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Since 1990 two departments of Pediatric Oncology in Indonesia and the Netherlands have worked together to improve staff capacities in the Estella Clinic in Yogyakarta and Indonesian clinics general, through workshops for pediatricians, nurses, technicians, psycho-social workers. Teleconferences were conducted weekly. Protocols for leukemia were developed. Joint research projects led to research experience for about 50 Dutch medical students, about 60 international publications and 8 PhD theses. The patients with acute Lymphoblastic Leukemia benefitted and showed increasing survival rates. Possible improvements in the future are also discussed. Keywords: Pediatric oncology, International cooperation, Leukemia

Background: Improving the quality of care in resource limited settings through an outreach program is challenging. Teleconferencing is increasingly being used and considered a breakthrough in medical education. We evaluated adherence with childhood oncology-hematology teleconferences between two academic hospitals in Indonesia and Netherlands. Methods: Teleconferences held during 12 months between an Indonesian and a Dutch academic hospital were evaluated using a standardized form. Both adherence with diagnostic and treatment advices for individual patients were explored in medical records. Results: During 38 teleconferences, difficult cases of 53 children were discussed by Dutch pediatric oncologists and Indonesian residents. Dutch oncologists advised diagnostic adjustments in 41 cases (77%). Most common diagnostic advices were: laboratory tests (68%), imaging (54%), physical examination (41%). Diagnostic advices were not adhered to in 12 children (30%). Common reasons for non-adherence were: not applicable in middle-income setting (25%), disagreement with Dutch advice (17%), CT scan is out of order (17%), patient died (17%). Dutch oncologists advised treatment adjustments in 40 cases (75%). Most common treatment advices were: change of protocol (38%), nutritional support (30%), prevention of tumor lysis syndrome (20%). Treatment advices were not adhered to in 9 children (22%). Common reasons for non-adherence were: poor condition of child (44%), not applicable in middle-income setting (22%), patient died (22%), disagreement with Dutch advice (11%). Twenty-four children (45%) died after teleconference was held. Twenty-nine children (55%) were alive. These children abandoned (38%), completed (31%) or were still under treatment (31%). Conclusion: Through teleconferencing, knowledge between high and low or middle-income countries can be shared to improve patient care. Locally applicable advices are required. Active participation by pediatric oncologists at both partner sites is recommended. Keywords: Outreach program, Childhood oncology-hematology, Teleconference, Adherence

Background: Randomized trials report that, compared to prednisone, dexamethasone has reduced CNS relapse and improved event-free survival (EFS), despite a trend toward a higher risk for induction death. Because toxic death is a specific problem in the Indonesian setting, this study compares the outcome of dexamethasone versus prednisone. Methods: In the period 2006 - 2011, 196 patients with childhood acute lymphoblastic leukemia (ALL) treated on the Indonesia-ALL-2006 protocol [first standard risk (SR) and later high risk (HR) patients] were randomized to receive dexamethasone or prednisone as steroid. Patients in the dexamethasone arm (n = 102: 68 SR, 34 HR) received dexamethasone 4 mg/m2/day (SR) or 6 mg/m2/day (HR), while the prednisone arm (n = 94: 66 SR, 28 HR) received prednisone 40 mg/m2/day (SR and HR). Results: Patients in the dexamethasone arm showed no significant difference compared to the prednisone arm in abandonment rate (24.5% vs. 25.5%, P = 0.91), death rate (17.7% vs. 14.9%, P = 0.54), or leukemic events (13.7 vs. 11.7%, P = 0.59). After stratification for risk group, a trend towards a higher death rate was found in the dexamethasone arm of SR patients (16.2 vs. 6.1%, P = 0.06). The 3-year survival for EFS in SR and HR patients for dexamethasone versus prednisone was 31.5% ± 6.6% vs. 41.5% ± 5.9% (P = 0.51), for leukemia-free survival (LFS) it was 63.7% ± 9.3% vs. 74.5% ± 7.6% (P = 0.47), and for overall survival (OS) it was 49.5% ± 7.7% vs. 69.3% ± 6.1% (P = 0.09). Conclusions: In our setting, a trend toward higher induction deaths was observed in the dexamethasone arm of SR patients and the 3-year EFS; LFS and OS rates were lower in the dexamethasone group; however, these differences were not significant.

Background Use of complementary and alternative medicine (CAM) is common among patients with childhood cancer. Health-care providers (HCP) should address this need properly. Geographical and cultural differences seem likely. This study explores perspectives on CAM of HCP involved in the care of children with cancer in Netherlands and Indonesia. Health beliefs, components of CAM, encouraging or discouraging CAM, and knowledge about CAM were assessed. Procedure We conducted a cross-sectional study using semi-structured questionnaires at a Dutch and Indonesian academic hospital. Results A total of 342 HCP participated: 119 Dutch (response rate 80%) and 223 Indonesian (response rate 87%). Chemotherapy can cure cancer according to more Dutch than Indonesian HCP (87% vs. 53% respectively, P

Item does not contain fulltext PURPOSE: To elucidate incidence and risk factors of bone mineral density and fracture risk in children with Acute Lymphoblastic Leukemia (ALL). METHODS: Prospectively, cumulative fracture incidence, calculated from diagnosis until one year after cessation of treatment, was assessed in 672 patients. This fracture incidence was compared between subgroups of treatment stratification and age subgroups (Log-Rank test). Serial measurements of bone mineral density of the lumbar spine (BMDLS) were performed in 399 ALL patients using dual energy X-ray absorptiometry. We evaluated risk factors for a low BMD (multivariate regression analysis). Osteoporosis was defined as a BMDLS

Background. Event-free survival of pediatric patients with acute lymphoblastic leukemia (ALL) in Yogyakarta, Indonesia was low (20%). The aim of the study was to evaluate the effectiveness of using amedicationdiary-bookonthetreatmentoutcomeofchildhoodALL. Procedure. A randomized study was conducted with 109 pediatric patients with ALL in a pediatric oncology center in Yogyakarta, Indonesia.Both interventionandcontrolgroupsreceiveda structured parental education program and donated chemotherapy. The intervention group received a medication diary-book to remind parents and families to take oral chemotherapy and present for scheduled appointments or admissions. Event-free survival estimate (EFS) at 3 years was assessed. Results. Among pediatric patients with ALL with highly educated mothers (senior high school or higher), the EFS-estimate at 3 years of the intervention group was significantly higher than the EFS-estimate at 3 years of the control group (62% vs. 29%, P ¼0.04). Among pediatric patients with ALL with loweducated mothers, no significant difference was found in the EFSestimates at 3 years betweenthe intervention and control group(26% vs. 18%, P ¼0.86). Conclusions. We conclude that a medication diary-book might be useful to improve the survival of pediatric patients with ALL in resource-limited settings, particularly in patients with highly educated mothers. Pediatr Blood Cancer 2013;60:1593‐ 1597. # 2013 Wiley Periodicals, Inc.

