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Purpose: Lung metastasis is responsible for nearly all deaths caused by osteosarcoma, the most common pediatric bone tumor. How malignant bone cells coerce the lung microenvironment to support metastatic growth is unclear. The purpose of this study is to identify metastasis-specific therapeutic vulnerabilities by delineating the cellular and molecular mechanisms underlying osteosarcoma lung metastatic niche formation., Experimental Design: Using single-cell RNA sequencing, we characterized genome- and tissue-wide molecular changes induced within lung tissues by disseminated osteosarcoma cells in both immunocompetent murine models of metastasis and patient samples. We confirmed transcriptomic findings at the protein level and determined spatial relationships with multiparameter immunofluorescence and spatial transcriptomics. Based on these findings, we evaluated the ability of nintedanib, a kinase inhibitor used to treat patients with pulmonary fibrosis, to impair metastasis progression in both immunocompetent murine osteosarcoma and immunodeficient human xenograft models. Single-nucleus and spatial transcriptomics were used to perform molecular pharmacodynamic studies that define the effects of nintedanib on tumor and nontumor cells within the metastatic microenvironment., Results: Osteosarcoma cells induced acute alveolar epithelial injury upon lung dissemination. Single-cell RNA sequencing demonstrated that the surrounding lung stroma adopts a chronic, nonresolving wound-healing phenotype similar to that seen in other models of lung injury. Accordingly, the metastasis-associated lung demonstrated marked fibrosis, likely because of the accumulation of pathogenic, profibrotic, partially differentiated epithelial intermediates and macrophages. Our data demonstrated that nintedanib prevented metastatic progression in multiple murine and human xenograft models by inhibiting osteosarcoma-induced fibrosis., Conclusions: Fibrosis represents a targetable vulnerability to block the progression of osteosarcoma lung metastasis. Our data support a model wherein interactions between osteosarcoma cells and epithelial cells create a prometastatic niche by inducing tumor deposition of extracellular matrix proteins such as fibronectin that is disrupted by the antifibrotic tyrosine kinase inhibitor (TKI) nintedanib. Our data shed light on the non-cell-autonomous effects of TKIs on metastasis and provide a roadmap for using single-cell and spatial transcriptomics to define the mechanism of action of TKI on metastases in animal models., (©2024 The Authors; Published by the American Association for Cancer Research.)

Feeling a texture typically involves sliding the fingers of a hand across that surface or rubbing the surface between the thumb and another digit. Texture signals appear to be integrated across the digits of a hand with perceived roughness at one finger swayed in the direction of texture touched by another finger of the same hand. To date, one study has reported similar integrative effects when the pairs of digits belong to different hands. This contrasts with observations from studies of tactile detection and tactile attention where the patterns of interactions between the digits depend on whether the digits belong to the same hand or not. The present experiments revisit the question of hand identity on multidigit roughness perception using two interval forced choice (2IFC) discrimination and single interval absolute magnitude estimation (AME). Pairs of tactile gratings were actively touched using the thumb and index fingers from the same or different hands. Attention was directed towards roughness at the thumb and index finger sensations were to be ignored. For both discrimination and ratings tasks, roughness perceived at the thumb varied with the textures touched by the index finger suggesting integration of roughness cues from the two digits. This integration occurred despite differences in the two tasks such as working memory requirements. Notably, roughness signals were integrated when originating in pairs of digits on the same hand but not when from different hands. These findings add to a body of evidence based on experiments using different stimuli and tasks, suggesting that hand identity affects interactions across the digits., Competing Interests: Declarations. Competing interests: The author declares no competing interests., (© 2024. The Author(s).)

Trends in diagnostic biopsy sample collection approaches for primary bone sarcomas have shifted in the past 2 decades. Although open/incisional biopsies used to be the predominant approach to obtain diagnostic material for Ewing sarcoma and osteosarcoma, image-guided core needle biopsies have increased in frequency and are safe for patients. These procedures are less invasive and reduce recovery times but have potential limitations. The quantity and quality of tissue obtained through these procedures vary between institutions. Acquired viable tissue volumes can be low, limiting the conduct of downstream expanded clinical workup, molecular analyses, and research. Patients with advanced Ewing sarcoma and osteosarcoma continue to have overall poor outcomes despite dose-intensive cytotoxic chemotherapy. The biology of treatment resistance is not currently well understood, partly due to limited availability of relevant tissue to study. There is a need for access to quality tumor specimens for molecular and other analyses to identify high-risk tumor subsets and drive discovery to improve patient outcomes. Given broad variability in bone tumor tissue procurement and processing across member institutions, the Children's Oncology Group Bone Tumor Committee convened a multidisciplinary group of experts to outline the current and near-future tissue needs for optimal clinical care and access to research platforms. The goal of this working group was to provide high-level guidance on biopsy practices that safely meet these evolving needs. Harmonizing tissue collection practices is paramount to improving the care of children, adolescents, and young adults diagnosed with Ewing sarcoma and osteosarcoma.

Patients with osteosarcoma (OS), a debilitating pediatric bone malignancy, have limited treatment options to combat aggressive disease. OS thrives on insulin growth factor (IGF)-mediated signaling that can facilitate cell proliferation. Previous efforts to target IGF-1R signaling were mostly unsuccessful, likely due to compensatory signaling through alternative splicing of the insulin receptor ( IR ) to the proliferative IR-A isoform. Here, we leverage splice-switching oligonucleotides (SSOs) to mitigate IR splicing toward the IR-B isoform. We show that SSOs can modulate cancer cell hallmarks and anoikis-resistant growth. Furthermore, we engineered the SSO sequence in an U7 snRNA packaged in an adeno-associated virus (AAV) to test the feasibility of viral vector-mediated gene therapy delivery. We noted modest increases in IR-B isoform levels after virus transduction, which prompted us to investigate the role of combinatorial treatments with dalotuzumab, an anti-IGF-1R monoclonal antibody. After observing additive impacts on phosphoprotein phosphorylation and anoikis-resistant growth with the dalotuzumab and SSO combination, we treated OS cells with dalotuzumab and the AAVrh74.U7 snRNA IR virus, which significantly slowed OS cell proliferation. While these viruses require further optimization, we highlight the potential for SSO therapy and viral vector delivery, as it may offer new treatment avenues for OS patients and be translated to other cancers., Competing Interests: The AAVrh74.U7 snRNA viruses shown in this work are the subject of an international patent application (USSN 63/572,178) with A.S.V., P.Y.W., N.W., D.S.C., and T.P.C. as inventors. T.P.C. is a member of the Molecular Therapy Oncology board and Editor-in-Chief. D.S.C. is a member of the Molecular Therapy Oncology editorial board. F.R. is affiliated with Ionis Pharmaceuticals., (© 2024 The Authors.)

