Establishment and characterization of NCC-ASPS2-C1: a novel patient-derived cell line of alveolar soft part sarcoma.

Alveolar soft part sarcoma (ASPS) is a rare mesenchymal tumor characterized by rearrangement of the ASPSCR1 and TFE3 genes and a histologically distinctive pseudoalveolar pattern. ASPS progresses slowly, but is prone to late metastasis. As ASPS is refractory to conventional chemotherapy, the only curative treatment is complete surgical resection. The prognosis of advanced and metastatic cases is poor, highlighting the need for preclinical research to develop appropriate treatment options. However, ASPS is extremely rare, accounting for < 1% of all soft tissue sarcomas, and only one patient-derived ASPS cell line is available from public cell banks worldwide for research. This study reports the establishment of a novel ASPS cell line derived from the primary tumor tissue of an ASPS patient, named NCC-ASPS2-C1. This cell line retains the ASPSCR1-TFE3 fusion gene, which is characteristic of ASPS. The characterization of this cell line revealed stable growth, spheroid formation, and invasive properties. By screening a drug library using NCC-ASPS2-C1, we identified several drugs that inhibited the proliferation of ASPS cells. In conclusion, the establishment of NCC-ASPS2-C1 provides a valuable resource for advancing ASPS research and developing novel treatments for this challenging disease.

IDH-negative chondrosarcoma with metachronous dedifferentiation only in the metastatic site-A diagnostic pitfall.

Dedifferentiated chondrosarcoma is a subtype of chondrosarcoma with a biphasic histological appearance of a chondrosarcoma component transitioning to a high-grade, noncartilaginous sarcoma. It is particularly difficult to confirm the diagnosis when a sarcoma lacking cartilaginous component occurs at a distant location from the primary lesion. The patient was a 72-year-old woman with multiple lesions in the pelvis, lungs, and liver, 18 months after resection of grade 2 central chondrosarcoma of the sternum. Imaging showed no cartilage component in any location. Although a needle biopsy from the pelvic region confirmed the diagnosis as high-grade sarcoma without a cartilage component, it was difficult to distinguish between a new primary sarcoma and metachronous metastatic lesions from patient's known prior dedifferentiated chondrosarcoma. We therefore performed a comparative molecular analysis by whole-exome sequencing of the biopsy sample and the resected sternal central chondrosarcoma. Both lesions had no IDH1/2 mutations but shared 19 somatic mutations and wide-range chromosomal losses, indicating similar origin. This case illustrates the challenge is coupling a diagnosis of metastatic dedifferentiated chondrosarcoma when no chondroid component is evident. Our study also highlights the benefit of genomic analysis in this differential diagnosis, especially in the context of dedifferentiated chondrosarcoma lacking IDH1/2 mutations.

Dedifferentiated Osteosarcoma of the Distal Ulna: A Case Report.

Osteosarcoma is the most common malignant primary bone tumor that occurs most frequently in the second decade of life but rarely in patients over 40 years of age. The most common primary sites of osteosarcoma are the distal femur followed by proximal tibia and proximal humerus, and involvement of the wrist is extremely rare. Moreover, dedifferentiated osteosarcoma is also a rare condition that progresses to high-grade osteosarcoma from low-grade osteosarcoma, usually central low-grade osteosarcoma or parosteal osteosarcoma that bears MDM2 and/or CDK4 gene amplifications. We herein report an extremely rare case of dedifferentiated osteosarcoma arising in the distal ulna of an adult over 40 years of age. The patient was a 46-year-old man with a 2-month history of pain in his left swollen wrist. The initial radiological findings suggested a benign bone tumor in the distal ulna, and the lesion was marginally excised at the nearby hospital. Although the pathological diagnosis at the nearby hospital suggested a benign cartilaginous tumor, the tumor recurred in an aggressive manner 8 months after the initial surgery. The patient was referred to our hospital, and an incisional biopsy showed a high-grade osteosarcoma. The primary tumor was retrospectively re-evaluated at our hospital and diagnosed as low-grade osteosarcoma. Since neoadjuvant chemotherapy failed to shrink the tumor, the patient had to undergo below the elbow amputation to cure the disease. Although the tumor was negative for MDM2 nor CDK4, the definitive diagnosis of dedifferentiated osteosarcoma was made according to the clinical course and the histological findings. Lung metastases were found 10 months after the amputation, which were successfully treated by neoadjuvant chemotherapy and surgery. The patient has been doing well with no evidence of disease for 1 year and 6 months. Surprisingly, the literature review revealed that many low-grade osteosarcomas of the distal ulna progressed to high-grade dedifferentiated osteosarcomas. One should bear in mind that the diagnosis and treatment for bone-forming tumors of the distal ulna should be made very carefully because, although rare, it is possible that the tumor may initially appear as a benign or low-grade malignant tumor and may progress to high-grade osteosarcoma.

