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Precise mechanisms underlying interleukin-7 (IL-7)-mediated tumor invasion remain unclear. Thus, we investigated the role of IL-7 in tumor invasiveness using metastatic prostate cancer PC-3 cell line derivatives, and assessed the potential of IL-7 as a clinical target using a Janus kinase (JAK) inhibitor and an IL-7-blocking antibody. We found that IL-7 stimulated wound-healing migration and invasion of PC-3 cells, increased phosphorylation of signal transducer and activator of transcription 5, Akt, and extracellular signal-regulated kinase. On the other hand, a JAK inhibitor and an IL-7-blocking antibody decreased the invasiveness of PC-3 cells. IL-7 increased tumor sphere formation and expression of epithelial–mesenchymal transition (EMT) markers. Importantly, lentiviral delivery of IL-7Rα to PC-3 cells significantly increased bone metastasis in an experimental murine metastasis model compared to controls. The gene expression profile of human prostate cancer cells from The Cancer Genome Atlas revealed that EMT pathways are strongly associated with prostate cancers that highly express both IL-7 and IL-7Rα. Collectively, these data suggest that IL-7 and/or IL-7Rα are promising targets of inhibiting tumor metastasis.

Background This study aimed to investigate the characteristics and clinical outcomes in a series of patients with extremity soft tissue sarcoma (STS) who underwent amputation at a large East Asian referral center. Patients and methods Of the 652 patients who underwent surgery for extremity STS, data of 37 consecutive patients who underwent amputation were reviewed retrospectively. The median follow-up period was 96.0 months (range, 15–216). The patients were classified in to three cohorts. The primary localized (PL) group included patients who underwent amputation as a primary surgical procedure with curative intent. The recurrent localized (RL) group included patients who underwent amputation as a revision procedure after failure of previous limb sparing surgeries. The metastatic group included patients who underwent amputation as a palliative procedure. Results There were 22 cases of amputation in 596 STS patients and the amputation rate was 3.6% (22/596). Further, 1.8% (9/490) of patients with primary localized STS underwent amputation. Patients with localized STS who underwent amputation had a 5-year disease-specific survival (DSS) rate of 89.9% (95% Confidence Interval (CI), 87.1–92.7%), a local-recurrence-free survival (LRFS) of 84.1% (95% CI, 80.5–87.6%), and a metastasis-free survival (MFS) of 84.6%. (95% CI, 81.1–88.0%) Compared with previous studies, our results showed higher DSS and MFS rates with similar LRFS. Conclusions The amputation rate of extremity STS in our institute in East Asia was similar but slightly lower than that reported in Western studies. The oncologic outcome of amputation reported in this study was higher than that indicated in Western studies and oncologic outcome of amputation was not statistically different from those of limb salvage surgery. However, considering the small cohort in single institute study, there is a possibility of selection bias and future multi-center study is necessary. From our results, amputation is still a feasible option for appropriately selected patients unsuitable for limb-conserving surgery.

