The genomic landscape of rare disorders in the Middle East.

BACKGROUND: Rare diseases collectively impose a significant burden on healthcare systems, especially in underserved regions, like the Middle East, which lack access to genomic diagnostic services and the associated personalized management plans. METHODS: We established a clinical genomics and genetic counseling facility, within a multidisciplinary tertiary pediatric center, in the United Arab Emirates to locally diagnose and manage patients with rare diseases. Clinical genomic investigations included exome-based sequencing, chromosomal microarrays, and/or targeted testing. We assessed the diagnostic yield and implications for clinical management among this population. Variables were compared using the Fisher exact test. Tests were 2-tailed, and P < .05 was considered statistically significant. RESULTS: We present data on 1000 patients with rare diseases (46.2% females; average age, 4.6 years) representing 47 countries primarily from the Arabian Peninsula, the Levant, Africa, and Asia. The cumulative diagnostic yield was 32.5% (95% CI, 29.7-35.5%) and was higher for genomic sequencing-based testing than chromosomal microarrays (37.9% versus 17.2%, P = 0.0001) across all indications, consistent with the higher burden of single gene disorders. Of the 221 Mendelian disorders identified in this cohort, the majority (N = 184) were encountered only once, and those with recessive inheritance accounted for ~ 62% of sequencing diagnoses. Of patients with positive genetic findings (N = 325), 67.7% were less than 5 years of age, and 60% were offered modified management and/or intervention plans. Interestingly, 24% of patients with positive genetic findings received delayed diagnoses (average age, 12.4 years; range 7-37 years), most likely due to a lack of access to genomic investigations in this region. One such genetic finding ended a 15-year-long diagnostic odyssey, leading to a life-threatening diagnosis in one patient, who was then successfully treated using an experimental allogenic bone marrow transplant. Finally, we present cases with candidate genes within regions of homozygosity, likely underlying novel recessive disorders. CONCLUSIONS: Early access to genomic diagnostics for patients with suspected rare disorders in the Middle East is likely to improve clinical outcomes while driving gene discovery in this genetically underrepresented population.

Pediatric immune deficiencies: current treatment approaches.

PURPOSE OF REVIEW: To summarize the currently available definitive therapies for patients with inborn errors of immunity (IEIs) with a strong focus on recent advances in allogeneic hematopoietic cell transplantation (HCT) and gene therapy, including the use of alternative donors, graft manipulation techniques, less toxic approaches for pretransplant conditioning and gene transfer using autologous hematopoietic stem cells. RECENT FINDINGS: In the absence of a matched sibling or a matched related donor, therapeutic alternatives for patients with IEIs include alternative donor transplantation or autologous gene therapy, which is only available for selected IEIs. In recent years, several groups have published their experience with haploidentical hematopoietic cell transplantation (HHCT) using different T-cell depletion strategies. Overall survival and event free survival results, although variable among centers, are encouraging. Preliminary results from autologous gene therapy trials with safer vectors and low-dose busulfan conditioning have shown reproducible and successful results. Both strategies have become valid therapeutic options for patients with IEIs. A new promising and less toxic conditioning regimen strategy is also discussed. SUMMARY: Definitive therapies for IEIs with HCT and gene therapy are in stage of evolution, not only to refine their efficacy and safety but also their reach to a larger number of patients.

Anti-plasma cell treatment in refractory autoimmune hemolytic anemia in a child with multivisceral transplant.

BACKGROUND: Warm-antibody AIHA is known to complicate solid organ (SOT) and HSCT, the disease maybe refractory to standard therapy. Immunosuppressive therapies as well as IVIG, and rituximab have been the main stay of treatment. Over the past decade, B-lymphocyte targeted, anti-CD-20 antibody has been recognized in the treatment of autoimmune diseases and utilized in AIHA. Bortezomib, a proteasome inhibitor that causes apoptosis of plasma cells, is an appealing targeted therapy in secondary AIHA and has demonstrated efficacy in HSCT patients. From our experience, we advocate for early targeted therapy that combines B cell with plasma cell depletion. CASE REPORT: We describe a 4-year-old-girl with stage III neuroblastoma, complicated with intestinal necrosis needing multivisceral transplant developed warm AIHA 1-year after transplantation, and following an adenovirus infection. She received immunoglobulin therapy, rituximab, sirolimus, plasmapheresis, and long-term prednisolone with no sustained benefit while developing spinal fractures related to the latter therapy. She received bortezomib for intractable AIHA in combination with rituximab with no appreciable adverse effects. Three years later the child remains in remission with normal reticulocyte and recovered B cells. In the interim, she required chelation therapy for iron overload related to blood transfusion requirement during the treatment of AIHA. CONCLUSION: We propose early targeted anti-plasma cell therapy with steroid burst, IVIG, rituximab, and possible plasmapheresis may reduce morbidity in secondary refractory w-AIHA.

