A Novel Approach to Reducing Lung Metastasis in Osteosarcoma: Increasing Cell Stiffness with Carbenoxolone.

AIM: Primary malignant bone tumor osteosarcoma can metastasize to the lung. Diminishing lung metastasis would positively affect the prognosis of patients. Our previous studies demonstrated that highly metastatic osteosarcoma cell lines are significantly softer than low-metastasis cell lines. We therefore hypothesized that increasing cell stiffness would suppress metastasis by reducing cell motility. In this study, we tested whether carbenoxolone (CBX) increases the stiffness of LM8 osteosarcoma cells and prevents lung metastasis in vivo. METHODS: We evaluated the actin cytoskeletal structure and polymerization of CBX-treated LM8 cells using actin staining. Cell stiffness was measured using atomic force microscopy. Metastasis-related cell functions were analyzed using cell proliferation, wound healing, invasion, and cell adhesion assays. Furthermore, lung metastasis was examined in LM8-bearing mice administered with CBX. RESULTS: Treatment with CBX significantly increased actin staining intensity and stiffness of LM8 cells compared with vehicle-treated LM8 cells (p < 0.01). In Young's modulus images, compared with the control group, rigid fibrillate structures were observed in the CBX treatment group. CBX suppressed cell migration, invasion, and adhesion but not cell proliferation. The number of LM8 lung metastases were significantly reduced in the CBX administration group compared with the control group (p < 0.01). CONCLUSION: In this study, we demonstrated that CBX increases tumor cell stiffness and significantly reduces lung metastasis. Our study is the first to provide evidence that reducing cell motility by increasing cell stiffness might be effective as a novel anti-metastasis approach in vivo.

What is a useful marker for predicting survival in patients with high-grade soft tissue sarcoma who have non-inflammatory conditions?

BACKGROUND: The modified Glasgow prognostic score (mGPS) is a reliable system for identifying patients at high risk of death among patients with soft tissue sarcoma (STS). The scoring systems use a combination of C-reactive protein (CRP) and albumin levels. Although patients with high-grade STS are at risk of metastasis and death, even if their mGPS is 0, the prognostic indicators in these patients are unknown. Therefore, we investigated useful prognostic indicators for survival and the development of metastasis in patients with high-grade STS and an mGPS of 0. METHODS: One hundred and four patients with CRP and albumin levels of <1.0 mg/dl and >3.5 g/dl, respectively, indicating an mGPS of 0, were included. The mean follow-up period was 79 months. RESULTS: The 5-year disease-specific survival (DSS) rate was 79.2%. Cox proportional analysis showed that tumor size and absolute neutrophil count (ANC) were prognostic variables in multivariate analyses. Patients with higher ANC (ANC>3370/µl) had a worse DSS than those with lower ANC. The 5-year DSS was 74.7% vs. 91.7%, respectively (p = 0.0207). The 5-year metastasis-free survival was 67.2%. Tumor size and ANC remained significant variables for predicting the development of metastasis in the multivariate analysis. Patients with higher ANC had a worse metastasis-free survival than those with lower ANC. The 5-year metastasis-free survival was 59.5% vs. 87.3%, respectively (p = 0.00269). CONCLUSIONS: When patients with high-grade STS have an mGPS of 0, the ANC and tumor size should be carefully evaluated. A higher neutrophil count and larger tumor size may increase the risk of metastasis development.

Artifactual hypoglycaemia may be common in patients with soft tissue sarcoma who received pegfilgrastim-supported chemotherapy.

