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Biomedical subjects

H J Groen

Publications and source records attributed to H J Groen.

At least 19 recordsLinked to original sources
PubMed2004

[The biopsying of at least 5 mediastinal lymph node stations for presurgical staging in patients with a non-small-cell lung carcinoma].

OBJECTIVE: To determine the additional value of mediastinoscopy/tomy in the pre-surgical staging of non-small-cell lung carcinoma. DESIGN: Retrospective. METHODS: Patients who underwent mediastinoscopy/tomy for staging of non-small-cell lung carcinoma from 1994 to 2000 at Groningen University Hospital, the Netherlands, were evaluated. Starting with data on history, physical examination, data imaging tests and bronchoscopy, the additional value of the mediastinoscopy was then evaluated using a logistic regression model. Not only was the additional value of a limited, routinely performed mediastinoscopy (whereby only lymph nodes at the site of the primary tumour are biopsied) examined, but also that of the comprehensive standard mediastinoscopy (conforming to the minimal requirements regarding number and localization of biopsied lymph nodes, i.e. lymph-node stations 2L, 2R, 4R, 4L, 7). The outcome against which all the test results were measured was the result of final pathological tumour staging. RESULTS: A total of 176 evaluable patients were included. History, physical examination and bronchoscopy played a small but significant role in predicting the percentage of patients in which resection was possible, 58% (95% CI: 50-67). Age was an important predictor. The subsequent addition of the limited and routinely performed mediastinoscopy to the model increased the correct prediction to 69% (95% CI: 61-77), while adding the standard mediastinoscopy to the model showed a significantly higher correct prediction of 81% (95% CI: 75-88). CONCLUSION: The standard mediastinoscopy involving a minimum of five different lymph node stations was of greater diagnostic value than limited mediastinoscopy.

Adult↗
PubMed2002

[Factors involved in the etiology of hypomineralized first permanent molars].

Severe hypomineralized first permanent molars (cheese molars) can be found in children. The aetiology of this phenomenon is unknown. The aim of this study is to collect more information about the causes of such molars. Parents of 24 children with severe cheese molars and of 21 controls without cheese molars, matched for age, living area and sex were interviewed. The mean age of the 45 children was 9.9 year (; ssd: 2.02). A questionnaire about the medical data from birth to four years of age and the medical situation of the mother during pregnancy was sent to the parents. No significant differences were found concerning weight and length at the time of birth between the two groups. Also no significant differences were found for the period of breast-/and bottle-feeding and for problems of the mother during pregnancy and child delivery. The mothers were healthy during pregnancy. Compared to the control group the children with cheese molars were ill more often Significant differences were found for pneumonia, high fever and inflammation of the middle ear.

Adult↗
PubMed2002

Factors involved in the aetiology of molar-incisor hypomineralisation (MIH).

AIM: This study aimed to collect more information on factors associated with molar-incisor hypomineralisation (MIH), which is a frequent developmental enamel defect with unknown aetiology. MATERIALS AND METHODS: A questionnaire was sent to the parents of 45 children (average age 9.9 years; SD+/-2.02), 24 with affected first molars and 21 controls. The two groups of children were similar in terms of age, gender and living conditions. Questions were asked about the health of mother and child during pregnancy, the birth and health of the child up to age four years. RESULTS: Birth weight and length in the two groups of children were similar, as was the duration of breast- and/or bottle-feeding and the incidence of complications during pregnancy and birth. The children with MIH were ill more frequently during the first four years of life. CONCLUSION: Knowledge of the type of disease that might be involved in the development of such molars is still inadequate, but there appears to be an association with pneumonia, otitis media and high fevers.

Journal Article↗
PubMed2001

Population pharmacokinetics of ifosfamide and its 2- and 3-dechloroethylated and 4-hydroxylated metabolites in resistant small-cell lung cancer patients.

