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The management of soft-tissue tumors of 2-5 cm is not specified. We investigated the management of these cases.Among 105 cases with soft-tissue tumors from 2014 to 2021, 38 with tumors of 2-5 cm were retrospectively reviewed. The clinical characteristics, diagnosis, and management were investigated.The study population included 14 males and 24 females (mean age=57 years). Common histological diagnoses included lipoma, epidermal cyst, and hemangioma as benign tumors, and leiomyosarcoma (n=2) and metastatic soft-tissue carcinoma (n=1) as malignant tumors. Magnetic resonance imaging, needle and excisional biopsy were performed in 35, 19 and 19 cases, respectively. The mean follow-up period was 7 months. No recurrence was observed.Malignancy exists, even in soft-tissue tumors of 2-5 cm (3/38; 8%). To avoid unplanned excision, needle biopsy should be considered for cases with magnetic resonance imaging abnormalities.

Background/Aim: Little is known about the clinical characteristics in older patients of ≥75 years of age with primary osteosarcoma due to its rarity. We aimed to understand the clinical characteristics in these patients in order to make an appropriate diagnosis and provide treatment. Patients and Methods: The medical records of eight patients of ≥75 years of age with primary osteosarcoma were retrospectively reviewed. We investigated their clinical features, imaging findings, histopathological findings, treatment methods, and oncological outcomes. Results: There were two male and six female patients, with a mean age of 80 years. The mean follow-up period was 44 months. The initial symptom was pain in five, swelling in two, and a mass in one. The initial diagnosis was osteoarthritis in two, lumbar canal stenosis in two, benign bone tumor in four. The mean period from the first time the patient noticed symptoms to referral was 25 months. Two patients had a history of surgical curettage at their previous hospital for bone tumor that was considered benign. Lung metastasis was observed at presentation in three patients. The mean tumor size was 129 mm in its greatest dimension. Surgical treatment was performed on six patients, including frozen autograft reconstruction in one. Carbon-ion radiotherapy was conducted in one patient due to an unresectable pelvic lesion. Conclusion: Diagnosis requires care because the radiological and histological findings of primary osteosarcoma in patients ≥75 years of age are often non-specific, in addition to their delayed consultation. Individualized treatment including surgical procedure and radiotherapy is essential for older patients to maintain a good quality of their lives.

Background Synovial sarcoma is an aggressive but chemosensitive soft-tissue tumor. We retrospectively analyzed the efficacy of perioperative chemotherapy for synovial sarcoma with data from the nationwide database, Bone and Soft Tissue Tumor Registry in Japan. Methods This study included 316 patients diagnosed with synovial sarcoma between 2006 and 2012. Oncologic outcomes were analyzed using a Cox-hazard regression model. Moreover, the effects of perioperative chemotherapy on outcomes were evaluated using a matched-pair analysis. The oncologic outcomes of patients who did or did not receive chemotherapy were compared (cx + and cx-). Results Multivariate analysis revealed significant correlations of age (over 40, hazard ratio [HR] = 0.61, p = 0.043), margin status (marginal resection, HR = 0.18, p p = 0.013 versus wide resection) with overall survival; surgical margin type (marginal resection, HR = 0.14, p = 0.001 and intralesional resection, HR = 0.09, p = 0.035 versus wide resection) with local recurrence; and postoperative local recurrence (HR = 0.30, p = 0.027) and surgical margin (marginal resection, HR = 0.31, p = 0.023 versus wide resection) with distant relapse-free survival. Before propensity score matching, perioperative chemotherapy was mainly administered for young patients and patients with deeper tumor locations, larger tumors, more advanced-stage disease, and trunk location. The 3-year overall survival, local control, and distant relapse-free survival rates were 79.8%/89.3% (HR = 0.64, p = 0.114), 89.6%/93.0% (HR = 0.37, p = 0.171) and 71.4%/84.5% (HR = 0.60, p = 0.089) in the cx+/cx- groups, respectively. After propensity score matching, 152 patients were selected such that the patient demographics were nearly identical in both groups. The 3-year overall survival, local control, and distant relapse-free survival rates were 71.5%/86.0% (HR = 0.48, p = 0.055), 92.5%/93.3% (HR = 0.51, p = 0.436) and 68.4%/83.9% (HR = 0.47, p = 0.046) in the cx+/cx- groups, respectively. Conclusion This large-sample study indicated that the margin status and postoperative disease control were associated directly or indirectly with improved oncologic outcomes. However, the efficacy of perioperative chemotherapy for survival outcomes in synovial sarcoma patients was not proven in this Japanese database analysis.

Although immunotherapy is thought to be a promising cancer treatment, most patients do not respond to immunotherapy. In this post hoc analysis of a phase 1/2 study, associations of programmed death ligand 1 (PD-L1), PD-L2, and HLA class I expressions with responses to dendritic cells (DCs)-based immunotherapy were investigated in patients with advanced sarcoma. This study enrolled 35 patients with metastatic and/or recurrent sarcomas who underwent DC-based immunotherapy. The associations of PD-L1, PD-L2, and HLA class I expressions in tumor specimens, which were resected before immunotherapy, with immune responses (increases of IFN-γ and IL-12) and oncological outcomes were evaluated. Patients who were PD-L2 (+) showed lower increases of IFN-γ and IL-12 after DC-based immunotherapy than patients who were PD-L2 (−). The disease control (partial response or stable disease) rates of patients who were PD-L1 (+) and PD-L1 (−) were 0% and 22%, respectively. Disease control rates of patients who were PD-L2 (+) and PD-L2 (−) were 13% and 22%, respectively. Patients who were PD-L1 (+) tumors had significantly poorer overall survival compared with patients who were PD-L1 (−). No associations of HLA class I expression with the immune response or oncological outcomes were observed. This study suggests that PD-L1 and PD-L2 are promising biomarkers of DC-based immunotherapy, and that addition of immune checkpoint inhibitors to DC-based immunotherapy may improve the outcomes of DC-based immunotherapy.

Background A mouse model of metastatic osteosarcoma is imperative to identify effective agents for metastatic osteosarcoma, which is a recalcitrant disease. In the present study, we established osteosarcoma patient-derived cells (OS-PDCs) and transfected them with green fluorescent protein (GFP). Materials and methods The OS-PDCs were transfected with GFP-lentivirus. GFP-expressing OS-PDCs (2.0×105) were then injected into the tibia of nude mice to establish the patient-derived orthotopic cell (PDOC) model (n=3). Six weeks after injection, the primary tumor and each organ were resected and imaged. Results Primary orthotopic tumors were established in two out of three mice. The GFP-expressing OS-PDCs in the PDOC model were visualized. Multiple GFP-expressing lung metastases were detected in one of the two mice with primary tumor. Conclusion The present study proves the concept that a GFP-expressing PDOC model can mimic clinical lung-metastatic osteosarcoma. This model can serve as a paradigm to screen for effective drugs for osteosarcoma lung metastasis.

BackgroundIntramedullary osteosclerosis (IMOS) is a rare condition without specific radiological findings except for the osteosclerotic lesion and is not associated with family history and infection, trauma, or systemic illness. Although the diagnosis of IMOS is confirmed after excluding other osteosclerotic lesions, IMOS is not well known because of its rarity and no specific feature. Therefore, these situations might result in delayed diagnosis. Hence, this case report aimed to investigate three cases of IMOS and discuss imaging findings and clinical outcomes.Case presentationAll three cases were examined between 2015 and 2019. The location of osteosclerotic lesions were femoral diaphyses in the 60-year-old man (Case 1) and 41-year-old woman (Case 2) and tibial diaphysis in the 44-year-old woman (Case 3). All cases complained of severe pain and showed massive diaphyseal osteosclerotic lesions in plain radiograms and computed tomography (CT) scans. Cases 2 and 3 were examined using the triphasic bone scan, and a fusiform-shaped intense area of the tracer uptake on delayed bone image was detected in both cases without (Case 2) or slightly increased vascularity (Case 3) on the blood pool image, which was reported as a specific finding of IMOS. Open biopsy was performed in all cases, and histologic section showed trabecular bone sclerosis with hypocellular fibrous tissues, finally diagnosed as IMOS. The pain was sharply improved after biopsy and kept at the latest follow-up periods (34, 33, and 6 months in Cases 1, 2, and 3, respectively).ConclusionsMassive sclerotic lesions with severe pain in the diaphyseal region of long bones should be considered as IMOS to avoid the delayed diagnosis, although other sclerotic bony lesions should be carefully excluded. Triphasic bone scan with a fusiform-shaped intense area of tracer uptake on delayed bone image and without or slightly increased vascularity on the blood pool image will help confirm IMOS. The role of open biopsy was to confirm the diagnosis of IMOS and to give the severe pain relief immediately in the three cases, although more cases and long-term follow-up are necessary.

