SARS-CoV-2 Infection in the Pediatric Oncology Population: The Definitive Comprehensive Report of the Infectious Diseases Working Group of AIEOP.

OBJECTIVE: The objective of this study was to assess the clinical impact and outcome of the SARS-CoV-2 infection on children with cancer or those who received a hematopoietic stem cell transplantation. METHODS: AIEOP (Italian Association of Pediatric Hematology and Oncology) performed a nationwide multicenter observational cohort study, including consecutive patients between April 2020 and November 2022. RESULTS: Twenty-five Italian centers participated and 455 patients were enrolled. We reported a significant increasing trend of symptomatic cases over the years, while the number of nonmild infections remained stable. Early infection after oncologic diagnosis (<60 days) and severe neutropenia were identified as independent risk factors for developing moderate, severe, or critical infections. The percentage of patients who were asymptomatic and mildly symptomatic and who stopped chemotherapy reduced over the years of the pandemic. Nine patients died, but no death was attributed to SARS-CoV-2 infection. CONCLUSIONS: SARS-CoV-2 infection presented a self-limiting benign course in the Italian pediatric oncohematology population during the pandemic, and its main consequence has been the discontinuation of cancer-directed therapies. The rate of patients who were asymptomatic and stopped chemotherapy reduced over the years, suggesting that the continuation of chemotherapy is a feasible option.

Pediatric gray zone lymphoma according to the 2022 WHO classification: An Italian cohort study.

BACKGROUND: The 2022 World Health Organization (WHO) classification redefines the concept of gray zone lymphoma (GZL), restricting it in practice to cases of mediastinal/thymic origin (mediastinal gray zone lymphoma, MGZL) with overlapping features between primary mediastinal B-cell lymphoma (PMBCL) and classical Hodgkin lymphoma (CHL). Cases with histological characteristics of GZL but occurring without mediastinal involvement are better classified as diffuse large B-cell lymphoma, not otherwise specified (DLBCL NOS), with few exceptions. PROCEDURE: We collected clinical and pathological data about all Italian pediatric patients diagnosed with GZL over a 20-year period. RESULTS: We identified only four cases of bona fide MGZL. All patients were adolescent and presented with a mediastinal disease, always associated with other nodal involvement. B symptoms and increased levels of both erythrocyte sedimentation rate (ESR) and lactate dehydrogenase (LDH) were observed. Only two patients achieved a first complete remission, suggesting a more aggressive clinical behavior than either PMBCL or CHL. CONCLUSION: Prospective studies evaluating prognostic factors and establishing the most effective first-line therapy for MGZL are highly needed.

Oral Lactoferrin Supplementation during Induction Chemotherapy Promotes Gut Microbiome Eubiosis in Pediatric Patients with Hematologic Malignancies.

Induction chemotherapy is the first-line treatment for pediatric patients with hematologic malignancies. However, several complications may arise, mainly infections and febrile neutropenia, with a strong impact on patient morbidity and mortality. Such complications have been shown to be closely related to alterations of the gut microbiome (GM), making the design of strategies to foster its eubiosis of utmost clinical importance. Here, we evaluated the impact of oral supplementation of lactoferrin (LF), a glycoprotein endowed with anti-inflammatory, immunomodulatory and antimicrobial activities, on GM dynamics in pediatric oncohematologic patients during induction chemotherapy. Specifically, we conducted a double blind, placebo-controlled trial in which GM was profiled through 16S rRNA gene sequencing before and after two weeks of oral supplementation with LF or placebo. LF was safely administered with no adverse effects and promoted GM homeostasis by favoring the maintenance of diversity and preventing the bloom of pathobionts (e.g., Enterococcus). LF could, therefore, be a promising adjunct to current therapeutic strategies in these fragile individuals to reduce the risk of GM-related complications.

Pediatric cancer and hematopoietic stem cell transplantation patients requiring renal replacement therapy: results of the retrospective nationwide AIEOP study.

In children affected by malignancies and/or who received hematopoietic stem cell transplantation (HSCT), acute kidney injury (AKI) may occur causing a high mortality rate, despite the implementation of renal replacement therapy (RRT). We performed a nationwide, multicenter, retrospective, observational cohort study including consecutive patients between January 2010 and December 2019. One hundred and fourteen episodes of AKI requiring RRT coming from nine different Italian centers were included. The overall mortality rate was 61.4%. At the 3-month follow-up, the mortality rate was 47.4%. The mortality rate was higher in transplanted patients than those receiving chemotherapy. In particular, HSCT (p = 0.048) and invasive mechanical ventilation (p = 0.040) were significantly associated with death at three months after the end of dialysis in the multivariate analysis. Pediatric patients affected by malignancies complicated by AKI requiring RRT have a high mortality. The main factors associated to death are respiratory failure and having received HSCT.

