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Innate immune signaling pathways are essential mediators of inflammation and repair following myelin injury. Inflammasome activation has recently been implicated as a driver of myelin injury in multiple sclerosis (MS) and its animal models, although the regulation and contributions of inflammasome activation in the demyelinated central nervous system (CNS) are not completely understood. Herein, we investigated the NLRP3 (NBD-, LRR- and pyrin domain-containing protein 3) inflammasome and its endogenous regulator microRNA-223-3p within the demyelinated CNS in both MS and an animal model of focal demyelination. We observed that NLRP3 inflammasome components and microRNA-223-3p were upregulated at sites of myelin injury within activated macrophages and microglia. Both microRNA-223-3p and a small-molecule NLRP3 inhibitor, MCC950, suppressed inflammasome activation in macrophages and microglia in vitro; compared with microglia, macrophages were more prone to inflammasome activation in vitro. Finally, systemic delivery of MCC950 to mice following lysolecithin-induced demyelination resulted in a significant reduction in axonal injury within demyelinated lesions. In conclusion, we demonstrate that NLRP3 inflammasome activity by macrophages and microglia is a critical component of the inflammatory microenvironment following demyelination and represents a potential therapeutic target for inflammatory-mediated demyelinating diseases, including MS. Cover Image for this issue: https://doi.org/10.1111/jnc.15422.

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system accompanied by chronic inflammation, axonal loss, and neurodegeneration. Traditionally, MS has been thought of as a T-cell mediated disease, but research over the past decade has demonstrated the importance of B cells in both acute demyelination and disease progression. The highly selective irreversible Bruton Tyrosine Kinase (BTK) inhibitors evobrutinib, tolebrutinib, and orelabrutinib, and the reversible BTK inhibitor fenebrutinib, all target B-cell activation and aspects of innate immunity, including macrophage and microglia biology. The c-KIT inhibitor masitinib mitigates neuroinflammation by controlling the survival, migration, and degranulation of mast cells, leading to the inhibition of proinflammatory and vasoactive molecular cascades that result from mast cell activation. This article will review and critically appraise the ongoing clinical trials of two classes of receptor tyrosine kinase inhibitors that are emerging as potential medical treatments for the varying subtypes of MS: BTK inhibitors and c-KIT inhibitors. Specifically, this review will attempt to answer whether BTK inhibitors have measurable positive clinical effects on patients with RRMS, SPMS with relapses, relapse-free SPMS, and PPMS through their effect on MRI T1 lesions; annualized relapse rate; EDSS scale; MSFC score; and time to onset of composite 12-week confirmed disability progression. Additionally, this review will examine the literature to determine if masitinib has positive clinical effects on patients with PPMS or relapse-free SPMS through its effect on EDSS or MSFC scores.

Resume Introduction La cupule Evora ® a double mobilite en alliage de chrome-cobalt revendique, par rapport aux cupules a double mobilite inox, un comportement de frottement different de la grande articulation limitant le risque de luxation intra-prothetique et d’usure. Ce travail actualise a 10 ans de recul minimum une serie prospective multicentrique de 200 cupules prealablement publiee au recul de 5 ans. Hypotheses L’usage du chrome-cobalt pour une cupule a double mobilite permet un faible taux d’echec a 10 ans de recul notamment pour l’osteolyse et les luxations intra-prothetiques. Materiel et methode Deux cent cupules en chrome-cobalt coule recouvertes d’hydroxyapatite sans interface titane etaient implantees sans ciment chez 194 patients d’âge moyen 70 ans (32–91). Les resultats etaient evalues au moyen des scores de Merle d’Aubigne et de Harris, de radiographies standards et par une analyse de survie. Resultats Au recul de 11 ans (10–13 ans), 56 patients etaient decedes, 31 perdus de vue. Quatre malades ont ete reoperes (3 pieces femorales et 1 cupule pour migration a 9 ans de recul avec disparition totale de l’hydroxyapatite). Cent neuf protheses etaient analysables chez 107 patients d’âge moyen de 81 ans (55–93). Au recul le score de Harris etait de 90 (75–96), le score PMA a 16,3 (14–18). Il n’y a pas eu de descellement de cupule (sauf le cas repris a 9 ans) et aucun lisere, ni geodes. Il y avait 2 liseres non evolutifs et 10 granulomes femoraux avec pour facteur de risque un diametre de tete superieur a 22 mm ( p p = 0,004). Il n’y a pas eu de luxation de la grande ou de la petite articulation. Le taux de survie a 10 ans etait de 99 % (IC 95 % : 97,3–100 %) en considerant l’evenement reprise de la cupule. Discussion L’absence de luxation (petite et grande articulations) confirme l’efficacite du principe de la double mobilite et suggere un avantage de la cupule en chrome-cobalt pour reduire le risque de luxation intra-prothetique en prevenant le blocage de la grande articulation grâce a un meilleur couple de frottement. Les granulomes etaient lies a l’usage de pivots en titane scelles et de tetes de calibre superieurs a 22 mm. Si la survie de la cupule a 10 ans etait de 99 % (reprise pour un echec de la cupule), nous deplorons un descellement de cupule avec disparition de l’hydroxyapatite qui incite a poursuivre la surveillance de cette cohorte. Niveau de preuve IV. Etude retrospective.

