Prospective External Validation of the Esbenshade Vanderbilt Models Accurately Predicts Bloodstream Infection Risk in Febrile Non-Neutropenic Children With Cancer.

PURPOSE: The optimal management of fever without severe neutropenia (absolute neutrophil count [ANC] ≥500/µL) in pediatric patients with cancer is undefined. The previously proposed Esbenshade Vanderbilt (EsVan) models accurately predict bacterial bloodstream infections (BSIs) in this population and provide risk stratification to aid management, but have lacked prospective external validation. MATERIALS AND METHODS: Episodes of fever with a central venous catheter and ANC ≥500/µL occurring in pediatric patients with cancer were prospectively collected from 18 academic medical centers. Variables included in the EsVan models and 7-day clinical outcomes were collected. Five versions of the EsVan models were applied to the data with calculation of C-statistics for both overall BSI rate and high-risk organism BSI (gram-negative and Staphylococcus aureus BSI), as well as model calibration. RESULTS: In 2,565 evaluable episodes, the BSI rate was 4.7% (N = 120). Complications for the whole cohort were rare, with 1.1% (N = 27) needing intensive care unit (ICU) care by 7 days, and the all-cause mortality rate was 0.2% (N = 5), with only one potential infection-related death. C-statistics ranged from 0.775 to 0.789 for predicting overall BSI, with improved accuracy in predicting high-risk organism BSI (C-statistic 0.800-0.819). Initial empiric antibiotics were withheld in 14.9% of episodes, with no deaths or ICU admissions attributable to not receiving empiric antibiotics. CONCLUSION: The EsVan models, especially EsVan2b, perform very well prospectively across multiple academic medical centers and accurately stratify risk of BSI in episodes of non-neutropenic fever in pediatric patients with cancer. Implementation of routine screening with risk-stratified management for non-neutropenic fever in pediatric patients with cancer could safely reduce unnecessary antibiotic use.

Cost-benefit analysis of a multicomponent breastfeeding promotion and support intervention in a developing country.

Background: Studies evaluating breastfeeding promotion and support interventions suggest some economic benefits. This study assessed the direct and indirect costs of a multicomponent breastfeeding promotion and support intervention during the first two years of the infant's life. Methods: This is a cost-benefit analysis of data generated from a randomized controlled trial that aimed at investigating whether provision of a multicomponent breastfeeding promotion and support intervention to Lebanese mothers in the first six months postpartum would improve breastfeeding rates compared to standard obstetric and pediatric care. Data on 339 participants included information on maternal socio-demographics and health, infant nutrition and health, and direct and indirect costs of the intervention. The primary outcome was the benefit-cost ratio (BCR) of the intervention at one, six, 12, and 24 months. Secondary outcomes included the overall costs of infant nutrition and infant-mother dyad health costs during the first two years. Multiple linear regression models investigated the effect of the multicomponent intervention (independent variable) on the overall infant nutrition cost and the overall mother-infant health costs (as dependent variables), adjusting for monthly income and number of children (confounders) at different time points in the first two years. Similar regression models investigated the association between infant nutrition type (exclusive breastfeeding, mixed feeding, artificial milk) and infant nutrition costs and infant-mother health costs. Intention to treat analyses were conducted using SPSS (version 24). Statistical significance was set at a p-value below 0.05. Results: The prevalence of Exclusive/Predominant breastfeeding among participants declined from 51.6% in the first month to 6.6% at the end of second year. The multicomponent breastfeeding intervention incurred 485 USD more in costs than the control group during the first six months but was cost-efficient by the end of the first year (incremental net benefits of 374 USD; BCR=2.44), and by the end of the second year (incremental net benefits of 472 USD; BCR=2.82). In adjusted analyses, the intervention was significantly associated with fewer infant illness visits in the first year (p=0.045). Stratified analyses by the type of infant nutrition revealed that infants who were on Exclusive/Predominant, or Any Breastfeeding had significantly more favorable health outcomes at different time points during the first two years (p<0.05) compared to infants receiving Artificial Milk only, with health benefits being highest in the Exclusive/Predominant breastfeeding group. Moreover, Exclusive/Predominant and Any Breastfeeding had significantly lower costs of infant illness visits, hospitalizations, and infant medications during the two years (p<0.05), but had additional cost for maternal non-routine doctor visits due to breastfeeding (all p values <0.05). Whereas the overall cost (direct and indirect) during the first six months was significantly lower for the Exclusive/Predominant breastfeeding infants (p=0.001), they were similar in infants on Mixed Feeding or Artificial Milk. Conclusions: Breastfeeding is associated with significant economic and infant health benefits in the first two years. In the context of the current economic crisis in Lebanon, this study provides further evidence to policymakers on the need to invest in national breastfeeding promotion and support interventions.

