Primary Bone Sarcomas Research Articles

HTRA3 transcriptionally inhibited by FOXP1 suppresses tumorigenesis of osteosarcoma via the PTEN/PI3K/AKT pathway

Despite recent advances in understanding the biological behavior of osteosarcoma (OS), OS is still the most common primary bone sarcoma that endangers the health of children and adolescents. High-temperature requirement A (HTRA) protease family plays an important regulatory role in numerous malignancies and acts as a prognostic biomarker. However, the function and underlying mechanisms of the HTRA family in OS development remain unknown. Through analyzing the GSE126209 dataset obtained from different Gene Expression Omnibus (GEO) databases, we found that HTRA3 as a member of the HTRA family was downregulated in OS tissues compared with that in normal tissues. Functional experiments indicated that HTRA3 overexpression suppressed malignant behaviors of OS cells in vitro and tumor growth in vivo. Mechanistically, we found that HTRA3 co-localized with the X-linked inhibitor of apoptosis protein (XIAP) and decreased XIAP stability. Further investigation showed that XIAP knockdown inhibited the degradation of phosphatase and tensin homolog (PTEN) and that HTRA3 caused the blockage of PTEN/phosphoinositide 3-kinase (PI3K)/AKT pathway, characterized as the reverse of cell function caused by HTRA3 overexpression after PTEN inhibitor BpV (HOpic) treatment. Detailed investigations showed that forkhead box protein 1 (FOXP1), an oncogene in OS progression, downregulated HTRA3 expression and inhibited the transcriptional activity of HTRA3, suggesting that HTRA3 was regulated negatively by FOXP1. In conclusion, our study demonstrates that HTRA3 is a repressor involved in OS development via the PTEN/PI3K/AKT pathway under the modulation of transcription factor FOXP1, and it may provide a therapeutic direction for OS patients.

Comprehensive genomic analysis of primary bone sarcomas reveals different genetic patterns compared with soft tissue sarcomas.

Sarcomas are classified into two types, bone sarcoma and soft tissue sarcoma (STS), which account for approximately 1% of adult solid malignancies and 20% of pediatric solid malignancies. There exist more than 50 subtypes within the two types of sarcoma. Each subtype is highly diverse and characterized by significant variations in morphology and phenotypes. Understanding tumor molecular genetics is helpful in improving the diagnostic accuracy of tumors that have been difficult to classify based on morphology alone or that have overlapping morphological features. The different molecular characteristics of bone sarcoma and STS in China remain poorly understood. Therefore, this study aimed to analyze genomic landscapes and actionable genomic alterations (GAs) as well as tumor mutational burden (TMB), microsatellite instability (MSI), and programmed death ligand-1 (PD-L1) expression among Chinese individuals diagnosed with primary bone sarcomas and STS. This retrospective study included 145 patients with primary bone sarcomas (n = 75) and STS (n = 70), who were categorized based on the 2020 World Health Organization classification system. Patients diagnosed with bone sarcomas were significantly younger than those diagnosed with STS (p < 0.01). The top 10 frequently altered genes in bone sarcoma and STS were TP53, CDKN2A, CDKN2B, MAP3K1, LRP1B, MDM2, RB1, PTEN, MYC, and CDK4.The EWSR1 fusions exhibited statistically significant differences (p < 0.01) between primary bone sarcoma and STS in terms of their altered genes. Based on the actionable genes defined by OncoKB, actionable GAs was found in 30.7% (23/75) of the patients with bone sarcomas and 35.7% (25/70) of those with STS. There were 4.0% (3/75) patients with bone sarcoma and 4.3% (3/70) patients with STS exhibited high tumor mutational burden (TMB-H) (TMB ≥ 10). There was only one patient with STS exhibited MSI-L, while the remaining cases were microsatellite stable. The positive rate of PD-L1 expression was slightly higher in STS (35.2%) than in bone sarcoma (33.3%), however, this difference did not reach statistical significance. The expression of PD-L1 in STS patients was associated with a poorer prognosis (p = 0.007). Patients with STS had a better prognosis than those with bone sarcoma, but the observed difference did not attain statistical significance (p = 0.21). Amplification of MET and MYC genes were negatively correlated with clinical prognosis in bone tumors (p<0.01). In conclusion, bone sarcoma and STS have significantly different clinical and molecular characteristics, suggesting that it is vital to diagnose accurately for clinical treatment. Additionally, comprehensive genetic landscape can provide novel treatment perspectives for primary bone sarcoma and STS. Taking TMB, MSI, PD-L1 expression, and OncoKB definition together into consideration, there are still many patients who have the potential to respond to targeted therapy or immunotherapy.

