Quality of life in a large multinational haemophilia B cohort (The B-Natural study) - Unmet needs remain.

INTRODUCTION: The B-Natural study is a multicentre, multinational, observational study of haemophilia B (HB) designed to increase understanding of clinical manifestations, treatment and quality of life (QoL). AIM: To characterise and compare QoL in HB across disease severity groups and individuals with inhibitors to identify gaps in treatment. METHODS: A total of 224 individuals from 107 families were enrolled from a total of 24 centres in North America (n = 16), Europe (n = 7) and Asia (n = 1). Of these, 68 (30.4%) subjects had severe (<1 IU/dL), median age 15.6 years, 114 (50.9%) moderate (1-5 IU/dL), age 13.3 years, and 42 (18.8%) mild (>5-< 40 IU/dL), age 12.1 years, disease. Twenty-nine participants had inhibitors or a history of inhibitors. Three versions of the EQ-5D instrument were used as a measure of QoL: proxy (ages 4-7), youth (ages 8-15) and self (age 16+). Each instrument included a visual analogue scale ranging from 100 (best health) to 0 (worst health) to assess current day's health (EQ VAS). Range-of-motion (ROM) for elbows, knees and ankles was assessed using a four-point scale, from which a composite score was calculated. RESULTS: In all severity groups, a proportion of subjects showed less than optimal QoL. The majority of the mild and moderate severe participants reported a normal EQ-5D health profile (79% and 72%, respectively), whereas about half (47%) of the severe participants and only 13% of the inhibitor participants reported this profile. CONCLUSION: The B-Natural study reveals impacted QoL in all disease severities of HB including those with inhibitors. Unmet needs remain and include nonsevere HB.

The B-Natural study-The outcome of immune tolerance induction therapy in patients with severe haemophilia B.

INTRODUCTION: Inhibitors develop less frequently in haemophilia B (HB) than haemophilia A (HA). However, when present, the success of tolerization by immune tolerance induction (ITI) therapy is lower and the risk of complications higher. AIM: To evaluate the use and outcome of ITI in patients with HB and inhibitors. METHODS: Subjects include singletons or siblings with a current/history of inhibitors enrolled in B-Natural-an observational study designed to increase understanding of clinical management of patients with HB. Patients were followed for 6 months and information on demographics, medical and social history, and treatment were recorded. RESULTS: Twenty-nine patients with severe HB and inhibitors were enrolled in 24 centres. Twenty-two underwent one or more courses of ITI with or without immune suppression. Eight patients (36.4%) were successfully tolerized after the first course of ITI. One of these successes (12.5%) experienced allergic manifestations, whereas the corresponding number for the 10 treatment failures was five (50%). One of seven (14.2%) patients with large deletions and three of eight (37.5%) with nonsense mutations were tolerized at the first attempt, and all patients experiencing nephrosis either failed or were on-going. At study end, 11 (50%) were considered successfully tolerized after one or more ITI courses, three were unsuccessful, and eight were still undergoing treatment. CONCLUSION: Our data underscore the possibilities and difficulties of achieving tolerization in patients with HB with inhibitors. The type of mutation and complications appear to correlate with ITI outcome, but more accurate definitions of successful ITI are warranted.

Health promotion competencies for promoting child-oral health: Victorian multidisciplinary workforce perspectives.

