Recombinant Methioninase Is Selectively Synergistic With Doxorubicin Against Wild-type Fibrosarcoma Cells Compared to Normal Cells and Overcomes Highly-Doxorubicin-resistant Fibrosarcoma.

BACKGROUND/AIM: Doxorubicin is first-line therapy for soft-tissue sarcoma, but patients can develop resistance which is usually fatal. As a novel therapeutic strategy, the present study aimed to determine the synergy of recombinant methioninase (rMETase) and doxorubicin against HT1080 fibrosarcoma cells compared to Hs27 normal fibroblasts, and rMETase efficacy against doxorubicin-resistant HT1080 cells in vitro. MATERIALS AND METHODS: The 50% inhibitory concentrations (IC50) of doxorubicin and rMETase, as well as their combination efficacy, against HT1080 human fibrosarcoma cells, Hs27 normal human fibroblasts and doxorubicin-resistant HT1080 (DR-HT1080) cells were determined. Dual-color HT1080 cells which expressed red fluorescent protein (RFP) in the cytoplasm and green fluorescent protein (GFP) in the nuclei were used to visualize nuclear fragmentation during treatment. Nuclear fragmentation was observed with an IX71 fluorescence microscope. RESULTS: The IC50 for doxorubicin was 3.3 µM for HT1080 cells, 12.4 µM for DR-HT1080 cells, and 7.25 µM for Hs27 cells. The IC50 for rMETase was 0.75 U/ml for HT1080 cells, 0.42 U/ml for DR-HT1080 cells, and 0.93 U/ml for Hs27 cells. The combination of rMETase and doxorubicin was synergistic against fibrosarcoma cells but not against normal fibroblasts. The combination of doxorubicin plus rMETase also caused more fragmented nuclei than either treatment alone in HT1080 cells. rMETase alone was highly effective against the DR-HT1080 cells as well as the parental HT1080 cells. CONCLUSION: The present results indicate the future clinical potential of rMETase in combination with doxorubicin for fibrosarcoma, including doxorubicin-resistant fibrosarcoma.

Combination therapy with immune checkpoint inhibitors and denosumab improves clinical outcomes in non-small cell lung cancer with bone metastases.

BACKGROUND: The concomitant use of denosumab and immune checkpoint inhibitor (ICI) treatment may have synergistic effects and enhance antitumor activity; however, this has not been fully evaluated. This study aimed to evaluate the clinical outcomes of non-small cell lung cancer (NSCLC) patients with bone metastases receiving combination therapy and to identify the best combination regimen. METHODS: Eighty-six NSCLC patients with bone metastases who received ICI treatment were enrolled in this study. The patients were divided into two groups; a denosumab combination group (D + ICI group; n = 47) and a non-combination group (non-D + ICI group; n = 39). The response rate (RR) for bone metastases, disease control rate (DCR), overall survival (OS), real world progression-free survival (rwPFS), and the incidence of immune-related adverse events (irAEs) were evaluated. Additionally, the time when denosumab treatment should commence and concomitant treatment duration were evaluated. RESULTS: The D + ICI group showed significantly better RR (40.4 % vs. 20.5 %, p = 0.01), DCR (67.3 % vs. 38.7 %, p = 0.02), OS (14.2 vs. 8.6 months, p = 0.02), and rwPFS (7.4 vs. 3.6 months, p < 0.01) than the non-D + ICI group; however, incidence of irAEs showed no difference (29.7 % vs. 12.8 %, p = 0.07). Although clinical outcomes did not differ regardless of whether denosumab was initiated before or after ICI treatment, the group that received concomitant denosumab for more than four months had significantly better RR (46.2 % vs. 17.4 %, p = 0.03), OS (20.3 vs. 3.8 months, p < 0.01), and rwPFS (10.9 vs. 2.8 months, p < 0.01) than the group that received concomitant denosumab for less than four months. However, the landmark analysis showed no significant differences in OS (20.4 vs. 12.7 months, p = 0.11) and rwPFS (22.8 vs. 11.2 months, p = 0.21), and the results of denosumab duration were influenced by long-term survivors. CONCLUSION: Denosumab showed favorable synergistic effects with ICI treatment and may significantly improve the response to bone metastasis and prognosis without increasing the incidence of irAEs.

