Methylation-mediated silencing of protein kinase C zeta induces apoptosis avoidance through ATM/CHK2 inactivation in dedifferentiated chondrosarcoma.

BACKGROUND: Dedifferentiated chondrosarcoma (DDCS) is an aggressive bone tumour with a poor prognosis and no effective treatment. Because changes in DNA methylation play critical roles in DDCS, we explored the roles that DNA methylation plays in oncogenesis to potentially identify an effective epigenetic treatment. METHODS: We identified genes downregulated in DDCS vs. conventional chondrosarcoma (CCS) due to DNA methylation using in silico analysis. The results were validated in DDCS clinical samples, and the molecular functions of the genes of interest were investigated in multiple chondrosarcoma cell lines (NDCS-1, SW1353, and OUMS-27). The therapeutic effect of decitabine, a DNA methyltransferase inhibitor, was evaluated in vitro and in vivo. RESULTS: PRKCZ was specifically downregulated by DNA methylation in DDCS. Overexpression of PRKCZ decreased the proliferation of NDCS-1 and SW1353 cells. PRKCZ directly bound to and activated ATM, which was followed by phosphorylation of CHK2 and subsequent apoptosis. Decitabine increased PRKCZ expression through de-methylating the promoter region of PRKCZ, which activated the ATM/CHK2 pathway and inhibited cell proliferation by inducing apoptosis. CONCLUSIONS: Increased DNA methylation and reduced expression of PRKCZ prevents apoptosis via inactivation of the ATM/CHK2 pathway in DDCS. Decitabine-induced expression of PRKCZ represents a promising therapy for DDCS.

An Analysis of 20 Cases of Radiation-Associated Sarcoma, Including 4 Cases Treated by Carbon Ion Radiotherapy.

INTRODUCTION: Radiation-associated sarcoma (RAS) is one of the most life-threatening complications associated with the treatment of malignant neoplasms. Because all RAS patients have a history of radiotherapy, there have been no effective treatment options when RAS is not completely resected. METHODS: We retrospectively reviewed 20 RAS patients, including 4 unresectable cases treated by carbon ion radiotherapy (CIRT). RESULTS: The primary diseases targeted by radiotherapy included malignant lymphoma (n = 4), cervical cancer (n = 3), pharyngeal cancer (n = 3), breast cancer (n = 2), lung cancer (n = 1), rectal cancer (n = 1), maxillary cancer (n = 1), synovial sarcoma (n = 1), and benign neoplasms (n = 4). The histological diagnoses of RAS included osteosarcoma (n = 8), leiomyosarcoma (n = 3), undifferentiated pleomorphic sarcoma (n = 3), rhabdomyosarcoma (n = 1), angiosarcoma (n = 1), malignant peripheral nerve sheath tumor (n = 1), spindle cell sarcoma NOS (n = 1), and sarcoma not further specified (n = 2). The median survival time from the diagnosis of RAS was 26 months. Eleven patients underwent surgery. Five of these patients achieved a continuous disease free (CDF) status or showed no evidence disease. Four patients underwent CIRT. One of these patients with leiomyosarcoma achieved a CDF status, and the other patient with osteosarcoma achieved a partial response. On the other hand, 2 patients experienced grade 3 toxicities that required surgical treatment. CONCLUSION: RAS originates from various types of diseases that are treated by radiotherapy and shows diverse pathological features. Complete resection achieves a good prognosis. CIRT can be an effective and feasible option for unresectable RAS.

Efficacy and safety of tranexamic acid in patients undergoing surgery for bone and soft tissue tumors: a propensity score matching analysis.

