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Background: Sarcopenia and malnutrition are increasing in older populations and are reported to be among the risk factors for functional impairment after hip fracture surgery. The aim of this study was to investigate the associations between loss of skeletal muscle mass, malnutrition, and postoperative walking ability in older adults with hip fractures. Methods: We retrospectively reviewed the medical records of patients who underwent surgery for intertrochanteric fractures between 2015 and 2020 at our institute. The psoas muscle index (PMI), the controlling nutritional status (CONUT) score, and the functional ambulation category (FAC) score were used for the evaluation of skeletal muscle mass, nutritional status, and walking ability. Patients were assigned to a disturbance gait (DG) or independent gait (IG) group based on walking ability 6 months after surgery. Using multivariate binomial logistic regression analysis, skeletal muscle mass, nutritional status, and other factors were used to predict the risk of being assigned to the DG group. Results: This study included 95 patients with a mean age of 85.2 years. Seventy patients were female. Low skeletal muscle mass was prevalent in 66 patients, 35 suffered from malnutrition, and 28 had both low skeletal muscle mass and malnutrition. Malnutrition and low skeletal muscle mass were significantly associated with postoperative gait disturbance (FACConclusions: Both skeletal muscle loss and malnutrition before surgery were risk factors for poor walking ability after intertrochanteric fracture surgery. Preventive interventions should focus on maintaining or building skeletal muscle mass and improving nutrition in older adults who are at risk of experiencing hip fractures to optimize postoperative functional outcomes if surgery is required.

Seat belts with shoulder restraints have decreased the frequency of life-threatening severe chest trauma caused by car accidents. However, the introduction of seat belt legislation has led to an increase in a specific pattern of blunt trauma known as seat belt syndrome, which includes rib, clavicle, spine, and sternum fractures, as well as rupture of hollow pelvic and abdominal viscera, mesenteric tears, and major vessel injuries. The shoulder restraint part of the three-point seat belt commonly rests near or over the female and male breast. A 54-year-old female presented to our emergency department complaining of swelling and pain in her left breast immediately after a traffic accident. The patient had used a seat belt with a shoulder restraint. Bruising was noted along her chest where there had been seat belt contact. Her breast hematoma was most likely caused by breast tissue compression between her rib and the seat belt. Contrast-enhanced computed tomography demonstrated a sizable breast hematoma with active arterial contrast material extravasation, as well as multiple left rib fractures. The patient was conservatively treated with analgesic and anti-inflammatory drugs. Complete resolution was achieved, and her breast returned to its normal appearance. Although endovascular treatment and surgical hemostasis have been proposed for the treatment of breast injuries with active bleeding, conservative treatment such as compression hemostasis may be feasible.

BACKGROUND: Postoperative thrombosis of the external iliac artery (EIA) following open reduction and internal fixation for acetabular fracture is extremely rare. PURPOSE: To report a patient with EIA thrombosis following open reduction and internal fixation using the modified ilioinguinal approach for acetabular fractures. STUDY DESIGN: This is a case report of a 69-year-old male with a left acetabular fracture who was treated surgically. METHODS: A 69-year-old male presented with left hip pain after a 1.5-m fall. Radiographs revealed left acetabular anterior wall and posterior hemitransverse fractures with dome impaction. Computed tomography (CT) showed atherosclerotic changes in many arteries. Open reduction and internal fixation were performed using the modified ilioinguinal approach. Adhesion around the external iliac vessels was severe, and the external iliac vein (EIV) ruptured during exposure. After EIV repair, anatomical reduction was achieved and the fracture was fixed using a reconstruction plate. Nine hours after surgery, the left lower limb showed acute ischemic symptoms. Contrast-enhanced CT indicated complete occlusion of the left EIA. The patient was immediately taken for a thrombectomy via EIA cut-down using a Fogarty catheter. Postoperatively, he had palpable dorsalis pedis and posterior tibial pulses; however, post-reperfusion compartment syndrome developed. Fasciotomy of the left leg was performed. RESULTS: At the 2-year and 4-month follow-up, he was pain-free in his hip and leg. Although he was walking with a cane, activity was limited due to a mild foot drop. CONCLUSIONS: It is very important for surgeons to consider EIA thrombosis as a potential complication following open reduction and internal fixation. In this case, EIA thrombosis could be explained by preoperative atherosclerotic changes and intraoperative vascular handling procedures. Preoperative screening and management, and meticulous surgical procedures are necessary for patients with a high risk of thrombosis.

