Fluorescence-guided assessment of bone and soft-tissue sarcomas for predicting the efficacy of telomerase-specific oncolytic adenovirus.

Bone and soft-tissue sarcomas are rare malignancies with histological diversity and tumor heterogeneity, leading to the lack of a common molecular target. Telomerase is a key enzyme for keeping the telomere length and human telomerase reverse transcriptase (hTERT) expression is often activated in most human cancers, including bone and soft-tissue sarcomas. For targeting of telomerase-positive tumor cells, we developed OBP-301, a telomerase-specific replication-competent oncolytic adenovirus, in which the hTERT promoter regulates adenoviral E1 gene for tumor-specific viral replication. In this study, we present the diagnostic potential of green fluorescent protein (GFP)-expressing oncolytic adenovirus OBP-401 for assessing virotherapy sensitivity using bone and soft-tissue sarcomas. OBP-401-mediated GFP expression was significantly associated with the therapeutic efficacy of OBP-401 in human bone and soft-tissue sarcomas. In the tumor specimens from 68 patients, malignant and intermediate tumors demonstrated significantly higher expression levels of coxsackie and adenovirus receptor (CAR) and hTERT than benign tumors. OBP-401-mediated GFP expression was significantly increased in malignant and intermediate tumors with high expression levels of CAR and hTERT between 24 and 48 h after infection. Our results suggest that the OBP-401-based GFP expression system is a useful tool for predicting the therapeutic efficacy of oncolytic virotherapy on bone and soft-tissue sarcomas.

Larger sagittal inter-screw distance/tibial width ratio reduces delayed union or non-union after arthroscopic ankle arthrodesis.

BACKGROUND: Arthroscopic ankle arthrodesis (AAA) has risks of complications, such as delayed union and non-union. The number and direction of the inserted screws have been reported as important factors affecting the time to union of AAA. However, the ratio of inter-screw distance (ISD) to tibial width (TW) in different planes has not been investigated. Therefore, we aimed to explore the effect of this ratio on bone union following AAA. METHODS: We retrospectively enrolled 63 patients (64 ankles) undergoing AAA from 2013 to 2019. Then, their age, body mass index (BMI), sex, diabetes mellitus (DM) status, Takakura-Tanaka classification, number of screws and radiographic parameters were analysed. RESULTS: The patients had a mean age of 70.3 (range, 45-91) years. Bone fusion was achieved in 57 ankles (89%) in a mean period of 3.3 (range, 2-6) postoperative months. There were four cases of delayed union and three of non-union. No significant differences in age, BMI, sex, DM, Takakura-Tanaka classification, and number of screws could be detected between the groups. However, the sagittal ISD/TW ratio was significantly larger in the union group than in the delayed/non-union group with a cut-off value of 57.0%. CONCLUSION: Larger sagittal ISD/TW ratios result in reduced post-AAA delayed union or non-union. The surgeon should be aware that the anterior and posterior screw widths should be approximately 60% or more of the anteroposterior width of the tibia.

Association between Immediate Postoperative Radiographic Findings and Failed Internal Fixation for Trochanteric Fractures: Systematic Review and Meta-Analysis.

Failed internal fixations for trochanteric fractures have a strong negative impact owing to increased postoperative mortality and high medical costs. However, evidence on the prognostic value of postoperative radiographic findings for failed internal fixations is limited. We aimed to clarify the association between comprehensive immediate postoperative radiographic findings and failed internal fixation using relative and absolute risk measures. We followed the meta-analysis of observational studies in epidemiology guidelines and the Cochrane handbook. We searched specific databases in November 2021. The outcomes of interest were failed internal fixation and cut-out. We pooled the odds ratios and 95% confidence intervals using a random-effects model and calculated the number needed to harm for each outcome. Thirty-six studies involving 8938 patients were included. The certainty of evidence in the association between postoperative radiographic findings and failed internal fixation or cut-out was mainly low or very low except for the association between intramedullary malreduction on the anteromedial cortex and failed internal fixation. Moderate certainty of evidence supported that intramedullary malreduction on the anteromedial cortex was associated with failed internal fixation. Most postoperative radiographic findings on immediate postoperative radiographs for trochanteric fractures were uncertain as prognostic factors for failed internal fixations.