Background Childhood cancer survival in low-income countries is low. Objective Our study investigated health-care providers' perspectives on childhood cancer treatment in Indonesia. Their health beliefs and attitudes toward parental financial difficulties, protocol adherence, parental education, and communication were explored. Methods A self-administered questionnaire was filled in by 222 health-care providers (156 doctors, 51 nurses, 6 social workers, 9 administrators) Results Health of children with cancer is beyond doctor's control and determined by luck, fate or God according to 35% of health-care providers, 30% were uncertain about this statement, and 35% disagreed. Combination of chemotherapy and alternative treatment is best to achieve cure according to 15% of health-care providers, 50% were uncertain, and 35% disagreed. Prosperous parents adhere better with treatment (67%). Doctors adhere better with cancer treatment for prosperous patients (55%). When dealing with poor families, less elaborate explanation is given (62%), more difficult vocabulary is used (49%), and less cooperation is offered (46%). Reasons for non-adherence with treatment protocol were as follows: financial difficulties parents (82%), side-effects (77%), lack of motivation parents (75%), and inadequate drugs supply at pharmacy (70%). Information about cancer and treatment makes parents more afraid or depressed about future, and parents prefer not to know according to 27% of health-care providers, 20% were uncertain, and 53% disagreed. Communication with parents is hindered by differences in status and social hierarchical structures (83%). Conclusions Health-care providers' beliefs about childhood cancer treatment are characterized by much uncertainty and contradiction. This likely affects adherence of health-care providers, parents, and childhood cancer treatment outcome. Copyright © 2013 John Wiley & Sons, Ltd.

Purpose CNS-directed chemotherapy (CT) and cranial radiotherapy (CRT) for childhood acute lymphoblastic leukemia or lymphoma have various neurotoxic properties. This study aimed to assess their impact on the maturing brain 20 to 30 years after diagnosis, providing a much stronger perspective on long-term quality of life than previous studies. Patients and Methods Ninety-three patients treated between 1978 and 1990 at various intensities, with and without CRT, and 49 healthy controls were assessed with magnetic resonance diffusion tensor imaging (DTI) and neuropsychological tests. Differences in fractional anisotropy (FA)—a DTI measure describing white matter (WM) microstructure—were analyzed by using whole brain voxel-based analysis. Results CRT-treated survivors demonstrated significantly decreased FA compared with controls in frontal, parietal, and temporal WM tracts. Trends for lower FA were seen in the CT-treated survivors. Decreases in FA correlated well with neuropsychological dysfunction. In contrast to the CT group and controls, the CRT group showed a steep decline of FA with age at assessment. Younger age at cranial irradiation and higher dosage were associated with worse outcome of WM integrity. Conclusion CRT-treated survivors show decreased WM integrity reflected by significantly decreased FA and associated neuropsychological dysfunction 25 years after treatment, although effects of CT alone seem mild. Accelerated aging of the brain and increased risk of early onset dementia are suspected after CRT, but not after CT.

Severe congenital neutropenia (SCN) is a BM failure syndrome with a high risk of progression to acute myeloid leukemia (AML). The underlying genetic changes involved in SCN evolution to AML are largely unknown. We obtained serial hematopoietic samples from an SCN patient who developed AML 17 years after the initiation of G-CSF treatment. Next-generation sequencing was performed to identify mutations during disease progression. In the AML phase, we found 12 acquired nonsynonymous mutations. Three of these, in CSF3R, LLGL2, and ZC3H18, co-occurred in a subpopulation of progenitor cells already in the early SCN phase. This population expanded over time, whereas clones harboring only CSF3R mutations disappeared from the BM. The other 9 mutations were only apparent in the AML cells and affected known AML-associated genes (RUNX1 and ASXL1) and chromatin remodelers (SUZ12 and EP300). In addition, a novel CSF3R mutation that conferred autonomous proliferation to myeloid progenitors was found. We conclude that progression from SCN to AML is a multistep process, with distinct mutations arising early during the SCN phase and others later in AML development. The sequential gain of 2 CSF3R mutations implicates abnormal G-CSF signaling as a driver of leukemic transformation in this case of SCN. (Blood. 2012; 119(22): 5071-5077)

Background In most developing countries, incidence data for childhood cancers are less reliable, because very few population-based registries exist. The aim of this study was to present the epidemiology of childhood leukemia in the Dr. Sardjito Hospital (DSH) region, which catchment area extends beyond the boundaries of the Yogyakarta Special Province (YSP). Procedure Health records of children, 0–14 years of age, who were diagnosed with leukemia between January 1998 and December 2009, were reviewed. Diagnosis of leukemia was confirmed by morphological and histochemical examination of marrow samples. Results The estimated average annual incidence rate (AAIR) of childhood acute leukemia in DSH was 46.2 per million per year. Interestingly, the annual incidence rate (AIR) of childhood acute leukemia from the catchment area of DSH significantly increased from 35 in 1999 to 70 in 2009 (ANOVA, P = 0.003). The YSP population data, analyzed separately, showed an increase in AIR from 15.7 to 32.9 (ANOVA, P = 0.325) and an AAIR of 28.8. Remarkably, a relatively high frequency (25.5% in DSH and 27.7% in YSP) of children with AML was found in the group of acute leukemias. Conclusion The DSH incidence calculations may be overestimated due to an underestimation of the population number. Since the population count for YSP is more precise, the data of YSP were used for comparison with developed countries. AAIR of ALL (20.8) is relatively low compared to Western countries (22.4–37.9). The AAIR of AML (8.0) is similar to Western countries (5.0–8.0) resulting a relatively high percentage of AML versus ALL (27.7%) in YSP. Pediatr Blood Cancer 2011; 57: 588–593. © 2011 Wiley-Liss, Inc.

Purpose We studied cumulative incidence, risk factors, therapeutic strategies, and outcome of symptomatic osteonecrosis in pediatric patients with acute lymphoblastic leukemia (ALL). Patients and Methods Cumulative incidence of osteonecrosis was assessed prospectively in 694 patients treated with the dexamethasone-based Dutch Child Oncology Group–ALL9 protocol. Osteonecrosis was defined by development of symptoms (National Cancer Institute grade 2 to 4) during treatment or within 1 year after treatment discontinuation, confirmed by magnetic resonance imaging. We evaluated risk factors for osteonecrosis using logistic multivariate regression. To describe outcome, we reviewed clinical and radiologic information after antileukemic treatment 1 year or more after osteonecrosis diagnosis. Results Cumulative incidence of osteonecrosis at 3 years was 6.1%. After adjustment for treatment center, logistic multivariate regression identified age (odds ratio [OR], 1.47; P < .01) and female sex (OR, 2.23; P = .04) as independent risk factors. Median age at diagnosis of ALL in patients with osteonecrosis was 13.5 years, compared with 4.7 years in those without. In 21 (55%) of 38 patients with osteonecrosis, chemotherapy was adjusted. Seven patients (18%) underwent surgery: five joint-preserving procedures and two total-hip arthroplasties. Clinical follow-up of 35 patients was evaluated; median follow-up was 4.9 years. In 14 patients (40%), symptoms completely resolved; 14 (40%) had symptoms interfering with function but not with activities of daily living (ADLs; grade 2); seven (20%) had symptoms interfering with ADLs (grade 3). In 24 patients, radiologic follow-up was available; in six (25%), lesions improved/disappeared; in 13 (54%), lesions remained stable; five (21%) had progressive lesions. Conclusion Six percent of pediatric patients with ALL developed symptomatic osteonecrosis during or shortly after treatment. Older age and female sex were risk factors. After a median follow-up of 5 years, 60% of patients had persistent symptoms.

