Publications (39)221.08 Total impact
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Article: Peripheral T-Cell Lymphomas: An Analysis of the Histology, Staging and Response to Treatment of 208 Cases at a Single Institution.
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ABSTRACT: Condensed abstract Prognosis of peripheral T cell lymphoma is poor despite the use of bone marrow transplantation. Some new drugs offer real hope. There are no funding sources for the manuscript. Background: Peripheral T-cell lymphomas are characterized by a poor clinical outcome. Design and Methods: We retrospectively analyzed 208 adults treated in our institution between 2000 and 2011. Results: Median age at diagnosis was 55. Fifty-one percent had B symptoms and 51% serum elevated LDH levels. ECOG was 0-1 in 63% and 2-4 in 37%. According to Ann Arbor classification, 16% were at stage I-II and 84% at stage III-IV. The histological subtypes were: 39% of peripheral T-cell NHL unspecified (PTCL-U), and 19.5% anaplastic large cell lymphoma (ALCL), with 9.5% ALK+ and 10% ALK-, 25% of angio-immunoblastic lymphoma (AILT). Primary extranodal lymphoma represented 17% and 8% were diagnosed with hemophagocytosis. Induction chemotherapy was CHOP in 87% of patients. The median number of chemotherapy was 2 (1-7). A complete response was obtained for 57% of the patients. Among them, 32% had ASCT and 10% allogenic SCT, while 38 % were primary refractory. Five-year overall survival (OS) was 28.5% (22.3-36.3), and five year event-free survival (EFS) was 18.4 % (13.4-25.3). A multivariate analysis showed that ALCL-ALK+ (p=0.008), AILT (p<0.001), extranodal involvement (p=0.005), PS>1 (p<0.016), LDH>N (p=0.003), and hemophagocytosis (p=0.001) are independent adverse factors for OS. Conclusion: Conventional chemotherapy with intensive treatment is not sufficient to improve response rate. Optimal management is required.Leukemia & lymphoma 02/2013; · 2.40 Impact Factor -
Article: Two days of antithymocyte globulin are associated with a reduced incidence of acute and chronic graft-versus-host disease in reduced-intensity conditioning transplantation for hematologic diseases.
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ABSTRACT: BACKGROUND: The optimal combination of fludarabine, busulfan, and antithymocyte globulin (ATG) for reduced-intensity conditioning (RIC) transplantation has not been established. ATG plays a pivotal role in the prevention of graft-versus-host disease (GvHD), but it is associated with a higher relapse rate and an elevated incidence of infections when high doses are used. METHODS: The authors retrospectively compared 2 different doses of ATG combined with fludarabine and busulfan in 229 adult patients who underwent transplantation at their institution. ATG was administered over 1 day (FBA1) or over 2 days (FBA2) at a daily dose of 2.5 mg/kg. RESULTS: There were 124 patients in the FBA2 cohort and 105 patients in the FBA2 cohorts. Patients in the FBA2 cohort were older and more frequently underwent transplantation from an unrelated donor; 93% of patients in the FBA2 cohort received intravenous busulfan versus only 5% in the FBA1 cohort. The incidence of grade 2 through 4 acute GvHD was 23% in the FBA2 cohort versus 42% in the FBA1 cohort (P = .002); the incidence of grade 3 through 4 acute GvHD was 10% versus 23%, respectively (P = .006); and the incidence of chronic GvHD was 35% versus 69%, respectively (P < .0001). The 2-year rates of overall survival, nonrelapse mortality, and relapse/progression for the FBA1 and FBA2 cohorts were 65% versus 67%, respectively (P = .99), 20% versus 19%, respectively (P = .61), and 30% versus 19%, respectively (P = .09). The results were confirmed in multivariate analysis. CONCLUSIONS: The use of ATG at a dose of 5 mg/kg was correlated significantly with reduced incidence and severity of GvHD without impairing disease control. Taken together, the current results suggest that this conditioning represents a step forward in the optimization of RIC. Cancer 2012. © 2012 American Cancer Society.Cancer 10/2012; · 4.77 Impact Factor -
Article: Outcome of acute myeloid leukaemia following myelodysplastic syndrome after azacitidine treatment failure.
