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Biomedical subjects

R J van Klaveren

Publications and source records attributed to R J van Klaveren.

At least 19 recordsLinked to original sources
PubMed2007

Neglectable benefit of searching for incidental findings in the Dutch-Belgian lung cancer screening trial (NELSON) using low-dose multidetector CT.

The purpose of this study was to prospectively determine the frequency and spectrum of incidental findings (IFs) and their clinical implications in a high risk population for lung cancer undergoing low-dose multidetector computed tomography (MDCT) screening for lung cancer. Scans of 1,929 participants were evaluated for lung lesions and IFs by two radiologists. IFs were categorised as not clinically relevant or possibly clinically relevant. Findings were considered possibly clinically relevant if they could require further evaluation or could have substantial clinical implications. All possibly clinically relevant IFs were reviewed by a third radiologist, who determined its clinical relevance. Of all 1,929 participants, 1,410 (73%) had not clinically relevant IFs and 163 (8%) had possibly clinically relevant IFs of which 129 (79%) were indeed considered clinically relevant. Additional imaging was performed mainly by ultrasound (112 of 118, 96%). All but one lesion were concluded to be benign, mostly cysts (n = 115, 80%). Only 21 (1%) participants had findings with clinical implications. In one participant a malignancy was found, yet without any clinical benefit since no curative treatment was possible. Based on our results, we advise against systematically searching for and reporting of IFs in lung cancer screening studies using low-dose MDCT.

Aged↗
PubMed2006

Lessons to learn from EORTC study 08981: a feasibility study of induction chemoradiotherapy followed by surgical resection for stage IIIB non-small cell lung cancer.

The present EORTC phase II feasibility study in stage IIIB (T4-N3) NSCLC was conducted to investigate whether an induction regimen with concurrent chemoradiotherapy followed by surgery after restaging by re-mediastinoscopy and/or fluorodeoxyglucose-positron emission tomography (FDG-PET) was feasible in a multicenter setting. Unfortunately, the study closed prematurely because of poor accrual. The combination of more stringent selection criteria, the incorrect prevailing view of Ethical Boards that a tri-modality approach is too toxic, competing studies in the participating centers and the fact that patients with N3 disease could only be enrolled if a re-mediastinoscopy could be performed, underlie the low accrual. Although this study illustrates that the conduct of a tri-modality study across Europe appeared to be difficult at that time, the number of centers with highly qualified and experienced specialists involved in this kind of multi-modality approaches is rapidly increasing. Future initiatives should, therefore, certainly be encouraged. Minimally invasive procedures such as EUS and EBUS should preferably be used for up-front mediastinal staging, mediastinoscopy with or without EUS should preferably be reserved for restaging, and especially right-sided pneumonectomies should be avoided. Though evident, the feasibility to complete this kind of studies within a reasonable time period is still a condition sine qua non.

Carcinoma, Non-Small-Cell Lung↗
PubMed2005

Prognostic factors in non-small cell lung cancer surgery.

AIMS: Complete surgical resection of primary tumours remains the treatment with the greatest likelihood for survival in early-stage non-small cell lung cancer (NSCLC). Although TNM stage is the most important prognostic parameter in NSCLC, additional parameters are required to explain the large variability in postoperative outcome. The present review aims at providing an overview of the currently known prognostic markers for postoperative outcome. METHODS: We performed an electronic literature search on the MEDLINE database to identify relevant studies describing the risk factors in NSCLC surgery. The references reported in all the identified studies were used for completion of the literature search. RESULTS: Poor pulmonary function, cardiovascular disease, male gender, advanced age, TNM stage, non-squamous cell histology, pneumonectomy, low hospital volume and little experience of the surgeon were identified as risk factors for postoperative outcome. However, with the exception of TNM stage and extent of resection, the literature demonstrates conflicting results on the prognostic power of most factors. The role of molecular biological factors, neoadjuvant treatment and adjuvant treatment is not well investigated yet. CONCLUSIONS: The advantage of knowing about the existence of comorbidity and prognostic risk factors may provide the clinician with the ability to identify poor prognostic patients and establish the most appropriate treatment strategy. The assessment of prognostic factors remains an area of active investigation and a promising field of research in optimising therapy of NSCLC patients.

