Upgrading the evidence for the use of ambroxol in Gaucher disease and GBA related Parkinson: Investigator initiated registry based on real life data.

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.

Immunoglobulin Heavy Chain Gene Rearrangements in Patients with Gaucher Disease.

BACKGROUND: Several studies support the evidence of increased incidence of hematological complications in Gaucher disease including monoclonal and polyclonal gammopathies and blood malignancies, especially multiple myeloma. METHODS: Serum concentrations of immunoglobulins and PCR analysis of the IGH gene rearrangements were performed. The clonal PCR products were directly sequenced and analyzed with the appropriate database and tools. Serum monoclonal proteins were detected and identified by electrophoresis. RESULTS: Among 27 Gaucher patients, clonal IGH rearrangement was discovered in eight, with 5/8 having also serum monoclonal protein. Elevated immunoglobulins were detected in 9/27 patients. Follow-up data for 17 patients showed that the clonal rearrangement remained the same in four of them, however, in one patient it disappeared after the follow-up period. The remaining 12/17 patients were without previous IGH clonal rearrangement and remained so after the follow-up. CONCLUSIONS: Although clonal expansion may occur relatively early in the disease course, at least judging by the IGH gene rearrangements in Gaucher patients, the detected clones may be transient. A careful clinical follow-up in these patients is mandatory, including monitoring for lymphoid neoplasms, especially multiple myeloma.

Lymphoblastic lymphomas in children ­ A single-center experience from Serbia.

Introduction: Intensive treatment protocols used for non-Hodgkin lymphoma in children lead to eventfree survival rates ranging from 80% to 90%. However, the results are less successful in developing countries. Lymphoblastic lymphoma (LBL) is the second most frequent type of lymphoma in children, contributing with about one third to all non-Hodgkin lymphoma in childhood. Objective: The aim of the study was to evaluate the results of LBL treatment in University Children's Hospital (UCH), Belgrade. Methods: A retrospective analysis of patient records at UCH from 1997 to 2015 was carried out in patients aged 0­18 years, in whom the diagnosis of LBL had been established. Twenty-two children were included in the analysis. Results: Mean age at diagnosis was 10 years, with preponderance of male patients. All patients were treated according to Berlin-Frankfurt-Münster-based chemotherapy protocols. With median follow-up of 91.5 months, five-year probability of event-free survival was 79.5% for all patients, while overall survival was 81.8%. Conclusion: Our results, although slightly inferior to those of leading international groups, reflect a good treatment outcome in our patients.

Extreme Hypertriglyceridemia in an Infant with Hemophagocytic Lymphohistiocytosis and Hydroxycobalamin Deficiency.

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory condition characterized by fever, cytopenias, hepatosplenomegaly and hemophagocytosis. HLH may be primary or secondary to infection, autoimmune disease or malignancy. Hypertriglyceridemia is a common abnormality in HLH and one of the HLH-2004 diagnostic criteria. CASE OUTLINE: We present an infant with severe hypotonia and hypoproteinemic edema who also had extreme hypertriglyceridemia (21 mmol/l) and was diagnosed with HLH based on six of eight HLH-2004 criteria (fever, hepatosplenomegaly, bicytopenia, hypertriglyceridemia with hypofibrinogenemia, slL-2R > 2400 IU/ml, hemophagocytosis). The presence of IgM antibodies to Epstein-Barr virus and cytomegalovirus indicated a probable infectious trigger. The child was cured by the HLH-2004 protocol for secondary HLH (consisting of dexamethasone and cyclosporine). He was also found to have low serum hydroxycobalamin levels, promptly corrected upon hydroxycobalamin administration. CONCLUSION: The presented case history underlines the need to ascertain the presence or absence of each of the eight HLH-2004 criteria in any patient suspected to suffer from HLH.

Non-Hodgkin lymphomas in childhood: how to move on?

Non-Hodgkin lymphomas of childhood represent a diverse group of neoplasms with different clinical, pathological, immunophenotypical and genetic features. A vast majority of childhood non-Hodgkin lymphomas could be classified into one of the three major histological subgroups: mature B-cell neoplasms, lymphoblastic lymphomas or anaplastic large cell lymphomas. Modern therapeutic strategies lead to cure in more than 80% of patients. Conversely, refractory diseases, as well as disease relapse convey a dismal prognosis. This fact requires much better stratification based on prognostic markers which would ideally recognize distinct groups of patients requiring different therapeutic regimens. Defining novel diagnostic and prognostic markers should improve diagnosis and prognosis as well as patient follow-up. It should also allow introduction of individually tailored treatment regimens in selected groups of patients with non-Hodgkin lymphomas, with the main goal of improving treatment results and decreasing short- and long-term complications.

