IBD-PODCAST Spain: A Close Look at Current Daily Clinical Practice in IBD Management.

BACKGROUND: Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) that contributes in part to irreversible bowel damage and long-term complications, reduced quality of life, invalidity, and economic burden. Suboptimal control of IBD is associated with higher healthcare resource utilization (HCRU), impaired quality of life (QoL), and reduced work productivity. AIMS: The IBD-PODCAST study aimed to assess the proportion of IBD patients with suboptimal control and its associated impact. METHODS: IBD-PODCAST is a cross-sectional, multicenter study that aimed to characterize the CD and UC population with optimal or suboptimal control according to the STRIDE-II criteria and patient- and physician-reported measures. Here we present the results of the Spanish cohort (n = 396). RESULTS: A total of 104/196 (53.1%) CD and 83/200 (41.5%) UC patients were found to have suboptimal disease control. Long-term treatment targets according to STRIDE-II were applied in 172 (87.8%) CD and 181 (90.5%) UC patients. 125 of 172 (72.7%) CD and 74 of 181 (40.9%) UC patients were currently treated with targeted immunomodulators. Patients with CD and UC and suboptimal disease control showed impaired QoL, higher HCRU and direct costs, and also loss of work productivity compared to those with optimal control. CONCLUSION: Despite a high rate of targeted immunomodulator therapy, a substantial proportion of IBD patients show suboptimal disease control according to the STRIDE II criteria. Those patients with suboptimal disease control exhibit impaired QoL, less work productivity, and higher HCRU, suggesting that there is considerable need for better treatment approaches in IBD.

Improving the quality of care in the molecular era for children and adolescents with medulloblastoma.

PURPOSE: Elevated mortality and morbidity rates persist in pediatric patients with medulloblastoma. We present a clinical audit of a real-world cohort of patients in search for pragmatic measures to improve their management and outcome. METHODS/PATIENTS: All pediatric patients with medulloblastoma treated between 2003 and 2016 at a Spanish reference center were reviewed. In the absence of internationally accepted quality indicators (QIs) for pediatric CNS tumors, diagnostic, therapeutic, survival, and time QIs were defined and assessed. RESULTS: Fifty-eight patients were included, 24% were younger children (< 3 years), 36% high risk (anaplastic, metastasis, or surgical residue > 1.5 cm2), and 40% standard risk. Five-year OS was 59.2% (95% CI 47-75); 5-year PFS 36.4% (95% CI 25-53). Five main areas of quality assurance were identified: diagnosis, global strategy, frontline treatment modalities, outcomes, and long-term and end-of-life care. A set of 34 QIs was developed and applied. Lack of central pathology review, delay in the incorporation of novel molecular markers, and absence of a neurocognitive and quality-of-life evaluation program were some of the audit findings. CONCLUSIONS: This real-world research study resulted in the development of a pragmatic set of QIs, aimed to improve clinical audits and quality of care given to children and adolescents with medulloblastoma. We hope that our findings will serve as a reference to further develop a quality assurance system with specific QIs for pediatric CNS tumors in the future and that this will ultimately improve the survival and quality of life of these patients.

Outcome of childhood leukaemia survivors and necrosis of the femoral head treated with autologous mesenchymal stem cells.

PURPOSE: Corticoid-induced osteonecrosis (ON) of femoral head can lead to severe hip joint impairment and hip replacement, with negative impact in young survivors of acute lymphoblastic leukaemia (ALL) with long life expectancy. We aim to improve quality of life in these patients with a novel approach. METHODS/PATIENTS: Based on the regenerative capacities of mesenchymal stem cells (MSCs), we performed locally implanted autologous cell therapy in two adolescents suffering of bilateral femoral ON. This required a simple, minimally invasive surgical procedure. RESULTS: Both patients experienced significant pain relief and restoration of gait kinematic values. Radiographic evaluation showed cessation of hip collapse. No toxicities/complications were observed after a 4-year follow-up. CONCLUSIONS: Our preliminary results suggest that autologous MSCs can be considered as a novel treatment for children and young adults with ON after overcoming ALL. It may avoid hip replacement and improve quality of life of leukaemia survivors.

Management and outcome of children with neuroendocrine tumors of the appendix in Spain: Is there room for improvement?

