Sarcoma de Ewing extraesquelético: reporte de caso / Extraskeletal Ewing's Sarcoma: a Case Report

Introducción: El sarcoma de Ewing es un tumor maligno de alto grado con localización principalmente ósea; se han reportado aproximadamente 12% con presentación extra-esquelética. Actualmente, existen alrededor de 20 casos descritos en la literatura con origen mediastinal y 10 casos con origen pulmonar. Caso clínico: Se presenta el caso de una mujer de 25 años con un mes de disnea y dolor torácico, con el hallazgo de derrame pleural masivo y tumoración mediastinal en hemitórax derecho. Se le realiza toracotomía anterior bilateral con esternotomía transversa de Clamshell, con resección parcial que demuestra, por patología, sarcoma monomórfico de alto grado e inmunohistoquímica concluyente de sarcoma de Ewing. Conclusión: Este caso es una entidad rara y conlleva un reto diagnóstico para el clínico; sin embargo, debe sospecharse considerando la presentación clínica y radiológica del paciente, buscando incrementar la tasa de supervivencia mediante el diagnóstico y tratamiento oportuno.

Introduction: Ewing's sarcoma is a high-grade malignant tumor with mainly bony lo-calization; approximately 12% have been reported with extraskeletal presentation. Currently, there are about 20 cases described in the literature with mediastinal origin and 10 pulmonary cases. Case Report: We present the case of a 25-year-old woman with one month of dysp-nea and chest pain, with massive pleural effusion and mediastinal tumor in the right hemithorax who underwent bilateral anterior thoracotomy with Clamshell transverse sternotomy, with partial resection demonstrating, by pathology, high-grade monomorphic sarcoma and conclusive immunohistochemistry of Ewing's sarcoma. Conclusion: This case is a rare entity and involves a diagnostic challenge for the clinician; however, it should be suspected considering the clinical and radiological presentation of the patient, seeking to increase the survival rate through timely diagnosis and treatment.

Deciphering the effect of a Cu(II)-hydrazone complex on intracellular cell signalling pathways in a human osteosarcoma 2D and 3D models.

New therapeutic strategies for osteosarcoma (OS) have demonstrated the potential efficacy of copper compounds as anticancer drugs and as a substitute for the often used platinum compounds. OS is a type of bone cancer, primarily affecting young adults and children..The main objective of this work is to discover the molecular targets and cellular pathways related to the antitumor properties of a Cu(II)-hydrazone toward human OS  2D and 3D systems. Cell viability study using MG-63 cells was evaluated in OS monolayer and spheroids. CuHL significantly reduced cell viability in OS models (IC50 2D: 2.6 ± 0.3 µM; IC50 3D: 9.9 ± 1.4 µM) (p<0.001). Also, CuHL inhibits cell proliferation and it induces cells to apoptosis. The main mechanism of action found for CuHL are the interaction with DNA, genotoxicity, the ROS generation and the proteasome activity inhibition. Besides, 67 differentially expressed proteins were found using proteomic approaches. Of those 67 proteins, 40 were found overexpressed and 27 underexpressed. The response to stress and to unfolded protein, as well as ATP synthesis were the most affected biological process among upregulated proteins, whilst proteins related to DNA replication and redox homeostasis were downregulated.

Metallocompounds as anticancer agents against osteosarcoma.

Metallocompounds are a class of anticancer compounds largely used in the treatment of several types of solid tumors, including bone cancer. Osteosarcoma (OS) is a primary malignant bone tumor that frequently affects children, adolescents and young adults. It is a very invasive type of tumor, so ∼40% of patients develop distant metastases, showing elevated mortality rates. In this review, we present an outline of the chemistry and antitumor properties of metal-based compounds in preclinical (in vitro and in vivo) and clinical OS models, focusing on the relationship between structure-activity, molecular targets and the study of the mechanism of action involved in metallocompound anticancer activity.

[Delayed diagnosis of osteosarcoma in adults: a prognostic factor to be considered]. / Retraso en el diagnóstico de osteosarcoma en adultos: un factor pronóstico que debemos considerar.

INTRODUCTION: different variables have been associated with a worse prognosis of patients with osteosarcoma (OS), highlighting tumor size, location in the axial skeleton and the presence of metastases. The objective of this study is to analyze the prognostic impact of diagnostic delay in osteosarcoma in adults in the Mexican population in a center specialized in sarcomas. MATERIAL AND METHODS: retrospective cohort study from January 1, 2005, to December 31, 2016, 96 patients over 21 years of age with a diagnosis of osteosarcoma were analyzed. RESULTS: the median time to diagnosis from the onset of symptoms was six months (range: 2-36). This variable was dichotomized by applying the operator-dependent curve (ROC) analysis and we determined a cut-off value greater than five months, with an area under the curve (AUC) = 0.93 [95% CI 0.86-0.97], sensitivity 93.2% and specificity 94.6%. CONCLUSION: time until diagnosis is a critical factor in the survival of adult patients with osteosarcoma, highlighting its influence on disease progression and the appearance of metastasis. The correlation between diagnostic delay and an unfavorable prognosis reinforces the need for rapid and efficient evaluation in suspected cases of osteosarcoma.

