[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Solitary Fibrous Tumor is a rare type of soft tissue tumor of intermediate malignant potential which may recur or metastasize in 15-20% of cases. Data on the management of patients with advanced SFT is scarce: chemotherapy has been described as ineffective, while recent data suggests that anti-angiogenic therapies may be more efficient. METHODS: We conducted a retrospective study on patients treated for advanced SFT at a single institution: from January 1994 to December 2011, 30 patients were treated in the Centre Leon Berard for an advanced SFT. RESULTS: Twenty-three patients received cytotoxic chemotherapy as first-line therapy. Best responses were 2 (9%) partial responses, 13 (57%) stable diseases (SD) and 8 (35%) progressive diseases (PD). Median Progression Free Survival (PFS) was 5.2 (95%CI: 3.2-7.1) months and 9 patients were free of progression at 6 months. Ten patients received an anti-angiogenic treatment (sunitinib or pazopanib) as a 2nd, 3rd or 4th line. Best responses were 5 SD and 5 PD; median PFS was 5.1 months (95%CI 0.7-9.6). Four patients (36%) were progression-free for more than 6 months. Two patients receiving pazopanib were without progression at 6 and 8 months and two patients receiving sunitinib were free of progression at 30 months. CONCLUSION: Response rate with standard chemotherapy was low and PFS appear similar between cytotoxic chemotherapy and anti-angiogenic agents.
BMC Cancer 03/2013; 13(1):109. · 3.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Leiomyosarcoma (LMS) represent 15 % of adult sarcomas. The aim of this work was to identify novel altered pathways in LMS, which may be of therapeutic value for patients. Thirteen fresh frozen samples of soft tissue and visceral LMS were analyzed and compared with normal smooth muscle uterine tissue (NSM) for phosphoproteomic profile. Four proteins were found differentially expressed including Tyro3. The functional role of Tyro3 and its ligand Gas6 was investigated in two LMS cell lines, SK-LMS-1 and CNIO-AA. Four proteins and phosphoproteins were differentially expressed in LMS samples vs NSM: A loss of FAK Y397 phosphorylation was observed in all LMSs, while Tyro3, MSH2 and PKC theta were consistently overexpressed. Gas6, the major ligand of Tyro3, was expressed in 8 of the 13 LMS samples, and Gas6 expression highly correlated to Akt Y473 phosphorylation and to a lesser extent to Erk1/2 phosphorylation. SK-LMS-1 and CNIO-AA LMS expressed Tyro3, Axl and Gas6 at high level in CNIO-AA while at low levels in SK-LMS-1. Exposure of both cell lines to foretinib, a tyrosine kinase inhibitor of Met, Axl and Tyro3, reduced cell viability and induced caspase 3/7 activation. Transfection of CNIO-AA with small interfering RNA directed against Tyro3 and Axl genes induced a reduction of the expression of the specific proteins and, when combined, significantly reduced CNIO-AA cell viability. Leiomyosarcomas overexpress Tyro3. Gas6, a ligand of Tyro3, exerts an autocrine activities though Tyro3 and Axl in a subgroup of LMS.
[Show abstract][Hide abstract] ABSTRACT: Purpose
Diagnosis of alveolar rhabdomyosarcoma (aRMS) is typically histological and immunohistochemical. Since 1993, we know that this tumor harbors specific fusion transcripts called PAX3-FOXO1 and PAX7-FOXO1. Detection by RT-PCR of one of these transcripts in bone marrow or circulating blood can reveal infra-cytological metastasis. The objective of this study was to determine the frequency of detection of bone marrow (BMM) and/or blood micrometastasis (CMM) in children with aRMS at diagnosis and to assess its prognostic value.
This is a French national clinico-biological retrospective study of 34 children and adolescents with rhabdomyosarcoma (RMS), metastatic or localized, of which the initial tumor harbors at least one specific transcript. They all had, at diagnosis, a bone marrow and/or blood sample to search micrometastasis.
Sixteen percent of patients with localized disease had BMM and 53 % of all aRMS had a CMM. Results indicate that the presence of BMM at diagnosis is associated with a significant decrease in overall survival (10 % vs 60 % ; P = 0.0058) and event-free survival (10 % vs 50 %; P = 0.0008), as well as in metastatic stage and localized tumors. We find, moreover, 83 % of relapse or progression in presence of blood micrometastasis.
