What are the Optimal Systemic Treatment Options for Rhabdomyosarcoma?

OPINION STATEMENT: Rhabdomyosarcoma, a soft tissue sarcoma commonly observed in childhood, requires multidisciplinary treatment, including surgical tumor resection, chemotherapy, and radiation therapy. Although long-term survival can be expected in patients with localized rhabdomyosarcoma, the clinical outcomes in patients with metastatic or unresectable rhabdomyosarcoma remain unsatisfactory. To improve the outcomes of rhabdomyosarcoma, it is important to explore effective systemic treatments for metastatic rhabdomyosarcoma. Currently, multiagent chemotherapy comprising vincristine, actinomycin D, and ifosfamide/cyclophosphamide remains standard systemic treatment for rhabdomyosarcoma. On the other hand, new treatment, such as immune checkpoint inhibitors and molecular targeted drugs, have demonstrated superior clinical outcomes compared to those of standard treatments in various type of malignancies. Therefore, it is necessary to assess the efficacies of these treatments in patients with rhabdomyosarcoma. Recent clinical studies have shown efficacies and safeties of temozolomide combined with vincristine/irinotecan, olaratumab combined with doxorubicin or vincristine/irinotecan, and long-term maintenance therapy. Furthermore, basic researches demonstrated new therapeutic targets. Future studies using these approaches are required to assess their clinical significances.

Instrumentation failure following pediatric spine deformity growth-sparing surgery using traditional growing rods or vertical expandable prosthetic titanium ribs.

BACKGROUND: Instrumentation failure (IF) is a major complication associated with growth-sparing surgery for pediatric spinal deformities; however, studies focusing on IF following each surgical procedure are lacking. We aimed to evaluate the incidence, timing, and rates of unplanned return to the operating room (UPROR) associated with IF following each surgical procedure in growth-sparing surgeries using traditional growing rods (TGRs) and vertical expandable prosthetic titanium ribs (VEPTRs). METHODS: We reviewed 1,139 surgical procedures documented in a Japanese multicenter database from 2015 to 2017. Of these, 544 TGR and 455 VEPTR procedures were included for evaluation on a per-surgery basis. IF was defined as the occurrence of an implant-related complication requiring revision surgery. RESULTS: The surgery-based incidences of IF requiring revision surgery in the TGR and VEPTR groups were 4.3% and 4.0%, respectively, with no significant intergroup difference. Remarkably, there was a negative correlation between IF incidence per surgical procedure and the number of lengthening surgeries in both groups. In addition, rod breakage in the TGR group and anchor-related complications in the VEPTR group tended to occur relatively early in the treatment course. The surgery-based rates of UPROR due to IF in the TGR and VEPTR groups were 2.0% and 1.5%, respectively, showing no statistically significant difference. CONCLUSIONS: We found that IF, such as anchor related-complications and rod breakage, occurs more frequently earlier in the course of lengthening surgeries. This finding may help in patient counseling and highlights the importance of close postoperative follow-up to detect IF and improve outcomes.

Knee flexor strength at 6 months after anterior cruciate ligament reconstruction using hamstring tendon can be predicted from that at 3 months.

PURPOSE: This study aimed to identify factors influencing persistent muscle weakness in knee flexor strength after anterior cruciate ligament (ACL) reconstruction using the hamstring tendon and establish a clear cut-off value at 3 months postoperatively for the limb symmetry index (LSI) to exceed 90% at 6 months postoperatively. METHODS: One hundred forty-eight patients undergoing ACL reconstruction were included and categorised into two groups based on knee flexor strength at 6 months postoperatively: patients with LSI of 90% or greater (achieved group: n = 114) and patients with LSI less than 85% (nonachieved group: n = 34). Items with significant differences between the two groups (preoperative waiting period, LSI to body weight ratio of knee flexor and extensor strength at 3 months postoperatively and peak torque angle of knee flexor muscle) were included in the multiple logistic regression analysis. Additionally, a receiver operating characteristic curve was used to calculate the cut-off value of the LSI at 3 months postoperatively, which was required to achieve the LSI criteria for knee flexor strength 6 months postoperatively. RESULTS: Multiple logistic regression analysis extracted the preoperative waiting period and LSI for knee flexor strength at 3 months postoperatively. The cut-off value at 3 months postoperatively was 76.9% (area under the curve value, 0.82; sensitivity, 0.76; and specificity, 0.81) of the LSI. CONCLUSION: The LSI of at least 76.9% for knee flexor strength at 3 months after ACL reconstruction was an indicator for achieving the 6 months postoperatively. This is a criterion to aim for, considering the stress on the graft and the regeneration process of the semitendinosus tendon. LEVEL OF EVIDENCE: Level III.

