BACKGROUND/AIM:Osteosarcoma is the most common malignant bone tumor in pediatric and young adult patients. Osteosarcoma is also refractory to immune checkpoint inhibitors (ICIs). It has been recently demonstrated that methionine restriction (MR) increases the response to ICIs in melanoma and colon cancer. The present study aimed to determine whether MR alone can be an immunotherapeutic for osteosarcoma. MATERIALS AND METHODS:K7M2 murine osteosarcoma cells and 143B human osteosarcoma cells were used for the present study. Cell viability and the half-maximal effective concentration (EC50) of methionine for K7M2 and 143B were determined with the WST-8 cell-viability reagent. Western immunoblotting was used to compare programmed cell death receptor ligand 1 (PD-L1) expression in K7M2 and 143B cells treated with and without MR. K7M2 cells were subcutaneously implanted in immunocompetent BALB/c mice and T-cell-deficient nude (nu/nu) mice to determine the efficacy of an MR diet on tumor growth and enhancing CD8-positive T-cell tumor infiltration in BALB/c mice. Tumor-infiltrating lymphocytes in the tumor of BALB/c mice were determined with immunohistochemistry. RESULTS:The EC50 values of methionine for K7M2 and 143B were 14.18 μM and 20.85 μM, respectively. Both cell lines had a strong dependence on methionine at the concentration range of 4 to 32 μM. MR using methionine-depleted medium in vitro decreased PD-L1 expression in 143B and K7M2, compared to untreated control cells (p<0.05, respectively). The MR diet significantly suppressed the growth of K7M2 tumors in immunocompetent BALB/c mice (p<0.05), but not in T-cell-deficient nu/nu mice. The MR diet enhanced CD8-positive T-cell infiltration in the K7M2 tumor growing in BALB/c mice (p<0.05). CONCLUSION:MR alone is a potential immunotherapeutic for osteosarcoma. The present results suggest MR is a T-cell stimulant and not a cause of T-cell exhaustion.

BACKGROUND/AIM:In the present study we compared the glucose and glutamine requirements of cancer and normal cells to determine if the Warburg effect is cancer specific. MATERIALS AND METHODS:143B human osteosarcoma, HT1080 human fibrosarcoma, HCT116 human colon cancer and normal Hs27 human fibroblasts were cultured in Dulbecco's modified Eagle's medium (DMEM) with and without glucose; with and without glutamine; or with and without methionine. The EC50 of glucose, glutamine and methionine was compared in cancer and normal cells. Co-culture of Hs27 normal fibroblast with each cancer cell line was performed by using 12-well plates with and without glucose or methionine. Cell viability was determined with the WST-8 viability reagent, by phase-contrast microscopy or fluorescence microscopy. RESULTS:The EC50 of glucose for the three cancer cell lines ranged from 0.54 to 4.88 mM. The EC50 of glucose for Hs27 normal fibroblasts was 0.35 mM, which was not significantly lower than in HCT116 cells (p=0.2225). The EC50 for glutamine ranged from 0.15 to 0.54 mM for the cancer-cell lines and 0.24 mM for normal fibroblasts, which did not distinguish normal from cancer cells. For comparison the EC50 of cancer cells for methionine ranged from 3.8 μM to 21.4 μM while for normal fibroblasts the EC50 for methionine was 2.3 μM, which was significantly lower than in all the cancer cell lines (p<0.0167). In co-culture of cancer and normal fibroblasts, glucose-free or glutamine-free medium resulted in loss of cell viability by day 7 for both the cancer and normal cells. In contrast, in methionine-free medium, the normal fibroblasts were alive and healthy at day 7. CONCLUSION:The Warburg effect of glucose and glutamine addiction is not cancer specific in comparison to methionine addiction (Hoffman effect), which is cancer specific, suggesting the Warburg effect is not a cancer paradigm.

