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Background and Objectives: Intraoperative frozen section analysis is commonly used to evaluate marrow margins during extremity bone sarcoma resections, but its efficacy in the era of magnetic resonance imaging is debated. This study aimed to compare the accuracy of intraoperative frozen section assessment with final pathology, assess its correlation with gross intraoperative margin assessment, and evaluate its impact on surgical decision making., Methods: Consecutive patients undergoing extremity bone sarcoma resections from 2010 to 2022 at a single sarcoma center were included. Intraoperative frozen section and gross margin assessments were compared to final pathology using positive predictive values (PPV) and negative predictive values (NPV). Changes in surgical decisions due to positive intraoperative margins were recorded., Results: Of 166 intraoperative frozen section marrow margins, four were indeterminant/positive, with two false positive/indeterminant findings and two false negatives compared to final pathology. Gross intraoperative assessment had no false positives and two false negatives. Frozen section analysis yielded a PPV of 50% (95% confidence interval [CI]: 16%-84%) and NPV of 98.8% (95% CI: 97%-100%), while gross assessment had a PPV of 100% (95% CI: 16%-100%) and NPV of 98.8% (95% CI: 97%-100%). Positive frozen section margins led to additional resections in three of four cases., Conclusions: Intraoperative frozen section analysis did not offer added clinical value beyond gross margin assessment in extremity bone sarcoma resections. It exhibited a low PPV and led to unnecessary additional resections. Gross intraoperative assessment proved adequate for margin evaluation, potentially saving time and resources., (© 2024 The Author(s). Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Background: Pleomorphic rhabdomyosarcoma is a rare sarcoma in adults. The clinical characteristics, outcomes and prognostic factors associated with pleomorphic rhabdomyosarcoma remain unclear., Methods: We retrospectively analyzed data from the Bone and Soft Tissue Tumor Registry of Japan, and enrolled patients with pleomorphic rhabdomyosarcoma. Disease-specific overall survival, local recurrence-free survival and distant metastasis-free survival were estimated using the Kaplan-Meier method; Cox regression model was used to identify prognostic factors., Results: In total, 182 patients with pleomorphic rhabdomyosarcoma were included. Median age was 63 (range 20-95) years. The lower extremity (48%) was the most frequent tumor origin site, while head and neck were rare (4%). A total of 43 patients (24%) had distant or regional nodal metastases at first presentation. In all cases, the 2-year and 5-year survival rates were 66.3% and 54.1%, respectively. Distant metastasis was a significant poor prognostic factor (Hazard ratio 6.65; 95% confidence intervals, 3.00-14.75, P < 0.0001), with median survival of such patients being 9.4 (95% confidence intervals: 5.3-12.2) months. In 134 localized cases, the 2-year and 5-year survival rates were 91.5% and 68.3%, respectively. Large tumor size and older age were associated with poorer prognosis. Through data from localized and locally curative cases extracted and adjusted by propensity score matching, we found that perioperative chemotherapy did not improve disease-specific overall survival, distant metastasis-free survival or local recurrence-free survival., Conclusions: Clinical characteristics and outcomes of pleomorphic rhabdomyosarcoma are similar to those of other high-grade soft tissue sarcomas. Pleomorphic rhabdomyosarcoma may be less chemosensitive, and a strategy other than the standard cytotoxic chemotherapy is required to improve its prognosis., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

BRAF alterations, including V600E and non-V600E mutations and fusions, in soft tissue sarcoma (STS) have been identified in a limited case series. Here, we aimed to evaluate the frequency of BRAF mutations and concurrent alterations in STS to understand their therapeutic action. In this retrospective analysis, we included data from 1964 patients with advanced STS who underwent comprehensive genomic profiling tests at hospitals in Japan between June 2019 and March 2023. The prevalence of BRAF and recurrent concurrent gene alterations were also investigated. BRAF mutations were detected in 24 (1.2%) of 1964 STS patients, with a median age of 47 (range 1-69) years. BRAF V600E was detected in 11 (0.6%) of the 1964 patients with STS, BRAF non-V600E mutations in 9 (4.6%), and BRAF fusions were detected in 4 (0.2%). BRAF V600E was identified in 4 (0.2%) cases of malignant peripheral nerve sheath tumors. The most common concurrent alteration was CDKN2A (11 cases, 45.8%), and the frequency was equivalent to that of the BRAF V600E (5/11 cases, 45.5%) and non-V600E (5/9 cases, 55.6%) groups. Recurrent concurrent alterations, such as TERT promoter mutations (7 cases, 29.2%), were detected at the same frequency in the V600E and non-V600E groups. In contrast, TP53 alterations (4/9 cases, 44.4%) and mitogen-activated protein kinase (MAPK)-activating genes, including NF1, GNAQ, and GNA11 (3/9 cases, 33.3%), were identified as relatively higher in the non-V600E group than in the V600E group (each 1/11 case, 9.1%). We identified BRAF alterations at a rate of 1.2% in all patients with advanced STS. Among them, BRAF V600E and BRAF fusions account for 45.8% and 16.7%, respectively. Collectively, our findings support the clinical characteristics and therapeutic strategies for patients with BRAF-altered advanced STS., (© 2023 The Authors. Genes, Chromosomes and Cancer published by Wiley Periodicals LLC.)

