics of Lung Cancer
Authors: Sekido Yoshitaka , Fong Kwun M. , Minna John D.
Published: January 2003

Lung cancer results from multiple changes in the genome of susceptible pulmonary cells caused by exposure to carcinogens found in tobacco smoke, the environment, or the workplace. Recent studies suggest that histologically apparent lung cancer is due to the sequential accumulation of specific genetic and morphologic changes to the normal epithelial cells of the lung. Positive signallers, such as those mediated by the oncogene RAS, and negative signallers, such as those mediated by the tumor suppressor retinoblastoma protein (RB), contribute to unchecked cell growth and proliferation. Other key molecular derangements can also be considered hallmarks of cancer, including evasion of apoptosis and senescence, angiogenesis, tissue invasion, and metastases. Epigenetic inactivation of genes via DNA methylation provides another novel way of evading normal cellular control mechanisms. The new knowledge of the human genome coupled with global methods of detecting genetic abnormalities and profiling gene expression in tumor cells may enable us to understand the signaling pathways of lung cancer cells. These are molecular targets for new cancer therapeutics such as receptor tyrosine kinase inhibitors. This information could advance risk assessment, early detection, prognosis, and therapy for lung cancer.
The Biomedical Challenges of Space Flight
Authors: Williams David R.
Published: January 2003

Space medicine has evolved considerably through past U.S. missions. It has been proven that humans can live and work in space for long durations and that humans are integral to mission success. The space medicine program of the National Aeronautics and Space Administration (NASA) looks toward future long-duration missions. Its goal is to overcome the biomedical challenges associated with maintaining the safety, health, and optimum performance of astronauts and cosmonauts. This program investigates the health effects of adaptation to microgravity: the nature of their pathologies, the effects of microgravity on pathophysiology, and the alterations in pharmacodynamics and treatment. A critical capability in performing research is the monitoring of the health of all astronauts and of the spacecraft environment. These data support the evidence-based approach to space medicine, incorporating past studies of microgravity-related conditions and their terrestrial counterparts. This comprehensive approach will enable safe and effective exploration beyond low Earth orbit.
Standards of Care in Geriatric Practice
Authors: Luchi Robert J. , Gammack Julie K. , Narcisse Victor J. , Storey C. Porter
Published: January 2003

We propose a set of standards to aid the physician in the care of older patients. These standards are based on the practical experiences of our own group and of others with years of clinical practice in geriatric medicine. The standards also reflect the guidelines, position papers, and deliberations of various organizations concerned with the care of older people. This article does not discuss specific illnesses or the common geriatric syndromes. The proposed standards cover comprehensive care and assessment, especially of vulnerable elders and prevention of disease and disability. We also propose standards for facilitation of care across the health service continuum, care of the nursing home resident, and palliative and hospice care.
The Influence ofHLAGenotype on AIDS
Authors: Carrington Mary , O'Brien Stephen J.
Published: January 2003

Genetic resistance to infectious diseases is likely to involve a complex array of immune-response and other genes with variants that impose subtle but significant consequences on gene expression or protein function. We have gained considerable insight into the genetic determinants of HIV-1 disease, and the HLA class I genes appear to be highly influential in this regard. Numerous reports have identified a role for HLA genotype in AIDS outcomes, implicating many HLA alleles in various aspects of HIV disease. Here we review the HLA associations with progression to AIDS that have been consistently affirmed and discuss the underlying mechanisms behind some of these associations based on functional studies of immune cell recognition.
Atheroprotective Effects of High-Density Lipoproteins
Authors: Assmann Gerd , Nofer Jerzy-Roch
Published: January 2003

Observational studies provide overwhelming evidence that a low high-density lipoprotein (HDL)–cholesterol level increases the risk of coronary events, both in healthy subjects and in patients with coronary heart disease. Based on in vitro experiments, several mechanistic explanations for the atheroprotective function of HDL have been suggested. However, few of these were verified in vivo in humans or in experiments with transgenic animals. The HDL functions currently most widely held to account for the antiatherogenic effect include participation in reverse cholesterol transport, protection against endothelial dysfunction, and inhibition of oxidative stress. This review summarizes current views on the molecular mechanism underlying these atheroprotective effects of HDL.
The Antiphospholipid Syndrome
Authors: Rand Jacob H.
Published: January 2003

The antiphospholipid (aPL) antibody syndrome is an autoimmune condition in which vascular thrombosis and/or recurrent pregnancy losses occur in patients with laboratory evidence for antibodies that bind to phospholipids. There have been significant advances in the recognition of the role of phospholipid-binding cofactors, primarily β2GPI, as the true immunologic targets of the antibodies. Recent evidence suggests that the antibodies disrupt phospholipid-dependent anticoagulant mechanisms and/or that aPL antibodies induce the expression of procoagulant and proadhesive molecules on endothelial cells. Current diagnosis is based on clinical findings and empirically derived tests, such as assays for antibodies that bind to phospholipids or putative cofactors and coagulation assays that detect inhibition of phospholipid-dependent coagulation reactions. Current treatment relies primarily on anticoagulant therapy. Research advances are expected to bring mechanistically based diagnostic tests and improved therapy that target the roots of the disease process.
Functional Genomics of the Paraoxonase (PON1) Polymorphisms: Effects on Pesticide Sensitivity, Cardiovascular Disease, and Drug Metabolism
Authors: Costa Lucio G. , Cole Toby B. , Jarvik Gail P. , Furlong Clement E.
Published: January 2003

