Nationale Des Centres De Lutte Research Articles

Skp2 Overexpression Is Highly Representative of Intrinsic Biological Aggressiveness and Independently Associated with Poor Prognosis in Primary Localized Myxofibrosarcomas

Two SCF(Skp2) ubiquitin ligase-related proteins, Skp2 and cyclin-dependent kinase subunit 1 (Cks1), are involved in posttranscriptional degradation of p27(Kip1) tumor suppressor. We analyzed the prognostic utility of p27(Kip1) and its interacting cell cycle regulators in myxofibrosarcomas. Clinicopathologic features and tissue microarray-based immunohistochemical expression of p27(Kip1), Skp2, Cks1, cyclin E, cyclin A, Ki-67, and minichromosome maintenance protein 2 (Mcm2) were assessed in 70 primary myxofibrosarcomas and correlated with clinical outcomes. Skp2 mRNA expression and the relationship between Skp2 and p27(Kip1) proteins were examined in six cases by semiquantitative reverse transcription-PCR and Western blotting, respectively. High indices of Skp2 (> or =10%), cyclin A (> or =10%), and Mcm2 (> or =50%) were adverse prognosticators at the univariate level. Furthermore, co-overexpression of Skp2 and cyclin A identified highly lethal cases in the entire cohort [P < 0.0001 for disease-specific survival (DSS), P = 0.0004 for overall survival (OS)] and the lower-grade subset (Fédération Nationale des Centres de Lutte Contre le Cancer grade 1 and 2; P = 0.0006 for DSS, P = 0.0093 for OS). In multivariate analyses, Skp2 overexpression overshadowed most intrinsic clinicopathologic factors and independently correlated with worse metastasis-free survival (P = 0.0012), DSS (P = 0.0234), and OS (P = 0.0056). Notably, positive margins independently predicted inferior local recurrence-free survival (P = 0.0012) and also negatively affected metastasis-free survival (P = 0.0471), DSS (P = 0.0152), and OS (P = 0.0173). Reverse transcription-PCR showed up-regulation of Skp2 mRNA in four cases and Western blotting displayed a matched expression pattern of Skp2. Margin status and intrinsic property of myxofibrosarcomas both affect patient survival. Skp2 overexpression is highly representative of the biological aggressiveness of myxofibrosarcomas and plays an important prognostic role.

133 INVITED Modulating radiotherapy approaches for sarcoma heterogeneity

Needle core biopsy (NCB) of soft tissue sarcomas (STSs) presents problems for French Federation Nationale des Centers de Lutte Contre le Cancer (FNCLCC) histological grading because small sample size hinders determination of necrosis and mitotic activity. We graded 53 STSs on NCB using a modified FNCLCC grading system that substitutes Ki-67 immunoexpression for mitotic count and uses a radiological assessment of necrosis, and compared the results with those obtained by conventional FNCLCC grading of the corresponding untreated, surgically resected specimen. Forty-eight of the 53 tumors were classified as malignant on NCB (concordance = 91%). The modified FNCLCC grade correctly separated high-grade (grades II and III) from low-grade sarcomas in 70% of cases and predicted the traditional FNCLCC grade given to the resected specimen in 49% of cases. Ki-67 scores of 2 or 3 were observed in 5 tumors classified as low-grade neoplasms on NCB but upgraded to a high-grade dedifferentiated liposarcoma on resection. Underestimated NCB grades were commonly encountered with lipomatous tumors due to sampling error, whereas Ki-67 or radiologic necrosis scores higher than the corresponding histological scores were responsible for the vast majority of overestimated NCB grades. Our FNCLCC grading scheme replacing conventional mitosis counting and histologic assessment of necrosis with surrogate markers is useful in separating high- and low-grade STSs on NCB for STS treatment planning. High Ki-67 rate should raise suspicion of a higher-grade component, particularly with fatty tumors.

