Current management of giant-cell tumor of bone in the denosumab era.

Giant-cell tumor of bone is a rare, locally aggressive and rarely metastasizing primary bone tumor. The mainstay of treatment remains controversial and is decided by the balance between adequate surgical margin and sufficient adjacent joint function. Although curettage with a high-speed burr and local adjuvants can maintain normal joint function, many reports have revealed a high local recurrence rate. Conversely, en bloc resection and reconstruction with prostheses for highly aggressive lesions have reportedly lower local recurrence rates and poorer functional outcomes. Denosumab-a full human monoclonal antibody that inhibits receptor activator of nuclear factor-kappa ß ligand-was approved by the Food and Drug Authority in 2013 for use in surgically unresectable or when resection is likely to result in severe morbidity for skeletally mature adolescents and adults with giant-cell tumor of bone. However, subsequent studies have suggested that the local recurrence rate would be increased by preoperative use of denosumab. In systematic reviews of the local recurrence rate after preoperative use of denosumab, conclusions vary due to the small sample sizes of the studies reviewed. Therefore, controversy regarding the treatment of giant-cell tumor of bone is ongoing. Here, this review elucidates the management of giant-cell tumor of bone, especially with the local adjuvant and neoadjuvant use of denosumab, and presents the current, evidence-based treatment for giant-cell tumor of bone.

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

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

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.

Limitations and benefits of FDG-PET/CT in NF1 patients with nerve sheath tumors: A cross-sectional/longitudinal study.

The purposes of this study were to re-confirm the usefulness of PET/CT in the differentiation of benignity/malignancy of neurogenic tumors in NF1 patients, and to analyze the natural course of plexiform neurofibroma (pNF) and clarify whether PET/CT is also useful for detecting tumors other than neurogenic tumors. PET/CT was prospectively imaged in 36 NF1 patients. There were 14 malignant peripheral nerve sheath tumors (MPNSTs) in 14 patients, and 54 pNFs in 30 patients. Nine patients had both MPNST and pNF. Maximal standardized uptake value (SUVmax) was significantly higher in MPNST (median 7.6: range 4.1-10.4) (P < .001) compared with that of pNF (median 3.7: range 1.6-9.3). The cut-off value of 5.8 resulted in a sensitivity of 78.6% and specificity of 88.9%. Median age was 29 y, and median maximum tumor diameter was 82 mm in 14 MPNST patients. The 5-y overall survival rate was 46.8%. Three patients with low-grade MPNST were alive without disease at the time of this report. In 9 patients in which pNF and MPNST co-existed, 2 showed a higher SUVmax of pNF than that of MPNST. Natural history analysis of pNF (n = 43) revealed that no factors significantly correlated with increased tumor size. Nine lesions other than neurogenic tumors were detected by PET/CT including 5 thyroid lesions and 3 malignant neoplasms. This study revealed the usefulness and limitation of PET/CT for NF1 patients. In the future, it will be necessary to study how to detect over time the malignant transformation of pNF to MPNST, via an intermediate tumor.

Preoperative T staging of advanced colorectal cancer by computed tomography colonography.

PURPOSE: Accurate preoperative T staging is important when determining the treatment strategy for advanced colorectal cancer. We have previously reported the usefulness of preoperative T staging based on the spatial relationship of tumors and "bordering vessels" by computed tomography colonography (CTC) with multiplanar reconstruction (MPR). The aims of this study were to evaluate the external validity of this method and to determine whether there is a difference in the accuracy of T staging between the mesenteric and antimesenteric sides. METHODS: The study subjects were 110 patients with colorectal cancer who underwent preoperative CTC and surgical resection from June 2016 to March 2018. Preoperative T stage was determined by CTC based on the relationship between the tumor and the bordering vessels and compared with the pathological T stage. The influence of tumor location, namely, whether the tumor was on the antimesenteric or mesenteric side, on preoperative T staging was assessed in 78 patients with colorectal cancer. RESULTS: Sensitivity, specificity, accuracy, positive, and negative predictive values were respectively, 65%, 91%, 83%, 76%, and 85% for T2 (n = 34); 76%, 82%, 81%, 50%, and 94% for T3 (n = 23); and 77%, 93%, 87%, 86%, and 88% for T4a disease (n = 39). Overall right answer rate was 83.3% (15/18) for the mesenteric side and 65% (39/60) for the antimesenteric side (n = 0.14). CONCLUSION: Diagnostic criteria based on the bordering vessels seen on CTC images with MPR are useful for T staging of colorectal cancer. However, the accuracy differs between the antimesenteric and mesenteric sides.

