Background and Objective:Vertebral body repair comprises surgical procedures aimed at restoring height and stability of injured vertebrae, thereby re-establishing spinal structural integrity and load-bearing function. Bone fusion and biomaterial incorporation or integration are key determinants of long-term clinical outcomes, providing biological stability. The ideal biomaterial for vertebral body repair remains undefined. Despite the increasing number of available materials, achieving an optimal balance between mechanical load-bearing capacity and biological potential for progressive bone substitution-key requirements for restoring spinal biomechanics-remains a major challenge. Therefore, this narrative review examines biomaterials used in vertebral body repair, with emphasis on bone fusion outcomes. Methods:A literature review of MEDLINE/PubMed was performed using two separate searches: one on vertebral body augmentation and another on total vertebral body replacement. Original clinical studies involving the mobile spine reporting bone fusion outcomes were included, whereas studies with unclear methods for assessing bone healing were excluded. Key Content and Findings:Among the vertebral augmentation fillers analyzed, the most notable were bioactive bone cements, including calcium phosphate (16 studies), calcium sulfate (6 studies), and composite cements (3 studies). Regarding total vertebral body replacement, the most commonly reported implants were titanium mesh cages (85 studies), with bone fusion rates (BFRs) of 70-100%, and expandable titanium cages (58 studies), with BFRs ranging from 23.5% to 100% across various conditions. Other notable materials included bioactive ceramics (4 studies, 95-100%), carbon fiber (3 studies, 80-97.5%), thermoplastic polymers (8 studies, 70-100%), and carbon fiber-reinforced polymers (CFRPs) (2 studies, 100%). Porous metallic static cages (8 studies) exhibited BFRs of 76.9-100%, whereas nanohydroxyapatite/polyamide-66 (HA/PA66) cages (13 studies) showed BFRs ranging from 72.7% to 100%. Benefits and limitations of each biomaterial used in vertebral body repair were summarized and discussed. Conclusions:Current biomaterials for vertebral body repair demonstrate high BFRs; however, challenges remain concerning mechanical load-bearing capacity and biological interactions, including their potential for progressive bone substitution. Composite biomaterials that combine the most desirable properties of multiple materials represent promising solutions. Future studies on the development of optimal biomaterials are essential to achieve accurate vertebral body reconstruction from both biomechanical and biological perspectives.

Soft tissue sarcomas (STS) encompass over 50 histologic subtypes, representing more than 1% of solid tumors. Standard treatments include surgical resection and therapies such as anthracyclines or trabectedin for advanced cases, though challenges persist due to the tumor microenvironment’s complexity and limited immune profiling data. This study evaluates Trabectedin therapy in 22 refractory STS patients, analyzing progression-free survival (PFS) and immune responses. Immune monitoring included deep immunophenotyping (200+ parameters), gene expression profiling (103 genes), and soluble proteome analysis (99 analytes). Using RECIST1.1 criteria, 68.2% of patients achieved stable disease (SD), while 31.8% exhibited progression disease (PD). Therapy duration revealed 59.1% treated for less than 12 months (<12M) and 40.9% for 12 or more months (≥12M). A significant PFS improvement was observed in SD versus PD patients (p=0.0154), while therapy duration showed no effect (p=0.5433). PD patients showed reduced eosinophils (p<0.05) and Th2 cells (p<0.05). Gene expression analysis identified changes in BTRC (decreased), IFNA1 (increased), and IL9 (increased) in PD versus SD patients (p<0.05). Patients treated ≥12M exhibited increased activated HLA-DR Th2 cells (p<0.05) and decreased exhausted B cells and NK cell subsets (p<0.05). Principal component and hierarchical clustering analyses identified distinct immune profiles associated with RECIST1.1 and therapy duration, underscoring immune profiling’s role in understanding treatment responses. These findings support further research into immune monitoring for future clinical trials.

