Combined preoperative denosumab and adjuvant microwave ablation for high-risk giant cell tumor of bone: a retrospective study in a single center.

BACKGROUND: Giant cell tumor of bone (GCTB) is a locally aggressive neoplasm with a high propensity for recurrence following intralesional curettage. The introduction of denosumab, a RANKL inhibitor, has shown potential in facilitating joint-sparing surgery. However, concerns exist regarding its impact on local recurrence rates. This study aimed to evaluate the efficacy and safety of combined preoperative denosumab with adjuvant microwave ablation (MWA) for the treatment of high-risk GCTB. METHODS: We conducted a retrospective review of 19 patients with high-risk GCTB who underwent preoperative denosumab treatment followed by curettage and adjuvant MWA. The primary outcome measure was the local recurrence rate, with secondary outcomes including functional status assessed by the Musculoskeletal Tumor Society (MSTS) score and safety profile of the treatment. RESULTS: In this retrospective analysis, we evaluated the outcomes of 19 patients with high-risk GCTB treated with preoperative denosumab and adjuvant MWA. The median follow-up duration was 33.1 months, 3 patients (15.8%) experienced local recurrence at a median of 21.6 months postoperatively and the local recurrence-free survival was 81.2% at two years. Notably, no patient developed lung metastasis, and all recurrences were successfully managed with repeat curettage and MWA, with a mean MSTS score of 27.3. No patient required joint replacement due to tumor recurrence, resulting in a 100% joint preservation rate. CONCLUSION: The combination of preoperative denosumab and adjuvant MWA is a feasible and effective strategy for the management of high-risk GCTB, providing effective local control with preserved joint function. This approach may offer a surgical alternative for young patients where joint preservation is paramount.

Pay Attention to the Osteochondromas in Fibrodysplasia Ossificans Progressiva.

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is an extremely rare disease characterized by malformation of the bilateral great toes and progressive heterotopic ossification. The clinical features of FOP occur due to dysfunction of the bone morphogenetic protein (BMP) signaling pathway induced by the mutant activin A type I receptor/activin-like kinase-2 (ACVR1/ALK2) which contributes to the clinical features in FOP. Dysregulation of the BMP signaling pathway causes the development of osteochondroma. Poor awareness of the association between FOP and osteochondromas always results in misdiagnosis and unnecessary invasive operation. CASE PRESENTATION: In this study, we present a case of classical FOP involving osteochondroma. An 18-year-old male adolescent, born with deformity of bilateral big toes, complained multiple masses on his back for 1 year. The mass initially emerged with a tough texture and did not cause pain. It was misdiagnosed as an osteochondroma. After two surgeries, the masses became hard and spread around the entire back region. Meanwhile, extensive heterotopic ossification was observed around the back, neck, hip, knee, ribs, and mandible during follow-up. Osteochondromas were observed around the bilateral knees. No abnormalities were observed in the laboratory blood test results. Whole exome sequencing revealed missense mutation of ACVR1/ALK2 (c.617G > A; p.R206H) in the patient and confirmed the diagnosis of FOP. CONCLUSION: In summary, classical FOP always behaves as a bilateral deformity of the big toes, as well as progressive ectopic ossification and osteochondromas in the distal femur and proximal tibia. An understanding of the association between osteochondromas and FOP aids in diagnosis and avoids unnecessary invasive management in patients.

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

Introduction: 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. Methods: 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. Results: 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%. Conclusion: 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.

Intercalary reconstruction with successful joint preservation by uncemented 3D­printed endoprosthesis following tumor resection in distal radius: A case report.

The distal radius is an extremely rare site for epithelioid hemangioendothelioma. Joint preservation to maintain a good wrist joint function is rarely reported. The present study described a case of joint preservation surgery in the distal radius with an uncemented 3D-printed endoprosthesis and evaluated the endoprosthesis design and short-term outcomes. A 14-year-old boy was diagnosed with epithelioid hemangioendothelioma in radius. Due to the extensive defect and the excessively short length of the residual distal radius after resection, a custom-made 3D-printed custom-made endoprosthesis was designed and fabricated to reconstruct the defect, with the preservation of the wrist joint. The patient had a favorable wrist function and no endoprosthesis-related complications were observed. The present study presented a case of en bloc tumor resection with joint preservation of the wrist and reconstruction using a 3D-printed endoprosthesis. Satisfactory postoperative function and low complication rates were found.

