Pain Assessment in People with Intellectual Disability: Improving Skills of Health and Educational Personnel at Istituto Serafico of Assisi, Italy.

BACKGROUND: Assessment of pain in people with intellectual disability (PWID) is a difficult clinical task. Poor knowledge and confidence in assessing pain in PWID result in underestimation and undertreatment. Available resources for healthcare personnel and caregivers on pain assessment in PWID are still very limited. The aim of the study was to measure the level of knowledge and confidence in assessing pain in PWID of health and education personnel at Istituto Serafico, before and after training. SUBJECTS AND METHODS: The Istituto Serafico is a neuro-rehabilitation center caring for people with complex disabilities. Nurses, rehabilitation therapists, social health workers (SHW) and educators were invited to participate in a 4-hours theoretical and practical training. Participants were assessed through a knowledge and confidence questionnaire on pain assessment in PWID, administered before and after the training. RESULTS: 123 participants attended both the theoretical and practical sessions. Median age was 43 years (range 23-67); 89 were females and 34 males. They were 10 (8%) nurses, 9 (7%) rehabilitation therapists, 77 (63%) SHW, 27 (22%) educators. Only 7 (6%) participants (5 nurses and 2 SHW) declared to have previously received formation on pain. Participants who felt "quite confident" in assessing pain increased from 28% to 73% after the training. The median score to the 24 knowledge questions raised from 15/24 correct answers (range 6-22, 62.5%) in the pre-test to 21/24 (range 11-24, 87.5%) in the post-tests (p=0.001) Conclusions: The study highlights the great need of education programs for health and educational personnel working with PWID on pain assessment and the potential to improve knowledge and confidence through theoretical and practical training. A greater awareness of pain causes, clinical manifestations and consequences of untreated pain, could improve patient care, quality of life and rehabilitation goals.

Stimulation of Treg Cells to Inhibit Osteoclastogenesis in Gorham-Stout Disease.

Gorham-Stout disease (GSD) is a very rare syndrome displaying excessive bone erosion and vascular lesion. Due to the rarity of the disease and to the limited studies, its etiopathogenesis is not entirely known. The involvement of immune system in the progressive osteolysis was recently suggested. Indeed, extensive reciprocal interactions between the immune and skeletal systems have been demonstrated. This study aimed to evaluate alterations of immune cells in GSD. An increase of CD8+ cells and reduction of CD4+ and CD4+CD25+CD127low cells was revealed in patients. Interestingly, patients' regulatory T cells maintain the ability to respond to extracellular stimuli and to regulate osteoclastogenesis; GSD cells proliferate under aCD3/CD28 signal reaching similar levels to those observed in control culture and exert their immunomodulatory activity on effector T cells. GSD Treg cells preserved their inhibitory effects on the osteoclastogenesis. These results suggest that stimulation of Treg cells could open the way for the identification and testing of new therapeutic approaches for patients affected by GSD.

Dysregulated miRNAs in bone cells of patients with Gorham-Stout disease.

Gorham-Stout disease (GSD) is a very rare disease characterized by increased bone erosion with angiomatous proliferation. The mechanisms underlying this disorder have not been deeply investigated. Due to its rarity, no guidelines are currently available for treatment and management of GSD. We recently evaluated the cellular alterations of the bone remodeling in patients showing that osteoclast precursors displayed increased ability to differentiate into osteoclasts and that affected osteoclasts resorb bone more actively than control cells. Moreover, osteoblasts isolated from a patient showed a defective ability to form mineralized nodules. In this paper, we investigated the molecular pathways involved in the cellular defects of GSD bone cells. For this study, we recruited nine patients and performed miRNome analysis of bone cells. Between the 178 miRNAs robustly expressed in GSD osteoclasts, significant modulation of three miRNAs (miR-1246, miR-1-3p, and miR-137-3p) involved in the regulation of osteoclast formation and activity or in the angiomatous proliferation was found in patients' cells. Interestingly, miR-1246 was also up-regulated in serum exosomes from patients. Analysis of miRNAs from patient osteoblasts suggested alteration of miR-204a-5p, miR-615-3p and miR-378a-3p regulating osteoblast function and differentiation. The resulting miRNA pattern may help to understand better the mechanisms involved in GSD and to identify new potential therapeutic targets for this rare disease.

