Role of catecholamine synthases in the maintenance of cancer stem-like cells in malignant peripheral nerve sheath tumors.

Malignant peripheral nerve sheath tumors (MPNSTs) are malignant tumors that are derived from Schwann cell lineage around peripheral nerves. As in many other cancer types, cancer stem cells (CSCs) have been identified in MPNSTs, and they are considered the cause of treatment resistance, recurrence, and metastasis. As an element defining the cancer stemness of MPNSTs, we previously reported a molecular mechanism by which exogenous adrenaline activates a core cancer stemness factor, YAP/TAZ, through ß2 adrenoceptor (ADRB2). In this study, we found that MPNST cells express catecholamine synthases and that these enzymes are essential for maintaining cancer stemness, such as the ability to self-renew and maintain an undifferentiated state. Through gene knockdown and inhibition of these enzymes, we confirmed that catecholamines are indeed synthesized in MPNST cells. The results confirmed that catecholamine synthase knockdown in MPNST cells reduces the activity of YAP/TAZ. These data suggest that a mechanism of YAP/TAZ activation by de novo synthesized adrenaline, as well as exogenous adrenaline, may exist in the maintenance of cancer stemness of MPNST cells. This mechanism not only helps to understand the pathology of MPNST, but could also contribute to the development of therapeutic strategies for MPNST.

Identification of ENO-1 positive extracellular vesicles as a circulating biomarker for monitoring of Ewing sarcoma.

The lack of circulating biomarkers for tumor monitoring is a major problem in Ewing sarcoma management. The development of methods for accurate tumor monitoring is required, considering the high recurrence rate of drug-resistant Ewing sarcoma. Here, we describe a sensitive analytical technique for tumor monitoring of Ewing sarcoma by detecting circulating extracellular vesicles secreted from Ewing sarcoma cells. Proteomic analysis of Ewing sarcoma cell-derived extracellular vesicles identified 564 proteins prominently observed in extracellular vesicles from three Ewing sarcoma cell lines. Among these, CD99, SLC1A5, and ENO-1 were identified on extracellular vesicles purified from sera of patients with Ewing sarcoma before treatment but not on extracellular vesicles from those after treatment and healthy individuals. Notably, not only Ewing sarcoma-derived extracellular vesicles but also Ewing sarcoma cells demonstrated proteomic expression of CD99 and ENO-1 on their surface membranes. ENO-1+CD63+ extracellular vesicle detection was reduced after tumor resection while both CD99+CD63+ and ENO-1+CD63+ extracellular vesicles were detected in serum from Ewing sarcoma-bearing mice. Finally, the accuracy of liquid biopsy targeting these candidates was assessed using extracellular vesicles from the sera of patients with Ewing sarcoma. Elevated ENO-1+CD81+ extracellular vesicles in the serum of patients before treatments distinguished patients with Ewing sarcoma from healthy individuals with an area under the curve value of 0.92 (P < 0.001) and reflected the tumor burden in patients with Ewing sarcoma during multidisciplinary treatments. Collectively, circulating ENO-1+CD81+ extracellular vesicle detection could represent a novel tool for tumor monitoring of Ewing sarcoma.

High-quality expert annotations enhance artificial intelligence model accuracy for osteosarcoma X-ray diagnosis.

Primary malignant bone tumors, such as osteosarcoma, significantly affect the pediatric and young adult populations, necessitating early diagnosis for effective treatment. This study developed a high-performance artificial intelligence (AI) model to detect osteosarcoma from X-ray images using highly accurate annotated data to improve diagnostic accuracy at initial consultations. Traditional models trained on unannotated data have shown limited success, with sensitivities of approximately 60%-70%. In contrast, our model used a data-centric approach with annotations from an experienced oncologist, achieving a sensitivity of 95.52%, specificity of 96.21%, and an area under the curve of 0.989. The model was trained using 468 X-ray images from 31 osteosarcoma cases and 378 normal knee images with a strategy to maximize diversity in the training and validation sets. It was evaluated using an independent dataset of 268 osteosarcoma and 554 normal knee images to ensure generalizability. By applying the U-net architecture and advanced image processing techniques such as renormalization and affine transformations, our AI model outperforms existing models, reducing missed diagnoses and enhancing patient outcomes by facilitating earlier treatment. This study highlights the importance of high-quality training data and advocates a shift towards data-centric AI development in medical imaging. These insights can be extended to other rare cancers and diseases, underscoring the potential of AI in transforming diagnostic processes in oncology. The integration of this AI model into clinical workflows could support physicians in early osteosarcoma detection, thereby improving diagnostic accuracy and patient care.

