Primary Malignant Bone Research Articles

Amputation and limb-sparing surgery in childhood sarcoma: Post-operative imaging appearances and complications.

Limb-sparing surgery and amputation are common surgical techniques used to achieve local tumour control in childhood primary bone and soft tissue malignancy of the limbs. The interpretation of post-operative limb imaging in these frequently complex cases is assisted by knowledge of the surgical techniques employed. This review discusses the rationale underpinning the most common surgical techniques used for these patients as well as their expected post-operative imaging appearance and complications. Amputation, long bone resection, endoprosthetic reconstruction, allograft reconstruction, the use of fibular autografts, allograft-prosthetic composite reconstruction and arthrodesis are discussed.

A deep learning model to enhance the classification of primary bone tumors based on incomplete multimodal images in X-ray, CT, and MRI

BackgroundAccurately classifying primary bone tumors is crucial for guiding therapeutic decisions. The National Comprehensive Cancer Network guidelines recommend multimodal images to provide different perspectives for the comprehensive evaluation of primary bone tumors. However, in clinical practice, most patients’ medical multimodal images are often incomplete. This study aimed to build a deep learning model using patients’ incomplete multimodal images from X-ray, CT, and MRI alongside clinical characteristics to classify primary bone tumors as benign, intermediate, or malignant.MethodsIn this retrospective study, a total of 1305 patients with histopathologically confirmed primary bone tumors (internal dataset, n = 1043; external dataset, n = 262) were included from two centers between January 2010 and December 2022. We proposed a Primary Bone Tumor Classification Transformer Network (PBTC-TransNet) fusion model to classify primary bone tumors. Areas under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity were calculated to evaluate the model’s classification performance.ResultsThe PBTC-TransNet fusion model achieved satisfactory micro-average AUCs of 0.847 (95% CI: 0.832, 0.862) and 0.782 (95% CI: 0.749, 0.817) on the internal and external test sets. For the classification of benign, intermediate, and malignant primary bone tumors, the model respectively achieved AUCs of 0.827/0.727, 0.740/0.662, and 0.815/0.745 on the internal/external test sets. Furthermore, across all patient subgroups stratified by the distribution of imaging modalities, the PBTC-TransNet fusion model gained micro-average AUCs ranging from 0.700 to 0.909 and 0.640 to 0.847 on the internal and external test sets, respectively. The model showed the highest micro-average AUC of 0.909, accuracy of 84.3%, micro-average sensitivity of 84.3%, and micro-average specificity of 92.1% in those with only X-rays on the internal test set. On the external test set, the PBTC-TransNet fusion model gained the highest micro-average AUC of 0.847 for patients with X-ray + CT.ConclusionsWe successfully developed and externally validated the transformer-based PBTC-Transnet fusion model for the effective classification of primary bone tumors. This model, rooted in incomplete multimodal images and clinical characteristics, effectively mirrors real-life clinical scenarios, thus enhancing its strong clinical practicability.

Immune-related glycosylation genes based classification predicts prognosis and therapy options of osteosarcoma

Osteosarcoma is the most common primary bone malignancy, with a very poor prognosis. Aberrant glycosylation is close involvement in osteosarcoma. Accordingly, this study aimed at investigating the role of glycosylation genes in the prognosis and therapy options of osteosarcoma. The microenvironment of osteosarcoma was assessed using estimate algorithm. A total of 20 immune-related glycosylation genes (IRGGs) was identified using Pearson correlation analysis. Accordingly, osteosarcoma patients were divided into C1 and C2 type using consensus clustering. Multiple algorithms (Xcell, MCP-counter, ssGSEA, epic, quantiseq), cancer immune cycle analysis, and GSVA were applied to estimate the immune, molecule and metabolism characteristics of osteosarcoma, indicating that C1 type was featured with high immune infiltration, high glycosylation, enriched MEK signaling, and good prognosis, while C2 type was characterized by more metastasis, enriched immunotherapy-positive gene signatures, high tumor mutation burden, and poor prognosis. Results from TIDE algorithm and immunotherapy datasets suggested the C2 type’s preference of immune checkpoint inhibitors (ICIs), while data of GDSC, CMap analysis and cell experiments indicated that C1 type was sensitivity to MEK inhibitor PD0325901. In addition, univariate Cox and Lasso analysis was combined to establish an IRGGs’ risk score containing 6 genes (B3GNT8, FUT7, GAL3ST4, GALNT14, HS3ST2, and MFNG). The data of DCA and ROC indicated its well prediction of prognosis in osteosarcoma. Finally, cellular location analysis showed that the 6 genes not only distributed in tumor cells but also in immune cells. In summary, the classification and risk score based on IRGGs effectively predicted the prognosis and therapy options of osteosarcoma. Further studies on IRGGs may contribute to the understanding of cancer immunity in osteosarcoma.

