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N H Mulder

Publications and source records attributed to N H Mulder.

At least 37 records · Page 2Linked to original sources
PubMed2001

A phase I and pharmacokinetic study of intraperitoneal topotecan.

PURPOSE: To evaluate the feasibility and pharmacology of intraperitoneal (IP) topotecan. PATIENTS AND METHODS: Fifteen patients with recurrent ovarian cancer in a phase I trial were treated with escalating IP topotecan doses (5-30 mg/m(2)) for pharmacokinetic analysis. RESULTS: Dose limiting toxicity (DLT) was acute hypotension, chills and fever at the 30 mg/m(2) dose level. Haematological toxicity and abdominal pain were mild for all dose levels studied. PHARMACOKINETICS: Peak plasma levels of total topotecan were reached at 2.7 +/- 1.1 h after IP instillation. The apparent V(ss) was 69.9 +/- 25.4 L/m(2), plasma clearance 13.4 +/- 2.5 L/h/m(2) and plasma T1/2 3.7 +/- 1.3 h. The plasma AUC was correlated with the dose (R = 0.95, P < 0.01). The plasma AUC ratio of lactone versus total topotecan (lactone + carboxy-forms) increased with the dose from 16% to 55%, (R = 0.84, P < 0.01). Peritoneal total topotecan was cleared from the peritoneal cavity at 0.4 +/- 0.3 L/h.m(2) with a T1/2 = 2.7 +/- 1.7 h. The mean peritoneal/plasma AUC ratio for total topotecan was 54 +/- 34. CONCLUSION: A substantial dose of topotecan can be delivered by the IP route, achieving cytotoxic plasma levels of topotecan, with acceptable toxicity. The recommended dose for further phase II trials is 20 mg/m(2) IP, which enables combination with active doses of other cytotoxic drugs, in view of its limited myelotoxicity when given by this route.

Adult↗
PubMed2001

Telomere length in breast cancer patients before and after chemotherapy with or without stem cell transplantation.

High-dose chemotherapy and peripheral blood stem cell transplantation (PBSCT) may accelerate telomere length loss in haematopoietic stem cells. As data including pre-and post-treatment samples are lacking, we studied leukocyte telomere length and telomerase activity before and after treatment in breast cancer patients randomized to receive 5 adjuvant courses FEC (5-FU, epirubicin and cyclophosphamide) (n = 17), or 4 x FEC followed by high-dose cyclophosphamide, thiotepa, carboplatin and autologous PBSCT (n = 16). Haemoglobin, MCV, leukocyte-and platelet numbers were assessed prior to (t(0)), 5 months after (t(1)) and 9 months after chemotherapy (t(2)); these parameters were decreased at t(1)and t(2)compared to t(0)(high-dose: all parameters; standard-dose: leukocytes and platelets), and all parameters were lower after high-dose than standard-dose treatment at t(1). Paired individual leukocyte samples of t(0)and t(1)showed telomere length change (determined by telomere restricted fragment (TRF) assay) ranging from +0.8 to -2.2 kb, with a decreased TRF length in 9 patients of both groups. Telomerase activity (determined by TRAP assay) was below detection limit in leukocyte samples of t(0)and t(1). Thus, standard-and high-dose chemotherapy negatively affect haematological reconstitution in this setting. In individual patients, telomere length can be remarkably changed following haematological proliferative stress after treatment.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Improved long term survival of patients with metastatic nonseminomatous testicular germ cell carcinoma in relation to prognostic classification systems during the cisplatin era.

