Prolonged cytopenias are a non-specific sign with a wide differential diagnosis. Among inherited disorders, cytopenias predisposing to leukemia require a timely and accurate diagnosis to ensure ...appropriate medical management, including adequate monitoring and stem-cell transplantation prior to the development of leukemia. We aimed to define the types and prevalences of the genetic causes leading to persistent cytopenias in children. The study comprises children with persistent cytopenias, myelodysplastic syndrome, aplastic anemia, or suspected inherited bone marrow failure syndromes, who were referred for genetic evaluation from all pediatric hematology centers in Israel during 2016-2019. For variant detection, we used Sanger sequencing of commonly mutated genes and a custommade targeted next-generation sequencing panel covering 226 genes known to be mutated in inherited cytopenias; the minority subsequently underwent whole exome sequencing. In total, 189 children with persistent cytopenias underwent a genetic evaluation. Pathogenic and likely pathogenic variants were identified in 59 patients (31.2%), including 47 with leukemia predisposing syndromes. Most of the latter (32, 68.1%) had inherited bone marrow failure syndromes, 9 (19.1%) had inherited thrombocytopenia predisposing to leukemia, and 3 each (6.4%) had predisposition to myelodysplastic syndrome or congenital neutropenia. Twelve patients had cytopenias with no known leukemia predisposition, including nine children with inherited thrombocytopenia and three with congenital neutropenia. In summary, almost one-third of 189 children referred with persistent cytopenias had an underlying inherited disorder; 79.7% of whom had a germline predisposition to leukemia. Precise diagnosis of children with cytopenias should direct follow-up and management programs and may positively impact disease outcome.
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Background
Acute Lymphoblastic Leukemia (ALL) is the most common cancer seen in the pediatric age group. The treatment consists of an initial intensive phase of chemotherapy followed by a prolonged ...period of maintenance chemotherapy intended to reduce the risk of relapse. Children are commonly seen in clinic every 4-6 weeks for bloodwork and physical examination during the maintenance phase. The COVID-19 pandemic has prompted consideration of alternative means of providing medical care. The objective of this study was to determine the proportion of in-person clinic visits during ALL maintenance therapy for which the outcome of the physical examination resulted in a change of patient management.
Methods
A retrospective chart review of children diagnosed with precursor-B ALL between January 2017 and December 2018, and who were in maintenance therapy between September 2019 and February 2020, was conducted. All routine maintenance visits were reviewed to identify new physical examination findings and patient outcomes and classified as either “could be managed virtually” or “essential in-person visit”. For the latter, a second classification was conducted to distinguish between visits necessitating a change of management versus not.
Results
Eighty-five children were diagnosed with precursor B ALL and continued to maintenance treatment during the study period. 10 children were excluded as not meeting the inclusion criteria or not evaluable. Of the remaining 75 children, 54 were male (72%) and 21 female (28%). The median age at diagnosis was 4.83 years (0.73 - 14.8 years). 39 patients (52%) had standard risk ALL, 35 patients (46.7%) had high risk ALL and one patient had Infant ALL (1.3%) A total of 240 routine maintenance visits were included in the final analysis. An abnormal physical exam finding was noted in 20 visits (8.3%) and of these, new findings were noted in 14 (5.8%). 6 visits were classified as essential in-person visits (2 for new bruising, 1 for new limp, 1 for new lymphadenopathy, 1 for acute otitis media, and 1 for new wheezing). Among the 14 visits with new exam findings, only 5 had an impact on patient management and of these, only 2 (0.8%) were classified as obligate in-person visit for requiring immediate management (acute otitis media and wheezing).
Conclusion
Our results demonstrate that most in-person visits can be provided as virtual visits without affecting patient outcomes. The results of this study provide the foundation for a prospective study that will evaluate the benefits, risks and families' preferences associated with virtual visits and delineate the optimal frequency and timing of in-person clinic visits during ALL maintenance therapy.
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No relevant conflicts of interest to declare.
