Musculoskeletal Sarcomas Research Articles

Xenografting Human Musculoskeletal Sarcomas in Mice, Chick Embryo, and Zebrafish: How to Boost Translational Research.

Musculoskeletal sarcomas pose major challenges to researchers and clinicians due to their rarity and heterogeneity. Xenografting human cells or tumor fragments in rodents is a mainstay for the generation of cancer models and for the preclinical trial of novel drugs. Lately, though, technical, intrinsic and ethical concerns together with stricter regulations have significantly curbed the employment of murine patient-derived xenografts (mPDX). In alternatives to murine PDXs, researchers have focused on embryonal systems such as chorioallantoic membrane (CAM) and zebrafish embryos. These systems are time- and cost-effective hosts for tumor fragments and near-patient cells. The CAM of the chick embryo represents a unique vascularized environment to host xenografts with high engraftment rates, allowing for ease of visualization and molecular detection of metastatic cells. Thanks to the transparency of the larvae, zebrafish allow for the tracking of tumor development and metastatization, enabling high-throughput drug screening. This review will focus on xenograft models of musculoskeletal sarcomas to highlight the intrinsic and technically distinctive features of the different hosts, and how they can be exploited to elucidate biological mechanisms beneath the different phases of the tumor's natural history and in drug development. Ultimately, the review suggests the combination of different models as an advantageous approach to boost basic and translational research.

Surgical Margins in Musculoskeletal Sarcoma.

» Negative margin resection of musculoskeletal sarcomas is associated with reduced risk of local recurrence.» There is limited evidence to support an absolute margin width of soft tissue or bone that correlates with reduced risk of local recurrence.» Factors intrinsic to the tumor, including histologic subtype, grade, growth pattern and neurovascular involvement impact margin status and local recurrence, and should be considered when evaluating a patient's individual risk after positive margins.» Appropriate use of adjuvant therapy, critical analysis of preoperative advanced cross-sectional imaging, and the involvement of a multidisciplinary team are essential to obtain negative margins when resecting sarcomas.

CT and MRI radiomics of bone and soft-tissue sarcomas: an updated systematic review of reproducibility and validation strategies.

To systematically review radiomic feature reproducibility and model validation strategies in recent studies dealing with CT and MRI radiomics of bone and soft-tissue sarcomas, thus updating a previous version of this review which included studies published up to 2020. A literature search was conducted on EMBASE and PubMed databases for papers published between January 2021 and March 2023. Data regarding radiomic feature reproducibility and model validation strategies were extracted and analyzed. Out of 201 identified papers, 55 were included. They dealt with radiomics of bone (n= 23) or soft-tissue (n = 32) tumors. Thirty-two (out of 54 employing manual or semiautomatic segmentation, 59%) studies included a feature reproducibility analysis. Reproducibility was assessed based on intra/interobserver segmentation variability in 30 (55%) and geometrical transformations of the region of interest in 2 (4%) studies. At least one machine learning validation technique was used for model development in 34 (62%) papers, and K-fold cross-validation was employed most frequently. A clinical validation of the model was reported in 38 (69%) papers. It was performed using a separate dataset from the primary institution (internal test) in 22 (40%), an independent dataset from another institution (external test) in 14 (25%) and both in 2 (4%) studies. Compared to papers published up to 2020, a clear improvement was noted with almost double publications reporting methodological aspects related to reproducibility and validation. Larger multicenter investigations including external clinical validation and the publication of databases in open-access repositories could further improve methodology and bring radiomics from a research area to the clinical stage. An improvement in feature reproducibility and model validation strategies has been shown in this updated systematic review on radiomics of bone and soft-tissue sarcomas, highlighting efforts to enhance methodology and bring radiomics from a research area to the clinical stage. • 2021-2023 radiomic studies on CT and MRI of musculoskeletal sarcomas were reviewed. • Feature reproducibility was assessed in more than half (59%) of the studies. • Model clinical validation was performed in 69% of the studies. • Internal (44%) and/or external (29%) test datasets were employed for clinical validation.

In-phase and opposed-phase Dixon chemical shift imaging for the assessment of skeletal marrow lesions: comparison of measurements from longitudinal sequences to those from axial sequences.