Background: Treatment refusal and abandonment are common causes of treatment failure in childhood acute lymphoblastic leukemia (ALL) in many developing countries. In most studies reasons for abandonment were based on the opinion of health-care providers (HCP), very few studies have focused on the parental point-of-view. Aims of the study were to analyze the parents' reasons of abandonment and to ascertain the fate of children who abandoned treatment in a pediatric oncology centre in Yogyakarta, Indonesia. Methods: We conducted home-visits to interview families of ALL patients, diagnosed between January 2004 and August 2007, who refused or abandoned treatment. Results: From January 2004 to August 2007, 159 patients were diagnosed with ALL of which 40 children (25%) refused or abandoned therapy. Thirty-seven (93%) of these children were home-visited. Reasons for abandonment were complex. Most parents mentioned several reasons. Financial and transportation difficulties were not the only, or even the main reasons, for abandonment. Belief of ALL incurability, experience of severe side effects and dissatisfaction with HCP were also important considerations. Most patients (64%) abandoned treatment during the diagnostic-evaluation or remission-induction phase. Of the 37 patients who refused or abandoned treatment, 26 (70%) children died, and 11 (30%) children were still alive, 2 of them more than 2 years after abandonment. Conclusions: Reducing treatment abandonment of childhood ALL in developing countries requires not only financial and transportation support, but also parental education, counseling and psychosocial support during therapy, improvement of quality-of-care and adequate management of side effects. Copyright © 2009 John Wiley & Sons, Ltd.

Chemotherapy-only treatment has increasingly become the standard of treatment for childhood acute lymphoblastic leukemia (ALL). The objective of this review is to assess the present state of knowledge of the neurocognitive effects of central nervous system (CNS)-directed chemotherapy in children with ALL, and to formulate directions for future research. We performed a review of studies published since 1997, that included an ALL group treated with chemotherapy only and a control group. Twenty-one studies met our inclusion criteria. There is evidence of subtle long-term neurocognitive deficits survivors of childhood ALL after treatment with chemotherapy only. These involve mainly processes of attention and of executive functioning, while global intellectual function is relatively preserved. Young age at diagnosis and female sex emerged as risk factors. Pediatr Blood Cancer 2009;52: 447-454. (c) 2008 Wiley-Liss, Inc

Previously, we found that the access to donated chemotherapy for childhood leukaemia patients in Indonesia was limited: only 16% of eligible families received donations. After the introduction of a structured parental education programme, we examined the access of parents of children with leukaemia to donated chemotherapy in an Indonesian academic hospital. The programme consisted of a video-presentation in hospital, information-booklet, audiocassette, DVD, procedures for informed-consent, statement of understanding for donated chemotherapy and a complaints-mechanism. Of 72 new patients, 51 parents (71%) were interviewed by independent psychologists using questionnaires. Parents of 21 patients (29%) did not participate because their children dropped-out (n = 10) or died (n = 11) before an interview took place. Four patients had health insurance and did not need donated chemotherapy. Access to donated chemotherapy was improved: 46/47 patients (98%) received donations. Structured parental education improved the access to donated chemotherapy. Outreach-programmes may benefit from this approach. This may enable more patients from poor socio-economic backgrounds in the developing countries to receive aid and achieve cure.

Non-compliance with childhood acute lymphoblastic leukemia (ALL) protocol is an important determinant of poor treatment outcome. Non-compliance with protocol may not only concern parents or patients, but may also concern health-care providers (HCP). Our study examines the accuracy of leukemia risk classification and attitude of HCP toward protocol compliance in Indonesia.A combined retrospective study of medical records (MR) and a cross-sectional questionnaire study with HCP were conducted. Accurate ALL risk classification in MR was assessed. HCP' knowledge of risk classification and their attitude toward protocol compliance were examined.A total of 164 MR patients with ALL were assessed and 97 HCP were interviewed. The protocol criteria for high-risk (HR) were not complete in 82 MR (50%). Of 97 HCP, 95% did not mention all five protocol criteria for HR. Both in the MR as well as in the questionnaires lymphoblast count on day 8 of chemotherapy, as early response to treatment, was the most frequently missed item (missing in 35% of MR and 85% of questionnaires). Only 14% of respondents actually checked with parents whether they administered the prescribed medicines.Our study shows that HCP should improve their knowledge and assessment of childhood ALL risk classification, especially lymphoblast count on day 8 of chemotherapy. Proper risk classification and subsequent correct treatment may enable more children to be cured of leukemia.

Background. Children with T-lineage acute lymphoblastic leukemia MALL) have an inferior outcome with combination chemotherapy compared to B-lineage ALL, and still about 30% of the patients relapse within the first 2 years following diagnosis. As CD34 has been related with poor outcome in ALL in general, we investigated the prognostic significance of the stem cell marker CD34, as well as the association of CD34 positivity with the expression of several multidrug resistance (MDR) genes. Procedure. In this retrospective study, we investigated the prognostic significance of the expression of the early T-cell differentiation marker CD34 and the expression of MDR genes in relation to outcome in a cohort of 72 newly diagnosed pediatric T-ALL patients. Results. CD34 expression was related to a poor 5-year-disease-free-survival and a poor 5-year overall Survival. Using the Cox proportional hazard model, CD34 expression predicted for increased risk for relapse and death. Expression of CD34 was associated with elevated MDR1 and MRP1 mRNA expression levels. For the entire T-ALL cohort, these expression levels of MDR1 or MRP1 did not independently predict for poor outcome. Conclusions. We conclude that CD34-positive T-ALL has a relatively poor survival that is not explained by the mRNA expression levels of MDR1, LRP, or MRP1. Pediatr Blood Cancer 2008;51:737740. (c) 2008 Wiley-Liss, Inc.

In this study, we determined if in vitro resistance to prednisolone and dexamethasone could be circumvented by cortivazol or methylprednisolone, or reversed by meta-iodobenzylguanidine in pediatric lymphoblastic and myeloid leukemia. As there were strong correlations between the LC50 values (drug concentration inducing 50% leukemic cell kill, LCK) of the different glucocorticoids and median prednisolone/methylprednisolone, prednisolone/dexamethasone and prednisolone/cortivazol LC50 ratios did not differ between the leukemia subtypes, we conclude that none of the glucocorticoids had preferential anti-leukemic activity. Meta-iodobenzylguanidine however, partially reversed glucocorticoid resistance in 19% of the lymphoblastic leukemia samples.