BACKGROUND/AIM:Recently, there have been numerous publications on the induction of ferroptosis by cysteine restriction in cancer cells. The present report aimed to determine whether cysteine restriction (CR) is a cancer-specific vulnerability in comparison with methionine restriction (MR), which is a known cancer-specific vulnerability. MATERIALS AND METHODS:Human cancer cell lines (HCT116 colon cancer, 143B osteosarcoma or HT1080 fibrosarcoma) and normal human fibroblasts (Hs27) were cultured in Dulbecco's modified Eagle's medium (DMEM) with dialyzed fetal bovine serum from which methionine or cysteine or both or neither had been depleted. Cancer and normal cells were co-cultured in 12-well plates under the above conditions. HCT116 cells expressing green fluorescent protein, and 143B and HT1080 cells expressing red fluorescent protein, were visualized by fluorescence microscopy. Normal fibroblasts and cancer cells were visualized by phase-contrast microscopy as well. RESULTS:In co-culture, of either 143B, HCT116 or HT1080 with Hs27 human fibrosarcoma, CR was toxic to Hs27 normal fibroblasts as well as to all three cancer cell lines. In contrast, MR was toxic only to the cancer cells but not normal fibroblasts. Dual CR and MR was toxic to normal and cancer cells. CONCLUSION:For all three cancer cell lines, HCT116 colon cancer, HT1080 fibrosarcoma and 143B osteosarcoma, both MR and CR were highly inhibitory in the co-cultures with Hs27 normal fibroblasts. In all cases MR had only a slight effect on normal fibroblasts, but CR was highly toxic to normal fibroblasts. Thus, MR is a cancer-specific vulnerability in contrast to CR which is toxic to both normal and cancer cells and is not a cancer-specificity vulnerability. Therefore, attempting to induce ferroptosis of cancer cells by CR does not appear to have potential as an effective cancer therapy.

BACKGROUND/AIM:Glutamine (GLN) addiction has been proposed as a cancer vulnerability and a therapeutic target. However, the glutamine requirement of normal cells is poorly understood. In the present study, we used a unique co-culture model to study the glutamine requirement of cancer cells compared to normal cells co-cultured together. MATERIALS AND METHODS:The human fibrosarcoma cell line HT1080 and normal human fibroblasts HS27 were co-cultured in 12-well dishes seeded with equal numbers of cells of each type. Additionally, HS27 cells were cultured alone in 6-well plates. The cells were grown in Dulbecco's Modified Eagle's Medium (DMEM) which did not contain GLN, methionine (MET), or cystine (CYS). 150 μM L-cystine 2HCl was added to all media. Co- and mono- cultures were grown under the following conditions: Complete medium (GLN 4 mM and MET 100 μM); MET restriction [Methionine restriction (MR), GLN 4 mM and MET 0 μM]; GLN restriction [Glutamine restriction (GR), GLN 0 mM and MET 100 μM] and MR+GR (GLN 0 mM and MET 0 μM). Cells were observed under phase-contrast and fluorescence microscopy for seven days. ImageJ was used to compare the three groups: MR, GR and MR+GR. RESULTS:In complete DMEM, HT1080 fibrosarcoma cells dominated HS27 normal fibroblasts in co-culture. Under MR, HT1080 cells became mostly non viable, but HS27 cells remained viable. Under GR and MR+GR, both HT1080 and HS27 cells became mostly non-viable. Monoculture experiments showed that normal cells survived under MR but not GR. CONCLUSION:GR is not a cancer-specific vulnerability, while MR is. Therefore, GR is not a promising cancer-therapy strategy.