Background:Although recognition of avascular necrosis of the vertebral body in post-traumatic cases has increased, it remains underdiagnosed and is one of the most unpredictable and challenging complications in spinal trauma. Vertebral arterial supply may play a key role in fracture healing, yet this remains unproven and is not currently considered in treatment algorithms. Surgical decisions between preserving or replacing the vertebral body in burst fractures are difficult, mainly due to limited knowledge of the biological factors influencing bone repair. This study aims to demonstrate the impact of vertebral vascular disruption on vertebral body fracture healing. We developed an experimental model in Wistar rats to replicate an L1 vertebral body fracture and analyze the normal healing sequence. Additionally, we examined the effects of disrupting the anterolateral blood supply on bone regeneration. Methods:Seventy female Wistar rats were divided into two groups. Group 1 (n=35) underwent an L1 burst fracture induced by ultrasonic tools. Group 2 (n=35) received the same fracture, followed by electrocauterization of the anterolateral vertebral surfaces and placement of a synthetic barrier to prevent revascularization. Vertebral specimens were collected weekly for 6 weeks. Healing was assessed macroscopically and histologically using an image-processing algorithm trained to identify inflammatory, fibroblastic/cartilaginous, and bone tissue. The predominant tissue type was used to determine the healing stage. Results:At week 1, the vascular disruption group showed significantly more inflammatory tissue (56.34%) than controls (24.25%, P=0.03), while fibroblastic/cartilaginous tissue was more common in controls (58.82% vs. 19.18%, P=0.03). By week 6, this tissue remained more prevalent in the intervention group (37.4%), while bone tissue predominated in controls (66.71% vs. 45.54%, P=0.009). Among animals already in the bone phase, trabecular structures were significantly more developed in controls (80% vs. 20%, P=0.031). Notably, all control animals reached the soft callus stage by week 1, whereas intervention animals only transitioned out of the inflammatory phase after the first week. Across all phases, progression was consistently faster in the control group, with statistical significance in the soft callus stage (P=0.002). Conclusions:Disruption of the anterolateral vascular supply significantly delays healing in L1 vertebral body fractures in rats, evidenced by slower phase transitions and reduced bone maturation. These findings underscore the essential role of vascularization in successful vertebral repair and suggest it should be considered in future therapeutic strategies.

Background:The factors influencing bone healing in complete burst fractures-key to deciding between stabilization or vertebral replacement-remain poorly defined. Arterial vascularization and bone nutrition are known to affect healing or progression to necrosis. However, the role of vascular injury in vertebral fractures is not yet conclusively demonstrated and is not currently factored into the decision-making for ad initium vertebral body replacement surgery. This study aims to analyze the vascularization of the L1 vertebral body in Wistar rats and compare it to human anatomy. The goal is to evaluate the suitability of the Wistar rat as a model for studying vertebral blood supply. Methods:Forty-three female Wistar rats (3 months old, 250-350 g) were used. After intraventricular injection of acrylic resin, three specimens underwent vascular corrosion-fluorescence. Twenty rats received latex injections and were converted into modified Spalteholz-cleared specimens. The remaining 20 underwent histological analysis of axial slices at upper, intermediate, and lower vertebral body levels. Cell nuclei of vascular endothelium, bone, cartilage, and marrow components were identified and analyzed by quadrant and central/peripheral distribution. Results:Several vascular structures observed macroscopically matched human anatomy, including: lumbar segmental arteries (100%), horizontal metaphyseal anastomoses (Hma) (56.52%), vertical anastomoses between adjacent vertebrae (34.78%), primary periosteal arteries (Ppa) (60.87%), anterior spinal canal branch (Ascb) of the lumbar artery (69.57%), its ascending and descending branches (52.17%), posterior intervertebral anastomoses (17.39%), posterior nutritive artery origins (47.83%), medial spinal branches (86.96%) and radicular branches (Rbs) (65.22%). Histologically, the vascular density averaged 101.09 endothelial nuclei per mm2. There was a clear predominance of endothelial cells in the anterocentral region. Statistically significant differences were found in cell density and proportion between central (CA) and peripheral (PA) areas (P<0.001), within central versus lateral regions (P<0.001), and between anterior and posterior regions (P=0.03). The distribution of vascular endothelium, bone, cartilage, and bone marrow components is described. Conclusions:The vascular architecture of the L1 vertebral body in Wistar rats shows strong similarity to that of humans. These findings support the Wistar rat as a valid model for future studies on vertebral body vascularization and the role of ischemia in fracture healing and related pathologies.