PURPOSE: Neuroendocrine tumors (NETs) are, after lymphomas, the most frequent gastrointestinal tumors in children, mainly located in the appendix. Best management remains unclear, given the absence of pediatric guidelines. We present the first Spanish series of pediatric patients with NETs. PATIENTS AND METHODS: Retrospective study of all pediatric patients (<18 years) with NET treated in four oncology reference institutions in Spain between 1994 and 2015. RESULTS: Seventeen patients were included. All patients presented with acute abdomen. TNM stage was T1a (82%) and T1b (12%). Extension study was heterogenous, with only 4 patients undergoing an OctreoScan. Four patients met criteria for second surgery (affected surgical margins or mesoappendix invasion), but it was only performed in two. Despite the diverse management, none of the patients relapsed during follow-up. CONCLUSIONS: The disparity in diagnostic tests, second surgery criteria and follow-up shown in this study highlights the need for specific pediatric guidelines.

Landscape of early clinical trials for childhood and adolescence cancer in Spain.

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.

[Establishment of a preclinical neuroblastoma model in immunocompetent mice]. / Establecimiento de un modelo preclínico de neuroblastoma en ratones inmunocompetentes.

AIM: To develop a NB animal model which makes possible studies related to tumor immunity. MATERIALS AND METHODS: Two types of NB cells were used. Cell line 36769 was derived from TH-MYCN+ mouse in which overexpression of the MYCN gene is governed by rat tyrosine hydroxylase promotor. Cell line 4040 was derived from TH-MYCN/ALK mice, which in addition express an activating mutation of ALK gene. For each cell type, 1x106 neurospheres were implanted in 129/SVJ mice (with the same genetic background as donors, n=8), via orthotopic injection in the left suprarenal gland by intraperitoneal approach, through a transverse supraumbilical laparotomy. Daily postsurgical clinical follow-up of the animals was done until they were sacrificed at four weeks. The tumor presence was macroscopically confirmed. The tumoral sample was excised and was processed for cellular immunity and molecular tolerance mediator's studies. The existence of metastasis was investigated by flow cytometry in the spleen, bone marrow and peripheral blood. RESULTS: 1) Orthotopic Neuroblastoma was generated in all the transplanted mice. 2) The tumors were infiltrated by several immune subpopulations, with effector, regulatory and suppressor inmunophenotype. This was similar to the inmunophenotype described in human NB. Furthermore, the molecular mediators of the environment point to a state of protumoral tolerance. CONCLUSION: The orthotopic implantation of NB neurospheres in syngeneic mice has allowed us to generate a NB model in which it has been possible to study the tumor immunity.

OBJETTIVO: Desarrollar un modelo animal de neuroblastoma (NB) que posibilite estudios relacionados con la inmunidad tumoral. MATERIAL Y METODOS: Se utilizaron dos tipos de células NB. La línea 36769 procedía del ratón TH-MYCN+ en el que la sobreexpresión del gen MYCN está gobernada por el promotor de la tirosín hidroxilasa de rata. La línea 4040 procedía de ratones TH-MYCN+/ALK+, que además expresan una mutación activadora del gen ALK. De cada tipo celular se implantaron 1x106 neurosferas en ratones 129/SVJ (mismo fondo genetico que los donantes, n=8), mediante inyección ortotópica en glándula suprarrenal izquierda por abordaje intraperitoneal, a través de laparotomía transversa supraumbilical. Se realizó seguimiento clínico diario postquirúrgico de los animales hasta su sacrificio a las 4 semanas. La presencia de tumor se confirmó macroscópicamente. La pieza tumoral se extirpó y se procesó para estudios de inmunidad celular y mediadores moleculares de tolerancia. Se investigó la existencia de metástasis por citometría de flujo en bazo, médula ósea y sangre periférica. RESULTADOS: 1) En todos los ratones trasplantados se generó NB ortotópico. 2) La pieza tumoral se encontró infiltrada por diversas subpoblaciones inmunes, con inmunofenotipo efector, regulador y supresor, similar a la situación descrita en los NB humanos. Además, los mediadores moleculares del microambiente apuntan a un estado de tolerancia protumoral. CONCLUSIONES: La implantación ortotópica de neurosferas NB en ratones singénicos nos ha permitido generar un modelo de NB en el que ha sido posible estudiar la inmunidad tumoral.

[Low-grade gliomas: review of 10 years]. / Gliomas de bajo grado: revisión de 10 años.

