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Purpose: To describe the pathologic characteristics and prognostic factors of primary breast sarcomas (PBSs). Patients and Methods: We reviewed the clinical records and pathologic slides of 83 women with PBS treated in our institution between 1954 and 1991, with a median follow-up of 7.8 years. The majority of patients had undergone surgical treatment. Results: The main histologic type was malignant fibrohistiocytoma (n = 57). For the whole population, the 10-year overall survival (OS) and disease-free survival (DFS) rates were 62% and 50%, respectively. For Fédération Nationale des Centres de Lutte Contre le Cancer grade 1, 2, and 3 tumors, the 10-year OS and DFS rates were 82% and 61%, 62% and 51%, and 36% and 25%, respectively (P = .00007 and .004, respectively). For tumors measuring less than 5 cm, 5 to 10 cm, and more than 10 cm, the 10-year OS and DFS rates were 76% and 66%, 68% and 55%, and 28% and 15%, respectively (P = .002 and .009, respectively). In the multivariate analysis, the tumor size and histologic grade were correlated with the 10-year DFS rate (P = .04 and .01, respectively), but only the histologic grade was correlated with OS (P = .01). Angiosarcoma was the only histologic type significantly associated with a poorer outcome in the multivariate analysis. Conclusion: PBSs have the same clinical history and prognostic factors as sarcomas arising at other sites. Therefore, it is legitimate to use a similar treatment strategy for PBS as for other sarcomas.

PURPOSE The study investigated the therapeutic effects of a combination of Navelbine (vinorelbine or 5'noranhydrovinblastine; Pierre Fabre Médicament, Boulogne, France) and doxorubicin in women who had received no prior chemotherapy for locally advanced or metastatic breast cancer. PATIENTS AND METHODS Ninety-seven patients with progressive and assessable advanced or metastatic breast cancer who had received no prior chemotherapy except in an adjuvant setting were entered onto the study. Eighty-nine patients were assessable for toxicity and response by World Health Organization (WHO) criteria; the other eight patients were excluded because they did not meet entry criteria or because of protocol violations. Navelbine was administered at 25 mg/m2 by 30-minute intravenous (IV) infusion on days 1 and 8, and doxorubicin at 50 mg/m2 by slow IV infusion on day 1, with each course repeated at 3-week intervals. Patients were treated for a maximum of 11 cycles or until progression or major toxicity. RESULTS Objective responses were observed in 66 of 89 assessable patients (74%; 95% confidence interval, 63% to 85%). There were nineteen (21%) complete responses (CRs) and 47 (53%) partial responses (PRs). In addition, 20 patients (22.5%) had stable disease and three (3.5%) progressed while on treatment. Responses were observed at all sites of metastatic disease. Forty-one of 58 patients with visceral disease responded (71%) and 25 of 31 with soft tissue and bone disease experienced an objective response (81%). The median duration of response was 12 months (range, 2.4 to 40.5), and the median overall survival was 27.5 months (range, 4 to 46). Neutropenia was dose-limiting, with 36 patients (41%) experiencing grade 3 or 4 toxicity. Of 727 cycles administered, there were 20 admissions (3%) for treatment of febrile neutropenia, involving 14 of 89 patients (16%). Treatment-related cardiotoxicity at grade 2 to 4 was experienced by 10% of patients and necessitated the interruption of treatment in 1.5% of cycles. Other side effects were uncommon or manageable by conventional means. CONCLUSION The encouraging response rates and duration achieved with this combination of Navelbine/doxorubicin under the conditions of this study deserve further randomized comparative trials with standard regimens.

PURPOSE This study was designed to test the feasibility of administering doxorubicin at an optimal dose-intensity (> 70 mg/m2 per 21 days) in combination with ifosfamide under recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) cover in patients with metastatic soft tissue sarcomas. PATIENTS AND METHODS One hundred four eligible patients (of 111 entered) in 16 centers received doxorubicin 75 mg/m2 plus ifosfamide 5 g/m2 every 3 weeks for up to seven cycles. rhGM-CSF (250 micrograms/m2) was administered once or twice daily by subcutaneous injections for up to 14 days between cycles of chemotherapy. RESULTS Full protocol dose-intensity of chemotherapy was administered to the majority of patients with only 15 of 293 cycles being complicated by febrile episodes that required hospitalization. There were two treatment-related deaths: one from septicemia and one from cardiac failure. The main toxicities attributed to rhGM-CSF were pruritus and rash. A 45% response rate (10% complete remission [CR]) was seen, with a median response duration of 9 months and median survival of 15 months. CONCLUSION This high-dose regimen of chemotherapy was feasible under rhGM-CSF cover and produced a higher response rate and median survival than previously seen by the European Organization for Research and Treatment of Cancer (EORTC) Soft Tissue Sarcoma Group. A randomized phase III study is now underway comparing this regimen with conventional-dose doxorubicin/ifosfamide to test the dose-response relationship.

