Anatomical evaluation of the superficial medial collateral ligament distal tibial attachment of the knee.

This study aimed to evaluate the superficial medial collateral ligament distal tibial attachment (sMCL-dTA) morphologically and morphometrically. Seventeen unpaired formalin-fixed cadaveric knees were used. The sMCL was divided into anterior and posterior sections in the paracoronal plane along the midline of the sMCL. The distance from the medial edge of the tibial plateau and the joint line to the proximal margin, center, and distal margin of the sMCL-dTA and the length of the sMCL-dTA were measured in the anterior section, respectively. The sMCL-dTA was histologically observed in the posterior section with hematoxylin and eosin and Masson's trichrome staining. The distance from the medial edge of the tibial plateauto the proximal margin, center, and distal margin of the sMCL-dTA were 38.1 ± 4.2, 49.7 ± 4.4, and 61.5 ± 5.1 mm, respectively. The perpendicular distance from the joint line to the proximal margin, center, and distal margin of the sMCL-dTA were 36.1 ± 4.0, 47.4 ± 4.2, and 59.1 ± 4.8 mm, respectively. The length of the sMCL-dTA was 23.6 ± 3.2 mm. Histologically, the sMCL-dTA was formed by two layers of collagen fibers: the unidirectional fibrous layer and the multidirectional fibrous layer. The respective thicknesses of the two layers both decreased distally. The anatomical location, the length, and the attachment morphology of sMCL-dTA have been clarified using human cadaveric knees. Anatomical data in the present study contribute to the quality of surgery associated with sMCL-dTA.

What Are the Complications, Function, and Survival of Tumor-devitalized Autografts Used in Patients With Limb-sparing Surgery for Bone and Soft Tissue Tumors? A Japanese Musculoskeletal Oncology Group Multi-institutional Study.

