Advance Care Planning for Children With Rare Diseases: A Pilot RCT.

BACKGROUND AND OBJECTIVE: Pediatric rare diseases are often life-limiting conditions and/or require constant caregiving. Investigators assessed the initial efficacy of the FAmily CEntered (FACE) pediatric advance care planning (pACP), FACE-Rare, intervention on families' quality of life. METHODS: A pilot-phase, single-blinded, intent-to-treat, randomized controlled clinical trial enrolled families from 1 pediatric quaternary hospital between 2021 and 2023. Intervention families received 3 weekly 60-minute (FACE-Rare pACP) sessions: (1) Carer Support Needs Assessment Tool or Action Plan, (2) Carer Support Needs Assessment Tol Action Plan Review, and (3) Pediatric Next Steps: Respecting Choices pACP. Controls received treatment as usual (TAU). Outcome measures were Beck Anxiety Inventory, Family Appraisal of Caregiving, Functional Assessment of Chronic Illness Therapy (FACIT)-Spirituality, and health care utilization. Generalized mixed effect models with γ response assessed the intervention effect at 3-month follow-up. RESULTS: Children (n = 21) were aged 1 to 10 years, 48% male, 24% Black; and 100% technology dependent. Primary family caregivers (n = 21) were aged 30 to 43 years, 19% male, 19% Black; and 27% household income below the Federal poverty level. Dyads underwent 1:1 randomization: 9 to FACE-Rare and 12 to TAU. TAU caregivers reported statistically lower meaning and peace than FACE-Rare caregivers (0.9, P = .03, confidence interval [CI]: 0.75-0.99). Black caregivers reported significantly less caregiver distress (0.7, P = .04, CI: 0.47-0.98) than non-Black caregivers. Poor families reported more anxiety (3.5, P = .002, CI: 1.62-7.94), more caregiver strain (1.2, P = .006, CI: 1.07-1.42); and less family well-being (0.8, P = .02, CI: 0.64-0.95). CONCLUSIONS: FACE®-Rare was feasible, acceptable, safe, and demonstrated initial efficacy, providing greater feelings of meaning and peace to caregivers. Poverty impacted well-being. A multisite trial is needed to determine generalizability.

Neutralizing antidrug antibody to emicizumab in patients with severe hemophilia A: Case report of a first noninhibitor patient and review of the literature.

Background: Hemophilia A (HA) is a genetic bleeding disorder characterized by the deficiency of the coagulation protein factor (F) VIII (FVIII). The development of neutralizing antidrug antibodies (ADAs) to factor concentrates (inhibitors) created an unmet need for novel therapies. The first agent to address this need is emicizumab. Key Clinical Question: Can emicizumab ADA occur in patients with HA without FVIII inhibitors? Clinical Approach: A new case (the first in a noninhibitor patient) presented with unexpected and excessive bleeding and a prolonged activated partial thromboplastin time. The patient was evaluated by assessing FVIII levels, and the previously published modified version of the Bethesda assay was used to determine the level of ADA to emicizumab. Conclusion: Although emicizumab is very effective and has minimal immunogenicity, ADAs, albeit rare, can still occur. There have been 4 previously published anti-emicizumab ADA cases with severe HA with inhibitors, and herein, we describe 1 new case with severe HA without inhibitors.

Real-world cost estimates of initiating emicizumab in US patients with haemophilia A.

INTRODUCTION: Emicizumab is the first approved non-factor therapy for haemophilia A. It provides superior prophylactic bleeding control compared to other products in both patients with and patients without inhibitors. However, there is no real-world data about the monetary consequences of starting emicizumab. AIM: To examine the estimated costs of starting emicizumab in a cohort of real-world haemophilia A patients with and without inhibitors. METHODS: The cost of haemostatic therapy for 6 months before and after initiating emicizumab for participants in a multicentre observational study was calculated based on the type of product and dosing that was used for prophylaxis and treating breakthrough bleeds, the number of treated bleeds and the participant weight. RESULTS: Ninety-two patients were included, 18 with an active inhibitor. The median age was 8.7 years. The median total cost for all patients decreased from $176,720 to $128,099 (p = .04) after initiating emicizumab, largely because of decrease in the total cost of high-cost outliers. The cost of prophylaxis and the total cost of bleeds also significantly decreased after starting emicizumab, both for patient with and patients without inhibitors. CONCLUSIONS: Starting or switching to prophylaxis with emicizumab results in decreased costs for the treatment of patients with haemophilia A. This real-world data could inform on payer decisions as well as future cost-effective analysis.

