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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., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Purpose: The aim of the present study was to determine whether metabolic reduction is capable of reflecting the histopathologic response and outcome after neoadjuvant chemotherapy in patients with high-grade sarcoma., Patients and Methods: Forty-two patients with histologically proven high-grade sarcoma underwent neoadjuvant chemotherapy followed by surgical resection. Quantitative F-18 fluorodeoxyglucose (F-18-FDG) positron emission tomography (PET)/computed tomography scans were acquired before and after the first cycle and after completion of neoadjuvant chemotherapy. Standardized uptake values (SUVs) and metabolic reduction rates were compared with histopathologic response, progression-free survival, and overall survival., Results: Baseline SUVmax was 10.9 ± 3.6 (range, 3.8-19.6). Therapeutic effect resulted in 10 patients (24%) with a satisfactory response and in 32 patients (76%) with an unsatisfactory response after completion of neoadjuvant chemotherapy. The SUV decreased to 7.8 ± 3.4 after the first cycle (t1) of chemotherapy and to 5.2 ± 3.4 after completion (t2) of chemotherapy. Histopathologic response and percentage SUV (t2) reduction rate were independent predictors of progression-free survival and overall survival in the multivariate analyses., Conclusion: Metabolic reduction after neoadjuvant chemotherapy evaluated by F-18 FDG PET or computed tomography can be used for stratification of the histopathologic response in patients with high-grade sarcoma.

Purpose: In the management of soft tissue sarcomas, perioperative radiation therapy has been used to reduce the risk of local recurrence after resection. However, a significance of postoperative high-dose rate brachytherapy (HDRBT) remains to be studied. Retrospective analysis was performed to elucidate the role of postoperative HDRBT., Methods and Materials: Twenty-five patients with 26 soft tissue sarcoma lesions underwent postoperative HDRBT using (192)Ir remote afterloader without external beam radiation therapy. Ninety-two percent of the lesions were Grade 2 or 3 malignancies, and 50% were resected with positive surgical margins. The remaining 50% had very close margins. Fourteen lesions were treated for local recurrences after previous resections. Applicators of HDRBT were placed during the operation to include only the tumor bed excluding surgical scars. Applied dose was mainly 36Gy/6 fractions/3 d b.i.d., Results: Five-year local recurrence-free survival was 78.2% in all the 26 lesions. Recurrences were not seen within the treated volume of HDRBT. Two groups were defined according to the marginal status and number of previous operations. Group 1 was the lesions with a positive margin and foregoing resections. The remaining lesions were classified as Group 2. Five-year local recurrence-free survival was 43.8% and 93.3% in Group 1 and Group 2, respectively with a statistically significant difference (p=0.004)., Conclusions: Postoperative HDRBT was effective in controlling local lesions; but in Group 1 lesions, addition of a wide field external beam radiation therapy seems to be necessary to improve the local control rate., (Copyright © 2010 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

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.

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.

We performed a global protein expression study on soft-tissue sarcoma in order to develop novel diagnostic biomarkers and allow molecular classification. 2-D difference gel electrophoresis was used to generate the global protein expression profiles of 80 soft-tissue sarcoma samples with seven different histological backgrounds. We found that 67 protein spots distinguished the subtypes of soft-tissue sarcoma. Hierarchical clustering with these 67 protein spots resulted in the grouping of all 80 sarcoma samples corresponding to the histological classification. We found that the expression pattern of tropomyosin isoforms was different in conventional and pleomorphic leiomyosarcomas. We also identified five proteins, including alpha-1-antitrypsin, alpha-actinin 1, HSP27, and elongation factor 2, that could differentiate between malignant fibrous histiocytomas and leiomyosarcomas in grade III into low-risk and high-risk groups, which differed significantly with respect to survival. These results establish proteomics as a powerful tool to develop novel biomarkers for diagnosis and molecular classification of soft-tissue sarcomas. Identification of proteins associated with survival in grade III sarcoma will allow delineation of a high-risk group that may benefit from adjuvant therapy and the exclusion of low-risk patients in whom additional therapies are unlikely to exhibit clinical benefit.

