A T van Oosterom

Catholic University of Louvain, Лувен-ла-Нев, Walloon, Belgium

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Publications (307)1653.75 Total impact

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    ABSTRACT: Purpose: In this first-in-human study of AEE788, a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), HER-2, and VEGFR-2, a comprehensive pharmacodynamic program was implemented in addition to the evaluation of safety, pharmacokinetics, and preliminary efficacy of AEE788 in cancer patients. Experimental design: Patients with advanced, solid tumors received escalating doses of oral AEE788 once daily. Primary endpoints were to determine dose-limiting toxicities (DLTs) and maximum-tolerated dose (MTD). A nonlinear model (Emax model) was used to describe the relationship between AEE788 exposure and target-pathway modulation in skin and tumor tissues. Results: Overall, 111 patients were treated (25 to 550 mg/day). DLTs included rash and diarrhea; MTD was 450 mg/day. Effects on biomarkers correlated to serum AEE788 concentrations. The concentration at 50% inhibition (IC(50)) for EGFR in skin (0.033 μmol/L) and tumor (0.0125 μmol/L) were similar to IC(50) in vitro suggesting skin may be surrogate tissue for estimating tumor EGFR inhibition. No inhibition of p-MAPK and Ki67 was observed in skin vessels at ≤ MTD. Hence, AEE788 inhibited EGFR, but not VEGFR, at doses ≤ MTD. A total of 16 of 96 evaluable patients showed a >10% shrinkage of tumor size; one partial response was observed. Conclusion: Our pharmacodynamic-based study showed effective inhibition of EGFR, but not of VEGFR at tolerable AEE788 doses. Emax modeling integrated with biomarker data effectively guided real-time decision making in the early development of AEE788. Despite clinical activity, target inhibition of only EGFR led to discontinuation of further AEE788 development.
    Clinical Cancer Research 09/2012; 18(22). DOI:10.1158/1078-0432.CCR-12-1499 · 8.72 Impact Factor
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    ABSTRACT: This multicenter phase 2 study assessed the tolerability and efficacy of motesanib, an oral inhibitor of Kit, platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptors (VEGFR), in patients with imatinib-resistant gastrointestinal stromal tumors (GIST). Patients with advanced GIST who failed imatinib mesylate after ≥8 weeks of treatment with ≥600 mg daily received motesanib 125 mg orally once daily continuously for 48 weeks or until unacceptable toxicity or disease progression occurred. The primary endpoint was confirmed objective tumor response per RECIST and independent review. Secondary endpoints included progression-free survival (PFS), time to progression (TTP); objective response by (18)FDG-PET and by changes in tumor size and/or density (Choi criteria); pharmacokinetics and safety. In the patients evaluable for response (N = 102), the objective response rate was 3%; 59% of patients achieved stable disease, with 14% achieving durable stable disease ≥24 weeks; 38% had disease progression. Higher objective response rates were observed per (18)FDG-PET (N = 91) (30%) and Choi criteria (41%). The median PFS was 16 weeks (95% CI = 14-24 weeks); the median TTP was 17 weeks (95% CI = 15-24 weeks). The most common motesanib treatment-related grade 3 adverse events included hypertension (23%), fatigue (9%), and diarrhea (5%). Motesanib did not accumulate with daily dosing. In this study of patients with imatinib-resistant GIST, motesanib treatment resulted in acceptable tolerability and modest tumor control as evident in the proportion of patients who achieved stable disease and durable stable disease.