In-phase and opposed-phase chemical shift imaging (CSI) is a useful technique for assessing skeletal lesions. This study determined the frequency of significant differences in measurements obtained from longitudinal (coronal or sagittal) sequences to those obtained from axial sequences. Chemical shift imaging was undertaken in 96 consecutive patients referred from the Musculoskeletal Sarcoma and Spinal Oncology services for assessment of possible bone tumours as part of a standard tumour protocol, which included turbo spin echo and inversion recovery sequences. For spinal lesions, CSI was obtained in the sagittal and axial planes, while for all other sites, it was obtained in the coronal and axial planes. The study included 49 (51.0%) males and 47 (49.0%) females with mean age 42.4 years (range 2-91 years). In 4 cases, 2 individual lesions were assessed, making a total of 100 lesions. Based on typical imaging features (n = 57) or histology (n = 43), 22 lesions (22%) were classified as non-neoplastic, 44 (44%) as benign neoplasms, 6 (6%) as intermediate-grade neoplasms, and 28 (28%) as malignant neoplasms. A significant discrepancy, wherein a lesion was classified as fat-containing (% SI drop >20%-25%) in the longitudinal plane, while in the axial plane it was classified as fat-replacing (% SI drop <20%-25%), or vice versa, occurred in 9%-14% of cases. However, this discrepancy had no appreciable effect on overall diagnostic accuracy, which was calculated at 79% for the longitudinal plane and 75%-80% for the axial plane. Significant differences in CSI measurements occur in 9%-14% of cases based on imaging plane, but with no significant effect on diagnostic accuracy. Radiologists should be aware that CSI measurements in different planes appear to have significant differences in up to 14% of lesions. However, diagnostic accuracy does not seem to be significantly affected.

Barriers to care for musculoskeletal sarcoma patients: a public health perspective.

This study seeks to investigate the barriers to care that exist for patients presenting with sarcomas of musculoskeletal origin. Understanding the roots of delays in care for patients with musculoskeletal sarcoma is particularly important given the necessity of prompt treatment for oncologic diagnoses. Investigators reviewed relevant studies of publications reporting barriers to care in patients undergoing diagnosis and treatment of musculoskeletal tumors. A comprehensive literature search was conducted using Scopus, Embase, Web of Science, and PubMed-MEDLINE. Twenty publications were analyzed, including a total of 114,056 patients. Four barrier subtypes were identified: Socioeconomic Status, Geographic Location, Healthcare Quality, Sociocultural Factors. Socioeconomic status included access to health insurance and income level. Geographic location included distance traveled by patients, access to referral centers, type of hospital system and resource-challenged environments. Healthcare quality included substandard imaging, access to healthcare resources, and healthcare utilization prior to diagnosis. Sociocultural factors included psychological states, nutrition, education and social support. After identifying the most significant barriers in this study, we can target specific public health issues within our community that may reduce delays in care. The assessment of barriers to care is an important first step for improving the delivery of oncologic patient care to this patient population.

Biopsy tract seeding in musculoskeletal sarcomas: myth or reality?

Background: It is a common practice in oncology in general and musculoskeletal oncology that the biopsy tract must be resected together with the tumor while performing limb-sparing surgery. Our study aims to assess the need for routine excision of biopsy scars in musculoskeletal malignancies by analyzing the presence of tumor in the biopsy tracts. Methods: We conducted a prospective study from January 2021 to April 2023, including 48 soft tissue and bone sarcoma patients. Neoadjuvant chemotherapy was administered to all cases of Ewings sarcoma and osteosarcoma. All of them underwent surgical resection with appropriate reconstruction. Biopsy tracts were sent separately and analyzed for tumor infiltration. Results: Two of the 48 patients included in the study had tumor deposits in their biopsy tracts. One patient with undifferentiated pleomorphic sarcoma and another patient with high-grade myxoid liposarcoma had tumor seeding in their biopsy tracts. Conclusions: The rate of biopsy tract seeding in our study was 4.2% (2 out of 48). Even though this might seem very less, it is still significant considering the rarity of bone and soft tissue sarcomas. Despite the low risk of tumor seeding, it is advisable to continue routinely excising the biopsy tract. Whether inappropriately placed biopsy tracts warrant an amputation instead of limb salvage is a question that will be best answered in the future with large-scale prospective randomized studies.