Direct conversion of osteosarcoma to adipocytes by targeting TNIK.

Osteosarcoma (OS) is an aggressive mesenchymal tumor for which no molecularly targeted therapies are available. We have previously identified TRAF2- and NCK-interacting protein kinase (TNIK) as an essential factor for the transactivation of Wnt signal target genes and shown that its inhibition leads to eradication of colorectal cancer stem cells. The involvement of Wnt signaling in the pathogenesis of OS has been implicated. The aim of the present study was to examine the potential of TNIK as a therapeutic target in OS. RNA interference or pharmacological inhibition of TNIK suppressed the proliferation of OS cells. Transcriptome analysis suggested that a small-molecule inhibitor of TNIK upregulated the expression of genes involved in OS cell metabolism and downregulated transcription factors essential for maintaining the stem cell phenotype. Metabolome analysis revealed that this TNIK inhibitor redirected the metabolic network from carbon flux toward lipid accumulation in OS cells. Using in vitro and in vivo OS models, we confirmed that TNIK inhibition abrogated the OS stem cell phenotype, simultaneously driving conversion of OS cells to adipocyte-like cells through induction of PPARγ. In relation to potential therapeutic targeting in clinical practice, TNIK was confirmed to be in an active state in OS cell lines and clinical specimens. From these findings, we conclude that TNIK is applicable as a potential target for treatment of OS, affecting cell fate determination.

Feasibility of Targeting Traf2-and-Nck-Interacting Kinase in Synovial Sarcoma.

BACKGROUND: The treatment of patients with metastatic synovial sarcoma is still challenging, and the development of new molecular therapeutics is desirable. Dysregulation of Wnt signaling has been implicated in synovial sarcoma. Traf2-and-Nck-interacting kinase (TNIK) is an essential transcriptional co-regulator of Wnt target genes. We examined the efficacy of a small interfering RNA (siRNA) to TNIK and a small-molecule TNIK inhibitor, NCB-0846, for synovial sarcoma. METHODS: The expression of TNIK was determined in 20 clinical samples of synovial sarcoma. The efficacy of NCB-0846 was evaluated in four synovial sarcoma cell lines and a mouse xenograft model. RESULTS: We found that synovial sarcoma cell lines with Wnt activation were highly dependent upon the expression of TNIK for proliferation and survival. NCB-0846 induced apoptotic cell death in synovial sarcoma cells through blocking of Wnt target genes including MYC, and oral administration of NCB-846 induced regression of xenografts established by inoculation of synovial sarcoma cells. DISCUSSION: It has become evident that activation of Wnt signaling is causatively involved in the pathogenesis of synovial sarcoma, but no molecular therapeutics targeting the pathway have been approved. This study revealed for the first time the therapeutic potential of TNIK inhibition in synovial sarcoma.

Pseudomyogenic hemangioendothelioma of bone treated with denosumab: a case report.

BACKGROUND: Pseudomyogenic hemangioendothelioma (PMHE) is a rare endothelial neoplasm that involves the bones in only 14% of all cases. The optimal treatment strategy has not been established. We herein report a case of primary PMHE in which denosumab treatment showed activity in both imaging studies and the clinical outcome. CASE PRESENTATION: A 20-year-old woman presented with worsening pain in her left ankle. Imaging studies showed multifocal fluorodeoxyglucose (FDG)-avid [maximum standardized uptake value (SUVmax), 15.95] osteolytic lesions in the bones of her left lower extremity. While waiting for the definitive pathologic diagnosis of PMHE, denosumab, a human immunoglobulin G2 monoclonal antibody against RANKL, was initiated to treat progressive bone absorption after curettage of one of the lesions. Denosumab induced osteosclerosis around the lesions and pain relief and was discontinued 4 years after its initiation. Although all of the multifocal lesions remained, they all became less FDG-avid (SUVmax, 2.6), and the patient developed no signs of new lesions or distant metastasis. CONCLUSION: Denosumab plays a certain role in prevention of bone destruction by PMHE through suppression of osteoclast-like giant cells and would be an excellent treatment for bone absorption by PMHE of bone.

