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Resumen: Introducción: El cáncer es la primera causa de muerte por enfermedad entre el primer año de vida y la adolescencia. Algunos tipos de enfermedad siguen constituyendo un reto en términos de curación. Existe por tanto una necesidad imperiosa de nuevos fármacos. Algunos descubrimientos recientes en la biología del cáncer abren la puerta al desarrollo de terapias dirigidas contra alteraciones moleculares concretas e inmunoterapia. Esto se ha traducido en resultados prometedores sobre todo en oncología de adultos, y en menor medida todavía en niños. Presentamos la actividad en ensayos clínicos precoces (fase i-ii) en oncología pediátrica en España. Material y métodos: A través de la Sociedad Española de Oncología y Hematología Pediátrica (SEHOP) contactamos a sus miembros para identificar los ensayos fase i-ii en cáncer pediátrico abiertos entre 2005 y 2015. Resultados: En este periodo se abrieron 30 ensayos: 21 (70%) en tumores sólidos y 9 (30%) en hemopatías malignas y se incluyó a 212 pacientes. La mayoría están promovidos por la industria farmacéutica (53%). Desde 2010, 4 centros se han integrado en el consorcio internacional ITCC cuyo objetivo es desarrollar nuevas terapias en cáncer infantil. Esto ha permitido ampliar el abanico de posibilidades terapéuticas. Los resultados de ensayos clínicos terminados muestran la contribución de los investigadores españoles, la introducción de terapias dirigidas y sus beneficios. Conclusiones: La actividad en ensayos clínicos precoces ha aumentado en estos años. La SEHOP está comprometida a desarrollar y participar en ensayos clínicos académicos colaborativos, que favorezcan el avance en las terapias frente al cáncer infantil. Abstract: Introduction: Cancer is the leading cause of death between the first year of life and adolescence, and some types of diseases are still a major challenge in terms of cure. There is, therefore, a major need for new drugs. Recent findings in cancer biology open the door to the development of targeted therapies against individual molecular changes, as well as immunotherapy. Promising results in adult anti-cancer drug development have not yet been translated into paediatric clinical practice. A report is presented on the activity in early paediatric oncology trials (phase I-II) in Spain. Material and methods: All members of the Spanish Society of Paediatric Haematology Oncology (SEHOP) were contacted in order to identify early clinical trials in paediatric cancer opened between 2005 and 2015. Results: A total of 30 trials had been opened in this period: 21 (70%) in solid tumours, and 9 (30%) in malignant haemopathies. A total of 212 patients have been enrolled. The majority was industry sponsored (53%). Since 2010, four centres have joined the international consortium of Innovative Therapies for Children with Cancer (ITCC), which has as its aim to develop novel therapies for paediatric tumours. A significant number of new studies have opened since 2010, improving the treatment opportunities for our children. Results of recently closed trials show the contribution of Spanish investigators, the introduction of molecularly targeted agents, and their benefits. Conclusions: The activity in clinical trials has increased in the years analysed. The SEHOP is committed to develop and participate in collaborative academic trials, in order to help in the advancement and optimisation of existing therapies in paediatric cancer.

Introduction High-risk (HR) metastatic (stage IV) Wilms tumours (WTs) have a particular poor outcome. Methods Here, we report the results of HR (diffuse anaplastic [DA] or blastemal type [BT]) stage IV WT treated patients according to the HR arm in the SIOP2001 prospective study. Results From January 2002 to August 2014, 3559 patients with WT were included in the SIOP2001 trial. Among the 525 patients (15%) with metastatic WT, 74 (14%) had stage IV HR-WT. The median age at diagnosis was 5.5 years (range: 1.4–18.3). Thirty-four patients (47%) had BT-WT and 40 (53%) had DA-WT. Five-year event-free survival rates were 44 ± 17% and 28 ± 15% for BT-WT and DA-WT, respectively (p = 0.09). Five-year overall survival rates were 53 ± 17% and 29 ± 16% for BT-WT and DA-WT, respectively (p = 0.03). Metastatic complete response after preoperative treatment was significantly associated with outcome in univariate and multivariate analyses (hazards ratio = 0.3; p = 0.01). Postoperative radiotherapy of metastatic sites might also be beneficial. Forty-three of 74 patients experienced a relapse or progression predominantly in the lungs (80%). The median time to relapse/progression after diagnosis was 7.3 months (range: 1.6–33.3) and 4.9 months (range: 0.7–28.4) for BT-WT and DA-WT, respectively (p = 0.67). This is the first prospective evidence of inferior survival of stage IV BT-WT as compared with historical intermediate-risk WT. Survival of patients with stage IV DA-WT has not improved compared to the previous SIOP93-01 study. Conclusion These results call for new treatment approaches for patients with HR stage IV WT.