DNA-Binding Agent Trabectedin Combined With Recombinant Methioninase Is Synergistic to Decrease Fibrosarcoma Cell Viability and Induce Nuclear Fragmentation But Not Synergistic on Normal Fibroblasts.

BACKGROUND/AIM: The alkylating agent trabectedin, which binds the minor groove of DNA, is second-line therapy for soft-tissue sarcoma but has only moderate efficacy. The aim of the present study was to determine the synergistic efficacy of recombinant methioninase (rMETase) and trabectedin on fibrosarcoma cells in vitro, compared with normal fibroblasts. MATERIALS AND METHODS: HT1080 human fibrosarcoma cells expressing green fluorescent protein (GFP) in the nucleus and red fluorescent protein (RFP) in the cytoplasm and Hs27 normal human fibroblasts, were used. Each cell line was cultured in vitro and divided into four groups: no-treatment control; trabectedin treated; rMETase treated; and trabectedin plus rMETase treated. The dual-color HT1080 cells were used to quantitate nuclear fragmentation in each treatment group. RESULTS: The combination of rMETase and trabectedin was highly synergistic to decrease HT1080 cell viability. In contrast, there was no synergy on Hs27 cells. Moreover, nuclear fragmentation occurred synergistically with the combination of trabectedin and rMETase on dual-color HT1080 cells. CONCLUSION: The combination treatment of trabectedin plus rMETase was highly synergistic on fibrosarcoma cells in vitro suggesting that the combination can improve the outcome of trabectedin alone in future clinical studies. The lack of synergy of rMETase and trabectedin on normal fibroblasts suggests the combination is not toxic to normal cells. Synergy of the two drugs may be due to the high rate of nuclear fragmentation on treated HT1080 cells, and the late-S/G2 cell-cycle block of cancer cells by rMETase, which is a target for trabectedin. The results of the present study suggest the future clinical potential of the combination of rMETase and trabectedin for soft-tissue sarcoma.

Clinical features of patients with carcinoma soft tissue metastases as surgical indications: a retrospective cohort study.

BACKGROUND: Soft-tissue metastasis of carcinoma is rare. In the present study, we investigated the surgical indications and clinical features of patients with soft tissue metastases of carcinoma. METHODS: In this retrospective cohort study, we enrolled 26 patients with soft tissue carcinoma metastasis referred to our department for treatment. Sex, age, location, size, depth, pain due to the tumor, primary origin, serum C-reactive protein (CRP) level, MRI examinations, diagnosis by a previous physician, carcinoma markers from blood, history of carcinoma, other metastases, performance status (PS), and surgical procedures were documented. Associations between variables and surgery were statistically analyzed. RESULTS: The primary cancer origin was found to be the lung (n = 10), kidney (n = 7), esophagus (n = 2), stomach (n = 1), breast (n = 1), liver (n = 1), ureter (n = 1), anus (n = 1), and unknown (n = 2). The mean CRP level of all patients was 2.3 mg/dL. Seven tumors (26.9%) were originally suspected to be soft tissue metastases of carcinoma, while 19 tumors (73.1%) were considered soft tissue sarcomas or inflammatory lesions by the previous treating physician. Twenty patients (76.9%) had other metastases. The PS of the 12 patients (46.2%) was zero. Eleven patients (42.3%) underwent surgery for soft tissue metastases. Diagnosis of soft tissue metastasis by a previous physician and good PS (p < 0.05) were significantly associated with surgery. CONCLUSION: Overall, the present results show that surgical indications for soft tissue metastasis of carcinoma include diagnosis by the referring physician or good PS of the patients.

Safety and Efficacy of Early Rehabilitation With Assistance From a Single-Joint Hybrid Assistive Limb in Patients With Total Knee Arthroplasty: A Randomized Controlled Clinical Pilot Study.