The aim of this study was to develop a population pharmacokinetic model that could describe the pharmacokinetics of ifosfamide. 2- and 3-dechloroethylifosfamide and 4-hydroxyifosfamide, and calculate their plasma exposure and urinary excretion. A group of 14 patients with small-cell lung cancer received a 1-h intravenous infusion of 2.0 or 3.0 g/m2 ifosfamide over 1 or 2 days in combination with 175 mg/m2 paclitaxel and carboplatin at AUC 6. The concentration-time profiles of ifosfamide were described by an ifosfamide concentration-dependent development of autoinduction of ifosfamide clearance. Metabolite compartments were linked to the ifosfamide compartment enabling description of the concentration-time profiles of 2- and 3-dechloroethylifosfamide and 4-hydroxyifosfamide. The Bayesian estimates of the pharmacokinetic parameters were used to calculate the systemic exposure to ifosfamide and its metabolites for the four ifosfamide schedules. Fractionation of the dose over 2 days resulted increased metabolite formation, especially of 2-dechloroethylifosfamide, probably due to increased autoinduction. Renal recovery was only minor with 6.6% of the administered dose excreted unchanged and 9.8% as dechloroethylated metabolites. In conclusion, ifosfamide pharmacokinetics were described with an ifosfamide concentration-dependent development of autoinduction and allowed estimation of the population pharmacokinetics of the metabolites of ifosfamide. Fractionation of the dose resulted in increased exposure to 2-dechloroethylifosfamide, probably due to increased autoinduction.

Adult↗
PubMed2001

Dose-finding and pharmacological study of ifosfamide in combination with paclitaxel and carboplatin in resistant small-cell lung cancer.

BACKGROUND: To find the maximum tolerated dose for ifosfamide in combination with paclitaxel and carboplatin in small-cell lung cancer patients (SCLC), who are resistant to cyclophosphamide, doxorubicin and etoposide (CDE). PATIENTS AND METHODS: Different dose schedules of ifosfamide were combined with fixed doses of paclitaxel 175 mg/m2 and carboplatin AUC 6 mg/ml min. Included were 30 patients, with a median age of 60 years, and median time off prior cytotoxic treatment of 8 weeks. All patients were previously treated with CDE and 11 had received re-induction CDE. RESULTS: Dose limiting toxicity of our schedule was persistent thrombocytopenia. None of the patients developed neutropenic fever. Non-haematological toxicity was mild, although two treatment-related deaths occurred. Fifty-four percent of patients had a partial response and median survival time was twenty-five weeks. CONCLUSIONS: The maximum tolerated dose of this combination for patients with resistant SCLC is ifosfamide 2000 mg/m2 in combination with paclitaxel 175 mg/m2 and carboplatin AUC 6 mg/ml min administered on the first day of a 21-day cycle.

Adult↗
PubMed2001

Single-agent gemcitabine in patients with resistant small-cell lung cancer.

OBJECTIVE: This study was conducted to assess the activity and toxicity ofgemcitabine in patients with resistant small-cell lung cancer (SCLC). PATIENTS TAND METHODS: Forty-one patients with limited- or extensive-stage SCLC, who were previously treated with at least one chemotherapeutic regimen and progressed during or within three months of finishing the last regimen, were treated with 1000 mg/m2 gemcitabine on days 1, 8, and 15 of a four-week cycle. RESULTS: Thirty-eight patients were evaluable for response. Five partial and no complete responses were seen, for an overall response rate of 13% (95% confidence interval (CI): 6%-27%). Time to progression varied from 4 to 20 weeks, with a median of 8 weeks. Median survival was 17 weeks (range 4-84 weeks). Hematological toxicity mainly consisted of NCI-CTC grade 3 thrombocytopenia (29% of patients) and, to a lesser extent, grade 3 leukopenia (18% of patients). Non-hematological toxicity was mild, with nausea being the most commonly reported event. CONCLUSIONS: Gemcitabine has modest activity in patients with resistant SCLC. There is some non-cross resistance to most agents against SCLC.

Adult↗
PubMed2001

Clinical pharmacokinetics and pharmacodynamics of ifosfamide and its metabolites.