Background:The vertebral body plays a crucial role in supporting compressive loads and maintaining spinal biomechanics. An ideal biomaterial for total vertebral body replacement should combine biological and mechanical properties, yet no current material fulfills all criteria. This pilot study explores the use of a novel three-dimensional (3D)-printed porous polylactic acid (PLA) implant for total L1 vertebral body replacement. Methods:This study had four stages: first, design, optimization, and 3D printing of the PLA device; second, in vitro evaluation of biocompatibility and cell growth using indirect cytotoxicity assay, direct cell viability assay, and cytochemical analysis via confocal microscopy; third, in vivo testing in 35 Wistar rats that underwent anterior retroperitoneal abdominal access for total L1 replacement with the PLA device; and finally, sequential histological analysis to assess osseointegration at 2, 4, and 6 months post-implantation. A pixel-based algorithm quantified proportions of PLA material, inflammatory and granulation tissue, fibroblastic and cartilaginous tissue, immature woven bone, and mature trabecular bone. The PLA-posterior wall interface was also examined for continuity and bone bridging. Results:The PLA device had a parallelepiped shape with pore sizes from 150 to 500 µm, confirmed by scanning electron microscopy (SEM). In vitro tests showed no cytotoxicity and good biocompatibility, with successful growth of pre-osteoblasts on both irradiated and non-irradiated PLA. In vivo results were satisfactory, with no toxicity, a 14.29% mortality rate, and 13.33% neurological deficits. Histology showed the PLA device was mostly present at 2 months (69.55%±8.16%), with significant inflammatory tissue (22.63%±9.45%). By 4 months, woven bone (19.63%±5.81%) and fibrocartilaginous tissue (18.41%±8.87%) predominated. At 6 months, mature trabecular bone was the main tissue (43.12%±9.72%), with only 7.68%±11.24% of PLA remaining. Bone bridging at the PLA-posterior wall interface was continuous in 66.67% of rats at 6 months. Conclusions:This pilot study shows promising in vitro and in vivo outcomes of a porous 3D-printed PLA scaffold for total L1 vertebral body replacement. Its microstructural properties, particularly porosity, supported osseointegration and bone repair. The implant presents as a strong candidate for vertebral reconstruction and may achieve enhanced results when combined with bioactive agents.

Leiomyosarcomas (LMSs) are malignant neoplasms of soft muscle differentiation that can be classified into five distinct groups according to site-related origin: intra-abdominal, subcutaneous or deep soft tissue of the limbs, cutaneous, external genitalia, and vascular. This distinction reflects different biological behaviors as well as molecular changes, thus reflecting different prognoses and therapeutic options. Vascular LMSs are the least frequent, arising from the walls of the blood vessels, most commonly from the inferior vena cava. Due to its deep location, symptoms are non-specific, and the disease presents at an advanced stage, sometimes with metastases. Surgery is the treatment of choice, associated with chemo- and radiotherapy. Due to its rarity, most departments have minimal experience handling this disease. This article reviews the current knowledge on vascular leiomyosarcomas, particularly the inferior vena cava leiomyosarcoma.