OBJECTIVE: The aim of this study was to investigate the efficacy and safety of tranexamic acid in patients undergoing surgery for bone and soft tissue tumors. METHODS: Data were retrospectively collected from 454 consecutive patients with bone and soft tissue tumors who underwent open biopsy, marginal resection, curettage or wide resection between January 2017 and December 2018. We performed propensity score matching of patients who received tranexamic acid with those who did not. The primary outcome variables were intra-operative, peri-operative and estimated blood loss (IBL, PBL and EBL, respectively). RESULTS: Tranexamic acid (+) and tranexamic acid (-) groups were defined according to whether patients received tranexamic acid or not. Among the 454 patients, open biopsy was performed in 102, marginal resection in 175, curettage in 54 and wide resection in 123. Intra-operative blood loss was significantly lower in the tranexamic acid (+) group than in the tranexamic acid (-) group for both marginal and wide resection (marginal resection: 17.3 vs. 70.3 g, respectively, P = 0.045; wide resection: 128.8 vs. 273.1 g, respectively, P = 0.023). Peri-operative blood loss and estimated blood loss were also significantly lower in the tranexamic acid (+) group for wide resection (peri-operative blood loss: 341.5 vs. 686.5 g, respectively, P = 0.0039; estimated blood loss: 320.7 vs. 550.6 ml, respectively, P = 0.030). No venous thromboembolism occurred in either group. CONCLUSION: This study suggests that TXA administration safely and effectively reduces blood loss, in particular for wide resection, with no increase in the rate of adverse events.

Long-term outcome after en bloc resection and reconstruction of the spinal column and posterior chest wall in the treatment of malignant tumors.

BACKGROUND: Malignant tumors occurring around both the spinal column and posterior chest wall are uncommon. Surgical resection of chest wall tumors adjacent to the spinal column is still challenging due to the surrounding anatomical structures. The purpose of the present study was to evaluate the long-term outcomes of surgical management in malignant tumors involving the spinal column and posterior chest wall. METHODS: Between 1999 and 2007, 10 consecutive patients underwent en bloc resection combined with the posterior chest wall in the treatment of malignant tumors around the spinal column. There were 6 males and 4 females with a mean age at the surgery of 40.9 years old (range, 14-62 years old). The mean postoperative follow-up period was 159.7 months (range, 84-245 months). The clinical history, physical examination, laboratory data, radiological findings, and operative findings for each patient were retrospectively reviewed. RESULTS: All surgeries were performed via a combined anterior and posterior approach. The mean numbers of partially resected vertebrae and ribs were 3.1 and 4.1, respectively. Lower or upper lobectomy was performed in four patients, and the diaphragm was partially resected in two patients. The surgical margin was wide in seven patients and marginal in two patients. Although five patients had postoperative respiratory problem, all patients improved immediately without life-threatening complications. There were no patients with respiratory insufficiency after surgery. One patient with osteosarcoma died of lung metastases 99 months after surgery. At the final follow-up, only one patient had local recurrence, five had been continuously disease-free, and three were alive with no evidence of disease. CONCLUSIONS: En bloc resection and reconstruction in selected patients with malignant tumors involving both the spinal column and posterior chest wall demonstrated good long-term results for local control and the respiratory function.

Clinical features of multiple spinal schwannomas without vestibular schwannomas.

BACKGROUND: Multiple spinal cord tumors in a single patient are very rare and most often seen in cases of neurofibromatosis and associated disorders. Schwannomatosis, which is characterized by the development of multiple schwannomas without vestibular schwannomas, has been newly defined as a distinct form of neurofibromatosis. The purpose of the present study was to describe and review the clinical and radiological features and the management of patients with multiple spinal schwannomas without vestibular schwannomas. METHODS: Between 1986 and 2016, 19 patients with multiple spinal schwannomas without vestibular schwannoma were diagnosed and treated. Of the 19 patients, 13 were males, and 6 were females. The mean age at the first surgery for spinal schwannoma was 45.2 years old. The mean follow-up period was 123.4 months. The clinical features and radiological findings of the patients with multiple spinal schwannomas were retrospectively reviewed. RESULTS: Among the 19 patients, there were more than 140 spinal schwannomas. The most common area of spinal schwannoma was the thoracolumbar-lumbar region. Initial symptoms and chief complaints caused by spinal schwannomas were primarily pain in the trunk or extremities in 17 (89.5%) of 19 patients. More than 60 spinal schwannomas were surgically resected. Multiple spinal surgeries were required in six patients. In all 19 patients, surgical treatment has provided successful relief of symptoms and neurological recovery. CONCLUSIONS: Surgical treatment was safe and effective in patients with multiple spinal schwannomas without vestibular schwannomas. After surgery, we recommend that all patients be followed with magnetic resonance imaging to monitor for asymptomatic tumors or detect new tumors early.

