Irinotecan and temozolomide in combination with dasatinib and rapamycin versus irinotecan and temozolomide for patients with relapsed or refractory neuroblastoma (RIST-rNB-2011): a multicentre, open-label, randomised, controlled, phase 2 trial.

BACKGROUND: Neuroblastoma is the most common extracranial solid tumour in children. Relapsed or refractory neuroblastoma is associated with a poor outcome. We assessed the combination of irinotecan-temozolomide and dasatinib-rapamycin (RIST) in patients with relapsed or refractory neuroblastoma. METHODS: The multicentre, open-label, randomised, controlled, phase 2, RIST-rNB-2011 trial recruited from 40 paediatric oncology centres in Germany and Austria. Patients aged 1-25 years with high-risk relapsed (defined as recurrence of all stage IV and MYCN amplification stages, after response to treatment) or refractory (progressive disease during primary treatment) neuroblastoma, with Lansky and Karnofsky performance status at least 50%, were assigned (1:1) to RIST (RIST group) or irinotecan-temozolomide (control group) by block randomisation, stratified by MYCN status. We compared RIST (oral rapamycin [loading 3 mg/m2 on day 1, maintenance 1 mg/m2 on days 2-4] and oral dasatinib [2 mg/kg per day] for 4 days with 3 days off, followed by intravenous irinotecan [50 mg/m2 per day] and oral temozolomide [150 mg/m2 per day] for 5 days with 2 days off; one course each of rapamycin-dasatinib and irinotecan-temozolomide for four cycles over 8 weeks, then two courses of rapamycin-dasatinib followed by one course of irinotecan-temozolomide for 12 weeks) with irinotecan-temozolomide alone (with identical dosing as experimental group). The primary endpoint of progression-free survival was analysed in all eligible patients who received at least one course of therapy. The safety population consisted of all patients who received at least one course of therapy and had at least one post-baseline safety assessment. This trial is registered at ClinicalTrials.gov, NCT01467986, and is closed to accrual. FINDINGS: Between Aug 26, 2013, and Sept 21, 2020, 129 patients were randomly assigned to the RIST group (n=63) or control group (n=66). Median age was 5·4 years (IQR 3·7-8·1). 124 patients (78 [63%] male and 46 [37%] female) were included in the efficacy analysis. At a median follow-up of 72 months (IQR 31-88), the median progression-free survival was 11 months (95% CI 7-17) in the RIST group and 5 months (2-8) in the control group (hazard ratio 0·62, one-sided 90% CI 0·81; p=0·019). Median progression-free survival in patients with amplified MYCN (n=48) was 6 months (95% CI 4-24) in the RIST group versus 2 months (2-5) in the control group (HR 0·45 [95% CI 0·24-0·84], p=0·012); median progression-free survival in patients without amplified MYCN (n=76) was 14 months (95% CI 9-7) in the RIST group versus 8 months (4-15) in the control group (HR 0·84 [95% CI 0·51-1·38], p=0·49). The most common grade 3 or worse adverse events were neutropenia (54 [81%] of 67 patients given RIST vs 49 [82%] of 60 patients given control), thrombocytopenia (45 [67%] vs 41 [68%]), and anaemia (39 [58%] vs 38 [63%]). Nine serious treatment-related adverse events were reported (five patients given control and four patients given RIST). There were no treatment-related deaths in the control group and one in the RIST group (multiorgan failure). INTERPRETATION: RIST-rNB-2011 demonstrated that targeting of MYCN-amplified relapsed or refractory neuroblastoma with a pathway-directed metronomic combination of a multkinase inhibitor and an mTOR inhibitor can improve progression-free survival and overall survival. This exclusive efficacy in MYCN-amplified, relapsed neuroblastoma warrants further investigation in the first-line setting. FUNDING: Deutsche Krebshilfe.

Analysis of self-reported activities of daily living, motor performance and physical activity among children and adolescents with cancer: Baseline data from a randomised controlled trial assessed shortly after diagnosis of leukaemia or non-Hodgkin lymphoma.