Carcinoma, Non-Small-Cell Lung↗
PubMed2002

Multicentre phase II study of gemcitabine and cisplatin in malignant pleural mesothelioma.

UNLABELLED: Malignant pleural mesothelioma is a notoriously chemoresistant tumour. However, a recent single institution study showed an impressive activity of gemcitabine and cisplatin. Our aim is to investigate the efficacy and toxicity of a gemcitabine and cisplatin combination in selected and chemo-naive patients with histologically proven malignant pleural mesothelioma. METHOD: Gemcitabine 1250 mg m(-2) was administered on day 1 and day 8 and cisplatin 80 mg m(-2) was administered on day 1 in a 3-week cycle with a maximum of six cycles. Response and toxicity evaluations were performed according to WHO and NCIC-CTC criteria. Pathology and radiology were centrally reviewed. Results show that in 25 evaluable patients, four PR were observed (ORR 16%, 95% CI 1-31%). Responses of seven patients were unevaluable. No unexpected toxicity occurred. Time to progression was 6 months (5-7 months) with a median survival from registration of 9.6 months (95% CI 8-12 months). In conclusion this trial excludes with 90% power a response rate of greater than 30% in patients with malignant pleural mesothelioma using a combination of gemcitabine and cisplatin at the proposed dose and schedule.

Aged↗
PubMed2002

A phase II EORTC study of temozolomide in patients with malignant pleural mesothelioma.

The aim of this study was to investigate the anti-tumour activity of temozolomide in patients with malignant pleural mesothelioma. 27 chemotherapy-naïve patients with histologically-proven malignant mesothelioma were treated with temozolomide 200 mg/m2/day, given orally on days 1-5 of each 28-day cycle. Therapy continued up to 10 cycles unless disease progression or excessive toxicity mandated discontinuation. Toxicity, symptom improvement and pain intensity were regularly assessed. With a median relative dose intensity of 97%, toxicity was moderate with grade 3 or more nausea, vomiting, thrombocytopenia, leucocytopenia, neutropenia, febrile leucocytopenia, arthralgia, infection and fever with infection occurring in 13, 13, 10, 3, 7 and 3% of patients for the remaining events, respectively. Overall, 1 objective response was observed (response rate 4%, 95% Confidence Interval (CI): 0.1-19). Median survival was 8.2 months. Symptom assessment showed no improvement and an increase of pain was observed during the study. Thus, oral temozolomide is an inactive agent in malignant mesothelioma.

Adult↗
PubMed2001

[Screening for lung cancer in the Netherlands: the role of spiral CT scan].

The very poor prognosis of lung cancer has barely changed in the last two decades despite all efforts. However, prognosis is better when the disease is detected earlier, so that curative surgery or radiotherapy can be applied. Lung cancer screening in the past by chest X-ray did not lead to a decrease in lung cancer mortality, because the chest X-ray has low sensitivity for early invasive stages. With the advent of the low-dose spiral CT scan it has become feasible to detect early invasive stage I lung cancer in 80-90%. Modern screening for lung cancer by spiral CT scan could possibly decrease lung cancer mortality. Despite the first favourable results of screening the question remains whether lung cancer screening will be cost-effective. These questions can only be resolved in a randomised controlled trial with lung cancer mortality as unbiased end-point. Such a study should be initiated in the Netherlands, a country with large experience in screening trials and a good health care system. Only after lung cancer screening has proven to be cost-effective can appropriate implementation be recommended to prevent uncontrolled and opportunistic diffusion of this new screening technique into clinical practice in the near future.

Clinical Trials as Topic↗
PubMed2001

Lung cancer screening by low-dose spiral computed tomography.

