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A van Oosterom

Publications and source records attributed to A van Oosterom.

At least 19 recordsLinked to original sources
PubMed2003

18FDG-Positron emission tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate (Glivec).

Imatinib mesylate (Glivec, formerly STI571) is the first effective systemic treatment for gastrointestinal stromal tumours (GISTs). Major changes in tumour volume, however, tend to occur late after the start of treatment. The aim of this study was to evaluate if [18F]-fluorodeoxyglucose-positron emission tomography (FDG-PET) can be used for the early evaluation of response to imatinib mesylate treatment in soft-tissue sarcomas (STS). 21 patients (17 GIST, 4 other STS) underwent FDG-PET imaging prior to and 8 days after the start of treatment. PET response (European Organization for Research and Treatment (EORTC) guidelines) was observed in 13 GISTs (11 Complete Responders, 2 partial responders. Subsequent computerised tomography (CT) response Response Evaluation Criteria in Solid Tumours (RECIST) was observed in 10 of these patients after a median follow up of 8 weeks. Stable or progressive disease was observed on PET in 8 patients and none of them achieved a response on CT. PET response was also associated with a longer progression-free survival (PFS) (92% versus 12% at 1 year, P=0.00107). We conclude that FDG-PET is an early and sensitive method to evaluate an early response to imatinib treatment.

Adult↗
PubMed2003

Imatinib mesylate (STI-571 Glivec, Gleevec) is an active agent for gastrointestinal stromal tumours, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target. Results from an EORTC Soft Tissue and Bone Sarcoma Group phase II study.

The aim of this study was to assess the antitumour response and time to progression (TTP) of patients treated with imatinib mesylate (Glivec, Gleevec, formerly STI-571) who had advanced and/or metastatic gastrointestinal stroma tumours (GIST) or other soft tissue sarcomas (STS). Patients with measurable lesions and adequate organ function were entered. They were treated with imatinib mesylate at the dose of 400 mg twice daily (bid). All tumours were subject to a stringent pathological review by an expert panel. Immunohistochemical expression of KIT expression was evaluated. A total of 51 patients (27 GIST, 24 other STS), median age 53 years, median World Health Organization (WHO) performance score 1, were entered. 71% of the patients had received prior chemotherapy. The most frequent side-effects were anaemia (92%), periorbital oedema (84%), skin rash (69%), fatigue (76%), nausea (57%), granulocytopenia (47%) and diarrhoea (47%). Most of these side-effects were mild to moderate and no patient was taken off study due to side-effects. Skin rash and periorbital oedema frequently seem to be self limiting, despite continued treatment. In GIST patients, the current response rates (RRs) are 4% complete remission (CR), 67% partial remission (PR), 18% stable disease (SD) and 11% progression (PD). 73% of GIST patients are free from progression at 1 year. In the other STS group, there were no objective responses. The median time to progression in this subgroup was only 58 days. Imatinib mesylate is well tolerated at a dose of 400 mg bid. This dose is active in patients with KIT-positive GIST, but patients with other STS subtypes unselected for a molecular target are unlikely to benefit.

Adult↗
PubMed2002

Solidifying the solid angle.

This paper evaluates the position of the solid angle in its application to modeling in electrocardiology. Particular attention is paid to the use of the solid angle for linking cardiac electric activity to the potentials observed on the body surface. In this application, the solid angle is a dominant factor in the expression of the sources during depolarization known as the uniform double layer. In the related equivalent double layer model, the contributions of the elementary sources are also expressed in terms of solid angles, their strength not being uniform. A recently developed theory allows the equivalent double layer to be applied to both depolarization and repolarization.

Body Surface Potential Mapping↗
PubMed2002

Three-layer volume conductor model and software package for applications in surface electromyography.

On comparing multichannel surface electromyographic measurements of the m. biceps brachii with simulations performed with a previously developed two-layer volume conduction model, we found substantial discrepancies. To incorporate an apparent distorting effect of the skin tissue, the model was extended to three layers. This new model describes the potential resulting from an eccentric bioelectric source in a finite, cylindrical, and anisotropic volume conductor consisting of three layers, representing muscle, subcutaneous fat, and skin tissue. This contribution presents the governing mathematical equations of the three-layer volume conductor model as well as our approach to their solution. A comparison of various models shows that the three-layer model best describes measured potential distributions. Furthermore, we present the "ANVOLCON" (analytical volume conductor) software package. This package has been developed to facilitate the use of the model for scientific and educational purposes and is freely available from http://www.mbfys.kun.nl/knf

Action Potentials↗
PubMed2001

In vivo antitumor effect of vascular targeting combined with either ionizing radiation or anti-angiogenesis treatment.

