Japanese Orthopaedic Association (JOA) clinical practice guidelines on the management of soft tissue tumors 2020 - Secondary publication.

BACKGROUND: These clinical practice guidelines are intended to provide recommendations based on the best evidence obtained to date on key issues in clinical practice to improve the prognosis, diagnostic and therapeutic processes for patients with soft tissue tumors. METHODS: The Guidelines Development Committee and Systematic Review Committee were composed of a multidisciplinary team of specialists who play an important role in soft tissue tumor care. Clinical questions (CQs) were determined by choosing key decision-making points based on Algorithms for the diagnosis and treatment of soft tissue tumors. The guidelines were developed according to the "Medical Information Network Distribution Service (Minds) Handbook for Clinical Practice Guideline Development 2014" and "Minds Manual for Clinical Practice Guideline Development 2017." Recommendation strength was rated on two levels and the strength of evidence was rated on four levels. The recommendations were decided based on agreement by 70% or more voters. RESULTS: Twenty-two CQs were chosen by the Guidelines Development Committee. The Systematic Review Committee reviewed the evidence concerning each CQ, a clinical value judgment was added by experts, and the text of each recommendation was determined. CONCLUSION: We established 22 CQs and recommendations for key decision-making points in the diagnosis and treatment of soft tissue tumors according to the Minds Clinical Practice Guideline development methods. We hope that these guidelines will assist the decision-making of all medical staff engaged in the treatment and diagnosis of soft tissue tumors, and eventually lead to improved soft tissue tumor care in the country.

18F-Fluorodeoxyglucose Positron Emission Tomography Is Useful in the Evaluation of Prognosis in Retroperitoneal Sarcoma.

Background: Retroperitoneal sarcomas are rare neoplasms that occur in the retroperitoneum. Complete surgical resection is the only effective treatment option. The prediction of prognosis by histological diagnosis has not yet been established. The purpose of this study was to identify the usefulness of [18-F] fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging for validating the prognosis of retroperitoneal sarcoma (RPS) established by histological diagnosis. Methods: We retrospectively reviewed 201 patients with RPS treated at the Osaka International Cancer Institute between 2010 and 2021. We extracted the clinical data, including standardized uptake values (SUVs), evaluated with FDG-PET, and statistically analyzed the data. Results: The median age of patients was 64 years (range, 31-85 years). A total of 101 (50.2%) patients were men, and 100 (49.8%) were women. Surgical resection was performed in 155 (77.1%) patients. On histological analysis, 75 (37.3%), 52 (25.9%), and 29 (14.4%) patients were diagnosed with dedifferentiated liposarcoma, well-differentiated liposarcoma, and leiomyosarcoma, respectively. The median survival time for patients with high maximum SUV (SUVmax) (≥4) or low SUVmax (<4) was 275.8 months and 79.5 months, respectively. Furthermore, among the patients with dedifferentiated liposarcoma, the overall survival rate for patients with high SUVmax (≥4) was significantly lower than that of those with low SUVmax (<4). Conclusions: The present study demonstrated that SUVmax calculated with FDG-PET was useful as a prognostic factor in RPS, especially in dedifferentiated liposarcoma and Grade2 RPS. To devise a treatment strategy for RPS, SUVmax during FDG-PET scan may be considered for clinical assessment.

Complication rate, functional outcomes, and risk factors associated with carbon ion radiotherapy for patients with unresectable pelvic bone sarcoma.

