bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase I study of 9‐nitrocamptothecin given concurrently with capecitabine in patients with refractory, metastatic solid tumors
Authors: Michaelson M. Dror , Ryan David P. , Fuchs Charles S. , Supko Jeffrey G. , Garcia‐Carbonero Rocio , Paul Eder J. , Clark Jeffrey W. 
Published: December 2002

AbstractBACKGROUND9‐Nitrocamptothecin (9‐NC) is an orally available camptothecin analog with antineoplastic activity that results from the inhibition of DNA topoisomerase I. Previous studies have suggested that it has significant clinical efficacy. The primary toxicities of 9‐NC include gastrointestinal upset, cystitis, and myelosuppression at the maximum tolerated dose (MTD) of 1.5 mg/m2 per day. Capecitabine is a prodrug of 5‐fluorouracil that is approved for use in patients with metastatic breast carcinoma and colorectal carcinoma, and it offers the convenience of oral administration. This trial examined the combination of these two oral agents in patients with metastatic solid tumors.METHODSCapecitabine was administered twice daily at a total daily dose of 1300 mg/m2 per day for 14 days followed by a 1‐week break. 9‐NC was taken daily 5 days per week for 2 weeks in a dose‐escalation scheme. The starting dose was 0.5 mg/m2 per day, and cohorts of 3 patients were enrolled until the dose level reached 1.25 mg/m2 per day.RESULTSTwenty‐one patients were evaluable for toxicity and response, and nausea and emesis were the dose‐limiting toxicities. Despite antiemetic prophylaxis with 5‐hydroxytryptamine‐3 antagonists, 2 of 3 patients at the 1.0 mg/m2 per day dose level had Grade 2–3 nausea; while at the MTD of 0.75 mg/m2 per day, 3 of 14 patients had Grade ≥ 2 nausea. The incidence of hand‐foot syndrome, stomatitis, diarrhea, and myelosuppression did not exceed that expected with capecitabine alone, suggesting that 9‐NC does not exacerbate these side effects. No objective responses were seen. Stable disease was observed in 9 patients (43%) with a median duration of 11 weeks, including 3 patients with responses that lasted from 20 weeks to 40 weeks.CONCLUSIONSThe combination of 9‐NC and capecitabine with the current schedule was limited in dose by nausea and had minimal clinical efficacy in a group of patients with refractory solid tumors. Cancer 2003;97:148–54. © 2003 American Cancer Society.DOI 10.1002/cncr.11038
Cancer chronotherapy: Principles, applications, and perspectives
Authors: Mormont Marie‐Christine , Levi Francis 
Published: December 2002

AbstractBACKGROUNDCell physiology is regulated along the 24‐hour timescale by a circadian clock, which is comprised of interconnected molecular loops involving at least nine genes. The cellular clocks are coordinated by the suprachiasmatic nucleus, a hypothalamic pacemaker that also helps the organism adjust to environmental cycles. The rest‐activity rhythm is a reliable marker of the circadian system function in both rodents and humans. This circadian organization is responsible for predictable changes in the tolerability and efficacy of anticancer agents, and possibly also may be involved in tumor promotion or growth.METHODSExpected least toxic times of chemotherapy were extrapolated from experimental models to human subjects with reference to the rest‐activity cycle. The clinical relevance of the chronotherapy principle (i.e., treatment administration as a function of rhythms) has been investigated previously in randomized multicenter trials.RESULTSIn the current study, chronotherapeutic schedules were used to safely document activity of the combination of oxaliplatin, 5‐fluorouracil, and leucovorin against metastatic colorectal carcinoma and to establish new medicosurgical management for this disease, and were reported to result in unprecedented long‐term survival.CONCLUSIONSChronotherapy concepts appear to offer further potential to improve current cancer treatment options as well as to optimize the development of new anticancer or supportive agents. Cancer 2003;97:155–69. © 2003 American Cancer Society.DOI 10.1002/cncr.11040
Slower molecular response to treatment predicts poor outcome in patients with TEL/AML1 positive acute lymphoblastic leukemia
Authors: Madžo Jozef , Zuna Jan , Mužíková Kateřina , Kalinová Markéta , Krejčí Ondřej , Hrušák Ondřej , Otová Berta , Starý Jan , Trka Jan 
Published: December 2002

