Bone Tumor In Children Research Articles

Overexpression of the Ubiquitin Specific Proteases USP43, USP41, USP27x and USP6 in Osteosarcoma Cell Lines: Inhibition of Osteosarcoma Tumor Growth and Lung Metastasis Development by the USP Antagonist PR619.

Osteosarcoma (OS) is the most common malignant bone tumor in children and teenagers. In many cases, such as poor response to treatment or the presence of metastases at diagnosis, the survival rate of patients remains very low. Although in the literature, more and more studies are emerging on the role of Ubiquitin-Specific Proteases (USPs) in the development of many cancers, few data exist regarding OS. In this context, RNA-sequencing analysis of OS cells and mesenchymal stem cells differentiated or not differentiated into osteoblasts reveals increased expression of four USPs in OS tumor cells: USP6, USP27x, USP41 and USP43. Tissue microarray analysis of patient biopsies demonstrates the nucleic and/or cytoplasmic expression of these four USPs at the protein level. Interestingly, Kaplan–Meyer analysis shows that the expression of two USPs, USP6 and USP41, is correlated with patient survival. In vivo experiments using a preclinical OS model, finally demonstrate that PR619, a USP inhibitor able to enhance protein ubiquitination in OS cell lines, reduces primary OS tumor growth and the development of lung metastases. In this context, in vitro experiments show that PR619 decreases the viability of OS cells, mainly by inducing a caspase3/7-dependent cell apoptosis. Overall, these results demonstrate the relevance of targeting USPs in OS.

GH and IGF System: The Regulatory Role of miRNAs and lncRNAs in Cancer.

Growth hormone (GH) and the insulin-like growth factor (IGF) system are involved in many biological processes and have growth-promoting actions regulating cell proliferation, differentiation, apoptosis and angiogenesis. A recent chapter in epigenetics is represented by microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) which regulate gene expression. Dysregulated miRNAs and lncRNAs have been associated with several diseases including cancer. Herein we report the most recent findings concerning miRNAs and lncRNAs regulating GH and the IGF system in the context of pituitary adenomas, osteosarcoma and colorectal cancer, shedding light on new possible therapeutic targets. Pituitary adenomas are increasingly common intracranial tumors and somatotroph adenomas determine supra-physiological GH secretion and cause acromegaly. Osteosarcoma is the most frequent bone tumor in children and adolescents and was reported in adults who were treated with GH in childhood. Colorectal cancer is the third cancer in the world and has a higher prevalence in acromegalic patients.

Multidisciplinary Team Support for Psychological Aspect of Osteosarcoma Amputation in Children: A Case Report

Introduction. Osteosarcoma is the most common primary bone tumor in children. The current management is the surgical method (amputation) and continued chemotherapy. When someone is expected to do this treatment, there will be various possible psychological reactions occur. This amputation condition will affect psychological symptoms both before and after the procedure.
 Case presentation. A girl, Ms. D, seven years old, first grade of elementary school, planned to be amputated with a diagnosis of right tibia proximal osteosarcoma. The patient is a child the second of 3 siblings. The patient was taken to Dr. Soetomo General Hospital, after checking at the hospital in Ponorogo, then a referral was given for further treatment. Patient is referred because the swelling in the right knee is getting bigger day by day. The patient is being treated and will be planned for surgery with a diagnosis of proximal osteosarcoma right tibia. The patient is consulted by a psychiatrist for assistance considering the patient will be carried out right leg amputation surgery.
 Conclusion.Chemotherapy with various side effects will also have an effect on the psychological condition of the patient. So there is a need for full involvement multidisciplinary in dealing with pediatric patients with osteosarcoma that will be carried out amputation to obtain optimal therapeutic results.

Diagnosis and staging of malignant bone tumours in children: what is due and what is new?