The impact of donor total estimated blood volume on nucleated cell yield in bone marrow harvests for hematopoietic stem cell transplantation.

BACKGROUND: Nucleated cell yields of marrow harvests depend on factors related to donors, the procedure itself, and the volume of marrow harvested. Few attempts have been made to relate donor characteristics to harvest volume. We hypothesize that the percentage of total donor blood volume accessed for harvesting impacts the nucleated cell yield per ml of marrow collected. METHODS AND MATERIALS: We investigated 481 consecutive unrelated marrow harvests from a single center. Donor characteristics including weight, body mass index (BMI), white blood cells (WBCs), hemoglobin (Hgb), and platelet counts, as well as estimated total blood volume, were recorded and compared with nucleated cell yields and harvest volumes. RESULTS: The percentage of donor blood volume accessed for marrow harvesting was inversely related to nucleated cell yields (r = -0.57). The donor-recipient weight differential impacted cell yields as well (r = 0.35), with heavier recipients requiring increased marrow volumes from smaller donors to satisfy their nucleated cell needs. 3.73 × 108 /kg of recipient weight could be collected with 95% certainty when harvest volumes did not exceed 16.1% of donor total blood volume. In a stepwise multiple regression analysis, 45.4% of cell yield variance was explained by blood volume percentage accessed for harvesting, donor weight, and WBC. Donor sex, BMI, and platelet counts did not contribute further to cell yield variance. Smokers had higher cell yields than nonsmokers (20.4 vs. 18.3 × 106 /ml; 95% confidence interval 0.62, 3.47) independent of other parameters. CONCLUSION: Establishing the relationship between percentage of estimated donor total blood volume and recipient cell needs can facilitate donor selection for successful hematopoietic cell (HPC) transplants.

Case Report: Fatal Complications of BK Virus-Hemorrhagic Cystitis and Severe Cytokine Release Syndrome Following BK Virus-Specific T-Cells.

BK virus (BKV)-hemorrhagic cystitis (HC) is a well-known and rarely fatal complication of hematopoietic stem cell transplantation (HSCT). Treatment for BKV-HC is limited, but virus-specific T-cells (VST) represent a promising therapeutic option feasible for use posttransplant. We report on the case of a 16-year-old male with dedicator of cytokinesis 8 (DOCK8) deficiency who underwent haploidentical HSCT complicated by severe BKV-HC, catastrophic renal hemorrhage, and VST-associated cytokine release syndrome (CRS). Gross hematuria refractory to multiple interventions began with initiation of posttransplant cyclophosphamide (PT/Cy). Complete left renal arterial embolization (day +43) was ultimately indicated to control intractable renal hemorrhage. Subsequent infusion of anti-BK VSTs was complicated by CRS and progressive multiorgan failure, with postmortem analysis confirming diagnosis of hepatic sinusoidal obstruction syndrome (SOS). This case illustrates opportunities for improvement in the management of severe BKV-HC posttransplant while highlighting rare and potentially life-threatening complications of BKV-HC and VST therapy.

Efficacy and feasibility of ruxolitinib in chronic steroid-refractory GVHD in a pediatric intestine transplant.

Acute graft-versus-host disease (GvHD) has been a clinical problem in solid organ transplant that includes intestine due to the donor lymphoid tissue mass which accompanies the intestinal component of the graft. We report a case that demonstrated the efficacy and feasibility of ruxolitinib a JAK 1/2 inhibitor in the treatment of chronic steroid-refractory GVHD (SR-GVHD). The child developed SR-GVHD following a composite intestine transplant (small bowel, colon, liver, and pancreas). And after receiving ruxolitinib 1.25 mg (0.15 mg/kg/dose) per gastric tube (G-tube) daily, the child appeared to have improved skin rash and sigmoidoscopy was negative. Nonetheless, we encourage close monitoring of hematologic and infectious adverse effect during dose escalation, and individualizing patient maximum effective dose with the least adverse effect possible. We stress the importance of early diagnosis and hyper-alertness of GVHD in intestinal transplant patients.