Introduction Cancer and blood disorders in children are rare. The progressive improvement in survival over the last decades largely relies on the development of international academic clinical trials that gather the sufficient number of patients globally to elaborate solid conclusions and drive changes in clinical practice. The participation of Spain into large international academic trials has traditionally lagged behind of other European countries, mainly due to the burden of administrative tasks to open new studies, lack of financial support and limited research infrastructure in our hospitals. Methods The objective of ECLIM-SEHOP platform (Ensayos Clínicos Internacionales Multicéntricos-SEHOP) is to overcome these difficulties and position Spain among the European countries leading the advances in cancer and blood disorders, facilitate the access of our patients to novel diagnostic and therapeutic approaches and, most importantly, continue to improve survival and reducing long-term sequelae. ECLIM-SEHOP provides to the Spanish clinical investigators with the necessary infrastructural support to open and implement academic clinical trials and registries. Results In less than 3 years from its inception, the platform has provided support to 20 clinical trials and 8 observational studies, including 8 trials and 4 observational studies where the platform performs all trial-related tasks (integral support: trial setup, monitoring, etc.) with more than 150 patients recruited since 2017 to these studies. In this manuscript, we provide baseline metrics for academic clinical trial performance that permit future comparisons. Conclusions ECLIM-SEHOP facilitates Spanish children and adolescents diagnosed with cancer and blood disorders to access state-of-the-art diagnostic and therapeutic strategies.

Multidisciplinary tumour boards (MDTs) are conducted worldwide for the management of patients with cancer, and they deliver a higher standard of care by simultaneously involving different specialists in diagnosis and treatment planning. However, information of paediatric MDTs functioning is scarce. A pilot study was conducted in Spain in the frame of the European Expert Paediatric Oncology Reference Network for Diagnostics and Treatment (ExPO-r-Net). A specific questionnaire was designed regarding various features of MDT practice. Data collected included information on the centres and the team, infrastructure for meetings, MDT organization/logistics and clinical decision-making. The survey was distributed to all Paediatric Oncology Units that register patients in the Spanish Registry of Childhood Tumours (RETI-SEHOP). 32 out of 43 contacted centres responded the questionnaire (74 % response rate; 88 % response rate for centres with > 25 new patients/year). All units with > 25 new patients/year have a dedicated Paediatric MDT compared to 76 % of units with aecurrency sign25 new patients/year. MDTs should be improved at institutional level by clear protected time in service planning for all specialists involved, incentives for attendance and attendance registration. Clinical decision-making process and follow-up of recommendation adherence should be assessed and potential legal responsibilities for physicians participating in Tumour Board defined. Network collaboration through virtual MDTs, using available videoconferencing tools, is an opportunity to share expertise among centres.

The impact of biopsying Wilms tumour (WT) at diagnosis on assigning the tumour stage and recommended treatment remains controversial. To address this important question, we analysed the potential association of all types of biopsy with local recurrence in patients treated in the SIOP WT 2001 trial, where needle biopsy was permitted without 'upstaging' the tumour to stage III. Only open biopsy required treatment as stage III.Among 2971 patients with unilateral WT (stages I-IV), 420 relapsed (139 local). Risk factors for recurrence were analysed by Cox proportional hazard methods.Biopsy was performed in 969 of 2971 (33%) patients (64% cutting needle, 30% fine needle aspiration [FNA] and 6% open biopsy). Biopsied patients were older, with larger tumours and a greater proportion with high-risk histology. In multivariate analysis that included all factors associated with local recurrence in univariate analysis, only high-risk histology (hazard ratio [HR] = 2.32; 95% confidence interval [CI]: 1.58-3.42, p=0.0001), age≥2 years (HR = 2.24; 95% CI: 1.22-4.09, p = 0.01) and preoperative tumour volume (HR = 1.07 per 100 ml; 95% CI: 1.02-1.12, p = 0.01) were significant. The HR for the association of local recurrence and event-free and overall survival with biopsy was not significant (HR = 1.4; 95% CI: 0.9-2.17, p = 0.13; HR = 1.1; 95% CI: 0.85-1.42, p = 0.46 and HR = 1.13; 95% CI: 0.79-1.62, p = 0.51, respectively). These results were not materially different whether FNA or open biopsy were included in the biopsy group or not.This post hoc analysis provides some reassurance that needle biopsy is not an independent adverse factor for either local recurrence or survival after adjustment for all relevant risk factors. Needle biopsy should not be an automatic criterion to 'upstage' WT.

