Exagamglogene Autotemcel for Transfusion-Dependent ß-Thalassemia.

BACKGROUND: Exagamglogene autotemcel (exa-cel) is a nonviral cell therapy designed to reactivate fetal hemoglobin synthesis through ex vivo clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 gene editing of the erythroid-specific enhancer region of BCL11A in autologous CD34+ hematopoietic stem and progenitor cells (HSPCs). METHODS: We conducted an open-label, single-group, phase 3 study of exa-cel in patients 12 to 35 years of age with transfusion-dependent ß-thalassemia and a ß0/ß0, ß0/ß0-like, or non-ß0/ß0-like genotype. CD34+ HSPCs were edited by means of CRISPR-Cas9 with a guide mRNA. Before the exa-cel infusion, patients underwent myeloablative conditioning with pharmacokinetically dose-adjusted busulfan. The primary end point was transfusion independence, defined as a weighted average hemoglobin level of 9 g per deciliter or higher without red-cell transfusion for at least 12 consecutive months. Total and fetal hemoglobin concentrations and safety were also assessed. RESULTS: A total of 52 patients with transfusion-dependent ß-thalassemia received exa-cel and were included in this prespecified interim analysis; the median follow-up was 20.4 months (range, 2.1 to 48.1). Neutrophils and platelets engrafted in each patient. Among the 35 patients with sufficient follow-up data for evaluation, transfusion independence occurred in 32 (91%; 95% confidence interval, 77 to 98; P<0.001 against the null hypothesis of a 50% response). During transfusion independence, the mean total hemoglobin level was 13.1 g per deciliter and the mean fetal hemoglobin level was 11.9 g per deciliter, and fetal hemoglobin had a pancellular distribution (≥94% of red cells). The safety profile of exa-cel was generally consistent with that of myeloablative busulfan conditioning and autologous HSPC transplantation. No deaths or cancers occurred. CONCLUSIONS: Treatment with exa-cel, preceded by myeloablation, resulted in transfusion independence in 91% of patients with transfusion-dependent ß-thalassemia. (Supported by Vertex Pharmaceuticals and CRISPR Therapeutics; CLIMB THAL-111 ClinicalTrials.gov number, NCT03655678.).

Use of HSC Targeted LNP to Generate a Mouse Model of Lethal α-Thalassemia and Treatment via Lentiviral Gene Therapy.

-Thalassemia (AT) is one of the most commonly occurring inherited hematological diseases. However, few treatments are available, and allogeneic bone marrow transplantation (BMT) is the only available therapeutic option for patients with severe AT. Research into AT has remained limited due to a lack of adult mouse models, with severe AT typically resulting in in utero lethality. By using a lipid nanoparticle (LNP) targeting the receptor CD117 and delivering a Cre mRNA (mRNACreLNPCD117), we were able to delete floxed -globin genes at high efficiency in hematopoietic stem cells (HSC) ex vivo. These cells were then engrafted in the absence or presence of a novel α-globin expressing lentiviral vector (ALS20I). Myeloablated mice transplanted with mRNACreLNPCD117-treated HSC showed a complete knockout of -globin genes. They demonstrated a phenotype characterized by the synthesis of hemoglobin H (-tetramers,  or HbH), aberrant erythropoiesis, and abnormal organ morphology, culminating in lethality approximately eight weeks following engraftment. Mice receiving mRNACreLNPCD117-treated HSC with at least one copy of ALS20I survived long-term with normalization of erythropoiesis, decreased the production of HbH, and ameliorated the abnormal organ morphology. Furthermore, we tested ALS20I in erythroid progenitors derived from -globin-KO CD34+ and cells isolated from patients with both deletional and non-deletional HbH disease, demonstrating improvement in -globin/-globin mRNA ratio and reduction in the formation of HbH by HPLC. Our results demonstrate the broad applicability of LNP for disease modeling, characterization of a novel severe mouse model of AT, and the efficacy of ALS20I for treating AT.

