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The aim of this study was to determine the economic burden from a societal perspective and the health-related quality of life (HRQOL) of patients with histiocytosis in Europe. We conducted a cross-sectional study of patients with histiocytosis from France, Germany, Italy, Spain, Bulgaria, the UK, and Sweden. Data on demographic characteristics, health resource utilisation, informal care, loss of labour productivity and HRQOL were collected from the questionnaires completed by patients or their caregivers. HRQOL was measured with the EuroQol 5-domain (EQ-5D) questionnaire. A total of 134 patients (35 France, 32 Germany, 30 Italy, 24 Spain, 7 Bulgaria, 4 UK and 2 Sweden) completed the questionnaire. The average annual costs ranged from € 6832 to € 33,283 between countries, the year of reference being 2012. Estimated direct healthcare costs ranged from € 1698 to € 18,213; direct nonhealthcare costs ranged from € 2936 to € 17,622 and labour productivity losses ranged from € 1 to € 8855. The mean EQ-5D score for adult histiocytosis patients was estimated at between 0.32 and 0.85, and the mean EQ-5D visual analogue scale score was estimated at between 50.00 and 66.50. The main strengths of this study lie in our bottom-up approach to costing and in the evaluation of histiocytosis patients from a broad perspective (societal costs). This type of analysis is very scarce in international literature for rare diseases in comparison with other illnesses. We conclude that histiocytosis patients incur considerable societal costs and experience substantial deterioration in HRQOL.

X-linked lymphoproliferative disease is a rare T and NK cell immune deficiency which most frequently presents as fulminant infectious mononucleosis following infection with the Epstein-Barr virus (EBV). We report the case of a 4-year-old boy from a Spanish family presenting with severe infectious mononucleosis. In the course of the disease he developed hepatic failure, pancytopenia and neurologic impairment, leading to death after less than 2 months. The results of bone marrow biopsy and autopsy indicated a histological diagnosis of both high-grade B-cell lymphoma and virus-associated haemophagocytic syndrome, thereby confirming the simultaneous presence of two different manifestations of X-linked lymphoproliferative disease (XLP) in this patient. The family history revealed four close male relatives dying under similar circumstances, one of whom died following a vaccination against measles. Molecular genetic studies identified a novel mutation in the SH2D1A gene in several members of the family, establishing the diagnosis of XLP. Fatal EBV infection in male infants is highly indicative of XLP. Virus-associated haemophagocytic syndrome and B-cell lymphoma can occur concomitantly and may be difficult to distinguish due to their similar histological pictures.

Children with Langerhans cell histiocytosis (LCH) and single-bone CNS-risk lesions have been reported to be at increased risk of diabetes insipidus (DI), central nervous system neurodegeneration (CNS-ND), and recurrence of disease. However, it is unknown whether the addition of chemotherapy or radiotherapy changes outcomes in these patients.Ten pediatric institutions across North America and Europe contributed data of their patients with LCH and single-bone CNS-risk lesions. Clinical information on age, sex, specific craniofacial site involvement, and intracranial extension at diagnosis, therapy, and disease course was collected for all eligible patients.The final analysis included 93 eligible children who were either treated with systemic therapy (chemotherapy, chemo-radiotherapy, or radiotherapy) or local therapy (biopsy, curettage, and/or intralesional steroids). Fifty-nine patients had systemic and 34 had local therapy. The 5-year event-free survival (EFS) and overall survival (OS) were 80 ± 5% and 98 ± 2% in the systemic therapy group versus 85 ± 6% and 95 ± 5% in the local therapy group. There was no statistically significant difference between either group with regard to EFS (P = 0.26) and OS (P = 0.78). On multivariable analysis, there was no significant difference among the two treatment groups after adjusting for site and intracranial soft tissue extension, nor any trend favoring systemic therapy (HR = 2.26, 95% CI = 0.77-6.70; P = 0.14).Systemic therapy may not reduce the risk of recurrence or late sequelae in children with LCH and single-bone CNS-risk lesions as compared to local treatment.

We report the case of a 2-year-old boy with hypereosinophilia who presented with fever, muscle pain and heart, CNS and skin involvement. He was treated with steroids with partial response. Six months after diagnosis of hypereosinophilia, several scalp nodules were surgically removed and Hypoderma bovis larvae were found, which led to the diagnosis of cutaneous myiasis. Following removal of the larvae, the clinical and hematological manifestations returned to normal.