PurposeAlthough malignant bone tumours in children are infrequent, it is important to know how to properly diagnose and stage them, in order to establish an adequate treatment.MethodsWe present a review of the diagnostic workflow of malignant bone tumours in children, including history and clinical examination, imaging, laboratory tests and biopsy techniques. Moreover, the two most commonly used staging systems are reviewed.ResultsHistory, clinical examination and laboratory tests are nonspecific for diagnosing malignant bone tumours in children. Radiographs remain the mainstay for initial diagnosis, with MRI the modality of choice for local assessment and staging. Fluorine-18 labelled fluoro-deoxy-glucose-positron emission tomography scans provide a noninvasive method to assess the aggressiveness of the tumour and to rule out metastasis and is replacing the use of the bone scintigraphy. Biopsy must be always performed under the direction of the surgeon who is to perform the surgical treatment and after all diagnostic evaluation has been done. Staging systems are useful to study the extent of the tumour and its prognosis. They are expected to evolve as we better understand new molecular and genetic findings.ConclusionWhen a malignant bone tumour is suspected in a child, it is essential to make a correct diagnosis and referral to an experienced centre. Following an appropriate workflow for diagnosis and staging facilitates, prompt access to treatment improves outcomes.Level of EvidenceLevel V Expert opinion

Lower limb reconstruction for malignant bone tumours in children.

Malignant bone tumours of the lower limb represent the majority of cases in both osteosarcoma and Ewing sarcoma in the growth period. Surgical treatment represents a key element of treatment. Different localizations and age groups require a differentiated surgical approach. Life and limb salvage are first on the list of treatment goals, followed by functional and cosmetic considerations. This review article delivers and discusses current surgical treatment strategies and outcomes for lower limb malignant bone tumours in children.

Primary malignant bone tumours of spine and pelvis in children.

PurposeAxial malignant bone tumours are rare in children and adolescents, and their prognosis is still relatively poor due to non-specific symptoms, such as back or groin pain, which may result in late hospital presentation. Therefore, it is very important to raise awareness regarding this pathology.MethodsWe performed a narrative review, including scientific publications published in English. We searched Medline and Google Scholar databases for information on the incidence and prognosis of axial malignant bone tumours in children and adolescents (< 18 years). Outcomes of different surgical management strategies and reconstruction options were assessed.ResultsThe incidence of primary malignant bone tumours before the age of 18 years is approximately five per one million population; around 25% of these tumours are located in the axial skeleton. With a five-year survival rate of 50%, tumours in an axial location (chest cage, spine, pelvis) are associated with a poorer prognosis than tumours in more peripheral locations. En bloc excision with clear margins has been shown to improve local control and overall survival, even though obtaining adequate surgical margins is difficult due to the close location of large neurovascular structures and other major organs. Spinal reconstruction options include instrumented fusion with allograft or expandable cage. Pelvic reconstruction is needed in internal hemipelvectomy, and the options include biological, endoprosthetic reconstructions, hip transposition, arthrodesis or creation of pseudoarthrosis and lumbopelvic instrumentation.ConclusionEarly diagnosis, a timely adequate multidisciplinary management, appropriate en bloc excision, and reconstruction improve survival and quality of life in these patients.Level of EvidenceV

Biology and technology in the surgical treatment of malignant bone tumours in children and adolescents, with a special note on the very young.