Background Extracellular matrix metalloproteinase inducer (EMMPRIN), a cell-surface glycoprotein, is overexpressed in several cancer types. EMMPRIN induces a metastatic phenotype by triggering the production of matrix metalloproteinase proteins (MMPs) such as MMP1 and MMP2, and vascular endothelial growth factor (VEGF) in cancer cells and the surrounding stromal cells. The purpose of this study was to investigate the expression and role of EMMPRIN in osteosarcoma. Methods The level of EMMPRIN expression was evaluated using reverse transcriptase polymerase chain reaction (RT-PCR) in 6 tumor-derived osteosarcoma cell lines and compared with that in normal osteoblasts. To study the prognostic significance of EMMPRIN expression, immunohistochemistry was carried out in prechemotherapy biopsies of 54 patients. siRNA knockdown of EMMPRIN in SaOS-2 cells was conducted to explore the role of EMMPRIN. To study the role of EMMPRIN in tumor-stromal interaction in MMP production and invasion, co-culture of SaOS-2 cells with osteoblasts and fibroblasts was performed. Osteosarcoma 143B cells were injected into the tail vein of BALB/c mice and lung metastasis was analyzed. Results EMMRIN mRNA expression was significantly higher in 5 of 6 (83%) tumor-derived cells than in MG63 cells. 90% of specimens (50/54) stained positive for EMMPRIN by immunohistochemistry, and higher expression of EMMPRIN was associated with shorter metastasis-free survival ( p  = 0.023). Co-culture of SaOS-2 with osteoblasts resulted in increased production of pro-MMP2 and VEGF expression, which was inhibited by EMMPRIN-targeting siRNA. siRNA knockdown of EMMPRIN resulted in decreased invasion. EMMPRIN shRNA-transfected 143B cells showed decreased lung metastasis in vivo. Conclusions Our data suggest that EMMPRIN acts as a mediator of osteosarcoma metastasis by regulating MMP and VEGF production in cancer cells as well as stromal cells. EMMPRIN could serve as a therapeutic target in osteosarcoma.

Liquid-liquid phase separation (LLPS) facilitates the formation of membraneless organelles within cells, with implications in various biological processes and disease states. AT-rich interactive domain-containing protein 1A (ARID1A) is a chromatin remodeling factor frequently associated with cancer mutations, yet its functional mechanism remains largely unknown. Here, we find that ARID1A harbors a prion-like domain (PrLD), which facilitates the formation of liquid condensates through PrLD-mediated LLPS. The nuclear condensates formed by ARID1A LLPS are significantly elevated in Ewing’s sarcoma patient specimen. Disruption of ARID1A LLPS results in diminished proliferative and invasive abilities in Ewing’s sarcoma cells. Through genome-wide chromatin structure and transcription profiling, we identify that the ARID1A condensate localizes to EWS/FLI1 target enhancers and induces long-range chromatin architectural changes by forming functional chromatin remodeling hubs at oncogenic target genes. Collectively, our findings demonstrate that ARID1A promotes oncogenic potential through PrLD-mediated LLPS, offering a potential therapeutic approach for treating Ewing’s sarcoma. ARID1A is a chromatin remodeling protein frequently mutated in cancer. Here the authors report that ARID1A plays a role in forming membraneless organelles through liquid-liquid phase separation (LLPS). ARID1A condensates were elevated in Ewing’s sarcoma patients.

Background Actuarial survival based on the Kaplan–Meier method can overestimate actual long-term survival, especially among those with factors of poor prognosis. Patients with American Joint Committee on Cancer stage III soft tissue sarcoma (STS) represent a subset with a high risk of STS-specific mortality. Therefore, we aimed to characterize the clinicopathological characteristics associated with actual long-term survival in patients with stage III STS. Methods We retrospectively reviewed 116 patients who underwent surgical resection for stage III STS with curative intent between March 2000 and December 2013. Long-term survivors ( n  = 61), defined as those who survived beyond 5 years, were compared with short-term survivors ( n  = 36), who died of STS within 5 years. Results Multivariate logistic regression analyses showed that a tumor size < 10 cm [odds ratio (OR) 3.95, p  = 0.047], histological grade of 2 (OR 8.12, p  = 0.004), and American Society of Anesthesiologists (ASA) score of 1 (OR 11.25, p  = 0.001) were independently associated with actual 5-year survival. However, 66% of the long-term survivors exhibited factors of poor prognosis: 36% had a tumor size > 10 cm and 48% had a histological grade of 3. Leiomyosarcoma (3 of 10) was negatively associated with actual long-term survival. Conclusions Actual 5-year survival after resection of stage III STS was associated with tumor size, histological grade, and ASA score. However, majority of the actual 5-year survivors exhibit factors of poor prognosis, suggesting that aggressive treatment should be offered for a chance of long-term survival in these patients.