Extraskeletal myxoid chondrosarcoma is a rare soft tissue tumour with a high local and distant metastasis rate and limited response to chemotherapy.Meckel's diverticulum is the most frequent congenital anomaly, and it is associated with a considerable risk of malignant transformation.In this case report, we describe a 50-year-old female patient with a history of extraskeletal myxoid chondrosarcoma of the lower limb and metastasis to the forearm who went to the emergency department with abdominal pain. The investigations revealed a caecal volvulus. A lesion in the middle third of the ileum was incidentally discovered and removed during surgery.Pathology examination revealed a Meckel's diverticulum adenocarcinoma, with metastasis of extraskeletal myxoid chondrosarcoma.Resection was complete; however, the patient had diffuse metastatic pulmonary disease and died eight months later due to disease progression.This mechanism of tumour-to-tumour metastasis is described in other locations, but, regarding the Meckel's diverticulum, this is a unique situation, previously unreported in the literature.

Studying the tumor microenvironment and surrounding lymph nodes is the main focus of current immunological research on soft tissue sarcomas (STS). However, due to the restricted opportunity to examine tumor samples, alternative approaches are required to evaluate immune responses in non-surgical patients. Therefore, the purpose of this study was to evaluate the peripheral immune profile of STS patients, characterize patients accordingly and explore the impact of peripheral immunotypes on patient survival. Blood samples were collected from 55 STS patients and age-matched healthy donors (HD) controls. Deep immunophenotyping and gene expression analysis of whole blood was analyzed using multiparametric flow cytometry and real-time RT-qPCR, respectively. Using xMAP technology, proteomic analysis was also carried out on plasma samples. Unsupervised clustering analysis was used to classify patients based on their immune profiles to further analyze the impact of peripheral immunotypes on patient survival. Significant differences were found between STS patients and HD controls. It was found a contraction of B cells and CD4 T cells compartment, along with decreased expression levels of ICOSLG and CD40LG; a major contribution of suppressor factors, as increased frequency of M-MDSC and memory Tregs, increased expression levels of ARG1, and increased plasma levels of IL-10, soluble VISTA and soluble TIMD-4; and a compromised cytotoxic potential associated with NK and CD8 T cells, namely decreased frequency of CD56dim NK cells, and decreased levels of PRF1, GZMB, and KLRK1. In addition, the patients were classified into three peripheral immunotype groups: "immune-high," "immune-intermediate," and "immune-low." Furthermore, it was found a correlation between these immunotypes and patient survival. Patients classified as "immune-high" exhibited higher levels of immune-related factors linked to cytotoxic/effector activity and longer survival times, whereas patients classified as "immune-low" displayed higher levels of immune factors associated with immunosuppression and shorter survival times. In conclusion, it can be suggested that STS patients have a compromised systemic immunity, and the correlation between immunotypes and survival emphasizes the importance of studying peripheral blood samples in STS. Assessing the peripheral immune response holds promise as a useful method for monitoring and forecasting outcomes in STS.

Current immune research on soft tissue sarcomas (STS) primarily focuses on analyzing the tumor microenvironment and adjacent lymph nodes. However, alternative methods are necessary to monitor immune responses in non-surgical patients due to limited opportunities to study tumor-infiltrating lymphocytes. This study aimed to assess the peripheral immune profile of STS patients and its impact on patient survival. Blood samples were collected from 55 STS patients and age-matched healthy individuals. Flow cytometry and qRT-PCR were conducted on whole blood, to proceed with deep immunophenotyping and gene expression quantification, respectively. Proteomic analysis was also performed on plasma samples by xMAP technology. Unsupervised clustering analysis was used to classify patients based on their immunotype. Significant differences were found between STS patients and healthy individuals. STS patients showed lymphopenia, particularly affecting B and CD4 T cells, with an expansion of myeloid cells such as granulocytes and monocytic-derived suppressor cells (M-MDSC). Gene expression analysis revealed decreased levels of activatory and cytotoxic-related factors, along with increased expression of ARG1, which may inhibit anti-tumoral activity. A tendency for increased levels of IL-10 and soluble checkpoint inhibitors VISTA and TIMD-4 were also observed in plasma samples. Furthermore, patients were classified into three distinct immunotypes: "immune-high," "immune-intermediate," and "immune-low." These immunotypes correlated significantly with time after collection (TAC), which refers to the time from sample collection to the end of the study or occurrence of a death event. "Immune-high" patients had elevated levels of immune-related factors associated with cytotoxic/effector activity and longer TAC, while "immune-low" patients had increased levels of immune-related factors associated with inflammation and inhibition, and shorter TAC. The correlation between immunotypes and survival times emphasizes the importance of studying peripheral blood samples in STS. Evaluating the peripheral immune response can be a valuable tool for monitoring and predicting outcomes in STS patients.