INTRODUCTION: Central nervous system (CNS) tumors are the most common solid tumors in children. Among these, the low-grade gliomas are the most common type, accounting for up to 30-50% of them. PATIENTS AND METHODS: A retrospective analysis was carried out on the epidemiology, clinical characteristics, tumor location, histology, treatment, outcome and long-term sequelae of 111 patients diagnosed with low-grade glioma in the Niño Jesús Children's Hospital of Madrid from January 2002 to December 2011. RESULTS: Of the 111 patients, there were 57 boys and 54 girls. The mean age was 7.26 years (range, 2 months - 19 years). The most common symptoms of presentation were headache (27%) and vomiting (19%). The most common locations were the cerebral hemispheres (38%), followed by the brainstem (27.4%), and cerebellum (18.5%). Histological examination was performed in 89 patients (80.18%). Pilocytic astrocytoma was the most common histological type. Diagnostic biopsy was performed in 20 patients (22.5%), partial resection in 38 patients (42.7%), and total resection in 31 patients (34.8%). Sixteen patients received chemotherapy (14%), and eighteen patients received radiotherapy (16%). Overall survival was 88.3%. Long term hearing, visual and endocrine sequelae were note in 1, 5, and 4 patients, respectively. CONCLUSIONS: The most common histological type is pilocytic astrocytoma. Overall survival was 88.3%. Only 9% of patients had some kind or auditory, visual or endocrine sequelae.

[Transformation of myelodysplastic syndrome to acute lymphoblastic leukemia: 2 new cases]. / Transformación de síndrome mielodisplásico a leucemia linfoblástica aguda: 2 casos nuevos.

Myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic stem cells, with a variable risk of transformation to acute myeloid leukemia. Progression into acute lymphoblastic leukemia (ALL) is an extremely rare event, with very few cases published in children. In this report, we describe two cases of myelodysplastic syndromes that progressed to ALL. Moreover, we review previously reported cases of MDS transformation to acute lymphoblastic leukemia in the pediatric population whose prognosis seems to be similar to that for adults.

[Tumours in the pineal region in the paediatric age. Reports of 23 cases and a review of the literature]. / Tumores de la region pineal en la edad pediatrica. Presentacion de 23 casos y revision de la bibliografia.

INTRODUCTION: Tumours in the pineal region are located at a meeting point of several neurovascular structures that are difficult to reach surgically and for which the possibility of resection is limited; as a result the management of these lesions usually requires associated adjunctive treatment with radiotherapy and/or chemotherapy. PATIENTS AND METHODS: This study is a retrospective analysis of the epidemiological, clinical, neuroimaging and pathological characteristics of 23 patients with tumours in the pineal region who were treated between the years 1997 and 2010 in the Hospital Infantil Niño Jesús. The factors involved in the prognosis of this cohort following surgical or adjunctive treatment are also discussed. RESULTS: Subjects included in the study were 6 girls and 17 boys with ages ranging from 4 months to 18 years. It was found that the initial symptoms in 95% of the patients were signs of acute or subacute hydrocephalus, which required the placement of a ventriculoperitoneal shunt (82%). A histological sample of the tumour tissue was collected in all cases. Biopsy samples were taken in the case of five patients and 18 underwent surgery involving a craniotomy. Germinoma (eight cases) and mature teratoma (one case) were the tumours with the longest survival times; non-germinomatous tumours (three cases), those of the pineal parenchyma (four cases) and gliomas (five cases) presented the highest rates of recurrence and a poorer prognosis. CONCLUSIONS: The study of tumour markers can be used to guide the diagnosis of certain tumours of the pineal region. At present, the recommended procedure involves taking a histological sample of the tumour in order to establish an accurate diagnosis and a specific oncological treatment.

Exercise training and cytokines in breast cancer survivors.