This review discusses several issues in the clinical pharmacology of the antitumour agent ifosfamide and its metabolites. Ifosfamide is effective in a large number of malignant diseases. Its use, however, can be accompanied by haematological toxicity, neurotoxicity and nephrotoxicity. Since its development in the middle of the 1960s, most of the extensive metabolism of ifosfamide has been elucidated. Identification of specific isoenzymes responsible for ifosfamide metabolism may lead to an improved efficacy/toxicity ratio by modulation of the metabolic pathways. Whether ifosfamide is specifically transported by erythrocytes and which activated ifosfamide metabolites play a key role in this transport is currently being debated. In most clinical pharmacokinetic studies, the phenomenon of autoinduction has been observed, but the mechanism is not completely understood. Assessment of the pharmacokinetics of ifosfamide and metabolites has long been impaired by the lack of reliable bioanalytical assays. The recent development of improved bioanalytical assays has changed this dramatically, allowing extensive pharmacokinetic assessment, identifying key issues such as population differences in pharmacokinetic parameters, differences in elimination dependent upon route and schedule of administration, implications of the chirality of the drug and interpatient pharmacokinetic variability. The mechanisms of action of cytotoxicity, neurotoxicity, urotoxicity and nephrotoxicity have been pivotal issues in the assessment of the pharmacodynamics of ifosfamide. Correlations between the new insights into ifosfamide metabolism, pharmacokinetics and pharmacodynamics will rationalise the further development of therapeutic drug monitoring and dose individualisation of ifosfamide treatment.

Animals↗
PubMed2001

L-3-[123I]iodo-alpha-methyl-tyrosine SPECT in non-small cell lung cancer: preliminary observations.

UNLABELLED: L-3-[123I]iodo-alpha-methyl-tyrosine (IMT) is a modified amino acid that is avidly taken up by many tumors. Uptake is based on the increased transmembrane transport of amino acids in malignancies. IMT is the only amino acid tracer suitable for SPECT. The aim of this study was to determine the feasibility of IMT SPECT in the detection, staging, and treatment evaluation of non-small cell lung cancer. METHODS: We evaluated 44 IMT SPECT studies in 17 patients with histologically proven non-small cell lung cancer, stage III. IMT SPECT and planar imaging of the chest was performed before, 2 wk after, and 3 mo after 60 Gy radiotherapy. Staging was based on the findings of bronchoscopy, chest CT, mediastinoscopy, or explorative thoracotomy. After radiotherapy, CT and bronchoscopy were repeated to assess tumor response. RESULTS: In 15 of 16 evaluable primary tumors, avid IMT uptake was present (sensitivity, 94%), with a mean (+/-SD) tumor-to-background ratio (T/B) of 2.95 +/- 0.78 (range, 1.7-4.9). In 12 of 14 patients (86%) with mediastinal involvement, IMT SPECT detected one or more mediastinal metastases. However, only 13 of 20 mediastinal metastases were detected in lesion analysis (lesion-based sensitivity, 65%). For lesions < 2 cm in diameter, sensitivity was 42%. FDG PET (available for 5 patients) detected more known and unknown lesions than did IMT SPECT. After radiotherapy, T/B had fallen to 1.84 +/- 0.29 (P < 0.001 vs. baseline), and 3 mo later to 1.61 +/- 0.41 (not statistically significant vs. second study). Considerable nonspecific uptake was found in irradiated normal lung tissue (mean ratio to nonirradiated tissue, 1.79 +/- 0.53), persisting for > 3 mo. No relationship was observed between various IMT uptake parameters and the presence of residual viable tumor tissue or survival. CONCLUSION: IMT SPECT has a high sensitivity for the detection of primary non-small cell lung cancer. Although patient-based sensitivity in detecting mediastinal spread was adequate, sensitivity for individual lesions, especially for small metastases (<2 cm in diameter) was too low to be clinically helpful. Radiotherapy caused considerable nonspecific IMT uptake, which also limits applicability in evaluating the results of treatment.