Management of Superficial Leiomyosarcoma: A Retrospective Study of 10 Cases

Superficial leiomyosarcoma is a rare soft-tissue tumor. Management of this tumor, including pathological evaluations and therapies, is not clearly defined in the existing literature. Ten patients with superficial leiomyosarcoma treated in our institutes were recalled and scheduled for examination. Assessments were carried out according to clinical characteristics, therapies used, histological grade (based on the grading system of the Fédération Nationale des Centres de Lutte Contre Le Cancer), tumor-node-metastasis stage (using the American Joint Committee on Cancer staging system), recurrences rates, state of metastases, and the current condition of each patient. No local recurrences or distant metastases were seen in eight patients with low-grade and early-stage disease, whereas two patients with high-grade and advanced-stage disease had recurrence and one of these two patients died of the disease. This study indicates that evaluations using the Fédération Nationale des Centres de Lutte Contre Le Cancer grading system and the American Joint Committee on Cancer tumor staging system were useful. The authors advocate that surgical treatment of low-grade cutaneous leiomyosarcoma by complete excision with a narrow margin is adequate. For low-grade and early-state subcutaneous or soft-tissue leiomyosarcoma, wide excision with a minimum 2-cm lateral margin and one-tissue barrier deep margin is recommended. Management of high-grade leiomyosarcomas is still difficult; adequate wide excision may be the only option.

C-REACTIVE PROTEIN: A BIOMARKER OF SURVIVAL IN PATIENTS WITH METASTATIC RENAL CELL CARCINOMA TREATED WITH SUBCUTANEOUS INTERLEUKIN-2 BASED IMMUNOTHERAPY

In patients with metastatic renal cell carcinoma treated with low dose subcutaneous interleukin-2 based immunotherapy we evaluated a panel of biohumoral and clinical parameters before treatment to verify their correlation with clinical outcome. We analyzed the records of 110 patients treated at our institution. Before treatment total lymphocytes, lactate dehydrogenase, the erythrocyte sedimentation rate, albumin, C-reactive protein (CRP) and fibrinogen were analyzed and correlated with clinical parameters, namely performance status, patient age, sex, prior nephrectomy, number and sites of disease, and disease-free interval (DFI) from nephrectomy to metastatic disease. Median survival was 12 months (partial and complete response 33, stable disease 14 and progression 7). The overall response was 24% for a partial and complete response, 37% for stable disease and 39% for progression. On univariate analysis good performance status (p = 0.0000), prior nephrectomy (p = 0.0001), DFI longer than 12 months (p = 0.0003), bone disease site (p = 0.0013), a low number of metastatic sites (p = 0.0449), normal albumin (p = 0.0001), low/normal fibrinogen (p = 0.0140), low/normal lactate dehydrogenase (p = 0.0430) and low/normal CRP (p = 0.0000) were related to better survival. On final multivariate analysis only CRP (p = 0.002) and DFI (p = 0.0497) were found to have an independent role in survival. When we correlated clinical and biohumoral factors, only CRP correlated with DFI (p = 0.021) and prior nephrectomy (p = 0.041). Our data confirm that some clinical and biohumoral factors may be strongly related to survival in metastatic renal cell carcinoma. The interesting new aspect emerging from this study is the prognostic value of CRP and fibrinogen, which are able to discriminate a good from a poor prognosis.

Histologic grade, but not SYT-SSX fusion type, is an important prognostic factor in patients with synovial sarcoma: a multicenter, retrospective analysis.

To assess the prognostic value of SYT-SSX fusion type, in comparison with other factors, in a population of 165 patients with synovial sarcoma (SS). Data on 165 patients with SS (141 with localized disease at diagnosis) were studied retrospectively. The following parameters were examined for their potential prognostic value: age at diagnosis, sex, tumor site (extremities v proximal/truncal), size, histology, mitotic count, necrosis, histologic grade (Federation Nationale des Centres de Lutte Contre le Cancer system), stage (1997 tumor-node-metastasis system classification), surgical margin status (assessed histologically), and fusion type (SYT-SSX1 v SYT-SSX2). Median follow-up time was 37 months (range, 2 to 302 months). Among those patients with localized disease at diagnosis, median and 5-year disease-specific survivals (DSS) for the SYT-SSX1 and SYT-SSX2 subgroups were 126 months and 67.4% versus 82 months and 63.2%, respectively (P = .12). Median and 5-year metastasis-free survivals (MFS) were 84 months and 54.2% for SYT-SSX1 versus 50 months and 47.6% for SYT-SSX2 (P = .76). Univariate analyses showed that high histologic grade (grade 3), high mitotic count (>/= 10 mitoses/10 high-power fields), stage III disease, size greater than 7 cm, tumor necrosis, and presence of areas of poorly differentiated morphology were significant adverse prognostic factors for DSS and MFS, whereas SYT-SSX fusion type, tumor histology (biphasic v monophasic), and patient sex were not. Age greater than 35 years adversely affected DSS but not MFS. In multivariate analyses, histologic grade was the most significant prognostic factor for both DSS and MFS. For patients with localized SS, histologic grade but not SYT-SSX fusion type is a strong predictor of survival.

