An EORTC Phase II study of caspofungin as first-line therapy of invasive aspergillosis in haematological patients.

OBJECTIVES: Caspofungin was evaluated as first-line monotherapy of invasive aspergillosis (IA) in patients with haematological malignancies and undergoing autologous transplants. METHODS: Adults with proven or probable IA, defined strictly according to EORTC-MSG criteria, were eligible. Those with possible IA were enrolled, but were not evaluable for efficacy unless upgraded to proven/probable disease within 7 days of registration based on investigations performed within 48 h after enrolment. Caspofungin dosage was 70 mg (day 1) followed by 50 mg/day. The primary endpoint was the proportion of patients with complete or partial response at the end of caspofungin therapy in the modified intention to treat (MITT) group; secondary endpoints were response and survival at day 84 and safety. RESULTS: In the MITT group (n = 61), 75% of patients had cancer not in remission (relapsing or refractory), 85% were neutropenic at enrolment and 49% had a Karnofsky score of < or =50. At end of treatment, 1 and 19 patients had complete and partial response, respectively [success rate 33% (20/61)], 9 (15%) achieved stabilization and 31 (51%) had disease progression. One patient was not evaluable. The 6 and 12 week survival rates were 66% (40/61) and 53% (32/60), respectively. Baseline characteristics associated with survival at day 84 were an underlying disease in remission (not relapsing or refractory) and Karnofsky score. Recovery from neutropenia at the end of treatment was also significantly associated with survival. No serious drug-related adverse events or discontinuations due to drug-related adverse events were observed. CONCLUSIONS: Caspofungin provided an observed response rate compatible with the null hypothesis of a true response rate of < or =35%. Underlying disease-related factors had a major impact on results.

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The hematopoietic stem cell (HSC) is probably the best characterized somatic stem cell and is still the only one regularly used in clinical practice. Nevertheless, expansion of HSCs in vitro has been surprisingly unsuccessful, limiting their full therapeutic potential. During homeostasis, the vast majority of HSCs are found in the bone marrow (BM) localized to specific microenvironments called stem cell "niches." Over the last few years our knowledge of cellular niche components and the signaling molecules that coordinate the crosstalk between HSCs and niche cells has dramatically increased. Here we review the two main niche types found in the BM: the endosteal and the vascular niches, and provide an overview of the different signaling and cell adhesion molecules that form the HSC-niche synapse. Signals from BM niches not only control HSC dormancy, but also regulate the balance between self-renewal and differentiation. In the future, successful expansion of HSCs for therapeutic use will require three-dimensional reconstruction of a stem cell-niche unit.

L'ostéolyse expansive familiale : manifestations otologiques et dentaires d'origine génétique

RESUME Nous rapportons l'étude d'une famille de 49 membres sur 5 générations. Parmi 35 membres étudiés, 18 sont atteints d'Osteolyse Expansive Familiale (OEF). L'OEF est une dysplasie osseuse génétique rare, autosomique dominante, dont les altérations locales et générales du squelette ont une distribution périphérique prédominante qui devient manifeste à partir de la deuxième décennie de vie. Une résorption ostéoclastique progressive, accompagnée d'une faible activité ostéoblastique, est à l'origine d'une expansion médullaire osseuse. Cette dernière est caractérisée par une raréfaction de la moelle osseuse qui est remplacée par du tissu fibreux et de la graisse. L'amincissement de la moelle osseuse aboutit à des déformations invalidantes, sévères et douloureuses du squelette, avec tendance aux fractures spontanées. La première manifestation clinique de la maladie est une surdité de transmission très précoce résultant d'une lyse de la chaîne ossiculaire. Radiologiquement, il existe toujours une pneumatisation marquée de la mastoïde et du rocher. Les dents montrent des signes importants de résorption osseuse au niveau de la région apicale et/ou du collet, dont l'aspect est caractéristique et unique. La phosphatase alcaline sérique, l'hydroxyproline et la deoxypiridoline urinaire sont élevées à des taux variables. Le taux de calcium et d'hormone parathyroïdienne est normal. Le traitement par les diphosphonates, la calcitonine et la vitamine D est inefficace. Histologiquement, l'OEF présente des similitudes avec la maladie de Paget, mais l'âge de début, la distribution des lésions osseuses, les altérations dentaires et de l'oreille moyenne, ainsi que la progression clinique sont différents. Il en va de même pour la dysplasie fibreuse, l'ostéite fibro-kystique et l'ostéogénèse imparfaite. Le gêne responsable de la maladie se localise dans la région du chromosome 18q21-22. Récemment, des mutations du TNFRSF 11A, gêne qui codifie le RANK, ont été identifiées comme étant la cause de l'OEF. La duplication de la 18ème paire de base au niveau de l'exon 1 suggère qu'il correspond au site de l'anomalie. La technique chirurgicale et les résultats audiométriques à court et long terme de 13 interventions chez 8 patients sont présentés. ABSTRACT Objectives: Familial Expansive Osteolysis (EEO) is a rare autosomal dominant bone dys¬plasia. The disease can show general and focal skeletal alterations, the latter having a pre¬dominantly peripheral distribution. Onset occurs after the second decade of life. Patients and methods: We present the study, of 30 years, of a family consisting of 49 members covering five generations. Results: Among the 35 members studied, 18 have familial expansive osteolysis (FEO). The first clinical sign of the condition is transmission deafness at an early age. The features of the teeth has a unique and characteristic appearance. Thinning of the corti¬cal bone leads to severe, painful, disabling deformities. Serum alkaline phosphatase, and urinary hydroxyproline and deoxipyridinoline are elevated. Calcium and parathyroid hor¬mone are normal. Treatment with diphosphonates, calcitonin and vitamin D has been unsuccessful. We present the surgical technology and the results to short and long term of 13 interventions on 8 patients. Conclusion: Progressive osteoclastic reabsorption accompanied by weak osteoblastic activ¬ity results in medullary expansion characterized by rarefaction of the bone marrow, which is replaced by fibrous tissue and fat. FE0 is histologically similar to Paget disease, but the age of onset, the distribution of the bone lesions, the dental and middle ear alterations, and the clin¬ical progression are different. These features also differentiate FE0 from fibrous dysplasia, fibrocystic osteitis and imperfect osteogenesis. The gene responsible for EEO is located in the 18q21-22 chromosome region. Mutations in TNFRSF11A, the gene encoding receptor activa¬tor of nuclear factor-kappa-B (RANK), has been recently identified as the cause of FEO. A duplication of 18 base pairs in exon 1 of the TNFRSF11A gene suggests that this corresponds to the site of the anomaly and can be considered a "hot spot" for mutations.