Real-world use of emicizumab in patients with haemophilia A: Bleeding outcomes and surgical procedures.

INTRODUCTION: Emicizumab is a recombinant humanized bispecific antibody that bridges factor IXa and factor X to mimic the cofactor function of factor VIII. It is approved to prevent bleeding in patients with haemophilia A (HA). Outside of clinical trials, there is limited data on outcomes of patients treated with emicizumab, particularly in children without inhibitors. AIM: To report our experience treating patients with emicizumab, including (a) bleeding rates pre and postemicizumab, (b) peri-procedural management and outcomes and (c) serious drug-related adverse events. METHODS: Multicentre observational study in patients with HA who started emicizumab prior to 15 May 2019. Data collection continued until 15 October 2019 and included demographics, disease history, bleeding events, invasive procedures, thrombotic events and death. Annualized bleeding rates (ABR) prior to emicizumab were compared to postemicizumab. RESULTS: Ninety-three patients (including three females) met inclusion criteria, 19 with an active inhibitor. Median age was 8.6 years; patients <12 years without inhibitors (n = 49) accounted for the majority. ABR dropped from 4.4 (inhibitors) and 1.6 (non-inhibitors) to 0.4 (both groups) on emicizumab, P = .0012 and .0025, respectively. There were 28 minor (21 port removals) and two major procedures. Three patients received 1-2 doses of unplanned factor postoperatively to treat minor bleeding events. No patient discontinued therapy, and there were no thrombotic events or deaths. DISCUSSION: Our favourable clinical experience with emicizumab is similar to that reported in the clinical trials. Notably, this is the largest cohort of patients <12 years without inhibitors treated with emicizumab.

A 17-Year-Old Girl With Weight Loss and Elevated Inflammatory Markers.

A 17-year-old girl presented to her primary care physician with a history of unintentional weight loss and vague sensory symptoms, including tingling of her lower extremities. She had a nonrevealing neurology workup and a largely normal rheumatology workup apart from mild elevation in her inflammatory markers. She also had a nonfocal examination apart from a posterior cervical lymph node (2 × 1 cm). Given that she was well appearing, with a nonfocal examination and only mild laboratory abnormalities, she was told to follow-up with rheumatology in 3 months. Around that time, she re-presented to her medical home for a well-child visit, during which she was noted to have continued weight loss, now amounting to 17 lb in 1 year, and marked further elevation in her inflammatory markers. Her laboratory results were also significant for a profound microcytic anemia requiring inpatient admission for blood transfusion. During her admission, she was seen by the rheumatology, gastroenterology, and oncology subspecialty teams. Despite imaging studies and extensive laboratory workup, there was no unifying diagnosis at the time of her hospital discharge. Ultimately, an outpatient imaging study revealed the etiology.

Focusing in on use of pharmacokinetic profiles in routine hemophilia care.

BACKGROUND: Emergence of population pharmacokinetic models for prediction of individual pharmacokinetic (PK) profiles facilitates individualization of prescribed prophylactic therapy for patients with hemophilia A and B and may have a favorable impact on clinical outcomes and annual factor utilization. How providers approach the integration and application of these data into routine clinical practice is not clear. OBJECTIVE: To explore the potential application of and barriers to incorporating PK profiles into current hemophilia prophylaxis decision making. METHODS: A facilitated group discussion of hematologists practicing within the federally-supported United States Hemophilia Treatment Center Network was conducted. Separately, a group of parents of patients with severe hemophilia less than 18 years of age participated in a focus group on individualizing prophylactic factor regimens with the use of PK data. RESULTS: Physician participants constructed a conceptual model for factors that determined their selection of hemophilia prophylaxis. These factors clustered in five groupings. When charged with creating a prophylaxis regimen for a specific clinical case including PK data, eight of nine providers generated a unique regimen. Parent focus group supported PK data use as they preferred data driven treatment decisions. CONCLUSIONS: Clinician application of PK data for prophylaxis decision making is heterogeneous. Prospective evaluation of the use of PK-tailored prophylaxis in routine care and its impact on patient outcomes is needed. Parents perceived that, while obtaining blood draws could be challenging, images of factor activity decay informed their decisions about physical activity timing and provided an opportunity for partnership and shared decision making with their provider.

