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To assess the natural history of retinal manifestations in von Hippel-Lindau (VHL) disease and to study the genotype-phenotype correlation.Data concerning 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations were extracted from the French VHL database. A retrospective study was performed by questionnaire. Patients were classified into three visual morbidity groups. Molecular analysis of the VHL gene was performed in 196 patients.The mean age of ocular manifestations detection was 24.8 years. In half of the cases, the ocular manifestations revealed the disease. Half of the cases had bilateral involvement. Visual morbidity was significantly associated with the retinal hemangioblastoma count but not with other ocular or general characteristics. One third of the patients were classified in the worst visual morbidity group at the end of follow-up. Mutations were detected in 81% of patients with retinal hemangioblastomas and in 71% of patients without retinal involvement. Using a Poisson model and a marginal approach, the number of hemangioblastomas, age-adjusted, was 2.1 times higher in patients who had a substitution than in patients with a truncation (95% CI, 1.05-4.44; P0.05).Visual loss remains one of the major complications of VHL disease, confirming the importance of early ophthalmologic screening. Visual morbidity was not related to the type of extraocular manifestation but appeared to be related to the type of germline mutation. However, only further genetic and clinical studies in a larger series of patients will clearly determine the genotype-phenotype relationship.

In France, the prevalence of End-Stage Renal Disease (ESRD) is not precisely known. The sources of information are scattered and not coordinated. Consequently, care is ill adapted to meet the demand. The Multi-Source Information System is the basis of the Renal Epidemiology and Information Network (REIN). It is dedicated to improve and organise our medical and epidemiological knowledge of ESRD and to aid public health decision-making in this area. The proposed approach is based on the datawarehouses. This model allows a unified vision of scattered data into distinct databases, for a better management, be it particular (patient follow-up) or global (regional follow-up), with a finality of aid in decision-making. Several categories of problems were considered: the global conception of the information system, the organisation of the datawarehouse, which offers different viewpoints of the data, the integration of heterogeneous data coming from different sources, data exchange and definition of a specific ontology.

BACKGROUND The growing use of abdominal ultrasonography during pregnancy and in the postnatal period is leading to the discovery of an increasing number of suprarenal masses. The optimal diagnosis and treatment of these masses has not yet been determined. METHODS The authors reviewed the files of patients with suprarenal masses detected prenatally or during the first 3 months of life, between 1986 and 1999, in the pediatric surgery and oncology departments of Paris hospitals. RESULTS Thirty masses were detected prenatally and 23 postnatally. In the latter group of patients, the diagnosis was based on ultrasound in 8 cases and on the palpation of a mass in 15 cases, 13 of which were neuroblastoma. At birth, the masses were cystic in 19 cases, solid in 17, and mixed in 13. Sensitivities of methyliodobenzylguanidine and urinary catecholamine assay were 70% and 52% respectively. Surgery was performed in 38 cases with a median age of 42 days. Histologic analysis showed 31 neuroblastomas, 1 adrenal hemorrhage, 2 necrotic masses, 1 bronchogenic cyst, and 3 sequestrations. All the patients were alive and disease free, at a follow-up ranging from 3 months to 13 years. CONCLUSIONS In this series, 58% of the suprarenal masses diagnosed perinatally were localized neuroblastoma with a favorable outcome. All other cases either regressed spontaneously or turned out to be benign lesion. Thus, the management of these masses must strike a compromise between aggressive treatment and a wait-and-see attitude. This requires appropriate initial assessment and a close follow-up in a specialized center. Cancer 2002;94:2474–80. © 2002 American Cancer Society. DOI 10.1002/cncr.10502

Study objectives: The association between genotype and phenotype in cystic fibrosis (CF) has been clearly established for pancreatic status, but not for lung disease. Design: Retrospective study. Setting: A respiratory unit of a teaching hospital. Patients: We studied 51 adult CF patients for whom current data and genotype were available. Thirty-seven patients carried two severe mutations associated with pancreatic insufficiency phenotype (group S). Fourteen patients carried at least one mild (and dominant) mutation associated with pancreatic sufficiency phenotype (group M). Measurements: We compared the course of the disease between the two groups, looking for a genotype/phenotype association for lung disease. Results: The mean age of the population was 30 years. Patients with two severe mutations presented more severe disease with earlier onset (1.7 years vs 7.9 years, p 0.0001). They presented with a more severe respiratory impairment, with a lower mean FEV1 (29% of predictive value vs 58% of predictive value, p < 0.001); a higher Pseudomonas colonization rate (97% vs 57%, p < 0.01); a more frequent end-stage respiratory insufficiency, defined by a FEV1 < 30% (73% vs 29%, p < 0.05); and a more marked yearly decline of FEV1 (3% vs 1.4%, p < 0.001). By multivariate logistic regression analysis, carrying two severe mutations was the only independent predictor of a terminal respiratory insufficiency (relative risk, 6.75; 95% confidence interval, 1.79 to 26.50; p 0.003). Conclusion: This study suggests that pulmonary disease appears to be associated with the severity of CF transmembrane regulator mutations. (CHEST 2002; 121:73– 80)