INTRODUCCIÓN: diferentes variables se han asociado con un peor pronóstico de los pacientes con osteosarcoma, destacando el tamaño tumoral, la localización en esqueleto axial y la presencia de metástasis. El objetivo de este estudio fue analizar el impacto pronóstico del retraso diagnóstico en osteosarcoma en adultos en población mexicana en un centro especializado en sarcomas. MATERIAL Y MÉTODOS: estudio de tipo cohorte retrospectiva del 1 de Enero del 2005 al 31 de Diciembre de 2016, se analizaron 96 pacientes mayores de 21 años con diagnóstico de osteosarcoma. RESULTADOS: la mediana de tiempo al diagnóstico desde el inicio de síntomas fue de seis meses (rango: 2-36). Esta variable se dicotomizó aplicando el análisis de curva dependiente de operador (ROC) y determinamos un valor de corte mayor a cinco meses con un área bajo la curva (AUC) = 0.93 [IC95% 0.86-0.97], sensibilidad 93.2% y especificidad 94.6%. CONCLUSIÓN: el tiempo hasta el diagnóstico es un factor crítico en la supervivencia de los pacientes adultos con osteosarcoma, destacando su influencia en la progresión de la enfermedad y la aparición de metástasis. La correlación entre el retraso diagnóstico y un pronóstico desfavorable refuerza la necesidad de una evaluación rápida y eficiente en casos sospechosos de osteosarcoma.

Parosteal osteosarcoma with low grade chondrosarcoma and liposarcoma components. A rare histologic variant. Case report and literature review.

INTRODUCTION: conventional parosteal osteosarcoma is an uncommon malignant bone tumor, comprising 4% of all osteosarcomas. Although rare, parosteal osteosarcoma is the most common type of osteosarcoma of the bone surface. We present the clinical, histological and imaging characteristics of a rare histologic variant of a parosteal osteosarcoma, review the literature and emphasize the importance of radio-pathological correlation as well as the interpretation of a representative biopsy in order to obtain the correct diagnosis. CASE REPORT: a 36-year old woman began her condition one year prior to admission to the hospital with increased volume in the left knee and pain. Image studies showed a juxtacortical heterogeneous tumor localized on the posterior surface of the distal femoral metaphysis. An incisional biopsy was performed, with the diagnosis of a Parosteal Osteosarcoma and a wide surgical resection was undertaken. According to the findings of the surgical specimen, the diagnosis of a Parosteal Osteosarcoma with low grade chondrosarcoma and liposarcoma components was made. The knowledge of this rare parosteal osteosarcoma variant can lead the orthopedic oncologists to avoid overlooking the adipose component and provide adequate surgical margins. CONCLUSION: we present the clinical, histological and imaging characteristics of a Parosteal Osteosarcoma with low grade liposarcoma and chondrosarcoma components.

INTRODUCCIÓN: el osteosarcoma parosteal convencional es un tumor óseo maligno poco común, que comprende el 4% de todos los osteosarcomas. Aunque es poco común, el osteosarcoma parosteal es el tipo más común de osteosarcoma de la superficie ósea. Presentamos las características clínicas, histológicas y de imagen de una variante histológica rara de un osteosarcoma parosteal, revisamos la literatura y enfatizamos la importancia de la correlación radio-patológica, así como la interpretación de una biopsia representativa para obtener el diagnóstico correcto. REPORTE DE CASO: mujer de 36 años inició su cuadro un año antes de su ingreso al hospital con aumento de volumen en rodilla izquierda y dolor. Los estudios de imagen mostraron una tumoración heterogénea yuxtacortical localizada en la superficie posterior de la metáfisis femoral distal. Se realizó biopsia incisional, con diagnóstico de osteosarcoma parosteal y se realizó resección quirúrgica amplia. De acuerdo con los hallazgos de la pieza quirúrgica se realizó el diagnóstico de osteosarcoma parosteal con componentes de condrosarcoma y liposarcoma de bajo grado. El conocimiento de esta rara variante de osteosarcoma parosteal puede llevar a los ortopedistas oncólogos a considerar otros componentes y proporcionar márgenes quirúrgicos adecuados. CONCLUSIÓN: presentamos las características clínicas, histológicas y de imagen de un osteosarcoma parosteal con componentes de liposarcoma y condrosarcoma de bajo grado.

