Development of T cell receptor-engineered T cells targeting the sarcoma-associated antigen papillomavirus binding factor.

We previously identified papillomavirus binding factor (PBF) as an osteosarcoma antigen recognized by an autologous cytotoxic T lymphocyte clone. Vaccination with PBF-derived peptide presented by HLA-A24 (PBF peptide) elicited strong immune responses. In the present study, we generated T cell receptor-engineered T cells (TCR-T cells) directed against the PBF peptide (PBF TCR-T cells). PBF TCR was successfully transduced into T cells and detected using HLA-A*24:02/PBF peptide tetramer. PBF TCR-T cells generated from a healthy donor were highly expanded and recognized T2-A24 cells pulsed with PBF peptide, HLA-A24+ 293T cells transfected with PBF cDNA, and sarcoma cell lines. To establish an adoptive cell therapy model, we modified the PBF TCR by replacing both α and ß constant regions with those of mice (hybrid PBF TCR). Hybrid PBF TCR-T cells also showed reactivity against T2-A24 cells pulsed with PBF peptide and to HLA-A24+ 293T cells transfected with various lengths of PBF cDNA including the PBF peptide sequence. Subsequently, we generated target cell lines highly expressing PBF (MFH03-PBF [short] epitope [+]) containing PBF peptide with in vivo tumorigenicity. Hybrid PBF TCR-T cells exhibited antitumor effects compared with mock T cells in NSG mice xenografted with MFH03-PBF (short) epitope (+) cells. CD45+ T cells significantly infiltrated xenografted tumors only in the hybrid PBF TCR T cell group and most of these cells were CD8-positive. CD8+ T cells also showed Ki-67 expression and surrounded the CD8-negative tumor cells expressing Ki-67. These findings suggest that PBF TCR-T cell therapy might be a candidate immunotherapy for sarcoma highly expressing PBF.

Clinical outcomes in patients with adamantinoma: Report from the bone and soft tissue tumor registry in Japan.

BACKGROUND: Adamantinomas are rare malignant bone tumors. Due to their low incidence, there are few reports on the clinical results of adamantinoma. OBJECTIVES: This study aims to clarify outcomes in patients with adamantinoma using data from the National Bone and Soft Tissue Tumor Registry. METHODS: From 2006 to 2019, 38 cases of tibial origin were included. Twenty-four were male and 14 were female, with a mean age of 37 (6-87) years and a mean follow-up of 35 (1-128) months. RESULTS: Surgery was performed in 33 cases (87%) (curettage: 4 cases, wide resection: 27 cases, amputation: 2 cases). Reconstruction was performed in 27 patients who underwent wide resection. A total of 12 additional surgeries were performed in 11 patients. The main reason for the additional surgeries was nonunion of grafting bone in 6 cases. Oncologic outcomes were DOC (death from other causes) in one case and NED (no evidence of disease) in 37 cases. CONCLUSIONS: The results of treatment of adamantinomas in Japan have been extremely favorable. This may be due in part to the large number of cases with wide resection.

Coefficient of variation of T2-weighted MRI may predict the prognosis of malignant peripheral nerve sheath tumor.

BACKGROUND: We investigated whether non-enhancement MRI features, including measurement of the heterogeneity of the tumor with MR T2 imaging by calculating coefficient of variation (CV) values, were associated with the prognosis of non-metastatic malignant peripheral nerve sheath tumors (MPNST). METHODS: This retrospective study included 42 patients with MPNST who had undergone surgical resection (mean age, 50 years ± 21; 20 male participants). Non-enhancement MR images were evaluated for signal intensity heterogeneity on T1- and T2-weighted imaging, tumor margin definition on T1- and T2-weighted imaging, peritumoral edema on T2-weight imaging, and CV. We measured the signal intensities of MR T2-weighted images and calculated the corresponding CV values. CV is defined as the ratio of the standard deviation to the mean. The associations between factors and overall survival (OS) were investigated via the Kaplan-Meier method with log-rank tests and the Cox proportional hazards model. RESULTS: The mean CV value of MR T2 images was 0.2299 ± 0.1339 (standard deviation) (range, 0.0381-0.8053). Applying receiver operating characteristics analysis, the optimal cut-off level for CV value was 0.137. This cut-off CV value was used for its stratification into high and low CV values. At multivariate survival analysis, a high CV value (hazard ratio = 3.63; 95% confidence interval = 1.16-16.0; p = 0.047) was identified as an independent predictor of OS. CONCLUSION: The CV value of the signal intensity of heterogenous MPNSTs MR T2-weighted images is an independent predictor of patients' OS.