CRISPR-Cas9 Gene Editing for Sickle Cell Disease and ß-Thalassemia.

Transfusion-dependent ß-thalassemia (TDT) and sickle cell disease (SCD) are severe monogenic diseases with severe and potentially life-threatening manifestations. BCL11A is a transcription factor that represses γ-globin expression and fetal hemoglobin in erythroid cells. We performed electroporation of CD34+ hematopoietic stem and progenitor cells obtained from healthy donors, with CRISPR-Cas9 targeting the BCL11A erythroid-specific enhancer. Approximately 80% of the alleles at this locus were modified, with no evidence of off-target editing. After undergoing myeloablation, two patients - one with TDT and the other with SCD - received autologous CD34+ cells edited with CRISPR-Cas9 targeting the same BCL11A enhancer. More than a year later, both patients had high levels of allelic editing in bone marrow and blood, increases in fetal hemoglobin that were distributed pancellularly, transfusion independence, and (in the patient with SCD) elimination of vaso-occlusive episodes. (Funded by CRISPR Therapeutics and Vertex Pharmaceuticals; ClinicalTrials.gov numbers, NCT03655678 for CLIMB THAL-111 and NCT03745287 for CLIMB SCD-121.).

Iron chelation therapy for children with transfusion-dependent ß-thalassemia: How young is too young?

In this review, we provide a summary of evidence on iron overload in young children with transfusion-dependent ß-thalassemia (TDT) and explore the ideal timing for intervention. Key data from clinical trials and observational studies of the three available iron chelators deferoxamine, deferiprone, and deferasirox are also evaluated for inclusion of subsets of young children, especially those less than 6 years of age. Evidence on the efficacy and safety of iron chelation therapy for children ≥2 years of age with transfusional iron overload is widely available. New data exploring the risks and benefits of early-start iron chelation in younger patients with minimal iron overload are also emerging.

Evidence that platelets from transfusion-dependent ß-thalassemia patients induce T cell activation.

A hypercoagulable state leading to increased risk for thrombotic events represents one of the most common complications observed in transfusion-dependent ß-thalassemia (TDT) patients. TDT patients have increased frequencies of circulating activated platelets. However, there is no information so far if platelets from TDT patients can activate T cells. In the present study we showed that T cells treated with platelets from TDT patients showed significant increased surface expression of CD69 compared to the T cells treated with platelets from healthy individuals. Patients with splenectomy showed increased T cell activation compared to patients with intact spleen. No T cell activation was observed following incubation with plasma alone, nor with platelets from healthy subjects. The percentages of regulatory T cells (Tregs) were also examined. TDT patients showed statistically significant increased percentages of Tregs compared to healthy controls. Additionally, we observed a positive statistically significant correlation between the percentages of Tregs and the platelet-induced activated T cells in patients who were not treated with aspirin. TDT patients showed increased levels of sP-selectin, suPAR and GDF-15, molecules implicated in platelet activation. We show that platelets from TDT patients can activate T cells in vitro. This activation correlates with markers of platelet activation and increased numbers of Tregs, perhaps in an effort to eliminate immune dysregulation, conceivably secondary to platelet activation.

Management of luspatercept therapy in patients with transfusion-dependent ß-thalassaemia.

Patients with transfusion-dependent ß-thalassaemia require lifelong, regular red blood cell transfusions for survival; however, frequent blood transfusions are associated with an increased risk of iron overload, transfusion-transmitted disease and alloimmunization, as well as reduced quality of life. Luspatercept, an erythroid maturation agent that promotes late-stage erythroid maturation independently of erythropoietin, has demonstrated efficacy in reducing transfusion burden in patients with transfusion-dependent ß-thalassaemia. In this review, we discuss treatment initiation, ongoing evaluation, dose adjustment and management of adverse events in transfusion-dependent patients with ß-thalassaemia receiving luspatercept, and we provide guidance on how to determine whether patients are deriving clinical benefit.