Pediatric T-cell acute lymphoblastic leukemia (T-ALL) is characterized by chromosomal rearrangements possibly enforcing arrest at specific development stages. We studied the relationship between molecular- cytogenetic abnormalities and T-cell development stage to investigate whether arrest at specific stages can explain the prognostic significance of specific abnormalities. We extensively studied 72 pediatric T-ALL cases for genetic abnormalities and expression of transcription factors, NOTCH1 mutations and expression of specific CD markers. HOX11 cases were CD1 positive consistent with a cortical stage, but as 4/5 cases lacked cytoplasmatic-beta expression, developmental arrest may precede beta-selection. HOX11L2 was especially confined to immature and pre- AB developmental stages, but 3/17 HOX11L2 mature cases were restricted to the gamma delta-lineage. TAL1 rearrangements were restricted to the alpha beta-lineage with most cases being TCR-alpha beta positive. NOTCH1 mutations were present in all molecular-cytogenetic subgroups without restriction to a specific developmental stage. CALM-AF10 was associated with early relapse. TAL1 or HOX11L2 rearrangements were associated with trends to good and poor outcomes, respectively. Also cases with high vs low TAL1 expression levels demonstrated a trend toward good outcome. Most cases with lower TAL1 levels were HOX11L2 or CALM-AF10 positive. NOTCH1 mutations did not predict for outcome. Classification into T-cell developmental subgroups was not predictive for outcome.

Body mass index and change in body mass index during treatment may influence treatment outcome of pediatric patients with acute lymphoblastic leukemia. However, previous studies in pediatric acute lymphoblastic leukemia reported contradictory results. We prospectively collected data on body composition from a cohort of newly diagnosed Dutch pediatric patients with acute lymphoblastic leukemia (n=762, age 2-17 years). Patients were treated from 1997-2004 and the median follow-up was 9 years (range, 0-10). Body mass index at diagnosis was expressed as age-and gender-matched standard deviation scores and on the basis of these scores the patients were categorized as being underweight, of normal weight or overweight. Multivariate analyses showed that patients who were underweight (8%) had a higher risk of relapse [hazard ratio: 1.88, 95% confidence interval (1.13-3.13)], but similar overall survival and event-free survival as patients who had a normal weight or who were overweight. Patients with loss of body mass index during the first 32 weeks of treatment had a similar risk of relapse and event-free survival, but decreased overall survival [hazard ratio: 2.10, 95% confidence interval (1.14-3.87)] compared to patients without a loss of body mass index. In addition, dual X-ray absorptiometry scans were performed in a nested, single-center cohort. Data from these scans revealed that a loss of body mass consisted mainly of a loss of lean body mass, while there was a gain in the percentage of fat. In conclusion, being underweight at diagnosis is a risk factor for relapse, and a decrease in body mass index early during treatment is associated with decreased survival. In addition, loss of body mass during treatment seems to consist mainly of a loss of lean body mass. This study was approved by the Medical Ethical Committee in 1996 (trial number NTR460/SNWLK-ALL-9).

Osteonecrosis and decline of bone density are serious side effects during and after treatment of childhood acute lymphoblastic leukemia. It is unknown whether osteonecrosis and low bone density occur together in the same patients, or whether these two osteogenic side-effects can mutually influence each other's development. Bone density and the incidence of symptomatic osteonecrosis were prospectively assessed in a national cohort of 466 patients with acute lymphoblastic leukemia (4-18 years of age) who were treated according to the dexamethasone-based Dutch Child Oncology Group-ALL9 protocol. Bone mineral density of the lumbar spine (BMDLS) (n=466) and of the total body (BMDTB) (n=106) was measured by dual X-ray absorptiometry. Bone density was expressed as age- and gender-matched standard deviation scores. Thirty patients (6.4%) suffered from symptomatic osteonecrosis. At baseline, BMDLS and BMDTB did not differ between patients who did or did not develop osteonecrosis. At cessation of treatment, patients with osteonecrosis had lower mean BMDLS and BMDTB than patients without osteonecrosis (respectively, with osteonecrosis: -2.16 versus without osteonecrosis: -1.21, P

intellectual functioning (verbal, performance and full-scale IQ) in 43 children treated for acute lymphoblastic leukaemia (ALL) with chemotherapy-only was evaluated in a nationwide, prospective, sibling-controlled study. Intellectual assessment was performed at diagnosis and repeated shortly after cessation of 2 years treatment, including intrathecal and systemic chemotherapy. Using hierarchical regression analysis, patients' and siblings' (n = 27) scores were longitudinally analysed and compared to assess possible changes and differences over time. At both assessments, before and after treatment, patients showed average scores on intelligence tests compared to population norms. Longitudinal analysis and cross-sectional comparisons revealed no significant differences between patients and controls. Young patients showed a small relative decline, albeit not significant, on performance-IQ compared to healthy siblings. Despite intensive and potentially neurotoxic treatment, no evident negative effects on intelligence were found. However, it cannot be precluded that younger patients are at risk for a small decline in PIQ. (c) 2006 Elsevier Ltd. All rights reserved.

BACKGROUND The improved prognosis of childhood cancer makes monitoring of functional outcome important. The purpose of this study was to evaluate behavioral and educational functioning in survivors of childhood acute lymphoblastic leukemia (ALL) or a Wilms tumor. In this study, children with ALL received central nervous system directed chemotherapy without cranial irradiation. METHODS In a multicenter study, behavioral functioning and school performance was examined in 199 children age 4 to 18. Sixty-four children were at least 1 year from finishing treatment with chemotherapy for ALL (n = 28) or a Wilms tumor (n = 36). They were compared with siblings (n = 37) and with a control group of healthy schoolchildren (n = 98). RESULTS A moderately increased risk of behavioral and educational problems was found in children with ALL but not in children with Wilms tumor. School performance was poorer in children with ALL attending primary school compared with same-age peers; however, the rate of utilization of special education services was low. Teacher-rated behavior and mathematics performance was correlated with attention function in children with ALL. An excess of problem behavior and underperformance at school was found in the ALL high-risk group compared with the standard-risk group. No differences were found between siblings and controls. CONCLUSION Evidence is provided of subtle but significant behavioral and educational problems in survivors of childhood ALL, but no dysfunctions in survivors of a Wilms tumor. Careful follow-up of children with ALL treated with chemotherapy only is warranted. Cancer 2006. © 2006 American Cancer Society.

Aims: To study neuropsychological functioning of newly diagnosed children with acute lymphoblastic leukaemia (ALL) within two weeks after diagnosis in order to determine the feasibility of a sibling controlled prospective study design. Methods: Fifty consecutive patients (median age at testing 6.6 years, range 4–12) were included in a prospective, longitudinal, nationwide study. Treatment would include intrathecal and systemic chemotherapy according to the DCLSG ALL-9 protocol. Children were evaluated with an extensive neuropsychological battery including measures of intelligence, memory, attention, language, visual-constructive function, and fine-motor abilities within two weeks after start of the chemotherapy. The control group consisted of 29 healthy siblings (median age at testing 8.2 years, range 4–12), who were tested

Treatment for childhood acute lymphoblastic leukemia (ALL), which includes CNS prophylaxis, is associated with central and peripheral neurotoxicity. The purpose of the present study was to analyze the effects of chemotherapy on various levels of visuomotor control in survivors of childhood ALL treated without cranial irradiation, and to identify risk factors for possible deficits. Visuomotor function was compared between children after treatment for ALL (n = 34), children after treatment for Wilms tumor, which consists of non-CNS directed chemotherapy (n = 38), and healthy controls (n = 151). Three tasks were administered: a simple visual reaction time task and two tasks measuring visuomotor control with one requiring a higher level of cognitive control than the other. Visuomotor deficits were detected only in the ALL group, with poorer performance restricted to the condition requiring the highest level of control. Significant risk factors for poorer performance were female gender and a short time since end of treatment, and a trend was found for a young age at diagnosis. A high cumulative methotrexate dose was an adverse predictive factor in girls. The results indicate that chemotherapy-induced central neurotoxicity in childhood ALL treatment is associated with higher order visuomotor control deficits. Girls appear to be particularly vulnerable.

