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Aim: Previously, glutamine-enriched enteral nutrition in very low birth weight infants (VLBW) decreased the incidence of atopic dermatitis at age 1 year. The aim of this study was to determine whether this effect is related to changes in intestinal bacterial species that are associated with allergy, such as bifidobacteria, clostridium histolyticum, clostridium lituseburense (Chis/lit group) and Escherichia coli at age 1 year. Methods: Eighty-nine infants were eligible for this follow-up study, conducted at a Tertiary care hospital. Bifidobacteria, Chis/lit group and E. coli were measured by fluorescent in situ hybridization in faecal samples collected at age 1 year. Information on allergic and infectious diseases was previously determined by questionnaire. Results: Seventy-two of 89 (81%) infants were participated. Prevalence of all studied species was not different between glutamine-supplemented and control groups. Allergic infants were less frequently colonized with bifidobacteria than nonallergic infants (p = 0.04). Between neonatal period and 1 year, prevalence of bifidobacteria was increased (p < 0.001), of Chis/lit group was unchanged (p = 0.84), and of E. coli was decreased (p < 0.001). Conclusion: The beneficial effect of glutamine-enriched enteral nutrition on the incidence of atopic dermatitis in the first year of life in VLBW infants is not related to changes in bifidobacteria, Chis/lit group or E. coli. Allergic VLBW infants are less frequently colonized with bifidobacteria compared to nonallergic VLBW infants. © 2010 Foundation Acta Paediatrica/Acta Paediatrica.

Purpose To determine the significance of blasts in the CSF without pleiocytosis and a traumatic lumbar puncture in children with acute lymphoblastic leukemia (ALL). Patients and Methods We retrospectively studied a cohort of 526 patients treated in accordance with the virtually identical Dutch protocols ALL-7 and ALL-8. Patients were classified into five groups: CNS1, no blasts in the CSF cytospin; CNS2, blasts present in the cytospin, but leukocytes less than 5/μL; CNS3, blasts present and leukocytes more than 5/μL. Patients with a traumatic lumbar puncture (TLP; > 10 erythrocytes/mL) were classified as TLP+ (blasts present in the cytospin) or TLP− (no blasts). Results Median duration of follow-up was 13.2 years (range, 6.9 to 15.5 years). Event-free survival (EFS) was 72.6% (SE, 2.5%) for CNS1 patients (n = 304), 70.3% (SE, 4.7%) for CNS2 patients (n = 111), and 66.7% (SE, 19%) for CNS3 patients (n = 10; no significant difference in EFS between the groups). EFS was 58% (SE, 7.6%) for TLP+ patients (n = 62) and 82% (SE, 5.2%) for TLP− patients (n = 39; P < .01). Cox regression analysis identified TLP+ status as an independent prognostic factor (risk ratio, 3.5; 95% CI, 1.4 to 8.8; P = .007). Cumulative incidence of CNS relapses was 0.05 and 0.07 in CNS1 and CNS2 patients, respectively (not statistically significant). Conclusion In our experience, the presence of a low number of blasts in the CSF without pleiocytosis has no prognostic significance. In contrast, a traumatic lumbar puncture with blasts in the CSF specimen is associated with an inferior outcome.

BACKGROUND: EUROCARE-3 collected data from 45 population-based cancer registries in 20 countries on 24 620 European children aged from 0 to 14 years diagnosed with malignancy in the period 1990-1994. METHODS: Five-year survival between countries was compared for all malignancies and for the major diagnostic categories, adjusting for age, and estimated average European survival weighting for differences in childhood populations. RESULTS: For all cancers combined, survival variation was large (45% in Estonia to 90% in Iceland), and was generally low (60-70%) in eastern Europe and high (> or =75%) in Switzerland, Germany and the Nordic countries (except Denmark). The Nordic countries had the highest survival for four of the seven major tumour types: nephroblastoma (92%), acute lymphoid leukaemia (85%), CNS tumours (73%) and acute non-lymphocytic leukaemia (62%). The eastern countries had lowest survival: 89% for Hodgkin's disease, 71% for nephroblastoma, 68% for acute lymphoid leukaemia, 61% for non-Hodgkin's lymphoma, 57% for central nervous system (CNS) tumours and 29% for acute non-lymphocytic leukaemia. CONCLUSIONS: The Nordic countries represent a survival gold standard to which other countries can aspire. Since most childhood cancers respond well to treatment, survival differences are attributable to differences in access (including referral and timely diagnosis) and use of modern treatments; however, the obstacles to access and application of standard treatments probably vary markedly with country.

