Autoinflammation in patients with leukocytic CBL loss of heterozygosity is caused by constitutive ERK-mediated monocyte activation.

Patients heterozygous for germline CBL loss-of-function (LOF) variants can develop myeloid malignancy, autoinflammation, or both, if some or all of their leukocytes become homozygous for these variants through somatic loss of heterozygosity (LOH) via uniparental isodisomy. We observed an upregulation of the inflammatory gene expression signature in whole blood from these patients, mimicking monogenic inborn errors underlying autoinflammation. Remarkably, these patients had constitutively activated monocytes that secreted 10 to 100 times more inflammatory cytokines than those of healthy individuals and CBL LOF heterozygotes without LOH. CBL-LOH hematopoietic stem and progenitor cells (HSPCs) outgrew the other cells, accounting for the persistence of peripheral monocytes homozygous for the CBL LOF variant. ERK pathway activation was required for the excessive production of cytokines by both resting and stimulated CBL-LOF monocytes, as shown in monocytic cell lines. Finally, we found that about 1 in 10,000 individuals in the UK Biobank were heterozygous for CBL LOF variants and that these carriers were at high risk of hematological and inflammatory conditions.

Epilepsy after acute central nervous system complications of pediatric hematopoietic cell transplantation: A retrospective, multicenter study.

BACKGROUND: Acute central nervous system (CNS) complications are common and well described among pediatric patients undergoing haematopoietic cell transplantation (HCT). However, their long-term outcomes are not known. The aim of this study is to describe the incidence, characteristics, and risk factors of long-term epilepsy in pediatric patients with acute CNS complications of HCT. METHODS: This retrospective study included pediatric patients who developed acute CNS complications from autologous or allogeneic HCT between 2000 and 2022. Clinical, therapeutic and prognostic data including long-term outcomes were analyzed. A diagnosis of epilepsy was provided if unprovoked seizures occurred during follow-up. RESULTS: Ninety-four patients (63 males, 31 females, median age 10 years, range 1-21 years) were included. The most common acute CNS complications were posterior reversible encephalopathy syndrome (n = 43, 46 %) and infections (n = 15, 16 %). Sixty-five patients (69 %) had acute symptomatic seizures, with 14 (16 %) having one or more episodes of status epilepticus (SE). Nine patients (9.6 %) were diagnosed with long-term focal epilepsy during the follow-up (5-year cumulative incidence from the acute complication, 13.3 %). Acute symptomatic SE during neurological complications of HCT was associated with an increased risk of long-term epilepsy (OR=14, 95 % CI 2.87-68.97). CONCLUSIONS: A higher occurrence of epilepsy has been observed in our cohort compared to the general population. Acute symptomatic SE during HCT was associated with a higher risk of long-term epilepsy. Pediatric patients with CNS complications during HCT could benefit from specific neurological follow-up. Further studies are needed to characterize mechanisms of epileptogenesis in pediatric patients undergoing HCT.

Venetoclax: a new player in the treatment of children with high-risk myeloid malignancies?

ABSTRACT: Venetoclax selectively inhibits B-cell lymphoma 2 (BCL-2) and restores apoptotic signaling of hematologic malignant cells. Venetoclax, in combination with hypomethylating and low-dose cytotoxic agents, has revolutionized the management of older patients affected by acute myeloid leukemia (AML) and that of patients unfit to receive intensive chemotherapy. In a single phase 1 pediatric trial conducted on relapsed or refractory AML, the combination of venetoclax and intensive chemotherapy was shown to be safe and yielded promising response rates. In addition, several retrospective studies in children with AML reported that venetoclax, when combined with hypomethylating agents and cytotoxic drugs, seems to be a safe and efficacious bridge to transplant. The promising results on the use of venetoclax combinations in advanced myelodysplastic syndromes (MDS) and therapy-related MDS/AML have also been reported in small case series. This review summarizes the available current knowledge about venetoclax use in childhood high-risk myeloid neoplasms and discusses the possible integration of BCL-2 inhibition in the current treatment algorithm of these children. It also focuses on specific genetic subgroups potentially associated with response in preclinical and clinical studies.

Managing the Risk of Foodborne Infections in Pediatric Patients with Cancer: Is the Neutropenic Diet Still an Option?

