ATP-Binding Cassette Transporter of Clinical Significance: Sideroblastic Anemia.

The ATP-binding cassette (ABC) transporters are a vast group of 48 membrane proteins, some of which are of notable physiological and clinical importance. Some ABC transporters are involved in functions such as the transport of chloride ions, bilirubin, reproductive hormones, cholesterol, and iron. Consequently, genetic or physiological disruption in these functions is manifested in various disease processes like cystic fibrosis, Tangier disease, and sideroblastic anemia. Among other etiologies, primary sideroblastic anemia results from a genetic mutation in the ATP-binding cassette-7 (ABCB7), a member of the ABC transporter family. There are not many articles specifically tackling the disease processes caused by ABC transporters in detail. Some testing methodologies previously reported in the available literature for investigating sideroblastic anemia need updating. Here, we expound on the relevance of ABCB7 as a clinically important ABC transporter and a rare participant in the disease process of Sideroblastic anemia. The other genetic and secondary etiologies of sideroblastic anemia, which do not involve mutations in the ABCB7 protein, are also described. We review the pathophysiology, clinical course, symptoms, diagnosis, and treatment of sideroblastic anemia with a focus on modern technologies for laboratory testing.

Rapid recognition and optimal management of hemophilia in the emergency department: A quality improvement project.

Objectives: This study aimed to assess the effectiveness of a continuous quality improvement initiative at the University of Florida Health Physicians practice in reducing the time to administer factor replacement therapy (FRT) for hemophilia patients presenting with bleeding in the emergency department (ED). Methods: The study, a quasi-experimental, interventional design, was conducted between January 2020 and January 2023. The intervention, implemented in September 2021, involved training ED physicians, creating a specialized medication order set within the electronic health record (EHR), and a rapid triage system. The effectiveness was measured by comparing the time from ED arrival to factor administration before and after the intervention and benchmarking it against the National Bleeding Disorders Foundation's Medical and Scientific Advisory Council (MASAC)-recommended 1-hour timeline for factor administration. An interrupted time series (ITS) analysis with a generalized least squares model assessed the intervention's impact. Results: A total of 43 ED visits (22 pre-intervention and 21 post-intervention) were recorded. Post-intervention, the average time from ED arrival to factor administration decreased from 5.63 to 3.15 hours. There was no significant increase (27% vs. 29%) in the patients receiving factor within 1-hour of ED arrival. The ITS analysis predicted a 20-hour reduction in the average quarterly time to administer factor by the end of the study, an 84% decrease. Conclusions: The quality improvement program decreased the time to administer FRT for patients with hemophilia in the ED. However, the majority of patients did not achieve the 1-hour MASAC-recommended timeline for factor administration after ED arrival.

Effectiveness of Virtual Reality in Reducing Perceived Pain and Anxiety Among Patients Within a Hospital System: Protocol for a Mixed Methods Study.