EUROCARE-3 analysed the survival of 1815584 adult cancer patients diagnosed from 1990 to 1994 in 22 European countries. The results are reported in tables, one per cancer site, coded according to the International Classification of Diseases (ICD)-9 classification. The main findings of the tables are summarised and commented on in this article. For most solid cancers, wide differences in survival between different European populations were found, as also reported by EUROCARE-1 and EUROCARE-2, despite a remarkable (10%) overall increase in cancer survival from 1985 to 1994. Survival was highest in northern Europe (Sweden, Norway, Finland and Iceland), and fairly good in central-southern Europe (France, Switzerland, Austria and Spain). Survival was particularly low in eastern Europe, low in Denmark and the UK, and fairly low in Portugal and Malta. The mix of tumour stage at diagnosis explains much of the survival differences for cancers of the digestive tract, female reproductive system, breast, thyroid, and also skin melanoma. For tumours of the urinary tract and prostate, the differences were explained mainly by differences in diagnostic criteria and procedures. The case mix by anatomic subsite largely explains differences in survival for head and neck cancers. For oesophagus, pancreas, liver and brain cancer, with poor prognoses, survival differences were limited. Tumours, for which highly effective treatments are available, such as testicular cancer, Hodgkin's lymphoma and some haematological malignancies, had fairly uniform survival across Europe. Survival for all tumours combined (an indicator of the overall cancer care performance of a nation's health system) was better in young than old patients, and better in women than men. The affluence of countries influenced overall cancer survival through the availability of adequate diagnostic and treatment procedures, and screening programmes.

Summary International differences and trends in cancer survival withinEurope are larger than can reasonably be accounted for by arte-fact, bias or chance. The geographical patterns and trends in sur-vival are often broadly consistent with geographical differences ortrends in the type of cancer, diagnostic investigations or overallinvestment in health care, and for several major cancers, support-ing evidence is available from population-based studies of clinicalinformation. Incomplete ascertainment of cancer cases, particu-larly of long-term survivors, may contribute to some regional andinternational differences in survival, however, and more system-atic information on completeness is required. We may concludethat large international differences in survival do exist for manycancers, but we should be cautious in drawing quantitative orcausal conclusions from observational survival data.We do not yet have a fully satisfactory interpretation of thesedifferences, but we have few alternatives to this type of study if weare to understand the determinants of improved outcome for allcancer patients, and to enable better planning of their health care.The EUROCARE Working Group has developed several strategiesto disentangle the various possible explanations [73]. These includefurther development of high-resolution studies to examine theimpact on survival differences of disease stage, staging techniquesand treatment; and further development of mathematical modelsof cure. Extension of systematic international survival compari-sons to other regions of the world, such as Australia, Canada, Japanand the USA, is also in progress (the CONCORD study) [22].Oncologists and epidemiologists may provide insight into thegeographic differences and trends in survival reported by thisstudy, and may suggest further lines of enquiry. Do we need morerefined studies of survival to monitor progress against cancer andto plan future cancer care? Will such analyses help us quantify theeffect of new treatments arising from recent progress in the basicsciences and genomics on population cancer survival rates? Sub-stantial human and financial resources are required to improve theoutcome of cancer treatment. Will future investments in cancerservices include matching investment to monitor their impact onsurvival and mortality?Earlier diagnosis and prompt, universal access to optimal treat-ment would be expected to reduce international differences incancer survival in Europe. To achieve this, oncologists and healthcare planners will need better information on the comparativeperformance of their health systems. Population-based cancer reg-istries provide some of the information for such comparisons, buttheir traditional output may no longer be sufficient to evaluate theeffectiveness of health systems, and especially to explain geo-graphical differences in survival. In some countries, their role isalso under threat. Confidentiality constraints recently inhibitedthe collection of cancer registration data in the UK [90], and thelinkage of cancer registrations and deaths is currently illegal inEstonia [91]. Both activities are essential for internationally com-parable survival rates. Legal protection for cancer registrationacross Europe will be required.The mission of cancer registries should be reconsidered, and thepriority shifted from classical descriptive epidemiology and geo-graphical pathology toward more analytical monitoring ofprogress against cancer, including the probability of survival andcure, the burden of cancer prevalence, and the late effects oftherapy. Several European studies of this type have been reportedrecently [3, 36, 9294] and others are in progress. Many cancer–registries are developing closer relationships with cancer clini-cians and general practitioners, and some now systematicallycollect detailed clinical information that was collected eitherirregularly or not at all in the past. These developments willimprove the power of population-based cancer data to explain dif-ferences in cancer survival, and should enhance their relevance toclinical practice.European average survival rates are useful for comparativepurposes, but they should not become the goal for cancer controlprogrammes: the benchmark should always be the highest achiev-able survival rates.The aim of exploring geographic differences in cancer survivalis not to establish international league tables or to excite nationalrivalries, but to estimate the range of survival rates, and to identifyregions or countries in which survival could be improved.

