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Biomedical subjects

L van den Broek

Publications and source records attributed to L van den Broek.

At least 19 recordsLinked to original sources
PubMed1999

The utility of mitotic index, oestrogen receptor and Ki-67 measurements in the creation of novel prognostic indices for node-negative breast cancer.

INTRODUCTION: Prognostic factors can be useful to identify node-negative patients at increased risk of relapse who should receive adjuvant treatment. In the past, oestrogen receptor status and mitotic index have been shown to be significant predictors of prognosis. Different techniques for the measurement of these prognostic factors are available. METHODS: Paraffin-embedded tumour specimens from 441 pre-menopausal patients with node-negative breast cancer who were previously randomized onto a trial comparing peri-operative chemotherapy with no further therapy were studied. Oestrogen receptor status was determined by the classical biochemical assay and by immunohistochemistry (ER-IA). Mitotic index was assessed by counting the number of mitoses and by calculating the percentage of tumour cells positively staining for the antibody Ki-67. RESULTS: There was a good correlation between ER-IA and the biochemical ER-assay (P<0.01), and the percentage of Ki-67 positive tumour cells and mitotic counts (P<0.01) respectively. However, ER-IA significantly predicted disease-free survival (RR=2.67, 95% CI: 1.60-4.44, P<0.01) whereas the biochemical assay was only borderline significant (RR=1.54, 95% CI: 1.00-2.36, P=0.05). Similarly, Ki-67 was a stronger indicator of prognosis (RR=2.84, 95% CI: 1.80-4.48, P<0.01) than mitotic counts (RR=1.56, 95% CI: 1.22-2. 00, P<0.01). CONCLUSIONS: We conclude that ER-IA performs better in predicting prognosis than the classical biochemical oestrogen receptor assay. Ki-67 is a more accurate marker for tumour cell proliferation and predicts prognosis of patients with breast cancer better than do mitotic counts.

Adult↗
PubMed1998

p53 protein accumulation and response to adjuvant chemotherapy in premenopausal women with node-negative early breast cancer.

PURPOSE: Thirty percent of women with node-negative breast cancer will have a recurrence within 10 years after diagnosis. Molecular markers may identify those patients and predict whether they benefit from adjuvant therapy. The European Organization for Research and Treatment of Cancer (EORTC) conducted a randomized trial (EORTC 10854) to compare perioperative treatment with one course of fluorouracil, doxorubicin, and cyclophosphamide (FAC) versus no further therapy. We studied tumors from premenopausal patients with node-negative breast cancer randomized in this trial to determine whether p53 accumulation, c-erbB-2 expression, percentage of Ki-67-positive cells, estrogen receptor (ER-immunoassay [IA]), progesterone receptor (PR-IA), and angiogenesis could be used as prognostic factors and predictors of responsiveness to adjuvant chemotherapy. PATIENTS AND METHODS: Paraffin-embedded tumor specimens from 441 premenopausal women with node-negative breast cancer were collected from the larger EORTC trial. Paraffin sections from the tumors were analyzed for immunohistochemical expression of p53, c-erbB-2, Ki-67, ER, PR, and angiogenesis. RESULTS: Patients with p53-negative tumors showed a significant benefit from perioperative chemotherapy (P < .01), whereas patients who had p53-positive tumors did not (P = .80). At a median follow-up time of 49 months, univariate analyses for disease-free survival (DFS) failed to show prognostic value for p53, c-erbB-2 and angiogenesis. Both univariate and multivariate results showed Ki-67 positivity, ER-IA negativity, and a younger age to be associated with a worse prognosis. CONCLUSION: p53 accumulation was associated with a poor response to one perioperative course of FAC chemotherapy. Ki-67, ER-IA, and age are important prognostic factors in premenopausal women with node-negative breast cancer.

Adult↗
PubMed1997

Tumor eradication by wild-type p53-specific cytotoxic T lymphocytes.