Is Information About Musculoskeletal Malignancies From Large Language Models or Web Resources at a Suitable Reading Level for Patients?

Patients and caregivers may experience immense distress when receiving the diagnosis of a primary musculoskeletal malignancy and subsequently turn to internet resources for more information. It is not clear whether these resources, including Google and ChatGPT, offer patients information that is readable, a measure of how easy text is to understand. Since many patients turn to Google and artificial intelligence resources for healthcare information, we thought it was important to ascertain whether the information they find is readable and easy to understand. The objective of this study was to compare readability of Google search results and ChatGPT answers to frequently asked questions and assess whether these sources meet NIH recommendations for readability. (1) What is the readability of ChatGPT-3.5 as a source of patient information for the three most common primary bone malignancies compared with top online resources from Google search? (2) Do ChatGPT-3.5 responses and online resources meet NIH readability guidelines for patient education materials? This was a cross-sectional analysis of the 12 most common online questions about osteosarcoma, chondrosarcoma, and Ewing sarcoma. To be consistent with other studies of similar design that utilized national society frequently asked questions lists, questions were selected from the American Cancer Society and categorized based on content, including diagnosis, treatment, and recovery and prognosis. Google was queried using all 36 questions, and top responses were recorded. Author types, such as hospital systems, national health organizations, or independent researchers, were recorded. ChatGPT-3.5 was provided each question in independent queries without further prompting. Responses were assessed with validated reading indices to determine readability by grade level. An independent t-test was performed with significance set at p < 0.05. Google (n = 36) and ChatGPT-3.5 (n = 36) answers were recorded, 12 for each of the three cancer types. Reading grade levels based on mean readability scores were 11.0 ± 2.9 and 16.1 ± 3.6, respectively. This corresponds to the eleventh grade reading level for Google and a fourth-year undergraduate student level for ChatGPT-3.5. Google answers were more readable across all individual indices, without differences in word count. No difference in readability was present across author type, question category, or cancer type. Of 72 total responses across both search modalities, none met NIH readability criteria at the sixth-grade level. Google material was presented at a high school reading level, whereas ChatGPT-3.5 was at an undergraduate reading level. The readability of both resources was inadequate based on NIH recommendations. Improving readability is crucial for better patient understanding during cancer treatment. Physicians should assess patients' needs, offer them tailored materials, and guide them to reliable resources to prevent reliance on online information that is hard to understand. Level III, prognostic study.

Osteosarcoma Metastasis to the Thorax: A Pictorial Review of Chest Computed Tomography Findings.

Background: Osteosarcoma, a primary bone malignancy in children and adolescents, frequently metastasizes to the lungs, contributing significantly to morbidity and mortality. Lung Metastases: At diagnosis, 15-20% of patients present with detectable lung metastases. Chest computed tomography (CT) is vital for the early detection and monitoring of these metastases. Lung involvement typically presents as multiple nodules of varying sizes and can include atypical features such as cavitation, cystic lesions, ground-glass halos, intravascular tumor thrombi, and endobronchial disease. Additional Findings: Pleural metastasis often occurs alongside pulmonary disease, and complications like spontaneous pneumothorax may arise. Additional findings may include thoracic lymphadenopathy, cardiac tumor thrombus, and chest wall deposits. Conclusion: Familiarity with these imaging patterns is essential for radiologists to ensure timely diagnosis and effective management. This review highlights the critical role of chest CT in detecting and characterizing osteosarcoma metastasis.

