Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European organisation for research and treatment of cancer-soft tissue and bone sarcoma group (EORTC study 62043).

PURPOSE Given the importance of angiogenesis in soft tissue sarcoma (STS), pazopanib, an oral angiogenesis inhibitor that targets vascular endothelial growth factor receptor and platelet-derived growth factor receptor, was explored in patients with advanced STS. PATIENTS AND METHODS Patients with intermediate- or high-grade advanced STS who were ineligible for chemotherapy or who had received no more than two prior cytotoxic agents for advanced disease, who had documented progression, who had adequate performance status, and who had good organ function were eligible. Pazopanib 800 mg was given daily. The primary end point was progression-free rate at 12 weeks (PFR(12 weeks)). Secondary end points were response, safety, and overall survival. Four different strata were studied: adipocytic STS, leiomyosarcomas, synovial sarcomas, and other STS types. A Simon two-stage design was applied (P1 = 40%; P0 = 20%; alpha = beta = .1) for each stratum. Results One hundred forty-two patients were enrolled. The adipocytic STS stratum was closed after the first stage, given insufficient activity (PFR(12 weeks), five [26%] of19). PFR(12 weeks) was 18 (44%) of 41 patients in the leiomyosarcoma cohort, 18 (49%) of 37 in the synovial sarcomas, and 16 (39%) of 41 in the other STS types. Compared with historical controls who were treated with second-line chemotherapy, progression-free and overall survivals were prolonged in the three cohorts in which the primary end point was reached. The most frequent drug-related toxicities were hypertension, fatigue, hypopigmentation, and nausea. Other toxicities included liver enzyme elevations, myelosuppression, and proteinuria, all of which were mostly grades 1 to 2. The most frequent grades 3 to 4 toxicities were hyperbilirubinemia (6.3%), hypertension (7.7%), and fatigue (7.7%). CONCLUSION Pazopanib is well tolerated in patients with relapsed, advanced STS and demonstrates interesting activity that warrants additional study in patients with leiomyosarcomas, synovial sarcomas, and other STS types.

Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: a European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study.

PURPOSE: Single-agent doxorubicin remains the standard treatment for advanced soft tissue sarcomas. Combining doxorubicin with standard-dose ifosfamide has not been shown to improve survival and is associated with a significantly increased toxicity; it is not known whether higher dose single-agent ifosfamide is superior to doxorubicin. PATIENTS AND METHODS: This randomized prospective multicenter phase III trial was designed to compare progression-free survival of patients with advanced soft tissue sarcoma receiving either regimen of standard doxorubicin 75 mg/m2 every 21 days, ifosfamide 9 g/m2 over 3 days continuous infusion, or ifosfamide 3 g/m2 per day in 3 hours over 3 days. The primary end point was progression-free survival. Secondary end points included overall survival, response rate, and toxicity. RESULTS: The study included 326 patients. Grade 4 leukopenia, neutropenia, febrile neutropenia, and encephalopathy were more frequent in the ifosfamide arms. Progression-free survival, overall survival, and response rates were not significantly different between the three arms. An independent data monitoring committee reviewed the interim data and recommended early closure of the trial for futility (ie, no significant difference would be shown). CONCLUSION: Single-agent doxorubicin remains the treatment of choice for patients with advanced soft tissue sarcoma.

Her-2 oncogene amplification, chromosome 17 and DNA ploidy status in synovial sarcoma.

The treatment options for synovial sarcoma (SS) are very limited, though this type of sarcoma seems to be more heterogeneous than it has been traditionally considered. The present study investigates the Her-2 oncogene status of 20 cases of SS, to determine whether Her-2 amplification can be considered as a prognostic factor. Her-2 oncogene amplification was determined on smears (frozen material was used from our tumor bank in each case), using fluorescence in situ hybridization technique (dual color FISH with centromeric probe for chromosome 17 and specific probe for Her-2 oncogene). Moreover, protein expression was assessed by immunohistochemistry, and DNA ploidy status was measured using image analysis. We had 5 biphasic and 15 monophasic SSs, patients' age ranged from 13 to 68 years (mean, 39.8 years). Tumor size was larger than 5 cm in each case. Follow-up time ranged from 6 to 78 months (mean, 38.5 months). For statistical analysis the chi-square test was used. Her-2 oncogene amplification was found in three cases (15.0%) of 20 SSs. These cases proved to be 2+ positive by immunohistochemistry, but massive amplification, characteristic of a subset of breast carcinomas, was not observed. Her-2 oncogene amplification was significantly associated with a lower risk of developing metastasis (P<0.05) (none of the 3 amplified cases had metastases), while no association was found with recurrence. Six cases proved to be aneuploid and 14 were diploid, but no association was found between Her-2 amplification status and ploidy, and between ploidy status and metastasis or recurrence. Our results emphasize and confirm that Her-2 oncogene amplification is a rare event in SS, but the small subset of SS with Her-2 amplification has a better overall prognosis. Furthermore, this may open a theoretically new treatment possibility with Trastuzumab for Her-2-amplified cases of SS.

Application of curve fitting in thin-layer chromatography-flame ionization detection analysis of the carbohydrate fraction in marine mucilage and marine snow samples from Italian seas.