AbstractBACKGROUNDThe translocation t(12;21)(p13;q22), which produces the TEL/AML1 fusion gene, is the most frequent chromosomal abnormality in patients with childhood acute lymphoblastic leukemia (ALL) and generally is associated with a favorable prognosis. Furthermore, real‐time quantitative‐polymerase chain reaction (RQ‐PCR)‐based detection of TEL/AML1 represents an accurate technique for the reproducible assessment of minimal residual disease (MRD).METHODSThe authors employed RQ‐reverse transcriptase‐PCR (RQ‐RT‐PCR) technology to analyze MRD levels in 57 newly diagnosed patients with TEL/AML1 positive ALL in a prospective study.RESULTSOn Day + 33, a particularly important time point in terms of outcome prediction based on MRD monitoring, 75% of patients reached negativity, 13% of patients were positive at very low levels (< 10−4; i.e., 1 or more leukemic cell per 104 normal cells), and another 13% of patients were positive at the level of 10−2 to 10−4 cells. No patient showed MRD levels ≥ 10−2 cells at this time. The data demonstrate that patients with TEL/AML1 positive ALL had a better response to induction chemotherapy on Day + 33 compared with a group of unselected patients with ALL (P = 0.0001). However, four patients with TEL/AML1 positive ALL developed relapse disease. Remarkably, these children were positive for MRD on Day + 33 at a level between 10−2 cells and 10−4 (n = 3 patients) and at < 10−4 (n = 1 patient). Kaplan–Meier analysis of disease free survival showed the statistical significance of this distribution (MRD positive vs. MRD negative; log‐rank P = 0.0016).CONCLUSIONSThe authors conclude that, although the TEL/AML1 positive leukemias generally are associated with a favorable outcome, MRD positivity assessed by RQ‐RT‐PCR analysis at the end of induction therapy represents a significantly negative prognostic feature. Cancer 2003;97:105–13. © 2003 American Cancer Society.DOI 10.1002/cncr.11043
Granulocyte‐macrophage–colony‐stimulating factor added to a multipeptide vaccine for resected Stage II melanoma
Authors: Weber Jeffrey , Sondak Vernon K. , Scotland Ronaldo , Phillip Ramila , Wang Flora , Rubio Valerie , Stuge Tor B. , Groshen Susan G. , Gee Conway , Jeffery Georgia G. , Sian Shirley , Lee Peter P. 
Published: December 2002

AbstractBACKGROUNDForty‐eight patients with resected Stages IIA and IIB melanoma were immunized with two tumor antigen epitope peptides derived from gp100209–217 (210M) (IMDQVPSFV) and tyrosinase368–376 (370D) (YMDGTMSQV) emulsified with incomplete Freund's adjuvant (IFA). Patients were assigned randomly to receive either peptides/IFA alone or with 250 μm of granulocyte‐macrophage–colony‐stimulating factor (GM‐CSF) subcutaneously daily for 5 days to evaluate the toxicities and immune responses in either arm. Time to recurrence and survival were secondary end points.METHODSImmunizations were administered every 2weeks × 4, then every 4 weeks × 3, and once 8 weeks later. A leukapheresis to obtain peripheral blood mononuclear cells for immune analyses and skin testing with peptides and recall reagents was performed before and after eight vaccinations.RESULTSLocal pain and granuloma formation, fever, and lethargy of Grade 1 or 2 were observed. Transient vaccine‐related Grade III and no Grade IV toxicity was observed. Seventeen of the 40 patients for whom posttreatment skin tests were performed developed a positive skin test response to the gp100 peptide, but only 1 of the 40 patients developed a positive skin test response to tyrosinase. Immune responses were measured by release of interferon‐gamma (IFN‐γ) in an enzyme‐linked immunosorbent assay (ELISA) by effector cells in the presence of peptide‐pulsed antigen‐presenting cells, by cytokine release of IFN‐γ, GM‐CSF, and tumor necrosis factor‐alpha in a Luminex assay, or by an antigen‐specific tetramer flow cytometry assay. Thirty‐four of the 39 patients for whom the ELISA data were performed demonstrated an immune response after vaccination, as did 37 of 42 patients by tetramer assay. Enzyme‐linked immunosorbent assay, Luminex, and tetramer responses in the GM‐CSF/peptide/IFA group were higher than in the peptide/IFA group. Epitope spreading to the MART‐1/MelanA 27‐35 and 26‐35 (27L) epitopes was detected by tetramer assay in 10 patients. Seven of 48 patients experienced disease recurrence with a median of 24 months of follow‐up and 2 patients in this intermediate to high risk group have died.CONCLUSIONThese data suggest a significant number of patients with resected melanoma mount an antigen‐specific immune response against a peptide vaccine. There is a trend for GM‐CSF to modestly increase the immune response and support further development of GM‐CSF as a vaccine adjuvant. Cancer 2003;97:186–200. © 2003 American Cancer Society.DOI 10.1002/cncr.11045
Pathologic characteristics of breast parenchyma in patients with hereditary breast carcinoma, including BRCA1 and BRCA2 mutation carriers
Authors: Adem Camilo , Reynolds Carol , Soderberg Cheryl L. , Slezak Jeffrey M. , McDonnell Shannon K. , Sebo Thomas J. , Schaid Daniel J. , Myers Jeffrey L. , Sellers Thomas A. , Hartmann Lynn C. , Jenkins Robert B. 
Published: December 2002

