Azzam F G Taktak

Institut Curie, Lutetia Parisorum, Île-de-France, France

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Publications (37)79.52 Total impact

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    ABSTRACT: This Correspondence relates to the article by Lake et al that reported copy number and genotyping analysis on formalin-fixed, paraffin-embedded samples using genome-wide SNP arrays version 6.0.
    American Journal Of Pathology 08/2013; 183(2):638-40. · 4.60 Impact Factor
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    American Journal Of Pathology 08/2013; 183(2):638-40. · 4.60 Impact Factor
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    ABSTRACT: Metastatic death from uveal melanoma occurs almost exclusively with tumors showing monosomy of chromosome 3. However, approximately 5% of patients with a disomy 3 uveal melanoma develop metastases, and a further 5% of monosomy 3 uveal melanoma patients exhibit disease-free survival for >5 years. In the present study, whole-genome microarrays were used to interrogate four clinically well-defined subgroups of uveal melanoma: i) disomy 3 uveal melanoma with long-term survival; ii) metastasizing monosomy 3 uveal melanoma; iii) metastasizing disomy 3 uveal melanoma; and iv) monosomy 3 uveal melanoma with long-term survival. Cox regression and Kaplan-Meier survival analysis identified that amplification of the CNKSR3 gene (log-rank, P = 0.022) with an associated increase in its protein expression (log-rank, P = 0.011) correlated with longer patient survival. Although little is known about CNKSR3, the correlation of protein expression with increased survival suggests a biological function in uveal melanoma, possibly working to limit metastatic progression of monosomy 3 uveal melanoma cells.
    American Journal Of Pathology 01/2013; · 4.60 Impact Factor
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    ABSTRACT: Survival in choroidal melanoma was modelled using accelerated failure time models. We combined pathological, clinical and genetic data, using imputation techniques. Performance was assessed using n-fold cross-validation. Using data from 3653 patients, we generated two models; the first using clinical data only and the second using clinical and laboratory data. The c-index of discrimination was 0.75 for the clinical model and 0.79 for the laboratory model. Calibration showed good correlation between predicted and observed mortality (p-value: 0.699 for clinical model and 0.801 for laboratory model). We conclude that our model provides reasonably reliable prognosis relevant to individual patients.
    Int. J. of Biomedical Engineering and Technology. 01/2012; 8(1):18 - 35.
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    ABSTRACT: To determine the occurrence of BRAF V600E gene mutations and copy number changes of all autosome arms and genes known to be frequently altered in tumorigenesis in primary and metastatic conjunctival melanomas (CoMs). DNA (200 ng) was analyzed by three multiplex ligation-dependent probe amplification assays (P027 uveal melanoma, P036 human telomere, and P206 spitzoid melanoma). Eight of 16 primary tumor samples and 4 of 6 metastatic samples showed BRAF V600E gene mutations. CDKN1A and RUNX2 (both 6p21.2) were amplified in 11 and 16 of 21 primary CoMs, respectively. In metastatic CoMs, MLH1 (3p22.1) and TIMP2 (17q25.3) were frequently amplified, and MGMT (20q26.3) and ECHS1 (10q26.3) were frequently deleted. The BDH (3q), FLJ20265 (4p), OPRL1 (20q), and PAO (10q) genes, representing the telomeres of their respective chromosome arms in the P036 assay, were frequently amplified in metastatic CoMs. No statistically significant associations were identified between BRAF mutation or CDKN1A or RUNX2 amplification and sex, age, histologic cell type, or patient survival. No copy number changes were associated exclusively with metastatic CoMs. However, further investigation of the role of CDKN1A and RUNX2 in CoMs development and that of MLH1, TIMP2, MGMT, and ECHS1 in metastatic CoMs is warranted. Validation of the observed gene and chromosome arm copy number changes in a larger cohort of primary and metastatic CoMs is necessary to identify the patients at highest risk for CoMs metastasis.