High tibial osteotomy alone does not decrease medial meniscus extrusion in the setting of medial meniscus posterior root tear: A cadaveric study.

PURPOSE: This study investigated whether inducing valgus alignment and shifting the load laterally through high tibial osteotomy (HTO) alone decreases the extent of medial meniscus extrusion (MME) in the setting of medial meniscus posterior root tear(MMPRT) using ultrasound evaluation. METHODS: Eight fresh-frozen human cadaveric knee specimens were tested using a six-degree-of-freedom robotic testing system and ultrasound. Each specimen was tested in five conditions: (1) intact, (2) MMPRT, (3) medial meniscus repair (MMR), (4) combined medial open-wedge HTO + MMR, and (5) HTO + MMPRT. Measurements were obtained over the medial collateral ligament (MCL, central image) and posterior to the MCL (posterior image) with a 250 N axial load at 0°, 30°, and 90° of knee flexion. Statistical analysis was performed using a two-factor repeated-measures ANOVA. RESULTS: MME was significantly greater in HTO + MMPRT(0°: 2.44 ± 0.41mm, 30°: 2.47 ± 0.37mm, 90°: 2.41 ± 0.28mm) than HTO + MMR in central images (mean difference +0.83 mm, p < .001). No significant difference was found between HTO + MMPRT and MMPRT in MME . MMR had significantly less MME than MMPRT (mean difference -0.58mm, p < .001, posterior image at 0°and central image at 90°, p=.002). HTO + MMR showed significantly less MME than MMR alone at 30° and 90° knee flexion in central image (30°: -0.38 ± 0.05mm, 90°: -0.45 ± 0.06mm, p < .001) and 90° knee flexion in posterior image (-0.38 ± 0.08mm, p = .004). CONCLUSION: HTO alone did not decrease MME in the setting of MMPRT, while MMR alone decrease MME after MMPRT. Additionally, HTO + MMR decreases MME aftrer MMPRT compared to MMR alone, although the clinical significance was uncertain. CLINICAL RELEVANCE: The findings of this study provide clinicians with valuable insights for improving MME. HTO alone does not decrease MME in cases of MMPRT.

Impact of surgical treatment on patient reported outcome in patients with spinal metastases from prostate cancer.

OBJECTIVE: This study aimed to elucidate postoperative outcomes in patients with spinal metastases of prostate cancer, with a focus on patient-oriented assessments. METHODS: This was a prospective multicenter registry study involving 35 centers. A total of 413 patients enrolled in the Japanese Association for Spine Surgery and Oncology Multicenter Prospective Study of Surgery for Metastatic Spinal Tumors were evaluated for inclusion. The eligible patients were followed for at least 1 year after surgery. The Frankel Classification, Eastern Cooperative Oncology Group Performance Status, visual analog scale for pain, face scale, Barthel Index, vitality index, indications for oral pain medication, and the EQ-5D-5L questionnaire were used for evaluating functional status, activities of daily living, and patient motivation. RESULTS: Of the 413 eligible patients, 41 with primary prostate cancer were included in the study. The patient-oriented assessments indicated that the patients experienced postoperative improvements in quality of life and motivation in most items, with the improvements extending for up to 6 months. More than half of the patients with Frankel classifications B or C showed improved neurological function at 1 month after surgery, and most patients presented maintained or improved their classification at 6 months. CONCLUSION: Surgical intervention for spinal metastases of prostate cancer significantly improved neurological function, quality of life, and motivation of the patients. Consequently, our results support the validity of surgical intervention for improving the neurological function and overall well-being of patients with spinal metastases of prostate cancer.

The Prognostic Significance of Surgical Treatment for Excessive Elderly Soft Tissue Sarcoma Patients over 90 Years Old: A Clinicopathological Study of 16 Cases.

