Search PubMed⌕ Search

Biomedical subjects

P Sonneveld

Publications and source records attributed to P Sonneveld.

At least 19 recordsLinked to original sources
PubMed2006

Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials.

In multiple myeloma, deletion of chromosome 13 (del(13)) is associated with poor prognosis regardless of treatment. This study analyzed the impact of del(13) status on response and survival following treatment with either bortezomib or high-dose dexamethasone in patients in the SUMMIT and APEX trials. Additionally, matched-pairs subset analyses were conducted of patients with and without del(13), balanced for age and International Staging System parameters. In both SUMMIT and APEX, prognosis appeared to be poorer in bortezomib-treated patients with del(13) compared with patients with no del(13) by metaphase cytogenetics. In the SUMMIT and APEX matched-pairs analysis, response and survival appeared comparable in bortezomib-treated patients with or without del(13) by metaphase cytogenetics. However, patients with del(13) receiving dexamethasone in APEX appeared to have markedly decreased survival compared with those without del(13) by metaphase cytogenetics. These matched-pairs analyses suggest that bortezomib may overcome some of the poor impact of del(13) as an independent prognostic factor. However, sample sizes were very small; these findings require confirmation from further studies.

Aged↗
PubMed2006

The role of superoxide anions in the development of distant tumour recurrence.

We hypothesise that reactive oxygen species (ROS) released from activated polymorphonuclear leucocytes during surgery play a crucial role in enhanced tumour recurrence seen after surgery. Therefore, the effect of ROS on adhesion of tumour cells to microvascular endothelium in a reproducible human in vitro model was studied. Preincubation of microvascular endothelial cells with the superoxide anion producing xanthine-xanthine oxidase complex significantly increased adhesion of the human colon carcinoma cells HT29 (167% vs control, P < 0.01), Caco2 (164% vs control, P < 0.01) and of the pancreas carcinoma cells PanC1 (180% vs control, P < 0.01). Addition of the antioxidant enzymes superoxide dismutase or catalase significantly decreased tumour cell adhesion (P < 0.01). Exposure of endothelial cells to superoxide anions increased the apoptotic rate to 7.9 times the normal rate. Additionally, exposure increased expression of the endothelial adhesion molecules E-Selectin, ICAM-1, and VCAM-1 of maximally 170% vs control (P < 0.01). In conclusion, this study shows that superoxide anions promote the adherence of tumour cells to the microvasculature by inducing endothelial apoptosis that subsequently induces the expression of various adhesion molecules for tumour cells. This indicates that by tackling the production of ROS preventing tumour recurrence at distant sites might be feasible.

Adenocarcinoma↗
PubMed2006

International uniform response criteria for multiple myeloma.

New uniform response criteria are required to adequately assess clinical outcomes in myeloma. The European Group for Blood and Bone Marrow Transplant/International Bone Marrow Transplant Registry criteria have been expanded, clarified and updated to provide a new comprehensive evaluation system. Categories for stringent complete response and very good partial response are added. The serum free light-chain assay is included to allow evaluation of patients with oligo-secretory disease. Inconsistencies in prior criteria are clarified making confirmation of response and disease progression easier to perform. Emphasis is placed upon time to event and duration of response as critical end points. The requirements necessary to use overall survival duration as the ultimate end point are discussed. It is anticipated that the International Response Criteria for multiple myeloma will be widely used in future clinical trials of myeloma.

Humans↗
PubMed2006

Acute dystonic reaction to metoclopramide in patients carrying homozygous cytochrome P450 2D6 genetic polymorphisms.

BACKGROUND: Extrapyramidal syndromes (EPS) are clinically relevant side effects of metoclopramide which are often not anticipated. PATIENTS AND METHODS: Two patients who received metoclopramide developed an acute dystonic reaction. Symptoms disappeared after biperiden or trihexyphenidyl were given. Molecular analysis of the CYP2D6 gene was performed using a PCR-based method. RESULTS: Both patients were homozygous for inactive CYP2D6 alleles (CYP2D6*4/*4 and CYP2D6*4/*5), which are associated with slow drug metabolism. CONCLUSION: Metoclopramide-induced acute dystonic reactions may occur in patients carrying a CYP2D6 genetic polymorphism.