Purpose: Pharmacologic therapies for neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PNs) are limited; currently, none are US Food and Drug Administration-approved for adults., Methods: ReNeu is an open-label, multicenter, pivotal, phase IIb trial of mirdametinib in 58 adults (≥18 years of age) and 56 children (2 to 17 years of age) with NF1-PN causing significant morbidities. Patients received mirdametinib capsules or tablets for oral suspension (2 mg/m 2 twice daily, maximum 4 mg twice daily), regardless of food intake, in 3 weeks on/1 week off 28-day cycles. The primary end point was confirmed objective response rate (ORR; proportion of patients with a ≥20% reduction of target PN volume from baseline on consecutive scans during the 24-cycle treatment phase) assessed by blinded independent central review (BICR) of volumetric magnetic resonance imaging., Results: Twenty-four of 58 adults (41%) and 29 of 56 children (52%) had a BICR-confirmed objective response during the 24-cycle treatment phase; in addition, two adults and one child had confirmed responses during long-term follow-up. Median (range) target PN volumetric best response was -41% (-90 to 13) in adults and -42% (-91 to 48) in children. Both cohorts reported significant and clinically meaningful improvement in patient- or parent proxy-reported outcome measures of worst tumor pain severity, pain interference, and health-related quality of life (HRQOL) that began early and were sustained during treatment. The most commonly reported treatment-related adverse events were dermatitis acneiform, diarrhea, and nausea in adults and dermatitis acneiform, diarrhea, and paronychia in children., Conclusion: In ReNeu, the largest multicenter NF1-PN trial reported to date, mirdametinib treatment demonstrated significant confirmed ORRs by BICR, deep and durable PN volume reductions, and early, sustained, and clinically meaningful improvement in pain and HRQOL. Mirdametinib was well-tolerated in adults and children.

Introduction: The topoisomerase 1 (TOP1) inhibitor irinotecan is a standard-of-care agent for relapsed Ewing sarcoma (EWS), but its efficacy is limited by chemical instability, rapid clearance and reversibility, and dose-limiting toxicities, such as diarrhea. Indenoisoquinolines (IIQs) represent a new class of clinical TOP1 inhibitors designed to address these limitations., Methods: In this study, we evaluated the preclinical efficacy of three IIQs (LMP400, LMP744, and LMP776) in relevant models of EWS. We characterized the pharmacokinetics of IIQs in orthotopic xenograft models of EWS, optimized the dosing regimen through tolerability studies, and tested the efficacy of IIQs in a panel of six molecularly heterogeneous EWS patient-derived xenograft (PDX) models. For each PDX, we conducted whole genome and RNA sequencing, and methylation analysis., Results: We show that IIQs potently inhibit the proliferation of EWS cells in vitro, inducing complete cell growth inhibition at nanomolar concentrations via induction of DNA damage and apoptotic cell death. LMP400 treatment induced ≥30% tumor regression in two of six PDX models, with more durable regression compared to irinotecan treatment in one of these models. RNA sequencing of PDX models identified a candidate predictive biomarker gene signature for LMP400 response. These data, along with pharmacogenomic data on IIQs in sarcoma cell lines, are available at a new interactive public website: https://discover.nci.nih.gov/rsconnect/EwingSarcomaMinerCDB/., Discussion: Our findings suggest that IIQs may be promising new agents for a subset of EWS patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lee, Szabova, Collins, Gordon, Johnson, Householder, Jorgensen, Lu, Bassel, Elloumi, Peer, Nelson, Varriano, Varma, Roberts, Ohler, Figg, Sharan, Pommier and Heske.)

We previously reported that the DNA alkylator and transcriptional-blocking chemotherapeutic agent trabectedin enhances oncolytic herpes simplex viroimmunotherapy in human sarcoma xenograft models, though the mechanism remained to be elucidated. Here we report trabectedin disrupts the intrinsic cellular antiviral response which increases viral transcript presence in the human tumor cells. We also extended our synergy findings to syngeneic murine sarcoma models, which are poorly susceptible to virus infection. In the absence of robust virus replication, we found trabectedin enhanced viroimmunotherapy efficacy by reducing infiltrating immunosuppressive CD4 T and myeloid cells and stimulating granzyme expression in infiltrating T and natural killer cells to cause immune-mediated tumor regressions. Thus, trabectedin enhances both the direct virus-mediated killing of tumor cells and the viral-induced activation of cytotoxic effector lymphocytes to cause tumor regressions across models. Our data provide a strong rationale for clinical translation as both mechanisms should be simultaneously active in human patients., Competing Interests: L.B. is an employee of JJP Biologics. T.P.C. is a member of the Molecular Therapy editorial board and the editor-in-chief of Molecular Therapy Oncology. D.A.L. and P.R. are associate editors for Molecular Therapy Oncology., (© 2024 The Author(s).)

Purpose: Lung metastasis is responsible for nearly all deaths caused by osteosarcoma, the most common pediatric bone tumor. How malignant bone cells coerce the lung microenvironment to support metastatic growth is unclear. The purpose of this study is to identify metastasis-specific therapeutic vulnerabilities by delineating the cellular and molecular mechanisms underlying osteosarcoma lung metastatic niche formation., Experimental Design: Using single-cell transcriptomics (scRNA-seq), we characterized genome- and tissue-wide molecular changes induced within lung tissues by disseminated osteosarcoma cells in both immunocompetent murine models of metastasis and patient samples. We confirmed transcriptomic findings at the protein level and determined spatial relationships with multi-parameter immunofluorescence and spatial transcriptomics. Based on these findings, we evaluated the ability of nintedanib, a kinase inhibitor used to treat patients with pulmonary fibrosis, to impair metastasis progression in both immunocompetent murine osteosarcoma and immunodeficient human xenograft models. Single-nucleus and spatial transcriptomics was used to perform molecular pharmacodynamic studies that define the effects of nintedanib on tumor and non-tumor cells within the metastatic microenvironment., Results: Osteosarcoma cells induced acute alveolar epithelial injury upon lung dissemination. scRNA-seq demonstrated that the surrounding lung stroma adopts a chronic, non-resolving wound-healing phenotype similar to that seen in other models of lung injury. Accordingly, metastasis-associated lung demonstrated marked fibrosis, likely due to the accumulation of pathogenic, pro-fibrotic, partially differentiated epithelial intermediates and macrophages. Our data demonstrated that nintedanib prevented metastatic progression in multiple murine and human xenograft models by inhibiting osteosarcoma-induced fibrosis., Conclusions: Fibrosis represents a targetable vulnerability to block the progression of osteosarcoma lung metastasis. Our data support a model wherein interactions between osteosarcoma cells and epithelial cells create a pro-metastatic niche by inducing tumor deposition of extracellular matrix proteins such as fibronectin that is disrupted by the anti-fibrotic TKI nintedanib. Our data shed light on the non-cell autonomous effects of TKIs on metastasis and provide a roadmap for using single-cell and spatial transcriptomics to define the mechanism of action of TKI on metastases in animal models.