Successful long-term outcome after combined hematopoietic stem cell transplantation and small bowel transplantation: A case report and review of the literature.

Combining HSCT with SOT is an unusual and challenging undertaking given the complexities of immune modulation, the need to balance comorbidities, and the cumulative potential for complications. Early life-threatening complications include infections and related effects, graft rejection, and GVHD can be expected to be increased especially if the HSCT is indicated for high-risk cases such as individuals with severe combined immune deficiency and SOT that includes an intestine graft. Herein, we report such a case. Our patient is unique as a long-term survivor. We review the literature and the features of our case, especially the timing of transplants and human leukocyte antigen matching for HSCT that resulted in a successful outcome and discuss how this may be applied to others in the future.

Management of intracranial hemorrhage in severe factor V deficiency and definitive treatment with liver transplantation.

FV is primarily produced in the liver, and congenital FV deficiency is a disorder with an incidence of one in 1 million. Standard care is to treat severe bleeding phenotypes with FFP as there is no recombinant or plasma-derived FV concentrate. We present a case of a neonate with known severe FV deficiency diagnosed after prolonged bleeding after circumcision who represented at age 2 months with a large left intraparenchymal hemorrhage. His bleed was treated with FFP, platelet transfusion, recombinant VIIa, and emergent evacuation. He was maintained on plasma infusions but was unable to space his infusions beyond 48 hours. Liver transplantation was considered as a definitive treatment for this condition. While awaiting a suitable liver, his FV trough levels occasionally dropped below 5%, and he suffered from a second acute intracranial bleed. He received an orthotopic liver transplant at age 5 months, resulting in correction of his FV levels. He has not required any plasma infusions post-transplantation and has had no further bleeding episodes. Liver transplantation should be considered as definitive treatment early in the course for patients with severe FV deficiency and first time life-threatening bleed.

Safety, Tolerability, and Pharmacokinetics of Liposomal Amphotericin B in Immunocompromised Pediatric Patients.

The safety, tolerability, and pharmacokinetics of the liposomal formulation of amphotericin B (L-AMB) were evaluated in 40 immunocompromised children and adolescents. The protocol was an open-label, sequential-dose-escalation, multidose pharmacokinetic study with 10 to 13 patients in each of the four dosage cohorts. Each cohort received daily dosages of 2.5, 5.0, 7.5, or 10 mg of amphotericin B in the form of L-AMB per kg of body weight. Neutropenic patients between the ages of 1 and 17 years were enrolled to receive empirical antifungal therapy or treatment of documented invasive fungal infections. The pharmacokinetic parameters of L-AMB were measured as those of amphotericin B by high-performance liquid chromatography and calculated by noncompartmental methods. There were nine adverse-event-related discontinuations, four of which were related to infusions. Infusion-related side effects occurred for 63 (11%) of 565 infusions, with 5 patients experiencing acute infusion-related reactions (7.5- and 10-mg/kg dosage levels). Serum creatinine levels increased from 0.45 ± 0.04 mg/dl to 0.63 ± 0.06 mg/dl in the overall population (P = 0.003), with significant increases in dosage cohorts receiving 5.0 and 10 mg/kg/day. At the higher dosage level of 10 mg/kg, there was a trend toward greater hypokalemia and vomiting. The area under the concentration-time curve from 0 to 24 h (AUC0-24) values for L-AMB on day 1 increased from 54.7 ± 32.9 to 430 ± 566 µg · h/ml in patients receiving 2.5 and 10.0 mg/kg/day, respectively. These findings demonstrate that L-AMB can be administered to pediatric patients at dosages similar to those for adults and that azotemia may develop, especially in those receiving ≥5.0 mg/kg/day.

Population Pharmacokinetics of Liposomal Amphotericin B in Immunocompromised Children.