British Journal of Haematology 03/2012; 157(6):764-6. · 4.94 Impact Factor -
Article: Protein expression, survival and docetaxel benefit in node-positive breast cancer treated with adjuvant chemotherapy in the FNCLCC-PACS 01 randomized trial.
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ABSTRACT: The PACS01 trial has demonstrated that a docetaxel addition to adjuvant anthracycline-based chemotherapy improves disease-free survival (DFS) and overall survival of node-positive early breast cancer (EBC). We searched for prognostic and predictive markers for docetaxel's benefit. Tumor samples from 1,099 recruited women were analyzed for the expression of 34 selected proteins using immunohistochemistry. The prognostic and predictive values of each marker and four molecular subtypes (luminal A, luminal B, HER2-overexpressing, and triple-negative) were tested. Progesterone receptor-negativity (HR = 0.66; 95% CI 0.47 to 0.92, P = 0.013), and Ki67-positivity (HR = 1.53; 95% CI 1.12 to 2.08, P = 0.007) were independent adverse prognostic factors. Out of the 34 proteins, only Ki67-positivity was associated with DFS improvement with docetaxel addition (adjusted HR = 0.51, 95% CI 0.33 to 0.79 for Ki67-positive versus HR = 1.10, 95% CI 0.75 to 1.61 for Ki67-negative tumors, P for interaction = 0.012). Molecular subtyping predicted the docetaxel benefit, but without providing additional information to Ki67 status. The luminal A subtype did not benefit from docetaxel (HR = 1.16, 95% CI 0.73 to 1.84); the reduction in the relapse risk was 53% (HR = 0.47, 95% CI 0.22 to 1.01), 34% (HR = 0.66, 95% CI 0.37 to 1.19), and 12% (HR = 0.88, 95% CI 0.49 to 1.57) in the luminal B, HER2-overexpressing, and triple-negative subtypes, respectively. In patients with node-positive EBC receiving adjuvant anthracycline-based chemotherapy, the most powerful predictor of docetaxel benefit is Ki67-positivity.Breast cancer research: BCR 11/2011; 13(6):R109. · 5.24 Impact Factor -
Article: High expression of indoleamine 2,3‐dioxygenase in the tumour is associated with medullary features and favourable outcome in basal‐like breast carcinoma
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ABSTRACT: Medullary breast cancer (MBC) is a basal-like breast carcinoma (BLBC) with a favourable outcome, whereas nonmedullary BLBC has a poor prognosis. Tumour infiltrating lymphocytes (TILs) are present in both MBC and BLBC. We hypothesized that the immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) could modulate the TILs effects among these tumours and explain their different outcomes. The amount of TILs and IDO expression were analysed using immunohistochemistry (IHC) in 155 BC cases including MBC (n = 17), atypical MBC (n = 13) and non-MBC (n = 125). Messenger RNA expression of the INDO gene, which encodes IDO, was measured in 262 cases from our institution. INDO mRNA expression and histoclinical data of 1,487 BC cases were collected from public databases. IDO immunostaining was present in both neoplastic and stromal cells in 100% of MBC and was associated with histological medullary features among non-MBC cases. There was a significant correlation between IDO positivity and TIL amounts. In our series including mostly grade-3 BC, IDO immunostaining was the most significant marker (p = 0.02) associated with better survival in multivariate analysis. Among our 262 analysed BC cases, INDO mRNA showed significant overexpression in BLBC as compared to luminal A tumours, and in MBC as compared to basal-like non-MBC. In the pooled series of 1,749 BC cases, INDO mRNA was overexpressed in BLBC and was the most significant predictor of better survival in this subtype using multivariate analysis (p = 0.0024). In conclusion, high IDO expression is associated with morphological medullary features and has an independent favourable prognostic value in BLBC.International Journal of Cancer 10/2011; 130(1):96 - 104. · 5.44 Impact Factor -
Article: Non sentinel node involvement prediction for sentinel node micrometastases in breast cancer: nomogram validation and comparison with other models.