BACKGROUND: Tumor-devitalized autografts treated with deep freezing, pasteurization, and irradiation are biological reconstruction methods after tumor excision for aggressive or malignant bone or soft tissue tumors that involve a major long bone. Tumor-devitalized autografts do not require a bone bank, they carry no risk of viral or bacterial disease transmission, they are associated with a smaller immunologic response, and they have a better shape and size match to the site in which they are implanted. However, they are associated with disadvantages as well; it is not possible to assess margins and tumor necrosis, the devitalized bone is not normal and has limited healing potential, and the biomechanical strength is decreased owing to processing and tumor-related bone loss. Because this technique is not used in many countries, there are few reports on the results of this procedure such as complications, graft survival, and limb function. QUESTIONS/PURPOSES: (1) What was the rate of complications such as fracture, nonunion, infection, or recurrence in a tumor-devitalized autograft treated with deep freezing, pasteurization, and irradiation, and what factors were associated with the complication? (2) What were the 5-year and 10-year grafted bone survival (free from graft bone removal) of the three methods used to devitalize a tumor-containing autograft, and what factors were associated with grafted bone survival? (3) What was the proportion of patients with union of the tumor-devitalized autograft and what factors were associated with union of the graft-host bone junction? (4) What was the limb function after the tumor-devitalized autograft, and what factors were related to favorable limb function? METHODS: This was a retrospective, multicenter, observational study that included data from 26 tertiary sarcoma centers affiliated with the Japanese Musculoskeletal Oncology Group. From January 1993 to December 2018, 494 patients with benign or malignant tumors of the long bones were treated with tumor-devitalized autografts (using deep freezing, pasteurization, or irradiation techniques). Patients who were treated with intercalary or composite (an osteoarticular autograft with a total joint arthroplasty) tumor-devitalized autografts and followed for at least 2 years were considered eligible for inclusion. Accordingly, 7% (37 of 494) of the patients were excluded because they died within 2 years; in 19% (96), an osteoarticular graft was used, and another 10% (51) were lost to follow-up or had incomplete datasets. We did not collect information on those who died or were lost to follow-up. Considering this, 63% of the patients (310 of 494) were included in the analysis. The median follow-up was 92 months (range 24 to 348 months), the median age was 27 years (range 4 to 84), and 48% (148 of 310) were female; freezing was performed for 47% (147) of patients, pasteurization for 29% (89), and irradiation for 24% (74). The primary endpoints of this study were the cumulative incidence rate of complications and the cumulative survival of grafted bone, assessed by the Kaplan-Meier method. We used the classification of complications and graft failures proposed by the International Society of Limb Salvage. Factors relating to complications and grafted autograft removal were analyzed. The secondary endpoints were the proportion of bony union and better limb function, evaluated by the Musculoskeletal Tumor Society score. Factors relating to bony union and limb function were also analyzed. Data were investigated in each center by a record review and transferred to Kanazawa University. RESULTS: The cumulative incidence rate of any complication was 42% at 5 years and 51% at 10 years. The most frequent complications were nonunion in 36 patients and infection in 34 patients. Long resection (≥ 15 cm) was associated with an increased risk of any complication based on the multivariate analyses (RR 1.8 [95% CI 1.3 to 2.5]; p < 0.01). There was no difference in the rate of complications among the three devitalizing methods. The cumulative graft survival rates were 87% at 5 years and 81% at 10 years. After controlling for potential confounding variables including sex, resection length, reconstruction type, procedure type, and chemotherapy, we found that long resection (≥ 15 cm) and composite reconstruction were associated with an increased risk of grafted autograft removal (RR 2.5 [95% CI 1.4 to 4.5]; p < 0.01 and RR 2.3 [95% CI 1.3 to 4.1]; p < 0.01). The pedicle freezing procedure showed better graft survival than the extracorporeal devitalizing procedures (94% versus 85% in 5 years; RR 3.1 [95% CI 1.1 to 9.0]; p = 0.03). No difference was observed in graft survival among the three devitalizing methods. Further, 78% (156 of 200 patients) of patients in the intercalary group and 87% (39 of 45 patients) of those in the composite group achieved primary union within 2 years. Male sex and the use of nonvascularized grafts were associated with an increased risk of nonunion (RR 2.8 [95% CI 1.3 to 6.1]; p < 0.01 and 0.28 [95% CI 0.1 to 1.0]; p = 0.04, respectively) in the intercalary group after controlling for confounding variables, including sex, site, chemotherapy, resection length, graft type, operation time, and fixation type. The median Musculoskeletal Tumor Society score was 83% (range 12% to 100%). After controlling for confounding variables including age, site, resection length, event occurrence, and graft removal, age younger than 40 years (RR 2.0 [95% CI 1.1 to 3.7]; p = 0.03), tibia (RR 6.9 [95% CI 2.7 to 17.5]; p < 0.01), femur (RR 4.8 [95% CI 1.9 to 11.7]; p < 0.01), no event (RR 2.2 [95% CI 1.1 to 4.5]; p = 0.03), and no graft removal (RR 2.9 [95% CI 1.2 to 7.3]; p = 0.03) were associated with an increased limb function. The composite graft was associated with decreased limb function (RR 0.4 [95% CI 0.2 to 0.7]; p < 0.01). CONCLUSION: This multicenter study revealed that frozen, irradiated, and pasteurized tumor-bearing autografts had similar rates of complications and graft survival and all resulted in similar limb function. The recurrence rate was 10%; however, no tumor recurred with the devitalized autograft. The pedicle freezing procedure reduces the osteotomy site, which may contribute to better graft survival. Furthermore, tumor-devitalized autografts had reasonable survival and favorable limb function, which are comparable to findings reported for bone allografts. Overall, tumor-devitalized autografts are a useful option for biological reconstruction and are suitable for osteoblastic tumors or osteolytic tumors without severe loss of mechanical bone strength. Tumor-devitalized autografts could be considered when obtaining allografts is difficult and when a patient is unwilling to have a tumor prosthesis and allograft for various reasons such as cost or socioreligious reasons. LEVEL OF EVIDENCE: Level III, therapeutic study.

Impact of spinal surgery on locomotive syndrome in patients with lumbar spinal stenosis in clinical decision limit stage 3: a retrospective study.

BACKGROUND: Locomotive syndrome (LS) is characterized by reduced mobility. Clinical decision limit (CDL) stage 3 in LS indicates physical frailty. Lumbar spinal canal stenosis (LSS) is one of the causes of LS, for which lumbar surgery is considered to improve the CDL stage. This study aimed to investigate the efficacy of lumbar surgery and independent factors for improving the CDL stage in patients with LSS. METHODS: This retrospective study was conducted at the Department of Orthopaedic Surgery at our University Hospital. A total of 157 patients aged ≥ 65 years with LSS underwent lumbar surgery. The 25-Question Geriatric Locomotive Function scale (GLFS-25) was used to test for LS, and the Timed Up and Go test (TUG) was used to evaluate functional ability. Lower limb pain was evaluated using a visual analog scale. Patients with at least one improvement in the CDL stage following lumbar surgery were included in the improvement group. Differences in lower limb pain intensity between the groups were evaluated using the Wilcoxon rank-sum test. The Spearman's rank correlation coefficient was used to determine correlations between Δ lower limb pain and Δ GLFS-25. Logistic regression analysis was used to identify factors associated with improvement in LS. RESULTS: The proportion of patients with improved CDL stage was 45.1% (improvement/non-improvement: 32/39). Δ Lower limb pain was significantly reduced in the improvement group compared with that in the non-improvement group (51.0 [36.3-71.0] vs 40.0 [4.0-53.5]; p = 0.0107). Δ GLFS-25 was significantly correlated with Δ lower limb pain (r = 0.3774, p = 0.0031). Multiple logistic regression analysis revealed that TUG and age were significantly associated with improvement in LS (odds ratio, 1.22; 95% confidence interval: 1.07-1.47). CONCLUSIONS: Lumbar surgery effectively improved the CDL stage in patients with LSS. In addition, TUG was an independent factor associated with improvement in the CDL.