Pelvic bone sarcomas, prognostic factors, and treatment: A narrative review of the literature.

Primary sarcomas of bone are rare malignant mesenchymal tumors. The most common bone sarcomas are osteosarcoma, Ewing's sarcoma, and chondrosarcoma. The prognosis has improved over the years, but bone sarcomas are still life-threatening tumors that need a multidisciplinary approach for diagnosis and treatment. Bone sarcomas arising in the pelvis present a unique challenge to orthopedic oncologists due to the absence of natural anatomical barriers, the close proximity of vital neurovascular structures, and the high mechanical demands placed on any pelvic reconstruction following the excision of the tumor. While radiotherapy has an important role especially in Ewing's sarcoma and chemotherapy for both Ewing's sarcoma and osteosarcoma, surgery remains the main choice of treatment for all three entities. While external hemipelvectomy has remained one option, the main aim of surgery is limb salvage. After complete tumor resection, the bone defect needs to be reconstructed. Possibilities to reconstruct the defect include prosthetic or biological reconstruction. The method of reconstruction is dependent on the location of tumor and the surgery required for its removal. The aim of this article is to give an insight into pelvic bone sarcomas, their oncological and surgical outcomes, and the options for treatment based on the authors' experiences.

Distal Humeral Replacement in Patients with Primary Bone Sarcoma: The Functional Outcome and Return to Sports

Distal humeral replacement (DHR) is a limb-salvage option for the endoprosthetic reconstruction of bone defects following the resection of a primary bone sarcoma. As primary bone sarcomas are only occasionally located around the distal humerus, there is a paucity of information regarding postoperative function, and patients’ resumption of sporting activities. With advances in diagnostics and in surgical and oncological treatment leading to an increased patient life expectancy and higher quality of life, patients’ functional outcome and return to sports activities are of increasing interest. Between 1997 and 2021, a total of 24 patients underwent DHR with a single-design modular implant at a tertiary sarcoma center. A total of 14 patients who died of their disease were excluded, leaving a study cohort of 10 patients, with a median age of 30 years on the day of surgery (IQR 20–37). At the last follow-up, after a median of 230 months (IQR 165–262), the median MSTS was 19 (IQR 13–24), the median TESS was 79 (IQR 66–87), the median SEV was 38% (IQR 24–53), the median TS was 6 (IQR 4–7), and the median WAS was 3 (IQR 1–8). Among the variables of gender, surgery on the dominant extremity, intraoperative nerve resection, extra-articular tumor resection, chemotherapy, radiotherapy, and revision surgeries, none were associated with a better/lower functional outcome score or return to sports activities. However, a higher level of sports performance prior to diagnosis (WAS &gt; 10) was associated with a higher level of sports performance postoperatively (p = 0.044).

Mixed Reality Improves 3D Visualization and Spatial Awareness of Bone Tumors for Surgical Planning in Orthopaedic Oncology: A Proof of Concept Study.