Clinical features and outcomes of spine surgery in patients with ankylosing spondylitis.

OBJECTIVES: The study aimed to comprehend the clinical features and outcomes of surgical treatments for spinal disorders in patients with ankylosing spondylitis. METHODS: This retrospective study enrolled patients with ankylosing spondylitis who underwent spine surgery between 2000 and 2019 in our facility. RESULTS: Thirteen patients with ankylosing spondylitis underwent spine surgeries. The mean age was 56.2 years, and the mean disease duration was 25.1 years at the time of surgery. Nine patients had vertebral fracture, two had kyphotic deformity, and two had myelopathy due to the spinal ligament ossification. Fracture cases included five patients with secondary pseudarthrosis/delayed palsy due to conservative treatment failure. Spinal fixation was performed in all patients. Pedicle subtraction osteotomy for kyphosis and laminectomy for myelopathy were also conducted. All patients improved after surgeries. One patient with kyphotic deformity underwent additional surgery of bilateral hip prosthesis, which resulted in better spine alignment. Four cases of perioperative complications were observed. CONCLUSION: Myelopathy was newly found as the aetiology requiring surgery in patients with ankylosing spondylitis. This summarized case series could help physicians to identify patients with surgically treatable spinal disorders among patients with ankylosing spondylitis.

Association between female urinary urgency and aponeurotic ptosis: Results from a community-based cross-sectional study in Japan.

AIMS: To investigate the relationship between urinary urgency (UU) and aponeurotic ptosis (AP) in a health promotion project. METHODS: This cross-sectional study analyzed 658 women in Aomori, Japan. The presence of UU was evaluated using the Overactive Bladder Symptom Score. The distance from the light reflex on the cornea to the upper eyelid (margin reflex distance-1 [MRD-1]) was measured. AP was defined as MRD-1 of less than 2.0 mm. The daily salt intake amount was estimated using the dietary questionnaire. Daily salt intake was defined as excessive if it was 10 g/day or higher. Independent factors of UU and AP were analyzed via multivariable logistic regression model. RESULTS: The number of women with UU and AP was 193 and 65, respectively. Similar background differences were observed in age, cardiovascular disease history, renal function, hypertension, diabetes mellitus, dyslipidemia, and daily salt intake between participants with UU and those with AP. Participants with UU had a higher prevalence of AP (19% vs. 6.2%) than those without. Moreover, more than 50% of the women with AP experienced UU. Multivariable logistic analysis on UU showed that age (≥65 years), diabetes mellitus, daily salt intake (≥10 g/day), and AP (odds ratio, 2.07, p = .014) were independent factors. Multivariable analysis on AP revealed that age (≥65 years), hypertension, daily salt intake (≥10 g/day), and UU were independent factors. CONCLUSIONS: AP was an independent indicator of UU, in addition to excessive daily salt intake. Women with AP may tend to intake excessive salt and experience UU.

Clinical results of carbon-ion radiotherapy with separation surgery for primary spine/paraspinal sarcomas.

PURPOSE: To evaluate the clinical outcome of combination of carbon-ion radiotherapy with separation surgery (CIRT-SS) in patients with primary spinal/paraspinal sarcoma (PSPS) and epidural spinal cord compression (ESCC). METHODS: CIRT-SS was performed in 11 consecutive patients. Patients treated in the primary and salvage settings were categorized into Group A (n = 8) and Group B (n = 3), respectively. Clinical results and imaging findings were collected, with a particular focus on ESCC grade, treatment-associated adverse events (AEs), and the locoregional control (LRC) rate and overall survival (OS). RESULTS: The median follow-up period from the start of CIRT-SS was 25 months (7-57 months). ESCC was improved by SS in all cases. No patients exhibited radiation-induced myelopathy (RIM), but three developed Grade 3 vertebral compression fracture (VCF) during follow-up. Locoregional recurrences were observed in four patients [Group A: 1 (12.5%), Group B: 3 (100%)]. Over the entire follow-up period, three patients developed distant metastases and two patients died. The 2-year LRC rate and OS were 70% and 80%, respectively. CONCLUSION: CIRT-SS in the primary setting achieved acceptable LRC and OS without RIM in patients with PSPS and with ESCC. VCF was the most frequent AE associated with CIRT-SS.