Background This study aimed to evaluate the safety and effectiveness of knee exercise within four hours after total knee arthroplasty (TKA) using a single-joint hybrid assistive limb (HAL-SJ). Materials and methods This pilot single-blind randomized controlled trial included participants who underwent TKA for osteoarthritis and were randomly allocated to the early rehabilitation (n = 14) or control rehabilitation (n = 16) group. Knee rehabilitation exercises using the HAL-SJ began within four hours postoperatively in the early group and seven days after surgery in the control group. Knee circumference, range of motion (ROM), pain, muscle strength, and extension lag were assessed before and one and two weeks after surgery. Results Circumferences at 1 and 10 cm from the upper edge of the patella did not differ between the groups before surgery or one week postoperatively. The extension lag and knee flexion ROM after one week were significantly better in the early intervention group than in the control group. However, the quadriceps and hamstring isometric knee strength and pain scores did not differ between the groups at one and two weeks postoperatively. HAL-SJ-related complications were not reported. Conclusion Rehabilitation knee exercises using the HAL-SJ within four hours after TKA improved extension lag and knee flexion ROM without exacerbating knee swelling and pain.

Development and validation of a nomogram to predict surgical site infection after soft-tissue sarcoma resection.

Aims: Surgical site infection (SSI) after soft-tissue sarcoma (STS) resection is a serious complication. The purpose of this retrospective study was to investigate the risk factors for SSI after STS resection, and to develop a nomogram that allows patient-specific risk assessment. Methods: A total of 547 patients with STS who underwent tumour resection between 2005 and 2021 were divided into a development cohort and a validation cohort. In the development cohort of 402 patients, the least absolute shrinkage and selection operator (LASSO) regression model was used to screen possible risk factors of SSI. To select risk factors and construct the prediction nomogram, multivariate logistic regression was used. The predictive power of the nomogram was evaluated by receiver operating curve (ROC) analysis in the validation cohort of 145 patients. Results: LASSO regression analysis selected possible risk factors for SSI, including age, diabetes, operating time, skin graft or flap, resected tumour size, smoking, and radiation therapy. Multivariate analysis revealed that age, diabetes, smoking during the previous year, operating time, and radiation therapy were independent risk factors for SSI. A nomogram was developed based on the results of multivariate logistic regression analysis. In the development cohort, the incidence of SSI was 4.5% in the low-risk group (risk score < 6.89) and 26.6% in the high-risk group (risk score ≥ 6.89; p < 0.001). In the validation cohort, the incidence of SSI was 2.0% in the low-risk group and 15.9% in the high-risk group (p = 0.004). Conclusion: Our nomogram will enable surgeons to assess the risk of SSI in patients with STS. In patients with high risk of SSI, frequent monitoring and aggressive interventions should be considered to prevent this.

Associations between measured masticatory function and cognitive status: A systematic review.

OBJECTIVE: This systematic review aimed to provide an overview of the most recent evidence on the association between measured masticatory function and cognitive status. MATERIALS AND METHODS: Literature and manual searches were conducted using three electronic databases (PubMed, Web of Science and CINAHL). Observational studies published between 2011 and 2021 investigating the association between masticatory function, dementia and cognitive status in adult humans were abstracted and reviewed by three reviewers. Studies that assessed participants' masticatory function using objective and subjective measurements and that individually examined its association with cognitive function were included. The included studies were divided into cross-sectional and cohort studies, and the quality of each study was analysed using critical appraisal skills checklists. Additionally, the main conclusions and strength of the evidence were assessed for each article. RESULTS: A total of 21 studies (11 cross-sectional studies that objectively evaluated masticatory function, 9 cross-sectional studies that subjectively evaluated masticatory function and 1 prospective cohort study) were evaluated. The poorer masticatory function was associated with lower cognitive status even after adjusting for potential risk factors of dementia in four of 11 and six of nine cross-sectional studies where the masticatory function was respectively evaluated objectively and subjectively. One prospective cohort study also demonstrated that masticatory function, as evaluated based on measurements of occlusal force, predicted cognitive decline during the follow-up period. CONCLUSION: Several studies demonstrated a positive association between masticatory function and cognitive status. However, further studies, particularly longitudinal studies, are required to determine whether the association is causal.