OBJECTIVE: Cancer diagnosis, treatment side effects and physical inactivity can lead to reduced muscle strength. Patients undergoing acute treatment experience many burdens that can restrict their mobility and autonomy, leading to limited independence and loss of resources to cope with everyday tasks. In this work, we analyse the status quo and potential influencing factors for the accomplishment of activities of daily living (ADLs) shortly after cancer diagnosis. METHODS: We recruited participants ages 4-18 years diagnosed with acute leukaemia or non-Hodgkin lymphoma. For the baseline analysis, we assessed (1) physical function limitations using the Activities Scale for Kids©, (2) exercise-related ADLs simulated with the Functional ADL Screen, (3) motor performance using the Motor Performance in Paediatric Oncology test and (4) physical activity (PA) level measured using an accelerometer. RESULTS: We conducted the baseline assessment 19.2 ± 12.6 days post-diagnosis in 41 patients. All participants reported functional limitations in ADLs and PA. Motor performance was reduced for all abilities. Cumulative steroid dose was negatively correlated with hand grip strength (r = -0.50, p = 0.009). CONCLUSION: Shortly after diagnosis of paediatric cancer, patients experience various physical impairments that can be counteracted with regular, instructed exercise interventions.

Allogeneic hematopoietic stem cell transplantation from unrelated donors is associated with higher infection rates in children with acute lymphoblastic leukemia-A prospective international multicenter trial on behalf of the BFM-SG and the EBMT-PDWP.

Severe infections (SI) significantly impact on non-relapse mortality after hematopoietic stem cell transplantation (HSCT). We assessed 432 children and adolescents with acute lymphoblastic leukemia (ALL) after total body irradiation based myeloablative HSCT within the multicenter ALL-BFM-SCT 2003 trial for SI grade 3 or higher according to common terminology criteria for adverse events. A total 172 patients experienced at least one SI. Transplantation from matched unrelated donors (MUD) was associated with any type of SI in the pre-engraftment period (hazard ratio [HR]: 2.57; P < .001), and with any SI between day +30 and + 100 (HR: 2.91; P = .011). Bacterial (HR: 2.24; P = .041) and fungal infections (HR: 4.06; P = .057) occurred more often in the pre-engraftment phase and viral infections more often before day +30 (HR: 2.66; P = .007) or between day +30 and + 100 (HR: 3.89; P = .002) after HSCT from MUD as compared to matched sibling donors. Chronic GvHD was an independent risk factor for any type of SI after day +100 (HR: 2.57; P < .002). We conclude that allogeneic HSCT from MUD in children and adolescents with pediatric ALL is associated with higher infection rates, which seems attributable to an intensified GvHD prophylaxis including serotherapy and methotrexate.

Outcome of relapse after allogeneic HSCT in children with ALL enrolled in the ALL-SCT 2003/2007 trial.

Relapse remains the major cause of treatment failure in children with high-risk acute lymphoblastic leukaemia (ALL) undergoing allogeneic haematopoietic stem-cell transplantation (allo-SCT). Prognosis is considered dismal but data on risk factors and outcome are lacking from prospective studies. We analysed 242 children with recurrence of ALL after first allo-SCT enrolled in the Berlin-Frankfurt-Munster (BFM) ALL-SCT-BFM 2003 and ALL-SCT-BFM international 2007 studies. Median time from allo-SCT to relapse was 7·7 months; median follow-up from relapse after allo-SCT until last follow-up was 3·4 years. The 3-year event-free survival (EFS) was 15% and overall survival (OS) was 20%. The main cause of death was disease progression or relapse (86·5%). The majority of children (48%) received salvage therapy without second allo-SCT, 26% of the children underwent a second allo-SCT and 25% received palliative treatment only. In multivariate analyses, age, site of relapse, time to relapse and type of salvage therapy were identified as significant prognostic factors for OS and EFS, whereas factors associated with first SCT were not statistically significant. Combined approaches incorporating novel immunotherapeutic treatment options and second allo-SCT hold promise to improve outcome in children with post allo-SCT relapse.

Impact of Pathological Fractures on the Prognosis of Primary Malignant Bone Sarcoma in Children and Adults: A Single-Center Retrospective Study of 205 Patients.