Modeling Myxofibrosarcoma: Where Do We Stand and What Is Missing?

Myxofibrosarcoma (MFS) is a malignant soft tissue sarcoma (STS) that originates in the body's connective tissues. It is characterized by the presence of myxoid (gel-like) and fibrous components and typically affects patients after the fifth decade of life. Considering the ongoing trend of increasing lifespans across many nations, MFS is likely to become the most common musculoskeletal sarcoma in the future. Although MFS patients have a lower risk of developing distant metastases compared with other STS cases, MFS is characterized by a high frequency of local recurrence. Notably, in 40-60% of the patients where the tumor recurs, it does so multiple times. Consequently, patients may undergo multiple local surgeries, removing the risk of potential amputation. Furthermore, because the tumor relapses generally have a higher grade, they exhibit a decreased response to radio and chemotherapy and an increased tendency to form metastases. Thus, a better understanding of MFS is required, and improved therapeutic options must be developed. Historically, preclinical models for other types of tumors have been instrumental in obtaining a better understanding of tumor development and in testing new therapeutic approaches. However, few MFS models are currently available. In this review, we will describe the MFS models available and will provide insights into the advantages and constraints of each model.

An exploratory study of cell stiffness as a mechanical label-free biomarker across multiple musculoskeletal sarcoma cells

BackgroundCancer cells are characterized by changes in cell cytoskeletal architecture and stiffness. Despite advances in understanding the molecular mechanisms of musculoskeletal cancers, the corresponding cellular mechanical properties remain largely unexplored. The aim of this study was to investigate the changes in cellular stiffness and the associated cytoskeleton configuration alterations in various musculoskeletal cancer cells.MethodsCell lines from five main sarcoma types of the musculoskeletal system (chondrosarcoma, osteosarcoma, Ewing sarcoma, fibrosarcoma and rhabdomyosarcoma) as well as their healthy cell counterparts (chondrocytes, osteoblasts, mesenchymal stem cells, fibroblasts, skeletal muscle cells) were subjected to cell stiffness measurements via atomic force microscopy (AFM). Biochemical and structural changes of the cytoskeleton (F-actin, β-tubulin and actin-related protein 2/3) were assessed by means of fluorescence labelling, ELISA and qPCR.ResultsWhile AFM stiffness measurements showed that the majority of cancer cells (osteosarcoma, Ewing sarcoma, fibrosarcoma and rhabdomyosarcoma) were significantly less stiff than their corresponding non-malignant counterparts (p < 0.001), the chondrosarcoma cells were significant stiffer than the chondrocytes (p < 0.001). Microscopically, the distribution of F-actin differed between malignant entities and healthy counterparts: the organisation in well aligned stress fibers was disrupted in cancer cell lines and the proteins was mainly concentrated at the periphery of the cell, whereas β-tubulin had a predominantly perinuclear localization. While the F-actin content was lower in cancer cells, particularly Ewing sarcoma (p = 0.018) and Fibrosarcoma (p = 0.023), this effect was even more pronounced in the case of β-tubulin for all cancer-healthy cell duos. Interestingly, chondrosarcoma cells were characterized by a significant upregulation of β-tubulin gene expression (p = 0.005) and protein amount (p = 0.032).ConclusionModifications in cellular stiffness, along with structural and compositional cytoskeleton rearrangement, constitute typical features of sarcomas cells, when compared to their healthy counterpart. Notably, whereas a decrease in stiffness is typically a feature of malignant entities, chondrosarcoma cells were stiffer than chondrocytes, with chondrosarcoma cells exhibiting a significantly upregulated β-tubulin expression. Each Sarcoma entity may have his own cellular-stiffness and cytoskeleton organisation/composition fingerprint, which in turn may be exploited for diagnostic or therapeutic purposes.