The first national plan for rare diseases (2005-2008) set the network for care and research in the rare diseases (RD) field across all French hospitals. The 131 RD centers of expertise (CE) initiated then various IT projects to register electronically their RD patients. The CEMARA project [1] up to now registered 235,000 RD patients, from 62 RDCE (out of 131), 383 units of care and described over 4000 rare diseases. The identified limits of the CEMARA model were: i) data collection was not incorporated in the care setting, ii) exposed to data re-entry, iii) coping with data privacy new regulations and iv) gaining a wide national consensus on the data to collect for all RDs and from all CEs. To overcome these limits, the 2nd national plan for rare diseases (2010-2014) promoted the creation of a national data repository for all rare diseases (BNDMR) based on the CEMARA model with the following objectives: i) identifying RD patients within the health information systems in care setting, ii) describing the RD demand of care, and the adequacy of the supply and iii) identifying patients eligible for clinical trials or cohorts. The proposed national architecture incorporates a national minimum data set for all rare diseases (F-MDS-RD) into hospital information care systems to enable electronic patient files re-use for epidemiological studies or research [2]. To ensure a full interoperability between local hospital information systems and the BNDMR, a national interoperability framework is defined. It is set on 3 pillars: i) defining a national patient ID for rare diseases that will help to identify patients across different health IS, ii) defining a common data format for all rare diseases, compatible with EHR standards such as HL7, and iii) setting the necessary technical data flows complying with strict security rules for data privacy [3] and security. The minimum data set for rare diseases is now being implemented in several local systems, and connectors are being rolled out with several database suppliers. Data re-entry is nowadays a major concern for clinicians. Enabling data re-use is not only an interoperability problem; data must be structured, qualified, standardized [4] and suitable for research [5]. The structuration of the data collected is set on a variety of standard terminologies such as Orphanet or the Human Phenotype Ontology which requires to be accompanied with the necessary IT tools to help clinicians coding the data [6].

Background Many randomized clinical trials in trauma have failed to demonstrate a significant improvement in survival rate. Using a trauma patient database, we simulated what could happen in a trial designed to improve survival rate in this setting. Methods The predicted probability of survival was assessed using the TRISS methodology in 350 severely injured trauma patients. Using this probability of survival, the authors simulated the effects of a drug that may increase the probability of survival by 10-50% and calculated the number of patients to be included in a triad, assuming alpha = 0.05 and beta = 0.10 by using the percentage of survivors or the individual probability of survival. Other distributions (Gaussian, J shape, uniform) of the probability of survival were also simulated and tested. Results The distribution of the probability of survival was bimodal with two peaks (< 0.10 and > 0.90). There were major discrepancies between the number of patients to be included when considering the percentage of survivors or the individual value of the probability of survival: 63,202 versus 2,848 if the drug increases the probability of survival by 20%. This discrepancy also occurred in other types of distribution (uniform, J shape) but to a lesser degree, whereas it was very limited in a Gaussian distribution. Conclusions The bimodal distribution of the probability of survival in trauma patients has major consequences on hypothesis testing, leading to overestimation of the power. This statistical pitfall may also occur in other critically ill patients.

The objective of this study was to determine the incidence and prevalence of end-stage renal disease (ESRD) requiring maintenance dialysis in the Ile-de-France district (Paris area), and the characteristics of patients at start of dialysis.This is a prospective epidemiological study with the cooperation of all dialysis facilities of the Ile-de-France district (population 10.7 million inhabitants as of March 1999). All consecutive ESRD patients who started dialysis from January 1 to December 31 1998, with demographic and clinical characteristics, and of the total number of patients on dialysis with their distribution according to dialysis modality were recorded.The total number of ESRD patients in 1998 was 1155, including 29 (2.5%) children agedor =17 years and 86 (7.4%) returns to dialysis following kidney graft failure. Incidence of first-dialysed patients was 100 per million population (p.m.p.) and overall incidence, including returns from transplantation, was 108 p.m.p. The mean age of first-dialysed adult patients was 59.8+/-16.8 years, with 21.6% agedor =75 years. Patients with vascular renal disease were 22.5% and those with diabetic nephropathy 20.6%. As a whole, 36.5% of patients were referred to the nephrologistor =6 months before start of dialysis, including 32.2% referredor =1 month before starting. Prevalence of cardiovascular disease was nearly twice as high in patients referred6 months of starting dialysis than in those who benefited from effective nephrological care for3 years in the predialysis period. By multivariate analysis, this difference persisted after adjustment for age and other confounding covariates. The total number of patients on maintenance dialysis increased from 417 to 433 p.m.p. (a yearly 3.8% increase) from the beginning to the end of 1998.This recent epidemiological study in a large French urban area indicates an annual incidence of 100 new ESRD patients p. m.p., with a high proportion of older, vascular and diabetic patients. Overall incidence, including returns from transplantation, reached 108 p.m.p. Cardiovascular disease was significantly less frequent in patients who received nephrological care foror =3 years prior to start of dialysis than in late referred patients, underlining the benefits of early nephrological management of renal patients.

Clinical trials provide a framework to search for more effective and less toxic immunosuppressive agents to control renal transplant rejection. Some methodological aspects are presented. Patient selection and the choice of study endpoints are discussed with emphasis on standardized definitions and classification of histopathology, and on qualification and quantification of chronic rejection. Choosing a Bayesian or a frequentist approach and the afferent hypotheses is discussed together with the interpretation of a P-value and a confidence interval. Strategies for limiting the number of patients, increasing power and feasibility are reviewed, including discussion of surrogate endpoints. New approaches to statistical analysis are then presented, including intention-to-treat versus per-protocol analysis, analysis of correlated data, dependent censoring, and meta-analysis applied to renal transplantation. Pharmacoeconomics are finally introduced as necessary for implementation of decision making regarding therapeutic strategies. Reporting research increases its standards, and the CONSORT (Consolidated Standards of Reporting Trials) and QOROM (Quality of Reporting of Meta-analyses) criteria are to be integrated in the process of clinical trial procedures. In conclusion, observational studies are presented as part of an evidence-based approach in the hierarchy of evidence, keeping in mind that high quality, randomized, controlled trials are still necessary to decrease uncertainty in the field of renal transplantation.

