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SIOPEL 2 was a pilot study designed to test the efficacy and toxicity of two chemotherapy (CT) regimens, one for patients with hepatoblastoma (HB) confined to the liver and involving no more than three hepatic sectors ('standard-risk (SR) HB'), and one for those with HB extending into all four sectors and/or with lung metastases or intra-abdominal extra hepatic spread 'high-risk (HR) HB'. SR-HB patients were treated with four courses of cisplatin (CDDP), at a dose of 80 mg/m(2) every 14 days, delayed surgery, and then two more similar CDDP courses. HR-HB patients were given CDDP alternating every 14 days with carboplatin (CARBO), 500 mg/m(2), and doxorubicin (DOXO), 60 mg/m(2). Two courses of CARBO/DOXO and one of CDDP were given postoperatively. Between October 1995 and May 1998, 77 SR-HB (10 of whom were actually treated with the HR protocol) and 58 HR-HB patients were registered and all 135 could be evaluated. Response rates for the entire SR-HB and HR-HB groups were 90% (95% CI 80-96%) and 78% (95% CI 65-87%). and resection rates were 97% (95% CI 87-99%) and 67% (95% CI 54-79%) including several children undergoing liver transplantation. For SR-HB patients, 3-year overall and progression-free survivals were 91% (+/-7%) and 89% (+/-7%) and for the HR-HB group 53% (+/-13%) and 48% (+/-13%), respectively. The short-term toxicity of these regimens was acceptable, with no toxic deaths. A treatment strategy based on CDDP monotherapy and surgery thus appears effective in SR-HB but, despite CT intensification, only half of the HR-HB patients are long-term survivors. For SR-HB patients, the efficacy of CDDP monotherapy and the CDDP/DOXO ('PLADO') combination are now being compared in a prospective randomied trial (SIOPEL 3). (C) 2003 Elsevier Ltd. All rights reserved.

C/EBP is a transcription factor that regulates terminal granulocytic differentiation. CEBPA mutations have been associated with improved outcome in both adult and pediatric patients with acute myeloid leukemia (AML). However, the impact in different treatment protocols, as well as the different outcome between single and double mutants, is still to be definitively established. We evaluated the prevalence and prognostic significance of CEBPA mutations in children with de novo non promyelocitic AML treated in Italy with the AIEOP-LAM 2002/01 pediatric protocol. Among 205 patients enrolled in the protocol between December 2002 and December 2007, 103 were successfully analyzed for CEBPA mutations by PCR amplification of TAD and bZIP domains of the gene, and through sequencing of positive cases after DHPLC analysis. Characteristics of analyzed and non analyzed patients were not statistically different. Two types of CEBPA mutations, N-terminal (TAD) truncating mutations and in-frame bZip domain mutations, were detected in 13/103 (12.6%) patients tested; 8 of them (61.5%) harboured both mutation types. Laboratory, clinical characteristics and outcomes for patients with CEBPA mutations were compared to those of patients with wild-type CEBPA. CEBPA mutations were significantly more common in older patients (8/13 vs 30/90 children were older than 10 years), in patients with FAB M1 (7/13 vs 4/90), and in patients with normal cytogenetics (13/13). None of the CEBPA mutated cases carried either FLT3 or NPM1 mutations. Only 1 mutated case was found in Standard Risk patients (defined as children carrying isolated CBF abnormality and achieving complete remission after 1 cycle of induction therapy), while the other 12 patients belonged to the High Risk group. Although the values did not reach statistical significance because of the low prevalence of CEBPA mutations, with a median follow up of 39 months (range 4–86) the event-free survival probability at 5 years was 76.9% vs. 59.6% for children with or without CEBPA mutations, respectively. The values for Disease-Free Survival were 83.3% vs. 65.4% and those for Overall Survival were 90.0%. 66.4%, respectively. No difference in terms of outcome was found between patient with a single and those with double mutants, neither between those with TAD- and bZIP- mutations. Therefore, patients in the AIEOP-LAM 2002/01 pediatric trial carrying CEBPA mutations seem to have a lower relapse rate and improved outcome, their overall survival approaching that of children belonging to the Standard Risk group (90% vs. 97%). If confirmed in a larger cohort of patients and with longer follow-up, these data suggest that CEBPA mutation analysis could be usefully employed to identify patients at lower risk of treatment failure and for allocating them into different classes of risk.

Since 1982, four consecutive studies on childhood acute myeloid leukaemia (AML) (namely LAM-82, -87, -87M and -92) have been conducted in Italy by the Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP) group. The induction therapy of the first three studies consisted of daunorubicin and cytarabine structured in a 3+7 backbone. In the most recent protocol (LAM92), patients received two induction courses including idarubicin, cytarabine and etoposide. Patients with acute promyelocytic leukaemia (20% of diagnoses) were included in LAM-87 and 87M studies. Postremissional therapy significantly changed over time, with an ever-increasing role given to stem cell transplantation (SCT). The long-term outcome of patients enrolled in the LAM-82, 87 and 87M studies was comparable, whereas that of children treated according to LAM-92 study was significantly better (P

BACKGROUND: As lowering glycated hemoglobin (HbA1c) levels is still the main goal of insulin treatment, severe hypoglycemia (SH) remains a common experience in children with Type 1 diabetes mellitus (T1DM) and their families. AIM: This study aims to evaluate the incidence and the clinical features of SH episodes in our Centre in the last 20 yr. SUBJECTS AND METHODS: We analyzed SH incidence in 269 patients (pts) diagnosed from 1990 to 2010 (total follow-up 2212.9 pts/yr). Inclusion criteria were at least 3 visits/yr and 1-yr follow- up. SH episode was defined as any condition of low blood glucose requiring third-party assistance. RESULTS: 50.2% of patients experienced at least 1 SH episode for a total of 345 episodes. Whole incidence was 15.6/100 pts/yr, slightly different between first and second decade (12.6 vs 16.5, p=0.047). HbA1c at the time of SH was lower in the non-basal bolus group (7.4±1.3 vs 8.2±1.4; p=0.0001) and worsened 3 months later (p=0.0001). Impaired awareness was the main or only symptom in 43.5%. SH occurred at night in 32% of patients; they were significantly younger than those with SH at other times. Five SH episodes or more occurred in 8.1% of patients who presented a lower HbA1c, a younger age and shorter disease duration than the other patients. HbA1c at first SH was negatively correlated with number of SH (r=-0.20; p=0.05). CONCLUSIONS: Despite the advent of new insulin regimens, we confirm that SH still represents a relevant risk and a current threat for patients with T1DM and their families.