BACKGROUND: To the authors' knowledge, carbon ion radiotherapy (CIRT) is one of the few curative treatments for unresectable pelvic bone sarcoma. The current study investigated the complications, functional outcomes, and risk factors of CIRT. METHODS: Of 112 patients who were treated with CIRT for unresectable pelvic bone sarcoma, the authors enrolled 29 patients who were without local disease recurrence or distant metastasis. The mean follow-up was 93 months. Complications, functional outcomes, and quality of life scores were assessed. Risk factors were analyzed, including the dose-volume histogram of the femoral head. RESULTS: Femoral head necrosis occurred in approximately 37% of patients, pelvic fractures were reported in 48% of patients, and neurological deficits were noted in 52% of patients. Femoral head necrosis was found to be significantly more prevalent among patients with periacetabular tumors (P = .018). The dose-volume histogram of the femoral head indicated tolerable volume percentages of the femoral head to be <33% for 40 grays (relative biological effectiveness) and 16% for 60 grays ( relative biological effectiveness). The mean Musculoskeletal Tumor Society score and Toronto Extremity Salvage Score were 53% and 64%, respectively, and the mean EuroQol 5 dimensions questionnaire index was 0.587. Patients aged >50 years and those with periacetabular tumors were found to have significantly lower Toronto Extremity Salvage Scores. CONCLUSIONS: Femoral head necrosis, pelvic fracture, and nerve damage are common complications with the use of CIRT for pelvic bone sarcoma. To prevent femoral head necrosis, the radiation dose to the femoral head should be kept below the estimated tolerance curve presented in the current study. The functional outcome is nearly equivalent to that of surgery. CIRT may be a promising alternative to surgery for patients with unresectable pelvic bone sarcoma.

Clinical Outcomes of Osteoarticular Extracorporeal Irradiated Autograft for Malignant Bone Tumor.

METHODS: We retrospectively reviewed 33 patients who underwent osteoarticular ECIA after bone tumor resection from 1988 to 2014. We investigated complications, radiographic changes by the International Society of Limb Salvage graft evaluation criteria, and functional outcomes according to the Musculoskeletal Tumor Society scoring system. RESULTS: Fifteen patients were reoperated upon due to infection (n = 9), protruding fixation implant (n = 4), or fracture of the grafted bone (n = 2). The average radiographic evaluation score was 66.4%, and the median functional score was 23 (77%). The radiographic score for the proximal humerus or proximal tibia was lower than that for the other locations. The functional score was not different among the autograft sites but was related to the radiographic score. CONCLUSION: Although osteoarticular ECIA is one of the reasonable surgical options for patients with tumors for which reliable prostheses are not available, we do not recommend osteoarticular ECIA as a routine procedure because of high complication rate.

A long-term follow-up study of extracorporeal irradiated autografts in limb salvage surgery for malignant bone and soft tissue tumors: A minimum follow-up of 10 years after surgery.

BACKGROUND AND OBJECTIVES: The aim of this study is to assess the survival, function, radiographic appearance, and modes of failure of extracorporeal irradiated (ECI) autografts in a long-term setting. METHODS: We retrospectively reviewed 87 patients who were treated for bone and soft tissue tumors using ECI autografts between 1988 and 2009. RESULTS: The 56 patients had a minimum follow-up of 10 years, and the median follow-up period was 16.5 years. The reimplantation procedures included 24 osteoarticular grafts, 16 intercalary grafts, 10 autograft-prosthetic composite grafts, and 6 hemicortical grafts. The 15-year graft and event-free survival rates were 76.8% and 47.9%, respectively. Infection and structural failure were the most common reasons for additional surgery. The time for additional surgery was significantly longer in patients with composite grafts (P < .01). The median Musculoskeletal Tumor Society score and the International Society of Limb Salvage score were 80% and 84%, respectively. CONCLUSIONS: ECI autografts are a durable option for reconstruction after resection of musculoskeletal tumors and provide good function over more than 15 years. Most graft failures occurred within 5 years of the index surgery. However, composite grafts showed a tendency to fail more than 10 years after the surgery.

Time lapse analysis of tumor response in patients with soft tissue sarcoma treated with trabectedin: A pooled analysis of two phase II clinical trials.