This review focuses on the functional genomics of the human paraoxonase (PON1) polymorphisms. Levels and genetic variability of the PON1 position 192 isoforms (Gln/Arg) influence sensitivity to specific insecticides or nerve agents and risk for cardiovascular disease. A more recent area of investigation, the role of PON1 in drug metabolism, is also discussed. We emphasize the importance of considering both PON1 isoforms and PON1 levels in disease/sensitivity association studies.
Open Surgical Repair Versus Endovascular Therapy for Chronic Lower-Extremity Occlusive Disease
Authors: Schermerhorn Marc L. , Cronenwett Jack L. , Baldwin John C.
Published: January 2003

Chronic lower-extremity occlusive disease is most often manifested by mild symptoms of claudication that can be managed conservatively. When conservative therapy fails, endovascular procedures may be effective, particularly if the disease extent is minimal. Surgery may be considered for selected patients with claudication who fail endovascular therapy or are not candidates for it. Patients with more severe symptoms of lower-extremity occlusive disease typically have more extensive disease that is treated best with surgery or with a combination of surgery and endovascular therapy. Occasionally, endovascular procedures are performed on patients with more extensive disease who are poor candidates for traditional open surgery because of severe comorbidity. Further advances in endovascular technology may improve patency after endovascular procedures in these patients.
Randomized Cross-Over Evaluation of Body-Surface Area–Based Dosing Versus Flat-Fixed Dosing of Paclitaxel
Authors: Smorenburg Carolien H. , Sparreboom Alex , Bontenbal Marijke , Stoter Gerrit , Nooter Kees , Verweij Jaap
Published: January 2003

Purpose: Despite dose calculation using body-surface area (BSA), pharmacokinetics of most anticancer drugs show wide interindividual variability. In this study, we evaluated the role of BSA in paclitaxel disposition.

Patients and Methods: Paclitaxel pharmacokinetics were prospectively studied in 12 patients that were treated in a randomized cross-over design with paclitaxel (3-hour infusion at a 3-week interval) at 175 mg/m2 in cycle 1 (A) and a flat-fixed dose of 300 mg in cycle 2 (B), or vice versa. Blood samples were collected up to 24 hours after dosing and analyzed for total and unbound paclitaxel.

Results: The area under the curves (AUC) of unbound paclitaxel were similar in both dosing groups, with mean values ± SD (A v B) of 1.34 ± 0.158 versus 1.30 ± 0.329 μM•h, indicating that BSA-based dosing reduced the coefficient of variation by 53.3%. Unbound and total paclitaxel clearance was also significantly related to various body-size measures, including BSA (R ≥ 0.617; P ≤ .033), weight (R ≥ 0.621; P ≤ .031), and lean-body mass (r ≥ 0.630; P ≤ .028). We hypothesize that this is caused by the association of paclitaxel in the circulation with Cremophor EL, the distribution of which is linked to total blood volume, and thus to BSA.

Conclusion: This study indicates that paclitaxel disposition is significantly related to BSA. This provides a pharmacokinetic rationale for BSA-based dosing of this drug.
Osteosarcoma of the Pelvis: Experience of the Cooperative Osteosarcoma Study Group
Authors: Ozaki Toshifumi , Flege Silke , Kevric Matthias , Lindner Norbert , Maas Rainer , Delling Günter , Schwarz Rudolf , von Hochstetter Arthur R. , Salzer-Kuntschik Mechthild , Berdel Wolfgang E. , Jürgens Heribert , Exner G. Ulrich , Reichardt Peter , Mayer-Steinacker Regine , Ewerbeck Volker , Kotz Rainer , Winkelmann Winfried , Bielack Stefan S.
Published: January 2003

Purpose: To define patients and tumor characteristics as well as therapy results, patients with pelvic osteosarcoma who were registered in the Cooperative Osteosarcoma Study Group (COSS) were analyzed.

Patients and Methods: Sixty-seven patients with a high-grade pelvic osteosarcoma were eligible for this analysis. Fifteen patients had primary metastases. All patients received chemotherapy according to COSS protocols. Thirty-eight patients underwent limb-sparing surgery, 12 patients underwent hemipelvectomy, and 17 patients did not undergo definitive surgery. Eleven patients received irradiation to the primary tumor site: four postoperatively and seven as the only form of local therapy.

