Immune evasion in lung metastasis of leiomyosarcoma: upregulation of EPCAM inhibits CD8+ T cell infiltration.

BACKGROUND: Leiomyosarcomas are among the most common histological types of soft tissue sarcoma (STS), with no effective treatment available for advanced patients. Lung metastasis, the most common site of distant metastasis, is the primary prognostic factor. We analysed the immune environment targeting lung metastasis of STS to explore new targets for immunotherapy. METHODS: We analysed the immune environment of primary and lung metastases in 38 patients with STS using immunohistochemistry. Next, we performed gene expression analyses on primary and lung metastatic tissues from six patients with leiomyosarcoma. Using human leiomyosarcoma cell lines, the effects of the identified genes on immune cells were assessed in vitro. RESULTS: Immunohistochemistry showed a significant decrease in CD8+ cells in the lung metastases of leiomyosarcoma. Among the genes upregulated in lung metastases, epithelial cellular adhesion molecule (EPCAM) showed the strongest negative correlation with the number of CD8+ cells. Transwell assay results showed that the migration of CD8+ T cells was significantly increased in the conditioned media obtained after inhibition or knock down of EPCAM. CONCLUSIONS: EPCAM was upregulated in lung metastases of leiomyosarcoma, suggesting inhibition of CD8+ T cell migration. Our findings suggest that EPCAM could serve as a potential novel therapeutic target for leiomyosarcoma.

Effects of interleukin-6 signal inhibition on Treg subpopulations and association of Tregs with clinical outcomes in rheumatoid arthritis.

OBJECTIVES: Anti-IL-6 receptor antibodies are clinically efficacious in the management of rheumatoid arthritis (RA) with an associated increase in regulatory T cells (Tregs); however, the role of functional Treg subsets has yet to be clarified. This study aimed to evaluate how functional Treg subsets are altered by IL-6 receptor blockade and to analyze the relationship between these Treg subsets and the clinical outcome of RA. METHODS: We collected frozen peripheral blood mononuclear cells (PBMCs) from 40 patients with RA who started tocilizumab (TCZ) with or without MTX and 11 healthy controls (HCs). We fractionated Tregs with flow cytometry based on markers of phenotype and function and measured the proportions of detailed Treg subsets sequentially from baseline to week 52. RESULTS: The proportions of resting Tregs (rTregs) and rTregs+activated Tregs (aTregs) were significantly lower in RA patients at baseline than in HCs. The proportions of all those CD127low Tregs, rTregs, aTregs, and rTregs+aTregs were significantly increased with TCZ treatment. In patients treated with TCZ without MTX, rTreg were increased. Patients with an increase in the proportion of rTregs at week 12 had significantly less arthritis flares during the observation period. CONCLUSIONS: Blocking IL-6 receptor with TCZ increased the proportion of rTregs, a functional Treg subpopulation. Patients with an early increase in rTregs showed a favorable treatment course, and this increase in rTregs may reflect molecular remission induced by IL-6 signal inhibition.

Geriatric nutritional risk index as a predictor for surgical site infection in malignant musculoskeletal tumours of the trunk.

BACKGROUND AND OBJECTIVE: Surgical site infection (SSI) is common in surgery for malignant musculoskeletal tumours, specifically those arising from the trunk. In this study, we investigated the risk factors for SSI after resection of musculoskeletal tumours of the trunk. METHODS: This retrospective observational study included 125 patients (72 males, 53 females) with musculoskeletal tumours of the trunk in our hospital from 1 April 2008 to 31 August 2023. The incidence of SSI and its risk factors were investigated. RESULTS: SSI was observed in 26% (32/125), and the median time to SSI was 22 days. On multivariate analysis, the following were identified as risk factors for SSI: tumours arising caudal to Jacoby's line (hazard ratio [HR] 4.04; P = .0107), soft tissue reconstruction (HR 3.43; P = .0131), and low Geriatric Nutritional Risk Index (GNRI) (HR 0.96; P = .0304). Patients were classified into two risk categories based on GNRI scores: the risk group (GNRI ≤98) and no risk group (>98). The risk group showed a significantly lower overall noninfection survival rate (P = .023). CONCLUSION: Tumours arising caudal to Jacoby line, soft tissue reconstruction, and lower GNRI were risk factors for SSI. Preoperative and postoperative nutritional interventions should be considered to improve GNRI.