Using comprehensive genomic and functional analyses for resolving genotype-phenotype mismatches in children with suspected CMMRD in Lebanon: an IRRDC study.

Constitutional mismatch repair deficiency (CMMRD) is an aggressive and highly penetrant cancer predisposition syndrome. Because of its variable clinical presentation and phenotypical overlap with neurofibromatosis, timely diagnosis remains challenging, especially in countries with limited resources. Since current tests are either difficult to implement or interpret or both we used a novel and relatively inexpensive functional genomic assay (LOGIC) which has been recently reported to have high sensitivity and specificity in diagnosing CMMRD. Here we report the clinical and molecular characteristics of nine patients diagnosed with cancer and suspected to have CMMRD and highlight the challenges with variant interpretation and immunohistochemical analysis that led to an uncertain interpretation of genetic findings in 6 of the 9 patients. Using LOGIC, we were able to confirm the diagnosis of CMMRD in 7 and likely exclude it in 2 patients, resolving ambiguous result interpretation. LOGIC also enabled predictive testing of asymptomatic siblings for early diagnosis and implementation of surveillance. This study highlights the varied manifestations and practical limitations of current diagnostic criteria for CMMRD, and the importance of international collaboration for implementing robust and low-cost functional assays for resolving diagnostic challenges.

Heritable cancer predisposition testing in pediatric cancer patients excluding retinoblastoma in a middle-income country.

Resource-limited settings often have financial barriers to genetic testing for heritable cancer. This retrospective study investigated the pattern of heritable cancer predisposition testing in a middle-income country over the period 2014-2021, excluding retinoblastoma. After establishing a specific fund in 2019, rate of tests increased from 1.1% to 10.9% of new diagnoses. Most common testing was for constitutional mismatch repair deficiency (CMMRD), rhabdoid predisposition syndrome, TP53 (tumor protein 53) mutation, and hereditary cancer panel. Of 33 patients, 13 (39%) tested positive, 12 (36%) negative, and eight (24%) had variants of unknown significance. Positivity rate was 43% for a clinical phenotype and 44% for a tumor type indication.

Vincristine-induced neurotoxicity in pediatric patients with rhabdomyosarcoma: A retrospective analysis of clinical features and outcome.

Vincristine is an essential component of rhabdomyosarcoma treatment. However, it can cause motor neurotoxicity, necessitating dose reductions. We retrospectively reviewed the rates and patterns of vincristine-induced motor neuropathy in children treated for rhabdomyosarcoma, and investigated effects on outcome. Fifteen of 43 patients (35%) developed motor neuropathies necessitating dose reductions, which ranged from 1.7% to 58% of planned cumulative dose. Older age was the only significant clinical risk factor. Almost half (47%) recovered during treatment with subsequent dose escalation. Most patients had complete resolution of symptoms upon follow-up. There was no discernible effect of treatment reduction on survival or relapse rates.

A GRIN3A polymorphism may be associated with glucocorticoid-induced symptomatic osteonecrosis in children with acute lymphoblastic leukemia.

Aim: To evaluate the association between candidate genetic polymorphisms and glucocorticoid-induced osteonecrosis in Arab children treated for acute lymphoblastic leukemia. Methods: A total of 189 children treated for acute lymphoblastic leukemia were genotyped for four SNPs with allele discrimination assays. The incidence and timing of radiologically confirmed symptomatic grade 4 osteonecrosis were classified based on the Ponte di Legno toxicity working group consensus definition. Results: Thirteen children developed grade 4 osteonecrosis (6.8%), of whom 12 received the intermediate/high-risk treatment protocol. GRIN3A variant allele carriers had to stop dexamethasone therapy earlier resulting in significantly shorter duration of dexamethasone treatment (mean [95% CI]: 75.17 [64.28-86.06] vs 85.90 [81.22-90.58] weeks; p = 0.054) and lower cumulative dose (mean [95% CI]: 1118.11 [954.94-1281.29] vs 1341.14 [1264.17-1418.11] mg/m2; p = 0.011). Conclusion: This is the first pharmacogenomics evaluation of the association between GRIN3A variants and glucocorticoid-induced osteonecrosis in Arab children.