Tumor-induced Osteomalacia Successfully Treated by En Bloc Tumor Excision and Reconstruction Using a Tumor-bearing Frozen Autograft: A Case Report.

BACKGROUND/AIM: Tumor-induced osteomalacia (TIO) is a rare pathology caused by overproduction of fibroblast growth factor 23 (FGF23). Its common clinical features include generalized muscle weakness, bone pain, and fractures. Complete resection of the offending tumor is the mainstay treatment. In this report, we present the first case of TIO by an FGF23 producing tumor treated using a tumor-bearing autograft treated with liquid nitrogen. CASE REPORT: A 63-year old female presented with generalized body pain, particularly in the left arm. The patient was diagnosed with a FGF23 producing tumor of the left humerus. Wide resection of the involved tumor was performed using a tumor-bearing autograft that was treated with liquid nitrogen. Postoperatively, the FGF23 and alkaline phosphatase (ALP) levels significantly decreased and inorganic phosphate normalized. There was also subsequent relief of generalized body pain. Immediately after the operation, range of motion of the left shoulder and elbow was initiated. The patient was instructed to perform forward flexion and abduction up to 90° with a rotational restraint. Almost complete bone union was observed at 12 months post procedure. Postoperative functional results were as follows: Musculoskeletal Tumor Society (MSTS) score of 27/30, 90% and International Society of Limb Salvage (ISOLS) score of 26/30, 87%. Ten years after the surgery, osteotomy line was completely obscured based on radiographs. The patient was disease free and without activity limitation. CONCLUSION: This is the first case report of wide excision of a FGF23 producing tumor and reconstruction using a tumor-bearing frozen autograft performed with excellent outcomes.

Extensive Synergy Between Recombinant Methioninase and Eribulin Against Fibrosarcoma Cells But Not Normal Fibroblasts.

BACKGROUND/AIM: The aim of the present study was to determine the synergy of recombinant methioninase (rMETase) and the anti-tubulin agent eribulin on fibrosarcoma cells, in comparison to normal fibroblasts, in vitro. MATERIALS AND METHODS: HT1080 human fibrosarcoma cells and HS27 human fibroblasts were used for in vitro experiments. Four groups were analyzed in vitro: No-treatment control; eribulin; rMETase; eribulin plus rMETase. Dual-color HT1080 cells which express red fluorescent protein (RFP) in the cytoplasm and green fluorescent protein (GFP) in the nuclei were used to visualize cytoplasmic and nuclear dynamics during treatment. RESULTS: Eribulin combined with rMETase greatly decreased the viability of HT 1080 cells. In contrast, eribulin combined with rMETase did not show synergy on Hs27 normal fibroblasts. Eribulin combined with rMETase also caused more fragmentation of the nucleus than all other treatments. CONCLUSION: The combination treatment of eribulin plus rMETase demonstrated efficacy on fibrosarcoma cells in vitro. In contrast, normal fibroblasts were resistant to this combination, indicating the potential clinical applicability of the treatment.

High Clinical Concordance of Drug Resistance in Patient-derived Orthotopic Xenograft (PDOX) Mouse Models: First Step to Validated Precise Individualized Cancer Chemotherapy.

Finding an effective drug for individual cancer patients among the many chemotherapies available and ruling out ineffective drugs are important challenges, especially for patients with advanced cancer. To accomplish this goal, we have pioneered and developed the patient-derived orthotopic xenograft (PDOX) nude mouse model for all cancer types, enabling the discovery and evaluation of novel therapeutics, as well as individualized therapy of patients with cancer. PDOX models can more precisely reproduce the original tumor microenvironment (TME) compared to subcutaneous-implanted xenografts including patient-derived xenograft (PDX) models. The present review presents the concordance of drug resistance in individual cancer patients and their PDOX models. There are 28 PDOX publications with 12 PDOX models from patients who were treated with chemotherapy. Sixteen chemotherapeutics were administrated to these patients and all of them were clinically ineffective. In PDOX models established from these patients' tumors, fourteen chemotherapeutics were resistant with a concordance rate of 88%. PDOX models should be established as early as possible from patients to predict and improve outcome. PDOX models mimic the clinical tumor aggressiveness, therefore enabling a high concordance with clinical outcomes. The present review shows a high concordance for drug resistance between cancer patients and their corresponding PDOX models. Future studies will include prospective clinical trials comparing both drug efficacy and resistance in patients and their PDOX models.