Targeting the B-cell lymphoma 2 (Bcl-2) family proteins has been the backbone for hematological malignancies with overall survival improvements. The Bcl-2 family is a major player in apoptosis regulation and, has captured the researcher's interest in the treatment of solid tumors. Sarcomas are a heterogeneous group of diseases, comprising several entities, with high morbidity and mortality and with few specific therapies available. The treatment for sarcomas is based on platinum regimens, with variable results and poor outcomes, especially in advanced lesions. The high number of different sarcoma entities makes treatment standardization as well as the performance of clinical trials difficult. The use of Bcl-2 family members modifiers has revealed promising results in in vitro and in vivo models and may be a valid option, especially when used in combination with chemotherapy. In this article, a revision of these results and possibilities for the use of Bcl-2 family members inhibitors in sarcomas was performed.

ABSTRACT Objective Present the preliminary results of a case series using the surgical ankle arthrodesis technique with an intramedullary retrograde nail for bone tumors. Methods We present the preliminary data of 4 patients, 3 males and 1 female, with a mean age of 46,2 (range 32 to 58) years, with histology proven Giant Cell Tumour of bone in 3 and osteosarcoma in 1. The mean resection length of distal tibia was 11,75 (range 9 to 16) cm, and all the patients underwent reconstruction with a tibiotalocalcaneal arthrodesis with an intercalary allograft fixed by a retrograde intramedullary nail. Results Oncological follow-up evolved without evidence of local recurrence or disease progression in all patients. After a mean time of 69.5 (range 32 to 98 months), patients had a mean MSTS12 functional score of 82.5% (range 75 to 90). All tibial arthrodesis and diaphyseal osteotomy sites were fused within 6 months with a return to activities without complications related to coverage skin or infection. Conclusion No complications were recorded; all arthrodesis and diaphysial tibial osteotomy sites fused by 6 months, and the mean follow-up of those patients was 69,5 (range 32 to 988) months, with a mean functional MSTS score of 82,5% (range 75-90). Level of Evidence: IV; Retrospective Case Series.

Abstract Background Lung metastasis is the most adverse clinical factor and remains the leading cause of osteosarcoma-related death. Deciphering the mechanisms driving metastatic spread is crucial for finding open therapeutic windows for successful organ-specific interventions that may halt or prevent lung metastasis. Methods We employed a mouse premetastatic lung-based multi-omics integrative approach combined with clinical features to uncover the specific changes that precede lung metastasis formation and identify novel molecular targets and biomarker of clinical utility that enable the design of novel therapeutic strategies. Results We found that osteosarcoma-bearing mice or those preconditioned with the osteosarcoma cell secretome harbour profound lung structural alterations with airway damage, inflammation, neutrophil infiltration, and extracellular matrix remodelling with increased deposition of fibronectin and collagens by resident stromal activated fibroblasts, favouring the adhesion of disseminated tumour cells. Systemic-induced microenvironmental changes, supported by transcriptomic and histological data, promoted and accelerated lung metastasis formation. Comparative proteome profiling of the cell secretome and mouse plasma identified a large number of proteins involved in extracellular-matrix organization, cell-matrix adhesion, neutrophil degranulation, and cytokine-mediated signalling, consistent with the observed lung microenvironmental changes. Moreover, we identified EFEMP1, an extracellular matrix glycoprotein exclusively secreted by metastatic cells, in the plasma of mice bearing a primary tumour and in biopsy specimens from osteosarcoma patients with poorer overall survival. Depletion of EFEMP1 from the secretome prevents the formation of lung metastasis. Conclusions Integration of our data uncovers neutrophil infiltration and the functional contribution of stromal-activated fibroblasts in ECM remodelling for tumour cell attachment as early pro-metastatic events, which may hold therapeutic potential in preventing or slowing the metastatic spread. Moreover, we identified EFEMP1, a secreted glycoprotein, as a metastatic driver and a potential candidate prognostic biomarker for lung metastasis in osteosarcoma patients. Graphical abstract Osteosarcoma-derived secreted factors systemically reprogrammed the lung microenvironment and fostered a growth-permissive niche for incoming disseminated cells to survive and outgrow into overt metastasis. Daily administration of osteosarcoma cell secretome mimics the systemic release of tumour-secreted factors of a growing tumour in mice during PMN formation; Transcriptomic and histological analysis of premetastatic lungs revealed inflammatory-induced stromal fibroblast activation, neutrophil infiltration, and ECM remodelling as early onset pro-metastatic events; Proteome profiling identified EFEMP1, an extracellular secreted glycoprotein, as a potential predictive biomarker for lung metastasis and poor prognosis in osteosarcoma patients. Osteosarcoma patients with EFEMP1 expressing biopsies have a poorer overall survival.

