Gertjan J L Kaspers

VU University Medical Center, Amsterdamo, North Holland, Netherlands

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Publications (343)1895.74 Total impact

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    ABSTRACT: Methotrexate (MTX) eradicates leukemic cells by disrupting de novo nucleotide biosynthesis and DNA replication, resulting in cell death. Since its introduction in 1947, MTX-containing chemotherapeutic regimens have proven instrumental in achieving curative effects in acute lymphoblastic leukemia (ALL). However, drug resistance phenomena pose major obstacles to efficacious ALL chemotherapy. Moreover, clinically relevant molecular mechanisms underlying chemoresistance remain largely obscure. Several alterations in MTX metabolism, leading to impaired accumulation of this cytotoxic agent in tumor cells, have been classified as determinants of MTX resistance. However, the relation between MTX resistance and long-term clinical outcome of ALL has not been shown previously. We have collected clinical data for 235 childhood ALL patients, for whom samples taken at the time of diagnosis were also broadly characterized with respect to MTX resistance. This included measurement of concentrations of MTX polyglutamates in leukemic cells, mRNA expression of enzymes involved in MTX metabolism (FPGS, FPGH, RFC, DHFR, and TS), MTX sensitivity as determined by the TS inhibition assay, and FPGS activity. Herein we demonstrate that higher accumulation of long-chain polyglutamates of MTX is strongly associated with better overall (10-year OS: 90.6 vs 64.1 %, P = 0.008) and event-free survival (10-year EFS: 81.2 vs 57.6 %, P = 0.029) of ALL patients. In addition, we assessed both the association of several MTX resistance-related parameters determined in vitro with treatment outcome as well as clinical characteristics of pediatric ALL patients treated with MTX-containing combination chemotherapy. High MTX sensitivity was associated with DNA hyperdiploid ALL (P < 0.001), which was linked with increased MTX accumulation (P = 0.03) and elevated reduced folate carrier (RFC) expression (P = 0.049) in this subset of ALL patients. TEL-AML1 fusion was associated with increased MTX resistance (P = 0.023). Moreover, a low accumulation of MTX polyglutamates was observed in MLL-rearranged and TEL-AML1 rearranged ALL (P < 0.05). These findings emphasize the central role of MTX in ALL treatment thereby expanding our understanding of the molecular basis of clinical differences in treatment response between ALL individuals. In particular, the identification of patients that are potentially resistant to MTX at diagnosis may allow for tailoring novel treatment strategies to individual leukemia patients.
    Journal of Hematology & Oncology 05/2015; 8(1):61. DOI:10.1186/s13045-015-0158-9 · 4.93 Impact Factor
  • Molecular Cancer Research 05/2015; DOI:10.1158/1541-7786.MCR-14-0660-T · 4.50 Impact Factor
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    ABSTRACT: Placement of a totally implantable venous access device in children with cancer often leads to hypertrophic scars after its removal. This study investigates whether the use of silicone gel sheets has a beneficial effect on scar outcome in children with cancer. In a three-arm randomized controlled trial, the effects of use of silicone gel sheets for 2 and 6 months were assessed and compared with no intervention in children with cancer after removal of the totally implantable venous access device. Silicone gel sheets were first administered 14 days after surgery. The 1-year follow-up included measurements at seven time points. Next to scar size assessment, the modified Vancouver Scar Scale was used to assess scar outcome. Thirty-six children participated. For hypertrophy, no significant differences were found between the two intervention groups and the control group. However, at 1-year follow-up, the 2-month application group showed significantly smaller scars compared with the group receiving silicone gel sheet treatment for 6 months (p = 0.04), but not when compared with the control group (p = 0.22). Longitudinal multilevel analyses could not confirm these findings and showed no significant intervention effects on both outcomes. This study provides no strong evidence to support the use of silicone gel sheets after totally implantable venous access device removal in children with cancer. There seems to be a small benefit for scar width with application for 2 months. However, for hypertrophy, the scar outcome shows no significant difference between the control group and the 2-month and 6-month treatment groups. Therapeutic, I.