e17565 Background: Oncology is a specialty requiring a combination of multidisciplinary expertises, novel technology, integration of innovation into care and research efforts in order to improve the quality of life and survival of patients. Provision of high-quality care and improvement of disease outcome should be promoted in cancer centers. Methods: The Organization of European Cancer Institutes developed an Accreditation Programme combining: 1-a quantitative questionnaire assessing the human, technical and financial resources and activities in care, research and education dedicated to oncology; 2- a set of standards and criteria for high-quality cancer management integrated in an electronic tool with a scoring system of compliance; 3- a peer-review process for review of the self-assessment outcome and on-site visits; 4- a report and improvement plan allowing to designate comprehensive cancer centers complying with required criteria for high-quality comprehensive cancer patient management. All components of the Accreditation Programme were tested in 8 different voluntary cancer centers in Europe. The objectives were to assess the feasibility, reproducibility and acceptance of the Accreditation Programme; to improve the standards and criteria in terms of understanding and consensus; to validate the peer review methodology and establish a method for reporting and implementing an improvement plan; to provide with a preliminary system of designation of comprehensive cancer centers based on criteria of high-quality integrated research, care and education. Results: The 2 consecutive pilot tests allowed to validate 1- relevant items for the quantitative questionnaire; 2-criteria and standards for high-quality integrated multidisciplinary cancer patient's management. 3-The impact of the Accreditation Programme on improvement of patients management and professionals involvement. Conclusions: The OECI Accreditation Programme is ready for dissemination. Participation to the Programme allows development of improvement plans for innovative and integrated comprehensive cancer patients management in cancer centers. No significant financial relationships to disclose.

10586 Background: Previously irradiated and pre-treated locally advanced pelvic cancers, particularly when unresectable, have limited treatments options. IPP by the balloon occlusion technique prov...

9539 Background: DCE-US combined with perfusion software VRI (Vascular Recognition Imaging) and contrast agent injection (Sonovue-Bracco) is a simple and reproductible imaging technique that allows an early and accurate evaluation of IM activity in GIST patients (Lassau et al, ASCO 2004). The objective of this study was to correlate the results observed with DCE-US with the outcome of c-Kit-positive GIST pts treated with IM and to early detect secondary resistance to IM. Methods: 36 pts with advanced GIST were prospectively included in a monocentric imaging trial. DCE-US was performed before IM administration (d0) on days 1, 7, 14, 60, and then every 3 months up to 33 months. The percentage of contrast uptake was evaluated on each tumor target by two radiologists and results were compared to PFS. Results: A total of 371 examinations were performed. At d7, the good responders (GR: 25 pts) and poor responders (PR: 11 pts) presented a statistically significant difference in contrast uptake of DCE-US (p=0.004). There was no significant difference between the 2 groups in tumor volume modification (WHO and RECIST criteria at 2 months). After a median follow-up of 510 days, the median PFS of GR an PR were 602 days and 252 days respectively. A resumption of contrast uptake, before any increase in tumor volume was depicted 6 months before any modification of CT-scan in 7 patients. Conclusion: DCE-US is a new functional non invasive imaging technique that allows: 1) to predict after d7 the PFS 2) an early evaluation of secondary resistance to IM. No significant financial relationships to disclose.

2554 Background: The C-type lectin-like stimulatory immune receptor Natural Killer group 2 receptor (NKG2D) is expressed by NK and CD8+ T cells. NKG2D engagement is a natural mediator of immunosurveillance which can be compromised by locally sustained ligand expression. In cancer patients with NKG2D ligand- expressing tumors, NK and CD8+ T cells often express low levels of NKG2D and are functionally compromised. Dentritic cell-derived-exosomes (Dex) are nanomeric vesicles harboring functional MHC/peptide complexes capable of promoting T cell immune responses and tumor rejection in mice. Two Dex Phase I trials highlighted the and the safety of exosome administration. The observation of clinical regressions in the absence of detectable T cell responses prompted the search for alternate effector mechanisms. We study NKG2D expression and NK cells function in peripheral lymphocytes before and after Dex therapy. Methods: Exosomes were purified from day 7 autologous monocyte derived-DC cultures. Fifteen patients were enrolled and received exosome vaccinations. NK cells functions prior or following exosome vaccines were tested in standard Na251CrO4 chromium release assays. NKG2D and NKG2D ligand expression were studied using flow cytometry and/or western blot experiments. Results: In sharp contrast with DC, Dex bear functional NKG2D ligands leading to a selective downregulation of NKG2D activating receptors on autologous NK cells in vitro. Long term administration of Dex could enhance NKG2D expression levels on NK and CD8+ T cells in 50% of patients, restoring killing of NKG2D ligand expressing K562 and autologous tumour. In contrast to NKG2D ligands shed by tumors mediating immunosuppressive activity, exosomal NKG2D ligands promote NKG2D-dependent effector functions in vivo, that might account for the non MHC restricted-antitumor effects observed in the trial. Conclusions: NK cell activation represent a new pharmacodynamic for Dex leading to tumor recognition and regression in vivo. The Phase II trial using Dex shall include the monitoring of NKG2D ligands on Dex preparation and follow up NKG2D levels, functions and polymorphism in patients. No significant financial relationships to disclose.

