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.

A multicentre retrospective study on extra-thoracic solitary fibrous tumour: preoperative MRI findings predict intraoperative findings and postoperative prognosis.

OBJECTIVE: The present study investigated the relationships between the preoperative and operative findings of solitary fibrous tumour (SFT) and between preoperative findings and prognosis. METHODS: We reviewed 50 SFT patients treated at our musculoskeletal oncology hospital group. We analyzed preoperative clinical findings, particularly MRI imaging findings, and intraoperative information as well as the relationship between preoperative findings and outcomes. RESULTS: Mean age was 48.9 years and the mean follow-up was 51.8 months. Prior to surgery, needle biopsy was performed on 27 patients and open biopsy on 14. T2-weighted images showed a high signal intensity in 24 patients and heterogeneous signal intensity in 20. Tumours had polylobular contours in 17 patients and smooth and round contours in 27. Collateral feeding vessels were detected in 22 patients. Gd-enhanced MRI was performed on 23 patients, and showed 15 with homogeneous enhancement and 8 with heterogeneous enhancement. Surgical times were significantly longer in patients with a retroperitoneal origin, a tumour of 10 cm or more, and polylobular-type tumours. Intraoperative blood loss was significantly greater in patients with a retroperitoneal origin and heterogeneous Gd-MRI-enhanced tumours. In histopathological evaluations, surgical margins were positive in 12 patients. Local recurrence was observed in one patient. Distant metastasis was noted in eight patients, four of whom had pulmonary metastases. Positive surgical margins were more common in polylobular-type tumours. Distant metastases were more likely to appear in patients with observable collateral feeding vessels and heterogeneous Gd-MRI enhancement. CONCLUSION: The present results suggest that preoperative clinical findings in SFT patients predict longer surgical times and the risk of increased intraoperative blood loss. Moreover, the risk of a positive surgical margin and postoperative distant metastases may be predicted based on preoperative MRI.

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.

Preoperative Denosumab Therapy Against Giant Cell Tumor of Bone is Associated with an Increased Risk of Local Recurrence After Curettage Surgery.

INTRODUCTION: Denosumab has been shown to be highly effective at suppressing the progression of giant cell tumor of bone (GCTB). However, recent studies have observed a potential increased risk of local recurrence after surgery following the use of denosumab, raising concerns on the use of this agent against GCTB in combination with surgery. METHODS: We retrospectively reviewed the medical records of 234 patients with GCTB who were surgically treated at multiple institutions from 1990 to 2017. Patient background, tumor characteristics, treatment methods, local recurrence-free survival rate, distant metastasis rate, oncologic outcome, and limb function at final follow-up were analyzed and compared between cases treated with and without denosumab. RESULTS: The 3-year local recurrence-free survival rate was significantly lower in patients who underwent preoperative denosumab therapy (35.3%) compared with those treated without denosumab (79.9%) (P < 0.001). Among patients who were preoperatively treated with denosumab, those who had a local recurrence all underwent curettage surgery. CONCLUSIONS: Preoperative denosumab therapy in combination with curettage surgery was significantly associated with an increased risk of local recurrence in Campanacci grade 3 tumors. Our data suggest that clinicians seeing GCTB patients should be aware to this increased risk when planning preoperative denosumab therapy.

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

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

Indications for fertility preservation not included in the 2017 Japan Society of Clinical Oncology Guideline for Fertility Preservation in Pediatric, Adolescent, and Young Adult Patients treated with gonadal toxicity, including benign diseases.