    Plastic and Reconstructive Surgery 04/2015; 135(4):1086-1094. DOI:10.1097/PRS.0000000000001053 · 3.33 Impact Factor
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    ABSTRACT: The purpose of this study is to explore the applicability of a psychosocial intervention in childhood cancer patients. This individualized structured psychosocial program to enhance social-emotional functioning and coping with disease-related effects includes six sessions for children and two sessions for parents. This program was part of a combined intervention with physical exercise. Questionnaires are used to evaluate completion of the psychosocial intervention, coping and satisfaction with the psychosocial intervention by patients and psychologists, and ranking of the individual topics by patients, parents, and psychologists. Of the 30 patients (mean age 13.0 (SD 3.0); 53.3 % male; 30 % still on treatment) who participated in the psychosocial intervention, two dropped out due to medical complications and one due to lack of time; 90 % completed the psychosocial intervention. Overall, patients liked participation in the intervention (4.2 on a 5-point scale; SD 0.8) and were positive about the psychologists (8.1 on a 10-point scale; SD 1.3). Psychologists rated the intervention on several points (e.g., clarity of the manual and content of the intervention), and mean scores ranged from 7.1 (SD 1.1) to 8.6 (SD 0.9) on 10-point scales. Minor adaptations were suggested by patients and psychologists, including customizing according to age and a more patient-tailored approach. This psychosocial intervention for childhood cancer patients appears to be applicable. Future studies need to establish whether this intervention combined with a physical exercise intervention actually improves psychosocial functioning of childhood cancer patients. When proven effective, this combined intervention can be offered to childhood cancer patients and may enhance their physical health and quality of life.
    Supportive Care Cancer 01/2015; DOI:10.1007/s00520-014-2576-6 · 2.50 Impact Factor
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    ABSTRACT: Over the past decade, the proteasome inhibitor bortezomib (Velcade) has not only gained a cornerstone position in the treatment of hematological malignancies, particularly multiple myeloma and mantle cell lymphoma, but also in experimental therapeutics of acute leukemia. However, the therapeutic efficacy of bortezomib is hampered by the emergence of acquired resistance, for which multifactorial mechanisms have been identified. This review summarizes the current status of the molecular mechanisms underlying resistance to proteasome inhibitors that emerged in preclinical therapeutic studies, and discusses these findings in the clinical perspective of novel therapeutic modalities of hematological malignancies. The specific topics that will be addressed in the current review include the recently established mechanisms of resistance to proteasome inhibitors: the role of constitutive and immunoproteasomes, mutations in proteasome subunits, unfolded protein response, XBP1 and MARCKS proteins, multidrug efflux transporters, aggresomes and autophagy, as well as the impact of pro-survival signaling pathways and bone marrow microenvironment. The growing knowledge of the determinants that confer bortezomib resistance and/or toxicity has provided the basis for the rational development of second generation proteasome inhibitors, some of which were recently approved or that are undergoing clinical evaluation as novel strategies to overcome bortezomib resistance as well as to enhance clinical therapeutic efficacy along with minimal side effects. Collectively, these combined approaches should enhance therapeutic efficacy and outcome in patients with hematological malignancies.
    Drug Resistance Updates 12/2014; 18. DOI:10.1016/j.drup.2014.12.001 · 8.82 Impact Factor
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    ABSTRACT: Background Wilms tumour postoperative chemotherapy is ideally stratified according to the pathologist's assessment of tumour stage and risk classification (tumour type). In sub-Saharan Africa results are often not available in time to influence therapy and in Malawi surgical staging has been used to stratify postoperative chemotherapy. Here we compare the results from surgical and both local pathology and central pathology review.ProcedureChildren diagnosed with a Wilms tumour in Blantyre, Malawi between 2007 and 2011 were included if they had a nephrectomy and the pathology slides were available. All tumour specimens were assessed in three different ways: the local surgeon documented the surgical stage of the tumour, and the risk classification and pathology stage were assessed both by the local pathologist and by a SIOP central review pathologist in Europe.ResultsFifty patients had complete data available and were included in the analyses. Tumour risk classification differed between the local and central pathology review in only two patients (4%). Using central pathology review as the gold standard 60% of patients received the correct postoperative chemotherapy treatment based on surgical staging and 84% based on the local pathology stage and risk classification.Conclusion Local pathology capacity building is needed to enable timely assessment and reporting. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 12/2014; 61:2180-2184. DOI:10.1002/pbc.25138 · 2.56 Impact Factor
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    ABSTRACT: Children with and after cancer are found to have a decreased physical fitness, frequently resulting in decreased physical functioning. The gold standard test for assessing aerobic fitness, a component of physical fitness, is the respiratory gas analyses--based cardiopulmonary exercise test (CPET). However, equipment for gas analysis is often unavailable in local physical therapy centres and non--university hospitals. The Steep Ramp Test (SRT), is a cycle ergometer test with a fast increase in workload, a short duration, and does not require respiratory gas analysis equipment. The aim of this study was to compare the results of the CPET and the SRT, in children with cancer, and to assess whether the SRT can be used for aerobic fitness assessment in clinical practice in this population. This study is a cross--sectional assessment using baseline data of a randomized controlled trial. The study was performed in a hospital setting. Sixty--one children (mean age 12.9 years; 33 boys) with cancer were included in the analysis; 16 children were on non--intensive chemotherapy treatment, 45 were in the first year thereafter. Participants performed both the SRT and the CPET on a cycle ergometer with respiratory gas analysis. Data of the two tests were compared and regression analyses were performed. CPET test results revealed a higher impact on the cardiovascular system, as shown by higher peak ventilation (47.8 versus 52.0 Litres per min) and peak heart rates (173 versus 191 beats per min), compared to the SRT. In addition, the test time was significantly longer (90 s versus 390 s). Yet, the primary outcome of the SRT (peak work rate) was able to reliably estimate the peak oxygen uptake of the CPET. The peak oxygen uptake was comparable between the SRT and the CPET, although the peak work rate was significantly higher during the SRT. This study showed that the SRT is a valid instrument to assess aerobic fitness in children with cancer. The SRT is less time consuming and can be performed without gas analysis in a non--clinical setting, making it less demanding for children.