Clinical value of serum bone resorption markers for predicting clinical outcomes after use of bone modifying agents in metastatic bone tumors: A prospective cohort study.

Bone modifying agents (BMAs) have become a standard treatment to prevent skeletal-related events (SREs) in bone metastases (BMs). The aim of our study is to determine the clinical value of serum bone resorption markers for predicting clinical outcomes after using BMAs in patients with BM. Patients were enrolled between May 2013 and October 2017 at the Nagoya University Hospital, Japan. We prospectively observed changes in pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP) and tartrate-resistant acid phosphatase 5b (TRACP-5b) during treatment with BMAs. The relationship between serum markers before and after treatment and clinical outcomes such as progression of bone disease (BD), SREs and overall survival (OS) were evaluated. Pearson chi-square test and Kaplan-Meier product limit methods were used for analysis. Sixty-seven patients were analyzed. The primary tumor sites were 21 lung, 16 breast and 30 others. Forty and 27 patients were treated with Denosumab and Zoledronic acid, respectively. Progression of BDs, SREs and death were observed in 10, 16 and 31 cases, respectively. The median follow-up period after using BMAs was 12.3 (range 0.3-66.3) months. ICTP at 3-4 weeks was significantly correlated with increasing BD progression, SREs and death after treatment in both the whole and lung cancer cohorts. Base line ICTP and TRACP-5b were also associated with increasing BD progression in the whole cohort. Our study showed that early posttreatment ICTP is useful for predicting BD progression, SREs and OS after use of BMAs in patients with BM and even in patients with lung cancer BM.

Desmoid with biweekly methotrexate and vinblastine shows similar effects to weekly administration: A phase II clinical trial.

Low-dose methotrexate (MTX) plus vinblastine (VBL) chemotherapy is an effective treatment for desmoid-type fibromatosis (DF). However, previous reports have described a weekly regimen, with no reports available on a biweekly one. The aim of this study was to determine the clinical outcomes of a biweekly regimen in a cohort prospectively treated in our single institution. Since 2010, we have prospectively treated refractory DF patients with biweekly MTX (30 mg/m2 ) + VBL (6 mg/m2 ). Efficacy, progression-free survival (PFS), and correlating factors were analyzed. Adverse events (AEs) were recorded. In total, 38 patients received low-dose MTX + VBL therapy, and its efficacy was assessed in 37 of them. Nineteen (51%) patients showed partial response (PR). Clinical benefit rate was 95%. PFS at 5 y was 80.8%. In PR cases, median time to response was 10 mo. Longer duration of therapy was significantly associated with the response of PR (P = .007) by univariate analysis. There was no clear association between various clinicopathological factors, including tumor size, location, catenin beta-1 (CTNNB1) mutation status with effect. Only 3 AEs of grade 3/4 were observed. Tumor regrowth after MTX + VBL discontinuation was observed in 5 (20%) of 25 patients. Biweekly administration of MTX + VBL chemotherapy was well tolerated compared with weekly administration, and its efficacy was anticipated in DF patents, although the time needed to achieve a response may be relatively long. The treatment interval should be determined taking into account both the condition of the tumor and the patient's preference.

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.

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

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

A randomized phase III trial of denosumab before curettage for giant cell tumor of bone: Japan Clinical Oncology Group Study JCOG1610.

A randomized phase III trial was planned to commence in October 2017. Resectable giant cell tumor of bone (GCTB) without possible postoperative large bone defect has been treated by curettage with local adjuvant treatment, with the local recurrence rate found to be as high as 24.6-30.8%. The aim of this study is to confirm the superiority of preoperative denosumab for patients with GCTB without possible postoperative large bone defect. A total of 106 patients will be accrued from 34 Japanese institutions over 5 years. The primary endpoint is relapse-free survival (RFS). Secondary endpoints include overall survival, joint-preserved survival, local RFS, metastasis-free survival, adverse events, serious adverse events, surgical and postoperative complications, and discontinuation of denosumab. This trial is conducted by the Bone and Soft Tissue Tumor Study Group in the Japan Clinical Oncology Group and has been registered in the UMIN Clinical Trials Registry as UMIN000029451 [http://www.umin.ac.jp/ctr/index.htm].

Osteogenic differentiation in dedifferentiated liposarcoma: a study of 36 cases in comparison to the cases without ossification.