SummaryBlastemal histology in chemotherapy-treated pediatric Wilms tumors (nephroblastoma) is associated with adverse prognosis. To uncover the underlying tumor biology and find therapeutic leads for this subgroup, we analyzed 58 blastemal type Wilms tumors by exome and transcriptome sequencing and validated our findings in a large replication cohort. Recurrent mutations included a hotspot mutation (Q177R) in the homeo-domain of SIX1 and SIX2 in tumors with high proliferative potential (18.1% of blastemal cases); mutations in the DROSHA/DGCR8 microprocessor genes (18.2% of blastemal cases); mutations in DICER1 and DIS3L2; and alterations in IGF2, MYCN, and TP53, the latter being strongly associated with dismal outcome. DROSHA and DGCR8 mutations strongly altered miRNA expression patterns in tumors, which was functionally validated in cell lines expressing mutant DROSHA.

The preparation and characterization of a novel chiral macrocycle S,S-[FeII(PhCH2OCH2)2(N3O2)(CN)2] (4) is presented. Magnetic susceptibility studies reveal that this complex undergoes a gradual spin crossover in the solid state with no thermal hysteresis. Variable temperature X-ray diffraction studies on single crystals of 4 reveal that at 150 K the complex is comprised of two crystallographically independent octahedral Fe(II) centres. Warming the crystal to 300 K results in a subtle change in coordination geometry of one of the octahedral Fe(II) centers towards a 7-coordinate, pentagonal bipyramidal geometry that is accompanied by a conformation change in one of the PhCH2OCH2 substituents.

Background Topotecan has been variably incorporated in the treatment of patients with relapsed Wilms tumour (WT) who failed initial treatment with three or more effective drugs. Our objective was to describe outcome and to retrospectively investigate the potential role of topotecan in relapsed WT patients. Methods Children who were treated with topotecan as part of their chemotherapeutic regimens for relapsed WT were identified and included in our retrospective study. Patient charts were reviewed for general patient characteristics, histology and stage at initial diagnosis, number and type of relapse, salvage treatment schedules, toxicity, response to treatment and outcome. Results From 2000 to 2012, 30 children (median age at relapse 5.5 years, range 1.6–14.5 years) were identified to have received topotecan as part of their salvage regimens (primary progressive disease n = 3, first, second and third relapse n = 13, 9 and 2 respectively, partial response n = 3). Topotecan was administered as a single agent (12 patients) or in combination with other drugs (18 patients). Sixteen patients had high-risk histology according to the SIOP classification, 15 died within 12 months because of progressive disease. Fourteen patients had SIOP intermediate-risk histology of which four patients displayed objective responses to topotecan. Overall, 6 out of 14 intermediate-risk patients survived (median follow up of 6 years), however, three of whom (stage V) had bilateral nephrectomy after topotecan treatment. Conclusions Topotecan does not seem to show effectiveness in the treatment of relapsed WT patients with initial high-risk histology. In patients with intermediate-risk histology, the role of topotecan might deserve further attention, to prove its efficacy.

The metal-templated synthesis of the bimetallic macrocyclic complex {CoII(N3O2)Cl(OH2)}2·2Cl·H2O (2) containing two N3O2 macrocyclic binding pockets was achieved from the metal-templated Schiff-base condensation of 2,2′-6,6′-tetracetyl-4,4′-bipyridine together with 3,6-dioxaoctane-1,8-diamine. Slow diffusion of (2) with K4[Fe(CN)6] in a (1:1) mixture of methanol and water afforded the 1-D coordination polymer [{Co(N3O2)(OH2)}2{Fe(CN)6}]⋅5H2O (5) whose structure was determined by X-ray diffraction. The polymer comprises two covalently tethered pentagonal bipyramidal Co(II) macrocycles both axially coordinated to a single [Fe(CN)6]4− unit in a zig-zag arrangement, highlighting the versatility of this family of dimeric building blocks for the self-assembly of higher order structures. Magnetic studies on (2) reveal that the ions exist as isolated S = 3/2 spin systems with no first-order spin–orbit coupling, but with significant axial zero field splitting (D = 23 cm−1, giso = 2.37), indicating that the back-to-back N3O2 macrocyclic ligand does not offer an efficient magnetic exchange pathway. The magnetic response of (5) in the high temperature region (T > 50 K) is identical to (2) indicating dominant zero field splitting effects. However, on further cooling an upturn in χT is consistent with weak ferromagnetic exchange (J/k = +7.8 K) via the [Fe(CN)6]4− bridging unit, affording weakly-coupled CoII dimer units within the polymer chain of (5).