Muscular dystrophy comprises a group of hereditary muscle disorders characterized by progressive muscle weakness and atrophy, ultimately resulting in the loss of ambulation and wheelchair dependence or confinement to a bed. However, the effects of prolonged hospitalization and immobilization on bone health in patients with advanced muscular dystrophy remain poorly characterized. Therefore, this study aimed to assess osteoporotic characteristics in patients with muscular dystrophy who experienced long-term hospitalization. Patients with muscular dystrophy undergoing long-term hospitalization were retrospectively reviewed in this cross-sectional study. Bone mineral density (BMD) and bone metabolism markers—including serum albumin, calcium, 25-hydroxy vitamin D [25(OH)D], tartrate-resistant acid phosphatase-5b (TRACP-5b), and bone-specific alkaline phosphatase (BAP)—were evaluated. A total of 32 patients with muscular dystrophy were included (median age, 50 years). The median duration of hospitalization was 2,287 days (range, 707–16,861 days). Regarding BMD assessment, the median T-scores for the lumbar spine and femoral neck were − 2.2 (interquartile range [IQR], − 4.1 to 0) and − 4.1 (IQR, − 4.6 to − 2.1), respectively. The median serum levels of albumin, calcium, 25(OH)D, TRACP-5b, and BAP were 3.5 g/dL (IQR, 3.2–3.9), 9.0 mg/dL (IQR, 8.8–9.3), 18.8 ng/mL (IQR, 8.7–24.9), 341 mU/dL (IQR, 221–403), and 12.8 U/L (IQR, 10.7–16.0), respectively. Patients with muscular dystrophy exhibited markedly reduced femoral neck BMD and low 25(OH)D levels, whereas lumbar spine BMD was less severely reduced. Levels of serum calcium, TRACP-5b, and BAP were within reference ranges. Patients with muscular dystrophy who required long-term hospitalization and were wheelchair-dependent or bedbound exhibited femoral neck osteoporosis and vitamin D insufficiency/deficiency. These findings may help inform strategies for osteoporotic treatment and nutritional care in this patient population.

Background/aimMany studies in the present century have stated that restriction of serine is a cancer-specific vulnerability. The present study aimed to determine whether restriction of serine, compared to restriction of methionine, distinguishes cancer and normal cells.Materials and methods143B-RFP osteosarcoma cells, HT1080-RFP fibrosarcoma cells, HCT116-GFP colon-cancer cells, and Hs27 normal fibroblasts were used in the present study. All cells are of human origin. Cancer and normal cells were cultured in RPMI-1640 medium without serine and glycine for serine/glycine restriction, and in Dulbecco’s modified Eagle’s medium without methionine for methionine restriction, each supplemented with 10% dialyzed fetal bovine serum. Cancer and normal cells were cultured in 96-well plates at 2 × 103 cells/well. Serine, glycine, and methionine were added back as controls. Cell viability was measured with the WST-8 cell-viability reagent to establish dose-response curves for serine (with or without glycine) and for methionine in cancer and normal cells. Each cancer cell line was also co-cultured with Hs27 normal fibroblasts in 12-well plates. Each cell type was evaluated by phase-contrast and GFP/RFP fluorescence microscopy to determine the effects of serine/glycine restriction or methionine restriction.ResultsSerine restriction alone did not distinguish cancer and normal cells. Both 143B osteosarcoma and Hs27 normal fibroblasts maintained approximately 100% viability without serine in glycine-containing medium. The HT1080-RFP and HCT116-GFP cancer cells lost approximately 40% of their viability without serine and showed increasing viability with increasing serine concentration. When both serine and glycine were restricted, Hs27 fibroblasts lost approximately 20% viability, whereas all cancer cells lost about 40% viability. Neither serine restriction nor serine/glycine restriction could lower the viability of cancer cells to 50% of control. In co-culture, the removal of serine and glycine still left many cancer cells viable. In contrast, methionine removal caused a much greater reduction in cancer-cell viability than removal of serine/glycine. Hs27 normal fibroblasts survived well under both serine/glycine and methionine restriction.ConclusionSerine restriction and serine/glycine restriction are not as cancer-specific as methionine restriction.