With all the limitation of a retrospective analysis – and despite the limited number of patients – this is the first study to examine the pejorative prognostic value of the presence of bone marrow or blood micrometastasis at diagnosis in children with aRMS. It is the first step leading to a large-scale on going prospective study to confirm this assumption. If this is confirm in a larger setting, this would classify patients with bone marrow or blood micrometastasis in a high-risk population, to be treated more intensively or with new therapeutic strategies.
[Show abstract][Hide abstract] ABSTRACT: A minority of patients with advanced sarcoma achieve prolonged progression free survival (PFS) with insulin growth factor type 1 receptor (IGF-1R) monoclonal antibody (Ab) therapy. A biomarker identifying those patients beforehand would be useful to select patients for the development of these agents.
This single centre series includes patients with unresectable or metastatic soft tissue sarcomas (STS), Ewing sarcoma (ES) and osteosarcoma treated with IGF-1R Ab (R1507, IMC-A12, SCH 717454 and CP-751.871) in the Centre Léon Bérard. Tumour samples were analysed by immunohistochemistry for expression of IGF-1R, insulin-like growth factor binding protein type 3 (IGFBP-3), Ki67, epidermal growth factor receptor (HER1) and human epidermal growth factor receptor 2 (HER2). Predictive factors for PFS and overall survival (OS) were investigated.
All tumour samples had a positive IGF-1R immunostaining on 60% to 100% of tumour cells. IGFBP-3 immunostaining was observed in 12 (75%) samples with 5% to 100% of positive cells. IGF-1R immunostaining was nuclear (n=9, 56%), cytoplasmic (n=4, 25%), or nuclear +cytoplasmic (n=3, 19%). Neither IGFBP-3 expression, nor Ki67 was correlated to PFS. HER2 and HER1 staining were positive in 0 and 2 samples respectively (both primary resistant to IGF-1R Ab therapy). Exclusive intra-nuclear immunoreactivity for IGF-1R was significantly associated with a better PFS (p=0.01) and OS (p=0.007).
Exclusive nuclear localisation of IGF-1R is an easily testable biomarker associated with a better PFS and OS for patients treated with IGF-1R Ab therapy. Nuclear localisation of IGF-1R in tumour cells might be a hallmark of pathway activation.
European journal of cancer (Oxford, England: 1990) 06/2012; 48(16):3027-35. · 4.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Inactivation of SMARCB1 tumor-suppressor gene was originally described as highly specific for rhabdoid tumors (RTs). Nevertheless, recent reports have illustrated that SMARCB1 alterations also characterize other tumors; in particular, some familial schwannomatosis and epithelioid malignant peripheral nerve sheath tumors, both from peripheral nervous system (PNS) origin, lack BAF47 expression. To document the putative role of SMARCB1 in PNS, we reviewed PNS tumors referred to our institution for a molecular analysis of SMARCB1 because of histologic features compatible with RT.
Clinicopathologic, radiologic, and molecular characteristics were detailed for the 12 cases showing loss of expression and/or biallelic inactivation of SMARCB1. The status of the NF2 gene, likely to synergize with SMARCB1 in PNS tumors, was also analyzed.
Patients' age ranged from 0 to 45 years (median age, 6.6 y). Neurological symptoms were observed in 7/12 cases with radiologic features evoking a neuroblastic tumor in 6 cases and a peripheral nerve tumor in 4 cases. The mean delay before diagnosis was 3 months. Histologic examination revealed rhabdoid features in 11/12 tumors. All tumors showed a complete loss of SMARCB1 expression. Interestingly, adjacent nervous proliferation resembling neurofibromas were observed in 3 cases, suggesting a multistep transformation. Three tumors harbored a hemizygous deletion at the NF2 locus, but all NF2 sequences were normal.
We report the first series of PNS RT. In patients with aggressive PNS tumors, RT should be suspected, and anti-SMARCB1 immunohistochemical analysis should be performed. SMARCB1 inactivation, occasionally associated with NF2 deletion, might have oncogenic effects in peripheral nerves.