Contains fulltext : 48224.pdf (Publisher’s version ) (Closed access) The relationship between vincristine pharmacokinetics and its antileukaemic effect in children is unknown. Since vincristine plays a key role in the treatment of childhood acute lymphoblastic leukaemia (ALL), it is worthwhile to explore if efficacy can be improved by individual dose adjustment. Therefore, we studied the relationship between vincristine antileukaemic effect and pharmacokinetics in children newly diagnosed with ALL before the start of standard induction chemotherapy. Vincristine plasma concentration was measured by high-pressure liquid chromatography analysis with electrochemical detection. Primary pharmacokinetic parameters were estimated by maximum a posteriori parameter estimation with a Bayesian algorithm using the ADAPT II software package. Secondary pharmacokinetic parameters were calculated from the model. Response to a single dose of vincristine was determined on bone marrow (BM) and peripheral blood (PB) smears after 3 days. Variability of vincristine pharmacokinetics did not explain variability of response to vincristine monotherapy. Our results do not support the clinical application of pharmacokinetically guided adaptation of a standard body surface area-based dose of vincristine.

BACKGROUND: Central nervous system (CNS) directed chemotherapy is replacing prophylactic cranial irradiation in treatment protocols for childhood acute lymphoblastic leukemia (ALL), mainly to reduce long-term neuropsychological sequelae. We evaluated the effects of chemotherapy on attentional function in survivors of ALL and examined whether possible deficits are related to treatment intensity.METHODS: In a multi-center study, we compared attentional function in 36 children at least 1 year after finishing treatment with chemotherapy only for ALL, with a cancer control group consisting of 39 Wilms tumor patients and with 110 healthy children. We differentiated between standard- and intensified ALL treatment. The role of previously reported risk factors for neuropsychological deficits was also assessed.RESULTS: After chemotherapy, attentional deficits were detected in patients with ALL, but not in Wilms tumor patients. Children treated according to standard ALL protocols performed worse than healthy controls on only 1 of 10 outcome measures (P = 0.004), while those who had received intensified treatment performed worse on four outcome measures (0.0001 < P < 0.004). Higher treatment intensity, young age at diagnosis, and female gender were associated with worse performance.CONCLUSIONS: CNS-directed chemotherapy, even in the absence of cranial irradiation, is associated with attentional dysfunction in survivors of childhood ALL, particularly in case of intensified treatment protocols. These sequelae stress the importance of reducing doses of neurotoxic chemotherapy as much as possible in the design of future treatment protocols for ALL.

An online method was developed to monitor BCRP mediated efflux of fluorescent substrates in suspension cells. To this end, a 2-compartment system consisting of a transwell cup and a cuvette was used. In this system we were able to observe differences in efflux kinetics between BCRP overexpressing RPMI 8226/MR cells and parental myeloid RPMI 8226(s) cells using only 50,000 cells per experiment. 8226/MR cells displayed a larger cellular efflux rate of the BCRP substrate Hoechst 33342, as compared to the wildtype cells. This difference in efflux rate was completely decreased in the presence of the BCRP inhibitor Ko143.

Objective: Our objective was to investigate the effect of single nucleotide polymorphisms (SNPs) in the P-glycoprotein MDR1 gene on vincristine pharmacokinetics and side effects in childhood acute lymphoblastic leukemia. Methods. From 52 of 70 children who participated in a previous study on vincristine pharmacokinetics, patient material was available for investigation of the MDR1 genetic variants. The SNPs C3435T and G2677T were determined by use of polymerase chain reaction-restriction fragment length polymorphism. Vincristine side effects were scored retrospectively from patient records. Results. No association was observed between C3435T or G2677T and vincristine pharmacokinetic variables. When haplotypes were assigned, haplotype 1/1 carriers (3435C/2677G) showed a longer elimination half-life than noncarriers (1156 versus 805 minutes, P = .038). In contrast, haplotype 1/2 carriers (3435T/2677G) had a shorter elimination half-life than noncarriers (805 versus 1180 minutes, P = .044). However, this significance was lost after Bonferroni correction for multiple testing. The haplotypes did not affect the other pharmacokinetic parameters, such as clearance and area under the concentration-time curve, suggesting that the observed effect on elimination half-life is of very limited relevance. Moreover, SNPs in the MDR1 gene did not identify patients with an increased risk for vincristine-induced constipation. Conclusion: The genetic variants in the MDR1 gene alone cannot explain the large variability in vincristine pharmacokinetics.

Childhood acute lymphoblastic leukemia (ALL) is curable with chemotherapy in approximately 80 percent of patients. However, the cause of treatment failure in the remaining 20 percent of patients is largely unknown.We tested leukemia cells from 173 children for sensitivity in vitro to prednisolone, vincristine, asparaginase, and daunorubicin. The cells were then subjected to an assessment of gene expression with the use of 14,500 probe sets to identify differentially expressed genes in drug-sensitive and drug-resistant ALL. Gene-expression patterns that differed according to sensitivity or resistance to the four drugs were compared with treatment outcome in the original 173 patients and an independent cohort of 98 children treated with the same drugs at another institution.We identified sets of differentially expressed genes in B-lineage ALL that were sensitive or resistant to prednisolone (33 genes), vincristine (40 genes), asparaginase (35 genes), or daunorubicin (20 genes). A combined gene-expression score of resistance to the four drugs, as compared with sensitivity to the four, was significantly and independently related to treatment outcome in a multivariate analysis (hazard ratio for relapse, 3.0; P=0.027). Results were confirmed in an independent population of patients treated with the same medications (hazard ratio for relapse, 11.85; P=0.019). Of the 124 genes identified, 121 have not previously been associated with resistance to the four drugs we tested.Differential expression of a relatively small number of genes is associated with drug resistance and treatment outcome in childhood ALL.