In orthopedic oncology, computer navigation and 3D-printed guides facilitate precise osteotomies only after surgical exposure. Before surgeries start, it is challenging to mentally process and superimpose the virtual medical images onto patients' anatomy for preoperative surgical planning. Mixed Reality (MR) is an immersive technology merging real and virtual worlds, and users can interact with digital objects in real time. Through Head-Mounted Displays, surgeons directly visualize holographic models that overlaid on tumor patients. The technology may facilitate surgical planning before skin incisions. Nine bone tumor patients were included (July 2021 - Dec 2022). There were six primary bone sarcomas, two benign bone tumors, and one revision pelvic prosthesis. MR applications were created using patients' preoperative medical images. The surgeon examined each patient clinically using the conventional method of viewing 2D images and MR via HMD, Hololens 2. A Likert-Scale (LS) questionnaire and The National Aeronautics and Space Administration-Task Load Index (NASA-TLX) score were used to evaluate and compare the effectiveness of surgical planning and the surgeon's clinical cognitive workload for the two methods. The qualitative survey of the LS questionnaire suggested that the MR group had superior spatial awareness of tumors and was considered more effective as a preoperative planning tool than the conventional group. For NASA-TLX scores, the overall cognitive workload was lower in MR 3D hologram group than in the 2D Group for preoperative clinical assessment. When using MR technology with HMDs, the surgeon reported no discomfort. MR technology may improve 3D visualization and spatial awareness of bone tumors in patients' anatomies and may facilitate surgical planning before skin incisions in orthopedic oncology surgery. With less cognitive load and better ergonomics, surgeons can focus on patients and surgical tasks with MR technology. Further studies must investigate whether MR technology improves clinical outcomes.

Surgical Outcomes in Paediatric Lower Limb Sarcomas: A Single Institutional Experience.

Primary bone sarcomas are rare tumours, comprising approximately 1-2% of adult and around 13-15% of all paediatric cancers. Limb salvage surgery is a challenge in complex musculoskeletal tumours. Young age adds to its complexity, since the growth potential of the reconstruct has to be considered to have optimal function of the salvaged limb. An observational retrospective study performed on 52 paediatric patients between Jan 2011 and Dec 2018 with malignant bone tumour of lower limbs had been assessed for postoperative functional outcomes with questionnaires and clinico-radiological examination for functional and oncological outcome. Out of 52 patients, 44 (85%) were diagnosed with osteosarcoma and the rest (15%) were diagnosed with Ewing sarcoma. Mean age was 12.88 years. Three-year overall survival rate was found to be 61.73%. Fifteen patients (28%) had metastasis at the time of presentation; non-metastasis patients (56.33 months) had a higher mean survival time, as compared to metastasis patient (29.06 months). Overall survival in group of patients undergoing biological, prosthesis and amputation surgeries were found to be similar. Mean MSTS score at final follow-up was 24.05 (80.1%), and in our study, 3.85% (2 out of 52) had local recurrence, and local recurrence free rate was found to be 96.15% (50 out of 52). The present study had excellent functional and oncological outcome at final follow-up which is comparable to the world literature. Complete surgical resection, if feasible, remains essential for cure.

Local surgery feasibility and safety after carbon ion radiotherapy for primary bone sarcomas

BackgroundIt is known that several complications are caused by local surgery after radiotherapy. Clinical reports that describe the postoperative complications associated with surgery after carbon ion radiotherapy are sparse. This study aimed to elucidate local surgery feasibility after carbon ion radiotherapy specifically for primary bone sarcomas. MethodsThe medical, surgical, and irradiation records of patients who had local surgery at the area irradiated with carbon ion beams between 2004 and 2018 were reviewed retrospectively to evaluate the feasibility and indication of local surgery after CIRT. ResultsThere were eight patients who had 10 local surgeries at the irradiated sites among the 42 carbon ion radiotherapy patients. There were seven males and one female with a median age of 50 years (range 26–73 years). The reasons for surgery were three for skin toxicity and associated infection, five for bone collapse, and associated implant failure, and two for tumor regrowth. All surgical fields included the area of more than 60 Gy (RBE) irradiated dose. All three surgical cases caused by skin toxicity and associated infection had Grade I wound complication after surgery according to the Clavien–Dindo Classification. ConclusionLocal surgery after CIRT appeared feasible in selected patients with primary bone sarcoma, especially for the patients with bone collapse and associated implant failure. However, infection and prescribed irradiation dose at the incision site must be carefully evaluated.

