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.

Adrenergic microenvironment driven by cancer-associated Schwann cells contributes to chemoresistance in patients with lung cancer.

Doublecortin (DCX)-positive neural progenitor-like cells are purported components of the cancer microenvironment. The number of DCX-positive cells in tissues reportedly correlates with cancer progression; however, little is known about the mechanism by which these cells affect cancer progression. Here we demonstrated that DCX-positive cells, which are found in all major histological subtypes of lung cancer, are cancer-associated Schwann cells (CAS) and contribute to the chemoresistance of lung cancer cells by establishing an adrenergic microenvironment. Mechanistically, the activation of the Hippo transducer YAP/TAZ was involved in the acquisition of new traits of CAS and DCX positivity. We further revealed that CAS express catecholamine-synthesizing enzymes and synthesize adrenaline, which potentiates the chemoresistance of lung cancer cells through the activation of YAP/TAZ. Our findings shed light on CAS, which drive the formation of an adrenergic microenvironment by the reciprocal regulation of YAP/TAZ in lung cancer tissues.

Changes in Spinal Instability After Conventional Radiotherapy for Painful Vertebral Bone Metastases.

OBJECTIVE: Precise assessment of spinal instability is critical before and after radiotherapy (RT) for evaluating the effectiveness of RT. Therefore, we retrospectively evaluated the efficacy of RT in spinal instability over a period of 6 months after RT, utilizing the spinal instability neoplastic score (SINS) in patients with painful spinal metastasis. We retrospectively evaluated 108 patients who received RT for painful vertebral metastasis in our institution. Mechanical pain at metastatic vertebrae, radiological responses of irradiated vertebrae, and spinal instability were assessed. Follow-up assessments were done at the start of and at intervals of 1, 2, 3, 4, and 6 months after RT, with the pain disappearing in 67%, 85%, 93%, 97%, and 100% of the patients, respectively. The median SINS were 8, 6, 6, 5, 5, and 4 at the beginning and after 1, 2, 3, 4, and 6 months of RT, respectively. Multivariate analysis revealed that posterolateral involvement of spinal elements (PLISE) was the only risk factor for continuous potentially unstable/unstable spine at 1 month. In conclusion, there was improvement of pain, and recalcification results in regaining spinal stability over time after RT although vertebral body collapse and malalignment occur in some irradiated vertebrae. Clinicians should pay attention to PLISE in predicting continuous potentially unstable/unstable spine.

Role of catecholamine synthases in the maintenance of cancer stem-like cells in malignant peripheral nerve sheath tumors.

Malignant peripheral nerve sheath tumors (MPNSTs) are malignant tumors that are derived from Schwann cell lineage around peripheral nerves. As in many other cancer types, cancer stem cells (CSCs) have been identified in MPNSTs, and they are considered the cause of treatment resistance, recurrence, and metastasis. As an element defining the cancer stemness of MPNSTs, we previously reported a molecular mechanism by which exogenous adrenaline activates a core cancer stemness factor, YAP/TAZ, through ß2 adrenoceptor (ADRB2). In this study, we found that MPNST cells express catecholamine synthases and that these enzymes are essential for maintaining cancer stemness, such as the ability to self-renew and maintain an undifferentiated state. Through gene knockdown and inhibition of these enzymes, we confirmed that catecholamines are indeed synthesized in MPNST cells. The results confirmed that catecholamine synthase knockdown in MPNST cells reduces the activity of YAP/TAZ. These data suggest that a mechanism of YAP/TAZ activation by de novo synthesized adrenaline, as well as exogenous adrenaline, may exist in the maintenance of cancer stemness of MPNST cells. This mechanism not only helps to understand the pathology of MPNST, but could also contribute to the development of therapeutic strategies for MPNST.

Effect of hardware removal and second-look arthroscopy after open-wedge high tibial osteotomy.