Conservative surgical management of simple monostotic fibrous dysplasia of the proximal femur in a 19-year-old basketballer: a case report.

BACKGROUND: Fibrous dysplasia is a rare benign, intramedullary, fibro-osseous lesion. It is thought to be a developmental disorder of bone maturation where normal lamellar bone is replaced by irregular trabecular bone ensnared with fibrous dysplastic tissue that is unable to complete maturation resulting in significant loss of mechanical strength. This, together with the inability to mineralize sufficiently, leads to deformity, pain, and pathological fractures. It typically presents in young adults, with an equal representation in both genders. Surgical intervention is necessary in mild cases with chronic symptoms to prevent pathological fractures or to correct deformities. CASE PRESENTATION: A 19-year-old Chinese woman presented with non-traumatic, nonspecific left hip pain during basketball training. X-rays demonstrated a ground glass lesion, 10 cm in length, in her left femoral neck, which is a classic sign of fibrous dysplasia. No other deformities were noted. She was managed conservatively with analgesia for 6 months; however, her condition did not improve and a decision was made for surgical intervention. The lesion was a type 1 lesion according to the Ippolito radiological classification of fibrous dysplasia, which is a lesion with mild deformities. Therefore, we performed minimal curettage and insertion of a free autologous fibula strut harvested from her left leg, for structural stability. No implants were used. The operation was successful and her postoperative course was uneventful. Histology confirmed the diagnosis of fibrous dysplasia. She achieved partial weight bearing at 4 weeks postoperation, and full weight bearing at 8 weeks, and returned to basketball at 12 weeks. At 1-year follow-up, she returned to competitive basketball and remained pain free with no complications. CONCLUSIONS: Fibrous dysplasia is a rare and benign fibrous tumor of the bone that presents mostly in a young patient population. From our case, we have shown that it is possible to treat young patients with uncomplicated Ippolito type 1 fibrous dysplasia with a minimally invasive approach of using a cortical bone graft for structural augmentation of the affected area, without the use of implants. They are able to fully return to an active and vigorous lifestyle without restriction of activities or long-term risks of orthopedic implant complications.

A giant popliteal lipoblastoma in a 23-month-old girl: a case report.

BACKGROUND: Lipoblastomas are rare benign tumors that arise from embryonic white fat and almost always occur in babies and children. Here, we report a case of a giant popliteal lipoblastoma in a 23-month-old Japanese girl that was successfully treated via complete resection. CASE PRESENTATION: Our patient was a 23-month-old Japanese girl. At 6 months of age, she presented at a nearby hospital with a mass on the popliteal side of her lower right leg. She had no symptoms and was diagnosed as having a benign adipose tumor via magnetic resonance imaging. The mass gradually increased in size, and she was referred to our hospital at 1 year and 11 months of age. A physical examination and radiology revealed a localized mass 13 × 10 × 7 cm in size in the aforementioned area that restricted knee movement and caused proximal tibia deformity. Magnetic resonance imaging showed a giant circumscribed subcutaneous mass with multiple partitions that was hyperintense on T1-weighted and T2-weighted images but not fat-saturated on T2-weighted images. Based on these findings, she was diagnosed as having a lipoblastoma. Because the mass surrounded her popliteal artery and vein and part of the popliteal nerve, surgical resection was considered risky, and we opted to simply observe her. However, owing to rapid growth of the mass and the worsening of symptoms, she underwent complete resection at 2 years and 6 months of age. A histological examination confirmed the diagnosis of a lipoblastoma. She was discharged from our hospital 3 days after surgery with no symptoms. She could walk without pain at the 6-month follow-up, and no local recurrence was observed. CONCLUSIONS: We successfully treated a giant popliteal lipoblastoma without complications by performing a total resection. Our report provides evidence that lipoblastomas should be considered for surgical resection when they progress or symptoms appear.

Osteoid osteoma of the acetabulum successfully treated with computed tomography-guided resection and ablation using a standard electrosurgical generator: a case report.

