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Allogeneic hematopoietic stem cell transplantation (SCT) contributes to improved outcome in childhood acute leukemia (AL). However, therapeutic options are poorly defined in the case of post-transplantation relapse. We aimed to compare treatment strategies in 334 consecutive children with acute leukemia relapse or progression after SCT in a recent 10-year period. Data could be analyzed in 288 patients (157 ALL, 123 AML and 8 biphenotypic AL) with a median age of 8.16 years at transplantation. The median delay from first SCT to relapse or progression was 182 days. The treatment consisted of chemotherapy alone (n=108), chemotherapy followed by second SCT (n=70), supportive/palliative care (n=67), combination of chemotherapy and donor lymphocyte infusion (DLI; n=30), or isolated reinfusion of donor lymphocytes (DLI; n=13). The median OS duration after relapse was 164 days and differed according to therapy: DLI after chemotherapy=385 days, second allograft=391 days, chemotherapy=174 days, DLI alone=140 days, palliative care=43 days. A second SCT or a combination of chemotherapy and DLI yielded similar outcome (hazard ratio (HR)=0.85, P=0.53) unlike chemotherapy alone (HR=1.43 P=0.04), palliative care (HR=4.24, P<0.0001) or isolated DLI (HR=1,94, P<0.04). Despite limitations in this retrospective setting, strategies including immunointervention appear superior to other approaches, mostly in AML.

We analyzed the impact of cytogenetics on 193 children enrolled in two successive French trials (LAME89/91 and ELAM02), who received hematopoietic stem cell transplantation during CR1. Detailed karyotype was available for 66/74 (89%) in LAME89/91 and 118/119 (99%) in ELAM02. Several karyotype and transplant characteristics differed according to therapeutic protocol: unfavorable karyotypes were more frequent in ELAM02 (36% vs 18%), pretransplant chemotherapy included high-dose cytarabine in ELAM02 and not in LAME89/91, IV replaced oral busulfan in the conditioning regimen, methotrexate was removed from post-transplant immunosuppression, and matched unrelated donor and cord blood transplantation were introduced. Five-year overall survival (OS) was 78.2% in LAME89 and 81.4% in ELAM02. OS was significantly lower for the unfavorable cytogenetic risk group in LAME89/91 when compared with intermediate and favorable groups (50% vs 90.6 and 86.4%, P=0.001). This difference was no longer apparent in ELAM02 (80.9% vs 71.3% and 5/5, respectively). Survival improvement for children with unfavorable karyotype was statistically significant (P=0.026) and was due to decrease in relapse risk. Five-year transplantation-related mortality was 6.75% in LAME89/91. In ELAM02, it was 3.2% for patients with a sibling donor and 10.9% with an unrelated donor or cord blood. We conclude that the outcome of children with unfavorable karyotype transplanted in CR1 has improved.

L’inhibition du facteur de croissance endothélial vasculaire A ou de ses récepteurs fait maintenant partie de l’arsenal thérapeutique du traitement du cancer. Cependant, les résultats sont encore modestes, notamment en raison de la multitude et de la redondance des facteurs stimulant l’angiogenèse tumorale. On peut espérer que des thérapies ciblant la cellule endothéliale elle-même pourraient être plus efficaces. Les tétraspanines sont des molécules transmembranaires qui sont dépourvues d’activité enzymatique intrinsèque mais peuvent s’associer entre elles et avec d’autres molécules comme les intégrines ou des protéines de la superfamille des immunoglobulines pour former un réseau. Les tétraspanines sont présentes à la surface des cellules endothéliales et l’inhibition in vitro de ces molécules par des anticorps ou des petits ARN interférents suggère que les tétraspanines jouent un rôle dans l’angiogenèse. Ces premières données ont été confirmées par l’étude de xénogreffes de cellules cancéreuses à des souris déficitaires en tétraspanines, qui présentent une angiogenèse tumorale diminuée ainsi qu’une diminution significative de la taille de la tumeur. In vivo, il a été montré que l’administration intraveineuse d’un anticorps monoclonal (ALB6) dirigé contre la tétraspanine CD9 diminue la croissance et l’angiogenèse tumorale et que l’injection intravitréenne d’un petit ARN interférant avec le CD9 diminue de façon significative la néovascularisation choroïdale induite par laser. Enfin, des effets anti-angiogéniques et antitumoraux puissants sont observés par l’administration intra-péritonéale de GS-168AT2, un peptide dérivé du CD9-Partner 1, molécule appartenant à la superfamille des immunoglobulines, qui interagit fortement avec le CD9 et le CD81. Ces différentes données suggèrent que la modulation pharmacologique du réseau des tétraspanines constitue une nouvelle stratégie anti-angiogénique prometteuse.

The aim of this paper is to emphasize the studies carried out for the new generation hydrazine pump system in term of nonlinear control in order to simplify the existing controllers that have been designed for this system. It consists of a classical PID structure based on a nonlinear feedback function which allows having a simple control input on the device. Our purpose is thus to implement a relatively simple controller on the new hydrazine pump to make it reliable and cost-effective.

Overexpression of RhoA in cancer indicates a poor prognosis, because of increased tumor cell proliferation and invasion and tumor angiogenesis. We showed previously that anti-RhoA small interfering RNA (siRNA) inhibited aggressive breast cancer more effectively than conventional blockers of Rho-mediated signaling pathways. This study reports the efficacy and lack of toxicity of intravenously administered encapsulated anti-RhoA siRNA in chitosan-coated polyisohexylcyanoacrylate (PIHCA) nanoparticles in xenografted aggressive breast cancers (MDA-MB-231). The siRNA was administered every 3 days at a dose of 150 or 1500 µg/kg body weight in nude mice. This treatment inhibited the growth of tumors by 90% in the 150-µg group and by even more in the 1500-µg group. Necrotic areas were observed in tumors from animals treated with anti-RhoA siRNA at 1500 µg/kg, resulting from angiogenesis inhibition. In addition, this therapy was found to be devoid of toxic effects, as evidenced by similarities between control and treated animals for the following parameters: body weight gain; biochemical markers of hepatic, renal, and pancreatic function; and macroscopic appearance of organs after 30 days of treatment. Because of its efficacy and the absence of toxicity, it is suggested that this strategy of anti-RhoA siRNA holds significant promise for the treatment of aggressive cancers.