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    ABSTRACT: Background: According to the results of the international study Relapsed AML 2001/01 response was better after re-induction with L-DNR/FLAG (liposomal daunorubicin, fludarabine, cytarabine, G-CSF) compared to FLAG only but survival rate was not improved. However, the findings might be group-specific. Method: Patient characteristics, actual therapy given and long-term course of the disease in 155 pediatric patients (including non-randomized) with first relapse and 10 primary nonresponders treated in Germany were analyzed. Results: Overall 4-year survival rates after relapse were similar in the 2 treatment groups L-DNR/FLAG and FLAG (0.43±0.05 vs. 0.47±0.06, p(log-rank)=0.47). The rate of randomization was low (65%) and 5% of the 101 randomized patients changed the treatment arm. Therefore, induction was based in 40% patients on an individual decision with preference for L-DNR/FLAG. There were less patients with favorable cytogenetics and morphology in the L-DNR/FLAG-group (p<0.04). Response to the first re-induction course at day 28 tended to be more unfavorable with FLAG only. In this patient group protocol intensifications were more frequent as compared to the L-DNR/FLAG-group (p=0.07), and late CR could be achieved after intensification in 9/18 poor responding patients. Conclusion: The initial selection bias of relapse patients with unfavorable risk factors to the disadvantage of the L-DNR/FLAG-group and the more drug- and time-intensive treatment after 1(st) re-induction given in the FLAG-group may have nullified the initial beneficial effect of L-DNR containing re-induction therapy and led to similar and relatively favorable survival rates in both treatment groups in Germany. © Georg Thieme Verlag KG Stuttgart · New York.
    Klinische Pädiatrie 11/2014; 226(6/07):323-331. DOI:10.1055/s-0034-1385918 · 1.90 Impact Factor
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    ABSTRACT: Our study explores socioeconomic, treatment-related, and psychological experiences of parents during cancer treatment of their children at an academic hospital in Kenya.
  • Cancer Research 10/2014; 74(19 Supplement):4764-4764. DOI:10.1158/1538-7445.AM2014-4764 · 9.28 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):3775-3775. DOI:10.1158/1538-7445.AM2014-3775 · 9.28 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):LB-169-LB-169. DOI:10.1158/1538-7445.AM2014-LB-169 · 9.28 Impact Factor
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    ABSTRACT: Systemic delivery of therapeutic agents remains ineffective against diffuse intrinsic pontine glioma (DIPG), possibly due to an intact blood-brain-barrier (BBB) and to dose-limiting toxicity of systemic chemotherapeutic agents. Convection-enhanced delivery (CED) into the brainstem may provide an effective local delivery alternative for DIPG patients.