The Clinical Impact of Methotrexate-Induced Stroke-Like Neurotoxicity in Paediatric Departments: An Italian Multi-Centre Case-Series.

Introduction: Stroke-like syndrome (SLS) is a rare subacute neurological complication of intrathecal or high-dose (≥500 mg) Methotrexate (MTX) administration. Its clinical features, evoking acute cerebral ischaemia with fluctuating course symptoms and a possible spontaneous resolution, have elicited interest among the scientific community. However, many issues are still open on the underlying pathogenesis, clinical, and therapeutic management and long-term outcome. Materials and Methods: We retrospectively analyzed clinical, radiological and laboratory records of all patients diagnosed with SLS between 2011 and 2021 at 4 National referral centers for Pediatric Onco-Hematology. Patients with a latency period that was longer than 3 weeks between the last MTX administration of MTX and SLS onset were excluded from the analysis, as were those with unclear etiologies. We assessed symptom severity using a dedicated arbitrary scoring system. Eleven patients were included in the study. Results: The underlying disease was acute lymphoblastic leukemia type B in 10/11 patients, while fibroblastic osteosarcoma was present in a single subject. The median age at diagnosis was 11 years (range 4-34), and 64% of the patients were women. Symptoms occurred after a mean of 9.45 days (± 0.75) since the last MTX administration and lasted between 1 and 96 h. Clinical features included hemiplegia and/or cranial nerves palsy, paraesthesia, movement or speech disorders, and seizure. All patients underwent neuroimaging studies (CT and/or MRI) and EEG. The scoring system revealed an average of 4.9 points (± 2.3), with a median of 5 points (maximum 20 points). We detected a linear correlation between the severity of the disease and age in male patients. Conclusions: SLS is a rare, well-characterized complication of MTX administration. Despite the small sample, we have been able to confirm some of the previous findings in literature. We also identified a linear correlation between age and severity of the disease, which could improve the future clinical management.

Consensus on COVID-19 Vaccination in Pediatric Oncohematological Patients, on Behalf of Infectious Working Group of Italian Association of Pediatric Hematology Oncology.

Vaccines represent the best tool to prevent the severity course and fatal consequences of the pandemic by the new Coronavirus 2019 infection (SARS-CoV-2). Considering the limited data on vaccination of pediatric oncohematological patients, we developed a Consensus document to support the Italian pediatric hematological oncological (AIEOP) centers in a scientifically correct communication with families and patients and to promote vaccination. The topics of the Consensus were: SARS-CoV-2 infection and disease (COVID-19) in the pediatric subjects; COVID-19 vaccines (type, schedule); who and when to vaccinate; contraindications and risk of serious adverse events; rare adverse events; third dose and vaccination after COVID-19; and other general prevention measures. Using the Delphi methodology for Consensus, 21 statements and their corresponding rationale were elaborated and discussed with the representatives of 31 centers, followed by voting. A high grade of Consensus was obtained on topics such as the potential risk of severe COVID-19 outcome in pediatric oncohematological patients, the need for vaccination as a preventative measure, the type, schedule and booster dose of vaccine, the eligibility of the patients for vaccination, and the timing, definition, and management of contraindications and serious adverse events, and other general prevention measures. All 21 of the statements were approved. This consensus document highlights that children and adolescents affected by hematological and oncological diseases are a fragile category. Vaccination plays an important role to prevent COVID-19, to permit the regular administration of chemotherapy or other treatments, to perform control visits and hospital admissions, and to prevent treatment delays.

Ecthyma Gangrenosum in Children With Cancer: Diagnosis at a Glance: A Retrospective Study From the Infection Working Group of Italian Pediatric Hematology Oncology Association.

BACKGROUND: To depict ecthyma gangrenosum (EG) clinical presentation and evolution in a large multicenter pediatric retrospective collection of children with malignancies or bone marrow failure syndromes, to facilitate early diagnosis. METHODS: EG episodes diagnosed in the period 2009-2019 were identified by a retrospective review of clinical charts at centers belonging to the Italian Pediatric Hematology Oncology Association. RESULTS: Thirty-eight cases of EG occurring in children (male/female 16/22; median age 5.2 years) with hematologic malignancy (29), allogeneic stem cell transplantation (2) or relapsed/refractory solid tumor (3) were collected. The involved sites were: perineal region (19), limbs (10), trunk (6), head and the iliac crest (3). Bacteremia was present in 22 patients. Overall, the germs isolated were Pseudomonas aeruginosa (30), Stenotrophomonas maltophilia (3) and Escherichia coli (1); 31% of them were multidrug-resistant. All patients received antibacterial treatment, while surgery was performed in 24 patients (63.1%). Predisposing underlying conditions for EG were severe neutropenia (97.3%), corticosteroid treatment (71%) and iatrogenic diabetes (23.7%). All patients recovered, but EG recurred in 5 patients. Nine patients (24%) showed sequelae (deep scars, with muscle atrophy in 2). Four patients (10.5%) died, 1 due to relapse of EG with Carbapenem-resistant Enterobacteriaceae co-infection and 3 due to the progression of the underlying disease. CONCLUSIONS: EG requires early recognition and a proper and timely treatment to obtain the recovery and to avoid larger necrotic lesions, eventually evolving in scarring sequelae.

