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The effects on long-term outcome in childhood acute lymphoblastic leukaemia (ALL) of the duration and the intensity of maintenance chemotherapy need to be assessed reliably. With this objective the Childhood ALL Collaborative Group coordinated a worldwide overview of all randomised trials that began before 1987.Individual patient data were sought for about 3900 children in trials of longer vs shorter maintenance (eg, 3 vs 2 years), 3700 in trials of intensive "reinduction" chemotherapy during maintenance, and 4400 in trials of various other questions, including 1300 in trials of pulses of vincristine and prednisone (VP) during maintenance. Analyses were of survival in first remission, overall survival, and cause-specific mortality.Deaths during remission were increased by longer maintenance (2.7 percent vs 1.2 percent), VP pulses (4.0 vs 3.2 percent), and intensive reinduction (4.8 percent vs 3.3 percent), but these increases were counterbalanced by reductions in relapses. Total events (relapse or death) were significantly reduced by longer maintenance (23.3 percent vs 27.6 percent), VP pulses (31.2 percent vs 40.4 percent) and intensive reinduction (27.8 percent vs 35.8 percent) (each 2p0.001). Many of those who relapsed were successfully re-treated, however, and only for intensive reinduction was overall survival significantly improved (18.5 percent vs 22.3 percent; 2p=0.01).Intensive reinduction chemotherapy in these trials produced an absolute improvement of about 4 percent in long-term survival; if the extra deaths in remission had been avoided, this would have been a 5 percent benefit. Further improvements in survival seem more likely to be obtained with intensive treatment than with longer low-level maintenance.

PURPOSE To assess the occurrence and possible causes of pulmonary thromboembolism (PTE) in children with hematologic malignancies evaluated in a single pediatric hematology center. PATIENTS AND METHODS Four hundred fifty-two patients admitted for leukemia in different stages of disease were evaluated whenever they presented with PTE-related acute respiratory failure (ARF). Diagnosis was based on a perfusional lung scan and a digital pulmonary angiography in most cases. When necessary, patients with ARF were transferred to the pediatric intensive care unit (ICU) for cardiorespiratory monitoring and support. Thrombolytic treatment was usually performed with urokinase at a loading dose of 2,000 to 4,560 IU/kg as single bolus followed by 2,000 to 4,530 IU/kg/h for 12 to 42 hours. Before thrombolytic therapy was discontinued, heparin was started at a daily dose of 100 to 500 IU/kg as a continuous infusion and continued for 6 to 26 days. RESULTS Twelve of 452 children developed 17 PTE episodes, which were resolved completely after appropriate therapy in 15 cases. Univariate analysis showed a statistical correlation between PTE and the diagnosis of acute myeloid leukemia (AML) (P < .001). No major bleeding was observed after thrombolytic treatment. CONCLUSION Our findings indicate that PTE is not an extremely rare event in children with leukemia and should be ruled out when sudden tachypnea develops in patients with risk factors such as previous tumor lysis, central venous catheter (CVC) malfunction, coagulation abnormalities, and drug-induced pulmonary toxicity. Complete resolution of PTE may be obtained in a high proportion of cases with early diagnosis and proper treatment.

A retrospective pharmacokinetic analysis was done of methotrexate serum levels after high-dose treatment (HD-MTX, four cycles at two-week intervals of 5 g/sq.1m. over 24 h i.v.) in children with non-B acute lymphoblastic leukemia (ALL) with the specific aim of seeking differences in patients of different ages, including infants under one year. A total of 122 children (seven infants aged 3 months-1 year, 26 children aged 1-3 years, 68 children aged 3-10 years and 21 adolescents aged 10-15 years) with normal liver and renal function, receiving consolidation therapy at the Pediatric Clinic of Monza between May 1988 and April 1992, were enrolled in this study. MTX was given as an intravenous infusion in 24 h and serum concentrations were measured up to at least 72 h after the start of infusion by an enzyme immunoassay (TDX Abbot, Dallas, TX) in order to modulate folinic acid rescue. Pharmacokinetic analysis of MTX levels according to a two-compartment open model indicated that, compared to all children up to 10 years old, in adolescents older than 10 years the drug reached higher concentrations in serum and was cleared at a lower rate. Steady-state levels and AUC were from 60% higher to more than double and the total clearance of the compound, expressed either per square meter surface area or per kg body weight, in each cycle was significantly lower in adolescents > 10 years of age, sometimes being only one-third of the clearance in infants (0.2 vs. 0.6 1/h/kg and 6.6 vs. 10.7 1/h/sq.m). The relationship between each age and systemic clearance was highly significant as measured by regression analysis. Methotrexate systemic clearance progressively decreased as a function of age. Subsequent treatments did not induce changes in MTX pharmacokinetics. These data suggest that the better tolerance of HD-MTX in children may have a pharmacokinetic basis. The faster elimination of MTX in infants, who usually show the worst prognosis, suggests that full doses could be safely used in order to maximize the antileukemic effect without a high risk of toxicity.

The outcome of 171 children with ALL who relapsed for the first time after elective cessation of therapy (1–86 mo) and followed over 10 years (median 60 mo; range 1–232 mo) has been evaluated. One hundred and three patients relapsed in the bone marrow (BM), 29 in the testis (T), 21 in the central nervous system (CNS), 14 in the BM plus another site and 4 in other sites. Second remission was achieved in 97% of patients (97% BM, 100% T, 90% CNS, respectively) with reinduction schedules including three or more drugs. All but 4 out of 100 patients who relapsed in the BM received cranial reprophylaxis with intrathecal CT alone or CT plus radiotherapy. Seven patients in second CR underwent allogeneic bone marrow transplantation from an HLA matched sibling. The overall survival was 34% and disease-free survival (DFS) probability at 100 years was 22%. A second relapse was observed in 73% of patients. Forty children are alive in second continuous remission and 24 are alive after a second or subsequent relapse. Patients with isolated T relapse showed a significant better outcome than those with BM or CNS involvement. Most patients (62%) with isolated BM relapse showed a further disease recurrence in BM, and DFS was shorter when relapse occurred within 12 months from off-therapy. Eighty-two patients in second CR stopped the treatment a second time and showed a survival and DFS probabilities, respectively, of 69% and 43%. Thus, children with ALL who relapse after cessation of therapy still have a high risk of further late relapses and should be treated with intensive chemotherapy and CNS reprophylaxis. BMT must be considered for all patients relapsing in the BM within 12 months from off-therapy. © 1995 Wiley-Liss, Inc.