Measurements of chest wall circumference are commonly used by physical therapists in clinical practice in order to determine chest wall mobility. However, the variability in the method for measuring this has not been reported previously among patients with chronic obstructive pulmonary disease.To analyze the reliability and accuracy of chest wall mobility measurements and to investigate the association between chest wall mobility and inspiratory capacity.Twenty-six patients with chronic obstructive pulmonary disease (forced expiratory volume in the first second = 45 +/- 14% of predicted) were evaluated over 2 visits. Spirometry was performed during the first visit, to characterize the sample. At each visit, 2 independent observers made chest wall mobility measurements twice, at the levels of the axillary, xiphisternal, and abdominal regions (total of 4 measurements), using a measuring tape.Despite high variability at all levels, the main results were that (1) two measurements made on the same day by the same observer showed good reliability (intraclass correlation coefficient 0.84-0.95); (2) two independent observers making the measurements on the same day showed fair-good reliability (intraclass correlation coefficient 0.69-0.89); (3) the same observer making the measurements at different visits, at least 2 days apart, showed good reliability (intraclass correlation coefficient 0.64-0.84); (4) inspiratory capacity was not associated with axillary and xiphisternal mobility, but it was closely related to measurements taken at the abdominal level.In summary, despite high reliability of intra-observer and inter-observer measurements, both within and between visits, high variability was observed in all chest wall mobility measurements. Although there was an association between inspiratory capacity and measurements made at the abdominal level, chest wall mobility did not correlate with pulmonary function.

Product quality directly relates to costumer satisfaction, thus it is important to define peach quality on the basis of consumer requirements and acceptance. Consumer science states that for a favorable purchase decision appearance (visible quality) of fruit is a primary criterion, specific consumer tests can assess fruit visual appeal. As related to eating quality, peach flavour depends on a delicate balance of sugars, acids, phenolics, and aromatic compounds, with a number of additional factors, such as pulp texture, also influencing perceived quality. Sensory evaluation is a unique source of information for monitoring and enhancing peach fruit eating quality. Sensory traits of peaches and nectarines from Regione Emilia Romagna, that received from UE the IGP label (Protected Geographical Indications), were investigated. Sensorial profiles of the cultivars 'Big Top' (Yellow Nectarine), 'Caldesi 2000' (White Nectarine), 'Royal Gem' (Yellow Peach), 'Silver Rome' (White Peach) were identified with the contribution of trained assessors with the aim of developing standard peach fruit sensory evaluation protocols for monitoring fruit quality and evaluating standard and new cultivars. Acidity, astringency and sweetness were the traits found more consistently with a positive correlation with overall appreciation.

SIOPEL 2 was a pilot study designed to test the efficacy and toxicity of two chemotherapy (CT) regimens, one for patients with hepatoblastoma (HB) confined to the liver and involving no more than three hepatic sectors ('standard-risk (SR) HB'), and one for those with HB extending into all four sectors and/or with lung metastases or intra-abdominal extra hepatic spread 'high-risk (HR) HB'. SR-HB patients were treated with four courses of cisplatin (CDDP), at a dose of 80 mg/m(2) every 14 days, delayed surgery, and then two more similar CDDP courses. HR-HB patients were given CDDP alternating every 14 days with carboplatin (CARBO), 500 mg/m(2), and doxorubicin (DOXO), 60 mg/m(2). Two courses of CARBO/DOXO and one of CDDP were given postoperatively. Between October 1995 and May 1998, 77 SR-HB (10 of whom were actually treated with the HR protocol) and 58 HR-HB patients were registered and all 135 could be evaluated. Response rates for the entire SR-HB and HR-HB groups were 90% (95% CI 80-96%) and 78% (95% CI 65-87%), and resection rates were 97% (95% CI 87-99%) and 67% (95% CI 54-79%) including several children undergoing liver transplantation. For SR-HB patients, 3-year overall and progression-free survivals were 91% (+/-7%) and 89% (+/-7%) and for the HR-HB group 53% (+/-13%) and 48% (+/-13%), respectively. The short-term toxicity of these regimens was acceptable, with no toxic deaths. A treatment strategy based on CDDP monotherapy and surgery thus appears effective in SR-HB but, despite CT intensification, only half of the HR-HB patients are long-term survivors. For SR-HB patients, the efficacy of CDDP monotherapy and the CDDP/DOXO ('PLADO') combination are now being compared in a prospective randomised trial (SIOPEL 3).

