High-content drug screening in zebrafish xenografts reveals high efficacy of dual MCL-1/BCL-XL inhibition against Ewing sarcoma.

Ewing sarcoma is a pediatric bone and soft tissue cancer with an urgent need for new therapies to improve disease outcome. To identify effective drugs, phenotypic drug screening has proven to be a powerful method, but achievable throughput in mouse xenografts, the preclinical Ewing sarcoma standard model, is limited. Here, we explored the use of xenografts in zebrafish for high-throughput drug screening to discover new combination therapies for Ewing sarcoma. We subjected xenografts in zebrafish larvae to high-content imaging and subsequent automated tumor size analysis to screen single agents and compound combinations. We identified three drug combinations effective against Ewing sarcoma cells: Irinotecan combined with either an MCL-1 or an BCL-XL inhibitor and in particular dual inhibition of the anti-apoptotic proteins MCL-1 and BCL-XL, which efficiently eradicated tumor cells in zebrafish xenografts. We confirmed enhanced efficacy of dual MCL-1/BCL-XL inhibition compared to single agents in a mouse PDX model. In conclusion, high-content screening of small compounds on Ewing sarcoma zebrafish xenografts identified dual MCL-1/BCL-XL targeting as a specific vulnerability and promising therapeutic strategy for Ewing sarcoma, which warrants further investigation towards clinical application.

Evaluation of geranylgeranyl diphosphate synthase inhibition as a novel strategy for the treatment of osteosarcoma and Ewing sarcoma.

Rab GTPases are critical regulators of protein trafficking in the cell. To ensure proper cellular localization and function, Rab proteins must undergo a posttranslational modification, termed geranylgeranylation. In the isoprenoid biosynthesis pathway, the enzyme geranylgeranyl diphosphate synthase (GGDPS) generates the 20-carbon isoprenoid donor (geranylgeranyl pyrophosphate [GGPP]), which is utilized in the prenylation of Rab proteins. We have pursued the development of GGDPS inhibitors (GGSI) as a novel means to target Rab activity in cancer cells. Osteosarcoma (OS) and Ewing sarcoma (ES) are aggressive childhood bone cancers with stagnant survival statistics and limited treatment options. Here we show that GGSI treatment induces markers of the unfolded protein response (UPR) and triggers apoptotic cell death in a variety of OS and ES cell lines. Confirmation that these effects were secondary to cellular depletion of GGPP and disruption of Rab geranylgeranylation was confirmed via experiments using exogenous GGPP or specific geranylgeranyl transferase inhibitors. Furthermore, GGSI treatment disrupts cellular migration and invasion in vitro. Metabolomic profiles of OS and ES cell lines identify distinct changes in purine metabolism in GGSI-treated cells. Lastly, we demonstrate that GGSI treatment slows tumor growth in a mouse model of ES. Collectively, these studies support further development of GGSIs as a novel treatment for OS and ES.

[Update and interpretation of 2021 National Comprehensive Cancer Network (NCCN) "Clinical Practice Guidelines for Bone Tumors"].

The incidence of primary malignant bone tumors is low, and clinical cognition is insufficient. The establishment of diagnostic criteria is of great significance for prognosis of tumors. National Comprehensive Cancer Network (NCCN) regularly publishes "Clinical Practice Guidelines for Bone Tumors" to summarize the latest treatment progress of bone tumors. In the latest version of the guidelines released in November 2020, surgery is the main treatment for chondrosarcoma, chordoma, and giant cell tumor of bone, which can be combined with radiotherapy or targeted therapy. Ewing's sarcoma and osteosarcoma are treated by surgery combined with chemotherapy. Immunotherapy can be used to treat high-grade undifferentiated pleomorphic sarcoma. For recurrent tumors, surgery combined with radiotherapy, chemotherapy, and/or targeted therapy can be used for control. The guidelines provide a reference for the standard treatment of bone tumors.

Receptor tyrosine kinase inhibitors for the treatment of osteosarcoma and Ewing sarcoma.