Radiographic knee osteoarthritis severity has no impact on fall risk: the locomotive syndrome and health outcomes in the aizu cohort study (LOHAS): a cross-sectional study.

BACKGROUND: To investigate factors that have an impact on the risk of falls and determine whether radiographic knee osteoarthritis (KOA) is a factor involved in falls independent of knee pain, psychological factors, and physical function. METHODS: A cross-sectional analysis was conducted on 1083 subjects for the 2009 Locomotive Syndrome and Health Outcomes in the Aizu Cohort Study (LOHAS). A logistic regression analysis was performed to examine the relationship between radiographic KOA and fall history. RESULTS: Fall history was significantly associated with the severity of knee pain. Compared to subjects with no knee pain, the odds ratio (OR) was 1.53 times higher in the subjects with mild knee pain (95% confidence interval [CI]: 1.04-2.25), 1.69 times higher in those with moderate knee pain (95%CI: 1.03-2.79), and 2.98 times higher in those with severe knee pain (95%CI: 1.67-5.30). In subjects with depression, the OR was 1.91 (95%CI: 1.25-2.92), and in those with decreased mobility, the OR was 1.70 (95%CI: 1.08-2.69). Age, gender, knee crepitus, BMI, OLST, and sleeping pill use were not significantly associated with fall risk. In a multivariate analysis, radiographic KOA severity was not significantly associated with fall risk (OR 0.81, 95%CI 0.44-1.50 in mild OA; OR 1.10, 95%CI 0.57-2.14 in severe OA). CONCLUSION: Knee pain, decreased mobility, and depression, but not the radiographic KOA severity, were significantly associated with a fall risk. Regardless of the individual's radiographic KOA severity, the risk of falls may be reduced by treating his/her knee pain, mobility problems, and/or psychological factors.

Eldecalcitol Induces Minimodeling-Based Bone Formation and Inhibits Sclerostin Synthesis Preferentially in the Epiphyses Rather than the Metaphyses of the Long Bones in Rats.

This study aimed to examine minimodeling-based bone formation between the epiphyses and metaphyses of the long bones of eldecalcitol (ELD)-administered ovariectomized rats. Sixteen-week-old female rats were divided into four groups: sham-operated rats receiving vehicle (Sham group), ovariectomized (OVX) rats receiving vehicle (Vehicle group), or ELDs (30 or 90 ng/kg BW, respectively; ELD30 and ELD90 groups). ELD administration increased bone volume and trabecular thickness, reducing the number of osteoclasts in both the epiphyses and metaphyses of OVX rats. The Sham and Vehicle groups exhibited mainly remodeling-based bone formation in both regions. The epiphyses of the ELD groups showed a significantly higher frequency of minimodeling-based bone formation than remodeling-based bone formation. In contrast, the metaphyses exhibited significantly more minimodeling-based bone formation in the ELD90 group compared with the ELD30 group. However, there was no significant difference between minimodeling-based bone formation and remodeling-based bone formation in the ELD90 group. While the minimodeling-induced new bone contained few sclerostin-immunoreactive osteocytes, the underlying pre-existing bone harbored many. The percentage of sclerostin-positive osteocytes was significantly reduced in the minimodeling-induced bone in the epiphyses but not in the metaphyses of the ELD groups. Thus, it seems likely that ELD could induce minimodeling-based bone formation in the epiphyses rather than in the metaphyses, and that ELD-driven minimodeling may be associated with the inhibition of sclerostin synthesis.

Time Course of Asymptomatic Stenosis in Multiple Lumbar Spinal Stenosis-Five-Year Results of Selective Decompression of Symptomatic Levels.

