Fatigue perception in a cohort of children with chronic immune thrombocytopenia and their caregivers using the PedsQL MFS: Real-life multicenter experience of the Italian Association of Pediatric Hematology and Oncology (AIEOP).

BACKGROUND: Fatigue is an important clinical and psychological aspect for a significant number of children affected by immune thrombocytopenia (ITP). To date, few studies have explored fatigue and its relationship with chronic ITP in pediatric age. The aim of the present multicentric pilot study is to determine fatigue perception in a large group of children with chronic ITP and their caregivers using the PedsQL Multidimensional Fatigue Scale (PedsQL MFS), and to compare the results with those of healthy control subjects. PROCEDURE: Children with chronic ITP aged 5-18 years and/or caregivers of children aged 2-18 years were enrolled. Child/adolescent self-report was used for patients aged 5-18 years, and parent proxy-report for patients aged 2-18 years. The questionnaire was offered as online survey. PedsQL MFS is composed of 18 items covering three dimensions: General Fatigue Scale, Sleep/Rest Fatigue Scale, and Cognitive Fatigue Scale. RESULTS: One hundred ninety-one patients affected by chronic ITP and 248 caregivers answered the PedsQL MFS. We have highlighted that lower values of PedsQL MFS scores are obtained in the 13-18 age group. Moreover, sleep/rest fatigue domain appears to be more compromised in all age groups. For all PedsQL MFS scores, pediatric patients with chronic ITP and their caregivers reported statistically significant worse fatigue than healthy children. CONCLUSIONS: This study suggests that fatigue is relevant among children and adolescents affected by chronic ITP. The PedsQL MFS represents an adequate instrument for measuring fatigue in patients with chronic ITP. Therefore, symptoms of fatigue should be routinely assessed in clinical practice.

Primary immunodeficiencies, autoimmune hyperthyroidism, coeliac disease and systemic lupus erythematosus in childhood immune thrombocytopenia.

AIM: To evaluate the cumulative prevalence of coeliac disease, systemic lupus erythematosus, autoimmune hyperthyroidism and primary immunodeficiencies in children with either newly diagnosed/persistent or chronic immune thrombocytopenia (ITP). METHODS: Monocentric retrospective analysis of the clinical and biochemical features of 330 consecutive patients with ITP referred to our Pediatric Hematology Unit between January 2009 and December 2018. RESULTS: The prevalence of systemic lupus erythematosus (0.3%), coeliac disease (0.3%) and autoimmune hyperthyroidism (0.6%) was not increased compared to general paediatric population. Of note, the prevalence of underlying primary immunodeficiencies was 2.4%, remarkably higher than the general paediatric population (P = .005). All the patients diagnosed with immunodeficiency developed either bi-/trilinear cytopenia or splenomegaly. CONCLUSION: Whilst autoimmune and immunological screening is already recommended at the onset of immune thrombocytopenia, we recommend that primary immunodeficiencies be regularly screened during follow-up, especially in case of additional cytopenia or lymphoproliferation.

Lentiviral gene therapy corrects platelet phenotype and function in patients with Wiskott-Aldrich syndrome.

BACKGROUND: Thrombocytopenia is a serious issue for all patients with classical Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT) because it causes severe and life-threatening bleeding. Lentiviral gene therapy (GT) for WAS has shown promising results in terms of immune reconstitution. However, despite the reduced severity and frequency of bleeding events, platelet counts remain low in GT-treated patients. OBJECTIVE: We carefully investigated platelet defects in terms of phenotype and function in untreated patients with WAS and assessed the effect of GT treatment on platelet dysfunction. METHODS: We analyzed a cohort of 20 patients with WAS/XLT, 15 of them receiving GT. Platelet phenotype and function were analyzed by using electron microscopy, flow cytometry, and an aggregation assay. Platelet protein composition was assessed before and after GT by means of proteomic profile analysis. RESULTS: We show that platelets from untreated patients with WAS have reduced size, abnormal ultrastructure, and a hyperactivated phenotype at steady state, whereas activation and aggregation responses to agonists are decreased. GT restores platelet size and function early after treatment and reduces the hyperactivated phenotype proportionally to WAS protein expression and length of follow-up. CONCLUSIONS: Our study highlights the coexistence of morphologic and multiple functional defects in platelets lacking WAS protein and demonstrates that GT normalizes the platelet proteomic profile with consequent restoration of platelet ultrastructure and phenotype, which might explain the observed reduction of bleeding episodes after GT. These results are instrumental also from the perspective of a future clinical trial in patients with XLT only presenting with microthrombocytopenia.