Resume La double mobilite a ete proposee par G. Bousquet au debut des annees 1980. L’interet de ce type d’implant dans le traitement preventif et curatif de l’instabilite prothetique a deja ete demontre. Les mobilisations precoces et des douleurs inguinales etaient des complications precoces qui en limitaient les resultats. Les auteurs proposent une evolution avec une prothese d’un volume inferieur, en chrome–cobalt, une fixation primaire assuree par un accroissement annulaire asymetrique, des picots d’ancrage et une fixation secondaire par hydroxyapatite avec repousse osseuse dans une surface macrogeometrique. Deux cents protheses, chez 194 malades, ont ete implantees dans le cadre d’une evaluation multicentrique continue, prospective, non randomisee. Elles ont ete suivies avec un recul minimum de cinq ans. A la revision, 17 patients etaient decedes, huit etaient perdus de vue et cinq etaient grabataires. Trois malades ont ete reoperes (un descellement femoral, une fracture du femur traumatique et une infection hematogene). Cent soixante-dix protheses etaient analysables au-dela de cinq ans. Il n’y a pas eu de reprise pour cause acetabulaire, aucune douleur inguinale et aucune luxation. Les evolutions proposees apportent une solution aux complications precoces de la cupule originale de Bousquet sans effet deletere sur la stabilite prothetique.

S. HEISS-BLANQUET, Y. BENOIT, C. MARECHAUX AND F. MONOT. 2005. Aims: A molecular tool for extensive detection of prokaryotic alkane hydroxylase genes (alkB) was developed. AlkB genotypes involved in the degradation of short-chain alkanes were quantified in environmental samples in order to assess their occurrence and ecological importance. Methods and Results: Four primer pairs specific for distinct clusters of alkane hydroxylase genes were designed, allowing amplification of alkB-related genes from all tested alkane-degrading strains and from six of seven microcosms. For the primer pair detecting alkB genes related to the Pseudomonas putida GPo1 alkB gene and the one targeting alkB genes of Gram-positive strains, both involved in short-chain alkane degradation (

In recent years, it has become increasingly evident that the problems related to soil and groundwater pollution are of major concern in industrial countries. The persistence of contamination in the environment and the toxicity of pollutants have led to important investigations and researches in this field. The competent authorities have set up regulations and methodologies to face the problems of contaminated sites in order to repair the errors of the past in a pragmatic way. These are risk based tools and take into account both water resources and health. They allow the treatment to be adjusted to the future use of the site. In this context, understanding the mechanisms of pollution transfer from the soil to the water phase becomes crucial to evaluate the quantitative and qualitative impact on the water resources. As a matter of fact, numerous processes-physical, chemical and in particular biological-are susceptible to affect the quantity and particularly the composition of the contaminant. This paper will present methodologies allowing the biological fate and the physical state of hydrocarbons in water to be perceived. Results from two real cases will be presented: the first one contaminated with gasoline and generating an important plume of dissolved monoaromatic compounds and the other one contaminated with coal tars inducing a pollution with polyaromatic hydrocarbons.

The last forty years have witnessed major improvements in the survival of pediatric cancer patients with an evolution of acute tymphoblastic leukemia as an untreatable disease to acute lymphoblastic leukemia with a survival rate of more than 90%. This has become possible due to improvements in the various modalities of cancer therapy and supportive care. The aim of this commentary is to give an overview of the history of pharmacological treatment for children with acute Lymphoblastic leukemia.

The volar locking plate is a popular implant for surgical management of unstable distal radial fractures. We routinely utilize this system for all distal radial fractures except for those with entrapped intra-articular fragments and fractures with a displaced dorsomedial facet fracture (which is hard to capture with the volar approach alone). In this video, we describe in detail the necessary steps for successful placement of the volar locking plate, starting with preoperative planning and ending with expected outcomes. The approach that we utilize is through the flexor carpi radialis tendon sheath and avoids the radial artery. In the video, we describe 4 variations on the application of a volar locking plate: (1) the standard technique after appropriate reduction and provisional fixation with Kirschner wires, (2) regaining length through a shortened distal radial fracture, (3) using the volar plate to assist in the reduction and regain volar tilt, and (4) intraoperative management of coronal shift of the distal fragment. Complications reported for the volar locking plate have decreased with newer low-profile plate designs; however, they still include volar tendon irritation and/or rupture and median neuropathy. Postoperatively, we advise a brief 2-week period of immobilization for wound-healing, which is followed by a period during which a removable wrist splint is used and patients are instructed on the performance of a hand therapy regimen.