INTRODUCTION: Open-wedge high tibial osteotomy (OWHTO) is the standard and safe procedure for medial compartment osteoarthritis. Although hardware removal (HWR) is performed after post-OWHTO bone union, the effects of HWR on OWHTO have been rarely reported. We hypothesised that HWR would improve range of motion (ROM) and implant-related complications. Thus, this study aimed to investigate the effects of HWR on postoperative ROM, the Japan Orthopaedic Association (JOA) score/visual analogue scale (VAS) score and hardware-related complications after OWHTO. METHODS: Patients who underwent OWHTO between January 2016 and June 2018 and HWR were retrospectively reviewed. To perform OWHTO, locking plates and prosthetic bone were used to achieve optimal stabilisation of biplanar osteotomy. HWR was performed after a second-look arthroscopy through the previous skin incision. For clinical evaluation, the JOA score, VAS score, and ROM were assessed before and 1 year after HWR using the Wilcoxon rank test. Logistic regression analysis was performed to identify the predictors of post-HWR improvement. RESULTS: Of 98 knees examined (91 patients), 80 (73 patients; 39 men and 34 women) were included. At the time of OWHTO, mean age was 64.0 ± 9.7 years and body mass index, 25.5 ± 3.1 kg/m2; Kellgren-Lawrence (KL) grade 1 was seen in 20 cases, KL-2 in 46, and KL-3 in 14. Mean periods between OWHTO and HWR were 13.4 ± 2.0 months, and 11.9 ± 1.2 months between HWR and evaluation. The JOA score and flexion angle significantly improved after HWR (The JOA score: p = 0.026 flexion angle: p < 0.001); however, the VAS score and extension angle did not (VAS score: p = 0.162, extension angle: p = 0.934). Hardware irritation was observed in four cases (5%), which improved after HWR. Logistic regression analysis revealed that lower preoperative KL grade and flexion angle were predictors of improvement after HWR [KL grade: p = 0.008; odds ratio 3.244, 95% confidence interval (CI) 1.350-7.794; flexion angle: p < 0.001; odds ratio 1.150, 95% CI 1.062-1.245]. CONCLUSION: HWR improves flexion angle, clinical outcomes and hardware-related complications after OWHTO. Preoperative KL grade and flexion angle are predictors of improvement after HWR in patients who have undergone OWHTO.

Results of resection of forearm soft tissue sarcoma.

PURPOSE: Soft tissue sarcomas (STS) of the forearm are rare. We aim to assess their oncological and functional outcomes. METHODS: We retrospectively evaluated 34 patients who underwent surgical excision for forearm STS at our institution between 1993 and 2020. We analyzed postoperative Musculoskeletal Tumor Society rating scale (MSTS) and local recurrence-free survival (LRFS), metastasis-free survival, and overall survival (OS) rates. The significance of the following variables was determined: age, sex, histology, tumor size, Fédération Nationale des Centres de Lutte contre le Cancer grade, American Joint Committee on Cancer stage, surgical margin, unplanned excision, metastases upon initial presentation, receipt of chemotherapy, and radiotherapy (RT). RESULTS: The postoperative median MSTS score was 28. Bone resection or major nerve palsy was the only factor that influenced MSTS scores. The median MSTS scores in patients with or without bone resection or major nerve palsy were 24 and 29, respectively (P < 0.001). The 5-year LRFS rates was 87%. Univariate analysis revealed that the histological diagnosis of myxofibrosarcoma was the only factor that influenced LRFS (P = 0.047). The 5-year MFS rates was 71%. In univariate analysis, no factors were associated with MFS. The 5-year OS rates was 79%. Age was the only factor that influenced OS (P = 0.01). CONCLUSION: In the treatment of forearm STS, reconstruction of the skin and tendon can compensate for function, while bone resection and major nerve disturbance cannot. Careful follow-up is important, especially in patients with myxofibrosarcoma, due to its likelihood of local recurrence.

Vertebral body collapse after radiotherapy for spinal metastases.