PurposeThe main challenge in reconstruction after malignant bone tumour resection in young children remains how and when growth-plates can be preserved and which options remain if impossible.MethodsWe describe different strategies to assure best possible long-term function for young children undergoing resection of malignant bone tumours.ResultsDifferent resources are available to treat children with malignant bones tumours: a) preoperative planning simulates scenarios for tumour resection and limb reconstruction, facilitating decision-making for surgical and reconstructive techniques in individual patients; b) allograft reconstruction offers bone-stock preservation for future needs. Most allografts are intact at long-term follow-up, but limb-length inequalities and corrective/revision surgery are common in young patients; c) free vascularized fibula can be used as stand-alone reconstruction, vascularized augmentation of structural allograft or devitalized autograft. Longitudinal growth and joint remodelling potential can be preserved, if transferred with vascularized proximal physis; d) epiphysiolysis before resection with continuous physeal distraction provides safe resection margins and maintains growth-plate and epiphysis; e) 3D printing may facilitate joint salvage by reconstruction with patient-specific instruments. Very short stems can be created for fixation in (epi-)metaphysis, preserving native joints; f) growing endoprosthesis can provide for remaining growth after resection of epi-metaphyseal tumours. At ten-year follow-up, limb survival was 89%, but multiple surgeries are often required; g) rotationplasty and amputation should be considered if limb salvage is impossible and/or would result in decreased function and quality of life.ConclusionSeveral biological and technological reconstruction options must be merged and used to yield best outcomes when treating young children with malignant bone tumours.Level of EvidenceLevel V Expert opinion

Double Endoprosthesis in the Management of Refractory Metastatic Primary Bone Tumors in Children and Young Adults.

Background Although not all children can be cured yet, much more emphasis is placed on the quality of life during and after cancer treatment. In the case of recurrence, mutilating treatment is still the prevalent option. In our study, we explored the role of limb salvage surgery for young patients with metastatic malignant bone tumors after endoprosthesis reconstruction during the first line of treatment and evaluated the impact of the local control modality in disease control and functional outcomes. Materials and Methods Eleven patients with bone tumor treated between 2007 and 2018 were included in this study. Both during primary treatment and during recurrence, limb salvage surgery was performed using a modular or expandable custom-made replacement system. Peri- and postoperative care for both surgeries were similar. All patients were given chemotherapy before and after both surgeries, according to the oncological guidelines. Results Seven patients (63.6%) are alive with a median follow-up of 6.5 years from diagnosis. None had local recurrence. Five-year estimates of event-free survival and overall survival were 36.27% and 79.55%, respectively. Median time between the first and second surgery was 2.7 years. Three patients presented with postoperative complications following both surgeries and required resurgical intervention. Three months following the second surgery, the Musculoskeletal Tumor Society Scale (MSTS) scores were 15–27 points (21 points on average—60%). Conclusions Limb salvage surgery is feasible and offers good chance of cure with a reasonable rate of complications and good function in patients with recurrent bone sarcoma after endoprosthesis reconstruction during the first line of treatment.

Circular RNA circNRIP1 plays oncogenic roles in the progression of osteosarcoma.

Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents. Increasing evidence suggests that aberrant expression of circRNAs is associated with the occurrence and progression of many cancers. Here, we investigated the role of circNRIP1 in osteosarcoma and explored its possible underlying mechanisms. Three pairs of osteosarcoma tissues and adjacent normal tissues were applied to the detection of altered expression of circRNAs through circRNAs microarray. And the level of circNRIP1 expression was elevated in osteosarcoma tissues. Compared with that in adjacent normal tissue, circNRIP1 expression level was obviously elevated in 100 osteosarcoma tissues. Besides, circNRIP1 knockdown inhibited proliferation and migration, promoted apoptosis of osteosarcoma cells. Bioinformatic analysis demonstrated circNRIP1 contributed to FOXC2 expression by sponging miR-199a. Furthermore, METTL3 elevated circNRIP1 expression level via m6A modification. In short, METTL3-induced circNRIP1 exerted an oncogenic role in osteosarcoma by sponging miR-199a, which may provide new ideas for the treatment of osteosarcoma.