Results: Local failure occurred in 47 of all 67 patients (70%) and in 31 of 50 patients (62%) who underwent definitive surgery. Five-year overall survival (OS) and progression-free survival rates were 27% and 19%, respectively. Large tumor size (P = .0137), primary metastases (P = .0001), and no or intralesional surgery (P < .0001) were poor prognostic factors. In 30 patients with no or intralesional surgery, 11 patients with radiotherapy had better OS than 19 patients without radiotherapy (P = .0033). Among the variables, primary metastasis, large tumor, no or intralesional surgery, no radiotherapy, existence of primary metastasis (relative risk [RR] = 3.456; P = .0009), surgical margin (intralesional or no surgical excision; RR = 5.619; P < .0001), and no radiotherapy (RR = 4.196; P = .0059) were independent poor prognostic factors.

Conclusion: An operative approach with wide or marginal margins improves local control and OS. If the surgical margin is intralesional or excision is impossible, additional radiotherapy has a positive influence on prognosis.
Biology of Prostate-Specific Antigen
Authors: Balk Steven P. , Ko Yoo-Joung , Bubley Glenn J.
Published: January 2003

Prostate-specific antigen (PSA) is an androgen-regulated serine protease produced by both prostate epithelial cells and prostate cancer (PCa) and is the most commonly used serum marker for cancer. It is a member of the tissue kallikrein family, some of the members of which are also prostate specific. PSA is a major protein in semen, where its function is to cleave semenogelins in the seminal coagulum. PSA is secreted into prostatic ducts as an inactive 244–amino acid proenzyme (proPSA) that is activated by cleavage of seven N-terminal amino acids. PSA that enters the circulation intact is rapidly bound by protease inhibitors, primarily alpha1-antichymotrypsin, although a fraction is inactivated in the lumen by proteolysis and circulates as free PSA. This proteolytic inactivation, as well as the cleavage of proPSA to PSA, is less efficient in PCa. Serum total PSA levels are increased in PCa, and PSA screening has dramatically altered PCa presentation and management. Unfortunately, although high PSA levels are predictive of advanced PCa, a large fraction of organ-confined cancers present with much lower total PSA values that overlap those levels found in men without PCa. Measurement of free versus total PSA can increase specificity for PCa, and tests under development to measure forms of proPSA may further enhance the ability to detect early-stage PCa. PSA is also widely used to monitor responses to therapy and is under investigation as a therapeutic target. Finally, recent data indicate that there may be additional roles for PSA in the pathogenesis of PCa.
Phase II Trial of Irinotecan in Patients With Metastatic Epithelial Ovarian Cancer or Peritoneal Cancer
Authors: Bodurka Diane C. , Levenback Charles , Wolf Judith K. , Gano Jacalyn , Wharton J. Taylor , Kavanagh John J. , Gershenson David M.
Published: January 2003

Purpose: To evaluate the efficacy and toxicity of irinotecan in patients with metastatic platinum-resistant or platinum-refractory epithelial ovarian cancer or primary peritoneal cancer.

Patients and Methods: Thirty-one patients with measurable disease were enrolled in our study at The University of Texas M.D. Anderson Cancer Center. Twenty-five of these patients were treated with irinotecan at a dose of 300 mg/m2 intravenously for 90 minutes every 3 weeks; the remaining six patients were treated with 250 mg/m2 because their age was greater than 65 years. Median age was 57 years (range, 38 to 74 years). The majority (84%) had a Zubrod performance status of 0. All patients were evaluated for irinotecan toxicity, and 29 (94%) were evaluable for response.

Results: The overall response rate was 17.2%. One patient (3%) had a complete response, four (14%) had partial responses, 14 (48%) had stable disease, and 10 had (35%) disease progression. Median progression-free survival was 2.8 months (range, 1.1 to 16 months), median duration of response was 1.4 months (range, 0.7 to 10.1 months); median survival from primary diagnosis was 24.3 months (range, 6.5 to 85.7 months); and median survival from initiation of irinotecan was 10.1 months (range, 2.3 to 34 months). Major toxicities included fatigue (16 patients), neutropenia (11 patients), diarrhea (nine patients), nausea (10 patients), and anorexia (seven patients). Eleven patients required dose reductions because of these toxicities. No treatment-related deaths occurred.

Conclusion: Irinotecan has moderate efficacy and substantial toxicity in patients with metastatic platinum-resistant or platinum-refractory epithelial ovarian or primary peritoneal cancer.
Epoetin Alfa Treatment Results in Clinically Significant Improvements in Quality of Life in Anemic Cancer Patients When Referenced to the General Population
Authors: Cella David , Zagari Martin J. , Vandoros Christina , Gagnon Dennis D. , Hurtz Hans-Jürgen , Nortier Johan W.R.
Published: January 2003

Purpose: Anemia, highly common among cancer patients, is often an underlying cause of cancer-related fatigue and other quality-of-life (QOL) deficits. Although randomized clinical trials have shown that treatment with epoetin alfa increases hemoglobin levels, reduces fatigue, lessens transfusion requirements, and improves overall QOL, cancer-related anemia and fatigue remain undertreated. This is, in part, because scales and measures of QOL are still relatively unfamiliar to most clinicians and because population-based reference ranges are lacking, thus making clinical trial results difficult to interpret.