OBJECTIVE: To retrospectively assess at national level whether the addition of molecular data to clinical/histopathological factors could have modified the initial risk factors for survival in children with medulloblastoma. METHODS: A 40 years (1975-2015) retrospective study of 218 patients (0-18 years) from 24 national hospitals was performed. Histology and molecular review, including CTNNB1 gene mutations (RT-PCR) p53(immunohistochemistry) and MYCC/MYCN (FISH), was centralized. The patients were reclassified as standard (SR) or high-risk (HR) according to current knowledge. RESULTS: 187 cases had valid data. Median age 6.9 years (76%

PURPOSE: Despite numerous advances, survival remains dismal for children and adolescents with poor prognosis cancers or those who relapse or are refractory to first line treatment. There is, therefore, a major unmet need for new drugs. Recent advances in the knowledge of molecular tumor biology open the door to more adapted therapies according to individual alterations. Promising results in the adult anticancer drug development have not yet been translated into clinical practice. We report the activity in early pediatric oncology trials in Spain. METHODS: All members of the Spanish Society of Pediatric Hematology Oncology (SEHOP) were contacted to obtain information about early trials open in each center. RESULTS: 22 phase I and II trials were open as of May 2015: 15 for solid tumors (68 %) and 7 for hematological malignancies (32 %). Fourteen (64 %) were industry sponsored. Since 2010, four centers have joined the Innovative Therapies For Children With Cancer, an international consortium whose aim is developing novel therapies for pediatric cancers. A substantial number of studies have opened in these 5 years, improving the portfolio of trials for children. Results of recently closed trials show the contribution of Spanish investigators, the introduction of molecularly targeted agents and their benefits. CONCLUSIONS: Clinical trials are the way to evaluate new drugs, avoiding the use of off-label drugs that carry significant risks. The Spanish pediatric oncology community through the SEHOP is committed to develop and participate in collaborative academic trials, to favor the advancement and optimization of existing therapies in pediatric cancer.

Resumen: El linfoma anaplásico de células grandes (LACG) es una enfermedad poco frecuente en la infancia. Su localización más habitual es ganglionar o cutánea; la presentación endobronquial es extremadamente rara. A continuación se presenta el caso clínico de un varón de 10 años, en el que se llegó al diagnóstico de LACG endobronquial casualmente, al realizarle estudios por una lesión ósea benigna, debido a la ausencia de síntomas respiratorios inicialmente. Abstract: Anaplastic large cell lymphoma is a very rare disease in childhood. The most common location of this lymphoma is lymph node and skin, with endobronchial involvement being extremely rare. We report a case of a 10-year-old boy diagnosed by chance with an endobronchial anaplastic large cell lymphoma, while he was being investigated for a a benign bone disease, due to the initial absence of respiratory symptoms.

Resumen: El timoma maligno es una neoplasia rara en sujetos pediátricos y generalmente se asocia con síndromes paraneoplásicos; el más típico es la miastenia grave. También se describen alteraciones hematológicas, como la aplasia pura de serie roja o la aplasia medular completa. A continuación se presenta el caso de un varón de 12 años con un timoma maligno de gran tamaño tratado con poliquimioterapia. El sujeto desarrolló una aplasia medular grave después de la cirugía, con mala respuesta al tratamiento inmunosupresor, que evolucionó a hemorragia pulmonar masiva. Abstract: Malignant thymoma is a very rare neoplasm in paediatric patients; it is usually associated with para-neoplastic syndromes, the most frequent is myasthenia gravis; some haematological abnormalities may also be present, such as pure red cell aplasia or aplastic anaemia. We report a 12-year-old boy suffering from a very large thymoma, treated with multiple chemotherapy, and who developed a severe aplastic anaemia after surgery. He had a poor response to immunosuppressive treatment and later developed massive pulmonary bleeding as a complication.