Acute Disease↗
PubMed2005

[Modern treatment methods for multiple myeloma: guidelines from the Dutch Haemato-Oncology Association (HOVON)].

The treatment for multiple myeloma has undergone many changes over the past decade. Intensive therapy with autologous stem-cell support has improved the clinical outcome significantly in younger patients. Reduced intensity conditioning regimens have lowered the high treatment-related mortality of myeloablative allogeneic transplantation. New effective anti-myeloma drugs such as bortezomib and thalidomide analogues have become available. These new developments have made it necessary to formulate recommendations to facilitate decisions concerning the management of myeloma patients. The Myeloma Working Party of the Dutch Haemato-Oncology Association (Stichting Haemato-Oncologie voor Volwassenen Nederland) has developed therapy guidelines based on phase-II and phase-III studies as well as the expertise of the working party. These include upfront induction therapy followed by autologous transplantation for patients aged up to 65 years and oral melphalanprednisone treatment for patients with severe co-morbidities and patients over the age of 65 years. Patients under the age of 66 with an HLA-identical (family) donor are candidates for non-myeloablative stem-cell transplantation following autologous stem-cell transplantation. For second-line treatment, thalidomide, combined with dexamethasone is recommended. Younger patients responding to second-line treatment are candidates for a second autologous transplant. Bortezomib is indicated for those patients refractory to the previous two lines of treatment. All patients should receive long-term bisphosphonates. Erythropoietin may be considered in symptomatic anaemia as well as antibiotic prophylaxis during induction therapy which includes dexamethasone.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

[Adolescents with acute lymphatic leukaemia achieve significantly better results when treated following Dutch paediatric oncology protocols than with adult protocols].

OBJECTIVE: To compare the results, in adolescents with acute lymphatic leukaemia (ALL), of treatment according to the protocols of the Netherlands Foundation for Paediatric Oncology (DCOG) or according to the protocols for adults of the Dutch Foundation for Adult Haemato-Oncology (HOVON). DESIGN: Retrospective. METHOD: During the period from May 1985 to November 1999, 120 15-20-year-old adolescents with ALL were treated: 47 according to a DCOG protocol and 73 according to a HOVON protocol. The records of the integrated cancer centres indicate that this represented about two-thirds of all known adolescents with ALL in the Netherlands. RESULTS: Adolescents with ALL treated according to the DCOG protocols had significantly better 5-year survival rates (79% versus 38%), a significantly lower probability of relapse (27% versus 55%) and a lower treatment-related mortality (4% versus 25%) than the adolescents treated according to the HOVON protocols. CONCLUSION: This difference in outcome was most likely related to differences in structure and content between the DCOG and HOVON protocols. The HOVON protocols consisted of relatively short, intensive chemotherapy, often followed by autologous or allogeneic bone-marrow transplantation. Several treatment elements present in the DCOG protocols, such as high-dose methotrexate, reinduction therapy and maintenance therapy were absent in the HOVON protocols. Moreover, the cumulative dosages of dexamethasone, mercaptopurine, asparaginase and vincristine were lower in the HOVON protocols.

Acute Disease↗
PubMed2005

Short intensive sequential therapy followed by autologous stem cell transplantation in adult Burkitt, Burkitt-like and lymphoblastic lymphoma.

The feasibility and efficacy of up-front high-dose sequential chemotherapy followed by autologous stem cell transplantation (ASCT) in previously untreated adults (median age 33 years; range 15-64) with Burkitt lymphoma (BL), Burkitt-like lymphoma (BLL) or lymphoblastic lymphoma (LyLy), both without central nervous system or extensive bone marrow involvement was investigated in a multicenter phase II study. Treatment consisted of two sequential high-dose chemotherapy induction courses incorporating prednisone, cyclophosphamide, doxorubicin, etoposide and mitoxantrone, without high-dose methotrexate or high-dose cytarabine. Patients with at least PR went on with BEAM and ASCT. Protocol treatment was completed by 23/27 (85%) BL/BLL and 13/15 (87%) LyLy patients. Median treatment duration until BEAM was 70 (range: 50-116) days. No toxic deaths occurred. Response to treatment was complete response (CR) 81% and partial response (PR) 11% for BL/BLL, CR 73% and PR 20% for LyLy. At a median follow-up of 61 months of patients still alive, six BL/BLL and eight LyLy patients have died. The actuarial 5-year overall and event-free survival estimates are 81 and 73% for BL/BLL vs 46 and 40% for LyLy patients. In conclusion, this short up-front high-dose sequential chemotherapy regimen, followed by ASCT is highly effective in adults with BL/BLL with limited bone marrow involvement, but less so in patients with LyLy.