    Journal of Neuroscience Methods 09/2014; 238. DOI:10.1016/j.jneumeth.2014.09.020 · 1.96 Impact Factor
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    ABSTRACT: Adrenocortical carcinoma (ACC) is rare in both adult and pediatric populations. Literature suggests significant differences between children and adults in presentation, histological properties and outcome. The aim of this first nationwide study on pediatric ACC was to describe the incidence, presentation, pathological characteristics, treatment and survival in The Netherlands. All ACC patients aged <20 years at diagnosis and registered in the population-based Netherlands Cancer Registry between 1993 and 2010 were included. Clinical data were extracted from medical records. Archival histological slides were collected via the Dutch Pathology Registry (PALGA). We compared our findings to all clinical studies on pediatric ACC that were found on PubMed. Based on the results, 12 patients were identified: 8 females and 4 males. The median age was 4.1 years (range 1.1-18.6). The population-based age-standardized incidence rate for patients <20 years was 0.18 per million person-years. Autonomous hormonal secretion was present in 10 patients. Seven patients were aged ≤4 years at diagnosis, 5 presented with localized disease and 2 with locally advanced disease. Five patients were aged ≥5 years, 3 presented with distant metastases and 1 with locally advanced disease. For all patients, histological examination displayed malignant characteristics. All patients aged ≤4 years at diagnosis survived; the median follow-up was 97 months (57-179 months). All patients aged ≥5 years died; the median survival was 6 months (0-38 months). Pediatric ACC is extremely rare in the Western world. The clinical outcome was remarkably better in patients aged ≤4 years. This is in accordance with less advanced stage of disease at presentation, yet contrasts with the presence of adverse histological characteristics. Clinical management in advanced disease is adapted from adult practice in the absence of evidence regarding pediatric ACC.
    Oncology Reports 09/2014; DOI:10.3892/or.2014.3506 · 2.19 Impact Factor
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    ABSTRACT: Several studies in adults have shown patient reported outcomes (PROs) to be effective in enhancing patient-physician communication and discussion of Health Related Quality of Life outcomes. Although less studied, positive results have been demonstrated in children. A PRO-intervention needs to be feasible in clinical practice to be successful. In the current study, 74 parents of children who successfully completed their cancer treatment and 21 pediatric oncologists (POs) evaluated a PRO-intervention and gave recommendations for future use in their practice. Most parents and POs suggested PROs to be an important part of standard care, starting during treatment, with an assessment frequency of every 3 months. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 09/2014; 61(9). DOI:10.1002/pbc.25034 · 2.56 Impact Factor
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    ABSTRACT: Improvement in survival of pediatric acute lymphoblastic leukemia (ALL) has increased the attention to quality of life (QoL) . QoL is impaired during maintenance treatment, but little is known about QoL during induction therapy. Identification of patients with poor QoL during induction will provide opportunities for early interventions, and may subsequently improve future QoL. This national multi-center study aimed to assess QoL and its determinants during ALL induction treatment. Proxy reports of the Child Health Questionnaire (CHQ) and the PedsQL cancer version were collected. Child, treatment, and parental characteristics were analyzed as potential determinants in a multiple regression model. One hundred thirty parents of children participated (response rate 82 %), median child age was 5.7 years and 48 % were female. QoL, as measured with the CHQ, was significantly lower than the norm, the effect sizes were large, and the differences were clinically relevant. Physical QoL was more often affected than psychosocial QoL. Regression models could be constructed for 4/ 10 CHQ scales and 6/ 8 PedsQL cancer scales, accounting for 7 to 36 % of the variance in scores. Impaired QoL was most often associated with older children, girls, and time since diagnosis. Also, father respondents seem to have a lower QoL perception compared to mother respondents although this needs to be confirmed in future research. Specific counseling for subsets of patients with a higher risk of low QoL during the early phases of therapy is warranted.
    Supportive Care Cancer 07/2014; 22(12). DOI:10.1007/s00520-014-2349-2 · 2.50 Impact Factor
  • Pediatric Hematology and Oncology 07/2014; DOI:10.3109/08880018.2014.924611 · 0.96 Impact Factor
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    ABSTRACT: Outcome for relapsed paediatric acute myeloid leukaemia (AML) remains poor. Strong prognostic factors at first relapse are lacking, which hampers optimization of therapy. We assessed the frequency of molecular aberrations (FLT3, NRAS, KRAS, KIT, WT1 and NPM1 genes) at first relapse in a large set (n = 198) of relapsed non-French-American-British M3, non-Down syndrome AML patients that received similar relapse treatment. We correlated molecular aberrations with clinical and biological factors and studied their prognostic relevance. Hotspot mutations in the analysed genes were detected in 92 out of 198 patients (46·5%). In 72 of these 92 patients (78%), molecular aberrations were mutually exclusive for the currently analysed genes. FLT3-internal tandem repeat (ITD) (18% of total group) mutations were most frequent, followed by NRAS (10·2%), KRAS (8%), WT1 (8%), KIT (8%), NPM1 (5%) and FLT3-tyrosine kinase domain (3%) mutations. Presence of a WT1 aberration was an independent risk factor for second relapse (Hazard Ratio [HR] = 2·74, P = 0·013). In patients who achieved second complete remission (70·2%), WT1 and FLT3-ITD aberrations were independent risk factors for poor overall survival (HR = 2·32, P = 0·038 and HR = 1·89, P = 0·045 respectively). These data show that molecular aberrations at first relapse are of prognostic relevance and potentially useful for risk group stratification of paediatric relapsed AML and for identification of patients eligible for personalized treatment.