OBJECTIVES: The incidence of soft tissue sarcomas (STSs) among older patients is increasing. Although surgical treatment of elderly patients with STS has been reported to improve their prognosis, most of these studies included patients with STS aged <85 years. This study aimed to analyze the clinical features and prognostic factors of STS in elderly patients aged ≥90 years. SUBJECT AND METHODS: We retrospectively identified patients aged ≥90 years with STS who were treated at our two hospitals between 1994 and 2022. Data on clinical information and detailed assessments were collected. We evaluated the features and factors affecting the prognosis of patients with older-extremity STS. In addition, we compared the clinical courses and results of patients treated with surgery and radiotherapy for primary tumors. RESULTS: Among 454 patients with STS, 16 were aged ≥90 years. Kaplan-Meier curves for overall survival showed a significantly poorer prognosis in patients who did not receive surgical treatment (p = 0.0348) and those who received radiotherapy (p = 0.0070). Moreover, we investigated the difference in prognosis between surgical treatment and radiotherapy, excluding two cases with distant metastasis at initial diagnosis and one case with no treatment. Kaplan-Meier curves for overall survival showed a significantly better prognosis in patients who underwent surgical treatment (p = 0.0161). Univariate analysis revealed that only primary tumor size was a significant predictor of poor prognosis (p = 0.0426). CONCLUSION: In patients with STS aged ≥90 years old, aggressive surgical treatment may improve the prognosis more than radiotherapy.

A phase 1 trial of NY-ESO-1-specific TCR-engineered T-cell therapy combined with a lymph node-targeting nanoparticulate peptide vaccine for the treatment of advanced soft tissue sarcoma.

The efficacy of immune checkpoint inhibitors is limited in refractory solid tumors. T-cell receptor gene-modified T (TCR-T)-cell therapy has attracted attention as a new immunotherapy for refractory cold tumors. We first investigated the preclinical efficacy and mode of action of TCR-T cells combined with the pullulan nanogel:long peptide antigen (LPA) vaccine in a mouse sarcoma model that is resistant to immune checkpoint inhibition. Without lymphodepletion, the pullulan nanogel:LPA vaccine markedly increased the number of TCR-T cells in the draining lymph node and tumor tissue. This change was associated with enhanced CXCR3 expression in TCR-T cells in the draining lymph node. In the phase 1 trial, autologous New York esophageal squamous cell carcinoma 1 (NY-ESO-1)-specific TCR-T cells were infused twice into HLA-matched patients with NY-ESO-1+ soft tissue sarcoma (STS). The pullulan nanogel:LPA vaccine contains an epitope recognized by TCR-T cells, and it was subcutaneously injected 1 day before and 7 days after the infusion of TCR-T cells. Lymphodepletion was not performed. Three patients with refractory synovial sarcoma (SS) were treated. Two out of the three patients developed cytokine release syndrome (CRS) with low-to-moderate cytokine level elevation. We found obvious tumor shrinkage lasting for more than 2 years by tumor imaging and long-term persistence of TCR-T cells in one patient. In conclusion, NY-ESO-1-specific TCR-T-cell therapy plus vaccination with the pullulan nanogel carrying an LPA containing the NY-ESO-1 epitope without lymphodepletion is feasible and can induce promising long-lasting therapeutic effects in refractory SS (Registration ID: JMA-IIA00346).

Development of CAR-T cells specifically targeting cancer stem cell antigen DNAJB8 against solid tumours.

BACKGROUND: As therapy for solid tumours, various tumour antigens have been selected as targets, but CAR-T cells targeting these antigens have shown limited efficacy, in contrast to the effectiveness of CAR-T cells targeting haematological malignancies. In a previous report, we identified a cancer-testis antigen, DNAJB8. DNAJB8 plays a major role in tumorigenicity in cancer stem-like cells/cancer-initiating cells (CSCs/CICs). Here, we report a DNAJB8-reactive CAR yielding anti-tumour effects against renal cell carcinoma (RCC) and osteosarcoma. METHODS: We constructed a second-generation chimeric antigen receptor (CAR) against HLA-A*24:02/DNAJB8-derived peptide (DNAJB_143) complex (B10 CAR). The reactivity of B10-CAR T cells against T2-A24 cells pulsed with the cognate peptide and an RCC and osteosarcoma cell lines were quantified. The effects of adoptive cell transfer (ACT) therapy were assessed using in vivo xenografted mice models. RESULTS: B10 CAR-T cells recognised DNAJB8_143-pulsed T2-A24 cells and HLA-A*24:02(+)/DNAJB8(+) renal cell carcinoma and osteosarcoma cell lines. Moreover, ACT using B10 CAR-T cells showed anti-tumour effects against RCC and osteosarcoma cells. CONCLUSION: B10 CAR-T cells could show specific cytotoxicity against RCC and osteosarcoma cells in vitro and in vivo. B10 CAR-T cells targeting the CSC/CIC antigen DNAJB8 might be a candidate immunotherapy for carcinoma and sarcoma.