The purpose of this randomized controlled trial was to determine the effects of an 8-week (aerobic+strength) exercise training program (3 sessions/week) on the circulating cytokine levels of breast cancer survivors. We randomly allocated 16 female survivors of breast cancer (mean±SD age: 50±5 years) to an intervention or usual care (control) group (N=8 in each group). The intervention group followed an 8-week exercise program consisting of 3 sessions/week (session duration: 90 min). We measured the levels of the following cytokines before and after the intervention: beta-NGF, CTACK, eotaxin, FGF basic, G-CSF, gmCSFα, HGF, ICAM1, IFNα2, IFNγ, IL1α, IL1ß, IL1ra, IL2, IL2ra, IL3, IL4, IL6, IL7, IL8, IL9, IL10, IL12, IL13, IL15, IL16, IL17, IL18, IP10, LIF, MCS-F, MIP1α, MIP1ß, MIF, MCP1, MCP3, MIG, PDGF bb, SCF, SCGFß, SDF1α, TRAIL, TNFα, TNFß, VCAM1, and VEGF. We only observed a significant interaction (group*time) effect for CTACK ( P=0.016), with mean values remaining stable in the intervention group but increasing over time in controls. The intervention program did not induce a significant decrease in the main breast cancer-related cytokines such as IL6 and IL8. A combined (aerobic+strength) 8-week exercise training intervention did not induce major changes in the basal cytokine levels of breast cancer survivors.

[Hepatosplenic candidiasis in paediatric haematology-oncology patients]. / Candidiasis hepatoesplénica en pacientes hemato-oncológicos pediátricos.

INTRODUCTION: In the last few decades, the survival of children with haematology-oncological malignancies has increased due to more aggressive chemotherapy regimens. This has led to an increase of fungal infections causing significant morbidity and mortality in these patients. Hepatosplenic candidiasis is a disseminated candida infection that affects most commonly the liver and spleen, although other organs may be involved. PATIENTS AND METHODS: We performed a retrospective study of 13 paediatric patients diagnosed with hepatosplenic candidiasis from January 2002 to February 2010 in our paediatric haematology-oncology department following the criteria proposed by the EORTC/MSG (European Organization for Research and Treatment of Cancer and Mycoses study group) updated in 2008. We analysed the clinical characteristics, diagnostic methods, treatment and outcome. RESULTS: The most common symptom of presentation of hepatosplenic candidiasis in our series was persistent fever, up 84.6% of cases, almost all associated with other symptoms. Risk factors for development are non-specific and were present in 92.3% of our patients. The diagnosis of proven infection, which is made by histology or culture, is usually difficult to obtain and in our series it was obtained only in 23.1% of cases. As in our series, diagnosis is often presumptive. Laboratory tests are not useful in the paediatric population and only in one patient we observed an increase in alkaline phosphatase at diagnosis. This result differs from the behaviour of this biological marker in adults. Although prolonged treatment is often necessary for the resolution of the lesions, survival is high with appropriate treatment, 100% in our series. CONCLUSIONS: The mortality of hepatosplenic candidiasis is low with early and adequate treatment.

[What is the prognosis of chronic immune thrombocytopenia?]. / ¿Cuál es el pronóstico de la trombopenia inmunitaria crónica?

OBJECTIVES: To analyse the characteristics of children with chronic ITP (chronic immune thrombocytopenia) in the Hospital Infantil Universitario Niño Jesús (HIUNJ) between 2003 and 2008. To also evaluate whether clinical variables as age, gender, initial platelet count, and treatment have any prognostic significance on the outcome of ITP. PATIENTS AND METHODS: Data were retrospectively collected from 288 patients diagnosed with "Purpura and other haemorrhagic illnesses". Forty-two out of these 288 satisfied the criteria for "chronic ITP". RESULTS: Ten patients out of 42 (23.8%) achieved remission with splenectomy, and 25 (almost 60%) achieved it without splenectomy (14 were complete remissions and 11 were partial remissions). Eight patients (almost 20% of patients with chronic ITP) had spontaneous remissions between 6 and 12 months from initial diagnosis. None of the clinical variables analysed were related to the outcome of the disease and the prognosis of the disease. CONCLUSIONS: Almost 60% of children with chronic ITP achieve remission without treatment regardless of age, gender, initial treatment or platelet count. Splenectomy is one of the treatments with best results; however the high spontaneous recovery rate in children with cITP, the low percentage of bleeding, and the generally benign outcome should encourage delaying this as long as possible. As it is possible to have a remission between 6 and 12 months from the initial diagnosis, the term "chronic" should be reserved for patients with ITP lasting more than 1 year.

Treatment of metastatic neuroblastoma with systemic oncolytic virotherapy delivered by autologous mesenchymal stem cells: an exploratory study.

