Indoleamine 2,3-dioxygenase gene expression and kynurenine to tryptophan ratio correlation with nasopharyngeal carcinoma progression and survival.

INTRODUCTION: Indoleamine 2,3-dioxygenase (IDO) is an immunosuppressive tryptophan-depleting enzyme expressed in nasopharyngeal carcinoma (NPC) tissue. However, IDO has not been reported in the peripheral blood of NPC patients. The aim of this study was to analyze, IDO1 and IDO2 messenger RNA (mRNA) expression, the kynurenine (Kyn) and tryptophan (Trp) plasma levels, their clinical values and their relationship with cytokine levels in NPC. METHODS: We evaluated IDO1 and IDO2 mRNA expression in peripheral blood mononuclear cells (PBMC) by quantitative real-time PCR, plasma Trp and Kyn levels by HPLC, and cytokine levels by ELISA in 75 NPC patients and 51 healthy controls. RESULTS: Compared to controls, IDO1 mRNA expression was significantly upregulated and IDO2 mRNA expression was significantly downregulated in PBMC of patients. Also compared to controls, plasma Kyn levels and Kyn/Trp ratio were significantly higher in patients. At the time of diagnosis, the plasma Kyn/Trp ratio was associated with advanced cancer status and was an independent prognostic factor for worse disease-specific survival. According to cancer stages, IDO1 mRNA expression was positively correlated with plasma Kyn/Trp ratio in patients with earlier stages (I-II-III) but negatively correlated in patients with the late-stage cancer (IV). Tumor necrosis factor-α, interleukin (IL)-6 and IL-10 levels were significantly higher in patients compared to controls. Moreover, and despite treatment, patients simultaneously carrying high plasma Kyn/Trp ratio and high plasma IL-6 and IL-10 levels at diagnosis died approximately 1 year after first diagnosis. CONCLUSION: Measuring blood IDO mRNA expression and Kyn/Trp ratio at diagnosis could be a potential marker to evaluate NPC progression and predict survival outcome.

Arginase is involved in cervical lesions progression and severity.

BACKGROUND: Little is known about the relationship between arginase, an immunosuppressive enzyme, and cervical lesions. The present study is aimed at evaluating arginase activity in plasma and mRNA arginase isoforms expression in cervical cells of patients with abnormal cytology and identifying their relationship with Human papillomavirus (HPV) related parameters such as: HPV type, HPV circulating viral load and anti-HPV16 IgG. METHODS: This study included 77 women with cervical lesions and 95 matched controls. Arginase activity was detected by colorimetric assay. Arginase mRNA expression and HPV viral load were evaluated by quantitative real time PCR and anti-HPV16 antibodies were assessed by ELISA. RESULTS: Compared to controls, the arginase activity was higher among women with cervicitis / low grade squamous intraepithelial lesions (LSIL) (OR: 1.872, 95% CI: 0.833-4.210), and also among women with high-grade squamous intraepithelial lesions (HSIL) / squamous cell carcinoma (SCC) (OR: 3.358, 95% CI: 1.670-8.910). Compared to controls, mRNA expression was significantly upregulated in women with cervical cervicitis and SIL for ARG1, and in women with cancer lesions for ARG2. Arginase activity was positively correlated to ARG2 mRNA expression but not to ARG1. High arginase activity was associated with HPV16, high levels of HPV viral load, and low levels of anti-HPV16 antibodies. CONCLUSIONS: Our findings demonstrated that arginase activity and isoforms expression were enhanced in women with HPV-related precancerous lesions and cervical cancer. Further studies are needed to identify how arginase enzyme induces disease progression and severity.

Contribution of BRCA1 5382insC mutation in triple negative breast cancer in Tunisia.

