Healthcare costs and resources utilization in children with difficult-to-control asthma treated with biologic therapies: A population-based cohort study.

INTRODUCTION: Asthma is one of the most common diseases in children, with a variable range of severity. In recent years, treatment for severe asthma has been largely improved by the availability of targeted biologic therapies. Nevertheless, studies reporting real-world data and cost-effectiveness analyses are lacking. The aim of this study was to evaluate, on a population-based cohort of children with asthma, the impact of the treatment with biologics on healthcare service utilization and associated costs. METHODS: Data were retrieved from Healthcare Utilization database of Lombardy region (Italy). A cohort of 46 asthmatic children aged 6-11 in treatment with dupilumab, mepolizumab or omalizumab was identified during 2017-2021. We compared healthcare resources use between the year before ("baseline period") and the year after the treatment initiation ("follow-up period"). Average 1-year healthcare costs were also calculated. RESULTS: Comparing the baseline with the follow-up period, the number of patients with at least one exacerbation-related hospitalization and ER access decreased by 75.0% and 85.7%, respectively. The use of biologic agents, namely omalizumab, mepolizumab and dupilumab, significantly reduced oral corticosteroids (OCS), short-acting ß2-agonists and the association inhaled corticosteroids/long-acting ß2-agonists use. ER admissions for non-respiratory causes were also significantly reduced, while discontinuation rate was low (6.5%). The overall costs increased, due to the costs of the biologic agents, but the hospital admission-related costs due to respiratory causes reduced significantly. CONCLUSIONS: Our real-world investigation suggests that biologic agents reduced hospital admissions for respiratory causes and use of anti-asthmatic drugs, including OCS. However, long-term healthcare sustainability still needs more in-depth assessments.

Pubertal attainment and Leydig cell function following pediatric hematopoietic stem cell transplantation: a three-decade longitudinal assessment.

Introduction: Impaired testosterone secretion is a frequent sequela following hematopoietic stem cell transplantation (HSCT) in pediatrics, but long-term longitudinal trendlines of clinical and biochemical findings are still scanty. Methods: Monocentric, retrospective analysis. Male patients transplanted <18 years between 1992 and 2021, surviving ≥2 years after HSCT and showing, upon enrollment, clinical and biochemical signs consistent with pubertal onset and progression were included. Clinical and biochemical data collected every 6-12 months were recorded. Results: Of 130 patients enrolled, 56% were prepubertal, while 44% were peri-/postpubertal upon HSCT. Overall, 44% showed spontaneous progression into puberty and normal gonadal profile, while the remaining experienced pubertal arrest (1%), isolated increase of FSH (19%), compensated (23%) or overt (13%) hypergonadotropic hypogonadism. Post-pubertal testicular volume (TV) was statistically smaller among patients still pre-pubertal upon HSCT (p 0.049), whereas no differences were recorded in adult testosterone levels. LH and testosterone levels showed a specular trend between 20 and 30 years, as a progressive decrease in sexual steroids was associated with a compensatory increase of the luteinizing hormone. A variable degree of gonadal dysfunction was reported in 85%, 51%, 32% and 0% of patients following total body irradiation- (TBI), busulfan-, cyclophosphamide- and treosulfan-based regimens, respectively. TBI and busulfan cohorts were associated with the lowest probability of gonadal event-free course (p<0.0001), while it achieved 100% following treosulfan. A statistically greater gonadotoxicity was detected after busulfan than treosulfan (p 0.024). Chemo-only regimens were associated with statistically larger TV (p <0.001), higher testosterone (p 0.008) and lower gonadotropin levels (p <0.001) than TBI. Accordingly, the latter was associated with a 2-fold increase in the risk of gonadal failure compared to busulfan (OR 2.34, CI 1.08-8.40), whereas being pre-pubertal upon HSCT was associated with a reduced risk (OR 0.15, CI 0.08-0.30). Conclusions: a) patients pre-pubertal upon HSCT showed a reduced risk of testicular endocrine dysfunction, despite smaller adult TV; b) patients showed downwards trend in testosterone levels after full pubertal attainment, despite a compensatory increase in LH; c) treosulfan was associated to a statistically lower occurrence of hypogonadism than busulfan, with a trend towards larger TV, higher testosterone levels and lower gonadotropins.