This paper presents a thin-layer chromatographic-flame ionization detection (TLC-FID) procedure to characterize the carbohydrate fraction of marine mucilage and marine snow samples from the Italian Seas. The identification of the different carbohydrate subfractions is supported by the application of a deconvolution procedure based on a new mathematical function for describing chromatographic peaks and enhancing their resolution. The joint-approach TLC-FID analysis and deconvolution procedure allows for the characterization of the carbohydrate fraction of the marine samples in a single step without using the different derivatization procedures requested by the most common gas chromatography and high-performance liquid chromatographic methods for carbohydrate analysis. In fact, the results obtained by the TLC-FID procedure show that different neutral, uronic acid, and aminosugar subfractions can be present simultaneously in these samples. Moreover, the results support some hypotheses about the causes of the presence of mucilages in the Italian Seas.

Diagnosis of soft tissue tumors by fine-needle aspiration with combined cytopathology and ancillary techniques.

The diagnosis of mesenchymal neoplasm by fine-needle aspiration biopsy (FNAB) has presented a diagnostic challenge. Most reports claim an accuracy approaching 95%, but while they distinguish benign and malignant lesions, the most problematic group, the intermediary malignant group, is omitted. The purpose of this study was to determine whether rapid cytologic diagnosis of soft-tissue tumors could guide surgeons in therapeutic decisions without the need for a tissue biopsy. Ninety-four FNA cytologic specimens were examined by the National Soft Tissue Consortium of Hungary and compared with the corresponding histology. Ordinary lipomas were excluded. Morphologic evaluation was supplemented by ancillary techniques such as fluorescence in situ hybridization (FISH), DNA cytometry, and immunocytochemistry. From a practical clinicopathological point of view, the cases were grouped in the following categories: 1) tumors with definitive diagnosis: a) high-grade malignant neoplasms (high-grade sarcomas, metastatic carcinomas, lymphoma), b) tumors with precise histogenetic origin by cytogenetics, c) benign tumors; 2) tumors of questionable nature. In the first group there were 74 tumors: 22 high-grade sarcomas, six metastatic carcinomas, one malignant lymphoma, 16 malignant tumors in which the precise histogenetic origin could be established by cytogenetic studies, and 29 benign soft-tissue tumors other than lipomas. In the second group there were 20 tumors comprising benign and malignant soft tissue tumors of low grade, wherein the precise nature of the neoplasm could not be established with confidence on cytologic study, even using ancillary techniques. FNAB of soft-tissue tumors combined with ancillary techniques should be considered a viable diagnostic technique for therapeutic protocols. Although the second group is fairly large, we have reliable, well-characterized categories which provide great freedom for preoperative and surgical treatment, thus providing the best chance for healing.

P53 Overexpression as an Indicator of Overall Survival and Response to Treatment in Osteosarcomas.

The p53 gene located at chromosome 17p13 is found to be altered (allelic loss or other mutation) in multiple human cancers, including osteosarcomas. The mutated gene produces a protein with a prolonged half-life thus rendering it detectable by conventional immunohistochemistry. We examined the correlation between p53 expression and clinical prognosis as well as response to therapy. Twenty-one patients with previously untreated and histologically verified highly malignant osteosarcoma were used for this study. Biopsy material taken both prior to the start of COSS 91 protocol and at the time of surgery (ten weeks later) was examined for alterations in p53 protein expression and drug resistance. Two patients who had strong (+++) p53 protein expression and three others who became positive during the chemotherapy had significantly worse prognosis (all of them died within one year) than those who showed no p53 expression both at biopsy and after chemotherapy (all 11 patients are alive, average follow-up time: 3.5 years). All patients who showed any kind of positive p53 protein expression on initial biopsy were non-responders to chemotherapy. In contrast, 69% (9 out of 13) of those who exhibited no p53 expression on initial biopsy were responders or intermediate responders to chemotherapy. We concluded that p53 expression may be a useful prognostic factor in osteosarcomas. The direct correlation between p53 positive expression and resistance to therapy can help in identifying patients who are in need of a more vigorous or different chemotherapeutical protocol.

Allelic Losses from Chromosome 17 in Human Osteosarcomas.

Genetic alterations of chromosome 17 have been reported to occur frequently both in human sporadic and familial malignancies. The present study was undertaken to explore the possible involvement of chromosome 17 genes including TP53 and the breast cancer susceptibility sarcoma. Fifteen patients were screened by polymerase chain reaction (PCR) for loss of heterozygosity (LOH) using four highly polymorphic markers. Loss of heterozygosity at the TP53 locus was detected in 40% (6/15) of informative cases while it was 14% (2/14) at the locus of thyroid hormone receptor alpha (THRA1), 21% (3/14) at the D17S855 locus intragenic to BRCA1 and 27% (4/15) at the D17S579 locus. In 53% of the cases studied at least one locus on chromosome 17 was affected by LOH. In our panel, the overall LOH frequency on 17p and 17q was observed to be 40% (6/15) and 27% (4/15), respectively. Comparison of LOH frequencies with clinical and prognostic features revealed significant correlation only with tumor recurrence. Our results confirm that the role of the TP53 tumor suppressor gene is important in the pathogenesis of sporadic osteosarcoma and suggest that 17q12-21 region abnormalities may be involved in the development and/or progression of this tumor.