The American journal of surgical pathology 05/2012; 36(7):964-72. · 4.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Germline hSNF5/INI1 mutations are responsible for hereditary cases of rhabdoid tumors (RT) that constitute the rhabdoid predisposition syndrome (RPS). Our study provides the first precise overview of the prevalence of RPS within a large cohort of RT.
hSNF5/INI1 coding exons were investigated by sequencing and by multiplex ligation-dependent probe amplification.
Seventy-four constitutional DNAs from 115 apparently sporadic RT were analyzed from 1999 to 2009. Germline mutations were found in 26 patients (35%). Data from 9 individuals from 5 RPS families (siblings) were also studied. The median age at diagnosis was much lower (6 months) in patients with germline mutation (P < 0.01) than in patients without (18 months). Nevertheless, 7 of 35 patients with germline mutation (20%) developed the disease after 2 years of age. The mutation could be detected in only 1 parent whereas germline blood DNA was wild type in the 20 other parent pairs, therefore indicating the very high proportion of germ-cell mosaicism or of de novo mutations in RPS. The former hypothesis could be clearly documented in 1 case in which prenatal diagnosis was positive in a new pregnancy. Finally, the 2 years' overall survival was 7% in mutated and 29% in wild-type patients, mainly due to the worse outcome of RT in younger patients.
Our results show a high proportion of germline mutations in patients with RT that can be found at any age and up to 60% in the youngest patients. Genetic counseling is recommended given the low but actual risk of familial recurrence.
Clinical Cancer Research 01/2011; 17(1):31-8. · 7.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Alterations of the p53 pathway are among the most frequent aberrations observed in human cancers. We have performed an exhaustive analysis of TP53, p14, p15, and p16 status in a large series of 143 soft tissue sarcomas, rare tumors accounting for around 1% of all adult cancers, with complex genetics. For this purpose, we performed genomic studies, combining sequencing, copy number assessment, and expression analyses. TP53 mutations and deletions are more frequent in leiomyosarcomas than in undifferentiated pleomorphic sarcomas. Moreover, 50% of leiomyosarcomas present TP53 biallelic inactivation, whereas most undifferentiated pleomorphic sarcomas retain one wild-type TP53 allele (87.2%). The spectrum of mutations between these two groups of sarcomas is different, particularly with a higher rate of complex mutations in undifferentiated pleomorphic sarcomas. Most tumors without TP53 alteration exhibit a deletion of p14 and/or lack of mRNA expression, suggesting that p14 loss could be an alternative genotype for direct TP53 inactivation. Nevertheless, the fact that even in tumors altered for TP53, we could not detect p14 protein suggests that other p14 functions, independent of p53, could be implicated in sarcoma oncogenesis. In addition, both p15 and p16 are frequently codeleted or transcriptionally co-inhibited with p14, essentially in tumors with two wild-type TP53 alleles. Conversely, in TP53-altered tumors, p15 and p16 are well expressed, a feature not incompatible with an oncogenic process.
American Journal Of Pathology 10/2010; 177(4):2080-90. · 4.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Spontaneous pneumothorax may be one of the presenting manifestation of metastatic epithelioid sarcoma even if imaging does not show evident metastatic nodules. We report the case of a 24-year-old man presenting a bilateral spontaneous pneumothorax in association with an epithelioid sarcoma developed in the right foot. CT-scan revealed bilateral microcystic lesions with no evidence of metastatic disease. A left thoracoscopy and a pleurodesis were performed. Persistent air leakage led to a thoracotomy during which lung biopsies were carried out. Histopathological examination of the pulmonary biopsies revealed rare millimetric nodules, composed of very atypical epithelioid cells, growing along alveolar walls reminiscent of a bronchiolo-alveolar carcinoma. However, these cells and primary neoplastic cells of the foot tumour were morphologically and immunohistochemically similar and the atypical pulmonary cells were TTF1 negative. All these constatations allowed a diagnosis of pulmonary metastases of the epithelioid sarcoma. This very unusual case underlines that sarcomatous metastases may be a clinical and pathological pitfall.
