[Show abstract][Hide abstract] ABSTRACT: Background: Retinoblastoma is a pediatric eye cancer associated with RB1 loss or MYCN amplification (RB1+/+MYCNA). There are controversies concerning the existence of molecular subtypes within RB1−/− retinoblastoma. To test whether these molecular subtypes exist, we performed molecular profiling.
Methods: Genome-wide mRNA expression profiling was performed on 76 primary human retinoblastomas. Expression profiling was complemented by genome-wide DNA profiling and clinical, histopathological, and ex vivo drug sensitivity data.
Findings: RNA and DNA profiling identified major variability between retinoblastomas. While gene expression differences between RB1+/+MYCNA and RB1−/− tumors seemed more dichotomous, differences within the RB1−/− tumors were gradual. Tumors with high expression of a photoreceptor gene signature were highly differentiated, smaller in volume and diagnosed at younger age compared with tumors with low photoreceptor signature expression. Tumors with lower photoreceptor expression showed increased expression of genes involved in M-phase and mRNA and ribosome synthesis and increased frequencies of somatic copy number alterations.
Interpretation: Molecular, clinical and histopathological differences between RB1−/− tumors are best explained by tumor progression, reflected by a gradual loss of differentiation and photoreceptor expression signature. Since copy number alterations were more frequent in tumors with less photoreceptorness, genomic alterations might be drivers of tumor progression.
Research in context: Retinoblastoma is an ocular childhood cancer commonly caused by mutations in the RB1 gene. In order to determine optimal treatment, tumor subtyping is considered critically important. However, except for very rare retinoblastomas without an RB1 mutation, there are controversies as to whether subtypes of retinoblastoma do exist. Our study shows that retinoblastomas are highly diverse but rather than reflecting distinct tumor types with a different etiology, our data suggests that this diversity is a result of tumor progression driven by cumulative genetic alterations. Therefore, retinoblastomas should not be categorized in distinct subtypes, but be described according to their stage of progression.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
Plastic and Reconstructive Surgery 04/2015; 135(4):1086-1094. DOI:10.1097/PRS.0000000000001053 · 3.33 Impact Factor
[Show abstract][Hide abstract] 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
[Show abstract][Hide abstract] 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
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: Objectives: Relapsed/refractory pediatric AML has a poor prognosis despite salvage therapy including stem-cell transplantation. Chemotherapy using FLAG plus liposomal daunorubicine (FLAG-DNX) is currently considered the standard in 1strelapse in Europe. FLAG is based on potentiation of cytarabine (Ara-C) by fludarabine (Flu) by increasing Ara-CTP levels. Clofarabine (CLO) is a novel purine nucleoside analog, designed to have improved efficacy. Methods: We initiated an ongoing phase 1B dose-escalation study using a '3 × 3 design' to define the optimal dose of CLO, replacing FLU in FLAG-DNX. Dosages consisted of Ara-C 2gr/m2/day (day 1-5), with escalation of DNX from 40, 60 to 80 mg/m2/day (day 1, 3 and 5), and CLO from 20, 30 to 40 mg/m2/day (day 1-5) in 5 dose-levels, without GCSF priming. At day 6 intrathecal Ara-C was administered. Serum and CSF were collected for pharmacokinetics (PK). CLO plasma and CSF concentrations were analyzed using LC-MS/MS. Results: We report safety and PK data on all dose levels after accrual of 33 AML patients. Patients were treated at 5 dose-levels (DL). Updated results and DLTs will be presented at the meeting. PK samples were available from 19 patients. At day 1 the median AUC was 28 ng/ml.mg.hr (range 6-401), with a mean T1/2 of 1.5 hrs. Day 1 and day 5 results were similar. CSF levels were not measurable in most patients and were 0.1-0.2 ng/ml.mg in the 3 patients with detectable levels. Conclusions: The RP2D of CLO in a CLARA/DNX course in relapsed/refractory pediatric AML is 40 mg/m2, excluding patients with evidence of prior subclinical aspergillus. There is no evidence for PK interaction between CLO and the other drugs. We are currently testing the safety of an augmented dose of DNX (80 mg/m2) in 1strelapse AML patients (n = 4). Reponses are centrally reviewed and will be disclosed at the meeting.
[Show abstract][Hide abstract] ABSTRACT: Our study explores socioeconomic, treatment-related, and psychological experiences of parents during cancer treatment of their children at an academic hospital in Kenya.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.