This is the tenth official document of the SIOP Working Committee on psychosocial issues in pediatric oncology, instituted in 1991. It is addressed to the pediatric oncology community. Children clearly have a right to participate in medical decisions regarding their own treatment, based on the developmental level of the child. The objective of these guidelines is to encourage physicians to share with the child developmentally relevant medical information specific to that particular child's health status, in the context of the child's own culture, so that he or she can actively participate in the decision-making process regarding his or her own health. These guidelines, geared toward this objective, discuss the child's right to medical information, the parents' legal responsibility for but not exclusive right over the child's health, and ways of encouraging the younger child's active participation in his or her own health care at an age-appropriate level of understanding. For adolescents, there should be a full and legally mandated power to make their own decisions regarding medical treatment.

Since the early 1970s, a cure for childhood cancer has become a reality: over 80% of cases are now cured. Yet, despite the relatively high cure rate, the diagnosis of leukemia continues to place a heavy burden on family functioning. The parents must walk the narrow line between focusing too much on the child’s disease and treatment and maintaining a normal family life. Because cure is such a real possibility, the children must be prepared for a full and active participation in adult life, just like their peers. Proper discipline must be maintained within as normal a family life as possible. The child’s continued attendance at school and participation in normal childhood activities is imperative in the child’s preparation for adulthood.

The antileukaemic efficacy of L-asparaginase is related to the ability of the enzyme to induce the complete disappearance from plasma of L-asparagine, an amino acid essential to lymphoblastic leukaemia cells. It is not feasible to monitor L-asparagine plasma levels in patients under L-asparaginase treatment using the usual analytical procedures as the enzyme continues the hydrolysis of L-asparagine after blood sampling and during plasma extraction. A method was therefore developed for the determination of L-asparagine in patients receiving L-asparaginase. Sulphosalicylic acid is added to blood samples to deproteinize and inactivate L-asparaginase rapidly. The samples are then analysed by HPLC using a Novapack C18 column and fluorescence detection. With the same method L-asparagine is determined in blood cells and, by difference, plasma levels are calculated. This method is highly specific and sufficiently simple and sensitive for clinical use.

Bone marrow (BM) and peripheral blood (PB) cells from patients with juvenile chronic myelogenous leukemia (JCML) exhibit spontaneous in vitro proliferation. Several cytokines including granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 beta (IL-1 beta), and tumor necrosis factor alpha (TNF alpha) have been implicated in supporting the growth of leukemic monocyte-macrophage colonies either by autocrine or paracrine pathways. In seven untreated JCML patients, we investigated the role of IL-1 in the spontaneous growth of these cells by specifically blocking IL-1 receptors. The IL-1 receptor antagonist (IL-1 Ra) was added to the clonogenic assays, and in each case significant (mean = 63%, range = 35% to 82%) inhibition of spontaneous proliferation was observed. Uncultured circulating cells from PB or BM of four out of five patients expressed IL-1 beta-specific mRNA and secreted the protein into the culture supernatants. Moreover, by means of reverse transcriptase-polymerase chain reaction (RT-PCR), we demonstrated that most of the spontaneously growing leukemic colony- forming unit cells (CFU-C) obtained from BM cells of two patients were positive for the presence of the IL-1 beta-specific mRNA. Despite the presence of a measurable amount of GM-CSF in JCML cell culture supernatants, GM-CSF-specific mRNA in CFU-C cells of four cases was not detected by RT-PCR. These data further support a central role for IL-1 beta in the pathogenesis of JCML and suggest that the use of IL-1 Ra could represent a novel therapeutic strategy against this disorder.

Background. The event-free survival for pediatric leukemia in low-income Countries is much lower than in high-income countries. Late diagnosis, which is regarded as a contributing factor, may be due to “parental” or “medical” delay.Procedures. The present study analyses determinants of lag time from first symptoms to diagnosis of leukemia, comparing pediatric (0–16 years old) patients in two referral centers, one in Nicaragua and one in Italy. An observational retrospective study was conducted to assess factors influencing the time to diagnosis.Results. 81 charts of children diagnosed with acute myeloid leukemia or lymphoblastic leukemia were analyzed from each centre. Median lag time to diagnosis was higher in Nicaragua than in Italy (29 versus 14 days,P<0.001) and it was mainly due to “physician delay” (16.5 versus 7 days,P<0.001), whereas “patient delay” from symptoms to first medical assessment was similar in the two centers (7 versus 5 days,P=0.27). Moreover, median lag time from symptoms to diagnosis was decreased in Nicaraguan districts were a specific training program upon childhood oncological diseases was carried out (20.5 versus 40 days,P=0.0019).Conclusions. Our study shows that delay in diagnosis of childhood leukemia is mainly associated with “physician delay” and it may be overcome by programs of continuous medical education.

The chromosomal breakpoints of t(4;11) translocation of acute lymphoblastic leukemia (ALL) have been recently identified at molecular level and shown to involve the AF4 (FEL) gene on chromosome 4 and the ALL-1 (MLL, Hrx) gene on chromosome 11. The ALL-1/AF4 fusion gene is transcribed into a chimeric mRNA. Using primer sets derived from ALL-1 and AF4 cDNAs by reverse transcription-polymerase chain reaction (RT- PCR), we were able to amplify the breakpoint sites of the fusion transcript of all 15 ALL cases with karyotypic or molecular evidence of the t(4;11). DNA fragments of different size were obtained as the consequence of different breakpoints on chromosome 11 and the presence of alternative splicing of ALL-1 exon 8. The feasibility of monitoring the residual cells carrying the t(4;11) in 2 ALL patients with different clinical outcome was evaluated. Overall, the presented results provide evidence that RT-PCR can be used as a rapid method for detecting this chromosomal abnormality and following the patient's response to therapy.

The pattern of hepatitis C virus (HCV) serum markers and liver disease was investigated in 11 leukemic children showing anti-HCV reactivity at least once during long-term observation to define the role of HCV infection and the behavior of HCV serologic markers in this patient cohort. Antibodies to HCV by first- and second-generation enzyme-linked immunosorbent assay (ELISA) and by second-generation (four antigens) recombinant immunoblotting assay (RIBA) and HCV-RNA by nested polymerase chain reaction (PCR) were serially examined in serum. Liver disease was defined according to transaminase levels. Seven of 11 patients were found HCV-RNA positive during chemotherapy and after blood transfusion, 3 of 11 became viremic during follow-up, and 1 of 11 was always HCV-RNA negative. Seroconversion to anti-HCV positivity by second-generation ELISA occurred in all the HCV-RNA positive children either during or after chemotherapy. Alanine aminotransferase (ALT) levels were elevated in all the HCV-RNA positive patients during antileukemic treatment and normalized in seven of them after therapy withdrawal, despite persisting viremia. These results indicate that HCV- RNA testing by polymerase chain reaction is required to correctly identify HCV infection in patients with leukemia while on chemotherapy. Viremia did not correlate with ALT levels and anti-HCV patterns.

