Biomedical subjects

H Gelderblom

Publications and source records attributed to H Gelderblom.

At least 19 recordsLinked to original sources

PubMed2006

[Long-term beneficial effects of cetuximab in a woman with metastasised rectal carcinoma without expression of the epidermal growth factor receptor].

A 37-year-old woman presented with an epidermal growth factor-(EGFR)-negative rectum carcinoma with liver metastases. After extensive treatment, consisting of first-line chemotherapy, low anterior resection, isolated liver perfusion, second- and third-line chemotherapy and a pericardiodesis with bleomycin, she was subsequently treated with combination irinotecan and cetuximab therapy. At her last follow-up she had had long-term stable disease for 18 months with clinical benefit. Cetuximab is a monoclonal antibody which targets EGFRR. This exceptional case illustrates that treatment with cetuximab may be of benefit to a patient with EGFR-negative colorectal cancer. The exact mechanism of action and the role ofcetuximab in the treatment of advanced colorectal cancer have still to be determined.

Adult↗

PubMed2005

Survival of patients with ovarian cancer due to a mismatch repair defect.

PURPOSE: Hereditary non-polyposis colorectal cancer (HNPCC, Lynch syndrome) is characterized by the development of cancer of the colorectum, endometrium and other cancers. Cancer of the ovaries (OC) has frequently been reported in HNPCC. Colorectal cancer associated with HNPCC has a better survival chance compared to sporadic colorectal cancer. It is yet unknown whether patients with OC from HNPCC families (OC-HNPCC) also have a better survival. Therefore, the aim of the study was to compare the survival between patients with OC-HNPCC and a control group. METHODS: A total of 26 patients with OC were identified from the Dutch HNPCC Registry. A control group (52 cases) matched for age, stage and year of diagnosis was derived from the population-based Eindhoven Cancer Registry. Data on treatment were collected for all patients. Kaplan-Meier analysis was used to calculate the crude survival. RESULTS: The mean age at diagnosis of OC-HNPCC was significantly lower than the age of sporadic OC (49.5 vs 60.9 years). Compared to sporadic OC, OC-HNPCC was diagnosed at an earlier stage. The survival rate was not significantly different between patients with OC-HNPCC and the controls with sporadic OC. The cumulative 5-year-survival rates were 64.2 and 58.1% respectively. CONCLUSION: On the basis of our findings, we recommend to treat OC-HNPCC similar to sporadic OC.

Adult↗

PubMed2005

Pharmacology of oxaliplatin and the use of pharmacogenomics to individualize therapy.

Oxaliplatin is a relatively new platinum analogue that is currently used in pharmacotherapy of metastatic colorectal cancer. Its dose-limiting toxicity is sensory neuropathy, which can be modulated by infusion of calcium and magnesium. Oxaliplatin exerts its anti-tumour effects by platinum-adduct formation, binding to cellular proteins and possibly interfering with RNA synthesis as well. If they are not removed from DNA, oxaliplatin adducts are lethal. Cellular defense mechanisms prevent adduct formation (e.g., glutathione-S-transferase) or remove DNA adducts (e.g., nucleotide excision repair). Depending on the activity of necessary enzymes in these cellular defense pathways, oxaliplatin induced damage varies from one individual to another. There is growing evidence that polymorphisms in genes coding for DNA repair enzymes and metabolic inactivation routes contribute to the interindividual differences in anti-tumour efficacy and toxicity of oxaliplatin. Single nucleotide polymorphisms (SNPs) may yield inactive enzymes, or increased gene transcription and hence increased enzyme production. This review covers findings of recent investigations on the associations of SNPs and clinical outcome after oxaliplatin chemotherapy in metastatic colorectal cancer.

Antineoplastic Agents↗

PubMed2004

Fatal outcome of a hypersensitivity reaction to paclitaxel: a critical review of premedication regimens.

Hypersensitivity reactions (HSRs) to paclitaxel are frequently encountered in patients receiving this antitumour drug. Administration of histamine H1- and H2-receptor antagonists and corticosteroids has been shown to reduce significantly the risk of developing an HSR in patients receiving taxanes. In this case report, we describe the fatal outcome of an HSR in a patient receiving paclitaxel despite short-course premedication. The level of evidence supporting the short-course i.v. premedication schedule is challenged, as it is not compatible with the pharmacokinetic properties of dexamethasone.

Anti-Inflammatory Agents↗

PubMed2003

[Several patients with a metastasised gastrointestinal stroma-cell tumor for whom the tide turned by the introduction of imatinib].

