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Sickle cell disease is a hereditary multiorgan disease that is considered rare in the EU. In 2017, the Rare Diseases Plan was implemented within the EU and 24 European Reference Networks (ERNs) were created, including the ERN on Rare Haematological Diseases (ERN-EuroBloodNet), dedicated to rare haematological diseases. This EU initiative has made it possible to accentuate existing collaborations and create new ones. The project also made it possible to list all the needs of people with rare haematological diseases not yet covered health-care providers in the EU to allow optimised care of individuals with rare pathologies, including sickle cell disease. This Viewpoint is the result of joint work within 12 EU member states (ie, Belgium, Cyprus, Denmark, France, Germany, Greece, Ireland, Italy, Portugal, Spain, Sweden, and The Netherlands), all members of the ERN-EuroBloodNet. We describe the role of the ERN-EuroBloodNet to improve the overall approach to and the management of individuals with sickle cell disease in the EU through specific on the pooling of expertise, knowledge, and best practices; the development of training and education programmes; the strategy for systematic gathering and standardisation of clinical data; and its reuse in clinical research. Epidemiology and research strategies from ongoing implementation of the Rare Anaemia Disorders European Epidemiological Platform is depicted.

Thyroid nodules are not uncommon, and may affect 2 to 6 percent of the population. When thyroid scans are performed to diagnosis thyroid disease, many of these nodules do not take up the radioactive tracer, and are therefore referred to as 'cold'; cold nodules may be cancerous. However, because nodules are so common and only infrequently cancerous, the surgical removal of all cold nodules is not practical. When there is concern that a cold thyroid nodule might be cancerous, a simple method of evaluation is fine needle aspiration biopsy, which can provide important diagnostic information on the basis of a rapid, safe, and inexpensive procedure. A total of 5,605 nodules from 4,609 patients were evaluated by biopsy and classified as malignant, follicular lesions, or benign growths. The results of the aspiration biopsy of 827 nodules from patients who then underwent surgery were compared with the pathological analysis of the surgical specimens. Six nodules that had not been judged cancerous at biopsy were found to be malignant; three of these were among nodules that had been classed as suspicious, and the other three had been classed as benign. The total false-negative rate was 2.3 percent. Of the nodules that had been considered malignant at biopsy, 1.1 percent proved to be benign at surgery. The authors conclude that the fine needle aspiration biopsy is an accurate method for assessing cold thyroid nodules and provides a rational basis for determining which patients require surgical intervention. (Consumer Summary produced by Reliance Medical Information, Inc.)

Primary autoimmune neutropenia (pAN) is typified by onset in early infancy and a mild/moderate phenotype that resolves within 3 years of diagnosis. In contrast, secondary AN is classically an adult disease associated with malignancy, autoimmunity, immunodeficiency, viral infection, or drugs. This study describes a cohort of 79 children from the Italian Registry who, although resembling pAN, did not fully match the criteria for pAN because neutropenia either appeared after age 5 years (LO-Np) or lasted longer than 3 years (LL-Np). These 2 categories compared with classical pAN showed a far inferior rate of resolution (P < .001), lower severity of neutropenia (P = .03), leukopenia (P < .001), lymphopenia (P < .001) with low B+ (P = .001), increased need of granulocyte colony-stimulating factor (P = .04), and increased frequency of autoimmunity over the disease course (P < .001). A paired comparison between LO-Np and LL-Np suggested that LO-Np had a lower rate of resolution (P < .001) and lower white blood cell (P < .001) and lymphocyte (P < .001) values, higher occurrence of apthae (P = .008), and a stronger association with autoimmune diseases/markers (P = .001) than LL-Np, thus suggesting a more pronounced autoimmune signature for LO-Np. A next-generation sequencing panel applied in a small subgroup of LO-Np and LL-Np patients identified variants related to immune dysregulations. Overall, these findings indicate that there are important differences among pAN LL-Np and LO-Np. Forms rising after 3 years of age, with low tendency to resolution, require tight monitoring and extensive immune investigations aimed to early identify underlying immunologic disease.