A total of 2192 children with acute lymphoblastic leukaemia who had reached cessation of therapy in complete remission were followed for a median time of 52 months after treatment suspension. Of the 485 relapses observed, 62.3% occurred in the first year off therapy and 68.9% involved the bone marrow. Eight relapses were reported more than 5 years (62–143 months) after treatment withdrawal. Males fared worse than females consistently, experiencing 1.5 times more relapses ( P 20 years) were married and 16 have had 21 healthy children. Twenty-four per cent of patients experienced an unfavourable event. Relapses accounted for 93% of failures. Central nervous system late effects and second malignancies were the major causes of non-leukaemic morbidity and mortality.

Modern treatment of childhood acute leukemias started with the use of methotrexate (MTX) by Farber and colleagues in 1948 (reviewed in Dawn of Chemotherapy of Childhood Cancer) (Wolff 1999). The first observations of risk categorizations came in 1949 when Wolf Zuelzer noted that in patients treated with supportive care alone, those with initial white blood cell (WBC) counts of less than 10,000/μL survived longer than those with higher WBC counts (Zuelzer 1949). Subsequently, Dr. Roger Hardisty called attention to a lymphosarcoma variant that is detectable on chest X-ray by the presence of mediastinal enlargement. In 1975, two groups of investigators (from St. Jude Children’s Hospital, Memphis and Children’s Hospital of Michigan, Detroit) simultaneously showed that the so-called lymphosarcoma variant is of T-cell lineage (Ravindranath et al. 1975; Sen and Borella 1975), and in 1978 Secker-Walker, Lawler, and Hardisty (Secker-Walker et al. 1978) showed the critical importance of cytogenetics in childhood common acute lymphoblastic leukemia (ALL). Shortly thereafter, immunophenotyping and cytogenetic evaluation of childhood ALL became a standard practice.

Background High dosage anthracyclines in pediatric patients with acute lymphoblastic leukemia (ALL) is associated with cardiotoxicity. However, data on the cardiac effects of lower cumulative doses of these drugs are not conclusive. The aim of this study was to assess the cardiac effects of low cumulative anthracycline doses in long-term survivors of ALL. Procedure Echocardiograms were performed on 62 long-term ALL survivors, without any overt or sub-clinical signs or symptoms of heart failure. The interval after stopping therapy was 12.6 ± 4.3 years; the mean cumulative dose of anthracyclines was 228.2 ± 42.3 mg/m2. Left ventricular (LV) structure and function were studied by echocolor-Doppler. An age, gender and body surface area (BSA) matched group of healthy subjects was used as controls. Cardiac data were analyzed before and after BSA normalization. Results Long term survivors of ALL, showed a lower LV mass index, interventricular septal and posterior wall thickness, which were independently related to gender and to age at which the ALL diagnosis was made. Data analyzed according to gender showed that abnormalities were confined to the female group. No alterations were observed in the ALL male group versus the corresponding control group. No relationship was observed between the echocardiografic abnormalities and the duration of follow-up or the anthracycline mean dose employed. Conclusions In the absence of any signs or symptoms of heart failure, female ALL survivors treated with low cumulative anthracycline doses, showed a reduced LV mass and wall thickness. This suggests that in female ALL survivors an echocardyographic follow-up should be recommended. Pediatr Blood Cancer. 2010;55:1343–1347. © 2010 Wiley-Liss, Inc.

Unusual sites of relapses following bone marrow transplantation (BMT) for childhood acute lymphoblastic leukemia (ALL) are rarely reported. We report the case of a 16-year-old girl who presented with an isolated right breast relapse 8 months after allogeneic BMT for ALL in second remission. Biopsy showed an ALL infiltrate. Bone marrow and CSF were normal. The girl never showed before extramedullary involvement. She was treated with local radiotherapy and mild systemic chemotherapy. Nine months after breast relapse, she presented an isolated central nervous system relapse. The treatment of isolated extramedullary relapses following BMT is still controversial.

Since its foundation in 1991, the SIOP Working Committee on Psychosocial Issues in Paediatric Oncology1 has developed and published 12 sets of Guidelines for health-care professionals treating children with cancer and their families. Those elements considered essential in the process of cure and care of children with cancer are summarized in this document as a formal statement, developed at the 2007 SIOP annual meeting in Mumbai. Elaboration of the concepts with detailed strategies for practice can be found in the referenced guidelines [1-12] and in a companion publication [13]. This article is a summary of what practitioners considered critical elements in the optimal care of the child with cancer, with the goal of stimulating a broader application of these elements throughout the SIOP membership.

Abstract 319 Aim: The Italian Association of Pediatric Haematology and Oncology (AIEOP) patients, diagnosed in the period September 2000-July 2006, were treated in the context of the AIEOP-BFM ALL 2000 Study. Some differences in high risk (HR) treatment and hematopoietic stem cell transplantation (HSCT) indications justify separate reporting of results obtained by AIEOP and BFM respectively. We report here the AIEOP experience. Patients and methods: Overall, 1999 AIEOP Ph negative Acute Lymphoblastic Leukemia (ALL) patients were eligible to the AIEOP-BFM ALL 2000 Study. High Risk (HR) criteria were: t(4;11) translocation, Prednisone Poor Response (PPR), no complete remission (CR) at day 33, high minimal residual disease (MRD) levels (≥10-3) at day 78 (HR-MRD). Treatment consisted of protocol I (patients were randomised to receive either dexametasone or prednisone in induction), 3 HR polychemotherapy blocks, a randomized comparison between delayed intensification based on protocol II repeated twice or protocol III repeated thrice, cranial radiotherapy (CRT), maintenance therapy for a total of 2 years of treatment. Results: 311 patients were classified as being at HR (15.6% of the total ALL population) and had an overall event-free survival (EFS) and Survival of 58.7%(standard error 2.9) and 70.1%(2.7), respectively. For the 204 patients randomized to different steroids in protocol I, we observed a 5-year EFS of 62.7%(5.0) and 62.3%(4.8) and a 5-year Survival of 72.7%(4.7) and 72.8%(4.3) for dexamethasone and prednisone arm, respectively. The 5-year EFS was 44.4%(4.5) in 132 patients at HR for MRD, 36.4%(14.5) for the 11 patients at HR for t(4;11), 41.2%(11.9) for the 17 patients at HR for no CR at day 33, 74.6%(3.7) for the 151 patients at HR only for PPR. Patients at HR with Conclusions: These data show that AIEOP-BFM ALL 2000 HR therapy is very effective for patients defined at HR for PPR. These patients could thus be considered for some treatment reduction, i.e. sparing most toxic therapeutic elements such as CRT. MRD identifies patients at HR (8.7% of the analysed population, 42% of HR patients), who have a poor outcome despite receiving intensive BFM treatment, including HSCT, and who may thus be eligible for innovative therapies. Disclosures: No relevant conflicts of interest to declare.