The tumor suppressor protein p53 is overexpressed in close to 50% of all human malignancies. The p53 protein is therefore an attractive target for immunotherapy. Cytotoxic T lymphocytes (CTLs) recognizing a murine wild-type p53 peptide, presented by the major histocompatibility complex class I molecule H-2Kb, were generated by immunizing p53 gene deficient (p53 -/-) C57BL/6 mice with syngeneic p53-overexpressing tumor cells. Adoptive transfer of these CTLs into tumor-bearing p53 +/+ nude mice caused complete and permanent tumor eradication. Importantly, this occurred in the absence of any demonstrable damage to normal tissue. When transferred into p53 +/+ immunocompetent C57BL/6 mice, the CTLs persisted for weeks in the absence of immunopathology and were capable of preventing tumor outgrowth. Wild-type p53-specific CTLs can apparently discriminate between p53-overexpressing tumor cells and normal tissue, indicating that widely expressed autologous molecules such as p53 can serve as a target for CTL-mediated immunotherapy of tumors.

Adoptive Transfer↗
PubMed1997

Comparison of vecuronium with ORG 9487 and their interaction.

PURPOSE: To compare the pharmacodynamic behaviour of vecuronium with that of ORG 9487, we measured the time-course of action of equipotent doses of ORG 9487 and vecuronium and investigated their mutual interaction when given in succession. METHODS: Sixty ASA I-II patients were anaesthetized with thiopentone, fentanyl, halothane and nitrous oxide and assigned randomly to four groups. Each patient received an initial dose (ID) of either vecuronium (V) or ORG 9487 (O) followed by maintenance doses (MDn) of either V or O (ID/MD: O/O, V/O, O/V, and V/V). The time course of action was measured mechanomyographically, determining the duration until 25% recovery of the single twitch (DUR25). RESULTS: The onset time of an ID of ORG 9487 was shorter than that of an ID of vecuronium (96 vs 203 sec, P < 0.001). The DUR25 of the ID of ORG 9487 was less than half that of vecuronium (10.7 +/- 2.8 vs 28.8 +/- 6.1 min, P < 0.001). The DUR25 of MD1 and MD2 of ORG 9487 were shorter than those of vecuronium (O/O: 7.3 +/- 2.8 and 8.5 +/- 2.4 min; V/O: 12.7 +/- 3.3 and 11.5 +/- 3.5 min, vs O/V: 16.4 +/- 4.5 and 20.6 +/- 4.7 min; V/V: 18.8 +/- 3.0 and 20.1 +/- 3.8 min, respectively, P < 0.05). AN ID of vecuronium prolonged the DUR25 of MD1 and MD2 of ORG 9487 (P < 0.05). CONCLUSION: ORG 9487 is a muscle relaxant with a shorter duration of action than vecuronium. Maintenance doses of ORG 9487 are also shorter acting than roughly equipotent maintenance doses of vecuronium, irrespective of which relaxant is given initially.

Adolescent↗
PubMed1997

Cardiovascular effects of an intubating dose of rocuronium 0.6 mg kg-1 in anaesthetized patients, paralysed with vecuronium.

We have studied, in adult patients, ASA I-II, the cardiovascular effects of an intubating dose of rocuronium 0.6 mg kg-1. After induction, patients were paralysed with vecuronium and the trachea intubated. Heart rate (HR) and non-invasive mean arterial pressure (MAP) were measured every 1 min. After stabilization of HR and MAP, defined as < 3% change over three measurements, rocuronium (n = 20) or saline (n = 10) was injected at random. Mean HR increased initially from 66.6 to 72.1 beat min-1, 4 min after rocuronium, and then decreased gradually to 69.6 beat min-1, that is a net increase of 3.3 beat min-1 over 10 min (P < 0.001), whereas after saline there was a gradual decrease from 65.8 to 60.9 beat min-1 (P < 0.001) over 10 min. From the third minute, HR was significantly higher in the rocuronium group. Mean MAP decreased in both groups within 10 min to a similar extent after rocuronium and saline, that is from 74.9 to 72.1 mm Hg and from 74.7 to 72.2 mm Hg, respectively (both P < 0.001). There were no differences in MAP at any time between the rocuronium and saline groups. We conclude that an intubating dose of rocuronium, in the absence of haemodynamic effects related to paralysis itself, resulted in a limited increase in HR without change in MAP, probably because of its weak vagolytic activity.

Adolescent↗
PubMed1995

Effects of hypothermic cardiopulmonary bypass on the pharmacodynamics and pharmacokinetics of rocuronium.