Supplemental Digital Content is available in the text.T-lineage ALL is an aggressive disease that needs to be treated with intensive treatment schedules. A late relapse rarely occurs and a clear choice for second-line treatment is on debate. We report on a young adult with a very late isolated extramedullary relapse of PICALM-MLLT10positive T-ALL, successfully treated with a chemotherapy-based and radiotherapy-based pediatric protocol. We demonstrate that relapse can occur in T-ALL although a SR-MRD behavior treated with a high-risk protocol; specific molecular diagnostic aberrations, as PICALM-MLLT10, are still conserved at very late relapse; a second-line treatment based on pediatric protocol can be effective.

Background.Successful treatment of B-lineageAcute Lymphoblastic Leukemia (B-ALL) in children has been related to novel biological findings and a better supportive therapy. Genomic aberrations have a major role in development of ALL and in the treatment response. Conventional treatment is based on chemotherapy, mainly acting on the structure of DNA in both leukemic and host cells. The result is a complete achievement of durable remission and/or a high incidence of toxicity. The role of DNA repair machinery in the occurrence of de novoor relapsed ALL and of high-grade toxicity is still unclear. We decide to dissect genes involved in the Fanconi Anemia (FA) pathway ( BRCA1, BRCA2, FANCD2 and PALB2), which cooperates with the Nijmegen breakage syndrome ( NBS1) gene. We evaluate the correlation of DNA repair machinery alterations with occurrence of relapse and/or with severe (III-IV grade - CTCAE) toxicity during chemotherapy treatment.

Supplemental Digital Content is available in the text.

Hepatoblastoma (HB), a primary liver tumor in childhood, is often accompanied by alpha-fetoprotein (AFP) secretion, and sometimes by ß-human chorionic gonadotropin hormone (ß-hCG) secretion, and this can cause peripheral precocious puberty (PPP). We describe a case of PPP associated with HB. Laboratory tests showed an increase in AFP, ß-hCG and testosterone values, and suppression of follicle-stimulating hormone and luteinizing hormone levels. After chemotherapy and surgery, AFP, ß-hCG and testosterone levels normalized and signs of virilization did not progress further. The child did not show evidence for tumor recurrence after 16 months of follow-up. New therapeutic approaches and early diagnosis may ensure a better prognosis of virilizing HB, than reported in the past. Assessment of PPP should always take into account the possibility of a tumoral source.

EDITOR--The clinical review on leishmaniasis by Davies et al focuses on new developments in developing countries, where the disease is endemic. (1) However, leishmaniasis also occurs in all Mediterranean areas, [...]

Abnormalities of platelet size are one of the distinguishing features of inherited thrombocytopenias (ITs), and evaluation of blood films is recommended as an essential step for differential diagnosis of these disorders. Nevertheless, what we presently know about this subject is derived mainly from anecdotal evidence. To improve knowledge in this field, we evaluated platelet size on blood films obtained from 376 patients with all 19 forms of IT identified so far and found that these conditions differ not only in mean platelet diameter, but also in platelet diameter distribution width and the percentage of platelets with increased or reduced diameters. On the basis of these findings, we propose a new classification of ITs according to platelet size. It distinguishes forms with giant platelets, with large platelets, with normal or slightly increased platelet size, and with normal or slightly decreased platelet size. We also measured platelet diameters in 87 patients with immune thrombocytopenia and identified cutoff values for mean platelet diameter and the percentage of platelets with increased or reduced size that have good diagnostic accuracy in differentiating ITs with giant platelets and with normal or slightly decreased platelet size from immune thrombocytopenia and all other forms of IT.

• Individual variability in pain perception and differences in the efficacy of analgesic drugs are complex phenomena and are partly genetically predetermined.• Analgesics act in various ways on the peripheral and central pain pathways and are regarded as one of the most valuable but equally dangerous groups of medications.• While pharmacokinetic properties of drugs, metabolism in particular, have been scrutinised by genotype–phenotype correlation studies, the clinical significance of inherited variants in genes governing pharmacodynamics of analgesics remains largely unexplored (apart from the µ-opioid receptor).• Lack of replication of the findings from one study to another makes meaningful personalised analgesic regime still a distant future.• This narrative review will focus on findings related to pharmacogenetics of commonly used analgesic medications and highlight authors’ views on future clinical implications of pharmacogenetics in the context of pharmacological treatment of chronic pain.

