Amel Mezlini

Systemic therapy in the management of metastatic or advanced salivary gland cancers

Salivary gland cancers are very rare tumors. They are characterized by a histologic heterogeneity and a poor outcome. According to this rarity, few prospective data are available to date. No standard recommendations could be held for the use of systemic therapy in these tumors. Several case reports and small studies have investigated the contribution of different agents of chemotherapy. With the extension of molecular biology approach in oncology several signaling pathways have been discovered in different cancers including salivary gland cancers; thus a number of targeted therapies have been investigated. This paper reviewed exhaustively the studies investigating the role of systemic therapies (chemotherapy, targeted therapy, hormone therapy) in salivary gland cancers.

Significant association between IL23R and IL17F polymorphisms and clinical features of colorectal cancer

Th17cells are involved in inflammatory and autoimmune diseases. These cells may be involved in pathological processes mainly producing pro-inflammatory cytokines. Recently, it was shown that the IL23/IL17 pathway plays an important role in the development of inflammatory bowel disease. In general, genes encoding cytokines are genetically polymorphic and polymorphisms in genes IL23R el IL17F were shown associated with susceptibility to Crohns disease and ulcerative colitis which in their turn are considered as risk factors for developing colorectal cancer (CRC). Our approach is to study IL17F and IL23R polymorphisms as risk factor associated with CRC in the Tunisian population in patients and healthy controls. Interesting, we noted a significant association between IL17F and IL23R polymorphisms and tumor location (p=0.0001 and p=0.049, respectively), tumor histology (p=0.007 and p=0.049, respectively) and tumor architecture (p=0.0000000001 and p=0.07, respectively) in CRC patients. We also showed a significant association of IL17F variant with an increased risk of TNM stage III/IV (p=0.007), showing an increased risk of advanced stage. Finally, we observed a positive link between IL17F polymorphism and CRC patients with lymph nodes (p=0.0000000001) and metastasis (p=0.00000009). However, we found no evidence to support a significant association between IL17F and IL23R polymorphisms and colorectal cancer susceptibility. Our findings suggest that IL17F and IL23R polymorphisms were significantly associated with clinical features variables. The IL17F cytokine appear to be involved in the control of tumor growth and invasion of gastrointestinal tumors. IL17 and IL23 polymorphisms or those of their receptors as important determinants of susceptibility to colorectal cancer are still subject to questioning.

Positive link between variant Toll-like receptor 4 (Asp299Gly and Thr399Ile) and colorectal cancer patients with advanced stage and lymph node metastasis

Toll-like receptors (TLRs) are considered as major endotoxin-signaling receptor and as crucial sensors of innate immunity. TLRs recognize pathogen-associated molecular patterns; induce effectors genes involving inflammatory cytokines and therefore initiation of adaptative immune responses against pathogens. Recently, it has been shown that TLRs are involved in tumor progression. In fact, increased level of TLR4 is associated with progression of colon malignancies. Even, TLR4 polymorphism has been shown associated with susceptibility to have colorectal cancer. Our study aimed to investigate an association between TLR4 Asp299Gly (D299G) and Thr399Ile (T399I) polymorphisms in Tunisian patients with colorectal cancer. Using a primer extension method (SNaPshot), we genotyped two variants of TLR4 D299G and T399I in 100 patients with colorectal cancer and 140 healthy controls in Tunisian population. Interesting, we noted a significant association between T399I polymorphism and tumor differentiation (p = 0.027) and tumor architecture (p = 0.02) in colorectal cancer (CRC) patients. We also showed a significant association of D299G with an increased risk of advanced stage (p = 0.03). Finally, we observed a positive link between D299G and T399I polymorphisms and CRC patients with lymph node (p = 0.00024; p = 0.0005, respectively) and metastasis (p = 0.001; p = 0.002, respectively). However, we found no evidence to support a significant association between TLR4 D299G and T399I polymorphisms and colorectal cancer susceptibility. Our findings suggest that TLR4 D299G and T399I polymorphisms are significantly associated with clinical features variables. TLR4 polymorphisms may serve as biomarker of disease progression. Therefore, our results need confirmation in even larger studies.

