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Cisplatin is an effective treatment for hepatoblastoma but often leads to lifelong irreversible hearing loss. The addition of sodium thiosulfate 6 hours after cisplatin administration preserved the antitumor effect and led to a lower risk of hearing loss (33% vs. 63%).

Neuroblastoma is the most common extra-cranial solid tumor in children, representing approximately 8% of all malignant childhood tumors and 15% of pediatric cancer-related deaths. Recent sequencing and transcriptomics studies have demonstrated the RAS-MAPK pathway’s contribution to the development and progression of neuroblastoma. This review compiles up-to-date evidence of this pathway’s involvement in neuroblastoma. We discuss the RAS-MAPK pathway’s general functioning, the clinical implications of its deregulation in neuroblastoma, and current promising therapeutics targeting proteins involved in signaling.

Deletion of the long arm of chromosome 11 (11q deletion) is one of the most frequent events that occur during the development of aggressive neuroblastoma. Clinically, 11q deletion is associated with higher disease stage and decreased survival probability. During the last 25 years, extensive efforts have been invested to identify the precise frequency of 11q aberrations in neuroblastoma, the recurrently involved genes, and to understand the molecular mechanisms of 11q deletion, but definitive answers are still unclear. In this review, it is our intent to compile and review the evidence acquired to date on 11q deletion in neuroblastoma.

Background Respiratory syncytial virus (RSV) is associated with significant mortality rates amongst hematopoietic stem cell transplant (HSCT) recipients, with less known about other immunocompromised patients. Methods Ten-year retrospective cohort study of immunocompromised patients presenting with RSV disease documented at University Hospitals of Lausanne and Geneva. Severe RSV-related outcomes referred to RSV documented respiratory conditions requiring hospital admission, presenting as lower respiratory tract infection (LRTI) or pneumonia. We used multivariable logistic regression to assess clinical and laboratory correlates of severe RSV disease. Results From 239 RSV-positive immunocompromised in and out-patients 175 were adults and 64 children of whom 111 (47.8%) presented with LRTI, which resulted in a 38% (89/239) admission rate to hospital. While immunocompromised children were more likely to be admitted to hospital compared to adults (75% vs 62.9%, p  = 0.090), inpatients admitted to the intensive care unit (17/19) or those who died (11/11) were mainly adults. From multivariable analyses, adults with solid tumors (OR 5.2; 95% CI: 1.4–20.9 P = 0.015 ) or those requiring chronic immunosuppressive treatments mainly for rheumatologic conditions (OR 4.1; 95% CI: 1.1–16.0; P = 0.034 ) were significantly more likely to be admitted to hospital compared to hematopoietic stem cell (HSCT) recipients. Bacterial co-infection was significantly and consistently associated with viral LRTI and pneumonia. Conclusions From our findings, RSV-related disease results in a significant burden among adults requiring chronic immunosuppressive treatments for rheumatological conditions and those with solid tumors. As such, systematic screening for respiratory viruses, should be extended to other immunocompromised populations than HSCT recipients.

Cloning is a key molecular biology procedure for obtaining a genetically homogenous population of organisms or cell lines. It requires the expansion of new cell populations starting from single genetically modified cells. Despite the technical progress, cloning of many cell lines remains difficult. Cloning often fails either due to the strenuous conditions associated with manipulating cells or because many cells don’t tolerate a single-cell state. Here we describe a new cloning method utilizing low adhesion microcavity plates. This new technique, named microcavity-assisted cloning (MAC) was developed to clone difficult-to-clone HepG2 cells. The clones were produced following CRISPR/Cas9 knockout of the GSTA1 gene by a random distribution of 200, 400, and 800 cells into 550 microcavities of a 24-well low adhesion plate originally designed for the culture of spheroids. The knockout of GSTA1 was verified at the protein level using Western blotting. The advantages of the MAC method are its low cost, ease of the procedure, and the possibility of scaling up the throughput and automatization.

Genotype-phenotype analyses of rare diseases often suffer from a lack of power, due to small sample size, which makes identifying significant associations difficult. Sinusoidal obstruction syndrome (SOS) of the liver is a rare but life-threatening complication of hematopoietic stem cell transplantation (HSCT). The alkylating agent busulfan is commonly used in HSCT and known to trigger SOS. We developed a novel pipeline to identify genetic determinants in rare diseases by combining in vitro information with clinical whole-exome sequencing (WES) data and applied it in SOS patients and controls. First, we analysed differential gene expression in six lymphoblastoid cell lines (LCLs) before and after incubation with busulfan. Second, we used WES data from 87 HSCT patients and estimated the association with SOS at the SNP and the gene levels. We then combined the results of the expression and the association analyses into an association statistic at the gene level. We used an over-representation analysis to functionally characterize the genes that were associated with a significant combined test statistic. After treatment of LCLs with busulfan, 1708 genes were significantly up-, and 1385 down-regulated. The combination of the expression experiment and the association analysis of WES data into a single test statistic revealed 35 genes associated with the outcome. These genes are involved in various biological functions and processes, such as \"Cell growth and death\", \"Signalling molecules and interaction\", \"Cancer\", and \"Infectious disease\". This novel data analysis pipeline integrates two independent omics datasets and increases statistical power for identifying genotype-phenotype associations. The analysis of the transcriptomics profile of cell lines treated with busulfan and WES data from HSCT patients allowed us to identify potential genetic contributors to SOS. Our pipeline could be useful for identifying genetic contributors to other rare diseases where limited power renders genome-wide analyses unpromising. For the clinical dataset: Clinicaltrials.gov: NCT01257854. https://clinicaltrials.gov/ct2/history/NCT01257854.