The following recommendations, which aim at improving the clinical diagnosis ofTRALI and the laboratory investigations that can support it, were drawn up by a working group of the Superior Health Council. TRALI is a complication of blood transfusion that is both serious and underreported. Systematic reporting may help to develop preventive actions. Therefore, the Superior Health Council recommends that there should be a more stringent surveillance of patients who receive a blood component transfusion. The clinician should pay very close attention to any change in the patient's respiratory status (cf. dyspnoea and arterial desaturation), which should be notified systematically to the haemovigilance contact person in the hospital.

Intracranial germ cell tumors are rare tumor entities in childhood and adolescents. Extra- and intracranial germ cell tumors are identical in their histologic pattern and occur in preferential midline localizations such as the pineal and the suprasellar region. Germ cell neoplasms show increasing incidence rates over the last 30 years. The majority of intracranial germ cell neoplasms are germinomas. About 90% of the patients with pure germinomas can be salvaged by radiotherapy alone according to modern protocols. Non-germinomatous malignant CNS-germ cell tumors are considered to have a poor prognosis. In order to improve the survival of patients affected by these tumors different treatment approaches adding chemotherapy to conventional surgery and radiotherapy have been initiated by various study groups throughout the world. Due to the rarity of these neoplasms only a very limited number of patients has been enrolled in each study. In 1993 an international working group on these tumors was established by the International Society of Pediatric Oncology (SIOP).

Resume Un patient de 56 ans devait beneficier dˈun pontage aorto-coronarien pour des lesions tritronculaires severes. Peu apres l’induction, il a presente un bronchospasme, accompagne rapidement d’un collapsus et d’une eruption cutanee erythemato-papuleuse. Les explorations allergologiques initiales (immunoglobulines E specifiques et tryptase plasmatique) ont confirme le diagnostic de choc anaphylactique au rocuronium et ont permis d’adapter la technique d’anesthesie au patient sans differer de maniere prolongee la chirurgie.

Overcoming childhood cancers is critically dependent on the state of research. Understanding how, with whom and what the research community is doing with childhood cancers is essential for ensuring the evidence-based policies at national and European level to support children, their families and researchers. As part of the European Union funded EUROCANCERCOMS project to study and integrate cancer communications across Europe, we have carried out new research into the state of research in childhood cancers. We are very grateful for all the support we have received from colleagues in the European paediatric oncology community, and in particular from Edel Fitzgerald and Samira Essiaf from the SIOP Europe office. This report and the evidence-based policies that arise from it come at a important junction for Europe and its Member States. They provide a timely reminder that research into childhood cancers is critical and needs sustainable long-term support., peer-reviewed

International audience; One of the options considered to mitigate greenhouse gas concentrations in the atmosphere is underground storage of CO2. There is a strong need for enhancing and developing methods that would help throughout the duration life of such underground storage, to ensure the safety and able to monitor the evolution of the injected CO2 plume. Among these, geochemical methods can play an important role. Here, we describe results acquired under the research programme “Géocarbone-Monitoring”, partially funded by the French National Research Agency, on the Montmiral natural analogue in South-Eastern France. Other results obtained under the same research programme in the French Massif Central are reported elsewhere in this volume.Spot sampling methods allowing a great geographical coverage and continuous measurements on selected points were undertaken in 2006 and 2007, in order to determine soil gas concentrations and fluxes as well as carbon isotope ratio determinations. One important result is that without any evidence of deep CO2 leakage, both CO2 concentrations and fluxes appear to be higher than can be explained only by biological activities. Further investigations are thus needed to understand the gas evolution better throughout the year.

We present a six-year follow-up of a boy with a novel type of hypolipoproteinemia, with clinical and biochemical features distinct from classical hypoalphalipoproteinemias. There were abnormally low concentrations of total and high-density lipoprotein (HDL) cholesterol, apolipoprotein (apo) B, apo A-I, and apo A-II, and the phospholipids were decreased. The most striking abnormality was an extra fraction containing mainly phospholipids and apo A-I in the HDL3 subfraction. This fraction is reminiscent of concentric 20- to 50-nm-diameter lamellar phospholipid liposomes. Plasma lecithin:cholesterol acyltransferase activity was strongly decreased. We noted a persisting polyclonal hypergammaglobulinemia, hematological abnormalities (hemolytic anemia and thrombocytopenia), and a progressive splenomegaly. After the five-year follow-up, the patient had recurrent severe infections; moderate hematuria and proteinuria developed gradually. Treatment with corticosteroids and immunoglobulins improved thrombocytopenia and hypolipoproteinemia. These clinical and biochemical findings differ from those in the known primary and secondary hypo-alpha-lipoproteinemia syndromes. Although investigation of the relatives suggests a familial predisposition for hypo-alpha-lipoproteinemia, the subject's condition can be regarded as acquired.