BACKGROUND: The current study reviews chronologic changes in the long term outcome of patients with metastatic nonseminomatous testicular germ cell tumors (NSTGCT) who were treated at a single institution during the past two decades. The 10-year survival of prognostic subgroups according to the classification of the International Germ Cell Consensus Classification Group (IGCCCG) and various other prognostic classifications is examined in time to evaluate whether cumulative experience has led to an improved outcome of patients with metastatic NSTGCT and to explore differences in outcome of prognostic subgroups. METHODS: Two hundred ninety-nine patients with metastatic NSTGCT who were treated with cisplatin-based polychemotherapy during the period from 1977 to 1996 were staged retrospectively according to the Royal Marsden (RM) classification and the following prognostic classifications: IGCCCG, Indiana, Medical Research Council (MRC), and European Organization for Research and Treatment of Cancer (EORTC). The numbers of patients who were treated during the periods 1977-1986 and 1987-1996 were 146 and 153, respectively. Survival curves were constructed using the Kaplan-Meier method, and disease specific 10-year survival rates of prognostic subgroups treated during the two consecutive 10-year periods were compared using the log rank test. RESULTS: The median follow-up of surviving patients during the periods 1977-1986 and 1987-1996 was 14.7 years (range, 0.2-20.6 years) and 7.0 years (range, 0.4-11.4 years), respectively. The actuarial disease specific 10-year survival rate of patients with metastatic NSTGCT increased from 76% during the period 1977-1986 to 88% during the period 1987-1996 (relative risk [RR], 0.51; 95% confidence interval [95% CI], 0.29-0.89; P < 0.05). The 10-year survival rates of patients with good, intermediate, and poor prognoses according to the IGCCCG classification were 95%, 74%, and 37%, respectively, during the period 1977-1986 and 94%, 87%, and 66%, respectively, during the period 1987-1996. Patients with a poor prognosis according to the IGCCCG classification showed the greatest increase in 10-year survival (RR, 0.43; 95% CI, 0.18-1.04; P = 0.06). Analysis using the RM, Indiana, and EORTC classifications also showed an improved 10-year survival rate of patients with a poor prognosis who were treated during 1987-1996 compared with those who were treated during 1977-1986. CONCLUSIONS: The 10-year survival rate of patients with metastatic NSTGCT who were treated with cisplatin-based chemotherapy significantly increased from 76% during the period 1977-1986 to 88% during the period 1987-1996. This improvement during the cisplatin era resulted mainly from an increase in the survival of patients with metastatic disease who had a poor prognosis. These results indicate that the management of patients with NSTGCT is still improving.

Adolescent↗
PubMed2001

Ultrastructural morphology and localisation of cisplatin-induced platinum-DNA adducts in a cisplatin-sensitive and -resistant human small cell lung cancer cell line using electron microscopy.

Ultrastructural morphology (transmission electron microscopy) and localisation of cisplatin-induced platinum (Pt)-DNA adducts (immunoelectron microscopy) were analysed in the human small cell lung cancer cell line GLC(4) and its 40-fold in vitro acquired cisplatin-resistant subline GLC(4)-CDDP, which is characterised by, among other things, a decreased DNA platination. Immunolabelling of Pt-DNA adducts was performed with the polyclonal antibody GPt, known to detect the main Pt-containing intrastrand and interstrand DNA adducts. Morphological analysis of GLC(4) and GLC(4)-CDDP at the ultrastructural level showed cells with a high nucleus/cytoplasm ratio with the majority of nuclei containing one or more nucleoli. GLC(4)-CDDP showed, in contrast to GLC(4), an extensive Golgi apparatus and an increased number of mitochondria. DNA platination was detectable in both GLC(4) and GLC(4)-CDDP. Immunoelectron microscopy showed Pt-DNA adducts primarily in the nucleus, preferentially at loci with high-density chromatin (e.g. heterochromatin, pars granulosa around nucleoli, condensed DNA in proliferating and apoptotic cells), and in mitochondria. The level of detectable Pt-DNA adducts was cell cycle status-dependent. In both cell lines, Pt-DNA adduct levels increased from non-dividing interphase cells to dividing cells and were highest in cells undergoing apoptosis. Overall localisation of Pt-DNA adducts was comparable in GLC(4) and GLC(4)-CDDP cells.

Antibodies↗
PubMed2001

Endothelium in vitro: a review of human vascular endothelial cell lines for blood vessel-related research.

Endothelial cells (EC) are currently used as in vitro model systems for various physiological and pathological processes, especially in angiogenesis research. Primary EC have a limited lifespan and display characteristics that differ from batch to batch due to their multidonor origin. In recent years many groups have established EC lines. This Review gives an overview of the advantages and disadvantages of currently available vascular EC lines. Its aim is to help the investigator to decide which cell line matches his or her research goal best. Truly immortalized cell lines are generally better characterized and more stable in their endothelial traits than EC that were given an extended life span. Presently the best characterized macro- and micro-vascular EC lines are EA.hy926 and HMEC-1, respectively.