Abstract 203: A characterization of drug sensitivity and resistance in sarcoma

Abstract Bone and soft tissue sarcomas are a rare and diverse family of malignancies. Sarcomas disproportionally impact young patients, and most subtypes have limited therapeutic options. Given the rarity of these tumors and their heterogenous nature, there is a need for developing clinically relevant models to broadly characterize the landscape of drug resistance and sensitivity in sarcoma in order to identify effective therapies. We leverage patient-derived tumor organoids (PDTOs) to create models across an array of bone and soft tissue sarcomas. We have procured n=193 specimens from n=127 patients undergoing biopsies or surgical resections at UCLA Health hospitals and successfully generated PDTOs from over 100 samples so far originating from primary, recurrent, or metastatic bone and soft tissue sarcomas. We performed molecular and histologic characterization to compare the PDTOs with the parent tumor and monitored PDTOs growth using a machine learning-based imaging pipeline (Al Shihabi et al, 2022). Our results show that sarcoma PDTOs closely resemble the tumor of origin in their molecular features and exhibit diverse growth patterns across subtypes. We leveraged our existing organoid high-throughput drug screening pipeline (Phan et al, 2019) to perform functional screenings of chemotherapies, targeted agents, and combination therapies, with results within one week from surgery. By screening a large number of samples, we could identify patterns of response with respect to diagnosis, prior treatment, patient age, lesion type, and disease trajectory. We observe tumor-specific susceptibilities with high heterogeneity both across and within sarcoma subtypes. As an example, we will focus on osteosarcoma, a bone tumor common in the pediatric and AYA population. We characterized PDTOs from n=33 osteosarcoma specimens and observed significant heterogeneity in response to NCCN-recommended therapies, suggesting that some patients may benefit from a personalized selection of approved therapeutic regimens. Finally, we compare functional and genomic screening to show how drug sensitivity and resistance characterization can facilitate optimal drug selection, avoid ineffective therapies, and mirror patient outcomes. Citation Format: Ahmad Al Shihabi, Peyton J. Tebon, Huyen T. Nguyen, Jomjit Chantharasamee, Sara Sartini, Ardalan Davarifar, Alexandra Jensen, Miranda Diaz-Infante, Hannah Cox, Alfredo Gonzalez, Nasrin Tavanaie, Sarah Dry, Arun Singh, Bartosz Chmielowski, Joseph G. Crompton, Anusha Kalbasi, Fritz C. Eilber, Francis J. Hornicek, Nicholas Bernthal, Scott D. Nelson, Paul C. Boutros, Noah Federman, Jane Yanagawa, Alice Soragni. A characterization of drug sensitivity and resistance in sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 203.

Staged Management of Infection with Adjustable Spacers After Megaprosthesis Implantation in Primary Sarcoma Patients.

While periprosthetic joint infection has always been a significant concern for orthopaedic surgeons, the rate of infection is five to ten times higher after tumor prosthesis implantation. With the growing use of mega-implants, the number of these infections has also increased. We aimed to investigate the results of our patients with a primary malignant musculoskeletal tumor, who underwent two-stage revision surgery for an infected mega-prosthesis. We also presented the emerging complicatons and required soft tissue reconstruction procedures. The study included 32 primary bone and soft tissue sarcoma patients who underwent a two-stage revision procedure for infection. After a rigorous bone and soft tissue debridement procedure at the first stage, antibiotic-loaded bone cement was wrapped around a cloverleaf type intramedullary nail and inserted into the forming gap. After a minimum of 6 weeks of antibiotic therapy, depending on patients' clinical signs and serum infection markers, the reimplantation stage was undertaken. The mean oncologic follow-up period was 28 months (range 5-96 months). During this period, 11 patients died because of non-infection related causes, 12 patients were alive with their disease, whereas 9 patients were totally free of their oncologic condition. The infection was eradicated in all survivors except one patient, where a high-level transfemoral amputation became necessary. Periprosthetic infection after tumor proshesis implantation in cancer patients can be managed with same principles as conventional arthroplaty procedures, taking care that they are immunocompromised and vulnerable patients and their bone stock loss is significant which makes surgical options more challenging.