Alteration in the Expression of Circular Rnas and its association with the Development and Progression of Osteosarcoma, an Integrative Review with High Sensitivity Research.

BACKGROUND: Osteosarcoma is the most common primary malignant bone tumor, mainly affecting children, young adults, and the elderly. It is an aggressive cancer with a poor prognosis, exhibiting low survival rates even with standard treatment. Recently, circular RNA molecules capable of influencing gene expression through various functions, with their main role being acting as microRNA sponges and reducing their intracellular expression, have been identified. Recent studies have linked circular RNAs to osteosarcoma development and progression. Therefore, the present study aimed to investigate the alteration in circular RNA expression during osteosarcoma development and progression. METHODS: An integrative literature review was conducted from September 10th to November 12th, 2021, using the following databases: PubMed/MEDLINE, SCOPUS, Web of Science, OVID, and EMBASE. 129 full articles were included in the review. The obtained data were organized using a standardized data collection instrument, which included the following information: altered expression profile of circular RNAs, associated cancer hallmarks, clinical-pathological relationships of circular RNAs, and perspectives on the studied circular RNAs. RESULTS: A total of 94 distinct circular RNAs were identified, predominantly showing an increased expression pattern. Approximately 91% of the studies that aimed to identify the mechanisms of action of circular RNAs highlighted the function of circular RNAs as microRNA sponges. The most associated cancer hallmarks with the identified circular RNAs were proliferative signaling induction, invasion and metastasis, and resistance to cell death. The altered expression of these circular RNAs generally correlated with a worse prognosis for patients, as evidenced by clinical features such as shorter survival, advanced Enneking and/or TNM stage, higher incidence of metastasis, larger tumor size, and increased chemoresistance. CONSLUSION: These findings indicate the significance of circular RNA molecules in osteosarcoma carcinogenesis, suggesting their potential as new prognostic and/or diagnostic biomarkers, as well as alternative therapeutic targets in the fight against osteosarcoma.

Osteosarcoma cells exhibit functional interactions with stromal cells, fostering a lung microenvironment conducive to the establishment of metastatic tumor cells.

BACKGROUND: Osteosarcoma (OS) stands out as the most common bone tumor, with approximately 20% of the patients receiving a diagnosis of metastatic OS at their initial assessment. A significant challenge lies in the frequent existence of undetected metastases during the initial diagnosis. Mesenchymal stem cells (MSCs) possess unique abilities that facilitate tumor growth, and their interaction with OS cells is crucial for metastatic spread. METHODS AND RESULTS: We demonstrated that, in vitro, MSCs exhibited a heightened migration response toward the secretome of non-metastatic OS cells. When challenged to a secretome derived from lungs preloaded with OS cells, MSCs exhibited greater migration toward lungs colonized with metastatic OS cells. Moreover, in vivo, MSCs displayed preferential migratory and homing behavior toward lungs colonized by metastatic OS cells. Metastatic OS cells, in turn, demonstrated an increased migratory response to the MSCs' secretome. This behavior was associated with heightened cathepsin D (CTSD) expression and the release of active metalloproteinase 2 (MMP2) by metastatic OS cells. CONCLUSIONS: Our assessment focused on two complementary tumor capabilities crucial to metastatic spread, emphasizing the significance of inherent cell features. The findings underscore the pivotal role of signaling integration within the niche, with a complex interplay of migratory responses among established OS cells in the lungs, prometastatic OS cells in the primary tumor, and circulating MSCs. Pulmonary metastases continue to be a significant factor contributing to OS mortality. Understanding these mechanisms and identifying differentially expressed genes is essential for pinpointing markers and targets to manage metastatic spread and improve outcomes for patients with OS.

Inhibition of anlotinib-induced autophagy attenuates invasion and migration by regulating epithelial-mesenchymal transition and cytoskeletal rearrangement through ATG5 in human osteosarcoma cells