The time course of the response to each drug is important to avoid inappropriate termination of treatment by misjudging tumor progression; however, little is known about soft tissue sarcoma (STS) regarding this matter. This study aimed to perform a time-lapse analysis of tumor response in patients with STS treated with trabectedin from 2 phase II clinical trials. We examined 66 patients with translocation-related sarcoma registered in 2 Japanese phase II clinical trials. All patients previously received standard therapy before the administration of trabectedin at 1.2 mg/m2 every 3 weeks. Imaging evaluation was performed according to the study protocol. The sum of the maximum diameters of the target lesions was calculated and analyzed over time. Among the 66 patients, 9 (13.6%) showed partial response (PR) to trabectedin. Histological diagnoses of these 9 responders comprised 6 myxoid liposarcoma, 2 synovial sarcoma, and a mesenchymal chondrosarcoma. The median period from treatment initiation to the first PR was 123 (range, 34-328) days. The pattern of tumor response to trabectedin showed an increasing tendency in size in the initial stage, usually followed by a size decrease with repeated administration. STS response to trabectedin was characterized as delayed and potentially persistent. Clinicians treating STS with trabectedin should know the features of the response pattern to avoid interrupting the treatment before maximal efficacy is achieved.

Clinical outcomes of chondroblastoma treated using synthetic bone substitute: risk factors for developing radiographic joint degeneration.

BACKGROUND: Chondroblastoma (CB) is a rare locally aggressive bone tumor that commonly occurs in the epiphysis or apophysis of long bones. Although surgical treatment of CB carries potential risk for physeal or articular cartilage damage, risk factors for joint degeneration have not been well described. In addition, we have mainly used synthetic bone substitute (SBS) to fill the bone defect after intralesional curettage as treatment for CB. This study thus aimed to evaluate the incidence of and risk factors for adjacent-joint radiographic degeneration after SBS treatment for CB. METHODS: We retrospectively reviewed 48 patients treated for CB at our institutions between 1996 and 2017. Clinical data, radiographic images, treatments, and local recurrence were analyzed. RESULTS: We identified 40 patients [29 males and 11 females with a mean age of 19 years (range, 8-35 years)] who received SBS to fill the defect after curettage with a minimum follow-up of 1 year. The mean follow-up period was 71 months (range, 13-239 months). A total of 8 patients (20%) developed local recurrence. Radiographic analysis showed that 5 patients (16.7%) developed radiographic joint degeneration. Joint degeneration was significantly associated with the affected joint (p = 0.004). CONCLUSIONS: Curettage and SBS filling had been found to be a reasonable treatment method for CB, which commonly occurs in the epiphysis or apophysis. Radiographic joint degeneration was not uncommon after CB treatment, especially in the talus and proximal humerus.

Author Correction: Establishment of a novel human CIC-DUX4 sarcoma cell line, Kitra-SRS, with autocrine IGF-1R activation and metastatic potential to the lungs.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Eribulin Suppresses Clear Cell Sarcoma Growth by Inhibiting Cell Proliferation and Inducing Melanocytic Differentiation Both Directly and Via Vascular Remodeling.

Clear cell sarcoma (CCS) is a rare but chemotherapy-resistant and often fatal high-grade soft-tissue sarcoma (STS) characterized by melanocytic differentiation under control of microphthalmia-associated transcription factor (MITF). Eribulin mesilate (eribulin) is a mechanistically unique microtubule inhibitor commonly used for STS treatment, particularly liposarcoma and leiomyosarcoma. In this study, we examined the antitumor efficacy of eribulin on four human CCS cell lines and two mouse xenograft models. Eribulin inhibited CCS cell proliferation by inducing cell-cycle arrest and apoptosis, shrunk CCS xenograft tumors, and increased tumor vessel density. Eribulin induced MITF protein upregulation and stimulated tumor cell melanocytic differentiation through ERK1/2 inactivation (a MITF negative regulator) in vitro and in vivo Moreover, tumor reoxygenation, probably caused by eribulin-induced vascular remodeling, attenuated cell growth and inhibited ERK1/2 activity, thereby upregulating MITF expression and promoting melanocytic differentiation. Finally, downregulation of MITF protein levels modestly debilitated the antiproliferative effect of eribulin on CCS cells. Taken together, eribulin suppresses CCS through inhibition of cell proliferation and promotion of tumor differentiation by acting both directly on tumor cells and indirectly through tumor reoxygenation.