Chondromyxoid fibroma (CMF) is a benign cartilaginous neoplasm that accounts for less than 1

BACKGROUND/AIM:Drug-resistance in osteosarcoma results in a very poor clinical prognosis and has been a recalcitrant problem over many decades. We have previously reported the development of super methotrexate (MTX)-resistant osteosarcoma cells (143B-MTXSR), selected from parental 143B osteosarcoma cells (143B-P) 143B-MTXSR cells were previously selected by culturing the cells with increasing concentrations of MTX, resulting in osteosarcoma cells which are 5,500 times more MTX-resistant than the parental cells, due to extreme over-expression of dihydrofolate reductase (DHFR). In the present study, the potential therapeutic efficacy of methionine restriction, using recombinant methioninase (rMETase), was explored to overcome super MTX-resistant osteosarcoma cells. MATERIALS AND METHODS:Previously-selected 143B-MTXSR cells were used for the present study. Sensitivity to methionine restriction by rMETase was determined using the WST-8 assay and compared between 143B-MTXSR and parental 143B-P cells. RESULTS:143B-MTXSR cells (rMETase IC50: 0.38 U/ml) were very sensitive to methionine restriction by rMETase, very similar to 143B-P (rMETase IC50: 0.36 U/ml). CONCLUSION:rMETase overcame a 5,500-fold MTX-resistance of osteosarcoma cells. The present results suggest methionine restriction by rMETase can be a potential clinical strategy to overcome recalcitrant drug-resistance in osteosarcoma.

Chemotherapy resistance in osteosarcoma results in a very poor patient prognosis, with the 5-year survival rate of approximately 20%, which not improved for over three decades; thus, the development of novel therapeutic strategies is required. Methionine addiction is a fundamental and general hallmark of cancer, termed the Hoffman effect. Cancer cells need larger amounts of exogenous methionine in order to grow compared to normal cells, despite their ability to synthesize normal or greater amounts of methionine from homocysteine, due to increased transmethylation reactions in cancer cells. Methionine restriction therapy, including recombinant methioninase (rMETase), arrests cancer cells in the late-S/G2 phase of the cell cycle by targeting methionine addiction. First-line chemotherapy for osteosarcoma, including methotrexate (MTX), doxorubicin (DOX), and cisplatinum (CDDP), targets cells in the S/G2-phase, where cancer cells are also inhibited by methionine restriction, resulting in the synergy of methionine restriction to overcome drug resistance. In the present review, we describe the synergistic efficacy of conventional chemotherapy and methionine restriction therapy, including rMETase, in overcoming the drug resistance of osteosarcoma. The clinical potential of this new paradigm to overcome the drug resistance of osteosarcoma is discussed.

Background/aim: The present study aimed to assess the relationship between the maximum standardized uptake value (SUVmax) on F-18-fluorodeoxyglucose positron emission tomography computed tomography (F-18-FDG-PET/CT) and the geriatric nutritional risk index (GNRI) in patients with soft-tissue sarcomas (STSs). Patients and methods: The present single-center retrospective observational study included patients who underwent F-18-FDG-PET/CT and for whom serum albumin levels, height, and body weight were measured prior to therapeutic intervention. Results: A total of 81 patients were included in the study. The mean SUVmax was 11.1 +/- 9.9. The 5-year overall survival (OS) and disease-free survival (DFS) rates were 79.7% and 52.4%, respectively, for the higher SUVmax group (>= 11.1) and 91.0% and 73.0%, respectively, for the lower SUVmax group (<11.1). For the GNRI, the 5-year OS and DFS rates were 89.6% and 64.3%, respectively, for the negative-risk group, and 73.3% and 77.1% for the positive-risk group, respectively, with no significant differences. The mean SUVmax was 9.7 +/- 8.1 and 19.1 +/- 14.9 for the negative- and positive-risk groups, respectively. The positive-risk group had a significantly higher SUVmax than the negative-risk group (p=0.03). Furthermore, there was a negative correlation between the SUVmax and GNRI (r=-0.48, p<0.05). Conclusion: A higher SUVmax and lower GNRI in patients with STS may contribute to a poor prognosis. The deregulatory elevation of tumor glucose metabolic activity may affect serum albumin levels and weight loss in patients with STS, resulting in a decrease in the GNRI.