Adjuvant chemotherapy for osteosarcoma and Ewing sarcoma consists of conventional cytotoxic regimens that have changed little over the past decades. There is an urgent need for agents that are more effective and have less long-term toxicity. Receptor tyrosine kinases regulate cell growth and proliferation of these tumors, and small-molecule inhibitors for many of these kinases are now available. In this article, we review published phase II trials for patients with recurrent disease and highlight the pathways targeted by available agents, as well as the toxicity and efficacy results seen to date. We also discuss the difficulties in identifying biomarkers to facilitate rational patient selection, as well as published and proposed strategies for how these inhibitors can be combined with conventional chemotherapy or other targeted agents. It is hoped future trials can capitalize on this growing experience to optimize the use of this exciting class of agents.

Drug Screening by Resazurin Colorimetry in Ewing Sarcoma.

In Ewing sarcoma (EwS), development of new therapeutic strategies is crucial in order to refine treatment and improve patient survival, especially in metastatic or recurrent disease stages. Thus, preclinical drug screening is a key issue in EwS research. As especially in such drug screening assays, the cell viability aspect of cell proliferation is important, resazurin colorimetry shall be reviewed here as a fast, high-throughput method with automated readout to efficiently screen for potency of drugs via measurement of cell viability.

Evaluation of VTP-50469, a menin-MLL1 inhibitor, against Ewing sarcoma xenograft models by the pediatric preclinical testing consortium.

BACKGROUND: VTP-50469 is a potent inhibitor of the menin-MLL1 interaction and is implicated in signaling downstream of EWSR1-FLI1. PROCEDURE: VTP-50469 was evaluated against seven Ewing sarcoma (EwS) xenograft models and in vitro against EwS cell lines. RESULTS: VTP-50469 showed limited antitumor activity, statistically significantly slowing tumor progression in four tumor models but with no evidence of tumor regression. In vitro, the IC50 concentration was 10 nM for the mixed lineage leukemia (MLL)-rearranged leukemia cell line MV4;11, but > 3 µM for EwS cell lines. CONCLUSIONS: In contrast to its high level of activity against MLL1-rearranged leukemia xenografts, VTP-50469 shows little activity against EwS models.

Early versus delayed administration of granulocyte-colony stimulating factor following chemotherapy in pediatric patients with Ewing sarcoma.

BACKGROUND: The optimal timing of initiating granulocyte-colony stimulating factor following chemotherapy in pediatric patients has not been clearly defined. This study aimed to compare the administration of granulocyte-colony stimulating factor on day 1 versus day 3 postchemotherapy in pediatric patients with Ewing sarcoma. METHOD: A retrospective study of pediatric patients with Ewing sarcoma who received granulocyte-colony stimulating factor following chemotherapy between January 2016 and September 2018 at a comprehensive cancer center. The institution's chemotherapy protocol for Ewing sarcoma was modified in April 2017 to include granulocyte-colony stimulating factor initiation on day 3 instead of day 1 post-chemotherapy. Febrile neutropenia requiring hospitalization, duration of hospital stay, and chemotherapy delay were compared for patients before and after the protocol change. RESULTS: Over the study period, 250 cycles were evaluated with day 1 granulocyte-colony stimulating factor and 221 cycles with day 3 granulocyte-colony stimulating factor. There were no differences between the day 1 and day 3 groups in the number of cycles associated with Febrile neutropenia requiring hospitalization (34 vs. 19, p = 0.086), and the length of Febrile neutropenia-related hospitalization (mean 4 ± 2.1 vs. 4.6 ± 1.8, p = 0.123). However, delay in chemotherapy due to neutropenia was reported in significantly more cycles in the day 1 group, compared to the day 3 group (37 vs. 16, p = 0.01). CONCLUSIONS: Febrile neutropenia resulting in hospital admission and the length of hospital stay was not different between pediatric patients with Ewing sarcoma who received granulocyte-colony stimulating factor on day 1 or day 3 post-chemotherapy. Chemotherapy delay due to neutropenia was higher in patients who received granulocyte-colony stimulating factor on day 1. Larger studies are required to fully determine the impact of delayed initiation of granulocyte-colony stimulating factor.

Toosendanin induces the apoptosis of human Ewing's sarcoma cells via the mitochondrial apoptotic pathway.