Liposomal amphotericin B (LAmB) is widely used in the treatment of invasive fungal disease (IFD) in adults and children. There are relatively limited pharmacokinetic (PK) data to inform optimal dosing in children that achieves systemic drug exposures comparable to those of adults. Our objective was to describe the pharmacokinetics of LAmB in children aged 1 to 17 years with suspected or documented IFD. Thirty-five children were treated with LAmB at doses of 2.5 to 10 mg kg-1 daily. Samples were taken at baseline and at 0.5- to 2.0-h intervals for 24 h after receipt of the first dose (n = 35 patients) and on the final day of therapy (n = 25 patients). LAmB was measured using high-performance liquid chromatography (HPLC). The relationship between drug exposure and development of toxicity was explored. An evolution in PK was observed during the course of therapy, resulting in a proportion of patients (n = 13) having significantly higher maximum serum concentrations (Cmax) and areas under the concentration-time curve from 0 to 24 h (AUC0-24) later in the course of therapy, without evidence of drug accumulation (trough plasma concentration accumulation ratio of <1.2). The fit of a 2-compartment model incorporating weight and an exponential decay function describing volume of distribution best described the data. There was a statistically significant relationship between mean AUC0-24 and probability of nephrotoxicity (odds ratio, 2.37; 95% confidence interval, 1.84 to 3.22; P = 0.004). LAmB exhibits nonlinear pharmacokinetics. A third of children appear to experience a time-dependent change in PK, which is not explained by weight, maturation, or observed clinical factors.

Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia.

BACKGROUND: Silent cerebral infarcts are the most common neurologic injury in children with sickle cell anemia and are associated with the recurrence of an infarct (stroke or silent cerebral infarct). We tested the hypothesis that the incidence of the recurrence of an infarct would be lower among children who underwent regular blood-transfusion therapy than among those who received standard care. METHODS: In this randomized, single-blind clinical trial, we randomly assigned children with sickle cell anemia to receive regular blood transfusions (transfusion group) or standard care (observation group). Participants were between 5 and 15 years of age, with no history of stroke and with one or more silent cerebral infarcts on magnetic resonance imaging and a neurologic examination showing no abnormalities corresponding to these lesions. The primary end point was the recurrence of an infarct, defined as a stroke or a new or enlarged silent cerebral infarct. RESULTS: A total of 196 children (mean age, 10 years) were randomly assigned to the observation or transfusion group and were followed for a median of 3 years. In the transfusion group, 6 of 99 children (6%) had an end-point event (1 had a stroke, and 5 had new or enlarged silent cerebral infarcts). In the observation group, 14 of 97 children (14%) had an end-point event (7 had strokes, and 7 had new or enlarged silent cerebral infarcts). The incidence of the primary end point in the transfusion and observation groups was 2.0 and 4.8 events, respectively, per 100 years at risk, corresponding to an incidence rate ratio of 0.41 (95% confidence interval, 0.12 to 0.99; P=0.04). CONCLUSIONS: Regular blood-transfusion therapy significantly reduced the incidence of the recurrence of cerebral infarct in children with sickle cell anemia. (Funded by the National Institute of Neurological Disorders and Stroke and others; Silent Cerebral Infarct Multi-Center Clinical Trial ClinicalTrials.gov number, NCT00072761, and Current Controlled Trials number, ISRCTN52713285.).

Improved survival after transplantation of more donor plasmacytoid dendritic or naïve T cells from unrelated-donor marrow grafts: results from BMTCTN 0201.