Constitutional varus knee due to tibial deformity is common and represents a good indication for high tibial osteotomy in Japanese population: Consideration of 1010 knees.

PURPOSE: This study aimed to elucidate the characteristics of varus knee deformities in the Japanese population, prevalence of various around knee osteotomy procedures and influence of femoral and tibial bowing. METHODS: Varus knee deformity was defined as a weight-bearing line ratio of <50%. A total of 1010 varus knees were selected from 1814 varus knees with weight-bearing full-length radiographs, obtained at two facilities, based on exclusion criteria. Various parameters were measured, and around knee osteotomy simulations based on the deformity centre were conducted using digital planning tools. Bowing of the femoral and tibial shafts was measured, with bowing defined as follows: ≤ -0.6° indicating lateral bowing and ≥ 0.6° indicating medial bowing. Statistical analysis was performed to investigate age-related correlations and their impact on surgical techniques. RESULTS: The study revealed that the proximal tibia was the centre of deformity in Japanese varus knees (42.8%), and high tibial osteotomy was frequently indicated (81.6%). Age demonstrated a mild correlation with femoral shaft bowing (r = -0.29), leading to an increase in the mechanical lateral distal femoral angle and to a decrease in the hip-knee-ankle angle and weight-bearing line ratio (r = -0.29, 0.221, 0.219). The tibial shaft bowing was unaffected by age (r = -0.022). CONCLUSION: A significant proportion of Japanese individuals with varus knees exhibit a deformity centre located in the proximal tibia, making them suitable candidates for high tibial osteotomy. No age-related alterations were discerned in tibial morphology, indicating that the occurrence of constitutional varus knees is attributable to tibial deformities in the Japanese patient cohort. LEVEL OF EVIDENCE: Level IV.

Artificial Intelligence-Based Surgery Support Model Using Intraoperative Radiographs for Assessing the Acetabular Component Angle.

BACKGROUND: This study aimed to develop an artificial intelligence-based surgical support model for assessing the acetabular component angle using intraoperative radiographs during total hip arthroplasty and verify its accuracy. METHODS: A total of 268 hips were analyzed. At first, 268 preoperative and intraoperative anteroposterior pelvic radiographs were amplified to 536. These radiographs were used to create a learning model to estimate the acetabular component angle from the radiographs intraoperatively. The ground truth was the anteversion and inclination angles obtained from the computed tomography-based navigation system intraoperatively. Bone landmarks on the preoperative and intraoperative radiographs were manually annotated. The distances and angles between each landmark were used as predictor variables. The estimation accuracy was assessed for internal and external test datasets. Mean absolute error (MAE) and R2 values were used as accuracy measures. RESULTS: The MAE and R2 for the internal test set showed 2.19 and 0.850 for anteversion, and 1.18 and 0.805 for inclination, respectively. The MAE and R2 for the external test set showed 2.78 and 0.789 for anteversion, and 1.56 and 0.744 for inclination, respectively. CONCLUSIONS: We developed an artificial intelligence-based surgical support model for accurately assessing the acetabular component angle using intraoperative radiographs. Excellent estimation accuracy was confirmed for the external test set. In the future, the model may help to reduce the risk of adverse postoperative events.

Efficacy of adipose-derived stem cells in preventing peripheral nerve adhesion and promoting nerve regeneration: A laboratory investigation in a rat model.

BACKGROUND: Neurolysis alone or administration of anti-adhesion products after neurolysis is performed to treat peripheral nerve adhesion; however, the recovery of nerve function is poor. This study aimed to investigate the efficacy of adipose-derived stem cells (ADSCs) for peripheral nerve adhesion in a rat model. METHODS: As a nerve adhesion procedure, the neural bed was coagulated, and the epineurium of the sciatic nerve was sutured to the coagulated neural bed using nylon. Neurolysis was performed 6 weeks after the nerve adhesion procedure, and saline (control group) or ADSCs (ADSC group) were administered around the nerve where neurolysis was performed. Evaluations were performed 6 weeks after the administration. RESULTS: The wet weight ratio of the tibialis anterior muscle and nerve conduction velocity, which are indicators of nerve regeneration, were significantly better, while tensile strength, which is an indicator of the severity of nerve adhesion, was significantly lower in the ADSC group than in the control group. In the nerve, the expression of interleukin-10 and transforming growth factor-ß in the nerve was significantly higher and that of tumor necrosis factor-α was significantly lower in the ADSC group than in the control group. Furthermore, significantly fewer M1 macrophages and significantly more M2 macrophages were observed in the ADSC group than in the control group. In the perineural scar, significantly fewer perineural collagen fibers and significantly more vascularization were observed in the ADSC group than in the control group. CONCLUSIONS: ADSCs prevented peripheral nerve adhesion by reducing perineural scarring and enhancing vascularization. Additionally, ADSCs promoted nerve regeneration by decreasing inflammatory cytokine levels and increasing anti-inflammatory cytokine levels, as ADSCs regulated macrophage polarization from M1 to M2 macrophages. These findings hold promise for using ADSCs to treat nerve adhesion.