    Cancer Chemotherapy and Pharmacology 07/2011; 68(1):69-77. DOI:10.1007/s00280-010-1431-9 · 2.77 Impact Factor
  • EJC Supplements 09/2009; 7(2):597-597. DOI:10.1016/S1359-6349(09)72013-0 · 9.39 Impact Factor
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    ABSTRACT: Smoking is a potent inducer of cytochrome P450 (CYP) 1A2 and may affect the pharmacokinetics of CYP1A2 metabolized drugs. The effect of smoking on the pharmacokinetics of imatinib, which is metabolized by CYP3A4 and partly by CYP1A2, is unknown. We studied the effect of smoking on imatinib pharmacokinetics, safety, and efficacy. Imatinib pharmacokinetics, safety, and efficacy was analyzed in 45 patients with gastrointestinal stromal tumors (GIST) or soft-tissue sarcoma included in two European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group trials, including 15 smokers and 30 nonsmokers. Apparent oral clearance, distribution volume, elimination half-life, and dose-standardized area under the concentration curve (AUC) were assessed in 34 patients using nonlinear mixed-effect modeling. Mean +/- SD pharmacokinetic variables in smokers (n = 9) versus nonsmokers (n = 25) groups were 9.6 +/- 5.5 versus 9.2 +/- 4.6 L/h (apparent oral clearance), 216.5 +/- 114.3 versus 207.0 +/- 116.9 L (distribution volume), 16.1 +/- 6.0 versus 16.5 +/- 6.0 h (elimination half-life), and 133.6 +/- 71.0 versus 142.3 +/- 84.0 ng h/mL mg area under the concentration curve; P > 0.05. Smokers experienced more grade 2/3 anemia (P = 0.010) and fatigue (P = 0.011) and those with GIST had a significantly shorter overall survival (P = 0.037) and time to progression (P = 0.052). This retrospective study suggests that the pharmacokinetics of imatinib is not affected by smoking. However, smokers have an increased risk of anemia and fatigue. Smokers with GIST have a shorter overall survival and time to progression.
    Clinical Cancer Research 12/2008; 14(24):8308-13. DOI:10.1158/1078-0432.CCR-08-1303 · 8.72 Impact Factor
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    ABSTRACT: To evaluate the activity of imatinib in treating advanced, life-threatening malignancies expressing one or more imatinib-sensitive tyrosine kinases. This was a phase II, open-label, single arm study. Patients > or = 15 years old with malignancies showing histologic or molecular evidence of expression/activation of imatinib-sensitive tyrosine kinases were enrolled. Patients were treated with 400 or 800 mg/d imatinib for hematologic malignancy and solid tumors, respectively. Treatment was continued until disease progression or unacceptable toxicity. The primary objective was to identify evidence of imatinib activity with tumor response as the primary end point. One hundred eighty-six patients with 40 different malignancies were enrolled (78.5% solid tumors, 21.5% hematologic malignancies). Confirmed response occurred in 8.9% of solid tumor patients (4 complete, 9 partial) and 27.5% of hematologic malignancy patients (8 complete, 3 partial). Notable activity of imatinib was observed in only five tumor types (aggressive fibromatosis, dermatofibrosarcoma protuberans, hypereosinophilic syndrome, myeloproliferative disorders, and systemic mastocytosis). A total of 106 tumors were screened for activating mutations: five KIT mutations and no platelet-derived growth factor receptor mutations were found. One patient with systemic mastocytosis and a partial response to therapy had a novel imatinib-sensitive KIT mutation (D816T). There was no clear relationship between expression or activation of wild-type imatinib-sensitive tyrosine kinases and clinical response. Clinical benefit was largely confined to diseases with known genomic mechanisms of activation of imatinib target kinases. Our results indicate an important role for molecular characterization of tumors to identify patients likely to benefit from imatinib treatment.
    Clinical Cancer Research 05/2008; 14(9):2717-25. DOI:10.1158/1078-0432.CCR-07-4575 · 8.72 Impact Factor
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    ABSTRACT: Forty-four of 50 adult patients with advanced soft-tissue sarcoma who had received previous chemotherapy were evaluable for response after treatment with DTIC. The therapeutic schedule consisted of DTIC 1.2 g/m2 infused over 20 minutes, and repeated every 3 weeks. There were 1 complete and 7 partial remissions (objective activity 18%, 95% C.I. 7%-29%), with a median duration of 8 weeks (range 5–19), with the complete remission lasting 1 yr. Hematologic toxicity was dose-limiting; W.H.O. 3 values were observed for WBC in 36%, and for platelets in 26% of patients. The non-hematologic toxicity included nausea and vomiting (90%), a flu-like syndrome (49%), diarrhea (35%), pain in the infused vein (28%) and hypotensive episodes (4%). Intermittent high-dose DTIC is active in advanced soft-tissue sarcoma and should be considered for inclusion in combination regimens.
