Comparison of clinical outcome between surgical treatment and particle beam therapy for pelvic bone sarcomas: A retrospective multicenter study in Japan.

BACKGROUND: Few studies have compared the clinical outcomes of patients with pelvic bone sarcomas treated surgically and those treated with particle beam therapy. This is a multicenter retrospective cohort study which compared the clinical outcomes of patients with pelvic bone sarcoma who underwent surgical treatment and particle beam therapy in Japan. METHODS: A total of 116 patients with pelvic bone sarcoma treated at 19 specialized sarcoma centers in Japan were included in this study. Fifty-seven patients underwent surgery (surgery group), and 59 patients underwent particle beam therapy (particle beam group; carbon-ion radiotherapy: 55 patients, proton: four patients). RESULTS: The median age at primary tumor diagnosis was 52 years in the surgery group and 66 years in the particle beam group (P < 0.001), and the median tumor size was 9 cm in the surgery group and 8 cm in the particle beam group (P = 0.091). Overall survival (OS), local control (LC), and metastasis-free survival (MFS) rates were evaluated using the Kaplan-Meier method and compared among 116 patients with bone sarcoma (surgery group, 57 patients; particle beam group, 59 patients). After propensity score matching, the 3-year OS, LC, and MFS rates were 82.9% (95% confidence interval [CI], 60.5-93.2%), 66.0% (95% CI, 43.3-81.3%), and 78.4% (95% CI, 55.5-90.5%), respectively, in the surgery group and 64.9% (95% CI, 41.7-80.8%), 86.4% (95% CI, 63.3-95.4%), and 62.6% (95% CI, 38.5-79.4%), respectively, in the particle beam group. In chordoma patients, only surgery was significantly correlated with worse LC in the univariate analysis. CONCLUSIONS: The groups had no significant differences in the OS, LC, and MFS rates. Among the patients with chordomas, the 3-year LC rate in the particle beam group was significantly higher than in the surgery group.

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.

Hip Transposition Can Provide Early Walking Function After Periacetabular Tumor Resection: A Multicenter Study.

BACKGROUND: Reconstruction after periacetabular bone tumor resection involves important tradeoffs; large bone grafts or endoprostheses are reported to offer fair walking function in general but can be technically demanding and carry a high risk of severe complications. Conversely, hip transposition avoids implant-related risks, but stability and functional return may be less consistent. Fewer studies are available on hip transposition, which is also appealing in more resource-constrained environments, and little is known about the time course from surgery to functional return after hip transposition. QUESTIONS/PURPOSES: (1) What is the time course of recovery of walking function after hip transposition, especially in the first 6 months? (2) What factors are associated with a greater likelihood of early functional recovery? (3) Is early (2-month) functional recovery associated with a greater likelihood of walking ability and higher Musculoskeletal Tumor Society (MSTS) scores? METHODS: Between 2009 and 2019, six tertiary care centers in Japan treated 48 patients with internal hemipelvectomy for malignant tumors. During that time, the preferred reconstructive approach was hip transposition, and 92% (44 of 48) of our patients were treated with this procedure. Among them, 86% (38 of 44) had follow-up of at least 6 months, had no local recurrence during that time, and were included in our retrospective study. We chose 6 months as the minimum follow-up duration because the endpoints in this study pertained to early recovery rather than reconstructive durability. Hip transposition involved moving the proximal end of the femur (femoral head, resection end of the trochanteric area, and spacers such as prostheses) upward to the underside of the resected ilium or the lateral side of the sacrum if sacroiliac joint resection was performed. The end of the proximal femur was stabilized to the remaining ilium or sacrum using polyethylene tape, polyethylene terephthalate mesh, an iliotibial tract graft, or an external fixator, according to the surgeon's preference. The median age at surgery was 46 years (range 9 to 76 years), there were 23 women and 15 men, and the median follow-up duration was 17 months (range 6 to 110 months). The postoperative time course of functional recovery was assessed with a record review, the timing of functional milestones was identified (wheelchair, walker, bilateral crutches, single crutch or cane, and walking without an aid), and the MSTS score at the final follow-up was assessed. Additionally, demographic and surgical factors were reviewed, and their association with short-term functional recovery and the final functional outcome was analyzed. RESULTS: Patients started using a walker at median postoperative day (POD) 20 (IQR 14 to 36) and with bilateral crutches at median POD 35 (IQR 20 to 57). At POD 60, which was the approximate median date of discharge, 76% (29 of 38) of patients were able to walk using bilateral crutches (the early recovery group) and 24% (nine of 38) of patients were not able to do so (the delayed recovery group). No baseline factors were different between the two groups. The early recovery group had a higher median MSTS score than the delayed recovery group: 57% (range 17% to 90%) versus 45% (13% to 57%) (p = 0.047). Moreover, more patients acquired better function (a single crutch or cane or more) in the early recovery group, with a median of 5 months (95% CI 4 to 11) than did those in the delayed recovery group (median not reached) (p = 0.0006). The HR was 15.2 (95% CI 2.5 to 93). Forty-two percent (16 of 38) underwent additional surgery for wound management. CONCLUSION: It took patients a fair amount of time to recover walking function after hip transposition, and patients who could not walk on bilateral crutches at POD 60 seemed less likely to regain walking function and were likely to have lower MSTS scores thereafter. Wound-related complications were frequent. This method may be a realistic alternative for younger patients who have the strength for a long rehabilitation period or those who want to minimize prosthesis-related complications. Future studies with more patients are necessary to understand the risk factors associated with delayed recovery.Level of Evidence Level III, therapeutic study.