Catheter-Related Venous Thrombosis in Hospitalized Pediatric Patients with Inflammatory Bowel Disease: Incidence, Characteristics, and Role of Anticoagulant Thromboprophylaxis with Enoxaparin.

OBJECTIVE: To describe the incidence and characteristics of central venous catheter (CVC)-related thrombosis in hospitalized pediatric patients with active inflammatory bowel disease (IBD) and report the potential usefulness of anticoagulant thromboprophylaxis (AT). STUDY DESIGN: We conducted a retrospective study of patients who were admitted to our children's hospital in the last 2 years with active IBD and required a CVC and identified all patients with an objectively confirmed symptomatic CVC-related thrombosis. To assess the usefulness of a recently implemented institutional AT protocol, we compared the frequency of CVC-related thrombosis, nadir hemoglobin, and red blood cell transfusion requirements in patients who received AT with those who did not during the study period. RESULTS: A total of 40 patients with IBD who required 47 consecutive hospitalizations were included. AT was administered during 24 of 47 hospitalizations (51%). Patients who received AT were similar to those who did not receive AT with regard to demographics, IBD phenotypes, extent of colonic involvement, and thrombotic risk factors. CVC-related thrombosis occurred in 5 of 23 hospitalizations (22%) in which AT was withheld compared with 0 of 24 hospitalizations (0%) in which patients received AT (P = .02). The red blood cell transfusion requirements and nadir hemoglobin were not significantly different between the 2 groups. CONCLUSIONS: We observed a high incidence of CVC-related thrombosis in hospitalized children with IBD. Administration of AT in our population was associated with significant reduction in CVC-related thrombosis without evidence of increased bleeding.

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.

A 17-Year-Old With Chest Pain.

A 17-year-old male subject with a history of deep venous thrombosis presented with acute unilateral severe chest pain. His examination was nonspecific, and vital signs were normal. His initial laboratory evaluation revealed mild thrombocytopenia, elevated troponin levels, and critically elevated activated partial thromboplastin time. A computed tomography angiogram of the chest revealed a pulmonary embolus, and anticoagulation therapy was initiated. His course was complicated by the development of multiple thrombi and respiratory failure. Extensive evaluation revealed a rare, underlying diagnosis in time for life-saving treatment to be initiated.

Homozygous α-thalassemia: Challenges surrounding early identification, treatment, and cure.

The prognosis for homozygous α-thalassemia is changing. Prenatal diagnosis and intrauterine transfusions (IUT) reduce maternofetal morbidity and mortality; hematopoietic stem cell transplant (HSCT) is curative. Empiric evidence to support IUT and HSCT to treat homozygous α-thalassemia is lacking. The first case of curative HSCT for homozygous α-thalassemia was reported in 1997. Nearly 20 years later, five additional reports are published. We review the literature and report an institutional experience with three homozygous α-thalassemia patients. The first died shortly after birth. The second underwent HSCT after years of chronic transfusion therapy. The third benefited from IUT and HSCT. These cases exemplify the varied outcomes associated with this condition.

Small ncRNA Expression-Profiling of Blood from Hemophilia A Patients Identifies miR-1246 as a Potential Regulator of Factor 8 Gene.

Hemophilia A (HA) is a bleeding disorder caused by deficiency of functional plasma clotting factor VIII (FVIII). Genetic mutations in the gene encoding FVIII (F8) have been extensively studied. Over a thousand different mutations have been reported in the F8 gene. These span a diverse range of mutation types, namely, missense, splice-site, deletions of single and multiple exons, inversions, etc. There is nonetheless evidence that other molecular mechanisms, in addition to mutations in the gene encoding the FVIII protein, may be involved in the pathobiology of HA. In this study, global small ncRNA expression profiling analysis of whole blood from HA patients, and controls, was performed using high-throughput ncRNA microarrays. Patients were further sub-divided into those that developed neutralizing-anti-FVIII antibodies (inhibitors) and those that did not. Selected differentially expressed ncRNAs were validated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis. We identified several ncRNAs, and among them hsa-miR-1246 was significantly up-regulated in HA patients. In addition, miR-1246 showed a six-fold higher expression in HA patients without inhibitors. We have identified an miR-1246 target site in the noncoding region of F8 mRNA and were able to confirm the suppressory role of hsa-miR-1246 on F8 expression in a stable lymphoblastoid cell line expressing FVIII. These findings suggest several testable hypotheses vis-à-vis the role of nc-RNAs in the regulation of F8 expression. These hypotheses have not been exhaustively tested in this study as they require carefully curated clinical samples.