PurposeTo identify risk factors present at admission in adult patients hospitalised due to influenza virus infection during the 2009/10 and 2010/11 seasons—including whether infection was from pandemic or seasonal influenza A infections—that were associated with the likelihood of developing severe pneumonia with multilobar involvement and shock.MethodsProspective cohort study. Patients hospitalised due to influenza virus infection were recruited. We collected information on sociodemographic characteristics, pre-existing medical conditions, vaccinations, toxic habits, previous medications, exposure to social environments, and EuroQoL-5D (EQ-5D). Severe pneumonia with multilobar involvement and/or shock (SPAS) was the primary outcome of interest. We constructed two multivariate logistic regression models to explain the likelihood of developing SPAS and to create a clinical prediction rule for developing SPAS that includes clinically relevant variables.ResultsLaboratory-confirmed A(H1N1)pdm09, EQ-5D utility score 7 days before admission, more than one comorbidity, altered mental status, dyspnoea on arrival, days from onset of symptoms, and influenza season were associated with SPAS. In addition, not being vaccinated against seasonal influenza in the previous year, anaemia, altered mental status, fever and dyspnoea on arrival at hospital, difficulties in performing activities of daily living in the previous 7 days, and days from onset of symptoms to arrival at hospital were related to the likelihood of SPAS (area under the curve value of 0.75; Hosmer–Lemeshow p value of 0.84).ConclusionsThese variables should be taken into account by physicians evaluating a patient affected by influenza as additional information to that provided by the usual risk scores.

To compare the capacity of the 2004 diagnostic guidelines for hemophagocytic lymphohistiocytosis (HLH-2004) with the capacity of the preliminary diagnostic guidelines for systemic juvenile idiopathic arthritis (JIA)-associated macrophage activation syndrome (MAS) to discriminate MAS complicating systemic JIA from 2 potentially confusable conditions, represented by active systemic JIA without MAS and systemic infection.International pediatric rheumatologists and hemato-oncologists were asked to retrospectively collect clinical information from patients with systemic JIA-associated MAS and confusable conditions. The ability of the guidelines to differentiate MAS from the control diseases was evaluated by calculating the sensitivity and specificity of each set of guidelines and the kappa statistics for concordance with the physician's diagnosis. Owing to the fact that not all patients were assessed for hemophagocytosis on bone marrow aspirates and given the lack of data on natural killer cell activity and soluble CD25 levels, the HLH-2004 guidelines were adapted to enable the diagnosis of MAS when 3 of 5 of the remaining items (3/5-adapted) or 4 of 5 of the remaining items (4/5-adapted) were present.The study sample included 362 patients with systemic JIA and MAS, 404 patients with active systemic JIA without MAS, and 345 patients with systemic infection. The best capacity to differentiate MAS from systemic JIA without MAS was found when the preliminary MAS guidelines were applied. The 3/5-adapted HLH-2004 guidelines performed better than the 4/5-adapted guidelines in distinguishing MAS from active systemic JIA without MAS. The 3/5-adapted HLH-2004 guidelines and the preliminary MAS guidelines with the addition of ferritin levels ≥500 ng/ml discriminated best between MAS and systemic infections.The preliminary MAS guidelines showed the strongest ability to identify MAS in systemic JIA. The addition of hyperferritinemia enhanced their capacity to differentiate MAS from systemic infections. The HLH-2004 guidelines are likely not appropriate for identification of MAS in children with systemic JIA.

Cerebral and meningeal involvement in patients with primary extracranial neuroblastoma (NB) is unusual although it is generally present in disseminated disease. The intensification of chemotherapy that has prolonged survival in these children has changed the pattern of relapse presentation, as occurs with isolated central nervous system (CNS) disease. We report 4 patients with secondary CNS metastases. Three infants of 16, 14, and 10 months of age, diagnosed with primary abdominal NB stage 4, presented neuromeningeal metastases during maintenance chemotherapy with seizures and cranial hypertension as the first manifestation. Another 8-year-old patient diagnosed with NB stage 3 presented local relapse with later neuromeningeal metastases. All died in the following 3 months. The possibility of CNS relapse in patients with NB should be considered when neurological symptoms and signs appear. These new relapse forms overshadow the prognosis of these children.