The aim of the present study was to determine the effects of exclusive oral iron supplementation (iron sulphate 2 mgkgdie) in asymptomatic children with severe iron-deficiency anemia median hemoglobin (Hb) level before treatment 6.3 gdL; range 4.5 to 7 gdL and to investigate the accuracy of Hb, reticulocyte hemoglobin content (CHr), and absolute reticulocyte count (ARC) as markers for monitoring early response to treatment. The increase in ARC and CHr was statistically significant at day 3. There was a significant association between suitable logarithmic functions of the percentage increase in CHr and ARC at day 3 and the fraction of required Hb increase compared with baseline to reach the mean reference value for age and sex at day 14. If these results are confirmed in a larger population, ARC and CHr could be considered affordable and widely available markers to detect early responders to oral iron therapy, and to switch unresponsive children to parenteral iron supplementation or transfusion.

Urinary clearance of 18F-FDG and variability in bladder wall FDG uptake may hamper the interpretation and limit the use of FDG-PET/CT for imaging bladder tumors. Nevertheless, careful combined evaluation of both CT and FDG-PET images of the urinary tract can provide useful findings. We present 2 cases of bladder cancer detected by FDG-PET/CT. These cases suggest that FDG uptake can be indicative of malignancy in bladder cancer when viewed in conjunction with CT scans and that whole-body FDG-PET/CT scans should always be reviewed with particular attention to the urinary tract because abnormalities suggestive of bladder cancer can be found unexpectedly.

To verify the existence of a symptomatic form of restless legs syndrome (RLS) secondary to multiple sclerosis (MS) and to identify possible associated risk factors.

This work focuses on the study of uniaxial elongational flow and its effects on morphology and stiffness of polyamide‐6 based nanocomposites prepared by melt compounding. The elongational flow characterization was realized by converging flow method and fiber spinning technique. During the haul‐off tests, fibers of the neat polyamide‐6 and the hybrids (at 3 and 6 wt% of silicate) were collected at different draw ratios. Mechanical properties of the produced fibers were investigated and correlated to their nanostructure through analytical techniques sensitive to different aspects of morphology, such as DSC and TEM analysis. Rheological results, obtained with a capillary rheometer, indicate that the shear viscosity decreases with the silicate loading, while the extentional viscosity increases. Moreover, the presence of the silicate in polymer matrix leads to enhancements of draw‐down force and reduction of the breaking draw ratio. In hybrid fibers an enhanced degree of exfoliation of the filler was observed upon drawing. Moreover, DSC analyses suggest that the crystalline structure of the fibers is the result of two opposite effects: the presence of the silicate which stabilizes the γ form and the drawing which promotes the α crystal phase. The degree of silicate exfoliation and the amount of the different crystal phases strongly affect the tensile properties of the fibers.

Introduction

Data on epidemiology and survival after fungal infections in patients with cancer are primarily based on studies in adults, whereas few data are available on children.

The record history of running, swimming and ice-skating, over various distances, was analyzed. A mean period of about 66 years for the 18 male events and of about 50 years for the 14 female events was studied. Over a given distance the velocity (v) was related to the dates of the records minus 1900 (T) according to polynomial functions like: $${\text{v}} = {\text{ a}}_{\text{0}} + {\text{a}}_{\text{1}} {\text{T}} + {\text{a}}_{\text{2}} {\text{T}}^{\text{2}} + ..... + {\text{a}}_{\text{n}} {\text{T}}^{\text{n}}$$