Factors affecting the incorporation of extracorporeally irradiated autograft for the treatment of bone tumours-a retrospective analysis from a tertiary referral centre.

Re-implantation of the tumor bearing autograft following extracorporeal radiation therapy (ECRT) has been established as an oncologically safe biological reconstruction technique following resection of bone sarcomas. However, factors affecting the ECRT graft-host bone incorporation have not been fully investigated. An insight into the factors that influence graft incorporation can circumvent the complications and increase graft survival. A total of 96 osteotomies in 48 patients with intercalary resections of primary extremity bone sarcomas (mean age 15.8years, mean follow-up 42.1months) were analyzed retrospectively for factors ECRT autograft-host bone union. On univariate analysis, age < 20years, metaphyseal osteotomy site, V-shaped diaphyseal osteotomy, and use of additional plate at diaphyseal osteotomy had a significantly faster time to union, while gender, tumour type, bone involved, resection length, chemotherapy, type of fixation, and use of intra-medullary fibula did not influence union time. In multivariate analysis, V-shaped diaphyseal osteotomy and use of additional plate at diaphyseal ostetomy were the independent factors with favourable time to union. None of the analyzed factors was found to have a significant effect on the union rate. The major complications were non-union in 11.4% patients, graft failure in 2.1%, infection in 12.5%, and soft tissue local recurrences in 14.5% patients. Modified diaphyseal osteotomy and augmentation of the stability of the reconstruction using additional small plates enhance the incorporation of ECRT autograft.

Risk factors for recurrent infection in the surgical treatment of infected massive endoprostheses implanted for musculoskeletal tumours

BackgroundInfection is a devastating complication of endoprosthetic replacement (EPR) in orthopaedic oncology. Surgical treatments include debridement and/or one- or two-stage exchange. This study aims to determine the infection-free survival after surgical treatment for first and recurrent EPR infections and identify the risk factors associated with infection recurrence.MethodsThis single-centre cohort study included all patients with primary bone sarcomas or metastatic bone disease treated for infected EPR between 2010 and 2020. Variables included soft tissue status using McPherson classification, tumour type, silver coating, chemotherapy, previous surgery and microorganisms identified. Data for all previous infections were collected.Survival analysis, with time to recurrent infection following surgical treatment, was calculated at 1, 2 and 4 years. Cox regression analysis was used to assess the influence of different variables on recurrent infection.ResultsThe cohort included 99 patients with a median age of 44 years (29–58 IQR) at the time of surgical treatment. The most common diagnoses were osteosarcoma and chondrosarcoma.One hundred and thirty-three surgical treatments for first or subsequent infections were performed. At 2 years of follow-up, overall success rates were as follows: two-stage exchange 55.3%, one-stage exchange 45.5%, DAIR with an exchange of modular components 44.6% and DAIR without exchange of modular components 24.7%.Fifty-one (52%) patients were infection-free at the most recent follow-up. Of the remaining 48 patients, 27 (27%) were on antibiotic suppression and 21 (21%) had undergone amputation.Significant risk factors for recurrent infection were the type of surgical treatment, with debridement alone as the highest risk (HR 4.75: 95%CI 2.43–9.30; P < 0.001); significantly compromised soft tissue status (HR 4.41: 95%CI 2.18–8.92; P = 0.001); and infections due to Enterococcus spp.. (HR 7.31: 95%CI 2.73–19.52); P = 0.01).ConclusionsTwo-stage exchange with complete removal of all components where feasible is associated with the lowest risk of recurrent infection. Poor soft tissues and enterococcal infections are associated with higher risks of recurrent infection. Treatment demands an appropriate multidisciplinary approach. Patients should be counselled appropriately about the risk of recurrent infection before embarking on complex treatment.

Identification of RALA as a Therapeutic Target and Prognostic Predictor of Osteosarcoma.

