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Introduction For the last three decades, enzyme replacement therapy (ERT) for Gaucher disease (GD) has been available. We aimed to evaluate the effect of ERT on the pregnancy and obstetric outcome in a unique group of multiparous women with type 1 GD (GD1) who had pregnancies with and without ERT. Study design The Gaucher Unit database (1987-2019) was searched for multiparous women who had pregnancies before and after the institution of ERT. Data were collected from the clinic files and study-specific questionnaires. Descriptive, correlation analysis and generalized estimating equations (GEE) were used to study the effect of ERT and confounding variables on study outcomes. Results We identified 19 women with 105 pregnancies, among which 26 (24.7%) terminated in first-trimester miscarriage. The risk for miscarriage was associated with the severity of GD1 genotype and phenotype, but not with ERT usage. Early postpartum hemorrhage (PPH) was reported in 16 (84%) women after 25 deliveries (31.6%, 95% CI 21.6%-43.1%). The risks of early PPH and red blood cell (RBC) transfusions were significantly lower when ERT was used during pregnancy, OR (95% CI) 0.13 (0.03-0.54) and 0.27 (0.08-0.94), respectively, compared to pregnancies without the use of ERT. Conclusion Enzyme replacement therapy during pregnancy is risk reducing for early PPH and RBC transfusions in women with GD1. We suggest considering ERT for the benefit of all pregnant women with GD1, including mild GD1. This article is protected by copyright. All rights reserved.

Ambroxol hydrochloride is an oral mucolytic drug available over-the-counter for many years as cough medicine. In 2009 it was identified as a pharmacological chaperone for mutant glucocerebrosidase, albeit in a several-fold higher dose. Unfortunately, there have been no pharma-driven clinical trials to establish its use. Thus, real-world observational data are needed on the safety and efficacy of ambroxol for patients with Gaucher disease (GD) and GBA-Parkinson disease (GBA-PD). Clinicians treating patients with ambroxol for GD and GBA-PD were approached to collaborate in an investigator-initiated registry. Anonymized data were collected, including demographics, GD type, GD-specific therapy (when applicable), adverse events (AEs), and, when available, efficacy data. We report the data of the first 41 patients (25 females) at a median (range) age 17 (1.5-74) from 13 centers; 11 with GD type 1(four diagnosed with PD), 27 with neuronopathic GD (nGD), and three GBA mutation carriers with PD. The median (range) treatment period and maximum dose of ambroxol were 19 (1-76) months and 435 (75-1485) mg/day, respectively. One patient with type 2 GD died of her disease. No other severe AEs were reported. Twelve patients experienced AE, including minor bowel discomfort, cough, allergic reaction, mild proteinuria, dizziness and disease progression. Clinical benefits were reported in 25 patients, including stable or improved neurological status, increased physical activity, and reduced fatigue. Until the approval of specific therapies for nGD and disease-modification for GBA-PD, these preliminary data may be encouraging to physicians and patients who consider an off-label use of ambroxol.

Background Venous thromboembolism (VTE) is an increasingly recognized problem among children and adolescents. Although inferior vena cava (IVC) filter placement for pulmonary embolism prevention is well reported in adults, data regarding safety and efficacy in the pediatric age group are lacking. Procedure At a large university hospital with a level I trauma center, medical records of children and adolescents who underwent IVC filter insertion were reviewed. Appropriateness of referral for retrieval was assessed in each case. Results Fifty-nine children and adolescents (mean age 16 years) successfully underwent IVC filter insertion. All filters placed were retrievable. In 47 patients (79.7%), prophylactic filters were placed in the absence of acute VTE in the setting of trauma. In eight patients (13.5%), filters were placed due to contraindication to anticoagulation therapy with concomitant lower extremity deep vein thrombosis or pulmonary embolism. Filters were successfully retrieved in only 12 patients (20.3%), although an attempt at removal was appropriate and feasible in over 90% of cases. Mean duration of follow-up was 2.1 (range 0.4–7.3) years. A significantly higher retrieval rate was found in patients followed at our thrombosis clinic (P