Post-carbon-ion radiotherapy vertebral pathological fractures in upper cervical primary malignant spinal tumors treated by occipito-cervical fusion.

PURPOSE: To describe the characteristic features of post-carbon-ion radiotherapy (CIRT) vertebral pathological fractures (VPFs) in upper cervical primary malignant spinal tumors (PMSTs) treated by occipito-cervical (OC) fusion. METHODS: OC fusion was performed for three consecutive patients with post-CIRT VPFs. The clinical results and imaging findings, including bone single-photon emission computed tomography (SPECT)/CT were prospectively collected. RESULTS: No surgery-related wound complication and surgical site infection were noted. One patient experienced re-fracture and displacement of dens with the loosening of occipital screws and was treated by posterior revision surgery. At the final follow-up, all patients were alive without evidence of disease, and the solid OC fusion was confirmed. Bone SPECT/CT clearly revealed the effect of CIRT on bone turnover in the irradiated field. CONCLUSION: The OC fusion with autologous bone grafts was a reliable option for the treatment of post-CIRT VPCs in the patients with upper cervical PMSTs. In addition, evaluation of the bone turnover at the irradiated field by bone SPECT/CT would help surgeons select an effective plan of care, such as fusion level and postoperative care.

The neurological outcome of radiotherapy versus surgery in patients with metastatic spinal cord compression presenting with myelopathy.

PURPOSE: While radiotherapy is generally an acceptable treatment for metastatic spinal cord compression, surgical intervention is controversial due to the invasiveness and diversity of diseases in the patients being considered. The ideal treatment, therefore, depends on the situation, and the most acute treatment possible is necessary in patients presenting with myelopathy. We compared the neurological outcomes between radiotherapy and surgery in patients with metastatic spinal cord compression presenting with myelopathy. METHODS: A total 54 patients with metastatic spinal cord compression presenting with myelopathy treated in our institution between 2006 and 2016 were analyzed retrospectively. Twenty patients were selected by radiotherapy alone (radiation group), and 36 patients were selected by decompression and stabilization surgery with or without radiotherapy (surgery group). The neurological outcomes and complications were compared between the two treatment groups. RESULTS: Seven patients initially in the radiation group underwent surgery because of a substantial decline in their motor strength during radiotherapy. One of the remaining 13 patients (8%) in the radiation group and 30 of the 34 patients (88%) in the surgery group showed improvement in their neurological symptoms (P < 0.01). One patient (8%) in the radiation group and 21 patients (62%) in the surgery group were ambulatory after treatment (P < 0.01). There were no major complications related to radiotherapy, but surgery-related complications occurred in 9 of 34 (26%) patients, and 6 (18%) patients needed reoperation. CONCLUSIONS: Surgical decompression and stabilization may be required to improve the neurological function in patients with metastatic spinal cord compression presenting with myelopathy. However, the high rate of complications associated with surgery should be taken into consideration.

Development of a clinical prediction score for perioperative complications following metastatic spinal surgery (PERCOM) score.

Background: Spinal metastases can impair mobility, worsening the Karnofsky Performance Status (KPS). Surgery for spinal metastases has the potential to improve KPS and extend prognosis, but it is crucial to recognize the elevated risk of perioperative complications. Therefore, the development of a new scoring system to accurately predict perioperative complications in spinal metastatic surgery is essential. Methods: We conducted a retrospective observational study with 86 patients who underwent surgical intervention for spinal metastases. Patients were divided into two groups based on the presence or absence of perioperative complications within 14 days after surgery. Various factors related to perioperative complications were assessed through univariate and multivariate analyses. We established a clinical prognostic scoring system called the Perioperative Complications following Metastatic Spinal Surgery (PERCOM) score and evaluated its precision using receiver operating characteristic (ROC) analysis. Results: Five variables (age, KPS, primary prostate cancer, Albumin, and Hemoglobin) identified in the univariate analysis were assigned binary values of 0 or 1. The PERCOM score was then calculated for each patient by summing the individual points, ranging from 0 to 5. The optimal threshold determined by ROC curve analysis for the PERCOM score was 2 points, with a sensitivity of 86 % and a specificity of 56 %. Conclusions: The composite PERCOM score effectively predicted perioperative complications in spinal metastasis surgery. To further validate its precision, a prospective multicenter study is needed.

miR-125b develops chemoresistance in Ewing sarcoma/primitive neuroectodermal tumor.