Methods: To aid in the interpretation of QOL results from clinical trials, we administered the Functional Assessment of Cancer Therapy–Anemia (FACT-An) QOL instrument to a nationally representative sample of 1,400 people using an Internet survey panel in the United States. We then compared the FACT-An data from the Internet survey with the QOL data of a 375-patient randomized, double-blind clinical trial evaluating epoetin alfa versus placebo in anemic cancer patients.

Results: FACT-An, as administered to the survey population, displayed good psychometric properties and was able to discriminate between respondents with histories of specified illnesses, including anemia and cancer, and those without. Comparison of the population norm and clinical trial data showed that treatment with epoetin alfa resulted in clinically meaningful as well as statistically significant improvements in QOL (P < .01).

Conclusion: Reliable population norm data are now available to aid in the interpretation of clinical trial results where the FACT-An questionnaire is administered. In the clinical trial, treatment with epoetin alfa overcame much of the QOL deficit seen in anemic cancer patients compared with the norm population sample.
SarCNU, a Nitrosourea Analog on a Day 1, 5, and 9 Oral Schedule: A Phase I and Pharmacokinetic Study in Patients With Advanced Solid Tumors
Authors: Panasci L. , Stinson S.F. , Melnychuk D. , Sandor V. , Miller W.H. , Batist G. , Patenaude F. , Bangash N. , Panarello L. , Alaoui-Jamali M. , Sausville E.
Published: January 2003

Purpose: 2-Chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU) is a novel chloroethylnitrosourea that demonstrates selective cytotoxicity in athymic mice bearing human glioma. SarCNU demonstrates selective cytotoxicity in vitro against human glioma at least in part because of the selective SarCNU uptake by the extraneuronal monoamine transporter. The purpose of this phase I study was to determine the maximum-tolerated dose (MTD), the toxicity profile, the pharmacokinetics profile, and recommended phase II dose.

Patients and Methods: Forty-three eligible patients with advanced solid tumors were enrolled. SarCNU was administered orally on days 1,5, and 9 every 28 days. The dose ranged from 30 to 1,075 mg/m2. Pharmacokinetic evaluation was done on the first cycle (one dose was given intravenously on day 1 or 5 of the first cycle to determine bioavailability).

Results: Delayed myelosuppression (thrombocytopenia and neutropenia occurring 4 to 6 weeks after administration) was the dose-limiting toxicity (DLT). Anemia occurred but was mild. Nonhematologic toxicity was generally mild, but one patient died with pulmonary toxicity that was probably secondary to SarCNU. There were no partial or complete responses, but eight patients had stable disease for 19 to 46 weeks. The oral bioavailability of SarCNU was 80% ± 37%. The terminal phase half-life was similar after intravenous (58.4 ± 23.5 minutes) or oral (64.0 ± 34.8 minutes) administration. The total plasma clearance was 20.4 ± 8.8 L/h/m2, and the apparent volume of distribution was 29.9 ± 17.6 L/m2. The area under the plasma concentration–time profile increased proportionally with the dose, and the pharmacokinetics seemed to be independent of the route of administration and the number of doses.

Conclusion: SarCNU was well tolerated and the MTD was 1,075 mg/m2. The recommended starting dose for phase II trials is 860 mg/m2 orally on days 1, 5, and 9 every 6 weeks.
Diagnostic Cerebrospinal Fluid Examination in Children With Acute Lymphoblastic Leukemia: Significance of Low Leukocyte Counts With Blasts or Traumatic Lumbar Puncture
Authors: Bürger Britta , Zimmermann Martin , Mann Georg , Kühl Joachim , Löning Lutz , Riehm Hansjörg , Reiter Alfred , Schrappe Martin
Published: January 2003

Purpose: To determine the significance of leukemic blasts or traumatic lumbar puncture (TLP) in diagnostic CSF of children enrolled in the Berlin-Frankfurt-Münster (BFM) Acute Lymphoblastic Leukemia–BFM-95 trial.

Patients and Methods: A total of 2,021 patients were retrospectively evaluated according to initial central nervous system (CNS) status. Patients were classified as follows: CNS1 (CNS negative, n = 1,605), CNS2 (≤ 5 WBC/μL CSF with blasts, n = 103), CNS3 (CNS positive, n = 58), TLP+ (TLP with blasts, n = 135), or TLP− (TLP without blasts, n = 111). Patients with CNS2 and TLP+ status were eligible for two additional doses of intrathecal (IT) methotrexate (MTX). CNS3 patients received additional IT MTX and cranial irradiation (18 Gy).

Results: CNS2, CNS3, and TLP+ groups contained a higher percentage of patients with unfavorable characteristics. Cox regression analysis identified TLP+ and CNS3 status as prognostically significant (CNS3): risk ratio (RR) = 2.3; 95% confidence interval [CI], 1.4 to 3.6; P = .0005; TLP+: RR = 1.5; 95% CI, 1.02 to 2.2; P = .04. Overall 5-year event-free survival (EFS) is 79%, for CNS1 it is 80%, and for TLP− it is 83%. CNS2 patients have an EFS of 80%, but the cumulative incidence of relapses with CNS involvement is higher compared with CNS1 patients (0.10 v 0.04). TLP+ patients have a significantly reduced EFS (73%, P = .003) because of an increased incidence of CNS relapses. CNS3 patients suffer from more systemic and CNS relapses (EFS 50%).