PURPOSE: Interference with the tumor blood vessels through anti-angiogenesis or vascular targeting can indirectly suppress tumor growth. Vascular targeting of solid tumors, using tubulin-compromising agents, seems a promising and selective novel treatment. We aimed to evaluate the potential (hypothesis-based) benefit from combinations of vascular targeting using combretastatin A-4 phosphate (combreAp) with either ionizing radiation or anti-angiogenesis. METHODS AND MATERIALS: Rhabdomyosarcoma tumor pieces were inplanted subcutaneously (s.c.) in the lower flank region of syngeneic adult WAG/Rij rats. Tumors were grown until different sizes and stratified for the various treatment groups: small (1-3 cm3), medium (3.1-7 cm3), and large (7.1-14 cm3). CombreAp was injected i.p.; injections of TNP-470 were s.c. in the neck area. Localized single-dose (8 Gy) irradiations of tumors were done under Nembutal anesthesia, always 1 day before a single combreAp (25 mg/kg) injection. The TNP-470 treatment (3 times 30 mg/kg in 1 week) started 1 day after a double (8 days interval between both) combreAp administration. Tumor responses were evaluated by the growth delay assay, and statistical significance of tumor growth change was computed. RESULTS: Large tumors responded better to combreAp treatment given alone than did the smaller ones, confirming our previous data with this tumor model. Combining irradiation with combreAp also resulted in a tumor size-dependent growth delay. With small and medium tumor volumes, a similar response was measured after the combination treatment when compared with irradiation only. Large tumors, however, showed a strong (at least additive) increase of the growth delay with the combined therapy; the difference in tumor growth between the two treatment groups was very significant (p < 0.0001). m When TNP-470 was combined with combreAp, no significant lengthening of the growth delay, irrespective of the tumor size, was present with the applied schedule. CONCLUSION: The current data show a significant advantage in the combination of combreAp with irradiation in rhabdomyosarcomas having a large size (7-14 cm3) at treatment. Such a benefit in tumor response was not observed with the smaller tumors, seemingly because irradiation as such was very effective. No significant gain in growth delay for any tumor size was observed when TNP-470, showing efficacy on its own specifically with tumors measuring <7 cm3, was added to the combreAp treatment. This presumably reflects only little angiogenesis during the first week of rhabdomyosarcoma regrowth after the combreAp treatment.

Angiogenesis Inhibitors↗
PubMed2001

Overlap of attention and movement-related activity in lateralized event-related brain potentials.

OBJECTIVE: In tasks that involve lateralized visuospatial attention and a lateralized motor response, the associated brain electrical potentials, i.e. the attention-related N2pc and the lateralized readiness potential, typically overlap at central scalp sites. The manifestation of the N2pc at central electrode sites is commonly attributed to electric volume conduction effects, assuming the N2pc to be generated in occipito-temporal brain areas. We evaluated this explanation in a simulation study. METHODS: Using a forward modeling approach with a realistically shaped volume conduction model, we calculated the range of amplitude ratios between occipital and central electrode sites when a single source is assumed in area V4 or in area TO, at the temporo-occipital convexity. RESULTS: A comparison of the simulated amplitude ratios with reported data indicates that volume conduction effects from the investigated source origins in the occipito-temporal region are insufficient to explain the experimental data. CONCLUSIONS: We conclude that the anterior spread of the N2pc from its occipito-temporal maximum to central electrode sites is probably due to simultaneous attention-related activity in posterior and central brain areas.

Attention↗
PubMed2001

Specific targeting of cytosine deaminase to solid tumors by engineered Clostridium acetobutylicum.

The presence of severe hypoxia and necrosis in solid tumors offers the potential to apply an anaerobic bacterial enzyme/prodrug approach in cancer treatment. In this context the apathogenic C. acetobutylicum was genetically engineered to express and secrete E. coli cytosine deaminase (CDase). Considerable levels of functional cytosine deaminase were detected in lysates and supernatants of recombinant C acetobutylicum cultures. After administration of the recombinant Clostridium to rhabdomyosarcoma bearing rats used as a model, cytosine deaminase could be detected at the tumor site. Moreover, following administration of the vascular targeting agent combretastatin A-4 phosphate significantly increased levels of cytosine deaminase were detected at the tumor site as a consequence of enlarged tumor necrosis and subsequently improved growth of C. acetobutylicum. The results provide evidence for the potential application of Clostrisdium-based therapeutic protein transfer to tumors in anticancer therapy.