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    ABSTRACT: A reversed phase high-performance liquid chromatographic (HPLC) method with UV detection was developed for the simultaneous determination of imatinib (Gleevec, Glivec, STI571) and AMN107 in cultured tumour cells, using clozapine as an internal standard. The compounds of interest were extracted by liquid-liquid extraction using TOXI-TUBES((R)) A extraction tubes. Chromatographic separation was performed on a Phenomenex Gemini C18 reversed phase column (150 mm x 2.0 mm, 5 microm particle size), using a mixture of 65% CH(3)OH (methanol) and 35% NH(4)Ac (Ammonium acetate) buffer (20mM, pH 10). Separation was achieved under isocratic conditions at a flow rate of 0.5 ml/min. Imatinib, clozapine and AMN107 are detected by UV detection at 260 nm. Calibration curves were linear from 50 to 7500 ng/ml with correlation coefficients (r(2)) better than 0.998. The limit of quantitation (LOD) was 50 ng/ml. The method has been successfully applied to a cellular kinetics study.
    Journal of Chromatography B 03/2007; 846(1-2):341-5. DOI:10.1016/j.jchromb.2006.08.004 · 2.73 Impact Factor
  • EJC Supplements 11/2006; 4(12):171-171. DOI:10.1016/S1359-6349(06)70568-7 · 9.39 Impact Factor
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    ABSTRACT: The majority of gastrointestinal stromal tumors harbor mutations in the receptor tyrosine kinases KIT or platelet-derived growth factor receptor A (PDGFRA), and respond to treatment with the tyrosine kinase inhibitor imatinib. Some tumors, however, show primary resistance to imatinib treatment, and most others become resistant during treatment. The most common mechanism of imatinib resistance involves specific mutations in the kinase domains of KIT or PDGFRA. We tested the activity of SU11248, an orally active small-molecule tyrosine kinase inhibitor, to inhibit important imatinib-resistant KIT and PDGFRA mutants. Primary imatinib-resistant tumor cells and cell lines expressing clinically identified imatinib-resistant KIT-V654A, KIT-T670I, or PDGFRA-D842V mutant isoforms were evaluated for sensitivity to SU11248 by Western immunoblotting and proliferation assays. Three patients with the KIT-V654A mutation were treated with SU11248. Based on ex vivo assays, SU11248 potently inhibits KIT kinase activity of V654A and T670I mutants and suppresses proliferation of the cells expressing these mutations. Sensitivity of KIT-V654A and KIT-T670I mutants to SU11248 was confirmed using cell lines expressing these mutants. In contrast, SU11248 did not potently inhibit the PDGFRA-D842V mutant. In agreement with these results, two of the three imatinib-resistant patients with the KIT-V654A mutation responded to SU11248 treatment. These studies suggest that SU11248 may be a useful therapeutic agent to treat gastrointestinal stromal tumors harboring the imatinib-resistant KIT-V654A or KIT-T670I mutations, but it has no effect on the activity of the PDGFRA-D842V mutant. Specific kinase inhibitors should be designed to inhibit the constitutive activating PDGFRA mutation at codon 842.
    Clinical Cancer Research 05/2006; 12(8):2622-7. DOI:10.1158/1078-0432.CCR-05-2275 · 8.72 Impact Factor
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    ABSTRACT: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. KIT and PDGFRA activating mutations are the oncogenic mechanisms in most sporadic GISTs. In addition to sporadic occurrences, GISTs are increasingly being recognized in association with neurofibromatosis type 1 (NF1), yet the underlying pathogenic mechanism remains elusive. To gain an insight into the mechanisms underlying GIST formation in NF1 patients, we studied seven GISTs from three NF1 patients with a combination of different techniques: mutation analysis (KIT, PDGFRA and NF1), western blotting, array CGH and ex vivo imatinib response experiments. We demonstrate that (i) the NF1-related GISTs do not have KIT or PDGFRA mutations, (ii) the molecular event underlying GIST development in this patient group is a somatic inactivation of the wild-type NF1 allele in the tumor and (iii) inactivation of neurofibromin is an alternate mechanism to (hyper) activate the MAP-kinase pathway, while the JAK-STAT3 and PI3K-AKT pathways are less activated in NF1-related GIST compared with sporadic GISTs. In conclusion, we report for the first time the molecular pathogenesis of GISTs in NF1 individuals and demonstrate that this type of tumor clearly belongs to the spectrum of clinical symptoms in NF1.