    Investigative ophthalmology & visual science 06/2011; 52(8):5598-604. · 3.43 Impact Factor
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    ABSTRACT: To determine whether biopsy of extraocular extension of uveal melanoma (UM) is representative of the intraocular tumor with respect to copy number of chromosomes 1p, 3, 6, and 8. Multiplex ligation-dependent probe amplification (MLPA) using the P027 assay was performed on formalin-fixed, paraffin-embedded sections from 10 UMs. The intraocular and extraocular parts of the tumor were microdissected and analyzed separately. Of the 10 UMs analyzed, seven showed heterogeneity for at least one chromosome arm; the most frequently heterogeneous chromosome arm was 6p. No heterogeneity of 8p was observed between the intraocular and extraocular areas of the tumor. One tumor showed monosomy 3 in the intraocular area of the tumor but loss of the 3q arm only for the extraocular area. Biopsy of an extraocular tumor extension may not be representative of the underlying UM with respect to chromosome 1p, 3, 6, and 8q abnormalities detectable by MLPA. These results suggest that for UM with extraocular extension, both the intraocular and the extraocular parts of the tumor should be sampled for accurate genetic prognostic testing.
    Investigative ophthalmology & visual science 06/2011; 52(8):5559-64. · 3.43 Impact Factor
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    ABSTRACT: Choroidal melanoma is fatal in about 50% of patients. This is because of metastatic disease, which usually involves the liver. Kaplan-Meier survival curves based only on tumor size and extent do not give a true indication of prognosis. This is because the survival prognosis of choroidal melanoma correlates not only with clinical stage but also with histologic grade, genetic type, and competing causes of death. We have developed an online tool that predicts survival using all these data also taking normal life-expectancy into account. The estimated prognosis is accurate enough to be relevant to individual patients. Such personalized prognostication improves the well-being of patients having an excellent survival probability, not least because it spares them from unnecessary screening tests. Such screening can be targeted at high-risk patients, so that metastases are detected sooner, thereby enhancing any opportunities for treatment. Concerns about psychological harm have proved exaggerated. At least in Britain, patients want to know their prognosis, even if this is poor. The ability to select patients with a high risk of metastasis improves prospects for randomised studies evaluating systemic adjuvant therapy aimed at preventing or delaying metastatic disease. Furthermore, categorization of tissue samples according to survival prognosis enables laboratory studies to be undertaken without waiting many years for survival to be measured. As a result of advances in histologic and genetic studies, biopsy techniques and statistics, prognostication has become established as a routine procedure in our clinical practice, thereby enhancing the care of patients with uveal melanoma.
    Progress in Retinal and Eye Research 05/2011; 30(5):285-95. · 9.44 Impact Factor
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    ABSTRACT: Purpose:  Almost 40% of uveal melanomas (UM) are fatal, because of metastatic disease that usually involves the liver. Partial or complete deletion of chromosome 3 (i.e., monosomy 3) is a strong predictor of metastatic mortality; however, genetic analysis is not always possible. The aim of this study was to determine whether heat shock protein 27 (HSP-27) protein expression could reliably predict prognosis. Methods:  Immunohistochemical analysis of HSP-27 protein expression was performed on formalin-fixed, paraffin-embedded sections from 99 UM of known chromosome 3 status, as determined by multiplex ligation-dependent probe amplification. Slides were evaluated blind by three independent observers. The percentage of tumour cells staining for HSP-27 was categorized as: 0 (<1%); 1 (1-24%); 2 (25-49%); 3 (50-74%) or 4 (>74%). The staining intensity was categorized as: 0 (no staining); 1 (weak); 2 (moderate) and 3 (strong). These two categories were multiplied together to obtain the HSP-27 expression score. All data were processed in spss for statistical analyses. Results:  Heat shock protein 27 score was lower in monosomy 3 melanomas than in disomy 3 tumours (p < 0.001; Mann-Whitney U-test). An 'accelerated failure time model' was used to generate predicted survival for all patients included in the study. Kaplan-Meier analysis indicated a significantly decreased predicted 8-year survival rate for patients with an HSP-27 Score ≤6 (p = 0.03; Log rank test). Predicting monosomy 3 was enhanced by considering the HSP-27 score together with basal tumour diameter, melanoma cytomorphology and mitotic rate. Conclusions:  Low HSP-27 expression correlates with monosomy 3 in UM and with increased predicted mortality. When assessed together with other clinical and pathological variables, the HSP-27 score enhances estimation of survival probability.