Animals↗
PubMed2001

Genesis of the T wave as based on an equivalent surface source model.

This article shows the use of the equivalent surface source model in its application to the genesis of the surface ECG in which the sources are of the double layer type. This model has previously been shown to yield an accurate description of body surface potentials during the QRS interval. Its application to the genesis of the T wave is now worked out in greater detail. In this source model, the full spatio-temporal character of the cardiac electric generator is expressed by means of an equivalent double layer situated at the boundary of ventricular tissue. The timing of local depolarization and of repolarization of the cells near this boundary is used to simulate the surface ECG. The background of this source model is discussed, as well as its validity. A matrix formulation is presented of the forward problem of computing the resulting body surface potentials. Based on this forward formulation, an inverse computation of the timing of the repolarization process was performed. Simulated T waves, based on this timing, showed a close correspondence with measured body surface potentials. By taking the inversely computed timing of repolarization as representing the true situation, the model can be used to study in which way perturbations in the timing of local repolarization effect the shape of T waves. An analysis based on this model indicates that the amplitude of the T wave is proportional to the dispersion of the repolarization times at the ventricular surface. The model is also shown to be capable of simulating the ECG changes during local ischemia.

Body Surface Potential Mapping↗
PubMed2001

Geometrical aspects of the interindividual variability of multilead ECG recordings.

The electrocardiogram (ECG) as measured from healthy subjects shows a considerable interindividual variability. This variability is caused by geometrical as well as by physiological factors. In this study, the relative contribution of the geometrical factors is estimated. In addition a method aimed at correcting for these factors is described. First, a measure (RV) for quantifying the overall variability is presented, and for healthy individuals its value is estimated as 0.52. Next, based on a simulation study using the individual (heart-lung-torso) geometry of 25 subjects, the variability caused by geometrical factors is estimated as 0.40, indicating that in healthy subjects the RV for healthy individuals resulting from electrophysiology is of the order of 0.33. In an evaluation of the correction procedure, applied to realistic, simulated body surface potentials, it is shown that RV caused by geometrical factors can be reduced from 0.40 to 0.06. When applying the correction procedure to measured ECG data no reduction of the RV value could be demonstrated. These results indicate that the involved procedure of the inverse computation of a cardiac equivalent source, at the present time, is of insufficient quality to cash in on the substantial reduction of RV values from 0.52 down to 0.33 that might be obtainable.

Body Surface Potential Mapping↗
PubMed2001

Improvement of Clostridium tumour targeting vectors evaluated in rat rhabdomyosarcomas.

Previous studies have demonstrated the feasibility of using apathogenic clostridia as a promising strategy for hypoxia-specific tumour targeting. The present study shows that the use of the vascular targeting compound combretastatin A-4 phosphate could significantly (P<0.001) increase the number of Clostridium vegetative cells in rat rhabdomyosarcomas with sizes between 0.2 cm(2) and 3 cm(2). Furthermore, this study showed that administration of metronidazole for a 9-day period was sufficient to eliminate systemically administered Clostridium from the tumour. Moreover, previous Clostridium spore administration did not effect tumour colonisation, regardless of the immune response status of the host.

Animals↗
PubMed2000

Comparison of different computer models of the neural control system of the lower urinary tract.

This paper presents a series of five models that were formulated for describing the neural control of the lower urinary tract in humans. A parsimonious formulation of the effect of the sympathetic system, the pre-optic area, and urethral afferents on the simulated behavior are included. In spite of the relative simplicity of the five models studied, behavior that resembles normal lower urinary tract behavior as seen during an urodynamic investigation could be simulated. The models were tested by studying their response to disturbances of the afferent signal from the bladder. It was found that the inhibiting reflex that results from including the sympathetic system or the pre-optic area (PrOA) only counteracts the disturbance in the storage phase. Once micturition has started, these inhibiting reflexes are suppressed. A detrusor contraction that does not result in complete micturition similar to an unstable detrusor contraction could be simulated in a model including urethral afferents. Owing to the number of uncertainties in these models, so far no unambiguous explanation of normal and pathological lower urinary tract behavior can be given. However, these models can be used as an additional tool in studies of the mechanisms of the involved neural control.