Liquid Biopsy Targeting Monocarboxylate Transporter 1 on the Surface Membrane of Tumor-Derived Extracellular Vesicles from Synovial Sarcoma.

The lack of noninvasive biomarkers that can be used for tumor monitoring is a major problem for soft-tissue sarcomas. Here we describe a sensitive analytical technique for tumor monitoring by detecting circulating extracellular vesicles (EVs) of patients with synovial sarcoma (SS). The proteomic analysis of purified EVs from SYO-1, HS-SY-II, and YaFuSS identified 199 common proteins. DAVID GO analysis identified monocarboxylate transporter 1 (MCT1) as a surface marker of SS-derived EVs, which was also highly expressed in SS patient-derived EVs compared with healthy individuals. MCT1+CD9+ EVs were also detected from SS-bearing mice and their expression levels were significantly correlated with tumor volume (p = 0.003). Furthermore, serum levels of MCT1+CD9+ EVs reflected tumor burden in SS patients. Immunohistochemistry revealed that MCT1 was positive in 96.7% of SS specimens and its expression on the cytoplasm/plasma membrane was significantly associated with worse overall survival (p = 0.002). Silencing of MCT1 reduced the cellular viability, and migration and invasion capability of SS cells. This work describes a new liquid biopsy technique to sensitively monitor SS using circulating MCT1+CD9+ EVs and indicates the therapeutic potential of MCT1 in SS.

Radiographic and clinical assessment of unidirectional porous hydroxyapatite to treat benign bone tumors.

Unidirectional porous hydroxyapatite (UDPHAp) was developed as an excellent scaffold with unidirectional pores oriented in the horizontal direction with interpore connections. The purpose of this study was to assess radiographic changes and clinical outcomes and complications following UDPHAp implantation to treat benign bone tumors. We retrospectively analyzed 44 patients treated with intralesional resection and UDPHAp implantation for benign bone tumors between 2010 and 2015. Clinical and radiographic findings were evaluated postoperatively at regular follow-up visits. The mean follow-up was 49 months. Radiographic changes were classified into five stages based on bone formation in the implanted UDPHAp according to Tamai's classification. All patients showed excellent bone formation inside and around implanted UDPHAp. Absorption of UDPHAp and bone marrow cavity remodeling was identified in 20 patients at a mean of 17 months postoperatively, and was significantly more common in young patients. Preoperative cortical thinning was completely regenerated in 26 of 31 patients on average 10 months after surgery. There were no cases of delayed wound healing, postoperative infection, or allergic reaction related to implanted UDPHAp. UDPHAp is a useful bone-filling substitute for treating benign bone tumor, and the use of this material has a low complication rate.

Clinical relevance and functional significance of cell-free microRNA-1260b expression profiles in infiltrative myxofibrosarcoma.

Infiltrative tumor growth into adjacent soft tissues is a major cause of the frequent recurrence and tumor-related death of myxofibrosarcoma (MFS), but no useful biomarkers reflecting tumor burden and infiltrative growth are available. While emerging evidence suggests a diagnostic and functional role of extracellular/circulating microRNA (miRNA) in various malignant diseases, their significance in MFS patients remains unknown. Global miRNA profiling identified four upregulated miRNAs in MFS patient sera and culture media of MFS cells. Among these, serum miR-1260b level was significantly upregulated in patient serum discriminating from healthy individuals and closely correlated with clinical status and tumor dynamics in MFS-bearing mice. In addition, high miR-1260b expression in serum was correlated with radiological tail-like patterns, characteristic of the infiltrative MFS. The extracellular miR-1260b was embedded in tumor-derived extracellular vesicles (EVs) and promoted cellular invasion of MFS through the downregulation of PCDH9 in the adjacent normal fibroblasts. Collectively, circulating miR-1260b expression may represent a novel diagnostic target for tumor monitoring of this highly aggressive sarcoma. Moreover, EV-miR-1260b could act as a transfer messenger to adjacent cells and mediate the infiltrative growth of MFS, providing new insights into the mechanism of infiltrative nature via crosstalk between tumor cells and their microenvironment.

