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Although primary tumor control rates after surgery and/or radiation therapy (RT) are generally high in patients with Ewing sarcoma (EWS), those with unresectable tumors have failure rates approaching 30% and experience poorer outcomes. Additionally, although metastatic site irradiation is associated with improved survival, dose, and volume effects influence the long‐term toxicity risk. Consequently, it is important to identify novel systemic agents to enhance the therapeutic ratio of RT. Given the reported DNA damage response deficits in EWS, we hypothesized that PARP inhibitors (PARPis) would preferentially potentiate radiation relative to standard‐of‐care (SOC) chemotherapeutics. We investigated primary and recurrent SOC drugs and PARPis with varied trapping potential in combination with radiation in EWS cell lines. At physiologically relevant concentrations, the strong PARP trapper talazoparib (TAL) potentiated radiation to a greater extent than did SOC or other PARPis, although the magnitude of the effect was modest. The radiosensitizing effect of TAL was mediated through the induction of DNA double‐strand breaks, rather than through the catalytic inhibition of PARP1. Drug + RT combinations were further tested in vivo by using orthotopic xenograft models of EWS treated with image‐guided fractionated radiation. The addition of RT to the combination of TAL plus irinotecan (IRN), a recently evaluated clinical regimen for relapsed pediatric solid tumors, significantly prolonged survival and reduced tumor burden in all EWS‐treated mice. This triplet therapy (TAL + IRN + RT) was feasible and yielded responses in several patients with EWS and may represent a useful salvage strategy in recurrent or progressive disease. The addition of RT to the combination of TAL plus irinotecan (IRN), a recently evaluated clinical regimen for relapsed pediatric solid tumors, significantly prolonged survival and reduced tumor burden in EWS mouse models. This triplet therapy (TAL + IRN + RT) was feasible and yielded responses in several patients with EWS and may represent a useful salvage strategy in recurrent or progressive disease.

Administration of chemoimmunotherapy using concurrent chemotherapy and an anti-GD2 monoclonal antibody (mAb), dinutuximab (DIN), demonstrated efficacy for the treatment of relapsed and refractory neuroblastoma. Chemoimmunotherapy, using a humanized anti-GD2 mAb, demonstrated a signal of activity in a phase 2 study for the treatment of patients with newly diagnosed high-risk neuroblastoma (HRNBL). In this single-institution retrospective study, patients with HRNBL received an Induction chemotherapy regimen plus DIN in all Induction cycles. Toxicity and response data were abstracted from the electronic medical record. Toxicities were graded by CTCAE v.5.0. The end of Induction (EOI) objective response rate was determined using the Revised International Neuroblastoma Response Criteria. Twenty-seven patients with HRNBL (23 newly diagnosed, 16 females, median age 3.9 years) started Induction chemoimmunotherapy from 27 January 2017 to 28 December 2022. All patients received DIN with all cycles of Induction therapy, and all but one patient completed Induction therapy. The most common non-hematologic grade ≥ 3 toxicities included fever (44%), hypoxemia (20%), and hypoalbuminemia (11%). End of Induction responses included eighteen with a complete response (CR), seven with a partial response (PR), one with progressive disease (PD), and zero with a minor response or stable disease. Twenty-six of twenty-seven patients (96%) completed all Induction cycles and were evaluable for a response. The EOI response of PR or better in the evaluable cohort was 96%. Dinutuximab was well tolerated with all Induction cycles, demonstrated an encouraging EOI response rate, and should be evaluated in a randomized study.

BackgroundNatural killer (NK) cells are one of the main effector populations of immunotherapy with monoclonal antibody and cytokines, used in combination with chemotherapy to treat children with high-risk neuroblastoma on this phase II trial. However, the impact of chemoimmunotherapy on NK cell kinetics, phenotype, and function is understudied.MethodsWe prospectively examined NK cell properties from 63 children with newly diagnosed neuroblastoma enrolled in a phase II trial (NCT01857934) and correlated our findings with tumor volume reduction after 2 courses of chemoimmunotherapy. NK cell studies were conducted longitudinally during chemoimmunotherapy and autologous hematopoietic cell transplantation (autoHCT) with optional haploidentical NK cell infusion and additional immunotherapy.ResultsChemoimmunotherapy led to significant NK cytopenia, but complete NK cell recovery reliably occurred by day 21 of each therapy course as well as after autoHCT. Haploidentical NK cell infusion elevated the NK cell count transiently during autoHCT. NK cell cytotoxicity increased significantly during treatment compared with diagnosis. In addition, NK cells maintained their ability to respond to cytokine stimulation in culture longitudinally. Unsupervised cluster analysis of CD56bright NK cell count and tumor volume at diagnosis and after two courses of chemoimmunotherapy identified two patient groups with distinct primary tumor sizes and therapy responses.ConclusionAfter profound NK cytopenia due to chemoimmunotherapy, endogenously reconstituted NK cells exhibit enhanced NK cytotoxicity compared with pretherapy measurements. Our data suggest a relationship between CD56bright expression and tumor size before and after two courses of chemoimmunotherapy; however, future studies are necessary to confirm this relationship and its predictive significance.Trial registration number NCT01857934.