In recent years, local governments in Japan have established a public financial support system for fertility preservation in pediatric, adolescent, and young adult cancer patients. Fertility preservation has become popular for patients with cancers included in the gonadal toxicity risk classification of the 2017 edition of the Guideline for Fertility Preservation in Children, Adolescents and Young Adult Cancer Patients from the Japan Society of Clinical Oncology. However, patients with cancer and non-cancer diseases that are not included in the Guideline's gonadal toxicity risk classification also often receive treatment that may affect fertility, but they are often denied the opportunity of fertility preservation because no public financial support is available for diseases not listed in the Guideline. The national research project proposes including these diseases in the indications and treatment for fertility preservation. Therefore, we cooperated with the Japan Society for Fertility Preservation and the Ministry of Health, Labour and Welfare research group to solicit opinions from experts in each therapeutic area and reviewed the literature and overseas guidelines. This paper summarizes the findings of the project. We believe that it will be an important source of information for clinicians treating patients who need fertility preservation but note that the appropriateness of fertility preservation for the disorders listed in this report needs to be continuously reviewed as medical care advances.

Japan Society of Clinical Oncology Clinical Practice Guidelines 2017 for fertility preservation in childhood, adolescent, and young adult cancer patients: part 2.

The Japan Society of Clinical Oncology (JSCO) published the "JSCO Clinical Practice Guidelines 2017 for Fertility Preservation in Childhood, Adolescent, and Young Adult Cancer Patients" in 2017. This was the first guideline in cancer reproductive medicine in Japan. In the field of cancer reproductive medicine, close cooperation between an oncologist and a physician for reproductive medicine is important from before treatment initiation until long after treatment. The guideline takes into consideration disease specificity and provides opinions from the perspective of oncologists and specialists in reproductive medicine that are in line with the current state of the Japanese medical system. It is intended to serve as a reference for medical staff in both fields regarding the availability of fertility preservation therapy before the start of cancer treatment. Appropriate use of this guideline makes it easier to determine whether fertility preservation therapy is feasible and, ultimately, to improve survivorship in childhood, adolescent, and young adult cancer patients. In this article (Part 2), we describe details by organ/system and also for pediatric cancer.

Japan Society of Clinical Oncology Clinical Practice Guidelines 2017 for fertility preservation in childhood, adolescent, and young adult cancer patients: part 1.

In 2017, the Japan Society of Clinical Oncology (JSCO) published the JSCO Clinical Practice Guidelines 2017 for Fertility Preservation in Childhood, Adolescent, and Young Adult Cancer Patients. These were the first Japanese guidelines to address issues of oncofertility. In this field of medicine, sustained close cooperation between oncologists and reproductive specialists is essential from the diagnosis of cancer until many years after completion of cancer treatment. These JSCO guidelines were intended to guide multidisciplinary medical staff in considering the availability of fertility preservation options and to help them decide whether to provide fertility preservation to childhood, adolescent, and young adult cancer patients before treatment starts, with the ultimate goal of improving patient survivorship. The guidelines are presented as Parts 1 and 2. This article (Part 1) summarizes the goals of the guidelines and the methods used to develop them and provides an overview of fertility preservation across all oncology areas. It includes general remarks on the basic concepts surrounding fertility preservation and explanations of the impacts of cancer treatment on gonadal function by sex and treatment modality and of the options for protecting/preserving gonadal function and makes recommendations based on 4 clinical questions. Part 2 of these guidelines provides specific recommendations on fertility preservation in 8 types of cancer (gynecologic, breast, urologic, pediatric, hematologic, bone and soft tissue, brain, and digestive).

Recurrent malignant peripheral nerve sheath tumor presenting as an asymptomatic intravenous thrombus extending to the heart: a case report.

BACKGROUND: Malignant peripheral nerve sheath tumor (MPNST) is a rare soft tissue sarcoma mainly treated via surgical resection. Herein, we report a case of MPNST wherein a massive tumor thrombus extended to the major veins and heart. CASE PRESENTATION: A 39-year-old female with a history of neurofibromatosis type 1 developed MPNST from the right radial nerve. In addition to adjuvant chemotherapy, she underwent wide tumor resection and concomitant radial nerve resection, followed by postoperative radiotherapy. Histological evaluation revealed marked venous invasion. The 2-year follow-up CT revealed an asymptomatic recurrent tumor thrombus extending from the right subclavian vein to the heart. An urgent life-saving operation was performed to ligate the base of the right subclavian vein and remove the entire intravenous thrombus that extended to the right ventricle. The remaining tumor in the right subclavian vein increased in size 3 months after thrombectomy. After confirming the absence of any metastatic lesions, the patient underwent extended forequarter amputation to achieve surgical remission. One year later, a new metastasis to the right diaphragm was safely resected. The patient remains alive without any evidence of disease 2 years after the extended forequarter amputation. CONCLUSIONS: In cases of a previous history of microscopic venous invasion, recurrence can occur as a massive tumor thrombus that extends to the great vessels.