Acute myeloid leukemia in Baraitser-Winter cerebrofrontofacial syndrome.

Baraitser-Winter malformation syndrome (BWMS), Fryns-Aftimos syndrome (FA), and craniofrontofacial syndromes (CFFs) have all been recently proposed to be part of the same phenotypic spectrum of Baraitser-Winter cerebrofrontofacial syndrome (BWCFF), which is characterized by facial dysmorphism, ocular coloboma, brain malformations, and intellectual disabilities. In addition to that, the recent discovery of missense mutations in one of the two ubiquitously expressed cytoplasmic ß- and γ-acting-encoding genes ACTB (7p22.1) and ACTG1 (17q25.3) in patients carrying a clinical diagnosis of BWSM, FA, or CCF has provided further evidence that these clinical conditions do indeed belong to the same entity at the molecular level. Two cases of BWCFF patients presenting with malignancies (i.e., acute lymphocytic leukemia and cutaneous lymphoma) have been published thus far. Here, we report a 21-year-old female with molecularly confirmed FA, who developed acute myeloid leukemia (AML). The present finding may indicate that actinopathies could be cancer-predisposing syndromes although small numbers and publication bias should be taken into account. © 2016 Wiley Periodicals, Inc.

Thrombocytopenia and Cornelia de Lange syndrome: Still an enigma?

Cornelia de Lange Syndrome (CdLS) is a rare genetic disorder caused by mutations in the cohesion complex and its regulators. The syndrome is characterized by multiple organ system abnormalities, pre- and post-natal growth retardation and typical facial features. Thrombocytopenia is a reduction in platelet count to <150 × 10(9) L. It can be caused by congenital or acquired decreased production, increased destruction, or sequestration of platelets. In recent years, several papers reported thrombocytopenia and immune thrombocytopenia in patients affected by CdLS. In 2011, Lambert et al. estimated the risk of idiopathic thrombocytopenia purpura in CdLS patients to be 31-633 times greater than in the general population. We describe the incidence of thrombocytopenia in 127 Italian CdLS patients, identifying patients with transient or persistent thrombocytopenia, but a lower incidence of true idiopathic thrombocytopenic purpura (ITP).

Practices of pediatric oncology and hematology providers regarding fertility issues: a European survey.

BACKGROUND: Fertility is impaired in many survivors of childhood cancer following treatment. Preservation of fertility after cancer has become a central survivorship concern. Nevertheless, several doctors, patients, and families do not discuss fertility and recommendations for fertility preservation in pediatrics are still lacking. Recommendations based on scientific evidence are needed and before their development we wanted to assess the practice patterns of fertility preservation in Europe. PROCEDURES: On behalf of the PanCare network, we sent a questionnaire to pediatric onco-hematology institutions across Europe. The survey consisted of 21 questions assessing their usual practices around fertility preservation. RESULTS: One hundred ninety-eight institutional representatives across Europe received the survey and 68 (response rate 34.3%) responded. Pre-treatment fertility counseling was offered by 64 institutions. Counseling was done by a pediatric onco-hematologist in 52% (33/64) and in 32% (20/64) by a team. The majority of institutions (53%) lacked recommendations for fertility preservation. All 64 centers offered sperm banking; eight offered testicular tissue cryopreservation for pre-pubertal males. For females, the possibility of preserving ovarian tissue was offered by 40 institutions. CONCLUSIONS: There is a high level of interest in fertility preservation among European centers responding to our survey. However, while most recommended sperm cryopreservation, many also recommended technologies whose efficacy has not been shown. There is an urgent need for evidence-based European recommendations for fertility preservation to help survivors deal with the stressful topic of fertility.