Adolescent↗
PubMed2004

A phase I and pharmacologic study of the MDR converter GF120918 in combination with doxorubicin in patients with advanced solid tumors.

BACKGROUND: Resistance to chemotherapy can partly be explained by the activity of membrane bound P-glycoprotein. Competitive inhibition of P-glycoprotein, by multidrug resistance (MDR) converters, may overcome this MDR. Previously studied MDR converters either have serious intrinsic side effects or considerably influence the pharmacokinetics of cytotoxic agents at concentrations theoretically required to convert MDR. GF120918 is a third-generation MDR converter with high affinity for P-glycoprotein and can be given orally. We performed a phase 1 study with escalating doses of GF120918 in combination with doxorubicin. PATIENTS AND METHODS: The study group comprised 46 patients with advanced solid tumors. Doxorubicin was administered on day 1 (cycle 1), GF120918 on days 22-24 (cycle 2), and on days 29-33 with doxorubicin administered on day 31 (cycle 3). Pharmacokinetics of both GF120918 and doxorubicin were studied. The starting daily dose of GF120918 was 50 mg and was to be increased in subsequent cohorts until a steady state plasma level of 100 ng/ml was reached. The starting dose of doxorubicin was 50 mg/m2 and was to be increased after reaching the target dose level of GF120918. RESULTS: In 37 of the 46 patients, full pharmacokinetic data from the three scheduled cycles were obtained. Pharmacokinetics of GF120918 showed a less than linear increase in Cmax with increasing doses, with considerable interpatient variation. The target steady-state plasma level for GF120918 was exceeded in 12 out of 19 patients who received 400 mg GF120918 alone twice daily and in 12 of 17 patients who received 400 mg GF120918 twice daily in combination with doxorubicin. GF120918 pharmacokinetics were not influenced by coadministration of doxorubicin. The doxorubicin AUC was only marginally influenced by GF120918 and only at the highest dose levels. In these patients there was a significant increase in the AUC of doxorubicinol in cycle 3 as compared to cycle 1. Hematologic toxicity mainly consisted of neutropenia and was more severe in cycle 3 than in cycle 1 (13 vs 5 patients with grade 4 neutropenia, P=0.003). Neutropenic fever was the dose-limiting toxicity at a doxorubicin dose of 75 mg/m2 with 400 mg GF120918 twice daily. The toxicity of GF120918 was limited to somnolence in eight patients and occasional gastrointestinal complaints. CONCLUSION: GF120918 is an MDR converter with only minimal side effects at a dose level yielding concentrations able to convert the action of P-glycoprotein in vitro. A doxorubicin dose of 60 mg/m2 on day 3 in combination with 400 mg GF120918 twice daily on days 1-5 is an acceptable regimen for further clinical trials.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

A cost-utility analysis comparing intensive chemotherapy alone to intensive chemotherapy followed by myeloablative chemotherapy with autologous stem-cell rescue in newly diagnosed patients with stage II/III multiple myeloma; a prospective randomised phase III study.

A prospective randomised phase III study in patients < or =65 years old with previously untreated multiple myeloma (MM), intensive chemotherapy followed by myeloablative chemotherapy and autologous stem-cell rescue was compared with intensive chemotherapy alone. This economic evaluation was based on detailed data from patient charts and hospital information systems. In the intention-to-treat analysis, mean total treatment and follow-up costs of the myeloablative treatment arm were 81,643 euros compared to 68,802 euros for the chemotherapy arm (P=0.09). Costs per quality-adjusted life year were 51,357 euros versus 37,328 euros. In the clinical study, no significant differences were found in overall survival after a median follow-up of 33 months from randomisation. Intensive chemotherapy is regarded as standard therapy for younger patients with previously untreated MM. Cost-effectiveness of myeloma therapy after 3 years of follow up seems not to be favoured by myeloablative treatment with autologous stem-cell rescue.