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.

Reliability and accuracy of the critical shoulder angle measured by anteroposterior radiographs: using digitally reconstructed radiograph from 3-dimensional computed tomography images.

BACKGROUND: Accuracy of current standard radiographic measurement of the critical shoulder angle (CSA) is not well established. This study analyzed the reliability and accuracy of the CSA measurements obtained via anteroposterior (AP) radiographs, using a digitally reconstructed radiograph (true AP view) generated from a computed tomography image as the gold standard. METHODS: The CSA was measured on the radiographs and true AP views of 88 consecutive patients who had undergone shoulder arthroscopy for rotator cuff tears. Intraobserver and interobserver reliabilities of the CSA, measured by 2 orthopedic surgeons, were evaluated, and the average deviation of the CSA between radiographs and true AP views was calculated. Moreover, we compared the deviation of CSA between standard AP films (types A1 and C1) and nonstandard AP films (other types) against the Suter-Henninger criteria. RESULTS: Intraobserver and interobserver reliabilities were almost perfect on radiographs (0.96, 0.86) and true AP views (0.93, 0.85). The average deviation of CSA was 2.1° ± 1.6° for observer 1 and 2.2° ± 1.9° for observer 2. The percentage of cases with deviations of 2° or more when compared with the true AP view was 42% (37 of 88) for observer 1 and 53% (47 of 88) for observer 2. Only 22% (19 of 88) of films were standard AP films. The average deviation of CSA was not significantly different between standard and nonstandard AP films for observer 1 (standard 1.9° ± 1.3°; nonstandard 2.1° ± 1.7°; P = .76) and observer 2 (standard 1.6° ± 1.5°; nonstandard 2.4° ± 1.9°; P = .09). CONCLUSION: The CSA measurements using radiography were highly congruent, but a large measurement deviation occurred between radiographs and true AP views. The clinical usefulness and role of CSA in diagnosis require careful consideration.

Static stretching of the ankle prevents cold hypersensitivity associated with limb immobilization in model mice.

BACKGROUND: Limb immobilization is considered to contribute to limb pain including hyperalgesia. Approximately 50% of patients with such chronic limb pain complain that their abnormal pain worsens after exposure to cold. However, there have been few studies on the relationship between limb immobilization and cold hypersensitivity. The aim of this study was to examine whether limb immobilization induces cold hypersensitivity, and whether physical exercise such as ankle stretching prevents its induction in model mice. METHOD: We used forty-four 8-week-old male C57Bl/6J mice, consisting of 32 immobilized mice and 12 control mice. The bilateral hind limbs of the mice were immobilized by a thermoplastic cast. After limb-immobilization for 1 week, changes in mechanical, thermal and cold hypersensitivity, and the expression levels of TRPV1, TRPA1, TRPM8, IL-1ß, IL-6, and TNFα in the spinal cord, dorsal root ganglia and the affected hind paw were evaluated in comparison with those in the control mice. In addition, we examined the effect of ankle stretching on the hypersensitivity and expression levels in the limb-immobilized mice. RESULTS: Mechanical, thermal and cold hypersensitivity were significantly increased in the limb-immobilized mice. In addition, ankle stretching during the immobilization period significantly prevented the increases in those hypersensitivities. There were no significant differences in the expression levels of TRPV1, TRPA1 and TRPM8 among the control, and limb-immobilized mice with and without ankle stretching. The expression levels of IL-1 and IL-6 were significantly increased in the immobilized hind limb paw. Furthermore, ankle stretching significantly prevented the increases in their expression levels. CONCLUSION: Limb-immobilization induced cold hypersensitivity as well as mechanical and thermal hypersensitivity, and ankle stretching significantly prevented the hypersensitivity induction in the model mice. It would be of great interest to clarify whether a patient with limb-immobilization experiences cold hypersensitivity and whether ankle stretching might prevent hypersensitivity induction in the future.