Background: Pediatric patients with metastatic and/or recurrent solid tumors have poor survival outcomes despite standard-of-care systemic therapy. Stereotactic ablative radiation therapy (SABR) may improve tumor control. We report the outcomes with the use of SABR in our pediatric solid tumor population., Methods: This was a single-institutional study in patients < 30 years treated with SABR. The primary endpoint was local control (LC), while the secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity. The survival analysis was performed using Kaplan-Meier estimates in R v4.2.3., Results: In total, 48 patients receiving 135 SABR courses were included. The median age was 15.6 years (interquartile range, IQR 14-23 y) and the median follow-up was 18.1 months (IQR: 7.7-29.1). The median SABR dose was 30 Gy (IQR 25-35 Gy). The most common primary histologies were Ewing sarcoma (25%), rhabdomyosarcoma (17%), osteosarcoma (13%), and central nervous system (CNS) gliomas (13%). Furthermore, 57% of patients had oligometastatic disease (≤5 lesions) at the time of SABR. The one-year LC, PFS, and OS rates were 94%, 22%, and 70%, respectively. No grade 4 or higher toxicities were observed, while the rates of any grade 1, 2, and 3 toxicities were 11.8%, 3.7%, and 4.4%, respectively. Patients with oligometastatic disease, lung, or brain metastases and those who underwent surgery for a metastatic site had a significantly longer PFS. LC at 1-year was significantly higher for patients with a sarcoma histology (95.7% vs. 86.5%, p = 0.01) and for those who received a biological equivalent dose (BED10) > 48 Gy (100% vs. 91.2%, p = 0.001)., Conclusions: SABR is well tolerated in pediatric patients with 1-year local failure and OS rates of <10% and 70%, respectively. Future studies evaluating SABR in combination with systemic therapy are needed to address progression outside of the irradiated field.

Context: Evidence suggesting the benefits of compassionate, person-centred care, for both patients and physicians is accruing. Medical selection, for example, aims to choose future health professionals that possess the correct attitudes, beliefs and personal attributes to deliver such care. Moreover, once in training, these desirable personal qualities should be developed and maintained, sometimes in the face of adverse health care service conditions. However, advances in selecting for, and developing, these abilities and attributes in health care have been hindered by a lack of clarity regarding how the relevant skills and traits should be defined, measured, developed and maintained in clinicians., Methods: In this article, we demonstrate how developments in the emotional intelligence (EI) field can be applied to the challenge of selecting for, and developing, relevant interpersonal care skills in medical students and physicians. The concept of EI itself has been somewhat controversial. However, a more nuanced understanding of EI has evolved in the light of research findings that can be applied to medical selection and education. Specifically, we propose modifications to the existing 'cascading' model of EI. This model identifies, and relates, several key socioemotional skills and traits that could be considered as 'the elementary particles' of EI required to deliver compassionate, person-centred care., Conclusions: Our model of EI, which is relevant to care delivery, identifies putative targets for both medical selection and training. Selection for medical school and subsequent clinical education should focus on screening out those with low levels of the traits and abilities less amenable to training. Conversely, medical education should be concerned with developing and maintaining the socioemotional skills, attitudes and behaviours critical to the delivery of compassionate, person-centred care. This is especially important for specialties characterised by high levels of emotional labour and possible resultant compassion fatigue., (© 2023 The Authors. Medical Education published by Association for the Study of Medical Education and John Wiley & Sons Ltd.)

We previously reported that the DNA alkylator and transcriptional-blocking chemotherapeutic agent trabectedin enhances oncolytic herpes simplex viroimmunotherapy in human sarcoma xenograft models, though the mechanism remained to be elucidated. Here we report trabectedin disrupts the intrinsic cellular anti-viral response which increases viral transcript spread throughout the human tumor cells. We also extended our synergy findings to syngeneic murine sarcoma models, which are poorly susceptible to virus infection. In the absence of robust virus replication, we found trabectedin enhanced viroimmunotherapy efficacy by reducing immunosuppressive macrophages and stimulating granzyme expression in infiltrating T and NK cells to cause immune-mediated tumor regressions. Thus, trabectedin enhances both the direct virus-mediated killing of tumor cells and the viral-induced activation of cytotoxic effector lymphocytes to cause tumor regressions across models. Our data provide a strong rationale for clinical translation as both mechanisms should be simultaneously active in human patients.

Competing Interests: The authors declare no competing interests.

Purpose: For patients with osteosarcoma, disease-related mortality most often results from lung metastasis-a phenomenon shared with many solid tumors. While established metastatic lesions behave aggressively, very few of the tumor cells that reach the lung will survive. By identifying mechanisms that facilitate survival of disseminated tumor cells, we can develop therapeutic strategies that prevent and treat metastasis., Methods: We analyzed single cell RNA-sequencing (scRNAseq) data from murine metastasis-bearing lungs to interrogate changes in both host and tumor cells during colonization. We used these data to elucidate pathways that become activated in cells that survive dissemination and identify candidate host-derived signals that drive activation. We validated these findings through live cell reporter systems, immunocytochemistry, and fluorescent immunohistochemistry. We then validated the functional relevance of key candidates using pharmacologic inhibition in models of metastatic osteosarcoma., Results: Expression patterns suggest that the MAPK pathway is significantly elevated in early and established metastases. MAPK activity correlates with expression of anti-apoptotic genes, especially MCL1. Niche cells produce growth factors that increase ERK phosphorylation and MCL1 expression in tumor cells. Both early and established metastases are vulnerable to MCL1 inhibition, but not MEK inhibition in vivo. Combining MCL1 inhibition with chemotherapy both prevented colonization and eliminated established metastases in murine models of osteosarcoma., Conclusion: Niche-derived growth factors drive MAPK activity and MCL1 expression in osteosarcoma, promoting metastatic colonization. Although later metastases produce less MCL1, they remain dependent on it. MCL1 is a promising target for clinical trials in both human and canine patients., (© 2023. The Author(s).)

How does vision affect active touch in judgments of surface roughness? We contrasted direct (combination of visual with tactile sensory information) and indirect (vision alters the processes of active touch) effects of vision on touch. Participants judged which of 2 surfaces was rougher using their index finger to make static contact with gratings of spatial period 1580 and 1620 μm. Simultaneously, they viewed the stimulus under one of five visual conditions: No vision, Filtered vision + touch, Veridical vision + touch (where vision alone yielded roughness discrimination at chance), Congruent vision + touch, Incongruent vision + touch. Results from 32 participants showed roughness discrimination for touch with vision was better than touch alone. The visual benefit for touch was strongest in a filtered (spatially non-informative) vision condition, thus results are interpreted in terms of indirect integration. An indirect effect of vision was further indicated by a finding of visual benefit in some but not all visuo-tactile congruency conditions., (© 2024. The Author(s).)

Introduction: Psychophysical studies suggest texture perception is mediated by spatial and vibration codes (duplex theory). Vibration coding, driven by relative motion between digit and stimulus, is involved in the perception of very fine gratings whereas coarse texture perception depends more on spatial coding, which does not require relative motion., Methods: We examined cortical activation, using functional Magnetic Resonance Imaging associated with fine and coarse tactile spatial gratings applied by sliding or touching (sliding vs. static contact) on the index finger pad., Results: We found regions, contralateral to the stimulated digit, in BA1 in S1, OP1, OP3, and OP4 in S2, and in auditory cortex, which were significantly more activated by sliding gratings but did not find this pattern in visual cortex. Regions in brain areas activated by vibrotactile stimuli (including auditory cortex) were also modulated by whether or not the gratings moved. In a control study we showed that this contrast persisted when the salience of the static condition was increased by using a double touch., Discussion: These findings suggest that vibration from sliding touch invokes multisensory cortical mechanisms in tactile processing of roughness. However, we did not find evidence of a separate visual region activated by static touch nor was there a dissociation between cortical response to fine vs. coarse gratings as might have been expected from duplex theory., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Roberts, Loomes, Kwok, Wing and Allen.)