BACKGROUND: The purpose of this study was to investigate whether pathological fractures (PF) influence the prognosis of patients with osteosarcoma (OS) or Ewing tumor (ET) regarding 5-year survival, occurrence of metastases, and local recurrence. METHODS: We retrospectively analyzed 205 patients with metastatic and nonmetastatic OS or ET. Survival analysis was performed for all patients and differentiated for patients with OS (n = 127) and ET (n = 78) as well as for adults (n = 101) and children (n = 104). RESULTS: Patients with PF showed survival rates of 64% compared to 83% for those without PF (p = 0.023). Local recurrence occurred in 7% of the patients without and in 24% of those with PF (p = 0.023). In patients with ET and in children, survival analysis showed no significant difference between patients with and without PF in survival and local recurrence rates. In patients with OS, survival rate decreased from 83 to 59% (p = 0.024) and local recurrence rate increased from 13 to 30% (p = 0.042). In adults, survival rate decreased from 78 to 51% (p = 0.004) and local recurrence rate increased from 13 to 42% (p < 0.001). In multivariate analysis, age and PF were associated with inferior survival. CONCLUSION: This study suggests that the occurrence of PF has a negative impact on survival and implicates an increased risk of local recurrence. In children and in patients with ET, PF did not have a prognostic impact.

Genome-wide analysis of somatic copy number alterations and chromosomal breakages in osteosarcoma.

Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. It is characterized by highly complex karyotypes with structural and numerical chromosomal alterations. The observed OS-specific characteristics in localization and frequencies of chromosomal breakages strongly implicate a specific set of responsible driver genes or a specific mechanism of fragility induction. In this study, a comprehensive assessment of somatic copy number alterations (SCNAs) was performed in 160 OS samples using whole-genome CytoScan High Density arrays (Affymetrix, Santa Clara, CA). Genes or regions frequently targeted by SCNAs were identified. Breakage analysis revealed OS specific unstable regions in which well-known OS tumor suppressor genes, including TP53, RB1, WWOX, DLG2 and LSAMP are located. Certain genomic features, such as transposable elements and non-B DNA-forming motifs were found to be significantly enriched in the vicinity of chromosomal breakage sites. A complex breakage pattern-chromothripsis-has been suggested as a widespread phenomenon in OS. It was further demonstrated that hyperploidy and in particular chromothripsis were strongly correlated with OS patient clinical outcome. The revealed OS-specific fragility pattern provides novel clues for understanding the biology of OS.

Mesenchymal stromal cells from pooled mononuclear cells of multiple bone marrow donors as rescue therapy in pediatric severe steroid-refractory graft-versus-host disease: a multicenter survey.

To circumvent donor-to-donor heterogeneity which may lead to inconsistent results after treatment of acute graft-versus-host disease with mesenchymal stromal cells generated from single donors we developed a novel approach by generating these cells from pooled bone marrow mononuclear cells of 8 healthy "3(rd)-party" donors. Generated cells were frozen in 209 vials and designated as mesenchymal stromal cell bank. These vials served as a source for generation of clinical grade mesenchymal stromal cell end-products, which exhibited typical mesenchymal stromal cell phenotype, trilineage differentiation potential and at later passages expressed replicative senescence-related markers (p21 and p16). Genetic analysis demonstrated their genomic stability (normal karyotype and a diploid pattern). Importantly, clinical end-products exerted a significantly higher allosuppressive potential than the mean allosuppressive potential of mesenchymal stromal cells generated from the same donors individually. Administration of 81 mesenchymal stromal cell end-products to 26 patients with severe steroid-resistant acute graft-versus-host disease in 7 stem cell transplant centers who were refractory to many lines of treatment, induced a 77% overall response at the primary end point (day 28). Remarkably, although the cohort of patients was highly challenging (96% grade III/IV and only 4% grade II graft-versus-host disease), after treatment with mesenchymal stromal cell end-products the overall survival rate at two years follow up was 71±11% for the entire patient cohort, compared to 51.4±9.0% in graft-versus-host disease clinical studies, in which mesenchymal stromal cells were derived from single donors. Mesenchymal stromal cell end-products may, therefore, provide a novel therapeutic tool for the effective treatment of severe acute graft-versus-host disease.

Effect of a single autologous cord blood infusion on beta-cell and immune function in children with new onset type 1 diabetes: a non-randomized, controlled trial.