Background: Little is known about the expression of receptor tyrosine kinases in adult soft tissue sarcomas (STS). In the current study, the authors analyzed the expression of epidermal growth factor receptor (EGFR), ERBB2, and KIT in 281 patients with STS who were treated in a single institution. Verification of the presence of an association with prognosis was performed., Methods: The current study included 281 adult patients with STS of the extremity and trunk who were diagnosed and treated in the National Cancer Center, Tokyo. Expression was assessed using immunohistochemical stains for EGFR, ERBB2, and KIT on formalin-fixed, paraffin-embedded tissue sections by standard avidin-biotin peroxidase complex technique and EGFR detection system., Results: Positive staining of EGFR was observed in 168 of 281 (60%) patients. Positive staining was common in pleomorphic malignant fibrous histiocytomas (89%), myxofibrosarcomas (89%), synovial sarcomas (76%), malignant peripheral nerve sheath tumors (89%), and leiomyosarcomas (73%). It was less common in well differentiated liposarcomas (38%), fibrosarcomas (36%), and myxoid liposarcomas (6%). In contrast, positive staining of ERBB2 and KIT was very limited. Increased levels of EGFR were significantly associated with a decreased probability of overall survival (P = 0.01), although by univariate analysis; probability of overall survival at 5 years was 64% in patients with increased levels of EGFR and 79% in patients without such overexpression. The overexpression of EGFR was significantly associated with histologic grade (P < 0.001). Moreover, stratified log-rank test revealed that there is an interrelation between EGFR overexpression and histologic grade., Conclusions: EGFR overexpression was found to be a negative prognostic factor of adult STS, which is strongly associated with histologic grade. STS patients with EGFR overexpression may benefit from treatment with currently available biospecific inhibitors for EGFR., ((c) 2005 American Cancer Society.)

Doxorubicin and ifosfamide are the two most active agents used to treat soft tissue sarcomas. However, because of their overlapping side effects, concurrent administration to achieve optimal doses of each agent is difficult. We therefore conducted a Phase II trial to investigate the efficacy and feasibility of a novel alternating sequential chemotherapy regimen consisting of high dose ifosfamide and doxorubicin/cyclophosphamide in advanced adult non-small round cell soft tissue sarcomas. Adult patients with non-small round cell soft tissue sarcomas were enrolled. The treatment consisted of four sequential courses of chemotherapy that was planned for every 3 weeks. Cycles 1 and 3 consisted of ifosfamide (14 g/m(2)), and cycles 2 and 4 consisted of doxorubicin (60 mg/m(2)) and cyclophosphamide (1200 mg/m(2)). Forty-two patients (median age 47 years) were enrolled. Of the 36 assessable patients, 1 complete response and 16 partial responses were observed, for a response rate of 47.2%. Responses were observed in 57% of patients who had received no previous chemotherapy and 13% of those who had previously undergone chemotherapy. Grade 3-4 neutropenia was observed during 70% of all cycles. Sequential administration of high-dose ifosfamide and doxorubicin/cyclophosphamide has promising activity with manageable side effects in patients with advanced adult non-small round cell soft tissue sarcomas.

Several histological grading systems have been proposed and found as strong indicators of outcome in soft-tissue sarcomas. However, a putative independent prognostic influence of recently developed biological and molecular markers remains to be established. This study investigated the prognostic relevance of a histological grading system based on the assessment of proliferative activity in adult soft-tissue sarcomas of the extremities, trunk, head, and neck. Tissue blocks from 95 of 108 patients without distant metastases or regional lymph node involvement were available. Immunohistochemical staining for MIB-1 and p53 was done on paraffin-embedded sections. All clinicopathologic and immunohistochemical variables and patient survival were assessed using univariate and multivariate analyses. Variables included histological grading based on the modified Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) system using the MIB-1 score for the estimation of the proliferative potential of the tumors. Variables associated with overall survival were tumor site in the trunk, head and neck, mitosis count, necrosis, MIB-1 score, FNCLCC grade, modified FNCLCC grade using the MIB-1 score, and stage (all p values <0.05). In multivariate analysis, the modified grade proved to be the most significant predictor of shortened overall survival, in addition to tumor site in the trunk, head, and neck. Overexpression of p53 did not correlate with increased risk of tumor mortality. Using MIB-1 to replace mitosis counts in the FNCLCC system improves grading of soft-tissue sarcomas, and this in conjunction with other important factors appear to be more accurate prognostic factors for survival, and for patient selection in investigational adjuvant treatment trials., (Copyright 2000 S. Karger AG, Basel)