Infections pose a significant threat to morbidity and mortality during treatments for pediatric cancer patients. Efforts to minimize the risk of infection necessitate preventive measures encompassing both environmental and host-focused strategies. While a substantial number of infections in oncologic patients originate from microorganisms within their native microbiological environment, such as the oral cavity, intestines, and skin, the concrete risk of bloodstream infections linked to the consumption of contaminated food and beverages in the community cannot be overlooked. Ensuring food quality and hygiene is essential to mitigating the impact of foodborne illnesses on vulnerable patients. The neutropenic diet (ND) has been proposed to minimize the risk of sepsis during neutropenic periods. The ND aims to minimize bacterial entry into the gut and bacterial translocation. However, a standardized definition for ND and consensus guidelines for specific food exclusions are lacking. Most centers adopt ND during neutropenic phases, but challenges in achieving caloric intake are common. The ND has not demonstrated any associated benefits and does not ensure improved overall survival. Consequently, providing unified and standardized food safety instructions is imperative for pediatric patients undergoing hematopoietic cell transplantation (HCT). Despite the lack of evidence, ND is still widely administered to both pediatric and adult patients as a precautionary measure. This narrative review focuses on the impact of foodborne infections in pediatric cancer patients and the role of the ND in comparison to food safety practices in patients undergoing chemotherapy or HCT. Prioritizing education regarding proper food storage, preparation, and cooking techniques proves more advantageous than merely focusing on dietary limitations. The absence of standardized guidelines underscores the necessity for further research in this field.

Phase II Study of Allogeneic Hematopoietic Stem Cell Transplantation for Children with High-Risk Neuroblastoma Using a Reduced-Intensity Conditioning Regimen: Results from the AIEOP Trial.

Despite aggressive multimodal treatment, the outcomes of pediatric patients with high-risk (HR) neuroblastoma (NB) remain poor. The rationale for allogeneic hematopoietic stem cell transplantation (allo-HCT) to treat NB was based on the possible graft-versus-tumor effect; however, toxicity limits its efficacy. We sought to prospectively assess the feasibility and efficacy of allo-HCT using a reduced-intensity conditioning regimen in pediatric patients with HR NB in a multicenter phase II trial. Primary endpoints were the rate of neutrophil and platelet engraftment, 5-year transplantation-related mortality (TRM), and disease-free survival (DFS). Secondary endpoint measures included the incidence of acute graft-versus-host disease (aGVHD) and chronic GVHD. Fifty-one patients were enrolled in the study. The 5-year cumulative incidence (CuI) of TRM was 29.4 ± 6.4%, and that of DFS was 11.8 ± 4.5%. Patients undergoing allo-HCT within 1 year of diagnosis or with bone marrow as their stem cell source had a higher DFS probability. The CuI of neutrophil engraftment, platelet engraftment, and grade II-IV aGVHD was 97.9 ± 2.1%, 93.8 ± 3.5%, and 47.1 ± 7.0%, respectively. The development of new therapeutic strategies could further improve disease control.

Ruxolitinib for the treatment of acute and chronic graft-versus-host disease in children: a systematic review and individual patient data meta-analysis.

Steroid-refractory graft-versus-host disease (SR-GvHD) represents a major complication of pediatric allogenic hematopoietic stem cell transplantation. Ruxolitinib, a selective JAK 1-2 inhibitor, showed promising results in the treatment of SR-GvHD in adult trial, including patients >12 years old. This systematic review aims to evaluate ruxolitinib use for SR-GvHD in the pediatric population. Among the 12 studies included, ruxolitinib administration presented slight differences. Overall response rate (ORR) ranged from 45% to 100% in both acute and chronic GvHD. Complete response rates (CR) varied from 9% to 67% and from 0% to 28% in aGvHD and cGvHD, respectively. Individual-patient meta-analysis from 108 children under 12 years showed an ORR and CR for aGvHD of 74% and 56%, respectively, while in cGvHD ORR was 78% but with only 11% achieving CR. Treatment-related toxicities were observed in 20% of patients, including cytopenia, liver toxicity, and infections. Age, weight, graft source, previous lines of therapy, and dose did not significantly predict response, while a higher rate of toxicities was observed in aGvHD patients. In conclusion, ruxolitinib shows promising results in the treatment of SR-GvHD in children, including those under 12 years. Specific pediatric perspective trials are currently ongoing to definitely assess its efficacy and safety.

Current practices for nutritional evaluation and care during the treatment of pediatric oncology patients: a survey among AIEOP centers.