Pathology, Diagnosis, and Management of Sarcoma.

Due to the rarity and heterogeneity of sarcoma, investigation into molecular targets and new treatments has been particularly challenging [...].

Biomechanical investigation of long spinal fusion models using three-dimensional finite element analysis.

BACKGROUND: This study represents the first finite element (FE) analysis of long-instrumented spinal fusion from the thoracic vertebrae to the pelvis in the context of adult spinal deformity (ASD) with osteoporosis. We aimed to evaluate the von Mises stress in long spinal instrumentation for models that differ in terms of spinal balance, fusion length, and implant type. METHODS: In this three-dimensional FE analysis, FE models were developed based on computed tomography images from a patient with osteoporosis. The von Mises stress was compared for three different sagittal vertical axes (SVAs) (0, 50, and 100 mm), two different fusion lengths (from the pelvis to the second [T2-S2AI] or 10th thoracic vertebra [T10-S2AI]), and two different types of implants (pedicle screw or transverse hook) in the upper instrumented vertebra (UIV). We created 12 models based on combinations of these conditions. RESULTS: The overall von Mises stress was 3.1 times higher on the vertebrae and 3.9 times higher on implants for the 50-mm SVA models than that for the 0-mm SVA models. Similarly, the values were 5.0 times higher on the vertebrae and 6.9 times higher on implants for the 100-mm SVA models than that for the 0-mm SVA models. Higher SVA was associated with greater stress below the fourth lumbar vertebrae and implants. In the T2-S2AI models, the peaks of vertebral stress were observed at the UIV, at the apex of kyphosis, and below the lower lumbar spine. In the T10-S2AI models, the peaks of stress were observed at the UIV and below the lower lumbar region. The von Mises stress in the UIV was also higher for the screw models than for the hook models. CONCLUSION: Higher SVA is associated with greater von Mises stress on the vertebrae and implants. The stress on the UIV is greater for the T10-S2AI models than for the T2-S2AI models. Using transverse hooks instead of screws at the UIV may reduce stress in patients with osteoporosis.

Clinical outcomes following total en bloc spondylectomy for spinal metastases from lung cancer.

BACKGROUND: The current guidelines for the treatment of non-small cell lung cancer encourage local curative treatment for selected patients with oligometastases. This study evaluated the surgical results of total en bloc spondylectomy (TES) for isolated spinal metastases originating from lung cancer in carefully selected patients. METHODS: We retrospectively reviewed 14 patients (7 men and 7 women) who underwent TES for spinal metastases originating from lung cancer between 2000 and 2017. The primary outcome measure was the postoperative overall survival time. The histological types included adenocarcinoma (n = 12), pleomorphic carcinoma (n = 1), and small cell lung carcinoma (SCLC) (n = 1 patient). We assessed postoperative survival using Kaplan-Meier analysis and the log-rank test. RESULTS: The median postoperative survival time was 83.0 months (6-162 months) in 13 patients with non-small cell lung carcinoma (NSCLC) and 6 months in 1 patient with SCLC. The 3-, 5-, and 10-year overall survival rates in patients with NSCLC were 61.5%, 53.8%, and 15.4%, respectively. Poor postoperative performance status (PS) and Frankel grade, and preoperative irradiation to the vertebrae to be resected were significantly associated with short-term survival after TES in patients with NSCLC (p < 0.05). CONCLUSIONS: The surgical results of TES for spinal metastases of lung cancer were relatively favorable among carefully selected patients. TES may be indicated for spinal metastases of lung cancer in patients with controlled primary lung cancer, NSCLC histology, prospect of good postoperative PS, and preferably no irradiation to the target vertebrae.

The influence of costal resection on pulmonary function after total en bloc spondylectomy for spine tumor.