Effect of Lateral Gutter Osteophyte Resection on Correction of Varus Deformity in Arthroscopic Ankle Arthrodesis.

BACKGROUND: Recently, arthroscopic ankle arthrodesis has been performed for moderate-to-severe varus-deformed ankle osteoarthritis. However, the effect of osteophyte resection in the lateral gutter in arthroscopic ankle arthrodesis has not been clarified. We hypothesized that a varus-deviated ankle with lateral gutter osteophytes can be corrected by osteophyte resection. METHODS: Thirty-nine ankles of 38 patients were included. The mean age of patients was 70.0 (45-83) years. The patients were divided into the following groups: group with an osteophyte in the lateral gutter (osteophyte) and group with no osteophytes (nonosteophyte). Preoperative and postoperative tibiotalar angle, tibial plafond angle, and tibiotalar angle under valgus stress, as well as the Japanese Society for Surgery of the Foot (JSSF) ankle/hindfoot scale, were recorded. Twelve ankles underwent lateral gutter osteophyte resection, whereas the other 27 ankles did not require osteophyte resection. RESULTS: Preoperative tibiotalar angle was higher in the osteophyte group than in the nonosteophyte group (21.8 vs 11.2 degrees, P = .01). The tibiotalar angle in the preoperative valgus stress imaging was higher in the osteophyte group (12.9 vs 5.7, P < .01). However, the postoperative tibiotalar angle was similar between the 2 groups (7.1 vs 5.4, P = .183). JSSF ankle/hindfoot scale improved in both groups. CONCLUSION: Lateral gutter osteophyte resection enabled correction of the varus malalignment in arthroscopic ankle arthrodesis. LEVEL OF EVIDENCE: Level III, retrospective comparative series.

The Masquelet technique for septic arthritis of the small joint in the hands: Case reports.

Septic arthritis in distal interphalangeal (DIP) joints sometimes occurs in association with mucous cysts or after the surgical treatment of mallet fingers. Recently, several studies have demonstrated the effectiveness of the Masquelet technique in the treatment of bone defects caused by trauma or infection. However, only few studies have reported the use of this technique for septic arthritis in small joints of the hand, and its effectiveness in treating septic arthritis in DIP joints remains unclear. We report the clinical and radiological outcomes of three patients who were treated with the Masquelet technique for septic arthritis in DIP joints. One patient had uncontrolled diabetes and another had rheumatoid arthritis treated with methotrexate and prednisolone. The first surgical stage involved thorough debridement of the infection site, including the middle and distal phalanx. We placed an external fixator from the middle to the distal phalanx and then packed the cavity of the DIP joint with antibiotic cement bead of polymethylmethacrylate (40 g) including 2 g of vancomycin and 200 mg of minocycline. At 4-6 weeks after the first surgical stage, the infection had cleared, and the second surgical stage was performed. The external fixator and cement bead were carefully removed while carefully preserving the surrounding osteo-induced membrane. The membrane was smooth and nonadherent to the cement block. In the second surgical stage, an autogenous bone graft was harvested from the iliac bone and inserted into the joint space, within the membrane. The bone graft, distal phalanx, and middle phalanx were fixed with Kirschner wires and/or a soft wire. Despite the high risk of infection, bone union was achieved in all patients without recurrence of infection. Although the Masquelet technique requires two surgeries, it can lead to favorable clinical and radiological outcomes for infected small joints of the hand.

Clinical outcomes of treatment with locking compression plates for distal femoral fractures in a retrospective cohort.