A protocol producing orthotopic patient-derived xenografts at diagnosis, recurrence, and autopsy demonstrates proof of principle for using these tumours for basic and translational research on paediatric solid tumours. Xenograft archive Preclinical models of paediatric solid tumours that could help identify predictive biomarkers of a patient's sensitivity to therapy have been lacking. Over five years, the authors have developed an open access collection of orthotopic xenografts of 12 types of paediatric tumour. Genomic and epigenetic characterization reveals that xenografts retain characteristics of the tumour of origin. A high-throughput drug screen provides a resource for the community to identify potentially efficacious drug combinations. Paediatric solid tumours arise from endodermal, ectodermal, or mesodermal lineages 1 . Although the overall survival of children with solid tumours is 75%, that of children with recurrent disease is below 30% 2 . To capture the complexity and diversity of paediatric solid tumours and establish new models of recurrent disease, here we develop a protocol to produce orthotopic patient-derived xenografts at diagnosis, recurrence, and autopsy. Tumour specimens were received from 168 patients, and 67 orthotopic patient-derived xenografts were established for 12 types of cancer. The origins of the patient-derived xenograft tumours were reflected in their gene-expression profiles and epigenomes. Genomic profiling of the tumours, including detailed clonal analysis, was performed to determine whether the clonal population in the xenograft recapitulated the patient’s tumour. We identified several drug vulnerabilities and showed that the combination of a WEE1 inhibitor (AZD1775), irinotecan, and vincristine can lead to complete response in multiple rhabdomyosarcoma orthotopic patient-derived xenografts tumours in vivo .

Some neuroblastomas carry disabling mutations in BARD1 , a homologous recombination repair gene. A child with refractory neuroblastoma and a BARD1 mutation had a sustained response after treatment with the PARP inhibitor talazoparib.

PurposeImage-defined risk factors (IDRFs) are associated with surgical risks in neuroblastoma. We sought to evaluate the impact of neoadjuvant therapy on IDRFs and associated ability to achieve gross total resection (GTR) of locoregional disease in patients with high-risk neuroblastoma.MethodsWe retrospectively reviewed charts of patients treated on four consecutive high-risk neuroblastoma protocols over a 20-year period at a single institution. The number of IDRFs at diagnosis and just prior to surgery, and the percent decrease of tumor volume from just prior to surgery to the end of induction were determined.ResultsEighty-eight patients were included. There were 438 IDRFs (average 5.0 ± 3.1 per patient) at diagnosis and 198 (average 2.3 ± 1.9 per patient) after neoadjuvant chemotherapy (p < 0.01). A reduction in IDRFs was seen in 81.8% of patients with average decrease of 2.9 ± 2.5 per patient. The average percent reduction in tumor volume was 89.8 ± 18.9% and correlated with the number of IDRFs present after chemotherapy (p < 0.01). Three or fewer IDRFs prior to surgery was associated with the highest odds ratio for > 90% GTR at 9.33 [95% confidence interval 3.14–31.5].ConclusionNeoadjuvant chemotherapy reduced the number of IDRFs in the majority of patients with high-risk neuroblastoma. The number of IDRFs present after neoadjuvant therapy correlated with the extent of resection.