The introduction of imatinib for gastrointestinal stroma-cell tumours (GISTs) reversed the chances of 3 cancer patients who had given up hope. One 40-year-old man with multiple chemotherapy-resistant GIST responded well to imatinib treatment in a phase-I setting. Another patient, a woman aged 77 years, was initially considered too old for chemotherapy, but was later accepted for treatment in an imatinib phase-III trial due to the positive results in other patients. The last patient, a woman aged 48 years, also responded to treatment with imatinib despite a massive tumour load and a WHO performance status of 3. She was almost free of complaints within a period of just a few weeks. Until recently, the prognosis for metastatic or irresectable GIST was almost certain death within 1 year after diagnosis. The recent registration of imatinib has dramatically changed the prognosis of this disease. These case reports also demonstrate that some patients in phase-I studies can actually benefit from participation in such trials. Furthermore, treating GIST patients in a poor condition with imatinib is justified by the high response rates and mild toxicity.

Adult↗

PubMed2003

[Imatinib, a specific tyrosine-kinase inhibitor, for the treatment of patients with a gastrointestinal stroma cell tumor].

The c-kit oncogene, encoding for a transmembrane growth-factor receptor with tyrosine-kinase activity (KIT), plays an important role in the tumourigenesis of gastrointestinal stroma-cell tumours (GISTs). GISTs are a heterogeneous group of mesenchymal tumours, mainly localised in the abdomen. Immunohistochemical staining using antibodies directed towards the c-kit protein on the cell surface, is a useful tool in the often difficult differential diagnosis of GISTs from other mesenchymal tumours. The correct diagnosis of GISTs is crucial for the new treatment option with imatinib, the tyrosine-kinase inhibitor specifically targeted against KIT. The clinical development of imatinib for patients with GISTs has been extraordinarily rapid. As a result of the short period of time between the drug's experimental introduction and actual registration, many unanswered questions about its use for the treatment of GISTs remain. These can only be answered in well-designed clinical trials. It is therefore recommended that patients with these rare tumours are referred to a centre with experience in the diagnosis and treatment of these soft-tissue sarcomas.

Antineoplastic Agents↗

PubMed2003

Influence of the cisplatin hydration schedule on topotecan pharmacokinetics.

The study described here was designed to investigate the influence of the hydration schedule of cisplatin on the pharmacokinetics of topotecan. To test this hypothesis, 13 adult cancer patients were treated with intravenous (i.v.) cisplatin followed by i.v. topotecan for 5 days every 3 weeks using a short hydration schedule (SHS) for cisplatin in the first course and a hyper-hydration schedule (HHS) in the second course or vice versa. Topotecan pharmacokinetic analysis was performed in plasma, whole blood and red blood cells in both courses on days 1, 2 and 5. 11 patients received both courses and were pharmacokinetically evaluable. No significant differences between the two studied schedules were noted in the clearances of topotecan on day 1 in the different matrices. However, in both hydration schedules, on average, slightly lower topotecan clearances were observed on both days 2 and 5 compared with day 1 in all of the matrices, while no differences were noted between days 2 and 5. This alteration was independent of the schedule used and was less pronounced than that which has been initially reported for SHS and, overall, will not have clinical consequences.

Adult↗

PubMed2002

Modulation of cisplatin pharmacodynamics by Cremophor EL: experimental and clinical studies.

The paclitaxel vehicle Cremophor EL (CrEL) has been shown to selectively inhibit the accumulation of cisplatin in peripheral blood leucocytes, but not in tumour cells in vitro, and we hypothesised that this phenomenon is responsible for the improvement of the therapeutic index of cisplatin observed in combination studies with paclitaxel. Here, we report on studies assessing the interaction between CrEL and cisplatin in a murine model, and involving the potential clinical applicability of CrEL as a protector for cisplatin-associated haematological side-effects. In mice, CrEL (0.17 ml/kg, intravenous (i.v.)) given in combination with cisplatin (10 mg/kg, intraperitoneal (i.p.)) did not change the pharmacokinetics of cisplatin. Cisplatin-induced haematological toxicity, expressed as white blood cells (WBC) at nadir, was significantly reduced by CrEL from 5.05+/-0.95 to 6.50+/-1.31 x 10(9)/l (P=0.0009). Data obtained from cancer patients treated with cisplatin (70 mg/m(2), 3-h i.v.) and topotecan (0.45 or 0.60 mg/m(2)/day x 2) preceded by CrEL (12 ml, 3-h i.v.) (n=6) or without CrEL (n=10) similarly indicated significant differences in the percent decrease in WBC between the groups (46.5+/-18.7 versus 67.2+/-15.0%; P=0.029). Likewise, the percent decrease in platelet count was significantly greater in the absence of CrEL (23.9+/-5.38 versus 73.3+/-15.5%; P=0.0003). Pharmacokinetic parameters of unbound and total cisplatin and of topotecan lactone and total drug were not significantly different from historic control values (P>or=0.245). Overall, this study provides further evidence on the important role of CrEL in the pharmacological and toxicological profile of cisplatin, and implies that reformulation of cisplatin with CrEL for systemic treatment might achieve an improvement of its therapeutic index, particularly in the setting of a weekly dose-dense concept.