Efficacy and safety of nivolumab monotherapy in patients with unresectable clear cell sarcoma and alveolar soft part sarcoma (OSCAR Trial/NCCH1510).

BACKGROUND: Clear cell sarcoma (CCS) and alveolar soft part sarcoma (ASPS) are rare, and standard systemic therapy is not established except for sunitinib in ASPS. It is known that CCS and ASPS have a common biological feature of melanoma and Xp11.2/TFE3 translocation renal cell carcinoma, and immune-checkpoint inhibitors (ICIs) are effective in these tumors. The authors conducted a phase 2 trial to evaluate the efficacy and safety of nivolumab for CCS and ASPS. METHODS: The number of patients expected to be enrolled was 15-25 and was determined based on the Bayesian design. The primary end point was the confirmed objective response rate (ORR) according to the central review and the secondary end points included ORR, progression-free survival (PFS), overall survival (OS), and safety. RESULTS: A total of 26 patients (CCS, 12; ASPS, 14) were enrolled. Efficacy and safety were analyzed on 25 and 26 patients, respectively. The minimum number of responses required for a positive conclusion regarding the efficacy was four. However, only one patient (4.0%) with ASPS had a partial response. Complete response, stable disease, progression disease, and not evaluable were 0%, 60%, 32%, and 4.0%, respectively. Adverse events of grade 3 or 4 occurred in 57.7% (15 of 26). The median PFS was 4.9 months (95% confidence interval [CI], 3.7-8.6 months) and the median OS was 15.8 months (95% CI, 8.2-not reached). CONCLUSIONS: The primary end point of the ORR was not met for CCS and ASPS on the central review. Further studies are needed to evaluate ICIs in patients with ASPS.

PRRX1-TOP2A interaction is a malignancy-promoting factor in human malignant peripheral nerve sheath tumours.

BACKGROUND: Paired related-homeobox 1 (PRRX1) is a transcription factor in the regulation of developmental morphogenetic processes. There is growing evidence that PRRX1 is highly expressed in certain cancers and is critically involved in human survival prognosis. However, the molecular mechanism of PRRX1 in cancer malignancy remains to be elucidated. METHODS: PRRX1 expression in human Malignant peripheral nerve sheath tumours (MPNSTs) samples was detected immunohistochemically to evaluate survival prognosis. MPNST models with PRRX1 gene knockdown or overexpression were constructed in vitro and the phenotype of MPNST cells was evaluated. Bioinformatics analysis combined with co-immunoprecipitation, mass spectrometry, RNA-seq and structural prediction were used to identify proteins interacting with PRRX1. RESULTS: High expression of PRRX1 was associated with a poor prognosis for MPNST. PRRX1 knockdown suppressed the tumorigenic potential. PRRX1 overexpressed in MPNSTs directly interacts with topoisomerase 2 A (TOP2A) to cooperatively promote epithelial-mesenchymal transition and increase expression of tumour malignancy-related gene sets including mTORC1, KRAS and SRC signalling pathways. Etoposide, a TOP2A inhibitor used in the treatment of MPNST, may exhibit one of its anticancer effects by inhibiting the PRRX1-TOP2A interaction. CONCLUSION: Targeting the PRRX1-TOP2A interaction in malignant tumours with high PRRX1 expression might provide a novel tumour-selective therapeutic strategy.

Changes in Spinal Instability After Conventional Radiotherapy for Painful Vertebral Bone Metastases.

