Efficacy and safety of porous hydroxyapatite/type 1 collagen composite implantation for bone regeneration: A randomized controlled study.

BACKGROUND: Porous hydroxyapatite/collagen composite (HAp/Col) is a bioresorbable bone substitute composed of nano-scale HAp and porcine type 1 collagen. In this study, the efficacy and safety were assessed in comparison to commercially available porous ß-tricalcium phosphate (ß-TCP). METHODS: Patients with bone defects caused by benign bone tumors, fractures, or harvesting of autografts were randomly allocated for implantation of porous HAp/Col (n = 63) or porous ß-TCP (n = 63). X-ray images were scored and used to evaluate the efficacy of the implantation until 24 weeks after surgery. Blood tests and observation of the surgical site were also performed to evaluate the safety of the implants. In total, 59 and 60 cases were analyzed in the porous HAp/Col and ß-TCP groups, respectively. RESULTS: At 18 and 24 weeks after surgery, the highest grade of bone regeneration was more frequent in the porous HAp/Col group than in the porous ß-TCP group (p = 0.0004 and 0.0254 respectively). Wilcoxon's rank sum test confirmed the superiority of porous HAp/Col from early time points onward (p = 0.0084, 4 w; p = 0.0037, 8 w; p = 0.0030, 12 w; p < 0.0001, 18 w; and p = 0.0316, 24 w). The incidence of adverse effects was higher in the porous HAp/Col group than in the ß-TCP group. However, no serious adverse events were reported and no cases needed to drop out of the clinical trial. CONCLUSIONS: The superiority of porous HAp/Col for bone regeneration in comparison to an established porous ß-TCP was confirmed. Although the incidence of side effects associated with the porous HAp/Col implant was higher than that in the ß-TCP group, no serious adverse events occurred that resulted in rejection of the implants.

Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Pazopanib, a multitargeted tyrosine kinase inhibitor, has single-agent activity in patients with advanced non-adipocytic soft-tissue sarcoma. We investigated the effect of pazopanib on progression-free survival in patients with metastatic non-adipocytic soft-tissue sarcoma after failure of standard chemotherapy. METHODS: This phase 3 study was done in 72 institutions, across 13 countries. Patients with angiogenesis inhibitor-naive, metastatic soft-tissue sarcoma, progressing despite previous standard chemotherapy, were randomly assigned by an interactive voice randomisation system in a 2:1 ratio in permuted blocks (with block sizes of six) to receive either pazopanib 800 mg once daily or placebo, with no subsequent cross-over. Patients, investigators who gave the treatment, those assessing outcomes, and those who did the analysis were masked to the allocation. The primary endpoint was progression-free survival. Efficacy analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00753688. FINDINGS: 372 patients were registered and 369 were randomly assigned to receive pazopanib (n=246) or placebo (n=123). Median progression-free survival was 4·6 months (95% CI 3·7-4·8) for pazopanib compared with 1·6 months (0·9-1·8) for placebo (hazard ratio [HR] 0·31, 95% CI 0·24-0·40; p<0·0001). Overall survival was 12·5 months (10·6-14·8) with pazopanib versus 10·7 months (8·7-12·8) with placebo (HR 0·86, 0·67-1·11; p=0·25). The most common adverse events were fatigue (60 in the placebo group [49%] vs 155 in the pazopanib group [65%]), diarrhoea (20 [16%] vs 138 [58%]), nausea (34 [28%] vs 129 [54%]), weight loss (25 [20%] vs 115 [48%]), and hypertension (8 [7%] vs 99 [41%]). The median relative dose intensity was 100% for placebo and 96% for pazopanib. INTERPRETATION: Pazopanib is a new treatment option for patients with metastatic non-adipocytic soft-tissue sarcoma after previous chemotherapy. FUNDING: GlaxoSmithKline.

Extraskeletal myxoid chondrosarcoma: a review of 23 patients treated at a single referral center with long-term follow-up.