Blastemal-type Wilms tumour (BT-WT) has been identified as a high risk histological subgroup in WT assessed after pre-nephrectomy chemotherapy in trials of the International Society of Paediatric Oncology (SIOP) Renal Tumour Study Group. Therefore, in SIOPWT2001, post-operative chemotherapy for BT-WT was intensified aiming to improve survival. Survival analysis of all unilateral BT-WT patients (SIOPWT2001) (n = 238), was compared with historical BT-WT controls (SIOP93-01) (n = 113). 351/4061 (8.6%) unilateral non-metastatic BT-WT patients (SIOP93-01/SIOPWT2001) were studied. Median age at diagnosis was 43 months (Inter Quartile Range (IQR) 24-68 months), stages: I (n = 140, 40%), II (n = 106, 30%), III (n = 105, 30%). BT-WTs were higher staged, showed greater volume decrease after pre-operative chemotherapy and were diagnosed at an older median age compared to other WT patients. Patient characteristics did not differ substantially between SIOP93-01 and SIOPWT2001. Univariate analysis showed a 5-year event-free survival (EFS) of 80% (95% confidence interval (CI): 75-86%) (SIOPWT2001) compared to 67% in SIOP93-01 (95% CI: 59-76%; p = 0.006) and overall survival (OS) of 88% (95% CI: 83-93%) (SIOPWT2001) compared to 84% (95% CI: 77-91%; p = 0.4) in SIOP93-01. 95% of relapses were distant metastases (SIOP93-01/SIOPWT2001). Treatment protocol, age at diagnosis, tumour stage (III versus I/II) and volume (at surgery), were prognostic variables for EFS (uni- and multivariate Cox regression analysis). Independent prognosticators for OS were age at diagnosis, tumour stage and volume (at surgery). The most significant survival benefit of intensified treatment, was observed in Stage I (EFS 96% in SIOPWT2001 (OS 100%), 71% in SIOP93-01 (OS 90%)). BT-WT derived benefits from more intensive chemotherapy as reflected by a reduction in relapse risk. However, the benefit of the more intensive chemotherapy to improve OS was only observed in stage I BT-WTs, by adding doxorubicin. (C) 2014 Elsevier Ltd. All rights reserved

Topotecan has been variably incorporated in the treatment of patients with relapsed Wilms tumour (WT) who failed initial treatment with three or more effective drugs. Our objective was to describe outcome and to retrospectively investigate the potential role of topotecan in relapsed WT patients.Children who were treated with topotecan as part of their chemotherapeutic regimens for relapsed WT were identified and included in our retrospective study. Patient charts were reviewed for general patient characteristics, histology and stage at initial diagnosis, number and type of relapse, salvage treatment schedules, toxicity, response to treatment and outcome.From 2000 to 2012, 30 children (median age at relapse 5.5 years, range 1.6-14.5 years) were identified to have received topotecan as part of their salvage regimens (primary progressive disease n = 3, first, second and third relapse n = 13, 9 and 2 respectively, partial response n = 3). Topotecan was administered as a single agent (12 patients) or in combination with other drugs (18 patients). Sixteen patients had high-risk histology according to the SIOP classification, 15 died within 12 months because of progressive disease. Fourteen patients had SIOP intermediate-risk histology of which four patients displayed objective responses to topotecan. Overall, 6 out of 14 intermediate-risk patients survived (median follow up of 6 years), however, three of whom (stage V) had bilateral nephrectomy after topotecan treatment.Topotecan does not seem to show effectiveness in the treatment of relapsed WT patients with initial high-risk histology. In patients with intermediate-risk histology, the role of topotecan might deserve further attention, to prove its efficacy.