Relationship of common vascular endothelial growth factor polymorphisms and haplotypes with the risk of cervical cancer in Tunisians

OBJECTIVE We investigated the association between common vascular endothelial growth factor (VEGF) single nucleotide polymorphisms (SNPs) and the risk of cervical cancer (CC) in Tunisian patients and control women. METHODS Study subjects comprised 86 CC cases and 124 control women. Genotyping of VEGF rs699947, rs833061, rs1570360, rs2010963, rs25648, rs833068, rs833070, rs3025039 SNPs was done by real-time PCR. RESULTS Higher minor allele frequencies (MAF) of rs699947 (-2578C/A) [P=0.04; OR (95% CI)=1.52 (1.02-2.29)], and rs1570360 (-1154G/A) [P=0.04; OR (95% CI)=1.58 (1.01-2.47)] were seen in CC cases compared to control women. Marked differences in the distribution of rs699947 (P=9×10(-4)) and rs1570360 (P=0.03) genotypes were seen between CC cases and control groups; the distribution of the remaining SNPs was comparable between CC cases and control women. The association of rs699947 and rs1570360 with heightened CC risk with was seen in the heterozygous, and more so in the homozygous states. Haploview analysis revealed high LD between rs699947, rs833061, rs1570360, rs2010963, rs25648, rs833068 and rs833070 but weak or no LD between rs3025039 and the other SNPs. Seven-locus (rs699947/rs833061/rs1570360/rs2010963/rs25648/rs833068/ rs833070) haploview analysis identified only CTGCCAG haplotype to be positively associated with CC [P=0.022; OR(95% CI)=1.74 (1.08-2.79)]. CONCLUSION Specific VEGF variants (rs699947, rs1570360) and haplotype (CTGCCAG) may contribute to the development of CC among Tunisian women.

Involvement of Toll-like receptors in cervical cancer susceptibility among Tunisian women

Previous studies underscored the importance of genetic factors in the pathogenesis of certain cancers, including cervical cancer. Epidemiological evidence supports an association between specific polymorphisms of Toll-like receptors (TLR) with several human pathological states, including cervical cancer. The aim of this study was to investigate the link between specific gene variants in TLR2 (-196 to -174 del), TLR3 (c.1377 C>T), TLR4 (Asp299Gly), and TLR9 (2848 G>A) and susceptibility to cervical cancer in Tunisian women. Study subjects comprised 122 women with histopathologically-confirmed cervical cancer, and 260 unrelated age- and ethnically-matched healthy females, who served as controls. TLR genotyping was done using PCR-restriction fragment length polymorphism. The C/C genotype of TLR3 (c.1377 C>T) is associated with cervical cancer susceptibility (OR: 1.71, CI: 1.08-2.70). For TLR4 (Asp299Gly), the Asp/Asp genotype and the Asp allele were associated with higher risk of developing cervical cancer (OR: 4.95, CI: 1.97-13.22) and (OR: 5.17, CI: 2.11-13.50) respectively. We demonstrated no association between the TLR2 (-196 to -174 del) and the TLR 9 (2848 G>A) polymorphisms and the susceptibility of cervical cancer among Tunisian women. However, the C/C genotype for the TLR3 (c.1377 C>T) polymorphism and the Asp/Asp genotype and the Asp allele for (Asp299Gly) TLR4 polymorphism were found to be associated with a higher risk of cervical cancer.

IL-10 gene promoter and intron polymorphisms as genetic biomarkers of cervical cancer susceptibility among Tunisians

OBJECTIVE We investigated the association between polymorphisms in the promoter and intron regions of the interleukin-10 (IL-10) gene with the risk of cervical cancer (CC) in Tunisian patients and control women. METHODS Study subjects comprised 86 CC cases and 126 control women. Genotyping of IL-10 intron (rs3024491, rs3024490) and promoter (rs1800872, rs1800871, rs1800896) variants was done by real-time PCR, with defined clusters. RESULTS The minor allele frequencies of the five tested IL-10 SNPs were not significantly different between cervical cancer cases and control women. However, significantly higher frequencies of homozygous minor allele-carriers in cases was seen for rs3024490 (P=0.023), rs1800872 (P=0.037), and rs1800871 (P=0.028). IL-10 serum levels were significantly reduced in rs3024490 T/T vs. G/G genotype carriers, and in rs1800871 T/T than C/C genotype carriers. While carriage of rs1800872 and rs3024491 minor allele was associated with reduced IL-10 secretion, this was not statistically significant. Haploview analysis demonstrated high linkage disequilibrium (LD) among the IL10 SNPs studied, and only seven haplotypes were common, capturing 98.8% of the total possible haplotypes. Reduced frequency of haplotypes GTCCA (P<0.001) and TGATG (P<0.001) was seen in cervical cancer cases than in control women, thus conferring disease protection nature to these haplotype. This association remained significant for GTCCA (Pc=0.006) and TGATG (P=0.045) after correcting for multiple comparisons. CONCLUSION Specific IL-10 variants (rs3024490, rs1800872, and rs1800871) and haplotype (GTCCA and TGATG) may contribute to the development of cervical cancer among Tunisian women.