BACKGROUND: Recently, we identified artifactual hypoglycemia in patients with soft tissue sarcoma (STS) who received pegfilgrastim-supported chemotherapy. In the present study, we measured white blood cell count and fasting blood glucose levels after the administration of pegfilgrastim in patients with STS and showed the relationship between artifactual hypoglycemia and white blood cell count. PATIENTS: A total of 19 patients were included in this study. The mean age of the patients was 54 years. They received chemotherapy and administration of pegfilgrastim. Pegfilgrastim was injected subcutaneously 48 h after chemotherapy. No patient had a history of diabetes mellitus. RESULTS: Fifty-nine cycles were administered to 19 patients. One hundred and twenty-eight samples were obtained within one week after the of pegfilgrastim administration. Hypoglycemia was observed in 38 of the 13 patients. There were no symptoms of hypoglycemia in any patient. The white blood cell count in samples from patients with hypoglycemia was significantly higher than that in samples without hypoglycemia (p < 0.001). The median white blood cell count in samples with hypoglycemia was 29,415 and 3420 in samples without hypoglycemia. Age, sex, body mass index, performance status, and red blood cell count were not associated with hypoglycemia. White blood cell count was strongly negatively correlated with fasting blood glucose levels (Pearson's r: 0.786, 95% confidence interval: 0.844-0.709, p < 0.001). Of the 38 samples with hypoglycemia, 32 were measured within 2 days after pegfilgrastim administration. CONCLUSION: If a lack of symptoms due to hypoglycemia and leukocytes is confirmed, physicians should wait and identify the normalization of the level of glucose according to the neutrophil nadir following temporal leukocytes, which prevents further invasive examination for hypoglycemia.

Do coagulation or fibrinolysis reflect the disease condition in patients with soft tissue sarcoma?

BACKGROUND: Coagulation and fibrinolysis are distinct processes that are highly correlated. Cells control coagulation and fibrinolysis by expression of tissue factor and urokinase-type plasminogen activator receptor on their surface. Tumor cells express these proteins, adjust their microenvironment and induce tumor exacerbation. We hypothesized that the expression of plasma markers for coagulation and fibrinolysis in patients with soft tissue sarcomas (STSs) was dependent on the level of tumor malignancy. To elucidate which markers are predictive of recurrence, metastasis and prognosis, coagulation or fibrinolysis, we analyzed the correlation between plasma levels of thrombin-antithrombin III complex (TAT), soluble fibrin (SF), plasmin-α2 plasmin inhibitor complex (PIC), D-dimer (DD) and clinical parameters in patients with STSs. METHODS: TAT, SF, PIC or DD were measured in pre-treatment blood samples from 64 patients with primary STSs and analyzed with clinicopathological parameters, and 5-year recurrence free survival (RFS), 5-year metastasis free survival (MFS) and 5-year overall survival (OS) were evaluated. RESULTS: The metastasis group had significantly higher DD (p = 0.0394), PIC (p = 0.00532) and SF (p = 0.00249) concentrations than the group without metastasis. The group that died of disease showed significantly higher DD (p = 0.00105), PIC (p = 0.000542), SF (p = 0.000126) and TAT (p = 0.0373) than surviving patients. By dividing the patients into low and high groups, the group with high DD, PIC, SF and TAT showed significantly lower 5-year MFS and 5-year OS than the corresponding low group. Furthermore, in multivariate COX proportional hazard analysis of continuous variables for 5-year MFS, only PIC was found to be a significant factor (HR: 2.14). CONCLUSION: Fibrinolysis was better than coagulation at reflecting the disease condition of patients with STS. Notably, PIC levels ≥ 1.1 can not only predict the risk of metastasis and poor prognosis, but also increasing PIC levels correspond to further increases in risks of metastasis and poor prognosis.

Clinical outcome in patients who underwent amputation due to extremity soft tissue sarcoma: Tokai Musculoskeletal Oncology Consortium study.