Osteosarcoma (OS) is the most common primary aggressive sarcoma of bone, with massive aberrant expression of oncogenes related to the development of OS. RALA, a kind of small Ras-like guanosine triphosphatases, has been identified as a potential therapeutic target in several types of tumor, but its role in OS remains largely unknown. Abnormal expression of RALA was proven in the Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and RNA-sequence of samples and cell lines. The role of RALA in OS was analyzed in terms of DNA methylation, immune cell infiltration, and patient survival. The cancer-promoting effect of RALA was demonstrated in cell lines and xenograft osteosarcoma models. A prognostic scoring model incorporating RALA as an indicator was established with the clinical samples that we collected. The results showed that RALA was highly expressed in human OS tissues and cell lines. Survival analysis demonstrated that RALA was the sole independent risk factor for poor overall survival and disease-free survival in OS patients and impacted the proportion of infiltrating immune cells and DNA methylation in the OS tumor microenvironment. By gene-gene interaction analysis, we found that the expression of RALA was highly correlated to the expression of ABCE1. Similar to RALA, upregulated ABCE1 is correlated with poor survival outcome of OS patients. In addition, the functional experiment demonstrated that higher expression of RALA promoted the proliferation, migration, and invasion of OS cells. In vivo results were similar with the in vitro results. We examined m6a methylation-related genes and found that m6A methylation is responsible for the abnormal expression of RALA. Finally, the prognostic prediction model of RALA could be used to predict the long-term outcome of OS patients. We identified RALA as an oncogene in OS, and RALA upregulation in a concerted manner with ABCE1 was significantly associated with worse outcomes of OS patients. Targeting RALA may prove to be a novel target for OS immunotherapy in future clinical practice.

Descriptive Epidemiology and Survival Rate of Osteosarcoma: The First National Population-Based Study in the Middle East (2008-2014).

The epidemiology of osteosarcoma (OS), the most common primary bone sarcoma, was not evaluated in the Middle East. Therefore, this study aimed to examine the incidence, demographic characteristics, epidemiology, and survival rate of patients with different subtypes of OS, based on data derived from the Iran National Cancer Registry (INCR) to evaluate the influence of ethnicity and race. All OS patients registered in the INCR between March 20, 2008, and March 20, 2014, were enrolled in this study, and information such as age, gender, cancer location, OS subtype, and survival time were evaluated statistically. The Age-Standardized Incidence Rate (ASIR) for OS was 3.02 per million person-years, with a mean age of 25.6 years and a male-female ratio of 1.54:1. Not Otherwise Specified (NOS) OS, chondroblastic OS, and central OS had the highest frequencies among the subtypes of OS. The overall one-, three-, and five-year survival rates were 87%, 61%, and 49%, respectively, with a mean duration of 6.16 years. The ASIR of OS in our country was similar to that in the US and higher than that in China. The peak frequency was between 15-19 years old. The male-female ratio in our patients was higher than the OS gender ratio in most series. Although it was not statistically significant, older age at the time of diagnosis, axial location, and male gender were the poorest prognosis factors.

Calcanectomy in primary high-grade sarcomas: Foot salvage without the need for any reconstruction

The calcaneum is a rare site for primary bone sarcomas. Calcanectomy is not considered for high-grade malignancies due to anticipated issues with obtaining negative margins, providing adequate soft-tissue coverage, and preserving satisfactory function. A below-knee amputation overcomes these difficulties and is very functional and, thus, the preferred local control option. The aim of this study is to evaluate the role of total calcanectomy, without any formal reconstruction, in high-grade calcaneal sarcomas. Over 14 years, three patients with high-grade calcaneal sarcomas underwent limb salvage surgery as opposed to amputation for their primary malignancy. Total calcanectomy was undertaken using a Cincinnati incision. No formal “calcaneal” reconstruction was undertaken after resection, essentially leaving the patient with an excision arthroplasty through the subtalar joint. The Achilles tendon was reattached to the posterior talus. Negative resection margins were achieved in all cases with the primary wound closure. Two patients are alive with no evidence of disease at 15 and 10 years. The third patient, at over 1 year postoperatively, has no evidence of local disease recurrence but has had metastasectomy for documented pulmonary metastases at the presentation. The average musculoskeletal tumor society score was 85.5%, and the average Toronto extremity salvage score was 88.5%. In our experience, even high-grade malignancies at this unusual site are potentially amenable to limb salvage. Our results show that perhaps ablative surgery should not be considered inevitable. Good functional outcomes can be achieved without reconstruction, thus minimizing potential “construct”-related morbidities.