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ABSTRACT: The risk of non sentinel node (NSN) involvement varies in function of the characteristics of sentinel nodes (SN) and primary tumor. Our aim was to determine and validate a statistical tool (a nomogram) able to predict the risk of NSN involvement in case of SN micro or sub-micrometastasis of breast cancer. We have compared this monogram with other models described in the literature. We have collected data on 905 patients, then 484 other patients, to build and validate the nomogram and compare it with other published scores and nomograms. Multivariate analysis conducted on the data of the first cohort allowed us to define a nomogram based on 5 criteria: the method of SN detection (immunohistochemistry or by standard coloration with HES); the ratio of positive SN out of total removed SN; the pathologic size of the tumor; the histological type; and the presence (or not) of lympho-vascular invasion. The nomogram developed here is the only one dedicated to micrometastasis and developed on the basis of two large cohorts. The results of this statistical tool in the calculation of the risk of NSN involvement is similar to those of the MSKCC (the similarly more effective nomogram according to the literature), with a lower rate of false negatives. this nomogram is dedicated specifically to cases of SN involvement by metastasis lower or equal to 2 mm. It could be used in clinical practice in the way to omit ALND when the risk of NSN involvement is low.Breast (Edinburgh, Scotland) 10/2011; 21(2):204-9. · 2.09 Impact Factor -
Article: Outcome of high-risk myelodysplastic syndrome after azacitidine treatment failure.
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ABSTRACT: Azacitidine (AZA) is the current standard of care for high-risk (ie, International Prognostic Scoring System high or intermediate 2) myelodysplastic syndrome (MDS), but most patients will experience primary or secondary treatment failure. The outcome of these patients has not yet been described. Overall, 435 patients with high-risk MDS and former refractory anemia with excess blasts in transformation (RAEB-T) were evaluated for outcome after AZA failure. The cohort of patients included four data sets (ie, AZA001, J9950, and J0443 trials and the French compassionate use program). The median follow-up after AZA failure was 15 months. The median overall survival was 5.6 months, and the 2-year survival probability was 15%. Increasing age, male sex, high-risk cytogenetics, higher bone marrow blast count, and the absence of prior hematologic response to AZA were associated with significantly worse survival in multivariate analysis. Data on treatment administered after AZA failure were available for 270 patients. Allogeneic stem-cell transplantation and investigational agents were associated with a better outcome when compared with conventional clinical care. Outcome after AZA failure is poor. Our results should serve as a basis for designing second-line clinical trials in this population.Journal of Clinical Oncology 08/2011; 29(24):3322-7. · 18.37 Impact Factor -
Article: Gene expression profile predicts outcome after anthracycline-based adjuvant chemotherapy in early breast cancer.
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ABSTRACT: Prognosis of early beast cancer is heterogeneous. Today, no histoclinical or biological factor predictive for clinical outcome after adjuvant anthracycline-based chemotherapy (CT) has been validated and introduced in routine use. Using DNA microarrays, we searched for a gene expression signature associated with metastatic relapse after adjuvant anthracycline-based CT without taxane. We profiled a multicentric series of 595 breast cancers including 498 treated with such adjuvant CT. The identification of the prognostic signature was done using a metagene-based supervised approach in a learning set of 323 patients. The signature was then tested on an independent validation set comprising 175 similarly treated patients, 128 of them from the PACS01 prospective clinical trial. We identified a 3-metagene predictor of metastatic relapse in the learning set, and confirmed its independent prognostic impact in the validation set. In multivariate analysis, the predictor outperformed the individual current prognostic factors, as well as the Nottingham Prognostic Index-based classifier, both in the learning and the validation sets, and added independent prognostic information. Among the patients treated with adjuvant anthracycline-based CT, with a median follow-up of 68 months, the 5-year metastasis-free survival was 82% in the "good-prognosis" group and 56% in the "poor-prognosis" group. Our predictor refines the prediction of metastasis-free survival after adjuvant anthracycline-based CT and might help tailoring adjuvant CT regimens.Breast Cancer Research and Treatment 06/2011; 127(2):363-73. · 4.43 Impact Factor -
Article: A gene expression signature identifies two prognostic subgroups of basal breast cancer.