BACKGROUND: Extraskeletal myxoid chondrosarcoma (EMC) is a rare soft tissue sarcoma. Although it has been regarded as a low-grade sarcoma unassociated with tumor-related death, a recent study has suggested an insidious nature with a high propensity for relapse during a long disease course. The aim of this study was to clarify the long-term clinical features of EMC treated at a single referral center using state-of-the-art techniques. METHODS: A retrospective review of 23 consecutive patients (10 males, 13 females; mean age 58 years) treated between 1979 and 2008 (mean follow-up; 109 months) was performed. RESULTS: Surgery for the primary tumor was performed in 22 patients, and 7 cases recurred locally due to inadequate resection. Eleven patients had metastatic disease, either at diagnosis (3) or developing later (8). The 5/10-year overall survival rates were 91/84 %, and the 5/10-year local recurrence-free and metastasis-free survival rates for patients with localized disease were 89/62 and 89/61 %, respectively. Larger tumor size (>10 cm) and metastases at diagnosis were significant negative prognostic factors. Four patients received ifosfamide-based chemotherapy with no objective response. There was no local recurrence in three patients who underwent R1 resection followed by adjuvant radiotherapy. Clinical palliation and retarded progression of the metastatic disease were achieved in three patients who underwent radiotherapy. CONCLUSIONS: EMC is indolent but has a high propensity for relapse over 5 years of follow-up. Definitive initial surgery and careful monitoring for a prolonged period are important. Radiotherapy seems beneficial in an adjuvant setting and as palliative therapy for metastatic disease.

Alveolar soft part sarcoma: a single-center 26-patient case series and review of the literature.

Background. Alveolar soft part sarcoma (ASPS) is a rare tumor, and little information is available regarding its clinical features and appropriate treatments. Methods. A retrospective review of 26 consecutive ASPS patients (12 male, 14 female; mean age of 27 years) treated at our institution over 30 years (mean followup; 71 months) was performed. Results. The primary tumor developed in the lower extremity (12), trunk (8), and upper extremity (6), with an average size of 7.2 cm (range, 2-14 cm). The AJCC stage at presentation was IIA (7), III (3), and IV (16). Surgical excision was performed in 20 patients (R0 18, R1 plus radiotherapy 2) without local recurrence. Six patients (stage IIA 3/7, stage III 3/3) later developed metastases after an average period of 28.7 months. The median survival of the 26 patients was 90 months, with overall 5/10-year survival rates of 64%/48%. AJCC stage and tumor size were significant prognostic factors. Significant palliation and slowing of metastasis progression were achieved with gamma knife radiotherapy. Nine patients receiving chemotherapy showed no objective response. Conclusions. ASPS is indolent but has a high propensity for metastasis. Early diagnosis and complete excision of the small primary tumor are essential in the treatment of ASPS.

Immunohistochemical analysis of MDM2 and CDK4 distinguishes low-grade osteosarcoma from benign mimics.

Parosteal osteosarcoma and low-grade central osteosarcoma are two types of low-grade osteosarcoma that show similar clinical behaviors, histological features, and genetic background (ie, amplified sequences of 12q13-15, including MDM2 and CDK4). Low-grade osteosarcoma is often confused with benign lesions, and ancillary techniques to enhance diagnostic accuracy have been awaited. This study explores the use of MDM2 and CDK4 immunohistochemistry for the histological diagnosis of low-grade osteosarcoma. We studied 23 cases of low-grade osteosarcoma from 21 patients (parosteal osteosarcoma (n=14), low-grade central osteosarcoma (n=9)) and 40 cases of benign histological mimics (myositis ossificans (n=11), fibrous dysplasia (n=14), osteochondroma (n=6), desmoplastic fibroma (n=1), florid reactive periostitis (n=4), Nora's lesion (n=3), and turret exostosis (n=1)). Low-grade osteosarcoma labeled for MDM2 in 16 cases (70%) and for CDK4 in 20 cases (87%). All low-grade osteosarcomas expressed one or both markers (100%), with 13 cases (57%) expressing both. Staining pattern was diffuse in most cases, and the majority expressed moderate or strong intensity for either antibody. MDM2/CDK4 immunostaining was shown irrespective of low-grade osteosarcoma histological subtype. In contrast, only 1 Nora's lesion out of the 40 miscellaneous benign processes showed immunoreactivity for MDM2 or CDK4. The combination of these two markers thus shows 100% sensitivity and 97.5% specificity for the diagnosis of low-grade osteosarcoma. MDM2 and CDK4 immunostains therefore reliably distinguish low-grade osteosarcoma from benign histological mimics, and their combination may serve as a useful adjunct in this difficult differential diagnosis.