Screening for MicroRNA combination with engineered exosomes as a new tool against osteosarcoma in elderly patients.

The most common primary malignant bone sarcoma is Osteogenic sarcoma (OS) which has a bimodal age distribution. Unfortunately, the treatment of OS was less effective for elderly patients than for younger ones. The study aimed to explore a new microRNA (miRNA) which can bind to combining engineered exosomes for treatment of older OS patients. Based on GSE65071 and miRNet 2.0, two up-regulated miRNAs (miR-328, miR-107) and seven down-regulated miRNAs (miR-133b, miR-206, miR-1-3p, miR-133a, miR-449a, miR-181daysay, miR-134) were selected. Next, we used FunRich software to predict the up-stream transcription factors (TFs) of differentially expressed miRNAs (DE-miRNAs). By comparing target genes predicted from DE-miRNAs with differentially expressed genes, we identified 12 down-regulated and 310 up-regulated mRNAs. For KEGG analysis, the most enriched KEGG pathway was Cell cycle, Spliceosome, and Protein digestion and absorption. By using protein-protein interactions network, topological analysis algorithm and GEPIA database, miR-449a /CCNB1 axis was identified. Experiments in vitro were conducted to confirm the results too. MiRNA-449a is down-regulated in osteosarcoma and suppresses cell proliferation by targeting CCNB1. Our findings not only reveal a novel mechanism of miR-449a /CCNB1 in OS but also had laid the groundwork for further investigation and analysis in the field of exosome engineering.

Function and return to sports after proximal humeral replacement in patients with primary bone sarcoma

BackgroundImproved patient and limb survival rates have led to an increased interest in the functional outcome and return to sports of patients undergoing megaprosthetic reconstruction in musculoskeletal oncology. This study evaluates the functional outcome and postoperatively performed level of sports in patients undergoing proximal humeral replacement (PHR) following resection of a primary bone sarcoma and identifies potential beneficial and limiting factors.Patients and methodsBetween 2007 and 2020, a total of 606 patients underwent resection of a primary bone sarcoma and reconstruction with a single-design modular implant. For 112 (18%) patients, the location of the tumour was the proximal humerus. Exclusion criteria were death (n = 65), patients living overseas (n = 8), and subsequent amputation (n = 1), leaving 38 patients for evaluation, of whom 32 were available for the study (13 women, median age 42 years). Clinical data regarding oncological and surgical treatment as well as subsequent complications were obtained from the patients’ electronic medical records. Functional outcome was determined using the Musculoskeletal Tumor Society Score (MSTS) and Toronto Extremity Salvage Score (TESS) as well as the Subjective Shoulder Value (SSV). Return to sports was assessed using the Tegner Activity Score (TS) and the modified Weighted Activity Score (WAS).ResultsAt the last follow-up after a median of 30 months (IQR 22–58), median MSTS was 18 (IQR 12–24), median TESS was 80% (IQR 69–87), median SSV was 35% (IQR 10–58), median TS was 5 (IQR 4–6) and median WAS was 5 (IQR 0–10). Preservation of the axillary nerve, a reverse shoulder reconstruction and a WAS of > 10 prior to surgery were associated with better functional outcome and return to sports activity scores.ConclusionFollowing PHR, good to excellent functional outcomes are possible, and patients regularly return to participate in sports activities—most commonly in low-impact types of sports, but some individuals are even able to participate in high-impact sports activities.Level of evidenceIV.