A comparison of cemented and cementless intra-neck curved stem use during hip-preserving reconstruction following massive femoral malignant tumor removal.

Background: Patients who undergo massive femoral malignant tumor (MFMT) resection often exhibit shortened femoral metaphyseal juxta-articular segments. The use of a customized femoral endoprosthesis (CFE) with an intra-neck curved stem (INCS) has emerged as a viable reconstructive surgical strategy for these individuals. Relative to a cemented INCS, it remains unclear as to whether cementless INCS use is associated with improvements in functionality or reconstructive longevity. As such, the present study was conducted to compare functional outcomes, endoprosthetic survival, and endoprosthesis-related complication rates in patients undergoing cemented and cementless INCS implantation. Methods: A total of 24 patients undergoing lower limb salvage and reconstructive surgical procedures utilizing cemented or cementless INCS endoprostheses were retrospectively included. Patient-functional outcomes, endoprosthetic survival, and complication rates were compared as a function of age; diagnosis; the length of femoral resection; residual proximal femur length; Musculoskeletal Tumor Society (MSTS) scores; visual analog scale (VAS) scores; and the rates of implant breakage, periprosthetic infections, periprosthetic fractures, and aseptic loosening. Results: The mean follow-up was 56 months. Significant differences in the length of femoral resection (p<0.001) and residual proximal femur length were observed (p<0.001) between the cemented and cementless INCS groups. There were no differences in overall patient survival and aseptic loosening-associated endoprosthesis survival in the cemented and cementless groups. None of the included patients experienced periprosthetic fractures, infections, or implant breakage. Average respective MSTS and VAS scores did not differ between groups. Conclusion: For patients undergoing treatment for MFMTs, the use of a CFE with an INCS has emerged as a viable approach to hip-preserving reconstructive surgery. With appropriately designed individualized rehabilitative programs, good functional outcomes can be achieved for these endoprostheses, which are associated with low complication rates. Moreover, the selection between cemented or cementless INCS in the clinic should be made based on patient-specific factors, with cementless INCS implementation being preferable in younger patients with good-quality bone, the potential for long-term survival, and the osteotomy site near the lesser trochanter, whereas cemented INCS use should be favored for individuals who are older, have a shorter life expectancy, or have poor bone quality.

Case Report: Gene Heterogeneity in the Recurrent and Metastatic Lesions of a Myxoid Chondrosarcoma Patient With Aggressive Transformation.

Extraskeletal myxoid chondrosarcoma (EMC) is a rare soft tissue sarcoma. In view of the indolent course throughout the prolonged natural history of EMC, it was considered as a low-grade soft-tissue sarcoma. However, recent studies have revealed a high recurrence and metastatic potential in EMC, and the invasiveness of EMC may progress during the protracted clinical course. The mechanism for this aggressive transformation remains unknown. Here, we present a rare case of EMC with aggressive behavior. This case was confirmed via pathology and NR4A3 fluorescent in situ hybridization. To verify the genetic characteristics of this rare case, a total gene sequencing analyses was performed in the recurrent and metastatic lesions. Intriguingly, different gene mutations were determined in the recurrent and metastatic lesions, which implied the genetic heterogeneity among the different lesions might be related to the aggressiveness of EMC. Furthermore, we discuss a few potential agents against the mutated genes in this case, which may provide novel insights regarding the targeted therapy of EMC.

Case Report: Reconstruction of Medialis Malleolus (1/4 of the Ankle Joint) After Resection of Distal Tibia Tumor With an Uncemented Three-Dimensional-Printed Prosthesis.

