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.

Ten-year outcome of unilateral leg replantation after bilateral lower leg amputation following traumatic injury: A case report.

The absolute indications for lower limb replantation are not unequivocally established; rather, this procedure is still challenging and controversial. We report a case of a young male who underwent bilateral leg amputation, followed by unilateral replantation. The patient demonstrated good 10-year outcomes. A 23-year-old man had both of his lower legs crushed by heavy machinery that fell from the back of a truck, leading to amputation of bilateral lower limbs. Although bilateral amputation was recommended due to severe contusion on both sides, the patient and his family strongly requested replantation of the right leg, and surgery was started approximately 3 h after the injury. In addition to the emergency replantation, six surgeries were performed thereafter. Five months after the first surgery, the patient was fitted with a left lower leg prosthesis and started gait training. He was discharged 8 months later. Ten years after the replantation, the patient is satisfied with his leg. He has a normal gait with a prosthesis and has integrated into society with no functional deficit. There are still no clear standards for replantation after leg amputation, and individual decisions must be made based on the severity of the injury and the patient's general condition. In this case, we respected the patient's strong will to preserve the right leg and decided on the treatment plan. As a result, the patient was highly satisfied, and the spared right leg facilitated the patient's physical and mental recovery.

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.

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.

Rare pancreatic metastasis of undifferentiated pleomorphic sarcoma originating from the pelvis: A case report.

INTRODUCTION: Undifferentiated pleomorphic sarcoma (UPS) is a reclassification of malignant fibrous histiocytoma by the World Health Organization in 2002. UPS, the most common soft tissue sarcoma reported in adults, mostly recurs as lung disease. Pancreatic metastasis of UPS is extremely rare. We present a rare case of pelvic UPS with pancreatic metastasis. PRESENTATION OF CASE: A 69-year-old man was identified as having mediastinal lymphadenopathy on follow-up computed tomography (CT), 2 years after undergoing surgery for gastric adenocarcinoma (pT4aN3M0/IIIC). Subsequent positron emission tomography-CT (PET/CT) indicated pelvic lesions and magnetic resonance imaging (MRI) showed multiple tumors of the left pubis and femur. Histopathology of diagnostic thoracoscopic lymph node dissection and CT-guided needle biopsy of the left pubic lesion showed UPS. Systemic chemotherapy and targeted molecular therapy reduced multiple pelvic and metastatic tumors. Left pubic primary lesion contraction was achieved with intensity-modulated radiation therapy. CT performed 4 years after treatment initiation showed a 40-mm pancreatic head mass. Lesions other than the pancreatic tumor were in remission, and a pancreatoduodenectomy was performed. Histological analysis confirmed pancreatic metastasis of anaplastic pleomorphic sarcoma. DISCUSSION: Reports of pelvic UPS with pancreatic metastasis, as that of the present case, are extremely rare. UPS is malignant potential tumor, and complete excision is the first treatment option, while the usefulness of chemotherapy or radiation therapy remains uncertain. CONCLUSIONS: Complete resection is vital for local control in pancreatic metastasis of UPS. Sites of recurrence are rare; hence, patients must be carefully followed up.

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.

Mini-open excision of osteoid osteoma using intraoperative O-arm/Stealth navigation.

BACKGROUND: Although osteoid osteomas have traditionally been treated by surgical excision, radiofrequency ablation (RFA) has gained favor as a less invasive procedure. However, RFA is contraindicated for osteoid osteomas close to the skin or crucial neurovascular structures, and is not covered by national health insurance in Japan. The aim of the present study was to evaluate the efficacy of surgical excision of osteoid osteomas using intraoperative navigation. METHODS: We performed a retrospective review of five patients with osteoid osteoma who underwent a mini-open excision using O-arm/Stealth navigation at our institution. The osteoid osteomas were excised using a cannulated cutter or curetted out with the assistance of navigation. RESULTS: Complete excision was achieved in all patients, which was confirmed by pathological examination. The mean skin incision was 2.1 cm (range, 1.5 to 3.0 cm) and the mean duration required for setup three-dimensional image was 15 min (range, 12 to 20 min). Although the mean visual analog scale score was 7 (range, 4 to 8) before surgery, all patients experienced relief from their characteristic pain immediately after surgery, with the mean scores of 2.2 (range, 1 to 3) and 0 at 2 days and 4 weeks after surgery, respectively. There was no intra-operative complication related to the navigation and no recurrence was observed during the mean follow-up period of 25 months (range, 13 to 33 months). CONCLUSIONS: Mini-open excision using intraoperative O-arm/Stealth navigation is a safe and accurate procedure for patients with osteoid osteoma, which could cover the limitation of RFA.

The morphology of the femur in elderly Japanese females: Analysis using 3D-CT.

BACKGROUND: While various implants are currently used for the treatment of femoral trochanteric fractures in Japan, 'mismatches' have been known to occur between patient and implant type. The purpose of this study is to identify morphological characteristics of elderly Japanese females, both in terms of the shape of proximal femur and its anterior curvature in order to evaluate the suitability of implants for treatment of femoral trochanteric fractures using 3D-computed tomography (CT) scanning. METHODS: This study used CT scan data taken from 50 elderly females (aged 70 years or older). Neck-shaft (NS) angle and height of the greater trochanter (GT) were measured under defined conditions (TPI: theoretical plane to place implant). Anterior curvature of the femoral shaft was also measured. RESULTS: On average, the NS angle was found to be 128.1° and GT height was 62.4 mm. Average curvature radius was 1040 mm. As for the NS angle, the centrum-collum-diaphysis angles of existing implants (125° or 130°) are reasonable. In elderly Japanese patients, the proximal femur shows specific characteristics. As GT height is very short, the implant may easily interfere with the lateral cortex. Additionally, the curvature radius calculated (1040 mm) was smaller than that of past reports, indicating strong curvature in the Japanese elderly. CONCLUSION: Our measurement results are potentially useful in the avoidance of intraoperative trouble caused by mismatch of implants.

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.