Dexmedetomidine as an Adjuvant to Analgesic Strategy During Vaso-Occlusive Episodes in Adolescents with Sickle-Cell Disease.

Patients with sickle-cell disease (SCD) can experience recurrent vaso-occlusive episodes (VOEs), which are associated with severe pain. While opioids are the mainstay of analgesic therapy, in some patients with SCD, increasing opioid use is associated with continued and increasing pain. Dexmedetomidine, an α2 -adrenoreceptor agonist with sedative and analgesic properties, has been increasingly used in the perioperative and intensive care settings and has been shown to reduce opioid requirement and to facilitate opioid weaning. Therefore, there might be a role for dexmedetomidine in pain management during VOEs in patients with SCD. Here, we present the hospital course of 3 patients who during the course of VOEs had severe pain unresponsive to opioids and ketamine and were treated with dexmedetomidine. Dexmedetomidine infusions that lasted for 3 to 6 days were associated with marked reduction in daily oral morphine-equivalent intake and decreases in pain scores (numeric rating scale). There were no hemodynamic changes that required treatment with vasoactive or anticholinergic agents. These preliminary findings of possible beneficial effects of dexmedetomidine in decreasing opioid requirements support the hypothesis that dexmedetomidine may have a role as a possible analgesic adjuvant to mitigate VOE-associated pain in patients with SCD.

Kaposiform lymphangiomatosis: unifying features of a heterogeneous disorder.

Kaposiform lymphangiomatosis (KLA) is a rare proliferation of abnormal lymphatic vessels often complicated by pleural/pericardial effusions and a consumptive coagulopathy that may lead to life threatening hemorrhage. Establishing the diagnosis is challenging due to the clinical heterogeneity and variable findings in laboratory values, radiographic features, and pathologic characteristics. We report three patients who had slowly progressive symptoms and presented with pleural or pericardial effusions, evidence of a consumptive coagulopathy and anemia. Despite being a rare and challenging diagnosis, KLA should be considered in patients presenting with non-specific indolent symptoms, pleural or pericardial effusions and laboratory evidence of a consumptive coagulopathy.

Primary CNS lymphoma in children and adolescents: a descriptive analysis from the International Primary CNS Lymphoma Collaborative Group (IPCG).

PURPOSE: To describe the demographic and clinical features and outcomes for children and adolescents with primary CNS lymphoma (PCNSL). EXPERIMENTAL DESIGN: A retrospective series of children and adolescents with PCNSL was assembled from 10 cancer centers in 3 countries. RESULTS: Twenty-nine patients with a median age of 14 years were identified. Sixteen (55%) had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1 or greater. Frontline therapy consisted of chemotherapy only in 20 patients (69%), while 9 (31%) had chemotherapy plus cranial radiotherapy. Most patients received methotrexate (MTX)-based regimens. Overall response rate was 86% (complete remission 69%, partial remission 17%). The 2-year progression-free survival (PFS) and overall survival (OS) rates were 61% and 86%, respectively; the 3-year OS was 82%. Univariate analyses were conducted for age (≤ 14 vs. >14 years), PS (0 or 1 vs. >1), deep brain lesions, MTX dose, primary treatment with chemotherapy alone, intrathecal chemotherapy, and high-dose therapy. Primary treatment with chemotherapy alone was associated with better overall response rates with an odds ratio (OR) of 0.125 (P = 0.02). There was a marginally significant relationship between higher doses of MTX and response (OR = 1.5, P = 0.06). ECOG-PS of 0 to 1 was the only factor associated with better outcome with hazard ratios of 0.136 (P = 0.017) and 0.073 (P = 0.033) for PFS and OS, respectively. CONCLUSION: This is the largest series collected of pediatric PCNSL. The outcome of children and adolescents seems to be better than in adults. PS of 0 to 1 is associated with better survival.