ISSUE ADDRESSED: Population oral health (OH) improvements depend on successful, coordinated execution of oral health promotion (OHP) programs by both oral and general health professionals with key competencies (skills, abilities, knowledge and values). This study explored multidisciplinary professionals' perspectives of the competencies required for the successful implementation of a community-based OHP program called Smiles 4 Miles (S4M) in early childhood settings in Victoria, Australia. METHODS: Convenience sampling was used to recruit multidisciplinary professionals working in the S4M early childhood health promotion program in Victoria. Semi-structured focus groups were conducted with program managers/coordinators (n = 26) from 21 S4M sites and the state-wide program coordination team (n = 5). Focus groups explored OHP competency needs, capacity to promote child OH and strategies for enhancing OHP competencies. The competencies identified through focus groups were then compared to the International Union for Health Promotion and Education (IUHPE) competencies framework. RESULTS: Strategies to enhance individual and organisational OHP competencies included intersectoral collaborations; working in multidisciplinary teams; support networks and partnerships; sharing skills and expertise between health professionals. The OHP competencies identified by the participants were consistent with key IUHPE domains including ethical values and health promotion knowledge base underpinning, enabling change, advocacy for health, mediating through partnerships, communication, leadership, assessment, planning, implementation, evaluation and research. CONCLUSION: A multidisciplinary workforce based in community settings can play key and complementary roles in OHP and widen avenues for oral disease prevention. SO WHAT?: Integrated collaborative workforce models involving multidisciplinary professionals beyond the OH sector can more effectively support efforts to address the burden of oral disease.

A protocol of situation-dependent transfusion, erythropoietin and tranexamic acid reduces transfusion in fronto-orbital advancement for metopic and coronal craniosynostosis.

PURPOSE: Assess the effect of a protocol of preoperative erythropoietin (EPO) and ferrous sulfate in addition to perioperative tranexamic acid (TXA) on blood transfusions in patients with coronal or metopic craniosynostosis undergoing cranial vault remodeling (CVR) with fronto-orbital advancement (FOA). METHODS: Retrospective review of all coronal and metopic craniosynostosis patients undergoing CVR and FOA from March 2010 to June 2019 was performed. Before 2014 ("Control group"), all patients received blood transfusion at the start of surgery. In 2014, a protocol of preoperative EPO and ferrous sulfate with perioperative TXA and non-automatic transfusion was instituted ("Study group"). Patient demographics and anthropometrics, perioperative hemoglobin (Hb) levels, and transfusion details were collected and compared. RESULTS: Thirty-six patients met inclusion criteria. Twenty-one patients were in the control group, and 15 in the Study group. Nineteen patients had metopic synostosis, 11 had unicoronal synostosis, and 6 had bicoronal synostosis. There were no significant differences between groups in demographics, operative time, intraoperative crystalloid volume, craniofacial syndromes, or sutures affected. The Study group had higher preoperative Hb (13.9 ± 1.0 vs. 12.6 ± 0.8 g/dL, p < 0.001), lower intraoperative Hb nadir (7.4 ± 1.8 vs. 9.2 ± 1.2 g/dL) lower intraoperative transfusion rate (66.7% vs. 100%, p = 0.008), lower postoperative transfusion rate (0% vs 28.6%, p = 0.03), and exposure to fewer unique units of packed red blood cells (0.7 ± 0.6 vs. 1.5 ± 0.9 units). CONCLUSION: Our protocol resulted in decreased transfusion needs. These results add valuable information to the growing body of work on transfusion reduction in craniosynostosis surgery.

Natural history study of factor IX deficiency with focus on treatment and complications (B-Natural).

INTRODUCTION: Haemophilia B (HB) is less well studied than haemophilia A (HA); despite similarities between the two inherited bleeding disorders, important differences remain that require further research. AIM: B-Natural is a multi-centre, prospective, observational study of HB, designed to increase understanding of clinical manifestations, treatment, quality-of-life (QoL), inhibitor development, immune tolerance induction (ITI) outcome, renal function and create a biorepository for future investigations. METHODS: Participants include sibling pairs/groups without a current/history of inhibitors and singletons or siblings with a current/history of inhibitors followed for six months. Demographics, medical, social history and treatment were recorded. A physical examination including joint range of motion (ROM) was performed; QoL was assessed. Samples were collected for F9 gene mutation, HLA typing, non-inhibitory antibodies and renal function testing. RESULTS: Twenty-four centres enrolled 224 individuals from 107 families including 29 with current/history of inhibitors. Of these, 68, 30.4%, had severe (<1% FIX level of normal); 114, 50.9%, moderate (1%-5%); and 42, 18.8%, mild (>5-<40%) disease. At enrolment, 53.1% had 50 + exposure days to exogenous FIX. Comparison of joint scores showed significant (P < .05) differences between those with severe (with/without inhibitors), and those with moderate/mild disease. The majority with severe disease, 80.0% with current/history of inhibitors and 64.3% of those without, were treated with prophylaxis. CONCLUSION: B-Natural provides data supporting an increased understanding of HB and its impact throughout life. The need for optimal disease control to normalize physical and psychosocial outcomes is underscored, and further analyses will contribute to an increased understanding of critical issues in HB.