ACCELERATE and European Medicines Agency Paediatric Strategy Forum for medicinal product development of checkpoint inhibitors for use in combination therapy in paediatric patients.

The third multistakeholder Paediatric Strategy Forum organised by ACCELERATE and the European Medicines Agency focused on immune checkpoint inhibitors for use in combination therapy in children and adolescents. As immune checkpoint inhibitors, both as monotherapy and in combinations have shown impressive success in some adult malignancies and early phase trials in children of single agent checkpoint inhibitors have now been completed, it seemed an appropriate time to consider opportunities for paediatric studies of checkpoint inhibitors used in combination. Among paediatric patients, early clinical studies of checkpoint inhibitors used as monotherapy have demonstrated a high rate of activity, including complete responses, in Hodgkin lymphoma and hypermutant paediatric tumours. Activity has been very limited, however, in more common malignancies of childhood and adolescence. Furthermore, apart from tumour mutational burden, no other predictive biomarker for monotherapy activity in paediatric tumours has been identified. Based on these observations, there is collective agreement that there is no scientific rationale for children to be enrolled in new monotherapy trials of additional checkpoint inhibitors with the same mechanism of action of agents already studied (e.g. anti-PD1, anti-PDL1 anti-CTLA-4) unless additional scientific knowledge supporting a different approach becomes available. This shared perspective, based on scientific evidence and supported by paediatric oncology cooperative groups, should inform companies on whether a paediatric development plan is justified. This could then be proposed to regulators through the available regulatory tools. Generally, an academic-industry consensus on the scientific merits of a proposal before submission of a paediatric investigational plan would be of great benefit to determine which studies have the highest probability of generating new insights. There is already a rationale for the evaluation of combinations of checkpoint inhibitors with other agents in paediatric Hodgkin lymphoma and hypermutated tumours in view of the activity shown as single agents. In paediatric tumours where no single agent activity has been observed in multiple clinical trials of anti-PD1, anti-PDL1 and anti-CTLA-4 agents as monotherapy, combinations of checkpoint inhibitors with other treatment modalities should be explored when a scientific rationale indicates that they could be efficacious in paediatric cancers and not because these combinations are being evaluated in adults. Immunotherapy in the form of engineered proteins (e.g. monoclonal antibodies and T cell engaging agents) and cellular products (e.g. CAR T cells) has great therapeutic potential for benefit in paediatric cancer. The major challenge for developing checkpoint inhibitors for paediatric cancers is the lack of neoantigens (based on mutations) and corresponding antigen-specific T cells. Progress critically depends on understanding the immune macroenvironment and microenvironment and the ability of the adaptive immune system to recognise paediatric cancers in the absence of high neoantigen burden. Future clinical studies of checkpoint inhibitors in children need to build upon strong biological hypotheses that take into account the distinctive immunobiology of childhood cancers in comparison to that of checkpoint inhibitor responsive adult cancers.

Dissecting the mechanisms of bone loss in Gorham-Stout disease.

Gorham-Stout disease (GSD) is a rare disorder characterized by progressive osteolysis and angiomatous proliferation. Since the mechanisms leading to bone loss in GSD are not completely understood, we performed histological, serum, cellular and molecular analyses of 7 patients. Increased vessels, osteoclast number and osteocyte lacunar area were revealed in patients' bone biopsies. Biochemical analysis of sera showed high levels of ICTP, Sclerostin, VEGF-A and IL-6. In vitro experiments revealed increased osteoclast differentiation and activity, and impaired mineralization ability of osteoblasts. To evaluate the involvement of systemic factors in GSD, control cells were treated with patients' sera and displayed an increase of osteoclastogenesis, bone resorption activity and a reduction of osteoblast function. Interestingly, GSD sera stimulated the vessel formation by endothelial cells EA.hy926. These results suggest that bone cell autonomous alterations with the cooperation of systemic factors are involved in massive bone loss and angiomatous proliferation observed in GSD patients.

Susceptibility to allergy in adoptive children: a cross-sectional study at "Bambino Gesù Children's Hospital".

