A Novel Approach to Reducing Lung Metastasis in Osteosarcoma: Increasing Cell Stiffness with Carbenoxolone.

AIM: Primary malignant bone tumor osteosarcoma can metastasize to the lung. Diminishing lung metastasis would positively affect the prognosis of patients. Our previous studies demonstrated that highly metastatic osteosarcoma cell lines are significantly softer than low-metastasis cell lines. We therefore hypothesized that increasing cell stiffness would suppress metastasis by reducing cell motility. In this study, we tested whether carbenoxolone (CBX) increases the stiffness of LM8 osteosarcoma cells and prevents lung metastasis in vivo. METHODS: We evaluated the actin cytoskeletal structure and polymerization of CBX-treated LM8 cells using actin staining. Cell stiffness was measured using atomic force microscopy. Metastasis-related cell functions were analyzed using cell proliferation, wound healing, invasion, and cell adhesion assays. Furthermore, lung metastasis was examined in LM8-bearing mice administered with CBX. RESULTS: Treatment with CBX significantly increased actin staining intensity and stiffness of LM8 cells compared with vehicle-treated LM8 cells (p < 0.01). In Young's modulus images, compared with the control group, rigid fibrillate structures were observed in the CBX treatment group. CBX suppressed cell migration, invasion, and adhesion but not cell proliferation. The number of LM8 lung metastases were significantly reduced in the CBX administration group compared with the control group (p < 0.01). CONCLUSION: In this study, we demonstrated that CBX increases tumor cell stiffness and significantly reduces lung metastasis. Our study is the first to provide evidence that reducing cell motility by increasing cell stiffness might be effective as a novel anti-metastasis approach in vivo.

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.

What is a useful marker for predicting survival in patients with high-grade soft tissue sarcoma who have non-inflammatory conditions?

BACKGROUND: The modified Glasgow prognostic score (mGPS) is a reliable system for identifying patients at high risk of death among patients with soft tissue sarcoma (STS). The scoring systems use a combination of C-reactive protein (CRP) and albumin levels. Although patients with high-grade STS are at risk of metastasis and death, even if their mGPS is 0, the prognostic indicators in these patients are unknown. Therefore, we investigated useful prognostic indicators for survival and the development of metastasis in patients with high-grade STS and an mGPS of 0. METHODS: One hundred and four patients with CRP and albumin levels of <1.0 mg/dl and >3.5 g/dl, respectively, indicating an mGPS of 0, were included. The mean follow-up period was 79 months. RESULTS: The 5-year disease-specific survival (DSS) rate was 79.2%. Cox proportional analysis showed that tumor size and absolute neutrophil count (ANC) were prognostic variables in multivariate analyses. Patients with higher ANC (ANC>3370/µl) had a worse DSS than those with lower ANC. The 5-year DSS was 74.7% vs. 91.7%, respectively (p = 0.0207). The 5-year metastasis-free survival was 67.2%. Tumor size and ANC remained significant variables for predicting the development of metastasis in the multivariate analysis. Patients with higher ANC had a worse metastasis-free survival than those with lower ANC. The 5-year metastasis-free survival was 59.5% vs. 87.3%, respectively (p = 0.00269). CONCLUSIONS: When patients with high-grade STS have an mGPS of 0, the ANC and tumor size should be carefully evaluated. A higher neutrophil count and larger tumor size may increase the risk of metastasis development.

Artifactual hypoglycaemia may be common in patients with soft tissue sarcoma who received pegfilgrastim-supported chemotherapy.