BackgroundPatients with traumatic cardiac arrest (TCA) are known to have poor prognoses. In 2003, the joint committee of the National Association of EMS Physicians and the American College of Surgeons Committee on Trauma proposed stopping unsuccessful cardiopulmonary resuscitation (CPR) sustained for > 15 min after TCA. However, in 2013, a specific time-limit for terminating resuscitation was dropped, due to the lack of conclusive studies or data. We aimed to define the association between emergency medical services transport time and survival to demonstrate the survival curve of TCA.MethodsA retrospective review of the Japan Trauma Data Bank. Inclusion criteria were age ≥ 16, at least one trauma with Abbreviated Injury Scale score (AIS) ≥ 3, and CPR performed in a prehospital setting. Exclusion criteria were burn injury, AIS score of 6 in any region, and missing data. Estimated survival rate and risk ratio for survival were analyzed according to transport time for all patients. Analysis was also performed separately on patients with sustained TCA at arrival.ResultsOf 292,027 patients in the database, 5336 were included in the study with 4141 sustained TCA. Their median age was 53 years (interquartile range (IQR) 36–70), and 67.2% were male. Their median Injury Severity Score was 29 (IQR 22–41), and median transport time was 11 min (IQR 6–17). Overall survival after TCA was 4.5%; however, survival of patients with sustained TCA at arrival was only 1.2%. The estimated survival rate and risk ratio for sustained TCA rapidly decreased after 15 min of transport time, with estimated survival falling below 1%.ConclusionThe chances of survival for sustained TCA declined rapidly while the patient is transported with CPR support. Time should be one reasonable factor for considering termination of resuscitation in patients with sustained TCA, although clinical signs of life, and type and severity of trauma should be taken into account clinically.

CD4+ CD25+ regulatory T cells (Treg), an essential subset for preventing autoimmune diseases, is implicated as a negative regulator in anti-tumor immunity. We found that metformin (Met) reduced tumor-infiltrating Treg (Ti-Treg), particularly the terminally-differentiated CD103+ KLRG1+ population, and also decreased effector molecules such as CTLA4 and IL-10. Met inhibits the differentiation of naïve CD4+ T cells into inducible Treg (iTreg) by reducing forkhead box P3 (Foxp3) protein, caused by mTORC1 activation that was determined by the elevation of phosphorylated S6 (pS6), a downstream molecule of mTORC1. Rapamycin and compound C, an inhibitor of AMP-activated protein kinase (AMPK) restored the iTreg generation, further indicating the involvement of mTORC1 and AMPK. The metabolic profile of iTreg, increased Glut1-expression, and reduced mitochondrial membrane-potential and ROS production of Ti-Treg aided in identifying enhanced glycolysis upon Met-treatment. The negative impact of Met on Ti-Treg may help generation of the sustained antitumor immunity., Highlights • Metformin downregulates CD4+ CD25+ regulatory T cells (Treg) in tumors but not in peripheral lymphoid tissues. • Metformin administration results in activation of mTORC1 in Treg in tumors. • Metformin administration results in elevation of glycolysis, while suppressing oxidative phosphorylation in Treg in tumors. CD4+ CD25+ regulatory T cells (Treg) is a negative regulator that inhibits T cell mediated anti-tumor immunity. Therefore, targeting Treg is one of the important therapeutic intervention in cancers. We found that metformin reduces Treg in the number and the function in tumors. Metabolism of Treg is usually dependent on oxidative phosphorylation through fatty acid oxidation (FAO). However, metformin treatment causes metabolic reprogramming of Treg toward the glycolysis, resulting in the failure in survival in tumors. Metformin as a metabolic modifier for Treg may contribute to generation of sustained anti-tumor immunity, combined with currently emerging cancer immunotherapy.