Computer Simulation↗
PubMed2000

Carzelesin phase II study in advanced breast, ovarian, colorectal, gastric, head and neck cancer, non-Hodgkin's lymphoma and malignant melanoma: a study of the EORTC early clinical studies group (ECSG).

PURPOSE: In a phase II trial, the activity of carzelesin, a cyclopropylpyrroloindole prodrug analog, was assessed. PATIENTS AND METHODS: Carzelesin was used as second- or third-line chemotherapy in patients with breast, ovarian, head and neck cancer and non-Hodgkin's lymphoma, and as first-line chemotherapy in patients with colorectal and gastric cancer and melanoma. The drug was given as a bolus infusion at a 4-weekly dose of 150 microg/m2. A total of 140 patients were entered and a total of 285 courses were administered. RESULTS: In general, the compound was well tolerated. Myelotoxicity was the most common toxicity. Grade 3 and 4 leukopenia was observed in 18.6% of the courses, neutropenia in 20.3%, thrombocytopenia in 16.2% and anemia in 8.7%. Double nadirs were seen in a total of 41 courses for neutrophils, in 40 for leukocytes and in 3 for platelets. Non-hematological toxicity was very mild. Only one partial response in a patient with melanoma was seen. CONCLUSIONS: At this dose and schedule carzelesin did not yield activity in the types of tumors studied.

Adult↗
PubMed2000

Vascular targeting of solid tumours: a major 'inverse' volume-response relationship following combretastatin A-4 phosphate treatment of rat rhabdomyosarcomas.

Tumour-specific vascularisation may be therapeutically approached in two different ways: by antiangiogenic treatments specifically directed to dividing and migrating endothelial cells, or by agents that target principally the inadequate and ill-structured tumour vasculature. Combretastatin A-4 phosphate (combreAp), a recently synthesised prodrug (OXiGENE, Lund, Sweden), is a vascular targeting agent of the latter kind. We evaluated the effect of a single intraperitoneal (i.p.) combreAp injection on the growth of rhabdomyosarcomas syngeneic in WAG/Rij rats. Different tumour volume groups, ranging between 0.1 and 27 cm(3), were selected to assess the relationship between the size at treatment time and the response to combreAp. A double combreAp treatment (2x25 mg/kg) was investigated within the same overall aim: the relationship between growth delay and tumour size. Our results show that the systemic administration of combreAp induces a clear-cut differential growth delay in the solid rat rhabdomyosarcomas: with very large tumours (>/= 14 cm(3)), a 17.6-fold stronger effect was measured than with very small tumours (<1 cm(3)). This is the 'inverse' of the volume-response seen with the conventional therapeutic approaches (radiotherapy, chemotherapy or surgery). These combreAp antitumour responses were observed without treatment limiting systemic toxicity in the rats. With clinical digital subtraction angiography, using microsurgical cannulation of a major tumour draining vessel, and with histopathology, we demonstrate that growth delay is related to an early (within 3-6 h) and extensive breakdown of tumour blood vessels. The experiments involving a second injection also indicate a volume-dependent effect of combreAp in reducing the regrowth rate of small or large rhabdomyosarcomas. This significant differential volume-response obtained with 'selective' vascular targeting, stronger in larger tumours than smaller ones, suggests the potential of broadening the therapeutic window.

Angiography, Digital Subtraction↗
PubMed2000

Effect of high-dose ifosfamide in advanced soft tissue sarcomas. A multicentre phase II study of the EORTC Soft Tissue and Bone Sarcoma Group.

In this phase II study the effect of high-dose ifosfamide (HDI) given as a 3-day continuous infusion at a dose of 12 g/m2 repeated every 4 weeks with adequate mesna protection and hydration was evaluated in patients with advanced soft tissue sarcomas. A total of 124 patients entered the trial of which 10 were ineligible. HDI was given both as first-line and second-line chemotherapy. Median age was 46 years (19-66 years). Median World Health Organization (WHO) performance status was 1 (0-1). Fifty two per cent of the patients were males. The predominant histology was leiomyosarcoma (33%). A maximum of six cycles was given. At the time of analysis 55 patients have died. The partial response (PR) rate was 16%. The median time to progression was 15 weeks. 8 of the 18 responding patients (44%) had synovial sarcomas, whereas only 5% of the patients having leiomyosarcomas responded. The grade 3 + 4 haematological toxicity encountered was neutrophils in 78% and platelets in 12%. The major grade 3 + 4 non-haematological toxicities encountered were febrile neutropenia in 39%, infection in 20%, and acute renal failure in 4%. In conclusion, it is possible to administer HDI on a multicentre basis, but the toxicity is substantial. HDI given as a continuous infusion at this dose cannot be recommended as the standard treatment of advanced soft tissue sarcomas, even in selected patients.