Dislocation is a well-known complication of total hip arthroplasty. The risk can be reduced to one or two cases per thousand using a double mobility cup. The survival rate achieved with the Bousquet implant is 95% at 10 years. The complications with this implant are early mobilization and inguinal pain. An overly large cup and insufficient primary and secondary fixation can be implicated. The design of the original implant was later modified to limit these early complications. The purpose of this work was to check the validity of the changes made.The chromium-cobalt moulded cup was used. The outer surface of this cup presents large geometric striations and is coated with hydroxyapatite. The cup has the shape of a half sphere of 180 degrees and a posterior wall prolongation measuring 6.5mm. Three mechanisms were used for the primary fixation: an asymmetrical growth ring, four anchorage stems, and a superior screw. Two hundred cups were implanted in 194 patients. The femoral piece was a Charnley stainless steel implant (n=139), a titanium SEM implant (n=59) or another implant (n=12). Cement was used for 193 implantations. The series included 97 women and 103 men with osteoarthritis (n=180), necrosis (n=16), surgery for fracture and primary arthroplasty (n=9). The Harris and Postel-Merle-d'Aubigné scores were noted. Eight radiographic criteria were analyzed to assess the position of the cup and the radiological course of the interface.Mean time to surgery was six years. Mean age at surgery was 70 years (range: 32-91) and varied depending on the operators from 67 to 73 years. At last follow-up: 17 patients had died, eight were lost to follow-up and five were bedridden. Three patients underwent revision surgery. Thus, this analysis included 170 prostheses followed for more than five years (mean: six years, range: 5-7 years). The Harris score improved from 48 to 92 and the Postel-Merle-d'Aubigné score from 2/5/4 to 5.8/5.9/5.5 (range: 4-6/5-6/1-6). None of the patients complained of anterior pain during hip flexion against resistance. Cup inclination was 46 degrees on average (range: 62-22 degrees ). Medialization, lateralization or ascension greater than 10mm of the centre of rotation was not observed on the postoperative films. At last follow-up, no measurable mobilization or migration could be identified on plain X-rays. Lucent lines, condensations and bony defects around the cup, when visible postoperatively, were not found on the last follow-up X-rays. There were two cemented femoral pieces, which developed a lucent line in the nonspecific metaphyseal area. There were no cases of granuloma and no cam effect. Three patients underwent revision for femoral loosening, fracture of the femur below the prosthesis, and hematogenous infection. There were no cases of dislocation.Changing the design of the implant to modify its volume, material and primary fixation has eliminated the early mobilizations and inguinal pain described for the original Bousquet cup. These options have not had any deleterious effect on prosthesis stability. The question of long-term wear remains an important problem and requires optimization: a neck as thin as possible, optimized surfacing, elimination of laser marks, extraction leads, head skirts.

Summary Purpose of the study Dislocation is a well-known complication of total hip arthroplasty. The risk can be reduced to one or two cases per thousand using a dual-mobility cup. The survival rate achieved with the Bousquet implant is 95% at 10 years. The complications with this implant are early mobilization and inguinal pain. An overly-large cup and insufficient primary and secondary fixation can be implicated. The design of the original implant was later modified to limit these early complications. The purpose of this study was to check the validity of these design changes. Patients and methods The chromium–cobalt moulded cementless cup was used. The outer surface of this cup presents large geometric striations and is coated with hydroxyapatite. The cup has the shape of a 180° half sphere and a posterior wall prolongation measuring 6.5 mm. Three mechanisms were used for the primary fixation: an asymmetrical growth ring, four anchorage stems and a superior screw. Two hundred cementless cups were implanted in 194 patients. The femoral piece was a Charnley stainless-steel implant ( n = 139), a titanium SEM implant ( n = 59) or another implant ( n = 12). Cement was used for femoral fixation in 193 implantations. The series included 97 women and 103 men with osteoarthritis ( n = 180), necrosis ( n = 16) and surgery for fracture and primary arthroplasty ( n = 9). The Harris and Postel–Merle-d’Aubigne scores were noted. Eight radiographic criteria were analyzed to assess the position of the cup and the radiological course of the interface. Results The mean follow-up was six years and the minimum was five years. The mean age at surgery was 70 years (range, 32 to 91). At last follow-up, 17 patients had died, eight were lost to follow-up and five were bedridden. Three patients underwent revision surgery. Thus, this analysis included 170 prostheses followed for more than five years (mean, six years; range, five to seven years). The Harris score improved from 48 to 92 and the Postel–Merle-d’Aubigne score from 2/5/4 to 5.8/5.9/5.5 (range, 4 to 6/5 to 6/1 to 6). None of the patients complained of anterior pain during active hip flexion in supine position (related to ilio-psoas irritation). Cup inclination was 46° on average (range, 62 to 22°). Medialization, lateralization or ascension greater than 10 mm from the center of rotation was not observed on the postoperative films. At the last follow-up, no measurable mobilization or migration could be identified on plain X-rays. Radiolucent lines, condensations and bony defects around the cup, when visible postoperatively, were not found on the last follow-up X-rays. There were two cemented femoral pieces that developed a radiolucent line in the nonspecific metaphyseal area. There were no cases of granuloma and no cam effect. Three patients underwent revision for femoral loosening, fracture of the femur below the prosthesis and hematogenous infection. There were no cases of dislocation. Discussion Changing the design of the implant to modify its volume, material and primary fixation has eliminated the early mobilizations and inguinal pain described for the original Bousquet cup. These options have not had any deleterious effect on prosthesis stability. The question of long-term wear remains an important problem and requires optimization: a neck as thin as possible, optimized surfacing, elimination of laser marks, extraction leads and head skirts.