Acute lymphoblastic leukemia (ALL) in infants under 1 year is strongly associated with translocations involving 11q23 (MLL gene), CD10-negative B-lineage (proB) immunophenotype, and poor outcome. The present study analyses the relationship between age, MLL rearrangements, proB-lineage, and in vitro drug resistance determined using the MTT assay. Compared to 425 children aged over 1 year with common/preB (c/preB) ALL, the 44 infants were highly resistant to steroids (for prednisolone (PRED) more than 580-fold, P=0.001) and L-asparaginase (L-ASP) (12-fold, P=0.001), but more sensitive to cytarabine (AraC) (1.9-fold, P=0.001) and 2-chlorodeoxyadenosine (2-CdA) (1.7-fold, P0.001). No differences were found for vincristine, anthracyclines, thiopurines, epipodophyllotoxines, or 4-hydroperoxy (HOO)-ifosfamide. ProB ALL of all ages had a profile similar to infant ALL when compared with the group of c/preB ALL: relatively more resistant to L-ASP and PRED (and in addition thiopurines), and more sensitive to AraC and 2-CdA. Age was not related to cellular drug resistance within the proB ALL group (1 year, n=32, vs/=1 year, n=19), nor within the MLL-rearranged ALL (1 year, n=34, vs/=1 year, n=8). The translocation t(4;11)(q21;q23)-positive ALL cases were more resistant to PRED (7.4-fold, P=0.033) and 4-HOO-ifosfamide (4.4-fold, P=0.006) than those with other 11q23 abnormalities. The expression of P-glycoprotein, multidrug-resistance protein, and lung-resistance protein (LRP) was not higher in infants compared to older c/preB ALL patients, but LRP was higher in proB ALL and MLL-rearranged ALL of all ages. In conclusion, infants with ALL appear to have a distinct in vitro resistance profile with the proB immunophenotype being of importance. The role of MLL cannot be excluded, with the t(4;11) being of special significance, while age appears to play a smaller role.

FLT3 is a receptor tyrosine kinase involved in the proliferation and differentiation of hematopoietic stem cells. FLT3 internal tandem duplications (FLT3/ITDs) are reported in acute myeloid leukemia (AML) and predict poor clinical outcome. We found FLT3/ITDs in 11.5% of 234 children with de novo AML. FLT3/ITD-positive patients were significantly older and had higher percentages of normal cytogenetic findings or French-American-British (FAB) classification M1/M2 and lower percentages of 11q23 abnormalities or FAB MS. FLT3/ITD-positive patients had lower remission induction rates (70% vs 88%; P = .01) and lower 5-year probability rates of event-free survival (pEF) (29% vs 46%; P = .0046) and overall survival (32% vs 58%; P = .037). Patients with high ratios (higher than the median) between mutant and wild-type FLT3 had significantly worse 2-year EFS rates than FLT3/ITD-negative patients (pEFS 20% vs 61%, P = .037), whereas patients with ratios lower than the median did not (pEFS 44% vs 61%; P = .26). FLT3/ITD was the strongest independent predictor for pEFS, with an increase in relative risk for an event of 1.92 (P = .01). Using an MTT (methyl-thiazol-tetrazolium)-based assay, we studied cellular drug resistance on 15 FLT3/ITD-positive and 125 FLT3/ITD-negative AML samples, but we found no differences in cellular drug resistance that could explain the, poor outcomes in FLT3/ITD-positive patients, We conclude that FLT3/ITD is less common in pediatric than in adult AML. FLT3/ITD is a strong and independent adverse prognostic factor, and high ratios between mutant and WT-FLT3 further compromise prognosis. However, poor outcomes in FLT3/ITD-positive patients could not be attributed to increased in vitro cellular drug resistance.

Purpose : To confirm the prognostic value of a drug resistance profile combining prednisolone, vincristine, and L-asparaginase (PVA) cytotoxicity in an independent group of children with acute lymphoblastic leukemia (ALL) treated with a different protocol and analyzed at longer follow-up compared with our previous study of patients treated according to the Dutch Childhood Leukemia Study Group (DCLSG) ALL VII/VIII protocol.Patients and Methods: Drug resistance profiles were determined in 202 children (aged 1 to 18 years) with newly diagnosed ALL who were treated according to,,the German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia (COALL)-92 protocol.Results: At a median follow-up of 6.2 years (range, 4.1 to 9.3 years), the 5-year disease-free survival probability (pDFS) rate +/- SE was 69% +/- 7.0%,83% +/- 4.4%, and 84% +/- 6.8% for patients with resistant (PVA score 7 to 9), intermediate-sensitive (PVA score 5 to 6), and sensitive (SPVA score 3 to 4) profiles, respectively (sensitive and intermediate-sensitive v resistant, P less than or equal to .05). Resistant patients were at increased risk of an early event (nonresponse or relapse within 2.5 years of diagnosis) compared with sensitive and intermediate-sensitive patients (P = .03). The profile did not identify patients at higher risk of late relapse, which was also observed for DCLSG ALL-VII/VIII patients now analyzed at a median of 7.5 years of follow-up (range, 4.4 to 10.8 years). Despite being nondiscriminative for late relapses, the resistant profile was still the strongest prognostic factor for COALL-92 patients in a multivariate analysis including known: risk factors (P = .07).Conclusion: Drug resistance profiles identify patients at higher risk of early treatment failures and may, therefore, be used to improve risk-group stratification of children with ALL. (C) 2003 by American Society of Clinical Oncology.

There is a distinct difference in prognosis between childhood versus adult acute lymphoblastic leukaemia (ALL). To define whether multidrug resistance (MDR) genes might contribute to this distinction, the expression and functional activity of P-glycoprotein (P-gp) and MDR associated proteins (MRP) were determined with RT-PCR (MDR-1, MRP1, MRP2, MRP3) and flow cytometry (P-gp and MRP). Patient samples were obtained from 36 children and 35 adults with de novo ALL. Of these patients, 38 showed a T-lineage and 33 showed a B-lineage immunophenotype. In the samples, large variability in P-gp activity (0.8-4.9) and MRP activity (1.1-13.9) was observed. Most T-ALL patients with high P-gp activity were adults (89%). The mRNA expression of MDR-1 correlated weakly with P-gp activity. In contrast, MRP activity did not correlate with the mRNA expression of MRP1, MRP2 and MRP3. In T-ALL, a worse overall survival and event-free survival was observed with increasing P-gp activity. P-gp activity had no prognostic impact in B-lineage ALL. In addition, high MRP activity did not influence treatment outcome in either T- or B-lineage ALL. Multivariate Cox regression analysis, showed P-gp activity to be the only unfavourable prognostic factor for overall survival in T-ALL. In conclusion, this study demonstrates the prognostic relevance of P-gp activity in T-ALL. Since the majority of the patients with high P-gp activity were adults, P-gp might contribute to the poor prognosis of adult T-ALL.

We reviewed Dutch patients and those described in the literature with congenital leukaemia in the past 25 years, with the intention to obtain an overview of the characteristics of this rare disease. Among the 117 patients reviewed, acute myeloid leukaemia (AML) was more frequent (64%) than acute lymphoblastic leukaemia (ALL, 21%). Most patients had a high leukaemic cell load with hepatosplenomegaly, leukaemia cutis and hyperleucocytosis. Cytogenetic abnormalities were found in the majority of the patients tested (72%); 11q23 abnormalities were found in less than half of them (42%). The probability of overall survival at 24 months was only 23%. When congenital AML and ALL were compared, clinical characteristics and overall survival were not significantly different. However, in patients at risk, the probability of event-free survival (EFS) and disease-free survival (DFS) were significantly higher in AML than in ALL, 43% versus 13% and 68% versus 0% respectively. Among the congenital AML cases, six spontaneous remissions have been described. In conclusion, the clinical characteristics of congenital leukaemia differ from those of leukaemia in older children and prognosis is generally poor. Once complete remission is achieved, patients with AML fare better than those with ALL. Chemotherapy for congenital leukaemia needs improvement to increase the sustained remission rate.