Nutritional status plays a crucial role in the mortality rates of the pediatric oncology patients. However, there is a lack of systematic approaches for nutritional assessment in this population. This study aims to assess the current practice for nutritional assessment and care of pediatric cancer patients in Italy. A 25-items web-based, nation-wide questionnaire was circulated as of January 9, 2023 among physicians within the AIEOP network, composed of 49 national centers, out of which 21 routinely perform HCT. This survey examined the practices of 21 Italian pediatric oncology centers, revealing significant heterogeneity in nutritional practices. Only half of the centers routinely assessed all patients, utilizing different clinical and biochemical parameters. The use of neutropenic diets remained prevalent after chemotherapy or stem cell transplantation. CONCLUSION: This study underscores the pressing need for unified recommendations to improve nutritional care and potentially enhance outcomes for pediatric cancer patients. WHAT IS KNOWN: • The assessment and support of nutrition are gaining interest in the overall care of children with cancer. • The assessment and management of nutritional needs in pediatric cancer patients, including those undergoing hematopoietic cell transplantation, currently lack a systematic approach. WHAT IS NEW: • There is considerable variability in the nutritional assessment and support among Italian centers treating pediatric patients with cancer. • To enhance nutritional assessment and support for pediatric cancer patients, it is essential to establish shared national and international guidelines.

Body Mass Index (BMI) Is the Strongest Predictor of Systemic Hypertension and Cardiac Mass in a Cohort of Children.

BACKGROUND: Hypertension (HTN) is a well-established cardiovascular (CV) risk factor in adults. The presence of HTN in children appears to predict its persistence into adulthood. Early diagnosis of HTN is crucial to reduce CV morbidity before the onset of organ damage. AIM: The aim of this study is to investigate cardiac damage in HTN, its risk factors (RFs), and evolution. METHODS: We conducted a prospective/retrospective study involving children referred to the Childhood Hypertension Outpatient Clinic. This study included clinical and echocardiographic assessments of cardiac morphology and function at three time points: enrollment (T0) and follow-up (T1 and T2). RESULTS: Ninety-two patients (mean age 11.4 ± 3 years) were enrolled. Cardiac eccentric and concentric hypertrophy were present in 17.9% and 9%, respectively, with remodeling in 10.5%. Overweight/obese subjects exhibited significantly higher systolic blood pressure (SBP), frequency of HTN, and body mass index (BMI) at T0 compared with patients with chronic kidney disease (CKD). SBP and BMI persisted more during follow-up. Normal-weight vs. overweight/obese patients were significantly more likely to have normal geometry. Positive correlations were found between BMI and left ventricular (LV) mass at T0, BMI and SBP at T0 and T1. Gender, BMI, SBP, and diastolic blood pressure (DBP) significantly predicted LV mass index (LVMI), but only BMI added significance to the prediction. During follow-up, the variation of BMI positively correlated with the variation of SBP, but not with LVMI. CONCLUSIONS: In our cohort, body weight is strongly associated with HTN and cardiac mass. Importantly, the variation in body weight has a more significant impact on the consensual variation of cardiac mass than blood pressure (BP) values. A strict intervention on weight control through diet and a healthy lifestyle from early ages might reduce the burden of CV morbidity in later years.

Gut microbiota diversity before allogeneic hematopoietic stem cell transplantation as a predictor of mortality in children.

The correlation existing between gut microbiota diversity and survival after allogeneic hematopoietic stem cell transplantation (allo-HSCT) has so far been studied in adults. Pediatric studies question whether this association applies to children as well. Stool samples from a multicenter cohort of 90 pediatric allo-HSCT recipients were analyzed using 16S ribosomal RNA amplicon sequencing to profile the gut microbiota and estimate diversity with the Shannon index. A global-to-local networking approach was used to characterize the ecological structure of the gut microbiota. Patients were stratified into higher- and lower-diversity groups at 2 time points: before transplantation and at neutrophil engraftment. The higher-diversity group before transplantation exhibited a higher probability of overall survival (88.9% ± 5.7% standard error [SE] vs 62.7% ± 8.2% SE; P = .011) and lower incidence of grade 2 to 4 and grade 3 to 4 acute graft-versus-host disease (aGVHD). No significant difference in relapse-free survival was observed between the 2 groups (80.0% ± 6.0% SE vs 55.4% ± 10.8% SE; P = .091). The higher-diversity group was characterized by higher relative abundances of potentially health-related microbial families, such as Ruminococcaceae and Oscillospiraceae. In contrast, the lower-diversity group showed an overabundance of Enterococcaceae and Enterobacteriaceae. Network analysis detected short-chain fatty acid producers, such as Blautia, Faecalibacterium, Roseburia, and Bacteroides, as keystones in the higher-diversity group. Enterococcus, Escherichia-Shigella, and Enterobacter were instead the keystones detected in the lower-diversity group. These results indicate that gut microbiota diversity and composition before transplantation correlate with survival and with the likelihood of developing aGVHD.

