Prospective Hemophilia Inhibitor PUP Study reveals distinct antibody signatures during FVIII inhibitor eradication.

Factor VIII (FVIII) inhibitor formation is a major clinical concern during replacement therapy in patients with hemophilia A. Immune tolerance induction (ITI) is the only therapeutic approach to attempt inhibitor eradication and establishment of long-term immune tolerance to FVIII. Hemophilia Inhibitor Previously Untreated Patient (PUP) Study (HIPS) was a prospective clinical trial to investigate changes in the immune system of PUPs with severe hemophilia A. Five patients who developed persistent FVIII inhibitors during HIPS entered an ITI extension arm (HIPS-ITI). During HIPS-ITI, inhibitor patients received ITI with the same FVIII product (a single source of recombinant, human full-length FVIII) used in HIPS until successful tolerance, declared failure, or a maximum of 2 years after HIPS-ITI enrollment, whichever came first. Blood samples and clinical data were collected monthly. Longitudinal FVIII-binding antibody signatures, associated binding specificities, and apparent affinities were determined for each patient at each sampling time point. ITI was successful or partially successful in 2 patients and failed in 3. Both groups presented with distinct FVIII-specific antibody signatures. ITI success required the disappearance of FVIII inhibitors, which was associated with the eradication or sustained titer minimization of high-affinity FVIII-specific antibodies, particularly of the immunoglobulin G1 (IgG1) and IgG4 subclasses. In contrast, ITI failure, as reflected by FVIII inhibitor persistence, was associated with persistent high-affinity FVIII-specific antibodies. Interestingly, 1 patient with partial ITI success and 1 patient with ITI failure developed apparent oligoreactive FVIII-binding antibodies during ITI. The explanation of the true nature of these antibodies requires more comprehensive follow-ups in future studies. This trial was registered at www.clinicaltrials.gov as #NCT01652027.

A Prospective Observational Study of Antihemophilic Factor (Recombinant) Prophylaxis Related to Physical Activity Levels in Patients with Hemophilia A in the United States (SPACE).

INTRODUCTION: High collision-risk physical activity can increase bleeding risk in people with hemophilia A, as can increasing the time between factor VIII (FVIII) administration and physical activity. FVIII prophylaxis may be tailored to planned activities to prevent activity-related bleeding. AIM: To explore the relationship between physical activity levels, FVIII infusion timing, and occurrence of bleeding in patients with severe/moderately severe hemophilia A without FVIII inhibitors receiving antihemophilic factor (recombinant) (rAHF; ADVATE®; Baxalta US Inc., a Takeda company, Lexington, MA, USA). METHODS: SPACE was a 6-month, prospective, multicenter, observational outcomes study (NCT02190149). Enrolled patients received an eDiary application and a wearable activity tracker, which recorded physical activity, rAHF infusion, and occurrence of bleeding. Physical activity risks were ranked using National Hemophilia Foundation criteria. RESULTS: Fifty-four patients aged 11-58 years (n = 47 prophylaxis, n = 7 on-demand) were included in the analysis. Patients had a mean (SD) 8.14 (10.94) annualized bleeding rate, and recorded 4980 intervals between an rAHF infusion and physical activity; 1759 (35.3%) of these intervals were ≤24 hours. Analysis of recorded eDiary data showed that the risk of activity-related bleeding did not significantly increase with time between last infusion and activity, but did increase with higher-risk physical activities. Analysis of activity tracker recorded data showed that the risk of bleeding reported by patients as spontaneous increased with prolonging time (≤24 to >24 hours) from last infusion to physical activity start (odds ratio 2.65, p < 0.05). Joint health data collected at baseline were not included in the regression analysis because of small sample size; therefore the study could not assess whether patients with more joint disease at baseline were at higher risk of injury-related and reported spontaneous occurrence of bleeding. CONCLUSION: These results show that activities with a high risk of collision lead to an increased risk of bleeding. Further investigation is warranted to explore potential benefits of FVIII infusion timing to reduce the risks of activity-related occurrence of bleeding.

Blood's Concentration of Lead and Arsenic Associated with Anemia in Peruvian Children.

This exploratory, descriptive cohort study (N = 60) determined lead (Pb) and arsenic (As) blood concentrations in Peruvian children and their association with hematological parameters of iron-deficient anemia (IDA) and anthropometric measurement. The mean age of children was 10.8 months (SD = 4.7) and ranged from 3 to 24 months old. Anemia (Hb levels below 10.5 g/dL) was found in 20% of this cohort. Additionally, microcytosis (MCV < 70 fL) was present in 54%, and hypochromia (MCH < 23 pg) in 42% of the group of children. Chi-square analysis showed that 88% of the children with anemia also had microcytosis and hypochromia (p < 0.001). Pb and As were detected in 100% of the infants' blood samples, and the concentrations were significantly higher in older infants than in younger ones. Pb and As were not associated with the sex, anthropomorphic parameters, or infant hemogram changes. Infants who received iron supplementation were 87% less likely to have low Hb compared with those who did not (OR = 0.13, 95% CI = 0.02-0.88, p=0.04). Herbal tea intake was significantly associated with microcytosis and hypochromia. Our finding uncovered that hematological parameters for anemia are modified in Peruvian children with high levels of microcytosis and hypochromia. Concentrations of Pb and As were above method detection limits in all Peruvian children, but these were not associated with IDA or anthropometric measurements. A large study, including other variables, would benefit from allowing a more complex model predicting anemia in Peruvian children.