In order to evaluate the risk of malignancy of cold thyroid nodules occurring in young as compared with adult patients, we studied a consecutive series of 2327 patients with a solitary cold thyroid nodule over a 6-year period. None of these patients had been previously irradiated in the neck or head. Fine needle aspiration of the nodule and cytologic examination were carried out in all patients and, on the basis of this evaluation and clinical examination 391 patients were selected for surgery; 109 patients were 4–20 years old and 2218 patients were older than 20 years. Malignancy was found in 11 (10.1%) and in 112 (5.0%) of cold thyroid nodules occurring in young and adult patients, respectively. The annual incidence of cold thyroid nodules in the population of the area studied was 5.2 vs 55.9 (per 105inhabitants) in the young and in the adult group, respectively, and the annual incidence of thyroid cancer was 0.53 vs 2.82 (per 105inhabitants) in the young and in the adult patients, respectively. The present study indicates, therefore, that in the absence of head or neck irradiation, cold thyroid nodules are much less frequent in young age, but that the malignancy rate of cold nodules occurring in young patients is 2-fold higher than in adults patients

No relevant conflicts of interest to declare.

Colombatti: Global Blood Therapeutics: Consultancy; Novartis: Consultancy; AddMedica: Consultancy.

Background: Acute Chest Syndrome (ACS) is the second cause of hospitalization in Sickle Cell Disease (SCD), burdened by significant morbidity and mortality. The guidelines regarding management of ACS are sometimes difficult to follow in the real world and the prevention and treatment strategies of ACS are often applied in an uneven manner in the various settings (community care, regional hospitals, reference university centers). Moreover, epidemiology, clinical phenotype and outcomes as well as risk factors could vary in different populations according to ethnicity, genotype or health care system organization.

No relevant conflicts of interest to declare.

Origa: Apopharma: Honoraria; Novartis: Honoraria; Bluebird Bio: Consultancy; Cerus Corporation: Research Funding. Forni:Apopharma: Other: DSM Board; Celgene: Research Funding; Novartis: Other: travel expenses, Research Funding; Shire: Research Funding; Roche: Consultancy.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

Gaucher disease (GD) is an autosomal recessive lysosomal storage disease characterized by the deficient activity of beta-glucocerebrosidase (GBA). GBA deficiency results in the accumulation of glucosylceramide in different organs, causing tissue damage. Typical GD features are spleno-hepatomegaly, peripheral blood cytopenias (mostly thrombocytopenia and/or anemia), growth retardation, bone involvement, gammopathies, increased risk of malignancies and, in some patients, neurological manifestations.

Background:Established indications for Hematopietic Stem Cell Transplantation (HSCT) in SCN include transformation to acute leukemia (AL) and/or myelodisplasia (MDS) and G-CSF resistance (need for >20mcg/kg/d). Indication for HSCT also appears appropriate in patients with poor response to G-CSF (10-20 mcg/kg/d) and, as a consequence, a high incidence of infectious events. Indication is less clear in cases requiring a G-CSF doses up to 10 mcg/kg but with good control of infections.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

Background. Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood and a major cause of childhood cancer-related mortality. Although the cure rate now approaches 90%, certain pediatric ALL subgroups present subsequent relapse. For this reason, analyses of cell signaling pathways will help to identify new markers and/or targets for tailored therapy. PI3K/AKT/mTOR activation is frequently found in both B-ALL and T-ALL. Protein kinase Ck2 (CSNK2) activity in pediatric ALL was increased and its inhibition restored PTEN phosphatase activity with subsequent inactivation of AKT. Moreover, Ck2 may serve the activity of oncogenes such as BCR-ABLand c-MYC, control the activation of other critical signaling cascades (JAK-STAT), and sustain multiple cellular stress-elicited pathway such as the proteotoxic stress, unfolded protein and DNA-damage responses. Ck2 has also been shown to have an essential role in tuning signals derived from the stromal tumor microenvironment (Piazza F et al, Oncogene2016).

Off Label Use: We used Imatinib Mesylate and PEG-L-Asparaginase in two children with AML: an off-label use for indication and age. .

Cattaneo: Eli Lilly Daiichi Sankyo: Honoraria; AstraZeneca: Honoraria, Research Funding.