OBJECTIVE: Precise assessment of spinal instability is critical before and after radiotherapy (RT) for evaluating the effectiveness of RT. Therefore, we retrospectively evaluated the efficacy of RT in spinal instability over a period of 6 months after RT, utilizing the spinal instability neoplastic score (SINS) in patients with painful spinal metastasis. We retrospectively evaluated 108 patients who received RT for painful vertebral metastasis in our institution. Mechanical pain at metastatic vertebrae, radiological responses of irradiated vertebrae, and spinal instability were assessed. Follow-up assessments were done at the start of and at intervals of 1, 2, 3, 4, and 6 months after RT, with the pain disappearing in 67%, 85%, 93%, 97%, and 100% of the patients, respectively. The median SINS were 8, 6, 6, 5, 5, and 4 at the beginning and after 1, 2, 3, 4, and 6 months of RT, respectively. Multivariate analysis revealed that posterolateral involvement of spinal elements (PLISE) was the only risk factor for continuous potentially unstable/unstable spine at 1 month. In conclusion, there was improvement of pain, and recalcification results in regaining spinal stability over time after RT although vertebral body collapse and malalignment occur in some irradiated vertebrae. Clinicians should pay attention to PLISE in predicting continuous potentially unstable/unstable spine.

Prognostic evaluation of the Ki-67 labeling system in histological grading of non-small round cell sarcoma: a supplementary analysis of a randomized controlled trial, JCOG1306.

BACKGROUND: Soft tissue sarcoma (STS) has various histological types and is rare, making it difficult to evaluate the malignancy of each histological type. Thus, comprehensive histological grading is most important in the pathological examination of STS. The Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading system is most commonly used in daily pathological analysis of STS. Among the FNCLCC grading system parameters, mitotic count is a key morphological parameter reflecting the proliferative activity of tumor cells, although its reproducibility may be lacking. Here, we compared the prognostic utility of the conventional and modified FNCLCC grading systems in JCOG1306. METHODS: We analyzed 140 patients with non-small round cell sarcoma. We performed Ki-67 immunostaining using open biopsy specimens before preoperative chemotherapy in all patients. We assessed histological grade in individual cases by conventional FNCLCC grading (tumor differentiation, mitotic count, and necrosis) and modified FNCLCC grading using the Ki-67 labeling index instead of mitotic count. We conducted univariable and multivariable Cox regression analyses to investigate the influence of grade on overall survival. RESULTS: In univariable analysis, prognosis was worse for patients with conventional FNCLCC Grade 3 tumors compared with Grade 1 or 2 tumors (hazard ratio [HR] 4.21, 95% confidence interval [CI] 1.47-12.05, P = 0.008). Moreover, prognosis was worse in patients with modified FNCLCC Grade 3 tumors compared with Grade 1 or 2 tumors (HR 4.90, 95% CI 1.64-14.65, P = 0.004). In multivariable analysis including both conventional and modified FNCLCC grading, the modified grading more strongly affected overall survival (HR 6.70, 95% CI 1.58-28.40, P = 0.010). CONCLUSIONS: The modified FNCLCC grading system was superior to the conventional system in predicting the prognosis of patients with non-small round cell sarcoma according to this supplementary analysis of data from the randomized controlled trial JCOG1306.

Treatments and prognostic factors for bone and soft tissue sarcoma in non-urban areas in Japan.

BACKGROUND: Although bone and soft tissue sarcoma is recognized as a rare cancer that originates throughout the body, few comprehensive reports regarding it have been published in Japan. PATIENTS AND METHODS: Bone and soft tissue sarcomas were tabulated from the Cancer Registries at eight university hospitals in the Chugoku-Shikoku region. Prognostic factors in cases were extracted in a single facility and have been analyzed. RESULTS: From 2016 to 2019, 3.4 patients with bone and soft tissue sarcomas per a general population of 100,000 were treated at eight university hospitals. The number of patients who underwent multidisciplinary treatment involving collaboration among multiple clinical departments has been increasing recently. In the analysis carried out at a single institute (Ehime University Hospital), a total of 127 patients (male/female: 54/73) with an average age of 67.0 y (median 69.5) were treated for four years, with a 5-year survival rate of 55.0%. In the analysis of prognostic factors by multivariate, disease stage and its relative treatment, renal function (creatinine), and a patient's ability of self-judgment, and a patient's mobility and physical capability were associated with patient prognosis regarding bone and soft tissue sarcomas. Interestingly, age did not affect the patient's prognosis (> 70 vs ≦ 70). CONCLUSIONS: Physical and social factors may affect the prognosis of patients with bone and soft tissue sarcomas, especially those living in non-urban areas.

Comparison of early clinical outcome in carpal tunnel release - mini-open technique with palmar incision vs. endoscopic technique with wrist crease incision.