Long-term safety and efficacy of N8-GP in previously treated pediatric patients with hemophilia A: Final results from pathfinder5.

BACKGROUND: N8-GP (turoctocog alfa pegol; Esperoct® , Novo Nordisk A/S, Bagsvaerd, Denmark) is a glycoPEGylated, extended half-life human recombinant factor VIII (FVIII). OBJECTIVE: Here, we report end-of-trial safety and efficacy results from the completed N8-GP pathfinder5 trial. METHODS: pathfinder5 (NCT01731600) was a multi-national, open-label, single-arm, non-randomized, non-controlled trial in previously treated male patients aged <12 years old with severe hemophilia A that comprised a main and an extension phase. During the main phase, patients received twice-weekly N8-GP 60 IU/kg for 50 exposure days (~26 weeks). During the extension phase, patients received the same regimen until the end of trial (first patient in main phase, 20 February 2013; trial end, 28 September 2018). RESULTS: Sixty-eight patients were exposed to N8-GP for a median time of ~4.9 years on regimen. Of the 63 patients who started in the extension phase, 62 completed the trial. No FVIII inhibitors (≥0.6 BU) or other safety concerns were detected. The overall estimated annualized bleeding rate was 1.08 (median 0.81), and nearly 20% of patients had no bleeds during the entire trial. The proportion of patients with no annual bleeds increased with time, with 56% of patients experiencing no bleeds and 86% experiencing no spontaneous bleeds during the fourth year of exposure. All baseline target joints of patients who participated in both phases of this trial were resolved in slightly over 2 years. CONCLUSION: Overall, data from the completed pathfinder5 trial show that long-term (median 4.9 years) N8-GP treatment was efficacious and well tolerated in previously treated pediatric patients with severe hemophilia A.

Long-Term Safety and Efficacy of Nonacog Beta Pegol (N9-GP) Administered for at Least 5 Years in Previously Treated Children with Hemophilia B.

Long-term safety and efficacy data of extended half-life factor IX (FIX) prophylaxis in children with hemophilia B (HB) are sparse. paradigm 5 is a multinational, open-label, single-arm, phase III trial assessing once-weekly (40 IU/kg) prophylactic nonacog beta pegol (N9-GP) in previously treated patients (PTPs) aged ≤ 12 years with HB (FIX activity ≤ 2%). Primary endpoint: incidence of anti-FIX inhibitory antibodies (≥ 0.6 Bethesda Units). We present a 5-year analysis (N = 25, including remaining patients with ≥ 5 years' follow-up) and compare with a 1-year analysis (≥ 52 weeks' exposure). The main phase enrolled 25 children; 22 entered the extension phase; 17 remained in trial at data cutoff. Median treatment period: 5.6 years/patient; median total number of N9-GP exposure days: 290.0/patient. No patients developed anti-FIX inhibitory antibodies. No other safety concerns, including thromboembolic events, were reported. Neurological examinations have not revealed any new abnormal findings. Sixteen (64.0%) patients remained free from spontaneous bleeds; all bleeds were mild/moderate in severity; 93.0% were controlled with 1 to 2 N9-GP injections. No intracranial hemorrhages were reported. Annualized bleeding rates (ABRs) were very low at 5 years (median/Poisson-estimated mean overall ABR: 0.66/0.99), having decreased from the 1-year analysis (1.00/1.44). Median/Poisson-estimated mean spontaneous ABRs for the 1- and 5-year analyses: 0.00/0.45 and 0.00/0.33. Mean FIX trough activity at 5 years: 17.9%. Mean polyethylene glycol plasma concentration reached steady state at 6 months, increasing slightly over time, in line with increased FIX trough activity. N9-GP administered for ≥ 5 years shows favorable long-term safety and efficacy in PTPs with HB (FIX activity ≤ 2%).