Sarcomas, malignant tumors from mesenchymal tissues, exhibit poor prognosis despite advancements in treatment modalities such as surgery, radiotherapy, and chemotherapy, with doxorubicin being a cornerstone treatment. Resistance to doxorubicin remains a significant hurdle in therapy optimization. This study aims to dissect the molecular bases of doxorubicin resistance in sarcoma cell lines, which could guide the development of tailored therapeutic strategies. Eighteen sarcoma cell lines from 14 patients were established under ethical approvals and classified into seven subtypes. Molecular, genomic, and transcriptomic analyses included whole-exome sequencing, RNA sequencing, drug sensitivity assays, and pathway enrichment studies to elucidate the resistance mechanisms. Variability in doxorubicin sensitivity was linked to specific genetic alterations, including mutations in TP53 and variations in the copy number of genomic loci like 11q24.2. Transcriptomic profiling divided cell lines into clusters by karyotype complexity, influencing drug responses. Additionally, pathway analyses highlighted the role of signaling pathways like WNT/BETA-CATENIN and HEDGEHOG in doxorubicin-resistant lines. Comprehensive molecular profiling of sarcoma cell lines has revealed complex interplays of genetic and transcriptomic factors dictating doxorubicin resistance, underscoring the need for personalized medicine approaches in sarcoma treatment. Further investigations into these resistance mechanisms could facilitate the development of more effective, customized therapy regimens.

Background Dedifferentiated liposarcoma of the extremities (DDL-E) is rare in comparison to that of the retroperitoneum. Its clinical features and surgical principle for resection margins at the dedifferentiated and the well-differentiated components are yet to be elucidated. Methods This retrospective multi-center study examined patients diagnosed with DDL-E from August 2004 to May 2023 at 5 sarcoma centers. Clinical features, oncologic outcomes, and prognostic factors were analyzed. Results A total of 107 patients were reviewed. The 5-year local recurrence free survival (LRFS), metastasis-free survival (MFS) and disease specific survival (DSS) were 84.7%, 78.6%, and 87.8%, respectively. Other primary malignancies and extrapulmonary metastasis were observed in 27 and 4 patients, respectively. The independent risk factor for local recurrence was R1/2 margin at the dedifferentiated component of the tumor. Metastasis was associated with tumor size in univariate analysis. The independent risk factor for DSS was tumor grade. Previous unplanned excision, de novo presentation, tumor depth, absence of the well-differentiated component, infiltrative border, R1/2 margin at the well-differentiated component were not associated with oncologic outcomes. Conclusions This is the largest study examining DDL-E to-date. Localized DDL-E has low potential for metastasis and carries an excellent prognosis. Other primary malignancy and extrapulmonary metastasis are more frequent in DDL-E, thus close monitoring of other sites during follow-up is recommended. While wide resection margin is the standard surgical approach for DDL-E, further investigation into moderated wide resection margin at the well-differentiated component is warranted.

Unplanned excision of extremity soft tissue sarcoma (STS) is common and has detrimental effects not only on patients' oncologic outcomes but also on functional and economic issues. However, no study has analyzed a nationwide population-based database. To estimate the incidence and treatment pattern of unplanned excision in extremity STS in the Korean population, a nationwide epidemiologic study was performed using the Korean Health Insurance Review and Assessment Service database, a centralized nationwide healthcare claims registry of Korea that covers the entire Korean population. Among 1,517 patients with extremity STS in the 4-year study period, 553 (36.5%) underwent unplanned excision (unplanned group). About 80% of unplanned excisions were performed in tertiary or general hospitals. Of the unplanned group, 240 (43.4%) underwent re-excision with or without radiation therapy and/or chemotherapy, and 51 (9.2%) did not undergo re-excision but were treated with radiation therapy and/or chemotherapy; whereas, 262 (47.4%) did not undergo any further treatment following unplanned excision. This study is the first nationwide population-based study on the unplanned excision of extremity STS. The results may have implications in establishing preventive or therapeutic measures to reduce the burden of unplanned excision of extremity STS.