AbstractBACKGROUNDBRCA1 and BRCA2 alterations are associated with an increased risk of developing breast carcinoma. The authors hypothesized that the progression of breast neoplasia may differ between patients with hereditary disease and patients with nonhereditary disease and that this difference in progression may be visualized by studying the prevalence of precursor lesions and neoplastic lesions.METHODSThe authors developed two case cohorts of high‐risk patients with a strong family history of breast carcinoma who underwent prophylactic mastectomy. The first cohort was comprised of women who underwent therapeutic mastectomy and contralateral prophylactic mastectomy, and the second cohort was comprised of women who underwent bilateral prophylactic mastectomy. Patients without a family history of breast carcinoma who underwent unilateral or bilateral prophylactic mastectomy were selected as a control group. DNA from peripheral blood leukocytes was screened for BRCA1 and BRCA2 mutations. The available pathologic materials were reviewed independently by two pathologists, and all neoplastic and precursor lesions were identified and classified. Proliferation activity was assessed using MIB‐1 immunohistochemistry on all available lesions from the unilateral mastectomy cohort.RESULTSThe 28 women from the unilateral cohort with deleterious BRCA1/2 mutations had a lower prevalence of proliferative fibrocystic changes (PFC) (7%) compared with their matched control group (25%) (P = 0.075) and with patients who had a family history but no BRCA1/2 mutation (22–33%). None of the 11 deleterious mutation carriers from the bilateral cohort (0%) had PFC compared with 36% of women in the matched control group (P = 0.03). There was no major difference in the prevalence of other precursor lesions (including in situ carcinoma) in either cohort. Invasive carcinomas from the deleterious mutation carriers in the unilateral cohort were of higher grade compared with the control group (P = 0.003) and patients without a mutation (P < 0.0001) but were of similar grade compared with carriers of unclassified variant BRCA1/2 alterations (P = 0.20). Neoplastic lesions from the deleterious mutation carriers in the unilateral cohort had higher MIB‐1 proliferation indices compared with other patients with and without a family history of breast carcinoma.CONCLUSIONSThe current data suggest that the progression rate of breast neoplasia is accelerated in women who carry BRCA1/2 deleterious mutations compared with other patients who have breast carcinoma with or without a family history. This increased progression rate should be taken into account when considering the surveillance of asymptomatic women. Cancer 2003;97:1–11. © 2003 American Cancer Society.DOI 10.1002/cncr.11048
Energy restriction early in life and colon carcinoma risk
Authors: Dirx Miranda J. M. , van den Brandt Piet A. , Goldbohm R. Alexandra , Lumey L. H. 
Published: December 2002