Whole genome and reverse protein phase array landscapes of patient derived osteosarcoma xenograft models

Osteosarcoma is the most common primary bone malignancy in children and young adults, and it has few treatment options. As a result, there has been little improvement in survival outcomes in the past few decades. The need for models to test novel therapies is especially great in this disease since it is both rare and does not respond to most therapies. To address this, an NCI-funded consortium has characterized and utilized a panel of patient-derived xenograft models of osteosarcoma for drug testing. The exomes, transcriptomes, and copy number landscapes of these models have been presented previously. This study now adds whole genome sequencing and reverse-phase protein array profiling data, which can be correlated with drug testing results. In addition, four additional osteosarcoma models are described for use in the research community.

Chalcones induce apoptosis, autophagy and reduce spreading in osteosarcoma 3D models

Osteosarcoma is the most common primary bone malignancy with a challenging prognosis marked by a high rate of metastasis. The limited success of current treatments may be partially attributed to an incomplete understanding of osteosarcoma pathophysiology and to the absence of reliable in vitro models to select the best molecules for in vivo studies. Among the natural compounds relevant for osteosarcoma treatment, Licochalcone A (Lic-A) and chalcone derivatives are particularly interesting. Here, Lic-A and selected derivatives have been evaluated for their anticancer effect on multicellular tumor spheroids from MG63 and 143B osteosarcoma cell lines. A metabolic activity assay revealed Lic-A, 1i, and 1k derivatives as the most promising candidates. To delve into their mechanism of action, caspase activity assay was conducted in 2D and 3D in vitro models. Notably, apoptosis and autophagic induction was generally observed for Lic-A and 1k. The invasion assay demonstrated that Lic-A and 1k possess the ability to mitigate the spread of osteosarcoma cells within a matrix. The effectiveness of chalcone as a natural scaffold for generating potential antiproliferative agents against osteosarcoma has been demonstrated. In particular, chalcones exert their antiproliferative activity by inducing apoptosis and autophagy, and in addition they are capable of reducing cell invasion. These findings suggest Lic-A and 1k as promising antitumor agents against osteosarcoma cells.

Disrupting YAP1-mediated glutamine metabolism induces synthetic lethality alongside ODC1 inhibition in osteosarcoma.

Osteosarcoma, a highly malignant primary bone tumor primarily affecting adolescents, frequently develops resistance to initial chemotherapy, leading to metastasis and limited treatment options. Our study aims to uncover novel therapeutic targets for metastatic and recurrent osteosarcoma. In this study, we proved the potential of modulating the YAP1-regulated glutamine metabolic pathway to augment the response of OS to DFMO. We initially employed single-cell transcriptomic data to gauge the activation level of polyamine metabolism in MTAP-deleted OS patients. This was further substantiated by transcriptome sequencing data from recurrent and non-recurrent patient tissues, confirming the activation of polyamine metabolism in progressive OS. Through high-throughput drug screening, we pinpointed CIL56, a YAP1 inhibitor, as a promising candidate for a combined therapeutic strategy with DFMO. In vivo, we utilized PDX and CDX models to validate the therapeutic efficacy of this drug combination. In vitro, we conducted western blot analysis, qPCR analysis, immunofluorescence staining, and PuMA experiments to monitor alterations in molecular expression, distribution, and tumor metastasis capability. We employed CCK-8 and colony formation assays to assess the proliferative capacity of cells in the experimental group. We used flow cytometry and reactive oxygen probes to observe changes in ROS and glutamine metabolism within the cells. Finally, we applied RNA-seq in tandem with metabolomics to identify metabolic alterations in OS cells treated with a DFMO and CIL56 combination. This enabled us to intervene and validate the role of the YAP1-mediated glutamine metabolic pathway in DFMO resistance. Through single-cell RNA-seq data analysis, we pinpointed a subset of late-stage OS cells with significantly upregulated polyamine metabolism. This upregulation was further substantiated by transcriptomic profiling of recurrent and non-recurrent OS tissues. High-throughput drug screening revealed a promising combination strategy involving DFMO and CIL56. DFMO treatment curbs the phosphorylation of YAP1 protein in OS cells, promoting nuclear entry and initiating the YAP1-mediated glutamine metabolic pathway. This reduces intracellular ROS levels, countering DFMO's anticancer effect. The therapeutic efficacy of DFMO can be amplified both in vivo and in vitro by combining it with the YAP1 inhibitor CIL56 or the glutaminase inhibitor CB-839. This underscores the significant potential of targeting the YAP1-mediated glutamine metabolic pathway to enhance efficacy of DFMO. Our findings elucidate YAP1-mediated glutamine metabolism as a crucial bypass mechanism against DFMO, following the inhibition of polyamine metabolism. Our study provides valuable insights into the potential role of DFMO in an "One-two Punch" therapy of metastatic and recurrent osteosarcoma.