    Human Molecular Genetics 04/2006; 15(6):1015-23. DOI:10.1093/hmg/ddl016 · 6.39 Impact Factor
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    ABSTRACT: Purpose. To evaluate the activity and safety of ecteinascidin (ET-743) in pretreated patients with advanced or metastatic soft tissue and bone sarcoma. Patients or subjects. Eighty-nine patients received ET-743 as a 24-hour continuous infusion at a dose of 900-1500 mug/m(2) every 3 weeks. Results. We observed one complete remission, 5 partial remissions, one minimal response, and 16 patients with a disease stabilization of 6 months or more. The objective response rate was 6.7% and the clinical benefit rate at 3 and 6 months was 37.7% and 23.4%, respectively. Responses were noted in patients with lipo-, leiomyo-, osteo-, and myogenic sarcoma, with a median duration of 9.85 months. Toxicity mainly involved an asymptomatic elevation of transaminases and neutropenia. Estimated 1- and 2-year survival rates were 39.4% and 15.8%. Median overall survival was 8.25 months. Discussion. This retrospective analysis confirms that ET-743 induces objective responses and progression arrest in a clinically relevant proportion of patients.
    Sarcoma 02/2006; 2006(1):56282. DOI:10.1155/SRCM/2006/56282
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    ABSTRACT: EORTC protocol 30924 is an international randomized trial reporting a 7.3 year update of a 2 weekly regimen of high-dose intensity chemotherapy with M-VAC plus granulocyte colony stimulating factor (HD-M-VAC) compared to classic M-VAC in advanced transitional cell carcinoma (TCC). Two hundred and sixty three untreated patients with bidimensionally measurable TCC were included. In an intention to treat analysis, there were 28 complete responses (CR) (21%) and 55 partial responses (PR) (41%), for an overall response rate (RR) of 64% on the HD-M-VAC arm. On M-VAC, there were 12 CR (9%) and 53 PR (41%), for an overall RR of 50% . The P-value for the difference in CR was 0.009; and for RR, was 0.06. After a median follow-up of 7.3 years, 24.6% are alive on the HD-M-VAC arm vs. 13.2% on the M-VAC arm. Median progression-free survival was better with HD-MVAC (9.5 months) vs. M-VAC (8.1 months). The mortality hazard ratio (HR) was 0.76. The 2-year survival rate for HD-M-VAC was 36.7% vs. 26.2% for M-VAC. At 5 years, the survival rate was 21.8% in the HD-M-VAC vs. 13.5%. Median survival was 15.1 months on HD-MVAC and 14.9 months on M-VAC. There was one death from toxicity in each arm; and more patients died to malignant disease in the M-VAC arm (76%) than in the HD-M-VAC arm (64.9%). With longer follow-up initial results have been confirmed, and shows that HD-M-VAC produces a borderline statistically significant relative reduction in the risk of progression and death compared to M-VAC.
    European Journal of Cancer 02/2006; 42(1):50-4. DOI:10.1016/j.ejca.2005.08.032 · 5.42 Impact Factor
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    ABSTRACT: Gastrointestinal stromal tumours (GIST) predominantly express activating mutations of the KIT tyrosine kinase receptor and are successfully treated with imatinib mesylate, a KIT inhibitor. As resistance to imatinib causes therapy failure, our aim was to develop an in vivo GIST model to evaluate KIT inhibitors and monitor therapy with small animal positron emission tomography (PET). The first mouse model of GIST xenografts was successfully established by injecting GIST882 cells subcutaneously into nude mice. Using the small animal PET, FDG up-take in xenografts was significantly decreased after 24 h of treatment with imatinib, which correlated with a response to treatment, e.g., with a decrease in tumour volume, the inhibition of KIT and downstream intermediate phosphorylation and arrest of tumour cell proliferation as evaluated after 7 days of treatment. This model is useful to study imatinib resistance and to evaluate novel targeted therapies.