BACKGROUND: Triple negative breast cancer (TNBC) has been classified as a disease subgroup defined by the lack of expression of estrogen and progesterone receptors as well as the absence of the human epidermal growth factor receptor-2 (HER2) overexpression. Germline mutations in the BRCA1 gene have been associated with TNBC. Approximately 70% of breast cancers arising in BRCA1 mutation carriers and up to 23% of breast cancers in BRCA2 carriers display a triple negative phenotype. However, the contribution and the frequency of BRCA1 mutations in individuals with TNBC, not specifically selected for age at diagnosis or enriched family history of breast/ovarian cancer, have not been investigated in the Tunisian population and are to be established. The aim of the present study was to assess the contribution and the prevalence of recurrent BRCA1 germline mutation (5382inC) in Tunisian women with TNBC unselected for family history or age at onset. METHODS: For BRCA1 5382inC mutation detection, the exon 20 coding region and exon-intron boundaries of BRCA1 was analyzed using direct DNA sequencing. A total of 33 DNA samples from Tunisian women diagnosed with TNBC and unselected for family history or age at onset were analyzed. RESULTS: The 5382inC mutation was identified in 2 out of 33 women with TNBC with an overall prevalence of 6% (2/33). The detection rate of the 5382inC mutation among TNBC women with family history of breast cancer was 25% (2/8). The two 5382inC mutation carriers were postmenopausal and diagnosed at the age of 50 and 57. When stratified by age, the frequency of BRCA1 mutation in patients diagnosed at age ≥ 50 years was 8.7% (2/23). CONCLUSIONS: Our results confirm a noticeable contribution of BRCA1 5382inC mutation in TNBC development in Tunisia and further indicate that screening for 5382insC mutation in the BRCA1 gene is of interest in genetic testing in our population. Additionally, our data highlight that receptor triple negativity could be an effective selection criterion for BRCA1 genetic test in our population and should therefore be considered in genetic testing guidelines in Tunisia.

Genetic Variation in CCL5 Signaling Genes and Triple Negative Breast Cancer: Susceptibility and Prognosis Implications.

Triple-negative breast cancer (TNBC) accounts for ~15-20% of breast cancer (BC) and has a higher rate of early relapse and mortality compared to other subtypes. The Chemokine (C-C motif) ligand 5 (CCL5) and its signaling pathway have been linked to TNBC. We aimed to investigate the susceptibility and prognostic implications of genetic variation in CCL5 signaling genes in TNBC in the present study. We characterized variants in CCL5 and that of six other CCL5 signaling genes (CCND1, ZMIZ1, CASP8, NOTCH2, MAP3K21, and HS6ST3) among 1,082 unrelated Tunisian subjects (544 BC patients, including 196 TNBC, and 538 healthy controls), assessed the association of the variants with BC-specific overall survival (OVS) and progression-free survival (PFS), and correlated CCL5 mRNA and serum levels with CCL5 genotypes. We found a highly significant association between the CCND1 rs614367-TT genotype (OR = 5.14; P = 0.004) and TNBC risk, and identified a significant association between the rs614367-T allele and decreased PFS in TNBC. A decreased risk of lymph node metastasis was associated with the MAP3K21 rs1294255-C allele, particularly in rs1294255-GC (OR = 0.47; P = 0.001). CCL5 variants (rs2107538 and rs2280789) were linked to CCL5 serum and mRNA levels. In the TCGA TNBC/Basal-like cohort the MAP3K21 rs1294255-G allele was associated with a decreased OVS. High expression of CCL5 in breast tumors was significantly associated with an increased OVS in all BC patients, but particularly in TNBC/Basal-like patients. In conclusion, genetic variation in CCL5 signaling genes may predict not only TNBC risk but also disease aggressiveness.

[Metastatic nasopharynx cancer at diagnosis: clinical and prognostic (study of 51 cases)]. / Cancer du cavum d'emblee metastatique: étude clinique et pronostique (à propos de 51 cas).

This retrospective study aimed to highlight the different epidemiological, clinical, therapeutic and prognostic features of nasopharinx cancer with inaugural metastases in patients hospitalized in a Tunisian Hospital. We here report 51 cases of histologically diagnosed nasopharynx cancer (NPC) with inaugural metastases. Data were collected in the ENT departments and in the radiation therapy departments at the University Hospital Farhat Hached, Sousse, Tunisia as well as at the Centre Medical Ibn Khaldoun, Hammam Sousse, between January 1995 and December 2010. We collected data on 51 patients with metastatic nasopharynx cancer at diagnosis. The average age was 49 years. Sex ratio was 6,2. Bone metastases were the most common finding (94.1%), followed by liver metastases (34.6%). In the majority of our patients therapeutic approach was based on chemotherapy (41 patients); 31 of these patients underwent chemotherapy in combination with radiation therapy. Adriamycin+cisplatin protocol was the most frequently used (92.6%). Twenty patients underwent cervicofacial radiation therapy with curative purposes (doses ≤ 70 Gy), fourteen patients underwent radiation treatment to the nasopharynx with symptomatic purposes (doses of 30Gy in 10 sessions) associated with radiation treatment to the metastatic sites in 9 cases. Overall survival at 2 years and 5 years was 29% and 10%, respectively. Nasopharinx cancer with inaugural metastases is a serious disease, rapidly fatal despite therapeutic advances. In view of our data and of those from the literature cisplatin-based chemotherapy and cervicofacial radiation therapy with curative doses and that of metastases resulted in long-term survival and even in complete responses. Future trials should focus on new molecules for therapeutic intensification.