Somatic mosaicism is a known cause of neurological disorders, including developmental brain malformations and epilepsy. Brain mosaicism is traditionally attributed to post-zygotic genetic alterations arising in fetal development. Here we describe post-zygotic rescue of meiotic errors as an alternate origin of brain mosaicism in patients with focal epilepsy who have mosaic chromosome 1q copy number gains. Genomic analysis showed evidence of an extra parentally derived chromosome 1q allele in the resected brain tissue from five of six patients. This copy number gain is observed only in patient brain tissue, but not in blood or buccal cells, and is strongly enriched in astrocytes. Astrocytes carrying chromosome 1q gains exhibit distinct gene expression signatures and hyaline inclusions, supporting a novel genetic association for astrocytic inclusions in epilepsy. Further, these data demonstrate an alternate mechanism of brain chromosomal mosaicism, with parentally derived copy number gain isolated to brain, reflecting rescue in other tissues during development., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Osteosarcoma (OS) is the most common primary bone malignancy that exhibits remarkable histologic diversity and genetic heterogeneity. The complex nature of osteosarcoma has confounded precise molecular categorization, prognosis, and prediction for this disease. In this study, we performed a comprehensive multiplatform analysis on 86 osteosarcoma tumors, including somatic copy-number alteration, gene expression and methylation, and identified three molecularly distinct and clinically relevant subtypes of osteosarcoma. The subgrouping criteria was validated on another cohort of osteosarcoma tumors. Previously unappreciated osteosarcoma-type-specific changes in specific genes' copy number, expression and methylation were revealed based on the subgrouping. The subgrouping and novel gene signatures provide insights into refining osteosarcoma therapy and relationships to other types of cancer.

Oncolytic viruses, modified for tumor-restricted infection, are a promising cancer immunotherapeutic, yet much remains to be understood about factors driving their activity and outcome in the tumor microenvironment. Here, we report that oncolytic herpes simplex virus C134, previously found to exert T cell-dependent efficacy in mouse models of glioblastoma, exerts T cell-independent efficacy in mouse models of medulloblastoma, indicating this oncolytic virus uses different mechanisms in different tumors. We investigated C134's behavior in mouse medulloblastomas, using single cell RNA sequencing to map C134-induced gene expression changes across cell types, timepoints, and medulloblastoma subgroup models at whole-transcriptome resolution. Our work details substantial oncolytic virus-induced transcriptional remodeling of medulloblastoma-infiltrating immune cells, 10 subpopulations of monocytes and macrophages collectively demonstrating M1-like responses to C134, and suggests C134 be investigated as a potential new therapy for medulloblastoma., Competing Interests: The authors in full transparency disclose the following commercial interactions. E.R.M. reports PACT Pharma LLC, scientific advisory board membership, honorarium, and stock options; Scorpion Therapeutics, LLC, scientific advisory board membership, honorarium, and stock options; Qiagen N.V., supervisory board membership, stock; Singular Genomics, Inc., board of directors membership and stock. K.A.C. reports stock in Mustang Bio licensure., (© 2023 The Author(s).)

Background: Tumors are complex tissues containing collections of phenotypically diverse malignant and nonmalignant cells. We know little of the mechanisms that govern heterogeneity of tumor cells nor of the role heterogeneity plays in overcoming stresses, such as adaptation to different microenvironments. Osteosarcoma is an ideal model for studying these mechanisms-it exhibits widespread inter- and intra-tumoral heterogeneity, predictable patterns of metastasis, and a lack of clear targetable driver mutations. Understanding the processes that facilitate adaptation to primary and metastatic microenvironments could inform the development of therapeutic targeting strategies., Results: We investigated single-cell RNA-sequencing profiles of 47,977 cells obtained from cell line and patient-derived xenograft models as cells adapted to growth within primary bone and metastatic lung environments. Tumor cells maintained phenotypic heterogeneity as they responded to the selective pressures imposed during bone and lung colonization. Heterogenous subsets of cells defined by distinct transcriptional profiles were maintained within bone- and lung-colonizing tumors, despite high-level selection. One prominent heterogenous feature involving glucose metabolism was clearly validated using immunofluorescence staining. Finally, using concurrent lineage tracing and single-cell transcriptomics, we found that lung colonization enriches for multiple clones with distinct transcriptional profiles that are preserved across cellular generations., Conclusions: Response to environmental stressors occurs through complex and dynamic phenotypic adaptations. Heterogeneity is maintained, even in conditions that enforce clonal selection. These findings likely reflect the influences of developmental processes promoting diversification of tumor cell subpopulations, which are retained, even in the face of selective pressures., (© 2023. The Author(s).)

Osteosarcoma is an aggressive malignancy characterized by high genomic complexity. Identification of few recurrent mutations in protein coding genes suggests that somatic copy-number aberrations (SCNA) are the genetic drivers of disease. Models around genomic instability conflict-it is unclear whether osteosarcomas result from pervasive ongoing clonal evolution with continuous optimization of the fitness landscape or an early catastrophic event followed by stable maintenance of an abnormal genome. We address this question by investigating SCNAs in >12,000 tumor cells obtained from human osteosarcomas using single-cell DNA sequencing, with a degree of precision and accuracy not possible when inferring single-cell states using bulk sequencing. Using the CHISEL algorithm, we inferred allele- and haplotype-specific SCNAs from this whole-genome single-cell DNA sequencing data. Surprisingly, despite extensive structural complexity, these tumors exhibit a high degree of cell-cell homogeneity with little subclonal diversification. Longitudinal analysis of patient samples obtained at distant therapeutic timepoints (diagnosis, relapse) demonstrated remarkable conservation of SCNA profiles over tumor evolution. Phylogenetic analysis suggests that the majority of SCNAs were acquired early in the oncogenic process, with relatively few structure-altering events arising in response to therapy or during adaptation to growth in metastatic tissues. These data further support the emerging hypothesis that early catastrophic events, rather than sustained genomic instability, give rise to structural complexity, which is then preserved over long periods of tumor developmental time., Significance: Chromosomally complex tumors are often described as genomically unstable. However, determining whether complexity arises from remote time-limited events that give rise to structural alterations or a progressive accumulation of structural events in persistently unstable tumors has implications for diagnosis, biomarker assessment, mechanisms of treatment resistance, and represents a conceptual advance in our understanding of intratumoral heterogeneity and tumor evolution., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Antibodies targeting insulin-like growth factor 1 receptor (IGF-1R) induce objective responses in only 5% to 15% of children with sarcoma. Understanding the mechanisms of resistance may identify combination therapies that optimize efficacy of IGF-1R-targeted antibodies. Sensitivity to the IGF-1R-targeting antibody TZ-1 was determined in rhabdomyosarcoma and Ewing sarcoma cell lines. Acquired resistance to TZ-1 was developed and characterized in sensitive Rh41 cells. The BRD4 inhibitor, JQ1, was evaluated as an agent to prevent acquired TZ-1 resistance in Rh41 cells. The phosphorylation status of receptor tyrosine kinases (RTK) was assessed. Sensitivity to TZ-1 in vivo was determined in Rh41 parental and TZ-1-resistant xenografts. Of 20 sarcoma cell lines, only Rh41 was sensitive to TZ-1. Cells intrinsically resistant to TZ-1 expressed multiple (>10) activated RTKs or a relatively less complex set of activated RTKs (∼5). TZ-1 decreased the phosphorylation of IGF-1R but had little effect on other phosphorylated RTKs in all resistant lines. TZ-1 rapidly induced activation of RTKs in Rh41 that was partially abrogated by knockdown of SOX18 and JQ1. Rh41/TZ-1 cells selected for acquired resistance to TZ-1 constitutively expressed multiple activated RTKs. TZ-1 treatment caused complete regressions in Rh41 xenografts and was significantly less effective against the Rh41/TZ-1 xenograft. Intrinsic resistance is a consequence of redundant signaling in pediatric sarcoma cell lines. Acquired resistance in Rh41 cells is associated with rapid induction of multiple RTKs, indicating a dynamic response to IGF-1R blockade and rapid development of resistance. The TZ-1 antibody had greater antitumor activity against Rh41 xenografts compared with other IGF-1R-targeted antibodies tested against this model., (©2023 American Association for Cancer Research.)

