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Inhibition of poly(ADP-ribose) polymerase (PARP) is an attractive therapeutic strategy because of the importance of this pathway in restoring DNA damage. Small-molecule inhibitors of PARP appear most effective when used to treat tumors with underlying defects in DNA repair, or when combined with DNA-damaging agents. Veliparib is one of several recently developed oral inhibitors of PARP currently in clinical trials. This review summarizes the pharmacology, mechanisms of action, toxicity, and activity of veliparib seen in clinical trials to date. Also discussed are proposed mechanisms of resistance, potential biomarkers of activity, and issues regarding patient selection and combination therapies that may optimize use of this exciting new agent.

While remarkable advances have been made in the treatment of pediatric leukemia over the past decades, new therapies are needed for children with advanced solid tumors and high-grade brain tumors who fail standard chemotherapy regimens. Immunotherapy with immune checkpoint inhibitors acting through the programmed cell death-1 (PD-1) pathway has shown efficacy in some chemotherapy-resistant adult cancers, generating interest that these agents may also be helpful to treat certain refractory pediatric malignancies. In this manuscript we review current strategies for targeting the PD-1 pathway, highlighting putative biomarkers and the rationale for investigation of these drugs to treat common pediatric tumors such as sarcoma, neuroblastoma, and high-grade glioma. We summarize the completed and ongoing clinical trial data available, and suggest potential applications for further study.

Although many patients with newly diagnosed Ewing sarcoma can become long-term survivors, relapse remains an important clinical problem for which there is no standard approach. Several prognostic factors have been identified, and these may help guide patient counseling and therapy decisions. A variety of chemotherapy regimens have produced responses in patients with recurrent Ewing sarcoma, but no comparative studies have been completed to show superiority of any one particular approach. In addition, the optimum length of therapy for salvage regimens and use of local control measures remains unknown. The likelihood of cure remains low and the gaps in our knowledge are great, and so enrollment on clinical trials should be strongly encouraged for these patients when feasible. Because Ewing sarcoma is relatively rare, some pediatric and adult oncologists may be less familiar with the management of relapsed patients. In this review, we address common questions facing the clinician and patient, and provide an update on new strategies for therapy.

Glycogen dysregulation is a hallmark of aging, and aberrant glycogen drives metabolic reprogramming and pathogenesis in multiple diseases. However, glycogen heterogeneity in healthy and diseased tissues remains largely unknown. Herein, we describe a method to define spatial glycogen architecture in mouse and human tissues using matrix‐assisted laser desorption/ionization mass spectrometry imaging. This assay provides robust and sensitive spatial glycogen quantification and architecture characterization in the brain, liver, kidney, testis, lung, bladder, and even the bone. Armed with this tool, we interrogated glycogen spatial distribution and architecture in different types of human cancers. We demonstrate that glycogen stores and architecture are heterogeneous among diseases. Additionally, we observe unique hyperphosphorylated glycogen accumulation in Ewing sarcoma, a pediatric bone cancer. Using preclinical models, we correct glycogen hyperphosphorylation in Ewing sarcoma through genetic and pharmacological interventions that ablate in vivo tumor growth, demonstrating the clinical therapeutic potential of targeting glycogen in Ewing sarcoma. Synopsis Development of a MALDI‐based assay for the spatial quantification of microenvironmental glycogen and glycogen biochemical architecture. Hyperphosphorylated glycogen was discovered in human Ewing sarcoma. Targeting tumor‐specific glycogen may be a potential therapeutic approach for Ewing sarcoma. Development of a MALDI‐based assay for the spatial quantification of microenvironmental glycogen. Ultra‐sensitivity allows visualization of glycogen in previously unknown but distinct cellular layers in multiple human tissues. Identification of glycogen‐rich and glycogen‐poor tumors such as Ewing sarcoma and prostate cancer, respectively. Targeting Ewing sarcoma glycogen by different modalities blunted tumor growth in immunodeficient mice. Graphical Abstract Development of a MALDI‐based assay for the spatial quantification of microenvironmental glycogen and glycogen biochemical architecture. Hyperphosphorylated glycogen was discovered in human Ewing sarcoma. Targeting tumor‐specific glycogen may be a potential therapeutic approach for Ewing sarcoma.