Febrile neutropenia requires adequate antibiotic treatment. A subgroup of patients are only at low risk for complications and could be treated at home/as outpatients (OHPAT) after a short initial admission for work up. This position paper by a Belgian panel of experts presents criteria defining low-risk in febrile neutropenia, gives an overview of the existing experience and examines the present obstacles to a more widespread use of OHPAT in this country.

A 56-year-old patient was scheduled for coronary artery bypass surgery, because of a severe coronary artery disease. Soon after induction of anaesthesia, he rapidly developed a cardiovascular collapse with bronchospasm and rash. Specific immunoglobulin E and tryptase measurements supported the diagnosis of grade III anaphylactic shock due to rocuronium bromide. A few days later, a general anaesthesia was administered without muscle relaxant and was uneventful.

Between 1991 and 2000, seven patients presented with symptomatic pineal cysts at our hospital (6 females, 1 male). Average age was 22 years (range 4-33 years). Headache was present in 6 patients, who were subsequently operated on. A scotoma and a transient inferior visual field deficit were minor signs in two patients respectively. A Parinaud syndrome with vertical gaze paralysis was found in none. In one child, paroxysmal pupillary dilatations and contractions ('springing pupils') constituted the only signs and a conservative policy was adopted. Four patients presented with hydrocephalus and were treated by an endoscopic resection of their pineal cysts (one stereotactically, three free-hand). Two other patients presented with a prolonged history of symptoms and signs: headache alone in one, headache with discrete neurological deficits in the other. Ventricles in these two patients were not dilated and therefore an open cyst resection by infratentorial supracerebellar approach was performed. Average follow-up in the six "operated" patients was 29 months (range 12-108 months). All four patients treated by endoscopy, are symptom-free at follow-up, whereas the two who were approached by open surgery, are not. Clinical presentation, radiological evaluation and treatment modalities of pineal cysts are discussed and compared with experiences reported in the literature. It is concluded that pineal cysts in the presence of obstructive hydrocephalus are a clear indication for endoscopy with a rigid endoscope.

Severe primary immunodeficiencies (PID) are rare; their global incidence is comparable to that of childhood leukemia; they include more than 100 different entities. Clinical manifestations are: unusually severe or frequent infections or infections that do not respond to adequate treatment; an increased risk of certain malignancies; sometimes auto-immune manifestations. Delayed diagnosis and management of PID can lead to severe and irreversible complications or to death. PID can become manifest only in the adult; in common variable immune deficiency, the median age at diagnosis is between the 2nd and the 3rd decade of life. PID are often transmitted genetically; recent progresses in molecular biology have allowed more precise and earlier, including antenatal, diagnosis. Molecular treatment of 3 infants with a severe immunodeficiency has recently been achieved in April 2000. Those progresses were mostly based on the study of immunodeficiency databases. We present here the work of a Belgian group specialized in PID; meetings have started in June 1997. This group establishes guidelines for the diagnosis and treatment of PID, adapted to the local situation. The elaboration of a national register of PID is also underway; this has to provide all guaranties of anonymity to patients and families. Such a register already exists at the European level; it has provided the basis for new diagnostic and therapeutic possibilities. The inclusion of Belgian data in this register should allow essential progresses essential for our patients.