Iron Overload Following Hematopoietic Stem Cell Transplantation: Prevalence, Severity, and Management in Children and Adolescents with Malignant and Nonmalignant Diseases.

Iron overload (IOL) is a frequently reported complication following hematopoietic stem cell transplantation (HSCT) that has been investigated extensively in the field of hemoglobinopathies but has not been thoroughly characterized after HSCT in pediatric malignancies. Our aim was to assess prevalence, severity, risk factors, and management of IOL, as defined using biochemical (serum ferritin) and radiologic tools (T2*-weighted magnetic resonance imaging [MRI]), in a cohort of pediatric patients who underwent HSCT for either malignant or benign diseases. This monocentric, retrospective, observational study included all the 163 patients alive and in continuous remission at 24 months post-HSCT out of the 219 consecutive children and adolescents who underwent HSCT at our institution between 2012 and 2018, were included in the study. IOL was classified into 4 categories: absent, mild, moderate, and severe. Among the 163 patients, 73% had some degree of IOL (mild in 37%, moderate in 29%, and severe in 7%). Moderate/severe IOL was more frequent among patients diagnosed with a malignant disease versus those with a benign disease (43% versus 19%; P = .0065). Trend lines for serum ferritin showed a "bell-shaped" distribution, with the highest levels recorded during the first 6 months post-HSCT, followed by a spontaneous reduction. Both pre-HSCT (1659 ng/mL versus 617 ng/mL; P < .001) and maximum post-HSCT (2473 ng/mL versus 1591 ng/mL; P < .001) median ferritin levels were statistically higher in the patients with malignancies. Radiologic assessment of IOL confirmed a more severe degree in patients with malignant disorders compared to those with benign disorders (median T2*-MRI, 4.20 msec [interquartile range (IQR), 3.0 to 6.40 msec] versus 7.40 msec [IQR, 4.90 to 11.00 msec]; P = .008). T2* levels were associated with the number of transfusions performed (P = .0006), with a steeper drop in T2* values for the first 20 transfusions and a milder slope for subsequent transfusions. T2* and ferritin values showed a statistically significant negative exponential relationship (P < .0001), although a ferritin level ≥1000 ng/mL showed poor specificity (48%) and low positive predictive value (53%) for discriminating moderate-to-severe IOL from absent-mild IOL as assessed by T2*-MRI, but with high sensitivity (92%) and negative predictive value (91%). In a multivariable model, >20 transfusions (odds ratio [OR], 4.07; 95% confidence interval [CI], 1.61 to 10.68; P = .003) and higher pre-HSCT ferritin level (P < .001) were associated with the risk of developing moderate-to-severe IOL. Use of a sibling donor (OR, .29; 95% CI, .10 to .77; P = .015) and a nonmalignancy (OR, .27; 95% CI, .08 to .82; P = .026) were protective factors. Phlebotomy (66%), low-dose oral chelators (9%), or a combined approach (25%) were started at a median of 12 months after HSCT in 78% of the patients with IOL. Six percent of the patients treated exclusively with phlebotomy (median, 14, significantly higher in patients >40 kg) discontinued phlebotomy owing to poor venous access, lack of compliance, or hypotension, whereas 39% of patients treated with chelators developed mild renal or hepatic side effects that resolved after tapering or discontinuation. Patients with malignancies showed statistically higher pre-HSCT and post-HSCT ferritin levels and lower T2* values. High ferritin level recorded on T2*-MRI showed unsatisfactory diagnostic accuracy in predicting IOL; thus, T2*-MRI should be considered a key tool for confirming IOL after HSCT in patients with an elevated serum ferritin level. IOL treatment is feasible after HSCT.