Receptor tyrosine kinases are critical for the growth and proliferation of many different cancers and therefore represent a potential vulnerability that can be therapeutically exploited with small molecule inhibitors. Over forty small molecule inhibitors are currently approved for the treatment of adult solid tumors. Their use has been more limited in pediatric solid tumors, although an increasing number of single-agent and combination studies are now being performed. These agents have been quite successful in certain clinical contexts, such as the treatment of pediatric tumors driven by kinase fusions or activating mutations. By contrast, only modest activity has been observed when inhibitors are used as single agents for solid tumors that do not have genetically defined alterations in the target genes. The absence of predictive biomarkers has limited the wider applicability of these drugs and much work remains to define the appropriate patient population and clinical situation in which receptor tyrosine kinase inhibitors are most beneficial. In this manuscript, we discuss these issues by highlighting past trials and identifying future strategies that may help add precision to the use of these agents for pediatric extracranial solid tumors.

Over the past 15 years, irinotecan has emerged as an important agent for treating pediatric sarcoma patients. This review summarizes the activity noted in previous studies, and outlines current issues regarding scheduling, route of administration, and amelioration of side effects. Also discussed are new pegylated and nanoliposomal formulations of irinotecan and its active metabolite, SN-38, as well as future plans for how irinotecan may be used in combination with other conventional cytotoxic as well as targeted agents.

Background High-resolution manometry (HRM) is the gold standard for diagnosing esophageal motility disorders. However, its short-term laboratory setting often fails to capture intermittent abnormalities. Long-term HRM (LTHRM, up to 24h) provides richer insights into swallowing behavior, but the resulting data volume is immense. Manual analysis by medical experts is laborious, time-consuming, and prone to errors, limiting its clinical feasibility. Methods We propose a deep learning-based approach for automatic analysis of LTHRM data. Our method detects both swallow events and secondary non-deglutitive motility disorders with high accuracy. Detected swallows are then clustered into distinct classes of similar events, creating a structured overview of motility patterns and their frequency. This reduces the analytical burden by allowing clinicians to focus on a small number of representative swallows rather than manually reviewing thousands of individual events. We evaluate our pipeline on 25 LTHRMs that were meticulously annotated, resulting in a dataset of more than 23,000 expert-labeled events. Results Our approach is able to detect more than 94% of all relevant events in LTHRM sequences, while the subsequent clustering is able to capture and group all relevant events into distinct swallow groups. To evaluate the overall approach, we conduct a user study with medical experts, demonstrating its effectiveness and positive clinical impact. Conclusions Our findings demonstrate that deep learning-based approaches to analyze LTHRM examinations are capable of providing a more reliable and efficient diagnostic process, ultimately making LTHRM assessments more feasible in clinical care. Plain language summary High-resolution manometry (HRM) is the standard test for diagnosing swallowing and esophageal motility disorders by analyzing swallowing and pressure patterns in a patient. This method uses short recording time and can often miss intermittent problems. Long-term HRM (LTHRM) captures a fuller picture but produces large datasets that are difficult to analyze manually. We present a computer learning-based method that automatically detects swallow events and abnormal motility patterns in these larger datasets and clusters them into groups of similar events. This structured representation reduces the data burden and allows experts to focus on representative examples. Evaluated on 25 recordings with over 23,000 labeled events, our method is able to detect more than 94% of all relevant events and is shown in a user study to improve efficiency in clinical interpretation. Geiger et al. present a deep learning-based pipeline for analyzing long-term high-resolution manometry (LTHRM) data by detecting swallow events and clustering them into representative groups. The approach achieves over 94% detection accuracy and is shown to reduce the overall LTHRM evaluation time while preserving diagnostic quality.

Purpose Integrating robotic scrub nurses in the operating room has the potential to help overcome staff shortages and limited use of available operating capacities in hospitals. Existing approaches of robotic scrub nurses are mainly focused on open surgical procedures, neglecting laparoscopic procedures. Laparoscopic interventions offer great potential for the context-sensitive integration of robotic systems due to possible standardization. However, the first step is to ensure the safe manipulation of laparoscopic instruments. Methods A robotic platform with a universal gripper system was designed to pick up and place laparoscopic as well as da Vinci ® instruments in an efficient workflow. The robustness of the gripper system was studied using a test protocol, which included a force absorption test to determine the operational safety limits of the design and a grip test to determine the system performance. Results The test protocol shows results regarding force and torque absorption capabilities of the end effector, which are essential when transferring an instrument to the surgeon to enable a robust handover. The grip tests show that the laparoscopic instruments can be safely picked up, manipulated and returned independent of unexpected positional deviations. The gripper system also enables the manipulation of da Vinci ® instruments, opening the door for robot–robot interaction. Conclusion Our evaluation tests have shown that our robotic scrub nurse with the universal gripper system can safely and robustly manipulate laparoscopic and da Vinci ® instruments. The system design will continue with the integration of context-sensitive capabilities.