Twenty-seven consecutive Italian patients with Fanconi's anaemia (FA) underwent stem cell transplantation (SCT) from an HLA-matched related donor in 10 Italian centres of the Associazione Italiana Ematologia ed Oncologia Pediatrica (AIEOP), Gruppo Italiano di Trapianto di Midollo Osseo (GITMO). Twenty-two patients (81.5%) were conditioned with low-dose (median 20 mg/kg) cyclophosphamide (Cy) and thoraco-abdominal or total body irradiation (median dose 500 cGy), five patients (18.5%) with high-dose Cy (median 120 mg/kg). Graft-vs.-host disease (GVHD) prophylaxis was carried out with cyclosporin A in 26 cases; methotrexate (MTX) was added in eight cases. One patient received MTX alone. The median follow-up was 36 months. Ninety-two percent of patients (25 out of 27) engrafted, grade II and III acute GVHD occurred in 28% and 8% of patients, respectively, with chronic GVHD in 12.5%. Conditioning-related toxicity was mild: 4% of patients had grade III mucositis, 7.4% had grade II haemorrhagic cystitis, 14.8% had grade III liver toxicity and 11.1% had grade III renal toxicity. Transplant-related mortality at 12 months was 19.2%, survival at 36 months was 81.5%, with a median Karnofsky score of 100%. No late tumours occurred after a mean follow-up of the survivors of 5 years. None of the studied variables significantly affected the survival, including conditioning regimen, acute GVHD and clinical non-haematological phenotype. Among the studied variables, only conditioning regimens containing high-dose Cy and the presence of genital abnormalities were significantly (P0.05) associated with an increased rate of acute GVHD. Our study demonstrates that the Italian FA patients undergoing SCT from an HLA-matched related donor have a very good outcome. These patients, when compared with others of different ethnic origin who underwent allogeneic bone marrow transplantation, showed a less severe non-haematological phenotype, raising the possibility that this milder phenotype may have, at least in part, contributed to the outcome. Our data may provide a useful tool for further studies aiming to correlate genotype with phenotype.

To evaluate the safety and efficacy of a preparative regimen consisting of fractionated total-body radiation (9.9 to 12 Gy) and melphalan (140 mg/m(2) in a single dose) in children with acute myeloid leukemia in first complete remission (CR) given autologous bone marrow transplantation (ABMT).Fifty-three children (30 males and 23 females; age range, 1.5 to 18 years) were enrolled onto the study. The median time from first CR to ABMT was 3.5 months (range, 1.4 to 13 months), with 45 patients (85%) undergoing transplantation within 6 months from the diagnosis. Forty-five patients received in vitro marrow purging with standard-dose mafosfamide (100 microg/mL), seven patients were treated with interleukin-2 before marrow collection, and in the remaining child, the marrow was unmanipulated. The median infused cell dose was 1.8 x 10(8)/kg (range, 0.4 to 5.8 x 10(8)/kg).All patients but one achieved hematopoietic engraftment, with a median time to neutrophil recovery of 24 days (range,11 to 66 days). Treatment-related toxicity was moderate and consisted mainly of mucositis. One patient died from cytomegalovirus interstitial pneumonia, and one died from pulmonary hemorrhage. Fourteen patients (26%) relapsed at a median time of 6 months after ABMT (range, 2 to 17 months), with a cumulative relapse probability of 29% (95% confidence interval, 16% to 42%). The 5-year Kaplan-Meier estimate of survival for all 53 patients was 78% (range, 65% to 90%), whereas the overall 5-year disease-free survival was 68% (range, 55% to 81%), with a median follow-up duration of 40 months (range, 7 to 130 months).These data suggest that, in our cohort of patients, the combination of total-body irradiation and melphalan is safe and associated with good antileukemia activity, making ABMT an appealing alternative for postremission therapy in children with acute myeloid leukemia in first CR.

Since 1985 data concerning patients affected by malignant and non-malignant diseases, aged17 years, grafted in 16 centers nationwide, have been collected and stored in a central data base organized at the Associazione Italiana di Ematologia ed Oncologia Pediatrica (AIEOP) Operation Office within the AIEOP BMT Registry. The information, collected and structurally integrated with other specific disease-oriented national data bases, permitted the elaboration and the following publication of several analyses on survival, relapse probability and transplant-related mortality for the different diseases.

Since 1993 pediatric patients affected by high-risk Ewing sarcoma for the presence at onset of a large pelvic mass and/or metastatic disease, were enrolled in a national pilot study comprehensive, finally, of a high-dose chemotherapy (HDCT) procedure with hemopoietic stem cell support. The HDCT procedure considered as consolidation of the disease status obtained after the first-line therapy was followed by the reinfusion of granulokine colony-stimulating factor-primed (G-CSF) peripheral blood progenitor cell (PBPCT). Here we present the results in terms of treatment-related toxicity, hospitalization and rescue of the bone marrow function, in 17 pediatric patients enrolled in such a pilot protocol and submitted to HDCT and PBPCT at the end of first-line therapy.

Previous studies have considered the prognostic significance of CD10 expression in childhood acute lymphoblastic leukemia (ALL) and showed its linkage to a more favorable prognosis. The aim of this study was to assess the independent significance of CD10 expression in a large population of ALL patients.We revised the independent clinical relevance of CD10 expression in 2038 children with acute lymphoblastic leukemia (ALL), who were consecutively entered in 4 sequential trials of the Italian Association for Pediatric Hematology and Oncology (i.e. AIEOP studies 82, 87, 88, 91); 1142 were males and 896 females, age ranged between 1 and 14 years (yrs) at diagnosis. Of the whole group, 1471 children (72.2%) were defined as having standard risk, 567 (27.8%) as having a high risk.CD10 was detected in blast cells from 1706 of 1784 (95.6%) patients with B-lineage ALL and 46 of 254 (18.1%) with T-cell ALL. In the B-lineage subgroup CD10 expression was associated with presenting features such as age9 yrs and inclusion in the standard risk category. No significant differences were found between CD10+ and CD10- cases in T-lineage ALL, concerning presenting features, except for FAB L2 in the former group. We compared the event-free survival (EFS) rates for patients with T-ALL or B-lineage ALL, regarding CD10 positivity, overall and by individual study. Patients with T-ALL fared worse than those with B-lineage ALL (5 and 10 yrs EFS: 46.8% vs. 68.5% and 44.5% vs. 63.7% respectively, p = 0.0001). In multivariate analysis of B-lineage subgroup poorer EFS was associated with male sex, higher WBC (or = 20 x 10(9)/L), age9 yrs. Only WBCor = 20 x 10(9)/L and age9 yrs were parameters linked to poorer EFS in the T-lineage subgroup. Finally, we compared EFS rates for four groups of patients categorized as having high or standard risk, and according to CD10+ and CD10- expression. High-risk patients fared statistically worse than standard risk patients both in the CD10- and in the CD10+ groups (42% vs. 50.7% and 63.6% vs. 66.8%, respectively).CD10 expression does not have independent prognostic significance in either the larger subgroup of B-ALL patients or in T-cell ALL.