Nearly 200 000 new patients started renal replacement therapy (RRT) throughout the world in 1996, while 1 million patients were prevalent [1]. Most developed countries have registries for characterizing end-stage renal disease (ESRD) populations: patient demographics and treatment modalities are useful for helping professionals, health care providers and health authorities to improve their decisions, appraise future trends, prevent the occurrence of renal diseases, slow the development of chronic renal failure, optimize the starting point of RRT, and anticipate future needs. Aspects of the epidemiology of RRT will be considered in four parts: what do we measure and how; the main trends in incidence and prevalence of RRT; patients’ characteristics at institution of RRT and their evolution over the last decade; and survival trends according to treatment modalities.

We analyzed the outcomes of 214 HLA non-identical T-cell-depleted bone marrow transplantations (BMTs), performed in 178 consecutive patients for treatment of severe combined immunodeficiencies (SCID). Patients were treated in 18 European centers between 1981 and March 1995. SCID variants, that is, absence of T and B lymphocytes (B-) or absence of T cells with presence of B lymphocytes (B+) were found to have a major influence on outcome. The disease-free survival was significantly better for patients with B+ SCID (60%) as compared with patients with B- SCID (35%) (P =.002), with a median follow-up of 57 months and 52 months, respectively. Other factors associated with a poor prognosis were the presence of a lung infection before BMT (odds ratio = 2.47 [1.99-2.94]) and the use of monoclonal antibodies for T-cell depletion of the graft (odds ratio = 1.67 [1. 18-2.15]). Additional factors influencing outcome were age at BMT (

Background. The long-term impact of hepatitis C virus (HCV) infection in renal transplant recipients remains controversial. We report here our experience, in a homogeneous single center, of 499 patients with a fairly long follow-up. Methods. We retrospectively studied 499 hepatitis B virus-negative patients who received an initial cadaver donor kidney transplantation at Necker Hospital between January 1, 1979 and December 31, 1994, with a graft or patient survival of at least 6 months. Anti-HCV antibodies were detected at time of transplantation in 112 patients (22%). Patient survival and causes of death were compared among anti-HCV-positive and -negative patients. Results. Our results clearly indicate that first cadaver kidney transplant recipients with anti-HCV antibodies had a significantly shorter patient and graft long-term survival than recipients without anti-HCV antibodies (P

Background JIA is a chronic disease. Transition from childhood to adulthood and socio-professional impact of the disease at adulthood deserve particular attention. Objectives To describe JIA patients assessment of the transition period and their social and professional status in adulthood. Methods Data were collected using an auto-questionnaire completed by JIA patients followed in 3 French paediatric rheumatology reference centres and having reached adulthood. Results 353 patients were included. In 124 patients, the transfer to adult specialist occurred within one year after a pediatric preparation. Satisfaction was recorded in 43%. In 74 patients where the transfer occurred two years or more after the paediatric follow-up, only 20% were satisfied (p=0.002) Risk factors significantly linked to this issue were: discontinuity feeling (p The patients had a higher academic level than the general French population: 44.3% of them had a diploma above bachelor, which is twice as much as in the general population (21.4%). The percentage of patients working as executive managers in our cohort was significantly higher (31.8%) than expected (10.4%), both for men (46.6% vs 13.1%) or women (24.4% vs 8.2%). Conversely, unemployment was lower in our cohort (7.2%) than in the general population (18.3%). However, 33.8% of the patients had already known at least a six-month unemployment period, which was not different from the national rates, adjusted for age and gender. More than a third of the patients (33.5%) had suffered reject or discrimination because of their disease, which was significantly greater than the expected rate in general population: 6.2% (p -3 ). Factors associated to a poor quality of life (QOL) were height Conclusions A better transitional care program appears important to ensure patients confidence in the continuity of care from paediatrics to adulthood. Among important factors, the recommendation of a first adult rheumatologist by the paediatric team and the choice of the right time for transition were highlighted. JIA patients seem to have higher educational achievements and a professional integration above average. QOL at least partly depends on the quality of disease care: it is important to better control disease activity (active disease seems to be related to a poorer QOL, as assessed by patients who require to be followed in rheumatology or treated with steroids) and prevent sequelae (growth retardation, uveitis). Other factors deserve further analyses such as the high percentage of feeling of discrimination and the negative impact of being a woman regarding QOL. Acknowledgements Work supported by the Foundation Wyeth-Pfizer pour l’enfant et l’adolescent Disclosure of Interest None Declared