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.

Clinical features and treatment outcomes of dedifferentiated and grade 3 chondrosarcoma: A multi-institutional study.

Chondrosarcoma is the second most common primary malignant bone tumor. In this multicenter study, we sought to evaluate the disease-specific survival (DSS) and disease-free survival (DFS), and prognostic factors in patients with dedifferentiated chondrosarcoma (DDCS) or grade 3 chondrosarcoma (G3CS) in Japan. We retrospectively investigated the treatment outcomes and prognostic factors in 62 patients with DDCS and 19 patients with G3CS at 15 institutions participating in the Japanese Musculoskeletal Oncology Group. We also clarified significant clinicopathological factors for oncological outcomes. In surgery for primary lesions aimed at cure, a histologically negative margin (R0) was obtained in 93% (14/15) of patients with G3CS and 100% (49/49) of patients with DDCS. The 5-year DSS was 18.5% in patients with DDCS and 41.7% in patients with G3CS (p = 0.13). Local control was obtained in 80% (12/15) and 79.6% (39/49) of patients with G3CS and DDCS in the primary lesion after surgery with a wide surgical margin, respectively. In multivariate analysis, stage and no treatment/palliative treatment for the primary lesion were independent prognostic factors for DSS of DDCS, and age and no treatment/palliative treatment for DSS of G3CS. The 5-year DFS rate was 22.8% in 26 patients with DDCS who did not receive adjuvant chemotherapy, and 21.4% in 14 patients who received adjuvant chemotherapy. The prognosis of DDCS remains poor, although R0 resection was carried out in most cases. Effective and/or intensive chemotherapeutic regimens or agents should be considered or developed for patients with high-grade chondrosarcoma, particularly for those with DDCS.

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.

Short-term clinical outcomes of Kyocera Modular Limb Salvage System designed cementless stems for the endoprosthetic reconstruction of lower extremities: a Japanese Musculoskeletal Oncology Group multi-institutional study.