Fifty-seven patients aged55 years with acute lymphoblastic leukemia (ALL) in second or third bone marrow (BM) relapse or refractory to first-line therapy were enrolled in an Italian cooperative study. The ALL R-87 protocol included idarubicin (IDA) plus intermediate dose cytarabine (IDARA-C) and Prednisone (PDN) as induction, followed by a consolidation phase and BMT. Complete remission (CR) was achieved in 41/57 patients (72%). The CR rate was significantly higher in patients aged15 years at diagnosis and at time of treatment compared to those agedor = 15 (84% vs 50%, p=0.01 and 85% vs 54%, p = 0.02, respectively). Nineteen of 41 responders (46.3%) underwent bone marrow transplant (BMT) (10 autologous and 9 allogeneic). The estimated probabilities of event free survival (EFS +/- SE) and survival +/- SE at 6 years were 0.13 +/- 0.05 and 0.20 +/- 0.06, respectively, for all enrolled patients. Univariate analysis showed that children had a better EFS rate compared to adults (0.16 +/- 0.07 vs 0.08 +/- 0.07, p = 0.014). The estimated probability of disease free survival (DFS +/- SE) at 6 years was 0.18 +/- 0.07 for all responders. No differences in DFS were observed between patients submitted to allogeneic or autologous BMT (0.33 +/- 0.16 vs 0.25 +/- 0.15). Among patients treated in second or third relapse, a first CR lengthor = 48 months favorably influenced both DFS (p = 0.014) and EFS (p = 0.018). Our results show the efficacy of the intermediate dose ARA-C plus IDA schedule for high risk adult and childhood ALL patients. No differences in disease outcome were observed between allogeneic and autologous BMT.

Between January 1989 and July 1995 the search for an unrelated donor (UD) was started for 379 consecutive Italian patients with Philadelphia positive (Ph+) chronic myelogenous leukaemia (CML). 89 (23%) were transplanted. The overall probability of transplant before and after December 1991 was 16% and 49%, respectively (P=0.0001), and average interval between search activation and graft was 23 months and 13 months, respectively (P=0.0001). Disease-free survival (DFS) following 60 consecutive transplants performed before February 1996 was 41.5% at 48 months and was 64% for patients grafted after January 1993. In univariate analysis, five variables had a favourable effect on DFS: year of bone marrow transplantation (BMT) after 1993 (P=0.0002), HLA-DRB1 donor/recipient (D/R) match (P=0.0006), total body irradiation (TBI) containing regimen (P=0.0006), graft-versus-host disease (GvHD) prophylaxis including 'early' cyclosporin before the transplant, and a marrow cell dose3 x 10(8)/kg of recipient body weight (P=0.04). Multivariate analysis confirmed that HLA identity (P=0.006), TBI-containing regimen (P=0.0001) and 'early cyclosporin' (P=0.04) were associated with higher DFS. Transplant-related mortality (TRM) was 67% in patients grafted before January 1993 and 30% in patients grafted subsequently (P=0.002). Multivariate analysis confirmed DRB1 identity (P=0.03) and TBI-containing regimen (P=0.0005) to be independent factors predictive of low TRM. This suggests that the outcome of patients transplanted from an HLA DRB1 matched donor, after a TBI-containing preparative regimen, is similar to results recently reported in patients transplanted from geno-identical siblings. These results indicate that the search should be initiated at diagnosis for patients45 years of age and UD BMT should be considered early in the disease course for those with an available DRB1-matched unrelated donor.

We report the preliminary results of a prospective randomized study on the impact of two different dosages of Cyclosporine A (Cs-A) on probability of development of acute and chronic GVHD, transplant-related mortality (TRM), relapse rate (RR) and event-free survival (EFS). Fifty-nine pediatric patients given BMT from an HLA-identical sibling were centrally randomized to receive either Cs-A at a dosage of 1 mg/kg/die (CsA1) or at a dosage of 3 mg/kg/die (CsA3) intravenously for the first 21 days after BMT. Patients given Cs-A at a dosage of 1 mg/kg/die had a higher probability of developing acute GVHD, but a lower relapse rate, which translated into a better probability of EFS. These preliminary results to be confirmed with a longer follow-up suggest that the use of low doses of CsA is feasible even though associated with a higher incidence of GVHD, but without any increment in TRM. The reduction of immunosuppressive treatment after BMT favoured the development of a graft-versus-leukemia effect, which seems to play a relevant role in preventing leukemia recurrence and in improving the cure rate.

Background and Objective. Since 1988 the AIEOP has used BFM-based chemotherapy for childhood ALL. Current organization and results and role of cranial irradiation in the AIEOP-ALL 91 study are reported. Design and Methods. From 1991 to 1995, 1194 children (1 year, non-T-ALL, BFM risk factor (RF)