Opioid exposure in haemophilia patients is common and underreported.

INTRODUCTION: In an era of increased opioid awareness, data on opioid exposure in haemophilia patients are lacking. AIM: The objectives of this study were to (a) provide a detailed description of opioid exposure in haemophilia patients based on written prescription data, (b) compare our findings to national haemophilia-specific and general population datasets and (c) identify predictors of opioid exposure in haemophilia patients. METHODS: Medical records of 183 adult and 135 paediatric patients from two haemophilia treatment centres (HTC) were reviewed over a 42-month period. Chronic exposure and acute opioid exposure were recorded, and results were compared to national haemophilia (ATHNdataset) and general population (CDC) data. RESULTS: We found that 56% of adult and 21% of paediatric patients were exposed to opioids, rates substantially higher than reported in the ATHNdataset (6%) and national population data from the CDC. In adults, but not children, severity of haemophilia was a significant predictor of opioid exposure. Most acute opioid prescriptions were not written by the HTC. CONCLUSIONS: This is the first study in the haemophilia population to examine opioid exposure based on prescription data. Opioid exposure was more common than predicted in both adult and paediatric study populations and was most often prescribed for acute pain or procedures by non-HTC providers. Haemophilia treatment centres need to take the lead in assessing pain in haemophilia patients, guiding treatment promoting non-opioid options, strengthen efforts to monitor opioid exposure and collect data on pain treatment in the haemophilia population.

Neuropsychological function in children with hemophilia: A review of the Hemophilia Growth and Development Study and introduction of the current eTHINK study.

Almost all of what is known about neurologic and cognitive development in hemophilia derives from the Hemophilia Growth and Development Study, conducted during an era when treatment regimens and comorbidities differed significantly from the current environment. Results suggested hemophilia and human immunodeficiency virus had independent effects, and hemophilia negatively impacts academic achievement, attention, and behavior. The introduction of prophylaxis treatment in hemophilia has created the need for re-evaluation of the effects of hemophilia on neurodevelopment and cognition. We outline the Evolving Treatment of Hemophilia's Impact on Neurodevelopment, Intelligence, and Other Cognitive Functions (NCT03660774) study, which aims to meet this need.

Minimizing transfusion in sagittal craniosynostosis surgery: the Children's Hospital of Minnesota Protocol.

PURPOSE: To assess the success of a protocol using preoperative erythropoietin (EPO) and iron with perioperative tranexamic acid (TXA) in reducing blood transfusion in sagittal craniosynostosis surgery. METHODS: A retrospective chart review of all sagittal craniosynostosis patients undergoing open repair at our institution since 2010 was conducted. A novel protocol of preoperative EPO with iron and perioperative TXA, along with a shift away from automatic transfusion, was initiated in 2014. Perioperative hemoglobin levels, length of stay, and transfusion rates were compared between the historical control and the study group receiving the protocol. RESULTS: A total of 36 patients met inclusion criteria. Twenty-eight patients were male and 8 were female. Twenty-two patients were in the control group receiving neither TXA nor EPO and automatically received a transfusion, while 14 were in the study group and received the full protocol. There were no significant demographic differences between groups. Within the control group, 100% of patients were transfused compared with 14.3% of the study group (p < 0.0001). The study group also had a shorter postoperative length of stay in the hospital (mean, 3.4 days; range, 3-6) than the control (mean, 4 days; range, 2-5.5, p = 0.038). The study group had a higher preoperative hemoglobin than the control (13.6 vs. 11.8 g/dL, p = 0.0001). CONCLUSION: Our protocol of preoperative EPO and iron with perioperative TXA increased the preoperative hemoglobin and was associated with a low transfusion rate without negatively impacting postoperative course.

Health-related quality-of-life and treatment satisfaction of individuals with hemophilia A treated with turoctocog alfa pegol (N8-GP): a new recombinant extended half-life FVIII.