// Tomohiro Fujiwara 1, 2, 3 , Koji Uotani 1 , Aki Yoshida 1 , Takuya Morita 1 , Yutaka Nezu 3 , Eisuke Kobayashi 4 , Akihiko Yoshida 5 , Takenori Uehara 1 , Toshinori Omori 1 , Kazuhisa Sugiu 1 , Tadashi Komatsubara 1 , Ken Takeda 6 , Toshiyuki Kunisada 7 , Machiko Kawamura 8 , Akira Kawai 4 , Takahiro Ochiya 3 , Toshifumi Ozaki 1 1 Department of Orthopedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan 2 Center of Innovative Medicine, Okayama University Hospital, Okayama, Japan 3 Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan 4 Department of Musculoskeletal Oncology, National Cancer Center Hospital, Tokyo, Japan 5 Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan 6 Department of Intelligent Orthopaedic System, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan 7 Department of Medical Materials for Musculoskeletal Reconstruction, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan 8 Department of Hematology, Saitama Cancer Center, Saitama, Japan Correspondence to: Tomohiro Fujiwara, email: tomomedvn@gmail.com Keywords: microRNA, liquid biopsy, osteosarcoma, biomarker, prognosis Received: September 24, 2016 Accepted: February 27, 2017 Published: March 23, 2017 ABSTRACT Background: Emerging evidence has suggested that circulating microRNAs (miRNAs) in body fluids have novel diagnostic and prognostic significance for patients with malignant diseases. The lack of useful biomarkers is a crucial problem of bone and soft tissue sarcomas; therefore, we investigated the circulating miRNA signature and its clinical relevance in osteosarcoma. Methods: Global miRNA profiling was performed using patient serum collected from a discovery cohort of osteosarcoma patients and controls and cell culture media. The secretion of the detected miRNAs from osteosarcoma cells and clinical relevance of serum miRNA levels were evaluated using in vitro and in vivo models and a validation patient cohort. Results: Discovery screening identified 236 serum miRNAs that were highly expressed in osteosarcoma patients compared with controls, and eight among these were also identified in the cell culture media. Upregulated expression levels of miR-17-5p and miR-25-3p were identified in osteosarcoma cells, and these were abundantly secreted into the culture media in tumor-derived exosomes. Serum miR-25-3p levels were significantly higher in osteosarcoma patients than in control individuals in the validation cohort, with favorable sensitivity and specificity compared with serum alkaline phosphatase. Furthermore, serum miR-25-3p levels at diagnosis were correlated with patient prognosis and reflected tumor burden in both in vivo models and patients; these associations were more sensitive than those of serum alkaline phosphatase. Conclusions: Serum-based circulating miR-25-3p may serve as a non-invasive blood-based biomarker for tumor monitoring and prognostic prediction in osteosarcoma patients.

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., 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...

CD11b+ myeloid subpopulations, including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), play crucial roles in the suppression of T-cell-mediated anti-tumor immunity. Regulation of these cell types is a primary goal for achieving efficient cancer immunotherapy. We found that metformin (Met) induces CD11b+-cell-mediated growth inhibition of a K7M2neo osteosarcoma independent of T cells, as growth inhibition of K7M2neo was still observed in wild-type (WT) mice depleted of T cells by antibodies and in SCID; this contrasted with the effect of Met on Meth A fibrosarcoma, which was entirely T-cell-dependent. Moreover, the inhibitory effect seen in SCID was abrogated by anti-CD11b antibody injection. PMN-MDSCs were significantly reduced in both spleens and tumors following Met treatment. In TAMs, production of IL-12 and TNF-α, but not IL-10, became apparent, and elevation of MHC class II with reduction of CD206 was observed, indicating a shift from an M2- to M1-like phenotype via Met administration. Metabolically, Met treatment decreased basal respiration and the oxygen consumption rate (OCR)/extracellular acidification rate (ECAR) ratio of CD11b+ cells in tumors, but not in the spleen. In addition, decreased reactive oxygen species (ROS) production and proton leakage in MDSCs and TAMs were consistently observed in tumors. Uptake of both 2-deoxy-2-d-glucose (2-NBDG) and BODIPY® decreased in MDSCs, but only BODIPY® incorporation was decreased in TAMs. Overall, our results suggest that Met redirects the metabolism of CD11b+ cells to lower oxidative phosphorylation (OXPHOS) while elevating glycolysis, thereby pushing the microenvironment to a state that inhibits the growth of certain tumors., Metformin reprograms myeloid cell metabolism to enhance anti-tumor immunity

Although multimodal therapies including surgery, chemotherapy, and radiotherapy have improved clinical outcomes of patients with bone and soft tissue sarcomas, the prognosis of patients has plateaued over these 20 years. Immunotherapies have shown the effectiveness for several types of advanced tumors. Immunotherapies, such as cytokine therapies, vaccinations, and adoptive cell transfers, have also been investigated for bone and soft tissue sarcomas. Cytokine therapies with interleukin-2 or interferons have limited efficacy because of their cytotoxicities. Liposomal muramyl tripeptide phosphatidylethanolamine (L-MTP-PE), an activator of the innate immune system, has been approved as adjuvant therapeutics in combination with conventional chemotherapy in Europe, which has improved the 5-year overall survival of patients. Vaccinations and transfer of T cells transduced to express chimeric antigen receptors have shown some efficacy for sarcomas. Ipilimumab and nivolumab are monoclonal antibodies designed to inhibit immune checkpoint mechanisms. These antibodies have recently been shown to be effective for patients with melanoma and also investigated for patients with sarcomas. In this review, we provide an overview of various trials of immunotherapies for bone and soft tissue sarcomas, and discuss their potential as adjuvant therapies in combination with conventional therapies.

