The paediatric cancer clinical research landscape in Spain: a 13-year multicentre experience of the new agents group of the Spanish Society of Paediatric Haematology and Oncology (SEHOP).

PURPOSE: Early phase trials are crucial in developing innovative effective agents for childhood malignancies. We report the activity in early phase paediatric oncology trials in Spain from its beginning to the present time and incorporate longitudinal data to evaluate the trends in trial characteristics and recruitment rates. METHODS: Members of SEHOP were contacted to obtain information about the open trials at their institutions. The study period was split into two equal periods for analysis: 2007-2013 and 2014-2020. RESULTS: Eighty-one trials and two molecular platforms have been initiated. The number of trials has increased over the time of the study for all tumour types, with a predominance of trials available for solid tumours (66%). The number of trials addressed to tumours harbouring specific molecular alterations has doubled during the second period. The proportion of industry-sponsored compared to academic trials has increased over the same years. A total of 565 children and adolescents were included, with an increasing trend over the study period. For international trials, the median time between the first country study approval and the Spanish competent authority approval was 2 months (IQR 0-6.5). Fourteen out of 81 trials were sponsored by Spanish academic institutions. CONCLUSIONS: The number of available trials, and the number of participating patients, has increased in Spain from 2007. Studies focused on molecular-specific targets are now being implemented. Barriers to accessing new drugs for all ranges of age and cancer diseases remain. Additionally, opportunities to improve academic research are still required in Spain.

Randomized clinical trial comparing endoscopic treatment with dextranomer hyaluronic acid copolymer and Cohen's ureteral reimplantation for vesicoureteral reflux: long-term results.

PURPOSE: To compare efficacy of Cohen's ureteral reimplantation and endoscopic treatment with Dx/HA in patients with primary VUR grades II, III and IV. METHODS: From April 2002 to June 2004, patients over 1 year old with VUR grade I, II, III or IV were included. Patients were randomized into two groups: endoscopic treatment (ET) or ureteral reimplantation (UR). In the ET group, an ultrasonography study was performed 24 h and 1 month after surgery, and two voiding cystourethrographies at 3 and 6 months post treatment. In the UR group, an ultrasonography study was done 7 days and 1 month after surgery and a micturial cystography 6 months post surgery. A postoperative nuclear direct cystogram was performed 5 years later in both groups. RESULTS: A total of 41 patients were included in this study: in ET 22 patients with 35 refluxing ureters and in UR 19 patients with 32 refluxing ureters. The VUR grades in ET were: 16 grade II, 16 grade III and 3 grade IV; and in UR: 15 grade II, 12 grade III and 5 grade IV. VUR was resolved in 91% (32/35) of ET (28% of ureters needed a second injection), and in 100% of UR group. Five years after the procedure, VUR was still resolved in 30/32 of ET and 32/32 of UR. CONCLUSION: Short- and long-term follow up shows that multiple endoscopic treatment of VUR grades II, III and IV with Dx/HA is as effective as ureteral reimplantation.

[Results of hematopoietic stem cell transplantation in hemoglobinopathies: thalassemia major and sickle cell disease]. / Resultados del trasplante de progenitores hematopoyéticos en hemoglobinopatías: talasemia maior y enfermedad drepanocítica.

BACKGROUND: The prevalence of hemoglobinopathies in Spain is increasing as a result of immigration. Thalassemia major presents with chronic hemolytic anemia that requires regular red blood cell transfusions within the first year of life. Patients with sickle cell disease suffer from chronic anemia, vasculopathy and progressive damage in almost any organ. There is decreased life expectancy in both conditions. Allogeneic hematopoietic stem cell transplantation represents the only potentially curative option. PATIENTS: Seventeen patients (fourteen thalassemia major, and three sickle cell disease) underwent allogeneic hematopoietic stem cell transplantations. RESULTS: In the thalassemia group, nine donors were HLA-geno-identical siblings, two were partially matched related donors (one HLA allele mismatch), and three unrelated donors. All three patients with sickle cell disease were transplanted from HLA-geno-identical siblings. The source of stem cells was bone marrow in sixteen cases. Median patient age at transplant was six years (range: 1-16) in the thalassemia group, and twelve years (range: 8-15) in the sickle cell disease group. The graft was successful in all patients. Secondary graft rejection was observed in two thalassemia patients rendering them dependent on blood transfusions. Complete chimerism was observed in thirteen patients and, although mixed chimerism occurred in two, with all of them showing normal hemoglobin levels after transplantation and not requiring further transfusion support. Patients affected by sickle cell disease did not present with new vaso-occlusive crises, and stabilization of pulmonary and neurological function was observed. Chronic graft-versus-host disease was detected in three patients affected by thalassemia, and hypogonadotrophic hypogonadism in five patients. CONCLUSIONS: We conclude that for thalassemia major and sickle cell disease, allogenic hematopoietic stem cell transplantation from HLA-geno-identical siblings offers a high probability of complication-free survival. Despite good results, morbidity and mortality associated with transplantation from unrelated donors is a risk that might be considered, in contrast to a non-curative medical treatment that offers a long term survival. For thalassemia major groups it could be an option, but not for sickle cell disease, which is still in the investigational phase.