Glioblastoma in children is an aggressive disease with no defined standard therapy. We evaluated hospital‐based demographic and survival patterns obtained through the National Cancer Database to better characterize children with glioblastoma. Our study identified 1173 patients from 0 to 19 years of age between 1998 and 2011. Comparisons were made among demographics, clinical characteristics, treatment, and survival variables. Fifty‐four percent of patients were over 10 years of age. Approximately 80% of patients underwent either partial or complete resection. Adjuvant therapy was used variably, and its use increased with patient age. Forty‐eight percent of patients received the combination of surgery, radiation, and chemotherapy, and 4% did not receive any treatment. As expected, patients ≤5 years of age had better 5‐year survival than those ages 6–10 (P = 0.01) or 11–19 years (P = 0.0077). Other factors associated with poor survival included black race and central tumor location. Better outcomes were associated with treatment that included surgery, radiotherapy, and chemotherapy compared to any other treatment combinations. Radiotherapy had no impact on survival in the 0 to 10‐year‐old age group, but was associated with improved survival for patients 11–19 years. We report an extensive demographic and survival analysis of pediatric glioblastoma. The observed differences likely reflect variances in tumor biology and likelihood of treatment receipt. Improved survival was associated with the use of surgery, radiotherapy, and chemotherapy. Radiation therapy was not associated with survival in patients younger than 10 years of age. This is the largest demographics and patterns of care study of pediatric glioblastoma. We found age and tumor location related differences in outcomes that reflect variances in tumor biology and of treatment receipt. Our findings demonstrated improved survival was associated with the use of multimodality treatment, particularly the combination of surgery, radiotherapy, and chemotherapy.

Canine and human osteosarcoma are similar in clinical presentation and tumor genomics. Giant breed dogs experience elevated osteosarcoma incidence, and taller stature remains a consistent risk factor for human osteosarcoma. Whether evolutionarily conserved genes contribute to both human and canine osteosarcoma predisposition merits evaluation. A multi-center sample of childhood osteosarcoma patients and controls underwent genome-wide genotyping and imputation. Ancestry-adjusted SNP associations were calculated within each dataset using logistic regression, then meta-analyzed across the three datasets, totaling 1091 patients and 3026 controls. Ten regions previously associated with canine osteosarcoma risk were mapped to the human genome, spanning ∼6 Mb. We prioritized association testing of 5985 human SNPs mapping to candidate osteosarcoma risk regions detected in Irish wolfhounds, the largest dog breed studied. Secondary analyses explored 6289 additional human SNPs mapping to candidate osteosarcoma risk regions identified in Rottweilers and greyhounds. Fourteen SNPs were associated with human osteosarcoma risk after adjustment for multiple comparisons, all within a 42 kb region of human Chromosome 7p12.1. The lead variant was rs17454681 (OR=1.25, 95 %CI: 1.12–1.39; P=4.1×10−5), and independent risk variants were not observed in conditional analyses. While the associated region spanned 2.1 Mb and contained eight genes in Irish wolfhounds, associations were localized to a 50-fold smaller region of the human genome and strongly implicate GRB10 (growth factor receptor-bound protein 10) in canine and human osteosarcoma predisposition. PheWAS analysis in UK Biobank data identified noteworthy associations of the rs17454681 risk allele with varied measures of height and pubertal timing. Our comparative oncology analysis identified a novel human osteosarcoma risk allele near GRB10, a growth inhibitor that suppresses activated receptor tyrosine kinases including IGF1R, PDGFRB, and EGFR. Epidemiologists may benefit from leveraging cross-species comparisons to identify haplotypes in highly susceptible but genetically homogenous populations of domesticated animals, then fine-mapping these associations in diverse human populations. •Genes involved in osteosarcoma (OS) predisposition may be conserved across species.•An OS risk locus in Irish wolfhounds conferred childhood OS risk in a large sample.•Cross-species mapping implicated GRB10, a key regulator of IGF-1R signaling.•Risk haplotypes from domesticated animals can be fine-mapped in human populations.