Background: We have recently shown that metformin, a prescribed drug for type 2 diabetes, can increase the number of CD8+ tumor infiltrating lymphocytes (CD8+ TILs) that can produce triple cytokines, thus, IFN-ã, IL-2 and TNF-á in mouse models. Increased numbers of such multifunctional CD8+ TILs have well correlated with tumor retardation, suggesting an underlying mechanism of metformin in tumor immunity. In the current study, we examined the effects of direct exposure of metformin in vitro to CD8+ T cells of cancer patients. Methods: Peripheral blood mononuclear cells (PBMC) from cancer patients and healthy volunteers were obtained for the analysis. We cultured the PBMC with or without metformin overnight, followed by stimulation with phorbol 12-myristate 13-acetate (PMA) / ionomycin in vitro in various glucose concentrations for 6 hours. Expressions of markers for immune-check points (PD-1 and Tim-3) were examined together with accumulated intracellular cytokines, IFN-ã, IL-2 and TNF-á by flow cytometry analysis. Results: PD-1 and Tim-3 expressions of cancer patients’ PBMC were apparently higher than those of healthy volunteers’. Increased production of multiple cytokines was observed in CD8+ T cells of almost all cancer patients by metformin pretreatment, whereas no changes were detected in the samples from healthy volunteers. Moreover, deprivation of glucose clearly limited the production of cytokines on CD8 + T cells in a cancer patient. These results suggested patient’ CD8 + T cells showed lower activity of glycolysis compared with a healthy volunteer and metformin might stimulate glycolysis followed by reversion of mitochondrial respiration in exhausted CD8 + T cells. Conclusion: Metformin treatment might be useful in reversion of exhausted CD8+T cells in cancer bearing patients. Citation Format: Mototsugu Watanabe, Shingo Eikawa, Takenori Uehara, Yuki Kunisada, Shinichi Toyooka, Shinichiro Miyoshi, Heiichiro Udono. Metformin improves multiple cytokine producing ability of exhausted peripheral CD8+ T cells of cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4865.

INTRODUCTION Synovial sarcoma (SS) is characterized by the SS18-SSX fusion gene, and the presence of this chromosomal translocation is clinically useful as a diagnostic marker. However, SS18-SSX does not reflect disease progression and can be detected only with tumor specimens surgically resected. Therefore, novel non-invasive biomarkers would help clinicians to diagnose or detect tumor progression, which could improve patients’ prognosis. We investigated the expression of the serum microRNA (miRNA) of SS patients, and evaluated its significance using in vitro and in vivo experimental models. METHODS In the screening phase, global analysis by miRNA microarray was performed using extracted RNA derived from patients’ serum and culture medium. The serum samples were collected from SS patients, age-matched non-SS patients, and healthy volunteers. The culture mediums were obtained from human SS cell lines and human mesenchymal stem cells (hMSCs) as controls. In the validation phase, the expression levels of miRNA derived from culture medium were evaluated by quantitative real-time PCR (qRT-PCR) to determine the secretory potential of miRNA candidates. SS cell lines and hMSCs were cultured and the culture medium was collected at 0, 24, and 48 hours. Furthermore, serum miRNA levels of SS-bearing mice were analyzed by qRT-PCR according to the tumor growth and tumor resection. RESULTS A miRNA microarray profiling revealed that four miRNAs were significantly highly expressed (p < 0.05) in SS patients’ serum and cell culture medium, compared to control samples, which were selected as candidates for further analysis. We then identified that one miRNA expression among four candidates in the culture medium from all SS cell lines increased with time and with increasing numbers of tumor cells. These data suggested that the detected miRNA is a secretory miRNA derived from SS cells. Next, we investigated whether the serum expression of the detected miRNA correlates with tumor progression using SS-bearing mice, which demonstrated that the detected miRNA expression in mice serum increased size-dependently (R = 0.78, p < 0.05). Moreover, it significantly reduced after tumor resection (p < 0.05), indicating that the detected serum miRNA level reflects tumor burden in vivo. Furthermore, the expression of the detected miRNA in serum collected from SS patients was significantly higher compared with that in serum collected from other soft tissue sarcoma patients. CONCLUSIONS Our results indicate that the serum expression of the detected miRNA could be useful for tumor monitoring as a non-invasive biomarker for SS. Moreover, the detected miRNA may contribute to SS progression. Citation Format: Koji Uotani, Tomohiro Fujiwara, Aki Yoshida, Takuya Morita, Yutaka Nezu, Tadashi Komatsubara, Kazuhisa Sugiu, Takenori Uehara, Toshinori Omari, Ken Takeda, Toshiyuki Kunisada, Junya Toguchida, Akira Kawai, Takahiro Ochiya, Toshifumi Ozaki. Circulating cell-free microRNA as a novel biomarker for synovial sarcoma patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 969.