Complications of surgery for giant cell tumor of bone in the extremities: Incidence, risk factors, management modality, and impact on functional and oncological outcomes.

BACKGROUND: Due to the wide variations in location, size, local invasiveness, and treatment options, the complications associated with surgery for giant cell tumor of bone have been sporadically reported. For quality assessment, fundamental data based on large-scale surveys of complications under a universal evaluation system is needed. The Dindo-Clavien classification is an evaluation system for complications based on severity and required intervention type and is suitable for the evaluation of surgery in a heterogeneous cohort. METHODS: A multi-institutional retrospective survey of 141 patients who underwent surgery for giant cell tumor of bone in the extremity was performed. The incidence and risk factors of complications, type of intervention for complication control, and impact of complications on functional and oncological outcomes were analyzed using the Dindo-Clavien classification. RESULTS: Forty-six cases (32.6%) had one or more complications. Of them, 18 (12.8%), 11 (7.8%), and 17 (12.1%) cases were classified as Dindo-Clavien classification grade I, II, and III complications, respectively. There were no cases with grade IV or V complications. Progression in Campanacci grading (p = 0.04), resection (over curettage, p < 0.0001), reconstruction with prosthesis (p = 0.0007), and prolonged operative duration (p = 0.0002) were significant risk factors for complications. Complications had a significant impact on function (p < 0.0001). Differences in the impact of complication types and tumor location on function were confirmed. Complications had no impact on local recurrence and metastasis development. CONCLUSION: The Dindo-Clavien classification could provide fundamental information, under a uniform definition and classification system, on postoperative complications in patients with giant cell tumor of bone in terms of incidence, type of intervention for complication control, risk factors, and impact on functional outcome. The data are useful not only for preoperative evaluation for the risk of complications under specific conditions but also for quality assessment of surgery for giant cell tumor of bone.

Phase II clinical trial of pazopanib for patients with unresectable or metastatic malignant peripheral nerve sheath tumors.

Malignant peripheral nerve sheath tumor (MPNST) often does not respond well to chemotherapy and develops against a background of NF1. The purpose of our study was to examine the efficacy of pazopanib against MPNST. Our study was designed as a physician-initiated phase II clinical trial in patients with advanced MPNST. Patients were registered from 11 large hospitals. The primary endpoint was set to clarify the clinical benefit rate (CBR) at 12 weeks according to response evaluation criteria in solid tumors (RECIST). Progression-free survival (PFS), overall survival (OS) and the CBR based on modified Choi evaluation at week 12 were set as secondary endpoints along with treatment-related safety. The study enrolled 12 patients. Median age was 49 years. Seven had Grade 2 and five Grade 3 according to the FNCLCC evaluation. Median follow-up period was 10.6 months. CBR at 12 weeks was both 50.0% (RECIST and Choi). The median PFS was 5.4 months for both RECIST and Choi, and the median OS was 10.6 months. Of special interest, the median PFS was 2.9 months for patients with FNCLCC Grade 2 and 10.2 months for Grade 3 (both RECIST and Choi). Grade 4 adverse events of neutropenia and lipase elevation were noted in one patient each. The results of this pazopanib therapy were generally better than those of any of the other single molecular targeted therapies reported previously. Although accumulation of more cases remains necessary, we conclude pazopanib treatment for MPNST to be a safe and promising treatment after doxorubicin-based chemotherapy.

Differences of tensile strength in knot tying technique between orthopaedic surgical instructors and trainees.