Background/aim In this study, we investigated the locations and surgical complications of schwannomas. Patients and methods Data of 130 patients with schwannomas were retrospectively reviewed. Pre- and post-operative neurological symptoms, tumor locations, and nerves of origin (sensory, motor, or mixed) were reviewed. Results Before surgery, 69 patients had Tinel-like signs, 56 patients had pain, 32 patients had numbness, four patients had motor deficits. After surgery, 20 patients had developed a new neurological deficit; 11 patients had motor deficits, ten patients had sensory deficits, and one patient had both motor and sensory deficits. Most schwannomas occurred in mixed nerves, including the median nerve in 17 patients and tibial nerve in 13 patients. Conclusion The most common site of schwannoma was the median nerve. Although the nerve of origin of the schwannoma could be identified in only 26.0% of cases, the data suggest that schwannomas occur in both sensory and motor nerves.

For excised tumor specimens, histological grades can differ between the biopsy diagnosis and the final diagnosis. We retrospectively investigated the diagnostic accuracies of histological grades for frozen-section and permanent-section diagnoses from patients with soft-tissue tumors. Frozen-section, permanent-section, and final diagnoses were classified as benign tumors/tumor-like lesions, intermediate malignancies, or malignant tumors. Diagnostic accuracies of the histological grades from the frozen and permanent sections were evaluated by comparing the final diagnoses for the resected specimens. The diagnostic accuracies of the histological grades for the frozen- and permanent-section diagnoses were 95% (387/408 lesions) and 97% (395/408 lesions), respectively. Among the tumor types, the diagnostic accuracies of the histological grades for the frozen-section and permanent-section diagnoses were 84% and 87% for adipocytic tumors, 87% and 91% for fibroblastic/myofibroblastic tumors, 99% and 100% for nerve-sheath tumors, 98% and 98% for fibrohistiocytic tumors, 90% and 98% for tumors of uncertain differentiation, 100% and 100% for vascular tumors, and 97% and 98% for other tumors, respectively. Histological grades from frozen-section diagnoses yielded low diagnostic accuracies in adipocytic and fibroblastic/myofibroblastic tumors. Treatment should be planned based on permanent-section diagnosis and radiological findings for these tumors.

Background/aim Matrix-producing breast carcinoma (MPBC) is a rare and usually aggressive triple-negative breast cancer (TNBC). In the present report, we determined the drug sensitivity for a triple-negative MPBC using a patient-derived orthotopic xenograft (PDOX) model. Materials and methods The PDOX model was established in the left 2nd mammary by surgical orthotopic implantation (SOI). MPBC PDOX models were randomized into 4 groups (6 mice per group) when the tumor volume became 80 mm3: G1, control group; G2, cisplatinum group [intraperitoneal (i.p.) injection, weekly, for 2 weeks]; G3, paclitaxel group (i.p., weekly, for 2 weeks); G4, eribulin group [intravenous (i.v.) injection, weekly, for 2 weeks]. All mice were sacrificed on day 15. Tumor volume and body weight were measured one time per week. Results The MPBC PDOX model was resistant to cisplatinum (p=0.800). Paclitaxel suppressed tumor growth compared to the control group (p=0.009). However, only eribulin regressed the tumor (p=0.001). Conclusion Eribulin has clinical potential for triple-negative MPBC patients.

Systemic inflammation responses have been associated with cancer development, progression and metastasis. Little is known about the risk of metastasis based on inflammatory-based scores in patients with osteosarcoma.A total of 65 osteosarcoma patients without metastasis at presentation were enrolled in this retrospective study. All had been diagnosed histologically, and their laboratory data at the first visit were collected from medical records. The inflammation-based scores, tumor size, location, staging, pathological fracture, treatment methods, follow-up periods, and metastasis-free duration were evaluated.A multivariate Cox regression analysis revealed that a high platelet-lymphocyte ratio (PLR)116 [hazard ratio (HR)=3.8, 95% confidence interval =1.5-9.3; p0.01], and neutrophil count (NC) ≤4,030/μl (HR=4.5, 95%CI=1.7-12.3; p0.01), were independent risk factors significantly associated with metastasis of osteosarcoma patients.The combination of a high PLR116 and NC ≤4,030/μl before treatment was a useful inflammatory-based prognostic indicator for metastasis in patients with osteosarcoma.

Background Giant cell tumor of bone (GCTB) is an intermediate tumor commonly arising from the epiphysis of the distal femur and proximal tibia. Standard GCTB treatment is joint-preserving surgery performed using thorough curettage and the filling of the cavity with allo-, auto-, polymethyl methacrylate (PMMA), or synthetic bone graft. Calcium phosphate cement (CPC) is an artificial bone substitute, which has the benefit of being able to adjust defects, consequently inducing immediate mechanical strength, and promoting biological healing. Secondary osteoarthritis may occur following GCTB treatment and may need additional surgery if severe. However, details regarding surgery for secondary osteoarthritis have not been fully elucidated. There are no reports on the use of total knee arthroplasty (TKA) for the treatment of secondary osteoarthritis following CPC packing. The insertion of an alignment rod is a standard procedure in TKA; however, it was difficult to perform in this case due to CPC. Therefore, we used a computed tomography (CT)-free navigation system to assist the distal femur cut. This study presents a knee joint secondary osteoarthritis case following CPC packing for GCTB curettage that was treated with standard TKA. Case presentation A 67-year-old Japanese woman, who was previously diagnosed with left distal femur GCTB and was treated by curettage and CPC packing 7 years ago, complained of severe knee pain. Left knee joint plain radiography revealed Kellgren and Lawrence (K-L) grade 4 osteoarthritis without evidence of tumor recurrence. Therefore, she was scheduled for TKA. There are no reports on the cutting of a femoral condyle surface with massive CPC with accurate alignment. Because it is difficult to insert the alignment rod intramedullary and cut the femoral condyle with CPC, we planned CT-free navigation-guided surgery for accurate bone cutting using an oscillating tip saw system to prevent CPC cracks. We performed standard TKA without complications, as planned. Postoperative X-ray showed normal alignment. Knee Society Knee Score (KSKS) and Knee Society Function Score (KSFS) ameliorated from 27 and 29 to 64 and 68, respectively The patient can walk without a cane postoperatively. Conclusion There was no report about the surface TKA guided by CT-free navigation after primary GCT surgery with CPC. We believe that this case report will help in planning salvage surgery for secondary osteoarthritis after CPC packing.

Follicular dendritic cell sarcoma (FDCS) is a very rare and highly recalcitrant disease. A patient's doxorubicin-resistant FDCS was previously established orthotopically on the right high thigh into the biceps femoris of mice to establish a patient-derived orthotopic xenograft (PDOX) model. The aim of the present manuscript was to identify an effective drug for this recalcitrant tumor. Here, we evaluated the efficacy of temozolomide (TMZ), trabectedin (TRAB) and pazopanib (PAZ) on the FDCS PDOX model. PDOX mouse models were randomized into five groups of eight to nine mice, respectively. Group 1, untreated control with PBS, i.p.; Group 2, treated with doxorubicin (DOX), 2.4 mg/kg, i.p., weekly for 3 weeks; Group 3, treated with PAZ, 50 mg/kg, oral gavage, daily for 3 weeks; Group 4, treated with TMZ, 25 mg/kg, oral gavage, daily for 3 weeks; Group 5, treated with TRAB, 0.15 mg/kg, i.v., weekly for 3 weeks. Body weight and tumor volume were assessed 2 times per week. TMZ arrested the FDCS PDOX model compared to the control group (p 0.05). PAZ and TRAB did not have significant efficacy compared to the control group (p = 0.99, p = 0.69 respectively). The PDOX tumor was resistant to DOX (p= 0.99). as was the patient. The present study demonstrates that TMZ is effective for a PDOX model of FDCS established from a patient who failed DOX treatment, further demonstrating the power of PDOX to identify effective therapy including for tumors that failed first line therapy.