Lay abstract This study aimed at uncovering variants in the genetic material of Arab children, that might predispose them to develop a specific treatment-related adverse effect, during their therapy for acute lymphoblastic leukemia (a type of blood cancer). We looked at specific changes in the DNA of our patient cohort that might predispose them to develop treatment-induced osteonecrosis. Osteonecrosis is by definition a loss of blood flow to the bone tissue in one's body, causing the bone to die. Osteonecrosis may be caused by long-term exposure to steroid-based medication, among which dexamethasone. Dexamethasone a main component of the combination of chemotherapeutic agents used to treat acute lymphoblastic leukemia. Our findings suggested that children who had one of the variants detected in a specific location of DNA, the GRIN3A gene, were more likely to develop osteonecrosis earlier and had to stop dexamethasone earlier during therapy.

The link between COVID-19 and VItamin D (VIVID): A systematic review and meta-analysis.

BACKGROUND: Disease severity and mortality rates due to COVID-19 infection are greater in the elderly and chronically ill patients, populations at high risk for vitamin D deficiency. Vitamin D plays an important role in immune function and inflammation. This systematic review and meta-analysis assesses the impact of vitamin D status and supplementation on COVID-19 related mortality and health outcomes. METHODS: We searched four databases until December 18th 2020, and trial registries until January 20th 2021. Two reviewers screened the studies, collected data, assessed the risk of bias, and graded the evidence for each outcome across studies, independently and in duplicate. Pre-specified outcomes of interest were mortality, ICU admission, invasive and non-invasive ventilation, hospitalization, time of hospital stay, disease severity and SARS-CoV-2 positivity. We only included data from peer-reviewed articles in our primary analyses. RESULTS: We identified 31 peer-reviewed observational studies. In our primary analysis, there was a positive trend between serum 25(OH)D level <20 ng/ml and an increased risk of mortality, ICU admission, invasive ventilation, non-invasive ventilation or SARS-CoV-2 positivity. However, these associations were not statistically significant. Mean 25(OH)D levels was 5.9 ng/ml (95% CI [-9.5, -2.3]) significantly lower in COVID-19 positive, compared to negative patients. The certainty of the evidence was very low. We identified 32 clinical trial protocols, but only three have published results to-date. The trials administer vitamin D doses of 357 to 60,000 IU/day, from one week to 12 months. Eight megatrials investigate the efficacy of vitamin D in outpatient populations. A pilot trial revealed a significant decrease in ICU admission with calcifediol, compared to placebo (OR = 0.003), but the certainty of the evidence was unclear. Another small trial showed that supplementation with cholecalciferol, 60,000 IU/day, decreased fibrinogen levels, but did not have an effect on D-dimer, procalcitonin and CRP levels, compared to placebo. The third trial did not find any effect of vitamin D supplementation on COVID-19 related health outcomes. CONCLUSION: While the available evidence to-date, from largely poor-quality observational studies, may be viewed as showing a trend for an association between low serum 25(OH)D levels and COVID-19 related health outcomes, this relationship was not found to be statistically significant. Calcifediol supplementation may have a protective effect on COVID-19 related ICU admissions. The current use of high doses of vitamin D in COVID-19 patients is not based on solid evidence. It awaits results from ongoing trials to determine the efficacy, desirable doses, and safety, of vitamin D supplementation to prevent and treat COVID-19 related health outcomes.

Childhood cancer care in the Middle East, North Africa, and West/Central Asia: A snapshot across five countries from the POEM network.

BACKGROUND: The Pediatric Oncology East and Mediterranean (POEM) network, through this report, provides a snapshot view of an expected child's treatment journey in five countries in the region. METHODS: Pediatric oncologists from cancer centers in Egypt, Lebanon, Iraq, Jordan, and Pakistan provided input on referral pathways, barriers to care, and patient outcomes, based on personal experience and published data. Outcome data were extracted from institutional registries. A literature review of articles and meeting abstracts was conducted, and results summarized. RESULTS: Countries across the Middle Eastern, North African, and West Asian region face common difficulties relating to the provision of pediatric oncology care. National registries are largely lacking, with unavailability of outcome data. Economic barriers are a common theme, leading to delays in patient diagnosis, and interruptions and abandonment of therapy. Insufficient infrastructure and human resources, high rates of toxic deaths, and lack of common national protocols are common. The establishment of successful fundraising organizations linked to specific cancer hospitals showcase several success stories, enhancing services, improving patient access, and leading to outcomes comparable to those in developed countries. All identified published literature is institution-based and from only one or a few hospitals. Therefore, outcomes at a national level likely differ due to disparate cancer care capabilities. CONCLUSION: Well-designed national registries are essential for identifying gaps, and clear referral networks are needed to address delays to diagnosis and therapy. National and transversal programs to improve infrastructure, facilitate knowledge transfer, and promote advocacy, are needed to accelerate progress in the region.