Treatment of metastatic tumors with engineered adenoviruses that replicate selectively in tumor cells is a new therapeutic approach in cancer. Systemic administration of these oncolytic adenoviruses lack metastatic targeting ability. The tumor stroma engrafting property of intravenously injected mesenchymal stem cells (MSCs) may allow the use of MSCs as cellular vehicles for targeted delivery. In this work, we study the safety and the efficacy of infusing autologous MSCs infected with ICOVIR-5, a new oncolytic adenovirus, for treating metastatic neuroblastoma. Four children with metastatic neuroblastoma refractory to front-line therapies received several doses of autologous MSCs carrying ICOVIR-5, under an approved preliminary study. The tolerance to the treatment was excellent. A complete clinical response was documented in one case, and the child is in complete remission 3 years after this therapy. We postulate that MSCs can deliver oncolytic adenoviruses to metastatic tumors with very low systemic toxicity and with beneficial antitumor effects.

KIR-ligand incompatibility in the graft-versus-host direction improves outcomes after umbilical cord blood transplantation for acute leukemia.

Donor killer cell immunoglobulin-like receptor (KIR)-ligand incompatibility is associated with decreased relapse incidence (RI) and improved leukemia-free survival (LFS) after haploidentical and HLA-mismatched unrelated hematopoietic stem cell transplantation. We assessed outcomes of 218 patients with acute myeloid leukemia (AML n=94) or acute lymphoblastic leukemia (n=124) in complete remission (CR) who had received a single-unit unrelated cord blood transplant (UCBT) from a KIR-ligand-compatible or -incompatible donor. Grafts were HLA-A, -B or -DRB1 matched (n=21) or mismatched (n=197). Patients and donors were categorized according to their degree of KIR-ligand compatibility in the graft-versus-host direction by determining whether or not they expressed HLA-C group 1 or 2, HLA-Bw4 or HLA-A3/-A11. Both HLA-C/-B KIR-ligand- and HLA-A-A3/-A11 KIR-ligand-incompatible UCBT showed a trend to improved LFS (P=0.09 and P=0.13, respectively). Sixty-nine donor-patient pairs were HLA-A, -B or -C KIR-ligand incompatible and 149 compatible. KIR-ligand-incompatible UCBT showed improved LFS (hazards ratio=2.05, P=0.0016) and overall survival (OS) (hazards ratio=2.0, P=0.004) and decreased RI (hazards ratio=0.53, P=0.05). These results were more evident for AML transplant recipients (2-year LFS and RI with or without KIR-ligand incompatibility 73 versus 38% (P=0.012), and 5 versus 36% (P=0.005), respectively). UCBT for acute leukemia in CR from KIR-ligand-incompatible donors is associated with decreased RI and improved LFS and OS.

[Brain-stem tumors in children]. / Tumores de tronco cerebral en la población pediátrica.

We report a large series of brain-stem tumors seen during 18 years of at our hospital. We diagnosed and treated a total of 42 patients between 1988 and 2006; 36 of them were operated with partial resection in most cases. Brain-stem tumors constitute a rare condition with very bad prognosis. A surgical complete resection of the mass is not possible in most cases, so the principal surgical objective is reduction and decompression. The best prognosis is seen in patients with low grade tumors with minimal neurologic deficit. Most of these tumors cause death in a short period, usually one year or less.

Benefits of intrahospital exercise training after pediatric bone marrow transplantation.

The purpose of this study was to determine if an eight-week intrahospital supervised, conditioning program improves functional capacity and quality of life (QOL) in children (4 boys, 4 girls) (mean [SD] age: 10.9 [2.8] years [range: 8-16]) who have undergone bone marrow transplantation (BMT) for leukemia treatment within the last 12 months. A group of 8 age and gender-matched healthy children served as controls. The experimental group performed 3 weekly sessions of resistance and aerobic training inside an intra-hospital gymnasium. A significant combined effect of group and time (p < 0.05) was observed for muscle functional capacity (Timed Up and Down Stairs [TUDS] test) and peak oxygen uptake (V.O(2peak)), i.e., with BMT children showing greater improvements than controls (V.O(2peak) at pre- and post-training of 25.9 (8.2) and 31.1 (7.6) mL/kg/min in diseased children). Muscle strength (6 RM test for bench and leg press and seated row) also improved after training (p < 0.05) in the BMT group. Concerning QOL, a significant combined effect of group and time (p < 0.05) was also observed for children's self-report of comfort and resilience and for parents' report of their children's satisfaction and achievement. In summary, children who have received BMT experience physical and overall health benefits after a relatively short-term (8 weeks) supervised exercise training program.