Annales de Pathologie 04/2010; 30(2):139-42. · 0.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Fibromatosis comprises distinct clinical entities, including sporadic extra-abdominal fibromatosis, which have a high tendency for recurrence, even after adequate resection. There are no known molecular biomarkers of local recurrence. We searched for beta-catenin mutations in a European multicentre series of fibromatosis tumours to relate beta-catenin mutational status to disease outcome.
Direct sequencing of exon 3 beta-catenin gene was performed for 155 frozen fibromatosis tissues from all topographies. Correlation of outcome with mutation rate and type was performed on the extra-abdominal fibromatosis group (101 patients).
Mutations of beta-catenin were detected in 83% of all cases. Among 101 extra-abdominal fibromatosis, similar mutation rates (87%) were observed, namely T41A (39.5%), S45P (9%), S45F (36.5%), and deletion (2%). None of the clinico-pathological parameters were found to be significantly associated with beta-catenin mutational status. With a median follow-up of 62 months, 51 patients relapsed. Five-year recurrence-free survival was significantly worse in beta-catenin-mutated tumours regardless of a specific genotype, compared with wild-type tumours (49 vs 75%, respectively, P=0.02).
A high frequency (87%) of beta-catenin mutation hallmarks extra-abdominal fibromatosis from a large multicentric retrospective study. Moreover, wild-type beta-catenin seems to be an interesting prognostic marker that might be useful in the therapeutic management of extra-abdominal fibromatosis.
British Journal of Cancer 03/2010; 102(6):1032-6. · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Thirty to 50% of patients with adult type soft tissue sarcoma will develop metastasis. At this stage, systemic chemotherapy
is then generally proposed when a complete resection of all metastasis is not feasible (Clark et al. 2005). The two most active therapeutic drugs for advanced soft tissue sarcomas are doxorubicin and ifosfamide; dacarbazine although
considered as the third active agent, actually shows a marginal activity. Initial response rates to doxorubicin single agent
regimens are 10–30% with 5–8% long term survivors (Blay et al. 2003, 2004). The combination of doxorubicin with ifosfamide has yielded higher response rate (25–70%), but with no survival improvement.
After failure of doxorubicin and ifosfamide, few therapeutic options are available. The combination of gemcitabine and docetaxel
was reported to induce high response rates and progression free survival (PFS) in leiomyosarcomas (Bay et al. 2006). ET-743, trabectedin, Yondelis®, is a tetrahydro-isoquinoline alkaloid isolated from Ectenascidia turbinata, a tunicate that grows on mangrove roots throughout the Caribbean sea. ET-743 interferes with the activity of several transcription
factors and traps protein from the nucleotide excision repair (NER) system, thus resulting in DNA damage, modulation of expression
of various genes, and blockade of cells in G2-M phase. After failure of doxorubicin and/or ifosfamide, as well as in first
line treatment, ET-743 at 1.5 mg/m2 in 24 h CI every 21 days yielded an overall response rate close to 8% and 30–40% stabilisation rates. Leiomyosarcomas, liposarcomas
(in particular myxoid liposarcomas), and synovial sarcomas may be the more sensitive histotypes. The major toxicities of ET-743
are hepatic, through biliary duct destruction, and hematologic. They are not cumulative. In vitro, ET-743 exerts synergistic
cytotoxic activity with doxorubicin or cisplatin, and in vivo with irinotecan. Phase I combination studies are in currently
progress. We detail all these aspects of ET-743.