Thalassaemia.

Thalassaemia is a diverse group of genetic disorders with a worldwide distribution affecting globin chain synthesis. The pathogenesis of thalassaemia lies in the unbalanced globin chain production, leading to ineffective erythropoiesis, increased haemolysis, and deranged iron homoeostasis. The clinical phenotype shows heterogeneity, ranging from close to normal without complications to severe requiring lifelong transfusion support. Conservative treatment with transfusion and iron chelation has transformed the natural history of thalassaemia major into a chronic disease with a prolonged life expectancy, albeit with co-morbidities and substantial disease burden. Curative therapy with allogeneic haematopoietic stem cell transplantation is advocated for suitable patients. The understanding of the pathogenesis of the disease is guiding therapeutic advances. Novel agents have shown efficacy in improving anaemia and transfusion burden, and initial results from gene therapy approaches are promising. Despite scientific developments, worldwide inequality in the access of health resources is a major concern, because most patients live in underserved areas.

A Phase 3 Trial of Luspatercept in Patients with Transfusion-Dependent ß-Thalassemia.

BACKGROUND: Patients with transfusion-dependent ß-thalassemia need regular red-cell transfusions. Luspatercept, a recombinant fusion protein that binds to select transforming growth factor ß superfamily ligands, may enhance erythroid maturation and reduce the transfusion burden (the total number of red-cell units transfused) in such patients. METHODS: In this randomized, double-blind, phase 3 trial, we assigned, in a 2:1 ratio, adults with transfusion-dependent ß-thalassemia to receive best supportive care plus luspatercept (at a dose of 1.00 to 1.25 mg per kilogram of body weight) or placebo for at least 48 weeks. The primary end point was the percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval. Other efficacy end points included reductions in the transfusion burden during any 12-week interval and results of iron studies. RESULTS: A total of 224 patients were assigned to the luspatercept group and 112 to the placebo group. Luspatercept or placebo was administered for a median of approximately 64 weeks in both groups. The percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval was significantly greater in the luspatercept group than in the placebo group (21.4% vs. 4.5%, P<0.001). During any 12-week interval, the percentage of patients who had a reduction in transfusion burden of at least 33% was greater in the luspatercept group than in the placebo group (70.5% vs. 29.5%), as was the percentage of those who had a reduction of at least 50% (40.2% vs. 6.3%). The least-squares mean difference between the groups in serum ferritin levels at week 48 was -348 µg per liter (95% confidence interval, -517 to -179) in favor of luspatercept. Adverse events of transient bone pain, arthralgia, dizziness, hypertension, and hyperuricemia were more common with luspatercept than placebo. CONCLUSIONS: The percentage of patients with transfusion-dependent ß-thalassemia who had a reduction in transfusion burden was significantly greater in the luspatercept group than in the placebo group, and few adverse events led to the discontinuation of treatment. (Funded by Celgene and Acceleron Pharma; BELIEVE ClinicalTrials.gov number, NCT02604433; EudraCT number, 2015-003224-31.).

Characteristics of Café-au-lait Macules and their Association with the Neurofibromatosis type I Genotype in a Cohort of Greek Children.

Cafe-au-lait macules are the most distinctive clinical finding in neurofibromatosis type I. The aim of this prospective study of Greek children diagnosed with neurofibromatosis type I was to describe the dermatological phenotype and to analyse the characteristics of cafe-au-lait macules and their association with genotype. Pigment intensity and melatonin content of cafe-au-lait macules were measured with a narrowband spectrophotometer. A total of 63 children aged 6 months to 16 years old were studied. Mean melanin content varied, both among patients, and within each patient (p < 0.001). Females had a higher number of cafe-au-lait macules than did males (p = 0.025), and the melanin content of cafe-au-lait macules was lower in females than males (p < 0.001). Patients with protein-truncating variants in the neurofibromatosis type I gene had higher melanin content of cafe-au-lait macules than other types of genetic variants t (55) = 2.196, p = 0.032. Plexiform neurofibromas were also detected in the majority of patients with protein- truncating variants, while juvenile xanthogranulomas were detected equally in patients with protein-truncating and non-protein-truncating variants. In conclusion, cafe-au-lait macules with high melatonin content are associated with patients carrying non-protein-truncating variants. Therefore, measurement of cafe-au-lait macule pigment intensity might provide useful information for initial assessment of patients with neurofibromatosis type I and the severity of their future phenotype.