Childhood cancer is rare, but it remains the leading cause of disease-related mortality among children 1-14 years of age. As exposure to environmental factors is lower in children, inherited genetic ...factors become an important player in the cause of childhood cancer. This review highlights the current knowledge and approach for cancer predisposition syndromes in children.
Current literature suggests that 10-18% of paediatric cancer patients have an underlying genetic susceptibility to their disease. With better knowledge and technology, more genes and syndromes are being discovered, allowing tailored treatment and surveillance for the probands and their families.Studies have demonstrated that focused surveillance can detect early malignancies and increase overall survival in several cancer predisposition syndromes. Various approaches have been proposed to refine early tumour detection strategies while minimizing the burden on patients and families. Newer therapeutic strategies are being investigated to treat, or even prevent, tumours in children with cancer predisposition.
This review summarizes the current knowledge about different cancer predisposition syndromes, focusing on the diagnosis, genetic counselling, surveillance and future directions.
Background
Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Treatment consists of an initial intensive phase of chemotherapy, followed by a prolonged period of maintenance ...chemotherapy intended to reduce the risk of relapse. During the COVID‐19 pandemic, the need arose to identify and reduce non‐essential hospital visits.
Objective
We aimed to determine which proportion of in‐person clinic visits during ALL maintenance therapy was associated with a change of management based on the results of the physical examination.
Patients and methods
Medical records of children receiving maintenance chemotherapy for B‐precursor ALL between September 2019 and February 2020 were reviewed. Visits with a new finding on physical examination were divided into those where an in‐person assessment was deemed essential versus not essential. Finally, we determined the proportion of essential in‐person visits that resulted in a change of management.
Results
A total of 240 maintenance visits by 75 children were analyzed. An abnormal finding on physical examination was noted during 20 visits (8.3%). Of those, 14 (5.8%) uncovered a new finding, six (2.5%) were classified as “in‐person visit essential,” and among those six visits, three (1.2%) resulted in a change of patient management (one for acute otitis media, one for wheezing, and one for limp).
Conclusion
Our findings support the evaluation of care delivery models other than in‐person visits during ALL maintenance therapy. A prospective study is required to delineate criteria, benefits/risks, and families’ perspectives associated with virtual care delivery and the optimal frequency of in‐person visits.
People with Li-Fraumeni syndrome (LFS) harbor a germline pathogenic variant in the TP53 tumor suppressor gene, face a near 100% lifetime risk of cancer, and routinely undergo intensive surveillance ...protocols. Liquid biopsy has become an attractive tool for a range of clinical applications, including early cancer detection. Here, we provide a proof-of-principle for a multimodal liquid biopsy assay that integrates a targeted gene panel, shallow whole-genome, and cell-free methylated DNA immunoprecipitation sequencing for the early detection of cancer in a longitudinal cohort of 89 LFS patients. Multimodal analysis increased our detection rate in patients with an active cancer diagnosis over uni-modal analysis and was able to detect cancer-associated signal(s) in carriers prior to diagnosis with conventional screening (positive predictive value = 67.6%, negative predictive value = 96.5%). Although adoption of liquid biopsy into current surveillance will require further clinical validation, this study provides a framework for individuals with LFS.
By utilizing an integrated cell-free DNA approach, liquid biopsy shows earlier detection of cancer in patients with LFS compared with current clinical surveillance methods such as imaging. Liquid biopsy provides improved accessibility and sensitivity, complementing current clinical surveillance methods to provide better care for these patients. See related commentary by Latham et al., p. 23. This article is featured in Selected Articles from This Issue, p. 5.
Objective
α‐Thalassemia, one of the most common genetic diseases, is caused by deletions or point mutations affecting one to four α‐globin genes. Molecular diagnosis is important to prevent the most ...severe forms of the disease. However, the diagnosis of α‐thalassemia is complex due to a high variability of the genetic defects involved, with over 250 described mutations. We summarize herein the findings of genetic analyses of DNA samples referred to our laboratory for the molecular diagnosis of α‐thalassemia, along with a detailed clinical description.