The power of art and the powers of adolescents with cancer: Age-specific projects at Italian pediatric oncology centers.

This article describes the oncology programs developed in Italy for adolescents and young adults with cancer, with a specific focus on the local projects created in pediatric oncology centers. A common feature of such projects is the emphasis on creative and artistic activities and laboratories (involving music, photography, novel writing, fashion design, and so on) designed to give young patients innovative means of expression.This article highlights the amazing powers of adolescents involved in these projects: the power to produce beautiful things in a place that is not normally associated with the idea of beauty; the power to make their doctors smile and grasp the profound sense of life; the power to make hospitals become places for producing culture.

Pediatric immune thrombocytopenia: a focus on eltrombopag as second-line therapy.

BACKGROUND: Immune thrombocytopenia (ITP) is the most common acquired bleeding disorder. In both children and adults, the primary goal of any therapeutic approach consists of cessation of bleeding and its prevention. Several options are currently available for first-line therapy in Europe, including corticosteroids and intravenous immunoglobulin (IVIg) infusion, which has a similar efficacy and safety profile in both the pediatric and adult populations. When second-line therapy is needed in the pediatric setting, current guidelines recommend eltrombopag as the drug of choice. PROCEDURE: The aim of this article is to summarize the available evidence and present real-life experience on eltrombopag as second-line therapy in pediatric patients with ITP, with a focus on dosing and response to therapy as well as its tapering and discontinuation. RESULTS: In our setting, eltrombopag is associated with good safety profile as well as promising efficacy; dose de-escalation was feasible in 94% of cases and often reached very low pro/kg dosage, with full discontinuation in 15% of cases. In daily practice, a standardized approach for discontinuation of eltrombopag in pediatric patients with ITP is still lacking. Herein, an easy-to-use scheme for tapering and discontinuation in candidate pediatric patients is proposed that proposes 25% dose reduction every four weeks. CONCLUSIONS: In future management of pediatric ITP patients, it will be crucial to assess if thrombopoietin receptor agonists might be more effective in earlier phases of the disease and can modify the course of the disease.

Long term use of eltrombopag in children with chronic immune thrombocytopenia: extended real life retrospective multicenter experience of the Italian Association of Pediatric Hematology and Oncology.

Background: The present multicenter retrospective study on eltrombopag administration in Italian children with chronic ITP aims to extend follow-up of our previous study. Materials and methods: This retrospective multicenter study was conducted in 17 centers affiliated to the Italian Association of Pediatric Hematology and Oncology (AIEOP). Patients were classified into three subgroups: group 1 included patients who discontinued treatment due to a stable platelet count; group 2 included patients who discontinued treatment due to ineffectiveness; group 3 included patients who did not permanently discontinue treatment. Results: 56 patients were eligible for analysis. The median duration of eltrombopag treatment was 40 months (7-71 months). Twenty patients (36%) discontinued permanently eltrombopag. The reasons of permanent discontinuation were adverse effects (n = 1), inefficacy (n = 10), stable platelet count (n = 9). All patients of group 1 maintained a durable response without additional treatments after eltrombopag discontinuation. We found that patients of group 2 were on treatment for less time (median treatment time: 13.5 months, min: 6.0 - max: 56.0) than patients of group 1 (median treatment time: 34 months, min: 16.0 - max: 62.0) (p < 0.05). Patients of group 2 mostly did not achieve a stable platelet count in the first 6 months of treatment and underwent concomitant therapies during follow-up respect of group 1 and group 3 (p < 0.01). Conclusion: Our study found that the benefits of eltrombopag treatment, in terms of platelet count improvement and use of additional therapies, are identifiable from the first 6 months of treatment.

Recommendations for the management of acute immune thrombocytopenia in children. A Consensus Conference from the Italian Association of Pediatric Hematology and Oncology.