Usefulness of SynCAM3 and cyclin D1 immunohistochemistry in distinguishing superficial CD34-positive fibroblastic tumor from its histological mimics.

Superficial CD34-positive fibroblastic tumor (SCPFT) is a fibroblastic/myofibroblastic soft tissue tumor of rarely metastasizing intermediate malignancy. Some recent studies have described a relationship between SCPFT and PRDM10-rearranged soft tissue tumor (PRT) based on SynCAM3 and PRDM10 expression on immunohistochemistry. We performed CD34, cytokeratin AE1/AE3, SynCAM3, and PRDM10 immunohistochemistry in SCPFT and its histological mimics, including myxoinflammatory fibroblastic sarcoma (MIFS), superficially localized myxofibrosarcoma (MFS), and undifferentiated pleomorphic sarcoma. We also examined cyclin D1 expression because it is expressed in MIFS and MFS. We conducted fluorescence in situ hybridization (FISH) of PRDM10 rearrangement in SCPFT cases. On immunohistochemistry, only SCPFT showed strong and diffuse SynCAM3 expression. SCPFT also exhibited strong nuclear and weak cytoplasmic cyclin D1 expression, which was similar to that observed in MIFS. Two of five SCPFT cases exhibited nuclear PRDM10 expression. FISH revealed PRDM10 split signals in 44% and 24% of tumor cells in two SCPFT cases showing nuclear PRDM10 expression on immunohistochemistry, respectively. A minority of non-SCPFT cases showed focal SynCAM3 expression, but a combination of SynCAM3 and cyclin D1 in addition to CD34 and cytokeratin AE1/AE3 may be useful for the differential diagnosis of SCPFT and its histological mimics.

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.

Standardization of evaluation method and prognostic significance of histological response to preoperative chemotherapy in high-grade non-round cell soft tissue sarcomas.

BACKGROUND: Preoperative chemotherapy is widely applied to high-grade localized soft tissue sarcomas (STSs); however, the prognostic significance of histological response to chemotherapy remains controversial. This study aimed to standardize evaluation method of histological response to chemotherapy with high agreement score among pathologists, and to establish a cut-off value closely related to prognosis. METHODS: Using data and specimens from the patients who had registered in the Japan Clinical Oncology Group study, JCOG0304, a phase II trial evaluating the efficacy of perioperative chemotherapy with doxorubicin (DOX) and ifosfamide (IFO), we evaluated histological response to preoperative chemotherapy at the central review board. RESULTS: A total of 64 patients were eligible for this study. The percentage of viable tumor area ranged from 0.1% to 97.0%, with median value of 35.7%. Regarding concordance proportion between pathologists, the weighted kappa coefficient (κ) score in all patients was 0.71, indicating that the established evaluation method achieved substantial agreement score. When the cut-off value of the percentage of the residual tumor area was set as 25%, the p-value for the difference in overall survival showed the minimum value. Hazard ratio of the non-responder with percentage of the residual tumor < 25%, to the responder was 4.029 (95% confidence interval 0.893-18.188, p = 0.070). CONCLUSION: The standardized evaluation method of pathological response to preoperative chemotherapy showed a substantial agreement in the weighted κ score. The evaluation method established here was useful for estimating of the prognosis in STS patients who were administered perioperative chemotherapy with DOX and IFO. TRIAL REGISTRATION: UMIN Clinical Trials Registry C000000096. Registered 30 August, 2005 (retrospectively registered).

Prognostic usefulness of a modified risk model for solitary fibrous tumor that includes the Ki-67 labeling index.

BACKGROUND: Predicting the prognosis of patients with solitary fibrous tumor (SFT) is often difficult. The prognostic risk models developed by Demicco et al. are now the standard for evaluating the risk of SFT metastasis in the current World Health Organization classification of soft tissue and bone tumors. METHODS: In this study, we examined the prognostic usefulness of a modified version of the Demicco risk models that replaces the mitotic count with the Ki-67 labeling index. We compared the three-variable and four-variable Demicco risk models with our modified risk models using Kaplan-Meier curves based on data for 43 patients with SFT. RESULTS: We found a significant difference in metastasis-free survival when patients were classified into low-risk and intermediate/high-risk groups using the three-variable (P = 0.022) and four-variable (P = 0.046) Demicco models. There was also a significant difference in metastasis-free survival between the low-risk and intermediate/high-risk groups when the modified three-variable (P = 0.006) and four-variable (P = 0.022) models were used. CONCLUSION: Modified risk models that include the Ki-67 labeling index are effective for prediction of the prognosis in patients with SFT.