Olaratumab (OLA) is a monoclonal antibody against platelet-derived growth factor receptor alpha. OLA has recently been used against soft-tissue sarcoma (STS) combined with doxorubicin (DOX), but with limited efficacy. The goal of present study was to determine the efficacy of OLA combined with gemcitabine (GEM) and docetaxel (DOC) on a chemotherapy-resistant STS patient-derived orthotopic xenograft (PDOX). Undifferentiated soft-tissue sarcoma (USTS) from a striated muscle of a patient was grown orthotopically in the right biceps femoris muscle of nude mice to establish the PDOX model. The USTS PDOX was treated with GEM alone, GEM combined with DOC, OLA combined with DOX or GEM, and OLA combined with GEM and DOC. Tumor size and body weight were measured during the 14 days of treatment. Tumor growth was arrested only by OLA combined with GEM and DOC. Tumors treated with OLA combined with GEM and DOC also had the most necrosis. The present study demonstrates the power of the PDOX model to identify the novel effective treatment strategy of the combination of OLA, GEM and DOC for drug-resistant soft-tissue sarcoma.

Background Osteosarcoma is the most frequent malignant bone neoplasm. The efficacy of combination therapy of a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor and a mammalian-target-of-rapamycin (mTOR) inhibitor was previously reported in several cancer types. In the present study, we evaluated the efficacy of a combination of palbociclib (CDK 4/6 inhibitor) and everolimus (mTOR inhibitor) on an osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model. Materials and methods osteosarcoma PDOX mouse models were randomized into five treatment groups of seven mice each: Group 1, untreated control; group 2, doxorubicin treatment; group 3, palbociclib treatment; group 4, everolimus treatment; group 5, palbociclib-everolimus combination treatment. Treatment duration was 2 weeks. Results The palbociclib-everolimus combination reduced the tumor-volume ratio in the osteosarcoma PDOX mouse model compared with the control and doxorubicin (p=0.018). Everolimus alone also inhibited osteosarcoma PDOX growth compared to the control (p=0.04), but less than the combination. Palbociclib alone and doxorubicin were ineffective. There were no significant body-weight losses in any group. Only the palbociclib-everolimus combination induced extensive tumor necrosis observed histopathologically. Conclusion The present study demonstrated that the combination of CDK4/6 and mTOR inhibitors can be a translatable approach for doxorubicin-resistant osteosarcoma in the clinic.

Osteosarcoma is the most common primary malignant bone tumor, and its standard treatment is a combination of surgery and chemotherapy. A poor response to chemotherapy causes unfavorable oncological outcomes. We investigated the correlation between osteoclast differentiation in biopsy specimens and the efficacy of neoadjuvant chemotherapy in resected specimens. Forty-nine patients who underwent neoadjuvant chemotherapy and subsequent surgical treatment at our institution between 1999 and 2018 were enrolled. Using medical records, we investigated the age, sex, tumor size, location, subtype, staging, chemotherapy agents (doxorubicin, cisplatin, ifosfamide, and methotrexate), number of neoadjuvant chemotherapy courses, number of osteoclasts in biopsy specimens, and efficacy of neoadjuvant chemotherapy according to the Rosen and Huvos classification (Grade I-IV) in resected specimens. Univariate and multivariate analyses were performed to identify factors predictive of a good response in resected specimens after neoadjuvant chemotherapy. A good response (Grade III/IV) was detected in 25, while a poor response (Grade I/II) was detected in 24. According to the multivariate analysis, ≥ 46 years old (odds ratio [OR], 0.05; 95% confidence interval [CI], 0.01-0.45; p 0.01) and ≥ 5 mature osteoclasts in a biopsy specimen (OR, 36.9; 95% CI, 6.03-225; p 0.01) were significantly associated with the neoadjuvant chemotherapy efficacy. The accuracy for predicting a good response to chemotherapy based on ≥ 5 osteoclasts in a biopsy specimen in patients 46 years old was 85%. The number of mature osteoclasts in biopsy specimens is a simple factor for predicting the efficacy of chemotherapy before treatment, although further studies will be required to determine the underlying mechanism.

Background Synchronous multicentric osteosarcoma (SMOS) is a rare disease characterized by simultaneous multicentricity of intraosseous osteosarcoma without visceral involvement. SMOS, including a skull lesion, which occurs relatively rarely, and reconstruction using a frozen autograft after the excision of a lesion of SMOS has been infrequently reported previously. Case presentation We report an 18-year-old girl with SMOS, with lesions located in the left distal femur, right proximal humerus, and left occipital bone. Her major complaint was pain and swelling around the left knee joint. Asymptomatic lesions of the humerus and skull bone were detected on a systemic bone scan. No visceral organ metastasis was observed. A biopsy of the distal femoral lesion revealed osteosarcoma. Based on the histological findings, multiple bone lesions, and absence of visceral lesion, the clinical diagnosis of SMOS was made. After five courses of neoadjuvant chemotherapy with a regimen of doxorubicin and cisplatin, reconstruction using a tumor prosthesis following wide excision of the left distal femur was performed, and total necrosis was histologically observed in the retracted specimen. Following three cycles of adjuvant chemotherapy, tumor excision and reconstruction with a frozen autograft treated with liquid nitrogen was conducted for both lesions of the humerus and skull, rather than tumor prosthesis or synthetics, in order to retain a normal shoulder function, and to obtain a good cosmetic and functional outcome after treatment of the skull lesion. Further adjuvant chemotherapy could not be administered after the completion of the surgical treatment for all lesions because the adverse events due to chemotherapy were observed. At over 5 years after the diagnosis, she remains clinically disease-free. Conclusions An early correct diagnosis, the proper management of chemotherapy, and surgical treatment for all lesions are essential for achieving a good clinical outcome, even in SMOS including a skull lesion. By performing reconstruction using a frozen autograft for a proximal humeral lesion and a skull lesion after confirming the good histological efficacy of neoadjuvant chemotherapy for the primary lesion, the excellent function of the shoulder joint and a good cosmetic outcome at the site of the skull lesion was acquired without complications or recurrence.

BackgroundAtypical fractures may occur due to the combined effect of severely suppressed bone turnover (SSBT) caused by long-term bisphosphonate treatment and chronic repetitive bone microdamage. Atypical fracture of the ulna due to SSBT is a rare entity; there is no standardized treatment strategy for this condition. We successfully treated a patient with atypical fracture of the ulna. Herein, we present this patient, review the relevant literature, and discuss the treatment strategy.Case presentationAn 84-year-old woman presented with atypical fracture of the left ulnar shaft due to SSBT. She had a history of bisphosphonate therapy (ibandronate and alendronate) since more than 10 years; her bone turnover was severely suppressed. We performed open reduction and internal fixation (ORIF) using dual plate with some additional treatments. These included drilling and decortication, use of autogenous bone graft, low-intensity pulsed ultrasound (LIPUS) treatment, and administration of teriparatide. Finally, bone union was observed at 11 months after surgery.ConclusionsBased on the literature review and our experience with this case, ORIF alone may not be adequate to achieve bone union; drilling, decortication, and use of cancellus bone graft is important to achieve favorable outcomes. Administration of teriparatide and LIPUS may facilitate early bone union, although further studies are required to provide more definitive evidence. Furthermore, ORIF using dual plate may help avoid implant failure owing to the long time required for bone union.