Background: Clinical characteristics of undifferentiated pleomorphic sarcoma of bone are not elucidated. Herein, we clarify its clinical features and analyze the efficacy of adjuvant chemotherapy in patients with undifferentiated pleomorphic sarcoma of bone., Methods: Prognostic factors and estimated disease-specific survival in 247 patients with primary undifferentiated pleomorphic sarcoma of bone were identified from a registry in Japan. The effect of adjuvant chemotherapy was evaluated in localized resectable cases, and the characteristics of the two groups treated with or without chemotherapy were adjusted using propensity score matching., Results: The 5-year disease-specific survival rates were 47.4% in the entire cohort and 56.4 and 16.9% in the M0 and M1 groups, respectively. Multivariate disease-specific survival analysis revealed that metastasis on initial presentation and age ≥ 65 years were poor prognostic factors. Overall, 132 localized and resectable primary lesions were extracted. Adjuvant chemotherapy administration was a favorable prognostic factor (hazard ratio: 0.43, P = 0.04), and it significantly prolonged disease-specific survival compared with no adjuvant chemotherapy (5-year disease-specific survival: 78.8% vs. 51.8%, P = 0.008). Adjuvant chemotherapy prolonged disease-specific survival in patients with tumor size <8 cm (5-year disease-specific survival: 100% vs. 54.6%, P = 0.02); however, its efficacy decreased in those with tumor size ≥8 cm (5-year disease-specific survival: 68.7% vs. 42%, P = 0.09). After propensity score matching, adjuvant chemotherapy was significantly associated with good disease-specific survival (P = 0.02)., Conclusions: Metastasis in the initial presentation was the poorest prognostic factor. On evaluating localized and resectable cases only, adjuvant chemotherapy significantly improved disease-specific survival, although its effect decreased in cases with large tumors., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: Primary tumor resection is the mainstay of treatment for undifferentiated pleomorphic sarcoma (UPS); however, the necessity of adjuvant chemotherapy has been debated. We aimed to clarify the effect of adjuvant chemotherapy on survival rates in patients with UPS with localized and resectable primary lesions., Methods: This retrospective analysis included data of 2112 patients with localized UPS arising in the extremities and trunk, extracted from a registry in Japan. We estimated overall survival (OS), identified prognostic factors, and adjusted patient characteristics in the two groups treated with or without chemotherapy using propensity score matching (PSM)., Results: The 5-year OS rate was 79.4%. In multivariate OS analysis, adjuvant chemotherapy was a good prognostic factor (hazard ratio 0.65; 95% confidence interval 0.48-0.9, P = 0.009). Large tumor size was the poorest prognostic factor, and OS decreased with the tumor size (P < 0.0001). In all patients, adjuvant chemotherapy prolonged OS (5-year OS: 82.3% vs. 78.6%, P = 0.03). Adjuvant chemotherapy did not affect OS in patients with tumor size < 5 cm; the benefit was strong in patients with tumor size 10 to < 15 cm (5-year OS: 79.5% vs. 66.8%, P = 0.003). Adjuvant chemotherapy efficacy was not pronounced in patients with tumor size 5 to < 10 cm (5-year OS: 87% vs. 80%, P = 0.06) and ≥ 15 cm (5-year OS: 60.7% vs. 49.5%, P = 0.08). After PSM, adjuvant chemotherapy was significantly associated with improved OS (P = 0.02)., Conclusions: In patients with localized UPS, adjuvant chemotherapy tended to improve OS when tumors were ≥ 5 cm, especially when they were 10 to < 15 cm., (© 2021. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background: Eribulin is a tubulin and microtubule-targeting drug that has clinical benefit in overall survival (OS) for patients with advanced soft tissue sarcoma. Eribulin's efficacy has been confirmed in several clinical trials, although no clinically useful biomarkers have been identified. We therefore sought to clarify the predictive factor of eribulin treatment, while focusing on systemic inflammation and immune response values., Methods: This study included 33 advanced STS patients treated with eribulin between March 2016 and September 2019. We evaluated the associations of clinical factors influencing the efficacy of eribulin treatment and systemic inflammatory and immune response, including the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), the lymphocyte-to-monocyte ratio (LMR), the systemic inflammation response index (SIRI), and the prognostic nutrition index (PNI), with progression-free survival (PFS) and OS using the Kaplan-Meier method and log-rank test., Results: NLR, LMR, PLR, SIRI, and PNI were unassociated with PFS. Compared with patients with SIRI <1.5, those with an SIRI ≥1.5 had a significantly shorter OS [median OS 15 months (95% confidence interval [CI] 8-not reached) vs. 7 months (95% CI 3-14), P = 0.04]. Moreover, the PFS tended to be shorter for patients with SIRI ≥1.5 who received chemotherapy after eribulin treatment than in those with SIRI >1.5 [median PFS 92.5 days (95% CI 27-204) vs. 133 days (95% CI 36-507), P = 0.08]., Conclusions: High SIRI values may predict poorer overall survival and the efficacy of subsequent drugs after eribulin treatment among patients with advanced soft tissue sarcoma., Competing Interests: Declaration of competing interest All authors declare that there are no conflicts of interest relevant to this manuscript., (Copyright © 2020. Published by Elsevier B.V.)