[Tunisian National Protocol for Adult Hodgkin's Lymphoma Treatment: Results of a therapeutic regimen adapted to the 2-cycle CT response, about 444 patients]. / Protocole national Tunisien prospectif de traitement du Lymphome de Hodgkin de l'adulte : résultats d'un schéma thérapeutique adapté à la réponse par tomodensitométrie à 2 cycles, à propos de 444 patients.

OBJECTIVE: In Tunisia, the management of Adult Hodgkin's Lymphoma (HL) has been standardized since 1999. We propose in this study to report the therapeutic results of the national protocol of adult HL treatment (MDH2008). PATIENTS AND METHODS: Our study is prospective multicenter interesting 444 patients followed for HL between July 2008 and June 2013 and treated according to the MDH2008 protocol. The median age of our patients was 30 years. B symptoms were present in 62.8 % of our patients. According to the Ann Arbor classification, our patients were in stages I, II, III and IV in 3 %, 42 %, 26 % and 29 %, respectively. The MDH2008 protocol is based on a strategy adapted to the therapeutic response to 2 cycles of chemotherapy. RESULTS: Response≥75 % to 2 courses of chemotherapy was achieved in 43 % of patients and the response rate at the end of treatment was 92.1 %. Forty-eight patients (11.4 %) had primary failure. In the multi-variant study, bulky mediastinal mass (IMT≥0.35) was an independent predictive factor of primary failure (P: 0.000). Nineteen toxic deaths (4.35 %) were reported. The relapse rate was 7.8 %. Event free survival, relapse-free survival and overall survival at 5years were 75 %, 89 % and 90 %, respectively. Adaptation of the treatment to the 2 cycles response was effective in unfavorable early stages and advanced stages. CONCLUSION: Compared to MDH2002 (second version of Tunisian prospective protocol), the MDH2008 reduced the primary failure rate, the rate of toxic deaths with escalated BEACOPP and the rate of relapse in Tunisian patients.

Molecular Diagnostic and Prognostic Subtyping of Gliomas in Tunisian Population.

It has become increasingly evident that morphologically similar gliomas may have distinct clinical phenotypes arising from diverse genetic signatures. To date, glial tumours from the Tunisian population have not been investigated. To address this, we correlated the clinico-pathology with molecular data of 110 gliomas by a combination of HM450K array, MLPA and TMA-IHC. PTEN loss and EGFR amplification were distributed in different glioma histological groups. However, 1p19q co-deletion and KIAA1549:BRAF fusion were, respectively, restricted to Oligodendroglioma and Pilocytic Astrocytoma. CDKN2A loss and EGFR overexpression were more common within high-grade gliomas. Furthermore, survival statistical correlations led us to identify Glioblastoma (GB) prognosis subtypes. In fact, significant lower overall survival (OS) was detected within GB that overexpressed EGFR and Cox2. In addition, IDH1R132H mutation seemed to provide a markedly survival advantage. Interestingly, the association of IDHR132H mutation and EGFR normal status, as well as the association of differentiation markers, defined GB subtypes with good prognosis. By contrast, poor survival GB subtypes were defined by the combination of PTEN loss with PDGFRa expression and/or EGFR amplification. Additionally, GB presenting p53-negative staining associated with CDKN2A loss or p21 positivity represented a subtype with short survival. Thus, distinct molecular subtypes with individualised prognosis were identified. Interestingly, we found a unique histone mutation in a poor survival young adult GB case. This tumour exceptionally associated the H3F3A G34R mutation and MYCN amplification as well as 1p36 loss and 10q loss. Furthermore, by exhibiting a remarkable methylation profile, it emphasised the oncogenic power of G34R mutation connecting gliomagenesis and chromatin regulation.