BACKGROUND: Knot tying technique is an extremely important basic skill for all surgeons. Clinically, knot slippage or suture breakage will lead to wound complications. Although some previous studies described the knot-tying technique of medical students or trainees, little information had been reported on the knot-tying technique of instructors. The objective of the preset study was to assess surgeons' manual knot tying techniques and to investigate the differences of tensile strength in knot tying technique between surgical instructors and trainees. METHODS: A total of 48 orthopaedic surgeons (postgraduate year: PGY 2-18) participated. Surgeons were requested to tie surgical knots manually using same suture material. They were divided into two groups based on each career; instructors and trainees. Although four open conventional knots with four throws were chosen and done with self-selected methods, knot tying practice to have the appropriate square knots was done as education only for trainees before the actual trial. The knots were placed over a 30 cm long custom made smooth polished surface with two cylindrical rods. All knots were tested for tensile strength using a tensiometer. The surgical loops were loaded until the knot slipped or the suture broke. The tensile strength of each individual knot was defined as the force (N) required to result in knot failure. Simultaneously, knot failure was evaluated based on knot slippage or suture rupture. In terms of tensile strength or knot failure, statistical comparison was performed between groups using two-tailed Mann-Whitney U test or Fisher exact probability test, respectively. RESULTS: Twenty-four instructors (PGY6-PGY18) and 24 trainees (PGY2-PGY5) were enrolled. Tensile strength was significantly greater in trainees (83.0 ± 27.7 N) than in instructors (49.9 ± 34.4 N, P = 0.0246). The ratio of slippage was significantly larger in instructors than in trainees (P < 0.001). Knot slippage (31.8 ± 17.7 N) was significantly worse than suture rupture (89.9 ± 22.2 N, P < 0.001) in tensile strength. CONCLUSIONS: Mean tensile strength of knots done by trainees after practice was judged to be greater than that done by instructors in the present study. Clinically, knot slippage can lead to wound dehiscence, compared to suture rupture.

Phase II trial of pazopanib in patients with metastatic or unresectable chemoresistant sarcomas: A Japanese Musculoskeletal Oncology Group study.

Alveolar soft part sarcoma (ASPS), epithelioid sarcoma (ES), and clear cell sarcoma (CCS) are known to be chemoresistant tumors. The aim of this study was to investigate the effect of pazopanib on these chemoresistant tumors. This study is designed as a single-arm, multicenter, investigator-initiated phase II trial. Patient enrollment was undertaken between July 2016 and August 2018 at 10 hospitals participating in the Japanese Musculoskeletal Oncology Group. The primary end-point is the CBR (CBR, including complete or partial response and stable disease) at 12 weeks after treatment with pazopanib according to RECIST. Eight patients were enrolled within the period. The histological subtypes were 5 ASPS, 2 ES, and 1 CCS. The median follow-up period was 22.2 (range, 4.9-24.9) months. All patients initially received pazopanib 800 mg once daily. The CBRs were 87.5% (7 of 8) and 75.0% (6 of 8) according to RECIST and Choi criteria at 12 weeks after pazopanib treatment, respectively. The CBRs at 12 weeks according to RECIST were 80.0%, 100.0%, and 100.0% in ASPS, ES, and CCS, respectively. Partial response was observed in 1 ASPS according to RECIST and 3 ASPS and 1 ES according to Choi criteria at 12 weeks after pazopanib treatment. This study documented antitumor activity of pazopanib, especially in ASPS. These results support the frontline use of pazopanib for ASPS. Prospective data collection is desired using both RECIST and Choi criteria for these rare chemoresistant tumors.

Prognostic factors of metastatic myxoid liposarcoma.