Background: Approximately 10% of the patients with soft tissue sarcoma show metastasis at initial diagnosis, and hence, poorer prognosis. However, the prognostic factors and whether definitive surgery for the primary lesion improves overall survival, especially when complete resection of metastasis is difficult, remain unclear., Methods: This retrospective analysis was based on the Bone and Soft Tissue Tumor Registry in Japan. Patients with soft tissue sarcoma having metastasis at diagnosis were enrolled, excluding those with Ewing's sarcoma, rhabdomyosarcoma and several other sarcomas with unique behavior and treatment strategies. Overall survival was estimated using the Kaplan-Meier method and compared among the common histologic subtypes. Multivariate analysis with the Cox regression model was used to identify the prognostic factors., Results: In total, 1184 patients were included, with a median follow-up duration of 10 months (range: 1-83). The median overall survival was 21 months (95% confidence interval: 18.2-23.8). The multivariate analyses indicated that tumor size, grade and histologic subtypes significantly correlated with overall survival. Moreover, surgery for the primary lesion, in addition to surgery for metastases and chemotherapy, showed significant association with better survival., Conclusions: The prognostic factors in patients with metastatic soft tissue sarcoma at diagnosis are generally similar to those in patients with localized disease. The overall survival in patients differed significantly according to histologic subtype. Surgical resection of primary lesions, especially those with a wide margin, may be an independent prognostic factor. Further studies are needed identify which subgroup of patients would benefit the most from primary lesion surgery., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: Soft tissue metastasis is rarer than bone metastasis. Patients with soft tissue metastasis generally have a dismal prognosis. The treatment for metastatic lesions is sometimes difficult, because the prognostic factors of patients with soft tissue metastasis remain unelucidated. Therefore, this study aimed to identify these prognostic factors., Methods: Thirty-one patients with soft tissue metastasis were included in the study. We evaluated associations of overall survival with clinical parameters and inflammatory markers using Kaplan-Meier curves and Cox proportional hazards models., Results: Twelve patients received surgery for soft tissue metastasis, while radiation therapy was performed in six cases. The median overall survival after the detection of soft tissue metastasis was 11 months. Univariate analysis revealed that detection of soft tissue metastasis after the multidisciplinary treatment (P = 0.01); solitary metastasis (P = 0.0003); and pretreatment C-reactive protein (CRP) level < 0.4 mg/dL (P < 0.0001), white blood cell count < 8500 × 10 3 /μL (P = 0.0003), and neutrophil-to-lymphocyte ratio < 5 (P = 0.02) were significant good prognostic factors. Multivariate analysis revealed that a CRP value < 0.4 mg/dL (P = 0.07) and solitary metastasis (P = 0.09) were possible significant predictors of survival. Furthermore, in case of CRP levels <0.4 mg/dL and metastatic tumor resection, patients had a good prognosis; however, when the CRP levels increased to 0.4 mg/dL and above, patients had a poor prognosis, irrespective of tumor resection., Conclusions: CRP is potentially useful for determining the indication of radical metastasectomy in soft tissue metastasis., Competing Interests: Declaration of competing interest All authors declare that there are no conflicts of interest relevant to this manuscript., (Copyright © 2020 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Objective: Malignant fungating wounds are ulcerating tumors that infiltrate the overlying skin. Little evidence exists regarding the prognosis or treatment of malignant fungating wound in soft tissue sarcoma. This study aimed to reveal the prognosis and outcome of surgical treatment of malignant fungating wound in soft tissue sarcoma., Methods: We retrospectively reviewed 26 patients with malignant fungating wound in high-grade soft tissue sarcoma between 2005 and 2018. The patients' characteristics, treatments, surgical wound complications, local recurrences and prognoses were analyzed. Overall survival was analyzed using the Kaplan-Meier method and compared with that of the control cohort, consisting of 236 consecutive patients with non-malignant fungating wound high-grade soft tissue