Cell Line↗
PubMed2001

Long-term haematological recovery following high-dose chemotherapy with autologous bone marrow transplantation or peripheral stem cell transplantation in patients with solid tumours.

long-term peripheral blood counts and factors influencing long-term trilineage haematological recovery of consecutive patients in a single institution treated with high-dose chemotherapy (hdc) and abmt or psct for solid tumours were examined. patients with a relapse-free survival of >1 year were included in the analysis (n = 131). Peripheral blood counts were examined 6 months and yearly following transplantation. Median follow-up was 4.1 years (range 1-10+ years). Three years after transplantation 91% of patients had normal white blood counts (WBC), 94% normal haemoglobin (Hb) and 75% normal platelets. Trilineage recovery was complete in 70% (n = 83) at 3 years and 85% (n = 50) at 5 years. Recovery of Hb occurred before WBC and platelet recovery. Approximately 25% of patients displayed an elevated MCV throughout the follow-up period. These long-term results were independent of age, high-dose regimen, number of reinfused stem cells and stem cell source. Double (n = 12) vs single (n = 119) transplantations showed significantly slower trilineage recovery and higher MCV. No secondary graft failure, myelodysplasia or leukaemia was encountered. In conclusion, complete trilineage recovery after HDC followed by ABMT or PSCT occurs slowly. PSCT and ABMT are capable of maintaining long-term haematopoiesis. Slower recovery is seen after double transplantations. The results suggest lasting implications for bone marrow function after autologous transplantation.

Adult↗
PubMed2001

Value and cost of follow-up after adjuvant treatment of patients with Dukes' C colonic cancer.

BACKGROUND: The clinical value and costs of different diagnostic tools used to identify potentially curable recurrent disease in patients treated adjuvantly for curatively resected Dukes' C colonic cancer were examined. METHODS: The study group comprised 496 patients treated with chemotherapy over a 1-year interval. Follow-up consisted of interim history, physical examination, liver ultrasonography or computed tomography (CT), measurement of carcinoembryonic antigen (CEA) levels, chest radiography and colonoscopy. RESULTS: Two hundred and thirteen patients had recurrent disease (median follow-up 43 months). Forty-two patients with recurrence (20 per cent) were treated with curative intent (median survival 38 months; 5-year survival rate 40 per cent). Recurrence was identified by liver ultrasonography or CT (n = 14), evaluation of symptoms (n = 12), colonoscopy (n = 8), CEA measurement (n = 3), chest radiography (n = 2), physical examination (n = 1) and other modalities in two patients. The mean cost of diagnostic procedures per curative resected recurrence for patients amenable to salvage surgery was US$9011. Of all treatable recurrences, 12 of 42 were identified by evaluation of symptoms only. Ultrasonography and colonoscopy identified 22 recurrences at a cost of US$11 790 per patient, while routine follow-up by CEA measurement, chest radiography and physical examination identified a further six at a cost of US$19 850 per patient. CONCLUSION: Potentially curable recurrences were detected primarily by liver imaging and colonoscopy. The yield of CEA measurement, chest radiography and physical examination was relatively low; such methods were expensive and should not be recommended in the routine follow-up of these patients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

A taste of taxol.

Explore the source record for details and available documents.

Alopecia↗
PubMed2000

Role of metallothionein in cisplatin sensitivity of germ-cell tumours.

Cisplatin (CDDP) is an extremely active drug in the treatment of germ-cell tumours. Earlier, we found an unexpected inverse correlation between the total amount of sulfhydryl groups and CDDP sensitivity in a panel of 3 human germ-cell-tumour and 3 colon-carcinoma cell lines. Major components of the sulfhydryl groups are glutathione and metallothionein (MT). We further investigated a possible role of MT in the CDDP sensitivity of germ-cell tumours. MT levels and functionality of the germ-cell-tumour and colon-carcinoma cell lines were found to be inversely correlated with CDDP sensitivity. No difference in sub-cellular localization of MT could be observed among the types of cell lines. In agreement with the in vitro data, immunohistochemical detection of MT was high in 11/14 primary human germ-cell tumours and low in 7/7 human colon carcinomas. MT-protein expression in primary germ-cell tumours did not discriminate between responding and non-responding patients. As compared with the primary tumours, MT-protein expression decreased in 5/7 post-chemotherapy residual vital tumours or remained undetectable (2/7). MT-protein expression in the germ-cell tumours was not related to total p53-protein expression. In summary, over-expression of MT was found in germ-cell tumours, both in cell lines and in human tumours. Although MT-protein over-expression seems to be associated with the CDDP sensitivity of germ-cell tumours, MT-protein expression in primary germ-cell tumours did not differ between responding and non-responding patients and therefore cannot be used to predict response to chemotherapy.

Antineoplastic Agents↗
PubMed2000

Monitoring of herpes simplex virus thymidine kinase enzyme activity using positron emission tomography.