Therapeutic impacts of GNE‑477‑loaded H2O2 stimulus‑responsive dodecanoic acid‑phenylborate ester‑dextran polymeric micelles on osteosarcoma.

Osteosarcoma (OS) is a highly malignant primary bone neoplasm that is the leading cause of cancer‑associated death in young people. GNE‑477 belongs to the second generation of mTOR inhibitors and possesses promising potential in the treatment of OS but dose tolerance and drug toxicity limit its development and utilization. The present study aimed to prepare a novel H2O2 stimulus‑responsive dodecanoic acid (DA)‑phenylborate ester‑dextran (DA‑B‑DEX) polymeric micelle delivery system for GNE‑477 and evaluate its efficacy. The polymer micelles were characterized by morphology, size and critical micelle concentration. The GNE‑477 loaded DA‑B‑DEX (GNE‑477@DBD) tumor‑targeting drug delivery system was established and the release of GNE‑477 was measured. The cellular uptake of GNE‑477@DBD by three OS cell lines (MG‑63, U2OS and 143B cells) was analyzed utilizing a fluorescent tracer technique. The hydroxylated DA‑B was successfully grafted onto dextran at a grafting rate of 3%, suitable for forming amphiphilic micelles. Following exposure to H2O2, the DA‑B‑DEX micelles ruptured and released the drug rapidly, leading to increased uptake of GNE‑477@DBD by cells with sustained release of GNE‑477. The in vitro experiments, including MTT assay, flow cytometry, western blotting and RT‑qPCR, demonstrated that GNE‑477@DBD inhibited tumor cell viability, arrested cell cycle in G1 phase, induced apoptosis and blocked the PI3K/Akt/mTOR cascade response. In vivo, through the observation of mice tumor growth and the results of H&E staining, the GNE‑477@DBD group exhibited more positive therapeutic outcomes than the free drug group with almost no adverse effects on other organs. In conclusion, H2O2‑responsive DA‑B‑DEX presents a promising delivery system for hydrophobic anti‑tumor drugs for OS therapy.

Oncolytic Viral Therapy in Osteosarcoma.

Primary bone malignancies, including osteosarcoma (OS), are rare but aggressive. Current OS treatment, involving surgical resection and chemotherapy, has improved survival for non-metastatic cases but remains ineffective for recurrent or metastatic OS. Oncolytic viral therapy (OVT) is a promising alternative, using naturally occurring or genetically modified viruses to selectively target and lyse cancer cells and induce a robust immune response against remaining OS cells. Various oncolytic viruses (OVs), such as adenovirus, herpes simplex virus, and measles virus, have demonstrated efficacy in preclinical OS models. Combining OVT with other therapeutics, such as chemotherapy or immunotherapy, may further improve outcomes. Despite these advances, challenges in reliability of preclinical models, safety, delivery, and immune response must be addressed to optimize OVT for clinical use. Future research should focus on refining delivery methods, exploring combination treatments, and clinical trials to ensure OVT's efficacy and safety for OS. Overall, OVT represents a novel approach with the potential to drastically improve survival outcomes for patients with OS.

