Combined therapy in children and adolescents with classical Hodgkin's lymphoma: A report from the SFCE on MDH-03 national guidelines.

Hodgkin's lymphoma (HL) in children and adolescents is highly curable, but children are at risk of long-term toxicity. The MDH-03 guidelines were established in order to decrease the burden of treatment in good-responder patients, and this report should be considered a step toward further optimization of treatment within large collaborative trials. We report the therapy and long-term outcomes of 417 children and adolescents treated according to the national guidelines, which were applied between 2003 and 2007 in France. The patients were stratified into three groups according to disease extension. Chemotherapy consisted of four cycles of VBVP (vinblastine, bleomycin, VP16, prednisone) in localized stages (G1/95 pts/23%), four cycles of COPP/ABV (cyclophosphamide, vincristine, procarbazine, prednisone, adriamycin, bleomycin, vinblastine) cycles in intermediate stages (G2/184 pts/44%) and three cycles of OPPA (vincristine, procarbazine, prednisone, adriamycin) plus three cycles of COPP in advanced stages (G3/138 pts/33%). Radiation therapy of the involved field was given to 97% of the patients, with the dose limited to 20 Gy in good responders (88%). With a median follow-up of 6.6 years, the 5-year event-free survival (EFS) and overall survival (OS) were 86.7% (83.1-89.7%) and 97% (94.5-98.1%), respectively. EFS and OS for G1, G2, and G3 were 98% and 100%, 81% and 97%, and 87% and 95%, respectively. Low-risk patients treated without alkylating agents and anthracycline had excellent outcomes and a low expected incidence of late effects. Intensification with a third OPPA cycle in high-risk group patients, including stage IV patients, allowed for very good outcomes, without increased toxicity.

High methotrexate exposure and toxicity in children with t(9;22) positive acute lymphoblastic leukaemia treated with imatinib.

WHAT IS KNOWN AND OBJECTIVE: Although there is one report on the possible reduced clearance of methotrexate in an adult patient when given concomitantly with imatinib, there is little information on the possible pharmacokinetic interaction. We report on three cases of delayed elimination of methotrexate in children with chromosome Philadelphia-positive acute lymphoblastic leukaemia treated concomitantly with imatinib. CASE SUMMARY: Three patients, aged 9-17 years, presented with high methotrexate blood levels following co-administration of imatinib and high-dose methotrexate. Two patients presented with clinical symptoms (nausea, epigastric pain and mucositis, acute renal failure, liver cytolysis). One patient required extra supplementary folinic acid doses than used in the standard protocol and one child required the use of carboxypeptidase-G2. WHAT IS NEW AND CONCLUSION: There is an apparent pharmacokinetic interaction between imatinib and methotrexate in children. Several mechanisms could explain this interaction, including competition for BCRP or ABCB transporters. Temporary withdrawal of imatinib may be necessary for preventing severe methotrexate-related adverse events.

Cost of complex abdominal wall reconstruction with biological prostheses in a French public hospital.

GOAL: Retrospective analysis of bioprosthetic abdominal wall reconstruction in our center with regard to expenses and reimbursement. PATIENTS AND METHODS: This study included all patients undergoing bioprosthetic abdominal wall reconstruction between 2009 and 2015. All costs were considered in determining the hospital expenditures. Next we compared the incoming revenue for each hospital stay based on disease-related groups (DRG) and additional daily hospital fees. RESULTS: Seventy-six patients underwent abdominal wall reconstruction, 67 of whom had economical data that were exploitable. On the average, our center lost €15,233 for every hospital stay associated with bioprosthetic abdominal wall reconstruction. The existing DRG system is not well adapted to provide adequate reimbursement for costs related to complex abdominal wall repairs, especially when post-operative morbidity leads to prolonged hospital stay and increased expenses. CONCLUSION: Abdominal wall repairs with bioprostheses are expensive and are poorly reimbursed in the French Health care system, mainly because they are often associated with complications that increase the costs considerably. In our opinion, it seems necessary that either reimbursement of this type of prosthesis should be higher than the current DRG allows, or that the DRG classification be redefined, or even, that a specific DRG be created for complex abdominal wall reconstruction.

MAGOS: multiple alignment and modelling server.