Toosendanin, a triterpenoid extracted from the root bark of Melia toosendan, has its origin from traditional Chinese medicine and has been used as a non­polluting and pesticide­free plant insecticide in China for fruit and vegetable production. In recent years, toosendanin has been found to inhibit tumor cell proliferation and promote tumor cell apoptosis. Ewing's sarcoma (ES) is the second most common primary malignant bone and soft tissue tumor in children and adolescents. Although the overall prognosis of ES has improved, the 5­year survival rate has not significantly increased. To analyze the role of toosendanin on ES progression, CCK­8 viability assay, flow cytometry, Hoechst 33258 staining and western blotting were performed. The present results suggested that toosendanin suppressed cell viability and induced apoptosis in human SK­ES­1 cells compared with DMSO treatment. In addition, in the present study, toosendanin was found to upregulate the expression of Bax and downregulate the expression of Bcl­2, altering the Bax/Bcl­2 ratio. Additionally, toosendanin promoted the release of cytochrome c, resulting in the activation of the mitochondrial apoptotic pathway, thus inducing the activation of caspase­9 and caspase­3, and the cleavage of PARP. Our results demonstrated that toosendanin inhibited the growth of ES cells in a dose­dependent manner and triggered mitochondrial apoptotic pathway to induce apoptosis. Therefore, toosendanin can potentially be utilized as an anticancer botanical drug for the treatment of ES.

Vascular modulation through exercise improves chemotherapy efficacy in Ewing sarcoma.

Recent studies in mouse models of cancer have shown that exercise improves tumor vascular function, thereby improving chemotherapy delivery and efficacy. However, the mechanisms underlying this improvement remain unclear and the effect of exercise on Ewing sarcoma (ES), a pediatric bone and soft tissue cancer, is unknown. The effect of exercise on tumor vascular hyperpermeability, which inversely correlates with drug delivery to the tumor, has also not been evaluated. We hypothesized that exercise improves chemotherapy efficacy by enhancing its delivery through improving tumor vascular permeability. We treated ES-bearing mice with doxorubicin with or without moderate treadmill exercise. Exercise did not significantly alter ES tumor vessel morphology. However, compared to control mice, tumors of exercised mice had significantly reduced hyperpermeability, significantly decreased hypoxia, and higher doxorubicin penetration. Compared to doxorubicin alone, doxorubicin plus exercise inhibited tumor growth more efficiently. We evaluated endothelial cell sphingosine-1-phosphate receptors 1 and 2 (S1PR1 and S1PR2) as potential mediators of the improved vascular permeability and increased function afforded by exercise. Relative to tumors from control mice, vessels in tumors from exercised mice had increased S1PR1 and decreased S1PR2 expression. Our results support a model in which exercise remodels ES vasculature to reduce vessel hyperpermeability, potentially via modulation of S1PR1 and S1PR2, thereby improving doxorubicin delivery and inhibiting tumor growth more than doxorubicin alone does. Our data suggest moderate aerobic exercise should be tested in clinical trials as a potentially useful adjuvant to standard chemotherapy for patients with ES.

Pathfinders in oncology from the end of the 19th century to the first description of Ewing sarcoma.

During the period 1884 to 1922, the only option in cases of operable cancers was radical surgery, and only a minority of patients were cured. Sporadic attempts were made to treat inoperable cancer patients with bacterial toxins; however, with the discovery of x-ray and radium, the era of radiation treatment as an alternative to surgery began. The discovery of transmissible cancers and experimental growth of cancer cells offered new information and not only led to a better understanding of the cellular composition of cancers but also yielded important information that ultimately paved the way to chemotherapy. These efforts also advanced the understanding of the pathogenesis of tumors and induced new clinical and pathologic classifications and subspecializations. It is important to emphasize that many of the initiatives and discoveries made in Europe in the second half of the 19th century were first put into clinical practice in the United States during the first 2 decades of the 20th century, including the use of x-ray and radium for irradiation and as diagnostic tools. All things considered, the progress made between 1884 and 1922 came about through the hard work of many eminent individuals; however, there were 7 foresighted pathfinders (3 surgeons, 2 pathologists, 1 internist, and 1 physicist) who-despite their widely diverse backgrounds, personalities, and expertise-made remarkable contributions to oncology to an extent that is still felt today.

Treatment Outcomes of Pediatric Patients With Ewing Sarcoma in a War-Torn Nation: A Single-Institute Experience From Iraq.