Background: In the diagnosis of lumbar spinal stenosis (LSS), finding stenosis with magnetic resonance imaging (MRI) does not always correlate with symptoms such as sciatica or intermittent claudication. We perform decompression surgery only for cases where the levels diagnosed from neurological findings are symptomatic, even if multiple stenoses are observed on MRI. The objective of this study was to examine the time course of asymptomatic stenosis in patients with LSS after they underwent decompression surgery for symptomatic stenosis. Materials and Methods: The participants in this study comprised 137 LSS patients who underwent single-level L4-5 decompression surgery from 2003 to 2013. The dural sac cross-sectional area at the L3-4 disc level was calculated based on preoperative MRI. A cross-sectional area less than 50 mm2 was defined as stenosis. The patients were grouped, according to additional spinal stenosis at the L3-4 level, into a double group (16 cases) with L3-4 stenosis, and a single group (121 cases) without L3-4 stenosis. Incidences of new-onset symptoms originating from L3-4 and additional L3-4-level surgery were examined. Results: Five years after surgery, 98 cases (72%) completed follow-up. During follow-up, 2 of 12 patients in the double group (16.7%) and 9 of 86 patients in the single group (10.5%) presented with new-onset symptoms originating from L3-4, showing no significant difference between groups. Additional L3-4 surgery was performed for one patient (8.3%) in the double group and three patients (3.5%) in the single group; again, no significant difference was shown. Conclusion: Patients with asymptomatic L3-4 stenosis on preoperative MRI were not prone to develop new symptoms or need additional L3-4-level surgery within 5 years after surgery when compared to patients without preoperative L3-4 stenosis. These results indicate that prophylactic decompression for asymptomatic levels is unnecessary.

Rib stress fracture in a female athlete caused by bouncing the barbell in bench press exercise: A case report.

Rib stress fractures can occur in sports involving repetitive trunk muscle contractions. Few documented cases show rib fractures from repetitive upper-limb training. This report presents a case of a rib stress fracture from micro blunt trauma during bench press exercises. The patient was a 24-year-old elite female sprinter with a history of left navicular stress fracture and secondary amenorrhea treatment a year prior. She modified her bench press technique to involve bouncing the barbell on her rib cage. Within weeks, she experienced anterior chest pain, exacerbated by sneezing. Computed tomography revealed a fifth rib fracture with callus formation. After refraining from bench presses for 4 weeks, her chest pain subsided, allowing her to resume upper-limb training. When athletes performing bench press exercises experience chest pain, rib fractures should be considered, even without acute trauma. Additionally, research on the safety of the bouncing bench pressing technique is required.

Atypical Fracture of the Scapular Spine: A Case Report.

Atypical fractures are gaining attention as a severe potential side effect of long-term treatment with bone-modifying agents (e.g., bisphosphonate and denosumab) for osteoporosis. Most atypical fractures occur in weight-bearing bones; the femur is the most frequent site. Atypical fractures occurring in non-weight-bearing bones are extremely rare. We describe an atypical fracture of the scapular spine in a 92-year-old Japanese woman with osteoporosis who had been treated with minodronate for ~7 years. Although the dislocation of the fracture site remained after conservative treatment, there was no obstacle to her daily life.

Effectiveness of capsulodesis in ganglion cysts caused by a medial meniscotibial ligament tear and medial meniscus extrusion.