Abstract 1578 Poster Board I-604 Background T-ALL accounts for about 15% of pediatric ALL and still represents a clinical challenge, because more than 20% of children experience a recurrent disease which has a dismal prognosis. Characterization of molecular alterations with prognostic impact may be useful for an early identification of patients at high risk of failure in whom more intensive treatments, including hematopoietic stem cell transplantation (HSCT) may be considered. CALM-AF10 results from a recurring t(10;11)(p13;q14-21) chromosomal translocation and is the most frequent fusion transcript in both adult and pediatric patients with T-ALL. Its presence has been associated with a poor prognosis (Asnafi V et al. Blood 2003; van Grotel M et al Haematologica 2006). The aim of the present study was i) to define the incidence of CALM-AF10 among homogeneously treated children with T-ALL and ii) to evaluate the outcome of these patients. Materials and Methods We studied 201 patients with T-ALL, diagnosed and enrolled between 9/2000 and 12/2007 in the ALL-2000 protocol and the subsequent modified 2000 study (ALL-R-2006) of the Associazione Italiana di Ematologia ed Oncologia Pediatrica (AIEOP) which consist of an intensive chemotherapy strategy based on BFM-ALL schedules. Patients were mainly stratified according to prednisone response evaluation (good response: blast count at day 8 less than 1000/mmc) and detection of minimal residual disease (MRD) performed at day 33 (Timepoint 1) and at day 78 (Timepoint 2). When both TPs were negative children were considered to be at Standard Risk (SR); patients with TP1 and/or TP2 positive and TP2 '10-3 were considered to be at Intermediate Risk (MR); children with TP2 positive ≥10-3 belong to the high risk (HR) group. Patients with prednisone poor response and MRD-HR were considered eligible for HSCT from a sibling donor in first complete remission. Event free survival (EFS) and overall survival (OS) estimates with 95% CIs were calculated through the Kaplan-Meier method and differences compared with the log-rank test. RT-PCR reactions for detection of CALM-AF10 were performed as previously reported (Asnafi V et al Blood 2003) Results Ten patients resulted not eligible and were excluded from analysis. Among the 191 evaluable children with T-ALL, 14 (7,3%) were positive for CALM-AF10. Twelve (85%) of these patients were males. Median age was 8 years (range 2 – 13). Immunophenotyping showed thymic/intermediate features in 6 cases, mature in 5, early in 1, biclonal in 1 and unknown in 1, respectively. Eight cases showed a poor prednisone (PDN) response. Based on a randomized study performed in induction in the frame of the ALL-2000 protocol on the efficacy of PDN vs dexametasone (DXM) 8 children were treated with PDN and 3 with DXM The remaining 3 cases, belonging to the ALL R-2006 protocol, were treated with DXM (n=2) and PDN (n=1). MRD-based stratification allowed the allocation of 3, 8 and 3 patients in the SR, MR and HR, respectively. Four cases relapsed (3 in the central nervous system and 1 in the bone marrow). EFS at 5 years of the 14 CALM-AF10 positive T-ALL children versus the 177 who were negative was 70.1% vs 63.9%, respectively (p-value log-rank=0.61). Small numbers did not allow to fully evaluate the impact of different variables such as initial steroid treatment (PDN vs DXM) or the MRD-based risk-group assignment Conclusions This study performed in a vast cohort of children with T-ALL shows that CALM-AF10 is found in about 7% of children with T-ALL and that does not predict a poor outcome when an intensive chemotherapy strategy is employed. Disclosures No relevant conflicts of interest to declare.

Purpose Speed of blast clearance is an indicator of outcome in childhood acute lymphoblastic leukemia (ALL). Availability of measurement of minimal residual disease (MRD) at an early time point with a reduced-cost method is of clinical relevance. In the AIEOP-BFM-ALL (Associazione Italiana Ematologia Oncologia Pediatrica and Berlin-Frankfurt-Münster Study Group) 2000 trial, patients were stratified by levels of polymerase chain reaction (PCR) MRD at day +33 and +78. AIEOP studied the prognostic impact of MRD measured by flow cytometry (FCM) at day 15 of induction therapy. Patients and Methods Bone marrow samples from 830 Italian patients were collected on day 15, after 14 days of steroids, and one dose of intrathecal methotrexate, vincristine, daunorubicine, and asparaginase. Cells were analyzed by four-color FCM for detection of leukemia-associated immunophenotypes. Results Three patient risk groups were identified by FCM: standard (< 0.1% blast cells; 42% of the total), intermediate (0.1 to < 10%; 47%), and high (≥ 10%; 11%). Their 5-year cumulative incidences of relapse were 7.5% (SE, 1.5), 17.5% (SE, 2.1), and 47.2% (SE, 5.9), respectively. In multivariate analysis, FCM was the most important prognostic factor among those available by day 15, with two-fold and five-fold increase in the risk of relapse compared with patients with less than 0.1%. PCR MRD, when added to the model, had significant prognostic impact; yet high levels of FCM MRD retained an independent ability to detect a significantly higher risk of relapse. Conclusion Measurement of FCM MRD in day 15 bone marrow was the most powerful early predictor of relapse, applicable to virtually all patients; it may complement PCR MRD–based stratification including later time points, thus allowing additional treatment tailoring.

Antibody to the recently identified hepatitis C virus (HCV) was investigated in sera of 50 leukemic children who had chronic liver disease (CLD), observed for 1 to 12.6 years after therapy withdrawal. All patients were tested for anti-HCV at regular intervals: Ortho- enzyme-linked immunosorbent assay (ELISA) test was performed in all cases. Reactive sera were also tested by recombinant immunoblotting assay to define the specificity of the results obtained by ELISA. Twelve cases (24%) were persistently positive (group A), 11 (22%) were transiently anti-HCV+ positive (group B), and 27 (54%) were negative. Mean SGPT peak during follow-up was significantly higher in group A (P = .014, A v B and P less than .00001, A v C). SGPT normalized off- therapy in 1 of 12 cases (group A), 10 of 11 (group B), and 19 of 27 (group C) (P = .0004, A v B and P = .012, A v C). Accordingly, liver histology, available in 37 patients, showed signs of chronic hepatitis in all patients in group A while most patients in group B and C had less severe liver lesions. These results indicate that HCV plays a significant role in the etiology of chronic hepatitis in leukemic patients and that persistent anti-HCV activity correlates with a more severe CLD, which could jeopardize the final prognosis of children cured of leukemia.