Adult↗
PubMed2001

PNU-145156E, a novel angiogenesis inhibitor, in patients with solid tumors: a phase I and pharmacokinetic study.

Our aim was to establish, in patients with solid tumors, the dose-limiting toxicity, maximum tolerated dose (MTD), and pharmacology of PNU-145156E, a new sulfonated distamycin A derivative that blocked circulating angiogenesis-promoting growth factors in animal studies and exhibited an antitumor effect in murine solid tumors. In a Phase I study, PNU-145156E was administered i.v. every 6 weeks. Included were patients with solid tumors; an Eastern Cooperative Oncology Group performance score </=1; and normal bone marrow, renal, and liver functions and blood clotting tests. Excluded were patients with brain metastases or on steroid medication. Toxicity was scored with the National Cancer Institute Common Toxicity Criteria. Plasma and urine PNU-145156E was measured for pharmacokinetic analysis. The effect of PNU-145156E on serum basic fibroblast growth factor (bFGF) was measured by sandwich ELISA. Twenty-nine patients (median age, 54 years; range, 33-71 years; 19 males and 10 females; median performance score = 1) were treated at dose levels of 100-1050 mg/m(2). We observed, during 47 treatment cycles, erratic but short-lasting decreases of antithrombin III levels (<75%) at all dose levels. Other clotting tests remained normal except during thromboembolic events. Dose-limiting toxicity was thrombophlebitis, pulmonary embolism, and grade 3 dyspnea. PNU-145156E disappeared from the circulation, decreasing triexponentially with a long terminal half-life of 1 month. No significant change in bFGF and no objective tumor responses were observed. Disease stabilization was achieved in four patients. In conclusion, the MTD of PNU-145156E was 1050 mg/m(2). Serum bFGF level was not affected by PNU-145156E up to the MTD.

Adult↗
PubMed2000

Treatment of brain metastases of small-cell lung cancer: comparing teniposide and teniposide with whole-brain radiotherapy--a phase III study of the European Organization for the Research and Treatment of Cancer Lung Cancer Cooperative Group.

PURPOSE: Approximately 60% of patients with small-cell lung cancer (SCLC) develop brain metastases. Whole-brain radiotherapy (WBRT) gives symptomatic improvement in more than 50% of these patients. Because brain metastases are a sign of systemic progression, and chemotherapy was found to be effective as well, it becomes questionable whether WBRT is the only appropriate therapy in this situation. PATIENTS AND METHODS: In a phase III study, SCLC patients with brain metastases were randomized to receive teniposide with or without WBRT. Teniposide 120 mg/m(2) was given intravenously three times a week, every 3 weeks. WBRT (10 fractions of 3 Gy) had to start within 3 weeks from the start of chemotherapy. Response was measured clinically and by computed tomography of the brain. RESULTS: One hundred twenty eligible patients were randomized. A 57% response rate was seen in the combined-modality arm (95% confidence interval [CI], 43% to 69%), and a 22% response rate was seen in the teniposide-alone arm (95% CI, 12% to 34%) (P<.001). Time to progression in the brain was longer in the combined-modality group (P=.005). Clinical response and response outside the brain were not different. The median survival time was 3.5 months in the combined-modality arm and 3.2 months in the teniposide-alone arm. Overall survival in both groups was not different (P=.087). CONCLUSION: Adding WBRT to teniposide results in a much higher response rate of brain metastases and in a longer time to progression of brain metastases than teniposide alone. Survival was poor in both groups and not significantly different.

Adult↗
PubMed2000

Preoperative staging of non-small-cell lung cancer with positron-emission tomography.