BACKGROUND: Prevalence of allergy has steeply increased during the past few decades, particularly in high-income countries. The development of atopy could present different characteristics in internationally adopted children with regard to incidence, specific patterns of allergies and timing of occurrence. We aimed to investigate the occurrence of allergic diseases among adopted children in Italy. METHODS: We collected demographic information, preadoption immunization data, infectious diseases screening results, immunological status, and performed hematological and biochemical tests according to a standardized protocol in 108 adopted children. RESULTS: At initial visit (mean age was 5.7 ± 3.2 years), 48 children displayed elevated total serum IgE levels with a prevalence of 56.5% (95%CI: 0.45; 0.67). The prevalences of children screened positive for one or more food allergens and inhalants were 30.1% (95%CI: 19.9%; 42.0%) and 34.3% (95%CI: 23.3%; 46.6%) respectively, only 9 children exhibited abnormal absolute eosinophil counts, 23 (21.3%) had a parasitic infection and 60 (55.6%) had received at least one dose of vaccine. CONCLUSIONS: Children without medical records or with a past medical history suggestive of atopy should perform a thorough allergy evaluation at the time of adoption. Our study offers also a glimpse at the vaccination status and immune-allergic profiles of recent migrant children in Italy.

Accuracy of serum procalcitonin for the diagnosis of sepsis in neonates and children with systemic inflammatory syndrome: a meta-analysis.

BACKGROUND: A number of biomarkers have been studied for the diagnosis of sepsis in paediatrics, but no gold standard has been identified. Procalcitonin (PCT) was demonstrated to be an accurate biomarker for the diagnosis of sepsis in adults and showed to be promising in paediatrics. Our study reviewed the diagnostic accuracy of PCT as an early biomarker of sepsis in neonates and children with suspected sepsis. METHODS: A comprehensive literature search was carried out in Medline/Pubmed, Embase, ISI Web of Science, CINAHL and Cochrane Library, for studies assessing PCT accuracy in the diagnosis of sepsis in children and neonates with suspected sepsis. Studies in which the presence of infection had been confirmed microbiologically or classified as "probable" by chart review were included. Studies comparing patients to healthy subjects were excluded. We analysed data on neonates and children separately. Our primary outcome was the diagnostic accuracy of PCT at the cut-off of 2-2.5 ng/ml, while as secondary outcomes we analysed PCT cut-offs <2 ng/ml and >2.5 ng/ml. Pooled sensitivities and specificities were calculated by a bivariate meta-analysis and heterogeneity was graphically evaluated. RESULTS: We included 17 studies, with a total of 1408 patients (1086 neonates and 322 children). Studies on neonates with early onset sepsis (EOS) and late onset sepsis (LOS) were grouped together. In the neonatal group, we calculated a sensitivity of 0.85, confidence interval (CI) (0.76; 0.90) and specificity of 0.54, CI (0.38; 0.70) at the PCT cut-off of 2.0-2.5 ng/ml. In the paediatric group it was not possible to undertake a pooled analysis at the PCT cut-off of 2.0-2.5 ng/ml, due to the paucity of the studies. CONCLUSIONS: PCT shows a moderate accuracy for the diagnosis of sepsis in neonates with suspected sepsis at the cut-off of 2.0-2.5 ng/ml. More studies with high methodological quality are warranted, particularly in neonates, studies considering EOS and LOS separately are needed to improve specificity. TRIAL REGISTRATION: PROSPERO Identifier: CRD42016033809 . Registered 30 Jan 2016.

Diagnostic value of soluble triggering receptor expressed on myeloid cells in paediatric sepsis: a systematic review.

BACKGROUND: Differential diagnosis between sepsis and non-infectious inflammatory disorders demands improved biomarkers. Soluble Triggering Receptor Expression on Myeloid cells (sTREM-1) is an activating receptor whose role has been studied throughout the last decade. We performed a systematic review to evaluate the accuracy of plasma sTREM-1 levels in the diagnosis of sepsis in children with Systemic Inflammatory Response Syndrome (SIRS). METHODS: A literature search of PubMed, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and ISI Web of Knowledge databases was performed using specific search terms. Studies were included if they assessed the diagnostic accuracy of plasma sTREM-1 for sepsis in paediatric patients with SIRS. Data on sensitivity, specificity, positive predictive value, negative predictive value, area under receiver operating characteristic curve were extracted. The methodological quality of each study was assessed using a checklist based on the Quality Assessment Tool for Diagnostic Accuracy Studies. RESULTS: Nine studies comprising 961 patients were included, four of which were in newborns, three in children and two in children with febrile neutropenia. Some data from single studies support a role of sTREM-1 as a diagnostic tool in pediatric sepsis, but cannot be considered conclusive, because a quantitative synthesis was not possible, due to heterogeneity in studies design. CONCLUSIONS: This systematic review suggests that available data are insufficient to support a role for sTREM in the diagnosis and follow-up of paediatric sepsis.