BACKGROUND: Soft tissue sarcomas are a diverse group of rare malignant tumours, mostly occurring in the lower extremities. Amputations are necessary for achieving local control when the soft tissue sarcomas are too large and/or have neurovascular involvement. Patients who require amputation have a poorer prognosis than those who undergo limb-salvage surgery. PATIENTS AND METHODS: We investigated the tumour characteristics and the clinical outcomes in 55 patients with primary soft tissue sarcomas, who underwent amputation. We excluded patients with amputation performed distal to the wrist or ankle joints and those with recurrent soft tissue sarcomas. RESULTS: The mean tumour size was 11.1 cm. Hip disarticulation was performed in 6 patients, 20 underwent above the knee amputation, 8 underwent knee disarticulation and 12 underwent below the knee amputation. Shoulder disarticulation was performed in three patients, five underwent above the elbow amputation, and one underwent below the elbow amputation. The 5-year disease-specific survival rate was 52.8%. The 5-year recurrence-free survival rate and 5-year metastasis-free survival rates were 90.1% and 38.5%, respectively. Larger tumour size, age and the distant metastases at first presentation were predictors of poor prognosis for survival in multivariate analysis. Twenty-eight patients could walk using artificial limbs. The level of amputation (above versus below the knee) showed a significant difference in achieving independent gait. CONCLUSION: Amputation is a useful treatment option for achieving local control in patients with large soft tissue sarcomas. Patients had an opportunity of walking, especially for those who underwent below the knee amputation.

Is no additional excision after unplanned excision with positive margins justified in patients with small (≤5 cm) high-grade soft-tissue sarcoma?: Analysis from the Bone and Soft Tissue Tumor registry in Japan.

BACKGROUND: This study aimed to elucidate the clinical outcomes of patients with small (≤5 cm) high-grade soft tissue sarcoma, who underwent unplanned excision with positive surgical margin, using data from the Bone and Soft Tissue Tumor registry in Japan. METHODS: We examined 174 patients (101 males and 73 females; mean age, 59 years) with primary non-metastatic soft tissue sarcoma. The tumor size was ≤5 cm, and tumor histological grade was high in all patients. The mean follow-up duration was 50 months. RESULTS: Unplanned excision with R1 and R2 margins was reported in 115 (66%) and 59 patients (34%), respectively. After unplanned excision, immediate additional excision was performed in 154 patients, whereas no additional excision was performed in the remaining 20. Of the 154 patients who underwent additional excision, wide surgical margin resection was achieved in 140 patients, while marginal and intralesional resections were achieved in 10 and 3 patients, respectively. Additionally, 93 patients (60%) underwent reconstruction after additional excision. During the last follow-up, 8 patients died of the disease, 22 developed distant metastasis, and 14 reported local recurrence. The 5-year disease-specific survival rate and 5-year metastasis-free survival rate was 93.5% and 85%, respectively. Tumor depth and additional excision after unplanned excision showed statistical significance in the multivariate analysis. The 5-year metastasis-free survival rate was 89.1% in patients with additional excision and 39.2% in those without. Univariate analysis showed an association between additional excision and local control. The 5-year local recurrence-free survival was significantly worse in patients without additional excision after unplanned excision (52.6%) than in those with additional excision (92.8%). CONCLUSION: If unplanned excision is performed in patients with small high-grade soft tissue sarcoma, additional excision is recommended for preventing metastasis, along with necessary preparations for reconstruction.

Cytoskeletal Actin Structure in Osteosarcoma Cells Determines Metastatic Phenotype via Regulating Cell Stiffness, Migration, and Transmigration.