BACKGROUND: Determining the stage of non-small-cell lung cancer often requires multiple preoperative tests and invasive procedures. Whole-body positron-emission tomography (PET) may simplify and improve the evaluation of patients with this tumor. METHODS: We prospectively compared the ability of a standard approach to staging (computed tomography [CT], ultrasonography, bone scanning, and, when indicated, needle biopsies) and one involving PET to detect metastases in mediastinal lymph nodes and at distant sites in 102 patients with resectable non-small-cell lung cancer. The presence of mediastinal metastatic disease was confirmed histopathologically. Distant metastases that were detected by PET were further evaluated by standard imaging tests and biopsies. Patients were followed postoperatively for six months by standard methods to detect occult metastases. Logistic-regression analysis was used to evaluate the ability of PET and CT to identify malignant mediastinal lymph nodes. RESULTS: The sensitivity and specificity of PET for the detection of mediastinal metastases were 91 percent (95 percent confidence interval, 81 to 100 percent) and 86 percent (95 percent confidence interval, 78 to 94 percent), respectively. The corresponding values for CT were 75 percent (95 percent confidence interval, 60 to 90 percent) and 66 percent (95 percent confidence interval, 55 to 77 percent). When the results of PET and CT were adjusted for each other, only PET results were positively correlated with the histopathological findings in mediastinal lymph nodes (P<0.001). PET identified distant metastases that had not been found by standard methods in 11 of 102 patients. The sensitivity and specificity of PET for the detection of both mediastinal and distant metastatic disease were 95 percent (95 percent confidence interval, 88 to 100 percent) and 83 percent (95 percent confidence interval, 74 to 92 percent), respectively. The use of PET to identify the stage of the disease resulted in a different stage from the one determined by standard methods in 62 patients: the stage was lowered in 20 and raised in 42. CONCLUSIONS: PET improves the rate of detection of local and distant metastases in patients with non-small-cell lung cancer.

Adult↗
PubMed2000

Lack of nephrotoxicity of new oral platinum drug JM216 in lung cancer patients.

PURPOSE: The purpose of this study was to assess renal function in patients treated with the oral platinum drug JM216 [bisacetato-ammine-dichloro-cyclohexylamine-platinum(IV)], since the effects of JM216 on renal function have only partly been investigated using serum parameters or 51Cr-EDTA clearance. We used a sensitive method that assessed glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and indicators of tubular and glomerular damage. METHODS: A group of 24 patients with either non-small-cell lung cancer (NSCLC) stage IIIb/IV or small-cell lung cancer (SCLC), limited disease (LD) or extensive disease (ED), treated with JM216 were studied. All patients had no prior chemotherapy, a performance score < 2, a life expectancy of more than 3 months and normal liver, renal and bone marrow functions before treatment. All patients received oral JM216 120 mg/m2 per day for 5 consecutive days, repeated every 21 days with a maximum of six cycles. In six SCLC patients the dose was escalated to 140 mg/m2 per day after the first cycle. Prior to treatment, after the first cycle and after the end of treatment renal function was assessed by 125I-sodium thalamate and 131-hippurate clearances to determine acute and cumulative changes in GFR and ERPF, respectively. Furthermore, tubular and glomerular damage were assessed by urinary excretion of beta2-microglobulin, lactic dehydrogenase (LDH), alkaline phosphatase (ALP), gamma-glutamyltransferase (GT) and albumin. RESULTS: In 20 evaluable patients no significant acute impairment of renal function was observed. Median (range) GFR, ERPF and filtration fraction (FF) before treatment were 101 ml/min (53-164 ml/min), 417 ml/min (227-719 ml/min), and 0.25 (0.19-0.33), respectively. After the first cycle values were 117 ml/min (71-189 ml/min), 418 ml/min (228-709 ml/ min) and 0.28 (0.21-0.33), respectively. Also, no indications of tubular or glomerular damage were found. In four patients renal function was evaluated at the end of treatment (one after three cycles, one after five cycles and two after six cycles). Median (range) GFR, ERPF and FF were 99 ml/min (74-139 ml/min), 401 ml/min (277-496 ml/min) and 0.26 (0.23-0.30), respectively, revealing no delayed nephrotoxicity. CONCLUSION: We conclude that oral JM216 shows no nephrotoxicity.

Administration, Oral↗
PubMed2000

Diffusion capacity and haemodynamics in primary and chronic thromboembolic pulmonary hypertension.