The poor prognosis of lung cancer has barely changed in the last decades, but the prognosis is better when the disease is detected earlier. Lung cancer screening by chest radiography did not lead to a decrease in lung cancer mortality, presumably because the chest radiograph is a poor screening tool with low sensitivity. With the advent of the low-dose spiral computed tomography (CT) scan it has become feasible to detect early invasive stage I lung cancer in 8-90% of cases. This technique could possibly decrease lung cancer mortality, but the extent of this effect is as yet unknown, and whether lung cancer screening will be cost-effective is yet to be determined. These questions can only be resolved in a randomized controlled trial with lung cancer mortality as an unbiased end-point. In this review, the initiatives to evaluate low dose spiral CT screening for lung cancer in Japan, USA and Europe are presented. In the USA and Japan, evaluation is in one-armed studies, whereas in many European countries randomized trials are now being planned and several one-armed studies have been initiated. A formal collaboration among these countries has now been set up. It is strongly recommended that lung cancer screening be evaluated in randomized trials in order to allow evidence-based health policy decisions to be made on this subject.

Adenocarcinoma↗
PubMed1999

Investigation of the transport of intact glutathione in human and rat type II pneumocytes.

The aim of the study was to investigate whether there is transmembrane transport of intact glutathione ([3H]-GSH, 0.1 microCi) in rat and human type II pneumocytes (T2P), and if this transport might be dependent on the redox state of the extracellular fluid. The T2P were pretreated with acivicin (250 microM) to inhibit gamma-glutamyltransferase activity and with L-buthionine-[SR]-sulfoximine (1 mM) to inhibit intracellular GSH synthesis. After 48 h in culture, initial GSH influx rate was 0.70 +/- 0.20 nmol/min/mg protein (37 degrees C) and 0.35 +/- 0.04 nmol/min/mg protein (4 degrees C) during the first 5 min in rat T2P. In human T2P, the initial GSH influx rate was 0.36 +/- 0.30 nmol/min/mg protein (37 degrees C) and 0.32 +/- 0.06 nmol/min/mg protein (4 degrees C) during the first 10 min. Thereafter no further influx was found. The influx of 1 mM GSH in freshly isolated rat and human T2P in suspension was 2.3 +/- 0.3 and 1.2 +/- 0.3 nmol/mg protein after 15 min at 37 degrees C, and 2.8 +/- 0.2 and 1.0 +/- 0.3 nmol/mg protein at 4 degrees C, respectively. When GSH influx was studied at different concentrations between 0 and 40 mM, a linear increase without saturation or difference between 37 degrees C and 4 degrees C was found. Pre-exposure to ouabain had no effect on GSH influx. Efflux of GSH was stimulated and influx inhibited by pre-exposure of the cells to reduced thiols, while disulphides inhibited efflux and favoured inward uptake. Thus, in human and rat T2P a GSH-carrier exists which operates as an effluxer. At GSH concentrations in the physiological range no uptake is seen, but some uptake can be observed at GSH concentrations above normal physiological levels. The uptake appears to be energy-independent and non-saturable. Efflux of GSH is stimulated and influx inhibited by reduced thiols, while disulphides inhibit the efflux and favour inward uptake. GSH uptake in T2P thus may depend on concentration gradients and driving forces, such as the redox state of the extracellular fluid.

Animals↗
PubMed1999

Role of reactive oxygen species in occupational and environmental obstructive pulmonary diseases.

Free radicals and their metabolites, also called reactive oxygen species (ROS), have been implicated in the pathogenesis of many diseases. Because of its continuous exposure to toxic pollutants in the ambient air, such as cigarette smoke, air pollution, and mineral dusts, the lung is very vulnerable to ROS-induced injury. In this review, the role of ROS in the pathogenesis of obstructive lung diseases is reviewed. A central theme in this review is the pivotal role of transition metals such as iron, vanadium, and nickel in ROS-induced cell damage, not only in exposure to mineral dusts but also in cigarette smoke and air pollution.

Air Pollutants↗
PubMed1998

Protective effects of the lazaroid U-74389G against hyperoxia in rat type II pneumocytes.

