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1.  A prospective epidemiological study of new incident GISTs during two consecutive years in Rhône Alpes region: incidence and molecular distribution of GIST in a European region 
British Journal of Cancer  2010;103(2):165-170.
Background:
Preliminary data indicate that the molecular epidemiology of localised gastrointestinal stromal tumour (GIST) may be different from that of advanced GIST. We sought to investigate the molecular epidemiology of sarcomas, including GIST, in the Rhone-Alpes region in France.
Patients and methods:
A prospective and exhaustive study in the Rhone-Alpes Region in France to assess the precise incidence of primary sarcomas with systematic centralised pathological review and molecular analysis was conducted for 2 consecutive years.
Results:
Among 760 patients with a confirmed diagnosis of sarcoma, 131 (17%) had a GIST. The majority of patients had gastric primaries (61%). Mutational analysis could be performed in 106 tumour samples (74%), and 71 (67%) had exon 11 mutations. PDGFRA mutations were found in 16% of cases, which is twice as high as previously reported for advanced GIST.
Conclusion:
Data indicate that PDGFRA mutations in localised GIST may be twice as high as what was previously reported in patients with advanced disease. This finding may have important consequences for patients offered adjuvant imatinib, although most of these tumours are in the low-risk group.
doi:10.1038/sj.bjc.6605743
PMCID: PMC2906738  PMID: 20588273
gastrointestinal stromal tumour (GIST); incidence; KIT; PDGFRA; kinase mutations
2.  A dose-escalating phase I of imatinib mesylate with fixed dose of metronomic cyclophosphamide in targeted olid tumours 
British Journal of Cancer  2013;109(10):2574-2578.
Background:
Preclinical findings suggest that imatinib mesylate (IM) and metronomic cyclophosphamide (MC) combination provides synergistic antiangiogenic activity on both pericytes and endothelial cells.
Methods:
We have designed a 3+3 dose-escalating phase I trial with a fixed dose of MC (50 mg two times daily) plus IM (400 mg per day; 300 and 400 mg two times daily). Enrolled patients had IM- and sutininib-refractory advanced gastrointestinal stromal tumours (GIST) (n=17), chordoma (n=7) and mucosal melanoma (n=2). Dose-limiting toxicities were monitored for the first 6 weeks. Progression-free survival (PFS) and response assessment are based on RECIST 1.0 guidelines. Pharmacokinetics of IM were measured before and after exposure to MC.
Results:
No dose-limiting toxicity was observed. Fourteen patients of the expanded cohort received 400 mg two times daily of IM with MC. Apart from a case of possibly related acute leukaemia occurring after 4 years of treatment, we did not see unexpected toxicity. No drug–drug pharmacokinetic interaction was observed. There was no objective response. We have observed long-lasting stable disease in chordoma patients (median PFS=10.2 months; range, 4.2–18+) and short-term stable disease in heavily GIST pretreated patients (median PFS=2.3 months; range, 2.1–6.6).
Conclusion:
This combination is feasible and may warrant further exploration in refractory GIST or chordoma patients.
doi:10.1038/bjc.2013.648
PMCID: PMC3833229  PMID: 24149182
chordoma; gastrointestinal stromal tumour; imatinib; metronomic cyclophosphamide
3.  Advanced chondrosarcomas: role of chemotherapy and survival 
Annals of Oncology  2013;24(11):2916-2922.
Background
There are limited data about the role of chemotherapy in patients with
advanced chondrosarcomas.
Methods
The medical charts of 180 patients with advanced chondrosarcomas having received chemotherapy in 15 participating institutions between 1988 and 2011 were reviewed.
Results
Median age was 52 years. Sixty-three percent of patients had conventional chondrosarcoma and 88% had metastatic disease. Combination chemotherapy was delivered in 98 cases (54.5%). One hundred and thirty-one patients (73%) received an anthracycline-containing regimen. Using RECIST, the objective response rate was significantly different according to histological subtype, being 31% for mesenchymal chondrosarcoma, 20.5% for dedifferentiated chondrosarcoma, 11.5% for conventional chondrosarcoma and 0% for clear-cell chondrosarcoma (P = 0.04). Median progression-free survival (PFS) was 4.7 months [95% confidence interval (CI) 3–6.5]. Performance status (PS) ≥2, number of metastatic sites ≥1 and single-agent regimen were independently associated with poor PFS. Median overall survival (OS) was 18 months (95% CI 14.5–21.6). PS, number of metastatic sites and palliative surgery were independently associated with OS.
Conclusions
Conventional chemotherapy have very limited efficacy in patients with advanced chondrosarcoma, the highest benefit being observed in mesenchymal and dedifferentiated chondrosarcoma. These data should be used as a reference for response and outcome in the assessment of investigational drugs in advanced chondrosarcoma.
doi:10.1093/annonc/mdt374
PMCID: PMC3811906  PMID: 24099780
chondrosarcoma; chemotherapy; prognosis; treatment
4.  GDC-0449 in patients with advanced chondrosarcomas: a French Sarcoma Group/US and French National Cancer Institute Single-Arm Phase II Collaborative Study 
Annals of Oncology  2013;24(11):2922-2926.