BACKGROUND: The purpose of this study was to examine two techniques for Carpal Tunnel Syndrome, mini-Open Carpal Tunnel Release (mini-OCTR) and Endoscopic Carpal Tunnel Release (ECTR), to compare their therapeutic efficacy. METHODS: Sixteen patients who underwent mini-OCTR in palmar incision and 17 patients who underwent ECTR in the wrist crease incision were included in the study. All patients presented preoperatively and at 1, 3, and 6 months postoperatively and were assessed with the Visual Analogue Scale (VAS) and the Disabilities of Arm, Shoulder and Hand Score (DASH). We also assessed the pain and cosmetic VAS of the entire affected hand or surgical wound, and the patient's satisfaction with the surgery. RESULTS: In the objective evaluation, both surgical techniques showed improvement at 6 months postoperatively. The DASH score was significantly lower in the ECTR group (average = 3 months: 13.6, 6 months: 11.9) than in the mini-OCTR group (average = 3 months: 27.3, 6 months: 20.6) at 3 and 6 months postoperatively. Also, the pain VAS score was significantly lower in the ECTR group (average = 17.1) than in the mini-OCTR group (average = 36.6) at 3 months postoperatively. The cosmetic VAS was significantly lower in the ECTR group (average = 1 month: 15.3, 3 months: 12.2, 6 months: 5.41) than in the mini-OCTR group (average = 1 month: 33.3, 3 months: 31.2, 6 months: 24.8) at all time points postoperatively. Patient satisfaction scores tended to be higher in the ECTR group (average = 3.3) compared to the mini-OCTR group (average = 2.7). CONCLUSIONS: ECTR in wrist increase incision resulted in better pain and cosmetic recovery in an early postoperative phase compared with mini-OCTR in palmar incision. Our findings suggest that ECTR is an effective technique for patient satisfaction.

Assessing the Frequency and Effectiveness of Various Arthroscopic Treatments in the Management of Symptomatic Isolated Medial Meniscus Injuries Including Medial Meniscus Posterior Root Tear: A Retrospective Observational Cohort Study.

The use of various strategies for arthroscopic meniscal repairs to save the meniscus and prevent the progression of knee osteoarthritis has gradually increased. We investigated the frequency of various arthroscopic treatments and the short-term clinical outcomes of symptomatic isolated medial meniscus (MM) injuries. This retrospective observational study included 193 patients (197 knees) who underwent arthroscopic meniscal treatment for isolated MM injuries between January 2016 and April 2019. Arthroscopic meniscal repairs were divided into two groups: transtibial pullout repairs of MM posterior root tears (MMPRTs) and arthroscopic meniscal repairs for other types of MM injuries. MMPRT pullout repair, other meniscal repairs, and partial meniscectomy were performed in 71.0%, 16.8%, and 12.2% of the knees, respectively. The ratio of women to men and the patient age were higher in the pullout-repair group than the meniscal-repair group. The Preoperative Knee Injury and Osteoarthritis Outcome Score subscale (as an index of daily living activities) was significantly lower in the pullout-repair group than the meniscus-repair group. However, no significant differences were observed in these scores among the two groups postoperatively. Our results suggest that familiarity with the diagnosis and treatment of MMPRTs is necessary for orthopedic surgeons to manage isolated MM injuries.

High Fracture Rate of AVANTA Silicone Implant Following Arthroplasty of the Thumb MCP Joint of Rheumatoid Arthritis Patients with Boutonniere Deformities.

We retrospectively investigated the mid-term outcomes of arthroplasty using the AVANTA silicone implant for thumb metacarpophalangeal (MCP) joints with boutonniere deformity in patients with rheumatoid arthritis (RA). This study involved 36 thumbs of 33 RA patients with a mean follow-up period of 5.1 years (range, 2.0-13.3). Postoperatively, the mean extension was significantly increased and the mean flexion was significantly decreased (p<0.001, p<0.001, respectively), resulting in the mean arc of range of motion (ROM) shifting in the direction of extension after surgery. Implant fracture was observed in 10 thumbs (28%), and 4 of these (11%) underwent revision surgery. The survivorship with implant fracture and revision surgery as endpoints were 73.4% and 91.8% at 5 years, respectively. The preoperative arc of ROM and the postoperative flexion range of the implant-fracture group were significantly greater than those in the no-implant-fracture group (p=0.039, 0.034, respectively). These results suggest the importance of patient education and careful rehabilitation to prevent excessive flexion. Overall, the AVANTA silicone implant showed a relatively high rate of implant fracture at our institute.

p53-Armed Oncolytic Virotherapy Improves Radiosensitivity in Soft-Tissue Sarcoma by Suppressing BCL-xL Expression.