Recent studies have shown the importance of the dynamic tumor microenvironment (TME) in high-grade gliomas (HGGs). In particular, myeloid cells are known to mediate immunosuppression in glioma; however, it is still unclear if myeloid cells play a role in low-grade glioma (LGG) malignant progression. Here, we investigate the cellular heterogeneity of the TME using single-cell RNA sequencing in a murine glioma model that recapitulates the malignant progression of LGG to HGG. LGGs show increased infiltrating CD4 + and CD8 + T cells and natural killer (NK) cells in the TME, whereas HGGs abrogate this infiltration. Our study identifies distinct macrophage clusters in the TME that show an immune-activated phenotype in LGG but then evolve to an immunosuppressive state in HGG. We identify CD74 and macrophage migration inhibition factor (MIF) as potential targets for these distinct macrophage populations. Targeting these intra-tumoral macrophages in the LGG stage may attenuate their immunosuppressive properties and impair malignant progression., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Osteosarcoma is the most common primary malignant tumour of the bone. Osteosarcoma incidence is bimodal, peaking at 18 and 60 years of age, and is slightly more common in males. The key pathophysiological mechanism involves several possible genetic drivers of disease linked to bone formation, causing malignant progression and metastasis. While there have been significant improvements in the outcome of patients with localized disease, with event-free survival outcomes exceeding 60%, in patients with metastatic disease, event-free survival outcomes remain poor at less than 30%. The suspicion of osteosarcoma based on radiographs still requires pathological evaluation of a bone biopsy specimen for definitive diagnosis and CT imaging of the chest should be performed to identify lung nodules. So far, population-based screening and surveillance strategies have not been implemented due to the rarity of osteosarcoma and the lack of reliable markers. Current screening focuses only on groups at high risk such as patients with genetic cancer predisposition syndromes. Management of osteosarcoma requires a multidisciplinary team of paediatric and medical oncologists, orthopaedic and general surgeons, pathologists, radiologists and specialist nurses. Survivors of osteosarcoma require specialized medical follow-up, as curative treatment consisting of chemotherapy and surgery has long-term adverse effects, which also affect the quality of life of patients. The development of osteosarcoma model systems and related research as well as the evaluation of new treatment approaches are ongoing to improve disease outcomes, especially for patients with metastases., (© 2022. Springer Nature Limited.)

Signal transducer and activator of transcription 3 (STAT3) dysregulation has been characterized in canine OS, with previous data suggesting that constitutive STAT3 activation contributes to survival and proliferation in OS cell lines in vitro. Recently, the contribution of STAT3 to tumour metabolism has been described across several tumour histologies, and understanding the metabolic implications of STAT3 loss may elucidate novel therapeutic approaches with synergistic activity. The objective of this work was to characterize metabolic benchmarks associated with STAT3 loss in canine OS. STAT3 expression and activation was evaluated using western blotting in canine OS cell lines OSCA8 and Abrams. STAT3 was deleted from these OS cell lines using CRISPR-Cas9, and the effects on proliferation, invasion and metabolism (respirometry, intracellular lactate) were determined. Loss of STAT3 was associated with decreased basal and compensatory glycolysis in canine OS cell lines, without modulation of cellular proliferation. Loss of STAT3 also resulted in diminished invasive capacity in vitro. Interestingly, the absence of STAT3 did not impact sensitivity to doxorubicin in vitro. Our data demonstrate that loss of STAT3 modulates features of aerobic glycolysis in canine OS impacting capacities for cellular invasions, suggesting a role for this transcription factor in metastasis., (© 2022 The Authors. Veterinary and Comparative Oncology published by John Wiley & Sons Ltd.)

A focus on implementing social and emotional (SE) learning into curricula continues to gain popularity in K-12 educational contexts at the policy and practitioner levels. As it continues to be elevated in educational discourse, it becomes increasingly clear that it is important to have reliable, validated measures of students' SE skills. Here we argue that framework and design are additional important considerations for the development and selection of SE skill assessments. We report the reliability and validity evidence for The Mosaic™ by ACT ® Social Emotional Learning Assessment, an assessment designed to measure SE skills in middle and high school students that makes use of a research-based framework (the Big Five) and a multi-method approach (three item types including Likert, forced choice, and situational judgment tests). Here, we provide the results from data collected from more than 33,000 students who completed the assessment and for whom we have data on various outcome measures. We examined the validity evidence for the individual item types and the aggregate scores based on those three. Our findings support the contribution of multi-method assessment and an aggregate score. We discuss the ways the field can benefit from this or similarly designed assessments and discuss how the assessment results can be used by practitioners to promote programs aimed at stimulating students' personal growth.

The advent of dose intensified interval compressed therapy has improved event-free survival for patients with localized Ewing sarcoma (EwS) to 78% at 5 years. However, nearly a quarter of patients with localized tumors and 60-80% of patients with metastatic tumors suffer relapse and die of disease. In addition, those who survive are often left with debilitating late effects. Clinical features aside from stage have proven inadequate to meaningfully classify patients for risk-stratified therapy. Therefore, there is a critical need to develop approaches to risk stratify patients with EwS based on molecular features. Over the past decade, new technology has enabled the study of multiple molecular biomarkers in EwS. Preliminary evidence requiring validation supports copy number changes, and loss of function mutations in tumor suppressor genes as biomarkers of outcome in EwS. Initial studies of circulating tumor DNA demonstrated that diagnostic ctDNA burden and ctDNA clearance during induction are also associated with outcome. In addition, fusion partner should be a pre-requisite for enrollment on EwS clinical trials, and the fusion type and structure require further study to determine prognostic impact. These emerging biomarkers represent a new horizon in our understanding of disease risk and will enable future efforts to develop risk-adapted treatment., (© 2022. The Author(s).)