Background
Pre-clinical data have suggested a therapeutic role of Hedgehog (Hh) pathway inhibitors in chondrosarcoma.
Methods
This phase II trial included patients with progressive advanced chondrosarcoma. They received GDC-0449 150 mg/day (days 1–28, 28-day cycle). The primary end point was the 6-month clinical benefit rate (CBR) defined as the proportion of patients with non-progressive disease at 6 months. A 6-month CBR of 40% was considered as a reasonable objective to claim drug efficacy.
Results
Between February 2011 and February 2012, 45 patients were included. Twenty had received prior chemotherapy. Thirty-nine were assessable for efficacy. The 6-month CBR was 25.6% (95% confidence interval 13.0–42.1). All stable patients had grade 1 or 2 conventional chondrosarcoma with documented progression within the 6 months before inclusion. All but one with available data also had overexpression of the Hh ligand. Median progression-free and overall survivals were 3.5 and 12.4 months, respectively. The most frequent adverse events were grade 1 or 2 myalgia, dysgeusia and alopecia.
Conclusions
GDC-0449 did not meet the primary end point of this trial. Results suggest some activity in a subset of patients with progressive grade 1 or 2 conventional chondrosarcoma. Further studies assessing its role in combination with chemotherapy are warranted.
ClinicalTrials.gov Identifier
NCT01267955.
doi:10.1093/annonc/mdt391
PMCID: PMC3811907  PMID: 24170610
chondrosarcoma; Hedgehog pathway; treatment; GDC-0449
5.  Trabectedin is a feasible treatment for soft tissue sarcoma patients regardless of patient age: a retrospective pooled analysis of five phase II trials 
British Journal of Cancer  2013;109(7):1717-1724.
Background:
This retrospective pooled analysis assessed the effect of age on the efficacy and safety of trabectedin in young and elderly patients with recurrent advanced soft tissue sarcoma (STS).
Methods:
Data from 350 adults with STS treated in five phase II trials with trabectedin were divided in the younger (<60 years; n=267) and the older cohort (⩾60 years; n=83).
Results:
The response rate did not differ with age (younger: 10.1% vs elderly 9.6%). No significant differences were found in median progression-free survival (PFS) in younger (2.5 months) and older (3.7 months) cohort with a comparable PFS rates at 3 (45.1% vs 55.1%) and 6 months (29.5% vs 36.4%). Similar median overall survival was observed in both cohorts (13.0 vs 14.0 months). Reversible neutropenia and aspartate aminotransferase/alanine aminotransferase elevation were the most common abnormalities. A higher incidence of grade 3/4 neutropenia (43.6% vs 60.2%) and fatigue (6.3% vs 14.4%) was observed in older patients. In 24 patients aged ⩾70 years, no significant differences in efficacy or safety outcomes were found.
Conclusion:
This analysis demonstrated that trabectedin is a feasible treatment in young and elderly patients with STS, with meaningful clinical benefits and an acceptable safety profile, essential in palliative treatment of elderly patients.
doi:10.1038/bjc.2013.524
PMCID: PMC3790176  PMID: 24022187
trabectedin; STS; sarcoma; elderly; older; age
6.  A phase II trial of panobinostat in patients with advanced pretreated soft tissue sarcoma. A study from the French Sarcoma Group 
British Journal of Cancer  2013;109(4):909-914.
Background:
Soft tissue sarcomas (STS) are rare tumours for which treatment options are limited in the advanced setting. Histone deacetylase inhibitors have shown activity in preclinical models of STS.
Methods:
We conducted a single-arm, open-label, multicentre phase II study to assess the efficacy and tolerability of panobinostat given orally, 40 mg thrice weekly in patients with advanced pretreated STS. The primary endpoint was the 3-month progression-free rate.
Results:
Forty-seven STS patients were enrolled between January 2010 and December 2010. Median age was 59 (range 21–79) years, 22 (47%) patients were males. Panobinostat dose was lowered to 20 mg thrice weekly after nine patients were enrolled, based on the recommendation of an independent safety committee. The most common grade 3/4 adverse events were thrombocytopenia, fatigue, lymphopenia and anaemia. Forty-five patients were evaluable for the primary endpoint. Among them, nine patients (20%, 95% CI (10–35%)) were progression-free at 3 months. No partial response was seen, but 17 patients (36%) had stable disease (SD) as their best response. Six patients were progression-free at 6 months.
Conclusion:
Panobinostat was poorly tolerated at 40 mg thrice a week. Efficacy in unselected advanced STS was limited, although some patients had prolonged SD.
doi:10.1038/bjc.2013.442
PMCID: PMC3749588  PMID: 23922114
soft tissue sarcoma; targeted therapy; metastatic/advanced disease
7.  Masitinib in advanced gastrointestinal stromal tumor (GIST) after failure of imatinib: A randomized controlled open-label trial 
Annals of Oncology  2014;25(9):1762-1769.