Advanced ovarian clear cell carcinoma (OCCC) is a recalcitrant disease, often resistant to the first-line platinum-based therapy. Using a novel patient-derived orthotopic xenograft (PDOX) nude-mouse model of OCCC, we tested whether oral-recombinant methioninase (o-rMETase) could enhance the efficacy of paclitaxel (PTX).The OCCC PDOX model was established and passaged in nude mice. The OCCC PDOX models were randomized into 5 groups. G1: untreated control; G2: paclitaxel (PTX) (20 mg/kg, intraperitoneal (i.p.) injection, weekly); G3: o-rMETase (100 units, oral, daily); G4: PTX (20 mg/kg, i.p. injection, weekly) + carboplatinum (CBDCA) (40 mg/kg, i.p. injection weekly); G5: PTX (20 mg/kg, i.p. injection, weekly) + o-rMETase (100 units, oral, daily). The treatment period was 2 weeks.The combination of PTX and o-rMETase arrested OCCC tumor growth (relative tumor volume: 1.09 ± 0.63 (mean ± SD)) compared with the untreated control (relative tumor volume: 3.92 ± 1.04 (mean ± SD)) (p 0.0001). There was no significant difference in relative tumor volume between PTX plus o-rMETase and PTX plus CBDCA (relative tumor volume: 1.39 ± 0.37 (mean ± SD)) (p = 0.93).PTX plus o-rMETase arrested the OCCC tumor growth. o-rMETase is readily administered and can greatly enhance first-line therapy of a recalcitrant cancer. The novel and effective treatment strategy in the present report has future clinical potential for patients with OCCC, especially for patients who cannot well tolerate platinum-based therapy.

In order to identify more effective therapy for recalcitrant osteosarcoma, we evaluated the efficacy of an mTOR-VEGFR inhibitor combination on tumor growth in a unique osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model derived from the lung metastasis of an osteosarcoma patient who failed doxorubicin therapy. We also determined the efficacy of this inhibitor combination on angiogenesis using an in vivo Gelfoam fluorescence angiogenesis mouse model implanted with osteosarcoma patient-derived cells (OS-PDCs). PDOX models were randomly divided into five groups of seven nude mice. Group 1, control; Group 2, doxorubicin (DOX); Group 3, everolimus (EVE, an mTOR and VEGF inhibitor); Group 4, pazopanib (PAZ, a VEGFR inhibitor); Group 5, EVE-PAZ combination. Tumor volume and body weight were monitored 2 times a week. The in vivo Gelfoam fluorescence angiogenesis assay was performed with implanted OS-PDCs. The nude mice with implanted Gelfoam and OSPDCs also were divided into the four therapeutic groups and vessel length was monitored once a week. The EVE-PAZ combination suppressed tumor growth in the osteosarcoma PDOX model and decreased the vessel length ratio in the in vivo Gelfoam fluorescent angiogenesis model, compared with all other groups (p

Age affects the clinical outcomes of cancer treatment, including those for bone sarcoma. Successful reconstruction using frozen autograft after excision of bone sarcoma has been reported; however, little is known about the clinical outcomes of frozen autograft reconstruction according to age. The purpose was to evaluate the clinical outcomes of the frozen autograft reconstruction focusing on skeletally mature adolescents and young adults (AYAs) that was 15 to 39 years of age. A total of 37 AYA patients with primary bone sarcoma on the appendicular skeleton were enrolled in this study. The mean follow-up period was 89 months. The graft survival (GS), overall survival (OS), recurrence-free survival (RFS), complications and the function were retrospectively evaluated using medical records. The 10-year GS, OS, and RFS rates were 76%, 84%, and 79%, respectively. Bone union was achieved with a rate of 94% within 1 year after surgery, and nonunion (n = 1) and fracture (n = 2) were infrequently observed. Graft removal was performed in 7 cases, and the most common reason for the removal was infection (n = 5). The Musculoskeletal Tumor Society score was excellent in 23 cases of the available 29 cases. Frozen autograft reconstruction for AYAs showed excellent clinical outcomes, although the long-term follow-up is required.

Methionine addiction is a fundamental and general hallmark of cancer. Gene expression analysis showed that methionine restriction (MR) of methionine-addicted cancer cells increases TNF-related apoptosis-induced ligand receptor-2 (TRAIL-R2) expression. Here, we determined the effects of MR on TRAIL-R2 targeted therapy in pancreatic cancer by the TRAIL-R2 agonist tigatuzumab. Human pancreatic cancer cell lines were cultured in control or methionine-free medium. The effects of MR on TRAIL-R2 expression and sensitivity to tigatuzumab were evaluated in vitro. An orthotopic pancreatic cancer mouse model was established to evaluate the efficacy of MR using oral recombinant methioninase (o-rMETase), and the efficacy of tigatuzumab and their combination. MR enabled tigatuzumab-induced apoptosis, by increasing TRAIL-R2 expression in pancreatic cancer cells in vitro. The protein expression level of the melanoma-associated antigen MAGED2, which reduces TRAIL-R2 expression, was decreased by MR. In the orthotopic pancreatic cancer mouse model, o-rMETase increased TRAIL-R2 expression level in the tumors and enabled the antitumor efficacy of tigatuzumab. MR, effected by o-rMETase, enabled the efficacy of the TRAIL-R2 agonist tigatuzumab by increasing TRAIL-R2 expression in pancreatic cancer. Our results suggest that o-rMETase has clinical potential for treating pancreatic cancer.

BACKGROUND/AIM Previous studies have identified pelvic tumors as a risk factor for surgical site infections (SSI). However, risk factors for extremity tumors are still unclear. This study investigated risk factors for postoperative deep infection in malignant bone tumors of the extremities. PATIENTS AND METHODS Data from 238 patients with 256 malignant bone tumor surgeries were reviewed. Univariate analysis and multiple logistic regression determined risk factors for deep infection. RESULTS Deep infection was found in 23 of 256 cases (9.0%). Tibial tumor (OR=6.04; 95%CI=2.14-17.05; p

Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disease (LSD) caused by a deficiency of the iduronate-2-sulfatase (IDS) that catabolizes glycosaminoglycans (GAGs). Abnormal accumulations of GAGs in somatic cells lead to various manifestations including central nervous system (CNS) disease. Enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT) are the currently available therapy for MPS II, but both therapies fail to improve CNS manifestations. We previously showed that hematopoietic stem cell targeted gene therapy (HSC-GT) with lethal irradiation improved CNS involvement in a murine model of MPS II which lacks the gene coding for IDS. However, the strong preconditioning, with lethal irradiation, would cause a high rate of morbidity and mortality. Therefore, we tested milder preconditioning procedures with either low dose irradiation or low dose irradiation plus an anti c-kit monoclonal antibody (ACK2) to assess CNS effects in mice with MPS II after HSC-GT. Mice from all the HSC-GT groups displayed super-physiological levels of IDS enzyme activity and robust reduction of abnormally accumulated GAGs to the wild type mice levels in peripheral organs. However, only the mice treated with lethal irradiation showed significant cognitive function improvement as well as IDS elevation and GAG reduction in the brain. These results suggest that an efficient engraftment of genetically modified cells for HSC-GT requires strong preconditioning to ameliorate CNS involvement in cases with MPS II.

Background/aim Matrix-producing breast carcinoma (MPBC) is a rare and usually aggressive triple-negative breast cancer (TNBC). In this study, we determined drug sensitivity for a triple-negative MPBC, without BRCA mutations, in a patient-derived orthotopic xenograft (PDOX) model. Materials and methods The MPBC PDOX model was established in the left 2nd mammary gland of nude mouse by implantation of the patient tumor using surgical orthotopic implantation (SOI). We randomized MPBC PDOX mice into 5 groups (n=5 mice/per treatment group) when the tumor volume reached 80 mm3: G1, control-no treatment; G2, bevacizumab [intra-peritoneal (i.p.), weekly, for 2 weeks]; G3, vinorelbine (i.p., weekly, for 2 weeks); G4, olaparib (oral., daily, for 2 weeks); G5, eribulin [intravenous (i.v.), weekly, for 2 weeks]. The mice in each treatment group were sacrificed on day 15. Tumor volume and body weight were measured once/week. Results The MPBC PDOX model was resistant to olaparib (p=0.22). The MPBC PDOX model treated with bevacizumab and vinorelbine showed significantly suppressed tumor growth compared to the untreated group (p=0.005 and 0.002, respectively). However, only eribulin regressed the tumor (p=0.0001). Eribulin was more effective than olaparib (p=0.0001), bevacizumab (p=0.0025) and vinorelbine (p=0.0061). Conclusion Eribulin has clinical potential as treatment for triple-negative MPBC patients that are resistant to a PARP inhibitor such as olaparib.