sarcoma treated during the same period., Results: Among the 26 patients, undifferentiated pleomorphic sarcoma was the most common subtype. Twenty-three patients, including 20 (87%) and 3 (13%), underwent limb-salvage surgery and amputation, respectively. Among the 20 patients who underwent limb-salvage surgery, 4 (20%) had surgical wound complications, which required additional surgical procedures. Excluding the patients who underwent palliative surgery, local recurrence occurred in 2 patients (11%). The 5-year overall survival rate for all high-grade malignant fungating wound and non-malignant fungating wound patients was 26.0 and 67.3% (P < 0.0001), respectively., Conclusions: Malignant fungating wounds in soft tissue sarcoma were significantly associated with a poor prognosis; however, the incidence of surgical complications and local recurrence after limb-salvage surgery was comparable to that of general soft tissue sarcoma cases. Limb-salvage surgery should be considered, if possible, to preserve the patient's quality of life because of the dismal prognosis of patients with malignant fungating wound in soft tissue sarcoma., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: It is unknown whether sarcopenia influences treatment outcome in patients with soft tissue sarcoma. Herein, we aimed to elucidate the impact of sarcopenia on sarcoma treatment., Methods: A total of 163 soft tissue sarcoma patients were included. Skeletal muscle measures were calculated using computed tomography images. Skeletal muscle area (SMA) and density (SMD) at the L3 level were extracted, and SMA was normalized by height as skeletal muscle index (SMI). The skeletal muscle gauge (SMG) was calculated by multiplying SMD × SMI. The relationship of skeletal muscle measures and clinical factors to wound complications and prognosis was evaluated, and classification and regression tree (CART) analysis was used to develop classification models for risk groups of surgical wound complications., Results: Thirty-three patients developed wound complications. In univariate analysis, age (P = 0.0022), tumour location of adductor compartment of the thigh (P = 0.0019), operating time (P = 0.010), blood loss (P = 0.030), SMD (P = 0.0004) and SMG (P = 0.0001) were significantly correlated with complications. In multivariate analysis, lower SMG was an independent risk factor (P = 0.031, OR = 3.27). CART analysis classified three risk groups of surgical wound complications by SMG, age, tumour location and operating time, and area under the receiver operating characteristic curve (AUROCC) was 0.75. SMG was not associated with prognosis in univariate analysis (P = 0.15)., Conclusions: The SMG does not affect overall survival but predicts surgical wound complications., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: Despite the clinical benefits of eribulin on overall survival of advanced soft tissue sarcoma (STS) patients, treatment-related toxicity reduces their QOL. Body composition metrics (BCMs) are associated with poor outcome and drug toxicities in several cancers. This study investigated whether BCMs could predict drug toxicity occurrence in advanced STS patients treated with eribulin., Methods: This study included 23 advanced STS patients treated with eribulin between March 2016 and April 2018. BCMs were evaluated using a CT scan obtained within 1 month before or after treatment initiation. The relationship of BCMs and other clinical factors was evaluated and CART analysis used to develop classification models for risk groups of drug toxicity., Results: Sixteen patients (69.6%) experienced any grade 3/4 toxicity. Eleven patients (47.8%) developed G4 hematologic toxicity, which was significantly higher in those with low skeletal muscle gauge (SMG) (P = 0.02) and low pretreatment neutrophil count (P = 0.0002). Six patients (26.1%) had grade 3/4 non-hematologic toxicity, and was higher in those with low SMG (P = 0.004), and low serum albumin level (P = 0.02). Five patients with high BMI (P = 0.03) experienced febrile neutropenia (FN) and low pretreatment neutrophil count (P = 0.02). CART analysis classified three risk groups, and area under the receiver operating characteristic curve (AUROCC) was 0.92, 0.88, 0.92 in G4 hematologic AE, G3/4 non-hematologic AE, FN, respectively., Conclusions: SMG is a significant predictive factor of eribulin drug toxicity in advanced STS patients. Risk classification of drug toxicity through combining predictive factors, could improve the therapeutic strategy used in chemotherapy.