The transfer factor of the lung for carbon monoxide (TL,CO) is decreased in patients with pulmonary hypertension. The pulmonary membrane diffusion capacity (Dm) and pulmonary capillary blood volume (Vc), were studied to establish: 1) the relative contribution of the components of the transfer factor to the decrease in TL,CO; 2) whether differences exist between primary pulmonary hypertension (PPH) and chronic thromboembolic pulmonary hypertension (CTEPH); and 3) the relationship between these parameters and haemodynamic parameters. Dm and Vc were determined in 19 patients with PPH and in eight patients with CTEPH. The patients had been referred for consideration for lung transplantation. Haemodynamic parameters were assessed by heart catheterization. In the PPH group, Vc was reduced in 12 of 19 patients (mean+/-SD Vc 72+/-14% of the predicted value) and Dm in 17 of 19 patients (60+/-22% pred). In the CTEPH group, Vc was reduced in six of eight patients and Dm in seven of eight patients. The mean TL,CO Dm and Vc values were similar to those in the PPH group. The reduction in pulmonary membrane diffusion capacity was significantly greater than that in pulmonary capillary blood volume. No differences in pulmonary and cardiovascular functional values were found between the groups. Right atrial pressure showed a significant negative correlation with pulmonary capillary blood volume and an increased pulmonary vascular resistance was associated with a decrease in pulmonary membrane diffusion capacity. These results suggest pronounced functional impairment of the alveolocapillary membrane in these patients.

Adult↗
PubMed2000

Clinical and radiographic judgement of occlusal caries in adolescents.

In this study, the clinical and radiographic material of two groups of 17- and 20-yr-old adolescents, born either in 1970 or in 1976, was compared to study changes in the prevalence of occlusal dentine caries and to determine the additional value of the bitewing radiographs. The first and second molars of 478 participants were included. Clinical data were derived from an epidemiological project. Two examiners judged the bitewing radiographs, of which about 10% was examined by both. The overall Cohen's kappa for interexaminer agreement was 0.87. The prevalence of occlusal caries had not changed for the two age groups; after clinical and radiographic examination, around 33% of the occlusal surfaces of the 17 yr olds and around 25% of the 20 yr olds exhibited dentine caries. The clinical prevalence of occlusal caries in first and second molars was highly underestimated when compared with the radiographs. In the 1976 group, more sealants were recorded during the clinical examination. On the bitewing radiographs, radiolucencies were found underneath one-half of the sealants of the 17 yr olds and underneath one quarter of the sealants present in the 20 yr olds.

Adolescent↗
PubMed2000

The blood-brain barrier and oncology: new insights into function and modulation.

The efficacy of chemotherapy for malignant primary or metastatic brain tumours is still poor. This is at least partly due to the presence of the blood-brain barrier (BBB). The functionality of the BBB can be explained by physicochemical features and efflux pump mechanisms. An overview of the literature is presented with emphasis on oncology. The BBB consists of capillary endothelial cells that lack fenestrations and are connected together with continuous tight junctions, with a high electrical resistance. Permeability of tight junctions can be increased in vitro by contraction of the cytoskeleton, caused by bradykinin agonists. Different efflux pumps are present in the BBB. Examples are P-glycoprotein (P-gp), organic anion transporters, (OAT) and multidrug-resistance-associated proteins (MRP)(1 and 3). These pumps act as a multi-specific efflux pump for various chemotherapeutic drugs. Experiments have shown that P-gp can be inhibited by different non-chemotherapeutic substrates such as cyclosporin A. The functionality in vivo of P-gp can be measured with positron emission tomography and [(11)C]-verapamil or with single photon emission computer tomography and(99m)Tc-sestamibi. MRP(1)and MRP(3)act as organic anion transporters that in vitro act as efflux pumps for substances that are conjugated or co-transported with glutathione and glucuronide, respectively. Methotrexate has been recently demonstrated to be transported by MRP(1)and MRP(3). Results of studies which demonstrate the clinical relevance and applicability of BBB modulators are eagerly awaited.

ATP Binding Cassette Transporter, Subfamily B, Mem↗