Clinical Application of Unidirectional Porous Hydroxyapatite to Bone Tumor Surgery and Other Orthopedic Surgery.

Unidirectional porous hydroxyapatite (UDPHAp) was developed as a remarkable scaffold characterized by a distinct structure with unidirectional pores oriented in the horizontal direction and connected through interposes. We evaluated the radiographic changes, clinical outcomes, and complications following UDPHAp implantation for the treatment of bone tumors. Excellent bone formation within and around the implant was observed in all patients treated with intralesional resection and UDPHAp implantation for benign bone tumors. The absorption of UDPHAp and remodeling of the bone marrow space was observed in 45% of the patients at a mean of 17 months postoperatively and was significantly more common in younger patients. Preoperative cortical thinning was completely regenerated in 84% of patients at a mean of 10 months postoperatively. No complications related to the implanted UDPHAp were observed. In a pediatric patient with bone sarcoma, when the defect after fibular resection was filled with UDPHAp implants, radiography showed complete resorption of the implant and clear formation of cortex and marrow in the resected part of the fibula. The patient could walk well without crutches and participate in sports activities. UDPHAp is a useful bone graft substitute for the treatment of benign bone tumors, and the use of this material has a low complication rate. We also review and discuss the potential of UDPHAp as a bone graft substitute in the clinical setting of orthopedic surgery.

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.

Ideal insertion point and projection of the infra-acetabular screw in acetabular fracture surgery.

BACKGROUND: In acetabular fracture surgery, an infra-acetabular screw (IAS) is inserted from the anterior to the posterior column through the infra-acetabular corridor to stabilize both columns. Although the IAS is useful for increasing fixation strength, proper placement requires proficiency and often results in extraosseous screw penetration. The complex anatomy of the infra-acetabular corridor and difficult intraoperative detection of the ideal insertion point and angle make proper placement of the IAS challenging. This study aimed to detect the ideal insertion point and angle of the IAS based on anatomical landmarks that can be directly identified intraoperatively. METHODS: We retrospectively reviewed the pelvic CT of 50 adults who underwent serial slice CT imaging. The pelvic inlet plane (PIP), which contains the anterior border of both the sacroiliac joint and posterior superior edge of the pubic symphysis, was used as the reference plane for the pelvic coordinate system to simulate the ideal insertion of IAS. The distance from the posterior superior edge of the pubic symphysis to the ideal insertion point of the IAS (IAS distance) and the angle and length of the IAS that could be inserted from the ideal insertion point were measured. RESULTS: The mean IAS distance was 61.0 ± 5.7 mm (57.6 ± 4.3 mm in men and 64.4 ± 4.9 mm in women). The mean angle between ideal IAS and yz-plane on the outlet view (α-angle) was 8.4 ± 6.6 ° (6.4 ± 5.6° in men and 10.5 ± 7.0° in women). The mean angle between ideal IAS and y-axis on the yz-plane (ß-angle) was 86.5 ± 10.6 ° (86.0 ± 10.3° in men and 87.0 ± 10.9° in women). The length of IAS was 97.1 ± 4.7 mm in men and 89.2 ± 3.6 mm in women. CONCLUSION: The IAS ideal insertion point detected as a distance from the pubic symphysis may aid in the proper insertion of the IAS during surgery. The insertion angle was parallel or tilted 10 ° laterally to the longitudinal axis in the pelvic outlet plane and almost perpendicular to the PIP in the sagittal plane when inserted from the ideal insertion point.

Associations among Preoperative Malnutrition, Muscle Loss, and Postoperative Walking Ability in Intertrochanteric Fractures: A Retrospective Study.

Sarcopenia and malnutrition are increasing in older adults and are reported risk factors for functional impairment after hip fracture surgery. This study aimed to investigate the associations between skeletal muscle mass loss, malnutrition, and postoperative walking ability in patients with hip fracture. We retrospectively reviewed patients who underwent intertrochanteric fracture surgery at our institute. The psoas muscle index, controlling nutritional status score, and functional ambulation category (FAC) were used to evaluate skeletal muscle mass, nutritional status, and walking ability, respectively. Six months after surgery, walking ability was assessed as either "gait disturbance" or "independent gait". Multivariate binomial logistic regression analysis, with skeletal muscle mass, nutritional status, and other factors, was used to predict the risk of being assigned to the gait disturbance group. This study included 95 patients (mean age, 85.2 years; 70 women). Sixty-six patients had low skeletal muscle mass, 35 suffered from malnutrition, and 28 had both. Malnutrition and low skeletal muscle mass were significantly associated with postoperative gait disturbance (FAC < 3). Preoperative low skeletal muscle mass and malnutrition were risk factors for postoperative poor walking ability. Further preventive interventions focusing on skeletal muscle mass and nutritional status are required.