UNLABELLED: MAGOS is a web server allowing automated protein modelling coupled to the creation of a hierarchical and annotated multiple alignment of complete sequences. MAGOS is designed for an interactive approach of structural information within the framework of the evolutionary relevance of mined and predicted sequence information. AVAILABILITY: The web server is freely available at http://pig-pbil.ibcp.fr/magos.

[Disposable vs reusable laryngeal mask airway: a cost-minimization analysis]. / Masques laryngés à usage unique vs réutilisable : une étude de minimisation de coûts.

JUSTIFICATION: According to French regulations concerning the risk of Creutzfeldt-Jakob disease transmission, traceability procedures of all sterile medical devices which need to be reused are mandatory. Despite sterilization processes, the reusable laryngeal mask airway (LMA) prion disease transmission remains possible. As a result, the disposable LMA has been introduced. OBJECTIVE: Assuming clinical equivalence was achieved, the cost of disposable vs reusable LMA was studied in a university hospital. STUDY DESIGN: A Cost-minimization analysis of disposable vs reusable laryngeal mask airway was realised. METHODS: Disposable LMA cost was calculated as the sum of product cost and elimination cost. Reusable LMA were autoclaved after hospital purchasing in two separate sterilizing processing units of the same hospital. Reusable LMA cost was determined combining materiel and labor costs. RESULTS: The reusable LMA cost depended on the sterilizing processing unit concerned and varied between 9.59 Euros and 9.69 vs 8.38 Euros for the single-use LMA. CONCLUSION: With the cost savings made possible by use of disposable LMA in both labor and consumables, this practice should be considered.

Improved outcome of children transplanted for high-risk leukemia by using a new strategy of cyclosporine-based GVHD prophylaxis.

There is currently a major concern regarding the optimal immunosuppression therapy to be administered after hematopoietic stem cell transplantation (HSCT) to reduce both the toxicity of GvHD and the rate of relapse. We report the outcome of high-risk leukemia children transplanted with a new way of managing cyclosporine (CsA)-based GvHD prophylaxis. A total of 110 HSCT in 109 ALL or AML children who received CsA without mycophenolate or methotrexate in matched related as well as in matched or mismatched unrelated stem cell transplantation were included. CsA dosage regimens were individualized to obtain specific trough blood concentrations values. The incidences of grade I-II and III-IV acute GvHD were 69.1% and 1.8%, respectively, and 8.4% for chronic GvHD. GvHD was neither more frequent nor severe in unrelated than in related HSCT. GvHD occurred in 87% of patients with a mean CsA trough concentration ⩽120 ng/mL versus 43% with concentration >120 ng/mL (P<0.0001). Five-year disease-free survival (DFS) and overall survival were 78% and 83.6%, respectively. DFS was 76.9% for ALL and 80.4% for AML patients. There was no difference in DFS between matched siblings and matched unrelated or mismatched unrelated HSCT. DFS in patients with minimal residual disease (MRD) ⩾10(-3) and in those with MRD <10(-3) before SCT was comparable. Our results indicate that a GvHD prophylaxis regimen based on CsA without mycophenolate or methotrexate is safe and effective whatever the donor compatibility is. These results suggest that GvL effect may be enhanced by this strategy of GvHD prophylaxis.

Nonequilibrium fluctuations in a resistor.

In small systems where relevant energies are comparable to thermal agitation, fluctuations are of the order of average values. In systems in thermodynamical equilibrium, the variance of these fluctuations can be related to the dissipation constant in the system, exploiting the fluctuation-dissipation theorem. In nonequilibrium steady systems, fluctuations theorems (FT) additionally describe symmetry properties of the probability density functions (PDFs) of the fluctuations of injected and dissipated energies. We experimentally probe a model system: an electrical dipole driven out of equilibrium by a small constant current I, and show that FT are experimentally accessible and valid. Furthermore, we stress that FT can be used to measure the dissipated power P = R I2 in the system by just studying the PDFs' symmetries.

Antioxidant status (selenium, vitamins A and E) and aging.