INTRODUCTION AND IMPORTANCE: Meniscotibial ligament (MTL) has received attention as a major meniscus stabilizer. An MTL injury results in instability and extrusion of the meniscus. Cases of knee ganglion cyst formation due to an MTL tear and medial meniscus extrusion (ME) are extremely rare. CASE PRESENTATION: A 42-year-old female Japanese childcare worker presented painful ganglion cysts on the proximal medial side of her left tibia. An MTL tear and medial ME were thought to be involved in the ganglion formation. Joint fluid flowed through the meniscotibial side of the extruded meniscus into the space between the medial collateral ligament and tibia, where the MTL tear acted as a check valve, forming ganglion cysts. Ultrasonography-guided aspiration of the ganglion was attempted, but ganglion cysts recurred within 1 month. We used an open excision for the ganglion cysts, and arthroscopic capsulodesis was performed to repair the MTL and internalize the medial meniscus to block the inflow route from the intra-articular space. CLINICAL DISCUSSION: We performed capsulodesis, which repaired the MTL and internalized the medial meniscus to prevent the recurrence of the ganglion cyst. Three months have passed since the surgery, with no recurrence of knee pain or ganglion cysts, indicating good short-term results. CONCLUSIONS: We encountered a rare case of ganglion cyst formation in the knee joint due to MTL tear and medial ME. Arthroscopic MTL repair and internalization of the meniscus by capsulodesis were effective in treating the ganglion cysts.

A Professional Basketball Player Who Suffered an Open Ankle Dislocation Without an Associated Fracture Achieves His Prior Performance Level Three Months Later.

An ankle dislocation without an accompanying fracture is extremely rare, and an open ankle dislocation is even rarer. Due to its rarity, there is no consensus on the optimal treatment strategy. A professional basketball player (a 28-year-old male) incurred an open ankle dislocation (with no accompanying fracture) during a basketball game due to plantar flexion and inversion of his ankle during the transition from dashing to stop motion. The same day, an emergency reduction under spinal anesthesia was performed with primary closure of the wound. Considering the complications of infection and decreased ankle range of motion (ROM), primary ligament repair was not performed. He was treated conservatively with cast immobilization for four weeks, and early weight-bearing and ROM exercises were initiated. At six weeks postoperatively, stress radiography did not reveal ankle instability. After three months of conservative treatment, the patient was able to play basketball at his previous performance level. Four weeks of cast immobilization without ligament repair plus early rehabilitation with weight-bearing and ROM exercises allowed for an early return without complications. Even in high-level athletes, open ankle dislocation without an accompanying fracture can be treated adequately with conservative therapy.

Congenital incomplete duplication of lower extremity (polymelia) accompanied with anorectal malformation and unilateral deafness.

Polymelia (supernumerary limbs) is an extremely rare congenital condition in humans. Because congenital anorectal malformation is a relatively common complication of polymelia and it may require emergency surgery as in the present case, accompanying malformations must be investigated.

Impact of ligand structure and base bead pore size on host cell protein removal during monoclonal antibody purification using multimodal chromatography resin.

Despite advancements in therapeutic monoclonal antibodies (mAbs) and cell line engineering, separating host cell proteins (HCPs) from mAbs during downstream purification remains challenging. Therefore, in this study, we developed a novel multimodal chromatography (MMC) resin to enhance HCP removal during mAb polishing processes. We evaluated the impact of both ligand structure and pore size of the MMC resin by purifying a post-protein A chromatography solution in flow-through mode. We observed that the efficiency of HCP clearance depended on the hydrophobic moiety structure of the ligand and predicted the mAb purification capability of MMC through linear salt-gradient elution experiments involving a mixture of transferrin, bovine serum albumin (BSA), and pepsin. Our findings revealed that the prototype immobilized 1,12-dodecanediamine via the formyl group exhibited the best performance attributed to its long alkyl chain. Furthermore, an investigation of effects of base bead pore size on HCP capacity using cellulose base beads of five different pore sizes showed that larger pore resin base beads had the highest HCP removal capacity. Specifically, MMC resins with a pore diameter exceeding 440 nm reduced the HCP level by three orders of magnitude under high mAb loading conditions (> 1000 mg/mL-resin). The MMC resin developed in this study, along with the insights gained into ligand structure and pore size, not only enhances mAb polishing efficiency but also contributes to improving downstream processes in mAb biopharmaceutical production.

Walking ability after resection of soft tissue sarcoma of the thigh and the sciatic nerve.