Nucleophosmin as a candidate prognostic biomarker of Ewing's sarcoma revealed by proteomics.

PURPOSE: We aimed to identify novel prognostic biomarkers for Ewing's sarcoma by investigating the global protein expression profile of Ewing's sarcoma patients. EXPERIMENTAL DESIGN: We examined the proteomic profile of eight biopsy samples from Ewing's sarcoma patients using two-dimensional difference gel electrophoresis. Three patients were alive and continuously disease-free over 3 years after the initial diagnosis (good prognosis group) and five had died of the disease within 2 years of the initial diagnosis (poor prognosis group). RESULTS: The protein expression profiles produced using two-dimensional difference gel electrophoresis consisted of 2,364 protein spots, among which we identified 66 protein spots whose intensity showed >2-fold difference between the two patient groups. Mass spectrometric protein identification showed that the 66 spots corresponded to 53 distinct gene products. Pathway analysis revealed that 31 of 53 proteins, including nucleophosmin, were significantly related to bone tissue neoplasms (P < 0.000001). The prognostic performance of nucleophosmin was evaluated immunohistochemically on an additional 34 Ewing's sarcoma cases. Univariate and multivariate analyses revealed that nucleophosmin expression significantly correlated with overall survival (P < 0.01). CONCLUSIONS: These results establish nucleophosmin as a candidate of independent prognostic marker for Ewing's sarcoma patients. Measuring nucleophosmin in biopsy samples before treatment may contribute to the effective management of Ewing's sarcoma.

Postoperative deep infection in tumor endoprosthesis reconstruction around the knee.

BACKGROUND: Although deep infection remains one of the most difficult complications to manage in the treatment of musculoskeletal tumor reconstructed with an endoprosthesis, limited information with respect to its incidence and risk factors has been reported. METHODS: This multicenter, retrospective, uncontrolled study reviewed the medical records of 82 patients who underwent reconstruction with an endoprosthesis or temporary spacer for bone-immature patients after resection of malignant bone tumor around the knee. Risk factors for deep infection and the impact of deep infection on prosthesis survival and oncological outcomes were analyzed. Deep infection was defined according to the Centers for Disease Control and Prevention (CDC) guidelines with minor modification. RESULTS: Deep infection occurred in 14 cases (17%), identified at a mean of 10.9 months (range <1 to 48 months) after initial surgery. Univariate analysis identified surface infection (P < 0.001) and skin necrosis (P < 0.001) as risk factors associated with deep infection. Conversely, tumor origin, chemotherapy, number of postoperative antibiotics, and length of bone resection were not associated with infection. Subclass analysis in femur cases identified a correlation between infection and the extent of partial resection of the quadriceps muscle (P = 0.04). In the multivariate analysis, surface infection represented an independent risk factor for deep infection (P = 0.03). Deep infection was a risk for endoprosthesis survival (P = 0.003) but did not affect the oncological outcome. CONCLUSIONS: A strong correlation between the condition of soft tissue and establishment of deep infection is suggested in this study. Although practical options for preventing deep infection seem limited, the present data allow a form of perioperative evaluation for patients with a higher risk of deep infection.

Pfetin as a prognostic biomarker of gastrointestinal stromal tumors revealed by proteomics.

PURPOSE: We aimed to develop prognostic biomarkers for gastrointestinal stromal tumors (GIST) using a proteomic approach. EXPERIMENTAL DESIGN: We examined the proteomic profile of GISTs using two-dimensional difference gel electrophoresis. The prognostic performance of biomarker candidates was examined using a large-scale sample set and specific antibodies. RESULTS: We identified 43 protein spots whose intensity was statistically different between GISTs with good and poor prognosis. Mass spectrometric protein identification showed that the 43 spots corresponded to 25 distinct gene products. Eight of the 43 spots derived from pfetin, a potassium channel protein, and four of the eight pfetin spots had a high discriminative power between the two groups. Western blotting and real-time PCR showed that pfetin expression and tumor metastasis were inversely related. The prognostic performance of pfetin was also examined by immunohistochemistry on 210 GIST cases. The 5-year metastasis-free survival rate was 93.9% and 36.2% for patients with pfetin-positive and pfetin-negative tumors, respectively (P < 0.0001). Univariate and multivariate analyses revealed that pfetin expression was a powerful prognostic factor among the clinicopathologic variables examined, including risk classification and c-kit- or platelet-derived growth factor receptor A mutation status. CONCLUSIONS: These results establish pfetin as a powerful prognostic marker for GISTs and may provide novel therapeutic strategies to prevent metastasis of GIST.