Background Studies about JIA outcome in adulthood are still limited. Objectives To describe medical outcome in adulthood of a cohort of JIA patients followed in 3 French paediatric rheumatology centers since the disease onset. Methods Data were collected through an auto-questionnaire completed by JIA patients. Results Three hundred fifty three patients were included. Median age at the time of evaluation was 26 years [range 20 50]. Fifty-six patients out of 353 had no more medical follow-up. The other patients were followed either by a general practitioner (79.4%), and or a rheumatologist (64.5%) and/or an ophtalmologist (47,6%). Twenty-eight percent patients had never seen a rheumatologist after the end of the paediatric care. At the time of the study, JIA activity was still present as follows: 1) 240 patients were complaining of joint pain during the last weeks, and 228 had at least one arthritis 2) Sixty three patients were affected by uveitis, which was still active in 26. Disease sequelae were 1) Growth retardation with height Auto-immune diseases in adulthood were reported in 20 patients out of 353: Crohn’s disease (n=5), ulcerative colitis (n=3), celiac disease (n=1), pulmonary interstitial syndrome (n=2), multiple sclerosis (n=1), myasthenia (n=1), diabetes (n=1), hypo- and hyper- thyroidism (n=5) and vitiligo (n=1). One hundred ninety six patients out of 348 still received medical treatment for their disease: 47% non-steroid anti-inflammatory drugs (NSAIDs), 31% steroids, 37.2% DMARDs, and 39% biologics. Conclusions In this series, disease’s activity and/or damage including eye involvement and growth retardation were observed in a large number of patients, reflecting probably in part the difficulty of JIA management before the era of “modern” therapies. Surprisingly, the high rate (6%) of auto-immune diseases in these patients, never been reported previously, deserves further investigations. Acknowledgements Work supported by the Foundation Wyeth-Pfizer pour l’enfant et l’adolescent. Disclosure of Interest None Declared

Objective The aim of this study was to describe the management of anaemia with a continuous erythropoietin receptor activator (C.E.R.A., methoxy polyethylene glycol epoetin-β), in patients with chronic kidney disease (CKD) not on dialysis, naive or non-naive to treatment with erythropoiesis-stimulating agents (ESAs) at inclusion. Design National, multicentre, longitudinal, observational prospective study. Setting 133 nephrologists practicing in France selected patients during their routine follow-up visits. The study was non-interventional. Participants They were adult CKD patients not on dialysis or kidney transplant patients, naive or not to ESA treatment: 524 patients not on dialysis (48% ESA-naive) and 92 kidney transplant patients (24% ESA-naive) were included and followed up every 3 months during 1 year. Outcome measures The two main endpoints were the percentage of patients who achieved target haemoglobin (Hb) levels as per European Medicines Agency guidelines (10–12 g/dl) around 6 months of treatment and modalities of treatment. Results Approximately one in two patients had an Hb level within 10–12 g/dl at baseline, and around 6 and 12 months of treatment. Ninety per cent of ESA-naive patients achieved at least +1 g/dl increase over baseline Hb levels or had Hb within 10–12 g/dl around 6 and 12 months. The Hb level remained at approximately 11.5 g/dl during the 12 months of follow-up. Around 6 months: almost all patients were receiving a once-monthly subcutaneous dose of C.E.R.A. (patients not on dialysis: 95±54 µg; kidney transplant patients: 121±70 µg); approximately half the patients did not require a change in C.E.R.A. dose. Adverse effects related to C.E.R.A. were observed in less than 5% of patients and led to modification or discontinuation of treatment in 2%. Conclusions The efficacy and safety of C.E.R.A. in CKD patients not on dialysis, with or without kidney transplantation, were confirmed in routine clinical practice.

BACKGROUND Sepsis is a major cause of acute renal failure in hospital patients, but its incidence and the associated prognostic factors have rarely been assessed prospectively by multivariate analysis. METHODS We conducted a prospective 6-month study in 20 multidisciplinary intensive care units to assess the prognosis of patients hospitalized with acute renal failure due to sepsis. Sepsis syndrome and septic shock were defined according to the criteria of the Society of Critical Care Medicine Consensus Conference. Severity scoring indexes (SAPS, APACHE II, and organ system failure (OSF)) were measured on ICU admission and on inclusion. The end-point was hospital mortality. RESULTS Acute renal failure had a septic origin in 157 patients (Group 1), comprising 68 with septic shock and 89 with sepsis syndrome, and did not result from infection in 188 patients (Group 2). Patients with septic acute renal failure were older (mean age: 62.2 versus 57.9 years, P

The role of HLA antigens in the chronicity of viral hepatitis is still being debated. We analyzed the relation between HLA status and viral hepatitis in 558 consecutive haemodialyzed patients who underwent kidney transplantation. HLA A, B, DR status, ABO-Rh blood group, duration of haemodialysis, and number of blood units transfused during the dialysis period were known for all patients. Serological status for hepatitis B virus and hepatitis C virus and results of liver biopsies were available in 495, 300 and 316 patients, respectively. After correction for the number of tests performed, frequencies of HLA antigens did not differ significantly for: 1. hepatitis B virus infection (compared to HBsAg-positive and anti-HBc and/or anti-HBs-positive nonvaccinated patients); 2. hepatitis C virus infection (compared to anti-HCV-negative and -positive patients); 3. histopathological status (compared to patients who had chronic viral hepatitis and those who did not). These results suggest that there is no evidence for a significant role of a particular HLA antigen in the development of chronic viral hepatitis in haemodialysis patients with similar underlying immunosuppression and exposure to infection by hepatotropic viruses.