PURPOSE: Ewing sarcoma (ES) is a relatively rare, highly malignant tumor of the musculoskeletal system. It is the second most common malignant bone tumor in children and adolescents in the age group of 5 to 20 years. The aim of this study was to identify the treatment outcomes of pediatric patients with ES in Sulaimani governorate, Iraq. PATIENTS AND METHODS: This was a retrospective study that reviewed the medical records of pediatric patients with ES who were managed between 2009 and 2015, with follow-up until late 2017. Patient- and tumor-related factors were correlated with clinical outcomes. RESULTS: A total of 31 pediatric patients with ES were included in this study. All the patients received chemotherapy and radiotherapy, whereas only 14 patients underwent surgical resection and just eight had free surgical margins. The median age at diagnosis was 13 years, 58% were male, and 42% were female. The presenting symptoms at diagnosis were mostly pain (67.7%) and palpable mass (25.8%). The primary tumor was located in the extremities (51.6%), the thoracic cage (19.4%), the pelvis (16.1%), and the lumbar vertebrae (12.9%). Approximately two thirds of the patients (61.3%) had localized disease at the time of presentation. The 5-year overall survival was 19%, and the 5-year recurrence-free survival was 34%. CONCLUSION: Clinical outcomes of ES in pediatric patients in our war-torn nation, Iraq, are still markedly inferior to the published outcomes from stable, developed nations. Additional large and multicenter national studies are required. Diagnostic and therapeutic measures need improvement, and multidisciplinary and comprehensive cancer-integrated approaches are vital for better outcomes.

Broad Spectrum Activity of the Checkpoint Kinase 1 Inhibitor Prexasertib as a Single Agent or Chemopotentiator Across a Range of Preclinical Pediatric Tumor Models.

PURPOSE: Checkpoint kinase 1 (CHK1) inhibitors potentiate the DNA-damaging effects of cytotoxic therapies and/or promote elevated levels of replication stress, leading to tumor cell death. Prexasertib (LY2606368) is a CHK1 small-molecule inhibitor under clinical evaluation in multiple adult and pediatric cancers. In this study, prexasertib was tested in a large panel of preclinical models of pediatric solid malignancies alone or in combination with chemotherapy. EXPERIMENTAL DESIGN: DNA damage and changes in cell signaling following in vitro prexasertib treatment in pediatric sarcoma cell lines were analyzed by Western blot and high content imaging. Antitumor activity of prexasertib as a single agent or in combination with different chemotherapies was explored in cell line-derived (CDX) and patient-derived xenograft (PDX) mouse models representing nine different pediatric cancer histologies. RESULTS: Pediatric sarcoma cell lines were highly sensitive to prexasertib treatment in vitro, resulting in activation of the DNA damage response. Two PDX models of desmoplastic small round cell tumor and one malignant rhabdoid tumor CDX model responded to prexasertib with complete regression. Prexasertib monotherapy also elicited robust responses in mouse models of rhabdomyosarcoma. Concurrent administration with chemotherapy was sufficient to overcome innate resistance or prevent acquired resistance to prexasertib in preclinical models of neuroblastoma, osteosarcoma, and Ewing sarcoma, or alveolar rhabdomyosarcoma, respectively. CONCLUSIONS: Prexasertib has significant antitumor effects as a monotherapy or in combination with chemotherapy in multiple preclinical models of pediatric cancer. These findings support further investigation of prexasertib in pediatric malignancies.

Antitumor effects of ß-elemene via targeting the phosphorylation of insulin receptor.

Ewing sarcoma family tumors (ESFTs) are a group of aggressive and highly metastatic tumors lacking efficient therapies. Insulin-like growth factor 1 receptor (IGF1R) blockade is one of the most efficient targeting therapy for ESFTs. However, the appliance is obstructed by drug resistance and disease recurrence due to the activation of insulin receptor (IR) signaling induced by IGF1R blockade. Herein ß-elemene, a compound derived from natural plants, exhibited a remarkable proliferation repression on ESFT cells, which was weakened by a caspase inhibitor Z-VAD. ß-elemene in combination with IGF1R inhibitors enhanced markedly the repression on cellular proliferation and mTOR activation by IGF1R inhibitors and suppressed the PI3K phosphorylation induced by IGF1R inhibitors. To investigate the mechanisms, we focused on the effects of ß-elemene on IR signaling pathway. ß-elemene significantly suppressed the insulin-driven cell growth and the activation of mTOR and PI3K in tumor cells, while the toxicity to normal hepatocytes was much lower. Further, the phosphorylation of IR was found to be suppressed notably by ß-elemene specifically in tumor cells other than normal hepatocytes. In addition, ß-elemene inhibited the growth of ESFT xenografts in vivo, and the phosphorylation of IR and S6 ribosomal protein was significantly repressed in the ß-elemene-treated xenografts. These data suggest that ß-elemene targets IR phosphorylation to inhibit the proliferation of tumor cells specifically and enhance the effects of IGF1R inhibitors. Thus, this study provides evidence for novel approaches by ß-elemene alone or in combination with IGF1R blockades in ESFTs and IR signaling hyperactivated tumors.