Case Report: Unresectable pulmonary metastases of a giant cell tumor of bone treated with denosumab: a case report and review of literature.

Giant cell tumors of bone (GCTB) sometimes metastasize to distant organs. In this case report, we present pulmonary metastases of GCTB mimicking malignancies. A 49-year-old man underwent two surgical treatments for a GCTB of the right proximal radius. At the time of the second surgery, no lesions were observed on chest radiography. Three years after surgery, the patient presented with cough and dyspnea, and chest radiography and computed tomography (CT) revealed multiple lung nodules. Positron emission tomography/CT revealed a high accumulation of 18F-fluoro-2-deoxy-D-glucose (18F-FDG) in multiple lesions. Based on the rapid growth and accumulation of 18F-FDG, a metastatic malignant tumor was suspected. CT-guided needle biopsy was performed, and the histology showed proliferation of spindle cells and multinuclear giant cells without malignant changes. Denosumab was administered because multiple lung lesions were unresectable. One month after denosumab treatment, CT showed marked shrinkage of the lesions, and the symptoms significantly improved. Eighteen months after the initial treatment with denosumab, the patient had no symptoms or tumor growth. Although its long-term efficacy and safety remain unclear, denosumab may be a treatment option for patients with unresectable pulmonary GCTB.

Graft Survivals after Reconstruction Using Tumor-Bearing Frozen Bone in the Extremities.

Tumor-bearing frozen autografts have been widely used for reconstruction of bone defects caused by tumor resection. However, some patients undergo removal of the grafted bone due to surgical site infection, tumor recurrence, or fractures of the grafted bone. In this retrospective cohort study, predictive factors for graft survival were investigated in 123 patients who underwent reconstructions using a tumor-bearing frozen autograft after bone tumor resection of the extremities. To determine the independent predictors of graft survival, the association between various parameters and graft survival was investigated. The graft survival rates were 83.2% at 5 years and 70.2% at 10 years. Among the 123 frozen autografts, 25 (20.3%) were removed because of complications. In univariate analyses, male sex, BMI of ≥23.6, tibia, and chemotherapy were significantly associated with poor graft survival, whereas the pedicle/hemicortical freezing procedure was significantly associated with better graft survival. Multivariate analysis using the Cox proportional hazards regression model revealed that BMI of ≥23.6 (HR, 3.4; p = 0.005), tibia (HR, 2.3; p = 0.047), and freezing procedure (HR, 0.3; p = 0.016) were independently associated with graft survival. Based on the results, pedicle or hemicortical freezing techniques are recommended in cases where these techniques can be applied.

Colon-cancer liver metastasis is effectively targeted by recombinant methioninase (rMETase) in an orthotopic mouse model.

BACKGROUND: Colorectal cancer liver metastasis (CCLM) is the most frequent cause of death of colorectal cancer. Development of novel new effective therapy is needed for CCLM patients to improve outcome. The aim of the present study was to investigate the efficacy of recombinant methioninase (rMETase) on a CCLM orthotopic mouse model of liver metastasis established using the human colon cancer cell line HT29 expressing red fluorescent protein (RFP). MATERIALS AND METHODS: Orthotopic CCLM nude mouse models were randomized into two groups: control group (n = 6, PBS 200 µl, i.p., daily); rMETase group (n = 6, 100 units/200 µl, i.p., daily). Tumor volume was measured on day 0 and day 15. Body weight was measured twice a week. All mice were sacrificed on day 15. RESULTS: rMETase significantly inhibited the increase of the liver metastasis as determined by RFP fluorescence area and intensity (p = 0.016 and 0.015, respectively). There was no significant difference of body weight between either group on any day. CONCLUSIONS: The present study suggests that rMETase has future potential therapy for CCLM in the clinic.