Antioxidant status can be evaluated by blood selenium, vitamins A and E. The level of selenium was determined in whole blood, erythrocytes and plasma of 170 French people (70-95 years old) healthy and with intercurrent illness, by using PIXE (proton-induced X-ray emission analysis). These results are discussed with other values from the literature. Plasma levels of vitamins A and E have been measured by HPLC. All data were compared with those obtained for younger subjects. Healthy elderly people residing in a geriatric home received selenium supplements during 1 month. The influence of this supplementation brought to light a deficiency for this trace element. The correlation of aging and nutritional requirements with immune function, heart and cancer death rate is presented and discussed.

Nonlinear Transition to a Global Mode for Traveling-Wave Instability in a Finite box.

Using hydrothermal waves in a long narrow channel as an ideal supercritical nonlinear wave system, we study the critical behavior at onset for a finite cell with poorly reflecting boundaries. We observe a spatially nonuniform global eigenmode localized near the end of the cell and associated with a wave front invading the cell. The onset of this mode-corresponding to the absolute instability transition-is shifted above the value corresponding to convective instability, measured in an annular channel with periodic boundary conditions. Experimental critical exponents are discussed in the framework of existing theoretical descriptions and quantitative comparison with the complex Ginzburg-Landau model is attempted.

Correlated motions and propagation of the effect of a local conformational change in the transmembrane helix of the c-erb B2 encoded protein and its V659E mutant, studied by molecular dynamics simulations.

A detailed study of the dynamical behavior of the 29-residue peptide including the transmembrane domain of p185c-erbB2 oncogene-encoded protein and of its V659E mutant is presented. In a first part of this work we analyse equal time correlation coefficients between the backbone dihedral angle fluctuations. Concerted motions are observed in the wild type transmembrane alpha-helix but not in the corresponding V659E intramembrane domain. The difference observed in the correlation pattern is attributed to the single amino acid replacement. In a second part, we investigate the propagation of the effect of a local conformational change along the transmembrane segment, one of the dominant hypotheses for signal transduction mechanisms of transmembrane receptors. The analysis of angular time correlation functions together with that of the response of the different residues to a local disturbance applied at the N-terminal side evidences a propagation phenomenon for the wild type peptide. This effect is much less clear for the mutated peptide. Furthermore we show that the first one is much more flexible than the second one.

Molecular dynamics simulations of the ErbB-2 transmembrane domain within an explicit membrane environment: comparison with vacuum simulations.

Two 500-ps molecular dynamics simulations performed on the single transmembrane domain of the ErbB-2 tyrosine kinase receptor immersed in a fully solvated dilauroylphosphatidyl-ethanolamine bilayer (DLPE) are compared to vacuum simulations. One membrane simulation shows that the initial alpha helix undergoes a local pi helix conversion in the peptide part embedded in the membrane core similar to that found in simulation vacuum. Lipid/water/peptide interaction analysis shows that in the helix core, the intramolecular peptide interactions are largely dominant compared to the interactions with water and lipids whereas the helix extremities are much more sensitive to these interactions at the membrane interfaces. Our results suggest that simulations in a lipid environment are required to understand the dynamics of transmembrane helices, but can be reasonably supplemented by in vacuo simulations to explore rapidly its conformational space and to describe the internal deformation of the hydrophobic core.

Time resolved fluorescence properties of phenylalanine in different environments. Comparison with molecular dynamics simulation.

Time resolved fluorescence of the phenylalanine residue (Phe) alone and included in the transmembrane domain (TMD) sequences of the epidermal growth factor receptor (EGFR) and ErbB-2 was studied using the synchrotron radiation source of light, and compared to molecular dynamics (MD) simulations. The fluorescence intensity decay is strongly sensitive to the environment. A mono-exponential decay was obtained for Phe amino acid alone in two different solvents and for Phe included in EGFR transmembrane sequence, with fluorescence lifetime values varying from 1.7 ns (EGFR) to 7.4 ns (Phe dissolved in water). In ErbB-2 transmembrane sequence three lifetimes were detected. The relative amplitude of the shortest one (0.14 ns) is smaller than 10%, whereas the others (0.6 and 2.2 ns) are almost equally represented. They have been attributed to different rotamers exchanging slowly. This interpretation is supported by MD simulations which evidence transitions in time series of the chi 1 dihedral angle of Phe observed in the case of ErbB-2. The anisotropy decays are similar for both peptides and indicate the presence of a correlation time in the nanosecond range (1-4 ns) and the probable existence of a very fast one (< 0.05 ns). Autocorrelation functions computed from MD simulations corroborate these results.