Walking ability may be fairly well maintained after sciatic nerve resection combined with wide resection of soft tissue sarcoma, therefore, surgeons should not hesitate to perform sciatic nerve resection to achieve an adequate surgical margin.

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.

Viable tumor cell density after neoadjuvant chemotherapy assessed using deep learning model reflects the prognosis of osteosarcoma.

Prognosis after neoadjuvant chemotherapy (NAC) for osteosarcoma is generally predicted using manual necrosis-rate assessments; however, necrosis rates obtained in these assessments are not reproducible and do not adequately reflect individual cell responses. We aimed to investigate whether viable tumor cell density assessed using a deep-learning model (DLM) reflects the prognosis of osteosarcoma. Seventy-one patients were included in this study. Initially, the DLM was trained to detect viable tumor cells, following which it calculated their density. Patients were stratified into high and low-viable tumor cell density groups based on DLM measurements, and survival analysis was performed to evaluate disease-specific survival and metastasis-free survival (DSS and MFS). The high viable tumor cell density group exhibited worse DSS (p = 0.023) and MFS (p = 0.033). DLM-evaluated viable density showed correct stratification of prognosis groups. Therefore, this evaluation method may enable precise stratification of the prognosis in osteosarcoma patients treated with NAC.

A reduction method for anterior opening displacement in thoracolumbarvertebral fractures with diffuse idiopathic skeletal hyperostosis using the skull clamp-assisted position.

Diffuse idiopathic skeletal hyperostosis (DISH) frequently occurs in the spine, resulting in unstable fractures. Treating thoracolumbar fractures in patients with DISH is often difficult because the anterior opening of the vertebral body is exacerbated by dislocation in the prone position, making reduction difficult. In this study, we introduced a novel skull clamp-assisted positioning (SAP) technique. The patient is placed in a supine position with a skull clamp used in cervical spine surgery before surgery to prevent the progression of dislocation and to restore the patient's position. Using this method, the mean difference in local kyphosis angle improved from -2.9 (±8.4)° preoperatively to 10.9 (±7.7)° postoperatively. Furthermore, posterior displacement decreased from a preoperative mean of 5.5 (±4.3) mm to 0.3 (±0.7) mm postoperatively. Complications such as neurological sequelae, implant fracture, and surgical site infection were not observed through one year of postoperative follow-up. SAP may decrease invasiveness and complications. Longer-term studies and larger sample sizes are needed to establish long-term efficacy and benefits.

IL-6 receptor antibody treatment improves muscle weakness in experimental autoimmune myasthenia gravis mouse model.

Myasthenia gravis (MG) is a chronic autoimmune disease characterized by muscle weakness and fatigue. It is caused by pathological autoantibodies against components expressed at neuromuscular junctions, such as acetylcholine receptor (AChR). Interleukin-6 (IL-6) has been suggested to play a role in the pathogenesis of MG, and IL-6 receptor (IL-6R) antibody treatment may provide a novel therapeutic option. In this study, we investigated the effects of IL-6R antibody treatment in an experimental autoimmune MG (EAMG) mouse model. We demonstrated that IL-6R antibody treatment improved muscle weakness, reduced IgG deposition at neuromuscular junctions, and the levels of AChR autoantibodies in serum. In addition, follicular helper T cells and Th17, plasma cells in lymph nodes were lower in IL-6R antibody treated mice. Our findings suggest that IL-6R blockade may be a novel and effective therapeutic strategy for the treatment of MG.

Case report: Atypical lipomatous tumor of the thigh in a four-year-old girl.