BACKGROUND: Myxoid liposarcoma (MLS) has the tendency to metastasize extrapulmonary. Although prognostic factors at the initial diagnosis of MLS have been reported, those at diagnosis of metastasis remain unclear. The purpose of this study was to investigate the prognostic factors for disease-specific survival at the initial diagnosis of metastasis. METHODS: This retrospective observational study was conducted at three cancer centers and two university hospitals in Japan. Of 274 MLS patients pathologically diagnosed between 2001 and 2015, 48 metastatic patients were examined. RESULTS: Lung metastases were detected in nine patients (18.8%) and extrapulmonary metastases in 45 (93.8%). Interval from primary diagnosis to the first metastasis was significantly shorter in patients with lung metastases than without (p = 0.007). Median disease-specific survival after diagnosis of metastases was 52.5 months in all patients. In multivariable analysis, liver metastasis (hazard ratio (HR), 2.71 [95% confidence interval (CI), 1.00-7.09]) and no evidence of disease (NED) achieved by radical treatment (resection with or without radiation therapy, or radiation therapy ≥60 Gy) or semi-radical (radiation therapy ≥40 Gy) treatment were significantly related to survival (HR, 0.36; 95%CI [0.13-0.95]). The number of metastases (odds ratio (OR), 0.44; 95%CI [0.25-0.78]) and abdominal/retroperitoneal metastases (OR, 0.09; 95%CI [0.008-0.95]) were the significant inhibitory factors of achieving NED. CONCLUSIONS: This is the first study to statistically demonstrate the importance of achieving NED with surgical resection or radiation therapy for longer survival in metastatic MLS patients. As number of metastases was a significant factor for achieving NED, early detection of metastases might be important.

What Factors Are Associated with Treatment Outcomes of Japanese Patients with Clear Cell Chondrosarcoma?