    Anticancer research 01/2006; 26(2A):1247-52. · 1.83 Impact Factor
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    ABSTRACT: New chemotherapy regimens are continuously explored in patients with high-risk malignant germ cell tumours (MGCTs). This multicentre phase II trial assessed the efficacy and toxicity of C-BOP/BEP chemotherapy in intermediate and poor prognosis MGCT (IGCCCG criteria). C-BOP/BEP treatment consisted of cycles of cisplatin, vincristine, bleomycin and carboplatin, followed by one cycle of vincristine and bleomycin and three cycles of BEP (bleomycon, etoposide, cisplatin). The trial was designed to demonstrate a 1-year progression-free survival rate of 80%, that is, to exclude a 1-year rate of 70% or less, with a one-sided significance level of 5%. Secondary end points included toxicity, overall survival and the postchemotherapy complete response rate. In total, 16 European hospitals entered 66 eligible patients (intermediate prognosis group: 37; poor prognosis group: 29). A total of 45 patients (68.2%, 95% confidence interval (95% CI): 56.9-79.4%) achieved a complete response (intermediate prognosis: 30; poor prognosis: 15). After a median observation time of 40.4 months (range: 13.7-66.3), the 1-year progression-free survival rate was 81.8% 95% CI: 72.5-91.1%). The 2-year overall survival was 84.5% (95% CI: 75.6-93.3%). In all, 51 patients experienced at least one episode of WHO grade 3/4 leucopenia, and at least one event of grade 3/4 thrombocytopenia occurred in 30 patients. There was no toxic death. With an 82% 1-year progression-free survival and a lower limit of the 95% CI above 70%, the efficacy of C-BOP/BEP is comparable to that of published alternative chemotherapy schedules in high-risk MGCT patients. The treatment's toxicity is manageable in a multicentre setting. In poor prognosis patients, C-BOP/BEP should be compared to standard chemotherapy of four cycles of BEP.
    British Journal of Cancer 12/2005; 93(11):1209-14. DOI:10.1038/sj.bjc.6602830 · 4.84 Impact Factor
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    ABSTRACT: The noninvasive assessment of anticancer treatment efficacy is very important for the improvement of therapeutic window. The purpose of the present study was to evaluate the antitumoral effects of the vascular targeting agent, combretastatin A-4 phosphate (CA-4-P), at selected time points after repeated intraperitoneal drug administrations (25 mg/kg), using diffusion-weighted magnetic resonance imaging (DW-MRI). The experiments were performed during an overall follow-up period of 3 weeks on WAG/Rij rats with subcutaneously growing rhabdomyosarcomas. Each animal served as its own baseline. The DW-MRI studies were quantified by calculating the apparent diffusion coefficient (ADC) for different low and high b-values to separate the effects on tumor vasculature and cellular integrity. The changes in ADC as well as the extent of necrosis development (proportional to the tumor volume), measured on the MR images, were of comparable magnitude after each treatment. All ADC values showed a significant decrease at 6 hours, followed by a significant increase at 2 days for various CA-4-P administrations. DW-MRI allowed us to monitor both reduction in perfusion and changes in the extent of tumor necrosis after CA-4-P injection. Repeated CA-4-P administration retains efficacy in rat rhabdomyosarcomas, with similar findings after each drug administration.