Summary version of the Standards, Options and Recommendations for the use of analgesia for the treatment of nociceptive pain in adults with cancer (update 2002)

All patients have the right to expect to receive the best therapeutic means available to reduce their suffering. Recent evaluation of the French ministerial 3-year plan for the fight against pain by the French Society of Public Health (http://www.sfsp-france.org/Plan-Lutte-Douleur/Plan-Lutte-Douleur.htm) and observations of current practice show that the information and training of health professionals in this area should be continued. The necessity to fight against cancer pain has only recently become a priority. In 1996 a working group, set up by the French National Federation of Cancer Centres (Federation Nationale des Centres de Lutte Contre le Cancer–FNCLCC), published clinical practice guidelines for pain management in adult and paediatric patients with cancer (Krakowski et al, 1996). These guidelines now require updating, but in this document only the pharmacological treatment of pain arising from excess nociception in adults with cancer is covered. The other sections of the original guideline are currently being updated in the context of a collaboration between the FNCLCC and the SETD (Society for the Study and Treatment of Pain (Societe d'Etude et de Traitement de la Douleur) French section of the International Association for the Study of Pain (IASP) subgroup on cancer pain).

Prognostic factors in primary breast sarcomas: a series of patients with long-term follow-up.

To describe the pathologic characteristics and prognostic factors of primary breast sarcomas (PBSs). 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. 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. 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.

Brachytherapy in cervix cancers: development of techniques and concepts

Brachytherapy plays an important role in the treatment of patients with cervical carcinoma. Technical modalities have evolved during the last years and have benefited from imaging modalities development, specially MRI. Imaging modalities contribute to a better knowledge of tumoral extension and critical organs. Ultrasound during brachytherapy has led to the almost complete eradication of uterine perforation. In the future, a more systematic use of systems allowing optimization may induce a better dose distribution in the tumor as well as in the critical organs. Recent data provided information in favor of a better analysis in the relative role of dose-rate, total dose and treated volume and their influence on the local control and complication incidence. Concomitant radiochemotherapy represents a standard in the treatment of patients with tumoral size exceeding 4 cm. Some questions still remain: is concomitant chemotherapy of benefit during brachytherapy? Is there any place for complementary surgery, specially in patients with complete response after external irradiation with concomitant chemotherapy and brachytherapy? In order to answer the former question, a phase III randomized trial is going to start, with the Fédération Nationale des Centres de Lutte Contre le Cancer as a promoter.

Prognostic Relevance of a Histological Grading System Using MIB-1 for Adult Soft-Tissue Sarcoma

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.

How Should We Grade Soft Tissue Sarcomas and What Are the Limitations?

Histologic grade has been shown repeatedly to be the most important prognostic factor in adult soft tissue sarcomas with regard to metastasis development and tumor morrality, although tumor size and tumor location (superficial versus deep) are also important parameters to consider. In this review, the advantages and limitations of histrologic grade are exposed, focusing on the grading system of the Fédération Nationale des Centres de Lutte Contre fe Cancer. The reproducibility issue and the impact of histologic grade on patient management are also discussed.

Invasive thymomas: The role of radiotherapy following incomplete resection or biopsy. A multicentric retrospective study of 90 cases : [formula omitted], M. Resbent, P. Richaud, G.M. Jung, X. Mirabel, C. Marchal, J.L. Lagrange, P. Rambert, G. Chaplain, T. D. Nguyen, J.M. Wihlm, P. Fuentes. Fédération Nationale des Centres de Lutte Contre le Cancer, Paris, France

Invasive thymomas: The role of radiotherapy following incomplete resection or biopsy. A multicentric retrospective study of 90 cases : [formula omitted], M. Resbent, P. Richaud, G.M. Jung, X. Mirabel, C. Marchal, J.L. Lagrange, P. Rambert, G. Chaplain, T. D. Nguyen, J.M. Wihlm, P. Fuentes. Fédération Nationale des Centres de Lutte Contre le Cancer, Paris, France