BACKGROUND: The application of autologous cord blood in children with type 1 diabetes has been found to be safe, but not to preserve beta-cell function in a previous study, which, however, had not included a control group. OBJECTIVE: To compare the changes of metabolic and immune function over time between cord blood infused children and natural controls. SUBJECTS AND METHODS: Seven children with newly diagnosed type 1 diabetes underwent a single autologous cord blood infusion and 10 children were enrolled as natural controls in a non-randomized, controlled, open label intervention trial. Primary analyses were performed 1 year following cord blood infusion. Cases and controls were compared regarding metabolic [area under the curve (AUC) and peak C-peptide, insulin use, and HbA1c] and immune outcome (islet autoantibody titer and T-cell response), adjusted for age, gender, diabetes duration, and baseline levels. RESULTS: There were no significant adverse events related to the infusion. Metabolic and immune outcomes were not significantly different at 12 months follow-up between infused children and controls (e.g., adjusted p = 0.244 for AUC C-peptide, adjusted p = 0.820 for insulin use, adjusted p = 0.772 for peripheral regulatory T cells). Six-month change of AUC C-peptide correlated significantly with the number of infused CD34+ cells (r = 0.931, p = 0.002). CONCLUSIONS: An autologous cord blood infusion does not change the natural course of metabolic and immune parameters after disease onset. However, the content of CD34+ cells in the stored blood sample might offer potential for improvement of future cell therapies.

First identification of Ewing's sarcoma-derived extracellular vesicles and exploration of their biological and potential diagnostic implications.

BACKGROUND INFORMATION: Exosomes are small RNA- and protein-containing extracellular vesicles (EVs) that are thought to mediate hetero- and homotypic intercellular communication between normal and malignant cells.Tumour-derived exosomes are believed to promote re-programming of the tumour-associated stroma to favour tumour growth and metastasis. Currently, exosomes have been intensively studied in carcinomas. However, little is known about their existence and possible role in sarcomas. RESULTS: Here, we report on the identification of vesicles with exosomal features derived from Ewing's sarcoma(ES), the second most common soft-tissue or bone cancer in children and adolescents. ES cell line-derived EV shave been isolated by ultracentrifugation and analysed by flow-cytometric assessment of the exosome-associated proteins CD63 and CD81 as well as by electron microscopy. They proved to contain ES-specific transcripts including EWS-FLI1, which were suitable for the sensitive detection of ES cell line-derived exosomes by qRT-PCRin a pre-clinical model for patient plasma. Microarray analysis of ES cell line-derived exosomes revealed that they share a common transcriptional signature potentially involved in G-protein-coupled signalling, neurotransmitter signalling and stemness. CONCLUSIONS: In summary, our results imply that ES-derived exosomes could eventually serve as biomarkers for minimal residual disease diagnostics in peripheral blood and prompt further investigation of their potential biological role in modification of the ES-associated microenvironment

Availability and adaption of exercise programs in pediatric oncology during the COVID-19 pandemic and beyond: a nationwide follow-up survey of providers in Germany.

Background: The COVID-19 pandemic has presented major challenges to clinical practice and delivery of care programs throughout all health care systems. Exercise programs, that are implemented in most centers for pediatric oncology in Germany, are a relatively new care program however with high clinical impact and health benefits. Objective: The impact and consequences of the pandemic on the delivery and availability of exercise programs in Germany for pediatric cancer patients and survivors are unknown. A national survey analyzed restrictions, challenges and novel approaches of exercise program delivery and scientific research. Method: A two-stage online survey was distributed to providers of exercise programs (acute clinics, non-clinical institutions, rehabilitation facilities) via the established Network ActiveOncoKids. Data was collected during the pandemic in 2022 and 2023 using a combination of open and closed questions. Results: In total, n = 27 (response rate: 82%) and n = 17 (response rate: 63%) providers participated in the first and second survey, respectively. Findings pointed out restrictions in 85% of all exercise programs in 2020 and 2021, with slight reductions in 2022. During pandemic, restrictions with major impact arose within exercise offers during follow-up and declined gradually. Whereas restrictions within the setting of acute therapy had medium or minor impact but persisted beyond. Delivery of provided exercise programs necessitated adaptions, including digital methods, supervised interventions from a distance and change of locations. Discussion: The findings highlight the adaptability, the demand and the potential of exercise programs in pediatric oncology. We assume that exercise professionals have used the pandemic-related challenges to review and modify existing concepts and made adaptations according to local conditions and novel tools for the provision of exercise programs. Nevertheless, a conspicuous lack of exercise-related care has become evident in certain patients and survivors. Further expansion of programs is imperative to address and accommodate all pertinent needs.