Intradural extramedullary tumor location in the axial view affects the alert timing of intraoperative neurophysiologic monitoring.

OBJECTIVE: Intraoperative neurophysiologic monitoring (IONM) reportedly helps prevent postoperative neurological complications following high-risk spinal cord surgeries. There are negative and positive reports about using IONM for intradural extramedullary (IDEM) tumors. We investigated factors affecting alerts of IONM in IDEM tumor surgery. METHODS: We analyzed 39 patients with IDEM tumors who underwent surgery using IONM at our hospital between January 2014 and March 2021. Neurological symptoms were evaluated pre- and postoperatively using the manual muscle test (MMT). All patients were evaluated to ascertain the tumor level and location in the axial view, the operative time, intraoperative bleeding volume, and histological type. Additionally, the intraoperative procedure associated with significant IONM changes in transcranial electrical stimulation muscle-evoked potential was investigated. RESULTS: There were 11 false-positive and 16 true-negative cases. There was one true-positive case and one false-negative case; the monitoring accuracy achieved a sensitivity of 50%, a specificity of 59%, a positive predictive value of 8%, and a negative predictive value of 94%. In the 22 alert cases, if the tumor was located anterolateral in the axial view, alerts were triggered with a significant difference (p = 0.02) during tumor resection. Alerts were generated for fifteen patients during tumor resection; nine (60%) showed waveform improvement by intervention and were classified as rescue cases. CONCLUSION: Alert is probably triggered during tumor resection for anterolaterally located tumors. Alerts during tumor resection procedures were more likely to be rescued than other procedures in IDEM tumor surgery.

New Insights into the Role of Synovial Fibroblasts Leading to Joint Destruction in Rheumatoid Arthritis.

Rheumatoid arthritis (RA), one of the most common autoimmune diseases, is characterized by multiple-joint synovitis with subsequent destruction of bone and cartilage. The excessive autoimmune responses cause an imbalance in bone metabolism, promoting bone resorption and inhibiting bone formation. Preliminary studies have revealed that receptor activator of NF-κB ligand (RANKL)-mediated osteoclast induction is an important component of bone destruction in RA. Synovial fibroblasts are the crucial producers of RANKL in the RA synovium; novel analytical techniques, primarily, single-cell RNA sequencing, have confirmed that synovial fibroblasts include heterogeneous subsets of both pro-inflammatory and tissue-destructive cell types. The heterogeneity of immune cells in the RA synovium and the interaction of synovial fibroblasts with immune cells have recently received considerable attention. The current review focused on the latest findings regarding the crosstalk between synovial fibroblasts and immune cells, and the pivotal role played by synovial fibroblasts in joint destruction in RA.

Perioperative Adriamycin plus ifosfamide vs. gemcitabine plus docetaxel for high-risk soft tissue sarcomas: randomised, phase II/III study JCOG1306.

BACKGROUND: This randomised phase II/III trial aimed to determine whether perioperative chemotherapy with gemcitabine plus docetaxel (GD) is non-inferior to the standard Adriamycin plus ifosfamide (AI) in terms of overall survival (OS) in patients with soft tissue sarcoma (STS). METHODS: Patients with localised high-risk STS in the extremities or trunk were randomised to receive AI or GD. The treatments were repeated for three preoperative and two postoperative courses. The primary endpoint was OS. RESULTS: Among 143 enrolled patients who received AI (70 patients) compared to GD (73 patients), the estimated 3-year OS was 91.4% for AI and 79.2% for GD (hazard ratio 2.55, 95% confidence interval: 0.80-8.14, P = 0.78), exceeding the prespecified non-inferiority margin in the second interim analysis. The estimated 3-year progression-free survival was 79.1% for AI and 59.1% for GD. The most common Grade 3-4 adverse events in the preoperative period were neutropenia (88.4%), anaemia (49.3%), and febrile neutropenia (36.2%) for AI and neutropenia (79.5%) and febrile neutropenia (17.8%) for GD. CONCLUSIONS: Although GD had relatively mild toxicity, the regimen-as administered in this study-should not be considered a standard treatment of perioperative chemotherapy for high-risk STS in the extremities and trunk. CLINICAL TRIAL REGISTRATION: jRCTs031180003.