Osteosarcoma is the most common primary malignant bone tumor. The cause of death due to osteosarcoma is typically a consequence of metastasis to the lung. Controlling metastasis leads to improved prognosis for osteosarcoma patients. The cell stiffness of several tumor types is involved in metastatic potential; however, it is unclear whether the metastatic potential of osteosarcoma depends on cell stiffness. In this study, we analyzed the cell stiffness of the low metastatic Dunn cell line and its highly metastatic LM8 subline, and compared actin organization, cell proliferation, and metastasis. Actin cytoskeleton, polymerization, stiffness, and other cellular properties were analyzed. The organization of the actin cytoskeleton was evaluated by staining F-actin with Alexa Fluor 488 phalloidin. Cell stiffness was measured using Atomic Force Microscopy (AFM). Cell proliferation, migration, invasion, and adhesion were also evaluated. All experiments were performed using mouse osteosarcoma cell lines cultured in the absence and presence of cytochalasin. In LM8 cells, actin polymerization was strongly suppressed and actin levels were significantly lower than in Dunn cells. Stiffness evaluation revealed that LM8 cells were significantly softer than Dunn. Young's modulus images showed more rigid fibrillar structures were present in Dunn cells than in LM8 cells. LM8 cells also exhibited a significantly higher proliferation. The migration and invasion potential were also higher in LM8 cells, whereas the adhesion potential was higher in Dunn cells. The administration of cytochalasin resulted in actin filament fragmentation and decreased actin staining intensity and cell stiffness in both LM8 and Dunn cells. Cells with high metastatic potential exhibited lower actin levels and cell stiffness than cells with low metastatic potential. The metastatic phenotype is highly correlated to actin status and cell stiffness in osteosarcoma cells. These results suggest that evaluation of actin dynamics and cell stiffness is an important quantitative diagnostic parameter for predicting metastatic potential. We believe that these parameters represent new reliable quantitative indicators that can facilitate the development of new drugs against metastasis.

Significance of coagulation and fibrinolysis markers for benign and malignant soft tissue tumors.

BACKGROUND: The intimate relationship between coagulation and fibrinolysis in malignant tumors is a well-known phenomena, with the malignant phenotype enhancing coagulation and fibrinolysis. We hypothesized that soft tissue sarcoma (STS) affects the expression of coagulation and fibrinolysis markers, which could be used to distinguish STS from benign soft tissue tumors. We analyzed the correlations between plasma levels of D-dimer (DD), plasmin-α2 plasmin inhibitor complex (PIC), soluble fibrin (SF), and thrombin-antithrombin III complex (TAT) in benign soft tissue tumors and STS to elucidate whether these markers can be used to predict STS. METHODS: Plasma DD, PIC, SF and TAT levels in primary soft tissue tumors (benign 67, STS 68) were measured before biopsy or treatment. The marker levels were analyzed and compared to various clinicopathological parameters. RESULTS: In malignancy (STS), the average DD, PIC and SF levels were significantly higher than in benign tumors. Multivariate logistic analysis of continuous variables indicated that only PIC exhibited a significant difference (OR: 24.5, 95%CI: 3.55-170, p = 0.0012). Receiver operating characteristic curve analysis produced area under the curve values for DD: 0.691, PIC: 0.784, SF: 0.734 and TAT: 0.588. Youden's index was used to establish thresholds of 0.37 (DD), 0.80 (PIC), 0.90 (SF) and 0.82 (TAT). Threshold values for PIC and SF indicated high specificity (0.881, 0.791) and high positive predictive value (0.818, 0.745), respectively. The highest accuracy value among the markers was observed for PIC (0.704). Significant differences in multivariate analysis of binary variables were demonstrated by categorizing low and high groups based on their threshold, PIC (≥0.80) (OR: 3.36, 95%CI: 1.19-9.43, p = 0.0212) and SF (≥0.90) (OR: 2.63, 95%CI: 1.04-6.66, p = 0.0404) . CONCLUSIONS: Of the coagulation and fibrinolysis markers studied, increased PIC levels were related to STS and over 0.80 PIC was the most suitable for the prediction of STS, which, along with other diagnostic tools, represents a helpful subsidiary tool for the prediction of STS.

Clinical outcome of latissimus dorsi reconstruction after wide resection of soft-tissue sarcoma.