Soft-tissue sarcoma (STS) is a heterogeneous group of rare tumors originating predominantly from the embryonic mesoderm. Despite the development of combined modalities including radiotherapy, STSs are often refractory to antitumor modalities, and novel strategies that improve the prognosis of STS patients are needed. We previously demonstrated the therapeutic potential of two telomerase-specific replication-competent oncolytic adenoviruses, OBP-301 and tumor suppressor p53-armed OBP-702, in human STS cells. Here, we demonstrate in vitro and in vivo antitumor effects of OBP-702 in combination with ionizing radiation against human STS cells (HT1080, NMS-2, SYO-1). OBP-702 synergistically promoted the antitumor effect of ionizing radiation in the STS cells by suppressing the expression of B-cell lymphoma-X large (BCL-xL) and enhancing ionizing radiation-induced apoptosis. The in vivo experiments demonstrated that this combination therapy significantly suppressed STS tumors' growth. Our results suggest that OBP-702 is a promising antitumor reagent for promoting the radiosensitivity of STS tumors.

Weight loss enhances meniscal healing following transtibial pullout repair for medial meniscus posterior root tears.

PURPOSE: This study investigated the impact of weight change on the success of transtibial pullout repair for medial meniscus (MM) posterior root tears (MMPRTs). METHODS: The study included 129 patients diagnosed with MMPRTs who had undergone transtibial pullout repair. The patients were screened between July 2018 and November 2021. Patient-reported outcomes were assessed preoperatively and at 12 months postoperatively using the Knee injury and Osteoarthritis Outcome Score (KOOS). MM extrusion (MME) and ΔMME (postoperative MME - preoperative MME) were calculated preoperatively and at 12 months postoperatively using magnetic resonance imaging. RESULTS: Patients were divided into weight loss (body mass index [BMI] decrease of at least 0.5 kg/m2 after primary repair; n = 63) and weight gain (BMI increase of at least 0.5 kg/m2 ; n = 66) groups. Both groups had similar demographic variables and preoperative clinical scores; patient-reported outcomes significantly improved postoperatively. The weight loss group had significantly greater improvement in KOOS-quality of life (weight loss, 29.4 ± 23.7; weight gain, 23.9 ± 27.6; p = 0.034), lower postoperative MME (weight loss, 3.9 ± 1.7 mm; weight gain, 4.2 ± 1.2 mm; p = 0.043) and lower ΔMME (weight loss, 0.8 ± 0.8 mm; weight gain, 1.2 ± 0.9 mm; p = 0.002) than the weight gain group. Total arthroscopic healing scores (weight loss, 7.6 ± 1.0; weight gain, 7.2 ± 1.5; p = 0.048) and associated subscales, including anteroposterior bridging tissue width (weight loss, 4.0 ± 0.0; weight gain, 3.8 ± 0.7; p = 0.004) and MM posterior root stability (weight loss, 2.6 ± 0.7; weight gain, 2.4 ± 0.7; p = 0.041), significantly differed between the groups. CONCLUSIONS: Weight loss was associated with better meniscal healing and less MME progression after MMPRT repair, highlighting the significance of weight management in individuals undergoing meniscal surgery. These findings provide valuable insights into the clinical significance of weight loss in the success of transtibial pullout repair for MMPRTs. LEVEL OF EVIDENCE: Level III.

Accurate tibial tunnel position in transtibial pullout repair for medial meniscus posterior root tears delays the progression of medial joint space narrowing.