AbstractBACKGROUNDThis study evaluated the effects of severe undernutrition during adolescence and subsequent colon carcinoma risk.METHODSThe authors evaluated The Netherlands Cohort Study on Diet and Cancer (NLCS) among 62,573 women and 58,279 men aged 55–69 years at baseline. Information on diet and risk factors was collected by questionnaire in 1986. Additional information was collected concerning residence during the hunger winter (1944–1945), the World War II years (1940–1944), and father's employment status during the economic depression of 1932–1940, which were used as indicators of exposure. After 7.3 years of follow‐up, 807 colon carcinoma cases (388 females and 419 males) were available for analysis.RESULTSMultivariate analysis showed that both men and women who had lived in a western city in 1944–1945 had a decreased colon carcinoma risk (men: relative risk [RR] = 0.85, 95% confidence interval [CI] = 0.62–1.16; women: RR = 0.80, 95%CI = 0.59–1.09). No association between colon carcinoma risk and urban versus rural residence was found during the war years (1940–1944). Having an unemployed father during the economic depression (1932–1940) was also associated with a small decrease in colon carcinoma risk for men (RR = 0.90, 95% CI =0.62–1.31) and women (RR = 0.75, 95%CI 0.49‐1.14). In subgroup analyses, a decreased colon carcinoma risk for men and women who were in their adolescent growth spurt and living in a western city during the hunger winter of 1944–1945 was noted (men: RR = 0.72, 95% CI = 0.31–1.65; women: RR = 0.88, 95% CI = 0.40–1.96). No associations were statistically significant because of the limited study size.CONCLUSIONSIn the current study, a weak inverse relation was found between energy restriction early in life and subsequent colon carcinoma risk for men and women. However, these findings need replication in a larger study. Cancer 2003;97:46–55. © 2003 American Cancer Society.DOI 10.1002/cncr.11052
Optimal distribution of linear control intensity over the frequency range
Authors: Corbi Ottavia 
Published: December 2002

AbstractIn this paper, a control strategy for structural systems is proposed and developed in the frequency domain. The algorithm is substantially based on a linear derivative feedback and a convolution of the control parameter, whose distribution in the frequency field is chosen in such a manner as to comply with the requirements of an ad hoc formulated constrained optimum problem, with the response data monitored until the instant of control action application. Some numerical testing is carried out by referring to given recorded accelerograms, showing a good performance of the proposed approach. Copyright © 2002 John Wiley & Sons, Ltd.
A neural network approach for structural identification and diagnosis of a building from seismic response data
Authors: Huang C. S. , Hung S. L. , Wen C. M. , Tu T. T. 
Published: December 2002

AbstractThis work presents a novel procedure for identifying the dynamic characteristics of a building and diagnosing whether the building has been damaged by earthquakes, using a back‐propagation neural network approach. The dynamic characteristics are directly evaluated from the weighting matrices of the neural network trained by observed acceleration responses and input base excitations. Whether the building is damaged under a large earthquake is assessed by comparing the modal parameters and responses for this large earthquake with those for a small earthquake that has not caused this building any damage. The feasibility of the approach is demonstrated through processing the dynamic responses of a five‐storey steel frame, subjected to different strengths of the Kobe earthquake, in shaking table tests. Copyright © 2002 John Wiley & Sons, Ltd.
Localization analysis in softening RC frame structures
Authors: Khaloo Ali R. , Tariverdilo Saeed 
Published: December 2002

AbstractThis paper discusses the sensitivity of softening reinforced concrete frame structures to the changes in input ground motion and investigates the possibility of localizations for this type of structure in static and dynamic analysis. A finite element model is used in which the sections resisting force are calculated using a proposed differential hysteretic model. This model is especially developed for modelling softening behaviour under cyclic loading. To obtain parameters of the differential model the moment–curvature of each section is evaluated using a microplane constitutive law for concrete and bi‐linear elasto‐plastic law for reinforcements. The capability of the procedure is verified by comparing results with available experimental data at element level, which shows good accuracy of the procedure. The effect of possible changes in ground motion is assessed using a non‐stationary Kanai–Tajimi process. This process is used to generate ground motions with approximately the same amplitude and frequency content evolution as those of base ground motion. The possibility of localization in static and dynamic loading is investigated using two structures. A measure for the possibility of localization in code‐designed structures is obtained. This study indicates that localization may occur in ordinary moment‐resisting structures located in high seismic zones. Localization may result in substantial drift in global response and instability due to P–δ effect. Also, it is shown that the structure becomes very sensitive to the input ground motion. It is concluded that allowance by some design codes of the use of ordinary moment‐resisting frames in regions with high seismicity should be revised or improvements should be made in the detailing requirements at critical sections of these structures. Copyright © 2002 John Wiley & Sons, Ltd.
Optimal maintenance strategies for structures in seismic zones
Authors: Montes‐Iturrizaga R. , Heredia‐Zavoni E. , Esteva L. 
Published: December 2002