Desmoplastic small round cell tumor (DSRCT) is a rare pediatric sarcoma with poor overall survival. This tumor is absolutely dependent on the continued expression and activity of its defining molecular lesion, the EWS-WT1 transcription factor. Unfortunately, the therapeutic targeting of transcription factors is challenging, and there is a critical need to identify compounds that inhibit EWS-WT1. Here we show that the compound lurbinectedin inhibits EWS-WT1 by redistributing the protein within the nucleus to the nucleolus. This nucleolar redistribution interferes with the activity of EWS-WT1 to reverse the expression of over 70% of the transcriptome. In addition, the compound blocks the expression of the EWS-WT1 fusion protein to inhibit cell proliferation at the lowest GI50 ever reported for this compound in any cell type. The effects occur at concentrations that are easily achievable in the clinic and translate to the in vivo setting to cause tumor regressions in multiple mice in a xenograft and PDX model of DSRCT. Importantly, this mechanism of nucleolar redistribution is also seen with wild-type EWSR1 and the related fusion protein EWS-FLI1. This provides evidence for a "class effect" for the more than 18 tumors driven by EWSR1 fusion proteins. More importantly, the data establish lurbinectedin as a promising clinical candidate for DSRCT., (©2022 American Association for Cancer Research.)

Objective: The objective of this study is to report disease outcomes and toxicity with the use of stereotactic body radiation therapy (SBRT) in the treatment of pediatric metastatic disease., Methods: All pediatric and adolescent young adult (AYA) patients' who received SBRT were included between the years 2000 and 2020. Study endpoints included local control (LC), progression-free survival (PFS), overall survival (OS), cumulative incidence (CI) of death or local failure and toxicity. The end points with respect to survival and LC were calculated using the Kaplan-Meier estimate. The cumulative incidence of local failure was calculated using death as a competing risk., Results: 16 patients with 36 lesions irradiated met inclusion criteria and formed the study cohort. The median OS and PFS for the entire cohort were 17 months and 15.7 months, respectively. The 1 year OS for the entire cohort was 75%. The 6- and 12 month local control was 85 and 78%, respectively. There were no local failures in irradiated lesions for patients who received a BED 10 ≥100 Gy. Patients who were treated with SBRT who had ≤5 metastatic lesions at first recurrence had a superior 1 year OS of 100  vs 50% for those with >5 lesions. One patient (6.3%) experienced a Grade 3 central nervous system toxicity., Conclusion: LC was excellent with SBRT delivered to metastatic disease, particularly for lesions receiving a BED 10 ≥100 Gy. High-grade toxicity was rare in our patient population. Patients with five or fewer metastatic sites have a significantly better OS compared to >5 sites., Advances in Knowledge: This study demonstrates that SBRT is safe and efficacious in the treatment of pediatric oligometastatic disease.

Principal Component Metrics is a novel theoretically-based and data-driven methodology that enables the evaluation of the internal structure at item level of maximum emotional intelligence tests. This method disentangles interindividual differences in emotional ability from acquiescent and extreme responding. Principal Component Metrics are applied to existing (Mayer-Salovey-Caruso Emotional Intelligence Test) and assembled (specifically, the Situational Test of Emotion Understanding, the Situational Test of Emotion Management, and the Geneva Emotion Recognition Test) emotional intelligence test batteries in an analysis of three samples (total N = 2,303 participants). In undertaking these analyses important aspects of the nomological network of emotional intelligence, acquiescent, and extreme responding are investigated. The current study adds a central piece of empirical validity evidence to the emotional intelligence domain. In the three different samples, theoretically predicted internal structures at item level were found using raw item scores. The validity of the indicators for emotional intelligence, acquiescent, and extreme responding was confirmed by their relationships across emotional intelligence tests and by their nomological networks. The current findings contribute to evaluating the efficacy of the emotional intelligence construct as well as the validity evidence surrounding the instruments that are currently designed for its assessment, in the process opening new perspectives for analyzing existing and constructing new emotional intelligence tests., Competing Interests: RR was employed by RAD Science Solution. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fontaine, Sekwena, Veirman, Schlegel, MacCann, Roberts and Scherer.)

Adults experiencing homelessness smoke conventional cigarettes and engage in concurrent tobacco product use at very high rates; however, little is known about how use patterns, perceived disease risk, barriers to quitting smoking, and smoking cessation intervention preferences differ by sex in this group. Participants comprised a convenience sample of 626 adult conventional cigarette smokers experiencing homelessness. Participants self-reported their sex, smoking history, mental health and substance use diagnosis history, other concurrent tobacco product use (CU), disease risk perceptions, perceived barriers to quitting smoking, and preferences regarding tobacco cessation interventions via a computer-administered survey. CU rates were 58.1% amongst men and 45.3% amongst women smokers. In both sexes, CUs started smoking earlier (p-values < 0.001) and were more likely to have been diagnosed with a non-nicotine substance use disorder (p-values < 0.014) relative to cigarette-only users. Among men only, CUs were younger, smoked more cigarettes per day and were more likely to identify as non-Hispanic White (p-values < 0.003) than cigarette-only users. Additionally, male CUs reported a greater risk of developing ≥1 smoking-related disease if they did not quit for good; were more likely to endorse craving cigarettes, being around other smokers, habit, stress/mood swings, and coping with life stress as barriers for quitting smoking; and were less likely to prefer medications to quit smoking relative to male cigarette-only users (p-values < 0.04). On the other hand, female CUs reported a greater risk of developing ≥1 smoking-related disease even if they quit for good; were more likely to endorse stress/mood swings and coping with life stress as barriers for quitting smoking relative to female cigarette-only users (p-values < 0.05); and did not differentially prefer one cessation medication over another. Overall, findings confirm high rates of CU among both sexes, characterize those who may be more likely to be CUs, and reveal opportunities to educate men and women experiencing homeless on the benefits of evidence-based interventions for smoking cessation.

This case report describes an 18-year-old woman with an unusual epithelioid tumor of the omentum with a novel PRRC2B-ALK fusion. Although the atypical pathologic features raised significant diagnostic challenges, expression of CD30 on tumor cells and detection of an ALK rearrangement provided critical information for selecting targeted therapy in a patient not suitable for surgical resection. Despite an initially promising therapeutic response, the patient died. The efficacy of treatment was confirmed by the lack of viable tumor cells at autopsy. This case highlights the role of timely targeted therapy in patients with rare tumors and novel actionable molecular targets.