Background Stage 4 and MYCN amplified (MNA) neuroblastoma in children have a poor prognosis. Our aim was to increase initial and long-term reponse in this population. Procedure High-risk children were studied according to the International Neuroblastoma Staging System, then treated with high-dose cyclophosphamide and high-dose carboplatin, followed by surgery and autologous stem cell transplant or maintenance chemotherapy. Results From June 1992 to December 1998, 83 children were admitted in the study (72 stage 4> 1 year, 5 stage 4 MNA infants, and 6 MNA stage 3 children); tumor tissue was obtained from 73, MYCN was performed in 65, being amplified in 21 (32%). Induction chemotherapy was administered in the expected time in 35% of patients. Its toxicity was mainly hematologic followed by infections, and there were 3 chemotherapy-related deaths. Delayed surgery was performed on 60 patients with complete or >90% resection in 80% of cases. Chemotherapy plus surgery produced some response in 90% of patients, 53% were in CR/VGPR; 49 children received autologous SCT, and 16 received maintenance chemotherapy for 9 months. Follow-up ranges are 1–87 months, mean 30 months. S and EFS at 4 years are 0.33 (SD 0.02). Conclusions High-dose cyclophosphamide and high-dose carboplatin are effective in the initial treatment of neuroblastoma; combined with surgery they produce some response in most patients. Nevertheless, the CR/VGPR rate reaches only 53%. Survival time has also been prolonged but most patients relapse with metastases. Med Pediatr Oncol 2001;37:537–542. © 2001 Wiley-Liss, Inc.

Purpose Clear Cell Sarcoma of the Kidney (CCSK) is a rare childhood renal tumour. Only a few homogeneously treated CCSK cohorts have been reported. This study aims to describe clinical characteristics and survival of CCSK patients treated according to recent International Society of Pediatric Oncology (SIOP) protocols. Patients and methods We analysed the prospectively collected data of patients with a histologically verified CCSK, entered onto SIOP 93-01/2001 trials. Results A total of 191 CCSK patients (64% male) were analysed, with a median age at diagnosis of 2.6 years. Stage distribution for stages I, II, III and IV was 42%, 23%, 28% and 7%, respectively. Pre-operative chemotherapy was administered to 169/191 patients. All patients underwent total nephrectomy and 189/191 patients received post-operative chemotherapy. Radiotherapy was applied in 2/80 stage I, 33/44 stage II, 44/54 stage III and 6/13 stage IV patients. Five year event-free survival (EFS) and overall survival (OS) were 79% (95% confidence interval (CI): 73-85%) and 86% (95% CI: 80-92%) respectively. Stage IV disease and young age were significant adverse prognostic factors for event-free survival. Factors such as gender, tumour volume and type of initial treatment were not found to be prognostic for EFS and OS. Conclusion In this largest SIOP cohort described so far, overall outcome of CCSK is reasonable, although treatment of young and advanced-stage disease patients is challenging. As further intensification of treatment is hampered by direct and late toxicity, future directions should include the development of targeted therapy based on specific molecular aberrations of CCSK.

Background Prognosis of relapsed and refractory neuroblastoma is uniformely fatal; new therapeutic approaches are needed. Procedure Relapsed and refractory neuroblastoma patients were treated with continuous infusion chemotherapy combined with MIBG. Results Over 4 years, 35 heavily pretreated patients were registered, 29 with bone or/and bone marrow metastases. Grade 3 or 4 hematologic toxicity was frequent, without toxic deaths. Sixteen patients responded. The probability of 5-year overall survival was 0.19. Conclusions This approach is feasible and toxicity manageable; it rescued some patients and prolonged their survival. It merits assay in newly diagnosed high-risk neuroblastoma patients. Med. Pediatr. Oncol. 35:724–726, 2000. © 2000 Wiley-Liss, Inc.

Anaplastic large cell lymphoma is a very rare disease in childhood. The most common location of this lymphoma is lymph node and skin, with endobronchial involvement being extremely rare. We report a case of a 10-year-old boy diagnosed by chance with an endobronchial anaplastic large cell lymphoma, while he was being investigated for a a benign bone disease, due to the initial absence of respiratory symptoms.

Malignant thymoma is a very rare neoplasm in paediatric patients; it is usually associated with para-neoplastic syndromes, the most frequent is myasthenia gravis; some haematological abnormalities may also be present, such as pure red cell aplasia or aplastic anaemia. We report a 12-year-old boy suffering from a very large thymoma, treated with multiple chemotherapy, and who developed a severe aplastic anaemia after surgery. He had a poor response to immunosuppressive treatment and later developed massive pulmonary bleeding as a complication.

We report a case of PHACES syndrome witch was effectively treated using vincristine. A female infant was referred at 8 months of age for evaluation with a segmental mandibular haemangioma with rapid growing and facial disfigurement. The infant was initially placed on oral prednisone with clinical response but she developed obstructive sleep apnoea. Vincristine was started at about 24 months and continued for 4 months with marked decrease in the size of the haemangioma. The only side effect was constipation.

