Pharmacology, Efficacy and Safety of a Triple-Secured Fibrinogen Concentrate in Children Less than or Equal to 12 Years with Afibrinogenaemia.

OBJECTIVE: To date, the use of a fibrinogen concentrate (FC) administered in children with inherited fibrinogen deficiency is poorly documented. Treatment modalities may differ from those of adults. The aim of this study was to investigate the pharmacokinetics (PK), efficacy (bleeding/surgery) and safety of a triple-secured FC (FibCLOT, LFB, France) in young patients aged of 12 years or less. METHODS: This was a prospective, non-comparative, multicentre, phase 2-3 study. Estimated PK parameters were based on population PK modelling. Target fibrinogen levels were 1.2 and 1.0 g/L for major and minor events, respectively. In vivo recovery (IVR) was calculated at study entry to tailor the dose. RESULTS: Sixteen afibrinogenaemia patients were treated with FC: 12 included in the PK study (6 aged ≤ 6 years and 6 aged 7-12 years). IVR at 1 hour post-infusion (geometric mean [coefficient of variation]) was 1.91 [20%] mg/dL per mg/kg and results were similar between the two age groups (1.87 [14%]) and (1.96 [27%]) with no statistical differences. Estimated half-life (t 1/2) was 49.0 hours [12%] with no observed differences between groups (46.6 hours [10%] and 51.6 hours [12%]). Overall efficacy was rated as excellent/good in 96.9% of 32 bleeds and in 100% of 11 surgeries. Most of the events (39/43, 90.7%) were managed with one infusion. There was no serious adverse drug reaction. CONCLUSION: Individually tailored dosing was efficacious in children who exhibited a lower IVR and shorter t 1/2 than those previously reported in adolescent and adult patients emphasising the importance of individualised dose optimisation.

Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination.

Axon pathfinding and synapse formation are essential processes for nervous system development and function. The assembly of myelinated fibres and nodes of Ranvier is mediated by a number of cell adhesion molecules of the immunoglobulin superfamily including neurofascin, encoded by the NFASC gene, and its alternative isoforms Nfasc186 and Nfasc140 (located in the axonal membrane at the node of Ranvier) and Nfasc155 (a glial component of the paranodal axoglial junction). We identified 10 individuals from six unrelated families, exhibiting a neurodevelopmental disorder characterized with a spectrum of central (intellectual disability, developmental delay, motor impairment, speech difficulties) and peripheral (early onset demyelinating neuropathy) neurological involvement, who were found by exome or genome sequencing to carry one frameshift and four different homozygous non-synonymous variants in NFASC. Expression studies using immunostaining-based techniques identified absent expression of the Nfasc155 isoform as a consequence of the frameshift variant and a significant reduction of expression was also observed in association with two non-synonymous variants affecting the fibronectin type III domain. Cell aggregation studies revealed a severely impaired Nfasc155-CNTN1/CASPR1 complex interaction as a result of the identified variants. Immunofluorescence staining of myelinated fibres from two affected individuals showed a severe loss of myelinated fibres and abnormalities in the paranodal junction morphology. Our results establish that recessive variants affecting the Nfasc155 isoform can affect the formation of paranodal axoglial junctions at the nodes of Ranvier. The genetic disease caused by biallelic NFASC variants includes neurodevelopmental impairment and a spectrum of central and peripheral demyelination as part of its core clinical phenotype. Our findings support possible overlapping molecular mechanisms of paranodal damage at peripheral nerves in both the immune-mediated and the genetic disease, but the observation of prominent central neurological involvement in NFASC biallelic variant carriers highlights the importance of this gene in human brain development and function.

Clinical pharmacology, efficacy and safety study of a triple-secured fibrinogen concentrate in adults and adolescent patients with congenital fibrinogen deficiency.