Therapeutic perspective for children and young adults living with thalassemia and sickle cell disease.

Hemoglobinopathies, including thalassemias and sickle cell disease, are the most common monogenic diseases worldwide, with estimated annual births of more than 330,000 affected infants. Hemoglobin disorders account for about 3.4% of deaths in children under 5 years of age. The distribution of these diseases is historically linked to current or previously malaria-endemic regions; however, immigration has led to a worldwide distribution of these diseases, making them a global health problem. During the last decade, new treatment approaches and novel therapies have been proposed, some of which have the potential to change the natural history of these disorders. Indeed, the first erythroid maturation agent, luspatercept, and gene therapy have been approved for beta-thalassemia adult patients. For sickle cell disease, molecules targeting vaso-occlusion and hemoglobin S polymerization include crizanlizumab, which has been approved for patients ≥ 16 years, voxelotor approved for patients ≥ 12 years, and L-glutamine for patients older than 5 years.    Conclusion: We herein present the most recent advances and future perspectives in thalassemia and sickle cell disease treatment, including new drugs, gene therapy, and gene editing, and the current clinical trial status in the pediatric populations. What is Known: • Red blood cell transfusions, iron chelation therapy and hematopoietic stem cell transplantation have been the mainstay of treatment of thalassemia patients for decades. • For sickle cell disease, until 2005, treatment strategies were mostly the same as those for thalassemia, with the option of simple transfusion or exchange transfusion. In 2007, hydroxyurea was approved for patients ≥ 2 years old. What is New: • In 2019, gene therapy with betibeglogene autotemcel (LentiGlobin BB305) was approved for TDT patients ≥ 12 years old non ß0/ß0 without matched sibling donor. • Starting from 2017 several new drugs, such as L-glutamine (approved only by FDA), crizanlizumab (approved by FDA and EMA for patients ≥ 16 years), and lastly voxelotor (approved by FDA and EMA for patients ≥ 12 years old).

Immune response and adverse events after vaccination against SARS-CoV-2 in adult patients with transfusion-dependent thalassaemia.

Patients with transfusion-dependent thalassaemia (TDT) are considered an at increased-risk population for severe and/or morbid coronavirus disease 2019 (COVID-19) infection. Timely vaccination is the main preventive method for severe COVID-19. Different adverse events and reactions after vaccination have been reported, with severe ones being extremely rare. Patients with TDT may have altered immunity due to chronic transfusions, iron overload and chelation therapy, and splenic dysfunction. Here, we show that adult patients with TDT following vaccination with the novel messenger RNA vaccines have mild adverse events and can produce protective antibodies comparable to the healthy population.

Uncoupling of Bone Turnover may Compromise Skeletal Health of Young Patients With Haemophilia A.