Intravenous tranexamic acid decreases intraoperative transfusion requirements and does not increase incidence of symptomatic venous thromboembolic events in musculoskeletal sarcoma surgery

Background and objectivesTranexamic acid (TXA) is poorly studied in patients with bone and musculoskeletal sarcoma due to perceived increased risk of venous thromboembolism (VTE). This study aims to assess the safety and efficacy of intravenous (IV) TXA for patients undergoing surgical resection of primary bone or soft-tissue sarcoma. MethodsA retrospective, single center review of adult patients with pelvic or extremity sarcoma who underwent surgical resections between January 2005 and March 2020 was performed. Patients between 2005 and 2012 were included as a historical comparison prior to the routine use of IV TXA for all sarcoma resections at our institution. ResultsThirty-nine non-TXA and 59 TXA resections were identified. Two non-TXA patients experienced symptomatic pulmonary embolism compared to zero VTEs amongst TXA patients. IV TXA administered at any dose significantly reduced the probability of intraoperative transfusion (p = 0.003) and the median units of blood transfused at the time of any perioperative transfusion (p = 0.007). Intraoperative times were significantly shorter for TXA patients (128 vs 190 min; p = 0.004). A subset of patients who underwent wide resection with endoprosthetic reconstruction and received TXA similarly showed decreased requirement for intraoperative transfusion (p = 0.014) and decreased procedure times (p = 0.009). ConclusionsDuring sarcoma resection, at least 1 g of IV TXA can safely decrease the need for any intraoperative transfusion and the median number of PRBCs transfused by 2 units when any perioperative transfusion is given.

Clinical outcomes after vascular reconstruction using synthetic grafts for limb salvage in patients with lower extremity sarcoma: a single-center retrospective experience.

Limb-salvage surgery has become the mainstream approaches for the treatment of sarcoma in the lower extremity. In cases where the sarcoma infiltrates the primary vessel, concurrent resection of the vessels and vascular reconstruction are required to ensure sufficient resection and preservation of limb function. The objective of this study is to assess the clinical outcomes of patients who underwent vascular reconstruction utilizing synthetic grafts for limb salvage, specifically in terms of postoperative complications and limb functional status. Between September 2016 and October 2021, 15 consecutive patients who underwent 15 arterial and 3 venous reconstruction procedures were included in this retrospective study. Incidence of postoperative morbidity, graft patency, rate of limb salvage, and overall survival of patients were analyzed. The median follow-up was 12.5 months (range, 4.5-72.0). Graft thrombosis occurred in 5 patients (33.3%) and graft occlusion occurred in 3 patients (20.0%). The median overall survival was 28.0 months with the estimated 2-year and 5-year overall survival of 57.8% and 43.4% respectively. The 1-year and 2-year estimated patency rates of arterial reconstructions were 82.3% and 62.1%, respectively. None of the included patients with limb amputation were observed as a consequence of severe vascular complications, while two patients underwent amputation due to the repeat recurrence, resulting in a limb salvage rate of 86.7%. Our results show that the combination of vascular reconstruction and oncologic resection is a feasible option for preserving limbs in cases of musculoskeletal sarcoma with vessel involvement in the lower extremity. When vascular reconstruction surgery is performed, synthetic substitutes can be effectively used with low perioperative morbidity and an acceptable rate of limb salvage.

Oncology

The February 2023 Oncology Roundup360 looks at: Is the number of national database research studies in musculoskeletal sarcoma increasing, and are these studies reliable?; Re-excision after unplanned excision of soft-tissue sarcoma is associated with high morbidity; Adjuvant radiation in atypical lipomatous tumours; The oncological outcomes of isolated limb perfusion and neoadjuvant radiotherapy in soft-tissue sarcoma patients - a nationwide multicentre study; Can low-grade chondrosarcoma be treated with intralesional curettage and cryotherapy?; Efficacy and safety of carbon ion radiotherapy for bone sarcomas: a systematic review and meta-analysis; Doxorubicin-polymeric meshes prevent local recurrence after sarcoma resection while avoiding cardiotoxicity; How important are skip lesions in Ewing’s sarcoma?; Improving outcomes for amputees: the health-related quality of life and cost utility analysis of osseointegration prosthetics in transfemoral amputees.

Skeletal Muscle Measurements in Pediatric Hematology and Oncology: Essential Components to a Comprehensive Assessment.