Background Cytochrome P450 1A2 (CYP1A2) is a cytochrome enzyme with a pivotal role in hepatic drug metabolism. Data from CYP1A2(−/−) mouse suggest that CYP1A2 plays a role in aspects of hepatic iron toxicity. The aim of this study was to assess the activity of CYP1A2 in relation to hepatic iron load in patients with transfusion-dependent β-thalassaemia major. Methods The 13C-methacetin continuous breath test was performed on 30 consecutive patients with transfusion-dependent β-thalassaemia major. CYP1A2 activity was measured by the rate at which the 13C substrate is metabolized and exhaled expressed as percentage dose recovery (PDR) per hour. CYP1A2 activity was correlated with clinical and laboratory parameters and hepatic iron accumulation by T2* magnetic resonance imaging (T2*MRI). Results Cytochrome P450 1A2 activity in patients with transfusion-dependent β- thalassaemia major was positivity correlated with plasma ferritin levels. No correlation was found with age, duration and amount of red blood cell transfusion and type of iron chelation therapy. Low CYP1A2 activity was negatively associated with hepatic iron accumulation (T2*MRI ≤ 6·3 ms); adjusted odds ratio (OR; 95% CI) for hepatic iron accumulation in patients with low CYP1A2 activity was 0·047 (0·003–0·72; P = 0·021). Of the six patients with decreased activity of CYP1A2, five had no hepatic iron accumulation and one had mild hepatic iron accumulation by T2*MRI. Conclusion Activity of CYP1A2 is associated with hepatic iron accumulation in patients with transfusion-depended β-thalassaemia major. Further studies are needed to assess the exact role of CYP1A2 in iron metabolism in human.

Background Although the use of central venous catheters (CVCs) has greatly improved the quality of care of children with cancer, these catheters increase the risk of deep vein thrombosis (DVT) and the potential long-term complication of post-thrombotic syndrome (PTS). We aimed to study PTS post-CVC removal using physical, functional and health related quality of life (HRQoL) domains in childhood cancer and bone marrow transplantation (BMT) survivors. Procedure We conducted a prospective study in a cohort of childhood cancer and BMT survivors post-CVC use. Participants were evaluated for PTS with the Modified Villalta Score (MVS) and the Manco-Johnson Instrument (MJI). HRQoL was assessed using the PedsQL™ questionnaire. Results A total of 158 children were enrolled at a median of 41 (4–149) months from CVC removal. Signs and symptoms of PTS were present in 34% (95% confidence interval [CI] 27–43%) (MVS criteria) and 30.5% (95% CI 23.1–37.8%) (MJI criteria). Diagnosis of PTS was associated with history of CVC occlusion, history of CVC-related DVT and the use of ≥2 CVCs. The presence of signs and symptoms of PTS was a predictor for low HRQoL tested by the PedsQL™ Total Scale scores and Physical Health Summary scores. Conclusions PTS post-CVC removal in pediatric cancer survivors is not a rare event. The association between PTS and the history of CVC occlusion confirms earlier findings, and suggests that CVC occlusion may indicate asymptomatic DVT. PTS is also associated with lower HRQoL scores highlighting the need to study preventive measures, especially for high risk groups. Pediatr Blood Cancer 2015;62:285–290. © 2014 Wiley Periodicals, Inc.

Background The use of central venous catheters (CVCs) has greatly improved the quality of care in children receiving chemotherapy, yet these catheters may cause serious infectious complications. The aim of this prospective registry study was to assess the host and CVC-related risk factors for blood stream infections (BSIs). Procedure Patients undergoing CVC insertion for chemotherapy were followed prospectively for CVC complications. At the time of enrollment demographic-, clinical- and CVC-related data were collected. Survival and Cox-regression analysis were performed. Results A total of 423 CVCs were inserted into 262 patients for a total of 76,540 catheter-days. The incidence of BSIs was 1.95 per 1,000 patient-days (95% CI 1.66–2.29). Myeloid leukemia and younger age were associated with higher risk for BSI. At least one BSI occurred in 187 CVCs with an incidence of 2.84 per 1,000 catheter-days (95% CI 2.47–3.24). Externalized CVCs, that is, tunneled externalized catheters and peripheral inserted central catheters, were associated with higher risk for BSI in the group of diseases with relatively lower rate of infection. However, in diseases with high rate of infection no such association was found. The type of BSI was associated with the diagnosis and the CVC type. CVC occlusion was associated with higher risk for recurrent BSI and for coagulase negative staph BSI. Conclusions Both patient and CVC-related factors are associated with higher risk of BSI in children receiving chemotherapy. The results of this study could be used in developing studies aiming to reduce the rate of BSIs in children with cancer. Pediatr Blood Cancer 2015;62:471–476. © 2014 Wiley Periodicals, Inc.