BACKGROUND: Total en bloc spondylectomy (TES) is one of the surgical procedures which has been recognized as a complete resection for spine tumors. Although the surgery achieves favorable local control for solitary spinal lesion, performing the procedure in the thoracic spine requires circumferential dissection around the vertebral body and bilateral rib resections which might result in decline of pulmonary function postoperatively. This study aimed to clarify whether the number of rib resections negatively impacts pulmonary function after the procedure. METHODS: This study included 31 patients who underwent vertebrectomy (17 males and 14 females) with a mean age of 54.2 years. Pulmonary function testing (PFT) was performed before surgery and at 1 month, 6 months, and 1 year postoperative visits. Patients with restrictive disorders such as space occupying lesions in the lung, obstructive problems such as a history of asthma, and smoking history were excluded from this study. Associations between the number of rib resections and PFT data were analyzed based on the resected level of the thoracic spine. RESULTS: There was a significant decrease in forced vital capacity (FVC) at 1 month (72% of preoperative value), followed by gradual recovery at 6 months (89%) and 1 year (90%). The percentage of predicted forced expiratory volume in 1 s remained stable. Patients who underwent three pairs of rib resections showed a significant decrease in the FVC (83.5% of the preoperative value) and FEV1 (82.1% of the preoperative value) compared with one or two pairs of rib resections. CONCLUSION: FVC decreased 1 month after vertebrectomy and returned to 90% of preoperative value at 1 year postoperatively. Three pairs of rib resections showed a significant decrease in FVC, suggesting the influence of a greater numbers of rib resections on pulmonary function.

Risk factors that hinder locomotive syndrome improvement following surgery for musculoskeletal diseases in older patients: A multicentre prospective study.

OBJECTIVES: This study aimed to evaluate preoperative and post-operative locomotive syndrome (LS) in older adults undergoing surgical treatment for musculoskeletal diseases of the lumbar spine and lower extremities and identify risk factors that impede LS improvement after surgery. METHODS: The baseline evaluation included 471 patients 65 years or older [276 in the pre-old-age (65-74 years) group; 195 in the old-age (75 years or older) group] and examined the preoperative and post-operative LS data. The second evaluation performed to identify risk factors, including anthropometric measurements, comorbidity, and frailty, that hinder LS improvement after surgery included 378 patients with preoperative LS Stage 3. RESULTS: Preoperatively, 80% of the patients had LS Stage 3; this rate decreased to 40% post-operatively. Half of the patients exhibited post-operative LS improvement. The LS improvement rate was higher in the pre-old-age group than in the old-age group. According to the multiple logistic regression analysis, old age, high body mass index, weak hand grip strength, and high 5-factor modified frailty index score were significant risk factors that hinder LS improvement after surgery. CONCLUSIONS: Ageing, obesity, weak muscle strength, and frailty can hinder LS improvement in older patients who undergo surgery.

The prevalence of locomotive syndrome and its associated factors in patients with Type 2 diabetes mellitus.

OBJECTIVES: We investigated the prevalence of locomotive syndrome (LS) and related musculoskeletal diseases [osteoarthritis (OA), lumbar spondylosis, and spinal alignment] in Type 2 diabetes mellitus (DM) patients. METHODS: Clinical data were collected from 101 patients (55 males; 46 females) admitted to our hospital for diabetes education from October 2018 to April 2021. Patients underwent full-spine and whole-legs standing radiography and physical measurements (10-m walking and grip strength tests and three LS risk tests). RESULTS: The estimated prevalence of LS was 86.1% (Stage 1: 44.5%, Stage 2: 41.6%), lumbar spondylosis was 11.9%, and hip, knee, and ankle OA were 16.9%, 51.5%, and 12.9%, respectively. Multiple logistic regression analysis identified grip strength [odds ratio (OR) = 0.89, confidence interval (CI) = 0.83-0.94], diabetic retinopathy (OR = 5.85, CI = 1.64-20.78), knee OA (OR = 3.34, CI = 1.11-10.02), and a sagittal vertical axis >40 mm (OR = 3.42, CI = 1.13-10.39) as significantly associated risk factors for worsening LS in Type 2 DM patients. CONCLUSIONS: This study clarified the epidemiological indicators of LS and associated factors in DM patients. Exercise therapy and DM management are effective strategies to reduce the occurrence and progression of LS.

Conditional inactivation of the L-type amino acid transporter LAT1 in chondrocytes models idiopathic scoliosis in mice.