CXCL6-CXCR2 axis-mediated PD-L2+ mast cell accumulation shapes the immunosuppressive microenvironment in osteosarcoma

Osteosarcoma (OS) is the most common primary bone malignancy and has a high propensity for local invasion and metastasis. The tumour microenvironment of OS is infiltrated by a large number of immune cells, which play a crucial role in its progression and prognosis. Mast cells are important innate immune cells in the tumour stroma and exhibit different phenotypes in diverse tumour microenvironments. However, the underlying mechanisms of mast cell accumulation and the phenotypic characteristics of mast cells in OS remain poorly understood. In this article, we found for the first time that mast cell accumulation in osteosarcoma tissue was modulated by the CXCL6-CXCR2 axis and that the number of infiltrating mast cells was significantly greater in tumour tissues than in adjacent nontumour tissues. These tumour-infiltrating mast cells express high levels of the immunosuppressive molecule PD-L2, and survival analyses revealed that patients in the PD-L2+ high-expression group had a worse prognosis. In vitro, mast cells were induced to express PD-L2 in a time- and dose-dependent manner using OS tissue culture supernatants to mimic the tumour microenvironment. Mechanistic studies revealed that tumour cell-derived G-CSF significantly induced mast cell PD-L2 expression by activating STAT3. Importantly, mast cells overexpressing PD-L2 inhibit tumour-specific CD8+ T-cell proliferation and tumour-killing cytokine secretion, which is reversed by blocking PD-L2 on mast cells. Therefore, our findings provide new insight into the immunosuppressive and tumorigenic roles of mast cells, as well as a novel mechanism by which PD-L2-expressing mast cells mediate immune tolerance.

Casticin induces ferroptosis in human osteosarcoma cells through Fe2+ overload and ROS production mediated by HMOX1 and LC3-NCOA4

Osteosarcoma is a primary solid bone malignancy, and surgery + chemotherapy is the most commonly used treatment. However, chemotherapeutic drugs can cause a range of side effects. Casticin, a polymethoxyflavonoid, has anti-tumor therapeutic effects. This study is aim to investigate the anti-osteosarcoma activity of casticin and explore the mechanism. Crystal violet staining, MTT assay, colony formation assay, wound healing assay, transwell assay, hoechst 33,258 staining, and flow cytometry analysis were used to investigate the effects of casticin on proliferation, migration, invasion, and apoptosis of osteosarcoma cells in vitro. The intracellular Fe2+, ROS, MDA, GSH/GSSG content changes were detected using the corresponding assay kits. The mRNA sequencing + bioinformatics analysis and western blot were used to detect the possible mechanism. We found that casticin caused G2/M phase cell cycle arrest in human osteosarcoma cells, inhibited the migration and invasion, and induced cell apoptosis and ferroptosis. Mechanistic studies showed the ferroptosis pathway was enriched stronger than apoptosis. Casticin up-regulated the expression of HMOX1, LC3 and NCOA4, meanwhile it activated MAPK signaling pathways. Animal experiments proved that casticin also inhibited the growth and metastasis of osteosarcoma cell xenograft tumor in vivo. In conclusion, casticin can induce ferroptosis in osteosarcoma cells through Fe2+ overload and ROS production mediated by HMOX1 and LC3-NCOA4. This provides a new strategy for osteosarcoma treatment.

Comprehensive single cell transcriptomics analysis of murine osteosarcoma uncovers Skp2 function in metastasis, genomic instability and immune activation and reveals additional target pathways.

Osteosarcoma (OS) is the most common primary pediatric bone malignancy. One promising new therapeutic target is SKP2, encoding a substrate recognition factor of the SCF E3 ubiquitin ligase responsible for ubiquitination and proteasome degradation of substrate p27, thus driving cellular proliferation. We have shown previously that knockout of Skp2 in an immunocompetent transgenic mouse model of OS improved survival, drove apoptosis, and induced tumor inflammation. Here, we applied single-cell RNA-sequencing (scRNA-seq) to study primary OS tumors derived from Osx-Cre driven conditional knockout of Rb1 and Trp53. We showed that murine OS models recapitulate the tumor heterogeneity and microenvironment complexity observed in patient tumors. We further compared this model with OS models with functional disruption of Skp2: one with Skp2 knockout and the other with the Skp2-p27 interaction disrupted (resulting in p27 overexpression). We found reduction of T cell exhaustion and upregulation of interferon activation, along with evidence of replicative and endoplasmic reticulum-related stress in the Skp2 disruption models, and showed that interferon induction was correlated with improved survival in OS patients. Additionally, our scRNA-seq analysis uncovered decreased activities of metastasis-related gene signatures in the Skp2-disrupted OS, which we validated by observation of a strong reduction in lung metastasis in the Skp2 knockout mice. Finally, we report several potential mechanisms of escape from targeting Skp2 in OS, including upregulation of Myc targets, DNA copy number amplification and overexpression of alternative E3 ligase genes, and potential alternative lineage activation. These mechanistic insights into OS tumor biology and Skp2 function suggest novel targets for new, synergistic therapies, while the data and our comprehensive analysis may serve as a public resource for further big data-driven OS research.