Essentials A novel fibrinogen concentrate was evaluated in patients with congenital fibrinogen deficiency. An open-label, phase 2-3 trial studied pharmacology, efficacy, and safety in patients >6 years. The product offers safe and effective therapy in the treatment and prophylaxis of bleeding. Data in recovery show the need of adjusted treatment and further investigation in children. SUMMARY: Background Single-factor replacement therapy is considered the most suitable treatment option for hereditary fibrinogen deficiency. A triple-secured plasma-derived human fibrinogen product was developed to increase the safety of the former fibrinogen concentrate. Objectives This non-randomized, open-label, prospective study investigated pharmacokinetics, efficacy, and safety of a novel fibrinogen concentrate (FibCLOT® /CLOTTAFACT® LFB, France) in inherited deficiency. Patients/Methods Fourteen patients ≥40 kg received fibrinogen concentrate for pharmacology and 16 ≥ 23 kg received treatment for bleeding or surgery. Each treatment was followed by a 3-week safety observation period. Key outcomes included number of infusions, dose, bleeding control, daily assessment, hemoglobin, blood loss, transfusions, and physicians' global assessment of response. Results Incremental recovery was 2.35 mg mL-1  per mg kg-1 and maximal concentration 1.41 g L-1 (geometric mean) after 0.060 g kg-1 infusion in 14 afibrinogenemic patients. Terminal half-life was 69.3 h (non-compartmental analysis). The maximum clot firmness was increased by a mean of 10.3 mm from baseline to maximal effect. Sixteen patients participated to the efficacy phase: 32 bleeding episodes were treated in 9 patients, and 15 patients underwent 38 surgical/invasive procedures. All patients achieved appropriate hemostasis: response to treatment was successful in all bleeds (95% CI, 0.89-1.00) and procedures (95% CI, 0.91-1.00). Most (94%) bleeds were controlled with a single infusion (median 0.050 g kg-1 ). Two patients experienced asymptomatic distal venous thromboses identified by systematic ultrasound. Conclusion FibCLOT® /CLOTTAFACT® showed a pharmacokinetic profile comparable to that of other fibrinogen concentrates and provides safe and clinically effective substitution therapy for fibrinogen-deficient patients.

Time to diagnosis of pediatric brain tumors: a report from the Pediatric Hematology and Oncology Center in Rabat, Morocco.

OBJECTIVE: Delayed diagnosis of pediatric brain tumors is known to occur worldwide but is not well studied in developing countries. Here, we examined the extent of delayed pediatric brain tumor diagnoses in Rabat, Morocco, and consider its potential causes and possible solutions. METHODS: We conducted a survey and interviews of the parents of children who were admitted to the Department of Hematology and Pediatric Oncology of Rabat Children's Hospital from January 1, 2016 to June 30, 2016. RESULTS: The families of 27 patients (14 girls and 13 boys) participated in the survey and interview. The median patient age was 7 years (range, 1-15 years). The most common presenting symptoms were vomiting (n = 18) and headache (n = 17). The tumor locations were supratentorial in 13 cases and infratentorial in 14 cases. The median time to diagnosis was 2 months (range, 0.25-20 months). The longest times to diagnosis occurred in children older than 5 years and in patients with supratentorial tumors or low-grade glioma. We did not observe any differences in the time to diagnosis according to sex, socioeconomic status, or urban or rural origin. CONCLUSIONS: Delayed diagnosis of pediatric brain tumors is a universal problem, evidenced by many studies in different countries. We propose that a paradigm shift in medical curricula addressing the delayed diagnosis of pediatric brain tumors should occur in medical schools and clinical training programs.

Cytogenetic Profile of Moroccan Pediatric Acute Lymphoblastic Leukemia: Analysis of 155 Cases With a Review of the Literature.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common malignancy in children, with a peak incidence at 2 to 3 years of age and accounting for almost 30% of all cancers in this age group. It is well established that the identification of cytogenetic abnormalities is highly relevant for the prognosis of and therapeutic decisions in ALL. The purpose of the present study was to define the frequency of recurrent chromosomal abnormalities of ALL in Moroccan patients referred exclusively to the BIOLAB Laboratory of the Children's Hospital of Rabat during a 4-year period and compare our findings to the reported data. PATIENTS AND METHODS: We performed conventional karyotyping of 155 ALL cases, with a successful cell culture rate of 94%. RESULTS: We identified chromosomal abnormalities in 66% of the total studied cases, of which 70% revealed important recurrent abnormalities with high prognostic value, such as hyperdiploidy, hypodiploidy, t(9;22), t(8;14), t(1;19), and MLL rearrangements. In total agreement with the reported data, most of the patients (56%) in the present study were aged 1 to 5 years, with a male predominance, and B-ALL was the most common blast phenotype (85%). CONCLUSION: The frequency of most chromosomal rearrangements successfully identified in our study and their lineage correlated with those reported in the published data.