BACKGROUND: Recently, we identified artifactual hypoglycemia in patients with soft tissue sarcoma (STS) who received pegfilgrastim-supported chemotherapy. In the present study, we measured white blood cell count and fasting blood glucose levels after the administration of pegfilgrastim in patients with STS and showed the relationship between artifactual hypoglycemia and white blood cell count. PATIENTS: A total of 19 patients were included in this study. The mean age of the patients was 54 years. They received chemotherapy and administration of pegfilgrastim. Pegfilgrastim was injected subcutaneously 48 h after chemotherapy. No patient had a history of diabetes mellitus. RESULTS: Fifty-nine cycles were administered to 19 patients. One hundred and twenty-eight samples were obtained within one week after the of pegfilgrastim administration. Hypoglycemia was observed in 38 of the 13 patients. There were no symptoms of hypoglycemia in any patient. The white blood cell count in samples from patients with hypoglycemia was significantly higher than that in samples without hypoglycemia (p < 0.001). The median white blood cell count in samples with hypoglycemia was 29,415 and 3420 in samples without hypoglycemia. Age, sex, body mass index, performance status, and red blood cell count were not associated with hypoglycemia. White blood cell count was strongly negatively correlated with fasting blood glucose levels (Pearson's r: 0.786, 95% confidence interval: 0.844-0.709, p < 0.001). Of the 38 samples with hypoglycemia, 32 were measured within 2 days after pegfilgrastim administration. CONCLUSION: If a lack of symptoms due to hypoglycemia and leukocytes is confirmed, physicians should wait and identify the normalization of the level of glucose according to the neutrophil nadir following temporal leukocytes, which prevents further invasive examination for hypoglycemia.

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.

Do coagulation or fibrinolysis reflect the disease condition in patients with soft tissue sarcoma?

BACKGROUND: Coagulation and fibrinolysis are distinct processes that are highly correlated. Cells control coagulation and fibrinolysis by expression of tissue factor and urokinase-type plasminogen activator receptor on their surface. Tumor cells express these proteins, adjust their microenvironment and induce tumor exacerbation. We hypothesized that the expression of plasma markers for coagulation and fibrinolysis in patients with soft tissue sarcomas (STSs) was dependent on the level of tumor malignancy. To elucidate which markers are predictive of recurrence, metastasis and prognosis, coagulation or fibrinolysis, we analyzed the correlation between plasma levels of thrombin-antithrombin III complex (TAT), soluble fibrin (SF), plasmin-α2 plasmin inhibitor complex (PIC), D-dimer (DD) and clinical parameters in patients with STSs. METHODS: TAT, SF, PIC or DD were measured in pre-treatment blood samples from 64 patients with primary STSs and analyzed with clinicopathological parameters, and 5-year recurrence free survival (RFS), 5-year metastasis free survival (MFS) and 5-year overall survival (OS) were evaluated. RESULTS: The metastasis group had significantly higher DD (p = 0.0394), PIC (p = 0.00532) and SF (p = 0.00249) concentrations than the group without metastasis. The group that died of disease showed significantly higher DD (p = 0.00105), PIC (p = 0.000542), SF (p = 0.000126) and TAT (p = 0.0373) than surviving patients. By dividing the patients into low and high groups, the group with high DD, PIC, SF and TAT showed significantly lower 5-year MFS and 5-year OS than the corresponding low group. Furthermore, in multivariate COX proportional hazard analysis of continuous variables for 5-year MFS, only PIC was found to be a significant factor (HR: 2.14). CONCLUSION: Fibrinolysis was better than coagulation at reflecting the disease condition of patients with STS. Notably, PIC levels ≥ 1.1 can not only predict the risk of metastasis and poor prognosis, but also increasing PIC levels correspond to further increases in risks of metastasis and poor prognosis.

Clinical outcome in patients who underwent amputation due to extremity soft tissue sarcoma: Tokai Musculoskeletal Oncology Consortium study.