Bone marrow (BM) transplantations performed between 1977 and 1991 at 13 European centers in 149 patients with 11 different primary immunodeficiency (ID) diseases (excluding severe combined immunodeficiency) were analyzed retrospectively. Overall survival among recipients of HLA genetically identical BM (n = 56) was 66%. Since October 1985, the date of a previous survey, a significant improvement in survival has been achieved in most ID diseases (overall survival, 81.5% v 51.7%; P < .01), primarily because of a decrease in the frequency of infectious complications. In long-term survivors, disease correction is excellent, with minimal sequelae in most patients. In 22 patients who received closely matched BM (ie, from phenotypically identical related donors, matched unrelated donors, or one HLA-ag- mismatched related donors), the survival rate (45.5%) was not significantly better than among 71 recipients of BM with 2 or 3 mismatched HLA antigens (38%). In the latter group, favorable outcome was associated with younger age, with transplantation since October 1985 (47% v 25%; P < .0001), and with a diagnosis of leukocyte adhesion deficiency. The improvement in outcome was mainly because of a higher engraftment rate and a decrease in the frequency of infections, although Epstein-Barr virus-induced B-lymphocyte proliferative disorders occurred in 16 patients (mainly those with Wiskott-Aldrich syndrome), 10 of whom died. The improvement in engraftment corresponded to the introduction of treatment in vivo with anti-LFA-1 antibody to prevent rejection of T-cell-depleted grafts (74% engraftment and 45% survival in 38 treated patients versus 37.5% and 21%, respectively, in 24 untreated patients.

Summary Introduction The aim of this study was to assess the burden of hospitalized wrist fractures between 2002 and 2006 in France. Methods Data were drawn from the French Hospital National Database. The number of admissions and the incidence rates were described as well as the type of entry and discharge from hospital, length of stay, and 2006 in-patients costs. Results Thirty-eight thousand seven hundred and ten and 38,979 hospitalizations for wrist fractures were registered in 2002 and 2006, respectively. The incidence rate of fractures increased with age whatever the year and decreased significantly from 2002 to 2006. Lengths of stay and mean inpatients costs increased with age. The overall in-patients 2006 costs was 79 millions with an average individual cost of 2100 € per hospitalized wrist fractures. Conclusion The incidence of hospitalizations for wrist fractures decreased in 2006 compared to 2002. The number of hospitalizations increased, as a consequence of ageing, (except for wrist fracture in men) with a subsequent increase in cost related to these fractures. The increase with age outlines the role of underlying osteoporosis and the relevance of appropriate care of patients at risk of for such fractures. Level of evidence IV.

Background: Hematopoietic stem cell transplantation remains the only treatment for most patients with severe combined immunodeficiencies (SCIDs) or other primary immunodeficiencies (non-SCID PIDs). Objective: To analyze the long-term outcome of patients with SCID and non-SCID PID from European centers treated between 1968 and 2005. Methods: The product-limit method estimated cumulative survival; the log-rank test compared survival between groups. A Cox proportional-hazard model evaluated the impact of independent predictors on patient survival. Results: In patients with SCID, survival with genoidentical donors (n = 25) from 2000 to 2005 was 90%. Survival using a mismatched relative (n = 96) has improved (66%), similar to that using an unrelated donor (n = 46; 69%; P = .005). Transplantation after year 1995, a younger age, B+ phenotype, genoidentical and phenoidentical donors, absence of respiratory impairment, or viral infection before transplantation were associated with better prognosis on multivariate analysis. For nonSCID PID, in contrast with patients with SCID, we confirm that, in the 2000 to 2005 period, using an unrelated donor (n = 124) gave a 3-year survival rate similar to a genoidentical donor (n = 73), 79% for both. Survival was 76% in phenoidentical transplants (n = 23) and worse in mismatched related donor transplants (n = 47; 46%; P = .016). Conclusion: This is the largest cohort study of such patients with the longest follow-up. Specific issues arise for different patient groups. Patients with B-SCID have worse survival than other patients with SCID, despite improvements in each group. For non-SCID PID, survival is worse than SCID, although more conditions are now treated. Individual disease categories now need to be analyzed so that disease-specific prognosis may be better understood and the best treatments planned. (J Allergy Clin Immunol 2010;126:602-10.)

Objectifs Recenser retrospectivement et prospectivement aupres des chirurgiens et oncologues pediatres, toutes observations de cancers pediatriques syndromiques. Des syndromes malformatifs augmentant le risque de cancer ont permis historiquement d’identifier des genes de predisposition. On observe que les malformations et maladies du developpement sont plus frequentes dans la population d’enfants atteints de cancer que dans la population generale, suggerant qu’une cause genetique unique puisse occasionnellement expliquer l’ensemble du phenotype. Les cancers syndromiques sont neanmoins peu recenses, et les associations fortuites peu distinguees des associations significatives. Materiels et Methodes Ces cas seront recenses sur la base de donnees CEMARA, en y precisant les echantillons biologiques constitutionnels et tumoraux disponibles. Ils feront l’objet d’etudes specifiques, orientees par des associations syndromiques decouvertes comme recurrentes ou par des associations semblant hautement significatives. Resultats/ Conclusion Ce projet biologique a vocation a s’etendre a toute equipe de recherche impliquee dans les thematiques «oncogenetique» et/ou «maladie du developpement». Il se construira autour d’un consortium scientifique reunissant les equipes ainsi identifiees.

We report three cases of primary aldosteronism associated with autosomal dominant polycystic kidney disease. The diagnosis of primary hyperaldosteronism was based on the presence of hypokalaemia with excessive urinary potassium excretion and/or the characteristic hormonal changes. Renal function impairment due to autosomal dominant polycystic kidney disease could mask hypokalaemia. The interpretation of adrenal imagery may be hindered by adjacent renal cysts. In one case an adrenal adenoma was detected and surgically removed, with only partial correction of the blood pressure. This could be explained by the persisting underlying autosomal dominant polycystic kidney disease. We conclude that in a hypertensive patient with polycystic kidney disease, extrarenal causes of hypertension may be present.