    Neoplasia 09/2005; 7(8):779-87. DOI:10.1593/neo.04748 · 4.25 Impact Factor
  • P Pauwels · M Debiec-Rychter · M Stul · I De Wever · A T Van Oosterom · R Sciot
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    ABSTRACT: The diagnosis of gastrointesinal stromal tumours (GISTs) is widely based on morphological features and KIT (CD117) immunoreactivity. Most patients with advanced GISTs show a major clinical response after treatment with imatinib mesylate. The histopathological features of GISTs in patients on prolonged imatinib treatment have, thus far, not been addressed in detail. In this report, we present three patients with metastatic GISTs, who received more than 1 year of therapy with imatinib, and whose tumours changed their morphological and immunohistochemical characteristics during continued treatment with the drug. All three primary GISTs from these patients were classical spindle-type tumours, showing diffuse, strong CD117, CD34, and focal alpha-smooth muscle actin expression. During treatment, two clinically progressive and one clinically stable GIST revealed a diffuse epithelioid, or pseudopapillary epithelioid growth pattern, characterized by rounded cells with eosinophilic cytoplasm and uniform round-to-ovoid nuclei. In addition, GIST specimens from patients on therapy showed complete loss of CD117 immunoreactivity. Remarkably, two of these tumours also became CD34 immunonegative and in one case the progression was accompanied by desmin expression. KIT mutational analysis revealed the presence of distinct exon 11 mutant isoforms in all cases examined, while the same genotype was sustained in the base line and on-therapy tumour specimens, proving the common origin of analysed specimens. GISTs subject to imatinib treatment can undergo striking (immuno)phenotypic changes, which are not necessarily corroborated by new genotypic modifications. Because these may mimic other tumour types, this feature creates a differential diagnostic challenge, of which the pathologist should be aware.
    Histopathology 08/2005; 47(1):41-7. DOI:10.1111/j.1365-2559.2005.02179.x · 3.45 Impact Factor
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    ABSTRACT: The development of an on-column focusing gradient capillary LC method coupled to tandem mass spectrometry (quadrupole-linear ion trap) for the quantitative determination of the anticancer agent ZD1839 (Gefitinib, Iressa) in blood plasma is described. Plasma samples (0.2 ml) were extracted with methyl tert-butyl ether. The analytes of interest, ZD1839 and the internal standard [(2)H8]ZD1839 (ZD1839-d8) were eluted on a 50 mm x 1 mm, 5 microm particle size, capillary ODS Hypersil column using an aqueous ammonium acetate gradient at 40 microl/min. Mass spectrometric detection was performed by a Q-Trap tandem mass spectrometer with electrospray positive ionisation, and monitored in the multiple reaction monitoring transitions 447 >128 and 455 >136, respectively. The limit of quantification of ZD18395 was 0.1 ng/ml. The method proved to be robust, allowing quantification of ZD1839 with sufficient precision, accuracy and sensitivity.
    Journal of Chromatography A 07/2005; 1082(1):2-5. DOI:10.1016/j.chroma.2005.04.043 · 4.17 Impact Factor
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    ABSTRACT: Imatinib pharmacokinetics (PK) may be affected by a number of factors that are related to the disease being treated and to the response of that disease to imatinib. Patients in the phase I and phase II trials conducted by the EORTC in patients with gastrointestinal stromal tumours (GISTs) and other sarcomas had detailed blood sampling for imatinib PK on day 1 and on day 29. Patients with GISTs also had repeat sampling, using a limited sampling strategy, after approximately 12 months on therapy. This population PK study was carried out to examine what covariates affected imatinib PK in GIST patients and what PK changes occurred over time. In the model producing the best fit, low clearance (CL) correlated with low body weight and high granulocyte count, whereas low haemoglobin correlated with low volume of distribution. For a patient with 77% of the median body weight or with 1.87 times the median granulocyte count, the apparent CL is 6.53 l/h, about 70% of the typical apparent CL of 9.33 l/h; for a patient of 84% of the typical haemoglobin level, the volume of distribution is about 70%. Total white blood cell count correlated closely with granulocyte count and there was a moderate correlation between haemoglobin and albumin (r = 0.454). There was a trend towards increased imatinib clearance after chronic exposure over 12 months. The typical apparent CL increased 33% from day 1. Nevertheless, the approximate 95% confidence interval of the increase of the typical apparent CL was 33 +/- 34.6%, which contains zero. It is not yet clear whether this is a significant factor in the amelioration of imatinib toxicity that occurs with time or is related to disease control, and further work is required to confirm this observation.