Abstract The cure rates for osteosarcoma have remained unchanged in the past three decades, especially for patients with pulmonary metastasis. Thus, a new and effective treatment for metastatic osteosarcoma is urgently needed. Anlotinib has been reported to have antitumor effects on advanced osteosarcoma. However, both the effect of anlotinib on autophagy in osteosarcoma and the mechanism of anlotinib-mediated autophagy in pulmonary metastasis are unclear. The effect of anlotinib treatment on the metastasis of osteosarcoma was investigated by transwell assays, wound healing assays, and animal experiments. Related proteins were detected by western blotting after anlotinib treatment, ATG5 silencing, or ATG5 overexpression. Immunofluorescence staining and transmission electron microscopy were used to detect alterations in autophagy and the cytoskeleton. Anlotinib inhibited the migration and invasion of osteosarcoma cells but promoted autophagy and increased ATG5 expression. Furthermore, the decreases in invasion and migration induced by anlotinib treatment were enhanced by ATG5 silencing. In addition, Y-27632 inhibited cytoskeletal rearrangement, which was rescued by ATG5 overexpression. ATG5 overexpression enhanced epithelial-mesenchymal transition (EMT). Mechanistically, anlotinib-induced autophagy promoted migration and invasion by activating EMT and cytoskeletal rearrangement through ATG5 both in vitro and in vivo. Our results demonstrated that anlotinib can induce protective autophagy in osteosarcoma cells and that inhibition of anlotinib-induced autophagy enhanced the inhibitory effects of anlotinib on osteosarcoma metastasis. Thus, the therapeutic effect of anlotinib treatment can be improved by combination treatment with autophagy inhibitors, which provides a new direction for the treatment of metastatic osteosarcoma.

Effects of Doxorubicin, Epirubicin, and Liposomal Doxorubicin (Anthracycline) on cardiac function in patients with osteosarcoma and their influencing factors.

OBJECTIVE: The objective of this study was to investigate the impact of Doxorubicin, Epirubicin, and Liposomal Doxorubicin (Anthracycline) on cardiac function in osteosarcoma patients and analyze the factors influencing this effect. METHODS: A retrospective study was conducted on 165 osteosarcoma patients admitted to our hospital from January 2020 to December 2022. Based on the chemotherapy regimen, the patients were divided into two groups: the control group (n = 62) treated with Cisplatin and cyclophosphamide, and the observation group (n = 103) treated with Doxorubicin, Epirubicin, and Liposomal Doxorubicin (Anthracycline). The general records of both groups were analyzed, and left ventricular ejection fraction (LVEF) was evaluated through echocardiography before and after chemotherapy. Blood cTnT and CK-MB levels were measured using immunoluminescence. The incidence of adverse reactions during chemotherapy was also analyzed. Univariate analysis was performed to identify patients with cardiotoxic events, and multiple logistic regression analysis was done to study the effects of Doxorubicin, Epirubicin, Liposomal Doxorubicin, and their dosages on cardiotoxicity in patients. RESULTS: The general records between the two groups showed no significant differences (P > 0.05). However, at the fourth cycle of chemotherapy, the observation group exhibited a lower LVEF (P < 0.05), and a higher percentage of LVEF decrease compared to the control group (P < 0.05). Moreover, the observation group had higher levels of blood cTnT and CK-MB (P < 0.05). The incidence of cardiotoxicity in the observation group was also higher (P < 0.05), but no significant differences were seen in other adverse reaction rates (P > 0.05). The occurrence of cardiotoxicity was found to be related to the choice and dosage of chemotherapy drugs (P < 0.05), but not significantly correlated with age, sex, and mediastinal irradiation in patients (P > 0.05). Furthermore, the use of Doxorubicin, Epirubicin, and Liposomal Doxorubicin in chemotherapy, as well as an increase in their dosages, was found to elevate the risk of cardiotoxicity in osteosarcoma patients (P < 0.05). However, age, sex, and mediastinal radiation were not significantly associated with cardiotoxicity in osteosarcoma patients (P > 0.05). CONCLUSION: We demonstrated that Doxorubicin, Epirubicin, Liposomal Doxorubicin (Anthracycline), and other drugs adversely affected cardiac function in osteosarcoma patients, increasing the risk of cardiac toxicity. Therefore, close monitoring of cardiac function during chemotherapy is crucial, and timely adjustments to the chemotherapy regimen are necessary. In addition, rational control of drug selection and dosage is essential to minimize the occurrence of cardiac toxicity.

Graphene Oxide (GO) for the Treatment of Bone Cancer: A Systematic Review and Bibliometric Analysis.