Objetivo El grupo de pacientes con neuroblastoma (NB) de alto riesgo tienen una pobre respuesta a la terapeutica habitual, con una supervivencia global a los 5 anos en torno al 20-30%. Por este motivo, existe un marcado interes en la busqueda de terapias mas efectivas. Esta demostrado el efecto de la radiacion dirigida a las celulas tumorales mediante el empleo de 131 I-MIBG terapeutica. Existen pocos estudios que muestren el manejo y posterior seguimiento y evolucion de los pacientes sometidos a esta terapia. Presentamos nuestra experiencia con el manejo de este tipo de terapeutica. Material y metodos Estudio retrospectivo de los pacientes con NB de alto riesgo tratados en nuestra unidad con 131 I-MIBG entre los anos 1981 y 2006. Se revisan datos epidemiologicos, anatomopatologicos, tipo de terapia previa, situacion clinica del paciente antes de la administracion del radionuclido, dosis total y por kilogramo empleada, numero de ciclos, el empleo de quimioterapia asociada, la necesidad de rescate con progenitores de sangre periferica, la toxicidad constatada y la situacion actual de los pacientes. Resultados En los ultimos 25 anos han sido diagnosticados y tratados en nuestra unidad un total de 91 pacientes pediatricos con neuroblastoma, perteneciendo al grupo de alto riesgo un total de 17 (todos estadio IV) (18,7 %), a los que se administro terapia intensiva segun el protocolo de tratamiento vigente. En cinco de estos pacientes se ha empleado terapia con 131 I-MIBG. Se trata de 4 varones y una nina, con edades comprendidas entre 2,3 y 14 anos al diagnostico, todos estadio IV, con tumor primario suprarrenal, paravertebral o toracico y metastasis en medula osea en todos los casos, y en higado u oseas en 2 pacientes. La histologia mostraba en tres de ellos un NB pobremente diferenciado y en dos, ganglioneuroblastoma. Solamente un paciente presentaba amplificacion del n-Myc, y en dos existia la delecion 1p. Los pacientes recibieron diferentes regimenes de quimioterapia, en funcion del protocolo SEOP o SIOP vigente en el ano de diagnostico, y al momento de emplear la 131 I-MIBG terapeutica se encontraban en situacion de enfermedad progresiva. La dosis de 131 I-MIBG oscila entre 10 y 20 mCi/kg de peso, administrandose en 1 o 2 ciclos, separados entre si desde 16 dias hasta 2,8 meses, con bloqueo tiroideo. Dos pacientes recibieron quimioterapia asociada. El principal efecto adverso asociado a este tipo de tratamiento es la trombocitopenia, que fue mas intensa en 2 pacientes y con una mediana de duracion de 17 semanas. En 2 pacientes se realizo rescate con progenitores de sangre hematopoyetica. Un paciente desarrollo leucemia no linfoblastica aguda en relacion con la dosis total acumulada de VP-16. No se ha constatado toxicidad tiroidea o cardiaca a largo plazo. La situacion actual de este grupo de pacientes es de dos vivos con enfermedad, y tres fallecidos, por progresion de la enfermedad o por el desarrollo de una leucemia mieloblastica aguda secundaria en un caso. Conclusiones La terapia con 131 I-MIBG es un arma mas en el tratamiento del NB de alto riesgo en pacientes pediatricos. Se considera una de las terapias que permiten cronificar la evolucion de los NB-IV, mejorando asi su supervivencia global. Su empleo esta al alcance de algunas unidades de oncologia infantil, con colaboracion con el servicio de medicina nuclear. Es una terapia en general bien tolerada, cuyo principal efecto secundario es la trombocitopenia transitoria.

Prognosis of relapsed and refractory neuroblastoma is uniformly fatal; new therapeutic approaches are needed.Relapsed and refractory neuroblastoma patients were treated with continuous infusion chemotherapy combined with MIBG.Over 4 years, 35 heavily pretreated patients were registered, 29 with bone or/and bone marrow metastases. Grade 3 or 4 hematologic toxicity was frequent, without toxic deaths. Sixteen patients responded. The probability of 5-year overall survival was 0.19.This approach is feasible and toxicity manageable; it rescued some patients and prolonged their survival. It merits assay in newly diagnosed high-risk neuroblastoma patients.