    British Journal of Haematology 06/2014; 166(6). DOI:10.1111/bjh.12989 · 4.96 Impact Factor
  • Acta Neuropathologica 06/2014; 128(4). DOI:10.1007/s00401-014-1307-x · 9.78 Impact Factor
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    ABSTRACT: Drug resistance is a major issue in the treatment of glioblastoma. Almost all glioblastomas are intrinsically resistant to chemotherapeutic temozolomide (TMZ) or develop resistance during treatment. The interaction networks of microRNAs (miRNAs) and mRNAs likely regulate most biological processes and can be employed to better understand complex processes including drug resistance in cancer. In this study, we examined if integrative miRNA/mRNA network analysis using the web-service tool mirConnX could be used to identify drug resistance factors in glioblastoma. We used TMZ-resistant glioblastoma cells and their integrated miRNA/mRNA networks to identify TMZ-sensitizing factors. TMZ resistance was previously induced in glioblastoma cell lines U87, Hs683, and LNZ308. miRNA/mRNA expression profiling of these cells and integration of the profiles using mirConnX resulted in the identification of plant homeodomain (PHD)-like finger 6 (PHF6) as a potential TMZ-sensitizing factor in resistant glioblastoma cells. Analysis of PHF6 expression showed significant upregulation in glioblastoma as compared to normal tissue. Interference with PHF6 expression in three TMZ-resistant subclones significantly enhanced TMZ-induced cell kill in two of these cell lines. Altogether, these results demonstrate that mirConnX is a feasible and useful tool to investigate miRNA/mRNA interactions in TMZ-resistant cells and has potential to identify drug resistance factors in glioblastoma.
    Scientific Reports 06/2014; 4:5260. DOI:10.1038/srep05260 · 5.58 Impact Factor

Publication Stats

6k Citations
1,895.74 Total Impact Points

Institutions

  • 2002–2015
    • VU University Medical Center
      • • Department of Clinical Genetics
      • • Department of Pediatrics
      • • Department of Haematology
      Amsterdamo, North Holland, Netherlands
  • 1994–2014
    • VU University Amsterdam
      • • Department of Pediatric Hematology/Oncology
      • • Department of Medical Oncology
      Amsterdamo, North Holland, Netherlands
    • Post University
      Post, Texas, United States
  • 2013
    • University Medical Center Utrecht
      Utrecht, Utrecht, Netherlands
    • University of New South Wales
      Kensington, New South Wales, Australia
    • National Heart, Lung, and Blood Institute
      • Hematology Branch
      Maryland, United States
  • 2006–2013
    • Dutch Childhood Oncology Group
      Rotterdam, South Holland, Netherlands
  • 2011
    • Leiden University Medical Centre
      • Department of Pediatrics
      Leiden, South Holland, Netherlands
  • 2010
    • Erasmus MC
      Rotterdam, South Holland, Netherlands
  • 2009
    • University of Groningen
      Groningen, Groningen, Netherlands
    • St. Jude Medical
      Little Canada, Minnesota, United States
    • Aarhus University Hospital
      • Department of Pediatrics
      Aarhus, Central Jutland, Denmark
  • 2008–2009
    • Charles University in Prague
      • Department of Paediatric Haematology and Oncology (2. LF)
      Praha, Praha, Czech Republic
    • Università degli Studi di Milano-Bicocca
      Milano, Lombardy, Italy
  • 2004
    • University of Münster
      Muenster, North Rhine-Westphalia, Germany
  • 2003
    • Universität Ulm
      Ulm, Baden-Württemberg, Germany
    • Kent Hospital
      Warwick, Rhode Island, United States
  • 1999–2002
    • University of Hamburg
      Hamburg, Hamburg, Germany
  • 2001
    • IT University of Copenhagen
      København, Capital Region, Denmark
  • 1993–2000
    • University of Amsterdam
      • Department of Paediatrics
      Amsterdamo, North Holland, Netherlands
  • 1995
    • Erasmus Universiteit Rotterdam
      Rotterdam, South Holland, Netherlands