AIMS: Ossification is found occasionally in dedifferentiated liposarcoma (DDLPS). The aims of this study were to elucidate whether the formed bone tissue is usually produced by tumour cells or by reactive non-neoplastic cells, and to reveal the clinicopathological characteristics of DDLPS with ossification. METHODS AND RESULTS: We examined 36 cases of ossified DDLPS by comparing them to 31 cases of non-ossified DDLPS. MDM2 amplification was confirmed in osteocytes and/or osteoblastic cells in all but one ossified DDLPS cases (27 of 28) using fluorescence in-situ hybridisation, although the morphological impression of ossification appeared to be mainly metaplastic (27 of 36) or high-grade osteosarcoma-like (six of 36). The bone tissue was often formed predominantly at the periphery of the DDLPS area near the well-differentiated liposarcoma component (18 of 36), and an organised structure such as bone marrow-like differentiation was not uncommon (12 of 36). According to a modified French Fédération Nationale des Centers de Lutte Contre le Cancer (FNCLCC) grading system, ossified DDLPS tended to be lower grade than non-ossified DDLPS (mean grade: 1.88 and 2.15, respectively). Ossification in DDLPS was associated significantly with shorter local recurrence-free survival by multivariate analysis (P = 0.02347), but metaplastic-appearing ossification tended to be associated with longer overall survival (P = 0.1400). CONCLUSIONS: The bone tissue formed in DDLPS was mainly neoplastic regardless of its morphology and maturity, which highlighted the osteogenic differentiation of the tumour cells. DDLPS patients with osteogenic differentiation tended to suffer from earlier local recurrences, which did not necessarily lead to poor life outcomes.

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

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

Single metastasis of myxoid liposarcoma from the thigh to thyroid gland: a case report.

BACKGROUND: Thyroid metastasis of soft tissue sarcoma is very rare, and the diagnosis is especially difficult when only a single lesion is present. CASE PRESENTATION: A 50-year-old man was diagnosed with myxoid liposarcoma of the right thigh and treated with wide resection. Two and a half years after the surgery, a growing low-density area was incidentally observed in the right lobe of his thyroid gland on follow-up chest computed tomography. Fine needle aspiration biopsy was performed twice, and the thyroid mass was suspected of being a sarcoma metastasis. He was treated by hemithyroidectomy, and the lesion was pathologically confirmed as a metastasis of myxoid liposarcoma. CONCLUSION: We experienced single thyroid gland metastasis in patients with myxoid liposarcoma in whom a growing mass is observed in the thyroid gland after radical surgery of the primary site.

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.

Antitumor effects of 4-methylumbelliferone, a hyaluronan synthesis inhibitor, on malignant peripheral nerve sheath tumor.

Hyaluronan (HA) has been shown to play important roles in the growth, invasion and metastasis of malignant tumors. Our previous study showing that high HA expression in malignant peripheral nerve sheath tumors (MPNST) is predictive of poor patient prognosis, prompted us to speculate that inhibition of HA synthesis in MPNST might suppress the tumorigenicity. The aim of our study was to investigate the antitumor effects of 4-methylumbelliferone (MU), an HA synthesis inhibitor, on human MPNST cells and tissues. The effects of MU on HA accumulation and tumorigenicity in MPNST cells were analyzed in the presence or absence of MU in an in vitro as well as in vivo xenograft model using human MPNST cell lines, sNF96.2 (primary recurrent) and sNF02.2 (metastatic). MU significantly inhibited cell proliferation, migration and invasion in both MPNST cell lines. HA binding protein (HABP) staining, particle exclusion assay and quantification of HA revealed that MU significantly decreased HA accumulation in the cytoplasms and pericellular matrices in both MPNST cell lines. The expression levels of HA synthase2 (HAS2) and HA synthase3 (HAS3) mRNA were downregulated after treatment with MU. MU induced apoptosis of sNF96.2 cells, but not sNF02.2 cells. MU administration significantly inhibited the tumor growth of sNF96.2 cells in the mouse xenograft model. To the best of our knowledge, our study demonstrates for the first time the antitumor effects of MU on human MPNST mediated by inhibition of HA synthesis. Our results suggest that MU may be a promising agent with novel antitumor mechanisms for MPNST.

MR elastography of the liver at 3.0 T in diagnosing liver fibrosis grades; preliminary clinical experience.