Introduction: Few patients presented with a distal tibial tumor that only invaded a small area of bone in the medial malleolus. There have been no previous cases in which only the medial or lateral malleolus was removed and reconstruction was complete. This article describes our attempt to reconstruct the medial malleolus (1/4 of the ankle joint) after resection of a distal tibial tumor with an uncemented three-dimensional (3D)-printed prosthesis. Case Description: A 39-year-old man presented with a lump in the right medial malleolus, and biopsy results suggested fibrosarcoma. To preserve the patient's normal bone and function, we only removed the medial malleolus and reconstructed the ankle joint using a personalized 3D-printed prosthesis. The patient had no complications other than necrosis of the skin flap that covered the wound. The patient recovered well after undergoing an additional skin flap transfer. Follow-up at 7 months and again at 3 years after surgery showed good ankle function and stability, with no pain or complications. Conclusion: The 3D-printed partial ankle prosthesis had a good matching degree, strength, and osseointegration ability, but also had a few complications. The patient achieved satisfactory ankle function and stability. However, a longer follow-up period is needed, and more research is required to confirm the efficacy of the prosthesis.

Hip-Preserved Reconstruction Using a Customized Cementless Intercalary Endoprosthesis With an Intra-Neck Curved Stem in Patients With an Ultrashort Proximal Femur: Midterm Follow-Up Outcomes.

Background: Hemiarthroplasty is widely used for proximal femoral reconstruction after tumor resection. However, complications of hemiarthroplasty include infection, hip dislocation, and acetabular wear. This study aimed to: (1) evaluate the reliability and validity of a customized cementless intercalary endoprosthesis (CCIE) with an intra-neck curved stem (INCS) to reconstruct femoral diaphyseal defects with an ultrashort proximal femur (UPF); (2) assess the lower extremity function after reconstruction with this endoprosthesis; and (3) identify the postoperative complications associated with the use of this endoprosthesis. Methods: Between October 2015 and May 2019, 13 patients underwent reconstruction with a CCIE with an INCS. The distance from the center of the femoral head to the midline of the body and the apex of the acetabulum was measured preoperatively. Additionally, the distance from the tip of the INCS to the midline of the body and the apex of the acetabulum was measured postoperatively. The femoral neck-shaft angle was also measured pre- and postoperatively. After an average follow-up duration of 46 months, the radiological outcomes of the CCIE with an INCS were analyzed. Function was evaluated with the Musculoskeletal Tumor Society (MSTS) score. Pain was measured using a paper visual analog scale (VAS) pre- and postoperatively, and complications were recorded. Results: Compared with our preoperative design, we found no significant difference in the postoperative distance from the tip of the INCS to the body midline (p = 0.187) and the apex of the acetabulum (p = 0.159), or in the postoperative femoral neck-shaft angle (p = 0.793). Thus, the INCS positions were deemed accurate. The average MSTS score was 26 (range: 24-28), and the VAS score was significantly decreased postoperatively compared with preoperatively (p < 0.0001). No patients developed aseptic loosening, infection, periprosthetic fracture, or prosthetic fracture as of the last follow-up. Conclusion: The CCIE with an INCS was a valid and reliable method for reconstructing femoral diaphyseal defects with a UPF following malignant tumor resection. Postoperative lower extremity function was acceptable, with an appropriate individualized rehabilitation program, and the incidence of complications was low.

Synchronous lung and multiple soft tissue metastases developed from osteosarcoma of tibia: a rare case report and genetic profile analysis.

BACKGROUND: Osteosarcoma is the most common primary malignant bone tumor with a highly metastatic propensity in children and young adolescents. The majority of metastases develope in the lung, while metastases to the extrapulmonary locations have rarely been discussed, especially in skeletal muscle. CASE PRESENTATION: We reported a young patient with pathologically diagnosed osteosarcoma of the right tibia who was initially treated with standard chemotherapy and complete surgical resection. However, pulmonary metastases and multiple soft tissue masses in skeletal muscle developed four years after the index surgical resection. Subsequently, a targeted next-generation sequencing assay based on an 806 oncogenes and tumor suppressor genes panel was performed to analyze genetic alterations in this patient with rare metastatic pattern. The genetic analysis revealed canonical somatic mutations of RB1 and germline variants of ALK (c.862 T > C), BLM (c.1021C > T), PTCH1 (c.152_154del), MSH2 (c.14C > A), RAD51C (c.635G > A). Using silico prediction programs, the germline variants of the MSH2 and RAD51C were predicted as "Possibly Damaging" by Polymorphism Phenotyping v2 (PolyPhen-2) and "Tolerated" by Sorting Intolerant from Tolerant (SIFT); BLM was classified as "Tolerated", while the germline variant of ALK was predicted to be pathogenic by both PolyPhen-2 and SIFT. CONCLUSIONS: Osteosarcoma with extrapulmonary metastases is rare, especially located in the skeletal muscle, which predicts a worse clinical outcome compared with lung-only metastases. The several novel variants of ALK, BLM, PTCH1 in this patient might expand the mutational spectrums of the osteosarcoma. All the results may contribute to a better understanding of the clinical course and genetic characteristics of osteosarcoma patients with metastasis.