The aggressive radiotherapy and chemotherapy used in conditioning regimens for children with leukaemia undergoing bone marrow transplantation (BMT) cause a severe catabolic state. Total parenteral nutrition (TPN) is indispensable in the management of these patients. 25 children with leukaemia undergoing BMT were studied to evaluate the efficacy of TPN and the value of anthropometric parameters and biochemical variables (albumin, retinol-binding protein and prealbumin) in monitoring nutritional status in the critical post-BMT phase. The complications of TPN were mainly metabolic, generally mild and easily controlled. The hyperalimentation solution and infusion line were not responsible for infection in any patient. The marked variations in anthropometric parameters and albumin expected in such patients were not observed in our children due to the nutritional support given. Prealbumin and retinol-binding protein showed statistically significant, positive variations (P less than 0.01), thus proving sensitive indices of the response to nutritional repletion.

Background Posterior reversible leukoencephalopathy (PRES) is a clinical-radiological event that can affect children undergoing chemotherapy regimen. Studies have shown that it is not always reversible, in spite of its original definition. We analyzed PRES cases which occurred during the last 10 years at our institute to focus on their clinical, radiological and EEG follow-up. Procedures We analyzed 12 cases of PRES in children who underwent intensive chemotherapy regimens, detailing the acute neurological presentation of the syndrome, their neuro-imaging characteristics (MRI) and EEG findings, in both an acute phase and during follow-up. Results All patients survived the acute event, showing a clinical recovery of the acute neurological signs in 1–3 days and normalization of the EEG pattern in a period ranging from 1 to 8 months. During long term follow-up, four patients developed either clinical impairment or EEG-MRI anomalies. Conclusions We suggest that a long term follow-up is necessary to determine the reversibility of the neurological events. Clinical observation, as well as EEG and MRI should be included in follow-up evaluations. Pediatr Blood Cancer 2008;51:629–633. © 2008 Wiley-Liss, Inc.

Detection of minimal residual disease (MRD) is the most sensitive method to evaluate treatment response and one of the strongest predictors of outcome in childhood acute lymphoblastic leukemia (ALL). The 10-year update on the I-BFM-SG MRD study 91 demonstrates stable results (event-free survival), that is, standard risk group (MRD-SR) 93%, intermediate risk group (MRD-IR) 74%, and high risk group (MRD-HR) 16%. In multicenter trial AIEOP-BFM ALL 2000, patients were stratified by MRD detection using quantitative PCR after induction (TP1) and consolidation treatment (TP2). From 1 July 2000 to 31 October 2004, PCR target identification was performed in 3341 patients: 2365 (71%) patients had two or more sensitive targets (≥10-4), 671 (20%) patients revealed only one sensitive target, 217 (6%) patients had targets with lower sensitivity, and 88 (3%) patients had no targets. MRD-based risk group assignment was feasible in 2594 (78%) patients: 40% were classified as MRD-SR (two sensitive targets, MRD negativity at both time points), 8% as MRD-HR (MRD ≤10-3 at TP2), and 52% as MRD-IR. The remaining 823 patients were stratified according to clinical risk features: HR (n=108) and IR (n=715). In conclusion, MRD-PCR-based stratification using stringent criteria is feasible in almost 80% of patients in an international multicenter trial.

Purpose Between May 1995 and August 2000 the Associazione Italiana di Ematologia Oncologia Pediatrica conducted the ALL-95 study for risk-directed, Berlin-Frankfurt-Muenster (BFM) –oriented therapy of childhood acute lymphoblastic leukemia, aimed at exploring treatment reduction in standard-risk patients (SR) and intensification during continuation therapy in intermediate-risk patients (IR) as randomized questions and treatment intensification in high-risk patients (HR). The prognostic value of DNA index was explored in this setting. Patients and Methods A total of 1,744 patients were enrolled (115, SR; 1,385, IR; and 244, HR). SR patients (DNA index ≥ 1.16 and < 1.60; age, 1 to 5 years; and WBC < 20,000, non–T-immunophenotype, with no high-risk features) received a reduced induction therapy (no anthracyclines); IR patients were randomly assigned to receive or not receive vincristine and dexamethasone pulses during maintenance; HR therapy was based on a conventional BFM schedule intensified with three chemotherapy blocks followed by a double reinduction phase. Results The event-free survival and overall survival probabilities at 10 years for the entire group were 72.5% (SE, 1.3) and 83.6% (SE, 0.9); 85.0% (SE, 3.4) and 95.5% (SE, 2.0) in SR, 75.1% (SE, 1.5) and 87.5% (SE, 0.9) in IR, and 51.0% (SE, 3.2) and 57.2% (SE, 3.3) in HR patients, respectively. Patients with a favorable DNA index had superior EFS in both IR (83.8% [2.7%] v 73.9% [1.7%]) and in HR (67.8% [9.4%] and 49.6% [3.5%]). Of the six patients with DNA index less than 0.8, only one remained in remission. Conclusion Favorable DNA index was associated with a better prognosis in IR and HR patients defined by presenting clinical criteria and treatment with a BFM-oriented chemotherapy.

The occurrence of liver disease and its relation to HBV markers were investigated in ten children with AML who were given HDARAC as late consolidation therapy. None of them developed jaundice or biochemical evidence of cholestasis. During therapy, SGPT values were normal in 5/10 patients, while in the other 5 a sharp increase was noted. These enzyme elevations followed an unusual timing, peaking just before each infusion of HDARAC. Evidence of long-lasting hepatocellular necrosis after therapy withdrawal was found in 8/8 cases. One child died of fulminant type B hepatitis and HBsAg positivity was found in 2/10 patients during therapy and 3/8 after withdrawal of the drug. Three children developed HBV antibodies during the observation period. We conclude that the use of HDARAC in childhood leukemia is not associated with major evidence of direct drug hepatotoxicity while it clearly affects the natural outcome of viral hepatitis.