The aims of this study were to investigate the effect of hyperoxia on O2(-.), H2O2 and .NO generation and iNOS mRNA levels in rat type II pneumocytes in vitro and the possible protective effect of the lazaroid U-74389G. Rat type II pneumocytes were exposed, 36 h after isolation, to air, 60% or 85% O2 for 48 h. At the beginning of the experiment and 24 h later, the cells were exposed for 30 min to either 30 microM U-74389G or only the vehicle for the lazaroid (control). Exposure to 60% and 85% O2 decreased nitrite production 2.9-fold and 3.9-fold, and increased O2(-.) and H2O2 generation 4.6-fold and 6.7-fold, respectively. In the 85% O2-exposed cells, hyperoxia increased lipid peroxidation (thiobarbituric acid reactive substances, TBARS production) 2-fold and iNOS mRNA production 5.4-fold. U-74389G prevented the decrease in nitrite and the rise in O2(-.) and H2O2 production, the increase in TBARS and the rise in iNOS mRNA after hyperoxia. We conclude that exposure of type II pneumocytes in vitro to subtoxic oxygen levels leads to a disturbance in the .NO-O2(-.) balance despite increased iNOS mRNA levels. The lazaroid U-74389G appears to be a useful compound in the protection of hyperoxic lung injury by restoration of this .NO-O2(-.) balance and prevention of TBARS formation.

Animals↗
PubMed1998

Determinants of the hypercapnic and hypoxic response in normal man.

The purpose of this study was: (1) to identify the determinants of the hypercapnic (HCR) and hypoxic response (HR) in normal man; (2) to find out if they are dependent on the HR model used; and (3) to investigate if the occlusion pressure (P0.1), in contrast to the VE HCR and HR, is independent of gender, anthropometrical and lung functional indices. A total of 26 men (42.4+/-12.4 years) and 25 women (40.1+/-13.7 years) were studied. We found that men and women have similar P0.1 respiratory drives, but VE differs and is higher in men because of their larger vital capacity. For comparisons of the HCR or HR either the P0.1, or the VE HCR and HR normalized for VC or FEV1 should be used. With advanced age the VE HCR decreases in women. Especially for the HR, the identification of determinants (including age) is dependent on the HR model used.

Adult↗
PubMed1998

A mathematical and physiological evaluation of the different hypoxic response models in normal man.

The purpose was: (1) to investigate which hypoxic response (HR) model(s) might be most suitable to measure the HR taking into account 'goodness of fit' to the individual data, clinical applicability and information obtained from each model; and (2) to investigate if the models are mutually exchangeable. The ventilatory (VE) and occlusion pressure (P0.1) HR were measured in 33 healthy volunteers (37+/-12 years). We found that the exponential, linear on oxygen saturation (LINSAT), hyperbolic with either a fixed (HYPV) or a variable position of the vertical asymptote (HYPH) models were comparable with respect to 'goodness of fit' to the individual data, but the correlation between the HR models was poor, except for the correlation between LINSAT and HYPV. Comparing HR data is justified when they are either provided by the same HR model, or by LINSAT or HYPV. Within each model the VE HR can be replaced by the P0.1 HR. LINSAT has the advantage of an easy applicable linear relationship, HYPH provides additional information about the O2-CO2 interaction component of the HR, but the model is more complex because two variables have to be determined by computerized iteration.

Adult↗
PubMed1997

Increase in gamma-glutamyltransferase by glutathione depletion in rat type II pneumocytes.

The purpose of our study was to investigate the effect of oxidative stress or intracellular glutathione (GSH) depletion on gamma-glutamyltransferase (gamma-GT) activity in cultured type II pneumocytes. Twenty-four hours after isolation, primary cultures of rat type II pneumocytes were preincubated with one of four compounds: 15, 30, 60, 125, 250 microM L-buthionine-[SR]-sulfoximine (BSO) for 3 h; 100, 200, 400, 800 microM tertiary-butylhydroperoxide (t-BOOH) for 45 min; 10, 25, 50, 100 microM menadione for 15 min; 100, 1000 microM paraquat for 1 h. GSH levels, H2O2 and O2.- generation were measured immediately after the incubation, gamma-GT activity and GSH levels also up to 24 h or 48 h later. Exposure to BSO led to a persistent GSH depletion without increase in H2O2 or O2.- production, together with a dose and time-dependent increase (doubling) of gamma-GT activity with a nonsignificant increase in gamma-GT mRNA expression 24 h after exposure to BSO. Exposure to 100 microM menadione, which increased H2O2 production, decreased gamma-GT activity. t-BOOH or paraquat did not give rise to a measurable increase in H2O2 or O2.-. Paraquat did not affect initial GSH levels, but increased GSH and decreased gamma-GT activity 24 h later. t-BOOH (400 and 800 microM) initially decreased GSH, and tended to increase GSH 24 h later, 100 and 200 microM increased gamma-GT activity 24 h later, but 800 microM decreased it. Restoration of intracellular GSH levels by addition of GSH to the culture medium completely prevented the increase in gamma-GT activity by BSO, while the addition of catalase or DMTU had no effect. We conclude that at least two effects are operating upon gamma-GT activity: GSH depletion seems to increase gamma-GT activity, while exposure to compounds generating oxidative stress correlates with a decrease in gamma-GT activity.