Cancer is a severe disease that, in 2022, caused more than 9.89 million deaths worldwide. One worrisome type of cancer is bone cancer, such as osteosarcoma and Ewing tumors, which occur more frequently in infants. This study shows an active interest in the use of graphene oxide and its derivatives in therapy against bone cancer. We present a systematic review analyzing the current state of the art related to the use of GO in treating osteosarcoma, through evaluating the existing literature. In this sense, studies focused on GO-based nanomaterials for potential applications against osteosarcoma were reviewed, which has revealed that there is an excellent trend toward the use of GO-based nanomaterials, based on their thermal and anti-cancer activities, for the treatment of osteosarcoma through various therapeutic approaches. However, more research is needed to develop highly efficient localized therapies. It is suggested, therefore, that photodynamic therapy, photothermal therapy, and the use of nanocarriers should be considered as non-invasive, more specific, and efficient alternatives in the treatment of osteosarcoma. These options present promising approaches to enhance the effectiveness of therapy while also seeking to reduce side effects and minimize the damage to surrounding healthy tissues. The bibliometric analysis of photothermal and photochemical treatments of graphene oxide and reduced graphene oxide from January 2004 to December 2022 extracted 948 documents with its search strategy, mainly related to research papers, review papers, and conference papers, demonstrating a high-impact field supported by the need for more selective and efficient bone cancer therapies. The central countries leading the research are the United States, Iran, Italy, Germany, China, South Korea, and Australia, with strong collaborations worldwide. At the same time, the most-cited papers were published in journals with impact factors of more than 6.0 (2021), with more than 290 citations. Additionally, the journals that published the most on the topic are high impact factor journals, according to the analysis performed, demonstrating the high impact of the research field.

Menadione and protocatechuic acid: A drug combination with antitumor effects in murine osteosarcoma cells.

Osteosarcoma (OS) is a primary malignant bone tumor that has an abnormal expression of oncogenesis and tumor suppressors and causes dysregulation of various signaling pathways. Thus, novel therapeutic strategies for OS are needed to overcome the resistance of traditional treatments. This study evaluated the cytotoxic and anticancer effects of the association between menadione (MEN) and protocatechuic acid (PCA) in murine OS cells (UMR-106). The concentrations were 3.12 µM of isolated MEN, 500 µM of isolated PCA, and their associations. We performed cell viability assays, morphology modification analysis, cell migration by the wound-healing method, apoptosis by flow cytometry, reactive oxygen species (ROS) production, gene expression of NOX by RT-qPCR, and degradation of MMP-2 and 9 by zymography. Our results showed that the association of MEN+PCA was more effective in OS cells than the compounds alone. The association decreased cell viability, delayed cell migration, and decreased the expression of NOX-2 and ROS. In addition, the MEN+PCA association induced a slight increase in the apoptotic process. In summary, the association can enhance the compound's antitumor effects and establish a higher selectivity for tumor cells, possibly caused by significant mitochondrial damage and antioxidant properties.

Exploring the logic and conducting a comprehensive evaluation of AdipoRon-based adiponectin replacement therapy against hormone-related cancers-a systematic review.

The potential benefits of adiponectin replacement therapy extend to numerous human diseases, with current research showing particular interest in its effectiveness against specific cancer forms, especially hormone-related. However, limitations in the pharmacological use of the intact protein have led to a focus on alternative options. AdipoRon is an extensively studied non-peptidic drug candidate for adiponectin replacement therapy. While researchers have explored the efficacy and therapeutic applications of AdipoRon in various disease conditions, their effects against cancer models advanced more, with no review regarding AdipoRon's efficacy against hormone-related cancers being published. The present systematic review aims to fill this gap. Preclinical evidence was compiled from PubMed, EMBASE, COCHRANE, and Google Scholar following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and the manuscript's quality assessment was conducted using the Joanna Briggs Institute (JBI) Checklist Critical Appraisal Tool for Systematic Reviews' Quality. The included nine studies incorporated various cell and animal models of the pancreas, gynaecological system, and osteosarcoma cancers. AdipoRon demonstrated effectiveness against pancreatic cancer by activating p44/42 MAPK, mitochondrial dysfunction, and AMPK-mediated inhibition of ACC1. In gynaecological cancers, it exhibited promising anticancer effects through the activation of AMPK, potential inhibition of mTOR, and modulation of the SET1B/BOD1/AdipoR1 signaling cascade. Against osteosarcoma, AdipoRon worked by perturbing ERK1/2 signaling and reducing p70S6K phosphorylation. AdipoRon shows promise in preclinical studies, but human trials are crucial for clinical safety and effectiveness. Caution is needed due to potential off-target effects, especially in cancer therapy with multi-target approaches. Structural biology and computational methods can help predict these effects.

Exploration in the Mechanism of Ginsenoside Rg5 for the Treatment of Osteosarcoma by Network Pharmacology and Molecular Docking.