OBJECTIVE: To study the influence of hypothermic cardiopulmonary bypass (CPB) on the pharmacodynamics and pharmacokinetics of rocuronium. DESIGN: Prospective, descriptive study. SETTING: Operating room at a university hospital. PARTICIPANTS: Ten ASA class III and IV patients, ranging in age from 35 to 75 years, scheduled for elective coronary artery bypass grafting. INTERVENTIONS: Neuromuscular transmission was monitored mechanomyographically. The time course of action of maintenance doses and plasma concentration-response relationships were determined before, during, and after CPB. The plasma concentration decay and renal elimination were studied simultaneously. Plasma and urine concentration of rocuronium were determined by high-performance liquid chromatography. MEASUREMENTS AND MAIN RESULTS: Hypothermic CPB prolonged the duration of action of maintenance doses and coincided with a lower plasma concentration at a twitch response of 5% of control. The duration of action of maintenance doses returned to prehypothermic CPB level after rewarming to a nasopharyngeal temperature of 37 degrees C. The plasma concentration-response relationship did not return to precooling control value, probably owing to persisting peripheral hypothermia. Both the renal elimination of rocuronium and the plasma concentration decay after the last maintenance dose under normothermic conditions resembled values obtained in patients not undergoing hypothermic CPB. CONCLUSIONS: Hypothermic CPB prolongs the duration of action of maintenance doses and alters the plasma concentration-response relationship of rocuronium. These changes may be the result of, on the one hand, an increased sensitivity of the neuromuscular transmission and/or decreased muscle contractility and, on the other hand, the result of a reduced plasma clearance during hypothermia.

Adult↗
PubMed1995

Time course of action and intubating conditions following vecuronium, rocuronium and mivacurium.

The purpose of this study was to compare the time course of action and tracheal intubating conditions of vecuronium, rocuronium and mivacurium in anaesthetised patients. Anaesthesia consisted of thiopentone, fentanyl, N2O/O2 and isoflurane. After a 2 x ED90 dose the first attempt at tracheal intubation was made at 90 s. If required, maintenance doses of 0.5 x ED90 were administered. The intubating conditions after rocuronium were significantly better than those after vecuronium and mivacurium. The average onset times of rocuronium (172 s) and vecuronium (192 s) were significantly shorter than that of mivacurium (229 s). The clinical duration and recovery time were significantly shorter after mivacurium (13 and 6 min, respectively) than with vecuronium (33 and 14 min, respectively) and rocuronium (28 and 11 min, respectively). We conclude that rocuronium might be of advantage whenever the interval between the administration of the muscle relaxant and tracheal intubation must be short, whereas mivacurium may be of benefit if fast spontaneous recovery is required.

Adolescent↗
PubMed1995

Rocuronium- and mivacurium-induced neuromuscular block and intubating conditions: a comparison with vecuronium.

The time-course of action after an initial 2 x ED90 dose and after maintenance doses of 0.5 x ED90, and intubating conditions at 90 s after a 2 x ED90 dose following rocuronium, vecuronium and mivacurium were evaluated in anaesthetized adult patients. Neuromuscular measurements were performed with mechanomyography. Rocuronium produced a significantly deeper neuromuscular block at 90 s (mean and (standard deviation)) (91 (11%), compared to vecuronium (61 (22%)%) and mivacurium (58 (23)%). The onset time following rocuronium (172 (71)s) was significantly shorter than that following mivacurium (229 (60)s). At 90 s, intubating conditions were significantly better in the rocuronium group than in the vecuronium or mivacurium group. Mivacurium offered a significantly faster recovery of neuromuscular block following the 2 x ED90 dose and following an average of 45 min of clinical muscle relaxation (single twitch response < or = 25%) compared to rocuronium and vecuronium: clinical duration 13 (4), 28 (9) and 33 (9) min, respectively, and recovery time from 25 to 75% recovery of the single twitch response: 6 (2), 11 (4) and 14 (7) min, respectively.

Adolescent↗
PubMed1995

Hypothermic cardiopulmonary bypass influences the concentration-response relationship and the biodisposition of rocuronium.