BACKGROUND: Soft tissue sarcomas are a diverse group of rare malignant tumours, mostly occurring in the lower extremities. Amputations are necessary for achieving local control when the soft tissue sarcomas are too large and/or have neurovascular involvement. Patients who require amputation have a poorer prognosis than those who undergo limb-salvage surgery. PATIENTS AND METHODS: We investigated the tumour characteristics and the clinical outcomes in 55 patients with primary soft tissue sarcomas, who underwent amputation. We excluded patients with amputation performed distal to the wrist or ankle joints and those with recurrent soft tissue sarcomas. RESULTS: The mean tumour size was 11.1 cm. Hip disarticulation was performed in 6 patients, 20 underwent above the knee amputation, 8 underwent knee disarticulation and 12 underwent below the knee amputation. Shoulder disarticulation was performed in three patients, five underwent above the elbow amputation, and one underwent below the elbow amputation. The 5-year disease-specific survival rate was 52.8%. The 5-year recurrence-free survival rate and 5-year metastasis-free survival rates were 90.1% and 38.5%, respectively. Larger tumour size, age and the distant metastases at first presentation were predictors of poor prognosis for survival in multivariate analysis. Twenty-eight patients could walk using artificial limbs. The level of amputation (above versus below the knee) showed a significant difference in achieving independent gait. CONCLUSION: Amputation is a useful treatment option for achieving local control in patients with large soft tissue sarcomas. Patients had an opportunity of walking, especially for those who underwent below the knee amputation.

Substrate stiffness modulates endothelial cell function via the YAP-Dll4-Notch1 pathway.

Endothelial cells adapt their functions as a consequence of sensing extracellular substrate stiffness; these alterations allow them to maintain their vascular structure and function. Substrate stiffness-mediated yes-associated protein 1 (YAP) activation plays an important role in mechano-transduction and pro-angiogenic phenotype of endothelial cells, and Delta-like ligand 4 (Dll4)-Notch1 signaling is closely related to angiogenesis; however, the impact of substrate stiffness-mediated interrelation of these pathways on endothelial cell functions remains elusive. We confirmed that endothelial cells on softer substrates not only elongate cellular aspects but also attenuate YAP activation compared to cells on stiffer substrates. Endothelial cells on softer substrates also upregulate the vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR2 mRNA expression that is enhanced by VEGF stimulation. We determined that endothelial cells on softer substrates increased Dll4 expression, but not Notch1 expression, via YAP signaling. Moreover, endothelial cells on soft substrates induced not only VEGFRs upregulation but also suppression of pro-inflammatory interleukin-6 and plasminogen activator inhibitor-1 mRNA expression and the facilitation of anti-coagulant thrombomodulin and pro-coagulant tissue factor mRNA expression. Our results suggest that endothelial cells activate the YAP-Dll4-Notch signaling pathway in response to substrate stiffness and dictate cellular function.

Is no additional excision after unplanned excision with positive margins justified in patients with small (≤5 cm) high-grade soft-tissue sarcoma?: Analysis from the Bone and Soft Tissue Tumor registry in Japan.

BACKGROUND: This study aimed to elucidate the clinical outcomes of patients with small (≤5 cm) high-grade soft tissue sarcoma, who underwent unplanned excision with positive surgical margin, using data from the Bone and Soft Tissue Tumor registry in Japan. METHODS: We examined 174 patients (101 males and 73 females; mean age, 59 years) with primary non-metastatic soft tissue sarcoma. The tumor size was ≤5 cm, and tumor histological grade was high in all patients. The mean follow-up duration was 50 months. RESULTS: Unplanned excision with R1 and R2 margins was reported in 115 (66%) and 59 patients (34%), respectively. After unplanned excision, immediate additional excision was performed in 154 patients, whereas no additional excision was performed in the remaining 20. Of the 154 patients who underwent additional excision, wide surgical margin resection was achieved in 140 patients, while marginal and intralesional resections were achieved in 10 and 3 patients, respectively. Additionally, 93 patients (60%) underwent reconstruction after additional excision. During the last follow-up, 8 patients died of the disease, 22 developed distant metastasis, and 14 reported local recurrence. The 5-year disease-specific survival rate and 5-year metastasis-free survival rate was 93.5% and 85%, respectively. Tumor depth and additional excision after unplanned excision showed statistical significance in the multivariate analysis. The 5-year metastasis-free survival rate was 89.1% in patients with additional excision and 39.2% in those without. Univariate analysis showed an association between additional excision and local control. The 5-year local recurrence-free survival was significantly worse in patients without additional excision after unplanned excision (52.6%) than in those with additional excision (92.8%). CONCLUSION: If unplanned excision is performed in patients with small high-grade soft tissue sarcoma, additional excision is recommended for preventing metastasis, along with necessary preparations for reconstruction.

