BACKGROUND:The aim of this study was to determine whether circulating C-reactive protein (CRP) levels before treatment predict the overall survival and disease-free survival in soft tissue sarcoma patients. METHODS: A total of 102 primary soft tissue sarcoma patients from 2003 to 2009 were retrospectively reviewed. The CRP levels were obtained before treatment for all patients. The patients who presented with metastases at diagnosis were excluded from this study. RESULTS: Elevated CRP levels were seen in 18 patients. The tumor histological grade and American Joint Committee on Cancer stage in the patients with elevated CRP levels were significantly higher than those in patients with normal CRP levels. Patients with elevated CRP levels before initial treatment had a poorer overall survival than patients with normal CRP levels (P ¼ .01). The overall survival estimates at 3 and 5 years were 75.3% and 53.8%, respectively, versus 90.3% and 81.3%, respectively. Patients with elevated CRP levels before initial treatment had poorer event-free survival after initial treatment than patients with normal CRP levels (P < .001). The event-free survival estimates at 2 and 5 years were 53.2% and 33.2%, respectively, versus 83.2% and 81.3%, respectively. A multivariate analysis also showed the preoperative CRP level to be an independent predictor of events. CONCLUSIONS:The pretreatment serum CRP level may be a marker of aggressive tumor characteristics. Pretreatment elevated CRP levels were found to be a poor prognostic factor for overall survival in a univariate analysis, and for disease-free survival in a multivariate analysis, for soft tissue sarcoma patients.

Patients with bone metastases in the extremities sometimes require surgical intervention to prevent deterioration of quality of life due to a pathological fracture. The use of localized radiotherapy combined with surgical reinforcement has been a gold standard for the treatment of bone metastases. However, radiotherapy sometimes induces soft tissue damage, including muscle induration and joint contracture. Moreover, cancer cells are not always radiosensitive. Hyperthermia has been studied since the 1940s using an experimental animal model to treat various types of advanced cancer, and studies have now reached the stage of clinical application, especially in conjunction with radiotherapy or chemotherapy. Nevertheless, bone metastases have several special properties which discourage oncologists from developing hyperthermic therapeutic strategies. First, the bone is located deep in the body, and has low thermal conductivity due to the thickness of cortical bone and the highly vascularized medulla. To address these issues, we developed new hyperthermic strategies which generate heat using magnetic materials under an alternating electromagnetic field, and started clinical application of this treatment modality. The purpose of this review is to summarize the latest studies on hyperthermic treatment in the field of musculoskeletal tumors, and to introduce the treatment strategy employing our novel hyperthermia approach.

IntroductionThe etiology of degenerative disc disease is unknown. Several investigators have reported the presence of proteolytic enzymes, such as the matrix metalloproteinase (MMP) and ADAMTS (a disintegrin and metalloprotease with thrombospondin-like repeats) families, in degenerated human discs. Glasson and colleagues recently reported that a significant reduction occurs in the severity of cartilage destruction in ADAMTS5 knockout mice compared with wild-type mice. The purpose of this study was to evaluate the suppressive effects of injections of ADAMTS5 small interference RNA (siRNA) oligonucleotide on intervertebral disc degeneration in the rabbit anular needle-puncture model.MethodsRabbit nucleus pulposus (NP) cells were transfected with siRNA oligonucleotides specific for ADAMTS5 or the control. The suppression of the ADAMTS5 gene by siRNA transfection was assessed by using real-time polymerase chain reaction (PCR), both in monolayer and alginate bead cultures with or without interleukin-1β (IL-1β) stimulation. The effect of siRNA was determined in vivo by using the rabbit anular needle-puncture model (control group: n = 8; ADAMTS5 group: n = 8). One week after the initial anular puncture, the animals received an injection of the control or anti-ADAMTS5 oligonucleotide (100 μg each at the L2/3 and L4/5 level; 16 discs/group). Disc height, magnetic resonance imaging (MRI) (Thompson classification and signal intensity), and safranin-O staining (histologic grade) were assessed.ResultsIL-1β treatment significantly increased the ADAMTS5 mRNA level in NP cells (P < 0.01). ADAMTS5 gene suppression was 70% compared with the control oligonucleotide in both monolayer and alginate bead culture with or without stimulation with IL-1β. The injection of anti-ADAMTS5 oligonucleotide in vivo resulted in improved MRI scores with increased signal intensity and improved histologic grade scores with statistical significance (P < 0.05). No significant change in disc height was observed.ConclusionsA single injection of ADAMTS5 siRNA induced the suppression of degradation in NP tissues, as shown by significantly improved MRI and histologic grades. The mechanism of response to siRNA may be worthy of exploration for possible therapeutic purposes.

We recommend the routine measurement of these markers to identify patients with a greater risk of death.

BackgroundGiant 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.MethodsWe 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.ResultsAnswers 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).ConclusionThe 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.