A randomized phase III trial of denosumab before curettage for giant cell tumor of bone. JCOG1610.

OBJECTIVES: The aim of JCOG1610 (randomized controlled phase III trial) was to confirm the superiority of preoperative denosumab to curettage with adjuvant local therapy for patients with giant cell tumor of bone without possible post-operative large bone defect. METHODS: The primary endpoint was relapse-free survival and the total sample size was set at 106 patients. Patient accrual began in October 2017. However, the accrual was terminated in December 2020 due to a recommendation from the Data and Safety Monitoring Committee because of poor patient accrual. Now, we report the descriptive results obtained in this study. RESULTS: A total of 18 patients had been registered from 13 Japanese institutions at the time of termination on December 2020. Eleven patients were assigned to Arm A (curettage and adjuvant local therapy) and 7 to Arm B (preoperative denosumab, curettage and adjuvant local therapy). Median follow-up period was 1.6 (range: 0.5-2.8) years. Protocol treatment was completed in all but one patient in Arm A who had a pathological fracture before surgery. All patients in Arm B were treated with five courses of preoperative denosumab. Relapse-free survival proportions in Arm A and B were 90.0% (95% confidence interval: 47.3-98.5) and 100% (100-100) at 1 year, and 60.0% (19.0-85.5) and 62.5% (14.2-89.3) at 2 years, respectively [hazard ratio (95% confidence interval): 1.51 (0.24-9.41)]. CONCLUSION: In terms of relapse-free survival, the superiority of preoperative denosumab was not observed in patients with giant cell tumor of bone without possible post-operative large bone defect.

Benefit of surgical resection of distant metastasis in soft tissue sarcoma: a systematic review.

OBJECTIVE: The aim of this systematic review was to evaluate the efficacy of metastasectomy for patients with advanced soft tissue sarcoma and to develop a recommendation outlining clinical guidelines for soft tissue sarcoma. METHODS: We searched the pertinent literature from January 1985 to December 2017. Two reviewers evaluated and screened the literature independently for eligibility and extracted data. We evaluated the quality of body of evidence and made a recommendation according to the Grading of Recommendations Development and Evaluation methodology. RESULTS: Among 244 identified studies, only 10 were finally included in this review and no randomized controlled trial reports were present. The median survival period after metastasectomy ranged from 9.6 to 39.6 months, and the 5-year survival rate ranged from 8 to 52%. The complication rate ranged from 7.3 to 25%, and the perioperative mortality rate was 0-1%. The guidelines committee proposed 'Metastasectomy can be offered for malignant soft tissue tumours with distant metastases'. This recommendation gained 100% consensus among the members of the guidelines group. CONCLUSIONS: Although the level of evidence is very low, many retrospective studies support a clinical advantage for metastasectomy, and surgical indications should be carefully considered for patients with metastasis from soft tissue sarcoma. Metastasectomy is an option for patients with metastasis and should be done only if it can be performed safely and if potential advantages outweigh disadvantages.

Mouse Acidic Chitinase Effectively Degrades Random-Type Chitosan to Chitooligosaccharides of Variable Lengths under Stomach and Lung Tissue pH Conditions.

Chitooligosaccharides exhibit several biomedical activities, such as inflammation and tumorigenesis reduction in mammals. The mechanism of the chitooligosaccharides' formation in vivo has been, however, poorly understood. Here we report that mouse acidic chitinase (Chia), which is widely expressed in mouse tissues, can produce chitooligosaccharides from deacetylated chitin (chitosan) at pH levels corresponding to stomach and lung tissues. Chia degraded chitin to produce N-acetyl-d-glucosamine (GlcNAc) dimers. The block-type chitosan (heterogenous deacetylation) is soluble at pH 2.0 (optimal condition for mouse Chia) and was degraded into chitooligosaccharides with various sizes ranging from di- to nonamers. The random-type chitosan (homogenous deacetylation) is soluble in water that enables us to examine its degradation at pH 2.0, 5.0, and 7.0. Incubation of these substrates with Chia resulted in the more efficient production of chitooligosaccharides with more variable sizes was from random-type chitosan than from the block-type form of the molecule. The data presented here indicate that Chia digests chitosan acquired by homogenous deacetylation of chitin in vitro and in vivo. The degradation products may then influence different physiological or pathological processes. Our results also suggest that bioactive chitooligosaccharides can be obtained conveniently using homogenously deacetylated chitosan and Chia for various biomedical applications.