BACKGROUND: Diverse functions of microRNAs (miRNAs), including effects on tumorigenesis, proliferation, and differentiation, have been reported, and several miRNAs have also been demonstrated to play an important role in apoptosis. In this study, we investigated the possible role that miRNAs may play in the development of chemoresistance in Ewing sarcoma/primitive neuroectodermal tumor (EWS). METHODS: We screened doxorubicin (Dox)-resistant EWS cells to identify any distinct miRNA sequences that may regulate the chemoresistance of EWS cells. The effects of miRNAs were evaluated using a chemosensitivity assay. The possible target genes of the miRNAs were predicted using a web-based prediction program. RESULTS: We found miR-125b to be upregulated in two different Dox-resistant EWS cell lines. The upregulation of miR-125b was also confirmed in the EWS tumors having survived chemotherapy regimen which includes doxorubicin. When miR-125b was knocked down in EWS cells, both the Dox-resistant and parental cells showed an enhanced sensitivity to doxorubicin, which was associated with the upregulation of the pro-apoptotic molecules, p53 and Bak. Inversely, the overexpression of miR-125b in parental EWS cells resulted in enhanced drug resistance, not only to doxorubicin, but also to etoposide and vincristine. CONCLUSIONS: Our findings suggest that miR-125b may play a role in the development of chemoresistance in EWS by suppressing the expression of the apoptotic mediators, such as p53 and Bak.

Destructive cervical spondylitis due to Cutibacterium acnes with synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome: A case report.

Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is a spectrum of heterogeneous diseases commonly recognised by skin and osteoarticular lesions. There have been reports of some surgical cases of the progressive, destructive spondylitis associated with SAPHO syndrome, wherein the destructive spondylitis was considered to have developed due to the progression of spondylitis with SAPHO syndrome as the pathogenic bacteria were not isolated. We herein report a surgical case of destructive cervical spondylitis associated with SAPHO syndrome. A 54-year-old woman with a history of palmoplantar pustulosis suffered severe neck pain for 6 months. Radiography and computeed tomography showed sclerosed and collapsed cervical vertebrae, and the patient was referred to our hospital for further evaluation and management upon suspicion of infection or spondylitis with SAPHO syndrome. For the severe neck pain and progressive destruction of cervical vertebrae, we performed posterior fusion surgery with subsequent anterior fusion. Cutibacterium acnes (C. acnes) was isolated by enrichment culture with thioglycolate broth from both the anterior and the posterior tissue samples. We diagnosed pyogenic spondylitis secondary to C. acnes infection and administered doxycycline for 6 weeks after the first surgery. The neck pain was resolved and cervical fusion was achieved one year postoperatively. C. acnes infection could elicit destructive spondylitis. An enrichment culture should be performed to isolate the pathogenic bacteria in cases of destructive spondylitis with SAPHO syndrome.

Cases requiring reoperation for recurrence of myelopathy by lamina closure after a double-door laminoplasty using a modified Kirita-Miyazaki suture method.

Background: Progression of kyphosis after laminoplasty sometimes results in the recurrence of myelopathy with lamina closure. However, only a few case reports have been published on the reoperation of double-door laminoplasty using the suture method. This study investigated the incidence and clinical features of reoperation cases caused by the recurrence of myelopathy with lamina closure after double-door laminoplasty using a modified Kirita-Miyazaki suture method. Methods: A total of 169 patients who underwent double-door laminoplasty were included in this study, with a mean follow-up duration of 6.6 years (range: 2-16). All surgeries were double-door laminoplasties in which the open lamina was sutured to the paravertebral muscle. The reoperation rate for myelopathy recurrence due to lamina closure and the associated risk factors were investigated. The risk factors included age, history, cervical alignment, C2-7 lordosis, the cervical sagittal vertical axis, and C7 slope. Results: The reoperation rate for recurrence of myelopathy by lamina closure was 3.0% (5/169). All patients showed kyphosis progression after surgery; the spinal cord was more compressed by closed lamina than before the initial surgery. The reoperation group had more patients with neuromuscular or psychiatric disorders (60% [3/5] vs. 2% [4/164]; p < 0.001), kyphotic alignments (60% [3/5] vs. 10% [16/164]; p < 0.001), and cases with less than -10° of C2-7 lordosis (60% [3/5] vs. 7% [11/164]; p < 0.001). Conclusions: Double-door laminoplasty with the suture method may not be suitable for patients with a neuromuscular or psychiatric disease or those with preoperative C2-7 lordosis less than -10°.