These findings may potentially influence future clinical practice, with encouraging long-term survival data and better safety of masitinib with respect to sunitinib indicating a positive benefit–risk ratio. Considered in the setting of effective subsequent therapies, data show that adding masitinib to the armaterium of drugs used to treat GIST generates a clinically relevant survival benefit.
Background
Masitinib is a highly selective tyrosine kinase inhibitor with activity against the main oncogenic drivers of gastrointestinal stromal tumor (GIST). Masitinib was evaluated in patients with advanced GIST after imatinib failure or intolerance.
Patients and methods
Prospective, multicenter, randomized, open-label trial. Patients with inoperable, advanced imatinib-resistant GIST were randomized (1 : 1) to receive masitinib (12 mg/kg/day) or sunitinib (50 mg/day 4-weeks-on/2-weeks-off) until progression, intolerance, or refusal. Primary efficacy analysis was noncomparative, testing whether masitinib attained a median progression-free survival (PFS) (blind centrally reviewed RECIST) threshold of >3 months according to the lower bound of the 90% unilateral confidence interval (CI). Secondary analyses on overall survival (OS) and PFS were comparative with results presented according to a two-sided 95% CI.
Results
Forty-four patients were randomized to receive masitinib (n = 23) or sunitinib (n = 21). Median follow-up was 14 months. Patients receiving masitinib experienced less toxicity than those receiving sunitinib, with significantly lower occurrence of severe adverse events (52% versus 91%, respectively, P = 0.008). Median PFS (central RECIST) for the noncomparative primary analysis in the masitinib treatment arm was 3.71 months (90% CI 3.65). Secondary analyses showed that median OS was significantly longer for patients receiving masitinib followed by post-progression addition of sunitinib when compared against patients treated directly with sunitinib in second-line [hazard ratio (HR) = 0.27, 95% CI 0.09–0.85, P = 0.016]. This improvement was sustainable as evidenced by 26-month follow-up OS data (HR = 0.40, 95% CI 0.16–0.96, P = 0.033); an additional 12.4 months survival advantage being reported for the masitinib treatment arm. Risk of progression while under treatment with masitinib was in the same range as for sunitinib (HR = 1.1, 95% CI 0.6–2.2, P = 0.833).
Conclusions
Primary efficacy analysis ensured the masitinib treatment arm could satisfy a prespecified PFS threshold. Secondary efficacy analysis showed that masitinib followed by the standard of care generated a statistically significant survival benefit over standard of care. Encouraging median OS and safety data from this well-controlled and appropriately designed randomized trial indicate a positive benefit–risk ratio. Further development of masitinib in imatinib-resistant/intolerant patients with advanced GIST is warranted.
doi:10.1093/annonc/mdu237
PMCID: PMC4143095  PMID: 25122671
GIST; imatinib-resistant GIST; phase II study; tyrosine kinase inhibitor
8.  Phase I study of humanized monoclonal antibody AVE1642 directed against the type 1 insulin-like growth factor receptor (IGF-1R), administered in combination with anticancer therapies to patients with advanced solid tumors 
Annals of Oncology  2012;24(3):784-791.
Background
Type 1 insulin-like growth factor receptor (IGF-1R) mediates resistance to chemotherapy and targeted agents. This study assessed the safety, pharmacokinetics (PK), and tolerability of humanized IGF-1R antibody AVE1642 with other cancer treatments.
Patients
Patients with advanced solid tumors received three weekly AVE1642 dosed at 6 mg/kg, chosen following previous study, with 75 (cohort A) or 100 mg/m2 (B) docetaxel, 1250 mg/m2 gemcitabine/100 mg erlotinib (C1), or 60 mg/m2 doxorubicin (D1). Blood samples were assayed for PK, IGFs, and IGF-BP3.
Results
Fifty-eight patients received 317 AVE1642 infusions. The commonest adverse events were diarrhea (37/58 patients), asthenia (34/58), nausea (30/58), and stomatitis (21/58). Dose-limiting toxic effects in cohorts C1 (diarrhea) and D1 (neutropenia) prompted addition of cohorts C2 (1000 mg/m2 gemcitabine/75 mg erlotinib) and D2 (50 mg/m2 doxorubicin). Grade 3–4 hyperglycemia (three cases) accompanied steroid premedication for docetaxel administration. No PK interactions were detected. There were three partial responses in cohorts B (melanoma) and C (leiomyosarcoma, two cases) and 22 stabilizations ≥12 weeks, giving a control rate of 25/57 (44%). On treatment IGF-II rose by 68 ± 25 ng/ml in patients discontinuing treatment <12 weeks, and fell by 55.5 ± 21 ng/ml with disease control (P < 0.001).