BACKGROUND/AIM:Tumor immunology and immunotherapy have been intensely researched recently, especially with the development of immune checkpoint inhibitors (ICIs). However, only a small percentage of patients respond to ICIs, and this response is limited to a minority of cancer types, such as colon cancer, lung cancer, and melanoma. The aim of the present study was to develop an imageable in-vivo-like in vitro system to directly visualize tumor immunology and immunotherapy in real-time, to further understand tumor immunology and develop improved tumor immunotherapy. MATERIALS AND METHODS:Lewis lung carcinoma cells labeled with red fluorescent protein (LLC-RFP) and peripheral blood mononuclear cells labeled with green fluorescent protein (PBMCs-GFP), derived from transgenic GFP mice, were cultured in two dimensions (2-D) on plastic or in three dimensions (3-D) in Gelfoam® histoculture, using RPMI-1640 culture medium with 10% fetal bovine serum, and 1% penicillin/streptomycin, and with concanavalin-A. RESULTS:LLC-RFP cells seeded on Gelfoam® formed glandular-like structures after 2 days of histoculture. PBMCs-GFP were seeded on Gelfoam® with LLC-RFP after one day to establish a co-culture. The PBMCs-GFP co-localized with many of the structures formed by the LLC-RFP cells after one day of seeding PBMCs-GFP, suggesting a very specific interaction necessary for an immunological interaction. In contrast, only a few randomized co-localizations of PBMCs-GFP and the LLC-RFP cells were seen on plastic in 2-D culture. CONCLUSION:The present results demonstrate a new 3-D co-culture color-coded system to visualize in real-time the interaction of PBMCs and cancer cells using fluorescence color-coded imaging. Future experiments will test drugs that can stimulate immune reactions between the PBMCs and cancer cells.

BACKGROUND/AIM:Positron emission tomography/computed tomography with 18F-fluorodeoxyglucose (18F-FDG PET/CT) is frequently used to differentiate schwannomas from malignant peripheral nerve sheath tumors. Schwannomas exhibit pathological heterogeneity, with highly cellular (Antoni A) and hypocellular (Antoni B) areas, but current PET/CT methods do not adequately reflect this heterogeneity. This study aimed to compare imaging characteristics of schwannomas in the trunk versus the extremities, with emphasis on metabolic heterogeneity. PATIENTS AND METHODS:This retrospective study included patients with solitary schwannomas who underwent MRI and 18F-FDG PET/CT before surgical excision (June 2013-September 2023). Exclusion criteria were plexiform, multiple, biopsy-only lesions, and tumors originating from internal organs. Tumors were classified as trunk or extremity lesions. MRI was used to determine size and volume, while PET/CT measured SUVmax, SUVmean, metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Heterogeneity was assessed using three indices: MTV-to-volume ratio (MTV/volume), SUV-based heterogeneity index (HISUV), and metabolic region-adjusted SUV-based heterogeneity index (MRA-HISUV). RESULTS:Fifty-six patients were included. Trunk schwannomas were larger than extremity tumors in diameter (4.33 cm vs. 2.77 cm; p<0.05) and volume (27.71 cm3 vs. 6.25 cm3; p<0.05). SUVmax (4.09 vs. 3.71) and SUVmean (2.47 vs. 2.22) did not differ significantly. MTV (18.43 cm3 vs. 6.19 cm3, p<0.05) and TLG (58.41 vs. 14.40, p<0.05) were higher in trunk tumors. MTV/volume ratio was lower (0.77 vs. 1.12, p<0.05), while HISUV and MRA-HISUV were higher in trunk schwannomas (1.79 vs. 1.65 and 2.36 vs. 1.49, p<0.05). CONCLUSION:Trunk schwannomas were larger and exhibited higher metabolic activity and heterogeneity. Novel parameters such as MTV/volume and MRA-HISUV may enhance the characterization of schwannoma heterogeneity.