Serum anti-Müllerian hormone as a marker of ovarian reserve after cancer treatment and/or hematopoietic stem cell transplantation in childhood: proposal for a systematic approach to gonadal assessment.

OBJECTIVE: Female patients treated with alkylating agents in childhood are at risk for ovarian impairment. We aimed at describing the pattern of residual ovarian function in a cohort of survivors of hematological malignancies and/or hematopoietic stem cell transplantation (HSCT) and assessing the relationship between cyclophosphamide equivalent dose (CED) and anti-Müllerian hormone (AMH). DESIGN AND METHODS: Gonadal health was clinically and biochemically assessed in 124 post-menarchal survivors who underwent treatment for pediatric hematological malignancies and/or HSCT between 1992 and 2019. RESULTS: Overt 'premature ovarian insufficiency' (POI) was detected in 72.1 and 3.7% of transplanted and non-transplanted patients, respectively; milder 'diminished ovarian reserve' (DOR) in 16.3 and 22.2%. In non-transplanted patients, increasing CED values were associated with lower AMH-SDS (P = 0.04), with the threshold of 7200 g/m2 being the best discriminator between DOR/POI and normal ovarian function (AUC: 0.75 on ROC analysis) and with an observed decrease of 0.14 AMH-SDS for each CED increase of 1 g/m2. In addition, age at diagnosis ≥10 years played a detrimental role on ovarian reserve (P = 0.003). In the HSCT group, irradiation was associated with a statistically significant reduction in AMH-SDS (P = 0.04). CONCLUSIONS: In non-transplanted patients, CED ≥ 7200 mg/m2 was associated with a DOR, while younger age at diagnosis played a protective role on ovarian reserve. As a result of the data collected, we propose a systematic algorithm to assess iatrogenic gonadal impairment in young female patients exposed to chemo-radiotherapy in childhood for hematological disorders.

Remote Assessment of Disease and Relapse in Epilepsy: Protocol for a Multicenter Prospective Cohort Study.

BACKGROUND: In recent years, a growing body of literature has highlighted the role of wearable and mobile remote measurement technology (RMT) applied to seizure detection in hospital settings, whereas more limited evidence has been produced in the community setting. In clinical practice, seizure assessment typically relies on self-report, which is known to be highly unreliable. Moreover, most people with epilepsy self-identify factors that lead to increased seizure likelihood, including mood, behavior, sleep pattern, and cognitive alterations, all of which are amenable to measurement via multiparametric RMT. OBJECTIVE: The primary aim of this multicenter prospective cohort study is to assess the usability, feasibility, and acceptability of RMT in the community setting. In addition, this study aims to determine whether multiparametric RMT collected in populations with epilepsy can prospectively estimate variations in seizure occurrence and other outcomes, including seizure frequency, quality of life, and comorbidities. METHODS: People with a diagnosis of pharmacoresistant epilepsy will be recruited in London, United Kingdom, and Freiburg, Germany. Participants will be asked to wear a wrist-worn device and download ad hoc apps developed on their smartphones. The apps will be used to collect data related to sleep, physical activity, stress, mood, social interaction, speech patterns, and cognitive function, both passively from existing smartphone sensors (passive remote measurement technology [pRMT]) and actively via questionnaires, tasks, and assessments (active remote measurement technology [aRMT]). Data will be collected continuously for 6 months and streamed to the Remote Assessment of Disease and Relapse-base (RADAR-base) server. RESULTS: The RADAR Central Nervous System project received funding in 2015 from the Innovative Medicines Initiative 2 Joint Undertaking under Grant Agreement No. 115902. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation program and European Federation of Pharmaceutical Industries and Associations. Ethical approval was obtained in London from the Bromley Research Ethics Committee (research ethics committee reference: 19/LO/1884) in January 2020. The first participant was enrolled on September 30, 2020. Data will be collected until September 30, 2021. The results are expected to be published at the beginning of 2022. CONCLUSIONS: RADAR Epilepsy aims at developing a framework of continuous data collection intended to identify ictal and preictal states through the use of aRMT and pRMT in the real-life environment. The study was specifically designed to evaluate the clinical usefulness of the data collected via new technologies and compliance, technology acceptability, and usability for patients. These are key aspects to successful adoption and implementation of RMT as a new way to measure and manage long-term disorders. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/21840.