Spinal metastases are common in patients with advanced stages of cancer and frequently cause vertebral body collapse (VBC). Although conventional radiotherapy (RT) is used for spinal metastases, the rates of occurrence of new VBC and progression of VBC at RT initiation have not been fully investigated. The present retrospective study assessed VBC and its associated risk factors after RT over time and evaluated new VBC and progression of VBC in patients who presented with VBC at RT initiation. The study evaluated 177 patients who received RT for vertebral metastases without paralysis between July 2012 and November 2016. Radiological responses of the irradiated vertebrae were assessed using computed tomography. Follow-up assessments were performed at RT initiation and 1, 2, 3, 4 and 6 months after RT. New VBC occurred in 12% of patients with no prior VBC within 1 month of RT. Multivariate analysis revealed that numeric rating scale (NRS) score (≥4) [relative risk (RR), 27.1; 95% confidence interval (CI), 1.86 to 394.9; P=0.016] was associated with the occurrence of new VBC at the 1 month follow-up time point. VBC progression occurred in 51% of the patients with collapse at RT initiation. Multivariate analysis revealed that bone quality (lytic metastases) (RR, 3.1; 95% CI, 1.28 to 7.70; P=0.013), NRS score (≥4) (RR, 3.0; 95% CI, 1.18 to 7.45; P=0.021) and tumor involvement of posterolateral elements of the spine (RR, 2.7; 95% CI, 1.03 to 7.29; P=0.04) were associated with the progression of VBC at the 1 month follow-up time point. The current study findings suggested that clinicians should pay attention to the factors that predict the occurrence of new VBC and VBC progression to ensure proper evaluation of conservative treatment effectiveness and facilitate the determination of patients who need close monitoring.

Mid-term results of medial open-wedge high tibial osteotomy based on radiological grading of osteoarthritis.

PURPOSE: To evaluate the mid-term results of medial open-wedge high tibial osteotomy (OWHTO) based on Kellgren-Lawrence (KL) grades. MATERIALS AND METHODS: We retrospectively evaluated clinical and radiographic outcomes of 93 patients (mean age 61.4 years, mean follow-up 64.2 months, 109 consecutive knees) who underwent OWHTO for medial compartment osteoarthritis (OA). KL grade was used to evaluate knee OA (KL-1 22 cases; KL-2, 51 cases; KL-3, 36 cases). The clinical outcomes were assessed using Japanese Orthopaedic Association (JOA) and Lysholm scores. Radiographic outcomes were assessed using pre- and post-operative mechanical axis percentage, femorotibial angle, medial proximal tibial angle, and joint line convergence angle. Hinge fracture frequency and OA progression were also evaluated based on KL grades. RESULTS: The JOA score improved significantly from 70.3 ± 14.9 to 96.2 ± 4.4, 64.1 ± 12.5 to 95.1 ± 5.1, and 68.6 ± 11.4 to 92.1 ± 6.1 in the KL-1, KL-2, and KL-3 groups, respectively. The JOA score in the KL-3 group was significantly lower than in the other groups. The Lysholm score improved significantly from 62.6 ± 8.8 to 97.7 ± 4.7, 62.1 ± 8.1 to 96.7 ± 4.2, and 59.2 ± 9.2 to 95.8 ± 4.6 in the KL-1, KL-2, and KL-3 groups, respectively. The post-operative Lysholm scores were not significantly different among the groups. There were significant differences in radiographic parameters pre-operatively, but not post-operatively, among the groups. Although there were no significant differences in hinge fracture frequency and OA progression, the KL-3 grade predicted OA progression on multivariate analysis. CONCLUSIONS: Mid-term results of OWHTO significantly improved. However, clinical score in the KL-3 group was lower than that in the KL-1 and KL-2 groups; radiological OA progression was a risk factor in KL-3.

Good clinical outcomes and return to sports after hybrid closed-wedge high tibial osteotomy.

PURPOSE: This study aimed to investigate preoperative sports participation and postoperative clinical outcomes including a return to sports (RTS) after hybrid closed-wedge high tibial osteotomy (CWHTO) for medial compartment osteoarthritis of the knee. Characteristic of Hybrid CWHTO was defined as extra-articular lateral closed and medial open wedge osteotomy. METHODS: The patients who underwent hybrid CWHTO from January 2016 to December 2018 were retrospectively reviewed and divided them into sports and non-sports groups. The preoperative demographic and radiographic characteristics were compared in both groups. And the clinical outcomes including the Japanese Orthopaedic Association (JOA) score, visual analogue scale (VAS), Lysholm score, University of California at Los Angeles (UCLA) activity score, and RTS in the sports group were also investigated. Statistical analysis was performed for comparisons among the preoperative factors between the two groups. Influence of sports impact and bone union of fibular osteotomy was also statistically investigated for RTS. RESULTS: Of the 161 knees (129 patients; 46 males, 83 females), 20 knees (16 patients; 13 males, 3 females; 12.3%) belonged to sports group. Although there were no significant differences regarding the age and radiographic parameters, there were significant differences in the body mass index and proportion of males between both groups. The JOA, VAS, Lysholm, and UCLA activity scores significantly improved after surgery. RTS was 80% at a mean duration of 7.2 ± 3.1 months. RTS in the high-impact sports group was significantly lower than that in the low-impact sports group (high-impact 60% vs. low-impact 100%, p = 0.043). There was no significant difference in RTS regarding bone union after fibular osteotomy. CONCLUSION: The clinical outcomes including RTS were satisfactory in patients with hybrid CWHTO. LEVEL OF EVIDENCE: IV.