Primary and secondary malignant intravascular tumours of the pulmonary artery occur infrequently and the diagnosis is usually delayed as symptoms and findings from conventional examinations are non-specific. The case is presented of a patient with a pulmonary artery sarcoma, probably arising from ribs resected some years previously, in which intravascular ultrasound (IVUS) provided important diagnostic findings.

TNM classification of bone and soft tissue sarcomas was published by UICC in 1987. Histological grading (G) is an important factor in this classification, but the criteria of G categories are not so clear. In addition, lymph node metastasis is very rare in bone and soft tissue sarcoma. Therefore, prognostic factors are limited to T, M and G categories. Since correlation between the stage (UICC) and the survival rate was not found in patients with osteosarcoma, TNM classification (UICC) has not been used widely in the field of orthopedic oncology. The Musculoskeletal Tumor Committee of the Japanese Orthopaedic Association proposed another TNM classification of osteosarcoma based on multivariate analysis. T1 is less than 15 cm and T2 is 15 cm or larger in maximal diameter. N and M are same with the UICC criteria. Serum alkaline phosphatase level (A) is included in this classification in which A0 is less than the normal value x2.5, and A1 is the normal value x2.5 or more. G categories are separated into two groups according to the mitotic rate in a high power field (x200); G1 is assigned to the tumor with 0-9/1 HPF and G2 is assigned to those with 10 or more/1 HPF. Reclassification of osteosar-coma by this modified TNM system indicated that there was a correlation between the survival rate and the stage.

The therapeutic results of pulmonary resection for metastatic soft tissue sarcomas were analyzed. From 1970 to 1992, 23 patients (15 male and 8 female) underwent 40 pulmonary resections for metastatic soft tissue sarcomas. Nine (39%) patients had multiple thoracotomies for recurrences (range, 2-6). The 5-year actuarial overall survival was 32% (median, 28 months). Statistical analysis showed that age, gender, location of primary tumor, histology, site of pulmonary metastasis, tumor doubling time, or chemotherapy did not impact on survival. Significant prognostic factors associated with improved survival (p < 0.05) included a disease-free interval, and completeness and extent of the initial pulmonary resection. Patients with disease-free intervals > or = 12 months survived longer (5-year survival, 48.5%) than patients with disease-free intervals < 12 months (12%). Patients who could be rendered free of disease at their initial thoracotomy, without extended chest-wall resection, achieved a better outcome (5-year survival, 44%) than the others (5-year survival, 0%).

Background: Tumor suppressor gene p53, located on the short arm of chromosome 17, frequently mutates in various types of cancers and plays a critical role in the multiple stages of carcinogenesis. However, there is little information about the clinicopathologic significance of alterations of the p53 gene in soft tissue sarcomas (STS)., Methods: Because it is known that nuclear accumulation of p53 protein correlates closely with the presence of mutations in the p53 gene, immunohistochemical detection of this protein was performed. A polyclonal antibody (RSP-53) raised against synthetic human p53 peptide was used to detect nuclear accumulation of the protein. Pathologic specimens of 96 patients with STS were collected from the surgical pathology files of the National Cancer Center Hospital and examined., Results: Nuclear accumulation of p53 protein was detected in 31 (32.3%) patients. The percentage of patients with a positive immunoreaction was high in patients with malignant schwannoma (100%), rhabdomyosarcoma (71.4%), and synovial sarcoma (50.0%), whereas it was low in patients with liposarcoma (13.6%) and 0% in those with fibrosarcoma. It was closely associated with the histologic grade of malignancy (grade 1, 12.0%; grade 2, 30.8%; grade 3, 44.4%) and the patient's age (younger than 40 years, 46.9%; 40 years of age or older, 25.0%). Both overall and metastasis-free survival rates were significantly lower for patients with a nuclear p53 immunoreaction than for those without it., Conclusions: The nuclear p53 immunoreaction is considered a marker of tumor aggressiveness and appears to be a useful prognostic factor for STS.