Establishment of a novel human CIC-DUX4 sarcoma cell line, Kitra-SRS, with autocrine IGF-1R activation and metastatic potential to the lungs.

Approximately 60-70% of EWSR1-negative small blue round cell sarcomas harbour a rearrangement of CIC, most commonly CIC-DUX4. CIC-DUX4 sarcoma (CDS) is an aggressive and often fatal high-grade sarcoma appearing predominantly in children and young adults. Although cell lines and their xenograft models are essential tools for basic research and development of antitumour drugs, few cell lines currently exist for CDS. We successfully established a novel human CDS cell line designated Kitra-SRS and developed orthotopic tumour xenografts in nude mice. The CIC-DUX4 fusion gene in Kitra-SRS cells was generated by t(12;19) complex chromosomal rearrangements with an insertion of a chromosome segment including a DUX4 pseudogene component. Kitra-SRS xenografts were histologically similar to the original tumour and exhibited metastatic potential to the lungs. Kitra-SRS cells displayed autocrine activation of the insulin-like growth factor 1 (IGF-1)/IGF-1 receptor (IGF-1R) pathway. Accordingly, treatment with the IGF-1R inhibitor, linsitinib, attenuated Kitra-SRS cell growth and IGF-1-induced activation of IGF-1R/AKT signalling both in vitro and in vivo. Furthermore, upon screening 1134 FDA-approved drugs, the responses of Kitra-SRS cells to anticancer drugs appeared to reflect those of the primary tumour. Our model will be a useful modality for investigating the molecular pathology and therapy of CDS.

Favorable outcomes of localized synovial sarcoma patients with a high utilization rate of neoadjuvant and/or adjuvant chemotherapy.

Synovial sarcoma (SS) is considered to be a chemosensitive, soft tissue sarcoma. Therefore, neoadjuvant and/or adjuvant chemotherapy (N/AC) is used for the treatment of high-risk SS patients. However, the role of N/AC remains controversial. The present study aimed to review the clinical outcomes of surgically treated localized SS and investigate the effects of N/AC with long-term observation. The clinical outcomes of 54 patients with surgically treated localized SS were retrospectively analyzed. The median patient age was 42 years (range, 8-81 years), and the median follow-up period was 94 months for survivors (range, 7-220 months). A total of 38 patients (70%) received chemotherapy. Of these, 32 (59%) patients received neoadjuvant chemotherapy, 33 (61%) received adjuvant chemotherapy, and 27 (50%) received neoadjuvant and adjuvant chemotherapy. Fourteen patients (26%) received adjuvant radiotherapy. Three patients (6%) had local recurrence and 13 patients (24%) developed distant metastasis. The overall survival (OS) rates at 5 and 10 years were 87 and 84%, respectively. N/AC did not improve survival. In conclusion, we found satisfactory long-term OS among patients with a high utilization rate of N/AC. Further study should be necessary to evaluate which population of SS would benefit from N/AC.

Rectotumoral fistula formation occurring more than 5 years after carbon ion radiotherapy for sacral chordoma: A case report.