Abstract 664 Severe combined immune deficiency (SCID) diseases, as well as other severe T-cell deficiencies like Omenn syndrome, are considered pediatric emergencies. To date, hematopoietic stem cell transplantation (HSCT) is the only curative therapy for these children. Considering the urgency of these transplants, for patients lacking an identical sibling donor, the use of mismatched related donors (MMRD) and unrelated umbilical cord blood (UCB) are important alternatives. In a retrospective study, we compared the outcomes of 175 children with severe T-cell deficiencies (SCID=152, Omenn syndrome=23) receiving MMRD transplants and 74 (SCID=52, Omenn syndrome=15) receiving UCB transplants, reported to the SCETIDE and Eurocord databases, from 1995 to 2005. MMRD transplants were performed in 12 different centers and UCB transplants were distributed among 30 different centers. Only 5 centers performed the two techniques. The median age at transplant was 6.4 months for the UCB group and 6.5 months for the MMRD group (p=0,87). Median time elapsed between diagnosis and transplant was 47 days for MMRD (range 4-485) and 55 days (range 17-526) for UCB transplants (p=0.06). There were no statistically significant differences between the two groups regarding gender and incidence of failure to thrive, chronic diarrhea or respiratory impairment before transplant. Patients receiving UCB had more often B-negative phenotype (61% UCB vs. 41% MMRD; p=0.009), while patients receiving MMRD had a greater incidence of viral infections prior to transplant (59% MMRD vs. 36% UCB; p=0.004). The year of transplantation also differed between the two groups, as more patients receiving UCB were transplanted between 2000-2005 (65%) compared to MMRD (50%) (p=0.014). Regarding HLA (considering HLA-A,B-low resolution and DRB1-high resolution), in the UCB group, 67% of patients had 0 or 1 disparities while 33% had 2 or 3 disparities. In the MMRD group, 10% had 1 disparity and 90% had 2 or 3 disparities. Seven patients receiving UCB (16%) transplants and 30 patients receiving MMRD (17%) did not receive any preparative regimen prior to graft infusion. Conditioning regimen was non-myeloablative in 45% of MMRD transplants and 30% of UCB transplants. The remaining received myeloablative regimens. Graft-versus-host disease (GVHD) prophylaxis was cyclosporine A-based in the majority of the UCB transplants (n=71). T-cell depletion was used in all transplants with MMRD and 52 patients received immunosuppressants, mostly cyclosporine A. The median follow-up time was 84 months for patients given a MMRD and 59 months for UCB transplants recipients. Sixty-one patients receiving UCB transplants engrafted (82%), all with full donor chimerism in CD3+ cells. On the CD3- compartment 75% had full donor, 5% mixed and 20% had recipient chimerism. In MMRD group, 130 patients engrafted (74%), 98% with full donor chimerism in CD3+ cells. On CD3- cells, 33% had full donor chimerism, 48% were mixed and 19% recipient chimerism. Forty-six patients in the MMRD group and 7 patients in the UCB group needed to receive second transplants. The cumulative incidence of acute GVHD had no statistically significant difference between groups (33% UCB vs. 23% MMRD; p=0.13). However, patients receiving UCB transplants had more chronic GVHD (22% UCB vs. 11% MMRD; p=0.04). In a univariate analysis, 5-year overall survival was 62 ± 4% for MMRD and 58% ± 6% for UCB transplants (p=0.83). In a multivariate analysis adjusting for differences between the two groups, 5-year overall survival was not statistically different (p=0.54). Regarding T-cell reconstitution, we analyzed the total lymphocyte, CD3+ and CD4+ cell numbers and there were no statistically significant differences between the two groups comparing absolute numbers at 6, 12 and 24 months after transplantation. In conclusion, both unrelated cord blood and mismatched related donors are choices for transplants in severe T-cell deficiencies lacking an HLA-identical sibling donor. The choice of donor type will depend on centre's strategy regarding the possibility of efficiently deplete MMRD grafts of T-cells, or find a rapidly available UCB unit. Disclosures: No relevant conflicts of interest to declare.

Abstract 1391 Poster Board I-413 Background: Primary immunodeficiency diseases (PID) encompass more than 200 different rare diseases that share at least two characteristics, inheritance and increased susceptibility to infections. The mechanisms imply different components such as B-cells, T-cells, phagocytes or complement, and more than 150 genes are known to be involved in PID. While several studies have analyzed specific PID, very little is known about the exact repartition of the different groups of deficiencies. To assess epidemiological characteristics of these heterogeneous diseases, the French National Reference Centre for PID (CEREDIH) was established in November 2005 and created a dedicated registry to determine the distribution of PID patients in France who are under care in expert University hospitals. Methods: The CEREDIH set up a national network of 18 regional centres including 58 University hospitals medical departments with experience in the care of both children and adults patients with PID. Data collected relied on the European Society for Immunodeficiencies core dataset. Overall, regional and detailed prevalence for major PID groups, and improvement of diagnosis over time were assessed. Data provided by our registry were compared to the ones previously reported by other National registries. Results: At April 2009, The CEREDIH registry encompasses a total of 3,083 patients. The overall prevalence is 4.4 cases for 100,000 inhabitants based on 2,682 alive patients. A majority of cases are children. Median age (Q1-Q3) at diagnosis was 3.3 years (0.7-10.3). Predominantly B-cell immunodeficiencies are the most common diseases observed (43%), the proportion of Common Variable Immunodeficiency (CVID) being 14%. Predominantly T cell disorders and phagocytic disorders were observed in 38% and 19.2% of patients, respectively. The 2 main phagocytic disorders were severe congenital neutropenias (65%) and chronic granulomatous diseases (27.6%). Immunoglobulin replacement therapy was given in 42% of all registered patients, by intravenous or subcutaneous route in 74% and 26% of cases, respectively. A significantly heterogeneous distribution of PID was observed in distinct geographical areas with variation in prevalence by a factor of 3. For B-cell deficiencies, there is a steady increase of identified cases between 1984 up to 2000. Noticeably, incidences for predominantly T cell and for innate immune deficiencies are likely to reach prevalence. Overall prevalence in France is quite similar to the one observed in other countries that have built a PID national registry, although the methodologies used were somehow different. The proportion of CVID is lower than in other national registries previously reported. Conclusion: These results suggest that, while detection and referral to expert centres is fairly adequate for children, it is not yet the case in France for adult patients. There are still a number of unrecognised patients with PID (or patients not referred to university medical centres) as depicted by the heterogeneous distribution of PID observed, also pinpointing to regional differences in patients' care. This analysis provides the basis for further studies in assessing causes for observed differences and for taking action to increase awareness of PID, notably in adults, at national and regional levels. The CEREDIH registry could be a useful tool for measuring improvements in access to care for French PID patients and referral to centres with expertise. Disclosures: No relevant conflicts of interest to declare.