OBJECTIVE: Osteosarcoma is a primary malignancy originating from mesenchymal tissue characterized by rapid growth, early metastasis and poor prognosis. Ginsenoside Rg5 (G-Rg5) is a minor ginsenoside extracted from Panax ginseng C.A. Meyer which has been discovered to possess anti-tumor properties. The objective of current study was to explore the mechanism of G-Rg5 in the treatment of osteosarcoma by network pharmacology and molecular docking technology. METHODS: Pharmmapper, SwissTargetPrediction and similarity ensemble approach databases were used to obtain the pharmacological targets of G-Rg5. Related genes of osteosarcoma were searched for in the GeneCards, OMIM and DrugBank databases. The targets of G-Rg5 and the related genes of osteosarcoma were intersected to obtain the potential target genes of G-Rg5 in the treatment of osteosarccoma. The STRING database and Cytoscape 3.8.2 software were used to construct the protein-protein interaction (PPI) network, and the Database for Annotation, Visualization and Integrated Discovery (DAVID) platform was used to perform gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. AutoDock vina software was used to perform molecular docking between G-Rg5 and hub targets. The hub genes were imported into the Kaplan-Meier Plotter online database for survival analysis. RESULTS: A total of 61 overlapping targets were obtained. The related signaling pathways mainly included PI3K-Akt signaling pathway, Proteoglycans in cancer, Lipid and atherosclerosis and Kaposi sarcoma-associated herpesvirus infection. Six hub targets including PIK3CA, SRC, TP53, MAPK1, EGFR, and VEGFA were obtained through PPI network and targets-pathways network analyses. The results of molecular docking showed that the binding energies were all less than -7 kcal/mol. And the results of survival analysis showed TP53 and VEGFA affect the prognosis of sarcoma patients. CONCLUSION: This study explored the possible mechanism of G-Rg5 in the treatment of osteosarcoma using network pharmacology method, suggesting that G-Rg5 has the characteristics of multi-targets and multi-pathways in the treatment of osteosarcoma, which lays a foundation for the follow-up experimental and clinical researches on the therapeutic effects of G-Rg5 on osteosarcoma.

Palladium (II) compounds containing oximes as promising antitumor agents for the treatment of osteosarcoma: An in vitro and in vivo comparative study with cisplatin.

Drug resistance, evasion of cell death and metastasis are factors that contribute to the low cure rate and disease-free survival in osteosarcomas (OS). In this study, we demonstrated that a new class of oxime-containing organometallic complexes called Pd-BPO (O3) and Pd-BMO (O4) are more cytotoxic than cisplatin (CDDP) for SaOS-2 and U2OS cells using the MTT assay. Annexin-FITC/7-AAD staining demonstrated a greater potential for palladium-oxime complexes to induce death in SaOS-2 cells than CDDP, an event confirmed using the pan-caspase inhibitor Z-VAD-FMK. Compared to CDDP, only palladium-oxime complexes eradicated the clonogenicity of SaOS-2 cells after 7 days of treatment. The involvement of the lysosome-mitochondria axis in the cell death-inducing properties of the complexes was also evaluated. Using LysoTracker Red to label the acidic organelles of SaOS-2 cells treated with the O3 and O4 complexes, a decrease in the fluorescence intensity of this probe was observed in relation to CDDP and the control. Lysosomal membrane permeabilization (LMP) was also induced by the O3 and O4 complexes in an assay using acridine orange (A/O). The greater efficiency of the complexes in depolarizing the mitochondrial membrane compared to SaOS-2 cells treated with CDDP was also observed using TMRE (tetramethyl rhodamine, ethyl ester). For in vivo studies, C. elegans was used and demonstrated that both complexes reduce body bends and pharyngeal pumping after 24 h of treatment to the same extent as CDDP. We conclude that both palladium-oxime complexes are more effective than CDDP in inducing tumor cell death. The toxicity of these complexes to C. elegans was like that induced by CDDP. These results encourage preclinical studies aimed at developing more effective drugs for the treatment of osteosarcoma (OS). Furthermore, we propose palladium-oxime complexes as a new class of antineoplastic agents.

Primary omentum extraskeletal osteosarcoma in a dog: case report.

A rescued male mixed-breed dog, approximately nine years old, was evaluated due to progressive weight loss and an enlarged abdomen. An ultrasound revealed a large, indeterminate mass with mineral-like margins visible on the radiographs. The animal underwent an exploratory laparotomy, and the mass was excised. Histopathological analysis revealed characteristics consistent with a primary omentum extraskeletal osteosarcoma. This rare neoplasm, originating from mesenchymal cell proliferation and bone matrix production, is highly malignant. It often results in death due to metastasis and local recurrence or necessitates euthanasia post-diagnosis in certain cases.