Chordoma is a rare tumor that originates from the notochord. Half of chordomas involve the sacral region. Surgery is considered to be the standard treatment for sacral chordoma. However, carbon ion radiotherapy (CIRT) has recently emerged as a promising treatment for unresectable sacral chordoma. Little is known about the long-term complications of CIRT. We present two cases of rectotumoral fistula formation that occurred >5 years after CIRT for sacral chordoma. We considered two possible explanations for fistula formation: radiation enterocolitis after CIRT might cause formation of the fistula long-term, and tumor regrowth might compress the rectum and cause fistula formation. A biopsy in Case 1 showed that regrowth tumor was post-CIRT. It is important to be aware of the possibility of rectal complications after CIRT, and if found, resection of the rectum should be considered. This is a first report of rectotumoral fistula formation that occurred >5 years after CIRT for sacral chordoma.

Survival analysis of elderly patients with osteosarcoma.

BACKGROUND: Few studies have described the characteristics and prognostic factors of elderly patients with osteosarcoma. We retrospectively investigated clinico-pathological features and prognostic factors in osteosarcoma patients > 40 years old. METHODS: Patients with high-grade osteosarcoma > 40 years old who were treated at our institutions from 2000 to 2016 were recruited for this study. Information on patient, tumour, and treatment-related factors was collected and statistically analyzed. The median follow-up was 26.5 months (range, 5-139 months) for all patients. RESULTS: Fifty patients (30 males and 20 females) were included. The median age at diagnosis was 59.5 years (range, 41-81 years). The primary lesions were found in the limbs in 32 patients, trunk in 12, and craniofacial bones in six. Primary and secondary osteosarcoma occurred in 41 and 9 patients, respectively. Eight patients exhibited initial distant metastasis. Definitive surgery and chemotherapy were performed in 39 patients each. The rate of good responders after neoadjuvant chemotherapy was 38%. The five year overall survival (OS) rates for all patients and those without distant metastasis at diagnosis were 44.5% and 51.1%, respectively. Multivariate analysis showed that definitive surgery was the only significant prognostic factor in non-metastatic patients. The five year OS and disease-free survival (DFS) rates for non-metastatic patients who received definitive surgery were 64.3% and 60%, respectively. Among these patients, neoadjuvant and/or adjuvant chemotherapy significantly improved both OS and DFS. CONCLUSIONS: Complete surgical resection and intensive chemotherapy should be performed for osteosarcoma patients > 40 years old despite distinct clinicopathological characteristics from those of younger patients.

Clinical outcomes and significant factors in the survival rate after decompression surgery for patients who were non-ambulatory due to spinal metastases.

BACKGROUND: The development of effective chemotherapy regimens and molecular targeting agents are improving the overall survival rates in patients with cancer. However, patients who are non-ambulatory due to metastatic epidural spinal cord compression (MESCC) may be assessed as unable to tolerate chemotherapy secondary to poor performance status. This means that the ambulatory status of patients with cancer might be significant for survival time. METHODS: We investigated the functional outcomes and factors influencing overall survival in 31 patients who were non-ambulatory due to MESCC and underwent decompression surgery. The functional outcome was determined by the Frankel grading system. RESULT: Twenty-one patients (68%) improved by at least 1 Frankel grade; 17 patients (55%) became ambulatory postoperatively. Most of postoperatively ambulatory patients could undergo postoperative chemotherapy (14/17, 82%). On the other hand, only a few postoperatively non-ambulatory patients could undergo postoperative chemotherapy (2/15, 13%). We observed a complication rate of 35.5% with specific complications including wound infection, pneumonia, and deep vein thrombosis/pulmonary embolus. The median survival duration was 7.0 months. Factors that significantly affected the overall survival in univariate analyses were revised Tokuhashi score (RTS) ≥ 4, postoperative chemotherapy, ambulatory status, and complications (RTS ≥ 4, P < 0.05; postoperative chemotherapy, P < 0.001; ambulatory status, P < 0.001; complications, P < 0.01). CONCLUSIONS: Decompression surgery for patients who are non-ambulatory due to MESCC directly contributes to functional outcomes and may indirectly contribute to overall survival. If non-ambulatory patients who are assessed as unable to tolerate chemotherapy due to poor performance status regain the ability to walk by decompression surgery, they will have a chance to receive postoperative chemotherapy, thereby increasing their chances of prolonging survival. However, postoperative complications may shorten their survival; therefore, we should carefully consider the surgical indications. RTS is useful for judging the surgical indication.