Scoliosis, usually diagnosed in childhood and early adolescence, is an abnormal lateral curvature of the spine. L-type amino acid transporter 1 (LAT1), encoded by solute carrier transporter 7a5 (Slc7a5), plays a crucial role in amino acid sensing and signaling in specific cell types. We previously demonstrated the pivotal role of LAT1 on bone homeostasis in mice, and the expression of LAT1/SLC7A5 in vertebral cartilage of pediatric scoliosis patients; however, its role in chondrocytes on spinal homeostasis and implications regarding the underlying mechanisms during the onset and progression of scoliosis, remain unknown. Here, we identified LAT1 in mouse chondrocytes as an important regulator of postnatal spinal homeostasis. Conditional inactivation of LAT1 in chondrocytes resulted in a postnatal-onset severe thoracic scoliosis at the early adolescent stage with normal embryonic spinal development. Histological analyses revealed that Slc7a5 deletion in chondrocytes led to general disorganization of chondrocytes in the vertebral growth plate, along with an increase in apoptosis and a decrease in cell proliferation. Furthermore, loss of Slc7a5 in chondrocytes activated the general amino acid control (GAAC) pathway but inactivated the mechanistic target of rapamycin complex 1 (mTORC1) pathway in the vertebrae. The spinal deformity in Slc7a5-deficient mice was corrected by genetic inactivation of the GAAC pathway, but not by genetic activation of the mTORC1 pathway. These findings suggest that the LAT1-GAAC pathway in chondrocytes plays a critical role in the maintenance of proper spinal homeostasis by modulating cell proliferation and survivability.

Tumor-Specific Immunoenhancing Effects after Local Cryoablation for Metastatic Bone Tumor in a Mouse Model.

We investigated the abscopal effect after cryoablation (CA) on bone metastasis using a mouse model. Breast cancer cells were implanted in the bilateral tibiae of mice. The left tumor was treated locally with CA, and the right abscopal tumor (AT) was left untreated. The mice were divided into four groups based on the combination of CA and intraperitoneal administration of anti-PD-1 antibody (PD) as treatment interventions (Control, CA, PD, and CA + PD). The reduction ratio of the size of AT, the quantitative immune effects at enzyme-linked immunospot (ELISPOT) assay, and the intensity of infiltration of immune-related cells to AT were compared among the groups. CA alone showed a significant immunoenhancing effect on the volume change ratio of AT from day 0 to day 14 (Control-CA: p < 0.05), ELISPOT assay (Control-CA: p < 0.01), and CD4+ cell count in immunostaining (Control-CA: p < 0.05). CA alone showed no significant immunoenhancing effect on CD8+ and Foxp3+ cell counts in immunostaining, but the combination of CA and PD showed a significant immunoenhancing effect (Control-CA + PD: p < 0.01 [CD8, Foxp3]). The results suggested that the abscopal effect associated with the local cryotherapy of metastatic bone tumors was activated by CA and enhanced by its combination with PD.

Evaluation of locomotive syndrome in patients receiving surgical treatment for degenerative musculoskeletal diseases: A multicentre prospective study using the new criteria.

OBJECTIVES: This study aimed to evaluate the condition of patients with locomotive syndrome (LS) and their improvement after undergoing surgery for degenerative musculoskeletal diseases using the new criteria, including stage 3. METHODS: In total, 435 patients aged ≥40 years (167 middle-aged and 268 older) were divided into four groups based on the disease location: the lumbar (n = 118), hip (n = 191), knee (n = 80), and foot and ankle (n = 46) groups. Patients were evaluated by pre- and 1 year postoperative LS risk tests, including the stand-up test, two-step test, and 25-Question Geriatric Locomotive Function Scale. RESULTS: The pre- and postoperative prevalence of LS stage 3 were 78% and 29%, respectively. The postoperative LS stage improved in 62% of patients (77% and 53% in the middle-aged and older groups, respectively). Overall, the knee group showed the worst results, and the foot and ankle groups showed the best pre- and postoperative results. The pre- and postoperative prevalence of LS stage 3 according to the 25-Question Geriatric Locomotive Function Scale were comparable to those based on the total assessment. CONCLUSIONS: The new LS stage criteria are appropriate, and the 25-Question Geriatric Locomotive Function Scale is a good option for evaluating patients requiring surgery.

Clinical outcomes and prognostic factors following the surgical resection of renal cell carcinoma spinal metastases.

The efficacy of surgical resection in metastatic renal cell carcinoma is an active and important research field in the postcytokine era. Bone metastases, especially in the spine, compromise patient performance status. Metastasectomy is indicated, if feasible, because it helps to achieve the best clinical outcomes possible compared with other treatments. This study examined the postoperative survival and prognostic factors in patients who underwent metastasectomy of spinal lesions. The retrospective study included 65 consecutive patients with metastatic renal cell carcinomas who were operated on by spinal metastasectomy between 1995 and 2017 at our institution. The cancer-specific survival times from the first spinal metastasectomy to death or the last follow-up (≥3 years) were determined using Kaplan-Meier analysis. Potential factors influencing survival were analyzed using Cox proportional hazard models. Planned surgical resection of all the spine tumors was achieved in all patients. Of these, 38 had complete metastasectomy of all visible metastases, including extraspinal lesions. In all patients, the estimated median cancer-specific survival time was 100 months. The 3-, 5-, and 10-year cancer-specific survival rates were 77%, 62%, and 48%, respectively. The survival times after spinal metastasectomy were similar in both cytokine and postcytokine groups. In multivariate analyses, postoperative disability, the coexistence of liver metastases, multiple spinal metastases, and incomplete metastasectomy were significant risk factors associated with short-term survival. Complete metastasectomy, including extraspinal metastases, was associated with improved cancer-specific survival. Proper patient selection and complete metastasectomy provide a better prognosis in metastatic renal cell carcinoma patients.