PURPOSE: To characterize relationships between specific immune cell subsets in bone marrow (BM) or granulocyte colony-stimulating factor-mobilized peripheral blood (PB) stem cells collected from unrelated donors and clinical outcomes of patients undergoing transplantation in BMTCTN 0201. PATIENTS AND METHODS: Fresh aliquots of 161 BM and 147 PB stem-cell allografts from North American donors randomly assigned to donate BM or PB stem cells and numbers of transplanted cells were correlated with overall survival (OS), relapse, and graft-versus-host disease (GvHD). RESULTS: Patients with evaluable grafts were similar to all BMTCTN 0201 patients. The numbers of plasmacytoid dendritic cells (pDCs) and naïve T cells (Tns) in BM allografts were independently associated with OS in multivariable analyses including recipient and donor characteristics, such as human leukocyte antigen mismatch, age, and use of antithymocyte globulin. BM recipients of > median number of pDCs, naïve CD8(+) T cells (CD8Tns), or naïve CD4(+) T cells (CD4Tns) had better 3-year OS (pDCs, 56% v 35%; P = .025; CD8Tns, 56% v 37%; P = .012; CD4Tns, 55% v 37%; P = .009). Transplantation of more BM Tns was associated with less grade 3 to 4 acute GvHD but similar rates of relapse. Transplantation of more BM pDCs was associated with fewer deaths resulting from GvHD or from graft rejection. Analysis of PB grafts did not identify a donor cell subset significantly associated with OS, relapse, or GvHD. CONCLUSION: Donor immune cells in BM but not PB stem-cell grafts were associated with survival after unrelated-donor allogeneic hematopoietic stem-cell transplantation. The biologic activity of donor immune cells in allogeneic transplantation varied between graft sources. Donor grafts with more BM-derived Tns and pDCs favorably regulated post-transplantation immunity in allogeneic hematopoietic stem-cell transplantation.

Associated risk factors for silent cerebral infarcts in sickle cell anemia: low baseline hemoglobin, sex, and relative high systolic blood pressure.

The most common form of neurologic injury in sickle cell anemia (SCA) is silent cerebral infarction (SCI). In the Silent Cerebral Infarct Multi-Center Clinical Trial, we sought to identify risk factors associated with SCI. In this cross-sectional study, we evaluated the clinical history and baseline laboratory values and performed magnetic resonance imaging of the brain in participants with SCA (HbSS or HbSß° thalassemia) between the ages of 5 and 15 years with no history of overt stroke or seizures. Neuroradiology and neurology committees adjudicated the presence of SCI. SCIs were diagnosed in 30.8% (251 of 814) participants who completed all evaluations and had valid data on all prespecified demographic and clinical covariates. The mean age of the participants was 9.1 years, with 413 males (50.7%). In a multivariable logistic regression analysis, lower baseline hemoglobin concentration (P < .001), higher baseline systolic blood pressure (P = .018), and male sex (P = .030) were statistically significantly associated with an increased risk of an SCI. Hemoglobin concentration and systolic blood pressure are risk factors for SCI in children with SCA and may be therapeutic targets for decreasing the risk of SCI. This study is registered at www.clinicaltrials.gov as #NCT00072761.

Donor transmission of pineoblastoma in a two-yr-old male recipient of a multivisceral transplant: a case report.

Transplant-transmitted malignances are rare but devastating events. Primary brain tumors are the least common among reported donor-derived malignancies. We report a case of donor-transmitted pineoblastoma, a PNET, in a two-yr-old male recipient, who presented with a rapidly growing mass in the right mandible, four months after multiple visceral organ transplantation. The recipient had liver, pancreas, and small bowel transplants because of end-stage liver failure and short gut syndrome, which was secondary to large bowel resection for management of gastroschisis complicated by intestinal volvulus. The donor autopsy results became available seven wk after transplantation, which found a pineoblastoma with meningeal spread. Evaluation of eyes, adrenal glands, bone marrow, and other organs did not identify metastasis outside the CNS. A biopsy of the recipient's right mandibular mass revealed a malignant small round blue cell tumor with the immunohistochemistry profile of a PNET. Staging evaluation revealed the tumor in the right mandible with bone marrow involvement. Further investigation showed that recipient's tumor and donor's pineoblastoma shared the same immunophenotype and HLA type, suggesting the recipient's tumor is a donor-transmitted pineoblastoma. This is the first case report of donor-transmitted pineoblastoma post-organ transplant.

Primary treatment of zygomycosis with liposomal amphotericin B: analysis of 28 cases.