Animals↗
PubMed1997

Putrescine uptake in rat type II pneumocytes correlates with gamma-glutamyltransferase activity.

gamma-Glutamyltransferase (gamma GT) is a key enzyme in glutathione metabolism and it is thought also to play a role in the uptake of polyamines such as putrescine. The aim of our study was to investigate if changes in gamma GT activity would alter total putrescine uptake [P(up)(tot)], as well as more specific uptake via the gamma GT pathway [P(up)(gamma GT)]. Forty-eight hours after their isolation, rat type II cells were exposed to 30, 60 or 125 microM L-buthionine-[SR]-sulfoximine (BSO) for 3 hr; 200 or 800 microM tertiary-butylhydroperoxide (t-BOOH) for 40 min; 10, 100 or 1000 microM paraquat (PQ) for 1 hr; and 60 or 85% O2 for 48 hr. The gamma GT activity, P(up)(tot) and P(up)(gamma GT) (assessed by inhibiting gamma GT) were measured immediately after the exposure to hyperoxia, or 24 hr after treatment with BSO, t-BOOH or PQ. From previous studies, it is known that these experimental conditions increased (BSO, 200 microM t-BOOH) or decreased (800 microM t-BOOH, PQ, hyperoxia) gamma GT activity. There was a strong correlation between the changes in gamma GT activity and the changes in P(up)(gamma GT) (r = 0.81, p < 0.001). These findings support the hypothesis that gamma GT partly regulates the uptake of putrescine, one of the polyamines required for cell growth and differentiation.

Animals↗
PubMed1997

Involvement of an NAD(P)H oxidase-like enzyme in superoxide anion and hydrogen peroxide generation by rat type II cells.

BACKGROUND: Although alveolar macrophages are considered to be the primary cellular mediators of host defence in the lung, there is increasing evidence that type II cells may also play an active role in host defence. A study was undertaken to investigate whether type II cells generate O2-. and H2O2 via an NADPH oxidase-like system and whether exposure of the type II cells to soluble or particulate stimuli known to activate NADPH oxidase in macrophages also leads to increased production of H2O2. METHODS: Rat type II cells and alveolar macrophages were exposed to 10, 100, or 1000 nM phorbol-12-myristate-13-acetate (PMA) and the production of O2-. and H2O2 was determined by chemiluminescence. Thirty minutes before stimulation with 1 microM PMA type II cells were also exposed to the same concentrations of a protein kinase C (PKC) antagonist GF109203x, the non-selective protein kinase inhibitor staurosporine (1, 10, or 100 nM), or the NADPH oxidase inhibitor diphenyliodonium chloride (DPI) (1, 10, 100, or 1000 microM). The effects of arachidonic acid, zymosan and Staphylococcus aureus on H2O2 production were determined. Cell membrane fractions from type II cells and macrophages were assayed for NADPH oxidase activity. RESULTS: After exposure to 1 microM PMA, O2-. and H2O2 generation increased 6.3-fold and 9.0-fold, respectively, in type II cells and 2.4-fold and 5.2-fold, respectively, in macrophages. In contrast to the macrophages, the increase in O2-. and H2O2 generation by type II cells was completely prevented by 1 mM KCN. Preexposure to GF109203x, staurosporine, or DPI completely prevented the rise in O2-. and H2O2 generation. Mean (SD) NADPH oxidase activity of 138 (38) nmol O2-./min/mg protein was found in membrane fraction I of the type II cells, and 102 (31) nmol O2-./min/mg protein in fraction II. Macrophages showed higher NADPH oxidase activity in membrane fraction II. In type II cells exposure to arachidonic acid led to a significant 5.3-fold increase in H2O2 generation, exposure to zymosan increased H2O2 generation 46-fold, and exposure to S aureus 25-fold with a maximum 30-50 minutes after addition of the bacteria. CONCLUSIONS: Type II cells generate O2-. and H2O2 via a PKC-mediated activation of an NAD(P)H oxidase-like membrane bound enzyme. Arachidonic acid, zymosan, and bacteria also give rise to increased H2O2 production. Type II cells might thus play an active role in host defence.