Postoperative Time Course of Avulsion-Type Herniation Focused on the Development of New Modic Changes and Their Effect on Short-Term Residual Low Back Pain.

STUDY DESIGN: Retrospective study. OBJECTIVE: To investigate the characteristics of newly developing Modic changes following discectomy and their impact on residual low back pain (LBP) in the early postoperative stage of lumbar disc herniation. METHODS: We included 96 patients who underwent microscopic discectomy. Through MRI, we assessed new developments of Modic changes and the progression of disc degeneration at the surgical level. The presence of cartilaginous endplates was evaluated using resected specimens, and the main outcome was assessed using the visual analog scale (VAS). Further, the prevalence and time course of Modic changes, and their effects on clinical outcomes in the early postoperative period were examined. RESULTS: A new development of Modic changes was detected in 28% of cartilaginous herniations at 6 months. Modic changes were observed more frequently in patients with cartilaginous herniation than in those without cartilaginous herniation postoperatively (P < .001). The VAS scores for LBP up to 6 months were greater in patients with Modic changes (P < .001) than those without; however, no significant differences were identified in the presence or absence of Modic changes over the year follow-up. The development of Modic changes was closely associated with residual LBP at 6 months (ß:0.511, P < .001). CONCLUSIONS: Modic changes develop predominantly in patients with avulsion-type herniation than in those with annular rupture at an earlier phase after discectomy. Furthermore, disc herniation with cartilaginous endplates may be associated with a slower decrease in LBP for up to 6 months, supporting the notion that newly developing endplate changes may cause residual LBP.

The Difference in Clinical Features between Small-Sized Soft Tissue Sarcomas and Benign Tumors.

BACKGROUND: Small-sized tumors tend to be resected without thorough assessment and are often managed in a sarcoma center after a malignancy is diagnosed. The lack of knowledge about the features of smallsized sarcomas may lead to unplanned resection. The features of small-sized soft tissue sarcomas were investigated by comparing them with those of small benign soft tissue tumors. METHODS: We included 17 soft tissue sarcoma cases (7 on the hands and feet and 10 on the limbs and trunk) with a diameter of under 2 cm. The features of small-sized sarcomas were compared to those of 39 benign soft tissue tumors with a diameter of under 2 cm and non-specific imaging findings (30 on the hands and feet and 9 on the limbs and trunk). The investigated features were age, sex, presence of pain, subjective increasing tumor size, and duration of observation. RESULTS: When we compared the tumors in the hands and feet, those <40 years of age (5/7 [71%] vs. 8/30 [27%], p=0.03) experiencing pain (7/7 [100%] vs. 13/30 [43%], p=0.007) were more common in patients with sarcomas than in patients with benign tumors. When we compared the tumors in the limbs and trunk, there was no significant difference in all investigated features. CONCLUSION: Although clinical features were ineffective in distinguishing malignancy in most small-sized soft tissue tumors, we should pay attention to painful tumors of the hands and feet in younger patients.

Older age at surgery and postoperative leg length discrepancy are risk factors for unfavourable patient-reported outcome measures of knee tumour endoprostheses following resection for musculoskeletal tumour of the lower limb.