Effect of bacterium in the malignant wounds of soft tissue sarcoma.

Malignant wounds (MWs) are rare skin lesions, which accompany ulceration, necrosis and infection caused by infiltration or damage by malignant tumor. The present study aimed to investigate the bacterial etiology implicated in MW in soft tissue sarcoma (STS), and the effectiveness of culture-guided perioperative antibacterial administration. A retrospective evaluation was conducted on medical records of patients who presented with MW between 2006 and 2020. A total of seven patients were included in the present study, in whom all tumors were relatively large (>5 cm) and high-grade. Subsequently, five patients underwent limb-sparing surgery, and three patients had distant metastases with a 5-year overall survival of 71%. Preoperative microbiological sampling from the wound identified 11 different bacterial strains in five patients. The infections were polymicrobial with an average of 2.6 strains isolated per patient (1 aerobic, 1.6 anaerobic bacteria). They were predominantly methicillin-sensitive Staphylococcus aureus. Patients with MWs from STS reported symptoms, including bleeding (71%), exudation (71%) and malodorous wound (43%) at the initial presentation; these completely resolved after surgery. All but one patient reported pain at the MW site with an average numeric rating scale of 4.4 at presentation that decreased to 1.4 (P=0.14) and 0.6 (P=0.04) one and two weeks after surgery, respectively. The patients had elevated C-reactive protein (71%), anemia (57%), low albumin (86%) and renal/liver dysfunction (14-29%). One patient was diagnosed with sepsis. Surgical resection afforded symptomatic relief and resolution of abnormal laboratory values. Although selected antibiotics were administered in four patients based on the preoperative antibiotic sensitivity test, surgical site infection (SSI) occurred in three patients. Therefore, the effectiveness of the selected antibiotics based on the results of the preoperative culture in preventing SSI needs to be investigated in the future. In conclusion, physicians should keep in mind that although surgical resection can improve the symptoms and abnormal values in laboratory examination form MW, it is accompanied with a high rate of SSI and poor prognosis.

Clinicopathological and histological analysis of secondary malignant giant cell tumors of bone without radiotherapy.

Giant cell tumor of bone (GCTB) is an intermediate bone tumor that rarely undergoes malignant transformation. Secondary malignant GCTB (SMGCTB) is defined as a lesion in which high-grade sarcoma occurs at the site of previously treated GCTB. The present study retrospectively reviewed the medical records of patients with GCTB treated at Okayama University Hospital between April 1986 and April 2020. The clinicopathological and histological features of patients with SMGCTB without prior radiotherapy were investigated. A total of three patients (4%) with SMGCTB were detected, and the tumor sites were the distal ulna, distal femur and sacrum. Two of the patients had been treated with curettage and bone graft, and one had been treated with denosumab. In all cases, the lesions were made up of two components, the conventional GCTB component and the malignant component. The Ki67 labeling index was higher in the malignant components of SMGCTB and metastatic lesions compared with that in primary and recurrent conventional GCTB, or the conventional GCTB component of SMGCTB. Moreover, p53 expression was higher in these same components in patients who underwent curettage and bone grafting; however, there was no difference in the patient that received denosumab treatment. In this patient, clinical cancer genomic profiling revealed loss of CDKN2A, CDKN2B and MTAP expression. All three patients developed distant metastasis. The patients with SMGCTB in the ulna and femur died 13 and 54 months after detection of malignant transformation, respectively. The patient with SMGCTB in the sacrum received carbon-ion radiotherapy to the sacrum and pazopanib; the treatment was effective and the patient was alive at the last follow-up 3 years later. In conclusion, p53 may be associated with malignant transformation in GCTB. Future studies should investigate the association of between denosumab treatment and malignant transformation, as well as molecular targeted therapy to improve the clinical outcomes of SMGCTB.