Multidisciplinary management of expanding bilateral neck hematomas in a patient with Hemophilia A with high-titer inhibitor.

There are multiple modalities by which trauma occurs to the neck. One of these includes minor suction trauma which usually results in a superficial bruising of the skin. While this usually self-resolves, patients with hemophilia are at higher risk for the development of bleeding from such trauma. Hematomas of the head and neck in patients with hemophilia have seldom been reported. We report a unique case of expanding bilateral neck hematomas secondary to suction trauma in a patient with Hemophilia A with high-titer inhibitor and highlight the importance of a multidisciplinary approach in the management of this complex patient.

Primary cutaneous CD30-positive anaplastic large cell lymphoma in childhood: report of 4 cases and review of the literature.

We present the clinicopathologic findings in 4 children with primary cutaneous anaplastic large cell lymphoma (C-ALCL). The patients ranged in age from 13 months to 8 years, with 3 females and 1 male. All presented with a rapidly enlarging mass involving the skin and subcutaneous tissue. Histologic evaluation showed sheets of large pleomorphic lymphoid cells that were diffusely and strongly CD30(+). Tumor cells were CD45(+) in 1 of 4 cases. Cells were of T-cell phenotype, with variable positivity for CD3 (3 of 4 cases) and CD5 (2 of 4 cases). All 4 cases were positive for CD4 and clusterin. Staining for anaplastic lymphoma kinase was negative in all cases. No evidence of systemic involvement was noted at initial presentation or over a follow-up of 5 to 78 months, although 3 patients had cutaneous recurrences. Primary C-ALCL has only rarely been described in the pediatric population. The high-grade histologic appearance of this lymphoma belies its generally favorable clinical course and prognosis. Recognition of this entity and its differentiation from other T-cell lymphomas that secondarily involve the skin is important to avoid unnecessarily aggressive therapy in these children.

N-butyldeoxynojirimycin inhibits murine melanoma cell ganglioside metabolism and delays tumor onset.

Aberrant ganglioside metabolism is linked to tumor progression. Since ganglioside depletion reduced tumorigenicity of MEB4 murine melanoma cells, we studied N-butyldeoxynojirimycin (NB-DNJ), an imino sugar administered orally to inhibit glucosylceramide (GlcCer) synthase in patients with glycosphingolipid storage diseases, for effects on MEB4 melanoma tumor cell ganglioside metabolism, cell biology, and tumorigenesis. Here we show that 50 microM NB-DNJ reduced MEB4 cell GlcCer synthase activity (by 70%), ganglioside synthesis (by 61%), and shedding (by 37%) while ceramide concentrations and cell viability were unaffected. Partial ganglioside depletion caused a delay in tumor onset but not in tumor incidence, possibly because of rapid (48 h) ganglioside recovery. The delay in tumor development by NB-DNJ treatment of MEB4 cells provides further support for the concept of tumor cell ganglioside metabolism as a therapeutic target in cancer.

Transfection of glucosylceramide synthase antisense inhibits mouse melanoma formation.

MEB4 murine melanoma cells synthesize G(M3) as the major ganglioside. Inhibition of G(M3) synthesis by a specific glucosylceramide synthase inhibitor resulted in reduced tumorigenicity and metastatic potential of these cells. We used a molecular approach--antisense transfection targeting the glucosylceramide synthase gene--to regulate glycosphingolipid synthesis by MEB4 cells and examine the influence on tumor formation. Antisense transfection inhibited the synthesis of the direct product of glucosylceramide synthase, glucosylceramide, and consequently G(M3) ganglioside, by MEB4 cells, reducing the concentration of G(M3) in the transfectants by up to 58%. Although neither morphology nor proliferation kinetics of the cultured cells was affected, the inhibition of glycosphingolipid synthesis and reduction of total ganglioside content caused a striking reduction in melanoma formation in mice. Only 1/60 (2%) of mice injected ID with 10(4) antisense-transfected MA173 cells formed a tumor, compared to 31/60 (52%) of mice receiving MEB4 cells and 7/15 (47%) of mice receiving the MS2 sense-transfected cells (p < 0.001 and p = 0.005, respectively). These findings demonstrate that stable transfection of glucosylceramide synthase antisense reduces cellular glycosphingolipid levels and reduces tumorigenicity, providing further experimental support for an enhancing role of gangliosides in tumor formation.