Conclusion: CNS2 patients have the same prognosis as patients with CNS1 status, whereas the EFS of TLP+ patients is inferior to CNS1 but superior to CNS3 patients (P = .001). Both subgroups may have benefitted from additional IT MTX.
Brief Physician-Initiated Quit-Smoking Strategies for Clinical Oncology Settings: A Trial Coordinated by the Eastern Cooperative Oncology Group
Authors: Schnoll Robert A. , Zhang Bin , Rue Montserrat , Krook James E. , Spears Wayne T. , Marcus Alfred C. , Engstrom Paul F.
Published: January 2003

Purpose: Although tobacco use by cancer patients increases the risk of relapse, diminishes treatment efficacy, and worsens quality of life, about one third of patients who smoked before their diagnosis continue to smoke. Because patients have regular contact with oncologists, the efficacy of a physician-based smoking cessation treatment was evaluated.

Methods:Cancer patients (n = 432) were randomly assigned to either usual care or a National Institutes of Health (NIH) physician-based smoking intervention. The primary outcome was 7-day point prevalence abstinence at 6 and 12 months after study entry.

Results: At the 6-month follow-up, there was no significant difference in quit rates between the usual care (11.9%) and intervention (14.4%) groups, and there was no significant difference between the usual care (13.6%) and intervention (13.3%) groups at the 12-month follow-up. Patients were more likely to have quit smoking at 6 months if they had head and neck or lung cancer, began smoking after the age of 16, reported at baseline using a cessation self-help guide or treatment in the last 6 months, and showed greater baseline desire to quit. Patients were more likely to have quit smoking at 12 months if they smoked 15 or fewer cigarettes per day, had head and neck or lung cancer, tried a group cessation program, and showed greater baseline desire to quit. Finally, there was greater adherence among physicians to the NIH model for physician smoking treatment for patients in the intervention versus the usual care group.

Conclusion: While training physicians to provide smoking cessation treatment to cancer patients can enhance physician adherence to clinical practice guidelines, physician smoking cessation interventions fail to yield significant gains in long-term quit rates among cancer patients.
Additional Prognostic Value of Bone Marrow Histology in Patients Subclassified According to the International Prognostic Scoring System for Myelodysplastic Syndromes
Authors: Verburgh E. , Achten R. , Maes B. , Hagemeijer A. , Boogaerts M. , De Wolf-Peeters C. , Verhoef G.
Published: January 2003

Purpose: The most recent and powerful prognostic instrument established for myelodysplastic syndromes (MDS) is the International Prognostic Scoring System (IPSS), which is primarily based on medullary blast cell count, number of cytopenias, and cytogenetics. Although this prognostic system has substantial predictive power in MDS, further refinement is necessary, especially as far as lower-risk patients are concerned. Histologic parameters, which have long proved to be associated with outcome, are promising candidates to improve the prognostic accuracy of the IPSS. Therefore, we assessed the additional predictive power of the presence of abnormally localized immature precursors (ALIPs) and CD34 immunoreactivity in bone marrow (BM) biopsies of MDS patients.

Patients and Methods: Cytogenetic, morphologic, and clinical data of 184 MDS patients, all from a single institution, were collected, with special emphasis on the determinants of the IPSS score. BM biopsies of 173 patients were analyzed for the presence of ALIP, and CD34 immunoreactivity was assessable in 119 patients. Forty-nine patients received intensive therapy.

Results: The presence of ALIP and CD34 immunoreactivity significantly improved the prognostic value of the IPSS, with respect to overall as well as leukemia-free survival, in particular within the lower-risk categories. In contrast to the IPSS, both histologic parameters also were predictive of outcome within the group of intensively treated MDS patients.

Conclusion: Our data confirm the importance of histopathologic evaluation in MDS and indicate that determining the presence of ALIP and an increase in CD34 immunostaining in addition to the IPSS score could lead to an improved prognostic subcategorization of MDS patients.
Prognostic Value of Thymidylate Synthase, Ki-67, and p53 in Patients With Dukes’ B and C Colon Cancer: A National Cancer Institute–National Surgical Adjuvant Breast and Bowel Project Collaborative Study
Authors: Allegra Carmen J. , Paik Soon , Colangelo Linda H. , Parr Allyson L. , Kirsch Ilan , Kim George , Klein Pamela , Johnston Patrick G. , Wolmark Norman , Wieand H. Samuel
Published: January 2003

Purpose: To define the value of thymidylate synthase (TS), Ki-67, and p53 as prognostic markers in patients with stage II and III colon carcinoma.