Comparison of Hodgkin's Lymphoma in Children and Adolescents. A Twenty Year Experience with MH'96 and LH2004 AIEOP (Italian Association of Pediatric Hematology and Oncology) Protocols.

Adolescents and young adults (AYAs) represent a distinct group of patients. The objectives of this study were: To compare adolescent prognosis to that of younger children; to compare the results achieved with the two consecutive protocols in both age groups; to analyze clinical characteristics of children and adolescents. Between 1996 and 2017, 1759 patients aged <18 years were evaluable for the study. Five hundred and sixty patients were treated with the MH'96 protocol and 1199 with the LH2004 protocol. Four hundred and eighty-two were adolescents aged ≥15 years. Patients in both age groups showed very favorable prognoses. In particular, OS improved with the LH2004 protocol, especially in the adolescent group and in the low risk group, where radiation therapy was spared. Adolescent characteristics differed significantly from the children's according to sex, histology, and the presence of symptoms. Remarkable is the decrease both in mixed cellularity in the children and in low stages in both age groups in the LH2004 protocol with respect to MH'96 protocol. Based on our experience, adopting pediatric protocols for AYA does not compromise patient outcomes.

Perceived well-being and mental health in haemophilia.

The investigation of mental health among persons with haemophilia is mostly focused on negative and disease-related indicators. Literature however shows that psychosocial resources and optimal daily functioning can co-exist with chronic disease. The Dual Continua Model operationalizes positive mental health as 'flourishing', a condition comprising emotional, psychological, and social well-being dimensions. In the present study physical and mental health were comparatively assessed through positive and negative indicators in adults with haemophilia and a control group. Participants included 84 Italian persons with severe haemophilia (Mage = 43.44; SDage = 13.04) and 164 adults without history of chronic illness (Mage = 40.98; SDage = 12.26), who completed the Short Form Health Survey, the Positive and Negative Affect Schedule, and the Mental Health Continuum Short Form. MANOVA and post-hoc t-tests provided evidence of worse general health, lower negative affect and higher psychological well-being among participants with haemophilia compared with the control group. Moreover, the percentage of flourishing individuals was higher among participants with haemophilia. Results support previous evidence suggesting that a chronic disease does not prevent mental well-being attainment. The identification of assets and strengths allowing people with haemophilia to flourish can be fruitfully used to design resource-centered interventions.

Consensus statements on vaccination in patients with haemophilia-Results from the Italian haemophilia and vaccinations (HEVA) project.

Vaccination against communicable diseases is crucial for disease prevention, but this practice poses challenges to healthcare professionals in patients with haemophilia. Poor knowledge of the vaccination requirements for these patients and safety concerns often result in vaccination delay or avoidance. In order to address this issue, a panel of 11 Italian haemophilia and immunization experts conducted a Delphi consensus process to identify the main concerns regarding the safe use of vaccines in patients with haemophilia. The consensus was based on a literature search of the available evidence, which was used by the experts to design 27 consensus statements. A group of clinicians then rated these statements using the 5-point Likert-type scale (1 = strongly disagree; 5 = strongly agree). The main issues identified by the expert panel included vaccination schedule for haemophilic patients; protocol and optimal route of vaccine administration; vaccination of haemophilic patients with antibodies inhibiting coagulation factor VIII (inhibitors); and vaccination and risk of inhibitor development. This manuscript discusses these controversial areas in detail supported by the available literature evidence and provides evidence- and consensus-based recommendations. Overall, participants agreed on most statements, except those addressing the potential role of vaccination in inhibitor formation. Participants agreed that patients with haemophilia should receive vaccinations according to the institutional schedule for individuals without bleeding disorders; however, vaccination of patients with haemophilia requires comprehensive planning, taking into account disease severity, type and route of vaccination, and bleeding risk. Data also suggest vaccination timing does not need to take into consideration when the patient received factor VIII replacement.

Classical pediatric Hodgkin lymphoma in very young patients: the Italian experience.