Primary talar bone tumors are rare. Surgical intervention on talar bone tumors is often challenging, even though most lesions are benign. Due to its unique anatomical and biomechanical characteristics, this surgical approach requires careful consideration. Although most benign talar tumors can be treated with curettage alone, insufficient visualization increases the risk of recurrence, making the selection of an appropriate surgical approach crucial. We performed a chevron-type medial malleolar osteotomy, a technique widely used for its excellent exposure and stability, to manage talar tumors. Herein, we report three cases of benign talar tumors that were successfully treated with chevron-type medial malleolar osteotomy. Case 1, with a giant cell tumor of the bone (GCTB), experienced recurrence after initial curettage but was managed effectively with improved exposure using chevron-type medial malleolar osteotomy. Using the chevron-type osteotomy, case 2 and 3 patients with aneurysmal bone cysts (ABC) and GCTB, respectively, had no recurrence or complications. The medial malleolus was osteotomized in a reverse V-shape while preserving the deltoid ligament and was flipped distally for exposure. This technique offers excellent visualization and stability, suggesting its utility in managing talar tumors. This three-case series is the first to report the use of a chevron-type medial malleolar osteotomy for managing talar bone tumors, potentially aiding the surgical management of talar tumors, particularly those involving the talar dome.

BACKGROUND/AIM:It has been recently demonstrated that a methionine-restricted diet increases the response to immune checkpoint inhibitors (ICIs) via an increase in PD-L1 in a syngeneic mouse colorectal-cancer model. Our laboratory has developed recombinant methioninase (rMETase) to restrict methionine. The aim of the present study was to determine if rMETase can increase PD-L1 expression in a human colorectal cancer cell line in vitro. MATERIALS AND METHODS:We evaluated the half-maximal inhibitory concentration (IC50) value of rMETase on HCT-116 human colorectal cancer cells. HCT-116 cells were treated with rMETase at the IC50 Western immunoblotting was used to compare PD-L1 expression in HCT-116 cells treated with and without rMETase. RESULTS:The IC50 value of rMETase on HCT-116 was 0.79 U/ml. Methionine restriction using rMETase increased PD-L1 expression compared to the untreated control (p<0.05). CONCLUSION:Methionine restriction with rMETase up-regulates PD-L1 expression in human colorectal cancer cells and the combination of rMETase and ICIs may have the potential to improve immunotherapy in human colorectal cancer.

Background/Aim: Methotrexate (MTX) resistance in osteosarcoma leads to a very poor prognosis. In the present study, in order to further understand the basis and ramifications of MTX resistance in osteosarcoma, we selected an osteosarcoma cell line that has a 5,500-fold-increased MTX IC50. Materials and Methods: The super MTX-resistant 143B osteosarcoma cells (143B-MTXSR) were selected from MTX-sensitive parental human 143B osteosarcoma cells (143B-P) by continuous culture with step-wise increased amounts of MTX. To compare the malignancy of 143B-MTXSR and 143B-P, colony-formation capacity was compared with clonogenic assays on plastic and in soft agar. In addition, tumor growth was compared with orthotopic xenograft mouse models of osteosarcoma. Expression of dihydrofolate reductase (DHFR), phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), and myelocytomatosis oncogene (MYC) was examined with western immunoblotting and compared in 143B-MTXSR and 143B-P cells. Results: 143B-MTXSR had a 5,500-fold increase in the MTX IC50 compared to the parental 143B-P cells. Expression of DHFR was increased 10-fold in 143B-MTXSR compared to 143B-P (p<0.01). 143B-MTXSR cells had reduced colony-formation capacity on plastic (p=0.032) and in soft agar (p<0.01) compared to 143B-P and reduced tumor growth in orthotopic xenograft mouse models (p<0.001). These results demonstrate that 143B-MTXSR had reduced malignancy. 143B-MTXSR also showed an increased expression of PI3K (p<0.01), phosphorylated (activated) AKT (p=0.031), phosphorylated mTOR (p=0.043), and c-MYC (p=0.024) compared to 143B-P. Conclusion: The present study demonstrates that the increased expression of DHFR, PI3K/AKT/mTOR and c-MYC appears to be linked to super MTX resistance and, paradoxically, to reduced malignancy. The present results suggest that DHFR may be a powerful tumor suppressor when highly amplified.