Introduction: Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia characterized by the accumulation of CD1a+ CD207+ histiocytes. Hemophagocytic lymphohistiocytosis (HLH), a non-malignant histiocytic disorder, is typified by the accumulation and activation of CD8+ T cells and macrophages, which secrete high levels of pro-inflammatory cytokines. The co-existence of LCH and HLH has been reported, albeit rarely, and is believed to be associated with a poorer outcome. To better understand the relationship between these two conditions, in this study we sought to describe the incidence, risk factors for development, and outcome of HLH when it develops in children and young adults with multisystem-LCH (MS-LCH). Methods: We conducted a retrospective study involving 14 centers and collected data on 384 MS-LCH patients aged less than 30 years and who were diagnosed between year 2000 and 2015. Data collected on the eligible patients included clinical information at the time of LCH diagnosis, clinical and laboratory parameters at HLH diagnosis (for those who developed HLH), treatment and disease outcome. Patients who developed HLH were classified as having "true-HLH", which was defined as disease fulfilling 5 of 8 HLH-2004 diagnostic criteria or as "HLH-like" disorder, which was defined as fulfilling Results: Of 384 MS-LCH patients, 44 (11%) were identified with HLH (29 with true HLH and 15 with an HLH-like disorder), ranging in age from 15 days to 20.6 years (median, 1.12 years). The majority of MS-LCH patients who also had HLH were females (n=27) and had accompanying risk organ (liver, spleen and/or hematopoietic system) involvement (RO+) (n=40), as opposed to non-HLH MS-LCH patients. Among nine HLH patients tested for BRAF V600E mutation status, eight were found to be positive. Twenty (45%) patients developed HLH (true or HLH-like) concurrent (±7 days) with LCH diagnosis, while 24 (55%) developed HLH >7 days before or after LCH diagnosis. The 3-year cumulative incidence of HLH (true or HLH-like) in MS-LCH was 16.8%. The 5-year overall survival of LCH patients without HLH was 98 ± 9%, while survival for those with an HLH-like disorder or true-HLH was 75 ± 12% and 70 ± 14%, respectively (P Conclusion: The development of HLH in patients with MS-LCH was not uncommon and associated with a poorer prognosis. Young females with RO+ MS-LCH who lack bone lesions at LCH diagnosis were at increased risk of developing HLH. Ferritin levels appear to be lower in comparison to patients who develop HLH in other contexts. There are overlapping features between MS-LCH and HLH that make the clinical distinction between these disorders difficult. Accordingly, improved biomarkers are needed to facilitate the identification of HLH in patients with MS-LCH. It is anticipated that early identification of HLH and prompt intervention may improve the outcome for affected individuals. Future prospective studies are needed to better understand the underlying mechanisms and identify more effective therapies. Disclosures No relevant conflicts of interest to declare.

These guidelines for the management of patients up to 18 years with Langerhans cell histiocytosis (LCH) have been set up by a group of experts involved in the Euro Histio Net project who participated in national or international studies and in peer reviewed publications. Existing guidelines were reviewed and changed where new evidence was available in the literature up to 2012. Data and publications have been ranked according to evidence based medicine and when there was a lack of published data, consensus between experts was sought. Guidelines for diagnosis, initial clinical work-up, and treatment and long-term follow-up of LCH patients are presented.

Cancer is the leading cause of death by disease among children and adolescents in many countries around the world. Most children with cancer live in countries with limited health care resources. As a result of the gradual decrease in child mortality from infections and malnutrition, the fight against cancer has become a worldwide public health priority. In the last decade numerous international initiatives have been developed to improve the care of children with cancer, research and professional training. Many countries have provided financial and political support for developing national strategies, establishing registers, authorising centres, defining care standards and formulating adapted protocols, as well as specific social and economic support programmes for families. Mexico is a good example of the benefits of national plans to combat acute lymphoblastic leukaemia (ALL) (since 2006) and other malignant neoplasms (2008), with a very positive impact in increasing survival rates and reducing treatment default. The distribution of types of tumours is very different in children and adults. Leukaemias (especially ALL) are the most common neoplasms in children, followed by brain tumours. Biological behaviour is also different in children and adults, even in tumours with similar histology or in children of different ages. Clinical research on these types of cancer, as in the articles by Estrada-Padilla et al. and by Pardal-Souto et al. in this journal, is very important for advancing our knowledge of childhood cancer.