[Show abstract][Hide abstract] ABSTRACT: Trabectedin was recently approved for patients failing doxorubicin, the standard treatment for advanced/metastatic sarcoma. This retrospective study aimed to compare trabectedin efficacy between compassionate use in unselected patients and clinical trials. From May 1999 to January 2006, 92 patients were treated at the Centre Léon Bérard, either in phase II studies or on a named patient compassionate basis. All cases were retrospectively analyzed to assess trabectedin efficacy in terms of response, progression-free, and overall survival.The objective response rate was 10% (N=9): 4% (N=2) for patients treated in compassionate use program and 16% (N=7) for those in clinical trials (P=0.18); 26 (28%) patients had stable disease for at least 6 months, 11 (23%) in the compassionate group and 15 (33%) in clinical trials. Median progression-free and overall survivals were, respectively, 2.2 [95% confidence interval (CI): 1.9-3.6] and 8.9 (95% CI: 6.4-14.2) months for all patients, 2.3 (95% CI: 1.9-4.3) and 10.4 (95% CI: 6.9-24.2) months for patients in clinical trials and 1.8 (95% CI: 1.4-3.4) and 6.4 (95% CI: 3.3-14.2) months for patients under compassionate treatment. In this retrospective analysis, the reported grade 3-4 toxicities were increased transaminase (34 patients, 37%) and neutropenia (38 patients; 42%). Higher efficacy was observed in phase II studies than with compassionate treatment, but no significant difference remained after adjustment in multivariate analysis for performance status, a well-established prognosis factor. The safety and tolerability of trabectedin shown in clinical trials is confirmed for patients in real-life situation treated in compassionate use programs, but its benefit is higher for patients with performance status 0-1.
[Show abstract][Hide abstract] ABSTRACT: The sacrococcygeal region may be the origin of germinal tumors, of paragangliomas, and, rarely, of extradural myxopapillary ependymomas (MPE) in the newborn and child. A case is presented of a preterm child with an abdominal tumor, originating from the precoccygeal area, that turned out to be a teratoma with a component of an MPE. The high levels of α-fetoprotein in this preterm baby were initially misleadingly interpreted as a tumoral marker. The differential diagnosis and the difficulties in interpreting tumoral markers in infants are discussed.
Pediatric Hematology and Oncology 07/2009; 15(5):437-441. · 0.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Epithelioid sarcoma (ES) is rare with a poor prognosis and for which a loss of INI1 expression has been recently reported. We report a study of 106 cases with clinical, histologic, and immunohistochemical data, including INI1 expression, and follow-up data. Of the 106 cases, 70 were the conventional subtype and 36 the large cell subtype. INI1 was negative in 86 cases (81.1%): 57 (81%) of 70 conventional and 29 (81%) of 36 large cell subtypes. Treatment modalities were available for 76 and follow-up for 80 patients. Of the 80 patients, 43 (54%) experienced metastasis and 25 (31%) died of the disease. Univariate analysis indicated that tumor size and mitotic index were significant for metastasis-free survival, whereas proximal location, tumor size, tumor multifocality, and mitotic index were significant for overall survival. Loss of expression of INI1 is frequent in the conventional and large cell subtypes of ES and can be used as a diagnostic marker, but it has no prognostic impact.
American Journal of Clinical Pathology 03/2009; 131(2):222-7. · 2.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent progress made in the field of sarcoma biology has shed new light on the pathophysiology of these numerous but rare diseases. Soft tissue sarcomas can be divided into 6 sub-types based on the underlying molecular biology of the disease: 1) translocation leading to fusion proteins involving transcription factors or growth factors (Ewing sarcoma, myxoid liposarcoma, dermatofibrosarcoma protuberans); 2) tyrosine kinase receptor mutations (gastrointestinal stromal tumors); 3) tumor-suppressor gene deletion (type 1 neurofibromatosis, rhabdoid tumors); 4) genetic alteration such as amplification of chromosomal regions (well differentiated/dedifferentiated liposarcoma); 5) sarcomas with more complex genetic alterations (leiomyosarcoma) and 6) abnormalities involving the cell-adhesion pathways (aggressive fibromatosis). Together with the current development of numerous targeted therapies, these recent progress are the basis of tomorrow's personalised medicine for patients with soft tissue sarcoma.