We describe a method for the direct application of MR images to navigation-assisted bone tumor surgery as an alternative to CT-MRI fusion. Six patients with an orthopedic malignancy were employed for this method during navigation-assisted tumor resection. Tumor types included osteosarcoma (4), high-grade chondrosarcoma (1), and adamantinoma (1). Mean patient age was 25.3 years (range 18–52 years). Mean duration of follow-up was 25.8 months (range 18–32 months). Resorbable pin placement and rapid 3-dimensional spoiled gradient echo sequences made the direct application of MR images to computer-assisted bone tumor surgery without CT-MR image fusion possible. A paired-point registration technique was employed for patient-image registration in all patients. It took 20 min on average to set up the navigation (range 15–25 min). The mean registration error was 0.98 mm (range 0.4–1.7 mm). On histologic examination, distances from tumors to resection margins were in accord with preoperative plans. No patient had a local recurrence or distant metastasis at the last follow-up. Direct patient-to-MRI registration is a very useful method for bone tumor surgery, permitting the application of MR images to intraoperative visualization without any additional costs or exposure of the patient to radiation from the preoperative CT scan.

Chondroblastoma has a predilection for the epiphyses or apophyses of long tubular bones. Management of lesions in the proximal tibia is challenging because it is difficult to gain access to intraepiphyseal lesions for completion of curettage. From October 2007 to December 2011, 9 patients with de novo chondroblastoma of the proximal tibia underwent surgery at the authors' institution. All patients initially presented with pain, and 5 patients had limitation of range of motion of the ipsilateral knee. Four lesions abutted the tibial attachment sites of the cruciate ligaments. Surgical procedures included intralesional tumor curettage, additional burring, and packing of the defect with bone graft and/or bone cement. The extra-articular approach was used according to tumor location. The medial or lateral parapatellar approach was used when the tumor was located in the anterior two-thirds of the horizontal plane. When a lesion was located in the posterior third, the posteromedial or posterolateral approach was used as the lesion was cornered. Mean duration of follow-up was 47.2 months (range, 27–80 months). No local recurrence or pulmonary metastasis was noted at latest follow-up. Mean functional score was 29.3 points (range, 28–30 points). All patients fully recovered range of motion in the affected knee. No avulsion fracture or anteroposterior instability of the knee joint was detected. Results of the current study suggest that intralesion curettage followed by additional burring with an extra-articular approach is a successful treatment option for chondroblastoma of the proximal tibia. [Chondroblastoma has a predilection for the epiphyses or apophyses of long tubular bones. Management of lesions in the proximal tibia is challenging because it is difficult to gain access to intraepiphyseal lesions for completion of curettage. From October 2007 to December 2011, 9 patients with de novo chondroblastoma of the proximal tibia underwent surgery at the authors' institution. All patients initially presented with pain, and 5 patients had limitation of range of motion of the ipsilateral knee. Four lesions abutted the tibial attachment sites of the cruciate ligaments. Surgical procedures included intralesional tumor curettage, additional burring, and packing of the defect with bone graft and/or bone cement. The extra-articular approach was used according to tumor location. The medial or lateral parapatellar approach was used when the tumor was located in the anterior two-thirds of the horizontal plane. When a lesion was located in the posterior third, the posteromedial or posterolateral approach was used as the lesion was cornered. Mean duration of follow-up was 47.2 months (range, 27–80 months). No local recurrence or pulmonary metastasis was noted at latest follow-up. Mean functional score was 29.3 points (range, 28–30 points). All patients fully recovered range of motion in the affected knee. No avulsion fracture or anteroposterior instability of the knee joint was detected. Results of the current study suggest that intralesion curettage followed by additional burring with an extra-articular approach is a successful treatment option for chondroblastoma of the proximal tibia. [ Orthopedics. 2016; 39(1):e80–e85.]