Von Willebrand's disease: case report and review of literature.

Von Willebrand Disease (VWD) is the most common human inherited bleeding disorder due to a defect of Von Willebrand Factor (VWF), which a glycoprotein crucial for platelet adhesion to the subendothelium after vascular injury. VWD include quantitative defects of VWF, either partial (type 1 with VWF levels < 50 IU/dL) or virtually total (type 3 with undetectable VWF levels) and also qualitative defects of VWF (type 2 variants with discrepant antigenic and functional VWF levels). The most bleeding forms of VWD usually do not concern type 1 patients with the mildest VWF defects (VWF levels between 30 and 50IU/dL). Von willebrand factor is a complex multimeric protein with two functions: it forms a bridge between the platelets and areas of vascular damage and it binds to and stabilizes factor VIII, which is necessary for the clotting cascade. By taking a clinical history of bleeding (mucocutaneous bleeding symptoms suggestive of a primary haemostatic disorder, a quantitative or qualitative abnormality of VWF is possible) it is important to think about VWD and to make the appropriate diagnosis. If the VWD is suspected diagnostic tests should include an activated partial thromboplastin time, bleeding time, factor VIII: C Ristocetin cofactor and vWF antigen. Additional testing of ristocetin induced plattlet adhesion (RIPA) the multimeric structure and collagen binding test and genanalysis allow diagnosing the different types of von. Willebrand Disease. The treatment of choice in mild forms is the synthetic agent desmopressin. In patients with severe type 1, type 2B, 2N and type 3 or in people who do not response to desmopressin, the appropriate treatment is a factor VIII concentrate that is rich of VWF. We report a case of infant in 27-month-old boy who had been referred due to haemorrhagic shock. His birth histories, his familie's social history and developmental milestones were unremarkable. He was born at full term with no antenatal or perinatal complications. Prior to the symptoms, the child was on a normal diet and was thriving appropriately. The child presented one days before his admission trauma to the inner face of the lower lip that caused an external acute bleeding loss. The laboratory data showed unfortunately, the most severe form of Von Willebrand's Disease; Type 3. The management was based on erythrocyte and fresh-frozen plasma (FFP) transfusions with administration of factor VII with good evolution.

[A hemophagocytic syndrome revealing a Griscelli syndrome type 2]. / Un syndrome d'activation macrophagique révélant un syndrome de Griscelli de type 2.

Griscelli syndrome type 2 is a rare autosomal recessive disorder, due to a mutation in RAB27A gene. It associates partial albinism, silver hair and immune deficiency. We report the case of a 6 year-old boy who was admitted to the Emergency department with severe sepsis complicated by hemophagocytic syndrome. Many clinical and biological criteria leads to the diagnosis of type 2 Griscelli syndrome: consanguineous family, recurrent infection, absence of psychomotor retardation, oculocutaneous albinism, silver hair, occurrence of hemophagocytic syndrome and especially the pathognomonic appearance on microscopic examination of the hair. The absence of giant organelles inclusion in all granulated cells eliminated Chediak-Higashi syndrome.

Pediatric rhabdomyosarcoma in Morocco.

BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in the first two decades of life. There is, however, a paucity of reports on the pattern of its occurrence in Africa. This study analyses the epidemiological pattern, clinical features, histology, and outcome in Moroccan children presenting with RMS. METHODS: We retrospectively studied 100 consecutive cases of histologically proven RMS in previously untreated children <15 years old followed at the Pediatric Oncology Unit of the Children's Hospital of Rabat from January 1995 to December 2004. RESULTS: RMS represented 5% of all the patients treated for cancer during this period. The male/female ratio was 2:1 with a mean age at diagnosis of 5 years. The embryonal subtype was the most frequent (73%) and the head and neck was the most common site of disease, followed by the genito-urinary tract and limbs. Chemotherapy was used in all patients; 44% also had a radical surgery and 23% radiation therapy. The event-free survival (EFS) at 10 years was 39% with relapse as the first cause of treatment failure. The overall survival at 10 years was 70%. The rate of treatment abandonment was 37%. CONCLUSION: Epidemiology and clinical features of RMS in Moroccan children does not differ from others countries. However, EFS is lower than that reported elsewhere due to occasional lack of availability of drugs, inadequate local control, and abandonment.