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ABSTRACT: Prognosis of basal breast cancers is poor but heterogeneous. Medullary breast cancers (MBC) display a basal profile, but a favorable prognosis. We hypothesized that a previously published 368-gene expression signature associated with MBC might serve to define a prognostic classifier in basal cancers. We collected public gene expression and histoclinical data of 2145 invasive early breast adenocarcinomas. We developed a Support Vector Machine (SVM) classifier based on this 368-gene list in a learning set, and tested its predictive performances in an independent validation set. Then, we assessed its prognostic value and that of six prognostic signatures for disease-free survival (DFS) in the remaining 2034 samples. The SVM model accurately classified all MBC samples in the learning and validation sets. A total of 466 cases were basal across other sets. The SVM classifier separated them into two subgroups, subgroup 1 (resembling MBC) and subgroup 2 (not resembling MBC). Subgroup 1 exhibited 71% 5-year DFS, whereas subgroup 2 exhibited 50% (P = 9.93E-05). The classifier outperformed the classical prognostic variables in multivariate analysis, conferring lesser risk for relapse in subgroup 1 (HR = 0.52, P = 3.9E-04). This prognostic value was specific to the basal subtype, in which none of the other prognostic signatures was informative. Ontology analysis revealed effective immune response (IR), enhanced tumor cell apoptosis, elevated levels of metastasis-inhibiting factors and low levels of metastasis-promoting factors in the good-prognosis subgroup, and a more developed cell migration system in the poor-prognosis subgroup. In conclusion, based on this 368-gene SVM model derived from an MBC signature, basal breast cancers were classified in two prognostic subgroups, suggesting that MBC and basal breast cancers share similar molecular alterations associated with aggressiveness. This signature could help define the prognosis, adapt the systemic treatment, and identify new therapeutic targets.Breast Cancer Research and Treatment 04/2011; 126(2):407-20. · 4.43 Impact Factor -
Article: Peritumoural vascular invasion: a major determinant of triple-negative breast cancer outcome.
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ABSTRACT: Triple-negative breast cancers (TNBC) have the worst outcome of all breast cancer subtypes. Nevertheless TNBC are heterogeneous in terms of pathological, biological and prognostic behaviours. We explored clinical and pathological factors correlated with outcome in this phenotype. We retrospectively studied clinical and pathological factors correlated with prognosis in a series of 344 early TNBC. Staining for blood (CD31) and lymphatic (Podoplanin) vascular endothelium markers was performed to best characterise peritumoural vascular invasion (PVI) in 108 cases available for pathological reviewing. Univariate and multivariate analyses performed on our whole cohort underlined PVI as an independent predictive factor of distant metastasis (p=0.00012, HR=2.72 [1.63-4.52]). Standardised pathological reviewing of 101 histologically confirmed TNBC showed that PVI, observed in 41% (28% by haematoxylin and eosin staining plus 13% by immunohistochemistry), was confirmed as the first prognostic factor in TNBC, particularly in node-negative tumours. Five-year metastasis-free survival in this subset was 87.5% and 50.8% without and with PVI, respectively (p=0.003). Vascular invasion diagnosis is improved by the combination of HES and IHC. Moreover it is a major prognostic feature and must take a greater part in therapeutic management of early TNBC with the possibility to adapt the adjuvant treatment according to the predicted relapse risk.European journal of cancer (Oxford, England: 1990) 03/2011; 47(10):1537-45. · 4.12 Impact Factor -
Article: Capecitabine after anthracycline and taxane exposure in HER2-negative metastatic breast cancer patients: response, survival and prognostic factors.