10058 Background: Breast cancer is a heterogeneous and complex disease beyond good/bad prognosis groups. Previous studies identified prognostic tools that are undergoing inter-group validation. Our present study aims at better defining pre-malignant vs. malignant lesions and tumors that will give local vs. distant metastases (DM) or early vs. late DM. Methods: We selected 3 groups of patients (pts) in a consecutive series of node-negative breast cancers with a very long follow-up (>10 years (y)) and available frozen tumor samples. Pts who did not receive any adjuvant treatment were selected: 60 with no relapse after 10 y, 29 with early DM before 5 y and 18 with late DM after 5y. Genomic profiling on 44K Agilent pangenomic arrays taking as reference non-relapsing pts (after 10y) or normal breast (Clonetech) allowed us to select specific genes related to DM occurrence or tumorigenesis. Random permutations were performed to assess the statistical significance of our prediction accuracy. Results: 1- we identified a 141 gene-profile and related genes distinguishing tumors with early DM from tumors with late DM (71% prediction accuracy). 2- Similarly, we identified a 285-gene signature for late DM vs. no relapse at 10 y (80% prediction accuracy). Genes were further classified according to family clusters allowing description of genes involved in DM occurrence. 3- a total of 435 genes were also significantly over-expressed in at least 90% of 148 tumours (compared to normal breast). Among those, a selection of the most significant genes were analysed for RT-PC expression throughout the various steps of tumour development (normal breast, benign tumors, in situ carcinomas, invasive carcinomas). Among the 15 most upregulated genes listed, 3 unknown genes appear, that are overexpressed in 98% of the tumors with an average fold change > 11 and are currently explored. Discussion: In this unique series of untreated node-negative breast cancers, identification of molecular profiles of early and late DM could be useful in better early prediction of breast cancer outcome. Based on genomic analysis, a molecular gene based classification of progression from benign tissue to aggressive tumors allows to dissect pathways towards malignancy and to identify early diagnostic markers or targets for prevention. No significant financial relationships to disclose.

8024 Background: Gene-expression profiling in human cutaneous melanomas is impaired by the difficulty in getting access to a retrospective collection of frozen tumors. Thus, compared to other tumors, gene expression profiling data on human cutaneous melanomas are scarce, and data with prognostic implication are entirely lacking. In order to better understand the progression of this tumor and to identify key genes involved in melanoma prognosis, we correlated gene-expression profiles with clinical outcome in a cohort of 83 patients with primary melanoma. Methods: A class comparison and class prediction analysis was performed to identify genes able to predict 4-years. distant metastasis free-survival in 58 primary melanomas with at least 4-years follow-up or intercurrent distant metastasis or death. Results were also validated at the protein level in an independent population of 176 primary melanomas with a median clinical follow-up of 8.5 years. Results: We identified a set of sequences discriminating between primary melanomas associated with good and poor prognosis. Some of these sequences correspond to key-genes in the regulation of replication origins firing, such as mini-chromosome maintenance genes and geminin. The prognostic value of overexpression of replication origins firing genes is independent from thickness, ulceration, age and sex. Conclusions: This study has identified key-genes associated with in vivo metastatic dissemination of cutaneous melanomas. Some of our data provide new diagnostic tools for the accurate diagnosis of melanoma and shed new light on the molecular mechanisms underlying poor prognosis in melanoma patients. As some of these molecules are currently under study as targets for therapy, our data can have significant impact on the development of new melanoma therapies. No significant financial relationships to disclose.

2516 We have recently reported that STI571 has not only a tumor cell autonomous effect but also acts on host dendritic cells (DC) to promote natural killer (NK) cell activation and NK cell-dependen...

9020 Background: High dose MTX in adult patients (pts) with LO is highly toxic. We have designed in 1995 an intensive protracted regimen without MTX (API-AI regimen) in LO Methods:. Preliminary res...