Animals↗

PubMed2001

Dose and schedule-finding study of oral topotecan and weekly cisplatin in patients with recurrent ovarian cancer.

Both weekly cisplatin chemotherapy and single agent topotecan have proven to be effective in recurrent ovarian cancer. Preclinical data show synergism between cisplatin and topotecan. Side effects for this combination are drug sequence dependent and predominantly haematologic. Since preclinical data suggest that Cremophor EL (CrEL), the formulation vehicle of paclitaxel, has a protective effect on haematological toxicity of cisplatin, CrEL was added to the combination cisplatin and topotecan. In this phase I study, escalating doses of oral topotecan administered on day 1, 2, 8, 9, 15, 16, 29, 30, 36, 37, 43, 44 were combined with weekly cisplatin 70 mg m(-2) d(-1) on day 1, 8, 15, 29, 36, 43 (scheme A) or with the presumably less myelotoxic sequence weekly cisplatin day 2, 9, 16, 30, 37, 44 (scheme B). In scheme C, CrEL 12 ml was administered prior to cisplatin in the sequence of Scheme A. 18 patients have received a total of 85 courses. In scheme A 4/10 patients, all treated with topotecan 0.45 mg m(-2) d(-1), experienced DLT: 1 patient had vomiting grade 4, 1 patient had grade 4 neutropenia >5 days, 1 patient had >2 weeks delay due to thrombocytopenia and 1 patient due to neutropenia. Both patients in scheme B (topotecan 0.45 mg m(-2) d(-1)) had DLT due to a delay > 2 weeks because of prolonged haematological toxicity. No DLT was observed in the first 3 patients in scheme C (topotecan 0.45 mg m(-2) d(-1)). However, 2 out of 3 patients treated at dose level topotecan 0.60 mg m(-2)d(-1) in scheme C experienced DLT due to >2 weeks delay because of persistent thrombocytopenia or neutropenia. We conclude that there is a modest clinical effect of CrEL on haematological toxicity for this cisplatin-based combination regimen, which seems to reduce these side effects but does not really enable an increase of the oral topotecan dose.

Administration, Oral↗

PubMed2001

Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation.

Cremophor EL (CrEL) is a formulation vehicle used for various poorly-water soluble drugs, including the anticancer agent paclitaxel (Taxol). In contrast to earlier reports, CrEL is not an inert vehicle, but exerts a range of biological effects, some of which have important clinical implications. Its use has been associated with severe anaphylactoid hypersensitivity reactions, hyperlipidaemia, abnormal lipoprotein patterns, aggregation of erythrocytes and peripheral neuropathy. The pharmacokinetic behaviour of CrEL is dose-independent, although its clearance is highly influenced by duration of the infusion. This is particularly important since CrEL can affect the disposition of various drugs by changing the unbound drug concentration through micellar encapsulation. In addition, it has been shown that CrEL, as an integral component of paclitaxel chemotherapy, modifies the toxicity profile of certain anticancer agents given concomitantly, by mechanisms other than kinetic interference. A clear understanding of the biological and pharmacological role of CrEL is essential to help oncologists avoid side-effects associated with the use of paclitaxel or other agents using this vehicle. With the present development of various new anticancer agents, it is recommended that alternative formulation approaches should be pursued to allow a better control of the toxicity of the treatment and the pharmacological interactions related to the use of CrEL.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

The rhesus model of Lyme neuroborreliosis.

Similarity of pathology and disease progression make the non-human primate (NHP) model of Lyme neuroborreliosis appropriate and valuable. In the NHP model of Lyme neuroborreliosis, spirochetal density in the nervous system and other tissues has been measured by polymerase chain reaction and correlated to anti-Borrelia burgdorferi antibody in the serum and cerebrospinal fluid and to inflammation in tissues. Despite the demonstrable presence of Borrelia burgdorferi, the causative agent of Lyme borreliosis, only minor inflammation of the central nervous system occurs, though inflammation can be demonstrated in other tissues. Infected animals also develop anti-Borrelia burgdorferi antibody in the serum, although increased amplitude of antibody is not predictive of higher levels of infection. The NHP model continues to provide important insight into the disease process in humans.