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.

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.

Aim-To evaluate academic career in long term survivors of childhood acute lymphoblastic leukaemia (ALL), in comparison to their healthy siblings.Patients-Ninety four children treated for ALL with cranial irradiation 18 or 25 Gy and intrathecal methotrexate as CNS prophylaxis. Median age at evaluation was 20 years; median follow up since diagnosis was 15 years at the time of the study.Methods-Patients and their 134 siblings completed a questionnaire on school career. The percentage of referrals to special primary schools for learning disabled, and the final level of secondary education in patients and siblings were compared, using a six point classification. Within the patient group, the effect of possible risk factors (age at diagnosis, irradiation dose, and gender) was investigated.Results-Significantly more patients than siblings were placed in special educational programmes. A significant difference was found for level of secondary education. No effect of gender or irradiation dose was found, but younger age at diagnosis was significantly related to both referrals and school levels.Conclusion-Treatment for childhood ALL with cranial irradiation and chemotherapy at a young age is clearly associated with poorer academic career.

As an important determinant of response to chemotherapy, accurate measurement of cellular drug resistance may provide clinically relevant information. Our objectives in this study were to determine the relationship between in vitro resistance to prednisolone (PRD) measured with the colorimetric methyl-thiazol-tetrazolium (MTT) assay, and (1) short-term clinical response to systemic PRD monotherapy, (2) long-term clinical outcome after combination chemotherapy within all patients and within the subgroups of clinical good and poor responders to PRD, and (3) in vitro resistance to 12 other drugs in 166 children with newly diagnosed acute lymphoblastic leukemia (ALL). The 12 clinical poor PRD responders had ALL cells that were median 88-fold more in vitro resistant to PRD than 131 good responders (P = .013). Within all patients, increased in vitro resistance to PRD predicted a significantly worse long-term clinical outcome, at analyses with and without stratification for clinical PRD response, and at multivariate analysis (P ≤ .001). Within both the clinical good and poor responder subgroups, increased in vitro resistance to PRD was associated with a worse outcome, which was significant within the group of clinical good responders (P < .001). LC50 values, ie, lethal concentrations to 50% of ALL cells, for PRD and each other drug correlated significantly with those of all other 12 drugs, with an average correlation coefficient of 0.44 (standard deviation 0.05). The highest correlations were found between structurally related drugs. In conclusion, in vitro resistance to PRD was significantly related to the short-term and long-term clinical response to chemotherapy, the latter also within the subgroup of clinical good responders to PRD. There was a more general in vitro cross-resistance between anticancer drugs in childhood ALL, although drug-specific activities were recognized.

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.

DNA per cell content was routinely recorded by single-parameter flow cytometry in leukemic blasts from 473 children with acute lymphoblastic leukemia (ALL), enrolled in national studies ALL V, VI, and VII (1979–1991) of the Dutch Childhood Leukemia Study Group. The parameters bonemarrow %S-value and DNA Index were compared with clinical features, with chromosome number based on cytogenetic analyses and with treatment results in study ALL VI. %S-values, ranging between 1 and 36%, were unrelated to initial white blood cell count, immunophenotype, and DNA index but were lowest in blasts with L1 morphology. In study ALL VI (non-high risk), the survival of patients with ≦6% S-phase cells was superior to that of patients with %S-values of >6 (P = 0.030). Hyperdiploidy, defined by a DNA index ≧1.16, was compared to the cytogenetic hyperdiploid classification of n > 50. Initially there were 25 discrepancies in 189 samples jointly analysed by flow cytometry and cytogenetics. After review only five discrepancies remained unresolved. Hyperdiploidy, independent of the method used, was found to be unrelated to blast morphology and %S-phase cells but closely associated with c-ALL and was absent in T-ALL. In study ALL VI, event-free survival at 8 years of hyperdiploid patients was 90.6% but was not significantly different from non-hyperdiploid patients (EFS = 82.1%; P = 0.08). Routine DNA flow cytometry appeared a valuable adjunct to cytogenetic analyses and allowed the identification of a large subset of non-high-risk ALL patients in study ALL VI with a DNA index ≥1.16 or %S-value of ≦6.0 with highest survival probability. © 1995 Wiley-Liss, Inc.