BACKGROUND: Clear cell chondrosarcoma is an extremely rare chondrosarcoma subtype; thus, its treatment outcomes and associated factors have not been widely studied. Knowing more about it is potentially important because clear cell chondrosarcomas are often misdiagnosed as other benign lesions and subsequently treated and followed inappropriately. QUESTIONS/PURPOSES: (1) What are the patient- and tumor-related characteristics of clear cell chondrosarcoma? (2) What proportion of patients with clear cell chondrosarcoma initially had a misdiagnosis or a misleading initial biopsy result? (3) What is the survivorship of patients with clear cell chondrosarcoma free from death, local recurrence, and distant metastasis, and what factors are associated with greater survivorship or a reduced risk of local recurrence? METHODS: Between 1985 and 2018, 12 Japanese Musculoskeletal Oncology Group (JMOG) hospitals treated 42 patients with a diagnosis of clear cell chondrosarcoma. All 42 patients had complete medical records at a minimum of 1 year or death, and were included in this multicenter, retrospective, observational study. No patients were lost to follow-up within 5 years of treatment but four were lost to follow-up greater than 5 years after treatment because their physicians thought their follow-up was sufficient. Clinical data were collected by chart review. The median (range) follow-up period was 69 months (2 to 392). In general, when a possibly malignant bone tumor was found on imaging studies, the histological diagnosis was made by biopsy before initiating treatment. Once the diagnosis had been made, the patients were treated by surgery only, complete resection if technically possible, because chondrosarcomas are known to be resistant to chemotherapy and radiotherapy. Unresectable tumors were treated with particle-beam radiation therapy. When patients with chondrosarcoma were referred after unplanned surgical procedures with inadequate surgical margins, immediate additional wide resection was considered before local recurrence developed. This diagnostic and treatment strategy is common to all JMOG hospitals and did not change during the study period. Primary wide resection was performed in 79% (33 of 42) patients, additional wide resection after initial inadequate surgery in 12% (five of 42), curettage and bone grafting in 5% (two of 42) patients, and radiotherapy was administered to 5% (two of 42). Surgical margins among the 40 patients who underwent surgery at JMOG hospitals were no residual tumor in 93% (37 of 42) of patients, microscopic residual tumor in 2% (one of 42), and macroscopic residual tumor or state after curettage or intralesional excision in 5% (two of 42). The oncological endpoints of interest were 5- and 10- year overall survival, disease-free survival, survival free of local recurrence, and survival free of distant metastases; these were calculated using the Kaplan-Meier method and compared using the log-rank test. Risk ratios with their respective 95% confidence intervals (CIs) were estimated in a Cox regression model. The Bonferroni adjustment was used for multiple testing correction. RESULTS: The sex distribution was 74% men and 26% women (31 and 11 of 42, respectively), with a mean age of 47 ± 17 years. Eighty one percent (34 of 42) of tumors occurred at the ends of long bones, and the proximal femur was the most common site accounting for 60% (25 of 42). The mean size of the primary tumors was 6.3 ± 2.7 cm. Definite pathologic fractures were present in 26% (10 of 42) and another 26% (10 of 42) had extraskeletal involvement. None had metastases at presentation. Twenty four percent (six of 25) tumors in the proximal femur were misdiagnosed as benign lesions and treated inadequately without biopsy. Twenty nine percent (10 of 35) patients had initial misdiagnoses by biopsy and core needle biopsies had a greater risk of resulting in inaccurate histological diagnoses. The study patients' 5- and 10-year overall survival rates were 89% (95% CI 74 to 96) and 89% (95% CI 74 to 96), respectively; 5- and 10- year disease-free survival rates 77% (95% CI 58 to 89) and 57% (95% CI 36 to 75), respectively; 5- and 10-year local recurrence-free survival rates 86% (95% CI 68 to 95) and 71% (95% CI 49 to 86), respectively; and 5- and 10-year distant metastasis-free survival rates 84% (95% CI 67 to 93) and 74% (95% CI 53 to 88), respectively. Notably, bone metastases (17%, seven of 42) were as common as pulmonary metastases (14%, six of 42); four patients developed both bone and pulmonary metastases. The difference between 10-year overall survival rates and 10-year disease-free survival indicated very late recurrence more than 5 years after the initial treatment. After controlling for multiple comparisons, the only factor we found that was associated with local recurrence-free survival was initial treatment (positive margin versus primary wide resection) (risk ratio 8.83 [95% CI 1.47 to 53.1]; p = 0.022 after the Bonferroni adjustment). Additional wide resection reduced the risk of local recurrence. CONCLUSIONS: The femoral head was the most common location of clear cell chondrosarcoma and had a high risk of misdiagnosis as common benign lesions that resulted in initial inadequate surgery and a consequent high risk of local recurrence. Immediate additional wide resection should be considered in patients who had initial inadequate surgery to reduce the risk of local recurrence. Because clear cell chondrosarcoma can recur locally or distantly in the bones and lungs in the long term, patients should be informed of the risk of very late recurrence and the necessity of decades-long with surveillance for local recurrence and lung and bone metastases. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Pseudomyogenic hemangioendothelioma of bone treated with denosumab: a case report.

BACKGROUND: Pseudomyogenic hemangioendothelioma (PMHE) is a rare endothelial neoplasm that involves the bones in only 14% of all cases. The optimal treatment strategy has not been established. We herein report a case of primary PMHE in which denosumab treatment showed activity in both imaging studies and the clinical outcome. CASE PRESENTATION: A 20-year-old woman presented with worsening pain in her left ankle. Imaging studies showed multifocal fluorodeoxyglucose (FDG)-avid [maximum standardized uptake value (SUVmax), 15.95] osteolytic lesions in the bones of her left lower extremity. While waiting for the definitive pathologic diagnosis of PMHE, denosumab, a human immunoglobulin G2 monoclonal antibody against RANKL, was initiated to treat progressive bone absorption after curettage of one of the lesions. Denosumab induced osteosclerosis around the lesions and pain relief and was discontinued 4 years after its initiation. Although all of the multifocal lesions remained, they all became less FDG-avid (SUVmax, 2.6), and the patient developed no signs of new lesions or distant metastasis. CONCLUSION: Denosumab plays a certain role in prevention of bone destruction by PMHE through suppression of osteoclast-like giant cells and would be an excellent treatment for bone absorption by PMHE of bone.