Non-ossifying fibromas and fibrous cortical defects around the knee - an epidemiologic survey in a Japanese pediatric population.

BACKGROUND: The aim of the present study was to evaluate the prevalence of non-ossifying fibroma (NOF) and fibrous cortical defect (FCD) in a Japanese pediatric population and the association between the lesion size and pain. METHODS: This retrospective study, conducted across 10 Japanese institutions, included patients aged 5-15 years who had undergone standard antero-posterior and lateral view radiography of the knee. Using these radiographs, we diagnosed the lesion as a NOF or FCD. Patient demographics, including age, sex, the size and location of the NOF, and chief complaint were recorded. The lesion size was determined using radiographs. Student's t-test was used to compare the associations between the lesion size and spontaneous pain. RESULTS: A total of 6222 subjects (3567 boys and 2455 girls) were included in this study. The number of NOF and FCD cases was 143 and 437, respectively, and the prevalence of NOF and FCD was 2.3% and 7.0%, respectively. The average size of NOF and FCD was 22.1 mm (range: 4-102 mm) and 13.2 mm (range: 5-21 mm), respectively. Three patients (2.1%) had pathological fractures due to NOF. Of the 140 NOFs and 437 FCDs, we obtained complaints from the medical records of 126 and 393 patients, respectively. The number of patients with spontaneous pain or other problems with NOF was 68 (54%) and 58 (46%), respectively, that of patients with FCD was 195 (50%) and 198 (50%) patients, respectively. The lesion size was not associated with spontaneous pain in either lesion (p = 0.67 and p = 0.27, respectively). CONCLUSION: The prevalence of NOF and FCD around the knee was lower than that reported in previous studies. The prevalence of NOF increased and that of FCD decreased with advancing age. In both lesions, the lesion size may not be associated with pain.

Factors associated with low back pain in patients with lumbar spinal stenosis: a cross-sectional study.

BACKGROUND: Low back pain (LBP) is a major symptom of symptomatic lumbar spinal stenosis (SLSS). It is important to assess LBP in patients with SLSS to develop better treatment. This study aimed to analyse the factors associated with LBP in patients with SLSS. METHODS: This cross-sectional study included consecutive patients with SLSS aged between 51 and 79 years who had symptoms in one or both the legs, with and without LBP. The participants were classified into two groups: the high group (LBP visual analogue scale [VAS] score ≥ 30 mm) and the low group (LBP VAS score < 30 mm). We performed multiple logistic regression analysis with the high and low groups as dependent variables, and a receiver operating characteristic (ROC) analysis. RESULTS: A total of 80 patients with LSS were included (35 men and 45 women; mean age 64.5 years), with 47 and 30 patients in the high and low groups, respectively. Multivariate logistic regression analysis revealed that the sagittal vertical axis (SVA; + 10 mm; odds ratio, 1.331; 95% confidence interval, 1.051 - 1.660) and pelvic incidence-lumbar lordosis (PI-LL; + 1°; odds ratio, 1.065; 95% confidence interval, 1.019-1.168) were significantly associated with LBP. A receiver operating characteristic analysis revealed cut-off values of 47.0 mm of SVA and 30.5° of PI-LL, respectively. CONCLUSION: Our results indicated that SVA and PI-LL were significant predictors for LBP in SLSS. It is suggested that these parameters should be taken into consideration when assessing LBP in patients with SLSS.

Delayed tendon healing after injury in tetranectin-deficient mice.