Comparison of screw versus locking plate fixation via sinus tarsi approach for displaced intra-articular calcaneal fractures.

BACKGROUND: The optimal treatment of displaced intra-articular calcaneal fractures (DIACF) is controversial. This study compared the fixation stability of screws and locking plates in DIACF treated via the sinus tarsi approach (STA). METHODS: We retrospectively evaluated 118 DIACF cases treated via STA and extracted data that could affect treatment outcomes. Loss of Böhler's angle after surgery was measured to compare fixation stability. RESULTS: The loss of Böhler's angles was significantly smaller in the locking plate group than in the screw group (2.6 ± 2.7º vs. 5.6 ± 5.3º, P < 0.01). There was no difference in the clinical outcomes between the groups. On multivariate logistic regression analysis, screw fixation was significantly associated with loss of Böhler's angle by> 10º (odds ratio, 8.63; 95% confidence interval, 1.16-64.4; P < 0.05). CONCLUSIONS: Locking plate fixation is more reliable than screw fixation for preventing correction loss in DIACF treated via STA. LEVEL OF EVIDENCE: III.

CSF1/CSF1R Signaling Inhibitor Pexidartinib (PLX3397) Reprograms Tumor-Associated Macrophages and Stimulates T-cell Infiltration in the Sarcoma Microenvironment.

Colony-stimulating factor 1 (CSF1) is a primary regulator of the survival, proliferation, and differentiation of monocyte/macrophage that sustains the protumorigenic functions of tumor-associated macrophages (TAMs). Considering current advances in understanding the role of the inflammatory tumor microenvironment, targeting the components of the sarcoma microenvironment, such as TAMs, is a viable strategy. Here, we investigated the effect of PLX3397 (pexidartinib) as a potent inhibitor of the CSF1 receptor (CSF1R). PLX3397 was recently approved by the Food and Drug Administration (FDA) to treat tenosynovial giant cell tumor and reprogram TAMs whose infiltration correlates with unfavorable prognosis of sarcomas. First, we confirmed by cytokine arrays of tumor-conditioned media (TCM) that cytokines including CSF1 are secreted from LM8 osteosarcoma cells and NFSa fibrosarcoma cells. The TCM, like CSF1, stimulated ERK1/2 phosphorylation in bone marrow-derived macrophages (BMDMs), polarized BMDMs toward an M2 (TAM-like) phenotype, and strikingly promoted BMDM chemotaxis. In vitro administration of PLX3397 suppressed pERK1/2 stimulation by CSF1 or TCM, and reduced M2 polarization, survival, and chemotaxis in BMDMs. Systemic administration of PLX3397 to the osteosarcoma orthotopic xenograft model significantly suppressed the primary tumor growth and lung metastasis, and thus improved metastasis-free survival. PLX3397 treatment concurrently depleted TAMs and FOXP3+ regulatory T cells and, surprisingly, enhanced infiltration of CD8+ T cells into the microenvironments of both primary and metastatic osteosarcoma sites. Our preclinical results show that PLX3397 has strong macrophage- and T-cell-modulating effects that may translate into cancer immunotherapy for bone and soft-tissue sarcomas.

Role of Tumor-Associated Macrophages in Sarcomas.

Sarcomas are complex tissues in which sarcoma cells maintain intricate interactions with their tumor microenvironment. Tumor-associated macrophages (TAMs) are a major component of tumor-infiltrating immune cells in the tumor microenvironment and have a dominant role as orchestrators of tumor-related inflammation. TAMs promote tumor growth and metastasis, stimulate angiogenesis, mediate immune suppression, and limit the antitumor activity of conventional chemotherapy and radiotherapy. Evidence suggests that the increased infiltration of TAMs and elevated expression of macrophage-related genes are associated with poor prognoses in most solid tumors, whereas evidence of this in sarcomas is limited. Based on these findings, TAM-targeted therapeutic strategies, such as inhibition of CSF-1/CSF-1R, CCL2/CCR2, and CD47/SIRPα, have been developed and are currently being evaluated in clinical trials. While most of the therapeutic challenges that target sarcoma cells have been unsuccessful and the prognosis of sarcomas has plateaued since the 1990s, several clinical trials of these strategies have yielded promising results and warrant further investigation to determine their translational benefit in sarcoma patients. This review summarizes the roles of TAMs in sarcomas and provides a rationale and update of TAM-targeted therapy as a novel treatment approach for sarcomas.