Phosphoinositide Signal Transduction Pathway and Osteosarcoma Metastases

: Metastasis spreading confers a worse prognosis to the clinical outcome among patients suffering from osteosarcoma, the most common primary bone tumor in childhood and adolescence. The detection of molecules involved in metastasis spreading might contribute to understanding tumor dissemination mechanisms, thereby opening the way to novel therapeutic strategies. The Ezrin-radixin-moesin (ERM) family proteins are activated after interacting with molecules belonging to the phosphoinositide signal transduction pathway. The phosphatydil inositol (4,5) bisphosphate (PIP2), a crucial molecule in the PI pathway, stabilizes the ERM proteins or a more efficient receptor binding. The PIP2 levels in the pathway are a critical element for regulating several cell events. The PIP2 levels are regulated using enzymes, including the PI-specific Phospholipase C family. A decrease in the PIP2 levels induces the dissociation of the ERM protein from the membrane. In this regard, the PI-PLC enzymes regulate this event. In this paper, the role of the PI signal transduction molecules in osteosarcoma metastases is discussed.

Abstract 1395: Humanized GD2 antibody for targeted radiopharmaceutical therapy of human and canine osteosarcoma

Abstract Osteosarcoma (OS) is the most frequently diagnosed bone tumor in children in the United States. The prognosis for metastatic or recurrent OS has remained poor (5-year survival&amp;lt;30%) with no new effective therapies developed during the past 30 years. The high expression of tumor antigen, ganglioside GD2, on a variety of tumors, including OS, with its restricted expression on normal tissue makes GD2 an ideal target for anti-OS radiopharmaceutical therapy. Since human and canine OS shares many biological and molecular features and the prevalence of OS in dogs is 27 times higher than that in humans, spontaneously occurring OS in dogs has been shown to be an ideal model for testing new treatments for human translation. In this study, we evaluated a humanized GD2 antibody, hu3F8, that was developed for neuroblastoma therapy, as a potential delivery vector for targeted radiopharmaceutical therapy of human and canine OS.The cross immunoreactivity of hu3F8 with canine OS cells (OSCA78) and tissue, and human OS cells was confirmed by immunohistochemistry staining and flow cytometry. The binding affinity of hu3F8 to GD2 was assessed in vitro in OSCA78 and IMR32 (a human neuroblastoma cell line known expressing GD2) cell lines using 111In-DTPA-hu3F8. The dissociation constant Kd was 7.4 ± 1.0 nM for OSCA78, and 6.2 ± 1.9 nM for IMR32. Biodistribution study was performed in Nu/Nu mice bearing either OSCA78 tumor or IMR32 tumor. At 24 h after 111In-DTPA-hu3F8 injection, the highest uptake was observed in the tumor, followed by the blood, spleen, lung, and kidneys. The mean tumor uptake was 12.0% ID/g for OSCA78 tumors and 15.0% ID/g for IMR32 tumors, with a tumor-to-muscle ratio of 10.6 and 21.1, and a tumor-to-blood ratio of 1.1 and 2.4, for OSCA78 and IMR32 tumors, respectively. The 72 h biodistribution study revealed the highest uptake of 111In-DTPA-hu3F8 in both OSCA78 (28.0% ID/g) and IMR32 (51.6% ID/g ) tumors, with a tumor-to-muscle ratio of 93.3 and 206.6, and a tumor-to-blood ratio of 6.7 and 8.4, for OSCA78 tumors and IMR32 tumors, respectively. The improved uptake of 111In-DTPA-hu3F8 in tumors at 72 h was indicative of selective binding of 111In-DTPA-hu3F8 to GD2 expressing tumors. SPECT imaging showed that both OSCA78 and IMR32 tumors with 111In-DTPA-hu3F8 had superior contrast to the background, while 111In-DTPA-Rituximab (an irrelevant antibody) injected OSCA78-bearing mouse only showed moderate contrast to the background in the kidney.The cross immunoreactivity and high binding affinity of hu3F8 to canine OS cells/tissue and its ability to deliver an imaging payload (111In) suggest that conjugating hu3F8 with a radionuclide, such as alpha-emitter, 225Ac, may provide a potent radiopharmaceutical therapy for human and canine OS. Citation Format: Yingli Fu, Jing Yu, Ioanna Liatsou, Anders Josefsson, Yong Du, Jeffrey Bryan, Dara L. Kraitchman, George Sgouros. Humanized GD2 antibody for targeted radiopharmaceutical therapy of human and canine osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1395.