BACKGROUND: The high rate of aseptic loosening of cemented stems has led to their frequent use in endoprosthetic reconstruction. However, problems, such as stem breakage and stress shielding at the insertion site, remain. The Japanese Musculoskeletal Oncology Group (JMOG) has developed Kyocera Modular Limb Salvage System (KMLS) cementless stems with a unique tapered press-fit and short fixation design. This study aimed to clarify the short-term postoperative outcomes of this prosthesis and validate the stem design. METHODS: One hundred cases of KMLS cementless stems (51 male patients; median age, 49 years; mean follow-up period, 35 months), with a minimum follow-up of 2 years, for the proximal femur (PF), distal femur (DF), and proximal tibia were prospectively registered for use. Prosthesis survival, complication rates, postoperative functional, and radiographical evaluation were analyzed. Complications or failures after insertion of the KMLS endoprostheses were classified into five types and functional results were analyzed according to the MSTS scoring system at postoperative 1 year. The diaphyseal interface and anchorage were graded by the ISOLS system at postoperative 2 years. RESULTS: The overall prosthesis survival rates at 2 and 4 years were 88.2 and 79.6%, respectively. The prosthesis-specific survival rate excluding infection and tumor recurrence was 90.2 and 87.9%, respectively. Younger age (p = 0.045) and primary tumor (p = 0.057) were associated with poor prognosis of prosthesis-specific survival excluding infection and tumor recurrence. Complications were observed in 31 patients, 13 patients underwent revision surgery. The mean MSTS functional score at 1 year postoperatively was 68%. Early implant loosening was significantly more common in the DF (p = 0.006) and PF/DF straight stem (p = 0.038). The ISOLS radiographic evaluation at 2 years after surgery revealed good bone remodeling and anchorage in most cases (bone remodeling: 90% / excellent and good, anchorage: 97% / excellent and good). CONCLUSIONS: Tumor endoprosthesis long-term fixation to the diaphysis of the lower extremity remains challenging. The KMLS cementless stem with a unique tapered press fit design showed good short-term results in maintaining bone stock. To prevent early loosening, a curved stem should be used in PF and DF, but long-term follow-up is necessary.

Marginal resection for patients with atypical lipomatous tumours of the extremities and trunk wall: a systematic review and meta-analysis.

BACKGROUND: This systematic review assessed and compared the efficacy of marginal resection to wide resection in patients with atypical lipomatous tumours (ALT) by evaluating the local recurrence rates, overall survival and adverse event rates. METHODS: We evaluated studies published between 1 January 1990 and 31 January 2019. The risks of bias in the selected studies were analyzed using the Cochrane Collaboration Risk of Bias Tool. The quality of the evidence was evaluated using the Grading of Recommendations, Assessment, Development and Evaluation approach. RESULTS: Three case-control studies and three case series studies were identified. A meta-analysis was performed of six studies to evaluate the local recurrence rate after resection. Comparison of marginal and wide resections showed that the local recurrence rate was not significantly higher in the marginal resection group (14.2 and 1.4%, odds ratio: 2.88, 95% confidence interval 0.99-8.33, P = 0.05). We observed no difference in overall survival. In one study, the rates of adverse events were 14.7% in the marginal resection group and 45.4% in the wide treatment group (odds ratio, 0.32; 95% confidence interval 0.11-80.91, P < 0.05). CONCLUSIONS: In our analyses, five of six studies reported no recurrence for wide resection, compared to three to seven recurrences in the marginal resection group. One study reported only one case of recurrence for wide resection. Because ALT has a relatively good prognosis, the use of marginal resection is acceptable to preserve musculoskeletal function.

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

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

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.

Aggressive and frequent resection of recurrences in retroperitoneal sarcoma contributes to long-term survival.

PURPOSE: Retroperitoneal sarcoma (RPS) is a rare tumor with a poor prognosis and is often undetected until it is significantly enlarged. While surgical resection remains the primary treatment, there is little research on its benefits, especially that concerning the reoperation of recurrent disease. This study investigated the impact of surgical procedures, especially reoperation of recurrent RPS, on prognosis. METHODS: This retrospective study included 51 patients who underwent radical resection surgery (R0 status) for primary or recurrent RPS without distant metastasis. Patient outcomes and prognosis were defined in terms of the clinicopathologic factors and surgical techniques performed. RESULTS: In all cases, the 5-year disease-free survival (DFS) rate was 28.2%, 5-year overall survival rate was 89.9%, and 5-year no residual liposarcoma rate was 54.3% after operation and re-reoperation. There was a statistically significant difference between the 5-year DFS rate and 5-year no residual liposarcoma rate due to frequent re-reoperation (p = 0.011). On univariate analysis of primary and recurrent lesions, the histological type and the number of organs involved were identified as statistically significant prognostic factors. Patients with well-differentiated liposarcomas had a statistically better prognosis than those with other cancer types (primary RPS, p = 0.028; recurrence, p = 0.024). CONCLUSIONS: Aggressive and frequent resection of recurrent RPS with combined resection of adjacent organs contributes to long-term survival. The establishment of a surgical strategy for RPS will require a prospective study.

Functional evaluation following deltoid muscle resection in patients with soft tissue sarcoma.