Patients and Methods: We retrospectively analyzed the prognostic value of TS, Ki-67, and p53 in 706 patients with Dukes’ B (291 patients) or Dukes’ C (415 patients) colon carcinoma who were treated with either surgery alone (275 patients) or surgery plus fluorouracil (FU)-leucovorin chemotherapy (431 patients) in National Surgical Adjuvant Breast and Bowel Project (NSABP) protocols C01-C04. All three markers were assayed using immunohistochemical techniques.

Results: Using 5 years of follow-up data, our retrospective analysis demonstrated an association between TS intensity (relapse-free survival [RFS]: risk ratio [RR] = 1.46, P = .01; overall survival [OS]: RR = 1.54, P = .002), Ki-67 (RFS: RR = 0.76, P = .05; OS: RR = 0.62, P = .001), and p53 (RFS: RR = 1.49, P = .01; OS: RR = 1.21, P = .18) for RFS and OS. High TS intensity levels and positive p53 staining were associated with a worse outcome. Tumors containing a high percentage of Ki-67-positive cells enjoyed an improved outcome compared with those patients whose tumors contained relatively few positive cells. An interaction with treatment was not identified for any of the markers.

Conclusion: This retrospective investigation demonstrated that TS, Ki-67, and p53 staining each had significant prognostic value for patients with Dukes’ B and C colon carcinoma. However, none of the markers could be used to clearly discern groups of individuals who would be predicted to derive greater or lesser benefit from the use of adjuvant chemotherapy.
Combination of Raltitrexed and Oxaliplatin Is an Active Regimen in Malignant Mesothelioma: Results of a Phase II Study
Authors: Fizazi K. , Doubre H. , Le Chevalier T. , Riviere A. , Viala J. , Daniel C. , Robert L. , Barthélemy P. , Fandi A. , Ruffié P.
Published: January 2003

Purpose: The aim of this open-label phase II study was to evaluate the activity of raltitrexed (Tomudex; AstraZeneca, Cergy, France) and oxaliplatin combination therapy in patients with diffuse malignant pleural mesothelioma.

Patients and Methods: Fifteen pretreated and 55 chemotherapy-naive patients (median age, 60 years; World Health Organization performance status of ≤ 2) were enrolled. Most patients (66%) had advanced disease. Patients received raltitrexed 3 mg/m2 followed by oxaliplatin 130 mg/m2 every 3 weeks.

Results: Twenty-four patients (34%) were classified as having a poor prognosis. In the overall study population, 14 patients (20%) had a partial response, and 32 patients (46%) had stable disease. The symptomatic response rates were as follows: shortness of breath, 36%; pain, 30%; activity, 23%; appetite, 21%; and asthenia, 20%. Median time to disease progression was 18 weeks (95% confidence interval [CI], 13 to 22 weeks). In chemotherapy-naive patients, median survival was 31 weeks (95% CI, 23 to 40 weeks) from the start of treatment and 49 weeks (95% CI, 40 to 52 weeks) from diagnosis of mesothelioma. In pretreated patients, median survival was 44 weeks (95% CI, 24 to 40 weeks) from the start of treatment and 226 weeks (95% CI, 63 to 292 weeks) from the diagnosis of mesothelioma. Overall 1-year survival was 26% (95% CI, 15.5% to 36.4%), survival was 22% (95% CI, 10.9% to 33.2%) in chemotherapy-naive patients and 40% (95% CI, 15.2% to 64.8%) in pretreated patients. Hematologic toxicity was mild, and there was no alopecia. The most common adverse events were asthenia, nausea/vomiting, and paraesthesia, and no treatment-related deaths were reported.

Conclusion: The raltitrexed and oxaliplatin combination is an active outpatient regimen in malignant mesothelioma and has an acceptable tolerability profile.
Cantuzumab Mertansine, a Maytansinoid Immunoconjugate Directed to the CanAg Antigen: A Phase I, Pharmacokinetic, and Biologic Correlative Study
Authors: Tolcher Anthony W. , Ochoa Leonel , Hammond Lisa A. , Patnaik Amita , Edwards Tam , Takimoto Chris , Smith Lon , de Bono Johann , Schwartz Garry , Mays Theresa , Jonak Zdenka L. , Johnson Randall , DeWitte Mark , Martino Helen , Audette Charlene , Maes Kate , Chari Ravi V.J. , Lambert John M. , Rowinsky Eric K.
Published: January 2003

Purpose: To determine the maximum tolerated dose and pharmacokinetics of cantuzumab mertansine, an immunoconjugate of the potent maytansine derivative (DM1) and the humanized monoclonal antibody (huC242) directed to CanAg, intravenously (IV) once every 3 weeks and to seek evidence of antitumor activity.

Patients and Methods: Patients with CanAg-expressing solid malignancies were treated with escalating doses of cantuzumab mertansine administered IV every 3 weeks. The pharmacokinetic parameters of cantuzumab mertansine, the presence of plasma-shed CanAg, and the development of both human antihuman and human anti-DM1 conjugate antibodies also were characterized.