Surgical Metastasectomy in the Spine: A Review Article.

BACKGROUND: The use of surgical metastasectomy (SM) has increased across cancer types in recent decades despite the increasing efficacy of modern systemic treatment modalities. Symptomatic spinal metastases severely compromise patients' performance status. However, as spinal SM is a complex surgery with potentially significant complications, it is not considered the treatment of choice. METHODS: We reviewed the articles on SM in several primary cancers with different types of metastatic lesions and extracted the data from relevant articles to provide a comprehensive review including the surgical techniques, indications, reported outcomes, and future prospects of SM in spinal metastases. RESULTS: Total en bloc spondylectomy (TES) is a method of spinal SM associated with a lower risk of tumor recurrence and complications. Intralesional transpedicular osteotomy using a fine threadwire saw allows prevention of spinal cord and nerve root injuries. Spinal SM is considered suitable for patients with controlled primary disease having no evidence of disseminated extraspinal metastases, a completely resectable solitary lesion in the spine, and adequate cardiopulmonary reserve to tolerate the surgery. Metastatic lesions from kidney and thyroid cancers have been reported as the best candidates for spinal SM. Although data about spinal SM are limited, the reported outcomes are favorable with acceptable local recurrence rates in long-term follow-up. CONCLUSION: In patients with isolated resectable spinal metastases, complete SM including TES is a useful option as it can improve function and survival. However, appropriate patient selection and surgical feasibility remain the most important aspects of management. IMPLICATIONS FOR PRACTICE: Surgical metastasectomy for spinal metastases may be a potentially curative treatment option with a low risk of local recurrence and lead to prolonged long-term survival if appropriate patients are selected and if the surgery is carried out by experienced surgeons in high-volume centers.

Radiation Disrupts the Protective Function of the Spinal Meninges in a Mouse Model of Tumor-induced Spinal Cord Compression.