Case Report: Pulmonary Metastases From Epithelioid Sarcoma in Extremity Favourably Responding to Immunotherapy With Camrelizumab.

Epithelioid sarcoma (ES) is a rare soft tissue sarcoma (STS), with limited therapies available for metastatic disease. Here, we describe a case of a 30-year-old male with ES of the left knee and underwent surgery and radiation therapy for the primary disease. After 2 years, he had local recurrence and underwent extensive resection surgery; however, adjuvant chemotherapies were delayed due to recurrent wound infection. Nine months after the second surgery, progressive disease was confirmed after detection of metastases to the lungs and inguinal lymph nodes. Amputation was performed for the local recurrence, followed by inguinal lymph nodes dissection. Pazopanib was transiently administered but discontinued as a result of wound dehiscence. The tumour specimens were detected with unexpected high level of PD-L1 expression and tumoural infiltrating lymphocytes. Subsequently, he received camrelizumab 2.0 mg/kg every 21 days for 18 cycles with rapid remission of the pulmonary metastases. This promising response to camrelizumab indicates that immunotherapies may be an alternative choice for patients with metastatic ES in lung based on analysing the tumour immune microenvironment.

Multiple Pulmonary Metastases of Recurrent Giant Cell Tumor of Bone with Expression of VEGFR-2 Successfully Controlled by Denosumab and Apatinib: A Case Report and Literature Review.

Giant cell tumor of bone (GCTB) is a rare, benign, but locally aggressive bone tumor. It has a high tendency for local recurrence, which may increase the incidence of lung metastasis. Currently, an optimal treatment strategy has not been established because of the rarity of pulmonary metastatic GCTB. Denosumab is the preferred regimen for unresectable metastatic lesions; however, there are no alternative treatment options when patients are resistant to denosumab. Apatinib is a small-molecule tyrosine kinase inhibitor that selectively competes for the vascular endothelial growth factor receptor 2 (VEGFR-2) ATP binding site, and several studies have analyzed the effectiveness of apatinib in advanced or metastatic tumors. However, there is no report of apatinib as an anti-angiogenesis therapy for pulmonary metastatic GCTB to date. Here, we present a case of a 26-year-old female who was diagnosed with recurrent and pulmonary metastatic GCTB. Immunohistochemical (IHC) staining indicated that the tumor cells were positive for VEGFR-2. Denosumab was administered to control the metastases; nevertheless, disease progression was confirmed after four months of treatment. Given the IHC results and rapid disease progression, apatinib was added to the treatment strategy. After 42 months of treatment, the patient showed noticeable symptomatic improvement and considerable tumor shrinkage.

Efficacy and safety of apatinib for patients with advanced extremity desmoid fibromatosis: a retrospective study.