A Simple RNA Target Capture NGS Strategy for Fusion Genes Assessment in the Diagnostics of Pediatric B-cell Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is the most frequent pediatric cancer. Fusion genes are hallmarks of ALL, and they are used as biomarkers for risk stratification as well as targets for precision medicine. Hence, clinical diagnostics pursues broad and comprehensive strategies for accurate discovery of fusion genes. Currently, the gold standard methodologies for fusion gene detection are fluorescence in situ hybridization and polymerase chain reaction; these, however, lack sensitivity for the identification of new fusion genes and breakpoints. In this study, we implemented a simple operating procedure (OP) for detecting fusion genes. The OP employs RNA CaptureSeq, a versatile and effortless next-generation sequencing assay, and an in-house as well as a purpose-built bioinformatics pipeline for the subsequent data analysis. The OP was evaluated on a cohort of 89 B-cell precursor ALL (BCP-ALL) pediatric samples annotated as negative for fusion genes by the standard techniques. The OP confirmed 51 samples as negative for fusion genes, and, more importantly, it identified known (KMT2A rearrangements) as well as new fusion events (JAK2 rearrangements) in the remaining 38 investigated samples, of which 16 fusion genes had prognostic significance. Herein, we describe the OP and its deployment into routine ALL diagnostics, which will allow substantial improvements in both patient risk stratification and precision medicine.

Paediatric non-Hodgkin lymphoma in low and middle income countries.

Great advances have been made in the treatment of paediatric non-Hodgkin lymphoma (NHL). In high-income countries (HIC), cure rates now exceed 85%. However, in low- and middle-income countries (LMIC), cure rates remain less than 50%. It is estimated that over 90% of paediatric NHL worldwide occur in LMIC; therefore, even modest improvements in outcome would have significant impact in reducing the burden of paediatric NHL globally. This article will discuss some of the issues required to improve the outcome of paediatric NHL in LMIC using data presented at the Fifth International Symposium on Childhood, Adolescent and Young Adult Non-Hodgkin Lymphoma held in Varese, Italy, 2015 to illustrate these issues. Additionally, potential bi-directional benefits for patients in both LMIC and HIC from future collaborations will be discussed.

Adolescents' Health Awareness and Understanding of Cancer and Tumor Prevention: When and Why an Adolescent Decides to Consult a Physician.

BACKGROUND: A feature often seen in adolescent patients with cancer is a lengthy symptom interval, especially in comparison with children. It has been suggested that inadequate awareness of cancer risk among adolescents may play an important role in this study. METHODS: The Società Italiana Adolescenti con Malattie Onco-ematologiche and the Fondazione Umberto Veronesi conducted a survey to investigate health awareness among healthy adolescents and their understanding of cancer and its signs and symptoms by commissioning a specialized agency (AstraRicerche). A questionnaire was administered to 500 Italian adolescents from the age group of 15 to 19 years using the computer-aided web interviewing method. RESULTS: Approximately 80% of the adolescents interviewed claimed to be well informed about their own health, 85% said they were aware that some lifestyle habits could influence their health, and 80% reported that they know that cancer can develop in adolescence too. It was also noted that, while some adolescents were worried about a given symptom, 22% of them reportedly preferred a wait-and-see approach (either to avoid alarming their parents, or they hoped that the symptom would be temporary). CONCLUSIONS: This study showed that a majority of adolescents are concerned about their own health, but sometimes prefer not to report their symptoms to anyone. Hence, it is important to develop information campaigns tailored to raise awareness among this age group and help them interpret their symptoms.