Late events and side effects are reported in 392 children cured of leukemia. They originated from 1193 consecutively newly diagnosed children between 1972 and 1982, in first continuous complete remission for at least 6 y after diagnosis, and were treated according to Dutch Childhood Leukemia Study Group protocols (70%) or institutional protocols (30%), all including cranial irradiation for CNS prophylaxis. Data on late events (relapses, death in complete remission, and second malignancies) were collected prospectively after treatment; late side effects were retrospectively collected by a questionnaire, completed by the responsible pediatrician. The event-free survival of the 6-y survivors at 15 y after diagnosis was 92% (+/- 2%). Eight late relapses and nine second malignancies were diagnosed, two children died in first complete remission of late toxicity of treatment, and one child died in a car accident. The most important long-term side effects reported were learning disabilities (50%), short stature, obesity, and delayed pubertal development. No increase in the incidence of cardiovascular, pulmonary, urogenital, or gastrointestinal tract diseases or an increased vulnerability of the musculoskeletal system was found. However, prolonged follow-up is necessary to study the full-scale late effects of cytostatic treatment and radiotherapy administered during childhood.

Ecto-5'-nucleotidase (ecto-5'NT) catalyzes the extracellular dephosphorylation of nucleotides like IMP. Cytoplasmic 5'NT (cyto-5'NT) and non-specific (e.g. acid- and alkaline) phosphatases (AP) regulate the intracellular degradation of nucleotides. High NT and AP activities might cause a resistance to the thiopurines 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG). We studied the relation between these enzymes and immunophenotype, drug resistance and prognosis in 77 children with acute lymphoblastic leukemia (ALL). Enzyme activities were assessed radiochemically; in vitro drug resistance was measured with the MTT assay. AP activities were higher in T-ALL and B-ALL than in precursor B-ALL. Cyto-5'NT activity was very low in all phenotypes and accounted for a significant proportion of total IMPase activity only in the very immature CD10- c mu- precursor B-ALL. CD10+ ALL cases with high ecto-5'NT activities showed a trend (p = 0.065) for a lower probability of continuous complete remission than those with a low activity. Ecto-5'NT activity was not related to in vitro drug resistance to 6-TG. A weak correlation was found between in vitro 6-TG resistance and cyto-5'NT and AP activities. We conclude that high ecto-5'NT activities do not cause a resistance to 6-thiopurines in childhood ALL. Some patients have high cyto-5'NT and AP activities associated with 6-thiopurine resistance.

Decreased activity of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT), responsible for the conversion of 6-mercaptopurine and 6-thioguanine (6-TG) to their cytotoxic nucleotides, may cause resistance to these thiopurines in experimental leukemic systems. The clinical significance of this mechanism is as yet unclear. In 83 children with untreated acute lymphoblastic leukemia (ALL), we determined the prognostic value of HGPRT activity and the relation between HGPRT activity and resistance to thiopurines. HGPRT activity was determined radiochemically; in vitro resistance to 6-TG with the MTT assay. HGPRT level was significantly lower in T-ALL than in B-lineage ALL; no differences were found between sequential differentiation stages of B-lineage ALL. HGPRT activity was inversely related to the white-blood-cell count (WBC). Among patients with cALL and pre-B-ALL with WBC less than 50 x 10(9)/l, cases with a low HGPRT had a significantly poorer prognosis than those with a high HGPRT. WBC, age, sex, organomegaly and differentiation stage were comparable in both patient groups. No correlation was found between HGPRT activity and in vitro 6-TG resistance in cALL and pre-B-ALL patients. T-ALL cases were not more 6-TG-resistant than cALL and pre-B-ALL cases. Cells from 6 relapsed ALL cases did not show decreased HGPRT activity. We conclude that: (a) HGPRT is lower in T- than in B-lineage ALL and is constant in sequential differentiation stages of B-lineage ALL; (b) HGPRT activity is inversely related to tumor load; (c) low HGPRT activities are correlated with a poorer prognosis in precursor B-ALL but this cannot be explained by thiopurine resistance because (d) there is no relation between HGPRT activity and in vitro 6-TG resistance.