PURPOSE: Desmoid fibromatosis (DF) is a locally aggressive connective-tissue tumor arising in deep soft tissues. Although multiple therapeutic modalities have been demonstrated effective for DF, there is no standard systemic treatment for progressive and recurrent DF. As a part of systemic treatment, tyrosine kinase inhibitors have shown promising activity against DF with tolerable toxicity profiles. Thus, the aim of this study was to investigate the efficacy and safety of apatinib, a novel multi-target angiogenesis inhibitor, in patients with DF. METHODS: We retrospectively analyzed the medical records of patients with advanced extremity DF regularly treated with apatinib between October 2017 and January 2020 in our center. Apatinib was initially administered with a dose of 250 mg daily and the dose was adjusted according to the toxicity. Tumor response was assessed by the Response Evaluation Criteria in Solid Tumors 1.1 criteria. The primary endpoint was progression-free survival (PFS); objective response rates and drug-related adverse events were also evaluated. RESULTS: A total of 22 (6 male, 16 female) patients with advanced extremity DF were included. The mean medication time was 17 months. None of the patients reached a complete response, but ten (45.5%) patients achieved partial response, and 11 patients (50%) achieved stable disease. One (4.5%) patient developed progressive disease, and the 1-year PFS rate was 95.2%. The disease control rate was 95.4% (21/22) and the objective response rate was 45.5% (10/22). Meanwhile, 18 (81.8%) patients with a tumor shrinkage were accompanied by a decreased signal intensity of lesions in T2-weighted magnetic resonance imaging. The most frequent adverse events included hand-foot syndrome (n = 7, 31.8%), fatigue (n = 6, 27.2%), local pain (n = 4, 18.1%), diarrhea (n = 4, 18.1%). CONCLUSION: Apatinib is an effective and well-tolerated option for patients with advanced extremity DF. Indeed, further prospective, randomized studies with larger cases are required to fully explore the clinical utility of apatinib in DF.

Exosomal Long Non-Coding RNA ANCR Mediates Drug Resistance in Osteosarcoma.

Osteosarcoma (OS) is rare cancer with bimodal age distribution with peaks observed in children and young adults. Typically, OS is treated with pre-surgery neoadjuvant therapy, surgical excision, and post-surgery chemotherapy. However, the efficacy of treatment on disease prognosis and objective response is not currently optimal, often resulting in drug resistance; in turn, highlighting the need to understand mechanisms driving resistance to therapy in OS patients. Using Doxycycline (Dox)-sensitive and resistant variants of OS cells lines KHOS and U2OS, we found that the resistant variants KHOS-DR and U2OS-DR have significantly higher in vitro proliferation. Treating the Dox-sensitive KHOS/U2OS cells with exosomes isolated from KHOS-DR/U2OS-DR made them resistant to treatment with Dox in vitro and in vivo and enhanced tumor growth and progression, while decreasing overall survival. Expression of the long non-coding RNA (lncRNA) ANCR was significantly higher in the KHOS-DR and U2OS-DR variants. SiRNA-mediated knockdown of ANCR decreased in vitro proliferation, while increasing sensitivity to Dox treatment in the KHOS-DR/U2OS-DR cells. Expression of the exosomal lncRNA ANCR was critical for drug resistance and OS tumor progression in xenografts and was correlated to resistance to Adriamycin and overall survival is patients with OS. These results establish lncRNA ANCR as a critical mediator of resistance to therapy in OS patients, highlighting it as a potential therapeutic target in OS patients.

The Activity and Safety of Anlotinib for Patients with Extremity Desmoid Fibromatosis: A Retrospective Study in a Single Institution.

PURPOSE: Desmoid fibromatosis (DF) is an aggressive fibroblastic neoplasm with a high propensity for local recurrence. Although multiple therapeutic modalities seem effective for DF, the standard systemic treatment for symptomatic and progressive DF remains controversial. As targeted therapy, tyrosine kinase inhibitors have been recently reported to contribute to the treatment of DF. Thus, the purpose of this study was to assess the efficacy and safety of anlotinib, a novel multi-kinase angiogenesis inhibitor, in patients with DF. PATIENTS AND METHODS: We retrospectively collected the clinical medical records of patients with extremity DF who received anlotinib between January 2019 and January 2020 in our center. Anlotinib was started with a dose of 8 mg daily and adjusted according to the drug-related toxicity. Tumor response was assessed by the Response Evaluation Criteria in Solid Tumors 1.1 criteria. Progression-free survival (PFS) was identified as the primary endpoint and analyzed using the Kaplan-Meier method. RESULTS: In total, 21 (6 male, 15 female) consecutive patients with DF were enrolled. The median medication time was nine months (Q1, Q3: 7.5, 10.5). None of the patients achieved a complete response, but eight (38.1%) patients achieved a partial response and ten patients (47.6%) achieved disease stability. Three (14%) patients developed progressive disease and the 3-, 6-, and 12-month PFS rates were 95.2%, 90.5%, and 84.0%, respectively. The disease control rate was 86.0% (18/21) and the objective response rate was 38.1% (8/21). Moreover, 15/21 (71.4%) patients achieved a reduction in tumor size, accompanied with a decrease in T2-weighted signal intensity on magnetic resonance imaging and clinical benefit. CONCLUSION: Anlotinib was effective against DF with an acceptable safety profile, and significantly slowed the disease progression. Further, multicenter studies with a longer follow-up time are needed to characterize fully the clinical application of anlotinib in DF.