Influence of a mutation in the transmembrane domain of the p185c-erbB2 oncogene-encoded protein studied by molecular dynamics simulations.

The c-erbB2 proto-oncogene encodes for a protein of 185kDa (p185) which becomes transforming upon the Val-->Glu transmembrane amino acid substitution. The transforming ability seems to be due to a substitution-resulting constitutive activation of the tyrosine kinase cytosolic domain of the protein. These observations prompted us to evaluate the structural and dynamical behavior of the transmembrane region of the wild and transforming p185 protein in order to understand the role of this region in the transduction mechanism. 160 ps molecular dynamics simulations in vacuo have been performed on two peptides corresponding to the sequence [651-679] of p185c-erbB2 protein and its transforming mutant Val659-->Glu659. These two sequences include the transmembrane domain and are initially postulated to be in an alpha-helix conformation. Noticeable differences in the flexibility of the two peptides are shown. The nontransforming sequence seems rather flexible and several conformational changes are detected at the junction of the mutation point [658-659] and at position Val665-Val666 during the 160 ps simulations. On the contrary, no transitions were observed for the mutated sequence which adopts a stable alpha-helix conformation. This difference in flexibility could be hypothesized as a factor involved in the regulation of the tyrosine kinase activity of p185c-erbB2.

Insight into signal transduction: structural alterations in transmembrane helices probed by multi-1 ns molecular dynamics simulations.

The hypothesis of structural alteration in transmembrane helices for signal transduction process is viewed by molecular dynamics simulation techniques. For the c-erbB-2 transmembrane domain involved in oncogenicity, the occurrence of conformational changes has been previously described as transition from the alpha to pi helix. This dynamical feature is thoroughly analyzed for the wild phenotype and oncogenic sequences from a series of 18 simulations carried out on one nanosecond time scale. We show that these structural events do not depend upon the conditions of simulations like force field or starting helix coordinates. We demonstrate that the oncogenic mutations Val659 Glu, Gln and Asp do not prevent the transition. Furthermore, we show that beta branched residues, in conjunction with Gly residues in the c-erbB-2 sequence, act as destabilizers for the alpha helix structure, pi deformations are tightly related to other local structural motifs found in soluble and membrane proteins. These structural alterations are discussed in term of structure-activity relationships for the c-erbB-2 activating mechanism mediated by transmembrane domain dimerization.

Analysis of time management in stroke patients in three French emergency departments: from stroke onset to computed tomography scan.

The aim of this study was to determine and identify the factors associated with shortening or lengthening time interval from stroke onset to performance of computed tomography (CT) scan in stroke patients admitted to three French emergency departments. All suspected stroke patients were eligible (n = 317). The time intervals between stroke onset and presentation to the emergency department and between CT scan request and CT scan performance were determined. Twelve variables likely to influence time interval before presentation to the emergency department, and five variables likely to influence time interval before CT scan performance were evaluated using stepwise regression analysis. Of the 317 patients included in the study, the mean time interval from stroke onset to CT scan performance for 180 patients was 7 hours 46 minutes (466 minutes). The mean time interval between stroke onset and presentation to the emergency department was 4 hours 36 minutes (276 minutes), varying according to the study site, level of initial severity, medical contact before admission, witnesses at stroke onset, and mode of transportation. The mean time interval between request and CT scan performance was 2 hours 14 minutes (134 minutes), varying upon the site, hour of CT scan request, type of stroke and level of severity at admission. It is concluded that current delays in stroke management are often incompatible with early treatment. The public needs to be informed and admission procedures reorganized. Improved response to the urgency of ischaemic stroke is required as well as direct access to the scanner during periods of scheduled use.

Traditional midwives, tetanus immunization, and infant mortality in rural Haiti.