Carbon ion radiotherapy for unresectable localized axial soft tissue sarcoma.

Carbon ion radiotherapy is known for its high-precision dose distribution and high biological effectiveness. We evaluated the results of carbon ion radiotherapy in 128 patients with unresectable localized axial soft tissue sarcoma at a single institution. The patients' median age was 54 years, and the median follow-up period was 49.4 (range 6.4-146.4) months. The median tumor volume was 356 cm3 . The 5-year local control, overall survival, and disease-free survival rates were 65%, 46%, and 39%, respectively. In the univariate analysis, tumor volume, local control, and incidences of metastases were significantly related to overall survival. In the multivariate analysis, tumor volume and local control were significantly related to overall survival. We did not find any factors related to local control. Five patients required surgical intervention because of adverse events in the bones. Carbon ion radiotherapy may be a treatment option for unresectable axial soft tissue sarcoma.

Carbon ion radiotherapy for inoperable pediatric osteosarcoma.

BACKGROUND: Unresectable pediatric osteosarcoma has poor outcomes with conventional treatments. RESULTS: Twenty-six patients aged 11-20 years (median 16) had inoperable osteosarcoma of the trunk (24 pelvic, 1 mediastinal and 1 paravertebral) without any other lesion at initial examination. There were 22 primary, 1 locally recurrent and 3 metastatic cases. Median CIRT dose was 70.4 Gy RBE (relative biological effectiveness) delivered in 16 fractions. Median follow-up was 32.7 months. Overall survival was 50.0% and 41.7% at 3 and 5 years, respectively. Ten patients survived for more than 5 years (range 5-20.7 years). Local control was 69.9% and 62.9% at 3 and 5 years, respectively and progression-free survival was 34.6% at 3 and 5 years. Only largest tumor diameter correlated with 5-year overall survival and local control. There were 4 grade 3-4 CIRT-related late toxicities, 1 case of bone fracture and no treatment-related mortalities. All patients (except 1) were able to ambulate after CIRT. CONCLUSIONS: CIRT was safe and efficacious in the treatment of inoperable pediatric osteosarcoma with improved local control and overall survival compared to conventional treatments. METHODS: We retrospectively reviewed the records of pediatric and adolescent patients who received carbon ion radiotherapy (CIRT) for inoperable osteosarcoma between 1996 and 2014.

Clinical outcomes of patients with epithelioid sarcomas: impact and management of nodal metastasis.

PURPOSE: An epithelioid sarcoma is a rare histological subtype of a soft tissue sarcoma with a high local recurrence rate, which frequently shows lymph node metastasis. However, because of the rarity of this tumor, the impact of nodal metastasis and its appropriate management remain unclear. The present study investigated the clinical outcomes of patients with epithelioid sarcomas, with a focus on lymph node metastasis. METHODS: We retrospectively evaluated the clinical outcomes of 27 patients with epithelioid sarcomas treated between 1985 and 2015. The log-rank test was used to assess the prognostic variables. RESULTS: The overall local recurrence rate was 33%, and the estimated overall 5-year survival rate was 62%. Hand and foot locations were associated with favorable overall survival. During the follow-up period, new nodal metastasis was noted in 14 patients (52%). The incidence of local recurrence was higher in patients with new nodal metastasis than in patients who did not develop nodal metastasis. The development of new nodal metastasis had a tendency to worsen survival; however, this association was not statistically significant. Lymphadenectomy did not affect overall survival. CONCLUSIONS: Peripheral tumor location is associated with a better prognosis. The development of new nodal metastasis tends to be associated with poor prognosis; however, among patients with nodal metastasis, resection of the metastatic lesions has a low impact on survival.