CD56+ T cells are generally recognized as a distinct population of T cells and are categorized as NKT-like cells. Although our understanding of NKT-like cells is far from satisfactory, it has been shown that aging and a number of disease situations have impacted these cells. To construct an overview of what is currently known, we reviewed the literature on human NKT-like cells. NKT-like cells are highly differentiated T cells with “CD1d-independent” antigen recognition and MHC-unrestricted cell killing. The genesis of NKT-like cells is unclear; however, it is proposed that the acquisition of innate characteristics by T cells could represent a remodeling process leading to successful aging. Additionally, it has been shown that NKT-like cells may play a significant role in several pathological conditions, making it necessary to comprehend whether these cells might function as prognostic markers. The quantification and characterization of these cells might serve as a cutting-edge indicator of individual immune health. Additionally, exploring the mechanisms that can control their killing activity in different contexts may therefore result in innovative therapeutic alternatives in a wide range of disease settings.

AbstractLung metastasis represents the leading cause of osteosarcoma-related death. Progress in preventing lung metastasis is pretty modest due to the inherent complexity of the metastatic process and the lack of suitable models. Herein, we provide mechanistic insights into how osteosarcoma systemically reprograms the lung microenvironment for metastatic outgrowth using metastatic mouse models and a multi-omics approach.We found that osteosarcoma-bearing mice or those preconditioned with cell-secretome harbour profound lung structural alteration with airways damage, inflammation, neutrophil infiltration, and remodelling of the extracellular matrix with deposition of fibronectin and collagen by stromal activated fibroblasts for tumour cell adhesion. These changes, supported by transcriptomic and histological data, promoted and accelerated the development of lung metastasis. Comparative proteome profiling of the cell secretome and mouse plasma identified a large number of proteins engaged in the extracellular-matrix organization, cell-matrix adhesion, neutrophil degranulation, and cytokine-mediated signalling, which were consistent with the observed lung microenvironmental changes. Moreover, we identified EFEMP1, a secreted extracellular matrix glycoprotein, as a potential risk factor for lung metastasis and a poor prognosis factor in osteosarcoma patients.

Clear cell chondrosarcoma is a rare histological subtype of chondrosarcoma, usually with a relatively non-aggressive clinical course. However, infrequently they may relapse and metastasize. We describe a case of a male patient, 53 years old, with rib cage metastases of a clear cell chondrosarcoma 11 years after the first surgical intervention, and review the literature.