PIP: Lessons learned from Haiti's integration of a training program for traditional birth attendants with the maternal and child health and family planning program are reported. The available data on illness and deaths reveal that Haiti has continuing problems of gastroenteritis, malnutrition, tuberculosis, malaria, and tetanus. The latter is of particular interest since neonatal tetanus derived from umbilical cord contamination continues to affect up to 10-20% of Haitian newborns in rural areas lacking health programs. Neonatal tetanus has largely disappeared in the Artibonite Valley due to a mass immunization program for the entire population, including young women, against tetanus. In the Albert Schweitzer Hospital program for indigenous midwives in Artibonite Valley, at least 36 midwives were reached on a regular basis in 1968 -- less than 1/3 of the midwives operating in the Artibonite Valley. There was a rapid decline in neonatal tetanus admissions during the period following 1968. This decline has been attributed to the use of rural health auxiliaries in immunizing the women in the hospital district, but indigenous midwives may have played a role. By 1970, the Albert Schweitzer Hospital program had grown from 36 midwives regularly attending midwife classes to 175 registered with the program during 1970. Although direct supervision proved difficult due to lack of communication and transport to the scene of delivery, some deliveries were observed and indirect supervision by the community became evident. An important finding of the traditional midwife training program of the Albert Schweitzer Hospital was the amount of time required for an indigenous midwife to have referred 50 newborns to the hospital for BCG vaccination. At the end of the 1st year of this program, only 2 midwives reached this goal. Another surprise was the increase in demand for "cord cut" services at the outpatient clinic rather than increased use of the nearby maternity unit. The elimination of neonatal tetanus as a cause of infant mortality was the most important outcome of the maternal and child health component of the community health program.^ieng

[Association of Kaposi sarcoma--multiple myeloma. A new case]. / Association maladie de Kaposi--myélome multiple. Un nouveau cas.

INTRODUCTION: Kaposi's disease is an angiogenic multifocal cancer process that has several forms, namely Mediterranean, African, HIV-associated, and secondary to a preexisting immunodepressive state (hematological disorder, corticosteroid therapy, immunodepressive treatment). Whatever its form, Kaposi's sarcoma is probably associated with a chronic viral human herpes type 8 infection (HHV8). EXEGESIS: This virus has been implicated in the pathogenesis of multiple myeloma (17 cases recorded to date). In the present study, a further case of Kaposi's sarcoma associated with multiple myeloma has been reported. However, Epstein-Barr virus, cytomegalovirus, hepatitis B and C, HIV and HHV8 serologies were negative. Radiotherapy on the lower limbs was initiated. CONCLUSION: It is concluded that HHV8 does not appear to play a pathogenic role in cases of multiple myeloma, given the rarity of the association between Kaposi's sarcoma/multiple myeloma/HHV8.

[Lacidipine efficacy and safety for high blood pressure treatment in pediatric oncohematology]. / Efficacité et tolérance de la lacidipine dans le traitement de l'hypertension artérielle en onco-hématologie pédiatrique.

In adults, lacidipine seems to have no CYP3A4-inhibiting action. This particular characteristic makes it advantageous when combined with drugs metabolized by CYP3A4, such as cyclosporine. Until now, no data on the efficacy or safety of this calcium antagonist have been available in children. Thirty-nine hypertensive children (age: 0.13-14 years) receiving lacidipine in oncohematology for a mean of 75 days were included in this retrospective study. The causes of high blood pressure were renal tumor (n=7), catecholamine-secreting tumor (n=4), corticoid treatment (n=5), and cyclosporine treatment (n=23). An initial dosage of 0.05 mg/kg/day was sufficient for 41% of the patients. The remaining patients needed to increase the dosage, by steps of 0.03 mg/kg/day, until reaching an average effective dosage of 0.1 mg/kg/day. Lacidipine significantly decreased blood pressure by 30 (±14) mmHg for systolic blood pressure and by 26 (±13) mmHg for diastolic blood pressure. A medication plan with twice-daily administration was not significantly more effective than a single administration per day. Lacidipine was well tolerated, and no toxicity-related withdrawal of treatment occurred. For 22 patients treated with both cyclosporine and lacidipine, renal function was not disturbed over time, suggesting its preservation by lacidipine. No significant increase in cyclosporine blood concentration was detected. Lacidipine seems to be an effective calcium antagonist in pediatric oncohematology, is well tolerated, has a kidney-protector effect and no drug interaction when combined with cyclosporine.