Children with hematologic and oncologic health conditions are at risk of impaired skeletal muscle strength, size, and neuromuscular activation that may limit gross motor performance. A comprehensive assessment of neuromuscular function of these children is essential to identify the trajectory of changes in skeletal muscle and to prescribe therapeutic exercise and monitor its impact. Therefore, this review aims to (a) define fundamental properties of skeletal muscle; (b) highlight methods to quantify muscle strength, size, and neuromuscular activation; (c) describe mechanisms that contribute to muscle strength and gross motor performance in children; (d) recommend clinical assessment measures; and (e) illustrate comprehensive muscle assessment in children using examples of sickle cell disease and musculoskeletal sarcoma.

Immunohistochemical Expression of p16 and CDK4 in Soft Tissue Tumors

Background: The large majority of soft tissue tumours are benign.Malignantmesenchymal neoplasms amount to less than 1% of the overall human burden of malignant tumours but they are life threatening and may pose a significant diagnostic and therapeutic challenge since there are more than 50 histological subtypes of STS, which are often associated with unique clinical, prognostic and therapeutic features. Methods: The study was undertaken in department of Pathology, King George’s Medical University, Lucknow. The Study Design was Retrospective and prospective study carried over a period of one year from September 2018 to august 2019 including 70 cases.Results: Most common diagnosis of malignant cases was Synovial saroma (21.4%) followed by Leiomyosarcoma (19.0%) and Undifferentiated pleomorphic sarcoma &amp; Fibromyxoid sarcoma (11.9% each). Less common diagnosis were Ewing’s sarcoma, Liposarcoma and Rhabdomyosarcoma (9.5% each), 1 (2.4%) case each was diagnosed as Chondrosarcoma, MPNST and Myxoid liposarcoma. Conclusions: Genetic alterations involving the 12q13-15 chromosomal region are common in musculoskeletal sarcomas, and many bone and soft-tissue malignant tumors showed amplification of various genes located in this region

Quantifying muscle strength, size, and neuromuscular activation in adolescent and young adult survivors of musculoskeletal sarcoma: Identifying correlates and responses to functional strengthening

BackgroundMedical and surgical treatment for musculoskeletal sarcoma (MSS) place survivors at risk for impairments in muscle properties including muscle strength, muscle size, and neuromuscular activation. The purpose of this study was to explore muscle properties, gross motor performance, and quality of life (QoL) and the changes in response to a 6-week functional strengthening intervention (PT-STRONG) in MSS survivors of childhood cancer (CCS). MethodsEight lower extremity MSS CCS (13–23 years old) performed baseline testing and three completed PT-STRONG. Participants completed measurements of knee extension strength using handheld dynamometry, vastus lateralis (VL) and rectus femoris (RF) muscle thickness using ultrasonography at rest, and neuromuscular activation using electromyography during strength testing and a step-up task. Participants also completed gross motor and QoL assessments. ResultsCompared with the non-surgical limb, MSS CCS had lower surgical limb knee extension strength, VL muscle thickness, and RF step-up muscle rate of activation (RoA). Compared with normative values, MSS CCS had decreased bilateral knee extension strength, gross motor performance, and physical QoL. Positive correlations among muscle strength, muscle thickness, and gross motor performance were identified. After PT-STRONG, MSS CCS had improvements in VL muscle thickness, VL and RF RoA duing step-up, gross motor performance, and physical QoL. ConclusionsPositive association between larger muscle thickness with greater knee extension strength, and higher knee extension strength with better gross motor performance indicate that comprehensive physical therapy assessment and interventions that identify and target impairments in muscle properties to guide clinical decision making should be considered for MSS CCS into survivorship.

CORR Insights®: Is the Number of National Database Research Studies in Musculoskeletal Sarcoma Increasing, and Are These Studies Reliable?

SELECTED PROCEEDINGS FROM THE 2021 MUSCULOSKELETAL TUMOR SOCIETY MEETING GUEST EDITOR H. THOMAS TEMPLE MD

CORR Insights®: What Proportion of Patients With Musculoskeletal Sarcomas Demonstrate Symptoms of Depression or Anxiety?