Conclusion
AVE1642 was tolerable with 75–100 mg/m2 docetaxel and 1000 mg/m2 gemcitabine/75 mg erlotinib, achieving durable disease control in 44%, with an association between IGF-II and response.
doi:10.1093/annonc/mds511
PMCID: PMC3574548  PMID: 23104723
AVE1642; chemotherapy; erlotinib; type 1 IGF receptor; monoclonal antibody
9.  Growth modulation index as metric of clinical benefit assessment among advanced soft tissue sarcoma patients receiving trabectedin as a salvage therapy 
Annals of Oncology  2012;24(2):537-542.
Background
The growth modulation index (GMI) is the ratio of time to progression with the nth line (TTPn) of therapy to the TTPn−1 with the n-1th line. GMI >1.33 is considered as a sign of activity in phase II trials.
Patients and Methods
This retrospective analysis evaluated the concordance between the GMI and the efficacy outcomes in 279 patients with advanced soft tissue sarcoma (ASTS) treated with trabectedin 1.5 mg/m² (24-h infusion every 3 weeks) in four phase II trials.
Results
One hundred and forty-two (51%) patients received one prior line and 137 ≥2 lines. The median TTPn was 2.8 months (range 0.2–26.8), whereas the median TTPn−1 was 4.0 months (0.3–79.5). The median GMI was 0.6 (0.0–14.4). Overall, 177 patients (63%) had a GMI <1; 21 (8%) a GMI equal to 1–1.33 and 81 (29%) a GMI >1.33, which correlated with the median overall survival in those patients (9.1, 13.9 and 23.8 months, respectively, P = 0.0005). A high concordance rate between the GMI and response rate (P < 0.0001) and progression-free survival (PFS, P < 0.0001) was observed. Good performance status (PS) was the only factor associated with GMI >1.33 (PS = 0; P < 0.04).
Conclusions
A high GMI was associated with favorable efficacy outcomes in patients treated with trabectedin. Further research is needed to assess GMI as an indicator in this setting.
doi:10.1093/annonc/mds470
PMCID: PMC4271084  PMID: 23117071
growth modulation index; sarcoma; time-to-progression ratio; trabectedin
10.  Sarcoma: concordance between initial diagnosis and centralized expert review in a population-based study within three European regions 
Annals of Oncology  2012;23(9):2442-2449.
Background
Sarcomas represent a heterogeneous group of tumors. Accurate determination of histological diagnosis and prognostic factors is critical for the delineation of treatment strategies. The contribution of second opinion (SO) to improve diagnostic accuracy has been suggested for sarcoma but has never been established in population-based studies.
Methods
Histological data of patients diagnosed with sarcoma in Rhone-Alpes (France), Veneto (Italy) and Aquitaine (France) over a 2-year period were collected. Initial diagnoses were systematically compared with SO from regional and national experts.
Results
Of 2016 selected patients, 1463 (73%) matched the inclusion criteria and were analyzed. Full concordance between primary diagnosis and SO (the first pathologist and the expert reached identical conclusions) was observed in 824 (56%) cases, partial concordance (identical diagnosis of connective tumor but different grade or histological subtype) in 518 (35%) cases and complete discordance (benign versus malignant, different histological type or invalidation of the diagnosis of sarcoma) in 121 (8%) cases. The major discrepancies were related to histological grade (n = 274, 43%), histological type (n = 144, 24%), subtype (n = 18, 3%) and grade plus subtype or grade plus histological type (n = 178, 29%).
Conclusion
More than 40% of first histological diagnoses were modified at second reading, possibly resulting in different treatment decisions.
doi:10.1093/annonc/mdr610
PMCID: PMC3425368  PMID: 22331640
concordance evaluation; histological review; medical decision; molecular biology; sarcoma
11.  Cytokine and angiogenic factors associated with efficacy and toxicity of pazopanib in advanced soft-tissue sarcoma: an EORTC-STBSG study 
British Journal of Cancer  2012;107(4):639-645.
Background:
Pazopanib has activity in relapsed non-adipocytic soft-tissue sarcomas (STS). A series of serum cytokines and angiogenic factors (CAFs) at baseline and changes in soluble vascular endothelial growth factor receptor-2 (sVEGFR2) or placental-derived growth factor (PlGF) levels during treatment were explored for their association with outcome.
Methods:
Twenty-three baseline CAFs, and sVEGFR2 and PlGF changes were measured in 85 and 32 patients, respectively. Associations between baseline CAF levels and efficacy parameters, plus between-week 12 sVEGFR2 and PlGF levels and pazopanib-specific toxicities were investigated.
Results:
At baseline, low interleukin (IL)-12 p40 subunit and MPC3 levels were associated with better progression-free survival (PFS) at 12 weeks (PFS12wks), low basic nerve growth factor and hepatocyte growth factor with a better PFS, and low inter-cellular adhesion molecule-1 and IL-2 receptor alpha with prolonged overall survival (OS; all P<0.05). Pazopanib decreased sVEGFR2 and increased PlGF levels. Low sVEGFR2 and high PlGF levels at week 12 were associated with higher-grade hypertension, with TSH elevations and with poorer PFS12wks, and OS (both P<0.05).