Medulloblastoma is the more frequent malignant cerebral tumor in childhood.This is an observational study of a retrospective cohort in which there were included all the patients diagnosed of medulloblastoma in the last 19 years (1989-2007) in Hospital de Cruces of Baracaldo, Vizcaya, Spain.There were included 37 patients, 20 men and 17 women, with ages between 1 and 48 years (average age 13.7 years with standard deviation 11.4). Tumor site and mortality according to initial dissemination were variables of statistic significance. Metastases were detected at diagnosis in two patients. The surgical resection was total in 75% of the patients. A relapse was diagnosed in the follow-up in 59.5% of the patients, with a positive spinal fluid in 27%. Sequelae were detected in 100% of the survivors, mainly with cerebellar and ocular alterations. One patient developed a meningioma and a maxillary sarcoma at the long term follow-up. It is important to emphasize the aggressiveness of medulloblastoma in both children and adults, with a global mortality of 56.8% and 48,6% at 5 years.It is considered necessary a multidisciplinary treatment and a long term monitoring of the patients and the sequelae of the survivors, including the possibility of second tumours.

We describe a 3 year-old male who presented with fever and cerebellar dysfunction after varicella. He developed transient hepatosplenomegaly, cytopenias, and progressive central nervous system involvement (coma, status epilepticus, and hydrocephalus). Despite normal initial cranial computed tomographic scan, diffuse swelling of the cerebellum with downward tonsillar herniation ensued. Diagnosis of hemophagocytic lymphohistiocytosis was difficult and delayed because of the relapsing course, and complete diagnostic criteria were not fulfilled at initial presentation. Central nervous system disease preceded the typical clinical picture of this disease; it dominated the clinical course and caused life-threatening complications and sequelae. The patient improved after treatment, according to the hemophagocytic lymphohistiocytosis protocol (HLH-94) of the Histiocyte Society, with dexamethasone, etoposide, and cyclosporine and unrelated cord blood stem cell transplantation. A mutation in the perforin gene confirmed the diagnosis of familial hemophagocytic lymphohistiocytosis.

Interferon-alpha (IFN-alpha) is a biological response modifier with antiviral and tumoral effect that is used in the treatment of chronic myelogenous leukemias. Adverse effects are well documented and cardiovascular disturbances mostly include hypotension and tachycardia and rarely cardiomyopathy. We report on an infant with chronic myelomonocytic leukemia (CML) diagnosed at 3 months of age who was treated with increasing IFN-alpha dosage (2.5-5.5 million U/m2/day) given subcutaneously for 7.5 months. At that age, he presented anorexia, general malaise, and nocturnal sweating for about a week, followed by respiratory distress and tachycardia. Diagnosis of congestive heart failure was suspected and documented by cardiomegaly and echographic changes of left ventricular dilated cardiomyopathy, with a 40% left ventricular ejection fraction (EF) and 20% fractional shortening (FS). He was treated with digoxin, furosemide, and angiotensin converting inhibitors, and IFN-alpha was discontinued. Progressive improvement of cardiac function was observed within 7 months of the events with normalization of the echocardiographic findings (EF 60%, FS 31%). We should emphasize the possibility of severe and reversible cardiac toxicity of IFN-alpha in infancy.