We compared the outcome of children with high-risk acute lymphoblastic leukaemia (HR-ALL) in first complete remission (first CR) treated with chemotherapy (CHEMO) or with allogeneic bone marrow transplantation (BMT) in a multicentre study. All children treated by the Italian Paediatric Haematology Oncology Association for HR-ALL in first CR between 1986 and 1994 were eligible for the study. 30 children were given BMT at a median of 4 months from first CR, with preparative regimens including total-body irradiation (n = 25/30). 130 matched controls for BMT patients were identified among 397 HR-ALL CHEMO patients. Matching on main prognostic factors and duration of first CR was adopted to control the selection and time-to-transplant biases. The comparative analysis was based on the results of a stratified Cox model. The estimated hazard ratios of BMT versus CHEMO at 6 months, 1 year and 2 years after CR were 1.38 (CI 0.59-3.24), 0.69 (CI 0.27-1.77) and 0.35 (CI 0.06-1.91), with an overall non-significant difference between the two groups (P = 0.34). With a median follow-up of 4 years, the disease-free survival was 58.5% (SE 9.3) in the BMT group and 47.7% (SE 4.8) in the CHEMO group, at 4 years from CR. Non-leukaemic death occurred in 4% of CHEMO and 10% of BMT patients. In the BMT group the estimated cumulative incidence of relapse at 1.5 years from CR was 31.5% (SE 8.8) and did not change thereafter, whereas in the CHEMO group the corresponding figure was 29.2% (SE 4.1) and the incidence continued to increase thereafter (48.2% (SE 4.8) at 4 years from CR). The results of this study suggest that, with respect to the CHEMO group, the higher risk of early failure in the BMT group is outweighed by the lower risk of relapse after 1 year. Results prompt the need for a prospective study, in order to demonstrate the likely advantage of BMT in HR childhood ALL in first CR.

The efficacy and feasibility of two intensive three-drug (idarubicin, cytarabine, etoposide) induction courses were tested in two consecutive AIEOP pilot studies (LAM 92P, LAM 93P) for the treatment of acute myeloid leukemia (AML) in children. From April 1992 to March 1993, 20 patients aged

This study reports a large cooperative experience in myeloablative therapy and bone marrow rescue undertaken to define better the outcome of children with disseminated neuroblastoma after megatherapy. Between 1984 and 1993, 135 children underwent myeloablative therapy with bone marrow transplantation (BMT) in nine Italian Centres. One hundred and seventeen children received unpurged autologous BMT, five allogeneic BMT and 13 peripheral blood progenitor cells as rescue. Of these 135 children, 57 were in 1st CR, 11 in 2nd or subsequent CR, 42 in 1st PR, and 25 had more advanced disease. Twelve children (9%) died of toxicity, 86 relapsed or progressed at 1-68 months (median 7 months) and 80 of these subsequently died of progressive disease. Forty-three children are still alive with 37 in continuous remission at a median of 65 months (30-123 months) after BMT. Overall and disease-free survival at 8 years are 28.5% (s.e. 4.3) and 26% (s.e. 4), respectively. Disease-free survival is 34.6% (s.e. 6.7) for the patients grafted in 1st complete remission, 23.6% (s.e. 6.6) for patients grafted in 1st partial remission, 36.4% (s.e. 14.5) for patients grafted in 2nd or subsequent CR, and 8% (5.4) for patients with advanced disease. We conclude these data confirm that early toxicity of myeloablative therapy is manageable and that myeloablative therapy with bone marrow rescue may contribute to an improved long-term survival of children with disseminated neuroblastoma but the objective of cure of all patients remains distant.

The Austrian-German-Italian (AGI) Pediatric Bone Marrow Transplantation Registry includes now data of 520 patients grafted for acute myeloid leukemia (AML) by autologous and allogeneic stem cells. In first complete remission (CR1) 145 patients with allografts had a possibility of event free survival (pEFS) of 0.57 and 140 patients with autografts a pEFS of 0.46. In second complete remission (CR2) autografted patients (n = 70) had a pEFS of 0.36 and allogeneic patients (n = 41) of 0.34. Patients with no CR went worse (allogeneic pEFS 0.15 n = 37; autologous pEFS 0.17 n = 6). Therefore, from the European data the following conclusions can be drawn: neither in CR1 nor in CR2 any statistical advantage for a particular transplantation type can be found. To assess the value of transplantation with family mismatch donors or matched unrelated donors (MUD) basing on these data pool is not possible. The following decisions should be reached: 1) BMT for AML with mismatched or unrelated donors should be done only within cooperative European trials. 2) Generally accepted definitions of indications for BMT in AML are needed. 3) Study protocols concerning conditioning are necessary.

Improved outcome of children with acute lymphoblastic leukemia (ALL) who received intensive chemotherapy was observed by the Italian Association for Pediatric Hematology Oncology (AIEOP). To verify if this improved outcome was also extended to T-cell acute lymphoblastic leukemia (T-ALL) patients after introduction of intensive chemotherapy, treatment responses of 2011 patients, including 184 with T-ALL treated over the decade 1982-1991, were analyzed. Further, the potential use of the association of presenting clinical and biologic features with treatment outcome to determine risk factors that might be useful for planning risk-directed therapeutic studies was analyzed.Of the 2011 children consecutively entered on the three sequential AIEOP trials ('82, '87, and '88), 1528 (76%) had successful immunologic studies of the bone marrow blasts. One hundred eighty-four (12%) had T-ALL. During these studies, four consecutive high-risk ALL treatment protocols (i.e., 8303, 8503, 8703, and 8803) were used. Because the treatment schedule in protocols 8503 and 8703 were almost identical, those patients were grouped together for the purpose of survival analysis. The 137 boys and 47 girls ranged in age from 16 months to 15.5 years (median, 7.8 years) at diagnosis, and 38% had a mediastinal mass. The rates of treatment response [i.e. complete remission (CR) and event free survival (EFS) rates] were compared for patients with T-ALL or B-cell progenitor ALL, overall and by individual study. Presenting features and early response to steroid monotherapy were also tested as possible prognostic factors.Overall, the CR rate was 94%, and the 7-year survival (SE) was 51.9% (4.2). T-ALL patients had a significantly worse outcome than B-lineage ALL patients [7-year EFS 40.4% (5.2) vs. 61.7% (1.7), P0.001]. Progressive improvement in EFS for T-ALL patients treated during 1 decade was observed, with 7-year EFS (SE) of 23.2% (8.3) for protocol 8303, 5-year EFS of 39.5% (7.1) for combined protocols 8503-8703, and 54.6% (7.1) for study '88, respectively. The analysis of prognostic factors for T-ALL patients showed that poor in vivo steroid response was the most unfavorable prognostic factor, followed by leukocyte level count50 x 10(9)/l (P = 0.04). The EFS for patients with T-ALL and good steroid response [63% (3.0)] was comparable with that of the unselected B-lineage ALL patients.EFS for patient with T-ALL has steadily increased in consecutive AIEOP ALL trials. However T-ALL patients still have a significantly worse EFS compared with patients with B-lineage ALL. Patients with T-ALL and a poor in vivo response to steroid monotherapy represent a particularly high risk treatment group.