Conclusion:
Several baseline CAFs were related to outcome parameters. Low sVEGFR2 and high PlGF at week 12 associate with several pazopanib-specific toxicities and poorer efficacy. If confirmed, these factors may be used as early markers for response to and toxicity from pazopanib, enabling further individualisation of STS treatment.
doi:10.1038/bjc.2012.328
PMCID: PMC3419967  PMID: 22805326
soft-tissue sarcomas; pazopanib; cytokines; prognosis
12.  Performance status is the most powerful risk factor for early death among patients with advanced soft tissue sarcoma The European Organisation for Research and Treatment of Cancer – Soft Tissue and Bone Sarcoma Group (STBSG) and French Sarcoma Group (FSG) study 
British Journal of Cancer  2011;104(10):1544-1550.
Background:
We investigated prognostic factors (PFs) for 90-day mortality in a large cohort of advanced/metastatic soft tissue sarcoma (STS) patients treated with first-line chemotherapy.
Methods:
The PFs were identified by both logistic regression analysis and probability tree analysis in patients captured in the Soft Tissue and Bone Sarcoma Group (STBSG) database (3002 patients). Scores derived from the logistic regression analysis and algorithms derived from probability tree analysis were subsequently validated in an independent study cohort from the French Sarcoma Group (FSG) database (404 patients).
Results:
The 90-day mortality rate was 8.6 and 4.5% in both cohorts. The logistic regression analysis retained performance status (PS; odds ratio (OR)=3.83 if PS=1, OR=12.00 if PS ⩾2), presence of liver metastasis (OR=2.37) and rare site metastasis (OR=2.00) as PFs for early death. The CHAID analysis retained PS as a major discriminator followed by histological grade (only for patients with PS ⩾2). In both models, PS was the most powerful PF for 90-day mortality.
Conclusion:
Performance status has to be taken into account in the design of further clinical trials and is one of the most important parameters to guide patient management. For those patients with poor PS, expected benefits from therapy should be weighed up carefully against the anticipated toxicities.
doi:10.1038/bjc.2011.136
PMCID: PMC3101912  PMID: 21505457
soft tissue sarcoma; early death; prediction
13.  Primary CNS lymphoma with intraocular involvement 
Neurology  2008;71(17):1355-1360.
Objective: To describe the demographics, diagnostic details, therapeutic management, and outcome in patients with primary CNS lymphoma (PCNSL) with ocular involvement.
Methods: A retrospective study of 221 patients was assembled from 16 centers in seven countries. Only HIV-negative, immunocompetent patients with brain and ocular lymphoma were included; none had systemic lymphoma.
Results: Median age at diagnosis was 60. Fifty-seven percent were women. Median Eastern Cooperative Oncology Group performance status was 2. Ocular disturbance and behavioral/cognitive changes were the most common presenting symptoms. Diagnosis of lymphoma was made by brain biopsy (147), vitrectomy (65), or CSF cytology (11). Diagnosis of intraocular lymphoma was made by vitrectomy/choroidal/retinal biopsy (90) or clinical ophthalmic examination (141). CSF cytology was positive in 23%. Treatment information was available for 176 patients. A total of 102 received dedicated ocular therapy (ocular radiotherapy 79, intravitreal methotrexate 22, and both 1) in addition to treatment for their brain lymphoma. Sixty-nine percent progressed at a median of 13 months; sites of progression included brain 52%, eyes 19%, brain and eyes 12%, and systemic 2%. Patients treated with local ocular therapy did not have a statistically significant decreased risk of failing in the eyes (p = 0.7). Median progression free survival and overall survival for the entire cohort were 18 and 31 months.
Conclusion: This is the largest reported series of primary CNS lymphoma (PCNSL) with intraocular involvement. Progression free and overall survival was similar to that reported with PCNSL. Dedicated ocular therapy improved disease control but did not affect overall survival.
doi:10.1212/01.wnl.0000327672.04729.8c
PMCID: PMC4109164  PMID: 18936428
14.  Identification of biological factors predictive of response to imatinib mesylate in aggressive fibromatosis 
British Journal of Cancer  2010;103(4):482-485.
Background:
Imatinib induces responses and disease stabilisations in non-resectable patients with aggressive fibromatosis (AF). The precise target of imatinib in AF and predictive factors for response to treatment are unknown.
Methods:
We investigated factors potentially predictive of response to imatinib in a series of 40 patients with progressive AF included in a phase II trial of imatinib: we tested the presence of KIT exon 10 variant (M541L), the expression of imatinib-sensitive kinases and cell cycle proteins by immunohistochemistry (IHC), and other clinical and biological factors.
Results:
Of 10 patients for whom DNA could be extracted, 3 had a KIT exon 10 variant (30%), with no correlation with response or progression-free survival (PFS). The expression of other imatinib targets (PDGFRA/B, macrophage colony-stimulating factor receptor (M-CSFR)) and of downstream components of the cell cycle, cell proliferation and proliferation pathway (cyclin D1, ERK, MEK 1–2) did not correlate with PFS. Pre-treatment lymphopenia (<1500/μl) and tumour size >120 mm correlated with shorter PFS in univariate and multivariate analyses.
