Francesca Vendemini

Retinoids in Pediatric Onco-Hematology: the Model of Acute Promyelocytic Leukemia and Neuroblastoma

Retinoids are lipophilic compounds derived from vitamin A, which have been extensively studied in cancer prevention and therapy. In pediatric oncology, they are successfully used for the treatment of acute promyelocytic leukemia (APL) and high-risk neuroblastoma (HR-NBL). APL is a subtype of acute myeloid leukemia (AML) clinically characterized by a severe bleeding tendency with a highrisk of fatal hemorrhage. The molecular hallmark of this disease is the presence of the promyelocytic leukemia (PML)-retinoic acid receptor-α (RAR α) gene fusion that plays a critical role in promyelocytic leukemogenesis and represents the target of retinoid therapy. The introduction in the late 1980s of all-trans retinoic acid (ATRA) into the therapy of APL radically changed the management and the outcome of this disease. Presently, the standard front-line therapeutic approach for pediatric APL includes anthracycline-based chemotherapy and ATRA, leading to a complete remission in almost 90% of the patients. Neuroblastoma (NBL) is an aggressive childhood tumor derived from the peripheral neural crest. More than half of patients have a high-risk disease, with a poor outcome despite intensive multimodal treatment. Although the exact mechanism of action remains unclear, the introduction of 13-cis-retinoic acid (13-cis-RA) in the therapy of NBL has improved the prognosis of this disease. Currently, the standard treatment for HR-NBL consists of myeloablative therapy followed by autologous hematopoietic stem cell transplantation (HSCT) and maintenance with 13-cis-RA for the treatment of minimal residual disease, leading to a 3-year disease-free survival rate (DFS) of about 50%. In this paper the authors provide a review of the peer-reviewed literature on the role of retinoids in the treatment of pediatric APL and HR-NBL, summarizing the most relevant clinical trial results of the last decades, analyzing the ongoing trials, and investigating future therapeutic perspectives of children affected by these diseases.

PRES in Children Undergoing Hematopoietic Stem Cell or Solid Organ Transplantation

Posterior reversible encephalopathy syndrome (PRES) is a clinical neuroradiologic entity that is becoming increasingly well known and documented in pediatrics. It is characterized by a variable association of seizures, headache, vomiting, altered mental status, visual disturbances, and seizures, as well as imaging suggesting white-gray matter edema involving the posterior regions of the central nervous system in most cases. The pathophysiology of PRES remains unclear. Although PRES has been associated with a widespread range of clinical conditions, namely infections, adverse drug events, autoimmune diseases, and many others, its onset after hematopoietic stem cell and solid organ transplantation remains the most commonly reported. Historically, PRES has proved to be generally reversible and associated with good clinical outcomes; however, severe complications, sometimes life-threatening, can also occur. Most reported cases of childhood PRES after hematopoietic stem cell or solid organ transplantation have been case reports or series across a broad spectrum of different transplant settings, and no clear consensus exists regarding how best to manage the syndrome. Thus, in this article, we provide a comprehensive review of the pathophysiological, clinical, and diagnostic aspects of PRES in children, with a specific focus on the transplant scenario. Differential diagnoses with other neurologic complications after pediatric transplantation are reviewed, and crucial issues in the management of PRES and the development of future research are ultimately addressed.

All-trans retinoic acid in the treatment of pediatric acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is a rare form of acute myeloid leukemia with specific epidemiological, pathogenetic and clinical features. Its frequency varies widely among nations, with a decreased incidence among ‘Nordic’ origin populations. The molecular hallmark of the disease is the presence of a balanced reciprocal translocation resulting in the PML/RAR-α gene fusion, which represents the target of the all-trans retinoic acid (ATRA) therapy. The introduction of ATRA in conjunction with anthracyclines marked a turning point in the treatment of APL, previously associated with a significant morbidity and mortality. Nowadays the standard front-line therapy for pediatric APL includes ATRA in every phase of the treatment, resulting in a complete remission rate of 90–95%. Here we provide an overview of the role of ATRA in the treatment of pediatric APL, summarizing the most relevant clinical results of recent decades and investigating future therapeutic perspectives for children with APL.

Clinical effectiveness of early treatment with hyperbaric oxygen therapy for severe late-onset hemorrhagic cystitis after hematopoietic stem cell transplantation in pediatric patients.

HC is a possible cause of morbidity and extended hospitalization after HSCT. Recent studies have reported the efficiency of HOT in adult patients who underwent allogeneic HSCT, but data in children are scarce. We report our single center experience with HOT in late‐onset HC after HSCT. Treatment with HOT consisted of daily sessions of breathing 100% O2 for a total of 75 min in the hyperbaric chamber with a minimum of eight sessions. HOT had been associated with a concomitant treatment with oral oxybutynin, hyperhydration and/or irrigation of the bladder through the catheter. Cidofovir had been administered based on the demonstration of viral infection. Between 2004 and 2011, 10 patients developed severe HC after a median of 26 days after HSCT. HOT was started after a median of six days since the clinical diagnosis of HC. After a median of 10 sessions of HOT, seven of 10 patients were in complete remission. HOT is a well‐tolerated procedure also in the pediatric setting. The early start of HOT might be effective in the treatment of HC offering advantages in terms of duration of symptoms and hospitalization.