Cytoskeletal Actin Structure in Osteosarcoma Cells Determines Metastatic Phenotype via Regulating Cell Stiffness, Migration, and Transmigration.

Osteosarcoma is the most common primary malignant bone tumor. The cause of death due to osteosarcoma is typically a consequence of metastasis to the lung. Controlling metastasis leads to improved prognosis for osteosarcoma patients. The cell stiffness of several tumor types is involved in metastatic potential; however, it is unclear whether the metastatic potential of osteosarcoma depends on cell stiffness. In this study, we analyzed the cell stiffness of the low metastatic Dunn cell line and its highly metastatic LM8 subline, and compared actin organization, cell proliferation, and metastasis. Actin cytoskeleton, polymerization, stiffness, and other cellular properties were analyzed. The organization of the actin cytoskeleton was evaluated by staining F-actin with Alexa Fluor 488 phalloidin. Cell stiffness was measured using Atomic Force Microscopy (AFM). Cell proliferation, migration, invasion, and adhesion were also evaluated. All experiments were performed using mouse osteosarcoma cell lines cultured in the absence and presence of cytochalasin. In LM8 cells, actin polymerization was strongly suppressed and actin levels were significantly lower than in Dunn cells. Stiffness evaluation revealed that LM8 cells were significantly softer than Dunn. Young's modulus images showed more rigid fibrillar structures were present in Dunn cells than in LM8 cells. LM8 cells also exhibited a significantly higher proliferation. The migration and invasion potential were also higher in LM8 cells, whereas the adhesion potential was higher in Dunn cells. The administration of cytochalasin resulted in actin filament fragmentation and decreased actin staining intensity and cell stiffness in both LM8 and Dunn cells. Cells with high metastatic potential exhibited lower actin levels and cell stiffness than cells with low metastatic potential. The metastatic phenotype is highly correlated to actin status and cell stiffness in osteosarcoma cells. These results suggest that evaluation of actin dynamics and cell stiffness is an important quantitative diagnostic parameter for predicting metastatic potential. We believe that these parameters represent new reliable quantitative indicators that can facilitate the development of new drugs against metastasis.

Significance of coagulation and fibrinolysis markers for benign and malignant soft tissue tumors.

BACKGROUND: The intimate relationship between coagulation and fibrinolysis in malignant tumors is a well-known phenomena, with the malignant phenotype enhancing coagulation and fibrinolysis. We hypothesized that soft tissue sarcoma (STS) affects the expression of coagulation and fibrinolysis markers, which could be used to distinguish STS from benign soft tissue tumors. We analyzed the correlations between plasma levels of D-dimer (DD), plasmin-α2 plasmin inhibitor complex (PIC), soluble fibrin (SF), and thrombin-antithrombin III complex (TAT) in benign soft tissue tumors and STS to elucidate whether these markers can be used to predict STS. METHODS: Plasma DD, PIC, SF and TAT levels in primary soft tissue tumors (benign 67, STS 68) were measured before biopsy or treatment. The marker levels were analyzed and compared to various clinicopathological parameters. RESULTS: In malignancy (STS), the average DD, PIC and SF levels were significantly higher than in benign tumors. Multivariate logistic analysis of continuous variables indicated that only PIC exhibited a significant difference (OR: 24.5, 95%CI: 3.55-170, p = 0.0012). Receiver operating characteristic curve analysis produced area under the curve values for DD: 0.691, PIC: 0.784, SF: 0.734 and TAT: 0.588. Youden's index was used to establish thresholds of 0.37 (DD), 0.80 (PIC), 0.90 (SF) and 0.82 (TAT). Threshold values for PIC and SF indicated high specificity (0.881, 0.791) and high positive predictive value (0.818, 0.745), respectively. The highest accuracy value among the markers was observed for PIC (0.704). Significant differences in multivariate analysis of binary variables were demonstrated by categorizing low and high groups based on their threshold, PIC (≥0.80) (OR: 3.36, 95%CI: 1.19-9.43, p = 0.0212) and SF (≥0.90) (OR: 2.63, 95%CI: 1.04-6.66, p = 0.0404) . CONCLUSIONS: Of the coagulation and fibrinolysis markers studied, increased PIC levels were related to STS and over 0.80 PIC was the most suitable for the prediction of STS, which, along with other diagnostic tools, represents a helpful subsidiary tool for the prediction of STS.