Conclusion:
Our findings show that a baseline biological characteristic of the patient is the major parameter influencing response to imatinib in aggressive fibromatosis. Tumour characteristics, including the presence of a KIT exon 10 M541L variant, may influence tumour control but this needs to be confirmed and better explained.
doi:10.1038/sj.bjc.6605783
PMCID: PMC2939782  PMID: 20664593
aggressive fibromatosis; imatinib mesylate; predictive factors
15.  High frequency of β-catenin heterozygous mutations in extra-abdominal fibromatosis: a potential molecular tool for disease management 
British Journal of Cancer  2010;102(6):1032-1036.
Background:
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 β-catenin mutations in a European multicentre series of fibromatosis tumours to relate β-catenin mutational status to disease outcome.
Methods:
Direct sequencing of exon 3 β-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).
Results:
Mutations of β-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 β-catenin mutational status. With a median follow-up of 62 months, 51 patients relapsed. Five-year recurrence-free survival was significantly worse in β-catenin-mutated tumours regardless of a specific genotype, compared with wild-type tumours (49 vs 75%, respectively, P=0.02).
Conclusion:
A high frequency (87%) of β-catenin mutation hallmarks extra-abdominal fibromatosis from a large multicentric retrospective study. Moreover, wild-type β-catenin seems to be an interesting prognostic marker that might be useful in the therapeutic management of extra-abdominal fibromatosis.
doi:10.1038/sj.bjc.6605557
PMCID: PMC2844024  PMID: 20197769
β-catenin mutation; fibromatosis; prognostic factor
16.  Prognosis and predictive value of KIT exon 11 deletion in GISTs 
British Journal of Cancer  2009;101(1):7-11.
Background:
KIT exon 11 mutations are observed in 60% of gastrointestinal stromal tumours (GIST). Exon 11 codes for residues Tyr568 and Tyr570, which play a major role in signal transduction and degradation of KIT. Our aim was to compare the outcome of patients with deletion of both Tyr568–570 (delTyr) and the most frequent deletion delWK557–558 (delWK).
Methods:
Pathology and clinical characteristics of 68 patients with delTyr (n=26) or delWK (n=42) were reviewed and compared.
Results:
GISTs with delTyr were more frequently extragastric than those with delWK (69 vs 26%, P<0.0005). After curative surgery, median relapse-free survival were 10.8 and 11.1 months for patients with delTyr (n=14) and delWK (n=29), respectively (P=0.92). All patients treated with imatinib for a non-resectable or metastatic GIST had an objective response (n=15) or a stable disease (n=21) as best response, regardless of mutation. Median progression-free survival with imatinib were 21.9 and 18.9 months for patients with GIST with delTyr (n=14) and delWK (n=22), respectively (P=0.43).
Conclusion:
In this large retrospective series, the type of KIT exon 11 mutation was correlated with the origin of GIST, but not with prognosis or response to imatinib.
doi:10.1038/sj.bjc.6605117
PMCID: PMC2713701  PMID: 19536093
gastrointestinal stromal tumour; GIST; metastasis; prognostic; survival
18.  Multivariate analysis of prognostic factors in patients with non HIV-related primary cerebral lymphoma. A proposal for a prognostic scoring. 
British Journal of Cancer  1993;67(5):1136-1141.
Between 1982 and 1991, 41 patients were treated for non HIV related primary cerebral lymphoma (PCL) in our institute. The purpose of this study was to perform a multivariate analysis of prognostic factors for survival in these patients. The presence of a CSF protein level over 0.6 g l-1 at diagnosis was found to be the most significant unfavourable prognostic factor in univariate analysis and had not previously been reported. Among the five significant prognostic factors at diagnosis, (age over 60 years, performance status--ECOG scale--over 2, memory dysfunction, non hemispheric tumour site, CSF protein level over 0.6 g l-1 at the diagnosis), three independent factors were identified in multivariate analysis: (1) CSF protein level (P = 0.007; RR = 4.7); (2) PS > 2 (P = 0.04, RR = 2.65); (3) age over 60 (P = 0.08; RR = 2.43). Using the regression coefficient of these three parameters, we determined a prognostic index which allowed us to distinguish three risk groups whose theoretical median survival is 4, 20 and 54, months respectively in patients with non HIV related PCL. These results indicate that PCL is an heterogeneous disease in terms of the prognostic in which three subgroups with discriminant survival can be identified.
PMCID: PMC1968460  PMID: 8494713
19.  Incidence and prognostic value of tumour cells detected by RT–PCR in peripheral blood stem cell collections from patients with Ewing tumour 
British Journal of Cancer  2006;95(10):1326-1333.