Adult↗
PubMed2004

Identification of multidrug resistance-associated protein 1 and glutathione as multidrug resistance mechanisms in human prostate cancer cells: chemosensitization with leukotriene D4 antagonists and buthionine sulfoximine.

OBJECTIVE: To assess the involvement of the multidrug resistance-associated protein 1 (MRP1) and the glutathione pathway in the multidrug resistant (MDR) phenotype of prostate cancer in vitro. MATERIALS AND METHODS: Chemoselection of human prostate cancer cell lines PC3 and DU145 with etoposide resulted in the resistant cell lines PC3-R and DU-R. Resistance against etoposide, doxorubicin and vincristine, and its reversal with leukotriene D4 antagonists MK-571 and zafirlukast, and buthionine sulfoximine (BSO), was assessed using tetrazolium-dye viability assays. Western blot analysis of MRP1 expression and glutathione content were measured, and MRP1 function assessed in fluorescence assays. RESULTS: MRP1 was increased in the MDR models; the glutathione content was significantly higher in PC3-R but there was no increase in glutathione in DU-R. Adding non-toxic doses of MK-571, zafirlukast or BSO significantly increased the sensitivity of the MDR models to cytotoxic drugs. MRP1 function was inhibited with MK-571 in the MDR models. CONCLUSION: MRP1 and glutathione mediate MDR in newly developed prostate cancer models.

Blotting, Western↗
PubMed2003

CHOP compared with CHOP plus granulocyte colony-stimulating factor in elderly patients with aggressive non-Hodgkin's lymphoma.

PURPOSE: To investigate whether the relative dose-intensity of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy could be improved by prophylactic administration of granulocyte colony-stimulating factor (G-CSF) in elderly patients with aggressive non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Patients aged 65 to 90 years (median, 72 years) with stage II to IV aggressive NHL were randomly assigned to receive standard CHOP every 3 weeks or CHOP plus G-CSF every 3 weeks on days 2 to 11 of each cycle. RESULTS: In 389 eligible patients, the relative dose intensities (RDIs) of cyclophosphamide (median, 96.3% v 93.9%; P =.01) and doxorubicin (median, 95.4% v 93.3%; P =.04) were higher in patients treated with CHOP plus G-CSF. The complete response rates were 55% and 52% for CHOP and CHOP plus G-CSF, respectively (P =.63). The actuarial overall survival at 5 years was 22% with CHOP alone, compared with 24% with CHOP plus G-CSF (P =.76), with a median follow-up of 33 months. Patients treated with CHOP plus G-CSF had an identical incidence of infections, with World Health Organization grade 3 to 4 (34 of 1,191 cycles v 36 of 1,195 cycles). Only the cumulative days with antibiotics were fewer with CHOP plus G-CSF (median, 0 v 6 days; P =.006) than with CHOP alone. The number of hospital admissions and the number of days in hospital were not different. CONCLUSION: In elderly patients, G-CSF improved the RDI of CHOP, but this did not lead to a higher complete response rate or better overall survival. G-CSF did not prevent serious infections.

Aged↗
PubMed2003

The vault complex.

Vaults are large ribonucleoprotein particles found in eukaryotic cells. They are composed of multiple copies of a Mr 100,000 major vault protein and two minor vault proteins of Mr 193,000 and 240,000, as well as small untranslated RNAs of 86-141 bases. The vault components are arranged into a highly characteristic hollow barrel-like structure of 35 x 65 nm in size. Vaults are predominantly localized in the cytoplasm where they may associate with cytoskeletal elements. A small fraction of vaults are found to be associated with the nucleus. As of yet, the precise cellular function of the vault complex is unknown. However, their distinct morphology and intracellular distribution suggest a role in intracellular transport processes. Here we review the current knowledge on the vault complex, its structure, components and possible functions.

Animals↗