PURPOSE: This study aimed to evaluate the association between the progression of medial joint space (MJS) narrowing, medial meniscus extrusion (MME) and clinical scores and the tibial tunnel position in pullout repairs for medial meniscus posterior root tears (MMPRTs). METHODS: This retrospective study examined 54 patients. Changes in MJS (ΔMJS), MME (ΔMME) and clinical scores and their relationship with the tibial tunnel position were evaluated using correlation coefficients. The distance from the anatomical to technical attachment position in the tibial tunnel position was measured in the anterior and medial directions, and the direct distance was measured using the Pythagorean theorem. RESULTS: The mean ΔMJS and ΔMME were 0.6 ± 0.8 and 1.3 ± 1.3 mm, respectively, and the mean anterior, medial and direct distances were 1.4 ± 2.3, 2.2 ± 1.7 and 3.4 ± 1.7 mm, respectively. ΔMJS had a significant positive correlation with the medial (r = 0.580, p < 0.001) and direct (r = 0.559, p < 0.001) distances, while ΔMME had a significant positive correlation with direct distance (r = 0.295, p = 0.030). Several clinical scores were significantly negatively correlated with these distances. CONCLUSION: In transtibial pullout repair for MMPRTs, accurate tibial tunnel position delayed the progression of MJS narrowing and MME, leading to improved clinical outcomes. The progression of MJS narrowing was associated with the mediolateral direction of the tibial tunnel position, while the clinical scores were associated with the anteroposterior direction of the tibial tunnel position. These findings indicate the need to orient the tip of the guide in a more posterolateral direction when creating the tibial tunnel. LEVEL OF EVIDENCE: Level IV.

Meniscal healing status after medial meniscus posterior root repair negatively correlates with a midterm increase in medial meniscus extrusion.

PURPOSE: The second-look arthroscopic score of pullout repair for medial meniscus posterior root tears (MMPRTs) is associated with contemporaneous clinical scores and progression of cartilage damage. However, the relationship among these scores, midterm clinical scores and magnetic resonance imaging (MRI) evaluations is unknown. The relationship between the second-look arthroscopic score at 1 year and the clinical scores or MRI at 3 years was evaluated. METHODS: Sixty-three patients were included. Medial meniscus extrusion (MME) was evaluated preoperatively and at 3 years postoperatively. Clinical scores were evaluated preoperatively, and 1 and 3 years postoperatively. Meniscal healing status was assessed using the semiquantitative second-look arthroscopic score at 1 year postoperatively. Correlation coefficients between patient characteristics, postoperative clinical scores or second-look arthroscopic score and the change in MME (ΔMME) were evaluated. Multiple regression analysis was performed on the ΔMME to evaluate the effects of patient characteristics and second-look arthroscopic scores. RESULTS: No significant correlation was observed between patient characteristics and ΔMME. In contrast, a significant correlation was found between the second-look arthroscopic score and ΔMME (p < 0.001) and visual analogue scale pain score (p = 0.016) at 3 years postoperatively. In the subitems of the second-look arthroscopic score, width (p < 0.001) and stability (p = 0.009) scores also showed significant correlations with ΔMME. Multiple regression analysis showed a significant association between the second-look arthroscopic score and ΔMME (p = 0.001). CONCLUSIONS: The second-look arthroscopic score at 1 year postoperatively correlated with the ΔMME and clinical score at 3 years postoperatively. Second-look arthroscopic scores predict midterm meniscal function after pullout repair of MMPRTs. LEVEL OF EVIDENCE: Level IV.

Intercondylar notch width and osteophyte width impact meniscal healing and clinical outcomes following transtibial pullout repair of medial meniscus posterior root tears.