BACKGROUND: Within hospital systems, diverse subsets of patients are subject to minimally invasive procedures that provide therapeutic relief and necessary health data that are often perceived as anxiogenic or painful. These feelings are particularly relevant to patients experiencing procedures where they are conscious and not sedated or placed under general anesthesia that renders them incapacitated. Pharmacologic pain management and topical anesthetic creams are used to manage these feelings; however, distraction-based methods can provide nonpharmacologic means to modify the painful experience and discomfort often associated with these procedures. Recent studies support distraction as a useful method for reducing anxiety and pain and as a result, improving patient experience. Virtual reality (VR) is an emerging technology that provides an immersive user experience and can operate through a distraction-based method to reduce the negative or painful experience often related to procedures where the patient is conscious. Given the possible short-term and long-term outcomes of poorly managed pain and enduring among patients, health care professionals are challenged to improve patient well-being during medically essential procedures. OBJECTIVE: The purpose of this pilot project is to assess the efficacy of using VR as a distraction-based intervention for anxiety or pain management compared to other nonpharmacologic interventions in a variety of hospital settings, specifically in patients undergoing lumbar puncture procedures and bone marrow biopsies at the oncology ward, patients receiving nerve block for a broken bone at an anesthesia or surgical center, patients undergoing a cleaning at a dental clinic, patients conscious during an ablation procedure at a cardiology clinic, and patients awake during a kidney biopsy at a nephrology clinic. This will provide the framework for additional studies in other health care settings. METHODS: In a single visit, patients eligible for the study will complete brief preprocedural and postprocedural questionnaires about their perceived fear, anxiety, and pain levels. During the procedure, research assistants will place a VR headset on the patient and the patient will undergo a VR experience to distract from any pain felt from the procedure. Participants' vitals, including blood pressure, heart rate, and rate of respiration, will also be recorded before, during, and after the procedure. RESULTS: The study is already underway, and results support a decrease in perceived pain by 1.00 and a decrease in perceived anxiety by 0.3 compared to the control group (on a 10-point Likert scale). Among the VR intervention group, the average rating for comfort was 4.35 out of 5. CONCLUSIONS: This study will provide greater insight into how patients' perception of anxiety and pain could potentially be altered. Furthermore, metrics related to the operational efficiency of providing a VR intervention compared to a control will provide insight into the feasibility and integration of such technologies in routine practice. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/52649.

Recombinant von Willebrand factor prophylaxis in patients with severe von Willebrand disease: phase 3 study results.

International guidelines conditionally recommend long-term prophylaxis in patients with von Willebrand disease (VWD) and severe and frequent bleeding. As recombinant von Willebrand factor (rVWF; vonicog alfa) may reduce the frequency of treated spontaneous bleeding events (BEs), we investigated the efficacy and safety of rVWF prophylaxis in adults with severe VWD. Patients with BEs requiring VWF therapy in the past year (on-demand VWF therapy [prior on-demand group] or plasma-derived VWF prophylaxis [pdVWF; switch group]) were enrolled in a prospective, open-label, nonrandomized, phase 3 study. The planned duration of rVWF prophylaxis was 12 months; starting rVWF dose was 50 ± 10 VWF: ristocetin cofactor (VWF:RCo) IU/kg twice weekly (prior on-demand group) or based on prior pdVWF weekly dose/dosing frequency (switch group). The primary endpoint was annualized bleeding rate (ABR) of treated spontaneous BEs (sABR) during rVWF prophylaxis. Over the 12-month study period, treated sABR decreased by 91.5% on-study vs historical sABR in 13 patients in the prior on-demand group, and by 45.0% in 10 patients in the switch group (model-based analysis ratio, 0.085; 95% confidence interval [CI], 0.021-0.346 and 0.550; 95% CI, 0.086-3.523, respectively). No treated spontaneous BEs were recorded in 84.6% (11/13) and 70.0% (7/10) of patients, respectively. The safety profile of rVWF was consistent with the previously established profile, with no new adverse drug reactions identified. Findings suggest that rVWF prophylaxis can reduce treated spontaneous BEs in patients previously receiving on-demand VWF therapy and maintains at least the same level of hemostatic control in patients who switch from prophylaxis with pdVWF to rVWF, with a favorable safety profile. This trial was registered at www.clinicaltrials.gov (#NCT02973087) and www.clinicaltrialsregister.eu (#EudraCT 2016-001478-14).

Preclinical development of plant-based oral immune modulatory therapy for haemophilia B.