Summary. Brain insults are a risk factor for neuropsychological and academic deficits across several paediatric conditions. However, little is known about the specific effects of intracranial haemorrhage (ICH) in boys with haemophilia. The study compared neurocognitive, academic and socio-emotional/behavioural outcomes of boys with haemophilia with and without a history of ICH. Of 172 consecutive patients seen at a Pediatric Comprehensive Care Hemophila Centre, 18 had a history of ICH. Sixteen boys between the ages of 3 and 17 years were available for study and were matched to controls with haemophilia of the same age and disease severity and on the basis of maternal education. Groups were compared on neuropsychological and academic outcomes. Attention, socio-emotional function and executive skills were compared using data from parent questionnaires. Differences were found in intellectual function, visual-spatial skill, fine motor dexterity and particularly language-related skills, including vocabulary, word reading and applied math problem solving. Despite these group differences, outcomes were within the average range for most boys with ICH. No group differences were found in behavioural and socio-emotional functioning. Although ICH in haemophilia is not benign, it was not associated with significant cognitive and academic consequences for most boys. Early neuropsychological assessment may be indicated when there is a history of ICH. Investigation of age at ICH and quantitative measures of brain in relation to neurocognitive outcomes in larger groups of boys with ICH would be useful.

Summary. Hepatitis in children with haemophilia was historically most often associated with transfusion-transmitted infections. However, with the use of recombinant clotting factor concentrates, acquisition of such infections has now become rare. We studied the profile of hepatitis in North-American children with haemophilia in the modern era of safe blood products and excess childhood obesity. A total of 173 boys (

Summary Patients with type I Gaucher Disease (GD) may have a clinically significant bleeding tendency that is disproportionate to their platelet count. We hypothesized that impaired platelet adhesion might contribute to bleeding tendency. Adult patients with type I GD with platelet counts ‡130 · 10 9 /l and haematocrit ‡30% (n = 48), obligatory carriers (n = 52), and healthy controls (n = 19) were studied. Platelet adhesion, using the IMPACT-R (Cone and Plate(let) Analyser), and platelet aggregation were determined. Type I GD patients had significantly lower platelet adhesion [surface coverage %, median (interquartile range)] 4AE 6( 3 AE2‐7AE5), compared to controls, 8AE7 (7AE6‐10AE3), or carriers, 8AE 1( 6 AE5‐9AE4; P =0 AE001). Platelet adhesion was not affected by the use of disease-specific enzyme replacement therapy but was improved in patients after splenectomy, 7AE 2( 5 AE8‐9AE3). Mixing tests showed that the reduced adhesion was an intrinsic platelet defect. Mucosal bleeding was reported in 17 (35AE4%) patients and was associated with abnormal adhesion [P =0 AE037, with an Odds Ratio (95% confidence interval) of 5AE73 (1AE1‐29AE6)]. Five patients (22%) had reduced platelet aggregation, all of whom had reduced platelet adhesion. Platelet aggregation defect was not associated with mucosal bleeding. In conclusion, platelet adhesion defect is a major thrombocytopathy in type I GD patients and can explain part of the increased tendency to bleeding.

A 3-year-old boy with failure to thrive and severe adenotonsillar hypertrophy with a clinical presentation of prolonged obstructive sleep apnea (OSA), was referred to the emergency room due to severe respiratory distress and anasarca. Echocardiography revealed right heart failure, a cystic lesion in the right ventricle and severe pulmonary hypertension. D-dimer was elevated but spiral computerized tomography (CT) and lung scan did not show any perfusion defects. Excision of the cardiac lesion during open-heart surgery, lung biopsy, and adenotonsillectomy were performed. Pathological examination showed an intracadiac organized thrombus and eccentric intimal fibrosis of the pulmonary arteries-which is a pathognomonic of pulmonary arterial microemboli. Brain CT revealed vein thrombosis of the left sigmoid sinus. Blood tests for inherited thrombophilia were normal. Today, 5 years after adenotonsillectomy, the child is normally developed, completely asymptomatic, free of any medications, and has a normal echocardiography. This case report may indicate that prolonged OSA can be a procoagulant state which can cause severe cardiovascular morbidity in children.