Animals↗
PubMed1997

N-acetylcysteine does not protect against type II cell injury after prolonged exposure to hyperoxia in rats.

Although the antioxidant properties of N-acetylcysteine (NAC) in vitro are widely accepted, the efficacy of NAC in the prevention of O2 toxicity in vivo is poorly documented. The aim of our study was to investigate the presumed protective effect of NAC on hyperoxic lung injury, focusing on gamma-glutamyltransferase (gamma-GT) activity and glutathione (GSH) levels in lung tissue, epithelial lining fluid (ELF), and isolated rat type II cells immediately after their isolation and 48 h later when kept in culture in normoxia. Thirty-four male Wistar rats were divided in three groups (n = 10-14) and were exposed to air or to 60 or 85% O2 for 7 days. One-half of the rats in each group received 200 mg/kg NAC intraperitoneally one time per day from 3 days before exposure until the end of the experiment, and the other one-half received the vehicle. In the 85% O2-exposed animals, NAC led to more respiratory distress and weight loss. NAC did not prevent the rise in bronchoalveolar lavage lactate dehydrogenase and alkaline phosphatase, but it did prevent the rise in calculated ELF volume. NAC decreased GSH levels (1.4-fold) and gamma-GT activity (1.8-fold) in the air-exposed type II cells. In the 60% O2-exposed group, no effects of NAC were seen (except for a decrease in gamma-GT mRNA expression), but, in the 85% O2-exposed group, NAC gave rise to higher GSH (2.6-fold) and higher gamma-GT activity (2.9-fold) in the ELF and lower GSH (6.9-fold) and higher gamma-GT activity (3.6-fold) in the type II cells. Even in culture, GSH levels remained 1.5-fold lower than in the cells from the air-exposed animals and 2-fold lower than in the cells from the 85% O2-exposed animals. There was increased DNA damage (as assessed by thymidine incorporation) and apoptosis after hyperoxia, especially after 60% O2, and this effect was amplified after NAC treatment. Although protective at the endothelial side, NAC treatment led to adverse effects at the epithelial side, despite, or probably because of, restoration of the ELF GSH levels in the presence of high O2 levels. Because NAC is rapidly metabolized to cysteine, it is plausible that the effects of NAC are manifested through the toxic effects of cysteine.

Acetylcysteine↗
PubMed1997

Cellular glutathione turnover in vitro, with emphasis on type II pneumocytes.

The most important extracellular antioxidant in the lung is glutathione (GSH). The epithelial lining fluid of normal lungs contains very high concentrations of this tripeptide, about 100 times higher than that found in the extracellular fluid of many other tissues. How these high extracellular GSH levels are established and the mechanisms for increases (e.g. smokers) or decreases (e.g. lung fibrosis) are still unknown, but more insight into the regulation of GSH turnover in type II pneumocytes has recently become available. The purpose of this review is to give an overview of the literature concerning cellular GSH turnover for different cell types in vitro, with an emphasis on alveolar type II epithelial cells. The main messages of this review are that: 1) GSH is, in fact, an important vehicle for stabilizing, detoxifying and transferring cysteine; 2) cysteine is the rate-limiting substrate for GSH synthesis, especially under conditions of oxidative stress; 3) various transport systems exist for the uptake of the constituents of GSH, of which gamma-glutamyltransferase appears to be important; 4) intracellular GSH levels of the type II cells are governed by different factors, including, probably, the extracellular redox state; and 5) a more reduced extracellular redox state appears to favour GSH efflux, whilst an oxidized state leads to retention of GSH inside the cell. These concepts should lead to reconsideration of some of the conventional approaches to increasing intracellular glutathione levels.

Animals↗