To retrospectively evaluate the incidence of tumour cell contamination of peripheral blood stem cell (PBSC) collections and to correlate these data with the clinical outcome after high-dose chemotherapy (HDCT) with stem cell rescue in patients with a high-risk Ewing tumour. Peripheral blood stem cell collections obtained from 171 patients were analysed. Tumour contamination was assessed by reverse transcriptase–polymerase chain reaction (RT–PCR). The files of 88 patients who underwent HDCT followed by PBSC reinfusion were reviewed in detail, and their outcome compared to the PBSC RT–PCR results. Seven of 88 PBSC collections (8%) contained tumour cells as detected by RT–PCR. Peripheral blood stem cells were collected after a median of five cycles of chemotherapy. No clinical factor predictive of tumour cell contamination of PBSC harvest could be identified. Event-free survival (EFS) and overall survival (OS) of the whole study population were 45.3 % and 51.8 % at 3 years from the date of the graft, respectively. Forty-five patients relapsed with a median time of 15 months after graft, only four of whom had tumour cell contamination of the PBSC harvest. Tumour cell contamination of PBSC collection is rare and does not seem to be associated with a significantly poorer EFS or OS in this high-risk population.
doi:10.1038/sj.bjc.6603438
PMCID: PMC2360590  PMID: 17088915
ewing tumour; PBSC; tumour cell contamination; RT–PCR; outcome
20.  Autoantibodies to endostatin in patients with breast cancer: correlation to endostatin levels and clinical outcome 
British Journal of Cancer  2006;94(7):1066-1070.
Circulating autoantibodies to self-antigens overexpressed by cancer cells are common in cancer patients. As specific proteins are expressed during neoangiogenesis, a similar phenomenon might occur with particular antigens of tumour vessels. Collagen XVIII, from which endostatin is cleaved, is highly expressed in the perivascular basement membrane of tumour-associated blood vessels and autoantibodies to endostatin have been reported in cancer patients. The present study analyses the incidence of naturally occurring autoantibodies to endostatin in the sera of breast cancer patients and their relation to endostatin serum levels and patient clinical outcome. Serum samples from 36 patients with localised breast cancer and 59 patients with a fully documented history of metastatic breast cancer were used. The immunoreactivity of serum samples was tested against purified recombinant human endostatin and endostatin levels were determined by immunoassay. We could detect anti-endostatin antibodies in the sera of 66% of the patients with localised disease and 42% of the patients with metastatic disease (P=0.03). There was no correlation between the presence of antibodies to endostatin and circulating levels of endostatin. The detection of autoantibodies to endostatin was associated with better prognosis in metastatic breast cancer patients (median survival time: 20 vs 8 months, P=0.03), as was the presence of low levels of serum endostatin (median survival time: 20 vs 9 months, P=0.007). These results show that a natural immune reaction against endostatin can occur in breast cancer patients. This could have important therapeutic implications with regard to endostatin therapy and raises the question of a possible role of this humoral reaction against endostatin in the neoplastic process.
doi:10.1038/sj.bjc.6603037
PMCID: PMC2361231  PMID: 16552441
collagen XVIII; endostatin; autoantibodies
21.  Prognostic value of serum levels of interleukin 6 and of serum and plasma levels of vascular endothelial growth factor in hormone-refractory metastatic breast cancer patients 
British Journal of Cancer  2003;88(11):1721-1726.
doi:10.1038/sj.bjc.6600956
PMCID: PMC2377148  PMID: 12771987
multivariate analysis; survival rate; human; biological markers
22.  Baseline and early lymphopenia predict for the risk of febrile neutropenia after chemotherapy 
British Journal of Cancer  2003;88(2):181-186.
doi:10.1038/sj.bjc.6600724
PMCID: PMC2377052  PMID: 12610500
febrile neutropenia; lymphopenia; toxicity; chemotherapy; risk factors; risk model
23.  A phase I/II study of 4 monthly courses of high-dose cyclophosphamide and thiotepa for metastatic breast cancer patients 
British Journal of Cancer  2002;87(10):1079-1085.
This pilot phase I/II study intended to determine the maximum tolerated dose of cyclophosphamide and thiotepa administered on four consecutive courses with peripheral blood progenitor cell and granulocyte-colony stimulating factor support, as first-line therapy for hormone-refractory metastatic breast cancer patients. Twenty-eight patients were entered in the study. After two courses of epirubicin (120 mg m−2) and cyclophosphamide (2 g m−2) followed by granulocyte-colony stimulating factor injection and leukaphereses, patients received four cycles of cyclophosphamide and thiotepa. Each cycle was followed by peripheral blood progenitor cell and granulocyte-colony stimulating factor supports, then repeated every 28 to 35 days. Six escalating dose levels of cyclophosphamide and thiotepa were planned, beginning at cyclophosphamide 1.5 g m−2 and thiotepa 200 mg m−2. At least three patients were enrolled for each dose level. Eighteen patients completed the study. The maximum tolerated dose was 3000 mg m−2 cyclophosphamide and 400 mg m−2 thiotepa per course. Haematological toxicity was manageable on an outpatient basis and did not increase significantly with dose escalation. Dose-limiting toxicity was chemotherapy-induced immuno-suppression, which resulted in one toxic death and two life-threatening infections. Median times to treatment failure and survival were 11 and 26 months, respectively. Three patients were alive, free of disease 30 months after completion of the study. Such therapy allows for high-dose intensity and high cumulative doses on a short period of time with manageable toxicity.