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.

Clinical outcome of latissimus dorsi reconstruction after wide resection of soft-tissue sarcoma.

BACKGROUND: We investigated the clinical outcomes of reconstruction using the latissimus dorsi (LD) flap after resection of soft-tissue sarcoma. MATERIALS AND METHODS: We analyzed 19 patients. Free LD flap was performed in 11 patients and pedicle flap in eight patients. The mean follow-up period after the surgery was 60 months. RESULTS: The mean age at diagnosis was 57 years. The mean tumor size was 9.8 cm. The median size of the LD flap was 140 × 100 mm. The mean surgical duration and bleeding were 510 min and 602 mL, respectively. Complications included partial skin and soft-tissue necrosis (n = 3) and wound dehiscence (n = 2). No additional free flap was not necessary for the closure of the defect due to the complications. The longer surgical duration was significantly associated with wound complications (P = 0.048). The 5-year survival rate was 80.7%, and the local recurrence-free survival rate was 89.2%. Two patients developed local recurrence, while 6 patients developed metastasis. None of the patients had any restrictions of daily life. CONCLUSION: The LD flap after surgical tumor resection in patients with soft-tissue sarcoma was useful for the coverage of soft tissue.

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.

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).

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.

Do exercise habits during middle age affect locomotive syndrome in old age?

OBJECTIVES: Locomotive syndrome (LS) encompasses conditions that may lead to the need for nursing services. We aimed to quantify the association between exercise habits during youth or the middle-age years and both physical function and the presence of LS in Japanese elderly people. METHODS: We examined 460 participants of the eighth, ninth, and tenth iterations of the Miyagawa study. Participants were divided into an LS group and a no-LS group according to their scores on the 25-question Geriatric Locomotive Function Scale. The following physical function tests were performed: grip strength, 6-m walk at normal and maximum speed, single-leg stance time with eyes open, and chair stand time. The frequency of past physical activity was determined by interview. RESULTS: Ninety-seven participants (21.1%) were classified as having LS. The LS group had worse physical function than the no-LS group. Exercise habits between the ages of 25 and 50 years were significantly related to later LS. CONCLUSIONS: Participants with LS were less likely to report a regular exercise habit between the ages of 25 and 50 years than participants without LS. Participants who reported regular exercise habits in middle age had better physical function during old age. Regular exercise habits in middle age appear to protect against LS during the older years.

Factors associated with the decision of operative procedure for proximal femoral bone metastasis: Questionnaire survey to institutions participating the Bone and Soft Tissue Tumor Study Group of the Japan Clinical Oncology Group.