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ABSTRACT: Capecitabine is a widely accepted option in pre-treated metastatic breast cancer (MBC) patients. However, little is known about specific activity in molecularly defined subgroups of patients. Here, response, survival and prognostic factors were examined in a prospectively characterized cohort of human epidermal growth factor receptor 2 (HER2) negative MBC patients receiving capecitabine following anthracycline and taxane failure. Medical records from 75 HER2-negative MBC pre-treated with anthracycline and/or taxane and receiving capecitabine monotherapy at the Institut Paoli-Calmettes between 2002 and 2009 were reviewed. Univariate and multivariate analysis according the Cox regression model were employed to identify factors predictive for response, progression-free survival (PFS) and overall survival (OS). Overall, the objective response rate (ORR) was 29.3% (95% CI: 20-40). The ORR in HER2-negative/hormonal receptor (HRe) positive and HER2-negative/HRe-negative patients were 37% (95% CI: 26-50) and 0% (95% CI: 0-19), respectively, (p=0.003, Fisher's test). With a median follow-up of 35.2 months after capecitabine initiation, median PFS was 6.6 months (95% CI: 4.7-10.4) and median OS was 18.4 months (95% CI:14.1-24.9). In univariate analysis, HRe-negative status was the strongest prognostic factor for PFS (hazard ratio (HR)=2.09; p-value=0.015, log-rank test). In multivariate analysis, only three variables (HRe-negative status, initial disease-free interval <24 months and extra-regional lymph node involvement) were considered independently associated with poor PFS, while five variables (grade 2/3, initial disease-free interval <24 months, central nervous system metastases, interval between diagnosis of metastases and capecitabine initiation <24 months, and number of metastatic sites on capecitabine initiation) were associated with poor OS. The median OS of pretreated patients with HER2-negative MBC receiving capecitabine is approximately 18 months, but HER2-negative/HRe-negative patients have a low probablility of response/disease control to capecitabine and require innovative therapies.Anticancer research 03/2011; 31(3):1079-86. · 1.73 Impact Factor -
Article: High expression of indoleamine 2,3-dioxygenase in the tumour is associated with medullary features and favourable outcome in basal-like breast carcinoma.
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ABSTRACT: Medullary breast cancer (MBC) is a basal-like breast carcinoma (BLBC) with a favourable outcome, whereas nonmedullary BLBC has a poor prognosis. Tumour infiltrating lymphocytes (TILs) are present in both MBC and BLBC. We hypothesized that the immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) could modulate the TILs effects among these tumours and explain their different outcomes. The amount of TILs and IDO expression were analysed using immunohistochemistry (IHC) in 155 BC cases including MBC (n = 17), atypical MBC (n = 13) and non-MBC (n = 125). Messenger RNA expression of the INDO gene, which encodes IDO, was measured in 262 cases from our institution. INDO mRNA expression and histoclinical data of 1,487 BC cases were collected from public databases. IDO immunostaining was present in both neoplastic and stromal cells in 100% of MBC and was associated with histological medullary features among non-MBC cases. There was a significant correlation between IDO positivity and TIL amounts. In our series including mostly grade-3 BC, IDO immunostaining was the most significant marker (p = 0.02) associated with better survival in multivariate analysis. Among our 262 analysed BC cases, INDO mRNA showed significant overexpression in BLBC as compared to luminal A tumours, and in MBC as compared to basal-like non-MBC. In the pooled series of 1,749 BC cases, INDO mRNA was overexpressed in BLBC and was the most significant predictor of better survival in this subtype using multivariate analysis (p = 0.0024). In conclusion, high IDO expression is associated with morphological medullary features and has an independent favourable prognostic value in BLBC.International Journal of Cancer 02/2011; 130(1):96-104. · 5.44 Impact Factor -
Article: Reduced-intensity conditioning with Fludarabin, oral Busulfan, and thymoglobulin allows long-term disease control and low transplant-related mortality in patients with hematological malignancies.