There is evidence that bone mass is decreased and bone metabolism is dysregulated in children with haemophilia (CWH). The objective of this study was to investigate the impact of haemophilia on skeletal health in children, with regards to bone mineral density (BMD) and metabolic bone profile. This study included 51 male CWH A. Dual-energy X-ray absorptiometry (DXA) was performed to assess BMD in lumbar spine (LS) and total body less head (TBLH) and Z-scores were calculated (low BMD Z-score<-2, low-normal BMD Z-score between -1 and -2). Serum levels of osteocalcin (OC), procollagen type I C-terminal propeptide (PICP), bone alkaline phosphatase (bALP), bone tartrate-resistant acid phosphatase 5b (TRAP5b), vitamin D, parathormone (PTH), urinary calcium/creatinine (uCa/uCr) and urine deoxypyridinoline/creatinine (uDPD/uCr) were measured. Mean BMD Z-scores were lower than predicted at both sites of measurement. More specifically, 10% of CWH A had low and 20% low-normal BMD Z-scores in LS, whereas 9.1% had low-normal TBLH BMD Z-scores and there were no patients with low BMD Z-scores at this site of measurement. 36.7% of CWH had low vitamin D levels and 19.6% had a history of fracture. Also, patients with haemophilia had lower OC and higher uDPD/uCr levels while OC positively correlated to BMD Z-scores and uDPD/uCr negatively correlated to BMD Z-scores at both sites. No statistically significant differences were observed with regards to mode of treatment, number of haemorrhages and the presence of target-joints. CWH A had decreased BMD Z-scores at both sites with an uncoupling of bone turnover LS BMD seemed to be more affected than TBLH BMD.

PATZ1 fusions define a novel molecularly distinct neuroepithelial tumor entity with a broad histological spectrum.

Large-scale molecular profiling studies in recent years have shown that central nervous system (CNS) tumors display a much greater heterogeneity in terms of molecularly distinct entities, cellular origins and genetic drivers than anticipated from histological assessment. DNA methylation profiling has emerged as a useful tool for robust tumor classification, providing new insights into these heterogeneous molecular classes. This is particularly true for rare CNS tumors with a broad morphological spectrum, which are not possible to assign as separate entities based on histological similarity alone. Here, we describe a molecularly distinct subset of predominantly pediatric CNS neoplasms (n = 60) that harbor PATZ1 fusions. The original histological diagnoses of these tumors covered a wide spectrum of tumor types and malignancy grades. While the single most common diagnosis was glioblastoma (GBM), clinical data of the PATZ1-fused tumors showed a better prognosis than typical GBM, despite frequent relapses. RNA sequencing revealed recurrent MN1:PATZ1 or EWSR1:PATZ1 fusions related to (often extensive) copy number variations on chromosome 22, where PATZ1 and the two fusion partners are located. These fusions have individually been reported in a number of glial/glioneuronal tumors, as well as extracranial sarcomas. We show here that they are more common than previously acknowledged, and together define a biologically distinct CNS tumor type with high expression of neural development markers such as PAX2, GATA2 and IGF2. Drug screening performed on the MN1:PATZ1 fusion-bearing KS-1 brain tumor cell line revealed preliminary candidates for further study. In summary, PATZ1 fusions define a molecular class of histologically polyphenotypic neuroepithelial tumors, which show an intermediate prognosis under current treatment regimens.

Genotype-phenotype association and variant characterization in Diamond-Blackfan anemia caused by pathogenic variants in RPL35A.

Diamond Blackfan anemia (DBA) is predominantly an autosomal dominant inherited red cell aplasia primarily caused by pathogenic germline variants in ribosomal protein genes. DBA due to pathogenic RPL35A variants has been associated with large 3q29 deletions and phenotypes not common in DBA. We conducted a multi-institutional genotype-phenotype study of 45 patients with DBA associated with pathogenic RPL35A germline variants and curated the variant data on 21 additional cases from the literature. Genotype-phenotype analyses were conducted comparing patients with large deletions versus all other pathogenic variants in RPL35A. Twenty-two of the 45 cases had large deletions in RPL35A. After adjusting for multiple tests, a statistically significant association was observed between patients with a large deletion and steroid-resistant anemia, neutropenia, craniofacial abnormalities, chronic gastrointestinal problems, and intellectual disabilities (p<0.01) compared with all other pathogenic variants. Non-large deletion pathogenic variants were spread across RPL35A with no apparent hot spot and 56% of the individual family variants were observed more than once. In this, the largest known study of DBA patients with pathogenic RPL35A variants, we determined that patients with large deletions have a more severe phenotype that is clinically different from those with non-large deletion variants. Genes of interest also deleted in the 3q29 region that could be associated with some of these phenotypic features include LMLN and IQCG. Management of DBA due to large RPL35A deletions may be challenging due to complex problems and require comprehensive assessments by multiple specialists including immunologic, gastrointestinal, and developmental evaluations to provide optimal multidisciplinary care.