Introduccion El neuroblastoma es uno de los tumores solidos mas frecuentes en la infancia. A pesar de los actuales tratamientos, la supervivencia en estadios avanzados es insatisfactoria, con un porcentaje importante de pacientes que recaen o progresan. El topotecan ha demostrado actividad en el neuroblastoma en ensayos fase II, con una buena farmacocinetica, siendo la mielotoxicidad el efecto secundario mas importante. Pacientes y metodos Estudio prospectivo cuyos criterios de inclusion son: – Pacientes mayores de un ano diagnosticados de neuroblastoma de cualquier estadio que hayan recaido. – Pacientes estadio 4 que sean refractarios al tratamiento inicial de induccion. – Pacientes menores de un ano que hayan recaido con metastasis oseas o de medula osea. – Todos ellos deben tener un aclaramiento de creatinina > 40 ml/m/1,73 m2, deben haber pasado al menos 14 dias desde el ultimo ciclo quimioterapico, es necesario el consentimiento de los padres. Se administran 2 ciclos de topotecan 1,5 mg/m2/dia × 5 dias × 2 semanas (cada 3 semanas); seguidos de 2 ciclos de ciclofosfamida + topotecan y 2 de ifosfamida + topotecan. Resultados Iniciaron el protocolo 20 pacientes (13 ninos y 7 ninas), todos eran mayores de un ano. El motivo de inclusion fue: recaida o metastasis (17/20) y no respuesta al tratamiento de induccion en 3 casos. Los protocolos de tratamiento que habian llevado antes de entrar en este estudio fueron: N-I-87 en 6 casos, N-II-92 en 8, N-AR-99 en 5, otros en un caso. El estadio al diagnostico era: 1 en 1 caso, 2A en 1 caso, 3 en 4, 4 en 14. Presentaban tumoracion local 16/20 (en 4 era la unica manifestacion de la enfermedad), y 17 presentaban metastasis (en medula osea = 10, oseas = 13, hepaticas = 2, ganglionares = 3, multiples = 10). La LDH estaba elevada en 5 casos, la ENE en 13 casos. La MIBG fue positiva en 19/20 (en el tumor en 5, en las metastasis en 7, en tumor + metastasis en 7) y negativa en 1. En 7 casos se realizo cirugia al inicio (biopsia = 4, reseccion = 2, reseccion con resto macroscopico = 1). Trece pacientes presentaron toxicidad hematologica grado 4 (65 %), 2 pacientes grado 3 (10 %). Diez pacientes presentaron toxicidad infecciosa (50 %), grado 3 en 2 casos, grado 2 en 5 casos, grado 1 en 3 casos. Toxicidad neurologica en 1 caso. Once pacientes tuvieron que ser hospitalizados, recibiendo GCSF 10 de ellos, transfusion de concentrado de hematies 12, de plaquetas 14 y antibioticos 9. Quince pacientes recibieron al menos 2 ciclos de quimioterapia. La respuesta tras los 2 ciclos fue: RC = 4, RP = 4, Rmixta = 1, PE = 3, fallecieron = 5. Se realizo cirugia durante el quinto ciclo en 9, durante el sexto en 6. Evaluacion final: 18 pacientes fallecieron, uno por el tratamiento, otro por neumonia y 16 por progresion de la enfermedad. Dos pacientes siguen vivos (uno con tumor local y otro libre de enfermedad), el primero tenia al diagnostico enfermedad local + medula osea y el otro tenia metastasis oseas. La media de tiempo de supervivencia libre de progresion desde la inclusion en el protocolo ha sido de 13,41 meses (rango: 1,43-28,43). Conclusiones A pesar de que el neuroblastoma suele ser resistente o con respuesta parcial en pacientes que han recaido o que presentan metastasis, se ha conseguido un buen control de la enfermedad en 2/20 pacientes tratados (uno vive libre de enfermedad), ambos presentaban metastasis al diagnostico (uno en medula osea y otro en hueso)¸ el tiempo de seguimiento ha sido de 56 y 42 meses, respectivamente. En los pacientes que han fallecido, se ha conseguido aumentar el tiempo libre de progresion.

This article show our group of liver neoplasm. We studied the presentation way in the benign and malignant tumors. Moreover we compared the therapeutics results between both groups. In our population was more frequent the malignant neoplasm. The first symptom was more frequent the malignant neoplasm. The first symptom was abdominal mass but with more general complaints in the last one. We checked the increase survival with therapeutics as ADR or CDDP.