[Severe congenital neutropenia: analysis of clinical features, diagnostic methods, treatment and long-term outcome]. / Neutropenia congénita grave: análisis de las características clínicas, estudios diagnósticos, tratamiento y seguimiento a largo plazo.

INTRODUCTION: Severe congenital neutropenia (SCN), a heterogeneous condition with onset at early ages, is characterised by primary myelopoiesis failure with an absolute neutrophil count (ANC) < 0.5 x10(9)/L, severe infections and risk of leukaemic transformation. OBJECTIVE: The aim of the study was to ascertain the long term outcome of patients with SCN. MATERIAL AND METHODS: The clinical features, diagnostic methods, treatment and outcome of 11 patients with SCN were analysed. RESULTS: The median age at diagnosis was 4 months (range: 3 days-12 years). The primary clinical manifestation was severe infection. Median ANC at diagnosis: 0.2 x 10(9)/L (range: 0-0.37). Bone marrow aspirate showed maturation arrest at promyelocyte stage in all cases. Genetic studies revealed 3 mutations, two in ELA-2 gene and 1 in G6PC3 gene, showing a correlation between genotype and phenotype. Granulocyte Colony Stimulating Factor (G-CSF) was the first-line treatment in 9 patients; six of whom showed a good response at doses between 5 and 15 µg/kg/day for 3-7 days/week. The remaining 3 patients failed to respond to G-CSF and allogeneic stem cell transplantation (SCT) was indicated. Furthermore, SCT was the treatment of choice in two cases. Median follow-up of the cohort was 5 years (range: 1-10 years) with 100% survival and no cases of leukaemic transformation. CONCLUSIONS: We conclude that genetic study is useful for establishing a correlation between genotype and phenotype. The treatment of choice for SCN is G-CSF to which 2/3 of patients should respond; while SCT is reserved for cases of poor response or those evolving to myelodysplastic syndrome (MDS) or leukaemia; thus close follow-up of this condition is essential.

[Protocol for the study and treatment of immune thrombocytopenic purpura (ITP). ITP-2010]. / Protocolo de estudio y tratamiento de la trombocitopenia inmune primaria (PTI-2010).

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.

[Pneumonia associated acute glomerulonephritis: a review of 6 cases]. / Glomerulonefritis aguda asociada a neumonía: revisión de 6 casos.

INTRODUCTION: There is an association between pneumonia and acute glomerulonephritis. Both processes start simultaneously. PATIENTS AND METHODS: A retrospective study of 6 patients admitted to our centre between 2001 and 2010 with acute glomeruolonephritis associated with pneumonia. The result of the smear and tonsil culture was negative and there was an absence of cutaneous infection. RESULTS: The average age of the patients on admission was 5.9 years with no differences in sex. The diagnosis for pneumonia was made at the time of admission, coinciding with the glomerular symptoms. The most frequent symptoms were fever and macrohaematuria. All had low levels of C3. A significant increase in ASLO was found in 5 cases. The majority of the cases had mild symptoms with the exception of one case of acute renal failure with an initial creatinine of 2.77mg/dL and glomerular filtration rate of 27ml/min/1.73m(2), and two cases with proteinuria in the nephrotic range. All of them progressed satisfactorily without treatment or with minimum diuretic or hypotensive treatment in addition to the appropriate antibiotic treatment with clinical resolution in 7 to 10 days, and C3 returning to normal within a period of less than 4 months. CONCLUSIONS: There is an association between acute glomerulonephritis and pneumonia, although it is very uncommon. The ASLOs in our series are not specific for Streptoccocus. pyogenes infection. The respiratory and renal prognosis was favourable in all cases.

Post-transplant lymphoproliferative disorders in children: the role of chemotherapy in the era of rituximab.

PTLD are the most frequent neoplasms in children postorgan transplantation. We describe our experience in the treatment of 14 children (three with early and 11 with late-onset disease) treated with a step-wise protocol developed at our institution. Treatment consisted of reducing immunosuppressants, followed by rituximab and chemotherapy if required. Rituximab, incorporated into the protocol in 2001, has been determinant for the total chemotherapy burden patients need to achieve remission. In seven patients who did not receive rituximab, anthracycline total dose ranged from 160 to 240 mg/m(2), while only one of the patients receiving rituximab required DOXO (range: 0-120 mg/m(2)) (p = 0.003). The use of alkylating agents was also notably lower in patients receiving rituximab (median dose = 1200 mg/m(2)) compared with those who did not receive rituximab (median dose = 5800 mg/m(2)) (p = 0.006). Twelve patients are in remission and two died, one from refractory disease and the other from septic shock. Two-year OS and EFS were 85.7% and 57%, respectively. In conclusion, our experience with the use of rituximab in children with PTLD after solid organ transplantation appeared to be associated with a lesser requirement for alkylating agents and anthracyclines compared with historical subjects, suggesting a reduction in the side effects of these agents.