    Acta ophthalmologica 11/2010; 90(6):534-9. · 2.44 Impact Factor
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    ABSTRACT: To determine intratumor genetic heterogeneity in uveal melanoma (UM) by multiplex ligation-dependent probe amplification (MLPA) in formalin-fixed, paraffin-embedded (FFPE) tumor tissues. DNA was extracted from whole tumor sections and from two to nine different areas microdissected from 32 FFPE UMs. Thirty-one loci on chromosomes 1, 3, 6, and 8 were tested with MLPA for copy number changes. The tumor was considered heterogeneous at a locus if (1) the difference in dosage quotients (DQs) of any two areas was 0.2 or more, and (2) the DQs of the areas belonged to different ranges. Comparison of MLPA data obtained from microdissected areas of the UMs showed heterogeneity in 1 to 26 examined loci in 24 (75%) tumors, with only 25% of the tumors being homogeneous. Intratumor heterogeneity of 3p12.2, 6p21.2, and 8q11.23 was most common, occurring in >30% of the UMs. Gains of chromosome 3 were observed in four UMs, with three of these tumors showing the highest degree of heterogeneity. Copy number variation was associated with differences in tumor cell type, but not with differences in tumor pigmentation or reactive inflammation. UMs with genetic heterogeneity across multiple sample sites showed equivocal MLPA results when the whole tumor section was examined. These results suggest that different clones dilute MLPA results. Heterogeneity of chromosomal abnormalities of chromosomes 1, 3, 6, and 8 is present in most UMs. This heterogeneity causes equivocal MLPA results. One random tumor sample may not be representative of the whole tumor and, therefore, may be insufficient for prognostic testing.
    Investigative ophthalmology & visual science 10/2010; 51(10):4898-905. · 3.43 Impact Factor
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    ABSTRACT: To detect deletions and loss of heterozygosity of chromosome 3 in a rare subset of fatal, disomy 3 uveal melanoma (UM), undetectable by fluorescence in situ hybridization (FISH). Multiplex ligation-dependent probe amplification (MLPA) with the P027 UM assay was performed on formalin-fixed, paraffin-embedded (FFPE) whole tumor sections from 19 disomy 3 metastasizing UMs. Whole-genome microarray analyses using a single-nucleotide polymorphism microarray (aSNP) were performed on frozen tissue samples from four fatal disomy 3 metastasizing UMs and three disomy 3 tumors with >5 years' metastasis-free survival. Two metastasizing UMs that had been classified as disomy 3 by FISH analysis of a small tumor sample were found on MLPA analysis to show monosomy 3. No ubiquitous gene deletions of chromosome 3 were seen in the remaining 17 metastasizing disomy 3 UMs by MLPA. aSNP analysis revealed 95 deleted genes and 16 genes with loss of heterozygosity (LOH) on chromosome 3 in the disomy 3 metastasizing UMs that were not deleted or showing LOH in the nonmetastatic tumors. MLPA can detect monosomy 3 cell populations in FFPE whole tumor sections previously missed by FISH performed on small tumor samples. Consistent deletion and LOH of genes on chromosome 3 occur in metastasizing disomy 3 UM and are detectable by aSNP analysis. Ninety-five genes were found to be deleted, and 16 genes showed LOH exclusively in disomy 3 metastasizing UM, suggesting a potential role for these genes in UM metastasis.
    Investigative ophthalmology & visual science 05/2010; 51(10):4884-91. · 3.43 Impact Factor
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    ABSTRACT: The mitotic count of uveal melanomas correlates with the risk of metastatic death, but with haematoxylin and eosin (H&E)-stained sections, it can be difficult to identify mitotic figures (MF) reliably. We investigated whether this measurement could be enhanced by immunohistochemistry, using the mitosis-specific marker Phospho-Histone H3 Ser10 (PHH3). Formalin-fixed, paraffin-embedded choroidal melanomas from patients treated by enucleation or trans-scleral local resection between 2006 and 2008 were used in this study. Sections from 132 tumours were stained with H&E and PHH3. Mitotic count was defined as the sum of MF counted in 40 high-power fields (HPF). In both H&E and PHH3-stained sections, mitotic count was determined independently by an experienced pathologist (SEC) and by a trainee ophthalmologist (MA). Data were assessed using the Kolmogorov-Smirnov (KS) statistical test and the Bland-Altman (BA) analysis. The mitotic count determined by SEC in H&E and PHH3-stained sections had median values of 4/40 HPF and 8/40 HPF, respectively (KS, Z = 2.585 p < 0.001; BA, mean difference -5.95 [CI -22.15-10.22]), indicating poor reproducibility between these two methods. Similarly, the mean difference between the H&E and the PHH3 methods for calculating the mitotic count by MA was -7.03 (BA) [CI -23.38-9.31]. In contrast, the median mitotic counts determined by SEC & MA using PHH3 were 8/40 HPF and 9/40 HPF, respectively (KS, Z = 0.308 p = 1; BA, mean difference -0.29 [CI -2.65-2.06]), indicating good reproducibility between examiners. MF were more easily identified following immunohistochemical staining with anti-PHH3. This resulted in higher mitotic counts than obtained with H&E sections. For PHH3, the mitotic count determined by a MA was virtually the same as those obtained by an experienced pathologist. PHH3 is now routinely used in our centre, and new prognostic thresholds for uveal melanoma will be defined in further studies.