We performed an 11 year retrospective study on 34 sickle-cell paediatric patients, focusing on efficacy, safety and costs of an exchange transfusion program in 13 high risk patients. A good clinical control with improvement in patients' quality of life, no disease related complications, no significant iron overload and no procedure related side effects were observed during periodic erythroexchange. Costs of periodic erythroexchange versus chronic transfusion regimen were comparable. Periodic erythroexchange appeared a good alternative to chronic transfusion regimen for controlling the most severe forms of disease, particularly in patients who do not tolerate or do not respond to hydroxyurea.

Background: Studies in the 1970s and 1980s suggested that the outcome of childhood acute lymphoblastic leukaemia (ALL) could be improved by intensification of conventional continuation chemotherapy with pulses of vincristine sulfate and steroids. We aimed to investigate the efficacy and toxic effects of vincristine-dexamethasone pulses as an addition to the continuation-therapy phase in a large cohort of children with intermediate-risk disease who were treated with the Berlin-Frankfurt-Münster (BFM) treatment strategy. Methods: 3109 children, diagnosed with ALL and intermediate-risk features, were enrolled by eight participating organisations in eleven countries. All were treated with very similar protocols based on the BFM treatment strategy, which included induction, consolidation, reinduction, and continuation-therapy phases. At the beginning of the continuation-therapy phase, those patients in complete remission were randomly assigned to either a treatment or a control group. Control patients were given conventional mercaptopurine and methotrexate chemotherapy only. Patients in the treatment arm were also given pulses of vincristine (1·5 mg/m2 weekly for 2 weeks) and dexamethasone (6 mg/m2 daily for 7 days) every 10 weeks for six cycles. The primary outcome measure was disease-free survival. Analysis was by intention to treat. The study is registered at http://www.clinicaltrials.gov with the identifier NCT00411541. Findings: 174 patients (5·6%) relapsed or died in complete remission before randomisation. Of the remaining 2935 patients, 2618 (89·2%) were randomly assigned: 1325 to the treatment group and 1293 to the control group. With median follow-up of 4·8 years, 240 children in the treatment group and 241 in the control group had relapses; 15 in the treatment group and 14 controls died in complete remission or developed second malignant neoplasms. The 5-year and 7-year disease-free survival estimates were 79·8% (SE 1·2) and 77·5% (1·5) in the treatment group and 79·2% (1·2) and 78·4% (1·3) in the control group, respectively. Treatment with pulses of vincristine and dexamethasone was associated with a non-significant 3% relative-risk reduction (hazard ratio 0·97; 95% CI 0·81-1·15; p=0·70). Interpretation: Children with intermediate-risk ALL who received intensive chemotherapy based on BFM protocols did not benefit from intensification of the continuation-therapy phase with a schedule of pulses of vincristine and dexamethasone. © 2007 Elsevier Ltd. All rights reserved.

Minimal residual disease (MRD), the most sensitive method to evaluate treatment response, has been adopted to stratify patients in study AIEOP-BFM ALL 2000. To assess whether PCR-MRD levels discriminate outcome in patients classified by WBC count, age at diagnosis, NCI criteria (Standard Risk, SR: WBC < 50,000/cmm and age 1–9 years; High Risk, HR: all others) and TEL/AML1 status. Between 07–2000 and 07–2006, 4,730 Ph-negative patients were enrolled in AIEOP-BFM ALL 2000 study. They were treated with BFM Induction (protocol IA) consolidation (protocol IB), extra-compartment/intensified consolidation (HD-MTX in non-HR patients, blocks in HR patients), reinduction therapy (one or more Protocols II or III), followed by maintainance. BM samples obtained at weeks 5 (Time Point 1, TP1) and 12 (TP2) of induction/consolidation therapy were used for PCR-based MRD analysis of patient specific gene targets. At least 2 sensitive markers (≥ 1 x 10−4) could be determined in 3,707 (78.4%) patients. SR was defined by MRD− at both TP1 and TP2; HR by MRD ≥1x10−3 at TP2; Intermediate Risk (IR): all others. Median follow-up was 3 years; 5-year percent EFS (SE) estimates are given.Patients at MRD-SR, IR or HR had, respectively, an EFS of 93.0 (1.0), 80.5 (1.5) and 43.4 (6.0) in patients with WBC

Between May 1995 and August 2000 the Associazione Italiana di Ematologia Oncologia Pediatrica (AIEOP) conducted the ALL-95 study for risk-directed, BFM-oriented therapy of childhood acute lymphoblastic leukemia (ALL), aimed at exploring treatment reduction in standard risk (SR) and intensification during continuation therapy in intermediate risk (IR) as randomized questions and treatment intensification in high risk (HR). The prognostic value of DNA index was explored in this setting. 1,744 patients were enrolled, 115 SR, 1,385 IR, and 244 HR risk. SR patients (DNA index ≥1.16 and

We compared the clinical and biologic features and treatment results of patients with DS-ALL (n=120, 1.9%), compared to those without DS (n=6237), enrolled in the AIEOP trials between 1988 and October 2004. DS patients had significantly more often the following characteristics: female gender (55.0% vs 44.9%, p=0.027), age 10 years or older (28.3 vs 17.7%, p=0.014), high risk by NCI criteria (41.7 vs. 33%, p=0.045); on the contrary significantly less often they belonged to high-risk group according to current stratification (10.8 vs. 20.3%, p=0.017) or had T-lineage immunophenotype (0.8 vs 11.8%, p=100K/mm3: 6.6 vs. 10.8%). TEL/AML1 rearrangement was found in only 1 of 44 tested (2.2%). Of the 120 DS patients, 5 died during induction (4.2 vs 1.2% in non-DS), 1 was resistant (0.8 vs 1.4%). Leukemia relapse occurred in 31.6% of DS patients, compared with 24.9% of non-DS: bone marrow 22.5 vs 15.5%, CNS isolated 4.2 vs 3.6%, testis 0.8 vs 1.6%, BM combined 3.3 vs. 3.6%, other site 0.8 vs 0.6%. Death in complete remission occurred in 4.2 vs 2.0%. No second malignancy was reported. Overall, 59.2% of DS patients remained in first remission, compared with 70.2% of non-DS patients. This translated into a probability of EFS (SE) at 10 years of 56.2% (4.8) versus 67.7% (0.6) and a survival of 60.8% (5.0) versus 77.2% (0.6). 57 DS patients were diagnosed