BACKGROUND: Prophylactic treatment regimens lead to improvements in health-related quality-of-life (HRQoL) among individuals with hemophilia. Turoctocog alfa pegol (N8-GP) provides the benefit of extending the duration of protection from bleeding and reducing the number of injections, which is expected to impact HRQoL and treatment satisfaction (TS). AIM: To investigate the HRQoL and TS of patients with severe hemophilia A from two phase III trials evaluating the safety and efficacy of N8-GP. METHODS: HRQoL was assessed using the Haemo-QoL (reported by children and their parents) and Haem-A-QoL (reported by adults). TS was assessed using Hemo-Sat. Domain and total scores for all questionnaires ranged from 0 to 100, with lower scores indicating a better HRQoL or TS. A negative change in score indicates an improvement in HRQoL/TS. RESULTS: Mean changes in HRQoL scores were reported for 14 children aged 4-7 years, 21 children aged 8-11 years, 10 adolescents aged 13-16 years, and 163 adults (17 years and above). Mean changes in children/adolescents-reported Haemo-QoL total score were -14.0 for ages 4-7 years, -3.6 for ages 8-11 years, and -0.1 for ages 13-16 years. Mean changes in parent-reported Haemo-QoL total scores were -11.5 for 4-7 years, -8.6 for ages 8-11 years, and -4.0 for 13-16 years. Adults' mean change in Haem-A-QoL total score was -3.1 for those receiving on-demand treatment and -2.3 for those receiving prophylaxis treatment. High levels of TS with N8-GP were reported by parents of children/adolescents and the adults at the end of the trial. CONCLUSION: While most patients reported a relatively good baseline HRQoL when entering the respective trials, the HRQoL of patients was either maintained or further improved when treated with N8-GP. Adults and parents of children and adolescents reported a high level of treatment satisfaction with N8-GP.

Once-weekly prophylaxis with glycoPEGylated recombinant factor VIII (N8-GP) in severe haemophilia A: Safety and efficacy results from pathfinder 2 (randomized phase III trial).

INTRODUCTION: Turoctocog alfa pegol (N8-GP) is a site-specific, 40 kDa glycoPEGylated recombinant factor VIII (FVIII) product with an extended half-life. The comprehensive main phase of the pivotal pathfinder 2 trial showed N8-GP dosed every 4 days (Q4D) provided favourable safety and efficacy for preventing bleeds in 175 patients with haemophilia A. AIM AND METHODS: We investigated the safety and efficacy of N8-GP prophylaxis when administered weekly (Q7D) for 24 weeks to patients with low bleeding rates in the pathfinder 2 extension trial. Patients (≥12 years) with ≤2 bleeds during the preceding 6 months of the pathfinder 2 main phase were eligible for randomization to receive N8-GP 50 IU/kg Q4D or 75 IU/kg Q7D. Safety and efficacy endpoints were incidence of FVIII inhibitors and annualized bleeding rate (ABR), respectively. RESULTS: Fifty-five of 143 (38.5%) patients on prophylaxis who continued into the extension phase were randomized to receive 50 IU/kg Q4D (n = 17) or 75 IU/kg Q7D (n = 38). Nine patients in the Q7D cohort reverted to 50 IU/kg Q4D. No inhibitors were detected. In both cohorts, >50% of patients experienced no bleeds. Median ABR for overall, joint, spontaneous, traumatic and muscle was 0.00 for both cohorts. Overall estimated success rate for treating bleeding episodes was 87.5%; 94.7% of bleeds were controlled with ≤2 injections. CONCLUSIONS: Weekly N8-GP was well tolerated and efficacious and may benefit selected "low bleeder" patients with haemophilia A.

Upfront eltrombopag monotherapy induces stable hematologic remission in pediatric patients with nonsevere idiopathic aplastic anemia.