Preclinical Efficacy of Endoglin-Targeting Antibody-Drug Conjugates for the Treatment of Ewing Sarcoma.

PURPOSE: Endoglin (ENG; CD105) is a coreceptor of the TGFß family that is highly expressed in proliferating endothelial cells. Often coopted by cancer cells, ENG can lead to neo-angiogenesis and vasculogenic mimicry in aggressive malignancies. It exists both as a transmembrane cell surface protein, where it primarily interacts with TGFß, and as a soluble matricellular protein (sENG) when cleaved by matrix metalloproteinase 14 (MMP14). High ENG expression has been associated with poor prognosis in Ewing sarcoma, an aggressive bone cancer that primarily occurs in adolescents and young adults. However, the therapeutic value of ENG targeting has not been fully explored in this disease. EXPERIMENTAL DESIGN: We characterized the expression pattern of transmembrane ENG, sENG, and MMP14 in preclinical and clinical samples. Subsequently, the antineoplastic potential of two novel ENG-targeting monoclonal antibody-drug conjugates (ADC), OMTX503 and OMTX703, which differed only by their drug payload (nigrin-b A chain and cytolysin, respectively), was assessed in cell lines and preclinical animal models of Ewing sarcoma. RESULTS: Both ADCs suppressed cell proliferation in proportion to the endogenous levels of ENG observed in vitro. Moreover, the ADCs significantly delayed tumor growth in Ewing sarcoma cell line-derived xenografts and patient-derived xenografts in a dose-dependent manner. CONCLUSIONS: Taken together, these studies demonstrate potent preclinical activity of first-in-class anti-ENG ADCs as a nascent strategy to eradicate Ewing sarcoma.

Establishment of a novel patient-derived Ewing's sarcoma cell line, NCC-ES1-C1.

Ewing's sarcoma is an aggressive mesenchymal tumor characterized by the presence of a unique EWSR1-FLI1 translocation. Ewing's sarcoma primarily occurs in the bone and soft tissues. Cell lines enable researchers to investigate the molecular backgrounds of disease and the significance of genetic alterations in relevant cellular contexts. Here, we report the establishment and characterization of a novel Ewing's sarcoma cell line following primary Ewing's sarcoma tumor tissue culture. The established cell line was authenticated by DNA microsatellite short tandem repeat analysis, characterized by in vitro assays, and named NCC-ES1-C1. The NCC-ES1-C1 cell line grew well for 15 mo and was subcultured more than 50 times during this period. Characterization of the cells revealed that they were not adherent and showed floating features. In conclusion, we successfully established a novel Ewing's sarcoma cell line, NCC-ES1-C1, from primary tumor tissue. The cell line has the characteristic EWSR1-FLI1 gene fusion and exhibits aggressive growth in vitro. Thus, the NCC-ES1-C1 cell line will be a useful tool for investigating the mechanisms of disease and the biological role of the EWSR1-FLI1 fusion gene.

Abemaciclib Is Active in Preclinical Models of Ewing Sarcoma via Multipronged Regulation of Cell Cycle, DNA Methylation, and Interferon Pathway Signaling.