Recommendations for diagnosis and treatment of methemoglobinemia.

Methemoglobinemia is a rare disorder associated with oxidization of divalent ferro-iron of hemoglobin (Hb) to ferri-iron of methemoglobin (MetHb). Methemoglobinemia can result from either inherited or acquired processes. Acquired forms are the most common, mainly due to the exposure to substances that cause oxidation of the Hb both directly or indirectly. Inherited forms are due either to autosomal recessive variants in the CYB5R3 gene or to autosomal dominant variants in the globin genes, collectively known as HbM disease. Our recommendations are based on a systematic literature search. A series of questions regarding the key signs and symptoms, the methods for diagnosis, the clinical management in neonatal/childhood/adulthood period, and the therapeutic approach of methemoglobinemia were formulated and the relative recommendations were produced. An agreement was obtained using a Delphi-like approach and the experts panel reached a final consensus >75% of agreement for all the questions.

Left ventricular deformation mechanics over time in patients with thalassemia major with and without iron overload.

BACKGROUND: Myocardial iron overload in patients with thalassemia major (TM) is one of the most important complications. The purpose of the study was to identify advanced echocardiography parameters for early identification of myocardial dysfunction during follow-up of patients with TM. METHODS: Forty TM patients who were 41 ± 5 years old were included in the study and divided into two groups according to cardiac magnetic resonance T2* results (Group 1: Τ2* > 25 ms, Group 2: Τ2* ≤ 25 ms). Liver T2* parameters were also measured. Conventional and deformational echocardiographic parameters were measured at baseline and approximately 2 years later. RESULTS: Thirty-two patients had Τ2* = 34 ± 4 ms (Group 1), and 8 had Τ2* = 17 ± 9 ms (Group 2). Blood consumption was 185 ± 60 and 199 ± 37 ml/kg/yr (p = 0.64), and liver T2* was 4 ± 5 and 17 ± 21 ms (p = 0.01) in Groups 1 and 2, respectively. At baseline, Group 1 had better left ventricular global longitudinal strain (GLS) (- 22 ± 3 vs. - 18 ± 5, p = 0.01) and similar left ventricular ejection fraction (LVEF) (62 ± 5% vs. 58 ± 10%, p = 0.086) than Group 2. At the 28 ± 11-month follow-up, LVEF, GLS, and T2* values in Group 1 (63 ± 3%, - 21 ± 3%, 34 ± 4 ms) and Group 2 (56 ± 11%, - 17 ± 4%, 17 ± 9 ms) did not change significantly compared to their corresponding baseline values. In 8 patients from Group 1, a worsening (> 15%) in LS (p = 0.001) was detected during follow-up, with a marginal reduction in LVEF. CONCLUSIONS: GLS seems to be an efficient echocardiographic parameter for detecting hemochromatosis-related cardiac dysfunction earlier than LVEF. It also seems to be affected by other factors (free radical oxygen, immunogenetic mechanisms or viral infections) in a minority of patients, underscoring the multifactorial etiology of cardiomyopathy.

Diamond-Blackfan Anemia: 2 Cases With a Twist.

BACKGROUND: Diamond-Blackfan anemia is a rare inherited bone marrow failure disease. Typical findings include hypoplastic macrocytic anemia, congenital anomalies, and a predisposition to cancer. The molecular basis of the disease is heterozygous mutations of ribosomal proteins without a strict correlation between genotype and phenotype. OBSERVATION: We present 2 cases of Diamond-Blackfan anemia diagnosed during infancy with interesting clinical, molecular, and family characteristics. CONCLUSIONS: A thorough evaluation of all family members is imperative to identify possible 'silent carriers' who are those with no physical stigmata and minor or absent hematologic manifestations. New mutations could add in the map of the disease.