Osteosarcoma is the most common bone tumor in children and young adults. Metastatic and relapsed disease confer poor prognosis, and there have been no improvements in outcomes for several decades. The disease's biological complexity, lack of drugs developed specifically for osteosarcoma, imperfect preclinical models, and limits of existing clinical trial designs have contributed to lack of progress. The Children's Oncology Group Bone Tumor Committee established the New Agents for Osteosarcoma Task Force to identify and prioritize agents for inclusion in clinical trials. The group identified multitargeted tyrosine kinase inhibitors, immunotherapies targeting B7-H3, CD47-SIRPα inhibitors, telaglenastat, and epigenetic modifiers as the top agents of interest. Only multitargeted tyrosine kinase inhibitors met all criteria for frontline evaluation and have already been incorporated into an upcoming phase III study concept. The task force will continue to reassess identified agents of interest as new data become available and evaluate novel agents using this method., (© 2021 Wiley Periodicals LLC.)

Osteosarcoma remains one of the deadliest cancers in pediatrics and young adults. We administered two types of immunotherapies, oncolytic virotherapy and immune checkpoint inhibition, to two murine osteosarcoma models and observed divergent results. Mice bearing F420 showed no response, whereas those with K7M2 showed prolonged survival in response to combination therapy. K7M2 had higher expression of immune-related genes and higher baseline immune cell infiltrates, but there were no significant differences in tumor mutational burden or predicted MHC class I binding of nonsynonymous mutations. Instead, we found several mouse endogenous retrovirus sequences highly expressed in K7M2 compared with F420. T cell tetramer staining for one of them, gp70, was detected in mice with K7M2 but not F420, suggesting that endogenous retrovirus proteins are targets for the anti-tumor immune reaction. Given prior observations of endogenous retrovirus expression in human osteosarcomas, our findings may be translatable to human disease., (© 2021 The Authors.)

Atypical facial morphology, particularly increased facial asymmetry, has been identified in some individuals with Autism Spectrum Conditions (ASC). Many cognitive, behavioural and biological features associated with ASC also occur on a continuum in the general population. The aim of the present study was to examine subthreshold levels of autistic traits and facial morphology in non-autistic individuals. Facial asymmetry was measured using three-dimensional facial photogrammetry, and the Autism-spectrum Quotient was used to measure autistic-like traits in a community-ascertained sample of young adults (n = 289). After accounting for covariates, there were no significant associations observed between autistic-like traits and facial asymmetry, suggesting that any potential facial morphology differences linked to ASC may be limited to the clinical condition.

Background: Several studies have explored relationships between parent broader autism phenotype and offspring communication, and have reported that autistic-like traits in parents are related to offspring communication difficulties and autism severity. However, past research has focused on studying such associations in childhood and we know very little about them in infancy. With accumulating evidence that interventions administered during infancy may be most effective in reducing ASD symptoms, it is imperative to examine whether relationships between parent autistic-like traits and child communication appear even earlier during this critical period of life., Method: This longitudinal study collected data from infant siblings of autistic children (N = 32) and infants with no family history of autism (N = 45) to explore how autistic-like traits in parents related to child developmental outcomes during infancy., Results: Parental communication difficulties and autistic-like traits were found to be associated with a range of child behaviours in the first two years of life, including social-emotional difficulties at 6 and 24 months, lower communication and emerging cognition at 24 months, and increased autistic behaviours at 24 months., Conclusions: Based on the results, it appears that some of the difficulties seen in parents are relayed to children genetically. These findings contribute to ASD research concerning early communication development in children and heritability of ASD traits and may have important implications in monitoring child development. Furthermore, since the current study found a significant association between autistic traits in parents and child social-emotional behaviour as early as 6 months of age, it provides evidence of the value of assessing interventions that target infancy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The objectives of this study were to investigate the HRQoL of residents living in central urban areas (CUA) and developing neighborhoods (DN) areas of North-China and to examine the relationship between health conditions and the physical and mental components of quality of life., Methods: A stratified random sample was taken and health survey scoring system questionnaire SF-36 was used to conduct the HRQoL survey among community residents in the two selected districts in 10 cities. A general questionnaire was also administered with questions that collected general information, population demographic characteristics and health behaviours, social relationships and perception of life satisfaction., Results: Five thousand eight hundred eighty-one questionnaires were returned from 6059 invitations with a effective response rate of 97%. The residents in DN had a higher score of physical function, role limitation due to physical problems and vitality than those living in CUA. The prevalence of several chronic diseases was lower in DN's residents than CUA's residents. Age, presence/absence of chronic diseases, leisure time exercise, regular daily routine, sleep quality, appetite, family and social relationships and life satisfaction were significant determinants of HRQoL., Conclusions: Residents living in newly developed neighborhoods in China while keeping some habits and lifestyles of their original rural communities are healthier in terms of chronic diseases and HRQoL. Together with other risk factors chronic diseases are an important determinant on HRQoL. Several healthy habits and behaviors such as having a regular daily routine and exercising during leisure time improved HRQoL in Chinese urban communities. Targeted policies of public health based on these findings can better the health-related quality of life.

This article describes (a) the origins of, (b) rationale underlying, and (c) preliminary validity evidence for, a new ability measure of emotional understanding (EU), a major component of emotional intelligence. A novel conceptual approach-the empathic agent paradigm (EAP)-provided the theoretical foundation. The EAP results in a veridical, logically defensible scoring key, a major development for the assessment of EI, which otherwise has relied on less defensible approaches. Validity evidence for test score interpretations of the Empathic Agent Paradigm Test (EAPT) was subsequently obtained in two studies. In Study 1, participants ( N = 321) completed the EAPT (α = .72 at testlet level), along with measures of classical intelligence, the Big Five personality traits, and a situational judgment measure of EU. This study provides factorial, convergent, and discriminant validity evidence for EAPT test score interpretations. In Study 2 ( N = 158), an important assumption about the response processes in the EAPT was verified experimentally, in the process providing further validity evidence for test score interpretations. In sum, findings suggest that the EAPT is a promising new maximum performance measure for the assessment of EU. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Forced choice (FC) measures may be a desirable alternative to single stimulus (SS) Likert items, which are easier to fake and can have associated response biases. However, classical methods of scoring FC measures lead to ipsative data, which have a number of psychometric problems. A Thurstonian item response theory (TIRT) model has been introduced as a way to overcome these issues, but few empirical validity studies have been conducted to ensure its effectiveness. This was the goal of the current three studies, which used FC measures of domains from popular personality frameworks including the Big Five and HEXACO, and both statement and adjective item stems. We computed TIRT and ipsative scores and compared their validity estimates. Convergent and discriminant validity of the scores were evaluated by correlating them with SS scores, and test-criterion validity evidence was evaluated by examining their relationships with meaningful outcomes. In all three studies, there was evidence for the convergent and test-criterion validity of the TIRT scores, though at times this was on par with the validity of the ipsative scores. The discriminant validity of the TIRT scores was problematic and was often worse than the ipsative scores.