Animals↗

PubMed2000

No induction of apoptosis by IFN-beta in human antigen-specific T cells.

Interferon (IFN)-beta, the most effective immunomodulatory treatment for MS, inhibits the proliferation of myelin-specific T cells. We report that IFN-beta moderately enhances the expression of the death receptor, CD95, at the surface of human antigen-specific T cells. However, T-cell apoptosis was not induced by IFNbeta-1a or IFNbeta-1b as assessed by caspase activity or DNA fragmentation. Immunomodulation mediated by IFN-beta does not directly involve apoptotic pathways in human T cells.

Adjuvants, Immunologic↗

PubMed2000

Abundant defective viral particles budding from microglia in the course of retroviral spongiform encephalopathy.

A pathogenetic hallmark of retroviral neurodegeneration is the affinity of neurovirulent retroviruses for microglia cells, while degenerating neurons are excluded from retroviral infections. Microglia isolated ex vivo from rats peripherally infected with a neurovirulent retrovirus released abundant mature type C virions; however, infectivity associated with microglia was very low. In microglia, viral transcription was unaffected but envelope proteins were insufficiently cleaved into mature viral proteins and were not detected on the microglia cell surface. These microglia-specific defects in envelope protein translocation and processing not only may have prevented formation of infectious virus particles but also may have caused further cellular defects in microglia with the consequence of indirect neuronal damage. It is conceivable that similar events play a role in neuro-AIDS.

Animals↗

PubMed2000

Phase I pharmacologic study of oral topotecan and intravenous cisplatin: sequence-dependent hematologic side effects.

PURPOSE: In in vitro studies, synergism and sequence-dependent effects were reported for the combination of topotecan and cisplatin. Recently, an oral formulation of topotecan became available. This phase I study was performed to assess the feasibility of the combination of oral topotecan and cisplatin, the pharmacokinetic interaction, and sequence-dependent effects. PATIENTS AND METHODS: Topotecan was administered orally (PO) daily for 5 days in escalating doses and cisplatin was given intravenously (IV) at a fixed dose of 75 mg/m(2) either before topotecan administration on day 1 (sequence CT) or after topotecan administration on day 5 (sequence TC) once every 3 weeks. Patients were treated in a randomized cross-over design. RESULTS: Forty-nine patients were entered onto the study; one patient was not eligible. Sequence CT induced significantly more severe myelosuppression than did sequence TC, and the maximum-tolerated dosage of topotecan in sequence CT was 1.25 mg/m(2)/d x 5. In sequence TC, the maximum-tolerated dosage of topotecan was 2.0 mg/m(2)/d x 5. Dose-limiting toxicity consisted of myelosuppression and diarrhea. Pharmacokinetics of topotecan and cisplatin were linear over the dose range studied; no sequence-dependent effects were observed. In addition, topotecan did not influence the protein binding of cisplatin or the platinum-DNA adduct formation in peripheral leukocytes in either sequence. CONCLUSION: The recommended dosages for phase II studies involving patients like the patients in our study are topotecan 1.25 mg/m(2)/d PO x 5 preceded by cisplatin 75 mg/m(2) IV day 1 once every 3 weeks, and topotecan 2.0 mg/m(2)/d PO followed by cisplatin 75 mg/m(2) IV day 5. No pharmacokinetic interaction could be discerned in our study. The antitumor efficacy of both schedules should be evaluated in a randomized phase II study.

Adult↗

PubMed2000

Topotecan lacks third space sequestration.

The objective of this study was to determine the influence of pleural and ascitic fluid on the pharmacokinetics of the antitumor camptothecin derivative topotecan. Four patients with histological proof of malignant solid tumor received topotecan (0.45 or 1.5 mg/m2) p.o. on several occasions in both the presence and absence of third space volumes. Serial plasma and pleural or ascitic fluid samples were collected during each dosing and analyzed by high-performance liquid chromatography for both the intact lactone form of topotecan and its ring-opened carboxylate form. The apparent topotecan clearance demonstrated substantial interpatient variability but remained unchanged within the same patient in the presence [110 +/- 55.6 liters/ h/m2 (mean +/- SD of eight courses)] or absence of pleural and ascitic fluid [118 +/- 31.1 liters/h/m2 (mean +/- SD of seven courses)]. Similarly, terminal half-lives and area under the concentration-time curve ratios of lactone:total drug in plasma were similar between courses within each patient. Topotecan penetration into pleural and ascitic fluid demonstrated a mean lag time of 1.61 h (range, 1.37-1.86 h), and ratios with plasma concentration increased with time after dosing in all patients. The mean ratio of third space topotecan total drug area under the concentration-time curve to that in plasma was 0.55 (range, 0.26-0.87). These data indicate that topotecan can be safely administered to patients with pleural effusions or ascites and that there is substantial penetration of topotecan into these third spaces, which may prove beneficial for local antitumor effects.