Multidisciplinary treatment including neo-adjuvant/adjuvant chemotherapy, radical surgery, and radiation is challenging for super elderly patients (aged > 80 years old) with soft-tissue sarcoma because due to deterioration of physiological function/tolerance for chemotherapy and medical complications. The purpose of the present study was to clarify clinical outcomes of elderly patients aged > 80 years old with soft-tissue sarcoma (STS) who underwent surgery without neo-adjuvant nor adjuvant chemotherapy. Twenty-three consecutive patients aged ≥ 80 years, who underwent surgical resections of STS between January 2013 and December 2022, were included. As prognostic factors, depth of the tumor, maximum diameter of the tumor, Geriatric Nutrition Index (GNRI) for geriatric status, High-sensitivity modified Glasgow Score (HS-mGSP) for inflammatory status, local recurrence, and distant metastasis were evaluated. The median age was 84 (range 80–91) years. The median follow-up period was 49 (range 6–119) months. Histological diagnoses were as follows: myxofibrosarcoma in 8 patients, undifferentiated pleomorphic sarcoma in 7 patients, dedifferentiated liposarcoma in 4 patients, leiomyosarcoma in 3 patients, and synovial sarcoma in 1 patient. The locations of the primary tumor were superficial in 13 patients and deep layer in 10 patients, respectively. All patients underwent surgical resections. R0 margins were achieved in all patients. The 1-, 2-, and 5-year disease-specific survival rates were 95.7%, 91.1%, and 85.%, (median 58 months). Univariate analysis showed local recurrence and distant metastasis may affect disease-specific survival (p < 0.05, respectively). GNRI and Hs-mGPS were not influenced on disease-specific survival. Multivariate logistic regression analysis showed that distant metastasis was independent risk factor for the disease-specific survival (p < 0.05). In the current study, we observed a comparable survival rate, despite no neo-adjuvant or adjuvant chemotherapies performed. Tumor resections with adequate margins might, at least in part, have contributed to the decent survival ratio regardless of histological grade.

Background/Aim: Methotrexate (MTX) resistance in osteosarcoma results in a very poor patient prognosis. We previously reported that super MTX-resistant osteosarcoma (143B-MTXSR) SR ) cells, selected from parental 143B osteosarcoma (143B-P) cells by culturing them with increasing concentrations of MTX, exhibited reduced malignancy, despite the over- expression of oncogenes. The present study explored the mechanism of reduced malignancy in the super MTX-resistant osteosarcoma cells. Materials and Methods: Previously selected 143B-MTXSR SR cells which are 5,500 times more MTX resistant than parental cells, were used for this study. The status of methylated histone H3K9me3 and H3K27me3 marks was examined with western immunoblotting and compared between 143B-MTXSR SR and parental 143B-P cells. Results: Histone H3K9me3 and H3K27me3 marks were over-expressed in 143BMTXSR SR compared to 143B-P (p<0.05, p<0.01, respectively). Conclusion: Over-expression of histone H3K9me3 and H3K27me3 marks may be related to super-MTX resistance and to the loss of malignancy of super MTX-resistant osteosarcoma cells due to the fundamental relationship of methylation and cancer.

Background/Aim: Androgen-independent prostate cancer (AIPC) is resistant to androgen-depletion therapy and is a recalcitrant disease. Docetaxel is the first-line treatment for AIPC, but has limited efficacy and severe side-effects. All cancers are methionine-addicted, which is termed the Hoffman effect. Recombinant methioninase (rMETase) targets methionine addiction. The purpose of the present study was to determine if the combination of docetaxel and rMETase is effective for AIPC. Materials and Methods: The half-maximal inhibitory concentrations (IC50) of docetaxel and rMETase alone were determined for the human AIPC cell line PC-3 and Hs27 normal human fibroblasts in vitro. The synergistic efficacy for PC-3 and Hs27 using the combination of docetaxel and rMETase at their IC50s for PC-3 was determined. Results: The IC50 of docetaxel for PC-3 and for Hs27 was 0.72 nM and 0.94 nM, respectively. The IC50 of rMETase for PC-3 and for Hs27 was 0.67 U/ml and 0.76 U/ml, respectively. The combination of docetaxel and rMETase was synergistic for PC-3 but not Hs27 cells. Conclusion: The combination of a relatively low concentration of docetaxel and rMETase was synergistic and effective for AIPC. The present results also suggest that the effective concentration of docetaxel can be reduced by using rMETase, which may reduce toxicity. The present results also suggest the future clinical potential of the combination of docetaxel and rMETase for AIPC.