BACKGROUND: Pathological fracture of the proximal femur is a main cause of cancer patients losing their ability to walk. Although both osteosynthetic devices (predominantly intramedullary nails) and prosthetic replacement have been widely performed for treatment, controversies exist regarding which procedure should be used for the various conditions. In order to decide the eligibility criteria of a planned randomized prospective study about the treatment of pathological fractures of the proximal femur, we assessed the factors affecting the selection of operative procedures using questionnaires sent to the members of the Bone and Soft Tissue Tumor Study Group (BSTTSG) of the Japan Clinical Oncology Group (JCOG). METHODS: Questionnaire surveys to evaluate (1) the priority levels of the factors, (2) the equipoise range of each factor in situations where either procedure could be applied, (3) risk and benefit of each procedure, and (4) the degree of bone destruction affecting the selection of operative procedures, were sent to 26 institutions. RESULTS: Over 80% of the institutions answered. Orthopaedic surgeons of BSTTSG decided on the procedure according to the following factors in descending order: life expectancy, performance status before fracture, the degree of bone destruction, walking ability before fracture, general complications, the number of bone metastases in other sites, and the visceral metastasis status. With regard to bone destruction, (1) the involvement of the head, neck, calcar, and intertrochanteric region, (2) transverse destruction >1/2, and (3) soft-tissue tumor extension, were the factors that led to the choice of prosthesis treatment. CONCLUSIONS: Using these identified factors, the inclusion criteria for the prospective randomized study of the surgical treatment of metastatic bone tumors of the proximal femur were optimized. The evaluation system about the bone destruction of metastases needs to be refined through the following prospective randomized study.

Minimally invasive surgery using intraoperative electron-beam radiotherapy for the treatment of soft tissue sarcoma of the extremities with tendon involvement.

BACKGROUND: When a soft tissue sarcoma (STS) is located at the distal part of an extremity and involves the tendon, a wide excision usually causes severe functional disability. We therefore developed a minimally invasive surgical technique using intraoperative electron-beam radiotherapy (IOERT) to reduce the incidence of post-operative functional disability in patients with peri-/intra-tendinous STS. We assessed the clinical outcomes of the novel minimally invasive surgery. METHODS: The study population included five patients who received treatment for distal extremity STSs. After elevating the tumor mass, including the tendon and nerve from the tumor bed with a wide margin, a lead board was inserted beneath the tumor mass to shield the normal tissue. IOERT (25-50 Gy) was then applied, and the tumor excised with care taken to maintain the continuity of the tendon. RESULTS: In a desmoid patient, local recurrence was observed outside the irradiated field. No cases of neuropathy or bone necrosis were observed. The mean limb function score was excellent in all patients. None of the high-grade sarcoma patients had local recurrence or distant metastasis. CONCLUSIONS: Although the current study is only a pilot study with a small number of patients, it shows that this minimally invasive procedure has the potential to become a standard treatment option for selected patients. TRIAL REGISTRATION: H17-250 (registered 2 November 2005) and H25-250 (modified from H17-250, registered 5 December 2013).

The role of C-reactive protein in predicting post-metastatic survival of patients with metastatic bone and soft tissue sarcoma.

Although elevated preoperative serum C-reactive protein (CRP) level is an indicator of a poorer prognosis in many cancers including non-metastatic bone and soft tissue sarcoma, there have been no reports focused on sarcoma patients with advanced stage who had distant metastases. The aim of this study is to determine whether the serum CRP level after metastasis is associated with post-metastatic survival in patients with bone and soft tissue sarcoma. A total of 71 patients were studied including 38 male and 33 female. Of all patients, 22 patients had metastases at presentation. The remaining 49 patients developed initial metastasis after the treatment of primary tumor. The average age at the diagnosis of metastasis was 55 years. Blood was obtained after initial detection of metastasis. CRP levels ranged from 0.1 to 165 mg/L with an average of 16.4 mg/L in all patients. Elevated CRP levels (>3 mg/L) were seen in 31 patients (range 3.1-165). The disease-specific survival after metastasis estimates at 3 and 5 years was 17.1 and 17.1 % for those with an elevated CRP vs. 59.5 and 45.3 % for those with a normal CRP (p < 0.0001). In 49 patients who developed lung metastasis after initial primary treatment, patients with elevated CRP levels also had a poorer post-metastatic survival than patients with normal CRP levels (p < 0.0001). In conclusion, we recommend routine measurement of CRP level to identify the patients who have high risk of death after metastasis.