    Cancer Chemotherapy and Pharmacology 05/2005; 55(4):379-86. DOI:10.1007/s00280-004-0876-0 · 2.77 Impact Factor
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    ABSTRACT: The cutaneous malignant tumor dermatofibrosarcoma protuberans (DFSP) is typically associated with a translocation between chromosomes 17 and 22 that places the platelet-derived growth factor-B (PDGFB) under the control of the collagen 1A1 promoter. The purpose of this study was to evaluate molecular, cytogenetic, and kinase activation profiles in a series of DFSPs and to determine whether these biologic parameters are correlated with the clinical responses of DFSP to imatinib. We analyzed the objective radiologic and clinical response to imatinib at 400 mg twice daily in eight patients with locally advanced DFSP and two patients with metastatic disease. Each of eight patients with locally advanced DFSP had evidence of t(17;22) and showed a clinical response to imatinib. Four of these patients had complete clinical responses. The two patients with metastatic disease had fibrosarcomatous histology and karyotypes that were substantially more complex than those typically associated with localized DFSP. One patient with metastatic DFSP and an associated t(17;22) had a partial response to imatinib but experienced disease progression after 7 months of therapy. In contrast, the other patient with metastatic disease had a tumor lacking t(17;22), and there was no clinical response to imatinib. Unexpectedly, there was minimal platelet-derived growth factor receptor-beta phosphorylation in the untreated DFSP, despite the documented presence of a PDGFB autocrine mechanism. Imatinib has clinical activity against both localized and metastatic DFSP with t(17;22). However, fibrosarcomatous variants of DFSP lacking t(17;22) may not respond to imatinib.
    Journal of Clinical Oncology 03/2005; 23(4):866-73. DOI:10.1200/JCO.2005.07.088 · 18.43 Impact Factor

Publication Stats

15k Citations
1,653.75 Total Impact Points


  • 2012
    • Catholic University of Louvain
      Лувен-ла-Нев, Walloon, Belgium
  • 1994–2011
    • Universitair Ziekenhuis Leuven
      • Department of General medical oncology
      Louvain, Flanders, Belgium
  • 1997–2008
    • University of Leuven
      • • Department of Oncology
      • • Laboratory of Experimental Transplantation
      • • Laboratory for Pharmaceutical Analysis
      Louvain, Flemish, Belgium
  • 2006
    • Vlaams Instituut voor Biotechnologie
      Gand, Flanders, Belgium
  • 2002
    • The Catholic University of America
      Washington, Washington, D.C., United States
  • 2001
    • Vincenzo Pansadoro Foundation
      Roma, Latium, Italy
  • 1982–2001
    • Leiden University Medical Centre
      • Department of Clinical Oncology
      Leyden, South Holland, Netherlands
  • 1988–2000
    • University of Antwerp
      • • Department of Pathology
      • • Department of oncology
      Antwerpen, Flanders, Belgium
  • 1999
    • Clinique Saint-Luc, Bouge
      Namen, Walloon Region, Belgium
    • European Organisation for Research and Treatment of Cancer
      Bruxelles, Brussels Capital Region, Belgium
  • 1988–1999
    • Netherlands Cancer Institute
      • Department of Medical Oncology
      Amsterdamo, North Holland, Netherlands
  • 1998
    • Erasmus MC
      • Department of Internal Oncology
      Rotterdam, South Holland, Netherlands
  • 1993
    • Universitair Ziekenhuis Antwerpen
      • Department of Radiology
      Antwerpen, Flanders, Belgium
  • 1991
    • Hospital Central de Asturias
      Oviedo, Asturias, Spain
  • 1979–1991
    • Leiden University
      Leyden, South Holland, Netherlands
  • 1990
    • VU University Amsterdam
      Amsterdamo, North Holland, Netherlands
  • 1987–1988
    • University of Amsterdam
      Amsterdamo, North Holland, Netherlands
    • Utrecht University
      • Division of Internal Medicine
      Utrecht, Utrecht, Netherlands
  • 1986
    • University Medical Center Utrecht
      Utrecht, Utrecht, Netherlands
    • Radboud University Nijmegen
      • Department of Medical Oncology
      Nymegen, Gelderland, Netherlands