Internal Hemipelvectomy for primary bone sarcomas using intraoperative patient specific instruments- the next step in limb salvage concept

BackgroundDuring pelvic Sarcoma resections, Surgeons often struggle to obtain negative margins while minimizing collateral damage and maintaining limb function. These complications are usually due to the complex anatomy of the pelvis. Here we present an accurate 3D surgical approach, including pre-operative printing of models and intraoperative patient-specific instruments (PSIs) for optimizing pelvic sarcoma resections.MethodsThis single-center retrospective study (N = 11) presents surgical, functional, and oncological outcomes of patients (average age 14.6 +/− 7.6 years, 4 males) who underwent pelvic sarcoma resections using a 3D surgical approach between 2016 and 2021. All patients were followed up for at least 24 months (mean = 38.9 +/− 30.1 months).ResultsOur results show promising surgical, oncological, and functional outcomes. Using a 3D approach, 90.9% had negative margins, and 63.6% did not require reconstruction surgery. The average estimated blood loss was 895.45 ± 540.12 cc, and the average surgery time was 3:38 ± 0.05 hours. Our results revealed no long-term complications. Three patients suffered from short-term complications of superficial wound infections. At 24 month follow up 72.7% of patients displayed no evidence of disease. The average Musculoskeletal Tumor Society (MSTS) score at 12 months was 22.81.Conclusion3D technology enables improved accuracy in tumor resections, allowing for less invasive procedures and tailored reconstruction surgeries, potentially leading to better outcomes in function and morbidity. We believe that this approach will enhance treatments and ease prognosis for patients diagnosed with pelvic sarcoma and will become the standard of care in the future.

What's New in Musculoskeletal Tumor Surgery.

What's New in Musculoskeletal Tumor Surgery.

Amino acid metabolism in primary bone sarcomas.

Primary bone sarcomas, including osteosarcoma (OS) and Ewing sarcoma (ES), are aggressive tumors with peak incidence in childhood and adolescence. The intense standard treatment for these patients consists of combined surgery and/or radiation and maximal doses of chemotherapy; a regimen that has not seen improvement in decades. Like other tumor types, ES and OS are characterized by dysregulated cellular metabolism and a rewiring of metabolic pathways to support the biosynthetic demands of malignant growth. Not only are cancer cells characterized by Warburg metabolism, or aerobic glycolysis, but emerging work has revealed a dependence on amino acid metabolism. Aside from incorporation into proteins, amino acids serve critical functions in redox balance, energy homeostasis, and epigenetic maintenance. In this review, we summarize current studies describing the amino acid metabolic requirements of primary bone sarcomas, focusing on OS and ES, and compare these dependencies in the normal bone and malignant tumor contexts. We also examine insights that can be gleaned from other cancers to better understand differential metabolic susceptibilities between primary and metastatic tumor microenvironments. Lastly, we discuss potential metabolic vulnerabilities that may be exploited therapeutically and provide better-targeted treatments to improve the current standard of care.

Induced resistance to ifosfamide in osteosarcoma cells suggests a more aggressive tumor profile

AimsOsteosarcoma (OS) is the most common primary malignant bone sarcoma among children and adolescents. Treatment is based on neo-adjuvant and adjuvant chemotherapy, using the standard drugs cisplatin, methotrexate, doxorubicin, and ifosfamide (IFO). Due to the high capacity of tumor resistance, the current work aimed to analyze genes related to cycle control and cell differentiation in OS cells sensitive to and with induced resistance to IFO. This was to assess whether the differentiated expression of these genes may affect resistance to the drug IFO used in OS treatment, and thus establish possible biomarkers of disease progression. Materials and methodsIn this work, the treatment-sensitive OS U2OS lineage was used, and the same lineage was submitted to the process of induction of IFO resistance. These cells were evaluated by MTT, migration and proliferation assays and submitted to gene expression analysis. Key findingsThe results demonstrate that after induction of resistance to IFO, resistant U2OS cells show a more aggressive tumor behavior, with greater capacity for cell migration, proliferation, and invasion compared to sensitive cells. Gene analysis indicates that resistance-induced cells have differentiated expression of the genes EPB41L3, GADD45A, IER3, OXCT1, UBE2L6, UBE2A ALPL, and EFNB2. Our results suggest new perspectives on possible resistance biomarkers, especially the genes EFNB2 and EPB41L3, given that these genes have rarely been studied their expression linked to osteosarcoma. They show how the resistance induction model can be useful for studies on tumor cell behavior.