Anti-drug antibody (ADA) formation is a major complication in treatment of the X-linked bleeding disorder haemophilia B (deficiency in coagulation factor IX, FIX). Current clinical immune tolerance protocols are often not effective due to complications such as anaphylactic reactions against FIX. Plant-based oral tolerance induction may address this problem, as illustrated by the recent first regulatory approval of orally delivered plant cells to treat peanut allergy. Our previous studies showed that oral delivery of plant cells expressing FIX fused to the transmucosal carrier CTB (cholera toxin subunit B) in chloroplasts suppressed ADA in animals with haemophilia B. We report here creation of the first lettuce transplastomic lines expressing a coagulation factor, in the absence of antibiotic resistance gene. Stable integration of the CTB-FIX gene and homoplasmy (transformation of ˜10 000 copies in each cell) were maintained in both T1 and T2 generation marker-free plants. CTB-FIX expression in lyophilized leaves of T1 and T2 marker-free plants was 1.0-1.5 mg/g dry weight, confirming that the marker excision did not affect antigen levels. Oral administration of CTB-FIX to Sprague Dawley rats at 0.25, 1 or 2.5 mg/kg did not produce overt adverse effects or toxicity. The no-observed-adverse-effect level (NOAEL) is at least 2.5 mg/kg for a single oral administration in rats. Oral administration of CTB-FIX at 0.3 or 1.47 mg/kg either mixed in food or as an oral suspension to Beagle dogs did not produce any observable toxicity. These toxicology studies should facilitate filing of regulatory approval documents and evaluation in haemophilia B patients.

Bivalirudin and Alteplase for Pulmonary Embolism Requiring Veno-Arterial Extracorporeal Membrane Oxygenation in an Adolescent.

Saddle pulmonary embolism (PE) remains a challenge to diagnose and manage in pediatric patients. Current literature encourages early consideration of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) in high-risk PE patients with impending right ventricular failure. We present a 17-year-old patient who was admitted to a pediatric cardiac intensive care unit with saddle PE requiring emergent VA-ECMO support because of cardiovascular collapse. Despite anticoagulation with bivalirudin and receiving systemic thrombolysis with alteplase, the clot burden was persistent with minimal improvement in right ventricular function. We proceeded to catheter thrombolysis while on VA-ECMO. This ultimately led to a successful resolution of the PE and allowed for weaning off VA-ECMO. PE is rare in children compared with adults, and pediatricians may be unaware of therapies becoming increasingly used in adults such as the use of VA-ECMO, with systemic and local thrombolysis. The concurrent use of a direct thrombin inhibitor for ECMO anticoagulation alongside the thrombolysis is a novel combination in this condition and age-group.

Primary pulmonary artery sarcoma in the pediatric patient: Review of literature and a case report.

Primary pulmonary artery sarcoma (PAS) is extremely rare in children. Nevertheless, distinguishing primary PAS from pulmonary embolism is critical to a child's survival. Primary PAS is commonly misdiagnosed as a pulmonary embolism due to similar presenting symptoms and radiographic findings. However, compared to adults, pulmonary embolism is rare in children, especially in patients who do not have predisposing factors or hypercoagulable state. We present a child with primary PAS which mimicked pulmonary embolism on presentation but eventually was resected and is doing well 5 years after resection. In the absence of predisposing factors or hypercoagulable state, solid tumors such as primary PAS should be considered when assessing a pediatric patient with presumed pulmonary embolism.

Development and Validation of a Population-Pharmacokinetic Model for Rurioctacog Alfa Pegol (Adynovate®): A Report on Behalf of the WAPPS-Hemo Investigators Ad Hoc Subgroup.

BACKGROUND AND OBJECTIVE: Rurioctacog alfa pegol (Adynovate) is a modified recombinant factor VIII concentrate used for treating hemophilia A. Aiming to improve treatment tailoring on the Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) platform for patients of all ages treated with Adynovate, we have developed and evaluated a population pharmacokinetic (PopPK) model. On the platform, PopPK models are used as priors for Bayesian forecasting that derive individual PK of hemophilia patients and are subsequently used for personalized dose regimen design. METHODS: Factor activity measurements and demographic covariate data from patients infused with Adynovate were extracted from the WAPPS-Hemo database. Evaluations testing the appropriateness of Bayesian forecasting included 10-fold cross validation, a limited sampling analysis (LSA), and an external evaluation using additional independent data extracted from the WAPPS-Hemo database at a later date. RESULTS: The model was constructed using 650 plasma factor activity observations (555 one stage assay and 95 chromogenic assay - 4.6% below limit of quantification) measured in 154 patients from 36 hemophilia centres. A two-compartment model including between subject variability on clearance and central volume was selected as the base model. Covariates were fat free mass on clearance and central volume, age on clearance and assay type on activity. The final model was well-suited to predict PK parameters of new individuals (n = 26) from sparse observations. CONCLUSIONS: The development of a PopPK model for Adynovate using real-world data increases the covariate space (e.g. age) beyond what is possible from clinical trial data. This model is available on the WAPPS-Hemo platform for tailoring treatment in hemophilia A patients.