Um canino macho de aproximadamente 9 anos de idade, sem raça definida, foi recebido para atendimento apresentando sinais de emagrecimento progressivo e aumento de volume abdominal. Um exame ultrassonográfico revelou uma formação de grandes dimensões e de origem indeterminada, apresentando característica de mineralização periférica pela radiografia. Foi realizada laparotomia exploratória com remoção da formação. A análise histopatológica revelou características compatíveis com osteossarcoma primário de omento, uma neoplasia rara originada da proliferação de células mesenquimais com produção de matriz óssea, com alto grau de malignidade, geralmente levando à óbito devido a metástases e recorrência local do tumor ou eutanásia após o diagnóstico em alguns casos.

Computed tomography aspects of thoracic metastases from osteosarcoma: pictorial essay.

Osteosarcoma is the most common primary bone tumor, with a higher incidence in the second decade of life, and it often leads to pulmonary metastases. The most common pattern seen on computed tomography is one of multiple well-defined nodules in the lung parenchyma, often with calcifications. Because of the variety of presentations of pulmonary metastases in osteosarcoma, including atypical forms, knowledge of the computed tomography aspects of these lesions is important for characterizing and evaluating the extent of the disease, as well as for distinguishing metastatic disease from other benign or malignant lung diseases. This essay discusses the main tomographic findings of pulmonary metastases from osteosarcoma.

O osteossarcoma é o tumor ósseo primário mais comum, com maior incidência na segunda década de vida, sendo as metástases pulmonares achado frequente. O padrão tomográfico mais comum das metástases pulmonares de osteossarcoma é o de múltiplos nódulos bem definidos no parênquima pulmonar, frequentemente com calcificações. Em razão da multiplicidade de apresentações das metástases pulmonares do osteossarcoma, inclusive com formas atípicas, o conhecimento dos aspectos dessas lesões na tomografia computadorizada do tórax é importante para a caracterização e avaliação da extensão da doença, além de permitir a diferenciação entre doença metastática e outras doenças pulmonares benignas ou malignas. Este ensaio discute os principais achados tomográficos das metástases pulmonares de osteossarcoma.

Contribution of Sonication to the Identification of Megaprosthesis Infection in Culture Negative Oncologic Patient.

Conventional central osteosarcoma mainly affects the metaphysis of long bones in young people. The use of megaprostheses in oncological patients has increased in recent years. However, this type of surgery is not exempt from complications, with infections being the most common. In recent years, the presence of biofilm-forming bacteria has increased. Biofilm characteristics allow bacteria to resist hostile environmental conditions. The application of long wave ultrasound (process known as sonication) on the rescued inert material before culture interrupts the biofilm and generates a significantly higher recovery of bacterial growth compared to conventional tissue culture. We present the case of a 12-year-old patient with osteosarcoma of the femur, who, after surgery, developed a prosthetic infection detected by sonication, with negative soft tissue culture.

Cu(II)-acylhydrazone complex, a potent and selective antitumor agent against human osteosarcoma: Mechanism of action studies over in vitro and in vivo models.

Osteosarcoma (OS) is a frequent bone cancer, affecting largely children and young adults. Cisplatin (CDDP) has been efficacious in the treatment of different cancer such us OS but the development of chemoresistance and important side effects leading to therapeutic failure. Novel therapies including copper compounds have shown to be potentially effective as anticancer drugs and one alternative to usually employed platinum compounds. The goal of this work is the evaluation of the in vitro and in vivo antitumoral activity and dilucidate the molecular target of a Cu(II) cationic complex containing a tridentate hydrazone ligand, CuHL for short, H2L=N'-'-(2-hydroxy-3-methoxybenzylidene)thiophene-2-carbohydrazide, against human OS MG-63 cells. Anticancer activity on MG-63 cell line was evaluated in OS monolayer and spheroids. CuHL significantly impaired cell viability in both models (IC50 2D: 2.1 ± 0.3 µM; 3D: 9.1 ± 1.0 µM) (p < 0.001). Additional cell studies demonstrated the copper compound inhibits cell proliferation and conveys cells to apoptosis, determined by flow cytometry. CuHL showed a great genotoxicity, evaluated by comet assay. Proteomic analysis by Orbitrap Mass Spectometry identified 27 differentially expressed proteins: 17 proteins were found overexpressed and 10 underexpressed in MG-63 cells after the CuHL treatment. The response to unfolded protein was the most affected biological process. In addition, in vivo antitumor effects of the compound were evaluated on human OS tumors xenografted in nude mice. CuHL treatment, at a dose of 2 mg/kg i.p., given three times/week for one month, significantly inhibited the progression of OS xenografts and was associated to a reduction in mitotic index and to an increment of tumor necrosis (p < 0.01). Administration of standard-of-care cytotoxic agent CDDP, following the same treatment schedule as CuHL, failed to impair OS growth and progression.