Osteosarcoma (OST) is the most common type of high-grade primary bone tumor, which mainly affects young adults. The current standard of care for OST combines surgical resection with chemotherapy. The clinical outcomes and the current options to treat OST patients are unsatisfactory and novel treatment strategies are needed. The crosstalk between tumor cells and immune cells is essential to the OST microenvironment. Despite the efforts that have been made to address the importance of immune-related factors in OST, there is still a lot to understand. The purpose of the current study was to evaluate the tumor-infiltrating lymphocytes (TIL), the expression of proteins involved in tumor biology, and their impact on the clinical outcome of OST patients. We studied 93 samples of OST patients using immunohistochemistry and histomorphometry. We looked for the infiltration of CD3+, CD4+, CD8+, TIA1+ and CD20+ cells and for the expression of CD44 standard (CD44s) and variant 6 (CD44v6), CD95/Fas, Fas-L, p53 and p-glycoprotein. All the parameters were analyzed for the influence on the occurrence of death and metastasis, plus patient overall survival (OS) and progression-free survival (PFS). The effect of sex, age, tumor location (distal femur or proximal tibia) and the combination with neoadjuvant chemotherapy was also assessed. Our results suggest that the presence of tumor-infiltrating CD4+ cells provides protection to OST patients, and that CD8+ cells have a significant impact on the patient's overall survival (OS) and progression-free survival (PFS), which is more evident in male patients. In addition, a strong association between tumor-infiltrating CD4+ cells and the presence of CD44s expression in tumor samples was observed. Analysis of TIL and tumor markers related to tumor biology could be useful to stratify patients and monitor the response to therapy, as well as to assist with the development of immunotherapy strategies to improve the effects of cytotoxic TIL to eradicate the tumor cells.

Soft-tissue sarcomas (STS) represent about 80% of sarcomas, and are a heterogeneous group of rare and malignant tumors. STS arise from mesenchymal tissues and can grow into structures such as adipose tissue, muscles, nervous tissue and blood vessels. Morphological evaluation has been the standard model for the diagnosis of sarcomas, and even in samples with similar characteristics, they present a diversity in cytogenetic and genetic sequence alterations, which further increases the diversity of sarcomas. This variety is one of the main challenges for the classification and understanding of STS patterns, as well as for their respective treatments, which further decreases patient survival (<5 years). Despite some studies, little is known about the immunological profile of STS. As for the immunological profile of STS in relation to NK cells, there is also a shortage of studies. Observations made in solid tumors show that the infiltration of NK cells in tumors is associated with a good prognosis of the disease. Notwithstanding the scarcity of studies to characterize NK cells, their receptors, and ligands in STS, it is noteworthy that the progression of these malignancies is associated with altered NK phenotypes. Despite the scarcity of information on the function of NK cells, their phenotypes and their regulatory pathways in STS, the findings of this study support the additional need to explore NK cell-based immunotherapy in STS further. Some clinical trials, very tentatively, are already underway. STS clinical trials are still the basis for adoptive NK-cell and cytokine-based therapy.

Soft Tissue Sarcomas (STS) are a heterogeneous and rare group of tumors. Immune cells, soluble factors, and immune checkpoints are key elements of the complex tumor microenvironment. Monitoring these elements could be used to predict the outcome of the disease, the response to therapy, and lead to the development of new immunotherapeutic approaches. Tumor-infiltrating B cells, Natural Killer (NK) cells, tumor-associated neutrophils (TANs), and dendritic cells (DCs) were associated with a better outcome. On the contrary, tumor-associated macrophages (TAMs) were correlated with a poor outcome. The evaluation of peripheral blood immunological status in STS could also be important and is still underexplored. The increased lymphocyte-to-monocyte ratio (LMR) and neutrophil-to-lymphocyte ratio (NLR), higher levels of monocytic myeloid-derived suppressor cells (M-MDSCs), and Tim-3 positive CD8 T cells appear to be negative prognostic markers. Meanwhile, NKG2D-positive CD8 T cells were correlated with a better outcome. Some soluble factors, such as cytokines, chemokines, growth factors, and immune checkpoints were associated with the prognosis. Similarly, the expression of immune-related genes in STS was also reviewed. Despite these efforts, only very little is known, and much research is still needed to clarify the role of the immune system in STS.