We present here the long-term results of three randomized clinical trials conducted on children with newly diagnosed acute lymphoblastic leukemia (ALL) between 1983 and 1998 by the Children Leukemia Cooperative Group (CLCG) from EORTC. In study 58831/32, the overall event-free survival (EFS) rates (+/- s.e.) at 6 and 10 years were 66% +/- 1.8% and 65% +/- 1.8%, respectively, and the risk of isolated central nervous system (CNS) relapse was 6% +/- 1% and 7% +/- 1%, respectively. In patients with a standard risk of relapse the omission of cyclophosphamide had no adverse effect on disease-free survival rates at 10 years (trial 58831). In medium- and high-risk patients the omission of radiotherapy did not increase the risk of CNS or systemic relapse (trial 58832). In study 58881 (1989-1998) the overall EFS rate at 8 years was 68.4% +/- 1.2% and the risk of isolated CNS relapse was 4.2%+/-0.5%. In this trial which adressed three randomized questions, the following results were obtained: the combination of cytarabine at high doses with methotrexate at high doses during interval therapy did not improve prognosis. The addition of 6-mercaptopurine iv during maintenance increased the risk of late relapse. E. coli asparaginase was more toxic and has a higher efficacy than Erwinia asparaginase. Leukocyte counts100 x 10(9)/l, specific genetic abnormalities, a poor initial response to steroids or a high level of minimal residual disease at early time points were consistently associated with an adverse prognosis in the 58881 trial.

We reviewed all unrelated donor bone marrow transplants (UDBMT) performed in Belgium up to December 1995 to identify prognostic factors for relapse, transplant-related mortality and survival.A total of 163 UDBMT were performed in 92 males and 71 females aged 1-55 (median 26) years. Patients were transplanted for ALL (n=35), AML (n=34), CML (n=51), other myeloid malignancies (n=14), SAA (n=21) or miscellaneous other diseases (n=8). Most patients had advanced disease; a few patients were in CR1 (n=10) or early chronic phase (CP) of CML (n=5).Overall survival at 5 yrs was 17% (95% confidence interval: 8-32%), but survival was significantly better for patients with non-malignant disorders (55% at 4 yrs). The relapse rate +/-SE was projected to be 40 (28-54)% at 5 yrs, 36 (20-56)% for standard-risk and 68 (43-85)% for high-risk malignancies (p=0.0029). There was no relapse in CML patients transplanted in 1st CP compared to 68% at 4 yrs with more advanced CML (p=0.0033). Grade II-IV acute graft-versus-host disease (aGVHD) occurred in 55% by day 100 and was strongly modulated by age, ranging from 41% in20-yr-old to 80% in40-yr-old patients (p=0. 0021). Transplant-related mortality (TRM) was projected to be 72 (52-87)% at 5 yrs including 2 very late deaths from lung fibrosis and secondary cancer. Main causes of death were original disease in 27, secondary malignancy in 2, GVHD in 28, interstitial pneumonia in 21, other infections in 19, and miscellaneous toxic causes in 21 patients. In multivariate analysis, the relapse rate was strongly dependent on the disease status (p=0.0029), TRM being significantly worse with older age (p=0.0049), and overall survival being significantly worse in more advanced disease (p=0.0006), after a second transplant (p=0.0166), in centers of smaller size (p=0.0316) and in older patients (NS).Although results have improved somewhat in recent years, UDBMT remains a procedure with a high TRM. UDBMT should be performed in patients with less advanced diseases and in centers with more experience, particularly in the treatment of adult patients.

Fifty patients affected by sickle cell anaemia underwent transplantation of HLA-identical haematopoietic stem cells (bone marrow, 48; cord blood, 2). Two groups of patients were considered for transplantation. Group 1 included 36 permanent residents of a European country who, retrospectively, met the inclusion criteria accepted at a consensus conference held in Seattle in 1990, wherein children were selected because they already had evidence of a morbid course. Group 2 included 14 patients who were transplanted earlier, had not received more than three blood transfusions and were transplanted because they had decided to return to their country of origin. Kaplan-Meier estimates of overall survival, event-free survival and disease-free survival at 11 years of the whole grafted population are 93, 82 and 85%, respectively. In group 1, overall survival, EFS and DFS were 88, 76 and 80% and in group 2, 100, 93 and 93%, respectively. Clinical manifestations of the disease, as well as disease associated haemolytic anaemia, disappeared in all successfully treated patients. Recovery of spleen function was present in seven out of 10 evaluated patients. Adverse events (death, absence of engraftment, mixed chimerism and relapse) occurred more frequently in group 1 than in group 2 (25% vs 7%, P< 0.001). Acute graft-versus-host disease (GVHD) was present in 20 patients (grade I or II, 19; grade III, 1), chronic GVHD in 10 (limited, 7; extensive, 3). One patient developed an acute myeloid leukaemia. Gonadal dysfunction was present in all patients (six boys and eight girls) transplanted close to or after puberty, although transient in one adolescent girl.