Hemophilia Gene Therapy: New Development from Bench to Bed Side.

Novel gene therapy strategies have changed the prognosis of many inherited diseases in recent years. New development in genetic tools and study models has brought us closer to a complete cure for hemophilia. This review will address the latest gene therapy research in hemophilia A and B including gene therapy tools, genetic strategies and animal models. It also summarizes the results of recent clinical trials. Potential solutions are discussed regarding the current barriers in gene therapy for hemophilia.

Perioperative haemostasis with full-length, PEGylated, recombinant factor VIII with extended half-life (rurioctocog alfa pegol) in patients with haemophilia A: Final results of a multicentre, single-arm phase III trial.

INTRODUCTION: Rurioctocog alfa pegol (BAX 855, TAK-660) is a PEGylated, full-length, recombinant factor VIII (rFVIII) with extended half-life developed from unmodified rFVIII (antihaemophilic factor [recombinant]). AIM: To determine the perioperative haemostatic efficacy and safety of rurioctocog alfa pegol in male previously treated patients (PTPs) with severe haemophilia A. METHODS: This multicentre, single-arm, phase III study included PTPs who were to undergo major or minor elective or minor emergency surgical, dental or other invasive procedures. Rurioctocog alfa pegol dose and frequency were individualized based on patients' pharmacokinetic profiles for major surgeries and by rurioctocog alfa pegol incremental recovery for minor surgeries. Haemostatic efficacy was assessed using the Global Haemostatic Efficacy Assessment score. RESULTS: Twenty-one patients aged 16-61 years underwent 21 major and five minor surgeries. For all 24 evaluable surgeries, overall haemostatic efficacy was rated as excellent and blood loss comparable to that expected in non-haemophilic patients. No blood transfusions were required intraoperatively but were administered postoperatively for four surgeries in three patients. Five injury-related postoperative bleeding episodes occurred in five patients, of which two required additional rurioctocog alfa pegol treatment. Two non-serious adverse events of mild severity (increased ALT level and headache) were considered possibly related to rurioctocog alfa pegol. There were no deaths or treatment-related serious adverse events. No patients developed inhibitory antibodies to FVIII or persistent IgG- or IgM-binding antibodies to FVIII, PEG-FVIII or PEG. CONCLUSION: Rurioctocog alfa pegol was well tolerated and effective for perioperative use in patients with haemophilia A and showed no signs of immunogenicity.

Late Effects After Radiotherapy for Childhood Low-grade Glioma.