Abstract 3110: ICAM-1(CD54) mediated bi-lineage differentiation in osteosarcoma

Abstract Introduction: Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents. The cell of origin in OS is still not known, however, OS cells maintain the capacity for tri-lineage differentiation with the ability to differentiate into osteoblasts (OBs), adipocytes and chondroblasts. The impact of surface antigens on OS differentiation capacity has not well studied. ICAM-1 (CD54) is a transmembrane protein that is involved in intercellular adhesion. We previously reported that ICAM-1 is differentially expressed in mesenchymal stem cells (MSCs) compared with mature osteoblasts. The effect of ICAM-1 on MSC and OS differentiation capacity has not been previously assessed. Methods: ICAM-1 RNA expression was measured in MSCs and OS cells lines and protein expression was assessed using western blot and flow cytometry. Human MSCs and OS cells (M1, M17, M31, M33, M36, M39R, M42, M43, M56, and M60) were placed in osteoblastic and adipogenic differentiation media for 21 and 14 days, respectively. Bi-lineage differentiation capacity was assessed by staining the cells with alizarin red and oil red, to determine the extent of OB and adipose differentiation, respectively at 4 times points (day 0, 7, 14, 21) and 3 time points (day 0, 5, 10, 15). Miscrocopic analysis and spectrophotometric assays were utilized to image and quantify the level of differentiation. Results: Flow cytometric analyses identified 3 cell lines with high surface CD54 expression (CD54high =M17, M33, and M39R) and 3 cell lines with low surface CD54 expression (CD54low=M36, M56, and M60). ICAM-1 expression increased significantly throughout osteoblastic differentiation of MSCs. However, when placed in adipogenic media, MSCs expressed decreasing expression of I-CAM-1. CD54high OS cells demonstrated earlier and more robust osteoblastic differentiation compared with CD54low OS cells. CD54low cells demonstrated earlier and more robust adipogenic differentiation. Conclusion and Future Directions: The CD54high expressing OS cells might retain intermittent osteoblast differentiation capacity. OS cells have a higher adipogenic capacity. Current studies are aimed on the validation of inhibitory effects of ICAM-1 towards OS cell proliferation in vitro and local tumor growth and the development of metastatic disease in preclinical patient derived xenograft in vivo models. We believe that further exploration of the role of surface markers in normal and aberrant osteogenic differentiation may lead to the identification of common tumor progenitor cells and new cell surface based therapeutic targets for the treatment of osteosarcoma. Citation Format: Sankaranarayanan Kannan, Yidan Zhang, Yifei Wang, Sylvester Jusu, Zhongting Zhang, Zhang Wendong, Zhaohui Xu, Michaeal Roth, Gill Jonathan Benjamin, Richard Gorlick. ICAM-1(CD54) mediated bi-lineage differentiation in osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3110.