Protein C inhibitor (PCI), a member of the serine protease inhibitor family, is produced in various human tissues, including the liver, kidney and testis. In addition to inhibiting the anticoagulant protein C pathway, PCI also inhibits urinary plasminogen activator (uPA), which is a well-known mediator of tumor cell invasion. In the present study, to clarify the biologic significance of PCI in the kidney, we compared the expression of PCI between human renal cell carcinoma (RCC) tissue and nontumor kidney tissue. The PCI antigen level in RCC tissue was found to be significantly lower than in nontumor kidney tissue, and expression of PCI mRNA was detected in normal renal proximal tubular epithelial cells (RPTEC), but not in RCC or in an RCC cell line (Caki-1 cells). Key words: protein C inhibitor; urinary plasminogen activator; renal cell carcinoma; tumor invasionProtein C inhibitor (PCI) was originally identified as an inhibitor of the anticoagulant protease, activated protein C, 1 and was subsequently found to inhibit other proteases involved in blood coagulation and fibrinolysis, such as thrombin, 2 thrombin-thrombomodulin complex, 3 factor Xa, 2 factor XIa, 4 plasma kallikrein 4 and urinary plasminogen activator (uPA). 5 Human plasma PCI is believed to be produced mainly by the liver, 6 but is also synthesized in the kidneys and the reproductive organs, including the testis, seminal vesicles and ovary. 7,8 Thus, besides its function in the regulation of blood coagulation, PCI may also play a role in the regulation of reproduction. Recently, Uhrin et al. 9 reported that PCI knockout male mice are apparently healthy but infertile, and that this infertility is caused by abnormal spermatogenesis induced by destruction of the Sertoli cell barrier. In the kidneys, PCI is mainly synthesized by proximal tubular epithelial cells, 10 and most urinary PCI is present in complex with uPA, 11 which it inhibits; hence, PCI is also referred to as plasminogen activator inhibitor-3 (PAI-3). However, the physiologic role of uPA inhibition by PCI in the urinary tract is unknown.It is known that metastasis and invasion of various tumor cells are mediated by uPA and its receptor. 12 uPA is inhibited by PAI-1 and PAI-2, 13 the former of which has been reported to be essential for regulation of tumor cell invasion and metastasis by promoting angiogenesis. 14,15 Previously, it was shown that the expression of uPA is lower, that the expression of uPA receptor is moderately higher and that the expression of PAI-1 is significantly higher in human renal cell carcinoma (RCC) than in nontumor kidney tissue. 16,17 Furthermore, Swiercz et al. 18 suggested that the expression of uPA, its receptor and PAI-1 correlate with the aggressive phenotype of RCC. These studies suggest the importance of the plasminogen activator system, including uPA, its receptor and PAI-1, in the process of RCC tumor cell invasion; however, there is no direct evidence yet that uPA regulates the invasiveness of RCC cells. It is also known that uPA and/or plasmin may ...

The aim of this study was to determine whether the high-sensitivity modified Glasgow prognostic score (Hs-mGPS) could predict the disease-specific survival and oncological outcome in adult patients with non-metastatic soft-tissue sarcoma before treatment. A total of 139 patients treated between 2001 and 2012 were retrospectively reviewed. The Hs-mGPS varied between 0 and 2. Patients with a score of 2 had a poorer disease-specific survival than patients with a score of 0 (p < 0.001). The estimated five-year rate of disease-specific survival for those with a score of 2 was 0%, compared with 85.4% (95% CI 77.3 to 93.5) for those with a score of 0. Those with a score of 2 also had a poorer disease-specific survival than those with a score of 1 (75.3%, 95% CI 55.8 to 94.8; p < 0.001). Patients with a score of 2 also had a poorer event-free rate than those with a score of 0 (p < 0.001). Those with a score of 2 also had a poorer event-free survival than did those with a score of 1 (p = 0.03). A multivariate analysis showed that the Hs-mGPS remained an independent predictor of survival and recurrence. The Hs-mGPS could be a useful prognostic marker in patients with a soft-tissue sarcoma.

It is well known that malignant cells show procoagulant activity, which is associated with their metastatic potential. Thrombin, the key enzyme of the blood coagulation system, is generated around tumor cells, promoting the migration and metastasis of tumor cells. In this study, we evaluated the effect of argatroban, a specific thrombin inhibitor, on the migration and metastasis of B16BL6 melanoma cells. In vitro argatroban dose-dependently inhibited cell migration, the maximum inhibition being observed in the presence of 10 µM argatroban (p < 0.0001). In order to investigate the antimetastatic effect of the thrombin inhibitor, we used an animal model that we have reported previously. C57BL6 mice which had received a bone (femur or tibia) transplanted into the dorsal subcutis were injected with B16 melanoma cells into the left heart ventricle. Intraperitoneal injection of argatroban (9 mg/kg/day for 4 weeks) significantly reduced the number of limbs with metastatic lesions as compared to a placebo (p < 0.05). These results suggest that argatroban was associated with reduced melanoma metastases by inhibiting cell migration. Our results showed that argatroban is effective for treatment of bone metastasis.