Cerivastatin is used in the treatment of hypercholesterolemia to inhibit 3-hydroxy 3-methylglutaryl coenzyme A reductase and thus prevent the synthesis of cholesterol precursors, such as farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), responsible, respectively, for translocation of Ras and Rho to the cell membrane, a step required for their cell signaling, leading to cell proliferation and migration. Recently, it has been suggested that non lipid-related effects of statins could play a beneficial role in cancer therapy. In this study, we have investigated the mechanisms by which statins inhibit cancer and the types of cancers which could benefit from this therapy. In MDA-MB-231 cells, an aggressive breast cancer cell line with spontaneous activation of Ras and NFkappaB and overexpression of RhoA, cerivastatin induced inhibition of both cell proliferation and invasion through Matrigel. This anti-proliferative effect was related to G(1)/S arrest due to an increase in p21(Waf1/Cip1). The anti-invasive effect was observed from 18 h and could be explained by RhoA delocalization from the cell membrane, resulting in disorganization of the actin fibers and disappearance of focal adhesion sites. The importance of RhoA inactivation in both these inhibitory effects was proved by their reversion by GGPP but not by FPP. Moreover, cerivastatin was also shown to induce inactivation of NFkappaB, in a RhoA inhibition-dependent manner, resulting in a decrease in urokinase and metalloproteinase-9 expression, two proteases involved in cell migration. The participation of Ras inactivation is considered a subsidiary mechanism for the effects of cerivastatin, as they were not rescued by FPP. Prolonged treatment of MDA-MB-231 cells with high doses of cerivastatin induced a loss of cell attachment. Interestingly, the effect of cerivastatin was considerably lower on poorly invasive MCF-7 cells. In conclusion, our results suggest that cerivastatin inhibits cell signaling pathways involved in the invasiveness and metastatic properties of highly invasive cancers.

Two new species belonging to the new genus Rivillina are described from two Ordovician sites in the Armorican Massif: R. schallreuteri sp. nov. (the type species) at Les Tanneries in the Domfront syncline from the lower part of the Pissot Formation (mid-Arenigian), and R. henningsmoeni sp. nov. at Laille in the Martigne-Ferchaud synclinorium from the lower part of the Traveusot Formation (Llanvirnian). At present, the systematic position of Rivillina is uncertain. It could have affinities with the order Bradoriida sensu stricto; alternatively, it may belong to the family Circulinidae Netskaya 1966 (suborder Binodicopina Schallreuter 1972; Order Beyrichiocopida Pokorny 1953).

Summary Different ratios of normal human plasma concentrations to fetal bovine serum concentrations have been tested on the in vitro proliferation of pluripotent hematopoietic progenitors. The slight modifications of the culture procedure described here resulted in significant enhancement of BFU-e formation whereas no significant differences in the formation of CFU-e, CFU-meg, CFU-gm, and CFU-mix were observed.

Autologous peripheral blood stem cells (PBSCs) are frequently used to reconstitute hematopoiesis following administration of megatherapy in children with advanced stage IV neuroblastoma. Some centers prefer the use of autografts enriched for CD34+ progenitor cells because the positive selection procedure is believed to reduce indirectly tumor cell contamination. In this study, we monitored the efficiency of tumor cell purging following CD34 selection in PBSCs from seven patients with advanced neuroblastoma by using a highly sensitive reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. Amplification of tissue-specific mRNA transcript of tyrosine hydroxylase gene with nested primers enabled the detection of residual neuroblastoma cells with a sensitivity of one malignantcell per 10⁶ normals. Using this method, contaminating tumor cells were detected in seven of nine leukapheresis products of the patients. After positive immunoselection of CD34+ cells on Ceprate™ column, only one of nine enriched stem cell fraction still contained tumor cells detectable by RT-PCR. In six cases, PCR positive PBSCs became PCR negative after selection. We conclude that tumor cell contamination may be frequently detected in PBSC harvests of stage IV neuroblastoma patients by sensitive molecular analysis. The load of contaminating malignant cells might be reduced following CD34 selection. Med. Pediatr. Oncol. 30:228–232, 1998. © 1998 Wiley-Liss,Inc.

Summary: Thirty-three families of indivduals with a history of spina bifida, with myelomeningocele were studied. Each member was HLA typed and had a spinal X-ray. The incidence of spina bifida occulta, and laminal asymmetry of the lumbo-sacral spine in sibs and parents is high. No association between these abnormalities the HLA system was found.

Thirty-three families of indivduals with a history of spina bifida, with myelomeningocele were studied. Each member was HLA typed and had a spinal X-ray. The incidence of spina bifida occulta, and laminal asymmetry of the lumbo-sacral spine in sibs and parents is high. No association between these abnormalities the HLA system was found.

Actinomycosis of the skull and/or the vertebral colum is extremely rare in previously healthy children and its diagnosis is difficult. A case is reported here involving the occipital bone and the atlas. The disease had started 4 years before diagnosis and presented as a neurosurgical affection in a 13-year-oldgirl. The disease spread towards the retropharyngeal space and probably disseminated to the liver and the lung. Actinomyces israeli grew from cultures. Antibiotic treatment was successful.