British Journal of Cancer (2002) 87, 1079–1085. doi:10.1038/sj.bjc.6600631 www.bjcancer.com
© 2002 Cancer Research UK
doi:10.1038/sj.bjc.6600631
PMCID: PMC2376188  PMID: 12402145
filgrastim; haematopoietic stem cell transplantation; breast neoplasms; chemotherapy
24.  Identification of patients at risk for early death after conventional chemotherapy in solid tumours and lymphomas 
British Journal of Cancer  2001;85(6):816-822.
1–5% of cancer patients treated with cytotoxic chemotherapy die within a month after the administration of chemotherapy. Risk factors for these early deaths (ED) are not well known. The purpose of this study was to establish a risk model for ED after chemotherapy applicable to all tumour types. The model was delineated in a series of 1051 cancer patients receiving a first course of chemotherapy in the Department of Medicine of the Centre Léon Bérard (CLB) in 1996 (CLB-1996 cohort), and then validated in a series of patients treated in the same department in 1997 (CLB-1997), in a prospective cohort of patients with aggressive non-Hodgkin's lymphoma (NHL) (CLB-NHL), and in a prospective cohort of patients with metastatic breast cancer (MBC series) receiving first-line chemotherapy. In the CLB-1996 series, 43 patients (4.1%) experienced early. In univariate analysis, age > 60, PS > 1, lymphocyte (ly) count ≤ 700 μl−1 immediately prior to chemotherapy (d1), d1-platelet count ≤ 150 Gl−1, and the type of chemotherapy were significantly correlated to the risk of early death (P ≤ 0.01). Using logistic regression, PS > 1 (hazard ratio 3.9 (95% Cl 2.0–7.5)) and d1-ly count ≤ 700 μl−1 (3.1 (95% Cl 1.6–5.8)) were identified as independent risk factors for ED. The calculated probability of ED was 20% (95% Cl 10–31) in patients with both risk factors, 6% (95% Cl 4–9) for patients with only 1 risk factor, and 1.7% (95% Cl 0.9–3) for patients with none of these 2 risk factors. In the CLB-97, CLB-NHL and MBC validation series, the observed incidences of early death in patients with both risk factors were 19%, 25% and 40% respectively and did not differ significantly from those calculated in the model. In conclusion, poor performance status and lymphopenia identify a subgroup of patients at high risk for early death after chemotherapy. © 2001 Cancer Research Campaignhttp://www.bjcancer.com
doi:10.1054/bjoc.2001.2011
PMCID: PMC2375083  PMID: 11556830
lymphopenia; treatment-related death; cancer; risk factors; chemotherapy; cancer; palliative
25.  Renal cell carcinoma induces interleukin 10 and prostaglandin E2 production by monocytes 
British Journal of Cancer  1999;79(1):119-130.
Immunotherapy with interleukin 2 (IL-2) is not an effective anti-cancer treatment in the majority of patients with renal cell carcinoma (RCC), suggesting that the activation of cytotoxic T cells or NK cells may be impaired in vivo in these patients. The production of immunosuppressive factors by RCC was investigated. Using immunohistochemistry, IL-10 was detectable in 10 of 21 tumour samples tested. IL-10 was undetectable in the supernatant of cell lines derived from these RCCs. However, these cell lines or their conditioned medium (RCC CM), but not normal renal epithelial cells adjacent to the RCC or breastcarcinoma cell lines, were found to induce IL-10, as well as prostaglandin E2 (PGE2) and tumour necrosis factor (TNF)α production by autologous or allogeneic peripheral blood mononuclear cells (PBMCs) and monocytes. IL-10 production induced by RCC CM was found to be dependent on TNF-α and PGE2 since an anti-TNF-α antibody (Ab) inhibited 40–70% of IL-10 production by monocytes, and the combination of anti-TNF-α Ab and indomethacin, an inhibitor of PGE2 production, inhibited 80–94% of RCC CM-induced IL-10 production by monocytes. The RCC CM of the five cell lines tested were found to induce a down-regulation of the expression of HLA-DR and CD86, as well as a strong inhibition of mannose receptor-dependent endocytosis by monocytes. The blockade of HLA-DR and CD86 expression was partially abrogated by indomethacin and anti-IL-10 Ab respectively, and completely abrogated by an anti-TNF-α Ab. The inhibition of mannose receptor-dependent endocytosis was partially abrogated by an anti-IL-10 Ab and completely abrogated by an anti-TNF-α Ab. These esults indicate that RCCs induce IL-10, PGE2 and TNF-α production by monocytes, which down-regulate the expression of cell-surface molecules involved in antigen presentation as well as their endocytic capacity. © 1999 Cancer Research Campaign
doi:10.1038/sj.bjc.6690021
PMCID: PMC2362183  PMID: 10408703
interleukin 10; prostaglandin E2; tumour necrosis factor α; renal cell carcinoma; immunosuppression

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