Abstract 405: The role of GALNT14 in chemoresistant and metastatic osteosarcoma

Abstract Introduction: Osteosarcoma is the most common bone tumor in children and adolescents. Many patients have disease progression through standard chemotherapy regimens of methotrexate, cisplatin, and doxorubicin. Presently, there are no salvage therapies that have added significant survival benefits, leaving minimal options for relapsed and resistant disease. Additionally, there are no clinically significant biomarkers for this disease that would predict treatment failures. N-acetylgalactosaminyltransferase 14 (GALNT14) is an enzyme that initiates O-linked glycosylation to outer membrane-bound and extracellular proteins. Using transcriptomic analyses, we identified GALNT14 overexpression correlated with poor tumor necrosis and survival outcomes. Therefore, we hypothesize that GALNT14 contributes to metastatic and chemoresistant phenotypes in pediatric osteosarcoma. Methods: Transcriptomic data from the Therapeutically Applicable Research for Generating Effective Treatments (TARGET) database and RNA-sequencing of institutional patient-derived xenografts (PDXs) revealed that overexpression of GALNT14 correlated to poor necrosis rates. Gene Set Enrichment Analysis (GSEA) also identified upregulation of glycosylation pathways. Aberrant expression of GALNT14 was confirmed using quantitative polymerase chain reaction (qPCR) and Western blot analyses in various osteosarcoma cell lines. Transient GALNT14 knockdown and overexpression were then analyzed for effects on proliferation, invasion, migration, and chemotherapy response in vitro. Kaplan-Meier curves demonstrating overall survival (OS) and event-free survival (EFS) were established using data from the TARGET database. Results: GALNT14 expression was higher in both commercial and PDX cell lines that were known to be more prone for chemoresistance and invasiveness. The highest quartile of patients based on GALNT14 overexpression had 40% OS and 25% EFS, compared to 80% (p=0.002) and 75% (p&amp;lt;0.001) for the lowest quartile of expression, respectively. Summary: GALNT14 shows promise as a predictive marker of chemoresistance and metastasis for pediatric osteosarcoma. Future functional genomic studies through gain and loss-of-function assays will evaluate the role of GALNT14 in osteosarcoma chemoresistance and metastatic potential. Citation Format: Zachary D. Prudowsky, Tajhal Patel, Kimal Rajapakshe, Christian Coarfa, Ryan Shuck, Nino Rainusso, Jason Yustein. The role of GALNT14 in chemoresistant and metastatic osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 405.

Endoprosthetic Reconstruction in Limb Salvage for Malignant Bone Tumours in Children

Background: The management of malignant bone tumors in children has come a long way in the past few decades. The transition from amputation to limb salvage has been made possible due to the rapid development in the diagnosis and the oncological management of these malignant tumors. However, there exist significant reservations regarding endoprosthetic reconstruction in children. Material and methods: A mini-review was conducted of articles detailing the use of prosthetic reconstruction following tumor resection in children. The data regarding complications and functional outcomes following surgery were collected and presented. Results: The studies reviewed reported a 5-year survival rate between 60 – 70 %. Uniform across the studies was the need for multiple surgeries when endoprosthesis was used for limb reconstruction, ranging between 2.8 – 3.5 surgeries. The most common complication noted across the studies was related to soft tissue problems such as joint instability followed by structural failure of the prosthesis. Infections were noted with a frequency of 10 – 15 %. Studies showed successful management of limb length discrepancy with expandible prosthesis. Musculoskeletal Tumor Society (MSTS) score used to evaluate the functional outcome showed satisfactory outcomes. Conclusion: Limb salvage surgery, with recent advances in technique and prosthesis design, is an attractive option in children with extremity malignant bone tumors. In recent time, endoprosthetic reconstruction of extremities have yielded good functional results and are well accepted by the child and the parents. The purpose of this mini-review is to shed some light on the use of endoprosthetic reconstruction in children following tumor resection with its potential benefits and drawbacks.

Charting a path for prioritization of novel agents for clinical trials in osteosarcoma: A report from the Children's Oncology Group New Agents for Osteosarcoma Task Force.

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

Distal Tibial Reconstruction in the Management of Primary Bone Tumors in Children and Adolescents.

Distal tibial primary bone tumors are rare, and options for limb salvage surgery are limited and challenging. Importantly, local control has shown to be crucial and necessary for cure, and radical surgery is one of the most important components of therapy for some bone sarcomas. We investigated the feasibility and functional and oncological outcomes of distal tibial reconstruction using endoprosthesis in children with malignant bone tumors. Fourteen patients (median age 13.6 years) with primary bone tumors (4 Ewing sarcoma [ES], 10 osteosarcoma) of the distal tibiae were treated during 2013-2019. All patients had reconstruction using a modular (13 patients) or expandable custom-made titanium bone replacement system (1 patient). All patients received chemotherapy before and after surgery. Twelve patients (85.7%) are alive with a median follow-up 20 months from diagnosis. Five-year estimates of event-free survival and overall survival were 60.6% and 76.4%, respectively. Three patients had postoperative complications requiring second surgery. Maximum dorsiflexion and plantar flexion of the foot were 20 degrees (range 0-20 degrees) and 20 degrees (range 5-20 degrees), respectively. For select distal tibial sarcomas, after neoadjuvant chemotherapy pretreatment and radical resection, reconstruction using an endoprosthesis as a radical surgery provides an option was associated with a low rate of short-term local complications and relatively good early function. Level IV, therapeutic study.