Human-Level Differentiation of Medulloblastoma from Pilocytic Astrocytoma: A Real-World Multicenter Pilot Study.

Medulloblastoma and pilocytic astrocytoma are the two most common pediatric brain tumors with overlapping imaging features. In this proof-of-concept study, we investigated using a deep learning classifier trained on a multicenter data set to differentiate these tumor types. We developed a patch-based 3D-DenseNet classifier, utilizing automated tumor segmentation. Given the heterogeneity of imaging data (and available sequences), we used all individually available preoperative imaging sequences to make the model robust to varying input. We compared the classifier to diagnostic assessments by five readers with varying experience in pediatric brain tumors. Overall, we included 195 preoperative MRIs from children with medulloblastoma (n = 69) or pilocytic astrocytoma (n = 126) across six university hospitals. In the 64-patient test set, the DenseNet classifier achieved a high AUC of 0.986, correctly predicting 62/64 (97%) diagnoses. It misclassified one case of each tumor type. Human reader accuracy ranged from 100% (expert neuroradiologist) to 80% (resident). The classifier performed significantly better than relatively inexperienced readers (p < 0.05) and was on par with pediatric neuro-oncology experts. Our proof-of-concept study demonstrates a deep learning model based on automated tumor segmentation that can reliably preoperatively differentiate between medulloblastoma and pilocytic astrocytoma, even in heterogeneous data.

Strong expression of CXCL12 is associated with a favorable outcome in osteosarcoma.

Hematogenous spread determines the outcome of osteosarcoma (OS) patients, but the pathogenesis of developing metastatic disease is still unclear. Chemokines are critical regulators of cell trafficking and adhesion, and have been reported to be aberrantly expressed and to correlate with an unfavorable prognosis and metastatic spread in several malignant tumors. The chemokine receptors CXCR4 and CXCR7 together with their common ligand CXCL12 form one of the most important chemokine axes in this context. To investigate a potential role of these chemokines in OSs, we analyzed their expression in a series of 223 well-characterized and pretherapeutic OS samples. Interestingly, we found the expression of CXCL12 and CXCR4 to correlate with a better long-term outcome and with a lower prevalence of metastases. These findings suggest a distinct role of CXCR4/CXCR7/CXCL12 signaling in the tumors of bone, as has also been previously described in acute leukemia. As many malignant tumors metastasize to bone, and tumor cells are thought to be directed to bone in response to CXCL12, OS cells expressing both CXCL12 and the corresponding receptors might be detained at their site of origin. The disruption of CXCR4/CXCR7/CXCL12 signaling could therefore be crucial in OSs for the migration of tumor cells from bone into circulation and for developing systemic disease.

EZH2 is a mediator of EWS/FLI1 driven tumor growth and metastasis blocking endothelial and neuro-ectodermal differentiation.

Ewing tumors (ET) are highly malignant, localized in bone or soft tissue, and are molecularly defined by ews/ets translocations. DNA microarray analysis revealed a relationship of ET to both endothelium and fetal neural crest. We identified expression of histone methyltransferase enhancer of Zeste, Drosophila, Homolog 2 (EZH2) to be increased in ET. Suppressive activity of EZH2 maintains stemness in normal and malignant cells. Here, we found EWS/FLI1 bound to the EZH2 promoter in vivo, and induced EZH2 expression in ET and mesenchymal stem cells. Down-regulation of EZH2 by RNA interference in ET suppressed oncogenic transformation by inhibiting clonogenicity in vitro. Similarly, tumor development and metastasis was suppressed in immunodeficient Rag2(-/-)gamma(C)(-/-) mice. EZH2-mediated gene silencing was shown to be dependent on histone deacetylase (HDAC) activity. Subsequent microarray analysis of EZH2 knock down, HDAC-inhibitor treatment and confirmation in independent assays revealed an undifferentiated phenotype maintained by EZH2 in ET. EZH2 regulated stemness genes such as nerve growth factor receptor (NGFR), as well as genes involved in neuroectodermal and endothelial differentiation (EMP1, EPHB2, GFAP, and GAP43). These data suggest that EZH2 might have a central role in ET pathology by shaping the oncogenicity and stem cell phenotype of this tumor.