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ABSTRACT: The development of reduced-intensity conditioning regimens rather than myeloablative regimens for allogeneic stem cell transplantation has led to decreased treatment-related mortality and increased use of this treatment modality, especially in older patients with hematological malignancies. No randomized controlled trials have been performed resulting in determining effectiveness on phase II studies, which rarely report on long-term survival. In an attempt to address this limitation, we analyzed a single-center cohort of 100 consecutive patients with hematological malignancies undergoing allogeneic stem cell transplantation from a human leukocyte antigen-matched related donor with median follow-up of 60 months. The reduced-intensity conditioning regimen consisted of oral Busulfan, rabbit anti-thymocyte globulin, and Fludarabin. Median age was 50 years (range, 18-64 years). The incidences of acute and chronic graft-vs.-host disease were 43% and 81%, respectively. The probability of nonrelapse mortality at 1 and 5 years was 15% and 25%, respectively. Nonrelapse mortality was adversely associated with acute graft-vs.-host disease (hazard ratio = 6; p = 0.0002). Of the 52 patients with measurable disease, 37 (71%) achieved a response. Relapse/progression occurred at a median of 11 months (range 1-52 months) in 21 patients, for a cumulative incidence of 22%. The probability of overall survival and progression-free survival at 5 years were 60% and 54%, respectively. Overall survival and progression-free survival were favorably influenced by having had previous autologous stem cell transplantation and a low CD34(+) cell dose. Overall survival, progression-free survival, and nonrelapse mortality improved over time in this cohort of patients. These results are encouraging for populations different in term of age, diagnosis, and disease status.Experimental hematology 12/2010; 38(12):1241-50. · 3.11 Impact Factor -
Article: Predictive factors of tumor response after neoadjuvant chemoradiation for locally advanced rectal cancer.
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ABSTRACT: Neoadjuvant chemoradiation followed by surgery is the standard of care for locally advanced rectal cancer. The aim of this study was to correlate tumor response to survival and to identify predictive factors for tumor response after chemoradiation. From 1998 to 2008, 168 patients with histologically proven locally advanced adenocarcinoma treated by preoperative chemoradiation before total mesorectal excision were retrospectively studied. They received a radiation dose of 45 Gy with a concomitant 5-fluorouracil (5-FU)-based chemotherapy. Analysis of tumor response was based on lowering of the T stage between pretreatment endorectal ultrasound and pathologic specimens. Overall and progression-free survival rates were correlated with tumor response. Tumor response was analyzed with predictive factors. The median follow-up was 34 months. Five-year disease-free survival and overall survival rates were, of 44.4% and 74.5% in the whole population, 83.4% and 83.4%, respectively, in patients with pathological complete response, 38.6% and 71.9%, respectively, in patients with tumor downstaging, and 29.1 and 58.9% respectively, in patients with absence of response. A pretreatment carcinoembryonic antigen (CEA) level of <5 ng/ml was significantly independently associated with pathologic complete tumor response (p = 0.019). Pretreatment small tumor size (p = 0.04), pretreatment CEA level of <5 ng/ml (p = 0.008), and chemotherapy with capecitabine (vs. 5-FU) (p = 0.04) were significantly associated with tumor downstaging. Downstaging and complete response after CRT improved progression-free survival and overall survival of locally advanced rectal adenocarcinoma. In multivariate analysis, a pretreatment CEA level of <5 ng/ml was associated with complete tumor response. Thus, small tumor size, a pretreatment CEA level of < 5 ng/ml, and use of capecitabine were associated with tumor downstaging.International journal of radiation oncology, biology, physics 11/2010; 80(2):483-91. · 4.59 Impact Factor -
Article: Improved outcome of patients with low- and intermediate-risk cytogenetics acute myeloid leukemia (AML) in first relapse with gemtuzumab and cytarabine versus cytarabine: results of a retrospective comparative study.
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ABSTRACT: Acute myeloid leukemia (AML) in first relapse is associated with a poor outcome even when treated with intermediate- to high-dose cytarabine (IHDAraC). Gemtuzumab ozogamycin (GO) used as a single agent has clinical activity in relapsed and refractory AML. Various combination regimens of GO have been developed, but few data are available regarding their efficacy compared with IHDAraC-based regimens. The authors performed a retrospective analysis of response and survival in 90 AML patients in first relapse treated with either IHDAraC (n = 56) or IHDAraC + GO (n = 34). Patient characteristics of the two groups were comparable. Median follow-up was 37 months. Compared with IHDAraC, IHDAraC + GO induction was associated with a better response rate (68% vs 45%, P = .04), a better overall survival (median, 35 months vs 6 months, P = .001), and a better event-free survival (24 months vs 6 months, P = .002). This effect was limited to patients with low-risk and intermediate-risk cytogenetics. In multivariate analysis, age, cytogenetic risk, first complete remission duration, and the use of IHDAraC + GO were independently associated with better results. This study showed that the addition of GO to IHDAraC is associated with a better efficacy for patients in first relapse of AML with low- or intermediate-risk cytogenetics. Prospective controlled studies of GO in this population are warranted. Patients with high-risk cytogenetics should be offered investigational new drugs.Cancer 10/2010; 117(5):974-81. · 4.77 Impact Factor -
Article: The cell polarity PTK7 receptor acts as a modulator of the chemotherapeutic response in acute myeloid leukemia and impairs clinical outcome.