PURPOSE: Ewing sarcoma (ES) is a rare and highly malignant cancer that occurs in the bone and surrounding tissue of children and adolescents. The EWS/ETS fusion transcription factor that drives ES pathobiology was previously demonstrated to modulate cyclin D1 expression. In this study, we evaluated abemaciclib, a small-molecule CDK4 and CDK6 (CDK4 and 6) inhibitor currently under clinical investigation in pediatric solid tumors, in preclinical models of ES. EXPERIMENTAL DESIGN: Using Western blot, high-content imaging, flow cytometry, ELISA, RNA sequencing, and CpG methylation assays, we characterized the in vitro response of ES cell lines to abemaciclib. We then evaluated abemaciclib in vivo in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models of ES as either a monotherapy or in combination with chemotherapy. RESULTS: Abemaciclib induced quiescence in ES cell lines via a G1 cell-cycle block, characterized by decreased proliferation and reduction of Ki-67 and FOXM1 expression and retinoblastoma protein (RB) phosphorylation. In addition, abemaciclib reduced DNMT1 expression and promoted an inflammatory immune response as measured by cytokine secretion, antigen presentation, and interferon pathway upregulation. Single-agent abemaciclib reduced ES tumor volume in preclinical mouse models and, when given in combination with doxorubicin or temozolomide plus irinotecan, durable disease control was observed. CONCLUSIONS: Collectively, our data demonstrate that the antitumor effects of abemaciclib in preclinical ES models are multifaceted and include cell-cycle inhibition, DNA demethylation, and immunogenic changes.

Target discovery screens using pooled shRNA libraries and next-generation sequencing: A model workflow and analytical algorithm.

In the search for novel therapeutic targets, RNA interference screening has become a valuable tool. High-throughput technologies are now broadly accessible but their assay development from baseline remains resource-intensive and challenging. Focusing on this assay development process, we here describe a target discovery screen using pooled shRNA libraries and next-generation sequencing (NGS) deconvolution in a cell line model of Ewing sarcoma. In a strategy designed for comparative and synthetic lethal studies, we screened for targets specific to the A673 Ewing sarcoma cell line. Methods, results and pitfalls are described for the entire multi-step screening procedure, from lentiviral shRNA delivery to bioinformatics analysis, illustrating a complete model workflow. We demonstrate that successful studies are feasible from the first assay performance and independent of specialized screening units. Furthermore, we show that a resource-saving screen depth of 100-fold average shRNA representation can suffice to generate reproducible target hits despite heterogeneity in the derived datasets. Because statistical analysis methods are debatable for such datasets, we created ProFED, an analysis package designed to facilitate descriptive data analysis and hit calling using an aim-oriented profile filtering approach. In its versatile design, this open-source online tool provides fast and easy analysis of shRNA and other count-based datasets to complement other analytical algorithms.

Uso de biofeedback de variabilidad de la frecuencia cardiaca durante la radioterapia como método de distracción cognitiva y autorregulación en un paciente pediátrico: Informe de caso / Biofeedback use of heart rate variability during radiotherapy as a method of cognitive distraction and self-regulation in a pediatric patient: A case report

Objetivo: Evaluar la efectividad del uso de biofeedback de variabilidad de frecuencia cardiaca (VFC) durante la radioterapia como método de distracción cognitiva y autoregulación emocional en un paciente pediátrico. Método: La paciente es una niña de 11 años con diagnóstico de sarcoma de Ewing en la pierna izquierda. Recibió 28 sesiones de radioterapia. Antes de iniciar tratamiento, se evaluó psicológicamente a la paciente con la entrevista Mini Kid, identificando que no tenía psicopatología. Dos semanas previas a iniciar, se evaluó la frecuencia cardiaca (FC) y variabilidad (VFC) de la misma (indicadores que han sido utilizados previamente como correlatos fisiológicos de estrés y relajación) con un software especializado llamado EmWave, identificando que sí presentaba activación fisiológica asociada a estrés. Se hizo entrenamiento en respiración diafragmática apoyado con el equipo de retroalimentación dos semanas previas a la radioterapia. El día que inició tratamiento, se volvió a evaluar la frecuencia y variabilidad antes de comenzar. Durante la radioterapia se instrumentó a la paciente al software y se permitió que ella escogiera el juego (que registra las variables de FC y VFC e interactúa conforme ella logra autoregulación fisiológica) y éste era proyectado en el techo de la sala mientras recibía la radiación. Resultados: Se identificaron cambios en la variabilidad de la frecuencia cardiaca, logrando una autoregulación, mostrando así que la paciente aprendió a relajarse y que lo puso en práctica durante la radioterapia. Conclusión: El uso del biofeedback es innovador en el tratamiento con radioterapia; permite al paciente integrar los dos métodos más utilizados como preparación para la misma: distraer el foco atencional y lograr una autoregulación. Se sugiere ampliar la muestra para conocer los efectos y generalizar los resultados (AU)