Gammopathy and B lymphocyte clonality in patients with Gaucher type I disease.

INTRODUCTION: We evaluated a novel approach for investigation of lymphocyte dysregulation in Gaucher patients by including determination of IgH and TCR gene rearrangements together with levels of immunoglobulins, natural autoantibodies as well as presence of monoclonal protein. MATERIALS AND METHODS: Measurement of serum immunoglobulins, monoclonal immunoglobulins, selected autoantibodies, as well as analysis of immunoglobulin heavy chain and T cell receptor gene rearrangements. RESULTS: Immunoglobulin disorder was detected in 29.6% patients, 40.7% demonstrated presence of B cell clonality and 44.4% demonstrated presence of autoantibodies. In five patients in our series, the presence of IgH gene rearrangement was the only detectable indicator of B cell dysfunction. TCR gene rearrangements were not found in any of the patients. CONCLUSION: Based on our results, we propose IgH gene rearrangements as a new biomarker for investigation of B cell dysfunction occurring as a complication of Gaucher disease.

Colon carcinoma in a child treated with oxaliplatin and antiangiogenic treatment regimens.

Colorectal carcinoma is an extremely rare tumor in childhood. Therefore, the role of adjuvant chemotherapy has not been adequately evaluated in children leading to limited data on safety profile and treatment response after application of novel drugs and novel targeted agents. In this report, we describe a case of colon adenocarcinoma in a 13-year-old girl treated with standard adult treatment as well as novel targeted therapy. This case report illustrates initial good disease control with FOLFOX therapy. On the other hand, targeted therapy revealed no improvement in disease control and good safety profile without significant adverse effects.

Pediatric non-Hodgkin lymphoma: a retrospective 14-year experience with Berlin-Frankfurt-Münster (BFM) protocols from a tertiary care hospital in Serbia.

Use of current intensive chemotherapy protocols in pediatric non-Hodgkin lymphoma (NHL) in high-income countries resulted in event-free survival (EFS) rates ranging from 80 to 90%. The results are inferior in less privileged countries with limited resources for medical care. There are no reports about comprehensive data analysis in pediatric NHL in Serbia. A retrospective study was carried out at University Children's Hospital, Belgrade, in children aged less than 18 years diagnosed with non-Hodgkin lymphoma from 1997 to 2011. Fifty-seven children were eligible for analysis. Fourteen were diagnosed with lymphoblastic lymphoma, 38 with mature B-cell NHL (B-NHL), and 5 with anaplastic large-cell lymphoma. Mean age at diagnosis was 9.2 years, with male to female ratio 2.35:1. Children were treated according to Berlin-Frankfurt-Münster (BFM) protocols. With median follow-up of 59.3 months, 5-year probability of EFS was 84.1% for all patients, whereas overall survival was 93%. These results with BFM protocol administration, although inferior to leading international groups, reflect good treatment outcome in our patients. To the best of the authors' knowledge, this article presents the first results regarding treatment and survival of childhood NHL in Serbia.

Biomarkers in Serbian patients with Gaucher disease.

OBJECTIVES: The aim of the study was to evaluate the efficiency of the biomarkers chitotriosidase (Chito), total acid phosphatase (TACP), angiotensin converting enzyme (ACE) and ferritin in the diagnosis of Gaucher disease (GD) and to assess the utility of biomarkers for monitoring the effects of enzyme replacement therapy (ERT). DESIGN AND METHODS: Forty treatment-naive Gaucher patients were studied. 27/40 GP were put on ERT and monitored every 6 months. RESULTS: The baseline median values of Chito, TACP, ACE and ferritin were highly elevated in GP: 10216 nmol/mL/h, 26.1 U/L, 253 U/L, 515 µg/L, and 555 µg/L, respectively. The only significant difference between mild and moderate GP subgroups is observed for Chito activity (p=0.0116). During ERT, Chito showed the steepest decrease in regard to TACP and ACE, mainly within the first year (71.4%). CONCLUSIONS: Among these biomarkers, Chito proved to be the most useful biomarker for diagnosing GD and monitoring the ERT.

Late vitamin K deficiency bleeding in an infant with choledochal cyst.