Aplastic anemia (AA) is characterized by multilineage cytopenias and bone marrow hypocellularity. Severe AA can be treated with immunosuppressive therapy (IST) and/or allogeneic hematopoietic stem cell transplantation. The thrombopoietin agonist eltrombopag has been shown to induce hematopoietic recovery and transfusion independence in adults with refractory and relapsed AA. Recently, upfront eltrombopag therapy in patients with AA in combination with IST has shown efficacy. Data for its use without concurrent IST in pediatric patients with AA remain sparse. Here we report two pediatric patients with AA not meeting severe criteria who achieved hematologic response with upfront eltrombopag monotherapy.

Ringed sideroblasts in ß-thalassemia.

Symptomatic ß-thalassemia is one of the globally most common inherited disorders. The initial clinical presentation is variable. Although common hematological analyses are typically sufficient to diagnose the disease, sometimes the diagnosis can be more challenging. We describe a series of patients with ß-thalassemia whose diagnosis was delayed, required bone marrow examination in one affected member of each family, and revealed ringed sideroblasts, highlighting the association of this morphological finding with these disorders. Thus, in the absence of characteristic congenital sideroblastic mutations or causes of acquired sideroblastic anemia, the presence of ringed sideroblasts should raise the suspicion of ß-thalassemia.

Iron Overload in Survivors of Childhood Cancer.

Iron overload is a significant cause of morbidity and mortality for patients who require frequent transfusions. We completed a prospective, cross-sectional study to evaluate the prevalence of iron overload in previously transfused childhood cancer survivors. Survivors recruited from the University of Minnesota Long-Term Follow-Up Clinic were stratified into 3 groups: oncology patients not treated with hematopoietic stem cell transplantation (HSCT) (n=27), patients treated with allogeneic HSCT (n=27), and patients treated with autologous HSCT (n=9). Serum ferritin was collected and hepatic magnetic resonance imaging (FerriScan) was obtained for those with iron overload (defined as ferritin ≥1000 ng/mL). The prevalence of iron overload in subjects with a history of allogeneic HSCT was 25.9% (95% CI, 9.4%-42.5%) compared with only 3.7% (95% CI, 0%-10.8%) in subjects treated without HSCT and 0% in subjects treated with autologous HSCT. No association was found between serum ferritin levels and the presence of cardiac, liver, or endocrine dysfunction. The prevalence of iron overload in subjects who received no HSCT or autologous HSCT is low in our study. A higher prevalence was found in patients receiving allogeneic HSCT, reiterating the importance of screening these patients for iron overload in accordance with the current Children's Oncology Group Long Term Follow-Up Guidelines.

Reviewing public policy for promoting population oral health in Victoria, Australia (2007-12).

OBJECTIVE: Government policy and planning set the direction for community decisions related to resource allocation, infrastructure, services, programs, workforce and social environments. The aim ofthe present study was to examine the policy and planning context for oral health promotion in Victoria, Australia, over the period 2007-12. METHODS: Key Victorian policies and plans related to oral health promotion in place during the 2007-12 planning cycle were identified through online searching, and content analysis was performed. Inclusion of oral health (and oral health-related) promotion initiatives was assessed within the goals, objectives and strategies sections of each plan. RESULTS: Six of the 223 public health plans analysed (3%) included oral health 'goals' (including one plan representing nine agencies). Oral health was an 'objective' in 10 documents. Fifty-six plan objectives, and 70 plan strategies related to oral health or healthy eating for young children. Oral health was included in municipal plans (44%) more frequently than the other plans examined. CONCLUSION: There is a policy opportunity to address oral health at a community level, and to implement population approaches aligned with the Ottawa Charter that address the social determinants of health.

Endometriosis in adolescents.

