Toru Hirozane

Case: Two women (aged 35 and 29 years) with intractable chronic knee infection of tumor prostheses opted for amputation. As only the trochanteric region could be preserved, we resected the remaining proximal femur and created a 15-cm long stump using unaffected proximal thigh soft tissue to avoid the drawbacks of ultra–high-thigh amputation and conventional hip disarticulation. Both had no contracture, could move their stump voluntarily, and ambulated using a standard transfemoral prosthesis without a pelvic belt at 4-year and 3-year follow-ups, respectively. Conclusion: Our procedure might benefit patients who require ultra–high-thigh amputation, with preservation of only the femoral trochanteric region.

Background: Chondroblastoma is classified as a benign bone tumor. However, postoperative local recurrence remains a concern. We analyzed the factors contributing to chondroblastoma local recurrence and the clinical challenges associated with treating these patients. Methods: This retrospective study examined 59 patients followed up at our hospitals for ≥ 1 year after surgery during 1990–2020. The most common lesion site was the epiphyses of long bones (42 cases, 71%), including the femur, tibia, and humerus. Curettage was performed in 57 cases; 2 cases with an iliac lesion underwent resection. The median postoperative follow-up period was 47 months. Clinical features of chondroblastoma were retrospectively investigated, and local recurrence and postoperative functional outcomes were assessed. Results: Local recurrence occurred in 9% (5/57) of patients after curettage but not in the resected cases. The median time to local recurrence was 14 months. The local recurrence-free survival (LRFS) rate for all patients was 92.7% at 2 years and 88.3% at 5 years. All patients with local recurrence were aged < 17 years at the time of surgery. Local recurrence was observed in the proximal humerus in two cases and the calcaneus, acetabulum, and distal femur in one case each. None of the adjuvant procedures (high-speed burr, ablation, bone replacement materials, and preoperative denosumab) helped reduce local recurrence risk (P > 0.05). Trends toward fewer local recurrences were observed in the group treated using the high-speed burr and in the group not treated using bone replacement materials. Among the groups treated with bone replacement materials, artificial bone achieved the best LRFS rate, followed by allograft and autograft. At the final follow-up, the mean Musculoskeletal Tumor Society score was 29.8 (range: 25–30), indicating excellent postoperative functional outcomes. Joint degeneration was observed in five patients. Patients with local recurrence had a high degree of disability and joint deformity (P < 0.05). Two patients received preoperative denosumab and neither experienced local recurrence nor functional impairments. Conclusions: Good oncological and functional outcomes were achieved. Age < 17 years was associated with a high risk of local recurrence after curettage (P = 0.0198). Patients with local recurrence exhibited poorer functional outcomes. High-speed burr may help reduce the recurrence risk. If bone grafts are necessary, materials with low biocompatibility, including artificial bone, may be optimal. Managing patients with chondroblastoma should encompass curative and functional aspects.

TK-ALCL1, a novel anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALK⁺ ALCL) cell line, was established from the primary tumor site of a 59-year-old Japanese male patient. The immune profile of TK-ALCL1 corresponds to that seen typically in primary ALCL cells, i.e., positive for ALK, CD30, EMA, and CD4, but negative for CD2, CD3, CD5, CD8a, and EBV-related antigens. The rearrangement of the T cell receptor-gamma locus shows that TK-ALCL1 is clonally derived from T-lineage lymphoid cells. FISH and RT-PCR analysis revealed that TK-ALCL1 has the nucleophosmin (NPM)-ALK fusion transcript, which is typical for ALK⁺ ALCL cell lines. When TK-ALCL1 was subcutaneously inoculated into 6-week-old BALB/c Rag2^−/−/Jak3^−/− (BRJ) mice, it formed tumor masses within 4–6 weeks. Morphological, immunohistochemical, and molecular genetic investigations confirmed that the xenograft and the original ALCL tumor were identical. The ALK inhibitors Alectinib and Lorlatinib suppressed proliferation in a dose-dependent manner. Thus, TK-ALCL1 provides a useful in vitro and in vivo model for investigation of the biology of ALK⁺ ALCL and of novel therapeutic approaches targeting ALK.

Atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDLPS) is usually a solitary adipocytic tumor. ALT/WDLPS shows no potential for metastasis unless it undergoes dedifferentiation. No case of multiple ALT/WDLPS has been reported in recent years. We present a rare case of multiple recurrent liposarcomas. A 71-year-old man with a history of scrotal ALT/WDLPS at 61 years presented with multiple large tumors spread throughout the body. The patient was bedridden and severely limited in his activities of daily living (ADL) due to multiple large tumors in the trunk and lower extremities. Radiological examination revealed multiple adipocytic tumors, mainly in the soft tissues of the trunk and extremities, with several visceral lesions. Tumors were resected in stages, starting with large tumors directly related to disability. Repeated palliative resections improved the patient’s ADL; he regained ambulation and was discharged 18 months after admission. Twelve surgeries were performed to remove 44 adipocytic tumors from the testis, left chest wall, perigastric area, ileum, left inguinal region, both buttocks, thighs, and lower legs. Histological examination revealed dedifferentiated components in five tumors, while 39 tumors were diagnosed as ALT/WDLPS. At the age of 76 years, the patient developed an unresectable dedifferentiated liposarcoma between the heart and aorta, leading to fatality at 79 years. The patient’s clinical course suggested multiple metastases of ALT/WDLPS of scrotal origin or ALT/WDLPS of multicentric origin. Although multicentric ALT/WDLPS or ALT/WDLPS metastases are rare, they should be considered when multiple large adipocytic tumors are found throughout the body. Despite the presence of numerous large malignant tumors, surgical treatments of the lesions can improve ADL and prolong life if the tumors are of low-grade malignancy.

Pleomorphic liposarcoma is a rare malignant adipocytic tumor showing undifferentiated pleomorphic sarcoma morphology with various degrees of epithelioid features. It is sometimes difficult to distinguish from carcinoma metastasis. Immunohistochemical panel is very important for differential diagnosis; however, there is a risk that unexpected staining could lead to misinterpretation. We report a pleomorphic liposarcoma, epithelioid variant, in an 88-year-old man, with tricky-positive staining for GATA3. Histological examination revealed a tumor with epithelioid morphology. The tumor consists of solid sheets of epithelioid tumor cells with focal aggregates of pleomorphic lipoblasts. Immunohistochemically, the adipocytic tumor cell areas were positive for S100 protein, and the epithelioid tumor cells showed CAM 5.2 positivity. GATA3 was diffusely positive. The combination of CAM 5.2 and GATA3 staining suggested the possibility of metastatic cancer, but systemic clinical examinations did not detect any presence of a primary tumor, including urinary bladder, breasts, and salivary glands. The pathological diagnosis of pleomorphic liposarcoma, epithelioid variant, was made because of the presence of malignant lipoblasts. Our report may contribute for differential diagnosis of pleomorphic liposarcoma, epithelioid variant, with unexpected positive immunoreaction for GATA3.

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.

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 (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. 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. 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.