SUMMARYTriggering of the CD3 molecule by in vivo injection of the hamster anti-murine CD3 monoclonal antibody 145-2C11 in adult BALB/c mice leads to massive although transient T cell activation. High levels of tumour necrosis factor (TNF), interferon-gamma (IFN-γ), IL-2, IL-3 and IL-6 are released into the circulation 1 to 8 h after a single 10 μg 145-2C11 i.v. injection. This release induces an impressive self-limited physical reaction associating hypothermia, hypomotility (as assessed by actimetry), diarrhoea, piloerection and even death when high doses (a single dose of > 100 μg/mouse injection) are administered. In vivo injection of 145-2C11 to other selected mouse strains, namely NZW, CBA/J and C3H/HeJ, induced both different cytokine release patterns and sickness. 145-2C11 induced significant release of TNF and IL-2 in all four strains. At variance. IFN-γ was only detected in BALB/c mice sera which, in terms of physical reaction (hypothermia and hypomotility) were the most affected. Higher and long-lasting circulating 1L-3/GM-CSF levels were present in CBA/J sera, correlating with a later recovery. These results underline heterogeneity in the in vivo cell activation pattern among different mouse strains, when triggering T lymphocytes via the CD3/Ti molecule as compared to exclusive targeting of monocyte/macrophages by means of lipopolysaccharide.

Rationnel Des travaux preliminaires ont montre une efficacite du recepteur antagoniste de l’interleukine (IL) –1 Anakinra dans la forme systemique d’arthrite juvenile idiopathique (FS-AJI). Objectifs Evaluer l’efficacite et la tolerance de l’anakinra dans la FS-AJI. Etudier la pharmacocinetique et l’effet du traitement sur differents parametres accessoires. Methode Essai multicentrique randomise contre placebo. Objectif principal : demontrer la superiorite d’un traitement par anakinra (2 mg/kg en une sous-cutanee par jour, maximum 100 mg) sur un placebo en comparant a un mois deux groupes de 12 patients. Reponse : jugee sur une amelioration d’au moins 30 % du score composite de Giannini (prenant en compte l’atteinte articulaire, l’evaluation de l’activite de la maladie par les parents et le medecin, le score fonctionnel CHAQ et la VS), une disparition de la fievre et des signes systemiques, une negativation ou une reduction d’au moins 50 % de la CRP et de la VS comparativement a J1. Analyse en intention de traiter. Objectifs secondaires : analyse sur 12 mois de l’efficacite et de la tolerance du traitement, de la possibilite de diminuer la dose de corticoides apres le premier mois. Marqueurs accessoires d’efficacite du traitement dont pharmacocinetique. Resultats Le taux de repondeurs a 1 mois (objectif principal) etait significativement plus eleve sous Anakinra (8/12 repondeurs) que sous placebo (1/12). Sur l’ensemble de l’etude, cinq effets indesirables graves ont ete repertories dont une atteinte ileocolique apres 2 mois s’averant etre une maladie de Crohn ; trois infections et un tassement vertebral n’ont pas requis l’interruption du traitement. Dans 7 cas, le traitement a ete interrompu pour injections trop douloureuses (2 cas, sous placebo), manque d’efficacite ou poussee de la maladie a la decroissance de la corticotherapie (4 cas), hepatite cytolytique transitoire (1 cas). L’etude des criteres secondaires de jugement suggere un interet de la pharmacocinetique et de l’etude du profil d’expression de certains genes. Conclusion Premier essai controle demontrant l’efficacite d’un traitement anti-IL-1 dans la FS-AJI.