Osteosarcoma in patients over 50 years of age: Multi-institutional retrospective analysis of 104 patients.

BACKGROUND: Primary osteosarcoma in elderly patients are rare malignant tumors. Its optimal treatment has not yet been determined. METHODS: This retrospective study included 104 patients aged >50 years with resectable, non-metastatic osteosarcoma treated by the members of the Bone and Soft Tissue Tumor Study Group of the Japan Clinical Oncology Group. The effects of adjuvant chemotherapy were estimated by comparing outcomes in patients who received surgery plus chemotherapy with those who underwent surgery alone. RESULTS: Median age at presentation was 59 years. Neoadjuvant and adjuvant chemotherapy was administered to 83 (79.8%) patients. Patients who underwent surgery plus chemotherapy and those who underwent surgery alone had 5-year overall survival (OS) rates of 68.6% and 71.7%, respectively (p = 0.780), and 5-year relapse free survival (RFS) rates of 48.2% and 43.6%, respectively (p = 0.64). Univariate analysis showed that resection with wide margins was significantly correlated with better prognosis. CONCLUSIONS: The addition of chemotherapy to surgery did not improve OS or RFS in patients aged >50 years with resectable, non-metastatic osteosarcoma. Surgery with wide margins was only significantly prognostic of improved survival. The effect of chemotherapy in elderly osteosarcoma patients was unclear.

Elevated Expression of Transforming Acidic Coiled-Coil Containing Protein 3 (TACC3) Is Associated With a Poor Prognosis in Osteosarcoma.

BACKGROUND: Transforming acidic coiled-coil containing protein 3 (TACC3) is expressed during the mitotic phase of nuclear division and regulates microtubules. Recently, high TACC3 expression in tumor cells of various cancers including soft tissue sarcoma has been reported. However, its role in osteosarcoma remains unknown. Because we have few prognostic markers for survival in osteosarcoma, we wanted to investigate the potential role of TACC3 in human osteosarcoma and determine if it is associated with survival. QUESTIONS/PURPOSES: (1) Is there a relationship between TACC3 expression and clinicopathologic characteristics such as sex, age (< 20 or ≥ 20 years), histologic type (osteoblastic or others), tumor location (femur or others), American Joint Committee on Cancer staging system (AJCC stage IIA or IIB), tumor necrosis percentage after chemotherapy (< 90% or ≥ 90%), p53 expression (low or high), and Ki-67 expression (low or high)? (2) Is TACC3 expression associated with event-free and overall survival in patients with osteosarcoma? METHODS: Forty-six conventional patients with osteosarcoma were treated at our institution from 1989 to 2013. Patients were excluded because of unresectable primary site (two patients) and no chemotherapy (two patients). Patients with metastasis at the initial visit (five patients), without pretreatment biopsy samples (two patients), or clinical charts (two patients) were also excluded. The left 33 patients who received neoadjuvant and adjuvant chemotherapy, which consisted of cisplatin/doxorubicin/methotrexate or cisplatin/doxorubicin/methotrexate/ifosfamide, and completed surgical resection with histologic wide tumor margins. Primary tumor samples before chemotherapy were used in this study. We investigated TACC3 expression using immunohistochemical staining and statistically analyzed the TACC3 expression, clinicopathologic characteristics, and event-free and overall survival in patients with osteosarcoma. RESULTS: High TACC3 expression was observed in 19 of 33 osteosarcoma specimens (58%), and this was associated with larger tumor size (ie, AJCC stage IIB in this study; p = 0.002), higher p53 expression (p = 0.007), and higher Ki-67 expression (p = 0.002). The estimated metastasis-free survival at 5 years was 21% (95% confidence interval [CI], 7%-41%) in patients with high TACC3 expression and 79% (95% CI, 47%-93%) in patients with low TACC3 expression (p < 0.001), and the estimated overall survival at 5 years was 34% (95% CI, 13%-56%) in patients with high TACC3 expression and 86% (95% CI, 54%-96%) in patients with low TACC3 expression (p < 0.001). Furthermore, high TACC3 expression was an independent poor prognostic factor for metastasis-free survival with a hazard ratio of 3.89 (95% CI, 1.07-19.78; p = 0.039) as well as overall survival with 4.41 (95% CI, 1.01-32.97; p = 0.049). CONCLUSIONS: High TACC3 expression was associated with aggressive clinicopathologic features and unfavorable prognosis in these patients with osteosarcoma. Our preliminary results suggest that further analysis about mutation or an inactive form of TACC3 would be useful to understand the mechanism of abnormal TACC3 expression in patients with osteosarcoma. If these findings are substantiated in larger studies, TACC3 might be useful for predicting survival and a potential therapeutic target for osteosarcoma. LEVEL OF EVIDENCE: Level III, therapeutic study.