From bimodal to unimodal: The transformed incidence of osteosarcoma in the United States

BackgroundOsteosarcoma is the most common primary bone malignancy. It has classically been described as having a bimodal incidence by age. We sought to identify whether the bimodal incidence distribution still exists for osteosarcoma using the SEER and NIS databases. MethodsIncidence rates of primary osteosarcoma between 2000–2021 were analyzed by age at diagnosis, year of occurrence, sex, and tumor site from the SEER Research Data, 17 Registries, Nov 2023 Sub (2000–2021). The incidence of cases in 35–64 year-olds and 65 and above was compared statistically to determine if there is an increased incidence in the later ages. Incidence of tumors of the long bones of the lower limbs from the NIS discharge database 2012–2019 was also analyzed for comparison. ResultsOverall, 5,129 cases of osteosarcoma were reported in the SEER database. Across the 22 calendar year span, a consistent first peak appeared in the second decade of life. There was no consistent second peak in the 35+ age group. There were 86,100 discharges with long bone tumors analyzed in the NIS data which exhibited nearly identical patterns. ConclusionsOur analysis shows that the incidence of osteosarcoma is no longer bimodally distributed but rather unimodally distributed.

Immunohistochemical Investigation into Protein Expression Patterns of FOXO4, IRF8 and LEF1 in Canine Osteosarcoma

Osteosarcoma (OSA) is the most common type of primary bone malignancy in people and dogs. Our previous molecular comparisons of canine OSA against healthy bone resulted in the identification of differentially expressed protein-expressing genes (forkhead box protein O4 (FOXO4), interferon regulatory factor 8 (IRF8), and lymphoid enhancer binding factor 1 (LEF1)). Immunohistochemistry (IHC) and H-scoring provided semi-quantitative assessment of nuclear and cytoplasmic staining alongside qualitative data to contextualise staining (n = 26 patients). FOXO4 was expressed predominantly in the cytoplasm with significantly lower nuclear H-scores. IRF8 H-scores ranged from 0 to 3 throughout the cohort in the nucleus and cytoplasm. LEF1 was expressed in all patients with significantly lower cytoplasmic staining compared to nuclear. No sex or anatomical location differences were observed. While reduced levels of FOXO4 might indicate malignancy, the weak or absent protein expression limits its primary use as diagnostic tumour marker. IRF8 and LEF1 have more potential for prognostic and diagnostic uses and facilitate further understanding of their roles within their respective molecular pathways, including Wnt/beta-catenin/LEF1 signalling and differential regulation of tumour suppressor genes. Deeper understanding of the mechanisms involved in OSA are essential contributions towards the development of novel diagnostic, prognostic, and treatment options in human and veterinary medicine contexts.

ASPECTS ÉPIDÉMIOLOGIQUES, DIAGNOSTIQUES, THÉRAPEUTIQUES ET PRONOSTIQUES DES TUMEURS OSSEUSES PRIMITIVES MALIGNES AU CENTRE HOSPITALO-UNIVERSITAIRE (CGU) GABRIEL TOURÉ, BAMAKO, MALI