Multiinstitutional phase II study of neoadjuvant chemotherapy for osteosarcoma (NECO study) in Japan: NECO-93J and NECO-95J.

BACKGROUND: Osteosarcoma is the most frequent primary malignant bone tumor. In Europe and the United States, its prognosis has been greatly improved by the use of multimodal treatment, including preoperative and postoperative chemotherapy as well as surgery. In Japan, however, only a few clinical studies on osteosarcoma have been carried out. METHODS: To evaluate the efficacy of neoadjuvant chemotherapy on nonmetastatic, operable osteosarcoma arising in the extremities, a prospective multi-institutional phase II trial, the Neoadjuvant Chemotherapy for Osteosarcoma (NECO) study, was conducted. Preoperative chemotherapy included high-dose methotrexate (HD-MTX), cisplatin (CDDP), and adriamycin (ADR). If the induction therapy was assessed as not effective, high-dose ifosfamide (IFO) was added to the chemotherapy regimen. A total of 124 patients were enrolled in this trial, and ultimately 113 patients were eligible. RESULTS: The 5-year overall survival (OAS) and event-free survival (EFS) rates in the NECO study were 77.9% and 65.5%, respectively. A good histological response to the induction chemotherapy resulted in favorable OAS (78.7%). The patients assessed as poor histological responders with progressive disease after the induction chemotherapy exhibited comparable outcomes (OAS 89.5%, EFS 68.2%). There were no significant differences between the OAS and EFS rates of the patients in terms of response to preoperative chemotherapy. CONCLUSIONS: We analyzed the results of the intensive neoadjuvant chemotherapy and the effects of adding IFO on patients with osteosarcoma in Japan. The results suggest efficacy of the high-dose IFO addition to the standard three-drug chemotherapy regimen. However, a randomized clinical study is needed to establish the true impact of IFO on patients with osteosarcoma.

Association of a missense single nucleotide polymorphism, Cys1367Arg of the WRN gene, with the risk of bone and soft tissue sarcomas in Japan.

Bone and soft tissue sarcomas (BSTSs) are rare malignant tumors of mesenchymal origin. Although BSTSs frequently occur in some hereditary cancer syndromes with germline mutations of DNA repair genes, genetic factors responsible for sporadic cases have not been determined. In the present study we undertook a case-control study and analyzed possible associations between the susceptibility to BSTS and the single nucleotide polymorphisms (SNPs) in DNA repair genes. Genomic DNAs extracted from case and control peripheral blood leukocytes were genotyped by pyrosequencing. For candidate polymorphisms, we chose 50 non-synonymous missense SNPs, which we have previously been identified by resequencing 36 DNA repair genes among the Japanese population. In the first screening, we analyzed 240 cases and 685 controls and selected six SNPs at the significance level of P < 0.1 (Fisher's exact test). The six SNPs were further analyzed in the second genotyping on an additional set of 304 cases and 834 controls. In the joint analysis (the first and second genotyping combined) of 544 cases and 1378 controls, Cys1367Arg of the WRN gene was found to be a protective factor of BSTS (odds ratio = 0.66, 95% confidence interval = 0.49-0.88, P = 0.005). An exploratory subgroup analysis without multiple comparison adjustment suggested that the WRN-Cys1367Arg SNP is associated with soft tissue sarcomas, sarcomas with reciprocal chromosomal translocations and malignant fibrous histiocytoma.

Prognostic implications of glucose transporter protein-1 (glut-1) overexpression in bone and soft-tissue sarcomas.