Local control in metastatic neuroblastoma in children over 1 year of age.

BACKGROUND: Local control is always considered in metastatic neuroblastoma (NBL). The aim of this study is to evaluate the impact of radical surgery on survival in children over 1 year of age. METHODS: Fifty-eight patients older than 1 year of age with metastatic NBL were treated with conventional plus high-dose chemotherapy with or without addition of local radiotherapy (RT, 21Gy). Surgery was classified as radical surgery (complete resection and gross total resection) or non-radical surgery. The Kaplan-Meier method and the Cox proportional hazard model were used to calculate the probability of progression free and overall survival (PFS and OS) and for multivariate analysis. RESULTS: The 5-year PFS and OS for patients with radical surgery were 26% (95% CI 14-40%) and 38% (95% CI 23-53%) respectively, while the PFS and OS for patients without radical surgery were 33% (95% CI 10-59%) and 31% (95% CI 10-55%) (respectively, P 0.85 and P 0.42). The 5-year PFS and OS for patients who received RT were 36% (95% CI 19-53%) and 46% (95% CI 26-64%) respectively, while the 5-year PFS and OS for patients who did not receive RT were 22% (95% CI 9-38%) and 27% (95% CI 13-42%) respectively (P 0.02 for PFS). Multivariate analysis confirmed the role of well-known prognostic factors, such as the presence of MYCN amplification, age and response before high-dose chemotherapy. CONCLUSIONS: Our data suggest that the degree of resection does not influence survival in metastatic NBL patients treated with high-dose chemotherapy; local RT contributes to local disease control.

Synchronous bilateral Wilms tumor: a report from the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP).

BACKGROUND: The optimal management of bilateral Wilms tumor (BWT) is challenging, and their survival is lower than for unilateral tumors. This report discusses a large series of BWTs treated in Italy in the last 2 decades. METHODS: This analysis concerns patients with synchronous BWT registered at Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) centers between 1990 and 2011; details on their treatment and outcome are presented and discussed. RESULTS: Ninety BWTs were registered in the AIEOP Wilms tumor database. Preoperative chemotherapy was given for a median 12 weeks before definitive tumor resection was attempted. Forty-eight percent of the patients had preservation of bilateral renal parenchyma. The proportion of bilateral nephron-sparing surgeries was not higher in the 37 patients initially given doxorubicin/vincristine/actinomycin D (32%) than in the 43 children receiving vincristine/actinomycin D alone (58%). The 4-year disease-free survival rate was 66.5% ± 5% and overall survival was 80% ± 5% for the cohort as a whole. The 4-year disease-free survival (overall survival) for 18 children with diffuse anaplasia or postchemotherapy blastemal-type tumors was 51% ± 13% (62% ± 13%), as opposed to 72% ± 3% (88% ± 4%) for 68 children with a favorable histology (log-rank P = .04 [P = .007]). CONCLUSIONS: These results provide further evidence that the optimal duration and choice of drugs for preoperative chemotherapy remain an open question. Outcome remained significantly worse for BWT than for unilateral Wilms tumor. To enable the conservative treatment of as many affected kidneys as possible, only centers with experience in BWT should manage such cases.

Trimming long-term tunneled central venous catheters in pediatric patients.

Long-term tunneled central venous catheters (CVC) are employed in critically ill patients. Manufacturers do not provide patient-customized devices; therefore, trimming is required for pediatric use. Scanning Electron Microscopy (SEM) coupled with energy-dispersive X-ray spectroscopy and attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) was used to assess changes induced by different trimming methods on single and double lumen Hickman-Broviac catheters. Increased roughness, exposure of inorganic macroaggreagates and increase in surface inorganic charges were generated by the trimming procedure, with the scalpel producing a smoother surface compared to scissors. Trimming produces changes on the CVC surface that may influence the rate of long-term complications.

Comparison of two different conditioning regimens before autologous transplantation for children with high-risk neuroblastoma.