Atypical lipomatous tumors (ALTs) are locally aggressive adipocytic malignancies that frequently occur in middle-aged adults. We report the rare case of an ALT of the thigh that occurred in a 4-year-old girl. Since the tumor was initially diagnosed as a lipoblastoma by incisional biopsy, marginal resection was performed. Histopathological findings of the surgical specimen revealed the proliferation of mature and variously sized adipocytes, as well as ectopic ossification; these features differ from the typical findings of lipoblastoma. Immunohistochemical findings showed nuclear positivity for a murine double minute 2 (MDM2) and cyclin-dependent kinase 4 (CDK4) and negativity for pleomorphic adenoma gene 1 (PLAG1). Fluorescence in situ hybridization showed abnormal amplification of the MDM2 gene. The patient was thus finally diagnosed as having an ALT. No signs of local recurrence or metastasis were noted 1 year postoperatively. This case is instructive in the differential diagnosis of primary adipocytic tumors. Lipoblastomas are the most common adipocytic tumors in children, but if a tumor is located in the deep tissue or imaging findings are not typical, the possibility of ALT should be considered and immunohistochemistry for MDM2 and CDK4 should be added.

A new era in the management of spinal metastasis.

Despite the recent advances in cancer treatment, the incidence of patients with spinal metastases continues to grow along with the total number of cancer patients. Spinal metastases can significantly impair activities of daily living (ADL) and quality of life (QOL), compared with other types of bone metastases, as they are characterized with severe pain and paralysis caused by skeletal-related events. Reduced ADL can also lead to treatment limitations as certain anticancer agents and radiation therapy are not compatible treatments; thus, leading to a shorter life expectancy. Consequently, maintaining ADLs in patients with spinal metastases is paramount, and spine surgeons have an integral role to play in this regard. However, neurosurgeon, orthopedic and spinal surgeons in Japan do not have a proactive treatment approach to spinal metastases, which may prevent them from providing appropriate treatment when needed (clinical inertia). To overcome such endemic inertia, it is essential for 1) spine surgeons to understand and be more actively involved with patients with musculoskeletal disorders (cancer locomo) and cancer patients; 2) the adoption of a multidisciplinary approach (coordination and meetings not only with the attending oncologist but also with spine surgeons, radiologists, rehabilitation specialists, and other professionals) to preemptive treatment such as medication, radiotherapy, and surgical treatment; and 3) the integration of the latest findings associated with minimally invasive spinal treatments that have expanded the indications for treatment of spinal metastases and improved treatment outcomes. This heralds a new era in the management of spinal metastases.

Foot Tapping Test as a Simple Quantitative Index of Motor Function for Lumbosacral Radiculopathy.

STUDY DESIGN: We conducted a retrospective review of data from patients who underwent surgical treatment for lumbosacral radiculopathy. OBJECTIVE: To assess the effectiveness of the foot tapping test (FTT) in evaluating lower limb motor function in patients with lumbosacral radiculopathy pre- and post-surgery. SUMMARY OF BACKGROUND DATA: Lumbosacral radiculopathy is becoming increasingly common in aging populations. Despite standard treatments, paralysis often leads to incomplete postoperative recovery, necessitating early detection and interventions. METHODS: We enrolled individuals who underwent surgery for lumbosacral radiculopathy at our facility between 2009 and 2020. Patients with a history of lumbar surgeries, dialysis, rheumatoid arthritis, and transitional vertebrae were excluded. The FTT score was measured by having the sole of the foot tap as many times as possible for 10 s while keeping the heel in contact with the floor. The L4, L5, and S1 groups were assigned using the scores on the side of the radiculopathy, and the control group was assigned using the scores on the intact side. Data were analyzed using Dunnett's test for group comparisons and paired t-tests for pre-post-surgery comparisons. RESULTS: Of the 522 eligible patients, 80 (159 nerve roots, one patient with hemi-prosthetic leg) were analyzed. The preoperative FTT scores in the L4 and L5 groups were significantly lower than those in the control group, indicating functional impairment. One year post-surgery, all groups showed improvements in FTT scores, with the L5 group exhibiting significant improvements compared to the control; this was supported by the results of sensitivity analyses considering the effects of paralysis and pain. CONCLUSION: The FTT is a valuable tool for the early detection of lower limb motor dysfunction in lumbosacral radiculopathy, particularly for L5 nerve root impairment, where it aids in timely surgical intervention and may improve postoperative outcomes and quality of life.