Patients with retinoblastoma (RB) are primarily treated by the ophthalmologist. Usually the pediatric oncologist only gets involved once chemotherapy is indicated. This article reviews the indications for chemotherapy, its current role including the recent changes, and remaining challenges. A wide variety of treatment modalities is available for RB: surgical enucleation of the eye [1,2], external beam radiotherapy (EBRT) [3–5], plaque radiotherapy [6,7], intraocular therapy. laser-, cryoor thermocoagulation performed by the ophthalmologist [8,9] and many different chemotherapy regimens [10–22]. The individual treatment strategy depends on many different parameters: tumor volume and localization, intraocular tumor extension (including Reese–Ellsworth (RE) classification, see Table I), extraocular stage of the disease (Grabowski– Abramson (GA) staging, see Table I), involvement of one or both eyes, heredity of the disease, and the age of the patient [23,24]. In reaching a decision on a specific treatment strategy all advantages and disadvantages must be taken into account. The major aim in RB treatment is to cure the patient with preservation of vision. The second aim in treatment is to reduce the diverse late complications of treatment like facial malformations [25,26] and even more important a reduction of second malignant neoplasms (SMN), which often emerge in the radiation field [27–35]. Chemotherapy is one of the possible treatment modalities to achieve these goals. Different strategies have been explored in combination with different local therapeutic interventions aiming at the most effective and least harmful treatment. This manuscript provides a literature review of clinical studies on chemotherapeutic treatment options in RB.

Item does not contain fulltext We studied vincristine pharmacokinetics in 70 children newly diagnosed with acute lymphoblastic leukemia, after a single dose of vincristine as monotherapy. Vincristine plasma concentrations were measured by HPLC analysis. A two-compartment, first-order pharmacokinetic model was fitted to the data by maximum a posteriori parameter estimation. In this group of children pharmacokinetic factors were highly variable: median (25th and 75th percentiles) total body clearance, 228 (128-360) mL.min(-1).m(-2); elimination half-life, 1001 (737-1325) min; apparent volume of distribution at steady state 262 (158-469) L/m(2). Vincristine clearance was substantially slower than has been reported previously for children receiving vincristine in combination with steroids as part of combination chemotherapy (median clearance, 228 mL.min(-1).m(-2) versus mean clearance, 381 and 482 mL. min(-1). m(-2), respectively). Steroids are known as inducers of vincristine-metabolizing cytochrome P(450) 3A4 enzymes. The absence of steroids during our study appears to be the most likely explanation for this difference. Furthermore, we found that vincristine clearance was faster in patients with hyperdiploid (>50 chromosomes) than in patients with diploid or hyperdiploid (46-50 chromosomes) leukemic blasts.

Specific cytogenetic abnormalities predict prognosis in childhood acute myeloid leukemia (AML). However, it is unknown why they are predictive and whether this is related to drug resistance. We previously reported that Down syndrome (DS) AML was associated with favorable resistance profiles. Here, we successfully analyzed drug resistance and (cyto-) genetic abnormalities of 109 untreated childhood AML samples using the 4-day total cell-kill methyl-thiazol tetrazolium (MTT) assay. Patients were classified according to the genetic abnormalities in the leukemic cells: t(8;21), inv(16), t(15;17), t(9;11), other 11q23 translocations, abnormalities of chromosome 5/7, trisomy 8 alone, normal karyotype, single random, and multiple (defined as 2 or more) abnormalities. The DS AML samples were excluded from the subgroup analysis. Samples with chromosome 5/7 abnormalities were median 3.9-fold (P = .01) more resistant to cytarabine than other AML samples. The t(9;11) samples were more sensitive to cytarabine (median 2.9-fold, P= .002), etoposide (13.1-fold, P = .001), the anthracyclines (2.9- to 8.0-fold, P < .01), and 2-chlorodeoxyadenosine (10.0-fold, P= .002) than other AML samples. The trisomy 8 and t(15;17) groups were too small for meaningful analysis. All other genetic subgroups did not show specific resistance profiles. Overall, we found no differences in drug resistance in samples taken at diagnosis between patients remaining in continuous complete remission (CCR) versus the refractory/relapsed patients. Within several genetic subgroups, however, relapsed/refractory patients were more cytarabine resistant when compared with patients remaining in CCR, but numbers were small and the results were not significant. We conclude that some, but not all, cytogenetic subgroups in childhood AML display specific drug-resistance profiles.

CD73 (5′-nucleotidase) expression has no prognostic value in children with acute lymphoblastic leukemia

Background: Efficacy of childhood cancer treatment in low-income countries may be impacted by parents’ and health-care providers’ perspectives on chemotherapy-related side-effects. This study explores prevalence and severity of side-effects in childhood cancer, and compares health beliefs about side-effects between parents and health-care providers, and between nurses and doctors in Indonesia. Materials and Methods: Semi-structured questionnaires were filled in by 40 parents and 207 health-care providers in an academic hospital. Results: Parents exporessed a desire to receive more information about side-effects (98%) and worried about this aspect of treatment (90%), although side-effects were less severe than expected (66%). The most frequent was behavior alteration (98%) and the most severe was hair loss. Only 26% of parents consulted doctors about side-effects. More parents, compared to health-care providers, believed that medicines work better when side-effects are more severe (p

The difference in the current cure rates between adult and childhood acute lymphoblastic leukaemia (ALL) may be caused by differences in drug resistance. Earlier studies showed that in vitro cellular drug resistance is a strong independent adverse risk factor in childhood ALL. Knowledge about cellular drug resistance in adult ALL is still limited. The present study compared the in vitro drug resistance profiles of 23 adult ALL patients with that of 395 childhood ALL patients. The lymphoblasts were tested by the MTT assay. The group of adult ALL samples was significantly more resistant to cytosine arabinoside, L-asparaginase, daunorubicin, dexamethasone and prednisolone. The resistance ratio (RR) was highest for prednisolone (31.7-fold) followed by dexamethasone (6.9-fold), L-asparaginase (6. 1-fold), cytosine arabinoside (2.9-fold), daunorubicin (2.5-fold) and vincristine (2.2-fold). Lymphoblasts from adult patients were not more resistant to mercaptopurine, thioguanine, 4-HOO-ifosfamide, mitoxantrone and teniposide. There were no significant differences in drug resistance between adult T-cell (T-) ALL (n = 11) and adult common/pre-B-cell (B-) ALL (n = 10). Additionally, adult T-ALL did not differ from childhood T-ALL (n = 69). There were significant differences between adult common/pre-B-ALL and childhood common/pre-B-ALL (n = 310) for prednisolone (RR = 302, P = 0.008), dexamethasone (RR = 20.9, P = 0.017) and daunorubicin (RR = 2.7, P = 0.009). Lymphoblasts from adults proved to be relatively resistant to drugs commonly used in therapy. This might contribute to the difference in outcome between children and adults with ALL.