Ewing sarcoma (EWS) is the second most common and aggressive type of metastatic bone tumor in adolescents and young adults. There is unmet medical need to develop and test novel pharmacological targets and novel therapies to treat EWS. Here, we found that EWS expresses high levels of a p53 isoform, delta133p53. We further determined that aberrant expression of delta133p53 induced HGF secretion resulting in tumor growth and metastasis. Thereafter, we evaluated targeting EWS tumors with HGF receptor neutralizing antibody (AMG102) in preclinical studies. Surprisingly, we found that targeting EWS tumors with HGF receptor neutralizing antibody (AMG102) in combination with GD2-specific, CAR-reengineered T-cell therapy synergistically inhibited primary tumor growth and establishment of metastatic disease in preclinical models. Furthermore, our data suggested that AMG102 treatment alone might increase leukocyte infiltration including efficient CAR-T access into tumor mass and thereby improves its antitumor activity. Together, our findings warrant the development of novel CAR-T-cell therapies that incorporate HGF receptor neutralizing antibody to improve therapeutic potency, not only in EWS but also in tumors with aberrant activation of the HGF/c-MET pathway., (© 2019 UICC.)

Background: About 80% of children with steroid-sensitive nephrotic syndrome (SSNS) have relapses. Of these children, half relapse frequently, and are at risk of adverse effects from corticosteroids. While non-corticosteroid immunosuppressive medications prolong periods of remission, they have significant potential adverse effects. Currently, there is no consensus about the most appropriate second-line agent in children who are steroid sensitive, but who continue to relapse. In addition, these medications could be used with corticosteroids in the initial episode of SSNS to prolong the period of remission. This is the fourth update of a review first published in 2001 and updated in 2005, 2008 and 2013., Objectives: To evaluate the benefits and harms of non-corticosteroid immunosuppressive medications in SSNS in children with a relapsing course of SSNS and in children with their first episode of nephrotic syndrome., Search Methods: We searched the Cochrane Kidney and Transplant Register of Studies up to 10 March 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov., Selection Criteria: Randomised controlled trials (RCTs) or quasi-RCTs were included if they involved children with SSNS and compared non-corticosteroid immunosuppressive medications with placebo, corticosteroids (prednisone or prednisolone) or no treatment; compared different non-corticosteroid immunosuppressive medications or different doses, durations or routes of administration of the same non-corticosteroid immunosuppressive medication., Data Collection and Analysis: Two authors independently assessed study eligibility, risk of bias of the included studies and extracted data. Statistical analyses were performed using a random-effects model and results expressed as risk ratio (RR) for dichotomous outcomes or mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). The certainty of the evidence was assessed using GRADE., Main Results: We identified 43 studies (91 reports) and included data from 2428 children. Risk of bias assessment indicated that 21 and 24 studies were at low risk of bias for sequence generation and allocation concealment respectively. Nine studies were at low risk of performance bias and 10 were at low risk of detection bias. Thirty-seven and 27 studies were at low risk of incomplete and selective reporting respectively. Rituximab (in combination with calcineurin inhibitors (CNI) and prednisolone) versus CNI and prednisolone probably reduces the number of children who relapse at six months (5 studies, 269 children: RR 0.23, 95% CI 0.12 to 0.43) and 12 months (3 studies, 198 children: RR 0.63, 95% CI 0.42 to 0.93) (moderate certainty evidence). At six months, rituximab resulted in 126 children/1000 relapsing compared with 548 children/1000 treated with conservative treatments. Rituximab may result in infusion reactions (4 studies, 252 children: RR 5.83, 95% CI 1.34 to 25.29). Mycophenolate mofetil (MMF) and levamisole may have similar effects on the number of children who relapse at 12 months (1 study, 149 children: RR 0.90, 95% CI 0.70 to 1.16). MMF may have a similar effect on the number of children relapsing compared to cyclosporin (2 studies, 82 children: RR 1.90, 95% CI 0.66 to 5.46) (low certainty evidence). MMF compared to cyclosporin is probably less likely to result in hypertrichosis (3 studies, 140 children: RR 0.23, 95% CI 0.10 to 0.50) and gum hypertrophy (3 studies, 144 children: RR 0.09, 95% CI 0.07 to 0.42) (low certainty evidence). Levamisole compared with steroids or placebo may reduce the number of children with relapse during treatment (8 studies, 474 children: RR 0.52, 95% CI 0.33 to 0.82) (low certainty evidence). Levamisole compared to cyclophosphamide may make little or no difference to the risk for relapse after 6 to 9 months (2 studies, 97 children: RR 1.17, 95% CI 0.76 to 1.81) (low certainty evidence). Cyclosporin compared with prednisolone may reduce the number of children who relapse (1 study, 104 children: RR 0.33, 95% CI 0.13 to 0.83) (low certainty evidence). Alkylating agents compared with cyclosporin may make little or no difference to the risk of relapse during cyclosporin treatment (2 studies, 95 children: RR 0.91, 95% CI 0.55 to 1.48) (low certainty evidence) but may reduce the risk of relapse at 12 to 24 months (2 studies, 95 children: RR 0.51, 95% CI 0.35 to 0.74), suggesting that the benefit of the alkylating agents may be sustained beyond the on-treatment period (low certainty evidence). Alkylating agents (cyclophosphamide and chlorambucil) compared with prednisone probably reduce the number of children, who experience relapse at six to 12 months (6 studies, 202 children: RR 0.44, 95% CI 0.32 to 0.60) and at 12 to 24 months (4 studies, 59 children: RR 0.20, 95% CI 0.09 to 0.46) (moderate certainty evidence). IV cyclophosphamide may reduce the number of children with relapse compared with oral cyclophosphamide at 6 months (2 studies, 83 children: RR 0.54, 95% CI 0.34 to 0.88), but not at 12 to 24 months (2 studies, 83 children: RR 0.99, 95% CI 0.76 to 1.29) and may result in fewer infections (2 studies, 83 children: RR 0.14, 95% CI 0.03 to 0.72) (low certainty evidence). Cyclophosphamide compared to chlorambucil may make little or no difference in the risk of relapse after 12 months (1 study, 50 children: RR 1.31, 95% CI 0.80 to 2.13) (low certainty evidence)., Authors' Conclusions: New studies incorporated in this review indicate that rituximab is a valuable additional agent for managing children with steroid-dependent nephrotic syndrome. However, the treatment effect is temporary, and many children will require additional courses of rituximab. The long-term adverse effects of this treatment are not known. Comparative studies of CNIs, MMF, levamisole and alkylating agents have demonstrated little or no differences in efficacy but, because of insufficient power; clinically important differences in treatment effects have not been completely excluded., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Roughness perception through fingertip contact with a textured surface can involve spatial and temporal cues from skin indentation and vibration respectively. Both types of cue may be affected by contact forces when feeling a surface and we ask whether, on a given trial, discrimination performance relates to contact forces. We examine roughness discrimination performance in a standard psychophysical method (2-interval forced choice, in which the participant identifies which of two spatial textures formed by parallel grooves feels rougher) while continuously measuring the normal and tangential forces applied by the index finger. Fourteen participants discriminated spatial gratings in fine (spatial period of 320-580 micron) and coarse (1520-1920 micron) ranges using static pressing or sliding contact of the index finger. Normal contact force (mean and variability) during pressing or sliding had relatively little impact on accuracy of roughness judgments except when pressing on surfaces in the coarse range. Discrimination was better for sliding than pressing in the fine but not the coarse range. In contrast, tangential force fluctuations during sliding were strongly related to roughness judgment accuracy.