E-cadherin genetic variants predict survival outcome in breast cancer patients.

BACKGROUND: E-cadherin is a major component of adherens junctions that regulates cell shape and maintains tissue integrity. A complete loss or any decrease in cell surface expression of E-cadherin will interfere with the cell-to-cell junctions' strength and leads to cell detachment and escape from the primary tumor site. In this prospective study, three functional single nucleotide polymorphisms (-347G/GA, rs5030625; -160C/A, rs16260; +54C/T, rs1801026), were found to modulate E-cadherin expression. METHODS: 577 DNA samples from breast cancer (BC) cases were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: We detected no significant correlations between each polymorphism and the clinical parameters of the patients whereas the GACC haplotype was significantly associated with low SBR grading. Overall survival analysis showed that both -347G/G and +54C/C wild (wt) genotypes had a significantly worse effect compared to the other genotypes (non-wt). Moreover, carrying simultaneously both the -347 and +54 wt genotypes confers a significantly higher risk of death. However, with metastatic recurrence, the death-rate was null in patients carrying the non-wt genotypes, and attained 37% in those carrying the wt genotype. A multivariate analysis showed that these two polymorphisms are independent prognostic factors for overall survival in BC patients. CONCLUSIONS: Our results support the fact that E-cadherin genetic variants control disease severity and progression and could be a marker of disease outcome. These findings could be useful in selecting patients that should be monitored differently.

Tunisian adult's Hodgkin lymphoma Study Group.

The Tunisian adult's Hodgkin lymphoma (HL) Study Group was created in 1999. It aimed to improve the management of this curable hematologic malignancy by standardizing the diagnosis, assessment of disease, treatment management and therapeutic evaluation in different Tunisian centers (Hematology, oncology and radiotherapy).Since 1998, four versions of the prospective national protocol for treating adult Hodgkin lymphoma have succeeded (MDH99, MDH2002, MDH2008, MDH2015). Each version was based on the results of the previous version and analyzed according to new data from the literature. Due to this national study group, the number of patients lost to follow decreased significantly (30% before the creation of the group and only 3% for patients treated with MDH2008), the complete and uncertain response rates have improved (75% before the creation of the group and 92% in patients treated with MDH2008) with dramatically improved rates of overall survival from 57% to 90%. On the other hand there was an improvement of toxic death rate (13% of toxic deaths in MDH2002 to 4.37% in the MDH2008) with a decrease of the respective rate of primary failure and relapse by 17% and 12.5% in MDH2002 against the 11.4% and 7.8% in the MDH2008. This resulted in an improvement in overall survival (90%) and event-free survival at 5 years (75%). Now with the introduction of positron emission tomography in Tunisia, we hope yet to finalize the assessment of response and thus better adapt the treatment of this disease. Our objective remains the improvement of event-free survival rate to reach 80%.

Prognostic value of indoleamine 2,3-dioxygenase activity and expression in nasopharyngeal carcinoma.

Indoleamine 2,3-dioxygenase (IDO) is an enzyme with an immunosuppressive effect whose function is diverted by tumor cells to counteract immune cell functions, inducing immune escape of tumor cells. The aim of this study was to investigate the clinical significance of IDO in nasopharyngeal carcinoma (NPC). Compared to controls, NPC patients' plasma IDO activity was significantly higher, especially among patients with metastatic cancer (p=0.005). The immunohistochemical analysis revealed that high IDO expression was observed in 74% of NPC tissues and the epithelial IDO expression was inversely correlated to T-cell infiltration. Kaplan-Meier survival analysis showed that whatever the localization, intratumoral or stromal, patients with a high IDO expression and low T-cell infiltration have significantly lower survival rates. Moreover, in multivariate analysis, intratumoral and stromal IDO expression were found to be independent prognostic factors for disease-free survival (p=0.016; HR: 3.52) and overall survival (p=0.015; HR: 4.76) respectively. Our findings provide evidence that IDO is involved in tumor immune evasion of NPC, suggesting that it could be a relevant therapeutic target for NPC.