Background. To investigate late cardiotoxicity in childhood acute lymphoblastic leukemia (ALL) survivors after induction treatment with or without daunorubicin (DNR; 25 mg/m(2), i.v., weekly, x4, cumulative dose 100 mg/m(2)). Procedure, Cardiac function was assessed in 90 event-free survivors of childhood ALL, 11.4-17.8 years (median 14.8 years) after treatment according to the DCLSG protocol ALL V. In this protocol patients were randomized to receive (group B) or not to receive (group A) DNR 25 mg/m(2)/week i.v. during the first 4 weeks of induction treatment. Age at diagnosis was 1.2-14.9 years (median 4.5 years). The cardiac evaluation consisted of a history, physical examination, electrocardiogram (ECC), 24 hr ambulatory EGG, and echocardiography. Results. Electrocardiographic data, arrhythmias, left ventricular dimensions, left ventricular contractility, wall stress, and diastolic function were within normal limits in both groups. No difference could be shown between data from group A (n = 40) and group B (n = 50). Conclusions. No late cardiac damage was demonstrated in childhood ALL survivors after induction treatment including a cumulative dose of 100 mg/m(2) DNR, compared to survivors who received the same treatment but without DNR. DNR 100 mg/m(2) given in 4 doses of 25 mg/m(2)/week appears to be a safe dose in induction treatment of ALL. 2000 Wiley-Liss, Inc.

Methotrexate (MTX) is not cytotoxic to patient-derived acute lymphoblastic leukemia (ALL) cells in total-cell-kill assays, such as the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, putatively due to the rescue effects of hypoxanthine and thymidine released from dying cells. This was mimicked by a diminished methotrexate (MTX) cytotoxicity for the cell lines HL60 and U937 in the presence of hypoxanthine, thymidine, or lysed ALL cells. However, enzymatic depletion or inhibition of nucleoside membrane transport did not result in MTX dose-dependent cytotoxicity in patient samples. Alternatively, a thymidylate synthase inhibition assay (TSIA), based on inhibition of the TS-catalyzed conversion of 3H-dUMP to dTMP and 3H2O, correlated with the MTT assay for antifolate sensitivity in four human leukemia cell lines with different modes of MTX resistance. For 86 ALL patient samples, TSI50 values after 21 hours exposure to MTX were not different between T- and c/preB-ALL (P = .46). After 3 hours incubation with MTX followed by an 18-hour drug-free period, T-ALL samples were 3.4-fold more resistant to MTX compared with c/preB-ALL samples (P = .001) reflecting the clinical differences in MTX sensitivity. TSI50 values correlated with MTX accumulation (r = −.58, P < .001). In conclusion, the TSIA, but not the MTT assay, can measure dose-response curves for MTX in patient-derived ALL cells and showed relative MTX resistance in T-ALL compared with c/preB-ALL.

The number of subjects that have successfully completed treatment for a cancer diagnosed during childhood and are entering adulthood is increasing over time. Members of the International Berlin-Frankfurt-Munster (I-BFM) Early and Late Toxicity Educational Committee (ELTEC) invited 45 paediatric cancer experts (representing oncologists, psychologists, nurses, epidemiologists, parents, and survivors) from 13 European countries (with five additional experts from North America) to Erice, Sicily (from October 27 to 29, 2006) to discuss the circumstances in which the word 'cure' should be used when speaking about children with cancer, and when and why continuing follow-up and care may be required. The objective of the gathering was to generate from the personal and professional experience of the participants an overview statement of the group's philosophy of cure and care of survivors of childhood cancer. The ten points reflect what the group considers essential in the survivors' cure and care.

The prognosis of infant ALL, characterized by a high incidence of the immature CD10 negative B-lineage ALL (proB ALL) is poor. This study aimed to determine the resistance profile of infant ALL cells. In vitro drug resistance was determined by the MTT assay of 395 children with ALL at initial diagnosis: there were 21 infants < 1.5 years of which nine < 1 year, 284 children aged 1.5-10 years (intermediate age group) and 90 children > 10 years. Immunophenotyping resulted in 310 cALL/preB ALL, 69 T-ALL, 15 proB ALL and one unknown cases. The following drugs were tested: daunorubicin, doxorubicin, mitoxantrone, idarubicin (Ida), prednisolone (Pred), dexamethasone (DXM), vincristine (VCR), Asparaginase (Asp), 6-MP, 6-TG, AraC, VM26 and 4-HOO-ifosfamide (Ifos). Infants < 1.5 years were significantly more resistant to Pred (> 500-fold), Asp (11-fold) and VM26 (2.7-fold) but significantly more sensitive to Ara-C (2.3-fold) compared to the intermediate age group. When analyzing infants < 1 year of age similar results were found. ProB ALL cells (seven infants < 1.5 years; eight children > 1.5 years) were significantly more resistant to glucocorticoids, Asp, thiopurines, anthracyclines and Ifos compared to cALL/preB ALL but more sensitive to Ara-C. Cells from children > 10 years were significantly more resistant to Pred, DXM, Asp, Ida and 6-MP. T-ALL cells showed a strong resistance to Pred, Asp and VCR and a mild but significant resistance to all other drugs except thiopurines and VM26. We conclude that the poor prognosis of infant ALL is associated with a resistance to glucocorticoids and Asp. However, ALL cells from infants show a relatively high sensitivity to Ara-C which suggests that infants with ALL might benefit from treatment schedules that incorporate more Ara-C than the current treatment protocols.

As an important determinant of the response to chemotherapy, measurements of cellular drug resistance may provide prognostically significant information, which could be useful for optimal risk-group stratification. The objective of this report is to determine the relation between in vitro resistance to 12 drugs, measured with the colorimetric methyl-thiazol-tetrazolium (MTT) assay, and long-term clinical response to chemotherapy in 152 children with newly diagnosed acute lymphoblastic leukemia. At risk-group stratified analyses, in vitro resistance to prednisolone, L-asparaginase, and vincristine were each significantly (P < .01) related to the probability of disease-free survival (pDFS) after combination chemotherapy. The combination of data for prednisolone, L-asparaginase, and vincristine provided a drug-resistance profile with prognostic independent significance superior to that of any single drug or any other factor. The 3-years pDFS was 100% for the group with the most sensitive profile, 20% of all patients, 84% (SE 6%) for the group with an intermediately sensitive profile, 40% of all patients, and 43% (SE 8%) for the remaining group with the most resistant profile (P < .001). In conclusion, the extent of in vitro cellular resistance to prednisolone, L-asparaginase, and vincristine, measured using the MTT assay, was significantly related to the clinical response to combination chemotherapy. Treatment failure in newly diagnosed childhood ALL can be predicted based on cellular drug resistance data.