In 10 patients scheduled for elective coronary artery bypass grafting under midazolam-sufentanil anaesthesia, the influence of hypothermia on the plasma concentration-response and biodisposition of rocuronium were investigated. Neuromuscular function was monitored mechanomyographically. Plasma and urine concentrations of rocuronium were determined by high performance liquid chromatography. Hypothermic cardiopulmonary bypass prolonged the duration of action of maintenance doses and altered the plasma concentration-response relationship. The elimination and distribution half-lives, following the last maintenance dose after rewarming, and the urinary excretion of rocuronium were similar to values obtained during normothermia. A diminished hepatic uptake and storage in the liver of rocuronium during hypothermia may explain the more pronounced prolongation of the duration compared to that of other steroidal neuromuscular blocking agents.

Adjuvants, Anesthesia↗
PubMed1995

Introducing smartcards in healthcare in the Netherlands.

New technologies may contribute to innovation and improvement of the quality of healthcare. A necessary condition to achieve this objective is a good relationships between all parties involved: healthcare providers, healthcare institutions, and healthcare insurance companies. The Delft project proves that a smartcard facilitates the linking up of activities of the various participants. As a result, the quality of care improves while, at the same time, administrative procedures and the financial settlement of transactions are simplified.

Medical Records Systems, Computerized↗
PubMed1994

Clinical pharmacology of ORG 7617, a short-acting non-depolarizing neuromuscular blocking agent.

The dose-response relationship and the time course of action of Org 7617, a short acting non-depolarizing neuromuscular blocking agent, were evaluated during thiopentone, fentanyl, halothane and N2O anaesthesia. Neuromuscular transmission was monitored mechanomyographically. The ED50 and ED90 were calculated after single bolus doses of the drug. Twelve, seven and three patients received 2.5, 3.75 or 5.0 mg.kg-1 Org 7617, respectively. Neuromuscular block was characterized by a short lag time (average 30 s) and rapid development of neuromuscular block (69-84 s). Maximum block approximated to 66%, 91% and 95%, and the duration until clinically adequate recovery (TOF ratio of 0.7) to 7.4, 12.1 and 12.2 min after 2.5, 3.75, 5 mg.kg-1 of Org 7617, respectively. The calculated ED50 and ED90 were 1.8 and 3.4 mg.kg-1. Adverse effects, including a moderate fall in systolic and diastolic arterial blood pressure and a concomitant increase in heart rate appeared to be dose-dependent. Some patients showed flushing. One patient given 5 mg/kg Org 7617 had serious adverse effects suggestive of histamine release, i.e. flushing, urticaria, tachycardia, hypotension and bronchospasm. Therefore further clinical investigations were terminated. Although its low potency and the adverse effects observed will prevent further clinical development of ORG 7617, the results do support the contention that it is feasible to develop short-acting non-depolarizing neuromuscular blocking agents from the steroidal series.

Adolescent↗
PubMed1994

Pharmacodynamics and pharmacokinetics of an infusion of Org 9487, a new short-acting steroidal neuromuscular blocking agent.

We have evaluated in 10 anaesthetized patients the time course of action, infusion requirements, reversibility and pharmacokinetics of Org 9487. Org 9487 was administered as a bolus dose of 1.5 mg kg-1, followed by an infusion to maintain a block of 75-85% for 60 min. After recovery from the bolus dose, a mean dose of Org 9487 3.4 (SD 1.0) mg kg-1 h-1 was administered to maintain a mean neuromuscular block of 83 (3)%. During the final 15 min of infusion, the infusion requirements were 2.5 (1.1) mg kg-1 h-1. In the five patients who were allowed to recover spontaneously, a TOF ratio of 0.7 was reached 37.9 (12.4) min after stopping the infusion of Org 9487. In the five patients who received neostigmine, a TOF ratio of 0.7 was reached after 14.5 (6.1) min. Plasma clearance was 8.5 (30%) ml kg-1 min-1. Volume of distribution at steady state was 293 (55%) ml kg-1. Terminal half-life and mean residence time were 71.7 (34%) and 33.4 (31%) min, respectively. The concentration of the 3-OH metabolite remained relatively low. Urinary excretion of Org 9487 and its metabolites was 22% in 24 h. In conclusion, a 1-h infusion of the short-acting drug Org 9487 changed its time course characteristics gradually from that of a short-acting neuromuscular blocking agent to that of a neuromuscular blocker with an intermediate duration of action.