Needle tract seeding of a sclerosing epithelioid fibrosarcoma in a biopsy tract: a case report.

BACKGROUND: A sclerosing epithelioid fibrosarcoma (SEF) is an uncommon tumor of the deep soft tissue. An SEF has been described as a low-grade tumor with high local recurrence and metastatic rates. Generally, in bone and soft tissue tumors, a resection of the biopsy route is recommended; however, there is limited evidence with respect to the dissemination of the tumor tissue during a needle biopsy. CASE PRESENTATION: A mass in the right pelvic cavity, with no symptoms, was observed in a 45-year-old woman during a gynecological examination. Computed tomography (CT) revealed a multilocular mass with calcification in the pelvic cavity. The magnetic resonance imaging (MRI) showed an iso-signal intensity on T1 weighted images and hypo- and iso-signal intensity on T2 weighted images. The CT-guided core needle biopsy was performed using a dorsal approach, and the biopsy diagnosis was a low-grade spindle cell tumor. The tumor was excised using an anterior approach. The tumor tissue comprised spindle cells and epithelioid cells with irregular nuclei, and the immunohistological analysis was positive for vimentin and epithelial membrane antigen, which was consistent with a diagnosis of sclerosing epithelioid fibrosarcoma. Five years after the surgery, the MRI showed a tumor recurrence in the subcutaneous tissue of the right buttock, which was consistent with the needle biopsy tract. The patient underwent a tumor excision, and the resected tumor was similar to the primary tumor. CONCLUSIONS: The recurrent tumor was excised with a surgical margin, and the tumor specimen had the histological features of a sclerosing epithelioid fibrosarcoma. It was difficult to investigate the association of the core needle biopsy with the tumor recurrence because the approach of the biopsy tract is usually same as that used in a tumor excision. However, the present case indicated the tumor may recur in the biopsy tract of a soft tissue sarcoma. Surgeons should be aware of the possibility of disseminating tumor tissues in a needle biopsy.

A validation study for the utility of serum microRNA as a diagnostic and prognostic marker in patients with osteosarcoma.

In our previous study, osteosarcoma advanced locally, and metastasis was promoted through the secretion of large number of small extracellular vesicles, followed by suppressing osteoclastogenesis via the upregulation of microRNA (miR)-146a-5p. An additional 12 miRNAs in small extracellular vesicles were also detected ≥6× as frequently in high-grade malignancy with the capacity to metastasize as in those with a low metastatic potential. However, the utility of these 13 miRNAs for determining the prognosis or diagnosis of osteosarcoma has not been validated in the clinical setting. In the present study, the utility of these miRNAs as prognostic and diagnostic markers was therefore assessed. In total, 30 patients with osteosarcoma were retrospectively reviewed, and the survival rate was compared according to the serum miRNA levels in 27 patients treated with chemotherapy and surgery. In addition, to confirm diagnostic competency for osteosarcoma, the serum miRNA levels were compared with those in patients with other bone tumors (n=112) and healthy controls (n=275). The patients with osteosarcoma with high serum levels of several miRNAs (miR-146a-5p, miR-1260a, miR-487b-3p, miR-1260b and miR-4758-3p) exhibited an improved survival rate compared with those with low levels. In particular, patients with high serum levels of miR-1260a exhibited a significantly improved overall survival rate, metastasis-free survival rate and disease-free survival rate compared with those with low levels. Thus, serum miR-1260a may potentially be a prognostic marker for patients with osteosarcoma. Moreover, patients with osteosarcoma had higher serum miR-1261 levels than those with benign or intermediate-grade bone tumors and thus may be a potential therapeutic target, in addition to being useful for differentiating whether or not a bone tumor is high-grade. A larger investigation is required to clarify the actual utility of these miRNAs in the clinical setting.

Novel predictors of immune checkpoint inhibitor response and prognosis in advanced non-small-cell lung cancer with bone metastasis.