OBJECTIVES: This single-institution report describes long-term disease control and late effects in pediatric patients with low-grade glioma (LGG) following radiotherapy (RT). MATERIALS AND METHODS: Twenty-nine pediatric patients with LGG were treated with photon-based RT from 1970 to 2004 (mean age at time of RT, 9.8 y; range, 0.6 to 19 y). One patient underwent gross total resection, 25 underwent subtotal resection or biopsy, and 3 were treated based on radiographic characteristics alone. Three patients underwent chemotherapy before RT. The median RT dose was 54 Gy (range, 40 to 55 Gy). RESULTS: The median follow-up was 17.8 years (range, 1.6 to 36.8 y) for all patients and 19.9 years (range, 1.6 to 36.8 y) for all living patients. The 5-, 10-, and 20-year local control and progression-free survival rates were equivalent at 82%, 74%, and 63%, respectively. The 5-, 10-, and 20-year cause-specific survival and overall survival rates were equivalent at 89%, 85%, and 58%, respectively. On univariate analysis, age below 4 years during treatment was associated with significantly inferior local control (P=0.0067), cause-specific survival (P=0.0021), and overall survival (P=0.0021). Of the 23 survivors analyzed for late toxicity, 15 (65%) developed grade 3+ toxicity. The most common Common Terminology Criteria for Adverse Events grade 3 toxicity (30% of survivors) was serious cognitive disability. Four patients (14%) died secondary to treatment complications, all occurring over a decade after completing RT. CONCLUSIONS: Over half of children diagnosed with LGG survive >20 years after RT; this report reveals the chronicity of toxicity beyond the typically reported follow-up. Our findings inform the therapeutic ratio of RT in this disease and may help guide late-effect screening recommendations.

Potential role of a new PEGylated recombinant factor VIII for hemophilia A.

Hemophilia A, a deficiency in the activity of coagulation factor (F) VIII, is an X-linked bleeding disorder with an approximate incidence of one in 5,000 male infants. Bleeding-related complications often result in greater severity of disease, poor quality of life, surgical interventions for severe joint destruction, and shortened life span. With the availability of plasma-derived and recombinant FVIII products, the benefits of primary prophylaxis were demonstrated and is now the standard of care for patients with severe factor deficiencies. Current hemophilia research is focusing on the creation of new factor replacement therapies with longer half-lives; accessing alternative mechanisms to achieve desired hemostasis and enhance bypassing activity; and limiting the immunogenicity of the protein. PEGylation involves the covalent attachment of polyethylene glycol (PEG) to a protein, peptide, or a small molecule drug. PEG effectively increases the molecular weight and size of the protein by creating a hydrophilic cloud around the molecule. This molecular change may reduce susceptibility of the molecule to proteolytic activity and degradation. It is also believed that PEGylation changes the surface charge of the protein that ultimately interferes with some receptor-mediated clearance processes. The half-life of PEGylated factor is more prolonged when compared to non-PEGylated full-length recombinant FVIII. The dawn of a new era in the care of hemophilia patients is upon us with the release of recombinant FVIII products with extended half-lives, and products with even more extended half-life will become available in a very short time. With all the promise of these new agents, many questions still remain.

Late toxicity following craniospinal radiation for early-stage medulloblastoma.

BACKGROUND: The purpose of this study is to review late toxicity following craniospinal radiation for early-stage medulloblastoma. MATERIAL AND METHODS: Between 1963 and 2008, 53 children with stage M0 (n = 50) or M1 (n = 3) medulloblastoma were treated at our institution. The median age at diagnosis was 7.1 years (range 1.2-18.5). The median craniospinal irradiation (CSI) dose was 28.8 Gy (range 21.8-38.4). The median total dose, including boost, was 54 Gy (range 42.4-64.8 Gy). Since 1963, the CSI dose has been incrementally lowered and the high-risk boost volume reduced. Twenty-one patients (40%) received chemotherapy in their initial management, including 12 who received concurrent chemotherapy. Late sequelae were evaluated by analyzing medical records and conducting phone interviews with surviving patients and/or care-takers. Complications were graded using the NCI Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: The median follow-up for all patients was 15.4 years (range 0.4-44.4) and for living patients it was 24 years (range 5.6-44.4). The overall survival, cause-specific survival, and progression-free survival rates at 10 years were 67%, 67%, and 71%, respectively. Sixteen patients (41% of patients who survived five years or more) developed grade 3 + toxicity; 15 of these 16 patients received a CSI dose > 23.4 Gy. The most common grade 3 + toxicities for long-term survivors are hearing impairment requiring intervention (20.5%) and cognitive impairment (18%) prohibiting independent living. Four patients developed secondary (non-skin) malignancies, including three meningiomas, one rhabdomyosarcoma, and one glioblastoma multiforme. Three patients (5.6%) died from treatment complications, including radionecrosis, severe cerebral edema, and fatal secondary malignancy. CONCLUSION: Ongoing institutional and cooperative group efforts to minimize radiation exposure are justified given the high rate of serious toxicity observed in our long-term survivors. Follow-up through long-term multidisciplinary clinics is important and warranted for all patients exposed to radiotherapy in childhood.