BACKGROUND: Recent advances in multidisciplinary treatments for various cancers have extended the survival period of patients with spinal metastases. Radiotherapy has been widely used to treat spinal metastases; nevertheless, long-term survivors sometimes undergo more surgical intervention after radiotherapy because of local tumor relapse. Generally, intradural invasion of a spinal tumor seldom occurs because the dura mater serves as a tissue barrier against tumor infiltration. However, after radiation exposure, some spinal tumors invade the dura mater, resulting in leptomeningeal dissemination, intraoperative dural injury, or postoperative local recurrence. The mechanisms of how radiation might affect the dura have not been well-studied. QUESTIONS/PURPOSES: To investigate how radiation affects the spinal meninges, we asked: (1) What is the effect of irradiation on the meningeal barrier's ability to protect against carcinoma infiltration? (2) What is the effect of irradiation on the meningeal barrier's ability to protect against sarcoma infiltration? (3) What is the effect of irradiation on dural microstructure observed by scanning electron microscopy (SEM)? (4) What is the effect of irradiation on dural microstructure observed by transmission electron microscopy (TEM)? METHODS: Eighty-four 10-week-old female ddY mice were randomly divided into eight groups: mouse mammary tumor (MMT) implantation 6 weeks after 0-Gy irradiation (nonirradiation) (n = 11), MMT implantation 6 weeks after 20-Gy irradiation (n = 10), MMT implantation 12 weeks after nonirradiation (n = 10), MMT implantation 12 weeks after 20-Gy irradiation (n = 11), mouse osteosarcoma (LM8) implantation 6 weeks after nonirradiation (n = 11), LM8 implantation 6 weeks after 20-Gy irradiation (n = 11), LM8 implantation 12 weeks after nonirradiation (n = 10), and LM8 implantation 12 weeks after 20-Gy irradiation (n = 10); female mice were used for a mammary tumor metastasis model and ddY mice, a closed-colony mice with genetic diversity, were selected to represent interhuman diversity. Mice in each group underwent surgery to generate a tumor-induced spinal cord compression model at either 6 weeks or 12 weeks after irradiation to assess changes in the meningeal barrier's ability to protect against tumor infiltration. During surgery, the mice were implanted with MMT (representative of a carcinoma) or LM8 tumor. When the mice became paraplegic because of spinal cord compression by the growing implanted tumor, they were euthanized and evaluated histologically. Four mice died from anesthesia and 10 mice per group were euthanized (MMT-implanted groups: MMT implantation occurred 6 weeks after nonirradiation [n = 10], 6 weeks after irradiation [n = 10], 12 weeks after nonirradiation [n = 10], and 12 weeks after irradiation [n = 10]; LM8-implanted groups: LM8 implantation performed 6 weeks after nonirradiation [n = 10], 6 weeks after irradiation [n = 10], 12 weeks after nonirradiation [n = 10], and 12 weeks after irradiation [n = 10]); 80 mice were evaluated. The spines of the euthanized mice were harvested; hematoxylin and eosin staining and Masson's trichrome staining slides were prepared for histologic assessment of each specimen. In the histologic assessment, intradural invasion of the implanted tumor was graded in each group by three observers blinded to the type of tumor, presence of irradiation, and the timing of the surgery. Grade 0 was defined as no intradural invasion with intact dura mater, Grade 1 was defined as intradural invasion with linear dural continuity, and Grade 2 was defined as intradural invasion with disruption of the dural continuity. Additionally, we euthanized 12 mice for a microstructural analysis of dura mater changes by two observers blinded to the presence of irradiation. Six mice (three mice in the 12 weeks after nonirradiation group and three mice in the 12 weeks after 20-Gy irradiation group) were quantitatively analyzed for defects on the dural surface with SEM. The other six mice (three mice in the 12 weeks after nonirradiation group and three mice in the 12 weeks after 20-Gy irradiation group) were analyzed for layer structure of collagen fibers constituting dura mater by TEM. In the SEM assessment, the number and size of defects on the dural surface on images (200 µm × 300 µm) at low magnification (× 2680) were evaluated. A total of 12 images (two per mouse) were evaluated for this assessment. The days from surgery to paraplegia were compared between each of the tumor groups using the Kruskal-Wallis test. The scores of intradural tumor invasion grades and the number of defects on dural surface per SEM image were compared between irradiation group and nonirradiation group using the Mann-Whitney U test. Interobserver reliabilities of assessing intradural tumor invasion grades and the number of dural defects on the dural surface were analyzed using Fleiss'κ coefficient. P values < 0.05 were considered statistically significant. RESULTS: There was no difference in the median (range) time to paraplegia among the MMT implantation 6 weeks after nonirradiation group, the 6 weeks after irradiation group, the 12 weeks after nonirradiation group, and the 12 weeks after irradiation group (16 days [14 to 17] versus 14 days [12 to 18] versus 16 days [14 to 17] versus 14 days [12 to 15]; χ2 = 4.7; p = 0.19). There was also no difference in the intradural invasion score between the MMT implantation 6 weeks after irradiation group and the 6 weeks after nonirradiation group (8 of 10 Grade 0 and 2 of 10 Grade 1 versus 10 of 10 Grade 0; p = 0.17). On the other hand, there was a higher intradural invasion score in the MMT implantation 12 weeks after irradiation group than the 12 weeks after nonirradiation group (5 of 10 Grade 0, 3 of 10 Grade 1 and 2 of 10 Grade 2 versus 10 of 10 Grade 0; p = 0.02). Interobserver reliability of assessing intradural tumor invasion grades in the MMT-implanted group was 0.94. There was no difference in the median (range) time to paraplegia among in the LM8 implantation 6 weeks after nonirradiation group, the 6 weeks after irradiation group, the 12 weeks after nonirradiation group, and the 12 weeks after irradiation group (12 days [9 to 13] versus 10 days [8 to 13] versus 11 days [8 to 13] versus 9 days [6 to 12]; χ2 = 2.4; p = 0.50). There was also no difference in the intradural invasion score between the LM8 implantation 6 weeks after irradiation group and the 6 weeks after nonirradiation group (7 of 10 Grade 0, 1 of 10 Grade 1 and 2 of 10 Grade 2 versus 8 of 10 Grade 0 and 2 of 10 Grade 1; p = 0.51), whereas there was a higher intradural invasion score in the LM8 implantation 12 weeks after irradiation group than the 12 weeks after nonirradiation group (3 of 10 Grade 0, 3 of 10 Grade 1 and 4 of 10 Grade 2 versus 8 of 10 Grade 0 and 2 of 10 Grade 1; p = 0.04). Interobserver reliability of assessing intradural tumor invasion grades in the LM8-implanted group was 0.93. In the microstructural analysis of the dura mater using SEM, irradiated mice had small defects on the dural surface at low magnification and degeneration of collagen fibers at high magnification. The median (range) number of defects on the dural surface per image in the irradiated mice was larger than that of nonirradiated mice (2 [1 to 3] versus 0; difference of medians, 2/image; p = 0.002) and the median size of defects was 60 µm (30 to 80). Interobserver reliability of assessing number of defects on the dural surface was 1.00. TEM revealed that nonirradiated mice demonstrated well-organized, multilayer structures, while irradiated mice demonstrated irregularly layered structures at low magnification. At high magnification, well-ordered cross-sections of collagen fibers were observed in the nonirradiated mice. However, disordered alignment of collagen fibers was observed in irradiated mice. CONCLUSION: Intradural tumor invasion and disruptions of the dural microstructure were observed in the meninges of mice after irradiation, indicating radiation-induced disruption of the meningeal barrier. CLINICAL RELEVANCE: We conclude that in this form of delivery, radiation is associated with disruption of the dural meningeal barrier, indicating a need to consider methods to avoid or limit Postradiation tumor relapse and spinal cord compression when treating spinal metastases so that patients do not experience intradural tumor invasion. Surgeons should be aware of the potential for intradural tumor invasion when they perform post-irradiation spinal surgery to minimize the risks for intraoperative dural injury and spinal cord injury. Further research in patients with irradiated spinal metastases is necessary to confirm that the same findings are observed in humans and to seek irradiation methods that prevent or minimize the disruption of meningeal barrier function.