BACKGROUND: The glucose transporter protein 1 (Glut-1) overexpression is associated with poor overall survival (OS) in various malignant tumors. The aim of this study was to investigate prognostic significance of Glut-1 overexpression in patients with bone and soft-tissue sarcomas. METHODS: A total of 67 patients (mean age, 43 years; range, 8-79 years) with bone and soft tissue sarcomas were analyzed. Pathologic confirmation was observed from surgical specimens in all patients. Pathologic variables including tumor differentiation, necrosis, mitotic index, MIB-1 (Ki-67) grade and Glut-1 expression were assessed. Clinical characteristics and pathologic variables were determined by Kaplan-Meyer curve of OS after treatment. RESULTS: Glut-1 overexpression was found in 56 patients (83%). The patients with Glut-1 overexpression showed significantly poor OS compared with those without Glut-1 overexpression (P = 0.029). The presence of metastasis, treatment without surgical resection, tumor differentiation, necrosis, mitotic index and MIB-1 grade were also significantly negative prognostic factors. The presence of metastasis was independently associated with poor OS (P = 0.031). CONCLUSIONS: Assessment of Glut-1 expression prior to treatment has a predictive potential effect in patients with bone and soft-tissue sarcomas.

Primary bone lymphoma: a new and detailed characterization of 28 patients in a single-institution study.

BACKGROUND: The incidence of primary bone lymphoma (PBL) is so rare that many of its aspects remain unknown. A number of studies have been reported from Western countries, but only a few reports are available from Asia. METHODS: We retrospectively analyzed 28 consecutive patients diagnosed with PBL initially treated at our hospital between 1995 and 2004. All patients underwent chemotherapy with half receiving radiotherapy as their initial treatment. A log-rank test was used in a univariate analysis to identify factors affecting overall survival. RESULTS: Fifteen (54%) patients were male and 13 (46%) female with a median age of 47 (range: 5-81). Although 19 (68%) patients had diffuse large B-cell lymphoma (DLBCL), other histopathological subtypes (three B-lymphoblastic lymphoma, two anaplastic large cell lymphoma, two indolent B-cell lymphoma, one NK/T-cell lymphoma (NTCL) and one Hodgkin lymphoma) were also included. The pelvis was the most frequently involved site (54%). While 68% of patients had stage IV disease, none of them showed bone marrow involvement at their initial diagnosis. Despite 61% high intermediate-risk and high-risk patients based on the International Prognostic Index, the estimated 3-year overall and progression-free survival rates were 84% and 77%, respectively. Only 'histopathological subtype (immunoblastic variant of DLBCL or NTCL versus others)' and 'response to initial treatment (progression versus remission)' were factors significantly affecting overall survival. CONCLUSIONS: Although the total number of patients was relatively small, the detailed clinical data analyses presented here revealed several new characteristics of PBL and some aspects that may be unique to Japanese patients.

Cyclooxygenase-2 overexpression associated with a poor prognosis in chondrosarcomas.

Recent studies have shown increased levels of cyclooxygenase (COX)-2 in various human malignancies, including some bone and soft tissue tumors, but little is known about the presence of COX-2 in chondrosarcomas. We performed immunohistochemical staining for COX-2 in 74 chondrosarcomas and compared the staining results with the characteristics and outcome of the patients. Thirty-seven men and 37 women between the ages of 14 and 81 years (median, 50 years) participated in the study. The tumors were located in the axial skeleton in 47 cases and in the long bones in 27 cases. The largest diameters of the tumors ranged from 2.7 to 32 cm (median, 8.0 cm). The immunohistochemistry findings revealed the overexpression of COX-2 in 16 (22%) of the 74 patients. Thirteen (41%) of 32 grade 2 and 2 (67%) of 3 grade 3 chondrosarcomas showed overexpression for COX-2, whereas only 1 (3%) of 39 grade 1 chondrosarcomas showed overexpression. Overexpression of COX-2 was significantly associated with histologic grade (P < .001) and a decreased disease-specific survival (P < .001). These findings suggest that COX-2 overexpression in chondrosarcoma is a negative prognostic factor that may be strongly associated with histologic grade.

Bilateral adrenal gland metastasis from malignant fibrous histiocytoma: value of [F-18]FDG PET-CT for diagnosis of occult metastases.