ROLE OF INCISIONAL VACUUM THERAPY IN ENDOPROSTHETIC BONE RECONSTRUCTION SURGERY.

Reconstructive surgery with endoprostheses is the chosen method for treating bone malignancies. Postoperative infections are frequent complications, and their treatment involves prolonged hospital stays and antibiotic therapy. Among the advancements aimed at reducing the rate of postoperative infection, the use of incisional negative pressure therapy (iNPT) has shown promising results, with no reports in the literature regarding its use in patients with such conditions. Objective: To evaluate the effectiveness of iNPT in reducing postoperative complications in surgeries for resection of bone tumors associated with modular endoprosthesis reconstruction. Methods: Retrospective case series of 16 patients diagnosed with osteosarcoma, who underwent resection and reconstruction with endoprosthesis associated with iNPT during the postoperative period. Follow-up was performed for a period of six months, and the evaluated outcomes were the incidence of postoperative infection and complications of the surgical wound. Results: The use of iNPT for a postoperative period of seven days resulted in only three (18.7%) cases of postoperative infection. No cases of wound dehiscence, seroma formation, or hematoma at the surgical site were observed. Conclusion: The rate of surgical wound complications in our case series is lower than that reported in most of the literature, and iNPT appears to be an efficient way to reduce the rate of local complications in reconstructive surgeries with endoprosthesis after resection of bone malignancies. Level of Evidence III, Retrospective Study.

A cirurgia reconstrutiva com endopróteses é o método escolhido no tratamento de malignidades ósseas. As infecções pós-operatórias são complicações frequentes, e seu tratamento envolve internações e antibioticoterapia prolongadas. Entre os avanços que visam reduzir a taxa de infecção pós-operatória, o uso da terapia com pressão negativa incisional (TPNi) vem mostrando resultados promissores, não havendo relatos na literatura de seu emprego em pacientes com tal quadro. Objetivo: Avaliar a eficácia da TPNi em reduzir complicações pós-operatórias em cirurgias de ressecção de tumores ósseos associadas à reconstrução com endopróteses modulares. Métodos: Série de casos retrospectiva de 16 pacientes diagnosticados com osteossarcoma, submetidos à ressecção e reconstrução com endoprótese associada à TPNi durante o pós-operatório. Foi realizado seguimento por um período de seis meses e os desfechos avaliados foram incidência de infecção pós-operatória e complicações da ferida operatória. Resultados: O uso da TPNi por um período pós-operatório de sete dias resultou em apenas três (18,7%) casos de infecção pós-operatória. Não foram observados casos em que ocorreu deiscência da ferida operatória, formação de seromas ou hematomas no sítio cirúrgico. Conclusão: A taxa de complicações de ferida operatória em nossa série de casos é menor que a da maior parte da literatura, e a TPNi parece ser uma forma eficiente de reduzir a taxa de complicações locais em cirurgias reconstrutivas com endoprótese após ressecção de malignidades ósseas. Nível de Evidência III, Estudo Retrospectivo.

Analysis of the Mutational Landscape of Osteosarcomas Identifies Genes Related to Metastasis and Prognosis and Disrupted Biological Pathways of Immune Response and Bone Development.

Osteosarcoma (OS) is the most prevalent type of bone tumor, but slow progress has been achieved in disentangling the full set of genomic events involved in its initiation and progression. We assessed by NGS the mutational spectrum of 28 primary OSs from Brazilian patients, and identified 445 potentially deleterious SNVs/indels and 1176 copy number alterations (CNAs). TP53 was the most recurrently mutated gene, with an overall rate of ~60%, considering SNVs/indels and CNAs. The most frequent CNAs (~60%) were gains at 1q21.2q21.3, 6p21.1, and 8q13.3q24.22, and losses at 10q26 and 13q14.3q21.1. Seven cases presented CNA patterns reminiscent of complex events (chromothripsis and chromoanasynthesis). Putative RB1 and TP53 germline variants were found in five samples associated with metastasis at diagnosis along with complex genomic patterns of CNAs. PTPRQ, KNL1, ZFHX4, and DMD alterations were prevalent in metastatic or deceased patients, being potentially indicative of poor prognosis. TNFRSF11B, involved in skeletal system development and maintenance, emerged as a candidate for osteosarcomagenesis due to its biological function and a high frequency of copy number gains. A protein-protein network enrichment highlighted biological pathways involved in immunity and bone development. Our findings reinforced the high genomic OS instability and heterogeneity, and led to the identification of novel disrupted genes deserving further evaluation as biomarkers due to their association with poor outcomes.