Background/Aim: Brain metastases are found in approximately 30% of patients with epidermal-growth-factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC). We compared the efficacy of two EGFR-tyrosine kinase inhibitors (TKIs), erlotinib and osimertinib on a PC-9-GFP EGFR mutant NSCLC growing in the brain of nude mice. Materials and Methods: The brain metastasis models were randomized into five groups and treated for 15 days: Control; 5 mg/kg erlotinib; 50 mg/kg erlotinib; 0.5 mg/kg osimertinib; 5 mg/kg osimertinib. Tumor volume was evaluated by non-invasive fluorescence imaging. Results: Only 5 mg/kg osimertinib, a low-dose compared to the clinically-equivalent dose, showed significant tumor regression compared to the control. Conclusion: This study strongly supports the high activity of osimertinib for intracranial lesions of EGFR-mutant NSCLC.

Aims The aims of this study were to evaluate the long-term outcome of surgery for bone or soft-tissue metastases from renal cell carcinoma (RCC) and to determine factors that affect prognosis. Patients and Methods Between 1993 and 2014, 58 patients underwent surgery for bone or soft-tissue metastases from RCC at our hospital. There were 46 men and 12 women with a mean age of 60 years (25 to 84). The mean follow-up period was 52 months (1 to 257). The surgical sites included the spine (33 patients), appendicular skeleton (ten patients), pelvis (eight patients), thorax (four patients), and soft tissue (three patients). The surgical procedures were en bloc metastasectomy in 46 patients (including 33 patients of total en bloc spondylectomy (TES)) and intralesional curettage in 12 patients. These patients were retrospectively evaluated for factors associated with prognosis. Results The one-, three-, five-, ten-, and 15-year overall survival (OS) rates were 89%, 75%, 62%, 48%, and 25%, respectively. The median survival time (MST) was 127 months for en bloc metastasectomy and 54 months for intralesional curettage and bone grafting. The median survival time was 127 months for the spine, 140 months for lesions of the appendicular skeleton, and 54 months for the pelvis. Multivariate analysis showed that non-clear cell type RCC and metastases to more than two sites were independent risk factors for a poor prognosis. Conclusion Patients with bone or soft-tissue metastases from a RCC have a reasonable prognosis, making surgical resection a viable option even in patients in whom the metastases are advanced. Cite this article: Bone Joint J 2018;100-B:1241–8.

BACKGROUND/AIM Positron emission tomography (PET) using 18fluorine-labelled fluorodeoxyglucose (FDG), is the most widely applied molecular imaging technique in oncology. The present study assessed the efficacy and limitations of FDG-PET by comparing FDG accumulation in bone and soft tissue lesions, as well as histopathological features. PATIENTS AND METHODS The study included 122 patients with 165 lesions, as assessed by histopathological examinations. The maximum standardized uptake values (SUVmax) of benign lesions were compared to those of primary, recurrent, or metastatic sarcomas, as well as those of other malignancies. RESULTS The sensitivity, specificity, and accuracy of SUVmax for differentiation between benign lesions and primary sarcomas were 67.9%, 92.9%, and 80.4%, respectively. There were no significant differences between benign lesions and recurrent or metastatic sarcomas. CONCLUSION Although FDG-PET is a useful imaging modality to differentiate primary sarcomas from benign lesions, it is difficult to differentiate residual or metastatic sarcomas from benign lesions.

Background Epiphyseal-preservation surgery for osteosarcoma is an alternative method which has been indicated carefully to selected patients. The tumor-devitalised autograft treated with liquid nitrogen procedure is one of the biological reconstruction method to reconstruct the defect after tumor excision. The limb length discrepancy is usually appeared in children with their growth after limb-sparing surgery. This study was aimed to investigated the growth of residual epiphysis following epiphyseal-preservation surgery for childhood osteosarcoma around the knee joint. Methods We retrospectively reviewed 12 patients with osteosarcoma who underwent epiphysis preserving tumor excision (8 in distal femur and 4 in proximal tibia) and reconstructed by using tumor-devitalized autograft treated with liquid nitrogen. The mean patient age was 11 (range, 6 to 14) years. The mean follow-up period were 63 (range, 41 to 90) months. Epiphysis transverse growth rate, epiphysis-width discrepancy (EWD) and collapse of epiphysis were evaluated by using pre- and post-operative whole standing leg radiographs. A retrospective chart review was performed to investigate functional outcome, complications and oncological status. Results The mean growth of epiphysis rate was 12.6% (range, 3.3 to 28.0%) of affected side and 12.7% (range, 3.8 to 28.9%) of contralateral side, mean EWD was 0.1 mm (range, − 1.0 to 1.7 mm), mean LLD was + 26.1 mm (range, + 1 to + 48 mm) and two patients with distal femoral reconstruction underwent limb lengthening of tibia. There was no collapse of the residual epiphysis. The mean MSTS score was 27.7 (range, 18 to 30). Conclusions Epiphysis transverse growth was not diminished, and there was absence of epiphyseal collapse even after epiphyseal-preservation surgery in this small series of childhood osteosarcoma around the knee. With careful assessment for epiphyseal tumor involvement, epiphyseal-preservation surgery shall be possible, and could be an alternative method worth considering.

The p53 protein in mesenchymal stem cells (MSCs) regulates differentiation to osteogenic or adipogenic lineage. Because p53 function is depressed in most malignancies, if MSCs in malignancy also have p53 hypofunction, differentiation therapy to osteogenic or adipogenic lineage may be an effective treatment. We therefore wished to begin to explore this idea by evaluating atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDL) cells, because murine double minute 2 (MDM2) gene amplification, which leads to p53 hypofunction, is found in almost all ALT/WDLs. We compared osteogenic and adipogenic differentiation potency between MSCs isolated and cultured from normal adipose tissues and ALT/WDLs from the same patients. During tumor resections in six patients with ALT/WDL, we analyzed 3 mL of tumor, and for comparison, we harvested a similar amount of normal-appearing subcutaneous adipose tissue from an area remote from the tumor for comparison. Adipogenic differentiation potency was quantitatively assessed using spectrometry after oil red O staining. Osteogenic differentiation potency was semiquantitatively assessed by measuring a specific colored area after alkaline phosphatase (ALP) and alizarin red S staining. ALP is related to preosseous cellular metabolism, and alizarin red is related to calcium deposits in cell culture. There were three observers for each assessment, and each assessment (including induced-differentiation and histologic analysis) was performed in duplicate. We then analyzed the mechanism of the difference of osteogenic differentiation potency using the MDM2-specific inhibitor Nutlin-3 at various concentrations. In terms of adipogenic differentiation potency, contrary to our expectations, more fatty acid droplets were observed in MSCs derived from normal fat than in MSCs derived from ALT/WDL, although we found no significant difference between MSCs derived from ALT/WDL and MSCs derived from normal fat; the mean differentiation potency values (normal adipose tissue versus ALT/WDL) (± SD) were 0.34 (SD, ± 0.13; 95% CI, 0.24–0.44) versus 0.25 (SD, ± 0.10; 95% CI, 0.18–0.33; p = 0.22). By contrast, we found greater osteogenic differentiation potency in MSCs derived from ALT/WDL than in MSCs derived from normal fat. The mean differentiation potency values (normal adipose tissue versus ALT/WDL) (±SD) based on ALP staining was 1.0 versus 17 (SD, ± 36; 95% CI, −2.8 to 38; p = 0.04). However, we found no differences based on alizarin red S staining; mean differentiation potency value (normal adipose tissue versus ALT/WDL) (± SD) was 1.0 versus 4.2 (SD, ± 4.8; 95% CI, 1.3–7.2; p = 0.58). The gap of osteogenic differentiation potency between MSCs from normal adipose tissue and ALT/WDL was decreased as MDM2-inhibitor Nutlin-3 concentration increased. MSCs derived from ALT/WDL had higher osteogenic differentiation potency based on ALP staining, which disappeared as Nutlin-3 concentration increased, suggesting that could be caused by amplified MDM2 in ALT/WDL. Future laboratory studies might mechanistically confirm the gene and protein expression, and based on the mechanism of the gap of differentiation potency, if p53 contrast between MSCs in tumor and normal tissue could be stimulated, less-toxic and more-effective differentiation therapy to MSCs in malignancies might be developed.