BACKGROUND: We investigated the clinical outcomes of reconstruction using the latissimus dorsi (LD) flap after resection of soft-tissue sarcoma. MATERIALS AND METHODS: We analyzed 19 patients. Free LD flap was performed in 11 patients and pedicle flap in eight patients. The mean follow-up period after the surgery was 60 months. RESULTS: The mean age at diagnosis was 57 years. The mean tumor size was 9.8 cm. The median size of the LD flap was 140 × 100 mm. The mean surgical duration and bleeding were 510 min and 602 mL, respectively. Complications included partial skin and soft-tissue necrosis (n = 3) and wound dehiscence (n = 2). No additional free flap was not necessary for the closure of the defect due to the complications. The longer surgical duration was significantly associated with wound complications (P = 0.048). The 5-year survival rate was 80.7%, and the local recurrence-free survival rate was 89.2%. Two patients developed local recurrence, while 6 patients developed metastasis. None of the patients had any restrictions of daily life. CONCLUSION: The LD flap after surgical tumor resection in patients with soft-tissue sarcoma was useful for the coverage of soft tissue.

Isolated proximal tibiofibular joint arthritis in a patient with juvenile idiopathic arthritis: A case report.

We report the case of a 14-year-old girl of juvenile idiopathic arthritis (JIA) with isolated and chronic proximal tibiofibular (PTF) joint arthritis. The clinical history, magnetic resonance imaging, and pathological findings of the patient are presented. We should be careful to evaluate the patient for chronic lateral knee pain, and consider concomitant evaluation for JIA, including rheumatoid arthritis.

C­reactive protein and related predictors in soft tissue sarcoma (Review).

C-reactive protein (CRP) is a useful predictor of poor survival in patients with several types of cancer because inflammation is strongly associated with cancer progression. The production of CRP in hepatocytes appears to be primarily induced at the transcriptional level following the elevation of circulating interleukin-6 (IL-6), which is produced by various cell types, including cancer cells and cancer-associated fibroblasts. Serum CRP levels are associated with serum IL-6 levels in patients with soft tissue sarcoma (STS). Additionally, patients with elevated CRP levels had worse oncological outcomes than those with normal CRP levels. It has been attempted to combine CRP levels with other inflammatory or immune markers, and the utility of this has been demonstrated. Therefore, a novel treatment strategy should be developed for patients with STS with elevated CRP levels. The present review aimed to clarify the role of CRP levels and related tools in predicting clinical outcomes in patients with STS.

The Combined Use of Inflammation Markers, Modified Glasgow Prognostic Score, and Sarculator Nomogram in Extremity Soft Tissue Sarcoma: A Multicenter Observational Study.

BACKGROUND: Sarculator is a validated nomogram designed to predict overall survival (OS) in extremity soft tissue sarcoma (STS). Inflammation plays a critical role in cancer development and progression. There were no reports which investigated the relationship between Sarculator and inflammation. METHODS: A total of 217 patients with extremity STS were included. The Sarculator-predicted 10-year probability of OS (pr-OS) was stratified into two subgroups: lower risk (10-year pr-OS ≥ 60%) and higher risk (10-year pr-OS < 60%). The modified Glasgow prognostic score (mGPS) varied from 0 to 2. RESULTS: Out of the 217 patients, 67 were classified as higher risk, while 150 were lower risk. A total of 181 patients had an mGPS of 0, and 36 had a score of 1 or 2. The 5-year OS was 83.3%. When patients were divided into two groups according to the 10-year pr-OS, those with a higher risk had poorer OS than those with a lower risk. Among the patients with a higher risk, those with an mGPS of 1 or 2 had poorer OS compared to those with a score of 0. CONCLUSIONS: The mGPS could potentially play an important role in identifying patients who are at high risk of death and metastasis in the higher-risk group on the Sarculator.

Prediction of prognosis using artificial intelligence-based histopathological image analysis in patients with soft tissue sarcomas.

