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Biomedical subjects

A van Oosterom

Publications and source records attributed to A van Oosterom.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1999

On selecting a body surface mapping procedure.

Throughout the world, various procedures related to body surface mapping have evolved. The large differences in these procedures make multicenter studies difficult. This paper discusses the problems involved in selecting the number of leads, lead placement, and map format. Methods are highlighted that have been developed for pooling of the data as obtained by different centers. Recommendations are included to newcomers in the field. (The work stems from an international study, the Noninvasive Evaluation of the Myocardium, a study group sponsored by the European Commission, which has as one of its objectives the standardization of body surface mapping procedures.)

Body Surface Potential Mapping↗
PubMed1999

Interindividual variability of multilead electrocardiographic recordings: influence of heart position.

The electrocardiogram (ECG) of normal, healthy subjects shows a large interindividual variability. Part of this variability is due to the heart position and orientation relative to the electrodes. In this report, the interindividual variability is quantified using the relative variability measure, computed as the averaged standard deviation in the ECGs, scaled by the average root mean square of the ECGs. The relative variability in the QRS complex is estimated as 0.52. The heart position and orientation relative to the lead positions is documented in 25 normal subjects. The long axis angle varies considerably among the subjects (27.1+/-8.8 degrees to the transversal plane and 38 degrees +/-5 degrees to the frontal plane). Moving the electrodes in the frontal plane to a position relative to a common reference point at the base of the heart (shift: 0.8+/-0.7 cm leftward and 2.4+/-2.3 cm downward) did not reduce the interindividual variability.

Adult↗
PubMed1999

The number of independent signals in body surface maps.

This paper reports on the number of independent signals in body surface maps measured using a variety of lead systems incorporating 32 up to 219 leads. The number of independent signals is estimated using the minimum description length. It is found that the number of independent signals in body surface maps is of the order of 10. For lead systems incorporating many leads the number of independent signals is only marginally larger than in lead systems incorporating fewer leads. A lead system incorporating 64 leads will suffice for most applications.

Algorithms↗
PubMed1999

Preliminary results of a phase I study with MTA (LY231514) in combination with cisplatin in patients with solid tumors.

MTA (multitargeted antifolate, LY231514) is a novel antimetabolite resulting from structure/activity studies of the lometrexol-type antifolates. It has been shown to inhibit various enzymes of folate pathways and has broad antitumor activity in a variety of in vitro and in vivo tumor models. Clinical phase 1 studies have been performed using different administration schedules, and subsequently the every-21-days schedule has been selected for further development. We report the preliminary findings from a combination phase I study of MTA and cisplatin administered every 21 days. In the first cohort (34 patients), both agents were administered on day 1 with a starting dose of 300 mg/m2 MTA and 60 mg/m2 cisplatin. In a second cohort (10 patients), MTA (500 or 600 mg/m2) was administered on day 1 followed by cisplatin (75 mg/m2) on day 2. The maximum tolerated doses were reached at 600 mg/m2 MTA/100 mg/m2 cisplatin (cohort 1) and 600 mg/m2 MTA/75 mg/m2 cisplatin (cohort 2). In cohort 1, dose-limiting toxicities consisted of reversible myelosuppression with leukopenia and neutropenia. In addition, delayed fatigue also was of clinical significance. Pharmacokinetic analyses indicated that hydration administered before the administration of cisplatin did not influence the major pharmacokinetic parameters of MTA. Eleven objective remissions were observed, including one complete response in a patient with relapsed squamous cell carcinoma of the head and neck and partial responses in four of seven patients with mesothelioma In contrast, the dose-limiting toxicities in patient cohort 2 consisted of neutropenic sepsis, diarrhea, and skin toxicity with two possibly treatment-related deaths on study. No objective remissions are presently observed in cohort 2. We conclude that the combination of MTA and cisplatin is feasible and clinically active when both agents are administered on day 1 and that it should be pursued for further clinical development.

Adult↗
PubMed1998

Lead system transformation of body surface map data.