Composite adrenal anaplastic neuroblastoma and virilizing adrenocortical tumor with germline TP53 R248W mutation.

Composite tumors are extremely rare. Such tumors in adrenal glands are usually of neuroendocrine-neural type and occur mostly in adults. Their pathogenesis remains elusive. We report a patient with composite neuroblastoma (NB), adrenocortical tumor (ACT), and Li-Fraumeni syndrome (LFS) with germline TP53 R248W mutation. LFS predisposes to the development of leukemia, sarcomas, adrenocortical and breast carcinomas, brain tumors and, questionably, NB. A unique correlation between a single TP53 mutation (R337H) and ACT has been reported in southern Brazilian children. It remains unclear at this time whether a similar association of NB and R248W in patients with LFS exists.

Faisalabad histiocytosis mimics Rosai-Dorfman disease: brothers with lymphadenopathy, intrauterine fractures, short stature, and sensorineural deafness.

Rosai-Dorfman disease (RDD) is a rare, sporadic histiocytic disorder characterized by painless but protracted lymphadenopathy. Its etiology remains unclear. The observation of congenital disease and reports of familial cases with seven pairs of siblings including three sets of identical twins suggests a genetic predisposition in some patients with this condition. We now report two brothers of consanguineous Palestinian parents, whose lymphadenopathy, lymph node histology, and polyclonal hypergammaglobulinemia indicated RDD. The presence of intrauterine fractures, short stature, and sensorineural hearing impairment suggested a rare familial form of the disorder. Moynihan et al. recently described a Pakistani family with a familial histiocytic disorder highly reminiscent of the brothers reported here, whose lymph node morphology was apparently consistent with RDD as well. The presence of sensorineural deafness, short stature, and joint contractures, however, suggested a separate, rare autosomal recessive syndrome referred to as Faisalabad histiocytosis, after the family's place of origin. We believe that the brothers described here represent a second family with Faisalabad histiocytosis, which mimics RDD histologically.

Prenatal presentation supports the in utero development of congenital leukemia: a case report.

Congenital leukemia is a rare disease developing within the first 4 to 6 weeks of life. We report a female infant born with facial mass and multiple subcutaneous nodules. The facial mass was discovered by ultrasound during a routine prenatal examination at the 36th week of gestation. Biopsies were consistent with the diagnosis of acute monoblastic leukemia (AML, FAB M5b). Cytogenetic studies showed 46 XX, t(11;19)(q23;p13.1), which is only found in acute monoblastic leukemia and involves the gene. The infant died at 12 days of age and autopsy revealed a large leukemic tumor burden in several body organs. The discovery of the facial mass prenatally and massive extramedullary leukemic burden support the notion of the in utero development of congenital leukemia.

Acute lymphoblastic leukemia with hypereosinophilia: report of a case with 5q deletion and review of the literature.

Peripheral blood eosinophilia as a presentation of acute lymphoblastic leukemia (ALL) has only rarely been reported. The eosinophilia is thought to be a nonneoplastic reaction to the neoplastic lymphoblasts. We present the case of a 5-year-old girl who developed peripheral hypereosinophilia with no circulating blasts prior to her diagnosis of B-cell lineage ALL. Cytogenetic study showed a hyperdiploid blast population with 5q deletion. Persistent peripheral hypereosinophilia should always be fully investigated, the possibility of a malignancy including ALL needs to be excluded, even in the absence of peripheral cytopenias and circulating blasts.