PURPOSE: This retrospective study aimed to investigate the relationship between intercondylar notch width (ICNW), osteophyte width (OW), and the healing of medial meniscus posterior root tears (MMPRTs) following arthroscopic pullout repair. METHODS: The study included 155 patients diagnosed with MMPRTs who underwent transtibial pullout repair. Meniscal healing status was evaluated on second-look arthroscopy using a previously reported meniscus healing score. Patients were divided into two groups based on this score: the high healing score (group HH, healing score ≥ 8 points) and suboptimal healing score (group SO, healing score ≤ 6 points) groups. Computed tomography scans were performed on patients 1 week postsurgery. ICNW and OW widths were measured and relatively evaluated based on their ratio to the intercondylar distance (ICD), represented as the ICNW/ICD ratio (%) and OW/ICD ratio (%), respectively. Patient-reported outcomes were assessed preoperatively and on second-look arthroscopy using the Knee injury and Osteoarthritis Outcome Score (KOOS) and visual analogue scale (VAS). RESULTS: There were no significant demographic differences between the SO and HH group (n = 35 and 120 patients, respectively). Regarding radiographic measurements, significant differences were observed in the ICNW/ICD ratio (group SO, 24.2%; group HH, 25.2%; p = 0.024), OW (group SO, 2.6 mm; group HH, 2.0 mm; p < 0.001), and OW/ICD ratio (group SO, 3.5%; group HH, 2.7%; p < 0.001). Both groups had similar preoperative clinical scores, but postoperative clinical scores, including KOOS-activities of daily living (group SO, 83.4; group HH, 88.7; p = 0.035) and VAS (group SO, 19.1; group HH, 11.3; p = 0.005), were significantly better in group HH. CONCLUSION: The study suggests that ICNW and OW may play a crucial role in MMPRT healing following arthroscopic pullout repair, as evidenced by the worse clinical outcomes associated with a narrower ICNW and wider OW. These findings highlight the potential significance of ICNW and OW assessments when evaluating meniscal repair indications. LEVEL OF EVIDENCE: Level III.

Inhibitory Effect of a Tankyrase Inhibitor on Mechanical Stress-Induced Protease Expression in Human Articular Chondrocytes.

We investigated the effects of a Tankyrase (TNKS-1/2) inhibitor on mechanical stress-induced gene expression in human chondrocytes and examined TNKS-1/2 expression in human osteoarthritis (OA) cartilage. Cells were seeded onto stretch chambers and incubated with or without a TNKS-1/2 inhibitor (XAV939) for 12 h. Uni-axial cyclic tensile strain (CTS) (0.5 Hz, 8% elongation, 30 min) was applied and the gene expression of type II collagen a1 chain (COL2A1), aggrecan (ACAN), SRY-box9 (SOX9), TNKS-1/2, a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), and matrix metalloproteinase-13 (MMP-13) were examined by real-time PCR. The expression of ADAMTS-5, MMP-13, nuclear translocation of nuclear factor-κB (NF-κB), and ß-catenin were examined by immunocytochemistry and Western blotting. The concentration of IL-1ß in the supernatant was examined by enzyme-linked immunosorbent assay (ELISA). TNKS-1/2 expression was assessed by immunohistochemistry in human OA cartilage obtained at the total knee arthroplasty. TNKS-1/2 expression was increased after CTS. The expression of anabolic factors were decreased by CTS, however, these declines were abrogated by XAV939. XAV939 suppressed the CTS-induced expression of catabolic factors, the release of IL-1ß, as well as the nuclear translocation of NF-κB and ß-catenin. TNKS-1/2 expression increased in mild and moderate OA cartilage. Our results demonstrated that XAV939 suppressed mechanical stress-induced expression of catabolic proteases by the inhibition of NF-κB and activation of ß-catenin, indicating that TNKS-1/2 expression might be associated with OA pathogenesis.

Influence of Janus kinase inhibitors on early postoperative complications in patients with rheumatoid arthritis undergoing orthopaedic surgeries.

OBJECTIVE: We retrospectively reviewed the records of rheumatoid arthritis (RA) patients who underwent orthopaedic surgery to examine the influence of the perioperative use of Janus kinase (JAK) inhibitors on early postoperative complications. PATIENTS AND METHODS: Thirty-two patients with RA under disease control with JAK inhibitors who underwent 49 orthopaedic procedures were included in the study. Patient records after surgery were investigated for surgical site infection (SSI), delayed wound healing (DWH), a flare-up of the disease, preoperative and postoperative absolute lymphocyte counts (ALCs), venous thromboembolism, and other postoperative complications. RESULTS: JAK inhibitors were continued during the perioperative period in 31 procedures. In the remaining 18 procedures, JAK inhibitors were discontinued perioperatively with a mean discontinuation period of 2.4 days. No instances of SSI were identified in any patient during at least 90 days' follow-up, while DWH was seen in one patient. Disease flare-up was noted in two patients after 3 and 9 days of discontinuation of JAK inhibitors, respectively. The ALCs significantly decreased on postoperative Day 1 (P < .0001), and there was a significant correlation between pre- and post-one-day ALCs (r = 0.75, P < .0001). CONCLUSION: JAK inhibitors seem to be safe during the perioperative period of orthopaedic surgery.