PTEN in osteosarcoma: Recent advances and the therapeutic potential.

Osteosarcoma is the most common primary malignant bone tumor, predominantly occurring in children and adolescents. Despite treated with surgery and neoadjuvant chemotherapy, osteosarcoma has a high potential of local recurrence and lung metastasis. Overall survival rates for osteosarcoma have plateaued in the past four decades, therefore, identification of novel targets and development of more effective treatment strategies are urgent. Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene that negatively regulates the phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) pathway. Over half of clinical osteosarcoma samples presented loss or low expression of PTEN, which usually indicated an advanced stage of tumor and a poor prognosis. The expression of PTEN is regulated by epigenetic silence, transcription regulation, post-translational modifications, and protein interactions in osteosarcoma. Therefore, explicating regulations to restore the anti-tumor function of PTEN might provide novel targeted therapies for osteosarcoma. Preclinical evidence suggested directly targeting the altered PTEN in osteosarcoma was promising. Current clinical application of PTEN related therapies in osteosarcoma are PI3K/mTOR inhibitors, and these drugs have shown the favorable efficacy in patients with advanced osteosarcoma.

Case Report: Primary Ewing Sarcoma of the Penis With Multiple Metastases.

Background: Ewing sarcoma is the second most common malignant bone tumor in children, but it rarely originates from extra-skeletal sites. The commonly involved sites of soft tissue include paravertebral spaces, lower extremities, the pelvis, head, and neck, while primary extra-skeletal Ewing sarcoma (EES) located in the genitals is extremely rare. Case Presentation: We report a young patient who presented to our hospital with a painful erection of the penis and limited motion of the left hip. Magnetic resonance imaging showed a hyperintense mass with invasion of adjacent tissue in the penis and a heterogeneously high signal lesion in the left proximal femur. 18F-fluorodeoxyglucose positron-emission tomography detected widespread metastatic lesions in the bilateral lung and multiple skeletons. An incisional biopsy of the penis was performed; the histopathological findings and EWS gene translocation identified by molecular analysis confirmed the diagnosis of Ewing sarcoma. Subsequently, the punch-biopsy specimen from the left femur showed undifferentiated small round cells, a finding consistent with the microscopic presence of Ewing sarcoma metastasis. However, after the first course of multiagent chemotherapy, the penile mass did not obtain stabilization but instead grew progressively with surface ulceration and multidrug resistant bacteria infection. Despite receiving antibiotics and maximal supportive therapy, the patient died from sepsis and lung metastasis complications in the intensive care unit 2 months later. Conclusion: This case indicates that although EES as a subtype of Ewing sarcoma is rare, it can occur virtually in any soft tissue site, even in the genitals. Therefore, clinicians need to distinguish this entity from other soft tissue sarcomas with rapid progression since early diagnosis and timely treatment of EES are pivotal for a favorable prognosis.

Role of crosstalk between STAT3 and mTOR signaling in driving sensitivity to chemotherapy in osteosarcoma cell lines.