Genotypic and Clinical Analysis of a Thalassemia Major Cohort: An Observational Study.

Thalassemia major (TM) is a hereditary disease caused by defective globin synthesis. Because of the significant increase in life expectancy, these patients are suffering from various health conditions, including endocrinopathies and low bone mineral density. The aim of the present study was to investigate the correlation between clinical and biochemical parameters as well as to identify possible relations in a genotype to phenotype pattern. Sixty-four patients with TM (32 men and 32 women) participated in a cross-sectional study design. The patients were recruited from "Aghia Sofia" Children's Hospital. Clinical and biochemical parameters were evaluated as well as specific mutations were identified. We have found significant correlations between biochemical parameters and iron chelation, hormone replacement treatment as well as TM genotype and hematocrit and T-score. To conclude, the current study showed that clinical parameters of TM patients correlate significantly with both biochemical factors and genotypical patient parameters. Our present study showed that there is a connection between genotype and phenotype as, for example, the identified relation between hematocrit and T-scores and TM-specific mutations. This connection indicates that there is still much more to learn about the role of mutations not only in the disease itself but also in the underlying comorbidities.

Dental late effects of antineoplastic treatment on childhood cancer survivors: Radiographic findings.

BACKGROUND: Dental anomalies are common late side effects of childhood cancer therapy and may lead to anatomical, functional, and aesthetic sequelae. AIM: The study aimed to record dental late effects of antineoplastic treatment and associate them with disease and treatment characteristics in order to identify possible risk factors. DESIGN: Orthopantomograms of 70 survivors aged 4-21 years, who were treated at ages 0-10 years for any type of malignancy and completed antineoplastic treatment at least one year before, were examined. Incidence of developmental disturbances was recorded. Their severity was calculated, and odds ratios for the development of severe defects were estimated. RESULTS: Root defects presented in 62% of the participants, with impaired root growth being the most common (58%). Increased incidence was associated with combination treatment protocols, irradiation to the head and neck region, and administration of antimetabolites, steroids, and vincristine. Mean DeI value was 17.46 with risk factors for the development of severe root defects being diagnosis of acute lymphoblastic leukemia, combination treatment protocols, administration of cyclophosphamide and steroids, and hemopoietic stem cell transplantation. CONCLUSIONS: Root defects are common among childhood cancer survivors, with their incidence and severity being affected by multiple disease and treatment characteristics.

A review of psychosocial interventions targeting families of children with cancer.

OBJECTIVE: Psychosocial interventions in families of children with cancer are considered an effective way of empowering family members to tackle the complex hurdles they face. The ability of parents to develop adaptive coping strategies during the child's treatment is not only important to their own mental and physical health, but also to their child's well-being and long-term adjustment with the disease. METHODS: The aim of this review was to evaluate the existing literature for the period from 2009 to 2017 on psychosocial interventions targeting families of children with cancer. We searched the PubMed database using the following combination of keywords: "cancer AND children AND (intervention OR training) AND (mothers OR primary caregivers OR parents OR fathers OR siblings)." RESULTS: After careful evaluation of 995 papers, 17 full-text papers were found to match our criteria (12 randomized controlled trials and 5 quasi-experimental studies). The quality of the studies was assessed using the Delphi score questionnaire, and the score of the reviewed studies ranged from 3 to 5. The findings suggest that most interventions reduced distress and improved coping strategies among participants. Interventions, mainly cognitive behavioral therapy and problem-solving skills training targeting maternal distress, were associated with improved adjustment outcomes in mothers of children with cancer. SIGNIFICANCE OF RESULTS: Psychosocial interventions are helpful, and efforts should be made to promote them in a larger scale. Protocols should be implemented to ensure that all parents benefit. Computer-assisted methods may provide additional benefit by improving cancer-related knowledge and cancer-related communication.