BACKGROUND: Prompt histopathological diagnosis with accuracy is required for soft tissue sarcomas (STSs) which are still challenging. In addition, the advances in artificial intelligence (AI) along with the development of pathology slides digitization may empower the demand for the prediction of behavior of STSs. In this article, we explored the application of deep learning for prediction of prognosis from histopathological images in patients with STS. METHODS: Our retrospective study included a total of 35 histopathological slides from patients with STS. We trained Inception v3 which is proposed method of convolutional neural network based survivability estimation. F1 score which identify the accuracy and area under the receiver operating characteristic curve (AUC) served as main outcome measures from a 4-fold validation. RESULTS: The cohort included 35 patients with a mean age of 64 years, and the mean follow-up period was 34 months (2-66 months). Our deep learning method achieved AUC of 0.974 and an accuracy of 91.9% in predicting overall survival. Concerning with the prediction of metastasis-free survival, the accuracy was 84.2% with the AUC of 0.852. CONCLUSION: AI might be used to help pathologists with accurate prognosis prediction. This study could substantially improve the clinical management of patients with STS.

The Effect of Photodynamic Therapy Using 5-Aminolevulinic Acid in Bone and Soft Tissue Sarcoma Cells.

BACKGROUND/AIM: 5-Aminolevulinic acid (5-ALA) is a natural amino acid and a precursor of protoporphyrin IX (PpIX). Following light irradiation, the PpIX generates reactive oxygen species (ROS) in the presence of oxygen. Increased ROS levels can cause apoptotic cell death and necrosis of targeted cancer cells. This study examined whether photodynamic therapy using 5ALA (5-ALA PDT) could be used as a potential adjuvant therapy for bone and soft tissue sarcomas. MATERIALS AND METHODS: The human osteosarcoma (143B), mouse osteosarcoma (LM8), human fibrosarcoma cell (HT1080) cell lines were used. In vitro, cultured cells were exposed to 5-ALA at various concentrations followed by strobe scope light irradiation for 10 min as 5-ALA PDT. Cell viability was then measured. In vivo, each tumor cell line was inoculated subcutaneously into the backs of mice. In the 5-ALA PDT group, 5-ALA (250 mg/kg) was administered intraperitoneally followed by light irradiation. Change in tumor volume by 5-ALA PDT were primarily evaluated. RESULTS: In vitro, treatment of sarcoma cells with 100 and 200 µg/ml 5-ALA PDT significantly inhibited cell proliferation at 24 and 48 h compared with the group treated with 0 and 10 µg/ml 5-ALA PDT. In vivo, in all cell lines, a significant inhibition of the tumor volume was observed in the 5-ALA-PDT group as compared to that in control, strobe scope light, and 5-ALA groups. CONCLUSION: 5-ALA PDT effectively inhibited proliferation of bone and soft tissue sarcoma cell lines. Further in vivo research using other subtypes of bone and soft tissue sarcoma is warranted to confirm the applicability in the clinical setting.

Release of Exosomal PD-L1 in Bone and Soft Tissue Sarcomas and Its Relationship to Radiotherapy.

(1) Background: Exosomal PD-L1 has garnered attention owing to its role in instigating systemic immune suppression. The objective of this study is to elucidate whether bone and soft tissue sarcoma cells possess the capacity to secrete functionally active exosomal PD-L1 and whether radiotherapy (RT) induces the exosomal PD-L1 release. (2) Methods: Human osteosarcoma cell line 143B and human fibrosarcoma cell line HT1080 were utilized. Exosomes were isolated from the culture medium and blood via ultracentrifugation. The expression of PD-L1 on both tumor cells and exosomes was evaluated. The inhibitory effect on PBMC was employed to assess the activity of exosomal PD-L1. Post radiotherapy, changes in PD-L1 expression were compared. (3) Results: Exosomal PD-L1 was detected in the culture medium of tumor cells but was absent in the culture medium of PD-L1 knockout cells. Exosomal PD-L1 exhibited an inhibitory effect on PBMC activation. In tumor-bearing mice, human-derived exosomal PD-L1 was detected in the bloodstream. Following radiotherapy, tumor cells upregulated PD-L1, and human-derived exosomal PD-L1 were detected in the bloodstream. (4) Conclusions: Exosomal PD-L1 emanates from bone and soft tissue sarcoma cells and is disseminated into the circulatory system. The levels of PD-L1 in tumor cells and the release of exosomal PD-L1 were augmented after irradiation with RT.