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ABSTRACT: The pseudo tyrosine kinase receptor 7 (PTK7) is an orphan tyrosine kinase receptor assigned to the planar cell polarity pathway. It plays a major role during embryogenesis and epithelial tissue organization. Here we found that PTK7 is also expressed in normal myeloid progenitors and CD34(+) CD38(-) bone marrow cells in humans. We performed an immunophenotyping screen on more than 300 patients treated for hematologic malignancies. We demonstrated that PTK7 is expressed in acute myeloid leukemia (AML) and is mostly assigned to granulocytic lineage differentiation. Patients with PTK7-positive AML are more resistant to anthracycline-based frontline therapy with a significantly reduced leukemia-free survival in a multivariate analysis model. In vitro, expression of PTK7 in cultured leukemia cells promotes cell migration, cell survival, and resistance to anthracycline-induced apoptosis. The intracellular region of PTK7 is required for these effects. Furthermore, we efficiently sensitized primary AML blasts to anthracycline-mediated cell death using a recombinant soluble PTK7-Fc protein. We conclude that PTK7 is a planar cell polarity component expressed in the myeloid progenitor compartment that conveys promigratory and antiapoptotic signals into the cell and that represents an independent prognosis factor of survival in patients treated with induction chemotherapy.Blood 09/2010; 116(13):2315-23. · 9.90 Impact Factor -
Article: Impact of prior invasive aspergillosis on outcome in patients receiving reduced-intensity conditioning allogeneic hematopoietic stem cell transplant.
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ABSTRACT: Invasive aspergillosis (IA) is a major cause of morbidity in patients with hematological malignancies, and a major impediment to the success of allogeneic stem cell transplant (allo-SCT). The aim of this single-center retrospective study was to determine the impact of pre-transplant IA on the outcome of allo-SCT after reduced-intensity conditioning (RIC). Twenty-eight cases of proven or probable IA were diagnosed prior to RIC allo-SCT at the Paoli-Calmettes Institute Cancer Center between January 2000 and January 2008. These cases were identified among 360 patients undergoing allo-SCT. IA was defined according to EORTC criteria. Patients had predominantly (82%) acute myeloid leukemia, were diagnosed with IA at a median of 8 months (range, 1-16) pre-transplant, and received antifungal therapy for a median of 5 months (range, 1-13). IA therapy included: voriconazole (71%); single-agent itraconazole (14%); and a combination of agents (14%). Secondary prophylaxis against aspergillosis was maintained during conditioning and post-transplant in 89% of patients. After transplant, only three patients (11%) had reactivation of their IA and one patient developed disseminated fusariosis. The latter four patients experienced severe acute GVHD treated with high-dose corticosteroids. None of these patients died of IA. Eighteen patients (64%) are still alive, with a median follow-up of 23.5 months (range, 12.6-48.5). Overall survival at 2 years was 59% (95% CI, 43-83%). These data suggest that patients with adequately controlled IA can tolerate RIC allo-SCT without significant post-transplant complications.Leukemia & lymphoma 09/2010; 51(9):1705-10. · 2.40 Impact Factor -
Article: ASXL1 mutation is associated with poor prognosis and acute transformation in chronic myelomonocytic leukaemia.