BACKGROUND: Immune thrombocytopenia (ITP) is an acquired immune-mediated bleeding disorder characterized by isolated thrombocytopenia. Its estimated yearly incidence in the pediatric population is 1.9-6.4/100,000. ITP in children is usually a self-limiting and benign disorder. The clinical management of children with ITP often remains controversial, as robust randomized trials on the management of this disorder are lacking. Treatments vary widely in clinical practice and existing guidelines from hematology societies on clinical management offer indications based largely on expert opinion rather than strong evidence. MATERIALS AND METHODS: The Coagulative Disorder Working Group of the Italian Association of Pediatric Hematology and Oncology (AIEOP) developed this document to collect shared expert opinions on the management of newly diagnosed ITP, updating previous guidelines and providing recommendations to pediatricians. Each statement has been given a score expressing the strength of evidence, appropriateness and agreement among participants. RESULTS: Clear-cut definitions of the clinical phases of the disease and clinical response are stated. Recommendations are given regarding the classification of bleeding symptoms, evaluation of bleeding risk, diagnosis, and prognostic factors. Specific recommendations for treatment include indications for first-line (intravenous immunoglobulins, steroids) and second-line (combined therapy, thrombopoietin receptor agonists, immunosuppressive drugs, rituximab) therapeutic agents, as well as hemorrhagic emergency and supportive treatment, including emergency splenectomy. The optimal follow-up schedule, the relation between ITP and vaccines and health-related quality-of-life issues are also discussed. DISCUSSION: The panel achieved broad consensus on issues related to how to treat children with newly diagnosed ITP, providing a comprehensive review of all relevant clinical aspects.

Pediatric immune myelofibrosis (PedIMF) as a novel and distinct clinical pathological entity.

Myelofibrosis is a rare myeloproliferative disorder. The detailed descriptions of myelofibrosis in children and adolescents is limited to a few case series and case reports describing fewer than 100 patients, thus suggesting the extreme rarity of this condition prior to adulthood. Though pediatric patients rarely present the typical features and outcomes usually observed in older people, pediatric myelofibrosis is not considered an independent entity. Here we aim to describe patients with pediatric myelofibrosis, showing different clinical and pathological features when compared to the World Health Organization 2016 Primary Myelofibrosis classification. We retrospectively collected and analyzed 14 consecutive pediatric myelofibrosis diagnosed in our Pediatric hematology outpatient clinic over a six-year period. According to clinical data and bone marrow biopsy findings, patients were classified into three subgroups: adult-like myelofibrosis, pediatric immune myelofibrosis, idiopathic myelofibrosis. Pediatric Immune Myelofibrosis was the predominant subgroup in our cohort (7/14). Pediatric Immune Myelofibrosis is characterized by peculiar bone marrow features (i.e., T lymphocyte infiltration) and a milder course compared to the other patients Pediatric Immune Myelofibrosis is a novel and distinct pathological entity. We suggest to carefully consider Pediatric Immune Myelofibrosis in case of bone marrow biopsies showing myelofibrosis that do not fulfill WHO criteria.

A Textual Analysis for Understanding the Relations and the Identity Construction in Adolescent Oncology Patients: Retrospective Personal Views in Order to Educate Health Professionals.

Patient input is critical for all aspects of value-based healthcare design. This contribution describes the following: the specifics of communications with doctors regarding the disease in adolescents and young adults with cancer; the patients' thoughts, emotions and changes in self-perception; "other meanings" taking shape along the treatment pathway; and reacting modes to the disease and treatments. Thirty-five Italian AYA patients in follow-up (age 18-24) were involved in a plenary interview on the cited aspects of their oncological experience. The answers were analyzed by MADIT (Analysis Methodology of Computerized Textual Data) with the software SPAD. MADIT allowed us to perform text analysis, describe the graphical outcomes and discuss the results. Respondents took a first-person perspective and their personal narrative recall had objective and unequivocal connotations. Experience was narrated mainly by maintenance repertoires that fix the reality of disease, its treatments and personal identity. The account focused on the tumor and on an agreed approach to it. The time "after" was described as a distressing space that defines them. Making sense of the events was considered a significant help. Professionals need to focus on the discursive repertoires of communication with which the inner and outer reality are built. Lastly, these patients required a two-way dialogue throughout the entire caring process.

Diagnostic Delay in Adolescents with Cancer During COVID-19 Pandemic: A New Price for Our Patients to Pay.