Chemotherapy-free treatment for acute promyelocytic leukemia: the pediatric view of a revolutionary tale.

The addition of all-trans retinoic acid (ATRA) to the standard anthracycline-base chemotherapy has revolutionized the treatment of acute promyelocytic leukemia (APL) over the last decades, becoming a model for precision medicine. The protocols based on the combination of ATRA and chemotherapy allowed obtaining excellent response rates both for children and adults. However, the persistence of anthracycline chemotherapy as a backbone was a matter of concern for both acute and long-term complications. Efforts in reducing anthracycline cumulative dose or even eliminating anthracycline have been pursued in more recent pediatric protocols thanks to the introduction of arsenic trioxide (ATO). The impressive results of the ATRA/ATO combinations led to the introduction of protocols completely chemotherapy-free for standard-risk adult patients as the standard of care, whereas pediatric chemo-free protocols are still currently under evaluation. In this Review, we will critically retrace the history of this unique revolution in precision medicine, discussing the peculiar advantages for pediatric patients with APL.

The role of presepsin in pediatric patients with oncological and hematological diseases experiencing febrile neutropenia.

Febrile neutropenia (FN) represents one of the main complications of pediatric patients with oncological and hematological diseases. In these patients, it is crucial to identify bacterial infections. The aim of this study is to evaluate presepsin as an early biomarker of bacterial infections during FN. We compared patients with oncological and hematological diseases and a 2:1 age-matched healthy control group. In the FN group, we evaluated 4 biomarkers, namely, C reactive protein (CRP), procalcitonin (PCT), interleukin 6 (IL6) and presepsin at the onset of fever (T0) and 48 h after T0 (T1). In the control group, we only evaluated presepsin. We enrolled a total of 41 children with oncological and hematological diseases disease experiencing 50 FN episodes and 100 healthy patients in the control group. In patients with FN, we found that presepsin was significantly higher than in the control group (p < 0.001). However, in the FN group, we did not find a statistically significant difference between patients with and without bacteremia (p = 0.989 at T0, p = 0.619 at T1). Presepsin values at T1 were higher in patients experiencing an unfavorable outcome (p = 0.025). This study shows that presepsin increases in neutropenic patients, but it only revealed useful in predicting an unfavorable outcome 48 h from the onset of fever.

The emerging role of nutritional support in the supportive care of pediatric patients undergoing hematopoietic stem cell transplantation.

Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) represents a potentially curative strategy for many oncological, hematological, metabolic, and immunological diseases in children. The continuous effort in ameliorating supportive care represents one of the cornerstones in the improvement of outcome in these patients. Nowadays, more than ever nutritional support can be considered a key feature. Oral feeding in the early post-transplant period is severely impaired because of mucositis due to conditioning regimen, characterized by, mainly by vomiting, anorexia, and diarrhea. Gastrointestinal acute graft-versus-host-disease (GvHD), infections and associated treatments, and other medications, such as opioids and calcineurin inhibitors, have also been correlated with decreased oral intake. The consequent reduction in caloric intake combined with the catabolic effect of therapies and transplantation-related complications with consequent extended immobilization, results in a rapid deterioration of nutritional status, which is associated with decreased overall survival and higher complication rates during treatment. Thus, nutritional support during the early post-transplantation period becomes an essential and challenging issue for allo-HSCT recipients. In this context, the role of nutrition in the modulation of the intestinal flora is also emerging as a key player in the pathophysiology of the main complications of HSCT. The pediatric setting is characterized by less evidence, considering the challenge of addressing nutritional needs in this specific population, and many questions are still unanswered. Thus, we perform a narrative review regarding all aspects of nutritional support in pediatric allo-HSCT recipients, addressing the assessment of nutritional status, the relationship between nutritional status and clinical outcomes and the evaluation of the nutritional support, ranging from specific diets to artificial feeding.

Role of Nutrition in Pediatric Patients with Cancer.