Longitudinal changes in medial meniscus extrusion and clinical outcomes following pullout repair for medial meniscus posterior root tears: a 3-year evaluation.

PURPOSE: We aimed to evaluate the longitudinal changes in medial meniscus extrusion (MME) and clinical scores at multiple time points up to 3 years after pullout repair for medial meniscus posterior root tears (MMPRTs). METHODS: This retrospective case series study included 64 patients who underwent pullout repair for MMPRTs and four MRI evaluations (preoperatively and at 3 months, 1 year, and 3 years postoperatively). MME was measured during the same time points. Clinical scores were assessed four times: preoperatively and at 1, 2, and 3 years postoperatively. Additionally, a multivariate analysis was performed on the change in MME (ΔMME) from the preoperative measurement point to 3 years postoperatively. RESULTS: The ΔMME per month from the preoperative measurement point to 3 months postoperatively, from 3 months to 1 year postoperatively, and from 1 to 3 years postoperatively were 0.30, 0.05, and 0.01 mm/month, respectively. All clinical scores significantly improved 3 years postoperatively (p < 0.001). In a multiple regression analysis for ΔMME from the preoperative measurement point to 3 years postoperatively, sex significantly affected the outcome (p = 0.039). CONCLUSION: Following pullout repair for MMPRTs with well-aligned lower extremities, although MME progression could not be entirely prevented, the rate of progression decreased over time, and clinical scores improved. In particular, MME progressed markedly during the first 3 months postoperatively. Additionally, sex had a significant influence on MME progression, suggesting that males may be able to expand the indications of pullout repair for MMPRTs.

Protocol for the 2ND-STEP study, Japan Clinical Oncology Group study JCOG1802: a randomized phase II trial of second-line treatment for advanced soft tissue sarcoma comparing trabectedin, eribulin and pazopanib.

BACKGROUND: Soft tissue sarcomas (STS) are a rare type of malignancy comprising a variety of histological diagnoses. Chemotherapy constitutes the standard treatment for advanced STS. Doxorubicin-based regimens, which include the administration of doxorubicin alone or in combination with ifosfamide or dacarbazine, are widely accepted as first-line chemotherapy for advanced STS. Trabectedin, eribulin, pazopanib, and gemcitabine plus docetaxel (GD), which is the empirical standard therapy in Japan, are major candidates for second-line chemotherapy for advanced STS, although clear evidence of the superiority of any one regimen is lacking. The Bone and Soft Tissue Tumor Study Group of the Japan Clinical Oncology Group (JCOG) conducts this trial to select the most promising regimen among trabectedin, eribulin, and pazopanib for comparison with GD as the test arm regimen in a future phase III trial of second-line treatment for patients with advanced STS. METHODS: The JCOG1802 study is a multicenter, selection design, randomized phase II trial comparing trabectedin (1.2 mg/m2 intravenously, every 3 weeks), eribulin (1.4 mg/m2 intravenously, days 1 and 8, every 3 weeks), and pazopanib (800 mg orally, every day) in patients with unresectable or metastatic STS refractory to doxorubicin-based first-line chemotherapy. The principal eligibility criteria are patients aged 16 years or above; unresectable and/or metastatic STS; exacerbation within 6 months prior to registration; histopathological diagnosis of STS other than Ewing sarcoma, embryonal/alveolar rhabdomyosarcoma, well-differentiated liposarcoma and myxoid liposarcoma; prior doxorubicin-based chemotherapy for STS, and Eastern Cooperative Oncology Group performance status 0 to 2. The primary endpoint is progression-free survival, and the secondary endpoints include overall survival, disease-control rate, response rate, and adverse events. The total planned sample size to correctly select the most promising regimen with a probability of > 80% is 120. Thirty-seven institutions in Japan will participate at the start of this trial. DISCUSSION: This is the first randomized trial to evaluate trabectedin, eribulin, and pazopanib as second-line therapies for advanced STS. We endeavor to perform a subsequent phase III trial comparing the best regimen selected by this study (JCOG1802) with GD. TRIAL REGISTRATION: This study was registered with the Japan Registry of Clinical Trials ( jRCTs031190152 ) on December 5, 2019.