Pediatric cancer programs in low-income countries (LIC) can improve outcomes. However, treatment must be tailored to the patient's living conditions and the availability of supportive care. In some cases, a more intense regimen will decrease survival since the increase in death from toxicity may exceed any decrease in relapse. Attempts to practice evidence-based pediatric oncology are thwarted by the lack of evidence derived from local experience in LIC to determine optimal therapy. This report summarizes treatment regimens used by pediatric oncologists from 15 countries of the Caribbean, Central and South America who participate in the Monza International School of Pediatric Hematology/Oncology (MISPHO). Patients with hepatoblastoma, Wilms tumor, and histiocytosis treated on unmodified published protocols had outcomes comparable to those in high-income countries (HIC). Those with rhabdomyosarcoma, osteosarcoma, Hodgkin lymphoma, and acute myeloid leukemia treated with unmodified regimens had event-free survival estimates 10%-20% lower than those reported in HIC due to higher rates of toxic death, abandonment of therapy, and relapse. Treatment of retinoblastoma is complicated by advanced stages and extraocular disease at diagnosis; improved outcomes depend on education of pediatricians and the public to recognize early signs of this disease. Use of unmodified protocols for Burkitt lymphoma and acute lymphoblastic leukemia have been associated with unacceptable toxicity in LIC, so MISPHO centers have modified published regimens by giving lower doses of methotrexate and reducing use of anthracyclines. Despite the use of all-trans-retinoic acid during induction for acute promyelocytic leukemia, the incidence of fatal hemorrhage remains unacceptably high.

We report the case of a 25-years-old male with beta-thalassemia major who developed acute heart failure, with severe systolic dysfunction, resulting from iron overload. Combined iron chelation with desferrioxamine and deferiprone together with standard cardiological treatment induced prompt and complete restoration of the cardiac function.

How does one help a family whose child has been diagnosed with a life-threatening illness? It is a deceptively simple question with complicated answers. This brief chapter is not meant to be a history of biopsychosocial pediatric oncology, and it does not cover every theme. The explosion of studies on children with cancer over these past decades (Pizzo & Poplack, 2001) renders a retrospective look formidable and subjective. The sole purpose of this retrospective examination into the earliest beginnings is to place into context some of the main themes that have appeared over the past years, so that they can serve as a foundation for our recommendations for future intervention and research in the field. That is our assigned task. Much of the review reflects personal respective experiences beginning in the late 1960s. The chapters that form this volume, written by many of the most experienced psychosocial researchers who have brought the field so far forward over these many years, are the state of the art, tell us where we have been most recently, and tell us in greater detail where we are at the moment. Where does our psychosocial history begin? What have we done these past many years to help the children and their families cope with the illness and its treatment? With due awareness of the subjectivity and inevitable unfairness of our venture, we undertake the task with due apologies for any omissions that may occur in this retrospective review. As we begin to look in some detail at the main themes formed over the past four decades, we place our review into the context of four preambles: a multidisciplinary and international effort; an alliance between physicians and parents; research and service; and a sharing of the research wealth with economically struggling countries. From the earliest years, the effort to care for the child with cancer has been multidisciplinary, multi-institutional, and international, involving a highly cooperative and collaborative effort of physicians, nurses, psychologists, social workers, and allied health care professionals working together across national borders.

The International Acute Lymphoblastic Leukemia Working Group, the so-called 'Ponte di Legno Workshop' has led to substantial progress in international collaboration in leukemia research. On April 27 -28, 2005, the 8th Meeting was held in Vienna, Austria, to continue the discussions about special common treatment elements in randomized clinical trials, ethical and clinical aspects of therapy. Furthermore, collaborative projects of clinical relevance with special emphasis on rare genetic subtypes of Childhood ALL were established. The following report summarizes the achievements and aspects of possible future cooperation. © 2006 Nature Publishing Group All rights reserved.

We prospectively evaluated the reconstitution of lymphocyte subpopulations in nine children with lysosomal diseases who underwent 11 allogeneic haematopoietic cell transplants (HCTs) following CD34(+) immunomagnetic enrichment, limited T-cell addback and in vivo B-cell depletion. Absolute lymphocyte count recovery was slow to cross the 5th percentile, occurring at a median of 10 months after HCT in patients with full chimaerism. Natural killer cells represented up to 90% of the total lymphoid population during the first 3 months. CD4(+) lymphocyte recovery occurred 9-18 months after HCT. In most patients, CD8(+) lymphocyte recovery was slow and comparable with that of CD4(+) lymphocytes. The CD4(+)/CD8(+) ratio normalised by 3-7 months after HCT in 50% of the patients. CD8(+) lymphocyte recovery was enhanced in patients with viral reactivation. Reconstitution of B-lymphocytes was particularly delayed in patients treated with rituximab. Declining chimaerism, rejection and viral reactivation were the most common problems in our series. Because of the unique graft manipulation, the pace of lymphocyte reconstitution was particularly slow, suggesting that these patients are at a significantly increased risk of infections for up to 2 years after HCT.

The clinical and diagnostic findings and the factors influencing the neurologic and radiologic outcome of symptomatic ischemic stroke were evaluated in a group of 2,318 children with acute lymphoblastic leukemia (ALL) treated according to the AIEOP (Italian Association of Pediatric Hematology and Oncology) study protocols. In this multicentric retrospective study, a questionnaire was sent to each of the 43 AIEOP centers participating in the study. The questionnaire was designed to obtain information on the number, type, and time of occurrence of ischemic strokes, biologic and immunologic features of each case, as well as clinical data of the recruited patients. A prevalence of 0.47% was found. All ischemic strokes were sinovenous thrombosis (SVT). The most common neurologic presentations were diffuse neurologic signs and seizures. MRI with or without venography revealed SVT in 100% of cases; superficial SVT was diagnosed in the majority of cases. Antithrombotic drugs, in particular unfractioned heparin and low-molecular-weight heparin, were administered without bleeding complications. This series shows an excellent long-term neurologic outcome in children with SVT. However, a complete radiologic resolution was found in only 54% of cases; the involvement of deep cerebral venous sinuses was associated with an unfavorable imaging outcome.