The value of routine bone marrow examination (RBME) in children during and after treatment for standard risk acute lymphoblastic leukemia (SR-ALL) was investigated. The clinical symptoms and peripheral blood findings at the time of bone marrow relapse of 28 children were reviewed and compared with those of 28 matched controls in continuous complete remission. Five (45%) children with bone marrow relapse during maintenance therapy and six (35%) after cessation of cytostatic treatment were asymptomatic at the time of relapse. Signs indicative of relapse during treatment were lymphoblast cells in the peripheral blood, thrombocytopenia, hepatomegaly, anemia, or leukopenia in decreasing order of frequency. After cessation of treatment these signs were lymphoblasts in the peripheral blood, hepatomegaly, splenomegaly, thrombocytopenia, or leukocytosis. Except for one case with thrombocytopenia, no signs suspicious for relapse were found in the control groups. When each sign was evaluated separately only the presence of lymphoblasts in peripheral blood and hepatomegaly were significant symptoms for relapse after cessation of treatment. The mean percentage of lymphoblasts in the bone marrow at the time of relapse was significantly lower for patients with an unpredicted relapse (46.8%) than patients with clinical and/or laboratory evidence of relapse (79.5%). When lymphoblasts were present in the peripheral blood the percentage of lymphoblasts in the bone marrow was always more than 40%, both during and after cessation of treatment. These data suggest a relation between clinical and laboratory symptoms and progression of the disease. It is concluded that 46% of relapses are detected by RBME in the absence of clinical or laboratory symptoms. This early detection may have a positive prognostic influence with more effective treatment for relapsed ALL.

Background. Sensitive techniques for detection of minimal residual disease (MRD) at degrees of one leukaemic cell per 103-106 cells (10-3-10-6) during follow-up of children with acute lymphoblastic leukaemia (ALL) can provide insight into the effectiveness of cytotoxic treatment. However, it is not yet clear how information on MRD can be applied to treatment protocols. Methods. We monitored 240 patients with childhood ALL who were treated according to national protocols of the International BFM Study Group. 60 patients relapsed and the patients in continuous complete remission (CCR) had a median event-free follow-up of 48 months. Bone-marrow samples were collected at up to nine time points during and after treatment. Standardised PCR analysis of patient-specific immunoglobulin and T-cell receptor gene rearrangements and TAL1 deletions were used as targets for semiquantitative estimation of MRD. Amount of MRD was classed as 10-2 or more, 10-3, and 10-4 or less. Findings. MRD negativity at the various follow-up times was associated with low relapse rates (3-15% at 3 years), but five-fold to ten-fold higher relapse rates (39-86% at 3 years) were found in MRD-positive patients. The distinct degrees of MRD appeared to have independent prognostic value (p [trend] < 0.001) at all separate time points, especially at the first two time points (at the end of induction treatment and before consolidation treatment). At these two time points a high degree of MRD (≥ 10-2) was associated with a three-fold higher relapse rate when compared with patients with a low degree of MRD (≤ 10-4). At later time points (including the end of treatment) even a low degree of MRD was associated with a poor outcome. Positivity in patients in CCR after treatment was rare (< 1%). With the combined MRD information from the first two follow-up time points, it was possible to recognise three different risk groups - 55 (43%) were in a low-risk group and had a 3-year relapse rate of only 2% (95% Cl 0.05-12%); 19 (15%) were in a high-risk group and had a relapse rate of 75% (55-95%); and 55 (43%) were in an intermediate-risk group and had a 3-year relapse rate of 23% (13-36%). Interpretation. Our collaborative MRD study shows that monitoring patients with childhood ALL at consecutive time points gives clinically relevant insight into the effectiveness of treatment. Combined information on MRD from the first 3 months of treatment distinguishes patients with good prognoses from those with poor prognoses, and this helps in decisions whether and how to modify treatment.