BACKGROUNDS: Immune checkpoint inhibitors (ICIs) can significantly prolong the survival of patients with advanced non-small-cell lung cancer (NSCLC); however, few studies on the therapeutic effects of ICIs on bone metastases were performed. METHODS: This retrospective study aimed to investigate the therapeutic effects of ICIs and determine predictors of favorable ICI response and prognosis in 55 advanced NSCLC patients with bone metastases who initiated ICI treatment between 2016 and 2019, with a mean follow-up period of 23.2 months. Patients were classified into responders (complete or partial response) and non-responders (stable or progressive disease) according to the MD Anderson Cancer Center (MDA) criteria, and the predictors of therapeutic response were identified using multivariate logistic regression analysis. Furthermore, overall survival from the time of ICI administration to the final follow-up or death was evaluated, and prognostic predictors were identified using Cox proportional hazards regression analysis. RESULTS: ICI response rate was 30.9% (complete in three cases, partial in 14). Median survival time was 9.3 months, with 1-year and 2-year survival rates of 40.6% and 19.3%, respectively. Responders survived significantly longer than non-responders (p = 0.03). Based on the receiver operating characteristic curve, the predictive cutoff value of the pretreatment neutrophil-to-lymphocyte ratio (NLR) was 2.1. Multivariate analysis identified female sex (p = 0.03), use of ICIs as first-line therapy (p < 0.01), and NLR <2.1 (p = 0.03) as significant predictors of therapeutic response, whereas concomitant use of a bone-modifying agent (p < 0.01), Katagiri score ≤6 points (p < 0.01), and NLR <2.1 (p = 0.02) were identified as significant predictors of good prognosis. CONCLUSIONS: This study identified some novel predictors for favorable therapeutic response and prognosis in advanced NSCLC patients with bone metastases undergoing ICI treatment. Pretreatment NLR less than 2.1 can be considered the most important predictor.

Kimura's Disease Diagnosed in the Department of Orthopedic Surgery Treated With Wide Excision: Report of Two Cases.

BACKGROUND/AIM: Kimura's disease is a rare chronic inflammatory disorder that commonly affects the head and neck regions, occurring predominantly in Asian men. Elevated eosinophil count and IgE levels in the peripheral blood examination are suggestive of this disease. In this study we report two cases of Kimura's disease, treated with wide excision. CASE REPORT: The first case was a 58-year-old man presented with asymptomatic left neck mass. The second case was a 69-year-old man with swelling of the right upper arm, which was suggestive of soft tissue mass. Needle biopsy results were suggestive of Kimura's disease in both cases. Elevated WBCs at 8,380/µl (neutrophils: 45%, eosinophils: 33%) for the first case and 5,370/µl (neutrophils: 61.8%, eosinophils: 3.5%) for the second one, and serum IgE at 14.988 IU/ml for the first case and 1,315 IU/ml for the second one were observ. For definitive treatment and diagnosis, wide excisions were performed. Final histopathological results revealed Kimura's disease. Surgical margins were negative even though an ill-demarcated lesion for the first case and high infiltration to the muscle for second case were confirmed. CONCLUSION: Wide excision was performed in both cases of Kimura's disease and no recurrence was observed until the final follow-up. Wide excision with negative surgical margin should be recommended for the treatment of Kimura's disease.

Clinical Benefits of LigaSure™ for Surgical Amputation Without Tourniquet Use in Patients With Musculoskeletal Tumor.