BACKGROUND: Although high-dose chemotherapy (HDC) represents the standard of treatment for high-risk neuroblastoma (NBL), the most effective conditioning regimen still remains to be identified. PATIENTS AND METHODS: Forty-one high-risk NBL entered into local protocol based on induction chemotherapy, surgery and HDC with either etoposide/thiotepa/cyclophophamide (ETC) or i.v. busulfan and L-PAM (Bu/L-PAM). RESULTS: Thirty-seven patients underwent HDC; 29 with ETC and 8 with Bu/L-PAM. No toxic deaths were recorded. The 5-year progression-free survival (PFS) of patients given ETC was 21% (95% confidence interval CI (9-36%), while PFS for patients given Bu/L-PAM was 88% (95% CI=39-98%) (p<0.05). In multivariate analysis, treatment with the ETC regimen predicted progression/recurrence with a hazard ratio (HR) of 16.8 (p<0.05), as well as MYCN amplification which had an HR of 4.4 (p<0.05). CONCLUSION: Although the number of studied cases is limited, our data suggest that in high-risk NBL the combination of Bu/L-PAM is superior to the ETC regimen.

A survey on hematology-oncology pediatric AIEOP centers: prophylaxis, empirical therapy and nursing prevention procedures of infectious complications.

A nationwide questionnaire-based survey was designed to evaluate the management and prophylaxis of febrile neutropenia in pediatric patients admitted to hematology-oncology and hematopoietic stem cell transplant units. Of the 34 participating centers, 40 and 63%, respectively, continue to prescribe antibacterial and antimycotic prophylaxis in low-risk subjects and 78 and 94% in transplant patients. Approximately half of the centers prescribe a combination antibiotic regimen as first-line therapy in low-risk patients and up to 81% in high-risk patients. When initial empirical therapy fails after seven days, 63% of the centers add empirical antimycotic therapy in low-and 81% in high-risk patients. Overall management varies significantly across centers. Preventive nursing procedures are in accordance with international guidelines. This survey is the first to focus on prescribing practices in children with cancer and could help to implement practice guidelines.

Bevacizumab in pediatric patients: how safe is it?

BACKGROUND: Bevacizumab is a monoclonal antibody directed against vascular endothelial growth factor (VEGF). The safety profile of bevacizumab was evaluated in a cohort of children with either recurrent or poor-prognosis malignancies. PATIENTS AND METHODS: Bevacizumab was administered intravenously at the dosage of 5-10 mg/kg every 14-28 days alone or in combination with other agents. Toxicity was reported according to common toxicity criteria version 4. RESULTS: Seventeen patients received a total of 156 bevacizumab doses (median 5 doses/pt) for a median treatment duration of 2 months (range 1-21). Grade II-III lymphopenia was recorded in 10 patients, while grade III proteinuria and grade I epistaxis occurred in one patient each. Grade III wound dehiscence was observed in one case and 3 severe adverse events (SAEs) were recorded: one reversible posterior leukoencephalopathy syndrome (RPLS) with grade IV seizures and grade IV hypertension, one grade IV hypertension and a post-operative grade IV entero-cutaneous fistula. CONCLUSION: In the present cohort, the overall incidence of SAEs (17%) was higher than previously reported, thus, further studies should be justified to better characterize the safety profile of bevacizumab in the pediatric population.

Recurrent metanephric stromal tumor in an infant.

A 9-month-old boy underwent nephrectomy for a renal mass. Congenital mesoblastic nephroma was diagnosed, and the patient received postoperative chemotherapy. Tumor recurred 6 months later as a scrotal mass. After orchiectomy, diagnosis of metanephric stromal tumor (MST) was made; review of the nephrectomy specimens confirmed this diagnosis. No additional treatment was given, and the child is alive and well 31 months later. Taking into account the histopathological entity of MST in the differential diagnosis of stromal renal tumors in childhood can spare the patient further, potentially toxic, treatment even in the case of relapse, as reported here for the first time.

Continuing response to subsequent treatment lines with tyrosine kinase inhibitors in an adolescent with metastatic renal cell carcinoma.

A 14-year-old girl with metastatic renal cell carcinoma was treated with nephrectomy, interferon, and several lines of the targeted agents sorafenib, bevacizumab, sunitinib, and everolimus, either alone or in combination. Treatment was well tolerated, but the patient developed hypothyroidism and significant hypertension with bevacizumab and sunitinib. She responded to all agents and was given radiation treatment twice at the time of symptomatic disease progression; she died 33 months from diagnosis.

'Tell me about your pain': abdominal pain and a history of bullying.