Clinical outcome of primary giant cell tumor of bone after curettage with or without perioperative denosumab in Japan: from a questionnaire for JCOG 1610 study.

BACKGROUND: Giant cell tumor of bone (GCTB) is an intermediate tumor known to be locally aggressive, but rarely metastasizing. To plan a prospective study of GCTB, we performed a questionnaire survey for institutions participating in the Bone and Soft Tissue Tumor Study Group (BSTTSG) in the Japan Clinical Oncology Group (JCOG) in 2015. METHODS: We reviewed 158 consecutive patients with primary GCTB treated with curettage without perioperative denosumab from 2008 to 2010 in Japan. We investigated local and distant recurrence rates after definitive curettage. We also investigated the recurrence rate after treatment with preoperative and/or postoperative denosumab with curettage in recent years. There were 40 patients treated with perioperative denosumab, and the factors affecting recurrence in them were investigated. RESULTS: Answers were available from 24 of 30 institutions (80.0%) participating in JCOG BSTTSG. Thirty (19.0%) and 4 (2.5%) of 158 patients developed local and distant recurrence after curettage without perioperative denosumab from 2008 to 2010, respectively. Campanacci grade and embolization before surgery were significantly associated with increasing incidence of local recurrence after curettage (p = 0.034 and p = 0.022, respectively). In patients treated with perioperative desnosumab, 120 mg denosumab was administered subcutaneously for a median 6 (2-41) and 6 (1-14) times in preoperative and postoperative settings, respectively. The recurrence rates were 6 of 21 (28.6%), 2 of 9 (22.2%), and 0 of 10 (0.0%) in the preoperative, postoperative, and both pre- and postoperative denosumab treatment groups, respectively. With all of the preoperative treatments, administration exceeding five times was significantly associated with a decreased incidence of local recurrence after curettage (p < 0.001). CONCLUSION: The recurrence rate of GCTB was still high after curettage, especially in Campanacci grade III, and improvements in the therapeutic strategy are needed in this cohort. There is a possibility that a sufficient dose of preoperative denosumab can reduce recurrence after curettage. Recently, we have started a clinical trial, JCOG1610, to investigate the efficacy of preoperative denosumab in patients who can be treated with curettage in GCTB.

Factors associated with the decision of operative procedure for proximal femoral bone metastasis: Questionnaire survey to institutions participating the Bone and Soft Tissue Tumor Study Group of the Japan Clinical Oncology Group.

BACKGROUND: Pathological fracture of the proximal femur is a main cause of cancer patients losing their ability to walk. Although both osteosynthetic devices (predominantly intramedullary nails) and prosthetic replacement have been widely performed for treatment, controversies exist regarding which procedure should be used for the various conditions. In order to decide the eligibility criteria of a planned randomized prospective study about the treatment of pathological fractures of the proximal femur, we assessed the factors affecting the selection of operative procedures using questionnaires sent to the members of the Bone and Soft Tissue Tumor Study Group (BSTTSG) of the Japan Clinical Oncology Group (JCOG). METHODS: Questionnaire surveys to evaluate (1) the priority levels of the factors, (2) the equipoise range of each factor in situations where either procedure could be applied, (3) risk and benefit of each procedure, and (4) the degree of bone destruction affecting the selection of operative procedures, were sent to 26 institutions. RESULTS: Over 80% of the institutions answered. Orthopaedic surgeons of BSTTSG decided on the procedure according to the following factors in descending order: life expectancy, performance status before fracture, the degree of bone destruction, walking ability before fracture, general complications, the number of bone metastases in other sites, and the visceral metastasis status. With regard to bone destruction, (1) the involvement of the head, neck, calcar, and intertrochanteric region, (2) transverse destruction >1/2, and (3) soft-tissue tumor extension, were the factors that led to the choice of prosthesis treatment. CONCLUSIONS: Using these identified factors, the inclusion criteria for the prospective randomized study of the surgical treatment of metastatic bone tumors of the proximal femur were optimized. The evaluation system about the bone destruction of metastases needs to be refined through the following prospective randomized study.

SOX9-mediated upregulation of LGR5 is important for glioblastoma tumorigenicity.