Ten-year follow-up results of perioperative chemotherapy with doxorubicin and ifosfamide for high-grade soft-tissue sarcoma of the extremities: Japan Clinical Oncology Group study JCOG0304.

BACKGROUND: Soft-tissue sarcomas (STS) are rare malignant tumors those are resistant to chemotherapy. We have previously reported the 3-year follow-up result on the efficacy of perioperative chemotherapy with doxorubicin (DXR) and ifosfamide (IFM) for high-risk STS of the extremities (JCOG0304). In the present study, we analyzed the 10-year follow-up results of JCOG0304. METHODS: Patients with operable, high-risk STS (T2bN0M0, AJCC 6th edition) of the extremities were treated with 3 courses of preoperative and 2 courses of postoperative chemotherapy, which consisted of 60 mg/m2 of DXR plus 10 g/m2 of IFM over a 3-week interval. The primary study endpoint was progression-free survival (PFS) estimated by Kaplan-Meier methods. Prognostic factors were evaluated by univariable and multivariable Cox proportional hazards model. RESULTS: A total of 72 patients were enrolled between March 2004 and September 2008, with 70 of these patients being eligible. The median follow-up period was 10.0 years for all eligible patients. Local recurrence and distant metastasis were observed in 5 and 19 patients, respectively. The 10-year PFS was 65.7% (95% CI: 53.4-75.5%) with no PFS events being detected during the last 5 years of follow-up. The 10-year overall survival was 78.1% (95% CI: 66.3-86.2%). Secondary malignancy was detected in 6 patients. The subgroup analysis demonstrated that there was significant difference in survival with regard to primary tumor size. CONCLUSIONS: Only a few long-term results of clinical trials for perioperative chemotherapy treatment of STS have been reported. Our results demonstrate that the 10-year outcome of JCOG0304 for patients with operable, high-risk STS of the extremities was stable and remained favorable during the last 5 years of follow-up. TRIAL REGISTRATION: This trial was registered at the UMIN Clinical Trials Registry as C000000096 on August 30, 2005.

Clinical characteristics and treatment outcomes in six cases of malignant tenosynovial giant cell tumor: initial experience of molecularly targeted therapy.

BACKGROUND: Although tenosynovial giant cell tumor (TGCT) is classified as a benign tumor, it may undergo malignant transformation and metastasize in extremely rare occasions. High aberrant expression of CSF1 has been implicated in the development of TGCT and recent studies have shown promising activity of several CSF1R inhibitors against benign diffuse-type TGCT; however, little is known about their effects in malignant TGCT. CASE PRESENTATION: Information from six consenting patients (3 men, 3 women) with malignant TGCT presenting to Dana-Farber Cancer Institute for initial or subsequent consultation was collected. Median age at initial diagnosis of TGCT was 49.5 years (range 12-55), and median age at diagnosis of malignant TGCT was 50 years (range 34-55). Two patients developed malignant TGCT de novo, while four other cases showed metachronous malignant transformation. All tumors arose in the lower extremities (3 knee, 2 thigh, 1 hip). Five patients underwent surgery for the primary tumors, and four developed local recurrence. All six patients developed lung metastases, and four of five evaluable tumors developed inguinal and pelvic lymph node metastases. All six patients received systemic therapy. Five patients were treated with at least one tyrosine kinase inhibitor with inhibitory activity against CSF1R; however, only one patient showed clinical benefit (SD or PR). Five patients were treated with conventional cytotoxic agents. Doxorubicin-based treatment showed clinical benefit in all four evaluable patients, and gemcitabine/docetaxel showed clinical benefit in two patients. All six patients died of disease after a median of 21.5 months from diagnosis of malignant TGCT. CONCLUSIONS: This study confirms that TGCT may transform into an aggressive malignant tumor. Lymph node and pulmonary metastases are common. Local recurrence rates are exceedingly high. Conventional cytotoxic chemotherapy showed clinical benefit, whereas tyrosine kinase inhibitors against CSF1R showed limited activity. Given its rarity, a prospective registry of malignant TGCT patients is needed to further understand the entity and to develop effective strategies for systemic treatment.