BACKGROUND: The present study aimed to determine functional outcomes in patients undergoing deltoid muscle resection for soft tissue sarcoma. METHODS: Between 2002 and 2014, 18 patients with soft tissue sarcoma of the shoulder who underwent wide resection including the deltoid muscle, and were followed up for more than 12 months, were retrospectively included in the study. In all, 11 patients were male and 7 were female. The median age was 59 years, median follow-up duration was 37 months. The extent of resection of deltoid muscle, with or without rotator cuff damage, reconstruction methods, adjuvant therapy, oncological outcomes, and the International Society of Limb Salvage (ISOLS) score as functional outcomes were analyzed. RESULTS: Six patients underwent total resection, and twelve underwent partial resections of deltoid muscle. The rotator cuff was resected in four patients. Soft tissue reconstruction was performed in 17 patients using a pedicled latissimus dorsi muscle flap. Two local recurrences and three distant metastases occurred during follow-up. Median overall survival was 72 months. The mean ISOLS score was 25.0 points (±4.6points). Univariate analysis revealed that there was no significant difference in ISOLS score regarding the extent of deltoid muscle resection. Multivariate analysis identified only combined resection of the rotator cuff as a significant prognostic factor for poor functional outcomes (P < 0.001). CONCLUSIONS: The extent of resection of the deltoid muscle might not affect the functional outcomes determined by ISOLS score. If the rotator cuff is resected concurrently, satisfactory functional outcomes might not be obtained.

Minimal clinically important differences in Toronto Extremity Salvage Score for patients with lower extremity sarcoma.

BACKGROUND: The Toronto Extremity Salvage Score (TESS) is the most widely used patient-reported outcome measure for orthopaedic oncology patients. However, minimal clinically important differences (MCIDs) in the TESS have not been analyzed. The aim of this study was to define the MCIDs of TESS in patients with lower extremity sarcoma. METHODS: A total of 85 patients were investigated to calculate the MCIDs for TESS. Three different methods were used: 1) distribution-based methods based on one-half of the standard deviation and standard error of measurement (SEM) at the baseline, 2) anchor-based and receiver operating characteristic (ROC) analysis, and 3) anchor-based using Akaike's Information Criterion (AIC) analysis. RESULTS: The MCIDs at 6 months were 4.9-7.8 by distribution-based methods and 4.3-4.4 by anchor-based methods. The MCIDs at 12 months were 4.0-6.9 by distribution-based methods and 10.6-11.6 by anchor-based methods. CONCLUSIONS: We calculated MCID values for the TESS based on distribution- and anchor-based approaches. Our results seem reasonable since MCIDs calculated by the different approaches had similar values. This knowledge will enable clinicians to identify meaningful functional improvements in sarcoma patients.

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

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

Development of a patient-oriented disease specific outcome measure of health-related quality of life (HRQOL) for musculoskeletal oncology patients.

BACKGROUND: According to improved functional outcome and life expectancy in orthopaedic oncology patients, there has been a growing interest in not only oncologic and functional outcomes but also health-related quality of life (HRQOL), including body image, mental status, or social activities, after surgery. However, there has been a lack of disease-specific measures focusing on the ability of orthopaedic oncology patients to evaluate their HRQOL comprehensively. Therefore, our aims in the present study were 1) to develop a patient-oriented disease-specific outcome measure of HRQOL for musculoskeletal oncology patients (COMMON-LE), and 2) to examine the practical applicability, reliability and validity of the COMMON-LE for patients with musculoskeletal tumors in the lower extremity. METHODS: The COMMON-LE was developed by expert committee of orthopaedic oncology and rehabilitation. A total of 101 patients were surveyed using the COMMON-LE, as well as the TESS, the MSTS score, and the SF-36, to assess their psychometric characteristics, including reliability, validity, and responsiveness. RESULTS: The COMMON-LE showed no marked floor and ceiling effects. Test-retest reliability and internal consistency determined using the intraclass correlation coefficient (0.928) and Cronbach's alpha (0.948-0.968), respectively, were excellent. Each domain of the COMMON-LE (pain, ADL, socioemotional condition and general health) was well correlated with the scores of the standard measures (SF-36, TESS, MSTS score). Factor analysis and the AIC network showed the questionnaire items of the COMMON-LE were clearly separable into three clusters according to their content, corresponding to each domain of the questionnaire. CONCLUSIONS: We have successfully developed and validated a disease-specific measure, the COMMON-LE, to evaluate not only physical function, but also various aspects of HRQOL in patients with musculoskeletal tumors. The COMMON-LE has sufficient reliability and internal consistency, and good validity, and appears to be practically applicable to this group of patients.