Combination Therapy of Cisplatin and other Agents for Osteosarcoma: A Review

Background:Osteosarcoma is the most common type of primary bone tumor in children and adolescents, which is associated with rapid progression and poor prognosis. Multimodal therapy is the most common approach utilized for osteosarcoma management, such as the application of chemotherapy in combination with surgery or radiation therapy. Cisplatin is one of the predominantly used chemotherapeutic agents for osteosarcoma. Optimally, it is employed in combination with other chemotherapeutic drugs along with surgery or radiation therapy. Despite the availability of numerous treatment approaches, the patient survival rate has not definitively improved over the past three decades.Methods:We have summarized all findings regarding the combination of cisplatin with other chemotherapeutic agents as well as with phytochemical compounds.Results:A combination of cisplatin with a phytochemical compound synergistically enhances the killing effect of cisplatin on osteosarcoma cells with fewer side effects compared to combination with other chemotherapeutic agents.Conclusion:Conclusively, a combination of cisplatin with selected chemotherapeutic drugs has been shown to be effective. However, the unchanged survival rate has posed an urge to search for a new combination regimen. As a collaborative effort to substantiate the therapeutic efficacy, the combination with phytochemical compounds shows a promising response both in vitro as well as in the preclinical study.

Predictive Study of the Active Ingredients and Potential Targets of Codonopsis pilosula for the Treatment of Osteosarcoma via Network Pharmacology.

Osteosarcoma (OS) is the most common type of primary bone tumor in children and adults. Dangshen (Codonopsis pilosula) is a traditional Chinese medicine commonly used in the treatment of OS worldwide. However, the molecular mechanisms of Dangshen in OS remain unclear. Hence, in this study, we aimed to systematically explore the underlying mechanisms of Dangshen in the treatment of OS. Our study adopted a network pharmacology approach, focusing on the identification of active ingredients, drug target prediction, gene collection, gene ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and other network tools. The network analysis identified 15 active compounds in Dangshen that were linked to 48 possible therapeutic targets related to OS. The results of the gene enrichment analysis show that Dangshen produces a therapeutic effect in OS likely by regulating multiple pathways associated with DNA damage, cell proliferation, apoptosis, invasion, and migration. Based on the network pharmacology approach, we successfully predicted the active compounds and their respective targets. In addition, we illustrated the molecular mechanisms that mediate the therapeutic effect of Dangshen in OS. These findings may aid in the development of novel targeted therapies for OS in the future.

IMPDH2 and HPRT expression and a prognostic significance in preoperative and postoperative patients with osteosarcoma