9-[(1-[18F]Fluoro-3-hydroxy-2-propoxy)methyl]guanine ([18F]FHPG) was evaluated as a tracer for noninvasive positron emission tomography (PET) imaging of herpes simplex virus type 1 thymidine kinase (HSV-tk) gene expression. C6 rat glioma cells with and without the HSV-tk gene were incubated with [18F]FHPG for 2 h. The in vitro tracer uptake in HSV-tk-containing C6tk cells was 35 +/- 5 times higher than that in control cells. In nude rats carrying both a C6 and a C6tk tumor, the average ratio of tracer accumulation between the tumors was 15 +/- 5 at 2 h postinjection. The tracer is rapidly cleared from nontarget tissue into the urine because only the HSV-tk-expressing tumor, kidneys, and bladder remained visible on the late PET images. HPLC analysis revealed that three metabolites, tentatively assigned as FHPG mono-, di-, and triphosphate, were formed in the C6tk tumors only. In conclusion, we have demonstrated that [18F]FHPG is a promising tracer for monitoring HSV-tk enzyme activity in vivo with PET.

Animals↗
PubMed2000

[(11)C]FMAU and [(18)F]FHPG as PET tracers for herpes simplex virus thymidine kinase enzyme activity and human cytomegalovirus infections.

[(11)C]-2'-Fluoro-5-methyl-1-beta-D-arabinofuranosyluracil ([(11)C]FMAU) and [(18)F]-9-[(3-fluoro-1-hydroxy-2-propoxy)methyl]guanine ([(18)F]FHPG), radiolabeled representatives of two classes of antiviral agents, were evaluated as tracers for measuring herpes simplex virus thymidine kinase (HSV-tk) enzyme activity after gene transfer and as tracers for localization of active human cytomegalovirus (HCMV) infections. In vitro accumulation experiments revealed that both [(11)C]FMAU and [(18)F]FHPG accumulated significantly more in HSV-tk expressing cells than they did in control cells. [(18)F]FHPG uptake in HSV-tk expressing cells, however, was found to depend strongly on the cell line used, which might be due to cell type dependent membrane transport or cell type dependent substrate specific susceptibility of the enzyme. In vitro, both tracers exhibited a good selectivity for accumulation in HCMV-infected human umbilical vein endothelial cells over uninfected cells. In contrast to [(18)F]FHPG, [(11)C]FMAU uptake in control cells was relatively high due to phosphorylation of the tracer by host kinases. Therefore, [(18)F]FHPG appears to be the more selective tracer not only to predict HSV-tk gene therapy outcome, but also to localize active HCMV infections with PET.

Antiviral Agents↗
PubMed2000

Negative inotropic effects of recombinant interleukin 2 in patients without left ventricular dysfunction.

UNLABELLED: Experimental data have shown that rIL2 has negative inotropic properties. This has not been investigated in humans with normal left ventricular function. Seventeen consecutive renal cell carcinoma patients who received rIL2 therapy because of dissemination were analyzed before and after treatment with a low dose of rIL2 subcutaneously. Left ventricular ejection fraction (echocardiography), heart rate variability parameters (24 h electrocardiography), and TNF alpha, IL1 beta and nitric oxide metabolites (NO(x)) were measured. LVEF decreased from 54+/-7 to 50+/-6% (mean+/-S.D.; P=0.012), with a concomitant increase in heart rate from 87+/-13 to 94+/-13 beats/min (P=0.031). All frequency domain HRV parameters decreased: the total power from 18.0+/-7.9 to 14.0+/-5.0 ms (P=0.001), the low frequency from 10.3+/-5.4 to 8. 3+/-3.4 ms (P=0.001), and the high frequency from 6.3+/-2.6 to 4. 5+/-1.1 ms (P=0.001). There was no measurable effect on TNF alpha, IL1 beta concentrations. Plasma levels of nitrate (NO(x)) increased from 22.8+/-14.4 to 41.8+/-26.6 micromol/l (P=0.007). CONCLUSIONS: A low dose of rIL2 has a negative inotropic effect that may be mediated by increased NO concentrations. It also reduces sympathetic activity as reflected in HRV parameters.

Adult↗
PubMed2000

The addition of low-dose leucovorin to the combination of 5-fluorouracil- levamisole does not improve survival in the adjuvant treatment of Dukes' C colon cancer. IKN Colon Trial Group.