The efficacy of surgical treatment on locomotive syndrome and physical function in patients with lumbar spinal canal stenosis.

BACKGROUND: Locomotive syndrome is a condition of reduced mobility due to problems with locomotive organs. Although lumbar spinal canal stenosis is one of the major diseases constituting locomotive syndrome, only few studies have focused on the association between the two pathologies. We aimed to investigate the effect of surgery on lumbar spinal canal stenosis with respect to locomotive syndrome using various physical function tests, including locomotive syndrome risk tests, before and after surgery. METHODS: Clinical data of 101 consecutive patients (male = 46; female = 55; mean age, 69.3 years) who underwent surgery for lumbar spinal canal stenosis at our institute were prospectively collected. Results of physical function tests, including stand-up test, two-step test, and 25-Question Geriatric Locomotive Function Scale, and the sagittal vertical axis were evaluated before and 1 year after surgery. The association between several parameters and improvement of risk level in locomotive syndrome was evaluated. RESULTS: In the total assessment, 93.1% of cases were in stage 2 and 6.9% in stage 1 preoperatively, while 72.4% were in stage 2, 22.4% in stage 1, and 5.2% in stage 0 at 1 year postoperatively. Postoperative improvement in the total assessment was observed in 28.7% of cases. Several physical function tests and sagittal vertical axis showed significant improvement after surgery. On multiple logistic regression analysis, age >75 years (odds ratio = 10.9, confidence interval = 1.09-109) and postoperative sagittal vertical axis >40 mm (odds ratio = 17.8, confidence interval = 1.78-177) were significant risk factors associated with non-improvement in risk level of locomotive syndrome. CONCLUSIONS: Surgical treatment for lumbar spinal canal stenosis improved physical function, including locomotive syndrome. Risk factors associated with non-improvement of locomotive syndrome were later-stage elderly and postoperative sagittal balance impairment.

Abscopal Effect of Frozen Autograft Reconstruction Combined with an Immune Checkpoint Inhibitor Analyzed Using a Metastatic Bone Tumor Model.

We evaluated the abscopal effect of re-implantation of liquid nitrogen-treated tumor-bearing bone grafts and the synergistic effect of anti-PD-1 (programmed death-1) therapy using a bone metastasis model, created by injecting MMT-060562 cells into the bilateral tibiae of 6-8-week-old female C3H mice. After 2 weeks, the lateral tumors were treated by excision, cryotreatment using liquid nitrogen, excision with anti-PD-1 treatment, and cryotreatment with anti-PD-1 treatment. Anti-mouse PD-1 4H2 was injected on days 1, 6, 12, and 18 post-treatment. The mice were euthanized after 3 weeks; the abscopal effect was evaluated by focusing on growth inhibition of the abscopal tumor. The re-implantation of frozen autografts significantly inhibited the growth of the remaining abscopal tumors. However, a more potent abscopal effect was observed in the anti-PD-1 antibody group. The number of CD8+ T cells infiltrating the abscopal tumor and tumor-specific interferon-γ (IFN-γ)-producing spleen cells increased in the liquid nitrogen-treated group compared with those in the excision group, with no significant difference. The number was significantly higher in the anti-PD-1 antibody-treated group than in the non-treated group. Overall, re-implantation of tumor-bearing frozen autograft has an abscopal effect on abscopal tumor growth, although re-implantation of liquid nitrogen-treated bone grafts did not induce a strong T-cell response or tumor-suppressive effect.