Adolescent↗
PubMed1994

Introduction of oxygen into the alkyl chain of N-decyl-dNM decreases lipophilicity and results in increased retention of glucose residues on N-linked oligosaccharides.

N-Alkylation of the alpha-glucosidase inhibitor 1-deoxynojirimycin (dNM) dramatically increases its inhibitory potency (Tan et al., J. Biol. Chem., 266, 14504-14510, 1991). However, the possibility of extending the alkyl chain to N-decyl-dNM is limited by an increase of detergent-like (amphiphilic) properties of long-chain alkylated dNM derivatives. Substitution of methylene groups in the N-decyl chain by oxygen reduced the amphiphilicity of N-decyl-dNM derivatives, while retaining their superior inhibitory properties. In intact HepG2 cells, the compound N-7-oxadecyl-dNM was found to result in the most pronounced retention of glucose residues on N-linked glycans. Permeabilization of the plasma membrane with the bacterial toxin Streptolysin O improves the inhibitory properties of the derivatives N-3,6,9-trioxadecyl-, N-7,10,13-trioxatetradecyl-, N-3-oxadecyl- and N-7-oxadecyl-dNM, but not those of dNM. These observations suggest differences in the mode of entry of the oxygen-substituted dNM derivatives in comparison with dNM. We observed that the dNM derivative N-3,6,9-trioxadecyl-dNM, devoid of inhibitory activity in intact cells, was inhibitory in Streptolysin O-permeabilized cells. Thus, the permeability barriers posed by plasma membrane and endoplasmic reticulum membrane are not equivalent. The use of a permeabilized cell system thus allows the elaboration of inhibitory principles for novel bioactive compounds where study of the isolated enzymes may not be possible, and where intact cells are not a suitable target due to permeability barriers.

1-Deoxynojirimycin↗
PubMed1994

Early and late reversibility of rocuronium bromide.

A computer simulation has been developed based on pharmacodynamic-pharmacokinetic modelling of the effect of neostigmine on rocuronium-induced neuromuscular blockade. The results of a previous study involving 60 patients were used as a test of the model. The model predicts that administration of neostigmine 40 micrograms kg-1 within 20 min of the administration of rocuronium does not decrease the duration of the block until 90% recovery has taken place. The optimum dose of neostigmine depends on the degree of block at the time of administration: for a more intense block the optimum dose is 80 micrograms kg-1 and for a less intense block is about 30 micrograms kg-1. The pharmacokinetic behaviour rather than the potency of the relaxant determines its reversibility.

Androstanols↗
PubMed1993

Time course of action and endotracheal intubating conditions of Org 9487, a new short-acting steroidal muscle relaxant; a comparison with succinylcholine.

In a randomized study, we evaluated lag time (time from the end of injection of muscle relaxant until the first depression of the train-of-four response [TOF]), onset time (time from the end of injection of muscle relaxant until the maximum depression of the first twitch of the TOF [T1]), neuromuscular block, and endotracheal intubating conditions at 1 min after 1 mg/kg succinylcholine (n = 15) and 1.5 mg/kg Org 9487 (n = 30). Two minutes after administration of Org 9487, 15 of the 30 patients received neostigmine for reversal. Recovery of neuromuscular block after succinylcholine, Org 9487 without and Org 9487 with neostigmine were compared using the time until T1 was 90% for the succinylcholine group, and the time until TOF was 70% for the Org 9487 groups. Neuromuscular transmission was monitored mechanomyographically. Onset time was similar (67 [20] and 83 [38] s for succinylcholine and Org 9487, respectively) and endotracheal intubating conditions were also similar after both muscle relaxants. Times until clinically sufficient recovery of neuromuscular block induced by succinylcholine (time until T1 = 90%: 10.6 [3.3] min) and Org 9487 with neostigmine (time until TOF = 70%: 11.6 [1.4] min) were not different. In contrast, in the Org 9487 without neostigmine group, more time was required until complete recovery (24.1 [6.2] min) (P < 0.05). In conclusion, ORg 9487 is a muscle relaxant suitable for endotracheal intubation and short-lasting interventions.

Adult↗