Adult↗

PubMed2000

Inter- and intrapatient variability in oral topotecan pharmacokinetics: implications for body-surface area dosage regimens.

Anticancer drugs still are dosed based on the body-surface area (BSA) of the individual patient, although the BSA is not the main predictor of the clearance for the majority of drugs. The relevance of BSA-based dosing has not been evaluated for topotecan yet. A retrospective pharmacological analysis was performed of kinetic data from four clinical Phase I studies in which topotecan was administered p.o. as a single agent combined with data from a combination study of topotecan and cisplatin. A strong correlation (r = 0.91) was found between the area under the plasma concentration time curve of the lactone and carboxylate forms of topotecan by plotting 326 data sets obtained from 112 patients receiving oral topotecan at dose levels ranging from 0.15-2.70 mg/m2. The intrapatient variability, studied in 47 patients sampled for 3 or more days, for the apparent lactone clearance, ranged from 7.4-69% (mean, 24 +/- 13%; median, 20%). The interpatient variabilities in the lactone clearance, calculated with the data of all studied patients, expressed in liter/h/m2 and in liter/h were 38% and 42%, respectively. In view of the relatively high inter- and intrapatient variabilities in topotecan clearance, in contrast to a variability of only 12% in the BSA of the studied patients, no advantage of BSA-based dosing was found over fixed dose regimens.

Administration, Oral↗

PubMed1999

[Primary cerebral highly-malignant B-cell lymphoma of the Burkitt type].

HISTORY AND CLINICAL FINDINGS: A 40-year-old man was admitted with acute onset of positional vertigo, nausea and vomiting. Neurological examination revealed a fatigable nystagmus to the upward ear in positional testing, to the right more than to the left, as well as latent paresis and rigidity of the left arm. INVESTIGATIONS: Magnetic resonance imaging of the brain revealed two space-occupying lesions in the cerebellum and pons. Open biopsy showed a highly malignant B-cell lymphoma of Burkitt type. There was no evidence of acquired or congenital immunodeficiency. As there were no significant abnormalities outside of the CNS, a primary lymphoma in this location was diagnosed. TREATMENT AND COURSE: Chemotherapy with a combination of drugs including methotrexate achieved only partial remission. Subsequent radiotherapy brought about full remission, which has now lasted for over a year. CONCLUSIONS: Treatment of first choice of a primary cerebral lymphoma in an immunocompetent patient is chemotherapy with cerebrospinal fluid-permeable cytostatics. Partial remission should be followed by radiotherapy.

Adult↗

PubMed1999

Cremophor EL-mediated alteration of paclitaxel distribution in human blood: clinical pharmacokinetic implications.

We have determined the in vitro and in vivo cellular distribution of the antineoplastic agent paclitaxel (Taxol) in human blood and the influence of Cremophor EL (CrEL), the vehicle used for i.v. drug administration. In the absence of CrEL, the blood:plasma concentration ratio was 1.07+/-0.004 (mean+/-SD). The addition of CrEL at concentrations corresponding to peak plasma levels achieved after the administration of paclitaxel (175 mg/m2 i.v. over a 3-h period; ie., 0.50%) resulted in a significant decrease in the concentration ratio (0.690+/-0.005; P < 0.05). Kinetic experiments revealed that this effect was caused by reduced erythrocyte uptake of paclitaxel by polyoxyethyleneglycerol triricinoleate, the major compound present in CrEL. Using equilibrium dialysis, it was shown that the affinity of paclitaxel for tested matrices was (in decreasing order) CrEL > plasma > human serum albumin, with CrEL present at or above the critical micellar concentration (approximately 0.01%). Our findings in the present study demonstrate a profound alteration of paclitaxel accumulation in erythrocytes caused by a trapping of the compound in CrEL micelles, thereby reducing the free drug fraction available for cellular partitioning. It is proposed that the nonlinearity of paclitaxel plasma disposition in patients reported previously should be reevaluated prospectively by measuring the free drug fractions and whole blood:plasma concentration ratios.

Aged↗