Osteosarcoma is one of the most aggressive bone tumors in children and adolescents. Development of effective therapeutic options is still lacking due to the complexity of the genomic background. In previous work, we applied a proteomics-guided drug repurposing to explore potential treatments for osteosarcoma. Our follow-up study revealed an FDA-approved immunosuppressant drug, mycophenolate mofetil (MMF) targeting inosine-5′-phosphate dehydrogenase (IMPDH) enzymes, has an anti-tumor effect that appeared promising for further investigation and clinical trials. Profiling of IMPDH2 and hypoxanthine–guanine phosphoribosyltransferase (HPRT), key purine-metabolizing enzymes, could deepen understanding of the importance of purine metabolism in osteosarcoma and provide evidence for expanded use of MMF in the clinic. In the present study, we investigated levels of IMPDH2, and HPRT in biopsy of 127 cases and post-chemotherapy tissues in 20 cases of high-grade osteosarcoma patients using immunohistochemical (IHC) analysis. Cox regression analyses were performed to determine prognostic significance of all enzymes. The results indicated that low levels of HPRT were significantly associated with a high Enneking stage (P = 0.023) and metastatic status (P = 0.024). Univariate and multivariate analyses revealed that patients with low HPRT expression have shorter overall survival times [HR 1.70 (1.01–2.84), P = 0.044]. Furthermore, high IMPDH2/HPRT ratios were similarly associated with shorter overall survival times [HR 1.67 (1.02–2.72), P = 0.039]. Levels of the enzymes were also examined in post-chemotherapy tissues. The results showed that high IMPDH2 expression was associated with shorter metastasis-free survival [HR 7.42 (1.22–45.06), P = 0.030]. These results suggest a prognostic value of expression patterns of purine-metabolizing enzymes for the pre- and post-chemotherapy period of osteosarcoma treatment.

Preclinical evaluation of an engineered oncolytic herpes simplex virus for pediatric osteosarcoma.

10040 Background: Osteosarcoma is the most common primary bone tumor in children. For those with relapsed or metastatic disease, the five-year survival rate is approximately 20%, and survivors often suffer from long-term disability from current therapies. The high morbidity and mortality for these patients highlight a great need for improved therapies. One such novel therapeutic approach is oncolytic herpes simplex virus (oHSV) immunovirotherapy. We previously demonstrated that M002, an engineered oHSV that contains deletions of the neurovirulence gene preventing infection of normal cells, effectively infects and kills neuroblastoma and rhabdomyosarcoma. Currently, similar oHSVs are being evaluated in early phase clinical trials for children and adults with relapsed or refractory brain tumors. To date, there has been limited investigation of oncolytic virotherapy in osteosarcoma. Thus, we sought to examine the ability of oHSV, M002, to infect and kill osteosarcoma cells in vitro. Methods: We evaluated two long-term passaged human osteosarcoma cell lines, U2-OS and MG-63. Flow cytometry was used to assess baseline expression of oHSV viral entry-mediated receptors (CD111, CD112, syndecan, HVEM). Single and multi-step viral recovery experiments measured virus infectivity and replication. Cells were infected with increasing multiplicity of infection (MOI) of M002, and cell viability was measured 72 hours post-infection via alamarBlue assay. Results: Both MG-63 and U2-OS cells expressed HSV entry molecules (Table) including high levels of the primary HSV entry molecule CD111. Single step virus recovery experiments in MG-63 cells infected at a MOI of 10 plaque-forming units (PFU)/cell demonstrated a 3 log-fold increase in virus titer from 12 to 24 hours post-infection. For multi-step experiments, MG-63 cells were infected with a MOI of 0.1 PFU/cell; viral replication significantly increased from 1.1x103 PFU at 6 hours post-infection to 3.8x1010 PFU at 72 hours post-infection. M002 successfully decreased osteosarcoma viability with a lethal dose in 50% of cells (LD50)of 2.82 and0.67 PFU/cell for MG-63 and U2-OS cells, respectively. Notably, at a virus MOI of 5 PFU/cell, viability was decreased by 64% ± 0.1% (p&lt;0.001 vs control) in MG-63 cells and 96% ± 0.1% (p&lt;0.001 vs control) in U2-OS cells. Conclusions: MG-63 and U2-OS osteosarcoma cells express high levels of HSV entry receptors. Virus recovery experiments demonstrated the ability of M002 to infect cells and replicate over time. The viability of osteosarcoma cells significantly decreased following infection with M002. These data suggest M002 may be a promising novel therapeutic option for patients with osteosarcoma and warrant further investigation for translation to the clinical setting.[Table: see text]