Association between Overall Survival and Activities of Daily Living in Patients with Spinal Bone Metastases.

Objective: This study aimed to investigate the association between overall survival (OS) and activities of daily living (ADL) in patients with skeletal-related events. In this study, 265 patients whose clinical parameters were available before radiotherapy were investigated. Methods: Age, sex, ADL, pain, the primary site, spinal level of bone metastases, spinal instability, treatment strategy, including chemotherapy or palliative treatment, and OS were investigated. ADL patients with a Barthel index of ≥90 were classified as the high ADL group, while those with a score < 90 were classified as the low ADL group. For OS, patients surviving ≥160 days were classified as the non-poor prognosis group, and those who survived <160 days were classified as the poor prognosis group. Results: Age, sex, ADL, pain, the primary site, and treatment strategy for OS were different between the two groups (p < 0.1). Logistic regression analysis revealed that ADL, the primary site, and treatment strategy were significant predictors of OS (p < 0.05). High ADL, breast cancer, and chemotherapy had a positive effect on OS. Conclusions: It is suggested that improvements may be obtained by performing rehabilitation interventions to maintain and improve ADL, by constructing a system for monitoring spinal bone metastases with images before ADL decreases, and by performing interventions such as changes in treatment methods such as RT or surgery at appropriate times.

Quality evaluation of spaceborne SiC mirrors (II): evaluation technology for mirror accuracy using actual measurement data of samples cut out from a mirror surface.

The authors studied the quality evaluation technology of a spaceborne large-scale lightweight mirror that was made of silicon carbide (SiC)-based material. To correlate the material property of a mirror body and the mirror accuracy, the authors evaluated the mirror surface deviation of a prototype mirror by inputting actually measured coefficient of thermal expansion (CTE) data into a finite element analysis model. The CTE data were obtained by thermodilatometry using a commercial grade thermal dilatometer for the samples cut from all over the mirror surface. The computationally simulated contour diagrams well reproduced the mirror accuracy profile that the actual mirror showed in cryogenic testing. Density data were also useful for evaluating the mirror surface deviation because they had a close relationship with the CTE.

Quality evaluation of spaceborne SiC mirrors (I): analytical examination of the effects on mirror accuracy by variation in the thermal expansion property of the mirror surface.

The Japan Aerospace Exploration Agency has studied a large-scale lightweight mirror constructed of reaction-bonded silicon carbide-based material as a key technology in future astronomical and earth observation missions. The authors selected silicon carbide as the promising candidate due to excellent characteristics of specific stiffness and thermal stability. One of the most important technical issues for large-scale ceramic components is the uniformity of the material's property, depending on part and processing. It might influence mirror accuracy due to uneven thermal deformation. The authors conducted systematic case studies for the conditions of CTE by finite element analysis to know the typical influence of material property nonuniformity on mirror accuracy and consequently derived a comprehensive empirical equation for the series of CTE's main factors. In addition, the authors computationally reproduced the mirror accuracy profile of a small prototype mirror shown in cryogenic testing and hereby verified wide-range practical computational evaluation technology of mirror accuracy.

Cryogenic optical testing of an 800 mm lightweight C/SiC composite mirror mounted on a C/SiC optical bench.

We tested the optical performance at cryogenic temperatures of an 800 mm diameter lightweight mirror, consisting of carbon-fiber reinforced silicon carbide and with a mass of 11.2 kg. The ceramic composite of the mirror was HB-Cesic, developed by ECM, Germany, and Mitsubishi Electric Corporation, Japan. The test was carried out while the mirror was mounted, via Invar stress relief supports, on a lightweight optical bench also made of HB-Cesic. During the test, both the mirror and the optical bench were cooled to 18 K in a liquid-helium chamber. The test consisted of measuring the mirror's change of surface figure with an interferometer installed outside the cryo-chamber. The cryogenic deformation of the mirror was 110 nm RMS with no significant residual deformation after cooling, which is very promising for the applicability of the HB-Cesic composite to large lightweight cryogenic space optics.