Genome-Wide Association Studies (GWAS) breast cancer susceptibility loci in Arabs: susceptibility and prognostic implications in Tunisians.

Genome-wide Association Studies (GWAS) revealed novel genetic markers for breast cancer susceptibility. But little is known about the risk factors and molecular events associated with breast cancer in Arab Population. Therefore, we designed a broad study to investigate the susceptibility and prognostic implications of the GWAS breast cancer loci in the Tunisian population. In a cohort of 640 unrelated patients with breast cancer and 371 healthy control subjects, we characterized the variation of 9 single nucleotide polymorphisms (SNPs), namely rs1219648, rs2981582; rs8051542, rs12443621, and rs3803662; rs889312; rs3817198; rs13387042 and rs13281615. Only 5 out of 9 GWAS breast cancer loci were found to be significantly associated with breast cancer in Tunisians: The rs1219648 (G vs. A allele: OR = 1.36, P = 1 × 10(-3)) and rs2981582 (A vs. G allele: OR = 1.55, P = 3 × 10(-6)) of FGFR2 gene; the rs8051542 of the TNRC9 gene (T vs. C allele: OR = 1.40, P = 4 × 10(-4)); the rs889312 of the MAP3K1 gene (C vs. A allele: OR = 1.33, P = 3 × 10(-3)) and the rs13281615 located on 8q24 (G vs. A allele: OR = 1.21, P = 0.03). Homozygous variant genotypes of rs2981582 were strongly related to lymph node negative breast cancer (OR = 3.33, P = 6 × 10(-7)) and the minor allele of rs2981582 was associated with increased risk of ER+ tumors (OR = 1.57, P = 0.02; OR = 2.15, P = 0.001, for heterozygous and homozygous variant genotypes, respectively) and increased risk of distant metastasis development (OR = 2.30, P = 4 × 10(-3); OR = 3.57, P = 6 × 10(-5), for heterozygous and homozygous variant genotypes, respectively) in a dose dependent manner. The association for rs8051542 was stronger for high-grade SBR tumors (OR = 2.54, P = 2 × 10(-4)). GG genotype of rs13387042 on 2q35 showed a significant association with the risk of developing distant metastasis (OR = 1.94, P = 0.02). The G allele of rs1219648 in FGFR2 and the A allele of rs13387042 on 2q35 indicated a better prognosis by showing a significantly higher overall survival rates (P = 0.013 and P = 0.005, respectively). In conclusion, GWAS breast cancer FGFR2, TNRC9, MAP3K1, and 8q24 loci are associated with an increased risk of breast cancer and genetic variation in FGFR2 gene may predict the aggressiveness of breast cancer in Tunisians.

FASL-844 T/C polymorphism: a biomarker of good prognosis of breast cancer in the Tunisian population.

The single nucleotide polymorphism, rs763110 (-844 T/C) of the FASL gene, is located within a putative binding motif of CAAT/enhancer-binding protein ß transcription factor. Higher basal expression of FASL is significantly associated with the FASL-844 C allele compared with the FASL-844 T allele suggesting that the FASL-844 T/C polymorphism may influence FASL expression and FASL-mediated signalling, and ultimately, the susceptibility to cancer. Therefore, we carried out a population-based study to estimate the FASL-844 C allele frequency in our population and to investigate, in a case-control study, the potential association of the FASL-844 T/C polymorphism with the risk and prognosis of breast cancer in Tunisia. FASL-844 T/C polymorphism was examined in a Tunisian population-based case-control of 438 patients with breast cancer and 332 control subjects using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. By using TT genotype as reference, no significant association was found between any genotype and the risk of developing breast cancer. The frequency of the FASL-844 C allele was 46.3% among the cases and 43.7% among the controls. Similarly, by using T allele as reference, this difference was also not statistically significant. We observed FASL-844 CC genotype and FASL-844 C allele were significantly associated with SBR 1-2 tumour grade (OR=0.42, P=0.007; OR=0.65, P=0.005, respectively). In patients with diagnosis age ≤ 50 years, FASL-844 CC genotype and C allele showed significant associations with T(1)-T(2) clinical tumour size (OR=0.34, P=0.01; OR=0.65, P=0.02, respectively) and SBR grade 1-2 (OR=0.41, P=0.02; OR=0.62, P=0.01, respectively). A marginally significant association was also found with negative nodal status (OR=0.53, P=0.06; OR=0.73, P=0.07, respectively). Thus, the FASL-844 CC genotype and C allele seem to be associated with a good prognosis in patients with diagnosis age ≤ 50 years.