LGR5 plays an important role in the self-renewal of stem cells and is used as a marker identifying self-renewing stem cells in small intestine and hair follicles. Moreover, LGR5 has been reported to be overexpressed in several cancers. SOX9 is a transcription factor that plays a key role in development, differentiation and lineage commitment in various tissues. It has also been reported that SOX9 is overexpressed in a variety of cancers and contributes to their malignant phenotype. Here we show that LGR5 is required for the tumorigenicity of glioblastoma cells. We further show that SOX9 is upregulated in glioblastoma cells and directly enhances the expression of LGR5. We also demonstrate that knockdown of SOX9 suppresses the proliferation and tumorigenicity of glioblastoma cells. These results suggest that SOX9-mediated transcriptional regulation of LGR5 is critical for the tumorigenicity of glioblastoma cells. We speculate that the SOX9-LGR5 pathway could be a potentially promising target for the therapy of glioblastoma.

Interfacial modification of NaCoO2 positive electrodes with inorganic oxides by simple mixing and the effects on all-solid-state Na batteries.

All-solid-state Na polymer batteries are desired as the next generation of high-capacity batteries owing to their high safety and abundant resources. However, the degradation of the positive electrode/electrolyte interface with cycling leads to a decrease in capacity and a significant increase in interfacial resistance. In this study, to suppress the interfacial degradation, we prepared positive electrode sheets through a combination of simple mixing and pasting with the addition of binders and conductive additives, using NaCoO2 coated with two types of inorganic oxides as the active material. The influence of the coatings on the electrochemical properties of the fabricated all-solid-state Na polymer battery was investigated by performing constant-current charge-discharge tests, and the coating morphology was characterized by electron microscopy and spectroscopic measurements. Compared with the non-coated positive electrode, the coated electrodes not only enhanced the battery capacity and improved the cycling characteristics but also effectively suppressed the formation of byproducts during charge-discharge cycling, owing to the electrochemical stability and Na+ conductivity of the inorganic oxide coatings. Moreover, despite the chemically unstable properties of powdered NaCoO2, the application of this mixing method effectively suppressed its degradation.

Intraoperative and Postoperative Ultrasonographic Spinal Cord Evaluation of Cervical Double-Door Laminoplasty.

BACKGROUND: Ultrasonography is a useful tool for the localization, morphology, and characterization of lesions and is increasingly being applied to spinal cord evaluation in cervical spine diseases. However, in conventional cervical laminoplasty, detailed evaluation is difficult because of ultrasound attenuation. Therefore, the purpose of this study was to perform a cervical laminoplasty using a modified surgical technique and evaluate the spinal cord. METHODS: The spinal cord was evaluated intraoperatively and one week postoperatively in 11 patients with cervical compressive myelopathy. Double-door laminoplasty was selected as the surgical method, and the shape and placement of the bone graft between the expanded laminas were devised to reduce ultrasonic attenuation, such that there was a large space in which the dura mater was visible. RESULTS: Intraoperative and postoperative spinal cord decompression, claudication, and pulsation were confirmed in all cases. A more precise diagnosis was possible using ultrasound attenuation using the grafted bone between the laminas as an indicator. CONCLUSION: Intraoperative and postoperative spinal cord decompression status and wave patterns of modified cervical double-door laminoplasty can be evaluated using ultrasonography. Ultrasound-based evaluations of the spinal cord may provide new insights.

Effects of adipose-derived cell supplementation on tendon-bone healing in a rat model of chronic rotator cuff tear with suprascapular nerve injury.

OBJECTIVE: To investigate the effect of adipose-derived cells (ADCs) on tendon-bone healing in a rat model of chronic rotator cuff tear (RCT) with suprascapular nerve (SN) injury. METHODS: Adult rats underwent right shoulder surgery whereby the supraspinatus was detached, and SN injury was induced. ADCs were cultured from the animals' abdominal fat. At 6 weeks post-surgery, the animals underwent surgical tendon repair; the ADC (+ve) group (n = 18) received an ADC injection, and the ADC (-ve) group (n = 18) received a saline injection. Shoulders were harvested at 10, 14, and 18 weeks and underwent histological, fluorescent, and biomechanical analyses. RESULTS: In the ADC (+ve) group, a firm enthesis, including dense mature fibrocartilage and well-aligned cells, were observed in the bone-tendon junction and fatty infiltration was less than in the ADC (-ve) group. Mean maximum stress and linear stiffness was greater in the ADC (+ve) compared with the ADC (-ve) group at 18 weeks. CONCLUSION: ADC supplementation showed a positive effect on tendon-bone healing in a rat model of chronic RCT with accompanying SN injury. Therefore, ADC injection may possibly accelerate recovery in massive RCT injuries.