Bulletin du cancer 11/2008; 95(10):963-74. · 0.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Superficial primitive Ewing's sarcomas are rare and have been reported to be of favorable prognosis compared to conventional deep-seated tumors. In the skin and subcutis, the diagnosis is often difficult, and performing molecular cytogenetic techniques may be helpful. We performed a retrospective analysis of 14 cases of superficial Ewing's sarcomas, all confirmed by molecular cytogenetics. Clinical, histological, immunohistochemical, molecular cytogenetic, therapeutic, and follow-up data are reported. There were 11 female and 3 male patients aged from 12 to 77 years (median: 17 years). Seven tumors occurred in the extremities, five in the trunk wall, and two in the head. Tumor size ranged from 1 to 5 cm (median, 3 cm). They were all small round-cell proliferations with a strong membranous positivity for CD99. Ewing's sarcoma translocations/fusion gene transcripts were detected in eight cases, both by FISH and reverse transcriptase (RT)-PCR. Four tumors were positive by RT-PCR alone (FISH not done in three cases and not interpretable in one case), and two cases were positive by FISH alone (RT-PCR not done). Surgical resection was performed in all patients. Chemotherapy was given in ten patients and radiotherapy in six. At last medical examination (median follow-up, 47 months), two patients who underwent surgical resection alone had died from the tumor. Our results confirm that superficial Ewing's sarcomas are of good prognosis. Given the difficulty of the diagnosis and the importance of an adapted treatment, a confirmation of the diagnosis by molecular or cytogenetic techniques is recommended when dealing with a superficial tumor.
Modern Pathology 10/2008; 22(1):87-94. · 5.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The molecular hallmark of gastrointestinal stromal tumours (GISTs), the mutation of the KIT gene, was discovered 10 years ago. GISTs have since been recognized as separate pathological entities among sarcomas, and have become a model for targeted treatment of solid tumours. Imatinib mesilate, which was approved in 2002 for the treatment of patients with advanced GIST, has dramatically changed the course of the disease.
This article will focus on the development of imatinib mesilate in the treatment of patients with GIST.
A Pubmed search was performed using the keywords 'imatinib', 'gastrointestinal stromal', 'GIST', 'KIT' and 'PDGFR'. Websites of the American Society of Clinical Oncology and the European Society of Medical Oncology were searched for data reported in abstract form at recent symposiums. Personal communications from opinion leaders were sought for additional information that might be relevant.
Imatinib has changed the clinical course of patients with advanced GISTs and further development in the adjuvant setting as well as prospective assessment of predictive factors are the current focus of ongoing research.
Expert Opinion on Pharmacotherapy 06/2008; 9(7):1211-22. · 2.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Imatinib mesylate (Gleevec, Glivec, Novartis, Basel, Switzerland) is a small molecule inhibitor of the tyrosine kinase c-abl, c-kit and the platelet derived growth factor receptor (PDGFR). Imatinib was developed for the treatment of chronic myeloid leukaemia (CML) but was approved both in Europe and the US fro the treatment of CML and gastrointestinal stromal tumors (GIST). Given its activity against both c-kit and PDGFR kinases and its remarkable safety profile, imatinib has been 'tried' in several solid tumors; results however have often been deceiving. We review the current data regarding the activity of imatinib in solid tumors, including GIST.
Bulletin du cancer 02/2008; 95(1):99-106. · 0.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Angiosarcomas are rare, heterogeneous and a retrospective study was conducted to describe their natural history.
We reviewed 161 files of angiosarcoma treated in three institutions of the French Sarcoma Group from 1980 to 2004. Survival and prognostic factors for survival were analyzed.
Median age was 52 years. Primary sites were the breast (35%), skin (20%) and soft tissues (13%). At initial diagnosis, 31 (19%) had metastases. Surgery was the first treatment in 121 (75%) patients combined with chemotherapy or radiotherapy in 34 and 32, respectively. Ninety (74%) of these 121 patients relapsed, mostly locally (50). With an average time since initial diagnosis of 8.1 years, 123 (76%) patients progressed and 76 (47%) died. Median survival was 3.4 years [95% confidence interval (CI) 2.4-5.8], and the 5-year overall survival (OS) rate was 43% (95% CI 33-53). In multivariate analysis, liver primary site [relative risk (RR) = 12.62], performance status (PS) of two or more (RR = 3.83), presence of metastases at diagnosis (RR = 2.50), soft tissue tumor (RR = 0.31) were correlated to OS. PS, liver and soft tissue tumors were identified as independent prognostic factors for progression-free survival.
Angiosarcomas have an overall poor outcome, but with a clearly distinct prognosis depending on the primary site.
Annals of Oncology 01/2008; 18(12):2030-6. · 7.38 Impact Factor