New policies to address the global burden of childhood cancers.

Childhood cancer is a major global health issue. Every year, almost 100 000 children die from cancer before the age of 15 years, more than 90% of them in resource-limited countries. Here, we review the key policy issues for the delivery of better care, research, and education of professionals and patients. We present a key list of time-limited proposals focusing on change to health systems and research and development. These include sector and system reforms to make care affordable to all, policies to promote growth of civil society around both cancer and Millennium Development Goals, major improvements to public health services (particularly the introduction of national cancer plans), improved career development, and increased remuneration of specialist health-care workers and government support for childhood cancer registries. Research and development proposals focus on sustainable funding, the establishment of more research networks, and clinical research specifically targeted at the needs of low-income and middle-income countries. Finally, we present proposals to address the need for clinical trial innovation, the complex dichotomy of regulations, and the threats to the availability of data for childhood cancers.

Toxicity assessment of molecularly targeted drugs incorporated into multiagent chemotherapy regimens for pediatric acute lymphocytic leukemia (ALL): review from an international consensus conference.

One of the challenges of incorporating molecularly targeted drugs into multi-agent chemotherapy (backbone) regimens is defining dose-limiting toxicities (DLTs) of the targeted agent against the background of toxicities of the backbone regimen. An international panel of 22 pediatric acute lymphocytic leukemia (ALL) experts addressed this issue (www.ALLNA.org). Two major questions surrounding DLT assessment were explored: (1) how toxicities can be best defined, assessed, and attributed; and (2) how effective dosing of new agents incorporated into multi-agent ALL clinical trials can be safely established in the face of disease- and therapy-related systemic toxicities. The consensus DLT definition incorporates tolerance of resolving Grade 3 and some resolving Grade 4 toxicities with stringent safety monitoring. This functional DLT definition is being tested in two Children's Oncology Group (COG) ALL clinical trials.

Standardization of flow cytometric minimal residual disease evaluation in acute lymphoblastic leukemia: Multicentric assessment is feasible.

BACKGROUND: Single-laboratory experience showed that flow cytometric (FCM) assessment of minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL) is feasible in most patients and gives independent prognostic information. It is, however, not known whether FCM analysis can reliably be standardized for multicentric application. METHODS: An extensive standardization program was installed in four collaborating laboratories, which study FCM-MRD in children treated with the AIEOP-BFM-ALL 2000 protocol. This included methodological alignment, continuous quality monitoring, as well as personnel education by exchange and performance feed-back. RESULTS: Blinded inter-laboratory tests of list-mode data interpretation concordance (n = 202 blood and bone marrow samples from follow-up during induction of 31 randomly selected patients of a total series of n = 395) showed a very high degree of inter-rater agreement among the four centers despite differences in cytometers and software usage (intraclass correlation coefficient [ICC] 0.979 based on n= 800 single values). Lower concordance was reached with amounts of MRD below 0.1%. Comparing data from sample exchange experiments (n = 42 samples; ICC 0.98) and from independent patient cohorts from the four centers (regarding positive samples per time-point of follow-up as well as risk estimates) concordance was also good. CONCLUSION: MRD-evaluation by FCM in ALL can be standardized for reliable multicentric assessment in large trials.

Assessment of submicroscopic genetic lesions by single nucleotide polymorphism arrays in a child with acute myeloid leukemia and FLT3-internal tandem duplication.

The same FLT3-internal tandem duplication (ITD) positive clone was detected at diagnosis and relapse, but not at birth, in a child with M1 acute myeloid leukemia. Single nucleotide polymorphism arrays demonstrated that chromosome 13 acquired uniparental disomy, in association with del(9q), represented a progressive event in the course of the disease, and it was responsible for the homozygous FLT3-ITD at relapse.