BACKGROUND AND OBJECTIVES: Women with endometriosis often report onset of symptoms during adolescence; however, the diagnosis of endometriosis is often delayed. The aim of this study was to describe the experience of adolescents who underwent laparoscopy for pelvic pain and were diagnosed with endometriosis: specifically, the symptoms, time from onset of symptoms to correct diagnosis, number and type of medical professionals seen, diagnosis, treatment, and postoperative outcomes. METHODS: We reviewed a series of 25 females ≤21 years of age with endometriosis diagnosed during laparoscopy for pelvic pain over an 8-year period. These patients were followed up for 1 year after surgery. RESULTS: The mean age at the time of surgery was 17.2 (2.4) years (range, 10-21). The most common complaints were dysmenorrhea (64%), menorrhagia (44%), abnormal/irregular uterine bleeding (60%), ≥1 gastrointestinal symptoms (56%), and ≥1 genitourinary symptoms (52%). The mean time from the onset of symptoms until diagnosis was 22.8 (31.0) months (range, 1-132). The median number of physicians who evaluated their pain was 3 (2.3) (range, 1-12). The adolescents had stage I (68%), stage II (20%), and stage III (12%) disease. Atypical endometriosis lesions were most commonly observed during laparoscopy. At 1 year, 64% reported resolved pain, 16% improved pain, 12% continued pain, and 8% recurrent pain. CONCLUSIONS: Timely referral to a gynecologist experienced with laparoscopic diagnosis and treatment of endometriosis is critical to expedite care for adolescents with pelvic pain. Once the disease is diagnosed and treated, these patients have favorable outcomes with hormonal and nonhormonal therapy.

Successful management of factor IX inhibitor-associated nephrotic syndrome in a hemophilia B patient.

BACKGROUND: Nephrotic syndrome (NS) is a recognized complication of immune tolerance induction (ITI) therapy, a treatment strategy used to treat inhibitors in patients with hemophilia B receiving factor IX concentrate. CASE DIAGNOSIS/TREATMENT: We present a 4-year-old boy with hemophilia B and an inhibitor who underwent ITI, and developed NS 19 months into this therapy. A percutaneous renal biopsy was safely performed with factor IX (FIX) concentrate administration both preceding and following the procedure. The patient's inhibitor level had increased to 1.4-1.6 Bethesda Units just prior to the onset of proteinuria. Histology confirmed segmental membranous nephropathy (MGN). The patient was continued on FIX concentrate as ITI and also received 4 weekly doses of rituximab and ongoing immunosuppression with mycophenolate mofetil. This resulted in the complete resolution of his inhibitor and his NS. He continues with a modified ITI regimen and remains inhibitor-free without proteinuria >12 months post-biopsy. CONCLUSIONS: Hemophilia B patients undergoing ITI should be regularly screened for NS. At first detection of proteinuria, with proper precautions, a percutaneous kidney biopsy can be performed safely in patients with low levels of inhibitor. Our patient had segmental MGN with complete remission of NS.

Clinical course and outcome in children with acute lymphoblastic leukemia and asparaginase-associated pancreatitis.

BACKGROUND: Asparaginase, an agent used in the treatment of acute lymphoblastic leukemia (ALL), is associated with the development of pancreatitis. The clinical course and long-term outcome of patients experiencing this complication has not been extensively detailed. PROCEDURE: We reviewed the clinical course for all children with ALL diagnosed with pancreatitis at the Dana-Farber Cancer Institute/Children's Hospital Boston between 1987 and 2003. The outcome of these patients was compared with that of patients with ALL who did not experience pancreatitis. RESULTS: Twenty-eight of 403 children (7%) were diagnosed with pancreatitis. Patients 10-18 years old at diagnosis had 2.4 times the risk of developing pancreatitis compared with younger patients. Pancreatitis typically occurred early in the course of therapy (median 4 weeks after first dose of asparaginase). Ninety-three percent of affected patients were hospitalized and 57% received parenteral nutrition. No patient developed chronic sequelae or died as a result of pancreatitis. Sixteen (57%) patients were re-treated with asparaginase, 10 of whom had another episode of pancreatitis. No significant differences in event-free survival were observed when comparing patients with and without a history of pancreatitis. CONCLUSION: Asparaginase-associated pancreatitis was more common in older children, and caused significant acute morbidity. It tended to occur after the first few doses of asparaginase, suggesting a predisposition to this complication rather than a cumulative drug effect. Re-treatment with asparaginase after an episode of pancreatitis was associated with a high risk of recurrent pancreatitis.