AbstractIn this paper an approach is developed for establishing optimal maintenance (repair) strategies of structures in seismic zones. The approach is based on expected future costs and the main decision variable is a damage threshold for repair given an acceptable reliability level. It is considered that structural damage accumulates over a number of earthquakes until a threshold is reached or exceeded, after which the structure is repaired so that there is no remaining damage. A Markov model is implemented for such a process of damage accumulation during future earthquakes. An algorithm is proposed for computing non‐linear structural response to earthquakes using a damage function model. This algorithm is used to evaluate transition probabilities between damage states based on simulations of future earthquakes of given intensities. Expressions are derived for evaluating expected life‐cycle damage costs and structural reliability as a function of time and of the damage threshold for repair. As an application, a single‐degree‐of‐freedom structural system is studied. In addition, the paper addresses the case of instrumented structures where information from earthquake response records is available. Such information is incorporated into the formulation for maintenance strategies by means of a Bayesian approach for updating the probability distribution of structural damage and of non‐linear behaviour parameters so that predictions about costs and reliability are improved. Copyright © 2002 John Wiley & Sons, Ltd.
The rocking spectrum and the limitations of practical design methodologies
Authors: Makris Nicos , Konstantinidis Dimitrios 
Published: December 2002

AbstractThis paper is concerned with the superficial similarities and fundamental differences between the oscillatory response of a single‐degree‐of‐freedom (SDOF) oscillator (regular pendulum) and the rocking response of a slender rigid block (inverted pendulum). The study examines the distinct characteristics of the rocking spectrum and compares the observed trends with those of the response spectrum. It is shown that the rocking spectrum reflects kinematic characteristics of the ground motions that are not identifiable by the response spectrum. The paper investigates systematically the fundamental differences in the dynamical structure of the two systems of interest and concludes that rocking structures cannot be replaced by ‘equivalent’ SDOF oscillators. The study proceeds by examining the validity of a simple, approximate design methodology, initially proposed in the late 1970s and now recommended in design guidelines to compute rotations of slender structures by performing iteration either on the true displacement response spectrum or design spectrum. This paper shows that the simple design approach is inherently flawed and should be abandoned, in particular for smaller, less‐slender blocks. The study concludes that the exact rocking spectrum emerges as a distinct intensity measure of ground motions. Copyright © 2002 John Wiley & Sons, Ltd.
The effects of repeated earthquake ground motions on the non‐linear response of SDOF systems
Authors: Amadio C. , Fragiacomo M. , Rajgelj S. 
Published: December 2002

AbstractIn many parts of the world, the repetition of medium–strong intensity earthquake ground motions at brief intervals of time has been observed. The new design philosophies for buildings in seismic areas are based on multi‐level design approaches, which take into account more than a single damageability limit state. According to these approaches, a sequence of seismic actions may produce important consequences on the structural safety. In this paper, the effects of repeated earthquake ground motions on the response of single‐degree‐of‐freedom systems (SDOF) with non‐linear behaviour are analysed. A comparison is performed with the effect of a single seismic event on the originally non‐damaged system for different hysteretic models in terms of pseudo‐acceleration response spectra, behaviour factor q and damage parameters. The elastic–perfect plastic system is the most vulnerable one under repeated earthquake ground motions and is characterized by a strong reduction of the q‐factor. A moment resisting steel frame is analysed as well, showing a reduction of the q‐factor under repeated earthquake ground motions even larger than that of an equivalent SDOF system. Copyright © 2002 John Wiley & Sons, Ltd.
A pseudo‐force iterative method with separate scale factors for dynamic analysis of structures with non‐proportional damping
Authors: Lin Feng‐Bao , Wang Yung‐Kuo , Cho Young S. 
Published: December 2002

AbstractDynamic equilibrium equations of structural systems with non‐proportional damping are coupled through the damping terms. Such coupling invalidates application of the classical modal superposition method. In this paper, a mode‐superposition pseudo‐force method is proposed. The coupled equilibrium equations are solved by an iterative process in which the coupling terms are treated as pseudo‐forces. A scale factor for each mode of the system is obtained by optimizing the iteration convergence. Through these uniquely solved scale factors, the modified modal equations not only converge much faster but also yield results with higher accuracy. A proof of the convergence of the iterative process is also presented. Copyright © 2002 John Wiley & Sons, Ltd.