BACKGROUND: The use of central venous catheters (CVCs) has greatly improved the quality of care in children with cancer, yet these catheters may cause serious infectious and thrombotic complications. The aim of this prospective registry study was to assess the host and CVC-related risk factors for CVC-created thrombotic complications. METHODS: Patients undergoing CVC insertion for chemotherapy were followed prospectively for CVC complications. At the time of enrollment, demographic, clinical, and CVC-related data, and family history of thrombosis were collected. Survival and Cox regression analyses were performed. RESULTS: A total of 423 CVCs were inserted into 262 patients for a total of 76,540 catheter days. The incidence of CVC-related deep-vein thrombosis (DVT) was 0.13 per 1000 catheter-days (95% confidence interval [CI], 0.06-0.24). Insertion of peripherally inserted central catheters (PICCs) and insertion in an angiography suite significantly increased the risk of symptomatic CVC-related DVT. The incidence of CVC occlusion was 1.35 per 1000 catheter-days (95% CI, 1.1-1.63). Positive family history of thrombosis significantly increased the risk of CVC occlusion (hazard ratio [HR], 2.16; 95% CI, 1.2-3.8). The CVC-related risk factors were insertion of Hickman catheters, insertion in angiography suite, and proximal-tip location. Patients developing at least 1 episode of both CVC occlusion and infection had an increased risk for developing symptomatic CVC-related DVT (HR, 4.15; 95% CI, 1.2-14.4). CONCLUSIONS: Both patient-related and CVC-related factors are associated with higher risk of symptomatic thrombotic complications. These risk factors could be used in the clinical setting and in developing future studies for CVC thromboprophylaxis. Cancer 2010;116:4197–205. V C 2010 American Cancer Society.

Background A potential long-term complication of central venous catheter (CVC)-related deep vein thrombosis (DVT), both symptomatic and asymptomatic, is development of post-thrombotic syndrome (PTS) characterized by persistent pain, swelling, and skin changes. Signs and symptoms of PTS were reported after CVC removal. The aim of this study was to assess the risk factors for development of PTS in childhood cancer survivors. Procedure Children followed at the after cancer follow-up clinic were enrolled. The patients were screened for PTS using Kuhle's PTS pediatric score. Patient's records were retrospectively reviewed for clinical and CVC-related data. Results Fifty-one children were enrolled at a median of 2.3 (range 0.33–7.5) years after removal of their CVC. The median age of the children the time of treatment was 6.5 (range 0.25–18) years. Mild PTS was present in 20 children (39%, 95% CI 26–54%). Pain symptoms were reported in five children (9.5%, 95% CI 3.3–21.4%). Higher rate of PTS was found in children with history of CVC occlusion. The odd ratio (95% CI) for PTS in children with history of occlusion was 3.7 (95% CI 1.1–12.5%) (P = 0.029). The occurrence of PTS was not associated with age at the time of treatment, time from CVC removal, duration of CVC, and history of infection. Conclusions Screening cancer survivors for PTS after CVC removal should be integrated to the after cancer follow-up clinic. Obstruction of CVC may indicate for asymptomatic DVT. Whether thromboprophylaxis and/or prevention of CVC occlusion can decrease the rate of PTS needs to be studied. Pediatr Blood Cancer 2010;55:153–156. © 2010 Wiley-Liss, Inc.

Factor VIII (FVIII) replacement by continuous infusion (CI) is used postoperatively or after significant bleeding. For young paediatric patients, CI may require FVIII dilution. Variable stabilities of diluted full-length recombinant FVIII Kogenate FS (KG-FS) have been reported under different storage conditions. We investigated the recovery and stability of diluted KG-FS in vitro and in vivo. Kogenate FS was diluted to 50-120 U mL(-1) and its recovery and stability in glass vials or polypropylene syringes was determined. Furthermore, stability of KG-FS diluted to 80 U mL(-1)'administered' via single- and double-pump mock CI systems was tested. Finally, the in vivo stability of KG-FS diluted to approximately 60 U mL(-1) and administered postsurgically by CI with the double-pump to a paediatric patient with severe haemophilia A undergoing implantable venous access device placement was investigated. Initial KG-FS dilution resulted in a 10-20% FVIII loss; a further 25-30% loss occurred over 72 h in vials or syringes. With the double-pump, 1 h recovery was 35%, increasing to 80% by 24 h; the initial losses were because of the Y-infusion of a 10-fold larger volume of saline concomitantly with the FVIII. In vivo, CI resulted in stable FVIII activity levels within the target range. These in vitro results are important for the generation of CI guidelines for diluted KG-FS in the paediatric haemophilic population. That FVIII losses occur upon dilution and with the double-pump does not preclude use of diluted KG-FS. Indeed, stable FVIII levels were maintained when diluted KG-FS was administered by CI with the double-pump to a paediatric patient postsurgically.