Pedicled flap transfer after chest wall malignant tumor resection and potential risk of postoperative respiratory problems for patients with low FEV1.0.

Introduction: Musculoskeletal transfer for chest wall tissue defects is a crucial method, and pedicled flaps around the chest wall are preferred in terms of location and simplicity of transfer. These require special care because of complications such as partial necrosis, fistula, wound dehiscence, infection, hematoma and restricted function of the arm or shoulder. However, studies of respiratory function are rare. In the present study, we investigated the complications including respiratory problems after wide resection for malignant chest wall tumors with musculoskeletal pedicle transfer. Methods: A total of 13 patients (15 operations) who underwent wide resection of primary, recurrent, or metastatic malignant chest wall tumors and musculoskeletal pedicle transfer for coverage of tissue defects were enrolled in the present study. A retrospective review of all patients was performed using data collected from hospital records and follow-up information. The complications of musculoskeletal transfer after chest wall wide resection, including respiratory problems, are evaluated. Results: Rib or sternal resection was performed in 12 operations, and only soft tissue resection was performed in 3 operations. Latissimus dorsi (LD) pedicle transfer was performed in 13 operations, and pectoralis major (PM) pedicle transfer was performed in 2 operations; basically, wounds were closed primarily. Surgical complications were observed following 5 of the 15 operations (33.3%). Respiratory complications were seen in 7 of the 15 operations (46.7%). Patients with respiratory complications showed significantly lower preoperative FEV1.0% values than those without respiratory complications (p = 0.0196). Skin resection area tended to be higher in the complication group than in the no complication group (p = 0.104). Discussion: Pedicled myocutaneous flap transfers such as LD, PM, and rectus abdominus can be used following multiple resections. After harvesting LD or PM, the wound can be closed primarily for an 8-10-cm skin defect in patients with normal respiratory function. However, for patients with low FEV1.0%, after primary closure of LD or PM transfer for wide soft tissue defects, attention should be paid to postoperative respiratory complications.

The Characteristics of magnetic resonance imaging and immunohistochemical findings in de-differentiated liposarcoma.

PURPOSE: Radiological imaging in Dedifferentiated liposarcoma (DDLPS) often shows the coexistence of fatty and non-fatty solid components; however, it has been shown that when fatty components were not identified on magnetic resonance imaging (MRI), the diagnosis of DDLPS would not have been diagnosed if immunohistochemical (IHC) staining had not been performed. The aim of this study was to investigate the pattern of MRI and relationship between MRI and IHC findings in DDLPS. METHODS: We retrospectively reviewed the cases of 25 patients with DDLPS. To identify the MRI spectrum of DDLPS, tumors were classified into the following four categories based on MRI findings: I = a well-defined fatty mass and juxtaposed well-defined non-fatty mass, II = a non-fatty component within a predominantly fatty mass, III = a focal fatty component within a large non-fatty mass, and IV = a non-fatty mass with atypical MRI findings. IHC staining for CDK4, MDM2, and p16 were evaluated. RESULTS: Category IV tumor was the most common tumor in this population. Of the 22 patients who underwent IHC staining, MDM2, CDK4, and p16 were positive in 21, 20, and 19 patients, respectively. MDM2 was positive in all 11 patients with category IV tumors; CDK4 and p 16 were positive in 10 and eight patients, respectively. There was no difference of survival between the patients with category I, II and III and category IV. CONCLUSIONS: DDLPS without fatty components on MRI scans was mostly found. We recommend IHC staining to screen for DDLPS even if the tumors in STS cases have a non-fatty component.

Histological Assessment of Synovial Sarcoma Before and After TCR-T Cell Therapy and Cryoablation: A Case Report.