Resumen: La trombocitopenia inmune primaria, anteriormente conocida como púrpura trombocitopénica inmune, es una enfermedad cuyo manejo diagnóstico y terapéutico ha sido siempre controvertido. La Sociedad Española de Hematología y Oncología Pediátricas, a través del grupo de trabajo de la PTI, ha actualizado el documento con las recomendaciones protocolizadas para el diagnóstico y tratamiento de esta enfermedad, basándose en las guías clínicas disponibles actualmente, revisiones bibliográficas, ensayos clínicos y el consenso de sus miembros. El objetivo principal es disminuir la variabilidad clínica en los procedimientos diagnósticos y terapéuticos con el fin de obtener los mejores resultados clínicos, con menor incidencia en la calidad de vida y los mínimos efectos adversos. Abstract: Primary immune thrombocytopenia (ITP), formerly known as immune thrombocytopenic purpura, is a disease in which clinical and therapeutic management has always been controversial. The ITP working group of the Spanish Society of Paediatric Haematology and Oncology has updated its guidelines for diagnosis and treatment of ITP in children based on current guidelines, literature review, clinical trials and member consensus. The primary objective was to lessen clinical variability in diagnostic and therapeutic procedures in order to obtain best clinical results with minimal adverse events and good quality of life.

Introduccion El NB (neuroblastoma) IV en ninos mayores de un ano sin factores biologicos desfavorables cursa con supervivencia No superiores al 30 %. Existe evidencia de prolongacion en la supervivencia en algunos casos con el uso de acido retinoico (AR), aunque a largo plazo se desconocen los efectos adversos. Este es el caso de un NB IV que lleva actualmente 7 anos de supervivencia con tratamiento prolongado de AR. Caso clinico Varon de 14 anos diagnosticado alos 7 de NB IV que consulto por dolores intermitentes de 1 ano de duracion, fiebre y anemia. Como datos positivos destacar al diagnostico: NSE (enolasa): 188, LDH 2.055, ferritina 496 y dopamina en orina 920. En la TC: tumoracion retroperitoneal de 3,7* 2,7 cm con metastasis ganglionares retroperitoneales, mesentericas y mediastinicas. Infiltracion masiva (92 %) en M.O. metastasis oseas multiples (MIBG). Inmunohistoquimica: 0-3 copias de amplificacion NMYC. Se inicio tratamiento con quimioterapia a altas dosis, exeresis parcial (10/99), TASP (11/99), RT abdominal (12/99) ante persistencia captacion por la masa, AR (6 + 6 tandas, hasta 1/01) y segunda cirugia por resto positivo en MIBG. En evalucion fin de tratamiento (3/00) se evidencia captacion pelvica, recibiendo por ello 131MIBG por 3 tandas de 100 mciI. En 1/2 se observa recaida en M.O. por lo que se administra quimioterapia (CFM y TPT), consiguiendo una respuesta parcial (MIBG + en huesos). En 10/02 se da TMZ (8 ciclos) y se consigue buena respuesta: MIBG negativa (2/03). Dado el alto riesgo se reinicia AR (12/03. 6 ciclos). Nuevamente en control de 5/04 se observa recaida en RM: metastasis oseas, por lo que recibe quimioterapia con CFM y TPT. Ya en el siguiente control del 5/05, la MIBG es –. Se reinicia AR y debe ser suspendido por hipertrigliceridemia (hasta 639). tres meses mas tarde es diagnosticado de hipotiroidismo, se inicia tratamiento sustitutivo y desde entonces lleva 7 meses con AR a dosis reducida al 75 % y sin problemas. En estudio de enfermedad minima residual (EMR) realizado en seguimiento presenta fluctuaciones de TH y anti-GD2 en MO y sangre periferica que se negativizan durante la administracion de AR y TPT. Conclusiones Observamos en este caso la supervivencia prolongada a costa de importantes efectos secundarios: hipotiroidismo (tratamiento con MIBG), hiperlipidemia mixta (AR e Hipotiroidismo), hemocromatosis con ferritina de 1942 y ecografia hepatica compatible, repetidas hospitalizaciones, hasta 20. La adaptacion y percepcion de la familia ha sido un factor muy importante. Actualmente cursa 3.° de E.S.O. y esta socialmente muy bien adaptado. Desconocemos cual habria sido la evolucion sin tratamiento modulador.

From experimental results obtained in a wide range of operating conditions (temperature and contact time) in an isothermal fixed bed integral reactor, the validity both of the kinetic models proposed in the literature as well as their modifications, for the methanol-to-gasoline (MTG) process at zero time on-stream, has been studied. The kinetic parameters for the various models have been calculated by solving the equation of mass conservation in the reactor for the lumps of the kinetic models. The usefulness of the model of Schipper and Krambeck for simulating the operation in the isothermal fixed bed integral reactor has been proven in the 573–648 K range.