Many studies have reported a more favorable outcome in younger patients with Hodgkin lymphoma (HL). The aims of this study were to find an appropriate age cutoff able to identify low-risk children and to describe the natural history of 135 very young patients affected by classic HL (cHL). The best age cutoff was identified at 7 years of age. EFS (p = .0451) and PFS (p = .00921) were significantly better in the group of younger patients. The OS rate at 10 years was 97.0% in the younger group and 92.5% in the older one (p = .0448). However, age was not found to be an independent prognostic factor in multivariate analysis and the better prognosis in younger patients seems to be related to more favorable disease characteristics at presentation.

Real-Life Management of Children and Adolescents with Chronic Myeloid Leukemia: The Italian Experience.

BACKGROUND: To date, no data on the adherence to specific guidelines for children with chronic myeloid leukemia (CML) in chronic phase (CP) have been reported. METHODS: Since 2001, guidelines for treatment with imatinib mesylate (IM) and monitoring in patients younger than 18 years with CP-CML have been shared with 9 pediatric referral centers (P centers) and 4 reference centers for adults and children/adolescents (AP centers) in Italy. In this study, the adherence to these guidelines was analyzed. RESULTS: Thirty-four patients with a median age of 11.4 years and 23 patients with a median age of 11.0 years were managed at 9 P and at 4 AP centers, respectively. Evaluations of bone marrow (BM) and/or peripheral blood (PB) were available for more than 90% of evaluable patients. Cytogenetics and molecular monitoring of PB were more consistently performed in AP centers, whereas molecular analysis of BM was carried out more frequently in P centers. Before 2009, some patients who responded to IM underwent a transplantation, contrary to the guidelines' recommendations. CONCLUSIONS: Our experience shows that having specific guidelines is an important tool for an optimal management of childhood CP-CML, together with exchange of knowledge and proactive discussions within the network.

Multicenter randomized, double-blind controlled trial to evaluate the efficacy of laser therapy for the treatment of severe oral mucositis induced by chemotherapy in children: laMPO RCT.

OBJECTIVES: To demonstrate the efficacy of laser photobiomodulation (PBM) compared to that of placebo on severe oral mucositis (OM) in pediatric oncology patients. The primary objective was the reduction of OM grade (World Health Organization [WHO] scale) 7 days after starting PBM. Secondary objectives were reduction of pain, analgesic consumption, and incidence of side effects. METHODS: One hundred and one children with WHO grade > 2 chemotherapy-induced OM were enrolled in eight Italian hospitals. Patients were randomized to either PBM or sham treatment for four consecutive days (days +1 to +4). On days +4, +7, and +11, OM grade, pain (following a 0-10 numeric pain rating scale, NRS) and need for analgesics were evaluated by an operator blinded to treatment. RESULTS: Fifty-one patients were allocated to the PBM group, and 50 were allocated to the sham group. In total, 93.7% of PBM patients and 72% of sham patients had OM grade < 3 WHO on day +7 (P = 0.01). A significant reduction of pain was registered on day +7 in the PBM versus sham group (NRS 1 [0-3] vs. 2.5 [1-5], P < 0.006). Reduced use of analgesics was reported in the PBM group, although it was not statistically significant. No significant adverse events attributable to treatment were recorded. CONCLUSIONS: PBM is a safe, feasible, and effective treatment for children affected by chemotherapy-induced OM, as it accelerates mucosal recovery and reduces pain.

Abdomen/pelvis computed tomography in staging of pediatric Hodgkin Lymphoma: is it always necessary?

The purpose of the study was to determine if abdomen/pelvis computed tomography (CT) can be safety omitted in the initial staging of a subgroup of children affected by Hodgkin Lymphoma (HL). Every participating center of A.I.E.O.P (Associazione Italiana di Ematologia ed Oncologia Pediatrica) sent local staging reports of 18F-fluorodeoxyglucose positron emission tomography (PET) and abdominal ultrasound (US) along with digital images of staging abdomen/pelvis CT to the investigation center where the CT scans were evaluated by an experienced pediatric radiologist. The local radiologist who performed the US was unaware of local CT and PET reports (both carried out after US), and the reviewer radiologist examining the CT images was unaware of local US, PET and CT reports. A new abdominal staging of 123 patients performed on the basis of local US report, local PET report, and centralized CT report was then compared to a simpler staging based on local US and PET. No additional lesion was discovered by CT in patients with abdomen/pelvis negativity in both US and PET or isolated spleen positivity in US (or US and PET), and so it seems that in the initial staging, abdomen/pelvis CT can be safety omitted in about 1/2 to 2/3 of children diagnosed with HL.