Purpose: To preserve the joint structure in order to maintain good limb function in patients with osteosarcoma, we perform epiphyseal or metaphyseal osteotomy and reconstruction using frozen autografts that contain a tumour treated with liquid nitrogen. There are two methods of using liquid nitrogen-treated autografts: the free-freezing method and the pedicle-freezing method. The purpose of this study was to evaluate the results of intentional joint-preserving reconstruction using the free-freezing method and the pedicle-freezing method in patients with osteosarcoma. Methods: Between 2006 and 2014, we performed joint-preserving surgery (12 with the free-freezing method and six with the pedicle freezing method) to treat 18 cases of osteosarcoma (12 distal femurs and six proximal tibias) in patients who had achieved a good response to neoadjuvant chemotherapy. Results: Among the 18 patients (nine boys and nine girls) who had a mean age of 11.6 years, 13 remained continuously disease-free, three showed no evidence of disease, one was alive with the disease, and one died from the disease. Functional outcomes were assessed as excellent in 15 patients and poor in three, with a mean follow-up period of 46.1 months. The mean Musculoskeletal Tumour Society (MSTS) score was 90.2%. Except for one patient who underwent amputation, all patients could bend their knee through >90° flexion, and nine achieved full ROM. All but two patients could walk without aid, and 11 were able to run normally throughout the follow-up period. No intraoperative complications were observed, such as surrounding soft-tissue damage, neurovascular injury, or recurrence from frozen bone. Conclusions: Joint-preserving reconstruction using frozen autografts yielded excellent function in patients with osteosarcoma. © 2017 The Author(s), Embargo Period 12 months

In 1999, we developed a technique using frozen autografts—tumour-containing bone treated with liquid nitrogen—for the reconstruction of malignant bone tumours. The purpose of this study was to evaluate the functional and oncological outcomes of frozen autografts for intercalary reconstruction of malignant bones and soft tissue tumours. This retrospective study was designed to assess 34 patients of mean age 35 (range, 6–79) years. The mean follow-up period was 62 (24–214) months. The median length of the frozen autografts was 138.4 ± 60.39 (50–290) mm. Postsurgically, 20 patients remained disease-free, seven patients survived with no evidence of disease, five patients were alive with disease, and two patients died of disease. The five- and ten-year survival rates of the frozen autografts were 91.2% and the mean International Society of Limb Salvage score was 90%. Complete bony union was achieved in 97% of the patients. There were five cases of nonunion, six cases of fracture, two cases of deep infection and four cases of local recurrence. Utilizing intercalary frozen autografts for patients with a nonosteolytic primary or secondary bone tumour without involvement of the subchondral bone is a good alternative treatment, because it is a straightforward biological technique and can provide excellent limb function.

Background Giant cell tumours (GCTs) of the bone are intermediate tumours that are locally aggressive. Denosumab, an antibody against receptor activator of nuclear factor kappa-B ligand (RANKL), was recently developed; however, it induces osteosclerotic change through an unknown mechanism. We determined whether osteosclerotic change could be induced by neoplastic stromal cells of giant cell tumours (GCTs). Patients and methods Participants included four patients with GCT of the bone who were treated with neoadjuvant denosumab. Expression of alkaline phosphatase (ALP), osteocalcin (OCN), RANKL and histone H3K36 trimethylation were assessed through immunohistochemistry of biopsy and surgical specimens. Results OCN expression was significantly elevated after denosumab treatment, whereas ALP and RANKL expressions were not significantly elevated. Immunofluorescence staining revealed OCN expression and H3K36 trimethylation while their co-localisation was confirmed in the surgical specimens. Conclusion Denosumab promoted OCN expression and might induce the osteogenic differentiation of GCT stromal cells.

Autoimmune hepatitis (AIH) is an uncommon chronic autoimmune liver disease. Several studies reported the association of polymorphisms between CD28, CTLA4 and ICOS gene cluster in 2q33.2 with autoimmune or inflammatory diseases. The previous genome-wide association study on type 1 AIH in a European population has reported a risk G allele of a single nucleotide polymorphism (SNP), rs4325730, in this region. Here, we conducted an association study of this SNP with type 1 AIH in a Japanese population, as a replication study.An association study of rs4325730 was conducted in 343 Japanese AIH patients and 315 controls.We found that rs4325730 is associated with AIH (P=0.0173, odds ratio (OR) 1.30, 95% confidence interval (CI) 1.05-1.62, under the allele model for G allele, P=0.0070, OR 1.62, 95% CI 1.14-2.31, under the dominant model for G allele). This SNP was strongly associated with definite AIH (P=0.0134, OR 1.36, 95% CI 1.07-1.74; under allele model for G, P=0.0035, OR 1.85, 95% CI 1.22-2.81, under dominant model for G).This is the first replication association study of rs4325730 upstream of ICOS with AIH in the Japanese population and rs4325730G is a risk allele.

Autoimmune hepatitis (AIH) is an autoimmune liver disease and cirrhosis is sometimes complicated with AIH at diagnosis, influencing its prognosis. TNFAIP3 gene encodes A20, an inhibitor of nuclear factor-κB pathway, and is a susceptibility gene for autoimmune diseases. We investigated deleterious variants in the coding regions of TNFAIP3 gene of Japanese AIH patients or those with cirrhosis. The deleterious variants in the coding regions of TNFAIP3 gene were analyzed by the cycle sequencing method and the frequencies of deleterious TNFAIP3 alleles of AIH or AIH with cirrhosis were compared with those of Japanese controls. The deleterious alleles in TNFAIP3 were not associated with AIH. A significant association was shown for the deleterious alleles in TNFAIP3 (P = 0.0180, odds ratio (OR) 4.28, 95% confidence interval (CI) 1.53–11.95) with AIH with cirrhosis at presentation. The serum IgM levels in AIH patients with deleterious alleles in TNFAIP3 were tended to be lower than those without (P = 0.0152, Q = 0.1216). The frequency of deleterious alleles in TNFAIP3 was higher in the AIH subset without the DRB1 risk alleles than that with (P = 0.0052, OR 5.10, 95%CI 1.55–16.74). The deleterious alleles in TNFAIP3were associated with AIH with cirrhosis.

Background/aim For cases of musculoskeletal sarcoma of the knee presenting to our institute, we prioritize joint preservation whenever possible. To investigate patient satisfaction and desire for joint preservation, a questionnaire survey was performed. Patients and methods Surveys were mailed to 62 patients with musculoskeletal sarcoma of the knee. Responses concerning the patient and their families' satisfaction were evaluated on a 5-point Likert scale and their priorities for the surgery were noted as well. Results The survey response rate was 67.7%. All but one person were above neutral for the 5-point Likert scale. Overall, the first priority was tumor removal followed by preservation of function. Conclusion Patients identified tumor removal as their first priority, which could increase satisfaction. Following that, better preservation of function could also increase patient satisfaction. Joint-preservation was consistent with these priorities.