Worldwide, the coronavirus 19 disease pandemic caused a worse chance of a timely diagnosis for cancer patients. We conducted a retrospective analysis of new diagnoses registered in the national pediatric oncology database, comparing the first lockdown period (March-May 2020) with the same period of 2015-2019. The total number of cases (0-19 years) dropped by 20.8% (from 441 between 2015 and 2019 to 349 in 2020). A major reduction was observed for adolescents (15-19 years) (-32.9%) and for adolescents with solid tumors (-56.4%, p = 0.03). Our data suggest that the enforced lockdown reduced the possibility for these already vulnerable patients to access the referral centers.

"CHildren with Inherited Platelet disorders Surveillance" (CHIPS) retrospective and prospective observational cohort study by Italian Association of Pediatric Hematology and Oncology (AIEOP).

Background: Inherited thrombocytopenias (ITs) are rare congenital bleeding disorders characterized by different clinical expression and variable prognosis. ITs are poorly known by clinicians and often misdiagnosed with most common forms of thrombocytopenia. Material and methods: "CHildren with Inherited Platelet disorders Surveillance" study (CHIPS) is a retrospective - prospective observational cohort study conducted between January 2003 and January 2022 in 17 centers affiliated to the Italian Association of Pediatric Hematology and Oncology (AIEOP). The primary objective of this study was to collect clinical and laboratory data on Italian pediatric patients with inherited thrombocytopenias. Secondary objectives were to calculate prevalence of ITs in Italian pediatric population and to assess frequency and genotype-phenotype correlation of different types of mutations in our study cohort. Results: A total of 139 children, with ITs (82 male - 57 female) were enrolled. ITs prevalence in Italy ranged from 0.7 per 100,000 children during 2010 to 2 per 100,000 children during 2022. The median time between the onset of thrombocytopenia and the diagnosis of ITs was 1 years (range 0 - 18 years). A family history of thrombocytopenia has been reported in 90 patients (65%). Among 139 children with ITs, in 73 (53%) children almost one defective gene has been identified. In 61 patients a pathogenic mutation has been identified. Among them, 2 patients also carry a variant of uncertain significance (VUS), and 4 others harbour 2 VUS variants. VUS variants were identified in further 8 patients (6%), 4 of which carry more than one variant VUS. Three patients (2%) had a likely pathogenic variant while in 1 patient (1%) a variant was identified that was initially given an uncertain significance but was later classified as benign. In addition, in 17 patients the genetic diagnosis is not available, but their family history and clinical/laboratory features strongly suggest the presence of a specific genetic cause. In 49 children (35%) no genetic defect were identified. In ninetyseven patients (70%), thrombocytopenia was not associated with other clinically apparent disorders. However, 42 children (30%) had one or more additional clinical alterations. Conclusion: Our study provides a descriptive collection of ITs in the pediatric Italian population.

Female Genital Hair-Thread Tourniquet Syndrome: A Case Report and Literature Systematic Review.

"Hair-thread tourniquet syndrome" (HTTS) describes the condition in which fibers of hair or thread wrap around an appendage (ie, toes, fingers, genital structures, tongue, uvula, and neck), eventually causing ischemia and tissue necrosis. To date, few cases of female genitalia HTTS have been described. We report a case of female genitalia HTTS in a 5-year-old girl and report the state of the art by systematically reviewing all existing evidence about female genital HTTS. A total of 29 studies, describing a total of 34 patients, were identified. The presence of a hair-thread wrapping genitalia should be suspected in prepubertal girls complaining of genital pain associated with vulvar/vaginal swelling, wide-based gait, and voiding symptoms. Genital examination disclosing an extremely tender, swollen, and erythematous lesion on the clitoris or labia minora encircled by a hair confirms the diagnosis. The aim of the management is to remove the hair-thread in the shortest time possible, with the use of forceps, scissors, or scalpels, and this is often performed under sedation/anesthesia because of the patient's pain reaction. When the hair-thread is difficult to find or when the lesion is necrotic, excision of the lesion itself can be the only option. Complications include partial or total amputation because of tissue necrosis and recurrence.