    Acta ophthalmologica 11/2009; 89(2):e155-60. · 2.44 Impact Factor
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    ABSTRACT: Time-to-event analysis is important in a wide range of applications from clinical prognosis to risk modeling for credit scoring and insurance. In risk modeling, it is sometimes required to make a simultaneous assessment of the hazard arising from two or more mutually exclusive factors. This paper applies to an existing neural network model for competing risks (PLANNCR), a Bayesian regularization with the standard approximation of the evidence to implement automatic relevance determination (PLANNCR-ARD). The theoretical framework for the model is described and its application is illustrated with reference to local and distal recurrence of breast cancer, using the data set of Veronesi (1995).
    IEEE Transactions on Neural Networks 10/2009; · 2.95 Impact Factor
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    ABSTRACT: Time-to-event analysis is important in a wide range of applications from clinical prognosis to risk modeling for credit scoring and insurance. In risk modeling, it is sometimes required to make a simultaneous assessment of the hazard arising from two or more mutually exclusive factors. This paper applies to an existing neural network model for competing risks (PLANNCR), a Bayesian regularization with the standard approximation of the evidence to implement automatic relevance determination (PLANNCR-ARD). The theoretical framework for the model is described and its application is illustrated with reference to local and distal recurrence of breast cancer, using the data set of Veronesi (1995).
    IEEE Transactions on Neural Networks 08/2009; 20(9):1403-16. · 2.95 Impact Factor
  • IEEE Transactions on Neural Networks. 01/2009; 20:1403-1416.
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    ABSTRACT: This paper describes a multicentre longitudinal cohort study to evaluate the predictive accuracy of a regularised Bayesian neural network model in a prognostic application. The study sample (n = 5442) comprises subjects treated with intraocular melanoma in two different centres in Liverpool and Paris. External validation was carried out by fitting the model to the data from Liverpool set and predicting for the data from Paris. The performance of the model in out-of-sample prediction was assessed statistically for discrimination of outcomes and calibration. It was also evaluated clinically by comparing against the accepted TNM staging system. The model had good discrimination with Harrell's C index > 0.7 up to ten years of follow-up. Calibration results were also good up to ten years using a Hosmer-Lemeshow type analysis (p > 0.05). The paper: 1) deals with the issue of missing data using methods that are well accepted in the literature; 2) proposes a framework for externally validating machine learning models applied to survival analysis; 3) applies accepted methods for dealing with missing data; 4) proposes an alternative staging system based on the model. The new staging system, which takes into account histopathologic information, has several advantages over the existing staging system.
    IJKESDP. 01/2009; 1:277-295.
  • Gut 01/2009; 58:A114-A114. · 10.73 Impact Factor
  • A.F.G. Taktak, A. Eleuteri, S.P. Lake, A.C. Fisher
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    ABSTRACT: This paper describes the development of a number of online tools for decision support in cancer. These tools are all based on already published and well validated methods. The paper also describes the development of a method for the dissemination of these tools on the Internet. Some of the ethical issues surrounding the use of online decision support are also discussed.