BACKGROUND/AIM At our institute, we prioritize joint-preservation whenever possible in cases of musculoskeletal knee sarcoma. This study aimed to evaluate patient satisfaction after joint-preservation surgery using different scales. PATIENTS AND METHODS Surveys were mailed to 62 patients with musculoskeletal knee sarcoma. We analyzed the responders' data based on the Musculoskeletal Tumor Society (MSTS) score, Toronto Extremity Salvage Score (TESS), and three component scores (physical, mental, and role/social) of the 36-Item Short-Form Health Survey according to whether they belonged to patients in the joint-preservation or in the joint-replacement groups. RESULTS The survey response rate was 67.7%. MSTS and TESS scores were higher in the patients in the joint-preservation group than in the joint-replacement group, although the differences lacked statistical significance. CONCLUSION Better physical outcomes improve patient satisfaction, as demonstrated by the high satisfaction in the group with joint-preservation.

Background Use of an implant is one of the risk factors for surgical site infection (SSI) after malignant bone tumor resection. We developed a new technique of coating titanium implant surfaces with iodine to prevent infection. In this retrospective study, we investigated the risk factors for SSI after malignant bone tumor resection and to evaluate the efficacy of iodine-coated implants for preventing SSI. Methods Data from 302 patients with malignant bone tumors who underwent malignant bone tumor resection and reconstruction were reviewed. Univariate analyses were performed, followed by multivariate analysis to identify risk factors for SSI based on the treatment and clinical characteristics. Results The frequency of SSI was 10.9% (33/302 tumors). Pelvic bone tumor (OR: 4.8, 95% CI: 1.8–13.4) and an operative time ≥ 5 h (OR: 3.4, 95% CI: 1.2–9.6) were independent risk factors for SSI. An iodine-coated implant significantly decreased the risk of SSI (OR: 0.3, 95% CI: 0.1–0.9). Conclusion The present data indicate that pelvic bone tumor and long operative time are risk factors for SSI after malignant bone tumor resection and reconstruction, and that iodine coating may be a promising technique for preventing SSI.

Ewing’s sarcoma (ES) is a rare and recalcitrant disease which is in need of a development of a novel effective therapy. The aim of this study was to investigate the efficacy of regorafenib on an ES tumor in a patient-derived orthotopic xenograft (PDOX) model. The ES PDOX models were established orthotopically in the right chest wall of nude mice to match the site of the tumor in the donor patient. The ES PDOX models were randomized into three groups (G) when the tumor volume reached 75 mm3: G1: untreated control; G2: doxorubicin (DOX) (i.p., 3 mg/kg, weekly, 2 weeks); G3: regorafenib (REG) (p.o., 30 mg/kg, daily, 2 weeks). Tumor volume and body weight were measured twice a week. All mice were sacrificed on day 15. DOX was ineffective compared to the control group (P = 0.229). REG regressed the tumor size (P

The efficacy of pharmacological chaperone therapy for Fabry disease depends on the type of α-galactosidase A (GLA) mutations. Here, we examined the mutation spectrum of the GLA gene among patients from 115 Japanese families with Fabry disease. Of these, no pathogenic mutations were identified in six families (5.2%). In total, 73 different disease-causing mutations were identified: 41 missense (56.2%), 11 nonsense (15.1%), four in frame deletion (5.5%), 10 frameshift (13.7%), six splice site (8.2%), and one intronic (1.4%) mutations. The GLA mutations detected in later-onset phenotype patients with end-stage renal disease overlapped with those seen in classical patients, indicating that it is difficult to differentiate between these two phenotypes from gene mutations. Additionally, 33 families (28.7%) had amenable mutations to the pharmacological chaperone migalastat. In conclusion, our study is informative when considering genetic counseling and pharmacological chaperon therapy for Fabry disease.

Mucopolysaccharidosis type II (MPS II) is an X-linked lysosomal storage disorder arising from deficiency of iduronate-2-sulfatase (IDS), which results in progressive accumulation of glycosaminoglycans (GAGs) in multiple tissues. Accumulated GAGs are generally measured as the amount of total GAGs. However, we recently demonstrated that GAG accumulation in the brain of MPS II model mice cannot be reliably detected by conventional dye-binding assay measuring total GAGs. Here we developed a novel quantitative method for measurement of disease-specific GAGs based on the analysis of 2-sulfoiduronic acid levels derived from the non-reducing terminal end of the polysaccharides by using recombinant human IDS (rhIDS) and recombinant human iduronidase (rhIDUA). This method was evaluated on GAGs obtained from the liver and brain of MPS II mice. The GAGs were purified from tissue homogenates and then digested with rhIDS and rhIDUA to generate a desulfated iduronic acid from their non-reducing terminal end. HPLC analysis revealed that the generated iduronic acid levels were markedly increased in the liver and cerebrum of the MPS II mice, whereas the uronic acid was not detected in wild-type mice. These results indicate that this assay clearly detects the disease-specific GAGs in tissues from MPS II mice.

Ewing's sarcoma (ES) is a recalcitrant disease in need of transformative therapeutics.The aim of this study was to investigate the efficacy of tumor-selective Salmonella typhimurium A1-R combined with tumor metabolism targeting with oral administration of recombinant methioninase (o-rMETase), on an ES patient-derived orthotopic xenograft (PDOX) model.The ES PDOX models were previously established in the right chest wall. The ES PDOX models were randomized into 5 groups when the tumor volume reached 80 mm3: G1: untreated control; G2: doxorubicin; G3: S. typhimurium A1-R; G4: o-rMETase; G5: S. typhimurium A1-R combined with o-rMETase. All mice were sacrificed on day 15. Body weight and tumor volume were assessed twice a week.S. typhimurium A1-R and o-rMETase respectively suppressed tumor growth as monotherapies (p = 0.050 and p = 0.032). S. typhimurium A1-R combined with o-rMETase regressed tumor growth significantly compared to untreated group on day 15 (p0.032). S. typhimurium A1-R combined with o-rMETase group was significantly more effective than S. typhimurium A1-R or o-rMETase monotherapy (p = 0.032, p = 0.032).The present results suggest that the combination of S. typhimurium A1-R and o-rMETase has promise to be a transformative therapy for ES.

Recurrence after wide excision or residual tumor after an unplanned excision of a malignant soft tissue sarcoma (STS) is a complex problem, due to a higher recurrence rate and poorer survival rate compared with primary resection. Regional hyperthermia was used, with the expectation that it will enhance the anti-tumor effects of chemotherapy and radiotherapy. This study aimed to assess the efficacy of neoadjuvant concomitant radiotherapy, hyperthermia, and chemotherapy (RHC) for salvage of recurrent or residual malignant STS.We identified 64 patients with recurrent or residual STS treated between 1994 and 2013. After excluding those with low-grade malignancy, with recurrent bone tumor in the soft tissues, with truncal STS, and who declined to participate, 23 patients (7 with recurrence and 16 with residual tumor) underwent RHC. The histologic diagnoses were undifferentiated pleomorphic sarcoma (n = 11), synovial sarcoma (n = 3), leiomyosarcoma and myxoid liposarcoma (n = 2 each), and other histologic types. As primary outcomes, the 5-year overall survival (OS), distant metastasis-free survival (D-MFS), and local control (LC) rates were evaluated by Kaplan-Meier analysis.The median follow-up period was 112.3 months. The 5-year OS, D-MFS, and LC were 86.4%, 77.4%, and 86.7%, respectively. In the univariate analysis, tumor depth was considered as a negative prognostic factor for OS and D-MFS, and a positive margin was also a negative prognostic factor for OS, D-MFS LC with retained on Cox proportional hazards model in OS, and D-MFS.RHC is an effective option for salvage treatment of recurrent and residual STS.

Undifferentiated/unclassified soft-tissue sarcomas (USTS) is recalcitrant neoplasms that is usually treated with doxorubicin (DOX)-containing regimens as first-line therapy. Nanoparticle albumin-bound paclitaxel (nab-PTX) is a nanotechnology-based drug and is widely used in pancreatic cancer in combination with gemcitabine (GEM). The major goal of the present study was to determine the efficacy of nab-PTX in combination with GEM, compared to conventional drugs such as docetaxel (DOC), GEM combined with DOC, or first-line drug DOX on a USTS not-otherwise specified (USTS/NOS) from a striated muscle implanted in the right biceps femoris muscle of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. USTS PDOX models were randomized into six groups: untreated control; DOX; DOC; nab-PTX; GEM combined with DOC; and GEM combined with nab-PTX. Tumor size and body weight were measured. Tumor growth was inhibited to the greatest extent by GEM combined with nab-PTX. Tumors treated with GEM combined with nab-PTX had the most necrosis. Body weight of the treated mice was not significantly different from the untreated controls. The present study demonstrates the power of the PDOX model to identify a novel effective treatment strategy of the combination of GEM and nab-PTX for recalcitrant soft-tissue sarcomas. These results suggest that combination of GEM and nab-PTX could be a promising therapeutic strategy for USTS.