Analysis of the Infiltrative Features of Chordoma: The Relationship Between Micro-Skip Metastasis and Postoperative Outcomes.

BACKGROUND: Chordomas are very rare primary malignant bone tumors that arise commonly from the sacrum (50-60%) and clivus (25-35%). Chordomas have a high rate of recurrence. The authors confirmed a unique histologic infiltration pattern of chordomas that resembles a skip-metastatic lesion in normal tissue around tumor, which they named "micro-skip metastasis." This study aimed to examine the correlations between the clinicopathologic features of chordomas, including micro-skip metastasis, and the clinical outcomes, including overall survival, local recurrence-free survival, and distant metastasis-free survival. METHODS: The study analyzed histopathologic and clinical data from patients with sacral chordomas who underwent en bloc resection from July 1991 through July 2014. Cases with a minimum follow-up period shorter than 20 months after resection were excluded. Kaplan-Meier survival analyses with log-rank tests were performed for overall survival, metastasis-free survival, and recurrence-free survival. RESULTS: The study retrospectively reviewed 40 patients. The mean follow-up period was 98.2 months (range 22-297 months). The local recurrence rate was 41.3%. Micro-skip metastases, observed in 17 patients (42.5%), were associated with a significantly increased risk of local recurrence (p = 0.023) but not with overall survival or distant metastasis-free survival. Poorer overall survival was associated with histologic vascular invasion (p = 0.030) and a greater maximum tumor diameter (p = 0.050). CONCLUSIONS: The presence of micro-skip metastasis was associated with a higher rate of local recurrence. The maximum tumor diameter and the presence of histologic vascular invasion were associated with poorer overall survival.

Predictors of complications in heat-treated autograft reconstruction after intercalary resection for malignant musculoskeletal tumors of the extremity.

BACKGROUND: Biological reconstruction with recycled heat-treated autografts has been an option for a segmental skeletal defect after intercalary resection for malignant musculoskeletal tumors in the extremity. This study was undertaken to evaluate the clinical outcomes in patients treated with this procedure and identify factors affecting the incidence of complications. METHODS: We retrospectively reviewed 24 patients treated with heat-treated autografts after intercalary resection at our institution between 1992 and 2015. RESULTS: The survival rate of the heat-treated autografts was 70.1% at 10 years. Of the 48 host-graft junctions in the 24 patients, nonunion occurred in 18 junctions (38%). In the univariate analysis, location in the upper extremity, intercalary grafts without vascularized fibula autografts (VFG), and junction at the diaphysis significantly increased the rate of nonunion (P = 0.003, P = 0.003, and P = 0.031, respectively). Location in the upper extremity was an independent factor associated with nonunion in the multivariate analysis (P = 0.006). Upper extremity location and intercalary grafts without VFG were also significant factors for bone absorption (P = 0.042 and P < 0.001, respectively). CONCLUSIONS: Our results can provide useful information to devise possibly novel clinical approaches to patients requiring intercalary reconstruction of the extremity.

What Is the Success of Repeat Surgical Treatment of a Local Recurrence After Initial Wide Resection of Soft Tissue Sarcomas?