Children with cancer are at high risk for developing short-term and long-term nutritional problems related to their underlying disease and side effects of multimodal treatments. Nutritional status (NS) can influence several clinical outcomes, such as overall survival (OS) and event-free survival (EFS), treatment tolerance, risk of developing infections and quality of life (QoL). However, the importance of nutrition in children with cancer is still underestimated. This review focuses on alterations of NS that occurs in children during cancer treatment. In particular, we reviewed the pathogenesis of undernutrition in oncological children, as well as how NS affects treatment tolerance and response, the immune system and the risk of infections of children with cancer. Thanks to recent advances in all types of supportive therapy and to the progress of knowledge on this topic, it has been realized that NS is a modifiable prognostic factor that can be intervened upon to improve the outcome of these patients. Currently, there is a lack of a systematic approach and standard recommendations for nutritional care in the pediatric cancer population. Literature analysis showed that it is essential to define the NS and treat any alterations in a timely manner ensuring proper growth and development. Nutritional follow-up should become an integral part of the care pathway. Regular nutritional monitoring should be performed at diagnosis, during treatment and during follow-up. A close collaboration and sharing of expertise between pediatric oncologists and nutrition specialists, combined with careful and participatory sharing of the feeding experience with the family and the child (after age 6 years), is strongly required.

ERCC6L2-related disease: a novel entity of bone marrow failure disorder with high risk of clonal evolution.

ERCC excision repair 6 like 2 (ERCC6L2) gene encodes for different helicase-like protein members of the Snf2 family involved in transcription-coupled nucleotide excision repair and in cell proliferation. Germline homozygous mutations in children and adults predispose to a peculiar bone marrow failure phenotype characterized by mild hematological alterations with a high risk of developing acute myeloid leukemia. The outcome for patients with leukemia progression is dismal while patients undergoing hematopoietic stem cell transplantation in the early stage have better outcomes. The ERCC6L2-related hematological disease presents a high penetrance, posing important questions regarding the treatment strategies and possible preemptive approaches. This review describes the biological function of ERCC6L2 and the clinical manifestations of the associated disease, trying to focus on the unsolved clinical questions.

Levofloxacin prophylaxis and parenteral nutrition have a detrimental effect on intestinal microbial networks in pediatric patients undergoing HSCT.

The gut microbiome (GM) has shown to influence hematopoietic stem cell transplantation (HSCT) outcome. Evidence on levofloxacin (LVX) prophylaxis usefulness before HSCT in pediatric patients is controversial and its impact on GM is poorly characterized. Post-HSCT parenteral nutrition (PN) is oftentimes the first-line nutritional support in the neutropenic phase, despite the emerging benefits of enteral nutrition (EN). In this exploratory work, we used a global-to-local networking approach to obtain a high-resolution longitudinal characterization of the GM in 30 pediatric HSCT patients receiving PN combined with LVX prophylaxis or PN alone or EN alone. By evaluating the network topology, we found that PN, especially preceded by LVX prophylaxis, resulted in a detrimental effect over the GM, with low modularity, poor cohesion, a shift in keystone species and the emergence of modules comprising several pathobionts, such as Klebsiella spp., [Ruminococcus] gnavus, Flavonifractor plautii and Enterococcus faecium. Our pilot findings on LVX prophylaxis and PN-related disruption of GM networks should be considered in patient management, to possibly facilitate prompt recovery/maintenance of a healthy and well-wired GM. However, the impact of LVX prophylaxis and nutritional support on short- to long-term post-HSCT clinical outcomes has yet to be elucidated.

Treatment of steroid-refractory graft versus host disease in children.

Systemic steroids are still the first-line approach in acute graft-versus-host disease (aGvHD), and the backbone of chronic GvHD management. Refractoriness to steroid represent a major cause of morbidity and non-relapse mortality after hematopoietic stem cell transplantation (HSCT). In both backgrounds, several second-line immunosuppressive agents have been tested with variable results in terms of efficacy and toxicity. Solid evidence regarding these approaches is still lacking in the pediatric setting where results are mainly derived from adult experiences. Furthermore, the number of treated patients is limited and the incidence of acute and chronic GvHD is lower, resulting in a very heterogeneous approach to this complication by pediatric hematologists. Some conventional therapies and anti-cytokine monoclonal antibodies used in the adult setting have been evaluated in children. In recent years, the increasing understanding of the biological mechanisms underpinning the pathogenesis of GvHD justified the efforts toward the adoption of targeted therapies and non-pharmacologic approaches, with higher response rates and lower immunosuppressive effects. Moreover, many questions regarding the precise timing and setting in which to integrate these new approaches remain unanswered. This Review aims to critically explore the current evidence regarding novel approaches to treat SR-GvHD in pediatric HSCT recipients.