Preliminary data from our group indicated that cyclosporin A induced frequent remissions of insulin dependency in a group of 40 insulin-dependent (type I) diabetic children if given at the onset of clinical manifestations of diabetes. We report a 2-yr analysis of the response to cyclosporin A in the group of 81 patients included in the initial study. As observed before, a remission could be obtained in most of the patients (65%) in association with a shorter duration of symptoms, less severe hyperglycemia, lower incidence of ketoacidosis, and higher plasma C-peptide concentrations. All remissions ended during the follow-up period after a mean ± SE duration of 316 ± 21 days (range 31–850 days). Two parameters were linked to the duration of remissions: the mean circulating level of cyclosporin during the first 3 mo and the duration of prediagnostic polyuria. We were unable to relate the end of a remission to variations in the cyclosporin regimen, titer of autoantibodies, or progression of β-cell failure. The euglycemic clamp technique revealed that insulin sensitivity decreases with time in patients not taking insulin. At 24 mo, the patients who had a remission of insulin dependency had better glycemic control, lower insulin dosages, and C-peptide levels two- to threefold higher than the nonremission patients and four- to sixfold higher than the historical control subjects. The cyclosporin regimen was well tolerated over the observed period: more specifically, serum creatinine remained unchanged, and kidney biopsies performed at 18–24 mo of treatment were within normal limits. We conclude that this immunosuppressive regimen given to patients with overt type I diabetes maintains a residual insulin secretion, which, however, does not allow >2-yr remissions of insulin dependency. It remains to be studied whether some preservation of β-cell function will thereafter be retained and whether this can improve the management and prognosis of the disease. It will also be necessary to test whether earlier diagnosis can ameliorate and prolong our results.

Context: Benefits of HU treatment in thalassemic patients are controversial. Most studies agree that HU decreases transfusion requirements in patients with TI, whereas results in patients with TM are inconsistent. Objectives: To assess the proportion of good responders to HU and the factors associated with good response. Methods: We initiated HU treatment in 54 thalassemic patients (9 TI and 45 TM). Median ages at first transfusion were 57 months (32–252) in TI and 13 months (4–60) in TM patients. Median ages at inclusion were 12.4 years (4.4–54.9) in TI and 9.9 years (2.0–21.0) in TM patients. Median numbers of erythrocyte concentrates (EC) transfused the year before HU were 3 (1–9) in TI and 12 (8–16) in TM patients (10–65). Good response was defined as more than 70% decrease of transfusional needs one year after beginning HU, partial response as a decrease between 40 and 70%, and non response as a decrease of less than 40%. Patients were transfused when their hemoglobin (Hb) level was < 6g/dL; not transfused when Hb was > 7 g/dL; decision to transfuse was based on clinical status for Hb level between 6 and 7 g/dL. Mean HU dose was 17 ± 2 mg/kg/d (13–21). Mean follow-up was 29.3 ± 14 months. Results: Eight (90%) TI and 20 (44.5%) TM patients had a good response to HU. No TI and 9 (20%) TM patients had a partial response to HU. One (10%) TI and 16 (35,5%) TM patients had no response to HU. Clinical and hematological tolerance were good except for one 55 yr old TI patient who developed in the 3rd year of treatment an acute myeloblastic leukemia. Retrospectively, a malignant transformation of a pre-existent myeloproliferative disorder can not be excluded and the responsibility of HU is questionable. A better response to HU was associated with a later beginning of transfusion (p=0.02), a higher pre-HU Hb (p= 0.0004), codon 6(-A) mutation (p= 0.002), and with TI diagnosis (p=0.03). On the contrary, Gγ-158 C/C genotype (Xmn1−/−) (p= 0.0001) was associated with a worse response. After adjustment, decrease of transfusional needs was associated with the number of CE transfused the year before HU treatment (p= 0.001), Xmn1 polymorphism (p= 0.003) and the age at the beginning of HU (p=0.03) but not with the type of thalassemia. In conclusion, HU may represent an alternative to transfusions for both TI and TM patients in countries with limited blood supplies when beginning early.

For the last 35 years or so, allogeneic hematopoietic stem cell transplantation (HSCT) has been the only curative approach for patients affected by severe combined immunodeficiencies (SCID), a medical emergency. According to the most recent European survey haploidentical transplants allow a survival rate at 3 years of 75% (taking only into account patients transplanted since 1995). The mortality rate is heavily influenced by age at transplantation (being very low within young infants), in correlation with the infection burden and also the incidence of acute graft-versus-host reaction (GVHD). Between 1998 and 2003, 6 patients with NK(−) B(+) SCIDs (either gc or JAK3 deficiency) received an haploidentical HSCT at Necker Hospital, 3 of them died from an infection, one in the context of a severe GVHD. In addition, despite the improvement in the survival rate, over the time a number of long-term concerns have been detected including a frequent persistence of a B cell deficiency, and a decline in T-cell functions related to the absence of donor stem cell engraftment and may be also to a premature decline in the thymus function. Therefore, several patients have received a second transplant with a low efficiency in an haploidentical setting. These significant limitations set the rationale for the development of an alternative strategy such as gene therapy. From March 1999 up to May 2002, ten children with gc deficiency under the age of one year were enrolled. All of them are alive today. The gc gene transfer into patients’ CD34(+) cells led in 9 out of 10 patients to the emergence of T and NK lymphocytes. It took 10 to 12 weeks to detect mature T cells in the periphery, a delay which is significantly faster than the one observed after haploidentical HSCT. In all but 2 patients, T cell counts normalized up to 5.3 years after gene therapy. The occurrence of two severe adverse events led to put transiently the trial on hold in order to understand the pathophysiology of these events and assess its overall risks. Following a thorough analysis of the retrospective data and a prospective analysis, it was concluded that the benefit/risk balance in favor of the gene therapy approach at least for patients older than 3 months, hence our gene therapy protocol has been reopened. An update of the clinical data will provided at the meeting.

Objective: To analyze the distribution of hepatitis C virus (HCV) genotypes among patients positive for antibody to HCV (anti-HCV) according to age, severity of liver disease, and duration of infec...