Adult↗
PubMed2000

Geometrical factors affecting the interindividual variability of the ECG and the VCG.

Various measures for quantifying the interindividual variability of the electrocardiogram and the vectorcardiogram in healthy subjects are presented. An analysis of factors that may cause this variability is performed, in particular of the geometrical factors of body size, heart size, heart position, and orientation. The results indicate that the variations in the magnitude of the electrocardiogram as observed through leads placed on the anterior thorax are dominated by the solid angle at which the outline of ventricular mass is seen from points on the thorax. Heart size and body size as such play only a secondary role. The limited spatial sampling of the anterior thorax directly overlaying the heart causes the mean values of all measures of amplitudes in women to be lower than in men. The vectorcardiogram magnitude was found to be much less dependent on overall geometry and heart position, and, hence, also to be less dependent on gender.

Adult↗
PubMed1999

The use of the spatial covariance in computing pericardial potentials.

This paper investigates the incorporation of the spatial covariance of the pericardial potentials, assumed known a priori as a regularization function, when computing the pericardial potential distribution from observed body surface potentials. The resulting inverse solutions are compared with those using as a regularization function: 1) the norm of the solution, 2) the norm of the surface Laplacian of the solution, as well as with those based on using the truncated singular value decomposition. The study uses a realistic source model to simulate potentials throughout the QRS-interval. This source is placed in an anatomically accurate inhomogeneous volume conductor model of the torso. The use of a single value of the regularization parameter is shown to be feasible: for data incorporating 2% noise, the use of the spatial covariance is demonstrated to result in a relative error over the entire QRS interval as low as 10%. Major errors are demonstrated to result if the effect of the inhomogeneity of the lungs is ignored. The spatial covariance based inverse is shown to be more robust with respect to the perturbations (noise; inhomogeneity) than the other estimators included in this study.

Body Surface Potential Mapping↗
PubMed1999

Clinical and pharmacokinetic phase I study of multitargeted antifolate (LY231514) in combination with cisplatin.

PURPOSE: Multitargeted antifolate (MTA; LY231514) has broad preclinical antitumor activity and inhibits a variety of intracellular enzymes involved in the folate pathways. This study was designed to (1) determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of MTA combined with cisplatin; (2) determine a recommended dose for phase II studies; and (3) collect anecdotal information on the antitumor activity of MTA combined with cisplatin. PATIENTS AND METHODS: Patients with solid tumors received MTA intravenously over 10 minutes and cisplatin over 2 hours once every 21 days. In cohort 1, both agents were administered on day 1 starting with MTA 300 mg/m(2) and cisplatin 60 mg/m(2). In cohort 2, MTA (500 or 600 mg/m(2)) was administered on day 1, followed by cisplatin (75 mg/m(2)) on day 2. RESULTS: In cohort 1, 40 assessable patients received 159 courses of treatment. The MTD was MTA 600 mg/m(2)/cisplatin 100 mg/m(2). DLTs were reversible leukopenia/neutropenia and delayed fatigue. Hydration before cisplatin therapy did not influence MTA pharmacokinetics. Eleven objective remissions included one complete response in a patient with relapsed squamous cell head and neck carcinoma, and partial responses in four of ten patients with epithelial pleural mesothelioma. In cohort 2, 11 assessable patients received 23 courses of treatment. The MTD was MTA 600 mg/m(2) and cisplatin 75 mg/m(2). DLTs were neutropenic sepsis, diarrhea, and skin toxicity. Two patients died of treatment-related complications during the study. Two patients had objective remissions (one mesothelioma patient, one colon cancer patient). CONCLUSION: The combination of MTA and cisplatin is clinically active, and administering both agents on day 1 is superior to a split schedule. Further development of this combination for mesothelioma is warranted.

Adult↗