Results: Thirty-seven patients received 110 courses of cantuzumab mertansine at doses ranging from 22 to 295 mg/m2. Acute, transient, and reversible elevations of hepatic transaminases were the principal toxic effects. Nausea, vomiting, fatigue, and diarrhea were common but rarely severe at the highest dose levels. Dose, peak concentration, and area under the concentration–time curve correlated with the severity of transaminase elevation. The mean (± SD) clearance and terminal elimination half-life values for cantuzumab mertansine averaged 39.5 (±13.1) mL/h/m2 and 41.1 (±16.1) hours, respectively. Strong expression (3+) of CanAg was documented in 68% of patients. Two patients with chemotherapy-refractory colorectal carcinoma had minor regressions, and four patients had persistently stable disease for more than six courses.

Conclusion: The recommended dose for cantuzumab mertansine is 235 mg/m2 IV every 3 weeks. The absence of severe hematologic toxic effects, preliminary evidence of cantuzumab mertansine tumor localization, and encouraging biologic activity in chemotherapy-refractory patients warrant further broad clinical development of this immunoconjugate in CanAg-expressing tumors.
Primary Chemotherapy in Resectable Oral Cavity Squamous Cell Cancer: A Randomized Controlled Trial
Authors: Licitra Lisa , Grandi Cesare , Guzzo Marco , Mariani Luigi , Vullo Salvatore Lo , Valvo Francesca , Quattrone Pasquale , Valagussa Pinuccia , Bonadonna Gianni , Molinari Roberto , Cantù Giulio
Published: January 2003

Purpose: Prognosis of patients with advanced oral cavity cancer is worth improving. Chemotherapy has been reported to be especially active in oral cavity tumors. Here we repeat the results of a randomized, multicenter trial enrolling patients with a resectable, stage T2–T4 (> 3 cm), N0–N2, M0 untreated, squamous cell carcinoma of the oral cavity.

Patients and Methods: Patients were randomly assigned to three cycles of cisplatin and fluorouracil followed by surgery (chemotherapy arm) or surgery alone (control arm). In both arms, postoperative radiotherapy was reserved to high-risk patients, and surgery was modulated depending on the tumor’s closeness to the mandible. Patients’ accrual was opened in 1989 and closed in 1999. It included 195 patients.

Results: In the chemotherapy arm, three toxic deaths were recorded. No significant difference in overall survival was found. Five-year overall survival was, for both arms, 55%. Postoperative radiotherapy was administered in 33% of patients in the chemotherapy arm, versus 46% in the control arm. A mandible resection was performed in 52% of patients in the control arm, versus 31% in the chemotherapy arm.

Conclusion: The addition of primary chemotherapy to standard surgery was unable to improve survival. However, in this study, primary chemotherapy seemed to play a role in reducing the number of patients who needed to undergo mandibulectomy and/or radiation therapy. Variations in the criteria used to select patients for these treatment options may make it difficult to generalize these results, but there appears to be room for using preoperative chemotherapy to spare demolitive surgery and/or radiation therapy in patients with advanced, resectable oral cavity cancer.
Morphologic Dysplasia in De Novo Acute Myeloid Leukemia (AML) Is Related to Unfavorable Cytogenetics but Has No Independent Prognostic Relevance Under the Conditions of Intensive Induction Therapy: Results of a Multiparameter Analysis From the German AML Cooperative Group Studies
Authors: Haferlach Torsten , Schoch Claudia , Löffler Helmut , Gassmann Winfried , Kern Wolfgang , Schnittger Susanne , Fonatsch Christa , Ludwig Wolf-Dieter , Wuchter Christian , Schlegelberger Brigitte , Staib Peter , Reichle Albrecht , Kubica Uschi , Eimermacher Hartmut , Balleisen Leopold , Grüneisen Andreas , Haase Detlef , Aul Carlo , Karow Jochen , Lengfelder Eva , Wörmann Bernhard , Heinecke Achim , Sauerland Maria Cristina , Büchner Thomas , Hiddemann Wolfgang
Published: January 2003

Purpose: On the basis of cytomorphology according to the French-American-British (FAB) classification, we evaluated the prognostic impact of dysplastic features and other parameters in de novo acute myeloid leukemia (AML). We also assessed the clinical significance of the recently introduced World Health Organization (WHO) classification for AML, which proposed dysplasia as a new parameter for classification.

Patients and Methods: We analyzed prospectively 614 patients with de novo AML, all of whom were diagnosed by central morphologic analysis and treated within the German AML Cooperative Group (AMLCG)-92 or the AMLCG-acute promyalocytic leukemia study.

Results: Patients with AML M3, M3v, or M4eo demonstrated a better outcome compared with all other FAB subtypes (P < .001); no prognostic difference was observed among other FAB subtypes. The presence or absence of dysplasia failed to demonstrate prognostic relevance. Other prognostic markers, such as age, cytogenetics, presence of Auer rods, and lactate dehydrogenase (LDH) level at diagnosis, all showed significant impact on overall and event-free survival in univariate analyses (P < .001 for all parameters tested). However, in a multivariate analysis, only cytogenetics (unfavorable or favorable), age, and high LDH maintained their prognostic impact. Dysplasia was not found to be an independent prognostic parameter, but the detection of trilineage dysplasia correlated with unfavorable cytogenetics.