Impact of Energy Malnutrition on Exacerbation Hospitalization in Patients with Chronic Obstructive Pulmonary Disease: Retrospective Observational Study.

Nutritional disorders in patients with chronic obstructive pulmonary disease (COPD) are associated with cachexia, sarcopenia, and weight loss. In particular, weight loss is a prognostic factor in COPD independent of pulmonary function, and energy malnutrition is a contributing factor. Frequent exacerbation hospitalization is also a prognostic factor for COPD patients. The impact of energy malnutrition on adverse events such as exacerbation hospitalization is unknown, and this study aimed to investigate that. We included 163 male subjects with COPD. Respiratory quotient (RQ), an index of energy malnutrition, was calculated by expiratory gas analysis using an indirect calorimeter. RQ <0.85 was categorized as the energy malnutrition group. Kaplan-Meier analysis was used to compare the hospitalization avoidance rate between the with and without energy malnutrition groups. Independent factors associated with exacerbation hospitalization were evaluated by Cox regression analysis. We finally analyzed data from 56 selected subjects (median age: 74 y). The exacerbation hospitalization rate was significantly higher in the energy malnutrition group. Fifty percent of the energy malnutrition group was hospitalized for an exacerbation, and the median hospitalization avoidance time was 701 d. In Cox regression analysis (adjusted for age, BMI, mMRC dyspnea scale score, %FEV1, and 6-min walk test), energy malnutrition was an independent factor associated with exacerbation hospitalization (HR 4.14, 95% CI 1.13-15.1, p=0.03). Energy malnutrition may be the risk factor for exacerbation hospitalization. Energy malnutrition may be an early nutritional disorder and early detection and intervention may reduce exacerbation hospitalizations.

Exploring Predictors of Hypertension Development With Pazopanib and Examining Predictive Performance Over Time.

BACKGROUND/AIM: Hypertension occurs frequently in patients taking pazopanib. Therefore, this study aimed to clarify the predictive factors for pazopanib-induced hypertension. PATIENTS AND METHODS: In total, 47 patients who started pazopanib treatment for renal cell carcinoma or soft tissue sarcoma during hospitalization at Kurume University Hospital from November 2012 to February 2020 were included in the study. Patient background factors associated with pazopanib-induced hypertension were analyzed using a logistic regression model. Subsequently, a time-dependent receiver operating characteristic (ROC) analysis was performed to evaluate changes in the predictive performance of predictors of pazopanib-induced hypertension over time. RESULTS: Logistic regression analysis showed that total bilirubin (t-bil) and sex are predictors of pazopanib-induced hypertension, along with systolic blood pressure (SBP) before pazopanib introduction. Additionally, evaluation of area under the curve (AUC) changes over time during the first 20 days of pazopanib treatment using time-dependent ROC showed that the AUC tended to be higher in the first half for SBP and in the second half for t-bil. Moreover, models including these two factors (SBP+t-bil and SBP+t-bil+sex) maintained a higher AUC from the early to late stages of the treatment period. CONCLUSION: Total bilirubin and sex can serve as predictors of pazopanib-induced hypertension. Total bilirubin may contribute to the prediction of the development of hypertension after day 5.

Comprehensive gene expression analysis using RNA sequencing between male and female patients with idiopathic carpal tunnel syndrome.

Idiopathic carpal tunnel syndrome is the most common entrapment neuropathy in hand surgery, and it is characterized by Noninflammatory fibrosis of subsynovial connective tissues. The prevalence and incidence differ between male and female individuals, and the mechanism underlying this difference remains largely unclear. In the present study, we collected subsynovial connective tissues from six male and six female patients diagnosed with idiopathic carpal tunnel syndrome during surgery. We performed a comprehensive gene expression analysis using RNA sequencing to compare the gene expression profiles between male and female patients with idiopathic carpal tunnel syndrome. We identified 26 genes with significantly different expressions between male and female patients, in which POSTN, COL1A1, and COL3A1, which are involved in extracellular matrix organization, and IGF1, an important fibrotic factor, were significantly upregulated in male patients. Immunohistochemistry confirmed the expression of proteins encoded by these genes in tissues, and male patients tended to show increased POSTN expression. Our results indicate that fibrosis of subsynovial connective tissues is induced by different mechanisms in male and female patients, and genes involved in extracellular matrix organization, especially POSTN, might be important factors in male patients. This study provides insight into the pathogenesis of idiopathic carpal syndrome and might contribute to the development of new treatment strategies.