A 7-year-old girl was brought to our outpatient clinic to investigate recurrent abdominal pain. She was unwilling to attend the school. Her mother reported bullying at school and nosebleeds. The girl rated her pain 9 on a visual analogue score card ranging from 1 to 10. Physical examination disclosed painful bruising and haematomas. Emergency laboratory blood tests indicated by the history, physical examination and the pain intensity showed reduced numbers of white blood cells and platelets. A bone marrow smear on admission disclosed 100% blasts and suggested an initial diagnosis of leukaemia but also disclosed the pseudo-rosettes typically seen in neuro-ectodermic tumours. The diagnosis of stage IV primary neuroblastoma was confirmed by trephine biopsies and high urinary catecholamines. The girl died 10 months later. This unusual case underlines the need for outpatient paediatricians to involve children in their initial diagnostic work-up by asking them about their pain thus expediting the diagnosis.

Microscopic neoplastic thrombosis in localised nephroblastoma: does it influence outcome?

INTRODUCTION: Microscopic neoplastic thrombosis (MNT) is reported to occur frequently in Wilms tumour (WT). The aim of this study is to determine whether MNT influences prognosis in localised WT. PATIENTS AND METHODS: Records and slides of 80 consecutive, unselected, localised WT patients were retrospectively reviewed. All patients received chemotherapy before surgery according to SIOP Protocol. The median follow-up was 9 years (range 0.5-25.8). The Kaplan-Meier method and the Cox proportional hazard model were applied. RESULTS: MNT was present in 14 (18%) cases. Out of 14 patients with MNT, 6 presented macroscopic thrombosis and 5 had either blastemal predominance or anaplastic histology. The 5-year overall survival (OS) and progression-free survival (PFS) for the whole population were 95% (95% confidence interval, CI, 87-98%) and 91% (95% CI 82-96%), respectively. The 5-year OS and PFS for MNT positive patients were 92% (95% CI 57-99%) and 77% (95% CI 44-92%), while the 5-year OS and PFS for MNT negative patients were 96% (95% CI 87-99%) and 94% (95% CI 85-98%), respectively; the difference was statistically significant (p<0.05) for PFS. In multivariate analysis, only the presence of anaplasia retained significance with a hazard ratio (HR) of 14.8 and 12.9 (p<0.05) for recurrence and death, respectively. CONCLUSION: These data suggest that the presence of MNT increases the risk of recurrence. MNT is associated with well-known prognostic factors, such as macroscopic thrombosis (possibly representing regression of macroscopic involvement) and anaplasia. Further prospective studies are needed to clarify the role of MNT as independent prognostic factor.

Short topotecan-based induction regimen in newly diagnosed high-risk neuroblastoma.

PURPOSE: Topotecan is an active drug in relapsed neuroblastoma. We investigated the efficacy and toxicity of a topotecan-based induction regimen in newly diagnosed neuroblastoma. METHODS: Patients older than 1 year with either metastatic or localised stage 2-3 MYCN-amplified neuroblastoma received 2 courses of high-dose topotecan (HD-TPT) 6mg/m(2) and high-dose cyclophosphamide (HD-CPM) 140 mg/kg, followed by 2 courses of ifosfamide, carboplatin and etoposide (ICE) every 28 days. After surgery on primary tumour, a fifth course with vincristine, doxorubicin and CPM was given, followed by high-dose chemotherapy with stem cell support. Response was assessed in accordance with the International Neuroblastoma Response Criteria. RESULTS: Of 35 consecutive patients, 33 had metastatic disease. The median length of induction phase was 133 days (range 91-207) and time to high-dose chemotherapy was 208 days (range 156-285). The median tumour volume reduction was 55% after two HD-TPT/HD-CPM courses and 80% after four courses. Radical surgery was performed in 16/27 patients after chemotherapy. After the fifth course, 29/34 patients (85%) had achieved a partial remission (12) or a CR/very good partial remission (17). CR of metastases was achieved in 13/32 (41%) and bone marrow was in complete remission in 16/24 patients (67%). Grade 4 neutropenia and/or thrombocytopenia occurred in 100% of HD-TPT/HD-CPM and in 95% of ICE courses, while non-haematological toxicities were manageable. CONCLUSIONS: These data indicate that our induction regimen is feasible and well tolerated. A major response rate of 85% with 41% complete metastatic response confirms this regimen as effective induction in high-risk neuroblastoma.