PURPOSE: To assess the effect of the addition of leucovorin to the combination of 5-fluorouracil (5-FU)-levamisole on recurrence risk and overall survival in patients after a resection with curative intent of a Dukes' C colon cancer. PATIENTS AND METHODS: Five hundred patients with Dukes' C colon cancer were randomly assigned to adjuvant treatment for one year with 5-fluorouracil (450 mg/m2 i.v. weekly) and levamisole (150 mg p.o. every two weeks), the C-group or with leucovorin (20 mg/m2 i.v.), 5-fluorouracil and levamisole, the L-group. The median follow-up for patients still alive is 36 months. Four patients were ineligible because of advanced disease at the time of randomisation. RESULTS: Sixty percent of the patients have completed all courses of chemotherapy. Of the remaining 40% of the patients who did not complete one-year treatment with chemotherapy, 46% discontinued because of toxic and/or emotional reasons. They were equally divided over both treatment arms. The addition of leucovorin increased toxicity (especially mucositis and conjunctivitis) without a significant increase in treatment withdrawal. Five-year disease-free interval (C-group: 49%, L-group: 46%; log-rank test, P = 0.86) and overall survival (C-group: 55%, L-group: 59%, log-rank test: P = 0.96) were very similar in both treatment arms. CONCLUSIONS: The addition of low dose leucovorin to the combination of 5-fluorouracil and levamisole in a 12-month adjuvant therapy for curatively resected Dukes' C colon cancer patients does not improve disease-free interval nor overall survival. The addition of leucovorin to the combination of 5-FU levamisole increases toxicity. Therefore leucovorin 5-FU levamisole is not recommended in a 12 months adjuvant regime of Dukes' C colon cancer.

Adenocarcinoma↗
PubMed2000

Biological activity and safety of adenoviral vector-expressed wild-type p53 after intratumoral injection in melanoma and breast cancer patients with p53-overexpressing tumors.

p53 mutations are common genetic alterations in human cancer. Gene transfer of a wild-type (wt) p53 gene reverses the loss of normal p53 function in vitro and in vivo. A phase I dose escalation study of single intratumoral (i.t.) injection of a replication-defective adenoviral expression vector containing wt p53 was carried out in patients with metastatic melanoma or breast cancer with increased p53 protein immunoreactivity in pretreatment tumor biopsies. The biological activity of the injected wt p53 was assayed by reverse transcriptase-polymerase chain reaction in tumor tissue. A total of six (five melanoma and one breast adenocarcinoma) patients were treated at dose levels dependent upon tumor size/dose escalation sequence. Five of six patients became positive for the transfer of wt p53 into tumor tissue 2 days after injection of the vector. Of the four patients assayed, all developed anti-adenoviral antibodies. Adverse reactions associated with i.t. injection were mild, with no obvious correlation between the incidence, severity, or relationship of the events and drug dose. p53 gene therapy by i.t. injection of a replication-defective adenoviral expression vector is safe, feasible, and biologically effective (with respect to transduction frequency) in patients with either metastatic melanoma or breast cancer.

Adenocarcinoma↗
PubMed2000

Intraperitoneal chemotherapy in ovarian cancer.

From a theoretical viewpoint, intraperitoneal therapy (IP) in patients with ovarian cancer, a malignancy which remains mainly confined to the peritoneal cavity, is logical. Over the past decades this approach has evolved into a therapeutic strategy for a selected group of patients. Data available at present suggest a beneficiary role (for IP therapy) as first-line treatment in patients with small residual disease and possibly following initial reduction of tumor load by systemic chemotherapy. The theoretical basis, the present status of IP therapy in different settings, pharmacology, factors limiting its clinical utility and future directions are reviewed.

Animals↗
PubMed2000

Limitations of the nested reverse transcriptase polymerase chain reaction on tyrosinase for the detection of malignant melanoma micrometastases in lymph nodes.

The specificity and sensitivity of the nested reverse transcriptase polymerase chain reaction (RT-PCR) on tyrosinase was studied, for the detection of micrometastases of malignant melanoma. The specificity was assessed in the blood of six healthy donors, four patients with non-melanoma cancers of which one patient was treated with granulocyte-colony stimulating factor. Lymph nodes of nine patients without malignant melanoma were tested and four cell lines of various other tumours. Six of the nine non-melanoma lymph nodes were positive in this assay. The sensitivity was tested in a spike experiment in vitro, using a melanoma cell line. The detection limit was ten melanoma cells per 10(7) peripheral blood lymphocytes.

Biomarkers, Tumor↗