BACKGROUND/AIM: Cancer/testis antigens (CTAs) are well-known molecular targets with expression restricted to testicular germ cells and malignant tumors. T-cell receptor (TCR)-engineered T-cell (TCR-T) therapy against CTAs in patients with sarcoma has shown substantial progress, but resistance to TCR-T therapy remains a critical problem. In this report, we present a case of synovial sarcoma treated with TCR-T therapy targeting the New York-esophageal squamous cell carcinoma (NY-ESO)-1 protein. Histological findings were compared before and after TCR-T therapy and before and immediately after cryoablation. CASE REPORT: A 68-year-old man received additional wide resection for synovial sarcoma in the left leg. Due to multiple metastases, he was enrolled in a clinical trial of TCR-T therapy for NY-ESO-1. The tumor demonstrated a 34.9% reduction in diameter. However, disease progression occurred by day 84 after TCR-T therapy. Six months after disease progression, cryoablation was performed for right posterior rib lesion and tumor specimens were obtained by needle biopsy both before and immediately after cryoablation. Ten months after the diagnosis of disease progression, the patient died. Expression levels of NY-ESO-1, human leukocyte antigen, and immune checkpoint proteins remained unchanged before and after TCR-T therapy. Beta catenin was up-regulated in recurrent tumor tissues after TCR-T therapy compared to levels observed before TCR-T therapy. Immediately after cryoablation, immunoreactivity for NY-ESO-1 showed a slightly reduction. CONCLUSION: Up-regulation of beta-catenin in synovial sarcoma with recurrence after TCR-T therapy may be involved in T-cell exclusion and resistance to TCR-T therapy. Needle biopsy after cryoablation can be performed with sufficient pathological diagnostic accuracy including immunostaining.

Combination of Everolimus and Bortezomib Inhibits the Growth and Metastasis of Bone and Soft Tissue Sarcomas via JNK/p38/ERK MAPK and AKT Pathways.

The combination of the mammalian target of rapamycin and proteasome inhibitors is a new treatment strategy for various tumors. Herein, we investigated the synergistic effect of everolimus and bortezomib on tumor growth and metastasis in bone and soft tissue sarcomas. The antitumor effects of everolimus and bortezomib were assessed in a human fibrosarcoma (FS) cell line (HT1080) and mouse osteosarcoma (OS) cell line (LM8) by MTS assays and Western blotting. The effects of everolimus and bortezomib on HT1080 and LM8 tumor growth in xenograft mouse models were evaluated using tumor volume and the number of metastatic nodes of the resected lungs. Immunohistochemistry was used to evaluate cleaved PARP expression. The combination therapy decreased FS and OS cell proliferation compared with either drug alone. This combination induced more intense p-p38, p-JNK, and p-ERK and activated apoptosis signals, such as caspase-3, compared with single-agent treatment. The combination treatment reduced p-AKT and MYC expression, decreased FS and OS tumor volumes, and suppressed lung metastases of OS. The combination therapy inhibited tumor growth in FS and OS and metastatic progression of OS via the JNK/p38/ERK MAPK and AKT pathways. These results could aid in the development of new therapeutic strategies for sarcomas.

Gastric metastasis in patients with leiomyosarcoma: A case report.

Soft tissue sarcomas (STS) are very rare tumors, accounting for <1% of all malignancies. Leiomyosarcoma (LMS), accounts for 10-20% of STS. Gastric metastasis of LMS is extremely rare, and only a few cases have been reported. In the present report, two clinical cases of LMS with gastric metastasis. In the present cases, the metastases presented as a solitary lesion and was located in the upper body anterior wall in case 1, and body-greater curvature in case 2. It is debatable whether to perform any local treatment for gastric metastasis due to its poor prognosis. However, the progression of metastatic cancer in the stomach can lead to gastric bleeding, abdominal pain, and dysphagia, which may further shorten survival and decrease a patient's quality of life. Therefore, metastasectomy was performed in the present cases. This should be considered if digestive tract symptoms occur during the treatment of LMS.