Osteosarcoma (OS) is a malignant bone neoplasm, mostly occurring in pediatric patients. OS is characterized by a highly aggressive and metastatically active tumor. Chemotherapy followed by surgical excision is the treatment of choice but is often associated with both chemoresistance and relapse. Hence, it is important to develop further understanding of OS pathogenesis and identify potential therapeutic targets. Both the signal transducer and activator of transcription 3 (STAT3) and mammalian target of rapamycin (mTOR) have been implicated in OS pathogenesis. Crosstalk between mTOR and STAT3 signaling has been shown to regulate hypoxia-induced angiogenesis in other diseases. In this study, we determined using OS cell lines if there is a crosstalk between these two pathways and how that impacts sensitivity to treatment with Rapamycin. OS cell lines exhibited differential sensitivity to mTOR inhibitor Rapamycin. Evaluation of phosphorylated STAT3 showed that in Rapamycin-sensitive 143B cells, the inhibitor decreased phosphorylation of STAT3 at Y705, but not at S727 whereas, in Rapamycin-resistant U2OS cells, the inhibitor decreased S727 phosphorylation but not Y705. However, knockdown of STAT3 in U2OS cells made them sensitive to Rapamycin. Immunofluorescence (IF) analysis showed that mTOR is constitutively activated in the 143B cells but is suppressed in the U2OS cells, indicating that this might be their reason for being resistant to Rapamycin. Both cell lines were sensitive to treatment with the STAT3 inhibitor Napabucasin (NP). Treatment with NP inhibited STAT3 activation at Y705 and additionally inhibited mTOR activation, indicating crosstalk between STAT3 and mTOR signaling pathways. Rapamycin could effectively prevent lung metastasis in an orthotropic OS mice model using 143B cells. However, Rapamycin could not inhibit lung metastasis in mice injected with U2OS cells. The STAT3 inhibitor NP attenuated lung metastasis with the U2OS cells. Our results thus established yet undefined crosstalk of STAT3 and mTOR signaling pathways in OS and highlight the possibility of using mTOR inhibitors for treatment in patients with OS.

Gorham-Stout disease of the malleolus: a rare case report.

BACKGROUND: Gorham-Stout disease, also known as vanishing bone disease, idiopathic massive osteolysis, is a rare entity of unknown etiopathology. This disease is characterized by destruction of osseous matrix and proliferation of lymphatic vascular structures and associated with massive regional osteolysis. It has a variable clinical presentation and is commonly considered as a benign disease with a progressive tendency and an unpredictable prognosis. The diagnosis is made by exclusion and based on combination with histological, radiological, and clinical features. Despite that several therapeutic options have shown certain efficacy, the effective treatment still remains controversial and there is no standard treatment to be recommended. CASE PRESENTATION: A previously healthy 40-year-old man presented with right lateral malleolus pain after an ankle sprain and was referred to our hospital. The radiographs indicated rapid massive bone destruction in the distal right lateral malleolus with an unclear margin. Based on the combination with histological, radiological, and clinical features, the diagnosis of Gorham-Stout disease was made. Considering that the residual function of malleolus had to be protected, prior bisphosphonate was used to control the progression of lesion, followed by surgical resection and biological reconstruction with autologous fibular bone grafting. The patient was followed up 8 years after surgery, he presented without progression and recurrence. CONCLUSIONS: We depict a case of Gorham-Stout disease at the right lateral malleolus and was successfully controlled by medication and surgical intervention. Based on the prior effective medical treatment, resection with biological reconstruction is a useful approach to treat Graham-Stout disease in bone.

Knockdown of FBXO39 inhibits proliferation and promotes apoptosis of human osteosarcoma U-2OS cells.

F-box proteins are essential components of the Skp-cullin-F-box complex (a type of E3 ubiquitin ligase), and participate in cell cycle and immune responses through the ubiquitin proteasome system. F-box protein 39 (FBXO39) belongs to the F-box family, which has been reported to be associated with cancer oncogenesis and progression. The present study aimed to investigate the role of FBXO39 in osteosarcoma (OS) cell proliferation and apoptosis in vitro. It was demonstrated that U-2OS cells exhibited high expression of FBXO39 compared with HOS and SaOS-2 osteosarcoma cells. Thus, knockdown of FBXO39 was performed using lentivirus-mediated short hairpin RNA (shRNA) transfection to validate the effect of FBXO39 in U-2OS cells. Western blotting and RT-qPCR analysis were used to confirm the efficiency of infection by analyzing the expression level of FBXO39. Using Celigo-based cell counting and MTT assays, it was demonstrated that FBXO39 knockdown significantly reduced the rate of cell proliferation compared with control. Caspase 3/7 activity assays and fluorescence-activated cell sorting confirmed the induction of apoptosis in U-2OS cells following FBXO39 knockdown. In conclusion, it was demonstrated that FBXO39 knockdown may significantly inhibit proliferation and promote apoptosis of U-2OS cells. Thus, FBXO39 may serve an important role in OS progression.