Nasopharyngeal cancer (NPC) around the Mediterranean area: standard of care.

Mediterranean area (MA) represents a zone of intermediate incidence (1-5/100,000) for NPC, the highest frequency being observed in North Africa (NA) where it is characterized by a bimodal age repartition due to a first adolescence peak. In MA and NA, NPC remain diagnosed at advanced stages which impact poorly on overall and disease-free survival. It's therapy in MA followed the progresses and standardisation of protocols, based on concomitant chemoradiotherapy (CCRT) alone or preceded by induction chemotherapy (ICT) in advanced (N2-3, T3-4) stages, while localized cases are managed irradiation alone. NPC overall an disease-free survival improved, due to the use of combined chemo and radiotherapy.

Hereditary breast cancer in Middle Eastern and North African (MENA) populations: identification of novel, recurrent and founder BRCA1 mutations in the Tunisian population.

Germ-line mutations in BRCA1 breast cancer susceptibility gene account for a large proportion of hereditary breast cancer families and show considerable ethnic and geographical variations. The contribution of BRCA1 mutations to hereditary breast cancer has not yet been thoroughly investigated in Middle Eastern and North African populations. In this study, 16 Tunisian high-risk breast cancer families were screened for germline mutations in the entire BRCA1 coding region and exon-intron boundaries using direct sequencing. Six families were found to carry BRCA1 mutations with a prevalence of 37.5%. Four different deleterious mutations were detected. Three truncating mutations were previously described: c.798_799delTT (916 delTT), c.3331_3334delCAAG (3450 delCAAG), c.5266dupC (5382 insC) and one splice site mutation which seems to be specific to the Tunisian population: c.212 + 2insG (IVS5 + 2insG). We also identified 15 variants of unknown clinical significance. The c.798_799delTT mutation occurred at an 18% frequency and was shared by three apparently unrelated families. Analyzing five microsatellite markers in and flanking the BRCA1 locus showed a common haplotype associated with this mutation. This suggests that the c.798_799delTT mutation is a Tunisian founder mutation. Our findings indicate that the Tunisian population has a spectrum of prevalent BRCA1 mutations, some of which appear as recurrent and founding mutations.

XRCC1 and hOGG1 genes and risk of nasopharyngeal carcinoma in North African countries.

Although genetic susceptibility to nasopharyngeal carcinoma (NPC) has been recognized for a long time, little is known about the responsible genes. X-Ray repair cross-complementing protein 1 (XRCC1) and human 8-oxo-guanine glycosylase 1 (hOGG1) genes are involved in deoxyribonucleic acid (DNA) repair and were found associated with NPC risk in three Asian case-control studies. The objective of the present study was to test these genes in a sample from North Africa, one of the major NPC endemic regions in the world. Three single nucleotide polymorphisms (SNPs) in the XRCC1 gene and one SNP in the hOGG1 gene were genotyped in 598 NPC cases from Morocco, Algeria, and Tunisia and 545 controls frequency matched by recruitment center, age, sex, and urban/rural household. The genotype and allelic distributions for the hOGG1 (326)Ser/Cys SNP and for the XRCC1 (399)Arg/Trp, (280)Arg/His, and (194)Arg/Trp SNPs did not differ significantly among NPC cases and controls. The XRCC1 (194)Trp allele frequency was significantly lower in the North African population than in Asian population (f = 0.04 vs. 0.31 in Cantonese Chinese and 0.21 Han Chinese). The hOGG1 (326)Ser allele frequency was significantly higher in the North African population (f = 0.73) than in Asian populations (f = 0.39 in Taiwanese). The results of the present study obtained from a large sample indicate that the XRCC1 and hOGG1 genes are unlikely to play a role in the susceptibility to NPC in North Africans. Our results do not corroborate those found in Asian population on smaller samples.

Epstein-Barr virus DNA quantification and follow-up in Tunisian nasopharyngeal carcinoma patients.