Introduction: Primary bone cancers account for less than 0.2% of malignancies. There are preferential locations according to the histological type. Objective: to study the epidemiological, diagnostic, therapeutic and evolutionary aspects of primary malignant bone tumors. Patients and method: This was a retrospective study of data from January 1, 2012 to December 31, 2022 on malignant bone tumors at the Gabriel Touré CHU. Results: During our study the hospital frequency was 0.10%. The sex ratio was 1.8 and the average age of patients 37.9. The average time to visit the hospital was six months. Biopsy was the majority 63.9%. The diagnosis has always been confirmed by anatomopathology. Osteosarcomas were common 27.78%. Well-differentiated forms accounted for 58.36%. The multidisciplinary consultation meeting was held in 36.33% of patients and 47.22% of patients received chemotherapy. Excision was the most commonly used surgical procedure 50% of cases. The survival rate was 30.6% at 5 years. Conclusion: Malignant primary bone tumors are relatively rare at Gabriel Toure UHC. Preferred location was the femur. The majority of our patients were seen late with advanced osteolytic lesions. The most common histological type was osteosarcoma. The low rate of amputation and improved survival under treatment are well known. However, survival at 5 years remains reserved.

ASPECTS EPIDEMIOLOGIQUES, DIAGNOSTIQUES ET THERAPEUTIQUES DES ADENOMES CORTICOTROPES AU CENTRE HOSPITALIER NATIONAL UNIVERSITAIRE (CHNU) DE FANN

Introduction: Primary bone cancers account for less than 0.2% of malignancies. There are preferential locations according to the histological type. Objective: to study the epidemiological, diagnostic, therapeutic and evolutionary aspects of primary malignant bone tumors. Patients and method: This was a retrospective study of data from January 1, 2012 to December 31, 2022 on malignant bone tumors at the Gabriel Touré CHU. Results: During our study the hospital frequency was 0.10%. The sex ratio was 1.8 and the average age of patients 37.9. The average time to visit the hospital was six months. Biopsy was the majority 63.9%. The diagnosis has always been confirmed by anatomopathology. Osteosarcomas were common 27.78%. Well-differentiated forms accounted for 58.36%. The multidisciplinary consultation meeting was held in 36.33% of patients and 47.22% of patients received chemotherapy. Excision was the most commonly used surgical procedure 50% of cases. The survival rate was 30.6% at 5 years. Conclusion: Malignant primary bone tumors are relatively rare at Gabriel Toure UHC. Preferred location was the femur. The majority of our patients were seen late with advanced osteolytic lesions. The most common histological type was osteosarcoma. The low rate of amputation and improved survival under treatment are well known. However, survival at 5 years remains reserved.

Ziyuglycoside II, a triterpene glycoside compound in Sanguisorbae officinalis l. extract, suppresses metastasis in osteosarcoma via CBX4-mediated Wnt/β-catenin signal pathway

BackgroundOsteosarcoma (OS), the most prevalent primary bone malignancy, exhibits rapid growth and a high tendency for lung metastasis, posing significant treatment challenges. Ziyuglycoside II (ZGS II), a main active compound derived from Sanguisorba officinalis l., has shown potential in cancer treatment. However, the effects of ZGS II and its potential mechanism in OS remain elusive. PurposeThis study aims to explore the anti-metastatic potential of ZGS II in OS, offering a novel therapeutic strategy for improved patient outcomes. MethodsCell viability and proliferation was detected by cell counting kit-8 (CCK-8) and clone formation assay, respectively. Transwell and wound-healing assay were applied to evaluate the potential metastatic abilities of OS cells in vitro. More critically, the chromobox protein homolog 4 (CBX4) and Wnt/β-catenin signaling pathway was investigated utilizing Western blotting, immunohistochemistry, shRNA knockdown and immunofluorescence. An orthotopic metastasis mouse model was utilized to evaluate the efficacy of ZGS II in suppressing OS metastasis in vivo, with molecular docking studies conducted to elucidate the interaction between ZGS II and the CBX4 protein. ResultsOur study demonstrated the potent inhibitory effects of ZGS II on OS cell proliferation and induced apoptosis in vitro, as evidenced by decreased cell viability, enhanced caspase-3 activation, and mitochondrial dysfunction. Furthermore, using an orthotopic metastasis mouse model, we illustrated that ZGS II effectively suppressed tumor growth and lung metastasis in vivo. Notably, our investigation revealed that the antitumor action of ZGS II is dependent on the reduction of CBX4 levels, leading to the attenuation of the Wnt/β-catenin signaling pathway activation. Molecular docking analyses supported this pathway's suppression, showing that ZGS II has the capability to directly bind and disrupt CBX4 function. To further confirm this mechanism, we utilized shRNA to silence CBX4 in OS cells, which significantly enhanced the inhibitory impact of ZGS II on cell migration. ConclusionOur study findings reveal that ZGS II efficiently suppresses both metastasis and tumor growth in OS by a novel mechanism that entails the inhibition of the CBX4-regulated Wnt/β-catenin pathway. These outcomes highlight the promising potential of ZGS II as a therapeutic agent for managing metastatic OS, thus justifying the need for additional clinical investigations