Methods
We utilized a diagnostic algorithm including Gap‐PCR, to detect known deletions, followed by sequencing of the α‐globin gene, to identify known and novel point mutations, and multiplex ligation‐dependent probe amplification (MLPA) for the diagnosis of rare or novel deletions.
Results
α‐Thalassemia was diagnosed in 662 of 975 samples referred to our laboratory. Most commonly found were deletions (75.3%, including two novel deletions previously described by us); point mutations comprised 25.4% of the cases, including five novel mutations. Our population included mostly Jews (of Ashkenazi and Sephardic origin) and Muslim Arabs, who presented with a higher rate of point mutations and hemoglobin H disease. Overall, we detected 53 different genotype combinations causing a spectrum of clinical phenotypes, from asymptomatic to severe anemia.
Conclusion
Our work constitutes the largest group of patients with α‐thalassemia originating in the Mediterranean whose clinical characteristics and molecular basis have been determined. We suggest a diagnostic algorithm that leads to an accurate molecular diagnosis in multiethnic populations.
Our goal was to describe childhood cancer incidence and survival in Israel and to identify demographic and epidemiologic variations among children and adolescents with cancer. We used data from the ...Israel National Cancer Registry to examine the incidence and survival of pediatric cancer in Israeli children aged 0 to 19 years, diagnosed during the years 1998 to 2007. Cases were analyzed according to sex, age, ethnicity, and geographic region. Among the 4255 cases of childhood cancer, there was a total age-adjusted incidence rate of 172.4 per million for children aged 0 to 19 years and 153.4 per million for children aged 0 to 14 years. The incidence rate for boys was higher than for girls (192.5 and 153.3, respectively) and higher for Jewish children than for Arab children (177.6 and 156.8, respectively). The largest groups were leukemias (22%), lymphomas (20.2%), and central nervous system tumors (17.4%). The number of new cases increased each year, but the incidence rate remained steady. The survival probability updated to December 2008 was estimated and the 5-year survival was calculated for the new cases until the end of 2003. The overall survival at 5 years was 80.8%, with 72.8% for the Arabic population and 83.2% for the Jewish population, and depended on the diagnosis. Incidence and survival in childhood cancer in Israel is at the same medium level compared with other parts of the world. This study may set the basis for investigating the genetic and environmental factors that cause pediatric cancer in Israel, delineating the genetic basis for ethnic origin disparities in survival.
Objective alpha-Thalassemia, one of the most common genetic diseases, is caused by deletions or point mutations affecting one to four alpha-globin genes. Molecular diagnosis is important to prevent ...the most severe forms of the disease. However, the diagnosis of alpha-thalassemia is complex due to a high variability of the genetic defects involved, with over 250 described mutations. We summarize herein the findings of genetic analyses of DNA samples referred to our laboratory for the molecular diagnosis of alpha-thalassemia, along with a detailed clinical description. Methods We utilized a diagnostic algorithm including Gap-PCR, to detect known deletions, followed by sequencing of the alpha-globin gene, to identify known and novel point mutations, and multiplex ligation-dependent probe amplification (MLPA) for the diagnosis of rare or novel deletions. Results alpha-Thalassemia was diagnosed in 662 of 975 samples referred to our laboratory. Most commonly found were deletions (75.3%, including two novel deletions previously described by us); point mutations comprised 25.4% of the cases, including five novel mutations. Our population included mostly Jews (of Ashkenazi and Sephardic origin) and Muslim Arabs, who presented with a higher rate of point mutations and hemoglobin H disease. Overall, we detected 53 different genotype combinations causing a spectrum of clinical phenotypes, from asymptomatic to severe anemia. Conclusion Our work constitutes the largest group of patients with alpha-thalassemia originating in the Mediterranean whose clinical characteristics and molecular basis have been determined. We suggest a diagnostic algorithm that leads to an accurate molecular diagnosis in multiethnic populations.
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