Conclusion: Our results indicate that cytomorphology and classification according to FAB criteria are still necessary for the diagnosis of AML but have no relevance for prognosis in addition to cytogenetics. Our results suggest that the WHO classification should be further developed by using cytogenetics as the main determinant of biology. Dysplastic features, in particular, have no additional impact on predicting prognosis when cytogenetics are taken into account.
Prognostic Scoring System for Primary CNS Lymphomas: The International Extranodal Lymphoma Study Group Experience
Authors: Ferreri Andrés J.M. , Blay Jean-Yves , Reni Michele , Pasini Felice , Spina Michele , Ambrosetti Achille , Calderoni Antonello , Rossi Andrea , Vavassori Vittorio , Conconi Annarita , Devizzi Liliana , Berger Françoise , Ponzoni Maurilio , Borisch Bettina , Tinguely Marianne , Cerati Michele , Milani Mario , Orvieto Enrico , Sanchez Juvenal , Chevreau Christine , Dell’Oro Stefania , Zucca Emanuele , Cavalli Franco
Published: January 2003

Purpose: To identify survival predictors and to design a prognostic score useful for distinguishing risk groups in immunocompetent patients with primary CNS lymphomas (PCNSL).

Patients and Methods: The prognostic role of patient-, lymphoma-, and treatment-related variables was analyzed in a multicenter series of 378 PCNSL patients treated at 23 cancer centers from five different countries.

Results: Age more than 60 years, performance status (PS) more than 1, elevated lactate dehydrogenase (LDH) serum level, high CSF protein concentration, and involvement of deep regions of the brain (periventricular regions, basal ganglia, brainstem, and/or cerebellum) were significantly and independently associated with a worse survival. These five variables were used to design a prognostic score. Each variable was assigned a value of either 0, if favorable, or 1, if unfavorable. The values were then added together to arrive at a final score, which was tested in 105 assessable patients for which complete data of all five variables were available. The 2-year overall survival (OS) ± SD was 80% ± 8%, 48% ± 7%, and 15% ± 7% (P = .00001) for patients with zero to one, two to three, and four to five unfavorable features, respectively. The prognostic role of this score was confirmed by limiting analysis to assessable patients treated with high-dose methotrexate-based chemotherapy (2-year OS ± SD: 85% ± 8%, 57% ± 8%, and 24% ± 11%; P = .0004).

Conclusion: Age, PS, LDH serum level, CSF protein concentration, and involvement of deep structures of the brain were independent predictors of survival. A prognostic score including these five parameters seems advisable in distinguishing different risk groups in PCNSL patients. The proposed score and its relevance in therapeutic decision deserve to be validated in further studies.
Evaluation of Monoclonal Humanized Anti-HER2 Antibody, Trastuzumab, in Patients With Recurrent or Refractory Ovarian or Primary Peritoneal Carcinoma With Overexpression of HER2: A Phase II Trial of the Gynecologic Oncology Group
Authors: Bookman Michael A. , Darcy Kathleen M. , Clarke-Pearson Daniel , Boothby Richard A. , Horowitz Ira R.
Published: January 2003

Purpose: To evaluate the feasibility, toxicity, and efficacy of single-agent monoclonal antibody therapy targeting the human epidermal growth factor receptor 2 (HER2)/neu receptor in ovarian and primary peritoneal carcinoma.

Patients and Methods: Eligible patients had measurable persistent or recurrent epithelial ovarian or primary peritoneal carcinoma with 2+ or 3+ HER2 overexpression documented by immunohistochemistry. Intravenous trastuzumab was administered initially at a dose of 4 mg/kg, then weekly at 2 mg/kg. Patients without progressive disease or excessive toxicity could continue treatment indefinitely. Those with stable or responding disease at 8 weeks were offered treatment at a higher weekly dose (4 mg/kg) at time of progression. Patient sera were analyzed for the presence of the soluble extracellular domain of HER2, host antibodies against trastuzumab, and trastuzumab pharmacokinetics.

Results: A total of 837 tumor samples were screened for HER2 expression, and 95 patients (11.4%) exhibited the requisite 2+/3+ expression level. Forty-five patients, all of whom received prior chemotherapy, were entered, and 41 were deemed eligible and assessable. There were only mild expected toxicities and no treatment-related deaths. Although an elevated level of the soluble extracellular domain of HER2 was detected in eight of 24 patients, serum HER2 was not associated with clinical outcome. There was no evidence of host antitrastuzumab antibody formation. Serum concentrations of trastuzumab gradually increased with continued therapy. An overall response rate of 7.3% included one complete and two partial responses. Median treatment duration was 8 weeks (range, 2 to 104 weeks), and median progression-free interval was 2.0 months.

Conclusion: The clinical value of single-agent trastuzumab in recurrent ovarian cancer is limited by the low frequency of HER2 overexpression and low rate of objective response among patients with HER2 overexpression.