Background/Aim:Lipomatous tumors, including lipomas, atypical lipomatous tumors (ALTs), myxoid liposarcomas (MLs), and dedifferentiated liposarcomas (DLs), are often diagnosed using magnetic resonance imaging (MRI). Differential diagnosis of lipomas and ALTs by MRI is often challenging. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) has recently been used for the diagnosis and evaluation of tumor staging and recurrence of soft tissue tumors. The maximum standardized uptake value (SUVmax) is positively associated with malignant grade in several cancers. This study aimed to evaluate SUVmax of 18F-FDG PET/CT in the differential diagnosis of lipomatous tumors.Patients and Methods:Patients who underwent 18F-FDG PET/CT for the diagnosis of lipomatous tumors between January 2013 and September 2021 were included in the study. Patients with lipomatous tumors, confirmed by pathological diagnosis or surgical specimens, were evaluated for lipomatous tumor SUVmax.Results:This study included 44 patients with lipomas (n=19), ALTs (n=12), MLs (n=9), and DLs (n=4). The mean SUVmax of lipomas, ALTs, MLs, and DLs was 0.99±1.41, 1.92±0.95, 5.21±4.94, and 9.29±1.43, respectively. Lipomas showed a significantly lower SUVmax than did ALTs, MLs, and DLs (p<0.05). ALTs demonstrated a significantly lower SUVmax than did MLs and DLs (p<0.05). No significant differences were observed between MLs and DLs.Conclusion:Lipomas or ALTs had a significantly lower SUVmax than lipomatous sarcomas. Lipomas had a significantly lower SUVmax than ALTs, aiding in their preoperative differentiation. 18F-FDG-PET/CT could serve as a potent tool for the differential diagnosis of lipomatous tumors.

Background: There is limited data on the impact of COVID-19 epidemic on the number of orthopaedic surgeries in Japan. Methods: We conducted a nationwide hospital survey asking for the monthly number of orthopaedic surgeries performed at each facility from January 2019 to June 2021. Those facilities that had performed at least 100 surgeries in 2019 were included for analyses. The facilities were further grouped by prefecture and by hospital characteristics. A brief health economic evaluation was also performed. Risk ratios were compared using univariate analyses with P < 0.05 considered statistically significant. Results: Questionnaire was sent to 1988 hospitals with 1671 hospitals (84%) responding. The survey data indicated a total number of orthopaedic surgeries decreased in 2020 compared to 2019 (1,061,541 vs 1,119,955 P < 0.01), and also for the first six months of 2021 compared to the same period in 2019 (530,388 vs 550,378 P < 0.01). In 2020, over 50% of all facilities in nearly all of the prefectures saw a decline in surgical procedures. The risk of incurring more than a 25% decease in the number of surgeries was significantly higher in 2020 for class I designated medical institutions compared to those that were not designated for any types of infectious diseases among the institutions with a tertiary emergency medical center in 2020 (crude risk ratio 2.9: 95% CI 1.2-7.4, p = 0.02) and in 2021 (crude risk ratio 4.7: 95% CI 1 0.9-12.1, p < 0.01). The estimated total nationwide decrease of revenue were in the range of approximately & YEN;29.2 to & YEN;116.8 billion per year for orthopaedic surgeries alone. Conclusion: There was a statistically significant decrease in the number of orthopaedic surgeries in Japan. The magnitude of the decline varied by prefectures and hospital characteristics, with the greater impact imposed on medical institutions with higher classification functions. The estimated immediate health economic impact was sizable. (c) 2023 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.