Acute myeloid leukemia in infants: biology and treatment.

Children aged 0–2 years (i.e., infants) with acute myeloid leukemia (AML) are a peculiar subgroup of patients in the childhood AML scenario. They present with distinctive biological and clinical characteristics, including a high prevalence of prognostically unfavorable risk factors and an increased susceptibility to therapy-related toxicity. Remarkable improvements have been achieved over the last two decades in the treatment of these patients and their outcome is becoming superimposable to that of the older age groups. In this review, we will focus on peculiarities of this young subgroup of children with AML, describing their clinical presentation, the biology of disease, and factors influencing outcome. Treatment results and toxicity data reported by major collaborative groups are also summarized and compared.

Mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia: a report from the Italian AIEOP study group

Juvenile myelomonocytic leukemia (JMML) is a rare aggressive disease of early childhood. Driver mutations in the Ras signaling pathways are a key feature of JMML patients. Mutations in SETBP1 and JAK3 were recently identified in a subset of JMML patients characterized by poor prognosis and progression of disease. In this study, we report the results of a screening for mutations in SETBP1 and JAK3 of a cohort of seventy Italian patients with JMML, identifying 11.4% of them harboring secondary mutations in these two genes and discovering two new mutations in the SKI domain of SETBP1. JMML xenotransplantation and colony assay provide an initial understanding of the secondary nature of these events occurring in early precursor cells and suggest a different propagating capacity of clones harboring particular mutations.

Recurrent pneumothorax, pneumomediastinum, and subcutaneous emphysema in late-onset noninfectious pulmonary complications (LONIPCs) after hematopoietic stem cell transplantation.

Pneumothorax, Pneumomediastinum, and Subcutaneous Emphysema in Late-onset Noninfectious Pulmonary Complications (LONIPCs) After Hematopoietic Stem Cell Transplantation To the Editor: We report the case of a 7-year-old boy presenting recurrent episodes of pneumothorax (PNX), pneumomediastin (PM), and subcutaneous emphysema (SE) complicating a treatment-refractory bronchiolitis obliterans (BO) after allogeneic hematopoietic stem cell transplantation (HSCT). The child, affected by acute lymphoblastic leukemia, underwent a bone marrow HSCT from a HLA-mismatched unrelated donor in second complete remission. Nine months after the HSCT, he developed chronic graft-versus-host disease (GVHD) affecting the skin, which was successfully treated with steroids. Six months later, he presented with shortness of breath on exertion and persistent cough. High-resolution computed tomography (CT) scan (Fig. 1A) was suggestive of interstitial lung disease with patchy infiltrated areas and evidence of air trapping on comparative inspiratory and expiratory films. Multiple bronchiectasis and bronchiolectasis associated with ground glass areas were evident in both the upper lobes. White blood cell count and C-reactive protein were normal. Serological and cultural blood analyses were negative. Microbiological analysis on bronchial alveolar lavage (BAL) fluid was negative. Pulmonary function tests showed an obstructive pattern consistent with BO: 83.2% forced vital capacity (FVC) as predicted, 56.6% forced expiratory volume in one second (FEV1) as predicted, and 68% FEV1/FVC. An open-lung biopsy was performed and revealed a histologic pattern compatible with BO characterized by the presence of chronic inflammatory cells, fibroblast, and collagen obliterating the lumen. The patient underwent immunosuppressive treatment with an association of oral tacrolimus (0.15mg/kg/d)

Impact of inflammatory cytokine gene polymorphisms on developing acute graft-versus-host disease in children undergoing allogeneic hematopoietic stem cell transplantation.

Single nucleotide polymorphisms (SNPs) in gene encoding pro- and anti-inflammatory factors have been associated with the occurrence of aGvHD. We retrospectively tested a wide panel of 38 polymorphisms in 19 immunoregulatory genes, aiming to first establish, in a pediatric HSCT setting, which SNPs were significantly associated with the development of aGvHD. A significant association was found between aGvHD grades II–IV and SNPs of donor IL10-1082GG, and Fas-670CC + CT and recipient IL18-607 TT + TG genotype. aGvHD grades III-IV resulted associated with donor IL10-1082GG, Fas-670CC + CT, and TLR4-3612TT as well as the use of peripheral CD34+ cells as stem cell source. The multivariate analysis confirmed the association between donor IL10-1082GG and Fas-670CC + CT and aGvHD grades II–IV and between donor IL10-1082GG and TLR4-3612TT and aGvHD grades III-IV. In conclusion we found an association between IL10, FAS, and TLR4 in the donor and IL18 in the recipient and an increased risk of developing aGvHD in transplanted children. Knowledge of the SNPs of cytokine genes associated with aGvHD represents a useful tool for an integrated pretransplantation risk assessment and could guide the physicians to an optimal and more accurate HSCT planning.