Wide-spread ignorance on the treatment of subcutaneous malignant tumors; a questionnaire-based study.

BACKGROUND: Subcutaneous malignant tumors are often treated by non-specialized clinicians in musculoskeletal oncology. While the resection of subcutaneous tumors appears technically feasible, unplanned resection of malignant tumors can result in a devastating clinical outcome. The aim of this study was to evaluate the potential estrangement in the awareness of and the treatment strategy for the patients with subcutaneous soft tissue tumors between musculoskeletal oncologists and non-specialized clinicians. METHODS: A questionnaire probing the clinical assessment of subcutaneous tumors was sent to orthopedic surgeons, dermatologists, plastic surgeons, and general surgeons. Results of the questionnaire were statistically analyzed. RESULTS: One hundred sixteen clinicians out of 150 responded to the questionnaire; the response rate was 77.3%. Among those, 46 clinicians had treated subcutaneous tumors. Thirty-nine of these 46 clinicians (27 musculoskeletal oncologists and 12 non-specialized clinicians) preoperatively performed enhanced MRI for diagnostic evaluation. Preoperative incisional biopsy to confirm the pathological diagnosis was performed by 36 of the 46 clinicians (29 musculoskeletal oncologists and seven non-specialized clinicians). These results indicate that musculoskeletal oncologists perform preoperative enhanced MRI (P = 0.08) and biopsy (P < 0.01) more frequently than non-specialized clinicians. The recognition rate of 'myxofibrosarcoma' was 60.8% among clinicians with an experience with sarcoma treatment (25 musculoskeletal oncologists and three non-specialized clinicians). The recognition rate of 'myxofibrosarcoma' between musculoskeletal oncologists and non-specialized clinicians was statistically significant (P < 0.01). CONCLUSIONS: Preoperative evaluations for subcutaneous tumors are more often inappropriate in non-specialized clinicians than those who are. Therefore, it will be mandatory to raise the awareness of this condition to improve the clinical outcome of patients with subcutaneous tumors.

Prospective comparison of various radiological response criteria and pathological response to preoperative chemotherapy and survival in operable high-grade soft tissue sarcomas in the Japan Clinical Oncology Group study JCOG0304.

BACKGROUND: Soft tissue sarcomas (STS) are rare malignant tumors. The efficacy of preoperative chemotherapy for STS is evaluated using various tumor size-based radiological response criteria. However, it is still unclear which set of criteria would show the best association with pathological response and survival of the patients with STS. METHODS: We compared radiological responses to preoperative chemotherapy for operable STS by the Response Evaluation Criteria in Solid Tumors (RECIST), modified RECIST, World Health Organization criteria, Japanese Orthopaedic Association criteria, and modified Choi criteria and analyzed the association with pathological response and survival using the data from the Japan Clinical Oncology Group (JCOG) study JCOG0304, a phase II clinical trial evaluating the efficacy of perioperative chemotherapy for STS in the extremities. RESULTS: Seventy eligible patients in JCOG0304 were analyzed. The results demonstrated that none of the size-based radiological response criteria showed significant association with pathological response to preoperative chemotherapy for STS. The difference between overall survival of the patients assessed as partial response and stable disease/progressive disease by RECIST was not significant (hazard ratio 1.37, p = 0.63), and calculated C-index was 0.50. All other response criteria also could not exhibit significant association between radiological responses and survival. CONCLUSION: In the present study, none of the radiological response criteria analyzed demonstrated association of response to preoperative chemotherapy with pathological response or survival of the patients with operable STS. Further prospective investigation is required to develop criteria to evaluate not only tumor shrinkage but biological effects of preoperative chemotherapy for the patients with localized STS. TRIAL REGISTRATION: UMIN Clinical Trials Registry C000000096. Registered 30 August, 2005 (retrospectively registered).