BACKGROUND: Osteoid osteoma accounts for approximately 10% of all benign bone tumors. The most common sites of osteoid osteoma are the subcortical shaft and metaphyses of long bones, but any other skeletal bone site can be involved. The acetabulum is a rare site according to past reports. This site presents challenges to optimal management because it is anatomically difficult to approach, and because its rarity leads to limited experience with therapeutic procedures. Here, we report for the first time a rare case of osteoid osteoma in the acetabulum that was successfully treated via resection of the nidus and ablation using a standard electrosurgical generator under computed tomographic guidance. CASE PRESENTATION: A 9-year-old Japanese girl presented at a clinic with left hip pain without apparent cause for 1 month. She was diagnosed as having coxitis simplex. However, her pain did not change for 1 year and she was admitted to another hospital where osteoid osteoma in her left acetabulum was suspected. She was then referred to our hospital approximately 1 year after first symptom presentation, where she presented with severe left hip pain and was completely unable to walk. Computed tomography examinations revealed a well-demarcated 5 mm mass with bone sclerosis in her left acetabulum. The mass was characterized by low intensity on T1 and high intensity on T2 magnetic resonance images. These findings were consistent with osteoid osteoma of left acetabulum. She underwent computed tomography-guided resection of nidus and ablation using a standard electrosurgical generator. A histological examination confirmed acetabular osteoid osteoma. Complete pain relief was achieved after the procedure and she experienced no complications. She could walk without any pain at the final follow-up 1 year post-treatment and no local recurrence was observed. CONCLUSIONS: We successfully treated acetabulum osteoid osteoma without any symptom recurrence by computed tomography-guided resection and ablation using a standard electrosurgical generator. In addition, we preserved our patient's sciatic nerve and triradiate cartilage. Our report provides evidence that a computed tomography-guided procedure should be considered the treatment of choice for osteoid osteoma of the acetabulum because it is a less invasive alternative to en bloc resection.

Diagnosis of extraskeletal myxoid chondrosarcoma in the thigh using EWSR1-NR4A3 gene fusion: a case report.

BACKGROUND: Extraskeletal myxoid chondrosarcoma is a rare soft tissue sarcoma that has unusual ultrastructural and molecular features. However, unlike other soft tissue sarcomas, it does not have specific clinical symptoms or radiological features, which can make its diagnosis difficult. Nevertheless, extraskeletal myxoid chondrosarcoma has a rare gene fusion (EWSR1-NR4A3) that is useful for making a differential diagnosis. CASE PRESENTATION: A 43-year-old Japanese man presented with a soft tissue mass in his right thigh. A physical examination and radiography revealed a large soft tissue mass. During magnetic resonance imaging, the mass exhibited isointensity on T1-weighted images and high intensity on T2-weighted images, as well as gadolinium enhancement at the side edge of the partition structure. Thus, we considered a possible diagnosis of a malignant myxoid soft tissue tumor, such as myxoid liposarcoma, myxofibrosarcoma, or metastatic carcinomas, including myoepithelial tumor and neuroendocrine tumor, and performed an incisional biopsy to make a definitive diagnosis. The pathological findings revealed a lobulated tumor with a myxoid structure and atypical spindle-shaped cells that created eosinophilic cord-like forms. Immunohistochemistry revealed that the tumor was positive for S-100 and negative for synaptophysin, chromogranin A, and pan keratin (AE1/AE3). The percentage of Ki-67 was 10 % in the hot spot area. Based on these clinicopathological findings, we initially considered the possibility of a myxoid liposarcoma, although we did not observe any lipoblasts. Therefore, we considered the possibility of an extraskeletal myxoid chondrosarcoma. As this tumor is very rare, we searched for the EWSR1-NR4A3 gene fusion using fluorescence in situ hybridization, which confirmed the diagnosis of extraskeletal myxoid chondrosarcoma. Positron emission tomography-computed tomography did not identify any obvious metastases, and we performed radical resection of our patient's vastus medialis and femur with a 3 cm margin. After the resection, we treated his resected femur using liquid nitrogen, and reconstructed his femur using autogenous fibula and plate fixation. No local recurrence or metastasis was observed at the 1-year follow-up. CONCLUSION: Genetic testing is useful for diagnosing extraskeletal myxoid chondrosarcoma based on the presence of the EWSR1-NR4A3 gene fusion.