Multicenter application of body surface map data (multilead electrocardiographic [ECG] data) is hampered by the fact that the centers involved in body surface mapping use lead systems differing in lead placement as well as in the number of leads. In this study, the performance of two methods for converting multilead ECGs from one lead system to another is evaluated in their application to the major lead systems presently in use throughout the world. The first method is based on Laplacian interpolation, and the second method is derived from the correlations between the signals in an extensive lead system. Through analyzing the representation errors, it was found that, for lead systems incorporating over 60 leads, both methods work well, yielding errors comparable to interbeat differences in individuals. For lead systems incorporating fewer leads, the correlation method is to be preferred.

Adult↗
PubMed1997

Volume conduction models for surface EMG; confrontation with measurements.

Volume conduction models are used to describe and explain recorded motor unit potentials (MUPs). So far it has remained unclear which factors have to be taken into account in a volume conduction model. In the present study, five different models are confronted with measured MUP distributions over the skin surface above the m. biceps brachii generated by MUs at different depths and recorded by small surface electrodes. All model simulations include fibres of finite length. The models differ in the size of the volume conductor (finite/infinite), the number of different layers (1, 2 or 3) and the conductivities of these layers (representing muscle, subcutaneous fat and skin). All measured and simulated MUPs contain a mainly negative propagating wave followed by a positive wave simultaneously present at all electrode positions. The magnitude of the different MUP components relative to each other and as a function of motor unit (MU) and electrode position differ between the models studied and the measurements. All simulated MUPs changed faster with observation distance than the measured MUPs. The three-layer model, in which muscle tissue was surrounded by a subcutaneous fat layer and by a layer of skin resulted in MUPs closest to the measured MUPs.

Journal Article↗
PubMed1997

Botryomycosis mimicking a liposarcoma.

Botryomycosis is an atypical reaction of the host to a common bacterial infection. A case of botryomycosis mimicking a liposarcoma as suspected on clinical and radiological grounds is described. The diagnosis was made by biopsy and culture of the lesion. A review of the literature is given.

Abdomen↗
PubMed1996

The surface Laplacian of the potential: theory and application.

The use of the surface Laplacian of the potential (Ls) in bioelectricity is discussed. Different estimates of Ls, in particular the field measured by coaxial electrodes, are compared to that of the true Laplacian. A method to compute Ls on the surface of an inhomogeneous volume conductor of arbitrary shape resulting from assumed electrical sources in introduced. In two applications the sensitivity of the body surface Laplacian is carried to that of body surface potentials. This comparison is carried out for dipolar sources within the human brain as well as for distributed sources within the heart.

Body Surface Potential Mapping↗
PubMed1995

Lead system transformation for pooling of body surface map data: a surface Laplacian approach.

In this paper, a method is described to transform Body Surface Map (BSM) data from one lead system to that of another. This enables pooling of BSM data between different centres. The transformation tool is based upon Laplacian interpolation. It is evaluated by inspecting transformations from lead systems having few leads to one having many leads.

Body Surface Potential Mapping↗
PubMed1994

Application of the boundary element method to the solution of anisotropic electromagnetic problems.

The paper discusses the application of the boundary element method to the computation of the electric potential and magnetic field generated by bioelectric sources in an anisotropic inhomogeneous volume conductor, using a proper coordinate transformation. It is shown that the co-ordinate transformation generally not only affects the conductivity and geometry of the volume conductor under consideration, but also the current source term and the continuity relation on the interfaces bounding regions of different conductivity. To illustrate these results, the electric potentials in an anisotropic finite length cylinder and in an anisotropic volume conductor of irregular (torso) shape, computed by the boundary element method, are compared with the results obtained by the analytical solution and the finite element method, respectively.

Anisotropy↗
PubMed1994

Docetaxel (Taxotere) in advanced renal cell cancer. A phase II trial of the EORTC Early Clinical Trials Group.

Docetaxel (Taxotere), an analogue of paclitaxel, was tested in a phase II study in advanced renal cell carcinoma. Consenting patients with measurable lesions, adequate organ functions and no prior chemotherapy received 100 mg/m2 of docetaxel as a 1-h infusion every 3 weeks. No premedication to avoid hypersensitivity reactions or nausea and emesis was given. 32 eligible patients received 100 treatment cycles. Short-lasting neutropenia was the dose-limiting toxicity. Acute hypersensitivity reactions (HSR), oedema and skin changes were other important side-effects. HSRs regressed spontaneously or were treated with antihistamines with or without corticosteroids. One partial remission was documented. At the dose and schedule used, docetaxel has only low activity against renal cell carcinoma.

Adult↗