Larynx preservation: What is the best non-surgical strategy?

The concept of larynx preservation in locally advanced laryngeal or hypopharyngeal squamous cell carcinoma has evolved during the last three decades, especially with the advancement of nonsurgical strategies. These nonsurgical strategies include: (1) radiotherapy alone; (2) concomitant chemoradiotherapy (CCRT); and (3) induction chemotherapy followed by radiotherapy or CCRT and concurrent anti-epidermal growth factor receptor (EGFR). To date, the best approach for larynx preservation has yet to be defined. In this article, we review and discuss important recent randomized phase II/III trials investigating larynx preservation in order to facilitate the selection of an appropriate strategy in the clinical setting. However, the decision of larynx preservation should always be a multidisciplinary approach.

Impact of lifestyle factors and nutrients intake on occurrence of gastrointestinal cancer in Tunisian population.

This study aims to show the relationship between lifestyle and risk of colorectal and gastric cancers in Tunisian population. The food frequency survey method was used to obtain information about the dietary intake and way of life. Nutrients intake was calculated according to the food composition database. According to our results, the consumption of vegetables, fruits, fish, as well as coffee seems to be protective against digestive cancer, while the consumption of citrus and olive oil is protective against gastric cancer. Tobacco, alcohol, and tea represent a risk against gastrointestinal cancer. Highly educated people are more conscious of the crucial role of prevention. In addition, nutrients were significantly associated with colorectal and gastric cancer. The findings suggest that lifestyle is associated with a risk of gastrointestinal cancer. Moreover, higher intake of nutrients from foods was observed more in cases with colorectal and gastric cancer than controls.

Lynch syndrome in Tunisia: first description of clinical features and germline mutations

PurposeHigh rates of early colorectal cancers (CRC) are observed in Tunisia suggesting genetic susceptibility. Nevertheless, up to now, no molecular study has been performed in the Tunisian population. In our research, we evaluated the clinical characteristics of Tunisian families suspected of Lynch syndrome and the contribution of DNA mismatch repair (MMR) genes.MethodsThirty-one unrelated families suspected of Lynch syndrome were studied. Probands were tested for the presence of germline mutations in the MMR genes MLH1, MSH2, MSH6 and in MUTYH. Available tumours were analysed for microsatellite instability and expression of MMR proteins. Detailed family and medical histories were collected.ResultsA total of 134 cancers were noted in the 31 families, the most frequent type of cancer corresponding to CRC (69%), followed by uterine cancer (7.5%). Germline mutations were identified in 11 (35.5%) families (six MSH2, five MLH1, including seven novel mutations), seven of which fulfilled the Amsterdam criteria (sensitivity, 63.6%; positive predictive value, 58.3%). Noteworthy, germline mutations were detected in 52.6% of male patients tested, but in only 8.3% of females (p = 0.02). Moreover, CRC were essentially left sided in families without detected mutation (p = 0.017). Ages of onset of cancers and tumour spectrum were very similar in families with or without MMR germline mutation, contrasting with previous studies performed in other populations.ConclusionsMMR genes contribute significantly to CRC susceptibility in the Tunisian population. However, the cause of early CRC susceptibility remains unknown in most cases, especially in women and in patients with early left colon or rectal cancer.

RETRACTED ARTICLE: Impact of Toll-Like Receptors 2/3/4/9, IL-1-α/β and TNF-α Polymorphisms in Cervical Cancer Susceptibility in Tunisia

– There are substantial parts in the article that were previously published in the article: “Involvement of Toll-like receptors in cervical cancer susceptibility among Tunisian women” by Sabrina Zidi, Hasibe Verdi, Yaprak YilmazYalcin, A.C. Yazici, Ezzedine Gazouani, Amel Mezlini, Fatma-Belgin Atac, Besma Yacoubi-Loueslati, Bulletin du Cancer, 2014; 101: E31-E35, DOI: 10.1684/bdc.2014. 2037. Although the article published in Pathology and Oncology Research uses a larger control group the two papers have very similar content, addressing the same problem with the same methodology and the differences in the articles were considered too minor. – In addition, this article was submitted to Pathology and Oncology Research without the knowledge or consent of all the authors.