The purpose of this study was to investigate Tl-201 as a tumor scanning agent in patients with malignant soft tissue sarcomas and to establish the sensitivity of this type of scintigraphy concerning local recurrences or metastases that may remain clinically suspected. Seventy-eight patients with malignant soft tissue sarcomas and 22 with benign soft tissue tumors were studied. Of these 78 malignant soft tissue sarcomas patients, the sensitivity of Tl-201 (81.2%) was higher than that of Ga-67 (68.8%). Thirty-three out of 78 patients received a total of 95 consecutive scintigraphic follow-up examinations. Therapeutic effects was assessed by comparing the results of Tl-201 examinations with the clinical findings. Of these 33 patients, the therapeutic effects observed were as follows: complete remission 1, partial remission 8, progress of disease 1, and no remarkable change 23. Tl-201 scintigraphy has proved itself very useful not only in clinically detecting the malignant soft tissue sarcomas and in assessing therapeutic effects on these diseases, but also in assessing the follow-up patients with malignant soft tissue sarcomas.

Nineteen patients with soft tissue sarcoma were treated by a combination modality of hyperthermia and radiation or chemotherapy. There were 26 treatment sites. The size of the tumours ranged from 2.5 x 2 cm to 24 x 26 cm. Hyperthermic treatments were given twice a week, for a total of five to 14 sessions. Twenty-one tumours were treated by hyperthermia combined with radiotherapy, 2 Gy daily, five times a week, for a total of 40-78 Gy. Three tumours were treated by hyperthermia and arterial infusion of adriamycin, 100-120 mg in five or six treatments. For the superficial tumours the complete response rate was 40 per cent, and for the deep-seated tumours 6.2 per cent. Among the 12 tumours with no response, nine in which the treatment was evaluated as effective histologically (necrosis of the tumour) and by X-ray CT findings (development of a prominent hypodensity area) were included. Six cases were studied to correlate the X-ray CT findings, angiography and histological findings before and after hyperthermic treatment. The data were also used to interpret the thermal curve. The increased hypodensity area was roughly proportional to the development of necrosis, but there was one case in which hypodensity was not correlated with the necrosis. On the contrary, even in the contrast-enhanced area around the tumour in which the presence of residual tumour was strongly suspected clinically, no tumour cells were visualized. Clinical evaluation of the effect by size of the tumour can be supplemented by CT findings and histology, but should be cautiously adopted.

Seventy-eight cases of adjuvant chemotherapy for primary soft tissue sarcoma including 51 cases of intra-arterial infusion chemotherapy were studied. The patients ranged in age from 1 to 92 years with a median age of 34 years. Thirty-nine patients were male and 39 were female. The seventy-eight cases were comprized of 17 rhabdomyosarcoma, 12 liposarcoma, 12 neurogenic sarcoma, 10 malignant fibrous histiocytoma, 8 leiomyosarcoma, 7 angiosarcoma, 8 others and 4 unclassified sarcomas. Fifty-one patients with soft tissue sarcoma of the extremities were treated by intra-arterial infusion chemotherapy with either VCQ (Vincristine and Carbazilquinone) or VCQ, A (Vincristine, Carbazilquinone and Adriamycin). Out of 42 patients with measurable lesions, 2 CR, 4 PR, 33 NC and 3 PD were obtained. Histological examinations demonstrated histological effect of GI 19, G IIa 11 and G IIb 7 by Ohboshi and Shimosato's criteria. Remarkable effects of treatment were noted in most rhabdomyosarcoma patients. After intra-arterial infusion chemotherapy, a variety of surgical procedures ranging from marginal resection and wide resection to radical amputation were employed in 44 patients. Local recurrence was 27% and distant metastasis developed in 47% of cases.