Between May 1984 and May 1992, 75 children 3-19 (median 9) years of age underwent autologous marrow transplant. Clinical data were obtained from the BMT Registry of the AIEOP (Italian Association of Pediatric Hemato/Oncology). Fifty-six children were transplanted after marrow +/- other site(s) relapse and 19 after an isolated extramedullary relapse. The transplant preparative regimens varied according to the center performing the transplant. Seven patients (9%) died of transplant-related complications. Forty-four (58.6%) of 75 patients relapsed again following autologous BMT. The 5-year DFS was 27.8%. An isolated extramedullary relapse was the only variable that statistically influenced DFS. In this retrospective study, autologous BMT for patients with ALL in second CR following marrow relapse did not offer an encouraging result (13% probability of DFS at 5 years), whereas autologous BMT following an (early) isolated extramedullary relapse resulted in nearly 70% DFS. Autologous BMT may be appropriate for this latter group of patients.

PURPOSE This study was conducted to assess the comparative values of allogeneic bone marrow transplantation (BMT) and autologous bone marrow transplantation (ABMT) with sequential postremission chemotherapy (SPC) in children with acute myelogenous leukemia (AML) in first remission. PATIENTS AND METHODS From March 1987 to March 1990, 161 assessable patients younger than 15 years of age with newly diagnosed AML were treated uniformly with two courses of daunorubicin and standard-dose cytarabine. After initial consolidation with a course of daunorubicin, cytarabine, and thioguanine (DAT), patients in complete remission (CR) were randomized to receive either ABMT or SPC, except for those with an HLA-matched sibling who were assigned to undergo BMT. SPC consisted of three additional courses of DAT, followed by three pairs of drugs administered sequentially for a total of six cycles. RESULTS Overall, 127 of 161 patients attained CR (79%). The estimated probabilities of survival and event-free survival (EFS) at 5 years for all patients were 42% and 25%, respectively (median follow-up, 28 months). For the 127 complete responders, the 5-year probability of disease-free survival (DFS) was 31%, with a cumulative risk of relapse of 64%. For the purpose of this study, all complete responders were evaluated for analysis of disease outcome according to the intent-to-treat principle, regardless of whether they actually received the intended therapy. The 5-year DFS was 51% for the BMT group (n = 24), significantly higher (P = .03) than that observed for the other cohorts: 21% for ABMT (n = 35), 27% for SPC (n = 37), and 34% for a group of 31 nonrandomized (NR) patients. Bone marrow relapse was the most frequent cause of postremission failure in all therapeutic subgroups, including the BMT cohort, in which no deaths attributable to the toxicity of the procedure were recorded. CONCLUSION The results of this study show that BMT is more effective than ABMT or SPC in preventing leukemia relapse and extending DFS duration in children with AML in first remission.

Only complete resection can give hope for cure to children affected by hepatic malignancies.. The study evaluate the question: Surgical resection D'Emblèe or after Primary Chemotherapy?

Summary. A detailed analysis of immunophenotype of 112 infants aged less than 18 months with acute lymphoblastic leukaemia (ALL) was performed. Patients were divided into three groups on the basis of age at presentation (under 6 months: group 1; 6–12 months: group 2; 13–18 months: group 3). There were three cases of T-ALL (2.6%). The proportion of other subtypes was: common ALL in 59 patients (52.68%), pre-B ALL in 15 patients (13.3%), pre-pre-B ALL in 27 (24.1%) and acute undifferentiated leukaemia (AUL) in eight patients (7.14%). In non-T ALL, positivity to CD10 (corresponding to C-ALL and pre-B ALL) was distributed in the three age groups as follows: 38.88% (group I) 65.38% (group II) and 86.36% (group III). Conversely, immature phenotypes (pre-pre-B and AUL) were found more often in the younger patients of groups I and II, as well as anomalous phenotypes, such as the presence of myeloid antigens (MyAg) and of CD7. Prognostic significance was evaluated as event-free survival (EFS) by statistical analysis. A better outcome in CD10-positive ALL than in CD01-negative ones (48% v. 25% of long-term survivors) was demonstrated in all infants. Similarly, EFS was significantly better in MyAg-negative than in MyAg-positive cases. These results were confirmed also when adjusting for white blood cell count. This allowed the identification of CD10-negative, MyAg-positive ALL, which were relatively more frequent in infants and had a poorer clinical outcome with the current therapies. This study stresses the prognostic relevance of the immunological study in infant leukaemias and its utility in choosing different therapeutic modalities for poor risk phenotypes.

ZusammenfassungDie Daten von 152 Sauglingen, die von 1975–1989 innerhalb multizentrischerStudien der Italienischen Padiatrischen Hamato-Onkologischen Gesellschaft behandelt wurden, wurden ausgewertet.