Introduction: Cure rates of ALL in children aged less than one year (i.e. infants) at diagnosis are in the range of 35–40%. Encouraging results have been recently reported in infants by using intensified treatment, including high dose chemotherapy, with or without allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission (CR). Aim: To evaluate the impact of the two treatment strategies adopted in the AIEOP ALL 91 and 95 studies on the outcome of ALL in infants. Patients and Methods: Fifty-two infants with ALL were enrolled between 1991 and 1999 in two consecutive studies, named AIEOP ALL 91 and ALL 95. Infants with an identified t(4;11) translocation had to be included in the high risk (HR) groups whilst those without this genetic abnormality could be treated in the intermediate (IR) or HR groups according to presenting features and treatment response. Patients belonging to the IR groups received a traditional BFM back-bone based treatment (protocols I, M and II), while those classified in the HR groups underwent an tensified treatment including induction (BFM protocol IA only, in study AIEOP ALL 91, and IA+IB in study ALL 95), consolidation with either 9 blocks of non-cross-resistant drugs (ALL 91) or 3 blocks followed by the 8-drug reinduction regimen - BFM protocol II - repeated twice (ALL 95). All patients were given a continuation phase (reinforced in HR patients of study ALL 95 by vincristine/prednisone pulses). Overall treatment duration was 2 years in both studies. Results: Infants in studies ALL 91 (n=21) and ALL 95 (n=31) had similar biological and clinical characteristics. The overall event-free survival (EFS) at 5 years was 45.0% (SE 7.0%). The EFS, after censoring for HSCT in 1st CR, was 38.1% (SE 11.4%) in ALL 91 and 51.6% (SE 9.9%) in ALL 95 (p-value=0.29). Patients treated in the IR arm of the two studies had a similar outcome. Better results were obtained in patients treated in the HR arm of ALL 95 study, where 9/17 chemotherapy-only patients and 3/4 HSCT patients are alive in CCR as compared to 1/7 and 0/2, respectively, in patients treated in the ALL 91 study. Discussion: These data show that full traditional BFM therapy intensified by 3 post-induction chemotherapy blocks and double protocol II (adopted in study ALL 95), is associated with a better outcome in infants with HR ALL.

Background In developing countries, implementation of effective pediatric cancer programs can reduce the overall rate of childhood mortality. To promote this objective, Monzas International School of Pediatric Hematology-Oncology (MISPHO)—for 14 countries with limited resources in Latin America—was launched in 1996. Methods A survey was conducted to evaluate the possible impact of MISPHO on the following areas: research, educational, and clinical activities, diagnostic services, transfusion medicine, supportive care, ancillary staffing complement, and parents' associations—before and after 1996. Results No institution lost resources or activities after 1996 and there were overall gains, in particular in educational activities, diagnostic capabilities, creation of single and multiple institutional treatment protocols. Conclusions Although notable improvements have occurred, there are still important needs that have to be satisfied. © 2004 Wiley-Liss, Inc.

SHP-2 is a protein tyrosine phosphatase functioning as signal transducer downstream to growth factor and cytokine receptors. SHP-2 is required during development, and germline mutations in PTPN11, the gene encoding SHP-2, cause Noonan syndrome. SHP-2 plays a crucial role in hematopoietic cell development. We recently demonstrated that somatic PTPN11 mutations are the most frequent lesion in juvenile myelomonocytic leukemia and are observed in a smaller percentage of children with other myeloid malignancies. Here, we report that PTPN11 lesions occur in childhood acute lymphoblastic leukemia (ALL). Mutations were observed in 23 of 317 B-cell precursor ALL cases, but not among 44 children with T-lineage ALL. In the former, lesions prevalently occurred in TEL-AML1(-) cases with CD19(+)/CD10(+)/cyIgM(-) immunophenotype. PTPN11, NRAS, and KRAS2 mutations were largely mutually exclusive and accounted for one third of common ALL cases. We also show that, among 69 children with acute myeloid leukemia, PTPN11 mutations occurred in 4 of 12 cases with acute monocytic leukemia (FAB-M5). Leukemia-associated PTPN11 mutations were missense and were predicted to result in SHP-2 gain-of-function. Our findings provide evidence for a wider role of PTPN11 lesions in leukemogenesis, but also suggest a lineage-related and differentiation stage-related contribution of these lesions to clonal expansion.

BACKGROUND: Countries with scarce resources have the right to appropriate essential health care but very few reports discuss how this can be achieved. We assessed the survival of a large cohort of pediatric oncological patients to provide hard data on which to base realistic evaluation and planning schemes. PATIENTS AND METHODS: This multicenter retrospective survey covered consecutively diagnosed and treated patients admitted to eight national level hospitals in seven countries in Central America and the Caribbean. The research protocol was discussed extensively, so the data to be collected and the criteria for their evaluation were clearly pre-defined. We analysed 2214 patients diagnosed between 1996 and 1999 with various cancers, classified as hemato-oncological disorders (70%) and solid tumors (30%). RESULTS: Three-year overall survival was 48.4% [standard error (SE) 1.3]. Detailed analysis of acute lymphoblastic leukemia highlighted the wide intercountry variability: 3-year survival was 62.2% (SE 5.3) in Cuba, 74.2% (SE 3.3) in Costa Rica, 61.7% (SE 4.9) in Nicaragua, and lower in the other four countries. CONCLUSIONS: The yield of diagnostic-therapeutic protocols depends largely on the context of care in which they are applied. This paper documents the importance of including epidemiological research in interventions for cooperation in complex health areas such as pediatric oncology.

Methods are now available to measure the magnitude of iron accumulation in the heart. Their validation currently relies on indirect evidence and not on chemical estimation in cardiac biopsies. All patients with symptomatic heart disease appear to have abnormal T2* values, but many patients without symptomatic heart disease also have evidence of increased myocardial iron. Although there is no proof to date that increased myocardial iron, as evidenced by abnormal magnetic resonance imaging, carries an adverse prognosis, it is likely that such new information will affect the chelating programme of patients. In these cases, there are a number of options available: (i) ongoing treatment with either desferrioxamine (DFO) or deferiprone may be intensified; (ii) the patient may be switched to the alternative chelator or (iii) combined chelation with both DFO and deferiprone may be started, which is more effective than using either chelator alone. For patients with symptomatic heart disease, continuous intravenous DFO with, or without deferiprone, remains the currently recommended treatment, in view of its documented ability to salvage these patients.

The Sixth International Childhood ALL Workshop was made possible by unrestricted educational grants from Sanofi-Synethelabo Inc., Glaxosmithkline, Enzon Inc., and Ilex. Preparation of the Meeting Report was supported in part by the Österreichische Kinderkrebshilfe and private donations to the Children's Cancer Research Institute; the Associazione Italiana Ricerca sul Cancro, Fondazione Tettamanti, and Consiglio Nazionale Ricerche-Ministero Instruzione Universitá Ricerca); the Deutsche Krebshilfe, Bonn, and Madeleine Schickedanz Foundation, Fürth, Germany; Cancer Research UKJ; grants from the US National Institutes of Health (CA-21765, CA-51001, CA-31566, CA-78824, CA-29139, CA-37379, GM-61393, and GM61374), a Center of Excellence grant from the State of Tennessee, and the American Lebanese Syrian Associated Charities (ALSAC). C-H Pui is the American Cancer Society - FM Kirby Clinical Research Professor. © 2004 Nature Publishing Group. All rights reserved.