Lipid formulations of amphotericin B are increasingly used in lieu of deoxycholate amphotericin B for primary treatment of zygomycosis, but little is known about the efficacy of the former antifungal in treating this fungal disease. We therefore undertook an analysis of a case series of all patients with zygomycosis who received L-AMB for primary antifungal therapy in five major mid-Atlantic medical centers. Among the categories of variables studied were demographics, methods of diagnosis, microbiology, sites of infection, global responses, and survival. The median patient age was 44 years and 71% were male. Immunosuppressive hematological disorders (54%) were the most common underlying condition. Pulmonary disease constituted 50% of infections, sinus infection 29%, and cutaneous disease 18%. Members of the genus Rhizopus were the most common recovered agents. Success as defined by complete or partial positive response was noted in 32% of the cases. Concomitant surgery was performed in 46% of the cases, with similar response rates (31%). Overall survival was 39%. L-AMB was effective as primary therapy in only some patients in this cohort of highly immunocompromised individuals with invasive zygomycosis underscoring the importance of host response and the need for further advances for treatment of this lethal infection.

Wnt10b induces chemotaxis of osteosarcoma and correlates with reduced survival.

BACKGROUND: Osteosarcoma (OS) is a primary malignant tumor of the bone that typically presents in the second decade of life and has a poor prognosis, especially in metastatic cases. Wnt signaling contributes to the pathogenesis of tumors such as colon cancer and malignant melanoma. Wnt signaling controls normal bone formation during embryogenesis and homeostasis in adult organisms, thus we evaluated Wnt signaling in OS. PROCEDURE: We surveyed the expression of Wnts, their receptors, Frizzleds and LRPs, and soluble Wnt inhibitors (sFRPs) in four OS cell lines by RT-PCR. We also tested biological response of OS cell lines to exogenous Wnts by measuring beta-catenin stabilization, Dvl phosphorylation, TOPFLASH activity and chemotaxis. Human OS tumor microarrays were evaluated for expression of Wnt10b by immunohistochemistry. RESULTS: All cell lines tested showed expression of at least three Wnts and one Frizzled. Exogenous Wnt3a and Wnt10b treatment induced Dvl phosphorylation, beta-catenin stabilization and TCF4 transcriptional activity in both metastatic and non-metastatic murine OS cell lines. Metastatic OS cell lines showed better chemotaxis response to Wnts than the non-metastatic OS cell lines. Immunohistochemistry studies of 44 human OS samples demonstrated that Wnt10b expression correlated with decreased overall survival. CONCLUSIONS: These results further supports a possible autocrine or paracrine Wnt pathway in metastatic potential of OS.

Hypercalciuria is the main renal abnormality finding in Human Immunodeficiency Virus-infected children in Venezuela.

Kidney involvement in children with Human Immunodeficiency Virus (HIV) infection is increasing in prevalence in parallel with the longer survival of HIV-infected patients and the side-effects of new antiretroviral drugs. However, there are only a few reports describing renal tubular disorders in HIV+ children. This is a cross-sectional, case series study evaluating kidney disease in 26 Venezuelan HIV-infected children. The study cohort consisted of 15 girls and 11 boys, with a median age of 5.9 years (25-75th percentile: 3.6-7.8), who had been treated with antiretrovirals for 2.8 +/- 0.4 years, Overall, the patients were short for their age and gender (Z-height: -3.1; 25-75th percentile: -4.94 to -1.98), and 15 showed signs of mild to moderate malnutrition. All of the children had a normal estimated glomerular filtration rate (136 +/- 22.6 ml/min/1.73 m2), and glomerular involvement was only observed in one patient with isolated proteinuria. None had nephromegaly. In contrast, tubular disorders were commonly found. Hypercalciuria was detected in 16 of the patients (UCa/Cr = 0.28; 25-75th percentile: 0.17-0.54 mg/mg), with five of these showing crystalluria. Eight children showed hyperchloremia, and three had frank metabolic acidosis. Kidney stones were absent in all, but one boy had bilateral medullary nephrocalcinosis. Conclusion, in Venezuelan children, HIV infection per se, or its specific treatment, was commonly associated with renal tubular dysfunction, especially hypercalciuria and acidosis, potentially leading to nephrocalcinosis and growth impairment. We recommend renal tubular evaluation during the follow-up of children with HIV infection.

Safety and pharmacokinetics of intravenous anidulafungin in children with neutropenia at high risk for invasive fungal infections.