ZusammenfassungAkute Leukamie (AL) bei Sauglingen (unter 12 Monate alt) ist selten und hat oft besondere klinische (hohe Leukozytenzahl, Organomegalie) und zellbiologische (besonders zytogenetische) E

MYCN is an oncogene frequently overexpressed in pediatric solid tumors whereas few evidences suggest his involvement in the pathogenesis of haematologic malignancies. Here we show that MYCN is overexpressed in a relevant proportion (40 to 50%) of adult and pediatric T-cell acute lymphoblastic leukemias (T-ALL). Focusing on pediatric T-ALL, MYCN-expressing samples were found almost exclusively in the TAL1-positive subgroup. Moreover, TAL1 knockdown in T-ALL cell lines resulted in a reduction of MYCN expression, and TAL1 directly binds to MYCN promoter region, suggesting that TAL1 pathway activation could sustain the up-regulation of MYCN. The role of MYCN in T-ALL was investigated by peptide nucleic acid (PNA-MYCN)-mediated transcriptional silencing of MYCN and by siRNAs. MYCN knockdown in T-ALL cell lines resulted in a reduction of cell viability, up to 50%, while no effect was elicited with a mismatch PNA. The inhibitory effect of PNA-MYCN on cell viability was due to a significant increase in apoptosis. PNA-MYCN treatment in pediatric T-ALL samples reduced cell viability of leukemic cells from patients with high MYCN expression, while no effect was obtained in MYCN-negative blast cells. These results showed that MYCN is frequently overexpressed in pediatric T-ALL and suggested his role as a candidate for molecularly-directed therapies.

On earlier occasions healthy subjects, and normal weight cold patients and obese subjects not suffering from hypoventilation were subjected to respiratory function tests in different postures using the plethysmographic and helium dilution methods. This protocol was then applied to a series of obese patients with the functional characteristics of alveolar hypoventilation identified in preliminary functional tests. The study revealed: a) significant differences between plethysmographic and helium dilution findings; b) not significant volumetric differences produces by different postures (standing or squatting) especially as far as Total Lung Capacity and the main lung volume parameters are concerned. These results confirm the findings of others (Sharp et al., 1986) that diaphragmatic adjustment to changes in posture is inadequate in the obese with bronchial obstruction in whom absence of the fibre-length compensation phrenophrenic reflex and by the muscle flattening cause by the alveolar hyperinsufflation. On the basis of these data and others already published an index of "diaphragmatic passivity" based on the ratio between TLC in squatting and TLC in standing x 100 is proposed as an indicator of the lung volume available for use. This simple system would indicate the functional condition of the diaphragm and provide information for the functional assessment of patients proposed for rehabilitation treatment during follow-up.

On earlier occasions healthy subjects, and chronic bronchopneumopathy patients were subjected to respiratory function tests in different postures using the plethysmographic and helium dilution methods. This protocol was then applied to a series of obese patients without the functional characteristics of alveolar hypoventilation identified in preliminary functional tests. The study revealed: a) non significant differences between plethysmographic and helium dilution findings; b) no significant volumetric differences produced by different postures (standing or squatting) especially as far as Total Lung Capacity is concerned. These results confirm the findings of others (Sharp et al., 1986) that diaphragmatic adjustment to changes in posture is inadequate in the obese even in the absence of hypoventilation.

Objectives Leukaemia is the most common cancer in children, but its aetiology is still poorly understood. We tested the hypothesis that traffic-related air pollution is associated with paediatric leukaemia because of chronic exposure to several potential carcinogens. Methods The Italian SETIL study (Study on the aetiology of lymphohematopoietic malignancies in children) was conducted in 14 Italian regions. All incident cases of leukaemia in children aged ≤10 years from these regions (period 1998–2001) were eligible for enrolment. Two controls per case, matched on birth date, gender and region of residence were randomly selected from the local population registries. Exposure assessment at birth residence included traffic indicators (distance to main roads and length of main roads within 100 m) and estimates of pollutants concentrations (particulate matter -PM 2.5 and PM 10 - and gases -NO 2 and O 3 -) from national dispersion model and land use regression models. The association between the exposure variables and leukaemia was assessed by logistic regression analyses. Results Participation rates were 91.4% among cases and 69.2% in controls; 620 cases (544 acute lymphocytic and 76 acute non-lymphocytic leukaemia) and 957 controls were included. Overall, when considering the residence at birth, 35.6% of cases and 42.4% of controls lived along busy roads, and the mean annual PM 10 levels were 33.3 (SD=6.3) and 33.4 µg/m 3 (SD=6.5), respectively. No association was found, and all ORs, independent of the method of assessment and the exposure windows, were close to the null value. Conclusions Using various exposure assessment strategies, air pollution appears not to affect the incidence of childhood leukaemia.

Survivors of retinoblastoma (Rb) are at high risk of dying from second malignant tumour. The occurrence of second malignant neoplasm (SMN) and related mortality in a cohort of 1111 cases from the Italian Retinoblastoma Registry was analysed, considering the possible role of both genetic and iatrogenic causes. Rb patients had a greater than 10-fold excess in overall mortality compared with the general population (standardized mortality ratio (SMR) 10.73, 95% CI 9.00-12.80). Their excess risk attributable to cancers other than Rb was 14.93 95% CI 10.38-21.49). Survivors of hereditary Rb had an SMR for all causes of 16.25 (95% CI 13.20-20.00), whereas their SMR for all cancers was 25.72 (95% CI 17.38-38.07). Survivors of unilateral sporadic Rb had an SMR of 4.12 from all cancers (95% CI 1.55-10.98) and a much higher excess for overall mortality (SMR 13.34, 95% CI 10.74-16.56). As expected, survivors of hereditary Rb had higher mortality from cancers of the bone (SMR 391.90, 95% CI 203.90-753.20) and soft tissue (SMR 453.00, 95% CI 203.50-1008.40), small intestine (SMR 1375.50, 95% CI 344.00-5499.70), nasal cavity (SMR 13.71, 95% CI 1.93-97.35) and cancers of the brain and central nervous system (SMR 41.14, 95% CI 13.2-127.55).

The proto-oncogene c-KIT, which encodes a receptor for stem cell factor (SCF), belongs to the type-III receptor of the tyrosine kinase subfamily and is characterized by five extracellular immunoglobulin-like domains, a single transmembrane helix (TM), a cytoplasmic juxtamembrane domain(JMD), and a kinase domain. Abnormal activation of c-KIT/SCF growth signal has been frequently documented to occur in cancers, including hematological malignancies, and has been frequently associated with poor prognosis in adults with acute myeloid leukemia (AML) harboring aberrancies at core-binding factor genes (CBF). c-KIT mutations have been reported in pediatric CBF-rearranged AML at frequencies ranging from 15 to 54.5%; however, their prognostic significance is still debated. Mutations of c-KIT occur in the extracellular portion of the receptor implicated in dimerization within exon 8, in the TM-JMD domain within exon 11 and in the activation loop of the tyrosine kinase domain within exon 17, this mediating the constitutive activation of the receptor.