The vast majority of soft tissue sarcomas metastasize initially to the lungs. We report a 71-year-old woman with malignant fibrous histiocytoma of the right buttock and thigh that metastasized to the bilateral adrenal glands without development of pulmonary metastasis. Whole-body [F-18]FDG PET-CT showed abnormal tracer uptakes in the bilateral adrenal glands in addition to high accumulation in the primary soft tissue tumors. CT-guided needle biopsy revealed that both of the adrenal lesions were metastatic malignant fibrous histiocytoma. There was no pulmonary or other visceral metastasis. To the authors' knowledge, this is the first report of malignant fibrous histiocytoma metastatic to the bilateral adrenal glands without development of pulmonary metastases. This case illustrates the excellence of [F-18]FDG PET-CT scan for diagnosis of occult metastases from soft tissue sarcomas.

Establishment of human osteosarcoma cell lines with high metastatic potential to lungs and their utilities for therapeutic studies on metastatic osteosarcoma.

Relevant animal models for metastasis of osteosarcoma is needed to understand the biology and to develop the treatment modality of metastasis of human osteosarcoma. Therefore, we screened six human osteosarcoma cell lines for metastatic ability in nude mice. The HuO9 cell line was identified as being metastatic to the lung after intravenous injection. We established two sublines, HuO9-M112 and HuO9-M132, with high metastatic potential to the lung from the parental HuO9 cells by in vivo selection. There were no differences between these two sublines and the parental cells in the growth rate in vitro and the tumorigenicity after subcutaneous injection in nude mice, however, mice injected with the metastatic sublines became moribund earlier than mice injected with the parental HuO9 cells did. Thus, adriamycin (ADR) and recombinant interleukin-12 (IL-12) were administered to mice injected with the HuO9-M112 subline to suppress experimental lung metastases. Production of lung colonies was significantly suppressed and the prognoses of mice were significantly improved by both ADR and IL-12 treatments. These results indicate that both ADR and IL-12 are effective agents against pulmonary metastatic osteosarcoma, and that these sublines are useful for studies on the biological behavior and treatment of pulmonary metastatic osteosarcoma.

Establishment and characterization of a biphasic synovial sarcoma cell line, SYO-1.

We describe here the establishment of a new synovial sarcoma cell line, SYO-1, derived from a biphasic synovial sarcoma that developed in the groin of a 19-year-old female. The cell line was maintained for more than 70 passages (more than 24 months) in vitro. The SYO-1 cells in monolayer culture exhibited a spindle shape without conspicuous pleomorphism. Immunohistochemically, the cells were positive for vimentin, type IV collagen, S-100, mdm2, bcl-2, c-Met and c-Kit. Tumors developed by their implantation in nude mice histologically showed biphasic features that were composed of areas of fascicles of spindle cells and areas of compact proliferation of polygonal to ovoid cells, which occasionally formed epithelial plaque and expressed cytokeratin and EMA. SYO-1 cells harbored the characteristic t(X;18)(p11.2;q11.2) translocation by chromosome analysis and SYT-SSX2 chimeric transcript by RT-PCR. The SYO-1 cells, the first characterized cell line derived from biphasic synovial sarcoma retaining the characteristic genetic and phenotypic features of the tumor, will be useful for various investigations on synovial sarcoma, especially for its epithelial differentiation.

Sclerosing perineurioma: a clinicopathological study of five cases and diagnostic utility of immunohistochemical staining for GLUT1.

We reviewed five cases of sclerosing perineurial tumor of the hand. Four patients were male and one was female with ages ranging from 11 years to 49 years (mean 26 years). The predominant reason for consultation at the outpatient clinic was a slowly growing painless mass. The sites of involvement were the thumb in two cases, and the ring finger, middle finger and palm in one case each. The lesions were hard and firm, well-circumscribed white masses with a fibrous consistency ranging from 1.2 cm to 4.0 cm (mean 2.5 cm) in maximum dimension. Microscopically, all the tumors were composed of thick collagen and variable numbers of small, epithelioid cells exhibiting corded, trabecular and whorled growth patterns. Electron microscopy showed long cytoplasmic processes with a discontinuous basal lamina and occasional pinocytotic vesicles in the tumor cells. Immunohistochemically, most of the tumor cells were positive for epithelial membrane antigen, vimentin, collagen type IV and CD10, but not for S-100 protein, CD34, desmin and cytokeratin. We also observed that the tumor cells were positive for the human erythrocyte glucose transporter (GLUT1) antigen, suggesting that GLUT1 may be a useful marker for the identification of sclerosing perineurioma.