Discussing communication issues and needs with adolescents with cancer.

Adolescents with cancer face unique medical and psychosocial challenges and it is important for their doctors to understand the psychological manifestations of cancer diagnosis and treatment in this age group. Using patient dialogues, we describe how simultaneous participation of physicians and patients could help to give voice to patient needs, in particular concerning communication.

Association of Immune Thrombocytopenia and Inflammatory Bowel Disease in Children.

BACKGROUND: The association between inflammatory bowel disease (IBD) and immune thrombocytopenia (ITP) is still uncertain. In this multicenter retrospective study, the coexistence of both diseases was investigated in children diagnosed from 1 January 2000 to 31 December 2019. METHODS: Clinical characteristics of both IBD and ITP, onset of disorders, and patient's response to treatment were collected through a structured form sent to 55 Italian pediatric referring centers for hematological disorders. RESULT: Centers responded to the survey and reported the coexistence of IBD and ITP in 14 children. The first diagnosis was ITP in 57.1% and IBD in 35.7% of patients: it was simultaneous in 7.1%. IBD was classified as ulcerative colitis (57.1%), Crohn disease (35.7%), and unclassified (7.1%). No therapy for IBD other than steroids had any effect on ITP course. Colectomy resulted in recovery from ITP in 1 of the 2 patients surgically treated. ITP was always mild but turned to be chronic in half of patients. CONCLUSIONS: In all patients, ITP was mild without any evident impact on IBD severity, but the incidence of chronic ITP seems to be higher than what is usually observed in the pediatric age group. Colectomy had unpredictable effects on ITP.

Association of Immune Thrombocytopenia and Celiac Disease in Children: A Retrospective Case Control Study

Objective: The association between celiac disease (CD) and immune thrombocytopenia (ITP) is still uncertain. The aim of this study was to characterize the coexistence of these two diseases in Italian children. Materials and Methods: This is a retrospective multicenter study investigating the occurrence of CD in 28 children with ITP diagnosed from January 1, 2000, to December 31, 2019. Results: The first diagnosis was ITP in 57.1% and CD in 32.1% of patients. In 3 patients (10.7%), the two diagnoses were simultaneous. All the potential and silent cases of CD in our cohort were diagnosed in the groups of "ITP first" and "simultaneous diagnosis". In all children ITP was mild, and in 2 out of 8 not recovered from ITP at the time of CD diagnosis a normalization of platelet counts (>100,000/µL) occurred 3 and 5 months after starting a gluten-free diet, respectively. Conclusion: We think that screening for CD should be considered in children with ITP regardless of the presence of gastrointestinal symptoms. Furthermore, some patients may recover from ITP after starting a gluten-free diet.

Evolving Services for Adolescents with Cancer in Italy: Access to Pediatric Oncology Centers and Dedicated Projects.

Purpose: To describe how the provision of services for adolescents with cancer has evolved in Italy, the study evaluated access to pediatric oncology centers affiliated to the national cooperative group Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP), and the development of dedicated local projects. Methods: We calculated the observed/expected (O/E) ratio of adolescent patients (15-19 years old) admitted to AIEOP centers during the years 2013-2017. Observed cases were obtained from the AIEOP database (model 1.01). Expected cases were calculated on the incidence rates derived from the population-based registries. In addition, a questionnaire investigated the presence of any formal upper age limits for admitting patients, and to the development of local projects. Results: In the years 2013-2017, 9534 cases of cancer were registered in the AIEOP database, that is, 8031 children (0-14 years) and 1503 adolescents (15-19 years). The overall O/E ratio was 0.81, that is, 1.06 for children, and 0.37 for adolescents, and differed according the different tumor types. Concerning the questionnaire, 26% of centers reported age limits <18 years. Nineteen centers reported to have local projects dedicated to adolescents. Conclusions: The study shows an improvement in the services for adolescents in Italy, with an increase percentage of cases treated at AIEOP centers (from 10% of previous study, to 37%), the decrease of centers with admission age limits <18 years (from 44% 10 years ago, to 26%), and the development of many specific local projects. Effective cooperation with adult oncology societies and government recognition remain goals to be achieved.