The utility of circulating tumor DNA (ctDNA) analysis has not been well-established for disease detection and monitoring of childhood cancers, especially leukemias. We developed PeCan-Seq, a deep sequencing method targeting diverse somatic genomic variants in cell-free samples in childhood cancer. Plasma samples were collected at diagnosis from 233 children with hematologic, solid and brain tumors. All children with hematologic malignancy (n = 177) had detectable ctDNA at diagnosis. The median ctDNA fraction was 0.77, and 97% of 789 expected tumor variants were identified, including sequence mutations, copy number variations, and structural variations responsible for oncogenic fusions. In contrast, ctDNA was detected in 19 of 38 solid tumor patients and 1 of 18 brain tumor patients. Somatic variants from ctDNA were correlated with minimal residual disease levels as determined by flow cytometry in serial plasma samples from patients with B-cell acute lymphoblastic leukemia (B-ALL). We showcase multi-tumor detection by ctDNA analysis for a patient with concurrent B-ALL and neuroblastoma. In conclusion, PeCan-seq sensitively identified heterogeneous ctDNA alterations from 1 mL plasma for childhood hematologic malignancies and a subset of solid tumors. PeCan-seq provides a robust, non-invasive approach to augment comprehensive genomic profiling at diagnosis and mutation-specific detection during disease monitoring.

Central line-associated bloodstream infections (CLABSIs) affect about 25% of children with cancer, and treatment failure is common. Adjunctive ethanol lock therapy might prevent treatment failure but high-quality evidence is scarce. We evaluated ethanol lock therapy as treatment and secondary prophylaxis for CLABSI in children with cancer or haematological disorders. This randomised, double-blind, placebo-controlled superiority trial, with two interim futility and efficacy analyses (done when the first 46 and 92 evaluable participants completed study requirements), was done at two paediatric hospitals in the USA and Australia. Patients aged 6 months to 24 years, inclusive, with cancer or a haematological disorder and new CLABSI were eligible. Participants were randomly assigned (1:1) to receive either ethanol lock therapy (70% ethanol) or placebo (heparinised saline) for 2–4 h per lumen daily for 5 days (treatment phase), then for up to 3 non-consecutive days per week for 24 weeks (prophylaxis phase). The primary composite outcome was treatment failure, consisting of attributable catheter removal or death, new or persistent (>72 h) infection, or additional lock therapy during the treatment phase, and recurrent CLABSI during the prophylaxis phase. This trial is registered with ClinicalTrials.gov, number NCT01472965. 94 evaluable participants were enrolled between Dec 14, 2011, and Sept 12, 2016, of whom 48 received ethanol lock therapy and 46 received placebo. The study met futility criteria at the second interim analysis. Treatment failure was similar with ethanol lock therapy (21 [44%] of 48) and placebo (20 [43%] of 46; relative risk [RR] 1·0, 95% CI 0·6–1·6; p=0·98). Some adverse events, including infusion reactions and catheter occlusion, were more frequent in the ethanol lock therapy group than in the placebo group. Catheter occlusion requiring thrombolytic therapy was more common with ethanol lock therapy (28 [58%] of 48) than with placebo (15 [33%] of 46; RR 1·8, 95% CI 1·1–2·9; p=0·012). Discontinuation of lock therapy because of adverse effects or patient request occurred in a similar proportion of participants in the ethanol lock therapy (nine [19%] of 48) and placebo groups (ten [22%] of 46; p=0·72). Ethanol lock therapy did not prevent CLABSI treatment failure and it increased catheter occlusion. Routine ethanol lock therapy for treatment or secondary prophylaxis is not recommended in this population. American Lebanese Syrian Associated Charities to St Jude Children's Research Hospital and an Australian Government Research Training Scholarship.

Infiltration of malignant cells into the central nervous system in hematological malignancies correlates with poor clinical outcomes. Investigations into the penetration of venetoclax into the central nervous system have been limited. We report venetoclax pharmacokinetics in plasma and cerebrospinal fluid samples from a Phase 1 study in pediatric patients with relapsed or refractory malignancies that demonstrate venetoclax ability to cross into the central nervous system. Venetoclax was detected in cerebrospinal fluid (CSF) samples, with concentrations ranging from < 0.1 to 26 ng/mL (mean, 3.6 ng/mL) and a plasma:CSF ratio ranging from 44 to 1559 (mean, 385). Plasma:CSF ratios were comparable among patients with AML and ALL and no clear trend was observed in the ratios over the course of treatment. Moreover, improvement in central nervous system (CNS) involvement status was observed in patients who had measurable concentrations of venetoclax in the CSF. CNS resolution was observed for up to six months while on treatment. These findings highlight the potential role of venetoclax and provide the opportunity to further investigate its utility in improving clinical outcomes for patients with CNS complications.