[Hemolytic-uraemic syndrome. A review of 58 cases]. / Síndrome hemolítico-urémico. Revisión de 58 casos.

OBJECTIVES: Our objectives were to determine epidemiology, clinical and laboratory characteristics of patients with haemolytic-uraemic syndrome (HUS) treated in our centre, to describe renal and extra-renal complications and the treatment required and to relate our findings with the existing bibliography. METHODS: We performed a 33-year retrospective review. We included all patients diagnosed with HUS and monitored in our hospital from January 1974 to August 2007. Clinical histories and imaging studies were reviewed. RESULTS: A total of 58 patients were included in our study, with a mean age of 2 years 11 months and most of them were admitted to hospital in summer. Familial hypocomplementaemia was present in one case. A total of 48 patients presented with typical HUS (with diarrhoea D+ HUS). Salmonella enteritidis and Escherichia coli O157:H7 were isolated from those patients. While 7 cases presented with atypical HUS (without diarrhoea, D- HUS), most of them associated with a respiratory tract infection due to Streptococcus. In one case platelet count was normal. Kidney biopsy was performed in 18 patients and 25 cases underwent peritoneal dialysis. As regards complications, one child with D+ HUS experienced renal cortical necrosis and required kidney transplant, while in the D-HUS group, the patient with familial hypocomplementaemia had severe hypertension. CONCLUSIONS: a) Incidence of HUS in our environment is low. b) HUS can be present even with a normal platelet count. c) We had one case of HUS in a patient with familial hypocomplementaemia who experienced severe hypertension. d) In our group of patients, the course of the disease was not influenced by the white blood cell counts, decreased diuresis or hypocomplementaemia.

[Neurologic presentation in haemolytic-uraemic syndrome]. / Manifestaciones neurológicas en el síndrome hemolítico urémico.

INTRODUCTION: Haemolytic-uraemic syndrome (HUS) is characterized by microangiopathic hemolytic anaemia, thrombopenia and multiorganic aggression, specially renal, gastrointestinal and central nervous system disturbances. Sporadic in Spain (2/1,500,000 inhabitants), its clinical onset includes acute renal failure, hypertension and central nervous system symptoms (irritability, drowsiness, convulsions, cortical blindness, hemiparesia or coma), due to metabolic distress, hypertension or central nervous system microangiopathy. Few long-term outcome studies have been published. PATIENTS AND METHODS: A retrospective analysis of a series of 58 patients with HUS between 1981 and 2006, is reported. Clinical onset, laboratory, electrophysiology, neuroimaging tests, and prognosis factors are reviewed, together with long-term clinical outcome. RESULTS: 22 children presented neurologic symptoms, seven had some neurological test; one patient died; in five some neurological sequelae persisted (hemiparesia, cognitive deficit, visual-perception deficit), the other 16 remaining asymptomatic. CONCLUSIONS: Neurological morbility is high in HUS (27% of the children with neurological symptoms), with a 1.7% mortality. Seizure at onset was not a poor prognosis factor in our group. No positive correlation can be established between neuroimaging and long-term outcome.

[Nephropathy in Schönlein-Henoch purpura: a retrospective study of the last 25 years]. / Nefropatía en la púrpura de Schönlein-Henoch: estudio retrospectivo de los últimos 25 años.

Schönlein-Henoch purpura is a systemic vasculitis due to IgA-mediated hypersensitivity, almost exclusively affecting the pediatric age group. Long-term prognosis is mainly conditioned by renal involvement, which can appear at onset or during the course of the disease. To evaluate renal involvement, 764 patients with Schönlein-Henoch purpura were retrospectively reviewed. Of these, 153 (20 %) had renal involvement, the most frequent form of presentation being non-nephrotic hematuria/proteinuria (67 patients) followed by isolated hematuria (41 patients). Renal biopsy was performed in 39 patients, and the most frequent pathological findings were diffuse mesangial proliferation with IgA deposits and less than 50 % of crescentic glomeruli. Treatment was not curative. Three patients (2 %) progressed to end-stage renal failure and required renal transplantation. One patient died. Notably, two of the patients who underwent renal transplantation had disease recurrence. We stress that nephropathy is usually benign and that it requires long-term follow-up.

Secondary malignancies and quality of life after stem cell transplantation.