BACKGROUND: Treatment for patients with locally recurrent soft tissue sarcomas after wide resection is challenging, and few studies have examined the results of treating these patients. In treatment of recurrent tumors, it has been reported that positive margins are correlated to local rerecurrence, but the relationship between surgical margin and survival remains controversial and risk factors for local recurrences after wide resection of soft tissue sarcomas are not well established. This study examined clinical outcomes and factors associated with survival and local rerecurrence in patients with local recurrence after initial surgical treatment who underwent another resection with a goal of negative margins. QUESTIONS/PURPOSES: The purpose of this study was to determine (1) oncologic outcomes (survival rates and local rerecurrence-free rates) of surgical treatment for patients with local recurrence after wide resection; (2) whether factors associated with survival and local rerecurrence-free rates can be determined; and (3) the proportion of patients treated by amputation at final followup. METHODS: Between 1992 and 2013, we treated 530 patients with soft tissue sarcoma without metastasis. Of those, 26 (5%) were lost before 3 years of followup but were not known to have died. Of the remainder, 59 have had a local recurrence. Of those with a local recurrence, 34 (58%) were treated with wide resection, whereas 25 (42%) were treated with nonsurgical treatment including chemotherapy and radiotherapy. During that period, our general indications for wide resection were patients (1) without distant metastasis; or (2) without distant lymph node metastasis, and contraindications were distant organ metastasis and/or distant lymph node metastasis. Of those treated with wide resection, 30 (88%) were available for followup. We conducted a retrospective analysis of these 30 patients with local recurrence (17 men, 13 women) who had previously undergone wide resection. Patient followup ranged from 1 to 12 years (median, 5 years). Survivorship (including overall survival and survival free from repeat recurrence) was ascertained by the Kaplan-Meier method. Factors associated with survival were evaluated by the log-rank test. Amputations were performed when limb-sparing surgery was deemed unsuitable because of extensive involvement of the limb by tumor, including invasion of multiple muscle compartments and neurovascular components. Survivorship free from amputation was ascertained by the Kaplan-Meier method. RESULTS: Overall 5- and 10-year Kaplan-Meier survival rates after resection were 70% (95% confidence interval [CI], 50%-91%) and 44% (95% CI, 12%-76%), respectively, and 12 patients (40%) developed distant metastases after the second operation. Ten patients (33%) had additional local recurrences, and overall 5- and 10-year local rerecurrence-free rates were 66% (95% CI, 48%-85%) and 50% (95% CI, 18%-81%), respectively. A positive margin was associated with further recurrence (5-year local rerecurrence-free rates of positive margin: 20% [95% CI, 0%-52%], negative margin: 89% [95% CI, 74%-100%], p < 0.01) and with survival (5-year survival rates of positive margin: 36% [95% CI, 0%-75%], negative margin: 91% [95% CI, 74%-100%], p < 0.01). The survival rate was lower in patients with recurrence developing after 2 years (5-year survival rates of within 2 years: 46% [95% CI, 2%-90%], after 2 years: 83% [95% CI, 62%-100%], p = 0.01). The overall 5- and 10-year amputation-free rates were 86% (95% CI, 74%-99%) and 81% (95% CI, 67%-96%), respectively. CONCLUSIONS: A surgical procedure with negative margins appears to be important for reducing the likelihood of local recurrences and improving survival of patients with rerecurrence after wide resection of soft tissue sarcomas. Although these findings need to be confirmed in larger studies, it appears that when tumor recurrence is evident within 2 years from the primary surgery, it is associated with a poor prognosis. Local recurrence within 2 years after wide resection may also be an indicator of aggressive tumor biology. LEVEL OF EVIDENCE: Level IV, therapeutic study.

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

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

Expression of colony-stimulating factor 1 is associated with occurrence of osteochondral change in pigmented villonodular synovitis.

Pigmented villonodular synovitis (PVNS) is a benign, translocation-derived neoplasm. Because of its high local recurrence rate after surgery and occurrence of osteochondral destruction, a novel therapeutic target is required. The present study aimed to evaluate the significance of protein expression possibly associated with the pathogenesis during the clinical course of PVNS. In 40 cases of PVNS, positivity of colony-stimulated factor 1 (CSF1), its receptor (CSF1R), and receptor activator of nuclear factor kappa-B ligand (RANKL) were immunohistochemically determined. The relationship between the positivity and clinical outcomes was investigated. High positivity of CSF1 staining intensity was associated with an increased incidence of osteochondral lesions (bone erosion and osteoarthritis) (p = 0.009), but not with the rate of local recurrence. Positivity of CSF1R and RANKL staining was not associated with any clinical variables. The number of giant cells was not correlated with positivity of any of the three proteins, or with the clinical outcome. Focusing on knee cases, CSF1 positivity was also associated with the incidence of osteochondal change (p = 0.02). CSF1R positivity was high in cases which had local recurrence, but not significantly so (p = 0.129). Determination of CSF1 and CSF1R expression may be useful as a prognosticator of the clinical course and/or outcomes of PVNS.