Abstract 3585 Introduction: The prognosis of paediatric patients (pts) with Acute Myeloid Leukemia (AML) has significantly improved over time not only in standard risk (SR) but also in high risk (HR) children. Pts < 1 year of age (infants) affected by AML are generally considered to be at HR. This is due to the prevalence of prognostically unfavourable clinical and cytogenetic/molecular features and to a greater vulnerability to treatment toxicities. We analyzed clinical and biological characteristics, as well as outcome of infants treated with the AIEOP AML 2002/01 protocol, comparing them to those of older children. Patients and Methods: Between 12/2002 and 06/2011, 63 infants with AML other than promyelocytic leukaemia were treated with the AIEOP AML 2002/01 protocol. Children with Down syndrome were excluded. Clinical and biological features compared to the ones of 3 different age groups (1–10 years) are reported in Table 1. Treatment was administered according to the following risk-based stratification: pts with isolated CBF-b+ leukemia achieving complete remission (CR) after the first induction course were considered to be at Standard Risk (SR), whereas all the others were assigned to the HR group. The treatment schedule administered to infants was: 2 courses of 7-day induction therapy (idarubicin, cytarabine and etoposide: ICE 3+5+7) and 2 consolidation courses based on high-dose cytarabine (HD-Ara-c), combined with either etoposide during the first course (AVE 3+4) or mitoxantrone during the second course (HAM 3+2). After consolidation, infants were eligible to allogeneic (ALLO) HSCT in first CR from a HLA-identical relative, if available, or from alternative donors, namely unrelated donors or HLA-mismatched relatives. CR rate, early death (ED), induction failure (IF), overall survival (OS) and event free survival (EFS) of infants were calculated and compared to those of other age groups. Results: Compared to pts of other age groups, infants had significantly more CNS involvement at diagnosis (P=0.002), were assigned to the FAB M7 subtype (P=0.000) and to the HR risk group (P=0.001) (Table 1). The median white blood cell (WBC) count at diagnosis was higher in infants (P=0.028), being 71,298×103/ml (range 3,100–653,000). Comparing pts with available cytogenetic data in the different age groups, infants showed a significantly higher incidence of 11q23/MLL-rearrangements (P=0.001). The incidence by partners of 11q23/MLL-rearrangements were 10%, 7%, 1%, 4% and 14% for t(9;11), t(10;11), t(11;19), t(1;11) and other translocation partners, respectively. Infants had CR, ED and IF rates of 84%, 8% and 8%, respectively, with no statistically significant differences with other age groups. Forty-five out of 63 infants (71%) received an ALLO HSCT in first CR. With a median follow up time of 57 months (range 3–130) the 8-year probability of OS and EFS of infants were 74% and 58%, respectively, with no significant differences compared with the other age groups. Conclusions: Infants < 1 year of age at diagnosis enrolled in the AIEOP AML 2002/01 protocol presented with a significantly higher incidence of prognostically unfavourable features, like high WBC count, FAB M7 subtype, 11q23/MLL-rearrangements and CNS involvement. Despite this, a treatment strategy including a wide use of ALLO HSCT in first CR for these pts resulted in a final outcome which was not statistically different from that observed in the other age groups. Our results compare favourably with previously published data on infants with AML. Disclosures: No relevant conflicts of interest to declare.

Introduction: High dose BUS is an important component of pre-transplant conditioning regimen in children with advanced hematological malignancies or solid tumor undergoing allogeneic or autologous stem cell transplantation. Variable intra and inter systemic drug exposure as measured by area under curve (AUC), can occurs following oral administration and may be influenced by age, body weight, absorption variability and, particularly in infants, by difficulties to assumption. Aims: to compare the PK, the toxicity and the compliance of iv versus oral BUS administration in children undergoing pre-transplant conditioning regimen. Patients and methods: 12 patients (pts), median age 37 (7–177) mos, body weight 6–69 kg, affected by AML (3), ALL (4), NB (3), Thalassemia (2), undergoing to autoSCT (4) or alloSCT (8), received as preparative regimen oral BUS at the dose of 1 mg/kg every 6 hours for a total of 16 doses (6 pts, GR1), or 2 hours i.v. infusion of BUS at the dose of 0.8 mg/kg every 6 hours for a total of 16 doses (6 pts, GR2). Four out of 6 GR1 pts (7–30 mos) had a nasogastric radiolus to allow BUS assumption. PK studies were performed after the first dose of BUS on blood samples collected at 0, 1, 2, 4, 6 hours after first administration in GR1 and at 0, 2, 3, 4, 6 hours from the beginning of the first infusion in GR2. BUS plasma level was determined by high-performance liquid chromatography as described by Henner et al. Results: GR were comparable as for age (p= 0.07) and body weight (p= 0.14). Comparison of PK median values (+SD) in GR1 versus GR2 didn’t highlighted statistically significant differences as for AUC (p= 0.20) and for T1/2 (p= 0.11). Peak concentration was higher in GR2 (p= 0.058). Bioavailability was 0.61. Variation factor (VF%) were constantly low in GR2. No pt showed acute or late treatment-related extra-medullary toxicity and all pts developed a rapid and sustained hematopoietic recovery. Conclusions: systemic exposure to 0.8 mg/kg iv BUS versus 1 mg/kg oral BUS is overlapping. Low VF% highlight a smaller interpatient variability in exposure compared to oral BUS. Moreover allows to avoid assumption difficulties in younger pts.

T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma in childhood are recognized to be two different pathologies with different biological basis and are treated according to different pediatric protocols.