Malignant diseases (MD) occurring after stem cell transplantation (SCT) are of particular concern as increasing number of patients survive and remain free of their original disease. The cumulative incidence at 15 years is 10-12%. The B-cell proliferative disorders (BCLP) are the most common MD in the first year after SCT; the incidence probability is 1% in allogeneic transplants but is much higher (until 14%) after HLA-identical, T-cell-depleted SCT in which Campath 1G or ATG are given. BCLP develop because of reactivation of the EBV and a depressed cellular immunity. Prediction of risk of BCLP can be made by frequent monitoring of EBV load in patients with risk factors. The most effective therapies are the early administration of anti-CD20 monoclonal antibody and adoptive immunotherapy with in vitro generated EBV-specific cytotoxic T cells. Myelodysplasia and acute myeloid leukemia with very poor prognosis have been described in 4-18% of patients with non-Hodgkin lymphoma and Hodgkin disease, 12-24 months after autologous SCT. The risk of development of solid tumors increases over time and the cumulative incidence among children who underwent an SCT at less than 10 years of age is 6-11% at 15 years. There are few studies evaluating quality of life (QOL) in children and adolescents who had received an SCT. The findings of these studies can be summarized as follows: (a) The majority of long survivors enjoy good QOL and return successfully to school or work. (b) A minority (10-15%) complain of physical problems or present moderate cognitive or psychological dysfunctions. (c) The importance of family, other social support and psychological adjustments is generally recognized. More extensive, longitudinal and comparative studies with other alternative therapies are required.

[Long-term effect of angiotensin-converting inhibitors in children with proteinuria]. / Efecto a largo plazo de los inhibidores de la enzima conversora de la angiotensina en niños con proteinuria.

BACKGROUND: Prolonged proteinuria is a risk factor for renal damage. Angiotensin-converting enzyme (ACE) inhibitors can reduce proteinuria in adults with different types of nephropathy. PATIENTS AND METHODS: We evaluated treatment with low doses of ACE inhibitors (captopril and enalapril) in nine children with proteinuria due to chronic glomerular nephropathy. The patients' diagnoses were Henoch-Schönlein nephropathy, Berger's disease, Alport's disease, and chronic glomerulonephritis (GN) (membranous GN, focal and segmental GN, and membranoproliferative GN). None of the patients were receiving concomitant treatment. Those who had received corticoids, immunosuppressive or hypotensive drugs during the previous 3 months were excluded. The medication was administered over a prolonged period (mean 26.6 6.36 months). RESULTS: Proteinuria was initially in the nephrotic range (M = 55.34 10.44 mg/m2/h). In all patients concentrations fell significantly after 6 months and at the end of the treatment(p = 0.01 and p = 0.05). No adverse reactions to the medication were observed. The decrease in glomerular filtration rate was not significant. No significant changes in arterial pressure were found during treatment. CONCLUSIONS: ACE inhibitors could be an effective alternative for reducing proteinuria in children with prolonged nephropathy. These inhibitors do not produce the adverse effects associated with other drugs and can therefore be used for long periods.

[Acute interstitial nephritis of probable pharmacological origin]. / Nefritis intersticial aguda de probable etiología medicamentosa.

Acute interstitial nephritis in children is rare. We present a case of acute interstitial nephritis in a 10-year-old boy, which was probably drug-induced. Initial symptoms included fever, loss of appetite, weight loss, alterations in urine analysis and mild renal failure. Treatment with steroids produced a good clinical response and renal function returned to normal within a few months.

[Nephrolithiasis in children]. / Litiasis renal en el niño.

We reevaluated the medical records of 112 children with urolithiasis. The prevalence of this condition was 1/4.500 children admitted to our hospital. The mean age was 8.2 years and 54.4% of the afflicted patients were males. Fifty percent of the patients studied had a family history of urolithiasis. The two most frequent etiologies were urinary tract infections and metabolic disorders (hypercalciuria states, distal renal tubular acidosis and cystinuria). The etiology of the urolithiasis was unknown in 15% of our patients. The levels of magnesium and citrate, inhibitors of crystallization, were moderately low in some of the cases in which it was determined. Fifty percent of the children with urolithiasis showed urinary or renal complications. The extracorporeal lithotripsy was an effective treatment of urolithiasis in the patients in which it was performed. The recurrence rate was 8%. In one third of the urolithiasis associated with urinary infections and/or urinary tract malformations we found chronic pyelonephritis.

[Syphilitic nephropathy. Apropos of 3 cases]. / Nefropatía luética. A propósito de tres casos.

Three cases of luetic nephropathy are presented. The authors review the literature on the subject stressing the current clinical and etiopathogenic concepts. They also emphasize, as a conclusion, the need for an early diagnosis and treatment and the consideration of this entity in the differential diagnosis of the nephrotic syndrome of the infant.