A Bout of High-Intensity Interval Training (HIIT) in Children and Adolescents during Acute Cancer Treatment-A Pilot Feasibility Study.

Low- and moderate-intensity exercise is safe and feasible during childhood cancer treatment. The feasibility of a bout of high-intensity interval training (HIIT) in this population has not been analyzed to date. Pediatric cancer patients aged between 6 and 18 years were selected based on clinical conditions to perform ten sets of 15 s HIIT (>90% of estimated maximal heart rate (HRmax)) and 1 min active recovery on a bicycle ergometer within the first three chemotherapy courses. We assessed safety and feasibility criteria and the following parameters: perceived exertion rate, heart rate, and lactate and adrenaline concentrations. Out of 212 eligible patients, 11 patients aged 13.9 ± 3.6 years (n = 7 ♂) with lymphoma, leukemia, rhabdomyosarcoma, nephroblastoma, and synovial sarcoma completed the bout of HIIT without serious adverse events. During exercise, patients reached a BORG value maxima of 16 ± 1.2, and their heart rates rose from 78 ± 17 beats per minute (bpm) at rest to 178 ± 12 bpm after exercise (90 ± 6% estimated HRmax). The power-to-weight ratio was 2 ± 0.5 W/kg (watt per kilogram). Blood lactate concentrations increased from 1.09 ± 0.50 mmol/L (millimole per liter) at rest to 5.05 ± 1.88 mmol/L post-exercise. Our preliminary data suggest that HIIT is applicable only in a small number of childhood cancer patients. Individually adapted exercise protocols for patients with multiple impairments are needed.

Effects of strength exercise interventions on activities of daily living, motor performance, and physical activity in children and adolescents with leukemia or non-Hodgkin lymphoma: Results from the randomized controlled ActiveADL Study.

Objectives: Pediatric patients with cancer experience impairments in muscle strength and physical activity (PA) that may reduce autonomy during hospitalization. To determine the effects of strength exercise interventions on the accomplishment of activities of daily living (ADLs), motor performance, and PA in children with leukemia or non-Hodgkin lymphoma, we randomly allocated patients (4-18 years) immediately after diagnosis into two exercise groups. Methods: The intervention group (IG; n = 21) received a specific strength training combined with a standard care exercise program, whereas the control group (CG; n = 20) was provided standard care exercise program without any targeted muscle strengthening. After the baseline visit, participants were followed-up three times until intensive treatment cessation. We assessed physical function limitations using the Activities Scale for Kids© (ASK) and Functional ADL Screen. Secondary outcomes were PA levels using accelerometer and motor performance as measured by MOON-test (motor performance in pediatric oncology-test). Results: In both groups, ADL accomplishment had significantly increased (p < 0.05). However, no significant between-group differences for ASK outcome were noted. Motor performance was reduced in all motor abilities. Conclusions: Both exercise interventions were effective to maintain ADLs and motor performance during intensive treatment. In comparison, regular strength exercise interventions in the course of therapy tended to be more beneficial with regards to muscular explosive and endurance strength.

Correlation of Transcriptomics and FDG-PET SUVmax Indicates Reciprocal Expression of Stemness-Related Transcription Factor and Neuropeptide Signaling Pathways in Glucose Metabolism of Ewing Sarcoma.