Spontaneous pyohaemothorax in a teenager with von Willebrand disease: a case report and review of literature.

An 18-year-old man with a history of type 3 von Willebrand disease (VWD) presented with a spontaneous pyohaemothorax. Type 3 VWD may present with both mucocutaneous and deep-seated bleeds, such as visceral haemorrhages, intracranial bleeds and haemarthrosis. There have been very few cases described in children of spontaneous pyohaemothorax. Management of this patient was challenging due to risks of bleeding following surgical drainage, requiring constant replacement with von Willebrand factor concentrate, while monitoring factor VIII levels to balance the risks of thrombosis.

Venous Thromboembolic Disease in Children and Adolescents.

The VTE is mainly a disease of the older adult, though its incidence has increased significantly in the pediatric population over the past several years. This trend is likely due to enhanced awareness and recognition of VTE, as well as increased prevalence of thromboembolic associated risk factors, such as increases in the proportion of children with predisposing medical conditions. The evaluation and management of a child with VTE is similar to that of adults, however pediatric patients have their own distinct aspects of care, stemming from particularities of the hemostatic system, age-related risk factors and differences in response to anticoagulant and antithrombotic therapy. This review addresses the risk factors and the evaluation and management of children with VTE.

A Pilot Study of Circulating Endothelial and Hematopoietic Progenitor Cells in Children With Sarcomas.

Utilizing a multiparametric flow cytometry protocol, we assessed various cell types implicated in tumor angiogenesis that were found circulating in the peripheral blood of children with sarcomas (cases) based on their cell surface antigen expression. Circulating endothelial cells (CECs), endothelial colony-forming cells (ECFCs), and the ratio of 2 distinct populations of circulating hematopoietic stem and progenitor cells (CHSPCs), the proangiogenic CHSPCs (pCHSPCs) and nonangiogenic CHSPCs (nCHSPCs) were enumerated. Multiparametric flow cytometry was analyzed in cases at baseline and at 4 additional timepoints until the end of treatment and levels compared with each other and with healthy controls. At all timepoints, cases had significantly lower levels of CECs, but elevated ECFCs and a pCHSPC:nCHSPC ratio compared with controls (all P-values <0.05). There was no significant difference in any of the cell types analyzed based on tumor histology, stage (localized vs. metastatic), or tumor size. After treatment, only the CECs among the complete responders were significantly lower at end of therapy (P<0.01) compared with nonresponders, whereas the ECFCs among all cases significantly increased (P<0.05) compared with baseline. No decline in the pCHSPC:nCHSPC ratio was observed despite tumor response. On the basis of these results, a validation of CECs as prognostic biomarker is now warranted.

Management of venous thrombosis in the pediatric patient.

The incidence of venous thromboembolism in children has increased significantly over the past decade. The evaluation and management of the child with venous thromboembolism, while based on the adult experience, has its own particularities dictated by the differences in the hemostatic system of the newborn and child. The current review addresses the evaluation of pediatric patient with thrombosis as well as the established and emerging treatment interventions.

A case report of hyperthyroid-associated thymic hypertrophy in a child, presenting as an anterior mediastinal mass.

We present the case of an 8-year-old boy with an anterior mediastinal mass and signs of hyperthyroidism. The anterior mediastinal mass had radiologic characteristics suggestive of thymic hypertrophy and regressed with antithyroid therapy. Though thymic hypertrophy is a known manifestation of hyperthyroidism, this is the youngest reported case. In selected cases, the diagnosis may be made based on the clinical picture, radiologic appearance, and response to antithyroid therapy without the need of a thymic biopsy or thymectomy.

Treatment of recurrent clear cell sarcoma of the kidney with brain metastasis.

BACKGROUND: Clear cell sarcoma of the kidney (CCSK) is known for its propensity to metastasize to bone, but it also spreads to other sites including the brain. This study was undertaken to describe the treatment and outcomes of patients with recurrent CCSK involving the brain. METHODS: A retrospective records review was conducted on eight patients with CCSK who developed brain metastases after complete responses to initial therapy. RESULTS: The recurrences occurred at a median of 24.5 months after initial diagnosis (range, 12-53 months). At the time of recurrence, patients were treated with multimodal therapy including biopsy or resection, radiation therapy, and chemotherapy. All patients received a variable number of courses of ifosfamide, carboplatin, and etoposide (ICE), with or without other agents. Four patients received high-dose chemotherapy with autologous stem cell rescue. One patient died from complications of bacteremia 8 weeks after starting chemotherapy. The other seven patients achieved a complete response after either surgery or ICE chemotherapy. Of these, six patients were alive without disease with a median follow-up of 30 months from the time of recurrence (range, 24 to 71 months). All six survivors received radiation therapy and four had gross total resections. Three survivors received high-dose chemotherapy with stem cell rescue. CONCLUSION: Patients with recurrent CCSK involving the brain can have durable survival after recurrence. ICE chemotherapy, together with radiation therapy and surgery, provides a reasonable salvage regimen for recurrent CCSK. It is unclear whether high-dose chemotherapy confers a benefit compared to conventional-dose chemotherapy.