OBJECTIVES: To clarify the usefulness of 3.0-T MR elastography (MRE) in diagnosing the histological grades of liver fibrosis using preliminary clinical data. MATERIALS AND METHODS: Between November 2012 and March 2014, MRE was applied to all patients who underwent liver MR study at a 3.0-T clinical unit. Among them, those who had pathological evaluation of liver tissue within 3 months from MR examinations were retrospectively recruited, and the liver stiffness measured by MRE was correlated with histological results. Institutional review board approved this study, waiving informed consent. RESULTS: There were 70 patients who met the inclusion criteria. Liver stiffness showed significant correlation with the pathological grades of liver fibrosis (rho = 0.89, p < 0.0001, Spearman's rank correlation). Areas under the receiver operating characteristic curve were 0.93, 0.95, 0.99 and 0.95 for fibrosis score greater than or equal to F1, F2, F3 and F4, with cut-off values of 3.13, 3.85, 4.28 and 5.38 kPa, respectively. Multivariate analysis suggested that grades of necroinflammation also affected liver stiffness, but to a significantly lesser degree as compared to fibrosis. CONCLUSIONS: 3.0-T clinical MRE was suggested to be sufficiently useful in assessing the grades of liver fibrosis. KEY POINTS: MR elastography may help clinicians assess patients with chronic liver diseases. Usefulness of 3.0-T MR elastography has rarely been reported. Measured liver stiffness correlated well with the histological grades of liver fibrosis. Measured liver stiffness was also affected by necroinflammation, but to a lesser degree. 3.0-T MRE could be a non-invasive alternative to liver biopsy.

Which system is better to predict prognosis of patients with hepatocellular carcinoma treated by transcatheter arterial chemoembolization as initial therapy? Comparison between CLIP and JIS in a Japanese population.

Background There has been no consensus as to which system, either the Cancer of the Liver Italian Program (CLIP) or the Japan Integrated Staging (JIS) system, is suitable to predict the prognosis of hepatocellular carcinoma (HCC) patients who underwent transcatheter arterial chemoembolization (TACE) as initial therapy. Purpose To retrospectively compare the usefulness of CLIP and JIS in predicting and stratifying the prognosis of HCC patients treated by TACE. Material and Methods Between 1995 and 2005, consecutive 728 patients with untreated HCC who underwent TACE in our institute were selected for this study. The survival rate and its prognostic factors were assessed by multivariate analysis. Patients were stratified according to the two systems, and their survival rates between the scores were compared. Results The mean follow-up period was 1689 days. The 1-year, 3-year, 5-year, and 10-year survival rates were 83.1%, 55.1%, 34.7%, and 12.8%, respectively. Both systems stratified the prognosis of patients well, but was slightly better in CLIP as compared to in JIS. As for multivariate factor analysis, less severe Child-Pugh classification ( P < 0.001), simple tumor morphology ( P < 0.001), absence of portal vein invasion ( P < 0.001), and lower alpha-fetoprotein (AFP) level ( P < 0.001) were suggested to be independent indicators for favorable survival rate. All of these independent factors were included in CLIP, whereas JIS lacked AFP level. Furthermore, the likelihood χ2-test value was higher, and the Akaike information criterion value was lower for CLIP than for JIS. Conclusion CLIP is more suitable than JIS for predicting prognosis of patients with HCC who would undergo TACE in a Japanese population.

Inhibition of hyaluronan synthesis alters sulfated glycosaminoglycans deposition during chondrogenic differentiation in ATDC5 cells.

In chondrogenic differentiation, expression and collaboration of specific molecules, such as aggrecan and type II collagen, in extracellular matrix (ECM) are crucial. However, few studies have clarified the roles of hyaluronan (HA) in proteoglycan aggregation during chondrogenic differentiation. We assessed the roles of HA in sulfated glycosaminoglycans deposition during chondrogenic differentiation by means of 4-methylumbelliferone (4-MU), an HA synthase inhibitor, using ATDC5 cells. ATDC5 cells were treated with 0.5 mM 4-MU for 7 or 21 days after induction of chondrogenic differentiation with insulin. Depositions of sulfated glycosaminoglycans were evaluated with Alcian blue staining. mRNA expression of ECM molecules was determined using real-time RT-PCR. The deposition of aggrecan and versican was investigated with immunohistochemical staining using specific antibodies. Effects of 4-MU on HA concentrations were analyzed by HA binding assay. 4-MU suppressed the positivity of Alcian blue staining, although this delay was reversible. Interestingly, stronger positivity of Alcian blue staining was observed at day 21 in cultures with 4-MU discontinuation than in the control. 4-MU significantly increased the mRNA expression of aggrecan, versican, and type II collagen, which was consistent with increased deposition of aggrecan and versican. The HA concentration in ECM and cell-associated region was significantly suppressed with 4-MU treatment. We conclude that the inhibition of HA synthesis slows sulfated glycosaminoglycans deposition during chondrogenic differentiation despite the increased deposition of other ECM molecules. Transient starvation of HA with 4-MU accelerates chondrogenic ECM formation, suggesting its potential to stimulate chondrogenic differentiation with adequate use.

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

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