BACKGROUND: In Ewing sarcoma (EwS), long-term treatment effects and poor survival rates for relapsed or metastatic cases require individualization of therapy and the discovery of new treatment methods. Tumor glucose metabolic activity varies significantly between patients, and FDG-PET signals have been proposed as prognostic factors. However, the biological basis for the generally elevated but variable glucose metabolism in EwS is not well understood. METHODS: We retrospectively included 19 EwS samples (17 patients). Affymetrix gene expression was correlated with maximal standardized uptake value (SUVmax) using machine learning, linear regression modelling, and gene set enrichment analyses for functional annotation. RESULTS: Expression of five genes correlated (MYBL2, ELOVL2, NETO2) or anticorrelated (FAXDC2, PLSCR4) significantly with SUVmax (adjusted p-value ≤ 0.05). Additionally, we identified 23 genes with large SUVmax effect size, which were significantly enriched for "neuropeptide Y receptor activity (GO:0004983)" (adjusted p-value = 0.0007). The expression of the members of this signaling pathway (NPY, NPY1R, NPY5R) anticorrelated with SUVmax. In contrast, three transcription factors associated with maintaining stemness displayed enrichment of their target genes with higher SUVmax: RNF2, E2F family, and TCF3. CONCLUSION: Our large-scale analysis examined comprehensively the correlations between transcriptomics and tumor glucose utilization. Based on our findings, we hypothesize that stemness may be associated with increased glucose uptake, whereas neuroectodermal differentiation may anticorrelate with glucose uptake.

No Improvement of Survival for Alveolar Rhabdomyosarcoma Patients After HLA-Matched Versus -Mismatched Allogeneic Hematopoietic Stem Cell Transplantation Compared to Standard-of-Care Therapy.

Background: Patients with stage IV alveolar rhabdomyosarcoma (RMA) have a 5-year-survival rate not exceeding 30%. Here, we assess the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for these patients in comparison to standard-of-care regimens. We also compare the use of HLA-mismatched vs. HLA-matched grafts after reduced vs. myeloablative conditioning regimens, respectively. Patients and Methods: In this retrospective analysis, we compare event-free survival (EFS), overall survival (OS), and toxicity of HLA-mismatched vs. -matched transplanted patients in uni- and multivariate analyses (total: n = 50, HLA-matched: n = 15, HLA-mismatched: n = 35). Here, the factors age at diagnosis, age at allo-HSCT, sex, Oberlin score, disease status at allo-HSCT, and HLA graft type are assessed. For 29 primarily transplanted patients, three matched non-transplanted patients per one transplanted patient were identified from the CWS registry. Outcomes were respectively compared for OS and EFS. Matching criteria included sex, age at diagnosis, favorable/unfavorable primary tumor site, and metastatic sites. Results: Median EFS and OS did not differ significantly between HLA-mismatched and -matched patients. In the mismatched group, incidence of acute GvHD was 0.87 (grade III-IV: 0.14) vs. 0.80 in HLA-matched patients (grade III-IV: 0.20). Transplant-related mortality (TRM) of all patients was 0.20 and did not differ significantly between HLA-mismatched and -matched groups. A proportion of 0.58 relapsed or progressed and died of disease (HLA-mismatched: 0.66, HLA-matched: 0.53) whereas 0.18 were alive in complete remission (CR) at data collection. Multivariate and competing risk analyses confirmed CR and very good partial response (VGPR) status prior to allo-HSCT as the only decisive predictor for OS (p < 0.001). Matched-pair survival analyses of primarily transplanted patients vs. matched non-transplanted patients also identified disease status prior to allo-HSCT (CR, VGPR) as the only significant predictor for EFS. Here, OS was not affected, however. Conclusion: In this retrospective analysis, only a subgroup of patients with good response at allo-HSCT survived. There was no survival benefit of allo-transplanted patients compared to matched controls, suggesting the absence of a clinically relevant graft-versus-RMA effect in the current setting. The results of this analysis do not support further implementation of allo-HSCT in RMA stage IV patients.

Osteosarcoma and causes of death: A report of 1520 deceased patients from the Cooperative Osteosarcoma Study Group (COSS).