1Department of Orthopaedics and Trauma, Medical University of Graz, Graz, Austria D. Andreou, Department of Orthopaedics and Trauma, Medical University of Graz, Auenbruggerplatz 5, 8036, Graz, Austria, Email: [email protected] This CORR Insights® is a commentary on the article “What Proportion of Patients With Musculoskeletal Sarcomas Demonstrate Symptoms of Depression or Anxiety?” by Polfer and colleagues available at: DOI: 10.1097/CORR.0000000000002295. The author certifies that there are no funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article related to the author or any immediate family members. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request. The opinions expressed are those of the writer, and do not reflect the opinion or policy of CORR® or The Association of Bone and Joint Surgeons®.

What Proportion of Patients With Musculoskeletal Sarcomas Demostrate Symptoms of Depression or Anxiety?

What Proportion of Patients With Musculoskeletal Sarcomas Demostrate Symptoms of Depression or Anxiety?

Is the Number of National Database Research Studies in Musculoskeletal Sarcoma Increasing, and Are These Studies Reliable?

Is the Number of National Database Research Studies in Musculoskeletal Sarcoma Increasing, and Are These Studies Reliable?

The EPH/Ephrin System in Bone and Soft Tissue Sarcomas' Pathogenesis and Therapy: New Advancements and a Literature Review.

Musculoskeletal sarcomas represent rare heterogenous malignancies of mesenchymal origin that can be divided in two distinct subtypes, bone and soft tissue sarcomas. Current treatment options combine the surgical excision of local tumors and multidrug chemotherapy to prevent metastatic widespread disease. Due to the grim prognosis that usually accompanies such tumors, researchers have attempted to shed light on the molecular pathways implicated in their pathogenesis in order to develop novel, innovative, personalized therapeutic strategies. Erythropoietin-producing human hepatocellular receptors (EPHs) are tyrosine-kinase transmembrane receptors that, along with their ligands, ephrins, participate in both tumor-suppressive or tumor-promoting signaling pathways in bone and soft tissue sarcomas. The EPH/ephrin axis orchestrates cancerous processes such as cell–cell and cell–substrate adhesion and enhances the remodeling of the intracellular cytoskeleton to stimulate the motility and invasiveness of sarcoma cells. The purpose of our study was to review published PubMed literature to extract results from in vitro, in vivo and clinical trials indicative of the role of EPH/ephrin signaling in bone and soft tissue sarcomas. Based on these reports, significant interactions between the EPH/ephrin signaling pathway and a plethora of normal and abnormal cascades contribute to molecular mechanisms enhancing malignancy during sarcoma progression. In addition, EPHs and ephrins are prospective candidates for diagnostic, monitoring and therapeutic purposes in the clinical setting against bone and soft tissue sarcomas.

Early Clinical Outcome of Limb Salvage Surgery of Osteosarcoma in the Lower Extremity Using Liquid Nitrogen

Background. Osteosarcoma in the lower extremity has become a challenge for orthopedic surgeons to manage because surgeons need to preserve the affected joint's functions and retain stability as physiologic as possible. Thus, limb salvage surgery may be the treatment of choice. One of the techniques using liquid nitrogen provides better functionality and efficacy in preventing recurrence.&#x0D; Methods. From October 2020 to October 2021, 7 patients with primary musculoskeletal sarcoma underwent limb salvage surgery (LSS) by wide resection of the tumor and reconstruction using recycled Autograft treated with liquid nitrogen. The resected bone was dipped in liquid nitrogen for 15 min and thawed at room temperature for 15 min. The recycled bone was re-implanted into its original site and stabilized with internal fixation, and some of them followed with arthroplasty.&#x0D; Results. Average age was 14.14 years old. The most common site was the distal femur which was found in 3 cases (42,8%). During the 6-months-follow-up period, all patients had a good function (mean functional MSTS score of 90%) with one case of local recurrence in the re-implanted bone and one case of infection. No metastasis was reported in any patient.&#x0D; Conclusion. Satisfying functional results were recorded in all subjects treated with cryosurgery in Dr. Mohammad Hoesin General Hospital Palembang with equal results with studies around the world.