Stage 4s neuroblastoma (NB) is a unique entity seen in infants less than 1 year of age, with metastatic disease confined to liver, skin, or bone marrow. Despite metastatic spread, stage 4s NB has a favorable outcome. An exception to this is seen in neonates who present with progressive enlargement of the liver with secondary respiratory compromise and liver failure. We describe a 4-week-old neonate who presented with 4s NB, with a rapidly enlarging liver, resulting in respiratory and hepatic failure, who had a rapid, sustained, and ongoing response to chemoembolization of the hepatic artery. This approach is feasible at this age, and may be effective in improving the outcome in this group of patients.

Desmopressin (DDAVP) increases plasma factor VIII coagulant activity (FVIII:C) levels in patients with mild/moderate haemophilia A. In some subjects, FVIII can be increased to haemostatic levels, thereby avoiding use of factor VIII concentrates. We reviewed our hospital's experience with 62 boys with FVIII:C levels 0.01-0.3 IU/ml who had a DDAVP challenge test (i.v. 0.3 microg/kg) following diagnosis. A therapeutic response was defined as a 1 h post-FVIII:C increase at least twofold over baseline and > 0.3 IU/ml. Of the total group, 29 (47%) boys responded to DDAVP, all of them with mild haemophilia (baseline FVIII:C > or = 0.05 IU/ml), yielding a response rate of 57% in this subgroup. Boys who responded to DDAVP had higher baseline FVIII:C levels (mean +/- SEM, 0.17 +/- 0.01 vs 0.10 +/- 0.01 IU/ml, P < 0.01) and were older (5.2 +/- 0.8 vs 3 +/- 0.4 years, P = 0.02) than those who failed to do so. The association between DDAVP response and age, however, remains unclear: seven boys who failed the initial challenge test responded to re-challenge after a mean of 6.3 years (median 4.9, range 0.5-12.5), increasing the response rate in boys with mild haemophilia to 71%. Age and FVIII:C association with DDAVP response are both important in boys with mild/moderate haemophilia A. Absence of response to DDAVP should therefore be confirmed by later re-challenge.

We report a successful umbilical cord blood transplantation (UCBT) in an 8-month male with Wiskott–Aldrich syndrome (WAS) and congenital cytomegalovirus (CMV) infection. The child presented at 3 months of age with symptomatic thrombocytopenia and CMV infection. Despite appropriate antiviral treatment no rise in the platelet count was observed. Genetic analysis confirmed the diagnosis of WAS. The clinical course was complicated by severe CMV retinitis with bilateral retinal hemorrhages and renal vasculitis. He underwent unrelated UCBT resulting in a rapid resolution of autoimmunity and thrombocytopenia. Pediatr Blood Cancer 2011; 57: 681–683. © 2011 Wiley-Liss, Inc.

We describe a 12-year-old boy male who presented with an expressive dysphasia after completion of treatment for unifocal Ewing sarcoma. CNS vasculitis was diagnosed by MRI/MRA and cerebral angiography. Extensive rheumatologic work-up failed to identify an underlying primary process. Restaging studies showed no evidence of tumor. Complete neurologic recovery was achieved on prednisone. Four months later the patient developed overt, extensive metastases, confirmed by biopsy to represent recurrent Ewing sarcoma. Despite intensive therapy the patient succumbed 6 months later. This case demonstrates the unique finding of isolated CNS vasculitis as a presenting sign of Ewing sarcoma. Pediatr Blood Cancer 2010;54:326–328. © 2009 Wiley-Liss, Inc.