PURPOSE: Most aspects of osteosarcoma have been addressed in detail, but there is no comprehensive analysis of deceased patients and causes of death. METHODS: The database of the Cooperative Osteosarcoma Study Group COSS (1980-03/31/2021; 4475 registered high-grade central osteosarcoma patients) was searched deaths from any cause. Affected patients were analyzed for demographic and baseline variables and disease-status at the time of demise. Deaths from causes other than osteosarcoma were analyzed in detail. RESULTS: A total of 1520 deceased patients were identified (median age (range) at osteosarcoma diagnosis 16 (2-78) years; 908 (59.7%) male, 612 (40.3%) female; primary tumor: extremities 1263 (83.1%), trunk 208 (13.7%), craniofacial 47 (3.1%) (site unknown 2); metastases at registration: absent 1.051 (69.1%), present 466 (30.7%) (3 no data). The median time from diagnosis to death was 2.22 (0.08-32.02) years. 1286 (84.6%) patients succumbed to osteosarcoma (370 without achieving complete remission, 488 first, 428 more than one recurrences), 146 (9.6%) to other, 88 (5.8%) to unknown causes. Chemotherapy-related infections (40), secondary malignancies (39), and perioperative complications (19) were among the most frequent potentially treatment-related causes, and high-dose methotrexate (19), doxorubicin (17), and ifosfamide (15) were the drugs most commonly held responsible. Patients with unknown causes of death had an unusually long median follow-up. CONCLUSION: The major cause of death of patients after osteosarcoma is this malignancy, mostly from one of its multiple relapses. However, almost 10% of fatalities are due to other documented causes. Some of these deaths may be preventable with the knowledge gained from comprehensive analyses such as this.

Linking transgene expression of engineered mesenchymal stem cells and angiopoietin-1-induced differentiation to target cancer angiogenesis.

OBJECTIVE: To specifically target tumor angiogenesis by linking transgene expression of engineered mesenchymal stem cells to angiopoietin-1-induced differentiation. BACKGROUND: Mesenchymal stem cells (MSCs) have been used to deliver therapeutic genes into solid tumors. These strategies rely on their homing mechanisms only to deliver the therapeutic agent. METHODS: We engineered murine MSC to express reporter genes or therapeutic genes under the selective control of the Tie2 promoter/enhancer. This approach uses the differentiative potential of MSCs induced by the tumor microenvironment to drive therapeutic gene expression only in the context of angiogenesis. RESULTS: When injected into the peripheral circulation of mice with either, orthotopic pancreatic or spontaneous breast cancer, the engineered MSCs were actively recruited to growing tumor vasculature and induced the selective expression of either reporter red florescent protein or suicide genes [herpes simplex virus-thymidine kinase (TK) gene] when the adoptively transferred MSC developed endothelial-like characteristics. The TK gene product in combination with the prodrug ganciclovir (GCV) produces a potent toxin, which affects replicative cells. The homing of engineered MSC with selective induction of TK in concert with GCV resulted in a toxic tumor-specific environment. The efficacy of this approach was demonstrated by significant reduction in primary tumor growth and prolongation of life in both tumor models. CONCLUSION: This "Trojan Horse" combined stem cell/gene therapy represents a novel treatment strategy for tailored therapy of solid tumors.

Psychometric properties of the Activities Scale for Kids-performance after allogeneic hematopoietic stem cell transplantation in adolescents and children : Results of a prospective study on behalf of the German-Austrian-Swiss GVHD Consortium.

BACKGROUND: The psychometric properties of an instrument, the Activity Scale for Kids-performance (ASKp), were assessed which was proposed to capture physical functioning after allogeneic hematopoietic stem cell transplantation (HSCT). Additionally, this multicenter observational prospective study investigated the influence of clinical correlates focusing on chronic graft-versus-host disease (cGVHD). METHODS: Patient-reported ASKp, clinician-reported Karnofsky/Lansky status (KPS/PSS), patient characteristics and cGVHD details were assessed of 55 patients with a median age of 12 years at baseline after day +100 post-HSCT and every 3 months during the next 18 months. The psychometric properties were evaluated and ASKp and KPS/PSS status was compared using ANOVAS and multiple regression models. RESULTS: The German version of the ASKp showed good psychometric properties except for ceiling effects. Discrimination ability of the ASKp was good regarding the need for devices but failed to predict cGVHD patients. Both the ASKp and the KPS/PSS were associated with patients after adoptive cell therapy being in need for devices, suffering from overlap cGVHD and from steroid side effects but not with patients' age and gender. In contrast to the KPS/PSS the ASKp only showed significant differences after merging moderate and severe cGHVD patients when comparing them to No-cGVHD (F = 4.050; p = 0.049), being outperformed by the KPS/PSS (F = 20.082; p < 0.001). CONCLUSION: The ASKp showed no clear advantages compared to KPS/PSS even though economical and patients' effort was higher. Further application range may be limited through ceiling effects. Both should be taken into consideration. Therefore, the results may not support the usage of ASKp after HSCT and rather suggest KPS/PSS, both patient and clinician reported.