The objective of this study was to evaluate the feasibility, the toxicity and the efficiency of a BFM-like treatment protocol for acute nonlymphoblastic leukemia (ANLL) of children in which mitoxantrone was substituted for conventional anthracycline. The chemotherapy called for induction (mitoxantrone, cytosine arabinoside, etoposide), consolidation (mitoxantrone, cytosine arabinoside, 6 thioguanine), followed by two intensification courses with cytosine arabinoside plus, respectively, mitoxantrone during the first and etoposide during the second courses. Maintenance therapy consisted of daily 6 thioguanine, four-weekly courses of cytosine arabinoside (s.c. daily during 4 days) and eight-weekly courses of mitoxantrone. The latter drug was pursued up to a total cumulative dose of 150 mg/sqm. Maintenance therapy was stopped at 2 years of diagnosis. Out of 108 patients, 84 (77%) achieved a complete remission, 10 died during induction of hemorrhage, sepsis or pulmonary infiltration by leukemic cells. A total of 32 relapses occurred. The median follow-up was 3.5 years. Actuarial event-free survival, disease-free survival and overall survival at 3 years as 41%, 52%, 56%, respectively. These results compare favorably with most reported data, and cytogenetic findings appear to be the most important prognostic factor.

Tropisetron (Navoban(R), Sandoz Pharma Ltd., Basel, Switzerland), a selective antagonist of the serotonin receptor (5-HT3) dosed once-daily at 0.2 mg/kg (with a maximum of 5 mg daily), was evaluated in the prevention of chemotherapy-induced nausea and vomiting in 131 children with a median age of 5 years (age 10 weeks to 21 years). Acute lymphocytic leukemia was the most common malignancy (49%). Most children (82%) had received cytotoxic chemotherapy before enrollment. Patients received tropisetron during one or more courses of chemotherapy (455 courses in total). Tropisetron was administered slowly intravenously as a single dose before the start of chemotherapy on day 1 and intravenously or by mouth the subsequent days as a single daily dose (median treatment duration: 5 days). Response to tropisetron per 24 hour period on the first 5 days of each chemotherapy course was graded as complete (absence of both nausea and vomiting), partial (one to four vomits and/or less than 5 hours of nausea), or failure. Overall complete response on day 1 was observed in 305 out of 455 chemotherapy courses (67%). The patients receiving intravenous chemotherapy (N = 92) had a 70% complete response rate and a 26% partial response rate on day 1, both for course 1 and course 2. The percentage of complete responders increased the subsequent days of the course. Emesis after day 1 was observed primarily during courses with the most emetogenic chemotherapy. No side-effects of tropisetron other than a single case of diarrhoea were documented in this study. (C) 1995 Wiley-Liss, Inc.

We describe here a 3-year-old boy with juvenile chronic myelomonocytic leukemia and monosomy 7 who underwent a second HLA matched bone marrow transplant from his sister. He developed hypothyroidism due to acute suppurative thyroiditis in the recovery phase of BMT. This is an extremely rare complication of BMT.

A multicenter EORTC study was conducted in children with acute lymphocytic leukemia to determine whether 5 g/m2 of methotrexate (MTX) (24 h i.v. infusion, four cycles) is an appropriate dosage for obtaining CSF drug concentrations approaching the critical cytotoxic level of 10(-6) M. A total of 193 cycles were analyzed for 58 patients. At the end of the 24 h infusion, the mean MTX serum level was 65.27 +/- 33.11 microM; the mean CSF MTX level was 1.47 +/- 1.1 microM; no significant difference in CSF MTX levels was observed between patients with (n = 20) and those without i.v. Ara-C (n = 38). The mean CSF MTX/serum MTX ratio was 0.029 +/- 0.027. CSF drug concentrations greater than or equal to 10(-6) M were achieved in 81% of the courses. The highest level was 8.4 X 10(-6) M. Only 5% of patients failed to achieve this drug concentration in at least one cycle. No significant correlation was observed between blood and CSF MTX levels. Mean CSF MTX levels were comparable from one cycle to another.

Valproate at 0.1 to 5 mM strongly inhibited oxidation of 1-(14C)-palmitate in isolated rat hepatocytes. Valproate at the same concentrations markedly decreased ketogenesis from 1 mM oleate. Valproate in a dose up to 5 mM did not significantly affect cellular concentration of ATP but lowered beta-hydroxybutyrate/acetoacetate and lactate/pyruvate ratios which paralleled its effect on ketogenesis. Moreover concomitant acetyl-CoA levels were drastically decreased by valproate. From this it may be concluded that inhibition of fatty acid oxidation by valproate results in reduced production of two carbons units and a drop of NADH/NAD+ ratio in rat hepatocyte. This suggests that valproate seriously interferes with beta-oxidation of physiological long-chain fatty acids.