BACKGROUND: Tetranectin, a plasminogen-binding protein, is present in human serum and has a role in tissue remodeling. The wound healing process is established and follows a similar cascade in tendon tissue as in other tissues. In this study, we investigated whether tetranectin has a role in regulating tissue formation of injured tendon. METHODS: Using the patella tendon injury model in the tetranectin-null mice, healing processes of the injured tendon were evaluated by histological and immunohistochemical analyses, and measurement of the expression of tetranectin, type 1 collagen (Col 1), tenomodulin, scleraxis, TGFß, IL-1ß, IL-6 and TNF-α. RESULTS: At the inflammatory phase within 7 days after the injury, involvement of inflammatory cells and the expressions of IL-1ß, IL-6 and TNF-α were significantly decreased in tetranectin-null mice. Tetranectin expression increased at 1 day and peaked at 3 days, and finally disappeared at 7 days after the injury in wild-type mice. The tendon healing period and maturity were significantly delayed in the tetranectin-null mice. Expression levels of type 1 collagen and tenomodulin in tetranectin-null mice were significantly lower than those in the wild-type mice until 70 days after injury. With regard to the long-term processes, the healing and maturation of the injured tendon in tetranectin-null mice were eventually completed. CONCLUSION: We believe that tetranectin might have a potential role in enhancing tissue formation of healing tendon at the inflammatory phase after injuries. The characteristics of tetranectin as a purified protein from human serum could be interested in an attractive candidate as a potential agent to enhance tendon healing after injury.

Atypical spindle cell/pleomorphic lipomatous tumor with a sarcomatous component showing high mitotic activity and Ki-67 labeling index: report of a unique case mimicking dedifferentiated liposarcoma.

Atypical spindle cell/pleomorphic lipomatous tumor (ASPLT) is a new entity of benign adipocytic tumor that spans a wide spectrum of histology from adipocytic to spindle cell/pleomorphic tumors. The latter non-adipocytic component rarely shows sarcomatous features although ASPLTs are not thought to dedifferentiate. A 78-year-old woman with ASPLT in the left thigh had a sarcomatous component with high mitotic activity and Ki-67 labeling index (LI) mimicking dedifferentiated liposarcoma. The adipocytic component consisted of various-sized adipocytic cells with few lipoblasts. The sarcomatous component consisted of a fascicular proliferation of atypical spindle cells with scattered large bizarre and multinucleated giant cells. Mitotic figures including atypical mitoses were frequently observed. Immunohistochemically, the tumor cells were positive for cluster of differentiation 34 but not mouse double minute 2 homolog (MDM2), cyclin-dependent kinase 4 (CDK4), or retinoblastoma (Rb) protein. Ki-67 LI in the sarcomatous component reached 40%. MDM2 and CDK4 genes were not amplified and 13q14 including the RB1 locus was deleted according to fluorescence in situ hybridization. The patient is alive with no evidence of local recurrence or distant metastasis 3.5 years after surgery. As ASPLT may exhibit morphological variation, it is important to rule out dedifferentiated liposarcoma with careful pathological examination.

Risk Factors for Postoperative Loss of Correction in Thoracolumbar Injuries Caused by High-Energy Trauma Treated via Percutaneous Posterior Stabilization without Bone Fusion.

Background and Objectives: Percutaneous pedicle screws were first introduced in 2001, soon becoming the cornerstone of minimally invasive spinal stabilization. Use of the procedure allowed adequate reduction and stabilization of spinal injuries, even in severely injured patients. This decreased bleeding and shortened surgical time, thereby optimizing outcomes; however, postoperative correction loss and kyphosis still occurred in some cases. Thus, we investigated cases of percutaneous posterior fixation for thoracolumbar injury and examined the factors affecting the loss of correction. Materials and Methods: Sixty-seven patients who had undergone percutaneous posterior fixation for thoracolumbar injury (AO classifications A3, A4, B, and C) between 2009 and 2016 were included. Patients with a local kyphosis angle difference ≥10° on computed tomography at the postoperative follow-up (over 12 months after surgery) or those requiring additional surgery for interbody fusion were included in the correction loss group (n = 23); the no-loss group (n = 44) served as the control. The degree of injury (injury level, AO classification, load-sharing score, local kyphosis angle, cuneiform deformity angle, and cranial and caudal disc injury) and surgical content (number of fixed intervertebral vertebrae, type of screw used, presence/absence of screw insertion into the injured vertebrae, and presence/absence of vertebral formation) were evaluated as factors of correctional loss and compared between the two groups. Results: Comparison between each group revealed that differences in the wedge-shaped deformation angle, load-sharing score, degree of cranial disc damage, AO classification at the time of injury, and use of polyaxial screws were statistically significant. Logistic regression analysis showed that the differences in wedge-shaped deformation angle, AO classification, and cranial disc injury were statistically significant; no other factors with statistically significant differences were found. Conclusion: Correction loss was seen in cases with damage to the cranial intervertebral disc as well as the vertebral body.