Infantile choledochal cyst (CC) usually presents as jaundice, vomiting, acholic stools, and hepatomegaly, and it can resemble biliary atresia. Although bleeding tendency is a rare clinical presentation of CC, it can be the first symptom, especially in infants less than 12 months of age. We report a case of a two-month-old infant with choledochal cyst presenting as late vitamin K deficiency bleeding (VKDB). Early recognition of diseases predisposing to VKDB and immediate investigation and treatment of warning bleeds help to prevent the worst consequences. Late VKDB is often the presenting feature of a serious underlying disease that may be recognized early. The sudden onset of bleeding tendency in infants with congenital liver or biliary tract disease may suggest not only biliary atresia but also, although extremely rare, CC. Early vitamin K administration leads to rapid normalization of hemostatic parameters, which enables major liver surgery.

Ruptured intramural intestinal hematoma in an adolescent patient with severe hemophilia A.

We report on a 17-year-old patient with severe hemophilia A without inhibitors who developed abdominal bleeding after an episode of severe cough. Abdominal ultrasound showed intramural intestinal hematoma as well as large amount of peritoneal fluid appearing as blood and right hematocele. Abdominal CT revealed markedly thickened intestinal wall in sigmoidal region. Patient was managed with replacement therapy as well as peritoneal drainage with favorable outcome. This is the first report on a hematoperitoneum in a hemophiliac due to ruptured intramural sigmoidal hematoma.

Bone marrow findings in juvenile idiopathic arthritis.

The diagnosis of juvenile idiopathic arthritis (JIA) is an exclusion one due to heterogeneous clinical presentation and lack of specific laboratory tests. The authors investigated bone marrow of 25 untreated children with JIA at the onset of the disease. Bone marrow smears were evaluated for cell populations as well as myelodysplastic features and compared to two control groups. The characteristic of bone marrow in JIA was myeloid hyperplasia and elevated plasmocyte count. There was no difference between JIA patients and control groups in terms of myelodysplastic features. These findings can be helpful in explaining hematological alterations in JIA.

[Treatment of psoas haematoma in a patient with haemophilia and inhibitors].

INTRODUCTION: Particular problem in treating haemophiliacs with serious muscle bleeding such as iliopsoas haematoma, are patients with inhibitor. CASE OUTLINE: Our study describes three episodes of psoas haematoma in a patient with haemophilia and inhibitor successfully treated with recombinant activated factor VII (rFVIIa). CONCLUSION: Based on our experience, initiating therapy within two hours in our patient, contributed to successful treatment, although small cumulative doses of rFVIIa were used. Therefore, introducing home treatment along with adequate patient and family education similar to developed countries becomes imperative in our environment, not only for providing better quality of life, but also from pharamaco-economic point of view.

[Rehabilitation in haemophilic children with inhibitors using recombinant activated factor VII].

INTRODUCTION: During invasive and orthopaedic procedure of the joints, physical therapy is a necessary modality for successful recovery, especially in patients with haemophilia. These patients require concurrent substitution therapy. Recombinant activated factor VII (rFVIIa) has been successfully used in treating haemophilia with inhibitor, especially during preoperative preparation. Nevertheless, optimal substitution therapy during perioperative physical therapy has been poorly defined. CASE OUTLINE: In our paper, we review the literature and the course of perioperative rehabilitation after synovectomy in a 16-year-old haemophilic patient with high-titre inhibitor, treated with rFVIIa. Rehabilitation was started on day 3 after surgery, with rFVIIa substitution lasting ten days and followed by intermittent dosages during episodes of pain. After concluding physical treatment, a significantly better function of the operated joint was recorded, which led to the recovery of walking without orthopaedic aid. CONCLUSION: Patients with inhibitors require individualized approach of a multidisciplinary team in order to achieve optimal results in elective orthopaedic procedures.

Myeloid sarcoma presenting with bilateral proptosis and kidney infiltration.

The authors describe a male infant with a history of transient pancytopenia who developed progressive bilateral proptosis associated with diffuse infiltration of the kidney and normal bone marrow. The histopathological examination of the kidney revealed diffuse infiltration of cells of myeloid origin with monocytic differentiation. Although orbital involvement by myeloid sarcoma, with or without concurrent acute myeloid leukemia, is well known, there are distinctive features in this patient that are not reported in the literature, namely bilateral proptosis and simultaneous presence of bilateral kidney infiltration, which enabled diagnosis.