Summary Introduction The Evora chromium–cobalt alloy dual mobility socket claims to display a large articulation tribology different from that of stainless steel models, limiting the risk of intraprosthetic dislocation and wear. The present study reports a minimum of 10 years’ follow-up in a multicenter prospective series of 200 sockets previously reported on at 5 years. Hypothesis The use of chromium–cobalt in dual mobility sockets provides a low rate of failure at 10 years, especially as regards to osteolysis and intraprosthetic dislocation. Materials and methods Two hundred hydroxyapatite-coated molded chromium–cobalt sockets without titanium interface were implanted without cement in 194 patients with a mean age of 70 years (range, 32–91 years). Clinical results were assessed on Postel Merle d’Aubigne and Harris scores, plain radiographs and survival analysis. Results At a mean 11 years’ follow-up (10–13 years), 56 patients had died and 31 were lost to follow-up. Four underwent surgical revision (3 femoral components, and 1 socket for migration at 9 years with complete disappearance of the hydroxyapatite). A total of 109 implants were analyzable in 107 patients with a mean age of 81 years (55–93 years). At follow-up, the mean Harris score was 90 (75–96) and the PMA score 16.3 (14–18). There were no cases of loosening (except for the case reoperated on at 9 years) and no acetabular radiolucency or cysts. There were 2 cases of non-evolutive femoral radiolucency and 10 of femoral granuloma, involving head size > 22 mm ( P P = 0.004) as risk factors. There were no dislocations in the large or small articulation. Ten-year survival was 99% (95% CI: 97.3%–100%) with socket revision as censorship criterion. Discussion The absence of dislocation in both small and large articulations confirmed the efficacy of the dual mobility concept and suggested an advantage for chromium–cobalt sockets in reducing the rate of intraprosthetic dislocation and preventing blockage of the large articulation by a better performance in the friction couple. Granulomas were associated with wear in cemented titanium stems and with heads greater than 22 mm in diameter. Ten-year survival was 99% (censorship criterion: revision for socket failure); there was, however, one case of socket loosening with disappearance of the hydroxyapatite, indicating that surveillance should be continued in this cohort. Level of evidence Level IV. Retrospective study.

In 1981, 13 French and Belgian institutions started a clinical study using the German BFM protocol for the treatment of children with acute lymphoblastic leukemia (ALL). The objectives of the study were (a) to evaluate the feasibility and toxicity of this aggressive regimen, (b) to reevaluate the weight of the prognostic factors (number of circulating blasts, hepatomegaly, and splenomegaly) used for the classification of patients into different risk categories, and (c) to identify other possible prognostic features.

The authors report five cases of familial erythrophagocytic lymphohistiocytosis (F.E.L.H.). Two patients are brothers. One case is associated with a striking extramedullary hematopoiesis. A cytophotometric study of nuclear DNA in the histiocytes was performed in all cases. The histiocytes are diploid and there is no aneuploidy. These findings allow the authors to exclude the hypothesis of the tumoral nature of F.E.L.H. The data collected from the literature about the familial incidence of F.E.L.H. militate for an autosomal recessive transmission. The extramedullary hematopoiesis, which has not yet been reported in association with F.E.L.H., is probably due to the intense lymphohistiocytic infiltration of the bone marrow.

Two hundred and seventeen patients, 1-50 yr old, with acute lymphoblastic leukemia in complete remission were randomized to receive a 1-yr consolidation chemotherapy of either type P, comprising 7 different drugs, or type M, consisting of methotrexate interspersed with prednisone and vincristine. Thereafter, they were randomized a second time to receive a 4-yr maintenance of either chemotherapy or immunotherapy, comprised of allogeneic blasts and bacillus Calmette-Guérin (BCG). Consolidation P caused more toxicity than consolidation M. However, comparison between the consolidation therapies P and M showed no significant difference, neither for disease-free interval nor for duration of survival. Chemotherapy showed more lethal toxicity in adults than in children. Comparison between chemotherapy (C) and immunotherapy (I) as maintenance treatment showed a significant (p = 0.016) superiority of C for disease-free interval (DFI). The difference was even more pronounced (p = 0.009) in the group with less than 8 g/dl of hemoglobin (Hb) at diagnosis before therapy. On the other hand, for patients with more than 8 g/dl Hb at diagnosis, presumably those with T-ALL, no difference in DFI was seen. No difference has been seen so far between maintenance therapies I and C concerning the duration of survival. The patients who were receiving maintenance I when they relapsed and who were consequently retreated by chemotherapy, survived longer from relapse than those patients retreated for relapse while receiving maintenance C.