BACKGROUND/AIM: Amputation is still a viable option for musculoskeletal tumors that are multi-compartmental, adjacent to neurovascular structures, and involving pathological fractures. Complications such as poor surgical margins, local recurrence and infection after limb salvage surgery are also indications for secondary amputation. An effective hemostatic technique is vital for preventing complications of massive blood loss and prolonged operative time. The use of LigaSure™ in the field of musculoskeletal oncology has not been well documented. PATIENTS AND METHODS: This retrospective study included 27 patients with musculoskeletal tumor who underwent amputation using either LigaSure™ system (n=12) or traditional hemostatic technique (n=15) from 1999 to 2020. The purpose of this study was to evaluate the effect of LigaSure™ in terms of intra-operative blood loss, blood transfusion rates, and duration of surgery. RESULTS: The use of LigaSure™ resulted in a significant decrease in intraoperative blood loss (p=0.027) and blood transfusion rates (p=0.020). There was no significant difference for the duration of surgery between the two groups (p=0.634). CONCLUSION: The LigaSure™ system can potentially improve clinical outcomes in patients with musculoskeletal tumor undergoing amputation surgeries. The LigaSure™ system is a safe and effective hemostatic tool for musculoskeletal tumor amputation surgeries.

Antibacterial effect and biological reaction of calcium phosphate cement impregnated with iodine for use in bone defects.

Calcium phosphate cement (CPC) is often used to repair bone defects that occur after bone tumor and fracture treatment. To address bone defect cases with a high infection risk, developing CPCs with a longlasting wide-spectrum antibacterial effect is critical. Povidone-iodine has a wide antibacterial spectrum. Though there have been some reports of CPC containing antibiotics, no report of CPC with iodine has been described. In this study, the antibacterial effect and biological reaction of CPC impregnated with iodine was investigated. Iodine release from CPC and bone cement with various iodine contents (2.5, 5, and 20%) was evaluated, and 5 %-iodine CPC retained more iodine than the other CPCs after one week. Antibacterial activity against Staphylococcus aureus and Escherichia coli was also investigated, showing that 5 %-iodine had an antibacterial effect for up to eight weeks. Cytocompatibility was assessed, and 5 %-iodine CPC showed the same amount of fibroblast colony formation as control samples. CPCs with varying iodine contents (0, 5, and 20%) were then inserted into lateral femora of Japanese white rabbits for histological analysis. Osteoconductivity was evaluated using scanning electron microscopy, and hematoxylin-eosin staining. Consecutive bone formation was observed around all CPCs at eight weeks. These results indicate that CPC impregnated with iodine exhibits antimicrobial activity and cytocompatibility, and therefore, it may be effective for bone defect cases with high infection risk.

Synergy of oral recombinant methioninase (rMETase) and 5-fluorouracil on poorly differentiated gastric cancer.

Gastric cancer is highly malignant and recalcitrant to first line chemotherapies that include 5-fluorouracil (5-FU). Cancer cells are addicted to methionine for their proliferation and survival. Methionine addiction of cancer is known as the Hoffman effect. Methionine restriction with recombinant methioninase (rMETase) has been shown to selectively starve cancer cells and has shown synergy with cytotoxic chemotherapy including 5-FU. The present study aimed to investigate the efficacy of rMETase alone and the combination with 5-FU on poorly differentiated human gastric cancer cell lines (MKN45, NUGC3, and NUGC4) in vitro and vivo. rMETase suppressed the tumor growth of 3 kinds of poorly differentiated gastric cancer cells in vitro. The fluorescence ubiquitination-based cell cycle indicator (FUCCI) demonstrated cancer cells treated with rMETase were selectively trapped in the S/G2 phase of the cell cycle. In the present study, subcutaneous MKN45 gastric cancer models were randomized into four groups when the tumor volume reached 100 mm3: G1: untreated control; G2: 5-FU (i.p., 50 mg/kg, weekly, three weeks); G3: oral-rMETase (o-rMETase) (p.o., 100 units/body, daily, three weeks); G4: 5-FU with o-rMETase (5-FU; i.p., 50 mg/kg, weekly, three weeks o-rMETase; p.o., 100 units/body, daily, three weeks). All mice were sacrificed on day 22. Body weight and estimated tumor volume were measured twice a week. 5-FU and o-rMETase suppressed tumor growth as monotherapies on day 18 (p = 0.044 and p = 0.044). However, 5-FU combined with o-rMETase was significantly superior to each monotherapy (p < 0.001 and p < 0.001, respectively) and induced extensive necrosis compared to other groups. The combination of 5-FU and o-rMETase shows promise for transformative therapy for poorly differentiated gastric cancer in the clinic.