    Advances in Medical, Signal and Information Processing, 2008. MEDSIP 2008. 4th IET International Conference on; 08/2008
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    ABSTRACT: Prognostic models are developed to assist clinicians in making decisions regarding treatment and follow-up management. The accuracy of these models is often assessed either in terms of their discrimination performance or calibration but rarely both. In this paper, we describe the development of an online tool for discrimination using Harrell C index and calibration using a Hosmer-Lemeshow type analysis (http://clinengnhs.liv.ac.uk/AADP/AADP_Welcome.htm). We show examples of using the tool on real data. We highlight situations where the model performed well in terms of either discrimination or calibration but not both depending on the sample size of the test set. We conclude that prognostic models should be assessed both in terms of discrimination and calibration and that calibration analysis should be carried out numerically and graphically.
    Computers in Biology and Medicine 08/2008; 38(7):785-91. · 1.48 Impact Factor
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    ABSTRACT: To describe neural networks predicting survival from choroidal melanoma (i.e., any uveal melanoma involving choroid) and to demonstrate the value of entering age, sex, clinical stage, cytogenetic type, and histologic grade into the predictive model. Nonrandomized case series. Patients resident in mainland Britain treated by the first author for choroidal melanoma between 1984 and 2006. A conditional hazard estimating neural network (CHENN) was trained according to the Bayesian formalism with a training set of 1780 patients and evaluated with a test set of another 874 patients. Conditional hazard estimating neural network-generated survival curves were compared with those obtained with Kaplan-Meier analyses. A second model was created with information on chromosome 3 loss, using training and test sets of 211 and 140 patients, respectively. Comparison of CHENN survival curves with Kaplan-Meier analyses. Representative results showing all-cause survival and inferred melanoma-specific mortality, according to age, sex, clinical stage, cytogenetic type, and histologic grade. The predictive model plotted a survival curve with 95% credibility intervals for patients with melanoma according to relevant risk factors: age, sex, largest basal tumor diameter, ciliary body involvement, extraocular extension, tumor cell type, closed loops, mitotic rate, and chromosome 3 loss (i.e., monosomy 3). A survival curve for the age-matched general population of the same sex allowed estimation of the melanoma-related mortality. All-cause survival curves generated by the CHENN matched those produced with Kaplan-Meier analysis (Kolmogorov-Smirnov, P<0.05). In older patients, however, the estimated melanoma-related mortality was lower with the CHENN, which accounted for competing risks, unlike Kaplan-Meier analysis. Largest basal tumor diameter was most predictive of mortality in tumors showing histologic and cytogenetic features of high-grade malignancy. Ciliary body involvement and extraocular extension lost significance when cytogenetic and histologic data were included in the model. Patients with a monosomy 3 melanoma of a particular size were predicted to have shorter survival if their tumor showed epithelioid cells and closed loops. Estimation of survival prognosis in patients with choroidal melanoma requires multivariate assessment of age, sex, clinical tumor stage, cytogenetic melanoma type, and histologic grade of malignancy.
    Ophthalmology 03/2008; 115(9):1598-607. · 5.56 Impact Factor
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    ABSTRACT: This paper describes the evaluation of a regularized Bayesian neural network model in prognostic applications. A total sample size of 5442 subjects treated with ocular melanoma in two centers; Liverpool and Paris was used to carry out external validation analysis of the model. The performance of the model was benchmarked against the traditional Cox regression model and a clinically accepted TNM staging system. The cumulative hazards curve for the neural network model was much closer to the empirical curve in the test data than the one produced by the Cox model. The neural network model showed equal performance to Cox's model in terms of discrimination. However, the neural network model was better than Cox's model in terms of calibration. The paper proposes an alternative staging system based on the model, which takes into account histopathological information. The new system has many advantages over the existing staging system.
    Seventh International Conference on Machine Learning and Applications, ICMLA 2008, San Diego, California, USA, 11-13 December 2008; 01/2008

Publication Stats

269 Citations
79.52 Total Impact Points

Institutions

  • 2013
    • Institut Curie
      Lutetia Parisorum, Île-de-France, France
  • 2004–2013
    • Royal Liverpool and Broadgreen University Hospitals NHS Trust
      • Department of Clinical Engineering
      Liverpool, England, United Kingdom
    • University of Liverpool
      • • Department of Molecular and Clinical Cancer Medicine
      • • Department of Electrical Engineering and Electronics
      Liverpool, ENG, United Kingdom
  • 2006
    • Liverpool John Moores University
      • School of Computing and Mathematical Sciences
      Liverpool, ENG, United Kingdom