The prognostic value of the Epstein-Barr virus (EBV) DNA load in sera of nasopharyngeal carcinoma (NPC) patients measured before any treatment, after treatment and before relapse was assessed. The real-time polymerase chain reaction was used to detect the viral load levels among 74 NPC subjects. Patients were followed up for a period going from 1 to 6 years (median 4 years). Before treatment, the EBV DNA load was correlated with lymph node involvement and advanced stages. After treatment, the viral load level declined significantly and patients presenting a viral load level lower than 1000 copies/ml showed a better overall survival (OS). Moreover, a significant result was found when the 6-year OS rates of patients having fewer or more than 15,000 copies/ml of viral load before relapse were compared. These results suggest that the EBV DNA load quantification after treatment may be a useful predictor of disease progression and survival.

[Medical treatment of nasopharyngeal cancers]. / Traitements médicaux des carcinomes du nasopharynx.

Nasopharyngeal cancers are essentially epidermoids (NPC) and dominated by the undifferentiated type (UCNT) in endemic areas. The standard treatment of NPC remain external beam radiotherapy but the results are poor in T3-4 lesions locally advanced (30-40% on event- free survival vs 80-90% in T1-T2) explained by a higher rate of relapse and metastases. Improvement of therapeutic results occurs with addition of chemotherapy to radiotherapy, specially with the concomitant scheme (weekly cisplatin), with an increase of overall and diseasefree survivals for the advanced stages (Meta-analysis data). Despite these progresses, we have to evaluate the risk of long term sequelae of combined therapies in children and adolescents. We are observing however an epidemiologic transition with the increase of more localized cases in term of T and N disease.

Lack of association between human leukocyte antigen-E alleles and nasopharyngeal carcinoma in Tunisians.

Nasopharyngeal carcinoma (NPC), a cancer with a remarkable geographical and worldwide ethnic distribution, has been strongly associated with human leukocyte antigen (HLA) class I genes. The presence of additional HLA risk factors has been suggested by several reports. In the present study, we analyzed the implication of HLA-E gene polymorphisms in NPC susceptibility in Tunisians, a population characterized by an intermediate incidence of NPC with specific clinical features. Peripheral blood DNA was obtained from 185 patients with NPC and 177 matched controls. Genotyping for three single-nucleotide polymorphisms, codon 83Gly/Arg, codon 157Arg/Gly, and codon 107Arg/Gly, was performed using the polymerase chain reaction method. The HLA-E*01:01 and HLA-E*01:03 were the only alleles found among Tunisians. The HLA-E*01:03 allele had a slight increase in patients with NPC (43%) compared with controls (37%), but the difference did not reach a statistical significance. Our results show the lack of association between HLA-E alleles and NPC in the Tunisian population. This is not in agreement with the previous studies, suggesting a potential implication of HLA-E gene polymorphisms in the susceptibility to NPC among populations with high-risk incidence. Our study further supports the dissimilarity of NPC between populations with different NPC incidence.

Association of HLA-G polymorphisms with nasopharyngeal carcinoma risk and clinical outcome.

The expression of human leukocyte antigen-G (HLA-G) in tumor cells may facilitate the escape of the tumor from immunosurveillance; thus the aim of this study was to evaluate the influence of HLA-G polymorphisms occurrence on nasopharyngeal carcinoma (NPC) susceptibility, severity, and survival. Using the restriction fragment length polymorphism-polymerase chain reaction and the amplification refractory mutation system-polymerase chain reaction method, 186 Tunisian patients and 189 healthy controls were genotyped for nonsynonymous polymorphisms in HLA-G codon 31Thr/Ser, codon 110Leu/Ile and codon 130Leu/framshift. When allele, genotype and haplotype frequencies between patients and controls were compared for each single nucleotide polymorphisms (SNP), no statistical significant differences were observed. According to the lymph node status and the tumor stages, the Ile110 allele was shown to be significantly less frequent among patients with a positive lymph node status and more severe tumor stages (stage I-II vs III-IV), respectively. Moreover, the codon 130C deletion occurrence was significantly associated with a decreased NPC free disease and overall survival. Altogether our results suggest a possible role for HLA-G locus in NPC progression and aggressiveness.