Background Difficult resection of tumors from regions with complex local anatomy, such as the pelvis and sacrum, is likely to result in inadequate surgical margins (intralesional or marginal); this is because three-dimensional osteotomy is difficult particularly around the acetabulum. Additionally, removal of the joint makes reconstruction very difficult; thus, retention of good function also becomes difficult. In musculoskeletal oncology, computer navigation systems are still not widely used to prevent tumor-positive margins. We performed wide excision with guidance from a computer navigation system and reconstruction using frozen bone autografts for malignant pelvic bone tumors in two patients, and we obtained excellent functional and oncological outcomes. Here we present these patients and discuss our approach. Case presentation Case 1: A 12-year-old girl presented with Ewing sarcoma of the left pelvis (PI-II). We performed wide excision assisted by a computer navigation system with the osteotomy of the load surface of acetabulum and reconstruction using a frozen bone autograft. At the final follow-up, she showed excellent function and was alive without the disease. Moreover, she did not have osteoarthritis of the left hip joint. Case 2: A 71-year-old woman presented with dedifferentiated chondrosarcoma of the right pelvis (PII-III). We performed wide excision assisted by a computer navigation system with osteotomy avoiding load surface of the acetabulum and reconstruction using a frozen bone autograft; there was no tumor at the load surface. At the final follow-up, she showed good function, was alive without the disease, and did not have osteoarthritis of the left hip joint. Conclusions Wide excision assisted by a computer navigation system and reconstruction using a frozen bone autograft are very useful for the management/treatment of extremely difficult cases such as malignant pelvic bone tumors, particularly those including the acetabulum.

BACKGROUND/AIM This study assessed the mid- to long-term outcomes of calcium phosphate cement (CPC) implantation in benign bone tumor surgery. PATIENTS AND METHODS Between 2000 and 2015, 130 patients underwent CPC implantation in benign bone tumor surgery. Radiographic findings and clinical outcomes were retrospectively evaluated. RESULTS The mean follow-up period was 52 months. CPC filling immediately after surgery was sufficient, regardless of the amount of CPC used and the usage of adjuvant substances, which resulted in 92% of the patients' radiological results being classified as good or excellent. Significantly more patients had better CPC filling among patients with less hemorrhage and patients with tourniquet. The number of patients with good or excellent CPC filling had significantly increased by the final follow-up. CONCLUSION CPC is a useful bone substitute for benign bone tumor surgery providing excellent osteoconductivity and long-lasting stability without internal fixation.

Several studies reported that autoimmune diseases share a number of susceptibility genes. Of these genes, a SNP rs7708392 in TNIP1 was reported to be associated with systemic lupus erythematosus (SLE). Autoimmune hepatitis (AIH), a rare chronic progressive liver disease, shares some clinical features with SLE. Therefore, we investigated whether the SNP is associated with Japanese AIH. An association study of rs7708392 was conducted in 343 Japanese AIH patients and 828 controls. We found that rs7708392 is associated with AIH (P = 0.0236, odds ratio (OR) 1.26, 95% confidence interval (CI): 1.03–1.54), under the allele model for C allele. Significant differences of clinical characteristics of the AIH patients with or without G allele of rs7708392 were not detected. Of interest, the association was stronger in AIH without HLA-DRB1*04:05 allele (P = 0.0063, Q = 0.0127, OR 1.48, 95% CI: 1.12–1.96), though the association was not detected in AIH with DRB1*04:05. The C allele of rs7708392 was associated with AIH, especially AIH without DRB1*04:05, an already established risk factor.

Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder caused by deficient activity of the iduronate-2-sulfatase. This leads to accumulation of glycosaminoglycans (GAGs) in the lysosomes of various cells. Although it has been proposed that bone marrow transplantation (BMT) may have a beneficial effect for patients with MPS II, the requirement for donor-cell chimerism to reduce GAG levels is unknown. To address this issue, we transplanted various ratios of normal and MPS II bone marrow cells in a mouse model of MPS II and analyzed GAG accumulation in various tissues. Chimerism of whole leukocytes and each lineage of BMT recipients' peripheral blood was similar to infusion ratios. GAGs were significantly reduced in the liver, spleen, and heart of recipients. The level of GAG reduction in these tissues depends on the percentage of normal-cell chimerism. In contrast to these tissues, a reduction in GAGs was not observed in the kidney and brain, even if 100 % donor chimerism was achieved. These observations suggest that a high degree of chimerism is necessary to achieve the maximum effect of BMT, and donor lymphocyte infusion or enzyme replacement therapy might be considered options in cases of low-level chimerism in MPS II patients.

BACKGROUND/AIM This study evaluated the outcome of wide resection for metastatic renal cell carcinoma (RCC) to the bone or soft tissue. PATIENTS AND METHODS Thirty patients who underwent surgery for bone or soft tissue metastatic lesions of RCC were retrospectively evaluated. The surgical procedures were wide resection in 14 patients (group 1) and intralesional resection in 16 (group 2). RESULTS The 3-, 5-, 10-, and 15-year overall survival (OS) was 76%, 48%, 35%, and 23%, respectively, and OS was significantly favorable in group 1. In addition, recurrence-free survival rate was significantly higher in group 1. In the multivariate analysis, intralesional resection was an independent risk factor for poor prognosis. There was no significant difference in surgical time, though intraoperative hemorrhage was significantly larger in group 2. CONCLUSION The wide resection of bone and soft tissue metastatic lesions of RCC is a favorable option for controlling local metastasis and improving prognosis.

Before the availability of an enzyme replacement therapy (ERT) for mucopolysaccharidosis type II (MPS II), patients were treated by bone marrow transplantation (BMT). However, the effectiveness of BMT for MPS II was equivocal, particularly at addressing the CNS manifestations. To study this further, we subjected a murine model of MPS II to BMT and evaluated the effect at correcting the biochemical and pathological aberrations in the viscera and CNS. Our results indicated that BMT reduced the accumulation of glycosaminoglycans (GAGs) in a variety of visceral organs, but not in the CNS. With the availability of an approved ERT for MPS II, we investigated and compared the relative merits of the two strategies either as a mono or combination therapy. We showed that the combination of BMT and ERT was additive at reducing tissue levels of GAGs in the heart, kidney and lung. Moreover, ERT conferred greater efficacy if the immunological response against the infused recombinant enzyme was low. Finally, we showed that pathologic GAGs might potentially represent a sensitive biomarker to monitor the therapeutic efficacy of therapies for MPS II.

Background: The purpose of this study was to compare radiological features between high tibial osteotomy (HTO) and tibial condylar valgus osteotomy (TCVO), in order to define the radiological indication criteria for TCVO. Methods: Thirty-two cases involving 35 knees that had undergone HTO and the same number that had undergone TCVO for knee osteoarthritis were retrospectively evaluated. Characteristics of both groups did not differ significantly. Lower limb alignment, bone morphology, joint congruity, and joint instability were measured in standing full-length leg and knee radiographs obtained before and after surgery. Results: Radiological features in the TCVO group included greater frequencies of advanced knee OA grade, varus lower limb malalignment, depression of the medial tibial plateau, and varus-valgus joint instability compared to the HTO group before surgery. However, tibial morphology, alignment of the lower limb, and joint instability improved to comparable levels after surgery in both groups. Conclusions: TCVO appears preferable in cases with advanced knee OA, destroyed or inclined medial tibial plateau, widened and subluxated lateral joint, and high varus-valgus joint instability., BMC Musculoskeletal Disorders, 20(1), art.no.409; 2019