Aims: To evaluate mid-to long-term patient-reported outcome measures (PROMs) of endoprosthetic reconstruction after resection of malignant tumours arising around the knee, and to investigate the risk factors for unfavourable PROMs. Methods: The medical records of 75 patients who underwent surgery between 2000 and 2020 were retrospectively reviewed, and 44 patients who were alive and available for follow-up (at a mean of 9.7 years postoperatively) were included in the study. Leg length discrepancy was measured on whole-leg radiographs, and functional assessment was performed with PROMs (Toronto Extremity Salvage Score (TESS) and Comprehensive Outcome Measure for Musculoskeletal Oncology Lower Extremity (COMMON-LE)) with two different aspects. The thresholds for unfavourable PROMs were determined using anchor questions regarding satisfaction, and the risk factors for unfavourable PROMs were investigated. Results: The thresholds for favourable TESS and COMMON were 64.8 and 70.4 points, respectively. Multivariate analysis showed that age at surgery (p = 0.004) and postoperative leg length discrepancy (p = 0.043) were significant risk factors for unfavourable TESS results, while age at surgery (p < 0.001) was a significant risk factor for unfavourable COMMON-LE results. Following receiver operating characteristic analysis, the threshold for both TESS and COMMON-LE was 29 years of age at surgery. Additionally, a leg length discrepancy of 8.2 mm was the threshold for unfavourable TESS. Conclusion: Patients aged > 29 years at the time of surgery require appropriate preoperative counselling and adequate postoperative physical and socioemotional support. Reconstruction equivalent to the length of the resected bone can reduce the risk of functional disabilities in daily living.

Reduced Neuroinflammation Via Astrocytes and Neutrophils Promotes Regeneration After Spinal Cord Injury in Neonatal Mice.

Neonatal spinal cord injury (SCI) shows better functional outcomes than adult SCI. Although the regenerative capability in the neonatal spinal cord may have cues in the treatment of adult SCI, the mechanism underlying neonatal spinal cord regeneration after SCI is unclear. We previously reported age-dependent variation in the pathogenesis of inflammation after SCI. Therefore, we explored differences in the pathogenesis of inflammation after SCI between neonatal and adult mice and their effect on axon regeneration and functional outcome. We established two-day-old spinal cord crush mice as a model of neonatal SCI. Immunohistochemistry of the spinal cord revealed that the nuclear translocation of NF-κB, which promotes the expression of chemokines, was significantly lower in the astrocytes of neonates than in those of adults. Flow cytometry revealed that neonatal astrocytes secrete low levels of chemokines to recruit circulating neutrophils (e.g., Cxcl1 and Cxcl2) after SCI in comparison with adults. We also found that the expression of a chemokine receptor (CXCR2) and an adhesion molecule (ß2 integrin) quantified by flow cytometry was lower in neonatal circulating neutrophils than in adult neutrophils. Strikingly, these neonate-specific cellular properties seemed to be associated with no neutrophil infiltration into the injured spinal cord, followed by significantly lower expression of inflammatory cytokines (Il-1ß, Il-6 and TNF-α) after SCI in the spinal cords of neonates than in those of adults. At the same time, significantly fewer apoptotic neurons and greater axonal regeneration were observed in neonates in comparison with adults, which led to a marked recovery of locomotor function. This neonate-specific mechanism of inflammation regulation may have potential therapeutic applications in controlling inflammation after adult SCI.

Macrophages play a leading role in determining the direction of astrocytic migration in spinal cord injury via ADP-P2Y1R axis.

After spinal cord injury (SCI), inflammatory cells such as macrophages infiltrate the injured area, and astrocytes migrate, forming a glial scar around macrophages. The glial scar inhibits axonal regeneration, resulting in significant permanent disability. However, the mechanism through which glial scar-forming astrocytes migrate to the injury site has not been clarified. Here we show that migrating macrophages attract reactive astrocytes toward the center of the lesion after SCI. Chimeric mice with bone marrow lacking IRF8, which controls macrophage centripetal migration after SCI, showed widely scattered macrophages in the injured spinal cord with the formation of a huge glial scar around the macrophages. To determine whether astrocytes or macrophages play a leading role in determining the directions of migration, we generated chimeric mice with reactive astrocyte-specific Socs3-/- mice, which showed enhanced astrocyte migration, and bone marrow from IRF8-/- mice. In this mouse model, macrophages were widely scattered, and a huge glial scar was formed around the macrophages as in wild-type mice that were transplanted with IRF8-/- bone marrow. In addition, we revealed that macrophage-secreted ATP-derived ADP attracts astrocytes via the P2Y1 receptor. Our findings revealed a mechanism through which migrating macrophages attract astrocytes and affect the pathophysiology and outcome after SCI.