Fever in neutropenia (FN) remains an unavoidable, potentially lethal complication of chemotherapy. Timely administration of empirical broad-spectrum intravenous antibiotics has become standard of care. But the impact of time to antibiotics (TTA), the lag period between recognition of fever or arrival at the hospital to start of antibiotics, remains unclear. Here we aimed to analyze the association between TTA and safety relevant events (SRE) in data from a prospective multicenter study. We analyzed the association between time from recognition of fever to start of antibiotics (TTA) and SRE (death, admission to intensive care unit, severe sepsis and bacteremia) with three-level mixed logistic regression. We adjusted for possible triage bias using a propensity score and stratified the analysis by severity of disease at presentation with FN. We analyzed 266 FN episodes, including 53 (20%) with SRE, reported in 140 of 269 patients recruited from April 2016 to August 2018. TTA (median, 120 min; interquartile range, 49–180 min) was not associated with SRE, with a trend for less SREs in episodes with longer TTA. Analyses applying the propensity score suggested a relevant triage bias. Only in patients with severe disease at presentation there was a trend for an association of longer TTA with more SRE. In conclusion, TTA was unrelated to poor clinical outcome in pediatric patients with FN presenting without severe disease. We saw strong evidence for triage bias which could only be partially adjusted.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative procedure in patients with Shwachman–Diamond syndrome (SDS) with bone marrow abnormalities. The results of 74 patients with SDS (6 acute myeloid leukemia, 7 myelodysplastic syndrome, and 61 bone marrow failure) treated with HSCT between 1988 and 2016 are reported. The donor source was: 24% sibling, 8% parent, and 68% unrelated donor. The stem cell source was: 70% bone marrow, 19% peripheral blood stem cells, and 11% cord blood. The conditioning regimen was myeloablative in 54% and reduced intensity in 46%. Neutrophil engraftment was achieved in 84% of patients after a median time of 17.5 days. Graft failure occurred in 15% of HSCTs. Grades I–IV acute and chronic GVHD were observed in 55% and 20% of patients, respectively. After a median follow-up of 7.3 years (95% CI 4.8–10.2), 28 patients died for progression/relapse (7) or toxicity (21). The 5-year overall survival and nonrelapse mortality were 63.3% (95% CI 50.8–73.4) and 19.8% (95% CI 10.8–30.8), respectively. In conclusion, this is the largest series so far reported and confirms that HSCT is a suitable option for patients with SDS. Further efforts are needed to lower transplant-related toxicity and reduce graft failure.

Methotrexate is an immunosuppressant and chemotherapeutic agent used in the treatment of a range of autoimmune disorders and cancers. Its main serious adverse effects, bone marrow suppression and gastrointestinal complications, arise from its antimetabolite effect. Nevertheless, hepatotoxicity and nephrotoxicity are two widely described adverse effects of methotrexate. Its hepatotoxicity has been studied mainly in the low-dose, chronic setting, where patients are at risk of fibrosis/cirrhosis. Studies of acute hepatoxicity of high dose methotrexate, such as during chemotherapy, are scarce. We present the case of a 14-year-old patient who received high-dose methotrexate and subsequently developed acute fulminant liver failure and acute kidney injury. Genotyping of MTHFR (Methylene tetrahydrofolate reductase gene), ABCB1 (codes for P-glycoprotein, intestinal transport and biliary excretion), ABCG2 (codes for BCRP, intestinal transporter and renal excretion) and SLCO1B1 (codes for OATP1B1, hepatic transporter) identified variants in all the genes analysed that predicted a reduced rate of methotrexate elimination and thus may have contributed to the clinical situation of the patient. Precision medicine involving pharmacogenomic testing could potentially avoid such adverse drug effects.

IntroductionThe improved survival rates of children with cancer have heightened concerns about treatment-related chronic health conditions, including platinum-induced hearing loss (PIHL). Cisplatin and carboplatin, widely used in paediatric cancer therapies, frequently cause irreversible sensorineural hearing loss. PIHL affects 1.7–90.1% of patients exposed to these drugs, yet known risk factors—including age, cisplatin dosage, cranial radiation and co-treatment with ototoxic drugs—fail to fully explain interindividual variability. Genetic factors likely play a role in susceptibility to PIHL. Since genetic susceptibility in children may differ from adults, and given the critical window of auditory development, a focused investigation of paediatric genetic factors using quantitative methods is warranted to detect small to moderate effects and understand the polygenic nature of PIHL.Methods and analysisIn this study, we will systematically review and conduct a meta-analysis of genetic polymorphisms associated with PIHL in individuals diagnosed before the age of 21 years. Following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, the review will include randomised controlled trials, cohort, case-control and cross-sectional studies that analyse the genetic influence on PIHL in paediatric populations treated with cisplatin and carboplatin. A comprehensive search of PubMed, EMBASE and Cochrane databases will be conducted, supplemented by backward citation searching. Data will be extracted on study design, treatment details, hearing loss assessment methods, genetic findings and covariates. We will use forest plots to present the results, and both Mantel-Haenszel fixed-effects model and random-effects model will be used for meta-analysis. Heterogeneity will be assessed with the I² index. The study will address potential heterogeneity, individual study quality, proportion of missing data and meta-analysis bias. The quality of the evidence of the meta-analysis will be assessed using the Grading quality of evidence and strength of Recommendations (GRADE) approach.DiscussionThis systematic review will enhance our understanding of the genetic contribution to PIHL in children and serve as a basis for further research for improvement of personalised treatment strategies for paediatric cancer care.PROSPERO registration numberCRD42024532664.Ethics and disseminationAll the included patient’s data are already published with an ethics approval for each study, respectively. No original data will be collected.