COMORBIDITY IN ONCOLOGY: MODERN CHALLENGES AND THE SEARCH FOR WAYS TO SOLVE THE PROBLEM

Introduction. The article is devoted to the current problem of modern oncology – increasing the treatment effectiveness of cancer patients with comorbidities. Comorbidity is accompanied by higher rates of mortality, disability, side effects of treatment, increased use of the patient's body resources, and lower quality of life. The aim of the study. To develop a method of recurrence prevention after bone lesions resection and bone replacement surgery for malignant primary bone tumors, which would ensure a longer duration of the 1st recurrence-free period in patients with comorbidities. Materials and methods. The study included a control group consisting of 27 patients who underwent bone replacement surgery after removal of primary malignant tumors of the pelvis and lower extremities. The study group included 25 patients who underwent biomin bone replacement surgery after removal of malignant primary tumors of the pelvic bones and lower limbs, as well as neuropeptide therapy with the drug dalargin. Results. The obtained data testify to the effectiveness of the proposed method of treatment with the use of dalargin: compaction of the structure of compact and spongy tissues and an increase in their heterogeneity have been established. Under the influence of dalargin, the structure of the interface, characteristic of intact bone tissue, is reorganized, accordingly, the restoration of strength is observed. 12 months after the operation, the bone density in the patients of the main group practically recovered to the values typical for the intact limb (p&lt;0.01). No such recovery was observed in patients of the control group. Within 11 to 23 months, 10 patients of the control group had tumor recurrences. Instead, in the study group, the analysis of the results revealed the following: within 21 months, only 1 patient had a recurrence of the tumor. Conclusions. Neuropeptide Dalargin helps to increase the duration of the 1st relapse-free period in patients with primary malignant bone tumors with polymorbidity. The proposed treatment method with integration into the therapeutic protocol of the neuropeptide dalargin allows to increase the complex therapy effectiveness and improve the prognosis of the course of the disease.

Targeted PLK1 suppression through RNA interference mediated by high-fidelity Cas13d mitigates osteosarcoma progression via TGF-β/Smad3 signalling.

Osteosarcoma is the most common primary bone malignancy in children and adolescents. Overexpression of polo-like kinase 1 (PLK1) is frequent in osteosarcoma and drives disease progression and metastasis, making it a promising therapeutic target. In this study, we explored PLK1 knockdown in osteosarcoma cells using RNA interference mediated by high-fidelity Cas13d (hfCas13d). PLK1 was found to be significantly upregulated in osteosarcoma tumour tissues compared to normal bone. sgRNA-mediated PLK1 suppression via hfCas13d transfection inhibited osteosarcoma cell proliferation, induced G2/M cell cycle arrest, promoted apoptosis, reduced cell invasion and increased expression of the epithelial marker E-cadherin. Proximity labelling by TurboID coupled with co-immunoprecipitation identified novel PLK1 interactions with Smad3, a key intracellular transducer of TGF-β signalling. PLK1 knockdown impaired Smad2/3 phosphorylation and modulated TGF-β/Smad3 pathway inactivation. Finally, invivo delivery of hfCas13d vectors targeting PLK1 substantially attenuated osteosarcoma xenograft growth in nude mice. Taken together, this study highlights PLK1 as a potential therapeutic target and driver of disease progression in osteosarcoma. It also demonstrates the utility of hfCas13d-mediated gene knockdown as a strategy for targeted therapy. Further optimization of PLK1 suppression approaches may ultimately improve clinical outcomes for osteosarcoma patients.