BACKGROUND: Plate fixation is one of the standard surgical treatments for distal femoral fractures. There are few reports on the relationship between the screw position and bone union when fixing by the bridging plate (relative stability) method. METHODS: This retrospective study included 71 distal femoral fractures of 70 patients who were treated with the locking compression plate for distal femur (DePuy Synthes Co., Ltd, New Brunswick, CA, USA). The following measurements were evaluated and analyzed: (1) bone union rate, (2) bridge span length (distance between screws across the fracture), (3) plate span ratio (plate length/bone fracture length), (4) number of empty holes (number of screw holes not inserted around the fracture), and (5) medial fracture distance (bone fracture distance on the medial side of the distal femur). Patient demographics (age), comorbidities (smoking, diabetes, chronic steroid use, dialysis), and injury characteristics (AO type, open fracture, infection) were obtained for all participants. Univariate analysis was performed on them. RESULTS: Of 71 fractures, 26 fractures were simple fractures, 45 fractures were comminuted fractures, and 7 fractures resulted in non-union. Non-union rate was significantly higher in comminuted fractures with bone medial fracture distance exceeding 5 mm. Non-union was founded in simple fractures with bone medial fracture distance exceeding 2 mm, but not significant (p = 0.06). In cases with simple fractures, one non-union case had one empty hole and one non-union case had four empty holes, whereas in cases with comminuted fractures, five non-union cases had two more empty holes. CONCLUSIONS: We concluded that bone fragment distance between fracture fragments is more important than bridge span length of the fracture site and the number of empty holes. Smoking and medial fracture distance are prognostic risk factors of nonunion in distal femoral fractures treated with LCP as bridging plate.

Clinical and Functional Significance of Intracellular and Extracellular microRNA-25-3p in Osteosarcoma.

Although there is considerable evidence indicating that the dysregulation of microRNAs (miRNAs) in malignant tumors plays a role in tumor development, the overall function of miRNAs and their clinicopathological significance are not well understood. In this retrospective analysis of 45 biopsy specimens from osteosarcoma (OS) patients, we investigated the functional and clinical significance of miR-25-3p in OS, which we previously identified as a highly expressed miRNA in OS patients' serum. We observed that miR-25-3p dysregulation in human OS tissues was negatively correlated with the clinical prognosis, whereas the expression level of its target gene, Dickkopf WNT Signaling Pathway Inhibitor 3 (DKK3), was positively correlated with the clinical prognosis. Endogenous miR-25-3p upregulation promoted tumor growth, invasion, and drug resistance, which was consistent with DKK3 silencing in OS cells. In addition, secretory miR-25-3p was embedded in tumor-derived exosomes, where it promoted capillary formation and the invasion of vascular endothelial cells. Overall, our results show that miR-25-3p has intracellular and extracellular oncogenic functions as well as clinicopathological relevance in OS, indicating its potential as a novel diagnostic and therapeutic tool for the clinical management of this disease.

Circulating MicroRNA-92b-3p as a Novel Biomarker for Monitoring of Synovial Sarcoma.

The lack of useful biomarkers is a crucial problem for patients with soft tissue sarcomas (STSs). Emerging evidence has suggested that circulating microRNAs (miRNAs) in body fluids have novel impact as biomarkers for patients with malignant diseases, but their significance in synovial sarcoma (SS) patients remains unknown. Initial global miRNA screening using SS patient serum and SS cell culture media identified a signature of four upregulated miRNAs. Among these candidates, miR-92b-3p secretion from SS cells was confirmed, which was embedded within tumour-derived exosomes rather than argonaute-2. Animal experiments revealed a close correlation between serum miR-92b-3p levels and tumour dynamics. Clinical relevance was validated in two independent clinical cohorts, and we subsequently identified that serum miR-92b-3p levels were significantly higher in SS patients in comparison to that in healthy individuals. Moreover, serum miR-92b-3p was robust in discriminating patients with SS from the other STS patients and reflected tumour burden in SS patients. Overall, liquid biopsy using serum miR-92b-3p expression levels may represent a novel approach for monitoring tumour dynamics of SS.