Aim: To assess the effectiveness of heart rate variability (HRV) biofeedback during radiotherapy as an intervention to promote cognitive distraction and emotional regulation un a paediatric patient. Method: Patient is an 11 years old female with Ewing Sarcoma on left leg. She recieved 28 radiotherapy sessions. Before initiating treatment, the patient was assessed with Mini International Neuropsychiatric Interview KID (MINI KID). She did not have a psychiatirc diagnostic, nor significative anxiety as rated by these instruments. Two weeks prior initiating radiotherapy, Heart rate (HR) and heart rate variability (HRV) (measures that have been used previously as physiologic corralates of stress and relaxation) were measured with a specialized software called EmWave. Results identified that there was a psysiologic activation related to stress. At the same session, the patient was trained in diaphragmatic breathing assisted with HRV biofeedback. The day the radiotherapy treatment started, HR and HRV were assessed an hour before. During radiotherapy, patient was instrumented to the software and the display was projected on the ceiling so that she could interact with the program at the same time she recieved radiotherapy. Patient was asked to choose the display she prefered (presented as interactive games by EmWave) and HR as well as HRV were measured during treatment. Results: Changes in HRV during radiotherapy were presented, these changes have been reported as indicative of self regulation, reflecting that the patient learned this behavior and was able to implement it during her treatment. Conclussion: The use of biofeedback is innovative in treatment with radiotherapy; it allows the patient to integrate the two most used methods for psychological preparation: attentional distraction and self regulation methods. It’s suggested to amplify the sample in order to learn more about the use of biofeedback in radiotherapy and generalize results (AU)

Effects of baicalein on proliferation, apoptosis, migration and invasion of Ewing's sarcoma cells.

Ewing's sarcoma (ES) is a rare tumor that is more frequent in pediatric and adolescent age groups. In the past few decades, long-term survival in affected patients has improved due to the success of multimodal therapy. However, long-term survival is inevitably restricted by the late side-effects of chemotherapy. Besides, early metastasis also contributes to the poor prognosis of ES. Recently, traditional Chinese medicines (TCMs) have increasingly attracted interest due to the promising clinical results and fewer side-effects for the treatment of cancers. Among the various TCMs, the root of Scutellaria baicalensis exerts anti-inflammatory properties as a well-known herb in traditional Chinese medicine. Baicalein (5,6,7-trihydroxyflavone) derived from the root of Scutellaria baicalensis is a bioactive compound, which possesses a powerful pro-apoptotic activity in various cancers such as hepatocellular carcinoma and myeloma. However, the effects of baicalein on ES cells remain still unknown. We anticipated that baicalein also has apoptotic activity in ES. The aim of the present study was to investigate the effects of baicalein on viability, apoptosis, migration and invasion of ES cells, and further to elaborate the molecular mechanism of baicalein-induced ES cell apoptosis. We found that baicalein markedly inhibited ES cells viability in a time- and dose-dependent manner, especially SK-ES-1 cells and could promote the apoptosis of ES cells. Additionally, baicalein was capable of upregulating the expression of the pro-apoptotic proteins Bax and cytochrome c, reducing the expression of the anti-apoptotic protein Bcl-2, elevating the ratio of Bax/Bcl-2, and triggering the mitochondrial apoptotic pathway, which led to caspase-3 and caspase-9 activation and PARP cleavage. Meanwhile, the activation of caspase-8 and the death receptor pathway was also observed. Besides, baicalein could reduce ES migration and invasion in vitro, which showed its potential to inhibit ES metastasis, besides contributing to the decrease in the expression of matrix metalloproteinases (MMP)-2 and MMP-9. In conclusion, baicalein has a potent tumor-suppressor activity by inducing cell apoptosis through the mitochondrial apoptotic pathway and the death receptor pathway in ES cells, thus it may serve as a novel and effective candidate agent for ES treatment.

A catheter-related bloodstream infection caused by Chryseobacterium indologenes successfully treated with antibiotic-lock rescue therapy.

We report the case of a catheter-related bloodstream infection caused by Chryseobacterium indologenes, an uncommon and multi-resistant pathogen, in a pediatric patient with a long-term vascular access device placed for chemotherapy treatment. The infection was successfully treated with ciprofloxacin antibiotic-lock therapy. This is the first report on successful salvage of a long-term device colonized by multi-resistant Chryseobacterium indologenes.