Anidulafungin is an echinocandin with activity against Candida species and Aspergillus species. Adult dosages under study are 50 mg/day for esophageal candidiasis and 100 mg/day for invasive candidiasis and aspergillosis. Little is known, however, about the safety and pharmacokinetics of anidulafungin in children. A multicenter, ascending-dosage study of neutropenic pediatric patients was therefore conducted. Patients were divided into two age cohorts (2 to 11 years and 12 to 17 years) and were enrolled into sequential groups to receive 0.75 or 1.5 mg/kg of body weight/day. Blood samples were obtained following the first and fifth doses. Anidulafungin was assayed in plasma, and pharmacokinetic parameters were determined. Safety was assessed using National Cancer Institute (NCI) common toxicity criteria. Pharmacokinetic parameters were determined for 12 patients at each dosage (0.75 mg/kg/day or 1.5 mg/kg/day). Concentrations and drug exposures were similar for patients between age cohorts, and weight-adjusted clearance was consistent across age. No drug-related serious adverse events were observed. One patient had fever (NCI toxicity grade of 3), and one patient had facial erythema, which resolved with slowing the infusion rate. Anidulafungin in pediatric patients was well tolerated and can be dosed based on body weight. Pediatric patients receiving 0.75 mg/kg/day or 1.5 mg/kg/day have anidulafungin concentration profiles similar to those of adult patients receiving 50 or 100 mg/day, respectively.

Treatment of immune thrombocytopenic purpura in children : current concepts.

Treatment of immune thrombocytopenic purpura (ITP), the most common bleeding disorder of childhood, is a controversial subject for most practitioners. Diagnosis and management of ITP has historically been based primarily on expert opinion rather than on evidence. Due to a paucity of carefully conducted clinical trials in children, the management of ITP varies widely, ranging from observation only, to aggressive management with intravenous immunoglobulin (IVIG), intravenous anti-D rhesus (Rh)0 immunoglobulin (IV RhIG), corticosteroids, and splenectomy. To address the controversies, the American Society of Hematology (ASH) and the British Society for Hematology (BSH) have developed ITP practice guidelines. These guidelines, based on expert opinion, differ in their recommendations for treatment. The ASH guidelines favor therapy based on a low platelet count, and the more current BSH guidelines recommend a more conservative 'wait and watch' approach. In addition to treating children with severe bleeding symptoms, there is a tendency (not evidence based) to treat early in order to prevent a life-threatening bleeding episode, including intracerebral hemorrhage. Corticosteroids are a highly effective therapy, inexpensive, and can usually increase the platelet count within hours to days. However, chronic or prolonged use is associated with toxicity. In the US, based on the knowledge of known toxicities of corticosteroids, as well as the efficacy of alternative treatments (IV RhIG, IVIG), many pediatricians prefer to treat with IVIG and IV RhIG, reserving corticosteroid treatment for serious bleeding or refractory disease. However, in the UK, for the most part, corticosteroids are used as first-line therapy in children with ITP. Splenectomy is rarely indicated in children except for those with life-threatening bleeding and chronic, severe ITP with impairment of quality of life. For children who develop chronic or refractory ITP, immunosuppressive drugs and/or chemotherapy agents may offer some promise. However, the long-term effects of these drugs in children are unknown and they should not be considered unless there is unequivocal evidence that the patient is refractory to IV RhIG, IVIG, and corticosteroids. To date, virtually all of the randomized clinical trials conducted in children with ITP have focused on platelet counts as the sole outcome measure. Only carefully designed, multicenter, randomized clinical trials comparing the effects of different treatment modalities in terms of bleeding, quality of life, adverse effects, and treatment-related costs will be able to address the controversies surrounding childhood ITP treatment and allow management of this condition to be based on scientific data rather than treatment philosophy.

Post-transfusion purpura.

Post-transfusion purpura (PTP) is a rare bleeding disorder caused by alloantibodies specific to platelet antigens. The antibody against the human platelet alloantigen (HPA)-1a is responsible for most of the cases. The majority of affected patients are multiparous women who presumably have been previously sensitized during pregnancy. Blood transfusions rarely have been implicated as the primary cause for alloimmunization in PTP. Thrombocytopenia is usually severe and resolves spontaneously within several weeks. However, patients may develop severe if not fatal bleeding during the course of this disease. The diagnosis is confirmed by demonstrating that the patient's serum contains antibodies to platelet-specific antigens. Treatments for PTP include intravenous immunoglobulin, corticosteroids, and plasmapheresis.