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ABSTRACT: Chronic myelomonocytic leukaemia (CMML) is a haematological disease currently classified in the category of myelodysplastic syndromes/myeloproliferative neoplasm (MDS/MPN) because of its dual clinical and biological presentation. The molecular biology of CMML is poorly characterized. We studied a series of 53 CMML samples including 31 cases of myeloproliferative form (MP-CMML) and 22 cases of myelodysplastic forms (MD-CMML) using array-comparative genomic hybridisation (aCGH) and sequencing of 13 candidate genes including ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, PTPN11, RUNX1, TET2 and WT1. Mutations in ASXL1 and in the genes associated with proliferation (CBL, FLT3, PTPN11, NRAS) were mainly found in MP-CMML cases. Mutations of ASXL1 correlated with an evolution toward an acutely transformed state: all CMMLs that progressed to acute phase were mutated and none of the unmutated patients had evolved to acute leukaemia. The overall survival of ASXL1 mutated patients was lower than that of unmutated patients.British Journal of Haematology 09/2010; 151(4):365-75. · 4.94 Impact Factor -
Article: The learning curve for the laparoscopic approach to conservative mesorectal excision for rectal cancer: lessons drawn from a single institution's experience.
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ABSTRACT: We aimed to determine the most sensitive markers of the learning process for laparoscopic conservative mesorectal excision (LCME) for rectal cancer to (1) generate a relevant training program for junior surgeons and (2) define appropriate settings for prospective trials. The learning process for the laparoscopic approach to treating rectal cancer has not yet been clearly described. Over a 42-month period, 127 patients received LCME at our institution. The procedure was performed or supervised by a single referent surgeon. The operative time, conversion to open procedure postoperative morbidity, microscopic margins, and local recurrence were thought to be the most relevant parameters related to the learning process. To give a comprehensive view of success, a single hybrid variable was generated. Curves were drawn using the moving average method for continuous variables and the CUSUM analysis was used for binary variables. A slow but continuous decrease in operative time was observed over all the study period. The overall and surgical morbidities were the most sensitive markers. The conversion rate and R0-resection rate remained stable at 14.9% and 91%, respectively. The overall local recurrence rate was 4.7% at a median follow-up time of 40 months and was not affected by the learning process. The success rate reached a steady state after 50 patients. Despite surgeons' early command of the conversion rate, the learning process for LCME affects morbidity for the first 50 patients operated on, but does not adversely affect the oncological results. Much emphasis should therefore be placed on technical training.Annals of surgery 02/2010; 251(2):249-53. · 7.90 Impact Factor -
Article: Aldehyde dehydrogenase 1-positive cancer stem cells mediate metastasis and poor clinical outcome in inflammatory breast cancer.
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ABSTRACT: To examine the role of cancer stem cells (CSC) in mediating metastasis in inflammatory breast cancer (IBC) and the association of these cells with patient outcome in this aggressive type of breast cancer. CSCs were isolated from SUM149 and MARY-X, an IBC cell line and primary xenograft, by virtue of increased aldehyde dehydrogenase (ALDH) activity as assessed by the ALDEFLUOR assay. Invasion and metastasis of CSC populations were assessed by in vitro and mouse xenograft assays. Expression of ALDH1 was determined on a retrospective series of 109 IBC patients and this was correlated with histoclinical data. All statistical tests were two sided. Log-rank tests using Kaplan-Meier analysis were used to determine the correlation of ALDH1 expression with development of metastasis and patient outcome. Both in vitro and xenograft assays showed that invasion and metastasis in IBC are mediated by a cellular component that displays ALDH activity. Furthermore, expression of ALDH1 in IBC was an independent predictive factor for early metastasis and decreased survival in this patient population. These results suggest that the metastatic, aggressive behavior of IBC may be mediated by a CSC component that displays ALDH enzymatic activity. ALDH1 expression represents the first independent prognostic marker to predict metastasis and poor patient outcome in IBC. The results illustrate how stem cell research can translate into clinical practice in the IBC field.Clinical Cancer Research 12/2009; 16(1):45-55. · 7.74 Impact Factor
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Institutions
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2011–2012
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Johns Hopkins University
Baltimore, MD, USA
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2007–2012
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Institut Paoli Calmettes
Marseille, Provence-Alpes-Cote d'Azur, France
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2005
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LE CHU DE NIMES : CENTRE HOSPITALIER UNIVERSITAIRE
Nîmes, Languedoc-Roussillon, France
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